Catalytic Asymmetric Synthesis, 3rd Edition

CATALYTIC ASYMMETRIC SYNTHESIS Third Edition Edited by IWAO OJIMA A JOHN WILEY & SONS, INC., PUBLICATION CATALYTIC A...

Author: Iwao Ojima

251 downloads 2936 Views 8MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

CATALYTIC ASYMMETRIC SYNTHESIS Third Edition

Edited by IWAO OJIMA

A JOHN WILEY & SONS, INC., PUBLICATION

CATALYTIC ASYMMETRIC SYNTHESIS

CATALYTIC ASYMMETRIC SYNTHESIS Third Edition

Edited by IWAO OJIMA

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright. com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data Catalytic asymmetric synthesis / [edited by] Iwao Ojima. – 3rd ed. p. cm. Includes index. ISBN 978-0-470-17577-4 (cloth) 1. Asymmetric synthesis. 2. Catalysis. I. Ojima, Iwao, 1945– QD262.C357 2010 547′.2–dc22 2009052132 Printed in the United States of America. 10

9

8

7

6

5

4

3

2

1

CONTENTS

Preface

ix

Preface to the Second Edition

xi

Preface to the First Edition Contributors

1

Catalytic Asymmetric Synthesis in Nonconventional Media/Conditions

xiii xv

1

Chikako Ogawa and Shu¯ Kobayashi

2

Asymmetric Organocatalysis 2A

Enantioselective Organocatalysis Involving Iminium, Enamine, SOMO, and Photoredox Activation

37

39

Allan J. B. Watson and David W. C. MacMillan 2B

Asymmetric Acid–Base Bifunctional Catalysis with Organic Molecules

59

Yi Wang and Li Deng 2C

Asymmetric Phase-Transfer and Ion Pair Catalysis

95

Seiji Shirakawa and Keiji Maruoka

3

Chiral Lewis Acids and Brønsted Acids in Asymmetric Synthesis

119

Hisashi Yamamoto and Cheol Hong Cheon v

vi CONTENTS

4

Asymmetric Synthesis through C–H Activation

163

Huw M. L. Davies and Jørn Hansen 5

Asymmetric Carbon–Heteroatom Bond-Forming Reactions

227

Yoshiji Takemoto and Hideto Miyabe 6

Enzyme-Catalyzed Asymmetric Synthesis

269

Harald Gröger 7

Transition Metal-Catalyzed Homogeneous Asymmetric Hydrogenation

343

Gao Shang, Wei Li, and Xumu Zhang 8

Asymmetric Carbon–Carbon Bond-Forming Reactions

437

8A

439

Catalytic Asymmetric Conjugate Addition Jian-Xin Ji and Albert S. C. Chan

8B

Enantioselective Allylic Substitutions with Carbon Nucleophiles

497

Günter Helmchen,Uli Kazmaier, and Sebastian Förster 8C

Asymmetric Carbometallation and Carbocyclizations

643

Iwao Ojima, Joseph J. Kaloko, Stephen J. Chaterpaul, Yu-Han Gary Teng, and Chi-Feng Lin 8D Asymmetric Ene Reactions and Cycloadditions

683

Koichi Mikami and Kohsuke Aikawa 8E

Catalytic Enantioselective Olefin Metathesis Reactions

739

Amir H. Hoveyda, Steven J. Malcolmson, Simon J. Meek, and Adil R. Zhugralin 9

Asymmetric Hydrosilylation of Carbon–Carbon Double Bonds and Related Reactions

771

Jin Wook Han and Tamio Hayashi 10

Asymmetric Carbonylations Cyril Godard, Aurora Ruiz, Montserrat Diéguez, Oscar Pàmies, and Carmen Claver

799

CONTENTS vii

11 Asymmetric Oxidations and Related Reactions

839

Kazuhiro Matsumoto and Tsutomu Katsuki 12

Asymmetric Amplification and Autocatalysis

891

Kenso Soai, Tsuneomi Kawasaki, and Takanori Shibata 13

Asymmetric Polymerization

931

Shingo Ito and Kyoko Nozaki Index

987

PREFACE

The first and second editions of Catalytic Asymmetric Synthesis published in the fall of 1993 and spring of 2000, respectively, were very warmly received by research communities in academia and industries, from graduate students, research associates, faculty, staff, senior researchers, and others. The first book was published at the very moment that the Food and Drug Administration (FDA) in the United States clarified the situation in “Chiral Drugs,” the word “chirotechnology” was created, and chirotechnology industries were spawning in the United States and Britain. In the Preface of the first edition, I correctly positioned the significance and advancement of catalytic asymmetric synthesis as follows: “Extensive research on new and effective catalytic asymmetric reactions will surely continue beyond the year 2000, and catalytic asymmetric processes promoted by man-made chiral catalysts will become mainstream chemical technology in the 21st century.” The second edition published in 2000 covered explosive development of catalytic asymmetric synthesis since 1993 by adding newly emerging reactions in that period, but keeping the historically important chapters in the first book. In 2001, the Nobel Prize in Chemistry was given to W. Knowles, K. B. Sharpless, and R. Noyori for their outstanding contributions to the advancement of catalytic asymmetric synthesis, pushing up this chemistry and chemical technology to a practical level for the benefit of mankind. Again, I wrote about their exceptional achievements in the Preface of the first edition as follows: “Among the significant achievements in basic research, (i) asymmetric hydrogenation of dehydroamino acids, a ground-breaking work by W. S. Knowles et al., (ii) the Sharpless epoxidation by K. B. Sharpless et al., and (iii) the second generation asymmetric hydrogenation processes developed by R. Noyori et al. deserve particular attention because of the tremendous impact that these processes have made in synthetic organic chemistry.” In many cases, Nobel Prize in Chemistry is given to scholar(s) in a certain field of research that is fully matured. However, this Nobel Prize recognized the chemical science that was still very actively growing and expanding, hence significantly fueled further advances in this field. Accordingly, 8 years after the second edition, it became very clear that an updated and/or newer version of this book was necessary for the synthetic chemistry community. Thus, a third edition was planned. This third edition, however, is organized in a manner different from that of the second edition. Since the chapters in the second edition are still very informative and the ingenious methodologies as well as innovative approaches described there are highly inspiring and stimulating even today, those chapters are regarded as “classics in catalytic asymmetric synthesis.” Thus, I decided to edit essentially a new book, which would ix

x PREFACE

become the most useful desktop reference and text, in addition to the “classics” in the second edition, for researchers at all levels, highlighting the most significant advances in catalytic asymmetric synthesis since 2000. Although the third edition does not aim to be comprehensive in nature, it covers the reactions most needed by today’s practicing researchers and graduate students in synthetic organic, medicinal, and materials chemistry. New to the third edition, six new chapters focusing on novel approaches to catalytic asymmetric synthesis are introduced, including non-conventional media/conditions, organocatalysis, Lewis and Bronsted acids, CH activation, carbon-heteroatom bond forming reactions, and enzyme-catalyzed asymmetric synthesis (Chapters 1–6). I believe it is time for synthetic organic chemists to recognize and embrace the importance and power of “enzyme-catalyzed reactions” in asymmetric synthesis. Moreover, another very important reaction (metathesis, the subject of the 2005 Nobel Prize in Chemistry) for catalytic asymmetric synthesis is introduced as a new chapter (Chapter 8E) in the section of the carbon-carbon bond forming reactions. Updated chapters are on hydrogenation (Chapter 7), carbon-carbon bond forming reactions (conjugate additions, allylic alkylations, carbometallations and carbocyclizations, transition metal catalyzed ene reactions, and cycloadditions) (Chapter 8), hydrosilylation (Chapter 9), carbonylations (Chapter 10), oxidations (Chapter 11), amplifications and autocatalysis (Chapter 12), and polymerization (Chapter 13). It is obvious that these reactions and processes provide powerful methods for the highly efficient synthesis of enantio-enriched or enantiopure compounds of biological, medicinal, agrochemical, and materials/nano-science–related interests. The authors of these chapters are all world leaders in this field, who provide systematic, in-depth state-of-the-art coverage of the basic principles, scope and limitations, strategies, and perspectives for future development of each reaction. I sincerely hope that this book attracts the interests of broad range of synthetic organic, medicinal, and materials chemists, especially among the younger generation researchers in both academia and industry, who will introduce original and creative ideas into this fascinating field of research and advance catalytic asymmetric synthesis by highly innovative approaches in the years to come. Iwao Ojima November 2009

PREFACE TO THE SECOND EDITION

The first edition of Catalytic Asymmetric Synthesis, published in the fall of 1993, was very warmly received by research communities in academia and industries from graduate students, research associates, faculty, staff, senior researchers, and others. The book was published at the very moment that the Food & Drug Administration (FDA) in the United States clarified the situation in “Chiral Drugs,” the word “chirotechnology” was created, and chirotechnology industries were spawning in the United States and Britain. As accurately predicted in the preface of the first edition, extensive research on new and effective catalytic asymmetric reactions has been continuing, in an explosive pace, and it is now obvious that these catalytic asymmetric processes promoted by man-made chiral catalysts will be the mainstream chemical technology in the 21st century. About five years from the publication of the original book, there was a clear demand in the synthetic community for an updated version of this book because advances in the field were accelerated during this period. Accordingly, I have agreed with the publisher to edit a second edition of this book. In the second edition, I intended to incorporate all important reaction types that I am aware of, while keeping the monumental discovery and initial development of certain processes from the first edition, and highlighting recent advances in this field. The original book had 13 chapters (9 general-reaction types), which covered most of the important developments at that time. However, the second edition has 21 chapters (11 general-reaction types) (a total of 21 chapters for the 21st century is intriguing, isn’t it?), reflecting the tremendous expansion in the scope of catalytic asymmetric synthesis in the past several years. In addition to the nine general-reaction types covered in the original book, the second edition includes “Asymmetric Carbometallations” (Chapter 4), “Asymmetric Amplification and Autocatalysis” (Chapter 9), and “Asymmetric Polymerization” (Chapter 11). “Cyclopropanation” in the original book has been replaced with “Asymmetric Carbene Reactions” (Chapter 5), which now includes powerful asymmetric intramolecular carbene insertion to C–H bonds. As the Table of Contents shows, there has been significant expansion and development in the asymmetric carbon–carbon bond-forming reactions (Chapter 8). Thus, this section consists of eight chapters dealing with cycloaddition reactions, aldol reactions, ene reactions, Michael reactions, allylic substitution reactions, cross-coupling reactions, and intramolecular Heck reactions. These processes provide very useful methods for the highly efficient synthesis of enantio-enriched or enantiopure compounds of biological, medicinal, agrochemical, and material science related interests. xi

xii PREFACE TO THE SECOND EDITION

Once again, the authors of these chapters are all world-leaders in this field, who outline and discuss the essence of each catalytic asymmetric reaction. Because the separate list of the chiral ligands in the original book was very well received, a convenient list of the chiral ligands with citation of relevant references appears in this book as an Appendix. This book will, once again, serve as an excellent reference book for graduate students as well as chemists at all levels in both academic and industrial laboratories. Iwao Ojima

PREFACE TO THE FIRST EDITION

Biological systems, in most cases, recognize a pair of enantiomers as different substances, and the two enantiomers will elicit different responses. Thus, one enantiomer may act as a very effective therapeutic drug whereas the other enantiomer is highly toxic. The sad example of thalidomide is well-known. It is the responsibility of synthetic chemists to provide highly efficient and reliable methods for the synthesis of desired compounds in an enantiomerically pure state, that is, with 100% enantiomeric excess (% ee), so that we shall not repeat the thalidomide tragedy. It has been shown for many pharmaceuticals that only one enantiomer contains all of the desired activity, and the other is either totally inactive or toxic. Recent movements of the Food & Drug Administration (FDA) in the United States clearly reflect the current situation in “Chiral Drugs,” that is, pharmaceutical industries will have to provide rigorous justification to obtain the FDA’s approval of racemates. Several methods are used to obtain enantiomerically pure materials, which include classical optical resolution via diastereomers, chromatographic separation of enantiomers, enzymic resolution, chemical kinetic resolution, and asymmetric synthesis. The importance and practicality of asymmetric synthesis as a tool to obtain enantiomerically pure or enriched compounds has been fully acknowledged to date by chemists in synthetic organic chemistry, medicinal chemistry, agricultural chemistry, natural products chemistry, pharmaceutical industries, and agricultural industries. This prominence is due to the explosive development of newer and more efficient methods during the last decade. This book describes recent advances in catalytic asymmetric synthesis with brief summaries of the previous achievements as well as general discussions of the reactions. A previous book reviewing this topic, Asymmetric Synthesis, Vol. 5—Chiral Catalysis, edited by J. D. Morrison (Academic Press, Inc., 1985), compiles important contributions through 1982. Another book, Asymmetric Catalysis, edited by B. Bosnich (Martinus Nijhoff, 1986) also concisely covers contributions up to early 1984. In 1971, an excellent book, Asymmetric Organic Reactions, by J. D. Morrison and H. S. Mosher, reviewed all earlier important work on the subject and compiled nearly 850 relevant publications through 1968, including some papers published in 1969. In the early 1980s, a survey of publications dealing with asymmetric synthesis (in a broad sense) indicated that the total number of papers in this area of research published in the 10 years after the Morrison/ Mosher book, that is, 1971–1980, was almost the same as that of all the papers published before 1971. This doubling of output clearly indicates the attention paid to this important xiii

xiv PREFACE TO THE FIRST EDITION

topic in 1970s. Since the 1980s, research on asymmetric synthesis has become even more important and popular when enantiomerically pure compounds are required for the total synthesis of natural products, pharmaceuticals, and agricultural agents. It would not be an exaggeration to say that the number of publications on asymmetric synthesis has been increasing exponentially every year. Among the types of asymmetric reactions, the most desirable and the most challenging is catalytic asymmetric synthesis because one chiral catalyst molecule can create millions of chiral product molecules, just as enzymes do in biological systems. Among the significant achievements in basic research: (i) asymmetric hydrogenation of dehydroamino acids, a ground-breaking work by W.S. Knowles et al.; (ii) the Sharpless epoxidation by K. B. Sharpless et al.; and (iii) the second-generation asymmetric hydrogenation processes developed by R. Noyori et al. deserve particular attention because of the tremendous impact that these processes have made in synthetic organic chemistry. Catalytic asymmetric synthesis often has significant economic advantages over stoichiometric asymmetric synthesis for industrial-scale production of enantiomerically pure compounds. In fact, a number of catalytic asymmetric reactions, including the “Takasago Process” (asymmetric isomerization), the “Sumitomo Process” (asymmetric cyclopropanation), and the “Arco Process” (asymmetric Sharpless epoxidation) have been commercialized in the 1980s. These processes supplement the epoch-making “Monsanto Process” (asymmetric hydrogenation), established in the early 1970s. This book uncovers other catalytic asymmetric reactions that have high potential as commercial processes. Extensive research on new and effective catalytic asymmetric reactions will surely continue beyond the year 2000, and catalytic asymmetric processes promoted by man-made chiral catalysts will become mainstream chemical technology in the 21st century. This book covers the following catalytic asymmetric reactions: asymmetric hydrogenation (Chapter 1); isomerization (Chapter 2); cyclopropanation (Chapter 3); oxidations (epoxidation of allylic alcohols as well as unfunctionalized olefins, oxidation of sulfides, and dihydroxylation of olefins) (Chapter 4); hydrocarbonylations (Chapter 5); hydrosilylation (Chapter 6); carbon–carbon bond-forming reactions (allylic alkylation, Grignard cross-coupling, and aldol reaction) (Chapter 7); phase-transfer reactions (Chapter 8); and Lewis acid-catalyzed reactions (Chapter 9). The authors of the chapters are all world-leaders in this field, who outline and discuss the essence of each catalytic asymmetric reaction. (In addition, a convenient list of the chiral ligands appearing in this book, with citation of relevant references, is provided as an Appendix.) This book serves as an excellent reference for graduate students as well as chemists at all levels in both academic and industrial laboratories. Iwao Ojima March 1993

CONTRIBUTORS

Kohsuke Aikawa, Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan Albert S. C. Chan, Department of Applied Biology and Chemical Technology, Room M1711, Li Ka Shing Tower, The Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong; Email: [email protected] Stephen J. Chaterpaul, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 Cheol Hong Cheon, Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue (GHJ 409), Chicago, IL 60637 Carmen Claver, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain; Email: [email protected] Huw M. L. Davies, Department of Chemistry, Emory University, 440 Atwood Hall, Emory University, 1515 Dickey Drive, Atlanta, GA 30322; Email: [email protected] Li Deng, Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454-9110; Email: [email protected] Montserrat Diéguez, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain Sebastian Förster, Organisch-Chemisches Institut der Universität Heidelberg, D-69120 Heidelberg, Germany Cyril Godard, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain Harald Gröger, Department of Chemistry and Pharmacy, University of ErlangenNuremberg, Henkestr. 42, 91054 Erlangen, Germany; Email: harald.groeger@chemie. uni-erlangen.de Jin Wook Han, Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 133-791, Korea xv

xvi CONTRIBUTORS

Jørn Hansen, Department of Chemistry, Emory University, 440 Atwood Hall, Emory University, 1515 Dickey Drive, Atlanta, GA 30322 Tamio Hayashi, Department of Chemistry, Faculty of Science, Kyoto University, Sakyoku, Kyoto 606-8502, Japan; Email: [email protected] Günter Helmchen, Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany; Email: G.Helmchen@oci. uni-heidelberg.de Amir H. Hoveyda, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467; Email: [email protected] Shingo Ito, Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan Jian-Xin Ji, Chendu Institute of Biology, Chinese Academy of Sciences, Chengdu, China Joseph J. Kaloko, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 Tsutomu Katsuki, Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, 6-10-1 Hakozaki Higashi-ku, Fukuoka 812-8581, Japan; Email: [email protected] Tsuneomi Kawasaki, Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan Uli Kazmaier, Institut für Organische Chemie, Universität des Saarlandes, D-66123 Saarbrücken, Germany Shū Kobayashi, Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 1130033, Japan; Email: [email protected] Wei Li, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854 Chi-Feng Lin, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 David W. C. MacMillan, Department of Chemistry, Frick Laboratory, Princeton University, Washington Road, Princeton, NJ 08544; Email: [email protected] Steven J. Malcolmson, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467 Keiji Maruoka, Department of Chemistry, Faculty of Science, Graduate School, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; Email: [email protected] Kazuhiro Matsumoto, Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, 6-10-1 Hakozaki Higashi-ku, Fukuoka 812-8581, Japan Simon J. Meek, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467 Koichi Mikami, Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan; Email: [email protected]

CONTRIBUTORS xvii

Hideto Miyabe, School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Kobe 650-8530, Japan Kyoko Nozaki, Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan; Email: [email protected] Chikako Ogawa, Eisai Research Institute, Lead Identification, 4 Corporate Drive, Andover, MA 01810 Iwao Ojima, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794; Email: [email protected] Oscar Pàmies, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain Aurora Ruiz, Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain Gao Shang, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854 Takanori Shibata, Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan Seiji Shirakawa, Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan Kenso Soai, Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan; Email: [email protected] Yoshiji Takemoto, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan; Email: [email protected] Yu-Han Gary Teng, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 Yi Wang, Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454-9110 Allan J. B. Watson, Department of Chemistry, Frick Laboratory, Princeton University, Washington Road, Princeton, NJ 08544 Hisashi Yamamoto, Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue (GHJ 409), Chicago, IL 60637; Email: [email protected] Xumu Zhang, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road Piscataway, NJ 08854; Email: xumu@rutgers. edu Adil R. Zhugralin, Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467

1 CATALYTIC ASYMMETRIC SYNTHESIS IN NONCONVENTIONAL MEDIA/ CONDITIONS Chikako Ogawa* and ShŪ Kobayashi Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

1.1. INTRODUCTION Conventionally, catalytic asymmetric synthesis has been carried out in organic solvents, because most organic materials are not soluble in other solvents. However, asymmetric catalysis in other solvents (nonconventional solvents) is now of interest for many reasons. First and most significantly, the negative characteristics of organic solvents have come to the fore recently; many organic solvents are volatile, flammable, sometimes explosive, and have a damaging effect on human health (e.g., mutagenic or carcinogenic) or on the environment. On the other hand, recovery and reuse of catalysts is crucial in organic synthesis not only from an economical aspect but also from an environmental point of view. Use of nonconventional solvents often enables the recovery and reuse of catalysts. In this chapter, water, fluorous solvents, supercritical fluids (SCFs), and ionic liquids (ILs) are discussed as nonconventional solvents, and characteristic features of asymmetric catalysis are surveyed. Microwave-assisted catalytic asymmetric synthesis is also described. 1.2. CATALYTIC ASYMMETRIC SYNTHESIS IN WATER Water is remarkable in nature; indeed, nature chooses water as a “solvent.” Many elegant in vitro reactions, mainly catalyzed by enzymes, are carried out in an aqueous

*Present address: Eisai Research Institute, Lead Identification, 4 Corporate Drive Andover, MA 01810 Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 1

2 CATALYTIC ASYMMETRIC SYNTHESIS IN NONCONVENTIONAL MEDIA/CONDITIONS

environment in our bodies. Given that nature so gracefully exploits water, why should mankind not perform synthesis in water too?

1.2.1. Chiral Lewis Acid Catalysis in Water In general, the formation of chiral Lewis acid complex is much more difficult in water than in organic media, since a chiral ligand competes with water in coordination with Lewis acid. Although there are successful reports to realize chiral Lewis acid catalyzed asymmetric reactions in aqueous media, it is still very challenging to use water as sole solvent [1,2]. 1.2.1.1. Mannich-Type Reaction in Water Asymmetric Mannich reactions provide useful routes for the synthesis of optically active β-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [3]. Diastereo- and enantioselective Mannich-type reactions of α-hydrazono ester 1 with silicon enolates in aqueous media can be successfully achieved with a ZnF2–chiral diamine L-1 complex (Scheme 1.1) [4]. This complex enables reactions in water without any organic cosolvents or additives to proceed smoothly, affording the corresponding products in high yields and high stereoselectivities (Conditions A) [5]. In the reaction of α-monosubstituted ketone-derived silyl enol ether with 1, cetyltrimethyl ammonium bromide (CTAB) is necessary to accelerate the reaction. It is also noted that, in contrast to most asymmetric Mannich-type reactions, either syn- or anti-adducts are stereospecifically obtained from (E)- or (Z)-silicon enolates in the present reaction (Conditions B). Moreover, the amount of ZnF2 and L-1 can be successfully reduced to 10 and 5 mol %, respectively, maintaining the same level of result (Conditions C).

Ph MeO

N EtO

H O 1

R1

NH HN

OSiMe3

L-1 (x mol %) ZnF2 (y mol %) CTAB (z mol %)

R3

0°C, H2O

NHBz +

Ph OMe

BzHN

NH

O

EtO

R2

R3 O R1 R2

(3.0 equiv) Conditions A: x = 10, y = 100, z = 0, R1 = R 2 = H, 20 h Conditions B: x = 10, y = 100, z = 2, 20 h Conditions C: x = 5, y = 10, z = 2, 40 h

Scheme 1.1.

1.2.1.2. Michael Reaction in Water AgOTf–PPh3 complex-catalyzed Michael additions of β-ketoesters to nitroalkenes proceed efficiently only in water but not in organic solvents (Scheme 1.2).

1.2. CATALYTIC ASYMMETRIC SYNTHESIS IN WATER 3

AgOTf (10 mol %)

O NO2 +

Ph

O

PPh3 (20 mol %)

COOt-Bu

Ph NO2

H2O, rt, 24 h

COOt-Bu 90% yield, dr 80/20

Reaction in CH2Cl2, THF, no solvent: 80% as the concentrations increased up to 2.0 M; however, no improvement was observed by further O

Me3SiO

Sc(DS)3(x mol %)

HCHO +

H2O, yM, 20°C, Time

HO

2

3

1a

1b 2 mol % 5 mol %

10 mol %

20 mol %

100 90 80 70 60 50 40 30 20 10 0

1.5 equiv

3.0 equiv

5.0 equiv

100 90 80 70 60 50 40 30 20 10 0 0

2

4 6 Equiv of HCHO

8

10

0

2

4 6 Reaction time (h)

8

1c 100 90 80 70 60 50 40 30 20 10 0 0

2 mol %

5 mol % 10 mol %

0.5

1 1.5 2 Concentration (M)

20 mol %

2.5

3

Scheme 1.11. Part 1a. Hydroxymethylation of 2 (catalyst loading and HCHO equiv, reaction concentration was 1.0 M, reaction time was 1 h). Part 1b. Hydroxymethylation of 2 (reaction time and HCHO equiv, reaction concentration was 1.0 M). Part 1c. Hydroxymethylation of 2 (catalyst loading and concentration, reaction time was 8 h).


increasing the concentration. In the cases of the lower Sc loading level (2 and 5 mol %), the yields leveled off at much lower concentrations, 0.5 and 1.0 M, respectively. These results indicated that Sc(DS)3 might be saturated by aq. HCHO. Based on the experiments, it can be said that, in spite of the extreme solubility of HCHO in water, the population of HCHO in the hydrophobic environment increases in the presence of Sc(DS)3 due to Lewis acid–Lewis base interaction between Sc(DS)3 and HCHO, and therefore, the reaction of HCHO with silicon enolate 2 can proceed smoothly even in water. Furthermore, the hydroxymethylation of various silyl enol ethers proceeded smoothly (Scheme 1.12). Consequently, these experiments suggest that Lewis acid-surfactant combined catalyst (LASC) reaction system can be applied to hydrophilic substrates as well as hydrophobic substrates.

OSiMe3 aq. HCHO (5.0 equiv)

+

R1

R3 R2

O

Sc(DS)3 (5 mol %) H2O, 1.0 M, 20°C, 6 h

R3 R1 R2 7 examples 69–94% yield

HO

Scheme 1.12.

Lewis acid-catalyzed asymmetric reactions in water using hydrophilic substrates are recognized as highly challenging [18], considering the importance of Lewis acid–Lewis base interactions, since Lewis acids lose their acidity upon coordination from chiral ligands. Additionally, chiral ligands compete with substrates and water molecules for coordination with Lewis acids. Therefore, the development of chiral Lewis acid-catalyzed hydroxymethylation using aq. HCHO with water as the sole solvent would make a great impact in the field. The investigation of asymmetric variants of hydroxymethylations using aq. HCHO revealed that the addition of a chiral ligand and a small amount of a surfactant suppressed the competitive hydrolysis of silicon enolates. Eventually, catalytic asymmetric hydroxymethylation reactions are successfully carried out in the presence of a catalytic amount of Sc(DS)3, chiral ligand L-3 [19], or L-4 [20] in the presence of additives to afford the desired products in high yields with high selectivities. It is noteworthy that thioketene silyl acetals, which are known to be much less stable than silyl enol ethers (ketone-derived silicon enolates) in water, reacted smoothly under the conditions to afford the desired hydroxymethylated adducts in good yields with high enantioselectivities (Scheme 1.13). This method could be applied to the synthesis of an artificial odorant (S)-(+)-3 (Scheme 1.14) [12]. Hydroxymethylation of 1 was performed using Sc(DS)3•L-3 as a catalyst. After the reaction, the reaction mixture was centrifuged (3000 rpm, 20 min) to separate the colloidal white dispersion into three phases. The upper, middle, and bottom phases are water, surfactant, and organic layers, respectively. After the separation of organic phase, followed by hydrogenation with polymer incarcerated palladium (PI-Pd) [13] in benzotrifluoride (BTF), the compound (S)-(+)-3 was obtained in 56% yield with 91% ee over two steps. It should be noted that the synthesis has been accomplished using a catalytic asymmetric reaction in water and a hydrogenation with an immobilized catalyst, which are suitable for green sustainable chemistry [3,14].

1.2. CATALYTIC ASYMMETRIC SYNTHESIS IN WATER 9 L-3 or L-4 Sc(DS)3 (10 mol %) or Sc[O3S(CH2)10CH3]3 (1–10 mol %) additive

OSiMe3 aq. HCHO

R1

+

O CH3

HO

O

*

O

O HO

Ph

R3

R1 R2

O HO

O HO

H2O, 0.5 M 5°C–rt, 20–110 h

R2

(5.0 equiv)

HO

R3

HO

Ph

Cl 81% yield, 91% ee

83% yield, 94% ee

O HO

OH

91% yield, 91% ee 92% yield, 90% ee

O

OH O

StBu

HO 84% yield, 91% ee

82% yield, 96% ee

73% yield, 91% ee

ON+ N

N

tBu

tBu

OH

O

O

CH3

90% yield, 92% ee

83% yield, 90% ee

HN

HO

StBu

65% yield, 90% ee

ON+ O O NH

HO L-3

L- 4

Scheme 1.13.

aq. HCHO (5.0 equiv) Sc(DS)3 (10 mol %) L-3 (12 mol %)

Me3SiO

H2O, 1.0 M, 20 h then centrifugation 3000 rpm, 20 min

1 PI-Pd (10 mol %) H2 (1 atm)

HO BTF, 80∞C, 8 h

3 56%, 91% ee

Scheme 1.14.

1.2.1.5. Silica Gel-Supported Scandium with Ionic Liquid (Silica-Sc-IL) A novel heterogeneous scandium catalyst system, Silica-Sc-IL, has been developed (Scheme 1.15) [21]. The catalyst 4 coated with an IL, [DBIm]SbF6, works efficiently in Mukaiyama aldol reaction in water (Scheme 1.16). The reaction proceeds much faster in water than in organic solvents, without solvent or in the absence of IL. These experiments clearly suggest that Silica-Sc-IL and IL forms hydrophobic reaction environments in water (Scheme 1.17). It should be noted that water-labile reagents

10 CATALYTIC ASYMMETRIC SYNTHESIS IN NONCONVENTIONAL MEDIA/CONDITIONS SO2Cl

1) SiO2

(MeO)3Si

Toluene, 110°C, 24 h

SO3H

O

SiO2 O Si 2) 2 N H2SO4, 12 h

O

Silica-PhSO3H Ion exchange capacity: 0.57 mmolH+/g

1) 1 N NaCl aq., 1 h 2) Neutralize to pH = 7.0 by 0.1 N NaOH aq. Sc(OTf)3 EtOH, 80°C, 20 h

SO3Na

O

SiO2 O Si O

Silica-Na SO3Sc(OTf)2

O

SiO2 O Si O

Silica-Sc 4

Scheme 1.15.

OSiMe3 PhCHO +

SEt 5

Silica-Sc 4 (0.27 mmol/g, 5.4 mol %) [DBIm]SbF6 (30 wt %) Solvent 15°C, 24 h

OH O Ph

SEt

Solvent: Et2O Hexane H2O H2O without Silica-Sc H2O without IL neat

22% yield 26% yield 97% yield 0% yield 31% yield 25% yield

Scheme 1.16.

Water Substrates

– + – + – + – + – + SO3Sc(OTf)2 SO3Sc(OTf)2 + + + – – + – – + – – + – + + – + + + – + – Si Si – O OO + – + – O OO – + – Silica supporting material

Scheme 1.17.

+ –

Product

Ionic liquid


such as 5 can work well in water under the conditions, and that this is the first demonstration of a combination of silica gel-supported metal catalysts and ILs to create efficient hydrophobic environments for organic reactions in water. Although there is room to improve the results, an asymmetric catalysis can be realized using Silica-Sc-IL combined with a ligand L-3 (Scheme 1.18).

aq. HCHO (5 equiv)

+

OSiMe3

L-3 (6–6.5 mol %) Silica-Sc 4 (0.24–0.28 mmol/g, 5 mol %) IL (50 wt %)

Ph

H2O, 35°C, 20–24 h N SbF6

N

N

O HO

*

Ph

47% yield, 49% ee N NTf2

28% yield, 66% ee

Scheme 1.18.

1.2.2. Chiral Organocatalysis in Water In contrast to metal-based catalysts, organocatalyses are easy to handle, since they are, in general, stable in water. Amino acids are representative of organocatalysts and their derivatives have been widely investigated. Tert-butyldimethylsilyl (TBS)-protected hydroxyproline L-5 catalyzes a direct-type aldol reaction, leading to the aldol adduct in good yield with high diastereo- and enantioselectivities. And a Michael reaction of a ketone or an aldehyde with β-nitrostyrene in brine can be catalyzed by a proline derivative L-6 to afford the corresponding product in good yield with good diastereo- and enantioselectivities (Scheme 1.19). Moreover, a threonine derivative L-7 catalyzes Mannich reaction to produce the product in good yield with high diastereo- and enantioselectivities (Scheme 1.20) [22]. The Diels–Alder reaction is a powerful transformation method in organic chemistry. Chiral imidazolidinone can successfully catalyze the reaction of α,β-unsaturated ketones with dienes, where chiral Lewis acid catalysts showed lower enantioselectivities (Scheme 1.21) [23,24]. 1.2.3. Others 1.2.3.1. Asymmetric Reactions Using Alkynes [25] Optically active propargylamines are important synthetic intermediates for various nitrogen-containing compounds, a structural feature of many biologically active compounds and natural products. The most reliable and efficient methods for the preparation of optically active propargylic amines are still dependent on the addition of appropriate organometallic reagents to chiral imine derivatives. While methods for catalyzed preparation of optically active propargylic amines are still limited, highly enantioselective direct-type alkyne-imine addition was recently reported using a chiral Cu(I)•L-9 complex. The process is simple and provides a diverse range of propargylic amines in high enantioselectivity (Scheme 1.22) [26].

12 CATALYTIC ASYMMETRIC SYNTHESIS IN NONCONVENTIONAL MEDIA/CONDITIONS tBuMe SiO 2

CO2H N H L-5 (10 mol %)

O +

PhCHO

OH O Ph

H2O

syn/anti = 1:19 61% yield, >99% ee (anti) C10H21 N

C10H21 N H L-6 (10 mol %)

O +

NO2

Ph

Ph

O

NO2

TFA, brine syn/anti = 95:5 93% yield, 89% ee

Scheme 1.19.

OCH3

O

O +

H

+

OBn

NO2

OTBDPS CO2H NH2 L-7 (10 mol %)

O

H2O, rt, 24 h NH2

NHPMP OR1

NO2

90% yield, syn/anti = 1:6, 93% ee (anti)

Scheme 1.20.

O + Et

O

O

N

Bn

N H

•HClO4

L-8 (20 mol %) H2O, 0°C

Et

O

89% yield, endo : exo = 25:1, 90% ee

Scheme 1.21.

The conjugate addition reaction of terminal alkynes to C=C bond can be catalyzed by copper in water. The reaction only proceeds with derivatives of Meldrum’s acids in the presence of Cu(I) produced by Cu(OAc)2 and sodium ascorbate in water, and a large excess amount of phenylacetylyne. Combined with chiral ligand L-10, enantioselective versions of this addition reaction can be achieved to 82–97% ee of products with useful yields [27] (Scheme 1.23).


O N

N

H 2O 35°C, 2 days

Ph

H

N

L-9 (10 mol %) CuOTf (10 mol %)

H

Ph

O

N

HN Ph

* Ph

68% yield 91% ee

Scheme 1.22.

O O

O O

+

Ph

L-10 (10 mol %) Cu(OAc)2•H2O (10 mol %) Na-ascorbate (20 mol %) H2O, 0°C, 14 h

(10 equiv)

R

O O

O O

R Ph

Ph

R = aromatic, aliphatic 6 examples

HN N N O

64–94% yield 82–97% ee PPh2

L-10

Scheme 1.23.

1.2.3.2. DNA-Based Asymmetric Catalysis in Water The DNA-based asymmetric Diels–Alder reaction proceeds in water. There are three key structural features: a DNAintercalating moiety, a spacer component, and a metal-binding group, which intimately anchored the metal complexes to DNA to use its chiral information. The substituent and the spacer length of the ligand are crucial for both of enantioselectivity and the enantiopreference [28]. 1.2.3.3. Pauson–Khand-Type Reaction in Water The chiral ligand BINAP [2,2′-bis(dip-tolylphosphino)-1,1′-binaphthyl] together with [RhCl(COD)]2/TPPTS (trisodium salt of 3,3′,3″-phosphanetriyl benzene sulfonic acid) is effective for the asymmetric Pauson– Khand-type reaction in water. Formaldehyde can be used as a source of carbon monoxide directly in water (Scheme 1.24) [29]. Rhodium-catalyzed asymmetric Pauson–Khand-type reactions in water work well in the presence of a chiral atropisomeric dipyridyldiphosphane ligand (S-P-Phos), transforming various enynes into the corresponding bicyclic cyclopentenones in good yields and ees (up to 95% ee) (Scheme 1.25) [30].


R X

+

HCHO (5–20 equiv)

[RhCl(cod)]2 (5 mol %) (S)-tol-BINAP (10 mol %) TPPTS(10 mol %) SDS (0.1–2.0 equiv)

R X

O

H2O, 100°C

* 47–83% yield 74–95% ee

X= C(CO2Et)2, O, NTs

Scheme 1.24.

R O

R'

[RhCl(cod)]2 (3 mol %) L-11 S-P-Phos (6 mol %) Cinnamylaldehyde

R O

H2O, 100°C, 36 h

O * R'

R = aromatic, aliphatic 49–93% yield 74–95% ee R' = H, Me O

O

N O

O PPh2 PPh2 L-11 S-P-Phos

Scheme 1.25.

1.2.4. Conclusion and Perspective Organic reactions in other, nonconventional solvents instead of organic solvents are now of interest in many aspects related to green sustainable chemistry. The first choice of a nonconventional solvent is water. Water is a clean, nontoxic, inexpensive, and the most environmentally friendly solvent. In addition, acid catalysis has occupied major parts of organic transformations. Therefore, the chiral acid catalysis in water we have discussed here will play a key role in this field. As we described, organic reactions in water are difficult because most organic materials are not soluble and many reactive intermediates and catalysts are not stable in water. In addressing these issues, many focused research efforts have led to rapid progress, exemplified by elegant asymmetric catalysis in water, which was believed to be impossible 10 years ago. Moreover, systems have been developed for the recovery and reuse of catalysts utilizing biphasic reaction conditions that incorporate water. As for the future of asymmetric catalysis in water, several important developments are predicted. Stereoselective carbon–carbon bond-forming reactions are still an important challenge in organic synthesis, and in particular, control of the stereogenic centers of products is crucial. From this aspect, the development of catalytic asymmetric reactions in water is still a major task, which represents significant challenges since most asymmetric catalysts, except for some late transition metal-based systems, are not stable in water.

1.3. CATALYTIC ASYMMETRIC SYNTHESIS IN ALTERNATIVE REACTION MEDIA

15

As such the design of water-compatible catalysts will be the key to the future of this work. Asymmetric aerobic oxidation in water is an important research target for the future. It will not be necessary to mention the importance of environmentally benign oxidation processes to this readership, but due to the high heat capacity and stability of water, the process is promising. The use of water-soluble small molecules such as formaldehyde and ammonia will be another critical area. These molecules are inexpensive and potentially useful carbon and nitrogen building blocks; however, they are not well utilized in conventional organic synthesis in organic solvents. Asymmetric catalysis using formaldehyde and ammonia will be a key project not only in academia but also in industry.

1.3. CATALYTIC ASYMMETRIC SYNTHESIS IN ALTERNATIVE REACTION MEDIA Since many chiral catalysts are valuable and indeed expensive, recovery and reuse of the catalysts is especially important in industry. For this purpose, nonconventional solvents have been investigated. In this section, fluorous solvents, SCFs, and ILs are described. 1.3.1. Fluorous Solvents Fluorous compounds with appropriate melting and boiling points can be used as solvents. Interestingly, these fluorous compounds are remarkably different from the corresponding hydrocarbons and form bilayers with conventional organic solvents. In terms of recovery and reuse of catalysts, fluorous media is of great interest. Since fluorous solvents tend to mix poorly with common organic solvents, some catalysts can be immobilized in fluorous solvents in biphasic systems. In addition, one of the characteristic points in fluorous-organic biphasic systems is that some combination of fluorous and organic solvents demonstrates increased miscibility at elevated temperature, and that heating can result in a completely homogeneous mixture in such cases. This is remarkably different from water-organic biphasic systems. Accordingly, in fluorous-organic biphasic systems, it is possible to carry out reactions under homogeneous conditions at elevated temperature, and after the reactions occur, the mixture is cooled to become two phases. While products are separated from organic solvent phases, catalysts can be recovered from fluorous solvent phases. Since the first report of fluorous biphasic systems (FBSs) [31], reactions using fluorous solvents have been recognized as green reactions due to simple procedures and use of chemically inert and low toxicity fluorous solvents. In the past decade, FBSs have been widely applied to asymmetric reactions. A typical and very successful application of FBS is chiral phase transfer catalyst for α-amino acid synthesis. Synthetically convenient 4,4′,6,6′-tetrasubstituted symmetrical chiral phase-transfer catalysts promote asymmetric alkylation of t-butylglycinate–benzophenone schiff base [32]. The substituent of the 4,4′,6,6′-positions of binaphthyl effects on chiral efficiency and the SiMe2(CH2CH2C8F17)-substituted catalyst designed as a recyclable fluorous chiral phase-transfer catalyst can promote the reaction’s good chiral efficiency and reusability (Scheme 1.26). The chiral fluorous complex tetrakis-dirhodium(II)-(S)-N-(n-perfluorooctylsulfonyl) prolinate (L-13) displays good chemo- and enantioselectivity in intermoleculer cyclopropanation and C–H bond activation reactions (Scheme 1.27). The catalyst can be simply and thoroughly separated from the reaction mixture and is recyclable [33].


Scheme 1.26.

+

N2

Ph

L-13 (10 mol %)

CO2Me

PFMC, rt

(10 equiv) O

MeO2C Ph Ph 79% yield, 62% ee

Rh

N O Rh O O S (CF2)7CF3 4

L-13 +

N2

Ph

L-13 (10 mol %)

CO2CH3

PFMC, 25°C

CO2Me Ph 71% yield, 61% ee

Scheme 1.27.


17

Rh-[Rf(CH2)3]2-BINAPHOS complex catalyzes hydroformylation of alkynes in fluorous solvents. The desired branch product from styrene is obtained in comparable or even higher regio- and enantioselectivities than those of the conventional Rh-BINAPHOS (L-14) system [34]. Rf

Rf

PPh2 O O P O

Rf

Rf [Rf(CH2)3]2-BINAPHOS (L-14) Rf = nC4H9,nC6H13,nC8H17

More applications of FBSs to asymmetric reactions such as the hydrogenation of ketones [35], epoxidations [36], and C–C bond formations [37–41] have been reported.

1.3.2. Catalytic Asymmetric Synthesis in SCFs SCFs are also focused as nonconventional solvents. SCFs are probably best known through their use for the decaffeination of coffee, which employs supercritical carbon dioxide (scCO2). SCFs represent a different type of nonconventional solvent from water, fluorous solvents, ILs, and even organic solvents, because they are not in the liquid state. An SCF is defined as a substance above its critical temperature (Tc) and pressure (Pc), but below the pressure required for condensation to a solid. The critical point represents the highest temperature and pressure at which the substance can exist as a vapor and liquid under equilibrium. Hence, in a closed system, as both temperature and pressure are increasing, the liquid becomes less dense due to thermal expansion, and the gas becomes dense as the pressure rises. The densities of both phases thus converge until they become identical at the critical point. At this point, the two phases become indistinguishable and an SCF is obtained. In such SCFs, remarkable reactivities and selectivities are sometimes observed. From a process perspective, scCO2 offers the advantage that simple depressurization removes residual scCO2, and, therefore, no hazardous solvent effluent is produced. This leads to a facile separation of products. This organic solvent-free process is of great interest in the pharmaceutical, cosmetic, food, and electronic industries where highly pure materials are very important. Catalytic asymmetric synthesis in SCFs has been investigated. Iridium-catalyzed asymmetric hydrogenation of imines is successfully carried out in scCO2 [42]. Cationic Ir(I)•L-15 complex with a perfluoroalkyl group in the counter anion is very effective for efficient asymmetric catalysis. In the presence of 0.078 mol % of the catalyst, an imine derived from acetophenone is reduced within 1 h in scCO2 at 40°C under H2 (30 bar) to afford the corresponding amine in high yield with high enantioselectivity (Scheme 1.28). It is noted that the catalyst loading is decreased dramatically by using scCO2 instead of conventional solvents such as dichloromethane (DCM). The product is readily separated from the catalyst, which can be reused several times without significant loss of activity.


N Ph

Ir•L-15 H2 (30 bar)

Ph

HN

scCO2, 40°C

CH3

Ph

Ph CH3

81% ee + CF3

O P

–

N

B

Ir CF3 4 Ir•L-15

Scheme 1.28.

Asymmetric hydrogenation also proceeds smoothly in scCO2 by using the perfluoroalkyl-substituted ligand (R,S)-3-H2F6-BINAPHOS (L-16) and Rh complex (Scheme 1.29) [43]. Another Rh•L-17 complex for asymmetric hydrogenation in scCO2 has also been reported (Scheme 1.30) [44]. In these cases, the catalysts are soluble in scCO2 to form homogeneous systems during the reactions.

O

[Rh(cod)2]BF4/L-16 N H

CO2Me

H2 (30 bar), CO2, 40°C

O N H

CO2Me

97.2% ee

Rf P

O P

O

O Rf Rf = CH2CH2(CF2)5CF3 (R,S)-3-H2F6-BINAPHOS (L-16)

Scheme 1.29.

On the other hand, the continuous flow scCO2 system [45] has been applied to asymmetric hydrogenation using [Rh(COD)2]+[BF4]–/H3O40PW12/alumina (CATAXA®) and Josiphos 001 ligand (L-18) as an immobilized chiral catalyst [46]. A mixture of H2, CO2, and a substrate (dimethyl itaconate) in 2-propanol is poured into a hydrogenation reactor with the chiral Rh catalyst, and the product is obtained with 83% ee (Scheme 1.31). In this system, neither perfluoroalkyl-substituted ligands nor counter anions with


O MeO

O

Rh•L-17 CO2Me

MeO

H2 (30 bar), CO2 40–45°C

Rh

–

CF3 B

OP Ar Ar Ar =

CO2Me 72% ee

+

Ar Ar OP

19

CF3 4

CH2CH2(CF2)6F Rh•L-17

Scheme 1.30.

P Fe PPh2

Josiphos 001 (L-18) Scheme 1.31.

Scheme 1.32.

perfluoroalkyl groups are used. scCO2 is utilized to dissolve H2 and for ease of product separation. A similar flow system with an immobilized chiral Ru•L-19 complex for asymmetric cyclopropanation reaction in scCO2 has been reported. It is demonstrated that productivity in scCO2 has been increased 7.7-fold compared with that in DCM. Environmental friendliness and ease of product separation are further merits (Scheme 1.32) [47].


An inverted scCO2/aqueous biphasic system has been used as reaction media for Rh-catalyzed asymmetric hydrogenation. Chiral CO2-philic catalysts are efficiently immobilized in scCO2 as the stationary phase, while polar substrates and products are contained in water as a mobile phase. The catalyst phase is reused several times with high conversion and product recovery of more than 85%. The chiral ligand (R,S)-3-H2F6BINAPHOS (L-16) allows highly enentioselective hydrogenation of itaconic acid and methyl-2-acetamidoacrylate under these conditions [48].

1.3.3. IL ILs are defined as materials that are composed of ions and have melting points below 100°C (the temperature may be flexible). ILs have many properties that lend themselves to clean chemical synthesis, perhaps most notably that they are nonvolatile and are therefore not lost to the atmosphere. The main advantages are that catalyst lifetimes can be extended, often considerably, and rates of reactions are accelerated in many cases. In addition, recovery and reuse of catalysts is possible using biphasic or multiphasic catalyst systems. Efficient reactions with organic compounds under homogeneous conditions in an IL, followed by extraction of the products with scCO2, provide an ideal process without any volatile organic solvents. Typical ILs are shown in Scheme 1.33.

[NRnH4-n]+X–

Alkyl ammonium salts

R1 N R2 + N N X R N-alkylpyridinium salts

X N,N'-dialkylimidazolium salts

X = hal, BF4, PF6, OTf, OAc, NTf2, SbF6, etc R1 N R2 + N X

Abbreviations C4C1im : R1 = C4H9, R2 = CH3 C4C2im : R1 = C4H9, R2 = C2H5 C2C1im : R1 = C2H5, R2 = CH3

Scheme 1.33. Major classes of ionic liquids.

1.3.3.1. Asymmetric Hydrogenation in ILs The catalytic enantioselective hydrogenation of unsaturated bonds such as C=C, C=O, and C=N in the presence of molecular hydrogen or hydrogen donor is one of the most useful chemical transformations. Since molecular hydrogen is used as the reactant in many cases, it is clear that the solubility of hydrogen gas in ILs is an important factor in catalyzed reactions. It has been suggested that increased reaction rates in biphasic hydrogenation reactions in ILs could be due to high solubility of hydrogen in the IL, and the correlation of ILs and the solubility of molecular hydrogen has been studied [49]. Since the first report of enantioselective metal-catalyzed reaction in ILs [50], asymmetric hydrogenation of carbon–carbon double bonds and carbon–heteroatom double bonds has been the most investigated transformation. Several combinations of transition metals, chiral ligands, and ILs have been studied for these reactions [51].


21

Rh and Ru-chiral phosphine or Ru-chiral diamine complexes are often combined with N,N′-dialkylimizazolium salts [52,53]. The Rh-catalyzed hydrogention of C=C bond such as α-acetoamide cinnamic acid and related enamides works well to give the corresponding products with high enantioselectivities (Scheme 1.34). The catalyst can be reused, and IL can suppress the catalyst aging in some cases; however, in other cases, the catalyst loses its activity in the process of recycling, probably because of leaching or deactivation [54]. Rh•L-20 H2 (2 bar), 25°C

CO2Me

CO2Me

[C4C2im][PF6]-iPrOH

NHAc

NHAc 83% conv., 93% ee

OTf P

P

Rh

Rh•L-20

Scheme 1.34.

Imidazolium moieties were introduced to chiral diphosphine ligand (L-21) in order to attach the catalyst to the IL phase. The modified catalyst can work efficiently in the hydrogenation and can be recovered and reused without significant loss of activity (Scheme 1.35) [55].

[Rh(cod)•L-21](BF4)3 H2 (1 bar), 20°C [C4C2im][PF6]-iPrOH

NHAc

NHAc

O N

N

N

N

Ph2P

N

N

PPh2

L-21 Scheme 1.35.

With a similar concept, Josephos ligands with an imidazolium tag can be applied to the asymmetric hydrogenation of methyl acetamidiacrylate and dimethyl itaconate in biphasic cosolvent/IL combinations (Scheme 1.36) [56,57]. The introduction of an imidazolium group in the Josephos ligand improves the affinity of the Rh complex for the IL to lead the suppression of catalyst leaching in the combination of t-butyl methyl ether (TBME)/[bmim]BF4. The catalyst can be recycled and reused with efficient product isolation.


CO2Me

Rh(NOD)2(BF4)3 + L-22 or L-23

CO2Me

R

S/C 200, H2 (1 bar), rt, 10 min TBME/[bmim]BF4

R

R = NHAc, CH2CO2Me

PCy2 R'2P

Fe

H H N

N

100% conv., 99% ee

N

(CF3SO2)2N O L-22: (R)-(S) R = Ph L-23: (R)-(S) R = 3,5-(CF3)2C6H3 Scheme 1.36.

Ru-BINAP and its derivative complexes are very common reagents for asymmetric hydrogenation [58]. [Ru(O2CMe)2•((R)-tolBINAP)] in [bmim][PF6]/H2O system promotes the hydrogenation of tiglic acid to give the corresponding product in excellent conversion with good ee (Scheme 1.37). The enantioselectivity depends on hydrogen pressure, and water enhances enantioselectivity at high pressure, while there is no effect of adding water at low pressure. To avoid the use of organic solvents, supercritical carbon dioxide (scCO2) can be applied to this reaction to recover the organic product from the reaction mixture. Since Ru catalyst is not soluble in scCO2, the product can be extracted from IL by scCO2 and is contaminated only by water. The catalyst can be immobilized to the IL layer, therefore efficiently reused multiple times without loss of activity and even with enhanced enantioselectivity [59].

CO2H

CO2H

Ru(O2CMe)2•(R)-tolBINAP, H2 (5 bar) [C4C1im ][PF6]/H2O (3/2)

* Extract with scCO2 99% conv., 85% ee

Scheme 1.37.

1.3.3.2. Asymmetric Diels–Alder Reaction in ILs Copper catalysts based on imidazolium-tagged bis(oxazolines) enhance the reaction rate and enantioselectivity of the corresponding product in the reaction of N-acyloyl and N-crotonyloxazolidinones with cyclopentadiene and 1,3-cyclohexadiene (Scheme 1.38) [60]. The introduction of an imidazolium tag into bis(oxazolines) significantly improves the recovery and reuse of the catalyst for reactions performed in IL. The catalyst can be recycled at least 10 times without loss of activity and enantioselectivity. Furthermore, the imidazolium-functioned ligand does not leach into the organic phase [61,62]. 1.3.3.3. Asymmetric Epoxidation in ILs Mn-salen complex 11 catalyzes asymmetric epoxidation of alkenes efficiently in IL [63,64]. Since IL is solidified at the reaction temperature, the reaction requires the use of DCM to form homogenous solution. IL


H3C

N

O

CH3

L-24 (11 mol %) Cu(OTf)2 (10 mol %)

O

O

+

23

O

Solvent, rt

O

N

O

in [C4C1im][NTf2], 20 min 100% conv. 83% endo (95% ee) in CH2Cl2 for 2 h: NR

N

NTf2 N O

O N

tBu

N tBu

L-24

Scheme 1.38.

(R,R)–L-25 (4 mol %) NaClO

O

O

[C4C1im][PF6]/CH2Cl2 (1/4) 0°C, 2 h

H

H N

tBu

N

Mn O Cl O tBu

O 1st: 86% yield, 96% ee 2nd: 73% yield, 90% ee 3rd: 73% yield, 90% ee 4th: 60% yield, 89% ee 5th: 53% yield, 88% ee

tBu tBu

(R,R)–L-25 Scheme 1.39.

enhances the catalyst’s reactivity, and, moreover, IL and chiral complex can be recycled up to five times with only slight loss of ee and catalyst activity (Scheme 1.39). 1.3.3.4. Asymmetric Ring Opening of Epoxides in ILs Cr(salen) complex (Cr•L-26) catalyzes ring opening of epoxides with TMSN3 in [C4C1im][PF6] and [C4C1im][OTf] at room temperature. The catalyst can be recycled up to five times without loss of ee and can even enhance its activity [65] (Scheme 1.40). Chiral Co(III)(salen) complex catalyzes hydrolytic kinetic resolution of racemic epoxides in ILs. Co(II)(salen) complex is oxidized without acetic acid to catalytically active Co(III)(salen) complex during the reaction, and this oxidation state is stabilized


Me3SiN3 Cr•(R,R)-L-26 (3 mol %)

CSA

[C4C1im][PF6]/[C4C1im][OTf] = (5/1) 20°C, 28 h

O

H

Cr O Cl O

But

tBu

N3

OH

1st: 68%, 94% ee 2nd: 72%, 93% ee 3rd: 85%, 93% ee 4th: 75%, 94% ee 5th: 76%, 93% ee

H N

N

OSiMe3

N3

MeOH

tBu

But

Cr•(R,R)-L-26 Scheme 1.40.

O Cl

Co•(R,R)–L-26•OAc (0.5 mol %) H2O

O Cl

+

OH Cl

THF-[C4C1im][PF6], 20°C 24–48 h >99% ee even after 10th use of the catalyst H N tBu

H N Co

O tBu

OH

tBu

O tBu

Co•(R,R)–L-26 Scheme 1.41.

against reduction to Co(II) complex. The catalyst can be reused 10 times without loss of ee and reactivity [66] (Scheme 1.41). 1.3.3.5. Asymmetric Dihydroxylation in ILs Osmium-catalyzed asymmetric dihydroxylation constitutes a versatile method for the synthesis of chiral vicinal diols from alkenes. Its industrial utility suffers from several disadvantages, mainly the high cost of osmium and chiral ligands and the toxicity of the metal, which may contaminate the optically active product. To address these issues, many efforts to modify these catalysts have been made. The main way to utilize chiral OsO4 catalysts efficiently is to immobilize the catalyst to polymers [67], porous resins [68], and the other various solid supports [69]. IL can also provide functions to support the catalysts [70]. In the asymmetric dihydroxylation of trans-stilbene catalyzed by OsO4 (1.5 mol %) and ligand L-27 (2.0 mol %) in the presence of N-methylmorpholine N-oxide (NMO) (2.6 mol %) and [C4C1im][PF6] (2 mL for 2-mmol scale) in acetone–water (v/v, 10/1) at 0°C, the catalyst can be recovered in IL phase and reused up to three times without significant loss of activity and ee with

1.4. MICROWAVE-ASSISTED CATALYTIC ASYMMETRIC SYNTHESIS 25

only a small amount of OsO4 (200:1 endo : exo 85–96% ee

Scheme 2A.2. Iminium-catalyzed Diels–Alder reaction of α,β-unsaturated ketones.

In addition to Diels–Alder transformations, several other enantioselective cycloaddition processes, including 1,3-dipolar cycloadditions [5], cyclopropanations [6], and epoxidations [7], have also proved susceptible to iminium catalysis leading to the enantioselective syntheses of a series of useful building blocks (Scheme 2A.3). The potential of iminium catalysis to mediate other enantioselective cycloaddition processes continues to be investigated. For example, an elegant preparation of enantioenriched seven-membered rings, via [4 + 3] cycloaddition, was described by Haramata and coworkers, representing the first catalytic approach to such ring systems (Scheme 2A.4) [8].

42 ENANTIOSELECTIVE ORGANOCATALYSIS INVOLVING IMINIUM, ENAMINE, SOMO Organocatalytic [3+2] cycloaddition reactions O

Z Z R

O

20 mol % cat.*

N

O

N -

O

R

R1

R

MeNO2, H2O, –20°C

Me N

Catalyst = Ph

CHO

Me

(eq 1)

N Me H •HClO4

70–98% yield 80:20–99:1 endo : exo 90–99% ee Organocatalytic cyclopropanation Me R

O

Me

20 mol % cat.*

S

R1

R

Catalyst =

R

-

CHCl3, –10°C

CO2H

(eq 2)

N H

CHO

63–85% yield 6:1–72:1 dr 89–96% ee Organocatalytic epoxidation F3C

20 mol % cat.* R

O

O R

O

CH2Cl2, AcOH Oxidant, –30°C

O

Me N

Catalyst =

72–95% yield 85–97% ee

CF3

t-Bu N H •HClO4

Ph

or

N H

F3C

(eq 3)

OTMS

CF3

Scheme 2A.3. Iminium-catalyzed cycloaddition reactions.

O

O OTMS

Me CHO

O

Me

20 mol % cat.* CHO

CH2Cl2, 0°C

Me

O Me

Me N

Catalyst = Ph

t-Bu N H •TFA

64% yield 89% ee

Scheme 2A.4. Iminium-catalyzed [4 + 3] cycloaddition.

2A.2.2. 1,4-Addition Reactions The enantioselective Michael addition of a nucleophile to an α,β-unsaturated carbonyl system represents a valuable method for the synthesis of enantioenriched products. In this regard, the value of iminium catalysis was further demonstrated by the development of enantioselective conjugate addition protocols that were previously unattainable using conventional acid or metal catalysis. More specifically, Friedel–Crafts alkylation of electron-rich aromatics [9–12] and conjugate addition of aryl trifluoroborate salts [13] were found to be particularly effective under the iminium catalysis manifold (Scheme 2A.5). The effectiveness of this methodology was further demonstrated by the concise synthesis of a number of natural products and bioactive compounds [14].

2A.2. IMINIUM-BASED CATALYSIS 43 Organocatalytic Friedel–Crafts alkylations of substituted pyrroles O

20 mol % cat.*

R1 R

R1

O

N

N

THF, H2O, –30 to –60°C

R2

Me N

Catalyst =

O R2

R

N H

Ph

68–90% yield 87–97% ee

Me

(eq 1)

Me •HX

HX = TFA, TCA or NCCH2CO2H

Organocatalytic Friedel–Crafts alkylations of substituted indoles R

R

O

20 mol % cat.*

R1 O

N R2

O R1

CH2Cl2, i-PrOH –50 to –87°C

Me N

Catalyst =

(eq 2) Ph

R2

t-Bu

N H

N

•TFA

70–94% yield 89–97% ee Organocatalytic conjugate addition of substituted anilines R

R2 R

20 mol % cat.*

O

R2 O

O

CH2Cl2 or CHCl3 –50 to 20°C

(R1)2HN

Me N

Catalyst =

(R1)2HN

(eq 3) t-Bu

N H

Ph

•HCl

65–97% yield 84–99% ee Organocatalytic Mukaiyama–Michael reaction O

20 mol % cat.* R

O

TMSO

R1

O

O O

R1 O

CH2Cl2, H2O –20 to –70°C

Me N

Catalyst = Ph

R

(eq 4) t-Bu

N H

•DNBA

73–87% yield 1:6–31:1 syn : anti 84–99% ee Organocatalytic Friedel–Crafts alkylations with trifluoroborate salts Ar

O

Ar

BF3K

O

20 mol % cat.* R

O

R

or

Me N

Catalyst =

or

t-Bu

N H

HF, DME, –20°C

(eq 5)

•HCl BF3K X

O

X

N R

Bn

69–97% yield 87–97% ee

Scheme 2A.5. Iminium-catalyzed alkylation of electron-rich aromatic/vinyl substrates.

More recently, several groups have reported expansions of the iminium catalysis paradigm to demonstrate the enantioselective conjugate addition of carbogenic nucleophiles such as nitroalkanes, malonates, 1,3-dicarbonyl compounds, and β-ketosulphones to a number of acyclic α,β-unsaturated ketones [1,2]. One particularly interesting use of iminium activation has been the enantioselective conjugate addition of amines to α,βunsaturated aldehydes. In this case, rational consideration of the stereoelectronic nature of both organocatalyst and nucleophile resulted in the development of a convenient method for the preparation of C–N stereogenic compounds with high enantioselectivity (Scheme 2A.6) [15].

44 ENANTIOSELECTIVE ORGANOCATALYSIS INVOLVING IMINIUM, ENAMINE, SOMO

PG R

O

N H

OTBS

20 mol % cat.*

PG

CHCl3, –20°C

R

N

O

OTBS

Me N

Catalyst = O Ph

t-Bu

N H

•p-TSA

69–92% yield 87–97% ee

Scheme 2A.6. Enantioselective conjugate addition of amines using iminium catalysis.

Jørgensen and others utilized a similar approach for the enantioselective βhydroxylation of aldehydes (Scheme 2A.7) [16]. In conjunction with enamine-controlled α-hydroxylation (vide infra), this provides convenient access to enantioenriched α- and β-hydroxyaldehydes.

F3C

10 mol % cat.* R

O

HO

N

Ph

N

Ph

PhMe, 4°C

O

R

60–75% yield 88–97% ee

Catalyst = O

CF3 N H

OTMS

F3C

CF3 •PhCO2H

Scheme 2A.7. Enantioselective β-hydroxylation using iminium catalysis.

2A.2.3. Transfer Hydrogenation The hydrogen atom is the most common discrete substituent found among stereogenic centers. It is, therefore, unsurprising that the field of asymmetric catalysis has focused great attention on the invention and development of enantioselective hydrogenation protocols. While these powerful methods rely mainly on the use of organometallic catalysts and molecular hydrogen, it is important to consider that the large majority of hydrogen-containing stereocenters are created in biological cascade sequences involving enzymes and organic cofactors. Based on this, a unique metal-free, biomimetic hydrogenation method was developed employing the LUMO-lowering iminium concept as the activating mechanism. Indeed, the selective reduction of β,β-disubstituted α,βunsaturated aldehydes and β-substituted α,β-unsaturated ketones could be accomplished under iminium control, employing Hantsch esters as the hydride donors, with high levels of enantiocontrol (Scheme 2A.8) [17,18]. A noteworthy feature of this transformation is that the sense of asymmetric induction is not related to the geometry of the olefin starting material. As a consequence, mixtures of E/Z-olefin isomers can be employed to provide enantiomerically pure hydrogenation adducts, a desirable, yet rare, feature for catalytic hydrogenations (Scheme 2A.9) [17].

2A.3. ENAMINE CATALYSIS 45 Organocatalytic 1,4-reduction of α,β-unsaturated aldehydes R1

EtO2C

O

Me

R

N H

O

CO2Et

20 mol % cat.*

Me

CHCl3, –30°C

R1

O

Me N

Catalyst =

(eq 1) t-Bu

N H

R

•TFA

74–95% yield 90–97% ee Organocatalytic 1,4-reduction of α,β-unsaturated ketones O

O

O t-BuO2C Me

n

R

CO2t-Bu N H

20 mol % cat.*

Me

Me N

Catalyst =

Et2O, 0°C

n

(eq 2) Ph

R

N H •TCA

O Me

66–89% yield 88–98% ee

Scheme 2A.8. Reduction of α,β-unsaturated carbonyl compounds using iminium catalysis.

E only O O

Me

Me

EtO2C

N N H

O

Me

t-Bu

Me

•TCA

CO2Et N H

O Me

Me

Same enantiomer (S)

Z only

Scheme 2A.9. Stereoconvergence of iminium-catalyzed hydride reduction.

2A.3. ENAMINE CATALYSIS [1,9] In the early 1970s, Hajos and Parrish reported the proline-catalyzed enantioselective intramolecular aldol reaction in their approach toward the Wieland–Miescher ketone (Scheme 2A.10) [19].

O

O

O

3 mol % cat.* DMF, RT

O

Catalyst = O

N H

CO2H

OH

100% yield 93% ee Scheme 2A.10. Hajos and Parrish’s proline-catalyzed asymmetric aldol reaction.


This extraordinary result was well received by the synthetic community; however, the underlying activation mode was not exploited outside of this initial intramolecular aldol reaction for more than 30 years. Indeed, it was not until the ingenious work of List, Lerner, and Barbas in 2000 that the utility of enamine catalysis truly came to fruition via application to a variety of carbonyl α-functionalization reactions. The first example of modern enamine chemistry arose through a catalytic asymmetric aldol reaction (Scheme 2A.11) [20].

O

R

OH

30 mol % cat.*

O H

DMSO, 23°C

O

Catalyst = N H

R

CO2H

54–97% yield 60–96% ee

Scheme 2A.11. List, Lerner, and Barbas’s proline-catalyzed catalytic asymmetric aldol reaction.

Mechanistically, enamine catalysis might be better described as a bifunctional catalysis as the amine catalyst typically interacts with an aldehyde or ketone substrate to form an enamine while simultaneously engaging an electrophilic reaction partner via either hydrogen bonding or electrostatic attraction. This general mode of activation has now been exploited in a wide range of enantioselective carbonyl α-functionalization processes, a selection of which is presented below.

2A.3.1. Asymmetric Aldol and Aldol-Type Reactions Following the work of List, Lerner, and Barbas [20], enamine-catalyzed enantioselective aldol reactions received considerable attention [1,21]. Although several novel catalyst structures can be utilized, many aldol processes can be performed using commercially available, and inexpensive, proline as the requisite organocatalyst allowing high efficiency and enantioselectivity. Of particular note was the intermolecular aldehyde–aldehyde crossed aldol reaction, a transformation that previously had only been accomplished within the realm of enzymatic catalysis (Scheme 2A.12) [22]. This procedure was elaborated further by MacMillan and co-workers to generate a two-step carbohydrate synthesis based on the enamine-catalyzed aldol dimerization of α-oxyaldehydes, followed by a Mukaiyama-aldol-cyclization event. This protocol generated a series of differentially substituted hexoses in high yield, with excellent levels of diastereoselectivity and enantiopurity (Scheme 2A.13) [23]. List reported the related three-component Mannich reaction of acetone, anisidine, and a range of aldehydes to furnish β-PMP-protected aminoketones (Scheme 2A.14) [24]. The process could be extended to α-oxyketones, the products of which can be readily converted to valuable amino alcohol building blocks. Barbas and co-workers later reported an extension of this methodology to allow the direct synthesis of aldehyde–aldehyde Mannich derivatives in a one-pot operation (Scheme 2A.15) [25].

2A.3. ENAMINE CATALYSIS 47 Proline-catalyzed aldehyde–aldehyde aldol reaction O H

OH

Catalyst =

R2

H

R1

H

O

10 mol % cat.*

O R

DMF, 4°C

R

(eq 1)

CO2H

N H

75–88% yield 91–>99% ee Imidazolidinone-catalyzed aldehyde–aldehyde aldol reaction O H

R

H

R1

O

OMe OH

10–20 mol % cat.*

O

Me N

Catalyst = R2

MeO

Et2O, MeOH, 4°C Amberlyst-15

R

N H

Ph

t-Bu •TFA

58–90% yield 90–97% ee

Scheme 2A.12. Organocatalytic crossed aldol reaction of aldehydes. Carbohydrate synthesis step 1: Organocatalytic aldol dimerization of α-oxyaldehydes O

10 mol % cat.*

O OTIPS

H

OH OTIPS

H

DMSO, 23°C

Catalyst =

CO2H

N H

OTIPS

92% yield 4:1 syn : anti 95% ee

Carbohydrate synthesis step 2: Lewis acid-mediated Mukaiyama aldol cyclization O

OH

OSiMe3

OTIPS

H

H

OTIPS

MgBr2•Et2O

O

TIPSO

OAc

Et2O, –20 to 4°C

OH

TIPSO

OAc OH

79% yield 10:1 dr 95% ee O

OH

OSiMe3

OTIPS

H

H

OTIPS

MgBr2•Et2O

OAc

CH2Cl2, –20 to 4°C

O

TIPSO

OH

TIPSO

OAc OH

87% yield >19:1 dr 95% ee O

OH

OSiMe3

OTIPS

H OTIPS

H

TiCl4

OAc

CH2Cl2, –78 to –40°C

O

TIPSO TIPSO

OH

OAc OH

97% yield >19:1 dr 95% ee

Scheme 2A.13. MacMillan’s two-step organocatalytic carbohydrate synthesis.

(eq 2)

48 ENANTIOSELECTIVE ORGANOCATALYSIS INVOLVING IMINIUM, ENAMINE, SOMO NH2

35 mol % cat.*

O

O H

R

O

NHPMP

OMe

Catalyst = N H

R

Acetone or CHCl3 or DMSO, RT

CO2H

35–90% yield 70–96% ee

Scheme 2A.14. Enamine-catalyzed three-component Mannich reaction.

NH2

H

R

NHPMP

i) 30 mol % cat.*, DMF, –20°C

O

O

HO H

Ar

ii) NaBH4 OMe

Ar

Catalyst =

R

N H

CO2H

77–92% yield 4:1–138:1 dr 84–>99% ee

Scheme 2A.15. Enamine-catalyzed aldehyde–aldehyde Mannich reaction.

2A.3.2. Carbonyl α-Halogenation, α-Nitrogenation, α-Oxygenation, and α-Sulfenylation The direct and enantioselective α-functionaliztion of carbonyls remains a broadly valued transformation, given the inherent value of the corresponding products. In this context, the extraordinary success of enamine activation has led to its implementation within a host of carbonyl α-functionalization strategies. In particular, the organocatalytic installation of heteroatoms is an area that has been explored with some tenacity. 2A.3.2.1. Carbonyl α-Halogenation The α-halogenation of aldehydes has been accomplished under enamine control using F-, Cl-, Br- and I-based electrophiles. MacMillan and coworkers found that α-fluorination and α-chlorination processes take place using the same imidazolidinone organocatalyst to provide α-halocarbonyl derivatives with excellent enantioselection (Scheme 2A.16, eq 1 and eq 2) [26]. Similarly, Jørgensen and others found a C2-symmetric pyrrolidine catalyst to be effective for α-bromination and α-iodination, although the α-iodination reactions are generally less selective (Scheme 2A.16, eq 3 and eq 4) [27]. 2A.3.2.2. Carbonyl α-Amination The ubiquitous nature of nitrogen within many biologically active compounds has rendered the installation of nitrogen functionality a major area of interest. The direct enantioselective formation of C–N bonds has therefore become an attractive pursuit for many practitioners of enamine catalysis. Using a suitable nitrogen electrophile, the direct α-amination of carbonyl compounds may be carried out under enamine catalysis. In this regard, azodicarboxylates have been found to be ideal sources of N+. In the presence of catalytic proline, α-aminoaldehyde derivatives are expediently prepared with high levels of enantiopurity (Scheme 2A.17) [28]. More recently, Maruoka and coworkers showed that careful consideration of the catalyst structure allows the use of nitrosobenzene as the electrophilic nitrogen source, providing an exceptionally selective procedure (Scheme 2A.18) [29].

2A.3. ENAMINE CATALYSIS 49 α-Fluorination of aldehydes O O

PhO2S

N

R

H

SO2Ph

F

i) 20 mol % cat.*, THF, i-PrOH, –10°C HO F

ii) NaBH4

Me N

Catalyst =

R

N H

Ph

Me

(eq 1)

Me •DCA

54–96% yield 91–99% ee

α-Chlorination of aldehydes O

Cl

N

Catalyst =

R

H

Acetone, –30°C

Cl

Me

O

5 mol % cat.*

Cl

R

H

O

Cl

Cl

O

Cl

Ph

N H

Me

(eq 2)

Me •TFA

Cl

71–92% yield 80–95% ee

α-Bromination of aldehydes O t-Bu

O

t-Bu

i) 20 mol % cat.*, CH2Cl2, pentane H2O, 23°C or –24°C

R

H

R

HO

Br

Catalyst = Ph

Br

ii) NaBH4 Br

Ph N H •PhCO2H

(eq 3)

72–95% yield 68–96% ee

α-Iodination of aldehydes O I

N

R

H

O

20 mol % cat.*

O

CH2Cl2, pentane, –24°C

Catalyst = Ph

R

H

Ph N H •PhCO2H

I

O

(eq 4)

30–78% yield 60–89% ee

Scheme 2A.16. Enamine-catalyzed α-halogenation of aldehydes.

O R1O2C

O R

H

i) 10 mol % cat.*, CH2Cl2, RT

N N

O CO2R1

N

ii) NaBH4 iii) NaOH

NHCO2R1

Catalyst = N H

CO2H

R

57–92% yield 89–95% ee

Scheme 2A.17. Enamine-catalyzed α-amination of aldehydes using azodicarboxylates.

Ph O H

O R

Ph

i) 10 mol % cat.*, THF, 0°C

Ph

N

ii) NaBH4

R

N

OH

Ph OH

Catalyst = OH

NH

70–90% yield 96–99% ee

OH Ph

Ph

Scheme 2A.18. Enamine-catalyzed α-amination of aldehydes using nitrosobenzene.


Enamine catalysis thus provides a convenient, modern strategy for the synthesis of amino acid and amino alcohol derivatives that compliments existing methods. 2A.3.2.3. Carbonyl α-Oxygenation Enantiopure stereogenic alcohols and 1,2-diols are valuable synthons in chemical synthesis. In this context, enamine catalysis has become a powerful strategy to facilitate carbonyl α-oxygenation. Using nitrosobenzene as the electrophilic oxygen source, MacMillan and coworkers demonstrated that a highly enantioselective protocol could be realized using proline, with catalyst loadings as low as 0.5 mol % retaining operational efficiency (Scheme 2A.19) [30].

O R

H

Ph

O

5 mol % cat.*

O

O

H

N

CHCl3, 4°C

NHPh

Catalyst = N H

R

CO2H

60–95% yield 97–99% ee

Scheme 2A.19. Enamine-catalyzed carbonyl α-oxygenation.

2A.3.2.4. Carbonyl α-Sulfenylation Chiral sulfur-containing compounds are biologically interesting and potentially useful intermediates. In this context, the α-sulfenylation of carbonyls has previously been achieved using auxiliary control; however, the direct enantioselective α-sulfenylation of carbonyl compounds remained elusive until recently. Indeed, Jørgensen and coworkers realized that enamine catalysis in conjunction with a thiotriazole electrophile could be utilized to effect this transformation (Scheme 2A.20) [31].

F3 C

O H

O

10 mol % cat.*

N R

N N

S Ph

S

H

PhMe, RT

R

60–94% yield 61–98% ee

Ph

CF3

Catalyst = N H

OTMS

CF3 F3C

Scheme 2A.20. Enamine-catalyzed carbonyl α-sulfenylation.

2A.3.3. Carbonyl α-Alkylation The direct enantioselective α-alkylation of carbonyl compounds is a highly attractive transformation that remains elusive to the field of catalysis. As expected, the success of enamine catalysis has prompted a range of investigations toward the development of an organocatalytic aldehyde α-alkylation. In this regard, enamine-catalyzed Michael addition processes have been thoroughly explored. Conjugate addition of a transiently generated enamine to a suitable Michael

2A.3. ENAMINE CATALYSIS 51

acceptor has been exploited for the synthesis of a diverse range of enantioenriched formal alkylation products, including carbocycles (Scheme 2A.21) [32]. O

O

R

H

THF, RT

X

O

O

10 mol % cat.*

R

Catalyst =

H

CO2H

N H

X

85–99% yield 8:1–49:1 anti : syn 80–97% ee

Scheme 2A.21. The first enamine-catalyzed Michael addition.

Both intra- and intermolecular processes are possible with good scope of the Michael acceptor; α,β-unsaturated aldehydes and ketones, and alkylidene malonates. Additionally, nitro-olefins [33] and vinyl sulfones [34] have been shown to readily participate in these conjugate addition reactions (Scheme 2A.22). Michael addition to nitro-olefins

R

H

R1

R1

O

20 mol % cat.*

O NO2

NO2

H

THF, RT

Catalyst =

N H

(eq 2)

N

R O

0–96% yield 85:15–98:2 dr 56–78% ee Michael addition to vinyl sulfones SO2Ph

O H

O

25 mol % cat.*

SO2Ph

H

R SO2Ph

CHCl3, –60°C

R

Catalyst =

N H

N

(eq 1)

SO2Ph

71–78% yield 0–80% ee

Scheme 2A.22. Enamine-catalyzed Michael additions.

A major breakthrough in the form of the intramolecular α-alkylation of bromo-, iodo-, and tosyloxy-aldehydes was achieved using a proline derivative as the organocatalyst providing access to enantioenriched carbocycles in good yield (Scheme 2A.23) [35]. While not a general solution to the enamine catalyzed α-alkylation problem, this work by Vignola and List provided great incentive to develop intermolecular variants. However, intermolecular organocatalytic carbonyl α-alkylation to date remains an elusive transformation using enamine activation. Recently, however, two conceptually new and complimentary organocatalytic activation modes have enabled the facile intermolecular α-alkylation of aldehydes in high yield and with excellent enantiocontrol (SOMO catalysis and photoredox organocatalysis, vide infra).

52 ENANTIOSELECTIVE ORGANOCATALYSIS INVOLVING IMINIUM, ENAMINE, SOMO O

O

20 mol % cat.*

Br

H

H

CO2H

Catalyst = N H

CHCl3, Et3N, –30°C EtO2C

EtO2C

CO2Et

Me

CO2Et

92% yield 96% ee Scheme 2A.23. Enamine-catalyzed intramolecular α-alkylation of aldehydes.

2A.4. NEW DEVELOPMENTS IN ORGANOCATALYSIS 2A.4.1. Merging Enamine and Iminium Activation: Organocascade Catalysis [36] Rapid access to compounds possessing elevated levels of structural complexity remains a preeminent goal for the chemical sciences. While the total synthesis approach to molecular complexity has traditionally focused on a “stop and go” sequence of individual reactions, it is intriguing to consider that biologic systems produce elaborate molecules in a continuous process, wherein enzymatic transformations are combined in highly regulated catalytic cascade cycles. A crucial requirement for the success of these processes is the capacity of transform-specific enzymes to coexist in the same reaction medium without detrimental interactions. Consideration of the conceptual blueprints of enzymatic catalysis in the context of organocatalysis has recently led to the development of a powerful synthetic concept whereby a cascade iminium and enamine activation sequence leads to highly functionalized products (Scheme 2A.24) [36].

R

O

O

Me N

Nucleophile (Nu) Ar

Electrophile (E)

N H

R t-Bu

Im

En

Nu

O E

Catalyst

Cascade catalysis

Cascade product

Scheme 2A.24. Organocascade catalysis concept.

A demonstration of the power and utility of this cascade hypothesis for the rapid construction of stereochemical complexity was first illustrated through the enantioselective synthesis of a series of β-aryl, α-chloroaldehydes (Scheme 2A.25) [37]. Notably, the diastereoselectivity of the second step of this reaction sequence was almost exclusively catalyst controlled. Additionally, this cascade strategy demonstrated good latitude in terms of the nucleophilic and electrophilic components by extension to encompass hydride nucleophiles and fluoride electrophiles [37]. As such, there is considerable potential for this technology to exceed its original design by increasing the number of bond-forming events occurring in the organocascade sequence. Indeed, a triple-cascade sequence, involving an enamine–iminium–enamine relay, was recently demonstrated by Enders and coworkers (Scheme 2A.26) [38].

2A.4. NEW DEVELOPMENTS IN ORGANOCATALYSIS 53

O Cl

Cl R

Cl

O

R

10–20 mol % cat.*

Cl

Nu

O

Nu

EtOAc, –40 to –60°C

Cl

Me N

Catalyst =

O

•TFA

67–97% yield 99->99% ee

Nu =

t-Bu

N H

Cl

Cl N Bn

Y R2

X

R3

X

N

OSi(R4)3

R1

Scheme 2A.25. Enantioselective organocascade synthesis of α-chloroaldehydes.

20 mol % cat.*

R1

O

En R3

R2 O

NO2

Im

En

R2

CHO

R3

R1

OTMS

Catalyst = N H

Ph

Ph

NO2

25–58% yield 7:3–10:1 dr 99–>99% ee

Scheme 2A.26. Enders’ triple organocascade sequence.

2A.4.2. New Activation Modes: OrganoSOMO Catalysis and Photoredox Organocatalysis To date, the concepts of iminium and enamine catalysis have provided more than 75 transformations for use in asymmetric synthesis [1]. However, a necessary objective for the continued advancement of the field of chemical synthesis is the design and implementation of new activation modes that enable previously unknown transformations. To address this requirement, the enamine-activation platform was recently extended beyond its original manifestation through the development of two innovative activation modes: OrganoSOMO catalysis [39–41] and photoredox organocatalysis [42]. 2A.4.2.1. OrganoSOMO Catalysis [39–41] This new activation mode is founded on the hypothesis that one-electron oxidation of an electron-rich enamine will selectively generate a reactive 3π-electron radical cation. The electrophilic character of this SOMO intermediate allows it to react with a variety of weakly nucleophilic carbon-based SOMOphiles at the α-carbon of the parent enamine, providing formal alkylation products (Fig. 2A.3). Applying the tenets of this design plan with a suitable one-electron oxidant has proven highly successful and has already yielded a series of enantioselective transformations complimentary to those derived from enamine chemistry, including α-allylation [39], α-vinylation [40], and α-enolation [41] of aldehydes (Scheme 2A.27). 2A.4.2.2. Photoredox Organocatalysis [42] The advent of SOMO activation demonstrated that organocatalysis is not limited to conventional two-electron pathways for enantioselective bond formations. Indeed, SOMO catalysis revealed not only that one-


Iminium catalysis LUMO activation

O

Enamine catalysis HOMO activation

SOMO catalysis SOMO activation

R

H

O

Me

O

Me

N O

Me

–H2O

N H

R1

N

N

O

Me

N

+2 e–

N R1

N

–1 e –

R1

N

R1 R

R

R

Figure 2A.3. SOMO catalysis via single-electron oxidation of a transiently formed enamine.

SOMO-catalyzed α-allyation of aldehydes O O

O

20 mol % cat.*

NBoc

N

Catalyst =

SiMe3 H

Me

NBoc

H

CAN, NaHCO3 DME, –20°C

(eq 1)

t-Bu N H •TFA

Ph

70% yield 93% ee SOMO-catalyzed α-vinylation of aldehydes O

n-Hex

H

KF3B

Ph

Me

O

20 mol % cat.*

O

Ph

H

CAN, NaHCO3 DME, H2O, –50°C

N

Catalyst =

n-Hex

Ph

(eq 2)

t-Bu N H •TFA

81% yield 94% ee SOMO-catalyzed α-enolation of aldehydes OTBS O H

O

O

20 mol % cat.*

O

H

n-Hex O

CAN, DTBP, –20°C DME, H2O

n-Hex O

Me N

Catalyst =

(eq 3) Ph

N H

t-Bu

77% yield 92% ee

Scheme 2A.27. SOMO-catalyzed enantioselective α-functionalization of aldehydes.

electron organocatalytic activation modes are accessible, but that they can also lead to the development of a series of useful catalytic asymmetric transformations. Recently, a conceptually novel one-electron asymmetric catalysis mode was brought to fruition via the marriage of photoredox catalysis and organocatalysis. Photoredox catalysis represents a powerful method of molecule activation that has found widespread application in inorganic chemistry. One of the most studied photoredox catalysts is Ru(bpy)3Cl2, which has found vast utility in several important fields of research (Fig. 2A.4) [43]. The combination of enamine and photoredox activation has led to the creation of a novel one-electron organocatalysis platform that is complementary to SOMO activation. As a first example of the utility of this synergic catalysis concept, the enantioselective intermolecular alkylation of aldehydes, a long-standing problem in asymmetric chemical

REFERENCES 55

Representative transformations H2O

Aldol

Amine catalysis

Representative utility

Photoredox catalysis

Light H2 production

Friedel–crafts

O

Me

N

N

Vinylation

N N

N H

Allylation

Ru2+ N

N

O2 production

N

CH4 production

Enolation Enal reduction

Energy storage

New organic transformations

Diels–alder

Figure 2A.4. New reactivity platforms: merging organocatalysis with photoredox catalysis.

O O H

20 mol % cat.*

O

O n-Hex

CO2tBu

n-Hex

Br

O

Ru(bpy)3Cl2 (0.5 mol %) 2,6-lutidine, DMF, 23°C fluorescent light

Me N

Catalyst = Me

CO2tBu

t-Bu N H •TfOH

70% yield 5:1 dr 99% ee

Scheme 2A.28. α-Alkylation of aldehydes via photoredox organocatalysis.

synthesis, was brought to fruition. The combination of Ru(bpy)3Cl2 and an imidazolidinone organocatalyst renders this important alkylation reaction highly enantioselective and operationally trivial (Scheme 2A.28) [42]. This dual catalysis strategy has provided a new foundation for the design and invention of a number of new transformations of importance to the practitioners of asymmetric chemical synthesis.

REFERENCES 1. For reviews of organocatalysis, see: (a) MacMillan, D. W. C. Nature 2008, 455, 304. (b) Chem. Rev. 2007, 107, issue 12, special issue devoted to organocatalysis. (c) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to Application in Asymmetric Synthesis. Weinheim: Wiley-VCH, 2005. (d) Adv. Synth. Catal. 2004, 346, issues 9 and 10, special issues devoted to organocatalysis. (e) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. Engl. 2004, 43, 5138. (f) Acc. Chem. Res. 2004, 37, issue 8, special issue devoted to organocatalysis. 2. For reviews of iminium catalysis, see: (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 78. (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. 3. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. 4. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. 5. Jen, S. W.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. 6. Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240.

56 ENANTIOSELECTIVE ORGANOCATALYSIS INVOLVING IMINIUM, ENAMINE, SOMO 7. Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413. 8. Haramata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchoefer, P. J. Am. Chem. Soc. 2003, 125, 2058. 9. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. 10. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. 11. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894. 12. Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. 13. Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438. 14. For example, see: Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482. 15. Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328. 16. Bertelsen, S.; Dinér, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536. 17. Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. 18. Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662. 19. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. See also: (b) Eder, U.; Sauer, R.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496. 20. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. 21. For reviews of enamine catalysis, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b) List, B. Acc. Chem. Res. 2004, 37, 548. (c) List, B. Synlett 2001, 1675. 22. (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (b) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 6722. 23. (a) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752. (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152. For a use in synthesis, see: (c) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696. 24. List, B. J. Am. Chem. Soc. 2000, 122, 9336. 25. Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F. J. Org. Chem. 2003, 68, 9624. 26. (a) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. (b) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108. See also examples cited in References 1 and 2. 27. Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005, 4821. 28. Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2002, 41, 1790. See also examples cited in References 1 and 2. 29. Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 6046. 30. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808. See also examples cited in References 1 and 2. 31. Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2005, 44, 794. 32. Fonesca, M. T. H.; List, B. Angew. Chem. Int. Ed. Engl. 2004, 43, 3958. 33. Betancourt, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737. 34. Moss, S.; Alexakis, A. Org. Lett. 2005, 7, 4361. 35. Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. 36. For a review of organocascade catalysis, see: Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. Engl. 2007, 46, 1570. 37. (a) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. See also: (b) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. 38. Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861.

REFERENCES 57

39. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582. 40. Jang, H.-Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004. 41. Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398. 42. Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77. 43. (a) Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159. (b) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85.

2B ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES Yi Wang and Li Deng Department of Chemistry, Brandeis University, Waltham, MA

2B.1. INTRODUCTION The emergence of asymmetric organocatalysis as a reliable strategy for the development of asymmetric reactions represents one of the remarkable advances of synthetic organic chemistry. Although the chemical mechanisms by which most chiral organocatalysts operate, such as enamine catalysis, iminium catalysis, general acid/base catalysis, nucleophilic catalysis, nucleophilic carbene catalysis, and phase-transfer catalysis, are well known, the spectacularly rapid evolutions of each of these modes of catalysis since the 1990s establish several new and broadly applicable concepts in catalytic asymmetric synthesis. Consequently, our view of what small organic molecules could do as a chiral catalyst has undergone a profound change. This has led to the emergence of enantioselective organocatalysis, a term invented by MacMillian, as a fastgrowing field [1]. Although acid catalysis and base catalysis, often in cooperation with each other, are among the most common mechanisms of enzyme-catalyzed reactions [2], literature reports of highly enantioselective asymmetric reactions based solely on either acid or base catalysis by organic molecules began to appear only a decade ago. The continuous progression of asymmetric acid and base catalysis has since then pointed to acid–base bifunctional organocatalysis as a potentially powerful concept for the development of efficient chiral catalysts. However, few, if any, anticipated the progress to be so remarkable that the studies of acid–base bifunctional organic catalysts would become one of the most active areas in asymmetric catalysis within 5 years of the first demonstration of “a proof of principle.” This review aims to capture the key conceptual evolutions and Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 59

60 ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES

to provide the reader with a glimpse of the “state of the art” developments in this area. Due to a space constraint and the vast amount of literature already accumulated on this topic, the authors could only strive to accomplish these goals by highlighting select literature reports. This review thus reflects the authors’ personal view of what is important in this area.

2B.2. HIGHLY ENANTIOSELECTIVE ACID AND BASE CATALYSIS BY MONOFUNCTIONAL ORGANIC CATALYSTS 2B.2.1. The Emergence of Highly Enantioselective Acid Catalysts Most organic reactions are electrophile–nucleophile reactions and, therefore, can be promoted with metallic and organic catalysts as either an acid or a base. Merely a decade ago, metal-based chiral Lewis acids provided the only proven and broadly applicable approach for the activation of electrophiles for asymmetric reactions [3]. Although organic molecules containing hydrogen bond donors had already been reported to be competent catalysts for various organic transformations, a highly enantioselective chiral variant was not yet established [4,5]. A decisive breakthrough in asymmetric catalytic reactions with an organic acid catalyst came in 1998 when Jacobsen and coworkers discovered that chiral urea and thiourea derivatives, such as 3, promoted highly enantioselective Strecker reactions with a broad range of aryl and alkyl imines 1 and HCN (Scheme 2B.1) [6]. The scope of the reaction was subsequently extended to methyl aryl ketoimines [7], and furthermore, the mechanism of the chiral urea- and thiourea-catalyzed Strecker reactions was investigated by kinetic studies, NMR, and computational studies [4]. Results from these studies formed the basis for a mechanistic proposal in which the activation of the imine by the urea or thiourea functionality of 3 through hydrogen-bonding interactions was the salient feature [4,8]. Subsequent studies from the Jacobsen group established efficient enantioselective Mannich reactions (Scheme 2B.3) of silylketene acetals 9 with N-Boc aromatic imines 8A and hydrophosphonylation of 8A (Scheme 2B.2), thereby demonstrating that the scope of both the electrophiles and the nucleophiles could be expanded [9]. These results provided compelling indications of chiral urea and thiourea derivatives as generally applicable organic acid catalysts for asymmetric synthesis [4]. Importantly, highly enantioselective chiral organic acid catalysts featuring other hydrogen bond donor functionalities, such as guanidine 14 [10], alcohols 21 and 14 [11], and amidinium ion 25 [12], were developed (Scheme 2B.4). Each of these pioneering studies introduced a new class of highly enantioselective acid catalysts to asymmetric synthesis in the infant stage of chiral acid organocatalysis. Consequently, they each contributed in a unique way to the establishment of acidic catalysis by organic molecules as a broadly useful concept for the activation of electrophiles in asymmetric reactions. Without a doubt, however, the results from Jacobsen’s systematic synthetic and mechanistic studies of chiral urea- and thiourea-catalyzed reactions have played a leading role in shaping the concept of enantioselective acid organocatalysis into one of the cornerstones of enantioselective organocatalysis. It should be noted that the further development and expansion of this concept is currently a topic of intense interest in catalytic asymmetric synthesis [4], and new classes of powerful chiral acid catalysts, such as chiral phosphoric acids, continue to emerge [13].

2B.2 HIGHLY ENANTIOSELECTIVE ACID AND BASE CATALYSIS 61

R

R2 1 N

t

Bu X N H

O

3

N H HO t

3a , R 1 3b , R1 3c, R 1 3d, R1

R

R3

Bu

= Bn, R 2 = H, R 3 = OMe, X = S, 70–91% ee = Bn, R2 = H, R3 = OC(O)But , X = O, 78–97% ee = Bn, R2 = H, R 3 = OC(O)But , X = O, 42–95% ee = Me, R2 = Me, R3 = OC(O)But, X = S, 86–99% ee 1. TMSCN/MeOH O Catalyst 3 (2 mol %) N Toluene, –70 to –75°C F3 C

"

N

N

R R'

R 2

2. TFAA '

1: R = aryl or alkyl, R = H, Me R" = Ph or CH=CH2

R" R'

Scheme 2B.1.

Ph

N R

H 4

O O + HP O

Ar

3d (10 mol %) Et2O

Ar 5 Ar = 2-nitrophenyl

Ph H2, Pd/C Ar O R P O O 6 Ar 81–99% ee

Scheme 2B.2.

t

N

Ph

Bu S N H

O

N H

N

HO 3e t

N

Boc

OTBS +

Ar

i

H 8A

O Pr

NH2

HN

Bu

t

Bu

1. 3e (2 mol %) Toluene

Boc

2. TFAA

Oi Pr 10 86–89% ee 84–89% isolated yield

9

Scheme 2B.3.

Ar

NH

O

R

OH P OH O 7

62 ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES N N H

N 14

14 (10 mol %), HCN (2 equiv)

N

– 40°C, Ar

H

NH 3

H3 O HN Ar

11

H COO

Ar

H CN 12

13

ee: 50–88% Yield: 80–99%

Ar

Ar Ar

Ar

22a Ar = 4-F-3,5-Me2 C6 H2 OH 22b Ar = 4-F-3,5-Et 2C 6 H2 OH

OH 21a Ar = phenyl 21b Ar = 2-naphthyl OH 21c Ar = 1-naphthyl

O O Ar

Ar Ar

Ar

TBSO

R

H

+

O N(CH3 )2 15 TBSO

21c or 22 (20 mol %) Toluene –80°C to –40°C

TBSO

R

CH3 COCl CH 2Cl2/toluene

O

17 ee: 92–98% Yield: 52–94%

16

R

CHO

21c (20 mol %)

TBSO

+

CHO R N(CH 3) 2

PhCH3 , –80°C N(CH3 )2 18

(i) LiAlH 4, Et2 O –78°C to rt, 2 h (ii) HF/CH 3CN 0°C to rt, 0.5 h

19

OTf H H NH HN N

N

Boc +

Ar

H 8A

NO2 R1 23

H

N HN

25 (10 mol %) –20°C

Scheme 2B.4.

O

–78°C

N(CH 3) 2

R

O

Ar

Boc NO 2

R1 24 ee: 60–95%, dr: 7:1–14:1 Yield: 57–69%

O

OH R 20 ee: 73–92% Yield: 77–83%


2B.2.2. The Emergence of Highly Enantioselective Base Catalysis A chiral acid or a chiral base can, in principle, promote an enantioselective nucleophile– electrophile reaction. However, the development of a broadly useful platform, with either metal complexes or organic molecules, for the activation of nucleophiles with base catalysis represented a major challenge in asymmetric catalysis [14]. Early attempts to meet this challenge centered on the use of cinchona alkaloids as readily available tertiary amine catalysts. The extensive pioneering investigations by Wynberg and coworkers in the 1970s and early 1980s showed that cinchona alkaloids were able to promote a wide range of reactions as either base or nucleophilic catalysts [15]. However, in the only cinchona alkaloid-catalyzed highly enantioselective reaction, a formal [2 + 2] cycloaddition between ketenes and aldehydes, the cinchona alkaloid catalyst clearly acted as a nucleophilic catalyst [15,16]. Another notable study of cinchona alkaloid-catalyzed reactions, carried out first by Oada and later by Aitken, is the investigation of the enantioselective alcoholytic ringopening reactions of meso-anhydrides in the 1980s. In a screening of natural cinchona alkaloids and their C9-epimers, Oada and coworkers obtained optimal, but still modest, enantioselectivity with cinchonine (Method A, Scheme 2B.5) [17]. Oada and others also detected a kinetic isotope effect with MeOD, thereby providing experimental evidence that implicated a general base catalysis mechanism for the reaction [17b]. Aitken et al. made the important observation that the enantioselectivity became higher when the catalyst loading increased [17c,d]. Eventually, Bolm and coworkers attained excellent enantioselectivity by employing 1.1 equivalents of quinine or quinidine (Method B, Scheme 2B.5) [18]. The continuing lack of success in achieving an efficient enantioselective reaction with a chiral amine as a base catalyst stood in contrast to the increasingly successful applications of cinchona alkaloids [19], chiral imidazoles [20], and DMAP derivatives [21] as efficient nucleophilic catalysts. In 2000, Deng and coworkers reported a highly enantioselective alcoholysis of mesoanhydrides 28 in toluene with a catalytic amount of modified cinchona alkaloids bearing a C9-aryl ether group such as DHQD-PHN 26 and (DHQD)2AQN 27 (Method C, Scheme 2B.5) [22]. At the same time, Bolm and coworkers found that the same transformation could be promoted in high enantioselectivity with 10 mol % quinidine in the presence of a stoichiometric amount of another tertiary amine, pempidine (Method D, Scheme 2B.5) [23]. Following their initial discovery, Deng and coworkers extended the 27-catalyzed alcoholysis to the highly enantioselective kinetic resolution of several distinct classes of racemic cyclic anhydrides (30, 33, and 36) [24–27]. In parallel to these synthetic studies, they also carried out kinetic studies on the 27-catalyzed methanolysis of the urethaneprotected N-carboxyanhydride (UNCA) 33, and found that the reaction demonstrated first-order dependence on the anhydride, the alcohol, and the catalyst 26. Moreover, a kinetic isotope effect was also detected for the alcoholysis with MeOD [25]. As described by Deng and coworkers in 2001, these results are only consistent with a general base catalysis mechanism in which catalyst 26 or 27 activates the nucleophile (methanol) by forming an amine alcohol hydrogen-bonding complex (Scheme 2B.6) [25,27]. These synthetic and mechanistic studies of the cinchona alkaloid-catalyzed alcoholysis demonstrated that, for the first time, the general base catalysis by a small chiral molecule could promote highly enantioselective reactions with a broad substrate scope. Importantly, this form of nucleophile-activating asymmetric catalysis is mediated via a hydrogenbonding interaction between the chiral catalyst and an acidic hydrogen, and is therefore


R'

R' OH

OH N

N N

H

H

Q, R' = OMe, quinine CD , R' = H, cinchonidine

QD, R' = OMe, quinidine CN , R' = H, cinchonine Et

N

MeO

H

O

DHQD-PHN(26)

n R

H

H

O

OMe

(DHQD)2AQN( 27) O

R

O

R R'

O

O H

H

MeO

N

Et

Et

N

O H

N

OH

R'

O

n

OMe

MeOH, PhMe, or PhMe/PhCl R

O

O 29

28

Method A (Oada): CN, QD, or QN (10 mol %), > 95% yield, 25–70% ee Method B (Bolm): QD, or QN (110 mol %), 84–99% yield, 84–98% ee Method C (Deng): 27 (5–30 mol %), 56–99% yield, 82–98% ee Method D (Bolm): QD (10 mol %), pempidine (1 equiv), 96–98% yield, 74–92% ee

R

O

O O 30 O

R

27 (15 mol %) R'OH

O OH + OR'

Ether, –24°C

R

O 31

O 32

O 26 or 27 (10–20 mol %) O O R R'OH R OR' + O O PN PN Ether, –78 to 0°C PHN 33 O S-33 O R -34

R

O R O

O

36 O

Ether, –78°C

O H 2O

R

R OR' + O

OH R -37

O

S-36 O

Scheme 2B.5.

OH

PHN S-35

O

O 27 (10 mol %), R'OH R

OR' OH

O H 2O

R

OH OH S-38


* NR 3

O

MeOH

26 or 27

Ph

OMe ZHN 34

Me * R 3 N---H-O

O

Ph

OMe O–

ZN O

* HNR 3

O Ph ZN 33a

O O

Scheme 2B.6.

only restricted by the acidity of the hydrogen. The successful activation of an alcohol (pKa = 29 in DMSO [28]) in the highly enantioselective reaction by catalysts 26 and 27 suggested that the asymmetric base catalysis by a tertiary amine could, in principle, be extended to a broad range of nucleophiles bearing C–H, O–H, N–H, S–H, and P–H bonds. However, the true generality had to be gauged experimentally. Experimental results implicating a considerable scope for the highly enantioselective base catalysis by cinchona alkaloids soon appeared in the literature. In 2002, Deng, McDaid, and others reported a highly enantioselective conjugate addition of aryl thiols to cyclic enones (Scheme 2B.7) [29]. In contrast to the moderate enantioselectivity reported earlier with natural cinchona alkaloids [30], Deng and McDaid showed that (DHQD)2PYR (39), another modified cinchona alkaloid bearing an aryl ether at the C9-position, afforded excellent enantioselectivity for the conjugate additions of aryl thiols 40 to six- to nine-membered cyclic enones. Interestingly, the sense of asymmetric induction by 39 was found to be opposite to that by quinidine [30]. However, as neither natural cinchona alkaloids nor O-acetyl quinidine was able to promote a Morita–Baylis– Hillman reaction with methyl vinyl ketone (MVK) as a nucleophilic catalyst under ambient conditions [31], it is almost certain that catalyst 39 mediated this highly enantioselective conjugate addition via the activation of the aryl thiol as a base catalyst. This extension of the highly enantioselective base catalysis by cinchona alkaloids to a reaction that is mechanistically distinct from the enantioselective alcoholysis provided the first indications of the tremendous potential of cinchona alkaloids as chiral base catalysts for asymmetric synthesis [32]. In 2004, Bella and Jorgensen reported another efficient enantioselective asymmetric conjugate addition catalyzed by a cinchona alkaloid (Scheme 2B.8). In this reaction, cinchona alkaloid 43 activated β-ketoesters 45, a carbon nucleophile, for a highly enantioselective reaction with alkynones 44 [33]. In parallel to the aforementioned studies, chiral base catalysis also evolved with another family of small organic molecules. In 2000, Miller, Guerin, and others reported an enantioselective conjugate addition with HN3, generated in situ from TMSN3 and tBuCO2H, catalyzed by peptide 49 bearing an imidazole side chain. Up to 85% ee was obtained with 49 (Scheme 2B.9) [34a]. The imidazole group, most likely, exercised its


Et

N

O

O H MeO

H

N

Et Ph

N

H

N

H OMe

Ph 39 SH

O

+

O

Toluene, –60°C R

R

0~4

O

0~4

42

41

40A O

S

39 (1.0 mol %)

O

O

O

O

O

O

41B 41C 41D 41E 41F 41A 41G 41H 92% ee 95% ee 93% ee 41% ee 97% ee 94% ee 97% ee >99% ee 71% yield 88% yield 88% yield 55% yield 77% yield 86% yield 82% yield 91% yield Scheme 2B.7.

Et

N

Et N

N N O H MeO

O

H

43 R

+ R 44

H

O

O n

O

1

H OMe

O

O R1

1) 43 (5 mol %) 2) Bu 3P n

45

46

O

44–95% ee 95–96% yield E/Z = 1–1.8:1

R

Scheme 2B.8.

catalytic role by the activation of HN3 via a general base catalysis mechanism. Through the development of a new peptide catalyst 50, the enantioselectivity of the reaction was further improved [34b]. These early reports of highly enantioselective reactions represent the first step toward establishing general base catalysis as a generally useful strategy for catalytic asymmetric synthesis. This important conceptual advancement drastically recalibrated our percep-

2B.3. ACID–BASE BIFUNCTIONAL CATALYSIS BY SMALL CHIRAL ORGANIC MOLECULES 67

O

O N

R

O

Catalytic peptide (2.5 mol %) TMSN 3 , t-BuCO2H, PhCH 3

O N

R 48

47 O

tBu N H

N COBHN

N3

O HN

O N N Bn

O N H

N Me

COBHN

a-Np

R

45–85% ee (2000)

O HN

O N N Bn

49

tBu

Me

a-Np 50

71–92% ee (2002) Scheme 2B.9.

tion about hydrogen bond-mediated enantioselective base organocatalysis. The development of efficient base catalysts [35–38], including those derived from cinchona alkaloids [35–37], is a topic of continuing interest. The evolvement of hydrogen bond-mediated enantioselective acid and base catalysis, in parallel to similarly remarkable development in other forms of organocatalysis [1], has established two broadly useful concepts in asymmetric synthesis. The respective yet complementary roles played by these two types of catalysis in asymmetric electrophile– nucleophile reactions logically raise the question: “Can acid and base catalysis be successfully coupled to perform powerful bifunctional asymmetric catalysis with a small molecule?” As described below, this is not the first visit to this fascinating question by organic chemists. However, this time, the outcome is different.

2B.3. ACID–BASE BIFUNCTIONAL CATALYSIS BY SMALL CHIRAL ORGANIC MOLECULES Highly enantioselective reactions have been realized with bifunctional organic catalysts that activate and orient the nucleophiles via the formation of a catalyst–substrate complex through a covalent bond linkage. This is exemplified by the Morrita–Baylis– Hillman reactions with iso-cuperidine 51 [19a] and the direct aldol reaction with proline 54 [39] (Scheme 2B.10). Catalysts 51 and 54 promote these reactions through the synergistic cooperation of acid catalysis with nucleophilic catalysis [19a] and enamine catalysis [39], respectively. Consequently, the presence of certain functional groups in the nucleophiles, such as the aldehyde, is a prerequisite for the operation of these bifunctional organocatalysts. In contrast, asymmetric acid–base bifunctional organocatalysis can be applied to both electrophiles and nucleophiles bearing various functional groups. In fact, the potential of such bifunctional catalysis has been long recognized. Extensive and systematic investigations with the goal of achieving efficient asymmetric reactions had been carried out


OH O N 51

N O

O + R

CF3 O 52

H 16

CF3

H

H

R

N

55

R

O

H

COR' O

H

N

O

OH R

DMSO

16

CF3

31–58% yield 91–99% ee

53

CO 2H N H 54 (30 mol %)

O

CF3

H

O

+

O

R DMF, –55°C O

O

OH

β-ICD (10 mol %)

56 54–97% yield 60–96% ee

N R

O H H

O

O

Scheme 2B.10.

by Wynberg and coworkers from 1970s to 1980s [15]. The pioneering studies by Wynberg and coworkers on cinchona alkaloid-derived catalysts showed that natural cinchona alkaloids, bearing a hydroxy group at the C9-position, often afforded superior activity and enantioselectivity to those afforded by modified cinchona alkaloids without the C9-OH group. Based on these observations, Wynberg and coworkers proposed that the superior catalytic properties of the natural cinchona alkaloids were due to their capacity to act as a bifunctional acid–base catalyst [15,30]. Even still, these early attempts were unsuccessful in achieving high enantioselectivity. Thus, the development of highly enantioselective acid–base bifunctional organocatalysis by small molecules stood as an unmet challenge. Whether or not the enthalpic gain afforded by the fragile hydrogen bonds between small molecules could meet the entropic demand for the efficient assembly of a highly ordered multimolecule transition state remained an important yet unanswered question for another two decades. Yet another important question was: “If efficient asymmetric acid–base bifunctional catalysis could be achieved, would it be general and


practical?” Only within the last 5 years have definitive answers to these fundamentally important questions in bifunctional asymmetric catalysis begun to appear.

2B.3.1. Highly Enantioselective Bifunctional Amino-Thiourea Catalysts Derived from Chiral Cyclic Diamines In 2003, Takemoto and coworkers reported that catalyst 57 promoted a highly enantioselective conjugate addition of malonates 58 to nitroalkenes 60 (Scheme 2B.11) [40a]. The catalyst was designed to utilize the tertiary amine to activate the malonate and the thiourea to activate the nitroalkenes. The enantioselectivity afforded by 57 showed a certain degree of dependence on the structure of the nitroalkenes. With aryl nitroalkenes the 1,4-adducts 61 were formed in 90–93% ee versus 81% ee obtained with an alkyl nitroalkene. In a full account of their investigations of the 57-catalyzed additions to nitroalkenes, Takemoto and coworkers disclosed in 2004 that the scope of the nucleophiles could be extended to β-ketoesters 45 and 1,3-diketones 59 [40b]. They also presented a transition state model to rationalize the sense of asymmetric induction by 57 (Scheme 2B.11) [40b]. Later, Takemoto and coworkers also used 57 to develop a highly enantioselective asymmetric conjugate addition of malononitrile to α,β-unsaturated imides 47 (Scheme 2B.12) [41]. Following Takemoto’s pioneering studies, investigations by Chen and

H N

F3 C

N

H N S

O

O

R2

R 4 + R1 R 58 45 59

57, 10 mol %

CF3

NO2

Toluene, rt

3

60

R 4OC R1

R3

COR2 H NO 2

61: R 2 = R 4 = OEt, R3 =H, 81–94% ee, 64–96% yield; 62: R 2 = aryl or alkyl, R4 = OMe or OEt, 57/43–96/4dr, 81–95% ee, 76–99% yield; 63: R 2 = R4 = Me, R3 = H, R1 =Ph, 89% ee, 80% yield. CF3 S F3 C

N H O

N

N H O

O R2

H O

R3 Scheme 2B.11.

R4

N


O

O

R

N 47 O

CH 2Cl2, 4Å MS,

Ph

() 0~1S 42

CH2 (CN) 2 57, (10 mol %)

O N H

85–93% ee 77–99% yield

O

ArSH 57, (10 mol %)

( ) 0~1 41 O

(NC) 2HC O CH 2 (CN) 2 O H 57, (10 mol %) R N Toluene, rt 64

(NC)2 HC H O

Ar

O

R' Toluene, rt

65

63–85% ee Ar 95–99% yield

N H

66

Ar

62–91% ee 28–95% yield

Scheme 2B.12.

P(O)Ph2

HN PG

57 (10 mol %)

N

+

RCH 2NO2

H

Ar

PG = P(O)Ph2 , 67 PG = Boc, 8A

Ar

R

75/25–97/3 dr 89–99% ee (major) 78–94% yield (major)

24

t -Bu

H N N N R H H N O n-Pr n-Pr 69 (2 mol %) 2

NO2 R

+

63–76% ee 57–91% yield

68 NHBoc

R = H, 23A R = alkyl, 23B

O R

Ar

CH2 Cl2

S

1

NO2

HCN Toluene, rt

70

HO R1

CN R2

84–98% ee 81–98% yield

71

Scheme 2B.13.

coworkers showed that 57 is an effective catalyst for conjugate additions of aryl thiols to cyclic enones 41 and α,β-unsaturated imides 47 [42] (Scheme 2B.12), thereby further expanding the scope of 57 with respect to asymmetric conjugate additions. Takemoto and coworkers also explored 57 as a catalyst for an asymmetric aza-Henry reaction, a 1,2-addition reaction of imines. In their initial report, 57 was found to afford only moderate enantioselectivity for the addition of nitromethane (23A) to aromatic N-phosphinoylimines 67 (Scheme 2B.13) [43a]. In a more recent study, Takemoto and coworkers discovered that the enantioselectivity of the aza-Henry reaction could be dramatically improved with aromatic N-Boc imines 8A [43b]. They also accomplished a highly enantioselective and diastereoselective reaction between various nitroalkanes


23B and aromatic N-Boc imines 8A with 57 as the catalyst [43b]. Utilizing the aminothiourea 69 that had been developed by catalyst optimizations guided by mechanistic and computational studies, Zuend and Jacobsen recently documented a highly enantioselective ketone cyanosilylation, thereby establishing a highly enantioselective nucleophilic addition to a carbonyl eletrophile (Scheme 2B.13) [44].

H N

F3 C

H N

N

O

R O

N O Ph 72

CF3

57 (5 mol %)

Allylic alcohol (1.5 equiv) Toluene, rt

O Ph

R O

N H

O 73

72–87% ee 67–96% yield Scheme 2B.14.

In 2005, Berkessel and coworkers reported a dynamic kinetic resolution of azalactones 72 via a 57-catalyzed asymmetric alcoholysis, which produced the corresponding α-amino acids 73 in up to 87% ee. Thus, 57 could also serve as an effective catalyst for an asymmetric acyl transfer reaction [45]. The report by Takemoto and coworkers of the 57-catalyzed conjugate addition of malonates to nitroalkenes in 2003 provided the first accomplishment of a highly enantioselective reaction with acid–base bifunctional catalysis by a small organic molecule [40a]. It is one of the most important recent breakthroughs in enantioselective organocatalysis. In subsequent studies, catalyst 57 has also been shown to be effective for a considerable range of reactions.

2B.3.2. Highly Enantioselective Bifunctional Catalysts Derived from Cinchona Alkaloids 2B.3.2.1. Bifunctional Catalysts Based on 6′-OH Cinchona Alkaloids As summarized earlier, the emergence of cinchona alkaloids as highly general and effective base catalysts introduced a broadly applicable approach for the development of asymmetric reactions through the activation of nucleophiles by a chiral catalyst. The introduction of hydrogen-bond donor motifs into the cinchona alkaloid skeleton has thus become another focus in the development of efficient acid–base bifunctional catalysis. Two highly enantioselective reactions with cinchona alkaloids containing a 6′-OH as the hydrogen-bond donor were reported simultaneously in 2004. Interestingly, one of the catalysts, β-ICD (51) [46], possessed a rigid C8–C9 bond between the basic quinuclidine unit and the 6′-OH quinoline group, and the other catalyst, a cupridine or cuprinine derivative 76, featured a rotational C8–C9 bond between these two active centers [47]. The β-ICD (51) was found by Jørgensen and coworkers to be a highly effective catalyst for asymmetric aminations of aryl cyanoesters 74, β-ketoesters 45, and 1,3-diketones


59 with dialkyl azadicarboxylates 75 (Scheme 2B.15) [46]. Although 51 clearly acted as an acid-nucleophilic bifunctional catalyst in the enantioselective Morita–Baylis–Hillman reaction reported by Hatakeyama and others [19a], here it probably activated the nucleophiles as a base catalyst. Although the authors neither showed the benefit of the presence of the 6′-OH to catalysis by control experiments nor commented on its potential as an acidic active site, the C6′-OH most likely served the role of activating the dialkyl azadicarboxylates 75 as an acid.

OH O 4' N

Y

Boc

X

R

+

NC

OR 3

Ar 74 89–98% ee 84–99% yield

*

HN Boc N Boc X O

O

O

Y Ar

Toluene

Boc

75

H

N 8

51 (0.1–5 mol %)

N N

O

9

O

O

Et

O

O

O t -Bu

OEt

OPh Me 45A

45B

59A

90% ee 99% yield

90% ee 99% yield

83% ee 90% yield

Scheme 2B.15.

Deng and coworkers reported that the C6′-OH cinchona alkaloids 76 catalyzed highly enantioselective conjugate additions of methylmalonates 58A and β-ketoesters 45C to nitroalkenes 60 (Scheme 2B.16) [47]. Notably, 76 afforded consistently excellent enantioselectivity for nitroalkenes 60 bearing either an aryl or an alkyl substituent. As outlined by Deng and coworkers, cinchona alkaloids 76 are designed to be tunable bifunctional catalysts with the quinuclidine nitrogen and the 6′-OH group as the basic and acidic active sites, respectively. Furthermore, they also showed that a range of analogues of such cinchona alkaloids could be prepared in one or two steps from either quinine or quinidine [47]. In this study, the critical role played by the C6′-OH group was demonstrated by the drastic difference in both activity and enantioselectivity between cupridine 76a and quinidine, the corresponding 6′-OMe bearing congener [47]. The use of the rotational C8–C9 bond as the link between the two active centers renders catalysts 76, in terms of conformational properties, different from the Takemoto catalyst 57 and β-ICD (51). From the viewpoint of minimizing the unfavorable entropic cost associated with acid–base bifunctional catalysis, the introduction of such conformational freedom should be avoided in the design of a bifunctional acid–base organic catalyst. On the other hand, this rotational linkage, as shown in a top view of Q-76, provides the bifunctional catalyst with another degree of flexibility in altering both the spatial


OH

OH

R

R OR'

OR' N

9 N

H

N

R

8

Catalyst: QD-76

N R'O N

8 9 H

H H

N

OH Top view of QD-76

Q-76

R = CH=CH 2, R' = H, 76a PHN = R = CH=CH 2, R' = Bn, 76b R = CH=CH 2, R' = PHN, 76c R = CH 2-CH 3 , R' = PYR, 76d Ph Cl R = CH=CH 2, R' = Bz, 76e PYR = N N R = CH=CH 2, R' = Ac, 76f Ph R = CH=CH 2 , R' = 3,5-(CF3 )2 C6 H3 CO, 76g

O R1 60

NO2

O

+

O

76a (10 mol %) OR 3

R2

R = aryl or alkyl

R

–20°C, THF

R2 = OMe, R3 = Me 58A R2 = Me, R3 = Et 45C

R

NO2

+

R2 R3

NO 2

R2 = OMe, R3 = Me 61 R2 = Me, R3 = Et. 62 O

X

*

R1

O 1

COOR 3

2

76a-c (10 mol %)

R2

–20 to 60°C,THF

R3 X * *

R1

NO 2

94–98% ee, 71–99% yield 91% ee, 93% yield

92–99% ee, 74–95% yield 6:1–50:1 d.r.

60 O

O

OR n = 1, R = Me, 45D n n = 2, R = Et, 45E

O

O

O

O

O

O NC

OR 45F

O

OR

O 45G

59B

O

74A

O2N

OR R' 77

Scheme 2B.16.

distance and angle between the acidic and basic center. The high enantioselectivity afforded by catalysts 76 showed that the rotational C8–C9 bond, instead of compromising catalyst efficiency, allowed the catalyst to adopt the optimal conformation to afford highly efficient bifunctional catalysis. The next question was: “Does such conformational flexibility make the bifunctional catalysts 76 highly general?” In a following report published in 2005, Deng and coworkers found that 76 could promote the conjugate additions of a wide range of trisubstituted carbon nucleophiles to nitroalkenes 60 in exceedingly high enantioselectivity and diastereoselectivity (Scheme 2B.16) [48]. Based on experimental results obtained from kinetic, conformational, catalyst structure-property studies and product configuration analysis, they also proposed a mechanistic model (Fig. 2B.1) [48]. This stereochemical model readily explains how 76 could be both efficient and general. The authors proposed that various nucleophiles, in their corresponding enol forms, were activated by a hydrogen-bonding interaction between the enol and the quinuclidine. Among the various transition states (78, 79, and


R"

N R1

R'O N H O H

H

O X

R2 R1

X

H

O

NO 2 COR 2

R3

H

N + O– R3 78

R"

R"

N

N R'O

R'O N

H

H X R1

H

R1

N+ – R2 O

R2

O

H

H

H

O

H O

R3

N

H

H

X N+ HR

79

O

O

3

O–

O 80

Figure 2B.1.

80) leading to the formation of different stereoisomers, transition state assembly 78 is the most favored. Relative to 78, transition state 79 is less stable due to fewer hydrogenbonding interactions between the nucleophile and the catalyst. On the other hand, transition state 80 is destabilized due to steric congestions. Furthermore, in transition state 78, the variable substituents (R1, R2, and R3) of the donors and acceptors are pointing away from the catalyst, which is interacting with the functional groups of the two substrates through a network of hydrogen bonds. Consequently, alterations of these substituents are well tolerated by the catalyst as they do not disrupt the networks of hydrogen-bonding interactions between the catalyst and the substrates (Fig. 2B.1). An interesting hypothesis, arising from this model, was that catalysts 76 might tolerate the replacement of the nitro group with other basic organic functionalities. This implied that 76 could potentially afford high enantioselectivity and diastereoselectivity for conjugate addition reactions with a wide range of Michael acceptors other than nitroalkenes. Subsequent studies guided by this hypothesis indeed led to the development of a series of highly enantioselective and diastereoselective asymmetric conjugate additions with α,β-unsaturated sulfones 81 [49a,d], ketones 41 [49b], and aldehydes 84 [49c] (Scheme 2B.17). In addition to their implications for bifunctional catalyst design and development, these synthetic and mechanistic studies of 76-catalyzed conjugate additions also established many unprecedented organocatalytic asymmetric transformations that address important and challenging synthetic problems, such as the construction of the quaternary stereocenters. Even in comparison with the best chiral metal


R1 X

Y

R1

+

R3

76c (20 mol %)

O

O

SO2 R2

X

SO2R 2 80–96% yield 81a: R1 = H, R 2 = Ar 86–97% ee 81b: R 1 = Ar, alkyl, R 2 = CF3 4.6:1–50:1 dr

82

O

O

COY

R3

O

O

CN

CN n n = 1, 2, 3. 74C-E

CN Ph 74F

O

74G

45H

O CN R5

CO 2R

COOEt 45I

74H

O

O

O

R1

OR

O 4

R

+

R2

76c (10 mol %) CH2 Cl2

R3

45

R

*

O

O

R

R1

O

OR R2

R3

45

84A, R3 = H; 84B, R3 = alkyl

R3

O R4 O

O *

R2

*

OH

OR

R3

EtOOC

CH2 Cl2

CN

82–99% yield 85–99% ee 86:14–96:4 dr

OR

O C11H 23 85 H (+)-Tanikolide 90–99% ee, 97–100% yield 18–25:1 dr

H

76 (0.1–10 mol %)

COOEt

*

83

41

1

O

R2

O

R4

1

R4 86

74

CN CHO

80–95% ee, 90–99% yield

NC Ar

*

HN Boc N Boc OR

Q-83b (5-10 mol %) NC Toluene

O (R)-87 82–95% ee, 71–99% yield

O Boc OR + Ar 74

HN Boc QD-83b (5–10mol %) NC N Boc N N OR Ar * Boc Toluene 75 O (S)-87 87–99% ee, 72–98% yield

Scheme 2B.17.


catalysts [50], 76 afforded much higher enantioselectivity and diastereoselectivity over a much broader scope of substrates in conjugate additions to enones 41 and enals 84. Notably, cinchona alkaloid 76c is the first highly enantioselective catalyst for conjugate additions with α,β-unsaturated sulfones 81 [49a]. Although a highly enantioselective amination of α-cyanoacetates 74 with dialkyl azadicarboxylate 74 was developed with β-ICD (51) [46] (Scheme 2B.15), catalysts 76 were explored by Deng and coworkers for this transformation to establish enantioselective access to both enantiomers of adducts 87, which are valuable chiral building blocks bearing an N-substituted tetrasubstituted stereocenter [51]. As summarized in Scheme 2B.17, in the presence of catalysts QD- and Q-76b, the aminations of 75 proceeded with excellent enantioselectivity to provide enantioselective access to both enantiomers of adduct 87. The remarkable ability of cinchona alkaloids 76 to achieve both highly efficient stereochemical control and to tolerate an extremely broad range of Michael donors and acceptors provided further validation of one of the key design features of 76, namely the use of a bond of rotational freedom to link the basic and acidic site. As part of an extensive investigation, studies to apply catalysts 76 to other asymmetric reactions were performed in parallel to those directed toward conjugate addition reactions. In 2005, a successful application of 76 in an enantioselective 1,2-addition to carbonyls was reported by Deng and coworkers, who realized a highly enantioselective nitroaldol reaction that is applicable to both alkyl, alkenyl, and aryl α-ketoesters 88 (Scheme 2B.18) [52a]. In addition to their implications in expanding the reaction scope of 76, these results provided the first highly enantioselective organocatalytic Henry reaction with ketones. Importantly, with a significantly more general scope than that established by metal catalysts [53], this reaction represented important progress in catalytic asymmetric Henry reactions. The resulting α-hydroxyl esters 89 could be transformed into other synthetically valuable chiral buiding blocks containing tetrasubstituted stereocenters. In recent years, the scope of the 76-catalyzed Henry reactions was further

O OEt

R1

+

88 O

CH 3NO2 23A

76e (5 mol %)

HO

CH 2Cl2, –20°C

1

O 93–97% ee, 84–99% yield

R1 = aryl, alkenyl, alkyl

O 1

R

76a or 76c (5 mol %) 2

P(O)(OR )2

+ CH 3NO2

90 R1 = aryl, alkyl

R1

THF

76g (5 mol %) R2

+

CH 3NO2 23A

HO R

1

*

NO2 P(O)(OR 2) 2

91 90–99% ee, 61–93% yield

23A

O

R * 89

NO2 OEt

CH 2Cl2 , –25°C

70A, R1 = aryl, alkyl; R 2= CF3 70B, R1 = aryl, alkyl; R 2= CHF2 Scheme 2B.18.

HO R1

*

NO 2 R2

91 76–99% ee 67–99% yield


extended by Zhao, Bandini, and others to other ketones such as 90 and 70 (Scheme 2B.18) [52b,c]. An enantioselective Freidel–Crafts reaction of indoles and carbonyls catalyzed by 76c was reported in 2006 by Deng and coworkers (Scheme 2B.19) [54]. High enantioselectivity was established for reactions of various indoles 92 with various carbonyls such as aryl aldehydes 16A and aryl pyruvates 88. However, attempts to extend the high enantioselectivity to simple aliphatic aldehydes and ketones have not yet been met with success.

R2 N H 92

76c (10 mol %)

O

+ R1

HO *

X

rt-70°C

16A: X = H, R1 = Ar 88: X = CO 2Et, R1 = H, Ar, alkynyl

X R1

R2 N H 93A: X = H 82–93% ee, 60–96% yield 93B : X = CO2 Et 81–99% ee, 52–97% yield

Scheme 2B.19.

In another significant expansion of the reaction scope of 76, Deng and coworkers documented the first efficient asymmetric Diels–Alder reaction with 2-pyrones 94 (Scheme 2B.20) [55]. It is noteworthy that 2-pyrones 94 presented a class of synthetically useful but inactive diene substrates for Diels–Alder reactions. As illustrated in a proposed stereochemical model presented in Scheme 2B.20, Deng and coworkers postulated that, in addition to directing the substrates toward the formation of exo-96 in high enantioselectivity and diastereoselectivity, the simultaneous activation of both the pyrone diene 94 and the dienophile 95 by catalyst 76c was critical in addressing the wellknown activity issues associated with D-A reactions of 2-pyrones 94 [55]. Toste and coworkers reported a synthetically interesting enantioselective fragmentation reaction, which also expanded the scope of catalysts 76. Specifically, Toste and others showed that catalyst 76f was very effective in the promotion of an asymmetric Kornblum–DeLaMare reaction, which produces optically active γ-hydroxyl enone 99 from cyclic meso-peroxides 98 (Scheme 2B.21) [56]. In contrast to the bond-forming reactions with electrophiles and nucleophiles, this reaction fragments the meso-peroxide enantioselectively to form a chiral product. In the proposed stereochemical model, the C6′-OH of 76f activates the peroxide bond as an acid while the basic quinuclidine deprotonates the acidic C–H. With this two-point interaction, the catalyst also induces the enantioselectivity by directing the peroxide 98 to adopt an orientation with its bulky substituents pointing to open space. As outlined in the first report of 76 as a highly efficient chiral catalyst, Deng and coworkers’ studies were inspired by Wynberg’s pioneering studies of natural cinchona alkaloids as acid–base bifunctional catalysts and Hatakeyama’s success in the use of the 6′-OH as an acidic center to activate aldehydes in the asymmetric Morita–Baylis–Hillman reaction with β-ICD 51. At the same time, catalysts 76 are designed to specifically address two key issues, inadequate acidity and conformational inflexibility, which prevent the natural cinchona alkaloids and β-ICD 51, respectively, from becoming highly efficient yet general chiral acid–base bifunctional catalysts. The importance in addressing


R3 R2

95 X 83c (5 mol %)

O R1

O

O

R2 R3

+ R1

R R3 2 exo-96

HO

94

O

O X

R1

Solvent, rt

OH

O

O

HO

X endo-96

O OEt

Ph

OEt

p-Br-Ph

O 95A, exo : endo = 93:7 exo: 94% ee

O 95B, exo : endo = 91:9 exo: 91% ee

H

O Ph

H

O

O

C

O 95C, exo : endo = 93:7 exo: 90% ee

N

H R'O

O

O Ph

H

N

N

O R' = PHN

Cl

95D, exo : endo = 24:76 exo: 94% ee endo: 91% ee

97

Scheme 2B.20.

O O R

76f (10 mol %) R

O

CH 2 Cl2 , 23°C 99

98 BnO

R R HO

Ts N

OBn

O

OAc

O N

HO

O 99A 96% ee 90% yield

HO

O 99B 91% ee 95% yield

HO

O 99C 73% ee 99% yield

N

100

O H

H R R O O

Scheme 2B.21.

these issues, from the viewpoint of developing powerful bifunctional catalysis, became immediately apparent upon the demonstration of 76 as highly efficient and general enantioselective catalysts. The design of new cinchona alkaloids as versatile acid–base bifunctional catalysts has quickly intensified. 2B.3.2.2. Bifunctional Catalysts Based on 9-Thiourea Cinchona Alkaloids In 2005, four groups reported various asymmetric conjugate additions with cinchona alkaloids 101–104, which bear a 9-thiourea group as the acidic center (Scheme 2B.22). Chen and


R2 H N

F3C

R2 N

H N

H

CF3

R

Ph

N H

PhSH 101, (10 mol %) CH2 Cl2 , 4Å MS, – 40°C

O

95C

SPh O Ph

65

105

Ph

CD-101 , 7% ee CN-101, –17% ee

O

Toluene, rt 106 Ar *

CH 2(CO2 Me) 2 NO 2 60A

N H

89–96% ee 80–94% yield R1

Ar

O

O2 N

MeNO 2 103, (10 mol %) R2

CF3

CN-101, R1 = H, R2 = CH=CH2 CN-102, R1 = H, R2 = CH2 CH 3 QD-103, R 1 = Me, R 2 = CH=CH 2 QD-104, R 1 = Me, R 2 = CH 2CH 3

R2 = CH=CH2 R2 = CH2 CH3 R2 = CH=CH2 R2 = CH2 CH3

Ph

CF3

S N

CD-101, R1 = H, CD-102, R1 = H, Q-103, R1 = Me, Q-104, R1 = Me, O

H N

1

N

O

H N

H R1

S

R1

N

MeOOC

R2

NO 2 COOMe

61

Method A (Connon): CN-101, (10 mol %), CH2Cl2, –20°C, 75–99% ee, 63–94% yield. Method B (Dixon): Q-104, (0.5 mol %), toluene, 0°C, 82–97% ee, 81–99% yield.

Scheme 2B.22.

coworkers reported the addition of thiophenol to α,β-unsaturated imide 65 with catalyst 101, albeit in very low enantioselectivity [57]. In a paper published simultaneously by Soos and coworkers, they showed that 103 mediated the 1,4-addition of nitromethane to chalcone derivatives 95C in high enantioselectivity [58]. Shortly thereafter, the Connon and the Dixon groups independently reported highly enantioselective conjugate additions of malonates to aromatic nitroalkenes 60A catalyzed by 101 and 104 [59,60]. These promising results in combination with the easy accessibility of the 9-thiourea cinchona alkaloids 101–104 quickly attracted further investigations to extend the utility of those catalysts in asymmetric conjugate additions. Some of the most important examples are highlighted in Scheme 2B.23. Dixon [61], Chen [62], Jørgensen [63], and Wennemers [64] expanded the scope of the nucleophiles for the 101–104-catalyzed conjugate additions to nitroalkenes. In the studies described by Dixon [61] and Chen [62], respectively, new classes of carbon nucleophiles (107 and 109) were successfully utilized in conjugate additions with nitroalkenes 60. The efficient additions of oxime 111 to nitroalkenes reported by Jørgensen provided a rare example of highly enantioselective organocatalytic conjugate additions with C–O bond formations [63]. The


Ph

O

O

107

F3 C CF3 101 (10 mol %)

NO 2

Ar

O

F3C

CF3 O

NO2

93–>98% de, 60–89% ee 50–88% yield

R 108

Toluene

60A R = aryl

O

O Ph

OH R'

109 NO 2

R

60 R = aryl, alkyl

OH

Toluene, –50°C 4 Å MS, 96h HO

N

NO2

R

NO 2

R' 101 (10 mol %) R'

R = alkyl

110

EtO2 C

111 CO2 Et

N

103 (10 mol %)

60B

85–94% ee 69–83% yield

*

R

Toluene, –24°C

89–93% ee 68–83% yield

O NO2

112

H N

F3C

N

H N

H OMe

O CF3

N

115 S NO2

R

MeO

OH O O 113

60B

115 (10 mol %)

R = alkyl

Toluene, –24°C

S

NO2 O

MeO 114

R 73–90% ee 13–97% yield

Scheme 2B.23.

decarboxylative Michael addition of β-ketoacid 113 reported by Wennemers and coworkers [64] presented a successful organocatalytic approach toward synthetically valuable asymmetric transformations that were previously only successful with chiral metal catalysts [65].


X

O X

Y +

Ar

Y

104 (10 mol %) R

O R

Ar

41 R = aryl, alkyl 85–98% ee 62–99% yield

X = Y = CO2 R(58), COR(59), CN(116) X = CO 2R, Y = COR( 45 ), NO2 (77)

OH

O

OH

R

O

103 (10 mol %) CO2 t-Bu

R1 R2

–25°C, toluene then p-TsOH, 80°C

R1

117 R = aryl, alkyl R1 = R2 = H R 1 = Me, OMe, R 2 = H

O X

+

SH 119

R

80–94% ee 65–97% yield

O H

O R2 118

Ar

OH O

O N

123 (1 mol %) O

Cl(CH2 )2 Cl

120A

X = H, 5-Me, 5-Cl, 4,6-Me, 5,6-(CH2 )4

X

O N

O

S Ar 121 91–99% ee 75–97% yield >20:1 dr

Scheme 2B.23. (Continued)

Building on Soos’ early report [58], the Wang and Chen groups reported a dramatic expansion in the scope of the nucleophiles for 104-catalyzed conjugate additions to α,β-unsaturated ketones 41 [66]. Scheidt disclosed a ring-forming intramolecular conjugate addition with an o-acyl phenol 117, which was applied to facilitate the asymmetric synthesis of flavanones and chromanones [67]. Although Chen’s group reported very low enantioselectivity for the addition of thiophenol to α,β-unsaturated imides 65, Wang and coworkers found that with o-formyl thiophenols 119 and α,β-unsaturated imides 120A, a highly efficient tandem Michael-aldol reaction sequence could be established [68]. As described earlier, there were several literature precedents of activations of imines by chiral thioureas and in activation of nucleophiles by cinchona alkaloids for various asymmetric reactions. These precedents suggested that 9-thiourea cinchona alkaloids might be able to efficiently promote enantioselective nucleophilic additions to imines (Scheme 2B.24). In 2005, Ricci and coworkers reported a cinchona alkaloid 103-catalyzed aza-Henry reaction of nitromethane and N-Boc or N-Fmoc aryl imines (8A, 122) [69], a reaction which Jacobsen and coworkers had previously shown

82 ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES 103 (20 mol %) CH 3 NO 2

NP Ar

H

HN * R

Toluene, –20°C

PG = Boc ( 8A ), Cbz (122)

PG NO 2

PG = Boc ( 24A ), Cbz (123)

PHN * Ar MeOOC N Ar

PG +

H

COOMe 58A

O

MeO

101 (10 mol %)

OMe O

83–97% ee 81–99% yield

O 124

O

PG = Boc (8A), Cbz (122)

PHN * Ar MeO2 C

OMe 45

84–87% ee 16:1–20:1 dr 70–97% yield

O * 125

R'OOC

NPG R

58A, R' = Me 58B , R' = Bn 58C , R' = Allyl

103 (10 mol %)

+

H

O

8A, R = aryl 8B, R = alkyl

PHN * R

COOR'

R'O

R"

PHN OAllyl * * R O

OAllyl

H

R 16

R"

R

SO 2Ar

O

5 mol % Pd(II) Methyl acetoacetate 126

CsOH (0.10 M) CH 2Cl2

129 PG = Boc, Cbz, A, R = Ar, B, R = alkyl

91–92% ee 66–99% yield Up to 3:1 dr

126

CH 2(COOBn) 2 103 (5–20 mol %)

PHN

O

O

PHN O 1) Pd/C, H2 MeOH, 10 h * OH 2) Toluene, ref lux R 127

O

88–99% ee 55–99% yield

O 124

45H, R' = Me 45I, R' = Et 45J , R' = i-Pr

124

OR'

CH2 Cl2

PHN * R

85–96% ee 46–99% yield

PHN R

O

*

R"

128

1) Pd/C, H2 MeOH, 10 h COOBn

COOBn 124

2)Toluene, reflux

PHN R

*

O OH

127

Scheme 2B.24.

to proceed with excellent enantioselectivity with monofunctional chiral thiourea catalysts [70]. In 2006, Dixon [71] and Deng [72a] simultaneously reported highly enantioselective additions of malonates 58 and β-ketoesters 45 to N-carbamate imines (8A, 122) catalyzed by 9-thiourea cinchona alkaloids 101 and 103, respectively. This unprecedented asym-


metric reaction produced Mannich adducts 124–126 that could be readily converted into important chiral building blocks such as β-amino acids 127 and β-amino ketones 128. In Dixon’s study, α-substituted β-ketoesters such as 45 were also found to be excellent substrates [71]. In Deng’s investigations, catalyst 103 was shown to afford excellent enantioselectivity for both aryl (8A) and alkyl (8B) imines, although the intrinsic instability of the N-carbamate alkyl imines 8B required a stoichiometric amount of 103 to be employed to make the asymmetric Mannich reaction competitive with the decomposition of 8B [72a]. To circumvent this problem, Deng and coworkers subsequently developed a one-pot protocol [72b]. In this protocol, the N-carbamate imines were generated from the corresponding α-amido sulfones 129 and then immediately consumed in situ in the Mannich reaction (Scheme 2B.24). Importantly, α-amido sulfones 129 are not only stable but can also be easily prepared from the corresponding aldehydes 16 in large quantities. Overall, a versatile and concise route for the asymmetric synthesis of β-amino acids 127 from simple aldehydes 16 was established. In 2006, Deng and coworkers also realized an efficient enantioselective Fridel–Crafts reaction of indoles 92 and imines 129 (Scheme 2B.25) [73]. This reaction is unique in affording excellent enantioselectivity for both aryl and alkyl imines. With a general scope to provide a direct and versatile enantioselective access toward the synthetically valuable 3-indolyl methanamine 130, this transformation is of considerable interest to the asymmetric synthesis of indole natural products.

PHN *

NP

R1 N H 92

+

R2

R2

103 (10 mol %)

H

EtOAc

129 R2 = aryl, alkyl P = Bs, Ts

R1 N H 130 83–97% ee 83–99% yield

Scheme 2B.25.

As part of their program for the development of effective catalysts for the synthetically important but challenging enantioselective Diels–Alder reaction, Deng and coworkers explored both the 6′-OH cinchona alkaloid 76 and the 9-thiourea cinchona alkaloid 103 as catalysts for D-A reactions with 2-pyrones 94 [55]. Interestingly, the former was identified as an effective catalyst for reactions with carbonyl dienophiles (Scheme 2B.20) while the latter was efficient for reactions with nitrile dienophiles 131 (Scheme 2B.26) [55]. These studies demonstrated 103 is an effective catalyst for asymmetric cycloadditions. In addition, these results constitute the first highly enantioselective Diels–Alder reaction with nitrile dienophiles. Recently, Connon and coworkers found that 103 could effectively catalyze the enantioselective alcoholysis of meso-anhydrides 133, thereby providing an example of a highly enantioselective acyl transfer reaction with 103 (Scheme 2B.27) [74]. As proven by the examples above, the 9-thiouera cinchona alkaloids 101–104 have afforded excellent stereochemical control over an impressive range of reactions. It is


O O OH 94a

X

Y

X

Catalyst (5 mol %) TBME

131

O

O

Y

HO

exo-132 CN

NC

CN

CN

CN 131B

131A exo : endo > 97:3; 92% (85%) ee; 85% (87%) yield.

131C exo : endo = 96:4 (93:7); 94% (93%) ee; 91% (87%) yield.

exo : endo = 93:7 (89:11); 97% (98%) ee; 81% (89%) yield. Scheme 2B.26.

H O O H O

MeOH 103 (1 mol %) TBME, rt

133

H

H

CO2 Me CO2 H

93% yield 96% ee

134 Scheme 2B.27.

safe to predict that these versatile catalysts will continue to find new applications in asymmetric synthesis.

2B.4. CONTROL OF ENANTIOSELECTIVITY AND DIASTEREOSELECTIVITY IN ASYMMETRIC TRANSFORMATIONS WITH ACID–BASE BIFUNCTIONAL ORGANIC CATALYSTS Catalytic asymmetric tandem reactions or reaction cascades that create multiple stereocenters provide especially efficient means to build stereocomplexity in both target- and diversity-oriented synthesis. To fully realize the potential of such reactions, not only must high enantioselectivity and diastereoselectivity be attained, but the sense of the stereochemical induction should also be under control by the catalysts. As the catalytic control of diastereoselectivity in such reactions remains a fundamentally unsolved problem, achieving these goals for synthetically important transformations represents one of the major challenges in asymmetric synthesis. Deng and coworkers investigated cinchona alkaloid 76 as a catalyst for the conjugate additions of a range of carbon nucleophiles to α-chloroacrylonitrile (136) (Scheme 2B.28) [75]. These conjugate additions create two stereocenters in two bond-forming steps: first, the nucleophilic addition and second, the protonation of the enolate inter-

2B.4 CONTROL OF ENANTIOSELECTIVITY AND DIASTEREOSELECTIVITY 85

O

O Y

X

Cl +

R

76c (10–20 mol %) CN

CN

X R Y Cl 137

Toluene, rt

136 76

76

Protonation

R'

N

R'

N

R''O N H O H

R''O H

N

H O H

Y

X

C H

H

H

Nucleophilic addition N

C

X R

Y

Cl T1 O

O

CN

O CN 74E

74G dr = 20:1, 96% ee

dr = 7:1, 91% ee

CN

O

O

dr = 10:1, 93% ee

O O tBu

O

O O tBu

45K

45J dr = 17:1, 98% ee

Ph

CO2 Et 74H

dr = 7:1, 91% ee

COSMe

N

Cl T2

CN

CN

135

O H

O

R

74C

H

H

dr = 20:1, 98% ee

dr = 4:1, 88% ee O

O O

CF3 CF3

45L dr = 9:1, 94% ee

Scheme 2B.28.

mediate. The synthetic impetus of this investigation was to develop asymmetric tandem reactions to provide one-pot constructions of 1,3-tertiary-quaternary stereocenters from simple starting materials. Such structure motifs, although commonly presented in natural products, are usually built via multistep synthetic sequences. Deng and coworkers first established that the 6′-OH cinchona alkaloids 83 could afford high enantioselectivity and diastereoselectivity for the tandem nucleophilic addition–protonation reaction involving a diverse array of carbon nucleophiles (Scheme 2B.28) [75]. They also showed that with DABCO, this reaction proceeded with hardly any diastereoselectivity, thereby establishing that catalyst 76 was responsible for both the enantioselectivity and the diastereoselectivity. This is consistent with a mechanistic model in which the catalyst serves a dual role, facilitating the enantioselective C–C bond-forming nucleophilic addition to generate the quaternary stereocenter and effecting the subsequent protonation of the transient enol intermediate to form the tertiary


stereocenter (Scheme 2B.28) [75]. Deng and coworkers further hypothesized that, with another catalyst presenting the hydrogen bond donor and acceptor in a different spatial relationship, the relative orientation between the two prochiral substrates could be altered [76]. In principle, such a catalyst could promote the reaction with a different sense of diastereoselectivity. Indeed, they discovered that the 9-thiourea cinchona alkaloid 103 afforded a sense of diastereoselectivity complementary to that by 76 [76]. Consequently, these two types of bifunctional catalysts, both easily synthesized from quinine and quinidine, enabled the one-step preparation of any of the four possible stereoisomers of products 137 in a highly stereroselective fashion (Scheme 2B.29) [76]. The synthetic application of such reactions was illustrated in the total syntheses of manzacidins A (138) and C (139) using the same route (Scheme 2B.29) [76]. Ar MeO Ar HN S OMe HN

OR N

N

N

CN X

R

Cl

1 CN R O (1S, 3S)- 137 9:1–15:1 dr, 94–97% ee 98–99% yield

CN X

Cl

COSMe 135 + Cl CN 136

H

CN 3

X

1 CN R O (1R, 3R)-137 9:1–16:1 dr, 94–98% ee 97–99% yield

1 CN O R (1S, 3R)-137 3:1–20:1 dr, 85–93% ee 45–95% yield

HN CN

93% ee, 10:1 dr 71% yield CN Cl

MeSOC

Cl

Br

Cl

N H

(1R, 3R)-137

Toluene, rt 12 h

CN 3

X

1 CN

4:1–20:1 dr, 86–96% ee 71–98% yield

MeSOC

QD-103 (10 mol %)

Cl

R O (1R, 3S)-137

CN

N Q-1

168

Cl

Toluene, rt 96 h

N

CN

3

QD-76f (20 mol %) CN

OR

H QD-1

+

O 74,135

3

OH

N

H QD-2

N

CN X

OH

NH

N H Q-2

NH

S

CN

(1R, 3S)-137 96% ee, 9:1 dr 98% yield

N

O

CO2 H

Me

O

138 Manzacidin A Br HN N H

O Me 139 Manzacidin C

N CO2 H

O

Scheme 2B.29.

Deng and coworkers successfully extended such complete catalytic stereochemical control to another distinct complex asymmetric transformation [47]. They observed that the asymmetric Diels–Alder reactions of 2-pyrone 94a with α-chloroacrylonitrile 136 preferred the formation of endo-140 with the 6′-OH cinchona alkaloid 76c, but exo-140 with the 9-thiourea cinchona alkaloid 103 (Scheme 2B.30). These results support the notion that manipulations of acid–base bifunctional catalysts could potentially provide a generally applicable means for establishing catalytic control of diastereoselectivity in complex asymmetric reactions.

2B.5. EMERGING ACID–BASE BIFUNCTIONAL CHIRAL ORGANIC CATALYSTS

O

O

(R)

(R) 85% ee Cl 87:13 dr (R) CN OH

DHQD-76c

O

O

(S)

75% ee 78:22 dr

DHQ-76c

(S)

HO

Cl O

(R)

Q- 103 NC

CN

(S)

89% ee 93:7 dr

O 85% ee 91:9 dr

(R)

Cl

endo-140

CN (R)

HO

94a

168 CN

Cl

(S)

(S)

(S)

QD-103

O O + Cl

O

O

OH

87

OH

ex o-140

Scheme 2B.30.

2B.5. EMERGING ACID–BASE BIFUNCTIONAL CHIRAL ORGANIC CATALYSTS The three types of broadly useful acid–base bifunctional organic catalysts discussed above have had the most significant impacts on establishing asymmetric acid–base bifunctional organocatalysis as a generally applicable strategy in asymmetric synthesis. Pioneering studies leading to the development and applications of these catalysts have stimulated widespread explorations of these catalysts in catalytic asymmetric reactions. On another level, these studies have stimulated the design and development of new acid–base bifunctional organic catalysts from natural and synthetic molecules. Listed in Schemes 2B.31–2B.36 are some of the most promising among these emerging

O O

O 2

H 3C

+ R O OR 1

O

N H

45

1) Cinchonine (10 mol %) Ar

N H

F3 C

97

R2 45

O

OR 1 142

F3C OH COOEt *

Ether, –8°C

N 144 H

O

O

N Bn

+ 145

83–95% ee 96–99% yield

R

143

R3

R1

COOEt

83–94% ee, 1–20:1 dr 81–96% yield

Ar

Cinchonidine or cinchonine (5 mol %)

+

R

OR 2

HN

H 3C

141

O

O

CH2 Cl2 , –35°C

O

Quinine or quinidine (10–20 mol %)

O O

CH2Cl2, –60 to –15°C

O

* 1

R

R2

* O

146

Scheme 2B.31.

R3

O N

Bn

82–98% ee, 4–49:1 dr 95–99% yield

88 ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES Ph O N N CF3

S HN HN

CF3 147A (10 mol %)

O Ar

+

H 16A

MeNO2 23A

THF, –20°C

OH

86–92% ee 91–99% yield

NO 2

Ar 148

O N N S

CF3

HN HN O

O N

R

O

147B +

CF3

R'SH

R *

R' = alkyl

R = alkyl, aryl

O N

SH

2-step

O

149 87–96% ee 84–99% yield

40B

120

SR' O

R

O

*

O 150

R= n-C 3H 7, 91% ee

Scheme 2B.32.

S

Ph CF 3 * * Ph N 1' 2' H HN S CF3 O O 151 (1R, 2R, 1'R, 2' R) NHBoc (10 mol %) NO2 R CH3 CN, –20°C, 4ÅMS R' 24

* * N 2 1 H N

NBoc Ar 8A

H

+

R'CH2 NO 2 23

Scheme 2B.33.

16:1–99:1 dr 96–99% ee 88–99% yield

CF 3 S N H H N

N H

CF3

N

NMe2 R

NO 2

+

NO2

Ar

NO2

(R)-153 (2 mol %)

60A

23 R = Et, n-Pr

NO 2

R

Benzene, 25°C

Ar 152

74:26–90:10 dr, 91–95% ee, 55–94% yield Scheme 2B.34.

CF3 O S O HN

F 3C

N

MeO O

R

N

O

R

153A (5 mol %) R'

n R

O MeOH, Et 2 O, rt

OH

R'

O

n R

28

OMe

91–98% ee 88–97% yield

O 29

O S O HN

N

MeO N O

O NO2

COOMe + Ar

R

45

153B (10 mol %) R CH 2Cl2, –40°C

60A

COOMe Ar NO2 154 3.1:1–50:1 dr 90–96% ee 71–99% yield

Scheme 2B.35. 89


F3 C O F3C

HN

O N

HN

O

N O Me

O Me

59C

+

NO2

Ar 60A

155 (0.5 mol %) CH 2Cl2, rt

O

Me Ar

Me 97–98% ee NO2 89–98% yield 63

Scheme 2B.36.

catalysts [77–82]. Interestingly, several groups examined, once again, natural cinchona alkaloids as acid–base bifunctional catalysts, and found them to be effective catalyst for several asymmetric reactions, although these natural cinchona alkaloid-catalyzed, highly enantioselective reactions involve active substrates (Scheme 2B.31) [77]. Although each of these catalysts has not yet achieved as wide a scope as those with either the 6′-OH cinchona alkaloids 76 or the 9-thiourea cinchona alkaloids 101–104, they have already proved that highly enantioselective acid–base bifunctional catalysis can be accomplished with a diverse range of small organic molecules. Significantly, some of these catalysts, such as 147 and 153, have been found to afford superior activity and selectivity for synthetically valuable and unprecedented catalytic asymmetric reactions (Scheme 2B.32).

2B.6. CONCLUSION AND OUTLOOK Remarkable progress has been made over the last 5 years in asymmetric acid–base bifunctional catalysis with organic molecules. The discovery and invention of powerful and accessible chiral bifunctional organic catalysts have led to the development of numerous new asymmetric transformations of synthetic importance. In light of the accessibility of the catalysts, the simplicity in the reaction protocol and the relatively general substrate scope, wide applications of these reactions in asymmetric organic synthesis are expected to grow rapidly in the future. Conceptually, these experimental advances in catalyst discovery and reaction development have clearly recalibrated our perceptions of acid and base catalysis relevant to asymmetric synthesis. This is most conspicuously reflected in the dramatic transformation of bifunctional acid–base organocatalysis from a dubious concept into one of the most active areas in catalytic asymmetric synthesis. For most of the reactions reported to date, a relatively high catalyst loading (5– 20 mol %) is still required. However, it is known that some of these catalysts, such as those derived from cinchona alkaloids, can be recycled easily and nearly quantitatively without deterioration in catalytic properties. For reactions involving highly active nucleophiles and electrophiles, such as the amination of α-aryl α-cyanoacetates 74 with

REFERENCES 91

dialkyl azadicarboxylates or the conjugate addition of β-ketoesters 45 to acrolein (84A), a catalyst loading as low as 0.1 mol % suffices to give clean and highly stereoselective reactions. These data indicate that the high catalyst loading observed with less active substrates is not due to catalyst decomposition or product inhibition, but instead it is limited by the slow catalyst turnover rate. Another commonly observed trend is that the enantioselectivity of the catalyst is quite insensitive to the steric properties of the substrates. Instead, the enantioselectivity of the catalyst was often found to depend on the activity of both the nucleophile and electrophile. For example, a broader range of nucleophiles can be successfully employed in conjugate additions with a class of relatively active Michael acceptors such as nitroalkenes 60 versus those with less active Michael acceptors such as α,β-unsaturated ketones 41 [47,48,49b]. In parallel, a more active Michael donor, such as β-ketoesters 45, could be successfully applied in reactions with a broader range of Michael acceptors. Thus, the development of new classes of more active acid–base bifunctional catalysts is of central importance from the viewpoint of expanding the reaction scope as well as improving the practicality of asymmetric acid–base bifunctional catalysis. ACKNOWLEDGMENTS We are grateful for the financial support from the National Institute of Health (National Institute of General Medical Sciences, R01-GM61591) and Daiso. We sincerely thank our colleagues, Mr. Xiaojie Lu and Dr. Yan Liu, for their help during the preparation of the chapter. REFERENCES 1. (a) Acc. Chem. Res. 2004, 37, 487, Special Issue: Asymmetric Organocatalysis. (b) Chem. Rev. 2007, 107, 5413, Special Issue: Organocatalysis. 2. Silverman, R. B. The Organic Chemistry of Enzyme-Catalyzed Reactions. San Diego, CA: Academic Press, 2000. 3. (a) Yamamoto, H. Lewis Acids in Organic Synthesis. New York: Wiley, 2000. (b) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis. Berlin: Springer, 1999; Vols. 1–3. (c) Satelli, M.; Pons, J.-M. Lewis Acid and Selectivity in Organic Synthesis. Boca Raton, FL: CRC Press, 1996. 4. For reviews of asymmetric catalysis by hydrogen-bond donors, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl. 2006, 45, 1520. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. 5. Selected examples of hydrogen bond-donor catalyzed racemic reactions: (a) Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990, 31, 3381. (b) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259. (c) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647. 6. (a) Sigman, J. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b) Sigman, J. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl. 2000, 39, 1279. 7. Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. 8. Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. 9. (a) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. 10. Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. 11. (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662. (b) Huang, Y.; Unni, A. K.; Rawal, V. H. Nature 2003, 424, 146. (c) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci.

92 ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES U.S.A. 2004, 101, 5846. (d) Du, H.; Zhao, D.; Ding, K. Chem. Eur. J. 2004, 10, 5964. (e) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336. 12. Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418. 13. For reviews of chiral phosphoric acid-catalyzed asymmetric reaction, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008, 4097. (c) Connon, S. J. Angew. Chem. Int. Ed. Engl. 2005, 45, 3909. 14. For a recent review, see: Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. Engl. 2008, 47, 1560. 15. For a review, see: Wynberg, H. Top. Stereochem. 1986, 16, 87. 16. Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166. 17. (a) Hiratake, J.; Yamamoto, Y.; Oada, J. J. Chem. Soc. Chem. Commun. 1985, 1717. (b) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oada, J. J. Chem. Soc. Perkin. Trans. 1 1987, 1053. (c) Aitken, R. A.; Gopal, J.; Hirst, J. A. J. Chem. Soc. Chem. Commun. 1988, 632. (d) Aitken, R. A.; Gopal, J. Tetrahedron Asymmetry 1990, 1, 517. 18. Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195–196. 19. (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. (b) Calter M. A. J. Org. Chem. 1996, 61, 8006. 20. Miller, S. Acc. Chem. Res. 2004, 37, 601. 21. Fu, G. C. Acc. Chem. Res. 2004, 37, 542. 22. Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542. 23. Bolm, C.; Schiffers I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984. 24. Chen, Y.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302. 25. Hang, J.; Tian, S.-K.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2001, 123, 12696. 26. Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870. 27. For a review of enantioselective alcoholysis, see: Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965. 28. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456, 463. 29. McDaid, P.; Chen, Y.; Deng, L. Angew. Chem. Int. Ed. Engl. 2002, 41, 338. 30. Hemistra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417. 31. Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015. 32. Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. 33. Bella, M.; Jorgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672. 34. (a) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem. Int. Ed. Engl. 2000, 39, 3635. (b) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134. 35. Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jorgensen, K. A. Angew. Chem. Int. Ed. Engl. 2005, 44, 2896. 36. Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.; Sambri, L. Angew. Chem. Int. Ed. Engl. 2005, 44, 6219. 37. Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005, 127, 14566. 38. For highly enantioselective reactions catalyzed by chiral base catalysts derived from quanidine, see: (a) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 16044. (b) Terada, M.; Ikehara, M.; Ube, H. J. Am. Chem. Soc. 2007, 129, 14112. 39. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (b) List, B. Acc. Chem. Res. 2004, 37, 548. (c) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. 40. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 120. 41. (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed. Engl. 2005, 44, 529, 4032. (b) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413. 42. Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603.

REFERENCES 93

43. (a) Okino. T.; Nakamura, S.; Furukawa, T.; Takemoto, T. Org. Lett. 2004, 6, 625. (b) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem. Eur. J. 2006, 12, 466. 44. Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15827. 45. Berkessel, A.; Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem. Int. Ed. Engl. 2005, 44, 807. 46. Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. 47. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. 48. Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed. Engl. 2005, 44, 105. 49. (a) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948. (b) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem. Int. Ed. Engl. 2006, 45, 947. (c) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem. Int. Ed. Engl. 2006, 45, 4301. (d) Li, H.; Song, J.; Deng, L. Tetrahedron 2009, 65, 3139. 50. For metal catalyzed conjugate addition for the construction of quaternary stereocenter, see: (a) Sasai, H.; Arai, H.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571. (b) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561. (c) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240. (d) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295. 51. Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167. 52. (a) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (b) Mandal, T.; Samanta, S.; Zhao, C.-G. Org. Lett. 2007, 9, 943. (c) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem. Commun. 2008, 4360. 53. Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875. 54. Li, H.; Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063. 55. Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364. 56. Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12658. 57. Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. 58. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967. 59. McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. Engl. 2005, 44, 6367. 60. Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. 61. Hynes, P. S.; Stranges, D.; Stupple, P. A.; Guarna, A.; Dixon, D. J. Org. Lett. 2007, 9, 2107. 62. Liu, Y.-Y.; Cui, H.-L.; Chai, Q.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem. Commun. 2007, 2228. 63. Dinér, P.; Neilsen, M.; Bertelsen, S.; Niess, B.; Jørgensen, K. A. Chem. Commun. 2007, 3646. 64. Lubkoll, J.; Wennemers, H. Angew. Chem. Int. Ed. Engl. 2007, 46, 6841. 65. (a) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284. (b) Fortner, K. C.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 1032. 66. (a) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xue, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (b) Gu, C.-L.; Liu, L.; Sui, Y.; Zhang, J.-L.; Wang, D.; Chen, Y.-J. Tetrahedron Asymmetry 2007, 18, 455. 67. Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 3830. 68. Zu, L.; Wang, J.; Li, H.; Xe, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. 69. Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sagarzani, V. Tetrahedron 2006, 62, 375. 70. Yoon, T. P.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl. 2005, 44, 466. 71. Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. 72. (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (b) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603. 73. Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156. 74. Peschiulli, A.; Gun’ko, Y.; Connon, S. J. J. Org. Chem. 2008, 73, 2454.

94 ASYMMETRIC ACID–BASE BIFUNCTIONAL CATALYSIS WITH ORGANIC MOLECULES 75. Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. 76. Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. 77. (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. J. Am. Chem. Soc. 2005, 127, 11256. (b) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem. Int. Ed. Engl. 2005, 44, 3086. (c) Bartoli, G.; Bosco, M.; Garlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem. Int. Ed. Engl. 2006, 45, 4966. 78. Marcelli, T.; van der Hass, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed. Engl. 2006, 45, 929. 79. Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606. 80. Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524. 81. Oh, S.-H.; Rho, H.-S.; Lee, J.-W.; Lee, J.-E.; Youk, S.-H.; Chin, J.; Song, C.-E. Angew. Chem. Int. Ed. Engl. 2008, 47, 7872. 82. Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416.

2C ASYMMETRIC PHASE-TRANSFER AND ION PAIR CATALYSIS Seiji Shirakawa and Keiji Maruoka Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

2C.1. INTRODUCTION Phase-transfer catalysis has long been recognized as a versatile methodology for organic synthesis in both industry and academia, featuring simple experimental operations, mild reaction conditions, inexpensive and environmentally benign reagents and solvents, and the possibility of conducting large-scale preparations in process chemistry [1]. In particular, in the recent past, asymmetric phase-transfer catalysis based on the use of structurally well-defined chiral, nonracemic catalysts has become a topic of great scientific interest, and recent efforts have resulted in notable achievements, making it feasible to perform various bond formation reactions under mild phase-transfer catalyzed conditions [2]. This chapter focuses on the recent aspects of asymmetric transformations using various types of chiral phase-transfer catalysts. Also, related chiral quaternary ammonium and phosphonium salts as ion pair catalysts are introduced in this chapter.

2C.2. PIONEERING WORK Although initial work on asymmetric alkylation of carbonyl compounds by chiral phasetransfer catalyst has yielded disappointing results, a first efficient chiral phase-transfer catalyst, N-(4-trifluoromethylbenzyl)cinchoninium bromide (1a), has been devised in 1984 by the Merck group for asymmetric alkylation of 6,7-dichloro-5-methoxy-2-phenyl1-indanone, giving the corresponding methylation product with 92% ee in this particular case (Scheme 2C.1) [3].

Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 95

96 ASYMMETRIC PHASE-TRANSFER AND ION PAIR CATALYSIS

Cl

Cl

O

Cl

1a (10 mol %)

Ph MeO

+

CH3Cl

Me 50% NaOH aq Ph MeO Toluene 95%, 92% ee 20°C, 18 h

OH

– Br

OH N+

N H

N

O

Cl

N

Cinchonine

H 1a

CF3

Scheme 2C.1.

2C.3. ALKYLATION 2C.3.1. Asymmetric Synthesis of α-Alkyl-α-Amino Acids After 5 years of the groundbreaking work by the Merck group, similar N-benzyl cinchoninium halide 1b has been successfully utilized by O’Donnell and others as a chiral phase-transfer catalyst for the asymmetric alkylation of glycine Schiff base 2a. This produced the alkylation product (R)-3a in good yield and moderate enantioselectivity (Scheme 2C.2) [4]. Although asymmetric phase-transfer alkylation of glycine Schiff base 2a can be achieved by using chiral phase-transfer catalysts derived from the relatively inexpensive, commercially available cinchona alkaloid, research in this area had made little progress until recently after O’Donnell’s milestone reports. However, the new class of cinchona alkaloid-derived catalysts 1c and 4a,b bearing an N-anthracenylmethyl function developed by Lygo, Corey, and others independently [5,6] has opened a new era of asymmetric phase-transfer catalysis. In 1999, we designed and prepared the structurally rigid, chiral spiro ammonium salts of type 5 derived from commercially available (S)- or (R)-1,1′-bi-2-naphthol as a new C2-symmetric chiral phase-transfer catalyst and successfully applied it to the highly efficient, catalytic enantioselective alkylation of 2a under mild phase-transfer conditions (Scheme 2C.3) [7]. A significant effect of aromatic substitution (Ar) at the 3,3′-position of one binaphthyl subunit of the catalyst 5 was observed for enantiofacial discrimination. (S,S)-5e was revealed to be the catalyst of choice for the preparation of a variety of essentially enantiopure α-amino acids by this transformation. Compared with cinchona alkaloid-derived phase-transfer catalysts, 1 mol % of 5e is sufficient for smooth alkylation. Since both enantiomers of the catalyst of type 5 can be readily assembled starting from either (S)- or (R)-1,1′-bi-2-naphthol, a wide variety of natural and unnatural αamino acids can be synthesized in enantiomerically pure form by the phase-transfer catalytic alkylation of 2a. These reports have accelerated research into improvements of the asymmetric alkylation of 2a, and have resulted in the emergence of a series of cinchona alkaloid-derived catalysts, as well as the elaboration of purely synthetic chiral quaternary ammonium

2C.3. ALKYLATION 97

O Ph2C N

Ot-Bu + PhCH2Br 2a

O

Catalyst

Ph2C N *

Conditions

X – Cl

OH N N

H

H

N

+

Ph

–

+

OR N

Ar

1b (Ar = Ph) 1c (Ar = 9-anthracenyl) 1b (10 mol %) 50% NaOH aq CH2Cl2 25°C, 9h 75%, 66% ee (R)

Ot-Bu

H 3a

4a (R = H, X = Cl) 4b (R = allyl, X = Br)

4a (10 mol %) 1c (10 mol %) 4b (10 mol %) 50% KOH aq 50% KOH aq CsOH•H2O CH2Cl2 Toluene Toluene rt, 18 h –78°C, 23 h rt, 18 h 63%, 89% ee (R) 68%, 91% ee (S) 84%, 94% ee (S)

Scheme 2C.2.

O Ph2C N

(S,S)-5 (1 mol %) Ot-Bu

+

RBr 50% KOH aq Toluene, 0°C

2a Ar

O Ph2C N

Ot-Bu

H R 3

5a: 73%, 79% ee 5b: 81%, 89% ee 5c: 95%, 96% ee 5d: 91%, 98% ee 5e: 90%, 99% ee 5e: 90%, 99% ee (R : 1-NpCH2) (R : CH2=CHCH2) 5e: 80%, 99% ee (R : PhCH2)

– Br + N

Ar (S,S)-5

Ph

F F

Ar = H (5a), Ph (5b) Ph 5c

5d

F 5e

Scheme 2C.3.

salts. The performances of the representative catalysts in the benzylation of 2a are summarized in Schemes 2C.4 and 2C.5. To fully induce the potential catalytic activity of N-spiro chiral ammonium salt such as 5d, we have developed binary phase-transfer catalysis using an appropriate achiral cocatalyst. For instance, the phase-transfer-catalyzed alkylation of 2a with benzyl bromide under the influence of 5d (0.05 mol %) turned out to be sluggish to give 3a in

98 ASYMMETRIC PHASE-TRANSFER AND ION PAIR CATALYSIS O Ph2C N

Ot-Bu + PhCH2Br 2a

O

Catalyst

Ph2C N *

Conditions

H 3a

Cinchona alkaloid derivatives – Br H

N

+

F

O N 6a

– Br 6a (10 mol %) 50% KOH aq F Toluene-CHCl3 (7:3) 0°C 90%, 96% ee (S) N F Park, Jew, and others [8]

Q H

N+ =Q

X

H

+

N+ O– 6b

Q

– 2Br 7a (X = H) 7b (X = F)

N O

Q

O N

Ot-Bu Ph

– 3Br

Q 7c

Q

6b (5 mol %) 50% KOH aq Toluene-CHCl3 (7:3) 0°C 94%, 96% ee (S) Park, Jew, and others [9]

7 (3–5 mol %) 50% KOH aq Toluene-CHCl3 (7:3) 0°C 7a: 91%, 90% ee (S) 7b: 93%, 94% ee (S) –20°C 7c: 94%, 94% ee (S) Park, Jew, and others [10,11]

Tartrate derivatives

MeO OMe 4-MeO-C6H4 8a (10 mol %) H H + CsOH·H2O N+ N – Cl (7:3) Toluene-CH 2 2 4-MeO-C6H4 2I 4-MeO-C6H4 –70°C N N 87%, 93% ee (R) O H N+ H O – Me 4-MeO-C6H4 Cl Shibasaki and others [12] Me Me 9 8a Me

Me

O

t-Bu

O

9 (30 mol %) 1M KOH aq CH2Cl2 0°C 55%, 90% ee (R) Nagasawa and others [13]

Scheme 2C.4.

only 4% yield (92% ee), while similar benzylation of 2a in the presence of 18-crown-6 (0.05 mol %) proceeded smoothly to furnish 3a in 90% yield with 98% ee. The origin of this dramatic rate enhancement would be the ability of the crown ether to extract KOH into toluene phase, accelerating otherwise slow deprotonation process (Scheme 2C.6) [21]. We discovered the very powerful chiral quaternary ammonium bromide 16 possessing flexible straight-chain alkyl groups instead of a rigid binaphthyl moiety functions as an unusually active chiral phase-transfer catalyst. Most notably, the reaction of 2a with various alkyl halides proceeded smoothly under mild phase-transfer conditions in the presence of only 0.01–0.05 mol % of (S)-16 to afford the corresponding alkylation products with excellent enantioselectivities (Scheme 2C.7) [22]. The enantioselective synthesis of α-amino acids employing easily available and reusable chiral catalysts or reagents presents clear advantages for large-scale application. Nájera and others prepared resin-supported ammonium salt 17a by reaction of crosslinked chloromethylated polystyrene (Merrifield resin) and employed it as a chiral phase-transfer catalyst for the alkylation of glycine isopropyl ester-derived Schiff base 2b [23]. Optimization of the reaction parameters for the benzylation led to the formation of 3b in 90% yield with 90% ee (Scheme 2C.8). Cahard, Plaquevent, and others suc-

2C.3. ALKYLATION 99

O Ph2C N

O

Catalyst Ot-Bu + PhCH2Br

2a

Ph2C N

50% KOH aq Toluene, 0°C

Ot-Bu

H 3a

Maruoka R

Ar Ar

R

R

– Br + N

Ph

R

– Br + N

R

Ar (S,S)-10 [14] (Ar = 3,5-Ph2-C6H3): (1 mol %): 88%, 96% ee R2

R1

R2

R1

R R

Ar

R (S,S)-11a [15] (R = 3,5-Ph2-C6H3) (1 mol %): 87%, 97% ee (S,S)-11b [16] (R = SiMe2Oct) (1 mol %): 96%, 99% ee

– Br + N

Ar (S)-12 [17] (R1 = 3,5-Ph2-C6H3, R2 = Ph) (1 mol %): 81%, 95% ee R

Ar – Br + N

N

Ar

Ar

R

Ar

– Br + N

R R (R,R)-14a [19] (R = H) (1 mol %): 94%, 65% ee (S) (R,R)-14b [19] (R = CPhMe2) (1 mol %): 96%, 94% ee (S)

Ar N + – Br Ar

N Ar

(S)-13a [18] (Ar = H) (3 mol %): 76%, 63% ee (S) (S)-13b (Ar = 3,4,5-F3-C6H2) (3 mol %): 65%, 95% ee

Lygo

CF3 – Br

OMe t-Bu

CF3 + N H CF3

t-Bu OMe CF3

Scheme 2C.5.

15 [20] (1 mol %) 15 M KOH aq Toluene 0°C RX = PhCH2Br 89%, 97% ee


(R,R)-1d 18-crown-6 (0.05 mol % each)

O Ph2C N

+ PhCH2Br

Ot-Bu 2a Ar

50% KOH aq Toluene, 0°C, 3 h

– Br + N

O O

O

O

O Ph2C N

Ot-Bu H Ph 3a 90%, 98% ee 4% (w/o 18-crown-6)

O O

Ar (R,R)-5d (Ar = 3,5-Ph2-C6H3)

18-crown-6 Scheme 2C.6.

(S)-16 (0.01–0.05 mol %)

O Ph2C N

Ot-Bu

+

RBr

Ar

Ot-Bu H R 3 81–98% yields >97% ee

50% KOH aq Toluene 0°C, 2–64 h

2a – Br

F

+ Bu N Bu

O Ph2C N

F

Ar =

F (S)-16

Ar

Scheme 2C.7.

Catalyst (10 mol %)

O Ph2C N

OR 2b (R = i-Pr) 2a (R = t-Bu)

+

PhCH2Br

– Cl

N+

H

OH

OR H Ph 3b (R = i-Pr) 3a (R = t-Bu)

NaOH aq or CsOH•H2O Toluene

– Cl H

O Ph2C N

N

+

17a: 90%, 90% ee (3b) 17b: 67%, 94% ee (3b)

O N

N

17b

17a

Scheme 2C.8.

2C.3. ALKYLATION 101

ceeded in improving the enantioselectivity by attaching Merrifield resin on the hydroxy moiety of cinchonidine-derived catalyst possessing the 9-anthracenylmethyl group on nitrogen (17b) [24]. Itsuno and others reported a new type of immobilization method onto a polymer through ionic bond to sulfonate groups. Polymer-supported chiral quaternary ammonium salts 18a and 18b were easily prepared by reaction of the sulfonated polymer with a corresponding chiral ammonium salt. The polymeric catalysts could be applied to alkylation of 2a and reused without loss of reactivity and selectivity (Scheme 2C.9) [25].

O Ph2C N

Ot-Bu + PhCH2Br 2a

O

Catalyst

Ph2C N *

50% KOH aq Toluene, 0°C

H 3a

Ot-Bu Ph

18a (10 mol %): 73%, 95% ee (S) 18b (1 mol %): 84%, 98% ee (R)

R4N

+

– SO3 Ar

H

N

+

+

+ Bu N Bu

or

R4N = OH N

Ar 18b (Ar = 3,4,5-F3-C6H2)

18a

Scheme 2C.9.

A recyclable fluorous chiral phase-transfer catalyst 19 has been developed in our group and its high chiral efficiency and reusability have been demonstrated in the asymmetric alkylation of 2a. After the reaction, 19 could be easily recovered by the simple extraction with FC-72 (perfluorohexanes) as a fluorous solvent and could be used for the next run without any loss of reactivity and selectivity (Scheme 2C.10) [26].

2C.3.2. Asymmetric Synthesis of α,α-Dialkyl-α-Amino Acids Nonproteinogenic, chiral α,α-dialkyl-α-amino acids possessing stereochemically stable quaternary carbon centers have been significant synthetic targets not only because they are often effective enzyme inhibitors but also they are indispensable for the elucidation of enzymatic mechanisms. Accordingly, numerous studies have been conducted to develop truly efficient methods for their preparation [27], and phase-transfer catalysis has made unique contributions.


O Ph2C N

Ot-Bu

+ PhCH2Br

(R,R)-19 (3 mol %) 50% KOH aq Toluene 0°C, 96 h

2a Si

Si

– Br

Ot-Bu

H

Ph

3a

Si

Si

Reuse of 19

82% 90% ee 79% 92% ee

+ N

Si

O Ph2C N

Reuse of 19

81% 92% ee

Si Si Si (R,R)-19 [Si = SiMe2(CH2CH2C8F17)]

Scheme 2C.10.

O 1) CH2=CHCH2Br H2N O Ar

N

(S,S)-5e Ot-Bu (1 mol %)

20 (Ar =4-Cl-C6H4) Ar

2) PhCH2Br 3) 10% citric acid

Ot-Bu Ph

21 80%, 98% ee (R)

CsOH·H2O 1) PhCH Br 2 Toluene 2) CH2=CHCH2Br H N 2 –10~0°C 3) 10% citric acid Ph

O Ot-Bu

21 74%, 92% ee (S)

– Br + N

Ar (S,S)-5e (Ar = 3,4,5-F3-C6H2) Scheme 2C.11.

Since the aldimine Schiff base 20 can be readily prepared from glycine, direct stereoselective introduction of two different side chains to 20 by appropriate chiral phasetransfer catalysis would provide an attractive yet powerful strategy for the asymmetric synthesis of structurally diverse α,α-dialkyl-α-amino acids. This possibility of the onepot asymmetric double alkylation has been realized by using N-spiro chiral quaternary ammonium bromide 5e. Initial treatment of the toluene solution of 20 and (S,S)-5e (1 mol %) with allyl bromide (1 equiv) and CsOH•H2O at −10°C and the subsequent reaction with benzyl bromide (1.2 equiv) at 0°C resulted in the formation of the double alkylation product 21 in 80% yield with 98% ee after hydrolysis. Notably, in the double alkylation of 20 by the addition of the halides in a reverse order, the absolute configuration of the product 21 was confirmed to be opposite (Scheme 2C.11) [28].

2C.3. ALKYLATION 103

Since the stereochemistry of the newly created quaternary carbon center was determined in the second alkylation process, this method should be applicable to the asymmetric alkylation of the aldimine Schiff base 22 derived from the corresponding α-amino acids. Several groups pursued this approach, and the results are summarized in Scheme 2C.12.

O Ar

Catalyst H3O+ Ot-Bu + PhCH2Br Conditions

N

O H2N *

N N

+

H

– Br H

– Cl

1b (10 mol %) Ar = 4-Cl-C6H4 K2CO3/KOH aq CH2Cl2 rt 80%, 44% ee (R)

H

N

F F

O N

F 6a Ar

N

N

– 6a (10 mol %) 2BF4 Ar = 2-Np RbOH Me O Toluene –35°C t-Bu O 91%, 95% ee (S)

Me

4-MeO-C6H4 N+ 4-MeO-C6H4 4-MeO-C6H4 N+

Park, Jew, and others [31]

+ N

Ar (S,S)-5e (Ar = 3,4,5-F3-C6H2)

5e (1 mol %) Ar = 4-Cl-C6H4 CsOH·H2O Toluene 0°C 85%, 98% ee (R)

6c (10 mol %) Ar = 4-Cl-C6H4 K2CO3/KOH aq Toluene rt 95%, 87% ee (S) Lygo and others [30]

6c

Me

– Br

+

OH

O'Donnell and Wu [29]

1b

+

Ph 23

– Cl

OH

Ot-Bu

Me

Me 22

4-MeO-C6H4 8b Ar

8a (10 mol %) Ar = 4-Cl-C6H4 CsOH·H2O Toluene-CH2Cl2 –70°C 83%, 89% ee (R) Shibasaki and others [12b]

16 (0.05 mol %) Ar = 4-Cl-C6H4 + Bu CsOH·H2O Toluene N Bu 0°C 63%, 98% ee (R) – Br

Ar Maruoka and others [22] Maruoka and others [28] (S)-16 (Ar = 3,4,5-F3-C6H2)

Scheme 2C.12.

2C.3.3. Asymmetric Alkylation of β-Keto Esters Asymmetric alkylation of β-keto ester under phase-transfer condition can be a unique tool to construct an all-carbon chiral quaternary carbon center easily. Manabe designed chiral phosphonium salts of type 26 that have multiple hydrogen-bonding sites [32]. The utility of 26 was demonstrated in the asymmetric alkylation of β-keto ester 24 (Scheme 2C.13). Although the reactivity and selectivity need to be improved, this study advances in the development of a new chiral onium salt. N-benzyl cinchoninium bromide 1d is applied to the reaction and gives the benzylated compound 25 in an excellent chemical yield with 46% ee [33]. Efficient, highly enantioselective construction of quaternary stereocenter on β-keto esters under phase-transfer conditions has been achieved using N-spiro chiral quaternary ammoniumu bromide 5f as catalyst [34]. This system has a broad generality in terms of the structure of β-keto esters and alkyl halides.


O

O CO2t-Bu

Catalyst +

PhCH2Br

CO2t-Bu

*

Conditions

Ph 25

24 Ph O

OH

HO

NH

Ph

26 (1 mol %) K2CO3 O Toluene 0°C 44%, 50% ee (R)

HN

– Br + PPh

1d (5 mol %) K2CO3 Toluene rt 97%, 46% ee (S)

– Br

OH N+ H

N

26

1d

3

Ar

– Br

CF3

+ N

Ar = CF3

5f (1 mol %) CsOH·H2O Toluene –40°C 94%, 97% ee (S)

Ar (S,S)-5f Scheme 2C.13.

O CO2Et + ArF 27 O2N

Ar

O

4 (15 mol %)

Ar

CsOH Toluene-CHCl3 (9:1) –20°C NO2

Ar =

CO2Et 28

N+ OR

N

CO2Et 29

4c: 90%, 28/29 = 1.0:1 racemic for 28 4d: 89%, 28/29 = 16:1 80% ee for 28

– X H

O

+

4c (R = Bn, X = Br) 4d (R = Bz, X = Cl)

Scheme 2C.14.

Jørgensen and others developed the catalytic, regio- and enantioselective nucleophilic aromatic substitution reaction between activated aromatic compounds and 1,3-dicarbonyl compounds under phase-transfer conditions. Interestingly, examination on the addition of 2,4-dinitrofluorobenzene to 2-carboethoxycyclopentanone 27 revealed that the use of O-benzoylated cinchonidine-derived catalyst 4d was crucial for obtaining C-arylated product 28 predominantly with high enantioselectivity (Scheme 2C.14) [35].

2C.5. ALDOL AND MANNICH REACTIONS 105

2C.4. MICHAEL ADDITION The asymmetric Michael addition of active methylene or methine compounds to electron-deficient olefins, particularly α,β-unsaturated carbonyl compounds, represents a fundamental yet useful approach to construct functionalized carbon frameworks. Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized α-alkyl α-amino acids. These results are summarized in Scheme 2C.15.

O

O Ph2C N

Ot-Bu 2a – Br

H

N O

N 4b – 2BF4 Pr

O

Pr

O

+

X

+ O

Catalyst

Ph2C N

Conditions

Ot-Bu

H COX

4b (10 mol %) X = OMe CsOH·H2O CH2Cl2 –78°C 85%, 95% ee

NEt3 + O Ar O

– 2Br Ar

+ NEt3 Corey and others [36] 30 (Ar = 4-CF3-C6H4)

– 4-Me-C6H4 8c (5 mol %) Br X = OBn RO OR + Cs2CO3 4-Me-C6H4 N 4-Me-C6H4 PhCl RO OR –30°C N+ 84%, 81% ee Me 4-Me-C6H4 31 (R = 4-CF3-C6H4CH2) 8c Shibasaki and others [12] Me

N+

30 (1 mol %) X = Me Cs2CO3 PhCl –30°C 100%, 75% ee Arai and others [37]

31 (10 mol %) X = Ot-Bu CsOH·H2O t-BuOMe –60°C 73%, 77% ee Arai and others [38]

Scheme 2C.15.

Michael additions of malonates to chalcone derivatives have also been developed (Scheme 2C.16).

2C.5. ALDOL AND MANNICH REACTIONS Although phase-transfer-catalyzed, enantioselective direct aldol reactions of glycine donors with aldehyde acceptors could provide an ideal method for the simultaneous construction of the primary structure and stereochemical integrity of β-hydroxy-α-amino acids, extremely important chiral units, especially from the pharmaceutical viewpoint, the examples reported to date are very limited. We developed an efficient, highly diastereo- and enantioselective direct aldol reaction of 2a with a wide range of aliphatic aldehydes under mild phase-transfer conditions employing N-spiro chiral quaternary ammonium salt 5g as a key catalyst, leading to the establishment of general and practical


COOR

O

+

Ph

Ph

COOR Conditions

N

4e (10 mol %) R = Bn t-Bu K2CO3 Toluene rt OMe 91%, 70% ee

+

O N t-Bu

Ph COOR

Ph

COOR – Br OH

Ar Ar

– Br H

O

Catalyst

Ar 32 (3 mol %) R = Et K2CO3 Toluene –20°C 99%, 90% ee

+ N OH

Kim and others [39] Ar Ar Ar 32 (Ar = 3,5-Ph2-C6H3)

4e

Maruoka and others [40]

Scheme 2C.16.

O Ph2C N

Ot-Bu 2a

Ar

– Br + N

(R,R)-5g (2 mol %)

O

+ R

1 N HCl

OH

O

R Ot-Bu THF 1% NaOH aq NH2 (15 mol %) anti-33 NH4Cl (10 mol %) (anti/syn = 96:4) Toluene, 0°C F3C CF3 R = Ph(CH2)2 : 82%, 98% ee Me(CH2)4 : 79%, 97% ee i-Pr3SiOCH2 : 73%, 98% ee Me : 54%, 99% ee Ar = c-Hex : 83%, 98% ee CF3 (CPME as solvent) H

Ar (R,R)-5g CF3 Scheme 2C.17.

chemical process for the synthesis of optically active anti-β-hydroxy-α-amino esters 33 (Scheme 2C.17) [41]. Phase-transfer-catalyzed direct Mannich reaction of glycine Schiff base 2a with αimino ester 34 was achieved with high enantioselectivity by the utilization of N-spiro chiral quaternary ammonium bromide 5e as catalyst (Scheme 2C.18) [42]. The more general and highly diastereoselective Mannich-type reaction was developed by Ohshima and Shibasaki. The original tartrate-derived diammonium salt 8 was modified by introducing an aromatic ring at the acetal side chains, and 4-fluorophenyl-substituted 8d was identified as an optimal catalyst for the reaction of 2a with various N-Boc imines 35 under solid (Cs2CO3)-liquid (fluorobenzene) phase-transfer conditions as exemplified in Scheme 2C.18 [43].

2C.6. EPOXIDATION AND AZIRIDINATION 107

O Ph2C N

PMPN OEt

Ot-Bu + H 2a

34

O Ph2C N

Ot-Bu 2a

17% NaOH aq Mesitylene –20°C, 6 h

O

NBoc

+

H

Ar 35

Ar

(R,R)-5e (2 mol %)

– Br + N

O 1 N HCl

PMP OEt

t-BuO

THF

NH2 O 88% (syn/anti = 82:18) 91% ee (syn isomer) NHBoc CO2t-Bu

8d (10 mol %)

Ar Cs2CO3 (2 equiv) N PhF/Pentane (4:1) CPh2 –45°C, 48 h 95% (syn/anti = 95:5) (Ar = 4-MeO-C6H4) 82% ee (syn isomer)

4-F-C6H4

– 2BF4

Me

O

4-F-C6H4

4-Me-C6H4 N+ 4-Me-C6H4 4-Me-C6H4

O Ar (R,R)-5e (Ar = 3,4,5-F3-C6H2)

HN

N+ Me

4-Me-C6H4

8d Scheme 2C.18.

Palomo and others reported that N-benzyl quininium chloride 37 acted as a promising catalyst for the asymmetric aza-Henry reaction under solid–liquid phase-transfer conditions utilizing cesium hydroxide as a base. α-Amido sulfones 36 were used to generate reactive N-carbamoyl imines in situ and succeeded in aza-Henry reactions of not only aromatic imines but also aliphatic imines (Scheme 2C.19). The unprotected hydroxyl group on N-benzyl quininium chloride 37 was found to be crucial to obtain high enantioselectivities [44]. At the same time, Herrera, Bernardi, and others reported the same asymmetric aza-Henry reaction catalyzed by N-benzylquininium chloride 37 separately. In their report, freshly ground potassium hydroxide was utilized as a base (Scheme 2C.19) [45].

2C.6. EPOXIDATION AND AZIRIDINATION The catalytic asymmetric epoxidation of electron-deficient olefins, particularly α,βunsaturated ketones, has been the subject of numerous investigations and a number of useful methodologies have been elaborated. Among these, the method utilizing chiral phase-transfer catalysis occupies a unique place featuring its practical advantages, and it allows highly enantioselective epoxidation of trans-α,β-unsaturated ketones, particularly chalcone (Scheme 2C.20). Chiral aziridines have been used as chiral auxiliaries, chiral ligands for transition metals, and chiral building blocks for preparation of biologically active species such as


37 (10~12 mol %)

NHBoc + CH3NO2

R

SO2p-Tol 36 (R = alkyl, aryl)

N

R 80~98% ee

CsOH·H2O (130 mol %) or KOH (5 equiv) Toluene _ –40~–50°C Cl

OMe H

NHBoc NO2

+

OH N

37 Scheme 2C.19.

O Ph

Ph

N+ N

H 1e

I

O Ph

Ph

Conditions

1e (10 mol %) 30% H2O2 aq LiOH Bu2O 4°C 97%, 84% ee

– Br

OH

O

Catalyst

– Br H

N

6e (10 mol %) KOCl aq Toluene –40°C 96%, 93% ee

+

O N

Shioiri and others [46]

Corey and Zhang [47]

Ph 6e

– 2Br

OMe

N+ F

+N

OH

HO

H

H

N 38

38 (1 mol %) OMe 30% H2O2 aq 50% KOH aq i-Pr2O, Span 20 rt 95%, >99% ee N Park, Jew, and others [48] – Br OH

Ar Ar 39 (5 mol %) 8% NaOCl aq Toluene 0°C~rt 99%, –93% ee

N O Me

N H

+ N O H –

BF4

Me

Murphy and others [49]

39

Ar

+ N

32 (3 mol %) 13% NaOCl aq Toluene 0°C 99%, 96% ee

OH

Maruoka and others [50]

Ar Ar Ar 32 (Ar = 3,5-Ph2-C6H3) C8H17 + C8H17 N O I

–

O

O O

O 40

40 (10 mol %) 30% H2O2 aq 2 M KOH aq Toluene 0°C 85%, –70% ee Hori and others [51]

Scheme 2C.20.

2C.8. AMINATION 109

amino acids, β-lactams, and alkaloids. Murugan and Siva developed a new procedure for asymmetric aziridination reactions to achieve excellent level of enantioselectivity using new chiral phase-transfer catalysts 1f and 4f derived from cinchonine and cinchonidine, respectively (Scheme 2C.21) [52].

O OH

t-Bu

N Ph

CO2t-Bu

+

Me

O 2S

* CO2t-Bu

N 20% NaOH aq Ph Toluene 1f : 79%, 94% ee (S) 4f : 56%, 88% ee (R)

H O N

N

1f or 4f (10 mol %)

+

N

_

+

Br Me

_ Br

O Me

H

N

O2S

HO CHO

HO 1f

CHO

4f Me

Scheme 2C.21.

2C.7. STRECKER REACTION The catalytic asymmetric cyanation of imines, Strecker reaction, represents one of the most direct and viable methods for the asymmetric synthesis of α-amino acids and their derivatives. Numerous recent efforts in this field have resulted in the establishment of highly efficient and general protocols, although the use of either alkylmetal cyanide or anhydrous hydrogen cyanide generally at low temperature is inevitable. In this regard, we disclose the first example of phase-transfer-catalyzed, highly enantioselective Strecker reaction of aldimines using aqueous KCN based on the molecular design of chiral quaternary ammonium salts 41 bearing the tetranaphthyl backbone as a remarkably efficient catalyst (Scheme 2C.22) [53].

2C.8. AMINATION We developed catalytic asymmetric amination of β-keto esters catalyzed by a novel quaternary tetraalkylphosphonium bromide 42 (Scheme 2C.23) [54]. The reaction offers valuable method for preparing a key intermediate for asymmetric synthesis of aldose reductase inhibitor AS-3201 (Ranirestat) [55]. This is the first successful use of chiral quaternary tetraalkylphosphonium salt as phase-transfer catalyst in asymmetric synthesis with high enantioselectivity.


N R

41 (1 mol %) SO2Mes 2 M KCN aq (1.5 equiv) Toluene, 0°C 2–8 h Ar R = c-Hex

H

I Me Ar

SO2Mes CN

R

c-Oct (CH3)2CH PhCH2CH2 t-Bu

Ar Me N

HN

: 89%, 95% ee : 88%, 97% ee : 85%, 93% ee : 81%, 90% ee : 94%, 94% ee

Ar 41 (Ar = 4-CF3-C6H4) Scheme 2C.22.

CO2t-Bu + Boc

N

N

Boc

O Boc N

CO2t-Bu +

Boc

N

N

– Br + Bu P Bu

K2HPO4 Toluene –20°C, 14 h (S)-42 (3 mol %)

Boc

O Ar

O

(S)-42 (3 mol %)

O

K2HPO4 Toluene –20°C, 40 h

CO2t-Bu N NH Boc Boc 99%, 91% ee O Boc N O

CO2t-Bu N NH Boc Boc

99%, 92% ee

CF3 Ar = CF3

Ar

(S)-42 Scheme 2C.23.

2C.9. ION PAIR CATALYSTS 2C.9.1. Ammonium Fluorides Quaternary ammonium fluorides, particularly tetraalkylammonium fluorides, have been widely recognized as a convenient, organic-soluble source of naked fluoride ion. Their utility in modern organic synthesis has been well documented on numerous occasions taking advantage of either the nucleophilic affinity of fluoride ion to a silicon atom or its eminent basicity in aprotic solvents [56]. The former property enables the fluoridemediated generation of nucleophiles from organosilicon compounds, and the latter

2C.9. ION PAIR CATALYSTS 111

allows the direct generation of nucleophiles through a deprotonation process, both of which have been utilized for the subsequent selective bond-forming reactions under mild conditions. These synthetically useful metal-free methods have implications for the development of asymmetric versions based on the use of chiral, nonracemic quaternary ammonium fluorides, giving a unique platform for establishing otherwise difficult asymmetric transformations [57]. Shioiri and others investigated the preparation of N-benzylcinchonium fluoride 1g from the corresponding bromide 1d, and the catalytic activity as well as chiral efficiency of 1g was then evaluated in the asymmetric aldol reaction of enol silyl ether of 2-methyl1-tetralone with benzaldehyde (Scheme 2C.24) [58].

OSiMe3 PhCHO

O 1g (12 mol %) 1 N HCl

+

THF – X

OH N+ N

OH Ph

MeOH 74% (erythro/threo = 7:3) 70% ee (erythro isomer)

H

1d (X = Br), 1g (X = F) Scheme 2C.24.

Corey and others prepared the cinchonidine-derived bifluoride 4g. The catalytic activity and chiral efficiency of 4g have been demonstrated by the development of a Mukaiyama-type aldol reaction of ketene silyl acetal with aldehydes under mild conditions (Scheme 2C.25) [59].

O

Ot-Bu

Ph H

+

N

OSiMe3 Hexane-CH2Cl2 –78°C, 7 h – HF2

Ph

H

4g (10 mol %) 0.5 M citric acid

+ N O

N

Ph 4g Scheme 2C.25.

OH CO2t-Bu NH2 70% (syn/anti = 6:1) 95% ee (syn isomer)


We have succeeded in developing an asymmetric nitroaldol reaction of silyl nitronates with aldehydes promoted by ammonium fluorides by using a designer chiral quaternary ammonium bifluoride of type 5h as catalyst [60]. An asymmetric Michael addition of silyl nitronates with α,β-unsaturated aldehydes promoted by 5i was also developed (Scheme 2C.26) [61].

–

OSiMe3 +N + O

O H

OSiMe3 +N + Ph – O

(S,S)-5h (2 mol %) 1 N HCl Ph

CHO

THF –98°C ~ –78°C 3h

NO2 Ph

0°C

OH

92% (anti/syn = 92:8) 95% ee (anti isomer) Ph

(R,R)-5i (2 mol %) 1 N HCl Toluene –78°C, 1 h

0 °C

CHO NO2

99% (syn/anti = 81:19) 97% ee (syn isomer) F 3C Ar

CF3

– HF2 + N

Ar

t-Bu Ar =

CF3 5h

(S,S)-5

t-Bu 5i

CF3 Scheme 2C.26.

2C.9.2. Ammonium Phenoxides Mukaiyama and others prepared cinchona alkaloid-derived chiral ammonium phenoxide 4h and used it as an efficient organocatalyst for the tandem Michael addition and lactonization between α,β-unsaturated ketones and ketene silyl acetals (Scheme 2C.27) [62]. An asymmetric trifluoromethylation of ketones catalyzed by chiral ammonium phenoxide 4i was also developed (Scheme 2C.27) [63].

2C.9.3. Ammonium Betaines Ooi and others developed novel chiral quaternary ammonium betaines of type 43 and demonstrated its potential in a direct Mannich-type reaction (Scheme 2C.28). Chiral ammonium betaine 43 promoted the reaction efficiently and gave the desired product with excellent enantioselectivities [64].

2C.9. ION PAIR CATALYSTS 113

OSiMe3

O

+

OPh

Ph

Ph

THF –78° C, 1 h

O O 2N

+ Me3SiCF3

Ph

4h (5 mol %)

O

Ph 98%, 90% ee F3C OSiMe3

4i (10 mol %)

O2N

Toluene-CH2Cl2 (7:3) –78° C, 1 h 98%, 87% ee

– OPh•HOPh

F 3C – OPh

+ N

H

H

O

+ N

CF3

OH

N

N

F 3C 4h

CF3

4i

CF3 F3C

Scheme 2C.27.

N Ph

Boc

Me +

H

CO2t-Bu

43 (1 mol %) Toluene 0° C, 8 h

NO2

HN Ph

Boc CO2t-Bu

Me NO2 97% (syn/anti = 3.9:1) 99% ee (syn isomer)

ClCl + – OH N O Me Me Ph

43

Ph Scheme 2C.28.

2C.9.4. Phosphonium Carboxylates Ooi and others also developed novel chiral tetraaminophosphonium carboxylate 44. Chiral phosphonium carboxylate catalyst 44 could be applied to the highly enantioselective direct Mannich-type reaction of azlactones with N-sulfonyl imines (Scheme 2C.29) [65].


O

SO2Ar2

N

Ph O

N

+ Ph

Ar2O2S THF –50°C, 20 h

H

Ar1 Ar1 = 3,4,5-(MeO)3-C6H2 Ar2 = 2,5-xylyl

Ph

Ph

O Ph

N Ar1

99% (syn/anti = 7.1:1) 97% ee (syn isomer) –

H Ph

O

NH

44 (2 mol %)

OCOt-Bu•t-BuCO2H

Me Me H N + N P N Ph N H H Ph 44

Scheme 2C.29.

2C.10. CONCLUSION The development of various types of chiral phase-transfer and ion pair catalysts largely relies on the molecular design of both natural product-derived and purely synthetic chiral quaternary onium salts, which often delivers not only higher reactivity and stereoselectivity but also new synthetic opportunities, expanding the applicability of asymmetric catalysis in modern organic synthesis. Continuous efforts should be made toward understanding the relationship between the structure of the catalyst and its activity and stereocontrolling ability. Systematic accumulation of such knowledge will allow even better catalyst design for selective chemical synthesis with reliability and practical elegance, in anticipation of the forthcoming paradigm shift in worldwide production of highly valuable substances in this century.

REFERENCES 1. (a) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed. Weinheim: VCH, 1993. (b) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis. New York: Chapman & Hall, 1994. (c) Sasson, Y.; Neumann, R. (Eds.). Handbook of Phase-Transfer Catalysis. London: Blackie Academic & Professional, 1997. (d) Halpern, M. E. (Ed.). Phase-Transfer Catalysis. ACS Symposium Series 659. Washington, DC: American Chemical Society, 1997. 2. (a) Shioiri, T. In Handbook of Phase-Transfer Catalysis (Eds. Sasson, Y.; Neumann, R.). London: Blackie Academic & Professional, 1997; Chapter 14, p. 462. (b) O’Donnell, M. J. Phases—The Sachem Phase Transfer Catalysis Review 1998, Issue 4, 5. (c) O’Donnell, M. J. Phases—The Sachem Phase Transfer Catalysis Review 1999, Issue 5, 5. (d) Nelson, A. Angew. Chem. Int. Ed. Engl. 1999, 38, 1583. (e) Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry (Eds. Vögtle, F.; Stoddart, J. F.; Shibasaki, M.). Weinheim: Wiley-VCH, 2000; p. 123. (f) O’Donnell, M. J. In Catalytic Asymmetric Syntheses, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; Chapter 10, p. 727. (g) O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (h) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (i) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (j) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518. (k) Vachon, J.; Lacour, J. Chimia 2006, 60, 266. (l) Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed. Engl.

REFERENCES 115

2007, 46, 4222. (m) Ooi, T.; Maruoka, K. Aldrichmica Acta 2007, 40, 77. (n) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656. (o) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679. (p) Maruoka, K. Asymmetric Phase Transfer Catalysis. Weinheim: Wiley-VCH, 2008. 3. (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446. (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745. 4. (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. (b) Lipkowitz, K. B.; Cavanaugh, M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56, 5181. 5. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595. (b) Lygo, B.; Crosby, J.; Lowdon, T. R.; Wainwright, P. G. Tetrahedron 2001, 57, 2391. (c) Lygo, B.; Crosby, J.; Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G. Tetrahedron 2001, 57, 2403. 6. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. 7. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. (b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. 8. Jew, S.-S.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-G. Org. Lett. 2002, 4, 4245. 9. Yoo, M.-S.; Jeong, B.-S.; Lee, J.-H.; Park, H.-G.; Jew, S.-S. Org. Lett. 2005, 7, 1129. 10. (a) Jew, S.-S.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-G. Chem. Commun. 2001, 1244. (b) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, B.-S.; Kim, M. G.; Jew, S.-S. Tetrahedron Lett. 2003, 44, 3497. 11. Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Park, M.-K.; Huh, H.; Jew, S.-S. Tetrahedron Lett. 2001, 42, 4645. 12. (a) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539. (b) Ohshima, T.; Shibuguchi, T.; Fukuta, Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743. 13. Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem. Int. Ed. Engl. 2002, 41, 2832. 14. Hashimoto, T.; Maruoka, K. Tetrahedron Lett. 2003, 44, 3313. 15. Hashimoto, T.; Tanaka, Y.; Maruoka, K. Tetrahedron Asymmetry 2003, 14, 1599. 16. Shirakawa, S.; Ueda, M.; Tanaka, Y.; Hashimoto, T.; Maruoka, K. Chem. Asian J. 2007, 2, 1276. 17. (a) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2002, 41, 1551. (b) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Tetrahedron 2006, 62, 11425. 18. Kano, T.; Konishi, S.; Shirakawa, S.; Maruoka, K. Tetrahedron Asymmetry 2004, 15, 1243. 19. Ooi, T.; Kubota, Y.; Maruoka, K. Synlett 2003, 1931. 20. (a) Lygo, B.; Allbutt, B.; James, S. R. Tetrahedron Lett. 2003, 44, 5629. (b) Lygo, B.; Allbutt, B. Synlett 2004, 326. 21. Shirakawa, S.; Yamamoto, K.; Kitamura, M.; Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2005, 44, 625. 22. (a) Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2005, 44, 1549. (b) Kitamura, M.; Arimura, Y.; Shirakawa, S.; Maruoka, K. Tetrahedron Lett. 2008, 49, 2026. (c) Kitamura, M.; Shirakawa, S.; Arimura, Y.; Wang, X.; Maruoka, K. Chem. Asian J. 2008, 3, 1702. 23. (a) Chinchilla, R.; Mazón, P.; Nájera, C. Tetrahedron Asymmetry 2000, 11, 3277. (b) Chinchilla, R.; Mazón, P.; Nájera, C. Adv. Synth. Catal. 2004, 346, 1186. 24. Thierry, B.; Perrard, T.; Audouard, C.; Plaquevent, J.-C.; Cahard, D. Synthesis 2001, 1742. 25. Arakawa, Y.; Haraguchi, N.; Itsuno, S. Angew. Chem. Int. Ed. Engl. 2008, 47, 8232. 26. Shirakawa, S.; Tanaka, Y.; Maruoka, K. Org. Lett. 2004, 6, 1429. 27. (a) Vogt, H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406. (b) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127. (c) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron Asymmetry 1998, 9, 3517. (d) Schöllkopf, U. Top. Curr. Chem. 1983, 109, 65. 28. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228. 29. O’Donnell, M. J.; Wu, S. Tetrahedron Asymmetry 1992, 3, 591.

116 ASYMMETRIC PHASE-TRANSFER AND ION PAIR CATALYSIS 30. Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671. 31. Jew, S.-S.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee, Y.-J.; Park, B.-S.; Kim, M. G.; Park, H.-G. J. Org. Chem. 2003, 68, 4514. 32. (a) Manabe, K. Tetrahedron Lett. 1998, 39, 5807. (b) Manabe, K. Tetrahedron 1998, 54, 14465. 33. Dehmlow, E. V.; Düttmann, S.; Neumann, B.; Stammler, H.-G. Eur. J. Org. Chem. 2002, 2087. 34. (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2003, 42, 3796. (b) Ooi, T.; Miki, T.; Maruoka, K. Org. Lett. 2005, 7, 191. (c) Ooi, T.; Miki, T.; Fukumoto, K.; Maruoka, K. Adv. Synth. Catal. 2006, 348, 1539. 35. (a) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670. (b) Kobbelgaard, S.; Bella, M.; Jørgensen, K. A. J. Org. Chem. 2006, 71, 4980. 36. (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347. (b) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097. 37. Arai, S.; Tokumaru, K.; Aoyama, T. Chem. Pharm. Bull. 2004, 52, 646. 38. (a) Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43, 9535. (b) Arai, S.; Takahashi, F.; Tsuji, R.; Nishida, A. Heterocycles 2006, 67, 495. 39. Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42, 6299. 40. Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005, 7, 3195. 41. (a) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2002, 41, 4542. (b) Ooi, T.; Kameda, M.; Taniguchi, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685. 42. Ooi, T.; Kameda, M.; Fujii, J.-I.; Maruoka, K. Org. Lett. 2004, 6, 2397. 43. Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 2005, 44, 4564. 44. Palomo, C.; Oiarbide, M.; Laso, A.; López, R. J. Am. Chem. Soc. 2005, 127, 17622. 45. Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem. Int. Ed. Engl. 2005, 44, 7975. 46. (a) Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39, 7563. (b) Arai, S.; Tsuge, H.; Oku, M.; Miura, M.; Shioiri, T. Tetrahedron 2002, 58, 1623. 47. Corey, E. J.; Zhang, F-Y. Org. Lett. 1999, 1, 1287. 48. Jew, S.-S.; Lee, J.-H.; Jeong, B.-S.; Yoo, M.-S.; Kim, M.-J.; Lee, Y.-J.; Lee, J.; Choi, S.-H.; Lee, K.; Lah, M. S.; Park, H.-G. Angew. Chem. Int. Ed. Engl. 2005, 44, 1383. 49. Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. W. R. Tetrahedron Lett. 2003, 44, 8677. 50. Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 6844. 51. Hori, K.; Tamura, M.; Tani, K.; Nishiwaki, N.; Ariga, M.; Tohda, Y. Tetrahedron Lett. 2006, 47, 3115. 52. Murugan, E.; Siva, A. Synthesis 2005, 2022. 53. (a) Ooi, T.; Uematsu, U.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2548. (b) Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.; Maruoka, K. Tetrahedron Lett. 2007, 48, 1337. 54. He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2008, 47, 9466. 55. (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342. (b) Mashiko, T.; Kumagai, N.; Shibasaki, M. Org. Lett. 2008, 10, 2725. 56. (a) Clark, J. H. Chem. Rev. 1980, 80, 429. (b) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181. 57. Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526. 58. Ando, A.; Miura, T.; Tatematsu, T.; Shioiri, T. Tetrahedron Lett. 1993, 34, 1507. 59. Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843. 60. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054.

REFERENCES 117

61. (a) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 9022. (b) Ooi, T.; Morimoto, K.; Doda, K.; Maruoka, K. Chem. Lett. 2004, 33, 824. 62. (a) Tozawa, T.; Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Asian J. 2007, 2, 123. (b) Nagao, H.; Yamane, Y.; Mukaiyama, T. Heterocycles 2007, 72, 553. 63. Nagao, H.; Yamane, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2007, 80, 2406. 64. Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878. 65. Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 14088.

3 CHIRAL LEWIS ACIDS AND BRØNSTED ACIDS IN ASYMMETRIC SYNTHESIS Hisashi Yamamoto and Cheol Hong Cheon Department of Chemistry, The University of Chicago, Chicago, IL

3.1. INTRODUCTION This chapter describes recent advances in chiral Lewis acid and Brønsted acid catalysis, especially combined acid systems involving the combination of Lewis acids and Brønsted acids [1]. The concept of combined acid systems has been useful in asymmetric synthesis for over 20 years because the inherent reactivity of combined acids will be enhanced by associative interaction, and will also provide a more organized structure, which is very important in asymmetric induction. Although we have already summarized examples of combined acid catalysis in 2005 [1], herein we will discuss the recent representative examples of such catalysis. Combined acids can be classified into Brønsted acid-assisted Lewis acid (BLA), Lewis acid-assisted Lewis acid (LLA), Lewis acid-assisted Brønsted acid (LBA), and Brønsted acid-assisted Brønsted acid (BBA). This chapter will cover the recent advances in the areas of chiral BLA, LLA, and LBA catalyses. However, BBA, which is often considered as a hydrogen-bonding catalyst, is not discussed since it is covered in the following chapter. In addition, chiral phosphoric acid catalysis is included here, because it has recently emerged as a novel chiral catalyst. In contrast to the related reviews, which are arranged by reaction class or electrophiles as organized elements, this chapter is arranged by catalyst class.

3.2. BLA CATALYSIS Since their first report in 2002 of Brønsted acid-assisted chiral oxazaborolidine-based Lewis acid (BLA) for enantioselective Diels–Alder (D-A) reactions by Corey and coworkers [2], they have demonstrated that these chiral BLAs are exceptionally powerful Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 119

120 CHIRAL LEWIS ACIDS AND BRØNSTED ACIDS IN ASYMMETRIC SYNTHESIS

and versatile chiral Lewis acids for a wide range of catalytic asymmetric D-A reactions [2–8]. These chiral BLAs can be easily prepared by simple protonation of the chiral proline-derived oxazaborolidines with very strong protic acids, such as trifluoromethanesulfonic acid (TfOH) and bis(trifluoromethane)sulfonimide (Tf2NH) (Scheme 3.1) [2,4]. H Ar Ar

H Ar Ar N

B

O

BLA 1a: Ar = Ph, X = TfO BLA 1b: Ar = 3,5-dimethylphenyl X = TfO BLA 2a: Ar = Ph, X = Tf2N BLA 2b: Ar = 3,5-dimethylphenyl X = Tf2N

O N B H

HX X

Scheme 3.1. Generation of Corey’s BLAs from the oxazaborolidine with strong Brønsted acid.

A series of reports have shown that these chiral BLAs effectively catalyze a broad range of D-A reactions. This system can activate various electrophiles, including αsubstituted α,β-unsaturated enals, α,β-unsaturated ketones, esters, carboxylic acids, lactones, and various quinones toward [4 + 2] cycloaddition with various dienes [3,4]. The absolute stereochemical outcome of the D-A reactions can be successfully predicted on the basis of the pretransition state assemblies shown in Figure 3.1 [9]. Interestingly, the face selectivities of α,β-unsaturated esters, ketones, and acrylic acids are opposite to α-substituted α,β-unsaturated enals (Fig. 3.1).

Me

+

CHO

CHO

BLA 1b (6 mol %) CH2Cl2, –95°C

Me 97% yield 91:9 exo selective 96% ee

Scheme 3.2.

Me H X

Me

NB O

H

H

O

X R

R

TS 1 For α-substituted α,β-unsaturated enals

N B O H O

R

R TS 2 For α,β-unsaturated ketones, esters, carboxylic acids, lactones, and quinones

Figure 3.1. Proposed pretransition state assemblies.

3.2. BLA CATALYSIS 121

Ryu and Corey later found that different BLAs 2a and 2b, derived from protonation with triflimide (Tf2NH), have better stabilities than BLAs 1a and 1b [4]. It is interesting that simple change of the counteranion from triflate ( CF3 SO3− ) to triflimide ((CF3SO2)2N−) had a remarkably beneficial effect on catalyst stability, with no loss of potency. These new Lewis acids 2a and 2b are highly effective catalysts for a wide variety of enantioselective D-A reactions that were previously beyond the reach of synthetic chemists (Scheme 3.3). The D-A reactions of unsymmetrical benzoquinones are particularly challenging due to their multiple requirements of high enantioselectivity, orientational selectivity, and site selectivity. The Corey group examined the D-A reactions of various unsymmetrical O +

OEt

H

BLA 2a (20 mol %)

O OEt OEt

Toluene, –60°C

EtO

H

O

O 99% yield, >99% ee

O +

H

BLA 2a (20 mol %) OCH2CF3

O OEt

Toluene, –60°C

98:2 endo selective 97% yield, >99% ee H

O

O

BLA 2b (20 mol %) +

Neat, –20°C H 96% yield, 85% ee O H

BLA 2a (20 mol %) +

O

CH2Cl2, –95°C H

O

O 99% yield, >99% ee

O

H

O

H

O

BLA 2a (20 mol %) + CH2Cl2, –95°C O

+ H

H O

a 99% yield, >99% ee (a-isomer : b-isomer = 62:38)

Scheme 3.3.

O

b 93% ee


quinones with 2-triisopropylsilyloxy-1,3-butadiene catalyzed by chiral BLA 2a [6]. Remarkably, BLA 2a provided D-A adducts as a single regioisomer with excellent yields and enantioselectivities. From these results, they formulated the selection rules for D-A reactions of unsymmetrical 1,4-benzoquniones: (i) As long as an α-olefinic hydrogen is present, catalyst coordination will predominantly take place at the oxygen lone pair on the C–H side. (ii) When a double bond of the quinine bears two hydrogens, catalyst coordination will be formed with the more basic of the two 1,4-quinone oxygens (Scheme 3.4). It was reported that BLA 2a catalyzed the intramolecular D-A reaction of triene aldehydes and esters with excellent asymmetric induction to afford the corresponding trans-fused bicyclic structures (Scheme 3.5) [5]. Remarkably, the synthetic utility of Corey’s chiral BLAs is quite obvious from many successful applications to other carbon–carbon bond-forming reactions [10–14].

O

H

H TIPSO

Br

Me

CH2Cl2, –78°C

Me

TIPSO

Me Me O 96% yield, 97% ee

b

a O

H

H TIPSO

H

Me

CH2Cl2, –78°C

OMe

OMe Me O 84% yield, 90% ee

b

a

H H

H H

O H

BLA 2a (20 mol %) CH2Cl2, –78°C

OMe c

H

TIPSO

O

TIPSO

O

BLA 2a (20 mol %)

O Most basic

Br

BLA 2a (20 mol %)

O More basic

O

O

TIPSO

OMe O 95% yield, 91% ee H

Me H Tf2N Less reactive dienophile

N B O H O

H More reactive dienophile

H R1

O

Scheme 3.4.


CHO H

OHC BLA 2a (20 mol %) CH2Cl2, –78°C

H 93% yield, 98% de, 90% ee OHC

F3CH2CO2C

H H

BLA 2a (20 mol %) Neat, 35°C

H 75% yield, 98% de, 93% ee

CO2Me H MeO2C

CO2Me H HCl

BLA 2a (20 mol %) CH2Cl2, –50°C

H OTBS

OTBS

O

H

93% yield, 99% de, 96% ee

Scheme 3.5.

+

Ph3P=O

O TMSCN

+ R

+ CH3

BLA 2b (10 mol %) Ph3P=O Toluene, 0°C

H

O R

Ph3P(OTMS)(N=C:)

TMSCN

TMSCN

BLA 1b (10 mol %) Ph3P=O Toluene, 0°C

TMSO H R

CN

91–98% yield 90–97% ee 7 examples H OTMS R

CN

73–95% yield 85–96% ee 6 examples

Scheme 3.6.

Highly enantioselective cyanosilylation of aldehydes and methyl ketones has been achieved by the Corey group [10,11]. It was found that enantioselectivities were enhanced by the addition of various phosphine oxides since a more reactive cyanide donor, R3P(OTMS)(N=C:), is generated in situ from the phosphine oxide and TMSCN. Further, it is quite interesting that the absolute stereochemical course of the reaction is predicted clearly by pretransition state complexes, which were used earlier to explain the excellent enantioselectivity in D-A reactions (Scheme 3.6).


A highly enantioselective [3 + 2] cycloaddition reaction of several benzoquinones with 2,3-dihydrofuran using a chiral BLA 2a as a catalyst was developed, which allows rapid access to a variety of chiral phenolic tricycles with high enantioselectivities [12]. The utility of this new methodology was demonstrated in a short, enantioselective total synthesis of aflatoxin B2. By a trapping experiment using a large excess of 2,3-dihydrofuran, the reaction pathway was elucidated as shown in Scheme 3.7.

OH

OH

O 1

R

BLA 2a (20 mol %) CH2Cl2 : CH3CN (1:1)

O

2

R

R2

R1 H

R2

O

O

O

H O

H O 5 examples

32% yield 90% ee (R1 = OMe, and R2 = H)

65–75% yield 92–95% ee OH O ent-BLA 2a (20 mol %)

O

O

H

CH2Cl2 : CH3CN (1:1) –78°C, 2 h

O

H O 65% yield, 92% ee

Tf2N

MeO

O

O H

Aflatoxin B2

cat* H O N B O H O

H

O

Me H

O

O

MeO

MeO

H

R1

H

MeO H

H

O

O

MeO H

O

O

O

OH OH

MeO MeO

H

H O H H O

O H

O H O

Scheme 3.7.

Later, the application of BLAs was extended to the Michael additions of silyl ketene acetals to cyclic and acyclic α,β-unsaturated ketones [13]. Interestingly, they found that a catalytic amount of Ph3P=O increased the enantioselectivity because it could serve as a trap for any electrophilic Me3Si species formed during the reaction.


In addition, the absolute stereochemical course of the enantioselective Michael addition of 2-cyclohexenone can be rationalized by the previously proposed pretransition-state assembly. The enantioselective methodology is illustrated by application of the synthesis of the key intermediate, A, for the enantioselective synthesis of caryophyllene (Scheme 3.8).

R1 MeO

n

R1 OTMS

R R2

1

R = Me, –(CH2)5–

R1 H

BLA 2a (20 mol %) 2

R1

Ph3PO (25 mol %) i-Pr

O R = H, Me n = 1, 2 2

n

MeO2C O

OH

R2 R2

79–89% yield 82–92% ee

i-Pr Toluene, –20°C Me H Me O

MeO

Me OTMS

ent-BLA 2a (20 mol %) Ph3PO (25 mol %) Toluene, –20°C

Me MeO2C

Me H Me

Me H

O A

Caryophyllene

Scheme 3.8.

Gnanadesikan and Corey developed a new type of BLA 3, derived from precatalyst zwitterions and tributyltintriflate, for enantioselective synthesis of β-lactones from ketene and aldehydes [14]. Activation of the precatalyst by tri-n-butyltintriflate produced the ion pair, which by reaction with ketene should form the intermediate. The intermediate should be a sufficiently strong Lewis acid to coordinate with the aldehyde and generate the reactive complex. C–C bond formation, followed by extrusion of βlactone completes the catalytic cycle. It is noteworthy that β-lactone formation from α-branched aldehydes was demonstrated for the first time (Scheme 3.9). Recently, Payette and Yamamoto developed a new BLA 4 and successfully applied this catalyst system to enantioselective D-A reactions with 1- and 2-substituted cyclopentadienes (CPs). Activation of oxazaborolidine with the super Brønsted acid C6F5CHTf2 was found to produce even more reactive catalyst BLA 4 [15]. Interestingly, from the mixture of 1- and 2-substituted CPs, BLA 4 exclusively afforded adducts from 2-substituted CP as single isomers. D-A adducts of the remaining unreacting 1substituted CP remarkably could be obtained through a one-pot process with more reactive dienophiles such as quinone to afford highly diastero- and enantioselective compounds with two consecutive quaternary carbon centers. To rationalize the observed regio- and stereocontrolled D-A adducts, they proposed a hypothetical transition state (Scheme 3.10). In recent work, Balskus and Jacobsen applied modified BLA 5 to the transannular Diels–Alder (TADA) reaction [16]. Various sized macrocycles containing α,βunsaturated lactones and ketone could be cyclized to afford tricyclic endo products


O O R

BLA 3 (1 eq) H

H2C C O

Bu3SnOTf (1 eq) CH2Cl2, –78°C

Proposed mechanism H Ph

O

H

R 6 examples 62–78% yield 65–84% ee H Ph

Ph

O N B O HO

Ph

O

N B H O

Bu3SnOTf

TfO OSnBu3

BLA 3 H2C C O H Ph

Ph

O

O O R

H

N B O H O O

TfO H R CH2 OSnBu3

H Ph

Ph

O

N B H O

TfO CH2 O

OSnBu3

Actual catalyst

Scheme 3.9.

containing medium- to large-sized rings in good to excellent diastereo- and enantioselectivities. Interestingly, introducing o-fluorophenyl at boron in oxazaborolidine provided TADA products in significantly higher enantioselectivity than corresponding o-tolyl substituted BLA 1a (90% ee vs. 10% ee). Additionally, this methodology was successfully applied to the synthesis of lactone B, which could potentially serve as a precursor to a number of sesquiterpene targets (Scheme 3.11). The synthetic power of these excellent BLAs has also been well demonstrated by their applications to the enantioselective syntheses of biologically important molecules. Corey and others applied the catalytic enantioselective D-A reactions by BLAs as key steps for the synthesis of (+)-estrone [17], georgyone [18], palominol [19], and tamiflu [20]. An enantioselective total synthesis of (−)-rasfonin has been reported by Boeckman et al. using chiral BLA-catalyzed vinylogous Mukaiyama aldol reaction as the key step [21]. Recently, Yamamoto et al. utilized regioselective D-A reaction of 1- and 2-substituted CPs catalyzed by BLA 4 for their synthesis of plastansimycin [22].

3.2. BLA CATALYSIS 127 O R3 CO2Et R1 99:1 dr 81–99% yield 96–99% ee

R2

R1

BLA 4 (5 mol %)

(2.5 eq)

CO2Et

R1

CH2Cl2, –78°C, 1 h

O –78°C, 3 h

R1

CO2Et

H O Ph

R2

R1

Ph Tf O N B H C6F5 Tf Ph

R3

O >99:1 dr 43–96% yield >99:1 ee

BLA 4 For stereoselectivity

For chemoselectivity

H

H N B O H O

RO

RO

R1

H

N B O H O

H

N B O H O R

R

N B O H O R

R

1

R

O

O 1

R1

R

Favored

Disfavored due to steric hindrance between phenyl and R1

Disfavored due to steric hindrance between phenyl and R1

Favored

Scheme 3.10. H m

m

BLA 5 (20 mol %)

H

H

X n

m = 1, 2 n = 1, 2 X = O, CH2

H

H Ph Ph

O

N O B H Tf2N

n

69–80% yield 6:1 to 19:1 dr 88–92% ee

F

BLA 5 Me Me Me

O O Me Si Me

BLA 5 (20 mol %) Toluene, 0.3 M rt, 20 h

O Me O Me H Si Me H H Me Me

X

O

O Me Steps

O H H

H Me Me 83% ee, >20:1 dr Precursor to a number of sesquiterpene

Scheme 3.11.


3.3. LLA CATALYSIS The Corey-BAKSHI-SHIBATI (CBS) reduction [23] of prochiral ketones is a wellknown process that utilizes a chiral oxazaborolidine as a catalyst and borane as a stoichiometric reductant. It is believed that the active catalytic species is generated from coordination of boron reagent to the nitrogen in the oxazaborolidine, which makes the boron atom more Lewis acidic. Similarly, in 2005, the Yamamoto group reported that a new Lewis acid-assisted chiral Lewis acid (LLA 1), derived from chiral valine-based oxazaborolidine and SnCl4 as an activator, is a highly efficient catalyst for enantioselective D-A reactions of various classes of substrates [24]. Of interest was that, almost the same enantioselectivities of D-A adducts were observed even in the presence of large excess of SnCl4, which implies the higher reactivity of the chiral LLA 1 than that of SnCl4. In addition, this catalyst system can be tolerant to a small amount of Lewis bases, such as moisture and alcohol without any significant loss of enantioselectivity. They proposed that the coordination of the achiral Lewis acid (SnCl4) to the nitrogen atom of the chiral oxazaborolidine would increase the Lewis acidity of the boron atom (Scheme 3.12).

N

B

Ph Ph O

SnCl4

N

B

Ph Ph O

Cl4Sn

LLA 1 CHO

CHO

LLA 1 (1 mol %) CH2Cl2, –78°C

>99% yield 68:32 exo selective 95% ee (exo) 98% ee (endo) Other examples H

H COEt

H

O H

CO2Et

O

H

90% yield 99:1 endo selective 96% ee

96% yield 99:1 endo selective 95% ee

O 94% yield 20:1–14:1 anti, syn-selecitve

OMe X ent-HBM 4 (10 mol %) THF

NO2 OMe

R1

OH OMe 70–87% yield 10:1–5:1 syn, syn-selecitve

Boc

Nu NH H

R

ent-HBM 3

N H O

R H

H H

BocHN

ent-HBM 4

Boc H N O

Nu R H

H H-bond chelation model

NO2 OMe

R1

OH OMe

NHBoc Felkin–Anh model

O

Boc

R O

BocHN R1

NO2 OMe OH OMe

Scheme 3.21.

Brønsted acid not only increases its acidity but also restricts the orientation of proton, which may allow enantiofacial recognition of one prochiral face of olefin. In 2003, Yamamoto et al. described modified LBAs 1a and 1b, from optically active monoalkylated-1,2-diarylethane-1,2-diol·SnCl4, which was shown to be superior to the original BINOL-based LBA for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals [38]. Based on the X-ray crystal structure of a related LBA complex of 1a, the authors were able to specify the conformational direction of the H–O bond of LBA, which has some asymmetric inductivity. The stereochemical course in the enantioselective protonation would be controlled by a linear O–H···π bonding interaction with an initial step (Scheme 3.22).Another chiral LBA using TiCl4 was developed by Nakashima and Yamamoto and applied to the enantioselective protonation of silyl enol ethers [39]. In 1999, the Yamamoto group reported the enantioselective biomimetic cyclization of polyprenoids catalyzed by chiral LBA, which is the first example of a proton-induced enantioselective polyene cyclization in synthetic chemistry [40]. He and his colleagues developed a new chiral LBA 2 containing a pyrogallol skeleton for enantioselective polyene cyclizations as an “artificial cyclase” [41]. Various trans-fused tricyclic skeletons have been synthesized with good enantioselectivities in the presence of chiral LBA 2. Interestingly, the LBAs derived from pyrogallol derivatives are more effective Brønsted acids than BINOL derivatives for preparing LBA with SnCl4 (Scheme 3.23).


O

OTMS R1

R1

LBA 1a or 1b (1.1 eq)

3

R

Toluene, –78°C

2

R

R

>95% yield, Up to 90% ee

R3 = alkyl or OTMS CF3

F3C

CF3

MeCl O Cl Sn O Cl Cl

Ar H

H O SnCl4 O

F3C

R3 2

H

F3C TMSO

MeCl O Cl Sn Cl O Cl

Ar H

H

F3C

OTMS CF3

CF3 OTMS

X

OTMS

LBA 1a: X = H LBA 1b: X = F

Disfavored

Favored Scheme 3.22.

SnCl4 O Ar

O

O O

Ar

Ar

H Ar = m-xylyl

H

O

O SnCl4 Ar

LBA 2

SnCl4 (1 eq)

CF3CO2H (10 eq)

ArOH (2 eq), toluene –78°C, 1 day

SnCl4 (1 eq) i-PrNO2, –78°C, 1 day

H 90% for two steps 88% trans, 85% ee

O

H

O

O

Br

24% yield 94% trans, 83% ee

O

H 64% yield 86% trans, 79% ee Scheme 3.23.

3.4. LBA CATALYSIS 137

Yamamoto et al. devised a new chiral catechol-derived LBA 3 as an artificial cyclase for hydroxypolyprenoids [42]. The synthetic utility of LBA 3 was demonstrated by enantioselective cyclizations of various 2-(polyprenyl)phenol derivatives with good to excellent enantioselectivities (88–90% ee), leading to very short and efficient total syntheses of (−)-chromazonarol, (+)-epi-puupehedione, and (−)-11′-deoxytaondiol methyl ether (Scheme 3.24).

F O

O O

O

LBA 3, toluene –78°C, 2 days OH

O

then, CF3CO2H SnCl4, i-PrNO2 –78°C, 1 day

SnCl4

O

O

H

H OMe

40% yield 69% dr, 88% ee

LBA 3

OMe

O O

O

O

H

H

40% yield 69% dr, 88% ee ent-LBA 3 was used

62% yield 73% dr, 89% ee

HO OMe

LBA 3, toluene –78°C, 2 days H

OMe

H 22% yield, 48% dr, 90% ee

Scheme 3.24.

Yamamoto and his coworkers extended the utility of chiral LBA 3 as an artificial cyclase to the asymmetric syntheses of the (−)-caparrapi oxide and (+)-e-epicarparrapi oxide [43,44]. (−)-Caparrapi oxide and (+)-e-epicarparrapi oxide can be diastereoselectively synthesized from optically active hydroxypolyprenoid by the reagent control of LBA 3 and ent-LBA 3, respectively, regardless of the chirality of starting material (Scheme 3.25). In 2005, the Hall group found that strong Brønsted acids, such as triflic acid, could catalyze the addition of allylboronates to aldehydes [45]. Because, in general, chiral Lewis acid-catalyzed allylation to aldehydes led only to low levels of enantioselection,

138 CHIRAL LEWIS ACIDS AND BRØNSTED ACIDS IN ASYMMETRIC SYNTHESIS BnCO2 O 81

BnCO2 ent-LBA 3 (2 eq)

O H

O

3 steps

PrCl : CH2Cl2 (1:1) –80°C, 48 h 74% yield

to

H

H >99% ee

(–)-Caparrapi oxide

BnCO2 O

19 H

21% ee BnCO2 O 14

BnCO2 O H

H 27% ee

LBA 3 (2 eq) PrCl : CH2Cl2 (1:1) –80°C, 48 h 73% yield

to BnCO2 86

O

H 98% ee

O

3 steps H

(+)-8-Epicaparrapi oxide

Scheme 3.25.

they demonstrated that chiral LBA catalyzes the asymmetric allylation and crotylation to various aldehydes to afford products in excellent yields and moderate to good enantioselectivity [46,47]. The LBA 4 was found to exert a strong influence on the diastereofacial selectivity: High anti, syn diastereoselectivity was obtained in crotylation with matched LBA 4. Mechanical studies indicated that Lewis acid precludes a well-organized cyclic transition state due to steric hindrance, whereas a smaller activator such as proton is allowed to have chair-like transition structure, which might increase enantioselectivity using LBA (Scheme 3.26). Later, a new C2-symmetric BINOL-derived diol was prepared by Rauniyar and Hall and applied toward LBA for the asymmetric allylboronation of aldehydes [48].

3.5. CHIRAL PHOSPHORIC ACID CATALYSIS [49] Chiral phosphoric acid PA 1a (Fig. 3.5), derived from simple (R)-BINOL, has already been employed as a chiral resolving reagent [50], and its lanthanide salt was used as a catalyst for the hetero D-A reaction [51]. However, phosphoric acid itself had not been used as a chiral catalyst until the research groups of Akiyama et al. [52] and Uraguchi and Terada [53] independently reported the design of phosphoric acids derived from

3.5 CHIRAL PHOSPHORIC ACID CATALYSIS 139

HO O H Cl Sn Cl Cl Cl LBA 4 O R

O B

R1

+ H

OH

LBA 4 (10 mol %) O

Na2CO3 (20 mol %) Toluene, –78°C

R2

R R1 R2 Up to 99% yield Up to 80% ee

O TBSO

OH

LBA 4 (10 mol %) H

Na2CO3 (20 mol %)

OH

TBSO

TBSO

Toluene, –78°C, 24 h anti-syn O B

SnCl4 alone O

syn-syn

66

:

34 (81% yield)

LBA 4 (11 mol %)

95

:

5 (77% yield)

ent-LBA 4 (11 mol %)

68

:

32 (50% yield)

Scheme 3.26.

X O P

O

O OH X

PA 1a: X = H PA 1b: X = Ph PA 1c: X = 4-NO2C6H4 PA 1d: X = 4-β-naph-C6H4 PA 1e: X = 4-ClC6H4 PA 1f: X = 3,5-(CF3)2C6H3 PA 1g: X = 3,5-dimesitylphenyl

PA 1h: X = 1-naphthyl PA 1i: X = 2,4,6-(i-Pr)3C6H3 PA 1j: X = 9-anthryl PA 1k: X = 9-phenanthryl PA 1l: X = biphenyl PA 1m: X = 2-naphthyl PA 1n: X = SiPh3

Figure 3.5. Chiral phosphoric acids.

optically pure BINOL carrying bulky 3,3′-substituents as a novel class of chiral Brønsted acid catalysts. Since these seminal papers, many research groups have expanded the application of these catalysts to various organic transformations [49]. It was found that phosphoric acids are bifunctional catalysts bearing both a Brønsted acidic site and a Lewis basic site and that 3,3′-substituents play a crucial role in attaining high stereoinduction as well as high reactivity by controlling structural and electronic properties.

3.5.1. Nucleophilic Additions of Aldimines Akiyama et al. first reported that chiral phosphoric acids effectively catalyzed Mannichtype reaction of imines with ketene silyl acetals (Scheme 3.27) [52]. Although phosphoric acid PA 1a was not effective as a chiral catalyst, introduction of aryl substituents at


HO

HO OTMS N

+Me

cat. (30 mol %)

OMe

Ph

HN

Toluene, –78°C

Me

CO2Me

Ph

Me Me PA 1a: 57% yield, 0% ee PA 1b: >99% yield, 27% ee PA 1c: 96% yield, 87% ee HO

HO OTMS N Ar

+ H

PA 1c (10 mol %)

OR2

HN

Toluene, –78°C

1

R

CO2R2

Ar R1

11 examples 65–100% yield 86:14 to 100:0 syn selective 81–96% ee

R O P

O

O O R

H O H Ar

N H

TS 1 Scheme 3.27.

3,3′-positions has a beneficial effect on obtaining high levels of enantioselectivity. In addition, N-hydroxyphenyl-substituted aldimine is critical for asymmetric induction. DFT calculations were carried out to elucidate the stereoinduction. The reaction seems to be undertaken through the nine-membered zwitterionic transition state TS 1, which was used originally to explain enantioselectivity [54]. Shortly thereafter, Uraguchi and Terada independently reported that the direct Mannich reaction of acetoacetone with N-boc-protected imines was catalyzed by only 2 mol % of PA 1d to give the corresponding adducts with high enantioselectivities (Scheme 3.28) [53]. In 2007, Gong et al. reported the three-component direct Mannich reaction, wherein phosphoric acids, derived from H8-BINOL derivatives, were utilized as catalysts (Fig. 3.6) [55]. The one-pot Mannich reactions between in situ generated N-aryl imines and cyclic ketones as well as aromatic ketones catalyzed by PA 2a gave the corresponding adducts with excellent enantio- and/or diastereoselectivities. The authors postulated that acid-promoted enolization of the ketone forms the reactive enol, which adds to the protonated aldimine via TS 2 (Scheme 3.29). Hydrophosphorylation of aldimines with dialkyl phosphite has been developed by Akiyama and his colleagues [56]. This process afforded optically active α-amino phosphonates in good to high yields and enantioselectivities. Based on the observations, they


X O P

PA 2a: X = Ph PA 2b: X = 4-FC6H4 PA 2c: X = 4-ClC6H4

O

O OH X

Figure 3.6. Chiral H8-BINOL-based phosphoric acids.

O

N R1

O

O

H

O

Boc

HN

PA 1d (2 mol %)

Boc

Ac

R1

CH2Cl2, rt

Ac

H

6 examples 93–99% yield 90–98% ee Scheme 3.28. O +

PhNH2

+ H

X

R1

+

R2NH2

H

R X 18 examples 67–99% yield 75–98% ee 77:23 to 98:2 anti selective

O

PA 2b or 2c (5 mol %)

O

+

NHPh

Toluene, 0°C

R

X = CH2, O, S, N-boc

O

O

PA 1e (0.5 mol %) or PA 2a (2 mol %)

O

Toluene, 10°C

Ar

R1 = CH3, Ph, 4-F-Ph

R1

NHR2 Ar

6 examples 42–76% yield 70–86% ee *RO OR* P O O H H R3 N O R4

R1 R2 TS 2

Scheme 3.29.


proposed nine-membered transition state TS 3, where PA 1f serves as a bifunctional catalyst: The OH in phosphoric acid activated the aldimine as a Brønsted acid and the phosphoryl oxygen (P=O) activated the nucleophile as a Lewis base, thereby oriented both nucleophile and electrophile, which increased enantioselectivity (Scheme 3.30). Oi-Pr

H P O

OMe

Oi-Pr

OMe

PA 1f (10 mol %)

R

HN

m-Xylene, rt

N

R Oi-Pr

H

P HO

Oi-Pr

Oi-Pr P Oi-Pr O

11 examples 72–79% yield 52–90% ee

H O Oi-Pr R P Oi-Pr *RO O H H N PMP TS 3 *RO

O

P

Scheme 3.30.

3.5.2. aza-Friedel–Crafts (F-C) Reactions The first organocatalytic aza-F-C reaction of aldimines was reported by Terada and his coworkers using catalyst PA 1g [57]. It is remarkable that N-boc-protected aryl imines containing electron-donating or -withdrawing groups at either the ortho-, meta-, or parapositions were well tolerated in this condition. Interestingly, the absolute configuration of the products was opposite to that found previously in direct Mannich reaction [53] (Scheme 3.31).

MeO

N

O Ar

Boc

PA 1g (2 mol %) ClCH2CH2Cl, –35°C

MeO

O

HN Boc Ar

H

13 examples 80–96% yield 86–97% ee Scheme 3.31.

The Terada group reported the enantioselective aza-F-C reaction of indoles with enecarbamates as the precursor of iminium salts [58]. This is the first example of the F-C reaction initiated by an activation of an electron-rich multiple bond. Use of either pure regioisomers (E)- or (Z)-enecarbamate gave the identical product with the same level


of enantioselectivity; thus, they believed that the reaction proceeded through common intermediate, B, which was generated by the protonation of enecarbamates. It is interesting that this methodology is an efficient alternative to the generation of aliphatic imines, which are generally labile and difficult to isolate (Scheme 3.32).

Boc R1 N H

Boc

BocHN NH

PA 1i (5 mol %)

R2

H

R1

CH3CN, 0°C

R3

R3 N H 11 examples 63–98% yield 90–96% ee

NH BocHN

H Me (>99% E) or Boc

R2

NH

Me H (>99% Z)

PA 1i (5 mol %)

Boc

CH3CN, 0°C

N

H

O O P O O

H Me

N H N H From (E): 94% ee, (69% yield) From (Z): 93% ee, (93% yield)

B

Scheme 3.32.

The Zhou group reported a similar reaction between indole and various α-aryl enamides to give the F-C products with quaternary carbon center [59]. N-methylated enamide showed no reactivity, which provides further evidence that the reactive proceeded through the corresponding ketimines by protonation to enamides. The authors proposed the transition state, TS 4, similar to Akiyama’s hydrophosphylation, where activation of nucleophile via hydrogen bonding from the phosphoryl oxygen is essential in achieving high levels of enantioselectivity (Scheme 3.33). Additionally, You et al. reported another F-C reaction of indole with imines, derived from aromatic aldehydes [60]. Generally, high yields and excellent enantioselectivities were achieved for a wide range of imines (Scheme 3.34). List and his coworkers applied the phosphoric acid catalysts to the Pictet–Spengler reaction starting from geminally disubstituted tryptamines and obtained the resulting chiral tetrahydro-β-carbolines in good to excellent yields and enantioselectivities [61]. Geminal disubstitution of trypamine with electron-withdrawing groups facilitated the cyclization, presumably due to the Thorpe–Ingold effect and electronic effect (Scheme 3.35). The Hiemstra group subsequently reported the Pictet–Spengler reaction of N-tritylsulfenyl tryptamines with various aliphatic and aromatic aldehydes catalyzed by PA 1f [62]. The sulfenyl substituent stabilized the intermediate iminium ion and thus favored the Pictet–Spengler cyclization over undesired enamine formation. Additionally, they developed a one-pot procedure for the synthesis of tetrahydro-β-carbolines to avoid the isolation of the labile N-tritylsulfenyl products (Scheme 3.36).


O NHAc HN R1 N H

ent-PA 1i (10 mol %)

Ar

Toluene, 4A MS

N H 14 examples 94–99% yield 73–97% ee

O

X O P

O

O O

Ar

R1

H N H N

X TS 4 Scheme 3.33.

N

NHR''

R

R'' ent-PA 1h (10 mol %)

R N H

R' N H 19 examples 68–93% yield 82–99% ee

Toluene, –60°C R'

Scheme 3.34.

CO2Et CO2Et NH2

R N H

R O H

EtO2C

CO2Et

ent-PA 1h (20 mol %) R1

Na2SO4 Toluene, –30°C

N H

NH R1


Scheme 3.35.

Terada and others reported the quite interesting alkylation of α-diazoesters with Nacyl imines to afford β-amino α-diazoesters in high yields and enantioselectivities [63]. Diazoacetate is commonly employed in aziridine formation reactions under Lewis acidic and Brønsted acidic conditions (aza-Darzene reaction). Earlier, Williams and Johnston observed that Brønsted acids, such as TfOH, catalyzed aziridine formation from diazoacetate and N-benzyl imines [64]. After carefully considering the reaction mechanism


Ph HN

N H

S

HCl

RCHO PA 1f (5 mol %) Toluene, 0°C MS 3A, BHT

Ph Ph

PhSH

NH

N H

R 7 examples 77–90% yield 72–87% ee

Scheme 3.36. O RO2C

O

H +

N N

2

Ar

N H

Ar2

HN PA 1j (2 mol %) Toluene, rt

1

Ar

RO2C

1

Ar N N

19 examples 57–89% yield 86–97% ee RO2C

H N N

P R1

N

H A R2

P

N

R2 R1

RO2C N H N

RO2C

P N

R2 R1

H

Aziridine R1 R2

RO2C N H

N

N

P H

O O P OR* OR*

PHN R1 RO2C R1 N N "Friedel–Crafts adduct"

Scheme 3.37.

and choosing the protecting group on imines, the authors proposed that the competing aziridine formation was eliminated by decreasing nucleophilicity of resulting amine intermediates; thus, F-C-type adduct was obtained through C–H bond cleavage by the phosphoryl oxygen of phosphoric acid (Scheme 3.37).

3.5.3. D-A Reaction Akiyama et al. found that Danishefsky’s diene underwent the aza-D-A reaction with aldimines in the presence of phosphoric acids to give cycloadducts [65]. Interestingly, addition of acetic acid significantly improved both the chemical yields and enantioselectivities (Scheme 3.38). Although Brassard’s diene is known to be more reactive than Danishefsky’s diene, the application of Brassard’s diene to aza-D-A reaction using a Brønsted acid catalyst has been rare because of the lability of this diene in the presence of a strong Brønsted


Me

HO

OMe

N TMSO

Ar

OH

PA 1i (5 mol %)

Me

N

AcOH (1.2 eq) Toluene, –78°C

H

Ar

O

9 examples 72–100% yield 76–91% ee Me

HO

OMe

N TMSO

Ph

Me

PA 1i (5 mol %)

N

Toluene, –78°C

H

OH

Ph

O

Without AcOH: 29% yield, 34% ee With AcOH: 78% yield, 67% ee

Scheme 3.38.

HO N R

1) PA 1j (3 mol %) py (3 mol %) mesitylene –78°C

OTMS +

MeO OMe

2) PhCO2H (1 eq)

OH OMe N R

O


acid. Akiyama and coworkers disclosed that phosphoric acid is effective for the aza-D-A reaction of Brassard’s diene [66]. The use of the pyridinium salt of the phosphoric acid 1j improved the chemical yield, supposedly because use of less acidic pyridinium salt suppressed lability of Brassard’s diene in the reaction media (Scheme 3.39). The inverse electron-demand aza-D-A reaction of electron-rich alkenes with 2-aza dienes was reported by Akiyama and coworkers [67]. Tetrahydroquinoline derivatives were obtained in favor of the cis-isomers with excellent enantioselectivities. Because the existence of OH group is crucial for this reaction, the authors proposed a nine-membered cyclic transition state, which was previously proposed for their Mannich and hydrophosphorylation reactions (Scheme 3.40). The groups of Gong [68] and Rueping [69] independently developed direct aza-D-A reactions of aldimines with cyclohexenone to afford isoquinuclidines in good endo/exo selectivity and high yields and enantioselectivities, respectively (Scheme 3.41). While Gong employed only H8-BINOL-derived PA 2c, Rueping used chiral Brønsted acid PA 1l or lm in combination with acetic acid. Rueping proposed double Brønsted acid catalyzed activation of an electrophile (by a stronger Brønsted acid) and a nucleophile (by


OR OR N

Ar

+

1j (10 mol %) Toluene

OH

OH

N H

Ar

12 examples syn : anti 99:1 syn selective 59–95% yield 87–97% ee Scheme 3.40.

N R1

R2

O

cat. (x mol %)

2 N R

Toluene, RT

O

H

cat additive

R1 endo

2

N 1R R O exo

Gong

Rueping

PA 2c (5 mol %) _

PA 1m (10 mol %) AcOH

yield

70–82%

54–84%

endo : exo

4:1~5:1

3:1~8:1

ee (endo)

76–87%

82–88%

Scheme 3.41.

a less strong Brønsted acid), whereby both activation processes behave cooperatively (Fig. 3.7).

3.5.4. Transfer Hydrogenation A biomimetic transfer hydrogenation employing Hantzsch ester, a model of nicotinamide adenine dinucleoside (NADH), as a hydride source has been independently reported by Rueping et al. [70], List et al. [71], and MacMillan et al. [72]. Rueping and coworkers reported the first enantioselective phosphoric acid-catalyzed reduction of ketimines with Hantzsch ester [70]. With 20 mol % of PA 1f, excellent yields and good enantioselectivities were obtained under the mild reaction condition. Later, List and coworkers found that PA 1i bearing bulky 2,4,6-(i-Pr)3C6H2 at the 3,3′-positions of BINOL is a more efficient catalyst for enantioselective ketimine reductions (Scheme 3.42) [71]. MacMillan and others reported the first enantioselective organocatalytic reductive amination starting from aldehydes, amine, and Hanztsch ester as a hydride source catalyzed by chiral phosphoric acid PA 1n [72]. The three-component reductive amination


2 N R

O

*RO

O P

OH

*RO

1

N R1

R

O

OH

*RO

AcOH

*RO

O P

H

O R1

N

R2 H

R2 H

Figure 3.7. Cooperative Brønsted acid catalysis.

N R'

PMP Me

EtO2C

CO2Et

HN

PMP

+ R'

N H (1.4 eq)

(1.0 eq)

Me

Rueping

List

PA 1f (20 mol %)

ent-PA 1i (1 mol %)

Benzene, 60°C

Toluene, 35°C

46–91% yield 68–84% ee

80–98% yield 80–93% ee

Scheme 3.42.

O

EtO2C +

R R = alkyl or aryl

H2N

R1

CO2Et

+ N H

R1 PA 1n (10 mol %) 40–50°C, MS 5A Benzene

HN R 24 examples 49–92% yield 81–97% ee

Scheme 3.43.

reactions starting from ketones, amine, and Hantzsch ester proceeded in the presence of 5Å MS to give secondary amines with excellent enantioselectivities. This method can be applied to methyl aryl ketones as well as methyl alkyl ketones. Interestingly, the reductive aminated product of even methyl ethyl ketone was obtained in 83% ee (Scheme 3.43). Following these initial studies, Rueping et al. further expanded this protocol to the reduction of a wide range of heterocycles [73–75]: benzoxaxines, benzothiazines, benzoxazinones, pyridines, and quinolines. Reduction of benzoxazines, in particular, is highly efficient, lowering the catalyst loading of PA 1k to 0.1 mol % without considerable loss in reactivity and selectivity [73]. Furthermore, they applied these methodologies to


EtO2C N

R

EtO2C

R1 N

R

S

EtO2C

N

R

O R1

CO2Et

O EtO2C

O PA 1k (0.1 mol %) R1 Benzene, 60°C

R

S

R1

EtO2C N

R3

N R H 6 examples 50–78% yield 93–>99% ee

CO2Et N H (1.25 eq)

(1.0 eq)

N R H 6 examples 92–95% yield 98–>99% ee

PA 1k (1 mol %)

O PA 1k (1 mol %)

N

N R H 16 examples 54–95% yield 88–99% ee

Benzene, 60°C

N H (1.25 eq)

(1.0 eq)

R2

CO2Et N H (1.25 eq)

(1.0 eq)

PA 1k (2 mol %) Benzene, 60°C

N H (2.4 eq)

(1.0 eq)

O

CO2Et

CO2Et N H (4 eq)

Benzene, 60°C

O

R1 N R H 7 examples 55–92% yield 90–>99% ee R1

PA 1j (5 mol %) Benzene, 50°C

R2

N R3 H 10 examples 47–84% yield 84–92% ee

Scheme 3.44.

the synthesis of biologically active tetrahydroquinoline alkanoids: (+)-galipinine, (+)-cuspareine, and (+)-angustureind (Scheme 3.44) [74]. List and coworkers achieved catalytic asymmetric reductive amination of α-branched aldehydes and p-anisidine with Hantzsch ester as a hydrogen source via dynamic kinetic resolution to afford β-substituted amines in excellent yields and good to excellent enantioselectivities (Scheme 3.45) [76]. With the successful reduction of imines with Hantzsch esters, they developed the highly enantioselective synthesis of pharmaceutically relevant 3-substituted cyclohexylamines from 2,6-diketones via an aldolization–dehydration– conjugate reduction–reductive amination cascade reaction catalyzed by a chiral phosphoric acid (Scheme 3.46) [77].


R1

PA 1i (5 mol %)

CHO 2

H2NR3

+

MS 5 A Benzene, 6°C

R

O R1

N

+H2NR3 H

R1

–H 2O

R2

R1

NHR3 R2 17 examples 49–96% yield 39–98% ee

R3 H

HN R1

R3

N R1

H

R2 Racemization

R2

R3 H

R2

Reduction R1

NHR3 R2

Scheme 3.45.

O PA 1i (10 mol %) R2NH2 (1.5 eq) Hantzsch ester (2.2 eq) MS 5A, cyclohexane, 50°C

X O 1

R

HN

X

R1

Enamine catalysis N

R2

N

Aldol reaction O

12 examples 2:1 to 24:1 syn selective 35–89% yield 82–96% ee

1,2-reduction

NHR2 X

R2

R2

1,4-reduction X

R1

X

R1

R1

Scheme 3.46.

3.5.5. Novel Phosphoric Acids Several novel phosphoric acids have been reported (Fig. 3.8). TADDOL-based PAs 3a and 3b were synthesized and applied to the Mannich-type reaction by the Akiyama group [78]. In addition, Terada et al. developed phosphorodiamidic acid PA 4 as a Brønsted acid for the direct Mannich reaction [79]. Antilla and coworkers synthesized a novel phosphoric acid derivative PA 5a or 5b starting from (S)-VANOL or (S)-VAPOL and demonstrated its catalytic activity in the addition of nitrogen nucleophiles such as sulfonamides [80] and imides [81] to imines to produce protected aminals. Furthermore, PA 5b was found to be an excellent catalyst for the reduction of α-imino esters with Hantzsch ester to provide highly enantioselective αamino esters [82]. Interestingly, VAPOL-based PA 5b was proved to be a superior cata-


Ar

Ar

SO2Tol N O P N OH

O O P OH O

O O Ar

SO2Tol

Ar PA 3a: Ar = Ph PA 3b: Ar = 4-CF3Ph

O O P O OH

Ph Ph

PA 4

Ph Ph

VANOL PA 5a

O O P O OH

VAPOL PA 5b

Figure 3.8. Novel phosphoric acids.

O N

O PA 5b (5–20 mol %)

NH2R

O-t-Bu

Ar

HN

Ether, rt

R = sulfonyl or imide

Ar

O-t-Bu NHR

27 examples 80–99% yield 73–99% ee R2

R2 EtO2C

CO2Et

N R1

CO2Et

N H

PA 5b (5 mol %) Toluene, 50°C

HN 1

R

CO2Et


lyst over phosphoric acids derived from BINOL (77% yield, 80% ee with PA 1j vs. 99% yield, 96% ee with PA 5b) (Scheme 3.47). Later, the utility of PAs 5a and 5b was extended to ring opening of meso-aziridines [83]. This was the first example of organocatalytic desymmetrization of meso-aziridines. Introduction of more electron-withdrawing protecting groups on the nitrogen enhanced both yields and enantioselectivities of products. Mechanical studies proposed that the


reaction proceeded via the silylated phosphoric acid as the active catalyst. The resulting silane activates the aziridine by coordination of its carbonyl group, and subsequent attack of azide provides an intermediate and regenerates the phosphoric acid (Scheme 3.48).

O

O

R

CF3

N

PA 5a or 5b (10 mol %) TMS N3 DCE, rt

R

R

NH

R

N3

CF3

O R

NH

R

N3

R2

CF3

CF3 9 examples 49–97% yield 70–95% ee

OTMS

R

N R2

R

O

R'O

N3

P R'O

TMSN3

OH

HN3

HN3

R'O

R'O

O P

R'O

O P

O SiMe3

R'O

OTMS

O R

N

R2

R

Scheme 3.48.

Even though chiral phosphoric acids were successfully applied to various asymmetric processes, their utility has been limited to more basic nitrogen-based electrophiles such as imines and aziridines, because of the relatively low acidity of phosphoric acid. Yamamoto and coworkers designed stronger chiral Brønsted acids in efforts to expand the utility of chiral phosphoric acid-catalyzed reactions to a broad range of organic transformations (Fig. 3.9). Nakashima and Yamamoto prepared N-triflyl phosphoramide PA 6a, bearing a strong electron-withdrawing group, NTf, and applied this catalyst to the D-A reactions of α,β-unsaturated ketone with electron-rich dienes to give cyclohexene derivatives with high enantioselectivities [84]. By introducing a strong electron-withdrawing group (NTf) into =O in phosphoric acid, great enhancement in reactivity of the acid was observed. This is the first example of carbonyl activation with phosphoric acid derivatives (Scheme 3.49).


X

X

X

O P

O

O

O

P

Tf O N H X

O

P

Tf O N H X

Tf O N H X

PA 6a: X = 2,4,6-(i-Pr)3C6H2 PA 6b: X = 4-(1-Ad)-2,6-(i-Pr)2C6H2 PA 6c: X = 9-phenanthryl

PA 6d: X = SiPh3 PA 6e: X = 4-(MeO)C6H4

Y

PA 7a: Y = S, X = 2,4,6-(i-Pr)3C6H2 PA 7b: Y = S, X = 4-(t-Bu)-2,6-(i-Pr)2C6H2 PA 8: Y = Se, X = 2,4,6-(i-Pr)3C6H2

Figure 3.9. Chiral N-triflyl phosphoramides.

R1

Me

O

OTIPS

COEt

PA 6a (5 mol %) Et

Me

Toluene, –78°C

TIPSO

12 h

R1 7 examples Up to 99% yield Up to 92% ee

Scheme 3.49.

R1 H

N

O R2

OEt

PA 6b (5 mol %) CHCl3, –40 to –55°C

R1

N O

OEt

R2 16 examples 87:13 to 96:4 endo selective 69–99% yield 56–92% ee for endo product

Scheme 3.50.

The Yamamoto group later prepared a new N-triflyl phosphoramide PA 6b, carrying extremely bulky adamantyl group at the para-position of 3,3′-substituents, to asymmetric 1,3-dipolar cycloaddition of diaryl nitrones with ethyl vinyl ether [85]. Whereas aluminum-based Lewis acid catalysts provided the products in high exo selectivity, the Brønsted acid PA 6b afforded endo product as the major diastereomer. It is explained that the smaller acidic proton allows ethyl vinyl ether to approach in an endo selective way, which is not favored in Lewis acid catalysis due to steric repulsion. Interestingly, introduction of bulky substituents at the para-position of 3,3′-substituents increased the enantioselectivity as well as reactivity presumably by controlling the steric and electronic properties of PA 6b (Scheme 3.50). Rueping and coworkers reported the Nazarov cyclization reaction catalyzed by Ntriflyl phosphoramide PA 6c [86]. Although phosphoric acids can catalyze the cyclization


reaction, the use of N-triflyl phosphamides improved both reactivities and enantioselectivities. It is interesting that while the Lewis acid-catalyzed Nazarov reactions provide mainly the trans products, the methodology primarily generates cis products. The Rueping group later extended the application of this acid to the enantioselective Michael addition of indole with β,γ-unsaturated α-ketoesters [87]. This is not only the first example of a Brønsted acid-catalyzed activation of α,β-unsaturated carbonyl compounds, but it also provides the corresponding α-keto esters in good yields and with excellent enantioselectivities. More recently, Rueping et al. further expanded the application of these highly reactive phosphoramides to the first enantioselective carbonyl-ene reaction of α-ketoesters to afford a range of substituted α-hydroxyesters in good yields with excellent enantioselecitivities (Scheme 3.51) [88].

O

O

O

O

ent-PA 6c (2 mol %)

R1

O

O R1

CHCl3, 0°C R2

R1

R2

R2

11 examples 45–92% yield 1.5:1 to >99:1 cis selective 86–93% ee (cis) 90–98% ee (trans) R1 CO2R2

O

3

R

N Me

R1

CO2R2

O R

F3C

PA 6d (5 mol %) CH2Cl2, –75°C

N Me 10 examples 43–88% yield 80–92% ee F3C OH

PA 6e (1 mol %) CO2Et

o-Xylene, 10°C

O

R3

R

CO2Et 17 examples 55–95% yield 92–97% ee

R = aryl

Scheme 3.51.

Cheon and Yamamoto thereafter prepared N-triflyl thio- and selenophosphoramides and reported the first metal-free Brønsted acid-catalyzed asymmetric protonation reactions of silyl enol ethers using a chiral Brønsted acid in the presence of achiral Brønsted acid media [89]. Interestingly, replacement of sulfur and selenium into the N-triflyl phosphoramide increases both reactivities and enantioselectivities for protonation reactions. It is appealing that the catalyst loading for the protonation could be decreased to 0.05 mol % without any significant loss of enantioselectivity (Scheme 3.52).


TMS

O O R

R

PA 7a (down to 0.05 mol %) PhOH (1.1 eq)

n

Toluene, rt

n

10 examples Quantitative yield 52–90% ee

R = aryl, or alkyl n = 1, or 2 Scheme 3.52.

3.5.6. Asymmetric Counteranion Directed Catalysis (ACDC) In 2006, Mayer and List introduced ACDC as a new concept of enantioselective synthesis [90]. Using the morpholine salt of chiral anion of PA 1i as a catalyst, 1,4-transfer hydrogenation of α,β-unsaturated aldehydes was obtained with high asymmetric induction. The reduction proceeded via an iminium salt intermediate, wherein phosphate anion effectively shielded one of the enantiofaces of the iminium salt. Later, they extended this methodology to the reduction of α,β-unsaturated ketones [91]. In particular, they found that a new class of catalytic salts, in which both cation and anion are chiral, is more effective for the transfer hydrogenation of α,β-unsaturated ketones (Scheme 3.53).

CHO

MeO2C

CO2Me N H (1.1 eq)

Ar

CHO Ar 6 examples 63–90% yield 96– >99% ee

PA 1i (5 mol %)

O

EtO2C

R1 R2

PA 1i (20 mol %) morpholine (20 mol %) dioxane, 50°C

R3

CO2Et N H (1.2 eq)

H2N

CO2t-Bu

i-Pr (5 mol %) Bu2O, 60°C 48 h

O R1 R2

R3


Scheme 3.53.

Recently, the List group successfully applied ACDC to the asymmetric epoxidation of α,β-unsaturated aldehydes [92]. In previous studies of reductions of enals, the stereogenic center is created in the conjugate addition step, whereas in epoxidations of 2,2-disubstituted enals, the initial addition product is achiral. Consequently, they proposed a new catalytic cycle where the subsequent cyclization to iminium ion is the stereogenic center (Scheme 3.54).

156 CHIRAL LEWIS ACIDS AND BRØNSTED ACIDS IN ASYMMETRIC SYNTHESIS cat. (10 mol %)

CHO

CHO O

tBuOOH (1.1 eq) Dioxane, 35°C

R

CF3

R 14 examples 60–84% yield 94:6 to >99:1 dr 84–96% ee

Ar

F3C

O P

O H2N

O O cat. (10 mol %)

CHO R

CHO

R

Ar

O

tBuOOH (1.1 eq) TBME, 0°C

R

CF3


H2O

Ar

R

cat.

Ar

N

CHO

H

F3C

Ar = 2,4,6-(i-Pr)3C6H2

R

tBuOOH

TRIP

R

PIRT H

Ar

N H

t-Bu O

N H2

O

Ar

Product

Ar

O

Ar

N H

TRIP tBuOH

H2O

Scheme 3.54.

List et al. further extended this methodology to α,β-unsaturated ketones with the interesting finding that diamine salts had beneficial effects on both reactivity and enantioselectivity [93]. This is presumably because this catalyst may serve as a bifunctional catalyst to possibly activate the enone substrate via iminium ion formation and hydrogen peroxide via general base catalysis (Scheme 3.55). Recently, the Toste group extended this novel concept to the asymmetric transition metal catalysis [94]. Two different transformations, hydroamination and hydroalkoxylation of allenes, catalyzed by cationic gold(I) complexes generated products in excellent yields with the use of chiral phosphate anion. Notably, they demonstrated that the chiral counterion can be combined additively with chiral ligands to enable an asymmetric transformation that cannot be achieved by either method alone (Scheme 3.56). Rueping et al. reported a new dual catalysis procedure, where an enantioselective activation of imines by a Brønsted acid is combined with a metal-catalyzed alkynylation [95]. The α-amino acids were obtained in good yields and with excellent enantioselectivities. They assumed that the reaction mechanism involves the formation of a chiral silver


Ar NH2 X

O X=

N

P

O

O O

N

Ar Ar = 2,4,6-(i-Pr)3C6H2

MeO

O

O

cat (10 mol %)

R n

HOOH (1.1 eq) Dioxane, 30–50°C

R

O n

17 examples 49–84% yield 78–98% ee H

N

X NR2 O O

H

H Working model for asymmetric epoxidation of enones Scheme 3.55.

R2 R2 OH n R3

R1

R3

NHSO2Mes n R1

Ag-PA 1i (5 mol %) Benzene, rt

R2 R2 R1

dppm(AuCl)2 (2.5 mol %)

R3 R3

Ph(CH3)2PAuCl (5 mol %) Ag-PA 1i (5 mol %) Benzene, rt

Scheme 3.56.

R1

H

O

R3 R3 R1 n R2 R2 7 examples 79–91% yield 90–99% ee H SO2Mes N R3

R1

R3 n R2 R2 4 examples 73–97% yield 96–99% ee

R1


N MeO2C

PA 1k (10 mol %) AgOAc (5 mol %)

PMP + H

Toluene, rt

Ar

HN

PMP CO2Me

Ar 8 examples 73–93% yield 86–88% ee

O *

O

P

O O H

N

RO2C

Ar

PMP H

[M] Ar N RO2C

PMP H

O *

O

P

O

[M-X]

OH HN

PMP CO2R

Ar Scheme 3.57.

binol phosphate complex, which results in a new metal-catalyzed reaction in which the chiral counterion induces the enantioselectivity (Scheme 3.57).

3.6. CONCLUSION Significant progress has been made recently in the design and development of chiral Lewis acid and Brønsted acid catalysts for asymmetric reactions, as described herein. In particular, chiral phosphoric acid catalysts have emerged as novel catalysts in a number of synthetic reactions. Despite such great achievements, the combined acid and phosphoric acid catalysis is still in a state of infancy and there is still much more to learn with regard to the reactivity. The ultimate goal is to develop versatile catalysts with higher reactivities and better selectivities. We believe the realization of such an objective will have a tremendous effect on the development of organic synthesis.

REFERENCES 1. For a review of combined acid catalysis, see: Yamamoto, H.; Futatsugi, K. Angew. Chem. Int. Ed. Engl. 2005, 44, 1924–1942. 2. Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808–3809. 3. Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992–9993.

REFERENCES 159

4. Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388–6390. 5. Zhou, G.; Hu, Q. Y.; Corey, E. J. Org. Lett. 2003, 5, 3979–982. 6. Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802. 7. Ryu, D. H.; Zhou, G.; Corey, E. J. Org. Lett. 2005, 7, 1633–1636. 8. Ryu, D. H.; Kim, K. H.; Sim, J. Y.; Corey, E. J. Tetrahedron Lett. 2007, 48, 5735–5737. 9. Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321–1329. 10. Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8106–8107. 11. Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384–5387. 12. Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958–11959. 13. Liu, D.; Hong, S. W.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 8160–8161. 14. Gnanadesikan, V.; Corey, E. J. Org. Lett. 2006, 8, 4943–4945. 15. Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9536–9637. 16. Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736–1740. 17. Hu, Q. Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984–5986. 18. Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 1346–1352. 19. Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740–742. 20. Yeung, Y. Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311. 21. Boeckman, R. K.; Pero, J. E.; Boehmler, D. J. J. Am. Chem. Soc. 2006, 128, 11032–11033. 22. Li, P. F.; Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534–9535. 23. For a review of CBS reduction, see: Cho, B. T. Tetrahedron 2006, 62, 7621–7643. 24. Futatsugi, K.; Yamamoto, H. Angew. Chem. Int. Ed. Engl. 2005, 44, 1484–1487. 25. Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498–1499. 26. Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687. 27. Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708–1709. 28. Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 11926–11927. 29. Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174–2175. 30. For a review of heterobimetallic catalysis, see: Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2209. 31. Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 16178–16179. 32. Yamagiwa, N.; Qin, H. B.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419–13427. 33. Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413–3422. 34. Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 2008, 47, 3230–3233. 35. Sohtome, Y.; Kato, Y.; Handa, S.; Aoyama, N.; Nagawa, K.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2231–2234. 36. For a review of LBA catalysis, see: Ishibashi, H.; Ishihara, K.; Yamamoto, H. Chem. Rec. 2002, 2, 177–188. 37. Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179–11180. 38. Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 24–25. 39. Nakashima, D.; Yamamoto, H. Synlett 2006, 150–152. 40. Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 4906–4907. 41. Kumazawa, K.; Ishihara, K.; Yamamoto, H. Org. Lett. 2004, 6, 2551–2554. 42. Ishibashi, H.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 11122–11123. 43. Uyanik, M.; Ishibashi, H.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 1601–1604. 44. Uyanik, M.; Ishihara, K.; Yamamoto, H. Bioorg. Med. Chem. 2005, 13, 5055–5065. 45. Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 12808–12809.

160 CHIRAL LEWIS ACIDS AND BRØNSTED ACIDS IN ASYMMETRIC SYNTHESIS 46. Rauniyar, V.; Hall, D. G. Angew. Chem. Int. Ed. Engl. 2006, 45, 2426–2428. 47. Rauniyar, V.; Zhai, H. M.; Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481–8490. 48. Rauniyar, V.; Hall, D. G. Synthesis 2007, 3421–3426. 49. For a review of phosphoric acid catalysis, see: Akiyama, T. Chem. Rev. 2007, 107, 5744–5758. 50. Wilen, S. H.; Qi, J. Z.; Williard, P. G. J. Org. Chem. 1991, 56, 485–487. 51. Furuno, H.; Hayano, T.; Kambara, T.; Sugimoto, Y.; Hanamoto, T.; Tanaka, Y.; Jin, Y. Z.; Kagawa, T.; Inanaga, J. Tetrahedron 2003, 59, 10509–10523. 52. Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. Engl. 2004, 43, 1566–1568. 53. Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356–5357. 54. Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756–6764. 55. Guo, Q. X.; Liu, H.; Guo, C.; Luo, S. W.; Gu, Y.; Gong, L. Z. J. Am. Chem. Soc. 2007, 129, 3790–3791. 56. Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583–2585. 57. Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126, 11804–11805. 58. Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292–293. 59. Jia, Y. X.; Zhong, J.; Zhu, S. F.; Zhang, C. M.; Zhou, Q. L. Angew. Chem. Int. Ed. Engl. 2007, 46, 5565–5567. 60. Kang, Q.; Zhao, Z. A.; You, S. L. J. Am. Chem. Soc. 2007, 129, 1484–1485. 61. Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086–1087. 62. Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed. Engl. 2007, 46, 7485–7487. 63. Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005, 127, 9360–9361. 64. Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612–1613. 65. Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K. Synlett 2006, 141–143. 66. Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem. Int. Ed. Engl. 2006, 45, 4796–4798. 67. Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070–13071. 68. Liu, H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Org. Lett. 2006, 8, 6023–6026. 69. Rueping, M.; Azap, C. Angew. Chem. Int. Ed. Engl. 2006, 45, 7832–7835. 70. Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781–3783. 71. Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. Engl. 2005, 44, 7424–7427. 72. Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86. 73. Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem. Int. Ed. Engl. 2006, 45, 6751–6755. 74. Rueping, M.; Antonchick, A. R.; Theissmann, T. Angew. Chem. Int. Ed. Engl. 2006, 45, 3683–3686. 75. Rueping, M.; Antonchick, A. P. Angew. Chem. Int. Ed. Engl. 2007, 46, 4562–4565. 76. Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128, 13074–13075. 77. Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498–7499. 78. Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523–1526. 79. Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006, 133–136. 80. Rowland, G. B.; Zhang, H. L.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696–15697. 81. Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007, 4477–4479. 82. Li, G. L.; Liang, Y. X.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830–5831. 83. Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084–12085. 84. Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626–9627.

REFERENCES 161

85. Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem. Int. Ed. Engl. 2008, 47, 2411–2413. 86. Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J. Angew. Chem. Int. Ed. Engl. 2007, 46, 2097–2100. 87. Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem. Int. Ed. Engl. 2008, 47, 593–596. 88. Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem. Int. Ed. Engl. 2008, 47, 6798–6801. 89. Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246–9247. 90. Mayer, S.; List, B. Angew. Chem. Int. Ed. Engl. 2006, 45, 4193–4195. 91. Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368–13369. 92. Wang, X.; List, B. Angew. Chem. Int. Ed. Engl. 2008, 47, 1119–1122. 93. Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070–6071. 94. Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496–499. 95. Rueping, M.; Antonchick, A. R.; Brinkmann, C. Angew. Chem. Int. Ed. Engl. 2007, 46, 6903–6906.

4 ASYMMETRIC SYNTHESIS THROUGH C–H ACTIVATION Huw M. L. Davies and Jørn Hansen Department of Chemistry, Emory University, Atlanta, GA

4.1. INTRODUCTION Transition metal-catalyzed activation of carbon–hydrogen bonds in organic molecules for the purpose of functionalization (formation of C–C, C–O, C–N, or C–B bonds) has been subject to extensive investigation by the chemical community for the past 25 years [1–22]. Due to the ubiquity of C–H bonds in organic molecules, such transformations constitute an attractive approach for the direct synthesis of complex molecules, such as pharmaceuticals, natural products, and other industrially relevant targets, from simple starting materials [19]. However, since high-energy species are required to activate the relatively strong C–H bond, the issue of selective activation becomes of concern [18]. Much effort has been made to achieve practical, catalytic, and selective methods for C–H functionalization [13,14,18–20]. However, these remain major challenges. Two major directions have evolved (Fig. 4.1): (i) direct C–H activation, involving oxidative addition of the C–H bond onto an active metal center, which in turn can result in functionalization of the bond; and (ii) insertion of transition metal-coordinated carbenes or nitrenes into the C–H bond to afford functionalized products directly [23,24]. Direct activation of the C–H bond via oxidative addition to a suitable metal complex has been investigated at length by the organometallic community [4,5,13,15,17–21]. Many approaches have been described, but a major challenge has been to regenerate a catalytically active species and thereby achieve a catalytic process. While this has been developed in recent years, selectivity still remains a problem. Kakiuchi and Murai described the use of a coordinating moiety to direct the metal to the desired site of insertion [25]. Such directing groups can be a suitable heteroatomic moiety in the substrate. Oxidative addition usually forms a five- or six-membered metallacycle


164 ASYMMETRIC SYNTHESIS THROUGH C–H ACTIVATION

Carbenoid C–H activation

“Traditional” C–H activation C M H

H C C X Y M

X C H

M C Y

X M N

X C N H Nitrenoid C–H activation

Figure 4.1. Various modes of C–H activation.

intermediate, which is quite versatile in terms of constructing new functional group appendages onto the substrate. This approach has been applied to many elaborate systems by several groups [4,5,9,26–41]. The method of insertion of metal-coordinated carbenes has been developed to be the most generally practical and selective approach to date, showcased by extensive applications in natural product syntheses [1,3,4,7,11,14,16,19,24,42–61]. In this process, the activation of the C–H bond does not directly involve the metal center, but a concerted insertion of the metal-bound carbene [3,21,48,49]. Intramolecular C–H activation is the most investigated direction since regioselectivity can be effectively controlled in many cases [8,45,48–50,60]. Chiral catalyst development in this area has also been extensive based particularly on the dirhodium(II) framework [3,60,62–64]. The substituents on the coordinated metal carbene play a crucial role in reaction outcome in this chemistry, and it was only when aryl- and vinyldiazoacetates were developed as carbenoid precursors that selective asymmetric intermolecular processes were rendered feasible [3,42]. This chemistry has been expanded in many directions and has been used in the syntheses of natural products and pharmaceutical targets. Catalytic C–H amination is an attractive method for the formation of C–N bonds [12,14,19,21,23,51,65,66]. In recent years, this field has had a renaissance due to emerging technologies: In particular, the development of new catalysts and nitrene precursors have played a key role [12,23,67]. Furthermore, the applicability of catalytic C–H amination has been demonstrated impressively in total syntheses of very complex natural products such as tetrodotoxin by Du Bois and coworkers [68]. Dodd, Dauban, and coworkers developed a novel approach toward practical and stereoselective aminations by using a chiral nitrene source [69]. This review will first give a thorough overview of asymmetric C–H activation via metal carbenoid complexes along with a survey of important catalyst systems for both intra- and intermolecular processes. Focus will be placed on useful processes for organic synthesis. Furthermore, an overview of current achievements in asymmetric metal nitrene insertions will be presented. Although asymmetric nitrene reactions are not yet developed fully, the transformation is proving to be synthetically very powerful. This will be highlighted through a discussion of some recent, achiral, syntheses via C–H amination. Finally, the major advances in the area of “traditional” C–H activation will

4.2. ASYMMETRIC C–H ACTIVATION VIA METAL CARBENOID INSERTION

165

be presented, with focus on stereoselective transformations. Also here, asymmetric C–H functionalizations have not been developed to great extent, but the synthetic value of the reactions will be highlighted with achiral examples.

4.2. ASYMMETRIC C–H ACTIVATION VIA METAL CARBENOID INSERTION 4.2.1. Generation, Classification, and Reactions of Metal Carbenoids Metal carbenes are typically generated by metal-catalyzed nitrogen extrusion from diazo compounds [49]. Alternative carbene precursors include iodonium, phosphonium, sulfonium, sulfoxonium, and thiophenium ylides, but their synthetic use is less developed [70–78]. According to the currently accepted mechanism [79,80,81] for the generation of carbenes via dirhodium(II) complexes (Scheme 4.1), in the presence of the appropriate metal complex M, the diazo compound will coordinate reversibly to an open active site and undergo rate-limiting extrusion of nitrogen to form the highly reactive intermediate metal carbenoid complex [49,80–83]. The high reactivity of the electrophilic carbenoid complex will lead to immediate reaction with a suitable trapping agent present in the reaction mixture or embedded in the diazoacetate structure (k3 is large) [49,80]. Common reactions of metal carbenoids include cyclopropanation/propenation reactions [6,7,45,48,49,55,84,85], [3 + 2] cycloadditions [86–88], C–H insertions [3,6,7,45,48,55], and ylide formation [45,49,55]. C–H insertion processes will be discussed at length in this chapter.

R H R'

N2 k1

M

R

R'

k-1 k3

H

M

R

R'

k2

M R

N2

R'

N2 (g)

Scheme 4.1. Mechanism of carbenoid C–H insertion [79,80,81].

The transient metal carbenoid intermediate has a large number of reaction pathways available due to its reactive nature [6,7,46,48,49,52,54,56,61,85,89–92]. The development of practical methods for C–H activation via such high-energy intermediates has therefore centered on achieving control over the broad spectrum of reactions that can take place [3]. The intrinsic reactivity of the metal carbenoid intermediate is modulated by


Increasing reactivity Acceptor/acceptor carbenoid EWG

EWG M

EWG = CO2R COR NO2 PO(OR)2 SO2R CN

Increasing stability Acceptor carbenoid EWG

H

Donor/acceptor carbenoid EWG

M EWG = CO2R EWG = COR NO2 PO(OR)2 SO2R EDG =

EDG M CO2R COR PO(OR)2 CN CF3 vinyl aryl alkynyl heteroaryl

Figure 4.2. Classification of carbenoid intermediates [3].

(i) the metal [93–103], (ii) the ligands [61,96,97,99–102] on the metal complex, and (iii) the substituents on the carbenoid carbon [3,104–107]. Although the effect of the metal and its ligands on the reactivity of metal carbenoids has been studied extensively, the influences of substituents on the carbenoid carbon had not received much attention until the last decade [3,11,108]. It has become evident that these substituents play a dominant role in determining the selectivity of the carbenoid complex [108]. With the different substituent patterns currently used, the carbenoid complexes can be conveniently classified into three classes based on the carbenoid substituents [3] (Fig. 4.2): (i) acceptor carbenoids [49,61], which contain one electron-withdrawing group; (ii) acceptor/acceptor carbenoids [61],which contain two electron-withdrawing groups; and (iii) donor/ acceptor carbenoids [3], which contain an electron-donating as well as an electronwithdrawing group (Fig. 4.2). The simple acceptor and double acceptor systems have been used in metal carbenoid chemistry for over 50 years [61], whereas the donor/acceptor class has appeared in the last 20 years and has displayed superior selectivity for intermolecular C–H insertion processes due to the increased stability of the carbenoid imparted by the donor group [3,11]. Dirhodium(II) complexes have emerged as the chiral catalysts of choice for C–H insertion processes via carbenoid intermediates [3,6,7,46,49,52,62,92]. The major classes include the carboxylates, carboxamidates, phosphonates, and orthometallated phosphines. Dirhodium(II) complexes are generally superior for these C–H insertion processes with respect to both yield and selectivity. The catalyst complexes and the corresponding models of enantioinduction will be discussed in this chapter.

4.2.2. Catalysts 4.2.2.1. Dirhodium(II) Carboxamidate Complexes Dirhodium(II) carboxamidate catalysts, derived from enantiomerically pure α-carboxamides, were initially developed by Doyle (Fig. 4.3) [46,109].The complexes have overall C2-symmetry due to the inherent

167


R' N

O R

R''

N

Rh

R'O

Rh

N

O

R O R'

R' or R''

R''

N

N

Rh

O

Rh

O

R''

N

R R

O

N R'

O

N 2

C2 -symmetric

1

R''

R=

R' =

a

CH2

CO2Me

Rh2(5S-MEPY)4

a

CH3

Rh2(4S-MEAZ)4

b

O

CO2Me

Rh2(4S-MEOX)4

b

i-Bu

Rh2(4S-IBAZ)4

c

O

Bn

Rh2(4R-BNOX)4

c

Bn

Rh2(4S-BNAZ)4

d

O

Ph

Rh2(4S-PHOX)4

d

c-C6H11

Rh2(4S-CHAZ)4

e CH2C(Me)3

R'' =

e

N(CO)Me

CO2Me

Rh2(4S-MACIM)4

f

N(CO)CH2Bn

CO2Me

Rh2(4S-MPPIM)4

g

N(CO)CH2CH3 CO2Me

Rh2(4S-MCHIM)4

h

N

O

CO2Me

Rh2(4S-NEPAZ)4

Rh2(4S,S-BSPIM)4

PhO2S N

Figure 4.3. Dirhodium(II) carboxamidates [62].

preference for the carboxamide ligands to arrange themselves in the cis-(2,2) configuration, in which two oxygens and two nitrogens are attached to each rhodium in the dirhodium core [110,111]. This class of catalysts has been developed in many directions and consists of a number of complexes with somewhat different reactivity profiles. The major complexes are based on 2-oxopyrrolidines [112,113], 2-oxazolidinones [47], 2-azetidinones [114], and N-acylimidazolidin-2-ones [115,116]. These complexes are the superior catalysts for intramolecular transformations of acceptor and acceptor/acceptor carbenoids [49,50,60,117]. In particular, intramolecular cyclization of carbenoids derived from diazoacetamides and diazoesters displays exceptional stereo- and regiocontrol [3]. Acceptor-substituted carbenoids derived from diazoacetates can undergo intramolecular C–H insertions with excellent stereo- and regiocontrol when Rh2(4S-MPPIM)4 and Rh2(4S-MACIM)4 are used as catalysts [66]. With more sterically hindered diazoacetate systems, the less bulky catalysts such as Rh2(5S-MEPY)4 and Rh2(4S-MEOX)4 commonly give higher levels of stereo- and regiocontrol in the cyclization [66]. The elongation of the Rh–Rh bond in the azetidinone-based catalysts leads to more reactive complexes, which can even catalyze intramolecular reactions of aryldiazoacetates with moderate enantiocontrol [118–120]. 4.2.2.2. Dirhodium(II) Carboxylate Complexes N-phthaloyl-protected amino acidbased dirhodium(II) complexes were developed by Hashimoto, Ikegami, and coworkers


Rh

O

Rh

O

R

H N

O 3 R=

O

4

Rh

O

Rh

O

R'

Phthaloyl groups

O

H N

O 4

4 Rh2(S-PTPA)4

a

Bn

b

CH3

Rh2(S-PTA)4

c

i-Pr

Rh2(S-PTV)4

d

t-Bu

Rh2(S-PTTL)4

e

Ad

Rh2(S-PTAD)4

f

Ph

Rh2(S-PTPG)4

R' = C2 -symmetric

Rh2(S-BPTPA)4

a

Bn

b

CH3

Rh2(S-BPTA)4

c

i-Pr

Rh2(S-BPTV)4

d

t-Bu

Rh2(S-BPTTL)4

e

Ph

Rh2(S-BPTPG)4

Figure 4.4. Dirhodium(II) phthaloyl-protected carboxylates [62].

(Fig. 4.4) [49,121]. The complexes are assumed to preferentially exist in a C2-symmetric conformation, based on X-ray analysis, in which the phthaloyl portions act as bulky groups restricting the carbenoid conformations and substrate trajectories [122]. These catalysts have been developed into a diverse class by variation of the R-group [62]. In second generation catalysts, the phthaloyl moiety has been further modified by elongation with an additional benzene ring or by halogen substitution on the aromatic ring [89]. β-Lactam formation from α-methoxycarbonyl-α-diazoacetamides is best catalyzed by Rh2(S-PTA)4 and, for α-diazo-β-ketoesters Rh2(S-PTPA)4, is the most successful catalyst for intramolecular cyclizations [123]. High asymmetric induction is usually observed in a relatively broad spectrum of reactions with the tert-butyl derivative Rh2(S-PTTL)4. This complex has been successfully employed in the formation of γ-lactams from αmethoxycarbonyl-α-diazoacetamides [124] and intramolecular C–H insertion into methylene sites with aryldiazoacetates [125] and some α-diazo-β-ketoesters [126]. A recent addition to this class is the adamantyl derivative Rh2(S-PTAD)4, developed by the Davies group [127]. The development of the proline-derived dirhodium(II) complexes was sparked by the initial report by McKervey and others that an intramolecular C–H insertion with the dirhodium(II) prolinate complex Rh2(S-BSP)4 (5a, Fig. 4.5) could be achieved in an enantioselective manner [128,129]. For acceptor and acceptor/acceptor carbenoids, the prolinate complexes were found to be moderate in terms of enantiocontrol in intramolecular C–H insertions. Further development of the dirhodium(II) prolinates by Davies and others into the more soluble complexes Rh2(S-TBSP)4 and Rh2(S-DOSP)4 (Fig. 4.5) led to the discovery that these were excellent catalysts for asymmetric transformations of donor/acceptor carbenoids in nonpolar solvents [11,42,43,84,130,131]. The dirhodium(II) prolinates are proposed to preferentially exist in a D2-symmetric conformation in which the arylsulfonyl groups act as bulky groups sterically restricting the substrate trajectory and carbenoid alignment [42,62,84]. Second generation


H

H

O

O

Rh

N O ArO2S SO2Ar O N H O

SO2Ar N

O

Arylsulfonyl groups

O Rh

169

O

H

5

N SO2Ar

Ar =

D2 -symmetry

a

Ph

b

4-(t-Bu)Ph

Rh2(S-TBSP)4

c

4-(C12H25)Ph

Rh2(S-DOSP)4

Rh2(S-BSP)4

H

H

O

N SO2Ar O ArO2S O N H O H

Rh

O

H

SO2Ar H N

O O Rh 6

O

H

N H SO2Ar

Ar = a

4-(C12H25)Ph

b

2,4,6-tri-(i-Pr)Ph

Rh2(S-biDOSP)2 Rh2(S-biTISP)2

Figure 4.5. Dirhodium(II) prolinate complexes [62].

dirhodium(II) prolinates were designed by Davies and others that have the arylsulfonyl groups conformationally locked to give the complex overall D2-symmetry [42,84,132,133]. This class of catalysts can catalyze intermolecular C–H insertion processes of donor/ acceptor carbenoids with remarkably high levels of chemo- and stereoselectivity [3]. Furthermore, intramolecular C–H insertions into activated methylene sites with aryldiazoacetates have been successfully achieved [3]. 4.2.2.3. Dirhodium(II) Ortho-Metallated Arylphosphines The C2-symmetric orthometallated arylphosphine dirhodium(II) complexes developed by Perez-Prieto, Lahuerta, and coworkers displayed promising results in intramolecular C–H insertions of acceptor carbenoids derived from diazoketones (Fig. 4.6) [134–138]. However, this class has not yet found extensive application in C–H insertion chemistry [3]. 4.2.2.4. Copper(I) Complexes Traditionally, copper complexes have been used as catalysts for carbenoid reactions, but the high electrophilic character of the intermediate carbenoid complex renders it somewhat too reactive to achieve selective C–H insertions [49,57,73,139,140]. Nevertheless, copper(I) complexes, typically with C2-symmetric bidentate ligands, have been reported to give moderately good enantiocontrol in intramolecular C–H insertions of α-diazo-β-ketoesters [73]. The bisoxazoline class of ligands has achieved the most success [73,128,140–144], whereas binaphthyl and salen complexes resulted in low to moderate levels of enantiocontrol [57,72,73,128,145–147].


R' F3C F3C

O

Rh

PR2 PR2

O O

Rh

O 7

R'

R=

R' =

a

Ph

H

b

4-(Me)Ph

4-Me

c

4-(Me)Ph

3-Me

d 3,5-(Me)2Ph

3,5-(Me)2

e

4-(t-Bu)Ph

4-(t-Bu)

f

4-(F)Ph

4-F

g

Me

H

Figure 4.6. Dirhodium(II) orthometallated phosphines.

4.2.3. Intramolecular C–H Insertion Since highly electrophilic catalysts are required and selectivities are low for intermolecular C–H insertions with acceptor and acceptor/acceptor carbenoids, intramolecular versions were the first to be developed [3,45,49]. High selectivity for the intramolecular reaction, rather than an intermolecular process, can be achieved to form four- and fivemembered rings, but also three-, six-, and higher-membered ring sizes have been generated [3,45,48,49]. Intramolecular C–H insertions of diazocarbonyl compounds occur effectively in a very selective manner, even with relatively electron-rich catalyst systems. A variety of heterocyclic and carbocyclic structures can be generated with high regioand stereocontrol [8,49,59,61,139,148,149]. The most important results will be discussed in this section. 4.2.3.1. Synthesis of Carbocycles The first report of enantioinduction in an intramolecular C–H insertion was by McKervey and others, who employed the chiral dirhodium(II) prolinate complex Rh2(S-BSP)4 [150]. The cyclopentanone 9 was formed in good yield but with only about 12% ee (Scheme 4.2). However, this discovery paved the way for further developments in the field, and Ikegami, Hashimoto, and others subsequently reported cyclopentanone formation with diazocarbonyl compound 10 (Table 4.1) with enantioselectivities in the 33–80% ee range [123,151]. O

O SO2Ph

N2

Rh2(S-BSP)4 SO2Ph

CH2Cl2 Me

8

>90% yield, 12% ee

9

Scheme 4.2. First example of enantioselective C–H insertion.

Dirhodium(II) carboxylates are the most effective catalysts for reactions of acceptor/ acceptor diazo compounds since they can be made sufficiently electron deficient to be kinetically active for the decomposition of the relatively stable carbenoid precursors [42,152]. The more electron-rich dirhodium(II) carboxamidates are unable to form the


171

TABLE 4.1. Intramolecular C–H Insertion with Rh2(S-PTPA)4

O

O CO2CH(i-Pr)2

Rh2(S-PTPA)4

R

CO2CH(i-Pr)2

CH2Cl2, 0°C

N2

R

10

Compound a b c

11

R=

Yield (%)

ee (%)

Ph 4-(MeO)Ph 4-(CF3SO2)Ph

86 86

76 57

84

80

H

H

R

O H

CO2(i-Pr) III

IV II

O

R H

O CO2(i-Pr) R

CO2(i-Pr)

I

Figure 4.7. Model for cyclopentanone formation with Hashimoto’s catalysts [62,155].

carbenoid complex under ambient conditions [72,118]. The phthaloyl-protected amino acid-derived dirhodium complexes are the most effective catalysts for intramolecular C–H insertions of α-diazo-β-ketoesters (Table 4.1) [121,123,151,153,154]. The enantiocontrol was found to be very dependent on ester group size as well as substituents adjacent to the insertion site. The highest enantioselectivities (57–80% ee) were obtained with relatively large ester groups. Aryl substituents at the insertion site also increased enantiocontrol relative to vinyl or alkyl substituents. Electron-withdrawing groups on the aryl ring significantly enhanced the level of enantioinduction [3]. Figure 4.7 shows a schematic model that rationalizes the outcome of the intramolecular C–H insertion process to form cyclopentanones with Hashimoto’s catalyst systems [3,122,155]. The O–Rh–O plane is represented by a disk that is divided into four quadrants [62]. The phthaloyl groups are represented by rods, which sterically restrict the space above the O–Rh–O plane. Since these catalysts are proposed to be C2-symmetric, two pthaloyl groups will be present in adjacent quadrants II and III [62,122]. The bulky ester substituent on the carbenoid will minimize steric interactions with the blocking groups and therefore align along the y-axis, pointing away from quadrants III/IV. Furthermore, the ketone substituent will also minimize steric interactions such that the ring closure will mainly occur via quadrant IV to result in Si-face attack on the carbenoid carbon through a half-chair-type transition state [122,155]. This model successfully predicts the major products of these reactions. Taber and Malcolm reported a total synthesis of the marine secosteroid (−)-astrogorgiadiol, in which they employed chiral dirhodium(II) catalysts in the intramolecular C–H


TABLE 4.2. Synthetic Studies toward (−)-Astrogorgiadiol

O

O CO2Me

O

Rh(II)-cat.

CO2Me

N2 CH2Cl2, 20°C Me

CO2Me

H Me

12

H Me

13

14

HO

HO

Me 15

H

Me CO2Me H

Me

(–)-astrogorgiadiol d.r. Catalyst

13:14

Yield (%)

Rh2(S-PTPA)4

26:74

98

Rh2(5S-MEPY)4

43:57

66

Rh2(S-DOSP)4

36:64

94

Rh2(S-biTISP)2

21:79

38

insertion of α-diazo-β-ketoester 12 (Table 4.2) [156]. The goal was to optimize the diastereoselectivity of the reaction by screening various catalysts. The optimal selectivity for 14 was achieved with Rh2(S-biTISP)2, which gave 58% de but with a moderate yield of 38%. Rh2(S-PTPA)4 gave an excellent 98% yield but somewhat lower diastereoselectivity. The dirhodium(II) ortho-metallated arylphosphines (7), developed by Lahuerta, Perez-Prieto, and coworkers, have been shown to be effective catalysts for the intramolecular C–H insertions of certain diazoketones [102,134,137,138]. Carbenoids derived from diazoketones are well known for their high reactivity, and, consequently, the development of enantioselective processes for these reagents has been problematic [63,128,145,157]. Significant progress has been made with the introduction of the orthometallated arylphosphine dirhodium(II) complexes. Wide variations in yield and enantioselectivities were observed with a diversely functionalized set of arylphosphine ligands, but none of the catalysts appeared to display universal effectiveness [134]. Furthermore, the reactions were sensitive to the functional groups at the insertion site [134]. The best example is shown in Scheme 4.3, where the chloro-substituted system afforded the cyclopentanone 17 in 74% ee and 87% yield with catalyst 7c. In general, this system worked best with electron-withdrawing groups on the aryl portion, suggesting that the electron-withdrawing substituent deactivates the benzylic C–H bond to achieve a late transition state for the insertion and hence, increased selectivity [134].


O

O N2

CH2Cl2, 40°C 87% yield, 74% ee

Cl

Rh

O O

F3C

Cl 16

O

F3C

7c

173

PR2 PR2

Rh

O

17 7c

R = 3-(Me)Ph

Scheme 4.3. Diazoketone cyclization with ortho-metallated arylphosphine complex 7c.

N2

CO2Me CO2Me O O N2

O

O CO2Me Rh2(S-PTTL)4

CO2Me DMSO

Toluene, –10°C

18

120°C

O

O

78% yield 80% ee

19

20

Scheme 4.4. Formation of spiran 19 by double C–H insertion.

N2 Me

CO2Me O

Ph 21

CO2Me Rh2(S-TFPTTL)4

DMSO O

CH2Cl2, 0°C 2 min

Ph Me 22

O

120°C

Ph Me 90% yield 97% ee

23

Scheme 4.5. Desymmetrization of 21.

Synthetic utility is significantly enhanced if the stereocontrolled formation of quaternary stereocenters can be achieved. An outstanding example of this is the double C–H insertion reaction of 18 to form the chiral spiran system 19 catalyzed by Rh2(S-PTTL)4 (Scheme 4.4) [158]. After thermal decarboxylation, product 20 was obtained in 78% yield and with 80% ee. The less bulky catalyst Rh2(S-PTPA)4 gave much lower stereocontrol with only 25% ee [158]. Rh2(S-PTTL)4 has also been an effective catalyst for the desymmetrization of aryl-substituted diazo ketoesters (Scheme 4.5), and can catalyze the formal aromatic C–H insertion to form product 22 in 89% yield and 92% ee with a reaction time of 60 min [159]. Although this particular reaction proceeds via electrophilic aromatic substitution, it is an impressive example of the efficiency and potential of dirhodium(II) complexes as catalysts. The reaction was dramatically improved by employing the corresponding tetrafluorinated phthaloyl complex Rh2(S-TFPTTL)4 (dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate]), which afforded 90% yield and 97% ee with a reaction time of only 2 min [159]. Turnover numbers of up to 98,000 have been achieved, with a catalyst loading of only 0.001 mol %, without deterioration of yield and enantioselectivity [159]. A remarkable feature of this is that it shows that the catalyst can effectively distinguish between two enantiotopic phenyl groups.


A major problem in the formation of cyclopentanes via intramolecular C–H insertions of α-diazoesters is the competing β-elimination to form cis-alkenes [160]. Taber and Joshi reported that the ratio of C–H insertion versus β-elimination in such systems is influenced by the electronic nature of the catalyst as well as the steric bulk of the ligands [161]. Based on this work, significant progress in the area was reported by Hashimoto and coworkers (Scheme 4.6) [160]. Diazoesters 24 were reported to undergo exclusive insertion to form the corresponding cis-cyclopentanes 25 in 81–85% yield with 92–95% ee when catalyzed by Rh2(S-PTTL)4. Further exploration revealed that simple alkyl diazoester 26 (Scheme 4.7) also gave insertion products exclusively with the transdiastereomer as major product in 68% yield and 94% ee. A significant amount of the cis-diastereomer was also formed (7%). Reaction of the phenyl system 28 (Scheme 4.8) afforded the corresponding disubstituted cis-indane product 29 in 85% yield and 92% ee. A remarkable feature of these examples is that no trace of competing β-elimination was observed. These examples underscore the importance of choice of conditions and catalyst for carbenoid transformations [160].

CO2Me N2

CO2Me

Rh2(S-PTTL)4

R= H OMe Cl

Toluene, –78°C R

R

81–85% yield 92–95% ee

24

25

Scheme 4.6. Enantioselective cyclopentane formation.

CO2Me N2

CO2Me

Rh2(S-PTTL)4

CO2Me

Toluene, –78°C 26

cis-27 7% yield

trans-27 68% yield 94% ee

Scheme 4.7. Intramolecular reaction of alkyldiazoacetate 26.

CO2Me N2 Ph 28

Rh2(S-PTTL)4 CO2Me Toluene, –78°C 85% yield 92% ee

Ph 29

Scheme 4.8. Formation of substituted indane 29.


175

4.2.3.2. Synthesis of Lactone and Lactam Heterocycles Intramolecular C–H insertions of diazoacetates and diazoacetamides to form lactone and lactam heterocycles, respectively, have been developed extensively [3,45,48,53,61,96]. The optimal catalyst systems for these transformations are Doyle’s carboxamidates and Hashimoto’s phthaloyl catalysts [7,48,58,60,66]. Typically, diazoacetates decompose to form γ-lactones; however, β-lactones can also be formed in selected systems. The formation of the latter is not particularly favored since the activating effect of the adjacent oxygen is very small due to its resonance with the carbonyl group. The carboxamidates can achieve exceptional enantiocontrol in lactone formation from diazoacetates [46,48,61]. Factors that control product formation are (i) the reactivity of the C–H bond (3° > 2° >> 1°) and (ii) favorable five-membered ring formation [66]. Furthermore, regio- and chemoselectivities can be controlled effectively by the catalyst structure in many cases. Excellent examples are the reactions of substituted ethyl diazoacetates 30, which in the presence of chiral dirhodium(II) carboxamidates form the γ-butyrolactones 31 preferentially (Table 4.3) [162–165]. Five-membered ring formation is remarkably favored, since competing benzylic C–H functionalization to form a six-membered ring is not observed [162,165,166]. In this reaction, the second generation imidazolidinone catalyst Rh2(4SMPPIM)4 performs very well with yields of 50 to >98% and levels of enantioinduction in the 87–96% range [162,167]. The N-3-phenylpropanoyl substituent in this catalyst is believed to direct the orientation of the carbenoid intermediate and thus enhance enantiocontrol [168]. In comparison, the first generation catalysts Rh2(MEOX)4 and Rh2(MEPY)4 afforded only moderate enantiocontrol. An idealized model rationalizes the observed stereochemistry (Fig. 4.8) [3,49,60]. In the C2-symmetric carboxamidate complex, quadrants III and IV are blocked by the catalyst and thereby force the carbene to adopt the shown orientation. The other possible orientation is disfavored presumably because of more steric interactions with the blocking group in quadrant IV. The intramolecular attack can now occur through quadrant I via a half-chair conformation with the R-group pointing away from the catalyst [155]. In the desymmetrization reaction of cyclohexyldiazoacetate 32 (Table 4.4), both first and second generation carboxamidate catalysts give very good enantiocontrol for the reaction (95–97% ee for the syn-diastereomer) [63,169,170]. However, there is a distinct difference in terms of diastereoselectivity. Whereas the first generation catalysts Rh2(MEOX)4 and Rh2(MEPY)4 give mixtures of cis-fused and trans-fused products 33 and 34, respectively, Rh2(4S-MACIM)4 gives a 99:1 ratio of 33:34 in 70% yield and with 95% ee of the major product [63,98,169]. This is again attributed to the N-substituent in the second generation catalysts, which gives more control of the carbenoid orientation [3]. In the desymmetrization of acyclic diazoacetate system 35 (Table 4.5) with alkyl

R H

R H

H O

IV I

H

O III

H

H

O

R

O

II

Figure 4.8. Model for lactone formation with Rh2(4S-MPPIM)4.

O O


TABLE 4.3. Enantioselective γ-Lactone Formation

O

O Rh2(4S-MPPIM)4

O N2

O

CH2Cl2, 40°C R 31

R 30 Compound

R=

Yield (%)

ee (%)

a b c d

CH2Ph Ph CH2CH(Me)2 OMe

50 52 60

87 96 95 93

e

4-(Cl)Ph

>98 81

95

TABLE 4.4. Desymmetrization of Cyclohexyl Diazoacetate 32

O

O Rh(II)-cat.

O N2

H

O

O

CH2Cl2, 40°C

H

O

H

32

33 d.r.

H 34 ee (%)

ee (%)

Catalyst

33:34

Yield (%)

33

34

Rh2(4S-MACIM)4

99:1

70

97

65

Rh2(5S-MEPY)4

75:25

30

95

90

Rh2(4S-MEOX)4

55:45

50

96

95

substituents, second generation complexes Rh2(4S-MCHIM)4 and Rh2(4S-MPPIM)4 give excellent diastereo- and enantiocontrol (94–96% de, 99% ee), favoring the syn-diastereomer 36 in 81–87% yield [169,171,172]. First generation catalysts afford much lower diastereoselectivity (38–56% de) but retain excellent enantiomeric excess for the major syn-diastereomer 36 (98% ee) [169]. In the more activated dialkoxy system, where R = OMe, these catalysts give good yields (65–80%) as well as improved control over diastereoselectivity (82–88% de). Enantiocontrol over the major diastereomer 36 remains excellent throughout this series [171,172]. In the tertiary system 38 (Scheme 4.9), a mixture of the expected insertion into a methylene group and insertion into the methyl group is observed (9:1 ratio) [63,98]. The same product ratio was observed for both cyclopentane and cyclohexane systems with Rh2(4S-MACIM)4, which is the most effective catalyst for this reaction. Yield and enantioselectivity is somewhat lower for the cyclopentane system (56% yield, 85% ee) than

177


TABLE 4.5. Desymmetrization of Acyclic Diazoacetate System 35

O

O Rh(II)-cat.

O

H

N2 CH Cl , 40°C 2 2 R

O

O

H

O

H

R

H

R

R

35

R

R

36

37

d.r.

ee (%)

ee (%)

Catalyst

R=

36:37

Yield (%)

36

37

Rh2(4S-MCHIM)4

Me

98:2

87

99

—

Rh2(4S-MPPIM)4

Me

97:3

81

99

—

Rh2(5S-MEPY)4

Me

78:22

70

98

71

Rh2(4S-MEOX)4

Me

69:31

75

98

92

Rh2(5S-MEPY)4

OMe

94:6

65–80

97

45

Rh2(4S-MEOX)4

OMe

91:9

65–80

98

76

O

O Rh2(4S-MACIM)4

O Me

N2

Me

O

CH2Cl2, 40°C

n=

Yield (%) ee (%) 39

H n

n

n

38

O

O

39

0

56

85

1

68

90

40 90

:

10

Scheme 4.9. Desymmetrization of tertiary system 38.

for the cyclohexane system (68% yield, 90% ee) [63,98]. Very sterically hindered systems, such as adamantoyl diazoacetates 41 and 43 can be decomposed effectively in the presence of Rh2(4S-MEOX)4 to afford the desymmetrized products 42 and 44, respectively, with high levels of enantiocontrol (90–98% ee) [47] (Scheme 4.10). The (1S, 2R)-enantiomer of unsymmetrical diazoacetate 45 (Scheme 4.11) is observed to give mainly products (1S, 2R)-46 and (1S, 2R)-47 as well as minor by-products [168]. However, product 47 is significantly favored with Rh2(5S-MEPY)4 (94:6 product ratio) and product 46 with Rh2(5R-MEPY)4 (91:9 product ratio) [168]. Consequently, by employing racemic-45 with Rh2(5S-MEPY)4 as catalyst (Scheme 4.11), an effective kinetic resolution was observed to form products 46 and 47 in about 1:1 ratio with high levels of enantiocontrol (91–98% ee) [168]. Many remarkable examples of effective differential control of diastereo- and regioselectivity with such chiral dirhodium carboxamidate catalysts can be found in the literature [63,98,120,168,170,172].


N2 O H O 42 98% ee

O O

41

Rh2(4S-MEOX)4

O

O O

N2

O

H 44 90% ee

43

Scheme 4.10. Desymmetrization of adamantanoyl diazoacetates.

O

O

O N2

Me

(±)-45

CH2Cl2, 40°C

O O

O

Rh2(5S-MEPY)4 Me

Me

46 37% yield 98% ee

47 34% yield 91% ee

Scheme 4.11. Reaction of unsymmetrical diazoacetate 45.

Enantioselective γ-lactone formation via intramolecular C–H insertion of diazoacetates has been demonstrated to be a powerful technology in the synthesis of natural products and pharmaceutical targets (Scheme 4.12), such as (+)-isodeoxypodophyllotoxin (50) [162,164], (−)-enterolactone (52), (S)-(+)-imperanene [165] (54), and (R)-(−)baclofen [167] (56), which have been synthesized with the lactone formation as a key step catalyzed by Rh2(4S/R-MPPIM)4 from the appropriate diazoacetate precursors. Very high enantioselectivities have been obtained in many applications of this chemistry. The intramolecular cyclization with cyclohexyl aryldiazoacetate system 57 (Table 4.6) preferably formed the β-lactone system 58 when the azetidinone-based dirhodium(II) carboxamidate catalysts were used [119]. The same was also observed with carboxylate catalysts [120]. This is opposite to what was observed with unsubstituted diazoacetate systems, in which the γ-lactone products were formed exclusively. Chemoselectivities were high (>97% product selectivity), and the products were formed in 66–69% yield. However, good control of enantioinduction was not achieved, only 42–51% ee with the carboxamidate catalysts tested, and 63% ee with Rh2(S-DOSP)4 [119,168]. The acyclic system 60 only formed γ-lactone product 61 (Table 4.7). This reaction was effectively catalyzed by both Rh2(S-MEAZ)4 and Rh2(S-DOSP)4, although the former gave slightly higher yield and enantiomeric excess (94% yield, 90% ee) [118,119].

179


O

MeO

O

OMe OMe

O S-cat. O O

O O

O 50 (+)-Isodeoxypodophyllotoxin

49 67% yield 95% ee

O

O

O

O

R-cat. OH MeO 51 62% yield 93% ee

O Rh2(4S/R-MPPIM)4

O N2

MeO 52 (–)-Enterolactone

CH2Cl2, 40°C O

R 48

OH

O MeO S-cat. MeO

HO OH MeO 54 (S)-(+)-imperanene

TBDPSO 53 68% yield 93% ee O

CO2H

O H2N

S-cat.

55 81% yield 95% ee

Cl

Cl 56 (R)-(–)-baclofen HCl

Scheme 4.12. Synthetic applications of stereoselective γ-lactone formation.

HCl


TABLE 4.6. Desymmetrization of Cyclohexyl Phenyldiazoacetate 57

O Ph

O O

O

Rh(II)-cat. Ph

N2

57

O O Ph

58

59

Ratio

ee (%)

Catalyst

58:59

Yield (%)

58

Rh2(S-MEAZ)4

98:2

67

50

Rh2(S-IBAZ)4

97:3

66

51

Rh2(S-DOSP)4

98:2

69

63

TABLE 4.7. Lactonization of Acyclic System 60

O Ph

O O

Rh(II)-cat.

Ph O

N2 60

61

Catalyst

Yield (%)

ee (%)

Rh2(4S-MEAZ)4

94

90

Rh2(S-DOSP)4

89

86

O

O

O

O

N2

O O

N2 62

CH2Cl2, 40°C 90% yield

O

O

O

O

Rh2(4S,S-BSPIM)4

O

O

O

O

O

O 63 52 99% ee

64 :

48

65 :

0

Scheme 4.13. Kinetic amplification in double C–H insertion.

Carbenoid reactions have been used for amplification of asymmetric induction, in which sequential reactions with one chiral catalyst leads to a synergistic enhancement of enantioselectivity in the overall process (kinetic amplification) [173]. To synthesize tricyclic structures 63–65 (Scheme 4.13), sequential intramolecular C–H insertions on the meso-system 62 were carried out. The reaction usually afforded all three products


181

63–65, but 65 was not observed with certain catalysts. For example, with Rh2(4S,SBSPIM)4 about a 1:1 ratio of 63 and 64 was observed in 90% overall yield. Very high enantioselectivities were obtained with many dirhodium carboxamidate catalysts (95– 99% ee of 63), and both diastereo- and enantioselectivities were found to be catalyst controlled [173]. For intramolecular C–H insertion reactions of carbenoids derived from diazoacetates, the dirhodium(II) carboxamidate complexes are far superior to other catalyst classes in this field in terms of controlling stereo-, regio-, and chemoselectivities. The most successful system for the reaction of tertiary alkyl diazoacetates is Rh2(4SMACIM)4. For simple primary and secondary alkyl diazoacetates, Rh2(4S-MPPIM)4 is the catalyst of choice. Furthermore, in many systems containing pendant alkene moieties, Rh2(4S-MEOX)4 has been the most successful system for promoting C–H activation rather than the competing cyclopropanation reactions [63,98,120,168,170,172]. Intramolecular C–H insertion reactions of diazoacetamides typically lead to β- or γ-lactam formation [174–178]. The latter is generally the observed ring size for carbenoid cyclizations, but the β-lactam formation is electronically very favorable because of the activating influence of the nitrogen on the adjacent site [3]. The major control factors for regio- and stereoselectivities in such systems are (i) the nature of the catalyst and (ii) the electronic and conformational effects in the substrate. The effect of the electronic nature of the catalyst on regioselectivity in such reactions has been studied by several groups [53,97,174,179–183]. The more electron-rich systems based on dirhodium(II) carboxamidates favor the formation of γ-lactams over β-lactams relative to dirhodium(II) carboxylates. In the carboxamidate systems, the electrophilic carbenoid intermediate is more stabilized and therefore leads to relatively late transition states and hence an increase in selectivity [108]. When using α-diazo-α-(phenylsulfonyl)acetamides as carbenoid precursors with Rh2(OAc)4, γ-lactam formation was observed exclusively [184–187]. For the acyclic system 66 (Table 4.8), the substituent R at the 2-position of the Nalkyl chain plays an important role in determining the reaction outcome [188]. For simple alkyl groups, the γ-lactam product is favored (82–91% selectivity) with the β-

TABLE 4.8. Structure and Catalyst Control of β- versus γ-Lactam Formation

O

t-Bu N

O Rh(II)-cat.

N2

t-Bu

N

t-Bu

O

O

R

N

N

CH2Cl2, 40°C R

R 66

67

R 68

69

Ratio Catalyst

R=

67:68:69

Yield (%)

ee (%)

Rh2(4S-MEOX)4

OEt

100:0:0

97

78 (67)

Rh2(4S-MEOX)4

CO2Et

2:25:73

54

46 (68)

Rh2(5S-MEPY)4

CO2Et

2:9:89

64

—

Rh2(4S-BNOX)4

CO2Et

12:88:98% yield; up to 95% ee

Scheme 8A.22.

1 mol % (CuOTf)2 • C6H 6, (alkyl)2Zn, toluene, 22°C;

O R3Si

Me

2.5 mol % 33

Alkyl O R3Si

R3 = Me3, PhMe2 alkyl = Et, Me

Up to 96% yield, 96% ee

O Me

R3 = Me3, PhMe2 alkyl = Ph, p-OMeC6H 4, p-CF3C 6H4

1 mol % (CuOTf)2 • C6H 6, 1.5 eqiv (aryl)2Zn, DME, 0°C

R 3Si

i-Pr NHn-Bu

N PPh 2

Aryl O

2.5 mol % 33 R 3Si

Me

O

33

Me

Up to 82% yield, 94% ee

Scheme 8A.23.

Subsequently, a valine-based chiral phosphine ligand 33, which was found to be highly effective in the asymmetric conjugate addition of dialkylzinc and diarylzinc reagents to acyclic β-silyl-α,β-unsaturated ketones, was reported [33]. This protocol made it convenient to access allylsilanes containing a trisubstituted olefin in high diastereomeric and enantiomeric purity (Scheme 8A.23).

8A.2. CATALYTIC ASYMMETRIC CONJUGATE ADDITION OF ORGANOMETALLICS

449

Ojima and others also reported copper-catalyzed asymmetric conjugate addition of diethylzinc to nitroalkenes [34]. Using a new chiral monodentate phosphoramidite ligand 34, high enantioselectivities (up to 99% ee) were obtained (Scheme 8A.24).

Et R

NO 2

+

Et2 Zn

Cu(OTf)2/34

*

R

Toluene, –65°C

NO 2 Up to 99% ee

R1 R = p-Me-C6H 4, p-MeO-C6H 4, m-MeO-C6H 4, o-MeO-C6H 4, p-F-C6H4, m-F-C6H4, o-F-C6H4, p-CF3-C 6H4, o-CF 3-C 6H 4, furyl, thienyl, (MeO)2CH

Ph O P N O Ph

R1

34

Scheme 8A.24.

Chiral N-heterocyclic carbenes (NHC) are good ligands for copper-catalyzed conjugate addition of dialkylzinc reagents to various Michael acceptors. In 2007, Hoveyda and coworkers [35] disclosed a chiral NHC for the catalytic asymmetric conjugate additions of organozinc reagents to cyclic γ-keto esters. These transformations could also give rise to the enantioselective formation of all-carbon quaternary stereogenic centers bearing a readily functionalizable carboxylic ester with up to 95% ee (Scheme 8A.25).

O

O

2.5 mol % NHC-Ag complex 35 ( )n

CO2R1

2.5 mol % (CuOTf)2• C 6H 6, R 2 Zn, –30°C

n = 1 or 2; R1 = Me, t-Bu R = Me, i-Pr, Ph, Et, Me2CH(CH 2) 2

Ph

O Ph O S N O Ag

( )n

R CO2R

73–93% ee

1

N Ag

O O S N O Ph

N Ph

NHC complex 35

Scheme 8A.25.

P-chiral phosphinophenol and phosphinoanisole could be used as new chiral P/O hybrid ligands. In 2005, Imamoto and others [36] successfully used this class of ligands in the Cu-catalyzed asymmetric conjugate addition of diethylzinc to α,β-unsaturated carbonyl compounds. P-chiral phosphinophenol 36 exhibited high enantioselectivities in the reactions with various chalcone derivatives with up to 96% ee (Scheme 8A.26). The TADDOL (2,3-O-isopropylidene-1,1,4,4-tetraphenylthreitol) class of chiral trivalent phosphorus ligands was also promising for copper-catalyzed enantioselective conjugate addition. In 2000, Alexakis et al. reported the asymmetric conjugate additions of diethylzinc to enones with up to 96% ee using this kind of ligands (Scheme 8A.27 [37]). In 2006, Palacios and Vicario reported a Cu-catalyzed asymmetric conjugate addition of dialkylzinc to α,β-unsaturated imines by using a TADDOL-derived

450 CATALYTIC ASYMMETRIC CONJUGATE ADDITION

O R

1

O

Et2Zn (1.1eq), 36 (1.2 mol %) 2

R

R

CuOTf (1.0 mol %), CH2Cl 2, 0°C

R1 = Ph, 4-OMeC6H4, 4-ClC6H4, i Bu, Cy, n-hexyl, Me R2 = Ph, 4-OMeC6H4, 4-ClC6H4, 4-Me2NC6H4, i Pr, 4-CF 3C6H4,1-naphthyl, n-pentyl, t-Bu, Me

Et *

1

H3C 2

R

P

t-Bu

61–96% ee

OH

36

Scheme 8A.26.

O 1.2 Et 2Zn

O 0.5% Cu(OTf)2 ,1% ligand

+

CH2 Cl2

* Et

O

O

Ph

=

Me Ph

,

O

Ph O

,

2-napht

O

O Ligand =

O

O Ligand =

O

R=

P R

O

O O

O

R=

86% ee; R = 54% ee

1-napht

Ph

P R

R=

N CH3 49% ee H

O

96% ee; R =

82% ee O

Scheme 8A.27.

phosphoramidite complex 37 as chiral ligand with high enantioselectivity (Scheme 8A.28) [38]. Bräse and Höfener [39] presented the first copper-free asymmetric 1,4-addition of diethylzinc or diisopropylzinc to α,β-unsaturated aldehydes. This methodology supplemented the spectrum of synthetic methods for β-chiral aldehydes (Scheme 8A.29).

8A.2.3. Conjugate Addition of Organolithium Reagents Organolithium reagents are highly reactive species that can be used in various organic transformations, especiallly carbon–carbon formation. Thus, organolithium-based asymmetric conjugate addition methodologies are of high interests. In this section, we focus on the recent progress in enantioselective conjugate addition of organolithium reagents with achiral-activated olefin under the control of external chiral ligands or chiral catalysts.

451


Ph Ph O O P N O O Ph Ph 37

R2 N R1

EtO2 C

R2 NH

ZnEt 2, Cu(CH 3CN)PF6 Toluene, –30°C

Et * R1

EtO 2C

er = 88:12 to 94:6

1

R = p-Me-Ph, p-MeO-Ph, p-NO2-Ph R2 = p-NO2-Ph, p-Me-Ph

Scheme 8A.28.

R

O R1

H R2

1) R2Zn, 2 mol % 38a or 38b 2) NH4Cl

Up to 99% ee

a: R1 = Ph; R2 = H b: R1 = o-MeOC6H4; R 2 = H MeO c: R1 = p-ClC6H4; R 2 = H d: R1 = 3-C 4H3S; R 2 = H e

O

OH

1

+ H R2 1,4-Addition (main product) R

1

R

R R2 1,2-Addition

R OH

O

N

(Rp,S)-38a: R = Me (Rp,S)-38b : R = Ph

H Me O Me

Scheme 8A.29.

R

R

n-BuLi / 39, –78°C

NArBoc R = Ph or Me

R L39•Li

N N 39

Michael acceptor TMSCl NHArBoc

R = Ph or Me O Acceptor =

( )nO n = 1 or 2

O ,

,

NArBoc ( )n X er 90:10 to 97:3 O O

N Boc

Scheme 8A.30.

Koga and coworkers first reported the stereoselective Michael addition of organolithium reagents to cyclic α,β-unsaturated aldimines in 1989 [40]. From 1997 to 1998, Beak and coworkers continuously reported conjugate addition reactions of benzylic and allylic organolithium species to cyclic unsaturated ketones and esters under the influence of (−)-sparteine 39, which provided 1,4-addition products with generally high diastereomeric and enantiomeric ratios [41–43]. In 2001, Beak et al. [44] developed the conjugate addition of configurationally stable organolithium species to α,β-unsaturated cyclic carbonyl compounds, affording 1,4addition products in good yields and with high diastereomeric and enantiomeric ratios (Scheme 8A.30). Subsequently, the conjugate addition of allylic organolithiums to nitroalkenes, providing enecarbamates containing two contiguous stereogenic centers in


good yields and high diastereoselectivities and enantioselectivities (er > 97:3), was also reported (Scheme 8A.31) [45].

R2 R1

n-BuLi/(–)-sparteine 39 Ar

N

Toluene, –78°C

Boc

Li • L*

R1 Ar

N

R2

O2 N

O2N R1

Boc

R1 = Ph, Me; R2 = Ph, t-Bu

N Ar Boc

er >9 7: 3

Scheme 8A.31.

8A.2.4. Conjugate Addition of Organoborane Reagents The rhodium-catalyzed asymmetric conjugate addition of organoborane reagents in the presence of chiral phosphine ligands has been successfully developed by Hayashi et al. In 1998, these investigators reported the rhodium-catalyzed asymmetric conjugate addition of arylboronic and alkenylbronic acids to cyclic and acyclic α,β-unsaturated ketones in the presence of (S)-BINAP ligand with high enantioselectivity (Scheme 8A.32) [46].

O

O

Rh(acac)(C 2 H4)2 (S)-binap 40 + RB(OH) 2

( )n

Dioxane/H2 O

n = 0,1,2.

R

Up to 99% ee

R = aryl, alkenyl

R1

( )n

R2

+ RB(OH)2

O

Rh(acac)(C2 H 4) 2 (S)-binap Dioxane/H2O

R1 = Me, R2 = iPr or n-pent R = aryl, alkenyl

R1

R2

* R

PPh2 PPh2

41(S)- binap

O

Up to 97% ee Scheme 8A.32.

It was shown that the square-planar complex RhPh(PPh3)((S)-BINAP) was the key intermediate in the catalytic cycle of asymmetric 1,4-addition of phenylboronic acid to an α,β-unsaturated ketones [47], and this reaction proceeded through three intermediates including phenylrhodium, oxa-π-allylrhodium and hydroxorhodium complexes. The catalytic cycle, as shown in Scheme 8A.33, involved the insertion of an unsaturated compound into the aryl-rhodium bond followed by hydrolysis, giving the hydroarylation product and the hydroxorhodium species. In their subsequent studies, Hayashi et al. extended the scope of substrates from α,β-unsaturated ketones to 1-nitroalkenes [48] and 3-substituted maleimides [49]. These reactions afforded the desired products in high yields and enantioselectivities with phosphine ligands 40, 41, and 42, as shown in the Scheme 8A.34. Up to 99% ee and 97% ee


O

453

O RhX, L*

+ RB(OH) 2

R = aryl, alkenyl

Dioxane/H 2O(10:1)

O

*

*

R

RB(OH) 2 R

Hydrolysis

L Rh OH L Hydroxorhodium

Transmetallation

HO-B(OH) 2

H2 O O

L

L

Rh

Rh R L Arylrhodium complex O

L *

Oxa- π -allyl complex

R

Scheme 8A.33.

R

NO2 + RB(OH) 2

( )n

(S)-binap 40

NO2

Rh(acac)(C2H 4)2 (3 mol %)

n = 0,1,2 R = Ph, 4-MeC6H4, 4-CF3C6H4, 3-ClC6H4, (E)-n-4-C5H 11CH=CH, 2-naphthyl,

( )n Up to 99% ee O

O R1

NBn +

ArB(OH)2

[RhCl(C2H4)2] 2

41 or 42

O R1 = Et, Me, i-Pr Ar = Ph, 3-ClPh, 2-naphthyl, 2-MePh, 4-MeOPh, 4-FPh

R1 Ar

NBn

+

O

PPh2 PPh2

42 (R)-H 8-binap

Scheme 8A.34.

40 (S)-binap O

Ar

Main product Up to 97% ee

PPh2 PPh2

41 (R)-binap

PPh2 PPh2

R

NBn

1

O


were obtained with the 1-nitroalkenes and 3-substituted maleimides as the substrates, respectively. Sakuma and Miyaura studied the conjugate addition of arylboronic acids to α,βunsaturated amides in the presence of a chiral rhodium catalyst prepared in situ from Rh(acac)(CH2CH2)2 and (S)-BINAP [50]. The addition of phenylboronic acid to Nbenzyl crotonamide provided (R)-N-benzyl-3-phenylbutanamide with 93% ee (Scheme 8A.35). R1

R1 H

ArB(OR)2 NHR2 O

RhX/(S)-binap Base, dioxane-H2O 100°C

Ar

NHR

2

PPh2

O Up to 85% yield, 93% ee

R1 = Me, Me2CH, Ph, C5H 11; R2 = H, Ph, c-C6H11, CH2CH(CH3)2; Ar = Ph, 4-CF3C6H4, 4-MeC6H4, 4-MeOC 6H4; R = H, OC2H4, OC2Me4

PPh2

41 (S)- binap

Scheme 8A.35.

A rhodium-catalyzed enantioselective conjugate addition of organoborane reagents to enones in the presence of C2-symmetric chiral diene ligand was reported [51]. Hayashi et al. showed that rhodium-diene complex could be used to effect the asymmetric conjugate addition reaction and generate the desired products with high enantioselectivities (Scheme 8A.36).

O

O

[RhCl(C 2H 4 )2 ]2 + RB(OH) 2 or (RBO) 3 Ph Ph

R = Ph, 3-MeOC6 H4, 3-ClC 6H4 , 4-CF3 C6H 4, 2-naphthyl, (E)-n-C 5 H11Ch=CH

*

R

Up to 94% yield Up to 99% ee

Scheme 8A.36.

Besides bisphosphines and diene ligands, phosphoramidite ligands were also successfully developed. In 2003, Feringa et al. reported that monodentate phosphoramidite 44 was extremely effective in the rhodium-catalyzed conjugate addition of boronic acids and potassium trifluoroborates to enones [52,53]. This reaction afforded the desired products with excellent yields and enantioselectivities (Scheme 8A.37). Using phosphoramidite ligand 45, Feringa et al. in 2005 showed the conjugate addition of arylboroxanes in the preparation of 2-aryl-4-piperidones in high yield and with excellent enantioselectivity (up to 99% ee) (Scheme 8A.38) [54]. In 2008, Lee and Yun [55] described the asymmetric boration of acyclic α,βunsaturated carbonyl compounds, which provided the ready access to functionalized chiral organoboron compounds under mild reaction conditions. Using planar chiral


O

O Rh(acac)(C2H4)2(3 mol %) 44 (7.5 mol %)

X ( )n

ArB(OH)2, 3eq Dioxane/H2O, 100°C n = 0,1,2; X = CH2 or O Ar = Ph, 2-FC 6H4, 3-MeOC6H4, 3-MeC6H4, 4-MeC6H4,

( )n

Ar n = 0,1,2 O P N O

>98% ee

44

O

O BF3 K

X

455

+

4% Rh(acac)(eth)2 10% 44

X

Ethanol, reflux, 2 h

( )n n = 0,1,2; X = CH2 or O

( )n 100% conv; up to 99% ee

O +

ArBF3K

O

4% Rh(acac)(eth)2 10% 44 ethanol, reflux, 2 h

Ar

Ar = Ph, 4-MeC6H4, 3-ClC6H4, 3-MeOC6H4, thiophene

68–100% conv; 98–99% ee

Scheme 8A.37.

O

O Rh(acac)(C2H4)2 (3 mol %) (R)-45 (7.5 mol %)

N

O

N

(ArBO)3, dioxane/H 2O, 100°C

CO2Bn

CO2Bn

Ar = Ph, o-MeC6H4, p-MeC6H4, m-MeC6H4, p-MeOC 6H4, p-ClC6H4, p-FC6H4, m,p-(MeO)2C6H 3

R

O

P N

(R) -45

100% conv; up to 99% ee

Scheme 8A.38.

ligands 8 and 46, excellent yields and high enantiomeric excesses were obtained at room temperature (Scheme 8A.39). Wu and Chong [56] reported the asymmetric conjugate additions of B-1-alkynyldiisopropylboronates to enones catalyzed by binaphthols, which could afford alkyne products with high yields and enantiomeric excesses. A possible mechanism was also proposed as shown in Scheme 8A.40.

8A.2.5. Conjugate Addition of Organoaluminum Reagents Examples of enantioselective addition of trialkylaluminum reagents have been described for cyclic [57,58] and acyclic [59,60] enones, and nitro-olefins [61]. In 2005, Alexakis et al. reported a new way to build chiral quaternary centers, using 2-substituted


P R

EWG

Bpin

B2 pin2 Condition A or B

R = Me, CHMe 2 , (CH 2) 2Ph, Ph p-ClPh, o-MePh, p-MePh, o-OEtPh, m-OAcPh EWG = CO 2 Et or CN

R

NaBO3

EWG

P

OH R

THF/H 2 O(1:1)

Fe

CH3 H

EWG

8 (R,S)-Josiphos

ee:82–92%

Yield:87–97%

Ph

Ph P

CH3 N CH3 H

Fe

H P Ph H 3C N CH3 Ph 46(R)-(S)-NMe 2-PPh2 mandyphos

Condition A: 2% CuCl, 3% NaOtBu, 4% 8; condition B: 3% CuCl, 3% NaOtBu, 3% 46 with 1.1 equiv B2pin2 in THF at room temperature.

Scheme 8A.39.

i-PrO B i-PrO 2

I (S)

OH (cat.) OH

I O (20 mol %) 47 1 2 R R i-PrO B R3 R1 = Ph, 1-naphthyl, 2-furyl; i -PrO 2 R = Ph, Me; CH2Cl2, rt ~ reflux R3 = n-C6H13, Ph, CH 2OBn

R

3

O R

O R1 (S)

1

1

R

2

R2

Yield: 78–97% ee: 82–96%

Addition

*OH OH *O

R3

i-PrOH B

O

R

R1

O

R

R1

3 R

3

3

3

4

O* O B O R2

O iPr B Oi Pr R2

5

Disproportionation i -PrO B i-PrO

R3 2

Scheme 8A.40.

cyclohexenones as substrates [62]. Compared with 3-substituted cyclohexenones, 2-substituted analogues are known to be difficult substrates for asymmetric conjugate addition because of the steric hindrance. However, the present method allowed such an extension, and high yields and good enantioselectivities were achieved (Scheme 8A.41). In the same year, the use of chiral P,O-hemilabile ligand 51 in the Cu-catalyzed asymmetric conjugate addition of trialkylaluminum to cyclic and acyclic enones was reported (Scheme 8A.42) [63]. In their continuous investigation, Polet and Alexakis developed the conjugate addition of trialkylaluminum reagents to nitroalkenes [64] and α-halogenated enones [21]. They showed that trimethylaluminum could advantageously replace dimethylzinc in the Cu-catalyzed conjugate addition to a wide variety of nitroalkenes. Good to excellent yields and enantioselectivities were obtained in this reaction (Scheme 8A.43). High enantioselectivities (up to 94% ee) were achieved in the Cu-catalyzed conjugate addition of Me3Al to α-halogenated enones using phosphoroamidite ligand 53 (Scheme 8A.44).

457


O

O

CuTC (2 mol %) 48 or 49 (4 mol %)

+ 2Me3Al

Et 2O, –30°C, 18 h

R

R' O P N O R'

R Me

R= CH2CH 3, 48 (94% ee), 49 (96% ee) R= CH2CH(CH3)2, 48 (93% ee), 49 (93% ee) R= CH2CH 2CH=CH2, 48 (91% ee), 49 (95% ee) R= CH2CH 2CH2CH=CH2, 48 (93% ee), 49 (95% ee) R= CH2CH 2−

O

48 : R' = Ph 49 : R' = 2-Napht

49 (95% ee)

O

O

O

+ 1.4Et 3Al

CuTC (2 mol %) 50 (4 mol %)

O P N O

Et2O, –30°C 18 h 82%

trans, 84% ee cis, 91% ee

50

Scheme 8A.41.

PPh2 P(O)Ph2

PPh2 P(O)Ph2

51

51 O

2 mol % Cu(CH3CN)4PF6 4 mol % 51

O

2 mol % Cu(CH3CN)4PF6 4 mol % 51

O 1

2

R

Et2O, t °C () n ( )n R 1.5eq. R3Al R = Me, n = 1, 91% ee; R = Et, n = 1, 86% ee R = Me, n = 2, 89% ee; R = Et, n = 1, 75% ee R = Me, n = 10, 77% ee; R = Et, n = 1, 41% ee

R

R 1

R

Et2O, –45°C 1.5eq. R3Al

Me NO 2 + Me Al 3

R= R=

, 78% ee; R= OMe , S

R=

, 78% ee; R=

, 91% ee; R=

2% CuTC, 4% 52 Et2O, –30°C

NO2

R

, 86% ee

93% ee; R=

R=

2

R

R = Me, R1 = Ph, R2 = Me, 71% ee; R = Et, R1 = Ph, R2 = Me, 20% ee R = Me, R1 = Ph, R2 = Ph, 25% ee; R = Et, R1 = Ph, R2 = Ph, 16% ee R = Me, R1 = Hep, R2 = Me, 74% ee; R = Et, R1 = Hep, R2 = Me, 51% ee

Scheme 8A.42.

R

O

O

Cl ,

56% ee

, 84% ee

OMe

, 88% ee

OMe

Scheme 8A.43.

Ph O P N O Ph

52


O

O

1.5 equiv Me3Al 2% CuTC, 4% 53

Br

Br

Toluene, –30°C to RT

Me

trans : cis 75:25 94% ee

Ph O P N

Et

O

Et Ph

53

Scheme 8A.44.

O N H

N

N H

54 [66]

N H 59 [71]

N N N N H

55 [67]

56 [68]

n-C10H 21 N n-C 10H 21

N H

O

63 [75]

N H

TFA

NHSO 2CF3

H N

N H

N N N

N N H

Ph

N Ph H OTMS 57 [69]

64 [76]

65 [77]

O Ph 62 [74]

CF3 Bn

HN

N N H

NH Bn

N N H iPr 58 [70]

HO CF 3

H N

S 61 [73]

60 [72]

O NH

Ph

N

⋅HCl

NH

NH 2

HO O O 66 [78]

Figure 8A.1.

8A.3. CATALYTIC ASYMMETRIC CONJUGATE ADDITION OF OTHER CARBON-CENTERED NUCLEOPHILES 8A.3.1. Conjugate Addition of Aldehydes The conjugate addition of aldehydes to nitroalkenes can afford up to three stereogenic centers. The adducts are highly versatile synthetic intermediates, presumably due to the ability to transform the nitro group into other useful functional groups. In 2001, Betancort and Barbas [65] reported the catalytic asymmetric conjugate addition of aldehydes to β-nitrostyrenes using chiral diamine 54 as a catalyst. Various efficient organocatalysts such as 55–66 (Fig. 8A.1) appeared to promote conjugate addition of aldehydes to nitroalkane. Recently, Jacobsen et al. [79] reported the use of chiral primary amine-thiourea catalyst 67 in a highly enantioselective direct conjugate addition of α,α-unsymmetrically disubstituted aldehydes to nitroalkenes, affording chiral building blocks with contiguous quaternary and tertiary stereogenic centers (Scheme 8A.45). Melchiorre and Jørgensen [80] reported the asymmetric conjugate addition of aldehydes to α,β-unsaturated ketones using chiral amine (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine 68. Other efficient catalysts such as diphenylprolinol ethers 57, 69, and imidazolidinone 70 were also developed by others (Scheme 8A.46).

Ph

8A.3. CATALYTIC ASYMMETRIC CONJUGATE ADDITION 459

R2

O

O 1

R

H

2

R

+

67 (20 mol %), H2O

NO2

H

CH 2 Cl2 , r.t., 24 h

CH 3

NO2 1

R

CH 3

Bn

N H 67

O

Up to 98% yield Up to 50:1 syn/anti Up to 99% ee

R1 = aryl, alkyl R2 = aryl, alkyl

S

H N

N H

NH 2

Scheme 8A.45.

O

O +

Ph

O

Catalyst

O

H

H

Bn CH3

O HN 68

Ph N Ph H OTMS 57 [69]

78% yield 65% ee

Ph N Ph H OMe 69 [81]

N Bn

82% yield >95% ee

52% yield 97% ee

N H 70 [82] 52% yield 97% ee

Scheme 8A.46.

O

O

O

R

R

71 (10 mol %) O H

H

72 (10 mol %)

Up to 99% yield syn/trans: up to 2/98 Up to 97% ee

N H

• HCl

O R

H

N

71

O O

R = H, Ph, Me

CH 3

O

Up to 99% yield cis/trans: up to 89/11 Up to 99% ee

N H

S

NH2

F3 CCO2 72

Scheme 8A.47.

Hechavarria Fonseca and List achieved intramolecular conjugate addition of aldehydes to enones by employing MacMillan’s imidazolidinone 71 [83]. The cysteinederived organocatalyst 72 [84] was also used in the intramolecular conjugate addition to afford compounds containing three and two contiguous chiral centers in good yields and with high diastereo- and enantioselectivities (Scheme 8A.47).

8A.3.2. Conjugate Addition of Ketones A variety of chiral organocatalysts such as Cinchona alkaloid derivatives, chiral primary and secondary amines, small peptides, and so on have been applied in asymmetric


H

H Br

N H

OH

N

N

N

N

OH OCH3

OBn 75 [87]

74 [86]

OCH 3

N

Ph

N

OBn

OCH 3

N

O

OH

O N

OMe H3 CO

OBn

H

N

73 [85]

Br

OH

N

N

OCH 3 N

N

Ph

N

76 [88]

H

N

78 [88]

77 [88] Figure 8A.2.

organocatalytic conjugate addition of ketones under homogeneous and phase-transfer catalyst (PTC) conditions, delivering different enantiomerically enriched compounds. For example, Cinchona alkaloid-derived catalysts such as 73–78 were applied successfully in asymmetric conjugate addition (Fig. 8A.2). Catalyst 56 was recently employed in the conjugate addition of six-membered-ring ketones to α,β-unsaturated ketones, affording synthetically useful 1,5-dicarbonyl compounds (Scheme 8A.48) [89].

O

O O

56 (10 mol %)

+ Ar1 X X = CH 2, NH, O

Ar2

iPrOH,

rt

Ar1

O Ar2

X Up to 89% yield Up to 97% ee

NHSO 2CF3 N H

56

Scheme 8A.48.

Some of the chiral amines such as 59, 60, 64, and 79–89 were also very efficient for the addition of six-membered-ring ketones to β-nitrostyrene and derivatives (Fig. 8A.3). Huang and Jacobsen described a new catalyst 90 for the asymmetric conjugate addition of different aliphatic ketones with not only nitrostyrenes but also nitroalkenes bearing aliphatic β-substituents (Scheme 8A.49) [104]. A bifunctional mechanism promoted by catalyst 90 was proposed in this reaction. The authors pointed out that anti diastereoselectivity indicated the participation of a Z-enamine intermediate (Fig. 8A.4).


NHSO2CF3

N H 56 [90]

N H

N N

N N

N N H

N H

59 [93]

N H

NBu N C 12 H25OSO3

N

Ph

64 [94]

N H

83 [97]

S

S

N H

N

86 [100]

85 [99]

H N

O H 2N

HN

NHSO2CF3 N H 88 [102]

CF3

87 [101]

Br

82 [96] HN

84 [98] O

NEt

HN

CF3

N H

N H

81 [95]

N

HN

80 [92]

N

BF4

N H

N N

N H

NBu

N N H

H N

C10H 21

C10 H21 60 [72]

N H

79 [91] N

N H

nC 4F9

NHSO2

O

Ph Ph

89 [103]

Figure 8A.3.

R

R3

O

O 2

R1

3 + R

90 (10–20 mol %) NO2

r.t.

NO2

R1 R2

R1 = alkyl R2 = alkyl R3 = aryl, alkyl

Bn

Up to 78% yield Up to 20:1 dr Up to 30:1 rr Scheme 8A.49.

CH3 tBu S N Bn N N H H O NO2

HN 2

R

R3 Z-enamine intermediate

Figure 8A.4.

R1

CH3 N O

S N H 90

NH2


N

COOH

N H 91 [105] CH 3 N COOH Bn

N H 93 [108]

Bn

H N

N N HN

N H

N H 59 [106]

CH 3 N N N N N N H H 94 [109]

OH

O 92 [107] BocHN H N N H

N COOH O H m 95 [110] m = 2-3 N

BocHN

HN O

H N N H

O

COOH

H2 N

NH

96 [111]

N H

COOH

97 [112]

Figure 8A.5.

8A.3.3. Conjugate Addition of Nitroalkanes Aminocarbonyl compounds, aminoalkanes, and pyrrolidines can be produced from asymmetric conjugate additions of nitroalkanes to α,β-unsaturated ketones. A variety of chiral amines were applied in the conjugation reaction of nitroalkanes with cyclic and acyclic enones (Fig. 8A.5). Warrier and others reported the conjugate addition of 2-nitroalkanes to 2-cycloalkenones by applying 91 as catalyst with up to 99% ee (Scheme 8A.50) [105].

O

O 91 (10% mmol) n n = 0, 1, 2

trans-2,5-dimethylpiperazine CHCl3, rt O 2N

n NO2 n = 0, 1, 2 Up to 99% ee

Scheme 8A.50.

Jørgensen et al. [108,109] applied a new imidazolidine catalyst 93 for the enantioselective conjugate addition of nitroalkanes to α,β-unsaturated enones. A new, more soluble organocatalyst 94 was developed to improve the rate of reaction and enantioselectivity (Scheme 8A.51) [109]. A useful organocatalyst pyrrolidine-tetrazole 59 in combination with trans-2,5dimethylpiperazine as additive was applied in the conjugate addition of a variety of nitroalkanes to cyclic and acyclic enones with high enantioselectivities (94–97% ee) (Scheme 8A.52) [106].


NO 2 R1

O

R2

R1 R2 R3 R4

= = = =

O 2N

+

R3

R1

94 R4

R2

O R4

R3

r.t.

Up to 92% ee

H, alkyl H, Me, CO2 Et Ph, p-OH-Ph, p-NO2-Ph, 2-furyl Me, Et

Scheme 8A.51.

O O n

R1

R2 Up to 84% yield Up to 96% ee n NO2 1 R n = 0, 1

59 (15% mmol) R2

O2N

n = 0, 1

CH2 Cl2 , rt H N

R1

= H, Me R2 = H, Me, Et

N H

O R3

O 2N

R1

R2

CH 3

R 3 = Ph, CO2 Me

R3

O

Up to 88% yield Up to 89% ee CH 3

Scheme 8A.52.

Dipeptides and tetrapeptides were reported as organocatalysts in the conjugate addition of nitroalkanes to cyclic enones by Tsogoeva et al. [110,111]. Catalyst 96, a prolinebased dipeptide, was introduced to catalyze the conjugate addition with up to 88% ee and up to 100% yield in the presence of trans-2,5-dimethylpiperazine as a cocatalyst (Scheme 8A.53).

O

O + n n = 1, 2

NO 2 R1

R2

Peptide catalyst 96 (2 mol %) Trans-2,5-dimethylpiperazine CHCl3 , 5d, rt

n n = 1, 2

Up to 100% yield R2 Up to 88% ee NO2 R1

Scheme 8A.53.

Cinchona alkaloid-derived bases such as 98 [113], 99 [114], and 100 [115] were employed as catalysts for the conjugate addition of nitroalkanes to α,β-electro-deficient olefins in good yields and with good enantioselectivities (Fig. 8A.6).


OCH3 OH

N OH

NH N

N

N

CF3

S

H 98

OH

H N

N N

99

H 100

CF 3

Figure 8A.6.

PTCs, for example, Cinchona alkaloid-derived chiral quaternary ammonium salts, carbohydrate-derived azacrown ethers, C2-symmetric ammonium catalysts, and so on, were developed for catalytic asymmetric synthesis. Corey and Zhang reported that the N-(9-anthracenylmethyl)cinchonine derivative 101 was employed in the sequential synthesis of (R)-baclofen hydrochloride (Scheme 8A.54) [116].

O 101 (1 mol %) + CH 3NO2 CaF, tolunene –40°C, 36 h Cl

O

Br

OBn

NO 2 H

N N Cl

H

101

Scheme 8A.54.

Recently, Bakó et al. [117] investigated the conjugate addition of 2-nitropropane to chalcones catalyzed by carbohydrate-derived azacrown ethers. In those studies, some of D-glucose- and D-mannose-derived azacrown ethers such as 102–106 showed the best results (Scheme 8A.55). Other chiral PTCs such as C2-symmetric ammonium catalysts (e.g., spirocyclic guanidine 107) were reported to be effective in the conjugate addition of 2-nitropropane to chalcone, giving high yield and good enantioselectivity (Scheme 8A.56) [118]. N-spiro C2-symmetric chiral quaternary ammonium bromide 108 [119] and its derivatives 109 [120] enabled the efficient, highly stereoselective conjugate addition of nitroalkanes to alkylidenemalonates and cyclic enones, respectively. These reactions afforded products in good yields and high enantioselectivities (Scheme 8A.57).

8A.3.4. Conjugate Addition of Silyl Enol Ether MacMillan et al. reported the preparation of chiral γ-butenolides with good syn selectivity (up to 92% de) and high ee’s (84–99%) by using chiral imidazolidinones 110 as catalyst (Scheme 8A.58) [121].


O NO2

Ph

O

102 -106

+ t

Ph BuONa, tolunene , rt

NO2 Up to 82% yield Up to 94% ee

OR 1 O

O

O

O

O

N R2 O

O

OMe

O

OBu OBu

O

O

OH

O N

O O Ph

105

Ph

O

O

N H O

O

OR 1

O

O

106

102 R 1 = Me, R 2 = (CH 2) 4P(O)PH 2 103 R 1 = Me, R 2 = (CH 2)OH 104 R 1 = Me, R 2 = (CH 2) 2Ph Scheme 8A.55.

O

Ph

NO2

N

O

107 (10 mol %)

+

t

Cl

BuOK, THF, rt, 24 h

NO2 97% yield 86% ee

Ph

N N O BF H O 4 CH 3

107

Scheme 8A.56.

Zhang and Corey [122] performed the Mukaiyama–Michael addition of different silyl enol ethers to chalcones under PTC conditions when applying the quaternary ammonium salt N-(9-anthracenylmethyl)dihydrocinchonidinium bromide 111 as catalyst (Scheme 8A.59). Maruoka et al. reported the regio- and anti- selective Mukaiyama–Michael addition of silyl nitronates to α,β-unsaturated aldehydes [123], cyclic α,β-unsaturated ketones [124], and nitroalkenes [125] in the presence of N-spiro C2-symmetric chiral quaternary ammonium bifluorides 112 and 113, and 114 with good yields and enantioselectivities (Scheme 8A.60).

8A.3.5. Conjugate Addition of Malonates Imidazolidine catalyst 115 was used by Jørgensen et al. in the conjugate addition of malonates to α,β-unsaturated enones, resulting in a great diversity of α,β-unsaturated enones with excellent enantioselectivities and high yields (Scheme 8A.61) [126]. The enantioselective conjugate addition of malonates to aromatic α,β-unsaturated aldehydes was successfully achieved by using catalyst 116, affording the desired products in good yields and high enantioselectivities (Scheme 8A.62) [127].

CH 3


Ar Br N R1

NO2

O 2N

+ CH2O2R3

Ar

CO 2R3

R2 Toluene, base

R2

R1

108 (1 mol %)

CO 2R3

CO 2R3

108

F3C

CF3

Up to 99% yield syn/anti: up to 5/95 Up to 99% ee (anti)

R1 = Et, Me, Me2 CH R2 = c-hex, 2-naphyl, Ph R3 = Et, iPr, iBu

Ar =

CF3

CF3

Ar Br NO 2 + 109 (1 mol %) OH Toluene, base

R

N

O

Ar 109 F

R n

n n = 1, 2, 3

n = 1, 2, 3

F

N O2

Up to 99% yield syn/anti: up to 95/5 Up to 93% ee

R = Bn, Et, iPr

F

Ar = F F F

Scheme 8A.57.

R2 TMSO 1

O

+ R3 R1

R = H, Me, Et, CO2Et R2 = H, Me R3 = Me, Pr, Pri, Ph, CH2OBz

O

Catalyst 110 (20 mol %)

O

DNBA (20 mol %) R2 CH 2Cl2/H2O

O

R1

O

R3 Up to 87% syn/anti: up to 96/4 Up to 99%ee

Scheme 8A.58.

O N N H 110

CH3


O O Ar2

111

+ Ar1

H Br

O

Ar1

OTMS 50% KOH Toluene

Ph

Ph

H

Ar2

Up to 86% yield syn/anti: up to 20/1 Up to 99% ee (anti) Up to 95% ee (syn)

Ar1

= Ph, 4-F-Ph, 4-Br-Ph, 4-MeO-Ph Ar2 = 1-C 10 H 7, 4-NO2 -Ph, 4-Br-Ph

N OH

N 111

Scheme 8A.59.

Ph Et

Ph O 112 (2 mol%)

OTMS 87%, ant i/ syn: 90/10 98% ee

NO 2 OTMS O

O

N

Et

70%, anti/ sy n: 95/5 90% ee

Et

113 (2 mol%)

O2 N

OTMS Et

NO2

NO 2 NO2

H3 CO

114 (0.5–2 mol%)

H3 CO F3 C

X

Ar HF2 N

X

Ar

99%, ant i/ sy n: 95:5 91% ee

Bu

CF3

t

Ar = But

CF3

112 113 X = H 114 X = CF3 CF 3 Scheme 8A.60.

Maruoka and others performed the conjugate addition of diethyl malonate to chalcone derivatives in good enantioselectivity by the successful utilization of N-spiro C2symmetric quaternary ammonium bromide 117. The diarylhydroxymethyl functionalities of 117 were proposed as a recognition site for the prochiral electrophile (Scheme 8A.63) [128]. A new series of chiral bifunctional organic catalysts based on Cinchona alkaloids such as 118 was developed by Deng and others [129] (Scheme 8A.64).


CH 3

O R1

O R2

+ Bn

O

O

O

Bn 115 (10 mol%)

R1 O Up to 99% yield Up to 99% ee

neat, rt

R 1 = Ph, p-OH-Ph, p-Cl-Ph R 2 = Me, i Pr

N

R2

(BnO2 C) 2HC

Bn

COOH

N H

115

Scheme 8A.61.

F 3C O O R1 +

O

O

R2 O

116 (10 mol%) OR 2

EtOH, 0°C

OR2

2

O

R O O

R 1 = Ph, 2-Br-Ph, 2-naphthyl, 2-thienyl R 2 = Bn, Et, Me

CF3

R1

N H

OTMS

F3C

116


CF3

Scheme 8A.62.

Ar Ar O

O Ar 1

O Ar 2 + Et

O

O

Ar2

117 (3 mol %) (EtO2 C)2 HC O

Et

K2 CO 3 (10 mol %) Toluene

Ar1 = Ph, 4-MeO-Ph, 4-Cl-Ph, 2-pyridyl, 2-furyl, 2-thienyl Ar2 = Ph, Me, 2-thienyl

Ar

OH Br N

Ar1 Up to 99% yield Up to 94% ee

OH Ar

Ar Ar 117 Ar = 3,5-Ph2 -C 6H 3

Scheme 8A.63.

HO O R

NO 2 + H 3C

O

R = aryl, alkyl

O

COOMe

118 (10 mol %) MeOOC O

CH3 THF, –20°C

*

NO 2

R Up to 99% yield Up to 98% ee

Scheme 8A.64.

OH N N

H 118


OCH3 H

OCH3 H

N NH

N

N H N

NH

H N

CF3

N

CF3

O

O

120

119

CF 3

CF3 R

H N

F3C

t

Bu

H N N

Bu

t

CH 3 122 R =

S

Bu

CF3 121

R

Bu

t

t

Figure 8A.7.

Other organocatalysts, such as 119 [130], 120 [130], 121 [131], and 122 [132], were also employed in the asymmetric conjugate addition of malonates to nitroalkenes (Fig. 8A.7). 1,3-Diketones and malononitriles were also employed in asymmetric conjugate addition reaction. Deng and others [133] reported that 123 was an efficient catalyst in the conjugate addition of α-substituted β-ketoesters to α,β-unsaturated ketones (Scheme 8A.65).

O

O O

O

O

+ OtBu

123 (1 mol %) CH 3

OtBu

CH2 Cl2

100% yield 97% ee

O

OH

H3 C OR N

N

H

123 R =

Scheme 8A.65.

8A.3.6. Conjugate Addition of Amino Acid Derivatives Corey et al. [134] employed O(9)-allyl-N-9-anthracenylmethylcinchon idinium bromide 124 as a catalyst in the conjugate addition of N-(diphenylmethylene)glycine tert-butyl ester to several Michael acceptors. Since then, the classical procedure was modified


Br H

Me

N

O

Pr Pr

O

O

N

Ph

C 6H 4 -4-Me

N

C 6H 4 -4-Me 2BF4 C 6H 4 -4-Me

N

C 6H 4 -4-Me

N

O

C 6H 4 -4-Me

Me

Me O

C 6H 4 -4-Me C 6H 4 -4-Me 2BF4

N

C 6H 4 -4-Me

Me

Ph

125a

125b

124

CF3 R

Br H

NEt3

Br

N 2X

N

O N

N

R F

O 126

NEt 3

F

N

127 R =

128

F

O

O O

O

O

O O

O

O

O O

O

CF 3

O O

O O

129

Figure 8A.8.

O Ph Ph

O N

124 (10 mol %) CsOH, H2 O

OAc O OtBu +

R

OMe

CH2 Cl2, –78°C

R

OMe CO2tBu N CPh2

R = Ph, 4-NO2-Ph, 4-MeO-Ph, 2-thienyl, 2-pyridinyl

Up to 92% yield Up to 97 ee

Scheme 8A.66.

[135,136]. Subsequently, a variety of chiral PTCs such as 125, 126, 127, 128, and 129 were employed in the conjugate addition of enolates to Michael acceptors (Fig. 8A.8). Cinchonidine-derived catalyst 124 [137] also efficiently promoted the asymmetric synthesis of 4-alkylidene glutamic acid derivatives under phase-transfer conditions with up to 97% ee (Scheme 8A.66).


Recently, tartrate-derived chiral PTCs, such as 125a [138] and 125b [139a], were developed by Shibasaki et al. in the conjugate addition of amino acid derivatives to different Michael acceptors (Scheme 8A.67).

O Ph2C N

O

Ph

OBut

125a (10 mol %), Cs2CO3

CO2 But +

N

OBn

Ph

Chlorobenzene, –30°C

CO2 Bn 87%, 86% ee

Ph

O N

CO2 Bn + 5

Ph

O

O

125b (10 mol %), Cs 2CO3 C6 H13

C 6H 13

5

O Ph

3-Fluorotoluene, –40°C BuO2C

N

Ph

84%, 82% ee

Scheme 8A.67.

In the conjugate addition of benzophenone imine-derived glycinate to enones with high enantioselectivities (up to 97% ee), a significant counteranion dependence of enantioselectivity was observed in the employment of dimeric Cinchona alkaloid ammonium salts 126 (X = Br, BF4, PF6) (Scheme 8A.68) [139a].

O Ph

+

N Ph

CO2 Bu

t

126a/126b (5 mol %) Cs 2 CO 3 O CH 2Cl2, –78°C

Ph

N

OBu t

Ph

O 126a X = BF4 , 57%, 85/15 dr, 76% ee (major), 32% ee (minor) 126b X = PF6 , 32%, 93/7 dr, 97% ee (major), 68% ee (minor) Scheme 8A.68.

Chiral ammonium BINOL-derived catalyst 127 was used in the asymmetric conjugate addition of 2-naphthalen-1-yl-2-oxazoline-4-carboxylic acid tert-butyl ester to ethyl acrylate, giving α-(hydroxymethyl)glutamic acid in 93% yield and 97% ee [140] (Scheme 8A.69). Arai et al. developed a new chiral quaternary ammonium salt 128 derived from (S)BINOL in the conjugate addition of N-(diphenylmethylene)glycine tert-butyl ester to electron-poor alkenes, affording low to moderate enantioselectivities (32–75% ee) (Scheme 8A.70) [141].


O O N

Ot-Bu

CO2 Et

+

1) 127, BEMP CH2Cl2 , –60°C

H 2N

OH

OH

2) 6N-HCl

O

O OH

93%, 97% ee

Scheme 8A.69.

R + Ph

N

128 (1 mol %) Cs2 CO3

O Ph

CO2 But chlorobenzene

Ph R = CO 2Me, CONPh 2, CN, SO2 Ph

N

OBut

Ph R Up to 100% yield Up to 75% ee

Scheme 8A.70.

The 1,4-addition of N-(diphenylmethylene)glycine tert-butyl ester to vinyl ketones was promoted by the chiral crown ether 129, generating very good enantioselectivities (up to 96% ee) with low catalyst loading (0.2 mol %) (Scheme 8A.71) [142].

O Ph

N Ph

CO2 Et

129 (0.2 eq) t-BuOK

O +

R

CH2 Cl2 , –78 °C

R = Me, Et

Ph

N Ph

OEt COR


Scheme 8A.71.

Chiral guanidines such as 130 were applied in the conjugate addition of N(diphenylmethylene)glycine tert-butyl ester to vinyl ketones (Scheme 8A.72) [143].

8A.3.7. Conjugate Addition of α-Cyanoacetates Taylor and Jacobsen demonstrated that chiral (salen)Al complex 131 was an efficient catalyst for the conjugate addition of α-aryl α-cyanoacetates to a wide range of α,βunsaturated imides [144]. They also investigated the use of 132 for the enantioselective conjugate addition of α-cyanoacetates to acyclic α,β-unsaturated ketones [145]. This methodology provided access to a wide range of useful chiral building blocks in high yield and good ee (Scheme 8A.73).


R

O Ph

N

OBu t

Ph

O 130 (20 mol %)

+

Ph 2C=N

COR 1

OBu t

MeN

NMe

Ph

Ph

COR1 Up to 98% yield Up to 97% ee

R 1 = Me, OEt, OMe

OH

N

R = Bn or Ph 130

Scheme 8A.72.

O O 1

R

O N H

R2 + Ph NC

CO2 R3

O

131 (S,S)-[(salen)Al]2 O R2 (2.5–10 mol %) NC t-BuOH Cyclohexane

H 3 CO2 C

O or 1 Ph R

HN 1

R

76–98%, 86–98%ee

R 1 = n-Pr, Me, i-Bu, Ph R 2 = 2-CF 3C 6H 4, 4-MeOC 6H 4, Ph, 2-thiophenyl, NHBn

N

R 3 = Me, Et

NBn NC

CO2 Et

68–92%, 91–97%ee

N Al

O

O

(salen)Al O NC

CO2CH 3

+

R

1

R2

1

R = Ph, 2-thienyl, n-Pr CH 2CH2 OBn

132 : (R,R)-[(salen)Al] 2 O (1–5 mol %) Cyclohexane, 23°C

R1

O

NC H

R2 CO 2CH3 85–91% yield 75–93% ee

R2 = CH 3, n-Bu, Ph, i-Pr

Scheme 8A.73.

Deng et al. [146] developed the first highly enantioselective catalytic conjugate addition of α-aryl α-cyanoacetates to vinyl sulfones, affording the corresponding products in excellent yields (89–96%) and enantioselectivities (93–97% ee) (Scheme 8A.74). Chen and coworkers [147] reported a highly enantioselective Michael addition of α-substituted cyanoacetates to vinyl ketones catalyzed by simple bifunctional thiourea/ tertiary amine organocatalyst 134. A number of α-aryl or alkyl cyanoacetates could be successfully applied to give multifunctional compounds with carbon-substituted quaternary stereocenter with excellent enantioselectivities (82–97% ee) (Scheme 8A.75). Jørgensen et al. [148] developed the first example of nucleophilic attack from the α-position of an allylic chiral ion pair derived from alkylidene cyanoacetates to acrolein


OH EtO 2C

CN

SO2Ph

+

R

133 (20 mol %)

EtO 2C

Toluene, –25°C

R

H

N

CN

O

SO2Ph

N

89–96%, 93–97% ee

R = Ph, 4-Me-Ph, 4-MeO-Ph, 4-F-Ph, 4-Cl-Ph, 4-Br-Ph, 3-Cl-Ph, 2-naphthyl, 2-thienyl

133

Scheme 8A.74.

COOEt R1

O +

CN 1

NC 134 (10% mol %) 2

R

R

R1

R = aryl, R = alkyl, aryl

2

S

O

Toluene, 4A MS –60°C, 96 h

2

CF3

COOEt

61–99%, 82–97% ee

R 1 = alkyl, R 2 = aryl

N H

N

N H

CF3

134

Scheme 8A.75.

using Cinchona alkaloid catalyst 135. These highly functionalized catalytic products could be manipulated to give a wide range of useful intermediates, which were difficult to obtain via other procedures (Scheme 8A.76).

R 1O 2C NC

R2 +

Ph 3Si

R 1 O2C O

H

135 (10 mol %) CH2 Cl2 , –20°C

R 1 = Me, Et, Bn, t-Bu

NC

O

*

R2

2

R = Me, n-Hex, allyl,-Pr,Et (CH2 )3 OTBSi, t-Bu, Bn

OH

H

72-95%, 39-56% ee

N H

N 135

Scheme 8A.76.

8A.3.8. Conjugate Addition of Indoles Austin and MacMillan [149] successfully employed chiral imidazolidinone catalyst 110 to perform highly enantioselective asymmetric conjugate addition of indoles to enals, yielding the corresponding β-indolyl aldehydes in high yields and good enantioselectivities (Scheme 8A.77). Chiral thiourea catalysts such as 136 and 137 were reported in asymmetric conjugation addition of indole to nitro-olefin. Recently, Ricci et al. reported that chiral thiourea


R2

R2

N

R3

R

CHO

R4

110 (20 mol %)

+ R4

O

O

CH2 Cl2 / iPr OH –87 to –50°C

1

N R1

R3

R1 = H, Me, Bn, Allyl

Bn

N H

But

110


R2 = H, Me OMe R 3 = H, Cl R4 = Me, Prn , Pri , Ph, CH2OBn, CO 2Me

Me N

Scheme 8A.77.

136 promoted the alkylation of indoles with various aromatic and aliphatic nitroalkenes, providing the desired 2-indolyl-1-nitro derivatives in good yields and enantioselectivities (Scheme 8A.78) [150].

R2 N H

R1 +

R3

NO2

O2 N

136 (20 mol %)

R

CH2 Cl2, –24° C

CF3

R3

2

S R1

R 1 = H, Me

N H Up to 88% yield Up to 89% ee

R 2 = H, OMe, Cl R 3 = Ph, 2-furyl, 2-thienyl, n-pentyl, Pri

F3C

N H

N H

OH

136

Scheme 8A.78.

R N Me

+ R

NO 2 137 (10–20 mol %)

R = Ph, 4-CF3 C 6H 4, 4-BrC6 H 4, 2-MeC6 H4 , 2-thienyl, n-pentyl, cyclohexyl

CDCl3

F 3C *

NO 2

NH NH

F 3C N Me Up to 98% yield Up to 50% ee

S

S

CF3

HN HN CF3 137

Scheme 8A.79.

Connon et al. [151] investigated and developed thiourea-based axially chiral organocatalysts and found that catalyst 137 afforded the corresponding alkylated products in good yields (up to 98%) and moderate enantioselectivities (up to 50% ee) (Scheme 8A.79).


Jøgensen et al. reported the use of chiral bis-sulfonamides as effective catalysts for the enantioselective conjugate addition of indoles and N-methylindoles to a wide range of nitro-olefins (Scheme 8A.80) [152].

R1 +

138 (2 mol %)

R4

NO2

N R3

R2

R3 N

CHCl3, –24°C

R2 Ph

R4

Tf HN

NO2

R4 = Ph, 4-BrC6 H 4, 2-NO2 C6 H4 ,4-MeOC 6H 4 2-furanyl, 2-thienyl, n-pentyl, cyclohexyl R 3 = H, allyl, Bn, Me

NHTf 138

1

R = H, OMe R2 = H, Cl

Ph


Scheme 8A.80.

D-camphorsulfonic acid (CSA) and the ionic liquid 1-butyl-3-methyl-1H-imidazolium bromide (Bmimbr) constitute chiral Brønsted acid complex 139 [153], which could promote the asymmetric conjugate addition of indoles to aromatic enones, affording the corresponding β-indolyl ketones in excellent yields (74–96%) but low enantioselectivities (up to 58% ee) (Scheme 8A.81).

R3

BmimBr-CSA (139, 24 mol %)

+ R1 R 1 = H, 4-MeO

R3

HN

O

R2

R 2 = H, 2-Cl, 4-Cl, 4-MeO

CH 3CN, rt, 12 h

N H R 3 = H, 5-Br

O *

R1


R2

Scheme 8A.81.

8A.3.9. Conjugate Addition of Electron-Rich Arenes Iminium catalysis employing chiral imidazolidinone 110 was extended by MacMillan’s group [154] to the asymmetric alkylation of electron-rich benzene derivatives. The first enantioselective organocatalytic alkylation of aniline rings was achieved via this iminium activation strategy, which can afford complex benzylic carbon stereogenicity with simple α,β-unsaturated aldehydes and aryl substrates (Scheme 8A.82).

8A.3.10. Conjugate Addition of Cyanides Sammis and Jacobsen et al. [155] achieved the asymmetric conjugate addition of cyanide to α,β-unsaturated imides using 140a as catalyst. Generally high yields (70–96%) and


R3 R2 R3 110•HCl (10 mol %)

R1

R4

O

R2

O

+ R4

Bn

R1

O

R 1 = NMe 2, 1-pyrrolidino, NBn2 R 2 = H, Ph R 3 = H, OMe, SMe, Cl R 4 = alkyl, CO 2Me, CH 2 OBz, aryl

Me N N H

Bu t

110

Up to 97% yield Up to 97 ee

Scheme 8A.82.

excellent enantioselectivities (87–98%) were obtained with imide substrates bearing aliphatic β-substituents. They also developed a dual-catalyst protocol [156], in which two distinct chiral metal complexes (140b, 141) operate cooperatively to catalyze a highly enantioselective reaction (Scheme 8A.83).

N

N Al O XO

O

iPr

O N N Er N Cl Cl Cl iPr H H

140a: (S,S)-[Al(salen)Cl], X= Cl 140b: (S,S)-[Al(salen)Cl]2O, X = OAl(salen) O O NH Ph

R

TMSCN i PrOH 140a

Toluene R = Me, Et, n Pr, iPr, iBu (CH2)3 CHCH 2 , tBu, CH2 OBn

141 O O NH Ph

R NC

70–96%, 87–98% ee

Scheme 8A.83.

Shibasaki et al. recently developed a catalytic enantioselective conjugate addition of cyanide to various α,β-unsaturated N-acylpyrroles, including β-aryl, β-vinyl, and α,βdisubstituted derivatives, using a chiral gadolinium complex prepared from Gd(OiPr)3 and D-glucose-derived ligand 142 in a 1:2 ratio [157]. The Gd catalysts containing ligands 143 and 144 were tested in the asymmetric conjugate addition of cyanide to enones, yielding β-cyano ketones (1,4-adducts) with high enantioselectivity (Scheme 8A.84) [158].


R1 N

R2 O

Gd(Oi Pr) 3 (x mol %) 142 (2X mol%) TMSCN (0.5–1 equiv) HCN (2 equiv)

NC

CH3 CH 2 CN

1

2

R = Ph, 4-MeO-Ph, Ph(CH 2 )2 , R = H CH3 CH2 CH 2, i-propyl, t-Bu, cyclohexenyl

Ph

O R2

Ph

N R

P

O

O HO

1


O

F

HO

F

142 Ph

Ph R1

O R3

R2

1) Gd(O iPr) 3 ( x mol %)-143 or 144 (1.5X mol %) R1 O TBSCN (2 equiv), DMAP,THF NC R2 2) H + R3

R 1 = alkyl R 2 = alkyl, aryl R 3 = alkyl, H


P O

O

HO O

HO Y 143: X = Y = F 144: X= CN, Y = H

Scheme 8A.84.

OML n

Electrophilic trapping

Nucleophilic addition ∗

R O

O E

[Rm MLn ]

∗

∗

R L nM O ∗

Radical addition

X

Radical trapping R E = electrophile; L = ligand; M = metal; R = alkyl/aryl group; * = stereogenic center Scheme 8A.85.

8A.4. CATALYTIC ASYMMETRIC TANDEM CONJUGATE ADDITION REACTION Asymmetric tandem transformation was an enormously useful strategy for the construction of complex molecules from readily available starting materials through multistep transformations, constructing two or more contiguous stereogenic centers by using a single catalyst in one pot without the need of isolation of the intermediates. In recent years, through the use of conjugate additions catalyzed not only by metal complexes but also by various small organic molecules, considerable efforts have been made in developing catalytic asymmetric tandem transformations (Scheme 8A.85). According to the

479

8A.4. CATALYTIC ASYMMETRIC TANDEM CONJUGATE ADDITION REACTION

mechanism of the addition steps, the tandem conversions could be divided into anionic and radical processes. In 1997, the first metal-catalyzed asymmetric tandem conjugate addition reaction of organozinc reagents to α,β-unsaturated aldehydes was reported by Feringa and coworkers [159]. Since then, the asymmetric tandem conjugate additions was extended from aldehydes to acetals, ketals, ortho-esters, ketones, esters, and nitriles [160,161]. As shown in Scheme 8A.86, Krische and coworkers used ketones as electrophiles in coppercatalyzed conjugate addition reactions. When enones including pendant ketone, ester, and nitrile moieties as substrates reacted with organozinc reagents in the presence of catalytic Cu(OTf)2 and ligand 15, the reaction afforded cyclized products in excellent yields and enantioselectivities. These investigators also achieved a high level of stereochemical control for the creation of three contiguous stereogenic centers in a single manipulation [162]. This reaction was effected by rhodium catalyst with phenylboronic acid in the presence of excess of water, which was effective for the construction of fiveand six-membered-ring products. Particularly high enantioselectivity was observed for methyl-substituted enone precursors (up to 95% ee).

O + Me2 Zn +

CHO

O

O

1.2 mol % Cu(OTf )2 2.4 mol % 15

H

H

OH PCC

Toluene,–30°C

Me

Me Ph

Ph

O

2.5 mol % Cu(OTf)2 5 mol %15

O

Ph

+

1.5equiv ZnEt2, toluene,–40 °C 99%yield

Me

Me O

Et

2.3: 1d.r.

80% ee

O

O OH

Ph O P N

Me O 98% ee

O

Ph

15

O

O Me

O OH

Et

O

O

Me (C)n

n= 1,2

2.5 mol %[{Rh(cod)Cl} 2] 7.5 mol %(R)-binap 2 equiv PhB(OH)2 5equiv H 2 O dioxane(0.1M),95°C

Me

Me Ph

OH (C)n

69~88% yield 94~95% ee

Scheme 8A.86.

Hoveyda and coworkers [163] developed peptidic compounds 26 and 28 as chiral ligands for the copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to α,β-unsaturated ketones. The scope of this reaction was subsequently expanded with the use of alkyl halides and tosylates to give complex molecules with consecutive stereocenters. For example, when the zinc enolate, which was formed by the conjugate additions of dimethylzinc to cycloheptenone, was treated with 4-iodo-1-butene in the presence of Cu(OTf)2 and ligand 26 at −30°C, the desired products were obtained in high yields and good ee values (Scheme 8A.87). Morken and coworkers reported the first rhodium-catalyzed asymmetric conjugate reaction in 2000 [164]. This reaction mediated by [Rh (cod) Cl]2 and (R)-BINAP gave


Me N PPh 2

Me H N O

Me O NHBu Ph

N

Me Me H N

PPh 2

26

Me NHBu

10equiv 4-iodo-1-butene 10equiv HMPA,0°C

+ Me

Cl Cl Ar N Ru N Ar 145

OtBu

1 mol % Cu(OTf)2⋅C6 H 6 2.4 mol % 26 3equiv Me2Zn,–30°C

O

O

O 24

O

OTs

Me O

O

80% yield >15: 1d.r.,97%ee

2.5 mol % 145 CH 2 Cl2 1 mol % Cu(OTf)2⋅C6 H 6 5 mol % 24, 2equiv Et 2Zn, toluene,22°C,1h

Et

O Me

81% over all yield >98% anti, 95% ee

Scheme 8A.87.

the desired products in good yields and moderate enantioselectivities. In subsequent studies, they extended this reaction to the iridium catalyst system with ligand 146 [165]. Remarkable enantioselectivity was achieved when complex aldehydes were used as the electrophilic trapping reagents, such as benzaldehyde and α-alkoxy aldehydes. Following Noyori’s works [167], Morris and other groups [166] reported an important rhodium catalyst 147 that was used to catalyze Michael addition of malonates to α,βunsaturated ketone compounds. This system allowed a one-pot tandem asymmetric Michael addition/ketone hydrogenation protocol to create two stereogenic centers (Scheme 8A.88). Porter and coworkers [168] and Sibi and Chen [169] reported the addition of free radicals to oxazolidinone acrylates for the creation of chiral center. For example, using magnesium and copper salts as the catalyst in combination with a chiral bisoxazoline 148, this reaction could give the desired products with good yields and high enantioselectivities (Scheme 8A.89). Wang and coworkers [170] reported a new organocatalytic tandem Michael aldol reaction that was recognized as an efficient method for the preparation of chiral thiochromenes with high enantioselectivities. This reaction was mediated with catalyst 149 at room temperature and gave the product in 96% yield and 94% ee (Scheme 8A.90). Broad range of α,β-unsaturated aldehydes and 2-mercaptobenzaldehydes could also be tolerated in this process. Gaunt et al. developed a catalytic enantioselective tandem conjugate addition procedure for the preparation of synthetically versatile [n.1.0]bicycloalkanes as a single diastereoisomer. With a catalytic amount of chiral amine 150 or 151, this reaction afforded the desired enantiomer with high enantioselectivity (Scheme 8A.91) [171].

8A.4. CATALYTIC ASYMMETRIC TANDEM CONJUGATE ADDITION REACTION

481

H O

Ph2 P

O

N

Ph

N H2

Me

Ru

N

N

Ph2 P

P Ph2 BH4

146 147

+ Ph

OPh

H

O R

O

1) 2.5mol% [{Rh(cod)Cl}2] 6.5mol% (R)-binap Et2 MeSiH

O

O

H

OMe

147 / CH2 (CO2 Me) 2 C6H6

O

Ph

2) H3 O+

OPh Me

1) 2.5mol%[{Ir(cod)Cl} 2] 7.5mol% 146 Et 2MeSiH

O +

OH

OH

O

R

2) H 3 O+

OMe

Me Up to 96% ee 9.5:1 syn/ ant i

O

OH

OH

147/400psi H2 + CH(CO 2Me)2 C6 H6

CH(CO2 Me) 2

CH(CO2 Me) 2

tr an/ cis=30 :1

96% ee(S)

Scheme 8A.88.

O X

O N

O

Lewis acid/148 R +

R1I

X SnBu3 66–95% yield Up to 99:1 d.r. 43–97% ee

R= Ph, Me R 1= c-Hex, tBu, Et, iPr X = O, CH2 O

O N

N 148

Scheme 8A.89.

O N

R1 R


Ar Ar OSiMe3

N H 149 CHO

R

CHO

10 mol % 149 PhCO2H

SH

Toluene, rt 4ÅMS

+ X

CHO S

X

R

R = Ph, 2 or 4-MeOC6H4,4-FC6H4, 4-NO2C6H4,Me,Et,n-C3H7,n-C5H11 X = H,5-Cl, 5-MeO,5-Me, 3,4–(CH)4, 4,6–(MeO)2

Scheme 8A.90.

OMe N

MeO N

OMe N

N 151

150 O

O 20 mol % 150 or 151

Cl

H

O

O Ph

Na2CO3, MeCN, 80°C, additive

H 64–95% ee

Ph

Scheme 8A.91.

8A.5. CATALYTIC ASYMMETRIC CONJUGATE ADDITION OF HETEROATOM NUCLEOPHILES 8A.5.1. Conjugate Addition of Oxygen Nucleophiles Merschaert et al. [172] reported an intramolecular conjugate addition of phenolic nucleophiles to α,β-unsaturated esters for the asymmetric synthesis of 2-substituted chiral chromanes. This reaction was recognized as the first example of asymmetric catalysis of an exo-trig [173] cyclization with an oxygen nucleophile. In the presence of Cinchona alkaloids or their derivatives as catalysts, this reaction was carried out in toluene at 110°C under N2 for 48 h and afforded the product in 90% conversion and in 82:18 R/S ratio (Scheme 8A.92). Melchiorre et al. reported the first catalytic and highly enantioselective β-hydroxylation of O-centered nucleophiles to α,β-unsaturated ketones. In the presence of primary amine salt 152 as catalyst, this reaction afforded optically active products with up to 94% ee (Scheme 8A.93) [174].


N

HO

H

H

OH

N

CO2Me

O

Toluene

Me

CO2Me

Me 90% conv. R/S ratio 82:18

Scheme 8A.92.

X=1.5–2

Ph Boc N H

COO-

N H

X

OMe

NH3

N Catalytic salt 152 N

OH

O

1

R

R

Me Me

+ 3

O

C5H11

Catalytic salt 152 N

0.2 M.r.t., 3 h

O

C5H11

R2 1a R1, R 2, R 3 = H 1b R1, R 2, R 3 = OH 1c R2, R 3 = H, R1 = NO 2 1d R1, R 3 = OMe, R 2 = H

R3

R1 2

R

Scheme 8A.93.

8A.5.2. Conjugate Addition of Nitrogen Nucleophiles The first example of enantioselective aza-Michael addition of hydroxylamines to α,βunsaturated acceptors with 42% ee was reported by Falborg and Jørgensen in 1996 [175]. Shibasaki et al. developed an interesting heterobimetallic catalyst 153 that contained rare earth and alkali metals for the aza-Michael addition of O-alkylhydroxylamines to enones (Scheme 8A.94) and achieved up to 97% ee by using YLi3tris(binaphthoxide) as catalyst [176].


O M O

OM O Y

M=Li YLi3tris(binaphthoxide) (YLB)

O O M M=K YK3 tris(binaphthoxide) (YPB) 153

O Ph

Ph

+

RONH 2

O

(S)-YLB Ph

R= Me, Bn

NHOR Ph

91–97% ee

Scheme 8A.94.

Recently, a new method for the synthesis of α,β-azido carbonyl compounds that could be converted to amino acids was reported by Miller et al. [177]. With organic amine as catalyst, the conjugate addition of azide ion to enolates was carried out smoothly under mild conditions, and the product was obtained in 63% ee and 97% yield. When catalyst 155 was used, the improvement in enantioselectivity was noteworthy, as shown in Scheme 8A.95. Tomioka et al. developed a powerful method for constructing chiral β-amino carbonyl moieties through the asymmetric conjugate addition of lithium amides to enoates [178]. The addition reaction of lithium N-benzyltrimethylsilylamide to enoates afforded the desired products with high enantioselectivities and yields in the presence of chiral ligand 156 (Scheme 8A.96). MacMillan et al. developed an efficient method for the preparation of amino aldehydes through the catalytic asymmetric conjugate addition of nitrogen nucleophiles to α,β-unsaturated aldehydes [179]. This reaction was mediated by imidazolidinone 110pTSA in CHCl3, and the amino aldehyde product was obtained in 92% ee and 92% yield (Scheme 8A.97). Very recently, Palomo and coworkers [180] reported a highly enantioselective conjugate addition of carbamates to α,β-unsaturated ketones. Using chiral Lewis acid 157 as catalyst, the aza-Michael addition of carbamates to α′-hydroxy enones yielded the desired products with excellent enantioselectivities (Scheme 8A.98).

8A.5.3. Conjugate Addition of Phosphorous Nucleophiles Tedeschi and Enders reported the first asymmetric P–C bond formation. The reactions were carried out under heterogeneous conditions using KOH/Fe2O3 system [181]. The optically active β-substituted β-phosphono malonates were obtained in good yields and high enantioselectivities (Scheme 8A.99).


O

O N

tBu

HN

BOCHN

O

N

H O HN

BOCHN

Me

O

Me

O

H O HN

Me

N

N N Bn

tBu

HN

N Bn 154

O N

Me

155 TMSN3RCO2H catalyst 154

O

O

N3 Me

N

97% yield 63% ee O

O N

Me

O

TMSN3RCO2H catalyst 155

O

N3

N

Me 95% yield 78% ee

Scheme 8A.95.

MeO

R1 Li N R2

+

Ph

R 1 = i-Pr, Bn, TMS R2

CO2t-Bu

OMe 156

Ph 1

Toluene –78°C

=i-Pr, Bn,TMS

R

CO2 t-Bu N

R

2

R 1= TMS R 2 = Bn 97% yield, 97% ee

Scheme 8A.96.

In 2007, Córdova, Melchiorre, and others reported a new method of asymmetric P–C bond formation via the addition of phosphono nucleophiles to α,β-unsaturated aldehydes [182]. This reaction was catalyzed efficiently by simple chiral pyrrolidine derivatives, and the corresponding phosphine derivatives were obtained in high yields and excellent enantioselectivities (up to 99% ee; Scheme 8A.100). Togni et al. reported the use of [158](ClO4)2 complexes to mediate the asymmetric addition of P–H nucleophiles to vinyl nitriles [183]. The (Pigiphos)-nickel (II) complexes catalyzed the reaction of secondary phosphines and methacrylonitrile to give 2-cyanopropylphosphines in good yields and high enantioselectivities. A tentative mechanism, which involved the coordination of methacrylonitrile to the dicationic nickel catalyst, 1,4-addition of the phosphine, and a rate-determining proton transfer, was proposed (Scheme 8A.101).


Me

O N

Me N Me Me H

Ph

110

R = Me,n-Pr, O N

3

PG

+

O

R

PhCH 2CH 2 –

N H

OTBS

20 mol % 110-pTSA

PG

–20°C, CHCl3

N

OTBS O

R

PG = Cbz, BOC, Fmoc

CO2 Me, BnOCH 2 –

O Scheme 8A.97.

O

O

N Cu R TfO OTf R 157 N

O

O

O HO

R = t-Bu

R1

+

R1 = Ph(CH2)2, CH3(CH2)5,CH3CH2, (CH3)2CHCH2, (CH3)2CHCH2, c-C6H11, (CH3)3C

H2N

OR2

Cat. 157 Lewis acid

O HO

R2 = Bn, tBu, Me, Et

R1 Up to 98% ee

Scheme 8A.98.

Ph Me Me

O O Ph

CO2Me Ph R O CO2Me Fe2O3 / KOH O P TMSCl, NaI, H2O, CH2N2, two steps O H Ph

O MeO P MeO R

CO2Me CO2Me

84–94% ee

MeO

O R= O

Me

MeO OMe

Scheme 8A.99.

OR2

HN


F3C

CF 3

Ph N H

CF3

Ph OTMS

N H

57

O R

H

+

Ph

P H

Ph

OTMS

CF3

116

Cat.57 or 116 2-fluorobenzoic acid

Ph

P

Ph

O

R

Ph

NaBH4 H

R

O R = Ph, 4-NO2C6H 4 , 4-ClC6H 4 , 4-BrC6H 4, 2-Naph, BnO

Ph

BH3 P Ph

O

Scheme 8A.100.

P (R)-(S)-Pigiphos =

CN

Fe

Fe PPh2 Ph2P 158

[(Pigiphos)Ni(THF)][X]2 +

R2PH

R2P

CN

10–97% yield 32–94% ee R2PH = Ph2PH, tBu2PH, Cy2PH, iPr2PH, (1-adamantyl)2PH X = ClO4, BPh4, BF4 Scheme 8A.101.

In 2000, Enders and coworkers disclosed a convenient method for the synthesis of β-aminophosphonic acids via the addition of phosphorus compounds to nitroalkenes [184]. When a phosphite was allowed to react with a nitroalkene in the presence of Et2Zn and N,N,N′,N′-tetramethylenediamine (TMEDA), the desired product was afforded in good yields and high diastereoselectivities (Scheme 8A.102).

8A.5.4. Conjugate Addition of Sulfur Nucleophiles In 1977, Wynberg and coworkers [185] reported the first asymmetric organocatalyzed conjugate addition of sulfur nucleophiles to α,β-unsaturated ketones. In subsequent

OH

488 CATALYTIC ASYMMETRIC CONJUGATE ADDITION Ph Me

O

Me

O

Ph O O P H 159 O

Ph Ph Ph

R NO2

Phosphite 159

Me

TMEDA, Et2Zn, THF, –78°C

Me

86–91%

Ph O O P O O R Ph Ph

TMSCl, NaI, CH3CN, reflux

O

NO2

CH2Cl2/H2O, r.t.

O HO P HO

R

65–94% ee = 81–95%

de = 84–96% MeO R=

, , MeO

,

,

,

Fe

OMe

Scheme 8A.102.

studies, they developed a useful organocatalyst cinchonidine 160 for this reaction and obtained 75% ee (Scheme 8A.103) [186]. A bifunctional catalysis mechanism was proposed.

H

SH

N OH

N

NO2

O

O 160

But

+ S

But Scheme 8A.103.

Deng et al. identified that the dihydroquinidinepyrimidine catalyst (DHQD)2PYR 77 was effective for the asymmetric conjugate addition of (S)-nucleophiles to cyclic enones (Scheme 8A.104) [187]. This reaction afforded the corresponding Michael adducts in high yields and enantioselectivities when a wide variety of six- to nine-membered cyclic enones and substituted cyclopentenones as well as cyclohexenone were used as the acceptors. Because of the absence of hydrogen donor functionalities in 77, this catalyst was unable to promote the conjugate addition through a bifunctional catalysis mechanism similar to that proposed for 160.


Et

N

Ph

N

O

H

Et

O N

H3CO

OCH3

N Ph

N

N

77

O

O SH

(DHQD)2PYR (77) n R

+

n

Toluene

S

R R = H, Me n = 1~5

Scheme 8A.104.

CF3

CF3 OTMS

N H F3C R 1SH

+

R

2

R 1 = Bu t, Bn, EtO2 CCH 2 R 2 = alkyl, aryl

116 O

CF3 PhCO2H

NaBH4

SR1 R2

OH

73–87%, 89–97% ee

Scheme 8A.105.

Very recently, Jørgensen et al. reported an efficient reaction of the thiol addition to α,β-unsaturated aldehydes with L-proline-derived catalyst 116 [188]. This reaction was applicable for the addition of a wide variety of aliphatic thiols to different aromatic and aliphatic enals (Scheme 8A.105). The thiol addition to α,β-unsaturated aldehydes was a process in equilibrium, and the products generally racemized at ambient temperature. To overcome this problem, this reaction was performed at low temperatures with catalytic amounts of benzoic acid as a cocatalyst to improve the rate of reaction (Scheme 8A.105). In a speculated mechanism, catalyst 116 and the α,β-unsaturated aldehyde generated the corresponding iminium ion whose Si face was shielded by the silylated arm of the catalyst. Nucleophilic attack from the Re side afforded the corresponding (R)-configured enamine, which was hydrolyzed and reduced to give the desired product.


ACKNOWLEDGMENTS We thank the Hong Kong UGC Areas of Excellence Scheme (AoE/P-10/01) and the Hong Kong Polytechnic University Area of Strategic Development Fund for the financial support of this work.

REFERENCES 1. Perlmutt, P. Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemostry Series. Oxford: Pergamon Press, 1992; Vol. 9. 2. (a) Tomioka, K.; Koga, K. In Asymmetric Synthesis (Ed. J. D. Morrison). New York: Academic Press, 1983; Vol. 2, Chapter 7, pp. 201–224. (b) Posner, G. H. In Asymmetric Synthesis (Ed. J. D. Morrison). New York: Academic Press, 1983; Chapter 8, pp. 225–241. (c) Lutomoski, K. A.; Meyers, A. I. In Asymmetric Synthesis (Ed. J. D. Morrison). New York: Academic Press, 1984; Vol. 3, Chapter 3, pp. 213–274. 3. Oppolzer, W. Tetrahedron 1987, 43, 1969–2004. 4. Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308–2316. 5. Reviews: (a) Posner, G. H. Org. React. 1972, 19, 1–113. (b) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–631. 6. (a) Nakamur, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1997, 119, 4900–4910. (b) Krause, M.; Wagner, R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381–382. (c) Bertz, S. H.; Smith, A. J. J. Am. Chem. Soc. 1989, 111, 8276–8277. (d) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015–6018. 7. (a) Villacorta, G. M.; Rao, C. P.; Lippard, S. J. J. Am. Chem. Soc. 1988, 110, 3175–3182. (b) Ahn, K.-H.; Klassen, B.; Lippard, S. J. Organometallics 1990, 9, 3178–3181. 8. (a) Spescha, M.; Rihs, G. Helv. Chim. Acta 1993, 76, 1219–1230. (b) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467–4478. (c) van Klaveren, M.; Lambert, F.; Eijkelkamp, D. J. F. M.; Grove, D. M.; van Koten, G. Tetrahedron Lett. 1994, 35, 6135–6138. (d) Seebach, D.; Jaeschke, G.; Pichota, A.; Audergon, L. Helv. Chim. Acta 1997, 80, 2515–2519. 9. Stangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53, 16503–16510. 10. Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275–4278. 11. López, F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.; Feringa B. L. Angew. Chem. Int. Ed. Engl. 2005, 44, 2752–2756. 12. Mazery, R. D.; Pullez, M.; López, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966–9967. 13. den Hartog, T.; Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int. Ed. Engl. 2008, 47, 398–401. 14. López, F.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2006, 409–411 and references cited therein. 15. Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417. 16. Wang, S. Y.; Lum, T. K.; Ji, S. J.; Loh, T. P. Adv. Synth. Catal. 2008, 350, 673–677. 17. For reviews, see: (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771–806. (b) Krause, N. Angew. Chem. Int. Ed. Engl. 1998, 37, 283–285. 18. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–352. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236. 19. Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron Asymmetry 1993, 4, 2427–2430. 20. Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem. Int. Ed. Engl. 1997, 36, 2620–2632.

REFERENCES 491

21. Li, K.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2006, 45, 7600–7603. 22. Watanabe, T.; Kno1pfel, T. F.; Carreira, E. M. Org. Lett. 2003, 5, 4557–4558. 23. Esquivias, J.; Arrayás, R. G.; Carretero, J. C. J. Org. Chem. 2005, 70, 7451–7454. 24. Sewald, N. Angew. Chem. Int. Ed. Engl. 2003, 42, 5794–5795. 25. Palais, L.; Mikhel, I. S.; Bournaud, C.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2007, 46, 7462–7465. 26. Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779–781. 27. Hird, A. W.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2003, 42, 1276–1279. 28. Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2005, 44, 5306–5310. 29. Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192–8193. 30. Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700–3701. 31. Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 4584–4585. 32. Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988–14989. 33. Choi, H.; Hua, Z.; Ojima, I. Org. Lett. 2007, 9, 3187–3190. 34. Choi, H.; Hua, Z.; Ojima, I. Org. Lett. 2004, 6, 2689–2691. 35. Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2007, 46, 1097–1100. 36. Takahashi, Y.; Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.; Imamoto, T. J. Org. Chem. 2005, 70, 9009–9012. 37. Alexakis, A.; Burton, J.; Vastra, J. Eur. J. Org. Chem. 2000, 4011–4027. 38. Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405–5408. 39. Bräse, S.; Hoˇfener, S. Angew. Chem. Int. Ed. Engl. 2005, 44, 7879–7881. 40. Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111, 8266–8268. 41. Park, Y.-S.; Beak, P. J. Org. Chem. 1997, 62, 1574–1575. 42. Park, Y.-S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 10537–10538. 43. Pippel, D. J.; Weisenburger, G. A.; Beak, P. Angew. Chem. Int. Ed. Engl. 1998, 37, 2522–2524. 44. Lim, S. H.; Curtis, M. D.; Beak, P. Org. Lett. 2001, 3, 711–714. 45. Johnson, T. A.; Curtis, M. D.; Beak, P. Org. Lett. 2002, 4, 2747–2749. 46. Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579–5580. 47. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052–5058. 48. Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716–10717. 49. Shintani, R.; Duan, W. L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628–5629. 50. Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944–8946. 51. Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508–11509. 52. Boiteau, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003, 68, 9481–9484. 53. Duursma, A.; Boiteau, J. G.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2004, 69, 8045–8052. 54. Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2005, 7, 2433–2435. 55. Lee, J. E.; Yun, J. Angew. Chem. Int. Ed. Engl. 2008, 47, 145–147. 56. Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244–3245. 57. Su, L.; Li, X.; Chan, W. L.; Jia, X.; Chan, A. S. C. Tetrahedron Asymmetry 2003, 14, 1865–1869. 58. Digez, M.; Deeremberg, S.; Mies, O. P.; Claver, C.; van Leeuwen, P. W. N. M.; Kamer, P. Tetrahedron Asymmetry 2000, 11, 3161–3166. 59. Fraser, P. K.; Woodward, S. Chem. Eur. J. 2003, 9, 776–783. 60. Bennett, S. M. W.; Brown, S. M.; Muxworthy, J. P.; Woodward, S. Tetrahedron Lett. 1999, 40, 1767–1770. 61. Eilitz, U.; Lessmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron Asymmetry 2003, 14, 3095– 3097.

492 CATALYTIC ASYMMETRIC CONJUGATE ADDITION 62. d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2005, 44, 1376–1378. 63. Fuchs, N.; d’Augustin, M.; Humam, M.; Alexakis, A.; Tarasb, R.; Ladiali, S. Tetrahedron Asymmetry 2005, 16, 3143–3146. 64. Polet, D.; Alexakis, A. Tetrahedron Lett. 2005, 46, 1529–1532. 65. Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737–3740. 66. Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Synthesis 2004, 1509–1521. 67. Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527–2530. 68. (a) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed. Engl. 2005, 44, 1369–1371. (b) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J. 2006, 12, 4321–4332. 69. Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed. Engl. 2005, 44, 4212–4215. 70. (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611–3614. (b) Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal. 2004, 346, 1147–1168. 71. Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611–614. 72. Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966–4967. 73. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904. 74. Palomo, C.; Vera, S.; Mielgo, A.; Gómez-Bengoa, E. Angew. Chem. Int. Ed. Engl. 2006, 45, 5984–5987. 75. Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559–2562. 76. Luo, S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.; Cheng, J.-P. J. Org. Chem. 2006, 71, 9244–9247. 77. Barros, M. T.; Faisca Phillips, A. M. Eur. J. Org. Chem. 2007, 178–185. 78. Xu, Y.; Zou, W.; Sunden, H.; Ibrahem, I.; Cordova, A. Adv. Synth. Catal. 2006, 348, 418–424. 79. Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl. 2006, 45, 6366–6370. 80. Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151–4157. 81. Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253–4256. 82. Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598–11599. 83. Hechevarria Fonseca, M. T.; List, B. Angew. Chem. Int. Ed. Engl. 2004, 43, 3958–3960. 84. Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028–16029. 85. Trost, B. M.; Shuey, C. D.; Di Ninno, F., Jr.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284–1285. 86. (a) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097–1100. (b) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2004, 6, 3397–3399. 87. Ceccarelli, R.; Insogna, S.; Bella, M. Org. Biomol. Chem. 2006, 4, 4281–4284. 88. (a) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. Engl. 2003, 42, 828–831. (b) Bremeyer, N.; Smith, S. C.; Ley S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. Engl. 2004, 43, 2681–2684. (c) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. Engl. 2004, 43, 4641–4644. (d) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem. Int. Ed. Engl. 2006, 45, 6024–6028. 89. Wang, J.; Li, H.; Zu, L.; Wang, W. Adv. Synth. Catal. 2006, 348, 425–428. 90. Enders, D.; Chow, S. Eur. J. Org. Chem. 2006, 4578–4584. 91. Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077–3079. 92. Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624–9625. 93. Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611–614. 94. Luo, S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.; Cheng, J.-P. J. Org. Chem. 2006, 71, 9244–9247. 95. Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem. Int. Ed. Engl. 2006, 45, 3093–3097.

REFERENCES 493

96. Xu, D.; Luo, S.; Yue, H.; Wang, L.; Liu, Y.; Xu, Z. Synlett 2006, 2569–2572. 97. Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006, 3687–3689. 98. Zhu, M.-K.; Cun, L. F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron Asymmetry 2006, 17, 491–493. 99. Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558–9559. 100. Cao, Y.-J.; Lu, H. H.; Lai, Y.-Y.; Lu, L.-Q.; Xiao, W.-J. Synthesis 2006, 3795–3800. 101. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904. 102. Diez, D.; Gil, M. J.; Moro, R. F.; Marcos, I. S.; García, P.; Basabe, P.; Garrido, N. M.; Broughton, H. B.; Urones, J. G. Tetrahedron 2007, 63, 740–747. 103. Xu, Y.; Cordova, A. Chem. Commun. 2006, 460–462. 104. Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170–7171. 105. Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett. 2006, 8, 4787–4790. 106. (a) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem. Commun. 2005, 5346–5348. (b) Mitchell, C. E. T.; Brenner, S. E.; García-Fortanet, J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039–2049. 107. Hanessian, S.; Govindan, S.; Warrier, J. S. Chirality 2005, 17, 540–543. 108. Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331–8338. 109. Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897–3900. 110. Tsogoeva, S. B.; Jagtap, S. B.; Ardemasova, Z. A.; Kalikhevich, V. N. Eur. J. Org. Chem. 2004, 4014–4019. 111. Tsogoeva, S. B.; Jagtap, S. B.; Ardemasova, Z. A. Tetrahedron Asymmetry 2006, 17, 989–992. 112. Tsogoeva, S. B.; Jagtap, S. B. Synlett 2004, 2624–2626. 113. Latvala, A.; Stanchev, S.; Linden, A.; Hesse, M. Tetrahedron Asymmetry 1993, 4, 173–176. 114. Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–1969. 115. Wang, L.; Li, H.; Zu, L.; Jiang, W.; Wang, W. Adv. Synth. Catal. 2006, 348, 2047–2050. 116. Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257–4259. 117. Bakó, P.; Mako, A.; Keglevich, G.; Kubinyi, M.; Pal, K. Tetrahedron Asymmetry 2005, 16, 1861–1871 and references cited there. 118. Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. W. R. Tetrahedron Lett. 2003, 44, 8677–8680. 119. Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 11790–11791. 120. Ooi, T.; Takada, S.; Fujioka, S.; Maruoka, K. Org. Lett. 2005, 7, 5143–5146. 121. Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192–1194. 122. Zhang, F.-Y.; Corey, E. J. Org. Lett. 2001, 3, 639–641. 123. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 9022–9023. 124. Ooi, T.; Doda, K.; Takada, S.; Maruoka, K. Tetrahedron Lett. 2006, 47, 145–148. 125. Ooi, T.; Takada, S.; Doda, K.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 2006, 45, 7606–7608. 126. Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2003, 42, 661–665. 127. Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2006, 45, 4305–4309. 128. Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005, 7, 3195–3197. 129. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906–9907. 130. McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. Engl. 2005, 44, 6367–6370. 131. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–125. 132. Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454–1455. 133. Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem. Int. Ed. Engl. 2006, 45, 947–950. 134. Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347–5350.

494 CATALYTIC ASYMMETRIC CONJUGATE ADDITION 135. O’Donnell, M. J.; Delgado, F.; Dominguez, E.; de Blas, J.; Scott, W. L. Tetrahedron Asymmetry 2001, 12, 821–828. 136. Kim, D. Y.; Suh, K. H.; Huh, S. C.; Lee, K. Synth. Commun. 2001, 31, 3315–3322. 137. Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.; Reddy, M. V. R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005, 127, 13450–13451. 138. Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta, Y.; Nemoto, T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 11206–11207. 139. (a) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Sakuraba, S.; Ohshima, T.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 2006, 45, 4635–4637. (b) Chinchilla, R.; Mazón, P.; Nájera, C.; Ortega, F. J.; Yus, M. Arkivoc 2005, 6, 222–232. 140. Lee, Y.-J.; Lee, J.; Kim, M.-J.; Jeong, B.-S.; Lee, J.-H.; Kim, T.-S.; Lee, J.; Ku, J.-M.; Jew, S.-S.; Park, H.-G. Org. Lett. 2005, 7, 3207–3209. 141. Arai, S.; Tokumaru, K.; Aoyama, T. Chem. Pharm. Bull. 2004, 52, 646–648. 142. Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.; Yamaguchi, K. Chem. Commun. 2003, 1734–1735. 143. (a) Ma, D.; Cheng, K. Tetrahedron Asymmetry 1999, 10, 713–719. (b) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245–246. 144. Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204–11205. 145. Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313–1317. 146. Li, H-M.; Song, I.; Liu, X-F.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948–8949. 147. Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-Y.; Chen, Y.-C. Chem. Eur. J. 2007, 13, 319–327. 148. Bell, M.; Frisch, K.; Jørgensen, K. A. J. Org. Chem. 2006, 71, 5407–5410. 149. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173. 150. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem. Int. Ed. Engl. 2005, 44, 6576–6579. 151. Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron Lett. 2006, 47, 7037–7042. 152. Zhuang, W.; Hazell, R. G.; Jøgensen, K. A. Org. Biomol. Chem. 2005, 3, 2566–2571. 153. Zhou, W.; Xu, L.-W.; Li, L.; Yang, L.; Xia, C.-G. Eur. J. Org. Chem. 2006, 5225–5227. 154. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894–7895. 155. Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442–4443. 156. Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928–9929. 157. Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514–515. 158. Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072–6073. 159. (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem. Int. Ed. Engl. 1997, 36, 2620–2623. (b) Keller, E.; Maurer, J.; Naasz, R.; Schrader, T.; Meetsma, A.; Feringa, B. L. Tetrahedron Asymmetry 1998, 9, 2409–2413. (c) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841–5842. (d) Mandoli, A.; Arnold, L. A.; Salvadori, P.; Feringa, B. L. Tetrahedron Asymmetry 2001, 12, 1929–1937. (e) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244–7254. 160. (a) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358–4359. (b) Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835–3837. (c) Alexakis, A.; March, S. J. Org. Chem. 2002, 67, 8753–8757. 161. (a) Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528–4529. (b) Miura, T.; Harumashi, T.; Murakami, M. Org. Lett. 2007, 9, 741–743. 162. (a) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110–1111. (b) Bocknack, B. M.; Wang, L. C.; Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421–5424.

REFERENCES 495

163. (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755–756. (b) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779–781. 164. Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528–4529. 165. Zhao, C. X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829–1831. 166. (a) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125, 7508–7509. (b) Watanabe, M.; Ikagawa, A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148–11149. (c) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127, 516–517. 167. (a) Ohkuma, T.; Koizumi, M.; Hilt, G.; Kabuto, C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508– 6509. (b) Sandoval, C. A.; Ohkuma, T.; Muñiz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125, 13490–13503. 168. Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117, 11029–11030. 169. Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472–9473. 170. Wang, W.; Li, H.; Wang, J. J. Am. Chem. Soc. 2006, 128, 10354–10355. 171. Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. Engl. 2004, 43, 2681–2684. 172. Merschaert, A.; Delbeke, P.; Daloze, D. Tetrahedron Lett. 2004, 45, 4697–4701. 173. Baldwin, J. J. Chem. Soc. Chem. Commun. 1976, 734–737. 174. Carlone, A.; Bartoli, G.; Bosco, M.; Melchiorre, P. Eur. J. Org. Chem. 2007, 5492–5495. 175. Falborg, L.; Jørgensen, K. A. J. Chem. Soc. Perkin Trans. 1 1996, 2823–2826. 176. Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 16178–16179. 177. (a) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem. Int. Ed. Engl. 2000, 39, 3635–3638. (b) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134–2136. 178. (a) Doi, H.; Sakai, T.; Tomioka, K. J. Am. Chem. Soc. 2003, 125, 2886–2887. (b) Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71, 4706–4709. 179. Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328–9329. 180. Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gómez-Bengon, E.; Garcia, J. M. J. Am. Chem. Soc. 2004, 126, 9188–9189. 181. Tedeschi, L.; Enders, D. Org. Lett. 2001, 3, 3515–3517. 182. (a) Ibrahem, I.; Rios, R.; Córdova, A. Angew. Chem. Int. Ed. Engl. 2007, 46, 4507–4510. (b) Carlone, A.; Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. Engl. 2007, 46, 4504–4506. 183. (a) Sadow, A. D.; Haller, I.; Fadini L. J. Am. Chem. Soc. 2004, 126, 14704–14705. (b) Sadow, A. D.; Togni, A. J. Am. Chem. Soc. 2005, 127, 17012–17024. 184. Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem. Int. Ed. Engl. 2000, 39, 4605–4607. 185. Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2181–2182. 186. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417–430. 187. McDaid, P.; Chen, Y.; Deng, L. Angew. Chem. Int. Ed. Engl. 2002, 41, 338–340. 188. (a) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710–15711. (b) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 14986–14991.

8B ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES Günter Helmchen Organisch-Chemisches Institut der Universität Heidelberg, D-69120 Heidelberg, Germany

Uli Kazmaier Institut für Organische Chemie, Universität des Saarlandes, D-66123 Saarbrücken, Germany

Sebastian Förster Organisch-Chemisches Institut der Universität Heidelberg, D-69120 Heidelberg, Germany

8B.1. INTRODUCTION AND SCOPE The metal-catalyzed allylic substitution is an important tool in organic synthesis. It is schematically described in Scheme 8B.1. The reaction can be carried out with a variety of transition metals, substitution patterns of the allylic moiety, and nucleophiles in stoichiometric or catalytic fashion. Furthermore, addition of a nucleophile can occur at a terminal or the central carbon. The latter reaction mode is rare for palladium, however, very common for other metals. Mechanistic understanding of the reaction requires thorough knowledge of the properties of π- and σ-allyl metal complexes and their interconversion. The early work in this field centered on palladium. Smidt and Hafner [1], famous for their invention of the Wacker process (1956), reported the first (π-allyl)Pd complex in 1959. The possibility of a C–C bond-forming substitution reaction with (π-allyl)Pd complexes was discovered by Tsuji et al. in 1965, then an industrial chemist at Toray Industries [2]. Important improvements are due to other industrial chemists (Toray Industries, Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 497

498 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES

[M] [M]

Nu

X

+ Nu

Nu

[M]

Scheme 8B.1. Allylic substitution via allyl-metal complexes as intermediates.

Union Carbide), who demonstrated in 1970 that phosphines accelerate the reaction and palladium can be employed in catalytic amount [3,4]. The field was soon dominated by Trost and co-workers, who started their crusade in 1973 [5]. They were the first to achieve enantioselectivity in an allylic substitution, in stoichiometric (1973) [6] as well as catalytic (1977) reaction mode [7]. Thus, the stage was set for our topic, asymmetric catalysis. For a considerable time, progress was slow; however, in the 1990s, dramatic improvements were achieved for the Pd-catalyzed allylic substitution. The progress was periodically documented in excellent reviews [8–13]. In the present series of books, the field was last reviewed by Trost and Lee in 2000 [14]. At that time, Pd catalysis dominated the field. In the meantime, enormous advances have been made with Mo, Ir, Ru, Ni, and Cu catalysts, which have offered new opportunities, for example, for reactions with monosubstituted allylic substrates. An exhaustive coverage of the whole field by Lu and Ma, with emphasis on chiral ligands, was published in January 2008 [15]. In this chapter, we will follow Trost and Lee in the general ordering and will, in the first part, update the field of Pd-catalyzed reactions reported after ca. 2000 with preference for preparative applicability rather than benchmark examples, which have been fully presented by Lu and Ma. The emphasis will be placed, in the second part, on the reactions promoted by non-Pd catalysts as cited above. There are many examples of stereospecific rather than enantioselective reactions, which are typical for Fe and Rh complexes. These reactions are not covered in detail here.

8B.2. PALLADIUM-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS 8B.2.1. Fundamentals, Mechanistic Aspects Many aspects discussed in this chapter are valid for transition metal complexes in general. The corresponding reaction schemes are presented using the letter M, short for transition metal. Those facts that are specific for palladium are formulated with the element symbol Pd. 8B.2.1.1. Classification of Allylic Substitutions An allylic substitution begins with coordination of a low valent metal species to the double bond of an allylic system. Subsequent oxidative addition by expulsion of the leaving group X yields a π-allyl complex as intermediate (Scheme 8B.2). This intermediate can be a neutral or, presumed to be more reactive, a cationic complex, depending on the nature of the ligands and the coun-

8B.2. PALLADIUM-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS

499

X

X

[M]

[M]

[M]X

[M]

X

Nu Nu Nu [M]

Scheme 8B.2. Representative catalytic cycle of a transition metal-catalyzed allylic substitution.

terion X. In most cases, a soft carbanion is the nucleophile, which typically adds directly to a terminal carbon with inversion of configuration rather than via the metal cation with retention. The resultant olefin complex dissociates to yield the product and the regenerated catalyst. Usually, but not always, the substitution step is irreversible and turnover determining. However, there are examples where the formation of the olefin complex or isomerization among several π-complexes is slow. Rates of all these processes are dependent on ligands at the metal, and therefore can be influenced by additives, for example, halide salts, which introduce metal-coordinating species. It is helpful for the understanding of substitutions at π-allyl complexes to consider the fundamental types of substrates leading to chiral products as described in Scheme 8B.3. We are using here the classification of Trost and Lee. The presentation is general with respect to the metal as this classification is very broadly applicable. Type A:

Type B:

Types C, D:

meso-Compounds are used as substrates. Chirality is introduced in the oxidative addition step of the catalytic cycle. There are several structural types; only one particular is shown for illustration. Chiral racemic allylic derivatives with two identical substituents in positions 1 and 3 are used as starting materials. If an achiral metal fragment is present, the intermediary allyl complexes are achiral and the allylic termini enantiotopic. With a chiral ligand at the metal, the termini are diastereotopic and the rates of addition of a nucleophile are different. In this class, a racemic or prochiral substrate containing two identical geminal substituents R1 at one of the allylic termini reacts via a π-allyl intermediate, which can isomerize by the well-established π-σ-π mechanism (see below) [16]. Enantioselection can occur in the nucleophilic addition step or in the ionization step leading to the allyl intermediate (type D), depending on the relative rates of isomerization of allyl complexes and their reactions with the nucleophile.


Type A

U U

X

X

[M]

X

[M]

Nu

Nu

+

X

+

U

X

U

X

U

Nu

[M]

Type B R1

R1

[M]

R1

X

R1

R1

Nu

R1

*

Nu

[M]

Type C, D R1

R2 R1

X

R1

or R1 R1

[M]

R2

R1

Nu

R1

R1

[M]

R2

X

B

[M]

A

Nu

A

Type E X

2 * R

C

B C *

[M]

Scheme 8B.3. Fundamental types of enantioselective allylic substitutions.

Type E:

The reaction of a prochiral nucleophile with a (π-allyl)metal complex yields a product with a new chirality center. Upon introduction of a chiral ligand, the symmetry is broken.

A further reaction type F is added for completeness and as contrast, although this does not constitute an enantioselective synthesis. A reaction as described in Scheme 8B.4 proceeds via an intrinsically chiral allyl complex as intermediate. Normally, this does not undergo racemization; therefore, the enantiomeric purity of the substitution product will be the same as that of the starting material. Kinetic resolution can be effected upon addition of a chiral ligand. There are exceptions from the general behavior. For example, at very a high concentration of a Pd catalyst, partial racemization via ligand exchange or metal–metal displacement can take place. 8B.2.1.2. Isomerism of Allyl Complexes Mechanistic scenarios of allylic substitutions as described above are determined to a great extent by isomerization modes of intermediary isomeric π-allyl complexes. Among several isomerization modes, the π-σ-π mechanism is the most important and well established [17]. In Scheme 8B.5, π-σ-π isom-

501


Type F R1

R2 X

R1

R1

[M]

or R2

R2

Nu

R1

*

R2

Nu

[M]

X

Scheme 8B.4. Allylic substitution via a nonequilibrating chiral π-allyl complex.

R3

R1 R2 MLn

[MLn] R1

R3 L achiral:

R2

R1 = R3, R2 = H diasteroisomerization of meso-compound (type B)

π-σ-π R

2

R R1 MLn

3

R1 = R2 = R3 R [LnM]

2

R3

enantiomerization (type C)

R1 = R3, R2 = H diasteroisomerization (type F)

R1

Scheme 8B.5. Isomerization of (π-allyl) complexes via π-σ-π rearrangement.

erism of complexes with the most important substitution patterns is described. Note that in the σ-complex, rotation about a C–C bond leads to change of a terminal substituent between the syn- and anti-disposition relative to the central hydrogen, while rotation about the C–M bond corresponds to a rotation of the entire allyl moiety (apparent rotation). Furthermore, the σ-complex is coordinatively unsaturated. Thus, the π-σ-π rearrangement is influenced by coordinating species, notably halide anion [18]. The π-σ-π rearrangement is the reason why reactions according to type C, even if a branched, chiral allylic substrate is used, can yield a single enantiomer of a product via an equilibrating mixture of π-complexes, which are enantiomers in case of achiral and diastereomers in case of chiral ligands at the metal. In addition to the π-σ-π rearrangement, several other, less frequently encountered isomerization modes exist. Further details on these as well as illustrations of the π-σ-π rearrangement for individual reaction types of Pd complexes can be found in previous reviews [14,16]. 8B.2.1.3. Regioselectivity of Pd-Catalyzed Allylic Substitutions Regioselectivities of allylic substitutions are very dependent on the transition metal used and can only be discussed in the corresponding chapters. Here, the presentation is restricted to Pd complexes. In many cases, the regioselectivity of an allylic substitution reaction is determined by the stability of the resultant olefin complex rather than inherent properties of the π-allyl complex. Therefore, rationalization is very difficult. Nevertheless, a few simple rules seem to be generally valid (cf. Fig. 8B.1).


Proximal Distal Proximal: CH3, OR′ R

Distal: [Pd]

alkyl ≠ CH3, aryl, SR′, CH2OR′, CF3, SiMe3

Nu R R

[Pd]

Figure 8B.1. Regioselectivity of Pd-catalyzed allylic alkylations.

(1) Steric effects favor the sterically better accessible carbon atom of the allyl unit. This effect can be overruled by electronic effects. This is most apparent from the fact that 1-methyl- and 1,1-dimethylallyl derivatives display a preference for reaction at the methylated, proximal terminus, while general 1-alkylallyl derivatives show preference for reaction at the distal terminus. (2) Conjugating substituents (e.g., Ph, COOR, CN) favor the distal position, as would be expected for a late transition state reflecting the stability of the product olefin complex. (3) σ-Electron-withdrawing substituents (CH2OR, CF3 [19]) favor the distal terminus. (4) If all other factors are equivalent, the carbon center better stabilizing a positive charge seems to be preferred. Thus, OR′ [20] favors the proximal, SR′ [21] and SiMe3 [22] the distal center. There is only one example of a system, which is solely controlled by electronic effects of the substituents [23]. Note that a phenyl group directs to the distal position, despite its charge stabilizing effect, on an allyl cation not coordinated to Pd. (5) The electronic properties of the ligands are important in that relative positive charges at the allylic termini are enhanced in proportion to the acceptor strength of the ligands. There are examples of changeover of regioselectivity with ligands [24]. (6) Substituents in the allylic substrate or the ligand interacting with the nucleophile, for example, by hydrogen bonding or via the counter cation (cf. Section 8B.2.2.3), or PdII [25], can control the position of attack of the nucleophile. (7) Reactions proceeding via syn,anti-(π-allylic) complexes show a preference for the reaction at the anti-terminus, giving rise to trans- rather than cis-products, as would be expected for a late, product-like, transition state [26,27]. (8) If two different ligand donor centers are present, for example, P and N, substitution trans to the center possessing the higher trans influence is preferred. (9) Finally, the influence of the nucleophile can be dominant. A rare example are hydrazines, which add kinetically controlled at the substituted terminus of monosubstituted (allyl)Pd complexes [28]. Note that these rules refer to kinetically controlled reactions. Thermodynamic control has been observed several times and follows other rules, because the organic product is the one that has to be considered, while in kinetically controlled reactions, the (olefin) Pd complex is the product that counts.


503

8B.2.1.4. Special Reaction Conditions In many important allylic substitutions, a salt is used as source of a nucleophile. Dimethyl sodiomalonate is a typical example. Low solubility of the salt in THF, dichloromethane, and less polar solvents can cause a problem, particularly on scale-up. A second source of problems arising from the nucleophile is its basicity, which can effect side reactions, for example, elimination. Use of phase-transfer conditions can solve the solubility problem if the system tolerates water. This is not always possible. More generally applicable are techniques of generating the anionic nucleophile from the conjugate acid in situ. Two clever reaction modes have been devised: Trost’s N,O-bis(trimethylsilyl)acetamide (BSA) method and Tsuji’s procedure using allylic carbonate as substrates. These methods are also helpful for the adjustment of relative rates. Rates of oxidative addition or isomerization of (allyl)metal complexes and the rates of the reactions of the latter with the nucleophile can be similar. Often decrease of the concentration of the nucleophile, favoring the monomolecular isomerization processes, leads to improved selectivity. 8B.2.1.4.1. The BSA Method An ingenious method to keep the concentration of an anionic nucleophile low was invented by Trost and Murphy (Scheme 8B.6) [29]. A solution of an allylic acetate, the conjugate acid of a nucleophile, the catalyst and BSA is treated with a small amount of KOAc. This induces the formation of the base by desilylation. The concentration of the base, and of course also of the nucleophile, is then regulated by the liberation of the leaving group. 8B.2.1.4.2. Tsuji’s Method (Salt-Free Conditions) Oxidative addition of a low valent metal species to an allyl carbonate generates a positively charged (π-allyl) complex and carbonate anion; this is in equilibrium with alkoxide, which acts as base for the deprotonation of the conjugate acid of the nucleophile. Accordingly, an additional base is not required. Furthermore, decarboxylation accompanied by evolution of CO2 renders the

Pd0Ln OAc

Nu

Nu

L

Pd

L

AcO O

O H3C

N H

H3C

SiMe3 O

H-Nu H3C

N

SiMe3

Scheme 8B.6. The BSA method.

AcO-SiMe3

SiMe3 N

SiMe3


formation of the π-allyl complex an irreversible process, in contrast to the corresponding reaction of an allylic acetate. The method was introduced by Tsuji in 1984, and the designation “salt-free” was coined by Plietker [30,31]. Allylic carbamates can similarly be used under neutral conditions [32] (Scheme 8B.7). Pd0Ln O

Nu

OCH3 O

Nu

L

Pd

O

L

OCH3 O

CH3OH OCH3

H-Nu

CO2

Scheme 8B.7. Allylic alkylation with an allylic carbonate.

A related but less general example is provided by vinyl epoxides, which can also be reacted with the conjugate acid of a nucleophile without additional base (Scheme 8B.8). OH

O

O HNu

Nu

[M]

+ OH

[M] Nu Scheme 8B.8. Allylic alkylation with a vinyl epoxide.

8B.2.2. Alkylations with Soft Stabilized Carbanions 8B.2.2.1. Enantioselective Reactions of meso-Substrates with C-Nucleophiles The three known types of meso-substrates are described in Figure 8B.2. In allylic substitutions, the oxidative addition of [Pd0] constitutes the enantiodiscriminating step. In the case of the meso-compounds, A1 the Pd fragment coordinates to the alkene from the face opposite to the leaving groups X, and stereocontrol is equivalent to differentiation between the two enantiotopic leaving groups. Oxidative addition in case of geminal diesters A2 (X = OOCR′) involves both enantioface differentiating complexation and ionization in the enantiodiscriminating step [33,34]. Concerning enantioselective variants, substrate A3 has so far only been used in amination reactions.


X

U

X

R

X

X

X

H

A1

505

X

A2

A3

Figure 8B.2. Types of meso-substrates that have been used in Pd-catalyzed allylic substitutions.

O

O

P Ph 2

NH HN

P Ph 2

P Ph 2

(R,R)-DPPBA-1 (L1a)

Ph

P Ph 2

(R,R)-DPPBA-2 (L1b)

Ph O

O NH HN P Ph 2

O

O

NH HN

P Ph 2

(R,R)-DPPBA-3 (L1c)

O

O NH HN P Ph 2

P Ph 2

(R,R)-DPPBA-4 (L1d)

Figure 8B.3. The most often used DPPBA ligands [38].

Diesters of types A1 (U = O, (CH2)n) and A2 (X = OAcyl) have mainly been used by Trost and coworkers. The substitution products derived from substrates of type A1 can be transformed into nucleosides and carbanucleosides. The work before 2000 has been reviewed in detail by Trost and Lee [14]. In fact, Trost and coworkers’ important DPPBA ligands (Fig. 8B.3) have originally been successful in this class of compounds [35]. In the meantime, polymer-supported variants of these ligands have also been developed [36,37]. The configurational course of the DPPBA-controlled allylic substitutions can be predicted with the help of a working model developed by Trost and coworkers (Fig. 8B.4) [39]. The situation is more complex than this model suggests because most of the (allyl)(DPPBA)Pd intermediates seem to be oligomers [40], which makes elucidation of reaction mechanism exceedingly difficult. Furthermore, π-allyl complexes with C2symmetric ligands are C1-symmetric (cf. Section 8B.2.2.2.1) [41]. Despite these problems, the model has allowed to rationalize a large body of experiments coherently and to make predictions. 8B.2.2.1.1. Alkylations of Esters of Allylic meso-1,4-Diols A few benchmark examples of the reactions of a meso-diester are described in Table 8B.1 and Scheme 8B.9 [37]. In


O

O NH HN

P

P Pd

Flap

Pd

Flap

Wall

Wall Figure 8B.4. Trost’s cartoon model for description of a (DPPBA)Pd fragment.

TABLE 8B.1. Enantioselective Allylic Alkylations of Cyclic meso-Substrates

U

X

X

Nu

U

X

Nu

A: [Pd(π-C3H5)Cl]2, L* B: [Pd2(dba)3]CHCl3, L* Conditions

Yield (%)

ee (%)

Reference

(S,S)-DPPBA-1

A (1 mol %), THF

68

95

43

(1S,2R)-L2b

A, BSA, KOAc, CH2Cl2, −20°C B, BSA, KOAc, CH2Cl2, B, BSA, KOAc, CH2Cl2, Cs2CO3, H2O, 0°C, 18 h

85

96

44

75

99

45

84

99

45

56

91

46

Pronucleophile

U

X

L*

NaCH(CO2Me)2

(CH2)2

OBz

CH2(CO2Me)2

CH2

OAc

CH3NO2

CH2

OAc

(S,S)-DPPBA-1

CH3NO2

(CH2)2

OAc

(S,S)-DPPBA-1

CH2(CO2Et)2

CH2

OAc

L3

O

CH3 i-Pr

O R 2P

S

t-Bu (1R,2S)-L2a R = Ph (1R,2S)-L2b R = 1-naphthyl

O

PS

O

O

HN

(CH2)3

n L3

N

H N PPh2

these reactions, a chiral π-allyl complex is formed with inversion of configuration. Regioselectivity of the subsequent substitution is determined by preference for addition of the nucleophile at the allylic terminus distal to the electron-withdrawing acyloxy group. As the enantiodiscrimination in the ionization step is irreversible, the final enantiomeric excess of the substitution products is almost independent of the nucleophile [42]. Most often, C2-symmetric ligands, in particular the ligand DPPBA-1 (Fig. 8B.3), have been used; however, excellent results have been also obtained with the chelating P,S-ligand L2 and with the monodentate ligand L3 (Table 8B.1).


507

+ BzO

NaCH(CO2Me)2

OBz

OBz

[Pd(π-C3H5)Cl]2 (2.5 mol %) (R,R)-DPPBA-5 (15 mol %) THF, 0°C, 1 h

(MeO2C)2HC

[Pd]

OBz

98% ee (98%) +

CPh3 N Pd O

O

BzO

NH HN P Ph 2

P Ph2

CH(CO2Me)2

(R,R)-DPPBA-5 (L1e)

Scheme 8B.9. Enantioselective alkylation of a meso-diester [37].

As was pointed out above, Trost applied the allylic substitution at meso-substrates extensively in the field of nucleoside and carbanucleoside synthesis [47]. There are two general strategies that are schematically described in Scheme 8B.10 (X = O or CH2). Route A involves first Pd-catalyzed asymmetric allylic amination with a nucleobase, then regioselective Pd-catalyzed alkylation using a pronucleophile that constitutes a C1equivalent, that is, an equivalent of a HOH2C− or ROOC− species. In route B, the order of the steps is reversed.

ROCO

ROCO

Base U

A OCOR U

HOH2C

B

"HOH2C"

Base U

OCOR U

Scheme 8B.10. General strategies for the synthesis of nucleosides (U = O) and carbanucleosides (U = CH2).

Several interesting C1-equivalents have been devised. One example is illustrated by a synthesis of adenosine (Scheme 8B.11) [47]. Acetoxy Meldrum’s acid was used here as the C1-equivalent. The degradation of the corresponding substituent of the product was carried out by lead tetraacetate oxidation at a late stage of the synthesis. Another C1-nucleophile is represented by sodium [(phenyl-sulfonyl)methylen]nitronate (Scheme 8B.12). The primary alkylation product undergoes a subsequent intramolecular Oalkylation to generate another allylic moiety with a leaving group. This approach was recently used for a synthesis of adenosine [47] and earlier for a synthesis of (−)-carbovir and aristeromycin [48]. In conjunction with the synthesis of γ-lycorane, Chapsal and Ojima used a small library of chiral, monodentate phosphoramidites as ligands for desymmetrization of cyclohex-2-en-1,4-diyl dibenzoate (Scheme 8B.13) [49]. Some of the members of the set

508 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES O

NH2

O AcO

O O

BzO

O

O

OBz

CO

AcO

O

[Pd2(dba)3CHCl3] (2.5 mol %) (R,R)-DBPPA-1 (7.5 mol %) DBU, THF, –40°C

N

O

OC

HO

OBz

N

N N

O O

91% ee (82%)

O

Scheme 8B.11. Synthesis of adenosine [47].

BzO

SO2Ph

NO2Na

PhSO2

OBz

SO2Ph OBz

O 2N

Pd2(dba)3CHCl3/

O N O

(R,R)-DBPPA-1 THF, rt

96% ee (93%)

O N HO

N

MeO2CO

NH N

MeO2C

NH2 MeO2CO

(–)-Carbovir

HO

Scheme 8B.12. Synthesis of (−)-carbovir [47].

OLi MeO BzO

OBz

O

O N H

O

MeO2C

O

N H

O Br [Pd(π-C3 H5)Cl]2 (2 mol %), L4 (8 mol %), THF, –60°C, 8 h

O

Br

99% ee (83%) OBz 5 steps

49%

2-Naphthyl O P N

H

O OMe

L4

H

O O

N (+)-γ-Lycorane

Scheme 8B.13. Allylic alkylation as key step in the total synthesis of (+)-γ-lycorane.

H

509


were probed with dibenzyl malonate as pronucleophile, which gave products with moderate enantiomeric excess (95

92

51

Ph

Bn

100:0

75

51

H

CH3

5.5:1

>95 13

81b

51

CH3

CH3

11:1

92

86b,c

51

CH3

Bn

2.3:1

90

67b,c

51

n-C3H7

CH3

12:1

93

73b,c

51

a

ee value of A. Combined yield of A and B. c (S,S)-DPPBA-1 was used; ee value for ent-A. b


The ees obtained for the first allylation step were >90% in most cases; yields were generally high. A conceivable further substitution was not observed. Besides malonates, azlactones have been used as pronucleophiles, which are particularly important because they give rise to amino acids as products [53]. Deprotonation of azlactones generates prochiral nucleophiles (type E). This means that two chirality centers, that is, diastereoisomers, are formed. As an understanding requires a discussion of the reactions of azlactones with simpler allylic substrates (cf. section 8B.2.2.4.3), we will at this stage only present Trost’s synthesis of sphingofungins as an appetizer [54] (Scheme 8B.15).

H3C

ONa

N OAc t-BuPh2SiO

O OAc

Ph

OAc

O

t-BuPh2SiO

[Pd(π-C3H5)Cl]2 (0.5 mol %), (R,R)-DPPBA-1 (1.5 mol %), THF

O

H3C N

Ph

dr = 11:1, 89% ee (70%)

OH

OH

n-C6H13

X = OH: sphingofungin E X = H: sphingofungin F

CO2 O

NH3

OH X

Scheme 8B.15. Synthesis of sphingofungins via alkylation of a geminal diacetate with an azlactone.

8B.2.2.2. Enantioselective Allylic Alkylations of Allyl Derivatives with Identical Substituents in 1,3-Position 8B.2.2.2.1. Fundamentals and Scope Most of the reactions of type B (cf. Scheme 8B.3) have been carried out with the allylic substrates described in Scheme 8B.16 using dimethyl malonate as nucleophile.

R

R

[Pd0]

R

R

X

HNu or MNu

* R

R

Nu

[PdII] X

[PdII] [Pd0]

1

( )n-4

3

( )n-4

HNu or MNu

Nu ( )n-4

X = OAc, OBz, OCO2Me; R = Me, Ph Scheme 8B.16. Typical substrates in allylic alkylations of allylic acetates.


511

These reactions require differentiation between the allylic termini by the chiral ligand. Four fundamental ways to accomplish this are described in Figure 8B.5. (1) Traditional C2-symmetric chelate diphosphines developed for hydrogenations, for example, CHIRAPHOS and BINAP, belong to the convex class of ligands (a). A steric interaction from the “inside” of the π-allyl complex leads to a selective distortion favoring addition of the nucleophile at the terminal carbon with the longer bond to palladium. Pfaltz et al. nicely demonstrated this effect with C2-symmetric bisoxazolines [41,55]. Very high ee has been achieved with ligands of class (a) only in the case R = Ph. Note that the combination of a C2-symmetric

a

b

c

d

Figure 8B.5. Classification of chiral ligands.


ligand and a locally mirror-symmetric allylic unit leads to an asymmetric complex. The resulting distortion concerns not only differences in bond lengths but also the rotational state of the allylic moiety.

(2) Trost et al. introduced the DPPBA class of C2-diphosphines (cf. Fig. 8B.3), which yield Pd fragments with a large bite angle [35a]. As a consequence, the ligand extends beyond the allyl plane, that is, a concave situation or pocket is formed (class b). The pocket of the DPPBA ligands is small, and high enantioselectivities have been obtained with small, in particular, cyclic substrates, as was shown in the previous section, while broad substrates, that is, R = Ph in Scheme 8B.16, gave low enantioselectivity. R

R R

Pd

R Pd

P

P

Small bite angle, convex ligand

P

P

Large bite angle, concave ligand

(3) Guidance of the nucleophile by a directing group, for example, by an OH group via hydrogen bonding, that is, concept (c), was successfully realized by Ito, Hayashi, and others with phosphinoferrocenes that are particularly effective in allylic aminations [56]. This concept has more recently been very successful with monosubstituted allyl acetates as substrates (cf. Section 8B.2.2.3). (4) The concept of electronic differentiation (d) was early explored by Cesarotti and others [57]. It became particularly fruitful with P,N-ligands such as phosphinooxazolines (PHOX) [58–60] and QUINAP [61]. It is the aim of this chapter to update developments after the Trost–Lee review in 1999. This task has become somewhat difficult because of a dramatically large number of publications (cf. Fig. 8B.6) concerning as single case, the reaction of a derivative of 1,3-diphenylallyl alcohol with a malonate as nucleophile (cf. Scheme 8B.16, R = Ph). This reaction is commonly used when a new ligand is presented. As most examples have been recently reviewed [15], we have decided to limit our presentation to results achieved with ligands that have been additionally probed with a representative set of smaller


513

Figure 8B.6. Statistics of publications (SciFinder Scholar) on allylic alkylations according to Scheme 8B.16 (SciFinder analysis).

substrates such as derivatives of 1,3-dimethyl-allyl alcohol and a cyclic substrate (Scheme 8B.16, R = Me, n = 1–3). A note of caution is necessary with respect to reactions of the former substrate. It was found in our own work that in these reactions, cis isomers are formed as by-products, which falsify the enantiomeric excess determination if they are not properly taken into account. 8B.2.2.2.2. Catalysis with Pd Complexes of C2-Symmetric Ligands The situation is comparatively simple in the case of reactions promoted by a C2-symmetric bidentate ligand. In principle, three intermediary (π-allyl)-complexes are possible: a syn,syn-, a syn,anti-, and an anti,anti-complex [62]. In the case of a convex ligand the syn,syncomplex is generally the most stable one (Scheme 8B.17). However, with concave ligands and the dimethylallylic substrates (R = Me) the anti,syn-content can be high. The rate of substitution at the anti- is higher than that at the syn-position [27], and therefore, this type of isomerism leads to a reduction of enantioselectivity.

R

*

X [PdL*] R

R

L

R

a

L Pd

R

Nu

R a b

(syn,syn)

Nu

b

R

R Nu

Scheme 8B.17. Allylic substitution using a C2-symmetric ligand.

Results obtained with C2-symmetric phosphines as ligands are presented in Table 8B.3. With Trost’s ligands DPPBA-1 [63] and DPPBA-2 (entries 1–3), which belong to the class b of Figure 8B.5 [64], enantioselectivities and yields were excellent in alkylations of small substrates, that is, cyclic substrates and methyl (3-penten-2-yl) carbonate.

514

Ph

CH3

6

6

Ph

CH3

6

CH3

6

Ph

CH3

6

Ph

CH3

6

1

2

3

4

5

6

7

8

9

16

17

18

19

20

21

b

a

c

L8a

L8a

OAc

OAc

L8b

OAc

OAc

L7

L7

OAc

OAc

(R,R)-DXP B L7

(R,R)-DXP B

OAc

OAc

(R,R)-DXP A

OAc

(R,R)-DXP A

OAc

(R,R)-DPBBA-1 L5

OCO2Me

(R,R)-DXP A

(R,R)-DPBBA-1

OCO2t-Bu OAc

(R,R)-DPBBA-1

OCO2Me

L

R

P

O

X

P

R

1-Np

P

Ph

Ph

82 (S) 77 (S)

100c 100c 100c 84

CH2(CO2Me)2, BSA, KOAc, −20°C, 4 h CH2(CO2Me)2, BSA, KOAc, −10°C, 15 h CH2(CO2Me)2, BSA, KOAc, 20°C, 3 min CH2(CO2Me)2, BSA, KOAc, 0°C, 3 h

THF CH2Cl2

CH2(CO2Me)2, BSA, KOAc, 0°C, 10 h

CH2Cl2

>90

CH2(CO2Me)2, BSA, KOAc, −50°C, 1 h

CH2Cl2

83 (R)

12 (S)

>90

CH2(CO2Me)2, BSA, KOAc, 0°C, 10 min

94 (S)

26 (R)

73 (R) 9 (+) 63

77

CH2Cl2

CH2Cl2

CH2(CO2Me)2, BSA, KOAc, −10°C, 24 h CH2(CO2Me)2, BSA, KOAc, 25°C, 24 h

CH2Cl2

THF

THF

76

68 (S)

100c


CH2Cl2

93 (S)

66

71

71

71

70

70

70

68

68

68

68

68 97 (R)

100c


63

63 63

92b (R)

Reference 52 (R)

ee (%)

96 (S)

86

98

9

Yield (%)

>99 (S)

CH2Cl2

COX

PPh2

PPh2

L8a X = OMe, L8b X = Oi-Pr, L8b X = N(i-Pr)2

Fe

COX

64

CH2Cl2

NaCH(CO2Me)2/N(n-Hex)4Br CH2(CO2Me)2, BSA, LiOAc

CH2(CO2Me)2/Cs2CO3

CH2(CO2Me)2/Cs2CO3

Pronucleophile/Conditionsa

L7

Fe

P

1-Np

CH2Cl2

CH2Cl2

CH2Cl2

Solvent

(R,R)-DXP B (L6b) R = H, X = CMe2

(R,R)-DXP A (L6a) R = Me, X = S

PPh2

PPh2

OAc

X

[Pd(π-C3H5)Cl]2 was used as Pd source. ee of 94% was obtained with DPPBA-2. Conversion.

R or n

Entry

(S,S)-L5

O

NH HN

O

TABLE 8B.3. Allylic Substitutions according to Scheme 8B.16 with Dimethyl Malonate as Pronucleophile and C2-Symmetric Phosphines as Ligands


a

515

c

b O

O

X

NH HN

O P Ph2

P Ph2

Pd

P

Pd R

R

R

R

Pd 3

P 1

Figure 8B.7. π-Allyl complexes of ligands with a wide bite angle.

In contrast, results with 1,3-diphenyl-propenyl acetate as substrate were unsatisfactory. This actually corroborates the cartoon model already discussed. It was pointed out above (cf. Section 8B.2.2.1) that the DPPBA ligands are complex mixtures of oligomers. Only one π-allyl complex was so far obtained crystalline and was structurally characterized [65]. The cartoon model immediately illustrates that broad acyclic allylic moieties cannot be accommodated by the cavity of the DPPBA ligands (Fig. 8B.7b). Morimoto et al. claimed astonishingly high enantioselectivity for reactions of cyclic substrates catalyzed by a Pd complex of the comparatively flexible ligand L5 (entry 4) [66]. Ligands with a xanthene backbone possessing a wide bite angle were first used in 1997 for Pd-catalyzed allylic substitutions [67]. Remarkable results were soon achieved by the groups of van Leeuwen and Osborn with the variants described in Table 8B.3, designated duxanthphospholane (DXP) ligands [68], which gave excellent results for reactions of all model substrates (entries 5–9). Though their standard formulas implicate C2-symmetry, they are asymmetric and possess a roof-shaped conformation (Fig. 8B.7c). Nuclear magnetic resonance (NMR) investigations revealed that in solution isomeric π-allyl complexes (exo and endo) exist, as found in the case of nonsymmetric ligands (see below) [68b,69]. Such isomers are usually not observed individually in the case of C2-ligands because of fast isomerization. Furthermore, the NMR studies in conjunction with kinetic resolution experiments led to the conclusion that the (1,3-dimethylallyl)Pd complex preferentially exists in the syn,anti conformation in solution. Again, this complex reacts preferentially at the antiposition. Further insight into the mechanism of the allylic substitutions with the DXP ligands was obtained with a (cyclohexenyl)Pd complex, which was obtained crystalline. The X-ray crystal structure showed almost equal lengths of the bonds Pd–C1 and Pd–C3 (cf. Fig. 8B.7c). Osborn et al. convincingly argued that the substitution reaction traverses a late transition state, resembling the product olefin complex, and the direction of rotation of the allylic moiety determines the formation of the preferred product with (S)-configuration. P,P-ligands with an electron-rich ferrocene unit as backbone induce very high reactivity. Unfortunately, the interesting C2-symmetric ligands L7 [70] and L8 [71] do not give rise to high selectivity even in the case of the benevolent 1,3-diphenylallyl substrates (Table 8B.3, entries 16–21). Ligands with two nitrogen donor centers have been probed occasionally, but they are problematic because of low stability and reactivity of the corresponding catalysts. Typical results, obtained with the diamines L9 [72] and L10 [73], are shown in Table 8B.4. More often than not, reaction mixtures turn black because of instability of Pd0-complexes.

516

Ph

CH3

6

Ph CH3 6

Ph

CH3

1

2

3

4 5 6

7

8

R or n

Entry

L11a

L11b

OCO2Me

OCO2Me

OAc OAc OAc

ent-L9 L10 L10 L10

OAc

L9

L9

OAc

L

L9

OAc

X

Ph

THF

THF

DMF THF THF

THF

THF

THF

Solvent

H3C NH HN CH3

Ph

L10

N

S

S

NH HN S

S

HNu or NaNu/Conditions

R

R

CH2(CO2Me)2/Cs2CO3, [Pd(C3H3)Cl]2, AgSbF6, 0°C, 4 days

73

96

86 83 63

NaCH(CO2Me)2, [Pd(C3H3) L*], PF6, L*, 153°C, 0.3 h NaCH(CO2Me)2, [Pd(C3H3)L*]PF6, L*, 67°C, 16 h NaCH(CO2Me)2, [Pd(C3H3)L*]PF6, L*, 67°C, 2 h CH2(CO2Me)2, [Pd2(dba)3]CHCl3, BSA, KOAc, rt, 16 h

85

NaCH(CO2Me)2, [Pd(C3H3)Cl]2, 48 h

90

Yield (%)

L11a R = H L11b R,R = OCH2CH2O

84

R

R

NaCH(CO2Me)2, [Pd(C3H3)Cl]2, 48 h

NaCH(CO2Me)2 [Pd(C3H3)Cl]2, 48 h

N

TABLE 8B.4. Allylic Substitutions according to Scheme 8B.16 with C2-Symmetric Amines as Ligands

94 (S)

99 (S)

62 (−)

16 (S) 88 (+) 69 (+)

47 (S)

95 (S)

ee (%)

75

75

73 73 73

72

72

72

Reference


517

Umani-Ronchi et al. introduced the N,N-ligands L11 with additional oligothiophene units [74,75]. Remarkably high enantioselectivity was achieved even with the dimethylallyl substrate (Table 8B.4, entries 7,8). Both nitrogen centers of the ligands are bound to palladium according to an X-ray crystal structure of a (π-allyl)Pd complex and NMR studies. An additional interaction of an axial thienyl sulfur is postulated although the putative Pd–S bond is very long (>3A°) [75]. Good results were also achieved with polymer-bound ligands of this type [76]. Trisoxazoline ligands developed by Gade et al. are potentially tridententade ligands. However, recent careful studies have established a bidentate binding mode to PdII [77]. 8B.2.2.2.3. Catalysis with Pd Complexes of Nonsymmetric Ligands In the case of a nonsymmetric ligand, two isomeric syn,syn-complexes are possible, designated endoand exo-isomer, which usually undergo fast isomerization via π-σ-π rearrangement (Scheme 8B.18). Accordingly, there are, in general, four possible reaction modes. Of these, only two pairs are distinguishable with the help of the absolute configuration of the reaction products. The closely collaborating groups of Claver, Dieguez, Pamies, and others at Tarragona developed an extended series of modular P,P-ligands: bis-phosphites [78–81], phosphite/ phosphoramidites [82,83], and bis-phosphoramidites [84]). Most of these ligands are a combination of a sugar-derived backbone with very bulky binaphthyl or substituted biphenyl units (Table 8B.5). Enantioselectivities were moderate to excellent. Considerably higher enantioselectivities were obtained with related P,N-ligands (see below). Unfortunately, the authors usually present conversion values and only rarely yields. Only examples with more than 50% conversion are cited here. Very recently, a mechanistic rationale based on NMR studies of π-allyl complexes was reported [83]. Gilbertson et al. introduced a combinatorial approach by building peptides from phosphine-containing amino acids and natural amino acids [85–87]. An example is described in Table 8B.5. Up to 95% ee was achieved for cyclic substrates, in particular, the demanding cyclopentenyl acetate. Unfortunately, space does not permit to discuss this interesting work here in extenso.

*

B

A Pd

R

a

R a

X

b

[PdL*] R

R

R

R Nu

b c

*

B

A Pd

d

R R

d

R

R Nu

c Scheme 8B.18. Allylic substitutions with nonsymmetric ligands.


TABLE 8B.5. Results of Claver et al. and Gilbertson et al. for Reactions according to Scheme 8B.16 (HNu = CH2(CO2Me)2, X = OAc) Using Nonsymmetric P,P-Ligands O Ph O O P O O O t-Bu

O

Ph

R

NH P O O

X O P O

L12a

O

Y P O O

O

PR2 H N

O H3C O H

NH O

N H

N

L12b R = H, X = NH, Y = O L12c R = CH3, X = Y = O L12d R = H, X = Y = NH

P = P

CH3 CH3 O

R2P

O H N

O

iPr Ph O N H

O

O N H

CH3

CH3

L13

t-Bu

t-Bu

t-Bu

Entry

R or n

1

Ph

L

Solvent

L12a

Conditionsa

Yield (%)

ee (%)

CH2Cl2

KOAc, 5°C, 2 h

100b

Reference

99

83

THF

KOAc, rt, 0.3 h

100b

78

82,83

5

L12a L12c

CH2Cl2

KOAc, rt, 0.5 h

100b

68

80

4

6

L12d

THF

KOAc, rt, 2 h

100b

88

84

5

7

L12d

THF

KOAc, rt, 6 h

95

84

6 7

5 6

L13 L13

THF THF

TBAF, 0°C TBAF

51b 91

95 81

85 85

2

CH3

3

c

—d

[Pd(π-C3H5)Cl]2, BSA (start with KOAc or TBAF). Conversion. c A member of the L12b-type ligands with a binaphthalene unit at phosphorus gave 84% ee. d Not reported. a

b

Pd-catalyzed allylic substitutions with PHOX ligands, the prototypical P,N-ligands have been extensively explored [88]. Very high enantiomeric excess was obtained with the standard ligand L14a and the related QUINAP (L14g) (Table 8B.6) [61] upon use of 1,3-diphenylallyl acetate as substrate. In the case of L14a, low selectivity was obtained with 1,3-dimethylallyl- and cyclohexenyl acetate. Extensive mechanistic investigations [89] led to the development of ligands L14b [90] and L14c [91], which induced excellent selectivity. An X-ray crystal structure of a (cyclohexenyl)Pd complex is presented in Figure 8B.8 [91]. It is apparent that the allylic moiety sits in a pocket; in conjunction with the trans influence of the phosphorus center, the course of the addition reaction is well defined. Ligands L14d,e with two nonequivalent chiral dihydrooxazolyl groups have been reported by Yamagishi et al. Remarkably good results were obtained for the alkylation of dimethylallyl acetate with malonate as well as heterosubstituted malonates as nucleophiles (Table 8B.6, entries 6 and 7). (π-Allyl)Pd complexes were prepared and characterized by X-ray crystal structures and by NMR. The complexes displayed bidentate


519

TABLE 8B.6. Results Obtained for Reactions according to Scheme 8B.16 with Phosphinooxazolines (PHOX) and Related Ligands

O

Mn(CO)3 O

O

O N

PPh2

N

N N

PPh2

P

Ph

P Ph

R N

2-Bp

O R

L14a

L14b

L14c

L14d Y1 R = i-Pr L14e Y2 R = t-Bu

Boc N N

PPh2

O

N

PPh2

L14g

L14f

Entry

R or n

X

L

Solvent

1

Ph

OAc

L14a

CH2Cl2

2 3

Me Me

OAc OAc

L14a L14b

THF THF

4

6

OAc

L14c

DMF

5

Ph

OAc

L14d

THF

6

Ph

OAc

L14d

CH3CN

7

CH3

OAc

L14e

THF

8

5

OAc

L14f

CH3CN

9

6

OAc

L14f

CH3CN

10

7

OAc

L14f

CH3CN

Pronucleophile/ Conditionsa

Yield (%)

ee (%)

Reference

CH2(CO2Me)2, BSA, KOAc, 23°C, 1 h NaCH(CO2Me)2, rt, 1 h

98

98

59

99

57

90

NaCH(CO2Me)2, −40°C,

21

89.5

90

48 h NaCH(CO2Me)2, −20°C,

62

93

91

74

92

94

52

94

94

98

94

94

79

96

93

93

78

93

96

80

93

3h NaCH(CO2Me)2, [Pd(π-C3H5)L*]PF6, 25°C, 48 h NaCH(CO2Me)2, [Pd(π-C3H5)L*]PF6, 25°C, 48 h NaCH(CO2Me)2, [Pd(π-C3H5)L*]PF6, 25°C, 48 h CH2(CO2Me)2, BSA, TBAF, −35°C CH2(CO2Me)2, BSA, TBAF, rt CH2(CO2Me)2, BSA, TBAF, −20°C

[Pd(π-C3H5)Cl]2 was used as Pd source if not stated otherwise.

a


a

b

Figure 8B.8. Mechanistic aspects concerning phosphinooxazoline ligands. Left: X-ray crystal structure of a (π-allyl)Pd complex of L14c; right: (π-allyl)Pd complexes of Yamagishi’s ligands L14d,e.

O O N R

Pd

P Ph

N N O R'

Figure 8B.9. Intermediary (π-allyl)Pd complex postulated by Landis et al.

coordination with a stereogenic phosphorus center. Remarkably, one of two possible P-diastereomers is strongly preferred; furthermore, strong preference for exo-isomers was found, which explains the high selectivity indicated by these ligands (cf. Fig. 8B.8) [92]. Gilbertson and Xie [93] introduced PHOX derived from proline (L14f), which gave excellent results with small cyclic substrates (entries 8–10). Phosphite/oxazoline ligands were first used by Pfaltz et al. for Pd-catalyzed allylic alkylations [95]. Pamies et al. developed a new series of such ligands forming a sevenmembered chelate ring upon coordination to palladium [96]. As in the case of the related P,P-ligands presented above, the bulky tetra-tert-butyl-biphenyl unit is an essential module of these P,N-ligands. Excellent results with respect to activity and selectivity were achieved with carbocyclic substrates. Good results were also obtained with analogous carbohydrate-based P,N-ligands [97]. Clark and Landis introduced a series of putative P,N-ligands, which gave remarkably high enantioselectivity with 1,3-dimethylallyl acetate as substrate [98]. The authors proposed a P,N-chelate complex as intermediate (Fig. 8B.9). This proposal was mainly based on the observation that the results are not dependent on the ratio ligand/Pd (Table 8B.7). P,S-ligands are interesting with respect to activity of the corresponding catalysts. A number of such ligands have been developed. Early work of the Evans group still stands out as an example of a well-planned and exhaustively documented project (Table 8B.8).


521

TABLE 8B.7. Results Obtained for Reactions according to Scheme 8B.16 with P,N-Ligands Developed in Tarragona and Madison, WI

N

O t-Bu t-Bu

O

O

O

O

∗

O R*HNOC

R

O

∗

N

P

PPh HN R*

L16a : R* =

CO2Me

L16b: R* =

t-Bu t-Bu

N H

CO2 Me

L15a R = Ph L15b R = t-Bu L15c R = i-Pr

Entry

R or n

X

L

1

Ph

OAc

L15a

2

CH3

OAc

3

5

4

Conditionsa

Yield (%)

ee (%)

Reference

KOAc, rt, 5 min

100b

99

96

L15b

KOAc, rt, 30 min

100b

81

96

OAc

L15a

KOAc, rt, 30 min

100b

90

96

6

OAc

L15c

KOAc, rt, 30 min

100b

94

96

5

7

OAc

L15c

KOAc, rt, 30 min

100b

93

96

6 7

Ph CH3

OAc OAc

L16a L16b

NaOAc, rt NaOAc, rt

99 92

97 92

98 98

Pronucleophile and conditions: CH2(CO2Me)2, [Pd(π-C3H5)Cl]2, BSA, CH2Cl2, NaOAc, or KOAc. Conversion.

a

b

TABLE 8B.8. Reactions according to Scheme 8B.16 (X = OAc, NuH = CH2(CO2Me)2) with a P,S-Ligand Developed by Evans et al. [44] Entrya

R or n

L

Yield (%)

ee (%)

Reference R2P

O

1

Ph

(1R,2R)-L2a

97

98 (S)

44

2

CH3

(1R,2R)-L2a

87

65 (S)

44

S

3

6

(1S,2R)-L2b

91

94 (R)

44

t-Bu

*

L2a R = Ph L2b R = 1-naphth Reaction conditions: [Pd(π-C3H5)Cl]2, BSA, KOAc, CH2Cl2, −20°C.

a

8B.2.2.2.4. Allylic Alkylation of Selected Cyclic Substrates In addition to the standard substrates described above, further interesting cyclic allylic substrates, with a symmetric substitution pattern, were successfully used in Pd-catalyzed allylic alkylations. Examples of piperidine derivatives and other heterocycles are described in Table 8B.9. Some of the products were used in natural product synthesis. For example, the alkylated piperidine derivative was used in a short and efficient synthesis of nipecotic acid [99]. Hamada et al. [101] reported allylic alkylations of cycloalk-2-enyl carbonates with a substituent in position 2 (Table 8B.10). A monodentate ligand (9-PBN (L17)) was used


TABLE 8B.9. Allylic Substitutions with Ring-Substituted Derivatives of Cyclohex-2-Enol

[PdII]

X

[Pd0L*] U

U

Entry

U

Nu

Nu

X

L*

Solvent

1

NBoc

OAc

L14c

THF

2

NBoc

OCO2Et

L2b

CH2Cl2

3

S

OCO2Et

L2b

CH2Cl2

4

CHCO2Me

OCO2Me

L3

H2O

U

Pronucleophile/ Conditionsa NaC(OAc) (CO2Me)2, −20°C, 24 h CH2(CO2Me)2, BSA, -20°C CH2(CO2Me)2, BSA, −20°C CH2(CO2Me)2, Li2CO3, BSA, 40°C, 12 h

Yield (%)

ee (%)

Reference

84

98 (S)

99

94

94 (R)

44

60

50 (R)

44

71

90b (S)

100

[Pd(π-C3H5)Cl]2 was used as Pd source. The enantiomer with the inverse absolute configuration to the one described was formed.

a

b

(ratio L/Pd = 2:1). While the ee obtained with the parent compounds (R = H) was low, the 2-substituted substrates furnished enantioselectivity at a quite respectable level. Still better results were obtained in allylic aminations. More recently, the same research group has reported improved results with the unusual ligand Ph-DIAPHOX [102]. Trost et al. introduced racemic tetraacylated conduritol B as substrate for allylic substitutions (Scheme 8B.19). This C2-symmetric substrate possesses two homotopic leaving groups and gives rise to a Pd complex with a mirror-symmetric π-allyl moiety upon oxidative addition of the Pd catalyst. Ligand-directed addition of the nucleophile at one of the allylic termini yields the chiral product. Note that the alkylation product still contains an allylic moiety with a leaving group and thus can undergo further alkylation. Monoalkylation can be achieved with soft carbon nucleophiles, for example, Meldrum’s acid [103]. Cyclophellitol, an inhibitor of β-glucosidase as well as HIV, was synthesized from the reaction product of (phenylsulfonyl)nitromethane, a C1-equivalent (cf. Scheme 8B.12), by Trost et al. [104]. 8B.2.2.3. Enantioselective Allylic Alkylations via Monosubstituted and 1,1-Geminally Disubstituted (π-Allyl) Complexes Substrates with two identical substituents R at one allylic terminus are particularly interesting because of their ready availability (Scheme 8B.20). Intermediary (π-allyl)Pd complexes are chiral. However, usually a dynamic equilibrium between diastereomeric complexes exists, that is, preferential formation of a single enantiomer of the substitution product is possible. The essential issue that arises is regioselectivity. As a rule, Pd complexes preferentially react at the less substituted terminal carbon (cf. Section 8B.2.1.3). Thus, if R is different from hydrogen, a chiral product is obtained as desired. Substrates of this type (mostly R = Ph) were very

523


TABLE 8B.10. Allylic Alkylations at 2-Substituted 2-Cycloalkenyl Carbonates

R

R OCO2Me

CH(CO2Me)2

CH2(CO2Me)2

Pd(dba)2, L*, BSA, LiOAc, solvent

( )n-4

( )n-4 Ph

Ph

P

H N

N

H P

N

Ph DIAPHOX (L18)

9-PBN (L17)

Entry

n

R

1 2 3 4 5 6

CH3 Ph

7a

6 6 6 6 5 5 6

8a,b

6

Ph

Time (h)

Ligand

C⬅CSiMe3 2-Furyl CH3 Ph Ph

O

L17 L17 L17

12 2 3

L17 L17 L17 Ph-DIAPHOX (L18) Ph DIAPHOX (L18)

4 12 4 4 4

Solvent

Yield (%)

ee (%)

Reference

ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl THF ClCH2CH2Cl CH3CN

95 97 97 96 97 96 94

51 95 90 54 50 83 80

101 101 101 101 101 101 102

CH3CN

54

91

102

[Pd(π-C3H5)Cl]2 was used as Pd source. CH2(CO2Bn)2 was used as pronucleophile.

a

b

[PdII]

OCOR ROCO

OCOR

[Pd2(dba)3]CHCl3, (R,R)-DPPBA-1, THF

OCOR

(rac)

Nu Nu-H

Nu-H/Cs2CO3

ROCO

OCOR

ROCO

OCOR OCOR

OCOR

R = CH2CCl3 Nu-H

Yield (%) ee (%)

HO

O PhO2S

N

O

O

81

OH

88

ONa

O OH 95

OH

96

(–)-Cyclophellitol O

O

Scheme 8B.19. Conduritol B as substrate for the allylic alkylation.


R

L*Pd R

R' R PdL*

X

R

R'

R

[PdLn]

or R

R

R'

Nu

π-σ-π

R

R' R

R

Rotation R

R' R PdL*

R

Nu

R'

L*Pd

X

∗ R'

R

Scheme 8B.20. Isomerization of geminally disubstituted π-allyl complexes.

early studied in the development of the allylic substitution and will be briefly discussed at the end of this chapter. In a formal sense, regioselectivity can be enhanced by performing the allylic substitution as an intramolecular reaction, that is, the preferred ring size can direct the nucleophilic attack to the sterically more hindered position [105,106]. However, with Pd catalysts, results of intramolecular alkylations were not satisfactory so far. 8B.2.2.3.1. Allylic Alkylation via Monosubstituted (π-Allyl) Complexes Monosubstituted allylic acetates or carbonates (Scheme 8B.21) are particularly suited for applications in organic synthesis because many linear allylic alcohols, the standard precursors, are commercially available. A promising solution of the regioselectivity problem has been found by a team led by Dai and Hou at the Shanghai Institute of Organic Chemistry.

PdL* R

R'

CO2Me

R

X or

MeO2C Ph R'CH(CO2Me)2/ base

Pd0 / L*

X

b

PdL*

R

Ph R

l

CO2Me R' CO2Me

Scheme 8B.21. Asymmetric allylic alkylations via terminally monosubstituted (π-allyl)Pd complexes.

Results are given in Table 8B.11. For comparison, a reaction catalyzed by Pd/PPh3 is described in entry 1. A ratio PPh3/Pd = 2:1 is required for the allylation to proceed smoothly, yielding preferentially the linear product (cf. Scheme 8B.21). Upon use of a 1:1 ratio, conversion was low (60%). Early efforts for improvement were only partially successful with substrates R = Ar and failed for substrates with R = alkyl. Pfaltz et al. argued that a shift from an SN2-type mechanism (A) into the direction of an SN1-type mechanism (B) should enhance preference for the branched product (Scheme 8B.22). Assuming that transition state B would be favored by an electron-poor ligand,

525

(R)-MeO-MOP

(R)-MeO-MOP

l (Ph)

b (Ph)

l (Ph)

l (1-naphthyl)

b (Ph)

b (4-OMeC6H4)

3

4

5

6

7

8

2 PPh3

L19c

L19c

L19b

L19b

L19a

b (Ph)

l (Ph)

Ligand

1

Substrate (R)

2

Entry

98:2

85–95

90:10

82:18

84:16

85–95

96

66:34

82

97

76:24

86

NaCMe(CO2Me)2, THF, −30°C, 2 h

15:85 47:53

99

Regioselectivity (b/l)

87

Yield (%)

NaCMe(CO2Me)2, THF, −30°C, 6 h

NaCMe(CO2Me)2, THF, −20°C, 4 h CH2(CO2Me)2, BSA/KOAc, CH2Cl2, 23°C, 18 h CH2(CO2Me)2, BSA/KOAc, CH2Cl2, 23°C, 18 h CH2(CO2Me)2, BSA/KOAc, CH2Cl2, 23°C, 18 h CH2(CO2Me)2, BSA/KOAc, CH2Cl2, rt, 20 h CH2(CO2Me)2, BSA/KOAc, CH2Cl2, rt, 20 h

Pronucleophile, Conditions

TABLE 8B.11. Allylic Alkylations according to Scheme 8B.21 (X = OAc)

87 (S)

86 (S)

98 (S)

94 (S)

88 (S)

90 (S)

84 (S)

—

ee (%) (Config.)

109

109

108

108

95

95

95

109

Reference


SN1-type TS

SN2-type TS L

L

L

L

Pd

R

R Nu

B

A

Y X P Pd X

Y X P Pd X

Pd

R

R C

Nu

D

Scheme 8B.22. Transition states of allylic alkylations.

O O P O

O N

(F5C6)2P

O N t-Bu

t-Bu

Ts N O P N Ts

L19a

L19b

O

MeO

N PPh2 t-Bu

(R)-MeO-MOP (L20)

L19c

Figure 8B.10. Ligands used in the alkylations described in Table 8B.11.

Ar

NaCMe(CO2Me)2

Ar

AcO

Pd

L*

9:1

AcO

Pd

L*

Ar CMe(CO2Me)2

b: l = 88:12, 90% ee (S)

L* = (R)-MeO-MOP (L20 ) Scheme 8B.23. Stoichiometric reaction of an isolated (π-allyl)Pd complex [109].

phosphites were used as ligands [95]. Furthermore, steric hindrance caused by one bulky ligand or a bulky moiety of a chelate ligand is expected to favor the π-allyl complex C. In combination with nucleophilic attack at the π-allyl system trans to phosphorus [107], formation of the branched product is expected to be preferred. Ligands constructed in accordance with the guidelines enumerated above are described in Figure 8B.10, that is, the PHOX ligand L19a and the phosphite/oxazolines L19b [17]. The best results (Table 8B.11) were obtained with the bis(N-tosylamino) phosphine L19c (entries 5 and 6) [108]. The monodentate ligand (R)-MeO-MOP (L20) [109,110] induced formation of the branched isomer with good regioselectivity if the starting material was the branched allylic acetate (entries 7 and 8). The ratio phosphine/ Pd did not affect the catalytic activity nor the regioselectivity. A very clear mechanistic picture emerged by studying the reaction of an isolated π-allyl complex (Scheme 8B.23). Selectivities were in excellent agreement with those of the catalyzed reaction given in Table 8B.11. The group of Dai and Hou started with the idea to prepare ligands similar to L19b, but with a ferrocene backbone. In the attempt, the phosphorous amide described in


527

OH OH

Fe

Fe

Fe

(R)-BINOL P Et2N Et2N

N

P N NEt2 OH Bn

O

O

Bn

O

Et 2N

P O

N

O

OHBn

(S,SP,aR)-L21a

(S,RP,aR)-L21b

Scheme 8B.24. Preparation of the Dai–Hou ligands. Note that the “a” in aR means axial and the index P refers to phosphorus.

TABLE 8B.12. Allylic Alkylations of Linear Allylic Acetates (X = OAc) according to Scheme 8B.21 Using Ligand L21aa Entry

Substrate (R)

Yield (%)

Regioselectivity (b/l)

ee (%)

Reference

95:5 93:7 90:10

95 97 95 94

112 112 112 112

1 2 3 4

Ph 4-MeO-C6H4 4-CN-C6H4 CH3

98 97 96 83

5

(E)-(PhCH=CH)

80

>97:3 98:2

92

113

6

(E)-(PhCH=CHMe)

89

94:6

93

113

Conditions: [Pd(π-C3H5)Cl]2 (2 mol %), L21a (4 mol %), CH2(CO2Me)2, BSA, KOAc, CH2Cl2, rt.

a

Scheme 8B.24 was reacted with (R)-BINOL. Instead of an anticipated cyclic phosphonate, a monosubstitution product with a stereogenic phosphorus center was obtained as a pair of diastereomers (L21a, L21b), which could be separated. Their structures were characterized by X-ray crystal structure analysis. With these ligands, as well as corresponding ones obtained in the same way from (S)-BINOL, allylic alkylations as well as aminations according to Scheme 8B.21 were carried out [111,112]. Regioselectivities of Pd-catalyzed allylic substitutions were found to be superior to those cited above (Table 8B.12). Very high regioselectivities with dienylic substrates are particularly notable (entries 5 and 6) [113]. Interestingly, alkylations gave good results with ligands of type L21a, while aminations proceeded better with those of type L21b. The free OH group of the BINOL moiety is of crucial importance; its methylation is detrimental. An explanation for the strong preference for the branched products has been advanced only for aminations so far. Absolute configurations of the substitution products are known [114] but have been published only in the case of a substitution reaction giving rise to a quaternary carbon center with a high degree of regioselectivity [115]. Trost et al. developed an atom-economic method, designated hydrocarbonation of allenes, to derive (π-allyl)Pd intermediates from allenes by addition of hydrido-Pd complexes (Scheme 8B.25). This method gives access to the same products as the standard alkylation of allylic substrates. Initially Meldrum’s acid derivatives were used as pronucleophiles, which are sufficiently acidic to generate an HPdL2 species. It was then discovered that acid–base catalysis with additional acid and base, for example, benzoic


H R1

R1

R2 X

R2

H R1

L L

Pd0

R2 PdL 2

Nu H + X

L Pd H L

X H + Nu

Nu

Hydrocarbonation

Allylic substitution

L L

Pd0

Nu H

H R1

R2 Nu

Scheme 8B.25. Allylic alkylation and hydrocarbonation.

acid/NEt3, was possible. To get stereoselection in the addition of the nucleophile to the (π-allyl)Pd complex, monosubstituted allenes had to be used to get equilibrating intermediates. Good results were achieved with benzyloxy-allene, using DPPBA-1 as the chiral ligand (Table 8B.13) [116,117]. In addition to Meldrum’s acid derivatives, azlactones and a wide range of symmetric 1,3-dicarbonyl compounds have been used as addition partners. 8B.2.2.3.2. Allylic Alkylation via Trisubstituted (π-Allyl) Complexes Reactions proceeding via trisubstituted allyl complexes (Scheme 8B.20, R ≠ H) have been studied already in the 1980s in lieu of success with the monosubstituted allylic substrates. With diphenyl-substituted compounds (Scheme 8B.26), both electronic and steric effects guarantee a high degree of regioselectivity in favor of the chiral product. Up to 86% ee were achieved even with CHIRAPHOS [118] and Sparteine [119] as chiral ligands. This work is covered well in all previous reviews. Standard PHOX ligands such as L14a induced superior enantioselectivity; however, the reactions were generally slow (Scheme 8B.26) [120]. Higher degrees of reactivity were obtained with the very bulky ligands L22a (aminations) [121] and L22b (alkylations) [122]. A result with interesting mechanistic connotations shall be added. The reaction of the triphenylallyl acetate described Scheme 8B.26 must proceed via addition of the nucleophile at the secondary allylic carbon of the endo,trans (nt) or exo,cis (xc) isomer to yield the observed product (cf. Scheme 8B.27). A Pd complex was prepared and found to be the exo,trans (xt) isomer in the crystal and in solution [89]. As the presumably reactive complex is the xc isomer, reacting at the allylic carbon trans to phosphorus, it was concluded that its reaction is faster by a factor >10.000 than the reaction of the observed complex xt, yielding the minor enantiomer of the alkylation product via reaction at the carbon trans to N. This example illustrates once more the importance of the Curtin– Hammett principle.


529

TABLE 8B.13. Hydrocarbonation of an Allene

OBn

Nu

Nu-H [Pd], L*

•

BnO

O O

Pd(O2CCF3)2 (1 mol %), (S,S)-DPPBA-1 (1.25 mol %), F3CCO2 H (1 mol %), CH2Cl 2, rt

R O O

A

O

O [Pd(C3H5)Cl]2 (1.5 mol %), (R,R)-DPPBA-1 (3.75 mol %), PhCO2H (5 mol %), NEt3 (2.5 mol %), CH2 Cl2, rt R

B

Entry

Nu-H

R

1 2 3 4 5 6 7 8

A A A A A B B B

CH2C⬅CH CH2(2-furyl)

9

B

OAc

Yield (%)

ee (%)

Reference

75 61 82 81 63 86 83

99 88 96 94 82 99 98

116 116 116 116 116 117 117

97 95

98 93

117 117

CH3 CH2CH(CH3)2 CH2CH=CH2 CH2(2-furyl) OH CH2CH=CH2

R

Ph OAc Ph

NaCH(CO2Me)2 2.5 mol % [Pd(C3 H5)Cl]2 10 mol % L14a, THFt

R = Me R = Ph

O PPh 2

Ph

(MeO2C)2 CH

O

O N

PPh 2

H

N

PPh2

H

H L14a

Ph

95% ee (95%) 99% ee (88%)

H N

R *

L22a

L22b

Scheme 8B.26. Asymmetric allylic substitutions via trisubstituted (π-allyl)Pd complexes.

8B.2.2.3.3. Allylic Alkylations Using Vinylepoxides as Substrates Vinylepoxides are reactive substrates that would be expected to yield linear substitution products (cf. Scheme 8B.8). However, extensive work of the Trost group has established that aminations show a preference for the branched product due to interaction of the nucleophile


R Ph Pd

R

R R O

N

Ph N Pd

P

Ph

O P

Ph

nx (endo,cis)

xc (exo,cis) Reactive isomer

R

R Ph

Ph R Ph

Pd

O

N

O

N Pd

Ph

P

P

R

xt (exo,trans) Major isomer

nt (endo,tr ans)

Scheme 8B.27. Possible intermediates of the allylic alkylation described in Scheme 8B.26.

with an alkoxy or OH moiety generated by reaction with the Pd0 species (cf. Scheme 8B.28). This preference is enhanced by spatial constraints if DPPBA ligands are employed [38,123]. In contrast, the reaction of butadiene monoepoxide with a dialkyl malonate under standard salt-free conditions (cf. Section 2B.2.1.4.2) mainly yields the linear product.

O

O

NuH

R

[Pd]

[Pd]

R

Nu

H

[Pd]

O R

OH Nu R

Isomers via π-σ-π rearrangement

Scheme 8B.28. Pd-catalyzed allylic substitution with vinylepoxides as substrates.

However, the reaction of isoprene monoepoxide with β-keto esters preferentially gave the branched alkylation products in the form of hemiacetals (Scheme 8B.29). Success with these reactions required careful optimization of reaction conditions in dependence of the β-keto ester. In the case of ethyl acetoacetate (R = CH3), addition of a fluoride source was essential for gaining a useful level of regioselectivity. The extent


R O

CO2Et

531

CO2Et

O O

Pd 2dba3CHCl3, R = CH3: (S,S)-DPPBA-3, TBAT, benzene, 40°C R ≠ CH3 : (S,S)-DPPBA-1, CH2Cl 2, rt

EtO2C

R OH

+

R

OH n

O

93.5–99% ee (57–80%) Regioselectivity: 79:21 (R = CH3) 90:10 (R = cyclohexyl)

Scheme 8B.29. Allylic alkylation with isoprene monoepoxide (TBAT = N(n-Bu)4SiPh3F2).

of disubstitution was maximally 7%. One of the substitution products (R = CH2CH2SPh) was used as starting material for a natural products synthesis (viridenomycin [124]). In addition, it is worth mentioning that a single experiment with nitromethane as pronucleophile gave a promising result (97% ee, 51% yield) [123]. 8B.2.2.4. Enantioselective Allylic Alkylations with Prochiral Nucleophiles Allylic substitutions using prochiral nucleophiles, as described schematically in Scheme 8B.30, have been studied already in the 1970s. Ra

Nu R

X R1

[PdL*]

R

Nu* R1

NuH = H Rc

Rb

Scheme 8B.30. Allylic alkylation with a prochiral nucleophile.

Most often encountered is the formation of linear enantiomeric substitution products. Depending on the type of stereocontrol, several scenarios can be distinguished, which are schematically described in Figure 8B.11. Remembering the ligand classification presented in Figure 8B.5, it is immediately apparent that convex ligands of types a or d are less suited, because the nucleophile is isolated from the ligand by the “allyl wall” (Fig. 8B.11a). Asymmetric induction relies on the small difference in the interactions exerted by Hsyn and Hanti at the reacting allylic terminus. Indeed, Kagan et al. obtained low enantioselectivity with DIOP as ligand in their very early work in 1978 [125]. Considering transition state b of Figure 8B.11, it is obvious that concave ligands, as best exemplified by Trost’s DPPBA ligands, offer a chance to reach around the allyl moiety and exert a direct influence on the nucleophile. From 1997 onward, the Trost group has published impressive results. A third line of research was pursued over many years at Kyoto by the Ito group building on the prior development of ferrocene ligands by Hayashi and Kumada. The Ito group initially used ligands corresponding to Figure 8B.11c with some success. As an additional possibility, control of the nucleophile by coordination to a chiral rhodium fragment was probed with astonishing success; cf. Figure 8B.11d. Finally, the various types of allylic electrophiles discussed in the previous chapters, cf. Figure 8B.11e, can be used and lead to the additional problems of diastereoselectivity and perhaps regioselectivity (R ≠ R′).


Figure 8B.11. Allylic substitution with a prochiral nucleophile. (a) Diastereomeric transition states yielding enantiomeric products using a convex ligand. (b) Concave ligand. (c) Ligand with a coordinating side arm. (d) Stereocontrol by interaction with the nucleophile. (e) Formation of a product with two stereogenic centers.

8B.2.2.4.1. β-Keto Esters and β-Diketones as Pronucleophiles These pronucleophiles have been used successfully with a variety of Pd catalysts since Kagan’s pioneering work in 1978. In 1997, Trost et al. showed that high enantioselectivity can be reached with the help of the ligand DPPBA-1 (L1a) [126]. The development up to 1999 has been exhaustively reviewed by Trost and Lee [14]. The early achievements of Trost et al. and more recent results of others are schematically described in Table 8B.14. The best results were generally obtained with tetralones (up to 99% ee). Ito et al. described further examples using BINAP (L23a) as ligand, which gave rise to enantioselectivities in the range 80–90% ee. The authors described a few examples of reactions with acyclic β-diketones in addition to the customary cyclic β-keto esters. Excepting a single example, moderate selectivities were reached with the ligand QUIPHOS (L24) [127]. Hamada et al. achieved excellent results (typically 90–95% ee) with 2-carbomethoxycycloheanone and α-tetralone using the ligand Ph-DIAPHOX (L18) (cf. Fig. 8B.12). Essential for success with this unusual ligand was the application of the BSA method and Zn(OAc)2 as additive. The authors proposed that the ligand is silylated in situ to give a monodentate ligand, which gives rise to a Pd complex as described in Figure 8B.12. Thus, the good selectivities are probably the consequence of concave embedding of the allylic moiety according to Figure 8B.11b or c.


533

TABLE 8B.14. Results with Prochiral β-Keto Esters and β-Diketones as Pronucleophiles in the Allylic Alkylation according to Scheme 8B.30a O

O

O

O

O

OBn

O

O

O OBn

OBn

OBn MeO

86% ee (81%)

91% ee (98%)

L* = DPPBA-1 (L1a)

L* = DPPBA-1 (L1a)

R = H [126]

R = H [126]

O

O

O

O

O

95% ee (75%)

95% ee (81%)

L* = QUIPHOS (L24)

L* = DPPBA-1 (L1a) R = H, R1 = CH3 [126]

R = H [127] O

O

O OMe

Ph 85% ee (99%)

83% ee (90%)

L* = BINAP (L23a)

L* = BINAP (L23a)

89% ee (92%)

R = Ph [128]

R = Ph [128]

L* = BINAP (L23a) R = Ph [128]

94% ee (93%)

L* = Ph-DIAPHOX (L18) R1 = Ph [129]

a

If not stated otherwise, R1 = H, X = OAc.

H Ph N

Ph N H P N O Ph

Ph-DIAPHOX (L18)

Me3 Si

Me3Si SiMe3 R' O O R N N P P N Pd N R' R

N Ph R''

AcO

N

PPh2 O

N SiMe 3 Ph

PPh2

P N

PhN

H

QUIPHOS (L24)

(R)-BINAP (L23a)

Figure 8B.12. Some of the ligands and proposed allyl complexes used for allylic alkylations with prochiral β-keto esters and β-diketones.

The Trost group also achieved very high enantio- and diastereoselectivity, up to 99% ee and dr ≥ 98:2, respectively, with cycloalkenyl and 1,3-dimethylallyl carbonates as substrates [126]. 8B.2.2.4.2. α-Cyanopropionic Acid Derivatives and Related Pronucleophiles Good results in this area were obtained by Ito et al. with their ferrocene ligand L25 with a coordinating side arm (Fig. 8B.13) [130]. Truly spectacular results were achieved in an unusual way, by stereocontrol via the nucleophile with a chiral Rh complex coordinating to the cyano group [131]. This was accomplished with a bimetallic catalyst system consisting of Rh(acac)(CO)2, Pd(Cp)(π-C3H5) and the ligand AnisTRAP (L26), which was previously developed by the Ito group (Scheme 8B.31, Fig. 8B.13, and Table 8B.15).


Ar2P

O

O

Fe

X O

Fe

P Ph2 PPh2

N Me

O

P

Fe

N

O

P

*

P Pd

O

O

Me

H

O C

H

Me

PAr2

Me

Rh N C P

CH3

*

Ar = p-MeOC6H4, AnisTrap (L26a) Ar = Ph, PhTrap (L26b)

L25

Figure 8B.13. Ligands developed by Ito et al. and putative transition state for the reaction described in Scheme 8B.31.

O CN

i-PrO O

O O

O CH3

CF3

i-PrO

PdCp(π-C 3H 5)/Rh(acac)(CO)2 (S,S)-(R,R)-AnisTrap

CF3

* CN

99% ee (R) Scheme 8B.31. Ito’s allylic alkylation under control of Pd and Rh complexes.

TABLE 8B.15. Allylic Alkylations with α-Cyanopropionic Acid Derivatives and Related Compounds as Pronucleophiles according to Scheme 8B.30 (R, R1 = H) Cl

O O2N

Me 80% ee (92%)

L* = L25, X = OAc [130]

O CN

COt Bu Cl

CO2Me 60% ee (100% conv.)

L* = DPPBA-1 (L1a), X = OAc [132]

COi Pr

NC Me

99% ee (93%)

L* = AnisTRAP (L26a), X = OCO2CH(CF3)2 [131]

O

O NC

OMe

N Me Me 87% ee (94%)

L* = PhTRAP (L26a), X = OCO2CH(CF3)2 [131]

NC

P(OEt)2

Me 92% ee (91%)

L* = PhTRAP (L26a), X = OCO2CH(CF3)2 [131]

8B.2.2.4.3. Azlactones, α-Amino Esters, and α-Amino Ketones as Pronucleophiles These pronucleophiles are important as they can be used for the synthesis of chiral αamino acid derivatives. In most cases, quaternary chirality centers were created to avoid racemization of the products. However, there are also a few examples with secondary chirality centers in this area. The Trost group used azlactones as pronucleophiles (Table 8B.16). With cinnamyl acetate, 91% ee was achieved. However, with substrates such as cyclohexenyl acetate


535

TABLE 8B.16. Azlactones, α-Amino Ketones, and α-Amino Esters as Pronucleophiles in Allylic Alkylations according to Scheme 8B.30

SiMe3

PPh2 PPh2

BH3 BH3 Ph P P o-An o-An Ph Si

SiMe3 (R)-TMS-BINAP (L23b) O

O Bn

O N

Ph 91% ee (92%)

Ph

O P(OMe)2

HN CO Fe

NH OC P Ph2

P Ph2

(S,S)-L27

Fe

L28 O

O CO2Me

NHAc

NHAc

88% ee (78%)

93% ee (68%)

O Ph

N

Ph OMe

Ph 43% ee (42%)

N Ph

Ot-Bu Me

75% ee (95%)

L* = DPPBA-1 (L1a)

L* = BINAP (L23b)

L* = TMS-BINAP (L23b)

L* = L27

L* = L28

R = Ph, R1 = H [53,133]

R = Ph, R1 = H [134]

R = Ph, R1 = H [135]

R = R1 = H [136]

R1 = H [137] X = OCO2Et

ees up to 99% and excellent diastereoselectivities were reached using the ligand DPPBA1 (L1a) [53,133]. Another example was cited in Scheme 8B.15 in conjunction with Trost’s synthesis of sphingofungins. This early work has been extensively reviewed [14]. Good results have somewhat later also been achieved with BINAP (L23a) and TMS-BINAP (L23b) as ligands (Table 8B.16). The pronucleophile tert-butyl N-(diphenylmethylene)-glycinate is often used for the synthesis of amino acids. Its use as pronucleophile in standard allylic alkylations controlled by phosphine ligands furnished initially only low to moderate selectivities (Table 8B.16). Better results were obtained once again by stereocontrol via the nucleophile using chiral phase-transfer catalysts of the Corey–Lygo type (Scheme 8B.32). In a first attempt with catalyst L29a [138], the best ee achieved was 61%, even though double stereocontrol with the phase-transfer catalyst and BINAP as chiral phosphine was tried. Superior results were reached by Takemoto et al. with the very similar catalyst L29b [139]. Up to 96% ee and excellent yield were obtained under optimized conditions in the allylation with cinnamyl acetate. The racemic branched acetate furnished similar enantioselectivity but a low yield, because the branched substitution product was mainly formed [140]. The yield of the linear product could be increased by using L29b in combination with the chiral monodentate ligand (R)-MeO-MOP (L20). Formation of the branched product was anticipated under these conditions according to Section 8B.2.2.3.1; however, the linear product was mainly formed. In addition to those described in Scheme 8B.32, several other allylic acetates were successfully used as substrates.


Ph

Ph Ph

OAc or

Ph

Ph

N

CO2t-Bu

Ph

[PdCl(allyl)]2, LP L29b, 50% KOH, toluene

OAc

Ph

N

CO2t-Bu

Ph

Ph

+ Ph

CO2t-Bu

N

b

l

From linear carbonate, LP = P(OPh)3: 96% ee (89% l) From branched carbonate, LP = P(OPh)3: 89% ee (29% l) From branched carbonate, LP = L20: 90% ee (71% l)

N N

X MeO PPh 2

OR

L29a R = Allyl, X = Br L29b R = Me, X = I

(R)-MeO-MOP (L20)

Scheme 8B.32. Asymmetric allylic alkylations using phase-transfer conditions.

8B.2.2.4.4. Barbituric Acid Derivatives as Pronucleophile Some barbiturates of commercial significance pose a grim problem because of a very small deviation, an N-CH3 versus an NH group, from Cs-symmetry at a position remote from the reacting nucleophilic carbon (cf. Scheme 8B.33). Such barbituric acid derivatives were first used by Brunner et al. as prochiral nucleophiles in asymmetric allylic alkylations with allyl acetate. As anticipated, the enantiomeric purity achieved was low (34% ee) [141].

O

CH3 N O N

O OCO2Me

O H3C

H

Pd2(dba) 3 •CHCl3 (2.5 mol %),

O

N

N

*

H O

DPPBA-1 (5 mol %), CH2Cl2, rt

dr 2:1, 93% ee (78%) Scheme 8B.33. Enantioselective synthesis of a barbiturate.

There is only one additional report on this topic. Trost and Schroeder [142] used the DPPBA ligands, and even with these potentially embracing ligands, 37% ee was the best result for reactions with allyl acetate. The use of 1,3-disubstituted allylic carbonates furnished ees in the range >90% ee (Scheme 8B.33). In the context, short syntheses of


537

cyclopentobarbital and pentobarbital were provided. The high selectivity does not mean that the fundamental problem was solved, because the ratio of epimeric products with respect to the starred center was only on the order 2:1. Thus, there remains a challenge for the development of chiral ligands with a small confined cleft for the incorporation of the nucleophile. 8B.2.2.5. Preparation of Allenes via Allylic Alkylation The Pd-catalyzed enantioselective allylic alkylation allows the preparation of chiral allenes, which are of interest in natural product synthesis. Two general approaches have been developed, which differ in the starting material from which an exo-(alkylidene-π-allyl)Pd species is formed (Scheme 8B.34). This intermediate reacts with a soft nucleophile at the sterically less hindered allylic terminus and from the direction opposite to palladium. In principle, enantioselectivity can arise either in the oxidative addition step, if one of the diastereoisomeric exo-alkylidene-(π-allyl)Pd intermediates is formed preferentially, or/and because of differing reactivities of the equilibrating diastereoisomers in the attack of the nucleophile. The latter constitutes again a dynamic kinetic resolution process, and a sufficiently fast equilibration between the Pd complexes is essential for success. X

H R

• H

Br

R

R

R R

[Pd]

[Pd]

[Pd]

Nu H

Nu H

• R

Scheme 8B.34. Preparation of allenes via Pd-catalyzed allylic substitution.

8B.2.2.5.1. 1-Substituted 2-Bromo-1,3-Dienes as Substrates In the first attempt toward axially chiral allenes, Hayashi et al. [143] used 1-substituted-2-bromo-1,3-butadienes as substrates and BINAP as ligand (Table 8B.17). In this approach, an exo-(alkylideneπ-allyl)Pd intermediate is formed by oxidative addition of the Pd0-complex to the alkenyl bromide and subsequent σ-π-isomerization. Attack of the nucleophile occurred at the less hindered terminus and gave products with up to 89% ee. Hayashi et al. discovered that free dba enhanced the enantioselectivity of the reaction due to its ability to accelerate the equilibration between the diastereomeric exo-(alkylidene-πallyl)Pd intermediates. They were able to isolate an (alkylidene-π-allyl)Pd complex, a mixture of diastereomers in solution, and study stoichiometric substitution reactions. Good results were also obtained with TMS-BINAP [135] and SEGPHOS [144] as ligands.


TABLE 8B.17. Allylic Substitutions with 2-Bromo-1,3-Dienes as Substrates

EtO2C

NHAc

R

H R

Pd(dba)2 (10 mol %), L* (10 mol %), CsOt-Bu (1.2 equiv), CH2Cl2, 20°C

Br

Entry

CO2Et

Substrate (R)

CO2Et NHAc CO2Et

• H

O O

PPh2

O

PPh2

O (R)-SEGPHOS (L30)

L*

Yield (%)

ee (%)

Reference

1

Ph

(R)-BINAP

75

89

143

2

Ferrocenyl

(R)-BINAP

34

80

143

3

t-Bu

(R)-BINAP

74

75

143

4

n-Octyl

(R)-BINAP

73

54

143

5

t-Bu CH2SiMe3

(R)-TMS-BINAP (23b)

72

85

135

(R)-SEGPHOS (30)

63

87

144

6

8B.2.2.5.2. 2,3-Alkadienyl Phosphates and Acetates as Substrates In 2002, Murahashi et al. introduced racemic 2,3-alkadienyl phosphates as substrates for the direct synthesis of axial chiral allenes [145]. With (R)-MeO-BIPHEP as ligand ees up to 90% were obtained (Table 8B.18). A control experiment with an enantiomerically enriched substrate and 1,4-bisdiphenylphosphinobutane (dppb) as achiral ligand gave the racemic alkylation product. Accordingly, fast equilibration between the Pd intermediates can be assumed. The authors also found evidence for a σ-complex as described in Scheme 8B.34. This was formed upon reaction of a 2,3-alkadienyl phosphate with Pd(PPh3)4. Trost et al. reached slightly higher enantioselectivities with (S,S)-DPPBA-1 as ligand and racemic 2,3-alkadienyl acetates as substrates [146].

8B.2.3. Allylic Substitutions with Enolates as Nucleophiles The use of organometallic reagents such as organozinc or -boron compounds as pronucleophiles has not yet led to a successful application in enantioselective Pd-catalyzed allylic alkylation. Reactions with nonstabilized enolates of ketones and esters have been investigated thoroughly. They often cause problems resulting from coordination of the enolate toward the Pd [147]. In addition, usually a second stereogenic center is formed, whose configuration cannot be controlled easily. 8B.2.3.1. Allylic Alkylations of Ketone Enolates In 1980, Trost and Keinan reported the first allylic alkylations of ketone enolates [148]. Simple enolates, such as that of acetophenone, reacted with allyl acetate but gave the diallylated product preferentially (65% yield). Shortly afterward, Fiaud and Malleron published results with a monoallylation using sterically more demanding cyclohexenyl acetate [149]. The corresponding silyl enol ether also gave the monoallylation product exclusively, but this reaction could not be extended to substituted allyl acetates.


539

TABLE 8B.18. rac-2,3-Alkadienyl Phosphates and Acetates as Substrates R [Pd]

R

[Pd], L*

CR1(CO2R2)2

R

H

•

• X

H

R

CO2R2 R1 CO2R2

[Pd] Conditions A: [Pd2 (dba)3] CHCl3 (1 mol %), (R)-MeO-BIPHEP (4 mol %), BSA (1.2 equiv), THF, rt Conditions B: [Pd2 (dba)3] CHCl3 (2.5 mol %), (S,S)-DPPBA-1 (7.5 mol %), LiHMDS (1.1 equiv), n-Hex4NCI (5 mol %), THF, rt

MeO MeO

PPh2 PPh2

(R)-MeO-BIPHEP (L31)

Substrate Entry

X

R

1

OPO(OEt)2

2 3

OPO(OEt)2 OPO(OEt)2

n-C5H11 Me

4

OPO(OEt)2

5 6

OPO(OEt)2 OPO(OEt)2

7

OPO(OEt)2

8

OAc

9

OAc

10 11

OAc OAc

Nucleophile R

1

R2

Conditions

Yield (%)

ee (%)

Reference

NHAc

Et

A

76

73

145

NHAc NHAc

Et Et

A A

72 89

77 81

145 145

t-Bu Ph

NHAc

Et

A

69

90

145

NHAc

Et

A

80

60

145

n-C5H11

Me

Et

A

74

69

145

n-C8H17

H

Me

A

90

70

145

c-Hexyl

Me

Et

B

87

90

146

t-Bu C(CH3)2OBn C(CH3)2OBn

Me

Et

B

89

89

146

H

Me

B

63

86

146

Me

B

97

90

146

i-Pr

A variation of the counterion of the enolate brought a breakthrough. Switching to tin enolates led to a remarkable rapid and clean monoalkylation with high regioselectivity [150]. Similar results were obtained with boron enolates, while enolates with a wide range of other counterions (Mg, Al, Ti, Si) gave unsatisfying results [151]. The reactions proceed with retention of configuration, comparable to reactions with malonates, according to experiments with nonracemic chiral allylic substrates. In 1999, the first enantioselective Pd-catalyzed allylic alkylation of tin enolates was reported by Trost and Schroeder [152]. The tin enolate generated from 2-methyl-tetralone was subjected to allylations with a wide range of allylic substrates (Table 8B.19) in the presence of Trost’s bidentate ligand DPPBA-1 (Fig. 8B.14). Excellent yields and enantioselectivities were obtained with allyl acetate and crotyl carbonate (entries 1 and 2). Nucleophilic attack occurred at the sterically least hindered position of the unsymmetrical allylic substrate. Substrates with cis-configuration underwent π-σ-π isomerization under the reaction conditions used, giving rise exclusively to the trans-product (entry 3). 1,3-Dialkylallylic carbonates and phosphates gave the substitution product in excellent


TABLE 8B.19. Asymmetric Allylic Alkylations of 2-Methyltetralones O R

Bu 3SnCl

n

Entry

OSnBu3 R

LDA

R

n

1

CH3

1

2

CH3

1

3a

CH3

1

n

O Allyl substrate [Pd(π-C3H5)Cl] 2, (S,S)-DPPBA-1, DME, rt

Allylic Substrate

Product

OAc

OCOOMe

Allyl n

Yield (%)

ee (%)

O

99

88

O

84

90

72

82

41

>95

99

35

79

38

90

6

O

OCOOMe

R

R

R

4

CH3

1

5

i-Pr

1

OAc

6

CH3

0

OAc

7

CH3

2

OAc

O

OPO(OEt)2

O

i Pr

O

O

a

R = (CH2)3OSi(t-Bu)Ph2

O

O NH HN P Ph 2

P Ph2

(S,S)-DPPBA-1 (L1a)

HN CO Fe

P Ph2

NH OC P Ph 2 L28

O Fe

PPh2 N

PPh2

PPh2

(S)-t-Bu-PHOX (L31) (S)-BINAP (L23a)

Figure 8B.14. Some of the ligands used in allylic alkylations of ketones.


541

enantio- and diastereoselectivity (>95%) but moderate yield (entry 4). The methyl group at the tetralone could be replaced by several other substituents. While linear side chains also gave good results, the ee dropped significantly for the isopropyl derivative (entry 5). Variations of the ring size of the cyclic ketone also resulted in dramatically reduced selectivity (entries 7 and 8). In all examples investigated, the cyclic ketone with an α-substituent was used to generate a quarternary stereogenic center and avoid epimerization and double allylation. The stereochemical outcome of the reaction can be explained by Trost’s cartoon shown in Figure 8B.15. The ligand with (S,S)-configuration induces the allylated product with (R)-configuration. The approach of the nucleophile occurs in the open space created by a raised flap (favored). In the disfavored situation, the nucleophile encounters steric interactions with one of the flaps (which represent the phenyl groups at phosphorus). This model also explains the dependence of the enantioselectivity on the substituent at the 2-position. The decrease in ee with increase of the substituent results from interactions of this substituent with the lowered flap in the favored transition state. The group of Hou and Dai showed that lithium enolates of 2-alkyl-tetralones can be subjected successfully to allylic alkylations. As chiral ligand, they used the bidentate ferrocenylphosphine L28, which is similar to Trost’s ligand DPPBA-1 (L1a). Ees up to 95% could be obtained, especially if a ligand containing two molecules of crystal water was applied [153]. In conjunction with their investigations on asymmetric allylations using allyl enol carbonates (see Section 8B.2.3.2), Stoltz et al. also subjected cyclic silyl enol ethers to the reaction conditions optimized for the enol carbonates (Table 8B.20) [154]. Tetrabutylammonium triphenyldifluorosilicate (TBAT) was added to activate the silyl enol ether in situ. From the various ligands evaluated, the t-Bu-PHOX (L31) ligand was the one of choice giving rise to excellent yields and ees for a wide range of substrates. Recently, Paquin et al. investigated the asymmetric allylation of a range of 2-fluorotetralones, using silyl enol ethers as pronucleophiles (Scheme 8B.35) [155]. As was already established by Stoltz et al., best results were obtained with t-Bu-PHOX (L31) as ligand giving high ees and yield. Toluene was the solvent of choice. Comparably good results were obtained with several substituted tetralones and with ketones of different ring size. Even ketones missing the aromatic ring gave comparable ees, although the yield was lower with these substrates.

Favored

Pd −

Disfavored

Pd O−

O

(R)-product

(S)-product

Figure 8B.15. Rational for chiral recognition.


TABLE 8B.20. Allylic Alkylations with Silyl Enol Ethers according to Stoltz et al. Entry

Substrate

1 2 3 4 5

OSiMe3

6 7 8 9 10

OSiEt3

Product O

R1

R1

R2

n-5

n-5

O

R1 O

O

O

n

R1

R2

Yield (%)

ee (%)

6 6 6 7 8

Me Et Me Me Me Et Bn Allyl Me Me

H H Me H H H H Me Ph Cl

95 96 79 94 96 79 85 93 73 59

87 92 91 86 79 93 86 88 94 92

R1 O

R2

Conditions: A Entry 1–5, B Entry 6–10. A: [Pd2(dba)3] (2.5 mol %), (S)-t-BuPHOX (6.25 mol %), TBAT (35 mol %), di(R2-allyl)carbonate (1.05 equiv), THF, 25°C, 2–4 h. B: [Pd(dmdba)2] (5 mol %), (S)-t-BuPHOX (5.5 mol %), TBAT (1 equiv), di(R2-allyl)carbonate (1.05 equiv), toluene, 25°C, 5–10 h.

OSiMe3

O F

OCO2 Et

F

[Pd(π-C3H5)Cl]2, t-Bu-PHOX, TBAT, toluene, 40°C, 17 h 92% ee (85%)

Scheme 8B.35. Allylic alkylations of fluorinated silyl enol ethers.

O

OCO 2CH3

ClMgNiPr2

H3 C

CH 3

Pd2(dba)3 • CHCl3, (R)-BINAP (L23a)

O

CH3 CH3

dr = 99:1, 99% ee

Scheme 8B.36. Stereoselective allylic alkylations of cyclohexanone enolates.

Important contributions came from Braun et al. in 2000, who investigated the enantioand diastereoselectivity of Pd-catalyzed allylations [156]. Enolates of cyclohexanone and propiophenones were used as nucleophiles. The best results were obtained with Mg and Li enolates, especially in the presence of an achiral ferrocene-based diphosphine ligand. Interestingly, diastereoselectivity does not significantly depend on the enolate geometry. With (R)-BINAP (L23a) as chiral ligand, excellent enantio- and diastereoselectivities were obtained (Scheme 8B.36). The reaction could be extended also to 1,3-dimethylsubstituted allyl substrates. In this case, the more reactive Li enolates had to be used because of the less reactive electrophile. Addition of LiCl significantly increased the selectivities, providing the syn-product with a diastereomer ratio of 97:3 and 96% ee [156b].


543

In 2005, Hou et al. reported on highly stereoselective allylations of acyclic ketones in the presence of the ferrocene-based bidentate ligand L32 [157]. The choice of the base was essential for good results. Lithium bases proved to be more suitable than those containing potassium or sodium; LiHMDS was found to be the base of choice. Excellent yields and selectivities were obtained with a wide range of ketones, especially if AgBr (10 mol %) was added to the reaction mixture. The best enantioselectivities were obtained with α-alkoxy-substituted ketones, probably because of the formation of a (Z)-chelated enolate (Scheme 8B.37).

O

OAc

OMe

Ph LHMDS

O N

[Pd(π-C3 H5)Cl]2, L32, AgBr, THF, –20°C

Ph

Fe

OMe

Fe

N

P Ph2

P Ph2

L32

93% ee (98%)

Scheme 8B.37. Stereoselective allylic alkylations of acyclic ketone.

In 2007, the same group used ligand L33 for highly selective reactions using cinnamyl carbonates [158]. With these, the regioselectivity of the nucleophilic attack also has to be controlled. Best results were obtained if additional LiCl was added to the lithium enolates (Table 8B.21). The branched products were formed nearly exclusively (regioselectivity >98:2) and with good anti-selectivity and excellent ees. 8B.2.3.2. Allylic Alkylations of Ester Enolates The first example is due to Hegedus et al. in 1980 [159]. They investigated the allylation of branched ester enolates in the presence of various ligands. First examples were disappointing, providing only low yields. The enolate probably added preferentially to the metal rather than the allyl group [160], TABLE 8B.21. Regio- and Enantioselective Allylic Alkylations of Acyclic Ketones O

R2

OCO2Et

R1 LHMDS

O

[Pd(π-C3H5)Cl]2 , (R,R)-L33, LiCl, DME, –5°C

Fe

R2

OH P NEt2 N O

R1

O

(R,R)-L33

Entry

R1

R2

Yield (%)

anti : syn

ee (%)

1 2

Ph Ph

Ph

83 85

9:1 10:1

98 99

3 4 5

Ph 1-Naphthyl

m-BrC6H4 1-Naphthyl Ph

c-Hex

p-OMeC6H4

83 89 72

20:1 21:1 5:1

99 93 99


which led to the reduction of the complex rather than alkylation. Addition of HMPA completely suppressed the reduction and gave rise to the alkylation product, although not the expected one. Instead of the standard alkylation product, a γ,δ-unsaturated ester, a cyclopropyl derivative was obtained, resulting from an attack of the enolate at the central position of the π-allyl complex (cf. Scheme 8B.1). The mechanism of this unusual reaction was investigated by Hoffmann et al. [161]. They were able to isolate and characterize an intermediate palladacycle [162]. The reaction of silyl ketene acetals with allylic acetates was investigated by Musco, Santi, and others [163]. They used chelating phosphine ligands and obtained mainly the α-allylation product. Attack at the central position was also observed. In both cases, nucleophilic attack occurred from the face opposite to the palladium. Malacria et al. reported on ester enolate alkylations with vinyl epoxides [164]. In these cases, nucleophilic attack occurred at the sterically less hindered position, and E/Z mixtures of substitution products were generally obtained. An early application of chiral ligands to control the allylation of zinc enolates was described by Moorlag et al. in 1992 [165]. The dioxolane derivative of racemic mandelic acid was deprotonated with LHMDS and the lithium enolate transmetallated to the zinc enolate. Allylic alkylation in the presence of CHIRAPHOS (L34) gave the product with 33% ee (Scheme 8B.38). Other ligands and protecting groups gave even less satisfactory results.

Ph O

O O

Ph LHMDS ZnCl2

O

Ph

OZnCl O

OAc

O

O H3C

CH3

Ph2P

PPh2

O

Pd(dba)2, (R,R)-CHIRAPHOS (L34)

(R,R)-L34 33% ee (67%)

Scheme 8B.38. Asymmetric allylic alkylation of zinc enolates.

A breakthrough was the introduction of chelated amino acid ester enolates (cf. Scheme 8B.39) by Kazmaier and Zumpe in 1999 [166]. Chelation not only results in an enhancement of the thermal stability of these enolates, it also diminishes the tendency of the enolate to coordinate to the palladium. The allylation already takes place under very mild conditions at −78°C as a result of the high reactivity of these metal enolates. Under these conditions, isomerization processes such as π-σ-π isomerizations can be suppressed completely [27,167]. Asymmetric allylations have been carried out by using substrate control with chiral allylic substrates [168] or by incorporating the chelate enolate into a chiral peptide chain [169]. In 2002, Helmchen et al. reported the first asymmetric allylation of these enolates in the presence of chiral ligands [170]. As ligands phosphinoxazoline L14a, which is particularly suited for acyclic substrates, as well as the cymantrene derivative L14c, which proved superior for cyclic substrates, were used (Fig. 8B.16). High levels of selectivity were achieved with 1,3-diphenylacetate as substrate, and recrystallization of the crude product provided the enantio- and diastereomerically pure amino acid derivative. Allylic alkylations of cyclic substrates such as cyclohexenyl acetate gave a nearly 1:1 mixture of diastereomers with ees around 80% (Scheme 8B.39).

8B.2. PALLADIUM-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS OAc Ph

Ph

545

Ph

Ph

L* = L14a

TFAHN

COOt-Bu

Ot-Bu TFAHN

CO2t-Bu

LHMDS ZnCl2

95% ds, 94% ee (62%) TFA N

O Zn

[Pd(π-C3H5 )Cl]2/L* THF, −78°C rt syn: 77% ee anti: 89% ee

L* = L14c OAc

CO2t-Bu

TFAHN

52% ds (51%)

Scheme 8B.39. Asymmetric allylic alkylations of chelated enolates.

O Mn(CO)3 O

N

Fe

O N

PPh2

i-Pr

NEt2 P

N

O

P Ph

HO

2-Bp L14a

L14c

(S,S,S)-L35 Figure 8B.16. Chiral ligands used in the allylic alkylation of ester enolates.

O R

1

NPh 2 + R

2

OAc

O

LHMDS [Pd(π-C3H5)Cl]2, (S,S,S)-L35, LiCl, THF, rt

NPh2 R1 R2

R1 = Me, R2 = H

85% ee (82%) ( R)

R1 = Me, R2 = OPh

93% ee (99%)

Scheme 8B.40. Asymmetric allylic alkylations with an amide enolate as nucleophile.

Very recently, Hou et al. reported the first successful allylic alkylations of acyclic amides, using the ferrocene L35 as ligand [171]. By far, the best results were obtained with N,N-diphenylamides, while esters showed no reaction under the conditions employed. Only Li bases could be used in THF, and the highest yields and selectivities were obtained with 1 equiv of LiCl as additive (Scheme 8B.40). The absolute configuration of the products was rationalized by plausible models of the competing transition states (Fig. 8B.17).


O Fe Et N 2

O

N

i-Pr

Fe Et N 2

Pd

P

Ph2N

O

LiO

HO

N

i-Pr Pd

LiO

P O

Ph2N

HO Favorable attack

Unfavorable attack

O R

O S

NPh2

NPh2

Main product Figure 8B.17. Transition state model for the allylic substitution according to Scheme 8B.40.

8B.2.4. Decarboxylative Allylic Alkylation In the last few years, asymmetric allylic alkylations using the decarboxylative in situ generation of enolates [172,173], a method introduced by Saegusa et al. [174] and Tsuji et al. [175], have been successfully developed with Pd and very recently also with Ir catalysts. Two types of substrates for the decarboxylative generation of enolates can be envisioned (cf. Scheme 8B.41): (i) allylic β-keto carboxylates, that is, compounds that are alternatively used for the Carroll rearrangement and (ii) allylic enol carbonates. Both undergo facile decarboxylation after oxidative addition of a Pd0 species. Pd0Ln

O

O

R

R

R'

R'

R' L

Pd

R'

R'

or

O

L

O R'

O

R' L O

or

R

CO2

O

O

R'

O

R'

O or

R

O

R'

R

R

R'

O

Pd

O

O

R O

R' L

Pd

L

Scheme 8B.41. Decarboxylative allylic alkylation: catalytic cycle and types of substrates.

The first asymmetric decarboxylative allylic alkylation was described by Burger and Tunge [176], using Trost’s ligand (R,R)-DPPBA-1 (Table 8B.22). A series of mechanistic experiments [172] gave the following results: (i) Decarboxylation probably takes place


547

TABLE 8B.22. Decarboxylative Allylic Alkylation according to Burger and Tunge

O

O

R'

O O

R

R' R

R

O

( )n-4

O

R'

or R' ( )n-4

O

Entry

R or n

1 2 3 4 5 6

Me 5 6 7 6 6

7

6

R

[Pd2(dba)3] (0.2 mol %), (R,R)-DPPBA-1 (0.4 mol %), C6H6, rt

or

R′

Time (h)

Me Me Me Me Bn

15 15 24 45 27

i-Pr Ph

18a 18

O

Yield (%)

ee (%)

82 85 75 81 71 94

86 86 94 98 90 80

69

92

For the formula of the ligand, see Figure 8B.3. a

Reaction temperature: 50°C.

before the nucleophile adds to the (allyl)Pd complex and (ii) the nucleophile preferentially adds at the allylic face opposite to Pd. However, the reaction is not generally stereospecific. It was postulated that PdII is bound to the oxygen of the nonstabilized ketone enolate in the (π-allyl)Pd complex. Crossover experiment showed complete as well as incomplete scrambling depending on the substrates and the solvent. The experiments do not allow to distinguish between C–C bond formation in a solvent-separated ion pair and a bimolecular reaction of a Pd–O enolate with the (π-allyl)Pd complex. The first enantioselective transformation of an allylic enol carbonate into an α-allyl ketone was described by Behenna and Stoltz (Scheme 8B.42, A) [154a]. They found that the ligand t-Bu-PHOX (L31) is particularly well suited for the promotion of these transformations. The reaction allowed a variety of α-substituted cyclic ketones with a quaternary chirality center to be prepared. The reaction conditions employed were also suited for the transformation of racemic α-substituted 2-carboxyallylcyclohexanones into enantiomeric enriched α-allyl cyclohexanones (Scheme 8B.42, B) [177]. Crossover experiments with deuterium-labeled substrates showed a high degree of scrambling both between termini of the allylic moiety and between species derived from two substrates. Recently, Enquist and Stoltz used double asymmetric induction for the synthesis of a diallylated cyclohexane-1,4-dione that was the starting material for a short synthesis of the terpene (−)-cyanthiwigin F (Scheme 8B.43) [178]. Typical for double asymmetric induction, a very high degree of enantioselectivity is accompanied by a low degree of diastereoselectivity [179]. Trost and Xu used DPPBA-4 (L1d) (Fig. 8B.3) as ligand in the decarboxylative allylic alkylation of cyclic (Table 8B.23) [180] as well as acyclic (Table 8B.24) [181] enol


O O

O

O

R

R

O O

or A

Pd2(dba)3, (2.5 mol %), (S)-t -Bu-PHOX (L31)(6.25 mol %)

O

R

THF or Et2O, 25°C

B A R = Me R = Et R = t-Bu R = CH2Ph R = (CH2)3OBn

87% ee (85%) 92% ee (96%) 82% ee (55%) 85% ee (96%) 88% ee (87%)

B R = Me R = Prenyl R = (CH2 )2 CO2 Et R = CH2Ph R=F

88% ee (89%) 91% ee (97%) 90% ee (96%) 85% ee (99%) 91% ee (80%)

Scheme 8B.42. Enantioselective decarboxylative alkylation of enol carbonates derived from cyclic ketone enolates according to Behenna and Stoltz; for the formula of t-Bu-PHOX, see Figure 8B.14.

O

O

O

O O

O O

O

Pd(dmdba)2 (5 mol %), (S)-t-BuPHOX (5.5 mol %), Et2O, 25°C, 10 h

O meso

O (R,R)

dr = 4.4:1, 99% ee (78%) 6 steps

H H O (–)-Cyanthiwigin F

Scheme 8B.43. Decarboxylative allyllic alkylation with double asymmetric induction as key step in the total synthesis of (−)-cyanthiwigin F.

carbonates. In both cases, it was possible to produce not only quaternary but also tertiary chiral α-allyl ketones without significant racemization. Interestingly, the absolute configuration of the newly formed chirality center was inverse to that of the same compound prepared by standard alkylation with the Li enolate. Furthermore, only traces of mixed products could be detected in a crossover experiment. Trost and Xu invoked the alkylation as an inner sphere process of coordination and reductive elimination, that is, the solvent caged contact ion pair or Pd enolate formed after oxidative addition reacts faster than the exchange of the ions takes place. This is in conflict with the results obtained for the decarboxylative alkylations by Tunge and Stoltz. As already apparent from Tunge’s work, several mechanistic scenarios must be considered.

549


TABLE 8B.23. Decarboxylative Alkylation of Enol Carbonates Derived from Cyclic Ketones according to Trost and Xu Entry

Allylic Substrate

1

Product

O

Yield (%)

ee (%)

78

78

88

99

87

81

93

99

O

O

O

2

O

O O

CH3

O CH3

3

O O

O O

4

O

O O

O

Conditions: Pd2(dba)3.CHCl3 (2.5 mol %), (R,R)-DPPBA-4 (5.5 mol %), toluene, 23°C, 20 h.

TABLE 8B.24. Decarboxylative Alkylation of Enol Carbonates Derived from Acyclic Ketones according to Trost and Xu

O O

O R

R1

2

R1

Entry

Pd 2(dba)3CHCl3 (2.5 mol %), (R,R)-DPPBA-4 (5.5 mol %),

O R1 R2

Dioxane, rt R2

Time (h)

Z/E

Yield (%)

ee (%)

1

Ph

Me

2

>98:2

94

94

2

Ph

Bn

1

>98:2

75

88

3

Ph

24

>98:2

30

32

4

2-(MeO)C6H5

i-Pr Me

16

>98:2

99

98

5

2-FC6H5

Me

1

6 7 8

Mesityl Mesityl 2-Furyl

Me Me Me

16 6 4

>98:2 96:4 5:95 >98:2

80

94

Trace 99 89

— 96 88


The range of substrates was extended to include enol carbonates and β-keto esters derived from cyclic vinylogous esters and thioesters [182]. The procedure was also applicable to the enantioselective synthesis of α-tertiary hydroxyaldehydes and was used for a formal synthesis of (S)-oxybutynin [183]. Further work in this area was reported by the groups of Murakami et al. [184] and Nakamura et al. [185]. Murakami et al. used Trost’s ligand DPPBA-1 (L1a) for the asymmetric decarboxylative alkylation of allylic α-acetamido-β-ketocarboxylates to yield γ,δ-unsaturated α-aminoketones with ees up to 90%. Nakamura et al. used the same catalyst system as the group of Stoltz to transform allylic α-fluorinated β-ketocarboxylates into the corresponding ketones. For this reaction, only cyclic substrates gave high enantioselectivity (>85% ee).

8B.3. NICKEL- AND PLATINUM-CATALYZED ALLYLIC ALKYLATIONS Compared with the very popular palladium-catalyzed reactions, the comparable chemistry of neighboring metals nickel and platinum is by far much less developed.

8B.3.1. Nickel-Catalyzed Allylations 8B.3.1.1. Substitutions with Stabilized Enolates as Nucleophiles The reaction of allylic amines [186] and acetates was investigated by Mortreux et al. [187]. They checked the influence of a wide range of ligands on the regio- and stereoselectivity of the allylation step. With linear allylic substrates mixtures of regioisomers and with cyclic substrates such as cyclohexenyl acetate, where regioselectivity does not play a role, moderate enantioselectivities were observed. The best results were obtained with ligand L36, which gave the substitution product with 40% ee (Scheme 8B.44).

CH2(CO2Me)2 OAc

CO2Me

Ni(L36)2, BSA, THF

CO2Me

O

N PPh2 OPPh2 L36

40% ee Scheme 8B.44. Nickel-catalyzed allylic alkylations of soft nucleophiles using cyclic allylic substrates.

Detailed mechanistic investigations indicate that, especially overextended reaction times (e.g., if less active catalysts are used), the allylation step is reversible. This might explain the low selectivities obtained [188]. 8B.3.1.2. Substitutions with Nonstabilized Carbanions as Nucleophiles While only very few examples with soft nucleophiles are described, nickel complexes are more popular for allylations with hard nucleophiles such as boronic acids [189], borates [190], and Grignard reagents [191]. With such relatively reactive nucleophiles, one should keep

8B.3. NICKEL- AND PLATINUM-CATALYZED ALLYLIC ALKYLATIONS 551

in mind that they can react not only with the π-allyl intermediate formed but also with the carbonyl functionality of the leaving group, as far as carboxylates or carbonates are used. Therefore, in reactions with hard nucleophiles, preferentially, substrates containing a leaving group without an electrophilic center are applied such as amines [189], ethers [191], or even alcohols [192]. Consiglio et al. first reported on asymmetric couplings of Grignard reagents with allylphenyl ethers in the presence of the chiral ligand (S,S)-CHIRAPHOS (L34) [193]. The regio- and diastereoselectivities strongly depend on the Grignard reagent, but not on the allylic substrate used. The linear and the branched substrate gave the same results (Table 8B.25), but the aromatic Grignard reagent showed a much higher stereoselectivity. These results indicate that the reaction proceeds via π-allyl nickel complexes, and that these complexes are in a fast equilibration. By far, the highest selectivity was obtained in the allylation using cyclic substrates. Herewith, the ethyl Grignard reagent gave the coupling product with excellent 98% ee (R), while the corresponding phenyl reagent reacted completely unselective (Scheme 8B.45).

Ph

OPh EtMgBr

PhMgBr

NiCl2 (5 mol %), (S,S)-L34, 98% ee (85%) THF, rt, 22 h

NiCl2 (5 mol %), (S,S)-L34, THF, rt, 22 h

6% ee (90%)

Scheme 8B.45. Nickel-catalyzed allylic alkylations of hard nucleophiles using cyclic allylic substrates.

TABLE 8B.25. Nickel-Catalyzed Allylic Alkylations Using Linear and Branched Allylic Substrates

OPh

RMgBr

or b OPh

l

R

NiCl2, (S,S)-L34, THF, rt

+

l

b

R

Ph2P PPh2 (S,S)-L34 Entry

Substrate

RMgBr

t (h)

Yield (%)

l/b

ee (%)

1

l

EtMgBr

24

80

64:36

22 (S)

2

l

EtMgBr

24

75

62:38

18 (S)

3

b

PhMgBr

120

85

35:65

58 (R)

4

b

PhMgBr

60

85

35:65

61 (R)


MeMgBr Ni(COD)2 (5 mol %), (S,S)-L34, Et2O, rt, 24 h OMe 74% ee (81%)

MeMgBr

+

Ni(COD)2 (5 mol %), (S,S)-L34, Et2O, rt, 20 h

OMe 74% ee (64%)

79% ee (26%)

Scheme 8B.46. Nickel-catalyzed allylic alkylation using a diphenylallyl substrate.

Nomura and RajanBabu investigated the influence of the same ligand on the reaction of 1,3-diphenyl-substituted allyl ethers (Scheme 8B.46) [194]. With this substrate, the methyl ethers gave significantly better results than the corresponding phenyl ethers. The ethyl Grignard reagent reacted faster (12 h) than the methyl derivative (24 h) and gave a higher yield (91%), while the enantioselectivity was unaffected. Interestingly, if the reaction was quenched before complete consumption of the starting material, a significant kinetic resolution was observed. The starting material could be recovered with 79% ee. Chen and Deng used the same ligand (S,S)-L34 for the asymmetric allylation of alkynylborates, although the ees obtained were moderate (13% ee) [195]. Uemura et al. applied oxazolinylferrocenylphosphines as planar chiral ligand for cross-coupling reactions of allylic substrates with boronic acids [196] and Grignard reagents (Scheme 8B.47) [197]. In both reactions, the best results were obtained with the isopropyl-substituted ligand L37. In the reaction of cyclohexenyl acetate with a threefold excess of phenylboronic acid, Ni(acac)2 was used as precatalyst, which was reduced by Dibal-H [196]. The coupling product was obtained in 81% yield and 50% ee in the presence of KOH. The acetoxy group was superior to other leaving groups, followed by the hydroxy and the pyrrolidinyl group introduced by Trost and Spagnol [189]. In reactions of acyclic allylic substrates, both the yield and enantioselectivities were lower. The unsymmetrical linear hexenyl acetate gave rise to a 2:1 mixture of the linear and the branched product, which was obtained with 13% ee. Applying the same reaction conditions also to the coupling of Grignard reagents gave rise to the coupling product with high ee but moderate yield. But in this case, a reduction of Ni(acac)2 by Dibal-H is not necessary; obviously, the Grignard reagent (added in threefold excess) acts as a reducing agent. In the absence of Dibal-H, the yield increased to 97% in the reaction with phenylmagnesium bromide. The yields obtained with the corresponding chloride or iodide were significantly lower. Instead of the acetoxy group, other leaving groups such as OMe and OPh could also be used with similar results. Like in the reaction with the boronic acids, the ees obtained with linear allylic substrates were significantly worse (15–40% ee). The reaction of the terminal allylether gave rise to a 4:1 mixture of linear and branched product, which was obtained with 33% ee. Recently, Woodward et al. described an asymmetric allylic substitution of Baylis– Hillman-derived allylic substrates in the presence of various chiral ligands [198]. Based


PhB(OH)2 OAc

Ni(acac) (5 mol %), L37, Dibal-H (16 mol %), KOH, THF, Δ

Ph 50% ee (81%) Ph

PhB(OH)2 Pr

OAc

Ph

Pr

Ni(acac) (5 mol %), L37, Dibal-H (16 mol %), KOH, THF, Δ

+ Pr 13% ee (42%)

PhMgBr OAc

OPh

Pr

Ni(acac) (5 mol %), L37, KOH, THF, Δ

Ph 84% ee (97%) Ph

PhMgBr Pr

Ni(acac) (5 mol %), L37, KOH, THF, Δ pR

Ph

+ Pr 33% ee (85%)

O N

Fe PPh2 L37

Scheme 8B.47. Nickel-catalyzed allylic alkylation using oxazolinylferrocenyl phosphines as ligands.

R2 R1

L Ni Nu

Figure 8B.18. Nickel-catalyzed allylic alkylation using hard nucleophiles.

on the assumption that the reaction proceeds via a square planar Ni2+-allyl complex (Fig. 8B.18), and that a hard nucleophile is transferred via the Ni atom to the allyl ligand, they proposed that monodentate ligands should be more suitable for hard nucleophiles than chelating ligands, which should disturb the coordination of the nucleophile toward the Ni. Therefore, they compared a set of monodentate ferrophites L38–L39 and the ferrocenylphosphine L39d with the bidentate ligands (R)-BINAP (L23a) and (R,pS)JOSIPHOS ((R,pS)-L40a) (Fig. 8B.19). As nucleophile AlMe3 was used in the reaction with allylic substrates, containing different leaving groups (Table 8B.26). In contrast to copper-catalyzed allylations, which provide the γ-substitution product in a clean SN2′ substitution [199], in the nickel-catalyzed version mixtures of the two regioisomers, α


aR

O pR O P Ar

O O P Fe

pR

Ar

Ph2P

pR

Ph Fe

Fe

L38 a Ar = C6H5 b Ar = 1-C10H8

L39 a Ar = C6H5

L39d

c Ar = 3,5-Me2C6H3

b Ar = 1-C10H8

d Ar = 4-CF3C6H4

c Ar = 3,5-Me2C6H3

aR

Ph2P Ph2P R

PPh2 PPh2

pS

Fe

PPh2

O

PPh2

(R,R)-DIOP (L41)

(R,pS)-JOSIPHOS (L40a)

(R)-BINAP (L23a)

O

Figure 8B.19. Chiral ligands used in the nickel-catalyzed allylic alkylation of hard nucleophiles.

TABLE 8B.26. Asymmetric Allylic Alkylations in the Presence of Monodentate Ligands

CO2Me

X

AlMe3 Ni(acac), L, THF, –10/10°C, 3 days

Ph

CO2Me +

Ph

Ph

a

X = Cl, OAc, OMe Entry

CO2Me

Me

X

Ligand

g

Yield (%)

α/γ

63 8

>98:2 62:38

ee (%)

1

Cl

—

2

Cl

(R)-BINAP

—

3

Cl

16

25:75

4 (R)

4

Cl

(R,pS)-JOSIPHOS L38a

82

67:33

58 (S)

5

Cl

L38b

30

35:65

92 (S)

6

OAc

L38b

33

18:82

94 (S)

7

Cl

L38c

71

66:34

52 (S)

8

Cl

L38d

77

53:47

73 (S)

9

Cl

L39a

73

34:66

71 (S)

10

OAc

L39a

26

23:77

71 (S)

11

OMe

L39a

24

46:54

71 (S)

12

Cl

L39b

43

34:66

91 (S)

13

Cl

L39c

56

43:57

49 (S)

14

Cl

L39d

66

80:20

63 (S)

6 (R)


and γ were obtained, clearly indicating that the reaction proceeds via a π-allyl nickel complex. Most reactions were carried out with chloride as leaving group, which gave better yields as the acetate and the ether. In the absence of a chiral ligand, the α-substitution product was obtained exclusively (entry 1). As expected, the bidentate ligands were ineffective (entries 2 and 3). In contrast, the monodentate ferrophite ligands gave rise to the desired γ-product with up to 94% ee, although the α/γ selectivity was low in most cases. In 1998, Hoveyda et al. reported a detailed investigation of Grignard additions to cyclic unsaturated acetals (Table 8B.27) especially on the influence of phosphine ligands on the stereochemical outcome of the reaction [200]. The reactions proceeded with excellent regiocontrol (>98%) giving rise to substituted enol ethers, which could be hydrolyzed under mild acidic conditions to the corresponding ketones. While the reaction was slow in the presence of an Ni-PPh3 complex (entries 1 and 2), the corresponding dppe complexes gave the coupling products in good to excellent yield (entries 3–7). To figure out if the reaction can be carried out in an enantioselective fashion, they screened various chiral bidentate ligands. To minimize the background reaction (entries 1 and 2), chiral nickel complexes with (S,S)-CHIRAPHOS (L34) were probed and gave highly interesting results. While the in situ-prepared chiral catalyst gave only a very moderate selectivity in the reaction of the five-membered dimethyl acetal (entry 8), the preformed chiral Ni complex gave the coupling product with 53% ee (entry 9). Surprisingly, if the substrate with the six-membered ring was used, the opposite effect was observed (entries 10 and 11). The lower selectivity for the former substrate can be explained by a dominant background

TABLE 8B.27. Allylic Alkylations Using Cyclic Unsaturated Acetals

R

R

O

O

O +

R'MgX n

Entry 1 2 3 4 5 6 7 8 9 10 11 12

H3O

Ni-catalyst (5 mol %), THF, 22°C, 1–3 h

R or R,R

n

R′MgX

Catalyst

CH3 CH3

1 2

EtMgCl EtMgCl

(PPh3)2NiCl2 (PPh3)2NiCl2

CH3 CH2CH2 CH2CH2 CH2CH2 CH3 CH3 CH3 CH3 CH3 CH3

1 1 2 2 2 1 1 2 2 2

PhMgBr PhMgBr PhMgBr EtMgCl PhMgBr EtMgCl EtMgCl EtMgCl EtMgCl EtMgBr

dppeNiCl2 dppeNiCl2 dppeNiCl2 dppeNiCl2 dppeNiCl2 (PPh3)2NiCl2/L34 L34NiCl2 (PPh3)2NiCl2/L34 L34NiCl2 (PPh3)2NiCl2/L34

n

R'

Yield (%)

ee (%)

25

— —

20:1) were obtained where the substituents differ either sterically (entries 6 and 7) or electronically (entries 8–10). Nucleophilic attack occurs preferentially at the sterically least hindered position and/ or the double bond that remains in conjugation to the electron-withdrawing group. This new asymmetric cross-coupling approach was applied twice in the synthesis of fluvirucinine A2 (Scheme 8B.48).

O Cl ZnBr

O CO2Et

NiCl2 •glyme (5 mol %), L42a (5.5 mol %), NaCl, DMA/DMF (1:1), −10°C

O

EtO2C 96% ee (93%) O

1) H2, Pd/C 2) LiAlH4 3) PPh3PBr2 Et

O O CO2Et

CO2Et

Zn, I2

Cl

NiCl2 •glyme (5 mol %), L42a (5.5 mol %), NaCl, DMA/DMF (1:1), −10°C

O O

Br 89%

>98% ee (93%)

OH O NH

Fluvirucinine A1

58%

Scheme 8B.48. Synthesis of fluvirucinine A2 via enantioselective Negishi coupling.


8B.3.2. Platinum-Catalyzed Allylations In contrast to palladium-catalyzed reactions, reports on platinum-catalyzed allylic alkylations are extremely rare [202]. Platinum π-allyl complexes show a different reaction behavior compared with the corresponding palladium complexes. While terminal π-allylPd complexes are preferentially attacked at the terminal position, the Pt complexes give a higher ratio of branched product. Williams et al. observed a nearly complete retention of regiochemistry in reactions of branched allyl acetates if a tetrameric (allyl)-Pt chloride complex was used in combination with PCy3 as ligand (Scheme 8B.49) [203]. OAc

CH(CO2 Me)2

NaCH(CO2Me)2

+

[(allyl)PtCl]4 /PCy3

R

R

R

Up to

15

:

CH(CO2Me)2 1

Scheme 8B.49. Platinum-catalyzed regioselective allylations.

Brown and McIntyre were the first who studied asymmetric allylations in the presence of the bidentate (R,R)-DIOP ligand (L41) (Scheme 8B.50) [204]. Using linear butenyl acetate as substrate also, the branched product was formed preferentially, unfortunately with low ee. CH(CO2Me)2

NaCH(CO2Me)2 OAc O O

+

Ph2 P + Pt P Ph 2 BF −

11% ee

5

:

CH(CO2Me)2 1

4

Scheme 8B.50. Asymmetric platinum-catalyzed regioselective allylations.

Labeling experiments and detailed NMR-spectroscopic investigations indicated that in a solution, an interconverting mixture of all four possible isomeric π-complexes in comparable amount exists (Fig. 8B.20). All these complexes can react with the nucleophile, although in somewhat different rates. This might explain the relatively high amount of branched product formed and the low ee.

O

O

Ph2P

PPh2

O

Ph2P

PPh2

O

O

Ph2P

PPh2

O

O

Ph2P

PPh2 Pt

+

Pt

+

Pt

+

+

Pt

O

Figure 8B.20. Isomeric complexes formed in Pt-catalyzed allylations.

8B.4. MOLYBDENUM- AND TUNGSTEN-CATALYZED ALLYLIC ALKYLATIONS 559

TABLE 8B.29. Asymmetric Pt-Catalyzed Allylic Alkylations

CH(CO2Me)2

OAc NaCH(CO2Me)2 [(allyl)PtCl]4 (1.25 mol %), L* Entry

Ligand

T (°C)

t (h)

Conv. (%)

Yield (%)

ee (%)

1

5 mol % (S)-i-Pr-PHOX (L14a)

20

72

25

—

90

2


65

48

81

74

84

3


65

44

100

90

57

4

5 mol % (S)-i-Pr-PHOX (L14a)/PPh3

20

16

100

91

2

5

5 mol % (R,R)-L34

20

72

39

—

95

6

5 mol % (R,R)-L34

56

67

57

—

74

The factors affecting the reactivity and selectivity of π-allylplatinum complexes were investigated in detail by Williams et al. [203]. In palladium-catalyzed reactions bidentate ligands are often superior to monodentate ligands, because they favor the formation of cationic π-allyl complexes, which show a higher reactivity than the neutral complexes. In this case, the nucleophilic attack on the (π-allyl)Pd complex is the rate-determining step. Quite different is the situation for platinum complexes. The complex (dppe)2Pt is a less reactive catalyst than (PPh3)2Pt-stilbene. Therefore, attempts to carry out asymmetric allylations in the presence of a bidentate ligand such as the i-Pr-PHOX ligand (L14a) were not very successful if (PPh3)2Pt-stilbene was used as a platinum source. For example, 1,3-diphenylallyl acetate gave the substitution product with moderate 28% ee. In contrast, in a PPh3-free system where the (i-Pr-PHOX)Pt-complex was generated from K2PtCl4, (COD)PtCl2, or [(allyl)PtCl]4 [205], ees up to 90% could be obtained [206] (Table 8B.29, entry 1). The reaction is very slow and requires refluxing in THF for 2 days to go to completion (entry 2). Interestingly, if the ligand was used in excess, a drop in the enantioselectivity was observed (entry 3). Addition of PPh3 significantly accelerated the reaction, but resulted in the formation of nearly racemic material (entry 4). This clearly indicates that the bidentate ligand/Pt complexes are hemilabile. NMRspectroscopic studies indicate that besides the expected complex A, the more reactive monodentate complexes B or C are formed preferentially in solution, giving rise to the low ees observed (Fig. 8B.21). Interestingly, also with the bidentate ligand (R,R)CHIRAPHOS (L34), an excellent 95% ee was obtained at room temperature, but this reaction was also very slow and the conversion low (Table 8B.5, entries 5 and 6).

8B.4. MOLYBDENUM- AND TUNGSTEN-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS 8B.4.1. Molybdenum-Catalyzed Allylic Alkylations Although palladium is the most dominant metal in π-allyl chemistry, the analogue Mo-catalyzed reactions have developed also as powerful synthetic tools in organic synthesis. Molybdenum complexes were one of the first showing different regioselectivities


O O Ph2P

N Ph 2P

Pt Ph

Pt

Ph

Ph

N Ph2 P PPh2 Pt

O

O

N

PPh2 N Ph

Ph

Ph

B

A

C

Figure 8B.21. In situ-formed (allyl)Pt complexes.

Ph 2P

O CO

Cl

bipy

CO PPh 2

ONa

dppe

CO2Me

Mo

Ph2 P

PPh 2

N

N

70–75% CO2Me

THF 70%

OC OC

O

O CO2Me

N

CO2Me

+

Mo Cl

N

1

:

1

Scheme 8B.51. Allylic alkylations with stoichiometric Mo-allyl complexes.

compared with Pd catalysts. Nowadays, many other metals, such as W, Rh, Ir, Ni, Pt, and Cu were found to react in a similar behavior. The development of the asymmetric molybdenum-catalyzed reactions was reviewed by Belda and Moberg in 2004 [207]. 8B.4.1.1. Fundamentals of Mo-Catalyzed Allylic Substitutions Molybdenum is a very versatile metal with a vast range of oxidation (−4 to +6) and coordination numbers (4–8) in its complexes, which makes Mo-catalyzed reactions relatively complicated to understand [208]. But its ability to form π-allyl complexes easily makes it a good candidate for allylic alkylations. Trost and Lautens were the first to investigate the reaction behavior of π-allyl molybdenum complexes [209]. In their first experiments, they compared the stoichiometric reaction of a deprotonated cyclic β-keto ester with crotyl-Mo complexes bearing either dppe or bipy as a bidentate ligand (Scheme 8B.51). Both complexes showed a similar reactivity but interestingly different regioselectivity. While the dppe complex gave rise to the linear product preferentially (b/l 5:95) comparable to the Pd-catalyzed reaction, the bipy complex provided a 1:1 mixture of linear and branched product. This difference in selectivity was explained by different complex geometries and by the fact that bipy is a stronger σ-donor ligand compared with dppe.


Based on these results, a catalytic process was developed and the reaction of several allyl acetates with the same cyclic nucleophile or sodium malonate was investigated in the presence of several Mo complexes. While Mo(dppe)(CO)4 and Mo(TMEDA)(CO)4 were nearly ineffective, Mo(CO)6 and Mo(bipy)(CO)4 gave the expected allylation product in good yields, although the reactions, especially of the bipy complex, were rather slow. In general, 5–20 mol % of catalyst had to be used and the reactions had to be carried out in refluxing toluene to get acceptable yields. These are much harsher conditions compared with Pd-catalyzed reactions. Interestingly, the regioselectivity observed with these two Mo catalysts was opposite (Scheme 8B.52).

Ph ONa CO2Me OAc

Ph

CO2Me

Mo-Cat., toluene, Δ Mo(CO)6 Mo(bipy)(CO)4

Toluene, Δ

O

O

95 30

+

: :

5 70

Ph CO2Me

(73%) (75%)

CO2Me OAc

CO2Me

CO2Me

NaCH(COOMe)2

+ CO2Me

Mo-Cat., toluene, Δ Mo(CO)6 Mo(bipy)(CO)4

15 67

: :

85 33

(69%) (45%)

ONa CO2Me

O

O CO2Me

OAc

CO2Me

+

Mo(CO)6, solvent Toluene DME

95 15

: :

5 85

Scheme 8B.52. Catalytic Mo-catalyzed allylic alkylations.

The solvent has also a marked effect on the reaction in terms of rate and regioselectivity. Etheral solvents such as THF or dioxane decellerate the reaction relative to toluene, presumably due to their coordination ability for the metal, thereby reducing its electrophilicity. For example, the reaction of crotyl acetate in DME is not only slower than in toluene, but also shows a different regioselectivity (Scheme 8B.52). This effect can be explained by the formation of a new catalyst, that is, Mo(DME)(CO)4. DME as a strong σ-donor ligand, comparable to bipy, therefore shows a similar selectivity pattern.


8B.4.1.2. Asymmetric Mo-Catalyzed Allylic Alkylations 8B.4.1.2.1. Pyridylamide Ligands After these fundamental investigations, it took more than 15 years until the first catalytic asymmetric version was described [210], also by the Trost group [211]. They introduced a new class of ligands, the pyridylamides, with the parent ligand L43a (Fig. 8B.22). As a standard reaction used frequently for the evaluation and comparison of chiral catalysts, the reaction of cinnamyl carbonate (Ar = Ph) with sodium malonate was investigated (Table 8B.30). With Pd catalysts, this substrate gives preferential rise to the linear product. The active catalyst was obtained by heating a 1:1.5 mixture of (C2H5CN)3Mo(CO)3 and L43a in THF to 60°C for 1 h. Afterward, the allylic substrate and the malonate were added. If the reaction was carried out at room temperature, excellent regio- and enantioselectivities were observed (entry 1). Under reflux conditions, the yield could be increased to 88% without a significant loss of selectivity (entry 2). To figure out if this excellent enantioselectivity results from a strong differentiation of the catalyst for the enantiotopic faces of the achiral product, resulting in a preferred

R R

O

O

N

N

S S

O

NH

O

L43c

S S

O

NH HN

O

N

Ph O

NH HN

R R

Ph

Ph O

O

N L43g

R

N

N

N L43i

L43h

Ph S

O

O

S

O

NH HN N L43j

O

NH HN N

N

N

O

NH HN

NH HN

N

N L43f

L43e

O

O

NH HN

N

S S

N

R R

O

NH HN

L43d

O

N

L43b

S S

O

NH

NH HN N

L4 3a

O

O

NH HN

NH HN N

O

R R

O

L43k

Figure 8B.22. Pyridylamide ligands used in Mo-catalyzed allylic alkylations.


TABLE 8B.30. Allylic Alkylations Using In Situ-Formed Catalyst

OCO2 Me

Ar l or

MeO2C

NaCH(CO2Me)2

OCO2Me

CO2Me +

(C2H5CN)3Mo(CO)3, L43a, THF

CO2Me

Ar

Ar l

b

CO2 Me

Ar b Product Entry

Substrate

Ar

T (°C)

t (h)

Yield (%)

b :l

ee (%)

1

l

Ph

rt

3h

70

49:1

99 (S)

2

l

Ph

65

3h

88

32:1

99 (S)

3

b

Ph

rt

3h

61

32:1

97 (S)

4

b

Ph

65

3h

70

13:1

92 (S)

5

b

2-Thienyl

65

2h

78

19:1

88 (S)

6

b

2-Pyridyl

65

2h

69

8:1

96 (S)

7

b

1-Naphthyl

65

2h

82

99:1

87 (S)

MoL* Ar

Ar MoL*

Figure 8B.23. Possible (π-allyl)Mo complexes.

formation of one of the two possible π-allyl complexes (Fig. 8B.23), or if these two complexes are in a fast equilibrium, and the enantiodifferentiation results from a preferred attack on one of the complexes, the same reaction was also carried out with racemic branched substrates. If the equilibrium between the two allyl complexes is fast compared with the nucleophilic attack, one should get nearly the same result as with the linear substrate. On the other hand, if the equilibration is slow, one should expect more or less racemic products. In the reactions of the phenylallyl carbonates, the selectivities obtained with the branched were slightly lower compared with the linear substrates (entries 3 and 4), indicating that the equilibration is significantly faster than the nucleophilic attack. Other aryl- and hetaryl-substituted derivatives gave similar results (entries 5–7). The cycloheptatrienyl complex (C7H8)Mo(CO)3 can replace the (EtCN)3Mo(CO3) catalyst giving very similar results. The effectiveness of these precatalysts presumably derives from the lability of the EtCN- or C7H8-ligands, thus allowing a facile substitution with the chiral ligand [212]. But both complexes are air sensitive and are made from commercially available Mo(CO)6, which is air stable. Therefore, for applications in large scale, Mo(CO)6 is a much more attractive catalyst.


Palucki et al. at Merck & Co., Inc. investigated the allylic alkylation, especially the formation of the chiral catalyst from Mo(CO)6 in detail [213]. The complete catalyst formation is necessary to avoid unselective background reactions by Mo(CO)6. While the activation needed 4 h at 90°C if the reaction was carried out in toluene, the same result was obtained in THF after 2–3 h at 65°C, although the allylation reaction gave slightly better results in toluene (97% ee, 95% vs). Comparison studies carried out with Mo(CO)6, (EtCN)3Mo(CO)3, and (C7H8)Mo(CO)3 indicate that the same active chiral catalyst is formed, as all these precatalysts give comparable results. Nearly at the same time, Hallberg, Moberg, and others reported asymmetric allylation with Mo(CO)6 using microwave heating [214]. In the “standard reaction” using cinnamyl methyl carbonate as substrate and ligand L43a, the reaction was complete after 4 min at 165°C (Table 8B.31, entry 1). The yield and the regioselectivity were somewhat lower if the reaction was run in an oil bath at the same temperature for the same time (entry 2). They showed that this protocol is also suitable for solid-phase allylic alkylations. The optimized conditions were also used to investigate the effect of substituents with different electronic and steric properties (L44) on the outcome of the reaction (Table 8B.31) [215]. The influence of 4-substituents (R1) on the enantioselectivity was marginal (96– 99% ee), but the regioselectivity varied significantly (entries 3–6). Interestingly, substitu-

TABLE 8B.31. Allylic Alkylations Under Microwave Irradiation MeO2C

NaCH(CO2Me)2 OCO2Me

Ph

Mo(CO)6 (4 mol %), L*

CO2Me +

Ph

CO2Me

Ph

b

R R

O

L44 a b c d R1 e f

O

NH HN R1

Entry

N

N

R2

R2

Ligandb

l

CO2Me

R1 = OMe, R2 = H R1 = Cl, R2 = H R1 = NC4H8, R2 = H R1 = NO2, R2 = H R1 = H, R2 = Me R1 = H, R2 = OMe

T (°C)

t (min)

Yield (%)

b :l

ee (%) 98 (S)

1

L43a

165

4

86

19:1

2

L43a

5

59

11:1

98 (S)

3

L44a

165a 165

4

88

41:1

99 (S)

4

L44b

165

6

89

74:1

96 (S)

5

L44c

170

12

91

88:1

96 (S)

6

L44d

150

15

37

16:1

97 (S)

7

L44e

165

5

30

13:1

8 9

L44f L43b

160 160

6 25

0 95

0 99:1

79 (S) 0

a

Conventional heating. Ligands L43a-f are listed in (Figure 8B.22).

b

97 (S)


ents at the 6-position (R2) were detrimental on the reaction, probably due to steric effects (entries 7 and 8). π-Donor groups in the 4-position favored the formation of the branched product in high yields (entries 3–5), while the introduction of an electronwithdrawing NO2 group (entry 6) resulted in a significant drop in yield [215a]. Other substituted cinnamyl substrates as well as the isomeric branched substrates gave comparable results, indicating a fast equilibration of the isomeric Mo-allyl complexes involved (Fig. 8B.23) [215b]. The especially high regioselectivity obtained with the 4-amino-substituted ligand L44c forced the development of a recyclable resin-supported ligand L43b, which gave comparable results to L44c (entry 9) [216]. Meanwhile, a wide range of ligands based on the parent structure L43a (Fig. 8B.22) have been developed and investigated by Trost, Hughes, and others [217], and Kočovský et al. [218]. Their results are collected in Table 8B.32. To get further information about the binding mode of this multidentate ligands, in initial studies, Trost et al. replaced one picolinamide unit with a nicotinamide group (L43c) (entry 3). Surprisingly, the yield and selectivities were slightly better than those obtained with standard ligand L43a (entries 1 and 2), although the reaction was slower. The nitrogen

TABLE 8B.32. Asymmetric Allylations with Pyridylamide Ligands L43a-k

OCO2Me

Ph l

NaCH(CO2Me)2

or

MeO2C

Precatalyst, L*

CO2Me +

Ph

CO2Me

Ph

CO2Me

OCO2Me Ph b Product Entry

Substrate

Ligand

Precatalyst

Yield (%)

b :l

ee (%)

1

l

L43a

(C7H8)Mo(CO3)

90

28:1

99 (S)

2

b

L43a

(EtCN)3Mo(CO)3

70

13:1

92 (S)

3

l

L43c

(C7H8)Mo(CO3)

93

46:1

99 (R)

4

l

L43d

(C7H8)Mo(CO3)

90

60:1

99 (R)

5

b

L43d

(C7H8)Mo(CO3)

90

53:1

92 (R)

6

l

L43e

(C7H8)Mo(CO3)

35

1:1

24 (R)

7

l

L43f

(EtCN)3Mo(CO)3

29

19:1

98 (S)

8

l

L43g

(C7H8)Mo(CO3)

95

30:1

99 (R)

9

l

L43h

(C7H8)Mo(CO3)

95

19:1

99 (S)

10

l

L43i

(EtCN)3Mo(CO)3

64

8:1

92 (S)

11

b

L43i

(EtCN)3Mo(CO)3

72

12:1

88 (S)

12

l

L43j

(EtCN)3Mo(CO)3

69

13:1

89 (R)

13

b

L43j

(EtCN)3Mo(CO)3

68

13:1

74 (R)

14

l

L43k

(EtCN)3Mo(CO)3

68

32:1

98 (R)

15

b

L43k

(EtCN)3Mo(CO)3

59

38:1

97 (R)


atom of the nicotinamide group should not be able to bind to the Mo, and therefore this group was replaced by a nitrogen-free benzamide group (L43d). No significant change in the yield and selectivity was observed, which supports this hypothesis (entries 4 and 5). In contrast, replacing both picolinamides by benzamides (L43e) led to a very poor ligand in terms of rate and selectivity (entry 6). Steric factors also play a significant role as illustrated with ligand L43f, where one of the picoline rings was replaced by a quinoline (entry 7). The selectivities were satisfactory, but the yield was low. This is in good agreement with the results described by Moberg et al. (Table 8B.31, entries 7 and 8) [215]. A fourfold slower rate was observed, when the picolinamide was replaced by a pivalamide (L43g), but the yield and selectivities were high (entry 8). In principle, the cyclohexane ring system can be replaced by an acyclic structure such as in ligand L43h, although the regioselectivity was slightly lower (entry 9). Kočovský et al. proposed that one chiral center in the backbone might suffice to determine the sense of wrapping of the metal by the ligand, creating a similar chiral environment. To prove this hypothesis, they introduced ligand L43i. Although yield and selectivity were lower compared with L43a or L43h, the selectivities were still in the 90s. Little differences were observed between results obtained with the branched and the linear substrates (entries 10 and 11). For the improvement of the efficiency of the ligand, the phenyl substituent in the backbone was replaced by a benzyl group (L43j) and by an isopropyl group (L43k). Not unexpected, the sterically less demanding benzyl group resulted in a slight drop in selectivity (entries 12 and 13), while the isopropyl ligand L43k gave results comparable to the Trost ligand L43a (entries 14 and 15). These results clearly indicate that C2symmetric ligands are not required to obtain good enantioselectivities in this reaction. 8B.4.1.2.2. Bisoxazoline Ligands In 1999, Glorius and Pfaltz introduced another successful class of ligands for Mo-catalyzed allylic alkylations. These ligands L45–L47 (Fig. 8B.24) contain the same cyclohexylamide backbone as the Trost ligands, but the pyridine rings were replaced by oxazoline rings, containing additional stereogenic centers in these heterocyclic units [219]. These ligands were first tested with the branched and linear phenyl-substituted allylic substrates to allow a comparison of the results with those obtained with the Trost ligand L43a. The bisoxazolines L45 and L46b were found to induce similar levels of enantioselectivity as L43a; however, the amount of branched product was lower and the reaction was slower (Table 8B.33, entries 1–3). The corresponding branched substrate gave significantly lower ee (entry 4), an observation that was also made with ligand L43a (Table 8B.32, entry 2).

O

S S

O

O

NH HN O N

N L45

O

O

NH HN

O S

S S

S

S

O R

S

L46

O

NH HN N

N

R R

S

O R

O R

S

N

N L47

O R

Figure 8B.24. Bisoxazolines used as ligands in Mo-catalyzed allylic alkylations.

L46, L47 a R = Ph b R = Pr c R = i-Pr


TABLE 8B.33. Asymmetric Allylations Using L1 and Bisoxazoline Ligands L45-L47

R

Entry

OCO2Me

R

MeO2 C

NaCH(CO2 Me)2 (C2H5CN)3Mo(CO)3 (10 mol %), L*, THF, 70°C

Ligand

t (day)

CO2Me +

R

CO2Me

R

b

Yield (%)

l

b :l

CO2 Me

ee (%)

1

Ph

L43a

3h

70

49:1

99 (R)

2

Ph

L45

0.5

86

14:1

99 (R)

3

Ph

L46b

1

83

6:1

98 (R)

4

Ph

L46b

1

83

6:1

84 (R)

5

Pr

L43a

1.5

80

8:1

98 (−)

6

Pr

L47b

1.5

84

8:1

98 (−)

7

Pr

L47c

1.5

83

8:1

8 9 10

Pr Pr Me

L46b L46c L43a

2 2.5 1

69 65 85

2:1 2:1 5:1

97 (−) 96 (+) 86 (+)

11

Me

L45

1

88

1.5:1

94 (R)

94 (R)

12

Me

L46a

5

73

5:1

74 (R)

13

Me

L47a

3

76

7:1

85 (S)

14

Me

L46b

1

81

9:1

97 (R)

15

Me

L47b

2

80

11:1

96 (S)

16

Me

L46c

1.5

81

9:1

95 (R)

17

Me

L47c

1

86

7:1

92 (S)

18

PhO

L46b

2

79

20:1

98 (−)

Next, the alkyl-substituted substrates were investigated, which are more critical with respect to regio- and enantioselectivity. As expected, the (E)-hexenyl methyl carbonate was less reactive than the corresponding phenyl-substituted analogue and required reaction times of 1.5–2 days. Ligands L43a, L47b, and L47c all gave an 8:1 ratio of b : l with ees around 98% (entries 5–7). In contrast, the diastereomeric ligands L46b and L46c, derived from the enantiomeric 1,3-diaminocyclohexane, gave a lower b : l ratio, and in case of L46c, a significantly lower ee (entries 8 and 9). These ligands also induced the opposite configuration in the branched alkylation product, indicating that the enantioselectivity is mainly controlled by the diaminocyclohexane unit. All ligands were also applied to reactions of crotyl methyl carbonate. The ligand L45 gave the same high yield and ee as L43a, although the regioselectivity was lower (entries 10 and 11). The phenyl-substituted ligands L46a and L47a gave a higher branched/linear ratio, although at the expense of lower ees (entries 12 and 13). The best results were obtained with the n-propyl derivatives L46b and L47b, which were slightly superior to the isopropyl ligand L46c and L47c, and better than L43a (entries 14–17). Interestingly, the t-butyl-substituted ligand provided racemic material. Several other substituted allylic substrates were tested, including alkoxy- and phenoxy-substituted ones. For example, the phenoxy-substituted allylic carbonate gave branched/linear ratios >20:1 with all ligands and ees >93. The best results were obtained with L46b (entry 18).


N N

N

N

N

N L48

L49

L50

Figure 8B.25. Chiral bipyridine-ligands used in Mo-catalyzed allylic alkylations.

8B.4.1.2.3. Bipyridine Ligands Based on the fundamental investigations by Trost and Lautens using bipyridine as ligand [209], Kočovský et al. synthesized several chiral analogues (Fig. 8B.25) [220]. After complexation to Mo, they investigated the reaction of cinnamylacetate with sodium malonate. The reactions were carried out in 1,4-dioxane at 80°C. Unfortunately, the results obtained with these ligands were moderate and not competitive to the two ligand classes discussed before. The turnovers were low, and catalyst decomposition was observed in several cases. 8B.4.1.3. Mechanistic Investigations The operating mechanism of the Mo-catalyzed allylic alkylation has been less studied than that of the palladium-catalyzed process. In addition, the mechanism is more complex for Mo, because of a higher coordination number, resulting in a higher number of possible intermediates. In contrast to other metals (Ir, Rh, Ru), the Mo-catalyzed mechanism shows similarity to the Pd version with respect, that the π-allyl intermediates seem to undergo relatively fast π-σ-π isomerization. This allows the successful application of chiral ligands in reactions of linear and branched substrates as well. In Pd-catalyzed reactions, overall retention is observed, resulting from a double inversion in both steps. For the Mo-catalyzed process, Trost et al. also described reactions with overall retention in their pioneering work, but the stereochemical outcome of each step has not been elucidated. With respect to the similarity to the Pd-catalyzed process, one might assume also an inversion–inversion mechanism for the Mo-catalyzed reactions. Interestingly, in stoichiometric reactions, Faller and Linebarrier [221], Rubio and Liebeskind [222], and Kocienski et al. [223] could show that oxidative additions to cyclic and acyclic allylic acetates proceed with retention. On the other hand, it was also observed, that the oxidative addition is influenced by steric factors and the reaction conditions [224]. Obviously, the oxidative addition can proceed both under inversion and retention as well. Kočovský et al. faced this problem in their investigations of sterically constrained allylic substrates, a general technique introduced by Fiaud and Legros [225] (Table 8B.34). While the exo-substrates are inert to Pd-catalyzed allylic substitution, the endosubstrates react readily with PhZnCl under Pd catalysis but not with malonates [226]. This clearly indicates that attack on the allyl moiety from the endo-face is not possible, neither for the Pd (forming the π-allyl complex under inversion) nor the malonate (undergoing allylic alkylation under inversion). This should also be true for the Mo-catalyzed process. Interestingly, under standard conditions, the exo-acetate reacted in the presence of Mo(CO)6, giving rise to the substitution product with retention of configuration. While nearly complete conversion was observed after 4 h (Table 8B.34, entry 1), the diastereomeric endo-acetate showed only 6% conversion (entry 2). These results clearly indicate a retention–retention mechanism. Probably, the oxidative addition under retention was boosted by coordination of the Mo toward the carbonyl group of the acetate


TABLE 8B.34. The Fiaud Test with Mo(CO)6 as Catalyst

H

H H x

Retension

X

Mo(CO)6 Toluene, Δ

NaCH(CO2Me)2 H

H

Mo Inversion

H

Inversion

H

H H

CO2Me

MeO2C

H X

H

n Conversion (%) After Entry

Substrate

1 2 3 4 5 6 7b

X

1h

2h

4h

x n

OAc OAc

19

46 3

96 6

xa n x n n

OCONMe2

90% yield and 97% ee (entry 1). The ee did not change during the course of reaction, and the ratio of regioisomers was b/l = 35:1. Under identical conditions, the racemic branched substrate showed significantly lower selectivities (entry 2). Monitoring the reaction via chiral HPLC revealed that one enantiomer was reacting much faster than the other, signifying that a kinetic resolution took place. Reaction with the enantiomerically pure (R)-configured substrate clearly indicated, that the combination with (S,S)-L43a was the mismatched situation. The regio- and enantioselectivities were significantly lower compared with the racemic substrate (entry 3), while in the presence of (R,R)-L43a (matched case), enantiomerically pure product was obtained with excellent branched/linear ratio. Monitoring the reaction of the racemic substrate by HPLC revealed that a high product ee (98%) and b/l ratio (35:1) was produced during the first half of the reaction, but the ee eroded as the slower reaction of the second enantiomer took place. Obviously, the rate of the reaction of the π-allyl complex with the malonate is similar to the rate of the equilibration. But this equilibration is influenced by the solvent used. While other solvents such as tetrahyropyran, alkyl acetates, and MeCN (entries 5–7) gave similar results, showing a significant memory effect, in toluene, both enantiomeric substrates gave more comparable results (entries 8–10). This effect can be explained by the lower solubility of the malonate in toluene, allowing for a faster equilibration of the


π-allyl intermediate, before the nucleophilic attack occurs, minimizing the memory effect. 8B.4.1.4. Scope and Limitations In general, the asymmetric Mo-catalyzed allylic alkylation provides the required products with good regio- and enantioselectivity for a wide range of allylic substrates and nucleophiles. Thus, it is an interesting tool for asymmetric synthesis. 8B.4.1.4.1. Variation of the Allylic Substrate In most cases, allylic carbonates were applied as substrates, but the corresponding acetates and phosphates can be used as well. Moberg et al. investigated the reaction of several substituted cinnamyl-like substrates and their regioisomers under microwave irradiation and under conventional heating conditions (Table 8B.36). The different substituents had a significant influence on the regioselectivity of the reaction: The more electron donating the substituent, the higher the ratio of branched product (entries 1–3). In general, the linear allylic substrates showed a higher regioselectivity than the corresponding branched ones (entries 1 and 2 vs. 4 and 5) [215b]. Bulkier, 2-substitutetd malonates also afforded the products with good regio- and enantioselectivity (entries 6–9) [211]. Interestingly, no reaction was observed with some branched and cyclic substrates (Fig. 8B.27) [228]. Trost et al. investigated reactions of dienyl and polyenyl substrates in the presence of ligands L43a and L43h [234]. These substrates can be more complicated than normal allylic substrates, because in principle, three different products can be expected (Scheme 8B.55). TABLE 8B.36. Allylic Alkylation Using Different Aryl-Substituted Allylic Carbonates

X

Ar l

MeO2C

R

CO2Me

NaCR(CO2Me)2

or X

+

Mo(CO)6 (4 mol %), L43a

CO2Me

Ar

Ar

R CO2Me

b

l

Ar b Product Entry

Substrate

T (°C)

Yield (%)

b :l

ee (%)

1

l

4-Cl-Ph

OCO2Me

H

165a

2

l

4-CF3-Ph

51

32:1

96

OCO2Me

H

165a

50

11:1

3

l

99

4-MeO-Ph

OCO2Me

H

165a

59

51:1

4

98

b

4-Cl-Ph

OCO2Me

H

165a

78

26:1

96

5

b

4-CF3-Ph

OCO2Me

H

48

10:1

98

6 7 8 9

l l b b

Ph 2-Furyl 2-Furyl 2-Furyl

OCO2Me OCO2Me OAc OAc

Me Me Me All

165a 60 60 60 rt

67 71 65 50

24:1 32:1 32:1 99:1

98 97 87 98

a

Ar

Under microwave irradiation.

X

R


OCO2Me

OCO2Me

Ar

OCO2Me

OCO2Me

Ar

Figure 8B.27. Unreactive allylic substrates.

R

[Mo]

X

R

R

−X−

A

Mo

Mo

Nu

R

B

Nu

R

Nu l

R b

Nu

Nu

Scheme 8B.55. Allylic alkylations using highly unsaturated allylic substrates.

1.

OLi

Ph

N

OMe

Ph Ph

OPO(OEt)2

Ph (C7H8)Mo(CO)3 , L43a, THF, 0°C 2. 1 N HCl 3. Boc 2O, NEt3

CO2Me

+ Ph

CO2Me NHBoc

NHBoc 2

:

1

95% ds, 98% ee (quant.)

Scheme 8B.56. Allylic alkylations of imino glycinates.

Interestingly, only two of these products, namely the linear one and one of the branched ones (b), were observed, and in analogy to normal allylic substrates, the branched isomer was the major product (Table 8B.37). The lack of participation of the additional double bond is surprising. The results obtained suggest that no π-σ-π isomerization of the π-allyl complex A formed in the ionization step to the isomeric complex B occurs. 8B.4.1.4.2. Variation of the Nucleophile Although malonates are used as standard substrates in allylic alkylations, the malonate functionality is not one of the most useful substituents, even if it can be converted into other functional groups. Several other stabilized carbon nucleophiles have been investigated during the last years to enlarge the synthetic potential of the Mo-catalyzed allylations. For the synthesis of γ,δ-unsaturated amino acids, Trost and Dogra reacted imino glycinate with cinnamylphosphonate [235]. In the presence of L43a, the required amino acids were obtained in quantitative yield with excellent selectivities, although with moderate regioselectivity (Scheme 8B.56).


TABLE 8B.37. Allylic Alkylations Using Highly Unsaturated Allylic Substrates

MeO2C

R

OCO2Me

R

NaCH(CO2 Me)2 (C2H5CN)3Mo(CO)3 (10 mol %), L43a or L43h (15 mol %), toluene/THF 1:1, 80–90°C

Entry

R

CO2Me

b CO2Me

R

l

CO2Me

Ligand

Yield (%)

b :l

ee (%)

1

Ph

L43h

95

6.1:1

98

2

Ph

L43a

68

6.1:1

99

3

L43a

91

11.5:1

94

4

L43a

89

49:1

98

5

L43a

81

8.1:1

80

6

L43a

94

11.5:1

87

L43a

93

13.3:1

96

7

O

Next, a series of azlactones (5-oxazolones) were investigated (Table 8B.38). Best results were obtained with LHMDS as base, which gave nearly exclusively the branched product with excellent yield and selectivity (entry 1). The substituted azlactone was directly methanolyzed to the N-benzoylated aminoester. The results obtained with the methyl- and benzyl-substituted azlactones were comparable (entries 1–5), while larger side chains surprisingly gave some linear product (5–10%), although the yield and selectivity for the branched product was excellent (entries 6 and 7). Similar results were obtained with alkyl-substituted 4-oxazolones, which differ from the azlactones only in the relative position of the oxygen and nitrogen atoms [236]. These underdeveloped nucleophiles give easy access to α-hydroxyacids. Also here, the best results were obtained with LHMDS as base (Table 8B.39). Lithium turned out to be the counterion of choice with respect to yield and selectivity. Carbonate served as a slightly better leaving group than phosphate. In all cases, ees of 99% or better were observed, while the regio- and diastereoselectivities varied depending on the substitution pattern. The stereochemical outcome of the reaction with azlactones and the 4-oxazolones can be explained by the following mechanistic rational (Scheme 8B.57): Starting from the known π-allyl complex B, on attack of the nucleophile, the weakly bound amide group is dissociating, and the nucleophile takes its place as in C. The nucleophile is then internally delivered via the sterically least hindered transition state, giving rise to the stereoisomer observed.


TABLE 8B.38. Allylic Alkylation of Azlactones O

Ph

OLi

Ar

OCO2Me

O

R

N

K2CO3

R (C7H8)Mo(CO)3, L43a, THF, 65°C

Entry

Ar

R

1 2 3

Ph 3-Thienyl 2-Furyl

4

Ar

O

N

CO2Me

Ar

CH3OH

NHBoc

R

Ph

Yield (%)

Diast. Ratio

ee (%)

Me Me Me

92 84 84

97:3 96:4 >98:2

99 91 92

Ph

Bn

92

>98:2

96

5

3-Thienyl

Bn

86

>98:2

94

6

Ph

MeSCH2CH2

86

>98:2

92

7

Ph

i-Pr

76

>98:2

96

TABLE 8B.39. Allylic Alkylation of 4-Oxazolones LiO N R Ar

OCO2Me

O

(C7H8)Mo(CO)3, L43a, THF, 65°C

Entry

Ar

R

1

Ph

2

2,4-(MeO)2-Ph

3 4

O

R

Ph

O

Ar b

N

O

R +

Ar

N

O l

Ph a

dr

Ph

ee (%)a

Yield (%)

Ratio b/l

Me

91

99:1

12:1

>99

Me

82

12:1

18:1

2-Br-Ph Ph

Me Bu

78 86

27:1 49:1

24:1 9:1

>99 99

5

Ph

All

97

8:1

10:1

6

3-Thienyl

i-Bu

89

14:1

10:1

>99 99

7

Ph

i-Pr

70

5.5:1

20:1

99

>99

a

Selectivity of the major branched isomer.

dr, diastereomeric ratio.

Kočovský et al. reported on the use of a wide range of silyl enol ethers in their Mo(II)- and W(II)-catalyzed allylic alkylations (Fig. 8B.28). Although the reactions were carried out without a chiral ligand, these experiments indicate that these nucleophiles might be interesting alternatives to the standard nucleophiles (such as malonates). The silyl enolethers of aldehydes and ketones in particular are of interest, as they allow the allylation of nonstabilized enolates [212]. By comparison of silyl enolethers with phenylethers, they recognized that a wide range of electron-rich aromatics can


O O

X

CO N

CO Mo

N

R

NH

Y

CO

O

Ph

N Mo N

Ph

O Ph

NHCOPh

Ph

O

Ar

X

Y

Ph

R

X

C

B

O

R

CO

Azlactone: X = O, Y = N 4-Oxazolones: X = N, Y = O

Y Ph

Scheme 8B.57. Mechanistic proposal for the allylation of oxazolones.

Me3SiO MeO

O

Me3SiO OMe

OSiMe3

OSiMe3

O

NR2

OMe

OMe

R

R

OSiMe3 R1

R2 R

O R1

OR O

O

N R

Figure 8B.28. Nucleophiles used in Mo(II)-catalyzed allylations.

react as nucleophiles as well. But with these nucleophiles, the Mo(II) catalyst probably acts as a Lewis acid catalyst, giving a Friedel–Crafts-type alkylation rather than a metal template-controlled process [212c]. Very recently, Trost and Zhang described the first asymmetric allylation of 3-alkylated oxindoles (Table 8B.40). Optimization of the reaction parameters revealed that the counterion of the base had the largest effect on the enantioselectivity. Lithium bases gave the best results with unsubstituted allyl carbonates, and the best conversion was observed in the presence of 2 equiv of LiOt-Bu or a mixture of LiOt-Bu and LHMDS. In nearly all cases, excellent yields and enantioselectivities were obtained. A wide range of substituents on the indol ring are tolerated, and increasing the sterical size of the 3-substituent results in higher ees (entries 3–5) [237]. Cinnamyl carbonates and related aryl-substituted substrates give good yields and selectivities in the presence of NaOt-Bu (entries 6–9) [238].

8B.4.2. Tungsten-Catalyzed Allylic Alkylations Based on the great similarity of the group VI metals, Mo and W complexes were investigated together in most cases.[211,212b,e]. 8B.4.2.1. Fundamentals of W-Catalyzed Allylic Substitutions Like Mo complexes, the W complexes also give preferential rise to the branched products [239]. According to Trost and Hung, W complexes are less reactive than the corresponding Mo analogues [240]. No reaction was observed between dimethyl sodiomalonate and allylacetate in the presence of W(CO)6, while (MeCN)3W(CO)3 led to slow conversion (31% in 16 h).


TABLE 8B.40. Allylic Alkylation of Oxindoles R1 R1

O

R2

R1

R2

N R

R2

OCO2Me

O (C7H8)Mo(CO)3, L43a, THF, base

Entry

R1

R

R2

b

O

+

N R

N R

l

Base

Yield (%)

Ratio b/l

dra

ee (%)a

1

Me

Me

H

LiOt-Bu

99

81

2

Bn

Me

H

LiOt-Bu

93

75

3

Me

Bn

H

LiOt-Bu

95

93

4

Me

H

LiOt-Bu

96

91

5

Me

i-Pr CH2CN

H

LiOt-Bu

99

93

6

MOM

Ph

Ph

NaOt-Bu

90

19:1

7:1

92

7

Me

Ph

Ph

NaOt-Bu

88

18:1

8:1

88

8

Me

4-MeO-Ph

Ph

NaOt-Bu

92

18:1

8:1

92

9

Me

Ph

2-Furyl

NaOt-Bu

92

12:1

6:1

89

a

Selectivity of the major branched isomer. dr, diastereomeric ratio.

NaCH(CO2Me)2 Pd0 O

O

OCO2Me

CO2Me

CO2 Me

CO2Me 62%

OCO2Me

O

MeO2C

O O

O

OCO2 Me NaCH(CO2Me)2 W0

OCO2Me

CH(CO2CH3)2

O O

OCO2Me 84% MeO2C

CO2Me

NaCH(CO2Me)2 OCO2Me (MeCN)3W(CO)3, bipy

OCO2Me 61%

Scheme 8B.58. Allylic alkylations using allyl dicarbonates.

Addition of phosphines poisoned the catalyst, while the use of the more electrondonating bipyridine ligands leads to a significant improvement (65% in 16 h). Better results were obtained by switching from acetate to carbonates as better leaving groups. Interestingly, secondary carbonates are more reactive than primary ones (Scheme 8B.58) [241]. For example, if dicarbonates were reacted with malonates in the presence of Pd complexes, the primary substitution product was obtained as a mixture with the vinyl cyclopropane derivative, formed in a subsequent intramolecular allylic alkylation. Allowing the reaction to go to completion gave rise to the vinylcyclopropane as the sole product.


On the other hand, a tungsten catalyst prepared from (EtCN)3W(CO)3 and bipy (25 mol % each) provided the secondary monosubstitution product in high yield. Interestingly, if (Z)-allyl dicarbonates were used as substrates, substitution occurred with complete retention of the olefin geometry, that is, in strong contrast to the result of the Pd-catalyzed reaction. This observation clearly indicates that π-σ-π isomerization does not occur under the reaction conditions used. It was also found that (Z)-substrates are more reactive than the corresponding (E)analogues [241]. Similar selectivities were also obtained with other nucleophiles such as β-keto esters and substituted malonates. In contrast to Mo-catalyzed reactions [209], sulfone-stabilized anions can be used as well. (C7H8)W(CO)3 was found to be a more convenient catalyst precursor than (MeCN)3W(CO3), since it is air stable, sublimable, and readily soluble in THF [239c]. 8B.4.2.2. Asymmetric W-Catalyzed Allylic Alkylations An asymmetric version of this process has been realized first by Lloyd-Jones and Pfaltz using the W-catalyst A, based on the i-Pr-PHOX ligand (L14a) (Table 8B.41) [242]. This complex was obtained from (MeCN)3W(CO)3 and characterized by X-ray crystallography [243]. Alternatively, this complex can also be prepared in situ by heating the ligand with (MeCN)3W(CO)3 or (C7H8)W(CO)3 in THF at 60°C for 30 min and then adding the nucleophile and the allylic substrate. In an initial experiment, racemic methyl 1-phenyl-allyl carbonate was used as substrate, which gave an acceptable yield (71%) and regioselectivity (b/l: 78:22) but negligible enantioselectivity (5%). This is in good agreement with the observation that π-allyl W complexes do not undergo (significant) π-σ-π isomerization. Switching to linear substrates changed the situation dramatically. Although primary allylic carbonates show no conversion, the corresponding phosphates are more reactive and give the substitution product in good yield and selectivity (Table 8B.41). In general, good results were obtained with aryl-substituted substrates (entries 1–5), while (E)-2-butenylphosphate

TABLE 8B.41. Asymmetric W-Catalyzed Allylic Alkylations CH3 C N O Ph2 P OC

R

OPO(OEt)2

A

W

N

H

CO

MeO2C

CO2Me

CO

NaCH(CO2Me)2, THF, rt

+ R

l

b

Entry 1 2 3 4 5 6

CO2Me

R

CO2Me

R

t (h)

Yield (%)

Ratio b/l

ee (%)

Ph 4-Me-Ph 4-Cl-Ph 4-Ph-Ph 1-Naphthyl Me

71 136 136 136 136 19

89 86 94 98 93 77

74:26 80:20 78:22 79:21 95:5 27:73

96 94 88 91 86 65


reacted with reverse regioselectivity and moderate enantioselectivity (entry 6). (Z)allylic substrates react with complete retention of the olefin geometry. Interestingly, other chiral ligands such as L43a are not suitable for W-catalyzed allylations, although they give excellent results in the Mo-catalyzed process [211].

8B.5. IRON- AND RUTHENIUM-CATALYZED ALLYLIC ALKYLATIONS 8B.5.1. Iron-Catalyzed Allylic Alkylations Iron is probably the cheapest and least toxic transition metal, which can be used for cross-coupling reactions. Nevertheless, the Fe-catalyzed allylic alkylation is a rather underdeveloped field. First examples using stoichiometric amounts of (π-allyl)Fe complexes were carried out by Whitesides and Arhardt [244], Pearson [245], and Nicholas et al. [246]. Enders et al. investigated the steric course of iron-mediated allylic substitutions proceeding via π-allyl-Fe complexes [247]. The reactions proceed under complete retention of the configuration via a double inversion mechanism, comparable to the Pdcatalyzed reactions. First catalytic processes were carried out by Roustan et al. [248], Ladoulis and Nicholas [249], and Xu and Zhou [250] using iron-carbonyl-nitrosyl complexes. The reactions were slow and required relatively large amounts of catalyst (up to 25%). An important finding was that the reaction with the catalyst [Bu4N[Fe(CO)3NO]], developed by Roustan, preferentially occurs at the carbon carrying the leaving group with very high stereospecificity, similar to Rh-catalyzed allylic substitutions. Based on the early findings, Plietker recently developed an improved version [31,251]. Plietker observed that the toxic CO atmosphere previously required can be avoided if PPh3 is used as additional ligand to stabilize the intermediate Fe complexes. Best results were obtained with coordinating solvents such as DMF. Under optimized conditions the reactions proceeded with excellent regioselectivity (rs), while the incoming nucleophile is replacing the leaving group in a double SN2′ reaction (Scheme 8B.59).

OCO2i-Bu

CH2(CO2 Me)2 [Bu4N][Fe(CO)3(NO)] (2.5 mol %) PPh3, DMF, 80°C, 24 h

CH(CO2 Me)2

98% rs (81%)

Scheme 8B.59. Regioselective iron-catalyzed allylic alkylations.

Interestingly, a nearly 1:1 mixture of regioisomers was formed with acetonitrile as solvent; this indicates a reaction mechanism different from that with DMF as solvent. While the outcome of the reaction in DMF can best be explained via a (σ-allyl)Fe complex, the reaction in CH3CN probably proceeds via a (π-allyl)Fe complex. This dichotomy caused further detailed investigations and optimizations. If the PPh3 is replaced by a N-heterocyclic carbene ligand (NHC-ligand), DMF as solvent can be replaced by methyl tert-butyl ether (MTBE), which also allows the use of nonstabilized nucleophiles such as azlactones [252]. Interestingly, the related NHC ligands L51 and L52 (Fig. 8B.29) induced a complete different reaction behavior.

8B.5. IRON- AND RUTHENIUM-CATALYZED ALLYLIC ALKYLATIONS 581

N

N

N L51

N L52

Figure 8B.29. NHC-ligands used in Fe-catalyzed allylic alkylations. TABLE 8B.42. Iron-Catalyzed Allylic Alkylations in the Presence of NHC-Ligands OCO2i-Bu CH (CO i-Bu) 2 2 2 R

1

R

2

+

[Bu4N][Fe(CO)3(NO)] (2.5 mol %) Ligand, MTBE, 80°C, 5 h 1

CH(CO2i-Bu)2

CH(CO2i-Bu)2

2

Entry

R

R

1 2 3 4

H Me H Me

Me H Me H

l

b

Ligand

Yield (%)

b/l

L51 L51 L52 L52

71 64 67 63

91:9 12:88 17:83 15:85

While L51 gave rise to the substitution product with a high degree of regioretention (Table 8B.42, entries 1 and 2), the aryl-substituted ligand L52 provided nearly the same regioisomeric ratio, independent of the allylic substrate used (entries 3 and 4). This result is explained as follows. In the presence of L51, the reactions proceed via a σ-allyl complex in a double SN2′ mode, while with L52, probably a π-allyl complex is involved. To prove this proposal, nonracemic allylic substrates were subjected to allylic alkylations. While in the presence of L51, a high degree of chirality transfer was observed; the application of L52 resulted in a nearly complete loss of the enantiomeric excess, a clear indication for the formation of a symmetric (π-allyl)Fe intermediate (Scheme 8B.60). In principle, enantioselective allylations by using chiral carbene ligands should be possible. OCO2i-Bu

CH2(CO2i-Bu)2

CH(CO2i-Bu)2

[Bu4N][Fe(CO)3(NO)] Ligand, MTBE, 80°C 83% ee

With L51: 76% ee (79%) With L52: 12% ee (74%)

Scheme 8B.60. Stereoselective iron-catalyzed allylic alkylations in the presence of NHC-ligands.

8B.5.2. Ruthenium-Catalyzed Allylic Alkylations Although a wide range of transition-metal complexes can be used in allylic alkylations, the application of Ru catalysts is relatively underdeveloped [253]. In particular, asymmetric applications are very rare. The developments in this area are covered by a recent review of Bruneau et al. [254].


As reported by Trost et al., a complete chirality transfer can be obtained if chiral allylic substrates are submitted to Ru-catalyzed allylation (Scheme 8B.61) [255]. The reaction occurs regioselectively at the branched position with excellent yield. The nucleophile attacks the π-allyl complex from the face opposite the Ru [256], comparable to the Pd-catalyzed reactions. The perfect chirality transfer indicates that the nucleophilic attack is much faster than the equilibration of the π-allyl-ruthenium intermediates, although a terminal π-allyl complex is formed. Similar results were obtained with phenols as nucleophiles.

OCO2t-Bu

CH(CO2Me)2 NaCH(CO2Me)2 [(Cp*Ru(NCMe)3]PF6, DMF, rt

94% ee

94% ee (98%)

MeO2C

OCO2t-Bu

NHBoc CO2Me

NaC(NHBoc)(CO2Me)2 [(Cp*Ru(NCMe)3]PF6, DMF, rt

99% ee

99% ee (93%)

Scheme 8B.61. Regio- and stereoselective Ru-catalyzed allylic alkylations (Cp* = pentamethylcyclopentadienyl).

Burger and Tunge investigated the decarboxylative allylation of nonstabilized ketone enolates, formed from chiral β-keto allylic esters [257]. With a Ru-bipy complex as catalyst, excellent regioselectivities and a high chirality transfer were obtained (Scheme 8B.62). The not absolute perfect chirality transfer was explained by a slow isomerization of the branched, chiral allylic ester into the achiral linear allylic ester.

O

O

O O Ph

(Cp*RuCl)4, bipy, CH2Cl2, rt

Ph 83% cee (86%)

Scheme 8B.62. Regio- and stereoselective Ru-catalyzed decarboxylative allylation. cee, conservation of enantiomeric excess.

The first and so far only report on asymmetric allylic alkylations in the presence of chiral ligands came from the group of Takahashi et al. They obtained excellent yields and enantioselectivities in the presence of planar-chiral ruthenium complexes 53 con-

8B.5. IRON- AND RUTHENIUM-CATALYZED ALLYLIC ALKYLATIONS 583

TABLE 8B.43. Ligand-Controlled Stereoselective Ru-Catalyzed Allylic Alkylations

O R Ph

Ph OCO2Et

Entry

NaCR1(CO2Me)2

Ph

CR1(CO2Me)2

(S)-L53 (5 mol %), THF, 20°C, 6 h Catalyst

R

n

O

Ph

R1

MeCN MeCN Yield (%)

Ru

n

P Ph2

L53 ee (%)

1

(S)-L53a

Me

2

H

96

80 (R)

2

(S)-L53b

Ph

2

H

91

91 (S)

3

(S)-L53c

t-Bu

2

H

97

96 (S)

4

(S)-L53c

3

H

14

10 (S)

2

Me

82

63 (S)

2

Me

75

82 (R)

5

(S)-L53a

t-Bu Me

6

(S)-L53c

t-Bu

taining a tethered diarylphosphine group (Table 8B.43) [258]. The selectivity and, interestingly, also the direction of induction depends mainly on the substitution pattern on the cyclopentadiene ring and the tether length. Dimethyl sodiomalonate was used as pronucleophile for the evaluation of the ligands. The methyl-substituted complex L53a induced formation of the substitution product in excellent yield and 80% ee (Table 8B.43, entry 1). Increasing the steric size of the substituent R did not only lead to an increase of the enantioselectivity (entries 2 and 3) but also gave rise to the enantiomeric product. Increasing the size of the substituents on the phosphorus had only a marginal effect. In contrast, the tether length (n) had a strong influence not only on the selectivity but also on the yield. Prolonging the tether resulted in a dramatic drop in both (entry 4), while nearly no reaction was observed if the tether was removed completely. The yield also dropped if dimethyl sodiomalonate was replaced by the sterically more demanding dimethyl sodio(methyl)malonate (entries 5 and 6). Again, (S)-L53a and (S)-L53c gave rise to the opposite enantiomers, indicating that the substituents at the 4-position of the cyclopentadienyl ring play an extremely important role. Later on, Onitsuka et al. used the same complexes for the kinetic resolution of symmetrically substituted allylic carbonates (Table 8B.44) [259]. The reaction rates and ees were determined by HPLC showing a significant difference in the reaction rates of the two enantiomers (krel). Again catalyst L53c (entry 2) gave rise to the opposite enantiomer than catalyst L53a (entry 1). This was also true for other allylic substrates (entries 3 to 6). This different stereochemical outcome was explained via the formation of diastereomeric π-allyl complexes with different configuration at the metal center (Figure 8B.30). It should be mentioned that chiral ligands other than those mentioned above have been used in Ru-catalyzed allylic substitutions, for example, with phenols as pronucleophiles [260], but not with C-nucleophiles so far.


TABLE 8B.44. Ligand-Controlled Kinetic Resolution of Allylic Carbonates

R

R

NaCH(CO2Me)2 (S)-L53 (2.5 mol %), THF, 20°C, 3 h

OCO2Et (rac)

R

R

R

R

OCO2Et

CH(CO2Me)2

Substratea Entry

R

Catalyst

Conv. (%)

1

Me

(S)-L53a

72

2

Me

(S)-L53c

65

3

Et

(S)-L53a

57

4

Et

(S)-L53c

58

5

Ph

(S)-L53a

6

Ph

(S)-L53c

Alkylation Product

ee (%)

krel

Yield (%)

ee (%)

64 (S)

2.9

68

87 (R)

94 (R)

10.0

61

89 (S)

30 (S)

2.1

53

91 (R)

90 (R)

14.0

55

>99 (S)

54

18 (S)

1.6

50

95 (R)

58

50 (R)

3.4

55

92 (S)

a

Reisolated substrate.

O R

MeCN

O O

Ru

Ph Ph

P Ph2

R

O Ph

Ru

P Ph2

Ph MeCN

Figure 8B.30. Diastereomeric (π-allyl)Ru complexes.

O O

O

O RhH(PPh3)3 (5 mol %), PBu3, THF, 65°C, 2 h

67% Scheme 8B.63. Rh-catalyzed allylation of cyclic ketones.

8B.6. RHODIUM-CATALYZED ALLYLIC ALKYLATIONS In 1973, Onoue et al. reported for the first time on the use of rhodium complexes in the allylation of enamines using allyl phenylether as substrate [261]. As catalyst, they applied the Wilkinson catalyst [RhCl(PPh3)3], which proved to be less effective than the commonly used Pd complexes and required higher reaction temperatures. The first report on Rh-catalyzed C-allylations came from the group of Tsuji et al., describing the α-allylation of cyclic ketones starting from allyl vinyl carbonates (Scheme 8B.63) [262]. Interestingly, no reaction was observed with the Wilkinson catalyst, while RhH(PPh3)3 in the presence of PBu3 gave the best results.

8B.6. RHODIUM-CATALYZED ALLYLIC ALKYLATIONS 585

8B.6.1. Fundamentals of Rh-Catalyzed Allylic Alkylations Tsuji et al. first reported on the regioselectivity of Rh-catalyzed allylations of unsymmetric allylic substrates [30]. Under neutral conditions, the branched allylic carbonate reacted with acetylacetone to give the branched product exclusively (Table 8B.45, entry 1), while β-keto esters showed a lower regioselectivity (entry 2). Comparison of the Rhand the Pd-catalyzed version gave further insight into the reaction mechanism [263]. While the Pd-catalyzed reaction provided nearly the identical product ratios and yields (entries 3 and 4) independent on the substrate used, a strong difference was observed in the presence of the Rh complexes (entries 5 and 6). Tsuji et al. postulated that the Rh-catalyzed reaction might proceed via a σ-allyl-Rh complex and not via a π-allyl intermediate. On the other hand, the linear substrate gave nearly the identical product ratio (entries 4 and 6) with both metal complexes, which might indicate a similar catalytic intermediate. A breakthrough was the observation by Evans and Nelson that phosphites are much better ligands than phosphines, and that the reaction rate and regioselectivity toward the branched product could be increased significantly [264]. The reactions proceeded under much milder conditions, and the Wilkinson complex was found to be a suitable

TABLE 8B.45. Rhodium-Catalyzed Allylic Alkylations with 1,3-Dicarbonyl Compounds as Pronucleophiles

OCO2Me

l or

Nu Catalyst, react. cond.

OCO2Me

Nu

Nu + b

+

Nu (E)-l

(Z )-l

b Product Entry

Substrate

1

b

O

O

2

b

O

O

3

b

Nu-H

O

Catalyst

React. Cond.

Yield (%)

b : (E)-l : (Z)-l

RhH(PPh3)3

Dioxane, 100°C

86

100:0:0

PPh3 RhH(PPh3)3

Dioxane, 100°C

74

90:10:0

THF, rt

89

27:65:8

THF, rt

93

29:63:8

Dioxane, 100°C

81

86:12:2

Dioxane, 100°C

97

28:63:9

O

PPh3

O

Pd2(dba)3·CHCl3 PPh3

4

l

O

O

Pd2(dba)3·CHCl3 PPh3

5

b

O

O

RhH(PPh3)3 PPh3

6

l

O

O

RhH(PPh3)3 PPh3


catalyst. The effect was explained by a higher π-acidity of the phosphites, increasing the electrophilic nature of the (allyl)Rh intermediate [265]. An SN1-type allylic substitution might explain the higher ratio of the branched product. Tertiary allylic substrates give excellent regioselectivities in the presence of P(OPh)3, while for secondary allyl carbonates, P(OCH2CF3)3 is the ligand of choice (Scheme 8B.64) [266]. Similar results are obtained with P(OPh)3-modified [Rh(COD)Cl]2 complexes [267]. OCO2Me R

R

NaCH(CO2Me)2

CO2Me

RhCl(PPh 3)3 /P(OPh)3, THF, 30°C

CO2Me

R = Me R = i-Pr Ph

b/l = >99:1 (89%) b/l = 96:4 (73%)

CNa(CN)(CO2Me) RhCl(PPh3)3 /P(OCH2CF3)3, THF, 30°C

NC CO2Me b/l = 14:1 (92%)

Scheme 8B.64. Rh-catalyzed allylic alkylations in the presence of phosphites.

Besides malonates and β-keto esters, silyl enol ethers can also be used as ketone equivalents. Matsuda et al. screened several Rh catalysts for this interesting reaction and obtained good yields in the presence of an Rh-COD complex (Scheme 8B.65) [268]. Surprisingly, no regioselectivity was observed. RhH(PPh3)3 and the Wilkinson catalyst showed no activity under these conditions.

OCO2Me Ph

O

OSiMe3

O +

[Rh(COD)(MePh2P)2]OTf, CH2Cl2, rt

Ph

Ph 52

: (86%)

48

Scheme 8B.65. Rh-catalyzed allylic alkylations of silyl enol ethers.

The silyl enol ethers can be generated also in situ via Rh-catalyzed hydrosilylation of α,β-unsaturated ketones giving rise to a one-pot three-component coupling [269]. The regioselectivity could be dramatically increased by replacing the silyl enol ethers by Cu enolates [270]. Kazmaier and Stolz used chelated amino acid ester enolates as nonsymmetric nucleophiles [271]. γ,δ-Unsaturated amino acids were formed with good diastereoselectivity in the presence of the Wilkinson catalyst. The regioselectivity was found to depend strongly on the substitution pattern of the allylic substrate and also on the protecting group and the phosphite used. The best regioselectivities were obtained with 2-butenyl phosphate


TABLE 8B.46. Rh-Catalyzed Allylic Alkylations of Chelated Enolates OR' PG N

OPO(OEt)2 R

O Zn

PGHN

CO2R' +

[RhCl(PPh3)3]/P(OR)3, THF, −78°C rt

CO2R'

R

R

NHPG

l

b

R

R′

PG

P(OR)3

Yield (%)

b :l

1

Me

t-Bu

TFA

P(OMe)3

84

87:13

92:8

2

Me

t-Bu

TFA

P(OEt)3

85

89:11

91:9

3

Me

t-Bu

TFA

98

99:1

94:6

4

n-Pr

t-Bu

TFA

P(Oi-Pr)3 P(OEt)3

97

71:29

92:8

5

i-Bu

TFA

P(OEt)3

95

7:93

88:12

6

n-Pr

t-Bu Me

Cbz

P(OEt)3

65

Entry

97:3

dr

90:10

dr, diastereomeric ratio.

(Table 8B.46, entries 1–3), while the regio- and diastereoselectivity increased with the steric demand of the phosphite. Increasing the size of the substituent R at the allyl moiety shifted the product ratio toward the linear product (entries 4 and 5). While most reactions were carried out with trifluoroacetyl (TFA)-protected glycine enolates, other standard protecting groups can be used as well. The Cbz group gave the highest branched selectivity although in lower yield (entry 6). 8B.6.1.1. Asymmetric Rh-Catalyzed Allylations The stereochemical outcome of the reaction was investigated by Evans and Nelson [272]. The reactions of nonracemic 2-butenyl carbonate with soft nucleophiles proceeded with nearly complete retention of configuration (Scheme 8B.66). This is in strong contrast to results of the Pd-catalyzed reactions.

OCO2Me

97% ee

NaCH(CO2Me)2 RhCl(PPh3)3/P(OMe)3, THF, 30°C

CH(CO2Me)2

95% ee (86%)

Scheme 8B.66. Rh-catalyzed allylic alkylation with retention of configuration.

As intermediate, a configurationally stable enyl complex A (Scheme 8B.67) was postulated. Such complexes could be characterized by IR and NMR [273] and also by an X-ray structure analysis [274]. According to this model, the retention [275] of the regio- and stereochemical information can be explained by a hindered rotation around the σ-bond based on the coordination of the double bond toward the Rh. The nucleophilic attack is probably much faster than this isomerization (k2 >> k2), otherwise loss of the chiral information is expected.


LG

Rh

RhI

III

Nu k1

Nu

A k2 III

Rh k2 LG

Rh

RhI

III

Nu k1

Nu

ent-A Scheme 8B.67. Postulated mechanism for the Rh-catalyzed allylic alkylations.

TABLE 8B.47. Allylic Alkylations with Methyl Sodio(Phenylsulfonylacetate)

OCO2Me R

NaCH(CO2Me)(SO2Ph) RhCl(PPh3)3 /P(OMe)3, THF, 30°C

CO2 Me b

SO2Ph

Allylic Substrate Entry

R

1 2 3 4

BnOCH2 Me Bn TBSOCH2

CO2Me

+ R l

SO2Ph

Ratio

ee (%)

Yield (%)

b :l

ee (%)

94 97 94

86 86 86 78

99:1 36:1 9:1 3:1

92 95 92 99

>99

8B.6.1.1.1. Substrate-Controlled Asymmetric Allylic Alkylations Based on this mechanistic aspects, the easiest way for asymmetric allylations is the use of chiral allyl substrates, especially if symmetric nucleophiles such as malonates are used. Herewith, only one stereogenic center (in the allyl moiety) has to be controlled. The situation with unsymmetric nucleophiles is different, which generally give mixtures of diastereomers (in addition to regioisomers). Evans and Kennedy also investigated the reactions of phenylsulfonyl acetates [276]. Depending on the allylic substituent R, regioselectivity of up to 99%, high yield, and excellent chirality transfer to the branched product could be obtained (Table 8B.47). The branched product was obtained as a 1:1 mixture of diastereomers, and the linear product was formed as racemate. This can be explained by the high acidity of the sulfonyl acetates, which can epimerize under the reaction conditions used. This problem could be solved by Kazmaier and Stolz using chelated ester enolates [271]. The unsaturated amino acids obtained are configurationally stable, and as a result


TABLE 8B.48. Stereoselective Allylic Alkylation of Chelated Enolates Ot-Bu TFA N

OPO(OEt)2 R

O Zn

TFAHN

[RhCl(PPh3)3]/P(OR)3, THF, –78°C rt

CO2 t-Bu + R

R b

NHTFA

l

Allylic Substrate Entry

CO2t-Bu

Ratio

b

l

R

ee (%)

P(OR)3

Yield (%)

b :l

ds (%)

ee (%)

ee (%)

1 2

Me n-Pr

95 99

P(OiPr)3 P(OEt)3

95 97

98:2 71:29

94 92

93 98

n.d. 83

3

i-Pr

99

P(OEt)3

95

7:93

88

98

89

n.d., not determined.

of chelation, excellent diastereoselectivities are obtained. As mentioned previously, under these reaction conditions, a strong dependence of the regioselectivity on the allylic substitution pattern was observed (Table 8B.48). Surprisingly, an excellent chirality transfer was also observed toward the linear product (entries 2 and 3). Therefore, this approach was used for the synthesis of several functionalized amino acid derivatives (Scheme 8B.68). In contrast, in the presence of Pd catalysts, only racemic substitution products were obtained. Ot-Bu

O

TFA N

O OPO(OEt)2

O Zn

[RhCl(PPh3)3]/P(OEt)3, THF, –78°C rt

O

NHTFA

O CO2t-Bu ds = 95% (94%)

Scheme 8B.68. Synthesis of functionalized amino acids via stereoselective allylic alkylation.

Besides stabilized nucleophiles and ester enolates, hard nucleophiles such as boronic acids [277] or aryl zinc species [278] can also be coupled under Rh catalysis. If chiral nonracemic allylic substrates are used, the reaction proceeds under inversion of the configuration, comparable to the Pd-catalyzed process. Probably also here, the nucleophile first coordinates to the Rh and is transferred to the allyl fragment via reductive elimination. Interestingly, in contrast to the reaction with softer nucleophiles, no reaction was observed here with the Wilkinson catalyst, but a trispyrazolyl (Tp)-complex provided good yields and branched selectivities, especially with an electron-withdrawing leaving group and additional LiBr (Scheme 8B.69). 8B.6.1.1.2. Ligand-Controlled Allylic Alkylations Rama et al. were the first to report on a ligand-controlled allylation of phenols using phenyl carbonate and


i-Bu OCO2CH(CF3)2

p-BuC6H4ZnBr RhTp(C2H4 )2, Et2 O, LiBr, dba, 0°C

i-Bu

H l

b

b/l = 10:1, 95% ee (90%) Scheme 8B.69. Stereoselective allylic alkylation of organozinc compounds.

Ph O O

P

SEt

O N PPh2

L54

L55

Figure 8B.31. Ligands used in the Rh-catalyzed allylic alkylation of malonates.

(S,S)-CHIRAPHOS (L34) as a ligand [279]. The branched product was obtained with good regio- but moderate enantioselectivity (23% ee). The first asymmetric C-allylation was described by Pregosin et al. in 1999 [280]. They applied the phosphite ligand L54 as well as phosphinoxazoline L55 (Fig. 8B.31) in the asymmetric allylation using cinnamyl-type substrates (Table 8B.49). Ligand L54 gave rise to a 1:1 mixture of linear and branched product in excellent yield but low enantioselectivity (entry 1), while ligand L55 provided nearly exclusively the linear achiral product (entry 2). Better results were obtained with secondary allylic substrates (Scheme 8B.70). Although the yields were somewhat lower, high ees of up to 82% were obtained for the minor, proximal regioisomer, while the major one (distal) showed low selectivity. A significant improvement came from the group of Hayashi et al. in 2003 (Table 8B.49, entries 3–7) [281]. Based on the assumption that high ees can only be obtained from racemic allyl acetates if the lifetime of the intermediary (allyl)Rh complexes (Scheme 8B.67) is sufficiently long to allow equilibration, they run their reactions under high dilution conditions and with slow addition of the pronucleophile. As base, Cs2CO3 was used instead of NaH to decrease the amount of malonate nucleophile in solution. Under these conditions excellent enantio- and regioselectivities could be obtained (entries 3–6). Only the naphthyl derivative gave rise to a mixture of regioisomers (entry 7). Gong et al. investigated the reaction of cyclic nitroallyl acetates with hard nucleophiles such as boronic acids and organozinc reagents [282]. As ligands, they used BINAP (L23a) (Fig. 8B.32) and derivatives thereof. Good results were obtained with [Rh(OH) (COD)]2 and Rh(acac)(C2H4)2 as precatalysts. Up to 99% ees could be obtained with both organometallic reagents (Table 8B.50). The substituted nitroalkenes obtained are


TABLE 8B.49. Asymmetric Rh-Catalyzed Allylations Using Cinnamyl Derivatives as Substrates

OAc Ar b or

MeO2C

CH2(CO2Me)2 OAc

CO2Me

MeO2C

CO2Me

+

Rh complex/L, react. cond.

Ar

Ar b

Ar

l

l

Entry

Substrate

1 2 3 4 5 6 7

l l b b b b b

Ar

L

React. Cond.a

Ph Ph Ph 4-MeC6H4 4-CF3C6H4 4-ClC6H4 1-Naphthyl

L54 L55 L55 L55 L55 L55 L55

A A B B B B B

Yieldb (%) 95 95 94 97 97 93 94

Product b :l

ee (%)

Reference

49:51 2:98 98:2 88:12 99:1 97:3 60:40

14 — 97 94 97 95 95

280 280 281 281 281 281 281

a

Reaction conditions: A: NaCH(CO2Me)2, [Rh(COD)Cl]2, THF, 68°C; B: CH2(COOMe)2, Cs2CO3, Rh(dpm) (C2H4), toluene, 40°C, high dilution, slow addition of the nucleophile. Overall yield.

b

OAc Ph

R

p = proximal d = distal

NaCH(CO2Me)2

MeO2C

CO2Me

Ph

R

MeO2C

CO2Me

+

[Rh(COD)Cl]2 / L55, THF, 68°C

p

Ph

R d

R

Yield (%)

p/d

p (% ee)

d (% ee)

Me Et

75 70

10:90 14:86

80 82

13 26

Scheme 8B.70. Asymmetric Rh-catalyzed alkylations of secondary allylic substrates.

excellent Michael acceptors and were used for the stereoselective synthesis of a range of natural products such as the lycoranes. Lautens et al. investigated the desymmetrization of meso-substrates under catalysis with chiral Rh complexes, and they reported on the first rhodium-catalyzed asymmetric addition of boronic acids to oxabicyclic alkenes [283]. The reaction proceeds under very mild conditions and generates compounds with multiple stereogenic centers in high yield and excellent diastereo- and enantioselectivity (Table 8B.51). Best results were obtained if the reactions were run in THF with aq. Cs2CO3 as base and [Rh(COD)Cl]2 combined with ligand (R,pS)-L40b (Fig. 8B.32). o-Substituents at the aryl boronic acid are not accepted, but all other substituted boronic acids gave ees >94% (entries 1–4). Interestingly, alkenylboronic acids can be used as well (entry 5).


TABLE 8B.50. Asymmetric Rh-Catalyzed Allylations of Boronic Acids and Organozinc Reagents according to Gong et al.

NO2 OAc

NO2

ArM Rh complex, (R)- or (S)-BINAP, react. cond.

Ar

Entry ArM

Rh Complex

React. Cond.

1 2 3 4 5 6 7 8

Rh(acac)(C2H4)2 [Rh(OH)(COD)]2 [Rh(OH)(COD)]2 [Rh(OH)(COD)]2 [Rh(OH)(COD)]2 Rh(acac)(C2H4)2 Rh(acac)(C2H4)2 Rh(acac)(C2H4)2

Dioxane/H2O, 50°C, 20 h Dioxane/H2O, 50°C, 20 h Dioxane/H2O, 50°C, 20 h Dioxane/H2O, 50°C, 20 h Dioxane/H2O, 50°C, 20 h THF, 0°C, 25 h THF, 0°C, 25 h THF, 0°C, 25 h

PhB(OH)2 PhB(OH)2 4-F-C4H4B(OH)2 4-Cl-C4H4B(OH)2 3-MeO-C4H4B(OH)2 PhZnCl 4-MeO-C4H4ZnCl 4-F-C4H4ZnCl

Yield (%)

ee (%)

41 56 61 64 58 93 79 91

94 97 98 99 96 93 89 96

TABLE 8B.51. Enantioselective Ring Opening of Oxabicycles

O

OH

RB(OH)2

OR' OR'

R

[Rh(COD)Cl]2/ (R,pS)-L40b, THF, aq. Cs2CO3, rt, 15 h

Entry

R′

R

1 2 3 4 5

Me Me Me Me Pmb

Ph 4-Cl-C6H4 4-MeO-C6H4 3-Cl-C6H4 1-Hexenyl

OR' OR'

Yield (%)

ee (%)

91 95 87 73 95

95 95 96 99 92

OMe Cl PPh2 PPh2

P(tBu)2 Fe PPh2

N

MeO

PPh2

MeO

PPh2

(R,pS)-L40b

PXyl2

MeO

PXyl2 N

Cl (S)-BINAP (L23a)

MeO

L56

L57 OMe

Figure 8B.32. Ligands used in asymmetric Rh-catalyzed allylations of hard nucleophiles.

8B.7. IRIDIUM-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS

593

TABLE 8B.52. Asymmetric Rh-Catalyzed Allylations Using a meso-Dicarbonate

OCO2Et

Ar ArB(OH)2

OCO2Et

+

[Rh(COD)OH]2/L, THF, Cs 2CO3, 50°C

Ar OCO2Et p

Entry

Ar

L

OCO2Et d

Yield (%)

p/d

p (% ee)

a

d (% ee)

1

Ph

65:35

76

Ph

(S)-BINAP (L23a) L56

45

2

60a

50:50

90

72

3

Ph

L57

95:5

90

>98

4

4-MeOOC-C6H4

L57

70a 95

95:5

90

5 6

4-CF3-C6H4 2-Naphthyl

L57 L57

86 78

92:8 95:5

88 90

>98 n.d. n.d.

72

a

Conversion. n.d., not determined.

In 2006, Lautens et al. also reported on the enantio-, regio-, and diastereoselective rhodium-catalyzed desymmetrization of cyclic meso-allyl dicarbonates, also with boronic acids as hard nucleophiles (Table 8B.52) [284]. These meso-substrates are more challenging than the oxabicycles, because the allylic displacement can take place via an SN2 or SN2′ pathway, and the regioselectivity of the reaction has to be considered. Several ligands were screened under this point of view. Initial studies were carried out with phenylboronic acid as pronucleophile and (S)-BINAP (L23a) as ligand. The 1,2-transsubstituted product was the major one, in a 2:1 ratio over the 1,4-substituted product. Importantly, none of the cis isomers were obtained, and the ees of the product were moderate (entry 1). Unfortunately, the reaction was relatively slow and therefore the conditions were optimized by varying the chiral ligands. Biarylbisphosphines proved to be the most effective class of ligands. Excellent enantioselectivities were obtained with ligand L56, although without any regioselectivity (entry 2). By far, the best results were obtained with ligand L57, which induced both excellent regio- and enantioselectivity; conversion was acceptable (entry 3). With this ligand, a range of further arylboronic acids were investigated, and similar results were obtained (entries 4–6).

8B.7. IRIDIUM-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS The Ir-catalyzed allylic substitution was introduced by Takeuchi et al. in 1997 [285]. The first asymmetric variant followed in the same year [286]. Two years later, phosphoramidites were identified as particularly suitable ligands [287a]. Since then, the field has developed fast. Hartwig et al. added important contributions concerning allylic amination [288] and reaction mechanism [289]. Alexakis, Polet, and others introduced


a particularly effective phosphoramidite ligand [290]. Today, it is possible to carry out a wide range of alkylations, aminations and etherifications with a very high degree of regio- and enantioselectivity. As a result, many applications in natural products synthesis and medicinal chemistry have already been reported. The fast progress has induced several reviews of the field [285b,c,291].

8B.7.1. Fundamentals of Ir-Catalyzed Allylic Substitutions 8B.7.1.1. Reactivity and Regioselectivity Early work with achiral catalysts has identified a number of important general features of the Ir-catalyzed allylic substitution [287,292]. Examples are presented in Table 8B.53 and Schemes 8B.71–8B.73. (1) Screening of numerous Ir complexes for catalytic activity has identified the classical complex [Ir(COD)Cl]2 as best suited. To this day, it is the preferred precatalyst [292]. (2) The complex [Ir(COD)Cl]2 is catalytically active, but it induces low degrees of regioselectivity if the linear (E)-acetate is used as substrate. Reactivity and regi-

TABLE 8B.53. Ir-Catalyzed Allylic Alkylations of Allylic Acetates

OAc R1

l or OAc

R

1

b

CH(CO2Me)2

NaCH(CO2R2) 2 [Ir(COD)Cl]2 (2 mol %) L THF

CH(CO2Me)2

+

R1

R1

l

b

R1

R2

L

L/Ir

T (°C)

Time (h)

Yield (%)a

b/l

Ph Ph Ph Ph Ph Ph PhCH2CH2 PhCH2CH2

P(OPh)3 — PPh3 P(OPh)3 — PPh3 P(OPh)3 — P(OPh)3

1:1 — 1:1 1:1 — 1:1 1:1 — 1:1

rt 65 65 rt rt rt rt rt rt

3 24 24 3 3 3 3 3 3

98 89 58 99 98 15 99 0 90

98:2 32:68 64:36 98:2 98:2 98:2 95:5 — 96:4

Educt l l l b b b l l l

n-Pr

Me Me Me Me Me Me Me Me Et

l

n-Pr

Et

P(OPh)3

2:1

rt

3

89

96:4

l

n-Pr

Et

PPh3

2:1

65

16

6

24:76

l

n-Pr PhCH2CH2 PhCH2CH2 PhCH2CH2

Et

dppe

2:1

65

16

18

39:61

Me Me Me

P(OPh)3 P(OPh)3 —

1:1 2:1 —

rt rt rt

3 18 3

99 90 66

95:5 95:5 89:11

b b b a

Total yield of branched and linear product.

595


oselectivity are improved by addition of an electron-poor ligand, preferably P(OPh)3. (3) Best results were obtained with the monodentate ligand P(OPh)3 in a 1:1 ratio relative to Ir. Additional ligand led to decrease of the reaction rate. (4) Branched allylic substrates are more reactive than the corresponding linear substrates. This indicates the formation of an (allyl)Ir intermediate via SN2′ substitution or precoordination at the olefinic double bond. A similar observation was made for Rh-catalyzed substitutions [272,293]. (5) Under nonoptimal conditions, regioselectivity in favor of the branched reaction product is higher for reactions starting with the branched substrate than reactions starting with the linear allylic substrate. An exceptionally high level of regioselectivity was found in the case of dienylic acetates, which exclusively yielded the nonconjugated diene as product (Scheme 8B.71).

NaCH(CO2Et)2 [Ir(COD)Cl]2 /P(OPh)3 THF

OAc H3C

b1 (94%)

CH(CO2Et)2

+

H3C

b1 (84%)

OAc H3C

CH(CO2Et)2

CH(CO2Et)2

+

H3 C

b1

H3C

b2

l

Scheme 8B.71. Alkylation of dienylic acetates (both reactions: b1 : b2 : l = 100:0:0) [285b].

(6) Substitutions at allylic substrates with (Z)-configuration proceed with a high degree of stereoconservation to give products with (Z)-configuration (Scheme 8B.72).

CH(CO2Et)2 i-Pr

OAc

NaCH(CO2Et)2

i-Pr

[Ir(COD)Cl]2/P(OR)3 THF

CH(CO2Et)2 cis-l

+ i-Pr

CH(CO2Et)2

+ i-Pr trans-l

R = Ph

rt,

2h

70 : 5 : 25

(81%)

R = 2-(tert-butyl)4-methyl-phenyl

65°C, 5 h

90 : 7 : 3

(85%)

b

Scheme 8B.72. Alkylation of an allylic substrate with (Z)-configuration [292].

(7) Branched geminally disubstituted allylic substrates possess reactivity similar to that of corresponding monosubstituted ones (Scheme 8B.73) [292]. The reactivity of the linear isomers is much lower.


X

l

CH(CO2Et)2

NaCH(CO2Et)2

or

[Ir(COD)Cl]2/P(OPh)3 1:2 THF

X

CH(CO2Et)2

+

l

b

b Educt

X

T (°C) Time (h)

l l b

OCO2Me OPO(OEt)2 OAc

rfl rt rt

8 4 2

Yield (%)

b/l

No reaction 81 95:5 80 100:0

Scheme 8B.73. Substitutions at geminally disubstituted allylic substrates [285b].

An interesting observation was made upon the attempt to prepare an (allyl)(P(OPh)3) Ir complex, a putative intermediate of the allylic substitution [287b]. The reaction of [Ir(COD)Cl]2 with P(OPh)3 (2 equiv) gives the complex K1 (Scheme 8B.74). This is a 16 VE, that is, coordinatively unsaturated, d8-IrI complex; nevertheless, it did not react with allylic substrates. A reaction occurred upon addition of NaCH(CO2Me)2. Obviously, the nucleophile acts as base inducing C–H activation to afford an IrIII complex, which eliminates HCl to give a 16 VE IrI complex, which reacts with P(OPh)3 to furnish the 18 VE complex K2 [294]. P(OPh)3 must dissociate from the coordinatively saturated complex K2 to generate a catalytically active 16 VE d8-Ir complex. C–H activation of this type was also found later for (phosphoramidite) Ir complexes.

[Ir(COD)Cl]2 + 2 L

Ir

2

K1

Cl P(OPh)3

NaCH(CO2Me)2 THF, rt

P(OPh)3 Ir K2

P OPh OPh O

Scheme 8B.74. C–H activation of P(OPh)3 in an Ir complex.

8B.7.1.2. Fundamental Stereochemical Aspects The Ir-catalyzed allylic substitution with soft nucleophiles proceeds via two substitutions with inversion, that is, with net retention of configuration [287b]. In this respect, there is similarity to the Pd-catalyzed allylic substitution. Memory effects are small for Pd-catalyzed reactions at room temperature, because isomerization processes of (allyl)Pd complexes are fast [295]. As was demonstrated above, isomerization processes of (allyl)IrIII complexes are usually slow and memory effects are pronounced. Studies of substitutions at nonracemic allylic substrates have revealed that the configurational stability of (allyl)Ir intermediates of the Ir-catalyzed allylic substitution is high (Scheme 8B.75).


MeO2C

OAc

597

CO2Me

NaCH(CO2Me)2

H3C R

R

H3C R

[Ir(COD)Cl]2/P(OPh)3 THF, rt

R

85% ee (91%)

R=H >99% ee R = CH3 >99% ee

71% ee (83%)

Scheme 8B.75. Ir-catalyzed allylic alkylations with enantiomerically pure allylic substrates [287b].

These results and the conservation of the Z-configuration (cf. Scheme 8B.72) are proof that intermediates of the Ir-catalyzed reactions are nonsymmetric π- or σ-allyl-Ir complexes, which undergo slow racemization (or epimerization). Analogous Rhcatalyzed reactions display even higher degrees of stereospecificity. Evans and Nelson proposed π/σ- or enyl complexes as intermediates [272]. Whether the latter are synonyms for nonsymmetric π-complexes or distinct species is not clear. 8B.7.1.3. Asymmetric Catalysis—Early Work with PHOX as Ligands The first asymmetric Ir-catalyzed allylic substitution was carried out with dimethyl sodiomalonate and cinnamyl acetate as substrate. The PHOX i-Pr-PHOX (14a) was used as chiral ligand (Scheme 8B.76) [286]. Although the reaction was comparatively slow, regio- and enantioselectivities were high. Unfortunately, the PHOX-Ir catalysts turned out not to be generally suited; in particular, regioselectivities were generally low with alkylsubstituted substrates.

OAc R

MeO2C

CO2 Me

NaCH(CO2Me)2 [Ir(COD)Cl]2/i-Pr-PHOX THF, 65°C

+

R

b

CO2Me

R

l

CO2Me

R = Ph b/l = 95:5, 91% ee (99%) O N

PPh2

i-Pr i-Pr-PHOX (14a) Scheme 8B.76. First Ir-catalyzed asymmetric allylic substitution.

Preparation of (π-allyl)(PHOX)IrIII complexes was possible with the help of standard methods. The reaction of one of the complexes with dimethyl sodiomalonate was probed. Addition of the nucleophile occurred at the central rather than the terminal allylic carbon to give an iridacyclobutane [296a]. This reaction mode had in fact previously been encountered by Bergman, Stryker, and others and is found with many types of (π-allyl)IrIIIcomplexes [296b,c].


8B.7.1.4. Survey of Ligands Used for the Ir-Catalyzed Allylic Substitution Most asymmetric Ir-catalyzed allylic substitutions have been carried out with catalysts prepared from [Ir(COD)Cl]2 and a phosphoramidite. Phosphoramidites are usually air stable and can be conveniently prepared from appropriate secondary amines [297–299]. In addition to phosphoramidites, a number of ligands based on other frameworks have been used. The ligands that have been most often employed are described in Figure 8B.33. One has to bear in mind always that a ligand can be transformed in the course of a catalyzed reaction. Early on, the ligand Monophos-NMe2 (L58) [287a,300] was employed. It induced moderate to good results in allylic alkylations. For an unknown reason, it is inactive in aminations [287b]. The easily available ligand L59 [300] is usually the first one that is tried. Arguably, L60 [290] is generally the best ligand. However, enantiomerically enriched 1-(2-methoxyphenyl)ethylamine, which is needed for its synthesis, is not yet commercially available from fine chemicals suppliers [301]. Ligands with different aryl groups, for example, Ar = o-(MeO)C6H4 and Ar = Ph, have also been explored [299]. The corresponding ligand is easily available from (S)-1-phenylethylamine and in fact a good substitute for L60. For certain combinations of reactants, L61 [300] was found to be particularly effective. Excellent results have been obtained with ligands L62 [302a,b] and L63 [302b,c], which are simplified versions of L59–L61. Phosphites (L64a [303], L64b [304]), Ph-Pybox (L42c) [305], and DIAPHOX (L18) [306] have also been explored as chiral ligands in Ir-catalyzed allylic alkylations. The catalysts were prepared from [Ir(COD)Cl]2. These ligands have almost exclusively been used in reactions of arylallylic substrates, which are privileged substrates. The true value of a catalyst, however, becomes apparent from the results of allylic substitutions at alkylallyl derivatives. 8B.7.1.5. Ir-Complexes of Phosphoramidites as Precatalysts 8B.7.1.5.1. Catalyst Preparation, Reaction Conditions Ligands can be altered by C–H activation at aryl (see above) or CH3 groups in an Ir-catalyzed allylic substitution. Cata-

H3C aS

CH3 O P N O CH3

Monophos-NMe2 (L58)

aS

S

O P N O

aS

H3C S

Ar

L59 Ar = Ph L60 Ar = o-(MeO)C6H4 L61 Ar = α-naphthyl

aS

H3C S Ar O P N O c-C12H23

Ar

O P OR O

L62a Ar = Ph L62b Ar = o-(MeO)C6H4

O

N

Ph L64a R = Ph L64b R = (CH2)2SEt

Ph Ph-PYBOX (L42c)

L63a Ar = Ph L63b Ar = o-(MeO)C6H4

Ar1 N H P O N Ar2

O

N N

H3C S Ar O P N O c-C12H23

NH Ar1

DIAPHOX (L18)

Figure 8B.33. Chiral ligands employed for Ir-catalyzed allylic substitutions.


599

lyst preparation is therefore of great importance. Dry THF is normally used for catalyst preparation. A considerable number of protocols have been devised. (A) Dissolution of [Ir(COD)Cl]2 and ligand L* in 1:2 molar ratio in THF. A complex [Ir(COD)L*Cl] (K1) is formed by breaking up chloro bridges (Scheme 8B.77). The application of this procedure is limited to aminations with aliphatic amines [288,307]. It has been most successfully used in conjunction with ligand L60 [290]. (B) Procedure A with additional LiCl (1 equiv). This procedure gave good results for alkylations in combination with L60 [299,308]; it was less successful with L59 as ligand [287c,309]. (C) Addition of base (TBD [307], DABCO [310], n-propylamine [310], DBU [311c]) to a 1:2 mixture of [Ir(COD)Cl]2 and L* to effect C–H activation at a CH3 group (Scheme 8B.77) [289]. C–H activation is much faster for L60 than L59 [312]. This explains why procedure B is successful with ligand L60 but not L59. Likely, even weak bases such as malonate anion are able to effect C–H activation in the case of ligand L60. (D) This procedure was developed for alkylations in conjunction with ligand L59 [313]. TBD is added to a solution of [Ir(COD)Cl]2, L* and tetrahydrothiophene (THT) in THF at rt. After 2 h, the allylic carbonate and CuI are added. (E) Tsuji’s variant (salt-free conditions) [30]: The catalyst is prepared according to C, and the conjugate acid HNu of a nucleophile Nu− is used as pronucleophile [311,312]. An alkoxide is generated upon use of an allylic carbonate. This is a strong base, which deprotonates the pronucleophile HNu. 8B.7.1.5.2. Catalytic Cycle and Absolute Configuration of the Substitution Products The complexes K3 are coordinatively saturated. Dissociation of L appears necessary to generate the reactive species K4 (Scheme 8B.78). Marcović and Hartwig found that the product complex K6 is the resting state of the reaction of cinnamyl methyl carbonate with aniline (ligand L59) [314]. Remarkably, the allyl complex K5 was not found. The authors propose, on the basis of the reaction kinetics, that the formation of K5 is

[Ir(COD)L*Cl]

base

Ir

L

L P

K1

aS

O O

N

Me S

Ar

Ar

N

N

N N

N

N

H TBD

DABCO

K3

N DBU

Scheme 8B.77. Preparation of (phosphoramidite)Ir complexes K3 by C–H activation.


[Ir(COD)L*Cl]

Base L

(COD)

K3

O Ir

P

K1

* O

K4

N Nu

Ar

Ar R

R

OCOOMe

+

R

R Nu

(COD)

HNu

O

Ir

P

Ar

O

Ir P

O –

N K6

(COD)

*

N

H3COCO2 Ar

K5

* O

Ar

Ar

Scheme 8B.78. Catalytic cycle of the allylic substitution using Ir complexes of phosphoramidite ligands with all-S-configuration (L59–L63) as catalysts.

reversible and endergonic. The product complexes K6 were observed (NMR) as a mixture of diastereomers. The ratio of the diastereoisomers was in remarkably good agreement with the ratio of the enantiomers of the isolated product. Accordingly, the reaction K5 → K6 probably proceeds via a late transition state. The catalytic cycle and the structures of the intermediates seem to be fairly stable against variations. This is inferred from the observation that all allylic substitutions catalyzed by (phosphoramidite)Ir complexes follow the general rule described by Scheme 8B.78 concerning absolute configurations of the products. 8B.7.1.5.3. Variation of the Phosphoramidite Framework The modular construction of phosphoramidite ligands is an important asset of this class of compounds. The most important variants have already been presented in Figure 8B.33. Further important aspects are discussed with reference to the following general formula: X

R' H3C O P N O R R'

(a) For the binaphthalene derivatives with axial and central chirality (L59–L62), diastereoisomers with the (aS,S,S) and the (aS,R,R) configuration, or their enantiomers, that is, with l- or u-configuration, are possible. Investigations for ligands


(b)

(c)

(d)

(e)

601

L59 [8c,302b,c] as well as L60 [290] have revealed that the absolute configuration of the allylation products is controlled by the axial configuration. Ligands of the l series generally gave superior results. In the case of L59, the ligand with uconfiguration is inactive [302c]. One of the N-arylethyl groups can be replaced by a bulky alkyl or cycloalkyl group. The best results were obtained with the ligands L62 and L63 containing a cyclododecyl group [302a,b]. Despite the dominating influence of the axial chirality (cf. a), good results can be obtained with ligands containing a biphenyl instead of the binaphthyl unit (L63) [292c,302b]. Ligands with substituents R′ = CH3, OCH3, or aryl yield catalysts inducing low selectivity as well as activity [315,316]. This is understandable considering that the allyl complexes K5 are highly crowded. Of great importance is the group X, as demonstrated by excellent result obtained with ligand L60. Coordination of OCH3 to Ir has been proposed as reason. However, similar results have been obtained with a corresponding ligand with a methyl instead of a methoxy group [299]. Thus, it might be the increase of the steric bulk of X that is important. Increase of the steric bulk of L would be expected to facilitate dissociation of ligand L from complex K3.

8B.7.2. Alkylations with Stabilized Enolates as Nucleophiles 8B.7.2.1. Use of 1,3-Dicarbonyl and Related Compounds as Pronucleophiles 8B.7.2.1.1. Intermolecular Alkylations Ir-catalyzed allylic substitutions were initially carried out with dimethyl sodiomalonate and acetates as substrates and L59 as ligand (procedure B, cf. Section 8B.7.1.5) [287c]. Enantioselectivities were high; however, regioselectivities were not satisfactory (Scheme 8B.79). A remarkable improvement was achieved with L60 as ligand [299a]. Today, we know that L2 undergoes C–H activation faster than L1; thus, in situ C–H activation by malonate appears likely in the case of L60.

R

OAc

NaCH(CO2Me)2 [Ir(COD)Cl]2/L* /LiCl, THF, rt,

L*

R

L59

Ph Me i-Pr Ph n-Pr

L60

b/l 91: 9 75:25 55:45 99: 1 87:13

CH(CO2Me)2 +

R

R

b

Yield (%) 98 96 56 79 87

CH(CO2Me)2 l

Ee (%) 86 82 94 97 97

Scheme 8B.79. Allylic substitutions with allylic acetates.

Ref. 287c 287c 287c 299a 299a


Further work with procedure B showed that carbonates are superior to acetates as allylic substrates [309], and THF is an optimal solvent [287b]. Concerning ligands, L60 excelled with respect to activity, regio- and enantioselectivity [308]. Catalyst loading down to 0.1 mol % was possible under special conditions [315]. Procedure D furnished good results even with L59 as ligand (Table 8B.54) [313]. Nevertheless, running reactions on a multigram scale was problematic. This was caused by the generally low solubility of dimethyl sodiomalonate and related salts in THF. The

TABLE 8B.54. Allylic Alkylations Using Malonates and Related Compounds as Pronucleophiles

Nu

MNu or HNu R

OCO2Me

+

R

R

b

Nu l

B: [Ir(COD)Cl]2/L*/LiCl, THF, 25–35°C D: [Ir(COD)Cl]2/L*/TBD/CuI/THP, THF, rt E: [Ir(COD)Cl]2/L*/TBD, THF, rt (Salt-free conditions) Procedure

L*

B B

L60 L60

B B

R

NaNu or HNu

Yield (%)

b/l

ee (%)

Reference

Ph 2-(MeO)C6H4

NaCH(CO2Me)2 NaCH(CO2Me)2

82 98

99:1 >99:1

98 79

308 299a,318

L60

4-(MeO)C6H4

NaCH(CO2Me)2

99

>99:1

97

299a

L60

4-Cl-C6H4

NaCH(CO2Me)2

90

97

299a

B B B

L60 L60 L60

Cyclohexyln-Pr


65 92

>99:1 93:7 80:20

98 96

308 299a

O B O

NaCH(CO2Me)2

>70

81:19

84

317

D

L59

Ph

NaCH(CO2Me)2

D D

L59 L60

PhCH2CH2 Ph


88 92 92

99:1 81:19

313 313 315

D D

L60 L60

PhCH=CH PhCH2CH2


80 93

>99:1 99:1 91:9

96 96 98 98 98

315 315

E E

L59 L60

Ph Ph

CH2(CO2Me)2 CH2(CO2Me)2

92 96

99:1 99:1

97.5

312 312

E E

L60 L60

Me CH2OCPh3

CH2(CO2Me)2 CH2(CO2Me)2

90 88

98:2 78:22

E E E

L59 L59 L59

CH2OCPh3 CH2OSiPh2t-Bu CH2OSiPh2t-Bu

CH2(CO2Me)CN CH2(CO2Me)CN CH2(CN)2

70 72 77

87:13 88:12 84:16

>99 98.5 >99 97 99 98

312 312 319 312 312


603

remedy was provided by procedure E, that is, application of salt-free reaction conditions. With this protocol, enantiomeric excess of >98% ee can often be reached upon use of L60. The following conclusions concerning alkylations of allylic carbonates can be drawn (cf. Table 8B.54): (1) Particularly high selectivities and yields are obtained with alkenyl- and arylsubstituted allylic carbonates. Using ligand L59/procedures D or E or ligand L60/ procedures B, D, or E, enantiomeric excess >95% and regioselectivity ≥98:2 in favor of the branched product are typical. Exceptions are allylic substrates with an o-substituted aryl group, for example, R = 2-(MeO)C6H4. (2) Generally, enantioselectivities are high with alkyl-substituted allylic carbonates as substrates, while regioselectivities vary. Values >90:10 are typical in case of carbonates with small and rigid substituents (R = Me, cyclohexyl); values in the range 70:30 to 90:10 are found for reactions with substrates containing flexible or sterically very demanding substituents (R = n-Pr, n-octyl, PhCH2CH2, (t-Bu) Ph2SiOCH2). (3) The scope concerning substrates is broad. Even sensitive allylic boronates have been used [317]. The example cited in Table 8B.54 proceeded with excellent regioselectivity and enantiomeric excess of up to 84% ee, even though nonoptimal reaction conditions were used. Pd catalysts failed to promote the reaction. Of course, ligands other than phosphoramidites have been probed for allylic alkylations of malonates. It is a general observation that regioselectivity was high with arylallyl derivatives but low with alkylallyl acetates or carbonates. Examples are PHOX ligands (cf. Section 8B.2.3) [286a], i-Pr-Pybox [305b], phosphites of type L64 [303], and DIAPHOX ligands [306a]. Naturally, β-keto esters and 2-alkylmalonates have also been probed as pronucleophiles (Scheme 8B.80) [299a,315]. Generally, mixtures of epimers (ca. 1:1) are formed from β-keto esters. The allylation products prepared from 2-alkenylmalonates have been transformed into cyclopentene derivatives by Ru-catalyzed ring closing metathesis (RCM) [299a,315].

Procedure D:

Procedure B: O MeO

O

O OMe

b/l = >99:1, 97% ee (95%)

Me

O

O OMe

b/l = >99:1, 95% ee (dr = 53:47, 68%)

O

O OMe

b/l = 94:6, 95% ee (dr = 51:49, 79%)

MeO

O

O OMe

b/l = 96:4, 97% ee (74%)

O

MeO

OMe

b/l = 93:7, 92% ee (78%)

Scheme 8B.80. Allylic alkylations: sodium salts of 2-substituted malonates and β-keto esters with cinnamyl methyl carbonate; ligand: L60.


8B.7.2.1.2. Applications in Syntheses of Biologically Active Compounds In many applications, the allylic substitution has been combined with an RCM reaction. This strategy was first realized by Evans et al. with Rh-catalyzed allylic aminations [320] and etherifications [321]. An example is the synthesis of the prostaglandin analogue TEI-9826 described in Scheme 8B.81 [322]. The sodium salt of the malonic amide of the Weinreb type can be considered an equivalent of the enolate of a methyl ketone. The allylic alkylation gave the substitution product with 99% ee as 1:1 mixture of epimers. Further steps furnished a dienone suited as substrate for RCM to give 4-(n-octyl)-cyclopent-2-enone. This was transformed into the prostaglandin analogue TEI-9826 by aldol condensation. A related route was used for a synthesis of a lactam analogue of brefeldin C [319].

O

Na O

MeO

O N

OMe

MeO2C

N

Me R

OCO2Me

b/l = >98:2, 98% ee (88%) R = Ph b/l = 94:6, 95% ee (76%) R = Me R = n-Octyl b/l = 84:16, 99% ee (62%) O

R = n-Octyl

O

CO2Me

Grubbs' II n-Octyl

T EI-9826

Me

R

[Ir(COD)Cl]2/L60/TBD, THF, rt

O

OMe

CH2Cl2

n-Octyl

Scheme 8B.81. Ir-catalyzed allylic alkylation with a malonic amide and application in the synthesis of the prostaglandin analogue TEI-9826.

A formal synthesis of the serotonin reuptake inhibitor (−)-paroxetine has been presented by Hamada et al. (Scheme 8B.82) [306a]. The intermediary piperidine derivative was obtained from the allylic alkylation product in excellent 70% overall yield. The corresponding allylic alkylation product with a p-chlorophenyl substituent was transformed into (R)-baclofen hydrochloride (cf. Alexakis et al.) [299a]. 8B.7.2.1.3. Intramolecular Alkylations Intramolecular allylic substitutions often pose difficulties. For example, Pd-catalyzed intramolecular allylic alkylations are usually run at a low concentration because of competitive polymerization. In contrast, Ir-catalyzed cyclizations can be run without problems at 2 M concentration. Nevertheless, problems arise because of the competing noncatalyzed background reaction. In case of the fiveand the six-membered rings (Scheme 8B.83) [315], satisfactory yields were obtained by preparing the malonate anion at −78°C. The ligand L60 proved to be the best suited once more. However, these conditions were not suitable for the vinylcyclopropane and -butane. In these cases, application of the salt-free conditions gave excellent results [312].


605

O O H3CO2C

CO2CH3

HO

NH

O

F

F

NH

F

b/l = 99:1, 92% ee (93%)

(–)-Paroxetine

Scheme 8B.82. A formal synthesis of (−)-paroxetine.

MeO2CO

()

MeO2C

[Ir(COD)Cl]2/L60/TBD

CH(CO2CH3)2

CO2Me

()

n

n

n = 1/2: n = 3/4:

Salt-free–10/50°C Via lithiomalonate –78°C rt

97/98% ee (56/65%) 96/97% ee (77/79%)

Scheme 8B.83. Intramolecular allylic substitutions.

OCO2Me R

R1 NO2 R2 R1R2CH-NO2 [Ir(COD)Cl]2 /L60/TBD THF, rt

+

R

b

NO2

R

l

1

R R2

R1 = R2 = CH 3 (base: Cs2CO3):

R = Ph

R1 = H, R2 = CO2Et (no base):

R = Ph b/l = 99:1, 98% ee (90%) R = PhCH2CH2 b/l = 78:22, 98% ee (86%) R = n-Pr b/l = 90:10, 99% ee (92%)

b/ l = 96:4, 99% ee (84%)

Scheme 8B.84. Aliphatic nitro compounds as pronucleophiles in asymmetric allylic alkylations.

8B.7.2.1.4. Substitutions with Aliphatic Nitro Compounds as Pronucleophiles Allylic substitutions with nitromethane as pronucleophile furnished mixtures of mono- and dialkylation products. Good results were obtained with primary and secondary nitro compounds [323]. Nitronates were generated with cesium carbonate as base (Schemes 8B.84 and 8B.85). Ethyl nitroacetate served as the synthetic equivalent of nitromethane. An additional base was not required (salt-free conditions). Mixtures of epimers were formed as a consequence of the high acidity of the chirality center α to N. For the removal of the ethoxycarbonyl group, a new variant of the Krapcho reaction was developed.


Ph

OCO2 Me

NO2

O2N

[Ir(COD)Cl] 2/ent-L60, Cs2CO3, THF, rt

Ph

b/l > 99:1, 93% ee (82%) Grubbs' I

H2N

O2N

Ph

Ph

Scheme 8B.85. Synthesis of an antidepressant via Ir-catalyzed allylic alkylation in combination with RCM.

An Ir-catalyzed alkylation with a nitro compound and an RCM reaction were the key steps in a synthesis of (1S,2R)-trans-2-phenylcyclopentanamine, which possesses antidepressant activity (Scheme 8B.85) [323]. The reaction of 4-nitro-1-butene/Cs2CO3 with cinnamyl methyl carbonate proceeded with high selectivity and good yield. RCM using Grubbs’ I catalyst closed the five-membered ring. Subsequent treatment with NEt3 effected epimerization and yielded a trans-cyclopentene, which was reduced to the target compound in excellent yield.

Ph Ph

PO(OEt)2 O

Ph

N

Ph S

CO2t -Bu

[Ir(COD)Cl]2/(R)-L64b base

Ph2C

N S CO2t -Bu (S,S)

Ph S +

Ph2C

N R CO2t -Bu (S,R)

aq. 50% KOH, toluene, 0°C: (S,S)/(S,R)= 82:18 (82%), major diast. 97% ee LiN(T MS)2, T HF, 0°C: (S,S)/(S,R)= 12:88 (82%), major diast. 92% ee

aR

O P O O

(R)-L64b

SEt

Scheme 8B.86. Use of a glycine equivalent as pronucleophile.

8B.7.2.1.5. Allylic Alkylations with a Glycine Equivalent Takemoto et al. reported a stereoselective synthesis of β-substituted α-amino acid derivatives based on the use of ethyl diphenylimino glycinate as pronucleophile (Scheme 8B.86) [304,324]. The bidentate phosphite L64b was used as ligand. Allylic diethyl phosphates rather than carbonates were employed as substrates.


607

An intereresting aspect of the Takemoto system is the possibility of preparing both diastereoisomeric products selectively, depending on the cation provided by the base: With a lithium amide the (R,S)- and with KOH the (S,S)-diastereoisomer, respectively, was preferentially formed. The authors proposed for rationalization of this remarkable reversal, that with LiNR2 an N,O-chelated syn- and with KOH an anti-enolate is formed. The procedure also allowed the preparation of α,α-disubstituted amino acids.

8B.7.3. Allylic Substitutions with Nonstabilized Enolates, Enamines, Indole Derivatives, and Organozinc Compounds 8B.7.3.1. Silyl Enol Ethers as Pronucleophiles Nonstabilized enolates have been thoroughly studied as nucleophiles in Pd-catalyzed allylic substitution [147]. Lithium enolates, because of their comparatively strong basicity, can induce side reactions such as enolate equilibration, elimination, and cleavage of carbonates. Improved results have been obtained with Zn and Cu enolates. Graening and Hartwig reported highly regioand enantioselective reactions of allylic carbonates with enolates generated in situ from trimethylsilyl enol ethers (Scheme 8B.87) [325]. Use of cesium fluoride as standard desilylation reagent was unsatisfactory because of low degrees of regioselectivity and diallylation as side reaction. Diallylation could be suppressed by desilylation with a combination of CsF and ZnF2. Explicit catalyst activation was not necessary as C–H activation occurred in situ (31P NMR).

OSi(CH3)3 OCO2t-Bu R1

O

R2 [Ir(COD)Cl]2/ent-L59 Additives: CsF/ZnF2 1:3 DME, 50°C R1 = 2-furyl, R1 = 4-(F3C)C6H4, R1 = Ph, R1 = i -Pr,

R2

b

R2 = Ph R2 = Ph R2 = i -Pr R2 = Ph

O R1

+

R2

l

R1

b/l = 99:1, 96% ee (74%) b/l = 94:6, 95% ee (81%) b/l = 95:5, 91% ee (46%) b/l = 85:15, 94% ee (75%)

Scheme 8B.87. Alkylations with ketone enolates generated from silyl enol ethers.

Rate and selectivity of the reaction were strongly influenced by the substituent R2 of the silyl enol ether. Good results were obtained for compounds with R2 = aryl. However, reactions were slow and yields moderate for cases with R2 = alkyl. The absolute configuration of one of the products was determined and found to be in accordance with the general rule presented in Section 8B.7.1.5.2. The question of diastereoselectivity, arising upon use of silyl enol ethers with a substituent at the α-position, has not been addressed so far. 8B.7.3.2. Decarboxylative Allylic Alkylation The technique of allylic substitution via decarboxylative in situ generation of an enolate was introduced by Saegusa and Tsuji


[172]. Enantioselective variants have been developed for Pd and more recently also for Ir catalysts. You et al. (Scheme 8B.88) [316] obtained good selectivities with a broad range of arylallylic substrates, while regioselectivities with alkylallylic substrates were somewhat lower. Improved results will probably be achieved with ligands other than L59. For once, methylene chloride rather than THF was used as solvent. Concerning reaction mechanism, it was determined by crossover experiments that reactions proceeded intermolecularly. Furthermore, absolute configurations established for selected examples were as expected on the basis of the general rule (cf. Section 8B.7.1.5.2). O

O

R2

O [Ir(COD)Cl]2/L59/DBU CH2 Cl2, reflux

O

O

R2

R1

R2 +

R1

R1

b R1 = Ar, R1 = Me, R1 = n-C5H11,

R2 = Ar R2 = Ph R2 = Ph

l

b/l = 98:2, 91–95% ee (58–83%) b/ l = 94:6, 90% ee (61 %) b/ l = 80:20, 89% ee (52 %)

Scheme 8B.88. Decarboxylative transformation of allyl β-keto esters.

8B.7.3.3. Enamines as Nucleophiles Weix and Hartwig developed enamines as nucleophiles. Considerable difficulties had to be overcome to arrive at a useful procedure (Scheme 8B.89) [326]. Note that a pure complex ent-K3 (Ar = Ph, L = ent-L59, Scheme 8B.77) in combination with [Ir(COD)Cl]2 was used as catalyst. Furthermore, toluene was superior to THF as solvent. Only reactions with enamines derived from methyl ketones were reported so far.

N OCO2i-Pr R1

O

R2 ent-K3 (Ar = Ph)/[Ir(COD)Cl]2 ZnCl2 (0.5 equiv) Toluene, 25°C R1 = Ph, R1 = 2-furyl, R1 = n-Pr,

R1

R2 = i-Pr R2 = i-Bu R2 = i-Bu

O R2

+

R1 l

b

b/l = >99:1, b/l = 98:2, b/l = 89:11,

R2

95% ee (86%) 97% ee (90%) 83% ee (64%)

Scheme 8B.89. Ir-catalyzed allylic substitutions with enamines.

8B.7.3.4. Reactions with Indoles Indoles have been used successfully in Mo- and Pdcatalyzed allylic substitutions. Their application in the Ir-catalyzed allylic substitution was reported only recently by You et al. [327]. Initial results obtained under the standard


609

reaction conditions of the allylic alkylation were unsatisfactory. After considerable variation of base and solvent, the conditions described in Scheme 8B.90 were found. Dependence of selectivities follows the general characteristics described before, however, enantioselectivities are slightly lower than with stabilized carbanions.

R2 OCO2CH3 R1

R2

H

N (2.0 equiv) H [Ir(COD)Cl]2 (2 mol %) L59 (4 mol %) Cs2CO3 (1.0 equiv) Dioxane, reflux, 3–8 h

R2

H

N

N

R1

R1 b

l

R1 = Ph R2 = H R1 = 4-(MeO)C6H4, R2 = H R1 = 4-(MeO)C6H4, R2 = 5-(MeO) R1 = Me, R2 = H R2 = H R1 = n-Bu,

b/l = >97:3, b/l = >97:3, b/l = >97:3, b/l = 93:7, b/l = 87:13,

85% ee (49%) 92% ee (82%) 89% ee (85%) 88% ee (43%) 85% ee (55%)

Scheme 8B.90. Ir-catalyzed allylic alkylations with indoles as nucleophiles.

8B.7.3.5. Allylic Substitutions with Aryl Zinc Compounds On first view, it appears that organocopper compounds are the first choice if allylic substitutions with nonstabilized C-nucleophiles are concerned [328]. Scrutiny of the literature, however, shows that alkyl copper compounds yield branched, while aryl copper compounds yield mainly linear alkylation products. For this reason, Alexakis et al. [329] investigated Ir-catalyzed allylic substitutions with aryl zinc halides (Scheme 8B.91). PhMgBr/ZnBr2 /LiBr 1.5:0.75:1.5 R

OCO2Me

[Ir(COD)Cl]2/L60, THF, rt R = 4-FC6 H4, R = 3,4-Cl2C6H3, R = c-Hex,

Ph +

R b

R

Ph l

b/l = 50:50, 93% ee (83%) b/l = 57:43, 95% ee (89%) b/l = 69:31, 74% ee (72%)

Scheme 8B.91. Allylic substitutions with a phenyl zinc reagent as pronucleophile.

Diphenylzinc was postulated as key intermediate of which both phenyl groups are transferred. Regioselectivity was unsatisfactory; otherwise, the features typical for reactions with stabilized carbanions, including absolute configurations of the products, were observed. As application, a formal synthesis of the antidepressant sertraline was carried out (Scheme 8B.92).


NHMe Ph

Ph

Cl

Cross metathesis

Cl

Reduction

Cl

Cl

CO2Me

95% ee

Cl Cl Sertraline (Zoloft)

Scheme 8B.92. Using the Ir-catalyzed allylic alkylation for a synthesis of an antidepressant.

8B.8. COPPER-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS Although the palladium-catalyzed allylic alkylation is by far the most popular version, the poor regioselectivity observed with nonsymmetrical allylic substrates is a serious limitation of this protocol. In this respect, the copper-catalyzed process is an interesting alternative and caused a lot of research efforts during the last years. The attractiveness of copper also arises from the fact that it tolerates a wide range of hard, nonstabilized nucleophiles, such as organometallics. The developments in this important field are covered by various reviews on this topic [328a,330].

8B.8.1. Fundamentals of Cu-Catalyzed Allylic Substitutions If unsymmetric allylic substrates (R1 ≠ R2) are used in allylic alkylations, in principle, two different products can be expected, depending on the substitution mechanism. The nucleophile can either attack directly at the leaving group (Y) in an SN2-type reaction (α-product), or at the allylic position (γ-product) under migration of the double bond, what is called an SN2′ process (Scheme 8B.93). The regioselectivity is strongly influenced by the reaction parameters (solvent, temperature) as well as by the substrate and the organometallic source. In general, nucleophilic substitution of the leaving group (SN2 and SN2′) proceeds with clean inversion of the configuration.

R α

R1

R2 α-Product

RCu SN2

Y

γ

R1

α β

R2

RCu SN2'

R

γ

R1

R2 γ-Product

Scheme 8B.93. Regioselectivity in Cu-catalyzed allylations.

Corey and Boaz proposed a first mechanistic rational based on frontier molecules orbital considerations [331]. They proposed a simultaneous overlap of a full d-orbital of the copper with both the π* orbital (LUMO) of the allylic double bond and the antibind-

8B.8. COPPER-CATALYZED ENANTIOSELECTIVE ALLYLIC ALKYLATIONS

611

Figure 8B.34. Mechanistic proposal for Cu-catalyzed allylations under inversion.

Ph

Ph Me 2CuLi

+

γ

D OAc

Ph α

D

Me 51

Ph

:

49

Ph Me2CuLi

47 Ph

:

Ph

53

Ph

Ph +

γ

Me

α

D 98

PhHN

D Me

Me

Me 2CuLi D O

α

D

Me

D

Ph +

γ

OAc

Me D

:

2

via D Me

D

Me Cu

O NH

Ph

O

O Scheme 8B.94. Regio- and stereoselectivity in Cu-catalyzed allylations.

ing σ* orbital of the leaving group (Fig. 8B.34). Such a double overlap is only possible if the leaving group is orthogonal to the double bond, which explains the high anti-selectivity. For example, the diastereomeric cyclic allylic substrates provide the diastereomeric substitution products with excellent trans selectivity (Scheme 8B.94) [332], although as a regioisomeric mixture. Gallina and Ciattini investigated not only the reaction of cyclic acetates but also the substrates with a carbamate leaving group [333]. In contrast to the acetates, here only the cis substitution products were obtained via a clean SN2′ reaction. The outcome of the reaction can be explained by a coordination of the cuprate to the carbamate and an intramolecular transfer of the methyl group to the allyl position. Similar results were obtained with heterocyclic leaving groups, such as benzothiazoles [334] and phosphinobenzoates [335].


Bäckvall and van Koten proposed a mechanism for the Cu-catalyzed allylations, which explains the formation of both the α- and of the γ-product (Scheme 8B.95) [336,337]. According to this mechanism, the regioselectivity and the stereoselectivity are established at different stages. The stereocontrolling step is the first one, the coordination of the Cu reagent to the double bond (enantiotopic differentiation) forming a Cu-π complex A, which on oxidative addition (anti to the leaving group) is converted to a CuIII-σ complex B. Subsequent reductive elimination gives rise to the γ-product.

R1

X [RCuX] -

R1

R1

X

R1

Cu R

X A

R

X = alkyl

Y

Cu

Cu R

X B

X = CN, Cl

R1

R

D – CuX

– CuX R1

R

X

X C

R1

Cu

γ-Product

R

α-Product

Scheme 8B.95. Mechanism of the Cu-mediated allylic alkylation.

All factors that favor a rapid reductive elimination, such as electron-withdrawing substituents, also favor the formation of the SN2′ product. In contrast, electron-donating groups, such as alkyl groups (as in R2CuLi), stabilize the CuIII-complex B, giving it the possibility to equilibrate to D via a π-allyl complex C. Reductive elimination then provides the linear, sterically less hindered α-product [338]. Although such a π-σ-π isomerization causes a loss of regioselectivity, the stereochemical course is maintained in principle [339].

8B.8.2. Asymmetric Cu-Catalyzed Allylations Achiral linear allylic substrates give rise to chiral products under SN2′ conditions. To control the stereochemical outcome of this process, in principle, two different protocols are suitable. One can either use a chiral leaving group (auxiliary control), which directs the Cu in the coordination step to the one or the other face of the double bond, or one can coordinate chiral ligands onto the Cu ion. 8B.8.2.1. Auxiliary Controlled Allylic Alkylations The use of a chiral leaving group is quite an attractive approach, because the auxiliary is directly replaced in the substitution step. Alexakis and Mangeney were one of the first who used chiral acetals as ste-


613

reocontrolling elements [340]. The reaction of crotonaldehyde acetals with BuCu in the presence of BF3 occurred diastereoselectively but not regioselectively (Scheme 8B.96). In contrast, aryl [341] and alkenyl copper reagents [342] reacted completely regioselectively and also diastereoselectively. The best diastereoselectivites were obtained in the presence of PBu3. The olefin geometry of the allylic substrate also plays a significant role. The corresponding (Z)-isomer affords the substitution product with reverse absolute configuration, but with the same diastereoselectivity [342]. The enolether obtained can easily be hydrolyzed to the corresponding ketone or aldehyde, overall the product of an asymmetric 1,4-addition.

O

O +

Bu

Cu

Bu

F3B O O

Bu HO

HO

77% de 57

ArC

63% de :

43

u O Ar

H3O+

CHO Ar

HO

> 99% ee

Scheme 8B.96. Allylic alkylations using chiral acetals.

Denmark and Marble reported on the use of chiral carbamates as leaving groups [343]. They observed best results if the allyl carbamate was first deprotonated with RLi, before a suspension of the copper reagent was added. Under optimized conditions, the SN2′ product was obtained exclusively, with excellent enantiomeric excess (Scheme 8B.97).

O O

N H

OMe

R

1) BuLi, Et2O, 0°C 2) RCu, Et2O, 0°C 3) 0°C rt R = Me R = n-Bu R = Ph

95% ee (56%) 88% ee (64%) 91% ee (70%)

Scheme 8B.97. Allylic alkylations using chiral carbamates.

Gais et al. introduced chiral sulfoximines as directing leaving groups [344]. They investigated in detail the reaction of a range of cyclic allyl sulfoximines with copper nucleophiles (Table 8B.55). Interestingly, RCu reagents in the presence of BF3·OEt showed an excellent γ-selectivity (entries 1, 3, and 5–7), while the corresponding cuprates


TABLE 8B.55. Allylic Substitution of Cyclic Sulfoximines

NMe

O S

Ph

R Cu reagent/LiI

+

THF or Et2O, Me2S, –78°C

n

n

R

n

α-Product

γ-Product

R

Additive

Yield (%)

γ :α

ee (%)

RCu R2CuLi RCu

RO(CH2)4 RO(CH2)4 n-Bu

BF3•OEt — BF3•OEt

90 90 89

98:2 2:98 99:1

71 — 72

1

R2CuLi

n-Bu

—

87

2:98

—

5

2

RCu

n-Bu

BF3•OEt

83

99:1

60

6

3

RCu

n-Bu

BF3•OEt

90

98:2

60

7

0

RCu

n-Bu

BF3•OEt

40

98:2

27

Entry

n

Cu Reagent

1 2 3

1 1 1

4

reacted with a comparable selectivity at the α-position (entries 2 and 4). Therefore, it is relatively easy to get either the one or the other product by simply changing the reaction conditions. Best enantioselectivities were obtained with the five-membered-ring substrate (n = 1; entries 1, 3, and 5), while the four-membered ring especially showed a significant drop in the yield and the enantiomeric excess (entry 7) but not the regioselectivity. Recently, Breit and Breuninger described highly selective allylations controlled by a syn-directing diphenylphosphinobenzoate (DPPB) leaving group [345]. They investigated the reaction of Grignard reagents in the presence of different copper salts, and observed that the regioselectivity depended on the Grignard concentration and the addition time. The lower the concentration and the slower the addition, the higher the SN2′ selectivity. This clearly indicates that the reaction seems to proceed via an organocopper reagent rather than a cuprate. This is in good agreement with the results obtained by Bäckvall et al. [338] and Gais et al. [344]. If enantiomerically pure diphenylphosphinoferrocene carboxylates were used, ees up to 88% could be obtained at 0°C in Et2O (Table 8B.56, entry 1). Switching to CH2Cl2 increased the ee to 95% in a comparable yield (entry 2). Methyl and isopropyl substituents could also be introduced with good results (entries 3 and 4), while the enantiomeric excess dropped dramatically in the reaction of PhMgBr (entry 5). Aryl substituents at an (E)-allylic substrate are well tolerated (entries 6), while the corresponding (Z)-substrates gave significantly worse ees and the opposite enantiomer was formed preferentially. The stereochemical outcome of the reaction can be explained by coordination of the copper reagent toward the phosphino group (Fig. 8B.35). One can assume a conformation with minimized A1,3-strain in which the σ*-orbital of the leaving group is parallel to the p-orbitals of the double bond. Coordination of the copper reagent and internal alkyl transfer generates the (S)-configuration as obtained.


615

TABLE 8B.56. Leaving Group-Directed Asymmetric Allylic Alkylations

PPh2 O

R

Fe O

R'

R'MgBr

γ

CuBr SMe2

R

R

R′

1

c-Hex

n-Bu

2

c-Hex

3

c-Hex

n-Bu Me

4

c-Hex

82

98:2

81

c-Hex Ph

i-Pr Ph

Et2O/CH2Cl2

5

Et2O/CH2Cl2

n.d.

75:25

28

n-Bu

Et2O/CH2Cl2

86

87:13

78

Entry

6

Yield (%)

γ :α

ee (%)

Et2O

73

98:2

88

CH2Cl2

77

97:3

95

Et2O/CH2Cl2

56

93:7

82

Solvent


R

H

H H

H R' O LnCu Ph2P

O

Fe

Figure 8B.35. Mechanistic proposal for leaving group-directed allylic alkylations.

8B.8.2.2. Ligand-Controlled Allylic Alkylations The ligand-controlled coppercatalyzed allylic alkylation developed extremely well during the last years [330], and a wide range of chiral ligands found application. 8B.8.2.2.1. Allylic Alkylation of Grignard Reagents A first report using nontransferable chiral arylthiolates came from the groups of Bäckvall and van Koten [346]. Their pioneering work clearly indicated the inherent difficulties of this process. The enantiomeric excess strongly depends on many factors such as the temperature, the coordinating ability of the leaving group, and the addition mode of the reaction partners (Table 8B.57). Addition of nBuMgI to the allyl substrate in the presence of Cu complex K7 provided the γ-product exclusively with nearly the same enantiomeric excess at 20 and 0°C (entries 1 and 2), while the ee dropped significantly if the reaction was run at −20°C. Simultaneous addition of substrate and Grignard reagent to a solution of the catalyst provided the product with 42% ee (entry 3). Interestingly, other leaving groups such as trifluoroacetates, carbonates, or phosphates are less suited than the acetate. Other Grignard reagents also gave ees in the range of 35–40%, when the Cu catalyst was prepared in situ from CuI and the free ligand L65 (entries 4–7). Later, Bäckvall et al. found that ligand L66 (Fig. 8B.36) gives better results than L65, but still a fine tuning of the reaction parameters was necessary [347]. Best results were obtained in an Et2O/toluene mixture at room temperature (entry 8).


TABLE 8B.57. Cu Complexes and Ligands Used in Cu-Catalyzed Allylic Alkylations

Cu S

NMe2

RMgI X

Cu-Cat., Et2O K7

R

Entry

X

R

Cu-Cat.

Mol% Cat.

T (°C)

Yield (%)

ee (%)

1

OAc

n-Bu

K7

5

20

100

31

2

OAc

n-Bu

K7

5

0

100

29

3

OAc

n-Bu

K7

15

0

100

42

4

OAc

n-Bu

CuI/L65

15

0

100

40

5

OAc

i-Pr

CuI/L65

15

0

100

34

6

OAc

CuI/L65

15

0

80

40

7 8

OAc OAc

i-Bu Me3SiCH2

CuI/L65 CuI/L66

15 13

20 25

100 88

37 64

SH

n-Bu

NMe2

SH

NMe2

Ph

O O P O O O Ph Ph Ph

Fe

L65

Ph Ph

L6 6

O NMe 2

L67

Ph

O

Ph

O

P N O

L6 8

P N

(R,R,R)-L60

Me2N

PPh2

Fe PPh2 OMe

(S,S,aR)-L59

P N Ph

OMe O

O

TANIAPHOS L69

Figure 8B.36. Ligands used in the cross-coupling of allyl substrates with Grignard reagents.

Nearly at the same time, Alexakis et al. found by high throughput screening a TADDOL-based phosphite L67 giving up to 73% ee in the addition of EtMgBr to cinnamyl chloride (Table 8B.58, entry 1). CuCN was used as catalyst precursor, and a slow addition of the Grignard reagent was essential for good ees [348]. A further increase of the selectivity could be obtained with Cu thiophene carboxylate (CuTC) as copper


617

TABLE 8B.58. Allylic Alkylations Using Phosphite, Phosphoamidite, and Diphosphine Ligands

R

Entry

X

R

R1

R1MgBr

R1

CuX/L (1 mol %), CH2 Cl2, – 78°C

γ

X

CuX

R

Ligand

+

α

R

R1

Yield (%)

γ :α

ee (%)

1

Ph

Et

Cl

CuCN

L67

n.d.

94:6

73 (R)

2

Ph

Et

Cl

CuTC

L67

97

96:4

82 (R)

3

Ph

Me

Cl

CuTC

L67

95

31:69

61 (R)

4

Ph

n-Pr

Cl

CuTC

L67

96

80:20

75 (R) 46 (R)

5

Ph

CuTC

L67

100

88:12

Ph

i-Pr Me

Cl

6

Cl

CuTC

L68

83

12:88

62 (S)

7

Ph

Et

Cl

CuTC

L68

96

92:8

79 (S)

8

Ph

i-Pr

Cl

CuTC

L68

98

90:10

83 (S)

9

3-MeOPh

i-Pr

Cl

CuTC

L68

98

91:9

86 (S)

10

2-Naphthyl

CuTC

L68

97

92:8

85 (S)

Ph

i-Pr Et

Cl

11

Cl

CuTC

(R,R,R)-L60

86

99:1

96 (R)

12

4-MePh

Et

Cl

CuTC

(R,R,R)-L60

85

99:1

96 (R)

13

c-Hex B(OR)2

Et

Cl

CuTC

82

99:1

91 (−)

Et

Cl

CuTC

(R,R,R)-L60 L60

n.d.

97:3

95 (S)

14 15

Ph

Et

Br

CuBr SMe2

L69

99

82:18

96 (S)

16

Ph

Br

CuBr SMe2

L69

92

87:13

94 (S)

17

Ph

n-Bu Me

Br

CuBr SMe2

L69

91

97:3

98 (S)

18

nBu

Me

Br

CuBr SMe2

L69

99

100:0

92 (S)

19

BnOCH2

Me

Br

CuBr SMe2

L69

93

98:2

20 21

PhCOO PhCOO

Me Et

Br Br

CuBr SMe2 CuBr SMe2

L69 L69

85 87

99:1 99:1

92 (S) 96 (+) 98 (+)


source (entry 2) [349]. Other Grignard reagents reacted less selectively, giving enantiomeric excesses in the range of 60–75% (entries 3 and 4). The only exception was the iPrMgBr addition (entry 5). It should be pointed out that in the absence of the ligand, exclusively α-substituted products were obtained. A further improvement came by the introduction of the monodentate ligands L68 and (S,S,aR)-L59. Ligand L68 gave similar results as L67 with n-alkyl Grignard reagents (entries 6 and 7) but was superior in case of the addition of i-PrMgBr (entry 8). Similar results were obtained with a range of substituted cinnamyl substrates (entries 9 and 10). L68 gives the opposite enantiomer of the substitution product compared with L67. A further improvement came by the introduction of third-generation phosphoramidite ligand (R,R,R)-L60 (entries 11–13), which is the matched combination of the (R,R)amine and the (R)-BINOL unit [290,298,350]. Comparable results were also obtained with β-disubstituted allylic substrates [351], aliphatic endocyclic allyl chlorides, and


1,4-dihalo-2-butenes [352]. Very recently, Carosi and Hall used L60 and its semisaturated counterpart in the asymmetric alkylation of vinylboronates (entry 14) [353]. The substituted allylboronate obtained was directly coupled (without isolation) with aldehydes giving homoallylic alcohols with almost complete chirality transfer. Feringa et al. reported on excellent selectivities obtained with the bidentate ferrocenyl-based ligand (R,S)-TANIAPHOS (L69) [354]. Several Grignard reagents gave ees >94%, including MeMgBr (entries 15–18) in the reaction with allyl bromides. This catalytic system tolerates also a wide range of functionalities in the allyl substrate, such as allylic ethers (entry 19) and amides as well as vinyl esters (entries 20 and 21) [355]. As an alternative to this widely used phosphine and phosphite ligands, Okamoto et al. introduced chiral carbene complexes such as K8 in the copper-catalyzed allylation reaction [356]. Unfortunately, the selectivities are lower compared with the newest ligands (S,S,aR)-L59, (R,R,R)-L60, and L69, while the (Z)-substrates react more selectively than the (E)-isomers and give rise to the opposite enantiomer (Scheme 8B.98).

n-Hex

N n-HexMgBr O OTBS

TBSO

K8, Et2O, −20°C (Z): (E):

N

N CuCl

b/l 98:2, 70% ee (S) b/l 86:4, 60% ee (R)

K8

Scheme 8B.98. Allylic alkylations using chiral Cu-carbene complexes.

8B.8.2.2.2. Allylic Alkylation of Organozinc Reagents The development of the asymmetric coupling of organozinc reagents proceeded nearly parallel to the reactions with Grignard reagents. Shortly after the first publications by Bäckvall and van Koten on Grignard couplings [346], Dubner and Knochel reported on successful couplings of diorganozinc compounds in the presence of chiral ferrocenyl amines (Fig. 8B.37) [357]. In the presence of ligand L70, excellent γ/α-selectivities were obtained with ees in the range of 63–87%, as long as sterically demanding nucleophiles are used (Table 8B.59, entries 1–3). Temperature also has a strong influence on the selectivity. If the reactions are carried out at room temperature, a dramatic drop in the enantiomeric excess is observed (entry 4). Subsequent ligand screening identified ligand L71 to be more suitable than L70 giving higher ees not only with dineopentylzinc but also other alkylzinc reagents (entries 5–7). Best results were obtained by simultaneous addition of the substrate and the zinc reagent over a period of 3 h [358].

NH2

NH2

Ph O

Fe

Fe

P N

O

Ph O O

Ph L70

L71

L72

P N Ph

L73

Figure 8B.37. Ligands used in the cross-coupling of allylic substrates with organozinc reagents.


619

TABLE 8B.59. Cross-Coupling of Cinnamyl Substrates with Organozinc Reagents

Ar

Entry

X

Ar

R1

R2Zn CuX/L Solvent, T

R

X

CuX

+

Ar

R1

Ar

b

Ligand

l Solvent

T (°C)

Yield (%)

b :l

ee (%)

1

Ph

neoPent

Cl

CuBr L70 SMe2

THF

−90

68

95:5

82

2

4-CF3Ph

neoPent

Cl

CuBr L70 SMe2

THF

−90

72

97:3

87

3

3-Thienyl neoPent Ph neo-

Cl

L70 CuBr SMe2

THF

−90

70

94:6

63

Cl

L70 CuBr SMe2

THF

25

n.d.

n.d.

25

Cl

L71 CuBr SMe2

THF

−30

82

98:2

96

Cl

L71

THF

−30

88

98:2

65

L71

THF

−30

86

98:2

72

(R,R,aS)-L59 Diglyme

−40

65a

84:16

71

(R,R,aS)-L59 Diglyme

−40

70a

84:16

77

4

Pent 5

Ph

6

Ph

neoPent Pent

7

Ph

i-Bu

8

Ph

Bu

9

Ph

Et

CuBr SMe2 Cl CuBr SMe2 Br CuBr SMe2 Br CuBr

SMe2 Br CuOTf L72

THF

−60

n.d.

93:7

86

Br CuOTf

L72

THF

−60

n.d.

97:3

88

Br CuOTf

L73

Diglyme

−30

n.d.

88:12

74

10

Ph

Et

11

Ph

12

4-MePh

i-Pr Et

a

Conv. n.d., not determined.

In 2001, Ferringa et al. investigated the addition of dialkylzinc in the presence of phosphoramidite ligands (R,R,aS)-L59 (Fig. 8B.36) [359]. On screening the reaction conditions, they were able to optimize the diethylzinc addition in highly polar solvents, such as diglyme, up to 77% ee. Similar results were obtained with other alkyl reagents (entries 8 and 9). By switching to CuOTf as another Cu source, the selectivities could also be increased in THF (entries 10 and 11), especially with the partly hydrogenated ligand (L72) [297]. Zhou et al. reported on their results obtained with the spirophosphoramidite L73 in 2003 [360]. The selectivities obtained with this ligand were comparable to those with (R,R,aS)-L59 (entry 12). While most ligand optimizations were carried out with (substituted) cinnamyl halides, Woodward et al. investigated substrates derived from Morita–Baylis–Hillman reactions [361]. First experiments were carried out with binaphthol ligand L74 (Fig. 8B.38), which gave moderate ees with several aryl-substituted substrates (Table 8B.60, entry 1); the


SMe OH

N H

OH R

R

SMe L74

L75a R = H L75b R = OMe

Figure 8B.38. Ligands used in the reaction of Balyis–Hillman-type allylic substrates.

TABLE 8B.60. Addition of ZnEt2 toward Balyis–Hillman-Type Allylic Substrates

COOMe Et Zn 2

Cl Ar Entry

COOMe

CuX/L Solvent, T

Ar

Cu-Cat.

Ligand

1

Ph

[Cu(MeCN)4]BF4

L74

2

4-NO2Ph

[Cu(MeCN)4]BF4

L74

3

Ph

CuI

4

Ph

5

Ph

6 7

Ar Solvent

T (°C)

Yield (%)

ee (%)

THF

−20

35

36 (−)

THF

−40

64

64 (−)

L75a

THF

−20

50

64 (R)

CuI

L75b

THF

−20

70

78 (R)

CuTC/MAO

L75b

Toluene/DME

−40

92

87 (R)

4-MeOPh

CuTC/MAO

L75b

Toluene/DME

−40

80

90 (R)

4-NO2Ph

CuTC/MAO

L75b

Toluene/DME

−40

95

76 (R)

best result was obtained with the p-nitrophenyl derivative (entry 2). As a result of their high throughput ligand screening, Woodward and coworkers found that C2-symmetric chiral amines such as L75a and L75b are good alternatives to the binol ligand (entries 3 and 4). Even with the phenyl-substituted substrate, the enantiomeric excess could be increased to 78% (entry 4), while the free amine gave slightly better results than the hydrochloride. Detailed kinetic studies revealed that the enantioselectivity of the reaction decreased with the reaction time, especially when the ligands were used as HCl salt [199]. This clearly indicates that EtZnCl, whose concentration increases during the reaction, might be responsible for an unselective background reaction. This assumption could be confirmed by deliberate addition of EtZnCl, which led to a significant collapse in the selectivity (30% ee). Similar observations have been made earlier by Dubner and Knochel [357]. Therefore, removal of the EtZnCl formed should result in an increase of selectivity. This resulted in the idea to exploit the zinc Schlenk equilibrium with the help of methylaluminoxane (MAO). Indeed, in the presence of MAO, the selectivity could be further increased, giving ees up to 97% in the presence of CuTC as catalyst (entries 5–7). A completely different type of ligands was introduced by Hoveyda et al. in 2001 [362]. They used peptide-based Schiff bases as ligands (L76, L77; Fig. 8B.39) in the reaction


RL

H N

N N

O

RL

O N

NHBu

O

H N

NHBu

O R OH L77a RL = CH2c-Hex, R = n-Bu b RL = CH2CO2t-Bu, R = CH2i-Pr

Ph

L76a RL = c-Hex b RL = t-Bu

Oi-Pr

621

Figure 8B.39. Peptide-based ligands used in allylic alkylations.

TABLE 8B.61. Reaction of Allyl Phosphates in the Presence of Peptide-Based Ligands

R1

R12 Zn R

Entry

OPO(OEt)2

R1

R

Ligand

R γ

Cu-Cat./L THF, T RL

CuX

T (°C)

Yield (%)

ee (%)

1

Ph

Et

L76a

c-Hex

CuCN

−78

34

66

2

4-NO2Ph

Et

L76a

c-Hex

CuCN

−78

73

75

3

2-NO2Ph

Et

L76b

t-Bu

CuCN

−78

85

87

4

CO2t-Bu

Me

L77a

–CH2c-Hex

Cu(OTf)2

−50

80

90

5

CO2t-Bu

Et

L77a

–CH2c-Hex

Cu(OTf)2

−50

68

97

6

AcO(CH2)4

L77a

–CH2c-Hex

Cu(OTf)2

−50

85

95

7

CO2t-Bu Ph

Et

L77b

−15

61

95

8

2-NO2Ph

Et

L77b

CH2CO2t-Bu Cu(OTf)2 CH2CO2t-Bu Cu(OTf)2

−15

95

95

9

4-CF3Ph

AcO(CH2)4

L77b

−15

62

84

Ph

Et

L78

CH2CO2t-Bu Cu(OTf)2 — Cu(OTf)2

−78

93

40

10

of allyl phosphates with several dialkylzinc species (Table 8B.61). These ligands were found by an intense combinatorial ligand screening and gave good results with (substituted) cinnamyl phosphates. As reported previously by Dubner and Knochel [357], electron-withdrawing groups at the aromatic ring increased the yield and enantiomeric excess, while the ligand with the sterically demanding t-butyl side chain gave the best results (Table 8B.61, entries 1–3). Fortunately, this protocol is not limited to simple cinnamyl substrates and Et2Zn additions, but can also be applied to other zinc reagents and higher substituted allyl phosphates. This allows the stereoselective synthesis of quaternary stereogenic centers, as nicely illustrated in the total synthesis of sporochnol (Scheme 8B.99). By replacing the pyridine ring by a phenol or a naphthol ring system, the substrate spectrum could be enlarged also to α,β-unsaturated esters [363]. Especially good regioselectivities were obtained with t-butyl esters (γ/α > 20:1) and the enantiomeric excesses were always ≤90% (entries 4–6). In principle, this ligand type could also be applied to cinnamyl substrates if a t-butyl glutamate is incorporated into the ligand (L77b) [364].


OPO(OEt)2

Zn

1)

2

CuCN (10 mol %)/L76a, THF, −78°C, 48 h 2) KOH, EtOH, 80°C

TsO

82% ee (82%)

TsO

Sporochnol

Scheme 8B.99. Synthesis of sporochnol.

n-Hept

OPO(OEt)2

Ph

92% ee (73%)

OPO(OEt)2 92% ee (74%) N

Pent

Pent OPO(OEt)2

OH

OPO(OEt)2

CO2tBu O H N

NHBu

O L77b

91% ee (77%)

96% ee (76%)

Figure 8B.40. Substrates used in Et2Zn additions in the presence of ligand L77b.

O N H PPh2

O O S N H L78

Cl

N OH Cl

O O S N H L79

Figure 8B.41. Sulfonamide ligands used in Cu-catalyzed allylic alkylations.

Unfortunately, with this ligand, the γ,α-selectivity dropped, in some cases to a 1:1 mixture. But in most cases, the selectivities were satisfying (Fig. 8B.40). As the result of their excessive ligand screening, Hoveyda et al. were able to propose a mechanistic rational explaining the stereochemical outcome of the reaction (Scheme 8B.100). Complex A with a pseudotetrahedral Cu(I) represents the resting state of the chiral complex. Addition of the allylic substrates probably generates complex B where the allylic double bond is coordinated to the copper ion. The larger substituent Rl at the double bond is orientated away from the peptide backbone and the terminal amide functionality directs the allylphosphate via a zinc complex to one face of the ligand Cu complex. Finally, the catalytic alkylation probably proceeds through the formation of a CuIII-alkyl intermediate, followed by reductive elimination toward the desired product. In 2002, Piarulli, Gennari, and others described the use of structurally related sulfonamide ligands L78 (Fig. 8B.41) in the Et2Zn addition toward cinnamyl phosphates [365], giving 40% ee as the best selectivity (Table 8B.62, entry 10).


EtO

O

R

NH N O Cu O H alkyl AlkylZn

O

Rs NHn-Bu

Rl

R OPO(OEt)2

s

OEt P

O

LnZn H

Rl

R

N O Cu AlkylZn

A

623

O NH

O

NHn-Bu

H

alkyl B

Scheme 8B.100. Proposed mechanism for the copper-catalyzed allylic alkylation with peptide ligands.

TABLE 8B.62. Desymmetrization of meso-Substrates

(EtO)2OPO

OPO(OEt)2 R2Zn

n

Entry

n

R

Ligand

T (°C)

OPO(OEt)2

n

CuOTf/L, Toluene, THF, T

R

Yield (%)

ee (%)

Config.

1

1

Me

L79

−78

40

94

(S,S)

2

1

Et

L79

−78

88

88

(S,S)

−78 0

60

68

(S,R)

54

87

(R,R)

3

1

Ph

L79

4

1

Me

(R,R,aS)-L59

5

1

Et

(R,R,aS)-L59

−40

98

87

(R,R)

6

2

Et

(R,R,aS)-L59

−40

77

90

(R,R)

7

3

Et

(R,R,aS)-L59

−40

85

98

(R,R)

By combining the sulfonamide subunit with salicylaldimines such as in L79, they found an excellent ligand for regioselective (γ/α 99:1) desymmetrizations of cyclic mesocompounds [366]. Best results were obtained from the cyclopentenyl substrate (n = 0) with Me2Zn (94% ee), while the corresponding ethyl and phenyl reagents showed a lower selectivity (Table 8B.62, entries 1–3). Reaction of Et2Zn with the corresponding cyclohexenyl substrate (n = 1) gave SN2′ products from either inversion or retention, depending on the solvent and ligand used. The problem with the larger ring substrates could be solved by using Feringa’s phosphoramidite ligand (S,S,aR)-L59 (Fig. 8B.36) [367]. The enantiomer of this ligand (R,R,aS)-L59 gave excellent enantiomeric excess with various ring sizes and dialkylzinc reagents (entries 4–7). Interestingly, herewith also the cyclohexenyl substrate gave a mixture of the inversion and the retention product, while with the five- and six-membered ring, only inversion was observed. In parallel to these peptide-based ligands, Hoveyda et al. developed bidentate diaminocarbene-based ligands (NHC) such as L80 (Fig. 8B.42) as efficient chiral promoters for acyclic alkylations [368]. This ligand was found to be superior to the peptide-based ligand. The catalyst loading could be reduced to 2 mol % and the catalyst was suitable also for the generation of quaternary stereogenic centers. Best results were obtained by


Ph

Ph

Ph N

Ph

N

Ph

N+

Mes

Mes

Cl−

Cl− HO

N

Ph

N+

N+

Mes

HO L81

L80

SO3H Cl− L82

Figure 8B.42. Chiral carbene ligands used in allylic alkylations.

TABLE 8B.63. Allylic Alkylations Using Chiral Carbene Complexes

R1 R2

R1 R

R2Zn OPO(OEt)2

CuX/L THF, –15°C

R2 γ

R

R1

R2

CuX

Ligand

Yield (%)

ee (%)

1 2 3 4 5

Me Et Et Et Et

H H Me H H

Ph Ph Ph 1-Naphth

CuCl2 CuCl2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2

(Ag-L80)2 (Ag-L80)2 (Ag-L80)2 (Ag-L80)2 (Ag-L80)2

58 68 88 80 53

71 86 91 89 94

6 7 8

Et Et

H Me H

Cu(OTf)2 Cu(OTf)2 Cu(OTf)2

(Ag-L80)2 (Ag-L80)2 (Ag-L80)2

72 75 75

98 91 96

Cu(OTf)2 CuCl2 CuCl2 CuCl2

(Ag-L80)2 (Ag-L81)2 (Ag-L81)2 (Ag-L81)2

91 68 80 80

92 90 90 95

CuCl2 CuCl2

(Ag-L81)2 (Ag-L81)2

84 76

97 97

Entry

9 10 11 12

i-Pr Ph Me Et Et

13 14

Et Et

H H H H Me Me

c-Hex PhMe2Si PhMe2Si PhMe2Si PhMe2Si Ph Ph c-Hex Ph c-Hex

a dimeric Ag complex [(Ag-L80)2], which on addition of copper salts effectively generated the catalytically active copper-carbene complex (Table 8B.63, entries 1–5). This protocol is also suitable for the highly stereoselective addition of various zinc reagents toward silylated allylic substrates (entries 6–9), giving easy access to chiral allyl silanes [369]. The results could be further improved by using the new ligand L81, respectively its dimeric silver complex (Ag-L81)2 [370]. This NHC ligand bears a chiral diamine backbone and an achiral biphenol group. Upon coordination to the metal (Ag or Cu), the diamine subunit controls the coordination mode of the biphenol such that the complex is formed as a single atropisomer. Because the ligand does not require optically pure biaryl amino alcohol, its synthesis is much easier compared with the binaphthol ligand


625

L80. In addition, the selectivities obtained with this ligand were further improved (entries 10–14). 8B.8.2.2.3. Allylic Alkylations of Alkylaluminium Reagents Recently, this copper– carbene-catalyzed allylation was used in the synthesis of baconipyrone C [371]. Key step herein was a double asymmetric allylic alkylation using a C2-symmetric substrate. Initial experiments were carried out with Me2Zn and a racemic allyl phosphate to prove if the allylation is solely controlled by the chiral ligand, or if kinetic resolution of the racemic substrate occurs, but no reaction was observed with the Ag complexes of L80 and L81 (Table 8B.64, entries 1 and 2). Therefore, Hoveyda et al. switched to the more Lewis acidic and nucleophilic Me3Al. Interestingly, with the Ag-L80-dimer, a strong kinetic resolution was observed, and the anti-product was formed nearly exclusively with excellent ee in 45% yield (maximum 50%). The ligand L81 proved to be less effective. For an application in the investigated synthesis, this kinetic resolution is not required, or even detrimental. This caused a search for other ligands giving the required product solely under ligand-controlled conditions. Best results were obtained with the chiral NHC-sulfonate complex (Ag-L82)2 (entry 5) [372]. With this catalyst in hand, the C2-symmetric diallylphosphate was subjected to the same reaction conditions (Scheme 8B.101), giving rise to the methylated product with excellent enantiomeric excess.

TABLE 8B.64. Asymmetric Allylic Alkylation of Methylzinc and Aluminium Reagents OBn OPO(OEt)2

OBn

OBn

RnM

+

CuCl2 •2H2O (15. mol %), L, THF, –15°C, 24 h anti

Entry 1 2 3 4 5

syn

RnM

Ligand

Conversion (%)

anti : syn

ee (%)

Me2Zn Me2Zn Me3Al Me3Al Me3Al

(Ag-L80)2 (Ag-L81)2 (Ag-L80)2 (Ag-L81)2 (Ag-L82)2

— — 45 15 95

20:1 9:1 1.5:1

98 n.d. 89


OR (EtO)2OPO

OPO(OEt)2

Me3Al (4 equiv) CuCl2 2 H2O (15 mol %), (Ag-L82)2 (7.5 mol %), THF, −15°C, 16 h

OR

>98% ee (61%)

Scheme 8B.101. Stereoselective allylic alkylation of meso-diallyl substrates.


TABLE 8B.65. Cu-Catalyzed Allylic Alkylations of Vinylaluminium Reagents

R1 R

OPO(OEt)2

Entry

R

R1 Ali-Bu2

1 mol % CuCl2 •2 H2O 0.5 mol % (Ag-L82)2 THF, −15°C, 2–6 h R1

R

Yield (%)

ee (%)

1

Ph

n-Hex

84

92

2

2-NO2Ph

n-Hex

94

96

3

1-Naphth

n-Hex

88

91

4

Ph

91

91

5 6

Ph Ph

c-Hex 3-Cl-Pr

86 90

92 89

4-t-BuO-Bu

Very recently, Hoveyda et al. used the same ligand system also for the allylation of vinylaluminum reagents [373], easily obtained by hydroalumination of alkynes. The SN2′ product was formed nearly exclusively with a wide range of substrates in high yield and enantioselectivity (Table 8B.65). 8B.8.2.2.4. Kinetic Resolutions of Vinyl Epoxides Vinyl epoxides are excellent substrates for transition metal-catalyzed allylic alkylations. Most reactions were carried out under Pd catalysis [374], but chiral organocopper reagents can also be used for the regioselective ring opening of these allylic substrates. If racemic epoxides are reacted with 0.5 equiv of the copper reagent, kinetic resolution can occur. Pineschi, Feringa, and others were the first reporting on such kinetic epoxide openings with dialkyl zinc in the presence of chiral binaphthol-based phosphorus amidate (R,R,aS)-L59 [375]. The corresponding allylic alcohols were obtained with moderate to high regioselectivities. Both pathways, the direct SN2 (α-product) and the conjugate opening SN2′ addition (γ-product), seem to proceed with complete anti-selectivity. While the enantiomeric excess with the five-membered-ring substrate was moderate (Table 8B.12, entries 1 and 2), high selectivities were obtained with the larger six- and seven-membered substrates (entries 3–5). Equey and Alexakis performed the same experiments with commercially available Me3Al and ligand (S,S,aS)-L59 [376]. Comparable enantiomeric excesses were observed (entries 6 and 7), but the regioselectivities were lower compared with the experiments with the analogue zinc reagent (except for the six-membered ring). Best results were obtained with the ferrocene-based ligands (R,pS)-L40c/L40d (Fig. 8B.43) [377]. They allowed the highly selective addition of a wide range of Grignard reagents to the cyclohexenyl substrate (entries 8–12) (Table 8B.66). 8B.8.2.2.5. Desymmetrization of meso-Substrates Based on their good results obtained in the ring opening of vinyl epoxides, Pineschi et al. also investigated the ring opening of meso-epoxides such as the cyclooctatetraene monoepoxide (Scheme 8B.102), which


Ph

O O

O

P N

O

Ph

(R,R,aS)-L59

Ph

627

PR2

P N

Fe PPh2

Ph

(S,S,aS)-L59

(R,pS)-L40

c R = 3,5 Me2Ph d R = 3,5 Me2-4-MeOPh

Figure 8B.43. Chiral ligands used in the kinetic ring opening of epoxides.

TABLE 8B.66. Enantioselective Cu-Catalyzed Ring Opening of Vinyl Epoxides

R

α

O RmM n

Entry

n

RmM

γ

CuX/L, Solvent, T

R

OH

+

n

OH

n

CuX

Ligand

Solvent

T (°C)

Yield (%)a

γ :α

ee (%)b

1

1

Me2Zn

Cu(OTf)2

(R,R,aS)-L59

Toluene

−70

12

3:1

50

2

1

Et2Zn

Cu(OTf)2

(R,R,aS)-L59

Toluene

−70

8

12:1

54

3

2

Me2Zn

Cu(OTf)2

(R,R,aS)-L59

Toluene

−70

33

13:1

92

4

2

Et2Zn

Cu(OTf)2

(R,R,aS)-L59

Toluene

−70

32

59:1

91

5

3

Me2Zn

Cu(OTf)2

(R,R,aS)-L59

Toluene

−70

38

16:1

96

6

1

Me3Al

CuTC

(S,S,aS)-L59

THF

−40

10

1.54:1

87

7

2

Me3Al

CuTC

(S,S,aS)-L59

THF

−40

44

16:1

82

8

2

EtMgCl

CuBr

(R,pS)-L40c

Et2O

−78

40

99:1

84

9

2

n-BuMgCl

CuBr

(R,pS)-L40c

Et2O

−78

35

99:1

90

10

2

i-PrMgCl

CuBr

(R,pS)-L40c

Et2O

−78

n.d.

90:10

61

11

2

i-PrMgCl

CuBr

(R,pS)-L40d

Et2O

−78

36

99:1

74

12

2

c-HexMgCl CuBr

(R,pS)-L40d

Et2O

−78

33

95:5

64

a

Maximum yield: 50%. ee of the major γ-product. n.d., not determined. b

O

Et2Zn

OH

Cu(OTf)2 / (R,R,aR)-L59, 0°C Toluene, −78°C 94% ee (>95% conv.)

Scheme 8B.102. Stereoselective ring opening of meso-epoxides.


could be alkylated in the presence of ligand (R,R,aR)-L59 with excellent regio- (99%, SN2′) and enantioselectivity [378]. In principle, similar substitutions can also be carried out with other meso-substrates like oxanorbornadiene derivatives (Scheme 8B.103) [379]. Although this reactions are rather slow, they occur in a clean SN2′ fashion giving high ees especially with ligand (S,S,aR)-L59 (or its enantiomer (R,R,aS)-L59). Slightly faster reactions are observed if Grignard reagents are used instead of dialkyl zinc reagents [380].

OH Et2Zn

O

Cu(OTf)2 / (R,R,aS)-L59, Zn(OTf)2, toluene, rt

R

R

R=H 90% ee (98% anti) R = 6,7-F2 80% ee (83% anti) R = 5,8-Me2 99% ee (99% anti) Scheme 8B.103. Stereoselective Cu-catalyzed ring opening of oxanorbornadienes.

Another class of substrates used recently for asymmetric allylations are polycyclic hydrazines. With an excess of Me3Al ees up to 86% could be obtained in the presence of ligand (R,R,aR)-L59 (Table 8B.67) [381]. Interestingly, the “mismatched” ligand (S,S,aR)-L59 gave the opposite enantiomer of the coupling product with comparable selectivity. Probably, the Me3Al is able to react with the ligand replacing the naphthol

TABLE 8B.67. Desymmetrization of Polycyclic Hydrazines

N

R1

O Entry

R

O

O

N

R1

4 AlR3 Cu(OTf)2 /L, CH2Cl2, 0°C

R1

N N R

O

Ligand

Yield (%)

ee (%)

1

Me

NPh

(R,R,aR)-L59

98a

80 (+)

2

Et

NPh

(R,R,aR)-L59

98a

66 (+)

3

Me

1,2-C6H4

(R,R,aR)-L59

98a

86 (+)

4

Me

1,2-C6H4

(S,S,aR)-L59

98a

5

1,2-C6H4 NPh

(R,R,aR)-L59 L83a

98a 78

64 (−) 54 (+)

6

i-Pr Me

7

Me

NPh

L83b

81

94 (−)

8

Me

1,2-C6H4

L83b

90

89 (−)

9

Me

1,2-C6H4

L83b

85

86 (−)

a

Conversion.

90 (−)

NOTES AND REFERENCES 629

Ar Ph P N Ph Ar SimplePhos

a Ar = Ph b Ar = 2-Naph

L83 Figure 8B.44. SimplePhos ligands.

unit by two methyl groups, giving rise to a phosphinamine as active catalyst [382]. Based on this assumption, Alexakis et al. introduced a new generation of phosphinamine ligands L83, called simplePhos (Fig. 8B.44), which are superior to the previous ligands because it is untouched by Me3Al [383].

NOTES AND REFERENCES 1. Smidt, J.; Hafner, W. Angew. Chem. 1959, 71, 284. 2. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387–4388. 3. Hata, G.; Takahashi, K.; Miyake, A. J. Chem. Soc. Chem. Commun. 1970, 1392–1393. 4. Atkins, K. E.; Walker, W. E.; Manyik, R. M. Tetrahedron Lett. 1970, 11, 3821–3824. 5. Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292–294. 6. Trost, B. M.; Dietsche, T. J. J. Am. Chem. Soc. 1973, 95, 8200. 7. Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977, 99, 1649–1651. 8. Review: Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron Asymmetry 1992, 3, 1089–1122. 9. Review: Lübbers, T.; Metz, P. In Houben-Weyl E21, Stereoselective Synthesis (Eds. Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.). Stuttgart: Thieme, 1995; pp. 2371–2473 and 5643–5676. 10. Review: Acemoglu, L.; Williams, J. M. J. In Handbook of Organopalladium Chemistry for Organic Synthesis (Eds. Negishi, E.; De Meijere, A.). New York: Wiley, 2002; Vol. 2, pp. 1945–1980. 11. Review: Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422. 12. Review: Hayashi, T. In Catalytic Asymmetric Synthesis (Ed. Ojima, I.). Weinheim: VCH, 1993; pp. 325–365. 13. Review: Kazmaier, U.; Pohlmann, M. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds. De Meijere, A.; Diederich, F.). Weinheim: Wiley-VCH, 2004; Vol. 2, pp. 833–884. 14. Review: Trost, B. M.; Lee, C. B. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). Weinheim: Wiley-VCH, 2000; pp. 593–649. 15. Review: Lu, Z.; Ma, N. Angew. Chem. Int. Ed. Engl. 2008, 47, 258–297. 16. Review: Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catalysis (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Heidelberg: Springer, 1999; Chapter 24. 17. Review: Consiglio, G.; Waymouth, R. M. Chem. Rev. 1989, 89, 257. 18. (a) Hintermann, L.; Lang, F.; Maire, P.; Togni, A. Eur. J. Inorg. Chem. 2006, 1397–1412 and literature cited therein. (b) Fagnou, K.; Lautens, M. Angew. Chem. Int. Ed. Engl. 2002, 41, 26–47. 19. Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org. Chem. 2002, 67, 1768–1775. 20. Vicart, N.; Goré, J.; Cazes, B. Tetrahedron 1998, 54, 11063–11078. 21. (a) Godleski, S. A.; Villhauer, E. B. J. Org. Chem. 1984, 49, 2246–2252. (b) Yamamoto, Y.; Al-Masum, M.; Takeda, A. Chem. Commun. 1996, 831–832.

630 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES 22. (a) Romero, D. L.; Fritzen, E. L. Tetrahedron Lett. 1997, 38, 8659. (b) Tsuji, J.; Yuhara, M.; Minato, M.; Yamada, H.; Sato, F.; Kobayashi, Y. Tetrahedron Lett. 1988, 29, 343–346. (c) Sakaguchi, K.; Yamada, T.; Ohfune, Y. Tetrahedron Lett. 2005, 46, 5009–5012. 23. Prat, M.; Ribas, J.; Moreno-Manas, M. Tetrahedron 1992, 48, 1695–1706. 24. Tsuji, J. In Handbook of Organopalladium Chemistry for Organic Synthesis (Eds. Negishi, E.; De Meijere, A.). New York: Wiley, 2002; Vol. 2, pp. 1678–1679. 25. (a) Krafft, M. E.; Sugiura, M.; Abboud, K. A. J. Am. Chem. Soc. 2001, 123, 9174–9175. (b) Krafft, M. E.; Wilson, A. M.; Fu, Z.; Procter, M. J.; Dasse, O. A. J. Org. Chem. 1998, 63, 1748–1749. 26. Sjögren, M. P. T.; Hansson, S.; Åkermark, B.; Vitagliano, A. Organometallics 1994, 13, 1693–1671. 27. Kazmaier, U.; Stolz, D.; Krämer, K.; Zumpe, F. L. Chem. Eur. J. 2008, 14, 1322–1329. 28. Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem. Int. Ed. Engl. 2007, 46, 7259–7261. 29. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143–1145. 30. Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984, 25, 5157–5160. 31. Plietker, B. Angew. Chem. Int. Ed. Engl. 2006, 45, 1469–1473. 32. Minami, I.; Ohashi, Y.; Shimizu, I.; Tsuji, J. Tetrahedron Lett. 1985, 26, 2449–2452. 33. Trost, B. M.; Vercauteren, J. Tetrahedron Lett. 1985, 26, 131–134. 34. Trost, B. M.; Lee, C. B.; Weiss, J. M. J. Am. Chem. Soc. 1995, 117, 7247–7248. 35. (a) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327–9343. (b) Trost, B. M.; Van Vranken, D. L. Angew. Chem. Int. Ed. Engl. 1992, 31, 228–230. 36. Trost, B. M.; Pan, Z.; Zambrano, J.; Kujat, C. Angew. Chem. Int. Ed. Engl. 2002, 41, 4691–4693. 37. Song, C. E.; Jang, J. W.; Roh, E. J.; Lee, S.-G.; Ahn, J. H.; Han, H. Angew. Chem. Int. Ed. Engl. 2002, 41, 3852–3854. 38. Review: Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59–72. 39. Review: Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747–760. 40. (a) Fairlamb, I. J. S.; Lloyd-Jones, G. C. Chem. Commun. 2000, 2447–2448. (b) Lloyd-Jones, G. C.; Stephen, S. C.; Fairlamb, I. J. S.; Martorell, A.; Dominguez, B.; Tomlin, P. M.; Murray, M.; Fernandez, J. M.; Jeffery, J. C.; Riis-Johannessen, T.; Guerziz, T. Pure Appl. Chem. 2004, 76, 589–601. 41. Pfaltz, A. Acc. Chem. Res. 1993, 26, 339–345. 42. Trost, B. M.; Tanimori, S.; Dunn, P. T. J. Am. Chem. Soc. 1997, 119, 2735–2736. 43. Trost, B. M.; Richardson, J.; Yong, K. J. Am. Chem. Soc. 2006, 128, 2540–2541. 44. Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michale, F. E.; Gagne, M. R. J. Am. Chem. Soc. 2000, 122, 7905–7920. 45. Trost, B. M.; Surivet, J.-P. Angew. Chem. Int. Ed. Engl. 2000, 112, 3252–3254; Angew. Chem. Int. Ed. Engl. 2000, 39, 3122–3124. 46. Uozumi, Y.; Takenaka, H.; Suzuka, T. Synlett 2008, 1557–1561. 47. Review: Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. 48. Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114, 8745–8747. 49. Chapsal, B. D.; Ojima, I. Org. Lett. 2006, 8, 1395–1398. 50. Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016–2021. 51. Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3671–3686. 52. Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3687–3696. 53. Trost, B. M.; Ariza, X. Angew. Chem. Int. Ed. Engl. 1997, 36, 2635–2637. 54. Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 12191–12201. 55. (a) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A. Tetrahedron 1992, 48, 2143. (b) Von Matt, P.; Lloyd-Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.; Rüegger, H.; Pregosin, P. S. Helv. Chim. Acta 1995, 78, 265–284.


56. Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J. Am. Chem. Soc. 1989, 111, 6301–6311. 57. Cesarotti, E.; Demartin, F.; Grassi, M.; Prati, L. J. Chem. Soc. Dalton Trans. 1991, 2073–2082. 58. Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772. 59. von Matt, P.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1993, 32, 566–567. 60. (a) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993, 34, 3149–3150. (b) Coote, S. J.; Dawson, G. J.; Frost, C. G.; Williams, J. M. J. Synlett 1993, 509–510. 61. (a) Brown, J. M.; Hulmes, D. I.; Guiry, P. I. Tetrahedron 1994, 50, 4493. (b) Togni, A.; Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am. Chem. Soc. 1996, 118, 1031. 62. This nomenclature refers to the disposition of the terminal H relative to the central H. 63. (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089–4090. (b) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520–6521. (c) Trost, B. M. Acc. Chem. Res. 1996, 29, 355–364. 64. Trost, B. M.; Bunt, R. C. Angew. Chem. Int. Ed. Engl. 1996, 35, 99–102. 65. Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J. W. Angew. Chem. Int. Ed. Engl. 1995, 34, 2386–2388. 66. (a) Saitoh, A.; Misawa, M.; Morimoto, T. Tetrahedron Asymmetry 1999, 10, 1025–1028. (b) Saitoh, A.; Uda, T.; Morimoto, T. Tetrahedron Asymmetry 1999, 10, 4501–4511. 67. Hamada, Y.; Matsuura, F.; Oku, M.; Hatano, K.; Shioiri, T. Tetrahedron Lett. 1997, 38, 8961–8964. 68. (a) Dierkes, P.; Ramdeehul, S.; Barloy, L.; De Cian, A.; Fischer, J.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M.; Osborn, J. A. Angew. Chem. Int. Ed. Engl. 1998, 37, 3116–3118. (b) Ramdeehul, S.; Dierkes, P.; Aguado, R.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M.; Osborn, J. A. J. Chem. Soc. Chem. Commun. Int. Ed. Engl. 1998, 37, 3118–3121. 69. Malaisé, G.; Ramdeehul, S.; Osborn, J. A.; Barloy, L.; Kyritsakas, N.; Graff, R. Eur. J. Inorg. Chem. 2004, 3987–4001. 70. Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M. Tetrahedron Asymmetry 1997, 8, 3185–3188. 71. (a) Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron Lett. 1996, 37, 7994–7998. (b) Zhang, W.; Shimanuki, T.; Kida, T.; Nakatsuji, Y.; Ikeda, I. J. Org. Chem. 1999, 64, 6247–6251. 72. (a) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. J. Chem. Soc. 1994, 1417–1418. (b) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. Tetrahedron Asymmetry 1995, 6, 1109–1116. 73. Kang, J.; Cho, W. O.; Cho, H. G. Tetrahedron Asymmetry 1994, 5, 1347–1352. 74. Albano, V. G.; Bandini, M.; Melucci, M.; Monari, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A. Adv. Synth. Catal. 2005, 347, 1507–1512. 75. Albano, V. G.; Bandini, M.; Barbarella, G.; Melucci, M.; Monari, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A. Chem. Eur. J. 2006, 12, 667–675. 76. Bandini, M.; Benaglia, M.; Quinto, T.; Tommasi, S.; Umani-Ronchi, A. Adv. Synth. Catal. 2006, 348, 1521–1527. 77. Foltz, C.; Enders, M.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem. Eur. J. 2007, 13, 5994–6008. 78. Dieguez, M.; Jansat, S.; Gomez, M.; Ruiz, A.; Muller, G.; Claver, C. Chem. Comm. 2001, 1132–1133. 79. Pamies, O.; van Strijdonck, G. P. F.; Dieguez, M.; Deerenberg, S.; Net, G.; Ruiz, A.; Claver, C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. J. Org. Chem. 2001, 66, 8867–8871. 80. Dieguez, M.; Pamies, O.; Claver, C. Adv. Synth. Catal. 2005, 347, 1257–1266. 81. Dieguez, M.; Pamies, O.; Claver, C. J. Org. Chem. 2005, 70, 3363–3368. 82. Raluy, E.; Claver, C.; Pamies, O.; Dieguez, M. Org. Lett. 2007, 9, 49–52. 83. Pamies, O.; Dieguez, M. Chem. Eur. J. 2008, 14, 944–960. 84. Raluy, E.; Dieguez, M.; Pamies, O. J. Org. Chem. 2007, 72, 2842–2850.

632 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES 85. Greenfield, S. J.; Agarkov, A.; Gilbertson, S. R. Org. Lett. 2003, 5, 3069–3072. 86. Gilbertson, S. R.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc. 2000, 122, 6522–6523. 87. Agarkov, A.; Greenfield, S. J.; Ohishi, T.; Collibee, S. E.; Gilbertson, S. R. J. Org. Chem. 2004, 69, 8077–8085. 88. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345. 89. (a) Kollmar, M.; Goldfuss, B.; Reggelin, M.; Rominger, F.; Helmchen, G. Chem. Eur. J. 2001, 7, 4913–4927. (b) Kollmar, M.; Steinhagen, H.; Janssen, J. P.; Goldfuss, B.; Malinovskaya, S. A.; Vazquez, J.; Rominger, F.; Helmchen, G. Chem. Eur. J. 2002, 8, 3103–3114. (c) Zehnder, M.; Schaffner, S.; Neuburger, M.; Plattner, D. A. Inorg. Chim. Acta 2002, 337, 287–298. (d) Schaffner, S.; Mueller, J. F. K.; Neuburger, M.; Zehnder, M. Helv. Chim. Acta 1998, 81, 1223–1232. 90. Wiese, B.; Helmchen, G. Tetrahedron Lett. 1998, 39, 5727–5730. 91. Kudis, S.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 1998, 37, 3047–3050. 92. Masui, D.; Ohnuki, M.; Yamaguchi, M.; Yamagishi, T. Acta Crystallogr. 2003, C59(11), m487–m490. 93. Gilbertson, S. R.; Xie, D. Angew. Chem. Int. Ed. Engl. 1999, 38, 2750–2752. 94. Yamagishi, T.; Ohnuki, M.; Kiyooka, T.; Masui, D.; Sato, K.; Yamaguchi, M. Tetrahedron Asymmetry 2003, 14, 3275–3279. 95. Pretot, R.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1998, 37, 323–325. 96. Pamies, O.; Dieguez, M.; Claver, C. J. Am. Chem. Soc. 2005, 127, 3646–3647. 97. Mata, Y.; Dieguez, M.; Pamies, O.; Claver, C. Adv. Synth. Catal. 2005, 347, 1943–1947. 98. Clark, T. P.; Landis, C. R. J. Am. Chem. Soc. 2003, 125, 11792–11793. 99. Schleich, S.; Helmchen, G. Eur. J. Org. Chem. 1999, 2515–2521. 100. Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919–2920. 101. Hamada, Y.; Sakaguchi, K.; Hatano, K.; Hara, O. Tetrahedron Lett. 2001, 42, 1297–1299. 102. Jin, L.; Nemoto, T.; Nakamura, H.; Hamada, Y. Tetrahedron Asymmetry 2008, 19, 1106–1113. 103. Trost, B. M.; Patterson, D. E.; Hembre, E. J. J. Am. Chem. Soc. 1999, 121, 10834–10835. 104. Trost, B. M.; Patterson, D. E.; Hembre, E. J. Chem. Eur. J. 2001, 7, 3768–3775. 105. Yamamoto, K.; Tsuji, J. Tetrahedron Lett. 1982, 23, 3089–3092. 106. Koch, G.; Pfaltz, A. Tetrahedron Asymmetry 1996, 7, 2213–2216. 107. Goldfuss, B.; Kazmaier, U. Tetrahedron 2000, 56, 6493–6496. 108. Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814–1816. 109. Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997, 561–562. 110. Hayashi, T. Acc. Chem. Res. 2000, 33, 354–362. 111. You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471–7472. 112. Review: Hou, X. L.; You, S. L.; Tu, T.; Deng, W. P.; Wu, X. W.; Li, M.; Yuan, K.; Zhang, T. Z.; Dai, L. X. Top. Catal. 2005, 35, 87–103. 113. Zheng, W.-H.; Sun, N.; Hou, X.-L. Org. Lett. 2005, 7, 5151–5154. 114. Private communication of Prof. Hou to G. H. 115. Hou, X.-L.; Sun, N. Org. Lett. 2004, 6, 4399–4401. 116. Trost, B. M.; Jäkel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438–4439. 117. Trost, B. M.; Simas, A. B. C.; Plietker, B.; Jäkel, C.; Xie, J. Chem. Eur. J. 2005, 11, 7075–7082. 118. Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2033–2046. 119. Togni, A. Tetrahedron Asymmetry 1991, 2, 683–690. 120. (a) Review: Williams, J. M. J. Synlett 1996, 705–710. (b) Dawson, G. J.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1995, 36, 461–462. (c) Martin, C. J.; Rawson, D. J.; Williams, J. M. J. Tetrahedron Asymmetry 1998, 9, 3723–3730.


121. Sudo, A.; Saigo, K. J. Org. Chem. 1997, 62, 5508. 122. Evans, P. A.; Brandt, T. A. Org. Lett. 1999, 1, 1563–1565. 123. Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001, 123, 12907–12908. 124. Trost, B. M.; Jiang, C. Org. Lett. 2003, 5, 1563–1565. 125. Fiaud, J. C.; Degournay, A. H.; Larcheveque, M.; Kagan, H. B. J. Organomet. Chem. 1978, 154, 175–185. 126. Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879–7880. 127. Brunel, J. M.; Tenaglia, A.; Buono, G. Tetrahedron Asymmetry 2000, 11, 3585–3590. 128. Kuwano, R.; Uchida, K.; Ito, Y. Org. Lett. 2003, 5, 2177–2179. 129. Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.; Hatano, K.; Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690–3691. 130. Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org. Chem. 1996, 61, 9090–9096. 131. Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309–3310. 132. Nowicki, A.; Mortreux, A.; Agbossou-Niedercorn, F. Tetrahedron Asymmetry 2005, 16, 1295–1298. 133. Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727–10737. 134. Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1, 837–839. 135. Ogasawara, M.; Ngo, H. L.; Sakamoto, T.; Takahashi, T.; Lin, W. Org. Lett. 2005, 7, 2881–2884. 136. Darcel, C.; Kaloun, E. B.; Merdes, R.; Moulin, D.; Riegel, N.; Thorimbert, S.; Genet, J. P.; Juge, S. J. Organomet. Chem. 2001, 624, 333–343 and earlier work cited. 137. You, S.-L.; Hou, X.-L.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem. Commun. 2000, 1933–1934. 138. Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Asymmetry 2001, 12, 1567–1571. 139. Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 3329–3332. 140. Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem. 2002, 67, 7418–7423. 141. Brunner, H.; Deml, I.; Dirnberger, W.; Nuber, B.; Reißer, W. Eur. J. Inorg. Chem. 1998, 1, 43–54. 142. Trost, B. M.; Schroeder, G. M. J. Org. Chem. 2000, 65, 1569–1573. 143. Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089–2090. 144. Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217–219. 145. Imada, Y.; Ueno, K.; Kutsuwa, K.; Murahashi, S.-I. Chem. Lett. 2002, 31, 140–141. 146. Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005, 127, 14186–14187. 147. Reviews on enolate allyations: (a) Kazmaier, U. Curr. Org. Chem. 2003, 7, 317–328. (b) Kazmaier, U. J. Ind. Chem. Soc. 2003, 80, 957–967. (c) Braun, M.; Meier, T. Synlett 2006, 661–676. 148. Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2591–2594. 149. Fiaud, J. C.; Malleron, J. L. J. Chem. Soc. Chem. Commun. 1981, 1159–1160. 150. (a) Trost, B. M.; Self, C. R. J. Org. Chem. 1984, 49, 468–473. (b) Shi, G.-Q.; Huang, X.-H.; Zhang, F.-J. Tetrahedron Lett. 1995, 36, 6305–6308. 151. Negishi, E.-I.; John, R. A. J. Org. Chem. 1983, 48, 4098–4102. 152. (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759–6760. (b) Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174–184. 153. You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett. 2001, 3, 149–151. 154. (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–15045. (b) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem. Int. Ed. Engl. 2008, 47, 6873–6876. 155. Belanger, E.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc. 2007, 129, 1034–1035. 156. (a) Braun, M.; Laicher, F.; Meier, T. Angew. Chem. Int. Ed. Engl. 2000, 39, 3494–3498. (b) Braun, M.; Meier, T. Synlett 2005, 2968–2972.

634 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES 157. Yan, X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.; Dai, L.-X.; Hou, X.-L. Angew. Chem. Int. Ed. Engl. 2005, 44, 6544–6546. 158. Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. J. Am. Chem. Soc. 2007, 129, 7718–7719. 159. Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem. 1980, 45, 5193–5196. 160. (a) Murahashi, S. I.; Yamamura, M.; Mito, N. J. Org. Chem. 1977, 42, 2870–2874. (b) Murahashi, S. I.; Tamba, Y.; Yamamura, M.; Yoshimura, N. J. Org. Chem. 1978, 43, 4099–4105. 161. (a) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A. Angew. Chem. Int. Ed. Engl. 1992, 31, 234–235. (b) Otte, A. R.; Wilde, A.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1994, 33, 1280–1282. 162. Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams, D. J. Angew. Chem. Int. Ed. Engl. 1995, 34, 100–103. 163. Carfagna, C.; Mariani, L.; Musco, A.; Sallese, G.; Santi, R. J. Org. Chem. 1991, 56, 3924–3927. 164. (a) Elliott, M. R.; Dhimane, A.-L.; Malacria, M. J. Am. Chem. Soc. 1997, 119, 3427–3428. (b) Elliott, M. R.; Dhimane, A.-L.; Malacria, M. Tetrahedron Lett. 1998, 39, 8849–8852. 165. Moorlag, H.; de Vries, J. G.; Kaptein, B.; Schoemaker, H. E.; Kamphuis, J.; Kellog, R. M. Recl. Trav. Chim. Pays Bas 1992, 111, 129–137. 166. (a) Kazmaier, U.; Zumpe, F. L. Angew. Chem. Int. Ed. Engl. 1999, 38, 1468–1470. (b) Bauer, M.; Kazmaier, U. Recent Res. Dev. Org. Chem. 2005, 9, 49–69. 167. (a) Kazmaier, U.; Zumpe, F. L. Angew. Chem. Int. Ed. Engl. 2000, 39, 802–804. (b) Kazmaier, U.; Zumpe, F. L. Eur. J. Org. Chem. 2001, 4067–4076. (c) Kazmaier, U.; Pohlman, M. Synlett 2004, 623–626. (d) Kazmaier, U.; Krämer, K. J. Org. Chem. 2006, 71, 8950–8953. 168. (a) Kazmaier, U.; Lindner, T. Angew. Chem. Int. Ed. Engl. 2005, 44, 3303–3306. (b) Lindner, T.; Kazmaier, U. Adv. Synth. Catal. 2005, 1687–1695. 169. (a) Kazmaier, U.; Deska, J.; Watzke, A. Angew. Chem. Int. Ed. Engl. 2006, 118, 4973–4976; Angew. Chem. Int. Ed. Engl. 2006, 45, 4855–4858. (b) Deska, J.; Kazmaier, U. Angew. Chem. Int. Ed. Engl. 2007, 46, 4570–4573. (c) Deska, J.; Kazmaier, U. Chem. Eur. J. 2007, 13, 6204–6211. 170. Weiß, T. D.; Helmchen, G.; Kazmaier, U. J. Chem. Soc. Chem. Commun. 2002, 1270–1271. 171. Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y.-D. Angew. Chem. Int. Ed. Engl. 2008, 47, 1741–1744. 172. Review: Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715–1726. 173. Review: You, S.-L.; Dai, L.-X. Angew. Chem. Int. Ed. Engl. 2006, 45, 5246–5248. 174. Tsuda, T.; Chujo, Y.; Nishi, S.-I.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381–6384. 175. Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199–3202. 176. Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113–4115. 177. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem. Int. Ed. Engl. 2005, 44, 6924–6927. 178. Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228–1231. 179. Rieck, H.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 1995, 34, 2687–2689. 180. Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847. 181. Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180–17181. 182. Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. Engl. 2006, 45, 3109–3112. 183. Trost, B. M.; Xu, J.; Reichle, M. J. Am. Chem. Soc. 2007, 129, 282–283. 184. Kuwano, R.; Ishida, N.; Murakami, M. Chem. Comm. 2005, 3951–3952. 185. Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem. Int. Ed. Engl. 2005, 44, 7248–7251. 186. Bricout, H.; Carpentier, J.-F.; Mortreux, A. Chem. Commun. 1997, 1393–1394. 187. Bricout, H.; Carpentier, J.-F.; Mortreux, A. Tetrahedron Lett. 1996, 37, 6105–6108. 188. Bricout, H.; Carpentier, J.-F.; Mortreux, A. Tetrahedron Lett. 1997, 38, 1053–1056. 189. Trost, B. M.; Spagnol, M. D. J. Chem. Soc. Perkin Trans. 1, 1995, 2083–2096.


190. (a) Kobayashi, Y.; Ikeda, E. J. Chem. Soc., Chem. Commun. 1994, 1789–1790. (b) Kobayashi, Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996, 61, 5391–5399. (c) Kobayashi, Y.; Watatani, K.; Tokoro, Y. Tetrahedron Lett. 1998, 39, 7533–7536. 191. (a) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 7273–7274. (b) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. Tetrahedron 1998, 54, 1117–1130. 192. Consiglio, G.; Morandini, F.; Piccolo, O. Helv. Chim. Acta 1980, 63, 987–989. 193. Consiglio, G.; Morandini, F.; Piccolo, O. J. Chem. Soc. Chem. Commun. 1983, 112–114. 194. Nomura, N.; RajanBabu, T. V. Tetrahedron Lett. 1997, 38, 1713–1716. 195. Chen, H.; Deng, M.-Z. J. Organomet. Chem. 2000, 603, 189–193. 196. Chung, K. G.; Miyake, Y.; Uemura, S. J. Chem. Soc. Perkin Trans. 1 2000, 15–18. 197. Chung, K. G.; Miyake, Y.; Uemura, S. J. Chem. Soc. Perkin Trans. 1 2000, 2725–2729. 198. Novak, A.; Fryatt, R.; Woodward, S. C. R. Chim. 2007, 10, 206–212. 199. Goldsmith, P. J.; Woodward, S. Angew. Chem. Int. Ed. Engl. 2005, 44, 2235–2237. 200. Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649–7650. 201. Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756–2757. 202. (a) Kurosawa, H. J. Chem. Soc. Dalton Trans. 1979, 939–943. (b) Ohe, K.; Matsuda, M.; Morimoto, T.; Ogoshi, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 1994, 116, 4125–4126. (c) Clarke, M. L. Polyhedron 2001, 20, 151–164. (d) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.; Ohshima, T.; Mashima, K. Org. Lett. 2007, 9, 3371–3374. 203. Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Humphries, M. E.; Williams, J. M. J. Chem. Eur. J. 2000, 6, 353–360. 204. Brown, J. M.; MacIntyre, J. E. J. Chem. Soc. Perkin Trans. 2 1985, 961–970. 205. Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Williams, J. M. J. Organometallics 1999, 18, 2867–2873. 206. Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Williams, J. M. J. Chem. Commun. 1999, 913–914. 207. Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37, 159–167. 208. Curtis, M. D. In Encyclopedia of Inorganic Chemistry (Ed. King, R. B.). New York: John Wiley & Sons Ltd., 1994; pp. 2346–23261. 209. (a) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1982, 104, 5543–5545. (b) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1987, 109, 1469–1478. 210. For asymmetric alkylations with stoichiometric complexes, see: (a) Faller, J. W.; Chao, K.-H. J. Am. Chem. Soc. 1983, 105, 3893–3898. (b) Faller, J. W.; Chao, K.-H. Organometallics 1984, 3, 927–932. (c) Faller, J. W.; Mazzieri, M. R.; Nguyen, J. T.; Parr, J.; Tokunaga, M. Pure Appl. Chem. 1994, 66, 1463–1469. (d) Christopher, J. A.; Kociensky, P. J.; Procter, M. J. Synlett 1998, 425–427. (e) Christopher, J. A.; Kocienski, P. J.; Kuhl, A.; Bell, R. Synlett 2000, 463–466. 211. Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104–1105. 212. As alternative, Mo(II)-complexes can be used, which show a higher reactivity compared with Mo(CO)6: (a) Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J.; Kočovský, P. Tetrahedron Lett. 1997, 38, 4895–4898. (b) Malkov, A. V.; Baxendale, I. R.; Dvořák, D.; Mansfield, D. J.; Kočovský, P. J. Org. Chem. 1999, 64, 2737–2750. (c) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.; Kočovský, P. J. Org. Chem. 1999, 64, 2751–2764. (d) Malkov, A. V.; Spoor, P.; Vinader, V.; Kočovský, P. J. Org. Chem. 1999, 64, 5308–5311. (e) Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J.; Kočovský, P. J. Chem. Soc. Perkin Trans. 1 2001, 1234–1240. 213. Palucki, M.; Lem, J. M.; Conlon, D. A.; Yasuda, N.; Hughes, D. L.; Mao, B.; Wang, J.; Reider, P. J. Adv. Synth. Catal. 2001, 343, 46–50. 214. Kaiser, N. F.; Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3595–3598. 215. (a) Belda, O.; Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Hallberg, A.; Moberg, C. J. Org. Chem. 2000, 65, 5868–5870. (b) Belda, O.; Moberg, C. Synthesis 2002, 1601–1606.

636 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES 216. Belda, O.; Lundgren, S.; Moberg, C. Org. Lett. 2003, 5, 2275–2278. 217. Trost, B. M.; Dogra, K.; Hachiya, I.; Emura, T.; Hughes, D. L.; Krska, S.; Reamer, R. A.; Palucki, M.; Yasuda, N.; Reider, P. J. Angew. Chem. Int. Ed. Engl. 2002, 41, 1929–1932. 218. Malkov, A. V.; Spoor, P.; Vinader, V.; Kočovský, P. Tetrahedron Lett. 2001, 42, 509–512. 219. (a) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141–144. (b) Glorius, F.; Neuburger, M.; Pfaltz, A. Helv. Chim. Acta 2001, 84, 3178–3196. 220. Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.; Mansfield, D. J.; Valko, M.; Kočovský, P. Organometallics 2001, 20, 673–690. 221. Faller, J. W.; Linebarrier, D. Organometallics 1988, 7, 1670–1672. 222. Rubio, A.; Liebeskind, L. S. J. Am. Chem. Soc. 1993, 115, 891–901. 223. Kuhl, A.; Christopher, J. A.; Farrugia, L. J.; Kocienski, P. J. Synlett 2000, 1765–1768. 224. Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 897–898. 225. Fiaud, J.-C.; Legros, J.-Y. J. Org. Chem. 1987, 52, 1907. 226. Dvořák, D.; Starý, I.; Kočovský, P. J. Am. Chem. Soc. 1995, 117, 6130–6131. 227. Fiaud, J. C.; Legros, J. Y. J. Org. Chem. 1987, 52, 1907–1911. 228. Kočovský, P.; Malkov, A. V.; Vyskočil, S.; Lloyd-Jones, G. C. Pure Appl. Chem. 1999, 71, 1425–1433. 229. (a) Lloyd-Jones, G. C.; Krska, S. W.; Hughes, D. L.; Gouriou, L.; Bonnet, V. D.; Jack, K.; Sun, Y.; Reamer, R. A. J. Am. Chem. Soc. 2004, 126, 702–703. (b) Hughes, D. L.; Lloyd-Jones, G. C.; Krska, S. W.; Gouriou, L.; Bonnet, V. D.; Jack, K.; Sun, Y.; Mathre, D. J.; Reamer, R. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5379–5384. 230. Krska, S. W.; Hughes, D. L.; Reamer, R. A.; Mathre, D. J.; Sun, Y.; Trost, B. M. J. Am. Chem. Soc. 2002, 124, 12656–12657. 231. Similar Mo-malonate complexes have been reported: (a) Minato, M.; Kusishima, S.; Nagai, K.; Yamasaki, M.; Ito, T. Chem. Lett. 1994, 2339–2342. (b) Ito, T.; Shimada, K.; Ono, T.; Minato, M.; Yamaguchi, Y. J. Organomet. Chem. 2000, 611, 308–313. 232. Hughes, D. L.; Palucki, M.; Yasuda, N.; Reamer, R. A.; Reider, P. J. J. Org. Chem. 2002, 67, 2762–2768. 233. Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–14. 234. Trost, B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem. Soc. 1999, 121, 10416–10417. 235. Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256–7257. 236. Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004, 126, 1944–1945. 237. Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590–4591. 238. Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548–14549. 239. (a) Trost, B. M.; Hung, M.-H. J. Am. Chem. Soc. 1984, 106, 6837–6839. (b) Trost, B. M.; Lautens, M.; Hung, M.-H.; Carmichael, C. S. J. Am. Chem. Soc. 1984, 106, 7641–7643. (c) Lehmann, J.; LloydJones, G. C. Tetrahedron 1995, 51, 8863–8874. 240. Trost, B. M.; Hung, M.-H. J. Am. Chem. Soc. 1983, 105, 7757–7759. 241. Trost, B. M.; Tometzki, G. B.; Hung, M.-H. J. Am. Chem. Soc. 1987, 109, 2176–2177. 242. Lloyd-Jones, G. C.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1995, 34, 462–464. 243. Lloyd-Jones, G. C.; Pfaltz, A. Z. Naturforsch. B 1995, 50, 361–367. 244. Whitesides, T. H.; Arhardt, R. W. J. Am. Chem. Soc. 1971, 93, 5296–5298. 245. Pearson, A. J. Tetrahedron Lett. 1975, 16, 3617–3618. 246. Silverman, G. S.; Strickland, S.; Nicholas, K. M. Organometallics 1986, 5, 2117–2124. 247. (a) Enders, D.; Finkam, M. Synlett 1993, 401–403. (b) Enders, D.; Jandeleit, B.; Raabe, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1949–1951. (c) Enders, D.; Jandeleit, B. Synthesis 1994, 1327–1330. (d) Enders, D.; von Berg, S.; Jandeleit, B. Synlett 1996, 18–20.


248. Roustan, J. L.; Merour, J. Y.; Houlihan, F. Tetrahedron Lett. 1979, 20, 3721–3724. 249. Ladoulis, S. J.; Nicholas, K. M. J. Organomet. Chem. 1985, 285, C13–C16. 250. (a) Xu, Y.; Zhou, B. J. Org. Chem. 1987, 52, 974–977. (b) Zhou, B.; Xu, Y. J. Org. Chem. 1988, 53, 4419–4421. 251. Plietker, B. Angew. Chem. Int. Ed. Engl. 2006, 45, 6053–6056. 252. Plietker, B.; Dieskau, A.; Möws, K.; Jatsch, A. Angew. Chem. Int. Ed. Engl. 2008, 47, 198–201. 253. Kondo, T.; Mitsudo, T. In Ruthenium in Organic Synthesis (Ed. Murahashi, S.-I.). Weinheim: WileyVCH, 2004; pp. 129–151. 254. Bruneau, C.; Renaud, J.-L.; Demerseman, B. Chem. Eur. J. 2006, 12, 5178–5187. 255. Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem. Int. Ed. Engl. 2002, 41, 1059–1061. 256. (a) Morisaki, Y.; Kondo, T.; Mitsudo, T. Organometallics 1999, 18, 4742–4746. (b) Kondo, T.; Morisaki, Y.; Uenoyama, S.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc. 1999, 121, 8657–8658. 257. Burger, E. C.; Tunge, J. A. Chem. Commun. 2005, 2835–2837. 258. Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi, S. J. Am. Chem. Soc. 2001, 123, 10405–10406. 259. Onitsuka, K.; Matsushima, Y.; Takahashi, S. Organometallics 2005, 24, 6472–6474. 260. (a) Austeri, M.; Linder, D.; Lacour, J. Chem. Eur. J. 2008, 14, 5737–5741. (b) Mbaye, M. D.; Renaud, J.-L.; Demerseman, B.; Bruneau, C. Chem. Commun. 2004, 1870–1871. 261. Onoue, H.; Moritani, I.; Murahashi, S.-I. Tetrahedron Lett. 1973, 14, 121–124. 262. Tsuji, J.; Minami, I.; Shimizu, I. Chem. Lett. 1984, 1721–1724. 263. Tsuji, J.; Minami, I.; Shimizu, I. J. Organomet. Chem. 1985, 296, 269–280. 264. Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725–1728. 265. Tolman, C. A. J. Am. Chem. Soc. 1970, 92, 2956–2965. 266. Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 2001, 42, 7015–7018. 267. Takeuchi, R.; Kitamura, N. New. J. Chem. 1998, 22, 659–660. 268. Muraoka, T.; Matsuda, I.; Itoh, K. Tetrahedron Lett. 2000, 41, 8807–8811. 269. Muraoka, T.; Matsuda, I.; Itoh, K. J. Am. Chem. Soc. 2000, 122, 9552–9553. 270. Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125, 8974–8975. 271. Kazmaier, U.; Stolz, D. Angew. Chem. Int. Ed. Engl. 2006, 45, 3072–3075. 272. Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581–5582. 273. Lawson, D. N.; Osborn, J. A.; Wilkinson, G. J. Chem. Soc. A 1966, 1733. 274. Tanaka, I.; Jin-no, N.; Kushida, T.; Tsutsui, N.; Ashida, T.; Suzuki, H.; Sakurai, H.; Moro-oka, Y.; Ikawa, T. Bull. Chem. Soc. Jpn. 1983, 56, 657–661. 275. Ashfeld, B. L.; Miller, K. A.; Martin, S. F. Org. Lett. 2004, 6, 1321–1324. 276. (a) Evans, P. A.; Kennedy, C. J. Org. Lett. 2000, 2, 2213–2215. (b) Evans, P. A.; Kennedy, C. J. J. Am. Chem. Soc. 2001, 123, 1234–1235. 277. Kabalka, G. W.; Dong, G.; Venkataiah, B. Org. Lett. 2003, 5, 893–895. 278. Evans, P. A.; Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158–7159. 279. Consiglio, G.; Scalone, M.; Rama, F. J. Mol. Catal. 1989, 50, L11–L15. 280. Selvakumar, K.; Valentini, M.; Pregosin, P. S.; Albinati, A. Organometallics 1999, 18, 4591–4597. 281. Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. Org. Lett. 2003, 5, 1713–1715. 282. Dong, L.; Xu, Y.-J.; Yuan, W.-C.; Cui, X.; Cun, L.-F.; Gong, L.-Z. Eur. J. Org. Chem. 2006, 4093–4105. 283. Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311–1314. 284. Menard, F.; Chapman, T. M.; Dockendorff, C.; Lautens, M. Org. Lett. 2006, 8, 4569–4572. 285. (a) Takeuchi, R.; Kashio, M. Angew. Chem. Int. Ed. Engl. 1997, 36, 263–265. Reviews: (b) Takeuchi, R. Synlett 2002, 1954–1965. (c) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349–3366.

638 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES 286. Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025–8026. 287. (a) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741–742. (b) Bartels, B.; García-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. Inorg. Chem. 2002, 2569–2586. (c) Bartels, B.; García-Yebra, C.; Helmchen, G. Eur. J. Org. Chem. 2003, 1097–1103. For a very detailed account, see: (d) Bartels, B. Dissertation, Universität Heidelberg, 2001. 288. Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–15165. 289. Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272–14273. 290. Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2004, 43, 2426–2428. 291. Helmchen, G.; Dahnz, A.; Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675–691. 292. Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647–8655. 293. Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.; Martin, S. F. J. Org. Chem. 2007, 72, 9018–9031. 294. This complex had been characterized earlier in another context: Bedford, R. B.; Castillòn, S.; Chaloner, P. A.; Claver, C.; Fernandez, E.; Hitchcock, P. B.; Ruiz, A. Organometallics 1996, 15, 3990–3997. 295. (a) Lloyd-Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskočil, Š.; Kočovský, P. Chem. Eur. J. 2000, 6, 4348–4357. (b) Lloyd-Jones, G. C.; Stephen, S. C. Chem. Eur. J. 1998, 4, 2539–2549. 296. (a) García-Yebra, C.; Janssen, J. P.; Rominger, F.; Helmchen, G. Organometallics 2004, 23, 5459– 5470. (b) McGhee, W. D.; Bergman, R. G. J. Am. Chem. Soc. 1985, 107, 3388–3389. (c) Wakefield, J. B.; Stryker, J. M. J. Am. Chem. Soc. 1991, 113, 7057–7059. 297. van Zijl, A. W.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2004, 346, 413–420 (Supporting Information). 298. Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A. Synthesis 2004, 2586–2590. 299. For experimental details, see: (a) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem. Eur. J. 2006, 12, 3596–3609. (b) Polet, D.; Alexakis, A. Org. Lett. 2005, 7, 1621–1624 (Supporting Information). 300. Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353. 301. This compound is available from BASF AG, Ludwigshafen, in their ChiPros program. 302. (a) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dübon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239–1242. (b) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506–15514. (c) Leitner, A.; Shu, C.; Hartwig, J. F. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5830–5833. 303. (a) Fuji, K.; Kinoshita, N.; Tanaka, K.; Kawabata, T. Chem. Commun. 1999, 2289–2290. (b) Kinoshita, N.; Marx, K. H.; Tanaka, K.; Tsubaki, K.; Kawabata, T.; Yoshikai, N.; Nakamura, E.; Fuji, K. J. Org. Chem. 2004, 69, 7960–7964. 304. Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem. Int. Ed. Engl. 2003, 42, 2054–2056. 305. (a) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6, 4631–4634. (b) Lavastre, O.; Morken, J. P. Angew. Chem. Int. Ed. Engl. 1999, 38, 3163–3165. 306. (a) Nemoto, T.; Sakamoto, T.; Fukuyama, T.; Hamada, Y. Tetrahedron Lett. 2007, 48, 4977–4981. (b) Nemoto, T.; Sakamoto, T.; Matsumoto, T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 8737–8740. 307. Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896–897. 308. Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529–3532. 309. Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 116–117. 310. Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem. Int. Ed. Engl. 2004, 43, 4797–4800. 311. (a) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 2006, 45, 5546–5549. (b) Spiess, S.; Berthold, C.; Weihofen, R.; Helmchen, G. Org. Biomol. Chem. 2007, 5, 2357–2360. (c) Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 7094–7098. 312. Gnamm, C.; Förster, S.; Miller, N.; Brödner, K.; Helmchen, G. Synlett 2007, 790–794.


313. Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 2004, 43, 4595–4598. 314. Marković, D.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 11680–11681. 315. Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky, G.; Miller, N.; Helmchen, G. Chem. Commun. 2005, 2957–2959. 316. He, H.; Zheng, X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007, 9, 4339–4341. 317. Peng, F.; Hall, D. G. Tetrahedron Lett. 2007, 48, 3305–3309. 318. Similar results have been obtained with R1 = 2-MeC6H4 and R1 = 1-Naphthyl. Helmchen, G.; Beton, D. Unpublished results. 319. Förster, S.; Helmchen, G. Synlett 2008, 831–836. 320. Review: Leahy, D. K.; Evans, P. A. In Modern Rhodium-Catalyzed Organic Reactions (Ed. Evans, P. A.). New York: Wiley, 2005; p. 191. 321. (a) Leahy, D. K.; Evans, P. A. Chemstracts 2003, 16, 567–578. (b) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929–1931. (c) Evans, P. A.; Leahy, D. K.; Andrews, W. J.; Uraguchi, D. Angew. Chem. Int. Ed. Engl. 2004, 43, 4788–4791. 322. Schelwies, M.; Dübon, P.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 2006, 45, 2466–2469. 323. Dahnz, A.; Helmchen, G. Synlett 2006, 697–700. 324. Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6197–6201. 325. Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 17192–17193. 326. Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7720–7721. 327. Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Org. Lett. 2008, 10, 1815–1818. 328. Reviews: (a) Alexakis, A.; Malan, C.; Lea, L.; Tissot-Crosset, K.; Polet, D.; Falciola, C. Chimia 2006, 60, 124–130. (b) López, F.; Minaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179–188. 329. Alexakis, A.; El Hajjaji, S.; Polet, D.; Rathgeb, X. Org. Lett. 2007, 9, 3393–3395. 330. (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–631. (b) Karlström, A. S. E.; Bäckvall, J.-E. In Modern Organocopper Chemistry (Ed. Krause, N.). Weinheim: Wiley-VCH, 2002; pp. 259– 288. (c) Kanda, Y.; Onomura, O.; Maki, T.; Matsumura, Y. Chirality 2003, 15, 89–94. (d) Pineschi, M. New. J. Chem. 2004, 28, 657–665. (e) Yorimitsu, H.; Oshima, K. Angew. Chem. Int. Ed. Engl. 2005, 44, 4435–4439. (f) Kar, A.; Argade, N. P. Synthesis 2005, 2995–3022. (g) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 3765–3780. 331. Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063–3066. 332. (a) Goering, H. L.; Singleton, V. D., Jr. J. Am. Chem. Soc. 1976, 98, 7854–7855. (b) Goering, H. L.; Singleton, V. D., Jr. J. Org. Chem. 1983, 48, 1531–1533. (c) Goering, H. L.; Kantner, S. S. J. Org. Chem. 1984, 49, 422–426. 333. Gallina, C.; Ciattini, P. G. J. Am. Chem. Soc. 1979, 101, 1035–1036. 334. Caló, V.; Lopez, L.; Carlucci, W. F. J. Chem. Soc. Perkin Trans. 1 1983, 2953–2956. 335. (a) Breit, B.; Demel, P. Adv. Synth. Catal. 2001, 343, 429–432. (b) Breit, B.; Herber, C. Angew. Chem. Int. Ed. Engl. 2004, 43, 3790–3792. 336. Persson, E. S. M.; van Klaveren, M.; Grove, D. M.; Bäckvall, J.-E.; van Koten, G. Chem. Eur. J. 1995, 1, 351–359. 337. For alternative mechanistic proposals, see: (a) Berlan, J.; Battioni, J.-P.; Koosha, K. J. Organomet. Chem. 1978, 152, 359–365. (b) Bertz, S. H.; Dabbagh, G.; Mujsce, A. M. J. Am. Chem. Soc. 1991, 113, 631–636. (c) Lipshutz, B. H. In Organometallics in Synthesis (Ed. Schlosser, M.). Chichester: Wiley, 1994; pp. 283–382. 338. Bäckvall, J.-E.; Sellen, M.; Grant, B. J. Am. Chem. Soc. 1990, 112, 6615–6621. 339. For mechanistic studies, see also: (a) Karlstrom, A. S. E.; Bäckvall, J.-E.; Chem. Eur. J. 2001, 7, 1981–1989. (b) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 6287–6293. 340. Alexakis, A.; Mangeney, P. Tetrahedron Asymmetry 1990, 1, 477–511. 341. Mangeney, P.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1986, 27, 3143–3146.

640 ENANTIOSELECTIVE ALLYLIC SUBSTITUTIONS WITH CARBON NUCLEOPHILES 342. Mangeney, P.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1987, 28, 2363–2366. 343. Denmark, S. E.; Marble, L. K. J. Org. Chem. 1990, 55, 1984–1986. 344. (a) Bund, J.; Gais, H. J.; Erdelmeier, I. J. Am. Chem. Soc. 1991, 113, 1442–1444. (b) Gais, H. J.; Mueller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe, G. J. Am. Chem. Soc. 1995, 117, 2453–2466. 345. Breit, B.; Breuninger, D. Synthesis 2005, 147–157. 346. (a) van Klaveren, M.; Persson, E. S. M.; del Villar, A.; Grove, D. M.; Bäckvall, J.-E.; van Koten, G. Tetrahedron Lett. 1995, 36, 3059–3062. (b) Meuzelaar, G. J.; Karlstrom, A. S. E.; van Klaveren, M.; Persson, E. S. M.; del Villar, A.; van Koten, G.; Bäckvall, J.-E. Tetrahedron 2000, 56, 2895–2903. 347. Karlstrom, A. S. E.; Huerta, F. F.; Meuzelaar, G. J.; Bäckvall, J.-E. Synlett 2001, 923–926. 348. Alexakis, A.; Malan, C.; Lea, L.; Benhaim, C.; Fournioux, X. Synlett 2001, 927–930. 349. Alexakis, A.; Croset, K. Org. Lett. 2002, 4, 4147–4149. 350. Tissot-Croset, K.; Alexakis, A. Tetrahedron Lett. 2004, 45, 7375–7378. 351. Falciola, C. A.; Tissot-Croset, K.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2006, 45, 5995–5998. 352. Falciola, C. A.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2007, 46, 2619–2622. 353. Carosi, L.; Hall, D. G. Angew. Chem. Int. Ed. Engl. 2007, 46, 5913–5915. 354. Lopez, F.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2006, 409–411. 355. (a) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 15572–15573. (b) van Zijl, A. W.; Lopez, F.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2007, 72, 2558–2563. 356. (a) Tominaga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron Lett. 2004, 45, 5585–5588. (b) Okamoto, S.; Tominaga, S.; Saino, N.; Kase, K.; Shimoda, K. J. Organomet. Chem. 2005, 690, 6001–6007. 357. Dubner, F.; Knochel, P. Angew. Chem. Int. Ed. Engl. 1999, 38, 379–381. 358. Dubner, F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233–9237. 359. Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett. 2001, 3, 1169–1171. 360. Shi, W.-J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron Asymmetry 2003, 14, 3867–3872. 361. (a) Börner, C.; Goldsmith, P. J.; Woodward, S.; Gimeno, J.; Gladiali, S.; Ramazzotti, D. Chem. Commun. 2000, 2433–2434. (b) Bennet, S. M. W.; Brown, S. M.; Cunningham, A.; Dennis, M. R.; Muxworthy, J. P.; Oakley, M. A.; Woodward, S. Tetrahedron 2000, 56, 2847–2855. 362. Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2001, 40, 1456–1460. 363. Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690–4691. 364. Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 10676–10681. 365. Ongeri, S.; Piarulli, U.; Roux, M.; Monti, C.; Gennari, C. Helv. Chim. Acta 2002, 85, 3388–3399. 366. Piarulli, U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari, C. Angew. Chem. Int. Ed. Engl. 2003, 42, 234–236. 367. Piarulli, U.; Claverie, C.; Daubos, P.; Gennari, C.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 4493–4496. 368. Larsen, A. O.; Leu, W.; Oberhuber, C. N.; Campbell, J. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130–11131. 369. Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2007, 46, 4554–4558. 370. van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877–6882. 371. Gillingham, D. G.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2007, 46, 3860–3864. 372. Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew. Chem. Int. Ed. Engl. 2007, 46, 1097–1100.


373. Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 446–447. 374. (a) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969–5972. (b) Takahashi, T.; Kataoka, H.; Tsuji, J. J. Am. Chem. Soc. 1983, 105, 147–149. 375. Badalassi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.; Feringa, B. L. Tetrahedron Lett. 1998, 39, 7795–7798. 376. Equey, E.; Alexakis, A. Tetrahedron Asymmetry 2004, 15, 1531–1536. 377. Millet, R.; Alexakis, A. Synlett 2007, 435–438. 378. (a) Del Moro, F.; Crotti, P.; Di Bussolo, V.; Macchia, F.; Pineschi, M. Org. Lett. 2003, 5, 1971–1974. (b) Pineschi, M.; Del Moro, F.; Crotti, P.; Di Bussolo, V.; Macchia, F. Synthesis 2005, 334–337. 379. Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2002, 4, 2703–2705. 380. Zhang, W.; Wang, L.-X.; Shi, W. J.; Zhou, Q.-L. J. Org. Chem. 2005, 70, 3734–3736. 381. Pineschi, M.; Del Moro, F.; Crotti, P.; Macchia, F. Org. Lett. 2005, 7, 3605–3607. 382. Bournaud, C.; Falciola, C.; Lecourt, T.; Rosset, S.; Alexakis, A.; Micouin, L. Org. Lett. 2006, 8, 3581–3584. 383. Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.; Falciola, C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.; Bernadinelli, G.; Alexakis, A. Angew. Chem. Int. Ed. Engl. 2007, 46, 7462–7465.

8C ASYMMETRIC CARBOMETALLATION AND CARBOCYCLIZATIONS Iwao Ojima, Joseph J. Kaloko, Stephen J. Chaterpaul, Yu-Han Gary Teng, and Chi-Feng Lin Department of Chemistry, Stony Brook University, Stony Brook, NY

8C.1. INTRODUCTION Organometallics add to carbon–carbon multiple bonds forming a new organometallic species (Eq. 8C.1), where the new carbon–metal bond can be further modified affording new carbon–carbon bonds (Eq. 8C.2) [1]. These reactions are classified as “carbometallation reactions.” R Mm

R MLn R

(8C.1)

Mm

R 1MLn

E+

R2 R2 R1

A

B

MLn C

R2 R1

E D

(8C.2)

The term carbometallation refers primarily to a relationship between reactants and products and has no necessary mechanistic implications about the reaction system. Many of the so-called carbometallation reactions are in fact mechanistically independent of Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 643

644 ASYMMETRIC CARBOMETALLATION AND CARBOCYCLIZATIONS

one another. A full discussion of the mechanism and historical background can be found in the second edition of this book [2]. This chapter describes the advances in the field of asymmetric carbometallation reactions since 2000. Reactions catalyzed by zirconium, copper, palladium, and rhodium will be highlighted. In addition, several other asymmetric carbocyclization reactions will be discussed, as carbocylizations provide efficient methods for the rapid synthesis of “druglike” frameworks through only a few synthetic transformations.

8C.2. Zr-CATALYZED ASYMMETRIC CARBOALUMINATION (ZACA) REACTIONS 8C.2.1. ZACA Reaction of Unactivated Alkenes The ZACA of alkenes was first reported by Negishi and Kondakov in 1995 [3]. The ZACA reaction is believed to proceed via a noncyclic mechanism and involves a Zrcentered carbometallation [2,3]. The ZACA reaction is an enantioselective carbon– carbon bond-forming reaction with one-point binding. In contrast to other widely used asymmetric carbon–carbon bond-forming reactions for the synthesis of enantioenriched methyl- or alkyl-substituted acyclic compounds, the ZACA process is catalytic and does not require the presence of heterofunctional groups to achieve a useful level of asymmetric induction [4]. The Zr-catalyzed enantioselective methylalumination of monosubstituted alkenes 1 was reported to yield the corresponding 2-methyl-1-alkanols 2 after oxidation with molecular oxygen (Scheme 8C.1) [3]. A variety of chiral catalysts were explored for optimization of this process, and dichlorobis(1-neomenthylindenyl)zirconium, Cl2Zr(NMI)2 was found to be the catalyst of choice. Both carbon- and heteroatomsubstituted alkenes were shown to undergo the transformation in high yields and good enantioselectivity up to 75% ee. 1) Me3Al (NMI) 2ZrCl2 (8 mol %)

R

R

OH

2) O 2 1

2 Scheme 8C.1.

Although the enantioselectivity was moderate (65–75% ee), the results demonstrated that controlled, single-stage carboalumination of 1-alkenes using a zirconocene catalyst could be achieved selectively without generating unwanted side products [2]. The ethyl/n-propylalumination of monosubstituted alkenes was also reported [5]. In these cases, high to excellent enantioselectivity (86–96% ee) was achieved although the isolated yields of products were slightly lower than those for methylalumination. An extension of Zr-catalyzed asymmetric transformations, the tandem hydroalumination/Zr-catalyzed alkylalumination of unactivated alkenes 3 was developed, as shown in Scheme 8C.2, which gave 3-methylalkanols 4 with high enantiopurity (Table 8C.1) [6]. The reactions of terminal alkenes bearing proximal oxygenated substituents were, however, sluggish, presumably due to catalyst stabilization/deactivation by the oxygen-

8C.2. Zr-CATALYZED ASYMMETRIC CARBOALUMINATION (ZACA) REACTIONS 645

1)

DIBALH

R

AliBu2

R

OTBS n (NMI)2ZrCl2 (8 mol %) IBAO, CH2Cl2 R

2) H3O+

3

OTBS 4

Scheme 8C.2.

TABLE 8C.1. Enantioselective Synthesis of 3-Methyalkanols via Tandem HydroaluminationAlkylalumination Reaction Entry

R

n

Yield (%)

% ee

1

n-Pentyl

2

74

92

2

n-Hexyl 2-Methylpropyl 4-Methylpentyl Cyclohexyl PhMe2SiCH2

2

77

91

2 2 2 2 3

82 66 81 85 83

93 91 91 90 92

3 4

78 76

91 90

3 4 5 6 7

n-Hexyl 2-Methylpropyl

8 9

n-Hexyl

1) DIBALH 5

2)

OTBS n (NMI)2 ZrCl2 (5 mol %) IBAO, CH 2Cl2

HO 6 HO 7 (99% ee)

3) TBAF

Scheme 8C.3.

ated substituents. Then, it was found that the addition of methylaluminoxane (MAO) or isobutylaluminoxane (IBAO) could significantly accelerate the reactions without affecting the enantioselectivity. The use of IBAO was preferred since it gave the desired products 4 in higher yields than MAO. It should be noted that the tandem hydroalumination–alkylalumination process (Scheme 8C.2) gives products with significantly higher enantiopurity as compared with that achieved by the methylalumination process [3,6] (see Scheme 8C.1). The synthetic utility of this process was demonstrated by its application to the synthesis of key intermediate 7 with excellent enantioselectivity (99% ee) in the total synthesis of vitamin E [6].The hydroalumination–alkylalumination of 4-methyl-1pentene 5 followed by deprotection gave alcohol 6. Oxidation of 6, subsequent olefination, and the second hydroalumination–alkylalumination, followed by deprotection gave 7 in 55% overall yield (Scheme 8C.3) [6].


(S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyldocosane 15, isolated from the cuticula of cane beetle Antitrogus parvulus [7] was found to possess rarely seen anti-anti-anti4,6,8,10-methyl tetrad along with the usual syn-methyl diad [8]. The ZACA reaction has been applied to the synthesis of 15 [9]. The ZACA reaction was used to generate five of the six asymmetric carbon centers with the sixth being derived from (S)-β-citronellal. The key intermediate, aldehyde 13, was prepared from (S)-β-citronellal in nine steps including three ZACA reactions in 13% overall yield (Scheme 8C.4). Hexamethyldocosane 15 was obtained through coupling of aldehyde 13 having four of the requisite six chiral centers with phosphorane 14 (obtained from propene in six steps including two ZACA reactions in 23% overall yield) via Wittig olefination followed by hydrogenation in 85% yield for two steps (11% overall yield from (S)-β-citronellal) (Scheme 8C.5) [9].

1) (NMI)2 ZrCl2 (4 mol %) Me3 Al, CH 2Cl2

CH 2 =PPh 3 O

8

(S)-β-citronellal

2) O 2

1) (NMI) 2ZrCl2 (3 mol %) Me3 Al, CH2 Cl2

1) I 2 , PPh3

HO 9 60%, dr ≥ 95/5

2) ZnBr2 , CH2 =CHBr Pd(PPh3 )4 (2 mol %)

10

1) (NMI) 2ZrCl2 (4 mol %) Me3 Al, CH 2 Cl2 2) O2

11

2) Zn(OTf) 2, DMF, 70°C 3) Pd(DPEphos)Cl2 (3 mol %) DIBAL-H, CH 2=CHBr

HO 12 45%, dr ≥ 98/2

1) TsCl, Et3N 2) EtMgBr, 5% Li2 CuCl4 CHO 13 (9 steps from (S)-β-citronellal, 13% overall yield)

3) NMO, OsO4 (1 mol %) NaIO 4

Scheme 8C.4.

1) n-BuLi, THF CHO 13 (9 steps from (S)-β-citronellal, 13% overall yield)

+

IPh 3P 14 (6 steps from propene, 23% overall yield)

2) H 2, Pd

(S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyldocosane 15 (11 linear steps from (S)-β-citronellal, 11% overall yield)

Scheme 8C.5.


Although the synthesis of 15 is quite efficient compared with other reported syntheses [10–12], only moderate anti-anti diastereoselectivity (4/1 up to 6/1) was achieved in the ZACA reactions, which resulted in modest yields (45–60%) of desired stereochemically pure products. The results disclose a limitation of the current ZACA process, which is 1,3-syn-selective for 1-alkenes with a methyl or alkyl group at the C4 position [13–15]. It has been shown that the ZACA reaction of 1,4-pentadiene 16 gave a racemic alcohol 19 after oxidation with oxygen (Scheme 8C.6) [16,17]. It was proposed that the racemization would occur through cyclocarboalumination of the initially formed monocarboalumination product 17 to cyclobutane 18, followed by ring opening in the other direction to form the enantiomer of 17, that is, ent-17. The proposed mechanism was supported by the deuterium labeling experiment illustrated in Scheme 8C.6.

Me3 Al H* (– )-(NMI)2 ZrCl2 (cat.)

*H

H*

16

(R )

17

O2

H*

(R )

AlMe2

OH

(R)-19

H* H* = H or D H*

AlMe2 18

Me2Al

O2

H*

(S)

(S )

OH

H* (S)-19

ent-17

Scheme 8C.6.

However, the introduction of substituents to one of the two olefin moieties of 16 was found to block this racemization to occur, and thus the resulting substituted dienes 20 serve as viable substrates for the ZACA reaction. The ZACA reaction of 20 catalyzed by (NMI)ZrCl2 afforded the corresponding alkenols 21 in good yields with good to excellent enantioselectivity (Scheme 8C.7). Results are summarized in Table 8C.2.

R1

1) R 3 Al (NMI) 2ZrCl2 (5 mol %)

R2 R3

20

2) O 2

R1

R

R2

OH R3

21

Scheme 8C.7.

8C.2.2. ZACA Reaction of Activated Alkenes A tandem Claisen rearrangement–ZACA reaction of allyl aryl ethers 22 affords the corresponding 3-hydroxy-2-methylpropoylphenols 23 with good enantiopurity in good yields (Scheme 8C.8) [18]. This tandem process creates two new C–C bonds and one new C–O bond to provide polyfunctionalized chiral building blocks 23 for organic syntheses. Various ally aryl ethers 22 bearing an electron-donating or electron-withdrawing group in the aryl moiety are tolerated in this tandem process (Table 8C.3). Interestingly,


TABLE 8C.2. ZACA Reaction of Substituted 1,4-Pentadienes 20 R1

Entry 1 2

R2

R3

Me

R

(NMI)2ZrCl2 Yield (%)

R/S

H H

Me Me

+ —

75 74

13/87 89/11

3

H n-Hex H n-Hex H

H

Et

—

56

95/05

4 5 6

Ph Ph H

H H H

Me Et Me

— — —

75 60 86

90/10 97/03 88/12

7

H

—

72

86/14

H H H

n-Bu H H Me

Me

8 9 10

Me Et Me

— — —

72 57 79

85/15 95/05 89/11

11 12 13

H H H

Me Me2C=CH(CH2)2– Cl

Me Me Me

+ + —

73 68 73

11/89 10/90 90/10

14

H

15 16

Me Me3Si

17

n-Bu

H H n-Hex H TBS TBS n-Hex Me2C=CH(CH2)2– Me n-Hex n-Hex TBSO(CH2)2 n-Bu H

Cl

Et

—

69

96/04

H H

Me Me

— —

75 69

92/08 87/13

n-Bu

Me

—

84

88/12

1) Me3 Al (NMI)2 ZrCl2 (5 mol %) H 2O, CH2 Cl2 , 0°C

R O

OH

R

2) O2

OH

22

23

Scheme 8C.8.

the presence of water has been found critical as no product is formed in its absence. The role of water is currently under investigation. (−)-Spongidepsin 24, isolated from the Vanuatu marine sponge Spongia sp., has been shown to exhibit cytotoxic and antiproliferative activities against J774.A1, HEK-293, and WEHI-164 cancer cell lines [19]. Two key fragments 25 (C1–C5) and 26 (C6–C13), comprising the C1–C13 portion of this macrolide, were synthesized en route to the total synthesis of 24 in an efficient manner using fully reagent-controlled ZACA reactions [20]. The acid fragment 25 (dr ≥ 40:1 after chromatography of 5.5:1 dr product) was prepared from allyl alcohol in seven steps, including two ZACA reactions to install two methyl groups at the C2 and C4 positions. The alcohol fragment 26 (dr ≥ 40:1 after chromatography of 3.5:1 dr product) was obtained from 1,5-pentanediol in seven steps, including one ZACA reaction. It is noteworthy that unprotected ω-vinyl secondary alcohols were successfully used in the ZACA reaction [20]. This finding has extended the scope of the ZACA reaction. Subsequent esterification, amidation, ring-closing metathesis, and other functional group interconversions completed the total synthesis of 24 (Scheme 8C.9) [20].


TABLE 8C.3. Tandem Claisen-ZACA Reaction of Allyl Aryl Ethers 22 Entry

Substrate

1

Product

O

% ee

78

78

51

74

60

73

74

76

78

75

75

80

OH OH

F

F 22a

23a

2

O

OH OH

TIPSO

TIPSO 22b 3

23b O

OH

TIPSO

TIPSO 3

4

Yield (%)

OH 3

22c

O

23c

OH OH 23d

22d 5 O

OH HO 23e

22e 6

OH

O

OH 23f

22f

HO

2

O

4

O

25 (dr ≥ 40:1)

7 steps from allyl alcohol 18% overall yield

TBDPSO(H 2 C) 4 9

4

N

Ph

Me O

OH

2

O 7 9

7

26 (dr ≥ 40:1)

(–)-Spongidepsin (24)

7 steps from 1,5-pentanediol 20% overall yield Scheme 8C.9.


Siphonarienolone 28 is a polypropionate produced by the mollusks of the genus Siphonaria [21]. Efficient synthetic routes to 28 and two other structurally related siphonarienes 29 and 30, bearing three chiral centers (1,3,5-syn-syn) were devised using a series of ZACA reactions [13]. Key intermediate 27 was obtained in seven steps (three ZACA reactions) from 3-buten-1-ol with excellent enantio- and diastereoselectivity (Scheme 8C.10). Conversion of 27 to siphonarienolone 28 as well as siphonarienal 29 and siphonarienone 30 required only two to six additional steps (Scheme 8C.11).

1) (+)-(NMI) 2ZrCl2 (5 mol %) n-Pr3 Al, IBAO OH

1) Swern oxidation

+

2) H3 O

OH

2) CH 2=PPh3

90% ee 1) (+)-(NMI)2 ZrCl2 (5 mol %) Me3 Al, MAO

1) Iodination 2) CH 2=CHBr, [Pd] OH

2) O2

dr ≥ 40/1 50% over four steps from 3-buten-1-ol

3) (+)-(NMI) 2ZrCl2 (5 mol %) Me 3Al, MAO 4) O2

OH 27 dr ≥ 50/1 46 % for three steps

Scheme 8C.10.

OH

2 steps CHO

27 7 steps from 3-buten-1-ol 23% overall yield

Siphonarienal (29)

4 steps 4 steps

Siphonarienone (30)

OH O Siphonarienolone (28)

O

Scheme 8C.11.

One-pot tandem ZACA–Pd-catalyzed cross-coupling process has been successfully applied to the synthesis of α,ω-diheterofunctional reduced polypropioates, starting from styrene (Scheme 8C.12) [22]. The ZACA methylation of styrene catalyzed by (−)-(NMI)2ZrCl2, “(−)-ZACA,” generated the corresponding 2-phenyl-1-Me2Alpropane, which was subjected to the Pd-catalyzed cross-coupling reaction with bromoethene in one pot to give 4-phenyl-1-pentene 31 with 89% ee. The second ZACA methylation of 31 catalyzed by (+)-(NMI)2ZrCl2, “(+)-ZACA,” followed by oxidation afforded (2S,4S)-4-phenyl-1-pentanol 32 with 7:1 dr and 92% enantioselectivity in 50%

8C.3. ENANTIOSELECTIVE HYDROGEN-MEDIATED C–C BOND FORMATION

1) (–)-(NMI)2 ZrCl2 Me3 Al MAO or H2 O (1 eq.) 2) CH 2=CHBr [Pd]

2) RuCl3 •nH2 O (10 mol %) NaIO 4, CCl4, MeCN, H 2 O

1) (+)-(NMI) 2ZrCl2 Me3 Al MAO or H2 O (1 eq.) 2) O2

HO 2C

OAc

2) 2 N HCl

TBDPSO 35

32 (dr = 7/1, 99% ee, 50% f or two steps)

1) K2CO3 , MeOH

33 (75%, dr = 7/1, 99% ee)

MeO O

OH

31 (89% ee)

1) Ac2 O, pyridine

O

11% over 13 steps from styrene dr > 50/1

651

O 34 (100%, dr = 7/1, 99% ee) O

OH

36 9.3% from styrene, 99% ee

Scheme 8C.12.

yield from styrene. The enantiopurity of isolated 32 was estimated to be 99% ee. Acetylation followed by RuO4-catalyzed oxidative cleavage of the phenyl moiety and subsequent hydrolysis gave 5-acetoxy-2,4-dimethylpentanoic acid 33, which was further cyclized to afford lactone 34 in quantitative yield without epimerization. This tandem process has also been applied to the synthesis of α,ω-diheterofunctional reduced polypropioates 35 and 36, which are key components of inomycin and borrelidin, respectively. After chromatographic separation of minor diastereomers, stereochemical purity of 35 and 36 was estimated to be 99% ee and >50:1 dr.

8C.3. ENANTIOSELECTIVE HYDROGEN-MEDIATED C–C BOND FORMATION Catalytic hydrogenation is one of the most widely used chemical reactions in research laboratories and industries. Asymmetric hydrogenation accounts for more than half of the industrial production of chiral compounds [23]. Since the discovery of simple catalytic hydrogenation in the late 19th century, a couple of hydrogen-mediated carbon– carbon bond-forming reactions have emerged as powerful industrial processes to produce critical feedstock materials for chemical industry. For example, hydroformylation and Fischer–Tropsch reactions are two of the best known hydrogen-mediated C–C bondforming reactions. However, further investigation into this type of reactions had to wait until late 20th century. Hydrogen-mediated C–C bond-forming reactions pose several challenges. The foremost challenging issue is the circumvention of the conventional hydrogenation. This requires heterolytic activation of molecular hydrogen, enabling monohydride-based catalytic cycles, wherein the C–H reductive elimination pathway is disabled. Then, an


organometallic species formed by the addition of a metal hydride to an unsaturated C–C bond (i.e., alkene or alkyne) should be rapidly captured by an electrophile (e.g., aldehyde and imine), prior to the oxidative addition of molecular hydrogen to the metal or σ-bond metathesis of the metal–carbon bond with molecular hydrogen. Metal-dihydride route (leading to hydrogenation) and metal-monohydride route (leading to C–C bond formation) with an alkyne are illustrated in Scheme 8C.13 [24].

H H

H

M(X)L n

H

R1 R1

R2

MLn X

C–H reductive elimination

H

Simple reduction (homolytic activation of H2 to form metal dihydride)

H

R1 R2

H2 M-X X

R2

H

H ML n

R1

H M(X)L n H-X, base

R2

H

R3

Capture H2

X

R1

H R3

R2

C–C bond formation (heterolytic activation of H2 to form metal monohydride)

Scheme 8C.13.

Generation of monohydride organometallic species is highly dependent on the choice of catalyst system. For example, the heterolytic activation of molecular hydrogen has been observed with cationic rhodium complexes in the presence of a basic additive. A possible mechanism for the formation of an Rh-monohydride complex involves oxidative addition of molecular hydrogen to a metal species, LnRh-X, followed by a baseinduced H-X reductive elimination (Scheme 8C.14).

H2 L nRh

X

H L nRh

Base X

L nRh

X + HX

H Scheme 8C.14.

Jang and Krische investigated Rh-catalyzed reaction of none-aldehyde 37, which would undergo aldol reaction and simple hydrogenation to give 38 and 39, respectively (Scheme 8C.15) [25]. As Table 8C.4 shows, the nature of the Rh catalyst, ligand, and base exerts drastic influence on the preference of these two possible reaction pathways. Neutral catalyst, RhCl(PPh3)3, exclusively promotes simple hydrogenation (entry 1), while a cationic Rh complex with mildly basic phosphine ligand and a mild base, Rh(COD)2OTf–(p-CF3-C6H4)3P/KOAc, catalyzes the aldol reaction specifically (entry 5) [23]. This finding has brought about extensive studies on the hydrogen-mediated C–C bond-forming reactions and their applications to catalytic asymmetric transformations [23,25].


O

O

Ph

Catalyst (10 mol %) Ligand (24 mol %)

H

H 2 (1 atm), additive Dichloroethane, 25°C

37

O

OH

O

Ph

O

Ph

38 Aldol product (syn : anti)

653

H 39 Hydrogenation product

Scheme 8C.15.

TABLE 8C.4. Aldol Reaction versus Hydrogenation Pathways in the Reaction of 37 Entry

Catalyst

Ligand

Additive (mol %)

Yield (%) of 38 (syn : anti) 1 (99:1) 21 (99:1) 59 (58:1) 57 (14:1) 89 (10:1)

1 2 3 4

RhCl(PPh3)3 Rh(COD)2OTf Rh(COD)2OTf Rh(COD)2OTf

— PPh3 PPh3 (p-CF3C6H4)3P

— — KOAc (30) —

5

Rh(COD)2OTf

(p-CF3C6H4)3P

KOAc (30)

Yield (%) of 39 95 25 21 22 0.1

8C.3.1. Enantioselective Reductive Carbon–Carbon Coupling Reactions Hydrogenation of alkynes catalyzed by a cationic Rh complex should involve vinyl-Rh intermediate, which could be captured by electrophiles. Thus, the trapping of the vinylRh species with glyoxals and glyoxalates was investigated. It was found that the reductive coupling of diphenylbutadiyne (40a) with glyoxal 41 indeed proceeded in the presence of Rh(COD)2OTf (5 mol %) and triphenylphosphine (10 mol %) to give the condensation product 42 (Scheme 8C.16) [26]. Then, the enantioselective variant of this novel reaction was immediately studied using various commercially available chiral ligands [26]. The screening of those chiral ligands revealed that aromatic chiral diphosphine ligands afforded good results, while chiral ligands containing N-donor groups inhibited the reaction. Furthermore, asymmetric induction was noted to be critically dependent on the dihedral angle of the chiral diphosphine ligands [26]. Among the chiral ligands screened, (R)-Cl-OMe-BIPHEP was found to be the best ligand for this reaction, giving 42 in good yields and excellent enantioselectivity (Scheme 8C.16) [26]. The regioselectivity of this coupling reaction was also examined with 1-phenylbutadiynes 40 bearing different alkyl substituents with phenylglyoxal (41a) under the same conditions as those mentioned above [26]. It was found that coupling took place predominantly proximal to the phenyl moiety, yielding 43 with high to excellent enantiopurity (Scheme 8C.17). It should be noted that the minor regioisomeric products 44a,b were formed with high enantioselectivity as well. The reaction of phenyl-1,3-diyne 40 with glyoxalate 45 is also catalyzed by cationic Rh-diphosphine complexes to give reductive-coupling product 46 and/or 47 (Scheme 8C.18) [27]. Among the eight commercially available chiral ligands examined, (R)-ClOMe-BIPHEP was found to be the best ligand, as in the reaction with glyoxals 41 mentioned above. Regioselectivity in the reaction of methylphenyldiyne 40b was only


Cl

Ph

Rh(COD)2 OTf (R)-Cl-OMe-BIPHEP

O O

+ 40a

R

Ph

O MeO MeO

R

H2 (1 atm) Benzene, 25°C

41a-f

Ph

Ph

OH

42a-f

PPh 2 PPh 2

Cl (R)-Cl-OMe-BIPHEP

a b c d e f

R phenyl 2-napthyl t-butyl 1-methylpyrrol-2-yl 2-furyl 2-thienyl

Yield (%) of 42 74 77 72 71 78 74

% ee 91 90 95 86 91 93

Scheme 8C.16.

Ph

Rh(COD)2 OTf (R)-Cl-OMe-BIPHEP

O 40 b: R = Me c: R = n-Pr d: R = t-Bu e: R = TMS Me

+

O

Ph 41a

R

Ph

43 and/or 44 H2 (1 atm) Benzene, 25°C

Ph

O TMS

Ph

Ph

O Ph

Ph

n-Pr

Ph

O

O Ph

44b 89% ee

Ph 43c 98% ee

HO

64% yield 4:1

43b HO 85% ee t-Bu

O Ph

44a 88% ee

43a HO 83% ee n-Pr

Me

80% yield 5.2:1

HO

t -Bu

57% yield >99:1

O Ph

44c HO Not observed

HO

Scheme 8C.17.

modest (entries 8 and 9), while the reaction of t-butylphenyldiyne 40d gave 46c exclusively (entry 10). It is noteworthy to mention that the reaction of TMS-phenyldiyne 40e gave 47d exclusively with excellent enantioselectivity, that is, the complete reversal of regioselectivity was observed (entries 11 and 12).


Ph

Rh(COD)2 OTf Chiral ligand

O O

+ 40

Entry 1 2 3 4 5 6 7 8 9 10 11 12

R

1

OR2 45

R1

PAr 2 PAr 2

R1 Ph Ph Ph Ph Ph Ph Ph CH3 CH3 t-Bu TMS TMS

O OR2


Ligand (S)-BINAP (S)-tol-BINAP (S)-xylyl-BINAP (R)-DIFLUORPHOS (R,R)-xyxly-WALPHOS (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP

Ph

46

R2 Temp (°C) Et 25 Et 25 Et 25 Et 25 Et 25 Et 25 Et 45 Et 25 t-Bu 25 Et 40 Et 25 Et 40 F

O

F

O

F F

R1

Ph and/or

O OR2

47

OH

46:47 Yield (%) 46a=47a 51 46a=47a 50 46a=47a 73 46a=47a 76 46a=47a 17 46a=47a 78 46a=47a 83 3.3:1 78 3.0:1 52 >99:1 78 1:>99 74 1:>99 84

655

OH

% ee 69 (+), 46a 57 (+), 46a 49 (+), 46a 79 (-), 46a 72 (-), 46a 82 (-), 46a 78 (-), 46a 89 (-), 47b 87 (-), 47b 88 (+), 46c 93(+), 47d 91(+), 47d

Ar2P O

PPh2 PPh2

PAr2

Fe Me

O

(S)-BINAP: Ar= Ph (R)-DIFLUORPHOS (S)-tol-BINAP: Ar= 4-Me-C6H4(S)-xylyl-BINAP: Ar= 3,5-Me2C6H3-

(R,R)-xylyl-WALPHOS: Ar = 3,5-Me2C6H3-

Scheme 8C.18.

Following up this finding, the reactions of several other trialkylsilyldiynes 48 with 45 were studied under the optimal conditions mentioned above, which confirmed that hydrometallation and C–C bond formation took place exclusively on the acetylene moiety bearing a trialkylsilyl group to give 49 (Scheme 8C.19) [27,28]. The remarkable directing effect of trialkylsilyl group in this reaction can be accommodated by taking into account the enhanced π-acidity and hence π-back-bonding ability of trialkylsilylacetylene moiety of the 1,3-diyne system as well as oxarhodacycle 50 formation upon insertion of the aldehyde carbonyl moiety of glyoxalate (Scheme 8C.19) [27,28]. The enantioselective reaction of 1,3-enynes 51 in place of 1,3-diynes with glyoxalate 45 is also catalyzed by cationic chiral Rh-diphosphine complexes to give the corresponding dienyl-α-hydroxyesters 52 (Scheme 8C.20) [28,29]. Naturally, there is no regioselectivity issue in this reaction, and the C–C bond formation takes place at the acetylene moiety exclusively. A number of commercially available chiral diphosphine ligands were screened for the reaction of 1-phenylbutenyne (51a) with ethyl glyoxalate (45a). Among the chiral ligands examined, (R)-OMe-BIPHEP (75% ee, entry 3) and (R)-Cl-OMeBIPHEP (81% ee, entry 4) gave the best results. Optimization of OMe-BIPHEP ligands by introducing a very bulky substituent to the phosphine moiety led to a highly efficient


R1

Rh(COD)2OTf Chiral ligand

O

+ 48

Me

O

SiR3

OR2

45

R1

SiR3 O OR2


49

TMS O

TMS O

OH

TMS O

TBSO

OEt

OEt

OEt

OH

49b OH 71% yield, 89% ee

49a OH 78% yield, 94% ee

TBSO

TBS O

TBSO

49c 72% yield, 90% ee TBS O

OEt

OEt

49d OH 73% yield, 90% ee

49e OH 77% yield, 90% ee

Remarkable directing effect of silyl group Ph Ph

TMS

TMS

Ph

O

+

LnRh(I)

LnRh(I)+ 40e

TMS

Rh(III)Ln

OEt

Ph

TMS O

O

OEt LnRhIII O 50

Scheme 8C.19.

ligand, (R)-3,5-di-t-butylphenyl-OMe-BIPHEP, which achieved 90–93% ee in this reaction (entries 6–8) [28]. It should be noted that the addition of a bulky Brønsted acid was found to exert significant effect on chemical yield and enantioselectivity of this reaction. Thus, the reaction in the presence of Rh(COD)2OTf, (R)-(3,5-t-Bu-4-MeOPh)-MeO BIPHEP, and triphenylacetic acid (TPAA) gave 52a in 82% yield and 95% ee (entry 9). It has been proposed that Brønsted acid facilitates the heterolytic hydrogenolysis of the oxarhodacycle similar to 50 by forming six-centered transition state for the cleavage of the Rh–O bond through protonation of the oxygen, followed by the formation of an Rhcarboxylate species. According to computational study on the Rh–O bond hydrogenolysis, the direct hydrogenolysis with molecular hydrogen through four-centered-bond metathesis is a high-energy process. Thus, the Brønsted acid-cocatalyzed hydrogenolysis mechanism can bypass the σ-bond metathesis pathway to accelerate the catalytic cycle [28,29]. To assess the scope of this enantioselective reductive coupling process, the reactions of various 1-substituted 1,3-butenynes 51 were studied under the optimal conditions mentioned above. As Scheme 8C.21 shows, the corresponding coupling products 52 were obtained in 70–82% yields and 86–97% ee [28]. The result of 52a is also listed for comparison purpose.


Rh(COD) 2OTf (5 mol %) Ligand (5 mol %)

O Ph

+

OEt O

51a

45a

RO

PAr2

RO

PAr2

H2 (1 atm), 25°C Dichloroethane (0.2M)

Ph

657

O OEt

H OH 52a

PAr2 PAr2

(R)-BINAP: Ar= Ph (R)-(3,5-t-Bu-4-MeO-C6H2)-MeO-BIPHEP: R = Me (R)-xylyl-BINAP: Ar= 3,5-Me2C6H3 Ar = (3,5-t-Bu-4-MeO-C6H2 (R)-Cyclohexyl-SONIPHOS: R = c-C6H11CO, Ar = Ph

Entry 1 2 3 4 5 6 7 8 9 a

Catalyst a

Chiral Ligand

Acid

Rh(COD)2OTf Rh(COD)2OTf Rh(COD)2OTf Rh(COD)2OTf Rh(COD)2OTf Rh(COD)2OTf Rh(COD)2BF4 Rh(COD)2BARF Rh(COD)2OTf

(R)-BINAP (R)-3,5-xylyl-BINAP (R)-MeO-BIPHEP (R)-Cl-MeO-BIPHEP (R)-c-Hex-SONIPHOS (R)-(3,5-t-Bu-4-MeOPh)-MeO BIPHEP (R)-(3,5-t-Bu-4-MeOPh)-MeO BIPHEP (R)-(3,5-t-Bu-4-MeOPh)-MeO BIPHEP (R)-(3,5-t-Bu-4-MeOPh)-MeO BIPHEP

– – – – – – – – TPAA

Yield (%) 84 69 71 70 76 65 65 66 82

% ee 63 69 75 81 71 91 90 93 95

BARF = B(3,5-(CF3)2C6H3)4 Scheme 8C.20.

The enantioselective 1,3-enyne–glyoxal reductive coupling reaction was applied to the synthesis of the C-ring component of bryostatin 53 (Scheme 8C.22) [30]. Bryostatins are a family of marine natural products isolated from bryozoan Bugula neritina [31]. Bryostatins possess strong antineoplastic activity against a broad range of tumor types as well as other pharmacological activities [32]. The retrosynthetic analysis of the bryostatin C-ring component led to dienone 55, which can be constructed from α-ketoaldehyde 54 and 1,3-enyne 51h through Rh-catalyzed reductive coupling. Several commercially available chiral diphosphine ligands were screened for this reaction, and (R)-tol-BINAP was selected as the chiral ligand of choice. The reaction of 51h with 54 was run with 5 mol % of Rh(COD)2OTf and (R)-tol-BINAP in the presence of TPAA (1.5 mol %) at 65°C to give the key intermediate dienone 55 with 91% ee in 70% yield (Scheme 8C.22) [30]. The bryostatin C-ring component 53 was synthesized from 55 in four steps in 36% overall yield. Highly enantioselective vinylation of imines is still an elusive goal, to date. Nevertheless, it has been shown that Rh-catalyzed reductive coupling of acetylene (2 equiv) with


O

R

+

OEt O

51

45a

a b c d e f g h

OEt

Dichloroethane (0.2 M) Ph3CCO2H (5 mol %) H2 (1 atm), 25°C

R phenyl p-nitrophenyl 1-napthyl 2-thienyl cyclohexyl n-pentyl CH2CH2OTES 2-indolyl

O

R

Rh(COD)2OTf (5 mol %) (R)-(3,5-t-Bu-4-MeO-C6H2)-MeO-BIPHEP

OH

52

Yield (%) of 52 82 75 70 72 74 71 70 72

% ee 95 97 97 92 94 86 90 86

Scheme 8C.21.

O H

BnO Me Me O

54 + OTBS

51h

Me

BnO

Rh(COD)2OTf (5 mol %) (R)-tol-BINAP (5 mol %) Ph3CCO2H (1.5 mol %)

BnO

Me

OMe O

OH

4 steps

O

Dichloroethane (0.3 M) H2 (1 atm), 65°C TBSO

C7H15

55

O

CO2CH3

53 Bryostatin C-ring component

Scheme 8C.22.

N-arylsulfonylimines 56 (1 equiv) proceeds through formal vinylation (dienylation) of an aldimine (Scheme 8C.23) [33]. This unique reaction involves the initial dimerization of two acetylene molecules via carbometallation to form rhodacyclopentadiene 57, followed by insertion of the C=N bond of 56 to Rh-C, and hydrogenolysis to give the corresponding dienyl-N-arylsulfonylamine 58. The reaction is efficiently catalyzed by a cationic Rh complex, [Rh(COD)2]BARF (5 mol %), with (S)-Cl-OMe-BIPHEP (5 mol %) in the presence of m-nitrobenzoic acid (5 mol %) and sodium sulfate (200 mol %) in toluene at 45°C and 1 atm of hydrogen to give 58 (Z : E 95:5) in good to high yield and excellent enantioselectivity. Aromatic and aliphatic sulfonylaldimines react virtually in the same way in this process. Highly syn-diastereoselective, hydrogen-mediated reductive aldol coupling of alkyl vinyl ketones with various aldehydes was successfully achieved by the use of tri-2furylphosphine, (Fur)3P, with Rh(COD)2OTf in the presence of Li2CO3 [34]. However, the enantioselective process of this reaction had been challenging due to the lack of electronically appropriate, commercially available chiral ligands until it was found that


H

2

H

[Rh(COD)2]BARF NSO2Ar (S)-Cl-MeO-BIPHEP

+ H

R

56

H2 (1 atm) m-NO2C6H4CO2H Na2SO4 Toluene, 45°C

659

ArSO2N R

58

RhLn

57

a b c d e f g h i j k l

R phenyl tolyl p-chlorophenyl p-nitrophenyl p-methylbenzoate m-methoxyphenyl m-bromo-p-fluorophenyl m-nitro-p-bromophenyl 4-nitrothienyl cyclohexyl isopropyl cyclopropyl

Yield (%) of 58 86 71 74 83 75 72 70 71 73 68 70 65

Z:E 95:5 95:5 95:5 95:5 95:5 95:5 95:5 95:5 95:5 95:5 95:5 95:5

% ee 93 98 95 97 95 97 97 94 95 97 98 97

Scheme 8C.23.

TADDOL-based chiral phosphonite ligands were effective for this reaction. Optimization of these ligands led to the development of AbbasPhos-I, which achieved 86–96% enantioselectivity in the reductive aldol coupling of methyl or ethyl vinyl ketone 59 with various aldehydes 60, affording the corresponding aldol coupling products 61 in good to excellent yield and high syn-diastereoselectivity (Scheme 8C.24) [35]. This unique enantioselective aldol reaction complements other extensively studied aldol reaction processes.

8C.3.2. Enantioselective Reductive Carbocyclizations Mediated by Hydrogen Enantioselective reductive cyclization of 1,6-enynes 62 mediated by hydrogen was found to be catalyzed by Rh(COD)2OTf with chiral diphosphines to give 63 (Scheme 8C.25) [36]. This carbocyclization reaction tolerates various functional groups, but the chemical yield as well as enantioselectivity of the reaction is highly dependent on the structure of 1,6-enyne 62 and the chiral ligand used. Thus, the reactions of 1,6-enynes bearing amide and ester linkages conjugated to the acetylene moiety (62g and 62h) using (R)PHANEPHOS gave the corresponding lactam 63g and lactone 63h with 91% ee and 94% ee, respectively, whereas those using (R)-BINAP and (R)-Cl-OMe-BIPHEP gave products with only low enantiopurity (6–26% ee). On the contrary, (R)-BINAP and (R)-Cl-OMe-BIPHEP were highly efficient in achieving excellent enantioselectivity in the reactions of other 1,6-enynes (62a–f and 62i–l), while the use of (R)-PHANEPHOS


O O R

1

R

+

59

O

R2

H O

O

O

H

Li2CO3 H2 (1 atm) DCM, 25°C

R1 Me Et Et Me Me Et Et Et Et Me Me

OH

R1

Abbas-Phos–1

60

Entry a b c d e f g h

O

Rh(COD)2OTf

2

61

R2 phthalimido phthalimido OBn Ph Ph 3-furyl 3-N-methylindolyl 3-N-methylindolyl

Yield (%) of 61 88 94 85 70 76 83 92 97

S P

AbbasPhos-I

syn : anti 50:1 45:1 25:1 25:1 22:1 25:1 15:1 25:1

% ee 96 95 91 90 90 88 86 90

Scheme 8C.24. Rh(COD) 2OTf (3–5 mol %) Chiral ligand (3–5 mol %) H 2 (1 atm)

R1

Y X

R1 Y R2

X 2

Dichloroethane, 25°C, 2–3h

R

H 63

62 1

a b c d e f g h i j k l

R Me Ph Ph HO(CH2)2 BnO(CH2)2 BnO(CH2)2 Me Me CO2Me CO2Me CO2Me CO2Me

R2 H H H H H H H H c-PrCO PhCO 2-furan-CO 3,4-Cl2C6H3CO

X TsN O O O O O BnN O CH2 CH2 CH2 CH2

Y CH2 CH2 CMe2 CH2 CH2 CMe2 CO CO CH2 CH2 CH2 CH2

Ligand (R)-BINAP (R)-BINAP (R)-Cl-OMe-BIPHEP (R)-Cl-OMe-BIPHEP (R)-BINAP (R)-Cl-OMe-BIPHEP (R)-PHANEPHOS (R)-PHANEPHOS (R)-Cl-OMe-BIPHEP (R)-BINAP (R)-BINAP (R)-BINAP

Yield (%) of 63 79 80 85 77 77 82 73 73 68 66 72 63

% ee 93 97 84 95 98 98 91 94 98 96 96 94

Scheme 8C.25.

in those reactions resulted in either formation of a mixture of multiple products or complete reduction of the substrates. A plausible mechanism of this reaction was proposed on the basis of deuterium labeling control experiments [36]. As Scheme 8C.26 illustrates, the catalytic cycle begins with cycloaddition of an RhLn species and enyne 62 (R2 = H), forming rhodacyclopentene 64. Homolytic hydrogen activation via either oxidative addition of molecular hydrogen or σ-bond metathesis takes place to yield vinyl-rhodium vinyl species 65. The subsequent

8C.4. ASYMMETRIC CARBOCYCLIZATIONS 661

R1 Y

Y

RhIL

H(D)

X

n

H(D) 63 (R2 = H)

62 (R 2 = H)

R1 Y X 65

R1

X

R1

RhIIILnH(D)

Y X

RhIIILn 64

H(D)

H2 or D2 Scheme 8C.26.

reductive elimination affords the cyclization product 63 (R2 = H) and regenerates the RhLn species. As an extension of the 1,6-enyne cyclization, the enantioselective reductive carbocyclization of 5-alkynals 66 was also investigated. The reactions were found to proceed smoothly in the presence of Rh(COD)2OTf (5 mol %), (R)-Cl-MeO-BIPHEP (5 mol %) and 2-naphthoic acid (5 mol %) at 45°C and ambient pressure of hydrogen to give the corresponding five-membered-ring alcohols 67 in 63–99% yields and 91–99% ee (Scheme 8C.27) [37,38]. The proposed mechanism of this reaction is essentially identical to that of 1,6-enyne 62 (see Scheme 8C.26) by replacing the terminal methylene moiety with oxygen.

8C.4. ASYMMETRIC CARBOCYCLIZATIONS 8C.4.1. Tandem 1,4-Addition-Aldol Cyclizations 1,4-Conjugate addition of organometallic reagents to α,β-unsaturated carbonyl compounds provides a versatile method for carbon–carbon bond formation. Thus, extensive efforts have been made on the development of asymmetric 1,4-conjugate addition reactions [39–44]. Recently, a series of catalytic tandem reductive enolate formation–aldol cyclization processes, forming carbocycles and heterocycles have been developed [26,46– 52]. In 2003, Krische et al. reported the first reductive aldol cyclization of keto-enone 68a involving diastereo- and enantioselective carbometallation. A variety of chiral ligands were screened, and (R)-BINAP was found to be the best ligand, affording cyclized product 69a with 88% ee in 88% yield (Scheme 8C.28) [53]. A plausible mechanism (Scheme 8C.29) was proposed based on the mechanistic studies performed by Hayashi on the Rh-catalyzed asymmetric conjugate addition of boronic acids to enones [54]. The observed relative stereochemistry was rationalized by assuming Z-enolate formation via a Zimmerman–Traxler-type transition state [55].


X

Rh(COD) 2OTf (5 mol %) (R)-Cl,MeO-BIPHEP (5 mol %)

R1

Y R2

R1

X Y

R

2

2-Naphthoic acid (5 mol %) H 2 (1 atm) Dichloroethane, 45°C

O

R2

R2

OH

67

66

Ph

O

Ph

TsN

O

OH p-BrBnN

TsN

BnN OH

Me Me

OH

67a, 85%, 97% ee

67b, 67%, 95% ee

67c, 99%, 91% ee

OH

67d, 77%, 91% ee Me

Me Me Me TsN

Me O

O

Me Me

TsN

OH

OH

67e, 76%, 96% ee

67f, 63%, 98% ee

Me Me

OH

OH

67g, 86%, 99% ee

67h, 73%, 99% ee

Scheme 8C.27.

O Ph

Me

68a

(R)-tol-BINAP (R)-BINAP (R)-BINAPa (R)-BINAPb b

Ph

PhB(OH)2 (200 mol %) H 2O (500 mol %) Dioxane (0.1M), 95°C

Ligand

a

O HO Me

[Rh(COD)Cl]2 (2.5 mol %) Ligand (7.5 mol %)

O

Ph 69a

Yield (%)

% ee

94 90 80 88

62 77 87 88

TEA (1000 mol %) was added. Rh(C2H4)2(acac) was used as catalyst, and KOH (10 mol %) was added.

Scheme 8C.28.

This methodology was applied to the enantioselective desymmetrization of enonediones 72. This reaction gave rise to fused bicyclic products 73, embodying four contiguous stereocenters, with excellent stereochemical control (Scheme 8C.30) [56]. The products 73 would serve as synthons to implement contiguous chiral centers in the total synthesis of both natural and unnatural compounds of medicinal interest. To extend the scope of this reaction, the feasibility of Cu-catalyzed conjugate addition–aldol cyclization process was investigated. Cu-catalyzed addition of organozinc


ArB(OH)2

B(OH)3

RhILnCl KOH O

OH R2

R1

O

Rh LnOH

R2

O

R1

RhILnAr

I

Ar

68 69 H2O O

H

Ar

R1 R2

1

R

O O RhILn

ORhILn R2 1

R

Ar

71

O RhILn O R2

H

Ar

R1 R2 O O

Ar

70

RhILn

Scheme 8C.29.

O R1

[Rh(COD)(OMe)]2 (2.5 mol %) (S)-BINAP (7.5 mol %)

R2

O

R3

ArB(OH) 2 (200 mol %) KOH (10 mol %), H 2O (500 mol %) Dioxane (0.1 M), 95°C

n

Me O 72

1 2 3 4 5 6 7 8 9 10 11 12 13 14

R1 CH3 CH3 Ph CH3 CH3 CH3

Ph CH3 CH3 CH3 CH3 CH3 CH3 CH3

O OH R2

Ar n

R3 Me O 73

>99:1 de; 85->99% ee

n = 1, 2

Entry

R1

R2

R3

-(CH2)2-(CH2)2-(CH2)2-(CH2)2-(CH2)3-(CH2)3-(CH2)3-(CH2)3-(CH2)2-(CH2)2-(CH2)2-(CH2)31,2-phenylene CH3 CH3

n

Ar

Yield (%)

% ee

1 1 1 1 1 1 1 1 2 2 2 2 1 1

p-MeO-Ph Ph Ph p-Br-Ph p-MeO-Ph Ph Ph p-Br-Ph p-MeO-Ph Ph p-Br-Ph Ph Ph Ph

83 87 94 88 97 87 86 77 80 82 85 65* 93 95*

90 90 87 94 90 91 85 92 86 85 86 88 88 87

*Yield based on recovered starting material

Scheme 8C.30.


compounds to α,β-unsaturated carbonyl compounds has been well established [40– 42,57–59]. Also, the trapping of Zn enolates with aldehydes [40,58,60] and acetals/ketals (oxocarbenium ions) [62] has been reported. However, the use of ketones to trap Zn enolates was reported to have failed in the absence of a strong Lewis acid [61]. Nevertheless, the tandem conjugate addition–aldol cyclization of diethylzinc with ketones, esters, and nitriles was found to proceed in the presence of a catalytic amount of Cu(OTf)2-P(OEt)3 to give the corresponding products 75, 76, and 77, respectively, in excellent yields (Scheme 8C.31) [62]. O HO

R

O E

R

Et 2 Zn (150 mol %) Cu(OTf) 2 (2.5 mol %) P(OEt)3 (5 mol %)

Et

n

n

75 E = ketone

E

R

Dichloromethane 74

Et

OZnLn

Me

O

n

O O

R

n = 1, 2

Et

n

76 E = ester

NH 2

R Et

n

77 E = nitrile

Scheme 8C.31.

To demonstrate the feasibility of the enantioselective variant of this reaction, enonedione 78 was subjected to conditions of Scheme 8C.31, but using Feringa’s chiral phosphoramidite ligand [63] in place of P(OEt)3 [62]. The reaction gave a mixture of two diastereomers: 79 (80% ee) and epi-79 (98% ee) in a 2.3:1 ratio and nearly quantitative yield (Scheme 8C.32) [62].

Ph

Et2Zn (150 mol %) Cu(OTf )2 (2.5 mol %) Feringa ligand (5 mol %)

O O

Ph Et

O OH

Ph Et

O OH

Toluene, –40°C 78

Me O 99% combined yield, 2.3:1 dr

Me

Me

79 80% ee

epi-79 98% ee

O P N O

Feringa ligand

Scheme 8C.32.

8C.4.2. Reductive Aldol Cyclizations In 2001, Chiu et al. reported that a phosphine-stabilized copper hydride complex, [(Ph3P) CuH]6 (Stryker’s reagent), effectively promoted tandem reductive aldol cyclizations of keto-enones [64]. Following up this finding, Lam and Joensuu looked for a catalytic process and found that a catalytic amount of Cu(OAc)2·H2O with an achiral diphosphine

Ph Ph


ligand (DPPF or racemic BINAP) and a stoichiometric amount of 1,1,3,3-tetramethylhydrosiloxane (TMDS) in THF smoothly promoted the reaction of ketoalkyl acrylates 80, affording the cyclic aldol products 81 with excellent diastereoselectivity (>95:5) in fairly good yields (Scheme 8C.33) [50].

R2 R

O

1

Cu(OAc)2 •H2 O Diphosphine

O R3 80

n

TMDS, THF, rt n = 1, 2

O

O

R2

PPh2 O

R1 R3 81

Fe PPh2

n

OH

DPPF

Scheme 8C.33.

Several chiral diphosphine ligands were screened for enantioselective reactions of selected 82, and it was found that (R)-3,5-xyl-MeO-BIPHEP and (S)-Segphos gave the best results (i.e., >80% ee) (Scheme 8C.34) [66]. It appears that the reaction is sensitive to the substitution pattern and ring size. Thus, further investigation deems necessary to be practical. O

O R1

O 2

Cu(OAc)2•H2O (5 mol %) Ligand (5 mol %) TMDS, THF, rt, 24 h

R

83

82 Ligand

p-Cl-Ph PhCH2CH2 p-Cl-Ph PhCH2CH2 p-Cl-Ph PhCH2CH2

O HO

O

R1

1

Yield (%)

% ee

71 61 73 68 79 60

(R)-3,5-xyl-MeO-BIPHEP (R)-3,5-xyl-MeO-BIPHEP (S)-Segphos (S)-Segphos (S)-BINAP (S)-BINAP

83 80 82q 80q 73q 72q

qenantiomer opposite to that depicted.

O MeO MeO

P(3,5-xyl)2 P(3,5-xyl)2

O O

PPh2 PPh2

O

(R)-3,5-xyl-MeO-BIPHEP Scheme 8C.34.

(S)-SEGPHOS


The tandem reductive aldol cylization has been extended to the formation of βhydroxylactams 85 from α,β-unsaturated amides with tethered ketones 84 (Scheme 8C.35) [50,51]. The reaction gave 85 with high diastereoselectivity (>95:5) in 52–70% yields. However, the enantioselective variant of this process has not been reported yet.

O R1

R2

N Ar

O

Cu(OAc)2•H2O DPPF

O

R1

N

R2

TMDS, THF, rt

HO

84

Ar

85

Scheme 8C.35.

In 2008, Lipshutz et al. reported a highly efficient chiral CuH-catalyzed enantioselective reaction of keto-enones 86, giving cyclic reductive aldol products 87 as a single diastereomer with high enantiopurity (up to 97% ee) (Scheme 8C.36) [52]. As effective chiral ligands for the Cu catalyst in this process, ferrocenylphosphines, (S,R)-PPF-P(tBu)2 and (R,S)-(4-CF3-C6H4)2-P(t-Bu)2, were employed, and diethoxymethylsilane (DEMS) was used as hydride source. Results are summarized in Table 8C.5.

O

Cu(OAc)2•H2O Chiral ligand

O R2

R R1

O HO

n

∗

R

(EtO)2MeSiH Toluene

R1

86

R2 ∗

∗

n

87

PPh2 Me

Me

P(t-Bu)2

H P(t-Bu)2 Fe P(p-CF3Ph)2

H Fe

(S,R)-PPF-P(t-Bu)2

(R,S)-(4-CF3Ph)2PF-P(t-Bu)2 Scheme 8C.36.

The reactions of E- and Z-enone pairs of 86 gave the corresponding 87 in good yield and excellent enantioselectivity (entries 1 and 4; entries 2 and 5). Various substituents R and R1 of the enone moiety are well tolerated in this reaction for chemical yields, but enantioselectivity is affected in some cases (entries 3 and 6–9). The reaction of 86i using (S,R)-PPF-P(t-Bu)2 gave 87i with only 64% ee (entry 9), but the use of (R,S)-(4-CF3C6H4)2-P(t-Bu)2 as the chiral ligand significantly improved the enantioselectivity (97% ee, the other enantiomer) (entry 10). While the formation of the five-membered-ring product 87j is feasible, the reaction gave two isolable diastereomers (dr = 59:41) with 97% ee and 92% ee, respectively (entry 11).


TABLE 8C.5. Asymmetric Reductive Aldol Cyclization of Keto-Enones 86 Entry 1 2 3

Keto-Enone a: R = R1 = R2 = Me b: R = R1 = Me, R2 = Ph c: R = Ph, R1 = R2 = Me

O R

O R

1

R

O HO R2 R

2

R d: R = R1 = R2 = Me e: R = R1 = Me, R2 = Ph f: R = Ph, R1 = R2 = Me

O

5 6

R

O

R1 7

O HO R2 R

86d-f

87d-f

O

O HO i-Pr O

96 97 75

66

84

83

83

92 94

97b

75c

97, 92

87g

O

O HO

n-Bu

O Ph

n-Bu Ph

86h

87h

O

O HO n-Bu O

n-Bu

Ph

64

Ph

86i 11

88 75 98

85a

i-Pr

86g

9 10

96 97

i-Pr

i-Pr 8

91 77 98

87a-c

R1

R2

% ee

1

86a-c 4

Yield (%)

Product

87i

O

O

86j

O

HO

87j

Conditions: Cu(OAC)2 (3–5 mol %), (S,R)-PPF-P(t-Bu)2 (1 mol %), DEMS (1.5 equiv), toluene, 12 h, −10°C. a

At 20°C. (R,S)-(4-CF3Ph)2PF-P(t-Bu)2 (1 mol %). c Combined yield for two diastereomers (dr = 59:41). b

The CuH-catalyzed asymmetric reductive aldol cyclization of keto-enones 86 can also be carried out under heterogeneous as well as aqueous conditions (Scheme 8C.37). The reaction of 86a over Cu/C in the presence of (S,R)-PPF-P(t-Bu)2 (1 mol %) and NaOPh (10–20 mol %) with DEMS (4 equiv) in toluene at −10°C afforded 87a in 84% yield and 98% ee. The reaction of 86d was also carried out entirely in water despite the insolubility of the substrate. Thus, the reaction of 86d with phenylsilane (excess)


catalyzed by Cu(OAc)2·H2O (5 mol %)/(S,R)-PPF-P(t-Bu)2 (1 mol %) in the presence of nanomicelle-forming surfactant, polyoxyethanyl-α-tocopheryl sebacate (PTS) at 5°C gave 87d in comparable yield and enantioselectivity.

Cu/C (S,R)-PPF-P(t-Bu)2

O O

O HO

NaOPh, DEMS Toluene, –10°C, 6 h 87a

86a

84%, 98% ee O O

86d

5% Cu(OAC)2, (S,R)-PPF-P(t-Bu)2 PhSiH3 PTS/H2O, 5°C, 5 h

O HO

87d 81%, 94% ee

Scheme 8C.37.

8C.5. ASYMMETRIC HECK REACTIONS 8C.5.1. Heck Reaction and Its Application to Catalytic Asymmetric Synthesis The Heck reaction (more accurately “Mizoroki–Heck reaction”) is defined as a Pd(0)catalyzed coupling reaction of aryl or alkenyl halides with alkenes in the presence of an appropriate base. This reaction was first discovered and developed by Mizoroki et al. [65] and Heck and Nolley [66] in early 1970s. This coupling reaction has become one of the most widely used reactions in organic synthesis, which is mainly attributed to the fact that this reaction can construct tertiary and quaternary carbon centers through carbon–carbon bond formation. This feature has found numerous applications in the synthesis of complex natural products [67,68]. With the explosive development of chiral ligands for asymmetric catalysis over the past decades, the development of asymmetric Heck reaction attracted much attention [69]. The first successful examples of the intramolecular enantioselective reaction were reported independently by Shibasaki et al. [70] and Overman et al. [71] in 1989. In Shibasaki’s process, a chiral tertiary carbon center was introduced (46% ee) by the catalysis of Pd(OAc)2-(R)-BINAP in the presence of Ag2CO3 in N-methyl-2pyrrolidinone (NMP), while in Overman’s process, a chiral quaternary carbon center was created (45% ee) by using Pd(OAc)2-(R)-DIOP as the catalyst in the presence of Et3N in benzene (Scheme 8C.38). After these reports, a variety of intra- and intermolecular asymmetric Heck reactions emerged quickly with improved enantioselectivities. For example, enantioselective intramolecular Heck reaction of meso-cycloalkadienes 101, 104, and 107, bearing an enol triflate tether using Pd catalysts with (R)- or (S)-BINAP, gave key intermediates 102, 105, and 108 for the synthesis of various terpenoid natural products, including (+)-vernolepin 103, (−)-oppositol 106, and (−)-capnellene 109, respectively (Scheme 8C.39) [72–74]. The reaction has also been applied to the total synthesis of natural

8C.5. ASYMMETRIC HECK REACTIONS 669

CO2Me

Pd(OAc)2 (3 mol %) (R)-BINAP (9 mol %) Ag2CO3 (2 eq) NMP, 60°C

I

CO2Me (Shibasaki) H 98 74%, 46% ee

97

Pd(OAc)2 (10 mol %) (R,R)-DIOP (10 mol %) Et3N

OTf

(Overman)

Benzene, rt O

O 100 90%, 45% ee

99

Scheme 8C.38.

Pd(OAc)2 (5 mol %) (R)-BINAP (10 mol %)

CO2Me

101

OTBS

H 102 70%, 86% ee

K2CO3 (2 eq) Benzene, 60°C

O

Br Me -

H

H Me OH

105 63%, 73% ee

104

H

O (+)-Vernolepin 103

OTBS

Pd(OAc)2 (5 mol %) (R)-BINAP (10 mol %)

OH

O O

K2CO3 (2 eq) KOAc (1 eq) DCE, 60oC

TfO

OTf

CO2Me

(–)-Oppositol 106

[Pd(allyl)Cl]2, (S)-BINAP TBDPSO

CO2Et

OTf EtO Me 107

EtO2C CO2Et

OTBDPS

Me Me H H

ONa Me

NaBr, DMSO, rt 108 77%, 87% ee

H

(–)-Capnellene 109

Scheme 8C.39.

polyketides such as halenaquinone, xestoquinone, and wortmannin [67,68]. Moreover, the reaction has been employed as the key step in the synthesis of various alkaloids, for example, physostigmine, quadrigemine C, spirotryprostatin B, and minfiensine [67,68].


8C.5.2. Asymmetric Intramolecular Heck Reactions The intramolecular asymmetric Heck reaction has found numerous applications in organic syntheses, as mentioned above. Among those applications, the synthesis of optically active oxindoles bearing a quaternary asymmetric center has been extensively studied, mainly because enantiopure oxindoles can serve as versatile intermediates or synthons in the total synthesis of a variety of natural products [69,75,76]. The reaction of (E)-α,β-unsaturated-2-iodoanilide 110 was carried out using Pd2(dba)3-(R)-BINAP as catalyst and Ag3PO4 or 1,2,2,6,6-pentamethylpiperidine (PMP) as HI scavenger in N,Ndimethylacetamide (DMA), to give oxindoles (S)- or (R)-111 in good yield and fairly good enantioselectivity under cationic or neutral conditions (Scheme 8C.40). It should be noted that a dramatic switching in the direction of asymmetric induction was observed between these two conditions even though the same chiral ligand, (R)-BINAP, was used in both reactions. This was the first example that achieved fairly good enantioselectivity under neutral conditions.

O Pd2(dba)3-CHCl3 (5 mol %) (R)-BINAP (12 mol %)

O

Ag3PO4 (2 eq) DMA, 80°C

O

O

(S)-111 81%, 71% ee

N

O

I O

Pd2(dba)3-CHCl3 (5 mol %) (R)-BINAP (12 mol %)

O

110 PMP (5 eq) DMA, 110°C

N

N

O O (R)-111 77%, 66% ee

Scheme 8C.40.

In the same manner, the reactions of a series of N-cycloalkenoyl-2-iodoanilides, Ncycloalkenylmethyl-2-iodoaniline, and cycloalkenylmethyl 2-iodophenyl ether were investigated, and results are shown in Scheme 8C.41 [76]. It is worthy of note that the cationic conditions with Ag3PO4 are detrimental to the enantioselectivity in the reactions of N-cycloalkenoyl-2-iodoanilides, while neutral conditions with PMP do not give appreciable asymmetric induction in the reaction of N-cycloalkenylmethyl-2-iodoaniline and cycloalkenylmethyl 2-iodophenyl ether. Thus, this reaction appears to be highly sensitive to the matching or mismatching of the functional groups in substrate and reaction conditions. To optimize both enantioselectivity and regioselectivity of the reaction, new chiral ligands and modified substrates have been developed in the past 10 years. For example, Guiry and Kiely prepared aryl triflate 116 to investigate the regio- and enantioselectivity in the formation of oxindole 117 catalyzed by Pd(0) complex with oxazoline-based aminophosphine ligand 119 under cationic conditions (Scheme 8C.42) [77]. Excellent


Y

Y Pd2(dba)3-CHCl3 (5 mol %) (R)-BINAP (12 mol %)

Z

n

I

X2

O

n

Additive DMA

O

N

Z

X2

CO2Me N

N

O O

O

O

O 112 Neutral conditions Cationic contditions

113

50%, 88% ee 62%, 0% ee

114

96%, 56% ee 81%, 7% ee

115

51%, 8% ee 90%, 64% ee

66%, 0–7% ee 91%, 49–55% ee

Scheme 8C.41.

O Pd2(dba)3 (2.5 mol %) 119 (10 mol %)

N OTf

Proton sponge (5 eq) Solvent, 110°C, 168 h

116 O Fe

O

N

O

N

117 118 71%, 82% ee, >99:1 regioselectivity (in toluene) 30%, 85% ee, >99:1 regioselectivity (in DMA)

N PPh2 119 Scheme 8C.42.

regioselectivity (>99:1) and high enantioselectivity (up to 85% ee) were obtained using Pd2(dba)3, 119, and proton sponge as TfOH scavenger in toluene or DMA. A library of phosphinoimidazoline (BIPI) ligands 120 was developed by Busacca et al. for asymmetric intramolecular Heck reactions [78,79]. Through electronic tuning of three substituents in a ligand, high enantioselectivity was achieved. Two examples are shown in Scheme 8C.43. In addition to chiral oxindoles, other chiral nitrogen heterocycles have also been synthesized via intramolecular asymmetric Heck cyclization. For example, the reaction of endocyclic enamide 124 afforded indoloizidine 125 or its achiral isomer 127, depending on the solvent used (Scheme 8C.44) [80]. The reaction of 124 catalyzed by Pd-(R)BINAP in the presence of Ag3PO4 in DMF at room temperature gave 125 in 64% yield and 85% ee. However, when THF was employed as the solvent, 127 was formed exclusively (Scheme 8C.44). Indolizidine 126, a key intermediate for the synthesis of 5E,9Zindolizidine 223AB [81] and (+)-5-epiindolizine 167B [82], was obtained from 125 in four steps [80].


O

O

OTf 121

R3 N

PMP, Ph2O 95°C, 18 h

122 38%, 88% ee

O

O OTf

O

O

S-111 53%, 83% ee

123

N

P

R2 120

R1 O

PMP, Ph2O 95°C, 18 h

R1

N

Pd2(dba)3, 120

N

O

N

Pd2(dba)3, 120

N

R1 = 3,5-F2 R2 = (R,R)-3,5-F2C6H3 R3 = 2-naphthoyl

Scheme 8C.43.

O

O Pd-(R)-BINAP O

Br

Ag3PO4, DMF, rt 64%

N

N

N H 125 (85% ee)

H 126

O 124

Pd-(R)-BINAP

N

Ag3PO4, THF, rt 69%

127

Scheme 8C.44.

A sequential catalytic asymmetric Heck–iminium ion cyclization was employed for the enantioselective total synthesis of minfiensine, a strychnos alkaloid [83]. In this synthesis, the reaction of 128 catalyzed by Pd(OAc)2 with Pfaltz ligand 131 under microwave conditions gave tricyclic dienylcarbamate 129 in 85% yield and 99% ee (Scheme 8C.45). The total synthesis of (+)-minfiensine 130 was completed with another 16 steps from key intermediate 129. Desymmetrization of meso-1,4-cyclohexadienes with a vinyl iodide or triflate tether, forming the corresponding chiral bicyclic products can be achieved through intramolecular asymmetric Heck reaction. This methodology has proven to be powerful for the rapid and enantioselective construction of fused polycyclic compounds. The first example was reported by Shibasaki et al. [70]. The reaction of 132 catalyzed by Pd(OAc)2-(R)-BINAP gave cis-decalintrienes 133 in moderate yields and excellent enantioselectivity (up to 92% ee) (Scheme 8C.46). An efficient intramolecular Heck reaction of cyclohexadienone 134 gave 135 with high enantioselectivity (up to 96% ee) using a TADDOL-based monophosphoramidite

R2


NHBoc

NHBoc MeO2C N OTf

Pd(OAc)2, 131

OH

PMP, toluene MW,170°C, 30 min

N H N

N CO2Me

128

(+)-Minfiensine 130

129 85%, 99% ee

O N P

131 Scheme 8C.45.

R

Pd(OAc)2 (5 mol %) (R)-BINAP (10 mol %) K2CO3 (2 eq) Toluene, 60°C, 55 h

OTf 132

R a b c d

CO2Me CH2OPv CH2OTBS CH2OAc

R

H 133

Yield (%)

% ee

54 35 44 60

91 92 89 91

Scheme 8C.46.

ligand 136 instead of BINAP (Scheme 8C.47) [59]. It is noteworthy that excellent enantioselectivity can be achieved by a chiral monodentate phosphorus ligand in the absence of silver or thallium salt. The intramolecular asymmetric Heck reaction through desymmetrization of bicyclo[3.3.0]octadiene 137 gave the corresponding fused polycyclic product 138 in high yield and excellent enantioselectivity using Pd2(dba)3–(S)-p-tol-BINAP as catalyst in the presence of Ag3PO4 (Scheme 8C.48) [84]. In contrast, the reaction of bicyclo[4.4.0] decadiene, 139 or 142, with an aryl iodide or triflate tether under similar reaction conditions gave mixed results (Scheme 8C.48) [84]. The enantioselective desymmetrization of bicyclo[4.4.0]decadienes 145 catalyzed by Pd-(S,R)-JOSIPHOS complex gave fused tetracyclic product 146 with three stereogenic centers in excellent yield and 84% ee (Scheme 8C.49) [85].


O O Pd(OAc)2 (10 mol %) 136 (30 mol %) O

O I

Cy2MeN (4 eq) CHCl3, reflux 48 h

134

O

Ph Ph O

O

O

P N O O

Ph Ph 136

135 100% conversion, 96% ee Scheme 8C.47.

Pd2(dba)3-CHCl3 (5 mol %) (S)-p-tol-BINAP (11 mol %)

O I

O

Ag3PO4 (2 eq), DMA 80°C, 36 h 138 87%, 99% ee

137

Pd2(dba)3-CHCl3 (5 mol %) (S)-p-tol-BINAP (11 mol %) O I

O

Tl2CO3 (2 eq), CH3CN 80°C, 36 h 140

139

OTf

O

60% (1:5.6)

50% ee

Pd2(dba)3-CHCl3 (5 mol %) (S)-p-tol-BINAP (11 mol %) O

+

O

25% ee

+

DIPEA (2 eq), toluene 100°C, 12 h 140

60% (1:1.6) 82% ee

142

141

O

141 66% ee

Scheme 8C.48.

8C.5.4. Asymmetric Intermolecular Heck Reactions 8C.5.4.1. Dihyofurans In 1991, Hayashi et al. reported the first example of the asymmetric intermolecular Heck reaction, wherein the asymmetric arylation of 2,3dihydrofuran (148) with phenyl triflate (149) catalyzed by Pd-BINAP complex gave 2-phenyl-2,3-dihydrofuran (150) (93% ee) as the predominant product accompanied by a small amount of 2-phenyl-2,5-dihydrofuran (151) (Scheme 8C.50) [86].


CN

CN

Pd(dba)2 (5–10 mol %) (S,R)-JOSIPHOS (10 mol %)

P Me

O

DMF, 65–90°C, 24 h

O

I

Fe

146

145

P Ph

Ph

92%, 84% ee (S,R)-JOSIPHOS Scheme 8C.49.

OTf + O 148 (5.0 eq)

Pd(OAc)2 (3 mol %) (R)-BINAP (6 mol %) i-Pr2NEt (3 eq) Benzene, 40°C

149

+ O 150 71%, 93% ee

O 151 7%, 67% ee

Scheme 8C.50.

A plausible mechanism was proposed to explain the high enantiopurity of the major product 150 (R) and inversion of configuration in the formation of minor product 151 (S), which was further refined by Brown et al. (Scheme 8C.51) [86,87]. As Scheme 8C.51 illustrates, the insertion of the double bond of 148 into the Ar–Pd bond of 152 yields two diastereomeric Pd complexes 153 (via si-face attack) and 153′ (via re-face attack). Next, β-hydride elimination takes place to both intermediates to form π-olefin-Pd-H complex 154 and its diastereomer 154′. The π-complex 154 undergoes rapid hydropalladation to give 155, followed by β-hydride elimination and reductive elimination to afford 2-phenyl-2,3-dihydrofuran (150). Thus, for 154, the hydropalladation is much faster than the dissociation of 151. In contrast, the π-complex 151′ rapidly dissociates 2-phenyl-2,5-dihydrofuran (151′) rather than undergoes hydropalladation. Accordingly, the proposed mechanism involves a kinetic resolution process that enhances enantioselectivity of 150 by selectively eliminating 153′ through the formation of 151′ as the minor product. The asymmetric intermolecular Heck reaction, involving double-bond migration, has been extensively studied using various chiral P,N-ligands (Fig. 8C.1). As Scheme 8C.52 exemplifies, the reaction of 148 with 2-carbethoxycyclhexenyl triflate (164) gave 5-cyclohexenyl-2,3-dihydrofuran 165 with >96% ee exclusively [88]. In contrast, the reaction of 2,2-dimethyl-2,3-dihydrofuran (166) with phenyl triflate (149) afforded 2-phenyl-2,5-dihydrofuran (167) with 98% ee, as the sole product [89,90]. The reaction of 148 with 149 catalyzed by a Pd complex with (D-glucosamine)phosphiteoxazoline ligand 162 gave 151 with 99% ee and 97% regioselectivity [91]. Also, the reaction of 148 with cyclohexenyl triflate (168) catalyzed by a Pd complex with 163 gave 2-cyclohexenyl-2,5-dihydrofuran (169) with 98% ee and 98% regioselectivity [91]. A series of PHOX ligands, for example, 157 and 158, featuring a rigid chiral cyclopropyl backbone were applied to the asymmetric Heck reaction of 148 with 149. As


H O 153

+ OTf –

* P

P

+

* P P Pd

H

Ph

OTf –

O

Ph

+

Ph

154

O 148

Ph

O

P Pd

H

Ph

O

152

154'

151'

+ OTf –

P Pd

* Major

O 155

Ph

O 150

H P Pd * P

Minor

Ph

Ph

O

H

151

P *

Ph

P

+ OTf –

P Pd

P

+ OTf –

O

Ph

O

Ar

151 P

H

Major

P

TfO

P Pd

* Minor

+ OTf –

* P

H

*

OTf –

153'

Pd

O

+

* P P Pd

O 155'

Ph

+ OTf –

H Pd O

Ph

156'

156

Scheme 8C.51.

Scheme 8C.53 shows, the chirality in the oxazoline moiety of the PHOX ligands exerts a profound influence on the double-bond migration, forming either 150 or 151, exclusively [92]. A dramatic change in enantioface selection was observed when closely related chiral P,N-ligands 159 and 160, bearing chiral oxazolines with the same absolute configuration, were used in the reaction of 148 with aryl and cyclohexenyl triflates [93,94]. The ligand 160 led to the formation of (R)-2-substituted 2,5-dihydrofurans with up to 95% ee, while 159 bearing a gem-dimethyl group gave (S) products with up to 87% ee (Scheme 8C.53). 8C.5.4.2. Dihydrodioxepins Asymmetric arylation reaction of 4,7-dihydro-1,3dioxepins 172 through intermolecular Heck reaction has been studied in a similar manner as that for dihydrofurans. The resulting enol ether 174 can be readily transformed to chiral β-aryl-γ-butyrolactones 175, which are useful chiral building blocks in natural product synthesis. Shibasaki et al. reported the first example in 1994, wherein products 174 were obtained in variable yields and enantioselectivities, using Pd(OAc)2– (S)-BINAP as catalyst in the presence of potassium carbonate and 3 Å molecular sieves (Scheme 8C.54) [95]. The best results were obtained with 172a (R1 = R2 = H), giving 174 (R1 = R2 = H) in 48–86% yield and 60–75% ee [95]. The reaction of 172a (R1 = R2 = H) with 149 catalyzed by a Pd complex with a chiral oxazoline-based P,Nligand 161 gave 174a (R1 = R2 = H, Ar = Ph) in 70% yield and 92% ee (Scheme 8C.54)


O

(S) Bu2

N

(S)

Pt

O N

Fe PPh2

O R1

119

R2

R1

N PPh2

R2

159

157: = Ph, =H 158: R1 = H, R2 = Ph R2 O PPh2 N

tBu

160

161

R1 Ph O O P O O

O N PPh2

tBu

iPr

O

O N O

R R2 R1 1 162: R = Ph; R = SiMe3; R2 = H 163: R = Ph; R1 = R2 = tBu

Figure 8C.1. Chiral P,N-ligands for intermolecular Heck reaction.

+

CO2Et Pd[(R)-BINAP]2 (3 mol %) OTf Proton sponge (2 eq) Benzene, 40°C

O 148

164

OTf O 166 (5.0 eq)

O 148 (4.0 eq)

O 165 62%, >96% ee

(4.0 eq)

+

EtO2C

Pd2(dba)3 (3 mol %) 119 (6 mol %) NEt3 (3 eq) Benzene, 80°C

149

O 167 90%, 98% ee

[Pd2(dba)3]•dba (2.5 mol %) 162 (5.6 mol %) OTf i-Pr2NEt (2 eq)

+

THF, 50°C 149

O 151 86%, 99% ee

[Pd2(dba)3]•dba (2.5 mol %) 163 (5.6 mol %) OTf Proton sponge (2 eq) O 148 (4.0 eq)

+ THF, 50°C 168

O 169 90%, 98% ee

Scheme 8C.52.


Pd(OAc)2 (6 mol %) 158 (6 mol %) OTf Proton sponge (2 eq)

Pd(OAc)2 (6 mol %) 157 (6 mol %) Proton sponge (2 eq) O

O

THF, 90°C, 20 h

+

148 (4.0 eq)

151 98% ee

R O (S) 78–100% 39–87% ee (S)

O

THF, 90°C, 20 h 149

150 82% ee

Pd(dba)2 (3 mol %) 159 (6 mol %) i-Pr2NEt (2 eq)


+ ROTf O THF or benzene THF or benzene 148 60°C 60°C R = Ph, 2-naphthyl, p-MeO-C6H4, p-F-C6H4, p-Me-C6H4, cyclohexenyl

R O (R) 66–89% 81–95% ee (R)

Scheme 8C.53.

O Z R2 O

R1

+

ArOTf 173

Pd(OAc)2 (3 mol %) (S)-BINAP (9 mol %) K2CO3 (3 eq), 3 Å MS Benzene, 65°C

172 R1R2Z = H2C, Me2C, (CH2)5C, t-Bu2Si Ar = Ph, p-Cl-C6H4-, p-Me-C6H4-, p-MeO-C6H4-, 2-naphthyl

O Ar

174 13–86%, 5–75% ee

O

Ar

175

[Pd2(dba)3]•dba (1.5–2.5 mol %) L* (5.5 mol %) OTf i-Pr2NEt (2 eq) O

O + O 172a (3.0–4.0 eq)

O Z R2 O

R1

THF, 70°C 149 L* = 161 L* = 162

O 174a 70%, 92% ee 84%, 92% ee

Scheme 8C.54.

[96]. The same reaction using P,N-ligand 162 also afforded 172a in 84% yield and 92% ee (Scheme 8C.54) [91]. 8C.5.4.3. Other Substrates for Asymmetric Intermolecular Heck Reactions In addition to dihydrofurans and dihydrodioxepins, dihydropyrroles and cyclopentene have been employed as substrates for asymmetric intermolecular Heck reaction. For example, the reaction of 2,3-dihydropyrrole 178 with aryl triflate 149 catalyzed by Pd complex and chiral P,N-ligand 159 gave (S)-2-aryl-2,5-dihydropyrrole (S)-179 in good yield and up to 89% ee, while the same reaction catalyzed by Pd-160 afforded the enantiomeric (R)-179 in moderate yield and 60–70% ee (Scheme 8C.55) [94]. The reaction of cyclopentene

REFERENCES 679


Ar N CO2Me

Toluene, 80°C

(S)-179 63–83% 87–89% ee

+ ArOTf N 149 CO2Me 178


(R)-179 46–48% 60–70% ee

Ar = p-MeO-C6H4, p-F-C6H4

[Pd2(dba)3]•dba (2.5 mol %) 163 (5.6 mol %) OTf i-Pr2NEt (2 eq)

+

THF, 50°C 180 (4.0 eq)

R N CO2Me

Toluene, 80°C

149

181 76%, 95% ee

Scheme 8C.55.

(180) with 149 using Pd-163 as the chiral catalyst gave (R)-3-phenylcyclopent-1-ene (181) in good yield and 95% ee with 94% regioselectivity (Scheme 8C.55) [91].

REFERENCES 1. Olah, G. A.; Molnár, A. Hydrocarbon Chemistry. Toronto: J.P. Wiley, 1995. 2. Negishi, E.-I. In Catalytic Asymmetric Synthesis (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 165–189. 3. Kondakov, D. Y.; Negishi, E.-I. J. Am. Chem. Soc. 1995, 117, 10771–10772. 4. Negishi, E.-I. Dalton Trans. 2005, 827–848. 5. Kondakov, D. Y.; Negishi, E.-I. J. Am. Chem. Soc. 1996, 118, 1577–1578. 6. Huo, S., Shi, J.-I., Negishi, E.-I. Angew. Chem. Int. Ed. Engl. 2002, 41, 2141–2143. 7. Fletcher, M. T.; Chow, S.; Lambert, L. K.; Gallagher, O. P.; Cribb, B. W.; Allsopp, P. G.; Moore, C. J.; Kitching, W. Org. Lett. 2003, 5, 5083–5086. 8. Chow, S.; Fletcher, M. T.; Lambert, L. K.; Gallagher, O. P.; Moore, C. J.; Cribb, B. W.; Allsopp, P. G.; Kitching, W. J. Org. Chem. 2005, 70, 1808–1827. 9. Zhu, G.; Liang, B.; Negishi, E.-I. Org. Lett. 2008, 10, 1099–1101. 10. Herber, C.; Breit, B. Angew. Chem. Int. Ed. Engl. 2005, 44, 5267–5269. 11. Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512–3519. 12. Zhou, J.; Zhu, Y.; Burgess, K. Org. Lett. 2007, 9, 1391–1393. 13. Magnin-Lachaux, M.; Tan, Z.; Liang, B.; Negishi, E.-I. Org. Lett. 2004, 6, 1425. 14. Negishi, E.-I.; Tan, Z.; Liang, B.; Novak, T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5782–5787. 15. Tan, Z.; Negishi, E.-I. Angew. Chem. Int. Ed. Engl. 2004, 43, 2911–2914. 16. Liang, B.; Novak, T.; Tan, Z.; Negishi, E.-I. J. Am. Chem. Soc. 2006, 128, 2770–2771. 17. Tan, Z.; Liang, B.; Huo, S.; Shi, J.-C.; Negishi, E.-I. Tetrahedron Asymmetry 2006, 17, 512–515. 18. Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503.

680 ASYMMETRIC CARBOMETALLATION AND CARBOCYCLIZATIONS 19. Grassia, A.; Bruno, I.; Debitus, C.; Marzocco, S.; Pinto, A.; Gomez-Paloma, L.; Riccio, R. Tetrahedron 2001, 57, 6257–6260. 20. Zhu, G.; Negishi, E.-I. Org. Lett. 2007, 9, 2771–2774. 21. Norte, M.; Cataldo, F.; Gonzalez, A. G. Tetrahedron Lett. 1988, 29, 2879. 22. Novak, T.; Tan, Z.; Liang, B.; Negishi, E.-I. J. Am. Chem. Soc. 2005, 127, 2838–2839. 23. Jang, H.-Y.; Huddleston, R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156–15157. 24. Han, S. B.; Hassan, A.; Krische, M. J. Synthesis 2008, 2669–2679. 25. Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653–661. 26. Huddleston, R.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488–11489. 27. Cho, C.-W.; Krische, M. J. Org. Lett. 2006, 8, 3873–3876. 28. Hong, Y.-T.; Cho, C.-W.; Skucas, E.; Krische, M. J. Org. Lett. 2007, 9, 3745–3748. 29. Ngai, M.-Y.; Kong, J.-R.; Krische, M. J. J. Org. Chem 2007, 72, 1063–1072. 30. Cho, C.-W.; Krische, M. J. Org. Lett. 2006, 8, 891–894. 31. Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Clardy, E. J. Am. Chem. Soc. 1982, 104, 6846–6848. 32. Pettit, G. R. J. Nat. Prod. 1996, 59, 812–821. 33. Skucas, E.; Jong Rock, K.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 7242–7443. 34. Jung, C.-K.; Garner, S. A.; Krische, M. J. Org. Lett. 2006, 8, 519–522. 35. Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 2746–2747. 36. Jang, H. Y.; Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 6174–6175. 37. Rhee, J. U.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 10674–10675. 38. Rhee, J. U.; Jones, R.; Krische, M. Synthesis 2007, 3427–3430. 39. Lopez, F.; Feringa, B. L. Asymmetric Synth. 2007, 78–83. 40. Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244–7254. 41. Evans, D. A.; Rovis, T.; Johnson, J. S. Pure Appl. Chem. 1999, 71, 1407–1415. 42. Alexakis, A. Transit. Met. Org. Synth. 1998, 1, 504–513. 43. Posner, G. H. Org. React. 1972, 19, 1–113. 44. Hayashi, T. Synlett 2001, 879–887. 45. Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112–5113. 46. Huddleston, R. R.; Krische, M. J. Synlett 2003, 12–21. 47. Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143–1146. 48. Wang, L. C.; Jang, H. Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448–9453. 49. Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691–694. 50. Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225–4228. 51. Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743–5746. 52. Lipshutz, B. H.; Amorelli, B.; Unger, J. B. J. Am. Chem. Soc. 2008, 130, 14378–14379. 53. Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110–1111. 54. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052–5058. 55. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–1923. 56. Bocknack, B. M.; Wang, L.-C.; Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421–5424. 57. Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett. 1996, 37, 5141–5144. 58. Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. Mod. Organocopper Chem. 2002, 224–258. 59. Imbos, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 184–185.

REFERENCES 681

60. Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem. Int. Ed. Engl. 1997, 36, 2620–2623. 61. Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358–4359. 62. Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528–4529. 63. Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353. 64. Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901–1903. 65. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. 66. Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–2322. 67. Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533–1552. 68. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964. 69. Donde, Y.; Overman, L. E. In Catalytic Asymmetric Synthesis (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 675–697. 70. Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738–4739. 71. Carpenter, N. E.; Kucera, D. J.; Overman, L. E. J. Org. Chem. 1989, 54, 5846–5848. 72. Ohrai, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737. 73. Sato, Y.; Mori, M.; Shibasaki, M. Tetrahedron Asymmetry 1995, 6, 757. 74. Shibasaki, M.; Mase, T.; Ikegami, S. J. Am. Chem. Soc. 1986, 108, 2090. 75. Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571–4572. 76. Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477–6487. 77. Guiry, P. J.; Kiely, D. J. Organomet. Chem. 2003, 687, 545–561. 78. Busacca, C. A.; Grossbach, D.; So, R. C.; O’Brie, E. M.; Spinelli, E. M. Org. Lett. 2003, 5, 595–598. 79. Busacca, C. A.; Grossbach, D.; Campbell, S. J.; Dong, Y.; Eriksson, M. C.; Harris, R. E.; Jones, P.-J.; Kim, J.-Y.; Lorenz, J. C.; McKellop, K. B.; O’Brien, E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So, R. C.; Spinelli, E. M.; Vitous, J.; Zavattaro, C. J. Org. Chem. 2004, 69, 5187–5195. 80. Kiewel, K.; Tallant, M.; Sulikowski, G. A. Tetrahedron Lett. 2001, 42, 6621–6623. 81. Hart, D. J.; Tsai, Y. M. J. Org. Chem. 1982, 47, 4403. 82. Yoda, H.; Katoh, H.; Ujihara, Y.; Takabe, K. Tetrahedron Lett. 2001, 42, 2509. 83. Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186–10187. 84. Lautens, M.; Zunic, V. Can. J. Chem. 2004, 82, 399–407. 85. Lormann, M. E. P.; Nieger, M.; Brase, S. J. Organomet. Chem. 2006, 691, 2159–2161. 86. Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417–1419. 87. Hii, K. K.; Claridge, T. D. W.; Brown, J. M.; Smith, A.; Deeth, D. J. Helv. Chim. Acta 2001, 84, 3043–3056. 88. Ozawa, F.; Kobatake, Y.; Hayashi, M. Tetrahedron Lett. 1993, 34, 2505. 89. Hennessy, A. J.; Connolly, D. J.; Malone, Y. M.; Guiry, P. J. Tetrahedron Lett. 2000, 41, 7757–7761. 90. Hennessy, A. J.; Malone, Y. M.; Guiry, P. J. Tetrahedron Lett. 1999, 40, 9163–9166. 91. Mata, Y.; Dieguez, M.; Pamies, O.; Claver, C. Org. Lett. 2005, 7, 5597–5599. 92. Rubina, M.; Sherrill, W. M.; Rubin, M. Organometallics 2008, 27, 6393–6395. 93. Hou, X.-L.; Dong, D. X.; Yuan, K. Tetrahedron Asymmetry 2004, 15, 2189–2191. 94. Wu, W.-Q.; Peng, Q.; Dong, D.-X.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc. 2008, 130, 9717–9725. 95. Koga, Y.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1994, 35, 1227. 96. Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338–1345.

8D ASYMMETRIC ENE REACTIONS AND CYCLOADDITIONS Koichi Mikami and Kohsuke Aikawa Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan

8D.1. INTRODUCTION The Diels–Alder (D-A) diene (Scheme 8D.1a) and Alder ene (Scheme 8D.1b) reactions [1] were found by Diels and/or Alder, hence the name [2]. The D-A and ene reactions are mechanistically related. These reactions are defined as six-electron pericyclic processes between a “diene” or an alkene bearing an allylic hydrogen (an “ene”) and an electron-deficient multiple bond (a “dienophile” or an “enophile”) to form two σ-bonds with migration of the π-bond. In the ene reaction, the two electrons (HOMO) of the allylic C–H σ-bond (T2) replace the two π-electrons (T1) of the diene. Therefore, the activation energy is greater to break the C–H single bond, and higher temperatures are necessary in the ene reaction. Lewis acid-promoted reactions have been developed to lower the (di)enophile LUMO. This chapter covers the scope of the asymmetric catalysis of ene- and D-A-like reactions, which were reported after publication of the second edition in 2000, catalyzed by a chiral Lewis acid of which the complexation modes are first summarized.

8D.2. MECHANISTIC CONSIDERATIONS 8D.2.1. Transition State Conformations The transition state structures (cf. Scheme 8D.1) have been reported for the thermal D-A and ene reactions of ethylene with butadiene and propene, respectively [3]. The transition structure of the D-A reaction is highly symmetric [4]. In contrast, the ene


684 ASYMMETRIC ENE REACTIONS AND CYCLOADDITIONS

a

b Diene

Ene

HOMO

HOMO

H Y X Dienophile

X LUMO

Y

Y X

H

Y X Enophile

X LUMO

Y

T1

H Y X

T2 Scheme 8D.1.

a

b

c

M

M O

O H

H

H

O H

H

H

Figure 8D.1.

transition state is asymmetric because of the different types of C–C and C–H bond formations. The thermal ene reactions maximize allylic resonance by making the axis of the C–H single bond parallel to the double bond π-orbitals. The thermal ene transition structure is thus of envelope.

8D.2.2. The Lewis Acid-(Di)Enophile Complexes In the D-A [5], hetero D-A (HDA) [6], and ene reactions [7], the Lewis acid catalysis has been studied in detail. A high level of diastereo- and enantioselectivities can be attained by controlling the following complexation factors [8]: (1) linear versus bent geometry, (2) σ- and π-binding modes (η1 and η2), (3) in-plane versus out-of-plane complexation, (4) (di)enophile conformation (s-cis vs. s-trans), and (5) anti- and syn-complexation.

8D.2.3. Bent versus Linear Geometries Photoelectron spectroscopy shows that there are two nonequivalent lone pairs in a carbonyl compound (Fig. 8D.1) [9]. One is an sp-hybridized orbital along the C=O axis. The other is a higher energy p-like orbital perpendicular to the C=O axis (a). Upon complexation with the Lewis acid metal, a Cs-symmetric bent geometry of the carbonyl complexation is observed, because the remaining lone pair can be stabilized with more s-character in an sp2-like orbital (b). The C2v-symmetric linear geometry is favorable for the Lewis acid with another vacant orbital available (c).

8D.2. MECHANISTIC CONSIDERATIONS 685

8D.2.4. σ- and π- (η1 and η2) Binding Modes of the Lewis Acid/Carbonyl Complexation There are two binding modes in the Lewis acid and carbonyl complexation either by carbonyl lone pair electrons to form a σ- (η1) bond or by carbonyl π system to complex in an η2 form (Fig. 8D.2) [9]. Main group elements, early transition metals, and lanthanides (d0) generally complex to a carbonyl compound in σ- (η1) binding mode with varying angles (B–O=C: 112∼119, Al–O=C: 136 + 4, Sn–O=C: 127 + 10, Ti–O=C: 125+12). π- (η2) Bonding is observed in the d-electron late transition metal, which is favorable for back donation to an electron-poor carbonyl compound, for example, π-bonding Cp2Zr(II)-benzophenone complex [10], in sharp contrast to σ-bonding Cp*2Ti(IV)Cl-DMF complex [11] (Fig. 8D.3). Significantly, one enantioface of the carbonyl compound can be shielded in π-bonding so that a nucleophile can be directed toward the other enantioface.

8D.2.5. In-Plane versus Out-of-Plane Complexation The modes of the Lewis acid/carbonyl complexation can thus be defined by the bond length (γ), bond angle (θ), and dihedral angle (ϕ) [9], in the continuum from in-plane (ϕ = 0) σ-complexation mode to π-complexation mode via out-of-plane complexation (ϕ ≠ 0) (Fig. 8D.4). Significant example of out-of-plane complexation is seen in the X-ray

O

M

O R

M

R

H

H

1

σ (η )

π ( η2)

Figure 8D.2.

Cl O

Me N Me

H

Cp

Cp* Ti

Ph

Cp*

O

Ph Cp

167.0°

Zr

Zr Cp

Figure 8D.3.

H

θ

M r ϕ O

R Figure 8D.4.

Cp Ph O

Ph


analysis of acryloylmethyl lactate-TiCl4 complex [12]. In a seven-membered ring, two carbonyl groups chelate to TiCl4 with ϕ{Ti–O(1)–C–C} = 63.6 and ϕ{Ti–O(2)– C–C} = −132.2 (Fig. 8D.5). Interestingly, TiCl4 coordinates anti to acrylate of s-cis conformation.

8D.2.6. (Di)Enophile Conformation (s-cis vs. s-trans) Upon single bond rotation, α,β-unsaturated carbonyl compounds pose an opposite enantioface for (di)ene partners. Free (meth)acrolein and crotonaldehyde are in the s-trans conformer. Upon complexation with Lewis acid, the s-trans conformer is more favored. Corey et al. reported that the BF3-methacrolein complex is in the s-trans conformation by X-ray and HNMR analyses (Fig. 8D.6) [13]. Yamamoto et al. reported that chiral acyloxyborane (CAB)-crotonaldehyde complexes are in the equilibrium between s-trans and s-cis conformations, depending on the substituents of CAB, as clarified by NOE analysis (Fig. 8D.7) [14].

8D.2.7. anti- and syn-Complexation As shown above, the s-trans-anti-complexation has been well precedented for α,βunsaturated aldehydes. In sharp contrast, the syn-complexation has been reported experimentally and theoretically for the s-trans conformation of α,β-unsaturated carboxylic esters. Indeed, the X-ray analysis of SnCl4-ethyl cinnamate 1:2 complex showed the s-trans-syn-complexation (Fig. 8D.8) [15].

Cl (2) O

O

Cl

Ti

Cl O (1)

Cl O

Figure 8D.5.

F H

NOE H

F B

F

O Me

H s-trans, anti Figure 8D.6.

8D.2. MECHANISTIC CONSIDERATIONS 687

HO OiPr O

OO

HO OiPr O

R=H O O B R OiPr O H H R= NOE H Me s-trans, anti

OiPr CF3

O

O

O O B R O H H H

CF3

Me

s-cis, anti

Figure 8D.7.

Ph Et

O Cl O Cl

Sn Cl

Cl O O

Et

Ph Figure 8D.8.

8D.2.8. endo-Preference The endo-preference is the key issue in the D-A reaction, where the endo-transition structure can be stabilized by the secondary orbital interaction. Acrylate, crotonate, and cinnamate derivatives generally provide the endo-products. Cyclohexadiene and acyclic dienes provide the endo-products. However, the D-A reaction of α-substituted α,βunsaturated aldehydes with cyclopendadiene provides the exo-products (see Table 8D.3). An endo/exo-selectivity is not obvious in an ene reaction, since the ene reaction does not afford cyclic adducts. Few examples have been reported for the endo-preference in the ene reaction of butadiene with maleic anhydride. However, both the endo- and exotransition structures in the ene reaction show a relatively small energy difference, in contrast to the D-A reaction. Furthermore, our theoretical studies show that the electrostatic interaction of carbonyl oxygen and cationic central carbon of an ene component in the Lewis acid-promoted carbonyl-ene reaction is obvious rather than the secondary orbital interaction [16].


8D.3. INTERMOLECULAR CARBONYL-ENE REACTION This topic has already been discussed in the series Catalytic Asymmetric Synthesis, Second Edition, 2000. Therefore, significant and successful examples of asymmetric catalytic ene reactions developed mainly after 2000 are described.

8D.3.1. Chiral Ti Catalysts Asymmetric ene reaction catalyzed by chiral Lewis acid is one of the most efficient methodologies for atom economical carbon–carbon bond formation [7]. The first catalytic enantioselective version with aromatic aldehydes or chloral using a chiral BINOLAl complex is reported by Yamamoto et al. [17]. The enantioselective version of simple and atom economic reactions has been intensively investigated since 1989. Mikami and Nakai reported BINOL-Ti (1)-catalyzed “glyoxylate-ene” reaction. A variety of chiral Ti catalysts have been screened for the carbonyl-ene reaction. The best result was obtained with the BINOL-Ti (1) prepared in situ in the presence of MS 4A from TiX2(OiPr)2 (X = Cl or Br: Mikami et al. [18]; X = OiPr: Keck et al. [19]; TiF4: Carreira et al. [20]) and optically pure BINOL or 6-Br-BINOL (Scheme 8D.2). The solidified BINOL-Ti (1) can also be employed as the most catalytically active, stable and storable catalyst for months (or even years) [21].

X OH OH X

+

TiCl2(OiPr)2

(10 mol % each) Wet MS 4A CH2Cl2, r.t., 1 h

O Ph

H

OH

BINOL-Ti 1

+ CO2Me

CH2Cl2, –30°C

Ph

CO2Me

X=H 97% ee (82%) X = Br >99% ee (82%) Scheme 8D.2.

After Mikami and coworkers developed BINOL-Ti catalysts for various asymmetric carbonyl-ene reactions with high catalytic activity and enantioselectivity, various asymmetric carbonyl-ene and related carbonyl addition reactions by BINOL-Ti catalysts have been reported. We had better summarize here the relationship between BINOL-TiX2 (X = OiPr or halides) precatalysts and the “active BINOL-Ti catalyst (1)” (Scheme 8D.3), which has not been structurally determined yet by X-ray analysis. In the presence of dry (99%) 3c HO

OH

HO

OH

OH HO

OH

HO 2a

2c

HO

OH

HO

OH 2b Scheme 8D.4.

H OiPr O O Ti O i O H O Pr

Ti(OiPr)4

HO HO

Linker

Linker

3 2

n

OH OH

Scheme 8D.5.

8D.3.2. Chiral Pd, Pt, and Ni catalysts Mikami et al. reported square-planar dicationic late transition metal complexes (PP*-M2+: M = Pd, Pt) bearing C2-symmetric diphosphine ligands as highly efficient asymmetric Lewis acid catalysts instead of early transition metal Lewis acid catalysts. A chiral cationic (S)-BINAPs-Pd complex 4 has been developed for the asymmetric carbonyl-ene reaction with 1,1-disubstituted olefins (Scheme 8D.6) [26]. The combination

8D.3. INTERMOLECULAR CARBONYL-ENE REACTION 691

Ar2 P

NCMe 2+

Pd P Ar2

NCMe

2SbF6– (10 mol %)

(CH2Cl)2 r.t., 18 h

O + H

CO2Et 4c (10 mol %) (CH2Cl)2/toluene 1/2

4a: Ar = Ph 4-MeC6H4 4b: 3,5-Me2C6H3 4c:

OH CO2Et 4a 61% ee (82%) 4b 78% ee (88%) 4c 42% ee (87%) 84% ee (85%), r.t. (20 h) 88% ee (95%), 60°C (4 h)

Scheme 8D.6.

of dicationic (S)-BINAPs-Pd species with weakly coordinating anions such as SbF6− can be employed as an efficient catalyst system for glyoxylate-ene reactions. Significantly, the dicationic Pd catalyst affords the α-hydroxy esters with high enantioselectivity at relatively higher reaction temperature (60°C). The medium size of the Tol-BINAP ligand leads to higher enantioselectivity than those of the sterically less demanding BINAP and more bulky Xyl-BINAP. The best result of 88% ee is obtained in the reaction using [Pd{(S)-tol-binap}(MeCN)2](SbF6)2 (S)-4b as a catalyst and 1,2-dichloroethane/toluene (1/2 in volume) as a solvent system. The “naked” Pd(diphosphine)(SbF6)2 generated in situ from Pd(diphosphine)Cl2 and 2 equiv of AgSbF6 is highly catalytically active than the bench-stable acetonitrile complex 4 (Scheme 8D.7) [27]. On the basis of the X-ray structure of the BINAP-PdCl2 [28] and SEGPHOS-PdCl2 where the metal-centered geometry is close to square planar, effective shielding by the most obtuse dihedral angle of SEGPHOS is the origin of the highest enantioselectivity [29]. It should be noted that the “naked” Pd complex 5 achieves a high yield and enantioselectivity even with less reactive mono- and 1,2-di-substituted olefins in the trifluoropyruvate ene reactions (Table 8D.1). Significantly, the reaction of isobutene with trifluoropyruvate by using 0.002 mol % of (S)-BINAP-Pd2+(SbF6)2 5b proceeds smoothly to give the ene product in 96% yield with 96% ee even under solvent-free conditions (entry 10) [29]. The asymmetric ene reaction of ketone silyl enol ethers is synthetically important as a short access to optically active alcohols with not only the homo-allylic but also the remaining silyl enol ether functionality. Mikami et al. examined the extension of onedirectional carbonyl-ene reaction to two-directional keto ester-ene reaction and enealdol reaction. If the silyl enol ether group of the one-directional product sequentially reacts with the enophile, two-directional carbonyl-ene products would be obtained. The one-directional product might also react with different aldehydes to give two-directional ene-aldol products. To investigate the one-directional keto ester-ene reaction, the following two problems arise:


R1

O

R1

5a (5 mol %)

+

2

F3C

R

CO2Et

F3C OH

R2

CH2Cl2, r.t.

CO2Et

3

R3

R

O

Ph2 P Pd2+ P 2SbF6– Ph2

Ph2 P Pd2+ P 2SbF6– Ph2

O O O

5b

5a Scheme 8D.7.

TABLE 8D.1 Asymmetric Ene Reaction of (S)-SEGPHOS-Pd2+(SbF6)2 Complex 5a Entry

Olefin

Time (h)

1

n = 1: 0.25

2

n = 2: 0.25

n

3a 4

Ene Product

F3C OH CO2Et

n

n = 2: 5 0.5

F3C OH

% Yield

% ee

Ratio

84

97

Quant.

96

— —

Quant.

95

—

80

84 (anti) anti/syn 98/2

79

97

Quant.

96

100% (E)

Quant.

98

100% (E)

64

92 (anti) anti/syn 91/9

65

96 (anti) 100% (E)

CO2Et 5 6 7a 8

R

R = n-C3H7: 0.5 R = Ph: 0.5

R

F3C OH CO2Et

R = Ph: 48 1

F3C OH CO2Et

9

1

F3C OH

anti/syn 96/4

CO2Et 10b

2

F3C OH

100% (E)

96

96

—

CO2Et a

The reaction was examined at 0°C by using 5a (0.1 mol %) without solvent. The reaction was examined at −20°C by using 5b (0.002 mol %) without solvent.

b

(1) The competition with the Mukaiyama aldol reaction (Scheme 8D.8). There are three reaction pathways: (1) Mukaiyama aldol reaction via Pd-enolate formation, (2) Mukaiyama aldol reaction via silatropic ene process, and (3) prototropic ene process. To obtain the prototropic ene product selectively, the suppression of the Mukaiyama reaction is essential using sterically demanding silyl groups (Scheme


a) Pd Mukaiyama aldol reaction Pd cat* O

O

O

COR G Pd enolate b) O

Si

Si

O

Pd

O G OH * COR Aldol product

COR G Silatropic

+ O G

COR

c)

H

Pd cat* Si Ene reaction

O

O

Pd SiO G OH COR

G Prototropic

* COR Ene product

Scheme 8D.8.

8D.8a,b). Sodeoka, Lectka, and others reported the mechanistic difference between Pd(II) enolate [30] and Pd(II) Lewis acid catalysis [31] in the asymmetric aldol-type reaction with aldehydes or imines. The Pd enolate would be generated via transmetallation of the silyl group with Pd(II) aqua complex, which is generated from dicationic Pd(II) complex and H2O. The bulky and stable silyl group would be resistant to transmetallation. In the silatropic pathway, the sterically hindered silyl group should hardly involve in a pericyclic transition state. Therefore, bulky silyl group such as triisopropyl silyl should be employed to guide the prototropic ene reaction. (2) The decomposition of silyl enol ether and overreaction, namely two-directional reaction under the Lewis acid conditions. Therefore, the reaction should be carried out at low temperature to keep the one-directional product. The Pd-complex-catalyzed keto ester-ene reaction, which constructs highly optically active β-hydroxy silyl enol ether with quaternary carbon center, is reported [32]. Various dicationic Pd catalysts are in situ generated from chiral PP*-PdCl2 complex and 2.2 equiv of AgSbF6 in dichloromethane at room temperature. The reactions of silyl enol ethers with keto esters by using 5 mol % of (S)-SEGPHOS-Pd2+ 5a proceed smoothly to give ene product in 94->99% ee without Mukaiyama aldol-type product (Scheme 8D.9). Even with the smallest substrate/catalyst ratio (S/C 10,000), the high yield and enantioselectivity (85% yield, 90% ee) could be obtained. This is the first example of ene reaction on silyl enol ether with ketones to afford quaternary carbon centers. The chiral Pd complexes are (1) air and moisture stable, (2) easily synthesized, and (3) catalytically active (up to 0.01 mol %) with high yield and enantioselectivity.


O

OTIPS +

2

R

5a (5 mol %) 1

CH2Cl2

COR

–78°C, 2–48 h O R2 OH

TIPSO R2 OH COR1 R1 = OEt, R2 = Me 96% ee (93%) 98% ee (72%) R1 = OEt, R2 = Ph 94% ee (81%) R1 = Me, R2 = Me >99% ee (84%) R1 = Me, R2 = Et R1 = OEt, R2 = Me 90% ee (85%) (0.01 mol %, S/C 10,000)

+

COR1 Not observed

Scheme 8D.9.

OTIPS

O

+ G

CO2Et

(S)-SEGPHOS-Pd2+ 5a

OSi H P P Pd O O Et

P P Pd O O Et H O G

O G

SiO

TIPSO G OH

TIPSO G OH

CO2Et

CO2Et (R)-product

(S)-product Figure 8D.9.

The sense of enantioselectivity can be explained as follows (Fig. 8D.9). The keto ester-ene reaction should proceed through the six-membered transition state. Compared with the right transition state, the left transition state to give the (S)-product should be less favorable by steric repulsion between the equatorial phenyl group of SEGPHOS and silyl enol ether substrate. Therefore, the reaction via the right transition state should proceed to give the (R)-product.


The two-directional hetero-ene reaction sequence, first with pyruvate and then with glyoxylate, is attempted by using chiral SEGPHOS-Pd, and then BINOL-Ti catalysts, sequentially (Scheme 8D.10). (R)/(S)-diol product bearing both quaternary and tertiary carbon centers is obtained by using (S)-BINOL in 67% yield and >99% ee after desilylation by TBAF (dr = 92/8). In contrast, the treatment with (R)-BINOL-Ti gives the (R)/(R)-diol product in 61% yield and 97% ee (dr = 91/9).

TIPSO Me OH CO2Et 92% ee (R)

O +

1) (S)-BINOL/Ti(OiPr)4 (10 mol % each) 2) TBAF

Me OH O

CO2Et

H

1) (R)-BINOL/Ti(OiPr)4 (10 mol % each) 2) TBAF

Me OH O

OH CO2Et

EtO2C

OH

EtO2C

CO2Et (R)/(R)

(R)/(S) >99% ee (67%) dr = 92/8

97% ee (61%) dr = 91/9 Scheme 8D.10.

It is already reported that the asymmetric glyoxylate-ene reaction with silyl (TMS, TBDMS) enol ether catalyzed by chiral BINOL-Ti 1 affords chiral diol bearing silyl enol ether in high yield and enantioselectivity (Scheme 8D.11) [33]. In the BINOL-Ti catalytic system, the use of ketone instead of aldehyde as an enophile led to lower yield and enantioselectivity.

OSi

1) (R)-BINOL-Ti 1 (10 mol %)

O + 2 H

CO2Me

2) HCl/MeOH

Si = TBDMS TMS

OH O

OH CO2Me

MeO2C

>99% ee (>99% anti) H+

OSi OH

Two-directional ene reaction

OH OSi OH MeO2C

CO2Me Scheme 8D.11.

CO2Me


Using the electron-withdrawing benzonitriles as the labile, stabilizing ligands, the isolated bench-stable MeO-BIPHEP-Pd catalyst 6 have been developed, and it has been shown that complex 6b is more catalytically active compared with the in situ-generated catalyst 5c for the asymmetric ene reaction of ethyl glyoxylate (5c, 55% conv.; 6b, 70% conv.) (Scheme 8D.12) [34].

Pd cat. (2 mol %)

O +

H

CO2Et

CH2Cl2, 0°C, 5 h 6a 6b 5c

MeO MeO

Ph2 P Pd2+ – P Ph2 2SbF6 5c

OH CO2Et (50 ± 10% conv.) 81% ee (70 ± 10% conv.) 81% ee (55% conv.) Ph2 NCAr P Pd2+ P NCAr Ph2 2SbF6–

MeO MeO

6a: Ar = C6H5 6b: Ar = 3,5-CF3C6H3 Scheme 8D.12.

MeO-BIPHEPs-Pt complexes 7 with an OTf− as a counter anion are found to act as a catalyst for a similar asymmetric glyoxylate-ene reaction (Scheme 8D.13) [35]. Enantioselectivity up to 85% ee is achieved by addition of achiral acidic phenol that facilitates the reaction by trapping the OTf− anion and traces of water. tBuOH and water is, however, completely inactive. As the diphosphine electronic effects, it is indicated that 7c–d bearing more electron-rich ligands increase both reactivity and enantioselectivity. This method provides another solution to the problem of detrimental counter anion and water coordination to electrophilic cationic metal complexes. A further advanced asymmetric catalysis can be highlighted by the use of chirally flexible tropos (originated from tropos in Greek, meaning turn) [36] ligands. In 1998, we, for the first time, employed tropos BIPHEP [37] ligands for the catalytic asymmetric hydrogenation with the Ru catalysts [38]. The tropos BIPHEP ligand can also be used in dicationic Pd(II) complexes. A combination of chiral metal complexes derived from tropos BIPHEP ligand and the chiral DABN (2,2′-diamino-1,1′-binaphthyl) as a chiral activator [39] can also be used in a similar but more advantageous manner to atropos BINAP ligand [40]. With 1.0 equiv of (R)-DABN, complexation of both enantiomers of racemic BIPHEP-Pd takes place to afford a 1:1 ratio of a diastereomeric mixture of (R)/ (R)-9 and (S)/(R)-9. The diastereomeric mixture of 9 exhibits tropo-inversion of the BIPHEP-Pd portion at 80°C to afford favorable (R)/(R)-9 exclusively. In addition, the novel tetra(phosphanyl)triphenyl (TETRAPHOS) ligand is designed to exhibit nonplanar helicity upon metal complexation [41]. The single diastereomer TETRAPHOS-Pd/ DABN complex 7 is also quantitatively obtained through tropo-inversion under the heating conditions.


Pt cat. (2 mol %)

O +

MeO

CO2Et

Pt cat. 7a 7a 7a 7a 7b 7c 7d

Ar2 P OTf Pt2+ OTf P Ar2 7a Ar = Ph 7b Ar = p-CF3-C6H4 7c Ar = p-tBu-C6H4 7d Ar = p-OMe-C6H4

MeO

OH

Additive CH2Cl2, –50°C, 5 h

CO2Et

H

Additive % Conv. % ee – 36 74 t BuOH 0 – H2O 0 – C6F5OH 77 77 C6F5OH 63 68 C6F5OH 79 85 C6F5OH 78 83

RfO P

H

O

OEt

2+

Pt

* P

RfO RfO H H O H H O CF O S 3 RfO H H H O 2 RfO

O

Scheme 8D.13.

O +

Pd cat. (2.5~5 mol %) CO2Et

H

Ph2 N P Pd2+ N P Ph2 PPh2 4SbF6– Ph2P

Pd2+ N N

*

8

OH

CH2Cl2, r.t., 24 h

CO2Et

(P)-TETRAPHOS-Pd/(S)-DABN 8 81% ee (86%) (S)-BIPHEP-Pd/(S)-DABN 9 69% ee (78%) (S)-BINAP-Pd/(S)-DABN 10 78% ee (80%) *

Ph2 P N Pd2+ * N P Ph2 2SbF6–

9

N * = N

H2N H2N

(S)-DABN

Scheme 8D.14.

The enantiopure (P,S,S)-TETRAPHOS-Pd/(S)-DABN complex 8 is employed to exhibit higher levels of enantioselectivity and chemical yield than those obtained not only by BIPHEP-Pd/(S)-DABN 9 but also by (S)-BINAP-Pd/(S)-DABN 10. These results prove the efficiency of tropos but sterically demanding and hence relatively rigid helical TETRAPHOS ligands (Scheme 8D.14).


In a similar manner to our BIPHEP-Ru and -Pd complexes, the enantiopure BIPHEPPt complex is also reported by Gagné et al. (Scheme 8D.15) [42]. Racemic BIPHEPPt(CO3) with (S)-BINOL gives a 1:1 diastereomer mixture BIPHEP-Pt/(S)-BINOL complexes 11. The (S)/(S)-11 can be seen in a 96:4 ratio by tropo-inversion at 92–122°C. The (R)/(S)-11 isomer can be converted to a 95:5 ratio of the (S)/(S)-11 major isomer in pyridine at lower temperature (40°C). The thermodynamically less favorable (R)/ (S)-11 isomer can be obtained by recrystallization. The treatment of (S)/(S)-11 (95:5) with conc. HCl followed by recrystallization leads to the enantiopure (S)-12 with retention of configuration in 63% yield. Similarly, use of conc. HCl or TfOH for diastereopure (R)/(S)-11 leads to the enantiopure (R)-12 or (R)-13 complexes, respectively.

Ph2 P

Ph2 P

O

O Pt

Pt O

P Ph2

(R)/(S)-11

(S)/(S)-11 : (R)/(S)-11 = 95:5 1) HCl 2) Recry Ph2 P

Cl Pt

P Ph2

O

P Ph2

Cl

(S)-12

1) HCl 2) Recry Ph2 P Pt P Ph2 (R)-12

TfOH

Cl

Ph2 P

OTf Pt

Cl

OTf

P Ph2 (R)-13

Scheme 8D.15.

The enantiopure dicationic BIPHEP-Pt complexes, thus purified, act as chiral Lewis acids (Scheme 8D.16). In the carbonyl-ene reaction catalyzed by the dicationic species generated from BIPHEP-PtCl2 12 and AgSbF6, the (S)- and (R)-ene products are obtained with 72% ee (99% conv. at r.t.) and 70% ee (90% conv. at room temperature) from (R)- and (S)-12, respectively.

O

Pt cat. (2 mol %)

+ H

CO2Et

AgSbF6 (4 mol %) CH2Cl2, 0°C

OH * CO2Et (R)-12 70% ee (S) (S)-12 72% ee (R)

Scheme 8D.16.


Another approach for the asymmetric carbonyl-ene reactions using diastereopure Pt complex 11 bearing tropos BIPHEP ligand is reported (Scheme 8D.17) [43]. In the best case, the ene-product is obtained in 73% yield and 94% ee by using AgSbF6 of 2 equiv, even at low catalyst loading (0.1 mol %). AgOTf or TfOH decreases both the activity and enantioselectivity.

Ph2 P

O Pt

P Ph2

(R)/(S)-11 (5 mol %)

O + H

O

COPh

Additive (10 mol %)

OH COPh

CH2Cl2, r.t., 5 h Additive AgSbF6 AgOTf TfOH (R)/(S)-11 (0.1 mol %): AgSbF6

94% ee (73%) 73% ee (22%) 78% ee (12%) 91% ee (40%)

Scheme 8D.17.

In the neutral BIPHEP-Pt complex, the axial chirality of BIPHEP moiety is controlled by chiral diol BINOL as shown in Scheme 8D.15. However, the diastereomeric purity is not high enough (95:5). Therefore, recrystallization is essential to obtain the single BIPHEP-Pt diastereomer and subsequent enantiomer. Thus, the complete chirality control of both neutral BIPHEP-Pt complexes 14 and cationic 15 without recrystallization has been required (Scheme 8D.18) [44,45]. Interestingly, both enantiopure (S)- and (R)-BIPHEP-Pt complexes 12 can be obtained quantitatively through enantiodiscrimination by (R)-DABNTf and (R)-DABN with the same absolute configuration. In the neutral path through selective complexation, the (S)-12 complex is obtained without recrystallization by complete control of the axial chirality followed by the use of HCl. In the cationic path through nonselective complexation, the (R)-12 complex is, in turn, obtained without recrystallization by complete control of the axial chirality. The enantiopure complex 12 has since been employed as an atropos asymmetric catalyst up to 60°C for a variety of synthetic transformations. The enantiopure dicationic complex obtained by (R)-12 and AgSbF6 gives high yields and high levels of enantio- and (E)-selectivity in the keto ester-ene reaction of trifluoropyruvate with less reactive monosubstituted olefins (Scheme 8D.19). The tropos dicationic DPPF-Ni complex 16 is also a useful catalyst for the glyoxylateene reaction (Scheme 8D.20) [46]. The DPPF ligand is chirally dynamic and hence more readily controlled than the BIPHEP ligand by chiral diamine DABN. The single diastereomer 16/(R)-DABN catalyst provides higher levels of enantioselectivity. The 16/(R)-DABN catalyst gives higher levels of enantioselectivity (90% ee) at room


NHTf NHTf

(R)-DABNTf Neutral path PPh2 Pt

Ph2 P Pt P Ph2

Tf N

Ph2 P

+

H

Cl Pt

P Ph2

N Tf

Cl

(S)-12

(S)/(R)-14

PPh2

Cationic path

BIPHEP

NH2 NH2

Ph2 H2 P N Pt2+ P N Ph2 H2 2SbF6–

Ph2 P

+

H

Cl Pt

P Ph2 8 (R)-12

(R)/(R)-15 (R)-DABN Scheme 8D.18.

R

(R)-12 (5 mol %) AgSbF6 (11 mol %)

O

F3C OH R

+ F3C

CO2Et

CO2Et

CH2Cl2, –20°C, 1 h R = Ph

98% ee (83%) 100% (E)

R = n-C3H7 98% ee (92%) 100% (E) Scheme 8D.19.

Fe

Ph2 P Ni2+ –

2X P Ph2 16 (5 mol % ) (R)-DABN (5.5 mol %)

O

OH

+ Ph

H

CO2Et

CH2Cl2, r.t., 24 h

Ph

CO2Et

16a: X = SbF6 90% ee (84%) 16b: X = ClO4 76% ee (52%) Ni[(R)-DABN]SbF6 75% ee (87%) Scheme 8D.20.

Cl


temperature than without the DPPF ligand (75% ee). It is noted that the choice of the counter anion is critical to obtain high yield and enantioselectivity. The perchlorate counterpart affords lower yield and enantioselectivity than those obtained with the hexafluoroantimonate complex. Unfortunately, the Pd and Pt counterparts give only low enantioselectivity (7–44% ee).

8D.3.3. Chiral Cu and Sc Catalysts Evans and others reported that chiral C2-symmetric bis(oxazolinyl) (box) Cu(II) complexes 17 as Lewis acid catalysts effectively facilitate the glyoxylate-ene reactions (Scheme 8D.21) [47]. The bis(aqua) complex 17a, Cu((S,S)-tBu-box)(H2O)2(SbF6)2, is readily prepared as an air- and water-stable catalyst, with only a slight decrease in the reaction rate relative to the anhydrous complex, 18a. The 17a-catalyzed ene reaction affords not only the high level of enantioselectivity but also excellent control of regioselectivity in the glyoxylate-ene reactions with various 1,1-disubstituted olefins. The anhydrous Cu((S,S)-Ph-box)(OTf)2 complex 18b is also an effective catalyst but provides the opposite sense of asymmetric induction. The reversal in the enantioselectivity of the ene products depending on the oxazoline ring substituent (e.g., t-Bu vs. Ph) can be rationalized by the tetrahedral and square-planar intermediates to account for the absolute configurations of the products. It should be noted that the anhydrous box Cu(II) complex 18a achieves high yield and enantioslectivity even with less reactive monosubstituted and 1,2-disubstituted olefins, in contrast to BINOL-Ti-catalyzed glyoxylate-ene reactions, which does not provide any ene product with these olefins (Scheme 8D.22) [42].

Me Me O N tBu

Me Me

2+

O

O N

Cu tBu H2O OH2 17a

2SbF6–

N R

2+

O 2X–

N Cu

R

R = tBu, X = SbF6: 18a R = Ph, X = OTf: 18b OH

17a (1 mol %) CH2Cl2, 0–25°C O R

+

H

R

CO2Et

93–98% ee (62–97%) CO2Et

R = Me, Ph, CH2OBn CH2OTBDPS

OH

18b (10 mol %) CH2Cl2, 0–25°C

R

CO2Et

76–99% ee (85–99%) Scheme 8D.21.


C3H7

O +

OH

18a (10 mol %) CO2Et

H

C3H7

CH2Cl2, 25°C

CO2Et 92% ee (96%) E/Z 96:4 OH

O +

H

18 (10 mol %) CO2Et

* CO2Et

CH2Cl2, 25°C 18a: 98% ee (S) (95%) anti/syn 86/14 18b: 94% ee (R) (70%) anti/syn 95/5 Scheme 8D.22.

The glyoxylate-ene reactions by treatment of anhydrous box Cu(II) complexes 18 can be extended to the keto ester-ene reactions (Scheme 8D.23) [42]. Methyl pyruvate is examined as a carbonyl enophile to give low yield of the corresponding ene product bearing quaternary chiral center with 1,1-disubstituted olefin. The addition of a large excess of methylenecyclo-hexane or -pentane (10 or 5 equiv) under heated conditions (40°C) is necessary to provide high yield and enantioselectivity using 20 or 5 mol % of the Cu catalyst (Scheme 8D.23).

18a (X mol %)

O

Me OH

+ n 5 eq. 10 eq. 5 eq.

Me

CO2Me CH2Cl2, T °C, 48 h

1 eq. 1 eq. 1 eq.

n = 1, X = 10, T = 25 n = 1, X = 20, T = 40 n = 0, X = 5, T = 40

n

CO2Me

99% ee (35%) 98% ee (84%) 98% ee (98%)

Scheme 8D.23.

Evans and Wu also designed chiral C2-symmetric trivalent pybox-Sc complexes 19 and applied them to the asymmetric carbonyl-ene reactions with N-phenyl glyoxamide (Scheme 8D.24) [48]. When unsymmetrical 1,1,2-trisubstituted olefins 20a and 20b are used with the treatment of Sc complex 19, the ene products are obtained in excellent diastereo- and enantioselectivity, respectively. The regioisomeric products are not observed in both reactions. It is suggested that the major product is obtained via proton transfer from the β-cis substituent through an exo-transition state. In contrast, a general preference for endo-transition states is observed in the box-Cu complexes 18 in glyoxylate-ene reactions with cyclohexene as an enophile (see Section 8D.2.8).


O N N Sc N OTf Ph Ph TfO OTf Sc cat. 19 (5 mol %) O

Et

O +

Me

H N

H

Me

Ph

CH2Cl2, r.t.

OH Et Me

O

20a

H N

Ph

O

95% ee (83%) syn/anti 10/1 O

Me + Et Me

H N

H

Sc cat. 19 (5 mol %) Ph

O

CH2Cl2, r.t.

Me

OH

Me Me

20b

H R

Ph

O

99% ee (75%) syn/anti 20/1

Sc O O

H N

NHPh H Me H

exo TS Scheme 8D.24.

8D.3.4. Chiral Co and Cr Catalysts Optically active β-ketoiminato cationic Co complexes 21 are designed as the efficient catalysts for asymmetric carbonyl-ene reaction of 1,1-disubstituted olefin and glyoxal derivatives (Scheme 8D.25) [49]. Similar to the ene reaction using chiral dicationic Pd, Pt, and Ni complexes, hexafluoroantimonate as a counter anion is found to be the most effective. In spite of the low catalyst loading (0.2 mol %), both the isolated yield and enantioselectivity are maintained in the range of 80–93% and 93–95% ee. Highly enantioselective carbonyl-ene reactions catalyzed by the salen-Co complexes bearing a similar structure to β-ketoiminato complexes are also reported (Scheme 8D.26) [50]. The salen-cobalt complexes 22b–c with sterically demanding silyl group are more effective than salen complex 22a with the commercially available Jacobsen-type ligand. The reaction proceeds at room temperature even with 0.1 mol % of complex 22a to give excellent yield and enantioselectivity (99%, 92% ee). The use of an unactivated alkene and a monocarbonyl (pyridine-2-carboxaldehyde) in the presense of complex 22c also facilitates the reaction to afford the enantiopure product. Ruck and Jacobsen described the use of the interesting chiral tridentate Schiff base ligands in the Cr-catalyzed asymmetric carbonyl-ene-type reaction with 2-methoxypropene (Scheme 8D.27) [51]. The Cr complex 23a smoothly facilitates the reaction in good enantioselectivity. Electron-deficient benzaldehyde derivatives bearing o-substitution


Ph

Ph

N

O O + Ph

H

COPh

N Co+ O O SbF6– 21 (X mol %)

O OH

CHCl3, –20°C

Ph

COPh

X = 5 (3 h) 93% ee (93%) X = 0.5 (45 h) 95% ee (80%) X = 0.2 (80 h) 94% ee (80%) Scheme 8D.25.

Ph

Ph

N

t

Bu

+ CO2Et

H

t

Bu

R R 22 (X mol %)

O Ph

N Co+ O O SbF6–

Toluene, r.t.

OH Ph

22a: R = tBu X = 5 (15 h) 22b: R = TES X = 5 (2 h) 22c: R = TIBS X = 5 (2 h) X = 0.1 (24 h) O + H

N

22c (4 mol %)

CO2Et

46% ee (93%) 62% ee (98%) 98% ee (97%) 92% ee (99%) OH N

Toluene, r.t., 24 h >99% ee (84%) Scheme 8D.26.

(Br, Cl, CN, NO2) in particular show higher reactivity and enantioselectivity. BaO can act as a desiccant rather than as an acid scavenger. Hydrolysis or ozonolysis can easily transform the vinyl ether portions of the ene products to ketones or esters, respectively. Ruck and Jacobsen also examined the asymmetric ene reaction with silyl enol ether as an enophile (Scheme 8D.28) [52]. In a combination of Cr complex 23b, MS 4Å, and substoichiometric amounts of diisopropylethylamine (DIPEA) to trap a trace amount of Brønsted acid associated with the catalyst, even simple aliphatic aldehydes have been converted into the β-hydoxytrimethysilyl enol ether products in high yields and enanti-


t

Bu

Cl

N O H2O O Cr+ Cr+ O OH O Cl N

Y

Y

23a Y = tBu 23b Y = OTIPS 23c Y = Br

2

t

Bu

O

OMe +

X

OMe OH

23a (5 mol %)

H

X

BaO Acetone, 4°C X = H 88% ee (82%) X = Br 96% ee (97%)

O

OH Br

OMe OH

O3

HCl

H3C

O

Br

OH Br

H3CO 94%

97% Scheme 8D.27.

O

OTMS +

H

23b (5 mol %) R

DIPEA MS 4A 4°C

OH OTMS R

R = nPr 89% ee (87%) I Pr 90% ee (83%) TBDPSOCH2CH2 93% ee (90%)

1) TBSOTf, Et3N 2) Isobutyraldehyde BF3 OEt2 OH O

OH i

Pr

TBDPSO 83% (3 steps) syn/anti 59/41

Scheme 8D.28.

oselectivities under solvent-free conditions. These products are inactive as enophiles under the reaction conditions. Additionally, after protection as the TBS ether of the product (R = TBDPSOCH2CH2), a Mukaiyama aldol reaction is attempted in the presence of BF3·OEt2 to afford enantiopure product in a 59/41 (syn/anti) ratio. Enantioselective glyoxylate-ene reactions catalyzed by hindered salen-Cr complexes, which are readily accessible on a multigram scale [53], are also reported (Scheme 8D.29) [54]. It is demonstrated that introduction of the adamantyl group is important to give a good enantioselectivity. For example, the reaction with isobutene and ethyl glyoxylate in the presence of complex 24 is improved to 79% ee from 15% ee obtained by the Jacobsen-type complex.


N t

Bu

O

O

Cr+ BF4–

N t

O

Bu

24 (2 mol %)

OH

+ CO2Et

H

R

Toluene, r.t., 24 h

R R = Me t Bu Ph

CO2Et 79% ee (64%) 92% ee (63%) 61% ee (56%)

Scheme 8D.29.

8D.3.5. Organocatalysts The carbonyl-ene reactions in a combination of trifluoropyruvate and 1,1-disubstituted olefins proceed by H-bonding thioureas (Scheme 8D.30) [55]. The reaction at −20°C using the chiral thiourea 25 [56] with the binaphthyl backbone gives the corresponding product in 89% yield and 33% ee.

CF3 S N H H N

Ph

F3C

CF3 CF3

S 25 (10 mol %) CF3

O +

N H H N

CO2Et

CH2Cl2 –20°C, 210 h

F3C OH Ph

CO2Et

33% ee (89%)

Scheme 8D.30.

Recently, Terada et al. reported the highly diastereo- and enantioselective glyoxylate-ene reaction with enecarbamates catalyzed by the chiral phosphoric acid catalyst 26a (Scheme 8D.31) [57]. While the reaction of (Z)-enecarbamates needs longer times and leads to lower enantioselectivity of the anti-isomer, high catalytic activity and enantioselectivity can be achieved with (E)-enecarbamates. It is clarified by DFT computational analysis that the two hydrogen-bonding interactions between the chiral phosphoric acid and the glyoxylate are crucial to provide a high level of enantioselectivity [58].

8D.4. INTERMOLECULAR IMINE-ENE REACTION 707 t

O

Bu

O P

O

MeO2C R2

O

NH R1

+

H

t

26a (5 mol %) CO2Et

OH

R2

O +

CO2Et 1

R anti (1 h) (2 h) (24 h) (1 h)

Bu

H3O+

MS 4A, CH2Cl2 r.t. O

R1 = H, R2 = Ph R1 = Me, R2 = Ph (E) R1 = Me, R2 = Ph (Z) R1, R2 = -(CH2)4-

OH

99% (98% ee) >73% (>99% ee) 8% (72% ee) 79% (99% ee)

: : : :

OH

R2

CO2Et R1 syn – 25:1

Scheme 8D.32.

Ar2 P

R1

Cu+ – P Ar2 ClO4 (5 mol %)

NTs +

2

R

R1

NHTs

2

BTF, r.t.

CO2Et

H

28: Ar = 4-MeC6H4

CO2Et

R

R3 Ts CO2Et Ph

95% ee (85%) Ph

CO2Et

99% ee (95%)

CO2Et PhS

85% ee (90%)

NHTs CO2Et

90% ee (92%) NHTs

NHTs

CO2Et

CO2Et

CO2Et

98% ee (85%)

O

NHTs CO2Et

NHTs

NHTs

90% ee (91%)

N

NHTs

NHTs

MeO

99% ee (94%)

94% ee (77%) syn/anti 6/1

Scheme 8D.33.

of the enantioselective catalysis of imine-ene reaction untill 1998, because of the low ene reactivity of glyoxylate-imines as compared with the parent glyoxylates. Recently, Lectka et al. demonstrated the first effective enantioselective imine-ene reactions of readily available α-tosylimino ester with alkenes using Tol-BINAP-Cu(I) (ClO4) complex 28 (Scheme 8D.33) [64]. A variety of aromatic, cyclic, and simple acyclic

8D.4. INTERMOLECULAR IMINE-ENE REACTION 709

alkenes can be used in benzotrifluoride (BTF) as the best solvent. The Tol-BINAP-Cu(I) complexes with ClO4 or PF6 provide high yield and enantioslectivity. The asymmetric catalysis of imine-ene reactions is reported by dicationic SYNPHOSPd complex 5d (92% ee) rather than the BINAP-Pd complex 5b (89% ee) (Scheme 8D.34) [65]. Regardless of the high catalyst loading (20 mol %), it should be noted that the use of dicationic Pd complex 5 in the presence of MS 4Å leads to good yield and enantioselectivity. Additionally, (S)-Tol-BINAP-Pd/(±)-DABN complex 29 significantly enhances the catalytic activity and enantioselectivity.

NTs + H

CO2Et

Pd cat

NHTs

CH2Cl2, r.t., 20 h

CO2Et

5b (20 mol %, MS 4A) 89% ee (66%) 5d (20 mol %, MS 4A) 92% ee (65%) 29 (5 mol %) 92% ee (51%) O O O

Ph2 P Pd2+ – P Ph2 2SbF6

O 5d

Ar2 P

2+

H2 N

Pd P N Ar2 H2 2SbF–6 29 (Ar = 4-Me-C6H4) Scheme 8D.34.

While enamides can be easily prepared, handled, and stored at room temperature, their use as nucleophiles is limited in asymmetric synthesis. Recently, Kobayashi et al. reported the first example of Cu(II)-catalyzed enantioselective addition of enamides to imines (Scheme 8D.35) [66]. The Cu(II) complex 30 bearing chiral diamine ligand by the treatment of N-carbamate-protected imine and several enamides facilitates the azaene-type reaction to provide the adducts in high yields and enantioselectivities. The diamine product obtained by the one-pot treatment [67] can be converted into lactam with two chiral centers in high yield (Scheme 8D.36). This asymmetric aza-ene-type reaction of enamides to imines using chiral Cu complexes is applied to chiral Brønsted acid catalysis (Scheme 8D.37) [68]. The reaction using chiral phosphoric acid 26b smoothly proceeds to afford excellent yield and enantioselectivity without any detrimental effect even on a gram scale. Terada et al. extended their study to chiral Brønsted acid-catalyzed tandem aza-enetype reaction-cyclization cascade for the asymmetric synthesis of piperidine derivatives (Scheme 8D.38) [69]. The reaction of N-Boc aldimines with monosubstituted enecarbamates by chiral phosphoric acid 26c occurs to give the cyclic products piperidines in high diastereo- and enantioselectivity. The generation of more reactive intermediate by using the monosubstituted enecarbamates induces the second aza-ene-type reaction (Scheme 8D.39).


Ph

Ph

NH HN O 1

R

NH

N

+ Cu(OTf)2 30 (each 10 mol %)

R2

+

CH2Cl2, 0°C

CO2Et

H

Ph

O R1

N Ph

HN

R2

H+

R2

HN

O

CO2Et

Ph

CO2Et

1

R = Me, R2 = COC11H23 85% ee (83%) R1 = OBn, R2 = COC11H23 93% ee (94%) R1 = OBn, R2 = COCH3 94% ee (72%) Scheme 8D.35.

O BnO Ph

N

HN

O C

O C11H23

CO2Et

LiAlH(OtBu)3/LiI Et2O, –45°C

BnO

NH HN

O C

C11H23

CO2Et

Ph

87% anti/syn 86/14 H2 Pd/C O H N

C11H23 O

NH Ph

71%

Scheme 8D.36.

8D.5. INTRAMOLECULAR CARBONYL-ENE REACTION Mikami et al. reported the first examples of “catalytic” asymmetric intermolecular carbonyl-ene reaction by using BINOL-Ti catalyst 1 [70]. The chiral BINOL-Ti catalyst 1 in the presence of AgClO4 efficiently functions for both chiral recognition of the enantioface of the aldehyde and discrimination between the diastereotopic protons of the ene portion (Scheme 8D.40). A chiral box-Cu(II) complex-catalyzed asymmetric intramolecular carbonyl-ene reactions of unsaturated keto ester is reported (Scheme 8D.41) [71]. In spite of the high catalyst loading (20 mol %), the use of complex 18b provides the six-membered cycloadducts, and the diastereomeric ratio is more than 50:1.

8D.5. INTRAMOLECULAR CARBONYL-ENE REACTION 711

O

O

P O

O N Ph

0.005 mmol 3.5 mg

OH

O

O Ph

+

HN

H

OMe Ph

5.00 mmol 1.05 g

Ph

26b (0.1 mol %)

NH

N

CO2Me

CO2Et Ph 95% ee (89%)

Toluene, r.t.

5.05 mmol 0.90 g

4.45 mmol 1.72 g

Scheme 8D.37.

Ph

O P O

N R

Boc + H

HN

Cbz H

O OH

26c (2–5 mol %)

Ph

CH2Cl2, 0°C, 1–5 h HN Boc

Cbz

HN Boc

N

R

+ N H

Cbz

N

R

trans >99% yield 95 (>99% ee) R = Ph 95 (97% ee) R = Ph-CH=CH- 70% yield 68% yield 94 (97% ee) R = c-C6H11

Cbz

N H

Cbz

cis : : :

5 (40% ee) 5 (36% ee) 4 (48% ee)

Scheme 8D.38.

Jacobsen et al. recently reported an efficient enantioselective catalytic intramolecular carbonyl-ene reaction by chiral Cr complex (Table 8D.2) [72]. The complex 23c promotes highly diastereo- and enantioselective intramolecular carbonyl-ene reaction of a variety of alkenyl aldehydes to afford densely functionalized hetero- and carbocycles bearing up to three chiral centers.


1

N R

2

PG

HN

+ 2 H

PG

Tandem 1 aza-ene-type reaction G P

G

N *

R *

* N H

1st aza-ene PG1

NH

R *

PG2

HN

PG2

Cyclization

N

PG2

PG1

2nd aza-ene G≠H

G

PG2 PG2 N NH HN

R *

G ≠ H, G = H

H

*

Scheme 8D.39.

O H

OH

BINOL-Ti 1 (10 mol %) AgClO4 (20 mol %)

O

OH +

MS 4A

O

CH2Cl2, 0°C, 24 h

O trans

cis

50% yield 80 (84% ee)

:

20 (74% ee)

Scheme 8D.40.

O

O

O OEt

box-Cu 18b (20 mol %) EtO MS 4A CH2Cl2, r.t., 2 h

O OH

OH

EtO +

trans

81% yield >50 (91% ee)

cis :

1

Scheme 8D.41.

The Cr complex-catalyzed ene reaction leads prenylated 1,3-dialdehydes to bicyclo[3.2.1]octanes products bearing quaternary carbon centers as single diastereomers in high enantioselectivities (Scheme 8D.42).

8D.6 ENE-TYPE CYCLIZATION 8D.6.1. Chiral Rh Catalysts The first catalytic asymmetric cyclization of 1,6-enynes using cationic chiral Rh(I) complexes prepared in situ by a combination of [Rh(diphosphine)Cl]2 and 1.0 equiv AgSbF6 is reported by Zhang et al. (Scheme 8D.43) [73]. Reactions proceed smoothly at room

8D.6 ENE-TYPE CYCLIZATION 713

TABLE 8D.2. Intramolecular Carbonyl-Ene Reaction of Chiral Cr Complex

t

Bu

Cl

O H2O O Cr+ O OH O Cl N N

Br

Br

Cr+

2

R1 R1

t

Bu

1

CH3

1

23c

R R

R3

X 2

R

X

H

R2

MS 4A Toluene, 4°C

O

Substrate

3

R

Product R1 = CH3, X = O

R1 R1

CH3 H3C

H R1 = CH , X = NTs 3

X

R1 =

O

mol %

R1 R1 OH

X

OH

,X=O

% Yield

dr

% ee

0.8

77

>30:1

93

2.0

98

>30:1

98

1.0

96

>30:1

96

2.5 5.0

88 72

— —

94 93

5.0

78

>30:1

75

1.0

94

20:1

96

H3C 1

1

R R

H

X

R1 =

O

CH3

R1 = OCH3, X = CH2

CH3 H3C

H3C CH3 H O O CH3

R1 R1 OH

X

,X=O H3C CH3 O

OH CH3

H3C CH3 H3C

CH3

H3C CH3 H O O

H3C CH3 O

OH CH3 H3C

temperature, and bidentate diphosphines are effective as chiral ligands. In fact, the substrates and chiral ligands structure are important factors for increasing enantioselectivity. The use of DUPHOS ligand leads to high levels of enantioselectivity in aromatic substrates (R = Ph) with an oxygen tether. In sharp contrast, BICP ligand facilitates the reaction in the aliphatic substrates (R = C4H9), while DUPHOS complex is completely inactive. A number of chiral phosphine ligands and catalytic precursor have been screened, and reaction conditions have also been optimized to more efficient catalytic system for Rh-catalyzed ene-type cyclization (Scheme 8D.44) [74]. When BINAP (12 mol %) as the chiral ligand is used in the presence of [Rh(cod)Cl]2 (5 mol %) and AgSbF6 (20 mol %),


23c CH3 OHC CHO (10 mol %) H3C

MS 4A Toluene, r.t.

R

HO

CH3

CHO OH R

H

HO

H

R % yield

dr

% ee

R=

46

>30:1 92

R=

42

>30:1 93

Scheme 8D.42.

R

[Rh(diphosphine)Cl]2 (3–5 mol %) AgSbF6 (3–5 mol %)

R

(CH2Cl)2, r.t.

X

O

X = O, R = Ph X = O, R = C4H9 X =PhSO2N, R = Me P H P

(R,R)-Me-Duphos

H

PPh2

H

96% ee (62%) 98% ee (67%) 82% ee (98%)

H

PPh2

(R,R,R,R)-BICP

OPPh2 OPPh2

(R,R,R,R)-BICPO

Scheme 8D.43.

R1 R2 O

[Rh(cod)Cl]2 (5 mol %) (S)-BINAP (12 mol %) AgSbF6 (20 mol %) (CH2Cl)2, r.t. R1= Ph, R2 = H R1= Me, R2 = Me R1= CO2Et, R2 = Et R1= CH2OH, R2 = Me R1= Me, R2 = OAc Scheme 8D.44.

R2

R1 * O

>99.5% ee (96%) >99.9% ee (82%) >99.9% ee (82%) >99% ee (81%) >99.9% ee (92%)


high yield and enantioselectivity are observed at room temperature within 20 min. A number of functionalized tetrahydofuran derivatives are obtained in high yield and enantioselectivity. Even with lower catalyst loading (0.2 mol % Rh), the cyclization of the substrate (R1 = Me, R2 = Me) is completed within 35 min with high enantioselectivity retention (>99.9% ee). Zhang et al. extended their study to the catalytic asymmetric synthesis of functionalized γ-lactones and -lactams (Scheme 8D.45) [75]. As the trans-isomer predominates in the equilibrium, unprotected enyne amides are unreactive as substrates (Scheme 8D.46). Therefore, the protected enyne amides especially with benzyl group lead to excellent yields and enantioselectivities.

[Rh(cod)Cl]2 (5 mol %) (R)-BINAP (12 mol %) AgSbF6 (20 mol %)

R1 R2

R1 * O

(CH2Cl)2, r.t. within 2–10 min

O

X

R2

X = O, R1= Ph, R2 = Me R1= Me, R2 = Me R1= Ph, R2 = OAc X = NBn, R1= Ph, R2 = Et R1= CH2OMOM, R2 = H R1= Ph, R2 = OMe

O

>99% ee (92%) >99% ee (98%) >99% ee (96%) >99% ee (96%) >99% ee (98%) >99% ee (88%)

Scheme 8D.45.

R1 R2

R2 N H

O N H

O

cis

R1

trans Scheme 8D.46.

This Rh system can be applied to the formal synthesis of (+)-pilocarpine, one of the most important imidazole alkaloids, which is obtained in excellent yield and enantioselectivity (Scheme 8D.47). In the previous report, the key intermediate (4R)-(Z)dehydrohomophilopic aldehyde is synthesized from 2-acetylbutyrolactone in five steps in 92% ee and 20% total yield [76]. The chiral Rh catalyst system reported by Zhang et al. is an excellent example in terms of the facile cyclization even at room temperature but limited to disubstituted cis-olefinic substrates. We reported the ene-type cyclization of a trisubstituted olefinic ether using cationic Rh(I) catalyst with chiral bidentate diphosphine ligands (Scheme 8D.48) [77]. The ene-type cyclization in the presence of [Rh(diphosphine)]2(SbF6)2


[Rh(cod)Cl]2 (5 mol %) H BINAP (12 mol %) AgSbF6 (20 mol %) O (CH2Cl)2, r.t. within 2–10 min O

Me HO O

Me * O

O

5 steps

O

O

O

(R)-BINAP >99% ee (+) (99%) (S)-BINAP >99% ee (–) (98%) N Me

N

O

O

(+)-Pilocarpine Scheme 8D.47.

CO2Me

[Rh(diphosphine)] 2(SbF6)2 (5 mol %) CH2Cl2, r.t.

O

CO2Me * (S)-BINAP (S,S)-skewphos Ph2P

CO2Me *

+

O 28% ee (S) (90%) 93% ee (R) (59%)

O 18% ee (S) (10%) >95% ee (R) (6%)

PPh2 CO2Me [Rh{(S,S)-skewphos}] (SbF ) 2 6 2 (5 mol %) CH2Cl2, 0∞C, 96 h N Ts

CO2Me N Ts 90% ee (62%)

Scheme 8D.48.

proceeds even with such a sterically demanding trisubstituted olefinic ether, along with the formation of isomerized endo-cyclic secondary product. The key to success in increasing the enantioselectivity and olefinic regioselectivity is the use of (S,S)-skewphos ((2S,4S)-2,4-bis(diphenylphosphino)pentane (S,S)-BDPP) rather than BINAP. The reactions with (S,S)-skewphos proceed slowly, but olefinic regioselectivity increases up to 98%, maintaining high chemical yield and high enantioselectivity of the major


product. Furthermore, cyclization of amide substrate proceeds in good yield without olefin migration. The enantioselective spiro-ring construction is an important issue because many natural compounds have chiral spiro centers [78]. Some examples of catalytic spiro cyclizations have been reported by asymmetric intramolecular Mizoroki–Heck reactions [79]. In spite of a similar but higher potential, transition metal-catalyzed ene-type carbocyclization has never been applied to asymmetric spiro cyclizations. Spiro cyclizations can be catalyzed by the cationic (S,S)-skewphos-Rh(I) complex (Scheme 8D.49). Cyclization of the six-membered ring is executed to give moderate yield and high enantioselectivity, accompanied with olefin-migration product in high enantioselectivity. The reactivity increased dramatically at 80°C, and the cyclization completes within only 40 min to afford olefin-migration product in high enantioselectivity (44%, 91% ee). The spiro cyclization is also attained with pyran amide compound. Spiro cyclization proceeds to provide the desired spiro amide-pyran as an almost sole product with a high level of enantioselectivity (Scheme 8D.50).

CO2Me n

[Rh{(S,S)-skewphos}]2(SbF6)2 (5 mol %) CH2Cl2

O n

n

CO2Me

CO2Me

+

O

O n=2 n=2 n=4

r.t., 46 h 80°C, 40 min 40°C, 17 h

88% ee (53%) 67% ee (4%) 88% ee (12%)

97% ee (16%) 91% ee (44%) 88% ee (51%)

Scheme 8D.49.

O

CO2Me [Rh{(S,S)-skewphos}] (SbF ) 2 6 2 (5 mol %) CH2Cl2, r.t., 36 h N Ts

O CO2Me N Ts 94% ee (72%)

Scheme 8D.50.

The tropos or atropos nature of BIPHEP-Rh complexes at room temperature critically depends on the amines complexed therewith. The aliphatic DPEN (1,2diphenylethylenediamine) complex is atropos, while the aromatic DABN complex is tropos. However, at 5°C or below, even amine-free BIPHEP-Rh complexes are atropos and hence can be used as chiral catalysts. Therefore, ene-type cyclization in the presence of enantiopure BIPHEPs-Rh/DABN complexes 31 and 32 achieves the high level of


Et

Et 5 mol % Rh

Et

31 31 32 32 33 33 Ph2 N P Rh+ N P Ph2 PPh2 Ph2P

2SbF6–

Rh+ N N

*

33

+

* O

TfOH (10 mol %) (CH2Cl)2

O

rt, 12.5 h rt, 30 min rt, 5 min 5°C, 3 h rt, 15 min 5°C, 3 h

O

56% ee (74%) 59% ee (84%) 85% ee (70%) 96% ee (83%) 91% ee (91%) 99% ee (92%)

– – (23%) (5%) (3%) –

* Ar2 P Rh+ P Ar2

N

N * = (R)-DABN

* N

N

SbF6–

31: Ar = Ph 32: Ar = 3,5-Me2-C6H4 Scheme 8D.51.

yield and enantioselectivity (Scheme 8D.51) [80]. Additionally, the use of complex 33 bearing tetraphos ligand instead of BIPHEP leads to higher catalytic activity and enantioselectivity [81]. In the tetraphos case, the time-dependent enantioselectivity is not observed at all, even at room temperature during the reaction time. Diamine-free tetraphos-Rh complex is thus more rigid than BIPHEP-Rh complex, but surprisingly more flexible than the BIPHEP-Rh complex upon complexation with DABN.

8D.6.2. Chiral Pd Catalysts In 2001, Mikami et al. reported highly enantioselective ene-cyclization of 1,6-enyne to give tetrahydrofuran derivatives bearing quaternary chiral center via two different catalytic systems (Scheme 8D.52) [82]. One is the combination of neutral complex of Pd(OCOCF3)2 and SEGPHOS ligand in d6-benzene, and the other is the combination of cationic complex of [Pd(MeCN)4](BF4)4 and DM-SEGPHOS in DMSO. The C2symmetric bidentate chiral phosphine ligands such as SEGPHOSs are so effective in quantitatively giving the enantiomerically pure cyclo-product in both systems. A highly enantioselective spiro cyclization catalyzed by cationic chiral Pd complexes is reported with a new PN-ligand bearing achiral oxazoline unit substituted by sterically demanding gem-dialkyl groups (Scheme 8D.53) [83]. In Pd-catalyzed spiro cyclizations, PP-ligand such as SEGPHOS and BINAP provides the primary spiro products along with olefin migration, leading to secondary olefin regioisomer in low enantioselectivities. Our (aS)-PN-ligand doubly substituted by methyl groups provides the spiro products with higher enantiomeric excess (total 96% ee) in excellent yield.


CO2Me CO2Me

Pd cat. O

O

Pd cat.

Condition

Pd(OCOCF3)2 (5 mol %) (S)-SEGPHOS (10 mol %)

C6D6, 100°C

>99% ee (>99%)

[Pd(MeCN)4](BF4)2 (5 mol %) DMSO, 80°C >96% ee (>99%) (S)-DM-SEGPHOS (10 mol %) O O

PAr2

O

PAr2

O (S)-SEGPHOS (Ar = Ph) (S)-DM-SEGPHOS (Ar = 3,5-Me2-C6H3) Scheme 8D.52.

[Pd(MeCN)4](BF4)2 (5 mol %) O N PPh2

CO2Me n X Ring size 5 6 7 15 5 6 7 15

n

(10 mol %)

CO2Me

n

CO2Me

+

DMSO, 100°C

X

X

X =O

3h 22 h 3h 11 h

88% ee (88%) 84% ee (63%) 88% ee (13%) 83% ee (>90%)

– (7%) 31% ee (20%) 83% ee (78%) – (0%)

X =NTs

1h 1h 1h 1h

96% ee (90%) 84% ee (71%) 95% ee (6%) 84% ee (>95%)

– (9%) 35% ee (29%) 95% ee (93%) (0%) –

Scheme 8D.53.

This Pd(II)-catalyzed cyclization system is further developed for the asymmetric cyclization of 1,7-enynes (Scheme 8D.54) [84]. In the presence of [Pd(MeCN)4](BF4)2 and BINAP, cyclization of 1,7-enynes substrates bearing benzene ring, which is essentially needed for obtaining six-membered-ring products, leads to quinoline derivatives with quaternary stereogenic centers as single enantiomers and in quantitative yields.


R

[Pd(MeCN)4](BF4)2 (5 mol %) (S)-BINAP (10 mol %) HCOOH (1 eq.) DMSO, 100°C, 1–3 h

N Ts

N Ts

R

N Ts >99% ee (99%) R=H R = CO2Me >99% ee (99%)

15 15 [Pd(MeCN)4](BF4)2 (5 mol %) (S)-BINAP (10 mol %) HCOOH (1 eq.) DMSO, 100°C, 1 h

N Ts 86% ee (53%)

Scheme 8D.54.

The enantioselective quinoline cyclization to construct quaternary centers challenged four-, five-, and fifteen-membered spiro-ring cyclization. Especially with the terminal acetylenic substrate with fifteen-membered olefin, the olefin-migrated spiro product is obtained in moderate yield (53%) but with high enantioselectivity (86% ee). Late transition, metal-catalyzed asymmetric addition reactions of active methylene compounds to alkene or alkyne system are generally called as the Conia-ene reaction [85]. The enantioselective catalysis of the α-vinylation of carbonyl compounds to provide all carbon quaternary centers is attained by late transition metal catalysts such as chiral Pd(II) complexes (Scheme 8D.55) [86]. Chiral Pd(II) complexes with DTBM-SEGPHOS catalyze the Conia-ene cyclization to provide α-vinyl ketone compounds. The highly enantioselective version has been attained by the combined use of Yb(OTf)3 in dilute diethyl ether solution (0.02 M) to provide high yield and enantioselectivity.

8D.7. D-A-TYPE REACTION Recent successes in asymmetric intra- and intermolecular (hetero) D-A-type reactions catalyzed by chiral metal complexes are discussed. Chiral organocatalyst-catalyzed (such as proline, imidazolidinone, and Brønsted acid) reactions are reported in Chapter 2A by Watson and MacMillan and Chapter 3 by Yamamoto and Cheon. 8D.7.1. Intramolecular [4 + 2] Cycloaddition Transition metal-catalyzed D-A reactions [87] of unactivated dieneynes such as intramolecular [4 + 2] cycloaddition are powerful synthetic methods leading to 5,6- or 6,6-

8D.7. D-A-TYPE REACTION 721

X

O

34 (10 mol %) Yb(OTf)3 (20 mol %)

O OR

O O O

Ar2 P

O

OEt

AcOH (10 eq.) Et2O, r.t., 12 h X=H Me I R = allyl X = H Me

R = Et O

O

X

OTf Pd2+ OTf

P Ar2

89% ee (86%) 93% ee (80%) 85% ee (95%) 90% ee (80%) 94% ee (81%)

34

(R)-DM-SEGPHOS (Ar = 3,5-tBu2-4-OMe-C6H2) Scheme 8D.55.

Me

O

PPh2 PPh2 O 35 (6.0 mol %)

R TMS O

[Rh(coe)2Cl]2 (2.5 mol %)

TMS O H

Me

35a: R = Ph 87% ee (76%) 35 (6.0 mol %)

O

Me

Me

H

[Rh(coe)2Cl]2 (2.5 mol %)

Me

O H 35b: R = Me 73% ee (84%) 35c: R = tBu 54% ee (72%) 35a: R = Ph 47% ee (73%) Scheme 8D.56.

fused rings [88–90]. The fused structures thus obtained can be inducted into a variety of natural products whose syntheses are difficult without the use of transition metals. Therefore, a number of catalyst systems such as Rh complexes that perform intramolecular [4 + 2] cycloaddition in excellent yields have been developed over 15 years, and some asymmetric variants using chiral diphosphine or diene ligands have also been developed [91]. Livinghouse et al. reported the first examples of catalytic asymmetric intramolecular [4 + 2] cycloaddition with unreactive diene-yne or diene-ene (Scheme 8D.56) [92]. In


the diene-yne system, the use of DIOP derivative 35a as a chiral ligand leads to a high level of enantioselectivity. The effect of the 2-position of 1,3-dioxolane ring is examined to give the most efficient yield and enantioselectivity (84%, 73% ee) with ligand 35b. Interestingly, the cyclo-products obtained by 35a and 35c bear the opposite absolute configuration. Gilbertson et al. also reported that the efficient asymmetric [4 + 2] cycloaddition is achieved by using [Rh(diphosphine)(solvent)]+ complex generated in situ from the hydrogenation of [Rh(diphosphine)(nbd)]+ complex (Scheme 8D.57) [93]. In this catalytic system, substrates bearing an aromatic ring (R = Ar) on the terminal alkyne cannot be employed to show low enantioselectivity (vide infra).

P P

L: (S,S)-Me-Duphos

[Rh(L)(solvent)]+SbF6– (6 mol %)

R X Me

CH2Cl2/AcOEt 6/1 55°C, 4–11 h

R Me X H

R = H, X = O 87% ee (76%) R = Et, X = O 88% ee (76%) R = H, X = C(CO2Et)2 91% ee (78%)

O

Me

[Rh{(S)-BINAP}(solvent)]+SbF6– (6 mol %) AcOEt 55°C, 72 h

H

Me

O H >98% ee (64%)

Scheme 8D.57.

The key to efficient asymmetric catalysis lies in the creation of effective chiral catalysts by a suitable combination of chiral organic ligands and central metals. The asymmetric catalysts thus prepared can evolve into more activated catalysts with higher catalytic activity and enantioselectivity by chiral activators to additionally ligate (“asymmetric activation”) [34]. However, the additional ligation does not necessarily lead to higher catalytic activity, for which we propose the term “asymmetric synergy (effect)” leading to higher enantioselectivity without increase in the catalytic activity (even with decrease). A number of asymmetric cycloadditions based on Rh catalysts have been developed. The chiral Rh catalysts are generally prepared from achiral diene-Rh precatalysts and chiral diphosphine ligands, but the effect of the achiral dienes on enantioselectivity has been almost neglected. We have developed a highly efficient chiral Rh(I) catalysts in the synergistic combination of chiral diene-Rh complexes and chiral diphosphine ligands


to increase the enantioselectivity than simply by Rh-chiral diphosphine complex without a chiral diene (Scheme 8D.58) [94]. We have investigated the effect of chiral dienes such as C1-symmetric dienes 36 in a combination of chiral diphosphine ligands. A remarkable increase in enantioselectivity is observed by using chiral dienes. When the [RhCl(36)]2 is examined without chiral diphosphine ligand, the product is obtained in 91% yield within 30 min though with low enantioselectivity (26% ee). However, the combination of [RhCl(36)]2 with (R,R)-Me-DUPHOS provides an effective catalyst system to afford the product in high enantioselectivity and yield (89% ee). The use of (R,R)-Me-DUPHOS affords a higher level of enantioselectivity than that obtained with only chiral diene or the combination of (R,R)-Me-DUPHOS with achiral [RhCl(cod)]2. On the other hand, the use of (S,S)-Me-DUPHOS leads to the opposite enantiomer product with lower enantioselectivity (−9% ee). These results clearly show that both chirality of chiral dienes and Me-DUPHOS synergistically work in the right combination in the enantiodiscriminating step of the intramolecular [4 + 2] cycloaddition. (R,R)-Me-DUPHOS is the matched pair with the chiral dienes 36, and hence (S,S)-Me-DUPHOS is the mismatched pair. This is the first example of asymmetric synergy between chiral dienes and diphosphines. While the use of chiral dienes instead of achiral cod or nbd decreased the catalytic activity, hence, not asymmetric activation, the synergy effect by chiral dienes and diphosphine leads to a higher enantioselectivity than that by chiral diene itself without chiral diphosphine.

Ph

[RhCl(36)]2 (5 mol %) Ph

Me

Diphosphine (11 mol %)

O

O AgSbF6 (20 mol %) CH2Cl2, r.t.

Me

Me

– PPh3 (R,R)-Me-Duphos (S,S)-Me-Duphos (R,R)-Et-Duphos

OMe

H 26% ee (91%) 26% ee (85%) 88% ee (90%) –9% ee (96%) 95% ee (99%)

Me Me Me

Diene* 36 Scheme 8D.58.

In a possible mechanism (Scheme 8D.59), the substrate-coordinated intermediate A initially forms, and then oxidative cyclization of the dieneyne substrate affords the metallacyclopentane. Subsequently, allyl rearrangement and the reductive elimination lead to the desired cyclic product. It is proposed that chiral dienes coordinate to the Rh center in monodentate fashion in the enantiodiscriminating step A. Recently, Hayashi et al. reported the use of C2-symmetric chiral diene ligands for a highly active and enantioselective asymmetric [4 + 2] cycloadditions (Scheme 8D.60)


Ar

Ar

Me

O

O

Me H

Rh

*

Rh+ O

P * P

Reductive elimination

Ar

+

* Ar O

Me H

Rh+

P * P

H

Ar Allyl rearrangement

Oxidative cyclization

A

Rh+

O H

Scheme 8D.59.

MeO2C MeO2C

Me

R

[RhCl(diene*)]2 (2.5 mol %)

MeO2C

AgSbF6 (10 mol %)

MeO2C

R

CH2Cl2, 25°C, 1 h

Me

H

Ph

Ph Ph Ph

Ph R = Ph Me i

Pr

(S,S)-Ph-bod*

(S,S)-Bn-bod*

Ph (S,S)-Ph-bnd*

94% ee (87%) 97% ee (89%) >99% ee (95%)

5% ee (86%)

35% ee (58%)

Scheme 8D.60.

[95]. (S,S)-Ph-bod* as a chiral ligand in particular shows the highest performance. In this catalyst system, a variety of substitution patterns on the alkyne and the 1,3-diene portions are tolerated to give the cyclic products with high efficiency. The chiral diene (S,S)-Ph-bod*-complex can also be applied to the intermolecular versions between 1,3-dienes and alkyne to afford the corresponding 1,4-dienes in high enantioselectivity (Scheme 8D.61). Since the intramolecular [5 + 2] cycloaddition with the Wilkinson catalyst was reported, a variety of achiral Rh and Ru catalyst systems have been developed over 10 years [96]. Recently, the first asymmetric intramolecular [5 + 2] cycloaddition using a chiral Rh complex was reported by Wender et al. (Scheme 8D.62) [97]. The use of cationic [Rh{(R)-BINAP}(solvent)]SbF6 complex in dichloroethane promotes the cycloaddition of several vinylcyclopropanes (VCPs).


R

CO2Me + CO2Me

[RhCl{(S,S)-Ph-bod*}]2 (2.5 mol %)

R CO2Me

*

AgSbF6 (10 mol %) CH2Cl2, 25°C, 16 h

CO2Me

R = Et 83% ee (72%) nHex 87% ee (48%)

Scheme 8D.61.

R MeO2C MeO2C

[Rh{(R)-BINAP}(solvent)] +SbF6– (10 mol %) MeO2C (CH2Cl)2 50–70°C, 36–48 h

MeO2C

R

H

R = Me >95% ee (72%) R = CH2OBn >99% ee (80%) R=H 52% ee (73%) [Rh{(R)-BINAP}(solvent)] +SbF6– (10 mol %) X

(CH2Cl)2 r.t. –70°C, 48 h

X * X = NTs 56% ee (87%) X=O 22% ee (95%)

Scheme 8D.62.

8D.7.2. Intermolecular (Hetero) D-A Reaction Chiral oxazaborolidines 37 (R = H, Me, nBu, and Ar) have been one of the most useful catalysts for the asymmetric reduction of ketones by using BH3·THF or catecholborane as stoichiometric reductants [98]. Corey et al. extended their study to asymmetric C–C bond-forming reaction, especially D-A reaction, by a chiral cationic Lewis acid, which combines a proline-derived oxazaborolidine 37 with a triflic acid as an activator (Scheme 8D.63) [99]. In the presence of the catalysts 38, even at −95°C in dichloromethane, asymmetric D-A reaction of various dienes, even unreactive dienes such as simple 1,3-butadiene, leads to the corresponding cycloadducts in high yield and enantioselectivity (Table 8D.3). While the catalysts 38 are extremely efficient for the asymmetric D-A reaction with α-substituted α,β-enals and various acyclic and cyclic dienes, they are unstable to decompose at or above 0°C, limiting the range of practical application. Ryu and Corey succeeded in a modification of these catalysts that would increase their stability and catalytic activity by changing the counterion from OTf to NTf2 (Scheme 8D.64) [100]. The catalyst 39a obtained is more stable to retain the catalytic efficiency and functions well even at 20°C. Additionally, they applied the catalyst 39a to one of the key reactions in the total


H Ar

H Ar Ar N

B

Ar

TfOH

O N H B R OTf

O

R 37 H Ar Ar O

N H B R O

H Ar Ar

Methacrolein H

O N H B TfO R

TfO

R = 2-Me-Ph, Ar = Ph: 38a R = 2-Me-Ph, Ar = 3,5-Me2-Ph: 38b Scheme 8D.63.

H Ph

Ph

N O H B X

X = OTf: 38a X = NTf2: 39a

Me

O +

(20 mol %) OEt CH2Cl2

Me 38a: 4°C, 72 h 39a: 20°C, 16 h

H

H Me CO2Et

>98% ee (46%) endo : exo = 91/9 97% ee (94%) endo : exo = 89/11

Scheme 8D.64.

synthesis of Tamiflu, to provide the corresponding cycloadduct in high yield and enantioselectivity (97%, 97% ee) under neat conditions (Scheme 8D.65) [101]. Recently, Balskus and Jacobsen applied the oxazaborolidine catalyst to the asymmetric transannular D-A (TADA) reaction that provides polycyclic adducts in enantioselectivity (Scheme 8D.66) [102]. The TADA reaction proceeds smoothly at room temperature in toluene (0.3 M) by using the catalyst 40 to afford the corresponding polycyclic adducts in high diastereo- and enantioselectivity. This TADA can be employed as a key step in the total synthesis of the sesquiterpene 11,12-diacetoxydrimane. Corey et al. also reported that the oxazaborolidine-aluminum bromide catalyst (41) is exceedingly effective for the asymmetric D-A reactions (Scheme 8D.67) [103]. The catalyst (41) is conveniently prepared in situ by the combination of aluminum bromide


TABLE 8D.3. Intermolecular D-A Reaction of B Cat 38 Diene

Product CHO

B Cat (mol %)

°C (h)

% Yield

exo : endo

% ee

38a (6)

−95 (1)

99

91:9

91

38b (6)

−95 (1)

97

91:9

96

Me

38a (6)

−95 (1)

99

91:9

92

CHO

38b (6)

−95 (1)

99

91:9

96

Me CHO

38b (6)

−78 (13)

96

96

97

Br

38a (6)

−95 (1)

98

98

97

38b (6)

−95 (1)

98

98

97

Me CHO

38b (20)

−78 (24)

85

85

94

Br

38a (6)

−95 (2)

95

95

96

38b (6)

−95 (2)

97

97

96

38a (20)

−78 (24)

91

5:95

92

38b (20)

−78 (24)

58

6:94

92

38a (6)

−95 (2)

81

6:94

92

38b (6)

−95 (2)

85

7:93

92

Br CHO

CHO

Me CHO

Br CHO

in CH2Br2 and oxazaborolidine (ratio of 0.8:1.0). In most cases, the catalyst (41) using only 4 mol % leads to excellent yield and enantioselectivity and is more effective than catalysts 38–40 that generally require the high catalyst loading (10∼20 mol %). The use of furans as dienes produces chiral cyclohexane derivatives in which the six carbons are all functionalized in high yield and enantioselectivity. The asymmetric HDA reaction with Danishefsky’s diene catalyzed by Ti catalysts generated from a library of 13 chiral ligands or activators (L1–L13) has been reported by Ding et al. (Scheme 8D.68) [104]. A catalyst library contains 104 members. The Ti catalysts with L4, L5, L6, and L7 give 63–100% yield and 76.7–95.7% ee. On the other hand, ligands with sterically demanding substituents at the 3,3′-positions (L8–L13) are found to be detrimental to the reaction. It is clarified that both L5/Ti/L5 and L5/Ti/L6 as optimized catalysts are the most efficient for the reaction of a variety of aldehydes, including aromatic, aliphatic, and olefinic derivatives.


OCH2CF3

+

ent-39a (10 mol %) OCH2CF3

23°C, neat

O

O >97% ee (97%) 3 steps

O AcHN

I

+ H3N . H PO – 2 4

OEt HN

8 steps

O

O

Tamiflu Scheme 8D.65.

H Ph N O H B NTf2

Ph

F H

40 (20 mol %) n

m

O

H

Toluene, r.t., 20 h

m O

H n O

O m = 2, n = 1 m = 1, n = 1 m = 1, n = 2

H

90% ee, dr >19:1 (69%) 92% ee, dr >19:1 (80%) 90% ee, dr 5.9:1 (78%)

Scheme 8D.66.

H Ph N Br3Al

O Me

O

R

O R OEt

O +

41 (4 mol %) CH2Cl2, –40°C

EtO R

B

Ph

O

R

H

H CO2Et CO2Et

R = H (16 h) 99% ee (71%) R = Me (24 h) 91% ee (72%) (8 mol %) Scheme 8D.67.


OMe

Ti cat (Lm/Ti/Ln)

O +

R

TMSO

O

TFA

(0.05 mol %)

H

O

Aldehyde L5/Ti/L5 Benzaldehyde 99.3% ee (>99%) p-Nitrobenzaldehyde 97.3% ee (>99%) Furfural 99.2% ee (>99%)

R L5/Ti/L6 99.4% ee (82%) 99.4% ee (>99%) 99.7% ee (>99%)

Cl Ph

Ph HO

CO2Me

HO

CO2Me

O O Ph

L1

OH

OH

OH

OH

OH

OH

OH

OH

Ph

Cl

L2

L3

Br

Br

Br

OH

OH

OH

OH

OH

OH

OH

OH

Br

L6

L7

L8

Br

L9

Br

Ph

Ph

SPh

OH

OH

OH

OH

OH

OH

OH

OH

Br

L10

L5

L4

SPh

Ph

Ph

L11

L12

L13

Scheme 8D.68.

Ding et al. applied the BINOL/diimine/Zn system [105] to the asymmetric HDA reaction of benzaldehyde with Danishefsky’s diene (Scheme 8D.69) [106]. A library of chiral Zn catalysts is set up through the combination of a chiral diol library (12 members) with those of a diimine library (20 members) in the presence of Et2Zn. The high throughput screening of the resulting Zn catalyst library (240 members) shows that complex 42 is most efficient to give >99% yield and 98% ee. The chiral bis(oxazoline)-Cu(II) complexes also catalyze the HDA reactions of acyl phosphonates and α-keto ester with enol ethers to afford cyclic enols with high endoselectivity (Scheme 8D.70). As in the carbonyl-ene reactions, the HDA reactions catalyzed by the box-Cu(II) complexes (18) provide high chemical yield and enantioselectivity. The absolute configuration of the product is dependent on the oxazoline ring substituent. Evans and Jørgensen reported a variety of excellent and useful (H)DA reactions by using chiral Cu(II) catalysts, such as box-Cu(II) complexes [107]. Due to space limitations, we cannot describe the box-Cu(II) catalyses in detail.


Br

Ar

O

N Zn

O Br

OMe O + TMSO

Ph

N Ar

O

42 (10 mol %) TFA H

O

Ph

98% ee (>99%) Scheme 8D.69.

Me Me O

2+

O N

N

Cu R R R = Ph, X = OTf: 18b R = tBu, X = SbF6: 18c

Me

18 (10 mol %) + (MeO)2P O

O

2X–

OEt

CH2Cl2, –78°C

Me 4 2

(MeO)2P O OEt O 18b 94% ee (2S, 4S) endo : exo = >99:1 18c 99% ee (2R, 4R) endo : exo= 99:1

Scheme 8D.70.

Recently, Ishihara et al. developed the minimal artificial Diels–Alderases based on the Cu(II) cation-aromatic π attractive interaction (Scheme 8D.71) [108]. The crystal structure of bis(L-tyrosinato)Cu(II) complex has already been determined to clearly show a cation-phenol π interaction [109]. The best results of catalytic asymmetric D-A reactions is obtained with the cationic Cu(II) catalysts prepared in situ in the presence of Cu(OTf)2 or Cu(NTf2)2 and chiral ligand L-DOPA-derived monopeptide 43 in acetonitrile as a polar solvent. Since the first report of Jørgensen et al. on chiral Ag(I)-catalyzed HDA reaction [110], several chiral Ag(I) catalysts bearing diphosphine ligands have been applied to the asymmetric cycloadditions. Hoveyda et al. reported an excellent Ag(I)-catalyzed asymmetric HDA reaction between the Danishefsky’s diene and various arylimines (Scheme 8D.72) [111]. The reaction in the presence of AgOAc and the chiral ligand 44 (only 0.1–1.0 mol %) readily prepared from commercially available and inexpensive amino acid derivatives proceeds smoothly to provide enantioenriched cycloadducts. In addition, these catalytic asymmetric reactions can be carried out even without the use


OMe MeO

N NH R

O

R

43 (2.2 mol %)

H

Cu(OTf)2 (2.0 mol %) + O

N

N

N N

O

MeCN R = H: –40°C (6 h)

97% ee (>99%) endo : exo = 98:1

R = Me: 0°C (17.5 h)

89% ee (97%) endo : exo = 95:5

R = CO2Et: 0°C (10 h) 95% ee (>99%) endo : exo = 88:12 OMe

O

O

Cu2+

N H2

N

OH H2 N

Cu2+

N O

O

O

NOMe N H

O

OH

R

The known crystal structure

trans-s-cis TS Scheme 8D.71.

Me

Et H N

N PPh2

OMe

MeO +

N

TMSO Ar

O

OMe 44 (X mol %) AgOAc (X mol %) MeO iPrOH (1.0 eq.) THF, 4°C, 12 h then 10% aq. HCl X = 1.0 Ar = Ph Ph 0.1 2-Nap 0.5 Scheme 8D.72.

N O

Ar 93% ee (94%) 88% ee (78%) 95% ee (>98%)


of solvent or with undistilled THF in air. A supported chiral ligand that effectively promotes the asymmetric reaction can be recycled at least five cycles. Recently, Yamamoto and Kawasaki reported on Ag(I)-catalyzed asymmetric azo HDA reactions (Scheme 8D.73) [112]. The reaction with 2-azopyridine and siloxydiene catalyzed by the combination of AgOTf (10 mol %) and (R)-BINAP (5 mol %) proceeds in EtCN as a solvent to afford the corresponding cycloadducts in high yield and enantioselectivity. The cycloadduct (R1, R2 = Me) can be converted into the protected 1,4-diaminoalcohol by SmI2-mediated cleavage of the N–N bond with trifluoroacetyl group as a key step [113]. The practical asymmetric HDA reaction with less reactive methyl-substituted Danishefsky-type dienes in the presence of [Rh2{(S)-BPTP}]4 (45) was reported by

R2 N

+

R2

Troc (R)-BINAP (5 mol %) AgOTf (10 mol %)

N N

EtCN –78 to –40°C

TIPSO R1

N N

TIPSO

Troc Ar

R1

R1 = Me R2 = Me >99% ee (87%) Me n-C5H11 95% ee (84%) Bn Me 92% ee (74%)

TIPSO

Troc

N N

Ar

N N

TIPSO

CO2Me

NHTFA

SmI2

COCF3

NHCO2Me

TIPSO 71%

Scheme 8D.73.

R1 = OMe

O R3

O 2

R R2 = H, R3 = PhC C 92% ee (91%) 0.002 mol %: 91% ee (96%)

R1 O

45 (1 mol %)

+

3

H

Et3SiO

R

CH2Cl2

2

R

Me

then TFA

O

O H N

R1 = Me

N O

R3

O 2

O

R

Rh Rh 45 Scheme 8D.74.

R2 = Me, R3 = PhC C 97% ee (81%)

REFERENCES 733

Hashimoto et al. [114,115]. The reaction proceeds smoothly even with extremely low catalyst loading (0.0075–0.002 mol %) without decreasing the yield and enantioselectivity (Scheme 8D.74). REFERENCES 1. For review, see: (a) Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1969, 8, 556. (b) Snider, B. B. In Comprehensive Organic Synthesis (Eds. Trost, B. M.; Fleming, I.). London: Pergamon, 1991; Vol. 2, p. 527. (c) Snider, B. B. In Comprehensive Organic Synthesis (Eds. Trost, B. M.; Fleming, I.). London: Pergamon, 1991; Vol. 5, p. 1. Review on intramolecular reactions, see: (d) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1. (e) Oppolzer, W.; Snieckus, V. Angew. Chem. Int. Ed. Engl. 1978, 17, 476. (f) Taber, D. F. Intramolecular Diels-Alder and Alder Ene Reactions. Berlin: Springer Verlag, 1984. (g) Sarkar, T. K. J. Ind. Inst. Sci. 1994, 74, 329. 2. Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27. 3. (a) Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 6947. (b) Deng, Q.; Thomas, B. E.; Houk, K. N.; Dowd, P. J. Am. Chem. Soc. 1997, 119, 6902. 4. (a) Townshend, R. E.; Ramunni, G.; Segal, G.; Hehre, W. J.; Salem, L. J. Am. Chem. Soc. 1976, 98, 2190. (b) Storer, J. W.; Raimondi, L.; Houk, K. N. J. Am. Chem. Soc. 1994, 116, 9675. 5. For review, see: Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007. 6. For review, see: Waldmann, H. Synthesis 1994, 535. 7. For review, see: (a) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. (b) Berrisford, D. J.; Bolm, C. Angew. Chem. Int. Ed. Engl. 1995, 34, 1717. 8. (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Angew. Chem. Int. Ed. Engl. 1990, 29, 256. (b) Shambayati, S.; Schreiber, S. L. In Comprehensive Organic Synthesis (Eds. Trost, B. M.; Fleming, I.). Oxford: Pergamon, 1991; Vol. 1, p. 283. (c) Mikami, K.; Nakai, T. Kagaku Zokan 1995, 124, 177–192. Also, see: (d) Seebach, D. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624. (e) Boche, G. Angew. Chem. Int. Ed. Engl. 1989, 28, 277. 9. Kimura, K.; Katsumata, S.; Achiba, Y.; Yamazaki, T.; Iwata, S. In Handbook of He(I) Photoelectron Spectra of Fundamental Organic Molecules. New York: Halsted Press, 1981; p. 140. 10. Erker, G.; Dorf, U.; Czisch, P.; Petersen, J. L. Organometallics 1986, 5, 668. 11. Honold, B.; Thewalt, U. J. Organomet. Chem. 1986, 316, 291. 12. Poll, T.; Metter, J. O.; Helmchen, G. Angew. Chem. Int. Ed. Engl. 1985, 24, 112. 13. (a) Corey, E. J.; Loh, T.-P.; Sarshar, S.; Azimioara, M. Tetrahedron Lett. 1992, 33, 6945. Also, see the SnCl4 complex: (b) Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1993, 115, 3133. 14. Ishihara, K.; Gao, Q.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 10412. 15. Lewis, F. D.; Oxman, J. D.; Huffman, J. C. J. Am. Chem. Soc. 1984, 106, 466. 16. Yamanaka, M.; Mikami, K. Helv. Chim. Acta 2000, 85, 4264. 17. Maruoka, K.; Hoshino, Y.; Shirasaka, Y. H.; Yamamoto, H. Tetrahedron Lett. 1988, 29, 3967. (b) Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H. Annual Meeting of the Chemical Society of Japan, Abstract No. 1XIIB27, Tokyo, April 1–4, 1988. 18. Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111, 1940. (b) Mikami, K.; Terada, M.; Nakai, T. Annual Meeting of the Chemical Society of Japan, Abstract No. 1XIB43, Tokyo April 1–4, 1988. 19. (a) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543. (b) Keck, G. E.; Tarbet, K. H., Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467. (c) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363. (d) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998. 20. (a) Gauthier, D. R., Jr.; Carreira, E. M. Angew. Chem. Int. Ed. Engl. 1996, 35, 2363. (b) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837. (c) Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649.

734 ASYMMETRIC ENE REACTIONS AND CYCLOADDITIONS 21. Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812. 22. (a) Matsumoto, Y. Doctor Thesis, Tokyo Institute of Technology, 2004. (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg. Chim. Acta 1999, 296, 267. 23. Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. T. Annual Meeting of the Chemical Society of Japan, Abstract No. 2B5 39, Yokohama, 1999. 24. Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Chem. Commun. 1997, 281. 25. Guo, H.; Wang, X.; Ding, K. Tetrahedron Lett. 2004, 45, 2009. 26. (a) Hao, J.; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059. Hetero Diels–Alder versus ene reactions: (b) Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue, Y. J. Org. Chem. 1999, 64, 8660. 27. Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett. 2004, 45, 183. 28. Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T. Organometallics 1993, 12, 4188. 29. K. Mikami and K. Aikawa, unpublished results: PCT/JP2007/74290. 30. (a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450. (b) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648. (c) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474. (d) Fujii, A.; Hagiwara, E.; Sodeoka, M. Yuki Gosei Kagaku Kyokaishi 2000, 58, 14. 31. (a) Ferraris, D.; Young, B.; Dudding, T.; Lecktka, T. J. Am. Chem. Soc. 1998, 120, 4548. (b) Lectka, T. Acc. Chem. Res. 2003, 36, 10. 32. (a) Mikami, K.; Kawakami, Y.; Akiyama, K.; Aikawa, K. J. Am. Chem. Soc. 2007, 129, 12950. (b) Akiyama, K. PhD Thesis, Tokyo Institute of Technology, 2006. 33. (a) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039. (b) Mikami, K.; Matsukawa, S.; Nagashima, M.; Funabashi, H.; Morishima, T. Tetrahedron Lett. 1997, 38, 579. 34. Becker, J. J.; Orden, L. J. V.; White, P. S.; Gagné, M. R. Org. Lett. 2002, 4, 727. 35. Koh, J. H.; Larsen, A. O.; Gagné, M. R. Org. Lett. 2001, 3, 1233. 36. Kuhn, R. In Stereochemie (Ed. Freudenberg, H.). Leipzig-Wien: Franz, Deutike, 1933; pp. 803–824. (b) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002, 1561. 37. BIPHEP = 2,2′-bis(diphenylphosphanyl)-1,1′-biphenyl; this ligand was also named BPBP, but contrary to what was claimed in the publication, it was unsuccessfully synthesized to instead give the monophosphine derivative: (a) Uehara, A.; Bailar, J. C., Jr. J. Organomet. Chem. 1982, 239, 1. (b) Bennett, M. A.; Bhargava, S. K.; Griffiths, K. D.; Robertson, G. B. Angew. Chem. Int. Ed. Engl. 1987, 26, 260. (c) Desponds, O.; Schlosser, M. J. Organomet. Chem. 1996, 507, 257. (d) Desponds, O.; Schlosser, M. Tetrahedron Lett. 1996, 37, 47. (e) Mikami, K.; Aikawa, K.; Korenaga, T. Org. Lett. 2001, 3, 243–245. 38. (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem. Int. Ed. Engl. 1999, 38, 495. (b) Korenaga, T.; Aikawa, K.; Terada, M.; Kawauchi, S.; Mikami, K. Adv. Synth. Catal. 2001, 343, 284. 39. (a) Matsukawa, S.; Mikami, K. Enantiomer 1996, 1, 69. (b) Mikami, K.; Matsukawa, S. Nature 1997, 385, 613. (c) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem. Int. Ed. Engl. 2000, 39, 3532. (d) Mikami, K; Yamanaka, M. Chem. Rev. 2003, 103, 3369. 40. (a) Mikami, K.; Aikawa, K.; Yusa, Y.; Hatano, M. Org. Lett. 2002, 4, 91. (b) Mikami, K.; Aikawa, K.; Yusa, Y. Org. Lett. 2002, 4, 95. 41. Aikawa, K.; Mikami, K. Angew. Chem. Int. Ed. Engl. 2003, 42, 5458. 42. (a) Tudor, M. D.; Becker, J. J.; White, P. S.; Gagné, M. R. Organometallics 2000, 19, 4367. (b) Becker, J. J.; White, P. S.; Gagné, M. R. J. Am. Chem. Soc. 2001, 123, 9478. 43. Luo, H.-K.; Schumann, H. J. Mol. Catal. A Chem. 2006, 248, 42. 44. Mikami, K.; Kakuno, H; Aikawa, K. Angew. Chem. Int. Ed. Engl. 2005, 44, 7257–7260. 45. Tropos NUPHOS ligands: Doherty, S.; Goodrich, P.; Hardacre, C.; Luo, H.-K.; Nieuwenhuyzen, M.; Rath, R. K. Organometallics 2005, 24, 5945.

REFERENCES 735

46. Mikami, K.; Aikawa, K. Org. Lett. 2002, 4, 99. 47. (a) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936. (b) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824. 48. Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006. 49. (a) Kezuka, S.; Kogami, Y.; Ikeno, T.; Yamada, T. Bull. Chem. Soc. Jpn. 2003, 76, 49. (b) Kezuka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3, 1937. 50. Hutson, G. E.; Dave, A. H.; Rawal, V. H. Org. Lett. 2007, 9, 3869. 51. Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2882. 52. Ruck, R. T.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl. 2003, 42, 4771. 53. Chaladaj, W.; Kwiatkowski, P.; Jurczak, J. Synlett 2006, 3263. 54. Chaladaj, W.; Kwiatkowski, P.; Majer, J.; Jurczak, J. Tetrahedron Lett. 2007, 48, 2405. 55. Clarke, M. L.; Jones, C. E. S.; France, M. B. Beilstein J. Org. Chem. 2007, 3, (24) 1. 56. Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron Lett. 2006, 47, 7037. 57. Terada, M.; Soga, K.; Momiyama, N. Angew. Chem. Int. Ed. Engl. 2008, 47, 4122. 58. Corey, E. J.; Lee, T. Chem. Commum. 2001, 1312. 59. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed. Engl. 2005, 44, 4212. 60. Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.; Hayashi, Y. Angew. Chem. Int. Ed. Engl. 2006, 45, 6853. 61. (a) Borzilleri, R. M.; Weinreb, S. M. Synthesis 1995, 347. (b) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131. 62. (a) Williams, R. M. Synthesis of Optically Active Amino Acids. Oxford: Pergamon, 1989. (b) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids. New York: Wiley, 1987. 63. (a) Mikami, K.; Yajima, T.; Kaneko, M. J. Amino Acids 1998, 14, 311. Diastereofacial selective imine-ene reaction: (b) Mikami, K.; Kaneko, M.; Yajima, T. Tetrahedron Lett. 1993, 34, 4841. 64. (a) Ferraris, D.; Young B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67. (b) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10. (c) Drury, W. J., III; Ferraris, D.; Cox, C.; Young B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006. After Lectka’s report, Jørgensen also reported asymmetric imine-ene reaction using tolBINAP-Cu(I)(BF4) complex: (d) Yao, S.; Fang, X.; Jørgensen, K. A. Chem. Comm. 1998, 2547. 65. Kawakami, Y. Master Thesis, Tokyo Institute of Technology, 2006. 66. Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem. Int. Ed. Engl. 2004, 43, 1679. 67. Mori, Y.; Suzuki, M. Tetrahedron Lett. 1989, 30, 4383. 68. Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem. Int. Ed. Engl. 2006, 45, 2254. 69. Terada, M.; Machioka, K.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336. 70. (a) Mikami, K.; Sawa, E.; Terada, M. Tetrahedron Asymmetry 1991, 2, 1403. (b) Mikami, K.; Terada, M.; Sawa, E.; Nakai, T. Tetrahedron Lett. 1991, 32, 6571. 71. Yang, D.; Yang, M.; Zhu, N. Y. Org. Lett. 2003, 5, 3749. 72. Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl. 2008, 47, 1469. 73. (a) Cao, P.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2000, 39, 4104. (b) Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490. 74. (a) Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2002, 41, 3457. (b) Hashmi, A. S. K.; Haufe, P.; Nass, A. R. Adv. Synth. Catal. 2003, 345, 1237. 75. (a) Lei, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2002, 41, 4526. (b) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198. (c) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 11472. (d) Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 6370.

736 ASYMMETRIC ENE REACTIONS AND CYCLOADDITIONS (e) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601. (f) Hashmi, A. S. K.; Haufe, P.; Nass, A. R.; Bats, J. W. Adv. Synth. Catal. 2004, 346, 421. 76. Horne, D. A.; Fugmann, B.; Yakushiji, K.; Büchi, G. J. Org. Chem. 1993, 58, 62. 77. Mikami, K.; Yusa, Y.; Hatano, M.; Wakabayashi, K.; Aikawa, K. Chem. Commun. 2004, 98. 78. For review, see: (a) Martin, S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem. Rev. 1993, 93, 2037. 79. (a) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571. (b) Overman, L. E.; Poon, D. J. Angew. Chem. Int. Ed. Engl. 1997, 36, 518. (c) Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595. (d) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477. (e) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem. Rev. 1996, 96, 365. 80. Mikami, K.; Kataoka, S.; Yusa, Y.; Aikawa, K. Org. Lett. 2004, 6, 3699. 81. (a) Mikami, K.; Kataoka, S.; Aikawa, K. Org. Lett. 2005, 26, 5777. (b) Mikami, K.; Kataoka, S.; Wakabayashi, K.; Aikawa, K. Tetrahedron Lett. 2006, 47, 6361. 82. Hatano, M.; Terada, M.; Mikami, K. Angew. Chem. Int. Ed. Engl. 2001, 40, 249. 83. (a) Hatano, M.; Yamanaka, M.; Mikami, K. Eur. J. Org. Chem. 2003, 2552. (b) Hatano, M.; Mikami, K. J. Mol. Catal. A Chem. 2003, 196, 165. (c) Hatano, M.; Mikami, K. Org. Biomol. Chem. 2003, 1, 3871. (d) Mikami, K.; Hatano, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5767. 84. Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704. 85. For review, see: Conia, J. M.; Le Perchec, P. Synthesis 1975, 1. 86. Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168. 87. (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis. Berlin: Springer, 1999; Vol. 1–3. (b) Yamamoto, H. Lewis Acids in Organic Synthesis. Weinheim: Wiley-VCH, 2000; Vol. 1–2. (c) Kobayashi, S.; Jørgensen, K. A. Cycloaddition Reaction in Organic Synthesis. Weinheim: Wiley-VCH, 2002. (d) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. 88. Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions. Weinheim: Wiley-VCH, 2005. 89. Intramolecular [4 + 2] cycloaddition: (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432. (b) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc. 1990, 112, 4965. (c) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843. (d) Wender, P. A.; Smith, T. E. J. Org. Chem. 1996, 61, 824. (e) Gilbertson, S. R.; Hoge, G. S. Tetrahedron Lett. 1998, 39, 2075. (f) Kumar, K.; Jolly, R. S. Tetrahedron Lett. 1998, 39, 3047. (g) Paik, S. J.; Son, S. U.; Chung, Y. K. Org. Lett. 1999, 1, 2045. (h) Wang, B.; Cao, P.; Zhang, X. Tetrahedron Lett. 2000, 41, 8041. (i) Motoda, D.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Angew. Chem. Int. Ed. Engl. 2004, 43, 1860. (j) Yoo, W. J.; Allen, A.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 5853. (k) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung, I. G.; Choi, S. Y.; Chung, Y. K. J. Org. Chem. 2006, 71, 91. (l) Saito, A.; Ono, T.; Takahashi, A.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 2006, 47, 891. 90. Intermolecular [4 + 2] cycloaddition: (a) Matsuda, I.; Shibata, M.; Sato, S.; Izumi, Y. Tetrahedron Lett. 1987, 28, 3361. (b) Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y. Angew. Chem. Int. Ed. Engl. 1998, 37, 2248. (c) Paik, S. J.; Son, S. U.; Chung, Y. K. Org. Lett. 1999, 1, 2045. 91. For the Rh(I) catalysts: (a) McKinstry, L.; Livinghouse, T. Tetradedron 1994, 50, 6145. (b) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett 1998, 443. (c) Gilbertson, S. T.; Hoge, G. S.; Genov, D. G. J. Org. Chem. 1998, 63, 10077. (d) Heath, H.; Wolfe, B.; Livinghouse, T.; Bae, S. K. Synthesis 2001, 2341. For the Ir(I) catalysts: (e) Shibata, T.; Takasaku, K.; Takesue, Y.; Hirata, N.; Takagi, K. Synlett 2002, 1681. 92. (a) McKinstry, L.; Livinghouse, T. Tetradedron 1994, 50, 6145. (b) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett 1998, 443. (c) Heath, H.; Wolfe, B.; Livinghouse, T.; Bae, S. K. Synthesis 2001, 2341. 93. Gilbertson, S. T.; Hoge, G. S.; Genov. D. G. J. Org. Chem. 1998, 63, 10077. 94. Aikawa, K.; Akutagawa, S.; Mkami, K. J. Am. Chem. Soc. 2006, 128, 12648. 95. Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. Engl. 2007, 46, 7277. 96. Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720.

REFERENCES 737

97. Wender, P. A.; Haustedt, L. O.; Lim, J.; Love, J. A.; Williams, T. J.; Yoon, J.-Y. J. Am. Chem. Soc. 2006, 128, 6302. 98. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 7925. For a review, see: (c) Corey, E. J.; Helal, C. Angew. Chem. Int. Ed. Engl. 1998, 37, 1986. 99. (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992. 100. (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. 101. (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310. 102. Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736. 103. (a) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498. 104. (a) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc. 2002, 124, 10. (b) Yuan, Y.; Zang, X.; Ding, K. Angew. Chem. Int. Ed. Engl. 2003, 42, 5478. 105. (a) Ding, K.; Ishii, K.; Mikami, K. Angew. Chem. Int. Ed. Engl. 1999, 38, 497. (b) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929. 106. (a) Du, H.; Long, J.; Hu, J.; Li, X.; Ding, K. Org. Lett. 2002, 4, 4349. (b) Du, H.; Ding, K. Org. Lett. 2003, 5, 1091. (c) Du, H.; Zhang, X.; Wang, Z.; Ding, K. Tetrahedron 2005, 61, 9465. 107. Reviews for catalytic asymmetric (hetero) Diels–Alder reactions using chiral Cu(II) complexes, see: (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 525. (b) Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3558. (c) Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093. (d) Gouverneur, V.; Reiter, M. Chem. Eur. J. 2005, 11, 5806. 108. (a) Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921. (b) Ishihara, K.; Fushimi, M. J. Am. Chem. Soc. 2008, 130, 7532. (c) Ishihara, K.; Fushimi, M.; Akakura, M. Acc. Chem. Res. 2007, 40, 1049. 109. (a) van der Helm, D.; Lawson, M. B.; Enwall, E. L. Acta Crystallogr. 1972, B28, 2307. (b) Huhonen, H.; Hämäläinen, R. Finn. Chem. Lett. 1983, 120. 110. Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 1998, 37, 3121. 111. Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018. 112. (a) Kawasaki, M.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 16482. (b) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595. 113. (a) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637. (b) Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867. 114. Anada, M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima, M.; Shiro, M.; Hashimoto, S. Angew. Chem. Int. Ed. Engl. 2005, 43, 2665. 115. Doyle, M. P.; Phillips, I. M.; Hu, W. J. Am. Chem. Soc. 2001, 123, 5366.

8E CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS REACTIONS Amir H. Hoveyda, Steven J. Malcolmson, Simon J. Meek, and Adil R. Zhugralin Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA

8E.1. INTRODUCTION The advent of well-defined catalysts for olefin metathesis has brought this class of transformations to the forefront of chemical synthesis [1]. Among the olefin metathesis catalysts developed thus far, two major classes have emerged: Mo-based alkylidenes and Ru-based carbenes; the two types of complexes often exhibit complementary reactivity and functional group tolerance. In contrast to Mo alkylidenes, which are oxygen and moisture sensitive, Ru carbenes can often be handled and stored under an atmosphere of air. Ru catalysts might be inhibited by amines, phosphines, and disulfides, whereas Mo-based complexes are generally not tolerant of alcohol, aldehyde, or carboxylic acid functionalities. Since the late 1990s, chiral nonracemic versions of the two catalyst archetypes have been developed for enantioselective olefin metathesis processes (Schemes 8E.1 and 8E.2). Mo-based catalysts, representative examples of which are shown in Scheme 8E.1, can be categorized into diolate complexes 1–4, bearing a C2-symmetric biphenolate or binaphtholate ligand, and recently discovered stereogenic-at-Mo complexes 5–6. Solidsupported chiral Mo-diolate catalysts have also been disclosed [2]. The Ru-based chiral catalysts developed for enantioselective olefin metathesis are illustrated in Scheme 8E.2. Ru complexes may be divided into three categories: C2symmetric monodentate N-heterocyclic carbene (NHC)-Ru complexes 7–10, C1-symmetric bidentate NHC-Ru complexes 11–12, and C1-symmetric monodentate NHC-Ru complex 13.


740

Mo

N

R' Me

Me

R

Stereogenic-at-Mo complexes:

1a R = i-Pr R' = Ph 1b R = Me R' = Ph 1c R = Cl R' = Me (THF adduct)

O

O

R

Chiral Mo-diolate complexes:

2

Mo

R

N

i-Pr

Br

Ph Me

Me

i-Pr

5a R = H 5b R = Me

O

Mo

R N

Ph Me

Me

Ar Ph

Me Me

R

TBSO

Cl

R

N

i-Pr

O

Ph Me

Me

i-Pr

O

O

R

Mo

N

Ph Me

Me

i-Pr

4a R = t-Bu 4b R = CHPh2 (THF adduct)

R

i-Pr

6a R = H 6b R = Me

Cl

Mo

R N

Ar = 2,4,6-i-Pr3C6H2

Ar

Mo O

N

3a R = i-Pr 3b R = Cl

O

O

R

Scheme 8E.1. Chiral Mo-based olefin metathesis catalysts.

TBSO

Br

O

O

N

8E.1. INTRODUCTION 741

C2-symmetric monodentate chiral NHC-Ru complexes:

Ph i-Pr

Ph

Ph

N

N

i-Pr

i-Pr

i-Pr

L

Ru

Ph

L

PCy3

PCy3

7a L = Cl 7b L = I

i-Pr

Ph i-Pr

N

i-Pr

i-Pr

L

i-Pr

8a L = Cl 8b L = I

Ph

N

MeO

Ph

N

N Ru

Ph

L

t-Bu

i-Pr

L

t-Bu

Ru

Ph

i-Pr

Ru

Ph

L

Ph

N

N

i-Pr

L

Ph

L

PCy3

PCy3

10a L = Cl 10b L = I

9a L = Cl 9b L = I

C1-symmetric bidentate chiral NHC-Ru complexes:

Ph N

MesN

Ph

N

MesN L

L

Ru

Ru

O

O

Oi-Pr

Oi-Pr Ph

Ph

12a L = Cl 12b L = I

11a L = Cl 11b L = I

C1-symmetric monodentate chiral NHC-Ru complexes: t-Bu

t-Bu

N

MeN

i-Pr

Cl

Ph

Ru

Cl PCy3

13

Scheme 8E.2. Chiral Ru-based olefin metathesis catalysts.

OMe

742 CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS REACTIONS

Use of catalytic olefin metathesis in enantioselective synthesis has thus far largely concerned reactions of enantiomerically enriched substrates with achiral catalysts [1]; catalytic enantioselective olefin metathesis allows access to enantiomerically enriched molecules that cannot be readily prepared through the above, and commonly practiced, strategy (see below for specific examples). Unlike most enantioselective transformations, olefin metathesis, which entails the formation and cleavage of C–C double bonds, does not involve the direct formation of an sp3-hybridized stereogenic center. Instead, stereochemistry is established indirectly, frequently by desymmetrization of an achiral substrate (Scheme 8E.3), wherein the chiral catalyst must discriminate between enantiotopic groups or sites of the molecule [3]. Consequently, the products obtained would be difficult to synthesize through other enantioselective protocols (i.e., formation of a stereogenic center, followed by olefin metathesis with an achiral catalyst). Meso -achiral substrates

Achiral substrates

Me

O

Me

Ru or Mo catalyst

OBn Me

O

Ru or Mo catalyst

OBn

O Me

Ph

O

Ph

Scheme 8E.3. Desymmetrization in catalytic enantioselective olefin metathesis.

Detailed reviews of catalytic enantioselective olefin metathesis through 2003 have appeared [4]. This chapter will therefore focus on the developments that have been disclosed since the appearance of the above reports.

8E.2. ENANTIOSELECTIVE RING-CLOSING METATHESIS (RCM) REACTIONS 8E.2.1. Ru-Catalyzed Enantioselective RCM 8E.2.1.1. The Catalytic Enantioselective Method Ring-closing metathesis (RCM) is the most commonly used version of olefin metathesis in organic synthesis. While achiral Ru catalysts are widely employed for non-enantioselective RCM, mostly due to ease of handling, enantioselective RCM has largely been dominated by chiral Mo-based alkylidenes. Through 2001, there had been only one report of Ru-catalyzed enantioselective RCM [5]. Since 2002, however, a number of chiral Ru catalysts have been discovered to promote RCM. Several notable findings are summarized in Table 8E.1 and compared with the optimal Mo catalyst [6,7]. The state of the art in Ru-catalyzed enantioselective RCM is significantly less developed than the Mo-catalyzed variants (see Table 8E.1). Limited substrate scope is manifest upon comparison of entries 2–4 with 6–7 and 9–10 with 11–13 in Table 8E.1. Unlike Mo-based complexes, which readily promote enantioselective RCM of all substrates in Table 8E.1 (entries 1, 5, and 8), Ru complexes surveyed are restricted to desymmetrizations of trienes bearing trisubstituted E-olefins. For example, Ru complex 7b can be used to catalyze enantioselective RCM of the triene in entry 6 but fails to approach the same level of selectivity in entry 2 [5]; the same is true of the complex 13 (entry 7 vs. 4). To date, the highest enantioselectivity for Ru-catalyzed desymmetrization of the triene in

8E.2. ENANTIOSELECTIVE RING-CLOSING METATHESIS (RCM) REACTIONS 743

TABLE 8E.1. Comparison of Chiral Mo and Ru Catalysts in Enantioselective RCM Mo- or Ru-based chiral catalyst

O Me

O Me

Me

Me Chiral catalysts:

Me N Mo

O

O

Me

i-Pr

Me

Ar

i-Pr N

Me

Mo O

O

Ph Me

O

Ph Me

Ar

1b

3a Ar = 2,4,6-i-Pr3C6H2

Ph i-Pr

Ph

Ph

N

N

i-Pr

i-Pr

I

N

N

i-Pr

Cl

Ru

Ph

i-Pr

Ph

Ph

I

i-Pr

Ru

Cl

PCy3

PCy3

7b

8a t-Bu

t-Bu

N

MesN

N

MeN

Cl

i-Pr

Cl

Ru

O

Ph

Oi-Pr

Ru

Cl PCy3

Ph

Entry

Product

1 2 3

O Me Me

4 5 6

O Me

7

Me Me

13

11a Catalyst; mol %

Time (h); Temp (°C)

Conv (%); Yield (%) >98; 85 20; nd

ee (%)

1b; 1

5 min; 22

7b; 5 11a;5

2; 38 24; 60

93

>98; 58

13; 2.5

2; 40

>98; 80

33

1b; 2

5 min; 22

>98; 93

39 68

7b; 4

2; 40

>98; 64

>98 90

13; 2.5

2; 40

>98; 81

82


TABLE 8E.1. (Continued) Entry

Product

8

Me Me Si O

9 10

Me

Catalyst; mol %


Conv (%); Yield (%)

ee (%)

3a; 2

4; 60

>98; 98

7b; 4

2; 40

8a; 2

2; 40

98 nd

7b; 4 8a; 0.8

2; 40 2; 40

>98; 77

86 92

13; 2.5

2; 40

>98; 82

5

30

Me

11 12 13

Me Me Si O Me Me

68; nd

Me

nd = not determined.

entries 1–4 is afforded by complex 11a (entry 3), although a longer reaction time and elevated temperature are required. The necessity for the use of appropriate substrates (olefins bearing specific substitution patterns that afford high enantioselectivities), entailing nontrivial syntheses of the prochiral trisubstituted olefins, remains a significant limitation of Ru-catalyzed enantioselective RCM. A synthesis scheme that incorporates Ru-catalyzed enantioselective RCM would thus suffer the complication that subsequent elaboration must be accomplished through nontrivial chemo- and regioselective modification of product olefins. In contrast, a substrate bearing 1,1-disubstituted prochiral alkenes would afford a product with a combination of 1,1-disubstituted and endocyclic trisubstituted alkenes, thus diminishing the residual symmetry of the starting material. (For one approach to solving the problem of olefin differentiation after enantioselective RCM, see Section 8E.2.4). 8E.2.1.2. Mechanistic Models The current mechanistic models for Ru-catalyzed enantioselective RCM are outlined in Scheme 8E.4. Initiation of the complex proceeds through dissociation of either the phosphine ligand or chelated etherate moiety [8]. Subsequent coordination of the least-substituted olefin of the triene to the Ru center affords I (R=Ar for initiation or H for propagation), which upon [2 + 2] cycloaddition, followed by cycloreversion, furnishes II. As all the steps in the catalytic cycle are in principle reversible, any step that involves the substrate covalently bound to Ru can be enantiodetermining; release of the RCM product, however, is most likely irreversible, thus limiting the enantiodetermining step to olefin coordination (formation of II) or formation or cleavage of the ruthenacyclobutane. Olefin coordination is likely barrierless [9], while the latter two are microscopic reverses of one another for symmetrically substituted ruthenacyclobutanes. Thus, formation or cleavage of the ruthenacyclobutane can be enantiodetermining, depending on substrate and stereochemistry of the intermediates. The symmetry and polydentate nature of the ligand strongly affect the energetics of the catalytic cycle. For Ru complexes that bear a monodentate ligand, rotation about the CNHC–Ru bond has been shown to be facile at temperatures as low as −80°C [10].

8E.2. ENANTIOSELECTIVE RING-CLOSING METATHESIS (RCM) REACTIONS

O Me

Me

Ph

Ph

Ph

Ph

R1 N

N R 2

R1 N

N R 2

X

X

Ru

X

R

Ru

R

X

L

O O

Me

Me

Ph

Ph

R1 N

N R 2

I Me

X

Ph

Ph

R1 N X

R1 N X

X

N R 2 Ru

H

Me O

Me

X

Me

O

Me

II

R

Monodentate Ru catalysts Ph Ph

Ph

Ph

R1 N

R1 N

N R 2

X

Me

O

N R 2 Ru

X

R

Ph

Ph

Ru

N R 2

X

Ru

H

O

Me

Ru

X

Me

X

O

Me

Me

II

H

III

R1 R2 - nondegenerate NHC rotation R1 = R2 - degenerate NHC rotation

Bidentate stereogenic-at-Ru catalysts O Me

Me N

N

N

O

Ru

H

Ru

IV

N

O

Cl

Cl O

Me

Me

V

H

O Me Me

Scheme 8E.4. General mechanism for Ru-catalyzed enantioselective RCM.

745


Ph

i-Pr

Me

O

H

H

Stereogenic axis

Ru H

i-Pr N

N

L

Me

Ph

i-Pr

N

N O

Ph

Ph

i-Pr

O

L

Me

Ru

L

L O

Me Major

Me Me

H

Favored

Minor

Disfavored

Figure 8E.1. Stereogenicity transfer from the stereogenic axis of the Ru-carbene to the stereogenic center of the enantioselective RCM product.

Thus, II (when R1 ≠ R2) can exist as a thermodynamic mixture of rotamers (II III) if the aforementioned ligand rotation is sufficiently faster than the rate of ruthenacyclobutane formation, which may ultimately result in diminished enantioselectivity. Furthermore, CNHC–Ru rotation may be coupled to the catalytic cycle as has been illustrated for phosphine-Ru complexes [11]. The above considerations do not apply to reactions promoted by C2-symmetric ligands (R1 = R2), where various rotamers are degenerate. Moreover, such factors are irrelevant in the case of complexes that carry a bidentate ligand, as in such instances interconversion between diastereomeric Ru-carbenes (net stereomutation at the metal center) is possible through productive (as shown) or degenerate olefin metathesis (IV V). Alternative pathways, such as polytopal rearrangements, remain to be investigated. In contrast to Ru complexes 11–12, carbenes 7–10 and 13 do not bear a stereogenic metal center. One stereochemical feature that the above catalysts share is that the reactive metal-olefin complexes (I and II in Scheme 8E.4) possess a stereogenic axis (Ru=C bond). Control of this axis in the transition state for metallacyclobutane formation is critical for achieving high enantioselectivity (see Fig. 8E.1). Whereas monodentate ligands control the stereogenic axis through steric interaction with R1 or R2, relaying stereogenicity of the NHC backbone, the bidentate ligands in 11–12 rely on the difference in Ccarbene–Ru–X angles (X = halide or O) [12]. 8E.2.2. Temporary Tether Approach in Catalytic RCM: Net Mo-Catalyzed Enantioselective Cross-Metathesis (CM) To facilitate “difficult” transformations, tethering strategies have been employed in organic synthesis [13]. In 1992, application of such an approach to catalytic olefin metathesis was reported [14]. Subsequent to the initial disclosure, a number of research teams have been able to extend this concept, including applications in complex molecule synthesis [15]. A B-based tethering strategy in promoting highly enantioselective catalytic RCM was first disclosed in 2004. As illustrated in Scheme 8E.5, Mo-catalyzed enantioselective RCM of mixed allylboronates, which, after oxidation, affords chiral 1,4-diols, constitutes a net Z-selective CM [16]. Several points of this study are noteworthy: (1) The requisite substrate can be generated in situ through ligand exchange of an alcohol with an allyl boronic ester, allowing the process to be carried out in a single vessel. (2) Products from kinetic resolution and desymmetrization are obtained with high


5 mol %

i-Pr

Oi-Pr Me

OH

i-PrO Me

i-Pr N

Ar

Kinetic resolution

Me

B

O

C6H6, 22°C; remove i-PrOH

O

Me

OH

Me Ph Me

Ar 3a

Me

OH

Mo O

O

Oi-Pr B

747

Ar = 2,4,6-i-Pr3C6H2 C6H6, 22 °C, 80 min

H2O2

Me

NaOH

O H

Me

Oi-Pr B

Me

krel > 25, 37% yield

Representative functionalization

Mo-catalyzed desymmetrization products HO

Ph Me OH

Me

OH

38% yield, >98% ee

OH

O

Oi-Pr B O

Me Me

58% yield, >98% ee

O

Me

>98% ee

OH O


OH Me

Me

68% yield >98% de, >98% ee

Scheme 8E.5. Mo-catalyzed enantioselective RCM of allylboronates: one-pot net enantioselective cross-metathesis.

enantioselectivity, including chiral tertiary alcohols. (3) A direct CM of allyl alcohol with any Mo or Ru catalyst would be difficult to achieve due to facile catalyst decomposition [17]. (4) In addition to oxidation, the chiral cyclic allylboronates can be used as crotylating reagents, providing the desired diols in good yield and high diastereoselectivity.

8E.2.3. Synthesis of Bicyclic Lactams and Cyclic Amines through Mo-Catalyzed Enantioselective RCM Small- and medium-ring N-containing heterocycles are prevalent in biologically active molecules [18]; the development of catalytic enantioselective synthesis of azacycles thus constitutes an important objective in chemical synthesis. Enantioselective synthesis of N-containing compounds by catalytic olefin metathesis was first reported in 2002 [19]; in all such reactions, however, substrates contain an N-aryl group to reduce the possibility that the Lewis basic heteroatom may cause diminution of the catalytic activity of the chiral Mo complex [20]. Since access to enantiomerically enriched cyclic amines constitutes an important objective in organic synthesis, and because the removal of N-aryl


units can be inefficient and complicated, the development of catalytic enantioselective RCM processes involving other N-protecting groups is critical [21]. Several catalytic enantioselective RCM reactions that deliver cyclic unsaturated amines bearing NCbz or NBn units are illustrated in Table 8E.2 (entries 3–5). A variety of five-, six-, seven- and eight-membered-ring amines and amides can be accessed through enantioselective RCM efficiently and with high enantiomeric porities. Reactions are relatively sluggish, however, as high catalyst loadings and extended reaction times might be required (e.g., entry 1, Table 8E.2); slow rates of Mo-catalyzed enantioselective RCM in the above cases might be due to inhibition of catalyst activity through coordination of a Lewis base functional group to the Lewis acidic Mo center. Another noteworthy point is that the identity of the optimal catalyst for a given transformation is often difficult to predict, even among substrates that are similar in structure, highlighting the need for a family of chiral catalysts that can be prepared, tested, and modified readily. Substrates bearing enantiotopic terminal olefins usually deliver RCM products in low levels of enantiomeric purity [19a]. As is typically the case, 1,1-disubstituted olefins are TABLE 8E.2. Enantioselective Synthesis of N-Heterocycles through Mo-Catalyzed Enantioselective RCM O

O

N

N Me

Me Me

Me

Chiral catalysts:

Me

Me N

O

Mo

O

N

Me O

Ph Me

Mo

O

2

1b

i-Pr

i-Pr N

Ar O

Mo O

O

Me Ph Me

Ar

3a Ar = 2,4,6-i-Pr3C6H2

Me Ph Me


749

TABLE 8E.2. (Continued) Entry

Product

1

Catalyst; mol % O


Yield (%)

ee (%)

2; 15

48; 22

84

85

3a; 5

12; 22

92

88

2;5

24; 22

98

95

1b; 5

24; 22

94

97

1b; 5

24; 22

83

87

N Me Me

2

O N

3

Me H

Me

N Cbz

4

Me H

Me

N Cbz

5

BnN

Me

employed to limit the number of reaction pathways; for desymmetrizations, a catalyst may first initiate on a terminal olefin and subsequently react intramolecularly with one of the enantiotopic olefins. The product shown in entry 2 of Table 8E.2 provides a rare example of highly selective enantioselective RCM in the presence of only terminal olefins (88% ee). The finding summarized in entry 5 of Table 8E.2 demonstrates that substrates with 1,2-disubstituted olefins can participate in enantioselective RCM reactions. The product obtained from the process in entry 5 was converted in two steps to (R)-coniine. Although lactams, carbamates, and tertiary amines are tolerated by Mo alkylidenes, the presence of a secondary amine results in 98% yield and 94% ee (see Scheme 8E.6). Several additional aspects of this class of Mocatalyzed reactions are noteworthy: (1) Heterocyclic products bearing all-carbon quaternary stereogenic centers [25] can be obtained through enantioselective olefin metathesis with high levels of enantioselectivity. (2) Particularly in cases involving a quaternary carbon center, catalytic processes often require high catalysts loadings (≥10 mol %) and/or relatively long reaction times (>12 h). (3) Alkylidene 3a is the only effective Mo-based catalyst; it should also be noted that none of the available chiral Ru complexes promote RCM of enol ethers with high selectivity. The above findings underline the need for development of a more effective class of chiral olefin metathesis catalysts. 8E.2.4.2. Mechanistic Model A model that accounts for the sense and levels of enantioselectivity has been suggested (Fig. 8E.3). Subsequent to formation of the substratecatalyst complex, RCM might proceed through the more reactive anti-alkylidene [26]. The resulting complex may then coordinate with one of the enantiotopic olefins from the sterically most accessible C–N–O face such that the remaining butenyl group is situated pseudo-equatorially (I), thereby avoiding a syn-pentane interaction (II). For substrates that bear a quaternary carbon, the sterically less demanding sp2-hybridized ester unit may be positioned pseudo-axially to minimize unfavorable steric interactions (III). Additionally, the two olefins within the products could be differentiated with excellent site selectivity. As shown in Scheme 8E.7, hydrolysis of the enol ether, followed by oxidation, affords the δ-lactone as a 1:1 mixture of diastereomers. Alternatively, dihydroxylation of the enol ether moiety [27] and subsequent oxidation affords the αhydroxylactone in good yield as a single diastereomer.

8E.2.5. Control of Planar Stereogenicity through Catalytic Enantioselective RCM Although catalytic enantioselective olefin metathesis has been well established as a method to synthesize molecules containing stereogenic centers, this class of transformations had not been used in controlling other types of stereogenicity [28]. In 2006, kinetic


751

10 mol % i-Pr

i-Pr N

Ar O

Mo

O

O

Me Ar = 2,4,6-(i-Pr)3C6H2 Ph Me

Me

O

Me

Ar

O

Me

Me

3a

90% conv, 70% yield 90% ee

Et2O, 22°C, 6 h

15 mol % i-Pr

i-Pr N

Ar O

Mo O

O

O

Me Ar = 2,4,6-(i-Pr)3C6H2 Ph Me

O

Ar Me

CO2Me

Me

Me

CO2Me

3a

Me

>98% conv, 94% yield 94% ee

C6H6, 22°C, 17 h

Scheme 8E.6. Enantioselective synthesis of cyclic enol ethers bearing tertiary and all-carbon quaternary stereogenic centers through Mo-catalyzed enantioselective RCM.

O Me

O

1) 1 N HCl (20% in THF) Me

2) 5 mol % TPAP, NMO

Me

(83% ee)

1) AD-mix , MeSO2NH2 Me

(83% ee)

Me

67% yield (2 steps), 1:1 dr, 83% ee

O Me

O

2) Dess–Martin periodinane

O Me

O OH Me

69% yield (2 steps), >95:5 dr, 83% ee

Scheme 8E.7. Site-selective functionalization of products from enantioselective RCM of enol ethers.


syn-Pentane N

N

Me

Ar

Me

Ar

O

Mo

H

O

O

Me

O

Mo

O

Ar

Me O

Ar

I

H

II

N

Me

Ar

O

Mo

O

O OMe

O

Ar Me

III Figure 8E.3. Proposed model for enantioselectivity in the enantioselective RCM of enol ethers.

resolution of planar stereogenic ferrocenes by Mo-catalyzed enantioselective RCM reactions was reported [29]. Although the substrate scope in this study is limited, high levels of enantioselectivity are achieved with commercially available Mo alkylidene 4a. Alkene substitution patterns are crucial for effective kinetic resolution; substrates bearing a terminal and a 1,1-disubstituted olefin (Eq. 8E.1) furnish the best selectivities. Two additional points regarding this study merit mention: (1) Complex 4a is the only chiral complex examined; alternative chiral Mo complexes may deliver improved selectivity. (2) In many cases, significant homodimerization of the substrate occurred, rendering a precise determination of the selectivity difficult [30]. 10 mol %

i-Pr Me

Mo O

Ph

SiMe3

i-Pr N

Me

O

Me3Si

SiMe3

Me3Si

SiMe3 Fe

Me

Fe

ent-4a Racemic

C6H6 [5 mM], 50°C, 24 h

Me3Si

+

Fe

Me

Me 45% yield, 97% ee

52% yield, 81% ee

krel > 50

(8E.1)


Me

Mo Fe

Me

N O

O

Fe

753

N Mo O SiMe3 O

Me3Si

Me3Si

Me3Si

Matched enantiomer

Mismatched enantiomer

Figure 8E.4. Proposed model for enantioselectivity in the catalytic enantioselective RCM of ferrocenes.

The stereochemical outcome of the reaction depicted in Equation 8E.1 can be rationalized through the proposed mechanistic model shown in Figure 8E.4 [31]. After initiation at the terminal olefin of the substrate, the catalyst may coordinate to the 1,1-disubstituted olefin. In the mismatched enantiomer, steric interactions between the substituent on the cyclopentadienyl moiety and the tert-butyl group of the chiral ligand disfavor formation of the molybdacyclobutane. In the matched enantiomer, a proton takes the place of the bulky trimethylsilyl group, allowing for facile formation of the metallacycle. Therefore, it is critical that the terminal olefin is located on the substituted cyclopentadienyl ligand only; when both olefins are terminal, little or no enantioselectivity is observed.

8E.2.6. Stereogenic-at-Mo Complexes with Only Monodentate Ligands: Application to Enantioselective Synthesis of Quebrachamine The continuing quest for design and development of more effective catalysts (i.e., more reactive, longer living, more selective) stands as one of the most compelling goals of research in olefin metathesis [1b]. As illustrated above, in many examples, enantioselective olefin metathesis reactions require high catalyst loadings and/or long reaction times, regardless of whether Ru-based catalysts or the more active Mo complexes are utilized. At times, only one catalyst is capable of promoting the desired transformation (e.g., the enantioselective RCM of enol ethers in Scheme 8E.6). Recently, in the context of efforts toward total synthesis of Aspidosperma alkaloid quebrachamine (Scheme 8E.8), wherein the penultimate step features a desymmetrization by RCM [32], the need for a substantially more effective chiral olefin metathesis catalyst became abundantly clear. Although the RCM can be catalyzed by the available achiral Mo or Ru complexes, albeit not with high efficiency, none of the existing chiral Mo catalysts (e.g., 1–4) afford the desired enantiomerically enriched product, even under forcing conditions (up to 50 mol % catalyst, up to 80°C, up to 48 h). With chiral Ru catalysts, only racemic product could be obtained. Thus, the development of a new more reactive and selective class of catalysts proved to be imperative for successful completion of an enantioselective total synthesis of quebrachamine.


i-Pr

i-Pr N

R

R

N

R

Br

N H

Me

Mo

Ph

Me

N

i-Pr

R

OH

+

R

OTBS

C6H6, 22 °C, 1 h

R

R

i-Pr R N

N

Me

Mo O

Br

Br

Ph Me

TBSO

Br

5a R = H; >98% conv; dr = >20:1 5b R = Me; 95% conv; dr = 7:1 1 mol %

i-Pr

i-Pr N

N N

Cl

TBSO

Me

Mo O

Ph Me

Cl

N

6b (5:1 dr, in situ)

N H

N H

>98% conv, 84% yield 96% ee

C6H6, 22°C, 1 h

5 mol % PtO2 H2, EtOH, 22°C, 1 h

N Et

(+)-Quebrachamine N H 97% yield

Scheme 8E.8. Stereoselective synthesis of stereogenic-at-Mo complexes and application to enantioselective total synthesis of quebrachamine.

Based partly on recent theoretical studies by Eisenstein and coworkers regarding more reactive high oxidation state olefin metathesis catalysts [33], Mo-based complexes 5–6 were designed and prepared. These chiral complexes feature one relatively electrondonating ligand (pyrrolide) and one relatively electron-withdrawing ligand (aryloxide); consequently, Mo is a stereogenic center and, as with stereogenic-at-metal Ru-based catalysts (see Scheme 8E.4), undergoes inversion at the metal with each olefin metathesis transformation. The stereogenic-at-Mo complexes can be generated in situ through an unprecedented stereoselective protonation of a metal-N bond (complexes are formed in up to >20:1 dr), constituting the first stereoselective synthesis of a stereogenic-at-metal complex, bearing only monodentate ligands. Complexes containing a 2,5-dimethylpyrrolide ligand (e.g., 5b and 6b) are exceptionally reactive and promote enantioselective RCM with outstanding selectivity. Such developments have allowed the completion of

8E.3. CATALYTIC ENANTIOSELECTIVE (RORCM) AND (ROCM) 755

an enantioselective synthesis of quebrachamine—the Mo-catalyzed enantioselective RCM delivers the desired product in 84% yield and establishes the all-carbon quaternary center in 96% ee. Several additional points regarding this most recent development are noteworthy: (1) This study presents the first example of the use of a stereogenic-at-metal complex, bearing only monodentate ligands, as an efficient and selective catalyst for enantioselective synthesis. (2) The stereogenic-at-Mo complexes constitute a rare example of an alkoxide or aryloxide as a chiral ligand. (3) In situ-generated catalysts often display identical reactivity and selectivity to isolated, diastereomerically pure complexes, and the olefin metatheses studied can be performed in a fume hood on gram scale.

8E.3. CATALYTIC ENANTIOSELECTIVE RING-OPENING/ RING-CLOSING METATHESIS (RORCM) AND RING-OPENING/ CROSS-METATHESIS (ROCM) 8E.3.1. General Considerations Whereas RCM reactions are driven by entropy (e.g., formation of ethylene), RCM processes are enthalpy driven, often through release of a ring strain. Subsequent to ring opening, the resulting alkylidene/carbene may be trapped intramolecularly by a pendant olefin (RORCM, path A, Scheme 8E.9) or intermolecularly with a cross partner (ROCM, path B). In some cases, ROCM may be accompanied by RCM. Reaction pathways can

O

Me

Me O

M

H

M

R H

R

H

Me

Me

O

O

R

Path A intramolecular trap

M

R

O R

Me M

RORCM (R = H )

R O

Me Me

R R

O

R M

Path B intermolecular trap

ROCM (R = Ph)

Scheme 8E.9. Catalytic pathways resulting in the formation of enantioselective RORCM versus ROCM products.


be controlled by appropriate selection of the catalyst and cross partner. A variety of enantiomerically enriched products can therefore be generated from a common starting material. It should be noted that a number of olefin metathesis pathways are available in the absence of an intramolecular trap (i.e., in ROCM processes), possibly leading to a complex mixture of products. Catalyst control is thus critical for directing the reaction toward the desired product. 8E.3.2. Catalytic Enantioselective RORCM and ROCM of Substituted Norbornenes: Application to Total Synthesis of Africanol The first examples of enantioselective ROCM reactions were reported in 1999 [34]; these Mo-catalyzed processes largely involve aromatic olefins as the cross partner and proceed with good yield and selectivity with various norbornene derivatives. Through catalytic RORCM reactions of simple and readily accessible norbornenes [35], a variety of bicyclic and tricyclic structures can be synthesized in high enantiomeric purity; several examples are shown in Scheme 8E.10. Reactions might be performed in the absence of solvent, allowing efficient and selective access to the core of africanol; the catalytic enantioselective RORCM strategy was subsequently applied to an enantioselective synthesis of the natural product [36]. As before, the optimal catalyst for a given transformation depends on the substrate, emphasizing the need for a family of related but structurally diverse catalysts. As in our previous studies, norbornenes, bearing a sterically exposed strained olefin, undergo facile polymerization under identical conditions [34]. Instead of “intramolecular trapping” that affords enantiomerically enriched RORCM products, Mo alkylidenes may be trapped in an intermolecular fashion (e.g., with styrene) to furnish the enantioselective ROCM product in high yield and enantioselectivity (Scheme 8E.11). It should be noted that in general, E-olefins are generated with high selectivity. In the absence of styrene, however, the RORCM product is formed in 54% yield and 92% ee. When the 1,1-disubstituted olefin of the allyl ether moiety is changed to the sterically more accessible and reactive terminal olefin, only the RORCM product is obtained, even in the presence of styrene. In certain cases, chiral Ru-based catalysts promote tandem ring-opening/cross metathesis/ring-closing metathesis in the presence of styrene (Scheme 8E.11) [37]. Such a process, which likely proceeds through the intermediate shown, occurs with good enantioselectivity and with the product obtained as a single olefin isomer (with Ru-based catalysts bearing bidentate NHC ligands, the E-olefin is isolated exclusively). It should be noted that this process cannot be accomplished with Mo-based catalysts due to competing rapid polymerization of strained olefin substrates (cf. Scheme 8E.10). Catalytic enantioselective ROCM of norbornenes has more recently been revisited due to the development of new chiral Ru-based catalysts [37,38]; examples are depicted in Table 8E.3, and results from earlier investigations [6a] with chiral carbenes 11a–11b are shown for comparison. Ru complexes 10a–10b (entries 1, 2, and 6), bearing monodentate NHC ligands, have led to an improvement in reaction rates (i.e., lower catalyst loadings and shorter reaction times). Enantioselectivities are, however, generally lower than those obtained with bidentate NHC-containing complexes 11a–11b and 12b. Additionally, 10a–10b afford the products with poor E/Z selectivity (∼1:1 E/Z), whereas 11a–11b and 12b exclusively produce the E-isomer. As noted before, the Ru-I complexes are less reactive but more enantioselective than their Ru-Cl counterparts (compare entries 1 and 3 with 2 and 4, respectively) [12].


Ar = 2,4,6-i-Pr3C6H2

5 mol %

Cl

Cl N Mo O

Ar O

O

Ph Me

Ph

Ar

O

Ph

Me

3b

O

H

C6H6, 22 °C,12 h

93% yield, 86% ee

5 mol % N

Me

Mo

O

Ph Me

O O

O

H

2

H

C6H6, 22 °C, 3 h

80% yield, 96% ee

5 mol %

i-Pr

i-Pr N Mo

O

Me

Me Ph Me

O

O

Polymerization

1a C6H6, 22 °C

Ar = 2,4,6-i-Pr3C6H2

3 mol %

i-Pr

i-Pr

Ar O

N Mo O

O

TBSO Me

Me

Me Ph Me

OTBS Me

Ar 3a No solvent, 22 °C, 6 h

Me

OH

Me

Me H

97% yield, 87% ee

Me

H Me

(+)-Africanol

Scheme 8E.10. Mo-catalyzed enantioselective RORCM of norbornenes: application to enantioselective synthesis of africanol.


5 mol %

i-Pr

i-Pr N O

O

O

Me

Mo

Me

H

Ph Me

H H

1a

Me

+

O Me

H

Ph

O

98% E >98% ee

Ph

Ph

5 mol % N

MesN I

H

Ru

O

O

12b

Oi-Pr Ph

O

H

Ph 52% yield, >98% E 90% ee

Ph THF, 22 °C, 1 h

O [Ru]

Ph

Scheme 8E.11. Mo- and Ru-catalyzed enantioselective ROCM of norbornenes.

8E.3.3. Ru- and Mo-Catalyzed Enantioselective ROCM of Oxabicycles: Application to Total Synthesis of Baconipyrone C Metal-catalyzed ROCM can be utilized to establish multiple stereogenic centers in a single transformation through desymmetrization of relatively simple meso substrates. Application of Ru-catalyzed enantioselective ROCM to processes involving mesooxabicycles was disclosed in 2004 [39]; a report detailing Mo-catalyzed variants of these catalytic transformations appeared in 2007 [40]. Illustrative examples are provided in Table 8E.4. Endo-substituted oxabicycles (entries 1 and 2) react readily in the presence of 11b and 12b (>98% conversion with 5 mol % catalyst within 1–1.5 h) to provide the desired products with excellent enantioselectivities. With Ru catalysts, the reaction can be performed in the presence of a secondary alcohol; Mo-based catalysts, however, typically decompose in the presence of free hydroxyl groups, and protection of the alcohol as the benzyl ether gives rise to oligomerization of the substrate with Mo catalyst 2 [41].


TABLE 8E.3. Comparison of the Activity of Chiral Ru Catalyst in Enantioselective ROCM of Norbornenes Ru-based chiral catalyst

O

Ph

O

O

Ph O

Ph

Chiral catalysts:

i-Pr MeO

Ph

N

N

Ph

t-Bu

i-Pr

L

t-Bu

O

O

OMe

Ru

L PCy3

10a L = Cl 10b L = I

Ph N

MesN

Ph

N

MesN I

L

Ru

Ru

O

O

Oi-Pr

Oi-Pr Ph

Ph

11a L = Cl 11b L = I Catalyst; mol %

Equiv

10a; 1 10b; 3 11a;5

10 10 5

4

11b; 5

5

Entry 1 2 3

Product Ph O

O

O

6 7

Ph HO

Ph

12b


Yield (%); E/Z

1; 22 1; 22 0.4; 22

82; >98:2

5

2; 22

72; >98:2

12b; 5

5

2; 22

10a; 1 11a; 5

10 5

50; >98:2 30; 1.1:1

1; 22 0.25; 22

95; 1:1 96; 1:1

40; >98:2

ee (%) 76 80 78 >98 90 33 10

OH

Although full conversion of exo-substituted oxabicycles can be obtained with Ru catalyst 11b, reactions are relatively sluggish (entry 4), requiring 5 mol % catalyst loading and extended reaction times (36 h at 22°C) to deliver products in good yield and with high enantioselectivity. Development of Ru complex 12b has led to substantially improved reactivity: transformations can be performed at lower temperatures and with reduced catalyst amounts (see entry 5: at −15°C with 2 mol % 12b), allowing access to the desired products with greater enantioselectivity and requiring shorter reaction times (>98% ee in 15 h) [37]. Mo catalyst 2 offers the highest level of activity for this transformation,


TABLE 8E.4. Catalytic Enantioselective ROCM Reactions of meso-Oxabicycles OH

OH

Mo- or Ru-based catalyst

O

Ph

O

Ph Chiral catalysts:

N O

Me

Mo

Ph Me

O

2

Ph N

MesN

Ph

N

MesN I

I

Ru

Ru

O

O

Oi-Pr

Oi-Pr Ph

Entry 1

Product OH

2 O

Ph

11b

12b

Catalyst; mol %


Conv (%); Yield (%)

ee (%)

11b; 5

1.5; 22

>98; 80

94

12b; 5

1; 22

>98; 71

93

90

Ph

2; 2

1; 22

>98; 81

4

11b; 5

36; 22

>98; 85

90

5

12b; 2

15; −15

>98; 84

>98

3

OBn

O

Ph

2; 5

1; 22

>98; 76

97

7

11b; 2

5; 22

>98; 65

93

8

12b; 2

5; 22

>98; 70

82

6

I

O

Ph

delivering the desired product in 81% yield after only 1 h with 2 mol % loading (entry 3). Enantiomerically enriched pyrans with stereogenic centers bearing a halogen substituent can be synthesized efficiently and with a high degree of selectivity (entries 6–8, Table 8E.4) [42]. It should be noted that complex 2 is thus far the only Mo-diolate catalyst capable of carrying out enantioselective ROCM of oxabicycles. Ru-catalyzed enantioselective ROCM of meso-oxabicyclic substrates has been applied to enantioselective total synthesis of polypropionate (+)-baconipyrone C, which


was reported in 2007 (Scheme 8E.12) [43]. The fully substituted pyran is obtained in 88% ee with the requisite Ru-based complex 12b formed in situ from the corresponding Ag-NHC, Ru phosphine complex, and NaI, thus obviating the need for isolation of the catalyst. The core structure of the natural product was prepared by reductive ring cleavage of the pyran under dissolving metal conditions. The diketone fragment of baconipyrone C was synthesized through a double-enantioselective allylic alkylation, promoted by a chiral bidentate Cu-NHC complex that is structurally similar to that which resides within Ru-based catalyst 12b. The enantioselective total synthesis of baconipyrone C thus illustrates the utility of bidentate NHC metal complexes in a range of catalytic enantioselective transformations.

Ph

Ph

2 mol % N

MesN I

Ru

OPMB Me

Me

OPMB

O

Me

Oi-Pr

Me

O

12b

Ph

8 equiv styrene No solvent, –15°C, 20 h

Et

O

Me

Me

O Me

O

Ph

>98 % conv, 62 % yield, >98% E, 88 % ee

Me

Me

O

Me

O

Na, NH3, t-BuOH Et2O, –78°C, 3 min Me

O OH

O

Et

O

Me Et

Ph

PMBO

OH

70% yield

(+)-Baconipyrone C

Scheme 8E.12. Enantioselective synthesis of baconipyrone C by Ru-catalyzed enantioselective ROCM.

8E.3.4. Ru- and Mo-Catalyzed Enantioselective ROCM and RORCM of Azabicycles N-containing heterocycles, including 2,6-disubstituted piperidines, are found in an assortment of natural targets and medicinally important molecules. Metal-catalyzed enantioselective ROCM reactions of meso-azabicycles could allow efficient access to this important class of enantiomerically enriched molecules. A study of the comparative reactivity and selectivity of Ru- and Mo-based catalysts for enantioselective ROCM of azabicycles involving styrenyl alkenes was reported in 2007 [40,44]; representative key findings are shown in Table 8E.5. N-Me azabicycles undergo catalytic ROCM efficiently and with high enantioselectivity in the presence of Mo complex 2 (entry 1). In contrast, reactions with Ru-based catalysts proceed at a significantly lower rate (entry 2), likely due to coordination of the transition metal to the N heteroatom, and deliver the desired 2,6-disubstituted piperidines with relatively low enantioselectivity. When the corresponding N-Bn azabicycle is used as the substrate, however, Ru catalyst 11a promotes the ROCM reactions efficiently, delivering the


desired products in good yield and with excellent enantioselectivity within 24 h (e.g., entry 4, Table 8E.5). Although more active, Mo catalyst 2 furnishes products in lower enantiomeric purity (e.g., entry 3, Table 8E.5). The derived carbamates require higher loadings when either Ru- or Mo-based complexes are used. In the case of Mo complex 2, a longer reaction time is needed for high conversion (entries 5 and 6, Table 8E.5); such lower efficiency is likely due to the reversible nature of the ROCM process: as a result of A(1,3) strain caused by the carbamate group, the two vinyl substituents are situated axially within the six-membered heterocycle, allowing for facile reclosure of the piperidine products [45]. Chiral alkylidene 2 is again the only Mo complex capable of promoting the reactions enantioselectively [46]. Application of catalytic RORCM of azabicyclic substrates to enantioselective synthesis of an isoindole derivative has recently been reported [47]. In this disclosure, only one example of an enantioselective olefin metathesis process, where Ru-based complex 14 is utilized, is examined (Eq. 8E.2); enantioselectivity levels are relatively low (69% ee), and the desired product is obtained in moderate yield (61%). The Ru-catalyzed RORCM reaction is performed under an atmosphere of ethylene, presumably to facilitate catalyst release. Additionally, the direct product of olefin metathesis is unstable and therefore was isolated as its hydrogenated congener. 1) 10 mol %

Ph Me

O

Ph

N

N

Me

Cl

N

Ph

Ru

Cl

Et O

14

PCy3 Ethylene, CH2Cl2, 22°C, 12 h 2) Pd/C, H2, MeOH, 12 h

N H

61% yield, 69% ee

(8E.2)

8E.3.5. Ru-Catalyzed Enantioselective ROCM of Cyclopropenes: Extension of Cross Partner Scope through a Possible Remote Olefin Directing Effect The state of the art regarding catalytic enantioselective ROCM reactions has largely been restricted to processes involving aryl-substituted olefins. This limitation might eventually be overcome by the discovery of more selective catalysts. Recently, however, a class of directed Ru-catalyzed enantioselective ROCM reactions involving cyclopropenes and various unsaturated enoates has extended catalytic enantioselective ROCM beyond transformations that use aryl-substituted olefins as cross partners [48]. As the data in Table 8E.6 show, the presence of a remote olefin, which does not directly participate in olefin metathesis, is crucial for achieving high enantioselectivity; whereas 1-octene (entry 1) delivers the product with poor selectivity (41% ee), allyl methacrylate (entry 2) affords the ring-opened product with significantly higher enantioselectivity (85% ee). One plausible explanation for this effect is a chelation between the enoate and the Ru center in the transition state for the ring opening; detailed studies to elucidate the nature of this potential chelate are currently underway. Two other points regarding this report are noteworthy. (1) All-carbon quaternary stereogenic centers, bearing two differentiated vinyl groups can be obtained through the directed Ru-catalyzed reactions. It should be noted that this is a rare example of


TABLE 8E.5. Catalytic Enantioselective ROCM Reactions of meso-Azabicycles OTBS Me N

OTBS

Mo- or Ru-based chiral catalyst

N Me

Ph

Ph

Chiral catalysts:

N O

Me

Mo

Ph Me

O

2

N

MesN Cl

Ru

O Oi-Pr Ph

Entry 1

Product

Catalyst; mol % 2; 5

OTBS

2

11a; 5 N Me

3

N Cbz

1 36

Conv (%); Yield (%)

ee (%)

>98; 95 30; nd

33

94

1

>98; 85

21

11a; 5

24

>98; 80

>98

2; 10 11a; 10

24 24

83; 80 91; 70

−90

2; 5

OTBS

N Bn

Time (h)

Ph

4

5 6

11a

Ph

Ph

nd = not determined. All reactions performed at 22°C.

82


TABLE 8E.6. Ru-Catalyzed Enantioselective ROCM Reactions of Cyclopropenes: Influence of Cross Partner Substituent on Enantioselectivity

Ph

Ph

5 mol % N

MesN I

Ph

Ru

Me

O

G

Oi-Pr Ph 1–2 equiv

12b

Ph

Me

G

THF, 22 °C, 24 h

Entry

G

1

n-hex

Time (h); Temp (°C) 24; 22

2

48; 0 O

E :Z

Yield (%)

ee (%)

1.5:1

39

41

5:1

77

85

Me O

formation of all-carbon quaternary stereogenic centers through enantioselective olefin metathesis (see Sections 8E.2.4 and 8E.2.6). Accessing these products directly through CM would be exceedingly difficult due to the quaternary carbon in the α-position; ring opening of a highly strained cyclopropene provides a solution to this problem. (2) Additionally, the ester-containing products can easily be hydrolyzed to synthetically useful allylic alcohols [17]. One notable feature of ROCM reactions, catalyzed by chiral Ru carbenes 11–12 and exemplified in the ring opening of cyclopropenes, is the ability of the catalyst to cause minimal dimerization of the cross partner while promoting the desired transformation with only modest oligomerization. This aspect is likely because complexes 11 and 12 are stereogenic-at-metal and undergo stereomutation at the metal center through a single olefin metathesis step (cf. IV V, Scheme 8E.4). As catalytic enantioselective ROCM involves two metathesis steps, the overall reaction results in net retention of stereochemistry at the metal center. The two Ru carbene intermediates are diastereomeric and thus exhibit different kinetic profiles. The release of ring strain allows for an endoergic step (stereomutation to the higher in energy Ru-carbene) to proceed, while the sterically more encumbered Ru-diastereomer reacts with the sterically less hindered cross partner. The above feature has been applied in preparation of alternating copolymers through utilization of racemic stereogenic-at-Ru complex 15 [49]. The norbornene-cyclooctene copolymer (Eq. 8E.3) exhibits a high degree of sequence selectivity as evidenced by the low r value [50]. Stereogenic-at-Ru (racemic) 15 distinguishes between the two monomers by preferentially reacting with norbornene, as the ring strain of norbornene drives the formation of the higher in energy Ru-carbene (the reverse process is exergonic, and ring-strain relief for regeneration of the lower in energy diastereomer is not necessary). Thus, reaction with cyclooctene, which is present in large excess, causes reversal of the Ru-carbene to

8E.5. CONCLUSIONS AND FUTURE OUTLOOK 765

the original diastereomer; repeat of the above cycle furnished the desired copolymer in 89% yield (r = 0.04). 0.05 mol % P O

Ru

Cl (

O

)n

Cy

15

Cy

89% yield, r = 0.04

200 equiv cyclooctene, 0 °C, 1.5 h

(8E.3)

8E.4. CATALYTIC ENANTIOSELECTIVE CROSS-METATHESIS (CM) Catalytic enantioselective CM is the least developed class of enantioselective olefin metathesis reactions. Unlike ring-closing and ring-opening metathesis, transformations that are strongly thermodynamically driven, there is typically minimal driving force for CM. Chemoselectivity, selective reaction between two different cross partners versus homodimerization of each, can serve as a major complication as well. Such concerns are frequently addressed through manipulation of reagent stoichiometry. In 2006, the first examples of catalytic enantioselective CM reactions were reported (Scheme 8E.13) [38]. Of the catalysts investigated, Ru-based chiral carbene 9a is found to be optimal, delivering the desired products with modest levels of enantioselectivity and poor to moderate yields (E : Z ratios have not been disclosed). Two additional points regarding this study merit mention, underlining the inherent difficulty associated with the development of efficient catalytic enantioselective CM reactions: (1) The divinyl compounds, which are desymmetrized in the reaction, are incapable of undergoing RCM due to ring strain of the products. (2) Another cross partner employed is a symmetrical 1,2-disusbstituted olefin with Z geometry at the olefin, thereby giving the reaction a slight enthalpic push through a release of allylic strain.

8E.5. CONCLUSIONS AND FUTURE OUTLOOK Significant advances have been achieved during the last decade in the development of effective chiral catalysts for olefin metathesis and the use of such Mo- or Ru-based complexes in a number of related methods for enantioselective synthesis. Catalytic enantioselective RCM reactions can be used to access a range of O- and N-containing heterocyclic structures, five-, six-, seven- or eight-membered rings, with high degrees of enantioselectivity. A number of protocols that utilize metal-catalyzed RCM reactions have also emerged; Mo- or Ru-catalyzed enantioselective ROCM or RORCM transformations have been utilized to synthesize an assortment of carbo- and heterocyclic structures. The above catalytic processes allow access to small molecules of high enantiomeric purity that cannot be easily prepared by alternative methods, including application of achiral olefin metathesis catalysts to promote reactions of enantiomerically enriched substrates. Application to enantioselective total syntheses of natural products


Ph

5 mol %

i-Pr OTIPS

Ph

N

N

i-Pr

OTIPS

Ru

Ph (5 equiv)

i-Pr

i-Pr

Cl

OAc

Cl

9a

54% yield, 52% ee (E : Z not reported)

PCy3

1 equiv AcO

OAc

No solvent, 40°C, 6 h

Ph

5 mol %

i-Pr OTMS

OTMS

N

N

Ph 9a 1 equiv AcO

i-Pr OTMS

i-Pr

Cl

i-Pr

(1 equiv)

Ph

OAc

Ru

Cl

OTMS

PCy3 OAc

17% yield, 40% ee (E : Z not reported)

No solvent, 40°C, 6 h

Scheme 8E.13. Catalytic enantioselective cross-metathesis reactions.

(e.g., africanol, baconipyrone C, and quebrachamine) have highlighted the utility of chiral olefin metathesis catalysts as well as underlined a number of shortcomings that remain to be overcome. In spite of the above advances, we are far from achieving the full potential of what catalytic enantioselective olefin metathesis can offer. Among notable limitations to be overcome are the relatively high catalyst loadings typically required to promote reactions (i.e., use of ≤1 mol % loading remains unusual), the inactivity of many of the available catalysts in the presence of “difficult” substrates, such as those that bear a Lewis basic heteroatom, and the requirement for starting materials that must have a specific type of alkene substitution (e.g., effective catalytic enantioselective RCM processes with substrates that only carry terminal alkenes are scarce). Catalytic enantioselective ROCM reactions remain largely limited to those that utilize aryl-substituted olefins as cross partners, a shortcoming that hampers the utility of these potentially powerful transformations to synthesis of complex molecule natural products. Furthermore, several important classes of catalytic olefin metathesis reactions remain severely underdeveloped (e.g., catalytic enantioselective CM [51], catalytic enantioselective enyne metathesis [52]). Solutions to such challenging and important problems require the design and development of new classes of chiral catalysts with unique structural attributes that give rise to exceptional and unprecedented levels of reactivity and stereoselectivity [1b]. Most recent progress in connection with structurally flexible stereogenic-at-Mo complexes (see Scheme 8E.8), which can deliver significantly higher reactivity than previously developed catalysts, augurs well for exciting new developments in this critical area of research in enantioselective catalysis.

REFERENCES 767

ACKNOWLEDGMENTS We thank the NIH (Grant GM-59426) and the NSF (Grants CHE-0213009 and CHE0715138) for support of our programs in catalytic olefin metathesis. We are most grateful to Professor Richard R. Schrock and his coworkers who have collaborated with us since 1997 in connection with the development of Mo-based catalysts for enantioselective olefin metathesis. Finally, we particularly acknowledge the intellectual and experimental contributions of our former coworkers, J. S. Kingsbury, S. B. Garber, J. J. Van Veldhuizen, D. G. Gillingham, O. Kataoka, G. S. Weatherhead, J. A. Jernelius, E. S. Sattely, S. J. Dolman, G. A. Cortez, A. Puglisi, A.-L. Lee, C. A. Baxter, and D. C. Moebius.

REFERENCES 1. (a) Grubbs, R. H. (Ed.). Handbook of Metathesis. Weinheim: Wiley-VCH, 2003. (b) Zhugralin, A. R.; Hoveyda, A. H. Nature 2007, 450, 243–251. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490–4527. 2. (a) Dolman, S. J.; Hultzsch, K. C.; Pezet, F.; Teng, X.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2004, 126, 10945–10953. For an earlier disclosure of chiral Mo-diolate catalysts on a different solid support, see: (b) Hultzsch, K. C.; Jernelius, J. A.; Hoveyda, A. H.; Schrock, R. R. Angew. Chem. Int. Ed. 2002, 41, 589–593. 3. For a review of desymmetrization processes, see: (a) Willis, M. C. J. Chem. Soc. Perkin Trans. 1 1999, 1765–1784. Additionally, a number of other enantioselective transformations, where the stereochemical outcome is controlled indirectly through desymmetrization, have been reported. For Wittig-type reactions, see: (b) Rein, T.; Pedersen, T. M. Synthesis 2002, 579–594. (c) Lertpibulpanya, D.; Marsden, S. P.; Rodriguez-Garcia, I.; Kilner, C. A. Angew. Chem. Int. Ed. 2006, 45, 5000–5002. (d) Headley, C. E.; Marsden, S. P. J. Org. Chem. 2007, 72, 7185–7189. For oxidation of meso-diols, see: (e) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. (f) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535–7537. (g) Suzuki, T.; Morita, K.; Matsuo, Y.; Hiroi, K. Tetrahedron Lett. 2003, 44, 2003–2006. (h) Shimizu, H.; Onitsuka, S.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2005, 127, 5396–5413. (i) Onumura, O.; Arimoto, H.; Matsumura, Y.; Demizu, Y. Tetrahedron Lett. 2007, 48, 8668–8672. For silylation of meso-diols, see: (j) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443, 67–70. For enantioselective acylation and phosphorylation reactions, see: (k) Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610. For enantioselective Baeyer–Villiger reactions, see: (l) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K. Angew. Chem. Int. Ed. 2008, 47, 2840–2843 and references cited therein. For an enantioselective Schmidt reaction, see: (m) Ribelin, T.; Katz, C. E.; English, D. G.; Smith, S.; Manukyan, A. K.; Day, V. W.; Neuenswander, B.; Poutsma, J. L.; Aubé, J. Angew. Chem. Int. Ed. 2008, 47, 6233–6235. For ring opening of cyclic meso-anhydrides, see: (n) Spivey, A. C.; Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40, 3131–3134. 4. (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592–4633. (b) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8–23. 5. Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225–3228. 6. For enantioselective RCM promoted by Ru-based chiral catalysts, see: (a) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502– 12508. (b) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840–1846. (c) Fournier, P.-A.; Collins, S. K. Organometallics 2007, 26, 2945–2949. (d) Funk, T. W. Org. Lett. 2009, 11, 4998–5001. For related transformations, promoted by Mo-based complexes, see: (e) La, D. S.; Alexander, J. B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998,

768 CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS REACTIONS 120, 9720–9721. (f) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121, 8251–8259. 7. Tungsten-based catalysts have also been synthesized and applied to enantioselective RCM. Although they are equally selective as their Mo-based counterparts, they are typically less reactive, sometimes allowing for the isolation of intermediates within the catalytic cycle; see: Tsang, W. C. P.; Hultzsch, K. C.; Alexander, J. B.; Bonitatebus, P. J., Jr.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 2652–2666. 8. Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897. 9. Adlhart, C.; Chen, P. J. Am. Chem. Soc. 2004, 126, 3496–3510. 10. Sanford, M. S. PhD Thesis, California Institute of Technology, 2001. 11. Adlhart, C.; Chen, P. Angew. Chem. Int. Ed. 2002, 41, 4484–4487. 12. (a) Costabile, C.; Cavallo, L. J. Am. Chem. Soc. 2004, 126, 9592–9600. (b) Straub, B. F. Adv. Synth. Catal. 2007, 349, 204–214. 13. For reviews on tethering strategies for organic synthesis, see: (a) Fensterbank, L.; Malacria, M.; Sieburth, S. McN. Synthesis 1997, 813–854. (b) Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2289–2338. (c) Knapp, S. Chem. Soc. Rev. 1999, 28, 61–72. 14. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426–5427. 15. (a) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768–6769. (b) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429–1432. (c) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517–1519. (d) Gerash, T. M.; Chytil, M.; Didiuk, M. T.; Park, J. Y.; Urban, J.; Nolan, S. P.; Verdine, G. L. Org. Lett. 2000, 2, 3999–4000. (e) Denmark, S. E.; Yang, S.-M. Org. Lett. 2001, 3, 1749–1752. (f) Harrison, B. A.; Verdine, G. L. Org. Lett. 2001, 3, 2157–2159. (g) Van de Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J. Org. Lett. 2002, 4, 4105–4108. (h) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126, 12432–12440. 16. (a) Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron 2004, 60, 7345–7351. For nonenantioselective ring-closing metathesis of allylboronates, see: (b) Micalizio, G. C.; Schreiber, S. L. Angew. Chem. Int. Ed. 2002, 41, 152–154. (c) Micalizio, G. C.; Schreiber, S. L. Angew. Chem. Int. Ed. 2002, 41, 807–810. 17. For a discussion of the decomposition of Ru-based olefin metathesis catalysts in the presence of secondary allylic alcohols, see: (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125. For a general discussion of the decomposition pathways of Ru-based olefin metathesis catalysts, see: (b) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961–7968. 18. (a) Saxton, J. E. In The Alkaloids (Ed. Cordell, G. A.). New York: Academic Press, 1998; pp. 12–197. For a review, covering the synthesis of N-heterocycles through ring-closing metathesis, see: (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. For additional examples of N-heterocycle synthesis through ring-closing metathesis, see: (c) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75–90. (d) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Bieraugel, H. Eur. J. Org. Chem. 1999, 959–968. 19. (a) Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991–6997. (b) Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5, 4899–4902. 20. For a discussion of catalyst inhibition by Lewis bases during olefin metathesis, see: Edwige, C.; Lattes, A.; Laval, J. P.; Mutin, R.; Basset, J-M.; Nouguier, R. J. Mol. Catal. 1980, 8, 297–311. 21. Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526–8533. 22. For another example of an amide chelate to a Mo complex during olefin metathesis, see: Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324–7325. 23. For non-enantioselective ring-closing metathesis of enol ethers, see: (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029–4031. (b) Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623–9626. (c) Clark, J. S.; Kettle, J. G. Tetrahedron 1999, 55, 8231–8248. (d) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380–1386. (e) Liu, L.; Postema, M. H. D. J. Am.

REFERENCES 769

Chem. Soc. 2001, 123, 8602–8603. (f) Hekking, K. F. W.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron 2003, 59, 6751–6758. (g) Oliver, S. F.; Hogenauer, K.; Simic, O.; Antonello, A.; Smith, M. D.; Ley, S. V. Angew. Chem. Int. Ed. 2003, 42, 5996–6000. For an alternative approach to the synthesis of cyclic enol ethers through ring-closing metathesis, see: (h) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390–13391. 24. Lee, A-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 5153–5157. 25. (a) Christophers, J.; Baro, A. (Eds.). Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis. Weinheim: Wiley-VCH, 2006. (b) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146. 26. In one study, the anti-alkylidene isomer has been shown to be more reactive than the syn-isomer in the ring-opening-metathesis polymerization of 2,3-bis(trifluoromethyl)norbornadiene. See: Oskam, J. H.; Schrock, R. R. J. Am. Chem. Soc. 1993, 115, 11831–11845. 27. Use of OsO4 leads to low regioselectivity. For use of chiral dihydroxylation catalysts in synthesis, see: (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547. For catalytic dihydroxylation of enol ethers with chiral catalysts, see: (b) Curran, D. P.; Ko, S.-B. J. Org. Chem. 1994, 59, 6139–6141. 28. For racemic syntheses of molecules, bearing a stereogenic axis, through metathesis, see: (a) Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.; Flack, K.; Procopiou, P. A. Org. Lett. 2000, 2, 551–553. (b) Murakami, M.; Kadowaki, S.; Matsuda, T. Org. Lett. 2005, 7, 3953–3956. (c) Collins, S. K.; Grandbois, A.; Vachon, M. P.; Cote, J. Angew. Chem. Int. Ed. 2006, 45, 2923–2926. For an example of diastereoselective control of planar stereogenicity through metathesis with an achiral catalyst, see: (d) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775. 29. (a) Ogasawara, M.; Watanabe, S.; Fan, L.; Nakajima, K.; Takahashi, T. Organometallics 2006, 25, 5201–5203. For a related study, see: (b) Grandbois, A.; Collins, S. K. Chem. Eur. J. 2008, 14, 9323–9329. 30. The selectivity factor (krel) is calculated by the equation reported by Kagan, which is a first-order equation based on relative rates of enantiomers proceeding to a single product, and does not account for other processes that consume the starting material, such as homodimerization; see: Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330. 31. The mechanistic model proposed by the authors (Reference xxix) is inconsistent with previous mechanistic studies regarding enantioselective olefin metathesis with this class of catalysts. 32. (a) Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456, 933–937. (b) Sattely, E. S.; Mekk, S. J.; Malcolmson, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943–953. For additional examples of enantioselective transformations with this class of catalysts, see: (c) Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844–3845. (d) Lee, Y.-J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 10652–10661. 33. (a) Solans-Monfort, X.; Clot, E.; Copéret, C.; Eisenstein, O. J. Am. Chem. Soc. 2005, 127, 14015–14025. (b) Poater, A.; Solans-Monfort, X.; Clot, E.; Copéret, C.; Eisenstein, O. J. Am. Chem. Soc. 2007, 129, 8207–8216. 34. (a) La, D. S.; Ford, J. G.; Sattely, E. S.; Bonitatebus, P. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 11603–11604. For a full account of this work, see: (b) La, D. S.; Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 7767–7778. 35. For previously reported enantioselective RORCM processes that do not involve norbornenes, see: (a) Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828–1829. (b) Cefalo, D. R.; Kiely, A. F.; Wucherer, M.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 3139–3140. (c) Teng, X.; Cefalo, D. R.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 10779–10784. 36. Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5805–5809.

770 CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS REACTIONS 37. Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877–6882. 38. Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem. Int. Ed. 2006, 45, 7591–7595. 39. Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288–12290. 40. Cortez, G. A.; Baxter, C. A.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2007, 9, 2871–2874. 41. Endo-substituted [3.2.1]-bicycles are typically more reactive than the corresponding exodiastereomers due to increased ring strain. 42. For discussions regarding enantioselective formation of C-halogen bonds; see: (a) Ibrahim, H.; Togni, A. Chem. Comm. 2004, 1147–1155. (b) Gaunt, M. J.; Johansson, C. C. Chem. Rev. 2007, 107, 5596– 5605. (c) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903. (d) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 757–797. 43. Gillingham, D. G.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46, 3860–3864. 44. Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46, 4534–4538. 45. This concept has been applied to the synthesis of azabicycles through ring-closing metathesis; see: Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867–8878. 46. Although Mo complex 1b affords >98% conversion, the desired products are obtained in 90% yield

+ Cl3Si

R 60

59 ( 59/ 60 = 93/7) 1) EtOH/Et3 N 2) H2 O2 KF/KHCO3

OMe Ph2 P

OH R

(S )-MeO-mop (14)

(R )-61: 95% ee Scheme 9.12.

which enantioselectivity was determined to be 95% ee after Tamao oxidation, in a ratio of 7 to 93 (Scheme 9.12). High enantioselectivity as well as high regioselectivity has also been achieved with mop ligands in palladium-catalyzed asymmetric hydrosilylation of alkyl-substituted terminal alkenes. Recently spiro phosphoramidite ligand 23 was found to show a moderate enantioselectivity in the hydrosilylation of 1-hexene [19b]. Catalytic system of palladium/MeO-mop also showed high enantioselectivity and catalytic activity in the hydrosilylation of cyclic alkenes, such as norbornene and bicyclo[2.2.2]octene, 2,5-dihydrofuran, and norbornadiene [7c,36]. The hydrosilylation of norbornene (62) gave exo-adduct exclusively (Scheme 9.13) The hydrosilylated product was converted to exo-2-norbornanol (64) or endo-2-bromonorbornane (65) via the corresponding pentafluorosilicate. Chiral ferrocenylmonophosphines in addition to MeO-mop (14) were found to be effective ligands for the reaction [15e,f]. Planar chiral

9.2. ASYMMETRIC HYDROSILYLATION OF ALKENES 783

Pd/L*

+ HSiCl 3

KF SiCl3 H (1R,2R,4S )- 63

62

MCPBA

K2

SiF5

OH

or NBS

H

or Br

H 64

Me N N

Fe

H 65

R

PAr2

20

20a: R = Mes, Ar = Ph 20b: R = 9-Anthryl, Ar = Ph 20c: R = 2,4,6-(MeO)3 C6 H4 , Ar = Ph 20d: R = Mes, Ar = 3,5-(CF3 )2 C 6H 4 Scheme 9.13.

TABLE 9.5. Palladium-Catalyzed Asymmetric Hydrosilylation of Norbornene (62) with Trichlorosilane Entry Ligand L*

Catalyst (mol % Pd)

Temp (°C)

Time (h)

Yield (%)

1. (R)-(S)-ppfa (11)

0.01

70

40

2. (R)-(S)-20a

0.1

0

3. (R)-(S)-20b

0.1

4. (R)-(S)-20c

% ee

References

53

53

[7c]

56

91

[15e],[15f]

25

54

81

[15e],[15f]

0.1

0

30

82

[15e],[15f]

5. (R)-(S)-20d

0.1

0

59

99.5

[15e],[15f]

6. (R)-MeO-mop (14)

0.01

0

24

100

93

[36a]

7. (R)-MeO-mop (14)

0.01

−20

72

99

96

[36a]

pyrazole-containing ferrocenyl ligand 17 showed excellent enantioselectivities up to 99.5% ee (Table 9.5). Double stereoselection in the hydrosilylation of norbornadiene with palladium/ (R)-MeO-mop (14) enabled the disilylnorbornane 68a to reach more than 99% ee (Scheme 9.14) [36]. The reaction of norbornadiene (66) with 1.0 equiv of trichlorosilane followed by oxidation gave (1R,4R,5S)-exo-5-hydroxy-2-norbornene (67b) with 95% ee. In the reaction with 2.5 equiv of trichlorosilane, both double bonds in norbornadiene were hydrosilylated independently to give chiral disilylnorbornane 68a and the mesoisomer 69 in a ratio of 18 to 1. Tamao oxidation of the chiral isomer 68a provided the corresponding diol 68b with higher than 99% ee. This double hydrosilylation of norbornadiene has been repaid attention recently because of utilization of the enantiomerically pure diol 68b for asymmetric synthesis of (+)-sparteine (70), chiral diamine (71), and chiral norbornadiene ligand (72) [37].

784

ASYMMETRIC HYDROSILYLATION OF CARBON–CARBON DOUBLE BONDS

HSiCl3 (2.5 equiv)

HSiCl3 (1.0 equiv)

Pd/(R )-MeO-mop (14) (0.1 mol %)

Pd/(R )-MeO-mop (14) (0.1 mol %)

X X

68a: X = SiCl3 68b : X = OH

66

67a: X = SiCl3 67b : X = OH

>99% ee Cl3 Si

X

95% ee SiCl3

69

N H

N

NH2 NH2

70

71

Ph

Ph 72

Scheme 9.14.

A chiral yttrium hydride complex showed its high catalytic activity and enantioselectivity in asymmetric hydrosilylation of norbornene (Scheme 9.15) [38]. The reaction with phenylsilane in the presence of the chiral yttrium hydride 73, a d0 metal complex with non-Cp ligands, produced the corresponding exo-product 75 of 90% ee.

SiR3 OC4H8 N Me

Y N

SiR 3 R 3Si OC 4 H8 N N H Y Y H N N C4 H 8O SiR3 R3 Si 74

PhSiH3

OC4H8 SiR3

PhSiH2 CH 3

73

SiR 3 = SiMe 2Bu-t SiH 2Ph

PhSiH 3 62

73 (3 mol %) rt, 48 h, 100% yield

H 75

90% ee

Scheme 9.15.

Recently the first chirality transfer from silicon to carbon in a reagent-controlled palladium-catalyzed hydrosilylation of norbornenes with perfect stereoselectivity has been reported using chiral hydrosilane reagents (Scheme 9.16) [39]. Asymmetric amplification was observed in the reaction of norbornene with a chiral silane having siliconcentered chirality. The hydrosilylation of norbornene catalyzed by the palladium catalyst 78 with the chiral silane (R)-76 having 85% ee was found to form the hydrosilylated product 77 of 93% ee in good yield and with perfect diastereoselection.

9.2. ASYMMETRIC HYDROSILYLATION OF ALKENES 785

78

H Si

+

62

Si

77: 93% ee

(R )-76: 85% ee CF3

CH 3

N Pd N

OEt 2

B

CF3

4

78: [Pd(Me)(phen)(OEt2 )]+[BAr 4]– Scheme 9.16.

9.2.4. Asymmetric Intramolecular Hydrosilylation Asymmetric synthesis of optically active polyols from allylic alcohols has been achieved effectively by rhodium-catalyzed intramolecular hydrosilylation-oxidation of (allyloxy) hydrosilanes (Scheme 9.17). Rh/(R,R )-diop (5) (2 mol %) O

SiR 2H

30°C

O

79

Ph

Si H

Rh/(S )-binap (2 mol %)

Ph

OH

Ph

R2 Si

25°C

OH

81: Up to 93% ee

80

O 82

SiR2

O 83

OH

OH

84: 97% ee

PPh 2 PPh 2

(S )-binap (85)

Scheme 9.17.

The intramolecular hydrosilylation of hydrosilyl ethers 79 of di(2-propenyl)methanol with rhodium/(R,R)-diop (5) catalyst, followed by oxidation, gave the corresponding diol 81 of up to 93% ee [40]. High enantioselectivities were also observed in the intramolecular hydrosilylation of hydrosilyl ethers 82 of allyl alcohols in the presence of rhodium/ (S)-binap (85) catalyst to produce eantiomerically enriched diol 84 [41].

786


9.2.5. Asymmetric Cyclization/Hydrosilylation Asymmetric cyclization and hydrosilylation of α,ω-diunsaturated compounds, such as 1,6-dienes and 1,6-enynes, provides an efficient method for the synthesis of optically active functionalized carbocycles. The tandem reaction of diallylmalonate 86 in the presence of a cationic palladium catalyst 88 coordinated with a chiral pyridine-oxazoline ligand proceeded with high diastereoselectivity to give the corresponding trans-substituted cyclopentane 87 of 90% ee (Scheme 9.18) [42].

t-BuO2 C

+ HSiEt3

t-BuO2 C

(R )-88, NaBAr 4

t-BuO2C

–40°C

t-BuO2C

86

CH 3

87: 98% de, 90% ee

i-Pr O

SiEt3

Me

N Pd N

Cl

88

Scheme 9.18.

Enantioselective cyclization/hydrosilylation of 1,6-diynes catalyzed by a cationic rhodium complex of chiral bisphosphine ligands was reported to give the hydrosilylated alkylidenecyclopentanes with high enantioselectivity (Scheme 9.19) [43]. The reaction of enyne 89 with triethylsilane by cationic rhodium and (R)-biphemp (91) afforded the hydrosilylated alkylidene cyclopentane 90 in 92% ee. Recently a spiro diphoshine (R)sdp (94) was found to be an effective ligand for rhodium-catalyzed asymmetric hydrosilylation/cyclization of 1,6-enynes (Scheme 9.19) [44]. Nickel-catalyzed asymmetric cyclization of ω-formyl-1,3-dienes in the presence of hydrosilanes provides another method for the synthesis of chiral carbocycles (Scheme 9.20). In the cyclization of 1,3-dienes with a tethered formyl group (95) in the presence of triethoxysilane, five-membered carbocycle 96a of 73% ee was obtained exclusively by a zerovalent nickel complex of (2R,5R)-2,5-dimethyl-1phenylphospholane 97 [45]. Asymmetric cyclization/hydrosilylation of 1,5-dienes by a chiral yttrocene catalyst 100 having binol moieties was found to give five-membered carbocycles with low to moderate enantioselectivities (Scheme 9.21) [46].

9.3. ASYMMETRIC HYDROBORATION OF ALKENES Asymmetric hydroboration of olefins catalyzed by chiral rhodium catalysts provides optically active organoborane intermediates in organic synthesis [47]. The carbon–boron bond in the enantiomerically enriched organoboranes has been further transformed to several functional groups by subsequent carbon–oxygen, carbon–carbon, boron–

9.3. ASYMMETRIC HYDROBORATION OF ALKENES 787

Me

MeO2 C MeO2 C

[Rh(cod)2 ]SbF6 biphemp (5 mol %)

+ HSiEt 3

70°C

Me MeO 2C MeO 2C

SiEt 3 * 90: 92% ee

89 Me Me

PPh2 PPh 2 (R )-biphemp ( 91 )

H Ts N

+

H

[Rh(cod)2 ]BF 4 sdp (5 mol %)

HSiEt3

SiEt 3

Ts N

70°C

*

93: 98% ee

92 PPh 2 PPh2 (R )-sdp (94) Scheme 9.19.

MeO2 C

CHO

MeO2 C

+ HSi(OEt) 3

Ni(cod) 2 (R,R )-97 (10 mol %) MeO2 C –30°C

OSi(OEt)3 +

MeO2 C

MeO2 C

96a: 73% ee

95

OSi(OEt)3

MeO2 C

96b

P Ph (R,R )-97

Scheme 9.20.

[YL*] (2 mol %) +

PhSiH3

rt

98

SiH 2Ph

99: 50% ee Me3 Si Bu-t

[YL*] =

*

O Si O Me 3Si

Y H Bu-t

100 Scheme 9.21.

2

788


OH Ar CO2 H Ar +

Ar

chiral Rh cat O

B

O

O

B

CH 2OH

O

Ar

H

Ar

NH2 Ar

Scheme 9.22.

carbon, or carbon–nitrogen bond–forming reactions with retention of stereochemistry (Scheme 9.22) [47,48]. The first catalytic asymmetric hydroboration of norbornene (62) and 2-tert-butylpropene (101) with catecholborane (102) in the presence of a rhodium coordinated with chiral (R,R)-diop (5) or (S,S)-bdpp (105) was reported to give optically active 2-hydroxynorbornane (103) and 2,3,3-trimethylbutanol (104), respectively, after the treatment with an alkaline hydrogen peroxide solution (Scheme 9.23) [49].

OH 62

+ Me

O

1) [RhCl(cod)]2, L*, –25°C

O 102

2) H 2O 2, NaOH

H B

t -Bu

O

OH

104 H PPh 2

PPh 2 PPh 2 PPh 2 H (R,R )-diop (5) (S,S )-bdpp (105) O

Me t-Bu

101 L* =

103 H

olefin L* yield (%) 62 (R,R )-diop (5) 72 h >99 101 (R,R )-diop (5) 72 h >99 62 (S,S )-bdpp (105) 6 h >95

% ee 57 (R ) 69 (R ) 80 (R )

Scheme 9.23.

While using chiral rhodium catalysts complexed with chiral ligands and an achiral hydroborating agent is the most common approach for asymmetric hydroboration, another way of utilizing chiral hydroboranes has been reported in the combination with achiral rhodium catalysts. The hydroboration of 4-methoxystyrene (106) with a chiral borane 107 derived from pseudoephedrine in the presence of achiral rhodium catalysts gave the corresponding secondary alcohol 108a in 76% ee with a reasonable regioselec-


Ph + MeO 106

Me

O

NMe

B H 107

OH

1) [Rh(nbd)(ligand)]OTf (1 mol %), 20°C

OH +

2) H2 O2 , NaOH

MeO

MeO 108b

108a

ligand 108a/108b/109 % ee of 108a dppf 82/14/ 4 76 (S )-binap ( 85) 42/28/30 83

+ MeO 109

Scheme 9.24.

tivity and chemoselectivity (Scheme 9.24) [50]. Double asymmetric induction with both chiral Rh/(S)-binap catalyst and chiral borane 107 did not lead to significantly improved enantioselectivities. The reaction of vinylarenes with catecholborane has been most extensively investigated in the rhodium-catalyzed asymmetric hydrosilylation. As the first example of asymmetric hydroboration of styrene (6), a cationic rhodium/(R)-binap (85) complex was reported to catalyze the hydroboration at −78°C with complete branch selectivity to give 1-phenylethanol (8) with 96% ee after oxidation, with the regioselectivity being opposite to that observed in uncatalyzed reactions (Scheme 9.25) [51].

Ph

+ H B

O

1) [Rh(cod)2 ]BF4 , (R )-binap

O

2) H 2O2 , NaOH

OH Ph 8: 96% ee

6 PPh2 PPh2

(R )-binap (85)

Scheme 9.25.

The high regio- and enantioselectivities have been achieved by utilizing various chiral ligands including P,P-type ligands, P,N-type bidentate ligands, and monophosphines (Table 9.6). In addition to binap, the effective P,P-type ligands for the reaction of vinylarenes include josiphos (110), a new C2-symmetrical diphophine 113, and taddol-derived phosphine–phosphite 114. In the hydroboration of styrene with catecholborane, the planar chiral ferrocenyldiphosphine josiphos (110) showed 91.5% ee at −70°C with excellent regioselectivity [52]. Dendritic josiphos derivatives showed a similar selectivity with the parent ligand, and a josiphos-type ligand, where the original methyl group was changed to ethyl, was found to reduce the performance of the catalyst in the reaction [53].

790


TABLE 9.6. Rh-Catalyzed Asymmetric Hydroboration of Styrene (6) with Catecholborane Me Fe

CHPh 2

PPh2

PCy 2

Fe

Fe

PPh 2

PPh 2 (R)-(S)-josiphos (110)

PCy 2

PPh 2 PPh 2

PCy 2

CHPh2

(−)-111

(R,R)-113

(S,S)-112

Ph O

Ph

O

O P

O

O

Ph Ph

N

PPh 2

(R,R)-114

N

N

PPh2

(S)-quinap (115)

PPh2

O P

O

( R)-116

O

(S,S)-117

Me Ph

O

Me

Ph

N

N N

N PPh2

Ph

Me Me

N

PPh2

N

PPh2 N

N Ph2 P

Fe

Fe

PPh2 (R)-118

Entry Ligand L*

(S)-119

Catalyst (mol % Rh)

(R)-120

Solvent

(S)-(R)-121

Temp (°C)

Time (h)

Yield (%)

(R)-(R)-122

% ee

References

1. (R)-binap (85)

A (2)

DME

−78

2

91

96 (R)

[51]

2. (R)-(S)-josiphos (110)

B (2)

DME

−70

10

65

92 (R)

[52]

3. (−)-111

A (0.75)

DME

84 (S)

[54a]

A (2)

DME

−60 rt

12

4. (S,S)-112

1

100

85 (R)

[54b]

5. (R,R)-113

A (1)

DME

−35

3

85

92 (S)

[55]

6. (R,R)-114

A (2)

DME

63

91 (R)

[56]

C (0.2)

THF

−78 20

3.5

7. (S)-quinap (115)

8

75

91 (S)

[58]

8. (R)-116

C (1)

THF

rt

2

70

67 (R)

[59a],[59b]

9. (S,S)-117

C (1)

THF

rt

2

70

68 (S)

[59c]

C (1)

THF

rt

63 (R)

[59d]

10. (R)-118 11. (S)-119

C (1)

Toluene

rt

2

73

92 (R)

[60]

12. (R)-120

A (1)

THF

0

18

72

90 (R)

[61]

13. (S)-(R)-121

A (1)

THF

20

5

91

95 (R)

[62]

14. (R)-(R)-122

A (1)

THF

−45

16

64

92 (R)

[63]

A, [Rh(cod)2]BF4; B, [Rh(nbd)2]BF4; C, [Rh(cod)(L*)]OTf.


Ferrocenyldiphosphines 111 and 112 having only planar chirality were reported to show good enantioselectivities at lower temperatures [54]. A new C2-symmetrical diphophine 113, readily available from the corresponding 1,2-diol using a tandem [2,3] sigmatropic rearrangement of diphenylphosphinites, was applied to the hydroboration of styrene to show 92% ee at −35°C with perfect regioselectivity [55]. Phophine–phosphite ligands, suitable for screening catalytic system by a modular approach, have been employed in the hydroboration. The phosphine–hosphite ligand 114 derived from taddol was demonstrated to be the best ligand among the modular ligand library to give 91% ee at −78°C with high regioselectivity [56]. Recently, enantioselective hydroboration, of which catalytic system was optimized by screening a library of chiral phosphine–phosphite ligands, was applied in a total synthesis [57]. Asymmetric hydroboration/oxidation of styrene with catecholborane by rhodium complexes of quinap (115), the first successful axially chiral P,N-type ligands in asymmetric catalysis, proceeded with excellent regioselectivity to give 1-phenylethanol of 91% ee at 20°C [58]. While P,P-type ligands, such as binap, required low temperature for a high enantioselectivity, the quinap-based ligands showed high enantioselectivity at ambient temperature. Axially chiral P,N-type ligands, such as 116 having phenanthridine N-donor, 117 having a binol moiety, and 118 having quinazoline N-donor, were also found to give 63–68% ee in the reaction of styrene at room temperature [59]. An atropisomeric P,N-type ligand 119 readily available by facile resolutions was developed to show comparable regio- and enantioselectivities with quinap in the hydroboration of styrene [60]. An atropisomeric P,N ligand 120 was also applied to give 90% ee at 0°C with excellent regioselectivity [61]. P,N-type ligands having planar chirality were proven to be good ligands in the hydroboration of vinylarene. The hydroboration of styrene with pyrazole-containing ferrocenyl ligand 121 gave an excellent enantioselectivity at ambient temperature, although the regioselectivity was not good [62]. A planar chiral ferrocenyl ligand 122 containing 2-quinolyl moiety was found to give 92% ee at −45°C with modest regioselectivity [63]. Theoretical calculations for regio- and enantioselectivities, recoverable catalyst systems by immobilization, and application to material science have broadened the scope of the asymmetric hydroboration of vinylarenes [64]. Recently, asymmetric hydroboration has focused on new substrates, such as mesohydrazines, cyclopropenes, and heterofunctional allylic substrates, and a new hydroborating reagent, such as pinacolborane. It was reported that rhodium- and iridium-catalyzed asymmetric hydroboration with catecholborane was using meso-bicyclic hydrazines 123 as a substrate (Scheme 9.26) [65]. Asymmetric induction was accomplished by desymmetrization of meso-substrate, and a reversal of enantioselectivity was observed between rhodium and iridium catalysts. A cyclopropene 126 was employed as a substrate in rhodium-catalyzed asymmetric hydroboration with pinacolborane (127) as a new hydroborating agent (Scheme 9.27) [66]. Using pinacolborane rather than catecholborane enhanced the diastereoselectivity of the reaction by steric control between the substrate and the hydroborating agent. A range of bisphosphine ligands were found to give excellent diastereo- and enantioselectivities of the reaction, for example, (R)-binap (85, 94% ee), (S,S)-norphos (129, >99% ee), and (R)-phanephos (130, 97% ee). An allylsulfone 131 containing an electron-deficient heterofunctionality at the allylic position was examined to give almost complete regioselectivity for the secondary alcohol 132, with moderate enantioselectivities in asymmetric hydroboration/oxidation by rhodium catalysts of chiral bisphosphines (Scheme 9.28) [67].

792


1) [MCl(cod)]2 (2 mol % M), L*

O CO2 Bn N + H B N CO 2Bn O 123 O

L* = (S,S )-bdpp(105)

CO 2Bn N CO 2 Bn N

2) H 2O2 , NaOH

124

H PPh 2 PPh 2

O

PPh 2 PPh 2

HO

H (S,S )-diop (5)

PPh2

L* 105 105 5 5 125

M Rh Ir Rh Ir Ir

DME –50°C, 0.5 h 0°C to rt, 7 h DME DME –50°C, 0.5 h rt, 7 h DME 0°C, 4 h THF

yield % ee of 124 91% 84 (R ) 30% 32 (S ) 46% 54 (S ) 40% 44 (R ) 76% 71 (S)

N

(R,R )-125

Scheme 9.26.

Me

H + H B

MeO 2C

[RhCl(cod)]2 (3 mol %), L*

O

THF, rt

Me

PPh 2 H L* = (S,S )-norphos (129)

B O O 128

PPh2

PPh 2

H

MeO 2C

127

126

H

O

PPh2

L* (R )-binap (85) (S,S )-norphos (129) (R )-phanephos (130)

yield % ee of 128 96% 94 (1S,2R ) 86% >99 (1R,2S ) 89% 97 (1R,2S )

(R )-phanephos (130)

Scheme 9.27.

O

1) [RhCl(cod)]2, (R )-binap (85)

O

2) H2O 2, NaOH

SO2Ph + H B 131

SO2 Ph OH 132, 38% ee

Scheme 9.28.

Pinacolborane as a hydroborating agent in rhodium-catalyzed asymmetric hydroboration of vinylarene instead of catecholborane has been investigated recently. The reaction of styrene using josiphos ligand with pinacolborane was more enantioselective than with catecholborane (Scheme 9.29) [68]. In addition, the opposite enantiomer was obtained by the same catalytic systems except for the hydroborating agents.

9.4. ASYMMETRIC HYDROALUMINATION AND HYDROSTANNATION OF ALKENES

B(OR)2

HBPin (127) or HBCat (102) Ph

Ph

[Rh(cod)2 ]BF4, (R )-(S )-josiphos THF, 25°C

6

793

133

Me PCy2 Fe

HBPin (127) HBCat (102)

PPh 2

% ee of 133 84 (S ) 60 (R )

(R)-(S)-josiphos (110) Scheme 9.29.

Chiral monodentate phosphite 134 and phosphoramidite 135 derived from taddol were examined to afford high enantioselectivity and moderate regioselectivity in rhodium-catalyzed asymmetric hydroboration of vinylarenes with pinacolborane (Scheme 9.30) [69].

1) [RhCl(nbd)]2 (2 mol % Rh), L* DME, rt, 17 h

O Ph

O O Ph

8

Ph O P O O Ph

L* = (S,S,R,S)-134

Ph

2) H 2 O2, NaOH

O 127

6 Ph

OH

+ H B

Ph

Ph O O Ph

Ph Ph O P N Bn O

L* yield % ee of 8 134 75% 95 (R ) 135 79% 96 (R )

Ph

(S,S)-135 Scheme 9.30.

9.4. ASYMMETRIC HYDROALUMINATION AND HYDROSTANNATION OF ALKENES Hydroalumination and hydrostannylation of olefins have attracted significant interests for their synthetic utility [47e,70]. While asymmetric hydrosilylation and hydroboration of alkenes catalyzed by transition metal are well known, examples of asymmetric versions of catalytic hydroalumination and hydrostannation of alkenes using transition metal catalysts have been rare to date. Highly enantioselective catalytic hydroalumination of oxabicyclic alkenes was reported as using chiral nickel catalyst [71]. The reaction of 136 with iso-Bu2AlH catalyzed by a nickel complex of (R)-binap at rt gave the ring-opening product 137 in 97% ee (Scheme 9.31).

794


OMe

OMe O

OMe + H Al(Bu-i) 2

Ni(cod)2 (14 mol %), (R )-binap (85)

OMe

Toluene, rt,1 h

OH 137: 97% yield 97% ee

136 Scheme 9.31.

The first example of catalytic enantioselective hydrostannation of cyclopropenes using chiral rhodium catalysts was reported recently [72]. The reaction of 126 with Me3SnH promoted by rhodium catalysts coordinated with chiral diphenylphosphinobenzoic acid-derived ligand 139 at −30°C afforded the trans-cyclopropylstannane 138 in 94% ee with excellent regioselectivity (Scheme 9.32).

Me

H

MeO2 C

+ H SnMe3

[RhCl(cod)]2 (3 mol %), 139 THF, –30 °C, 45 min

126

Ph

Ph

O

O

Me MeO2 C

SnMe 3 H

138: 90% yield 94% ee

NH HN PPh 2 Ph2P (R,R )-139 Scheme 9.32.

9.5. CONCLUSION During the last decade, catalytic asymmetric hydrosilylation and hydroboration of carbon–carbon double bonds have been developed to expand their synthetic utilities by exploiting new catalytic systems including substrates, reagents, and catalysts, as well as to achieve very high catalytic activity and enantioselectivity. In the hydrosilylation reaction, scopes of substrates have been broadened to enable new utilizations of asymmetric hydrosilylation. For example, asymmetric hydrosilylation of olefins has been extended to palladium-catalyzed hydrosilylation of 1,3-enynes, giving optically active allenylsilanes and rhodium-catalyzed intramolecular cyclization/hydrosilylation of 1,6-dienes and 1,6-enynes giving a cyclic hydrosilylated product. Cyclopropenes, meso-hydrazines, and heterofunctional allylic compounds as new substrates and pinacolborane as a new hydroborating reagent have been successfully applied in the hydroboration reaction. It has been also discovered that hydrostannanes are added to carbon–carbon double bonds asymmetrically in the presence of a chiral catalyst. These asymmetric heterofunctionalizations of olefin are expected to be applied to industrial production of useful chiral compounds in near future.

REFERENCES 795

REFERENCES 1. (a) Ojima, I. In The Chemistry of Organic Silicon Compounds (Eds. Patai, S.; Rappoport, Z.). Chichester: John Wiley, 1989; p. 1479. (b) Brunner, H.; Nishiyama, H.; Itoh, K. In Catalytic Asymmetric Synthesis (Ed. Ojima, I.). New York: Wiley-VCH, 1993; p. 303. (c) Nishiyama, H.; Itoh, K. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; p. 111. (d) Hayashi, T. In Comprehensive Asymmetric Catalysis (I) (Eds. Jacobson, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin Heidelberg: Springer-Verlag, 1999; p. 319. (e) Tang, J.; Hayashi, T. In Catalytic Heterofunctionalization (Eds. Togni, A.; Grützmacher, H.). Weinheim: Wiley-VCH, 2001; p. 73. (f) Yamamoto, K.; Hayashi, T. In Transition Metals for Organic Synthesis (II) (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; p. 167. (g) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453. (h) Hayashi, T.; Yamasaki, K. In Comprehensive Organometallic Chemistry III, Vol. 10 (Eds. Crabtree, R. H.; Mingos, D. M. P.). Oxford: Elsevier Ltd., 2007; p. 815. 2. (a) Tamao, K. In Advances in Silicon Chemistry (Ed. Larson, G. L.). London: JAI Press, 1996; p. 1. (b) Tamao, K. In Organosilicon and Bioorganosilicon Chemistry (Ed. Sakurai, H.). Chichester: Ellis Horwood, 1985; p. 231. 3. (a) Hosomi, A.; Sakurai, H. J. Org. Synth. Chem. Jpn. 1985, 43, 406. (b) Kobayashi, S.; Nishino, K. J. Org. Chem. 1994, 59, 6620. (c) Masse, C. E.; Pane, J. S. Chem. Rev. 1995, 95, 1293. (d) Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942. 4. Marciniec, B. Comprehensive Handbook on Hydrosilylation. Oxford: Pergamon, 1992. 5. (a) Yamamoto, K.; Hayashi, T.; Kumada, M. J. Am. Chem. Soc. 1971, 93, 5301. (b) Yamamoto, K.; Hayashi, T.; Zembayashi, M.; Kumada, M. J. Organomet. Chem. 1976, 118, 161. (c) Yamamoto, K.; Uramoto, Y.; Kumada, M. J. Organomet. Chem. 1971, 31, C9. (d) Yamamoto, K.; Hayashi, T.; Uramoto, Y.; Ito, R.; Kumada, M. J. Organomet. Chem. 1976, 118, 331. 6. (a) Kiso, Y.; Yamamoto, K.; Tamao, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4373. (b) Yamamoto, K.; Kiso, Y.; Ito, R.; Tamao, K.; Kumada, M. J. Organomet. Chem. 1981, 210, 9. 7. (a) Hayashi, T. In Ferrocenes (Eds. Togni, A.; Hayashi T.). Weinheim: VCH, 1995; p. 105. (b) Hayashi, T. Pure Appl. Chem. 1988, 60, 7. (c) Hayashi, T.; Tamao, K.; Katsuro, Y.; Nakae, I.; Kumada, M. Tetrahedron Lett. 1980, 21, 1871. (d) Okada, T.; Morimoto, T.; Achiwa, K. Chem. Lett. 1990, 999. (e) Marinetti, A. Tetrahedron Lett. 1994, 35, 5861. (f) Marinetti, A.; Ricard, L. Organometallics 1994, 13, 3956. 8. Cullen, W. R.; Han, N. F. J. Organomet. Chem. 1987, 333, 269. 9. (a) Hayashi, T. Acta Chem. Scand. 1996, 50, 259. (b) Hayashi, T. Acc. Chem. Res. 2000, 33, 354. 10. Kitayama, K.; Uozumi, Y.; Hayashi, T. J. Chem. Soc., Chem. Commun. 1995, 1533. 11. Uozumi, Y.; Kitayama, K.; Hayashi, T. Tetrahedron: Asymmetry 1993, 4, 2419. 12. Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101. 13. (a) Hayashi, T.; Hirate, S.; Kitayama, K.; Tsuji, H.; Torii, A.; Uozumi, Y. Chem. Lett. 2000, 1272. (b) Hayashi, T.; Hirate, S.; Kitayama, K.; Tsuji, H.; Torii, A.; Uozumi, Y. J. Org. Chem. 2001, 66, 1441. 14. Uozumi, Y.; Tsuji, H.; Hayashi, T. J. Org. Chem. 1998, 63, 6137. 15. (a) Bringmann, G.; Wuzik, A.; Breuning, M.; Henschel, P.; Peters, K.; Peters, E.-M. Tetrahedron: Asymmetry 1999, 10, 3025. (b) Gladiali, S.; Pulacchini, S.; Fabbri, D.; Manassero, M.; Sansoni, M. Tetrahedron: Asymmetry 1998, 9, 391. (c) Dotta, P.; Kumar, P. G. A.; Pregosin, P. S. Organometallics 2004, 23, 2295. (d) Yasuike, S.; Kawara, S.; Okajima, S.; Seki, H.; Yamaguchi, K.; Kurita, J. Tetrahedron Lett. 2004, 45, 9135. (e) Pioda G.; Togni, A. Tetrahedron: Asymmetry 1998, 9, 3903. (f) Togni, A.; Dorta, R.; Kollner, C.; Pioda, G. Pure & Appl. Chem. 1998, 70, 1477. (g) Weber I.; Jones, G. B. Tetrahedron Lett. 2001, 42, 6983. (h) Gibson, S. E.; Rendell, J. T.; Rudd, M. Synthesis 2006, 3631. 16. Tamura, M.; Fujihara, H. J. Am. Chem. Soc. 2003, 125, 15742. 17. (a) Woo, T. K.; Pioda, G.; Rothlisberger, U.; Togni, A. Organometallics 2000, 19, 2144. (b) Magistrato, A.; Woo, T. K.; Togni, A.; Rothlisberger, U. Organometallics 2004, 23, 3218. (c) Magistrato, A.; Togni, A.; Rothlisberger, U. Organometallics 2006, 25, 1151.

796


18. (a) Pedersen H. L.; Johannsen, M. Chem. Commun. 1999, 2517. (b) Pedersen H. L.; Johannsen, M. J. Org. Chem. 2002, 67, 7982. 19. (a) Jensen, J. F.; Svendsen, B. Y.; la Cour, T. V.; Pedersen, H. L.; Johannsen, M. J. Am. Chem. Soc. 2002, 124, 4558. (b) Guo, X.-X.; Xie, J.-H.; Hou, G.-H.; Shi, W.-J.; Wang, L.-X.; Zhou, Q.-L. Tetrahedron: Asymmetry 2004, 15, 2231. 20. Shimada, T.; Mukaide, K.; Shinohara, A.; Han, J. W.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 1584. 21. Tsuchiya, Y.; Uchimura, H.; Kobayashi, K.; Nishiyama, H. Synlett 2004, 2099. 22. Molander, G. A.; Dowdy, E. D.; Noll, B. C. Organometallics 1998, 17, 3754. 23. (a) Tsuji, J.; Hara, M.; Ohno, K. Tetrahedron 1974, 30, 2143. (b) Ojima, I.; Kumagai, M. J. Organomet. Chem. 1978, 157, 359. 24. (a) Hayashi, T.; Kabeta, K.; Yamamoto, T.; Tamao, K.; Kumada, M. Tetrahedron Lett. 1983, 24, 5661. (b) Hayashi, T.; Matsumoto, Y.; Morikawa, I.; Ito, Y. Tetrahedron: Asymmetry 1990, 1, 151. 25. Gustafsson, M.; Bergqvist, K.-E.; Frejd, T. J. Chem. Soc. Perkin Trans. 1 2001, 1452. 26. Kitayama, K.; Tsuji, H.; Uozumi, Y.; Hayashi, T. Tetrahedron Lett. 1996, 37, 4169. 27. Hayashi, T.; Han, J. W.; Takeda, A.; Tang, J.; Nohmi, K.; Mukaide, K.; Tsuji, H.; Uozumi, Y. Adv. Synth. Catal. 2001, 343, 279. 28. (a) Han, J. W.; Hayashi, T. Chem. Lett. 2001, 976. (b) Han, J. W.; Hayashi, T. Tetrahedron: Asymmetry 2002, 13, 325. 29. (a) Ohmura, H.; Matsuhashi, H.; Tanaka, M.; Kuroboshi, M.; Hiyama, T.; Hatanaka, Y.; Goda, K. J. Organomet. Chem. 1995, 499, 167. (b) Hiyama, T.; Matsuhashi, H.; Fujita, A.; Tanaka, M.; Hirabayashi, K.; Shimizu, M.; Mori, A. Organometallics 1996, 15, 5762. 30. (a) Hatanaka, Y.; Goda, K-I.; Yamashita, F.; Hiyama, T. Tetrahedron Lett. 1994, 35, 7981. (b) Ohmura, H.; Matsuhashi, H.; Tanaka, M.; Kuroboshi, M.; Hiyama, T.; Hatanaka, Y.; Goda, K. J. Organomet. Chem. 1995, 499, 167. (c) Hiyama, T.; Matsuhashi, H.; Fujita, A.; Tanaka, M.; Hirabayashi, K.; Shimizu, M.; Mori, A. Organometallics 1996, 15, 5762. (d) Hayashi, T.; Kabeta, K. Tetrahedron Lett. 1985, 26, 3023. 31. Hayashi, T.; Hengrasmee, S.; Matsumoto, Y. Chem. Lett. 1990, 1377. 32. Han, J. W.; Tokunaga, N.; Hayashi, T. Helv. Chim. Acta 2002, 85, 3848. 33. Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915. 34. Ogasawara, M.; Ito, A.; Yoshida, K.; Hayashi, T. Organometallics 2006, 25, 2715. 35. (a) Uozumi, Y.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 9887. (b) Uozumi, Y.; Kitayama, K.; Hayashi, T.; Yanagi, K.; Fukuyo, E. Bull. Chem. Soc. Jpn. 1995, 68, 713. 36. (a) Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185. (b) Uozumi, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2335. 37. (a) Smith, B. T.; Wendt, J. A.; Aubé, J. Org. Lett. 2002, 4, 2577. (b) Berkessel, A.; Schröder, M.; Sklorz, C. A.; Tabanella, S.; Vogl, N.; Lex, J.; Neudörfl, M. J. Org. Chem. 2004, 69, 3050. (c) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. 38. Gountchev, T. I.; Tilley, T. D. Organometallics 1999, 18, 5661. 39. (a) Oestreich, M.; Rendler, S. Angew. Chem. Int. Ed. 2005, 44, 1661. (b) Rendler, S.; Oestreich, M.; Butts, C. P.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2007, 129, 502. 40. Tamao, K.; Tohma, T.; Inui, N.; Nakayama, O.; Ito, Y. Tetrahedron Lett. 1990, 31, 7333. 41. (a) Bergens, S. E.; Noheda, P.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1992, 114, 2121. (b) Bergens, S. E.; Noheda, P.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1992, 114, 2128. 42. (a) Perch, N. S.; Widenhoefer, R. A. J. Am. Chem. Soc. 1999, 121, 6960. (b) Perch, N. S.; Pei, T.; Widenhoefer, R. A. J. Org. Chem. 2000, 65, 3836. (c) Pei, T.; Widenhoefer, R. A. Tetrahedron Lett. 2000, 41, 7597. 43. Chakrapani, H.; Liu, C.; Widenhoefer, R. A. Org. Lett. 2003, 5, 157. 44. Fan, B.-M.; Xie, J.-H.; Li, S.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem. Int. Ed. 2007, 46, 1275.

REFERENCES 797

45. (a) Sato, Y.; Saito, N.; Mori, M. J. Am. Chem. Soc. 2000, 122, 2371. (b) Sato, Y.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 9310. 46. Muci, A. R.; Bercaw, J. E. Tetrahedron Lett. 2000, 41, 7609. 47. (a) Fu, G. C.; Evans, D. A.; Muci, A. R. In Advances in Catalytic Process, Vol. 1, (Ed. Doyle, M. P.). London: JAI Press Inc., 1995; p. 95. (b) Burgess, K.; Van der Donk, W. A. In Advances in Asymmetric Synthesis (Ed. Stephenson, G. R.). London: Chapman & Hall, 1996; p 181. (c) Hayashi, T. In Comprehensive Asymmetric Catalysis (I), Vol. 1, (Eds. Jacobson, E. N.; Pfaltz A.; Yamamoto, H.). Berlin Heidelberg: Springer-Verlag, 1999; p. 351. (d) Carroll, A.-M.; O’Sullivan, T. P.; Guiry, P. J. Adv. Synth. Catal. 2005, 347, 609. (e) Guiry, P. J.; Coyne, A. G.; Carroll, A.-M. In Comprehensive Organometallic Chemistry III, Vol. 10. (Eds. Crabtree, R. H.; Mingos, D. M. P). Oxford: Elsevier Ltd., 2007; p 839. 48. Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M. Chem. Eur. J. 2000, 6, 1840. 49. (a) Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1988, 53, 5178. (b) Burgess, K.; Van der Donk, W. A.; Ohlmeyer, M. J. Tetrahedron: Asymmetry 1991, 2, 613. 50. Brown, J. M.; Lloyd-Jones, G. C. Tetrahedron: Asymmetry 1990, 1, 869. 51. (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426. (b) Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron: Asymmetry 1991, 2, 601. 52. Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F; Landert, H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062. 53. (a) Köllner, C.; Togni, A. Can. J. Chem. 2001, 79, 1762. (b) Yasuike, S.; Kofink, C. C.; Kloetzing, R. J.; Gommermann, N.; Tappe, K.; Gavryushin, A.; Knochel, P. Tetrahedron: Asymmetry 2005, 16, 3385. 54. (a) Reetz, M. T.; Beuttenmüller, E. W.; Goddard, R.; Pastó, M. Tetrahedron Lett. 1999, 40, 4977. (b) Kang, J.; Lee, J. H.; Kim, J. B.; Kim, G. J. Chirality 2000, 12, 378. 55. Demay, S.; Volant, F.; Knochel, P. Angew. Chem. Int. Ed. 2001, 40, 1235. 56. Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.; Schmalz, H.-G. Adv. Synth. Catal. 2002, 344, 868. 57. Werle, S.; Fey, T.; Neudörfl, J. M.; Schmalz, H.-G. Org. Lett. 2007, 9, 3555. 58. (a) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743. (b) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Chem. Commun. 1995, 395. (c) Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320. 59. (a) Valk, J.-M.; Claridge, T. D. W.; Brown, J. M.; Hibbs, D.; Hursthouse, M. B. Tetrahedron: Asymmetry 1995, 6, 2597. (b) Valk, J.-M.; Whitlock, G. A.; Layzell, T. P.; Brown, J. M. Tetrahedron: Asymmetry 1995, 6, 2593. (c) Korostylev, A.; Gridnev, I.; Brown, J. M. J. Organomet. Chem. 2003, 680, 329. (d) McCarthy, M.; Guiry, P. J. Polyhedron 2000, 19, 541. 60. Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem. Int. Ed. 2004, 43, 5971. 61. Kwong, F. Y.; Yang, Q.; Mak, T. C. W.; Chan, A. S. C.; Chan, K. S. J. Org. Chem. 2002, 67, 2769. 62. (a) Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 1995, 34, 931. (b) Burckhardt, U.; Hintermann, L.; Schnyder, A.; Togni, A. Organometallics 1995, 14, 5415. (c) Schnyder, A.; Togni, A.; Wiesli, U. Organometallics 1997, 16, 255. 63. Kloetzing, R. J.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry 2003, 14, 255. 64. (a) Segarra, A. M.; Daura-Oller, E.; Claver, C.; Poblet, J. M.; Bo, C.; Fernandez, E. Chem. Eur. J. 2004, 10, 6456. (b) Segarra, A. M.; Guerrero, R.; Claver, C.; Fernandez, E. Chem. Commun. 2001, 1808. (c) Segarra, A. M.; Guerrero, R.; Claver, C.; Fernandez, E. Chem. Eur. J. 2003, 9, 191. (d) Segarra, A. M.; Guerrero, R.; Claver, C.; Fernandez, E. Tetrahedron: Asymmetry 2003, 14, 1611. (e) Polarz, S.; Kuschel, A. Adv. Mater. 2006, 18, 1206. 65. (a) Luna, A. P.; Bonin, M.; Micouin, L.; Husson, H.-P. J. Am. Chem. Soc. 2002, 124, 12098. (b) Luna, A. P.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson, H.-P. J. Org. Chem. 2002, 67, 3522. (c) Bunlaksananusorn, T.; Luna, A. P.; Bonin, M.; Micouin, L.; Knochel, P. Synlett. 2003, 2240. 66. (a) Rubina, M.; Rubin, A.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198. (b) Rubin, A.; Gevorgyan, V. Synthesis 2004, 796.

798


67. (a) Lillo, V.; Fernandez, E. Tetrahedron: Asymmetry 2006, 17, 315. (b) Lillo, V.; Fernandez, E.; Segarra, M. Tetrahedron: Asymmetry 2007, 18, 911. 68. Crudden, C. M.; Hleba, Y. B.; Chen, A. C. J. Am. Chem. Soc. 2004, 126, 9200. 69. Moteki, S. A.; Wu, D.; Chandra, K. L.; Reddy, S.; Takacs, J. M. Org. Lett. 2006, 8, 3097. 70. Lautens, M.; Rovis, T. In Comprehensive Asymmetric Catalysis (I) (Eds. Jacobson, E. N.; Pfaltz A.; Yamamoto, H.). Berlin Heidelberg: Springer-Verlag, 1999; pp. 337. 71. Lautens, M.; Chiu, P.; Ma, S.; Rovis, T. J. Am. Chem. Soc. 1995, 117, 532. 72. (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2004, 126, 3688. (b) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566.

10 ASYMMETRIC CARBONYLATIONS Cyril Godard, Aurora Ruiz, Montserrat Diéguez, Oscar Pàmies, and Carmen Claver Department of Physical Chemistry and Inorganic Chemistry, Universitat Rovira i Virgili, Campus Sescelades, C/Marcel.li Domingo s/n 43007, Tarragona, Spain

10.1. INTRODUCTION Transition metal–catalyzed carbonylation is one of the most straightforward tools to obtain fine chemicals intermediates from alkenes and other unsaturated products. Together with asymmetric hydrogenation, asymmetric C–C bond formation, and asymmetric allylic substitutions, the asymmetric carbonylations are among the most challenging homogeneous processes. Their potential is still to be made the most of, perhaps because of the complexity of these reactions where aldehydes, esters, or acids can be formed from simple olefins and enantiomerically pure products or enantiomeric enrichment of one of the products can be obtained when the transition metal catalyst is modified with a chiral ligand. The most famous asymmetric carbonylation process is the Rh-catalyzed hydroformylation of alkenes, together with the Pd-catalyzed hydroxy- or alkoxycarbonylation of alkenes. There are, however, important differences between these processes, as the rhodium-catalyzed hydroformylation is of greater industrial interest than the palladium carbonylations. From the mechanistic point of view, rhodiumcatalyzed hydroformylation has been much more studied and understood than the palladium-catalyzed carbonylations maybe because of the stability of rhodium species, as well as the applicability of spectroscopic high-pressure (HP) nuclear magnetic resonance (NMR) techniques for the study of the intermediates and the early application of rhodium hydroformylation in industry as “oxo” process. As a result, the last developments in rhodium-catalyzed hydroformylation led to a very good control of the regioselectivity to the desired product as well as the preparation of practically enantiomerically pure aldehydes. Palladium-catalyzed carbonylations, both alkoxycarbonylation and hydroxycarbonylation, have also been widely studied but present more issues to obtain


800 ASYMMETRIC CARBONYLATIONS

simultaneous regio- and enantioselectivities. Palladium-catalyzed carbonylation offers, however, the interest of its application in CO/olefins copolymerization and terpolymerization, where the use of Pd catalyst modified with chiral ligands allows the control of the steroselectivity. This chapter deals with all these topics, describing the catalytic cycles proposed in the literature, the important facts concerning these reactions, and the catalytic systems used, together with the most important applications. The reactions are studied in separated sections, namely, the Rh-catalyzed hydroformylation, the Pdcatalyzed hydroxy- and alkoxycarbonylations, and co- and terpolymerization reactions due to the different features of such processes.

10.2. ASYMMETRIC HYDROFORMYLATION 10.2.1. Development of Chiral Hydroformylation Catalysts The hydroformylation reaction, which converts olefins into aldehydes, is the largest volume homogeneous transition metal–catalyzed reaction. This reaction has been extensively studied, and, nowadays, a number of efficient catalysts allow to control the regioselectivity of the reaction in terminal or internal aldehydes (Scheme 10.1) [1].

H 2/CO R

R * CHO

[Catalyst]

+

R

CHO

Scheme 10.1.

Hydroformylation has been applied in the synthesis of intermediates and in fine chemicals in particular in vitamins and in flavors and fragrances [2]. Due to the versatile chemistry of the aldehydes obtained through the hydroformylation reaction, further conversions into alcohols, amines, carboxylic acid derivatives, and other products are available. For this reason, “tandem reaction” sequences under hydroformylation conditions appear as a clean and economical method of obtaining functionalized organic molecules and constructing complex structures [2b,c]. The asymmetric version of the hydroformylation of olefins is one of the most straightforward synthetic strategies for the preparation of optically active aldehydes, which are versatile intermediates for the synthesis of many biologically active compounds and for other synthetic transformations [3]. However, the simultaneous control of chemo-, regio-, and enantioselectivity along the reaction makes the hydroformylation process one of the most challenging reactions from both academic and industrial points of view. To date, much effort in this field has been concentrated on the hydroformylation of vinylarenes as a route to obtain enantiomerically enriched 2-aryl propionic acids, the profen class of nonsteroidal drugs. Although less studied, the application of the asymmetric hydroformylation of other substrates shows remarkable potential for the production of fine chemicals [4]. Although the first highly enantioselective examples of asymmetric hydroformylation of styrene were reported by Consiglio et al. in 1991 and used Pt–Sn systems achieving an ee of 86%, the most successful asymmetric hydroformylation catalysts for this substrate were all based on rhodium [5]. Platinum catalysts have several disadvantages: low reaction rates, hydrogenation of the substrate, and low regioselectivity to the branched

10.2. ASYMMETRIC HYDROFORMYLATION 801

aldehyde. Several reports describe the state of the art in asymmetric hydroformylation with both rhodium and platinum systems [4b,6]. After the discovery of the high enantioselectivity provided by rhodium/diphosphite and rhodium/phosphine–phosphite systems, with total conversion in aldehydes and high regioselectivities, rhodium systems became the catalysts of choice for the asymmetric hydroformylation reaction. An important breakthrough in this field has been the characterization of intermediates in the asymmetric hydroformylation of styrene through in situ infrared (IR) and HP-NMR studies. These facts have provided important insights in the understanding of the reaction [1,6c]. 10.2.2. Mechanism for Rhodium-Catalyzed Hydroformylation The catalytic cycle for rhodium hydroformylation has been extensively studied mainly for the RhH(CO)(PPh3)3 catalysis. A general proposal including all the steps of the reaction is shown in Scheme 10.2 [1].

O C CO L Rh Rh CO L CO C 9 O L

L

H2

OC 2ae

H

L

Rh CO L

L

H

H Rh L CO

L

1

CO H

CH3 CH2

L

CO

2e e

CO

O

L

Rh CO

H

OC Rh L L 3c

C H

C2H4

L Rh L CO 3t

L OC H2

CH3 CH2

O C

CH3 CH2

O C

OC L Rh L Rh CO OC L L CO 8ee 8ae

CH 3 CH 2

O CO

L Rh CO L 7c

CH3 CH 2

C

L Rh CO

L Rh L

L OC

CH3 CH2 Rh CO L

L L

CH3 CH2

L L 4

C L R C

L

CO 7t

L 4ae

CH3 CH2

O

C

H Rh

5c CO

Rh CO CO

Scheme 10.2.

With PPh3 as the ligand, a common starting complex is the species RhH(PPh3)3CO 1, which, under 1 bar of carbon monoxide, forms the complexes 2ee and 2ae, containing two phosphine ligands in equatorial positions or one in apical and the other ligand in an equatorial position. Dissociation of either equatorial L or equatorial CO from 1 or 2 leads to the square planar intermediates 3c and 3t (never observed), which have phosphines in cis- or trans- configuration, respectively. Complexes 3 react with ethene to give


species 4, again, in two isomeric forms axial–equatorial and equatorial–equatorial e, having a hydride in an apical position and ethene coordinating in the equatorial plane. Complex 4 undergoes migratory insertion to give the square planar alkyl complexes 5c and 5t, which contains the ligands L in cis- or trans-configuration, respectively. Complex 5 can undergo ß-hydride elimination, thus leading to isomerization when higher alkenes are used, or can react with CO to form the trigonal bipyramidal (TBP) complexes 6. Thus, under low pressure of CO, more isomerization may be expected. At low temperatures (10 bar), the insertion reaction is usually irreversible. Thus, the regioselectivity of hydroformylation of 1-alkenes is, at this point, determined. Complexes 6 undergo the second migratory insertion in this scheme to form the acyl complexes 7. These species can react either with CO to give the saturated rhodium-acyl intermediates 8, which have been spectroscopically observed, or with H2 to give the aldehyde product and the unsaturated intermediates 3. At low hydrogen pressures and high rhodium concentrations, the formation of dimeric rhodium species such as 9 becomes significant [1b]. The nature of the phosphorus ligand as well as the reaction conditions has a profound effect on each of the individual steps of the catalytic cycle determining the activity and selectivity of the reaction. The careful choice of the ligand can allow the formation of the desired aldehyde with high regioselectivity. The kinetic of the hydroformylation reaction has also been reported to differ, depending on the nature of the catalyst. Highpressure NMR and in situ IR have been recognized as powerful means to elucidate the intermediate complexes under hydroformylation conditions for both unmodified and phosphorus-modified rhodium catalysts [1].

10.2.3. Rhodium-Catalyzed Asymmetric Hydroformylation of Vinylarenes Asymmetric hydroformylation of vinylarenes (Scheme 10.3) is an attractive route for synthesizing enantiomerically pure aldehydes, which can be used as precursors for preparing high-value compounds such as pharmaceuticals, agrochemicals, biodegradable polymers, and liquid crystals. Since the early 1970s, rhodium–diphosphine complexes have been used as catalysts in the asymmetric hydroformylation of vinyl arenes. In general, the enantiomeric excesses obtained by using these catalysts have been moderate (below 60%) [7]. However, recently, the use of bisphophacyclic ligands [8] has emerged as an alternative to the most dominant ligand classes for this process: diphosphites [9] and phosphine-phosphite [10].

H2/CO

CHO

* CHO +

[M-Chiral Catalysts] R

R

R

Scheme 10.3.

Diphosphite Ligands The first successful report on asymmetric hydroformylation of vinyl arenes using diphosphite ligands appeared in 1992 when Babin and Witeker at the Union Carbide patented the asymmetric hydroformylation of various alkenes with ee’s up to 90% using bulky diphosphites 10a-c derived from homochiral (2R,4R)-pentane-


R

R'

O P

O

P

O

O

O

(2R, 4R) 10 R= 11 R= 12 R= 13 R=

O P

O

O

O P

O

O

14 (2R, 3R)

O P

O

O

O P

O

O 15 (2S, 5S)

O O

16 (2S, 4S)

R'= Me R'= Ph Me, R'= H Ph, R'= H R

O

O P

O

O

O

O P

O

=

R

R'

O

O

O

O

R

O

O

O

O

R

R'

a

R= t -Bu; R'= t -Bu

g

(R/S) ax R= SiMe3

b

R= t -Bu; R'= OMe

h

(R/S) ax R= SiEt3

c

R= H; R'= H

i

(R/S) ax R= Sit -BuMe 2

d

R= SiMe 3; R'= H

j

(R)ax R= H

e

R= SiEt3; R'= H

k

(S)ax R= H

f

R= Sit -BuMe 2; R'= H

l

(R)ax R= SiMe 3

m

(S)ax R= SiMe 3

n

o

Figure 10.1. Diphosphite ligands 10-16.

2,4-diol (Fig. 10.1) [9a]. Inspired by these excellent results, other research groups have studied several modifications in these types of ligand (Fig. 10.1) [9b,11]. They mainly studied the influence of the bridge length, the phosphite moieties, and the possibility of a cooperative effect between chiral centers on the performance of the catalysts. The influence of the bridge length was studied with diphosphite ligands based on (2R,4R)-pentane-2,4-diol (ligands 10a and 10b), (2R,3R)-butane-2,3-diol (ligands 14a and 14b), and (2S,5S)-hexane-2,5-diol (ligands 15a and 15b). In general, ligands 10, which have three carbon atoms in the bridge, provided higher enantioselectivities than ligands 14 and 15, which have two and four carbon atoms in the bridge [11a]. The effect of different phosphite moieties was studied with ligands 10a-o. In general, sterically hindered phosphite moieties are necessary for high enantioselectivities [9b,11b]. Thus, ligands 10c, 10j, 10k, 10n, and 10o show low asymmetric induction (ee’s up to 20%). Also, the results of using ligands 10a-i indicated that varying the ortho and para substituents on the biphenyl and binaphthyl phosphite moieties has a great effect on asymmetric induction. The optimal combination is therefore obtained with ligands 10b and 10d (ee’s up to 90% at 20 bar of syn gas and at 25°C).


TABLE 10.1. h-Catalyzed Asymmetric Hydroformylation of Styrene Using Diphosphites 10l, 10m, 16l, and 16ma Entry

Ligand

TOFb

%2-PPc

% eed

1

10l

28

95

38 (S)

2

10 m

17

88

69 (S)

3

16l

4

91

23 (S)

4

16 m

45

94

40 (R)

5e

10 m

11

92

86 (S)

a

[Rh(acac)(CO)2] = 0.02 mmol; ligand/Rh = 2.2; substrate/Rh = 1000; Toluene = 20 mL; PH2/CO = 10 bar. T = 25°C. TOF in mol styrene × mol Rh−1 × h−1 determined after 1-h reaction time. c Regioselectivity for 2-phenylpropanal. d Enantiomeric excess. e T = 15°C. b

The influence of the backbone substituent was studied by comparing ligands 10–13 (Fig. 10.1). Surprisingly, ligands 11, which have a more sterically hindered phenyl group, provided lower enantioselectivities than ligands 10 [11a] did. A possible cooperative effect between the different chiral centers was studied by using ligands 10l-o and 16l-o. Initially, van Leeuwen and coworkers studied the cooperative effect between the chiral ligand bridge and the axially chiral binaphthyl phosphite moieties by comparing ligands 10l, 10m, 16l, and 16m. The hydroformylation results clearly indicate a cooperative effect that leads to a matched combination for ligand 10m with (Sax, 2R, 4R, Sax) configurations (ee’s up to 86%) (Table 10.1) [9b]. Later, Bakos and coworkers, with ligands 10n, 10o, 16n, and 16o, found a similar cooperative effect between the chiral ligand bridge and the chiral phosphite moiety [11b]. However, the matched combination afforded poorer results (ee’s up to 17%) than those obtained with bulky biaryl phosphite ligands 10b, 10d and 10m (ee’s up to 90%) due to the lower steric bulk of the phosphite moieties n and o (vide supra). Interestingly, the hydroformylation results obtained with ligands 10b and 10d, which have conformationally flexible, axially chiral biphenyl moieties, are similar to those obtained with ligand 10m. This indicates that diphosphite ligands containing the conformationally flexible, axially chiral biphenyl moieties predominantly exist as a single atropoisomer in the [RhH(CO)2(diphosphite)] complexes when the right bulky substituents in the ortho positions are present (vide infra) [9b]. It is, therefore, not necessary to use expensive conformationally rigid binaphthyl moieties to reduce the degrees of freedom of the system. To investigate whether a relationship exists between the solution structures of the hydridorhodium diphosphite species [RhH(CO)2(diphosphite)] [12] and catalytic performance, van Leeuwen and coworkers extensively studied the rhodium-diphosphite complexes formed under hydroformylation conditions by HP-NMR techniques. It is well known that these complexes have a TBP structure. Two isomeric structures of these complexes, one containing the diphosphite coordinated in a bis-equatorial (ee) fashion and one containing the diphosphite in an equatorial–axial (ea) fashion, are possible (Fig. 10.2). Studies using diphosphite ligands 10 and 16 indicated that the stability and catalytic performance of the [RhH(CO)2(diphosphite)] species depend strongly on the configura-


H

H

P P

OC Rh

CO

P

Rh

CO

CO

P

ee

ea

Figure 10.2. Bis-equatorial (ee) and equatorial-axial (ea) coordination modes of diphosphite ligands in the [RhH(CO)2(diphosphite)] complexes.

O

O

O

P O

5

P O O

4

O O

O

O

P O

O

1

2 3

O

O O O

17 (1R, 2R, 3S, 4R)

O CH 3 O P O O O O P O

O

O

21

(1R, 2R, 3R, 4R, 5S)

P

O

O

O P O

O

O

O CH 3 O P O O O O P O O O

O

O O O

18 (1R, 2R, 3R, 4R )

O

CH3

O P O

O

O

CH3

O

P OO

O

O

P

19 (1R, 2R, 3R, 4R, 5R)

O

=

20 (1 R, 2R, 3S, 4R, 5R)

a-d , j -m

O

22 (1R, 2R, 3S, 4R, 5S)

Figure 10.3. Furanoside diphosphite ligands 17–22.

tion of the 2,4-pentanediol ligand backbone and the chiral biaryl phosphite moieties. Thus, for example, ligands 10b, 10d, and 10m, which form well-defined stable bisequatorial (ee) complexes, lead to good enantiomeric excesses, whereas enantioselectivities were low with ligands 10l and 16m, which form unidentified mixtures of complexes and ligand decomposition [9b,13]. Another successful family of ligands for the Rh-catalyzed hydroformylation of vinylarenes was the sugar-based furanoside ligands 17-22 (Fig. 10.3) [9c–e,14]. With these ligand, the effects of the different configurations of the carbohydrate backbone and the steric and electronic properties of the diphosphite substituents were studied. Ligands 20b,d and 21b,d show excellent enantioselectivities on both the S and R enantiomer of the product (up to 93%) and excellent regioselectivities (up to 98.8%) under mild conditions. The results of using the biphenyl-based ligands 17-22a-d indicated that (i) the presence of a methyl substituent in C-5 is necessary for high enantioselectivities and has a positive effect on reaction rates; (ii) the level of enantioselectivity is influenced by the


cooperative effect between the chiral sugar backbone stereocenters (C-3 and C-5) and the axial chiral binaphthyl phosphite moieties. Accordingly, ligands 20 and 21 provide better enantioselectivities than ligands 19 and 22; (iii) the absolute configuration of the product is governed by the configuration at the stereogenic center C-3. Accordingly, ligands 17, 20, and 22 with S configuration at C-3 gave (S)-2-phenylpropanal, while ligands 18, 19, and 21, with R configuration at C-3 gave (R)-2-phenylpropanal. These results overcome the problem presented by carbohydrate-derived ligands as they are available in only one enantiomeric form; and (iv) as observed with the previously mentioned ligands 10a-d, there is an influence on the substituents in the biaryl phosphite moieties. Thus, ligands 20b,d and 21b,d, with either methoxy substituents or trimethylsilyl groups, always produced the best enantioselectivities. The characterization of the rhodium complexes formed under hydroformylation conditions by NMR techniques and in situ IR spectroscopy showed that there is a relationship between the structure of the [RhH(CO)2(P-P)] (P–P = 17–22) species and their enantio-discriminating performance. In general, enantioselectivities were highest with ligands with a strong bis-equatorial (ee) coordination preference (Fig. 10.2), while the equilibrium of species with bis-equatorial (ee) and equatorial–axial (ea) coordination modes (Fig. 10.2) considerably reduced the ee’s [9d,e]. Through all these years, several authors have developed new diphosphite ligands with biaryl, spiro, pyranoside, mannitol, and macrocyclic backbones (Fig. 10.4) for asymmetric hydroformylation of vinyl arenes with low to moderate success (ee’s from 16% to 76%) [15]. Phosphine–Phosphite Ligands The first report on asymmetric hydroformylation using phosphite-phosphine ligands was carried out by Takaya and coworkers in 1993 [16]. With the aim to combine the effectiveness of the BINOL chemistry for asymmetric catalysis and the effectiveness of the phosphite moiety for asymmetric hydroformylation, they developed the (R,S)-BINAPHOS ligand 33. This turned out to be a very efficient ligand (Fig. 10.5). In the last few years, a wide range of structural variations has been reported. In this context, in 1997, Nozaki and coworkers used ligands 33–35 and found that the sense of enantioselectivity is governed by the configuration of the binaphthyl bridge, whereas the enantiomeric excess depends strongly on the configuration of both binaphthyl moieties (Fig. 10.5) [10a]. Enantioselectivity is therefore higher when the configurations of the two binaphthyl moieties are opposite (i.e., diastereoisomers R,S or S,R). Similar trends were observed with ligands 36 and 37, which have a chiral biphenyl bridge. To further understand the role of the chirality at the bridge and the axial chirality at the phosphite moiety in transferring the chiral information to the product outcome, ligands 38 and 39 were studied (Fig. 10.6) [10a]. Ligand 38, which has an (R)-binapthyl in the bridge, provides an ee of 83% (R). This value is close to the (R,S)-BINAPHOS value (94% (R) ee). This suggests that, in the formation of the Rh-complex, the binaphthyl bridge controls the conformation of the biphenyl phosphite moiety. Likewise, ligand 39 provides an ee of 69% (S), which suggests that the binaphthyl phosphite moiety also controls the conformation of the biphenyl bridge upon the coordination to rhodium. However, the control by the binaphthyl bridge is more efficient than that of the binaphthyl phosphite moiety. Next, the effect of several substituents in the phosphine moiety has been extensively studied by Nozaki’s group (Fig. 10.7). Their results indicate that both regio- and enantioselectivities can be increased by suitable choice of the aryl phosphine group. The best

10.2. ASYMMETRIC HYDROFORMYLATION 807 tBu

O O O

P

O

O

= O O O

O

P

O P

O

O P

O

= a, b, j, k

O

O

tBu

23

O

O O

, m, l

24 (1S, 5S, 6R)

p

25 (1R, 5R, 6S)

(ee's up to 16%)

(ee's up to 70%)

O O P O O P O O

O O P O O P O O

O

Ph

O O (RO) 2PO

= j , k, l, m, n

O

O OPh OP(OR)2 30

26 (S)ax

28 (S)ax

27 (R)ax

29 (R)ax

(ee's up to 36%)

(ee's up to 43%)

O O

O P O O

O O

O O

O

O P

O P

O = j, k

= j, k O O

O P

O O

31 (ee's up to 76%)

O O

O

O

O O

32 (ee's up to 76%)

Figure 10.4. Miscellaneous of diphosphite ligands 23–32. Enantioselectivities are shown in brackets.

combinations of regio- and enantio-selectivities were therefore obtained with ligands 40a and 40b [17]. Recently, ligand 40a has been successfully applied in the Rh-catalyzed hydroformylation of vinylfuranes (ee’s up to 99%) and vinylthiophenes (ee’s up to 93%) [18]. The characterization of the rhodium complexes formed under hydroformylation conditions by NMR techniques and in situ IR spectroscopy showed that there is a relationship between the structure of the [RhH(CO)2(BINAPHOS)] species and their enantiodiscriminating performance. Thus, (R,S) and (S,R)-BINAPHOS ligands show high equatorial-xial (ea) coordination preference with the phosphite moiety in the axial position. Meanwhile, the characterization of the (R,R)- and (S,S)-BINAPHOS ligands suggests that there is either a structural deviation of the monohydride complexes from an ideal TBP structure or an equilibrium between isomers [10a,19].


PPh2 O P O O

(R,S)-BINAPHOS

PPh2

PPh2

O

O

P O

33

O

(S,R)-BINAPHOS

(94% (R))

34

(R,R)-BINAPHOS

(95% (S))

Cl

P O O

35

(25% (R))

Cl PPh2 O P O

Cl

PPh2 O P

O

O

Cl

O

(S, R)- 36

(R, R)- 37

(94% (S))

(16% (R))

Figure 10.5. Rh-catalyzed asymmetric hydroformylation of styrene using ligands 33–37. Enantioselectivities obtained at 100 bar of syn gas and 60°C are shown in brackets.

PPh2 O P O

38 (R)

O

PPh2 O P O

O

39 (R)

Figure 10.6. BINAPHOS-related ligands 38 and 39.

Highly cross-linked polymer-supported BINAPHOS ligands were effective for the hydroformylation of styrene (ee’s up to 89%). Recovery and reuse of the catalyst were possible at low stirring conditions [20]. Perfluoroalkyl-substituted BINAPHOS ligand 40c (Fig. 10.7) was also developed for asymmetric hydroformylation of vinyl arenes in scCO2. With this ligand, high regio-and


PR 2 O P O

Ligand

R

%2-PP

%ee

33

C 6 H5

90.6

95.2 (R)

40a

3-MeO-C6 H 4

95.0

97.5 (R)

94.0

98.3 (R)

40c 3-C 6F13 CH 2CH2 -C 6 H4

92.7

90.6 (R)

40d

3-Me-C6 H4

93.4

94.1 (R)

40e

3,5-(MeO)2-C 6H 3

87.5

92.2 (R)

40f

4-MeO-C6 H 4

88.8

91.7 (R)

i

40b

3- PrO-C 6H 4

O

33, 40

Figure 10.7. Rh-catalyzed asymmetric hydroformylation of styrene using ligands 33 and 40.

O P O PPh 2 O O

O

PPh2

=

j, k

R1

O

O P O O 42

41

R2

O

O

O P O O

P Ph 43

(ee's up to 62%)

(ee's up to 44%)

R1 O Ph2 P

O P O

O

44 (ee's up to 49%)

R2

P

O

O O

= a, l, m, p

O

= a, b, j, k

Ph2P

O

O

P

O O

45 (ee's up to 20%)

O O

= j, m

O P O O

O O

46 (ee's up to 71%)

Figure 10.8. Miscellaneous of phosphine–phosphite ligands. Enantioselectivities are shown in brackets.

enantioselectivities (ee’s up to 93.6%) were achieved without the need of hazardous organic solvents [10b,21]. Inspired by the excellent results using the BINAPHOS ligands, new phosphine– phosphite ligands with different backbones have been developed in the last years (Fig. 10.8). Unfortunately, their Rh-hydroformylation provided low to moderate enantioselectivities (ee’s from 20% to 71%) [22]. Other Ligands Other types of homo- and heterodonor phosphorus ligands have also been developed for application in the asymmetric hydroformylation of vinyl arenes. In this context, several diphosphine ligands have been applied to this catalytic process. In general, they do not achieve ee’s as high as the Rh-system, with diphosphite or BINAPHOS. However, recently bisphosphacyclic ligands have emerged as interesting alternatives. For example, ligands 47–49 (Fig. 10.9) afforded an excellent regio- and enantiocontrol of the hydroformylation product [8].

= p


R

R P

P R

H P

R

tBu

tBu

P H

47a R= iPr ( 82% ee) 47b R= Ph ( 94% ee) 48 (94% ee)

R O

R O N N

P

P

N N

O R=

N H

Ph

O R

O R

49 (82% ee) Figure 10.9. Bis-phosphacycles 47–49. Enantioselectivities are shown in brackets.

PPh2 O N P O

50 Figure 10.10. Phopshite–phosphoroamidite ligand 50.

Recently, Zhang and coworkers developed a new phosphine–phosphoroamidite ligand 50 based on BINAPHOS (Fig. 10.10). This ligand provided excellent enantioselectivities (up to 99%) in the Rh-catalyzed hydroformylation of several vinylarenes [23]. Several heterodonor ligands containing a phosphite moiety have been developed with little success (Fig. 10.11) [24]. Recently, van Leeuwen and Reek reported the template-induced formation of chelating heterobidentate ligands by the selective self-assembly of two different monodentate ligands on a rigid bis-zinc(II)-salphen template with two identical binding sites (Fig. 10.12) [25]. These templated heterobidentate ligands induce much higher enantioselectivities (up to 72% ee, ligand 60) in the rhodium-catalyzed asymmetric hydroformylation of styrene than any of the corresponding homobidentate ligands or nontemplated mixed ligand combinations (up to 13% ee).


O O

O P O O

Ph H 3C

N P O O

O O

N P O O

O P O O

O

O

P OO

O

Ph

= a, b O

O

H3C

53 (ee's up to 58%) O

O O

HN P O O

= c, j , k

O P O O O O

RS O

= j, k

O

56

54 X= CH 2 55 X= CO (ee's up to 19%)

(ee's up to 32%)

O

O = a, j

P

O

P OO

= a

O

O

57 R= Me, iPr, Ph (ee's up to 5%)

N O

O

P

N P Ph

52 (ee's up to 65%)

51 (ee's up to 8%)

X

O

P HN

N

O

O P O

O

O

O O

= j, K

59

58

(ee's up to 5%)

(ee's up to 5%)

Figure 10.11. Miscellaneous of heterodonor ligands 51–59. Enantioselectivities are shown in brackets.

H 2/CO AcO

[M-Chiral Catalysts]

AcO * CHO

+

AcO

CHO

Scheme 10.4.

10.2.4. Rhodium-Catalyzed Asymmetric Hydroformylation of Vinyl acetate The Rh-catalyzed asymmetric hydroformylation of vinyl acetate is generally more challenging than the hydroformylation of vinylarenes. This process yields 2- and 3- acetoxypropanals with high selectivity (Scheme 10.4).


O

O P NH

PPh2

N

N

tBu

tBu

tBu

tBu

O

N

N

N

N

Zn O

O Zn O

But

tBu

tBu

tBu

Figure 10.12. Templated-heterobidentate ligand 60.

Ethyl acetate and acetic acid can also be found as by-products. One of the potential applications of the vinyl acetate hydroformylation is the production of enantiopure propane 1,2-diol. For the vinyl acetate hydroformylation, it has been proposed that the insertion of the alkene into the Rh-H at the branched carbon atom is stabilized by a five-membered ring intermediate, which has been observed by NMR spectroscopy [26]. Diphosphite and Phosphine–Phosphite Ligands In 1993, Takaya et al. published the first important results in the asymmetric hydroformylation of vinyl acetate with chiral diphosphites, in which they have achieved an ee up to 52% [27]. Later, in 1994, the (R,S)-BINAPHOS ligand 33 (Fig. 10.5) was found to deliver high regioselectivity in branched aldehyde, excellent yields, and and ee of up to 92% [28]. Its polymer-supported catalysts were also successfully applied [20]. In 2004, a multisubstrate screening approach has been used in the Dow Chemical Company to identify the best catalyst for hydroformylation of vinyl acetate. The chiral phosphite Kelliphite 23p (Fig. 10.4) gave up 88% ee and excellent branched selectivity in vinyl acetate hydroformylation [15j]. The same authors have recently extended their work to eight new biaryl-bridged diphosphite, related to Kelliphite, that allowed to them study the effect of the bridging biaryl moiety in enantioselectivity. They found that smaller dihedral angles increased regio- and enantioselectivities. However, none of the new modifications provided higher enantioselectivities than those obtained with 23p [15i]. More recently, Zhang an coworkers have found that the binol-based diphosphite 61 (Fig. 10.13) provided regioselectivities up to 98% and enantioselectivities up to 80% [29].


O O P O O P O O

O

= a

O

61 Figure 10.13. Binol-based diphosphite 61.

Ph N N P N N P Ph

O N

O O

N

O

P O Fe O P

O 62

63

N

O O

N O

Figure 10.14. Ligands 62 and 63.

Bis-Phosphacyclic Ligands Like the asymmetric hydroformylation of styrene, diphosphines usually provide lower ee than the related phosphite-containing ligands. However, recently, the diphospholane ligands 47–49 (Fig. 10.9) have also provided excellent regioand enantioselectivities (ee’s in the range of 82–96%) [8,30]. The best enantioselectivity was obtained with ligand 49, which represents the highest ee reported for a Rh catalyst in vinyl acetate asymmetric hydroformylation [8a,30]. Other Ligands Only three other type of ligands have been successfully applied in the asymmetric hydroformylation of vinyl acetate. The first one is the bis-(diazaphospholodine) ESPHOS 62 (Fig. 10.14) developed by Cole-Hamilton and coworkers. This ligand provided high regio- and enantioselectivities (up to 89%) [31]. The second one is the successful application of the previously mentioned phosphinephosphoroamidite ligand 50 (Fig. 10.10). This ligand provided enantioselectivities up to 96% [23]. Recently, a ferrocene-based phosphonite ligand 63 (Fig. 10.14) was successfully applied in this process (ee’s up to 83%) [32].

10.2.5. Rhodium-Catalyzed Asymmetric Hydroformylation of Allyl Cyanide The asymmetric hydroformylation of allyl cyanide (Scheme 10.5) has recently focused the interest of researchers because the iso-aldehyde derivative can be easily transformed


H2/CO NC

NC [M-Chiral Catalysts]

* CHO

+ NC

CHO

Scheme 10.5.

R O P N O R

64a R= H 64b R= t-Bu

Figure 10.15. Representative ligands 64.

into 2-methyl-4-butanol, a useful building block, for instance, for the asymmetric synthesis of tachikinin, a novel NK1 receptor agonist [33]. Diphosphite and Phosphine–Phosphite Ligands de Vries and coworkers found that, in the Rh-catalyzed hydroformylation of allyl cyanide, the use of phosphite and phosphoroamidites afforded preferentially the iso-aldehyde, while phosphines mainly provided the n-aldehyde [34]. The regioselectivity of the process was favored by the use of bulky phosphite ligands and low temperatures. They also found that R,S-BINAPHOS ligand 33 (Fig. 10.5) afforded a 66% ee, with an iso/n ratio of 2.57 when the reaction was performed at 30 bar, 50°C, 0.2 mol % Rh, and a ligand-to-metal ratio of 4. Later, with the previously mentioned multisubstrate screening approach developed in the Dow Chemical Company, they were able to identify Kelliphite ligand 23p (Fig. 10.4) as the best catalyst for hydroformylation of allyl cyanide (iso/n-ratio of >15% and 78% ee). They also found that the enantioselectivity obtained with that R,S-BINAPHOS ligand 33 could be increased to 76% when the reaction was conducted in acetone, although the regioselectivity still has a low iso/n ratio of 2.7 [15j]. The same authors developed other biaryl-bridged diphosphite ligands related to Kelliphite. However, none of the new modifications provided higher enantioselectivities than those obtained with 23p [15i]. Bis-Phosphacyclic Ligands As has been previously mentioned for the other substrate types, an important breakthrough in the Rh-catalyzed asymmetric hydroformylation has been the recent use of bisphosphacyclic ligands. Therefore, the diphospholane ligands 47–49 (Fig. 10.9) have also provided excellent regio- (iso/n ratio up to 7.1) and enantioselectivities (ee’s in the range of 90–96%) in the asymmetric Rh-catalyzed hydroformylation of allyl cyanide [8,30]. The best enantioselectivity was obtained with ligand 49, which represented the highest ee reported [8a,30]. Phosphoroamidite Ligands Ojima and coworkers reported the first succesful application of monodentate phosphoroamidite ligands, based on enantiopure 6,6`dimethylbiphenols′ with axial chirality, in the Rh-catalyzed asymmetric hydroformylation of allyl cyanide (Fig. 10.15). The presence of bulky tert-butyl groups at the ortho


positions of the biphenyl moiety has a beneficial effect of enantioselectivity. Therefore, ligand 64b provided excellent regio- (up to 96%) and enantioselectivities (up to 80%), while ligand 64a provided much lower enantioselecitivy (5% ee) [35].

10.2.6. Rhodium-Catalyzed Asymmetric Hydroformylation of Heterocyclic Olefins Although aldehydes obtained through the hydroformylation of heterocyclic olefins are interesting building blocks for organic synthesis, few studies have been reported on this subject. For these substrates, regioselectivity is of special interest because it is different from that of the corresponding acyclic ones. For example, in the hydroformylation of 2,5-dihydrofurane, the expected product is tetrahydrofuran-3-carbaldehyde A (Scheme 10.6). However, considerable amounts of 2,3-dihydrofuran and tetrahydrofuran-2-carbaldehyde B were present due to an isomerization process. This isomerization takes place simultaneously with the hydroformylation reaction. When the 2,5-dihydrofuran reacts with the rhodium hydride complex, the 3-alkyl intermediate is formed. This can evolve to the 2,3-dihydrofuran 3 via β-hydride elimination reaction. This new substrate can similarly evolve to produce the 2- and 3-alkyl intermediates. Although the formation of the 3-alkyl intermediate is thermodynamically favored, the acylation occurs faster in the 2-alkyl intermediate. Regioselectivity is therefore dominated by the rate of formation of the acyl complex [36b,c].

O

H [Rh]

O

O [Rh] 3-alkyl

[Rh] H O

H [Rh]

CO

O

O

[Rh] CO

O A CHO O

CHO

[Rh] H 2-alkyl

B

Scheme 10.6.

The modification of the phosphorus ligand and the conditions of the reaction make it possible to control the regioselectivity and prepare the 2- or 3-substituted aldehyde as the major product [36c]. As far as we know, only two reports have been published on the asymmetric hydroformylation of heterocyclic olefins using phosphine–phosphite [37] and diphosphite [38] ligands. The phosphine–phosphite R,S-BINAPHOS ligand 33 (Fig. 10.5) was first used in the Rh-catalyzed asymmetric hydroformylation of hereocyclic olefins such as 2,5-dihydrofuran, 3-pyrroline derivatives, and 4,7-dihydro-1,3-dioxepin derivatives (Table 10.2). It provided the optically active aldehydes as single products with enantioselectivities between 64–97% ee. In the hydroformylation of 2,5-dihydrofuran, the Rh-33 system gave up to 64%, with total regioselectivity in tetrahydrofuran-3-carbaldehyde A. Interestingly, the hydroformylation of 2,3-dihydrofuran led to a mixture of A and B (50/50) with an ee of 38% in A. The configuration of aldehyde A obtained from the


TABLE 10.2. Several Heterocyclic Olefins Efficiently Hydroformylated Using Rh-(R,S)BINAPHOS System Substrate

% eea

Product

X = O; 68 (R) X = NBoc; 73(R) X = NAc; 66 (−)

CHO X

* X

R = H; 76 (−) R = Me; 70 (R)

CHO

O R

O R

* O R

O R 38 (S)

CHO

O

* O

N Boc

97 (S)

* CHO N Boc

a

Enantiomeric excess.

H 2/CO [M-Chiral Catalysts]

OHC *

Scheme 10.7.

hydroformylation of 2,5-dihydrofuran is opposite to that which is obtained from the hydroformylation of 2,3-dihydrofuran with the same catalyst [37]. Recently, the previously mentioned diphosphite ligands 10a, 14a, 15a, 17a, and 20a (Figs. 10.1 and 10.3) were successfully applied for the first time in the Rh-catalyzed hydroformylation of 2,3- and 2,5-dihydrofuran. The results indicated that the backbone of the ligand is crucial to suppressing isomerization and obtaining high ee’s. High enantioselectivities for both substrates have therefore been obtained by using the furanoside diphosphite ligand 20a (75% ee). Note that both enantiomers of tetrahydrofuran-3carbaldehyde A can be synthesized by using the same ligand 20a by simple substrate change [38].

10.2.7. Rhodium-Catalyzed Asymmetric Hydroformylation of Bicyclic Olefins The asymmetric hydroformylation of bicyclic olefins such as norbornene has received little attention (Scheme 10.7).

10.3. ASYMMETRIC ALKOXYCARBONYLATION AND RELATED REACTIONS

817

H P

H

P

65 Figure 10.16. TangPhos ligand 65.

Their hydroformylation is interesting due to the following features: (a) desymmetrization of the olefin will generate three chiral carbon centers upon one C–C bond formation; (b) there are no regioselectivity issues due to the symmetry of such olefins, although high enantio-, endo-, and exoselectivities are important; and (c) functional groups located opposite to the C=C bond could be versatile, which may lead to interesting building blocks [39]. Despite these, the initial work in this field provided low selectivities (20–60 % ee) [40]. However, recently, Bunel and coworkers used a combinatorial approach (screening 130 chiral phosphine, phosphite, phosphine–phosphite, and phosphoroamidite ligands) and found that diphospholane ligand TangPhos 65 (Fig. 10.16) showed the highest enantioselectivities. It provided enantioselectivities up to 93% in the Rh-catalyzed asymmetric hydroformylation of several [2.2.1]-bicyclic olefins [39].

10.3. ASYMMETRIC ALKOXYCARBONYLATION AND RELATED REACTIONS 10.3.1 General Aspects The asymmetric synthesis of carboxylic acids and their related esters is performed from olefins, carbon monoxide, and water or alcohols (represented as R2OH in Scheme 10.8) in the presence of a chiral palladium catalyst. Considering that these chiral carboxylic acids are usually obtained from the oxidation of chiral aldehydes synthesized by hydroformylation of vinylarenes, the asymmetric hydroxy- and alkoxycarbonylation reactions attract much attention from both academic and industrial research groups [4b,6e,41]. However, less successful work has yet been reported on these reactions than on hydroformylation due to the difficulty of obtaining simultaneously both high regio- and enantioselectivities. The alkoxycarbonylation of vinylarenes is of particular relevance, as the products (2-arylpropionic acid and derivatives) are precursors for nonsteroidal antiinflammatory drugs, particularly ibuprofen and naproxen [42].

R1

2

[Pd]

+ CO + R OH

R1 *

R2 = H, alkyl Scheme 10.8.

O

O + OR2

R1

OR2


10.3.2. Catalytic Cycle For the alkoxycarbonylation reaction, two mechanisms have been suggested (Scheme 10.9) [43]. The catalytic cycle can either start from a hydrido-palladium complex (Cycle A) or an alkoxycarbonyl-palladium species (Cycle B). In the hydride cycle, the first step is the insertion of the alkene into the Pd-H bond to form an alkyl complex, followed by coordination and migratory insertion of CO to produce a Pd-acyl species. Alcoholysis of the Pd-acyl regenerates the Pd-H complex and yield the ester. In the alkoxycarbonyl cycle, the alkene is inserted into the Pd–carbon bond of the alkoxycarbonyl–palladium complex, followed by alcoholysis to yield an alkoxy–palladium complex and the ester. Coordination and migratory insertion of CO then regenerate the initial alkoxycarbonyl– palladium complex. The production of the Pd–H species from complexes formed in Cycle B was also demonstrated to occur through the β-elimination of an unsaturated ester after alkene insertion. When the substrate is a vinylarene, the branched alkyl intermediate can be stabilized through the formation of π-benzylic species, with the two complexes in equilibrium [44].

LnPdCOOR'

CO

R

B

LnPdOR'

R R'O

R'O

O

LnPd R

*

* COOR'

R'OH

R

+ O

COOR' + LnPd

β-elimination R LnPd-H R

A

R'OH LnPd

O

+ LnPd R

O *

R

LnPd

R + LnPd *

LnPd

CO Scheme 10.9.

The coexistence of these two cycles was suggested to be the origin of the regioselectivity of these reactions, based on steric factors that would favor the linear insertion of styrene into a Pd–hydride bond, whereas the branched insertion of styrene would be favored into a Pd–alkoxycarbonyl bond [45]. The regioselectivity of these reactions is of


819

critical importance when it is to be performed in an asymmetric manner, as only the branched product contains a chiral center. The use of bidentate ligands generally leads to a greater amount of linear products, whereas catalytic systems bearing monodentate ligands usually favor the formation of the branched products [46]. This difference in regioselectivity was suggested to be due to the ability of monodentate ligands to coordinate to the palladium center in a cis or a trans manner [44]. However, the study of the alcoholysis step, performed varying the bite angle of diphosphines, indicated that cis coordination of the phosphine ligands is required for this step to be efficient [47]. The dissociation/association of the phosphine ligands and the role of the acid counter-ion used have also been suggested to influence the regioselectivity [48]. The length of the alkylic chain of the diphosphine ligands Ph2P(CH2)nPPh2 (n = 1–6, 10) was also shown to dramatically influence the regioselectivity of the ethoxycarbonylation of styrene [49]. Later, it was demonstrated that the presence of electron-withdrawing substituents on diphosphine ligands can invert the regioselectivity of the methoxycarbonylation of styrene in favor of the branched ester [50]. Recent advances have been reported on the methanolysis step using DFT calculation methods [51]. However, the origin of the regioselectivity of these reactions is still to be established [44].

10.3.3. Asymmetric Alkoxycarbonylation of Vinylarenes Bidentate Diphosphines Diphosphine ligands play an outstanding role in homogeneous catalytic reactions and were shown to efficiently induce chirality in various asymmetric processes [52]. It is, therefore, quite logical that the use of these ligands in the asymmetric hydroxy- and alkoxycarbonylation of vinylarenes appeared in the early 1970s. Consiglio and coworkers used PdCl2 and (-)-DIOP 66 (Fig. 10.17) as catalyst system and studied the effects of the reaction conditions on the enantioselectivity of the reaction. In 1973, they described that the ethoxycarbonylation of α-methylstyrene yielded 10% ee and that, when styrene was the substrate, only 2% ee could be achieved [53]. Using the same catalytic system but in the presence of HCl, Consiglio reported in 1976 the methoxycarbonylation of α-ethylstyrene and of (Z)- and (E)-2-phenyl-2-butene and concluded that the formation of isomeric esters was taking place through different mechanisms [54]. Later, they reported the alkoxycarbonylation of α-methylstyrene using various alcohols and reaction conditions [55]. The results showed that the enantioselectivity of the reaction varied from 3% to 20% ee when the alcohol was changed from methanol to tert-butanol. The ee of the reaction was also demonstrated to be greatly increased by the use of a cosolvent such as benzene or THF. The CO pressure was shown to have the greatest effect on the enantioselectivity, as the ee varied from 3% to 50% when the pressure was increased from 50 to 700 atm. Interestingly, the highest ee value (ca. 59%) was achieved by using a Pd to DIOP ratio of 1/0.4, while, when a 1/1 ratio was used, the ee was lower than 50%. They later reported that, by adding PPh3 to the reaction mixture (containing the Pd to DIOP ratio of 1/0.4), the chemo- and regioselectivities of the reaction were improved without affecting the enantioselectivity [56]. Later, the use of ligands 67–72 (Fig. 10.17) was reported in the asymmetric alkoxycarbonylation of α-methylstyrene with isopropylalcohol under ca. 230 atm of CO at 100°C [57]. With ligands 67 and 69 bearing the dibenzophospholyl moiety, the ee values were much higher (in both cases, ca. 40%) than when the reactions were carried out by using ligands 70 and 72. When ligands 68 and 71 were used, however, the ee values were lower, and the highest ee was obtained by using 71 (ee = 22% with 71 and 7% with 68).


O

P

O

P

2

2

66

P

P

P

P

67

P

P

P

70

69

P

O O

P

72

PPh2

H

H O

73

PPh 2 MeO

Ph2 P

OMe OMe

Ph2 P

74 (R)-MeO-MOP

PPh2 H

CH 3

75

P

O

NMe 2 Fe

PPh 2 76

P

71

O

Fe

O

68

P

Ph2 P

P

O

N PPh2

i

Pr

Fe

2

C CH3 H PPh2

PPh2 77

78

Figure 10.17. Diphosphine ligands used in the asymmetric hydroxy- and alkoxycarbonylation of vinylarenes.


821

In 1997, a PdCl2-CuCl2-chiral diphosphine 73 (DDPPI) (Fig. 10.17) was reported to achieve 98% ee and 99% regioselectivity to the branched ester for the methoxycarbonylation of styrene at 80°C under 50 atm of CO [58]. Despite these very promising results, for some reasons, no further development was described later on this catalytic system. The use of several chiral diphosphines was reported in the hydroxycarbonylation of styrene, but only moderate regioselectivity (up to ca. 30%) and ee’s up to 11% were achieved [59]. Systems bearing recoverable water-soluble diphosphine ligands were also utilized in hydroxycarbonylation of vinylarenes and provided enantioselectivities up to 43% [60]. Heterogeneous catalytic systems formed by montmorillonitediphenylphosphinepalladium(II) chloride in the presence of chiral mono- and bidentate phosphines such as 74 and 75 (Fig. 10.17) were also reported in the methoxycarbonylation of styrene but afforded low enantioselectivities [61]. When the catalytic system containing the monodentate (R)-MeO-MOP ligand 74 was used at 125°C under 45 atm of CO and in the presence of concentrated HCl, total selectivity to the branched acid was achieved, but only 5% ee was obtained. Under the same conditions, the use of the bidentate phosphine 75 achieved total regioselectivity to the branched acid, together with 12% ee. The use of diphosphine ligands containing a ferrocenyl unit in the methoxycarbonylation of styrene was reported to induce high enantioselectivity, although the regioselectivity to the branched product, as in general for diphosphine ligands, was usually low [62]. In 1997, 86% ee was achieved by Inoue and coworkers, together with a regioselectivity of 44% to the branched ester using Pd(OAc)2 as palladium precursor in the presence of the chiral diphosphine (S,R)-BPPFA 76 (Fig. 10.17) and p-TsOH under mild conditions (20 atm of CO at room temperature). However, the branched product yield was, in this case, 17% [62a]. In 2003, Chan and coworkers reported the use of ferrocenyl phosphine containing oxazoline moieties in the methoxycarbonylation of styrene and achieved 64% ee using the bidentate phosphine 77 (Fig. 10.17) with PdCl2 as the Pd source in the presence of p-TsOH at 50°C under 170 atm of CO [62b]. Although this enantiomeric excess was relatively high, it should be noted that only 40% regioselectivity was obtained and that the conversion was low (14%). More recently, the use of the families of ferrocenyl diphosphine from Solvias (Josiphos, Mandyphos, Walphos, and Taniaphos) has been reported in the same reaction [62c]. High enantioselectivities (up to 86% using ligand 78) and conversions (ca. 80%) were achieved, but the regioselectivities to the branched ester were, in all cases, very low (ca. 15%). Hemilabile P-N Ligands The use of mixed bidentate pyridine–phosphine ligands 79–82 (Fig. 10.18) was reported in the ethoxycarbonylation of styrene, yielding total selectivity to the branched ester with ee’s up to 20% when the isolated precursor [PdCl2(79)] was used at 100°C under 105 atm of CO for 10 days [63]. In view of the results, the authors concluded that, under catalytic conditions, these ligands were coordinated in a monodentate manner. The use of the related ligand dipydiphos 80 yielded the same regioselectivity but a much lower enantioselectivity. Chan et al. reported the use of the P-N ferrocenyl phosphine-oxazoline (S,Sp)-81 ligand (Fig. 10.18) and achieved 45% ee, together with a regioselectivity to the branched ester of 79% using a PdCl2CuCl2-p-TsOH system [62b]. Interestingly, when the diastereoisomer (S,Rp)-82 ligand was used, the regioselectivity was found to increase (>99%), but both conversion and enantiomeric excess decreased considerably (Fig. 10.18). Monodentate Ligands Catalysts bearing chiral monodentate phosphines have found many applications in asymmetric catalysis [52]. A selection of chiral monodentate ligands


O

O

O

N

P

Ph

N

O

N

P

Ph 79

80

Chelucci ee =20% l/b = 0/100

Chelucci ee = 3% l/b = 0/100 O

Fe

N SiMe3 PPh2

Ph Ph

O

SiMe3 i

Pr

N

Fe

iPr

PPh2

(S ,Sp)-81

(S,Rp)-82

Chan ee = 45% l/b = 21/79

Chan ee = 28% l/b = 1/>99

Figure 10.18. P-N ligands 79-82 used alkoxycarbonylation reactions.

that have been used in the methoxycarbonylation of vinylarenes is shown in Figure 10.19. The use of the neomenthyldiphenylphosphine 83 (NMDPP) (Fig. 10.19) in the asymmetric methoxycarbonylation of styrene yielded 52% ee using Pd(dba)2 as precursor in the presence of trifluoroacetic acid at 50°C under atmospheric pressure of CO [64]. Ligand NMDPP 83 was also used in the asymmetric alkoxycarbonylation of styrene using a biphasic solvent system formed by an ionic liquid and an organic phase containing isopropanol [65]. By using the catalytic system PdCl2(NCPh)2-NMDPP-p-TsOH, high chemo- and regioselectivities were obtained, but only enantioselectivity up to 5% could be achieved. In 1990, Alper and Hamel reported high enantioselectivity (91% ee) and total regioselectivity to the branched acid (64% of isolated yield) using the PdCl2CuCl2-HCl-84 (BNPPA) system (Fig. 10.19) for the hydroxycarbonylation of 2-vinyl-6methoxynaphtalene under 1 atm of a mixture of CO and O2 at room temperature [66]. When p-isobutylstyrene was used as the substrate, the same catalytic system afforded 84% ee under the same conditions. By using the same ligand, the methoxycarbonylation of styrene was recently reported by Yang and Jiang, but only 38% ee was achieved under identical conditions [67]. In 1997, Nozaki and coworkers used the (S,S)-phospholane ligand 85 (Fig. 10.19) [61], but, although this system afforded high regioselectivity, the enantioselectivity was very low (2%). Later, the same authors reported on the application of palladium complexes with binaphthol-derived phosphines 86 (Fig. 10.19) in the methoxycarbonylation of 2-vinyl-6-methoxynaphthalene. By using a catalytic system formed by PdCl2 and 2 equivalents of 85 under 30 atm of CO at 40°C, 53% of ee were achieved for the branched ester, (S)-naproxen methyl ester, as the only reaction product [68]. In 2005, Claver and coworkers reported the first use of isolated Pd chiral monophosphine species in this


O O P O OH

PPh2

83

84

Cometti, 1982 ee = 52% b/l = 94/6

Alper, 1990 ee = 91% b/l = 100/O

2 P

85

O

P MeO

Nozaki, 1997 ee = 2.4% b/l = 98/2

823

P

86

87

Claver, 2005 ee = 29% b/l= 97%

Nozaki, 2004 ee = 53% b/l = 100/-

Figure 10.19. Monodentate phosphines used in asymmetric methoxycarbonylation of vinylarenes.

PPh2 PPh2

Figure 10.20. The BINAP ligand 88.

reaction. They showed that systems containing phosphetane ligands could also yield high regioselectivity to the branched ester and ee’s up to 29% in the methoxycarbonylation of styrene using [PdCl2(87)2] as precursor at 70°C under 35 atm of CO (Fig. 10.19) [69].

10.3.4. Other Substrates Using the Pd(OAc)2-DDPPI-p-TsOH (DDPPI = igand 73, Fig. 10.17) catalytic system for the methoxycarbonylation of norbornene, Zhou et al. achieved 92% ee under 50 atm of CO at 120°C [70]. In 2003, the asymmetric methoxycarbonylation of acenaphthylene was reported by using BINAP 88 (Fig. 10.20) as chiral ligand at 80°C in the presence of p-TsOH and under 30 atm of CO [71]. Interestingly, by using [PdCl2(NCPh)2] as Pd precursor, ee’s up to 45% with 12% conversion were achieved, while using Pd(OAc)2 only led to ee’s up to 34% but in 60% conversion under identical conditions.


An innovative application of hemilabile P–N ligands was reported through the use of a chiral ferrocenyl (R,S)-PPF-pyrrolidine system in the methoxycarbonylation of 1,2-dichlorobenzene-Cr(CO)3 in order to introduce planar chirality in π-complexes (Scheme 10.10) and achieved up to 95% ee by using the isolated precursor [PdCl2(P-N)] under 1 atm of CO at 60°C in the presence of NEt3 [72].

N

Cl

Cr OC

Fe

Cl

PdCl2 P Ph2

CO

CO, MeOH, NEt3

CO2Me Cl Cr OC

CO

CO CO

ee up to 95% Scheme 10.10.

10.3.5. Asymmetric Bis-Alkoxycarbonylation of Vinylarenes The enantioselective synthesis of optically active butanedioic acid derivatives is of interest, as they are important intermediates of pharmaceuticals [73] and building blocks for rennin inhibitors [74]. These products are formed by the bis-alkoxycarbonylation of alkenes (Scheme 10.11), reaction that was first reported by Heck in the early 1970s [75]. However, the first asymmetric version of this reaction was described more than 20 years later [76].

1

R

2

[Pd(II)]

+2 CO + 2 R OH

O

oxidant 2

R1 *

O OR2

R O

Scheme 10.11.

In this reaction, styrene is usually the substrate, and palladium systems containing bidentate phosphine ligands are generally used as catalysts. However, the presence of an oxidant in stoichiometric amount such as benzoquinone is required for this reaction. The role of the oxidant is to reoxidize the Pd(0) species formed during the process. In their initial report, Consiglio et al. used a Pd system containing the (R,R)-DIOP ligand, but only low enantioselectivity was achieved [76]. Chiral ligands later used in this reaction are presented in Figure 10.21. The use of atropoisomeric diphosphine ligands yielded high enantiomeric excess but low chemoselectivity. The selective formation of the bis-alkoxycarbonylation product is often a problem in this reaction, and by-products such as methyl-cinnamate, methyl-2-phenylpropionate, and methyl-3-phenylpropionate are usually formed during this process. In 1999, the screening of a series of ligands in the enantioselective bis-methoxycarbonylation of alkenes was reported [77]. When styrene was used as a substrate, the catalytic systems containing ligands such as 89 and 90 yielded high enantioselectivities (92%


R' R'

P P

MeO MeO

PR2 PR2

825

89

90

R = Ph; R'= OMe, Me: (S)-R'-BIPHEP ( all S)(R a)-MePHOS-MeO-BIPHEP R = Cy; R'= OMe, Me: (S)-R'-BICHEP R PR2 Fe

PPh2

O

PPh2 PPh2

R = Cy, Ph Josiphos

R'

N

N

i

i

Bu

(S)- Bu-PHOSOX

91

92

MeO MeO

P P

R R

PPh2 N

R' R

(S,S)-BDPP

R = R´ = H R = Me, R' = H R = H, R' = Me

93

94

N

N

N S

95 a

N

O

N S

N

O

95 b

Figure 10.21. Ligands used in enantioselective bis-alkoxycarbonylation of alkenes.

and 81%, respectively) with chemoselectivities of ca. 50% at 50°C under 350 atm of CO and in the presence of benzoquinone (ratio BQ/styrene = 1). When propene was the substrate, the highest enantioselectivity (60%) was achieved by using the (S)-MeOBICHEP ligand, although the chemoselectivity and conversion were poor (13% and 23%, respectively). When the substrate was 4-methyl-1-pentene, chemoselectivity up to 79% was achieved, but the enantioselectivity was found to be rather low (up to 14%). More recently, chiral dipyridylphosphines 94 were used in the enantioselective bismethoxycarbonylation of styrene and reached up to 84% ee and 79% chemoselectivity to dimethyl-2-phenylsuccinate at 50°C under 152 atm of CO in the presence of benzoquinone (ratio BQ/styrene = 0.5) [78]. In 2007, Marder and coworkers reported the use of Pd systems bearing new atropoisomeric chiral S,N-thiourea-oxazoline ligands 95a and 95b in the bis(methoxycarbonylation) of vinylarenes [79]. The diester product was obtained in high yields, and ee up to 75% was achieved at room temperature by using the Pd–allyl complex [PdCl(η3-C3H5)]2 as precursor and in the presence CuCl in MeOH under a balloon pressure of CO and O2 (ratio 4:1).


10.4. ASYMMETRIC ALTERNATING CO- AND TERPOLYMERIZATION OF OLEFINS WITH CO 10.4.1. Asymmetric CO/Olefin Copolymerization 10.4.1.1. General Aspects Over the last decades, the industrial interest in polyketones obtained via the catalytic copolymerization of carbon monoxide (Scheme 10.12) with one or more alkene monomers has relentlessly increased.

R

+

[Pd]

O

CO

n R

Scheme 10.12.

These materials represent a class of low-cost thermoplastics whose synthesis, properties, and applications are still the object of intense fundamental and applied research. At least two of these CO/olefins polymers were industrially produced: Carilon® from Shell [80] and Ketonex® from BP [81]. The properties of polyketones may be both modified and improved by changing the number or the nature of the comonomers and tuning the structure of the metal catalyst, which makes them superior to polyolefins, polyamides, and polyacetals [82]. 10.4.1.2. Mechanism A detailed mechanistic study of the Pd-catalyzed CO/ethene perfectly alternating copolymerization was first reported by Drent et al. in 1991. Since then, a large number of studies from both experimental and theoretical approaches have been reported and have contributed to a better understanding of each step of the catalytic reaction as well as to identify and obtain information on active species and resting states in the reaction. Most of these studies were previously reviewed [83–85], and only a brief description of the catalytic cycle, which is applicable to other alkenes, will be given here. As shown in Scheme 10.13, two competing cycles whose prevalence depends on the reaction conditions and that are connected via cross terminating steps are participating during the production of polyketones. One cycle initiates via a Pd–H species, which, by rapid insertion of ethane, gives an alkyl species that reacts reversibly with CO to yield an acyl complexes. This latter species then irreversibly inserts a second ethene molecule. The propagation thus occurs through alternating CO and ethene insertions. From this cycle, ketoesters and diketones can be produced, depending on the termination path. The methanolysis of an acyl species yields a ketoester, whereas protonolysis of an alkyl complex yields a diketone. The second cycle initiates by a Pd–methoxy species that reacts with CO to form a Pd–carbomethoxy complex. During this cycle, ketoesters are also produced, together with copolymers with diester structure that are produced via methanolysis of a Pd–acyl. Using organic oxidants, the palladium hydride species was the most probable initiator, and methanolysis is, therefore, the main termination mechanism. Kinetic studies have shown that ethene insertion is the rate-limiting step of the reaction [84]. Two competing chain-transfer mechanisms were proposed for the alternating copolymerization of CO and ethane [86].

10.4. ASYMMETRIC ALTERNATING CO- AND TERPOLYMERIZATION OF OLEFINS WITH CO 827 +

Pd

H

O O Diketone O

n-1

O

MeOH

+

Pd

nH

C2H4

nH

+

Pd-OMe

CO

O

Ketoester O

nH

Pd

MeOH

OMe

n

+

n CO n-1 C2H4

O MeOH O +

Pd

+

O OMe

+

Pd

H

+

Pd-H

Pd

OMe n C2H4

n C2H4 n-1 CO

O

+

CO

Pd

nOMe

O

MeOH MeO

O +

Pd

O

H

O O

n Diester O

OMe

n-1

Scheme 10.13.

In the CO/vinylarenes copolymerization, the main features of the catalytic cycle are comparable to those of the CO/ethene copolymerization. In particular, the propagation step is identical with alternating insertions of CO into Pd–alkyl bonds and of styrene into Pd-l bonds. However, the initiation and termination steps are distinct and depend on the nature of the olefinic substrate [84]. The termination pathway that prevails in methanol consists in fast β-hydrogen elimination from alkyl species and thus yields a Pd–H complex at the end of the cycle. 10.4.1.3. Asymmetric Copolymerization of CO with Propene and Aliphatic 1-Alkenes Unlike the reaction with ethene, the CO/propene copolymerization opens the possibility of stereoregular copolymers. In this process, the regio- and stereochemistry are of critical importance. The mode of insertion of the α-olefin into the Pd–acyl or Pd–carbomethoxy bond in a 1,2 or 2,1 fashion governs the regiochemistry of the reaction (Scheme 10.14). Assuming that a regioregular copolymer is formed, the stereochemistry of the reaction can lead to the production of isotactic, syndiotactic, or atactic structures (Fig. 10.22). In the copolymerization of CO and aliphatic alkenes, the best results are obtained by using catalyst-containing bidentate phosphine ligands. The electronic and steric properties of these ligands were shown to control the activity and productivity of the catalyst and the regio- and stereoselectivities of the reaction.


Me Pd Pd

O

1,2-insertion

X

2,1-insertion

O

Me

+

X

X X = R, OR Pd Me

O

Scheme 10.14.

O

O (R)

(R)

(R)

(R) O

isotactic

O

O

O (R)

(R) (S)

(S)

O

syndiotactic

O

O

O (R)

(R) (S) O

(R)

atactic

O

Figure 10.22. Possible structures of regioregular CO/propene copolymers.

The use of bis-triaryl diphosphines such as DIOP 65, BINAP 88, and BIPHEP 89 (where R = Ph, R′ = CH3, OMe) in CO/propene copolymerization was shown to yield regioirregular product with low stereoselectivity [87]. However, the substitution of phenyl rings by alkyl groups (ligands 89 with R = Cy, and 90) resulted in the production of highly isotactic (ca. 72% isotacticity) and regioregular copolymers [88,89]. To date, the most active class of ligands is that of C1-symmetry ferrocenyldiphosphines 96 (Fig. 10.23) [90]. The highest activity was obtained with bulky substituent on the phosphorus bonded to the chiral carbon and withdrawing groups on the aryl ring of the second phosphorus atom. A remarkable effect on catalyst activity was revealed by the use of ligands 97a and 97b as the catalyst containing the former ligand 97a was 84 times more active than its analogue with 97b, although highly isotactic materials were obtained in both cases [91]. Ligands 98–100 were also reported to yield highly regio- and stereoregular copolymers [92]. The catalysts for the copolymerization of CO with higher aliphatic 1-alkenes showed slightly lower activity than with propene. However, the regio- and stereoselectivities to isotactic copolymers achieved are as high as those obtained for propene [93]. 10.4.1.4. Asymmetric Copolymerization of CO with Vinylarenes Unlike aliphatic olefins, the copolymerization of styrene and its derivatives with CO requires the use of

10.4. ASYMMETRIC ALTERNATING CO- AND TERPOLYMERIZATION OF OLEFINS WITH CO 829

PR' 2 R Fe

PAr 2 PAr 2

PAr2

96

9 7a

PPh2

P

PPh2

P

PAr2 PAr2 97 b

PR2 O P O O

98 99

100

Figure 10.23. Selection of chiral ligands used in CO/propene copolymerization.

Pd(II) catalysts with chelating dinitrogen ligands to be successfully performed [3,6a,94,95]. By using Pd catalysts bearing diphosphine ligands, low molecular weight oligomers are usually obtained because the 2,1-insertion of styrene that is observed with this system is followed by rapid β-hydride elimination [84a,95c,f]. However, Nozaki and coworkers demonstrated that cationic Pd systems bearing the bidentate phosphine–phosphite BINAPHOS ligand 100 (Fig. 10.23, where R = Ph) are efficient catalysts for the copolymerization of CO with styrene derivatives and for the copolymerization of CO with aliphatic 1-alkenes [96]. They later demonstrated that the behavior of this system could be explained through an exclusive 1,2-insertion of styrene during the copolymerization process, thus limiting the termination by β-hydride elimination [97]. Sulfur-containing ligands have also been used in copolymerization reactions although bis-alkylthioethers systems were shown to be active in the copolymerization of CO/styrene, even if a loss of stereocontrol was reported [84a,98]. The use of the bis(thio)ether ligands [99] for this reaction yielded comparable results to those reported using chiral P–OP, N–N, and P–N ligands in terms of activity and molecular weights [93a,100]. The rather high polydispersity values and the nonlinear relationship between time and molecular weights indicated that these systems do not behave as living ones [95d]. Modular N–N′ Ligands for the Copolymerization of CO and Styrene Brookhart and coworkers reported the first enantioselective copolymerization of CO and styrene using a Pd(bisoxazoline) system (complex 101, Fig. 10.24) under 1 atm of CO at room temperature. The 4-t-butylstyrene was used as both solvent and substrate. and copolymers of both highly isotactic microstructure and high optical activity were obtained [101]. The use of palladium systems bearing pyridine–oxazoline ligand (complex 102, Fig. 10.24) leads to the production of mainly syndiotactic copolymers. By using a pyridine-imine system (complex 103, Fig. 10.24), the production of chiral alternating CO/ styrene copolymers was also reported, however with a lower stereoregularity [102]. The


O

BArF

O N

N

N

CH2OMe

Pd

O

O

N

N

Ph NCMe

103

102

iPr

NCMe 104

N Pd

BArF Me

Pd

N MeCN

Me

MeCN

101

Me

Ph

N

R R Pd Me MeCN R = iPr, Me

iPr

(BF4)2

BArF

O

Me

O

N

O

N

Me

O

N

O

N

106

105

Figure 10.24. Some systems used in Pd-catalyzed CO/styrene copolymerization.

R N N

Ph

N

Ph R = H 107a R = Bn 107b R = Me 107c R = Ts 107d R = Tf 107e

Figure 10.25. N-N′ ligands used in CO/TBS copolymerization.

production of highly isotactic optically active copolymers of CO and styrene or 4methylstyrene was reported by using a bisoxazoline catalytic system (complex 104, Fig. 10.24) [103]. By using palladium complexes bearing chiral diketimines or dialdimines, productivities as high as 21 g CP/g Pd h for average molecular weight copolymers were obtained at room temperature under a constant CO pressure of 1 bar [104]. Brookhart achieved the production of stereoblock polyketones by exchanging ligands during the catalytic reaction [105]. The use of systems bearing the atropoisomeric ligands 105–106 derived from bipyridine was also reported to be very active in this reaction under mild conditions [106]. However, with these systems, low asymmetric induction was observed, together with short isotactic sequences in the copolymer chain. Claver and coworkers investigated the alternating CO/4-t-butylustyrene (TBE) copolymerization reaction using systems bearing chelating asymmetric bisnitrogen N–N′ ligands (Fig. 10.25). Productivities between ca. 2 and 30 g CP/g Pd h were achieved with molecular weights comprised between 17,000 up to ca. 80,000 under mild conditions (PCO = 1 bar, RT, TBS/ Pd = 620). The catalysts bearing the less basic imidazol moieties 107d and 107e were found to be the most active [107].

10.4. ASYMMETRIC ALTERNATING CO- AND TERPOLYMERIZATION OF OLEFINS WITH CO 831

10.4.2. Asymmetric CO/Olefins Terpolymerization The CO/alkene copolymer chains are packed in orderly fashion, which makes them highly crystalline but also very fragile. One way to avoid this problem is to introduce another alkene to somehow disturb the crystal packing. The strictly alternating CO/ alkene polyketones obtained contains the two types of units: CO/alkene1 and CO/ alkene2 (Scheme 10.15).

R1

+

R2

O

[Pd]

R2

CO

R1

m

n O

Scheme 10.15.

Similar to the copolymerization catalysts, the terpolymerization of CO with aliphatic olefins is usually performed by using complexes bearing phosphorus-based ligands [108], while the only reported example of terpolymerization of CO with two vinylarenes was promoted by Pd(phenanthroline) complexes [109,110]. The terpolymerization of CO with propene and ethene using chiral diphosphine ligands 108 derived from carbohydrate (Fig. 10.26) was recently reported and showed that the presence of methoxy substituents on the phenyl rings bonded to the phosphorus atoms increased the degree of propene incorporation [111]. The terpolymerization of CO with one aliphatic and one aromatic olefins is somehow more versatile, and various types of ligand systems, such as P-P [112], P-OP [113], P-N [109,114] and N-N [94,95d,112,115–118], have been successfully used. Brookhart and Consiglio reported the use of chiral ligands (108 and 109, Fig. 10.26) in this reaction to produce optically active terpolymers. In contrast with the results obtained with dinitrogen ligands, the terpolymers produced by using the P–OP ligand (R,S)-BINAPHOS were shown to contain a much higher incorporation of aliphatic alkenes than vinylarenes. More recently, the use of the cationic palladium systems [PdMe(NCMe)(N-N′)] [BArF] containing pyridine-imidazoline ligands cis-107a, cis-107b, and cis and trans-107d was reported in the terpolymerization of CO/TBS/ethane, and circular dichroism analysis of the terpolymer obtained with the enantiomerically pure ligand 107d shows that it is optically active [119].

ArP

PAr O O

O

N

O

Ph

N

CH2OMe

O

O N

N

Me Ar = Ph, 2-OMe-Ph

109

110

Me

108 Figure 10.26. P-P and N-N ligands used for the Pd-catalyzed terpolymerization of CO with olefins.


10.5. CONCLUSIONS Asymmetric hydroformylation constitutes one of the most straightforward synthetic strategies for the preparation of optically active aldehydes, which are versatile intermediates for the synthesis of many biologically active compounds. In the last year, new ligands that, in combination with rhodium precursors, allow the control of the chemo-, regio-, and enantioselectivity for the production of aldehydes have appeared. The vinylarenes, which are the most studied substrates, can be hydroformylated with ee’s between 90% and 95%. Apart from the structurally unique BINAPHOS, which hydroformylates a wide range of olefins, diphosphite ligands constitute an efficient family of ligands for asymmetric rhodium hydroformylation reactions. Recently, the use of bisphophacyclic ligands has emerged as an alternative to diphosphite and phosphine-phosphite ligands use. The hydroformylation of substrates such as vinyl acetate, heterocyclic olefins, bicyclic olefins, and unsaturated nitriles opens new perspectives for the synthesis of a wide variety of products of biological interest. The characterization of intermediate species by HP NMR and in situ HP IR has provided a better understanding of the catalytic reaction. While great progress has been made over the last years in controlling the regioselectivity of the alkoxycarbonylation reaction, the stereoselectivity that is crucial in terms of pharmaceutical applications is still to be largely improved. However, due to this industrial interest, a number of patents have already been published [120]. The state of the art for this reaction can be summarized as follows: Pd(II) systems containing P monodentate or bidentate as well as P–N ligands are active precursors for the asymmetric alkoxycarbonylation of vinyl arenes. Interestingly, the regioselectivity can be controlled by an appropriate choice of the ligand and reaction conditions. Monodentate ligands and diphosphines with withdrawing substituents usually provide regioselectivities between 90% and 99% to the branched product. Although mechanistic studies have recently provided important advances, simultaneous control of regio- and enantioselectivities remains a challenge. In the case of the bis(alkoxycarbonylation), P–P ligands as well as P–N and N–N ligands have been used. Interestingly, nitrogen ligands such as bisoxazolines provide ee’s up to 66%. The highest ee values were achieved through the use of systems bearing phosphine ligands with axial chirality. The choice of the ligands is one of the key issues in this reaction. Although co- and terpolymerization of carbon monoxide and olefins has been the object of numerous investigations, the demand from industry to achieve new types of material makes this area still challenging and offers new possibilities. The use of N-N′ and S-S chiral ligands in the CO/styrene copolymerization can be used in order to control the stereochemistry of the catalysts and the stereoregularity of the resulting copolymers.

REFERENCES 1. (a) van Leeuwen, P. W. N. M.; Claver, C. Rhodium Catalysed Hydroformylation. Dordrecht: Kluwer Academic Press, 2000. (b) van Leeuwen, P. W. N. M. Homogeneous Catalysis “Understanding the Art”. Amsterdam: Elsevier, 2004. 2. (a) Cornils, B.; Herrmann, W. A. In Applied Homogeneous Catalysis with Organometallic Compounds, Vol. 1 (Eds. Cornils, B.; Herrmann, W.) Weinheim: VCH, 1996; p. 1. (b) Eilbracht, P.; Barfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. Rev. 1999, 99, 3329. (c) Yamashita, M.; Nozaki, K. In Comprehensive Organometallic Chemsity III (Eds. Mingos, M. P.; Crabtree, R. H.). Amsterdam: Elsevier, 2007; p. 435.

REFERENCES 833

3. (a) Breit, B.; Seiche, W. Synthesis, 2001, 1. (b) Castillón, S.; Férnandez, E. In Rhodium Catalyzed Hydroformylation (Eds. van Leeuwen, P. W. N. M.; Claver, C.). Dordrecht: Kluwer Academic Press, 2000; p. 145. (c) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. 4. (a) Nozaki, K.; Takaya, H.; Hiyama, T. Top. Catal. 1997, 4, 175. (b) Nozaki, K.; Ojima, I. Catalytic Asymmetric Synthesis (Ed. Ojima, I.). New York: Wiley-VCH, 2000, p. 429. 5. (a) Stille, J. K.; Su, H.; Brechot, P.; Parrinello, G.; Hgedus, L. S. Organometallics 1991, 10, 1183. (b) Consiglio, G.; Nefkens, S. C. A. Tetrahedron: Asymmetry 1990, 1, 417. (c) Consiglio, G.; Nefkens, S. C. A.; Borer, A. Organometallics 1991, 10, 2046. (d) Cserépi-Szücs, S.; Bakos, J. Chem. Commun. 1997, 635. 6. (a) Agbossou, F. F.; Carpentier, J. F.; Mortreux, A. Chem. Rev. 1995, 95, 2485. (b) Gladiali, S.; Bayón, J. C.; Claver, C. Tetrahedron: Asymmetry 1995, 7, 1453. (c) Consiglio, G. In Catalytic Asymmetric Syntheses (Ed. Ojima, I.). New York: VCH, 1993; 273. (d) Claver, C.; Diéguez, M.; Pàmies, O.; Castillón, S. In Topics in Organometallic Chemistry (Ed. Beller, M.). Berlin: Springer, 2006; 35. (e) Nozaki, K. In Comprehensive Asymmetric Catalysis (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer; 1999, 382. (f) Breit, B. Top. Curr. Chem. 2007, 279, 139. (g) Klosin, J.; Landis, C. R. Acc. Chem. Res. 2007, 40, 1251. 7. See for example: (a) Diéguez, M.; Pereira, M. M.; Masdeu-Bultó, A. M.; Claver, C.; Bayón, J. C. J. Mol. Catal. A: Chemical 1999, 143, 111; and references cited therein (b) Rampf, F. A.; Herrman, W. A. J. Organomet. Chem. 2000, 601, 138. 8. See for instance: (a) Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud, K. A. J. Am. Chem. Soc. 2005, 127, 5040. (b) Axtell, A. T.; Cobley, C. J.; Klosin, J.; Whiteker, G. T.; Zanotti-Gerosa, A.; Abboud, K. A. Angew. Chem. Int. Ed. 2005, 44, 5834. (c) Axtell, A. T.; Klosin, J.; Abboud, K. A. Organometallics 2006, 25, 5003. 9. For some successful applications, see: (a) Babin, J. E.; Whiteker, G. T. (Union Carbide Chem. Plastics Techn. Co.) WO 93/03839, 1993. Chem. Abs. 1993, 119, P159872h. (b) Buisman, G. J. H.; van deer Veen, L. A.; Klootwijk, A.; de Lange, W. G. J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Vogt, D. Organometallics 1997, 16, 2929. (c) Diéguez, M.; Pàmies, O.; Ruiz, A.; Castillón, S.; Claver, C. Chem. Commun. 2000, 1607. (d) Diéguez, M.; Pàmies, O.; Ruiz, A.; Castillón, S.; Claver, C. Chem. Eur. J. 2001, 7, 3086. (e) Diéguez, M.; Pàmies, O.; Ruiz, A.; Claver, C. New. J. Chem. 2002, 26, 827. 10. See for example: (a) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.; Mano, S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413. (b) Franciò, G.; Leitner, W. Chem. Commun. 1999, 1663. 11. (a) Buisman, G. J. H.; Vos, E. J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. J. Chem. Soc. Dalton Trans. 1995, 409. (b) Cserépi-Szûcs, S.; Tóth, I.; Párkányi, L.; Bakos, J. Tetrahedron: Asymmetry 1998, 9, 3135. (c) Abdallah, R.; Breuzard, J. A. J.; Bonnet, M. C.; Lemaire, M. J. Mol. Cat.: A Chem. 2006, 249, 218. 12. [RhH(CO)2diphosphite] species are known to be the resting state in the hydroformylation reaction. See for instance Reference 1a. 13. Buisman, G. J. H.; van der Veen, L. A.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Organometallics 1997, 16, 5681. 14. (a) Pàmies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2000, 11, 1097. (b) Diéguez, M.; Ruiz, A.; Claver, C. Dalton Trans. 2003, 2957. 15. (a) Cserépi-Szûcs, S.; Huttner, G.; Zsolnai, L.; Bakos, J. J. Organomet. Chem. 1999, 586, 70. (b) Cserépi-Szûcs, S.; Huttner, G.; Zsolnai, L.; Szölösy, A.; Hegebüs, C.; Bakos, J. Inorg. Chim. Acta 1999, 296, 222. (c) Vegehetto, V.; Scrivanti, A.; Matteoli, U. Catal. Commun. 2001, 2, 139. (d) Jiang, Y.; Xue, S.; Li, Z.; Deng, J.; Mi, A.; Chan, A. S. C. Tetrahedron: Asymmetry 1998, 9, 3185. (e) Jiang, Y.; Xue, S.; Yu, K.; Li, Z.; Deng, J.; Mi, A.; Chan, A. S. C. J. Organomet. Chem. 1999, 586, 159. (f) Kadyrov, R.; Heller, D.; Selke, R. Tetrahedron: Asymmetry 1999, 9, 329. (g) Freixa, Z.; Bayón, J. C. J. Chem. Soc., Dalton Trans. 2001, 2067. (h) Wang, L. L.; Guo, E.-W.; Li, Y.-M.; Chan, A. S. C. Tetrahedron: Asymmetry 2005, 16, 3198. (i) Cobley, C. J.; Froese, R. D. J.; Klosin, J.; Qin, C.; Witheker, G. T.; Abboud, K. A. Organometallics 2007, 26, 2986. (j) Cobley, C. J.; Klosin, J.; Qin, C.; Whiteker, G. T. Org. Lett. 2004, 6, 3277.

834 ASYMMETRIC CARBONYLATIONS 16. Sakai, N.; Mano, S.; Nozaki, K.; Takaya, K. J. Am. Chem. Soc. 1993, 115, 7033. 17. Nozaki, K.; Matsuo, T.; Shibahara, F.; Hiyama, T. Adv. Synth. Catal. 2001, 343, 61. 18. (a) Nakano, K.; Tanaka, R.; Nozaki, K. Helv. Chim. Acta 2006, 89, 1681. (b) Tanaka, R.; Nakano, K.; Nozaki, K. J. Org. Chem. 2007, 72, 8671. 19. Nozaki, K.; Matsuo, T.; Shibayara, F.; Hiyama, T. Organometallics 2003, 22, 594. 20. (a) Nozaki, K.; Itoi, Y.; Shibayara, F.; Shirakawa, E.; Ohta, T.; Takaya, H.; Hiyama, T. J. Am. Chem. Soc. 1998, 120, 4051. (b) Nozaki, K.; Shibahara, F.; Itoi, Y.; Shirakawa, E.; Ohta, T.; Takaya, H.; Hiyama, T. Bull. Chem. Soc. Jpn. 1999, 72, 1911. 21. Franciò, G.; Wittmann, K.; Leitner, W. J. Organomet. Chem. 2001, 621, 130. 22. (a) Deeremberg, S.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Organometallics 2000, 19, 2065. (b) Pàmies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2001, 12, 3441. (c) Arena, C. G.; Faraone, F.; Graiff, C.; Tiripicchio, A. Eur. J. Inorg. Chem. 2002, 711. (d) Rubio, M.; Suárez, A.; Álvarez, E.; Bianchini, C.; Oberhauser, W.; Peruzzini, M.; Pizzano, A. Organometallics 2007, 26, 6428. 23. Yan, Y.; Zhang, X. J. Am. Chem. Soc. 2006, 128, 7198. 24. (a) Lot, O.; Suisse, I.; Mortreux, A.; Agbossou, F. J. Mol. Catal. A: Chem. 2000, 164, 125. (b) Diéguez, M.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2001, 12, 2827. (c) Naili, S.; Suisse, I.; Mortreux, A.; Agbossou-Niedercorn, F.; Nowogrocki, G. J. Organomet. Chem. 2001, 628, 114. (d) Cessarotti, E.; Araneo, S.; Rimoldi, I.; Tassi, S. J. Mol. Catal. A: Chem. 2003, 204–205, 211. (e) Ewalds, R.; Eggeling, E. B.; Hewat, A. C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Voght, D. Chem. Eur. J. 2000, 6, 1496. (f) Pàmies, O.; Diéguez, M.; Net, G.; Ruiz, A.; Claver, C. Organometallics 2000, 19, 1488. (g) Saluzzo, C.; Breuzard, J.; Pellet-Rostaing, S.; Vallet, M.; Guyader, F. L.; Lemaire, M. J. Organomet. Chem. 2002, 643–644, 98. (h) Franció, G.; Drommi, D.; Graiff, C.; Faraone, F.; Tiripicchio, A. Inorg. Chim. Acta 2002, 338, 59. 25. (a) Kuil, M.; Goudriaan, P. E.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Commun. 2006, 4679. (b) Kuil. M.; Goudriaan, P. E.; Kleij, A. W.; Tooke, D. M.; Spek, A. L.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Dalton Trans. 2007, 2311. 26. Matsumoto, M.; Tamura, M. J. Mol. Cat. 1982, 16, 195. 27. Sakai, N.; Nozaki, K.; Mashima, K.; Takaya, H. Tetrahedron: Asymmetry 1993, 3, 583. 28. Higashizima, T.; Sakai, N.; Nozaki, K.; Takaya, H. Tetrahedron Lett. 1994, 35, 2023. 29. Zou, Y.; Yna, Y.; Zhang, X. Tetrahedron Lett. 2007, 48, 4781. 30. Thomas, P. J.; Axtell, A. T.; Klosin, J.; Peng, W.; Rand, C. L.; Clark, T. P.; Landis, C. R.; Abboud, K. A. Org. Lett. 2007, 9, 2665. 31. (a) Breeden, S.; Cole-Hamilton, D. J.; Foster, D. F.; Schwarz, G. J.; Wills, M. Angew. Chem. Int. Ed. 2000, 39, 4106. (b) Clarkson, G. J.; Ansel, J. R.; Cole-Hamilton, D. J.; Pogorzelec, P. J.; Whittell, J.; Mills, M. Tetrahedron: Asymmetry 2004, 15, 1787. 32. Peng, X.; Wang, Z.; Xia, C.; Ding, K. Tetrahedron Lett. 2008, 49, 4862. 33. Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ischichi, Y.; Fujishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Doi, T. J. Med. Chem. 1999, 42, 3982. 34. Lambers-Verstappen, M. M. H.; de Vries, J. G. Adv. Synth. Catal. 2003, 345, 478. 35. Hua, Z.; Vassar, V. C.; Choi, H.; Ojima, I. PNAS 2004, 101, 5411. 36. See for instance: (a) Reference 1a. (b) Polo, A.; Real, J.; Claver, C.; Castillón, S.; Bayón, J. C. J. Chem. Soc. Chem. Commun. 1990, 600. (c) Polo, A.; Claver, C.; Ruiz, A.; Castillón, S.; Bayón, J. C.; Real, J.; Mealli, C.; Massi, D. Organometallics 1992, 11, 3525. 37. Horiuchi, T.; Ohta, T.; Shirakawa, E.; Nozaki, K.; Takaya, H. J. Org. Chem. 1997, 62, 4285. 38. Diéguez, M.; Pàmies, C.; Claver, C. Chem. Commun. 2005, 1221. 39. Huang, J.; Bunel, E.; Allgeier, A.; Tedrow, J.; Storz, T.; Preston, J.; Correll, T.; Manley, D.; Soukup, T.; Jensen, R.; Syed, R.; Moniz, G.; Larsen, R.; Martinelli M.; Reider, P. J. Tetrahedon Lett. 2005, 46, 7831.

REFERENCES 835

40. Parrinello, G.; Deschenaux, R.; Stille, J. K. J. Org. Chem. 1986, 51, 4189. (b) Parrinello, G.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 7122. (c) Lu, S.; Li, X.; Wang, A. Catal. Today 2000, 63, 531. 41. Godard, C.; Muñoz, B. K.; Ruiz, A.; Claver, C. Dalton Trans. 2008, 853. 42. Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. Int. Ed. 2004, 43, 3368. 43. (a) Knifton, J. J. Org. Chem. 1976, 41, 793. (b) Cavinato, G.; Toniolo, L. J. Organomet. Chem. 1990, 398, 187. (c) Milstein, D. Acc. Chem. Res. 1988, 21, 428. (d) Kanawa, M.; Nakamura, S.; Watanabe, E.; Urata, H. J. Organomet. Chem. 1997, 542, 185. 44. del Río, I.; Claver, C.; van Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 2001, 2719, and references therein. 45. (a) Ali, B. E.; Alper, H. J. Mol. Catal. 1993, 80, 377. (b) Pisano, C.; Mezzetti, A.; Consiglio, G. Organometallics 1992, 11, 20. (c). Dekker, G. P. C. M.; Elsevier, C. J.; Vrieze, K.; van Leeuwen, P. W. N. M.; Roobeek, C. F. J. Organomet. Chem. 1992, 430, 357. 46. (a) Consiglio, G.; Marchetti, M. Chimia 1976, 30, 26. (b) Consiglio, G.; Nefkens, S. C. A.; Pisano, C.; Wenzinger, F. Helv. Chim. Acta 1991, 74, 323. 47. van Leeuwen, P. W. N. M.; Zuideveld, M. A.; Swennenhuis, B. H. G.; Freixa, Z.; Kamer, P. C. J.; Goubitz, K.; Fraanje, J.; Lutz, M.; Spek, A. L. J. Am. Chem. Soc. 2003, 125, 5523. 48. del Río, I.; Ruiz, N.; Claver, C. Inorg. Chem. Commun. 2000, 3, 166. 49. Sugi, Y.; Bando, K. Chem. Lett. 1976, 5, 727. 50. Guiu, E.; Caporali, M.; Muñoz, B.; Müller, C.; Lutz, M.; Spek, A. L.; Claver, C.; van Leeuwen, P. W. N. M. Organometallics 2006, 25, 3102. 51. (a) Zuidema, E.; Bo, C.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2007, 129(13), 3989. (b) Donald, S. M. A.; Macgregor, S. A.; Settels, V. D.; Cole-Hamilton, D. J.; Eastham, G. R. Chem. Commun. 2007, 6, 562. 52. Phosphorus Ligands in Asymmetric Catalysis. Synthesis and Applications (Ed. Börner, A.). Weinheim: Wiley-VCH, 2008. 53. Botteghi, C.; Consiglio, G.; Pino, P. Chimia 1973, 27, 477. 54. Consiglio, G. Helv. Chim. Acta 1976, 59, 124. 55. Consiglio, G.; Pino, P. Chimia 1976, 30, 193. 56. Consiglio, G. J. Organomet. Chem. 1977, 132, C26–27. 57. (a) Hayashi, T.; Tanaka, M.; Ogata, I. Tetrahedron Lett. 1978, 41, 3925. (b) Hayashi, T.; Tanaka, M.; Ogata, I. J. Mol. Catal. 1984, 26, 17. 58. Zhou, H.; Hou, J.; Cheng, J.; Lu, S.; Fu, H.; Wang, H. J. Organomet. Chem. 1997, 543, 227. 59. del Río, I.; Ruiz, N.; Claver, C.; van der Veen, L. A.; van Leeuwen, P. W. N. M. J. Mol. Catal. A: Chem. 2000, 161, 39. 60. Miquel-Serrano, M. D.; Aghmiz, A.; Diéguez, M.; Masdeu-Bultó, A. M.; Claver, C.; Sinou, D. Tetrahedron: Asymmetry 1999, 10, 4463. 61. Nozaki, K.; Kantam, M. L.; Horiuchi, T.; Takaya, H. J. Mol. Catal. A: Chem. 1997, 118, 247. 62. (a) Oi, S.; Nomura, M.; Aiko, T.; Inoue, Y. J. Mol. Catal. A: Chem. 1997, 115, 289. (b) Wang, L.; Kwok, W. H.; Chan, A. S. C.; Tu, T.; Hou, X.; Dai, L. Tetrahedron Asymmetry 2003, 14, 2291. (c) Godard, C.; Ruiz, A.; Claver, C. Helv. Chim. Acta 2006, 89, 1610. 63. Chelucci, G.; Cabras, M. A.; Botteghi, C.; Basoli, C.; Marchetti, M. Tetrahedron: Asymmetry 1996, 7, 885. 64. Cometti, G.; Chiusoli, G. P. J. Organomet. Chem. 1982, 236, C31. 65. Zim, D.; de Souza, R. F.; Dupont, J.; Monteiro, A. L. Tetrahedron Lett. 1998, 39, 7071. 66. (a) Alper, H.; Hamel, N. J. Am. Chem. Soc. 1990, 112, 2803. (b) Alper, H. Patent No. WO 9103452, 1991. 67. Yang, K.; Jiang, X. Chemical Journal on Internet, 2005, 7, 14. 68. Kawashima, Y.; Okano, K.; Nozaki, K.; Hiyama, T. Bull. Chem. Soc. Jpn. 2004, 77, 347.

836 ASYMMETRIC CARBONYLATIONS 69. (a) Muñoz, B. K.; Godard, C.; Marinetti, A.; Ruiz, A.; Benet-Buchholz, J.; Claver, C. Dalton Trans. 2007, 5524. (b) Muñoz, B.; Marinetti, A.; Ruiz, A.; Castillon, S.; Claver, C. Inorg. Chem. Commun. 2005, 8, 1113. 70. Zhou, H.; Hou, J.; Chen, J.; Lu, S.; Fu, H.; Wang, H. Chem. Lett. 1998, 19(3), 247. 71. Gironès, J.; Duran, J.; Polo, A.; Real, J. Chem. Commun. 2003, 1776. 72. Gotov, N.; Schmaltz, H.-G. Org. Lett. 2001, 3, 1753. 73. Kleeman, J.; Engel, A. Pharmazeutische Wirkstoffe. Stuttgart: Thieme Verlag, 1982. 74. (a) Yoshikawa, K.; Inoguchi, K.; Achiwa, K. Heterocycles 1990, 31, 1413. (b) Ito, Y.; Kamijo, T.; Harada, H.; Matsuda, F.; Terashima, S. Tetahedron Lett. 1990, 31, 2731. (c) Inoguchi, K.; Morimoto, T.; Achiwa, K. J. Organomet. Chem. 1989, 370, C9. (d) Jendralla, H. Tetrahedron Lett. 1991, 32, 3671. (e) Kammermeier, B.; Beck, G.; Holla, W.; Jacobi, D.; Napierski, B.; Jendralla, H. Chem. A. Eur. J. 1996, 2, 307. 75. Heck, R. F. J. Am. Chem. Soc. 1972, 94, 2712–2716. 76. Nefkens, S. C. A.; Sperrle, M.; Consiglio, G. Angew. Chem. Int. Ed. Engl. 1993, 2, 1719. 77. Sperrle, M.; Consiglio, G. J. Mol. Catal. A: Chem. 1999, 143, 263. 78. Wang, L.; Kwok, W.; Wu, J.; Guo, R.; Au-Yeung, T. T.-L.; Zhou, Z.; Chan, A. S. C.; Chan, K.-S. J. Mol. Catal. A: Chem. 2003, 196, 171. 79. Liang, B.; Liu, J.; Gao, Y.-X.; Wongkhan, K.; Shu, D.-X.; Lan, Y.; Li, A.; Batsanov, A. S.; Howard, J. A. H.; Marder, T. B.; Chen, J.-H.; Yang, Z. Organometallics 2007, 26, 4756. 80. Shell, Carilon® Thermoplastic Polymers, Information Sheet, 1994. 81. European Plastics News, October, 1995, 57. 82. (a) Lommerts, B. J. Eur. Patent 456306, 1991. (b) Ash, C. E. Int. J. Polym. Mater. 1995, 30, 1. 83. (a) Drent, E.; Budzelaar, P. H. M. Chem. Rev. 1996, 96, 663. (b) Bianchini, C.; Meli, A. Coord. Chem. Rev. 2002, 225, 35. 84. (a) Drent, E.; Budzelaar, P. H. M. Chem. Rev. 1996, 96, 663. (b) Bianchini, C.; Meli, A. Coord. Chem. Rev. 2002, 225, 35. 85. Sen, A. Acc. Chem. Res. 1993, 26, 303. 86. Zuideveld, M. A.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Klusener, P. A. A.; Stil, H. A.; Roobeek, C. F. J. Am. Chem. Soc. 1998, 120, 7977. 87. Consiglio, G. In Late Transition Metal Polymerisation Catalysts (Eds. Rieger, B.; Daunders-Baugh, L.; Kacker, S.; Striegler, S.). Weinheim: Wiley-VCH, 2003; p. 279, 88. Bronco, S.; Consiglio, G. Macromol. Chem. Phys. 1995, 197, 355. 89. Bronco, S.; Consiglio, G.; Hutter, R.; Batistini, A. Macromolecules 1994, 27, 4436. 90. Gambs, C.; Chaloupka, S.; Consiglio, G.; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 2486. 91. Xumu, Z. Pat. Appl. WO9713763, 1997. 92. (a) Batistini, A.; Consiglio, G.; Suter, U.W. Angew. Chem. Int. Ed. Engl. 1992, 31, 303. (b) Jiang, Z.; Sen, A. J. Am. Chem. Soc. 1995, 117, 4455. (c) Nozaki, K.; Yasutomi, M.; Nakamoto, K.; Hiyama, T. Polyhedron 1998, 17, 1159. 93. (a) Nozaki, K.; Hiyama, T. J. Organomet. Chem. 1999, 576, 248–253. (b) Nosaki, K.; Kawashima, Y.; Nakamoto, K.; Hiyama, T. J. Polymer 1999, 31, 1057. 94. Sen, A.; Jiang, Z. Macromolecules 1993, 26, 911–915. 95. (a) Drent, E. Eur. Pat. Appl. 229408, 1986. (b) Corradini, P.; De Rosa, C.; Panunzi, A.; Petrucci, G.; Pino, P. Chimia 1990, 44, 52. (c) Barsaccchi, M.; Consiglio, G.; Medici, L.; Petrucci, G.; Suter, U. W. Angew. Chem. Int. Ed. Engl. 1991, 30, 989. (d) Brookhart, M.; Rix, F. C.; DeSimone, J. M.; Barborak, J. C. J. Am. Chema Soc. 1992, 114, 5894. (e) Pisano, C.; Mezzetti, A.; Consiglio, G. Organometallics 1992, 11, 20. (f) Barsaccchi, M.; Batistini, A.; Consiglio, G.; Suter, U. W. Macromolecules 1992, 25, 3604. (g) Milani, B.; Alessio, E.; Mestroni, G.; Sommazzi, A.; Garbassi, F.; Zangrando, E.; BrescianiPahor, N.; Randaccio, L. J. Chem. Soc. Dalton Trans. 1994, 1903. (h) Milani, B.; Mestroni, G.; Sommazzi, A.; Garbassi, F. It. Patent MIA000337, 1995. (i) Feng, Y.; Sun, J.; Zhu, Y.; Chen, W. J. Polym.

REFERENCES 837

Sci. Part A: Polym. Chem. 1997, 35, 1283. (j) Feng, Y.; Sun, J.; Yao, F.; Yu, Y. J. Appl. Polym. Sci. 1997, 68, 855–857. 96. (a) Nozaki, K.; Sato, N.; Takaya, H. J. Am. Chem. Soc. 1995, 117, 9911. (b) Nozaki, K.; Sato, N.; Tonomura, Y.; Yasutomi, M.; Takaya, H.; Hiyama, T.; Matsubara, T.; Koga, N. J. Am. Chem. Soc. 1997, 119, 12779. (c) Nozaki, K.; Sato, N.; N.akamoto, N.; Takaya, H. Bull. Chem. Soc. Jpn. 1997, 70, 659. (d) Nozaki, K.; Yasutomi, M.; Nakamoto, K.; Hiyama, T. Polyhedron 1998, 17, 1159. (e) Nozaki, K.; Kawashima, Y.; Hiyama, T. Polym. J. 1999, 31, 1057. 97. Nozaki, K.; Komaki, H.; Kawashima, Y.; Hiyama, T.; Matsubara, T. J. Am. Chem. Soc. 2001, 123, 534. 98. Van Doorn, J. A.; Drent, E. Eur. Pat. Appl. 345847, 1989. 99. Bastero, A.; Claver, C.; Ruiz, A. Catal. Lett. 2002, 82(1–2), 85. 100. Yuan, J. C.; Lu, S. J. J. Polym. Sci. Part A: Polym. Chem. 2000, 38, 2919. 101. Brookhart, M.; Wagner, M. I.; Balavoine, G. G. A.; Haddou, H.A. J. Am. Chem. Soc. 1994, 116, 3641. 102. Jang, Z.; Adams, S. E.; Sen, A. Macromolecules 1994, 27, 2694. 103. Bartolini, S.; Carfagna, C.; Musco, A. Macromol. Rapid Commun. 1995, 16, 9. 104. Reetz, M. T.; Haderlein, G.; Angermund, K. J. Am. Chem. Soc. 2000, 122, 996. 105. Brookhart, M.; Wagner, M. I. J. Am. Chem. Soc. 1996, 118, 7219. 106. Milani, B.; Alessio, E.; Mestroni, G.; Zangrando, E.; Randaccio, L.; Consiglio, G. J. Chem. Soc. Dalton Trans. 1996, 1021. 107. Bastero, A.; Ruiz, A.; Reina, J. A.; Claver, C.; Guerrero, A. M.; Jalón, F. A.; Manzano, B. R. J. Organomet. Chem. 2001, 619, 287. 108. (a) Sesto, B.; Bronco, S.; Gindro, E. L.; Consiglio, G. Macromol. Chem. Phys. 2001, 202, 2059. (b) Bianchini, C.; Lee, H. M.; Meli, A.; Moneti, S.; Patinec, V.; Petrucci, G.; Vizza, F. Macromolecules 1999, 32, 3859. (c) Lindner, E.; Schmidt, M.; Wald, J.; Queisser, J. A.; Geprägs, M.; Wegner, P.; Nachtigal, C. J. Organomet. Chem. 2000, 602, 173. (d) Milani, B.; Vincentini, L.; Sommazzi, A.; Garbassi, F.; Chiarparin, E.; Zangrando, E.; Mestroni G. J. Chem. Soc. Dalton Trans. 1996, 3139. 109. Aeby, A.; Consiglio, G. J. Chem. Soc. Dalton Trans. 1999, 655. 110. Milani, B.; Scarel, A.; Durand, J.; Mestroni, G.; Seraglia, R.; Carfagna, C.; Binotti, B. Macromolecules, 2003, 36, 6295. 111. Muñoz-Moreno, B.; Claver, C.; Ruiz, A.; Bianchini, C.; Meli, A.; Oberhauser, W. Dalton Trans. 2008, 2741. 112. Kacker, S.; Sissano, J. A.; Schulz, D. N. J. Polym. Sci.: Part A: Polym. Chem. 2000, 38, 752. 113. (a) Nozaki, K.; Kawashima, Y.; Nakamoto, K.; Hiyama, T. Macromolecules 1999, 32, 5168. (b) Kawashima, Y.; Nozaki, K.; Hiyama, T. Inorg. Chim. Acta 2003, 350, 577. 114. Aeby, A.; Consiglio, G. Helv. Chim. Acta 1998, 81, 35. 115. Macchioni, A.; Bellachioma, G.; Cardaci, G.; Travaglia, M.; Zuccaccia, C.; Milani, B.; Corso, G.; Zangrando, E.; Mestroni, G.; Carfagna, C.; Formica, M. Organometallics 1999, 18, 3061. 116. Aeby, A.; Gsponer, A.; Sperrle, M.; Consiglio, G. J. Organomet. Chem. 2000, 603, 122. 117. Muellers, B.T.; Park, J.-W.; Brookhart, M.S.; Green, M.M. Macromolecules 2001, 34, 572. 118. (a) Milani, B.; Mistaro, A.; Mestroni, G. Abstract. Stockholm: ISHC12, 2000; p. 216. (b) Durand, J.; Scarel, A.; Milani, B.; Seraglia, R.; Gladiali, S.; Carfagna, C.; Binotti, B. Helv. Chim. Acta 2006, 89, 1752. 119. Bastero, A.; Ruiz, A.; Claver, C.; Bella, A. F.; Milani, B.; Moreno-Lara, B.; Jalón, F. A.; Manzano, B. R. Adv. Synth. Catal. 2005, 347, 839. 120. (a) Drent, E. Patent No. EP0106379, 1984. (b) Stephan, M. M.; Mohar, B. Patent No. WO 2006136695, 2006. (c) Klosin, J.; Whiteker, G.; Cobley, C. Patent No. WO 2006116344, 2006. (d) Holz, J.; Boermer, A.; Almena, J. J.; Kadyrov, R.; Monsees, A.; Riermeier, T. Patent No. WO 2006100169, 2006. (e) Holz, J.; Boermer, A.; Zayas, O.; Almena Perea, J. J.; Kadyrov, R.; Monsees, A.; Riermeier, T.

838 ASYMMETRIC CARBONYLATIONS Patent No. WO 2006100165, 2006. (f) Zhang, X.; Liu, D. Patent No. WO 2005058917, 2005. (g) Zhang, X.; Tang, W. Patent No. WO 2005117907, 2005. (h) Zhang, X. Patent No. US 2004072680, 2004. (i) Zhang, X.; Tang, W. Patent No. WO 2003042135, 2003. (j) Zhang, X. Patent No. WO 2002040491, 2002. (k) Zhang, X. Patent No. WO 2001034612, 2001. (l) Zhang, X. Patent No. WO 2001021625, 2001. (m) Zhang, X. Patent No. WO 9713763, 1997. (n) Alper, H. Patent No. EP 305089, 1989. (o) Botteghi, C.; Consiglio, G.; Pino, P. Patent No. CH 598184, 1978. (p) Consiglio, G. Patent No. CH 588438, 1977.

11 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS Kazuhiro Matsumoto and Tsutomu Katsuki Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, 6-10-1 Hakozaki Higashi-ku, Fukuoka 812-8581, Japan

11.1. GENERAL INTRODUCTION Oxidation is a fundamental technology for converting bulk chemicals into valuable materials and is also a useful tool for sophisticated functionalization of organic molecules. Thus, intensive research efforts have been devoted to the development of selective and practical oxidation methods, and a wide variety of chiral metal-based catalysts and organocatalysts have been developed for catalytic asymmetric oxidation reactions in industry and academia in the last half-century [1]. In contrast to the rapid improvement in stereoselectivity, the enhancement of atom economy [2] falls behind. While atom efficiency (especially active oxygen content in oxygenation reactions) of stoichiometric oxidants is a factor that should be considered, most of the catalytic asymmetric oxidations still use conventional stoichiometric oxidants of low atomefficiency such as peracids, alkyl hydroperoxides, hypervalent iodine reagents, hypochlorite, and N-oxide compounds (Table 11.1). The use of such oxidants causes the formation of large amounts of undesirable waste. From the viewpoint of ecological sustainability, oxidation with a higher atom-efficient, safe, abundant, and preferably inexpensive oxidant is favorable. Considering the requirements, molecular oxygen and hydrogen peroxide are the oxidants of choice [3]. Molecular oxygen offers a large advantage because it is abundant in air and is inexpensive. Aerobic oxidation that directly uses ambient air as an oxidant is similar to respiration in living organisms. Hydrogen peroxide is also recognized as a green oxidant. It is almost as equally atomefficient as molecular oxygen, and the by-product is safe and clean water. Moreover, its aqueous solution (typically 30–35%) is inexpensive and easy to handle. Consequently, the development of catalytic asymmetric oxidations with molecular oxygen Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima Copyright © 2010 John Wiley & Sons, Inc. 839

840 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS

TABLE 11.1. Active Oxygen Content Oxidant

By-product

O2 O2 H2O2 NaOCl

— H2O H2O NaCl

tBuOOH (TBHP) KHSO5 (Oxone®)

tBuOH KHSO4

mClC6H4CO3H (mCPBA) PhIO

mClC6H4CO2H PhI

Active Oxygen Content (%) 100 50 47.0 21.6 17.8 10.5 9.3 7.3

or hydrogen peroxide as oxidants is one of the most important issues to be addressed by organic chemists. Since the launch of the second edition, remarkable progress has been made in the field of catalytic asymmetric oxidation. This chapter mainly focuses on the recent developments of catalytic asymmetric oxidations using molecular oxygen or hydrogen peroxide as oxidants reported after 2000, and the notable advancements in oxidation using conventional oxidants are also reviewed.

11.2. ASYMMETRIC OXIDATION OF ALCOHOLS 11.2.1. Introduction Oxidation of alcohols to the corresponding carbonyl compounds is a pivotal process for organic synthesis, and many methods have been developed [4]. Among them, oxidations that employ readily available molecular oxygen, especially ambient air, as the stoichiometric oxidant are the most preferable. Therefore, the development of aerobic alcohol oxidations has attracted increasing interest, and some synthetically valuable protocols using transition-metal complexes and organic molecules as catalyst have been reported [5]. Recently, significant progress has also been made in the development of chiral catalysts. The asymmetric reactions are mainly divided into two classes: kinetic resolution of racemic secondary alcohols and desymmetrization of meso- or prochiral diols (Scheme 11.1).

Desymmetrization

Kinetic resolution OH R

R'

OH R

R'

OH OH

O

+ R

R'

R

n

R

OH O R

n

R

Racemic OH OH n

Scheme 11.1.

OH O n

H

11.2. ASYMMETRIC OXIDATION OF ALCOHOLS 841

11.2.2. Palladium Catalyst Among the transition-metal catalysts developed for aerobic oxidation of alcohols, palladium-based complexes, in particular, have been investigated. In 1977, Schwaltz and Blackburn reported the first synthetically valuable, palladium-catalyzed aerobic oxidation of alcohols that uses PdCl2 with NaOAc [6]. Although the following 20 years had seen few developments in this area, the palladium-catalyzed methods have received the most attention over the recent years [7,8]. A generally accepted catalytic cycle is illustrated in Scheme 11.2. The cycle consists of the two separate processes: alcohol oxidation and catalyst regeneration. In the alcohol oxidation process, palladium alkoxide is formed after alcohol coordination, and then β-hydride elimination occurs to give a carbonyl product. The resulting palladium hydride complex is converted to the corresponding palladium hydroperoxo species by the reaction with molecular oxygen, and the subsequent ligand exchange regenerates the initial catalyst. There are two possible pathways to give the PdII hydroperoxide species: direct insertion of molecular oxygen to PdIIhydride bond or reductive elimination/peroxo formation/protonolysis sequence. The feasibility of each pathway has been supported by experimental and theoretical studies. In 1998, Uemura and coworkers reported the palladium-catalyzed aerobic oxidation of alcohols, using a Pd(OAc)2, pyridine, and molecular sieve 3A system [8a,b]. Inspired by the report, Sigman et al. and Stoltz and Ferreira independently disclosed the palladium-catalyzed oxidative kinetic resolution of racemic alcohols, in which a naturally occurring diamine, (−)-sparteine, serves as an effective chiral source (Scheme 11.3) [9,10]. Sigman and coworkers employed the two reaction conditions: Pd(OAc)2 in dichloroethane (DCE) at 60°C and Pd(CH3CN)2Cl2 at 70°C. On the other hand, Stoltz’s methods utilized Pd(nbd)Cl2 with molecular sieves in toluene at 80°C. While there are slight differences between the reaction conditions of the methods, both systems efficiently resolve a range of benzylic alcohols with good to high krel values. An allylic alcohol and an aliphatic alcohol also undergo resolution albeit with moderate krel values.

Alkoxide formation X LnPdII Alcohol binding

HX

X

R

O H

LnPdII

X

R

O

β-Hydride elimination

R'

R'

OH R

O

R'

R

LnPdIIX2

LnPdII

Catalytic cycle O2

X

Alcohol oxidation process

H

Catalyst regeneration process

H2O2 HX HX LnPdII

X

Regeneration

OOH LnPdII HX

O O

LnPd0 O2

Scheme 11.2.

R'

842 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS PdII salt (5 mol %) (–)-sparteine (20 mol %)

OH R

solvent, additive, O2, temp.

R'

OH R

+

R'

Stoltz's method A: Pd(nbd)Cl2, PhCH3, MS3A, 80°C

O R

Sigman's method B: Pd(OAc)2, DCE, no additive, 60°C R'

OH

Sigman's method C: Pd(CH3CN)2Cl2, DCE, no additive, 70°C

OH

OH

Br 59.3% conv., 93.1% ee, krel 14.8 59.4% conv., 82.0% ee, krel 8.7 57.5% conv., 88.5% ee, krel 11.6

Method A: 59.9% conv., 98.7% ee, krel 23.1 Method B: 65.9% conv., 98.2% ee, krel 13.0 Method C: 53.9% conv., 86.9% ee, krel 17.5

43.5% conv., 66.1% ee, krel 23.6

Scheme 11.3. OH Pd[(−)-sparteine]Cl2 1 (5 mol %)

No oxidation

DCE, O2, 60°C N OH

Pd[(−)-sparteine]Cl2 1 (5 mol %) (−)-sparteine (10 mol %)

OH

O +

DCE, O2, 60°C

N

Pd Cl Cl 1

51.5% conv., 82.4% ee krel 20.1

Scheme 11.4.

OH

2 (2.5 mol %) (−)-sparteine (20 mol %)

OH

DCE, O2, MS3A, 65°C, 20 h

O +

(R,R)-2: 39.7% conv., 36.4% ee krel 4.5 (S,S)-2: 34.6% conv., 42.0% ee krel 11.8

Ph

Ph

Ar N

N Ar

Cl Pd Cl Cl Pd Cl Ar N

N Ar

Ph

Ph 2 Ar = 2,3,5,6-Me4C6H1

Scheme 11.5.

Moreover, Sigman et al. disclosed that the isolated Pd[(−)-sparteine]Cl2 complex 1 is incompetent as the catalyst, although catalytic activity is restored by the addition of (−)-sparteine (Scheme 11.4) [9,11]. The additional (−)-sparteine serves as an exogenous base to abstract a proton from a palladium-bound alcohol in the alkoxide formation process. The observation implies that the proton abstraction step might be an enantiomer differentiation process. Indeed, Sigman and Jensen reported that palladium complexes bearing chiral or achiral N-heterocyclic carbene ligands promote the oxidative kinetic resolution in the presence of (−)-sparteine (Scheme 11.5) [12]. (S,S)-2 makes a matched pair with (−)-sparteine and exhibits higher selectivity than (R,R)-2.


The complex 1, together with 20 mol % of (−)-sparteine in tBuOH, effectively promotes the kinetic resolution of benzylic alcohols with higher selectivity than that observed under the original conditions [13]. Kinetic resolution of nonbenzylic alcohols also proceeds with moderate to high krel values, and the method could be applied to desymmetrization of 1,3-meso-diols to give enantio-enriched β-hydroxyketones with good enantioselectivity (Scheme 11.6). On the other hand, Stoltz and coworkers reported that the addition of Cs2CO3 and tBuOH greatly accelerates the reaction, although a long reaction time (typically 4 days) is required to obtain high conversion of alcohols in their original conditions [10,14]. With these additives, the resolutions are achieved in less than 24 h at 60°C with comparable selectivity. Eventually, the group found that the optimal conditions use 5 mol % of Pd(nbd)Cl2 and 12 mol % of (−)-sparteine in chloroform in the presence of 0.4 equivalents of Cs2CO3 and molecular sieves at 23°C (Scheme 11.7) [15]. It is worth noting that ambient air is available instead of pure molecular oxygen under these conditions. It has been proposed that chloroform accelerates the reaction rate through hydrogen bonding with some intermediates and/or solvating to the chloride ion. The utility of the Pd/(−)-sparteine-catalyzed aerobic alcohol oxidation can be recognized by its application to the enantioselective preparation of key pharmaceutical

Pd[(−)-sparteine]Cl2 1 (5 mol %) (−)-sparteine (20 mol %)

OH

OH

O +

tBuOH, O2, 65°C, 20 h 60.9% conv., 97.2% ee krel 17.3 Pd[(−)-sparteine]Cl2 1 (5 mol %) (−)-sparteine (20 mol %)

OH OH Ar

OH O

tBuOH, O2, 65°C, 20 h

Ar

Ar

Ar

Ar = p-BrC6H4

78%, 85% ee (95% ee after recrystallization)

Scheme 11.6.

OH R

R'

OH

Pd(nbd)Cl2 (5 mol %) (−)-sparteine (12 mol %) Cs2CO3 (0.4 equiv.)

OH

O +

CHCl3, MS3A, air, 23°C

R

OH

R'

OH

R

R'

OH

Ph

55.5% conv., 98.0% ee krel 37.3

60.2% conv., 99.6% ee krel 28.0

64.7% conv., 98.9% ee krel 15.7

Scheme 11.7.

56.8% conv., 94.9% ee krel 21.7

844 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS CF3

Pd(nbd)Cl2 (5 mol %) (−)-sparteine (20 mol %)

OH NHBoc

OH

O

NHBoc

PhCH3, MS3A, O2, 80° C

NHCH3·HCl

Prozac¨

57.5% conv., 93.1% ee krel 17.9

OH

Pd(nbd)Cl2 (5 mol %) (−)-sparteine (20 mol %) Cs2CO3 (0.5 equiv.) tBuOH (1.5 equiv.)

HO

Br

CO2-Na+

HO

OH

HO

S

Br Cl

PhCH3, MS3A, O2, 80° C

N

Singulair¨

70.6% conv., 99.9% ee krel 15.3 F3C

OH

F

Pd(nbd)Cl2 (5 mol %) (−)-sparteine (12 mol %) Cs2CO3 (0.4 equiv.)

OH

F

CF3

O

Me

F

CHCl3, MS3A, O2, 23° C CO2Me

CO2Me

HN

50.8% conv., 94.7% ee krel 82.7

O

N

NMe

N H

Merck's h-NK1 receptor antagonist

Scheme 11.8.

TIPSO OMe

O O

OMe

Pd[(−)-sparteine]Cl2 1 (20 mol %) (−)-sparteine (20 mol %) 2-methyl-2-butene (20 mol %) CHCl3,Cs2CO3, O2, 23°C

TIPSO OMe

O O

OMe

HO

HO (±)-3

OMe

O O

N (+)-Amurensinine

(−)-3: 47%, >99% ee

Scheme 11.9.

substances including Prozac®, Singulair®, and Merck’s h-NK1 receptor antagonist reported by Stoltz and coworkers (Scheme 11.8) [16]. The total synthesis of (+)-amurensinine, a member of the isopavine family that exhibits important biological activities toward Alzheimer’s and Parkinson’s diseases, was also accomplished by using the palladium catalysis (Scheme 11.9) [17]. The racemic benzylic alcohol (±)-3 was efficiently resolved to (−)-3 with >99% ee.

11.2.3. Ruthenium Catalyst Ruthenium complexes have been known to be effective catalysts for the aerobic oxidation of alcohols [18]. In 2000, Katsuki and coworkers reported the first example of oxidative kinetic resolution of secondary alcohols with ambient air as the oxidant, in which chiral (nitrosyl)ruthenium(salen) complex 4 is employed as precatalyst [19].

OMe


The irradiation of visible light promotes dissociation of the nitrosyl ligand to generate a coordinatively unsaturated and catalytically active ruthenium species. Under ambient conditions, kinetic resolution of aryl, alkenyl, alkynyl, and alkyl carbinols efficiently proceeded with krel values up to 20 (Scheme 11.10). The addition of 1,3-diketones was found to improve the krel values up to 30 [20]. Katsuki and coworkers also reported that modified ruthenium complexes 5 serve as an efficient catalyst for oxidative desymmetrization of 1,4-meso-diols (Scheme 11.11) [21]. Kinetic studies disclosed that the ruthenium-catalyzed oxidation of alcohols proceeds through the following sequence, although the details differ between the apical ligands used (Scheme 11.12) [22]: A single electron is transferred from the ruthenium ion to dioxygen after dissociation of the nitrosyl group by the irradiation of visible light, and electron delocalization between the ruthenium ion and the donor oxygen atom of the salen ligand gives a cationic phenoxy radical. The following intramolecular hydrogen atom abstraction by the phenoxy radical and the subsequent exchange of the product and alcohol regenerate the alcohol-binding catalyst. It is noteworthy

OH

4 (2 mol %)

OH

O +

R

R

PhCl or toluene, hυ, air, RT

R N NON Ru O Cl O Ph Ph

krel up to 20 OH

OH

OH 4 60.7% conv., 90.6% ee krel 11

65.3% conv., >99.5% ee krel 20

57.8% conv., 82.1% ee krel 11

Scheme 11.10.

R R

OH OH OH

5 (2 mol %)

R O

air, hυ, RT R

Up to 93% ee

Me Me N NON Ru O X O Ar Ar

5: X = Cl or OH

Scheme 11.11.


X = OH

X = Cl

Single electron transfer R'

R H OP

•O 2H or •O 2–

N RuIV O OH P = none or H N

O

Single electron transfer R H

R' O2 N

hu

O

R' NO

OH

N RuIII O OH

N hu

N O

OP N RuIII O OH

X

O

R'

N hu

N

O R

R H OH

R H

OH

N RuIII O2 O Cl

R'

R'

OP1 N N O RuIV OP2 O O Cl P1 = none or H P2 = H or none

Catalytic cycle O2 R N

O •O2H H2O2 or •O 2– Hydrogen atom abstraction

hu

R'

OH

O N RuIII O OH

R H

R'

O

R

R'

R H

NO

N

Ru O

O

Catalytic cycle

R'

NO

R' OH O2

R

R'

R H

R H

R H OH

O

R H

R' O N RuIII O Cl

N H2O2

O

R' OP1 N O RuIII OP2 O Cl

Hydrogen atom abstraction

Scheme 11.12.

that the ruthenium complex can be regarded as a mimic of galactose oxidase, although each metal ion is not the same [23]. Although desymmetrization of meso-diols also traces a similar catalytic cycle, the hydrogen atom is intermolecularly abstracted by a hydroperoxy or superoxide radical as a consequence of the electron delocalization onto the substrate oxygen atom instead of the donor oxygen atom, due to the stabilization of the resultant cation radical by hydrogen bonding with another hydroxy group.

11.2.4. Vanadium Catalyst Two elegant reports on vanadium-catalyzed asymmetric aerobic oxidation of α-hydroxy carbonyl compounds were independently published by the groups of authors [24–26]. Toste and coworkers used a vanadium complex in situ prepared from VO(OiPr)3 and tridentate Schiff base ligand 6 derived from 3,5-di-tert-butylsalicylaldehyde and (S)-tert-leucinol, and achieved krel values ranging from 6 to >50 in the kinetic resolution of various α-hydroxy esters (Scheme 11.13). Aliphatic substrates as well as aryl, alkenyl, and alkynyl ones are efficiently resolved, although increased reaction times are required. In addition, α-hydroxy amides are also good substrates for the resolution. The mechanism via a radical species at the carbinol carbon is unlikely for this vanadium-catalyzed oxidation, because the reaction of an α-hydroxy ester having cyclopropyl group at the α-position gives no ring-opening product.


VO(OiPr)3 (5 mol %) 6 (5.5 mol %)

OH R2

R1

OH

Acetone, O2, RT

O

O R2

R1

+

O

R1 = aryl, alkenyl, alkynyl and alkyl

R2

R1

N

O

tBu

OH

krel 6 to >50

R2 = OMe, OEt, OiPr, OBn and NHtBu

OH

tBu 6

Scheme 11.13.

O OH X

R

OH

7 or 8 (3–5 mol %) Bn

O

PhCH3, O2, RT

X = O or NH

X

R

O

O X

Bn + R

O

Bn

O

tBu

Generally krel 10 to >100

N O O V OMe O O H Me tBu 7

N O O V OMe O O H Me

Br Br

8

Scheme 11.14.

OH

OBn P OBn O

OH

OBn P OBn O

8 (5 mol %) PhCH3, O2, RT

O +

OBn P OBn O

51% conv., 99% ee krel >99

Scheme 11.15.

On the other hand, Chen and coworkers have shown that α-amino acid–based vanadium(V) complexes 7 and 8 promote kinetic resolution of a wide variety of αhydroxy esters and amides (Scheme 11.14). In most substrates, high krel values ranging from 10 to >100 are obtained. Complex 8 can be also applied to asymmetric aerobic oxidation of α-hydroxyphosphonic acid derivatives, which are attractive targets in medicinal chemistry (Scheme 11.15) [27]. Various dibenzyl α-hydroxy phosphonates bearing aryl or vinyl substituent at the α-position are effectively resolved, generally with excellent selectivity (krel > 99). Although kinetic resolution is an attractive approach through which to prepare extremely enantio-enriched molecules, the maximum theoretical yield is 50%, and the inherent property limits the synthetic values. However, Toste and coworkers have shown a practical solution to the problem. They applied the vanadium-catalyzed oxidative kinetic resolution to the total synthesis of (−)-octalactin A, possessing cytotoxicity toward B-16-F10 murine melanoma and HCT-116 human colon tumor cell lines (Scheme 11.16) [28]. The key intermediate α-hydroxy ester 9 was effectively resolved into the alcohol and the ketone, with >95% ee and 90% ee, respectively. The two resolution products were combined after several transformations and led to (−)-octalactin A. This


BnO2C

VO(OiPr)3 (5 mol %) (R)-6 (5.5 mol %)

OTBS

BnO2C

Acetone, O2, 35°C

OH (±)-9

OTBS

+

BnO2C

OH

OTBS O

47% yield, >95% ee

49% yield, 90% ee

O HO

3 4

O

O

OH

BnO2C

3

8

H

4

8

OPMB

O

OTBS

O

(−)-octalactin A

Scheme 11.16.

resolution/recombination approach made it possible to construct the C3, C4, and C8 stereocenters in a single process.

11.2.5. Iridium Catalyst Chiral iridium amide complexes were identified as a catalyst for oxidative kinetic resolution of racemic secondary alcohols by Ikariya and coworkers [29]. The authors found that the treatment of iridium hydride complex 10 with molecular oxygen or air gave the corresponding amido complex 11 (Scheme 11.17) [29,30]. It is well established that iridium–amido complexes dehydrogenate alcohols to give the amine–hydride complexes and ketones in the asymmetric transfer hydrogenation of ketones [31]. Basing on the finding, they disclosed that chiral iridium complex 12 catalyzed kinetic resolution of benzylic alcohols with high krel values under air (Scheme 11.18). 1-Indanol underwent resolution efficiently, and the (R)-enantiomer was recovered in 50% with >99% ee.

Ph Ph

Ir N H H2

O2 THF-d8, RT

10

Ph Ph

Ir N H 11

Scheme 11.17.

Moreover, Ikariya and coworkers reported that iridium chloride complex 13, together with KOtBu, equally promoted the reaction with a krel value as high as 40.8 (Scheme 11.19) [29]. The rhodium analogue 14 also exhibited high catalytic performance in the presence of the base, but the related ruthenium complex 15 gave a diminished result.

11.3. ASYMMETRIC EPOXIDATION 849

OH Ar

OH

12 (10 mol %)

R

O

Ph

+

THF, O2, 30°C

Ar

R

Ar

R Ph

krel up to >100

OH

OH

Ms N Ir N H 12

OH

OH

MeO 48%, 98% ee krel 91.3

38%, 98% ee krel 17.2

50%, >99% ee krel >100

46%, >99% ee krel 77.6

Scheme 11.18.

OH

13–15 (10 mol %) KOtBu (1.5 equiv.)

OH +

THF, O2, 30°C

Ts N Ir N Cl H2 13: 45%, 98% ee, krel 40.8

Ph Ph

O

Ts N Rh N Cl H2

14: 46%, 93% ee, krel 28.9

Ph Ph

Ts N Ru N Cl H2

15: 78%, 23% ee, krel 12.3

Scheme 11.19.

11.3. ASYMMETRIC EPOXIDATION 11.3.1. Introduction Since the discovery of the Katsuki–Sharpless asymmetric epoxidation [32], a large number of chiral catalysts have been developed [33]. Recently, an increasing social demand for a fundamental solution to environmental problems and pure academic interests has been accelerating the advances of asymmetric epoxidation using greener oxidants, especially aqueous hydrogen peroxide. Remarkable progress has also been made in the development of chiral epoxidation catalysts using alkyl hydroperoxides as oxidant.

11.3.2. Ruthenium Catalyst Beller and coworkers reported ruthenium-catalyzed asymmetric epoxidation of olefins with aqueous hydrogen peroxide as oxidant [34,35]. On the basis of the


O N R

O

O N

R

R O

O

O

Ru(pybox)(pydic) 16

O

N N

N Ru

O

O

O

N

N Ru N

O R O

Ru(pyboxazine)(pydic) 17

Figure 11.1.

17a (5 mol %) AcOH (20 mol %)

+

30% H2O2

*

O

O

*

O

N N

N Ru

2-methylbutan-2-ol, RT

O 91%, 84% ee

O

O N

O

17a

Scheme 11.20.

Nishiyama’s report that Ru(pybox)(pydic) complexes 16 (pydic = 2,6-pyridinedicarboxylate) promote epoxidation of trans-stilbene with PhI(OAc)2 as oxidant [36], they designedRu(pyboxazine)(pydic)complexes17[pyboxazine=2,2′-pyridine-2,6-diylbis(5,6-dihydro4H-1,3-oxazine)] for the reaction (Fig. 11.1). The ruthenium complex 17a–bearing 2-naphthyl groups proved the most effective, and the highest ee value of 84% was achieved in the epoxidation of 2-methyl-1-phenyl-1-propene (Scheme 11.20). The addition of acetic acid improved the catalytic performances, and the authors suggested that the additional acid stabilizes the active intermediate.

11.3.3. Titanium Catalyst Katsuki and coworkers identified a chiral titanium complex as a catalyst for asymmetric olefin epoxidation [37]. They found that di-μ-oxo Ti(salalen) complex 18 (salalen = salen/ salan hybrid ONNO-type tetradentate ligand), which is readily prepared from Ti(OiPr)4 and the corresponding salen ligand 19 via an intramolecular Meerwein–Ponndorf– Verley reduction, efficiently promotes the epoxidation of unfunctionalized olefins in the presence of one equivalent of 30% hydrogen peroxide as the oxidant (Scheme 11.21). High yields and high enantioselectivities were obtained with 1 mol % of catalyst in the reaction of conjugated olefins (Scheme 11.22). The epoxidation of styrene, which is still a difficult substrate for asymmetric epoxidation with regard to both enantioselectivity and product selectivity, furnished styrene oxide with the high ee value of 93%, and synthetically important indene oxide was obtained with 99% ee. The reaction of 1,2-


H N

N

N Ti(OiPr)4

OH HO Ph Ph

N Ti

H2O

O O Ph Ph

CH2Cl2

O 18

2

19 H2O

Ti(OiPr)4

N

O

H

O N Ti O O OiPr

H

N

N O Ti O OiPr

Intramolecular Meerwein-Ponndorf-Verley reduction

Scheme 11.21. The salen ligand is simplified for clarity.

R2 + 30% H2O2

R1

CH2Cl2, RT

R3 O

19 (1 mol %)

O

O

R2 * R1

O *

R3 O

O Ph

90%, 93% ee

87%, 99% ee (in AcOEt)

92%, >99% ee (0.02 mol % of 21)

75%, 95% ee

64%, 88% ee (in AcOEt)

Scheme 11.22.

dihydronaphthalene proceeded smoothly in the presence of only 0.02 mol % of 19 to afford the epoxide in 92% yield with complete enantioselectivity. It is of note that the reaction is stereospecific and that an acyclic cis-substituted olefin underwent epoxidation to give the corresponding cis-epoxide as a sole product. While dichloromethane is the best solvent, more environmentally friendly ethyl acetate is also available as a solvent without loss of the enantioselectivity. The remarkable catalysis of complex 19 can be recognized in the results obtained with aliphatic olefins, which are the most challenging substrates for asymmetric olefin epoxidation, due to their inherently low reactivity toward electrophilic oxidant and the difficulty in their enantioface differentiation (Scheme 11.23) [38]. A variety of


19 (1–3 mol %)

R1 R2

O

*

+ 30% H2O2

R1

*

CH2Cl2, RT O

*

O

R2

O

*

O

*

O

BnO

*

*

Cy 85%, 82% ee

72%, 95% ee

49%, 81% ee

85%, 74% ee

77%, 70% ee

Scheme 11.23.

+

CH2Cl2, RT

5:1

54%, 82% ee

5

19 (1 mol %)

+ 30% H2O2

O

O

19 (1 mol %)

+ 30% H2O2

O

O

CH2Cl2, RT

+

5

51%, 82% ee

5

20:1

Scheme 11.24.

O N O

Ti

N H O Hydrogen bonding

O 20

Figure 11.2.

aliphatic olefins such as terminal and cis-substituted olefins underwent epoxidation with good to high enantioselectivity. The method was also applied to the regioand enantioselective epoxidation of substrates containing multiple carbon–carbon double bonds, and good regioselectivity as well as high enantioselectivity was observed (Scheme 11.24). Although complex 19 is an efficient catalyst for asymmetric epoxidation of olefins, its synthesis requires multiple steps. Moreover, the protocol that uses the intramolecular Meerwein–Ponndorf–Verley reduction is poorly applicable to the preparation of the related Ti(salalen) complexes. On the basis of the hypothesis that a peroxotitanium complex 20 (Fig. 11.2), in which the amino proton of the ligand forms hydrogen bond with the peroxo ligand, is the active species for the reaction, the authors further explored titanium-based epoxidation catalysts and found that titanium (salan) complexes 21

*


R1

O

R1 H N

H

21 (5 mol %)

N

+ 30% H2O2

Ti

CH2Cl2, RT

R3 21a: no reaction 21b: 99% ee

93%, 97% ee

22

Scheme 11.26.

promote the asymmetric olefin epoxidation (Scheme 11.25) [39]. A brief screening of salan ligands disclosed that complex 21d bearing cyclohexanediamine moiety and phenyl groups at the C3 and C3′ positions exhibited high asymmetric catalysis. It is worth noting that catalysts in situ prepared from Ti(OiPr)4 and the corresponding salan ligands also gave comparable results with the premade catalysts. The authors further screened salan ligands with the in situ protocol and found that the introduction of ortho-substituted aryl groups at the C3 and C3′ positions improved both yield and enantioselectivity [40]. In particular, salan ligand 22–bearing orthomethoxyphenyl groups, which can be easily prepared from 2,2′-biphenol in short steps, gives the highest enantioselectivity. The addition of a phosphate buffer improved the catalytic performances remarkably, and only 1 mol % of the catalyst loading was sufficient to yield the enantio-enriched epoxides with ee values ranging from 88 to >99% (Scheme 11.26) [41]. The reaction can be performed on a gram scale with catalyst loading of 1–2 mol %.

11.3.4. Platinum Catalyst Strukul and coworkers have developed cationic PtII/diphosphine complex 23 with electron-withdrawing pentafluorophenyl ligand and established its utility in enantioselective


R

+ 35% H2O2

23 (2 mol %)

O

R

Ph Ph P OH2 Pt+ F P F Ph Ph F 23

58–98% ee

O O

O

O

O

CF3SO3– F F

O 98%, 58% ee

48%, 83% ee

63%, 78% ee

64%, 87% ee

Scheme 11.27.

+ 35% H2O2

23 (2 mol %)

O 66%, 98% ee

+ 35% H2O2

23 (2 mol %)

O 93%, 63% ee

+ 35% H2O2

23 (2 mol %)

O

96%, 86% ee

Scheme 11.28.

epoxidation of aliphatic olefins with aqueous hydrogen peroxide (Scheme 11.27) [42]. Various terminal olefins with no substituent at the allylic position are efficiently converted to the corresponding epoxides with moderate to high enantioselectivity. It is worth noting that only one equivalent of 35% hydrogen peroxide is required to obtain an acceptable yield. Another advantage is the high regio- and chemoselectivities. Monosubstituted terminal olefins are selectively oxidized in the presence of internal or geminally disubstituted terminal olefins (Scheme 11.28). Although halogenated solvents are commonly used, the reaction is also performed in water in the presence of surfactants [43]. The researchers proposed that H2O2 binds to the meta- and para-fluorine atoms of the C6F5 ligand by hydrogen bonding and that the olefin coordinates to the platinum prior to the oxygen atom transfer [44]. Scheme 11.29 accounts for the limited substrate scope and the extraordinary regioselectivity observed in the epoxidation of dienes.


H2O O

P

solv Pt+

* P

R

F

F F

CF3SO3–

H2O2

F F

R H H P

O Pt+

* P

F

F F

H

P

Catalytic cycle

solv Pt+

*

O

P

F H F

H O O F H F

F

F

CF3SO3–

F

CF3SO3–

R H H P Pt+

* P

CF3SO3–

R H O O F H F

F

F F

Scheme 11.29.

+ 30% H2O2

Polymer-supported catalyst 24 (5 mol %)

*

O

O

*

N H HO

CH2Cl2/t BuOH 20% ee

HO H N

O N H

O

N

+ FeCl2 24

Scheme 11.30.

11.3.5. Iron Catalyst The development of not only more efficient and selective but also sustainable reactions has emerged as a research frontier in organic synthesis. In the field of metal-catalyzed reaction, iron-based catalysts are the most appealing due to the ubiquity and nontoxicity of iron. Indeed, processes in nature utilize various iron-containing enzymes in biotransformations. Thus, the improvement of asymmetric epoxidation catalysis of iron-based complexes is a topic of current interests [45]. In 1999, Francis and Jacobsen investigated a library of 5760 ligand–metal complexes by high-throughput combinatorial techniques and found that FeII/peptide complex 24 supported on a polystyrene resin can promote the asymmetric epoxidation of transβ-methylstyrene in the presence of aqueous hydrogen peroxide, albeit with the low ee value of 20% (Scheme 11.30) [46]. On the other hand, in the course of studies on


asymmetric cis-dihydroxylation of olefins, Que and coworkers found that FeII complex 25 together with aqueous hydrogen peroxide as the oxidant can oxidize trans-2-heptene to the epoxide (Scheme 11.31) [47]. Accompanying the cis-dihydroxylation product with 29% ee, trans-2-heptene oxide was obtained with 12% ee. Although the enantiomeric excesses are modest, these results indicated a potential of iron-based complexes as catalysts for asymmetric epoxidation.

O 12% ee

25 +

50% H2O2

N

N Fe2+ N N

+

CH3CN

OH

(CF3SO3– )2 OH

25

29% ee

Scheme 11.31.

In 2007, Beller and coworkers achieved the first highly enantioselective, iron-catalyzed epoxidation using aqueous hydrogen peroxide as an oxidant (Scheme 11.32) [48]. Chiral amine-based ligands were examined in combination with achiral H2pydic ligand, and N-benzyl-N′-toluenesulfonyl-1,2-diphenylethylenediamine 26 was found to exhibit high enantioselectivity in the epoxidation of trans-disubstituted aromatic olefins. The authors noted the importance of the sulfonyl group for an intramolecular hydrogen bonding. The method employs an inexpensive iron source, FeCl3·6H2O, and the best ee value of 97% is attained in the reaction of a substituted stilbene. Although the process has a limitation on the substrates, the promising asymmetric epoxidation catalysis of chiral iron-based complexes was proven. Spectroscopic and kinetic studies indicate that the reaction proceeds through benzyl radical intermediates [49]. While a high-valent Fe=O complex is proposed as the active species, further studies are necessary to ensure the mechanism.

Ar

R

FeCl3•6H2O (5 mol %) H2pydic (5 mol) 26 (12 mol %) + 30% H2O2 (2 equiv.)

2-methylbutan-2-ol, RT

Ph *

Ar

O

R

26

O

tBu 94%, 28% ee

O

tBu 82%, 81% ee

O NH HN S O

*

tBu O

Ph

40%, 97% ee

Scheme 11.32.


11.3.6. Vanadium Catalyst A combination of VO(acac)2 and alkyl hydroperoxides is one of the most reliable oxidation systems for hydroxy-directed epoxidation in organic transformation and enables highly diastereoselective synthesis of epoxy alcohols [50,51]. In 1977, Sharpless and coworkers identified chiral hydroxamic acids as effective ligands for the vanadiumcatalyzed asymmetric epoxidation of allylic alcohols with TBHP, in which the hydroxamic acid binds to the vanadium as a bidentate ligand, and moderate to good enantioselectivity of up to 80% was observed [52]. Although a singly coordinated species has been proposed as the active catalyst, the formation of inactive doubly or triply coordinated species reduces the efficiency of the vanadium–hydroxamic acid system [53]. Nevertheless, a variety of chiral hydroxamic acid ligands have been introduced by several groups in recent years [54]. For example, Yamamoto and coworkers designed hydroxamic acid 27 bearing axially-chiral binaphthyl group for the vanadium-catalyzed asymmetric epoxidation of allylic alcohols, and demonstrated for the first time that high enantioselectivity of up to 94% ee can be achieved in the vanadium-catalyzed asymmetric epoxidation in the presence of alkyl hydroperoxide as oxidant (Fig. 11.3) [55]. On the basis of this finding, they further screened α-amino acid–based hydroxamic acids and found that tert-leucine-derived 28 is an effective ligand for the reaction. The epoxidation proceeded effectively with high enantioselectivity in the presence of VO(OiPr)3 (1 mol %) and 28 (1.5 mol%) [56]. Eventually, Yamamoto and coworkers identified chiral C2-symmetric bishydroxamic acids 29 as efficient ligands for the vanadium-based method (Scheme 11.33) [57]. The

HO N

O

O

N

O

N OH

O

OMe

27

28 Figure 11.3.

R3 R1 R2

aq. TBHP OH + or CHP

O

VO(OiPr)3 (1 mol %) 29 (2 mol %)

R1

O

R3

R N

OH

N

R2

OH OH

O

R 29

O OH

50%, 93% ee (29a)

OH

71%, 92% ee (29b)

O

O

OH

78%, 97% ee (29c)

CH2CPh3 (29b), CH(3,5-dimethylphenyl)2 (29c)

92–97% ee

O

R = CHPh2 (29a),

OH

68%, 95% ee (29a)

Scheme 11.33.


ligands were designed to selectively generate a 1:1 vanadium/ligand complex in which each hydroxyl group coordinates to the vanadium atom. Indeed, the catalytic activity was kept with more than 1:3 vanadium/ligand ratio. Trans-disubstituted and trisubstituted allylic alcohols underwent epoxidation in high enantiomeric excesses, and the reaction of cis-substituted allylic alcohols, which are substandard substrates for the Katsuki–Sharpless epoxidation, also proceeded with high enantioselectivity. An intriguing feature of the catalyst system is the availability of aqueous TBHP as a stoichiometric oxidant. It is noteworthy that the method is very effective for the asymmetric epoxidation of small allylic alcohols, which has been unsolved for a long time. With the vanadium catalyst, small epoxy alcohols can be obtained in high yields with high enantioselectivity more than 90% ee by water-extraction technique. The catalytic system was also applied to the kinetic resolution of a racemic secondary alcohol, and both the allylic alcohol and the epoxy alcohol were obtained with high enantiomeric excesses (Scheme 11.34). The VO(OiPr)3/bishydroxamic acid system also promotes asymmetric epoxidation of homoallylic alcohols. High yields and enantioselectivities were obtained in the epoxidation of both cis- and trans-substituted homoallylic alcohols (Scheme 11.35) [58]. Moreover, racemic homoallylic alcohols were effectively resolved, and both the recovered homoallylic alcohols and the epoxides were isolated with high enantiomeric excesses (Scheme 11.36).

OH

+

aq. TBHP

VO(OiPr)3 (1 mol %) 29a (2 mol %)

O

OH

OH

+ CH2Cl2, 0°C

Ph

Ph

Ph

93% ee

51% conv., 95% ee

Scheme 11.34.

R1

OH + CHP

R2

O

VO(OiPr)3 (1 mol %) 29d (2 mol %)

O R1

OH

*

Toluene, RT, 24 h

CAr3 N

*

R2

N

93–99% ee

OH OH

Ar =

Et

CAr3

O

Et

Et

29d O

Ph *

*

OH

90%, 96% ee

Et

O

O OH

85%, 93% ee

OH Et 92%, 95% ee

Scheme 11.35.

R

OH + CHP

VO(OiPr)3 (0.5 mol %) 29d (1 mol %) Toluene, RT, 30 h

O OH R

R = Et = C4H9 Scheme 11.36.

+

OH R

51%, 95% ee

48%, 95% ee

51%, 96% ee

48%, 97% ee


11.3.7. Niobium Catalyst More recently, Egami and Katsuki disclosed that niobium(salan) complexes promote asymmetric epoxidation of allylic alcohols with hydrogen peroxide. The authors initially employed a chiral μ-oxo niobium(salan) complex 30 as catalyst together with urea·hydrogen peroxide (UHP) as oxidant and found that a range of allylic alcohols underwent epoxidation with high enantioselectivity (Scheme 11.37). [59]. While known catalysts for the epoxidation of allylic alcohols need alkyl hydroperoxides as oxidant, the method can utilize hydrogen peroxide. Subsequently to this, protocols using the catalyst in situ prepared from Nb(OiPr)5 and the corresponding salan ligand have been developed. More favorable aqueous hydrogen peroxide is available as an oxidant under the conditions (H. Egami and T. Katsuki, unpublished data).

R3 R1

30 (2 mol %)

OH

+

R2

UHP (4 equiv.)

O O


OH

O

OH

78%, 80% ee

R1

79%, 83% ee

O

R3 OH H

R2

OH

O

86%, 72% ee

N O N Nb O O Ph Ph

H

OH 2

O 30

83%, 68% ee

Scheme 11.37.

11.3.8. Molybdenum Catalyst Chiral C2-symmetric bishydroxamic acids 29 are effective auxiliaries for molybdenumcatalyzed asymmetric epoxidation of unfunctionalized olefins as well as the vanadiumcatalyzed epoxidation of allylic alcohols (Scheme 11.38) [60,61]. The suitable choice of the steric bulkiness of alkyl hydroperoxides leads to achievement of the high enantioselectivity in the asymmetric epoxidation of mono, di-, and tri-substituted olefins. It is worthy to note that the method is stereospecific and that the only cis-epoxide

R1

R3

+

R2

TBHP or CHP or THP

O

MoO2(acac)2 (2 mol %) 29 (2 mol %)

O R1

*

*

CH2Cl2, RT

CAr3 N

R3

R2

N

OH OH

50–96% ee

CAr3

O 29 O

O

O

O Ar =

O 94%, 92% ee (29e)

92%, 96% ee (29f)

R

R = Me (29e), tBu (29f ) 95%, 85% ee (29f)

Scheme 11.38.

95%, 85% ee (29f)


was obtained in the reaction of cis-β-methylstyrene. The molybdenum catalysts with alkyl hydroperoxides have a relatively strong oxidizing property so that less reactive 1-octene could be converted to the epoxide in high yield, albeit with moderate enantioselectivity of 50% ee. The reaction of vinylcyclohexane is more enantioselective, giving the epoxide with 85% ee. The catalyst was also effective for asymmetric oxidation of sulfides and disulfides [62].

11.3.9. Lanthanoid Catalyst Chiral lanthanoid-based complexes have emerged as versatile catalysts for a wide variety of enantioselective organic transformations, and the Shibasaki group proved that lanthanoid catalysts are remarkably effective for asymmetric epoxidation of α,β-unsaturated carbonyl compounds using alkyl hydroperoxides (Scheme 11.39) [63]. Basically, their catalysts consist of a Lewis acidic lanthanoid atom, BINOL-derived chiral ligand, and triphenylarsine oxide. Inanaga and coworkers also reported that addition of triphenylphosphine oxide enhances the epoxidation catalysis of the lanthanoid complexes [64]. The Shibasaki’s method has a broad substrate spectrum, and α,β-unsaturated ketones, esters, amides, and N-acyl pyrroles undergo epoxidation with high enantioselectivity. Recently, α,β-unsaturated phosphate was also included in the scope [65]. It is noteworthy that the geometry of cis-α,β-unsaturated ketone is considerably retained during epoxidation, although it proceeds stepwisely. They successfully utilized the lanthanoidcatalyzed epoxidation in an enantioselective synthesis of (+)-decursin and its related compounds, which exhibit cytotoxicity against various human cancer cell lines [66].

O Ph

Ph

+

TBHP (1.2 equiv.)

La(OiPr)3 (5 mol %) (R)-BINOL (5 mol %) Ph3As=O (5 mol %) MS4A, THF, RT

O Ph

O Ph

99%, 96% ee Scheme 11.39.

11.3.10. Organocatalyst Remarkable progress in the field of asymmetric organocatalysis has been seen in recent years, and it has been successfully applied to catalytic asymmetric epoxidation [67]. Chiral ketones, which were first identified as a catalyst for asymmetric epoxidation by Curci and coworkers in 1984, are some of the most developed epoxidation catalysts [68]. Active dioxirane is generated from ketone and oxone (potassium peroxomonosulfate) under mild reaction conditions. While many valuable chiral ketones have been reported [69], fructose-derived ketone 31 developed by Shi and coworkers is the most reliable catalyst in terms of the high enantioselectivity and broad substrate scope (Scheme 11.40) [70]. In the presence of 31 (typically 20–30 mol %), a variety of trans- and trisubstituted olefins including dienes, enynes, and enol ethers are efficiently converted to the epoxides.


R2 R1

R2

31 (10–30 mol %)

R3

+

Oxone

O

R1

R3

O

Ph O O Ph

Ph

O C6H13

98% ee

BzO O

C6H13 98% ee

O 31

97% ee

93% ee

Scheme 11.40.

O O

O

NBoc O

O O

O O

O

NBoc O

O

O O

NAr O

O

O 32

O

33

O

O O

AcO

O

AcO 34

35

Figure 11.4.

32 (15 mol %)

O

+ Oxone

92%, 81% ee

31 (30 mol %)

O O

O

O

Ph

Ph

95% ee

O

O

+ Oxone

90%, 24% ee

Scheme 11.41.

While ketone 31 generally displays high enantioselectivity for these olefins, the method is not effective for cis- and terminal olefins. On the basis of the mechanistic understanding, Shi and coworkers introduced a glucose-derived chiral ketone 32 containing an N-Boc oxazolidinone that exhibits high enantioselectivity for the epoxidation of cis- and terminal olefins (Fig. 11.4) [71]. The reaction of styrene with ketone 32 gave styrene oxide with 81% ee, in contrast to 24% ee with ketone 31 (Scheme 11.41). A carbocyclic analogue 33 and N-aryl-substituted variants 34 are also introduced for styrene derivatives and cis-disubstituted olefins [72,73]. In addition, chiral ketone 35 bearing electron-withdrawing acetate groups was found to be active enough to promote the epoxidation of α,β-unsaturated esters, and the epoxy esters were obtained in a high yield with high enantioselectivity [74].


Shi and coworkers successfully utilized the ketone-catalyzed method in an enantioselective synthesis of 2-arylcyclopentanones (Scheme 11.42) [75]. In the presence of 34a and oxone, benzylidenecyclobutanes underwent epoxidation with 86–96% ee, and the subsequent epoxide rearrangement using Lewis acid catalysts such as Et2AlCl and LiI gave the enantio-enriched 2-arylcyclopentanones [76]. The high enantiomeric excesses of the epoxides were generally maintained in the rearranged products. Choice of the Lewis acids determines the stereochemical course of the reaction, and the rearrangement with Et2AlCl proceeds via a concerted mechanism with inversion of the configuration. On the other hand, the reactions with LiI go through a stepwise process with double inversion to yield the retention products. Both enantiomers can be synthesized with the single epoxidation catalyst. Et2AlCl toluene Ar

34a (20 mol %) + Oxone

O

O Ar

O

O Ar

O LiI CH2Cl2

O

N O

O O Ar

34a

Scheme 11.42.

While oxone is the usual oxidant to generate active dioxiranes in the ketone-catalyzed epoxidation, Shi and Shu reported an alternative oxidant, a combination of hydrogen peroxide and acetonitrile (Scheme 11.43) [77]. In the reaction with ketone 31, a variety of epoxides were obtained in good yields with comparable enantioselectivity. N-Arylsubstituted, oxazolidinone-containing ketone 34 was also shown to promote asymmetric epoxidation with high enantioselectivity with hydrogen peroxide. R2 R1

R3 + 30% H2O2

R2

31 (10–30 mol %) CH3CN, K2CO3

R1

O

R3

89–99% ee Scheme 11.43.

Acetonitrile, which is usually employed as cosolvent, reacts with hydrogen peroxide to generate peroxyimidic acid and then reacts with the ketone to give the active dioxirane (Scheme 11.44). Under the conditions, a stoichiometric amount of the amide is produced as a by-product. Percarboxylic acids such as peracetic acid and mCPBA are common oxidants for olefin epoxidation in organic transformations. Although the utilization of chiral peracids, even as stoichiometric oxidants, has been studied, methods for achieving high enantioselectivity had not been reported. In 2007, however, Miller and coworkers demonstrated a unique acid/peracid catalytic cycle for asymmetric epoxidation (Scheme 11.45) [78]. At the initial stage of their study, the authors employed benzyl N-Boc l-aspartate 36 as catalyst for constructing the hypothesized acid/peracid shuttle system and applied carbodiimide activation technique in peptide synthesis to the purpose. Acid 36 is activated by carbodiimide, and the subsequent reaction with hydrogen peroxide

NH

RCN + H2O2 R

O

O

OOH

O O

O O

O

O

31 R2 R1

O

OH

O O

R3

O NH

O O

R

Catalytic cycle

R2 R1

O

R3

O

O

O R

O O

O O

NH2

Scheme 11.44.

O BocHN

OBn

O

CO2H

36

DIC

Catalytic cycle O DMAP, H2O2 or DMAP N-oxide, H2O2 or H2O2

BocHN

OBn O O H

DIC OBn O O O O BnO O

OBn O NHiPr

O

O BocHN

O BocHN

O

NHBoc O

O

NiPr

DMAP, H2O2 or DMAP N-oxide, H2O2 or H2O2 NHiPr NiPr

Scheme 11.45. 863


affords the active peracid. The peracid oxidizes the olefin to yield the epoxide along with the regeneration of the carboxylic acid catalyst 36. Although the formation of diacyl peroxide delays the oxygen atom transfer, the addition of DMAP as an acyl transfer catalyst accelerates the entire process and renders the reaction highly catalytic. While DMAP is oxidized to DMAP N-oxide under the reaction conditions, N-oxide may also serve as acyl transfer catalysts. Indeed, NMO instead of DMAP could promote the epoxidation, albeit with diminished productivity. With an effective acid/peracid shuttle, the authors introduced tripeptide catalyst 37—the sequence l-Pro-d-Val is well known to induce a β-turn structure that provides an effective asymmetric environment for other asymmetric reactions [79]—and found that trisubstituted olefins bearing carbamate functionality effectively underwent epoxidation with high enantioselectivity (Scheme 11.46). While allylic alcohol-derived substrates showed high enantioselectivity, the elongation of the tether led to the significant loss of the enantioselectivity. The limitation of the substrate scope suggests that hydrogen bonding between the catalyst and the substrate is essential for the enantiocontrol. Three transition state models have been proposed (Fig. 11.5). This study demonstrates that better understanding of peptidesubstrate–binding structure including hydrogen-bonding network will offer a potent approach to highly enantioselective epoxidation of other olefins.

37 (10 mol %) DIC (2.0 equiv.) DMAP (10 mol %)

O R

n

O

NHAr +

R

30% H2O2 (2.5 equiv.)

R

CH2Cl2–H2O

O

O

O n

O

N BocHN

NHAr

R

HN O HN

HO2C

O

Ph 37 O

O O

O NHPh

O

O

O

NHPh

O

O NHPh

Ph

O 80%, 76% ee (RT, 5 h) 99%, 8% ee (–10°C, 79 h) 97%, 89% ee (–10°C, 78 h) 76%, 92% ee (4°C, 33 h, with UHP in toluene)

95%, 86% ee (–10°C, 43 h)

73%, 10% ee (RT, 3.5 h)

Scheme 11.46.

O O H

N

Ar

R O H

H O H H O O

O

H

N H

N

O H NHBoc

iPr

N

Ph

O

O

H

ArHN

O

Me Figure 11.5.

R

O

Ar

O O

N H O

O O O H


Progress in the field of asymmetric organocatalysis of chiral amines has increased remarkably in recent years. The amine catalysis can be divided into two classes: iminium ion formation, which leads to lowering the LUMO energy, and generation of nucleophilic enamine intermediates [67,80]. The iminium/enamine catalysis has been successfully applied to asymmetric epoxidation. Jørgensen and coworkers identified chiral pyrrolidine 38 as a catalyst for asymmetric epoxidation of α,β-unsaturated aldehydes with aqueous hydrogen peroxide (Scheme 11.47) [81–83]. α,β-Unsaturated aldehydes having an aromatic substituent at the β-position are good substrates for the reaction, and the epoxides were obtained with high diastereo- and enantioselectivity. High stereoselectivity was also observed in the reaction of the alkyl-substituted, α,β-unsaturated aldehydes. While the reaction of β-disubstituted, α,β-unsaturated aldehydes smoothly proceeded, the enantioselectivity was slightly decreased. As described in Scheme 11.48, R2 R1

O Ph

R2

38 (10 mol %) + 35% H2O2

CHO

O

CHO

Et

80%, 96% ee 93:7 dr

CHO

O BnOH2C

>90%, 96% ee 97:3 dr

O

R1

CH2Cl2, RT, 4 h

O

CHO

84%, 94% ee 96:4 dr

F3C

CHO

CF3

N H

CHO

38

O

O H

R'

Ar OTMS

N H

Ar

H R

R'

38

N+

Ar OTMS Ar

O R

N+

Catalytic cycle

Ar OTMS Ar

OH−

OH−

R'

R

N

CF3

F3C

65%, 75% ee

Scheme 11.47.

O R

OTMS

H2O2

Ar OTMS Ar

O R' HO R Scheme 11.48.

R'

H2O


the reaction proceeds through the well-known Weitz–Scheffer mechanism. The conjugate addition of hydrogen peroxide, which is a good nucleophile and leaving group, to the β-carbon atom of the electrophilic iminium ion is reversible, and the attack on the electrophilic peroxygen atom by the nucleophilic enamine is the step determining the product’s stereochemistry. Asymmetric epoxidation of α,β-unsaturated aldehydes by the iminium/enamine catalysis has also been investigated by MacMillan and Lee (Scheme 11.49) [84]. They utilized chiral imidazolidinone salt 39 as a catalyst with not hydrogen peroxide but iodosobenzene as a stoichiometric oxidant. A combination of [(nosylimino)iodo]benzene (NsNIPh) and acetic acid slowly liberates the active iodosobenzene monomer. The reaction of β-substituted, α,β-unsaturated aldehydes furnished the epoxide with high enantioselectivity as single diastereomers, except for crotonaldehyde. List and coworkers also reported secondary amine-catalyzed asymmetric epoxidation of α,β-unsaturated aldehydes, and their strategy is very attractive, in which the authors utilized a catalyst 40 consist of achiral dibenzylamine and BINOL-derived chiral phosphoric acid (Scheme 11.50) [85]. Together with TBHP as oxidant, the catalyst 40a promotes the epoxidation of both β-mono- and disubstituted α,β-unsaturated aldehydes to give the epoxides with high diastereo- and enantioselectivities. When the two βsubstituents are identical, the enamine intermediate is achiral. However, the substrate underwent epoxidation with high enantioselectivity. Thus, the authors proposed that the chiral phosphoric acid must assist the ring-closing step. List and coworkers also discovered that chiral ammonium salts pairing chiral diamines and chiral/achiral acids catalyze the asymmetric epoxidation of cyclic enones using

CHO + NsNIPh

R

39 (20 mol %)

O R

CH2Cl2-AcOH, –30°C

CHO O

85–97% ee

O

O

CHO

Cy

88%, 93% ee 1:7 dr

O

CHO

Ph

77%, 92% ee

N O

CHO

p-NO2-C6H4

92%, 92% ee

N H

CHO

•HClO4 Ph

39

89%, 97% ee

Scheme 11.49.

R2 R1

R2

40a (10 mol %) CHO

+ TBHP

R1

O

CF3 CHO

NH2+ CHO

O

CHO

O C6H13

75%, 91% ee >99:1 dr

76%, 96% ee >99:1 dr

O

CHO

67%, 70/92% ee 94:6 dr

iPr

F3C

70–96% ee

O

iPr

CHO

83%, 94% ee

Scheme 11.50.

iPr O O P −O O iPr

F3C CF3

iPr iPr

40a


aqueous hydrogen peroxide as oxidant (Scheme 11.51) [86]. Although there have been enormous numbers of effective epoxidation catalysts for different classes of olefins, no catalyst had been successfully applied to cyclic enones. Ammonium salt 41 derived from 1,2-diphenyldiamine and BINOL-based phosphoric acid induces high enantioselectivity. TFA salts of 9-amino cinchona alkaloids 42 and 43 also proved especially suitable for the epoxidation of β-substituted cyclic enones. O

O + 50% H2O2

R

41 or 42•2TFA or 43•2TFA (10 mol %) R

CH2Cl2, RT, 4 h

O

n

n

78% to >99% ee iPr iPr iPr NH2 O O P + − O NH3 O iPr

OMe

NH2 N

N N

NH2 N iPr

OMe 43

42

iPr

41

Scheme 11.51.

Furthermore, Deng and coworkers recently discovered that cinchona alkaloid– derived chiral diamine 42 also serves as a catalyst for enantioselective peroxidation of α,β-unsaturated ketones [87]. Together with TBHP as nucleophile, optically active peroxides were preferentially obtained in high enantiomeric excesses at 23°C with small formation of epoxides. When using more bulky hydroperoxide such as cumene hydroperoxide, the selective synthesis of the peroxides needs the lower reaction temperature of 0°C (Scheme 11.52). On the other hand, complete inversion of the product selectivity was observed at higher temperature (23 or 55°C), and chiral epoxides were provided 42 (10 mol %) TFA (30 mol %)

O + CHP

Ph

Toluene, 0°C

cumylO

O

O

Ph

42 (10 mol %) TFA (20 mol %)

Ph

+ CHP

Toluene, 23°C

cumylO

O

86:14

O

O

+ Ph

O

Ph 1:99

Scheme 11.52.

O

Ph

74%, 94% ee

O

O

+

88%, 97% ee


with high enantioselectivity. While a peroxyenamine intermediate must take a conformation, allowing an interaction between σ ∗O − O orbital and enamine π orbial for epoxide ring closure, the diamine unit on the peroxyenamine regulates its conformation to make the epoxide formation difficult but accelerates the protonation. As the result, enantioenriched peroxides were selectively generated. However, the elevated temperature weakens the regulation, and the peroxyenamine undergoes the O–O bond cleavage. Phase transfer catalysis is a powerful methodology for organic synthesis under aqueous conditions and has been applied to asymmetric epoxidation of α,β-unsaturated carbonyl compounds [88]. Cinchona alkaloid–derived quaternary ammonium salts have been developed for the asymmetric epoxidation of α,β-unsaturated ketones by several research groups [89]. Dimeric cinchona phase transfer catalyst 44 was also identified by Jew and Park (Scheme 11.53) [90]. With aqueous hydrogen peroxide as oxidant, chalcone derivatives underwent epoxidation in high enantiomeric excesses. The addition of surfactants led to significant improvements not only in yield but also in enantioselectivity, and Span 20 (sorbitan monolaurate) was found to be most effective. The catalyst with naphthyl group as the spacer between the cinchona units and the corresponding monomeric catalysts bearing an arylmethyl group on nitrogen atom displayed no asymmetric induction, indicating the synergistic operation of the two cinchona units in the epoxidation event. 44 (1 mol %) Span 20 (1 mol %) 50% KOH (1 equiv.)

O Ph

Ph

+

30% H2O2 (10 equiv.)

O Ph

iPr2O, RT

O Ph

95%, >99% ee

OMe

Br−

N+

F

OH

N+

Br−

OMe

HO

N

N 44

Scheme 11.53.

Maruoka and coworkers have identified chiral spiro ammonium salts bearing an axially chiral binaphthyl unit as the phase transfer catalyst for a wide variety of organic synthesis [88] They designed a new phase transfer catalyst 45 (X = Br) with dual function for asymmetric epoxidation of enones using aqueous sodium hypochlorite as oxidant (Scheme 11.54) [91]. The hydroxyl groups are appropriately placed to recognize and activate the enone substrate through hydrogen bonding. Indeed, the removal of the hydroxyl groups considerably retarded the reaction’s progress and the enantioselectivity was diminished. X-ray crystallographic analysis of 45 (X = PF6) revealed that the diarylhydroxymethyl groups form chiral pockets close to the nitrogen cation and that the hexafluorophosphate anion, which is hypothetically regarded as hypochlorite anion in the epoxidation, is located in the chiral pocket.

11.4. ASYMMETRIC SULFIDE OXIDATION 869

O R

45 (X = Br) (3 mol %) 13% NaOCl

+

R'

O R

Toluene, 0°C

O R'

X− Ar

Ar Ar OH

89–99% ee N+ O

O

O

Ph

O

O Ph

O OH

Ph

Ar Ar

Ph

Ar

45 99%, 96% ee

91%, 99% ee

Ar = 3,5-Ph2-C6H3

98%, 96% ee

Scheme 11.54.

R1

S

46 (2 mol %) R2

+

UHP (1 equiv.)

MeOH, 0°C

R1

O– S+

R2

92–99% ee O– S+

O– S+

O– S+

88%, 99% ee

N Ti

O O Ph Ph O– S+

Cl 78%, 98% ee

N

O 91%, 93% ee

72%, 93% ee

2 46

Scheme 11.55.

11.4. ASYMMETRIC SULFIDE OXIDATION 11.4.1. Introduction Since the development of the titanium/tartrate-catalyzed asymmetric oxidation of sulfides that was independently reported by the Kagan and Modena groups in the early 1980s, significant efforts have been made to expand the scope of asymmetric sulfide oxidation [92–94]. There are a number of powerful catalysts for specific sulfides today. Current interests are directed toward the development of more sustainable methods using greener hydrogen peroxide as the oxidant and more enantioselective catalysts for challenging substrates such as dialkyl sulfides.

11.4.2. Titanium Catalyst While a number of asymmetric sulfide oxidations using titanium-based catalysts have been developed, there were few reports that used hydrogen peroxide as oxidant and achieved both high enantioselectivity and a wide substrate scope [95]. In 2001, Saito and Katsuki demonstrated that di-μ-oxo titanium(salen) complex 46 catalyzed asymmetric oxidation of sulfides with high enantioselectivity in the presence of UHP as the oxidant (Scheme 11.55) [96]. Not only aryl methyl sulfides but also ethyl phenyl sulfide and benzyl methyl sulfide gave high enantioselectivity. Ti(salen) complex 46 was also


successfully applied to desymmetrization of thioacetals and oxidative kinetic resolution of racemic 2-substituted-1,3-oxathianes (Scheme 11.56) [97]. NMR study indicates that the Ti(salen)(OMe)2 complex generated from complex 46 in methanol is further transformed into the active peroxo species upon treatment with hydrogen peroxide. Different from the corresponding Ti(salalen) complex 19, Ti(salen) complex 46 is incompetent to epoxidation. The employment of aqueous hydrogen peroxide instead of anhydrous UHP resulted in the loss of the enantioselectivity due to a partial participation of lowenantioselective titanium η1-hydroperoxo species.

S

46 (2 mol %)

S

+

Ph

UHP (1 equiv.)

–O

MeOH, 0°C

S+

S Ph

91%, 99% ee

S

46 (2 mol %)

O

+

Ph

UHP (1 equiv.)

–O

MeOH, 0°C

S+

O Ph

+

S

O Ph

krel 30 Scheme 11.56.

11.4.3. Vanadium Catalyst Vanadium complexes in situ prepared from VO(acac)2 and chiral aminoalcohol-derived tridentate Schiff bases 6 and 47a were first identified by Bolm and Bienewald as highly enantioselective catalysts for the sulfide oxidation in 1995 [98]. After the initial report, several groups reported modified Schiff base ligands (Fig. 11.6) [54]. Vetter

N N R2

OH

OH N

OH OH Ph

OH R1

6: R1 = R2 = tBu 47a: R1 = tBu, R2 = NO2 47b: R1 = R2 = I

48

Figure 11.6.

49

OH


and Berkessel examined several Schiff base ligands derived from chiral salicylaldehydes in combination with (S)-tert-leucinol, and the best enantioselectivity was observed with 48 bearing an axially chiral binaphthyl framework [99]. Katsuki and coworkers reported that (1S,2R)-1-amino-2-indanol and an axially chiral salicylaldehyde gave an effective ligand 49 for the reaction [100]. Simple diiodo ligand 47b was also introduced by Anson and coworkers [101]. Jackson and coworkers achieved the highly enantioselective synthesis of alkyl aryl sulfoxides by combining the vanadium-catalyzed sulfide oxidation and subsequent oxidative kinetic resolution of sulfoxides (Scheme 11.57) [102,103]. With diiodo ligand 47b, thioanisole is oxidized to methyl phenyl sulfoxide in the (R)-enriched form. The following kinetic resolution event slowly occurs, and the minor (S)-enantiomer is preferentially converted into the sulfone. Thus, the sulfoxide is obtained with extremely high enantiopurity. The krel value in the kinetic resolution has been measured to be as high as 7.7.

Ar

S

VO(acac)2 (1 mol %) (R)-47b (1.5 mol %) R + 30% H2O2 (1.2 equiv.)

O− S+

CHCl3

Ar

O− S+

70%, 96.7% ee

O− S+

70%, >99.5% ee

73%, >99.5% ee

O− S+

R

O− S+

86%, 98.3% ee

Scheme 11.57.

On the other hand, Zhu and coworkers examined ONNO-type tetradentate ligands for the vanadium-catalyzed asymmetric sulfide oxidation (Scheme 11.58) [104]. Interestingly, the most simplified ligand 50 that has no substituents on the benzene ring exhibited the highest enantioselectivity. The catalyst also applied to oxidative kinetic resolution of racemic sulfoxides, and the enantio-enriched sulfoxides were recovered in high enantiomeric excesses.

R1

S

VO(acac)2 (2 mol %) 50 (3 mol %) R2 + 30% H2O2 (1.5 equiv.)

CHCl3

O− S+ R1 R2 NH HN

O− S+

81%, 95% ee

O− S+

78%, 66% ee

O− S+

78%, 72% ee

Scheme 11.58.

O− S+

83%, 76% ee

OH HO 50


11.4.4. Niobium Catalyst Asymmetric oxidation catalysis of niobium-based complexes was first disclosed by Miyazaki and Katsuki and applied to asymmetric oxidation of sulfides (Scheme 11.59) [105]. A niobium complex in situ prepared from NbCl3(dme) and salen ligand 51 serves as an efficient catalyst for several sulfides including benzyl methyl sulfide in the presence of UHP as oxidant. High enantioselectivities of more than 80% ee were observed.

R1

S

R2

+ UHP

NbCl3(dme) (8 mol %) 51 (12 mol %)

O− S+ R1 R2

CH2Cl2, MS4A, –10°C, 48 h

O− S+

O− S+

94%, 86% ee

N

OH HO Ph Ph

O− S+

58%, 86% ee

N

61%, 80% ee

51

Scheme 11.59.

11.4.5. Iron Catalyst Legros and Bolm reported iron-catalyzed asymmetric sulfide oxidation that uses Fe(acac)3 and tridentate Schiff base ligand 47b with aqueous hydrogen peroxide [106]. The introduction of an iodine atom at C3 and C5 positions gave higher enantioselectivity than that of bulky alkyl substituents such as a tert-butyl group. However, only moderate yields and enantioselectivities were obtained under the original conditions. Thus, Bolm and coworker further explored the iron-catalyzed oxidations. On the basis of the Jacobsen’s observation that the addition of acetic acid led to significant improvements on the reaction efficiency in iron-catalyzed epoxidation using aqueous hydrogen peroxide [107], the authors examined the influence of carboxylic acids and found that addition of 0.5 equivalent of benzoic acid relative to Fe(acac)3 remarkably improved both the yield and enantioselectivity in the oxidation of methyl phenyl sulfide. Eventually, p-methoxybenzoic acid and its lithium salt were chosen as the additives (Scheme 11.60) [108]. In the

Ar

S

Fe(acac)3 (2 mol %) 47b (4 mol %) additive (1 mol %) R + 35% H2O2 (1.2 equiv.)

CH2Cl2, RT

Ar

O− S+

additive =

O− S+

O− S+

R

36%, 96% ee

67%, 95% ee

O− S+

O2N 63%, 90% ee

or

56%, 82% ee

Scheme 11.60.

O O-Li

OH MeO

O− S+

O

+

MeO


all cases, remarkable improvements were observed, and enantioselectivity higher than 80% ee was obtained in the oxidation of aryl methyl sulfides. From the observed positive nonlinear effect and the necessity of a half equivalent of the carboxylic acid/carboxylate additive with respect to iron, a monocarboxylate-bridged diiron(III) complex has been proposed as a key intermediate in the catalytic cycle. Egami and Katsuki also reported an iron-based catalyst for the reaction (Scheme 11.61) [109]. Fe(salan) complex 52 serves as an effective catalyst, with aqueous hydrogen peroxide as oxidant. The method employs the most favorable solvent, water, and can be performed even in the absence of a surfactant. It is noteworthy that not only alkyl aryl sulfides but also dialkyl sulfides underwent oxidation with high enantioselectivity. Scarso and Strukul also reported the platinum-catalyzed asymmetric sulfide oxidation in water, but their system requires the addition of a surfactant [110].

R1

S

R2

+

30% H2O2 (1.5 equiv.)

O– S+ R1 R2

52 (1 mol %) H2O, 20°C

Me N

81–96% ee O– S+

O– S+

92%, 96% ee

O– S+

78%, 81% ee

93%, 87% ee

Fe O Cl O Ph Ph

O– S+

C12H25

Me N

82%, 94% ee

52

Scheme 11.61.

11.4.6. Aluminum Catalyst Recently, Katsuki and coworkers identified aluminum(salalen) complexes as efficient catalysts for asymmetric sulfide oxidation using aqueous hydrogen peroxide (Scheme 11.62) [111]. Al(salalen) complex 53 promotes the oxidation of a wide variety of sulfides with high enantioselectivity even under aqueous conditions. Aryl methyl sulfides undergo highly enantioselective oxidation, and ethyl phenyl sulfoxide and benzyl methyl sulfoxide are also obtained with high enantioselectivity. Other sulfur-containing compounds such as cyclic sulfides and thioacetals are also good substrates for the oxidation system

S R1 R2

53 (2 mol %) pH 7.4 phosphate buffer +

30% H2O2 (1.1 equiv.)

O−

O−

S+

S+

MeOH

O− S+

R1

O− S+

80%, 91% ee

83%, 80% ee

Me N

N

Al O Cl O Ph Ph S+

S

O−

Ph 86%, 98% ee

R2

92%, 98% ee

Scheme 11.62.

S

S+

O−

Ph 89%, 99% ee

53


[112]. The author proposed a η2-hydroperoxide as the active species. It is noteworthy that the catalyst promotes the reaction under solvent-free conditions, and the exceptionally high turnover number of the catalyst is observed without erosion of the high enantioselectivity (Scheme 11.63) [113].

S

53 (0.002 mol %) pH 7.4 phosphate buffer +

30% H2O2 (1.1 equiv.)

O− S+

Solvent-free

92%, 96% ee TON 46,000 Scheme 11.63.

11.5. ASYMMETRIC BAEYER-VILLIGER OXIDATION The Baeyer–Villiger oxidation is a powerful method for obtaining esters from the carbonyl compounds [114,115]. The configuration of the migrating group is retained through the process, and the reaction is stereospecific at the migrating carbon. The predictable order of migrating groups and the broad tolerance of functionalities also offer a great advantage. In 1994, the Strukul and Bolm groups independently reported the first examples of the asymmetric Baeyer–Villiger oxidation using metal complexes as catalyst [116,117]. Strukul and coworkers discovered that chiral platinum catalyst 54 promotes the oxidative kinetic resolution of racemic mixture of cyclic ketones with aqueous hydrogen peroxide as oxidant and achieved ee values of up to 58% (Scheme 11.64). On the other hand, the Bolm’s group identified chiral copper catalyst 55 for the reaction of racemic 2-aryl cycloalkanones and obtained the lactones with up to 69% ee (Scheme 11.65). The method employs molecular oxygen as oxidizing agent in the presence of pivalaldehyde as a sacrificial reductant (the Mukaiyama condition) [118]. Since the initial reports on the metal-catalyzed asymmetric Baeyer–Villiger oxidations, significant advances have been seen in the field of the reaction. Especially, Bolm and coworkers have dedicated their research efforts to this area and found several useful catalysts. For example, an aluminum/BINOL complex was found to be an effective catalyst for the reaction [119]. Although a substoichiometric amount of the catalyst was required, 3-substituted cyclobutanones underwent in good enantiomeric excesses of up to 73% ee (Scheme 11.66). The parallel kinetic resolution of the racemic bicyclooctane

O

O nC5H11

+ 35% H2O2

54

O O

+ nC5H11

nC5H11

O Ph Ph P Pt P Ph O Ph

58% ee 54

Scheme 11.64.

OMe

11.5. ASYMMETRIC BAEYER-VILLIGER OXIDATION 875

O

O Ph

55 (1 mol %), t BuCHO O2

O O

O Ph

+

O

N

NO2

Cu

Ph

O2N

N

O

O

47%, 69% ee 55

Scheme 11.65.

Me2AlCl (50 mol %) (S)-BINOL (50 mol %)

O + R

CHP (1.5 equiv.)

O O

Toluene

R 58–73% ee O

Me2AlCl (50 mol %) (S)-BINOL (50 mol %)

O +

CHP (1.5 equiv.)

O O

Toluene 34% ee

O

+ 96% ee

Scheme 11.66.

R3O M

O O

R2 R1

Figure 11.7.

furnished the two lactones [120]. One is the lactone normally obtained in common Baeyer–Villiger reactions, and the enantiomeric excess is as high as 34%. The other is the constitutional isomer of the normal one and obtained with high enantioselectivity of 96% ee. The subsequent studies employing substituted BINOL derivatives provided a more efficient method that needs less catalyst, and the high ee value of up to 84% ee was achieved in the reaction of 3-phenylcyclobutanone [121]. The aluminum/BINOL system was proposed to proceed via a cyclic Criegee intermediate involving a pentacoordinated aluminum complex (Fig. 11.7). The conformational regulation of metal-bound Criegee intermediates by chelate formation was first proven as an efficient strategy by Uchida and Katsuki (Scheme 11.67) [122]. They reported that chiral cis-β cobaltIII complex 56 bearing axially chiral binaphthyldiamine catalyzes the Baeyer–Villiger oxidation of 3-substituted cyclobutanones in the presence of UHP. Interestingly, the corresponding cobalt(salen) complexes in a trans-configuration show no asymmetric induction. Aoki and Seebach have also reported that the regulation of Criegee intermediate is essential for chiral alkyl hydroperoxidemediated Baeyer–Villiger oxidation [123].


O

O

56 (5 mol %) +

R

UHP (1.3 equiv.)

O

EtOH, 0°C

N

N Co+ O O

R 75–78% ee

F

PF6−

F

F F

56

Scheme 11.67.

O

O

57 (5 mol %) + UHP

R

N L N Zr O L O Ph Ph

O

CH2Cl2, RT R

81–87% ee L = OPh 57 O

57 (8 mol %) + UHP

Racemic

O

O +

PhCl, RT 17%, 94% ee

O O 55%, 80% ee

+

O 25%, >99% ee

Scheme 11.68.

Subsequently, Katsuki and coworkers reported the zirconium-catalyzed Baeyer– Villiger reaction using UHP as oxidant (Scheme 11.68) [124]. In the presence of Zr(salen) complex 57, a range of 3-substituted cyclobutanone derivatives efficiently underwent oxidation to give the enantio-enriched lactones with high enantioselectivity. Zr(salen) complex 57 also promoted parallel kinetic resolution of racemic cyclobutanones, and the lactones and the recovered ketone were obtained in high enantiomeric excesses. The authors proposed that the salen ligand of 57 adopts a trans-topology in the resting state but that cis-β one in the transition state. The related hafnium(salen) complex also catalyzed the reaction with the comparable enantioselectivity [125]. A palladium complex has been identified by Ito and coworkers as a Baeyer–Villiger oxidation catalyst. A cationic palladiumII complex bearing P,N-ligand 58 promoted the reaction of cyclobutanones with good enantioselectivity (Scheme 11.69) [126]. The complete enantioselectivity was achieved in the reaction of a tricyclic ketone. Recently, Malkov and Kocˇ ovský also reported chiral terpene-derived P,N-ligands for the palladium-catalyzed reaction, and a good enantioselectivity of up to 81% ee was observed in the reaction of 3-substituted cyclobutanones [127].

11.5. ASYMMETRIC BAEYER-VILLIGER OXIDATION 877

PdCl2(PhCN)2 (5 mol %) 58 (5.5 mol %) AgSbF6 (10 mol %)

O + UHP

R

O O

R

THF

N O

O

O

PPh2

O O

O

O

Ph

p-ClC6H4

91%, 80% ee

O 58

2-naphtyl

76%, 73% ee

94%, 83% ee

89%, >99% ee

Scheme 11.69.

O 59 (10 mol %) AcONa (25 mol %)

O + 30% H2O2 R

N

N

O

N

O + N Et 2ClO4−

O

CF3CH2OH/MeOH/H2O

N

R 61–74% ee

N N

O

N+ Et O

59

Scheme 11.70.

60 (10 mol %) + 30% H2O2

R R'

Ar

O

O

CHCl3, –40°C

O O P O OH

O R R' 55–93% ee

Ar 60

Ar = pyren-1-yl

Scheme 11.71.

Metal-free, enzyme-catalyzed reactions are also effective methods for the Baeyer– Villiger reactions, and many developments have been reported [128]. Although high enantioselectivities have been realized for some substrates, the scope of enzymatic methods is inherently narrow. A bio-inspired organocatalyst based on flavin has been developed by Murahashi and Imada (Scheme 11.70) [129,130]. Planer-chiral bisflavin perchlorate 59 catalyzes the reaction of cyclobutanones with aqueous hydrogen peroxide as oxidant to give the corresponding γ-butyrolactones with 61–74% ee. Recently, chiral phosphoric acids were identified by Ding and coworkers as catalyst for the asymmetric Baeyer–Villiger oxidation of cyclobutanones with aqueous hydrogen peroxide as oxidant (Scheme 11.71) [131]. A phosphoric acid catalyst 60 that


Ar O P O

R

O H O O

O

Ar Figure 11.8.

O 61 (25 mol %) DIC (10 equiv.) DMAP (25 mol %)

O +

O

N HN

BocHN

O

O

30% H2O2 (12.5 equiv.)

HN

HO2C

29%, 42% ee

O Ph

NH 61

Scheme 11.72.

has the H8-BINOL backbone (H8-BINOL = 5,5′,6,6′,7,7′,8,8′-octahydro-,1′-bi-2naphtyl) exhibited higher enantioselectivity than the BINOL derivatives. Aromatic substituents at the C3 and C3′ positions also significantly affected the enantioselectivity, and the introduction of pyren-1-ly groups afforded the highest enantioselectivity in the reaction of 3-phenylcyclobutanone. On the basis of a mechanism proposed for the peracid-mediated Baeyer–Villiger oxidation, the authors suggested that the reaction proceeds via a cyclic Criegee intermediate and that the formation of the intermediate allows the highly enantioselective migration (Fig. 11.8). Today, a useful level of enantioselectivity has been achieved by several metal- and organo-catalyzed methods, but good substrates are quite limited to cyclobutanone derivatives. Unfortunately, most of the known catalysts cannot be applied to cycloalkanones with larger ring sizes, regarding reactivity and stereoselectivity. The development of more effective methods based on novel activation mechanisms will cross the bounds and open a new horizon in the field of asymmetric Baeyer–Villiger oxidation. Recently, Miller and coworkers demonstrated a simple method, the chiral peracidmediated asymmetric oxidation. Peracid is a standard reagent for the nonasymmetric Baeyer–Villiger reaction and it is utilized for a wide range of ketones irrespective of the ring size. The authors applied the peracid/carboxylic acid shuttle, which has been previously applied to asymmetric epoxidation of olefins [78], and achieved to render the reaction catalytic (Scheme 11.72) [132]. Aspartate-derived oligopeptide 61 catalytically promotes the oxidation of ketones to yield lactones with moderate but promising enantioselectivity.

O

11.6. ASYMMETRIC DIHYDROXYLATION 879

11.6. ASYMMETRIC DIHYDROXYLATION The Sharpless asymmetric dihydroxylation of olefins is an important chemical process, providing access to synthetically valuable 1,2-diols with two contiguous stereogenic centers [133]. Osmium tetroxide, together with cinchona alkaloid–derived ligands, is employed as a catalyst, and NMO and potassium ferricyanide/potassium carbonate are common oxidants for the reaction. Several types of chiral cinchona alkaloid–derived ligands have been introduced in accordance with the substitution pattern of olefins, and high enantioselectivity is obtained in most cases. There are two potential catalytic cycles for the osmium-catalyzed dihydroxylation of olefins using NMO as oxidant (Scheme 11.73). The left cycle, in which the chiral alkaloid ligand binds to the osmium, is called the first cycle, and the reaction proceeds with high enantioselectivity. On the other hand, the second cycle does not involve the chiral ligand but 1,2-diol ligand. In general, the participation of the second cycle leads to reduced enantioselectivity. Thus, rapid hydrolysis of Os(VIII) trioxoglycolate is essential for achieving high enantioselectivity. Recently, however, Fokin and Sharpless discovered a unique utilization of the second cycle for enantioselective dihydroxylation and aminohydroxylation [134], which is the aza-analogue of the dihydroxylation and a powerful approach to amino alcohols. In the course of further investigations of the osmium-catalyzed oxidations, the authors discovered that certain classes of olefins undergo rapid dihydroxylation or aminohydroxylation in the absence of the alkaloid ligand, even with very low catalyst loadings [135]. On the basis of the observation, the authors set out the research to account for the exceptional phenomenon and found that chiral N-sulfonyl-1,2-hydroxyamines serve as effective ligands for the asymmetric reactions via the second cycle (Scheme 11.74) [136].

H2O

OH OH

R

O O O Os O O L*

R' L*

R'

R R' R

L*

NMM

O

First cycle

Os O O O

R

Second cycle NMO

R L*

R L*

R

R'

O R' O Os O O L*

H2O

OH OH

R R' Scheme 11.73.

O O O Os O O

R' R

880 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS OsO4 (0.2 mol %) 62 or 63 (2 mol %)

O OR'

+

NMO (1.1 equiv.)

OH O OR'

tBuOH/H2O, pH 5, RT

R

R

OH 40–70% ee

R"

K2[OsO2(OH)4] (1 mol %) 62 or 63 (2–5 mol %) + TsN(Na)Cl• 3H2O (1 equiv.)

tBuOH/H2O, pH 8, RT

NHTs R"

OH R"

+

OH

NHTs

30–59% ee NHTs CO2H OH 62

24–55% ee

OH CO2H

or

NHTs 63

Scheme 11.74.

In the common procedures of the Sharpless asymmetric dihydroxylation, NMO or potassium ferricyanide/potassium carbonate is used as an oxidant to give the active osmium tetroxide. However, the cogeneration of stoichiometric amount of NMM or ferrocyanide is problematic from the viewpoint of atom economy. Thus, alternative methods for the catalytic regeneration of osmium tetroxide from an osmateVI species have been studied. Beller and coworkers achieved the asymmetric dihydroxylation using molecular oxygen without the addition of mediators (Scheme 11.75) [137]. While the elevated reaction temperature led to somewhat decreased enantioselectivity, optically active 1,2-diols could be obtained with reasonable enantioselectivity. Bäckvall and coworkers also disclosed that flavin 64 can mediate the osmium-catalyzed dihydroxylation in the presence of aqueous hydrogen peroxide as the terminal oxidant (Scheme 11.76) [138]. The reaction proceeded efficiently under the mild conditions, and high enantioselectivity was observed.

Ph

+

O2 (1 bar)

K2[OsO2(OH)4] (DHQD)2PHAL pH 10.4 buffer/tBuOH, 50°C

OH Ph

OH

52%, 90% ee Scheme 11.75.

The Sharpless asymmetric dihydroxylation displays excellent enantioselectivity for a wide range of olefins and is frequently utilized in organic synthesis. However, a major drawback of the Sharpless method is the toxicity of the osmium reagent and waste materials derived from it. Thus, the development of an alternative method using more environmentally benign metals has been urged. Que and coworkers for the first time discovered an iron-based catalyst for enantioselective cis-dihydroxylation of olefins. In the presence of aqueous hydrogen peroxide as

11.6. ASYMMETRIC DIHYDROXYLATION 881

OsO4 (2 mol %) (DHQD)2PHAL (6 mol %) 64 (5 mol %) TEAA (2 equiv.) NMM (50 mol %) Ph

+

30% H2O2 (1.5 equiv.)

H N

OH Ph

tBuOH/H2O, 0°C

N

OH N Et

88%, 99% ee

O N

O

Flavin 64 O R' N

OsO4

R R''

H2O

Flavin-OH

H2O2

NMM

O

R' OH OH

R

Flavin-OOH

OsO3

N O NMO

R''

Scheme 11.76.

the oxidant, ironII complex 65 bearing a tetraaza ligand promotes oxidations of olefins to yield diols and epoxides [47]. Terminal and trans-disubstituted olefins underwent epoxidation in an enantioselective manner, and good enantioselectivity of 82% ee is obtained in the dihydroxylation of trans-2-octene, while a small amount of the epoxidation product is produced (Scheme 11.77). The methyl group on the pyridine ring of 65 dramatically affects the product selectivity, and the related iron complex 25 without methyl groups preferentially yielded epoxides. X-ray analysis revealed that the tetraaza ligand in 65 adopts a cis-β topology, in which the two pyridine nitrogen atoms coordinate cis to each other, whereas 25 has a cis-α one.

OH

65

+

50% H2O2

N

CH3CN

OH 82% ee

N Fe2+ N N –

(CF3SO3 )2 65

Scheme 11.77.

Quite recently, Que and coworkers extended the iron catalysis for the reaction [139]. Replacing the trans-1,2-diaminocyclohexane backbone of 65 with rigid bipyrrolidine led to a significant improvement of both the product- and enantioselectivity. The iron catalyst derived from 66, which adopts a cis-α topology in the solid state, promoted the dihydroxylation of trans-disubstituted olefins in high enantiomeric excesses up to 97% ee (Scheme 11.78). The ee values are comparable to the Sharpless osmium-catalyzed system. Terminal olefins also underwent dihydroxylation with good enantioselectivity.


R'

R

+

H2 O 2

OH

66 R

CH3CN

R' N

OH

N Fe2+

OH

OH 97% ee

OH

OH

OH 96% ee

OH 76% ee

N

N

OH O OEt OH 78% ee

66

–

(CF3SO3 )2

Scheme 11.78.

While the process has not yet reached a level for practical use in terms of the requirement for limiting oxidant, future work will provide improvements that overcome this drawback. Recently, Chen and White disclosed the remarkable oxidation catalysis of the related iron catalyst for predictable stereoselective hydroxylation of unactivated C–H bonds [140].[141] As described above, the toxicity of osmium reagents is a serious problem for the Sharpless asymmetric dihydroxylation, and the development of alternative methods using nontoxic, environmentally benign catalysts is desirable. Que’s iron catalysts still fail to stand up to practical use, but further improvements will lead to truly powerful asymmetric dihydroxylation methods.

11.7. ASYMMETRIC AZIRIDINATION Aziridines, the nitrogen counterpart of epoxides, are versatile building blocks in organic synthesis and an important class of biologically active compounds. Significant progress has been made in the field of catalytic asymmetric aziridination of olefins [141]. Evans and coworkers first identified chiral copper/bisoxazoline complexes as catalysts for nitrene-transfer aziridination and enabled the highly enantioselective synthesis of chiral aziridines [142]. Simultaneously, Jacobsen and coworkers demonstrated the utility of chiral diimine ligands for copper-catalyzed aziridination [143]. Subsequent to the publications, a large number of copper-based variants have been reported, and manganese(porphyrin) and -(salen) complexes were also found to be effective catalysts for the reaction [144,145]. These reactions were proposed to proceed via active nitrenoid species and most of the known methods employ a hypervalent iodine reagent such as PhI=NTs as nitrenoid precursor. While chiral aziridines were yielded as the N-sulfonyl protected forms, the deprotection of N-sulfonyl groups usually requires harsh conditions. Thus, the development of catalytic asymmetric synthesis of optically active aziridines without a protecting group or with a readily removable group has attracted much attention in recent years. On the other hand, with respect to atom economy, the use of PhI=NTs as nitrene precursor is not favorable due to the generation of a copious amount of iodobenzene as a by-product. Azide compounds are an ideal nitrene precursor in terms of atom efficiency since they liberate only nitrogen gas along with the nitrene formation. p-Toluenesulfonyl azide (TsN3) is known to decompose, giving a free nitrene intermediate under ultraviolet irradiation or heating [146]. Jacobsen and coworkers employed TsN3 in their copper/diimine-catalyzed asymmetric aziridination under irradiation [147]. Mueller and coworkers also reported asymmetric aziridination using pNsN3 in the

11.7. ASYMMETRIC AZIRIDINATION 883

presence of a rhodium catalyst [148]. However, the enantioselectivities were only moderate. Katsuki and coworkers reported that chiral ruthenium(salen) complex 67 promotes the aziridination of olefins with TsN3 without irradiation at room temperature, and optically active aziridines were yielded in high enantiomeric excesses [149,150]. The authors further investigated azide compounds as nitrene precursors and found that p- and onitrobenzenesulfonyl azide (p- and o-NsN3) and 2-(trimethylsilyl)ethanesulfonyl azide (SESN3) also underwent aziridination enantioselectively [151]. Especially, the reaction with SESN3 efficiently proceeded to give aziridines with high enantioselectivity. It is noteworthy that less nucleophilic, α,β-unsaturated esters also underwent aziridination with complete enantioselectivity and that the SES-protecting group was readily removed by tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) without the loss of the enantioselectivity (Scheme 11.79) [152]. O

O

67 (2 mol %)

OBn

+ SESN3

CH2Cl2, RT

SESN

O

TASF OBn

81%, >99% ee

HN

OBn

>99% ee

N

N Ru O L O Ar Ar

L = CO 67

Ar = 3,5-Cl2-4-Me3SiC6H2

Scheme 11.79.

An aminimide that is produced by deprotonation of the corresponding aminimine has been reported to undergo aziridination of chalcone by the following sequence: conjugate addition and ring closure via N-N bond cleavage [153]. Shi and coworkers discovered that N-methylmorpholine-derived aminimide could be catalytically generated in the presence of O-mesitylenesulfonylhydroxylamine and CsOH·H2O. The reaction also works with a catalytic amount of a chiral tertiary amine, (+)-Tröger’s base 68, giving enantio-enriched aziridines (Scheme 11.80) [154]. Although the reaction is substoichiometric and the enantioselectivity is moderate, this method could produce nonprotected aziridines in a nonracemic form. Subsequent to this publication, Armstrong and coworkers also reported aminimide-mediated asymmetric aziridination of chalcone using quiniclidine and O-(diphenylphosphinyl)hydroxylamine (Scheme 11.81) [155]. Although the method needs a stoichiometric amount of quiniclidine 69, the enantio-enriched α-keto aziridine was yielded with 56% ee. The iminium/enamine catalysis, which has been successfully demonstrated in the secondary amine-catalyzed asymmetric epoxidation of α,β-unsaturated aldehydes, was also applied to asymmetric aziridination by using acetyl hydroxylcarbamate as nitrene equivalent by Córdova and coworkers. The reaction proceeds through a quite similar


O

O O S ONH2

+

¨ (+)-Troger's base 68 (30 mol %) CsOH•H2O (3.0 equiv.)

H O N

CH3CN/CH2Cl2, 0°C, 5 h

Cl

Cl 50%, 62% ee N N ¨ (+)-Troger's base 68

Scheme 11.80.

Ph

+

Ph

69 (1.05 equiv.) NaH, iPrOH

O Ph P ONH 2 Ph

O

H O N

CH2Cl2

Ph

OMe Ph

N

64%, 56% ee

OH N

69

Scheme 11.81.

R

CHO

+

R'

N H

OAc

R' N

70 (20 mol %)

CHCl3

R

R' = Cbz or Boc

Boc N

CHO

54%, 90% ee 5:1 dr

Cbz N Et

CHO

84–99% ee

CHO

60%, 97% ee 5:1 dr

Cbz N nPr

Ph OTMS

N H

Ph 70

CHO

62%, 99% ee 10:1 dr

Scheme 11.82.

pathway to that of the epoxidation [156]: iminium ion formation, conjugate addition of hydroxylamine to the iminium ion, enamine attack on the electrophilic nitrogen atom and hydrolysis of the iminium ion. Chiral pyrrolidine 70 promotes the reaction of enals bearing β-alkyl substituents to give the N-Boc- or N-Cbz-protected 2-formylaziridines with good diastereo- and high enantioselectivity (Scheme 11.82). The product 2formylaziridines are rather unstable under the reaction conditions due to the high reactivity. Thus, short reaction time at elevated temperature is recommended for obtaining 2-formylaziridines in higher yield.

REFERENCES 885

REFERENCES 1. (a) Comprehensive Organic Synthesis, Vol. 7 (Eds. Trost, B. M.; Fleming, I.). Oxford, Pergamon Press, 1991. (b) Modern Oxidation Methods (Ed. Bäckval, J.-E.). Weinheim: Wiley-VCH, 2004. 2. (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M. Angew. Chem. Int. Ed. Engl. 1995, 34, 259–281. 3. Lane, B. S.; Burgess, K. Chem. Rev. 2003, 103, 2457–2473. 4. Tojo, G.; Fernández, M. Oxidation of Alcohols to Aldehydes and Ketones. New York: Springer, 2006. 5. (a) Markó, I. E.; Giles, P. R.; Tsukazaki, M.; Gautier, A.; Dumeunier, R.; Doda, K.; Philippart, F.; Chellé-Regnault, I.; Mutonkole, J.-L.; Brown, S. M.; Urch, C. J. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 437–478. (b) Schultz. M. J.; Sigman, M. S. Tetrahedron 2006, 62, 8227–8241. (c) Sheldon, R. A.; Arends, I. W. C. E.; Dijksman, A. Catal. Today 2000, 57, 157–166. 6. Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun. 1977, 157–158. 7. (a) Muzart, J. Tetrahedron 2003, 59, 5789–5816. (b) Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400– 3420. (c) Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A. III. J. Am. Chem. Soc. 2004, 126, 7967–7974. (d) Zierkiewicz, W.; Privalov, T. Organometallics 2005, 24, 6019–6028. (e) Gligorich, K. M.; Sigman, M. S. Angew. Chem. Int. Ed. 2006, 45, 6612–6615. (f) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221–229. (g) Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348–4355. 8. (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron Lett. 1998, 39, 6011–6014. (b) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998, 63, 3185–3189. (c) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636–1639. (d) Iwasawa, T.; Tokunaga, M.; Ohbora, Y.; Tsuji, Y. J. Am. Chem. Soc. 2004, 126, 6554–6555. (e) Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org. Chem. 2005, 70, 3343–3352. 9. Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475–7476. 10. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. 11. Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124, 8202–8203. 12. Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63–65. 13. Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600–4603. 14. Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003, 5, 835–837. 15. Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem. Int. Ed. 2004, 43, 353–357. 16. Caspi, D. D.; Ebner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004, 346, 185–189. 17. Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–11753. 18. (a) Markó, I. E.; Giles, P. R.; Tsukazaki, M.; Chellé-Regnaut, I.; Urch, C. J.; Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661–12662. (b) Lenz, R.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997, 3291–3292. (c) Hanyu, A.; Takezawa, E.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998, 39, 5557– 5560. (d) Lee, M.; Chang, S. Tetrahedron Lett. 2000, 41, 7507–7510. (e) Dijksman, A.; MarinoGonzález, A.; Mairata, I.; Payeras, A.; Arends, I. W. C. E.; Sheldon, R. A. J. Am. Chem. Soc. 2001, 123, 6826–6833. (f) Miyata, A.; Furukawa, M.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2002, 43, 3481–3484. 19. Masutani, K.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000, 41, 5119–5123. 20. Nakamura, Y.; Egami, H.; Matsumoto, K.; Uchida, T.; Katsuki, T. Tetrahedron 2007, 63, 6383–6387. 21. (a) Shimizu, H.; Nakata, K.; Katsuki, T. Chem. Lett. 2002, 31, 1080–1081. (b) Shimizu, H.; Katsuki, T. Chem. Lett. 2003, 32, 480–481. 22. Shimizu, H.; Onitsuka, S.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2005, 127, 5396–5413. 23. Wang, Y.; DuBois, J. L.; Hedman, B.; Hodgson, K. O.; Stack, T. D. P. Science 1998, 279, 537–540. 24. (a) Kirihara, M.; Ochiai, Y.; Takizawa, S.; Takahata, H.; Nemoto, H. Chem. Commun. 1999, 1387– 1388. (b) Maeda, Y.; Kakiuchi, N.; Matsumura, S.; Nishimura, T.; Uemura, S. Tetrahedron Lett. 2001,

886 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS 42, 8877–8879. (c) Maeda, Y.; Kakiuchi, N.; Matsumura, S.; Nishimura, T.; Kawamura, T.; Uemura, S. J. Org. Chem. 2002, 67, 6718–6724. (d) Velusamy, S.; Punniyamurthy, T. Org. Lett. 2004, 6, 217–219. 25. Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 1090–1091. 26. Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-T. Proc. Natl. Acad. Sci. USA 2006, 103, 3522–3527. 27. Pawar, V. D.; Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128, 6308–6309. 28. Radosevich, A. T.; Chan, V. S.; Shih, H.-W.; Toste, F. D. Angew. Chem. Int. Ed. 2008, 47, 3755–3758. 29. Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem. Int. Ed. 2008, 47, 2447–2449. 30. (a) Heiden, Z. M.; Rauchfuss, T. B. J. Am. Chem. Soc. 2007, 129, 14303–14310. (b) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Chem Asian J. 2008, 3, 1479–1485. 31. (a) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308. (b) Ikariya, T; Murata, K.; Noyori, R. Org. Bio. Chem. 2006, 4, 393–406. (c) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226–236. (d) Samec, J. S.; Bäckvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237–248. 32. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976. (b) Katsuki, T.; Martin, V. S. Org. Rect. 1996, 48, 1–299. 33. (a) Katsuki, T. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer-Verlag, 1999; pp. 621–648. (b) Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer-Verlag, 1999; pp. 649–677. (c) Aggarwal, V. K. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer-Verlag, 1999; pp. 679–693. (d) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 231–280. (e) Katsuki, T. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 287–325. (f) Berkessel, A. In Asymmetric Synthesis—The Essentials. (Eds. Christmann, M.; Bräse, S.). Weinheim: Wiley-VCH, 2007; pp. 176–180. (g) Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215–1225. 34. Tse, M. K.; Döbler, C.; Bhor, S.; Klawonn, M.; Mägerlein, W.; Hugl, H.; Beller, M. Angew. Chem. Int. Ed. 2004, 43, 5255–5260. 35. (a) Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Döbler, C.; Spannenberg, A.; Mägerlein, W.; Hugl, H.; Beller, M. Chem. Eur. J. 2006, 12, 1855–1874. (b) Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Spannenberg, A.; Döbler, C.; Mägerlein, W.; Hugl, H.; Beller, M. Chem. Eur. J. 2006, 12, 1875–1888. 36. Nishiyama, H.; Shimada, T.; Itoh, H.; Sugiyama, H.; Motoyama, Y. Chem. Commun. 1997, 1863–1864. 37. Matsumoto, K.; Sawada, Y.; Saito, B.; Sakai, K.; Katsuki, T. Angew. Chem. Int. Ed. 2005, 44, 4935–4939. 38. Sawada, Y.; Matsumoto, K.; Katsuki, T. Angew. Chem. Int. Ed. 2007, 46, 4559–4561. 39. Sawada, Y.; Matsumoto, K.; Kondo, S.; Watanabe, H.; Ozawa, T.; Suzuki, K.; Saito, B.; Katsuki, T. Angew. Che. Int. Ed. 2006, 45, 3478–3480. 40. Matsumoto, K.; Sawada, Y.; Katsuki, T. Synlett 2006, 3545–3547. 41. Shimada, Y.; Kondo, Y.; S.; Ohara, Matsumoto, K.; Katsuki, T. Synlett 2007, 2445–2447. 42. Colladon, M.; Scarso, A.; Sgarbossa, P.; Michelin, R. A.; Strukul, G. J. Am. Chem. Soc. 2006, 128, 14006–14007. 43. Colladon, M.; Scarso, A.; Strukul, G. Adv. Synth. Catal. 2007, 349, 797–801. 44. Colladon, M.; Scarso, A.; Sgarbossa, P.; Michelin, R. A.; Strukul, G. J. Am. Chem. Soc. 2007, 129, 7680–7689. 45. (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217–6254. (b) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317–3321.

REFERENCES 887

46. Francis, M. B.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1999, 38, 937–941. 47. Costas, M.; Tipton, A. K.; Chen, K.; Jo, D.-H.; Que, L., Jr. J. Am. Chem. Soc. 2001, 123, 6722–6723. 48. Gelalcha, F. G.; Bitterlich, B.; Anikumar, G.; Tse, M. K.; Beller, M. Angew. Chem. Int. Ed. 2007, 46, 7293–7296. 49. Gelalcha, F. G.; Anikumar, G.; Tse, M. K.; Brückner, A.; Beller, M. Chem. Eur. J. 2008, 14, 7687–7698. 50. Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703–710. 51. Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron Lett. 1979, 20, 4733–4736. 52. (a) Michaelson, R. C.; Palermo, R. E.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 1990–1992. (b) Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979, 12, 63–73. 53. Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem. Int. Ed. 1995, 34, 1059–1070. 54. Bolm, C. Coord. Chem. Rev. 2003, 237, 245–256. 55. Murase, N.; Hoshino, Y.; Oishi, M.; Yamamoto, H. J. Org. Chem. 1999, 64, 338–339. 56. Hoshino, Y.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 10452–10453. 57. Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem. Int. Ed. 2005, 44, 4389–4391. 58. Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286–287. 59. Egami, H.; Katsuki, T. Angew. Chem. Int. Ed. 2008, 47, 5171–5174. 60. Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem. Int. Ed. 2006, 45, 5849–5852. 61. (a) Yamada, S.; Mashiko, T.; Terashima, S. J. Am. Chem. Soc. 1977, 99, 1988–1990. (b) Kühn, F. E.; Zhao, J.; Herrmann, W. A. Tetrahedron: Asymmetry 2005, 16, 3469–3479. 62. Basak, A.; Barlan, A. U.; Yamamoto, H. Tetrahedron: Asymmetry 2006, 17, 508–511. 63. (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329–2330. (b) Watanabe, S.; Kobayashi, Y.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7353–7356. (c) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725–2732. (d) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9474–9475. (e) Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.-Y.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544–14545. (f) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559–7570. (g) Tosaki, S.-Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 2147–2155. (h) Kakei, H.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 8962–8963. 64. Daikai, K.; Kamaura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39, 7321–7322. 65. Hara, K.; Park, S.-Y.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2008, 3, 1500–1504. 66. Nemoto, T.; Ohshima, T.; Shibasaki, M. Tetrahedron 2003, 59, 6889–6897. 67. Berkessel, A.; Gröger, H. Asymmetric Organocatalysis. Weinheim: Wiley-VCH, 2005. 68. (a) Curci, R.; Fiorentino, M.; Serio, M. R. J. Chem. Soc., Chem. Commun. 1984, 155–156. (b) Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995, 36, 5831–5834. 69. (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488–496. (b) Yang, D. Acc. Chem. Res. 2004, 37, 497–505. 70. (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806–9807. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224–11235. 71. (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551–11552. (b) H.; Tian, X.; She, J.; Xu, Shi, Y. Org. Lett. 2001, 3, 1929–1931. (b) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435–2446. 72. Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci. USA 2004, 101, 5794–5798. 73. (a) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293–296. (b) Goeddel, D.; Shu, L.; Yuan, Y.; Wong, O. A.; Wang, B.; Shi, Y. J. Org. Chem. 2006, 71, 1715–1717.

888 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS 74. Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792–8793. 75. (a) Shen, Y.-M.; Wang, B.; Shi, Y. Angew. Chem. Int. Ed. 2006, 45, 1429–1432. (b) Shen, Y.-M.; Wang, B.; Shi, Y. Tetrahedron Lett. 2006, 47, 5455–5458. 76. Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1972, 94, 4777–4779. 77. (a) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721–8724. (b) Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807–8810. (c) Shu L.; Shi, Y. Tetrahedron 2001, 57, 5213–5218. (d) Burke, C. P.; Shu, L.; Shi, Y. J. Org. Chem. 2007, 72, 6320–6323. 78. Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710–8711. 79. Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610. 80. (a) List, B. Chem. Commun. 2006, 819–824. (b) Erkkilä, A.; Majander, L.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. 81. Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–6965. 82. Zhuang, W.; Marigo, M.; Jørgensen, K. A. Org. Biomol Chem. 2005, 3, 3883–3885. 83. Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2006, 47, 99–103. 84. Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413–11424. 85. Wang, X.; List, B. Angew. Chem. Int. Ed. 2008, 47, 1119–1122. 86. Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070–6071. 87. Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134–8135. 88. (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.), New York: WileyVCH, 2000; pp. 727–756. (b) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656–5682. 89. (a) Helder, R.; Hummelen, J. C.; Laane, R. W. P.; M. Wiering, J. S.; Wynberg, H. Tetrahedron Lett. 1976, 17, 1831–1834. (b) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599–1602. (c) Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39, 7563–7566. (d) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287–1290. 90. Jew, S.-S.; Lee, J.-H.; Jeong, B.-S.; Yoo, M.-S.; Kim, M.-J.; Lee, Y.-J.; Lee, J.; Choi, S.-H.; Lee, K.; Lah M. S.; Park, H.-G. Angew. Chem. Int. Ed. 2005, 44, 1383–1385. 91. Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 6844–6845. 92. (a) Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan, H. B. J. Am. Chem. Soc. 1984, 106, 8188–8193. (b) Brunel, J.-M.; Diter, P.; Duetsch, M.; Kagan, H. B. J. Org. Chem. 1995, 60, 8086–8088. 93. Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325–326. 94. (a) Bolm, C.; Muñiz, K.; Hildebrand, J. P. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer-Verlag, 1999; pp. 697–710. (b) Kagan, H. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 327–356. (c) Kagan, H. B.; T. Luukas, O. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 479–495. (d) Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651–3705. 95. Colombo, A.; Marturano, G.; Pasini, A. Gazz. Chim. Ital. 1986, 116, 35–40. 96. (a) Saito, B.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3873–3876. (a) Saito, B.; Katsuki, T. Tetrahedron Lett. 2001, 42, 8333–8336. 97. (a) Tanaka, T.; Saito, B.; Katsuki, T. Tetrahedron Lett. 2002, 43, 3259–3262. (b) Saito, B.; Katsuki, T. Chirality 2003, 15, 24–27. 98. Bolm, C.; Bienewald, F. Angew. Chem. Int. Ed. 1995, 34, 2640–2642. 99. Vetter, A. H.; Berkessel, A. Tetrahedron Lett. 1998, 39, 1741–1744. 100. Ohta, C.; Shimizu, H.; Kondo, A.; Katsuki, T. Synlett 2002, 161–163. 101. Pelotier, B.; Anson, M. S.; Campbell, I. B.; Macdonald, S. J. F.; Priem, G.; Jackson, R. F. W. Synlett 2002, 1055–1060.

REFERENCES 889

102. Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem. Int. Ed. 2005, 44, 7221–7223. 103. (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 7624–7626. (b) Thakur, V. V.; Sudalai, A. Tetrahedron: Asymmetry 2003, 14, 407–410. (c) Jia, X.; Li, X.; Xu, L.; Li, Y.; Shi, Q.; Au-Yeung, T. T.-L.; Yip, C. W.; Yao, X.; Chan, A. S. C. Adv. Synth. Catal. 2004, 346, 723–726. 104. Sun, J.; Zhu, C.; Dai, Z.; Yang, M.; Pan, Y.; Hu, H. J. Org. Chem. 2004, 69, 8500–8503. 105. Miyazaki, T.; Katsuki, T. Synlett 2003, 1046–1048. 106. Legros, J.; Bolm, C. Angew. Chem. Int. Ed. 2003, 42, 5487–5489. 107. White, M. C.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 7194–7195. 108. (a) Legros, J.; Bolm, C. Angew. Chem. Int. Ed. 2004, 43, 4225–4228. (b) Legros, J.; Bolm, C. Chem. Eur. J. 2005, 11, 1086–1092. 109. (a) Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 8940–8941. (b) Egami, H.; Katsuki, T. Synlett 2008, 1543–1546. 110. Scarso, A.; Strukul, G. Adv. Synth. Catal. 2005, 347, 1227–1234. 111. Yamaguchi, T.; Matsumoto, K.; Saito, B.; Katsuki, T. Angew. Chem. Int. Ed. 2007, 46, 4729–4731. 112. (a) Matsumoto, K.; Yamaguchi, T.; Fujisaki, J.; Saito, B.; Katsuki, T. Chem. Asian J. 2008, 3, 351–358. (b) Matsumoto, K.; Yamaguchi, T.; Katsuki, T. Heterocycles 2009, 76, 191–196. 113. Matsumoto, K.; Yamaguchi, T.; Katsuki, T. Chem. Commun. 2008, 1704–1706. 114. Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625–3633. 115. (a) Bolm, C.; Beckmann, O. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer, 1999; pp. 803–810. (b) Bolm, C. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 267–274. (c) Bolm, C. In Asymmetric Synthesis—The Essentials (Eds. Christmann, M.; Bräse, S.). Weinheim: Wiley-VCH, 2007; pp. 57–61. (d) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev. 2004, 104, 4105–4123. 116. (a) Gusso, A.; Baccin, C.; Pinna, F.; Strukul, G. Organometallics 1994, 13, 3442–3451. (b) Strukul, G.; Varagnolo, A.; Pinna, F. J. Mol. Cat. A 1997, 117, 413–423. 117. Bolm, C.; Schlingloff, G.; Weickhardt, K. Angew. Chem. Int. Ed. Engl. 1994, 33, 1848–1849. 118. (a) Yamada, T.; Imagawa, K.; Nagata, T.; Mukaiyama, T. Chem. Lett. 1992, 2231–2234. (b) Mukaiyama, T.; Yamada, T.; Nagata, T.; Imagawa, K. Chem. Lett. 1993, 327–330. 119. Bolm, C.; Beckmann, O.; Palazzi, C. Can. J. Chem. 2001, 79, 1593–1597. 120. (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584–2585. (b) Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365–370. 121. Frison, J.-C.; Palazzi, C.; Bolm, C. Tetrahedron 2006, 62, 6700–6706. 122. (a) Uchida, T.; Katsuki, T. Tetrahedron Lett. 2001, 42, 6911–6914. (b) Uchida, T.; Katsuki, T.; Ito, K.; Akashi, S.; Ishii, A.; Kuroda, T. Helv. Chem. Acta 2002, 85, 3078–3089. 123. Aoki, M.; Seebach, D. Helv. Chim. Acta 2001, 84, 187–207. 124. (a) Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481–4485. (b) Watanabe, A.; Uchida, T.; Irie, R.; Katsuki, T. Proc. Natl. Acad. Sci. USA 2004, 101, 5737–5742. 125. Matsumoto, K.; Watanabe, A.; Uchida, T.; Ogi, K.; Katsuki, T. Tetrahedron Lett. 2004, 45, 2385–2388. 126. Ito, K.; Ishii, A.; Kuroda, T.; Katsuki, T. Synlett 2003, 643–646. 127. Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.; Kocˇovský, P. J. Org. Chem. 2008, 73, 3996–4003. 128. Berezina, N.; Alphand, V.; Furstoss, R. Tetrahedron: Asymmetry 2002, 13, 1953–1955. 129. Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem. Int. Ed. 2002, 41, 2366–2368. 130. (a) Murahashi, S.-I. Angew. Chem. Int. Ed. Engl. 1995, 34, 2443–2465. (b) Shinkai, S.; Yamaguchi, T.; Manabe, O.; Toda, F. J. Chem. Soc., Chem. Commun. 1988, 1399–1401.

890 ASYMMETRIC OXIDATIONS AND RELATED REACTIONS 131. Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K. Angew. Chem. Int. Ed. 2008, 47, 2840–2843. 132. Peris, G.; Miller, S. J. Org. Lett. 2008, 10, 3049–3052. 133. (a) Markó, I. E.; Svendsen, J. S. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer-Verlag, 1999; pp. 713–787. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 357–398. (c) Kolb, H. C.; Sharpless, K. B. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 275–298. (d) Muñiz, K. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 298–307. 134. (a) Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; pp. 399–428. (b) Kolb, H. C.; Sharpless, K. B. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 309–326. (c) Muñiz, K. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004, pp. 326–336. 135. (a) Rubin, A. E.; Sharpless, K. B. Angew. Chem. Int. Ed. 1997, 36, 2637–2640. (b) Pringle, W.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 5151–5154. (c) Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 3455–3457. 136. (a) Andersson, M. A.; Epple, R.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 472–475. (b) Wu, P.; Hilgraf, R.; Fokin, V. V. Adv. Synth. Catal. 2006, 348, 1079–1085. 137. (a) Döbler, C.; Mehltretter, G. M.; Beller, M. Angew. Chem. Int. Ed. 1999, 38, 3026–3028. (b) Döbler, C.; Mehltretter, G. M.; Sundermeier, U.; Beller, M. J. Am. Chem. Soc. 2000, 122, 10289–10297. 138. (a) Bergstad, K.; Jonsson, S. Y.; Bäckvall, J.-E. J. Am. Chem. Soc. 1999, 121, 10424–10425. (b) Jonsson, S. Y.; Färnegårdh, K.; Bäckvall, J.-E. J. Am. Chem. Soc. 2001, 123, 1365–1371. 139. Suzuki, K.; Oldenburg, P. D.; Que, L., Jr. Angew. Chem. Int. Ed. 2008, 47, 1887–1889. 140. Chen, M. S.; White, M. C. Science 2007, 318, 783–787. 141. (a) Jacobsen, E. N. In Comprehensive Asymmetric Catalysis, Vol. II (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). Berlin: Springer-Verlag, 1999; pp. 609–618. (b) Mößner, C.; Bolm, C. In Transition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds. Beller, M.; Bolm, C.). Weinheim: Wiley-VCH, 2004; pp. 389–402. (c) Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2919. 142. Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328–5329. 143. Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326–5327. 144. Lai, T.-S.; Kwong, H.-L.; Che, C.-M.; Peng, S.-M. Chem. Commun. 1997, 2373–2374. 145. Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37, 9245–9248. 146. Cenini, S.; La Monica, G. Inorg. Cheim. Acta. 1976, 18, 279–293. 147. Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5889–5890. 148. Mueller, P.; Baud, C.; Naegeli, I. J. Phys. Org. Chem. 1998, 11, 597–601. 149. (a) Omura, K.; Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T. Chem. Lett. 2003, 32, 354–355. (b) Omura, K.; Uchida, T.; Irie, R.; Katsuki, T. Chem. Commun. 2004, 2060–2061. 150. Katsuki, T. Chem. Lett. 2005, 34, 1304–1309. 151. (a) Kawabata, H.; Omura, K.; Katsuki, T. Tetrahedron Lett. 2006, 47, 1571–1574. (b) Kawabata, H.; Omura, K.; Uchida, T.; Katsuki, T. Chem. Asian J. 2007, 2, 254–256. 152. Nishimura, M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu, M. J. Org. Chem. 2002, 67, 2101–2110. 153. Xu, J.; P. Jiao, J. Chem. Soc., Perkin Trans. 1, 2002, 1491–1493. 154. Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem. Int. Ed. 2006, 45, 8005–8008. 155. Armstrong, A.; Baxter, C. A.; Lamont, S. G.; Page, A. R.; Wincewicz, R. Org. Lett. 2007, 9, 351–353. 156. Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Córdova, A. Angew. Chem. Int. Ed. 2007, 46, 778–781.

12 ASYMMETRIC AMPLIFICATION AND AUTOCATALYSIS Kenso Soai and Tsuneomi Kawasaki Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan

Takanori Shibata Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan

12.1. INTRODUCTION In experimental studies on catalytic asymmetric synthesis, considerable attention has been paid to the interaction between chiral catalysts and the reactants to achieve high enantioselectivity. However, very little attention has been paid to the interaction between the enantiomers of a chiral catalyst when this catalyst is not enantiomerically pure. Examples of catalytic asymmetric synthesis have been reported in which the enantiomeric purity of the product is much higher than that of the chiral catalyst. A positive nonlinear effect (NLE), that is, asymmetric amplification, is synthetically useful because a chiral catalyst with high ee is not needed to prepare a chiral product with high ee (Scheme 12.1). In asymmetric autocatalysis, the chiral catalyst P* and the product P* have the same structure; that is, the chiral product P* acts as a chiral catalyst P* for its own multiplication. Asymmetric autocatalysis differs from conventional catalytic asymmetric syntheses where the chiral catalyst C* and the product P* have different structures (Scheme 12.2). Highly enantioselective asymmetric autocatalysis has recently been reported. In such reactions, a trace amount of chiral molecule automultiplies without the assistance of another chiral molecule. Moreover, asymmetric autocatalysis with an amplification of


892 ASYMMETRIC AMPLIFICATION AND AUTOCATALYSIS

Chiral catalyst A

+

∗ C

X% ee ∗ D

B

Y% ee X95% ee

(R)-NOBIN

Scheme 12.26.

Oestreich and Rendler reported a reagent-controlled Pd-catalyzed reaction of norbornene with chiral hydrosilane 17 of 54% ee to give hydrosilylated product in 69% ee (Scheme 12.27) [39]. This is an unusual example of chiral transfer from silicon to carbon along with NLE.

12.3. ASYMMETRIC AUTOCATALYSIS 12.3.1. Background In 1953, Frank proposed a reaction mechanism, without showing any chemical structure for the molecules, in which a chiral product acts as a chiral catalyst for its own production (asymmetric autocatalysis) and prohibits the formation of its antipode [40]. In such

12.3. ASYMMETRIC AUTOCATALYSIS 905

+

Pd cat. (5 mol %)

H Si t-Bu

Si

CH2Cl2, –55°C

t-Bu 69% ee

17 54% ee N

Me

BARF–

Pd N

OEt2 Pd cat.

Scheme 12.27.

Stoichiometric

PhCHO

+

Et D OLi Ph 18 (70% ee)

Ph

Et

EtLi

H+

Ph

OLi

Et OH

19

17% ee

Chiral catalyst Et D Ph PhCHO

+

O

Ti 4

20 (70% ee)

Ph

Et

Et2Zn OZnEt 21

H+

Ph

Et OH

32% ee

Scheme 12.28.

a reaction, if it exists, the enantiomeric purity of the product would increase as the reaction progresses. Since then, asymmetric autocatalysis has attracted considerable attention [41]. Seebach and others recognized the importance of the effect of mixed aggregates of products (lithium enolates) on enantioselectivity [42]. Alberts and Wynberg reported an asymmetric autoinduction (Scheme 12.28) in which ethyllithium adds to benzaldehyde to give in situ lithium alkoxide of chiral 1-phenyl-1-propanol 19 with 17% ee in the presence of a stoichiometric amount of lithium alkoxide of 1-phenyl-1-propanol-d1 18 with the same configuration [43]. They also described an enantioselective addition (32% ee) of diethylzinc to benzaldehyde using titanium (IV) tetraalkoxide of chiral 1-phenyl-1propanol-l-d1 20. In this reaction, the structures of the chiral catalyst 20 and the product 21 (zinc alkoxide before quenching the reaction) are different [43,44]. Danda and others reported an asymmetric autoinductive cyanohydrin-forming reaction using


2,5-diketopiperazine as a chiral catalyst; the presence of a chiral product enhances the enantioselectivity of the chiral catalyst [45].

12.3.2. Discovery of Asymmetric Autocatalysis We have developed the addition of dialkylzincs to aldehydes using β-amino alcohols as the chiral ligand to afford sec-alcohols [7b]. The coordination of nitrogen and oxygen atoms to the zinc atom of dialkylzinc accelerates the nucleophilic attack of alkyl group to a suitable electrophile. The formation of the complex between dialkylzinc and amino alcohol enables the C–C bond-forming reaction [6]. Using appropriate chiral amino alcohols as a chiral ligand, asymmetric catalysis is available, especially N,N-dibutylnorephedrine (DBNE 22) [46–48] and diphenyl(1-methylpyrrolidin-2-yl)methanol (DPMPM 23) [49,50] are well-established chiral catalysts to afford chiral products in high yields and high enantiomeric excesses (Scheme 12.29). R

Chiral catalyst RCHO

+

R'2Zn

∗

R'

OH

Chiral catalyst Ph ∗

HO

∗

Me ∗

N(n-Bu)2

DBNE 22

N Me

Ph Ph OH

DPMPM 23

Scheme 12.29. Chiral amino alcohol-catalyzed asymmetric dialkylzinc addition to aldehydes.

During our continuing study on the enantioselective addition of dialkylzincs to nitrogen-containing aldehydes, we found in 1990, for the first time, that chiral 3-pyridyl alkanol 25 acts as an asymmetric autocatalyst in the addition of diisopropylzinc (i-Pr2Zn) to pyridine-3-carbaldehyde 24 (Scheme 12.30) [51]. In the enantioselective addition of i-Pr2Zn to 3-pyridinecarbaldehyde 24, (S)-3-pyridyl alkanol 25 with 86% ee acts as an

The same structure The same configuration

N

CHO + N 24

S OH Asymmetric autocatalyst (S)-25 (86% ee)

S OH

Zn 2

N Product (S)-25 (y. 67%, 35% ee)

Scheme 12.30. Asymmetric autocatalysis of chiral pyridyl alcohol.


O

∗

OH N

∗

i-Pr

N i-Pr

26

OH N

27

Figure 12.2. Asymmetric autocatalysts containing quinoline and carbamoylpyridine ring for the reaction of i-Pr2Zn and the corresponding aldehydes.

asymmetric autocatalyst to afford the same compound 25 with 35% ee. In this reaction, the resulting product 25 forms the amino alcohol moiety, and it acts as the chiral catalyst for the next i-Pr2Zn addition, that is, catalyzes its own production. This is the first experimental observation that realizes asymmetric autocatalysis. After searching various nitrogen-containing compounds, we found that the zinc alkoxide of 2-methyl-1-(3-quinolyl)propan-1-ol 26 catalyzes the enantioselective formation of itself with the same configuration in the reaction between quinoline-3-carbaldehyde and i-Pr2Zn to afford the product 26 in high ee (up to 94% ee) [52]. In addition, 5carbamoyl-3-pyridyl alkanol 27 can act as the efficient autocatalyst to catalyze its own production in highly enantioselective manner (up to 86% ee) (Fig. 12.2) [53]. Then, we discovered that chiral 2-methyl-1-(5-pyrimidyl)propan-1-ol 29 serves as a highly enantioselective asymmetric autocatalyst for the addition of i-Pr2Zn to pyrimidine-5-carbaldehyde 28 (Scheme 12.31) [54]. In this compound, the formyl group is connected to the symmetric pyrimidine ring instead of the pyridine ring. When highly enantioenriched (S)-pyrimidyl alkanol 29 with 99% ee was employed as an asymmetric autocatalyst, (S)-29 with 95% ee composed of both the newly formed and the initially used 8 was obtained. The yield of the newly formed 29 was calculated to be 67%, and the enantiomeric excess was 93% ee.

The same structure The same configuration S OH

N CHO

N N 28

N +

(S)-29 (99% ee)

Asymmetric autocatalyst

Zn

S OH

N N

2

Toluene, 0°C

Product (S)-29 (y. 67%, 95% ee)

Scheme 12.31. Highly enantioselective asymmetric autocatalysis of pyrimidyl alkanol in the enantioselective i-Pr2Zn addition.

The result of such a high enantioselectivity in asymmetric autocatalytic reaction encouraged us to investigate the enantioselective alkylation utilizing the asymmetric autocatalyst with low ee of 2%. In this pyrimidine system, we found for the first time asymmetric autocatalysis with amplification of enantiomeric excess, that is, the initial small enantioenrichment (2% ee) was significantly enhanced to the high


Enhancement of enantiopurity 88% ee

2% ee (after 4 rounds)

S OH

N N

1st 2nd 3rd 4th

round: 2% ee round: 10% ee round: 57% ee round: 81% ee

Zn 2

N

OZn

H+

N

N

29

10% ee 57% ee 81% ee 88% ee

S OH

N

29

Asymmetric autocatalysis Amplification of enantiomeric excess

CHO

N N 28

+

Zn 2

Scheme 12.32. Asymmetric autocatalysis with significant amplification of chirality from low (2%) to high (88%) ee.

enantioenrichment of 88% ee (Scheme 12.32) [55]. When the (S)-pyrimidyl alkanol 29 (20 mol %, 2% ee) was employed as an asymmetric autocatalyst, (S)-29 with 10% ee was obtained in 46% yield as a mixture of newly formed product and initial catalyst. The reaction was performed successively by serving the chiral product of one reaction as the autocatalyst of the next round of reaction, observing further enhancement of enantiomeric excess to reach 88% ee after four rounds of the reaction. The overall process was the asymmetric autocatalysis of (S)-29 starting from a low ee of 2% with significant amplification of chirality to 88% ee, without aid of any other chiral auxiliaries, along with the increase in the amount. This chemical process is the first example of realization of asymmetric autocatalysis with amplification of chirality [55].

12.3.3. Practically Perfect Asymmetric Autocatalysis The asymmetric autocatalysis in the addition reaction of i-Pr2Zn to pyrimidine-5carbaldehyde was examined using (S)-2-methyl-1-(5-pyrimidyl)-1-propanol 31 with high ee (Scheme 12.33). The treatment of the corresponding 2-methylpyrimidine-5carbaldehyde 30 with i-Pr2Zn in the presence of autocatalyst 31 with >99.5% ee resulted to a highly efficient asymmetric automultiplication to afford the product (S)-31 with 98.2% ee [54]. In addition, the result of the experiment using (S)-31 with 0.28% ee as autocatalyst has demonstrated the ability of asymmetric autoamplification in this pyrimidine autocatalytic system. That is to say, the enhancement of the enantioenrichment of 0.28% ee occurred to reach 87% ee by one-pot asymmetric autocatalysis [56]. This asymmetric autocatalytic process is a very powerful method for amplifying the tiny imbalance of enantiomer to high enantioenrichment. When a pyrimidyl alkanol with low ee was used as an asymmetric autocatalyst, the ee of the product was higher than


S OH (S)-31 (>99.5% ee)

N

Me

Me

CHO

N

+

N

N

Zn 2

N

S OH

Asymmetric autocatalyst Toluene, 0°C

Me

N Product

30

(S)-31 (98.2% ee)

Scheme 12.33. Highly enantioselective asymmetric autocatalysis of chiral pyrimidyl alkanol.

Extremely low ee ca. 0.00005% ee

S OH

N N

N

Extremely high ee >99.5% ee

+

Zn 2

33

Significant amplification of chirality

CHO

N

32

Asymmetric autocatalysis

S OH

N N 33

Scheme 12.34. Autocatalytic amplification of chirality from ca. 0.00005% ee to >99.5% ee.

that of the original catalyst. One of the advantages of asymmetric autocatalysis with amplification of ee over non-autocatalytic amplification of ee is that the product of one round is used as the asymmetric autocatalyst for the following round. Thus, extremely low enantioenrichment of pyrimidyl alkanol could be amplified to very high enantioenrichment by the consecutive asymmetric autocatalysis. We found efficient amplification of chirality by using (S)-2-(tert-butylethynyl)-5pyrimidyl alkanol 33 [57] from as low as ca 0.00005% ee to an almost enantiomerically pure (>99.5% ee) product 33 in only three consecutive asymmetric autocatalyses (Scheme 12.34) [58]. The first round of asymmetric autocatalysis using (S)-33 with ca. 0.00005% ee in the i-Pr2Zn addition to 2-alkynylpyrimidyne-5-carbaldehyde 32 gave (S)-33 in 96% yield with an enhanced ee of 57%. The second round of asymmetric autocatalysis using the autocatalyst of 57% ee produced (S)-33 with 99% ee, and the ee of (S)-33 finally reached >99.5% ee in the third round of asymmetric autocatalysis.


(S)-33

Initial conditions ca. 0.00005% ee

(R)-33

Run 1 57% ee Run 2 99% ee Run 3 >99.5% 300,000 Multiplication factor

600,000

Figure 12.3. The increase in the amount of (S)- and (R)-pyrimidyl alkanol 33 during consecutive asymmetric autocatalyses with significant amplification of ee.

During these three consecutive asymmetric autocatalyses, the initial slightly major (S)-enantiomer of 33 automultiplied by a factor of ca. 630,000, whereas the initially slightly minor (R)-enantiomer of 33 automultiplied by less than 1000 (Fig. 12.3). The tiny enantiomeric imbalance of ca. 0.00005% ee corresponds to only a few molecules of difference in the number of enantiomeric 33 in an almost racemic mixture of ca. 5,000,000 molecules of (S)-33 and ca. 5,000,000 molecules of (R)-33 [58]. Recently, Mauksch, Tsogoeva, and coworkers reported asymmetric autocatalysis of 34 without positive NLE in the organocatalytic Mannich reaction (Scheme 12.35) [59–61].

MeO

OMe (R)-34 (30 mol %, 99% ee)

O +

N H

Acetone (solvent)

O

CO2Et

HN CO2Et

(R)-34 Newly: 96% ee, 40% yield

Scheme 12.35. Asymmetric autocatalytic Mannich reaction.

12.3.4. Model and Mechanism of the Asymmetric Autocatalysis of Pyrimidyl Alkanol Kinetic analysis of asymmetric autocatalysis was performed to study the reaction mechanism of asymmetric autocatalysis. The relationship between the reaction time and the yields of the product was investigated [62]. The i-Pr2Zn addition to pyrimidine-5-carbaldehyde 32 was performed in the presence of enantiomerically pure autocatalyst, the reaction being monitored by high performance liquid chromatography (HPLC) using naphthalene as an internal standard. The plots shown in Figure 12.4a constitute S-shaped


b 0.025

120

0.020

100 Yield or ee (%)

Product (M)

a

0.015 0.010 0.005

80 60 40 20

0.000

0 0

10 Time (min)

20

0

500

1000 1500 2000 2500 Time (s)

Figure 12.4. Relationship between time versus concentration, yield, and ee in asymmetric autocatalysis of pyrimidyl alkanol 33. (a) Enantiopure (>99.5% ee) asymmetric autocatalyst was used. Experimental concentration of alkanol (filled circle), simulation (solid line) [62]. (b) Asymmetric autocatalyst with 59% ee was used. Experimental yield (open circle), experimental ee (filled circle) [63].

curves that are characteristic of an autocatalytic reaction. The relationship between time, yield, and enantiomeric excess was also measured in the asymmetric autocatalysis with amplification of ee using high to low ee of pyrimidyl alkanol as the catalyst (Fig. 12.4b) [63]. Portions of the reaction mixture were quenched periodically and analyzed by HPLC fitted with a chiral stationary phase. When pyrimidyl alkanols with high to good ee are used as the asymmetric autocatalyst, the observed values of yield and ee were well matched to our simulated kinetic model, that is, first order in i-Pr2Zn and pyrimidine-5carbaldehyde, and the second order in pyrimidyl alkanol. However, the analysis using a pyrimidyl alkanol with low (20%) ee exhibited higher ee than the predicted value of ee based on the above model. Therefore, we considered the possibility of the presence of an inhibition process other than our simulated kinetic model. The inhibition process, that is, the major enantiomer inhibits the production of the minor enantiomer, might enable the high magnitude of amplification of ee in asymmetric autocatalysis. The model and the mechanism of the reaction have also been studied by other groups. Blackmond, Brown, and coworkers showed second-order kinetics for zinc alkoxide of pyrimidyl alkanol by studying the kinetics using a microcalorimeter [64,65]. Brown, Gridnev, and coworkers performed the structural study for the catalyst of asymmetric autocatalysis by using NMR spectroscopy and DFT calculations [66–70]. Micheau, Buhse, and coworkers proposed the kinetic model for the asymmetric autocatalytic reaction to analyze the generation and amplification of ee [71–73]. Pályi, Caglioti, and coworkers suggested the empirical formula, which enables the quantitative calculation of ee in the asymmetric autocatalysis [74,75]. Lente reported the stochastic kinetic model of asymmetric autocatalysis [76], and Saito and Hyuga reported the theoretical model for the autocatalytic amplification in a closed system [77,78].


12.3.5. Asymmetric Autocatalysis in the Presence of Chiral Organic Compound As described in the preceding section, asymmetric autocatalysis is capable of amplifying the ee of initially added asymmetric autocatalyst. Low ee (ca. 0.00005%) of the initial pyrimidyl alkanol is amplified to almost enantiomerically pure (>99.5% ee) during consecutive asymmetric autocatalysis [58]. It was also found that not only the asymmetric autocatalyst itself but also other chiral organic compounds can act as a chiral trigger for asymmetric autocatalysis, that is, a slight asymmetry induced by the chiral organic compound is amplified by asymmetric autocatalysis to reach high enantioenrichment (Scheme 12.36) [79]. When pyrimidine-5-carbaldehyde is alkylated by i-Pr2Zn in the presence of a chiral organic compound, tiny enantiomeric excess should be induced in the initially formed product. The subsequent addition of i-Pr2Zn and pyrimidine-5-carbaldehyde to the reaction mixture leads to an asymmetric autocatalysis, and a highly enantiomerically enriched pyrimidyl alkanol is obtained. Therefore, the absolute configuration of the product alkanol with high ee is correlated to that of the chiral initiator that was originally used.

S-inducing enantiomer N N

R CHO

N

+

S OH

N N

R

Very low ee Asymmetric autocatalysis with amplification of ee

Chiral initiator

N

R

OZn

Zn

R OH

2

N

30: R = Me 32: R = t-Bu–C≡C–

R-inducing enantiomer

R

OZn N

S-inducing enantiomers

Ph OH Ph

CO2Me

R2

S

S

CO2H

OH

Me

Ph R2

R1 O

R

N

(R)-31, 33 High ee

R-inducing enantiomers

CO2H

OH

N

Very low ee

(S)-31, 33 High ee

R1

= Me, Ph

S

S R2 = H, n-Pr

OH Ph

CO2Me

R2

S

S

S

Me R2

R1 O

S

R1

= Me, Ph

R2 = H, n-Pr

Scheme 12.36. Asymmetric autocatalysis initiated by chiral organic compounds.

As shown in Scheme 12.36, various chiral organic compounds can act as chiral initiators of asymmetric autocatalysis. 2-Methylpyrimidine-5-carbaldehyde 30 was subjected to the addition of i-Pr2Zn in the presence of chiral butan-2-ol, methyl mandelate, and carboxylic acid [79]. When the chiral alcohol, (S)-butan-2-ol with ca. 0.1% ee was used as a chiral initiator of asymmetric autocatalysis, (S)-pyrimidyl alkanol 31 with 73% ee was obtained. In contrast, (R)-butan-2-ol with 0.1% ee induced the production of (R)-31 with 76% ee. In the same manner, methyl mandelate (ca. 0.05% ee) and a chiral carboxylic acid (ca. 0.1% ee) can act as chiral initiators of asymmetric autocatalysis; therefore, the

12.4. EXPERIMENTAL APPROACHES TO UNDERSTAND THE ORIGINS 913

S- and R-enantiomers of methyl mandelate and carboxylic acid induce the formation of (R)- and (S)-alkanol 31, respectively. Chiral propylene oxide (2% ee) and styrene oxide (2% ee) also induce the imbalance of ee in initially forming zinc alkoxide of the pyrimidyl alkanol in the addition reaction of i-Pr2Zn to pyrimidine-5-carbaldehyde 32 [80]. Further consecutive reactions enable the amplification of ee to produce the highly enantiomerically enriched pyrimidyl alkanol 33 (up to 96% ee) with the corresponding absolute configuration to that of the chiral epoxide. P- and M-tetrathia-[7]-helicenes with helical chirality can serve as chiral initiators of asymmetric autocatalysis to produce the enantiomerically enhanced chiral alkanol 33 with a good correlation between absolute configurations [81]. The chirality in the organic compound (even though with small ee) can be converted into almost enantiomerically pure pyrimidyl alkanol by asymmetric autocatalysis with amplification of chirality. 12.4. EXPERIMENTAL APPROACHES TO UNDERSTAND THE ORIGINS OF BIOLOGICAL HOMOCHIRALITY 12.4.1. Introduction Many of the biocompounds such as l-amino acids and d-sugars are chiral. Although they have left- and right-handed mirror image forms, biology uses essentially only one enantiomer, with only a few exceptions. One of the greatest puzzles in science is the question of biological homochirality, that is, why life on Earth is based on l-amino acids and dsugars, and not based on their mirror image molecules [82]. The homochirality of biomolecules might have been established before the origin of life, and the chiral homogeneity of biomolecules is considered to be closely related to the origin and evolution of life. How and when biomolecules achieved high enantioenrichment is an attractive issue requiring significant analysis. To date, several mechanisms have been proposed for elucidating the origins of the chirality of organic compounds, including circularly polarized light (CPL) [83–86], chiral inorganic crystals [87,88] such as quartz, chiral organic crystals composed of achiral organic molecules [89–94], spontaneous absolute asymmetric synthesis [71,95], parity-violating energy difference (PVED) [96,97], and so on. Although the initial enantiomeric imbalance can be introduced via these proposed mechanisms, a suitable amplification process for chirality is required to reach singlehandedness of biological organic compounds. Asymmetric autocatalysis with amplification of ee gives a strong correlation between the origin of chirality and the homochirality of organic compounds (Scheme 12.37), so an experiment on the effect of proposed chiral factors as the origin or trigger of biological homochirality can be performed using this autocatalytic reaction. In this section, we describe enantioselective synthesis, in combination with asymmetric autocatalysis, triggered by CPL, quartz, and chiral organic crystals formed from achiral compounds, including a spontaneous absolute asymmetric synthesis. 12.4.2. CPL Right (r)- and left (l)-handed CPL have long been proposed as one of the origins of chirality of organic compounds [83–86]. The occurrence of strong l- or r-CPL in nature has been observed in a star formation region of the Orion constellation [98]. However, because of the very small anisotropy (g) factors of organic compounds, only low enan-


Origins of chirality (proposed) Circularly polarized light Chiral inorganic crystals (quartz) Chiral organic crystals of achiral compounds Absolute asymmetric synthesis

Biological homochirality

Chiral compound with low ee

?

R H2N

Asymmetric autocatalysis with amplification of ee

H CO2H

L-Amino acid

HO

O HO

Base OH (H)

D-Sugar

Scheme 12.37. Proposed origins of chirality and the pathway to the biological homogeneity.

tioenrichments of organic compounds have been induced by the irradiation with CPL. For example, asymmetric photodecomposition of rac-leucine by r-CPL (213 nm) produces l-leucine with only 2% ee [99]. Hexahelicene with less than 2% ee is formed by asymmetric photosynthesis using CPL [100]. Irradiation of racemic alkylidenecyclohexanone with CPL induces a small enantiomeric imbalance (99.5% ee (Scheme 12.38). On the other hand, irradiation with right-handed (r) CPL, instead of l-CPL, formed (R)-33 with >99.5% ee. The process provides direct correlation of the handedness of CPL with that of the organic compound with high enantiomeric excess [105].

N t-Bu OH

N Racemate 33

r-CPL

l-CPL

Asymmetric photodegradation

N

N t-Bu

t-Bu N

N

OH

Cryptochiral (R)-33

OH

Cryptochiral (S)-33 N t-Bu

CHO 32

N

+ i-Pr2Zn


N t-Bu

N t-Bu

OH N (R)-33 >99.5% ee

OH N (S)-33 >99.5% ee

Scheme 12.38. Short pathway to obtain a near enantiopure compound by CPL irradiation followed by asymmetric autocatalysis.


12.4.3. Enantiomorphous Inorganic Crystal-Induced Asymmetric Autocatalysis Chiral crystals provide an environment for the discrimination of chiral molecules, so their possible roles in the origin of biological homochirality have been discussed for a long time [87]. In the Earth’s crust, there are a wide variety of chiral minerals, such as chiral oxides and silicates, which serve as accessible chiral surfaces in the prebiotic evolution of chiral organic molecules. However, no apparent asymmetric induction using chiral minerals has been observed. Only a very small asymmetric induction has been reported in an adsorption of chiral compounds on quartz [106]. The possible interaction between the chiral surface of minerals and the organic molecules remains obscure, so we performed an asymmetric autocatalysis triggered by quartz. When pyrimidine-5-carbaldehyde 32 was treated with i-Pr2Zn in the presence of d-quartz powder, (S)-pyrimidyl alkanol 33 with 97% ee was obtained in a yield of 95% (Scheme 12.39) [107]. In contrast, in the presence of l-quartz, (R)-33 with 97% ee was obtained in a yield of 97%. These reproducible results clearly show that the absolute configurations of the pyrimidyl alkanol formed were regulated by the chirality of quartz. A small enantiomeric imbalance of the initially formed pyrimidyl alkanol zinc alkoxide induced by quartz was amplified significantly by the subsequent consecutive asymmetric autocatalysis to produce pyrimidyl alkanol with very high ee.

S

N

OH N

N

d-Quartz

N

(S)-33 with high ee

t-Bu

CHO +

Zn 2

t-Bu

R

N

OH N

t-Bu

(R)-33 with high ee

I-Quartz

Scheme 12.39. Asymmetric autocatalysis utilizing inorganic crystals as an initial source of chirality.

The achiral inorganic ionic sodium chlorate (NaClO3) and sodium bromate (NaBrO3), both of which crystallize in enantiomorphs belonging to the cubic space group P213, also act as the origin of chirality of asymmetric autocatalysis to provide the enantioenriched alkanol [108]. The reaction of i-Pr2Zn to aldehyde 30 and 32 in the presence of d-NaClO3 crystal affords (S)-pyrimidyl alkanols 31 and 33, respectively. On the other hand, (R)alkanol 31 and 33 are formed in the presence of l-NaClO3 crystal. It should be noted that d-NaBrO3 has the opposite absolute configuration of the crystal structure to that of d-NaClO3. In other words, d-NaBrO3 and l-NaClO3 have the same absolute configuration of the crystal structure. Thus, d-NaBrO3 crystal affords (R)-alkanol 33, while lNaBrO3 crystal affords (S)-33.


12.4.4. Chiral Crystals of Achiral Organic Compounds Some achiral organic compounds form chiral crystals, with each crystal exhibiting one of the two possible enantiomorphs [89–94]. These chiral crystals composed of an achiral organic compound may serve as an efficient chiral seed in a prebiotic world; therefore, a study of asymmetric autocatalysis using these chiral organic crystals is an interesting subject. Cytosine 34, a constituent of DNA and RNA, is a base of cytidine and deoxycytidine, and is an essentially flat achiral molecule. It is conceivable that cytosine 34 was formed under prebiotic conditions [109] and already existed before the RNA world emerged. Thus, the investigation of the enantioselective reaction utilizing the crystal chirality of achiral cytosine is an important experimental approach to understanding of the origin of biological homochirality (Fig. 12.5). At first, we discovered that achiral cytosine 34, when crystallized from methanol with stirring without adding any seed crystal, affords powder-like crystals that exhibit either plus or minus Cotton effect in solid-state CD spectra [110] at ca. 310 nm. The stochastic behavior of the formation of [CD(+)310]- and [CD(–)310]-crystals of cytosine 34 was observed. Next, the chiral crystals that are spontaneously formed with stirring are used as chiral triggers for asymmetric autocatalysis (Scheme 12.40) [110]. When pyrimidine-5carbaldehyde 32 and i-Pr2Zn reacted in the presence of a [CD(+)310]-crystal of cytosine 34, enantioenriched (R)-pyrimidyl alkanol 33 was obtained after the subsequent autocatalytic amplification of ee. On the other hand, spontaneously obtained [CD(–)310]-cytosine crystal induced the production of enantioenriched (S)-alkanol 33. These results clearly exhibit the correlation between the chirality of the crystal of cytosine and the absolute configuration of the resulting alkanol. This sequence of reactions represents one of the chemical processes in which the scenario for the evolution of chirality from the achiral nucleobase cytosine was achieved in real chemical reactions. The sequential process of asymmetric induction in the organic product with an asymmetric carbon atom and the amplification of chirality through

Accessible via prebiotic synthesis from cyanoacetylene cyanate, urea, etc.

NH2

Enantiomorphous crystal of cytosine 34

N N H

Achiral cytosine O 34

Generation of chirality Chiral crystal of cytosine Chiral transfer Organic compound with tiny chirality Amplification of chirality H-bond Enantiopure organic compound

Left-handed M-crystal

Right-handed P-crystal

Helical arrangement of cytosine in crystal (P212121)

Figure 12.5. Proposed scenario for the evolution of chirality in nature using achiral cytosine as an origin of chirality.


[CD(+)310]-crystal of cytosine 34 CHO

N


S OH

N

t-Bu

N (S)-33

>99.5% ee

N t-Bu

32

+ i-Pr2Zn

R OH

N [CD(–)310]-crystal of cytosine 34

N t-Bu

(R)-33

>99.5% ee

Scheme 12.40. Highly enantioselective asymmetric autocatalysis using chiral crystal of cytosine.

asymmetric autocatalysis indicate the possibility that cytosine is the origin of biological homochirality. In addition, cocrystals of achiral tryptamine and p-chlorobenzoic acid, which belongs to a chiral space group (P212121) and have both clockwise (P) and counterclockwise (M) helicities in its crystal state, can act as a chiral source of asymmetric autocatalysis to afford enantioenriched pyrimidyl alkanol whose absolute configuration was controlled by the chirality of the cocrystal [111]. The enantiomorphous crystals composed of achiral hippuric acid, that is, naturally occurring N-benzoylglycine, have been used successfully as chiral inducers in asymmetric autocatalysis [112].

12.4.5. Spontaneous Absolute Asymmetric Autocatalysis in Conjunction with Asymmetric Autocatalysis Spontaneous absolute asymmetric synthesis, that is, the formation of enantioenriched compound without the intervention of any chiral factors, has been proposed as one of the origins of biological homochirality in nature [71,95]. It has been well accepted that, without the intervention of any chiral factor, the probability of the formation of R and S product is fifty-fifty (50:50); racemate is formed. However, according to the theory of statistics, the numbers of R and S enantiomers are not exactly the same, that is, there is almost always the fluctuation in numbers of enantiomers [95,113]. We thought that, when a reaction system involves asymmetric autocatalysis with amplification of ee, the initial small fluctuation of ee in racemic mixtures that arises from the reaction of achiral reactants can produce an enantiomerically enriched product. We anticipated that when iPr2Zn was treated with pyrimidine-5-carbaldehydes without adding any chiral substance, extremely slight enantioenrichment would be induced statistically in the initially formed zinc alkoxide of the alkanol, and that the subsequent amplification of chirality by asymmetric autocatalysis would produce the pyrimidyl alkanol with detectable enantioenrichment (Scheme 12.41). The reaction of pyrimidine-5-carbaldehyde 28 and 2-methylpyrimidine-5-carbaldehyde 30 with i-Pr2Zn without adding a chiral substance produced enantioenriched (S)- or (R)-pyrimidyl alkanol 29 and 2-methylpyrimidyl alkanol 31, respectively [114]. When 2-alkynylpyrimidine-5-carbaldehyde 32 reacted with i-Pr2Zn in a mixed solvent of ether and toluene, the subsequent one-pot asymmetric autocatalysis with amplification of ee gave enantiomerically enriched pyrimidyl alkanol 33 whose ee was well above the detec-


S OH

N

t-Bu

Without adding chiral substance

N t-Bu

N

CHO

N

Statistical fluctuation of ee

+ 32

(S)-33

Optically active

Asymmetric autocatalysis with amplification of ee R OH

N

Zn 2

N t-Bu

(S)-33

Optically active

Scheme 12.41. Spontaneous absolute asymmetric synthesis of pyrimidyl alkanol 33 without the addition of a chiral substance.

In the presence of achiral silica gel 0 (% ee)

(R)-pyrimidyl alkanol 33

(S)-pyrimidyl alkanol 33

50 (% ee)

10 8 6 Frequency (times)

4

2

100 0 (% ee) 0

R : S = 39:45

2

4

6 8 10 Frequency (times)

Figure 12.6. Histogram of the absolute configuration and the enantiomeric excess of pyrimidyl alkanol 33 formed by spontaneous absolute asymmetric synthesis in the presence of achiral silica gel.

tion level [115]. The absolute configurations of the pyrimidyl alkanol 33 exhibit an approximate stochastic distribution of S and R enantiomers (formation of S 19 times and R 18 times). In addition, we performed the asymmetric autocatalysis in the presence of an achiral silica gel in toluene under achiral conditions; the enantioenriched pyrimidyl alkanol 33 is generated from the reaction between 2-alkynylpyrimidine-5-carbaldehyde 32 and iPr2Zn in conjunction with the subsequent asymmetric autocatalysis (Fig. 12.6) [116]. The


reaction of pyrimidine-5-carbaldehyde 32 with i-Pr2Zn in the presence of achiral silica gel in toluene, followed by a one-pot asymmetric autocatalysis with amplification of ee gave the enantioenriched (S)- and (R)-5-pyrimidyl alkanol 33 with ee above the detection level. In order to examine the distribution of the absolute configuration of the predominantly formed enantiomers in each experiment, 84 experiments were run under the same reaction conditions. In all cases, enantioenriched 5-pyrimidyl alkanols with either S or R configurations were formed. The absolute configurations of the resulting 33 exhibited an approximate stochastic distribution, that is, the formation of the S form occurred 45 times and the formation of the R form occurred 39 times (Fig. 12.6). We have demonstrated the stochastic formation of (S)- and (R)-5-pyrimidyl alkanol 33 from pyrimidine-5-carbaldehyde 32 and i-Pr2Zn without the intervention of a chiral auxiliary. Even in the reactions performed in toluene alone, stochastic behavior of the formation of (S)- and (R)-33 was observed in the presence of achiral silica gel. We believe that the approximate stochastic behavior in the formation of alkanols fulfills one of the conditions necessary for chiral symmetry breaking by spontaneous absolute asymmetric synthesis.

12.5. CHIRAL DISCRIMINATION BY ASYMMETRIC AUTOCATALYSIS WITH AMPLIFICATION OF EE 12.5.1. Introduction Chirality plays a major role in many aspects of modern science. The fundamental prerequisite of a study on chirality is the availability of a method to discriminate between enantiomeric forms. Significant progress in chiral discrimination has been achieved in recent decades; however, there remains a class of compounds whose chiral discrimination has been very difficult to establish, or has not been possible at all. The compound is a chiral, but to all intents an optically inactive compound. Mislow called such hidden chirality “cryptochirality” [95,117]. Herein, we demonstrate that the asymmetric autocatalysis has enormous power to recognize the hidden cryptochirality.

12.5.2. Discrimination of Cryptochirality in a Saturated Quaternary Hydrocarbon by Asymmetric Autocatalysis Chiral saturated hydrocarbons form a class of compounds whose chiral discrimination has often been very difficult [118]. Unlike other functionalized compounds, chiral saturated hydrocarbons do not bear heteroatoms, π-electrons, or chromophores; therefore, the difference between the four substituents on the asymmetric carbon atom is very small. An example of a compound whose chiral discrimination poses the utmost difficulty is a saturated quaternary hydrocarbon bearing similar substituents on the asymmetric carbon atom, with a representative example being 5-ethyl-5-propylundecane, that is, (n-butyl)ethyl(n-hexyl)(n-propyl)methane 35 [119]. The enantiomer of this hydrocarbon exhibits the optical rotation (|α| < 0.001) below the detection level between 280 and 580 nm. We found that the chirality of the saturated quaternary hydrocarbon was successfully discriminated using asymmetric autocatalysis [120]. The asymmetric autocatalysis initiated by the chiral (R)-quaternary hydrocarbon using pyrimidine-5-carbaldehyde 32 and i-Pr2Zn produced (S)-pyrimidyl alkanol 33 with 97% ee and 93% yield. In contrast,

12.5. CHIRAL DISCRIMINATION BY ASYMMETRIC AUTOCATALYSIS 921

n-C3H7

C2H5 C

n-C4H9

n-C6H13 N

(R)-35 t-Bu N t-Bu

CHO N 32

(S)-33

Discrimination of cryptochirality by asymmetric autocatalysis

N

S OH

N

+

t-Bu Zn 2

C2H5

n-C3H7

(R)-33

N

R OH

C n-C6H13 n-C4H9 (S)-35

Scheme 12.42. Chiral discrimination of cryptochiral quaternary hydrocarbon.

asymmetric autocatalysis in the presence of the (S)-quaternary hydrocarbon 35 produced (R)-alkanol 33 with 94% ee in 91% yield (Scheme 12.42). These stereochemical correlations were found to be reproducible. The present chiral discrimination may involve the CH–π interactions between the CH group of the chiral hydrocarbon and the π-electrons of the pyrimidine-5-carbaldehyde 32. In addition, various chiral hydrocarbons with such as saturated tertiary hydrocarbons [120], 1,1′-binaphthyls [121], helicenes [122], olefins [123], allenes [124], and [2.2]paracyclophanes [125] also serve as chiral initiators in this asymmetric autocatalysis.

12.5.3. Recognition of Chirality Generated by the Isotope Substitution Isotopically chiral compounds form unique category of chiral compounds, which are not superimposable with its mirror image due to the substitution of isotopes. The chirality of hydrogen isotope enantiomers is mainly due to the very small difference between the lengths of carbon–deuterium and carbon–hydrogen bonds [126]. Thus, unlike other enantiomers whose chirality results from the difference in the number of protons in the atomic nucleus, these isotopic enantiomers are considered to show only very small differences in asymmetric reactions and recognition [127]. We investigated highly enantioselective asymmetric autocatalysis of a chiral compound induced by the isotopic enantiomer of a primary alcohol-α-d (Scheme 12.43) [128]. The correlation between the absolute configurations of the obtained pyrimidyl alkanol and the isotopic chiral compound is reproducible; thus, the small isotope chirality can be recognized by asymmetric autocatalysis. When aldehyde 32 was reacted with i-Pr2Zn in the presence of chiral (S)-benzyl alcohol-α-d 36, (R)-alkanol 33 with 96% ee was obtained with a yield of 95%. On the other hand, in the presence of (R)-deuterated alcohol (>95% ee), (S)-33 with 95% ee was obtained in 98% yield. Thus, (S)- and (R)-benzyl alcohol-α-d 36 acted as chiral inducers to give (R)- and (S)-pyrimidyl alkanols 33 with high ee after consecutive asymmetric autocatalysis, respectively. Furthermore, chiral tolyl methanol-α-d, 2,2-naphthyl methanol-α-d and 3-phenylpropanol-α-d acted as a chiral initiator in the enantioselective addition of i-Pr2Zn to aldehyde 32, and pyrimidyl alkanol (R)-33 with high ee was synthesized,


Chiral inducer

H D OH

D H HO

(S)-36

Isotopically chiral compound

(R)-36 N

t-Bu

CHO 32

N +

Asymmetric autocatalysis with amplification of ee Zn 2

R OH

N

Enantioenriched ordinary chiral compound

N

N t-Bu

S OH

N

33 High ee

t-Bu

33 High ee

Scheme 12.43. Enantioselective addition of i-Pr2Zn to aldehyde 32 using chiral α-deuterated alcohols as chiral inducers.

respectively [128]. Thus asymmetric autocatalysis is an efficient method to discriminate hydrogen isotope chirality.

12.5.4. Steric Discrimination of Chiral Secondary Alcohol by Asymmetric Autocatalysis When the isopropylation of pyrimidine-5-carbaldehyde 32 was examined in the presence of (S)-2-butanol with ca. 0.1% ee, (S)-pyrimidyl alkanol 33 with 83% ee was obtained [79]. (R)-2-butanol induced the formation of opposite (R)-enantiomer. In the present enantioselective reaction, the steric influence of the substituents (RL > RS) of a chiral secondary alcohol is discriminated by the asymmetric autocatalysis. Thus, the bulkiness of various substituents in the secondary alcohols was determined in comparison with the phenyl group, based on the correlation of the absolute configurations of sec-alcohol as the chiral initiator and the obtained pyrimidyl alkanol 33. Chiral secondary alcohols, that is, alkyl-substituted benzyl alcohols with ca. 10% ee were submitted to the asymmetric autocatalysis as the chiral initiator (Scheme 12.44) [129]. When the alkylation was examined in the presence of (S)-methyl phenyl carbinol 37, (S)-pyrimidyl alkanol 33 was obtained in high ee and yield and vice versa. The correlation ((S)-secondary alcohol induces (S)-33) is the same as 2-butanol. On the contrary, in the case of isopropyl phenyl carbinol 38, the correlation was opposite: (S)-secondary

12.5. CHIRAL DISCRIMINATION BY ASYMMETRIC AUTOCATALYSIS 923

H RS

OH RL

N t-Bu N

N t-Bu

CHO 32

H RL

N +

Enantioenriched (S)-33

S OH

OH RS

N t-Bu

i-Pr2Zn

N

Enantioenriched (R)-33

R OH

Steric discrimination of secondary alcohol by asymmetric autocatalysis OH

OH Ph (R)-37

Ph (R)-38

OH

OH Ph (R)-39

Ph (R)-40

Scheme 12.44. The concept of steric discrimination in the enantioselective alkylation of 32 using chiral secondary alcohols as chiral initiators.

alcohol 38 induces (R)-33. When the isopropyl group was replaced by a more bulky tertbutyl group, that is, tert-butyl phenyl carbinol 39 was subjected to the asymmetric autocatalysis, the correlation was the same as the result of 38. On the other hand, when alcohol 40 with the cyclopropyl group instead of isopropyl substitution was used, the correlation was opposite, which means that the correlation was the same as the case of methyl phenyl carbinol 37, that is, the cyclopropyl group was recognized as the smaller substituent than the phenyl group. We also investigated the unsaturated group-substituted benzyl alcohols such as phenyl isopropenyl carbinol, phenyl vinyl carbinol, and β-branched alkyl-substituted benzyl alcohols as chiral initiator of asymmetric autocatalysis.

12.5.5. Reversal Phenomena of Enantioselectivity in Asymmetric Autocatalysis Initiated by Mixed Catalytic System of Chiral and Achiral β-Amino Alcohols The use of achiral additives in asymmetric organometallic catalysis was shown to be a promising approach for the optimization of the enantioselectivity of chiral catalysts [130]. However, the achiral additives sometimes reverse the enantioselectivity of a chiral catalyst. We discovered an unexpected reversal of the enantiofacial selectivity of chiral βamino alcohol catalysts by a smaller amount of achiral β-amino alcohol catalysts in dialkylzinc addition to aldehyde (Scheme 12.45) [131]. The addition of i-Pr2Zn to aldehyde 32 using a catalytic amount of chiral (1R,2S)- or (1S,2R)-N,N-dimethylnorephedrine (DMNE 41, >99.5% ee) alone afforded (R)- or (S)-alkanol 33 with high ee, respectively. On the other hand, when the same reaction was catalyzed by a mixture of chiral (1R,2S)-DMNE 41 (0.5 mol %) and achiral N,N-dibutylaminoethanol (DBAE 44d, 19.5 mol %), alkanol 33 was obtained with the opposite S configuration to that of expected from chiral catalyst. And the subsequent asymmetric autocatalysis with significant asymmetric amplification affords a highly enantiomerically enriched product. The reversal of the sense of enantioselectivity was also observed by using the chiral catalyst


Pro-R chiral catalyst

N

OH

(R)-33 (high ee)

N CHO

N

t-Bu

Same source of chirality

N 32

t-Bu

Opposite configurations

+ i-Pr2Zn Pro-R chiral catalyst

+ Achiral catalyst

N

OH

(S)-33 (high ee)

N t-Bu R1 = Ph, R2 = Me : (1R, 2S)-DMNE 41 R1 = Ph, R2 = H : (R)-DMAPE 42 R1 = H, R2 = Me : (S)-DMA 43

Pro-R c hiral catalysts

R1

R2

HO

Achiral c atalysts HO

NMe2

NR32

R32 = Me2 : DMAE 44a R32 = (CH2)5 : PiE 44b R32 = Et2 : DEAE 44c R32 = Bu2 : DBAE 44d R32 = Oct2 : DOAE 44e

Scheme 12.45. Ph HO

NMe2

HO

(1R,2S)-DMNE 41

N

Ph

Zn

O

O

Zn

NMe2

DMAE 44a

N Mixed dimer

Figure 12.7. Calculated structure of mixed dimer resulting from the aggregation of isopropylzinc alkoxides of (1R,2S)-DMNE 41 and DMAE 44a.

with (1S,2R)-DMNE, and achiral DBAE, (R)-33 being obtained. Thus, the enantiofacial selectivity of the chiral catalyst was reversed by the achiral catalyst 44d. Kinetic studies of this reaction with various loadings of catalyst and ab initio molecular orbital calculations indicate that the reversal of the sense of enantioselectivity is due to the preferential formation of a catalytically active chiral heterodinuclear aggregate derived from zinc alkoxides of chiral and achiral ligands (Fig. 12.7) [132]. In these reac-

12.6. SUMMARY 925

tions, the chiral catalyst and achiral ligand possesses the same functionalities and similar catalytic activities in the addition of dialkylzinc. Thus, these observation may bring some new insights to the mechanism of the β-amino alcohol catalyzed addition of dialkylzincs to aldehydes, because only monomeric species have been proposed to be catalytically active in the dialkylzinc addition to aldehydes catalyzed by β-amino alcohols [133,134].

12.6. SUMMARY As described, there have been examples of positive NLE in catalytic asymmetric synthesis. NLE is very important not only for obtaining chiral products with higher ees using chiral catalysts with lower ees but also for elucidating the structure and mechanism of asymmetric catalysis. As to asymmetric autocatalysis, we found that chiral 5-pyrimidyl alkanol, 3-quinolyl alkanol and 5-carbamoyl-3-pyridyl alkanol are highly enantioselective asymmetric autocatalysts for the addition of i-Pr2Zn to the corresponding aldehydes, respectively. Among these, 2-alkynyl-5-pyrimidyl alkanol is a highly efficient asymmetric autocatalyst with more than 99.5% enantioselectivity. Moreover, asymmetric autocatalysis with amplification of ee from extremely low ee to more than 99.5% ee was realized for the first time by consecutive asymmetric autocatalysis without the need for any other chiral auxiliary. Kinetic analysis of pyrimidyl alkanol suggested that the reaction is second order in the zinc monoalkoxide of the pyrimidyl alkanol. Chiral organic compounds with low ee, when exposed to CPL serve as chiral triggers for asymmetric autocatalysis. The overall process correlates, for the first time, the chirality of CPL with an organic compound with very high ee. Chirality of the CPL was directly correlated with the chirality of the pyrimidyl alkanol with high ee by asymmetric photodegradation of racemic pyrimidyl alkanol in combination with asymmetric autocatalysis. Chiral inorganic crystals, such as quartz and sodium chlorate, act as chiral triggers and regulate the sense of the asymmetric autocatalysis. The process correlates, for the first time, the chirality of inorganic crystals with an organic compound with very high ee. Chiral organic crystals composed of achiral compounds such as cytosine act as the initial source of chirality of asymmetric autocatalysis to produce the highly enantiomerically pure product. In this reaction, chiral organic crystals are utilized as a chiral inducer, not as a reactant. Therefore, these results are the realization of the process, in which the crystal chirality of achiral organic compounds induces asymmetry in another organic compound and its chirality was amplified to produce a large amount of an enantiomerically pure organic compound, pyrimidyl alkanol, in conjunction with asymmetric autocatalysis. Spontaneous absolute asymmetric synthesis was described in the formation of enantiomerically enriched pyrimidyl alkanol from the reaction of pyrimidine-5-carbaldehyde and i-Pr2Zn without adding a chiral substance in combination with asymmetric autocatalysis. The approximate stochastic distribution of the absolute configurations of pyrimidyl alkanols strongly suggests that the reaction is a spontaneous absolute asymmetric synthesis. It was shown that the asymmetric autocatalysis of chiral pyrimidyl alkanol is the only possible method to discriminate cryptochiral quaternary saturated hydrocarbons, whose chirality is not capable of determination by any conventional methods. The discrimination of chirality due to deuterium substitution is also accessible by the highly sensitive


asymmetric autocatalysis. It is possible to discriminate the bulkiness of various substituents in the secondary alcohols by the comparison of the absolute configurations of secalcohol used as chiral initiator and the obtained pyrimidyl alkanol. In addition, we observed an unexpected reversal of the enantiofacial selectivity of chiral β-amino alcohol catalysts by a smaller amount of achiral β-amino alcohol catalysts in the asymmetric autocatalysis. As described, asymmetric autocatalysis is closely related to the origin of the homochirality of organic compounds.

ACKNOWLEDGMENT Financial support by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology is gratefully acknowledged. REFERENCES 1. Reviews: (a) Ojima, I.; Clos, N.; Bastos, C. Tetrahedron 1989, 45, 6901. (b) Brown, J. M.; Davies, S. G. Nature 1989, 342, 631. (c) Kagan, H. B.; Girard, C.; Guillaneux, D.; Rainford, D.; Samuel, O.; Zhang, S. Y.; Zhao, S. H. Acta Chem. Scand. 1996, 50, 345. (d) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios, J. C. Tetrahedron Asymmetry 1997, 8, 2997. (e) Soai, K. (Ed.). Amplification of Chirality. Berlin Heidelberg: Springer-Verlag, 2008; Vol. 284. 2. Reviews and accounts by our group: (a) Soai, K.; Shibata, T. In Advances in Biochirality (Eds. Pályi, G.; Zucchi, C.; Caglioti, L.). Oxford: Elsevier, 1999; Chapter 11, p. 125. (b) Soai, K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33, 382. (c) Soai, K. Enantiomer 1999, 4, 591. (d) Soai, K.; Shibata, T. Yuki Gosei Kagaku Kyokaishi 1997, 55, 994. (e) Soai, K.; Shibata, T. In Catalytic Asymmetric Synthesis, 2nd Ed. (Ed. Ojima, I.). New York: Wiley-VCH, 2000; Chapter 9, p. 699. (f) Soai, K.; Shibata, T.; Sato, I. Nippon Kagaku Kaishi 2001, 141. (g) Soai, K.; Sato, I.; Shibata, T. Chem. Rec. 2001, 1, 321. (h) Soai, K.; Sato, I. Chirality 2002, 14, 548. (i) Soai, K. In Fundamentals of Life (Eds. Pályi, G.; Zucchi, C.; Caglioti, L.). Paris: Elsevier, 2002; p. 427. (j) Soai, K.; Sato, I.; Shibata, T. Yuki Gosei Kagaku Kyokaishi 2002, 60, 668. (k) Soai, K.; Sato, I. Viva Orig. 2002, 30, 186. (l) Soai, K.; Sato, I.; Shibata, T. In Methodologies in Asymmetric Catalysis (Ed. Malhotra, S. V.). Washington, DC: American Chemical Society, 2004; p. 85. (m) Soai, K. Yuki Gosei Kagaku Kyokaishi 2004, 62, 673. (n) Soai, K.; Shibata, T.; Sato, I. Bull. Chem. Soc. Jpn. 2004, 77, 1063. (o) Soai, K.; Kawasaki, T. Chirality 2006, 18, 469. (p) Soai, K.; Kawasaki, T. Shokubai (Catalysts & Catalysis) 2006, 48, 346. (q) Soai, K.; Kawasaki, T. Top. Curr. Chem. 2008, 284, 1. (r) Soai, K.; Kawasaki, T. In Asymmetric Synthesis––The Essentials (Eds. Christmann, M.; Bräse, S.). Weinheim: Wiley-VCH, 2007; p. 212. (s) Soai, K.; Kawasaki, T. In New Frontiers in Asymmetric Catalysis (Eds. Mikami, K.; Lautens, M.). Hoboken, NJ: Wiley-Interscience, 2007; Chapter 9, p. 259. (t) Soai, K.; Kawasaki, T. Fine Chem. 2008, 37, 5. (u) Soai, K.; Kawasaki, T. In Recent Developments in Physical Chemistry (Eds. DiazHerrera, E.; Juaristi, E.). Melville, NY: American Institute of Physics, 2008; p. 68. 3. Reviews by other groups: (a) Bolm, C.; Bienewald, F.; Seger, A. Angew. Chem. Int. Ed. Engl. 1996, 35, 1657. (b) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios, J. C. Chem. Commun. 2000, 887. (c) Buschmann, H.; Thede, R.; Heller, D. Angew. Chem. Int. Ed. Engl. 2000, 39, 4033. (d) Todd, M. H. Chem. Soc. Rev. 2002, 31, 211. (e) Podlech, J.; Gehring, T. Angew. Chem. Int. Ed. Engl. 2005, 44, 5776. (f) Mikami, K.; Yamanaka, M. Chem. Rev. 2003, 103, 3369. (g) Caglioti, L.; Zucchi, C.; Pályi, G. Chimica Oggi 2005, 23, 38. (h) Stankiewicz, J.; Eckardt, L. H. Angew. Chem. Int. Ed. Engl. 2006, 45, 342. 4. Puchot, C.; Samuel, O.; Duñach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353.

REFERENCES 927

5. Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430. 6. Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455. 7. Reviews, see: (a) Soai, K.; Sato, I.; Kawasaki, T. In The Chemistry of Organozinc Compounds (Eds. Rappoprt, Z.; Marek, I.). Chichester, UK: John Wiley & Sons, 2006; Chapter 12, p. 555. (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (c) Soai, K.; Shibata, T. In Comprehensive Asymmetric Catalysis (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.). New York: Springer, 1999; Chapter 26.1, pp. 911–923. (d) Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49. (e) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757. 8. (a) Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988, 110, 7877. (b) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028. 9. Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R.; Zhai, Z.; Suga, H. J. Phys. Chem. 1994, 98, 12776. 10. Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327. 11. Ojima, I. (Ed.). Catalytic Asymmetric Synthesis, 2nd Ed. New York: Wiley-VCH, 2000. 12. Legrand, O.; Brunel, J.-M.; Buono, G. Tetrahedron Lett. 2000, 41, 2105. 13. Sarvary, I.; Wan, Y.; Frejd, T. J. Chem. Soc. Perkin Trans. 1 2002, 645. 14. Soai, K.; Hayasaka, T.; Ugajin, S. J. Chem. Soc. Chem. Commun. 1989, 516. 15. Bolm, C. Tetrahedron Asymmetry 1991, 2, 701. 16. deVries, A. H. M.; Jansen, J. F. G. A.; Feringa, B. L. Tetrahedron 1994, 50, 4479. 17. Hu, Y.; Liang, X.; Zheng, Z.; Hu, X. Tetrahedron Asymmetry 2003, 14, 2771. 18. Qin, Y.-C.; Liu, L.; Pu, L. Org. Lett. 2005, 7, 2381. 19. Zhou, X.; Liu, X.; Yang, X.; Shang, D.; Xin, J.; Feng, X. Angew. Chem. Int. Ed. Engl. 2008, 47, 392. 20. Saito, B.; Katsuki, T. Tetrahedron Lett. 2001, 42, 8333. 21. Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725. 22. (a) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812. (b) Mai, E.; Schneider, C. Chem. Eur. J. 2007, 13, 2729. 23. Villano, R.; De Rosa, M.; Salerno, C.; Soriente, A.; Scettri, A. Tetrahedron Asymmetry 2002, 13, 1949. 24. (a) Hanawa, H.; Hashimoto, T.; Maruoka K. J. Am. Chem. Soc. 2003, 125, 1708. (b) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K. Chem. Eur. J. 2003, 9, 4405. 25. Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669. 26. Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 6145. 27. Furuno, H.; Hanamoto, T.; Sugimoto, Y.; Inanaga, J. Org. Lett. 2000, 2, 49. 28. (a) Yuan, Y.; Long, J.; Sun, J.; Ding, K. Chem. Eur. J. 2002, 8, 5033. (b) Yuan, Y.; Li, X.; Sun, J.; Ding, K. J. Am. Chem. Soc. 2002, 124, 14866. 29. Ji, B.; Yuan, Y.; Ding, K.; Meng, J. Chem. Eur. J. 2003, 9, 5989. 30. Du, H.; Zhang, X.; Wang, Z.; Ding, K. Tetrahedron 2005, 61, 9465. 31. Shang, D.; Xin, J.; Liu, Y.; Zhou, X.; Liu, X.; Feng, X. J. Org. Chem. 2008, 73, 630. 32. Endeshaw, M. M.; Bayer, A.; Hansen, L. K.; Gautun, O. R. Eur. J. Org. Chem. 2006, 5249. 33. Nakano, K.; Hiyama, T.; Nozaki, K. Chem. Commun. 2005, 1871. 34. Mai, E.; Schneider, C. Chem. Eur. J. 2007, 13, 2729. 35. Hayashi, Y.; Matsuzawa, M.; Yamaguchi, J.; Yonehara, S.; Matsumoto, Y.; Shoji, M.; Hashizume, D.; Koshino, H. Angew. Chem. Int. Ed. Engl. 2006, 45, 4593. 36. Klussmann, M.; Iwamura, H.; Mathew, S. P.; Wells, D. H., Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621. 37. Satyanarayana, T.; Ferber, B.; Kagan, H. B. Org. Lett. 2007, 9, 251.

928 ASYMMETRIC AMPLIFICATION AND AUTOCATALYSIS 38. Belokon, Y. N.; Bespalova, N. B.; Churkina, T. D.; Cisarova, I.; Ezernitskaya, M. G; Harutyunyan, S. R.; Hrdina, R.; Kagan, H. B.; Kocovsky, P.; Kochetkov, K. A; Larionov, O. V; Lyssenko, K. A; North, M.; Polasek, M.; Peregudov, A. S; Prisyazhnyuk, V. V; Vyskocil, S. J. Am. Chem. Soc. 2003, 125, 12860. 39. Oestreich, M.; Rendler, S. Angew. Chem. Int. Ed. Engl. 2005, 44, 1661. 40. Frank, F. C. Biochim. Biophys. Acta 1953, 11, 459. 41. (a) Calvin, M. Chemical Evolution. London: Clarendon Press, 1969. (b) Wynberg, H. J. Macromol. Sci. Chem. A 1989, 26, 1033. 42. Seebach, D.; Amstutz, R.; Dunitz, J. D. Helv. Chim. Acta 1981, 64, 2622. 43. Alberts, A. H.; Wynberg, H. J. Am. Chem. Soc. 1989, 111, 7265. 44. For other asymmetric autoinductive reactions: (a) Soai, K.; Inoue, Y.; Takahashi, T.; Shibata, T. Tetrahedron 1996, 52, 13355. (b) Shibata, T.; Takahashi, T.; Konishi, T.; Soai, K. Angew. Chem. Int. Ed. Engl. 1997, 36, 2458. 45. Danda, H.; Nishikawa, H.; Otaka, K. J. Org. Chem. 1991, 56, 6740. 46. Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. J. Chem. Soc. Chem. Commun. 1987, 1690. 47. Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991, 56, 4264. 48. Soai, K.; Hayase, T.; Takai, K.; Sugiyama, T. J. Org. Chem. 1994, 59, 7908. 49. Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc. Chem. Commun. 1987, 467. 50. Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109, 7111. 51. Soai, K.; Niwa, S.; Hori, H. J. Chem. Soc. Chem. Commun. 1990, 982. 52. Shibata, T.; Choji, K.; Morioka, H.; Hayase, T.; Soai, K. Chem. Commun. 1996, 751. 53. Shibata, T.; Morioka, H.; Tanji, S.; Hayase, T.; Kodaka, Y.; Soai, K. Tetrahedron Lett. 1996, 37, 8783. 54. Shibata, T.; Morioka, H.; Hayase, T.; Choji, K.; Soai, K. J. Am. Chem. Soc. 1996, 118, 471. 55. Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767. 56. Shibata, T.; Hayase, T.; Yamamoto, J.; Soai, K. Tetrahedron Asymmetry 1997, 8, 1717. 57. Shibata, T.; Yonekubo, S.; Soai, K. Angew. Chem. Int. Ed. Engl. 1999, 38, 659. 58. Sato, I.; Urabe, H.; Ishiguro, S.; Shibata, T.; Soai, K. Angew. Chem. Int. Ed. Engl. 2003, 42, 315. 59. Mauksch, M.; Tsogoeva, S. B.; Martynova, I. M.; Wei, S. Angew. Chem. Int. Ed. Engl. 2007, 46, 393. 60. Mauksch, M.; Tsogoeva, S. B.; Wei, S.; Martynova, I. M. Chirality 2007, 19, 816. 61. Amedjkouh, M.; Brandberg, M. Chem. Commun. 2008, 3043. 62. Sato, I.; Omiya, D.; Tsukiyama, K.; Ogi, Y.; Soai, K. Tetrahedron Asymmetry 2001, 12, 1965. 63. Sato, I.; Omiya, D.; Igarashi, H.; Kato, K.; Ogi, Y.; Tsukiyama, K.; Soai, K. Tetrahedron Asymmetry 2003, 14, 975. 64. Blackmond, D. G.; McMillan, C. R.; Ramdeehul, S.; Schorm, A.; Brown, J. M. J. Am. Chem. Soc. 2001, 123, 10103. 65. Blackmond, D. G. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5732. 66. Gridnev, I. D.; Serafimov, J. M.; Brown, J. M. Angew. Chem. Int. Ed. Engl. 2004, 43, 4884. 67. Gridnev, I. D.; Serafimov, J. M.; Quiney, H.; Brown, J. M. Org. Biomol. Chem. 2003, 1, 3811. 68. Klankermayer, J.; Gridnev, I. D.; Brown, J. M. Chem. Commun. 2007, 3151. 69. Gridnev, I. D. Chem. Lett. 2006, 35, 148. 70. Brown, J. C.; Gridnev, I.; Klankermayer, J. Top. Curr. Chem. 2008, 284, 35. 71. Islas, J. S.; Lavabre, D.; Grevy, J. M.; Lamoneda, R. H.; Cabrera, H. R.; Micheau, J. C.; Buhse, T. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 13743. 72. (a) Buhse, T. Tetrahedron Asymmetry 2003, 14, 1055. (b) Buhse, T. J. Mex. Chem. Soc. 2005, 49, 328. 73. Lavabre, D.; Micheau, J.-C.; Islas, J. R.; Buhse, T. Top. Curr. Chem. 2008, 284, 67. 74. Micskei, K.; Pota, G.; Caglioti, L.; Pályi, G. J. Phys. Chem. A 2006, 110, 5982. 75. Micskei, K.; Rábai, G.; Gál, E.; Caglioti, L.; Pályi, G. J. Phys. Chem. B 2008, 112, 9196.

REFERENCES 929

76. Lente, G. J. Phys Chem. A 2005, 109, 11058. 77. Saito, Y.; Hyuga, H. J. Phys. Soc. Jpn. 2004, 73, 33. 78. Saito, Y.; Hyuga, H. Top. Curr. Chem. 2008, 284, 97. 79. Shibata, T.; Yamamoto, J.; Matsumoto, N.; Yonekubo, S.; Osanai, S.; Soai, K. J. Am. Chem. Soc. 1998, 120, 12157. 80. Kawasaki, T.; Shimizu, M.; Suzuki, K.; Sato, I.; Soai, K. Tetrahedron Asymmetry 2004, 15, 3699. 81. Kawasaki, T.; Suzuki, K.; Licandro, E.; Bossi, A.; Maiorana, S.; Soai, K. Tetrahedron Asymmetry 2006, 17, 2050. 82. Maddox, J. What Remains to be Discovered: Mapping the Secrets of the Universe, the Origins of Life, and the Future of the Human Race. New York: Free Press, 1998. 83. Kuhn, W.; Knopf, E. Z. Phys. Chem. B 1930, 7, 292. 84. Inoue, Y. Chem. Rev. 1992, 92, 741. 85. Bonner, W. A.; Rubenstein, E. Biosystems 1987, 20, 99. 86. Feringa, B. L.; van Delden, R. A. Angew. Chem. Int. Ed. Engl. 1999, 38, 3418. 87. Hazen, R. M. In Progress in Biological Chirality (Eds. Palyi, G.; Zucchi, C.). Oxford: Elsevier, 2004; Chapter 9, p. 137. 88. Hazen, R. M.; Sholl, D. S. Nat. Mater. 2003, 2, 367. 89. Green, B. S.; Lahav, M.; Rabinovich, D. Acc. Chem. Res. 1972, 12, 191. 90. Matsuura, T.; Koshima, H. J. Photochem. Photobiol. C Photochem. Rev. 2005, 6, 7. 91. Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025. 92. Sakamoto, M. Chem. Eur. J. 1997, 3, 684. 93. Hasegawa, M. Chem. Rev. 1983, 83, 507. 94. Claborn, K.; Isborn, C.; Kaminsky, W.; Kahr, B. Angew. Chem. Int. Ed. Engl. 2008, 47, 5706. 95. Mislow, K. Collect. Czech. Chem. Commun. 2003, 68, 849. 96. Mason, S. F.; Tranter, G. E. Mol. Phys. 1984, 53, 1091. 97. (a) Lente, G. Phys. Chem. Chem. Phys. 2007, 9, 6134. (b) Davankov, V. A. Chirality 2006, 18, 459. 98. Bailey, J.; Chrysostomou, A.; Hough, J. H.; Gledhill, T. M.; McCall, A.; Clark, S.; Menard, F.; Tamura, M. Science 1998, 281, 672. 99. Nishino, H.; Kosaka, A.; Hembury, G. A.; Aoki, F.; Miyauchi, K.; Shitomi, H.; Onuki, H.; Inoue, Y. J. Am. Chem. Soc. 2002, 124, 11618. 100. Kagan, H.; Moradpour, A.; Nicoud, J. F.; Balavoine, G.; Tsoucaris, G. J. Am. Chem. Soc. 1971, 93, 2353. 101. Suarez, M.; Schuster, G. B. J. Am. Chem. Soc. 1995, 117, 6732. 102. Soai, K.; Sato, I. Enantiomer 2001, 6, 189. 103. Sato, I.; Ohgo, Y.; Igarashi, H.; Nishiyama, D.; Kawasaki, T.; Soai, K. J. Organomet. Chem. 2007, 692, 1783. 104. Bernstein, W. J.; Calvin, M.; Buchardt, O. J. Am. Chem. Soc. 1972, 94, 494. 105. Kawasaki, T.; Sato, M.; Ishiguro, S.; Saito, T.; Morishita, Y.; Sato, I.; Nishino, H.; Inoue, Y.; Soai, K. J. Am. Chem. Soc. 2005, 127, 3274. 106. Bonner, W. A.; Kavasmaneck, P. R.; Martin, F. S.; Flores, J. J. Science 1974, 186, 143. 107. Soai, K.; Osanai, S.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Sato, I. J. Am. Chem. Soc. 1999, 121, 11235. 108. (a) Sato, I.; Kadowaki, K.; Soai, K. Angew. Chem. Int. Ed. Engl. 2000, 39, 1510. (b) Sato, I.; Kadowaki, K.; Ohgo, Y.; Soai, K. J. Mol. Catal. A Chem. 2004, 216, 209. 109. Robertson, M. P.; Miller, L. Nature 1995, 375, 772. 110. Kawasaki, T.; Suzuki, K.; Hakoda, Y.; Soai, K. Angew. Chem. Int. Ed. Engl. 2008, 47, 496. 111. Kawasaki, T.; Jo, K.; Igarashi, H.; Sato, I.; Nagano, M.; Koshima, H.; Soai, K. Angew. Chem. Int. Ed. Engl. 2005, 44, 2774.

930 ASYMMETRIC AMPLIFICATION AND AUTOCATALYSIS 112. Kawasaki, T.; Suzuki, K.; Hatase, K.; Otsuka, M.; Koshima, H.; Soai, K. Chem. Commun. 2006, 1869. 113. Mills, W. H. Chem. Ind. 1932, 51, 750. 114. Soai, K.; Shibata, T.; Kowata, Y. Japan Kokai Tokkyo Koho (Patent), 9 268 179, 1997. 115. Soai, K.; Sato, I.; Shibata, T.; Komiya, S.; Hayashi, M.; Matsueda, Y.; Imamura, H.; Hayase, T.; Morioka, H.; Tabira, H.; Yamamoto, J.; Kowata, Y. Tetrahedron Asymmetry 2003, 14, 185. 116. Kawasaki, T.; Suzuki, K.; Shimizu, M.; Ishikawa, K.; Soai, K. Chirality 2006, 18, 479. 117. Mislow, K.; Bickart, P. Isr. J. Chem. 1976–1977, 15, 1. 118. Eliel, E. L.; Wilen, S. W. In Stereochemistry of Organic Compounds (Ed. Eliel, E. L.; Wilen, S. W.). New York: Wiley, 1994; Chapter 4, pp. 71–99. 119. Wynberg, H.; Hekkert, G. L.; Houbiers, J. P. M.; Bosch, H. W. J. Am. Chem. Soc. 1965, 87, 2635. 120. Kawasaki, T.; Tanaka, H.; Tsutsumi, T.; Kasahara, T.; Sato, I.; Soai, K. J. Am. Chem. Soc. 2006, 128, 6032. 121. Sato, I.; Osanai, S.; Kadowaki, K.; Sugiyama, T.; Shibata, T.; Soai, K. Chem. Lett. 2002, 168. 122. Sato, I.; Yamashima, R.; Kadowaki, K.; Yamamoto, J.; Shibata, T.; Soai, K. Angew. Chem. Int. Ed. Engl. 2001, 40, 1096. 123. Sato, I.; Sugie, R.; Matsueda, Y.; Furumura, Y.; Soai, K. Angew. Chem. Int. Ed. Engl. 2004, 43, 4490. 124. Sato, I.; Matsueda, Y.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Soai, K. Helv. Chim. Acta 2002, 85, 3383. 125. (a) Sato, I.; Ahno, A.; Aoyama, Y.; Kasahara, T.; Soai, K. Org. Biomol. Chem. 2003, 1, 244. (b) Tanji, S.; Ohno, A.; Sato, I.; Soai, K. Org. Lett. 2001, 3, 287. 126. Bartell, L. S.; Roth, E. A.; Hollowell, C. D.; Kuchitsu, K.; Young, J. E., Jr. J. Chem. Phys. 1965, 42, 2683. 127. Barabas, B.; Caglioti, L.; Micskei, K.; Zucchi, C.; Pályi, G. Orig. Life Evol. Biosph. 2008, 38, 317. 128. Sato, I.; Omiya, D.; Saito, T.; Soai, K. J. Am. Chem. Soc. 2000, 122, 11739. 129. Shibata, T.; Iwahashi, K.; Kawasaki, T.; Soai, K. Tetrahedron Asymmetry 2007, 18, 1759. 130. Vogl, E. M.; Gröger, H.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 1999, 38, 1570. 131. Lutz, F.; Igarashi, T.; Kawasaki, T.; Soai, K. J. Am. Chem. Soc. 2005, 127, 12206. 132. Lutz, F.; Igarashi, T.; Kinoshita, T.; Asahina, M.; Tsukiyama, K.; Kawasaki, T.; Soai, K. J. Am. Chem. Soc. 2008, 130, 2956. 133. Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832. 134. (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028. (b) Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2001, 123, 2464.

13 ASYMMETRIC POLYMERIZATION Shingo Ito and Kyoko Nozaki Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8656, Japan

13.1. INTRODUCTION The asymmetric synthesis and application of optically active polymers have received much attention from a wide range of scientists. The reasons are that most biological polymers such as polypeptides, polysaccharides, and nucleic acids are optically active and that their chiral nature appears essential to exhibit various well-defined functions such as molecular recognition ability and catalytic ability. In this regard, optically active polymers are important not only because of their chiral structures and properties but also because of their possibilities to provide totally new functional polymeric materials [1–13]. These considerations arouse great interest in potential applications of optically active polymers: (chiral) molecular recognition, asymmetric catalysis, molecular scaffolding to control the alignment of functional groups or chromophores, materials for optical and optoelectronic devices, etc. However, although a variety of optically active polymers have already been reported, few of them were successfully applied to the practical use. One of the most challenging subjects in synthetic chemistry, therefore, is the construction of novel optically active polymers exhibiting groundbreaking functions that are comparable to or better than those of natural optically active polymers. Asymmetric polymerization is one of the methods to synthesize optically active polymers, which can be obtained either by polymerization of achiral monomers by using optically active catalysts or initiators that introduce chirality in the polymer main chain, or by polymerization of monomers having an optically active chiral auxiliary. The former type of polymerization is mainly reviewed in this chapter, which is divided into three major categories: asymmetric synthesis polymerization, helix-sense-selective polymerization, and enantiomer-selective polymerization. Although the last type of polymerization may be outside the scope of this book, some of them are included because of their


932 ASYMMETRIC POLYMERIZATION

significant contributions to the field of asymmetric polymerization. In addition, the reactions that give a racemic mixture of chiral polymers are not described even though each polymer molecule is optically active.

13.2. ASYMMETRIC SYNTHESIS POLYMERIZATION Asymmetric synthesis polymerization is a polymerization reaction of optically inactive, achiral monomers in the presence of optically active catalysts or initiators to give polymers with configurational chirality in the main chain. In general, chiral induction is achieved by differentiation of the enantiofaces of an olefinic unsaturated bond or by desymmetrization of a meso-compound. Therefore, a variety of alkenes or mesocompounds have been utilized as a monomer in this type of polymerization. Although it is difficult to determine the extent of chiral induction in most cases, it can be estimated by comparison with the corresponding oligomeric compounds prepared under the same conditions, or by the results of model reactions. The relation between the optical activity of polymers and the configuration of the main chain has been discussed in several reports [10–19].

13.2.1. Polymerization of Achiral Monomers 13.2.1.1. Polymerization of Alkenes Stereoregular polymers of 1-substituted or 1,1-disubstituted ethenes cannot be optically active even if effective chiral induction takes place through polymerization because the polymer chain has a mirror plane of symmetry and the main-chain chiral centers are pseudoasymmetric [10–25]. Polystyrene [21,22], polypropylene [23], polymethacrylate [24,25], and polyacrylonitrile [24] did not show optical activity arising from the chirality of the main chain although some of them exhibited optical activity, based on the asymmetric centers of chiral initiators attached to the polymer chain in the initiation step. However, if some higher-order tacticities in the main chain are realized for a vinyl polymer, it can be optically active. The chirality of a polymer chain can be tested by assuming a stereotactic infinite chain as a cyclic compound and checking the symmetry of the compound (Fig. 13.1) [2,10,11,19]. All the stereosequences of diad, triad, tetrad, and pentad are not chiral because they have a plane of symmetry. On the other hand, a hexad sequence having triad tacticity of mm/ mr/rr = 0/67/33 is chiral (Fig. 13.1 (T) and (U)). The number of chiral sequences increases as the stereosequence becomes longer. The chirality of copolymers can be tested in the same manner (Fig. 13.2). Among the three A-A-B sequences, the one shown as (D) is chiral. This method of chirality test can be applied to other vinyl polymers including 1,2-disubstituted ethenes. 13.2.1.1.1. Monosubstituted Ethenes Enantioselective oligomerization of monosubstituted ethenes has been investigated for propylene, 1-pentene, and 4-methyl-1-pentene by using optically active zirconium catalysts such as 1 and 2, with methylaluminoxane (MAO) under H2 atmosphere, producing optically active oligomers [26,27]. Chiral induction was also achieved by the oligomerization of 1-butene by using (R*O)2TiCl2/ MgCl2 (R* is an enantiomerically pure monosaccharide derivative) in the presence of organoaluminum cocatalysts [28].

13.2. ASYMMETRIC SYNTHESIS POLYMERIZATION 933

Me

O Zr

Zr

Me

O

1

2

Triad tacticity mm/ mr/ rr

Triad tacticity mm/ mr/ rr (A)

100/

0/

0

(L)

(B)

100/

0/

0

(M)

(C)

0/

0/100

(N)

(D)

100/

0/

0

(O)

50/ 33/ 17

0/ 67/ 33

(P)

33/ 67/

0

(Q)

17/ 33/ 50

25/ 50/ 25

(R)

0/ 67/ 33

(E) (F)

100/

(G)

0/

0

0/ 40/ 60 100/

0/

0

0

0

(S)

0/100

(T)

0/ 67/ 33

0/

0

(U)

0/ 67/ 33

40/ 40/ 20

(V)

0/

(H)

0/100/

(I)

0/

(J)

100/

(K)

20/ 80/

33/ 67/

0

0/100

Figure 13.1. (Reprinted with permission from reference 2. Copyright 1994 American Chemical Society.)

A

A

(A)

A

B

A

(D)

B

B

B

A

A

B

A

A

B

A

A

B

A

A

B

A

B

C

A

B

C

A A

(B)

B

A

B

(E) B

B A

A A

(C)

A B

A A

A

A

B

A

A

B

(F) C

B

Figure 13.2. (Reprinted with permission from reference 2. Copyright 1994 American Chemical Society.)


13.2.1.1.2. Methacrylates The synthesis of optically active polymethacrylates has been achieved by the anionic polymerization of 9-phenylfluoren-9-yl methacrylate (3) by using the complexes of N,N′-diphenylethylenediamine monolithium amide (DPEDALi) with (−)-sparteine (Sp), (+)-1-(2-pyrrolidinylmethyl)pyrrolidine (PMP), and (+)-2,3-dimethoxy-1,4-bis(dimethylamino)butane (DDB) [29]. Although a helix formation was not confirmed in these cases, the poly-3s exhibited significant optical rotations of [α]365 −54° to +119°, which were attributed to the configurational chirality of the main chain.

O

Ph

Li NPh

O PhHN

3

N N

N

N H

MeO

(+)-PMP

(−)-Sp

DPEDA-Li

NMe2

Me2N

OMe

(+)-DDB

13.2.1.1.3. Benzofuran Benzofuran (4) is a suitable alkene monomer for asymmetric cationic polymerization. The reaction of 4 with EtAlCl2 or AlCl3 in the presence of chiral co-catalysts such as β-phenylalanine, 10-camphorsulfonic acid, tetramethylammonium 10-camphorsulfonate, and (−)-brucine provided optically active polymers [18,30–32]. Catalytic systems consisting of AlCl3/(−)-menthoxytriethyltin, -germanium, and -silicon were also effective for asymmetric cationic polymerization of 4 [33,34]. The observed optical activity indicates that the obtained polymers have erythro- or threo-diisotactic structures possessing no plane of symmetry ((a) and (c) in Scheme 13.1). Note that the corresponding disyndiotactic polymers ((b) and (d) in Scheme 13.1) cannot be optically active since they are not chiral.

O

N R 5

O 4 R

O

O

N

N 6

R

O

O

O N

O

N

N

N Li Ph

Ph Ph 7a: R = Me 7b: R = Et

8

N Co

t-Bu

O t-Bu

O 9

t-Bu

t-Bu

13.2.1.1.4. Maleimides The anionic polymerization of achiral N-substituted maleimides (5) is known to proceed through trans-addition [35] to form polymers with two possible types of structures, as shown in Scheme 13.2 [36]. Only polymaleimides with threo-


H

H

O

H

H

H

H

H

O

O

O

(a) erythro-Diisotactic

4 H

H

O

H

H

H

H

H

H

H

O

O

(b) erythro-Disyndiotactic H

H

O

O

H

H

O

(c) threo-Diisotactic

H O

H

H

H

O

(d) threo-Disyndiotactic

Scheme 13.1.

S

H

O 5 S O

H S

H S N R

H

O O

N R H

S

R O O

H S

H R N R

H

O O

N R H

S

S

H S O

N R H

O O

threo-Diisotactic

H S N R

O

threo-Disyndiotactic

Scheme 13.2.

diisotactic structures can be optically active, whereas the polymer with threodisyndiotactic structures cannot exhibit optical activity because of the equivalence of chiral stereogenic centers. The first optically active poly-5s were synthesized by anionic polymerization using sparteine-based catalysts such as BuLi/(−)-Sp (N-phenylmaleimide: [α]435 −16.9° [37], N-cyclohexylmaleimide: [α]D −39.2° [38]) or BuLi-CuI/(−)-Sp (Nphenylmaleimide: [α]435 −23.7° [37]). A variety of optically active catalysts including lithium (−)-menthoxide [39], lithium (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidinylamide [39], BuLi/bisoxazolines (6, 7b) [36,40–44], Et2Zn/bisoxazolines [41–43,45,46], lithium oxazolidinylamide (8) [42,47], and Co(II)-salen complex (9) [48–50] have been reported to promote the asymmetric polymerization of 5. The polymer from N-1-naphthylmaleimides showed a remarkably high optical rotation presumably due to not only configurational chirality in the main chain but also a conformational one based on higher-order structures [41,43,45]. The highest value was observed when N-1-naphthylmaleimide was used in the presence of Et2Zn/7b catalyst in THF ([α]435 +296.6°) [45]. It should be noted that the optically active polymers such as poly(N-phenylmaleimide)s and poly(N-1anthrylmaleimide)s were successfully applied to chiral stationary phase for highperformance liquid chromatography (HPLC) separation [44,51].


13.2.1.2. Polymerization of Dienes 13.2.1.2.1. 1,3-Dienes Polymerization of 1,3-diene (10) yields the polymer (11), having stereogenic carbon centers in the main chain [18]. The enantioselective anionic polymerization of 1,3-dienes such as methyl and butyl 2,4-hexadienoates (sorbates), and butyl styrylacrylates successfully proceeded in the presence of ((+)-2-methylbutyl)lithium or BuLi/(−)-menthyl ethyl ether [52]. 1,3-Pentadiene also successfully underwent asymmetric polymerization in the presence of Et3Al/titanium tetra(−)-menthoxide or (+)-tris(2-methylbutyl)aluminum/Ti(OBu)4 catalysts to give optically active polymers [53]. The extent of chiral induction in the polymerization can be determined by analyses of chiral diacid compounds (12) obtained after ozonolysis of 11 (Scheme 13.3).

R2 2

R

1

R

∗

R2

O3

R 10

∗

R1

HO2C

n

1

CO2H

∗

∗

11

12

Scheme 13.3.

The polymerization of monomeric guest components in host components as a molecular flask is called “inclusion polymerization” [54,55]. If a host component is optically active, a monomer molecule is included in chiral environment, thus giving optically active polymers. A number of chiral solid matrices have been used for asymmetric inclusion polymerization. In 1967, the synthesis of an optically active polymer from trans-1,3pentadiene (13) by means of trans-anti-trans-anti-trans-perhydrotriphenylene (14) as a host container was reported for the first time: The γ-ray irradiation of 13 included in 14 gives an optically active, isotactic trans-1,4-polypentadiene (15) (Scheme 13.4) [56]. Deoxycholic acid (16) [57,58] and apocholic acid (17) [59,60] were also reported to be effective matrices for asymmetric inclusion polymerization of 1,3-dienes such as cis- or trans-1,3-pentadiene and cis- or trans-2-methyl-1,3-pentadiene in a highly stereoselective manner.

HO

HO CO2H

HO

HO

H

14

CO2H

H

16

17

γ rays 14

∗

∗

∗

15

13 Scheme 13.4.

∗

n


13.2.1.2.2. 1,5- and 1,6-Dienes Cyclopolymerization of 1,5-hexadiene (18) using chiral metallocene catalyst (R,R)-1 or (S,S)-1 in the presence of excess MAO gave optically active poly(methylene-1,3-cyclopentane)s (19), with optical rotations of [Φ]405 +51.0° and −51.2°, respectively (Scheme 13.5) [61,62]. The 13C NMR analysis showed that the polymerization reaction proceeded with high cyclization selectivity of >99%, and that the obtained polymers contain 72–73% trans-rings. Since the isotacticity is a requirement for chirality in the case of poly(methylene-1,3-cyclopentane), the observation of optical activity provides a strong evidence for isotactic microstructure. Optically active zirconocene (20) and hafnocene (21), which can be obtained by HPLC resolution [63], were also used for asymmetric cyclopolymerization of 18 [64,65]. Both (+)-20 and (+)-21 catalysts gave optically active 19, with optical rotations of [α]435 −40° and −52°, respectively. The optical activity and the content of trans-structure in the main chain of the polymers were comparable to those of the polymers synthesized by using 1.

1/MAO 18

n

19 Scheme 13.5.

N-Phenyl-N-allylmethacrylamide (22) was shown to be a remarkable diene monomer for radical cyclopolymerization to give a polymer having five-membered ring structures in the main chain with high cyclization selectivity of 95–98% [66]. The enantioselective polymerization in the presence of SnCl4/(−)-menthol gave optically active polymers with an optical rotation of [α]D −5.6°. Higher chiral induction was observed in the radical copolymerization of 22 with methyl methacrylate (MMA). Cationic cyclopolymerization of benzaldehyde divinyl acetal (23) using ZnCl2/10-camphorsulfonic acid (24) as an initiatior gave an optically active polymer having 1,3-dioxane structures in the main chain ([α]435 −17°) [67].

O M

O

N

O

O

SO3H

O

O

20: M = Zr 21: M = Hf

22

23

24

13.2.1.3. Alternating Copolymerization 13.2.1.3.1. Monosubstituted Ethenes and Carbon Monoxide Palladium-catalyzed alternating copolymerization of monosubstituted ethenes and carbon monoxide is an attractive methodology to obtain an alternating copolymer, poly(1,4-ketone), possessing seterogenic centers in the main chain. Optically active, isotactic polyketones could be produced if the catalyst preferentially differentiates one of two enantiofaces of a mono-


substituted ethene at the stage of incorporation during the polymerization process (Scheme 13.6). The representative ligands for palladium-catalyzed enantioselective alternating copolymerization of monosubstituted ethenes and CO are shown below.

PPh2 O O P O

P

O

PBu2

O

PBu2

PCy2 PCy2 P

25

26 (S)-BICHEP

Fe

O N

PPh2

(R,S)-BINAPHOS

(S,S)-Me-DUPHOS

O

PCy2

28

27

N

N

N

O

∗

Ph 30

29

31

Ph2 P

N 32

(R)(Sp)-JOSIPHOS

R

cat. Pd−L* +

CO

R ∗

O n Scheme 13.6.

The first synthesis of optically active copolymers of monosubstituted ethenes and CO ([α]D +10.4 in (CF3)2CHOH (HFIP)) was achieved in 1990 by using Pd(OAc)2/ (−)-4,5-bis(dibutylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane (25) as a catalyst [68]. In 1992, Consiglio and coworkers developed enantioselective alternating copolymerization catalyzed by palladium-(S)-BICHEP (26) complexes [69–72]. The polymers obtained with 26 have essentially complete head-to-tail regioselectivity and high like-diad stereoselectivity (>93%). However, the enatioselectivity has been either low or not determined except in a few cases. In 1995, a more effective catalyst, [Pd((S,S)-27)(MeCN)2] (BF4)2, was developed for the asymmetric alternating copolymerization of monosubstituted ethenes with carbon monoxide to form optically active, isotactic polymers [73,74]. The polymers synthesized in MeNO2/MeOH have both 1,4-ketone structures and spiroketal structures in the main chain. The pure propylene/CO poly(1,4-ketone) was prepared by reprecipitation of the poly(spiroketal/1,4-ketone) copolymers, showing optical rotations of up to [α]D +22° (in HFIP). The optical purity of the stereogenic centers in the main chain is over 90%, as estimated by NMR analysis using a chiral Eu shift reagent. The copolymerization of functionalized terminal alkenes with CO has also been investigated by using [Pd((S,S)-27)(MeCN)2](BF4)2 as a catalyst [74]. Recently, a modified (R)(Sp)-JOSIPHOS system (29) [75,76] was reported to show the highest catalytic activity (1797 g g(Pd)−1·h−1) for the copolymerization of propene/CO to give a polymer with


complete regioselectivity (>99%) and 97.5% of like-diad stereoselectivity. The polymer showed an optical rotation of [α]D −34.6 and circular dichroism of ε = +1.26 in HFIP. Our group contributed to the field of asymmetric alternating copolymerization of monosubstituted ethenes and carbon monoxide by developing a chiral bidentate phosphine–phosphite ligand, BINAPHOS (28) [77–80]. The palladium complex [Pd{(R,S)-28}(Me)(MeCN)][B{3,5-(CF3)2C6H3}4] was found to be a highly active catalyst to give the alternating copolymer with high molecular weight (Mn 65,000) and high optical activity of [α]D +40° (in HFIP) [81–83]. The degree of enantioselectivity of the copolymer was estimated by comparison with that of the oligomer (33) prepared under the similar reaction conditions. The fact that the enantiomeric excess of 33 was over 95% strongly suggests a remarkably high chiral induction during the polymerization reaction. The cyclocopolymerization of 1,4-pentadiene or 1,5-hexadiene with carbon monoxide proceeded via intramolecular cyclization to form copolymers that have the structures of 34 and 35, respectively. O

O

O

OMe O

n

O 33

34

n

O 35

Vinylarenes could be used as a comonomer for copolymerization with carbon monoxide. The enantioselective alternating coplymerization of p-t-butylstyrene with CO using a palladium complex of bisoxazoline ligand (30) was reported to give a polymer with isotacticity of over 98% and high optical activity ([α]D of −536° in CH2Cl2) [84,85]. Note that the use of 1,10-phenanthroline, 2,2′-bipyridine, or 2,2′-bipyrimidine as a ligand gave the polymers possessing high syndiotacticity [84,86]. Other bidentate sp2-nitrogen ligands such as 31 [87] and 32 [88,89] were reported to catalyze the asymmetric copolymerization although the observed values of enantioselectivity were rather low. The palladium complex of BINAPHOS (28) is also effective for this type of copolymerization of vinylarene and CO [82] and enantioselective terpolymerization of propylene, vinylarene, and CO [90]. 13.2.1.3.2. Ketenes and Aldehydes Asymmetric alternating copolymerization of ketenes and aromatic aldehydes has been reported [91]. The catalyst with initiator consisting of Et2Zn and i-Pr-Pybox (36) efficiently promoted enantioselective alternating copolymerization of ethylphenylketene and benzaldehyde in CH2Cl2 to give optically active copolymers (37) with [α]D up to −158° (Scheme 13.7). Degradation of the polymer 37 with LiAlH4 revealed that the enantiomeric excess was 80%. It is noteworthy that the optical activity of 37 has remarkable effects on their solubility and thermal properties. For instance, optically active copolymers showed much better solubility than racemic copolymers toward common organic solvents such as THF, toluene, CH2Cl2, and CHCl3. The weight loss temperatures (Td5s) can be raised by over 100°C if the enantiomeric excess increases. 13.2.1.4. Desymmetrization of Meso-Monomers 13.2.1.4.1. Ring-Opening Polymerization of Epoxides The desymmetrization of mesomolecules using a chiral catalyst is one of the most valuable strategies for asymmetric synthesis polymerization. Meso-epoxides and thiiranes, having two equivalent stereo-


Et2Zn

O

N

N O

Ph

C

O

N 36

Ph

O

H

Et

H Ph ∗

+ O

CH2Cl2, −78°C

∗

O

n

Et Ph 37

90% yield [α]D = −158°

Scheme 13.7.

genic centers of the opposite absolute configuration, are highly attractive substrates for desymmetrization. In SN2 ring-opening reactions of meso-monomers with nucleophiles, inversion takes place at one of the stereocenters to give products consisting of consecutive stereogenic sp3 carbon centers. Thus, the optically active polymers could be obtained if the catalyst prefers one of the two stereocenters at the ring-opening process (Scheme 13.8).

inversion at R Nu

Nu

R R

R S

H R XH

Nu

H R

X (X = O, S)

H R

R H inversion at S

Nu

HX

XH

Nu

H R

R H

Scheme 13.8.

Enantioselective polymerization of meso-thiiranes such as cis-2,3-dimethylthiirane and cyclohexene sulfide was carried out by using Et2Zn/(R)-3,3-dimethyl-1,2-butanediol (38) [92,93], Me2Cd/38 [93], Et2Zn/(R,R)-1,2-diphenyl-1,2-ethanediol (39) [92,93], and Et2Zn/(S)-binaphthol (40) [92,93] as catalysts to produce optically active, isotactic polymers. On the other hand, meso-oxiranes showed lower reactivity, giving no optically active polymers with the catalytic system of Et2Zn/38, Et2Zn/39, and Et2Zn/40. The catalyst Et2Zn/(1S,2R)-ephedrine (41) was found to be effective for the asymmetric polymerization of cis-2,3-dimethyloxirane and cyclohexene oxide [92,93].

t-Bu

38

OH

Ph

OH

OH

Ph

OH

39

OH OH

40

NHMe Ph

OH

41


13.2.1.4.2. Alternating Copolymerization of Epoxides and Carbon Dioxide The first alternating copolymerization of meso-epoxides and carbon dioxide using chiral zinc-based catalysts was reported in 1999 from our group [77–79]. Polymerization of cyclohexene oxide (42) with 30 atm of CO2 in the presence of Et2Zn/(S)-α,αdiphenylpyrrolidin-2-yl-methanol (45) at 40°C produced alternating copolymers (43) in excellent yield (Scheme 13.9) [94,95]. The complete alternating nature of the polymer was confirmed by 1H NMR analyses, which showed no signal corresponding to ether linkages. The degree of the asymmetric induction of the cyclohexene 1,2-diol unit in the main chain can be unambiguously determined to be 70% ee (R,R) by degradation of 43 into the corresponding diols (44) using NaOH in MeOH/THF. The intensive screening of catalysts and reaction conditions revealed that the highest enantioselectivity (80% ee) could be obtained when the catalyst 46 was employed for the polymerization [96]. Costes and coworkers also independently reported the altenating polymerization of cyclohexene oxide and CO2 using chiral β-diiminate zinc complex (47) [97]. Ph

Et2Zn +

Ph Ph OH

N H 45

i-Pr

Ph

O OEt N H Zn Zn H N Et O

Ar

Me3Si

O

Hydrolysis

S O

O

S

R O

42 Inversion at S

t-Bu SiMe3

n

Hydrolysis R O

O (R,R)-43

n

S HO

S OH (S,S)-44

S

(S,S)-43

+ CO2

N

47

O R

Zn N

Ar = 2,6-(i-Pr)2C6H3

Ph

Ph 46

Inversion at R

N

R HO

R OH

(R,R)-44

Scheme 13.9.

13.2.1.5. Condensation Polymerization 13.2.1.5.1. Diels–Alder Polymerization Enantioselective Diels–Alder polymerization between prochiral bisdienophiles (48, 49) and bisdienes (50) using chiral Lewis acids (51, 52) affords novel optically active polymers possessing main-chain configurational chirality [98]. For instance, the reactions of bismaleimide 48a and bisdiene 50b proceeded in CH2Cl2 in the presence of BINOL-derived chiral aluminum catalyst (51), leading to the


O ∗

cat. 51

O

N

48a + 50b

∗ ∗

N

O

CH2

∗

53

n

O

Scheme 13.10.

quantitative formation of optically active polymers (53), which showed a molar optical rotation of [Φ]D +243° (Scheme 13.10) [99]. α,β-Unsaturated esters (49) could also be used as a bisdienophile monomer, which underwent polymerization with 50b in the presence of chiral oxazaborolidinone catalyst (52) to give polymers with [Φ]D +42°, albeit lower yield (66%) and molecular weight (2,700) [100]. O

O

N R N R O

O

48a R = 48b R =

50a R =

CH2 (CH2)6

CH2CH2OCH2

CH2OCH2CH2

50b R =

O MeO2C

O O

O O

Al Cl O

CO2Me

O 49

51

Ts

N B H

O

52

13.2.1.5.2. Allylation Polymerization Lewis acid–catalyzed addition of allylsilanes to aldehydes to give homoallylic alcohols, Sakurai–Hosomi reaction, is another powerful tool for asymmetric condensation polymerization [98]. Repetitive allylation of dialdehydes and bis(allylsilane)s in the presence of chiral catalysts produced optically active polymers having asymmetric carbons in the main chain [101,102]. Among the monomers ever examined, dialdehyde (54) and bis(allylsilane) (55) showed excellent reactivity toward asymmetric polymerization in the presence of chiral (acyloxy)borane (56) [103,104] to give the polymer (57) with high molecular weight (14,000) and a high molar optical rotation of [Φ]405 +1144° [101]. The optical purity of 57 was estimated to be approximately 75% ee according to a model reaction between benzaldehyde and methallyltrimethylsilane although the exact enantiometric purity of the polymer is still unknown


[101]. Degradation of polymers is an effective method to estimate the enantiometric purity of optically active polymers. Thus, silicon-containing dialdehyde (58) and siliconcontaining bis(allylsilane) (59) were prepared and polymerized under the optimal conditions. After polymerization, Si–C bonds were cleaved by treatment with tetrabutylammonium fluoride (TBAF) to give the corresponding homoallylic alcohol (60). Thus, the enantiometric purity of the polymer was determined to be 57–72% by analyzing 60 using chiral HPLC [105,106].

OHC

CHO

i-Pr O

SiMe3 R=

O

O

OH O

O

R O2C(CH2)4CO2

O O B Oi-Pr Ar Ar = 3,5-(CF3)2C6H3

Me3Si

54

55

56 OH

OH ∗

O O

∗

O ( )4

O

n

57 OHC

CHO

Me3Si

SiMe3

Si Me2

OH

Si Me2 59

58

60 OH

SiMe3

OHC

SiMe3 Si Me2

OHC 61

62

Si Me2 63

n

Chiral Lewis acid–catalyzed, one-component self-polyaddition of compounds (61, 62) possessing both a formyl group and an allylsilane moiety also affords optically active polymers [107,108]. Chiral (acyloxy)borane (56) is highly effective for enantioselective polymerization of 62 to give the optically active polymers (63), whose optical purity was determined to be 78%, based on the degradation method [108].

13.2.1.5.3. Aldol Polymerization Repetitive asymmetric Mukaiyama aldol reactions of dialdehydes and bisenolates afford optically active poly(β-hydroxyester)s [98,109,110]. For instance, the reaction of dialdehydes (64, 65) and bis(triethylsilyl enol ether)s (66, 67) in the presence of chiral Lewis acid (68) gave optically active polymers (69) with high molecular weight [111]. The level of chiral induction in 69 was determined to be 66–76% ee by 1H NMR analysis of the degradation products derived from 69 via Si–C bond cleavages [111,112]. These results indicated that the high optical purity was obtained by the asymmetric aldol polymerizations.


OHC

OSiEt3

CHO O

OSiEt3

O 1

R 1

R2 2

SiMe2 SiMe2(CH2)2SiMe2

64: R = 65: R1 =

SiMe2 SiMe2(CH2)2SiMe2

66: R = 67: R2 =

O OH O

OH O N B HN Ts Ar Ar = 3,5-(CF3)2C6H3

O

O

O R1

R2

68

n

69

13.2.1.6. Oxidative-Coupling Polymerization 13.2.1.6.1. 2,3-Dihydroxynaphthalenes The asymmetric oxidative-coupling polymerization (AOCP) of 2,3-dihydroxynaphthalenes has been developed. The reaction of 70 in the presence of CuCl/(R)-bisoxazoline (71) under O2 atmosphere followed by acetylation produced optically active poly(2,3-acetoxy-1,4-naphthalene) (72) although the enantioselectivity was estimated to be low (ca. 40% ee) from the model reaction [113]. Later on, oxovanadium(IV) catalysts were found to be more effective for AOCP of 70 [114,115]. For instance, the polymerization of 70 using VOSO4/(R)-71 [114] or VO(stearate)2/disodium D-(−)-tartarate [115] as catalysts under O2 atmosphere and the subsequent acetylation of hydroxy groups gave polymers 72 with optical rotations of [α]405 +147° and +223°, respectively. The enantiomeric excess was estimated to be over 80% ee. The cobalt(II)–salen complex (9) was also reported to promote the AOCP efficiently [116]. The AOCP of tetrahydroxybinaphthalene or hexahydroxyternaphthalene derivatives were accomplished by using CuCl/TMEDA, CuCl/(+)PMP, or CuCl/71 under O2 atmosphere or by using CuCl2/(−)-Sp as a stoichiometric oxidant [117–119]. HO

AcO

OH O

O N

N

Ph 70

OAc

Ph 71

n 72

13.2.1.6.2. 2,2′-Binaphthyls A variety of optically active polybinaphthyls have been synthesized by AOCP of 2,2′-binaphthyl derivatives. The AOCP of unsymmetrical binaphthyls such as methyl and benzyl 6,6′-dihydroxy-2,2′-binaphthyl-7-carboxylate (73) produces polybinaphthyls (76) having three different types of 1,1′-bi-2-naphthol units, X, Y, and Z. Highly cross-coupling selective polymerization of 73a and 73b was achieved by means of CuCl/7a catalyst to afford a polymer with the selectivity of Y = 96% and 99%, respectively [120,121]. The catalytic system of CuCl/7a also showed remarkable activity for cross-coupling-selective, asymmetric oxidative-coupling copolymerization of two different binaphthyls, 74 and 75, to give an alternating-type copolymer with


cross-coupling selectivity of 93% and estimated enantioselectivity of 43% ee (S) [122]. Kozlowski and coworkers have demonstrated that the one-pot tandem AOCP/Glaser coupling of 77 in the presence of copper catalyst (78) was effective to synthesize highly functionalized polybinaphthyls (79) (Scheme 13.11) [123,124]. HO

CO2R

PivO

PivO

OH 73a: R = Me 73b: R = Bn HO

CO2Bn BnO2C

OH

HO OH

OH

HexO2C

74

HO

BnO2C

X

BnO2C

HO OH

CO2Hex

OH

75

OH

HO

BnO2C

Y 76

OH

HO OH

CO2Bn

n

Z

HO H N

CO2R

N H

RO2C CO2R

Cu+ BF4− OH 78 ∗

OH

O2

77 (R = n-C6H13)

OH OH CO2R n

RO2C HO

Scheme 13.11.

79


13.2.1.7. Topochemical Polymerization The chiral crystalline environment of a monomer itself can be a source of asymmetric induction in solid-state polymerization [125–128]. Prochiral monomers such as 80 give enantiomorphic crystals, one of which can be preferentially formed by recrystallization with a trace amount of optically active compounds. Photoirradiation of the crystal leads to [2 + 2] topochemical asymmetric synthesis polymerization in the solid state, giving polymers having cyclobutane structures in the main chain (81) (Scheme 13.12). Y

Y Z Z

hv

X X = 4-pyridyl, Y = H, Z = COOEt X = COOR', Y = CN, Z = COOR" 80

X

n

81

Scheme 13.12.

13.2.2. Polymerization of Chiral Monomers 13.2.2.1. Polymerization of Monosubstituted Ethenes 13.2.2.1.1. Monosubstituted Ethenes Homo- and copolymerizations of monosubstituted ethenes bearing an optically active side group have achieved the asymmetric control of acyclic stereochemistry. The first example of asymmetric polymerization of optically active chiral vinyl monomers was the copolymerization of (S)-α-methylbenzyl methacrylate with maleic anhydride in the presence of AIBN to give the polymer, which showed an optical rotation of [α]D +23° after the removal of chiral (S)-α-methylbenzyl group [129]. Another example is the copolymerization of optically active styrene derivative (82) with N-phenylmaleimide (5, R = Ph). The copolymerization and the subsequent removal of the chiral side group produced an optically active N-phenylmaleimide-styrene copolymer [130]. Asymmetric free-radical oligomerization of acrylamides bearing an optically active side group (83) is an effective method to achieve the chirality induction in the polymer chain. The in-chain stereogenic centers of the resulting oligomers had single-handed chirality due to the steric effects of the chiral auxiliary group [131–133]. The polymerization of 83b–83d by free-radical catalysis formed polyacrylamides with high isotacticity (mm ∼92%), which could be converted into the corresponding poly(acrylic acid) or polymethacrylate by hydrolysis and esterification [134]. Asymmetric oligomerization of optically active vinyl sulfoxides has also been developed [135–136]. CO2Et O B

O

CO2Et

O

O N

Ph N

83a

83b

O N

O 82

O

N O

83c

O 83d

13.2.2.1.2. Cyclopolymerization of Dienes Although the control of chirality arising from stereogenic relationship in the main chain of the polymers prepared from mono-


substituted ethenes was thought to be unattainable, cyclopolymerization of bifunctional vinyl monomers provides an effective solution for that [137]: Optically active distyrenic monomer (84) were found to be successfully used as a chiral template for the synthesis of optically active polymers. For example, free-radical copolymerization of 84 with styrene and the following removal of the chiral template moiety from the obtained copolymer led to polystyrene that showed optical activity of [α]365 −0.5° to 3.5° (Scheme 13.13) [138]. The optical activity was ascribed to chiral (S,S)-diad units generated in the polymer chain through the cyclopolymerization step [139]. Other different bifunctional monomers such as 85 [140], 86 [141], 87 [142], and 88 [143] have been reported to promote this type of copolymerization with styrene.

O

O

O

O O

O

O O

B

O

O

O

B

O

O

O

B

O

O

O

B

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

R 86

84

O

O

88 (R = H, Me)

87

85

∗

Radical copolymerization

∗

84 + R (S,S)-diad ∗

1) Hydrolysis 2) AgNO3/NH3

O

∗

R

Atactic

B

O

O

O

O

B

O

=

Atactic

Scheme 13.13.

13.2.2.2. Polymerization of Disubstituted Ethenes 13.2.2.2.1. Methacrylates Optically active poly(methyl methacrylate) (pMMA) was synthesized through the polymerization of a salt of methacrylic acid (MAA) and chitosan followed by hydrolysis and esterification of the resulting polymer [144]. The obtained pMMA and pMAA had optical activity due to the chirality in the polymer chain. The cyclopolymerization using dimethacrylate monomer (86) was effective for chiral induction in the main chain of pMMA [145]. Free-radical polymerization of 86 proceeds


via cyclization, and the resulting polymer can be converted into pMMA by hydrolysis and esterification. The pMMA exhibited optical activity ([α]405 −4.3° in CHCl3), and the tacticity was mm/mr/rr = 12/49/39. Oishi and coworkers extensively studied the polymerization properties of optically active chiral N-(2-methacryloyloxyethyl)carbamates (RMOC). They prepared a variety of RMOCs from 2-methacryloyloxyethylisocyanate (MOI) with optically active alcohols such as choresterol (89) [146], l-menthol (90) [146], amino alcohols (91–94) [147], BINOL (95) [148], cinchonine (96) [149], and cinchonidine (97) [149]. Radical polymerization of the RMOCs in the presence of AIBN afforded optically active polymers, which presumably have higher-order structures arising from hydrogen bondings between urethane moieties. However, the CD spectra indicated that chiral induction in the main chain did not take place [148]. Polymerization of methcrylates having urea moiety (RMOU) was also investigated: (S)-1-phenethyl (98) [150], (S)-(methoxycarbonyl)benzylmethyl (99) [150], (S)-1-cyclohexylethyl (100) [151], and (R)-1-naphthylethyl (101) [152] (2methacryloyloxyethyl)ureas have been used as a monomer. The poly(RMOC)- and poly(RMOU)-based chiral stationary phase resolved some racemic compounds by HPLC [147–152]. O O

N H

O

R

Ph

Ph R= H O

O

O

H 89

90

N

Ph

N

O

91

Ph

92 H H

Ph

Ph N

O

Ph

N

O

Ph

Ph

N

O MeO

O H

H

H

N

O H

Ph

93

94 Ph

Ph N H 98

N 97

N 96

95

N H

OMe O 99

N H 100

N H 101

13.2.2.2.2. Maleimides Polymerization of chiral N-substituted maleimides (RMIs) also gives optically active polymers. For example, the polymer obtained by asymmetric anionic polymerization of (R)-(+)-N-(1-phenethyl)maleimide ((R)-(+)-102) in the presence of Et2Zn/(−)-Sp showed an optical rotation of [α]435 −197.6° [153], whereas poly[(S)(−)-102] showed a high optical rotation of up to [α]435 +466.2° [154]. Other RMIs including (R)- or (S)-103 [155], (S)-104 [156], (R)-105 [157], and (S)-106 [158,159] were found to

13.3. HELIX-SENSE-SELECTIVE POLYMERIZATION 949

be suitable monomers for asymmetric polymerization. The CD analyses suggested that the chirality of these polymers was attributed not only to the chirality of monomer units but also to the stereogenic centers in the main chain.

O

N

O

O

N

O

O

O

N

OMe

Ph

(S)-102

(S)-103

O

O

N

O

O

N

O

Ph

O

O

(S)-104

(R)-105

R

O O (S)-106

13.2.2.3. Polymerization of Dienes The radical polymerization of (−)-3-p-menthyl sorbates produced an optically active polysorbate, which was converted to a poly(sorbic acid) by hydrolysis under alkaline conditions. The chirality induction seemed to take place during the polymerization process since the poly(sorbic acid) was still optically active [160]. Asymmetric copolymerization of (−)-menthyl sorbates and styrene is also feasible [161]. A chiral monomer salt prepared from 1,3-butadiene-1-carboxylic acid and optically active 1-phenylethylamine was found to be a good monomer for copolymerization with styrene. The optical activity was maintained even after the removal of the chiral ammonium moiety [162,163].

13.3. HELIX-SENSE-SELECTIVE POLYMERIZATION The helix is one of the most important and fundamental secondary structures found in many biomacromolecules such as DNA and polypeptides. Since right- (P-helix) and left-handed (M-helix) helices are a pair of enantiomers (atropisomers), helical polymers can be optically active even in the absence of stereogenic centers in the main chain. Thus, helix-sense-selective polymerization is defined as “the reaction which gives a polymer having a preferential single-handed helical conformation” [2,5]. It should be noted that there are two types of helical polymers: dynamic helical polymer and static helical polymers. Dynamic helical polymers have low helix inversion barriers that result in the frequent flipping of helical conformations. Since the dynamics of the polymer chain is generally extremely fast, excess of screw sense in a helical conformation is usually lost in solution. For example, isotactic polystyrene [21,22] and polypropylene [23] prepared in the presence of chiral catalysts do not show any optical activity arising from a helical conformation. If the polymers are static helical polymers, which have higher inversion barriers due to a rigid main chain or bulky side groups, the helical conformation with excess screw sense can be maintained even in solution.

13.3.1. Polymerization of Achiral Monomers 13.3.1.1. Polymerization of Alkenes 13.3.1.1.1. Propylene and 1-Butene Isotactic polypropylene and poly(1-butene) obtained by polymerization using an optically active zirconocene catalyst (107) have been reported to show large optical rotations in suspension ([α]D −123°, −250° for polypropylene; [α]D +130° for poly(1-butene)). The optical activity was ascribed to a preferential single-


handed helical conformation of the polymer chain in a solid state. However, such a helical conformation cannot be maintained when the polymers are heated or completely dissolved because of the fast solution dynamics of the main chain [164,165].

Cl Zr Cl

107 13.3.1.1.2. Methacrylates Polymerization of bulky methacrylates under asymmetric catalysis affords optically active, highly isotactic polymers that have a stable singlehanded helical structure. Although efficient helix-sense-selective polymerization of methacrylates has been mainly achieved by anionic polymerization, some examples by free-radical polymerization have also been developed. Some single-handed helical polymethacrylates showed excellent chiral recognition ability when applied to a chiral stationary phase for HPLC [166–168]. In 1979, Okamoto and coworkers reported that the anionic polymerization of triphenylmethyl methacrylate (108) initiated by BuLi/(−)-Sp complex produced optically active, highly isotactic polymers with a preferential single-handed helix (Scheme 13.14). This is the first example of an optically active vinyl polymer whose chirality arises not from stereogenic centers but exclusively from a single-handed helical conformation of the main chain [169]. Motivated by the breakthrough results, a variety of chiral catalysts and initiators have been developed for polymerization of 108. Thus, helical poly-108s could be obtained by anionic polymerization using other complexes of achiral organolithiums with optically active ligands such as (−)-Sp [170–174], (S,S)-(+)- and (R,R)-(−)DDB [172,175], (+)-PMP [172], and diamines 109–113 [176–178]. The optically active lithium amide (114) [169,170] is also an effective initiator for the helix-sense-selective polymerization. For example, polymerization of 108 in the presence of 9-fluorenyllithium (FlLi)/(−)-Sp, FlLi/(+)-DDB, or FlLi/(+)-PMP at −78°C in toluene gave poly-108s that exhibited high optical rotations of [α]D +383°, +344°, and +334°, respectively [172]. The obtained optically active polymers have almost perfect isotactic structures with a preferential single-handed helical conformation, which is stabilized by steric congestion

N O

N n

BuLi O

O Ph

Ph

Ph Ph 108

O Ph

Ph Single-handed helix Scheme 13.14.


of the bulky side groups. Therefore, the helical conformation is lost if the triphenylmethyl group is removed from the polymer chain.

N

N

NMe2

N

N

n

109a: n = 2 109b: n = 3

NMe2 111

110

MeO OMe

N N

MeO

OMe

MeO

Ph N NMe2

MeO

112

NLi

Ph

113

114

Other achiral methacrylate monomers bearing a bulky side group have been examined to produce optically active polymers with helical conformation: The monomers 115 [179a], 116 [179a], and 117 [180] successfully gave a single-handed helix, whereas the monomers 118 [179a], 119 [179b], 120 [1], 121 [179b], and 122 [180] gave unsuccessful results. The alkoxy groups of 118 and 119 would be too bulky, and those of 120–122 would be too small to give an isotactic, helical polymer. Monomer 123 [1] gave a syndiotactic polymer, suggesting that the ester group is too flexible to form a rigid helix of the main chain. R'

Cl

R'

R'

O OR

R=

Ph Ph R' = F, Cl

Ph R' R'= Me, Cl 116

115 Ph

Me

Ph

Ph

n-C17H35 Ph Ph

119

120

121

Ph

Ph

Ph

Ph

117

Cl

Ph Ph

Ph Si Ph Ph

122

123

Ph Me Me

124

Cl

Ph

125

Bu Bu 126

118


A variety of bulky methacrylate monomers bearing pyridyl groups have been prepared and polymerized under similar conditions. However, the control of stereochemistry by chiral ligands such as Sp and DDB was found to be ineffective because the pyridyl group competitively coordinates to the Li cation at the active end of the growing intermediates. In fact, the polymerizations of 127 using FlLi/Sp and FlLi/DDB catalysts afforded the polymers with low optical activity of [α]365 −153° and +132°, respectively, which suggests that the poly-127s are mixtures of right- and left-handed helices [180,181]. More than 20 other chiral tertiary diamine ligands have been examined for the helixsense-selective polymerization of 127 to give helical polymers exhibiting unsatisfactory optical rotations within the range of [α]365 −1170° to +1012° [177,182–184]. On the other hand, PMP was found to be the most effective ligand in helix-sense-selective polymerization of 127, giving the highly isotactic polymers with narrow molecular weight distributions and high optical rotations, as shown in Table 13.1 [182,185]. The pronounced effect of PMP could be explained in terms of the tight and close ligand coordination to a Li cation due to the smaller substituent on the nitrogen atom in PMP (i.e., hydrogen) [182]. The PMP ligand promoted helix-sense-selective polymerization of other monomers containing pyridyl, pyrimidyl, and piperidinyl groups such as 128 [186], 129 [187], 130 [188], 131 [189,190], 132 [191], 133 [192], 134 [193], 135 [194], and 136 [195]. It is noteworthy that optically active poly-127 [196], poly-128 [186], poly-130 [188], and poly-117 [183] readily underwent helix-to-helix transition of the main chain in solution through which a single-handed helix racemizes or stereomutates from a kinetically controlled form to a thermodynamically stable form. Me

N N

O OR

N

N

R=

Ph

Ph

N

Me

N

Ph

Ph

Ph

Ph

Ph

Ph

127

128

129

130

131

F Me

Me N

N N

N Ph

N Ph

F Ph

132

133

134

135

136

Single-handed helical poly(methacrylate)s can be used as a chiral ligand for enantioselective catalysis. Reggelin and coworkers synthesized helical poly-128, poly-130, and block copolymers of 130 and 108, demonstrating that the polymers proved to be effective ligands for palladium-catalyzed enantioselective allylic substitution reaction of diphenylpropenyl acetate with dimethyl malonate [197,198]. The substitution product was obtained with up to 60% ee, which resulted exclusively from the helical chiral nature of the polymeric ligand. Asymmetric allylation of benzaldehyde with allyltrichlorosilane by means of pyridine N-oxide substituted helically chiral polymers prepared by oxidation


TABLE 13.1. Asymmetric Polymerization of Methacrylate 127 with DPEDA-Li/(+)-PMP or FILi/(+)-PMP in toluene at −78°C RLi

127/Li

DPEDA-Li DPEDA-Li DPEDA-Li DPEDA-Li FILi FILi

15 20 30 50 15 30

[α]365

DP

Mw/Mn

+1325 +1406 +1651 +1675 +1530 +1641

27 30 45 81 30 60

1.04 1.08 1.13 1.12 1.14 1.10

of poly-131 with m-CPBA was also reported although the enantiomeric excess obtained was up to 19% [199]. Helix-sense-selective polymerization of methyl, benzyl, and t-butyl methacrylates was investigated by using optically active crown ethers (137, 138) and chiral diamine (139) as a ligand to obtain the optically active, helical polymers. However, the polymers gradually racemized at ambient temperature to give optical rotations close to zero, which suggests that these esters would be too small to maintain the single-handed helical conformation [200,201]. The complexes consisting of BuLi/109a and BuLi/110 were also examined to fail in producing an optically active, helical polymer in the polymerization of methyl and benzyl methacrylates [176b].

O

O O O

O

O

O

O

O

O O O

137

138

N N 139

Optically active, highly isotactic poly(methacrylate)s having a single-handed helical conformation are obtained not only by anionic polymerization but also by radical polymerization. Although the stereochemical control of radical polymerization is generally more difficult than that of anionic polymerization, some effective methods have been developed, in which an appropriate choice of monomers and reagents is the key to success. Thus, the helix-sense-selective polymerization of bulky monomers such as 1-phenyldibenzosuberyl methacrylate (124) [202–206] and 9-phenyl-9,10dihydroanthracen-9-yl methacrylates (125, 126) [207] was achieved by using optically active initiators (140, 141), chain transfer reagents (142, 143), solvents (144–146) [204],


and chiral cobalt catalyst (9) [205, 206]. Although the obtained polymers were mostly insoluble in common solvents due to the high degree of polymerization, the THF-soluble fraction exhibited optical activity. The highest value of optical rotation was obtained in the polymerization of 124, using 9 as a catalyst to give a polymer showing [α]365 +1379°, which is corresponding to 78% excess of helical sense.

O O

O O

O

O

O 2

2

(−)-140

SH (+)-142

SH (−)-142

(−)-141

SH (−)-143

OH

OH (-)-144

(+)-145

OH (+)-146

13.3.1.1.3. Other Acrylic Monomers The control of stereochemistry in the polymerization of acrylates and acrylamides is more difficult than that in the polymerization of methacrylates. Catalytic helix-sense-selective polymerization of acrylates (147, 148) has been investigated by using various chiral ligands [208,209]. Among the diamine ligands examined, (+)-PMP and (+)-DDB showed high activity in the polymerization of 147 and 148 to give the optical rotations of [α]365 +102° (poly-147 with (+)-PMP) and −94° (poly148 with (+)-DDB), respectively. The isotacticity was estimated to be 61–70%, which was high enough to form a single-handed helical conformation. The anionic polymerization of bulky acrylamides (149–158) has been initiated by organolithium/(−)-Sp, which was shown to be a better catalytic system than DDB and PMP complexes [210–215]. Although polyacrylamides were obtained generally in high yield with a narrow molecular weight distribution, the isotacticity was comparatively low to give a mixture of meso- and racemo-diads. The highest isotacticity (m = 87%) and optical activity ([α]365 −657°) were achieved in the polymerization of 158h using the FlLi/(−)-Sp complex as an initiator at −98°C [213]. Asymmetric coordination polymerization of acrylamides by optically active zirconocene catalyst (164) has been recently developed [216,217]. Optically active, single-handed helical poly-149 and poly-158h and their copolymers with methacrylate blocks were obtained in almost quantitative yield by using 164 as a catalyst. Radical polymerization of methacrylamides 159 [218], 160 [219], and 161 [220] was carried out in (−)-menthol as a solvent to afford optically active, highly isotactic helical polymers in good yield. A bulky α-(trityloxymethyl)acrylonitrile (162a) polymerized in the presence of FlLi/(+)-DDB to produce insoluble polymers showing an optical rotation of [α]D +115° in suspension, which was completely lost when the trityl groups were removed [221]. Helix-sense-selective polymerization of some other bulky monomers has been attempted using chiral initiators: Monomers 162b–d [222] and 163a [179b] did not give polymers probably due to the highly crowded monomer structures. On the other hand, bulky


crotonate (163b) afforded optically active, helical polymers by anionic polymerization in the presence of FlLi/DDB and FlLi/PMP [223,224].

O O

O R = Ph

R

Ph

N

Ph

Ph

Ph

N

Ph 147

148

149 N

N

N

Ph

150

153

154

Ph

N

Ar R4 158

156 Ar

Ph

N

a: R1 = Me, R2 = R3 = R4 = H b: R1 = R3 = R4 = H, R2 = Me c: R1 = R3 = R4 = H, R2 = Cl d: R1 = R3 = R4 = H, R2 = OMe e: R1 = R3 = R4 = H, R2 = OTBS f: R1 = R3 = R4 = H, R2 = OCOt-Bu g: R1 = R3 = R4 = H, R2 = OCOCH(Ph)Et h: R1 = R2 = R4 = H, R3 = Me i: R1 = R2 = R4 = H, R3 = n-C6H13 j: R1 = R2 = H, R3 = R4 = n-C6H13 k: R1 = R2 = H, R3 = R4 = n-C6H13

N

NMe

Ph

155

R1

R3

N

Ph

N

151

Me

S 152

R2

N

Ph

Ph

157 R

NH

NH

Ph

NH

Ar

R

159

160

161

a: Ar = Ph b: Ar = 4-BuC6H4

a: Ar = Ph b: Ar = 4-BuC6H4

a: R = Me b: R = Bu

R

O

Ph O

Ph Ph

162 a: R = CN b: R = CO2Me c: R = CO2Et d: R = Ph

R2 R1

Ph

Oi-Pr Ph

O

O

Ph

Zr O

163

a: R1 = H, R2 = Et b: R1 = Me, R2 = H [MeB(C6F5)3]− 164

13.3.1.1.4. Dibenzofulvene Anionic polymerization of 2,7-di-n-pentyldibenzofulvene (165) was initiated by the complexes of FlLi and chiral ligands such as (−)-Sp, (+)-DDB, and (−)-DDB to give optically active poly-165s, which showed intense circular dichroism in film or in suspension but not in solution (Scheme 13.15) [225]. Remarkable hypochromicity in absorption and exclusive dimmer emission in fluorescence spectra suggest the existence of π-stack structure [226,227]. Given that the polymers have no stereogenic centers, the chiroptical properties arise only from a helical chiral conformation of the main chain.

1) FlLi/(−)-Sp 2) MeOH

165

Scheme 13.15.

H fluorenyl

n


13.3.1.2. Polymerization of Alkynes Helically chiral polyacetylene was synthesized in optically active nematic liquid crystals as a chiral reaction field. Akagi and coworkers successfully performed helix-sense-selective polymerization of acetylene in the presence of Ti(OBu)4/Et3Al in the chiral nematic liquid crystals prepared from various chiral dopants such as 166 [228], 167 [229], and 168 [230]. The obtained helical polyacetylene films, which are hardly soluble, consist of clockwise or counterclockwise structure of fibrils, as exemplified by SEM analyses. The helix-sense-selective polymerization of achiral arylacetylenes, having two hydroxy groups (169) in the presence of [RhCl(nbd)]2 and optically active 1-phenethylamine, has been achieved [231–233]. The polymer showed clear Cotton effects attributed to the rigid and single-handed helical conformation, which was kinetically stabilized by intramolecular hydrogen bondings between the hydroxy groups in the polymer. The arylacetylene bearing an achiral galvinoxyl chromophore (170) was also found to be a suitable monomer for efficient helix-sense-selective polymerization [233–235]. The induction of excess single-handed helicity of achiral polyacetylenes by means of acid–base interaction or host–guest complexation, as well as its applications, has been intensely investigated by Yashima and coworkers. However, the detailed description is omitted here since it would be outside the scope of this chapter [236]. PCH506

PCH506

PCH506

R R PCH506 166 (R = H, OEt) PCH506

PCH506

O

O

O

O

O

O

n 167 (n = 1, 2, 3)

PCH506

PCH506

PCH5012

168

PCH506 = (CH2)5O

n-C5H11

PCH5012 = (CH2)12O

n-C5H11

PCH5012 t-Bu

O

OH

t-Bu

On-C12H25 t-Bu

OH 169

170

t-Bu

OH

13.3.1.3. Polymerization of Aldehydes Asymmetric anionic polymerization of trichloroacetaldehyde (chloral) led to the formation of single-handed helical, isotactic polymers (171) having a 41 helical conformation [237–245]. A variety of chiral lithium alkoxides, such as (+)- or (−)-172 [239], (+)- or (−)-173 [239], and 174 [239, 241], have been used


as an effective initiator, giving optically active 171 with high optical rotations ([α]D over 4,000°). Although the polymers 171 with high molecular weight are insoluble and their conformation cannot be directly elucidated, the helical structure of 171 has been verified by NMR analyses [242,243] and crystallographic analyses of the corresponding oligomers [244]. C8H17 CCl3 ∗

CO2Me

∗

∗

O n

Ph

OLi

OLi

LiO 171

172

H

173

174

3-Phenylpropanal (175) was found to be a suitable monomer for the synthesis of polyaldehydes with single-handed screw sense. The asymmetric polymerization of 175 initiated by Grignard reagent/(−)-Sp complexes such as EtMgBr/(−)-Sp and OctMgBr/ (−)-Sp afforded the polymers with negative rotations of [α]365 −33° to −56°, which may be attributed to a predominant single-handed helical conformation of the main chain [246]. Detailed investigations of the corresponding oligomers revealed that the polymer had a 3-phenylpropoxy group at the α-end and a (2-phenylethyl)carbonyl group at the ω-end, indicating that the true initiator for the polymerization was not Grignard reagents but (1-phenylpropoxy)magnesium bromide (177) formed by Tishchenko reaction shown in Scheme 13.16. O 1) RMgBr/Sp 2) 175

O Ph

H

O

MgBr Sp 175

Ph

175

Ph

H MgBr Sp H O

O

Ph

Ph

R

O Ph

O Ph

O

O

Ph

+ R

176

Ph

R

MgBr Sp O

H H 177

O

Ph n

Ph

O

Ph

Scheme 13.16.

13.3.1.4. Polymerization of Isocyanides 13.3.1.4.1. Monoisocyanides Polyisocyanides are known to have a 41 helical conformation when they have a bulky substituent due to the steric repulsion between the adjacent substituents [247–249]. The conformation is rigid enough to form two conformational isomers with right- (P) and left-handed (M) helices, which usually exist in a 1:1 mixture even in solution. The first optically active polyisocyanide was obtained by chromatographic resolution of poly(t-butyl isocyanide) using poly((S)-s-butyl isocyanide) as a chiral stationary phase [250]. The CD spectral analyses revealed that the levorotatory


polymer had a (P)-helical conformation and that the dextrorotatory polymer had a (M)helical conformation [251]. Helix-sense-selective polymerization of achiral bulky isocyanides in the presence of optially active catalysts has also been developed. Nolte and Drenth reported the catalyst consisting of Ni(CNR)4(ClO4)/optically active amines was effective to synthesize single-handed helical polymers with enantiomeric excess of up to 83% [252,253]. Dinuclear π-allyl Ni(II) complexes (178–180) were also employed for the polymerization although the molecular weight of the obtained polymers was rather low [254]. Takahashi and coworkers developed the helix-sense-selective polymerization of isocyanides using a dinuclear Pd/Pt complex containing a single-handed oligomeric isocyanide chain (183) prepared from chiral aryl isocyanide 182 with 181. The complex 183 efficiently promoted further polymerization of achiral aryl isocyanide (184) in a helix-sense-selective manner (Scheme 13.17) [255,256]. This methodology was applied to the synthesis of polyisocyanides bearing porphyrins as a pendant group. Helix-senseselective polymerization of aryl isocyanide 186 with 181 smoothly proceeded even in the presence of bulky porphyrin groups to give the polymer in which porphyrin units were regularly arranged face-to-face (Scheme 13.18) [257–259]. The helical sense of the polyisocyanides can be unequivocally determined based on the exciton-coupled CD spectra of the porphyrin Soret band [260].

F3C Ph MeO

MeO Ph F3C O

O

O

Ni O

Ni O

O

N

F3C

O

Ni

Ni

O

O

O

O

O

Ni

O

Ni CF3

OMe Ph CF3

CF3 Ph OMe 178

PR3 Cl Pd PR3

PR3 Pt Cl PR3 181

n Ar*MC 182

N

179

R3 P Cl Pd R3 P

C N Ar*

n

PR3 Pt Cl PR3 183

Ar* = m-C6H4CO2R* R* = (−)-menthyl

O

180

m Ar1NC 184

R3P Cl Pd R3P

C N Ar

m

C N Ar*

PR3 Pt Cl PR3 185 n

Ar1 = m-PrOCOC6H4 Ar1 = m,m-(PrOCO)2C6H3

Scheme 13.17.

Yashima and coworkers have developed helicity induction of achiral polyisocyanides bearing a less bulky substituent through acid–base interactions. Although optically inactive poly(p-carboxyphenyl isocyanide)s cannot maintain a 41 helical conformation, they can adopt a dynamic single-handed helical conformation upon complexation with chiral amines [261]. Surprisingly, if the helicity induction is performed in water, the macromolecular helicity is stably memorized after the complete removal of the amines. The


t-Bu m Ar2NC 186 181

R3P Cl Pd R3P

PR3 Pt Cl PR3

C N

NH

N

TPP =

t-Bu N

Ar2 = TPPOCOC6H4 CO2TPP

HN

n

187

t-Bu

Scheme 13.18.

authors postulated that hydrophobic and chiral ionic interaction in water might be necessary for the selective helix formation and the memory [262–264]. 13.3.1.4.2. 1,2-Diisocyanobenzenes Aromatizing polymerization of 1,2-diisocyanobenzenes (188) using palladium or nickel initiators, which leads to the formation of poly(quinoxalin-2,3-diyl)s (189, 190), has been developed (Scheme 13.19). Since the poly(quinoxalin-2,3-diyl)s adopt a stable helical structure, they can be optically active if the polymerization proceeds with a preference for a single-handed helix. Optically active poly(quinoxalin-2,3-diyl)s were synthesized for the first time by Ito and coworkers in 1992 [265–269]. Highly helix-sense-selective polymerization of 1,2-diisocyano-3,6-di-ptolylbenzene (188a) to form a mixture of diastereomeric pentamers (192) was achieved by using optically active arylpalladium initiator (191), followed by the separation into (+)-192 and (−)-192 by chiral HPLC. The enantiomerically pure 192 can be used as an initiator for further asymmetric polymerization of 188b to form single-handed helical copolymers, 193 and 194, after the treatment with MeMgBr/ZnCl2, which exhibits symmetrical CD spectra and the same optical rotations with opposite sign (Scheme 13.20) [265]. Thorough investigation of the helical stabilities of 189 and 190 revealed that the rate of racemization depends on (i) the bulkiness of the substituents at 5- and 8-positions on the quinoxaline rings; (ii) the oligomerization degree; and (iii) the bulkiness of the terminus group [269]. Furthermore, the enantioselective aromatizing polymerization R1 2

R

R1 NC

R2

PdL2MeBr

NC R1

188a: R1 = p-MeC6H4, R2 = H 188b: R1 = Me, R2 = PrOCH2

2

R

N

R2

Me

N n

R1

PdL2Br

189

Scheme 13.19.

MeMgBr ZnCl2

R1 2

R

N

R2

Me

N R1 190

Me n


p-Tol N

1) 188b 2) MeMgBr

188a (+)-192 Pd(L*)2MeBr 191

N

[α]D = −343°

p-Tol

OPr OPr

5 Me

p-Tol N

Me

N p-Tol

Me

5 192

n

193 [α]D = +165° p-Tol

Pd(L*)2Br Me

L* = PPh[(S)-2-methylbutyl]2

N

1) 188b 2) MeMgBr

(−)-192

N

PrO PrO

[α]D = +233°

p-Tol n

5

Me

194 [α]D = −171°

Scheme 13.20.

could be achieved by using the initiators based on chiral binaphthyl groups (195–197) to give optically active polymers [270–273]. In particular, the polymerization of 188b in the presence of 197 was found to give excellent helix-sense selectivity of over 95% [271]. The binaphthyl moiety served as both an efficient chiral initiator for the asymmetric polymerization and a stabilizer to prevent racemization of the resulting helical polymers. Effective initiators based on the phenyl groups possessing optically active ortho-substituents, such as chiral aminocarbonyl, oxazoline, and imidazoline groups, have been developed [274].

p-Tol N N

R

R=

OMe H

MeO

H

Pd(PMe2Ph)I

p-Tol 195

196

197

13.3.1.5. Polymerization of Isocyanates Polyisocyanate is a synthetic polymer that has a rigid main chain based on the structure of 1-nylon [275,276]. Although no asymmetric carbon center is contained in the main chain, polyisocyanate can be optically active since it possesses a dynamic helical conformation [277,278]. Asymmetric anionic polymerization of achiral isocyanates (198) was successfully performed in the presence of various optically active anionic initiators (199–205) (Scheme 13.21) [279–281]. Among the initiators, lithium amide 199 showed the best chiral-inducing ability: 199 gave the polymers derived from 198a and 198d with optical rotations of [α]365 +416° and [α]365 +819°, respectively. The optical activity of the polymers was presumably attributed to the helicity of the polymer main chains induced by a chiral initiator residue, which was attached to the end of the chain, rather than to a chiral initiator residue itself. Chiral discrimination of racemic amino acid derivatives using a single-handed helical polyisocyanate bearing a crown ether moiety was reported [282]. A single-handed helicity induction of achiral polyisocyanates by means of chiral acid–base interaction or host– guest complexation has recently been developed [236,283–286].


O OMe

N Li

N Li

OLi O

O

N

O

199

200

201

Ph

N Li

203

Me2N

Ph

Ph

204

O

C

205

N R

O

Initiator

N n R

198 Bu 198a

202

Ph OLi

OLi

R=

OLi

O

Me Ph

Ph 198b

198c

OMe 198f

Me 198d

Cl 198g

198e Me

198h Me 198i

Scheme 13.21.

13.3.1.6. Polymerization of Carbodiimides Helix-sense-selective polymerization of achiral carbodiimides (206) with optically active titanium catalysts has been developed to yield single-handed helical polycarbodiimides (207) (Scheme 13.22) [287,288]. The stability of the helix depends on the bulkiness of N-substituents of carbodiimides. For example, the polymer 207a–207c underwent racemization of the backbone at elevated temperature, whereas the polymer 207d, which has two ortho-substituents, never racemized under the same conditions. 13.3.1.7. Polymerization of Thiophenes Electrochemical polymerization has been used to produce a variety of conjugated polymers such as polypyrrole and polythiophene, which are usually obtained as an optically inactive form. Asymmetric polymerization of thiophenes has been achieved by using chiral nematic liquid crystal (N*-LC) as an effective chiral scaffold. Thus, optically active poly(3,4-ethylenedioxythiophene) (209) was successfully synthesized by electrochemical polymerization of 3,4-


O

Oi-Pr Ti

O

Oi-Pr

R2 N

R2 N C N 1

N

R1 2

206a: R = i-Pr, R = n-C6H13 206b: R1 = n-C6H13, R2 = n-C6H13 206c: R1 = Ph, R2 = n-C6H13 206d: R1 = 2-isopropyl-6-methylphenyl, R2 = Me

n R1 207a−d

Scheme 13.22.

O

O S 208

Electrochemical polymerization

O

(R)-N*-LC or (S)-N*-LC

O S 209

n

NC O O

(CH2)6O

n-C5H11

(CH2)6O

n-C5H11

n-C6H13 211

S

210

212

S

Scheme 13.23.

ethylenedioxythiophene (208) in N*-LC prepared from chiral dopant (210) and nematic liquid crystal (211) [289] or in lyotropic DNA N*-LC (Scheme 13.23) [290]. Optically active polybithiophenes were also synthesized from bithiophene (212) by using the electrochemical polymerization in the N*-LC [291]. The cross-coupling polymerization of achiral aryl dibromides and bis(trimethyltin)substituted bithiophenes proceeded in a helix-sense-selective manner in N*-LC to give the polymer, which showed a large optical rotation of [α]D −910.1° [292]. However, experimental data strongly implied that the chirality of the polymer was derived from the chiral aggregates produced during polymerization rather than from the helical structure of the main chain. 13.3.1.8. Polymerization of Silanes Polysilanes can adopt a stable, single-handed helical conformation when substituted with optically active end groups [293–295]. Helixsense-selective polymerization of masked disilene (213) was initiated by optically active potassium alkoxides such as potassium (+)-menthoxide and potassium (−)-menthoxide to form single-handed helical polysilanes (214) (Scheme 13.24). The conformation was stable in solution at low temperature as well as in solid state at room temperature [296,297].


Me Me Si n-C6H13 n-C6H13 Si

1) R*OK-cryptand[2,2,2] R*O 2) EtOH

Ph

Me n-C6H13 Si Si Me n-C6H13

H

R* = (+)-menthyl or (−)-menthyl 213

214

Scheme 13.24.

13.3.2. Polymerization of Chiral Monomers 13.3.2.1. Polymerization of Monosubstituted Ethenes The polymerization of optically active monosubstituted ethenes provides polymers that have a helical conformation with excess screw sense in solution due to the steric effects of the chiral side groups [18]. For example, the isotactic polymers obtained from a series of alkenes (215) using Ziegler–Natta type catalysts showed much larger optical activities than 215 or the model compounds (216). The discrepancy may be attributed to a single-handed helical conformation [298]. Similar optical properties have been observed for syndiotactic poly-(S)215b prepared with a homogeneous zirconium catalyst [299]. Isotactic polymers obtained by anionic polymerization from optically active vinyl ketones also adopt a helical conformation in solutions [300–302]. Polymerization of (+)- or (−)-m-tolyl vinyl sulfoxide (217) ([α]D +486°, −486°) in the presence of a 1:1 mixture of BuLi/(−)-Sp gave optically active poly-217, showing optical rotations of [α]D +310°, −307°, respectively. The optical activities were still maintained ([α]D +42°, −40°) even after the oxidation to poly(tolyl vinyl sulfone), suggesting that the optical activity might be attributed to a stable helical structure of the main chain [303]. ∗

R

∗

n

n

215a: n = 0 215b: n = 1 215c: n = 2 215d: n = 3

n = 0~3 R = H or Me 216

∗

S O 217

13.3.2.2. Polymerization of Methacrylic and Acrylic Monomers Helix-sense selection in the anionic or free-radical polymerization of optically active methacrylates was dependent on the chirality of either monomers or of initiators. The anionic polymerization of optically active (+)-131 ([α]D +88°) using both DPEDA-Li/(+)-DDB and DPEDA-Li/ (−)-DDB complexes gave optically active polymers ([α]D −315 to 357°), suggesting that the helix sense is independent of the chirality of initiators [304]. Similar helix-sense selection is also achieved in the radical polymerization of (+)-and (−)-131 [305]. On the other hand, the polymerization of (+)-132 ([α]365 +14°) using DPEDA-Li/(+)-DDB and DPEDALi/(−)-DDB systems proceeded with a ligand-directed helix-sense selection to give dextrorotatory ([α]365 +1125°) and levorotatory ([α]365 −845°) polymers, respectively. However, the latter polymer underwent the mutarotation in solution at 60°C through a helix-tohelix transition, which leads to a thermodanamically stable polymer showing a positive optical rotation of [α]365 +1481° [191]. Anionic polymerization of optically active monomer (218) ([α]365 −82°) proceeded without relation to the chirality of catalyst: The catalytic systems consisting of DPEDA-Li and amine ligands such as PMP, Sp, DDB, and TMEDA


gave isotactic polymers, all of which showed positive optical rotations of [α]365 +786 to +939°. The poly-218 exhibits reversible helix-to-helix transition in which the excess of screw sense is dependent on the solvent [306]. Cyclopolymerizations of bifunctional methacrylate (219) [307,308] and related monomers [309] under anionic or radical conditions are feasible to obtain single-handed helical polymers. O NMe O H O Ph Ph

Ph Ph O

O

O

218

O

O Ph Ph 219

13.3.2.3. Polymerization of Alkynes Helical polyacetylenes with excess screw sense can be obtained by metal-catalyzed polymerization of optically active alkynes [310]. Among transition metal catalysts ever reported, rhodium catalysts are remarkably powerful because of their nature to form exclusive cis-transoidal structures in the obtained polymer, which leads to the induction of helical conformations. In 1993, Aoki and coworkers reported the synthesis of helical poly(arylacetylene)s (221) by [RhCl(nbd)]2catalyzed polymerization of arylacetylenes (220) (Scheme 13.25) [311]. Since the report, a variety of single-handed helical poly(arylacetylene)s having optically active substituents such as carbamoyloxy groups [312], minidendric moieties [313,314], sugar-derived groups [315] oligopeptide pendants [316], and mesogenic groups [317] have been synthesized by rhodium-catalyzed polymerization. A series of helical disubstituted polyacetylenes have also been investigated [318–321].

n [RhCl(nbd)]2

H

THF O

O O

O

220

221 Scheme 13.25.

Masuda and coworkers have made significant contributions to the field of helical polyacetylene chemistry by synthesizing various optically active polyacetylenes, including poly(propionic ester)s [322–325], poly(propargyl alcohol)s [326], poly(N-propargylamide)s [327–350], poly(N-butynylamide)s [351], poly(N-propargylcarbamate)s [352,353], and poly(N-propargylphosphonamidate)s [354–356], and poly(arylacetylene)s [357–368]. Their chiroptical properties, as well as helical conformation and helicity inversion behavior, have been intensely investigated.


13.3.2.4. Polymerization of Isocyanides Optically active polyisocyanides with excess screw sense are obtained from optically active monomers by nickel-catalyzed polymerization. The polymers obtained from (R)-222, (R)-223, and (R)-224 have M-helical conformation with helical excess of 62%, 56%, and 20%, respectively [369]. The polymerization of optically active (S)-225 also gives a polymer with M-helicity. Interestingly, however, the copolymerization of achiral phenyl isocyanide with (S)-225 afforded a copolymer with P-helix [370,371]. The result is attributed to the difference of the polymerizability between two comonomers: The polymerization of bulky (S)-225 is slower than that of less bulky, achiral isocyanides. In the early stages of the copolymerization, therefore, the polymerization of phenyl isocyanide is predominant, and a racemic mixture of P- and M-helical growing chains is formed. (S)-225 is then preferentially incorporated into one of the two helices, M-helix. Thus, the further growth of the M-helix is inhibited as a result of the slower rate of polymerization of optically active comonomers. One of the significant contributions to the polyisocyanide chemistry is the polymerization of isocyanides bearing amino acids. The nickel-catalyzed polymerization of isocyanopeptides (226, 227) afforded novel synthetic analogues of β-helix, that is, the polymers that fold in a proteinlike fashion to give helical strands in which the peptide chains are arranged in β-sheet structures. The helical structure of poly(isocyanopeptide)s is stabilized by hydrogen bonds between the amide groups [372,373]. The polymerization of enantiomerically pure aryl isocyanides bearing chiral functional groups, such as Lalanine (228), L-alaninol (229), L-phenylalanine (230), and L-lactic acid residues (231) with a long n-decyl chain, proceeded diastereoselectively in the presence of NiCl2 to give either right- or left-handed helical polymers. The helical senses were significantly dependent on the pendant structure and the reaction conditions such as the solvent polarity and temperature, which suggests that the “on–off” fashion of the intermolecular hydrogen bondings between the amido groups strongly influences the outcome [374,375]. The control of helical conformation by electrical stimuli has been investigated. The helical polyisocyanides bearing ferrocenyl moieties were prepared by polymerization of optically active isocyanides (232) using a dinuclear Pt/Pd complex (181). Electrolytic CD and UV spectra suggested that the poly-232 exhibited reversible conformational change between helical structures and disordered structures in response to oxidation and reduction of the ferrocenyl pendants [376]. O NC

NC

NC

NC

CN

∗

N H

MeO2C O CN 222

223

NC

224

∗

225

NC

N H

∗

CO2Me 226

H N

∗

∗

227

O

NC

NC

CO2Me

NC

R O

NH

O

NH

O

NH

O

O

O

OCmH2m+1 228 (m = 2, 6, 10, 14)

O

On-C10H21 229

Ph 230

O

O

Fe

O

On-C10H21

On-C10H21 231

R = Me, n-C21H43 232


13.3.2.5. Polymerization of Isocyanates A variety of polyisocyanates having a helical conformation with excess screw sense have been successfully synthesized by polymerization of optically active isocyanates [278]. In 1970, Goodman and Chen first demonstrated that the optically active 2-phenylpropyl isocyanate gave polymers showing a large optical rotation of [α]D −468.8°, which may be attributed to a single-handed helical conformation [377,378]. After the pioneering work, Green and coworkers have extensively studied asymmetric polymerization of optically active isocyanate monomers such as (R)-233 [379–381], (R)-234 [382,383], (R)-235 [381,382,384], and (R)-236 [383] to afford the helical polyisocyanates. Optically active aromatic isocyanates, (S)-237 and (S)-238, were found to be effective for helix-sense-selective polymerization in the presence of Lipiperidide as an initiator [385,386]. The obtained poly-(S)-237 showed a large levorotation of [α]365 −1969°, which underwent only minimal changes upon heating. The results suggested that the poly-(S)-237 had an almost perfect single-handed helical conformation since the optical activity of polyisocyanates with chiral side chains is often dependent on temperature. Polymerization of aryl isocyanates bearing optically active alkoxy groups at the meta- or para-position at the phenyl ring was also investigated [387]. NCO ∗

O

O

NCO D H

H

NCO

Me

NCO

H

NCO

NCO

D

H N O

233

234

235

236

H Me

237

H N

Ph O

Et

H Me

238

13.3.2.6. Polymerization of Carbodiimides Titanium-initiated polymerization of optically active carbodiimide ((R)-239) produced optically active polyguanidine (240) ([α]365 +7.5°), which showed essentially the same optical rotation as (R)-239 ([α]365 +7.6°) (Scheme 13.26). When annealed, however, the optical rotation of 240 was increased to a value of [α]365 −157.5°, which suggested that kinetically controlled, disordered conformation evolved into thermodynamically controlled, highly ordered one [388]. The induction of helical chirality of racemic poly(di-n-hexylcarbodiimide) can be achieved by protonating the polymer with chiral camphorsulfonic acid [388].

N

N

CpTiCl2(i-OPr) C

N n-C6H13

rt

i-PrO

N n n-C6H13 240

239

Scheme 13.26.

13.3.2.7. Polymerization of Silanes Optically active, helical polysilanes were obtained by Wultz-type reductive polymerization of dichlorosilane monomers bearing a chiral side group [389–392]. Thus, single-handed helical conformation has been observed for

13.4. ENANTIOMER-SELECTIVE POLYMERIZATION 967

dialkylpolysilanes [393–396], alkyl-arylpolysilanes [397–401], and diarylpolysilanes [402], in which the use of (S)-2-methylbutyl group and (S)- or (R)-3,7-dimethyloctyl group as a side group was found to be essential for successful helical induction. 13.3.2.8. Polymerization of Other Monomers Optically active monomers bearing a binaphthyl unit were found to give polymers with a single-handed helical or propeller conformation [403,404]. Helical poly(biaryl carbonate)s have been synthesized by anionic ring-opening polymerization of optically active cyclic carbonates such as 241 [405] and 242 [406,407]. Polymer 243 obtained from 241 seemed to have a single-handed 41 helical conformation. The phenyleneethynylene-based polymers derived from L-glutamic acids were reported to show intense CD signals due to the predominant single-handed helical conformation [408]. O O

O

O O

241

O

O

242

O

O n

243

13.4. ENANTIOMER-SELECTIVE POLYMERIZATION Enantiomer-selective polymerization is a type of polymerization reaction in which one enantiomer of racemic chiral monomers is preferentially polymerized to give an optically active polymer. This is a kind of kinetic resolution of enantiomers. Thus, enantiomerselective polymerization has been mainly employed for racemic monomers in the presence of optically active catalysts and/or initiators. The degree of enantiomer selection is generally estimated by measuring the enantiomeric excess of the starting monomer as well as that of the resulting polymers. The ratio of the consumption rate of one enantiomer to that of the other enantiomer, krel, is used as a useful indicator to evaluate the catalytic performance. It should be noted that a racemic mixture of some chiral monomers can be converted into a mixture of polymers or stereoblock copolymers, which mainly consist of one enantiomer of the chiral monomer, with the aid of a chiral catalyst or an initiator in racemic form. Although this type of polymerization could be also categorized as enantiomer-selective polymerization, it is omitted in this chapter since there are already some comprehensive review articles [1,409].

13.4.1. Polymerization of Monosubstituted Ethenes The polymerization of racemic monosubstituted ethenes, 215b, 215c, 244, and 245, using achiral Ziegler-Natta catalysts proceeded stereoselectively to give a mixture of two types of polymers: one consisting of (R)-enantiomer and the other consisting of (S)enantiomer, which can be separated by chromatographic resolution [410–413]. When the polymerization was carried out in the presence of chiral catalysts such as TiCl4/Zn[(S)-2-


methylbutyl]2 and TiCl3/Al[(S)-4-methylhexyl]3, enantiomer-selective polymerization occurred to give optically active polyolefins [414–416]. The selectivity decreased as the distance between the vinyl group and the chiral center in a monomer increases, and no enantiomer selection was observed for 5-methyl-1-heptene (215c) [415,416]. A heterogeneous chiral Ziegler-Natta catalyst, MgCl2-supported TiCl3 modified with bis[(S)-2methylbutyl] phthalate, was also found to be effective for the enantiomer-selective polymerization [417]. Enantiomer selection was observed in copolymerization of optically active 244 and racemic 245, or that of optically active 245 and racemic 244 [418]. Enantiomer-selective polymerization of vinyl ethers has been attained. The copolymerization of rac-1-methylpropyl vinyl ether with optically active monomers [419] and polymerization of cis- and trans-1-methylpropyl propenyl ethers with chiral aluminum catalysts [420] afforded optically active polymers.

*

*

244

245

13.4.2. Polymerization of Methacrylates Highly enantiomer-selective polymerization of methacrylates has been achieved by using 1-phenethyl methacrylate (246) as a monomer. Thus, (S)-enantiomer of racemic 246 was found to be preferentially polymerized in the presence of cyclohexyl Grignard reagents/(−)-Sp in toluene at −78°C to give an optically active polymer. The enantiomeric excess of the remaining monomer 246 reached greater than 90% at 50–70% conversion [421–425]. The obtained polymer was highly isotactic, indicating that the chiral Sp-complex simultaneously differentiates enantiomers and enantiofaces (diastereotopic faces) of the double bond of the monomer. The polymerization with Grignard reagent alone gives an atactic polymer. Enantiomer-selective polymerization of 246 has also been attained by using the combination of cyclohexylmagnesium bromide/chiral amines such as 248 and 249 [426–428]. Furthermore, the Grignard reagent/(−)-Sp complexes are effective in enantiomer-selective polymerization of 247 [429–432].

O

R2

O

NH2 NH2

1

O

R

Ph

246

O

Ph

NMe2 NMe2

247 R1 R1 1

H, R2 = Me Et, R2 = Me 2

= = R = Me, R = Et, i-Pr, t-Bu

248

249

The anionic polymerization of racemic 131 using FlLi/(−)-DDB proceeded enantioselectively to give an optically active, highly isotactic polymer [188,189]. Although the

13.4. ENANTIOMER-SELECTIVE POLYMERIZATION 969

observed enantioselectivity was low in the early stages of polymerization, it increased as the reaction proceeded [189]. The enantiomer selection was governed by the helical conformation of a growing polymeric anion rather than a chiral ligand, as demonstrated by the polymerization using polymeric anions of various degrees of polymerization as initiators [189]. Enantiomer selection was achieved by free-radical polymerization of 250 [433] or by radical cyclopolymerization of racemic 2,4-pentanediyl dimethacrylates [434–436] although the selectivity was much lower than that observed in the anionic polymerization.

O

Ph O

O O 250

13.4.3. Polymerization of Epoxides and Thiiranes The first enantiomer-selective polymerization of epoxides was performed using propylene oxide (251) as a monomer. The polymerization of 251 in the presence of Et2Zn/ (+)-borneol or Et2Zn/(−)-menthol produced optically active polymers. The recovered monomer was found to be rich in (S)-isomer, suggesting that the (R)-isomer preferentially polymerized [437,438]. A variety of catalytic systems based on chiral zinc compounds [439–441] and aluminum compounds [442–444] have been developed for the enantiomer-selective polymerization of 251. Recently, Coates and coworkers reported an extremely selective bimetallic cobalt catalyst for enantiomer-selective polymerization of epoxides. The enantiomerically pure catalyst 252 exhibited krel of 370 for 251 [445]. The catalyst was active and selective for 1-butene oxide, 1-hexene oxide, and styrene oxide (krel = 63–330).

t-Bu

R

t-Bu

N

O O 251

R

N

M N R

O

S

O

R

M N O t-Bu

t-Bu

252 (M = CoCl)

Propylene sulfide was polymerized enantiomer-selectively in the presence of optically active zinc [446–449], lithium [450], or cadmium [451,452,455] catalysts. The ratio of consumption rate of (S)-monomer to that of (R)-monomer, kS/kR, reached up to 20 in the polymerization using Et2Zn/40 system [448,449]. Enantiomer-selective polymerization of racemic (phenoxymethyl)thiirane was also reported [453].


13.4.4. Polymerization of Lactones and Lactides Enantiomer-selective ring-opening polymerization of substituted lactones has been developed. Polymerization of 253a [454,455], 253b [456], and 253c [457] initiated by Et2Zn/(R)-38 gave optically active polymers with kR/kS values of 1.25, 1.02–1.07, and 1.7, respectively. Schiff base–type ligands were similarly effective for the enantiomerselective polymerization [443,458,459]. Enzyme-catalyzed synthesis of polyesters by homopolymerization or copolymerization of racemic lactones has recently received much attention [460–463]. Various optically active polyesters were prepared by using lipase as a catalyst [464–468]. Enantiomer-selective polymerization of a racemic mixture of meso-lactide (254) was achieved for the first time by using chiral aluminum complex (255) as an initiator [469]. At low or moderate conversion, D-enantiomer of racemic 254 was preferentially polymerized by complex 255 to yield optically active, essentially isotactic poly-D-254 with high optical purity. The kD/kL value was estimated to be 20. Recent development of polylactide synthesis has been summarized in several reviews [470–473]. O

R1

O

R2

O

O

O

R3

O

1

2

3

253a : R = Me, R = Pr, R = H 253b : R1 = Me, R2 = Et, R3 = H 253c : R1 = H, R2 = H, R3 = Me

N

N Al

254 O

O OMe 255

13.4.5. Polymerization of α-Amino Acid NCAs Enantiomer-selective polymerization of α-amino acid N-carboxyanhydrides (NCAs) [474] is initiated by optically active amines [475,476], polypeptides [476], organoaluminum complexes [478–480], nickel complexes [481,482], and ruthenium or iridium complexes [483]. The polymerization reactions of L-Glu- (257a) and D-Glu-NCA (257b) were performed independently in the presence of ruthenium complex (256) and dmpe, and the enantiomer selectivity (kD/kL) was determined to be greater than 6, which exceeds the values of systems ever reported [483]. O

BnO2C Ru HN

N Ts

Ph

Ph 256

H

N

O

BnO2C

O H

N

O L-Glu-NCA

D-Glu-NCA

257a

257b

O O

13.4.6. Enzymatic Polymerization The optically active polyesters can be synthesized by enzyme-catalyzed enantiomerselective polymerization. Thus, various enzymatic catalysts can be successfully employed

13.5. SUMMARY AND OUTLOOK 971

Ru HN HO O

OH 258 + OMe

MeO 259

NH 260 R

Ph O Novozym 435

O

O

R

O O

O 92% conversion Mw = 3,400; Mw/Mn = 1.6 R,R/R,S = 16:1 (R/S ≈ 33:1)

n

Scheme 13.27.

in polycondensation of diols and diesters [484,485], homopolymerization and copolymerization of hydroxyesters [486], and ring-opening polymerization of lactones [487,488]. In 2006, Heise and coworkers reported a novel concept for the synthesis of optically active polyesters based on dynamic kinetic resolution (DKR) polymerization [489]. Enzymatic polymerization of racemic chiral diol (258) and bifunctional acyl donor (259) was carried out under the in situ racemization process catalyzed by Ru catalyst (260). The enzyme Candida antarctica lipase B (CALB) acted on only the hydroxy groups of the (R)-configurated stereocenters. Simultaneous racemization of the (S)-configurated stereocenters into the (R)-configurated ones allowed the polymerization to reach 92% conversion (Scheme 13.27) [489,490]. The synthesis of chiral polyesters by ring-opening polymerization of 6-methyl-ε-caprolactone under the similar concept has been developed [491,492].

13.5. SUMMARY AND OUTLOOK In this chapter, asymmetric polymerization reactions of various chiral and achiral monomers to yield optically active polymers are comprehensively reviewed. Many investigations have been performed on asymmetric synthesis polymerization to obtain polymers possessing configurational chirality. The problem in this field is the difficulty in direct determination of optical purity arising from asymmetric centers in a polymer chain. One solution to this problem is the degradation of polymers, which enables direct determination of optical purity although the method can be applied to only limited types of polymers. The advance in asymmetric synthesis polymerization highly depends on the diversity of the synthetic methods in asymmetric organic synthesis. Therefore, their progress would be indispensable for further developments of asymmetric synthesis polymerization. Helix-sense-selective polymerization has become a central field of asymmetric polymerization. A variety of well-defined helical polymers have been designed and synthesized, aiming at the generation of interesting properties and functions based on the single-handed helicity. The helical polymers have been applied to the HPLC stationary phase, which is one of the few successful applications of helical polymers obtained from asymmetric polymerization. Various single-handed helical polymers have recently been


employed as a catalyst or a ligand to achieve unique asymmetric catalysis although the yield and enantioselectivity are not comparable to those obtained by the conventional catalysis of small molecules. The rational design of monomers would lead to the development of novel helically chiral polymers that will work as more efficient and selective catalysts. In enantiomer-selective polymerization, high enantiomer selectivity has been achieved in the polymerization of olefinic monomers and the ring-opening polymerization of cyclic monomers. However, the problem that inevitably arises in enantiomer-selective polymerization via kinetic resolution is that the conversion of the starting monomer is always lower than 50% since the only one enantiomer can be used for polymerization. In this regard, the relatively new concept of DKR polymerization offers a promising answer to the problem, providing an efficient route for the one-pot synthesis of chiral polymers from racemic nonnatural monomers. As described in this chapter, a broad range of synthetic methodologies for asymmetric polymerization have been developed by taking full advantage of asymmetric organic synthesis. Despite such a remarkable progress, however, novel polymerization systems that will further expand the scope of asymmetric polymerization are still needed since the current performance of the optically active polymers as practical functional materials is not satisfactory. Therefore, future challenges include the development of novel catalytic systems and monomers, which can construct complex polymeric architectures, and their applications as truly useful functional polymeric materials. Asymmetric polymerization is distinctly a growing field of polymer chemistry. A number of novel synthetic methodologies to obtain optically active polymers will be developed to expand the efficiency and versatility of asymmetric polymerization. It is our hope that the present review will induce new interests in asymmetric polymerization.

REFERENCES 1. Okamoto, Y.; Yashima, E. Prog. Polym. Sci. 1990, 15, 263–298. 2. Okamoto, Y.; Nakano, T. Chem. Rev. 1994, 94, 349–372. 3. Nakano, T.; Okamoto, Y. In The Polymeric Materials Encyclopedia (Ed. Salamone, J. C.); Boca Raton, FL: CRC Press, 1996; pp 417–423. 4. Nakano, T.; Okamoto, Y. In Catalysis in Precision Polymerization (Ed. Kobayashi, S.). Chichester, UK: John Wiley & Sons, 1997; pp. 271–309. 5. Nakano, T.; Okamoto, Y. Chem. Rev. 2001, 101, 4013–4038. 6. Vogl, O.; Jaycox, G. D. Polymer 1987, 28, 2179–2182. 7. Wulff, G. CHEMTECH 1991, 21, 364–370. 8. Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812–1832. 9. Wulff, G. In Synthesis of Polymers (Ed. Schluter, A. D.). Weinheim: Wiley-VCH, 1999; pp. 375–401. 10. Wulff, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 21–37. 11. Farina, M. Top. Stereochem. 1987, 17, 1–111. 12. Optically Active Polymers (Ed. Selegny, E.). Dordrecht: Reidel, 1979. 13. Ciardelli, F. In Encyclopedia of Polymer Science and Engineering, Vol 10. (Ed. Mark, H. F.; Bikales, N. M.; Overberger, C. G.; Menges, G.). New York: Wiley, 1987; pp. 463–493. 14. Arcus, C. L. J. Chem. Soc. 1955, 2801–2806. 15. Arcus, C. L. J. Chem. Soc. 1957, 1189–1196.

REFERENCES 973

16. Arcus, C. L. Prog. Stereochem. 1962, 3, 264–268. 17. Schulz, R. C.; Kaiser, E. Adv. Polym. Sci. 1965, 4, 236–315. 18. Pino, P. Adv. Polym. Sci. 1965, 4, 393–456. 19. Farina, M.; Peraldo, M.; Natta, G. Angew. Chem., Int. Ed. Engl. 1965, 4, 107–112. 20. Frisch, H. L.; Schuerch, C.; Szwarc, M. J. Polym. Sci. 1953, 11, 559–566. 21. Murahashi, S.; Nozakura, S.; Takeuchi, S. Bull. Chem. Soc. Jpn. 1960, 33, 658–659. 22. Braun, D.; Kern, W. J. Polym. Sci., Part C 1963, 4, 197–209. 23. Fray, G. I.; Robinson, R. Tetrahedron 1962, 18, 261–266. 24. Marvel, C. S.; Frank, R. L.; Prill, E. J. Am. Chem. Soc. 1943, 65, 1647–1652. 25. Arcus, C. L.; West, D. W. J. Chem. Soc. 1959, 2699–2704. 26. Pino, P.; Cioni, P.; Wei, J. J. Am. Chem. Soc. 1987, 109, 6189–6191. 27. Pino, P.; Galimberti, M.; Prada, P.; Consiglio, G. Makromol. Chem. 1990, 191, 1677–1688. 28. Fuhrmann, H.; Kortus, K.; Fuhrmann, C. Macromol. Chem. Phys. 1996, 197, 3869–3879. 29. Nakano, T.; Hidaka, Y.; Okamoto, Y. Polym. J. 1998, 30, 596–600. 30. Natta, G.; Farina, M.; Peraldo, M.; Bressan, G. Makromol. Chem. 1961, 43, 68–75. 31. Farina, M.; Bressan, G. Makromol. Chem. 1963, 61, 79–89. 32. Natta, G.; Farina, M. Tetrahedron Lett. 1963, 4, 703–709. 33. Takeda, Y.; Hayakawa, Y.; Fueno, T.; Furukawa, J. Makoromol. Chem. 1965, 83, 234–243. 34. Hayakawa, Y.; Fueno, T.; Furukawa, J. J. Polym. Sci., Part A-1 1967, 5, 2099–2109. 35. Cubbon, R. C. P. Polymer 1965, 6, 419–426. 36. Onimura, K.; Tsutsumi, H.; Oishi, T. Macromolecules 1998, 31, 5971–5976. 37. Okamoto, Y.; Nakano, T.; Kobayashi, H.; Hatada, K. Polym. Bull. 1991, 25, 5–8. 38. Oishi, T.; Yamasaki, H.; Fujimoto, M. Polym. J. 1991, 23, 795–804. 39. Liu, W.; Chen, C.; Chen, Y.; Xi, F. Polym. Bull. 1997, 38, 509–514. 40. Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. Bull. 1997, 39, 437–444. 41. Oishi, T.; Onimura, K.; Isobe, Y.; Tsutsumi, H. Chem. Lett. 1999, 28, 673–674. 42. Oishi, T.; Onimura, K.; Isobe, Y.; Yanagihara, H.; Tsutsumi, H. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 310–320. 43. Isobe, Y.; Onimura, K.; Tsutsumi, H. Oishi, T. J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 3556–3565. 44. Oishi, T.; Isobe, Y.; Onimura, K.; Tsutsumi, H. Polymer J. 2003, 35, 245–254. 45. Onimura, K.; Tsutsumi, H.; Oishi, T. Chem. Lett. 1998, 27, 791–792. 46. Isobe, Y.; Onimura, K.; Tsutsumi, H. Oishi, T. Macromolecules 2001, 34, 7617–7623. 47. Oishi, T.; Onimura, K.; Tanaka, K.; Horimoto, W.; Tsutsumi, H. J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 473–482. 48. Nakano, T.; Tamada, D.; Miyazaki, J.-I.; Kakiuchi, K.; Okamoto, Y. Macromolecules 2000, 33, 1489–1491. 49. Nakano, T.; Yade, T.; Okamoto, Y. Macromolecules 2003, 36, 3498–3504. 50. Lee, Y.-K.; Kitamura, S.; Onimura, K.; Tsutsumi, H. Oishi, T. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 6157–6162. 51. Isobe, Y.; Onimura, K.; Tsutsumi, H. Oishi, T. Polym. J. 2002, 34, 18–24. 52. Natta, G.; Farina, M.; Donati, M. Makromol. Chem. 1961, 43, 251–254. 53. Natta, G.; Porri, L.; Valenti, S. Makromol. Chem. 1963, 67, 225–228. 54. Takemoto, K.; Miyata, M. J. Macromol. Sci. Rev. Macromol. Chem. 1980, C18(1), 83–107. 55. Farina, M. In Inclusion Compounds, Vol. 3 (Eds. Atwood, J. L.; Davies, J. D. E.; MacNicol, D. D.). London: AcademicPress, 1984; pp. 297–329.

974 ASYMMETRIC POLYMERIZATION 56. Farina, M.; Audisio, G.; Natta, G. J. Am. Chem. Soc. 1967, 89, 5071. 57. Audisio, G.; Silvani, A. J. Chem. Soc., Chem. Commun. 1976, 481–482. 58. Miyata, M.; Kitahara, Y.; Takamoto, K. Polym. J. 1981, 13, 111–113. 59. Miyata, M.; Kitahara, Y.; Takemoto, K. Polym. Bull. 1980, 2, 671–674. 60. Miyata, M.; Kitahara, Y.; Takemoto, K. Makromol. Chem. 1983, 184, 1771–1779. 61. Coates, G. W.; Waymouth, R. M. J. Am. Chem. Soc. 1991, 113, 6270–6271. 62. Coates, G. W.; Waymouth, R. M. J. Am. Chem. Soc. 1993, 115, 91–98. 63. Habaue, S.; Sakamoto, H.; Okamoto, Y. Chem. Lett. 1996, 25, 383–384. 64. Habaue, S.; Sakamoto, H.; Okamoto, Y. Polym. J. 1997, 29, 384–386. 65. Habaue, S.; Sakamoto, H.; Baraki, H.; Okamoto, Y. Macromol. Rapid Commun. 1997, 18, 707–713. 66. Seno, M.; Kawamura, Y.; Sato, T. Macromolecules 1997, 30, 6417–6421. 67. Haba, O.; Kakuchi, T.; Yokota, K. Macromolecules 1993, 26, 1782–1783. 68. Wong, K. P. Eur. Pat. Appl. EP0384517, 1990. 69. Batistini, A.; Consiglio, G. Organometallics 1992, 11, 1766–1769. 70. Bronco, S.; Consiglio, G.; Hutter, R.; Batistini, A.; Suter, U. W. Macromolecules 1994, 27, 4436–4440. 71. Sperrle, M.; Consiglio, G. J. Am. Chem. Soc. 1995, 117, 12130–12136. 72. Bronco, S.; Consiglio, G. Macromol. Chem. Phys. 1996, 197, 355–365. 73. Jiang, Z.; Sen, A. J. Am. Chem. Soc. 1995, 117, 4455–4567. 74. Kacker, S.; Jiang, Z.; Sen, A. Macromolecules 1996, 29, 5852–5858. 75. Bronco, S.; Consiglio, G.; Di Benedetto, S.; Fehr, M.; Spindler, F.; Togni, A. Helv. Chim. Acta 1995, 78, 883–886. 76. Gambs, C.; Chaloupka, S.; Consiglio, G.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 2486–2488. 77. Nozaki, K. J. Polym. Sci., Part A: Polym. Chem. 2003, 42, 215–221. 78. Nozaki, K.; Kosaka, N.; Nakano, K.; Hiyama, T. Dalton Trans. 2003, 4039–4050. 79. Nozaki, K. Pure Appl. Chem. 2004, 76, 541–546. 80. Nozaki, K. Polym. J. 2005, 37, 871–876. 81. Nozaki, K.; Sato, N.; Takaya, H. J. Am. Chem. Soc. 1995, 117, 9911–9912. 82. Nozaki, K.; Sato, N.; Tonomura, Y.; Yasutomi, M.; Takaya, H.; Hiyama, T.; Matsubara, T.; Koga, N. J. Am. Chem. Soc. 1997, 119, 12779–12795. 83. Nozaki, K.; Sato, N.; Nakamoto, K.; Takaya, H. Bull. Chem. Soc. Jpn. 1997, 70, 659–664. 84. Brookhart, M.; Wagner, M. I.; Balavoine, G. G. A.; Haddou, H. A. J. Am. Chem. Soc. 1994, 116, 3641–3642. 85. Brookhart, M.; Wagner, M. I. J. Am. Chem. Soc. 1996, 118, 7219–7220. 86. Brookhart, M.; Rix, R. C.; DeSimone, J. M.; Barborak, J. C. J. Am. Chem. Soc. 1992, 114, 5894–5895. 87. Jiang, Z.; Adams, S. E.; Sen, A. Macromolecules 1994, 27, 2694–2700. 88. Aeby, A.; Consiglio, G. Helv. Chim. Acta 1998, 81, 35–39. 89. Aeby, A.; Gsponer, A.; Consiglio, G. J. Am. Chem. Soc. 1998, 120, 11000–11001. 90. Nozaki, K.; Kawashima, Y.; Nakamoto, K.; Hiyama, T. Macromolecules 1999, 32, 5168–5170. 91. Nagai, D.; Sudo, A.; Endo, T. Macromolecules 2006, 39, 8898–8900. 92. Sepulchre, M.; Kassamaly, A.; Spassky, N. Makromol. Chem., Macromol. Symp. 1991, 42/43, 489–500. 93. Spassky, N.; Momtaz, A.; Kassamaly, A.; Sepulchre, M. Chirality 1992, 4, 295–299. 94. Nozaki, K.; Nakano, K.; Hiyama, T. J. Am. Chem. Soc. 1999, 121, 11008–11009.

REFERENCES 975

95. Nakano, K.; Nozaki, K.; Hiyama, T. Macromolecules 2001, 34, 6325–6332. 96. Nakano, K.; Nozaki, K.; Hiyama, T. J. Am. Chem. Soc. 2003, 125, 5501–5510. 97. Cheng, M.; Darling, N. A.; Lobkovsky, E. B.; Coates, G. W. Chem. Commun. 2000, 2007–2008. 98. Itsuno, S. Prog. Polym. Sci. 2005, 30, 540–558. 99. Itsuno, S.; Tada, S.; Ito, K. Chem. Commun. 1997, 933–934. 100. Kamahori, K.; Tada, S.; Ito, K.; Itsuno, S. Macromolecules 1999, 32, 541–547. 101. Kumagai, T.; Itsuno, S. Macromolecules 2000, 33, 4995–4996. 102. Kumagai, T.; Itsuno, S. Macromolecules 2001, 34, 7624–7628. 103. Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 11490–11495. 104. Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561–562. 105. Kumagai, T.; Itsuno, S. Tetrahedron Asym. 2001, 12, 2509–2516. 106. Itsuno, S.; Kumagai, T. Macromolecules 2002, 35, 5323–5325. 107. Itsuno, S.; Kumagai, T. Synthesis 2002, 941–944. 108. Itsuno, S.; Kumagai, T. Helv. Chem. Acta 2002, 85, 3185–3196. 109. Komura, K.; Nishitani, N.; Itsuno, S. Chem. Commun. 1999, 35–36. 110. Komura, K.; Nishitani, N.; Itsuno, S. Polym. J. 1999, 31, 1045. 111. Itsuno, S.; Komura, K. Tetrahedron 2002, 58, 8237–8246. 112. Itsuno, S.; Watanabe, H. Polym. Bull. 2003, 51, 183–190. 113. Habaue, S.; Seko, T.; Okamoto, Y. Macromolecules 2003, 36, 2604–2608. 114. Habaue, S.; Murakami, S.; Higashimura, H. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 5872–5878. 115. Murakami, S.; Habaue, S.; Higashimura, H. Polymer 2007, 48, 6565–6570. 116. Habaue, S.; Aoyagi, H.; Murakami, S.; Higashimura, H. Polym. Bull. 2007, 59, 303–310. 117. Habaue, S.; Seko, T.; Okamoto, Y. Macromolecules 2002, 35, 2437–2439. 118. Habaue, S.; Seko, T.; Isonaga, M.; Ajiro, H.; Okamoto, Y. Polym. J. 2003, 35, 592–597. 119. Habaue, S.; Ajiro, H.; Yoshii, Y.; Hirasa, T. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 4528–4534. 120. Temma, T.; Habaue, S. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 6287–6294. 121. Temma, T.; Takahashi, Y.; Yoshii, Y.; Habaue, S. Polym. J. 2007, 39, 524–530. 122. Temma, T.; Hatano, B.; Habaue, S. Polymer 2006, 47, 1845–1851. 123. Xie, X.; Phuan, P.-W.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2003, 42, 2168–2170. 124. Morgan, B. J.; Xie, X.; Phuan, P.-W.; Kozlowski, M. C. J. Org. Chem. 2007, 71, 6171–6182. 125. Addadi, L.; Cohen, M. D.; Lahav, M. J. Chem. Soc., Chem. Commun. 1975, 471–473. 126. Addadi, L.; Lahav, M. J. Am. Chem. Soc. 1979, 101, 2152–2156. 127. Addadi, L.; van Mil, J.; Lahav, M. J. Am. Chem. Soc. 1982, 104, 3422–3429. 128. Chung, C.-M.; Hasegawa, M. J. Am. Chem. Soc. 1991, 113, 7311–7316. 129. Beredjick, N.; Schuerch, C. J. Am. Chem. Soc. 1958, 80, 1933–1938. 130. De, B. B.; Sivaram, S.; Dhal, P. K. Macromolecules 1996, 29, 468–470. 131. Porter, N. A.; Swann, E.; Nally, J.; McPhail. A. T. J. Am. Chem. Soc. 1990, 112, 6740–6741. 132. Porter, N. A.; Breyer, R.; Swann, T.; Nally, J.; Pradhan, J.; Allen, T.; McPhail A. T. J. Am. Chem. Soc. 1991, 113, 7002–7010. 133. Porter, N. A.; Bruhnke, J. D.; Wu, W.-X.; Rosenstein, I. J.; Breyer, R. A. J. Am. Chem. Soc. 1991, 113, 7788–7790. 134. Porter, N. A.; Allen, T. R.; Breyer, R. A. J. Am. Chem. Soc. 1992, 114, 7676–7683. 135. Buese, M. A.; Hogen-Esch, T. E. J. Am. Chem. Soc 1985, 107, 4509–4513.

976 ASYMMETRIC POLYMERIZATION 136. Buese, M. A.; Hogen-Esch, T. E. Macromolecules 1984, 17, 118–119. 137. Wulff, G.; Hohn, J. Macromolecules 1982, 15, 1255–1261. 138. Wulff, G.; Dhal, P. K. Angew. Chem., Int. Ed. Engl. 1989, 28, 196–198. 139. Wulff, G.; Kemmerer, R.; Vogt, B. J. Am. Chem. Soc. 1987, 109, 7449–7457. 140. Wulff, G.; Dhal, P. K. Macromolecules 1990, 23, 4525–4527. 141. Yokota, K.; Kakuchi, T.; Sakurai, K.-I.; Iwata, Y.; Kawai, H. Makromol. Chem. Rapid Commun. 1992, 13, 343–349. 142. Obata, M.; Kakuchi, T.; Yokota, K. Macromolecules 1997, 30, 348–353. 143. Kakuchi, T.; Haba, O.; Uesaka, T.; Obata, M.; Morimoto, Y.; Yokota, K. Macromolecules 1996, 29, 3812–3817. 144. Kataoka, S.; Ando, T. Polym. Commun. 1984, 25, 24–26. 145. Kakuchi, T.; Kawai, H.; Katoh, S.; Haba, O.; Yokota, K. Macromolecules 1992, 25, 5545–5546. 146. Lee, Y.-K.; Onimura, K.; Tsutsumi, H.; Oishi, T. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 4315–4235. 147. Lee, Y.-K.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. J. 2000, 32, 1007–1016. 148. Lee, Y.-K.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. J. 2001, 33, 411–418. 149. Lee, Y.-K.; Yamashita, K.; Eto, M.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polymer 2002, 43, 7539–7547. 150. Lee, Y.-K.; Hisamitsu, N.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. J. 2002, 34, 9–17. 151. Lee, Y.-K.; Nakashima, Y.; Onimura, K.; Tsutsumi, H.; Oishi, T. J. Appl. Polym. Sci. 2003, 90, 1018–1025. 152. Lee, Y.-K.; Nakashima, Y.; Onimura, K.; Tsutsumi, H.; Oishi, T. Macromolecules 2003, 36, 4735–4742. 153. Zhou, H.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. J. 2000, 32, 552–559. 154. Zhou, H.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. J. 2001, 33, 227–235. 155. Onimura, K.; Zhang, Y.; Yagyu, M.; Oishi, T. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 4682–4692. 156. Zhang, Y.; Onimura, K.; Tsutsumi, H.; Oishi, T. Polym. J. 2004, 36, 878–887. 157. Oishi, T.; Zhang, Y.; Fukushima, T.; Onimura, K. Polym. J. 2005, 37, 453–463. 158. Gao, H.; Isobe, Y.; Onimura, K.; Oishi, T. Polym. J. 2006, 38, 1288–1291. 159. Gao, H.; Isobe, Y.; Onimura, K.; Oishi, T. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 3722–3738. 160. Doiuchi, T.; Dodoh, T.; Yamaguchi, H. Makromol. Chem. 1990, 191, 1253–1260. 161. Doiuchi, T.; Dodoh, T.; Yamaguchi, H. Makromol. Chem. 1992, 193, 221–228. 162. Bando, Y.; Minoura, Y. Eur. Polym. J. 1979, 15, 333–338. 163. Yamaguchi, H.; Iwama, T.; Hayashi, T.; Doiuchi, T. Makromol. Chem. 1990, 191, 1243–1251. 164. Kaminsky, W. Angew. Makromol. Chem. 1986, 145/146, 149–160. 165. Kaminsky, W.; Kupler, K.; Niedoba, S. Makromol. Chem., Makromol. Symp. 1986, 3, 377–387. 166. Okamoto, Y. CHEMTECH 1987, 17, 176–181. 167. Okamoto, Y.; Hatada, K. In Chromatographic Chiral Separations (Eds. Zief, M.; Crane, L. J.). New York: Marcel Dekker, 1988; pp. 199–218. 168. Yamamoto, C.; Okamoto, Y. Bull. Chem. Soc. Jpn. 2004, 77, 227–257. 169. Okamoto, Y.; Suzuki, K.; Ohta, K.; Hatada, K.; Yuki, H. J. Am. Chem. Soc. 1979, 101, 4763–4765. 170. Okamoto, Y.; Suzuki, K.; Yuki, H. J. Polym. Sci., Polym. Chem. Ed. 1980, 18, 3043–3051. 171. Okamoto, Y.; Yashima, E.; Nakano, T.; Hatada, K. Chem. Lett. 1987, 16, 759–762. 172. Nakano, T.; Okamoto, Y.; Hatada, K. J. Am. Chem. Soc. 1992, 114, 1318–1329. 173. Wulff, G.; Sczepan, R.; Steigel, A. Tetrahedron Lett. 1986, 27, 1991–1994.

REFERENCES 977

174. Okamoto, Y.; Okamoto, I.; Yuki, H. J. Polym. Sci., Polym. Lett. Ed. 1981, 19, 451–455. 175. Okamoto, Y.; Shohi, H.; Yuki, H. J. Polym. Sci., Polym. Lett. Ed. 1983, 21, 601–607. 176. Kanoh, S.; Suda, H.; Kawaguchi, N.; Motoi, M. Makromol. Chem. 1986, 187, 53–59. 177. Kanoh, S.; Kawaguchi, N.; Sumino, T.; Hongoh, Y.; Suda, H. J. Polym. Sci., Part A: Polym. Chem. 1987, 25, 1603–1618. 178. Kanoh, S.; Sumino, T.; Kawguchi, N.; Motoi, M.; Suda, H. Polym. J. 1988, 20, 539–547. 179. (a) Okamoto, Y.; Yashima, E.; Ishikura, M.; Hatada, K. Polym. J. 1987, 19, 1183–1190. (b) Okamoto, Y.; Nakano, T. In Catalytic Asymmetric Synthesis, 2nd ed. (Ed. Ojima, I.). Weinheim: Wiley-VCH, 2000; pp. 757–796. 180. Okamoto, Y.; Nakano, T.; Fukuoka, T.; Hatada, K. Polym. Bull. 1991, 26, 259–264. 181. Okamoto, Y.; Ishikura, M.; Hatada, K.; Yuki, H. Polym. J. 1983, 15, 851–853. 182. Okamoto, Y.; Mohri, H.; Nakano, T.; Hatada, K. Chirality 1991, 3, 277–284. 183. Okamoto, Y.; Mohri, H.; Ishikura, M.; Hatada, K.; Yuki, H. J. Polym. Sci., Polym. Symp. 1986, 74, 125–139. 184. Okamoto, Y.; Mohri, H.; Hatada, K. Polym. Bull. 1988, 20, 25–30. 185. Okamoto, Y.; Mohri, H.; Hatada, K. Chem. Lett. 1988, 1879–1882. 186. Nakano, T.; Taniguchi, K.; Okamoto, Y. Polym. J. 1997, 29, 540–544. 187. Mohri, H.; Okamoto, Y.; Hatada, K. Polym. J. 1989, 21, 719–724. 188. Ren, C.; Chen, C.; Xi, F.; Nakano, T.; Okamoto, Y. J. Polym. Sci., Part A: Polym. Chem. 1993, 31, 2721–2728. 189. Yashima, E.; Okamoto, Y.; Hatada, K. Polym. J. 1987, 19, 897–904. 190. Yashima, E.; Okamoto, Y.; Hatada, K. Macromolecules 1988, 21, 854–855. 191. Okamoto, Y.; Nakano, T.; Asakura, T.; Mohri, H.; Hatada, K. J. Polym. Sci., Part A: Polym. Chem. 1991, 29, 287–289. 192. Wu, J.; Nakano, T.; Okamoto, Y. J. Polym. Sci., Part A: Polym. Chem. 1998, 36, 2013–2019. 193. Nakano, T.; Matsuda, A.; Mori, M.; Okamoto, Y. Polym. J. 1996, 28, 330–336. 194. Nakano, T.; Satoh, Y.; Okamoto, Y. Polym. J. 1998, 30, 635–640. 195. Nakano, T.; Ueda, K.; Okamoto, Y. J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 1610–1614. 196. Okamoto, Y.; Mohri, H.; Nakano, T.; Hatada, K. J. Am. Chem. Soc. 1989, 111, 5952–5954. 197. Reggelin, M.; Shultz, M.; Holbach, M. Angew. Chem., Int. Ed. 2002, 41, 1614–1617. 198. Reggelin, M.; Doerr, S.; Klussmann, M.; Shultz, M.; Holbach, M. Proc. Natl. Acad. Sci. USA 2004, 101, 5461–5466. 199. Müller, C. A.; Hoffart, T.; Holbach, M.; Reggelin, M. Macromolecules 2005, 38, 5375–5380. 200. Cram, D. J.; Sogah, D. Y. J. Am. Chem. Soc. 1985, 107, 8301–8302. 201. Okamoto, Y.; Nakano, T.; Hatada, K. Polym. J. 1989, 21, 199–201. 202. Nakano, T.; Mori, M.; Okamoto, Y. Macromolecules 1993, 26, 867–868. 203. Nakano, T.; Matsuda, A.; Okamoto, Y. Polym. J. 1996, 28, 556–558. 204. Nakano, T.; Shikisai, Y.; Okamoto, Y. Polym. J. 1996, 28, 51–60. 205. Nakano, T.; Okamoto, Y. Macromolecules 1999, 32, 2391–2393. 206. Nakano, T.; Tsunematsu, K.; Okamoto, Y. Chem. Lett. 2002, 31, 42–43. 207. Nakano, T.; Kinjo, N.; Hidaka, Y.; Okamoto, Y. Polym. J. 2001, 33, 306–309. 208. Habaue, S.; Tanaka, T.; Okamoto, Y. Macromolecules 1995, 28, 5973–5974. 209. Tanaka, T.; Habaue, S.; Okamoto, Y. Polym. J. 1995, 27, 1202–1207. 210. Okamoto, Y.; Adachi, M.; Shohi, H.; Yuki, H. Polym. J. 1981, 13, 175–177. 211. Okamoto, Y.; Hayashida, H.; Hatada, K. Polym. J. 1989, 21, 543–549. 212. Shiohara, K.; Habaue, S.; Okamoto, Y. Polym. J. 1996, 28, 682–685.

978 ASYMMETRIC POLYMERIZATION 213. Shiohara, K.; Habaue, S.; Okamoto, Y. Polym. J. 1998, 30, 249–255. 214. Habaue, S.; Shiohara, K.; Uno, T.; Okamoto, Y. Enantiomer 1996, 1, 55–62. 215. Uno, T.; Shiohara, K.; Habaue, S.; Okamoto, Y. Polym. J. 1998, 30, 352–355. 216. Miyake, G. M.; Mariott, W. R.; Chen, E. Y.-X. J. Am. Chem. Soc. 2007, 129, 6724–6725. 217. Miyake, G. M.; Chen, E. Y.-X. Macromolecules 2008, 41, 3405–3416. 218. Hoshikawa, N.; Hotta, Y.; Okamoto, Y. J. Am. Chem. Soc. 2003, 125, 12380–12381. 219. Amano, Y.; Okamoto, Y. Polym. J. 2005, 37, 629–632. 220. Azam, A. K. M. F.; Kamigaito, M.; Okamoto, Y. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 1304–1315. 221. Wulff, G.; Wu, Y. Makromol. Chem. 1990, 191, 2993–3003. 222. Wulff, G.; Wu, Y. Makromol. Chem. 1990, 191, 3005–3010. 223. Ute, K.; Asada, T.; Nabeshima, Y.; Hatada, K. Acta Polymer. 1995, 46, 458–462. 224. Ute, K.; Asada, T.; Nabeshima, Y.; Hatada, K. Macromolecules 1993, 26, 7086–7088. 225. Nakano, T.; Nakagawa, O.; Tsuji, M.; Tanikawa, M.; Yade, T.; Okamoto, Y. Chem. Commun. 2004, 144–145. 226. Nakano, T.; Yade, T. J. Am. Chem. Soc. 2003, 125, 15474–15484. 227. Yade, T.; Nakano, T. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 561–572. 228. Akagi, K.; Piao, G.; Kaneko, S.; Sakamaki, K.; Shirakawa, H.; Kyotani, M. Science 1998, 282, 1683–1686. 229. Akagi, K.; Guo, S.; Mori, T.; Goh, M.; Piao, G.; Kyotani, M. J. Am. Chem. Soc. 2005, 127, 14647–14654. 230. Goh, M.; Kyotani, M.; Akagi, K. J. Am. Chem. Soc. 2007, 129, 8519–8527. 231. Aoki, T.; Kaneko, T.; Maruyama, N.; Sumi, A.; Takahashi, M.; Sato, T.; Teraguchi, M. J. Am. Chem. Soc. 2003, 125, 6346–6347. 232. Sato, T.; Aoki, T.; Teraguchi, M.; Kaneko, T.; Kim, S.-Y. Polymer 2004, 45, 8109–8114. 233. Kaneko, T.; Umeda, Y.; Jia, H.; Hadano, S.; Teraguchi, M.; Aoki, T. Macromolecules 2007, 40, 7098–7102. 234. Umeda, Y.; Kaneko, T.; Teraguchi, M.; Aoki, T. Chem. Lett. 2005, 35, 854–855. 235. Kaneko, T.; Umeda, Y.; Yamamoto, T.; Teraguchi, M.; Aoki, T. Macromolecules 2005, 38, 9420–9426. 236. For details, see: Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3–12 and references cited therein. 237. Vogl, O.; Miller, H. C.; Sharkey, W. H. Macromolecules 1972, 5, 658–659. 238. Corley, L. S.; Vogl, O. Polym. Bull. 1980, 3, 211–217. 239. Vogl, O.; Corley, L. S.; Harris, W. J.; Jaycox, G. D.; Zhang, J. Makromol. Chem. Suppl. 1985, 13, 1–12. 240. Zhang, J.; Jaycox, G. D.; Vogl, O. Polym. J. 1987, 19, 603–612. 241. Jaycox, G. D.; Vogl, O. Makromol. Chem., Rapid Commun. 1990, 11, 61–66. 242. Ute, K.; Hirose, K.; Kashimoto, H.; Hatada, K.; Vogl, O. J. Am. Chem. Soc. 1991, 113, 6305–6306. 243. Ute, K.; Hirose, K.; Kashimoto, H.; Nakayama, K.; Hatada, K.; Vogl, O. Polym. J. 1993, 25, 1175–1186. 244. Vogl, O.; Xi, F.; Vass, F.; Ute, K.; Nishimura, T.; Hatada, K. Macromolecules 1989, 22, 4658–4660. 245. Ute, K.; Oka, K.; Okamoto, Y.; Hatada, K.; Xi, F.; Vogl, O. Polym. J. 1991, 23, 1419–1424. 246. Choi, S.-H.; Yashima, E.; Okamoto, Y. Macromolecules 1996, 29, 1880–1885. 247. Millich, F. Chem. Rev. 1972, 72, 101–113. 248. Mullich, F. Adv. Polym. Sci. 1975, 19, 117–141.

REFERENCES 979

249. Millich, F. Macromol. Rev. 1980, 15, 207–253. 250. Nolte, R. J. M.; van Beijnen, A. J. M.; Drenth, W. J. Am. Chem. Soc. 1974, 96, 5932–5933. 251. van Beijnen, A. J. M.; Nolte, R. J. M.; Drenth, W.; Hezemans A. M. F. Tetrahedron 1976, 32, 2017–2019. 252. Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Chem. Soc., Chem. Commun. 1986, 1789–1791. 253. Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Am. Chem. Soc. 1988, 110, 6818–6825. 254. Deming, T. J.; Novak, B. M. J. Am Chem. Soc. 1992, 114, 7926–7927. 255. Takei, F.; Yanai, K.; Onitsuka, K.; Takahashi, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1554–1556. 256. Takei, F.; Yanai, K.; Onitsuka, K.; Takahashi, S. Chem. Eur. J. 2000, 6, 983–993. 257. Takei, F.; Onitsuka, K.; Kobayashi, N.; Takahashi, S. Chem. Lett. 2000, 29, 914–915. 258. Takei, F.; Nakamura, S.; Onitsuka, K.; Ishida, A.; Tojo, S.; Majima, T.; Takahashi, S. Chem. Lett. 2003, 32, 506–507. 259. Fujitsuka, M.; Okada, A.; Tojo, S.; Takei, F.; Onitsuka, K.; Takahashi, S.; Majima, T. J. Phys. Chem., B 2004, 108, 11935–11941. 260. Takei, F.; Hayashi, H.; Onitsuka, K.; Kobayashi, N.; Takahashi, S. Angew. Chem., Int. Ed. 2001, 40, 4092–4094. 261. Ishikawa, M.; Maeda, K.; Yashima, E. J. Am. Chem. Soc. 2002, 124, 7448–7458. 262. Ishikawa, M.; Maeda, K.; Mitsutsuji, Y.; Yashima, E. J. Am. Chem. Soc. 2004, 126, 732–733. 263. Ishikawa, M.; Taura, D.; Maeda, K.; Yashima, E. Chem. Lett. 2004, 33, 550–551. 264. Maeda, K.; Ishikawa, M.; Yashima, E. J. Am. Chem. Soc. 2004, 126, 15161–15166. 265. Ito, Y.; Ihara, E.; Murakami, M. Angew. Chem., Int. Ed. Engl. 1992, 31, 1509–1510. 266. Ito, Y.; Ihara, E.; Murakami, Y.; Sisido, M. Macromolecules 1992, 25, 6810–6813. 267. Ito, Y.; Kojima, Y.; Murakami, M. Tetrahedron Lett. 1993, 34, 8279–8282. 268. Ito, Y.; Kojima, Y.; Suginome, M.; Murakami, M. Heterocycle 1996, 42, 597–615. 269. Ito, Y.; Kojima, Y.; Murakami, M.; Suginome, M. Bull. Chem. Soc. Jpn. 1997, 70, 2801–2806. 270. Ito, Y.; Ohara, T.; Shima, R.; Suginome, M. J. Am. Chem. Soc. 1996, 118, 9188–9189. 271. Ito, Y.; Miyake, T.; Ohara, T.; Suginome, M. Macromolecules 1998, 31, 1697–1699. 272. Ito, Y.; Miyake, T.; Hatano, S.; Shima, R.; Ohara, T.; Suginome, M. J. Am. Chem. Soc. 1998, 120, 11880–11893. 273. Ito, Y.; Miyake, T.; Suginome, M. Macromolecules 2000, 33, 4034–4038. 274. Suginome, M.; Collet, S.; Ito, Y. Org. Lett. 2002, 4, 351–354. 275. Shashoua, V. E. J. Am. Chem. Soc. 1959, 81, 3156. 276. Shashoua, V. E.; Sweeny, W.; Tietz, R. F. J. Am. Chem. Soc. 1960, 82, 866–873. 277. Bur, A.; Fetters, L. J. Chem. Rev. 1976, 76, 727–746. 278. Mayer, S.; Zentel, R. Prog. Polym. Sci. 2001, 26, 1973–2013. 279. Okamoto, Y.; Matsuda, M.; Nakano, T.; Yashima, E. Polym. J. 1993, 25, 391–396. 280. Okamoto, Y.; Matsuda, M.; Nakano, T.; Yashima, E. J. Polym. Sci., Part A: Polym. Chem. 1994, 32, 309–315. 281. Maeda, K.; Matsuda, M.; Nakano, T.; Okamoto, Y. Polym. J. 1995, 27, 141–146. 282. Sakai, R.; Otsuka, I.; Satoh, T.; Kakuchi, R.; Kaga, H.; Kakuchi, T. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 325–334. 283. Maeda, K.; Yamamoto, N.; Yashima, E. Macromolecules 1998, 31, 5924–5926. 284. Yashima, E.; Maeda, K.; Nishimura, T. Chem. Eur. J. 2004, 10, 42–51. 285. Sakai, R.; Satoh, T.; Kakuchi, R.; Kaga, H.; Kakuchi, T. Macromolecules 2003, 36, 3709–3713. 286. Sakai, R.; Satoh, T.; Kakuchi, R.; Kaga, H.; Kakuchi, T. Macromolecules 2004, 37, 3996–4003.

980 ASYMMETRIC POLYMERIZATION 287. Tian, G.; Lu, Y.; Novak, B. M. J. Am. Chem. Soc. 2004, 126, 4082–4083. 288. Tang, H.-Z.; Boyle, P. D.; Novak, B. M. J. Am. Chem. Soc. 2005, 127, 2136–2142. 289. Goto, H.; Akagi, K. Macromol. Rapid Commun. 2004, 25, 1482–1486. 290. Goto, H.; Nomura, N.; Akagi, K. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 4298–4302. 291. Goto, H.; Akagi, K. Macromolecules 2005, 38, 1091–1098. 292. Goto, H.; Akagi, K. Angew. Chem., Int. Ed. 2005, 44, 4322–4328. 293. Obata, K.; Kabuto, C.; Kira, M. J. Am. Chem. Soc. 1997, 119, 11345–11346. 294. Obata, K.; Kira, M. Macromolecules 1998, 31, 4666–4668. 295. Sanji, T.; Takase, K.; Sakurai, H. J. Am. Chem. Soc. 2001, 123, 12690–12691. 296. Sanji, T.; Takase, K.; Sakurai, H. Bull. Chem. Soc. Jpn. 2004, 77, 1607–1611. 297. Sanji, T.; Takase, K.; Sakurai, H. Polym. Bull. 2007, 59, 169–175. 298. Pino, P.; Ciardelli, F.; Lorenzi, G. P.; Montagnoli, G. Makromol. Chem. 1963, 61, 207–224. 299. Zambelli, A.; Grassi, A.; Galimberti, M.; Perego, G. Makromol. Chem. Rapid Commun. 1992, 13, 269–275. 300. Pieroni, O.; Ciardelli, F.; Botteghi, C.; Lardicci, L.; Salvadori, P.; Pino, P. J. Polym. Sci., Part C 1969, 22, 993–1007. 301. Thiên, N.-T.; Suter, U. W.; Pino, P. Makromol. Chem 1983, 184, 2335–2346. 302. Allio, A.; Pino, P. Helv. Chim. Acta 1974, 57, 616–622. 303. Toda, F.; Mori, K. J. Chem. Soc., Chem. Commun. 1986, 1059–1060. 304. Okamoto, Y.; Yashima, E.; Hatada, K. J. Polym. Sci., Part C, Polym. Lett. 1987, 25, 297–301. 305. Okamoto, Y.; Nishikawa, M.; Nakano, T.; Yashima, E.; Hatada, K. Macromolecules 1995, 28, 5135–5138. 306. Okamoto, Y.; Nakano, T.; Ono, E.; Hatada, K. Chem. Lett. 1991, 21, 525–528. 307. Nakano, T.; Okamoto, Y.; Sogah, D. Y.; Zheng, S. Macromolecules 1995, 28, 8705–8706. 308. Wulff, G.; Gladow, S.; Kühneweg, B.; Krieger, S. Macromol. Symp. 1996, 101, 355–362. 309. Zheng, S.; Sogah, D. Y. Tetrahedron 1997, 53, 15469–15485. 310. Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 165–180. 311. Aoki, T.; Kokai, M.; Shinohara, K.; Oikawa, E. Chem. Lett. 1993, 23, 2009–2012. 312. Yashima, E.; Huang, S; Matsushima, T.; Okamoto, Y. Maromolecules 1995, 28, 4184–4193. 313. Percec, V.; Rudick, J. G.; Peterca, M.; Wagner, M.; Obata, M.; Mitchell, C. M.; Cho, W.-D.; Balagurusamy, V. S. K.; Heiney, P. A. J. Am. Chem. Soc. 2005, 127, 15257–15264. 314. Percec, V.; Aqad, E.; Peterca, M.; Rudick, J. G.; Lemon, L.; Ronda, J. C.; De, B. B.; Heiney, P. A.; Meijer, E. W. J. Am. Chem. Soc. 2006, 128, 16365–16372. 315. Cheuk, K. K. L.; Lam, J. W. Y.; Li, B. S.; Xie, Y.; Tang, B. Z. Macromolecules 2007, 40, 2633–2642. 316. Maeda, K.; Tanaka, K.; Morino, K.; Yashima, E. Macromolecules 2007, 40, 6783–6785. 317. Liu, J.-H.; Yan, J.-J.; Chen, E.-Q.; Lam, J. W. Y.; Dong, Y.-P.; Li, D.-H.; Tang, B. Z. Polymer 2008, 49, 3366–3370. 318. Aoki, T.; Shinohara, K.; Kaneko, T.; Oikawa, E. Macromolecules 1996, 29, 4192–4198. 319. Aoki, T.; Kobayashi, Y.; Kaneko, T.; Oikawa, E.; Yamamura, Y.; Fujita, Y.; Teraguchi, M.; Nomura, R.; Masuda, T. Macromolecules 1999, 32, 79–85. 320. Lam, J. W. Y.; Dong, Y.; Cheuk, K. K. L.; Tang, B. Z. Macromolecules 2003, 36, 7927–7938. 321. Lam, J. W. Y.; Dong, Y.; Cheuk, K. K. L.; Law, C. C. W.; Lai, L. M.; Tang, B. Z. Macromolecules 2004, 37, 6695–6704. 322. Nakako, H.; Nomura, R.; Tabata, M.; Masuda, T. Macromolecules 1999, 32, 2861–2864. 323. Nomura, R.; Fukushima, Y.; Nakako, H.; Masuda, T. J. Am. Chem. Soc. 2000, 122, 8830–8836.

REFERENCES 981

324. Nakako, H.; Miyahara, Y.; Nomura, R.; Tabata, M.; Masuda, T. Macromolecules 2000, 33, 3978–3982. 325. Nakako, H.; Nomura, R.; Masuda, T. Macromolecules 2001, 34, 1496–1502. 326. Suzuki, Y.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromolecules 2007, 490, 1864–1867. 327. Nomura, R.; Tabei, J.; Masuda, T. J. Am. Chem. Soc. 2001, 123, 8430–8431. 328. Nomura, R.; Tabei, J.; Masuda, T. Macromolecules 2002, 35, 2955–2961. 329. Tabei, J.; Nomura, R.; Masuda, T. Macromolecules 2002, 35, 5405–5409. 330. Nomura, R.; Tabei, J.; Nishiura, S.; Masuda, T. Macromolecules 2003, 36, 561–564. 331. Tabei, J.; Nomura, R.; Masuda, T. Macromolecules 2003, 36, 573–577. 332. Gao, G.; Sanda, F.; Masuda, T. Macromolecules 2003, 36, 3932–3937. 333. Gao, G.; Sanda, F.; Masuda, T. Macromolecules 2003, 36, 3938–3943. 334. Tabei, J.; Nomura, R.; Sanda, F.; Masuda, T. Macromolecules 2004, 37, 1175–1179. 335. Sanda, F.; Araki, H.; Masuda, T. Macromolecules 2004, 37, 8510–8516. 336. Zhao, H.; Sanda, F.; Masuda, T. Macromolecules 2004, 37, 8888–8892. 337. Zhao, H.; Sanda, F.; Masuda, T. Macromolecules 2004, 37, 8893–8896. 338. Deng, J.; Tabei, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromolecules 2004, 37, 9715–9721. 339. Sanda, F.; Gao, G.; Masuda, T. Macromol. Biosci. 2004, 4, 570–574. 340. Tabei, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromolecules 2005, 38, 5860–5867. 341. Sanda, F.; Terada, K.; Masuda, T. Macromolecules 2005, 38, 8149–8154. 342. Tabei, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromolecules 2005, 38, 9448–9454. 343. Tabei, J.; Nomura, R.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromol. Chem. Phys. 2005, 206, 323–332. 344. Zhao, H.; Sanda, F.; Masuda, T. Macromol. Chem. Phys. 2005, 206, 1653–1658. 345. Zhao, H.; Sanda, F.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 5168–5176. 346. Sanda, F.; Araki, H.; Masuda, T. Chem. Lett. 2005, 34, 1642–1643. 347. Tabei, J.; Shiotsuki, M.; Sato, T.; Sanda, F.; Masuda, T. Chem. Eur. J. 2005, 11, 3591–3598. 348. Zhao, H.; Sanda, F.; Masuda, T. Polymer 2005, 46, 2841–2846. 349. Rahim, E. A.; Sanda, F.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 810–819. 350. Sanda, F.; Fujii, T.; Tabei, J.; Shiotsuki, M.; Masuda, T. Macromol. Chem. Phys. 2008, 209, 112–118. 351. Suzuki, Y.; Tabei, J.; Shiotsuki, M.; Inai, Y.; Sanda, F.; Masuda, T. Macromolecules 2008, 41, 1086–1093. 352. Nomura, R.; Nishiura, S.; Tabei, J.; Sanda, F.; Masuda, T. Macromolecules 2003, 36, 5076–5080. 353. Sanda, F.; Nishiura, S.; Shiotsuki, M.; Masuda, T. Macromolecules 2005, 38, 3075–3078. 354. Yue, D.; Fujii, T.; Terada, K.; Tabei, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromol. Rapid Commun. 2006, 27, 1460–1464. 355. Yue, D.; Shiotsuki, M.; Sanda, F.; Masuda, T. Polymer 2007, 48, 68–73. 356. Yue, D.; Fujii, T.; Terada, K.; Tabei, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 1515–1524. 357. Kwak, G.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2000, 39, 71–77. 358. Kwak, G.; Masuda, T. Macromolecules 2000, 33, 6633–6635. 359. Zhao, H.; Sanda, F.; Masuda, T. Macromol. Chem. Phys. 2006, 207, 1921–1926. 360. Qu, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromol. Chem. Phys. 2007, 208, 823–832. 361. Zhao, H.; Sanda, F.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2007, 245, 1691–1698. 362. Sanda, F.; Kawasaki, R.; Shiotsuki, M.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2007, 245, 4450–4458.

982 ASYMMETRIC POLYMERIZATION 363. Hu, Y.; Liu, R.; Sanda, F.; Masuda, T. Polym. J. 2008, 40, 143–147. 364. Hu, Y.; Liu, R.; Sanda, F.; Masuda, T. Polym. Bull. 2008, 60, 159–167. 365. Liu, R.; Sanda, F.; Masuda, T. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 4183–4192. 366. Teraguchi, M.; Masuda, T. Macromolecules 2002, 35, 1149–1151. 367. Teraguchi, M.; Suzuki, J.; Kaneko, T.; Aoki, T.; Masuda, T. Macromolecules 2003, 36, 9694– 9697. 368. Teraguchi, M.; Mottate, K.; Kim, S.-Y.; Aoki, T.; Kaneko, T.; Hadano, S.; Masuda, T. Macromolecules 2005, 38, 6367–6373. 369. van. Beijnen, A. J. M.; Nolte, R. J. M.; Drenth, W.; Hezemans, A. M. F.; van de Coolwijk, P. J. F. M. Macromolecules 1980, 13, 1386–1391. 370. Harada, T.; Cleij, M. C.; Nolte, R. J. M.; Hezemans, A. M. F.; Drenth, W. J. Chem. Soc., Chem. Commun. 1984, 726–727. 371. Kamer, P. C. J.; Cleij, M. C.; Nolte, R. J. M.; Harada, T.; Hezemans, A. M. F.; Drenth, W. J. Am. Chem. Soc. 1988, 110, 1581–1587. 372. Cornelissen, J. J. L. M.; Donners, J. J. J. M.; de Gelder, R.; Graswinckel, W. S.; Metselaar, G. A.; Rowan, A. E.; Sommerdijk, N. A. J. M.; Nolte, R. J. M. Science 2001, 293, 676–680. 373. Samorí, P.; Ecker, C.; Gössl, I.; de Witte, P. A. J.; Cornelissen, J. J. L. M.; Metselaar, G. A.; Otten, M. B. J.; Rowan, A. E.; Nolte, R. J. M.; Rabe, J. P Macromolecules 2002, 35, 5290–5294. 374. Kajitani, T.; Okoshi, K.; Sakurai, S.; Kumaki, J.; Yashima, E. J. Am. Chem. Soc. 2006, 128, 708–709. 375. Kajitani, T.; Okoshi, K.; Yashima, E. Macromolecules 2008, 41, 1601–1611. 376. Hida, N.; Takei, F.; Onitsuka, K.; Shiga, K.; Asaoka, S.; Iyoda, T.; Takahashi, S. Angew. Chem., Int. Ed. 2003, 42, 4349–4352. 377. Goodman, M.; Chen, S.-C. Macromolecules 1970, 3, 398–402. 378. Goodman, M.; Chen, S.-C. Macromolecules 1971, 4, 625–629. 379. Green, M. M.; Gross, R. A.; Crosby, C., III.; Schilling, F. C. Macromolecules 1987, 20, 992–999. 380. Green, M. M.; Gross, R. A.; Cook, R.; Schilling, F. C. Macromolecules 1987, 20, 2636–2638. 381. Green, M. M.; Reidy, M. P.; Johnson, R. J.; Darling, G.; O’Leary, D. J.; Willson, G. J. Am. Chem. Soc. 1989, 111, 6452–6454. 382. Green, M. M.; Andreola, C.; Munoz, B.; Reidy, M. P.; Zero, K. J. Am. Chem. Soc. 1988, 110, 4063–4065. 383. Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science 1995, 268, 1860–1866. 384. Green, M. M.; Garetz, B. A.; Munoz, B.; Chang, S.; Hoke S.; Cooks, R. G. J. Am. Chem. Soc. 1995, 117, 4181–4182. 385. Maeda, K.; Okamoto, Y. Macromolecules 1998, 31, 1046–1052. 386. Maeda, K.; Okamoto, Y. Macromolecules 1998, 31, 5164–5166. 387. Hino, K.; Maeda, K.; Okamoto, Y. J. Phys. Org. Chem. 2000, 13, 361–367. 388. Schlitzer, D. S.; Novak, B. M. J. Am. Chem. Soc. 1998, 120, 2196–2197. 389. Fujiki, M. Macromol. Rapid Commun. 2001, 22, 539–563. 390. Fujiki, M.; Koe, J. R.; Terao, K.; Sato, T.; Teramoto, A.; Watanabe, J. Polym. J. 2003, 35, 297–344. 391. Fujiki, M. J. Organomet. Chem. 2003, 685, 15–34. 392. Sato, T.; Terao, K.; Teramoto, A.; Fujiki, M. Polymer 2003, 44, 5477–5495. 393. Frey, H.; Möller, M.; Matyjaszewski, K. Macromolecules 1994, 27, 1814–1818. 394. Fujiki, M. J. Am. Chem. Soc. 1994, 116, 6017–6018. 395. Fujiki, M. J. Am. Chem. Soc. 1994, 116, 11976–11981.

REFERENCES 983

396. Fujiki, M. J. Am. Chem. Soc. 2000, 122, 3336–3343. 397. Toyoda, S.; Fujiki, M. Chem. Lett. 1999, 699–700. 398. Nakashima, H.; Fujiki, M.; Koe, J. R. Macromolecules 1999, 32, 7707–7709. 399. Nakashima, H.; Fujiki, M.; Koe, J. R.; Motonaga, M. J. Am. Chem. Soc. 2001, 123, 1963–1969. 400. Toyoda, S.; Fujiki, M. Macromolecules 2001, 34, 640–644. 401. Peng, W.; Motonaga, M.; Koe, J. R. J. Am. Chem. Soc. 2004, 126, 13822–13826. 402. Koe, J. R.; Fujiki, M.; Nakashima, H. J. Am. Chem. Soc. 1999, 121, 9734–9735. 403. Ma, L.; Hu, Q.-S.; Vitharana, D.; Wu, C.; Kwan, C. M. S.; Pu, L. Macromolecules 1997, 30, 204–218. 404. Puts, R. D.; Sogah, D. Y. Macromolecules 1997, 30, 6826–6836. 405. Takata, T.; Furusho, Y.; Murakawa, K.; Endo, T.; Matsuoka, H.; Hirasa, T.; Matsuo, J.; Sisido, M. J. Am. Chem. Soc. 1998, 120, 4530–4531. 406. Murakawa, K.; Furusho, Y.; Takata, T. Chem. Lett. 1999, 28, 93–94. 407. Takata, T.; Murakawa, K.; Furusho, Y. Polym. J. 1999, 31, 1051–1056. 408. Liu, R.; Sanda, F.; Masuda, T. Macromolecules 2008, 41, 5089–5097. 409. Tsuruta, T. J. Polym. Sci., Part D 1972, 6, 179–250. 410. Pino, P.; Lorenzi, G. P.; Lardicci, L. Chim. Ind. (Milan) 1960, 42, 712–721. 411. Pino, P.; Ciardelli, F.; Lorenzi, G. P.; Natta, G. J. Am. Chem. Soc. 1962, 84, 1487–1488. 412. Pino, P.; Montagnoli, G.; Ciardelli, F.; Benedetti, E. Makromol. Chem. 1966, 93, 158–179. 413. Pino, P.; Ciardelli, F.; Montagnoli, G. J. Polym. Sci., Part C 1968, 16, 3265–3277. 414. Pino, P.; Ciardelli, F.; Lorenzi, G. P. J. Am. Chem. Soc. 1963, 85, 3888–3890. 415. Pino, P.; Ciardelli, F.; Lorenzi, G. P. J. Polym. Sci., Part C 1963, 4, 21–36. 416. Pino, P.; Ciardelli, F.; Lorenzi, G. P. Makromol. Chem. 1964, 70, 182–190. 417. Vizzini, J.; Ciardelli, F.; Chien, C. W. Macromolecules 1992, 25, 108–115. 418. Ciardelli, F.; Carlini, C.; Montagnoli, G. Macromolecules 1969, 2, 296–301. 419. Chiellini, E. Macromolecules 1970, 3, 527–533. 420. Higashimura, T.; Hirokawa, Y. J. Polym. Sci., Polym. Chem. Ed. 1977, 15, 1137–1143. 421. Okamoto, Y.; Ohta, K.; Yuki, H. Chem. Lett. 1977, 6, 617–620. 422. Okamoto, Y.; Urakawa, K.; Ohta, K.; Yuki, H. Macromolecules 1978, 11, 719–723. 423. Okamoto, Y.; Ohta, K.; Yuki, H. Macromolecules 1978, 11, 724–727. 424. Okamoto, Y.; Suzuki, K.; Ohta, K.; Yuki, H. J. Polym. Sci., Polym. Lett. Ed. 1979, 17, 293–298. 425. Okamoto, Y.; Suzuki, K.; Kitayama, T.; Yuki, H.; Kageyama, H.; Miki, K.; Tanaka, N.; Kasai, N. J. Am. Chem. Soc. 1982, 104, 4618–4624. 426. Suda, H.; Kanoh, S.; Murose, N.; Goka, S.; Motoi, M. Polym. Bull. 1983, 10, 162–167. 427. Kanoh, S.; Kawaguchi, N.; Suda, H. Makromol. Chem. 1987, 188, 463–474. 428. Kanoh, S.; Goka, S.; Murose, N.; Kubo, H.; Kondo, M.; Sugino, T.; Motoi, M.; Suda, H. Polym. J. 1987, 19, 1045–1065. 429. Okamoto, Y.; Gamaike, H.; Yuki, H. Makromol. Chem. 1981, 182, 2737–2746. 430. Okamoto, Y.; Urakawa, K.; Yuki, H. J. Polym. Sci., Polym. Chem. Ed. 1981, 19, 1385–1395. 431. Okamoto, Y.; Yashima, E.; Hatada, K.; Kageyama, H.; Miki, K.; Kasai, N. J. Polym. Sci., Polym. Chem. Ed. 1984, 22, 1831–1837. 432. Yashima, E.; Okamoto, Y.; Hatada, K.; Kageyama, H.; Kasai, N. Bull. Chem. Soc. Jpn. 1988, 61, 2071–2077. 433. Nakano, T.; Kinjo, N.; Hidaka, Y.; Okamoto, Y. Polym. J. 1999, 31, 464–469. 434. Tsuji, M.; Sakai, R.; Satoh, T.; Kaga, H.; Kakuchi, T. Macromolecules 2002, 35, 8255–8257. 435. Tsuji, M.; Sakai, R.; Satoh, T.; Kaga, H.; Kakuchi, T. Polym. J. 2003, 35, 84–87.

984 ASYMMETRIC POLYMERIZATION 436. Tsuji, M.; Aoki, T.; Sakai, R.; Satoh, T.; Kaga, H.; Kakuchi, T. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 4563–4569. 437. Inoue, S.; Tsuruta, T.; Furukawa, J. Makromol. Chem. 1962, 53, 215–218. 438. Tsuruta, T.; Inoue, S.; Yoshida, N.; Furukawa, J. Makromol. Chem. 1962, 55, 230–231. 439. Furukawa, J.; Kumata, Y.; Yamada, K.; Fueno, T. J. Polym. Sci., Part C 1968, 23, 711–719. 440. Nakaniwa, M.; Kameoka, M.; Ozaki, K.; Furukawa, J. Makromol. Chem. 1970, 138, 209–214. 441. Coulon, C.; Spassky, N.; Sigwalt, P. Polymer 1976, 17, 821–827. 442. Haubenstock, H.; Panchalingam, V.; Odian, G. Makromol. Chem. 1987, 188, 2789–2799. 443. Vincens, V.; Le Borgne, A.; Spassky, N. Makromol. Chem., Makromol. Symp. 1991, 47, 285–291. 444. Vincens, V.; Le Borgne, A.; Spassky, N. Makromol. Chem., Rap. Commun. 1989, 10, 623–628. 445. Hirahata, W.; Thomas, R. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2008, 130, 17658–17659. 446. Furukawa, J.; Kawabata, N.; Kato, A. J. Polym. Sci., Polym. Lett. 1967, 5, 1073–1076. 447. Sepulchre, M.; Spassky, N.; Sigwalt, P. Macromolecules, 1972, 5, 92–94. 448. Sepulchre, M.; Spassky, N.; Mark, C.; Schurig, V. Makromol. Chem., Rapid Commun. 1981, 2, 261–266. 449. Sepulchre, M. Makromol. Chem. 1987, 188, 1583–1596. 450. Aliev, A. D.; Solomantia, I. P.; Krentsel, B. A. Macromolecules 1973, 6, 797–801. 451. Dumas, P.; Sigwalt, P.; Guerin, P. Makromol. Chem. 1981, 182, 2225–2231. 452. Dumas, P.; Sigwalt, P. Chirality 1991, 3, 484–491. 453. Imai, T.; Hayakawa, K.; Satoh, T.; Kaga, H.; Kakuchi, T. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 3443–3448. 454. Spassky, N.; Le Borgne, A.; Reix, M.; Prud’homme, R. E.; Bigdeli, E.; Lenz, R. W. Macromolecules 1978, 11, 716–719. 455. Le Borgne, A.; Spassky, N.; Sigwalt, P. Polym. Bull. 1979, 1, 825–832. 456. Le Borgne, A.; Greiner, D.; Prud’homme, R. E.; Spassky, N. Eur. Polym. J. 1981, 17, 1103–1106. 457. Le Borgne, A.; Spassky, N. Polymer 1989, 30, 2312–2319. 458. Takeichi, T.; Hieda, Y.; Takayama, Y. Polym. J. 1988, 20, 159–162. 459. Breteler, M. R.; Zhong, Z.; Dijkstra, P. J.; Palmans, A. R. A.; Peeters, J.; Feijen, J. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 429–436. 460. Kobayashi, S.; Uyama, H.; Kimura, S. Chem. Rev. 2001, 101, 3793–3818. 461. Verma, I. K.; Albertsson, A.-C.; Rajkhowa, R.; Srivastava, R. K. Prog. Polym. Sci. 2005, 30, 949–981. 462. Matsumura, S. Adv. Polym. Sci. 2006, 194, 95–132. 463. Albertsson, A.-C.; Srivastava, R. K. Adv. Drug Deliv. Rev. 2008, 60, 1077–1093. 464. Svirkin, Y. Y.; Xu, J.; Gross, R. A.; Kaplan, D. L; Swift, G. Macromolecules 1996, 29, 4591–4597. 465. Kikuchi, H.; Uyama, H.; Kobayashi, S. Macromolecules 2000, 33, 8971–8975. 466. Al-Azemi, T. F.; Kondaveti, L.; Bisht, K. S. Macromolecules 2002, 35, 3380–3386. 467. Kobayashi, S. Macromol. Symp. 2006, 240, 178–185. 468. van Buijtenen, J.; van As, B. A. C.; Verbruggen, M.; Roumen, L.; Vekemans, J. A. J. M.; Pieterse, K.; Hilbers, P. A. J.; Hulshof, L. A.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2007, 129, 7393–7398. 469. Spassky, H.; Wisniewski, M.; Pluta, C.; Le Borgne, A. Macromol. Chem. Phys. 1996, 197, 2627–2637. 470. Dechy-Cabaret, O.; Martin-Vaca, B.; Bourissou, D. Chem. Rev. 2004, 104, 6147–6176. 471. Wu, J.; Yu, T.-L.; Chen, C.-T.; Lin, C.-C. Coord. Chem. Rev. 2006, 250, 602–626.

13.5. SUMMARY AND OUTLOOK 985

472. Gupta, A. P.; Kumar, V. Eur. Polym. J. 2007, 43, 4053–4074. 473. Platel, R. H.; Hodgson, L. M.; Williams, C. K. Polym. Rev. 2008, 48, 11–63. 474. Kricheldorf, H. R. Angew. Chem., Int. Ed. 2006, 45, 5752–5784. 475. Lundberg, R. D.; Doty, P. J. Am. Chem. Soc. 1957, 79, 3961–3972. 476. Bührer, H. G.; Elias, H. G. Makromol. Chem. 1973, 169, 145–162. 477. Oguni, N.; Kuboyama, H.; Nakamura, A. J. Polym. Sci., Polym. Chem. Ed. 1983, 21, 1559–1565. 478. Tsuruta, T.; Inoue, S.; Matsuura, K. Makromol. Chem. 1963, 63, 219–221. 479. Matsuura, K.; Inoue, S.; Tsuruta, T. Makromol. Chem. 1964, 80, 149–157. 480. Makino, T.; Inoue, S.; Tsuruta, T. Makromol. Chem. 1971, 150, 137–162. 481. Yamashita, S.; Yamawaki, N.; Tani, H. Macromolecules 1974, 7, 724–727. 482. Cheng, J.; Deming, T. J. Macromolecules 1999, 32, 4745–4747. 483. Seidel, S. W.; Deming, T. J. Macromolecules 2003, 36, 969–972. 484. Margolin, A. L.; Crenne, J.-Y.; Klivanov, A. M. Tetrahedron Lett. 1987, 28, 1607–1610. 485. Wallace, J. S.; Morrow, C. J. J. Polym. Sci., Part A: Polym. Chem. 1989, 27, 2553–2567. 486. Khani, D., Kohn, D. H. J. Polym. Sci., Part A: Polym. Chem. 1993, 31, 2887–2897. 487. Al-Azemi, T. F.; Kondaveti, L.; Bisht, K. S. Macromolecules 2002, 35, 3380–3386. 488. Peeters, J.; Palmans, A. R. A.; Veld, M.; Scheijen, F.; Heise, A.; Meijer, E. W. Biomacromolecules 2004, 5, 1862–1868. 489. Hilker, I.; Rabani, G.; Verzijl, G. K. M.; Palmans, A. R. A. Heise, A. Angew. Chem., Int. Ed. 2006, 45, 2130–2132. 490. van As, B. A. C.; van Buijtenen, J.; Mes, T.; Palmans, A. R. A.; Meijer, E. W. Chem. Eur. J. 2007, 13, 8325–8332. 491. van As, B. A. C.; van Buijtenen, J.; Heise, A.; Broxterman, Q. B.; Verzijl, G. K. M.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2005, 127, 9964–9965. 492. van Buijtenen, J.; van As, B. A. C.; Meuldijk, J.; Palmans, A. R. A.; Vekemans, J. A. J. M.; Hulshof, L. A.; Meijer, E. W. Chem. Commun. 2006, 3169–3171.

INDEX

(Z)-2-(Acetamido) acrylic acid, 352 (Z)-2-(Acetamido) cinnamic acid, 352 2-acetylthiophene derivatives, 404 Acid–base bifunctional organic catalysts for controlling selectivity, 84–87 from chiral cyclic diamines, 69–71 from cinchona alkaloids, 71–84 from natural and synthetic molecules, 87–90 Acid catalysts, 60–62 (S)-Acromelobic acid, 363 1,4-Addition reaction iminium-catalyzed, 42–44 with 1,3-dicarbonyl compounds, 43 with malonates, 43 of O-methoxyamine, 131 with nitroalkanes, 43 with nucleophile, 42 Aldol reactions enamine-catalyzed, 46–48 proline-catalyzed, 45 Alkenes, 1,2-disubstituted and 1,2-trisubstituted, 216 2-Alkyl-tetralones, 543 3-Alkylated oxindoles, 579 Alkylidenes, molybdenum-based, 741 2-Alkynylpyrimidine-5-carbaldehyde, 908, 918

(Z)-Allyl dicarbonates, 581 O(9)-Allyl-N-9-anthracenylmethylcinchonidinium bromide, 471 Allylic alkylations Mo(II)- and W(II)-catalyzed, 578 Allylic amination catalysts nickel, 228 palladium, 228 phosphoramidate ligand, 229 ruthenium, 228 TBD, 231 triphenylboron (BPh3), 229 Allylic substitution, enantioselective applications of, 499–500 copper-catalyzed, 612–631 decarboxylative, 548–552 with enolates as nucleophiles, 540–548 iridium-catalyzed, 595–611 iron-catalyzed, 582–583 molybdenum-catalyzed, 561–578 nickel-catalyzed, 552–559 pd-catalyzed, classifications, 500–504 platinum-catalyzed, 560–561 rhodium-catalyzed, 586–595 rhutenium-catalyzed, 583–586 with soft stabilized carbanions, 506–539 tungsten-catalyzed, 579–582


988 INDEX

Amine ligands, 963 3-Amino glycol derivatives, 207 for synthesis of 2-deoxy sugars, 208 for synthesis of 2-oxygenated sugars, 208 (1S,2R)-1-Amino-2-indanol, 871 6-Amino penicillanic acid (6-APA), 286 Aminophosphine ligand, oxazoline-based, 672 (R)-Arbutamine, 393 (Z)-3-Aryl-3-(acylamino)acrylic acid derivatives, 364 (S)-2-Aryl-2,5-dihydropyrrole, 680 2-Aryl-4-piperidones, 456 Aziridination catalysts 4-phenylpyridine-N-oxide, 250 rhodium, 250 Asymmetric allylic alkylations molybdenum • ligand complex as catalysts of, 26 Asymmetric amplification, 894 aldol reactions, 899–900 alkylation, 896 allylation, 900–901 conjugate addition, 897 cyanation, 898 hetero-Diels–Alder reaction, 901–904 oxidation, 898–899 ring opening of meso-epoxide, 904–905 Asymmetric autocatalysis, 893–894, 906–915 chiral organic compounds-induced, 914–915 cryptochirality, discrimination of, 922–926 enantiomorphous inorganic crystals-induced, 918 of pyrimidyl alkanol, 912–914 spontaneous absolute asymmetric synthesis, 920–922 Asymmetric aziridination, 884–886 Asymmetric carbometallation C–C bond formation, hydrogen-mediated, 653–663 carboalumination, Zr-catalyzed, 646–652 carbocyclizations, 663–670 Heck reactions, 670–681 Asymmetric carbonylations alkoxycarbonylation, 819–827 catalytic cycle, 820–821 of vinylarenes, 821–825 hydroformylation, 802–819, 834 of olefins, bicyclic, 818–819 of olefins, heterocyclic, 817–818 of vinyl acetate, 814–815 of vinylarenes, 804–813 Asymmetric conjugate addition applications of, 442 of aldehydes, 460–461

of amino acid derivatives, 471–474 of α-cyanoacetates, 474–476 of cyanides, 478–480 of electron-rich arenes, 478, 479 of heteroatom nucleophiles, 484–491 of indoles, 476–478 of ketones, 461–463 of malonates, 467, 469, 470 of nitroalkanes, 464–466, 467 of organomettalics, 441–459 of silyl enol ether, 466–467, 469 tandem, 481–484 Asymmetric dihydroxylation, 881–884 osmium-catalyzed, 24 Asymmetric epoxidation, 851–870 Asymmetric hydrogenation of imines, 410–421 of ketones, 384–410 metal-catalyzed, advantages, 343 of olefins, 350–384 Rh-DIPAMP-catalyzed, 363 by Rh-Et-DuPhos, 363 Ru-catalyzed, 344, 382 of a trisubstituted α-dehydroamino acid derivative, 363 of unsaturated compounds, 350–410 Asymmetric hydrosilylation of alkyl-substituted alkenes, 782–787 cyclization/hydrosilylation, 788 of 1,3-dienes, 780–782 intramolecular, 787 of styrene, 774–779 Asymmetric Mannich reactions, 2 Asymmetric Negishi cross-couplings, Ni-catalyzed, 558 Asymmetric oxidation advantages and limitations, 841 of alcohols, 842–851 Bayer–Villiger oxidation, 876–880 with hydrogen peroxide, 841–842 with molecular hydrogen, 841–842 of sulfides, 871–876 Asymmetric polymerization, 933–934, 973 of achiral monomers, 934–948 of chiral monomers, 948–951 Asymmetric terpolymerization, alternating, 833 Base catalysts, 63–67 (2S,4S)-BCPM-Ir complex, 417 (S,S)-BDPP Ir(III) hydride complex, 417 (R)-Benzylmethylphenylphosphine, 772 bidentate NHC-Ru complexes, 741 (R)-BINAP, 663

INDEX 989

1,1′-Binaphthyl skeleton, 773 Biocatalysis, applications of, 269–270 Biological homochirality, sources of, 915–922 2,2′-Bipyridine, 939 2,2′-Bipyrimidine, 939 (S,S)-BnCH2-PYBOX, 559 (S,S)-BOXAX, in Wacker-type reaction, 248 BPE, 384 4-Bromophenyl diazoacetate, 194 Brønsted acid-assisted chiral Lewis acid (BLA) catalysis, 119–127 with bis(trifluoromethane)sulfonimide (Tf2NH), 120 BSA method for enantioselective allylic alkylation, 505 (S)-di-′Bu-MeOBIPHEP-Ru complex, 379 (S)-2-Butanol, 408 1-Buten-3-ynes substituted, 779 2-Butenyl phosphate, 588 (n-Butyl)ethyl(n-hexyl)(n-propyl)methane 35, 920 (R)-3,5-di-t-Butylphenyl-OMe-BIPHEP, 658 C1-symmetric monodentate NHC-Ru complex, 741 C–C bond formation, hydrogen-mediated, 653–663 C–H activation by direct C–H oxidation¸ 212–217 by metal carbenoid insertion, 165–204, 217–218 by metal nitrenoid insertion, 204–212, 218 Carbenes, Ru-based, 741 2-Carbethoxycyclohexenyl triflate, 677 Carbon–heteroatom bond formation, asymmetric reactions allylic substitution, 227–239 α-amination of carbonyl compounds, 252–256 α-oxygenation of carbonyl compounds, 252–256 aza-Claisen rearrangement, 239–242 aziridination of olefins, 250–252 diboration of unactivated olefins, 257 disilation of unactivated olefins, 257 hydroalkoxylation, 246–247 hydroamination, 243–246 silaboration of unactivated olefins, 257–259 Wacker-type reaction, 247–248 Carbonyl α-alkylation, enamine-catalyzed, 50–52 Carbonyl α-functionalization, by enamine activation, 48–50

Carbonyl-ene reaction intermolecular, catalysts, 690–712 intramolecular, catalysts, 712–714 (R)-Carnitine, 386 Catalytic asymmetric synthesis, solvent types organic vs. nonconventional, 1, 30 Catalytic asymmetric synthesis in water, trends, 14 (Z)-Chelated enolate, 545 Chiral Lewis acid catalysts, water as solvent for epoxide ring-opening reaction, 3–6 for Mannich-type reaction, 2 for Michael reaction, 2–3 for Pauson–Khand-type reaction, 13–14 Chiral ligands for asymmetric hydrogenation, 344–349 in total synthesis of (+)-Minfiensine, 29 Chiral N-heterocyclic carbenes (NHC), 451 Chiral (nitrosyl)ruthenium(salen) complex, 844 Chiral o-hydroxyaryldiazaphosphonamide, 894 Chiral pyrrolidine, 865, 884 Chiral ruthenium(salen) complex, 883 Chiral 1-o-octadecyl-3-o-trityl glycerol, 398 Chiral organocatalysis thiourea-based, 477 in water, 11–12 Chiral oxazaborolidines, 727 Chiral oxazolines, 678 Chiral P,O-hemilabile ligand, 458 Chiral Pd catalysts, 720 Chiral phase-transfer catalysts for aldol and Mannich reaction, 105–107 for amination reaction, 109–110 for asymmetric alkylation reaction, 96–104 for asymmetric Michael addition reaction, 105 Corey–Lygo type, 537 for epoxidation and aziridination reaction, 107–109 for Strecker reaction, 109 Chiral phosphine ligand, valine-based, 450 Chiral primary amine-thiourea catalyst, 460 Chiral quaternary ammonium salt, 473 Chiral ruthenium porphyrin complex for asymmetric C–H hydroxylation, 212 Chiral (salen)Al complex, 474 Chiral Ti catalysts, 690 Chiral tetrahydrobis(oxazole) ligand, 410 Chiral thiourea, 476 Chiral titanocene, 410 Chiral tosylsulfonylimidamide, 210 Chiral tridentate Schiff base aluminum complex for hydrophosphonylation of aldehydes, 260

990 INDEX

Chiral trivalent phosphorus ligands TADDOL (2,3-O-isopropylidene-1,1,4,4tetraphenylthreitol), 451 (S,S)-CHIRAPHOS, 553, 554, 561, 592 (R)-3-Chlorostyrene epoxide, 325 1,4-Cis-addition, 778 (R)-Citronellol, 380 (S)-Citronellol, 380 (R)-Cl-OMe-BIPHEP, 655, 660 (–)-Cyanthiwigin F, 549 Cyclic vinylsilane, 196 Cyclization catalysts, ene-type, 714–722 Chiral Pd, 720–722 Chiral Rh, 714–720 Cycloaddition reactions, iminium-catalyzed, 40–41 1,3-Cyclohexadiene, 22 Cyclopentadienes (CPs), 1- and 2-substituted, 125 1,3-Decadiene, 779 Dehydroamino acid and aryl enamide Rh-catalyzed hydrogenation of, 347 1,5-Dicarbonyl compounds, 462 Diels–Alder (D-A) reaction, asymmetric, 727–734 diastereo- and enantioselectivity, methods for controlling, 686–689 transannular Diels–Alder (TADA) reaction, 125 transition structure, 685–686 in water, DNA-based, 13 Diels–Alder-type reaction intramolecular [4 + 2] cycloaddition, 722–727 intermolecular (hetero) D-A reaction, 727–735 1,6-Dienes, 771, 936, 937 2,3-Dihydrofuran in BLA catalysis, 124 in Heck reactions, 28 Dihydronaphthalene, 851 2,3-Dihydropyrrole, 660 2,6-Diketones, 149 3-(2′,2′-Dimethoxyphenyl)-3-phenyl-2propenol, 381 1,1-Dimethylallyl derivatives, 504 (S)-2-[bis(3,5-Dimethylphenyl)-methyl] pyrrolidine, 460 1,3-Dimethylallyl alcohol, 514 (1,3-Dimethylallyl)Pd complex, 517 (R,R)-DIOP, 560 Dipeptide, proline-based, 465 1,3-Diphenyl-substituted allyl ethers, 554

1,3-Diphenylallyl alcohol, 514 (R,R)-1,2-Diphenylethylenediamine, 404 2-Diphenylphosphino-1,1′-binaphthyl, 775 1,3-Dipolar cycloaddition of nitrones with acrolein, 130 Dirhodium(II) carboxamidate complexes with N-acylimidazolidin-2-ones, 167 2-azetidinones, 167 2-oxazolidinones, 167 2-oxopyrrolidines, 167 Dirhodium(II) carboxylate complexes N-phthaloyl-protected amino acid-based, 167–168 Rh2(S-PTA)4, 168 Rh2(S-PTTL)4, 168 Dirhodium(II) complexes, for metal nitrenoid transformations Rh2(esp)2, 207 Rh2(S-nap)4, 207 Rh2(S-NTTL)4, 207 Rh2(S-TCPTAD)4, 207 Rh2(S-TCPTTL)4, 207 Dirhodium(II) complexes with orthometallated arylphosphine for metal cabernoid generation, 169 Dirhodium(II) tetrakis[N-tetrafluorophthaloyl(S)-tert-leucinate, 173 (S,S)-DPBA-1, 40 (S)-Duloxetine, 393 Enamine catalysis, 45–52 Enamine and iminium activation, 52–55 Enantioselective fluorination chiral Pd-BINAP complex-catalyzed, 25 Enantioselective organocatalysis enamine-based, 45–52 iminium-based, 39–45 Enantioselective ring-closing methathesis, Ru-catalyzed, 744 (Z)-Enecarbamates, 708 1,6-Enyne cyclization, 663 1,6-Enynes, 714, 771 Enzymatic catalysts for ammonolysis, 278 for asymmetric oxidations, 321–329 for C–C bond formations, 292–300 for enantioselective acylation of acohols and amines, 271–278 for enantioselective reductions, 300–321 for transesterification, 278 Enzyme-catalyzed asymmetric synthesis applications of, 269–270 Esters, BLA catalysis of, 122 (R)-4-Ethoxy-γ-lactam, 379

INDEX 991

3-Ethoxypyrrolidinone, 379 1-Ethylallyl derivatives, 504 Fluorous biphasic systems (FBS) for asymmetric reactions, 15 Fluorous solvents, use in catalytic asymmetric synthesis advantages, 15 catalytic reactions, 15 (S)-Fluoxetine, 393 (R)-Halohydrin, 272 Heck reactions in the synthesis of (+)-minfiensine, 28–29 Pd-catalyzed, 27–28 (P)-Hexahelicene, 914 3,4-Hydroisoquinolines, 418 2-Hydroxy-2′-amino-1,1′-binaphthyl (NOBIN), 904 (2R,4S)-α-Hydroxyl-γ-butyrolactone, 399 (2S,3R)-3-Hydroxylysine, 389 Ion pair catalysts ammonium betaines, 112–113 ammonium fluorides, 110–112 ammonium phenoxides, 112 phosphonium carboxylates, 113–114 Ionic liquids advantages, 20 for asymmetric Diels–Alder reaction, 20–22 for asymmetric dihydroxylation reaction, 24–25 for asymmetric epoxidation reaction, 22–23 for asymmetric fluorination reaction, 25 for asymmetric hydrogenation reaction, 20–22 for asymmetric ring opening of epoxide, 23–24 Lewis acid-assisted Brønsted acid (LBA) catalysts, 119, 134–138 for asymmetric allylboration reaction, 138 for biomimetic cyclization reaction, 135 for enantioselective cyclization reaction, 137 for protonation reaction, 134–135 Lewis acid-assisted Lewis acid (LLA) catalysts, 119, 128–134 for CBS reduction of prochiral ketones, 128 chiral oxazaborolidine, 128 for cycloaddition reactions, 129–130 for D-A reactions, 128–129 for 1,3-dipolar cycloaddition of nitrones, 130 Lithium N-benzyltrimethylsilylamide, 486

MacMillan’s imidazolidinone, 461 Malonates, 467, 576 Malononitriles, 471 Mannich reactions, 2, 910 Me-BPE, 363 Me-DuPhos, 363 (R,R)-Me-DUPHOS, 725 Meerwein–Ponndorf–Verley (MPV) reduction, 408, 850 Meldrum’s acids, 12, 445 MeO-BIPHEP, 380 540, 658, 667 (R)-MeO-MOP, 537 2-Mercaptobenzaldehyde, 482 Mercuriocyclization with substrates, 249 meso-Allyl dicarbonates, 595 meso-Cycloalkadienes, 670 meso-1,4-Cyclohexadienes, 674 meso-Diol, 332 meso-Lactide, 970 meso-Oxiranes, 940 meso-Substrates, 506 Metal carbenes from phosphonium, 165 from sulfonium, 165 from thiophenium ylides, 165 Metal carbenoid catalysts, for C–H activation Rh2(4S-MACIM)4, 175 Rh2(4S-MEOX)4, 175, 182 Rh2(5S-MEPY)4, 175, 178 Rh2(4S-MPPIM)4, 175 Rh2(4S/R-MPPIM)4, 178 (R)-Metalaxyl, 363 Metallacyclopentane, 725 Metallocene catalysts, 382 Methacrylates, 934, 952 Methacrylic acid (MAA), 947 2-Methacryloyloxyethylisocyanate (MOI), 948 Methionine, 286 (S)-Methoxyisoproylamine, 320 1-Methoxypropanone (2,6-dimethyl) anilineimine, 414 Methylaluminoxane (MAO), 622, 647, 932 Methyl 4-bromophenyldiazoacetate, 196 (S)-3-Methyl-2-butanol, 408 1-Methylcyclohexene, 196 functionalization of, 214 Methyldichlorosilane, 772 1-Methyl-3,4-dihydronaphthalene, 199 (2S,3R)-Methylglycidate, 389 Methyl ketones, in BLA catalysis, 123 Methyl (3-penten-2-yl) carbonate Methylphenyldiazoacetate, 189, 193

992 INDEX

Methylphenylvinyldiazoacetate, 200 2-Methylpyrimidine-5-carbaldehyde, 914, 918 2-Methylpyrimidyl alkanol, 918 (S)-2-Methyl-1-(5-pyrimidyl)-1-propanol, 908 Methyl pyruvate, 704 2-Methyl-1-(3-quinolyl)propan-1-ol, 907 2-Methylquinoxaline, 418 2-Methyl-tetralone, 541 Michael addition of 2-cyclohexenone, 125 of silyl ketene acetals, 124 Michael reaction, 11 bipyrrolidine-catalyzed, 30 Microwave-assisted catalytic asymmetric synthesis applications of, 25 for asymmetric allylic alkylations, 26 for asymmetric Heck reactions, 27–28 for bipyrrolidine-catalyzed Michael-type reaction, 30 for direct asymmetric Mannich reactions, 29 for enantioselective reactions, 26 for proline-catalyzed Mannich reactions, 29 for total synthesis of (+)-minfiensine, 28–29 Microwave irradiation, 25–26 (+)-Minfiensine, 674 Mizoroki–Heck reactions, 670, 719 Mn-salen complex, for asymmetric epoxidation, 22 Mn-salen complex, for aziridination of olefins, 250 MOD-DIOP, 417 Molybdenum-catalyzed reactions, 561–570 Monodentate phosphine ligands, 344 Monodentate phosphoramidite, 456 MonoPhos ligands, 346, 600 Monophosphoramidite ligand, TADDOLbased, 675 Mukaiyama aldol reaction, 694 vinylogous, chiral BLA-catalyzed, 126 Mukaiyama–Michael addition of silyl enol ethers to chalcones, 467 N-acyl hydrozones, 410 N-acyl imines, in aziridine formation, 144 N-acyl pyrroles, 860 N-acyl sulfonimides, 410 N-acylamino acid racemase, 286 NADH, 324 NADH-oxidase, 329 NAD(P)+, 328 N-(9-anthracenylmethyl)cinchonine derivative, 466

Naphthol ring system, 623 N-arenesulfonyl imidoiodinanes, 204 N-aryl-substituted variants, 861 N-arylsulfonylimines, 660 N-benzoylglycine, 918 N-benzoyliminopyridinium ylides, 420 N-benzyl-(R)-3-hydroxypyrrolidine, 327 N-benzyl-N-methylamine, 190 (R)-N-benzyl-3-phenylbutanamide, 456 N-benzylpyrrolidine, 327 N-Boc-aldimines, 711 N-Boc-asparate, 862 N-Boc-oxazolidinone, 861 N-Boc-pyrrolidine, 189 1-N-Boc-3-oxopyrrolidine, 321 N-carbamate-protected imine, 711 N-crotonyloxazolidinones, 22 N-cycloalkenoyl-2-iodoanilides, 672 N-cycloalkenylmethyl-2-iodoaniline, 672 N-(diphenylmethylene)glycine tert-butyl ester addition to vinyl ketones, 471 N-diphenylphosphinyl ketimines, 411 N-heterocyclic carbene ligand (NHC-ligand), 582 N-heterocyclic carbene (NHC)-Ru complexes, 741 N-(2-methacryloyloxyethyl)carbamates (RMOC), 948 N-methylmorpholine-derived aminimide, 883 N-N bond cleavage, 883 N-sulfinyl dienophile, 902 NbCl3(dme), 872 Ni-PPh3 complex, 557 Nickel catalysts for allylic amination, 228 for intermolecular carbonyl-ene reaction, 692 Niobium catalyst, 859 Nitrene reactions, 165 Nitrene-transfer aziridination, 882 Nitro-olefin, 51, 476 Nitroaldol reactions, 132–134 of nitroalkane with α-chiral aldehydes, 133 anti,syn-selective nitroaldol products, 133 complementary syn,syn-selective nitroaldol products, 133 Nitroalkenes, 453 1-Nitro-1-alkenes, 317 1-Nitroalkanes, 317 2-Nitroalkanes, conjugate addition to 2-cycloalkenones, 464 Nitromethane, 317 2-Nitropropane Nitrosobenzene, 50

INDEX 993

N-methylamines, 194 N-methylated enamide, 143 N-methylmorpholine N-oxide (NMO), in asymmetric dihydroxilation, 24 N-methyl-2-pyrrolidinone (NMP), 670 N,N-dibutylaminoethanol (DBAE), 923 N,N-dibutylnorephedrine (DBNE), 906 N,N-dimethylacetamide (DMA), 672 N,N-dimethylanilines, 191 (1S,2R)-N,N-dimethylnorephedrine (DMNE), 923 N,N-diphenylamides, 547 N,N,N′,N′-tetramethylenediamine (TMEDA), 489 Nonconventional media, catalytic asymmetric synthesis in, 30–31 N-phthaloyl-protected amino acid-based dirhodium(II) complexes, 167–168 N-spiro C2-symmetric chiral quaternary ammonium bromide, 466 N-substituted maleimides, 934, 948 N-triflyl selenophosphoramides, 152 N-triflyl thionophosphoramides, 152 N-tritylsulfenyl tryptamines, Pictet–Spengler reaction of, 143 Nucleophiles O-centered nucleophiles, 484 P–H nucleophiles, addition to vinyl nitriles, 487 phenolic, 484 prochiral, 533 pronucleophiles, 534, 537 sulfonamides, 150 tert-butyl N-(diphenylmethylene)glycinate, 537 O-(diphenylphosphinyl)hydroxylamine, 883 Olefin metathesis catalysts, classes of, 741–742 cross-metathesis (CM) reactions, 767 ring-closing metathesis (RCM) reactions, 744–757 ring-opening/cross-metathesis (ROCM), 757–767 ring-opening/ring-closing metathesis (RORCM), 757 Olefins aliphatic, in terpolymerization of CO, 831 aromatic, trans-disubstituted, 856 Rh-catalyzed hydrogenation of, 382 Ru-catalyzed hydrogenation of, 382 Sharpless asymmetric dihydroxylation of, 879 Oligopeptide, 878

(R)-OMe-BIPHEP, 657 O-mesitylenesulfonylhydroxylamine, 883 ONNO-type tetradentate ligands, 871 (−)-oppositol, 670 Organobrane reagents asymmetric conjugate addition by rhodium catalysts, 54–457 Organocascade catalysis, 52–55 Organocatalyst, 464 Organocatalyzed asymmetric reactions aldol reaction, chiral-organocatalyzed, 30 Mannich, proline-catalyzed, 29 Organometallic reagents, 441 Organoselenylation, 248 ortho-bromoacetophenone, 398 ortho-haloaryl ketones, 398 ortho-metalated Ir dihydride complex, 418 Osmium tetroxide, 897 Os(VIII) trioxoglycolate, 879 Oxaloacetate, 319 Oxanorbornadiene derivatives, 630 Oxarhodacycle, formation of, 657 Oxazaborolidine in BLA catalysis, 125 in LLA catalysis, 128 in transannular Diels–Alder reactions, 126 Oxazaborolidine-aluminum bromide catalyst, 728 Oxazolidinones, 40 in intramolecular C–H insertion, 208 Oxazolinylferrocenylphosphinesoxazolinylferrocenylphosphines, 554 Oxindole, 672 3-Oxo-3-phenylpropionic ester, 384 (S)-Oxybutynin, 552 Ozonolysis, 706 P450-monooxygenase, 326, 327 P–C bond formation, 486 P,N-ligand, 876 P,S-ligand, 508 Palladium-(S)-BICHEP, 938 Palladium catalysts, 692 for enantioselective activation of sp2 C–H bonds, 216 for intermolecular carbony-ene reaction, 692 Palominol, BLA synthesis of, 126 (R)-Pantolactone, 384 Parkinson’s diseases, 844 Parity-violating energy difference (PVED), 913 (−)-paroxetine, 606 Pauson–Khand-type reaction, 13 p-Benzoquinone, in Wacker-type reaction, 248

994 INDEX

P-chiral ligands, 344 P-chiral phosphinophenol, 451 P-chiral TangPhos, 346 P-chlorobenzoic acid, 918 p-Chlorophenylacetate, 273 Pd complexes of nonsymmetric ligands, 519 Pd-enolate formation, 694, 550 Pd–hydride bond, 818 Pd(II)-BINAP complex, for chlorohydroxylation, 248 Pd2(dba)3-(R)-BINAP, 672 Pd2(dba)3–(S)-p-tol-BINAP, 675 Pd(OAc)2-(R)-BINAP, 670 Pd(OAc)2–(S)-BINAP, 678 Pd(OAc)2-(R)-DIOP, 670 Pd(phenanthroline) complexes, 831 Pd(TFA)2, in Wacker-type reaction, 248 Penicillin acylase, 286 2,4-Pentadione, 399 1,3-Pentadiene, 936 Pentafluorophenyl ligand, 853 1,2,2,6,6-Pentamethylpiperidine (PMP), 672 (R,R)-2,4-Pentanediol, 399 2,4-Pentanediyl dimethacrylates, 969 2,7-di-n-Pentyldibenzofulvene, 955 Peracetic acid, 862 Percarboxylic acids, 862 Perfluoroalkyl-substituted BINAPHOS ligand, 808 (R)-3-Phenylcyclopent-1-ene, 681 Peptide-based ligand, 448 Peracids, 839, 878 Peroxo ligand, 852 PHANEPHOS, 384, 661 Ph-DIAPHOX, 524, 534 1,10-Phenanthroline, 939 Phenol ring system, 623 Phenyl triflate, 677 1-Phenyl-1,3-butadiene, 778 1-Phenylbutadiynes, 655 1-Phenylbutenyne, 657 2-Phenyl-2,3-dihydrofuran, 676 2-Phenyl-2,5-dihydrofuran, 677 1,2-Phenyl-linked DuPhos family, 345 3-Phenylpropanal, 957 2-Phenylpropyl isocyanate, 966 4-Phenylpyridine-N-oxide for aziridination of olefins, 250 Phenylsilane, 669, 777 1-Phenyl-1-silylethane, 772 Phenylsulfonyl acetates, 590 2-Phenyl-3,4,5,6-tetrahydropyridine, 418 (S)-Pheylethanol, 408 Phosphanes, 410

Phosphine oxide, 123 Phosphinite-oxazoline ligand, 382 Phosphinoanisole, 451 Phosphinoimidazoline (BIPI) ligands, 673 Phosphinoxazoline, 546, 592 Phospholane-oxazoline ligands, 379 Phosphite/oxazoline ligands, 522 Phosphoramidite complex, 452 Phosphoramidite ligands, 446, 456, 596, 602, 621 Phosphoric acid catalysts, chiral for aza-Friedel–Crafts (F-C) reaction, 142–145 for D-A reactions, 145–147, 152 for 1,3-dipolar cycloaddition of diaryl nitrones, 153 for enantioselective Michael addition of indoles, 154 ketene silyl acetals, 139, 546 for Mannich-type reaction, 139–142, 150–151 for meso-aziridine ring opening, 151 for Nazarov cyclization reaction, 153 N-hydroxyphenyl-substituted aldimine, 140 N-triflyl phosphoramide, 152 pyridinium salt, 146 TADDOL-based, 150 TADDOL-based, 150 for transfer hydrogenation reaction, 147–150 VAPOL-based, 150 Photoredox organocatalysis, 51, 53 using Ru(bpy)3Cl2, 54 PHOX, 381, 382, 414, 520, 522, 528, 599, 605 Phthalimide, 417 Pictet–Spengler reaction, 143 Piperidine derivatives, 523 (R)-4-Piperidinylglycine, 363 (Pigiphos)-nickel (II) complexes, 487 Plastansimycin, BLA synthesis of, 126 Platinum catalysts, 692 (PPh3)2Pt-stilbene, 561 Platinum-catalyzed allylic alkylations, 560 p-Nitrobenzenesulfonylimidoiodinane for C–H amination, 206 p-Nitrophenyl group, 178 p-Nitrophenylsulfonyl imidoiodinane, for C–H amination, 204 Polyacrylonitrile, 932 Polybinaphthyls , 944 Polycyclic hydrazines, 630 Poly(isocyanopeptide)s, 965 Polymerization, enantioselective enzymatic, 972 of alkenes, 932 of α-amino acid N-carboxyanhydrides (NCAs), 972

INDEX 995

of expoxides and thiiranes, 971 of lactones and lactides, 971–972 of methacrylates, 970–971 of monosubstituted ethenes, 969–970 topochemical, 946 titanium-initiated, 966 Polymethacrylate, 932 Poly(methyl methacrylate) (pMMA), 947 Polyoxyethanyl-α-tocopheryl sebacate (PTS), 668 2-(Polyprenyl)phenol derivatives, 137 Polystyrene, 932 Porphyrin complexes, Ru(II) and Mn(III) for C–H amination, 205 Ru(II) porphyrin complexes, 205 Potassium ferricyanide/potassium carbonate, 880 (S,R)-PPF-P(t-Bu)2, 668 Pr-CnrPhos, 399 Precatalyst zwitterions in development of BLA, 125 activation by tri-n-butyltintriflate, 125 Prochiral ketones, 320 Prochiral 3-substituted cyclobutanones, 322 Prochiral α,β-unsaturated compounds, 445 Proctic acids, use in BLA catalysis, 120 Proline, 903 Propargylic alcohols, 273 Propargylic amines in asymmetric C–H activation, 213 PROPHOS, 344 Propiophenone, 410 (S)-Propranolol, 393 Propylene and 1-Buten, 949 Propylene sulfide, 969 pro-R-ethyl group, functionalization of, 214 Prototropic ene process, 694, 699 Prozac, 844 Pseudomonas cepacia, 273 Pseudopterogorgia elisabethae, 202 Pseudotetrahedral Cu(I), 624 P-Toluenesulfonyl azide (TsN3), 882 Pyridine-2-carboxaldehyde, 705 Pyridine-imidazoline ligands, 831 Pyridine–oxazoline ligand, 829 Pyridine-phosphinite ligand, 421 Pyridine ring, 623 Pyridines, hydrogenation of, 148, 357 2-Pyridyl-alanine analogues, 357 Pyridylamide ligands, 564, 572 (2-Pyridylsulfonyl)imines of chalcones, 446 (2-Pyridyl)sulfonyl moiety Pyrimidine-5-carbaldehyde, 916, 917 Pyrimidyl alkanol, 910

(R)-Pyrimidyl alkanol, 914, 915, 917 Pyrrolide, 756 Pyrrolidine catalyst, C2-symmetric, 48 Quaternary carbon stereogenic centers, 448 Quebrachamine, 755 QUINAP, 520 Quiniclidine, 883 Quinolines, 148, 419 Quinones, in BLA catalysis, 120, 122 reaction with 2-triisopropylsilyloxy-1,3butadiene, 122 QUIPHOS, 534 Racemic 2,3-alkadienyl phosphates, 540 Racemic/meso-diols, 274 Racemic poly(di-n-hexylcarbodiimide), 966 Racemic tetraacylated conduritol B, 524 RCM, enantioselective, Ru-catalyzed, 744 Recovery and reuse of the catalysts, 15 Regiocontrol, in allylic substitution, 228 Reichstein S, 327 Reverse syn/anti selectivity, 389 [Rh(cod)2]BARF, 660 Rh-BDPP complex, 381 [Rh{(R)-BINAP}(solvent)]SbF6 complex, 726 Rh-BINAPINE, 364 Rh-BoPhoz complexes, 368, 384 Rh-ButiPhane, 421 Rh-catalyzed hydrosilylation of α,βunsaturated ketones, 588 Rh complexes of DBPP, 400 of DIOP, 400 of MCCPM, 384, 393 of phosphine ligands, 352 Rh-COD, 588, 592, 658 Rh-Diphosphine complexes, 655, 724 Rh-DuPhos complex, 361 Rh-chiral diphosphine complex, 725 Rh-JosiPhos, 367 Rh-Me-PennPhos catalyst, 400 Rh-monohydride complex, 654 Rh-phospholane complexes, 356 Rh-[Rf(CH2)3]2-BINAPHOS complex, 17 Rh-TRAP for catalytic hydrogenation of substituted indoles, 419 Rh2(OAc)4, for intramolecular C–H amination, 207 Rhodacyclopentadiene, 660 Rhodium catalysts for allylic amination, 228 ROCM, 757

996 INDEX

RORCM, 757 Ru-C3-TunePhos catalyst, 367, 393 Ru-chiral diamine complexes, 21 Ru complexes, for racemization, 273 Ru(BINAP)Br2, 386 [RuCl2(benzene)]2–PPh3, 419 RuCl2[(R,R)-BICP](tmeda), 404 RuCl2[(S)-BINAP](DMF)n catalyst, 399 [RuCl2(p-cymene)]2, 410 [RuCl2(p-cymene)(Tsdpen)], 410 RuCl3-(R)-MeO-BIPHEP catalytic system, 386 Ru-(–)-DTBM-SEGPHOS catalyst, 389 Ru-Noyori-type catalyst, 274 Ru-porphyrin complexes, for aziridination of olefins, 250 Ru(salen)(CO) complex, for aziridination of olefins, 251 Ru-TetraMe-BITIANP, 389 Ru-TetraMe-BITIOP, 389 Ru-TolBINAP(pica) catalysts, 398 Ru-XylBINAP/DAIPEN catalyst, 396 Ruthenium, as catalyst for allylic amination, 228

Stereocontrol in nitrene transfer to olefins, 250 s-trans-anti-Complexation 688 Stryker’s reagent, 666 Styrene for aziridination of olefins, 251 reaction with SESN3, 251 3-Substituted cyclohexenones for asymmetric conjugate addition, 458 4-Substituted indoles, synthesis of, 201 2-Substituted 3-nitropropanoates, 317 2-Substituted-1,3-oxathianes, 870 Succinic acid anhydride, 272 Sulfonamide (ArSO2NH2), for C–H amination, 204 Supercritical fluids (SCFs) definition and applications of, 15 in catalytic asymmetric reaction, 17–20 (−)-Swainsonine, synthesis of, 232 syn-Complexation, 688 Syndiotactic polymer, 951 syn-Directing diphenylphosphinobenzoate (DPBB), 616 SynPhos, 420

Sakurai–Hosomi reaction, 942 Salen complexes, Ru(II) and Mn(III), 205–206 chiral Ru(II) salen complex, 206 Salicylaldimines, 625 Scandium trisdodecylsulfate (Sc(DS)3), 3 SEGPHOS, 344, 420, 539, 693, 720, (+)-Sertraline, 199 Sharpless–Katsuki asymmetric epoxidation, 893 Silanes, polymerization of, 996–967 Silatropic ene process, 694 Silica gel-supported scandium with ionic liquid (Silica-Sc-IL), 9 Silyl enol ethers, 578 Silyl ketene acetals, 124, 138 SimplePhos, 447 Singulair, 844 SIPHOS, 347 (S,S)-Skewphos ((2S,4S)-2,4bis(diphenylphosphino)pentane (S,S)-BDPP), 718 Sodium bromate (NaBrO3), 916 Sodium chlorate (NaClO3), 916 SOMO catalysis, 51, 52–54 organoSOMO catalysis, 53 Sparteine, 530, 841 Sphingofungins, 537 Spirocyclic guanidine, 466

T. brockii, 323 Tachikinin, 814 Tandem transformation, 480 TangPhos, 357, 817 TaniaPhos, 399 (R)-(3,5-t-Bu-4-MeOPh)-MeO BIPHEP, 658 t-Bu-PHOX, 543, 549 t-Butyl esters, 623 t-Butyl glutamate, 623 t-Butyl methyl ether (TBME), 21 t-Butylphenyldiyne, 656 Terpolymerization of CO with aliphatic olefins, 831 tert-Butyl methyl ketone, 405 (S)-tert-Leucinol, 871 Tertiary amine diisopropylethylamine (DIPEA) in Wacker-type reaction, 247 Tetraalkoxysilane, 192 Tetrabutylammonium fluoride (TBAF), 943 Tetrafluorinated phthaloyl complex Rh2(STFPTTL)4, 173 Tetrahydro-β-carboline rings, 418 Tetrahydrofuran-2-carbaldehyde, 815 Tetrahydrofuran-3-carbaldehyde, 815 Tetrahydroquinoline alkanoids, 149, 420 derivatives from aza-D-A reaction, 146 Tetrahydroxybinaphthalene, 944

INDEX 997

TetraMe-BITIANP, 380, 384 TetraMe-BITIOP, 380, 384 1,1,3,3-Tetramethylhydrosiloxane (TMDS), 667 TETRAPHOS, 698 (P,S,S)-TETRAPHOS-Pd/(S)-DABN complex, 699 Thiiranes, 969 Thorpe–Ingold effect, 143 threo-Methylphenidate, 190 threo-Diisotactic structures, 934 Thyldiphenylphosphine, 773 Ti(OiPr)4, 416 Ti(salen) complex, 869 Ti(salalen) complex, 870 Tishchenko reaction, 957 Titanium catalysts, 850, 869 Titanium (IV) S)-butan-2-ol, 912 Titanocene, as metallocene catalyst, 382 TMS-BINAP, 537, 539 TMSCN, 123 TMS-phenyldiyne, 656 (R)-tol-BINAP, 659 Trichloroacetaldehyde (chloral), 956 tolylmethanol-α-d, 921 trans-2-Aryl-2,3-dihydrobenzofuran-3carboxylic acid ester, 185 trans-Cyclopentene, 608 trans-2,5-Dialkyl-substituted phospholane ligand BPE, 345 trans-1,2-Diaminocyclohexane, 881 trans-2,5-Dimethylpiperazine, 464 trans-β-methylstyrene, 855 (1S,2R)-trans-2-Phenylcyclopentanamine, 606 trans-RuCl2(BINAP)(1,2-diamine), 407 trans-[RuCl2(Bisphosphine)(1,2-diamine)] complex, 410 trans-[RuCl2(Diphosphine) (1,2-diamine)] catalyst system, 400 trans-[RuCl2((S)-MeO-BIPHEP)((S,S)ANDEN)], 417 trans-[RuCl2(R)-Tol-BINAP][(R,R)-dpen], 404 trans-RuCl2[(R)-XylBINAP][(R)-daipen], 392, 393, 400 trans-RuCl2[(R)-XylBINAP][(S)-daipen], 404 trans-RuH(η–1-BH4) (BINAP)(1,2-diamine), 404 Transaminase, 318 Transannular Diels–Alder (TADA) reaction, 125 o-fluorophenyl, effect on TADA products, 126 Transesterification reaction, 271

Transfer hydrogenation iminium-catalyzed reaction, 44 using nicotinamide adenine dinucleoside (NADH), 147 using phosphoric acid catalysts, 147–150 Transmission electron microscopy (TEM), 3 TRAP ligands, 363 Trialkylaluminum reagents, 457 Trialkylsilyldiynes, 657 Triaryl system, desymmetrization of, 216 Tributyltintriflate, activation of precatalyst by, 125 1-(Trichlorosilyl)-1-phenylethane, 773 Tricyclic skeletons, trans-fused, in LBA catalysis, 135 Tridentate nitrogen-base ligand AMBOX, 408 Triene aldehydes, in BLA catalysis, 122 Triflate (CF3SO−3), in BLA catalysis, 121 Triflate-bis(oxazoline) catalyst, 902 Triflimide ((CF3SO2)2N−), in BLA catalysis, 121 Triflimide (Tf2NH), in BLA catalysis, 121 2,2,2-Trifluoroethanol, 416 Trifluoroethyl acrylate, in LLA catalysis, 129 3-Trifluoromethylacetophenone, 410 2-Triisopropylsilyloxy-1,3-butadiene, BLA catalysis of, 122 2,3,3-Trimethylindolenine, 417 Trimethylsilane, 772 2-(Trimethylsilyl)ethanesulfonyl azide (SESN3), 883 Trioxazoline ligands, 572 Triphenylacetic acid (TPAA), 658 Triphenylphosphine, 655 Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), 883 Trisoxazoline ligands, 519 Trispyrazolyl (Tp)-complex, 591 (+)-Tröger’s base, 883 TsDPEN, 408 Tsuji’s method for enantioselective allylic alkylation, 505–506 Trifluoromethanesulfonic acid (TfOH) in aza-Darzene reaction, 144 in BLA catalysis, 120 in Michael reactions, 3 2,4,4-Trimethyl-2-cyclohexenone, 407 (3R,7R)-3,7,11-Trimethyldodecarol, 380 2-(Trimethylsilyl)ethanesulfonyl (SES) group for aziridination, 251 Vanadium catalyst, 846, 857 (+)-vernolepin, 670

998 INDEX

Vinyl epoxides, 628 Vinyl sulfones, 51 Vinylarenes, 802 Vinylcyclohexane, 860 Vinylcyclopropanes, 580, 726 Vinyldiazoacetates, 199 Vinyldiazoacetates, 202 Vinylepoxides, 531 VO(OiPr)3/bishydroxamic acid system, 858 Wacker-type cyclization by chiral Pd(II)/(−)-sparteine complex, 247 by chiral Pd(II)-spirobis(isoxazoline) catalyst, 247 WalPhos, 399 Weitz–Scheffer mechanism, 866 Wieland–Miescher ketone, in enamine catalysis, 45 Wilkinson catalyst [RhCl(PPh3)3], 586 Wittig reaction, 709 Xanthene backbone, 517 Xyl-P-Phos, 404

o-Xylyl-BINAPO, 384 Xylyl-PHANEPHOS, 404 Xyl-TetraPHEMP, 404 YLi3tris(binaphthoxide), 485 Z-Enamine intermediate, 462 Z-Enolate, formation of by Zimmerman–Traxler-type transition state, 663 Ziegler-Natta catalysts, 967 Zirconocene, 382, 411 Zirconium-catalyzed asymmetric carboalumination reactions of activated alkenes, 649–653 of 1,4-pentadiene, 649 of unactivated alkenes, 646–649 using RuO4 for oxidative cleavage of the phenyl moiety zirconocene as catalyst, 646 Zn enolates, 666 Zn(OAc)2, 534 Zn(OTf)2, 902 Zr(salen) complex, 876

Catalytic Asymmetric Synthesis, 3rd Edition

Catalytic Asymmetric Friedel–Crafts Alkylations

Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications

Asymmetric Organic Synthesis with Enzymes

Asymmetric Organic Synthesis with Enzymes

Asymmetric Catalysis In Organic Synthesis

Asymmetric Catalysis In Organic Synthesis

Organosulfur Chemistry in Asymmetric Synthesis

Chiral Diazaligands for Asymmetric Synthesis

Chiral Diazaligands for Asymmetric Synthesis

Asymmetric Catalysis In Organic Synthesis

Asymmetric Synthesis of Nitrogen Heterocycles

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

Asymmetric organocatalysis: from biomimetic concepts to applications in asymmetric synthesis

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

Advances in Asymmetric Synthesis, Volume 1, Volume 1 (Advances in Asymmetric Synthesis)

Principles and Applications of Asymmetric Synthesis

Green Approaches To Asymmetric Catalytic Synthesis (SpringerBriefs in Molecular Science: Green Chemistry for Sustainability)

Chiral Auxiliaries and Ligands in Asymmetric Synthesis

Advances in Asymmetric Synthesis, Volume 3, Volume 3 (Advances in Asymmetric Synthesis)

Principles and Applications of Asymmetric Synthesis

Asymmetric Synthesis with Chemical and Biological Methods

Asymmetric Synthesis with Chemical and Biological Methods

Catalysis in Asymmetric Synthesis (Postgraduate Chemistry Series)

Handbook of heterogeneous catalytic hydrogenation for organic synthesis

Asymmetric Catalysis In Organic Synthesis (Baker Lecture Series)

Catalytic Antibodies

Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis

Catalytic Heterofunctionalization

Catalytic Asymmetric Synthesis, 3rd Edition

Catalytic Asymmetric Friedel–Crafts Alkylations

Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications

Asymmetric Organic Synthesis with Enzymes

Asymmetric Organic Synthesis with Enzymes

Asymmetric Catalysis In Organic Synthesis

Asymmetric Catalysis In Organic Synthesis

Organosulfur Chemistry in Asymmetric Synthesis

Chiral Diazaligands for Asymmetric Synthesis

Chiral Diazaligands for Asymmetric Synthesis

Asymmetric Catalysis In Organic Synthesis

Asymmetric Synthesis of Nitrogen Heterocycles

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

Asymmetric organocatalysis: from biomimetic concepts to applications in asymmetric synthesis

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

Advances in Asymmetric Synthesis, Volume 1, Volume 1 (Advances in Asymmetric Synthesis)

Principles and Applications of Asymmetric Synthesis

Green Approaches To Asymmetric Catalytic Synthesis (SpringerBriefs in Molecular Science: Green Chemistry for Sustainability)

Chiral Auxiliaries and Ligands in Asymmetric Synthesis

Advances in Asymmetric Synthesis, Volume 3, Volume 3 (Advances in Asymmetric Synthesis)

Principles and Applications of Asymmetric Synthesis

Asymmetric Synthesis with Chemical and Biological Methods

Asymmetric Synthesis with Chemical and Biological Methods

Catalysis in Asymmetric Synthesis (Postgraduate Chemistry Series)

Handbook of heterogeneous catalytic hydrogenation for organic synthesis

Asymmetric Catalysis In Organic Synthesis (Baker Lecture Series)

Catalytic Antibodies

Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis

Catalytic Heterofunctionalization

Recommend Documents