Organosulfur Chemistry in Asymmetric Synthesis

Organosulfur Chemistry in Asymmetric Synthesis Edited by Takeshi Toru and Carsten Bolm Organosulfur Chemistry in Asymm...

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Organosulfur Chemistry in Asymmetric Synthesis Edited by Takeshi Toru and Carsten Bolm

Organosulfur Chemistry in Asymmetric Synthesis. Edited by Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

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Organosulfur Chemistry in Asymmetric Synthesis Edited by Takeshi Toru and Carsten Bolm

The Editors Prof. Dr. Takeshi Toru Nagoya Institute of Technology Graduate School of Engineering Department of Applied Chemistry Gokiso, Showa-ku Nagoya 466-8555 Japan

9 All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for

Prof. Dr. Carsten Bolm RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52056 Aachen Germany

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Bibliographic information published by the Deutsche Nationalbibliothek Die Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.d-nb.de. ª 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany Printed on acid-free paper Cover design Adam Design, Weinheim Typesetting Asco Typesetters, Hong Kong Printing Strauss GmbH, Mo¨rlenbach Bookbinding Litges & Dopf GmbH, Heppenheim ISBN 978-3-527-31854-4

V

Contents Preface

XI

List of Contributors

XIII 1

1

Asymmetric Synthesis of Chiral Sulfoxides Henri B. Kagan

1.1 1.1.1 1.1.2 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.3 1.3.1 1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.4 1.5 1.6

Chiral Sulfoxides 1 Introduction 1 The Main Routes to Chiral Sulfoxides 2 Use of Chiral Sulfur Precursors 3 Sulfinates (Andersen Method) 3 Diastereoselective Formation of Sulfinates 5 Sulfinates from Sulfites 7 Sulfinamides 9 Catalytic Enantioselective Sulfide Oxidation 12 Titanium Complexes 12 Diesters of Tartaric Acid 12 C 2-Symmetric 1,2-Diols as Ligands 14 Binaphthol and Derivatives 15 C3-Symmetric Triethanolamine Ligands 15 Ti (Salen) Catalysts 16 Manganese Complexes 17 Vanadium Complexes 18 Molybdenum Complexes 19 Iron Complexes 19 Miscellaneous 20 Catalytic Arylation of Sulfenate Anions 21 Enantioselective Oxidation of Sulfides 22 Summary 25 References 26


VI

Contents

2

Asymmetric Synthesis of Optically Active Sulfinic Acid Esters 31 Jo´zef Drabowicz, Piotr Kiełbasin´ski, Dorota Krasowska, and Marian Mikołajczyk

2.1 2.2 2.3

Introduction 31 Enantiomeric Sulfinic Acid Esters 32 Diastereomeric Sulfinic Acid Esters 40 References 53

3

Asymmetric Transformations Mediated by Sulfinyl Groups 55 Jose´ L. Garcıá Ruano, Jose´ Alemań, M. Beleń Cid, M. Ańgeles Fernańdez-Ibań˜ez, M. Carmen Maestro, M. Rosario Martıń, and Ana M. Martıń-Castro

3.1 3.2

Introduction 55 Nucleophilic Additions to CbO and CbN Bonds Mediated by a-Sulfinyl Groups 57 b-Ketosulfoxides 57 Reduction Reactions 57 Alkylation Reactions 70 Aldol Reaction with b-Ketosulfoxides Acting as Electrophiles 73 Hydrocyanation Reactions 76 b-Imino(enamino)sulfoxides 79 Conjugate Additions to a,b-Unsaturated Sulfoxides 83 Nucleophilic Additions 84 (E) and (Z)-2-Substituted Vinyl Sulfoxides 84 1-Substituted Vinyl Sulfoxides 88 Tandem Reactions 91 Radical Conjugate Additions and Other Reactions 95 Cycloadditions 96 Asymmetric Diels–Alder Reactions 96 Sulfinyl Dienophiles 96 Sulfinyl Dienes 107 Asymmetric Hetero Diels–Alder Reactions 109 Asymmetric 1,3-Dipolar Cycloadditions 111 Reactions with Nitrones 111 Reactions with Azomethine Ylides 115 Reactions with Nitrile Oxides 117 Reactions with Diazoalkanes 118 Reactions with Other Dipoles 121 Other Asymmetric Cycloadditions 122 Asymmetric Processes Stereocontrolled by Remote Sulfoxides 123 Nucleophilic Processes 123 Reactions with Sulfinylated Electrophiles 123 Reactions with Sulfinylated Nucleophiles 130 Asymmetric Pummerer Reaction 136 References 142

3.2.1 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.2 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.2 3.3.3 3.4 3.4.1 3.4.1.1 3.4.1.2 3.4.2 3.4.3 3.4.3.1 3.4.3.2 3.4.3.3 3.4.3.4 3.4.3.5 3.4.4 3.5 3.5.1 3.5.1.1 3.5.1.2 3.6

Contents

161

4

Synthesis and Applications of Chiral Dithioacetal Derivatives Philip C. Bulman Page and Benjamin R. Buckley

4.1 4.2 4.3 4.4

Introduction 161 Lithiated Dithianes 162 Alternative Methods 169 Oxidation Methods for the Construction of Chiral Dithioacetal Derivatives and Applications in Synthesis 171 Applications of Chiral Dithioacetal Derivatives in Natural Product and Biologically Active Compound Synthesis 176 Summary 177 References 177

4.5 4.6

179

5

Synthesis and Use of Chiral Sulfur Ylides Jean-François Brie`re and Patrick Metzner

5.1 5.1.1 5.1.2 5.1.3 5.2 5.2.1 5.2.1.1 5.2.1.2 5.2.1.3 5.2.1.4 5.2.1.5 5.2.2 5.3 5.3.1 5.3.2 5.4 5.4.1 5.4.2 5.5 5.6 5.7

Introduction 179 Reactions of Sulfonium Ylides 179 Methods of Preparation 180 Conditions for Stereocontrol and Theoretical Investigations Epoxidation Reaction 183 Stoichiometric Use of Sulfides 183 Stilbene Oxides 183 Unsaturated Epoxides 186 Aliphatic Epoxides 186 Terminal Epoxides 187 Functional Epoxides 187 Catalytic Use of Sulfides 188 Aziridination 189 Stoichiometric Aziridination, and Mechanism 190 Catalytic Aziridination 192 Cyclopropanation 194 Stoichiometric Cyclopropanation 195 Catalytic Cyclopropanation 197 [2,3]-Sigmatropic Rearrangement 199 Other Reactions 203 Conclusions 204 References 204

6

Synthesis and Use of Chiral Sulfoximines 209 Christin Worch, Agathe Christine Mayer, and Carsten Bolm

6.1 6.2 6.3 6.3.1

Introduction 209 Synthesis and Structural Modification 211 Applications in Asymmetric Synthesis 213 Use of Sulfoximines as Chiral Auxiliaries 214

182

VII

VIII

Contents

224

6.3.2 6.4

Use of Sulfoximines as Chiral Ligands Conclusions 229 References 229

7

Synthesis and Use of Chiral Sulfinamides 233 Chris H. Senanayake, Zhengxu Han, and Dhileepkumar Krishnamurthy

7.1 7.2 7.2.1 7.2.2 7.2.3 7.3 7.3.1 7.3.2 7.3.3 7.3.4

Introduction 233 Synthesis of Chiral Sulfinamides and Chiral Sulfinylimines 234 Background 234 Synthesis of Chiral Sulfinamides 235 Synthesis of Chiral Sulfinylimines 240 Use of Chiral Sulfinamides 241 Use as Chiral Sulfinyl Auxiliaries 241 Synthesis of Chiral Amines 241 Synthesis of Aziridines 249 Use of Chiral Sulfinamides as Ligands in Catalytic Asymmetric Reactions 252 Asymmetric Diels–Alder Reaction 252 Asymmetric Allylic Alkylation Reaction 254 Asymmetric Hydrogenation of Olefins 255 Application of Chiral Sulfinamides in the Synthesis of Biologically Active Molecules 256 Synthesis of SC-53116 256 Total Synthesis of (6R,7S)-7-Amino-7,8-Dihydro-a-Bisabolene 257 Asymmetric Synthesis of ( )-Pateamine 258 Synthesis of Polyoxamic Acid Lactone 259 Synthesis of Single Enantiomers of Sibutramine and Cetirizine 259 Summary 261 References 262

7.3.4.1 7.3.4.2 7.3.4.3 7.3.5 7.3.5.1 7.3.5.2 7.3.5.3 7.3.5.4 7.3.5.5 7.4

8

Asymmetric Catalysis Using Sulfoxides as Ligands 265 Inmaculada Fernańdez and Noureddine Khiar

Introduction 265 Some Considerations on the Coordination of Sulfoxides 266 Sulfoxides as Ligands in Metal-Catalyzed Asymmetric Catalysis 267 Catalytic Hydrogenations 267 Catalytic Cycloadditions 270 Addition of Diethylzinc to Benzaldehyde 272 Catalytic Allylic Substitutions 273 Utilization of Sulfoxides in Other Metal-Catalyzed Asymmetric Processes 279 8.3.5.1 Use of Sulfoxides in Lewis Acid–Lewis Base Bifunctional Asymmetric Catalysis 279 8.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5

Contents

8.3.5.2 Use of Sulfoxides as Chiral Ligands in Combination with Achiral Catalysts 281 8.3.5.3 Use of Sulfoxides as Ligands in Enantioselective Radical Allylation 283 8.3.6 Use of Sulfoxides as Neutral Coordinate-Organocatalysts 284 8.4 Conclusions 287 References 288 9

Sulfones in Asymmetric Catalysis 291 Juan Carlos Carretero, Ramoń Go´mez Arraya´s, and Javier Adrio

9.1 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.2.5 9.3 9.3.1 9.3.2 9.3.3 9.4 9.5 9.6

Introduction 291 Alkenyl Sulfones in Asymmetric Catalysis 292 Asymmetric Catalytic Conjugate Addition 292 Asymmetric Catalytic Conjugate Reduction 297 Asymmetric Catalytic Radical Addition 298 Asymmetric Catalytic Cycloadditions 300 Asymmetric Catalytic Dihydroxylation and Epoxidation Reactions 301 Ketosulfones 305 Asymmetric Reduction of Ketosulfones 305 Diels–Alder Reactions 308 Michael–Aldol Reactions 309 a-Diazo-b-Ketosulfones 311 Miscellaneous: Other Substituted Sulfones 314 Summary 315 References 317

10

Asymmetric Reaction of a-Sulfenyl Carbanions Shuichi Nakamura and Takeshi Toru

10.1 10.1.1 10.2

Asymmetric Reactions of a-Sulfenyl Carbanions 321 Introduction 321 Racemization Mechanism and Configurational Stability of a-Sulfenyl Carbanions 323 Diastereoselective Reaction of a-Sulfenyl Carbanions 326 Enantioselective Reaction of a-Sulfenyl Carbanions 329 Reaction Pathway of Enantioselective Reaction of a-Sulfenyl Carbanions 329 Enantioselective Reactions of a-Sulfenyl Carbanions 332 Enantioselective Reactions of a-Lithiated Dithioacetals 344 Conclusions 346 References 347

10.3 10.4 10.4.1 10.4.2 10.4.3 10.5

321

IX

X

Contents

11

Stereoselective Reactions with a-Sulfinyl Carbanions Alessandro Volonterio and Matteo Zanda

11.1 11.2 11.3 11.4 11.5 11.6

Introduction 351 Stereochemistry of a-Sulfinyl Carbanions 352 Alkylation of a-Sulfinyl Carbanions 354 Conjugated Additions with a-Sulfinyl Carbanions 357 Additions of a-Sulfinyl Carbanions to Carbonyl Compounds Additions of a-Sulfinyl Carbanions to Imines and Related Compounds 367 Conclusions 371 References 372

11.7

351

12

Asymmetric Reactions of a-Sulfonyl Carbanions Hans-Joachim Gais

12.1 12.2 12.3 12.4

Introduction 375 Configurationally Stable a-Sulfonyl Carbanions 380 Configurationally Labile a-Sulfonyl Carbanions 382 Configurationally Labile a-Sulfonyl Carbanions with an Additional Stereogenic Center 388 References 396

13

Computational Studies on Asymmetric Reactions with Sulfur Reagents 399 David Balcells and Feliu Maseras

13.1 13.2 13.3 13.4 13.5 13.6 13.7

Introduction 399 Directing Effect of Chiral Sulfur Substituents 400 Sulfur Centers in Chiral Intermediates 403 Synthesis of Chiral Sulfoxides from Prochiral Sulfides 405 Synthesis of Chiral Sulfoxides from Racemic Precursors 409 Other Systems Involving Chiral Sulfur Centers 413 Conclusions and Perspectives 414 References 415 Index

417

375

360

XI

Preface Sulfur has the atomic number 16, and is denoted by the symbol, S. In Nature, sulfur may be found in elemental form, and it is also widely present in gases such as H2S or SO2 and inorganic materials such as sulfates and sulfide-based minerals. The key role of sulfur in living systems (such as plants and animals) is exemplified by the importance of the sulfur-containing amino acids cysteine and methionine in polypeptides and proteins. Interestingly, both compounds are chiral and, even more so, they are enantiomerically pure. As they have stereogenic centers at carbon, a number of chiral sulfur-containing pharmaceuticals have also been developed. In having an interest in chirality on sulfur, many organic chemists have realized the synthetic opportunities and today, various chiral – and even achiral – organosulfur reagents have been recognized as highly effective tools to face the challenges of the asymmetric synthesis of complex organic molecules. In this book, Organosulfur Chemistry in Asymmetric Synthesis, we summarize various aspects of this fascinating area, the intention being to provide guidelines for new developments in modern organic chemistry. In this respect, the editors appreciate the scientific contributions of all authors, who all impressively demonstrated their high-level expertise in this emerging field of asymmetric synthesis. The overview begins with a presentation by Kagan, who summarizes asymmetric processes directed towards the synthesis of enantiopure sulfoxides. Related reactions can be applied in preparations of enantiomerically enriched sulfinic acid esters and chiral sulfinamides, as described by Drabowicz et al. and Senanayake et al., respectively. Once the stereogenic center at sulfur is established, the respective molecule can serve as a chiral auxiliary, which directs subsequent reactions. Along these lines, asymmetric transformations mediated by sulfinyl groups are presented by Garcıá Ruano et al. The use of enantiopure sulfoxides as ligands in asymmetric catalysis is summarized by Fernandez and Khiar, while Bulman Page and Buckley report on the chemistry of dithioacetals having stereogenic centers at both carbon and sulfur. If a sulfide is alkylated, sulfonium salts result, and these may be deprotonated by bases to yield sulfonium ylides. The syntheses and applications of chiral reagents of this type are presented by Brie`re and Metzner. Sulfoximines form the focus of the overview by Bolm and coworkers. Enantiopure derivatives are accessible by a variety of methods, including stereospecific iminations Organosulfur Chemistry in Asymmetric Synthesis. Edited by Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

XII

Preface

of sulfoxides, and alternative approaches, as well as the applications of sulfoximines in asymmetric synthesis, are described. In sulfones, the sulfur atom is in its highest oxidation state, and several asymmetric catalyses have utilized that class of organosulfur reagent, as summarized by Carretero and coworkers. Metallations of sulfides give rise to a-sulfenyl carbanions, the properties and chemical behavior of which in asymmetric reactions are presented by Nakamura and Toru. If sulfoxides are deprotonated with strong bases, then a-sulfinyl carbanions result, and their use in stereoselective CaC bond formation is highlighted by Volonterio and Zanda. Gais discusses structural aspects and the asymmetric reactions of a-sulfonyl carbanions. Finally, an insight into the theoretical background of asymmetric reactions with sulfur reagents is provided by Balcells and Maseras. Once again, the editors wish to express their sincere thanks to all contributors of this book. It has been an exciting enterprise, which began at a high energy level and seldom required any ‘human catalysis’ for adding essential activation energy. Hopefully, it will lead to a stable (market) product! Takeshi Toru Nagoya Institute of Technology

Carsten Bolm RWTH Aachen University

XIII

List of Contributors Javier Adrio Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Facultad de Ciencias 28049 Madrid Spain

Carsten Bolm RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52056 Aachen Germany

Jose´ Alemań Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain

Jean-François Brie`re INSA de Rouen, IRCOF-ECOFH CNRS, Universite´ de Rouen UMR COBRA 6014 rue Tesnie`re, BP 08 76131 Mont Saint-Aignan France

Ramoń Go´mez Arraya´s Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Facultad de Ciencias 28049 Madrid Spain David Balcells Institute of Chemical Research of Catalonia (ICIQ) Av. Paı¨sos Catalans, 16 43007 Tarragona/Catalonia Spain

Philip C. Bulman Page University of East Anglia School of Chemical Sciences and Pharmacy University Plain Norwich NR4 7TJ United Kingdom Benjamin R. Buckley Loughborough University Department of Chemistry Ashby Road Loughborough LE11 3TU United Kingdom


XIV


Juan Carlos Carretero Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Facultad de Ciencias 28049 Madrid Spain

Jose´ L. Garcıá Ruano Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain

M. Beleń Cid Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain

Zhengxu Han Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road P.O. Box 368 Ridgefield, CT 06877 USA

Jo´zef Drabowicz Center of Molecular and Macromolecular Studies Polish Academy of Sciences Department of Heteroorganic Chemistry Sienkiewicza 112 90-363 Ło´dz´ Poland Inmaculada Fernańdez Universidad de Sevilla Departamento de Quı´mica Orgańica y Farmaceútica Facultad de Farmacia 41012 Sevilla Spain M. Ańgeles Fernańdez-Ibań˜ez Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain Hans-Joachim Gais RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52056 Aachen Germany

Henri B. Kagan Universite´ Paris-Sud Institut de Chimie Molećulaire d’Orsay 91405 Orsay France Noureddine Khiar C.S.I.C-Universidad de Sevilla Instituto de Investigaciones Quı´micas c/ Ame´rico Vespucio, s/n. 41092 Sevilla Spain Piotr Kiełbasin´ski Center of Molecular and Macromolecular Studies Polish Academy of Sciences Department of Heteroorganic Chemistry Sienkiewicza 112 90-363 Ło´dz´ Poland


Dorota Krasowska Center of Molecular and Macromolecular Studies Polish Academy of Sciences Department of Heteroorganic Chemistry Sienkiewicza 112 90-363 Ło´dz´ Poland Dhileepkumar Krishnamurthy Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road P.O. Box 368 Ridgefield, CT 06877 USA M. Carmen Maestro Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain M. Rosario Martıń Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain Ana M. Martıń-Castro Universidad Autońoma de Madrid Departamento de Quı´mica Orgańica Cantoblanco 28049 Madrid Spain

Feliu Maseras Institute of Chemical Research of Catalonia (ICIQ) Av. Paı¨sos Catalans, 16 43007 Tarragona/Catalonia Spain Agathe Christine Mayer RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52056 Aachen Germany Patrick Metzner ENSICAEN Universite´ de Caen, CNRS Laboratoire de Chimie Molećulaire et Thioorganique 6, Boulevard du Marećhal Juin 14050 Caen France Marian Mikołajczyk Center of Molecular and Macromolecular Studies Polish Academy of Sciences Department of Heteroorganic Chemistry Sienkiewicza 112 90-363 Ło´dz´ Poland Shuichi Nakamura Nagoya Institute of Technology Graduate School of Engineering Department of Applied Chemistry Gokiso, Showa-ku Nagoya 466-8555 Japan

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Chris H. Senanayake Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road P.O. Box 368 Ridgefield, CT 06877 USA Takeshi Toru Nagoya Institute of Technology Graduate School of Engineering Department of Applied Chemistry Gokiso, Showa-ku Nagoya 466-8555 Japan Alessandro Volonterio C.N.R. - Istituto di Chimica del Riconoscimento Molecolare Dipartimento di Chimica Materiali ed Ingegneria Chimica ‘‘G. Natta’’ del Politecnico di Milano via Mancinelli 7 20131 Milan Italy

Christin Worch RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52056 Aachen Germany Matteo Zanda C.N.R. - Istituto di Chimica del Riconoscimento Molecolare Dipartimento di Chimica Materiali ed Ingegneria Chimica ‘‘G. Natta’’ del Politecnico di Milano via Mancinelli 7 20131 Milan Italy

1

1 Asymmetric Synthesis of Chiral Sulfoxides Henri B. Kagan

Abstract

Enantiopure sulfoxides are important auxiliaries in asymmetric synthesis, and some also have useful biological properties. In this chapter, the various routes to chiral sulfoxides are described, when these are based on asymmetric synthesis. Details are provided of the preparation and use of chiral precursors of sulfoxides such as sulfinates or sulfinamides. The enantioselective catalytic oxidation of sulfides is then discussed, with particular attention being paid to the various metal complexes which have been used. Finally, the stoichiometric oxidation of sulfides by chiral oxaziridines or other chiral organic oxidants is described.

1.1 Chiral Sulfoxides 1.1.1 Introduction

The first example of an optically active sulfoxide was described in 1926 [1]. This discovery was helpful for discussions regarding the nature of the SaO bond and the non-planarity of sulfur. Later, chiral sulfoxides slowly emerged as a class of compounds of interest in asymmetric synthesis (for reviews, see Refs. [2–7]). Enantiopure sulfoxides also became important in the pharmaceutical industry, due mainly to their biological properties. As a result, many types of pharmaceutical agents became of special interest, most notably one class of anti-ulcer drugs. Methods for the efficient preparation of chiral sulfoxides are also of particular interest [8]. Hence, this chapter will focus on approaches based on the asymmetric synthesis of chiral sulfoxides in a broad sense, where a chiral auxiliary is used in either a stoichiometric or catalytic manner and, preferentially, is also reusable.

Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

2

1 Asymmetric Synthesis of Chiral Sulfoxides

1.1.2 The Main Routes to Chiral Sulfoxides

The main routes to chiral sulfoxides are depicted in Scheme 1.1. The resolution of a racemic mixture (route i) was the first method used to produce chiral sulfoxides, by either a chemical approach or an enzymatic reaction. Since the 1960s, the transformation of a diastereochemically pure sulfinate has been a very useful method by which to obtain sulfoxides with high enantiomeric excess (ee) values (route ii). The enantioselective oxidation of prochiral sulfides by enzymatic or non-enzymatic methods represents a relatively direct way (route iii) to prepare enantioenriched sulfoxides. Another preparative method (route iv) is to modify the structure of some chiral sulfoxides without any loss of stereochemistry at the sulfur atom. In this chapter, attention will be focused on non-enzymatic asymmetric syntheses of sulfoxides, excluding the resolution processes. Two classes of reactions will be subsequently presented – the stoichiometric asymmetric syntheses, and the catalytic asymmetric syntheses.

Scheme 1.1 The main routes to chiral sulfoxides.

1.2 Use of Chiral Sulfur Precursors

1.2 Use of Chiral Sulfur Precursors 1.2.1 Sulfinates (Andersen Method)

Chiral sulfinates are excellent precursors of chiral sulfoxides, and this approach was pioneered by Andersen in 1962, using one diastereomer of menthyl ptolylsulfinate prepared from ()-menthol [9, 10]. The reaction was of preparative interest, and provided sulfoxides of very high ee-values. The inversion of configuration for the substitution reaction was firmly established [11, 12]. The now so-called Andersen method is illustrated schematically in Scheme 1.2 for the synthesis of the p-tolyl sulfoxides 2. Here, there are two important issues: (1) the need to prepare the menthyl p-tolylsulfinates 1 from ()-menthol; and (2) to separate the two epimers at sulfur. The p-tolylsulfinyl chloride (1) was prepared in situ by the reduction of p-tolylsulfonyl chloride according to a known procedure [13]. Subsequent separation of the two epimers could be achieved by crystallization, as (SS)-2 is crystalline and (RS)-2 is oily. Very soon, the Andersen method became the preferred approach when preparing enantiopure sulfoxides of known absolute configuration. The large majority of examples used as the starting material sulfinate (SS)-2 due to the ease of its preparation. An important improvement (giving 90% yield) of the preparation of ()-menthyl p-tolylsulfinate [(SS)-2] was introduced by Mioskowski and Solladie´ in 1980 [14]. These authors combined the crystallization step in acetone with an in-situ epimerization by a catalytic amount

Scheme 1.2 The Andersen method for the preparation of chiral sulfoxides.

3

4


of HCl. A modification of the preparation of sulfinates was proposed in 1987 by Sharpless et al. [15], based on the use of arylsulfonyl chlorides which are reduced in situ by trimethyl phosphite in the presence of triethylamine. In this way pure ()-menthyl p-toluenesulfinate was prepared at the 0.2 mole scale, with 66% yield. A wide range of sulfoxides 3 has been described in the literature (see Section 1.2.2) and subsequently used as synthetically useful chiral reagents. The reason for this is the ease of preparation of diastereochemically pure menthyl (SS)-ptoluenesulfinate 2, which is crystalline. Some other crystalline menthyl arylsulfinates have been synthesized for their use in the Andersen method; some examples are listed in Table 1.1. Menthyl alkylsulfinates (4, R ¼ alkyl), generally produce an oily material and are not suitable for the Andersen method. Alternatively, menthol may be replaced with another chiral and available alcohol; for example, cholesterol and methanesulfinyl chloride produce cholesteryl methanesulfinate epimers which may be separated by crystallization with moderate yields [19]. Many methyl alkyl sulfoxides (100% ee) could then be synthesized from these compounds by the addition of an appropriate Grignard reagent. In order to avoid the separation of diastereomeric sulfinates, the best solution is to directly produce one preponderant diastereomer in the esterification step (4 and chiral alcohol) (Scheme 1.3). Some kinetic diastereoselectivity (up to 10 : 1) has been observed by Whitesell and colleagues in sulfinate formation (7 and 8) from 2-phenylcyclohexanol 6 (Scheme 1.3) [20a,b]. One improvement in the synthesis of sulfinates was the intermediate formation of chlorosulfite esters by the action of thionyl chloride on trans-phenylcyclohexanol 6 (Scheme 1.3) [20b]. The mixture of diastereomeric chlorosulfites was then treated with various dialkylzincs over a range of conditions, and as a consequence sulfinate ester 7 was obtained with up to 97% yield and 92% diastereomeric excess (de). The authors assumed a dynamic kinetic resolution process where the chlorosulfinates were in

Table 1.1 Synthesis of some crystalline menthyl sulfinates.

Entry

R

1 2 3 4

1-Naphthyl 1-(2-Naphthyl) 1-(2-OMe-naphthyl) 4-Bromophenyl

Reference

10 16 17 18


Scheme 1.3 Use of 2-phenylcyclohexanol in the preparation of sulfinates.

rapid equilibrium in respect to the subsequent reaction with dialkylzincs, where one diastereomer reacts faster than the other. 1.2.2 Diastereoselective Formation of Sulfinates

Ridley and Smal prepared various arenesulfinic esters of dicyclohexyl-d-glucofuranose (DCG, 9) with a modest diastereoselectivity at sulfur (53 : 1) when the esterification was performed in pyridine–ether at 78 8C [21]. Crystallization led to the formation of one diastereomer, in low yield. In 1991, Llero, Fernandez and Alcudia made the important discovery that diacetone-d-glucose (DAG, 10) was converted stereoselectively in 90% yield into either (S)- or (R )-methanesulfinates from methanesulfinyl chloride, according to the nature of the amine which was taken as base [22]. Moreover, the two sulfinates were crystalline and could easily be purified. This methodology was optimized and extended to various DAG alkyl- or arylsulfinates (Scheme 1.4) [23a]. The isolated yields are excellent in diastereomerically pure sulfinates 11 and 12 (R ¼ Me, Et, n-Pr, p-Tol), except when R ¼ Cy because of decomposition during the isolation step. The tert-butyl sulfinates 11 and 12 were also prepared using the DAG approach, but the initial de-values were lower (72% and 84%, respectively) [23b]. The replacement of DAG 10 by other alcohols (menthol, cholesterol, borneol, etc.) surprisingly gave sulfinates with low de-values [24]. Metzner et al. used pure sulfinates 11 and 12 (R ¼ Cy) obtained by using the DAG technology [25]. Diastereomerically pure C2-symmetric bis-sulfinates esters were prepared by Khiar et al. from ethane-1,2-bis-sulfinyl chloride [26]. The mesodisulfinate was formed competitively and removed by crystallization. These authors discussed the effect of the base on the stereoselectivity and configuration of sulfinate esters produced using the DAG method, and favored a kinetic resolution mechanism involving the sulfinyl chloride and the base [27].

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Scheme 1.4 Diastereoselective formation of sugar sulfinates.

Recently, the asymmetric sulfinylation of achiral alcohols has been reported in the presence of stoichiometric or catalytic amounts of chiral tertiary amine. Toru et al. prepared in situ a combination of an arylsulfonyl chloride and a cinchona alkaloid (in stoichiometric amounts), acting as a chiral sulfinylating agent [28]. In this way, tert-butyl arylsulfinates 13 could be prepared with very high ee-values (Scheme 1.5). Ellman et al. devised a procedure where the cinchona alkaloids were taken as catalysts, in the presence of a proton sponge [29]. Benzyl tert-butylsulfinate 14 of 90% ee was obtained and its configuration established (after crystallization to upgrade its ee to 100%) by its transformation into enantiopure phenyl tert-butyl sulfoxide by the action of phenyllithium. Senanayake et al. described a very general sulfinylating process which allowed the asymmetric synthesis of sulfinates and sulfoxides from a stoichiometric amount of quinine or quinidine [30]. This is exemplified in Scheme 1.5 for the case of quinine. Quinine and thionyl chloride, in the presence of 2 equivalents of triethylamine at 78 8C, afforded a chlorosulfite the structure of which was modified by the formation of a pseudo five-membered ring through interaction with a vicinal tertiary nitrogen (‘‘ate’’ complex). The addition of a Grignard reagent (tert-butylMgCl) led to the formation of sulfinate 15 in high de. The subsequent addition of various alkylmagnesium chlorides generated almost enantiopure tertbutyl alkyl sulfoxides The addition of p-tolylmagnesium bromide to the ‘‘ate’’ complex generated the di-(p-tolyl)sulfoxide rather than the expected p-tolylsulfinate. Fortunately, p-tolylAlEt2 (prepared in situ from p-tolylMgBr and Et2AlCl) provided the p-tolylsulfinate derived from quinine (78% yield, 98% de, RS configuration) which could be transformed into various sulfoxides. For example, MeMgCl gave (S)-methyl p-tolyl sulfoxide (88% yield, 96% ee).


Scheme 1.5 Use of alkaloids in the preparation of sulfinates.

1.2.3 Sulfinates from Sulfites

Dissymmetrical sulfites have a stereogenic sulfur center and two different potential OR leaving groups. A degree of regioselectivity might be expected in the attack by 1 equivalent of an organometallic reagent, and this approach was investigated in 1991 by Kagan et al. (for a description, see Scheme 1.6) [31]. Crystalline cyclic sulfite 17 was prepared in 70% yield from diol 16 which itself was issued from (S)-ethyl lactate. The trans stereochemistry in sulfite 17 was established using X-ray crystallography. The addition of various Grignard reagents resulted in a clean monosubstitution reaction, with the formation of sulfinates 18, 19. The regioselectivity of the reaction was seen to depend on the Grignard reagent used; organometallics, such PhMgBr or BnMgBr did not provide any preferential ring cleavage of the sulfite 17. A hindered reagent such as t-BuMgBr or MesitylMgBr provided sulfinates (SS)18 (18 : 19 ¼ 95 : 5 and 88 : 12, respectively) which were easily purified by crystallization. MeMgI afforded an excess of 19 (19 : 18 ¼ 80 : 20). This approach was

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Scheme 1.6 From a chiral sulfite to chiral sulfinates.

useful for preparing tert-butylsulfinate 18 (R1 ¼ t-Bu), which in turn gave access to a variety of enantiopure sulfoxides. The stereochemistry of each substitution step was proved to occur with inversion of configuration. Cyclic sulfites derived from some C2-symmetric alcohols have been used as precursors of sulfinates. The two oxygen atoms of such sulfites are diastereotopic and should have different reactivities towards an achiral nucleophilic reagent. Kagan et al. established that sulfite 20, prepared from menthol and SOCl2, allowed production of the menthyl tert-butylsulfinate 21 in a monosubstitution process by using the combination t-BuLi : MgBr2 ¼ 2 : 1 (Scheme 1.7) [31]. The competitive reaction is the disubstitution giving directly the bis-tert-butyl sulfoxide (as observed with t-BuLi alone). Sulfinate formation could not be achieved with n-BuMgBr, which gave the di-n-butyl sulfoxide.

Scheme 1.7 Transformation of C2-symmetric sulfites into sulfinates.


Valleé et al. found that the cyclic sulfite 22 prepared from mannitol biscyclohexylidene could generate tert-butylsulfinates 23 with substantial stereoselectivity when it was attacked by tert-BuMgCl (Scheme 1.7) [32]. The de-values (prevalent RS configuration) were much improved (up to 96% de) by the addition of 1 equivalent of Et2AlCl, presumably due to the chelation of a magnesium atom at the sulfinyl group. The diasteroselectivity was moderate, with i-PrMgCl and BnMgCl (70 and 78% de, respectively). The sulfite of the bis-acetonide of mannitol was also investigated, but this led to a lower diastereoselectivity in the sulfinate formation. 1.2.4 Sulfinamides

It was established at an early stage that sulfoxides could be obtained from sulfinamides by the addition of methyllithium, with an inversion of configuration at sulfur [33]. Wudl and Lee prepared 1,2,3-oxathiazolidine-2-oxide 25 from ()ephedrine 24 and thionyl chloride in 80% yield as a mixture of diastereomers 25a and 25b (72 : 28) (Scheme 1.8) [34]. By using a combination of crystallization and HCl-catalyzed equilibration, pure 25a (100% de) could be isolated in 65% yield. The addition of a Grignard reagent or organolithiums gave sulfinamides 26 in good yields, but with only about 50% ee. The ring cleavage had occurred regioselectively. These authors discussed the stereochemical and mechanistic aspects of this reaction. The diastereochemically pure sulfinamide 26 was transformed into various enantiopure sulfoxides in excellent yields after treatment with CH3MgBr, CH3Li or PhLi. This approach to sulfoxides, using ephedrine as

Scheme 1.8 Use of 1,2,3-oxathiazolidine-2-oxide derived from ephedrine for the asymmetric synthesis of sulfoxides.

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a chiral auxiliary, was reinvestigated by Snyder and Benson in 1991 [35], and an improvement in the epimerization step generated 25 in 70% isolated yield. These authors optimized the transformation of 25 into sulfinamides 26 by using the Grignard reagents (to avoid epimerization at sulfur). In that way, various sulfinates 26 with de-values ranging between 95 and 99% could be isolated in excellent yields. In order to recover various dialkyl or alkyl aryl sulfoxides (499% ee) in good yields, the authors introduced AlMe3 before adding the Grignard reagents at 70 8C. Presumably, the AlMe3 generates an aluminum complex 27 prior to the attack by the Grignard reagent. Senananyake et al. synthesized the 1,2,3-oxathiazolidine-2-oxide system 29 from aminoalcohol 28 and thionyl chloride in 80% yield at the kilogram scale (Scheme 1.9) [36]. Here, nitrogen is connected to a sulfonyl moiety which acts as an electron-withdrawing group. As a consequence, the Grignard reagents cleave the ring with the release of nitrogen and formation of sulfinate 30 in excel-

Scheme 1.9 Use of 1,2,3-oxathiazolidine-2-oxide derived from a b-aminoalcohol for the asymmetric synthesis of sulfoxides.


lent yields and inversion of configuration. Enantiopure sulfoxides or sulfinamides were easily obtained subsequently. One interesting observation was the direct stereoselective transformation of alcohol 28 into 29 (diastereomeric ratio, dr ¼ 97 : 3) by using collidine or lutidine [tetrahydrofuran (THF), 45 8C] [37]. The epimer (at sulfur) of 29 was also diastereoselectively produced (dr ¼ 7 : 93) with 2,6-di-tert-butyl pyridine as base. The easy access to (RS)-29 or (SS-29) allowed the production of a large variety of chiral sulfoxides (495% ee) such as R1 ¼ t-Bu, R2 ¼ i-Pr. A further improvement was the selection of N-tosylnorephedrine 31 for the preparation of heterocyclic compound 32. The sequential addition of R1MgX and R2MgX generated, in a one-pot procedure, the sulfoxides (99% ee) with a configuration which depended on the order of introduction of the two Grignard reagents. Many types of sulfoxide have been synthesized using this approach. Likewise, t-Bu-S(O)-CH2CO2t-Bu (a useful reagent in asymmetric synthesis [38]) was prepared by the sequential addition of t-BuMgCl and Li enolate of tertbutyl acetate. The chiral templates 28 or 31 could be isolated and recycled, and the subsequent large-scale production of methyl p-tolyl sulfoxide from 32 has been described [39].

Scheme 1.10 Use of an Evans auxiliary for the synthesis of sulfoxides.

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Evans’s oxazolidinones, such as 34 and 36, represent starting materials for preparing a mixture of sulfinamides 35a, 35b or 37a, 37b which are crystalline and easy to separate by chromatography (Scheme 1.10) [40]. Another approach which has been investigated is based on the m-CPBA oxidation of N-arylthioand N-(alkylthio)oxazolidinones deriving from 36. The conversion of sulfinamides into sulfoxides 38 (495% ee) is excellent when using Grignard reagents or Reformatzky reagent (Zn þ tert-butyl bromoacetate). The only limitation is the initial separation step to obtain the diastereochemically pure sulfinamides 35a and 37a. These sulfinyl donors are complementary, as they afford sulfoxides of opposite absolute configuration. The chiral auxiliary 17 or 18 is released and could be recovered.

1.3 Catalytic Enantioselective Sulfide Oxidation

The catalytic enantioselective oxidation of sulfides represents the most direct approach to sulfoxides. Over the past 20 years a variety of catalytic systems have been developed, and some of these are now used at the industrial scale. There are, however, no fully generalized methods as the enantioselectivity is highly sensitive to the substrate structure. On occasion, a competitive overoxidation to sulfone is observed, together with some kinetic resolution which increases the ee-value of the isolated sulfoxide. This case will be not considered as the increase in ee is realized with a simultaneous decrease in the yield. The various families of chiral catalysts will be briefly presented below, the details and developments of which are available in various reviews [4, 8, 41–45]. 1.3.1 Titanium Complexes 1.3.1.1 Diesters of Tartaric Acid In 1984, the catalysts for the Sharpless asymmetric epoxidation of allylic alcohols were modified by the groups of Kagan and Modena in order that they may be applied to enantioselective sulfide oxidations. Kagan and colleagues used a titanium complex prepared from Ti (Oi-Pr) 4, (R,R )-diethyl tartrate (DET), water (1 : 2 : 1) with tert-butyl hydroperoxide (TBHP) [46, 47]. The reaction was run at 22 8C in methylene chloride. Initially, the titanium complex was taken in stoichiometric amounts, but a subsequent procedure was devised to function with substoichiometric amounts (50 to 10 mol.%) [48]. The replacement of TBHP with cumyl hydroperoxide led to a general improvement in the enantiomeric excess of the sulfoxide [48, 49]. By contrast, Modena et al. used a slightly different titanium system, with the combination Ti (Oi-Pr)4/(R,R )-DET ¼ 1 : 4 [50]. Optimization of the Kagan procedure with cumene hydroperoxide (CHP) as oxidant and stoichiometric amounts of the titanium complex allowed the preparation of ferrocenyl p-tolyl sulfoxide or methyl p-tolyl sulfoxide with 499% ee [51,


Scheme 1.11 Sulfoxidation in the presence of a Ti/DET complex.

52a]. A catalytic version, by decreasing the amount of the titanium complex (410 mol.%) was set up by replacing water with isopropanol in the combination Ti (Oi-Pr)4/(R,R )-DET/i-PrOH. Ee-values up of to 95% were observed for some aryl methyl sulfoxides [52b]. When the Modena protocol was recently reinvestigated [53] it gave interesting results for the enantioselective synthesis of sulfoxides using furylhydroperoxides instead of CHP. Some examples of the oxidation with both systems are included in Scheme 1.11. The mechanisms of the Kagan or Modena systems are, presumably, very similar, and NMR studies have demon-

Scheme 1.12 Industrial applications of the Ti/DET methodology.

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strated a great complexity for the species in equilibrium in solution [55]. The existence of a peroxotitanium species A (Scheme 1.11) has been postulated, and this has been well supported by the X-ray crystal structure of a peroxotitanium complex B [56]. The Kagan oxidation has been used on quite large scales to prepare sulfoxides of industrial interest, either as intermediates or products. Some examples (39 [57], 40 [58a], 41 [59], 42 [60], 43 [61]) are listed in Scheme 1.12. Von Unge et al. prepared esomeprazole 40 on a multi-kilogram scale using a modification of the Kagan procedure but with the addition of N,N-diisopropylethylamine to the titanium catalyst (4 mol.%) [58a]. The mechanism of this procedure, as recently discussed, is related to that proposed by Kagan et al.; however, it was suggested that the amine was present in the transition state because of hydrogen bonding to one of the reactants [58b]. The importance of the imidazole fragment was established, presumably because of an H-bonding (the NH of imidazole) to both the ester carbonyl of DET and the peroxo oxygen. 1.3.1.2 C 2-Symmetric 1,2-Diols as Ligands In the water-modified Kagan reagent, the DET ligand was replaced by a variety of chiral diols. For example, 1,2-diarylethane 1,2-diols 44 (Ar ¼ 2-methoxyphenyl) (Scheme 1.13) allowed stoichiometric, enantioselective oxidations of sulfides to be performed, sometimes with high ee-values [62a]. An asymmetric synthesis of sulindac esters (up to 94–96% ee, 50% yield) was recently described [62b]. Of special interest are the catalytic conditions developed by Rosini et al., using 44 (Ar ¼ Ph) [63]. Conditions have been identified which avoid the overoxidation of sulfides into sulfones. For example, aryl methyl or benzyl sulfides (ee-values up to 99%) are cleanly oxidized at 0 8C by TBHP in the presence of 10 mol.% of the combination Ti (Oi-Pr)4/44/H2O. The aryl benzyl sulfoxides represent a good starting material for the preparation of many sulfoxides, as the benzyl group can be displaced (with inversion of configuration) by various organometallics [64]. Among the C2 symmetric diols which were used instead of DET, mention might also be made of diol 45, as prepared by Imamoto et al. [65]. This gave moderate ee-values in the preparation of some sulfoxides, unless some subsequent kinetic resolution was allowed.

Scheme 1.13 Sulfoxidation in the presence of some Ti/1,2-diol complexes.


Scheme 1.14 Sulfoxidation in presence of some Ti/binaphthol complexes.

1.3.1.3 Binaphthol and Derivatives Uemura et al. developed a procedure for catalytic enantioselective oxidation by the in-situ formation of a Ti (IV) complex from binol 46, a titanium alkoxide and a large excess of water (Scheme 1.14) [66a]. For example, methyl p-tolyl sulfoxide was produced in 90% yield and 73% ee. Higher ee-values (but lower yields) could be achieved by combining this with a kinetic resolution [66b]; chiral diphenols 47 [67], 48 [68] and 49 [69] have been used instead of binol itself . One interesting application of the binol system is the formation of 50 (98% ee) under catalytic conditions [70]. Compound 50 is a good precursor of a variety of sulfoxides by a displacement reaction of CH2P(O)(OEt)2 by organometallics. 1.3.1.4 C3-Symmetric Triethanolamine Ligands Licini and Nugent investigated the use of 51 as ligand of a titanium catalyst of sulfoxidation (Scheme 1.15) [71]. The catalytic activity was good (1 mol.% catalyst could be used) and the ee-values were up to 85%. In this respect, an interesting mechanistic study has been conducted and a peroxo complex 52 isolated.

Scheme 1.15 A Ti/triethanolamine complex.

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1.3.1.5 Ti (Salen) Catalysts The Ti complexes with chiral salen ligands such as 53 (Scheme 1.16) were first investigated by Fujita et al. [72], although more recently Katsuki and colleagues have conducted extensive studies of new Salen–Ti (IV) catalysts for sulfoxidation by hydrogen peroxide [73]. Complex 54 was transformed, according to a procedure described by Belokon et al. [74] on another Salen–Ti (IV) complex, to a cis-m-dioxo dimer 55. This complex is an excellent catalyst precursor for the oxidation of sulfides at room temperature. For example, methyl phenyl sulfoxide was prepared at room temperature in 76% ee with aqueous H2O2, and in 94% ee with the urea hydrogen peroxide adduct (UHP). The procedure with UHP in methanol at 0 8C gave the best results, and was used for the oxidation of many aryl methyl sulfides (with ee-values in the range of 92–99%) in 80 to 90% yield. Benzyl ethyl sulfoxide was obtained with 93% ee and 72% yield. Presumably, UHP cleanly transforms complex 55 into the active peroxo complex 56. In the presence of water, 56 is in equilibrium with the less-stereoselective hydroperoxo (hydroxo)titanium species.

Scheme 1.16 Ti/salen catalysts for sulfoxidation.


1.3.2 Manganese Complexes

In 1991, Halterman et al. developed a D4 symmetric manganese tetraphenylporphyrin catalyst for the enantioselective oxidation of sulfides by iodosylbenzene [75]; subsequently ee-values of up to 68% have been obtained. The family of Salen manganese (III) provided some active enantioselective catalysts. For example, Jacobsen et al. prepared complex 57 (Scheme 1.17) which showed good catalytic activity (2 mol.%) for the oxidation alkyl aryl sulfides into sulfoxides (ee-values up to 68%) [76]. Later, Katsuki et al. prepared the Salen–manganese complexes 58–59 [77] and catalyzed the enantioselective oxidation of sulfides with ee-values of up to 90% (2-nitrophenyl methyl sulfoxide) with iodosobenzene as oxidant. Mukaiyama et al. have also studied the family of b-oxo aldiminato Mn (III) complex 60 using the combination pivaladehyde/molecular oxygen as an oxidant system [78]. In this way, methyl ortho-bromophenyl sulfoxide was obtained in 70% ee.

Scheme 1.17 Manganese catalysts for sulfoxidation.

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1.3.3 Vanadium Complexes

Nakajima et al. prepared oxo vanadium complexes derived from chiral Schiff bases such as 61 (Scheme 1.18), and which were catalysts for the oxidation of sulfides by CHP [79]. The enantioselectivity was at best 40% ee, although the catalytic activity was excellent (0.1 mol.% catalyst). A significant improvement was introduced by Bolm et al. in 1995 by the preparation of highly active vanadium catalysts (used at 0.01 mol.% amounts) derived from Schiff bases 62 and [VO(acac)2] [80a]. The oxidant was aqueous H2O2 (30%), and the sulfoxides were formed in 50 to 70% ee from aryl alkyl sulfides. These authors extended the reaction to the monooxidation of dithioketals or dithioacetals, and monosulfoxides could be obtained with ee-values up to 85% [80b]. Skarzewski et al. screened several Schiff bases (e.g. 63) deriving from (S)-valinol in the oxidation of thioanisol and acyclic disulfides [81], and the enantioselectivity was in the region of that achieved by Bolm et al. A bis-sulfoxide of 95% ee and 60% de has been obtained in 41% yield with ligand 63. This high ee was the result of the known amplification which arose from the two identical asymmetric reactions on a substrate with two prochiral centers. Katsuki et al. attempted to improve Bolm’s procedure by using new Schiff base tridentate ligands [82a]. The best of these ligands was 64, which gave 87% ee in methyl phenyl sulfoxide (for 1 mol.% catalyst). The Bolm procedure, when applied to the asymmetric synthesis of aryl ben-

Scheme 1.18 Vanadium catalysts for sulfoxidation.


zyl sulfoxides and some other sulfoxides (ee-values 490%), is often accompanied by a kinetic resolution [82b,c]. Ellman et al. used the Bolm catalyst for the monooxidation of di-tert-butyldisulfide into tert-butyl tert-butanesulfinate (90% ee) [83a]. The reaction was subsequently optimized for large-scale production [83b]. Salan–oxovanadium complexes were also shown to be excellent catalysts in asymmetric sulfoxidations using hydrogen peroxide as oxidant [84]. 1.3.4 Molybdenum Complexes

Molybdenum complexes as catalysts of enantioselective sulfoxidation have been explored but provided results inferior to those of the titanium or vanadium complexes [85]. Recently, Yamamoto and colleagues investigated the potential of a chiral Mo complex of a bis-hydroxamic acid 65 (Scheme 1.19) [86]. The best results were obtained with trityl hydroperoxide as oxidant at 0 8C in dichloromethane. The catalyst (2 mol.%) was prepared from MoO2(acac)2 and 65. In this way, p-tolyl methyl sulfoxide and 1-naphthyl methyl sulfoxide were prepared in good yields with 81% ee and 86% ee, respectively. Higher ee-values may be obtained by combining with a kinetic resolution through overoxidation to sulfone, albeit at the expense of the yield.

Scheme 1.19 A chiral bis-hydroxamic acid, ligand of molybdenum.

1.3.5 Iron Complexes

Although chiral iron (III) porphyrins are highly active catalysts of sulfoxidation, the enantiomeric excesses of the sulfoxides are modest [87]. Fontecave and colleagues studied the binuclear complex 66 (Scheme 1.20) compared to its mononuclear analogue, using hydrogen peroxide as oxidant, and found the ee-values of aryl methyl sulfoxides not to exceed 40% [88]. A successful approach was developed by Bolm et al. in 2003, who used 35% aqueous hydrogen peroxide and an iron complex (2 mol.%) derived from Fe (acac) 3 and the Schiff base 67 [89a]. This protocol was improved by the introduction of an additive (10 mol.%) as

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Scheme 1.20 Chiral iron catalysts for sulfoxidation.

p-methoxybenzoic acid [89b,c]. The oxidation of methyl p-chlorophenyl sulfide produced the corresponding sulfoxide in 92% ee and 60% yield. In some cases, kinetic resolution was also observed when the sulfone was produced. A mechanistic study of the iron-catalyzed oxidation of thioethers by iodosylarenes was recently reported by Bryliakov and Talsi [90b]. Iron complexes such as 68 and analogues have been screened, and are very active (0.02 mol.%) at room temperature. The highest enantioselectivity (77% ee) was achieved in the oxidation of isopropyl phenyl sulfide; the structure of the reaction intermediates has been established. 1.3.6 Miscellaneous

Recently, a chiral aluminum (salalen) complex 69a (Scheme 1.21) has been used as the catalyst of sulfoxidation by 30% hydrogen peroxide [90b]. The enantioselectivity was modest, after which the authors examined the binol-derived complex 69b [90]. The oxidation was run in methanol with 2 mol.% catalyst, a phosphate buffer (pH 7.4) and 1.1 equiv. 30% (v/v) H2O2. Many aryl methyl sulfoxides were produced with ee-values in the range of 97 to 99%, with sulfone formation between 51% and 10% according to the substrate. Some kinetic resolution was apparent if there was any overoxidation to sulfones. Polymeric chiral metalloporphyrin (Fe or Ru) complexes were used as insoluble catalysts of sulfide oxidation in toluene by 2,6-dichloropyridine N-oxide [91a], and ee-values of up to 75% were observed. A heterogeneous tungsten catalyst (WO3 aL*–30% aq. H2OaTHF; 0 8C or 25 8C) has been reported [91b], where

1.4 Catalytic Arylation of Sulfenate Anions

Scheme 1.21 Chiral Al catalysts for sulfoxidation.

L* ¼ (DHQD)2-PYR, a derivative of dihydroquinidine. This system allowed the asymmetric synthesis (84% yield, 88% ee) of (R )-lansoprazole, an anti-ulcer drug. Heterogeneous titanium complexes derived from multitopic binol ligands are excellent and robust catalysts of sulfoxidation [91c]. A new approach to catalytic sulfoxidation has been proposed by Fontecave and colleagues [91d] which is based on the preparation of ‘‘chiral-at-metal’’ octahedral Ru (III) catalysts, bearing only achiral ligands. Only modest enantioselectivities were reported, although some chiral copper catalysts permitted the production of sulfoxides (up to 81% ee) from aryl benzyl sulfides [91d].

1.4 Catalytic Arylation of Sulfenate Anions

A new approach has been devised by Poli, Madec and colleagues for the catalytic synthesis of sulfoxides, as described in Scheme 1.22 [92]. Racemic sulfoxide 70 underwent a retro-Michael reaction under the influence of a base, which gener-

Scheme 1.22 Asymmetric arylation of sulfenate ions.

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ated in situ sulfenate ion 71. This prochiral substrate is then coupled to an aryl iodide under the influence of a palladium (0) catalyst bearing a chiral diphosphine 72. Under optimized conditions (2 mol.% [Pd] and 2 mol.% 72, 4 equiv. Cs2CO3 in refluxing toluene) the isolated yields were excellent, with ee-values of up to 80% (p-tolyl p-nitrophenyl sulfoxide).

1.5 Enantioselective Oxidation of Sulfides

Classical oxygen donors are optically active peracids, and this approach has been monitored in the oxidation of sulfides, albeit without great success (ee-values 510%) [93]. Chiral hydroperoxides such as 73 represent another class of reagent which has provided higher enantiomeric excesses (Scheme 1.23), but the addition of Ti (Oi-Pr) 4 enhanced the ee-values to some extent [94]. Hydroperoxides such as 74 were also used as excellent chiral oxidants, with Ti (Oi-Pr) 4 as promoter [95]. (S)-Phenylethyl hydroperoxide oxidized methyl p-tolyl sulfide in the presence of a catalytic quantity of Ti (Oi-Pr) 4 [96]. The enantioselectivity was modest at low conversion, and increased with a subsequent kinetic resolution.

Scheme 1.23 Chiral hydroperoxides and oxaziridines.

1.5 Enantioselective Oxidation of Sulfides

An interesting chiral hydroperoxide 75 was briefly investigated by Seebach and Aoki for enantioselective sulfoxidation [97], whereby methyl phenyl sulfoxide was produced in 80% ee after oxidation at 30 8C in THF in 60% yield, but without sulfone formation. Davis and colleagues found several N-sulfonyloxazaridines to be interesting reagents for the transformation of sulfides into enantioenriched sulfoxides, with ee-values in excess of 95% in some cases [98]. These reagents are derived from camphor (for a review, see Ref . [99]), and some are currently available commercially. One crucial structural factor here is the presence of a gem-dihalo system in the vicinity of the oxaziridine ring (as in 76–77, Scheme 1.23). Typically, the reaction was carried out in CCl4 at room temperature. As an example, methyl p-tolyl sulfide provided the corresponding sulfoxide in 26% ee and 495% ee with 78b and 77b, respectively [98b], whereas 78a and 77a furnished methyl p-tolyl sulfoxide in 8% ee and 67% ee, respectively [98a]. Compound 78b proved to be an excellent reagent of quite broad applicability, and allowed the preparation of both benzyl tert-butyl sulfoxide (91% ee (S)) and methyl tert-butyl sulfoxide (94% ee (S)) [98a]. Bulman Page et al. prepared the dimethoxy analogue 79, which is a good enantioselective oxidant for non-aryl sulfides, and complementary of the Davis reagents [100]. The same authors also used the sulfonylimines 80 and aqueous hydrogen peroxide (30%) in the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in CH2Cl2 [101a]. In principle, this procedure should give rise to a catalytic version by respect to 80, with the in-situ generation of oxaziridines. In fact, the reaction was run under stoichiometric conditions, and in this way both methyl p-tolyl sulfoxide (60% ee) and methyl tert-butyl sulfoxide (86% ee) were prepared quantitatively. Bulman Page and colleagues also prepared and studied the pseudosaccharin derivatives 81 as chiral mediators in the hydrogen peroxidemediated oxidation of sulfides, although the ee-values remained below 35% [101b]. The imine 81 could be quantitatively recovered, however. A family of N-phosphinooxaziridines synthesized by Jennings et al. [102] proved capable of oxidizing various aryl alkyl sulfides with ee-values of between 35% and 70% (dichoromethane, 0 8C), without sulfone formation. The oxaziridine 82 and its oxaziridinium salt 83 (see Scheme 1.24) were easily prepared by Lusinchi and colleagues from norephedrine [103]. These authors oxidized methyl p-tolyl sulfide with an ee-value of less than 43%. In the presence of Bro¨nsted acids, some oxaziridines oxidize sulfides into sulfoxides without overoxidation to sulfones, presumably through an oxaziridinium intermediate. Thus, methanesulfonic acid catalyzes the oxygen transfer from 82 to an aryl methyl sulfide (ee 544%) [104]. Fontecave and colleagues, by using Lewis acids such as ZnCl2, were able to catalyze the enantioselective transfer of oxygen to sulfides from oxaziridine 84 [105]. This reaction was recently reinvestigated by Hanquet and coworkers with oxaziridines 85 (R ¼ H or Ph) containing a binaphthyl fragment [106], with the best results being observed for 85 (R ¼ H). With MeSO3H the oxygen transfer was very rapid (55 min), thus producing the sulfoxide and the iminium 86; tertbutyl methyl sulfoxide and methyl p-tolyl sulfoxide were formed in good yield with 60% ee and 47% ee, respectively. Replacement of the MeSO3H by triflic acid

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24


Scheme 1.24 Chiral oxaziridines.

greatly reduced the reaction rate but improved the ee-values (to 80% and 70%, respectively). The imine deriving from 86 could be recovered and recycled. It was of interest to note that, in the absence of acid, oxaziridine 85 (R ¼ H) may slowly oxidize tert-butyl methyl sulfide at room temperature, with a good enantioselectivity (70% ee). A completely different approach is the preparation of chiral hypervalent iodo compounds such as 87 [107] or 88 [108] (Scheme 1.25). These reagents are able to oxidize sulfides, thus providing sulfoxides 89 (ee-values560%) following a basic hydrolytic work-up. Oae and coworkers described a method for the asymmetric oxidation of diaryl sulfides using ()-menthol, pyridine and t-butylhypochlorite, followed by basic hydrolysis, giving modest ee-values [109]. Bromine oxidation of

Scheme 1.25 Some chiral oxidants.

1.6 Summary

an aryl methyl sulfide in the presence of ()-menthol also represents a means of preparing sulfoxonium compounds which are subsequently hydrolyzed into enantiomerically enriched sulfoxides [110]. The method of Oae was modified at the Otsuka Pharmaceutical company in order to prepare sulfoxide 90, the sodium salt of which (BOF-4272) will inhibit the enzyme, xanthine dehydrogenase [111]. With 4-cyanopyridine as base and 1-chlorobenzotriazole as oxidant, the crude sulfoxide was obtained almost quantitatively with 63% ee.

1.6 Summary

As illustrated by the above-described examples, the asymmetric synthesis of sulfoxides of very high ee-value is now possible using a wide variety of approaches. The stereochemically pure sulfinates serve as an excellent starting material for preparing enantiopure chiral sulfoxides, the key stage being to obtain a sulfinate of one epimer at sulfur, either by dynamic kinetic resolution induced by crystallization, or by the stereocontrolled sulfinylation of alcohols. The cyclic sulfites or the 1,2,3-oxathiazolidine-2-oxide systems are cyclic structures with two different leaving groups. The nucleophilic displacement of one of these groups can give rise to sulfinates or sulfinamides with a sulfur-defined stereochemistry, and such compounds may then easily be transformed into sulfoxides. The stoichiometric oxidation of sulfides is of preparative interest only in a limited number of cases. Whilst catalytic enantioselective oxidation is highly desirable, and can be used to generate sulfoxides with excellent ee-values, it suffers from a lack of generality, and the catalyst must also be optimized and able to adjust to the structure of the sulfide. Another problem is the competitive oxidation of sulfoxide into sulfone, which leads to a decrease in yield, although the ee-values may be increased by kinetic resolution (for some additional examples to those mentioned above, see Refs. [112–114]). The sulfinate approach and sulfide oxidation are complementary methods, as shown in Scheme 1.1. In the first of these methods at least one of the two groups of the sulfoxide is introduced as a nucleophile (organometallic chemistry), whereas the precursor of one group of the sulfide is usually of electrophilic character. It is remarkable that, when required, the large-scale asymmetric syntheses of sulfoxides has been realized in either stoichiometric or catalytic mode.

25

26


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2 Asymmetric Synthesis of Optically Active Sulfinic Acid Esters Jo´zef Drabowicz, Piotr Kiełbasin´ski, Dorota Krasowska, and Marian Mikołajczyk

Abstract

In this chapter a broad variety of methods of asymmetric synthesis of optically active enantiomeric and diastereomeric sulfinic esters is exhaustively presented. The majority of the described procedures are based on: direct esterification of sulfinic acids; reaction of sulfinyl chlorides with alcohols; carbon–sulfur bond formation; and the oxidation of prochiral, divalent sulfur precursors. The advantages and drawbacks of each approach are also discussed.

2.1 Introduction

Sulfinic acid esters having the general structure RS(O)OR1 constitute one of the oldest families of chiral organosulfur derivatives prepared in optically active forms [1]. Depending on the nature of substituents R and R1, these materials can be isolated either in enantiomeric forms (if R and R1 are achiral) or as diastereoisomeric mixtures (if R and R1 contain at least one stereogenic carbon atom). As a mater of fact, only a few diastereoisomeric sulfinic esters having chiral R and achiral R1 groups have been reported. The same is true for the structures having simultaneously chiral R and R1 groups. The configurational stability of sulfinic acid esters [1, 2] allows their use as key substrates in the synthesis of other optically active derivatives, and also as models in experiments aimed at establishing the absolute configuration of tri- and tetracoordinated sulfur compounds. A number of methods are available for the synthesis of sulfinic acid esters, and these are discussed comprehensively in the reviews listed in Ref . [3]. Unfortunately, only a few of the methods have been adapted for the asymmetric synthesis of optically active, enantiomeric or diastereomeric species. Among these are included procedures based on: Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

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2 Asymmetric Synthesis of Optically Active Sulfinic Acid Esters

• • • •

direct esterification of sulfinic acids, reaction of sulfinyl chlorides with alcohols, carbon–sulfur bond formation, oxidation of divalent sulfur precursors.

The procedures used for the preparation of the most important enantiomeric and diastereomeric sulfinic acid esters are listed below.

2.2 Enantiomeric Sulfinic Acid Esters

The application of enantiomeric, S-chiral sulfinic acid esters as substrates in the stereoselective synthesis of other optically active sulfinyl derivatives and models in mechanistic studies offer, in comparison with diastereomeric derivatives, at least two advantages. The first advantage results from the achiral nature of the alcohol moiety in these structures, since any optically active products generated from them will not therefore be contaminated by optically active byproducts, which usually are formed when diastereomeric esters are applied as substrates. The second advantage stems from the fact that enantiomeric esters can be prepared from alcohols which are miscible with, or at least easily soluble in, water. Such sulfinates afford, after conversion, water-soluble byproducts which can be easily removed from the resulting optically active products simply by waterwashing. In this way an isolation procedure is made much more convenient and so allows the final purification step to be speeded up. Consequently, the enantioselective synthesis of sulfinic esters continues to constitute the prime challenge for sulfur chemists.

Scheme 2.1 The first reported asymmetric oxidation of sulfenic esters


The oldest procedure for the asymmetric synthesis of enantiomeric sulfinic esters involved the stereoselective oxidation of sulfenate esters. Thus, treatment of O-methyl p-toluenesulfenate 1a with (þ)-monopercamphoric acid at 0 8C gave the corresponding O-methyl p-toluenesulfinate 2a which, upon reaction with benzylmagnesium chloride, afforded p-tolyl benzyl sulfoxide 3 with an optical purity of 2.2% (Scheme 2.1) [4a]. A similar reaction of benzhydryl p-toluenesulfenate 1b gave optically active benzhydryl p-toluenesulfinate 2b of low optical purity [4b]. Recently, with the use of a modified Sharpless chiral titanium reagent, a few sulfenic esters were converted into the corresponding optically active sulfinic acid esters with enantiomeric excess (ee)-values of up to 36% [4c]. The most general method for the preparation of enantiomeric sulfinates 2 and 4–10 is based on the reaction of racemic sulfinyl chlorides 11 with achiral alcohols in the presence of optically active tertiary amines 12 (Figure 2.1) and 13–14 (Scheme 2.2) as chiral auxiliaries and hydrogen chloride scavengers [Eq. (2.1)].

ð2:1Þ

This approach was applied for the first time using tertiary monoamines 12a,b in the present authors’ laboratory [5] for the preparation of a series of enantiomeric O-alkyl (aryl) alkane (arene) sulfinates 2 or 4–10 (as listed in Table 2.1), in-

Figure 2.1 Optically active tertiary amines used in the stoichiometric reaction of sulfinyl chlorides with achiral alcohols.

33

34


cluding O-methyl p-toluenesulfinate 2b labeled with the 14C atom in the methoxy group [Eq. (2.2)] [5c].

ð2:2Þ

More recently, the present authors applied heterocyclic tris-amine 12i [5b] (which is easily prepared from enantiomerically pure a-phenylethylamine [6]), while the Toru group used a few optically active diamines 12c–h [7a], and selected cinchona alkaloid derivatives 13 and 14 [7b]. Procedures based on the cinchona derivatives afforded O-benzyl t-butanesulfinate 10b and O-fluorenyl tert-butanesulfinate 10h with up to 36% ee and 94% ee, respectively.

Table 2.1 Asymmetric synthesis of sulfinic esters 2 or 4–10 by the

reaction of sulfinyl chlorides 11a–h and achiral alcohols or phenols in the presence of optically active amines 12a–h. Entry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Sulfinyl chloride 11 No.

R

a a b c d e f g h a a a a a a a a

p-Tol p-Tol Ph Me Et n-Pr i-Pr n-Bu t-Bu p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol

a) Not given.

Alcohol R1OH

Me Et n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr Ph t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu 1-Ad t-Bu

Amine 12b

(C)-12b (C)-12a (C)-12a (C)-12a (C)-12a (C)-12a (C)-12a (C)-12a (B)-12a 12c 12d 12e 12f 12g 12h 12h 12b

Sulfinic esters

Abs. config.

No.

Yield [%]

ee [%]

2a 2c 4a 5a 6a 7a 8a 9a 10a 2d 2d 2d 2d 2d 2d 2e 2d

a)

21.0 43.6 13.8 19.3 23.9 21.4 29.2 20.2 10 58 54 30 44 54 76 75 28

a) a) a) a)

69 72 75 74 48 63 47 53 32 84 89 40

R R R R R R R R S R R R R R R R R

Ref .

5a 5a 5a 5a 5a 5b 5b 5b 5b 7a 7a 7a 7a 7a 7a 7a 7a


The enantiomeric excesses of the sulfinic acid esters thus obtained depend heavily on the reaction temperature and also, to some extent, on the structure of all the reaction components. It should be noted that this procedure constitutes one of the first examples of enantioselective asymmetric synthesis based on the dynamic kinetic resolution (DKR) occurring under the reaction conditions through the rapid racemization of the sulfinyl chloride. Very recently, the catalytic versions of this approach were reported for the highly enantioselective asymmetric synthesis of O-benzyl and O-(9-fluorenyl) tert-butanesulfinates and O-tert-butyl arenesulfinates. A catalytic enantioselective synthesis of a series of O-arylmethyl tert-butanesulfinates 10b–g which was elucidated out in the Ellman laboratory [8, 9] was based on the reaction of racemic tert-butanesulfinyl chloride 11h with aryl-

Figure 2.2 Optically active tertiary amines used in the catalytic reaction of sulfinyl chlorides with achiral alcohols.

35

36


methyl alcohols in the presence of catalytic amounts of a variety of tertiary amines 12a, c and j–s (most of these are commercially available; see Figure 2.2) as chiral auxiliaries and at least equimolar amounts of hindered tertiary amines (Et3N, i-Pr2NEt, 1,2,2,5,5-pentamethylpiperidine-, 1,8-bis(dimethylamino)naphthalene) serving as bases to consume the liberated hydrogen chloride [Eq. (2.3)] (see Table 2.2).

ð2:3Þ

The experimental results collected in Table 2.2 indicate that commercially available cinchona alkaloids are superior catalysts for the reaction of tert-butanesulfinyl chloride 11h with a variety of benzylic alcohols. The highest selectivities were obtained for alcohols that have ortho substituents (e.g. 2,4,6-trichlorobenzyl alcohol). It is interesting to note that the chiral peptides 12s gave also the sulfinate 10b with up to 81% ee [8]. Table 2.2 Enantioselective synthesis of O-benzyl t-butanesulfinates 10b–g.a),b)

Entry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Chiral cat.a)

12j 12k 12a 12g 12l 12m 12n 12o 12p 12q 12r 12r 12r 12r 12r 12r 12r 12r 12s

Solvent

THF THF THF THF THF Toluene Toluene Toluene Toluene Toluene Toluene THF THF THF Toluene THF THF THF THF

Sulfinate 10b–g No.

R

Yield [%]

ee [%]

b b b b b b b b b b b c d e e f g g b

PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 p-MeOC6H4CH2 p-ClC6H4CH2 2,4-Cl2C6H3CH2 2,4-Cl2C6H3CH2 2,4-Cl2C6H3CH2 2,4-Cl2C6H3CH2 2,4-Cl2C6H3CH2 PhCH2

99 99 36 59 99 81 70 99 65 44 99 23 41 40 17 18 26 92 99

37 56 10 26 6 26 54 78 72 56 87 86 76 91 94 88 92 90 80

a) At 78 8C. b) With 2.5 equiv. of 1,8-(dimethyloamino)naphthalene as a base.

Reference

8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9


Scheme 2.2 Catalytic asymmetric sulfinylation of selected alcohols with cinchona esters.

Independently, combinations of the cinchona alkaloid esters 13–20 and arene (alkane)sulfinyl chlorides 11a,b and 11g–j were found by the Toru group to be a more general and excellent system for the catalytic asymmetric sulfinylation of selected alcohols, giving a series of the enantiomeric arene (alkane)sulfinates 2a–g, 4b, 21a–24a, with up to 99% ee (Scheme 2.2; Table 2.3) [7b, 10]. It is worth noting here that both enantiomers of the sulfinates 2a–g, 4b, 21a– 24a can be isolated in very high yields and with high enantiomeric excess by using either quinine or pseudoenantiomeric quinidine derivatives. It is also interesting to note that a cinchona alkaloid derivative and a sulfinyl chloride must be mixed prior to the addition of an alcohol in order to achieve its enantioselective sulfinylation. Another approach to the preparation of enantiomeric sulfinates having a relatively high optical purity is based on the reaction of prochiral sulfites 25 with tert-butylmagnesium chloride in the presence of aminoalcohols 12m, 12o, 12q, and 12r. This enantioselective conversion generates O-alkyl tert-butanesulfinates 10h–l, with the sulfinyl sulfur atom as the sole stereogenic center with 40–70% ee-values (Scheme 2.3; Table 2.4) [11]. A few O-alkyl arenesulfinates 2 or 4 having low optical purities were obtained in the esterification of the parent sulfinic acids 26 with alcohols carried out in the presence of optically active carbodimides 27 as condensation agents [Eq. (2.4)] [12].

ð2:4Þ

Similarly, the reaction of optically active O-alkylisoureas 28 with benzenesulfinic acid 26b afforded a series of O-alkyl benzenesulfinates 4 with a low (58%) enantiomeric excess [Eq. (2.5)] [13].

37

38

2 Asymmetric Synthesis of Optically Active Sulfinic Acid Esters Table 2.3 Enantioselective sulfinylation of alcohols by a cinchona

alkaloid/arenesulfinyl chloride system. Sulfinyl chloride 11 Entry Alkaloid No. R

1a) 2a) 3a) 4a) 5a) 6a) 7a) 8a) 9a) 10a) 11a) 12a) 13a) 14a) 15b) 16b) 17b) 18b) 19b) 20b) 21b)

13 14 15 15 13 14 16 17 18 19 20 20 13 13 20 13 20 20 13 20 20

a a a a a a a a a a a a a a b b g h h i j

p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol p-Tol Ph Ph p-ClC6H4 p-MeOC6H4 p-MeOC6H4 4-MeO-3-MeC6H3 2,4,6-Me3C6H2

Sulfinate

Alcohol R1OH

t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu Adc) c-C6H11d) Flue) t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu

Solvent

No. Yield ee Config. [%] [%]

MeCN/DCM MeCN/DCM MeCN/DCM Toluene DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM

2d 2d 2d 2d 2d 2d 2d 2d 2d 2d 2d 2e 2f 2g 4b 4b 21a 22g 22g 23a 24a

a) Reaction carried out at 78 8C. b) Reaction carried out at 90 8C. c) Ad ¼ 1-Adamanthyl. d) c-C6H11 ¼ Cyclohexyl. e) Flu ¼ Fluorenyl. DCM ¼ dichloromethane; nd ¼ not determined.

Scheme 2.3 Reaction of prochiral sulfites with t-butylmagnesium chloride in the presence of amino alcohols.

51 82 89 90 92 84 85 83 81 61 93 93 85 90 88 93 73 74 70 74 72

58 18 54 35 87 60 80 59 43 3 96 93 47 50 83 88 84 96 99 94 92

S R S S S S S S R R R R nd nd R S (þ)-nd (þ)-nd ()-nd (þ)-nd (þ)-nd

2.2 Enantiomeric Sulfinic Acid Esters Table 2.4 Enantioselective synthesis of O-alkyl t-butanesulfinates 10 (Scheme 2.3).

Entry

1 2 3 4 5 6 7

Sulfite 25 No.

R

a b c d e f g

Me Et n-Pr n-Pr n-Pr i-Pr n-Bu

Aminoalcohol

12r 12r 12r 12q 12o 12m 12r

Sulfinic ester 10 No.

R

Yield [%]

ee [%]

Abs. config.

h i j j j k l

Me Et n-Pr n-Pr n-Pr i-Pr n-Bu

62 62 79 69 63 70 84

53 69 74 20 28 43 62

R R R S S R R

ð2:5Þ

A few O-alkyl p-toluenesulfinates 2 of a low enantiomeric excess were prepared by the sparteine-catalyzed reaction of p-toluenesulfonyl cyanide with primary alcohols [Eq. (2.6)] [5b].

ð2:6Þ

A similar reaction of methanol and p-toluenesulfonyl cyanide carried out in the presence of optically active methyl-n-propyl-phenylphosphine gave dextrorotatory O-methyl p-toluenesulfinate 2a [Eq. (2.7)] [5b].

ð2:7Þ

39

40


2.3 Diastereomeric Sulfinic Acid Esters

The only diastereomeric sulfinic acid esters which have a C-chiral substituent connected with the sulfinyl sulfur atom and an achiral alkoxy group are the steroidal O-methyl sulfinates 29a,b and 30a,b. These were formed upon the treatment of 6b-mercapto-5a-cholestane 31 or the corresponding disulfide 32 with lead tetraacetate in methanol-chloroform (Scheme 2.4) [14]. The most common procedure for the preparation of diastereomeric sulfinic acid esters having a chiral ester functionality is based on the condensation of sulfinyl chlorides with the appropriately selected enantiomerically or diastereomerically pure alcohols, and carried out in the presence of an organic or inorganic base. This method is probably the oldest known for the synthesis of optically active sulfinic esters, and was first used in 1926. By using this approach, Phillips [15] obtained O-menthyl p-toluenesulfinate 2i, and found that the reaction between p-toluenesulfinyl chloride 11a and ()-(1R,2S,5R )-menthol in the presence of pyridine gave a mixture of the diastereomeric O-menthyl p-toluenesulfinates 2i (Scheme 2.5). From this reaction the pure solid diastereomer ()-(SS)-2i was isolated by crystallization from acetone. Because of the importance of ()-(SS)-2i as a substrate in the synthesis of optically active sulfoxides and N-alkylidene sulfinamides, a considerable effort has been devoted to improve its synthesis. The most important improvement is based on the observation reported as early as 1959 by Herbrandson and Dickerson [16], that the addition of hydrogen chloride gas to an ethereal solution of a mixture of the diastereomers of 2i containing also a catalytic amount of tetraalkyl ammonium salts causes epimerization of the liquid diastereomer (þ)-(R )-2i to its crystalline epimer ()-(SS)-2i, which was isolated with the yield exceeding 90%. Later,

Scheme 2.4 Synthesis of steroidal O-methyl sulfinates.


Scheme 2.5 Reaction of p-toluenesulfinyl chloride with ()-(1R,2S,5R)-menthol.

Mioskowski and Solladie [17] modified the conditions applied by Herbrandson and Dickerson, and were able to isolate the less-soluble ()-(SS)-2i isomer by a single epimerization protocol, also in 90% yield. In the present authors’ laboratory [18] the above-discussed isomerization procedures did not always give fully reproducible results. Indeed, it has been found that the most consistent results of epimerization of the sulfinates 2i are observed when the solid diastereomer, once formed, is dissolved in the mother liquid and the crystallization process is repeated. Another modification of the reaction between p-toluenesulfinyl chloride and ()-menthol, which allows isolation of the solid ()-(SS)-2i diastereomer in

Scheme 2.6 Condensation of p-toluenesulfinic acid with ()-(1R,2S,5R )-menthol carried out in the presence of condensing reagents.

41

42


a high yield, involves a very rapid addition of the reaction components [19]. The solid ()-(S)-2i diastereomer was also prepared, albeit in a much lower chemical yield, by the condensation of p-toluenesulfinic acid 26a with ()-menthol and carried out in the presence of each of the three condensing reagents: 1-methylchloropyridinium iodide; diethyl azidodicarboxylate/triphenylphosphine system; and dicyclohexylcarbodiimide (Scheme 2.6) [20]. The use of (þ)-(1S,2R,5S)-menthol leads obviously to the formation of (þ)-(R )O-menthyl p-toluenesulfinate. Both sulfinates 2i with the opposite configuration at the sulfinyl sulfur atom are now commercially available. The synthesis of diastereomeric O-menthyl sulfinates by using the Phillips approach is general in scope, and a great number of other diastereomeric sulfinates 4, 5, 9, and 33–39 have been prepared in a similar way, starting from the appropriate sulfinyl chlorides 11 [Eq. (2.8) and Table 2.5].

ð2:8Þ

It should be noted that ()-(SS)-O-menthyl benzesulfinate-4c was also prepared from benzenesulfinyl chloride 11b and 1-()-menthoxytrimethylsilane 40 in 91% yield [Eq. (2.9)] [29].

Table 2.5 Diastereoselective synthesis of O-()-menthyl

arene(alkane)sulfinates 4, 5, 9, and 33–39 [Eq. (2.8)]. Sulfinyl chloride 11

Sulfinic ester

No.

R

No.

[a]D

Abs. config.

de [%]

b i j k l m m c g n o

Ph p-MeOC6H4 p-ClC6H4 p-IC6H4 1-C10H7 PhCH2 PhCH2 Me n-Bu 2-MeO-C10H6 2-(iPrO)2P(O)-C6H4

4b 33 34 35 36 37 37 5b 9b 38 39

206.1 189.1 181.1 145.8 433.2 þ105.0 þ123.0 99.1 þ50.0 183.0 105.0

SS SS SS SS SS RS RS RS RS SS SS

100 100 100 100 100 90.5 100 13 47 100 33

Reference

21 22 2, 23 24 22a 25 26 22b 24 27 28


Scheme 2.7 Reaction of sulfonyl chlorides 41 with (1R,2S,5R)-menthol carried out in the presence of trimethyl phosphite or triphenylphosphine.

ð2:9Þ

Very useful and convenient modifications of the Phillips approach for the preparation of diastereomeric sulfinic esters were originally elucidated by the Sharpless group and later modified by the Toru groups. These are based on the condensation of ()-menthol with the transiently formed sulfinyl chlorides 11 which, in turn, are generated by the in-situ reduction of commonly available sul-

Table 2.6 Diastereoselective synthesis of O-menthyl arenesulfinates 2,

33, 34, and 42–48 from arenesulfonyl chlorides 41. Sulfonyl chloride No.

a b c d e f g h i j

R1

p-Tol p-MeOC6H4 p-ClC6H4 2-C10H7 2,4,6-(i-Pr)3C6H2 p-(t-Bu)C6H4 o-MeO2CC6H4 2,4,6-Me3C6H2 8-Quinolyl 2-Thienyl

a) From Ref . [30]. b) From Ref . [31]. c) Data not provided.

Sulfinic ester No.

2a 33 34 36 38 39 40 41 42 43

(MeO)3Pa)

Ph3Pb)

Yield [%]

S:R

Yield [%]

S:R

90 89 92 96 36 48

58 : 42 56 : 44 61 : 39 58 : 42

95 91 96

65 : 35 50 : 50 60 : 40

99

70 : 30

c)

70 52 92

61 : 39 61 : 39 60 : 40 65 : 35 64 : 36

43

44


Scheme 2.8 Synthesis of diastereomerically pure O-cholesteryl methanesulfinates.

fonyl chlorides 41 with trimethyl phosphite [30] or triphenylphosphine (Scheme 2.7) [31]. These modifications are especially convenient for the preparation of diastereomeric O-menthyl sulfinates, for which there are no readily available sulfinyl chloride precursors. A variety of O-menthyl sulfinates 2, 33, 34 and 42–48, which were prepared according to this procedure in up to 2 : 1 S/R diastereoselectivity, are listed in Table 2.6. O-Menthyl alkanesulfinates prepared from levo- and dextrorotatory menthol are liquids, and therefore cannot be isolated in a diastereomerically pure state by crystallization. In order to overcome this problem, a few other optically active alcohols were used instead of ()-menthol as the chiral reaction components. For example, starting from ()-cholesterol 49 and methanesulfinyl chloride 11c, diastereomerically pure O-cholesteryl methanesulfinates ()-(S)-50 and (þ)-(R )-50 were obtained by fractional crystallization (Scheme 2.8), albeit in low yields [32]. A number of O-cholesteryl a,b-unsaturated sulfinic esters 51 were prepared upon treatment of ()-cholesterol 49 with a,b-unsaturated sulfinyl chlorides 52 under various reaction conditions (Scheme 2.9; Table 2.7) [33]. The diasteromerically pure sulfinates 51b–d were isolated from the resulting diastereomeric mixtures by one or two recrystallizations from acetone. Similarly, diastereomerically pure methane- and tert-butanesulfinates ()-(S)-5c and ()-(S)-10i derived from l-N-methylephedrine (EphOH) were isolated, al-

Scheme 2.9 Synthesis of O-cholesteryl 1-alkenesulfinates.

2.3 Diastereomeric Sulfinic Acid Esters Table 2.7 Synthesis of O-cholesteryl 1-alkenesulfinates 51.

Conditionsa)

Sulfinic ester 51 R

No.

R1

R2

Base

Temp. [8C]

Addition moded)

1 2 3 4 5 6 7 8 9 10 11 12

a a a b b c c c d d e e

H H H CO2Me CO2Me t-Bu t-Bu t-Bu Ph Ph Ph Ph

H H H H H H H H H H Cl Cl

K2CO3 Quinine Quinidine K2CO3 Quinine K2CO3 Quinine Quinidine K2CO3 Quinine Quinine Quinidine

78 to 10 78 78 to 20 78 to 20 78 to 20 78 to 20 78 to 20 78 78 to 20 78 to 20 78 to rt 78 to rt

A A B A B A B B B B B B

a) b) c) d)

de [%] b)

Yield [%] b)

Abs. config.c)

24 51 55 63 89 42 76 94 48 73 88 89

13 35 22 56 6 0 50 65 3 43 10 9

SS RS SS RS SS RS SS SS RS RS SS

All reactions carried out in CH2Cl2. Yield and de refers to initial samples isolated by chromatography. For a major diastereomer. Addition mode: A ¼ alcohol and base added to sulfinyl chloride solution; B ¼ sulfinyl chloride solution added to alcohol and base solution. rt ¼ room temperature.

though in poor chemical yields, by flash chromatography of the crude products [Eq. (2.10)] [34].

ð2:10Þ

In the pool of enantiomerically pure chiral alcohols, sugar derivatives have been employed with good results in the preparation of diastereomerically pure sulfinic esters. The best results have been obtained with diacetone-d-glucose (DAG) 53a (a commercially available, sugar-derived secondary alcohol) and with dicyclohexylidene-O-glucose (DCG) 53b. The first sugar-containing diastereomeric arenesulfinates were prepared by the reactions of 53a with either ptoluenesulfinylimidazolide 54 [Eq. (2.11)] [35] or sulfinyl chlorides 11 (Scheme 2.10; Table 2.8) [36].

45

46


ð2:11Þ

Alcudia and coworkers [37] conducted a series of very systematic studies on the reaction between sulfinyl chlorides and DAG and DCG, and developed a general method for the asymmetric synthesis of both diastereomerically pure alkane- and arenesulfinates 55 and 56 (Scheme 2.10; Table 2.8). One point of interest here is that sulfinates having the SS-configuration are formed as the major isomers (diastereomeric excess, de, 89–95%) when i-Pr2NEt is used, whereas sulfinates with the RS-configuration are predominantly produced when pyridine is used as the HCl scavenger. The sulfinates 55b–f can be easily purified by using flash chromatography, the only exception being ptoluenesulfinate 55a, where the two diastereomers cannot be sufficiently resolved using chromatographic methods commonly used for separation. However, the (S)-p-toluenesulfinate 55a can be obtained in a diastereomerically pure state by recrystallization from hexane. The reaction of p-toluenesulfinyl chloride 11a (ca. 15 molar excess) with either cellulose or b-cyclodextrin, carried out in pyridine at ambient temperature and followed by pouring the reaction mixture into water and consecutive acidic and

Scheme 2.10 Reaction of sulfinyl chlorides with sugar alcohols DAG and DCG.

2.3 Diastereomeric Sulfinic Acid Esters Table 2.8 Reaction of DAG-53a or DCG-53b with sulfinyl chlorides 11 (Scheme 2.10).

Sulfinyl chloride 11

Sulfinic ester 55/56

No.

R

Base

Solvent

No.

R

R1

R/S ratio

Yield [%]

a a b i j l c c d d e f h h

p-Tol p-Tol Ph p-MeOC6H4 p-ClC6H4 1-C10H7 Me Me Et Et n-Pr i-Pr t-Bu t-Bu

Pyridine i-Pr2NEt – – – – Pyridine i-Pr2NEt Pyridine i-Pr2NEt Pyridine i-Pr2NEt NEt3 Pyridine

THF Toluene – – – – THF Toluene THF Toluene THF Toluene Toluene THF

55a 55a 56a 56b 56c 56d 55b 55b 55c 55c 55d 55e 55f 55f

p-Tol p-Tol Ph p-MeOC6H4 p-ClC6H4 1-C10H7 Me Me Et Et n-Pr i-Pr t-Bu t-Bu

53a 53a 53a 53b 53b 53b 53a 53a 53a 53a 53a 53a 53a 53a

86/14 6/94 – – – – 93/7 2/98 86/14 2/98 85/15 2/98 14/86 92/8

84 87 – – – – 87 90 85 90 75 50 74 50

THF ¼ tetrahydrofuran.

Figure 2.3 p-Toluenesulfinates derived from cellulose and b-cyclodextrin.

Reference

37 37 36 36 36 36 37b 37b 37b 37b 37b 37b 37c 37c

47

48


Scheme 2.11 Reaction of ethane 1,2-bis-sulfinyl chloride with sugar alcohols.

basic washing of the organic phase, provided stable tris(p-toluenesulfinates) of cellulose 57 or b-cyclodextrin with an unknown diastereomeric composition [38]. In this context, it is of interest to note that the diastereomerically pure mono (p-toluenesulfinate) of b-cyclodextrin 58 (Figure 2.3) was also isolated and fully characterized as a product of this reaction [39]. Both sugar alcohols 53a and 53b were used as inducers of chirality in their reactions with ethane 1,2-bis-sulfinyl chloride 59. The sulfinylation in this case resulted in a very high selectivity of the C2-symmetric bis-sulfinate esters 61a,b

Table 2.9 Diastereoselective reaction of ethane-1,2-bis-sulfinyl chloride

with sugar alcohols 53a,b. Entry

Alcohol a) R*OH

Base

Solventb)

dr c),d) (R,R)-61 : (S,S)-63 : (R,S)-62

1 2 3 4

53a 53a 53b 53b

Pyridine i-Pr2NEt Pyridine i-Pr2NEt

THF Toluene THF Toluene

82 : 1 : 17 0 : 88 : 12 84 : 1 : 15 0 : 85 : 15

a) 53a ¼ diacetone-d-glucose; 53b ¼ dicyclohexylidene-d-glucose. b) All reactions carried out at 75 8C. c) Determined for the crude mixture using 1H NMR. d) Obtained in almost quantitative yield. dr ¼ diastereomeric ratio; THF ¼ tetrahydrofuran.


(R,R ) or 63a,b (S,S), together with the meso bis-sulfinate esters 62a,b (R,S). Also in this reaction, changing the amine used to scavenge the generated HCl from pyridine to diisopropylethylamine led to a complete change in the diastereoselectivity of the reaction (Scheme 2.11; Table 2.9) [40]. An efficient preparation of diastereomerically pure sulfinic esters is based on the use of trans-2-phenylcyclohexanol 64 as a chiral auxiliary [41]. Its reaction with an excess of alkane- and arenesulfinyl chlorides 11a, 11c, 11f, and 11k afforded the corresponding sulfinic esters 65 [Eq. (2.12) and Table 2.10] in good yield and selectivity. The diastereomers were readily separated by chromatography and crystallization to give the SS-diastereomer. For example, the major diastereomer of 65a was obtained in 98% de after two crystallizations, with a recovery of 62%.

ð2:12Þ

Another general approach to the preparation of diastereomeric sulfinates with a high value of diastereomeric excess is based on the reaction between organometallic reagents and chiral sulfur acid derivatives such as acyclic chlorosulfites and cyclic sulfites. Thus, treatment of a near-equimolar mixture of two diastereomeric chlorosulfites 66a and 66b, prepared in situ from chiral trans-2phenylcyclohexanol 64 and thionyl chloride, with an equivalent amount of dialkylzinc reagents 67 afforded high levels of conversion of both chlorosulfites to almost single diastereomers of the corresponding sulfinate esters 65b,c,e (Scheme 2.12) [42]. On the other hand, the same mixture of chlorosulfites 66a,b gave upon treatment with arylorganometallics the sulfinates 65a,b and 65f (RbPh), with diastereomer ratios similar to those of the starting chlorosulfites (between 1 : 1 and 1 : 2).

Table 2.10 Diastereoselective reaction of 2-phenylcyclohexanol 64 with sulfinyl chlorides 11.

Sulfinyl chloride 11

[a]D (acetone)

Sulfinic ester 65

No.

R

No.

Yield [%]

S:R

S

R

a c f k

p-Tol Me i-Pr 2-Nph

a b c d

92 80 100 84

10 : 1 9:2 9:2 65 : 1

þ82.0 þ25.0 þ51.7 þ104.2

þ176.5 þ157.0 þ196.6 þ124.5

49

50


Scheme 2.12 Reaction of diastereomeric chlorosulfites with organometallic reagents.

A few diastereomerically pure sulfinates 68 and 69 were prepared in high chemical yields in the selective ring-opening reaction of cyclic sulfite 70 and various organometallic reagents (Scheme 2.13; Table 2.11) [43]. A similar ring-opening reaction of the cyclic, sugar-derived sulfite 71 [44] with organometallic reagents could be stopped at the stage of the corresponding sulfinates only in the reaction with tert-butylmagnesium chloride. This reaction

Scheme 2.13 Selective ring-opening reaction of cyclic sulfite with various organometallic reagents.

2.3 Diastereomeric Sulfinic Acid Esters Table 2.11 Diastereoselective reaction of cyclic sulfites 68 and 69 with organometallic reagents.

Entry

R1M

68 : 69

No.

Yield [%] a)

1 2 3 4 5 6 7 8

MeLi MeMgI EtMgBr n-OctMgBr t-BuMgBr t-BuMgCl CH2 bCHMgCl (CH3)3C6H2MgBr

75 : 25 80 : 20 92 : 8 95 : 5 10 : 90 5 : 95 95 : 5 12 : 88

68a, R1 ¼ Me 68a, R1 ¼ Me 68b, R1 ¼ Et 68c, R1 ¼ n-Oct 68d, R1 ¼ t-Bu 69d, R1 ¼ t-Bu 69e, R1CH2 bCH 69f, R1(CH3)3C6H2

55 70 80 60 70 60 50 70

a) For an isolated, diastereomerically pure sulfinate.

afforded the corresponding tert-butanesulfinate 72 as a single diastereomer formed with full inversion of configuration at the stereogenic sulfinyl sulfur atom (Scheme 2.14) [45].

Scheme 2.14 Ring-opening reaction of the cyclic, sugar-derived sulfite.

A few benzenesulfinates 39a–e bearing a phosphonate group at the orthoposition were prepared by the diastereoselective oxidation of the corresponding sulfenates containing C-chiral alkoxy substituents 73a–e. The de-values (up to 86%) of the resulting sulfinates 39 were found to depend heavily on the structure of substrates and to be sensitive to the oxidizing reagent used (Scheme 2.15; Table 2.12) [28].

51

52


Scheme 2.15 Diastereoselective oxidation of benzenesulfenates bearing a phosphonate group at the ortho-position.

Table 2.12 Oxidation of chiral benzenesulfenates into the corresponding sulfinates.

Entry

1 2 3 4 5 6 7 8 9

Sulfenic ester 73

Sulfinic ester 39

No.

Oxidant

Conditions

No.

Yield [%]

de [%]

a b b c c d d e e

NBSa) NBSa) (þ) oxb) NBSa) (þ) oxb) NBSa) (þ) oxb) MCPBAa) (þ) oxb)

MeCN-H2O/rt/15 min MeCN-H2O/rt/15 min CCl4/rt/10 days MeCN-H2O/rt/1 h CCl4/rt/4 days MeCN-H2O/rt/1 h CCl4/rt/8 days THF/ 78 to 0 8C/1 h CCl4/rt/7 days

a b b c c d d e e

95 70 79 67 76 92 84 95 85

76 65 85 74 16 25 10 38 86

a) NBS ¼ N-bromosuccinimide. b) ox ¼ (8,8-dichlorocamphorsulfonyl)oxaziridine. c) MCPBA ¼ methoxychloroperbenzoic acid. rt ¼ room temperature.

Acknowledgments

The writing of this chapter was supported financially by grant PBZ-KBN-126/ T09/02 (to J.D.) within a scientific project by the government fund during the period 2006–2009.

References

References 1 M. Mikołajczyk, J. Drabowicz, Topics Stereochem. 1982, 13, 333. 2 J. Drabowicz, S. Oae, Tetrahedron 1978, 34, 63. 3 (a) J. Drabowicz, P. Kiełbasin´ski, M. Mikołajczyk, in: S. Patai (Ed.), The Chemistry of Sulfinic Acid, Esters and their Derivatives, John Wiley & Sons, Chichester, 1990, pp. 351–429; (b) M. Mikołajczyk, J. Drabowicz, P. Kiełbasin´ski, Chiral Sulfur Reagents, CRC Press, Boca Raton, 1997; (c) A. Nudelman, in: S. Patai (Ed.), The Chemistry of Sulfinic Acids, Esters and their Derivatives, John Wiley & Sons, Chichester, 1990, pp. 35–85; (d) U. Zoller, in: S. Patai (Ed.), The Chemistry of Sulfinic Acids, Esters and their Derivatives, John Wiley & Sons, Chichester, 1990, pp. 217–237; (e) A. Nudelman, in: The Chemistry of Optically Active Sulfur Compounds, Gordon and Breach, New York, 1984; (f ) S. Collona, R. Annunziata, M. Cinquini, Phosphorous Sulfur 1981, 10, 197; (g) J. L. Kice, Adv. Phys. Org. Chem. 1980, 17, 66; (h) E. Wenschuh, K. Do¨lling, M. Mikołajczyk, J. Drabowicz, Z. Chem. 1980, 20, 122. 4 (a) L. Sagramora, P. Koch, A. Garbesi, A. Fava, Chem. Commun. 1967, 985; (b) F. Ciuffarin, M. Isola, A. Fava, J. Am. Chem. Soc. 1968, 90, 3594; ˜ ach, H. B. Kagan, (c) C. Nemecek, E. Dun Nouv. J. Chim. 1986, 10, 761. 5 (a) M. Mikołajczyk, J. Drabowicz, Chem. Commun. 1974, 547; (b) J. Drabowicz, M. Mikołaczyk, unpublished results; (c) M. Mikołajczyk, J. Drabowicz, H. S´lebocka-Tilk, J. Am. Chem. Soc. 1979, 101, 1302. 6 R. Amoroso, G. Cardillo, C. Tomasini, P. Tortoreto, J. Org. Chem. 1992, 57, 1082–1087. 7 (a) S. Nakayama, M. Tatayama, H. Sugimoto, M. Nakagawa, Y. Watanabe, N. Shibata, T. Toru, Chirality 2005, 17, 85; (b) N. Shibata, M. Matsunaga, T. Fukuzumi, S. Nakamura, T. Toru, Synlett 2005, 1699.

8 J. W. Evans, M. B. Fierman, S. J. Miller, J. A. Ellman, J. Am. Chem. Soc. 2004, 126, 8134. 9 H. M. Peltier, J. W. Evans, J. A. Ellman, Org. Lett. 2005, 7, 1733. 10 N. Shibata, M. Matsunaga, M. Nakagawa, T. Fukuzumi, S. Nakamura, T. Toru, J. Am. Chem. Soc. 2005, 127, 1373. 11 J. Drabowicz, S. Lege˛dz´, M. Mikołajczyk, Tetrahedron 1988, 44, 5243. 12 J. Drabowicz, M. Pacholczyk, Phosphorus and Sulfur 1987, 29, 257. 13 P. Kiełbasin´ski, R. Z˙urawin´ski, J. Drabowicz, M. Mikołajczyk, Tetrahedron 1988, 44, 6687. 14 D. N. Jones, W. Higgins, J. Chem. Soc. (C) 1970, 81. 15 H. Phillips, J. Chem. Soc. 1925, 127, 2552. 16 (a) H. F. Herbrandson, R. T. Dickerson, Jr., J. Am. Chem. Soc. 1959, 81, 4102; (b) H. F. Herbrandson, R. T. Dickerson, Jr., J. Weinstein, J. Am. Chem. Soc. 1956, 78, 2576. 17 (a) C. Miostkowski, G. Solladie, Tetrahedron 1980, 36, 227; (b) G. Solladie, Synthesis 1981, 185. 18 J. Drabowicz, B. Dudzin´ski, P. Łyz˙wa, M. Mikołajczyk, unpublished results. 19 R. E. Estep, D. F. Tavares, Int. J. Sulfur Chem. 1973, 8, 279. 20 M. Furukawa, T. Okawara, Y. Noguchi, M. Nishikawa, Synthesis 1978, 441. 21 (a) H. F. Herbrandson, C. M. Cusano, J. Am. Chem. Soc. 1961, 81, 2124; (b) U. Folii, D. Montanari, U. Tore, J. Chem. Soc. (C) 1968, 1317. 22 (a) K. K. Andersen, W. Gaffield, N. E. Papanikolaou, J. Foley, R. I. Perkins, J. Am. Chem. Soc. 1964, 86, 5637; (b) K. K. Andersen, J. Org. Chem. 1964, 29, 1953. 23 K. Burgess, I. Henderson, Tetrahedron Lett. 1989, 30 4235. 24 K. Mislow, M. M. Green, P. Laur, J. T. Melillo, T. Simmons, A. L. Ternay, Jr., J. Am. Chem. Soc. 1965, 87, 1958. 25 K. Mislow, M. M. Green, M. Raban, J. Am. Chem. Soc. 1965, 87, 2761. 26 M. Mikołajczyk, J. Drabowicz, J. Am. Chem. Soc. 1978, 100, 2518.

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2 Asymmetric Synthesis of Optically Active Sulfinic Acid Esters 27 S. G. Pyne, A. R. Hajipour, K. Prabakaran, Tetrahedron Lett. 1994, 35, 645. 28 M. Hamel, G. Grach, J. Abrunhosa, M. Gulea, S. Masson, M. Vazeux, J. Drabowicz, M. Mikołajczyk, Tetrahedron: Asymmetry 2005, 16, 3406. 29 D. H. Harpp, B. T. Friedlander, C. Larsen, K. Steliou, A. Stockton, J. Org. Chem. 1978, 43, 3481. 30 J. M. Klunder, K. B. Sharpless, J. Org. Chem. 1987, 52, 2598. 31 Y. Watanabe, N. Mase, M. Tatayama, T. Toru, Tetrahedron: Asymmetry 1999, 10, 737. 32 K. K. Andersen, B. Bujnicki, J. Drabowicz, M. Mikołajczyk, J. B. O’Brien, J. Org. Chem. 1984, 49, 4070. 33 R. R. Strickler, A. L. Schwan, Tetrahedron: Asymmetry 2000, 11, 4843. 34 J. Drabowicz, B. Bujnicki, M. Mikołajczyk, P. Biscarini, Tetrahedron: Asymmetry 1999, 10, 3177. 35 H. Redlich, W.-U. Meyer, Liebigs Ann. Chem. 1981, 1354. 36 (a) D. D. Ridley, M. A. Small, J. Chem. Soc., Chem. Commun. 1981, 505; (b) D. D. Ridley, M. A. Small, Aust. J. Chem. 1982, 35, 496. 37 (a) J. M. Llera, I. Fernandez, F. Alcudia, Tetrahedron Lett. 1991, 32, 7299;

38 39 40

41 42 43

44

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(b) I. Fernandez, N. Khiar, J. M. Llera, F. Alcudia, J. Org. Chem. 1992, 57, 6789; (c) N. Khiar, I. Fernandez, F. Alcudia, Tetrahedron Lett. 1994, 35, 5719. C. Roussel, C. Popescu, L. Fabre, Carbohydr. Res. 1996, 282, 307. H. Yamamura, J. Drabowicz, unpublished results. (a) N. Khiar, C. S. Arau´jo, F. Alcudia, J. Fernandez, J. Org. Chem. 2002, 67, 345; (b) N. Khiar, F. Alcudia, J. L. Espartero, L. Rodrigouez, I. Fernandez, J. Am. Chem. Soc. 2000, 122, 7598. J. K. Whitesell, M. S. Wong, J. Org. Chem. 1991, 56, 4552. J. K. Whitesell, M. S. Wong, J. Org. Chem. 1994, 59, 597. F. Robiere, O. Samuel, L. Ricard, H. B. Kagan, J. Org. Chem. 1991, 56, 5991. K. Borsuk, J. Frelek, R. Łysek, Z. Urbanćzyk-Lipkowska, M. Chmielewski, Chirality 2001, 13, 533. J. Drabowicz, A. Zaja˛c, D. Krasowska, B. Bujnicki, B. Dudzin´ski, M. Janicka, M. Mikołajczyk, M. Chmielewski, Z. Czarnocki, J. Gawron´ski, P. L. Polavarapu, M. W. Wieczorek, B. Marciniak, E. Sokołowska-Ro´z˙ycka, Heteroatom Chem. 2007, 18, 527.

55

3 Asymmetric Transformations Mediated by Sulfinyl Groups Jose´ L. Garcıá Ruano, Jose´ Alemań, M. Beleń Cid, M. Ańgeles Fernańdez-Ibań˜ez, M. Carmen Maestro, M. Rosario Martıń, and Ana M. Martıń-Castro

Abstract

This chapter describes some of the most important reactions using the sulfinyl group as a chiral auxiliary in asymmetric synthesis. Nucleophilic additions to CbO and CbN bonds, stereocontrolled by sulfinyl groups present at the substrate, and the different cycloadditions involving alkenyl sulfoxides, mainly Diels–Alder and 1,3-dipolar reactions, represent the most comprehensive part of the chapter because they have been profusely studied; however, other topics such as conjugate additions and Pummerer reactions have been included. Asymmetric processes stereocontrolled by remote sulfinyl groups are also considered. In addition to a detailed description of the main data reported in the literature, special attention has been paid to the rationalization of the results on the basis of the electronic and steric features of the sulfinyl group. In this way the reader should comprehend the role of this functional group on the reactivity and stereoselectivity of different processes, and predict its behaviour. The scope and limitations of the reactions have also been considered in many cases.

3.1 Introduction

Sulfoxides constitute a family of organic compounds which has gained enormous importance during the past decades. This has led to the appearance of a considerable number of examples of primary and secondary sources of chemical literature on the physical properties, synthesis, and reactivity of sulfinyl derivatives. The high chemical versatility of these compounds determines that they are one of the most important sulfur functional groups. In addition to the reactions that can directly modify the nature of the sulfur function (reduction and oxidation), there are many others which take place on the carbon skeleton which are sub-


56

3 Asymmetric Transformations Mediated by Sulfinyl Groups

stantially affected by – and also in many cases caused by – the presence of the sulfinyl group in the molecule. Additionally, the intrinsic chirality of the sulfinyl sulfur, as well as its configurational stability, makes possible the synthesis of optically pure sulfoxides which are of major importance in medical and pharmaceutical chemistry, and have contributed to enhance the synthetic importance of sulfoxides in the field of asymmetric synthesis. Consequently, many aspects related to the structure, methods of preparation and reactivity of sulfoxides have been previously reviewed and published in books and specialized journals. All those articles that will be mentioned in this introduction, despite being of a general scope, contain most of the published literature on sulfoxides. The first article is the chapter devoted to sulfoxides of the first edition of Houben-Weyl [1], that contains a fine selection of those references published until 1984. After this date, the chemistry of sulfoxides was comprehensively reviewed by Patai and colleagues in The Chemistry of Sulfones and Sulfoxides [2], several chapters of which deal with the structural aspects of sulfoxides, methods of synthesis, and a complete description of their chemical behavior. Following Patai and colleagues’ book, which provides a compulsory reference to the chemistry of sulfinyl derivatives until 1987, many other reviews covering different aspects of the chemistry of these compounds, most of them related to optically active sulfoxides, have been published. At this point only three volumes which the present authors consider more significant because of the general scope of their contents will be mentioned. The first volume [3] deals only with chiral sulfoxides, and collects contributions devoted to their synthetic methods as well as their applications in asymmetric synthesis. The second review [4] is mainly focused on the preparative methods of optically active sulfoxides, but also considers some particular aspects of their reactivity, such as the use of chiral sulfoxides on solid phases or in metal-catalyzed enantioselective reactions. The third volume [5] is an update of the applications of chiral sulfoxides in asymmetric synthesis. This chapter is devoted to the asymmetric transformations mediated by sulfinyl groups. Although this would mean all reactions involving optically pure sulfoxides where new chiral centers were created, only those where the sulfinyl group plays a significant role in the stereoselectivity control will be mentioned. Taking into account that this volume contains chapters devoted specifically to the asymmetric synthesis of chiral sulfoxides, these procedures – as well as the reactions involved in such transformations – have been avoided. Similarly, reactions of a-sulfinyl carbanions, as well as those involving the use of chiral sulfoxides as ligands in asymmetric catalysis (which are the specific topics of two other chapters) – will not be treated specifically at this point. The chapter is divided into five sections. In the first section, nucleophilic additions to CbO and CbN bonds controlled by sulfinyl groups located at C-a, and where reduction is the most important group of reactions, will be reviewed. Next, comment will be made on the conjugate additions to carbonyl and related compounds. The third section will be devoted to cycloadditions, mainly Diels–Alder and 1,3-dipolar reactions. In all these reactions the sulfinyl group controlling the stereoselectivity is directly joined, or very close, to the reaction center (1,2- or

3.2 Nucleophilic Additions to CbO and CbN Bonds Mediated by a-Sulfinyl Groups

1,3-asymmetric induction processes). The fourth section of the chapter will be related with those reactions involving the stereocontrol exerted by sulfinyl groups separated by more than two bonds from the reaction center (1,n-asymmetric induction processes, with n b3), that have been designated as the remote stereocontrol of sulfinyl groups. The final section will be devoted to discussing the main aspects concerning the Pummerer reactions.

3.2 Nucleophilic Additions to CyO and CyN Bonds Mediated by a-Sulfinyl Groups

In this section, the reactions of carbonyl compounds and their corresponding imines bearing a sulfinyl group at C-a will be considered. Such reactions are responsible for the stereoselectivity control and, in some cases, also modulate the reactivity. 3.2.1 b-Ketosulfoxides 3.2.1.1 Reduction Reactions The stereoselective reduction of b-ketosulfoxides is one of the most studied and applied reactions where the sulfinyl group is used as a chiral auxiliary. The pioneer investigations were conducted by Annunziata et al. [6], using NaBH4 and LiAlH4 at 70 8C (Scheme 3.1). With these reducing reagents the yields obtained were high and the diastereomeric excess (de) values ranged between 20% and 70%, although the configuration of the major diastereoisomer was not established. The use of chiral or achiral alkoxy-lithium aluminum hydrides resulted in a decrease in stereoselectivity.

Scheme 3.1

Solladie´ et al. [7] completed and extended the above study to other borohydrides [LiBH4, (n-Bu) 4NBH4, LiEt3BH, Li (s-Bu) 3BH], and obtained the (CR,SR )hydroxysulfoxide as the major diastereoisomer with de-values ranging from 32% [Zn (BH4) 2] to 70% [(n-Bu)4NBH4]. However, the reduction with diborane and diisobutylaluminum hydride (DIBAL) afforded the (CS,SR )-hydroxysulfoxide as the major isomer. As the best result was obtained with DIBAL, the study was completed [8] using this reagent under several experimental conditions with differently substituted ketosulfoxides [RCOCH2SOTol, R ¼ Ph, Ph (CH2) 2, Et,

57

58


n-C8H17, n-C9H19, n-C13H27]. It was also established that the addition of DIBAL to a ketosulfoxide solution containing 1 equivalent of ZnCl2 produced the hydroxysulfoxide exhibiting the opposite absolute configuration at the hydroxylic carbon (Scheme 3.2). Similar results were found by Kosugi [9] in the presence of a Lewis acid. Although the use of a catalytic amount (0.05–0.1 equiv.) of ZnCl2 was apparently enough in some cases for the reaction to reach completion [10], stoichiometric and even larger amounts of a Lewis acid were generally used.

Scheme 3.2

b-Hydroxysulfoxides were transformed (Scheme 3.2) into both enantiomers of differently substituted methylcarbinols, epoxides [8, 11], as well as into unsaturated [12] and saturated lactones [9]. b-Hydroxyesters, with or without asubstituents, were also obtained from b-hydroxysulfoxides [13]. Additionally, the thus-obtained chiral epoxides were transformed into important chiral fragments, such as the C(1)–C(12) subunit of the macrolide amphotericin B [14]. These were also used in total synthesis when preparing the aldol moieties of (R )-yashabushiketol [15] and the three active principles of ginger (Scheme 3.3) [16].


Scheme 3.3

The application of the reduction methodology to g,d-unsaturated-b-ketosulfoxides afforded the corresponding allyl carbinols after desulfurization with lithium in ethylamine [17]. The (SR,CbS) and (SR,CbR )-g,d-unsaturated-bhydroxysulfoxides (obtained by DIBAL or DIBAL/ZnCl2 reduction, respectively) were hydroxylated, thus exploiting the induction produced by the stereogenic hydroxylic carbon, via an osmium tetroxide-catalyzed reaction, to yield the corresponding (CbS,CgS,CdR )- and (CbR,CgR,CdS)-b,g,d-trihydroxysulfones, respectively, as the main diastereoisomers, with de-values ranging between 42% and 90% [18]. The synthesis of l-arabinitol derivatives was carried out using the above strategy from the corresponding g,d-unsaturated-b-hydroxysulfoxides (Scheme 3.4) [19, 20]. Optically enriched propargyl carbinols were also obtained from g,d-acetylenic-b-ketosulfoxides [21].

Scheme 3.4

The synthesis of enantio- and diastereoisomerically pure sulfinyl epoxides by DIBAL reduction of g-chloro-b-ketosulfoxides and the corresponding opening reactions with lithium vinylcyanocuprates afforded the corresponding homoallylic b-hydroxysulfoxides [1, 22]. This strategy was applied to the synthesis of the C(11)-C(20) fragment of leukotriene B4 [23] and to the preparation of the macrocyclic lactone (R )-recifeiolide (Scheme 3.5) [24].

59

60


Scheme 3.5

The total syntheses of an important variety of compounds were reported by applying the stereoselective reduction of b-ketosulfoxides with DIBAL or DIBAL/ ZnX2 as the key step to attain the desired configuration at the hydroxylic centers of the target molecules. This was the case of macrocyclic lactones such as methyl lasiodiplodin [25], (S)-zearalenone dimethyl ether [26], (R,R )-pyrenophorin and (R )-patulolide [27], ()-aspicilin [28, 29], (þ)-brefeldin A [30] and cladospolide A [31] (Figure 3.1). The asymmetric synthesis of (þ)-virol C [32], d- and l-hexose precursors [33] and ()-macrolactin A [34, 35] also involved DIBAL and DIBAL/ZnCl2 reductions as the key steps. In the latter case, the 1,3-diol fragment contained in the 24-membered macrolide ()-macrolactin A (Figure 3.1) was prepared from a homochiral g-chloro-b-hydroxyester. It has been shown that b-ketosulfoxides can be obtained from menthyl sulfinate linked to a Wang resin [36], and their DIBAL reduction evolved with stereoselec-

Figure 3.1 Macrocyclic lactones prepared by DIBAL or DIBAL/ZnX2 reduction methodology.


tivity similar to that reported for reactions in solution [37], which opens a route to combinatorial synthesis on solid support. The stereochemical results of DIBAL reductions were explained by assuming the association of the sulfinyl oxygen to the aluminum as a previous step to an intramolecular hydride transfer via the most stable chair-like transition state (A in Scheme 3.6) [38]. In the presence of ZnX2, the formation of a Zn-chelated species B, adopting a half-chair conformation, was assumed (Scheme 3.6). 1 H NMR studies on the association of ZnCl2 with different b-ketosulfoxides were reported [39]. The intermolecular attack of the hydride to the upper face in Scheme 3.6 was preferred because it evolved through a quasi-chair TS1, more stable than the quasi-boat TS2 resulting from the approach of the hydride to the bottom face [38]. The association of the aluminum to the lone electron pair at sulfur could reinforce the favored orientation (a similar association to the quasiaxial halogen had also been suggested [10]). As can be deduced from Scheme 3.6, the configurations induced at the hydroxylic center with DIBAL and DIBAL/ ZnX2 are opposite each other.

Scheme 3.6

All of the examples considered so far have involved reactions of b-ketosulfoxides without substituents at C-a, which restricts the applicability of the methodology to the synthesis of methyl carbinols. The presence of an additional chiral center at C-a was troublesome because a-alkyl-b-ketosulfoxides were always obtained as mixtures of a-epimers, the separation of which was quite difficult, and reduction of the mixture with DIBAL and/or DIBAL/ZnX2 provided complex mixtures of all possible isomers. These results suggested that C-a competes with the sulfinyl group in the stereoselectivity control. Despite the low selectivity, these reactions were applied to a-alkyl-b-ketosulfoxides in the synthesis of several g-lactones, such as umbelactone [40] and that known as ‘‘L factor’’ [41]. Garcıá Ruano et al. [42] demonstrated that a highly diastereoselective reaction of epimeric mixtures of a-alkyl-b-ketosulfoxides was achieved with DIBAL in the

61

62


presence of a small excess of ZnBr2 (1.4 equiv.), the stereoselectivity being governed almost exclusively by the sulfur configuration (1,3-induction), regardless of the configuration at C-2 (Scheme 3.7). Deviations from this rule are due to the imperfect chelation of the substrate with the zinc salt. In these cases, an increase in the amount of catalyst (5 equiv.) improved the selectivity. Such behavior can easily be understood from Scheme 3.7, as R2 had no major influence on the relative stability of TS1, whatever the configuration at C-2. This allowed the synthesis of enantiomerically pure alkyl carbinols (Scheme 3.7) and was applied to the synthesis of g- and d-lactones [43]. Reactions of a,a 0 -dialkyl-b-ketosulfoxides with DIBAL/ZnCl2 also evolved with high diastereoselectivities [44], controlled by the sulfoxide, which was used in the synthesis of juvenile hormone II.

Scheme 3.7

The presence of other oxygenated functions at the substrate can, however, dramatically decrease the stereoselectivity because of their competition for associating with Zn. In some of these cases, the use of DIBAL/Yb (OTf )3 [45–47] or catecholborane [48] afforded high de-values, with the epimer having the opposite configuration at the hydroxylic carbon to that obtained with DIBAL, being the major product. Finding a solution to the question of the low stereoselectivity observed in DIBAL reductions of a-alkyl-b-ketosulfoxides was much more intricate. Garcıá Ruano et al. [49] showed that the sulfinyl group completely controls the stereoselectivity for the evolution of one epimer, whereas for the second epimer sulfur and C-a compete and the stereoselectivity is quite low. The difficult separation of the epimers emerged as the main restriction to the use of this reaction in asymmetric synthesis. Toru et al. [50] reported that the reduction with DIBAL under basic conditions evolved stereoselectively as a consequence of the equilibration of the epimers and the faster reaction of the epimer for which the transformation was highly stereoselective. A six-membered cyclic transition state involving a SiaO interaction was postulated to account for differences in the evolution of both epimers. The reaction provided a convenient route to the synthesis of optically pure allylic alcohols (Scheme 3.8).


Scheme 3.8

The extension of the above methodology to the preparation of several enantiopure cyclic carbinols was developed by Garcıá Ruano et al., who noted that the stereochemical course was quite similar to that observed for acyclic molecules (Scheme 3.9). The stereoselectivity of DIBAL or DIBAL/ZnCl2 reduction of 2-(p-tolylsulfinyl)cyclohexanone (always obtained as a 75 : 25 epimeric mixture at C-2) was governed mainly by the sulfur configuration (1,3-induction), regardless of the configuration at the stereogenic carbon (Scheme 3.9) [38, 51]. The same behavior was observed in the DIBAL reduction of chiral 2-(p-tolylsulfinyl)cyclopentanone and cycloheptanone, whereas their reduction with L-Selectride was controlled mainly by the configuration at C-2 (induction 1,2) [52]. The methodology was applied to the synthesis of enantiomerically pure cyclohexenols [53, 54] and a precursor of the glycosidase inhibitor, mannostatin A [55].

Scheme 3.9

One of the most developed applications of the reduction of b-ketosulfoxides is the synthesis of optically pure diols, which was reviewed by Solladie´ [56] b-Hydroxysulfoxides, obtained by reduction of b-ketosulfoxides with DIBAL, were readily transformed into terminal diols by the Pummerer reaction, followed by reduction of the resulting hemithioketal. This methodology was used in the hemisynthesis of C-33 pentacyclic triterpenoids [57]. Internal diols were synthesized from bis-b-ketosulfoxides, and could be introduced either sequentially [58] or simultaneously. Thus, C2-symmetric R,R or S,S hexanediols and heptanediols were respectively obtained by DIBAL or DIBAL/ZnCl2 reduction with enantio-

63

64


meric excess (ee) values above 95% (Scheme 3.10) [59]. Myo-inositol and pyrrolidine derivatives [60] were obtained from either enantiomer of C2-symmetric bisb-ketodisulfoxides, obtained from d-()- or l-(þ)-dimethyl isopropylidenetartrate, respectively.

Scheme 3.10

DIBAL reduction of bis-b-ketosulfoxides bearing an additional carbonyl group protected as a cyclic ketal was applied to the asymmetric synthesis of 1,7dioxaspiro [5,5]undecane [61] and 1,6-dioxaspiro [4,4]nonane [62] and other dioxabicyclo derivatives [63, 64] (Scheme 3.11).

Scheme 3.11

DIBAL reduction of b,d-diketosulfoxides, readily obtained from b-ketoesters or b-diketones [65], followed by reduction of the resulting d-keto-b-hydroxysulfoxides by conventional methods, provided a good entry to syn and anti 1,3-diols [66].


This methodology was applied to the synthesis of a compactine analogue [67], ()-colletol [68], and other products of interest [69–72]. The presence of oxygenated functions (alkoxy, carbonyl, ester, amide, ketal, etc.) located far away from the b-ketosulfoxide moiety, had minimal influence on the diastereoselectivity [9, 16, 26, 27, 59]. At shorter distances, the influence depends on the nature of the function and the experimental conditions. Thus, the p-methoxybenzylether group at g-position in b-ketosulfoxides did not affect the stereoselectivity of DIBAL reductions [46, 73]. Similar results were obtained from b-ketosulfoxides with acetalic functions at the g and d-positions [49, 74], but their influence increased as the distance became shorter. The acetalic function at d-dioxolane [75–77] or b 0 -dioxolane [78] b-ketosulfoxides, and the N-Boc group at g-amino-b-ketosulfoxides [79–81], had no influence on reactions catalyzed by DIBAL, and only the latter had some influence on the DIBAL/Lewis acid reductions. The influence of two vicinal carbonyl groups (keto/ester or keto/Weinreb amide) was examined with b-ketosulfoxides derived from oxalic acid. DIBAL reduction proceeded with high stereoselectivity giving the expected diastereoisomer, whereas in the presence of ZnX2 the same epimer was obtained because the second carbonyl group competed with the sulfinyl group for the chelation with the metal (Scheme 3.12) [82, 83]. The resultant a-hydroxy esters were used to obtain the syn and anti-1,2-diol moieties [84], or else were further elaborated into the 10-membered lactone core of ascidiatrienolides and didemnilactones [83].

Scheme 3.12

Minimal influence of the ester group was detected in the stereoselective reduction of b-keto g-sulfinyl esters [85], mainly for bulky tert-butyl esters. Haminol-1 [86] and a fragment of the macrolide antibiotic nystatin A1 [87] were prepared following this procedure. Transformation of the obtained chiral a-hydroxyesters represents an alternative route to chiral syn or anti 1,2-diols (Scheme 3.13) [88].

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Scheme 3.13

The use of bulky protecting groups for oxygenated functions provided good results in other cases [89]. The stereoselective formation of cis-2,5-disubstituted tetrahydrofurans and cis2,6-disubstituted tetrahydropyrans was achieved from enantiopure b-ketosulfoxides bearing an alkoxycarbonyl group separated from the carbonyl group by three or four bonds. DIBAL/ZnCl2 reduction (not affected by the alkoxycarbonyl group), followed by reductive cyclization with Et3SiH/TMSOTf, afforded tetrahydrofurans and tetrahydropyrans [90]. The procedure was applied to the synthesis of ()centrolobine [91], to the tetrahydropyran ring of phorboxazol [92], to both enantiomers of the eight-membered cyclic ether cis-lauthisan [93], to an advanced intermediate of (þ)-isolaurepan [94], and to goniothalesdiol (Scheme 3.14) [95].

Scheme 3.14


The influence of a sulfenyl group at the a-position of b-ketosulfoxides has been widely studied. The reduction of a-sulfenyl-b-ketosulfoxides, obtained as a diastereoisomeric mixture at C-a from (S)-formaldehyde dithioacetal S-oxide and ethyl benzoate in the presence of NaH, was first reported by Ogura [96]. Only one diastereoisomer exhibiting R configuration at both chiral carbons, was obtained from the reaction with NaBH4 in a 9 : 1 mixture of MeOH/concentrated aqueous NH3, whereas other non-basic solvents, such as MeOH or MeOH:CH2Cl2, sharply decreased the stereoselectivity (Scheme 3.15). This suggests a rapid epimerization in basic media, and a faster evolution of one of the epimers.

Scheme 3.15

Guanti studied the reduction of the above sulfenylketosulfoxides with LiAlH4, NaBH4, and Bu4NBH4 with or without a base as an additive (preferentially NaOH or NaOEt). In reactions with LiAlH4 each of the two diastereoisomeric ketosulfoxides furnished only one of the two possible alcohols [97], whereas borohydrides [98] always afforded a mixture of two diastereoisomers starting from diastereoisomerically pure ketosulfoxides; this suggests a competitive epimerization of the ketosulfoxides in the presence of borohydride. The addition of bases to the reaction media under suitable conditions of solvent and temperature increased

Scheme 3.16

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the de-values (up to 80%), which became independent of the epimeric ratio of the starting ketosulfoxides (Scheme 3.15). This methodology was used in the synthesis of conocandin esters [99]. The highly stereoselective DIBAL reduction of syn and anti-2-acyl-2-alkyl-1,3dithiane 1-oxides was studied by Page et al. [100]. The selectivity was reversed when DIBAL was used in the presence of ZnCl2 (Scheme 3.16) [101], and hydrolysis of dithiane 1-oxide moiety with NBS/acetone/H2O gave the corresponding a-hydroxyketones with the same optical purity as that of the starting dithianes (Scheme 3.16). Application of this methodology to the synthesis of (R )-()-2,6dimethyl heptanoic acid was also reported [102]. Maycock et al. [103] reported the enantioselective synthesis of 3-benzoyloxybutan-2-one from butane-2,3-dione using a dithioacetal mono-S-oxide as the enantiocontrol element in a diastereoselective reduction. High yields (P92%) were obtained with both DIBAL and NaBH4, but the stereoselectivity was complete (498% de) only in the first case. The addition of ZnCl2 scarcely modified the stereochemical course of the reaction (92% de), the same diastereoisomer being favored (Scheme 3.17).

Scheme 3.17

2-Acylthiane S-oxides were reduced with DIBAL and DIBAL/ZnCl2 to give respectively the S or R alcohols [104], which were transformed into a variety of functionalized epoxides by opening reaction of the thiane ring (Scheme 3.18).

Scheme 3.18


The synthesis and behavior of mono or polyhalogenated (mainly fluoro derivatives) b-ketosulfoxides, and the corresponding imines, were reported and reviewed by Bravo et al. [105–109]. The DIBAL reduction of fluorinated b-ketosulfoxides was also studied by Bravo [108, 109] (Scheme 3.19). This high selectivity (496% de) was affected by neither the two methyl groups at a-position nor by the configuration at the fluorinated carbon [110]. a-Monosubstituted b-ketosulfoxides [111] required reduction with DIBAL in the presence of ZnCl2 or CdCl2 to obtain good stereoselectivities (Scheme 3.19).

Scheme 3.19

Difluorinated compounds (Scheme 3.20) afforded similar results in their reduction with DIBAL [112, 113], but g-trihalogenated b-ketosulfoxides were reduced by different borohydride species (in methanol/aqueous ammonia) or cyanoborohydrides (in methanol/acetic acid) with or without zinc chloride [114–116], but with low stereoselectivities (Scheme 3.20).

Scheme 3.20

The resultant hydroxysulfoxides were transformed into fluorinated alcohols (CaS hydrogenolysis), epoxides (via sulfonium salt), protected a-hydroxyaldehydes (Pummerer rearrangement) [112, 117], nitrogen-containing derivatives (Mitsunobu and non-oxidative Pummerer reaction) [118, 119], tetrahydrofurans [120], and sulfur-substituted difluorocyclohexanols [121, 122]. Intramolecular oxymercuration [123] or aminomercuration, to build up the piperidine ring of fluorinated analogues of nojirimycin and mannojirimycin, were also reported [124]. Additionally, (3R,4R,SS)-perfluorinated b-sulfinyl-g-hydroxyhexanoic acid was obtained as the major diastereoisomer by NaBH4 reduction of an epimeric

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mixture at b-ketosulfoxides bearing the CH2-CO2H fragment at the a-position (Scheme 3.21). This compound was converted into enantiomerically pure (S)pentafluoro-g-caprolactone (Scheme 3.21). (R )-Trifluoro-g-valerolactone was obtained using a similar procedure [125]. The unexpectedly high stereocontrol exerted by NaBH4 was attributed to an intramolecular hydride transfer from a transient carboxy-borohydride species.

Scheme 3.21

3.2.1.2 Alkylation Reactions Pioneering studies on the alkylation of the prochiral carbonyl group in bketosulfoxides were conducted on (R )-a-(p-tolylsulfinyl)acetophenone with Grignard reagents. The reactions evolved with moderate stereoselectivities in high yields to afford the (CR,SR )-hydroxysulfoxides as the major diastereoisomers (Scheme 3.22) [126]. The solvent proved to be crucial, since in tetrahydrofuran (THF) a preferential attack of the Grignard reagent to the sulfur atom occurred, causing their nucleophilic displacement with complete inversion of the configuration at the sulfur atom [127].

Scheme 3.22

Other methylating reagents (MeTiCl3, Me3Al, Me3Al/ZnBr2, MeMgBr/CeCl3) also evolved with poor diastereoselectivities in moderate yields (no reaction was produced with AlMe3/ZnBr2) [128]. Exceptionally, the reaction with trichloromethyltitanium (a well-known chelation control reagent), especially when using


aromatic b-ketosulfoxides bearing coordinating ether groups in the ortho position, afforded excellent results. This methodology was successfully applied to the synthesis of ()-sydowic acid (Scheme 3.23).

Scheme 3.23

The null reactivity obtained by Fujisawa’s group with AlMe3/ZnBr2 contrasts with the good yields and stereoselectivities achieved in the reaction of different acyclic and cyclic b-ketosulfoxides with the same reagent by Garcıá Ruano et al. [129]. This difference was attributed to the order in the addition of the reagents, which is crucial to attain good conversions. The reaction of acyclic derivatives (R ¼ Ph, Et, i-Pr, t-Bu) with 2 equiv. of the reagent at room temperature in CH2Cl2, afforded an epimeric mixture of b-hydroxysulfoxides, the major one with (CR,SR ) configuration, in yields ranging from 89 to 96% and diastereoisomeric ratios from 87 : 13 (R ¼ Ph, Et, i-Pr) to 95 : 5 (R ¼ t-Bu). These epimers were separated using chromatography (Scheme 3.24). A stereochemical model similar to that proposed to explain the reduction of the substrates with DIBAL/ ZnX2, accounts for the results observed in alkylation.

Scheme 3.24

Methylation of a-alkyl-b-ketosulfoxides with Me3Al (4 equiv.) or Me2AlCl (3 equiv.) [130] evolved with de-values above 90%, regardless of the configuration at C-a. This indicates that the sulfinyl group acts as the main controller of the stereoselectivity (Scheme 3.25). Removal of the sulfur function by hydrogenolysis or pyrolysis afforded enantiopure tertiary methyl ethyl or methyl vinyl carbinols, respectively.

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Scheme 3.25

Even better results were obtained in the reactions of a C-a epimeric mixture of (R )-2-(p-tolylsulfinyl)cycloalkanones with aluminum (RMe2Al; R ¼ Me, (E )CHbCH-Bu, CcCBu) and Grignard reagents in the presence of ZnX2 [131, 132]. Cyclohexanone derivatives gave mixtures of 2-sulfinyl cyclohexanols (epimers at C-2) in excellent yields (up to 95%), which indicates a complete control of the stereoselectivity exerted by the sulfinyl group (through a chelated species; Scheme 3.26) as well as an easy epimerization at C-2. The cyclopentanone derivative evolved in a completely stereoselective manner with AlMe3. The abovedescribed methodology was applied to the synthesis of (R )-4-hydroxy-4-methyl cyclohexenone [133] and the aggregation pheromone, seudenol [134].

Scheme 3.26

(R )-Syn and anti-2-acyl-2-alkyl-1,3-dithiane 1-oxides were used as electrophiles in reactions with Grignard reagents [135]. The carbinol of S configuration at the hydroxylic carbon was obtained as the major diastereoisomer from whichever syn or anti substrate.


3.2.1.3 Aldol Reaction with b-Ketosulfoxides Acting as Electrophiles The first asymmetric aldol reaction using enantiopure b-ketosulfoxides as the electrophilic counterpart was reported by Garcıá Ruano et al. [136]. The reaction of an epimeric C-2 mixture of (SR )-2-(p-tolylsulfinyl)cyclohexanone with lithium alkyl acetates took place with a highly efficient control of the configuration at the tertiary hydroxylic carbon. With prochiral enolates, mixtures of the two epimers at C-a of the ester group (10–82% de) were obtained, and their ratio was dependent on the size of the alkyl substituent (Scheme 3.27). The use of lactone enolates yielded only one diastereoisomer. The key of the stereoselectivity was the formation of a tricoordinated lithium species, which involved the enolate and the sulfinyl and carbonyl oxygens of the substrates. The syn pyrolytic sulfinyl removal yielded unsaturated b-hydroxyesters.

Scheme 3.27

Sulfenylation of (SR )-2-(p-tolylsulfinyl)cyclohexanone followed by in-situ aldol reaction with lithium ethylacetate enolate provided diastereoisomeric mixtures of b-hydroxyesters (the configuration of the major one was dependent on the configuration at C-a and, in turn, on the sulfenylating reagent) that, once separated, were transformed into enantiomerically pure ketones (Scheme 3.28) [137]. A similar methodology was applied to the preparation of acyclic substrates starting from non-racemic 2-acyl-2-alkyl-1,3-dithiane 1-oxide [138]. The asymmetric aldol reaction of prochiral ester- and lactone-derived lithium enolates, allowed the synthesis of enantiomerically pure tertiary a-substituted b-hydroxy-gketoesters, after ready separation of the diastereoisomeric adducts and hydrolysis of the dithiane oxide moiety (Scheme 3.29). It should be noted here that the

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Scheme 3.28

sense of the induced stereochemistry observed for ester and lactone enolates is different. The stereochemical course of these reactions is similar to that proposed in the preceding study with sulfinylcyclohexanone, involving tricoordinated lithium species as intermediates of the aldol reaction (see Scheme 3.27).

Scheme 3.29

(S)-g-Monofluorinated b-ketosulfoxides were also used as substrates in a Cu (I)catalyzed aldol reaction with methyl isocyanoacetate to afford diastereoisomeric oxazolines. Once separated, these were converted into optically pure 3-fluoromethylthreonine analogues (Scheme 3.30) [139]. Reactions of diazomethane with fluorinated b-ketosulfoxides leading to sulfinyl epoxides were studied by Bravo et al. (Scheme 3.31). Starting from (SR )-g-monofluorinated ketosulfoxide, the corresponding (2S,SR )-epoxide was obtained in 80% yield (96% de) (Scheme 3.31) [140, 141]. The presence of a


Scheme 3.30

phenyl group at the a-position did not modify the configuration of the resulting oxirane. Subsequently, both epimers (1R,SR )- and (1S,SR )-3-fluoro-1-phenyl-1-ptolylsulfinylpropan-2-one reacted separately with diazomethane to give the same (1R,2S,SR )-oxirane in high chemical yields with good selectivities, although the corresponding methyl enol ethers were isolated as byproducts. The exclusive formation of this single oxirane provided evidence of the equilibration of the epimers and the faster evolution of (1R,SR )-ketosulfoxide (Scheme 3.31) [142].

Scheme 3.31

The reaction of diastereoisomeric mixtures at C-a of (SR )-a-alkyl-g-fluoro-bketosulfoxides [143] gave a high 1,3-sulfinyl induction favoring the formation of 2S oxiranes, regardless of the configuration at a-carbon; however, the reactions

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were less stereoselective than those of a-phenyl derivatives. The behavior of perfluorinated a-alkyl or a-aryl-b-ketosulfoxides was similar to that of their monofluorinated counterparts [144]. As the stereochemistry of the epoxide ring was overwhelmingly controlled by the chirality of the sulfoxide moiety (1,3-induction), the present methodology was applied to the asymmetric synthesis of 2-alkyl-2fluoroalkyl epoxides, such as trifluoroanalogues of frontalin (Scheme 3.32) [107].

Scheme 3.32

The presence of groups such as Cl or OH (i.e. less electronegative than F) at the g-position had some influence on the chemo- and stereoselectivity of the reactions of b-ketosulfoxides with diazomethane. (SR )-g-chloroketosulfoxide [145] afforded mixtures of (2R,SR ) (71%) and (2S,SR ) (17%) epimers in methanol. In diethyl ether, the stereoselectivity improved but the yield decreased [36%, 17 : 1 diastereomeric ratio (dr)] due to the formation of an important amount of the diastereoisomeric enol ethers (23%) (Scheme 3.33). g-Hydroxy-substituted ketosulfoxides [146] afforded the corresponding epoxides, although the stereoselectivity was rather low (40% de) (Scheme 3.33). No selectivity at all was attained with b-ketosulfoxides bearing no electronegative substituents at their structure.

Scheme 3.33

The thus-obtained epoxides were used in the synthesis of open-chain derivatives (by opening the oxirane ring with different nucleophiles) [147]. Bravo developed a synthetic approach to new nucleoside analogues based on transformation of the sulfinyl group via a Pummerer rearrangement and reduction prior to the nucleophilic opening of the oxirane with purinic and pyrimidinic bases (see Scheme 3.31) [148, 149]. 3.2.1.4 Hydrocyanation Reactions The asymmetric hydrocyanation of b-ketosulfoxides was mainly studied by the group of Garcıá Ruano [150]. On the basis of the excellent results obtained in the reduction of b-ketosulfoxides with DIBAL, its structural similarity with Et2AlCN suggested that hydrocyanation of b-ketosulfoxides with this reagent


could be similarly successful, the aluminum being able to become associated with the sulfinyl oxygen. Enantiopure acyclic b-ketosulfoxides [151], as well as their a-alkyl-substituted derivatives [152], a-sulfinyl cycloalkanones [153] and asulfinyl aldehydes [154] were studied. The reaction was carried out in toluene by slow addition of the ketosulfoxide to a solution of Et2AlCN. Both, the order of the addition of the reagents and the reaction time (5–30 min) were crucial to achieve good yields (485%) of cyanohydrins. The addition of Lewis acids (MX2, M ¼ Zn or Mg, X ¼ Cl or Br) had scarce or no influence on the yields and the stereochemical course of the reaction. This contrasted strongly with the results obtained in the reduction of b-ketosulfoxides, and suggested some mechanistic differences (Scheme 3.34). The hydrocyanation of a-sulfinyl ketones was completely diastereoselective, in accordance with a 1,3-asymmetric induction process controlled by the sulfinyl group, with the R configuration at sulfur determining the S configuration at the hydroxylic carbon. In the case of acyclic or cyclic a-alkyl derivatives, bearing two chiral centers (C-a and the sulfur atom), a complete predominance of the 1,3induction (sulfur control) over the 1,2-induction (C-a control) was observed (Scheme 3.34).

Scheme 3.34

The stereochemical results were explained by assuming as intermediates chelated species involving the aluminum joined to carbonyl and sulfinyl oxygens (Scheme 3.35). The formation of these pentacoordinated species from Et2AlCN (never suggested for DIBAL) was explained by the high electronic deficiency of the aluminum induced by the cyano group. The apical CN group was topologi-

Scheme 3.35

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cally able to be transferred intramolecularly from the conformation displaying the p-tolyl group in a pseudoequatorial arrangement, through a chair-like transition state. Several synthetic applications of the sulfinyl cyanohydrins have been reported. Coupling of the stereoselective hydrocyanation with the intramolecular trapping of the Pummerer intermediate by a suitable aryl moiety (Scheme 3.36) was used as a stereocontrolled entry to precursors of the anthracyclinone family [155, 156]. The same strategy was applied to other compounds obtained by the reduction, methylation, alkynylation or vinylation of b-ketosulfoxides [157].

Scheme 3.36

Hydrolysis of the cyano group was used as the first step for many of the reported applications of sulfinyl cyanohydrins, in order to avoid their easy dehydrocyanation. Under very mild conditions, sulfinyl cyanohydrins were converted into sulfenyl carboxamides (HCl/ether or HBF4/NaI) [158] or sulfinyl carboxamides (HBF4/MeOH) [159] in high yields. These reactions evolved with anchimeric assistance of the sulfinyl group (Scheme 3.37).

Scheme 3.37

The sequence of hydrocyanation/hydrolysis allowed the synthesis of chiral 2-substituted [160] and 2,3-disubstituted glycidic acid derivatives [159], starting from acyclic b-ketosulfoxides (see Scheme 3.34). These glycidic acid derivatives underwent nucleophilic opening of the oxirane ring with different reagents [150, 161], as well as the corresponding opening in the presence of Lewis acids providing an easy access to oxazolines [162].


3.2.2 b-Imino(enamino)sulfoxides

b-Iminosulfoxides, and their enamine tautomers, are well-known useful intermediates in organic chemistry. Basically, four methodologies have been developed for obtaining these compounds: (1) the acid-catalyzed condensation of b-ketosulfoxides with amines [163–166]; (2) the addition of amines to allenyl [167] or alkynyl sulfoxides [168]; (3) the reaction of sulfinyl carbanions with nitriles [169, 170]; and (4) the addition of metallated alkyl imines to sulfinic esters [165, 166, 171–173]. The poor results obtained in the pioneering studies of Tsuchihashi et al. on the scarcely stereoselective reduction of acyclic b-iminosulfoxides with NaBH4 in methanol [169] were improved when starting from endocyclic a-sulfinyl ketimines (Scheme 3.38) by using Zn (BH3CN) 2 or LiEt3BH [172], DIBAL [174] or DIBAL/ZnCl2 [175]. In this situation the important role played by the Lewis acid on the stereoselectivity was clearly evident.

Scheme 3.38

The reduction of endocyclic sulfinyl enamines with NaBH4/MeOH proved to be more difficult and less stereoselective [176, 177], whereas the reduction with sodium cyanoborohydride of the related enamides [178] was completely stereoselective, allowing the synthesis of (R )-indolizidine (Scheme 3.39). The stereoselective reduction (up to 92% de) of b-substituted b-sulfinyl enamines with acetoxyborohydrides in the presence of carboxylic acids was also reported [173].

Scheme 3.39

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Pioneering investigations on cyclic a-sulfinyl imines were conducted by Garcıá Ruano and colleagues [179]. The N-phenyl iminic tautomer was formed as a 2 : 1 mixture of epimers at C-2 (Scheme 3.40). In turn, the N-benzyl derivative appeared exclusively as the enamine tautomer. The reduction of both epimeric imines (R ¼ Ph) or enamine (R ¼ Bn) was highly diastereoselective, giving exclusively the cis amino sulfoxide (1R,2S,SR )-2(p-tolylsulfinyl)cyclohexylamine in excellent yields (83–99%), regardless of the different electrophilic or nucleophilic nature of the reagents and their steric bulkiness. This clearly contrasts with the behavior of the corresponding ketones (Scheme 3.40).

Scheme 3.40

Garcıá Ruano et al. [165, 166] also studied the reduction of different acyclic N-benzyl a-sulfinyl imines with different hydrides. However, only DIBAL in the presence of ZnX2, which transformed the enaminic tautomer into the iminic form, afforded the (CR,SR )-amino sulfoxides in high yields with excellent diastereoselectivities (Scheme 3.41). The result was not dependent on the C-a configuration in a-alkyl derivatives, but on that of the sulfinyl group (1,3-induction). A similar model to that proposed by the same group for b-ketosulfoxides was used to account for the stereochemical results (Scheme 3.41).

Scheme 3.41


Acyclic (R )-a-(p-tolylsulfinyl) ketoximes were reduced with L-Selectride [180] with the same stereoselectivity as that observed for the related imines [165] (Scheme 3.42). This effect was explained on the basis of a non-chelated model, similar to that proposed for the DIBAL reduction of ketosulfoxides.

Scheme 3.42

Reduction and nucleophilic additions of g-fluoro-b-iminosulfoxides, prepared by the aza-Wittig reaction (Staudingen) of iminophosphoranes (Ph3PNR2, R2 ¼ Cbz or SiMe3) with b-ketosulfoxides [181] or by reaction of lithiated aryl alkyl sulfoxides with imidoyl chlorides [182–184] provided enantiopure fluorinated analogues of amines, amino alcohols and amino acids (Scheme 3.43). The same strategy was applied to the synthesis of enantiopure (S)-b-fluoroalaninols, fluorinated cyclic b-amino alcohol derivatives [185], and fluorinated oxazolidinones [186].

Scheme 3.43

Fluorosubstitution changes the usual reactivity of imines [187, 188]. Thus, NCbz a-(fluoroalkyl)-b-sulfinyl enamines did not react with BH(OAc)3, BH3.SMe2, L-Selectride, NaBH3CN and DIBAL, whereas NaBH4 in THF/H2O at room temperature produced scarcely stereoselective mixtures of amines. The best de-values (86%) were attained with K- and L-Selectride in THF (Scheme 3.44).

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Scheme 3.44

To the present authors’ knowledge, the stereoselective intramolecular Pictet– Spengler reaction of N-arylethyl g-trifluoro-b-imino sulfoxide, yielding enantiomerically pure fluorinated analogues of tetrahydroisoquinoline alkaloids (Scheme 3.45) [189], is the only significant example of the stereoselective arylation of biminosulfoxides.

Scheme 3.45

A poor stereocontrol was observed in the hydrocyanation of enantiopure Nbenzyloxycarbonyl b-(fluoroalkyl) b-enamino sulfoxides [190]. Stereoselective cyanosilylation of a-sulfinyl ketimines or enamine tautomers was reported (Scheme 3.46) [191], using trimethylsilylcyanide (TMSCN) or tert-butyldimethylsilylcyanide (TBDMSCN) in the presence of stoichiometric ZnCl2 in i-PrOH or catalytic Yb (OTf )3 (10 mol.%) in CH2Cl2 at room temperature.

Scheme 3.46

3.3 Conjugate Additions to a,b-Unsaturated Sulfoxides

The hydrocyanation of exocyclic, endocyclic, and acyclic a-sulfinylketimines with Et2AlCN was also reported [192], with good conversions and stereoselectivities being obtained exclusively for cyclic imines (Scheme 3.47). Imine–enamine equilibrium was seen to account for the incomplete conversions and low reactivity of the acyclic substrates. Stereoselectivity was explained by assuming the formation of the chelated species indicated in Scheme 3.47.

Scheme 3.47


a,b-Unsaturated sulfoxides have been used extensively in asymmetric synthesis as versatile chiral substrates in conjugate additions [3, 5, 193–195]. In this section, which details such reactions, the first subsection outlines the results of reactions of 1-sulfinylethylenes with different nucleophiles. The second subsection describes tandem processes involving a conjugate addition to vinyl sulfoxides as the first step, while conjugate additions promoted by radicals are considered in the final subsection. Although different explanations have been postulated to account for the stereochemical course of these reactions, in most of the cases it is assumed – as a general principle – that there exists a steric approach control, with the reagent attacking the less-hindered face of the vinyl sulfoxide at its most stable conformation. The outcome depends on the steric and electrostatic interactions of the sulfinyl group with the substituents at the double bond, as well as on the presence of a catalyst, which may produce chelated species that fix the conformation and thus determine the less-hindered face of the substrate. In some cases, an association of the reagent to the substrate was postulated, as a previous step to intramolecular nucleophilic transfer.

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3.3.1 Nucleophilic Additions

It is possible to distinguish between different situations depending on the relative position of the substituents at the substrate. 3.3.1.1 (E) and (Z )-2-Substituted Vinyl Sulfoxides The first asymmetric conjugate addition of carbon nucleophiles to vinyl sulfoxides, reported in 1973, was the reaction of diethyl malonate with (E )-styryl p-tolyl sulfoxide (Scheme 3.48) [196]. Low de-values (560%) and a strong dependence on solvent and counter cation [197] were observed. Lithium bis(dimethylphenylsilyl)cuprate also afforded Michael adducts in good yields (70%) with 54% de [198]. These are the general features of conjugate additions to this type of substrate exhibiting a scarcely marked conformational preference around the CaS bond. According to theoretical calculations on vinyl p-tolyl sulfoxide, the most stable rotamer is that displaying the sulfinyl oxygen in the s-cis arrangement, but the energetic differences with other conformations are very small [199].

Scheme 3.48

The high stereoselectivity (92% de) observed in some nickel-catalyzed additions of organozincates to 1-(4-pyridyl)-1-p-tolylsulfinyl ethylene (Scheme 3.49) [200] may be due to the dipolar repulsion CaPy and SaO, which strongly favors the s-cis arrangement of the sulfinyl oxygen. The low reactivity of b-carbon determines that harder nucleophiles attack the sulfur atom preferentially.

Scheme 3.49


The hydrocyanation of vinyl sulfoxides with Et2AlCN in THF occurs with a complete control of the stereoselectivity, allowing the synthesis of enantiomerically pure b-cyanosulfoxides containing tertiary or quaternary chiral centers [201], which are used as precursors of nitriles and amides (Scheme 3.50). This methodology was applied to the asymmetric synthesis of the fungicide systhane in a six-step sequence from commercially available 1-hexyne (35% overall yield, 92% ee) [202]. In this case, the stereochemical results were explained by assuming the intramolecular transfer of the cyanide from the associated species formed by the electrophilic reagent and the sulfinyl oxygen.

Scheme 3.50

Pyne reported the diastereoconvergent addition of benzylamine to (E ) and (Z)b-stiryl p-tolyl sulfoxide [203], which suggests a different reactive conformation for each stereoisomer (Scheme 3.51).

Scheme 3.51

The low stereoselectivity of intermolecular additions of nitrogenated and oxygenated nucleophiles to vinyl sulfoxides limited the application of this reaction in asymmetric synthesis. However, in 2002 Ma reported the synthesis of nelfinavir via the addition of ammonia to a vinyl sulfoxide (Scheme 3.52) [204], thereby taking advantage of the influence of the allylic carbon acting as an additional chiral inducer. Rayner and Forristal reported the first stereoselective conjugate addition of thiolate nucleophiles to (E )-g-hydroxy-a,b-unsaturated sulfoxides with moderate levels of diastereoselectivity (62% de), despite the presence of two stereocontrolling elements reinforcing their orientation [205]. Recently, Posner [206] established, by competition experiments and molecular modeling, that the size of the substituents joined to the sulfinyl sulfur affects the rate of conjugate addition of thiolates to vinyl sulfoxides (Et4i-Pr4t-Bu).

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Scheme 3.52

Intramolecular Michael addition provided good results. Thus, functionalized cyclohexane and cyclopentane derivatives were obtained by intramolecular reaction of vinyl sulfoxides with ester enolates generated from unsaturated esters with L-Selectride (Scheme 3.53) [207].

Scheme 3.53

The intramolecular additions of nitrogen nucleophiles (Scheme 3.54) are much easier than the intermolecular counterparts, and have been used in the synthesis of biologically interesting molecules [208–211]. Nitrogenated nucleophiles were used in the development of a new diastereoselective route to piperidine and indolizidine scaffolds from an enantiopure vinyl-

Scheme 3.54


Scheme 3.55

sulfinyl-containing amino alcohol (Scheme 3.55) [212]. The presence of a free homoallylic hydroxy group, which is able to form intramolecular hydrogen bonds with the sulfinyl oxygen, appears to be crucial for the stereochemical outcome of this intramolecular ‘‘one-pot’’ deprotection/conjugate addition process, since the corresponding methoxy derivatives afforded an approximately 1 : 1 mixture of cycloadducts.

Scheme 3.56

87

88


Figure 3.2 Favored approach of nucleophiles to a-sulfinyl-a,b-unsaturated esters.

The diastereoselective CaO formation by alkoxide addition to alkenyl sulfoxides has proved to be successful only in its intramolecular fashion. The levels of the achieved asymmetric induction are higher than those obtained with nitrogen nucleophiles. The reaction was used by Solladie´ [213] in the synthesis of the chroman ring of vitamin E; by Iwata [214–217] and Maignan [218] in the preparation of chiral spiroketals, and by Tanaka [219] and Fernańdez de la Pradilla [220] in the synthesis of highly diastereoselective dihydro- and tetrahydropyrans and tetrahydrofurans (Scheme 3.56). The base-promoted cyclization to dihydropyrans from Z,Z-sulfinyl dienols gave only one stereoisomer, whereas E,Z-dienols were found to be less reactive and less selective. 3.3.1.2 1-Substituted Vinyl Sulfoxides The presence of electron-withdrawing groups, such as CO and COOR, at C-1 exerts a positive influence on both reactivity and stereoselectivity. These exhibit strong electrostatic repulsion with the sulfinyl oxygen, thus favoring its s-cis arrangement. Under appropriate catalysts, they favor the formation of chelated species, which require the s-trans arrangement of the sulfinyl oxygen (Figure 3.2). Thus, reactions of organometallics with 2-sulfinylacrylates, followed by reductive removal of the sulfinyl moiety, allowed Posner to perform the synthesis of b-alkyl-substituted carboxylic acids in 59–65% ee (Scheme 3.57) [221], as well as to rationalize the stereochemical results by assuming the formation of the chelated species depicted in Figure 3.2.

Scheme 3.57

Better results were obtained in conjugate additions of Grignard reagents to the cyclic acceptors 2-sulfinylcyclopentenone [222–226], 3-sulfinylfuran-2(5H)one [227], or pyranone [228], the stereochemical courses of which could be inverted by the addition of chelating Lewis acids such as ZnBr2 (Scheme 3.58).


These reactions were used in the enantioselective synthesis of substituted cyclopentenones and natural products [229].

Scheme 3.58

Similarly, the addition of alkyl or aryl organometallic compounds to 3-arylsulfinyl2H-chromen-2-one or 4H-chromen-4-one was used by She [230], Solladie´ [231] and Wallace [232] in the stereodivergent synthesis of curcuphenol and flavones. In some of these reactions dilithium tetrachlorocuprate proved to be a very efficient catalyst for the conjugate addition of phenyl magnesium bromide. Alkylidene bis(sulfoxide) derivatives proved to be exceptional partners in highly yielding and totally diastereoselective Michael additions [233]. The use of heteronucleophiles (amines and alkoxides) afforded enantiopure a-amino and

Scheme 3.59

89

90


a-hydroxy acids, as well as b-amino alcohols and diols (Scheme 3.59). In these transformations, the methylene bis-sulfinyl moiety was used as a synthetic equivalent of the carboxylic group. Carbonated nucleophiles allowed the CaC bond formation, making possible the synthesis of (þ)-erythro-roccellic acid and fenoprofen (Scheme 3.59). Dienyl bis-sulfoxides derived from cinnamaldehyde provided the corresponding 1,4-addition products [234, 235]. Reaction with enolates derived from esters and ketones afforded the respective adducts in good yields, with de-values greater than 60% [236]. The stereoselectivity can be conveniently controlled by choosing the counterion (Liþ, Naþ versus Cuþ ), which determines the formation – or not – of the chelated species (Scheme 3.60).

Scheme 3.60

Intermolecular nucleophilic addition (oxygen, nitrogen and carbon nucleophiles) to a-phosphorylvinyl sulfoxides [237, 238] evolved with high facial stereoselectivity. However, epimerization at the a-carbon atom led to 2 : 1 mixtures of diastereoisomers. The presence of good leaving groups at the allylic position next

Scheme 3.61


to the sulfinyl group caused its elimination from the anions acting as intermediates in the conjugate addition. Thus, Marino’s group demonstrated that allylic mesyloxy sulfinylethylenes underwent an SN2 0 displacement with cyanocuprates in a highly stereoselective manner [239–241]. Spirocyclic bis-sulfinyl oxiranes were obtained by Aggarwal using a related methodology [242]. Similarly, a,bepoxy vinyl sulfoxides also evolved regioselectively with high de-values, the sulfinyl group bearing the main responsibility for the final result (Scheme 3.61) [243]. 3.3.2 Tandem Reactions

In this section, details of those tandem processes involving a Michael-type addition as the first step will be presented. A synthesis of a,b-epoxy sulfoxides, by nucleophilic epoxidation of vinyl or dienyl sulfoxides with MOO-t-Bu (M ¼ Li, Na, K) was reported via Michael addition–intramolecular substitution. The reaction of epoxidation (Scheme 3.62) [244–246] evolved in good yields, with complete preservation of the double-bond geometry in most cases, and with moderate to excellent diastereofacial selectivity. The stereochemical results of these reactions reinforce the concept that nucleophilic additions to vinyl sulfoxides are sterically controlled and occur preferentially syn to the sulfinyl electron lone pair.

Scheme 3.62

Satoh et al. reported the synthesis of 4,4-disubstituted 2-cyclopentenones by a tandem reaction from 1-chlorovinyl p-tolyl sulfoxides and cyanomethyllithium, followed by acidic hydrolysis of the resulting cyclopentadienyl enaminonitriles [247]. When this sequence was applied to asymmetric ketones and optically active sulfoxides, enantiomerically pure cyclopentenones were obtained [248], which were spiroderivatives when starting from cyclic ketones [249]. This sequence was applied to the synthesis of some natural products such as (þ)-a-cuperanone [250] or racemic acorone [249], and allowed the synthesis of 2,4,4-trisubstituted 2-cyclopentenones [251].

91

92


The formation of enaminonitriles seems to involve several steps (Scheme 3.63). The first step – the Michael-type addition of cyanomethyllithium to a chlorovinyl sulfoxide – is responsible for the high observed stereoselectivity. This was explained by assuming the formation of a five-membered chelate, with the lithium ion coordinated with the sulfinyl oxygen and the chlorine, where the approach of the cyanomethyllithium anion took place from the less-hindered face of the chelate (Scheme 3.64) [248]. The reaction of a-chlorovinyl sulfoxides with lithium ester enolates [252, 253] yielded the primary adducts (cyclization did not take place). The use of prochiral enolates also yielded optically pure compounds through a highly stereoselective 1,4-asymmetric induction process controlled by association of the lithium to the oxygen of the enolate (Scheme 3.64).

Scheme 3.63

Scheme 3.64

1-Chlorovinyl p-tolyl sulfoxides reacted with N-lithio arylamines affording aziridines (Scheme 3.65) [254], presumably via initial conjugate addition, elimination of chloride and intramolecular NaH insertion of the resulting carbene intermediate.

Scheme 3.65


The reaction of 2-(arylsulfinyl)-1,4-benzoquinone with 2-trimethylsilyloxyfuran afforded a moderately selective mixture of adducts (ca. 54% de) [255]. The reaction was almost completely stereoselective when using the tert-butylsulfinyl derivative (up to 96% de) [256]. The products result from a tandem process involving a Michael reaction (which determines the final diastereoselection), followed by an intramolecular cyclization of the intermediates (Scheme 3.66). Analogously N-BOC derivatives of 2-(tert-butyldimethylsilyloxy)pyrrole also reacted with sulfinylquinones in the presence of SnCl4, and pyrrolo [3,2-b]benzofuranes were obtained [257].

Scheme 3.66

The first asymmetric cyclopropanation of an a-sulfinyl ester via an initial Michael-type addition of sulfur ylides was reported in 1992 by Hamdouchi (Scheme 3.67) [258]. The stereoselectivity (72% de) was further improved on cyclic vinyl sulfoxides with a steroid skeleton [259].

Scheme 3.67

The reaction of 3-(p-tolylsulfinyl)furan-2(5H)-one (Scheme 3.68) [260] with diphenyl sulfonium methylide and benzylide gave a clean cyclopropanation with

Scheme 3.68

93

94


complete facial selectivity (anti with respect to the OEt group). Reactions of ylides with 2-[(S)-p-tolylsulfinyl]cyclopent-2-en-1-one were also reported [261]. An allyl cyclopropane was alternatively prepared by Michael addition of allyl Grignard reagent to optically active 2-(chloromethyl)cyclohex-1-en-1-yl p-tolyl sulfoxide [262]. Midura and Mikołajczyk studied the cyclopropanation of 1-phosphorylvinyl p-tolyl sulfoxides with sulfur ylides (Scheme 3.69) [263–268]. Although the stereoselectivity was moderate, this methodology was applied to the synthesis of enantiopure cyclic analogue of phaclofen and cyclopropylfosfonate analogues of nucleotides.

Scheme 3.69

Both enantiomers of (S)- and (R )-4-phenyl-1,5-diazacyclooctan-2-ones were stereoselectively synthesized with high enantiomeric excesses by the asymmetric conjugate addition of pyrazolidine to tert-butyl (E )-2-[(R )- and (S)-p-tolylsulfinyl]cinnamates, respectively. A synthesis of optically active homaline was reported

Scheme 3.70


starting from the adduct (Scheme 3.70) [269]. A similar strategy was applied to the synthesis of celacinnine from the same sulfoxide and piperidazine [270]. Acyclic nitrogen nucleophiles (ammonia, benzylamine, 1,3-diaminopropane, 1,4diaminobutane) also evolved via conjugate addition to afford the corresponding chiral b-amino esters. The diastereoselectivity of the reactions was good (49 to 89% de), and (S)-b-amino esters were obtained from (R )-sulfoxide, whereas (R )b-amino esters were synthesized from the (S)-isomer [271]. 3.3.3 Radical Conjugate Additions and Other Reactions

Vinyl sulfoxides behave as acceptors of nucleophilic radicals in inter- [272–276] and intramolecular [277] radical conjugate additions, with the sulfinyl group acting as the controller of the stereochemistry at both the a- and b-positions. Lewis acids catalyzed the reactions by association with the sulfinyl oxygen, and also controlled the stereoselectivity when chelated species were formed. Toru reported that carbonated radicals underwent intermolecular b-addition to cyclic and acyclic vinyl sulfoxides with high selectivities (92–96% de). The addition of bidentate Lewis acids reversed the stereoselectivity by the formation of chelated intermediates. The addition of alkyl radical to 2-(arylsulfinyl)-2cycloalkenones, bearing an sterically bulky aryl group such as 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl, was carried out by reaction with trialkylborane or alkyl iodide-triethylborane [272]. Malacria developed 5-exo-trig cyclizations of optically active b-alkoxy vinyl sulfoxides for the construction of tetrahydrofurans [277]. Cyclizations of E- or Zisomer using n-Bu3SnH or tris(trimethylsilyl)silane (TTMSS) resulted in the formation of different diastereoisomeric tetrahydrofurans (Scheme 3.71) with high de-values. Later, Lee reported the preparation of tetrahydrofuranyl allyl carbinols via radical cyclization of b-alkoxyvinyl sulfoxides [278]. Also, Malacria inves-

Scheme 3.71

95

96


tigated the construction of carbocycles via 5-exo-trig vinyl radical cyclization (Scheme 3.71) in an anti-Michael orientation, followed by b-elimination of the sulfinyl moiety to afford almost enantiopure alkylidenecyclopentanes (up to 98% de) [279]. The enantioselectivity could be reversed and improved by introducing the bulky MAD Lewis acid into the reaction medium. Finally, Malacria reported high diastereoselectivities both in 5-exo-trig and in 6-exo-trig intramolecular radical cycloaddition of 1,1-bis-sulfoxides (Scheme 3.71) [280]. In contrast to nucleophilic and radical additions, electrophilic addition reactions to vinyl sulfoxides are scarce (Scheme 3.72) [281].

Scheme 3.72

Some authors have assumed that the reduction of b-dialkylenaminosulfoxides with the complex borane-THF to give b-amino sulfoxides (74–46% de) is an electrophilic addition [282].

3.4 Cycloadditions 3.4.1 Asymmetric Diels–Alder Reactions

The sulfinyl group has been widely used as a chiral auxiliary in asymmetric Diels–Alder reactions [3, 5, 283–292]. The results obtained in this field will be presented in this subsection, taking into account which is the reactant (dienophile or diene) supporting the sulfoxide moiety directly joined to the reactive fragment. Other reactions mediated by remote sulfinyl groups will be considered in the final part of this section. 3.4.1.1 Sulfinyl Dienophiles Maignan and Raphael [293] were first to report the use of an optically pure vinyl sulfoxide as a dienophile. The reaction of (R )-(þ)-p-tolyl vinyl sulfoxide with cyclopentadiene took place when heated at 110 8C in a sealed tube, without solvent, to produce a mixture of the four possible adducts in high yields (Scheme 3.73). This behavior indicates that the sulfinyl group does not cause any significant improvement in the dienophilic reactivity of the double bond. Otherwise, the stereochemical results can be rationalized by assuming that a significant population of the s-cis and s-trans conformations exhibit both a similar reactivity and a steric approach control (a favored attack of the cyclopentadiene to the less-

3.4 Cycloadditions

Scheme 3.73

hindered face of the vinyl sulfoxide). From the composition of the mixture, a moderate endo-orientating character could be assigned to the sulfinyl group. The above-described results suggest that sulfinyl ethylenes are not good dienophiles due to their low reactivity and poor stereoselectivity [294–296]. Nevertheless, a vast number of reports – most of which have been produced by Koizumi – prove that the presence of additional activating groups at the double bond enhances the reactivity, improves the endo selectivity, and restricts the conformational mobility around the CaS bond, thus dramatically increasing the p-facial diastereoselectivity. A summary of the observed behavior of all three possible types of monosubstituted sulfinyl ethylene is shown in Figure 3.3. Due to limitations of space in this book, and given the large number of associated references, most of the examples will be collected into tables which pay special attention to the stereoselectivity, and their behavior will be outlined as a group. The terms endo and exo, which describe the approach mode of the reagents, will be used in this section taking the sulfinyl group as the reference, even though other functional groups of higher priority according to the sequence rules are present. The term p-facial selectivity is used to describe the proportion

Figure 3.3 Influence of the relative position of an electron-withdrawing group on the dienophilic features of vinyl sulfoxides.

97

98


of adducts resulting from the approach of the diene to each diastereotopic face of the sulfinylated fragment in its most stable conformation. By assuming (as most authors do) that these reactions are mainly governed by a steric approach control – that is, the preferred attack of dienes takes place at the less-hindered face at the dienophiles – the letters (c) or (t) used as suffixes of the endo or exo modes, denote the s-cis or s-trans conformation adopted by the sulfinyl oxygen to explain the formation of the designated adduct (see Scheme 3.73). An electronic approach control, which involves the preferred attack of the diene (acting as a nucleophile) and takes place avoiding the electron-rich face containing the lone electron pair at sulfur, was also postulated by Kahn and Hehre [199, 297–299]. However, this explanation was criticized by Koizumi [300]. When the substituent is located in a trans arrangement relative to the sulfinyl group its influence on the facial selectivity must be scarce or null, as it should have no influence on the composition of the conformational equilibrium around the CaS bond. On the other hand, the endo-orientating character of the substituent will compete with that of the sulfinyl group, and therefore a good endo-exo selectivity cannot be expected [301–305]. This was the case for the transsubstituted vinyl sulfoxides collected in Table 3.1, which exhibited very low endo and p-facial selectivities under thermal conditions (entries 1–3), as well as in the presence of Lewis acids (entries 4–6). When the substituent is located at the geminal position, and therefore it can exhibit strong electrostatic repulsions with the sulfinyl oxygen, the s-cis rotamer A will be favored (Figure 3.4). In these cases, a significant improvement in the p-facial selectivity was observed (Tables 3.2 and 3.3). Furthermore, the addition

Table 3.1 Asymmetric Diels–Alder reactions of trans-substituted sulfinyl

dienophiles with cyclopentadiene.

Entry

R1

R2

Conditions

A/B/C/D

Yield [%]

Reference

1 2 3 4 5 6

OEt OMe OBu OBu OBu n-Pr

Me H H H H H

90 8C, 5 h, sealed tube 4 8C, 60 h Benzene, reflux, 2 h BF3OEt2, 0 8C, 3.5 h SnCl4, 0 8C, 3.5 h BF3OEt2 (2 equiv.), 2 h

63/15/22/– 42/12/30/16 37/16/42/15 56/22/19/3 23/3/55/19 2/5/22/71

100 93 98 92 82 97

301 302, 306 303 303 303 305

3.4 Cycloadditions

Figure 3.4 Preferred rotamers for gem-disubstituted vinyl sulfoxides.

of a Lewis acid such as ZnCl2 shifts the conformational equilibrium around the CaS bond towards the s-trans rotamer, which will form the chelated species B (see Figure 3.4), which would provoke an inversion of the p-facial selectivity. The endo selectivity varies with the nature of the dienophile and the diene as the result of the competition between substituent and sulfinyl group. In the case of cyclic dienes (see Table 3.2), vinyl sulfoxides containing geminal groups such as ester (entries 1–5) [307–309], ketone [310], phosphonate (entry 6) [311], sulfone (entry 7) [312], or sulfoxide (entry 8) [313–316] were studied. These reacted with other dienes which were less reactive than cyclopentadiene, such as furan [309], Dane’s diene [308], or anthracene [317]. gem-Disubstituted vinyl sulfoxides were also used in the synthesis of shikimic and (þ)-5-epi-shikimic acids [309] and as chiral ketene equivalents [312–316, 318].

Table 3.2 Asymmetric Diels–Alder reactions of geminal sulfinyl dienophiles.

Entry

R

X

Conditions

A/B/C/D

Yield [%]

1 2 3 4 5 6 7 8

CO2Et CO2Et CO2Bn CO2Bn CO2t-Bu PO2Et SO2t-Bu SOTol

CH2 CH2 CH2 O O CH2 CH2 CH2

rt, 6 h ZnCl2, 0 8C, 3 h ZnI2, 20 8C, 1 h 13 kbar, 24 h 8 kbar, 6 h ZnCl2, 20 8C, 24 h Eu (fod)3, 42 h 60–70 8C, 4 h

2/23/11/64 19/2/77/2 13/–/87/– 21/11/44/24 18/15/45/22 75/–/25/– –/–/–/92a) –/80/20/–

– – 85 68b) 90b) – 62 98

a) Another diastereoisomer (8%) was also formed. b) Conversion.

Reference

307 307 308 309 309 311 312 313

99

100

3 Asymmetric Transformations Mediated by Sulfinyl Groups Table 3.3 Asymmetric Diels–Alder reactions of cyclic sulfinyl dienophiles with cyclopentadiene.

Entry

R1

R2

X

n

Conditions

A/B/C/D

Yield [%]

1 2 3 4 5 6

H H OEt H H H

H H H OEt H H

O O O O CH2 CH2

0 0 0 0 0 1

22 h, 13 kbar EtAlCl2, rt, 10 h ZnBr2, 0 8C, 1 h rt, 18 h EtAlCl2, rt, 1 h EtAlCl2, rt, 2 h

10/17/30/40 459/51/439/51 17/–/83/– –/12/–/88 60/–/40/– 83/–/17/–

81 92 84 85 92 77

Reference

319 319 320 320 321 321

Similar tendencies were observed in the reactions of cyclopentadiene with cyclic dienophiles (Table 3.3) [319–322], even in those cases bearing an additional chiral center (entries 3 and 4) [320]. Some of these dienophiles reacted with Dane’s diene, giving access to steroidal structures [319, 322]. One of the main problems inherent to the use of gem- and trans-substituted vinyl sulfoxides as dienophiles derives from the easy desulfinylation of the adducts to afford conjugated double bonds with the consequent loss of some of the newly created chiral centers and even aromatization. As can be seen in Figure 3.3, (Z)-substituted vinyl sulfoxides are able to restrict the number of conformers around the CaS bond by shifting the equilibrium towards the rotamer with the sulfinyl oxygen (by electrostatic repulsion) or by the p-tolyl group (by steric interactions) adopting an s-trans arrangement and, simultaneously, reinforcing the endo-orientating character of the sulfinyl group. As a consequence, the reactivity – as well as the endo- and p-facial selectivities – of this type of dienophile were usually high. Additionally, the adducts were less prone to desulfinylation yielding conjugated double bonds, which added to their synthetic potential – as noted by Danishefsky when preparing several natural products in their racemic version [323]. Hence, these dienophiles proved to be the most useful for asymmetric Diels–Alder reactions. Some representative results obtained from (Z)-substituted vinyl p-tolyl sulfoxides are collected in Table 3.4. The first report concerning the use of these dienophiles was made by Koizumi and colleagues (see Table 3.4, entry 1) [301], who used the resulting adducts to prepare b-santalol and epi-b-santalene [338, 339]. In order to increase the low reactivity of the initially studied esters (see Table 3.4, entries 2 and 3) [303, 306], it was necessary to synthesize sulfoxides bearing deactivated aromatic rings, such

3.4 Cycloadditions

101

Table 3.4 Asymmetric Diels–Alder reactions of (Z)-substituted vinyl p-tolyl sulfoxides.

Entry

R1

R2

R3

R4

X

Conditions

A/B/C/D

Yield [%]

Reference

1

Tol

CO2Et

Me

H

CH2

90 8C, 5 h

63/2/35/–

100

301

2

Tol

CO2Me

H

H

CH2

4 8C, 60 h

93/–/7/–

100

302, 306

a)

3

Tol

CO2Bu

H

H

CH2

80 8C, 2 h

85/3/12

91

303

4

2-Py

CO2Ment

H

H

CH2

70 8C, 4 h

496/–/–/–

93

324

5

2-Py

CO2Ment

H

H

O

Et2AlCl, rt, 7 days

56/5/38/1

80

325

6

OMe

O

0 8C, 6 days

496/–/–/–

–

326

7

H

CH2

BCl3, 78 8C, 5 h

endo/exo ¼ 96 : 4b)

88

327

8

H

O

25 8C, 15 h

endo/exo ¼ 499 : 1b)

95

328

9 c)

Isobornyl

CO2NH2

H

H

CH2

1.2 GPa

90/–/10/–

90

329, 330

10 c)

Isobornyl

CO2NH2

H

H

O

1.2 GPa

100/–/–/–

81

329, 330

11c)

Isobornyl

CO2NH2

H

OMe

O

1.2 GPa

92/–/8/–

d)

329, 330

12c)

Isobornyl

SO2Ph

H

H

CH2

0 8C, 12 h

100/–/–/–

90

331–333

13c)

Isobornyl

SO2Ph

H

H

O

ZnI2, rt, 7 days

100/–/–/–

91

334

14

H

CH2

ZnCl2, rt, 15 h

100/–/–/–

89

335, 304

15

H

CH2

8 Kbar, THF rt, 5 days

61/–/39/–

100

335, 304

102


Table 3.4 (continued)

Entry

R1

R2

R3

R4

X

Conditions

A/B/C/D

Yield [%]

Reference

16

Tol

CN

H, Bn, n-Bu

H

CH2

ZnBr2, rt, 1 h ZnBr2, rt, 20 h ZnBr2, rt, 70 h

90/–/10/– 58/–/42/– 45/–/55/–

75 81 82

336

17

Tol

CN

H, Bn, n-Bu

H

CH2

1) BF3, 2.5 h 2) MeOH

–/100/–/– –/100/–/– –/100/–/–

72e) 53e) 55e)

336, 337

a) The configuration of the exo-adduct was not determined. b) As it is a rigid system, no s-cis or s-trans conformation was possible for this dienophile. c) The enantiomer of the represented endo (t) adduct was formed when the opposite configuration at sulfur was used. d) Yield was calculated after dihydroxylation of adducts. e) This product had a carboxamide group instead of the cyano group, and exhibited configuration at sulfur opposite to that in the starting dienophile.

as the non-easily accessible pyridylsulfinyl derivatives [324–326, 340]. The dienophile indicated in entry 4 of Table 3.4 provided excellent results, affording the endo (t) adducts even in the presence of a chiral center at the ester [324]. These adducts were later used in the synthesis of neoplanocine and aristeromicine [341]. Substituted pyridylsulfinyl derivatives were able to react with furan (Table 3.4, entry 5) [325] and furan derivatives (entry 6) [326] to produce adducts that were used as precursors of C-nucleosides [342], methyl epishikimate [343], pseudosugars [344], and glyoxalase I inhibitors [326, 340]. Isobornyl sulfinyl derivatives were also successfully used by the groups of Lucchi [331–333] and Koizumi [330]. In the latter case, high-pressure conditions were used, such that the adducts obtained were transformed with 2-methoxyfurane into ()-COTC [330]. (þ)-6-Methoxy-1,3-benzoxathiolan-(Z)-2-carbomethoxypropenyl-3-oxide (Table 3.4, entry 7) was used as a chiral ketoester ketene equivalent [327]. Cyclic bis-sulfoxide shown in entry 10 of Table 3.4 exhibited excellent reactivity and selectivity, not only with cyclopentadiene but also with other dienes such as 1,3-cyclohexadiene and furan [328]. Amides (Table 3.4, entries 9–11) [329, 330] and stronger electron-withdrawing substituents such as sulfones (entries 12, 13) [331–334] and nitro groups (entries 14 and 15) [304, 335, 345] were also studied.

3.4 Cycloadditions

(Z)-Sulfinyl acrylonitriles – synthetic equivalents of (Z)-sulfinyl acrylates – may be considered as monoactivated vinyl sulfoxides with the best features as chiral dienophiles so far reported. Here, first mention will be made of the high p-facial and endo/exo selectivity of their reactions with dienes. The origin of this ability is related to the strong dipolar repulsion between the SaO and CaN bonds, which determines a complete shift of the conformational equilibrium around the CaS bond towards the s-trans rotamer (the favored rotamer in Scheme 3.74), with the p-tolyl group blocking one of the diastereotopic faces of the dienophilic double bond, thus totally controlling the p-facial selectivity. The endo/exo selectivity was higher than that of the corresponding sulfinyl acrylates (up to 80% de, when R ¼ H), and could be inverted and completely controlled under BF3 catalysis. The evolution accounting for these results with cyclopentadiene is depicted in Figure 3.5 [336]. Moreover, the reactivity of (Z)-sulfinyl acrylonitriles is higher than that of the corresponding acrylates (even the pyridyl derivatives), being able to react with furan and acyclic dienes in a similarly highly stereoselective manner [346, 347]. Sulfinyl ethylenes containing two additional electron-withdrawing groups exhibit higher dienophilic reactivity and endo/exo selectivity than monoactivated vinyl sulfoxides. In this field, three main groups of compounds were investigated: sulfinyl maleates [348–354]; sulfinyl maleimides [355–360]; and sulfinyl quinones [361–376]. In 1988, Koizumi and coworkers reported the Diels–Alder reaction of dimethyl (R)-2-(10-isobornylsulfinyl)maleate with cyclopentadiene catalyzed by ZnCl2 (Table 3.5, entry 1) to afford the adducts with complete p-facial selectivity. The major adduct was used to obtain an advanced intermediate in the synthesis of the carbocyclic nucleosides ()-aristeromycin and ()-neplanocin [352]. In the absence of any catalyst (Table 3.5, entry 2), the opposite p-facial selectivity was observed [353] and the adducts were converted into ()-boschnialactone.

Figure 3.5 (Z)-Sulfinyl acrylonitriles in Diels–Alder cycloaddition.

103

104

3 Asymmetric Transformations Mediated by Sulfinyl Groups Table 3.5 Asymmetric Diels–Alder reactions of sulfinyl maleates.

Entry

R1

R2

R3

Conditions

A/B/C/D

Yield [%]

Reference

1 2 3 4 5 6

Me t-Bu H t-Bu t-Bu Bn

Me H Me Me Me Me

isobornyl Tol Tol Tol Tol Tol

20 8C, 20 8C, 20 8C, 20 8C, 20 8C, 78 8C,

6/–/94– –/3/5/92 19b)/11/70 –/5/89/6 –/36/4/60 –/4/13/83

– 80a) – 95 81 84

352 348 349 348 348 354, 350

ZnCl2, 2.5 h 12 h 24 h ZnBr2, 7 h Eu (fod)3, 12 h TiCl4, 2 h

a) After methylation of the adducts. b) Ratio of A þ B adducts.

The two main restrictions of the dienophile of entry 1 in Table 3.5, which can be considered as a synthetic equivalent of dimethyl acetylene dicarboxylate [352, 353, 377], are the lack of differentiation between the two ester groups present in the molecule and the non-trivial preparation of isobornyl sulfoxides in their optically pure form. Both problems were circumvented by using p-tolylsulfinyl maleates with different carboxylic substituents [348–350, 354]. Amongst all the combinations of substituents (Table 3.5, entries 2–7), the most valuable dienophile was found to be the diester bearing one benzyl group and one methyl group, which gave high and opposite p-facial stereoselectivities according to the Lewis acid, either TiCl4 (Table 3.5, entry 6) or ZnBr2 (entry 7) used. These dienophiles also reacted with a wide variety of cyclic and acyclic dienes under different conditions [350, 351, 354], affording optically pure cyclohexadienes and functionalized [4.n.0] bicyclic compounds [351]. The stereochemical results were seen to depend heavily on the reaction conditions and the substrate structure, and were extensively discussed in the original reports. The effect of a sugar substituent at sulfur was also analyzed in this type of system, although a low reactivity was observed [378]. Enantiomerically pure N-alkylsubstituted a-(2-exo-hydroxy-10-bornylsulfinyl) maleimides underwent Diels–Alder reactions catalyzed by ZnCl2 with cyclopentadiene and furan in relatively short reaction times, affording the corresponding cycloadducts with high diastereoselectivities [355, 356, 360]. These adducts were

3.4 Cycloadditions

used for synthesizing functionalized pyrrolidines [356, 379], pyrrolizidines [357], and indolizidines [357–359]. The first Diels–Alder reaction of an enantiomerically pure sulfinylquinone was reported in 1989 [361]. (S)-2-p-Tolylsulfinyl-1,4-benzoquinone, the corresponding N-tert-butoxycarbonyl quinonimine [380], 3-chloro- and 3-ethyl-2-p-tolylsulfinyl1,4-benzoquinones [363] and sulfinyl naphthazarin [364, 365] reacted with cyclopentadiene through the unsubstituted double bond with very high p-facial selectivities (sensitive to the distance with respect to the sulfinyl group and the catalysts used), and complete endo/exo selectivities. These reactions are a typical case of asymmetric Diels–Alder reactions mediated by a remote sulfinyl group. Bis-adducts were obtained under an excess of cyclopentadiene [381, 382]. 2-Cyano-3-p-tolylsulfinyl-1,4-benzoquinone reacted with cyclopentadiene through the C2aC3 bond [383]. Some significant results of the most simple sulfinyl 1,4benzo and naphthoquinone reactions with cyclopentadiene are listed in Table 3.6. By contrast, acyclic dienes reacted through the sulfinylated double bonds to yield adducts in a completely regioselective manner; these adducts were easily transformed into aromatic derivatives [365, 385]. Differences in chemoselectivity

Table 3.6 Asymmetric Diels–Alder reactions of 2-sulfinyl quinones with

cyclopentadiene [362, 384].

Entry

Starting material

Conditions

Products

Yield [%]

1 2 3 4 5

I I II II II

EtOH, 20 8C, 6 h BF3OEt2, 20 8C, 30 min Eu (fod)3, 20 8C, 30 min CH2Cl2, 20 8C, 24 h ZnBr2, 20 8C, 1 h

A/B ¼ 86 : 14 A/B ¼ 10 : 90 A/B ¼ 89 : 11 C/D ¼ 6 : 94 C/D ¼ 497 :53

95 90 80 84a) 82a)

a) The corresponding product of elimination of sulfinyl group was obtained.

Reference

384 384 384 362 362

105

106


were explained by assuming destabilizing steric interactions between the methylene bridge of cyclic dienes (absent for acyclic dienes) and the substituents at sulfur. The important p-facial selectivity of these cycloadditions, where the sulfinyl group is far from the reaction center, could be a consequence of a desymmetrization of the p-cloud of the quinonic system, due to its electronic repulsion with the lone electron pair at sulfur [285, 362, 384]. The significant p-facial selectivity (up to 40% de) observed in reactions of 2-p-tolylsulfinyl naphthazarin, which in the presence of BF3 exclusively yielded the adducts on the C6aC7 double bond, cannot be explained on steric grounds (the sulfinyl group and the reaction center are too far apart), which reinforces the effect of the desymmetrization of the p-cloud as the main controller of the facial selectivity [365]. Sulfinyl naphthoquinones reacted with cyclic and acyclic dienes through the C2aC3 double bond to afford the adducts with excellent de-values [362, 386, 387] and complete control of both endo/exo and regioselectivity [362]. One remarkable finding was the kinetic resolution of racemic vinyl cyclohexenes to afford only enantiomerically pure or highly enriched angular tetracyclic quinones [367–369]. The reaction of 2-sulfinyl benzoquinones with Dane’s diene provided a ready and regiocontrolled entry to optically active tetracyclic quinones [370]. Diels–Alder reactions with divinyl benzenes, naphthalenes, dihydronaphthalenes, dihydrophenanthrenes or tetrahydrophenanthrenes allowed the enantioselective synthesis of different helicenequinones with high optical purities [371–374, 388]. An example of the formation of [7]helicene bisquinones in a one-pot, six-step process from 2-sulfinyl-1,4-benzoquinone is shown in Scheme 3.74 [388]. Sulfinyl quinones have also been used in the asymmetric synthesis of natural products, notably in the case of (þ)-royleanone [389], angucyclinone-type antibiotics such as (þ)-rubiginone B2 [375] and (þ)-ochromycinone [375], as well as the tetracyclic framework of colombiasin A [376].

Scheme 3.74

The syntheses of rubiginones A2 and C2 [390], as well as that of their 11methoxy regioisomers A 0 2 and C 0 2 [391], were also developed using this strategy (Figure 3.6). Vinyl sulfoxides bearing three additional activating groups have also been studied [392–394]. An additional ester group did not increase the reactivity as compared with that of sulfinyl maleates. Moreover, the p-facial and endo/exo

3.4 Cycloadditions

Figure 3.6 Retrosyntheses of rubiginones A2 and C2 and their regiosiomers A 0 2 and C 0 2.

selectivities of triesters were not as good as those obtained from the corresponding diesters [392]. The substitution of a geminal ester by a cyano group improved both reactivity and stereoselectivity, although the new dienophile was found to be optically unstable [394]. 2,3-bis-Tolylsulfinyl maleates [393] exhibited an unexpected low reactivity [318]. The low increase in dienophilic reactivity induced by double bonds by the sulfinyl groups, despite its presumably electron-withdrawing character (M and I effects), was rationalized by assuming that it can be compensated by a þM effect due to the lone electron pair at sulfur. This would be especially significant in the presence of other electron-withdrawing substituents at the dienophilic double bond. 3.4.1.2 Sulfinyl Dienes The number of reports on the use of sulfinyl dienes in asymmetric synthesis is considerably smaller than those reported for sulfinyl dienophiles, although they have been also collected in several reviews [283, 284]. For the revision of the results in this field, they will be divided according to the position of the sulfinyl group at the diene. 1-Sulfinyl Dienes Although a number of studies have been conducted with the racemic version, no clear conclusions regarding the diastereoselectivity of the processes could be deduced from the results obtained [298, 395–397]. The very low reactivity of the first reported enantiomerically pure 1-sulfinyl diene with both electron-rich (enamine) and electron-poor dienophiles (maleimide, maleic anhydride, methyl acrylate) is shown in Scheme 3.75. Nevertheless, the p-facial selectivity is efficiently controlled in those cases where the regioselectivity of the reactions allows an interaction of the sulfinyl group at C-1 with heteroatoms at the dienophilic substituents [398–400]. The main advantage of these dienes was the easy [2,3]sigmatropic rearrangement undergone by the resulting adducts to afford enantiomerically pure highly functionalized cyclohexenols [398–401]. Dienes with an

107

108


endocyclic double bond reacted with N-methyl [402] and N-phenyl [403] maleimides, giving rise – stereoselectively – to highly substituted bicyclo [2,2,2]octenes in a one-pot, four-step process.

Scheme 3.75

2-Sulfinyl Dienes In 1988, Gibbs and Okamura [404] described the first intramolecular Diels–Alder reaction of a non-racemic vinyl sulfinyl allene (as a mixture of epimers at sulfur), used to synthesize (þ)-sterpurene. The rather low reactivity of 1-sulfinyl dienes contrasts with the significant reactivity of 2-sulfinyl dienes, which were completely transformed into adducts in a few hours under mild conditions [284, 290, 405–409]. 2-Sulfinyl dienes reacted with both cyclic and acyclic electron-poor carbodienophiles such as methyl acrylate [406, 409, 410], dimethyl maleate [411], fumarate [411], maleic anhydride [412], and maleimides [411, 413, 414], undergoing cycloadditions at room or even lower temperatures. 2-Sulfinyl dienes were used in the synthesis of ()-(1S,5R )Karahana ether [412], but the difficult elimination of the sulfinyl group from the obtained adducts [415] (in some cases they were converted into ketones [416]) constitutes the main restriction to their use in total synthesis. Some results of the most studied 2-sulfinyl diene, [S,R]-E-3-[(1S)-isobornyl-10sulfinyl]-1-methoxy-1,3-butadiene, with different dienophiles in Diels–Alder reactions are represented in Scheme 3.76 [290, 409, 411]. The alkyl substituent at sulfur had no significant effect on asymmetric induction, which was markedly dependent on the sulfur configuration [406, 417]. The p-facial selectivity was rather moderate, except for some LiClO4-catalyzed reactions. 2-p-Tolylsulfinyl butadienes with an additional chiral center at C-1 also underwent Diels–Alder cycloadditions with a wide variety of dienes with high p-facial selectivity, presumably controlled by the chiral sulfur atom [418–420]. Intramolecular Diels–Alder reactions with 2-sulfinyl dienes were also described [419, 421].

3.4 Cycloadditions

Scheme 3.76

3.4.2 Asymmetric Hetero Diels–Alder Reactions

Sulfinyl dienes and vinyl sulfoxides have not been used frequently in asymmetric hetero Diels–Alder reactions [414, 422–431]. The first such example was reported in 1992, and describes an intramolecular cycloaddition of an a,b-unsaturated ketone bearing a chiral sulfinyl group at C-a, in the presence of monodentate Lewis acids, such as Et2AlCl, EtAlCl2, and BF3OEt2 (Scheme 3.77) [423, 424]. The intermolecular version of this reaction was first reported by Maignan et al. [414]. Treatment of (þ)-(S)-3-p-tolylsulfinyl-3-buten-2-one with 2-methylentetrahydrofuran gave a 1 : 1 mixture of spiroketals in a complete regioselective manner, but with very low p-facial diastereoselectivity. The reaction with styrenes

Scheme 3.77

109

110


proved to be highly stereoselective (Scheme 3.78) [425]. The reaction of the same heterodiene with a suitably substituted vinyl thioether was used in the synthesis of the Mus musculus pheromone [218]. 2-Sulfinyl-2-butenal dimethylhydrazone behaved as an aza-diene which underwent complete stereoselective cycloaddition with N-phenyl maleimide [430].

Scheme 3.78

Hetero Diels–Alder reactions of 1-sulfinyl dienes [427, 428, 431] with several heterodienophiles were also reported. (R )-1-(p-Tolylsulfinyl)-1,3-pentadiene reacted with 4-methyl-1,2,4-triazoline-3,5-dione [427, 428] and nitroso derivatives [431] under very mild conditions (Scheme 3.79). The adducts were easily transformed into the corresponding carbinols through a stereocontrolled sigmatropic [2,3]-rearrangement, giving access to 1-azagulofagomine analogues [427, 428] and a 1,4-imino-l-ribitol derivative [431], respectively. Hetero Diels–Alder reactions with 2-sulfinyl dienes were also reported [426, 430, 432].

Scheme 3.79

3.4 Cycloadditions

3.4.3 Asymmetric 1,3-Dipolar Cycloadditions

1,3-Dipolar cycloadditions (DC) are fundamental processes in organic chemistry [433–437]. In these reactions, up to four stereocenters can be introduced in a stereoselective manner in one single step. As a consequence, asymmetric dipolar cycloadditions (ADC) have become one of the most powerful tools for the construction of enantiomerically pure five-membered heterocycles [438–442]. Moreover, a range of different substituents can be introduced at dipole and dipolarophile, resulting in a broad range of useful cycloadducts as synthetic building blocks. In contrast to the large number of reports on asymmetric Diels–Alder reactions mediated by sulfoxides (see Section 3.4.1), the number of reports related to the use of enantiopure sulfoxides in ADC is much smaller, and almost all involve their use as chiral dipolarophiles. As it is the case for Diels–Alder reactions, the p-facial selectivity in ADC of non-functionalized vinyl sulfoxides is mainly dependent on the interactions of the sulfinyl group with other substituents present at the double bond. However, electrostatic interactions between charged dipoles and the strongly polarized sulfinyl group determine some differences in the behavior of sulfinyl ethylenes as dipolarophiles with respect to their behavior as dienophiles. In some cases, these differences are related to the facial selectivity, but they mainly affect the reactivity and the endo/exo selectivity. Thus, the reactivity of sufinyl ethylenes as dipolarophiles is much higher than their reactivity as dienophiles, and therefore ADC proceed under milder conditions. Moreover, the role of the sulfinyl group in the control of the endo/exo selectivity of ADC (it is the most difficult parameter to control in cycloaddition reactions) is usually more prominent than the role that it plays in Diels–Alder reactions, thus allowing ADC to evolve with better devalues. Taking into account that the low reactivity and the moderate endo/exo selectivity are the two main drawbacks limiting the usefulness of vinyl sulfoxides in asymmetric Diels–Alder reactions, it can be foreseen that they will be better substrates for ADC. In this section, the results reported in ADC according to the different dipoles used will be described. In all cases, those aspects supporting the features mentioned in the previous paragraph will be highlighted, which will lead to the conclusion that sulfinyl ethylenes are better dipolarophiles than dienophiles. 3.4.3.1 Reactions with Nitrones Nitrones are the most studied 1,3-dipoles in their reactions with vinyl sulfoxides. The first report describing the use of sulfinyl ethylenes as chiral dipolarophiles was made by Koizumi, who noted that the reaction of (R )-2-p-tolylsulfinyl vinyl sulfoxide with phenyl nitrones afforded only two isomers (both endo or exo adducts) in a completely regioselective process (Scheme 3.80) [443]. Configuration at benzylic C-3 was S for the major isomer and R for the minor one, but no comments on the stereochemical course of the reaction were provided. However, if a steric approach control for the reaction and the Z configuration of the acyclic

111

112


nitrones is assumed, then the major adduct would result from the attack of the nitrone at the less-hindered face of the sulfoxide in its s-trans conformation (O/R steric interactions decrease the stability of similar approaches of nitrones to the most stable s-cis rotamer). This suggests that protons adopt a trans relationship in the adducts as a consequence of the endo approach.

Scheme 3.80

A complete control of the p-facial selectivity was observed for Z-vinyl sulfoxides (as depicted in Scheme 3.81) [444, 445] due to the electrostatic repulsion between the oxygens at dipolarophile, which completely shifts the conformational equilibrium around the CaS bond towards the s-trans rotamer.

Scheme 3.81

The influence of alkyl substituents at the b-position depends on their relative stereochemistry; a higher selectivity was found with the Z-isomer (98% or b74% de) than with the E-isomer [446, 447]. This was rationalized by assuming a steric approach control to the preferred conformation of the dipolarophile; it adopts the s-cis arrangement for the lone electron pair at sulfur and the CbC in order to minimize the steric interactions of the R group. In this case, the exo approach is favored in order to avoid interactions of the sulfinyl group with the cyclic C-3 (Scheme 3.82). Adducts resulting from Z-vinyl sulfoxides and cyclic nitrones provided an efficient access to some natural products such as ()-Ncarbomethoxypelletierine, ()-hygroline, and (þ)-sedridine [446, 447]. Good results were obtained by Aggarwal [448] in ADC of acyclic and cyclic nitrones to

3.4 Cycloadditions

Scheme 3.82

trans-2-methylene-1,3-dithiolane 1,3-dioxide, with the reaction proceeding easily and affording one diastereoisomer with very high selectivity. Koizumi et al. [449] produced the first report on the use of activated vinyl sulfoxides as dipolarophiles. The 1,3-ADC of N-oxide 3,4-dihydro-2H-pyrrol and 2,3,4,5-tetrahydropyridine to sulfinylmaleimide afforded complex mixtures of regio- and stereoisomers. Garcıá Ruano et al. [450, 451] studied the reactions of 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones (differing in the configuration at C-5) with cyclic and acyclic nitrones under different conditions. All reactions were completely regioselective and afforded exclusively compounds with the oxygen at the nitrone bonded to C-4 at the furanone ring. The optically pure major adduct was easily isolated in good yield. The stereoselectivity of the reactions was dependent on the structure of the nitrone and dipolarophile. Reaction of (5R,SS)furanone with the morphanthridine N-oxide [451] evolved into only one adduct with complete control of the p-facial selectivity (anti with respect to the alkoxy group at C-5), endo/exo selectivity (endo with respect to the carbonyl group), and regioselectivity. A slight decrease in the endo selectivity was the only difference observed in its reaction with nitrone derived from pyrrolidine (Scheme 3.83) [450]. Reactions with (5S,SS)-furanone were less selective. At this point it is worth mentioning the influence of experimental conditions on the composition of the reaction mixtures. The previously indicated results were obtained under kinetic conditions, but under thermodynamic conditions (e.g. refluxing toluene for long reaction times) the composition of the mixtures dramatically changed in reactions where the nitrone is derived from pyrrolidine [450], the anti-exo adduct having been obtained as the major one in reactions with (5R,SS)-furanone (see Scheme 3.83). Based on these findings it is clear that these ADC may become easily reversible, which reveals the influence of the experimental conditions on the composition of the reaction mixtures – and therefore also in the stereochemical evolution of the process. The correct manipulation of the furoisoxazoloazepines allowed the synthesis of optically pure pyrroloazepines [451], which

113

114


exhibited a weak to moderate binding activity with different G-protein-coupled receptors (GPCRs). Results obtained for the reactions of sulfinyl furanones with acyclic nitrones were similar, and the endo/exo selectivity was improved under thermodynamic conditions (the anti-endo adduct was exclusively formed from (5R,SS)-furanone) [450].

Scheme 3.83

Substituted (Z)-2-p-tolylsulfinyl acrylonitriles react with cyclic nitrones, affording only one diastereoisomer (Scheme 3.84) [452]. The reactions were completely regioselective, and evolved with a total control of the p-facial selectivity (except for R ¼ H), which was explained by assuming that the s-trans arrangement of the sulfinyl oxygen would predominate in order to minimize the dipolar repulsion

Scheme 3.84

3.4 Cycloadditions

of the SaO and CaN bonds. The exo approach was also strongly favored to minimize the steric interactions (see Scheme 3.84). Aggarwal reported the intramolecular ADC of the nitrone derived from the ketene dithioacetal dioxide (as depicted in Scheme 3.85) to afford 5,5disubstituted isoxazolidine as a single diastereoisomer, in good yield [453, 454]. This reaction was used as the key step in the asymmetric synthesis of the naturally occurring antibiotic ()-cispentacin [454], its enantiomer [453], and (þ)-cis4-aminopyrrolidine-3-carboxylic acid [454].

Scheme 3.85

3.4.3.2 Reactions with Azomethine Ylides The first 1,3-ADC of 3-oxidopyridinium betaines (cyclic azomethine ylides) to a chiral vinyl sulfoxide was reported by Koizumi [455] (Scheme 3.86; R ¼ H). This evolved with complete regioselectivity and moderate facial selectivity to give an approximate 60 : 40 mixture of exo and endo adducts. The major exo adduct (R ¼ H) was converted to ()-2-a-tropanol, with the opposite absolute configuration to that of natural cocaine. Similar processes were further used in the synthesis of enantiomerically pure 2-alkyl-3-aryltropanes from the corresponding 1-methyl-4-aryl-3-oxidopyridinium betaine [456, 457]. Optically pure 2,5-dihydro-1H-pyrroles were readily obtained by 1,3-ADC of a-iminoester-derived azomethine ylides to optically pure vinyl sulfoxides and

Scheme 3.86

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116


subsequent pyrolytic desulfinylation [458]. 2-Sulfinyl acrylates exhibit a higher reactivity with N-metallated azomethine ylides than the corresponding desulfinylated acrylates. On the other hand, the presence of the sulfinyl group completely controls the endo-selectivity (Scheme 3.87). However, mixtures of two diastereoisomers (trans and cis; Scheme 3.87) were obtained as a consequence of the possibility of dipole to adopt both syn and anti stereochemistry. The approach of anti dipole/s-cis dipolarophile and syn dipole/s-trans dipolarophile to the lesshindered face of the vinyl sulfoxide in both cases afforded the two diastereoisomers (Scheme 3.87). By modifying the reaction conditions it was possible to obtain, respectively, the cis and trans isomers in good yields from mixtures where both were predominant.

Scheme 3.87

Azomethine ylides, obtained by reaction of a-iminoesters and DBU, reacted with 2-p-tolylsulfinyl cyclopentenone in the presence of silver salts in a completely regio- and endo-selective manner, but with a low facial selectivity affording a mixture of two cycloadducts (Scheme 3.88) [459]. When the ylide was gener-

Scheme 3.88

3.4 Cycloadditions

ated with lithium hexamethyldisilazide (LiHMDS), only one diastereoisomer was obtained in an almost quantitative yield. A tandem nucleophilic addition/ring closure process easily accounts for the stereochemical results. Pyrolytic and reductive elimination of the sulfinyl group provided a good access to optically pure bicyclic 2,5-dihydro and tetrahydropyrroles. Heteroaromatic azomethine ylides also reacted with b-sulfinyl acrylonitriles with a complete control of the p-facial and endo/exo selectivities, and only one diastereoisomer was obtained under very mild conditions. This provided an efficient access to enantiomerically pure polyfunctionalized pyrrolo[2,1-b][1,3]thiazoles and pyrrolo [2,1-a]isoquinolines (Scheme 3.89) [452]. Reactions with 3-sulfinylfuran2(5H)-ones have also been studied [460].

Scheme 3.89

3.4.3.3 Reactions with Nitrile Oxides The 1,3-ADC of nitrile oxides to sulfinyl ethylenes were first studied by Bravo and coworkers, starting from the sodium salts derived from b-ketosulfoxides [461]. The reactions were completely regioselective, affording 4-sulfinyl isoxazoles (Scheme 3.90). The spontaneous desulfinylation of the primary adducts into the aromatic isoxazoles was not easy to control, and constitutes the main restriction of these cycloadditions in asymmetric synthesis. When desulfinylation was not possible – as occurred in the reactions of these dipoles with sulfinyl enol ethers,

Scheme 3.90

117

118


as depicted in Scheme 3.90 [462] – only one diastereoisomeric 4-sulfinyl isoxazoline was formed. This provided evidence of the complete control of p-facial selectivity, and was explained as being the result of a high preference of the conformation with the sulfinyl oxygen in an s-trans arrangement. Garcıá Ruano et al. studied the 1,3-dipolar cycloaddition of nitrile oxides with acyclic and cyclic 2-p-tolylsulfinylbut-2-enoic acid derivatives [463–465]. The most interesting conclusion of these reports deals with the regioselectivity, as reactions of benzonitrile oxide with 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one and with its corresponding 4-sulfinyl derivative were both completely regioselective (Scheme 3.91), but provided a different regioisomer in each case. These findings evidenced the predominant role of the sulfinyl group in regioselectivity control. This approach has been used to develop a one-pot, two-step synthetic sequence for synthesizing regioisomeric isoxazolopyridazinones [464]. Although the primary adducts could be detected and characterized in the reactions with 5-ethoxy-3-ptolylsulfinylfuranone, they evolved spontaneously into 3-phenyl formylixoxazole carboxylic acid, thus minimizing the importance of the p-facial selectivity. These reports also clearly noted the improvement in dipolarophilic reactivity induced by the sulfinyl group.

Scheme 3.91

The stereoselectivity was low or moderate in the reactions of nitrile oxides with alkenes containing chiral sulfinyl groups not directly joined to the double bond [466–469]. 3.4.3.4 Reactions with Diazoalkanes The first 1,3-ADC of diazoalkanes to vinyl sulfoxides was reported by Garcıá Ruano et al. [470]. Excellent results were obtained in the cycloaddition of diazomethane to 5-ethoxy-3-sulfinyl furanones and their 4-methyl derivatives (Scheme 3.92). In addition, it was shown that the sulfinyl group at C-3 of furanone not only strongly increased the reactivity but also efficiently controlled the p-facial selectivity, with syn- or anti-adducts being obtained exclusively depending on the

3.4 Cycloadditions

configuration at C-5. It should be noted here that the efficiency of the sulfinyl group in controlling the p-facial selectivity of the reactions with these propargylallenyl type dipoles was higher than that of C-5, whereas the opposite situation had been observed with allyl-type dipoles such as nitrones or azomethine ylides.

Scheme 3.92

A more detailed study of these reactions with diazomethane and diazoethane was reported at a later date [471]. This revealed the significant role played by electrostatic factors (which can be modulated by the solvent) not only in determining the preferred conformation around the CaS bond but also in stabilizing the transition states that justify the observed p-facial selectivity. These conclusions were supported by density functional theory (DFT) computational methods. The reactions of diazoalkanes with 5-menthyloxy-4-phenylsulfinylfuran-2(5H)-one also provided evidence of the ability of the sulfinyl group to enhance the reactivity and to control the stereoselectivity [472].

Scheme 3.93

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120


Even more interesting were the results obtained with 3-p-tolylsulfinyl furan2(5H)-one [473]. Here, the reactions with diazomethane and diazoethane were almost quantitative, affording only one diastereoisomer. This indicates a complete control of the regioselectivity, as well as of the p-facial and endo/exo selectivities. The use of Lewis acids as catalysts allowed the p-facial selectivity to be inverted; this was also complete with Yb (OTf )3, thereby making possible the stereodivergent synthesis of diastereoisomeric pyrazolines in almost quantitative yields and with de-values higher than 98% (Scheme 3.93). The resultant pyrazolines provided a new entry for enantiopure cyclopropanes [474] by stereospecific denitrogenation with Yb (OTf )3 (Scheme 3.93). Similar – but less impressive – results than those depicted in Scheme 3.93 were obtained in reactions of diazoalkanes with 2-p-tolylsulfinyl-2-cyclopentenone [475]. Midura et al. [476] reported the synthesis of enantiomerically pure 1pyrazolines by reaction of diazopropane with 1-(diethoxyphosphoryl) vinyl sulfoxide (Scheme 3.94). Reaction with diphenyl diazomethane afforded one cyclopropane by the spontaneous extrusion of nitrogen.

Scheme 3.94

The excellent features of the acyclic sulfinyl acrylonitriles as dipolarophiles were also identified in their reactions with diazoalkanes [477]. A complete control of the p-facial selectivity, as well as the endo/exo selectivity, determined the formation of only one 1D-pyrazoline in high yields by reaction with diazomethane

Scheme 3.95

3.4 Cycloadditions

or diazoethane (Scheme 3.95) [478]. The 1D-pyrazoline could then be transformed into sulfonyl cyclopropanes (by pyrolytic extrusion of nitrogen from the corresponding sulfone) and desulfonylated at a later stage. 3.4.3.5 Reactions with Other Dipoles Only one example has been reported recently concerning 1,3-ADC of carbonyl ylides with sulfinyl ethylenes [479]. Reactions of o-(methoxycarbonyl)-adiazoacetophenone with Rh (OAc) 4 and then with epimeric sulfinyl furanones afforded mixtures of endo and exo adducts in good yields, with complete regioselectivity, and very high p-facial selectivity, which became complete for the (5R,SS)-sulfinyl furanone (Scheme 3.96). Separation of the resulting adducts, followed by reductive elimination of the sulfinyl groups, provided enantiomerically pure compounds in good yields.

Scheme 3.96

Malacria et al. reported a good level of asymmetric induction in reactions of vinyl sulfoxides with trimethylenmethane (Scheme 3.97) [480]. Recently, Garcıá Ruano et al. [481] reported that reactions of allenes bearing electron-withdrawing groups with 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones provide an excellent route to enantiomerically pure functionalized cyclopentanes (Scheme 3.98).

Scheme 3.97

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122


Scheme 3.98

3.4.4 Other Asymmetric Cycloadditions

The sulfinyl group has been used as a chiral auxiliary in other cycloadditions which differ from those included in the previous sections of this chapter. This is the case for the [4 þ 3] cycloaddition of 2-sulfinylfuran and 2-oxyallyl cations [482, 483], and the highly diastereoselective [5 þ 2] intramolecular cycloaddition of oxy-g-pyrones and vinyl sulfoxides [484–487], both of which allow the synthesis of seven-membered carbocycles. The [4 þ 3] processes evolved with complete cis-endo selectivity, and afforded two adducts only. The p-facial selectivity, which depended on the reaction conditions, was moderate but the conversion rather low (Scheme 3.99).

Scheme 3.99

A practical route to enantiopure 8-oxabicyclo [3.2.1]octane derivatives, as devel˜ as et al. [488] is based on the intramolecular [5 þ 2] pyroneoped by Mascaren sulfinylalkene cycloaddition. The trans arrangement of the sulfinyl group accelerated the reaction and led to excellent levels of diastereodifferentiation (Scheme 3.100). The value of this methodology was demonstrated by its application to a concise synthesis of (þ)-nemorensic acid [488]. A similar behavior was recognized for oxidopyrilium-alkenes, which yielded one single isomer only [489]. The stereochemical outcome of these reactions could be rationalized by assuming that the alkenyl sulfoxide moiety adopted an s-trans conformation in order to avoid repulsive dipole–dipole interactions with the pyrone, thus disfavoring the approach from the face of the sulfoxide displaying the tolyl group. This proposal was supported by DFT calculations [489].

3.5 Asymmetric Processes Stereocontrolled by Remote Sulfoxides

Scheme 3.100

Finally, the highly diastereoselective examples of intramolecular Pauson–Kahn reactions of vinyl sulfoxides are worthy of mention, since such a reaction can be considered as a formal [2 þ 2 þ 1] cycloaddition [490–492].


In the previous sections, different types of reactions have been considered in which the stereochemical course was controlled by sulfinyl groups close to the reaction center (one or two bonds). Additionally, sulfoxides proved capable of efficiently controlling the stereoselectivity when the chiral sulfur was separated from the reaction center by three or more covalent bonds (remote stereocontrol). In this section, attention will be focused on the two main groups of reactions studied to date which are stereocontrolled by remote sulfoxides, namely nucleophilic processes and cycloadditions. 3.5.1 Nucleophilic Processes

Most asymmetric transformations controlled by remote sulfoxides are processes which involve the reaction of nucleophilic and electrophilic species. As the stereochemical course of these reactions is heavily dependent on the location of the chiral auxiliary, they will be presented in terms of this location. 3.5.1.1 Reactions with Sulfinylated Electrophiles When the sulfinyl group is separated by three or more bonds from the electrophilic center, its efficiency in controlling the stereoselectivity is usually associated with the possibility of forming chelated species involving the sulfinyl oxygen, the heteroatom at the electrophilic center, and the catalyst. However, some intramolecular processes which involve the evolution of the species bearing the sulfinyl oxygen associated with the reagent, are also stereoselective. In the following subsections the results will be presented according to the distance between the electrophilic center and the chiral sulfur.

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1,4-Asymmetric Induction Processes The reduction of g-ketosulfoxides is one of the most widely studied 1,4-asymmetric induction processes. The first example, was reported by Arai in 1996 [493] (Scheme 3.101), and involved the moderately diastereoselective reduction of 3-(ptolylsulfinyl)-2-thienyl ketones with DIBAL (30% de). Inversion of the stereoselectivity was observed with L-Selectride [89% de; 95% de in the presence of Yb (OTf )3].

Scheme 3.101

Several authors have identified the problem that DIBAL has usually provided highly stereoselective reactions, whereas the use of other reducing agents or the addition of Lewis acids, such as Yb (OTf )3 or ZnCl2, decreased and even inverted the stereoselectivity. In this sense, special consideration should be given – deservedly – to the contributions of the groups of Solladie´ for the reduction of acyclic g-ketosulfoxides [82–84, 494, 495], and of Toru, who postulated that the stereochemical results obtained with DIBAL were a consequence of an intramolecular hydride transfer from the chelated twist-chair species formed by association of the metal to the sulfinyl and carbonyl oxygens, with the aluminum adopting a trigonal bipyramidal structure (Scheme 3.102) [496]. The reactions were highly stereoselective only when very bulky groups, such us 2,4,6-triisopropylphenyl (Tip), were joined to the sulfur, because they are the only groups capable of fixing the conformational equilibrium adopting the pseudoequatorial arrangement, as depicted in Scheme 3.102.

Scheme 3.102

The highly stereoselective reduction of 2-acyl-1-(arylsulfinyl)naphthalenes [497] and (arylsulfinyl)phenyl ketones [498] when the aryl group was Tip, was also reported. In 2005, Garcıá Ruano et al. reported the only existing example of


hydrocyanation of g-ketosulfoxides [499]. The reaction of (S)-2-p-tolylsulfinylbenzaldehyde with Et2AlCN and R3SiCN proceeded with high levels of diastereoselectivity only in the presence of Yb (OTf ) 3 (Scheme 3.103). This was explained by assuming the formation of a seven-membered chelate by coordination of the sulfinyl and carbonyl oxygens with the metal. The proposal was supported by theoretical calculations.

Scheme 3.103

˜ o et al. described the conjugate addition of organoaluminum reagents to Carren (R )-[(p-tolylsulfinyl)methyl]quinols with efficient desymmetrization [500, 501]. When the reaction evolved in the presence of an excess of the organoaluminum reagent at low temperature, only one out of the six possible isomers was obtained, resulting from the exclusive 1,4-addition of the organoaluminum reagent to the pro-R conjugate position syn to the face containing the hydroxylic substituent at C-4. A second 1,4-addition of the organoaluminum reagent to the obtained isomer also was completely stereoselective (Scheme 3.104). The elimination of the b-hydroxysulfoxide fragment gave the corresponding cyclohexenones or cyclohexanones (Scheme 3.104) [502]. This methodology was successfully applied to the synthesis of rubiginones A2 and C2 [390], as well as to that of natural polyoxygenated cyclohexanes and cyclohexenes [503].

Scheme 3.104

The stereoselective synthesis of heterocyclic cage compounds by domino conjugate additions of 2-(trimethylsilyloxy)furan with enantiopure 4-amino or 4hydroxy-3-methyl-4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-dienones in the presence of Bu4NF was also reported (Scheme 3.105) [504]. The addition of different organometallic reagents to 3-p-tolylsulfinyl furfural was reported in 1994. The best results were obtained with phenyl magnesium

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Scheme 3.105

bromide in the presence of ZnBr2 (Scheme 3.106) [505]. The allylations of the 3-sulfinyl derivatives of furfural [506] and thiofene [507] 2-carbaldehyde were efficiently performed with allyltriphenylstannane under Lewis acid catalysis.

Scheme 3.106

Toru reported that the Grignard reaction of naphthaldehydes [497, 508] and their corresponding N-arylimines [509] bearing a bulky (2,4,6-triisopropylphenyl)sulfinyl group at the 2-position occurred with high diastereoselectivities (Scheme 3.107), which was inverted under Yb (OTf )3 catalysis. This methodology was applied to benzaldehyde systems [498]. Similarly, both epimers of methyl carbinols derived from 2-p-tolylsulfinyl benzaldehyde were obtained with high de-values by reactions with aluminum and Grignard reagents, respectively [510].

Scheme 3.107


Another widely studied process is the asymmetric Mukaiyama reaction which is stereocontrolled by a remote sulfinyl group. In 1997, Arai et al. reported the high stereoselective aldol reaction of chiral 3-(p-tolylsulfinyl)furfural with silyl ketene acetal catalyzed by lanthanide triflate (Scheme 3.108) [511]. This methodology was successfully applied to the synthesis of (þ)-dihydrokawain-5-ol [512]. Reactions of the sulfinyl furfural with Danishefsky’s diene catalyzed by Ln (OTf )3 or Eu (thd) 3 afforded formal hetero Diels–Alder adducts in a highly stereoselective manner [513].

Scheme 3.108

In this context, the condensation of chiral 3-(p-tolylsulfinyl)-2-furaldimine with lithium enolates provided b-lactams in excellent yields (Scheme 3.109) [514, 515].

Scheme 3.109

The Mukaiyama aldol reaction of sulfinylnaphthaldehydes with trimethylsilyland tert-butyldimethylsilylketene acetals [497], in the presence of BF3OEt2 (2 equiv.) evolved in an almost completely stereoselective manner, which was

Scheme 3.110

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inverted under TiCl4 (1.1 equiv.) catalysis (Scheme 3.110). This difference was explained by assuming the formation of a chelated species with TiCl4. Reactions with 2-sulfinylbenzaldehyde proved to be much less stereoselective [498]. Recently, Toru et al. reported the first remote asymmetric nucleophilic trifluoromethylation of naphthaldehydes (Scheme 3.111) [516]. The high stereoselectivity of these reactions was attributed to the restricted rotation around the CaS bond, which determined that one of the faces of the carbonyl group was highly hindered by the bulky Tip group.

Scheme 3.111

1,5-Asymmetric Induction Processes Recently, Garcıá Ruano et al. reported on the behavior of d-ketosulfoxides [517] with different nucleophiles, demonstrating the efficiency of the sulfinyl group in controlling these reactions when the chiral sulfur was separated by four bonds from the reaction center. Reduction either with DIBAL/Yb (OTf ) 3 or with LSelectride provided a stereodivergent route to prepare alcohols with one of the two possible configurations in each case (Scheme 3.112) [518]. Even more efficient was the hydrocyanation with Et2AlCN/Yb (OTf ) 3, which afforded only one cyanohydrin [519].

Scheme 3.112

A hetero Diels–Alder reaction of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde with 1,3-dioxygenated dienes catalyzed by Yb (OTf ) 3 (Scheme 3.113) [520] occurred following a stepwise mechanism (the Mukaiyama intermediates could be isolated) with a high level of trans-selectivity for 4-methyl-substituted dienes.


Scheme 3.113

The Mukaiyama aldol reaction of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde and O-silylated ketenethioacetals also evolved with high levels of diastereoselectivity in the presence of Yb (OTf ) 3 [521]. Desulfinylation and further transformation of the resulting isomers provided a new access to 1,3-diols and b-hydroxy acids (Scheme 3.114).

Scheme 3.114

1,6-Asymmetric Induction Processes Very few reports have been made on this type of process as mediated by sulfoxides. The first to appear was the asymmetric reduction of e-ketosulfoxides with DIBAL and DIBAL/ZnCl2. These reagents provided different diastereoisomers (Scheme 3.115) and followed stereochemical courses which were similar to those proposed for b-ketosulfoxides [522].

Scheme 3.115

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2-p-Tolylsulfinyl pyrrol [523, 524] and indol [525] were both used as chiral auxiliaries in conjugate additions of arylcopper reagents to acrylic systems. The a,b-unsaturated amides, resulting from the reaction of acryloyl chlorides with the sulfinylated heterocycles, reacted with organocopper reagents to afford adducts in high yields and with high levels of diastereoselectivity (Scheme 3.116). The chiral auxiliary was recovered without any loss of optical purity by reaction with sodium alkoxide. a,b-Unsaturated amides derived from 2-p-tolylsulfinyl pyrrol also were efficient dienophiles in asymmetric Diels–Alder reactions [526, 527].

Scheme 3.116

3.5.1.2 Reactions with Sulfinylated Nucleophiles When the sulfinyl group was located at remote positions from nucleophilic centers, its efficiency in controlling the stereoselectivity of their reactions with different electrophiles was also demonstrated. This control was usually exerted by intramolecular association of the sulfinyl oxygen with the metal joined to the nucleophilic carbon, which located the chiral sulfur close to the reaction centers, allowing it to play a significant role on the stereochemical course. Most of the reactions herein considered are 1,4- and 1,5-asymmetric induction processes. The first report on 1,4-asymmetric induction processes was made by Que´guiner et al. [528], and consisted of the ortho-directed metallation of sulfinyl diazines and pyridines, and further reaction with aldehydes (Scheme 3.117).

Scheme 3.117


Recently, Metzner and colleagues studied the ortho-metallation of enantiopure aromatic sulfoxides and their addition to imines (Scheme 3.118) [529]. The same strategy was used on ferrocenes [530] by using alkyl and aryl imines bearing different nitrogen protecting groups as the electrophiles.

Scheme 3.118

Delgado et al. reported the details of a zinc-promoted allylation of aldehydes, mediated by sulfoxides, using Barbier-type conditions (Scheme 3.119) [531, 532]. The reactions proceeded with moderate diastereoselectivity, which was improved with chiral aldehydes in a double asymmetric induction process.

Scheme 3.119

Colobert and Solladie´ reported a Reformatsky-type reaction, promoted by SmI2, between homochiral a-bromo-a 0 -sulfinyl ketones and aldehydes (Scheme 3.120)

Scheme 3.120

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which afforded enantiomerically pure b-hydroxide ketones, which were converted into syn or anti 1,3-diols by DIBAL or DIBAL/ZnBr2 reductions [45]. Hua et al. reported the 1,4-conjugate additions of chiral sulfinyl allyl anions to cyclic enones [533, 534]. In the past, reactions with cyclopentenones (Scheme 3.121) were considered to be highly regioselective and stereoselective (70–96% ee) and were widely used in the synthesis of natural products [535–537]. The transfused ten-membered cyclic transition state (Scheme 3.121) proposed by Haynes [538, 539] accounts for the high stereoselectivity observed in these reactions. The results were much less satisfactory for cyclohexenones and cycloheptenones, however [533].

Scheme 3.121

Interesting results were obtained in the reactions which used the ortho-sulfinylated benzylcarbanions as nucleophiles. In 2000, two reports on this topic were published almost simultaneously. The first of these [540] details the preparation of lithium 2-p-tolylsulfinylbenzyl carbanions (Scheme 3.122) and their reactions with different electrophiles (ethyl chloroformate, alkyl halides and triflates, aldehydes and ketones). These evolved with an almost complete control of the configuration at the benzylic chiral center (derived from the prochiral nucleophile). By using prochiral electrophiles, the control exerted by the sulfinyl group at the second chiral center was only moderate, unless the electrophile also contained some additional chiral auxiliary. The easy desulfinylation of the resultant compounds led to this methodology being one of the most efficient reported to date for preparing enantiomerically pure benzylic chiral centers.

Scheme 3.122


The second of the reports [541] deals with an intramolecular nucleophilic addition of a benzylic anion to a formyl group, which evolved in a completely stereoselective way at the two simultaneously created chiral centers (Scheme 3.123).

Scheme 3.123

Subsequently, a systematic study of different reactions with 2-p-tolylsulfinyl benzylcarbanions was reported. Reactions with aldehydes [542] afforded mixtures of two diastereoisomers differing only in the configuration at the oxygenated carbon (Scheme 3.124). The fact that the anti and syn isomers were obtained, respectively, as the major components of the mixtures depending on the aromatic or aliphatic nature of the aldehydes, reveals that the stereochemical course of these reactions is more complex than that expected on steric grounds.

Scheme 3.124

Perhaps of more interest were the results obtained by using enantiomerically pure N-sulfinylimines as electrophiles [543], as these provided the possibility of achieving a complete control at the two stereogenic centers generated in the reaction by using the reagents with the appropriate configuration. Thus, reactions of (S)-sulfinyl benzylcarbanions with (S)-sulfinyl imines (that conform the matched pair) yielded only one anti stereoisomer, with de-values above 98% (Scheme 3.125). After removal of the sulfinyl group, these reactions provided one of the best reported methods for obtaining enantiomerically pure anti-1,2-disubstituted 1-propylamines. Starting from oxygenated benzylcarbanions, anti-1,2-disubstituted 1,2-aminoalcohols were also obtained in their optically pure form (Scheme 3.125) [544]. Similar results were obtained starting from sulfenylated carbanions, which

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allowed the synthesis of the corresponding 1,2-aminothioethers [545]. These methodologies were used in the synthesis of enantiomerically pure aziridines when R ¼ SMe [546], and for 2-(1-hydroxybenzyl) piperidine and pyrrolidine when R ¼ OTIPS (Scheme 3.125) [547].

Scheme 3.125

Of even more interest were the reactions with N-sulfinylketimines, because the evolution of both pairs of reagents, each with identical or opposite configuration at their chiral sulfur centers, were completely stereoselective, respectively yielding the syn and anti isomers containing a quaternary chiral center [548]. In these cases each sulfur atom was responsible for the stereoselectivity control at their respective nearest chiral carbon (Scheme 3.126). The results obtained from the reactions of these sulfinylbenzylcarbanions with N-arylimines were recently published [549]. Mixtures of syn and anti isomers

Scheme 3.126


were obtained, the composition being dependent on the electronic density of the aryl ring joined to the iminic carbon. This dependence allowed synthesis of the syn derivatives in a highly stereoselective manner, by using N-2,4,6-trimethoxy imines as the substrates. These reactions were complementary to those performed with N-sulfinylimines, which provided the anti derivatives in an optically pure form. Moreover, the strong inter-dependence between stereoselectivity and electronic density allowed the design of a consistent stereochemical model capable of explaining all these results. According to DFT calculations, the most stable structure for the ortho-sulfinyl benzylcarbanions is that depicted in Scheme 3.127, where the lithium is stabilized by the sulfinyl oxygen. This boat-type conformation of the chelated species has only one diastereotopic face accessible to the attack of the electrophile, which accounts for the complete control of stereoselectivity observed for the prochiral benzylic position. When the ring joined to the iminic carbon was electronically deficient, the p,p-stacking interactions with the carbanionic ring (acting as the donating moiety) stabilized those approaches such as IA (Scheme 3.127) affording the anti-isomers. By contrast, electronically enriched iminic rings – which were unable to act as acceptors in such p,p-stacking interactions – evolved through approaches such as IB, favored on steric grounds (the bulkiest aromatic groups adopted an antiperiplanar arrangement), affording the syn isomers (Scheme 3.127). This stereochemical model may be used to explain the results obtained from N-sulfinylimines and carbonyl compounds.

Scheme 3.127

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Alkylation reactions proceeded more slowly than the nucleophilic additions, and were only successful with highly reactive halides [550, 551], with de-values ranging from 65 to 90% (Scheme 3.128). These are the only reactions where the stereoselectivity control at the benzylic position was not complete. Once the corresponding diastereoisomers had been separated, hydrogenolysis of the CaS bond afforded arenes bearing benzylic chiral centers with high optical purities.

Scheme 3.128

Stereoselective quaternization of benzylic positions was possible starting from benzyl carbanions stabilized by some electron-withdrawing groups. This was the case of silylated cyanohydrins [552] or N-benzyl a-amino nitriles [553], both of which contained a 2-p-tolylsulfinyl benzyl group. Upon treatment with lithiumor potassium-HMDS these materials generated benzylic carbanions which in turn reacted with different electrophiles, including acylating and alkylating reagents, to form quaternary centers in an almost completely stereoselective manner and with very high yields (Scheme 3.129).

Scheme 3.129

3.6 Asymmetric Pummerer Reaction

The Pummerer reaction, which was discovered in 1909 [554, 555], is a powerful tool for the synthesis of a-substituted sulfur derivatives. Later, the reaction was revisited by Horner and Kaiser, who named it as the Pummerer rearrangement [556–560]. The synthetic value of this reaction justifies the production of many excellent reviews describing the progress and scope of the reaction [561–564]. In a general sense, the course of the so-called normal Pummerer reaction [565, 566] involves the reaction of a sulfoxide with an electrophile to afford the oxysul-


fonium salt I, which is transformed with a base into the reactive thionium intermediate II [567]. Finally, it undergoes the attack of some nucleophilic species (this may or may not be the EO generated in the previous step) to yield the a-functionalized sulfide III (Scheme 3.130). These reactions have been explored with a large number of different electrophiles such as acylating reagents (Ac2O, TFAA) [568–573], silyl derivatives (TMSOTf, TBSOTf, CH2 bCH2-SiCl3) [574– 578], Lewis acidic metals [Ti (Oi-Pr)4, Mg2N(i-Pr2)] [579–584] and iodoinium salts [e.g. PhI(OTFA) 2] [563, 585, 586]. The number of nucleophiles used is also large, with oxygenated compounds, arenes, alkenes, phenols, amides, and phosphites being amongst the most frequently used [587].

Scheme 3.130

When the usually intramolecular attack of the nucleophile is faster than the elimination process, it takes place on the sulfur at the oxosulfonium salt I to yield cyclic sulfonium salts IV [588–590]. These may evolve in different ways, with one of the most interesting routes (from the point of view of asymmetric synthesis) being that resulting from the attack of a second nucleophile (vide infra). As the intermediates II are not formed, these reactions are known as interrupted Pummerer reactions and formally involve the nucleophilic substitution of the sulfinyl group. The evolution of vinyl sulfoxides is different. The oxosulfonium salts V, which result from the first step, are initially attacked by the nucleophile at the b-position, yielding thionium intermediates VI; these then suffer a second nucleophilic attack at the a-position to afford a,b-doubly functionalized sulfides (Scheme 3.131). This reaction is known as the additive Pummerer reaction [591, 592]. By contrast, when intermediates V undergo 1,4-elimination into thionium intermediates VII (vinylogous of II in Scheme 3.130), which subsequently are attacked by the nucleophile giving the g-substituted vinyl thioethers [591, 593], the processes are known as vinylogous Pummerer Reactions (Scheme 3.131). The intramolecular character of most of these nucleophilic attacks, determines that the course of these reactions depends on the relative position of the nucleophile with respect to the sulfinyl group, and also on the acidity of the g-proton.

137

138


Scheme 3.131

The first examples of asymmetric Pummerer reactions were reported by Oae [594, 595] and Mikołajczyk [596]. The reaction of optically pure sulfoxides with Ac2O provided optically enriched a-acetoxy thioderivatives (up to 30% ee). These results can be rationalized by assuming the formation of an intimate ionic pair IX in the elimination step, which collapses into the final product without leaving the anion face which was originally occupied by the sulfinyl oxygen. The low stereoselectivity observed in these reactions was attributed to the formation of the achiral sulfurane intermediate X (resulting from an attack of the acetate to the acyloxy sulfonium salt intermediate VIII), which is in equilibrium with both enantiomers of the acyloxy sulfonium salt (VIII and ent-VIII in Scheme 3.132).

Scheme 3.132

Two main strategies were used to prevent the attack of the acetoxy group. On the one hand, the reactions were conducted in the presence of scavengers such as N,N-dicyclohexylcarbodiimide (DCC) [597, 598]; this improved the ee-values but


decreased the yields. The second strategy, which was developed by Kita et al., involved the use of ketene acetals as electrophiles (Scheme 3.133) [599–602]. Here, the silicon atom is attacked by the sulfinyl oxygen to generate an asymmetric silyloxy sulfonium intermediate XI and the corresponding enolate, which abstracts the a-proton from XI to afford an intimate ionic pair XII. The latter then collapses into the final product in moderate to good yields with high stereoselectivity (up to 90% ee).

Scheme 3.133

Kita’s group also demonstrated the crucial role of the chiral centers at the aposition on the stereochemical course of Pummerer reactions [599–601, 603], which contrasts with the scarcely significant role exerted by the b chiral centers [604–606]. More comprehensive studies on the influence of other chiral centers present at the sulfoxides have been recently reported [607]. The intramolecular interception of thionium intermediates by nucleophiles such as amidic nitrogen (Scheme 3.134) or electronically enriched aromatic rings (see Scheme 3.135) was widely used in the synthesis of natural products. Thus, Kita and coworkers [608] prepared optically enriched b-lactams (80–85% ee) by the reaction of enantiomerically pure b-sulfinyl N-alkylamides with O-methyl-Otert-butyldimethyl silyl ketene acetal, in the presence of a catalytic quantity of ZnCl2 (Scheme 3.134). This methodology was used in the synthesis of different penicillin analogues [609–611].

Scheme 3.134

Garcıá Ruano et al. [155–157] prepared bicyclic precursors of anthracyclinones by the reaction of appropriate d-aryl sulfoxides with TMSOTf/DIPEA, with the electron-rich ring acting as internal nucleophile (Scheme 3.135). A similar strategy was used by Enders in the synthesis of the tetrahydropalmitine [612].

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140


Scheme 3.135

One of the most fruitful applications of the asymmetric interrupted Pummerer reaction, claimed as the non-oxidative Pummerer reaction (NOPR), was developed by Zanda et al. [613, 614]. This involves a highly stereoselective SN2 displacement of the sulfinyl group at N-Cbz b-amino sulfoxides by an oxygenated function, thus affording b-amino alcohol derivatives with high ee-values (Scheme 3.136). Once the acyloxy sulfonium intermediate XIII with TFFA has formed, the base (sym-collidine) abstracts the NH proton (the most acidic one in these N-Cbz derivatives) to form a carbamate anion that attacks the sulfur, presumably affording a cyclic azasulfonium salt XIV; this is then opened by the trifluoracetate anion to yield the amino alcohol derivative (Scheme 3.136) [119]. This reaction was applied to the synthesis of different natural products, such as a-arylglycinols [615], g-trifluromethyl-GABOB [616], l-a- and d-a-trifluromethyl-allo-threoninate [119], statine [617], and saquinavir [618], as well as 1,2-dialkyl and 1,2,2-trialkyl2-aminoethanols [619, 620]. Reactions with oxalyl chloride (instead of TFFA) afforded b-chloroamines (instead of b-oxygenated amines) following a similar mechanism to that of the NOPR, but with the chloride acting as the nucleophile [621, 622]. The synthesis of g-aminoalcohol derivatives starting from the N-Cbz g-amino sulfoxides has been recently described [623]. In that report, competition experiments with external nucleophiles suggested an intramolecular attack of trifluoracetate, which must be produced simultaneously to the attack of the nitrogen on the sulfur atom, according to a concerted process.

Scheme 3.136


The asymmetric version of a reaction which is mechanistically similar to the vinylogous Pummerer reaction was described by Garcıá Ruano and Padwa et al. [624]. 2-p-Tolylsulfinylbenzyl stannanes and acetyl chloride were used as the starting materials (Scheme 3.137). The metal at the initially formed thionium salt XV was then attacked by the chloride, forcing the formation of the benzylic anion XVI, which was transformed into the intimate ionic pair XVII. This then collapsed into the stanna-Pummerer rearrangement product A (Scheme 3.137; R ¼ R 0 CO). Presumably, the excellent enantioselectivity (up to 98% ee) was due to the fact that the anion remained at the upper face of the cation (Scheme 3.137).

Scheme 3.137

The same research group reported the simplest way to obtain optically pure benzylic alcohol derivatives A9, starting from benzyl carbanions XVIII that had been generated by reaction of the corresponding sulfoxides with lithium diisopropylamide (LDA). Their reactions with TMSCl afforded the intermediates XVI9, which evolved into the final products A9 (Scheme 3.137) [550, 625].

Scheme 3.138

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Scheme 3.139

The synthesis of spirocyclic derivatives (up to 86% ee) from chiral indole-2sulfoxides (Scheme 3.138) [626] represents an excellent example of the asymmetric additive Pummerer reaction, although the authors expressed some doubts concerning the involved mechanism (Scheme 3.138). Another interesting Pummerer-type rearrangement was developed by Zanda et al. [627], starting from b-enamino sulfoxides. The latter compounds reacted with TFAA to give trifluoracetoxysulfonium intermediates XIX, which were then transformed into a-oxygenated thioethers via a Pummerer rearrangement (Scheme 3.139). After hydrolysis of the ester, an additional stereoselective rearrangement yielding a,a-heterodisubstituted aldehydes was observed. The optical purity was high (64% ee) for both asymmetric transformations. References 1 G. Kresze, in: D. Klamann (Ed.), Methoden der Organishchen Chemie (Houben-Weyl), Georg Thieme, Stuttgart, 1985, pp. 669–866. 2 S. Patai, Z. Rappoport, C. J. M. Stirling (Eds.), The Chemistry of Sulfones and Sulfoxides, Wiley, New York, 1988. ˜ o, Chemical Reviews 3 M. C. Carren (Washington, DC) 1995, 95, 1717–1760. 4 I. Fernańdez, N. Khiar, Chemical Reviews (Washington, DC) 2003, 103, 3651–3705. 5 H. Pellissier, Tetrahedron 2006, 62, 5559–5601. 6 R. Annunziata, M. Cinquini, F. Cozzi, J. Chem. Soc., Perkin Trans. 1: Organic Bio-Organic Chemistry (1972–1999) 1979, 1687–1690. 7 G. Solladie´, C. Greck, G. Demailly, A. Solladie´-Cavallo, Tetrahedron Lett. 1982, 23, 5047–5050.

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4 Synthesis and Applications of Chiral Dithioacetal Derivatives Philip C. Bulman Page and Benjamin R. Buckley

Abstract

In this chapter, methods of synthesis of chiral dithioacetals are detailed, together with their applications in synthesis. Synthetic methods include the reactions of metallated dithioacetals, principally 2-lithio-1,3-dithianes, thioacetalization of carbonyl species, and reactions of ketene dithioacetals. The stereoselective reactions of these materials are described for those cases where the stereoselectivity is induced by the chiral dithioacetal unit, including reactions of dithiane oxides. A selective discussion of the applications of chiral dithioacetals in the total synthesis of complex natural products is also included.

4.1 Introduction

The use of the dithioacetal moiety has been extensively studied since the initial investigations of Corey and Seebach [1]. Interest in this area is most likely due to the ability of dithioacetals – and particularly dithianes – to be used as ‘‘umpolung’’ synthons (Figure 4.1) [1c]. This, coupled with improved methods for the conversion of dithianes into the corresponding carbonyl compounds, makes them extremely useful intermediates for organic synthesis. Several reviews have been published that deal with the synthesis and application of dithioacetal derivatives [2].

Figure 4.1 1,3-Dithiane 2-anion as an acyl anion equivalent.


162

4 Synthesis and Applications of Chiral Dithioacetal Derivatives

There are two general approaches to the introduction of the 1,3-dithiane ring. By far the most commonly used method involves the reaction of the C-2 anion of 1,3-dithiane, with or without further substitution around the ring, with any one of a wide range of functional groups. The 1,3-dithiane ring may also be introduced by the thioacetalization of a carbonyl group, using Lewis acid or acid catalysis, or of a 1,1-dihalide, using transition metal catalysis. 1,3-Dithianes have been described as excellent strategic elements for the construction of complex natural products, and several excellent reviews have been prepared describing this subject [3]. Consequently, this chapter concentrates on the synthesis of chiral dithioacetal derivatives and their applications across a wide range of chemistry.

4.2 Lithiated Dithianes

The most successful sulfur-stabilized acyl anion equivalents that have been studied to date, in terms of availability, ease of preparation, and general suitability, are the cyclic 2-lithio-1,3-dithiane derivatives 2. As indicated in Scheme 4.1, the sulfur-stabilized anion 2 directly reverses the normal pattern of reactivity of the carbonyl group and is thus an equivalent of an acyl anion. After reaction with an electrophile, the dithioacetal moiety may be hydrolysed to provide the corresponding ketone. The term ‘‘umpolung’’ was coined by Corey and Seebach to describe this reversal of the characteristic pattern of reactivity of a functional group; the term has since been widely adopted. Since the introduction of 2lithio-1,3-dithiane [4], its use has become ubiquitous in the chemical literature.

Scheme 4.1


Abundant evidence based on qualitative metallation and quantitative acidity studies has shown that sulfur has a marked stabilizing effect on adjacent carbanions. Detailed quantitative investigations illustrating the increased carbanion stabilization in the series CH5O5S5Se have been published by Lehn [5]. One common explanation for this anion-stabilizing effect of sulfur has involved the idea of back-donation of electrons into vacant sulfur d-orbitals [6], but this is no longer generally accepted. Apart from an inductive effect, the possible stabilizing mechanisms include d-p p-resonance, negative hyperconjugation, and polarizability. Bernasconi and Kittredge have concluded from experimentation that the dominant interaction mechanism is the polarizability of the sulfur group [7]. Recent examples of the synthesis of chiral dithioacetal derivatives include the stereoselective ring-opening of epoxides with 2-lithio-1,3-dithiane, which produces enantiomerically pure b-hydroxylated compounds. Examples may be found in the synthesis of the C-24 to C-37 perimeter of altohyrtin A (Scheme 4.2) [8], in the synthesis of the western sector of okilactomycin 1 (Scheme 4.3) [9], in the synthesis of carbasugars (Scheme 4.4) [10, 11], and in the synthesis of 2,3,5trisubstituted tetrahydrofurans (Scheme 4.5) [12].

Scheme 4.2

Scheme 4.3

Scheme 4.4

163

164


Scheme 4.5

Multicomponent couplings, using the related 2-silyl dithianes and Brook-type rearrangements, have been achieved in good yields (Scheme 4.6) [13]. After an initial reaction of the lithio-dithiane with the first epoxide, the resulting alkoxide undergoes 1,4-Brook-type rearrangement, transferring the silyl group to oxygen and generating the 2-alkylated lithiated dithiane, which can in turn attack another molecule of epoxide, to afford the product. A one-pot epoxidation-nucleophilic opening sequence has been developed for vicinal diols (Scheme 4.7) [14]. Treatment of vicinal diols with N-(p-toluenesulfonyl)imidazole and sodium hydride in THF followed by the addition of 2-lithio-1,3-dithiane produces excellent yields of b-hydroxy dithianes, via the corresponding epoxides.

Scheme 4.6

Scheme 4.7

The addition of 2-lithio-1,3-dithiane to aldehydes or ketones gives the expected alcohol products. This methodology has been used to prepare intermediates for the synthesis of a range of natural products, for example, the anticancer natural product OSW-1 [15] and (2S,3S,4R )-phytosphingosine, a key intermediate in the synthesis of batrachotoxin binding-site antagonists [16, 17]. The modified asiloxyaldehyde approach developed by Smith has also found significant use in the synthesis of natural products [3a]. This approach has a range of advantages over the traditional aldol route, for example in the synthesis of FK506 (Scheme 4.8) [18].


Scheme 4.8

2-Lithio-2-phenyl-1,3-dithiane has been added to N-sulfinyl imines to form enantiomerically enriched a-amino-1,3-dithiane products with excellent levels of diastereoselectivity (495%) (Scheme 4.9; Table 4.1) [19]. The authors have proposed a transition state model to explain the asymmetric induction pattern of this reaction, involving a straightforward hypothesis of a chair-like transition state

Figure 4.2 Chair transition state for the addition of 2-lithio-2-phenyl-1,3-dithiane to N-sulfinylimines.

Table 4.1 Addition of 2-lithio-2-phenyl-1,3-dithiane to N-sulfinyl imines.

Entry

R

de [%]

Yield [%]

1 2 3 4 5 6 7 8 9

Ph 3-BrC6H4 4-FC6H4 1,3,4-MeC6H2 4-PhC6H4 2-Nap 2-Furyl i-Pr 3,4-MeC6H3

495 495 89 85 75 32 31 52 50

64 95 95 90 82 68 76 76 86

165

166


Scheme 4.9

(Figure 4.2), which is similar to that suggested by Davis (vide infra) [20]. It was also noted that even though this model can be used to explain the stereochemistry resulting from this reaction, a possible open-chain model cannot be excluded [21]. Davis has reported a related system using 2-lithio-2-methyl-1,3-dithiane, and has achieved the synthesis of N-sulfinyl-a-amino-1,3-dithianes in high diastereomeric excess (de) and good yields (Scheme 4.10). Davis also showed that these compounds could be selectively cleaved to form either the a-amino-1,3-dithianes

Scheme 4.10

Scheme 4.11


or the N-sulfinyl-a-amino ketones (Scheme 4.11). The value of this methodology was exemplified by the synthesis of the polyoxypeptin amino acid (2S,3R )-()-3hydroxy-3-methylproline 3. Several chiral dithianes have been synthesized by Tyrell from the corresponding aldehydes. Treatment of the lithiated dithiane 4 with methyl chloroformate, and subsequent hydrolysis, affords the a-oxoester 5 with high enantiomeric excess (Scheme 4.12) [22].

Scheme 4.12

Bosch has reported highly stereoselective conjugate addition to the a,bunsaturated ketone 6, using stabilized anions including 2-lithio-1,3-dithiane (Scheme 4.13) [23].

Scheme 4.13

trans-2,5-Disubstituted tetrahydrofurans have been prepared by 1,4-asymmetric induction based on the addition of a chiral 2-lithio-1,3-dithiane to aldehydes with subsequent cyclization to afford the desired products (Scheme 4.14) [24].

Scheme 4.14

The enantioselective reaction of acyclic a-lithiated dithioacetals using chiral bis(oxazoline)s as new chiral formyl anion equivalents has been reported by

167

168


Toru, and good to excellent levels of enantiomeric excess (ee) were observed (Scheme 4.15; Table 4.2) [25].

Scheme 4.15

Table 4.2 The enantioselective reaction of a-lithiated dithioacetals using chiral bis(oxazoline)s.

Entry

R

R9CHO

Temp. [8C]

Yield [%]

dr

ee anti

ee syn

1 2 3 4 5 6 7 8 9 10 11

t-Bu i-Pr Me t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu

PhCHO PhCHO PhCHO PhCHO MesCHO 2-NapCHO 4-MeOC6H4CHO 4-ClC6H4CHO i-PrCHO c-HexCHO t-BuCHO

78 78 78 95 95 95 95 95 95 95 95

91 85 99 93 83 92 65 91 57 63 71

83 : 17 65 : 35 60 : 40 86 : 14 90 : 10 80 : 20 81 : 19 85 : 15 63 : 37 68 : 32 55 : 45

85 84 72 85 85 83 75 88 80 81 84

76 60 73 69 69 55 71 65 64 70

The resulting products could be treated with acetic anhydride to give the acylated products, which, on reaction with HgCl2 and subsequent reduction with lithium aluminum hydride, afforded enantiomerically enriched diols (Scheme 4.16).

Scheme 4.16

4.3 Alternative Methods

4.3 Alternative Methods

Meyers has shown that methylenedithiolane is an excellent cycloaddition partner for reaction with chiral lactams [26]. Treatment of the lactams with dimethylaluminum chloride and the dithiolane, in toluene, gave excellent yields of the cyclobutane adducts as single diastereoisomers (Scheme 4.17; Table 4.3). The stereochemistry of the addition was readily shown to be the result of endoaddition of the dithiolane.

Table 4.3 Methylenedithiolane cycloadditions with chiral lactams.

Entry

R

Yield [%]

1 2 3 4

Me Ph n-Bu n-Hept

92 89 88 86

Scheme 4.17

l-Proline has been found to be a useful catalyst for the formation of a range of enantiomerically enriched dithiane crossed-aldol products (Scheme 4.18; Table 4.4) [27]. It was found that the aldol reaction can proceed exclusively through the crossed-aldol mechanism by the slow addition of propanal to an excess of the

Scheme 4.18

169

170


Scheme 4.19

electrophilic aldehyde. In these cases the corresponding crossed-aldol adduct was obtained with excellent levels of anti diastereoselectivity and enantiocontrol (up to 16 : 1 anti-syn, 99% ee), without production of dimerized propanal. The reaction products can then be used in a variety of applications (Scheme 4.19).

Table 4.4 The crossed-aldol reaction catalyzed by l-proline.

Entry

L-Proline [mol.%]

R

X

Yield [%]

anti : syn

ee [%]

1 2 3 4 5 6 7 8 9

10 10 10 10 10 10 20 20 10

1,3-dithiane 1,2-dithiane Et i-Pr 1,3-dithiane 1,3-dithiane 1,3-dithiane 1,3-dithiane 1,3-dithiane

Me Me Me Me n-Hex Bn OTBS H OH

85 77 70 41 75 73 52 91 88

16 : 1 8:1 10 : 1 8:1 420 : 1 420 : 1 13 : 1 – 420 : 1

499 99 97 98 97 97 70 96 499

Ley has reported that the treatment of the propargyl ketone 7 with sodium methoxide and 1,3-propanedithiol followed by removal of the silicon protecting groups with acid affords the corresponding spiroacetal 8, a subunit in the synthesis of the spongistatins (Scheme 4.20) [28].

4.4 Oxidation Methods for the Construction of Chiral Dithioacetal Derivatives

Scheme 4.20

4.4 Oxidation Methods for the Construction of Chiral Dithioacetal Derivatives and Applications in Synthesis

1,3-Dithiane-1-oxides have been used extensively as asymmetric building blocks for organic synthesis, and a chelation control model has been developed that has allowed rationalization – and in many cases prediction – of the stereochemical outcome of a range of reaction types [29]. For example, the sense of stereoselective addition of methyl magnesium iodide to the syn- and anti-dithiane oxides 9 and 10 can be predicted (Figures 4.3 and 4.4). In the case of the syn-dithiane oxide, the approach of the nucleophile is controlled by the steric bias of the DiTOX ring, and so addition to the carbonyl group occurs from the direction of the relatively small 2-methyl substituent (Figure 4.3). In the case of the anti-substrate, stereoselectivity is controlled by ability of the 2-methyl group to exert steric

Figure 4.3 Stereoselectivity of Grignard reagent addition to syn-dithiane oxides.

Figure 4.4 Stereoselectivity of Grignard reagent addition to anti-dithiane oxides.

171

172


Scheme 4.21

hindrance towards the approach of the incoming nucleophile (Figure 4.4) and, indeed, replacing this methyl group by a larger group increases stereoselectivity. There are several advantages when using 1,3-dithiane-1-oxides; they can be readily prepared, are generally stable, and are relatively inexpensive. Both sulfoxide enantiomers are readily available and, most importantly, the auxiliary can be easily removed, in high yield, without any loss of stereochemical integrity. Initial investigations using racemic 1,3-dithiane-1-oxide gave high levels of diastereoselectivity. In order to prepare the enantiomerically pure sulfoxides, a new method had to be developed, as the best reported asymmetric oxidation of a 1,3-dithiane was only approximately 20% ee. A modification of the Sharpless epoxidation originally reported by Kagan afforded either enantiomer of 2-acyl dithianes with up to 97% ee (Scheme 4.21) [30]. A rule of thumb for predicting the configuration at sulfur has been proposed [31], and for 2-substituted acyldithianes when using (þ)-tartrate this results in the R-configuration at sulfur (Scheme 4.22) with the anti-isomer predominating.

Scheme 4.22

More recently, several groups have reported highly enantioselective systems for the sulfoxidation of a variety of substrates including dithianes [32]. Enzymatic routes to chiral sulfoxides have been known since the early 1980s; for example, cyclohexanone mono-oxygenase (CMO) has given up to 98% ee for several dithianes (Scheme 4.23; Table 4.5) [33]. Modena has developed a system that is able to oxidize sulfides to sulfoxides with high selectivity, also based on a modification of the Sharpless epoxidation conditions; the proposed catalytic cycle is shown in Scheme 4.24 (see also Table 4.6) [34]. Bolm has developed a catalytic system formed in situ from VO(acac)2 and ligand 11 (Figure 4.5); this system is able to catalyse sulfoxide formation with only 0.01 mol.% catalyst (Scheme 4.25) [35].

Scheme 4.23

4.4 Oxidation Methods for the Construction of Chiral Dithioacetal Derivatives Table 4.5 Enantioselective cyclohexanone mono-oxygenase

(CMO)-catalyzed oxidation of sulfides. R

Scheme 4.24

R1

Yield [%]

ee [%]

Configuration

81

498

R

94

498

R

92

498

R

173

174

4 Synthesis and Applications of Chiral Dithioacetal Derivatives Table 4.6 Asymmetric oxidation of sulfides by TBHP in the presence of

Ti(O-i-Pr) 4 /(þ)-DET (1 : 4). Sulfide

Yield [%]

dr

ee

76

94 : 6

83

66

97 : 3

76

82

99 : 1

70

61

99 : 1

68

Scheme 4.25

With the chiral 1,3-dithiane 1-oxide building blocks readily available, several applications were reported, including the enantioselective synthesis of (R )-()2,6-dimethylheptanoic acid, a structural motif found in a number of analgesic compounds (Scheme 4.26) [36]; a-arylpropionic acids display anti-inflammatory activity (ibuprofen, is one such example) (Scheme 4.27) [37]. Either enantiomer

Scheme 4.26

4.4 Oxidation Methods for the Construction of Chiral Dithioacetal Derivatives

Scheme 4.27

of a-hydroxyketones such as those shown in Scheme 4.28, which are found in a variety of biologically active molecules, can be prepared by using the appropriate reduction conditions [37].

Scheme 4.28

trans-1,3-Dithiane-1,3-dioxides have also been used as chiral auxiliaries for a range of reactions. It has been found that chiral ketene dithioacetal bis-sulfoxides undergo inter- and intramolecular [3 þ 2] nitrone cycloadditions (Scheme 4.29) [38] and [4 þ 2] Diels–Alder reactions with high diastereocontrol [39]. The ketene dithioacetal bis-sulfoxides can also undergo highly diastereoselective nucleophilic epoxidation reactions [40]. An improved method for their preparation has also been reported [41].

Scheme 4.29

175

176


4.5 Applications of Chiral Dithioacetal Derivatives in Natural Product and Biologically Active Compound Synthesis

Given the developments outlined in this chapter, it is perhaps not surprising that chiral dithioacetal derivatives have been applied to the total synthesis of a wide variety of natural products. An excellent review in this specialized area has been reported by Foubelo [3b], while Smith has reported an account of his group’s efforts to synthesize a range of natural products using a dithiane strategy [3a]. Unfortunately, it is impossible to review here all of the elegant natural products prepared using chiral dithioacetal derivatives; several of these complex natural products are shown in Figure 4.5.

Figure 4.5 Natural products synthesized using chiral dithioacetals.

References

4.6 Summary

This chapter highlights the versatility of chiral dithioacetal derivatives, which can be used not only as masked carbonyl units or chiral auxiliaries but also in a variety of other highly efficient and stereoselective transformations. One of the major applications of chiral dithioacetals is as intermediates in natural product synthesis, and this structural unit is particularly attractive due to the ability of the dithiane moiety to act as an ‘‘umpolung’’ synthon.

References 1 (a) E. J. Corey, D. Seebach, Angew. Chem. Int. Ed. 1965, 4, 1075; (b) E. J. Corey, D. Seebach, Angew. Chem. Int. Ed. 1965, 4, 1077; (c) D. Seebach, M. Kolb, Chem. Ind. 1974, 7, 687; (d) D. Seebach, Angew. Chem. Int. Ed. 1979, 18, 239. 2 (a) T.-Y. Luh, Acc. Chem. Res. 1991, 24, 257; (b) P. C. B. Page, M. B. van Niel, J. C. Prodger, Tetrahedron 1989, 45, 7643; (c) S. M. Allin, P. C. B. Page, Org. Prep. Proc. Int. 1998, 30, 145; (d) T.-Y. Luh, J. Organomet. Chem. 2002, 653, 209; (e) T.-Y. Luh, C.-F. Lee, Eur. J. Org. Chem. 2005, 3875. 3 (a) A. B. Smith, III, C. M. Adams, Acc. Chem. Res. 2004, 37, 365; (b) M. Yus, C. Na´jera, F. Foubelo, Tetrahedron 2003, 59, 6147. 4 P. C. B. Page, B. R. Buckley, 2-Lithio-1,3dithiane, in: Encyclopaedia of Reagents for Organic Synthesis, 2005, DOI: 10.1002/ 047084289X.rl020. 5 J.-M. Lehn, G. Wipff, J. Am. Chem. Soc. 1976, 98, 1498. 6 A. Krief, Tetrahedron 1980, 36, 2531. 7 C. F. Bernasconi, K. W. Kittredge, J. Org. Chem. 1998, 63, 1944. 8 S. A. Hermitage, S. M. Roberts, D. J. Watson, Tetrahedron Lett. 1998, 39, 3567. 9 L. A. Paquette, S. L. Boulet, Synthesis 2002, 888. 10 Y. Le Merrer, C. Gravier-Pelletier, W. Maton, M. Numa, J.-C. Depezay, Synlett 1999, 1322. 11 C. Gravier-Pelletier, W. Maton, T. Dintinger, C. Tellier, Y. Le Merrer, Tetrahedron 2003, 59, 8705.

12 Y. Guindon, F. Soucy, C. Yoakim, W. W. Ogilvie, L. Plamondon, J. Org. Chem. 2001, 66, 8992. 13 A. B. Smith III, A. M. Boldi, J. Am. Chem. Soc. 1997, 119, 6925. 14 R. D. Cink, C. J. Forsyth, J. Org. Chem. 1995, 60, 8122. 15 W. Yu, Z. Jin, J. Am. Chem. Soc. 2002, 124, 6576. 16 M. Shimizu, I. Wakioka, T. Fujisawa, Tetrahedron Lett. 1997, 38, 1997. 17 S. R. Schow, D. P. Rossignol, A. E. Lund, M. E. Schnee, Bioorg. Med. Chem. Lett. 1997, 7, 181. 18 A. B. Smith III, K. Chen, D. J. Robinson, L. M. Laasko, K. J. Hale, Tetrahedron Lett. 1994, 35, 4271. 19 X. Xu, J. Liu, D. Chen, C. Timmons, G. Li, Eur. J. Org. Chem. 2005, 1805. 20 F. A. Davis, T. Ramachandar, H. Liu, Org. Lett. 2004, 6, 3393. 21 (a) D. A. Evans, J. Bartrolli, T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127; (b) M. A. Walker, C. H. Heathcock, J. Org. Chem. 1991, 56, 5747. 22 E. Tyrell, G. A. Skinner, J. Janes, G. Milsom, Synlett 2002, 1073. 23 M. Amat, M. Pe´rez, N. Llor, J. Bosch, Org. Lett. 2002, 4, 2787. 24 H. Chikashita, H. Yasuda, Y. Kimura, K. Itoh, Chem. Lett. 1992, 195. 25 S. Nakamura, Y. Ito, L. Wang, T. Toru, J. Org. Chem. 2004, 69, 1581. 26 A. I. Meyers, M. A. Tschantz, G. P. Brengel, J. Org. Chem. 1995, 60, 4359. 27 R. I. Storer, D. W. C. MacMillan, Tetrahedron 2004, 60, 7705.

177

178

4 Synthesis and Applications of Chiral Dithioacetal Derivatives 28 M. J. Gaunt, H. F. Sneddon, P. R. Hewitt, P. Orsini, D. F. Hook, S. V. Ley, Org. Biomol. Chem. 2003, 1, 15. 29 (a) P. C. B. Page, D. Westwood, A. M. Z. Slawin, D. J. Williams, J. Chem. Soc., Perkin Trans. 1 1989, 1158; (b) P. C. B. Page, J. C. Prodger, M. B. Hursthouse, M. Mazid, J. Chem. Soc., Perkin Trans. 1 1990, 167; (c) P. C. B. Page, J. C. Prodger, Synlett 1990, 460; (d) P. C. B. Page, A. M. Z. Slawin, D. Westwood, D. J. Williams, J. Chem. Soc., Perkin Trans. 1 1989, 185. 30 (a) P. C. B. Page, E. S. Namwindwa, S. S. Klair, D. Westwood, Synlett 1990, 457; (b) P. C. B. Page, E. S. Namwindwa, Synlett 1991, 80; (c) P. C. B. Page, J. P. Heer, D. Bethell, E. W. Collington, D. M. Andrews, Tetrahedron: Asymmetry 1995, 2911; (d) P. C. B. Page, R. D. Wilkes, J. V. Barkley, M. J. Witty, Synlett 1994, 547; (e) P. C. B. Page, R. D. Wilkes, E. S. Namwindwa, M. J. Witty, Tetrahedron 1996, 52, 2125. 31 (a) P. Pitchen, E. Dunach, M. N. Desmukh, H. B. Kagan, J. Am. Chem. Soc. 1984, 106, 8188; (b) P. Pitchen, H. B. Kagan, Tetrahedron Lett. 1984, 1049; (c) E. Dunach, H. B. Kagan, Nouv. J. Chim. 1985, 9, 1; (d) H. B. Kagan, E. Dunach, E. Nemecek, Pure Appl. Chem. 1985, 57, 1911; (e) H. B. Kegan, Phosphorus and Sulphur 1986, 27, 127; (f ) S.-H. Zaho, O. Samuel, H. B. Kagan, Tetrahedron 1987, 43, 5135; (g) K.-U. Baldenius, H. B. Kagan, Tetrahedron: Asymmetry 1990, 1, 597. 32 I. Fernańdez, N. Khiar, Chem. Rev. 2003, 103, 3651.

33 (a) G. Carrea, B. Redigolo, S. Riva, S. Colonna, N. Gaggero, E. Battistel, D. Bianchi, Tetrahedron: Asymmetry 1992, 3, 1063; (b) G. Ottolina, P. Pasta, G. Carrea, S. Colonna, S. Dallavalle, H. L. Holland, Tetrahedron: Asymmetry 1995, 6, 1375; (c) S. Colonna, N. Gaggero, A. Manfredi, L. Casella, M. Gullotti, J. Chem. Soc., Chem. Commun. 1995, 1123; (d) S. Colonna, N. Gaggero, P. Pasta, G. Ottolina, J. Chem. Soc., Chem. Commun. 1996, 2303. 34 F. Di Furia, G. Modena, R. Seraglia, Synthesis 1984, 325. 35 C. Bolm, F. Bienewald, Synlett 1998, 1327. 36 P. C. B. Page, S. M. Allin, E. W. Collington, R. A. E. Carr, Tetrahedron Lett. 1994, 35, 2607. 37 P. C. B. Page, M. Purdie, D. Lathbury, Tetrahedron Lett. 1996, 37, 8929. 38 (a) V. K. Aggarwal, R. S. Grainger, H. Adams, P. L. Spargo, J. Org. Chem. 1998, 63, 3481; (b) V. K. Aggarwal, S. J. Roseblade, J. K. Barrell, R. Alexander, Org. Lett. 2002, 4, 1227. 39 (a) V. K. Aggarwal, M. Lightowler, S. D. Lindell, Synlett 1992, 730; (b) V. K. Aggarwal, J. Drabowicz, R. S. Grainger, Z. Gu¨ltekin, M. Lightowler, P. L. Spargo, J. Org. Chem. 1995, 60, 4962; (c) V. K. Aggarwal, Z. Gu¨ltekin, R. S. Grainger, H. Adams, P. L. Spargo, J. Chem. Soc., Perkin Trans. 1 1998, 2771. 40 J. K. Barrell, J. M. Worrall, R. Alexander, J. Org. Chem. 1998, 63, 7128. 41 V. K. Aggarwal, R. M. Steele, Ritmaleni, J. K. Barrell, I. Grayson, J. Org. Chem. 2003, 68, 4087.

179

5 Synthesis and Use of Chiral Sulfur Ylides Jean-François Brie`re and Patrick Metzner

Abstract

A variety of enantioenriched sulfonium ylides has been prepared, mainly by deprotonation of sulfonium salts or reaction of metal carbenoids with sulfides. The careful design of chiral cyclic sulfides and mechanistic insights led to great achievements in terms of reactivity, diastereoselectivity and enantioselectivity. Recently, the use of substoichiometric amounts of sulfide has been demonstrated, raising this methodology to the requirements of the growing field of organocatalysis. Reaction of these ylides with carbonyl compounds furnished a variety of oxiranes with enantioselectivities in excess of 90% for the most efficient sulfides. Aziridination was also achieved enantioselectively with activated imines. Reaction of chiral ylides with activated alkenes yields asymmetric cyclopropanation. Sulfonium ylide-mediated [2,3]-sigmatropic rearrangement allowed formation of the CaC bond with control of up to two stereogenic centers. Thus, during the past 10 years major progress has been achieved with chiral sulfur ylides, and new sulfonium ylide reactions have emerged.

5.1 Introduction 5.1.1 Reactions of Sulfonium Ylides

Although the sulfonium ylide was first isolated in 1930 [1], the extensive use of these intermediates began only during the 1960s. As shown by the groups of Johnson [2, 3], Corey [4], and Franzen [5], reaction with aldehydes leads to oxiranes (Scheme 5.1). This involves a nucleophilic attack of the carbanionic center of 1 onto the carbonyl compound 2, formation of a betaine 5, and subsequent intramolecular nucleophilic substitution and generation of an oxirane 6 (X ¼ O), with elimination of sulfide 9. Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

180

5 Synthesis and Use of Chiral Sulfur Ylides

Scheme 5.1

The first examples of the formation of other three-membered rings, aziridines 7 and cyclopropanes 8, were reported soon afterwards by reaction with imines 3 [5–7] and Michael acceptors 4 [7, 8], and were followed by a variety of applications, in the racemic series [9–14]. The use of other types of ylides (e.g. sulfoxonium [15], sulfimides [16], sulfoximines [17, 18]) has been reported, as has that of other reactions such as [2,3]-sigmatropic rearrangements [19]. The subject matter of this chapter, which incorporates mainly recent literature between 1996 and 2006, is limited to chiral sulfonium ylides of type 1, and does not include any details of substrate stereocontrolled reactions. Although the general subject has been outlined in 1997 [19] and 2007 [20], Aggarwal and others have regularly reported accounts of their contributions [21–24], and various other reviews have also been prepared [25–29]. The early developments of asymmetric synthesis led Trost and coworkers [30], in 1973, to make use of a chiral non-racemic sulfide derivative. These authors resolved a methylethyladamantyl sulfonium salt and submitted its methylidene ylide to epoxidation of benzaldehyde. The obtained phenyloxirane was, unfortunately, almost racemic, although some optical activity was observed for a cyclopropanation reaction. By using aminosulfoxonium ylides, Johnson and coworkers [31] obtained phenyloxirane in 20% enantiomeric excess (ee). A breakthrough was reported by Furukawa et al. in 1989 [32], when chiral sulfides derived from camphorosulfonic acid were used in a one-pot benzylidenation reaction of two examples of aromatic aldehydes. Stilbene oxides were produced in a non-racemic fashion, with ee-values up to 47% (sulfide 10; see Table 5.1 and Section 5.2.1). Moreover, the reaction was shown to be feasible with a substoichiometric amount of sulfide, and this opened the way for further developments, mostly during the past 10 years. Within this period, two approximate areas of development have evolved, and this led to the chapter being organized according to the amount of sulfide used, whether stoichiometric (versus the substrates) or catalytic. Finally it must be stressed that, although the term had not been coined when chiral sulfonium ylides first began their development (during the mid-1990s), most of the reactions mentioned here form part of the organocatalysis ‘‘gold rush’’, and have been reviewed as such [26, 33, 34]. 5.1.2 Methods of Preparation

Basically, two types of procedure have been used for the reaction of non-racemic sulfonium ylides with electrophiles.

5.1 Introduction

Procedure A involves sulfonium salt formation by the reaction of a sulfide usually with an alkyl halide, deprotonation, and subsequent reaction with electrophiles (Scheme 5.2).

Scheme 5.2

Several variants of Procedure A are possible:

•

•

•

Preformation and isolation of the sulfonium salts is sometimes preferred or necessary for stoichiometric use of the sulfide. This allows epoxidation at lower temperatures. Although in-situ formation will be largely preferable, it will require a driving force to favor the salt formation, such as a solvating effect in a polar medium. Formation of the ylide is normally a facile deprotonation step, as a result of the acidity of the hydrogen atoms alpha to the sulfonium center. Deprotonation of the sulfonium salt has been achieved with a variety of bases: mineral (KOH, NaOH, NaH) or organic bases (NaHMDS, phosphazenes), generally in polar solvents. The aldehyde can be added in a final step, but most recent procedures now involve a one-pot reaction with all reagents being introduced simultaneously. This is of course necessary for the catalytic procedures. The main requirement is that the base is compatible with the substrate.

Procedure B involves direct formation of the ylide by reaction of a carbenoid species (Scheme 5.3). This was largely developed by Aggarwal [35] through the reaction of a sulfide with a diazoalkane, such as phenyldiazomethane, and a metal catalyst, usually Rh2(OAc) 4. Although a catalytic procedure was largely

Scheme 5.3

181

182


demonstrated, the hazard associated with the electrophile source has led to an insitu generation of the diazoalkane by the basic cleavage of tosylhydrazones [36, 37]. 5.1.3 Conditions for Stereocontrol and Theoretical Investigations

The major strategy developed involves the introduction of a stereogenic element within the sulfide. Although during the mid-1990s relatively few enantioenriched sulfides were available, it was easy to imagine a variety of routes for their synthesis. More challenging was the design of proper structures fulfilling all of the supposed criteria for a successful asymmetric synthesis of oxiranes, aziridines, and cyclopropanes. The numerous requirements for stereocontrol [38] revealed the complexity of these reactions:

•

•

•

•

•

Similar to other modern asymmetric processes, the chiral sulfide should be prepared in a straightforward manner (few steps, practical reaction conditions, scale-up) in both enantiomeric forms, from readily available chiral sources. In order to use it in substoichiometric amounts, it should be chemically robust. Reaction of the sulfide should preferably lead to the formation of a single diastereomeric sulfonium salt. The design of the sulfide must therefore incorporate an efficient differentiation of the two sulfur lone pairs. An alternative is the use of C2 symmetry, which avoids this difficulty. If the ylidic center is prochiral, one major concern is the conformation. The geometry is tetrahedral sp3 for the sulfur atom and planar sp2 for the ylidic carbon. It is generally accepted that the sulfur lone pair and the filled p orbital on the carbanion are orthogonal [39]. Rotation along the CaS bond has a low energy barrier (ca. 10 kcal mol1) [39]. Two conformations – syn and anti – are possible (Scheme 5.4). The design of the sulfide will usually involve steric hindrance of R1 and R2 in order to favor the anti ylide. Facial selectivity of the ylide is another crucial step which, basically, will necessitate differentiation of R1 versus R2. Knowledge of the geometry of the attack of the electrophile (aldehyde, imine, alkene) will help in the design of the sulfide. Models from theoretical investigations have been reported [40–42] which favor a cisoid approach with Coulombic interactions. For the reactions of prochiral ylides with prochiral electrophiles, one major concern will be the diastereoselectivity [38]. However, as this issue largely depends on the substrates, it will be dealt with later in the chapter according to the reaction involved (epoxidation, aziridination, cyclopropanation).

Scheme 5.4

5.2 Epoxidation Reaction


Epoxides are versatile and popular synthetic intermediates [43–47], which are prone to reaction with a variety of nucleophiles as a result of their ring strain. 5.2.1 Stoichiometric Use of Sulfides

By far, the initial investigations focused mainly on epoxidation carried out with a stoichiometric amount of sulfide. As the synthesis of stilbene oxide (Scheme 5.5, R1 ¼ R2 ¼ Ph) has provided a model example, results on the benzylidenation of benzaldehyde have been collected in Table 5.1 (sorted by publication date). This allows a comparison to be made of the enantioenriched sulfide structures, their chiral source and synthesis, the conditions of use, the yields, and diastereo- and enantio-selectivities.

Scheme 5.5

5.2.1.1 Stilbene Oxides A large variety of sulfides have been used. The highest enantioselectivities were observed by Solladie´-Cavallo with oxathiane 13 [51], by Aggarwal with sulfide 21 [63], and very recently with sulfide 22 [65]. Metzner simple C2 symmetric sulfide 16 was very easily prepared (two steps), did not require preformation of the sulfonium salt, and was reasonably efficient [55]. A variety of aromatic aldehydes (Scheme 5.5, R1 ¼ Ph) have been used, which can be found in the various reports indicated in Table 5.1. Less variety is available for the other partner, benzylic halide (R2 ¼ Ph) or aryldiazomethane but, in principle, many could be used. Ketones are sluggish partners; however, the use of a stoichiometric amount of a preformed sulfonium salt derived from sulfide 21 led to excellent enantioselectivities in some cases [63]. Heteroaromatic groups are non-trivial for the formation of epoxides. SolladieĆavallo was the first to show that enantioenriched pyridyl or furyl oxiranes are accessible through sulfonium ylide stoichiometric chemistry [66], but other reports have since followed [58, 63]. One important issue for these reactions is the diastereoselectivity [38]. The benzylidenation of aromatic aldehydes led mainly, or exclusively, to the trans stilbene oxides, whereas aliphatic aldehydes led to mixtures of trans and cis oxiranes. Mechanistic considerations and crossover experiments have been reported by Aggarwal and his group [67], showing that the formation of some betaines can

183

Sulfide

Camphorosulfonic acid chloride

Brucine resolution of thiolane-trans-2,5dicarboxylic acid

Camphoric acid

Pulegone



10

11

12

13

14

15

Source

3 (78)

2 (23)

3 (30)

MeI

PhCHN2

PhCH2OTf

PhCH2Br

PhCH2Br

PhCH2Br

b4 (NA)

6 (NA)

PhCH2Br

Electrophile

2 (51)

Synthesis steps [overall yield %]

one-pot

Rh2[OAC]4 cat

preformation (67%) (95%)

preformationa)

preformationa) (60–75%)

one-pot

Procedure

KOH MeCN

– CH2Cl2

CH2Cl2 (PTC) NaH CH2Cl2

NaOH

NaOH CH2Cl2 (PTC)

NaOH CH2Cl2 (PTC)

KOH MeCN

Base solvent

Conditions

Table 5.1 Asymmetric benzylidenation of benzaldehyde using a stoichiometric quantity of chiral sulfide.

87

70

80

80

46

53

100

Yield [%]

trans only

10 : 1

trans only

4.8 : 1

trans

NA

trans/cis dr or de

74

41

99

72

496

60

47

ee trans [%]

Stilbene oxide

1996

1995

1996

1992

1991

1990

1989

Year

53

52

51

50

49

48

32

Ref .

184


2,4-Hexanediol

Baker’s yeast reduction of a keto ester

Camphor

Tartaric acid

D-Mannitol

Camphor

Propylene oxide

16

17

18

19

20

21

22

Source

4 (31)

5 (56)

3 (76)

5 (NA)

5 (45)

NA (64)

2 (95)

Synthesis steps [overall yield %]

PhCH2OH

PhCH2OH

PhCH2Br

PhCH2Br

PhCH2Br

PhCH2Br

PhCH2Br

Electrophile

preformationa) (81%)

preformationa)

one-pot

one-pot

one-pot

one-pot

one-pot

Procedure

EtP2 CH2Cl2

KOH MeCN:H2O 9:1

NaOH MeCN:H2O 9:1

NaOH t-BuOH:H2O 9:1

K2CO3 MeCN

NaOH MeCN

NaOH t-BuOH:H2O 9:1

Base solvent

Conditions

a) The sulfonium salt was preformed in a separate step. NA ¼ not available; PTC ¼ phase-transfer catalysis.

Sulfide

Table 5.1 (continued)

78

75

59

97

72

79

92

Yield [%]

99 : 1

98 : 2

1 : 0.08

70 : 30

96 : 4

NA

86

trans/cis dr or de

499

98

97

68

56

78

88

ee trans [%]

Stilbene oxide

2006

2003 2006

2002

2002 2003

2001 2004

1999

1998 1999

Year

65

63 64

61 62

59 60

57 58

56

54 55

Ref .

5.2 Epoxidation Reaction 185

186


be reversible, in the case of epoxidation (Scheme 5.6). Density functional theory (DFT) calculations [40] have led Aggarwal and Harvey to consider that the preferred approach in epoxidation is cisoid, with electrostatic attraction of the aldehyde by the sulfonium ylide. A betaine is formed with gauche charged groups. Rotation along the CaC bond will provide the antiperiplanar arrangement required for the formation of the oxirane ring and elimination of the sulfide. A different thermodynamic pattern was calculated for the generation of trans and cis epoxides. The rate-determining step is the initial addition in the case of the anti betaine. With the cis betaine, the rate-determining step is the CaC bond rotation leading to an equilibrium step for the initial addition, and favors the production of the trans oxirane from the anti betaine. A number of factors [38] will affect diastereoselectivity: stability of the carbonyl group (higher trans selectivity of aromatic versus aliphatic aldehydes); reactivity of the ylide (electronic or steric effects); and the reaction media (solvents, additives).

Scheme 5.6

5.2.1.2 Unsaturated Epoxides The versatility of vinyl epoxides [68] has motivated an investigation of their access either from conjugated aldehydes or allyl halides. Their sensitivity towards a variety of reagents requires particularly efficient synthesis. The use of unsaturated aldehydes and stoichiometric chiral sulfonium ylides is both feasible and successful [56, 58, 59, 63, 65, 69]. Cyclopropanation is rarely observed [69]. In contrast, the allylidenation of aldehydes with ylides derived from allyl halides was considered problematic until a first report was obtained with the C2 symmetric sulfide 16 [70], when it was revealed that methallyl halides lead to enantioenriched vinyl oxiranes. Further examples were reported [63, 71, 72], and extended in a catalytic version (see Section 5.2.2). 5.2.1.3 Aliphatic Epoxides Aliphatic aldehydes represent a challenge as they often lead to self-condensation. Branched- or long-chain aldehydes [52, 55, 63, 65] afford enantioselectivities similar to those of aromatic compounds. However, mixtures of trans and cis oxiranes


are produced, in relation to their lower stability versus the aromatic aldehydes, and the reduced equilibration [67] of the syn betaine formation (Scheme 5.6). To date, alkyl halides cannot be used to provide alkyl aryl or dialkyl oxiranes in an asymmetric fashion. 5.2.1.4 Terminal Epoxides The important phenyl or naphthyl oxiranes are accessible by NaH treatment of preformed benzyl or naphthyl sulfonium salts, derived from oxathiane 13, and subsequent addition of paraformaldehyde in satisfactory yields (55–73%) and excellent ee (92–98%) [73]. A second major challenge in this field is the catalytic asymmetric methylidenation reaction of aldehydes, furnishing terminal epoxides. Earlier studies have shown that other types of sulfur ylides can lead to terminal epoxides by methylenation: (dialkylamino)aryloxosulfonium methylide [31, 74] furnishes very modest enantioselectivities (10–35%). The best results are those of Taylor [75] with a sulfimide ylide leading to ee-values of up to 70% with benzaldehyde, and 45% with acetophenone. Aggarwal investigated a Simmons–Smith-type reaction mediated by a variety of sulfonium ylides, and found the best ee-value for styrene oxide to be 47% with 2 equiv. of a bisoxazoline sulfide [76]. With a similar protocol and the use of a mannitol-derived sulfide 20 (Scheme 5.7), Goodman and Bellenie [77] prepared styrene oxides in good to excellent yields and with eevalues from 34 to 76%.

Scheme 5.7

5.2.1.5 Functional Epoxides The synthetic importance of glycidic derivatives [24] has led to an examination of the asymmetric induction in the reaction of aldehydes with sulfonium ylides bearing a carboxylic amide [58, 78, 79] or acid group [80]. The stoichiometric procedure, with preformation of the sulfonium salt, led to better results due to the relative stability of the intermediate ylide [81]. Dai and coworkers [82] were the first to show that a camphor hydroxy sulfide (analogous to 15; Table 5.1) led to excellent yields and ee-values up to 71%. Excellent yields and diastereo- and enantioselectivities were attained later by Aggarwal and colleagues, by replacing the hydroxyl with a methoxy group (Scheme 5.8) [78, 79]. An efficient application to the synthesis of a leukotriene antagonist has also been achieved [79]. The reaction of a benzyl sulfonium of camphor sulfide 21 (see Table 5.1) with glyceraldehyde acetonide [83] and methylidenation of chiral alpha-amino aldehydes [77] with sulfide 20 were achieved: here, the stereocontrol was dependent

187

188


Scheme 5.8

on both the reagent and substrate. An asymmetric access to functionalized pyrrolidines and piperidines was devised by reaction of the previous sulfonium salt of 21 and hemiaminals [84]. From the same sulfide, a vinylsulfonium salt was used for an elegant synthesis of aziridine- and epoxide-fused nitrogen heterocycles through an ylide-mediated reaction with amino aldehydes or ketones [85]. 5.2.2 Catalytic Use of Sulfides

Although some of the above-described sulfides may be prepared in a practical manner and can often be recovered, their cost remains a limiting factor for further developments. Hence, the ability to use these materials in substoichiometric quantities would cause the sulfur epoxidation reaction to become very attractive on an economic basis. During the first era of stoichiometric chiral sulfonium ylides, and since the breakthrough by Furakawa et al. [32] with sulfide 10 (Table 5.1; Scheme 5.5), several attempts have been made to design and achieve a catalytic process using 10– 20% sulfide. Despite the prospect of a one-pot procedure, many drawbacks have emerged, including: (1) Low to moderate enantioselectivities [32, 35, 52, 60, 86– 92]; (2) slow reactions [54, 57, 58, 93] or low yields [57, 58, 93]; and (3) a narrow scope in terms of substrates. Subsequently, two significant contributions appeared in 1996. First, Dai, Huang and their group reported [53] that 0.2 equiv. of camphor-derived sulfides 15 or their analogues (procedure A, Scheme 5.2) can effect the synthesis of trans stilbene oxides in excellent yields and with ee-values up to 60%. Second, Aggarwal and coworkers achieved a 90% level of enantioselectivity with their metal carbenoid ylide generation (procedure B, Scheme 5.3) from a camphor oxathiane (0.2 equiv.) with a compound analogous to 14 and phenyldiazomethane [94]. An extensive optimization study [95] was then conducted which included the screening of a variety of aldehydes, solvents and other factors which might affect stereocontrol. However, the practicality of this procedure was hampered by the hazardous handling of diazocompounds, and as a consequence the same group devised a method of generating the diazo derivative in situ by treating a tosylhydrazone with a base in the presence of a phase-transfer catalyst [96]. Despite this progress, the previous enantiopure oxathiane was not successful for asymmetric catalytic epoxidation. After examining a variety of new sulfides (see also Ref . [97]), the authors demonstrated [96] that bicyclic sulfide 21 (5–20% equiv.), obtained from camphorosulfonic acid chloride in five steps and 56% yield [64],

5.3 Aziridination

Scheme 5.9

was the best for the catalytic epoxidation (Scheme 5.9) for a variety of aldehydes [36]. The scope has been extended by the utilization of various hydrazones, leading to oxiranes with the R2 group being aromatic, heteroaromatic, or unsaturated. The Metzner epoxidation method (2,5-dimethylthiolane 16; Table 5.1) was subsequently converted into a catalytic procedure. Whilst substoichiometric use of the sulfide with the type A procedure (Scheme 5.2) was limited by very long reaction times, it was believed that the alkylation of the sulfide by benzyl bromide was a slow step. However, an acceleration could be achieved by the addition of sodium or tetra-n-butylammonium iodide to generate in situ the more reactive benzyl iodide [98]. Indeed, the reaction could be carried out with good yields of stilbene oxides. As some erosion of the enantioselectivity was observed, the analogous (2R,5R )-diethylthiolane was used, affording ee values 490%. In 2005, the Caen group [99] designed a new generation of thiolanes which was designed to be locked by a diacetal bridge in order to achieve an enhanced reactivity (Scheme 5.10). The sulfide 23 was easy to prepare from cheap d-mannitol in six steps, or in four steps from commercially available 3,4-isopropylidene mannitol. With 10–20% equivalent and NaOH as a base, this procedure allowed a one-pot, user-friendly organocatalyzed process to be completed in one to two days at ambient temperature, leading to excellent enantioselectivities.

Scheme 5.10

5.3 Aziridination

The ring opening of aziridines by nucleophiles is a useful reaction leading to chiral b-functionalized amino compounds which are ubiquitous substructures of

189

190


medicinally relevant agents [43, 100, 101]. Aziridines themselves also display pharmacological activities [102]. The stereoselective elaboration of these valuable three-membered heterocyclic rings has been tackled from alkenes via nitrene transfer [43, 103]. On the other hand, the enantioselective transformation of imines into aziridines was demonstrated via the addition of carbenoid species, a-halogeno carbanions (aza-Darzens reaction) or diazocompounds [24, 103]. Since 1996, the asymmetric addition of enantiopure sulfonium ylide reagents to imines was identified as an alternative and successful approach to aziridines [19], although the methodology has been studied to a much lesser degree than the analogous epoxidation. Several reviews [19, 26, 27, 103] have been prepared detailing the area of asymmetric aziridination, including that of sulfonium ylide chemistry. Very recent publications [24, 43] dedicated to the chemistry of epoxides and aziridines are recommended; the first chapter of Ref . [24] describes the asymmetric aziridination of imines. Here, an overview will be provided of these discoveries, with attention focused in particular on more recent results and mechanistic aspects. 5.3.1 Stoichiometric Aziridination, and Mechanism

In 1997, two reports [19, 104, 105] were made which dealt with the isolation (after simple alkylation of sulfide with alkyl bromides in acetone) and use of camphor-derived sulfonium salts in aziridination (Scheme 5.11). In the presence of a base, the ylides obtained mediated the addition–elimination process on to activated N-tosylimines (no reaction with alkyl or arylimines unless activated by a Lewis acid [27]). Dai and coworkers [27, 105] obtained almost exclusively the cis alkenyl aziridines in good yields. This high cis diastereoselectivity is uncommon for aziridination (vide infra) and unique to propargylic derivatives. The method demonstrated a very wide substrate scope for both aromatic imines and aliphatic imines (R3 ¼ H), along with ketimines (R3 ¼ Me), but the enantioselectivities were highly substrate-dependent. Hou and coworkers [104] documented the formation of racemic aziridinyl carboxamides, providing one asymmetric example with promising selectivities. Solladie´-Cavallo and coworkers [106] extended the use of the sulfonium salt derived from Eliel’s oxathiane by reaction with phosphazene bases (see Sections 5.2.1 and 5.4.1 for epoxidation and cyclopropanation reactions) to aziridination

Scheme 5.11

5.3 Aziridination

(Scheme 5.12). The outstanding enantioselectivities were explained by the Re face approach of the most populated sulfonium ylide conformation leading to (2R ) aziridines. The aziridines were obtained in good yields and moderate diastereoselectivities with aromatic imines (570 : 30 dr), whereas the bulkier tert-butyl and cyclohexyl N-tosylimines led to improved dr (496 : 4 cis:trans).

Scheme 5.12

By analogy with the epoxidation reaction [38], the aziridination of aromatic Nsulfonylimines has been studied both experimentally [29, 107, 108] and theoretically [41] with achiral sulfides (Scheme 5.13). The group on the nitrogen atom (which is absent from aldehydes) adds extra steric and electronic factors which affect the stereoselectivity of each step. This makes the mechanistic discussion slightly more subtle, and a general picture [41, 107, 108] will be provided here, along with relevant references for the provision of more detail. The three fundamental chemical steps (see Section 5.2.1.1 for comparison with aldehydes), and the intermediates thereof, were identified using a DFT method of investigation [41]: (1) the addition reaction; (2) the CaC bond rotation of cisoid betaines afforded transoid betaines; and (3) the ring-closing step (Scheme 5.13). For the anti betaines pathway, whether a semi-stabilized (R ¼ Ph) or stabilized ylide (R ¼ CO2Et) was used, the formation of a cisoid betaine occurred, followed by the CaC bond rotation and cyclization to trans aziridine. The quasi [2 þ 2] approach of the ylide via a cisoid addition transition state (TS-cisoid) is favored both by Coulombic attractive interactions and the ability of the sulfonyl group to form a hydrogen bond with a hydrogen atom in the a-position of the sulfonium moiety. In contrast, the cis epoxide pathway took place via a transoid addition (TStransoid) leading directly to the syn (transoid) betaine. A TS-cisoid, yielding the syn (cisoid) betaine, would have suffered from non-bonding interactions between the R ylidic moiety and the sulfonyl group. The obtained syn (transoid) betaine is subsequently equilibrated with the corresponding syn (cisoid) betaine. According to the highest TS energies [41], and cross-over experiments [108], it has been shown that the CaC bond-formation processes (TS-transoid and TS-cisoid) are the diastereoselectivity-determining steps for semi-stabilized ylides (R ¼ Ph), leading to a slight preference for trans-aziridine formation. Interestingly, the cis aziridines are in general the most stable. For stabilized ylides (R ¼ CO2Me), however, the ring-closing transition states determined the trans/cis ratio, the cis aziri-

191

192


dine being somewhat favored. In the latter case the addition and rotation steps are reversible. The energy differences of the highest energy points are not very large, and may explain the modest trans/cis ratios usually observed in sulfonium ylide aziridination. The high cis diastereoselectivities observed by Dai [105] (Scheme 5.11) with propargylic ylides should be noted, but these may be explained by the highest stability of the syn (cisoid) betaine (R ¼ CCSiMe3; Scheme 5.13).

Scheme 5.13

This general mechanistic pattern for stabilized ylides (R ¼ CONEt2) may also change with respect to the electronic nature of the imines (R1 ¼ p-tolylsulfonyl versus p-tolylsulfinyl), and the sulfide (Me2S versus Ph2S) may influence the reversibility of the addition step [29, 107]. The implication of hypervalent intermediates has been also proposed for sulfoxonium ylides [109]. Although these theoretical studies focused on the cis/trans ratio obtained from achiral ylides, the information should be useful for any discussions on asymmetric model. 5.3.2 Catalytic Aziridination

In 1996, the group of Aggarwal [19] described the first enantioselective addition of chiral sulfonium ylides to aromatic N-SES aziridines [b-(trimethylsilyl)ethanesulfonyl ¼ SES], an easily amenable protective (and activating) group. Based on the previous discovery [23] concerning catalytic epoxidation (see Section 5.1.2 for the catalytic cycle), the ylide reagent was generated from phenyldiazomethane, a transition metal (forming a carbenoid species) and a substoichiometric amount of sulfide 28 (see Section 5.4.2). The scope and limitations of this original process [110] were studied with respect to chiral sulfides and other ylide precursors such as diazoacetamides (see Scheme 5.11 for comparison). For safety reasons, the carbenoid species is today generated in situ from

5.3 Aziridination

Scheme 5.14

tosylhydrazone salts [37], leading thereby to an improved procedure (Scheme 5.14) [111]. In dioxane, this aziridination may be achieved with 20% to 5% of the depicted bicyclic sulfide with fairly good enantioselectivities for trans and cis aziridines, the former being slightly favored. The model accounting the asymmetric induction in epoxidation [96] could be applied to explain the enantioselectivities for cis and trans aziridines (selectivity is determined during the CaC bond formation). The selectivities were dependent on the N- and C-imine substituents. As shown in Table 5.2, the diastereoselectivities were improved by means of N-TcBocprotected imines [CO2(Me2)CCl3 ¼ TcBoc] instead of a N-SES, albeit a slight erosion of the ee-value and yields was observed (entries 1–2). This procedure was also successful for a-branched aliphatic aziridines (entry 3). A much better trans selectivity was achieved with an aziridine derived from trans-cinnamaldehyde (entry 4). Interestingly, this procedure performed the aziridination of a nonenolizable ketimine. This methodology was highlighted by the synthesis of furyl imines allowing an asymmetric elaboration of the taxol side chain [112]. Saito and coworkers [113] optimized a one-pot protocol with a camphor-derived sulfide in dry acetonitrile with potassium carbonate as a base affording the major trans aziridines with fairly good ee (Scheme 5.15). Although a catalytic amount of chiral sulfide could be employed, 1 equiv. was required to achieve effective yields and reaction rates.

Table 5.2 Asymmetric aziridination with respect to Scheme 5.14.

Entry

R1

R2

R3

Yield [%]

dr [trans:cis]

ee [% trans]

1 2 3 4

p-ClC6H5 p-ClC6H5 C6H11 PhCHbCH

H H H H

SES TcBoc SES SES

82 56 50 59

2:1 6:1 2.5 : 1 8:1

98 94 98 94

SES ¼ b-(trimethylsilyl)ethanesulfonyl.

193

194


Scheme 5.15

Scheme 5.16

The same group [113] achieved the chemoselective addition to vinylimines by means of a stoichiometric or catalytic protocol to afford the corresponding vinyl aziridine (Scheme 5.16). The access to vinyl aziridines using the transfer of allyl bromide to phenyl imine (the reverse protocol) led to moderate selectivities [113]. Much better results were obtained by Aggarwal [111] in one case with an alkenyltosylhydrazone salt as ylide precursor (see Scheme 5.14). The obtained enantioenriched vinyl aziridines proved to be useful precursors to access functionalized d-lactams.

5.4 Cyclopropanation

The strained cyclopropane ring is a versatile building block for further transformations into larger cycloalkanes or linear derivatives [114]. Moreover, the widespread occurrence of this three-membered carbocycle within both natural products and bioactive compounds has stimulated many investigations into their stereoselective synthesis [115, 116]. Many of the seminal studies into diazoalkane decomposition by chiral copper complexes [117] and the asymmetric Simmons– Smith reaction were performed during the mid- to late 1960s, since which time the major research efforts have focused on the formation of enantiopure carbenoid species which are competent to effect electron-rich alkene cyclopropanation [116]. Cyclopropanation of the electron-deficient CaC double bond, based on the addition–cyclization sequence of heteroatom ylide-derived reagents [19], has also evolved towards highly enantioselective processes [118–120]. In this context, the addition of enantiopure aminosulfoxonium ylides to enone, acrylate and maleate electrophiles, was pioneered by Johnson and coworkers during the late 1960s. Following this, the development of chiral sulfonium and sulfoxonium ylides for the asymmetric cyclopropanation reaction appeared, with few known examples,


until 1997 [19], after which time the asymmetric methodology underwent a steady improvement. Although more recent results relating to stereoselective cyclopropanation technologies up to 2003 have been discussed and emphasized [116], the following section relates to material published between 1997 and 2006. 5.4.1 Stoichiometric Cyclopropanation

In 1998, Solladie´-Cavallo and coworkers [121] documented a highly enantioselective one-pot cyclopropanation of unsubstituted ethyl acrylate (Scheme 5.17). By means of a stoichiometric quantity of benzylsulfonium salt derived from Eliel’s oxathiane, the ylide reagent was generated in situ at low temperature by using a strong organic phosphazene base, EtNaP(NMe2) 2-NaP(NMe2)3 (‘‘Et-P2’’), to afford – in a short time of 15–30 min – major trans-2-arylcyclopropane carboxylates. The enolizable methyl vinyl ketone was also successfully cyclopropanated (98.5% ee), but acrolein led to the competitive epoxidation (addition onto the carbonyl versus the CaC double bond). It has been hypothesized that the Michael acceptor would approach the less-hindered face of the ylide (Scheme 5.17) with participation of the resident salt.

Scheme 5.17

Recently, Huang and colleagues [122] extended this approach to other alkyl acrylates and the acrylonitrile, taking advantage of a readily available camphorderived sulfonium with t-BuOK as a base (Scheme 5.18). Although Huang’s group obtained good selectivities for the (R,R ) cyclopropanes, interestingly – when switching from t-BuOK to NaH – the opposite (S,S) isomer was obtained with a slight decrease in enantioselectivity. In the two aforementioned examples, it is remarkable that only one sulfonium salt diastereoisomer was formed upon alkylation with benzyl triflate or bromide, as in many cases this requirement is often crucial in order to achieve a highly selective asymmetric process.

Scheme 5.18

195

196


With the aim of synthesizing vinylcyclopropanes, which are common subunits within many biologically active compounds, Tang and coworkers [71, 123] developed the use of allylic sulfonium salt 25 derived from camphor (Scheme 5.19). Under optimized conditions, these authors succeeded in the cyclopropanation of a wide variety of enones, acrylates, acrylonitriles and – of special note – poor Michael acceptors such as acrylamides. With b-aryl- or -hydrogen-substituted electrophiles, excellent ee- and diastereomeric ratio (dr)-values were obtained for the major cyclopropanes 24. By making use of DFT calculations [71], a tenmembered ring transition state 26 was proposed to explain the selectivity, in which a hydrogen bond would reduce the activation energy. This transition state would directly lead to the cyclopropane, given the low energetic barrier for the ring-closure step. This proposal is in sharp contrast with the usually described formation of betaine intermediates after the nucleophilic addition of sulfonium ylides onto carbonyl, imine, and activated alkene compounds [42]. In fact, the alcohol moiety was also required for the transformation, as the methoxy counterpart of 25 did not afford any cyclopropane, but instead led to the [2,3]-sigmatropic rearrangement adduct. The ‘‘endo-sulfonium’’ analogue 27 provided the opposite enantio-induction.

Scheme 5.19

The allylic salts 25b and 27b (R ¼ Ph) displayed a better scope than 25a and 27b (R ¼ SiMe3), given the higher stability of the corresponding ylides. For instance, these ylide precursors (25b and 27b) carried out an efficient cyclopropanation of b-alkyl derivatives with excellent ee-values. Nevertheless, the diastereoselectivities were moderate and sharply dependent on the nature of the sulfonium salt for these more challenging substrates. Alternatively, Pyne and coworkers [124] showed that a diastereoselective 1,4addition–cyclization sequence of lithiated N-tosyl-S-allyl-S-phenylsulfoximines to enones furnished the corresponding vinyl cyclopropanes. The asymmetric addition of the ester-stabilized sulfonium ylide to cyclopentenone was described by Aggarwal and Grange [125] in order to synthesize a cyclo-


propane precursor of (þ)-LY354740, a potent agonist for the mGlu2 receptor (Scheme 5.20). The presence of a bulky ester group and the use of base-free conditions (the ylide was formed in a previous step by treatment with K2CO3/NaOH mixture) were crucial to reach high enantioselectivities. The in-situ formation of the ylide from the sulfonium salt in the presence of a base was seen to improve the diastereoselectivity, but to decrease the enantioselectivity due to epimerization of the betaine intermediates. Based on the results of this study, a mechanistic model was proposed to rationalize the stereoselectivity observed during the cyclopropanation of cyclic enones by ester-stabilized sulfonium ylides [42, 125]. Huang and colleagues [122] have also used ester-stabilized ylides derived from camphor sulfides (see Scheme 5.19 for analogues), although only moderate selectivities were obtained.

Scheme 5.20

The use of sulfonium ylides having a chiral auxiliary link to the ylidic carbon has also been examined [126] for the stereoselective cyclopropanation of various Michael acceptors. 5.4.2 Catalytic Cyclopropanation

The sub-stoichiometric formation of sulfonium ylide reagents (with 20% of sulfide) has been developed by two groups with either benzylic (21, 28–29) or allylic (25b) precursors (Scheme 5.21) [71, 111, 127]. The catalytic cycles are discussed in Section 5.1.2. The use of chiral oxathiane 28 and a benzyl rhodium–carbenoid species, was originally developed by Aggarwal and coworkers [23] for epoxidation and aziridi-

Scheme 5.21

197

198


nation reactions (Scheme 5.21). In 1997, this methodology was applied to enones in order to furnish cyclopropanes with excellent enantioselectivities (ee 497%), but with only moderate yields (38–14%) and diastereoselectivities (4 : 1 trans:cis) [127]. Subsequently, the process was greatly improved [37, 111] by generating in situ the hazardous phenyldiazomethane from a tosylhydrazone salt and a phasetransfer catalyst (Scheme 5.22). This approach required more robust chiral sulfides, and indeed the bicyclic sulfide 29, having a six-membered ring, was shown to be more efficient than 21. The phenyl ketone and chalcone derivatives furnished the major trans cyclopropane with good enantioselectivities. The corresponding methyl ketones or ethyl acrylate did react, but with only moderate yields (512%).

Scheme 5.22

By making use of a-amino acrylates as substrates, a straightforward enantioselective access to constrained three-membered ring amino acids was validated (Scheme 5.23). This methodology was also extended to enantioenriched vinyl cyclopropyl amino acids (75% ee), starting from a,b-unsaturated tosylhydrazone salts and 1 equiv. of sulfide 29. The enantioselectivity could be explained by the same model that accounted for the related epoxidation [96] via an efficient ylide face selection. However, the reasons for the moderate diastereoselectivities observed were not fully understood.

Scheme 5.23

As discussed in Section 5.4.1, the allylic camphor-derived sulfonium salt 25b is a competent ylide precursor for the synthesis of vinyl cyclopropanes. Under modified conditions (Cs2CO3 instead of t-BuOK; see Scheme 5.21), Tang and coworkers [71] conducted a catalytic cyclopropanation of chalcones with 20% of sulfonium salt 25b in favor of the trans cyclopropane (24: 77–88% ee, 67 : 33 to 87 : 13 dr), but with a slight decrease in selectivity. Similar results were obtained by using directly the corresponding sulfides, thus avoiding the preformation of the corresponding sulfonium salt.

5.5 [2,3]-Sigmatropic Rearrangement


The usefulness of the sulfonium ylide-mediated [2,3]-sigmatropic rearrangement relies on the formation of up to two stereogenic centers with a concomitant CaC bond formation [13, 14], which thus furnishes chiral synthetic intermediates. As the asymmetric processes and their mechanistic considerations have been reviewed [19, 128, 129] up until June 2000, at this point the first discoveries of background knowledge of these mechanisms will be summarized, after which attention will be focused on the recent catalytic processes, from 2001 to 2006. In 1973, Trost and colleagues [30] documented the first successful enantiospecific [2,3]-sigmatropic rearrangement of a resolved adamantyl allyl sulfonium salt in the presence of a base (Scheme 5.24). These studies established several important mechanistic statements: First, the relative stability of the sulfonium ylide configuration with regard to the rearrangement rate allowed a high chirality transfer from sulfur to carbon. This made a huge difference for analogous processes occurring with configurationally labile oxonium ylides. Second, the selectivities were nicely accounted for by a folded-envelope transition state; this involved a concerted rearrangement based on the orbital symmetry [14, 129], and which minimized the non-bonded interactions being favored (Scheme 5.24).

Scheme 5.24

Discrimination of the enantiotopic sulfur lone pairs, during ylide formation, is therefore of primary importance to achieve high ee-values. The selective transfer of transient chiral metal-complexed carbene species to prochiral sulfur atom may be achieved from a diazo compound (Scheme 5.25). The process leads to a catalytic rearrangement (with respect to the carbenoid intermediates), which is also referred to as the Doyle–Kirmse reaction [128].

Scheme 5.25

199

200


In 1995, Uemura and coworkers [130] were the first to demonstrate the ability of chiral rhodium 30 or copper 31 complexes to promote a catalytic [2,3]sigmatropic rearrangement of the benchmark transformation of cinnamyl phenyl sulfide by diazoacetate derivatives (Scheme 5.26). Later, Fukuda and Katsuki [131] and MacMillen and colleagues [132] reported on more efficient copper 32 or cobalt 33 pre-catalysts, although only moderate ee- and de-values were obtained. The results of these studies also highlighted that the use of a chiral diazoester [R2 ¼ ()-menthyl by Katsuki], or the bulkier allyl 2,6-dimethylphenyl sulfide (MacMillen), improved both the diastereo- and enantio-selectivities, and hence showed that the ylide structure influences the chirality transfer. Most importantly, the metal-complexed carbene structures had a minor influence on the anti-syn ratio (Scheme 5.25). Thus, the selective formation of a free ylide intermediate and its subsequent reaction are seen to control the enantioselectivity (for discussions of this subject, see Ref . [129]).

Scheme 5.26 (with respect to the reaction in Scheme 5.25)

In 1999, Aggarwal and coworkers [133] extended such processes to commercially available trimethylsilyldiazomethane (TMSD) in the presence of copper or rhodium pre-catalysts (30 as an example) to yield silylated derivatives with low selectivities (Scheme 5.27). The study results revealed a marked influence of the ligand surrounding the rhodium metal versus the anti-syn ratio, and also demonstrated that metal-associated ylides could be involved. The proposed transition state is depicted in Scheme 5.27.

Scheme 5.27


More recently, Hashimoto and coworkers [134] described N-phthaloyl-(S)amino acid-based rhodium complexes as pre-catalysts (Scheme 5.28), and showed that a free ylide mechanistic pathway was in operation. By increasing the steric bulk on the diazoester, the authors not only generated the anti-product selectively but also improved the ee-value.

Scheme 5.28

Wang and colleagues [135] disclosed an interesting extension to allenic sulfides and phenyldiazoacetate by furnishing alkynes with ee-values of up to 55% (Scheme 5.29). Among the various complexes tested (30, 36, etc.), the Cu (MeCN) 4PF6/ bis(oxazoline) 32 (10 mol.%) and rhodium derivatives 34 gave the best ee-values, the latter complexes being used at a lower loading in n-hexane as solvent. The ortho-chlorophenyl allenic sulfide was also shown to yield a lower ee.

Scheme 5.29

The same group conducted the reaction of methyl aryldiazoacetates (as depicted in Scheme 5.29) with either allylic sulfides [136] or propargyl sulfides [137], and obtained ee-values of up to 78–80% by means of the Cu (MeCN) 4PF6/ bioxazoline complex 32. The most impressive results were obtained when the authors [138] tackled the [2,3]-sigmatropic rearrangements of aryl allylic sulfides with a double asymmetric induction approach, both from the pre-catalyst and from the diazo compound bearing an Oppolzer’s camphor sultam auxiliary (Scheme 5.30). The resulting amide was subsequently reduced to afford b-hydroxy sulfides with good overall yields. The reaction proceeded smoothly in the presence of ligand 36, while a non-chiral Salen ligand 37 furnished the same level of induc-

201

202


tion in many cases. A matched and mismatched outcome was observed with ligands (R,R )-35 and (S,S)-36 (Scheme 5.30), but the sense of induction was still controlled by the chiral auxiliary. Ultimately, this process was found to be quite general for aryl-, methyl- and vinyl-substituted diazoacetamides, with the exception of para-nitrosubstituted phenyl derivatives.

Scheme 5.30

By making use of these newly developed conditions, propargyl phenyl sulfides could be transformed into functionalized allenic derivatives with excellent eevalues (Scheme 5.31). Interestingly, the rearrangement products bearing the chiral auxiliary were crystalline and could be enantioenriched by a simple recrystallization. A mechanistic insight into such processes revealed that the intermediate sulfonium ylide was strongly complexed with the Cu (I) catalyst, excluding a free ylide pathway; this was in opposition to the observations usually made with diazoesters. The double asymmetric induction approach has also been studied with enantiopure catalysts [139] and an allylic substrate bearing a chiral acetonide moiety. The influence of the catalyst nature upon selectivities was, however, moderate.

Scheme 5.31

5.6 Other Reactions

5.6 Other Reactions

For the past 10 years, the non-racemic chiral sulfonium ylides have mainly evolved towards the construction of three-membered ring frameworks (epoxides, aziridines, and cyclopropanes), and catalytic asymmetric [2,3]-sigmatropic rearrangement developments. During the same time period, only a few novel processes have been reported in the literature. Recently, the group of Aggarwal [140] suggested the addition of an enantiopure ylide to BR3 in order to generate the tetrasubstituted borane as an ate complex intermediate (Scheme 5.32). A stereoselective 1,2-migration then achieved expulsion of the sulfonium moiety to produce chiral boranes in situ. Depending on the treatment used, the secondary alcohols or amines were smoothly obtained in good yields and with excellent enantioselectivities (retention of configuration). Despite the oxidative conditions, the sulfide was recovered to a high degree (490%). In the case of triphenylborane, which furnished the mixed organoborane with two phenyl groups on the boron atom (R ¼ Ph), the corresponding amine was formed in low yields. A competitive migration between the phenyl and benzyl groups was assumed upon treatment with NH2OSO3H. However, by performing borane redistribution (BPh2 to BEt2) before the addition of NH2OSO3H, by means of an excess of triethylborane, the yields were greatly improved. The high enantioselectivities would be due to the approach of the incoming electrophile from the less-hindered face of the most stable ylide conformation (Scheme 5.32). This novel methodology was exemplified [140] by a straightforward synthesis of anti-inflammatory agents such as neobenodine and cetirizine.

Scheme 5.32

Gais and coworkers [141] performed an evaluation of the in-situ-formed sulfonimidoyl-substituted allyltitanium (IV) complexes with aldehydes (Scheme 5.33), which furnished the corresponding addition products with high diastereoand regio-selectivities at the a-position. An intensive NMR and ab initio-based studies emphasized the formation of both novel N-titanium allyl aminosulfoxonium ylides and a-titanated sulfoximines species, the equilibrium composition of which was dependent on the size (R1) and geometry of the CaC double bond

203

204


(E versus Z). Indeed, a rapid intramolecular 1,3-C,N shift of the titanium moiety took place in comparison with the slow addition reaction onto the aldehyde. Consequently, the authors proposed a model based on the Curtin–Hammett principle in order to explain the selectivities.

Scheme 5.33

5.7 Conclusions

Vast progress has been made over the past 10 years, from a period when almost no enantioselective version was available for the three-membered ring formation mediated by a chiral sulfonium ylide. Despite the apparent simplicity of these reactions, a variety of parameters had to be mastered simultaneously, and theoretical investigations led to further insight into the mechanisms involved. In addition, new efficient sulfides have been designed and utilized in stoichiometric or catalytic versions, providing enantiomeric excesses in excess of 90%. The major challenges for the future include organocatalyst loading, an extension of the scope of substrates, and development of applications, and for this purpose new asymmetric sulfonium ylide-promoted processes will continue to emerge.

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6 Synthesis and Use of Chiral Sulfoximines Christin Worch, Agathe Christine Mayer, and Carsten Bolm

Abstract

Since their discovery during the 1940s, sulfoximines have played a variety of roles in organic chemistry. First, they attracted attention due to their unusual structure and unexpected bioactivity, which resulted from their specific enzyme inhibitory properties. Later, when sulfoximines became more readily accessible, enantiopure derivatives were applied as chiral auxiliaries in asymmetric synthesis. Today, as the search for new applications of sulfoximines continues, recent advances have demonstrated their applicability as chiral ligands in asymmetric metal catalysis and value as highly active agents in medicinal chemistry and crop protection.

6.1 Introduction

Sulfoximines 1 are the mono-nitrogen analogues of sulfones 2 [1, 2], and as such belong to a group of compounds characterized by the presence of a highly oxidized sulfur atom being surrounded by four substituents. At least two of those are heteroatoms (oxygens or nitrogens). If R and R 0 as well as the heteroatoms are different from each other, then chiral compounds result. Many of those compounds having a tetrahedral arrangement at the central stereogenic sulfur can be obtained in enantiopure form. Other members of this group of compounds are sulfondiimides 3 [3] and sulfonimidamides 4 [4].


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6 Synthesis and Use of Chiral Sulfoximines

The relatively short history of sulfoximines begins in 1946 with the findings of Bentley and Whitehead, who studied the unusual behavior of dogs fed with NCl3bleached wheat [5]. The synthesis of methionine sulfoximine (5, MSO), as the responsible toxic factor, was reported soon after its identification. Subsequent studies showed this compound to be an effective inhibitor of the enzyme glutamine synthetase [6]. Current interest in this area is represented by the large number of reports related to buthionine sulfoximine (6, BSO), a specific inhibitor of g-glutamylcysteine synthetase and a close structural analogue of MSO [7].

Recently, other interesting biological activities of sulfoximines have been described. For example, Posner prepared a vitamin D3 analogue 7 and found it to be an extremely potent inhibitor of hydroxylase, with a high selectivity for cytochrome CYP24 (with an IC50 in the nanomolar range) [8]. Interest in the use of sulfoximines for medicinal chemistry is further represented by the increasing number of patents in this area. Thus, chemists at Bayer Schering Pharma described sulfoximines such as 8, which are selective cyclin-dependent kinase (CDK) inhibitors for potential application in the treatment of cancer [9]. Cadila Healthcare Ltd. used sulfoximines 9 as inhibitors of p38 MAP kinase for the treatment of diseases caused by pro-inflammatory cytokines/mediator (s) [10].

Recent applications of sulfoximines in crop protection were reported by Dow Agroscience [11] and Syngenta [12]. For example, compounds of type 10 and 11 revealed insecticidal activity, whereas 12 proved to have herbicidal properties.

6.2 Synthesis and Structural Modification

6.2 Synthesis and Structural Modification

Various synthetic routes towards sulfoximines are known, most of which rely on a reaction sequence starting from the corresponding sulfide [1]. The general process is illustrated in Scheme 6.1 for the preparation of methyl phenyl sulfoximine (15), which is the key intermediate for the synthesis of several other structurally more elaborate sulfoximine derivatives.

Scheme 6.1

In Scheme 6.1, sulfide 13 is oxidized to the corresponding sulfoxide 14, which is subsequently iminated to give sulfoximine 15 [13]. Both 14 and 15 are chiral, and thus stereochemical issues become relevant. For sulfoximine 15 an efficient resolution with camphor sulfonic acid is known, which affords both enantiomers in high yields. Most sulfoximines, however, cannot be resolved in this manner, and thus alternative processes for their preparations have been developed. Several methods utilize enantiopure sulfoxides, which are accessible by various routes [14]. As the commonly used sulfoxide imination with sodium azide under

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acidic conditions is known to lead to racemization, it became necessary to introduce other methods. A standard protocol involved O-mesitylenesulfonylhydroxylamine (MSH) [15]. Alternatively, metal-catalyzed imination reactions have been developed [16]. The advantage of these is that they can often be performed at ambient temperature using safe iminating agents such as combinations of PhI(OAc)2 and sulfonamides. The resulting N-protected sulfoximines 17 can then be converted into the synthetically valuable NH-derivatives 18 following standard transformations (Scheme 6.2). As these metal-catalyzed iminations proceed with a retention of configuration, enantiopure sulfoximimines can be prepared from the corresponding optically active sulfoxides.

Scheme 6.2

Recently, an alternative approach towards NH-sulfoximines has been described. Sulfides 19 are first iminated with a combination of N-bromosuccinimide (NBS) (or iodine) and cyanogen amine to give sulfilimines 20. Subsequent oxidation with meta-chloroperoxybenzoic acid (m-CPBA) gives N-cyano sulfoximines 21, which can then be converted into their corresponding NH-derivatives 18 upon reaction with acid [17]. Of particular note in this reaction sequence is that neither metals nor (other) toxic reagents are required for the preparation of the desired products. N-Cyano sulfoximines 21 also proved to be synthetically useful for the preparation of tetrazole derivatives 22 (Scheme 6.3) [18].

Scheme 6.3

Other N-substituted sulfoximines can be prepared, for example, by acylation reactions [19]. Two examples are shown in Scheme 6.4 affording, in the first case, C2-symmetric bis-sulfoximines 23 (and, after subsequent reduction, ethylene-

6.3 Applications in Asymmetric Synthesis

bridged 24) to be used as ligands in asymmetric metal catalysis [20]. The second acylation example illustrates the use of (S)-15 in the synthesis of amino acidsubstituted derivatives 25 [21] for the incorporation into sulfoximine-based pseudopeptides [22].

Scheme 6.4

Metal-catalyzed (Buchwald/Hartwig-type) N-arylation reactions lead to derivatives such as 27 and 29. In these coupling reactions, palladium, copper, and iron complexes proved highly useful (Scheme 6.5) [23].

Scheme 6.5


Since the pioneering studies of Johnson during the 1970s, sulfoximines have been widely applied for the preparation of optically active products [1]. In general, two approaches can be distinguished:

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1. The sulfoximidoyl unit is part of a reacting molecule, and its stereochemical information directs the selective generation of further stereogenic centers. Once the sulfur-containing fragment has fulfilled this purpose, it is eliminated leading to the desired stereochemically homogeneous product (or a suitable precursor thereof ). This strategy requires the use of stoichiometric amounts of sulfoximines (and hence is different from the second approach). 2. The sulfoximine serves as a metal-coordinating ligand, and the goal is to use as little as possible of the resulting coordination compound for catalyzing a given bond-forming transformation. Both approaches will be illustrated by a few selected examples from the literature in the following subsections. 6.3.1 Use of Sulfoximines as Chiral Auxiliaries

Some decades after the first reports of the discovery of MSO by Mellanby, Bentley, Whitehead and others, Johnson initiated a program which focused on the application of sulfoximines as chiral auxiliaries in asymmetric synthesis [1]. Epoxides, aziridines and cyclopropanes 33 were prepared by reacting sulfonimidoylstabilized carbanions 31 with aldehydes, ketones, imines and enones (Scheme 6.6) [24].

Scheme 6.6

Several examples of such stereoselective alkylidene transfer reactions are shown in Scheme 6.7. Optical purities in the range of 20 to 49% could be obtained. Thus, benzaldehyde (34) was converted to (R )-2-phenyloxirane [(R )-35] with an optical purity of 20% using (R )-31a as nucleophile. In the reaction of benzalacetophenone (36) with (R )-31a in dimethylsulfoxide (DMSO), (1S,2S)-1benzoyl-2-phenylcyclopropane [(1S,2S)-37] was obtained with 35% optical purity. Interestingly, when carbanion (R )-31b was used in tetrahydrofuran (THF), cyclopropane (1R,2R )-39 was isolated (with 49% optical purity).


Scheme 6.7

Lithiated N-methyl sulfoximine 41 can also be used as nucleophile, in particular in additions to carbonyl compounds [25]. In the first step, 41 is generated by treatment of 40 with butyllithium (Scheme 6.8). Subsequent addition of 41 to benzaldehyde (34) affords b-hydroxysulfoximine 42. After separation of the two diastereomers and reductive cleavage of the carbon–sulfur bond, optically pure (þ)-(R )-phenylethanol [(R )-43] is obtained [1, 26]. A few years later this methodology was extended to ketones [27]. In this case, the diastereomers of the b-hydroxysulfoximine could be separated using column chromatography and desulfurized using Raney nickel to give either enantiomer of the tertiary alcohol. This strategy has also been used for resolutions of chiral ketones. Accordingly, b-hydroxysulfoximines 45 were prepared from either (R )- or (S)-40 and various

Scheme 6.8

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ketones 44. After chromatographic separation of the resulting diastereomers of 45 and subsequent thermolysis (sometimes under vacuum), enantiomerically and diastereomerically pure (or enriched) ketones were obtained. At the same time, the chiral auxiliary 40 was regenerated (Scheme 6.9) [28].

Scheme 6.9

Several groups have successfully applied this strategy to the synthesis of natural products [29]. For example, Magnus reported the resolution of ketone 46 in the synthesis of key intermediate 51, which in turn can be further transformed into guanacastepene (52) (Scheme 6.10) [30]. Another application involves the resolution of spiro compounds [31]. Many applications of sulfoximines rely on the stereoselectivity of appropriately chosen metallated intermediates [1]. In this context, Reggelin described the generation of titanated 2-alkenylsulfoximines and their use in highly stereoselective allyl transfer processes [32]. The required allyl sulfoximines 54 and epi-54 were obtained from readily prepared cyclic sulfonimidates 53 and epi-53, respectively [33]. For the synthesis of isomerically pure substituted oxacycles [34], 54 (or epi-54) was metallated by treatment with n-BuLi followed by transmetallation with ClTi (Oi-Pr)3. The resulting titanated 2-alkenylsulfoximine was then reacted with enantiopure aldehyde 55 (or ent-55) to give tetrahydrofuran derivatives 56a–d after fluoride ion-induced cyclizations of the intermediately formed isomerically pure 5-siloxy-substituted vinylsulfoximine (Scheme 6.11). It was shown that the relative configuration of the stereogenic centers at C-3 and C-4 in the THF ring was a result of the interaction between the allylic nucleophile and the aldehyde during the g-hydroxyalkylation step. The asymmetric induction in the aldehyde addition step reached a maximum (resulting from an intramolecular matched situation), when both stereogenic centers in the allyl sulfoximine were homochiral (as in epi-54). In that case, the stereochemical information of the aldehyde remained irrelevant, and the relative configurations at C-3 and C-4 of the product were predominantly controlled by the stereogenic center at the sulfur atom. The stereochemistry of the ‘‘valine substituent’’ played only a minor role. The configuration at the C-2 position stemmed from the aldehyde,


Scheme 6.10

and solely the stereogenic center at C-5 was under substrate control. Thus, by fine-tuning and adjusting the sulfoximine/substrate combination, a highly regioand stereoselective synthesis of substituted tetrahydrofurans was achieved. This strategy was extended to the preparation of azapolycycles [35]. Starting from metallated valine-derived 2-alkenylsulfoximines 57 [32, 34b], the ghydroxyalkylation of N-protected a- or b-amino aldehydes 58 proceeded under almost complete stereocontrol. In the next step, an intramolecular Michael-type cyclization of 59 resulted in the formation of mono- to tetracyclic products 60 as single stereoisomers (Scheme 6.12) [35]. Four types of amino aldehydes 58 (acyclic, carbo-, hetero-, or heterobicyclic) in combination with two types of 2alkenylsulfoximines 57 (acyclic or cyclic) led to eight different products 60. Finally, the chiral auxiliary was removed by treatment with samarium iodide to yield highly functionalized azaheterocycles. Unfortunately, the latter reaction destroyed the auxiliary, which can be regarded as significant drawback of this method.

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Scheme 6.11

Scheme 6.12


Starting from 2-alkenylsulfoximines bearing an additional heterocycle, other functionalized azabicycles became accessible [36]. The required sulfoximines 62a–c were prepared from monoprotected piperidinones, cycloalkanones and pyrrolidinones, respectively, by an addition–elimination–isomerization (AEI) reaction sequence. The subsequent g-hydroxyalkylation/Michael addition route afforded enantiomerically pure azabicycles 64a–c in good yields (Scheme 6.13).

Scheme 6.13

In 1995, Gais reported the use of titanated N-methylated 2-alkenylsulfoximines [37]. These compounds can be obtained in good yields by an AEI route starting from (S)-N,S-dimethyl-S-phenylsulfoximine [(S)-40] and aldehydes [38]. During the following years, a number of excellent reports were published which further stressed the versatility and importance of these sulfoximine derivatives as chiral auxiliaries in asymmetric synthesis [39]. An approach towards chiral b- and d-sulfonimidoyl-substituted homoallylic alcohols 68 and 69, starting from enantiopure allylic sulfoximines (E )-67, was described in 2000 [38c]. Interestingly, the titanating agent had an unexpected effect on the substitution pattern of the product alcohol. If the lithiated allylic N-methyl sulfoximines were titanated with ClTi (Oi-Pr) 3, the resultant bis(2-alkenyl)diisopropyltitanium (IV) complexes reacted with aldehydes in the presence of ClTi (Oi-Pr)3 to give d-sulfonimidoyl-substituted anti-configured homoallylic alcohols (Z)-68. Both

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yields and selectivities were good, and the best result was achieved with 2.1 equiv. of ClTi (Oi-Pr)3 at ambient temperatures. (Z)-Substituted alkenyl sulfoximines (Z)-67 reacted more slowly and with less stereoselectivity. In contrast, titanation of (E )-67 with ClTi (NEt2) 3 furnished mono (2-alkenyl) tris(diethylamino)titanium (IV) complexes that, upon reaction with aldehydes, gave rise to bsulfonimidoyl-substituted syn-configured homoallylic alcohols (E )-69 (Scheme 6.14). Both yields and selectivities were high compared to those described above. In this case, (Z)-configured alkenyl sulfoximines (Z)-67 reacted in almost identical yields and stereoselectivities to the corresponding (E )-69. Hence, access to either isomer of the desired alcohol is possible and can be controlled by appropriate choice of the titanating agent.

Scheme 6.14

Both, sulfonimidoyl-substituted chiral homoallylic alcohols 68 and 69 found applications in further studies. Whereas the former were used for the synthesis of cycloalkenyl and alkenyl oxiranes [40], the latter were transformed into homopropargylic alcohols [41] and 2,3-dihydrofurans [42]. The treatment of homoallylic alcohols (Z)-68 with n-BuLi or MeLi did not result in the expected homopropargylic alcohols but instead gave quantitative a-lithiation. Hence, the sulfonimidoyl group was methylated with Me3OBF4 to generate a better leaving group, thereby circumventing the drawbacks of the former approach. Subsequent reaction of the resulting aminosulfoxonium ylide with LiN(H) t-Bu at 78 8C led to the loss of sulfinamide PhSONMe2 and formation of an alkylidene carbene species. The latter underwent a 1,2 H-shift to generate the desired homopropargylic alcohol 70 (Scheme 6.15). Substituents at the double bond adjacent to the sulfonimidoyl group changed the reactivity pattern. Whereas substituents in the a-position to sulfur resulted


Scheme 6.15

in the formation of non-terminal homopropargylic alcohols 72, b-substituted 2alkenyl sulfoximines 73 [42] gave rise to 2,3-dihydrofurans 74. The formation of the latter products can be rationalized as follows: As before, the reaction starts with the elimination of sulfinamide PhSONMe2. The resulting d-silyloxy alkylidene carbene then undergoes a 1,5-O,Si bond insertion. Furthermore, cyclic aminosulfoxonium salts reacted with 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or LiN(H) t-Bu to give a highly regioselective migratory cyclization, furnishing enantio- and diastereomerically pure bicyclic tetrahydrofuran derivatives in good yields (Scheme 6.16) [42].

Scheme 6.16

Very recently, a modular asymmetric approach towards functionalized azaspirocycles has been reported [43]. Alkenyl sulfoximines (E )-67 could also be reacted with N-protected imino esters 75 to afford functionalized vinyl sulfoximines in high yields and selectivities [44]. Cleavage of the sulfonamide protecting group led to amino acid esters 77 (Scheme 6.17). Furthermore, it was possible to cleave the chiral auxiliary and perform a nickel-catalyzed cross-coupling [45].

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Scheme 6.17

Furthermore, a fluorine-induced cyclization of vinylsulfoximine 76a (R 0 ¼ t-Bu) to give 3,4-dehydroprolines 78 is known (Scheme 6.18) [46].

Scheme 6.18

The striking advantage of Gais’ protocol over that of Reggelin is the recyclability of the auxiliary. The sulfoximine can be regenerated by reaction of the sulfinamide with MeMgCl followed by imination according to known procedures [19, 42, 47]. Harmata followed a different approach involving palladium-catalyzed crosscouplings followed by diastereoselective functionalizations and removal of the chiral auxiliary. The starting point was the synthesis of a cyclic sulfoximine using an N-arylation under Buchwald–Hartwig conditions [23a–e], followed by an intramolecular, stereoselective Michael addition [48] or Sonogashira coupling and subsequent intramolecular cyclization [49]. This reaction sequence was applied to the total synthesis of the naturally occurring antitubercular agent pseudopteroxazole (86) [50, 51]. Ester 79 was coupled with sulfoximine 15 to afford 80 in 81% yield [50]. In contrast to the behavior of a similar ester lacking the methyl group at the double bond, no benzothiazine formation was observed in this case [48]. Apparently, the methyl group in 79 prevented the formation of


the benzothiazine, and the sulfoximine was the only isolated product. After treatment of 80 with lithium diisopropylamide (LDA), the desired benzothiazine 81 was isolated as a 10 : 1 mixture of diastereomers. A combination of reduction, oxidation and epimerization was necessary to invert the stereogenic center at the methyl-bearing carbon atom adjacent to the ester function. Thus, the aldehydes 82a and 82b were obtained in a 1.6 : 1 mixture (Scheme 6.19). By using a diastereomeric mixture of both aldehydes, a Wittig reaction was carried out, followed by separation of diastereomers and cyclization to give 83a (3.6 : 1 mixture of diastereomers) and 83b (single diastereomer).

Scheme 6.19

Nine more reaction steps were required to complete the synthesis of pseudopteroxazole (86) [51]. First, deprotonation of 83b with LiHMDS followed by treatment with allyl bromide afforded 84 (as single diastereomer). Reductive desulfurization led to aniline 85. Activation of the aniline nitrogen and a subsequent intramolecular Heck reaction gave a tricyclic compound, which was further functionalized (involving a stereoselective reduction of the conjugated

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Scheme 6.20

double bond and the introduction of the oxazole ring) to finally afford pseudopteroxazole (86) (Scheme 6.20). Recently, a sulfoximine-based approach towards optically active quinolones has been described [52]. 6.3.2 Use of Sulfoximines as Chiral Ligands

Despite all recent advances in the synthesis of sulfoximines, their preparations still require several steps, making it desirable to use as little as possible of this valuable synthetic intermediate. Furthermore, a general challenge in organic chemistry is the switch from auxiliary-based asymmetric synthesis towards applications of chiral catalysts. Along these lines a research program focused on the search of sulfoximine derivatives applicable as chiral ligands in asymmetric metal catalysis was initiated during the early 1990s. A few selected results from these investigations are highlighted here. In the very first report on this topic, the use of b-hydroxysulfoximines in nickel-catalyzed conjugate additions to chalcones was described [53]. Such sulfoximine derivatives are readily available following protocols developed by Johnson [27], and most often these utilize methyl phenyl sulfoximine (15) as the initial building block. In the study of nickel catalysis [53], b-hydroxysulfoximine 89 gave


Scheme 6.21

the best results, affording the diethylzinc addition product 88 from chalcone (87) with 70% enantiomeric excess (ee) and 71% yield (Scheme 6.21). Subsequently it was shown that b-hydroxysulfoximines were also applicable in asymmetric 1,2-additions of dialkylzinc reagents onto aldehydes [54], enantioselective borane reductions of ketones and imine derivatives [55], and asymmetric cyanohydrine formations starting from aldehydes and trimethylsilyl cyanide (TMSCN) [56]. Recently, the use of such reagents has expanded even further, and it was also demonstrated that aryl transfer reactions onto aromatic aldehydes 91 affording synthetically valuable diarylmethanols [57] could be directed by bhydroxysulfoximines [58]. In that case, sulfoximine 90 proved to be most selective, leading to products 92 with up 93% ee (Scheme 6.22).

Scheme 6.22

Most likely, all of the reactions described so far have involved the formation of catalytically active zinc alkoxides being formed upon reaction of the bhydroxysulfoximines with organozinc reagents. Thus, in these CaC bond formations the zinc reagents played a ‘‘double role’’. On the one hand they were involved in the catalyst formation, and on the other hand they served as alkyl or aryl carrier. In contrast, sulfoximines can also be applied as purely coordinating ligands, rendering a given metal complex chiral. Interesting examples of this type are N,N-ligands 93 [59], which are part of a ligand series involving also sulfoximines such as 29 [23d, 60] and 94 [61], respectively.

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The preparation of 93 started from nitroarene 95 and involved three steps: (1) a metal (commonly palladium) -catalyzed cross-coupling to introduce the sulfoximidoyl moiety; (2) a nitro group reduction; and (3) a reductive alkylation of the resultant aniline derivative [59]. As a consequence of this rather modular synthesis, a significant number of derivatives varying in the substitution pattern at the sulfoximine, the aryl backbone and the N-benzyl group became readily accessible (Scheme 6.23).

Scheme 6.23

A reaction screening as well as mechanistic investigations [62] revealed that sulfoximines such as 29, 93, and 94 interacted with copper salts to form chiral complexes that were capable of catalyzing enantioselective CaC bond formations. Thus, C2-symmetric bis-sulfoximine 29 and related monosulfoximine 94 were

Scheme 6.24


applied in hetero-Diels–Alder as well as Diels–Alder reactions affording products with up to 98% ee [23d, 60, 61]. C1-symmetric 93 also proved useful in asymmetric catalysis. A combination of such N,N-ligands with copper salts led to efficient catalysts for Mukaiyama-type aldol reactions. For example, silyl enol ethers 96 reacted with pyruvate esters 97 in the presence of copper (II) triflate and 93a (10 mol% each) to afford addition product 98 with up to 99% ee in high yield (Scheme 6.24) [59]. The same ligand is capable of directing vinylogous Mukaiyama aldol reactions [63]. There, combinations of copper (II) triflate and 93a allowed the synthesis of unsaturated diesters 101 in up to 99% ee starting from pyruvates 99 and vinyl silyl ketene ketals 100 (Scheme 6.25).

Scheme 6.25

As an extension of this study, copper-catalyzed carbonyl-ene reactions were investigated, and N,N-ligands of type 99 again proved useful [64]. Surprisingly, however, the substitution pattern of the ligand had a remarkably strong effect, and finally, sulfoximine 99b proved to be the ligand of choice. Applying this in combination with copper (II) perchlorate afforded a-hydroxyesters 104 up to 91% ee (Scheme 6.26).

Scheme 6.26

All of the examples presented so far have involved metal-catalyzed asymmetric CaC bond formations. Whereas, N,O-chelating sulfoximines and their use in carbonyl addition reactions with organozinc reagents were discussed initially, the latter paragraphs have focused on N,N-type sulfoximines and their application in transformations such as Diels–Alder and Mukaiyama aldol reactions. Another interesting coordination mode involves the binding of phosphoryl substituents. In that context, P,N-type sulfoximines 106 have shown promise, although all initial attempts to apply palladium-catalyzed cross-coupling reactions for the introduction of the heteroatom fragments onto the arene have remained

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unsuccessful. Finally, copper-mediated N-arylations [23f ] proved to be successful, allowing the first access to P,N-type sulfoximines 106 in moderate to good yields (Scheme 6.27) [65, 66].

Scheme 6.27

Again, a reaction screening was performed, and the most interesting results were achieved in enantioselective imine hydrogenations using an iridium complex chirally modified with P,N-sulfoximine 106a (Scheme 6.28) [66]. For a number of substrates bearing an easily removable p-methoxy phenyl moiety (PMP) as protective group on the nitrogen, excellent enantioselectivities (up to 98% ee) were achieved.

Scheme 6.28

Besides the fundamental scientific merit of this development, other points are worthy to mention here. For example, the amine synthesis achieved by the Ir/106a-catalyzed hydrogenation of imines 107 is the first asymmetric transition metal-catalyzed reduction with a sulfoximine ligand. Previously, only carbonyl and imine reductions with borane catalyzed by b-hydroxysulfoximines had been known [55]. Furthermore, the hydrogenation reactions are highly chemoselective, leading to a significant reactivity difference between CbN-, CbO-, and CbCdouble bonds. Although such selectivity is desirable, it is often very difficult to achieve.

References

6.4 Conclusions

About 50 years ago sulfoximines were regarded as novel and rather unusual compounds, today they belong to the ‘‘standard toolbox’’ of modern organic chemistry. They have proved to be useful in auxiliary-based asymmetric synthesis, and increasingly can be applied as effective ligands in enantioselective metal catalysis. Whilst the initial protocols for their synthesis involved toxic and potentially dangerous reagents, recent advances have significantly improved their accessibility. Today, metal-catalyzed oxidations, iminations – and even functional group modifications – allow the straightforward synthesis of elaborate derivatives which surely will find further applications in a wide variety of research areas. Although the first successful steps in asymmetric catalysis and bio-oriented applications exemplify this progress well, the situation appears somewhat unpredictable, due mainly to the current limits in the mechanistic understanding of this subject. However, with the identification of new active and selective systems, as well as a general broadening of sulfoximine expertise, this barrier will surely be overcome with time. Hopefully, it will soon be possible to design, in rational mode, 100% ee sulfoximine-based catalysts, effective sulfoximine-based anticancer drugs, and highly selective sulfoximine-based herbicides.

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29 (a) N. Kawai, Y. Fujibayashi, S. Kuwabara, K.-i. Takao, Y. Ijuin, S. Kobayashi, Tetrahedron 2000, 56, 6467; (b) L. A. Paquette, D. Koh, X. Wang, J. C. Prodger, Tetrahedron Lett. 1995, 36, 673; (c) J. Wagner, E. Vieira, P. Vogel, Helv. Chim. Acta 1988, 71, 624; (d) L. A. Paquette, L.-Q. Sun, D. Friedrich, P. B. Savage, J. Am. Chem. Soc. 1997, 119, 8438; (e) For further examples, see Ref . [1c]. 30 P. Magnus, M. J. Waring, C. Ollivier, V. Lynch, Tetrahedron Lett. 2001, 42, 4947. 31 L. A. Paquette, D. R. Owen, R. T. Bibart, C. K. Seekamp, A. L. Kahane, J. C. Lanter, M. A. Corral, J. Org. Chem. 2001, 66, 2828; L. A. Paquette, F. Fabris, F. Gallou, S. Dong, J. Org. Chem. 2003, 68, 8625. 32 M. Reggelin, H. Weinberger, Angew. Chem. 1994, 106, 489; M. Reggelin, H. Weinberger, Angew. Chem. Int. Ed. Engl. 1994, 33, 444. 33 For a large-scale synthesis (several 100 g) of 53 and epi-53, see: M. Reggelin, B. Junter, Chem. – Eur. J. 2001, 7, 1232. 34 (a) M. Reggelin, H. Weinberger, T. Heinrich, Liebigs Ann./Recueil 1997, 1881; (b) M. Reggelin, H. Weinberger, M. Gerlach, R. Welcker, J. Am. Chem. Soc. 1996, 118, 4765. 35 M. Reggelin, B. Junker, T. Heinrich, A. Slavik, P. Bu¨hle, J. Am. Chem. Soc. 2006, 128, 4023. 36 M. Reggelin, J. Ku¨hl, J. P. Kaiser, P. Bu¨hle, Synthesis 2006, 2224. 37 H.-J. Gais, H. Mu¨ller, J. Decker, R. Hainz, Tetrahedron Lett. 1995, 36, 7433. 38 (a) M. Scommoda, H.-J. Gais, S. Bosshammer, G. Raabe, J. Org. Chem. 1996, 61, 4379; (b) J. Bund, H.-J. Gais, E. Schmitz, I. Erdelmeier, G. Raabe, Eur. J. Org. Chem. 1998, 1319; (c) H.-J. Gais, R. Hainz, H. Mu¨ller, P. R. Bruns, N. Giesen, G. Raabe, J. Runsink, S. Nienstedt, J. Decker, M. Schleusner, J. Hachtel, R. Loo, C.-W. Woo, P. Das, Eur. J. Org. Chem. 2000, 3973. 39 For an overview, see: H.-J. Gais, in: D. Enders, K.-E. Jaeger (Ed.), Asymmetric Synthesis with Chemical and Biological Methods, Wiley-VCH, Weinheim, 2007, p. 75, and references cited therein.

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6 Synthesis and Use of Chiral Sulfoximines 40 H.-J. Gais, G. S. Babu, M. Gu¨nter, P. Das, Eur. J. Org. Chem. 2004, 1464. 41 L. R. Reddy, H.-J. Gais, C.-W. Woo, G. Raabe, J. Am. Chem. Soc. 2002, 124, 10427. 42 H.-J. Gais, L. R. Reddy, G. S. Babu, G. Raabe, J. Am. Chem. Soc. 2004, 126, 4859. 43 A. Adrien, H.-J. Gais, F. Ko¨hler, J. Runsink, G. Raabe, Org. Lett. 2007, 9, 2155. 44 M. Schleusner, H.-J. Gais, S. Koep, G. Raabe, J. Am. Chem. Soc. 2002, 124, 7789. 45 (a) I. Erdelmeier, H.-J. Gais, J. Am. Chem. Soc. 1989, 111, 1125; (b) H.-J. Gais, G. Bu¨low, Tetrahedron Lett. 1992, 33, 461; (c) H.-J. Gais, G. Bu¨low, Tetrahedron Lett. 1992, 33, 465. 46 S. K. Tiwari, H.-J. Gais, A. Lindenmaier, G. S. Babu, G. Raabe, L. R. Reddy, F. Ko¨hler, M. Gu¨nter, S. Koep, V. B. R. Iska, J. Am. Chem. Soc. 2006, 128, 7360. 47 T. Bach, C. Ko¨rber, Eur. J. Org. Chem. 1999, 1033. 48 M. Harmata, X. Hong, J. Am. Chem. Soc. 2003, 125, 5754. 49 M. Harmata, K.-o. Rayanil, M. G. Gomes, P. Zheng, N. L. Calkins, S.-Y. Kim, Y. Fan, V. Bumbu, D. R. Lee, S. Wacharasindhu, X. Hong, Org. Lett. 2005, 7, 143. 50 M. Harmata, X. Hong, C. L. Barnes, Org. Lett. 2004, 6, 2201. 51 M. Harmata, X. Hong, Org. Lett. 2005, 7, 3581. 52 M. Harmata, X. Hong, Org. Lett. 2007, 9, 2701. 53 C. Bolm, M. Felder, J. Mu¨ller, Synlett 1992, 439. 54 (a) C. Bolm, J. Mu¨ller, G. Schlingloff, M. Zehnder, M. Neuburger, J. Chem. Soc., Chem. Commun. 1993, 182; (b) C. Bolm, J. Mu¨ller, Tetrahedron 1994, 50, 4355; (c) C. Bolm, N. Derrien, A. Seger, Synlett 1996, 386. 55 (a) C. Bolm, M. Felder, Tetrahedron Lett. 1993, 34, 6041; (b) C. Bolm, A. Seger,

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M. Felder, Tetrahedron Lett. 1993, 34, 8079; (c) C. Bolm, M. Felder, Synlett 1994, 655; (d) C. Bolm, N. Derrien, A. Seger, Chem. Commun. 1999, 2087. (a) C. Bolm, P. Mu¨ller, Tetrahedron Lett. 1995, 36, 1625; (b) C. Bolm, P. Mu¨ller, K. Harms, Acta Chem. Scand. 1996, 50, 305. For a review summarizing these transformations, see: F. Schmidt, R. T. Stemmler, J. Rudolph, C. Bolm, Chem. Soc. Rev. 2006, 35, 454. J. Sedelmeier, C. Bolm, J. Org. Chem. 2007, 72, 8859. (a) M. Langner, C. Bolm, Angew. Chem. 2004, 116, 6110; M. Langner, C. Bolm, Angew. Chem. Int. Ed. 2004, 43, 5984; (b) M. Langner, P. Re´my, C. Bolm, Chem. – Eur. J. 2005, 11, 6254. (a) C. Bolm, M. Martin, O. Simic, M. Verrucci, Org. Lett. 2003, 5, 427; (b) for the use of an ethylene-bridged derivative, see: C. Bolm, M. Verrucci, O. Simic, C. P. R. Hackenberger, Adv. Synth. Catal. 2005, 347, 1696. C. Bolm, M. Verrucci, O. Simic, P. G. Cozzi, G. Raabe, H. Okamura, Chem. Commun. 2003, 2826. (a) C. Bolm, M. Martin, G. Gescheidt, C. Palivan, D. Neshchadin, H. Bertagnolli, M. Feth, A. Schweiger, G. Mitrikas, J. Harmer, J. Am. Chem. Soc. 2003, 125, 6222; (b) C. Bolm, M. Martin, G. Gescheidt, C. Palivan, T. Stanoeva, H. Bertagnolli, M. Feth, A. Schweiger, G. Mitrikas, J. Harmer, Chem. – Eur. J. 2007, 13, 1842. P. Re´my, M. Langner, C. Bolm, Org. Lett. 2006, 8, 1209. M. Langner, P. Re´my, C. Bolm, Synlett 2005, 781. C. Moessner, C. Bolm, Angew. Chem. 2005, 117, 7736; C. Moessner, C. Bolm, Angew. Chem. Int. Ed. 2005, 44, 7564. For another type of sulfoximine-based P-ligand, see: M. T. Reetz, O. G. Bondarev, H.-J. Gais, C. Bolm, Tetrahedron Lett. 2005, 46, 5643.

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7 Synthesis and Use of Chiral Sulfinamides Chris H. Senanayake, Zhengxu Han, and Dhileepkumar Krishnamurthy

Abstract

The development of a general, practical, and stereoselective method for the synthesis of chiral sulfinamides is described in the first part of this chapter. This method is based on the chemoselective nucleophilic opening of oxathiozolidineS-oxide formed from N-tosyl-amino alcohols followed by reaction with nitrogen nucleophiles, from which sulfinamides with structural diversity were synthesized. The second part of the chapter describes the use of sulfinamides as chiral auxiliaries in the synthesis of biologically active compounds, and ligands (for catalytic asymmetric synthesis) possessing chiral amine functionalities are presented. Stereoselectivity in the synthesis of chiral amines was greatly improved by fine-tuning of the structure of sulfinamides and reaction conditions.

7.1 Introduction

During recent years, a variety of new methodologies for the asymmetric synthesis of enantiopure sulfinamides has emerged. The incentive for such extensive research lies in the numerous synthetic applications of these functionalities. Chiral sulfinamides have proven to be highly efficient as chiral auxiliaries, both for the synthesis of chiral amines [1] and as ligands in catalytic asymmetric reactions [2]. Despite the numerous reports which have been made on the preparation of sulfinamides, a general, practical and economical approach to these valuable functionalities has been lacking. Hence, the recent developments in the synthesis and application of sulfinamides are highlighted in this chapter.


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7 Synthesis and Use of Chiral Sulfinamides

7.2 Synthesis of Chiral Sulfinamides and Chiral Sulfinylimines 7.2.1 Background

Historically, chiral sulfinyl transfer agents have been used for the synthesis of chiral sulfoxides. Thus, all of the sulfinyl transfer agents shown in Figure 7.1 have been used in the asymmetric synthesis of chiral sulfoxides. However, only few of these have been demonstrated in the asymmetric synthesis of chiral sulfinamides. In 1962, Andersen used the first chiral sulfinyl transfer agent as (S)menthyl p-toluenesulfinate 1 for the production of sulfoxides via organometallic addition to the SaO bond of 1 in high yield and excellent enantioselection, albeit limited generality [3]. Davis and colleagues, during the mid-1990s, successfully prepared the first enantiomerically pure p-toluenesulfinamide 2 (p-TSA) from Anderson reagent 1 [4]. In 1972, Wudl and Lee disclosed the first cyclic sulfinyl transfer agent as 1,2,3-oxathiazolidine-2-oxide derived from ()-ephedrine 2 to prepare methyl aryl sulfoxides [5]. Kagan introduced cyclic sulfite 3, which led to a mixture of regiomeric sulfinate esters upon treatment with a variety of organometallic compounds [6]. Treatment of the purified sulfinate ester with a second organometallic agent produced chiral sulfoxides in excellent enantioselectivities with good yields (see Figure 7.1). Evans’ N-sulfinyloxazolidinone 4, and later, Oppolzer’s N-sulfinyl sultam 5, produced chiral sulfoxides in high enantioselectivities [7, 8], but these chiral sulfinyl transfer agents were mostly limited to the preparation of aryl sulfoxides. Ellman introduced the synthesis of t-butyl-t-butanethiosulfinate 6 for the production of a variety of t-butyl sulfoxides and t-butyl sulfinamides in excellent enantioselectivities and high yields [1, 9]. In order to overcome the limitations of the former method, Senanayake and coworkers designed N-activated 1,2,3-

Figure 7.1 Chiral sulfinyl transfer agents.

7.2 Synthesis of Chiral Sulfinamides and Chiral Sulfinylimines

oxathiazolidine-2-oxide derivatives 7, which enabled the highly general, selective, and practical synthesis of a wide range of chiral sulfoxides and sulfinamides in high yields, and excellent enantioselectivities (Figure 7.1; Scheme 7.1) [10]. The key to the success of this new technology resided in the utilization of readily available activated amino alcohols and thionyl chloride to build the novel and reactive sulfinyl transfer agent 7 (ACOO). Similar to Anderson’s approach, Alcudia and coworkers prepared optically active sulfoxides and sulfinamides from racemic aryl, or alkyl sulfinyl chlorides using diacetone d-glucose as a chiral controller [11, 12].

Scheme 7.1 N-Activated oxathiazolidine oxides as chiral sulfoxide and sulfinamide precursors.

7.2.2 Synthesis of Chiral Sulfinamides

Sulfinamides are useful and efficient chiral auxiliaries for the synthesis of chiral amines [1], a- and d-amino acids [2], amino alcohols [13], aziridines [14], amino phosphonic acids [15], and others. Despite the importance and utility of sulfinamides in asymmetric chemistry, few methods have been developed for their synthesis. The emergence of sulfinamide chemistry was largely due to the pioneering studies of Davis and coworkers on the first introduction of p-toluenesulfinimines during the early 1970s [16]. About ten years later, Cinquini and colleagues prepared enantiomerically pure p-toluenesulfinimines by using the Andersen reagent [17]. Although the highly asymmetric induction in the synthesis of compounds with chiral amine functionality was recognized, due to the difficulty associated with their preparation the sulfinimines were initially not widely used in the asymmetric synthesis. To overcome this problem, Davis et al., during the mid1990s, successfully prepared the first enantiomerically pure p-toluenesulfinamide 12 (p-TSA) from Anderson reagent 1a (Scheme 7.2). Following these studies, the sulfinamides were immediately accepted as useful and efficient building blocks in the asymmetric synthesis of amine derivatives [18, 19].

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Scheme 7.2 Asymmetric synthesis of p-toluenesulfinimine 13 and p-toluenesulfinamide 12 from Anderson reagent, and their reactions.

Sulfinamide 12 was found to be easily condensed with aldehydes and ketones to produce chiral sulfinyl imines [19]. The electron-withdrawing sulfinyl group in the sulfinimines not only stabilized imines but also activated them towards the addition of a wide range of nucleophiles [18]. Furthermore, this chiral substitution on the imine nitrogen provided high diastereofacial selectivity for nucleophilic addition, leading to chiral sulfinamides. Finally, the sulfinyl group was readily cleaved by brief treatment with acid, thus providing a very general approach for the asymmetric synthesis of a broad range of compounds containing chiral amine functionalities (Scheme 7.2) [13, 18–20a,b]. Later, at the end of the 1990s Ellman and coworkers developed a method for the synthesis of t-butanesulfinamide (t-BSA) 18 via displacement of t-butylthiolate from intermediate 17 with lithium amide [1]. Enantiomerically pure 18 was obtained by recrystallization from hexane. The key intermediate 17 was prepared using Bolm’s method [21a] by the asymmetric oxidation of di-t-butyldisulfide 16 using hydrogen peroxide with VO(acac)2 and ligand 19 in good yield and enantioselectivity. However, the initial procedure for the oxidation of 16 was not scalable because a heterogeneous reaction condition was used. Following the examination of various ligands and reaction conditions, Ellman and colleagues identified an improved homogeneous reaction condition, which can be carried out on the kilogram scale with ligand 20 (Scheme 7.3) [21b]. The overall differences of the t-butylsulfinyl (alkylsulfinyl) versus the p-tolyl (arylsulfinyl) group were thus demonstrated. Interestingly, t-butanesulfinamide proved to be more nucleophilic than p-toluenesulfinamide for direct condensation with aldehydes and ketones. It was also more stereo- and regioselective upon nucleophilic attack of sulfinylimine because of the greater steric hindrance and electron-donating properties of the t-butyl compared to the p-tolyl group. While t-BSA and p-TSA were used in many applications involving the asymmetric synthesis of chiral amines, many reactions require diverse aryl and alky sulfinamides with varied steric and electronic properties to tune both the reactiv-


Scheme 7.3 Asymmetric synthesis of tert-butanesulfinamide.

ity and diastereoselectivity. The Davis method is limited to the synthesis of p-TSA and its close analogues because optically active Anderson’s reagents are required. Unfortunately, only p-toluenesulfinate and its close analogues were prepared effectively by fractional crystallization. A biocatalytic route to access a number of arylsulfinamides was reported by Kaziauskas and coworkers in 2005, which is based on the subtilisin-catalyzed resolution of N-acyl arylsulfinamides [22]. Better selectivity was observed when N-chloroacetyl was employed, but very poor yield was encountered in the preparation of starting materials and in the resolution. The enantioselective oxidation developed by Ellman and coworkers, which relies on the stability of oxidation product, thiosulfinate, is limited to t-BSA only, and application to other sulfinamide was not reported. Having identified this need, Senanayake and coworkers, in early 2000, developed a general and practical method to access a variety of tertiary alkyl and aryl sulfinamides [10a]. Their approach was based on the nucleophilic displacement of cyclic sulfinyl transfer agents. During the early 1970s, Wudl and Lee demonstrated the utility of ()-ephedrine-derived 1,2,3-oxathiazolidine-2-oxide 21 for the enantioselective synthesis of chiral sulfoxides. When 21 was subjected to carbon nucleophiles, the reactive SaO bond was cleaved selectively and produced Nmethylsulfinamides 22. The synthesis of optically active sulfoxides 23 via the addition of a second carbon nucleophile to displace the SaN bond of these acyclic sulfinamides was found to be difficult, and resulted in poor yield and stereoselectivity (Scheme 7.4) [5]. Senanayake and coworkers reasoned that the strong SaN bond in 21 might be caused by the electron-donating methyl group, and that the order of bond strengths between SaO and SaN would be altered if electronwithdrawing groups were attached on the nitrogen of oxathiazolidine. Thus, substituting an electron-withdrawing group for the methyl group on nitrogen should act as an activator and reverse the bond strength and order of cleavage (SaN before SaO). To test this hypothesis, Senanayake and coworkers chose to use an arylsulfonyl group as a nitrogen-activating group and the indane platform as the conformation-

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Scheme 7.4 Wudl and Lee’s synthesis of chiral sulfoxides.

ally constrained backbone [10a]. Synthetic investigations aimed at preparation of the required 1,2,3-oxathiazolidine-2-oxide using N-tosyl-amino indanol as starting materials indicated that the base–solvent combination used in the reaction of aminoindanol 24 with SOCl2 had a pronounced effect on the endo/exo ratio of the product, 25 (see Scheme 7.5). After extensive base screening, it was determined that using 24 (Ar ¼ 2,4,6-mesityl) and 3,5-lutidine as base in tetrahydrofuran (THF) gave the best endo/exo selectivity of 97 : 3. The high endo selectivity was switched to an exo selectivity by a simple change in the pyridine substitution pattern in base. Thus, using sterically congested 2,6-di-tert-butylpyridine led to 2 : 98 (Ar ¼ p-tolyl) and 7 : 93 (Ar ¼ 2,4,6-mesityl) endo/exo selectivities. After recrystallization, both endo and exo isomers of 25 were prepared in kilogram quantities from one enantiomer of the indane platform in diastereomerically and enantiomerically pure forms.

Scheme 7.5 Asymmetric synthesis of endo or exo oxathiazolidine-2-oxides.

The power of this approach was evidenced by the efficient preparation of a diverse range of chiral sulfinamides in high yields and excellent selectivity. Treatment of either endo- or exo-25a with tert-butylmagnesium chloride at low temperature led to a chemoselective cleavage of the SaN bond in each to produce the corresponding diastereomers of 26 in 90% yields and with inversion of configuration at the sulfur atom. Reaction of (1R,2S,R)-26 or (1R,2S,S)-26 with Li/NH3/THF at 78 8C led to cleavage of the SaO bond with inversion of con-


figuration at the sulfur atom, and gave rise to the corresponding enantiomers of tert-butanesulfinamide in 490% yields. Most significantly, the auxiliary chiral amino alcohol 24 was recovered and could be reused in the next reaction cycles (Scheme 7.6) [23b].

Scheme 7.6 Synthesis of enantiomerically pure (R)- and (S)-tert-butanesulfinamides.

Other N-sulfonylamino alcohols were evaluated as the oxathiazolidine oxide precursors. Inexpensive and readily available N-toluenesulfonylnorephedrine, (1R,2S)-27 or (1S,2R)-27, was found to be an ideal template for the preparation of N-toluenesulfonyl-4-methyl-5-phenyl-1,2,3-oxathiazolidine-2-oxide (TMPOO, 28). Thus, optically pure 28 can be prepared in kilogram quantities in 95% isolated yield when pyridine (Py) was used as base in THF. Similarly to 25, the reaction of (2R,4S,5R)-28 first with t-BuMgCl and then with lithium amide, (S)-t-BSA, 29 was formed in 89% yield and 99% enantiomeric excess (ee) (Scheme 7.7). This methodology has a very broad scope. During the course of the study, it was discovered that the SaN bond of TMPOO could also be displaced with mild reagents such as organozincs of sterically congested halides (R ¼ Ad) to give the sulfinate intermediate; after subsequent treatment with lithium amide, 1-adamentylsulfinamide (29f ) was obtained in 99% ee and 80% yield. A supportbound tert-butanesulfinamide 29g had been prepared in many steps, but the expensive auxiliary 2-amino-1,1,2-triphenylethanol was destroyed after the reac-

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Scheme 7.7 Modular asymmetric synthesis of a variety of enantiopure sulfinamides.

tion [24]. By using this approach, 29g was prepared efficiently by doubleinversion nucleophilic displacement in excellent yield and optically purity. Other ether-functionalized sulfinamides (e.g. 29h) were also easily prepared and found to be potential precursors of ether-tethered support-bound sulfinamides [25]. Such methodology has provided the modular synthesis of this valuable family of enantiopure sulfinamides (see Scheme 7.7) [23b]. 7.2.3 Synthesis of Chiral Sulfinylimines

The most common and reliable method for the synthesis of sulfinimines (31), the key precursors of asymmetric synthesis, is through the condensation of sulfinamides with aldehydes and ketones (Scheme 7.8). It was first observed in 1997 by Davis et al. that p-TSA (29, R ¼ p-tolyl) could condense with benzaldehydes in the presence of CsF in fair to good yield, depending on the substrates [19b]; however, a poor yield was observed when unreactive aldehydes were used. Later, Ellman and colleagues studied the formation of sulfinimines using t-BSA (29, R ¼ tert-butyl) with a broad range of aldehydes and ketones [9a]. In the presence of Lewis acid, MgSO4 and PPTS, t-BSA condensed with many aldehydes to provide the desired imines in good yields. However, when using this method excess aldehydes were required, and the reaction with unreactive aldehydes and ketones was found to be only minimally successful. Yet, the use of a strong Lewis acid CuSO4 was found to be effective for aldehydes, without the need to use excess substrates for better yield, though still not sufficiently reactive for ketones. The screening of other Lewis acids revealed that Ti (OEt)4 was an effective agent in promoting the condensation. Subsequently, wide ranges of sulfinyl aldemines and ketimines of both arylsulfinamides and alkylsulfinamides were prepared successfully using this reaction condition. Later, Davis and coworkers screened many conditions for the condensation, and found 4 A˚ molecular sieves and

7.3 Use of Chiral Sulfinamides

Ti (OEt)4 to be the most efficient agents for this chemistry. Other conditions were also reported for the condensations, which is supplemental to the general methods developed by Ellman and Davis [26, 27].

Scheme 7.8 Synthesis of sulfinimines via condensation.

7.3 Use of Chiral Sulfinamides 7.3.1 Use as Chiral Sulfinyl Auxiliaries

Previously, chiral non-racemic sulfinimines have played a significant role in the preparation of enantiopure amines. This is because of their stereodirecting ability, the ease of formation of a diverse range of substrates under mild conditions, and the concomitant removal of protecting groups. In the following section, attention will be focused on the recent development of chiral sulfinimines in asymmetric synthesis. 7.3.2 Synthesis of Chiral Amines

Sulfinamides can be condensed with aldehydes and ketones to form N-sulfinyl imines in good yields. Nucleophilic addition, followed by cleavage of the sulfinyl group, leads to chiral primary amines. Davis and Ellman have used this method extensively to produce a variety of chiral amines using p-tolyl and t-butyl sulfin-

Scheme 7.9 Asymmetric synthesis of a-substituted cyclohexylamines.

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amides [19, 21b, 28]. Recently, Ellman reported the highly diastereoselective addition of alkyl or aryl Grignard reagents to N-sulfinyl imines derived from 3- and 4substituted cyclohexanones (Scheme 7.9). The reaction proceeded in good yield, but the selectivity is believed to be controlled by the ring substituents rather than by the sulfinyl group stereochemistry; hence, racemic t-butanesulfinamide can be employed. Cleavage of the sulfinyl group provided a-substituted cyclohexylamines, which is a prevalent substructure in drugs and drug candidates [29]. A novel and highly efficient synthesis of C2-symmetrical vicinal diamines was recently developed by Xu and coworkers. The homocoupling reaction of a variety sulfinyl aldimines proceeded smoothly using 2 equivalents of SmI2 and 2–6 equivalents of HMPA in THF at 78 8C, and produced the d/l-adduct as a single stereoisomer in moderate to high yield. Cleavage of the sulfinyl group led to enantiopure C2-symmetrical vicinal diamines (Scheme 7.10) [30].

Scheme 7.10 Asymmetric synthesis of C2-symmetrical vicinal diamines.

Davis and coworkers reported an efficient asymmetric synthesis of both syn(2R,3S)- and anti-(2S,3S)-ethyl diamino-3-phenylpropanoates (Scheme 7.11). The addition of differentially N-protected glycine enolates to enantiopure sulfinyl imines and subsequent deprotection afforded syn- and anti-a,b-diamino esters with high diastereoselectivities and good yields [31]. Senanayake and coworkers developed an efficient method for access to both syn- and anti-1,2-amino alcohols. The group prepared the anti-(3S,4R)-44

Scheme 7.11 Asymmetric synthesis of syn- and anti-a,b-diamino esters.


and syn-(3R,4R)-44, by the addition of chiral, non-racemic O-MOM-protected a-hydroxyorganolithium reagent derived from the corresponding stannanes to t-butanesulfinyl imines (S)-40 (Scheme 7.12) [32]. The addition proceeded with high diastereoselectivities and provided the adducts in good to excellent yields, with diastereoselectivities 498%. These products were readily converted to the corresponding enantiomerically enriched a-amino alcohols in high yields by treatment with HCl in methanol.

Scheme 7.12 Asymmetric synthesis of cis- and anti-1,2-amino alcohols.

Ellman and coworkers reported a remarkable general method for the asymmetric synthesis of both syn- and anti-1,3-amino alcohols (Scheme 7.13). In their report, the authors described the first application of metalloenamines derived from N-sulfinyl imines and their highly diastereoselective addition to aldehydes. The reduction of the resulting b-hydroxy N-sulfinyl imines 46 with catecholborane and LiBHEt3 provided syn- and anti-1,3-amino alcohols with very high diastereomeric ratios (dr). This method was found to be effective for a variety of substrates incorporating either aromatic or various aliphatic substituents. The convergent and efficient asymmetric syntheses of the two natural products, ()-8-epihalosaline and ()-halosaline, were also accomplished [33].

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Scheme 7.13 Ellman’s asymmetric synthesis of cis- and anti-1,3-amino alcohols.

Although the addition of metallo enolates to sulfinyl imines to afford b-amino esters has been well reported by the groups of both Davis and Ellman, the diastereoselective addition of ketone enolates to N-sulfinyl imines has received much less attention. Recently, Davis and coworkers reported a practical and elegant solution for the direct asymmetric synthesis of b-amino ketones from the addition of potassium enolates of methyl ketones to N-sulfinyl imines with high diastereoselectivities (Scheme 7.14) [34].

Scheme 7.14 Asymmetric synthesis of b-amino ketones.

A recent example of cis- and anti-1,3-amino alcohol synthesis was reported by Nelson and coworkers [35]. Lithium enolates derived from ketones were added to N-p-toluenesulfinyl imines, providing b-amino ketones in high diastereoselectivity. Interestingly, reduction of the b-amino ketones with LiBHEt3 gave opposite diastereoselectivity with that of the corresponding b-hydroxy-N-sulfinyl imines described above, providing the syn-1,3-amino alcohol derivative in high diastereomeric ratio. On the other hand, reduction with LiAlH4 gave the anti-1,3-amino alcohol as the major isomer (Scheme 7.15). Senanayake and coworkers recently demonstrated that both enantiomers of 1,4-amino alcohols could be obtained from a single enantiomer of a sulfinyl


Scheme 7.15 Nelson’s asymmetric synthesis of cis- and anti-1,3-amino alcohols.

imine, simply by tuning the reaction solvent. Indeed, the addition of Grignard reagents (R)- or (S)-55 to a common synthon (R)-40 allowed rapid access to all four isomers 60, 61, 62 and 63 by the correct choice of reaction conditions. Using THF as solvent, the addition of Grignard reagents (R)- or (S)-55 formed the chiral amine with the (R) configuration, while in CH2Cl2, the (S)-stereoisomer

Scheme 7.16 Asymmetric synthesis of 1,4-amino alcohols.

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predominated (Scheme 7.16). The phenomenon of the reversed diastereoselectivity in CH2Cl2 and THF implied that the reaction might pass through a chelated cyclic transition state in CH2Cl2, and a non-chelated acyclic transition state in THF. Hence, it was postulated that different aggregation states of Grignard reagents in CH2Cl2 or THF might have an influence on the rate of the reaction [32]. The group of Davis recently reported the preparation of N-sulfinyl a-amino 1,3dithioketals in high diastereomeric excess (de) and good yield by treating sulfinyl imines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups afforded stable a-amino 1,3-dithioketals and N-sulfinyl a-amino ketones, respectively (Scheme 7.17) [36].

Scheme 7.17 Asymmetric synthesis of a-amino ketones.

The preparation of a-amino acids by the asymmetric addition of cyanide to sulfinyl imines has been well reported from both the Davis and Ellman groups. Recently, Hou and coworkers described the reaction of chiral sulfinimines 68a–e derived from aliphatic aldehydes with TMSCN in the presence of CsF under mild conditions. This CsF-promoted addition complements Davis’ protocol. The addition gave a-amino nitriles in high diastereoselectivity (up to 98% de) and yield (92–99%) [37a]. a,b-Diamino acid derivatives were also obtained in high diastereoselectivity from the reaction of 2-aziridinesulfinimines 68f and 68g followed by ring-opening of the products with thiophenol (Scheme 7.18). The application of sulfinyl imines for the synthesis of b-amino acids has been well reported by Davis et al., as well as by Ellman and colleagues by treatment with enolates. This method is very general and allowed access to a variety of bsubstituted, a,b- and b,b-disubstituted, a,b,b- and a,a,b-trisubstituted amino acids in high stereoselectivities [37b–d]. While Grignard and lithium reagents have been widely used as nucleophiles in the addition to sulfinyl imines in the synthesis of chiral amines, in 2005, Ellman et al. [38a] disclosed an effective rhodium (I)-phosphine-catalyzed arylboronic acid addition. Good yield and excellent stereoselectivity were observed when 5 mol.% Rh was used in the presence of 1,2-bis(diphenylphosphino) benzene


Scheme 7.18 Asymmetric synthesis of amino acids.

(dppbenz) in dioxane at 70 8C. By optimizing the reaction conditions, Batey et al. [38b] were able to develop a milder reaction condition such that the reaction could be conducted at ambient temperature, without the use of external phosphine (Scheme 7.19) to produce a variety of chiral diarylamines in good yield and up to 98% de. The use of a heterogeneous solvent mixture of dioxane and water in 1 : 2 ratio and 2 equiv. of Et3N was crucial for the reaction’s success.

Scheme 7.19 Rh-catalyzed aryl boronic acid addition to sulfinimines.

Whilst sulfinyl imines are active electrophiles toward C-nucleophiles, their activity with other nucleophiles was rarely addressed. However, in 2005 Scheidt et al. reported that silyl anion could be readily added to tert-butanesulfinyl imines to form a-silylamines 74 with high stereoselectivity of up to 90% de (Scheme

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7.20) [39a]. This protocol was suitable for the synthesis of both aryl and alkyl a-silylamines, which formerly had been prepared with lower efficiency via a reverse aza-Brook reaction [39b].

Scheme 7.20 Synthesis of silylamines via silyl anion addition.

Triisopropylphenylsulfinamide (TIPP sulfinamide) was first introduced by Senanayake and coworkers, and successfully applied in the synthesis of the cetirizine intermediate, 4-chloro-phenylbenzylamine, with a higher stereoinduction than tert-butanesulfinamide [40a]. The scope of its application was extended to the synthesis of syn-a-substituted b-amino ketones that are important intermediates for the synthesis of chiral amino acids or amino alcohols, as reported by Davis et al. (Scheme 7.21) [40b]. The reactivity and stereoselectivity of prochiral Weinreb amide enolate of N-methoxyl-N-methylpropylamide addition to sulfinyl imines were investigated. It is of interest to note that addition of the enolate to tert-butanesulfinyl imine resulted in no reaction but, gratifyingly, good yields were resulted when arylsulfinyl imine was used. A good diastereo- and enantioselectivity were observed when both 2,4,6-trimethyl- and 2,4,6-triisopropylphenysulfinyl imines were employed, with the syn-isomer 76 predominating. Importantly, an easily isolatable product was generated when TIPP was used in the reaction.

Scheme 7.21 Synthesis of b-amino ketones via amide enolate addition.

Alternatively, the synthesis of chiral amines can also be accomplished by direct reduction of (or use of hydride as nucleophile) sulfinyl ketimines. First reported by Cozzi et al. [41a,b] and later by Ellman et al. [41c], the reduction of sulfinyl imines has attracted much attention in the synthesis of compounds containing chiral amine functionality, such as diamine, amino alcohol, amino acid, and aziridine, in high enantio- and diastereoselectivity [41d–i]. Readily available reductants such as diisobutylaluminum hydride (DIBAL), LiAlH4, NaBH4, BH3, and


9-borabicyclo [3.3.1]nonane (9-BBN) were commonly used in the reaction. Most importantly, in many cases the stereoselectivity was reversed with high order when the different reducing agent and reaction conditions were properly tuned, and this allowed the access of both isomers from one starting material. This strategy was employed by Andersen and coworkers for the effective access to many pharmaceutical intermediates [42j]. Recently, Sepracor reported a convenient process for the synthesis of trans-(1R,4S)-79, a central nervous system drug candidate, on a kilogram scale. The key step here involved the stereoselective reduction of 78. Reduction using 9-BBN resulted in the desired trans-isomer 79 in 99% de, whereas the syn-isomer 80 dominated when NaBH4 in MeOH was used as reductant (Scheme 7.22) [42k].

Scheme 7.22 Stereoselective reduction of chiral sulfinyl ketimine.

7.3.3 Synthesis of Aziridines

Optically active aziridines are versatile building blocks that have found widespread use in organic synthesis of, for example, a- or d-amino acids, amino alcohols, diamines, natural and biologically active products, and other compounds with amine functionalities, as well as ligands and auxiliaries in asymmetric synthesis [42]. Among many methods developed, the use of sulfinamide as the auxiliary provides a more direct and efficient pathway in the synthesis of chiral aziridines. During the early 1990s, Davis and colleagues developed a method for the synthesis of cis-N-(p-tolylsulfinyl)-2-carbomethoxylaziridines 82 via an aza-Darzenstype reaction of the lithium enolate of methyl bromoacetate with enantiopure sulfinyl imines 81 in good yield. High cis-stereoselectivity was observed in most of the cases. Compound 82 was found to be a versatile intermediate in organic synthesis for installing the stereochemistry in molecules (Scheme 7.23) [14, 43a,b]. Later, during the late 1990s, the same group applied these conditions which previously had been optimized for the aza-Darzens chemistry to the synthesis of aziridine-2-phosphates. The reaction between imine 84 and the lithium anion of diethyl chloromethylphosphonate was found to give undesired products 85 and 86

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which, upon treatment with NaH, furnished the aziridine-2-phosphates 87 or 88 in good yield (Scheme 7.24). The stereoselectivity of this reaction, however, was very poor. After screening the reaction conditions and substrates, a better selectivity was observed when iodomethylphosphate and lithium-hexamethyldisilazane (LHMDS) was used in THF to provide 85 as the major product [43c,d].

Scheme 7.23 Aza-Darzens-type chemistry for the synthesis of aziridines.

Scheme 7.24 Synthesis of aziridine-2-phosphates.

In order to achieve a better stereoselectivity, the steric effect of the auxiliary was then investigated. Reaction of the anion derived from iodo or tosyl methyl phosphate with imine generated from t-BSA and benzaldehyde formed the cisaziridine-2-phosphate directly in 82% and 32% yield, respectively [43e]. Initially, generation of the NaH aziridine via removal of the tert-butylsulfinyl group was difficult, but the problem was later solved by modifying the structure of auxiliaries. By using 2,4,6-trimethylphenyl (mesityl)sulfinamide instead of t-BSA as the auxiliary, the reaction resulted in the desired cis-aziridines in a one-pot reaction, and with good yields. The mesitylsulfinyl group was readily removed by treatment with 2 equiv. methylmagnesium bromide to give NaH aziridines in good yield [43f ]. The steric effect on the stereoselectivity of aziridination was also observed in the reactions of methylide with sulfinyl imines (Scheme 7.25). During investigations conducted by Garcia Ruano et al. and David et al., the outcome of products was found to depend on the methylene-transfer reagents used. Such product distributions were believed to be caused by differences in the chelating characters of the reagents. Hence, the major product 90 was formed preferentially when


non-chelating dimethylsulfonium methylide was used. However, 91 become the major isomer if dimethyoxosulfonium methylide was employed. Independent of the reagents used, the stereoselectivity was found to increase with the increase in the steric bulk of the substitute. Thus, changing p-tolyl to the naphthyl substitute resulted in an increased diastereoselectivity; indeed, using tert-butyl resulted in a pronounced improvement in selectivity of up to 90% de [44].

Scheme 7.25 Synthesis of aziridine via methylides.

By using t-BSA-derived imines and the addition of S-allyl sulfur ylides, Stockman et al. were able to synthesize chiral vinylzaridines 93 in good yield and excellent stereoselectivity. This protocol was found to be suitable for aromatic, heterocyclic, and branched and cyclic aliphatic substrates (Scheme 7.26) [45]. Tang and coworkers also reported the use of telluronium ylides in the reaction with t-BSA imines to synthesize chiral cis-vinylaziridines, with good yield and high stereoselectivity being obtained with a diverse set of aromatic, aliphatic, and unsaturated aliphatic substituted imines [45b].

Scheme 7.26 Asymmetric synthesis of vinyl aziridines.

Another efficient method for the preparation of enantiopure N-tert-butanesulfinyl aziridines (RS)-96 was described by Chemla and Ferreira. Condensation of enantiopure N-tert-butanesulfinyl imine 94 with racemic allenylzinc bromide 95 afforded trans-ethynyl aziridines (RS)-96 in good-to-excellent yields and with excellent diastereoselectivity (498%). The absolute stereochemistry of enantiopure (RS)-96 was shown to be (RS,2R,3R), and resulted from a chelation-type

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transition state in which the zinc atom of allenylzinc 95 coordinated both the nitrogen and oxygen atoms of the imine. Removal of the N-tert-butanesulfinyl auxiliary of aziridine 96 by treatment with HCl in MeOH led to the corresponding enantiomerically deprotected aziridines (Scheme 7.27) [46].

Scheme 7.27 Asymmetric synthesis of N-t-butanesulfinyl aziridines.

7.3.4 Use of Chiral Sulfinamides as Ligands in Catalytic Asymmetric Reactions 7.3.4.1 Asymmetric Diels–Alder Reaction Ellman and coworkers made an outstanding contribution to the chiral Lewis acid catalyzed Diels–Alder reaction of cyclic and acyclic dienes with N-acryloyl oxazolidinones using bis(sulfinyl)imidoamidine (SIAM) ligands [47f, 48]. Indeed, SIAM ligands proved to be far more powerful than previously developed sulfinylbased ligands [49]. For example, the Diels–Alder reaction of 97 (n ¼ 1) and 98 in the presence of 10 mol.% Cu (SbF6) 2 and 11 mol.% 99 provided the cycloadduct in 96% yield and 98% ee (Scheme 7.28). Modification of the substitution pattern in the SIAM ligand (101–103) resulted in no further improvement in reactivity

Scheme 7.28 Cu(SbF6) 2 –SIAM-catalyzed Diels–Alder reactions with cyclic dienes.


or selectivity; however, it is important to note that high selectivities for the reaction of 97 (n ¼ 1) and 98 were maintained. Ligands derived from t-butanesulfinamide and ketones (100 and 104) provided inferior results. The substrate scope of this Cu (SbF6)2 –SIAM 99 catalytic system was investigated, and high selectivities

Table 7.1 Cu(SbF6 ) 2 –SIAM-catalyzed Diels–Alder reactions with cyclic dienes.

Entry

n

Dienophile

Cycloadduct

Catalyst [%]

Time [h]

Temp. [8C]

Yield [%]

ee [%]

dr

1 2 3 4 5 6

1 1 1 1 1 2

H (98a) CH3 (98b) Ph (98c) CO2Et (98d) H (98a) H (98a)

105a 105b 105c 105d 105a 105a

10 10 10 10 1 10

0.1 8 16 2 8 16

78 40 0 78 78 0

96 76 58 85 95 50

98 97 94 96 98 90

99 : 1 98 : 2 95 : 5 97 : 3 99 : 1 98 : 2

Table 7.2 Cu(SbF6 ) 2 –SIAM-catalyzed Diels–Alder reactions with acyclic dienes.

Entry

Diene

Dienophile

SIAM

Time [h]

Temp. [8C]

Yield [%]

dr

ee [%]

1

R1 bCH3 R2 bR3 bH R1 bR2 bCH3 R3 bH R1 bR2 bH R3 bCH3 R1 bPh R2 bR3 bH R1 bCH2OTBDPS R2 bR3 bH R1 bR2 bCH3 R3 bH R1 bR2 bCH3 R3 bH

R4 bH

99

16

rt

83

–

93

R4 bH

99

16

0

96

–

92

R4 bH

99

16

rt

18

2.0 : 1.0 : 0.4

41

R4 bH

99

2

rt

87

–

45

R4 bH

99

16

rt

33

–

62

R4 bCO2Et

99

16

rt

565

–

53

R4 bCO2Et

101

16

rt

80

–

81

2 3 4 5 6 7

rt ¼ room temperature.

253

254


were observed for imides derived from crotonic acid (98b), cinnamic acid (98c), and fumaric acid (98d). With a more reactive system, a catalyst loading of down to 1 mol.% was well tolerated. Less-reactive dienes such as 97 (n ¼ 2) led to the cycloadduct in only 50% yield and 90% ee (Table 7.1). The Cu (II)–SIAM catalytic system proved to be more efficient than the usual bisoxazoline-based ligands, even for the more challenging Diels–Alder reaction with acyclic dienes [50]. Indeed, the use of Cu (SbF6)2 –SIAM catalysts led to high yields and excellent enantioselectivities for the cycloaddition of isoprene and 2,3-dimethylbutadiene (Table 7.2, entries 1 and 2). The incorporation of a substituent at the terminal position of a phenyl or ether group in dienes 110 resulted in poor selectivities. Cycloaddition of 110 with substituted dienophiles represented a more challenging set of substrates which provided disappointing results with ligand 99 (Table 7.2, entry 6). However, the use of a more reactive trifluoroethylsubstituted SIAM ligand 101 resulted in formation of the cycloadduct in 80% yield and 81% ee (Table 7.2). 7.3.4.2 Asymmetric Allylic Alkylation Reaction The utility of sulfinyl imine ligands for achieving excellent enantioselectivities in the palladium-catalyzed asymmetric allylation reaction has recently been reported by Ellman [51]. An initial optimization study was performed using

Table 7.3 Palladium-catalyzed allylic alkylation reaction using sulfinamide-based ligands.

Entry

Catalyst

Mol.% L (L : Pd)

Time [h]

ee [%]

1 2 3 4 5 6 7

108 109 110 111 112 112 112

30 (1 : 1.3) 30 (1 : 1.3) 30 (1 : 1.3) 30 (1 : 1.3) 30 (1 : 1.3) 30 (1 : 1) 5 (1 : 1)

8.5 425 5 24 2 1 6

93 0 56 49 96 96 94


phosphinooxazoline-based ligand 108 in the asymmetric alkylation of 1,3diphenylpropenyl acetate with dimethylmalonate. It was determined that the Pd complex generated from ligand 108 and a slight excess of [Pd (allyl)Cl]2 (1 : 1.3) in methylene chloride gave optimal results with a high conversion and 93% ee (Table 7.3, entry 1). Modified ligands (109 to 112) were prepared and studied in the reaction. Interestingly, the use of p-toluenesulfinyl ligand 109 led to a poor conversion and no selectivity. Although ketimine ligand 110 increased the rate of reaction, a significant reduction in stereoselectivity was also observed. Replacement of the phenyl substituents on the phosphorus atom in 108 by cyclohexyl groups in 111 produced disappointing results, as a longer reaction time was required and poor selectivity was obtained. Interestingly, the Pd complex derived from ligand 112 was found to be more active and selective, and provided 96% ee with complete conversion in 2 h. Additional experiments showed that ligand 112 tolerated various ligand : Pd ratios and high to low concentrations. More importantly, a lower catalyst loading (5 mol.%) provided complete conversion, with 95% isolated yield and 94% ee (Table 7.3, entry 7). 7.3.4.3 Asymmetric Hydrogenation of Olefins Ellman and coworkers also demonstrated the use of these sulfinamide-based P,N ligands in the asymmetric hydrogenation of olefins [52]. A recent report by Senanayake and coworkers on the modular synthesis of chiral sulfinamides encouraged Ellman et al. to incorporate sulfinamides with various steric and electronic substituents in their study. The initial optimization focused on the hydrogenation of trisubstituted olefin 113a using iridium complex 114 derived from t-butylsulfinamide. Treatment of 113a using 5 mol.% 114 with BARF as counterion in methylene chloride and 25 to 100 bar of hydrogen gas pressure were determined as the optimal reaction conditions, and provided 115 with 499%

Scheme 7.29 Asymmetric hydrogenation of olefins using sulfinamide-based P,N ligands.

255

256


conversion and 94% ee. In order to explore the effect of the catalyst structure on turnover and enantioselectivity, an array of catalysts with modified sulfinamide moiety or phosphine substituents was prepared (116–121), but unfortunately none was found as effective as 114. Other functionalized olefins (103b and 103c) were hydrogenated using catalyst 114 and provided 115b and 115c with 499% conversion and 65% and 70% ee. Although a survey of other catalysts (116–121) provided only disappointing results, these studies nonetheless expanded the scope of the P,N-sulfinyl imine-based catalyst to challenge unfunctionalized olefin substrate and to obtain valuable structure–activity relationship data for sulfinyl imine-based ligands in the iridium-catalyzed asymmetric hydrogenation of olefins (Scheme 7.29). 7.3.5 Application of Chiral Sulfinamides in the Synthesis of Biologically Active Molecules 7.3.5.1 Synthesis of SC-53116 Ellman took advantage of the self-condensation of metalloenamines derived from t-butylsulfinamide and novel microwave-assisted thermal decomposition of Nsulfinyl imines to nitriles in a recent efficient and elegant asymmetric synthesis of SC-53116, a drug candidate for a serotonin 5-HT4 receptor agonist. The reaction of sulfinyl imine 122 in the presence of 0.5 equiv. LHMDS and 1.0 equiv. 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) in THF led to compound 123 in 55% isolated yield and good diastereomeric ratio. Selective decom-

Scheme 7.30 Synthesis of SC-53116.


position of the functionalized 123 to nitrile 124 proceeded with 84% yield, using a microwave reactor. Subsequent functionalization of 125 led to SC-53116 in three steps. This synthetic five-step sequence provided SC-53116 in 29% overall yield, and was also significantly more efficient than the previously reported synthesis (Scheme 7.30) [53]. 7.3.5.2 Total Synthesis of (6R,7S)-7-Amino-7,8-Dihydro-a-Bisabolene Although the addition of metalloeneamines derived from N-sulfinyl ketimines to aldehydes was highly successful in providing 1,3 amino alcohols, Ellman and coworkers observed that the corresponding addition to electrophiles (e.g. alkyl halides) suffered from the reduced nucleophilicity of the metalloeneamine. Therefore, the research group engineered metalloenamines derived from N-sulfinyl amidines to increase the nucleophilicity. This methodology has been successfully demonstrated in the first asymmetric total synthesis of (6R,7S)-7-amino-7,8dihydro-a-bisabolene 129. The key-step allylation of amidine 125 was performed at 78 8C with allyl bromide in the presence of potassium-hexamethyldisilazane (KHMDS) to provide 126 in 82% yield as a single diastereomer. The desired ketimine 127 was prepared in 82% yield using a CeCl3-mediated addition of MeLi to amidine 126. Subsequent ring-closing metathesis of 127 proceeded in 87% yield, using a Grubb’s second-generation catalyst. This organometallic addition to N-sulfinyl ketimines provided the only general method for the asymmetric synthesis of tertiary carbinamines to date. Finally, precomplexation of imine 128 with Me3Al at 78 8C, followed by the addition of organolithium reagent and deprotection with HCl in MeOH, led to natural product 129 in 49% yield as a single diastereoisomer. The elegant feature of this synthesis lies in the use of a single chiral sulfinyl imine to control the formation of two consecutive stereocenters (Scheme 7.31) [54].

Scheme 7.31 Synthesis of (6R,7S)-7-amino-7,8-dihydro-a-bisabolene.

257

258


Scheme 7.32 Asymmetric synthesis of ()-pateamine.

7.3.5.3 Asymmetric Synthesis of (C)-Pateamine Recently, Davis and coworkers applied the asymmetric addition of functionalized enolates to sulfinimines to produce concise and convergent synthesis biologically active compounds [55]. The synthesis of ()-pateamine 133, a unique thiazolecontaining 19-membered bis-lactone isolated from a marine sponge that exhibited ˜ ań and Pattenden potent immunosuppressant activity, was described by Remuin [56]. The synthesis involved the asymmetric addition of a functionalized enolate derived from 131 to imine 130. The resulting complex b-amino ester 132 was isolated in 63% yield and 85% diastereomeric excess. Further synthetic manipulations led to the natural product (Scheme 7.32) [55].

Scheme 7.33 Synthesis of polyoxamic acid lactone.


7.3.5.4 Synthesis of Polyoxamic Acid Lactone The sulfinyl imine-based asymmetric Strecker reaction represents one of the most efficient and practical methods for the synthesis of optically active a-amino acids. Polyoxamic acid 136, the key structural unit in natural product polyoxin J 137, was recently synthesized in an asymmetric fashion by the addition of Et2AlCN to functionalized p-toluenesulfinyl imine 134. Thus, treatment of 2 equiv. Et2AlCN in the presence of 1.5 equiv. isopropanol at 78 8C provided nitrile 135 in 66% yield and 91 : 9 diastereomeric ratio. Subsequent deprotection and cyclization led to 136 (Scheme 7.33) [56]. 7.3.5.5 Synthesis of Single Enantiomers of Sibutramine and Cetirizine The first application of tunable alkyl or aryl sulfinamides was recently reported for the asymmetric synthesis of 139, a biologically active metabolite and key intermediate of enantiopure sibutramine. The racemic form of sibutramine is currently used for the treatment of obesity. Among the variety of sulfinamides examined, t-butylsulfinamide and (triethyl)methylsulfinamide (TESA) provided the best yield and selectivity for this process. After further optimization with respect to temperature, additives and solvent, it was determined that the use of THF as solvent at 78 8C with BF3OEt2 as an additive gave (R)-DDMS in excellent yield and 499% chiral purity. The use of (R)-(triethyl)methylsulfinyl imine gave excellent selectivity and, unlike the (R)-t-butylsulfinyl imine derivative, did not generate any undesired odor during the acid-mediated deprotection. A chromatography-free process was demonstrated in a single vessel using commercially available 138 as a starting material (Scheme 7.34). Thus, treatment of nitrile with Red-Al in toluene followed by condensation with (R)-(triethyl)methylsulfinamide gave the sulfinyl imine. Diastereoselective addition of i-BuLi in the presence

Scheme 7.34 Asymmetric synthesis of the sibutramine metabolite.

259

260


of BF3OEt2 at 78 8C followed by cleavage of the chiral auxiliary afforded (R)DDMS in 99% ee. (R)-DDMS was isolated as the d-tartrate in 83% overall yield, 499% ee and 499.5% chemical purity (Scheme 7.34) [57]. Recently, Senanayake and coworkers described a novel and direct approach for the asymmetric synthesis of (R)-sibutramine via chiral amine 143 using Ntosyl-1,2,3-oxathiazolidine-2-oxide (141) as a recyclable chiral auxiliary [58]. Chiral sulfinate imine 142 was obtained by treatment of 141 with the imine intermediate formed from the reaction of a nitrile 140 and i-BuMgCl which, upon reduction, provides an optically active amine 143 with high enantiopurity. The sulfinate ketimine can be easily prepared by reaction of imine nucleophile with an oxathiazolidine-2-oxide. These oxathiazolidine-2-oxides are readily reformed by treating recycled 144 with thionyl chloride (Scheme 7.35). Furthermore, it has been demonstrated that the structural backbone of these auxiliaries could be readily altered by simply varying the starting amino-alcohol derivatives. Hence, these enantiopure oxathiazolidine-2-oxides can be used to tune the diastereoselective reduction process of chiral sulfinate ketimines in the production of valuable optically active amines.

Scheme 7.35 A direct synthesis of sibutramine from 140.

(S)-Cetirizine2HCl is a non-sedating histamine H1-receptor antagonist which is used for the treatment of allergy, and in Europe is currently marketed as Xyzal0. An effective asymmetric method was identified by Senanayake and coworkers for the synthesis of enantiopure key intermediate (S)-4-chlorophenylphenylmethylamine 146. The addition of PhMgBr to N-t-butanesulfinyl-p-chlorobenzaldimine 145 in toluene, followed by mild acidic hydrolysis, gave 146 as the major enantiomer with moderate enantiopurity (75% ee) [59]. Further optimization of the reaction conditions to improve the selectivity was unsuccessful; hence, a variety of sulfinamides was evaluated in the asymmetric addition of PhMgBr. The modification of aliphatic sulfinamides did not provide any major improvement in the selectivity, however, a good trend was observed when the structures of aromatic sulfinamides were changed from tolyl to mesityl to triisopropylphenyl. Thus, the use of triisopropyl sulfinamide provided a 91% ee at 0 8C and 94% ee at 20 8C. This example clearly demonstrated the power of tunable sulfinamides in the efficient synthesis of structurally challenging chiral amines (Table 7.4) [41a].

7.4 Summary Table 7.4 The use of tunable chiral sulfinamides in Grignard addition.

R

Yield [%]

ee [%]

t-Bu Ad (Ethyldimethyl)methyl (Triethyl)methyl p-tolyl Mesityl 2,4,6-triisopropyl phenyl t-Bu 2,4,6-triisopropyl phenyl

81 85 79 88 77 83 84 83 80

75 68 76 79 10 50 91 82 94

7.4 Summary

As evidenced from the information presented in this chapter, the scope and generality of the applications of chiral sulfinamides have grown substantially during the past five years. Furthermore, the field of chiral ligands based on sulfinimines is also currently growing at a rapid rate. Unfortunately, however, the stereoselective synthesis of such important chiral auxiliaries has been limited to very few approaches, such as the asymmetric oxidation of pro-chiral sulfides or disulfides, or the use of chiral sulfinyl transfer agents. It is quite remarkable that recent progress in the general and modular synthesis of chiral sulfinamides using activated 1,2,3-oxathiazolidinone-2-oxides will provide an easy access to many structurally challenged sulfinamides, and in turn may be used for the asymmetric synthesis of a variety of complex molecules with many useful properties. It is anticipated that the use of this array of sulfinamides and sulfoxides will increase over time as the availability of these reagents reaches commercial scale. Today, the main burden rests on the synthetic organic chemists, not only in academia but also in the industrial arena, to effectively identify and integrate the use of these sulfinamides in applications that will bring an economical and safe solution to the large-scale production of biologically important targets.

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7 Synthesis and Use of Chiral Sulfinamides J. L. Garcıá-Ruano, M. C. Maestro, L. M. Martıń Cabrejas, Tetrahedron: Asymmetry 1993, 4, 727; (d) R. Tokunoh, M. Sodeoka, K.-i. Aoe, M. Shibasaki, Tetrahedron Lett. 1995, 36. 8035; ˜ ez, V. Guerrero de la Rosa, (e) M. Ordoń V. Labastida, J. M. Llera, Tetrahedron: Asymmetry 1996, 7, 2675; (f ) D. T. Owens, J. F. Hollander, A. G. Oliver, J. A. Ellman, J. Am. Chem. Soc. 2001, 123, 1539; (g) H. K. Cotton, F. F. Huerta, J.-E. Ba¨ckvall, Eur. J. Org. Chem. 2003, 15, 2756; (h) K. Hiroi, I. Izawa, T. Takizawa, K.-i. Kawai, Tetrahedron 2004, 60, 2155; (i) S. Nakamura, T. Fukuzumi, T. Toru, Chirality 2004, 16, 10. 48 T. D. Owens, A. J. Souers, J. A. Ellman, J. Org. Chem. 2003, 68, 3. 49 D. A. Evans, D. M. Barnes, J. S. Johnson, T. Lectka, P. Von Matt, S. J. Miller, J. A. Murry, R. D. Norcross, E. A. Shaughnessy, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 7582.

50 K. Hiroi, I. Izawa, T. Takizawa, K. Kawai, Tetrahedron 2004, 60, 2155. 51 L. B. Schenkel, J. A. Ellman, Org. Lett. 2003, 5, 545. 52 L. B. Schenkel, J. A. Ellman, J. Org. Chem. 2004, 69, 1800. 53 L. B. Schenkel, J. A. Ellman, Org. Lett. 2004, 6, 3621. 54 T. Kochi, J. A. Ellman, J. Am. Chem. Soc. 2004, 126, 15652. 55 F. A. Davis, K. R. Prasad, P. J. Carroll, J. Org. Chem. 2002, 67, 7802. ˜ ań, G. Pattenden, 56 M. J. Remuin Tetrahedron Lett. 2000, 41, 7367. 57 Z. Han, D. Krishnamurthy, D. Pflum, P. Grover, S. A. Wald, C. H. Senanayake, Org. Lett. 2002, 4, 4025. 58 Z. Han, D. Krishnamurthy, C. H. Senanayake, Tetrahedron Lett. Org. Process. Res. Dev. 2006. 10, 327. 59 D. A. Pflum, D. Krishnamurthy, Z. Han, S. A. Wald, C. H. Senanayake, Tetrahedron Lett. 2002, 43, 923.

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8 Asymmetric Catalysis Using Sulfoxides as Ligands Inmaculada Fernańdez and Noureddine Khiar

Abstract

This chapter describes the application of chiral sulfoxides in enantioselective homogeneous catalysis. Owing to the ambidentate character of sulfoxides as ligands, the chapter begins with a description of the parameters affecting the bonding mode of sulfoxides in metal complexes. There follows a compilation of the main uses of sulfoxides as ligands in metal-catalyzed asymmetric transformations, such as the asymmetric hydrogenation of olefins and ketones, enantioselective Diels–Alder reaction, and Pd-catalyzed enantioselective allylic alkylation. In addition to applications in enantioselective radical allylation, recent uses of chiral sulfoxides in Lewis acid–Lewis base bifunctional catalysts, in combination with achiral catalysts and also neutral coordinate-organocatalysts, are reviewed.

8.1 Introduction

Currently, the so-called ‘‘chiral market’’ is experiencing a continuous rise as a consequence of the significance of optically pure compounds in important areas such as agriculture, fragrances, and medicine. As an illustration of this popularity, the worldwide sales value of single-enantiomer drugs exceeded more than US$ 159 billion in 2002, and more than 50% of drugs currently on the market are enantiopure compounds [1]. Consequently, the design of new and efficient processes which allow the synthesis of chiral compounds as single enantiomers with high optical purities represents an important goal for synthetic chemists both in academia and in the industrial arena [2]. Among the many different ways to ensure diastereomeric transition states, enantioselective catalysis is the method of choice, as it combines both efficiency and versatility. Enantioselective catalysis is usually achieved by using a transition metal bound to a chiral organic ligand, which is responsible for the enantiodiscrimination. An analysis of the massive literature on metal-catalyzed asymmetric synthesis shows that most of the Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

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8 Asymmetric Catalysis Using Sulfoxides as Ligands

ligands developed to date have been based on the use of a discrete framework, with mostly phosphorus, nitrogen – and to a lesser extent, oxygen – as the ligating atoms [4]. Surprisingly, while chiral sulfoxides have been used extensively in asymmetric synthesis as privileged chiral auxiliaries (see for example, Chapter 3) [5, 6], few investigations have been reported on their application in enantioselective homogeneous catalysis. This is particularly perplexing as the coordination chemistry of these materials is well known [7] and they are ideally suited for the construction of diverse metal–ligand complexes with a well-defined chiral environment as a result of the close proximity of the chiral sulfur atom to the coordination sphere of the metal. On the other hand, as shown in Chapters 1 and 2, the past decade has witnessed a genuine revolution in the synthesis of chiral sulfoxides [6, 8]. These advances have greatly facilitated the design and synthesis of tailored steric and electronic sulfoxides for use as ligands in asymmetric catalysis.

8.2 Some Considerations on the Coordination of Sulfoxides

Due to the ambidentate character of the sulfoxide group, the resulting ligands may coordinate the metal through either the oxygen or the sulfur atoms. Although there are some exceptions, as a general rule sulfoxides coordinate to hard metals via oxygen, whereas coordination by sulfur occurs mostly with soft metals (Figure 8.1). Nevertheless, it should be noted that the ‘‘hardness’’ or ‘‘softness’’ of a metal ion can be affected by the nature of the coordinated ligands, and steric effects can force O-bonding even in softer metal ions. In addition, the introduction of highly electronegative substituents with ancillary ligands lowers the electron charge density on the metal, favoring O-bonding. Therefore, in mixed ligands the preferred coordinating atom of sulfoxides is determined in part by the ability of other ligands at the metal center to compete for electron density. The presence of strong p-electron acceptors withdraws electron density from the metal, and causes ‘‘softer’’ metals to become ‘‘harder’’. This reduction in electron density at the metal may be accompanied by a change in coordination of the ligand from

Figure 8.1 Coordination modes of sulfoxides.

8.3 Sulfoxides as Ligands in Metal-Catalyzed Asymmetric Catalysis

a ‘‘soft’’ to a ‘‘hard’’ donor atom to optimize orbital overlap. When considering the Periodic Table as a whole, there is a prevalence of O-bonding, but S-bonding seems nevertheless to be favored in d6 and d8 transition metal ion complexes, most likely through p back-bonding contributions. O-bonding may also be induced by the ligand bulkiness, and may also derive from entropic contributions. In conclusion, the bonding mode in sulfoxide-based ligands is the result of a delicate balance between electronic and steric factors. In sulfoxide–metal complexes, the coordination mode of the sulfoxides is easily determined using 1H NMR and infra-red (IR) spectroscopy [9]. Generally, O-bonding of sulfoxides results in small downfield chemical shifts of the a protons (50.5 ppm), while larger downfield chemical shifts (1 ppm) are seen for coordination through the S-atom; moreover, this trend is also observed for the b- and, to a lesser extent, the g-protons. Upon coordination of sulfoxide, a greater shift is observed in the sulfur–oxygen IR stretching frequency, nSO, in S-bonded than O-bonded sulfoxides.


The main sulfoxide-based ligands used in published reports are bidentate, there being a clear prevalence of those with C1-symmetry design over the widely used C2-symmetry design. In this respect it should be noted that the s-donor properties of sulfoxide exceed those of N-based ligands, while its p-acidic properties mirror that of olefins. In addition, recent structural studies have shown that in the case of late transition metals, the use of a sulfoxide within a bidentate framework yields a trans influence greater than typical N-based ligands and lower than thioethers and phosphine-based ligands [10]. 8.3.1 Catalytic Hydrogenations

To the present authors’ knowledge, the first study describing the use of chiral sulfoxides in asymmetric catalysis was made in 1976, by B. R. James and coworkers. The group used (þ)-methyl p-tolyl sulfoxide as ligand in the Ru- and Rh-catalyzed hydrogenation of olefins, but achieved disappointing results [11]. However, inspired by the good catalytic results of rhodium and ruthenium derived from the C2-symmetric diphosphine diop developed by Kagan and Dang [12], James and McMillan synthesized three bis-sulfoxides which they named bdios (3), dios (4) and ddios (5), all of which were derived from l-tartaric acid (Scheme 8.1) [13]. Surprisingly, although the dios-type and the MBMSO (6) sulfoxides used in the study consisted of a mixture of diastereoisomers (epimeric at sulfur), the corresponding Ru (II) catalysts induced only a moderate degree of asymmetry. However, by using the catalyst [RuCl2(4)(5)], up to 25% enantiomeric excess (ee) was obtained in the hydrogenation of itaconic acid 1 to succinic acid 2 (see Scheme

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268


Scheme 8.1

8.1). For the same reaction, [RuCl2(6) 2]3 gives an ee-value of only 15%, while no asymmetric induction has been observed with cationic rhodium complexes [Rh (diene)(PPh3)(4)]þ as catalyst. Alcock et al. have reported on the synthesis of a-phosphinosulfoxides 7 as ligand in Rh-catalyzed asymmetric hydrogenation (Scheme 8.2) [14]. Ligands of type 7 proved to be stable when purified as there was no internal oxygen transfer, and the corresponding Rh (I) complex 8 was active in the hydrogenation of styrene and hex-1-ene. Unfortunately, olefinic substrates with polar functional groups suppressed the catalytic activity.

Scheme 8.2

Promising results were obtained for the rhodium-catalyzed asymmetric transfer hydrogenation of prochiral ketones using amino sulfoxide as a chiral ligand by Kvintovics, James and Heil (Scheme 8.3) [15]. The ligand used was a 1 : 1 diastereomeric mixture of N-acetyl-(S)-methionine (R,S)-sulfoxide 9. The in-situgenerated catalyst using KOH as cocatalyst and i-PrOH as hydrogen source, operated optimally with a Rh : 9 : KOH ratio of 1 : 2 : 4–5, and afforded the hydrogenated product with up to 75% ee.


Scheme 8.3

Recently, the van Leewen group has used similar ligands derived from cysteine and norephedrine in the iridium-catalyzed transfer hydrogenation using formic acid as hydrogen donor in order to avoid the reversibility of the reaction [16]. The use of the diastereomeric mixture, the optically pure 10-(RS) or 10-(SS), clearly demonstrates a chiral cooperativity of the sulfoxide and the chiral backbone. Accordingly, when ligands were used in a 1 : 1 diastereomeric mixture, the R-carbinol was obtained in 35% ee. Interestingly, when the S-benzyl-(R)-cysteinol (SS)-sulfoxide, 10-(SS), was used in combination with [IrCl (COD)] 2, the epimeric S-carbinol was obtained with 27% ee. The use of the other diastereoisomer 10(RS) afforded the (R) carbinol with up to 65% ee, and in 99% conversion after 1 h.

Scheme 8.4

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270


The use of ligands derived from (1R,2S)-norephedrine afforded similar results. A large difference in reaction rate (32% versus 9% conversion) and enantioselectivity (32% versus 2% ee) was observed for the two diastereoisomers 11-(RS) and 11-(SS) in the iridium (I)-catalyzed transfer hydrogenation of acetophenone, using formic acid as hydrogen donor (Scheme 8.4). A catalyst optimization allows the (S) carbinol to be obtained in 80% ee and 57% yield using {Substrate : [IrCl (COD)] 2 : 11-RS} ¼ (400 : 1 : 5). The same trend has been observed by Anderson using bicyclic amino sulfoxides 12 as ligands, where one of the diastereomeric sulfoxides was more active and highly enantioselective than the other, and afforded the R-carbinol in 52% yield and 80% ee [17]. In a project directed toward the use of carbohydrate-tethered sulfur as cheap ligands in asymmetric catalysis [18], the present authors have used the amino sulfinyl glycoside 13 in the same reaction (see Scheme 8.4). The product was obtained with very low yield and a deceptively low 24% ee [19]. An interesting ligand 14, derived from a phosphine-phosphonium ylide with a chiral sulfinyl group, has been recently reported. The reaction of 14 with [Rh (cod) 2]PF6 gave stable cationic disymmetrically P,C-chelated rhodium complexes 15 and 16 (Scheme 8.5), with the concomitant creation of a new chiral center, controlled by the sulfoxide moiety [20]. Interestingly, each of the diastereomeric Rh-complexes 15 and 16 can be obtained in high diastereoselectivity, depending on the reaction conditions. Both complexes were active in the hydrosilylation of acetophenone and also in the hydrogenation of (Z)-a-acetamidocinnamic acid, although the products were obtained mostly racemic.

Scheme 8.5

8.3.2 Catalytic Cycloadditions

In the hierarchy of carbon–carbon bond constructions, the Diels–Alder reaction occupies a preeminent position [21]. It is one of the rare reactions which allows the rapid development of molecular complexity, as it permits the stereoselective formation of as many as four stereogenic centers and as many as three carbocyclic rings in the intramolecular and transannular variation. Although chiral auxil-


iary (including chiral sulfoxides) -based reactions retain a position of central importance, catalytic variants are developing rapidly. The promotion of the Diels– Alder reaction by a substoichiometric amount of chiral Lewis acid has developed to a relatively high level of sophistication as a result of the extensive research in this field. Nevertheless, the first application of chiral sulfoxides in a catalytic Diels–Alder reaction was carried out by Khiar and Fernańdez in 1993 [23]. The ligands used were C2-symmetric bis-sulfinylmethane derivatives, 19 and 20, obtained using a method developed by Kunieda (Scheme 8.6).

Scheme 8.6

An in-situ catalyst (19.FeI3) or (20.FeI3) was used as a chiral catalyst of the Diels–Alder reaction between 3-acryloyl-1,3-oxazolidin-2-one 17 and cyclopentadiene, affording the Diels–Alder adduct 18 in excellent diastereoselection (90– 92%), and in 56% ee (Scheme 8.6). The use of magnesium complexes of b-hydroxyl sulfoxide 21 in the same model reaction afforded the endo adduct 18-(S) in 88% ee (Scheme 8.6) [24]. Various S,N-ligands formed by 1,3-oxazoline ring and a chiral sulfinyl function (22–25) were recently assayed in the same reaction using diverse metal precursors [25]. Among the various Lewis acids used [Cu (OTf )2, CuI2, FeI3, MgCl2, MgBr2, MgBr2Et2O, MgI2 and Mg (OTf )2], MgI2 was shown to be the best for the rigid S/N ligand 22, affording the adduct in up to 92% ee,

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Figure 8.2 Proposed model for the favored endo-attack in the Diels–Alder cycloaddition with ligand 22.

while Cu (OTf )2 gave the best enantioselectivity (66% ee) in the case of the more flexible S/N ligand 24 (Scheme 8.6) [26]. As the chirality can be introduced on the sulfinyl sulfur and on the oxazoline ring, a study on the substituent has shown that the asymmetric induction was a consequence of a synergetic effect of the two chiral centers, as the loss of chirality on the oxazoline or on the sulfoxide provided much lower enantioselectivity. In all of the above-described catalytic processes the reactivity as well as the selectivity has been rationalized by the intermediacy of metal complexes where the sulfoxide group was coordinated to the metal center through the oxygen. Accordingly, the high enantioselectivity obtained with ligand 22, has been accounted for by an endo attack of the cyclopentadiene on the sterically accessible dienophile Re diastereoface. The accessibility of the re face on both magnesium complex intermediates, is a direct consequence of the steric hindrance of the 2-methoxyisopropyl at the oxoazoline moiety, and the 2-methoxy-1-naphthyl groups at the sulfinyl sulfur, which explains the observed synergetic effect of the two chiral centers on the enantioselectivity (Figure 8.2). 8.3.3 Addition of Diethylzinc to Benzaldehyde

The enantioselective addition of diethyl zinc to aldehydes (Scheme 8.7), mediated by chiral non-racemic ligands, is one of the best-studied examples of ligandaccelerated catalysis [27]. From a practical perspective, it is placed among the most powerful methodologies for the production of secondary alcohols in enantiomerically pure form. Several characteristics of the reaction, such as the very important non-linear effects [28, 29], autocatalysis phenomena, and the derived amplification of enantiomeric excess, make it attractive both from intellectual and industrial perspectives, provided that sufficiently active catalytic ligands are developed. In 1993, Ruano’s group reported on the first use of b-hydroxysulfoxides as chiral bidentate ligands in the enantioselective addition of diethyl zinc to benzaldehyde (Scheme


Scheme 8.7

8.7) [30]. The ligands used were cyclic and acyclic b-hydroxysulfoxides, with two or three stereocenters, having either a secondary or a tertiary carbinols. The best ligands were hydroxysulfoxides 26 (35% ee) in the case of acyclic ligands, and 27 in the case of cyclic ligands (45% ee). S,N-Ligands 28a–c (Scheme 8.7), developed by Chelucci et al. and using sulfoxides tethered to pyridine, afforded the desired carbinol in very low enantioselectivity (up to 19% ee) [31]. The best system for this transformation reported to date is the mixed sulfoxide/sulfonamide 29 developed by Carretero. This catalyst was shown to promote the addition of ZnEt2 to diverse aromatic aldehydes, affording the desired products with good yields and excellent enantioselectivities (up to 96% ee) [32]. 8.3.4 Catalytic Allylic Substitutions

Within the plethora of existing synthetic methods for the formation of carbon– carbon and carbon–heteroatom bonds, the palladium-catalyzed allylic alkylation is one of the most prominent [33]. The large amount of data accumulated to date indicates that palladium-catalyzed asymmetric allylic alkylation (Pd AAA) is among the few reactions where the mechanism is well understood, and this has allowed the development of a number of rationally designed ligands, and their applications in several natural product syntheses. One of the benchmark reactions used to determine the efficiency of a chiral ligand, is the palladium-catalyzed allylic substitution of 1,3-diphenyl propenyl acetate 30 with soft nucleophiles. As the reaction proceeds via symmetrical complexes, the regioselectivity of the nucleophilic attack is equivalent to the enantioselectivity and determines the enantiomer of substitution product, 31-(R) or 31-(S), that is obtained.

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Scheme 8.8

While bidentate ligands with C2 symmetry have been dominating the field of asymmetric catalysis, recent advances have shown that well-designed bidentate C1-symmetric ligands can lead to highly effective catalysts. Ligands containing two different donor atoms are able to impart an electronic distortion upon the allyl moiety in the intermediate palladium allyl complex, and nucleophilic addition to the complexed allyl is predicted to occur trans to the better p-acceptor. In the case of allylic substitution, successful ligands belong to the second approach, and include P-N [34] and P-S donors [35], while classical C2-symmetrical diphosphine ligands such as binap and chiraphos are less successful [36]. In the case of sulfoxides as ligands, both ligand designs have been followed, and the same trends have been observed. The use of C2-symmetric bis-sulfoxides was pioneered by Shibasaki’s group in 1995 [37]. The rigid bis-sulfoxide synthesized 32 (named BTSB) was active as the ligand, even though up to 20 mol.% was necessary to afford the allylated product (S)-31, in modest to good yields (25–82%)

Figure 8.3 C2-symmetric bis-sulfoxides used in Pd-catalyzed asymmetric substitution.


and modest enantioselectivities (20–64%). Surprisingly, pyrrolidine-based bissulfoxides 36 (as reported by Skarewski [38]), as well as acyclic ethylene-bridged bis-sulfoxides 33–35 (as reported by Khiar and Fernańdez [39]) were shown to be mostly inactive in the Pd AAA, even though up to 20 mol.% of the ligands were assayed. In contrast, the use of 20 mol.% of the thioether-sulfoxide 37 related to 36, affords the allylated product in 71% yield and 88% ee (Figure 8.3) [38]. Better results were obtained using C1-symmetric ligands which rely on the trans influence for control of the enantioselectivity. Williams, one of the pioneers of the concept of Pd AAA, reported the first use of chiral sulfoxides embedded to an oxazoline ring in the reaction of 1,3-diphenylpropenyl acetate with dimethyl malonate (Scheme 8.8) [40, 41]. The S,N ligands synthesized 38–39 (Figure 8.4) were shown to be highly efficient in palladium-catalyzed asymmetric substitution as they produce the substitution product 31 in good yields and moderate to good enantioselectivities. Interestingly, ligand 39-(SS) provides both much greater enantioselectivity (88% versus 42%) and also chemical yield (96% versus 55%) than does the diastereomeric ligand 39-(RS). This result, associated with the reasonable level of enantioselectivity with ligands 38a and 38b, where the chirality is

Figure 8.4 Mixed sulfoxide/nitrogen ligands used in Pd-catalyzed asymmetric substitution.

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276


imparted solely by the sulfoxide group, is indicative that the stereochemistry of the sulfur is important in determining the stereochemical outcome of the reaction. Nevertheless, the success of ligands 39 depends greatly on the oxazoline moiety, as shown by the results obtained with ligands 40–43. Hiroi’s group has reported on the synthesis and applications of large number of chiral bidentate ligands having a nitrogen atom either as dialkyl amine or sulfonamide (40–42) (Figure 8.4) [42]. In general, these ligands were shown to be less effective than 39, as both yields and enantioselectivities were from low to modest, with the exception of ligand 41a where the allylated product was obtained in 91% ee, although in low yield (42%). The same tendency has recently been observed when applying the imino sulfinyl glycoside 43, which afforded the allylated product almost racemic and in a deceptive (28%) yield (Figure 8.4). The use of mixed sulfoxides/phosphine ligands investigated thoroughly by Hiroi’s group met with more success, and afforded better results than the aforementioned ligands [43, 44]. Different platforms were used in the construction of the catalysts, having the sulfoxide as sole chiral center such as 44, 45, 47, 48 and 49, or in combination with other chiral centers, such as those derived from proline, 46a–c (Figure 8.5) [43]. Among the ligands prepared, those having a sterically demanding 2-naphthyl group were shown to be superior to those having a p-tolyl group, and allowed the synthesis of the allylated product in high enantioselectivities. For instance, the catalyst formed by ligand 46b and (PdClC3H5) 2 (6 mol.%) gave the product of allylic alkylation 31-(S) (see Scheme 8.8) in 71% yield and 82% ee, while ligand 45b gave the same product in 97% ee, albeit in low yield (49%). Ligand 46b has also been shown to afford good results in the palladium-catalyzed allylic amination. Use of the former catalytic system (6%) using benzylamine as nucleophile gave the aminated alkene in 85% ee and 51% yield. Toru has recently reported the synthesis of 1-phosphinyl-1 0 -sulfinylferrocene 50, as well as its evaluation in the palladium-catalyzed allylic alkylation [45]. These ligands were shown to be effective in the test reaction as the product was generally obtained in high yield; nevertheless, the enantioselectivity was modest (up to 68% ee). Recently, the sulfoxide/imine/phosphine derived from carbohydrate 51 has been employed in the Pd AAA; the consequent yield of the allylated product was excellent (92%) but the ee-value was very low (14%), which was in clear contrast to the behavior of the analogue thioglycoside, which afforded the product with 90% ee [46]. Most of the enantioselectivities observed in the aforementioned reactions were explained on the basis of the transition-state intermediate depicted in Scheme 8.8. Mechanistic studies have shown that soft nucleophiles (such as the malonate anion) directly attack one of the two terminal carbons of the allyl moiety from the opposite face to the coordinated palladium atom [36]. Therefore, the site of formation of the new asymmetric center is far from the chiral ligand, which explains the initially low enantioselectivities observed in this transformation. Nevertheless, during the past few years different approaches have been designed to circumvent this obstacle, and indeed a number of ligands did in fact afford high enantioselectivities in excess of 90%. In the case of bidentate ligands (such


Figure 8.5 Mixed sulfoxide/phosphorus ligands used in Pd-catalyzed asymmetric substitution.

as those used in this section) the mechanistic justifications of the observed selectivity are summarized in Figure 8.6 [47]. In Figure 8.6, route (a) shows the use of a pendant group to direct the nucleophilic attack on one of the allylic termini [48], while route (b) indicates, in the case of mixed ligands, electronic interactions such as the trans effect to differentiate between both termini [49]. Also indicated are the use of steric effects acting

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Figure 8.6 Models proposed to explain the enantioselectivity in the Pd(0)-catalyzed allylic substitution.

either at an early transition state (c), or at late transition state (d) [50]. In the case of C2-symmetric ligands both mechanisms (c) and (d) have been advanced to account for the observed selectivity. Mechanism (c) depends on intramolecular steric effects and the attendant charge separation in the PdaC bonds of the p-allyl termini. Mechanism (d), which assumes that the reaction has a late transition state, is based on the relative stabilities of the intermediate Pd (p)–olefin pcomplexes which result from addition of the nucleophile to the p-allyl complexes.

Figure 8.7 Proposed model for the enantioselectivity obtained in the palladium-catalyzed allylic substitution with ligand 48.


In the case of mixed sulfoxides/phosphine ligands 48, the high enantioselectivity observed has been rationalized by the operation of the trans-influence together with a well-defined steric discrimination in the transition state. Accordingly, due to the non-bonding steric interaction of the substituent of the sulfinyl sulfur and the phenyl substituent of the g-allyl system, the M-type p-allyl intermediate is sterically more favored than the W-type (Figure 8.7). On the other hand, taking into account the higher trans influence of the phosphorus atom compared to the sulfinyl sulfur, the nucleophilic attack of malonate anion takes place trans to the phosphorus and cis to the stereogenic sulfoxide to afford the S-isomer in high enantioselectivity (see Figure 8.7). 8.3.5 Utilization of Sulfoxides in Other Metal-Catalyzed Asymmetric Processes 8.3.5.1 Use of Sulfoxides in Lewis Acid–Lewis Base Bifunctional Asymmetric Catalysis The recent years have witnessed the development of new and imaginative concepts in ligand design and their applications in significant asymmetric transformations. One such concept is the Lewis acid–Lewis base bifunctional asymmetric catalysis developed by Shibasaki [51]. The approximation, which is based on the dual activation of both the nucleophile and electrophile by the same catalyst (Figure 8.8), has been applied with success to different chiral transformations. The high electron donor efficiency of sulfoxides, their high optical stability, associated with their affinity to silicon makes them ideal chiral Lewis bases. In 2003, Rowlands reported on the use of a sulfoxide-based ligand as the precursor of a dual catalyst in the titanium-catalyzed cyanosilylation of aldehyde [52]. The best ligand identified was the phenolic oxazoline-tethered tert-butyl sulfoxide 52, which afforded the alkyl and aryl cyanohydrin 53 in good yields and moderate enantioselectivities (31–61% ee) (Scheme 8.9). The sulfoxide moiety was found to be crucial in the catalytic activity of the system, as shown by the results obtained upon oxidizing the sulfoxide to the sulfone, or by removing the sulfoxide group.

Figure 8.8 Schematic representation of dual activation of a nucleophile and an electrophile with a bifunctional catalyst.

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Scheme 8.9

Recently, Shibasaki reported on the first enantioselective Reissert reaction of pyridine derivatives en route to enantiomerically pure piperidine derivatives, which are important building blocks for the synthesis of biologically active molecules. The strategy is based on the aluminum-catalyzed addition of trimethylsilyl cyanide (TMSCN) to nicotinic amide 54 in the presence of a chlorocarbonate and a bifunctional asymmetric catalyst [53].

Scheme 8.10


The optimal ligand found for this transformation was the BINOL-tethered bisulfoxide 55, which most likely acts by a dual activation of the acyl pyridinium salt by the Lewis acid (aluminum) and the TMSCN by the sulfoxide (Lewis base). Excellent yields and enantioselectivities were obtained in this transformation, which was used for the formal synthesis of the dopamine D4 receptor-selective antagonist, CP-293,019 (57; see Scheme 8.10). 8.3.5.2 Use of Sulfoxides as Chiral Ligands in Combination with Achiral Catalysts The great difficulty of the main catalytic processes generally excludes rational approaches based on structural and mechanistic criteria. Consequently, the discovery of efficient catalysts still actually deeply depends on empirical factors such as chance, intuition, and the screening of a large number of ligands. In order to avoid the costly, laborious, and time-consuming sequential modification of the chiral ligand, a new approach based on the use of an enantiopure Ligand (L*) in combination with achiral Ligand (L) in a catalyst M(L*)(L), has received great interest [54]. Based on this concept, Nguyen has reported on the asymmetric cyclopropanation of alkenes with ethyldiazoacetate (EDA), mediated by a combination of achiral (salen)ruthenium (II) catalysts, and a catalytic amount of chiral sulfur derivatives as chiral Lewis bases [55]. Four achiral (salen) ruthenium (II) catalysts (61–64), eight chiral sulfur derivatives, including sulfinate esters 65, sulfite 66, sulfinamide 67, and sulfoxides 68a–c and 69, were assayed in the cyclopropanation of styrene with EDA.

Scheme 8.11

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8 Asymmetric Catalysis Using Sulfoxides as Ligands Table 8.1 The cyclopropanation of styrene and EDAwith achiral ruthenium

complexes 61–64 and chiral sulfur derivatives 65–69.a) Entry

[Ru]

L*

Yield [%] b)

cis : trans

cis ee [%]c)

trans ee [%]c)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15d) 16e)

None 62 62 62 62 62 62 62 62 62 61 63 63 64 62 62

None 65-(SS) 65-(RS) 68a-(S) 68a-(R) 67-(S) 68b-(R) 68c-(R) 69-(S) 66-(SS) 68a-(R) 68a-(R) 68a-(R) 68a-(R) 68a-(R) 68a-(R)

92 86 87 84 86 85 96 90 90 87 87 86 90 89 90 90

1 : 7.5 1 : 7.3 1 : 7.3 1 : 7.5 1 : 7.6 1 : 7.2 1 : 7.4 1 : 7.3 1 : 7.3 1 : 7.4 1 : 7.6 1 : 7.6 1 : 5.7 1 : 7.8 1 : 7.4 1 : 6.7

23 (S,R) 23 (R,S) 50 (S,R) 57 (R,S) 40 (R,S) 51 (R,S) 56 (R,S) 41 (S,R) 33 (R,S) 41 (R,S) 57 (R,S) 27 (R,S) 0 85 (R,S) 93 (R,S)

5 (S,S) 5 (R,R) 42 (S,S) 46 (R,R) 10 (R,R) 29 (R,R) 29 (R,R) 45 (S,S) 16 (R,R) 19 (R,R) 46 (R,R) 13 (R,R) 0 81 (R,R) 87 (R,R)

a) Reaction conditions: EDA (0.5 mmol), styrene (2.5 mmol), catalyst (1 mol.%), CH2Cl2 at room temperature. b) Yield determined by gas chromatography based on EDA with undecane as an internal standard. c) Absolute configuration determined from chiral gas chromatography analysis by comparison with known standards. d) Reaction performed at 0 8C. e) Reaction performed at 78 8C in undiluted styrene.

The study results showed that all sulfur derivatives afforded some enantioselections, with sulfoxides being the best additives (Table 8.1, entries 4, 5, 7–9, 11–16) and methyl p-tolyl sulfoxides 68a the ligand of choice. Optimization of the reaction conditions allowed the synthesis of cyclopropane 60 in excellent diastereoselectivity and enantioselectivity (Table 8.1, entry 16), using only 1 mol.% of the catalyst and 10 mol.% of the ligand.

Scheme 8.12


Figure 8.9 Proposed mechanism for the asymmetric induction by an achiral catalyst through the addition of (R)-methyl p-tolyl sulfoxide.

In the study of the scope of the reaction, the combination of catalyst 62 and ligand 68a was shown to be highly effective for the enantioselective synthesis of various cyclopropyl esters 70 (Scheme 8.12). The observed asymmetric induction has been rationalized by a chiral environment amplification induced by the axial coordination of the chiral sulfoxide to the ruthenium center in the catalytic cycle (Figure 8.9). The initial reaction of EDA with axial triphenylphosphane ligands 62–64 causes rapid formation of phosphorus ylides, which do not bind significantly to the metal center. This leaves the axial positions of the catalyst open to coordination by the chiral additive. Once the sulfoxide is coordinated to the metal, the asymmetry is conveyed/amplified to the opposite axial position where a ruthenium carbene can interact stereoselectively with an olefin to complete the cyclopropanation cycle (Figure 8.9). 8.3.5.3 Use of Sulfoxides as Ligands in Enantioselective Radical Allylation Owing to the high synthetic values of radical processes in CaC bond formation, major efforts have been directed towards the development of efficient enantioselective versions. While sulfoxides have been efficiently used as chiral auxiliaries in the diastereoselective free radical reactions [56], their use as chiral ligands is scarce. In 2000, Hiroi reported on the use of the known C2-symmetric bissulfoxide 20, and the hydroxysulfoxides 71 and 72, in the intermolecular allylation of sulfonamide 73, in the presence of Mg (OTf ) 2 as Lewis acid [57]. The use of 1 equiv. of the ligand in methylene chloride at 78 8C afforded the allylated product 75 in moderate yields (41–65%) and modest to good enantioselectivities (50–83% ee) (Scheme 8.13).

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Scheme 8.13

The high enantioselectivity observed with the hydroxysulfoxide ligand 71, has been rationalized by the formation of a six-six-membered metal complex with the ligand and the substrate coordinated through the oxygen atoms (Figure 8.10). In the conformational equilibrium, it is assumed that the s-cis conformation of the methyl group at the a-carbon of the carboxamide is preferred to the s-trans conformation as a consequence of a severe A1,3 strain between the Nbenzyl substituent and the methyl group (see Figure 8.10). On the other hand, the steric interaction between the aromatic phenyl ring of the ligand and the p-tolyl substituent of the sulfonamide favors one of the conformations at equilibrium. Consequently, the allyl radical approach takes place from the back side of the bulky p-tolyl group of the sulfonamide, affording selectively the adduct 75 with the S absolute configuration at the newly created chiral center.

Figure 8.10 Proposed mechanism for the asymmetric radical allylation of sulfonamide 73 with hydroxysulfoxide 71.

8.3.6 Use of Sulfoxides as Neutral Coordinate-Organocatalysts

While the use of metals in catalysis has many benefits, it also presents equal or even more drawbacks, including toxicity, product contamination, waste treatment and, of course, high prices. As an alternative, the past decade has witnessed an


impressive expansion in catalytic methods conveyed solely by organic molecules where, in many cases, the use of these small molecules has resulted in extremely high enantioselectivities. This new and rapidly growing field has been named ‘‘organocatalysis’’ or ‘‘organic asymmetric catalysis’’, in contrast to metalmediated enantioselective catalysis [58]. There are many obvious advantages in the development of purely organocatalytic systems, including low prices, a higher stability to aerobic conditions (even in wet solvents), and the facility to be anchored onto solid support to produce heterogeneous, reusable catalysts. While many metal centers are good Lewis acids, the main organic catalysts tend to react as heteroatom-centered Lewis bases. Surprisingly, whilst a large number of P(O) and N(O)-based Lewis bases have been used in many organocatalytic transformations, sulfoxides have seldom been used. Sulfoxides are considerably less electron-donating than phosphoramides (the most prevalent Lewis base catalysts), but are better than the amides (e.g. dimethylformamide) which have found use in Lewis base catalysis. Based on the known affinity of sulfoxides towards silicon, all of the organocatalytic processes developed so far have dealt with the addition of silicon-based nucleophiles to diverse electrophiles. Kobayashi and colleagues found that the addition of allyl trichlorosilane 77 to benzoyl hydrazones 76 takes place in good yields and moderate to excellent enantioselectivities in the presence of simple aryl alkyl sulfoxides [59]. A struc-

Scheme 8.14

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286


ture–activity study has shown that the structure of the sulfoxide is of sum importance to achieve high enantioselectivity in the process. The best results were obtained using 3 mol. equiv. of the known (R)-methyl p-tolyl sulfoxide 68a in methylene chloride at 78 8C in the presence of 2-methyl-2-butene, the latter being used to suppress racemization of the sulfoxide (Scheme 8.14). Recently, the electron-rich alkyl ferrocenyl sulfoxides 81a–c have also been found to be excellent promoters of this transformation. A pronounced effect on the enantioselectivity of the steric environment of the sulfinyl group has been observed. While the i-propyl ferrocenyl sulfoxide 81a afforded the hydrazine in 95% yield and 82% ee, the tert-butyl ferrocenyl sulfoxide 81c afforded the product in mostly racemic form (see Scheme 8.14) [60]. Asymmetric crotylation of benzoyl hydrazones with (Z)- and (E )-crotyltrichlorosilane 82 was shown to take place in high yield and excellent stereospecificity using (R)-methyl p-tolyl sulfoxide 68a as promoter. (E )-82 afforded syn-adducts 83, while anti-adducts 83 were obtained from (Z)-82 with excellent diastereoselectivity and good to excellent enantioselectivities (Scheme 8.15). The allylation of aldehydes has also been investigated using sulfoxides as promoters. Ligands with the sulfinyl group as exclusive chiral center, as well as ligands with the sulfoxide and other heteroatom (mainly nitrogen) were assayed with moderate yields and enantioselectivities (Scheme 8.16). In this case, the use of (R)-methyl p-tolyl sulfoxide (68a) also afforded homoallylated alcohols 84 with good yields and moderate enantioselectivities (42–55% ee) [61]. Various oxazolineembedded sulfoxides 85–88, were used as promoters in this transformation, affording the products with good to excellent yields and moderate enantioselectivities, even though in this case only 1 equiv. of ligand was needed (see Scheme 8.16) [62].

Scheme 8.15

8.4 Conclusions

Scheme 8.16

8.4 Conclusions

Based on the preceding discussions, some concluding remarks may be drawn with respect to the use of chiral sulfoxides as ligands in asymmetric catalysis, and some future applications anticipated. While sulfoxides have mostly been assayed in model reactions used to assess the value of a given ligand in asymmetric catalysis, in none of these did the sulfoxide-based ligands compete with the ‘‘gold standard’’ catalysts that have been reported in the literature. A paradigmatic example is the Pd-catalyzed asymmetric alkylation, for which a large number of catalysts actually afford the allylated product with near-100% ee, using very low catalyst loading. As has been seen, in the case of sulfoxide-based ligands, the best members afforded the product with 92% ee, using a 6 mol.% ligand content. Whilst a number of reasons can be given to explain this state of affairs, perhaps the most important is the inherent weak coordinating properties of the sulfoxides as ligands. As a matter of fact, complexes with sulfoxides containing the heavier metals of Groups 8 to 10 of the Periodic Table are readily isolable only in weakly coordinating solvents. On the other hand, the ligands used to date have employed relatively few sulfoxide-type substituents. Although a large number of methods which allow the synthesis of any form of sulfoxide are available, the ligands used in catalysis still use the Anderson menthyl sulfinates to a wide degree. Consequently, the final ligands obtained have an aromatic substituent at sulfur, which is probably not the best choice to imprint electronic and steric differentiation

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with regards to the sulfinyl oxygen. Exceptions to these scenarios are the use of sulfoxides as co-ligands not only in Lewis acid–Lewis base dual catalysts, but also in combination with achiral catalysts, as shown by the studies of Shibasaki and Nguyen. In both cases, the catalyst design does not rely on the coordinating ability of the sulfoxide to create a chiral Lewis acid catalyst, but rather uses the sulfinyl group as a helper or as an external ligand, to create a well-defined chiral environment. Although the subject is still in its infancy, the use of sulfoxides as chiral Lewis bases in organocatalysis is worthy of mention here, as the results obtained have shown great promise. In all of the aforementioned successful applications, coordination of the sulfoxide ligand takes place through the sulfinyl oxygen. This is not surprising bearing in mind that the success of sulfoxides as chiral auxiliaries is a consequence of the good coordinating ability of the sulfinyl oxygen, combined with a well-defined chiral environment derived from the steric and stereoelectronic differences between the lone pair of electrons, and the sulfinyl substituents. Consequently, those catalytic processes based on the coordination ability of sulfinyl oxygen, associated with the possibility of modulating the electronic and steric characteristics of the sulfoxide, will lead in future to good catalyst candidates. The use of the trans influence in ligand design has also shown itself to be a potent approach to efficient catalysts. This holds also for the use of sulfoxide-based ligands, where the combination with phosphorus has afforded the best catalysts to date. The use of this catalyst design, in combination with the new methodologies on record for the modular synthesis of chiral sulfoxides, will undoubtedly be widely used in the future. Finally, the excellent results obtained with thioether-based ligands in general – and with thioether/ phosphorus mixed ligands in particular – indicate that future important applications of sulfoxides-based ligands will undoubtedly be as intermediates for the synthesis of their reduced congeners [35].

References 1 S. C. Stinson, Chem. Eng. News 2001, 79, 45. 2 Recently, two issues of the Proceedings of the National Academy of Sciences of the USA were dedicated to the Special Feature of asymmetric catalysis, see: Proc. Natl. Acad. Sci. USA, No. 15, April 13, 2004, and Proc. Natl. Acad. Sci. USA, No. 16, April 20, 2004. 3 See 2001 Nobel Lectures: Angew. Chem. Int. Ed. 2002, 41, 998. 4 (a) J. Seyden-Penne (Ed.), Chiral Auxiliaries and Ligands in Asymmetric Synthesis, Wiley Interscience, New York, 1995; (b) E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric

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Catalysis, Vols. I–III Springer, Berlin, 1999. ˜ o, Chem. Rev. 1995, 95, 1717. C. Carren I. Fernańdez, N. Khiar, Chem. Rev. 2003, 103, 3651. (a) E. Alessio, Chem. Rev. 2004, 104, 4203; (b) M. Calligaris, Coord. Chem. Rev. 2004, 248, 351; (c) H. B. Kagan, B. Ronnan, Rev. Heteroatom. Chem. 1992, 7, 92; (d) K. U. Baldenius, H. B. Kagan, Tetrahedron: Asymmetry 1990, 1, 597. C. Senanayake, D. Krishnamurthy, Z-H. Lu, Z. Han, I. Gallou, Aldrichim. Acta 2005, 38, 93. (a) W. Kitching, C. J. Moore, D. Doddrell, Austr. J. Chem. 1969, 22, 1149;

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˜ ez, V. Gureero-de la Rosa, 24 M. Ordon V. Labastida, J. M. Llera, Tetrahedron: Asymmetry 1996, 7, 2675. 25 K. Hiroi, K. Watanabe, I. Abe, M. Koseki, Tetrahedron Lett. 2001, 42, 7617. 26 K. Watanabe, T. Hirasawa, K. Hiroi, Chem. Pharm. Bull. 2002, 50, 372. 27 D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew. Chem., Int. Ed. Engl. 1995, 34, 1050. 28 C. Girard, H. B. Kagan, Angew. Chem., Int. Ed. Engl. 1998, 37, 2922. 29 R. Noyori, M. Kitamura, Angew. Chem., Int. Ed. Engl. 1991, 30, 49. ˜ o, J. L. Garcia Ruano, 30 M. C. Carren M. C. Maestro, M. L. Cabreras, Tetrahedron: Asymmetry 1993, 4, 727. 31 G. Chelucci, D. Berta, A. Saba, Tetrahedron: Asymmetry 1997, 3843–3848. 32 (a) J. Priego, O. G. Mancheno, S. Cabrera, J. C. Carretero, Chem. Commun. 2001, 2026; (b) J. Priego, O. G. Mancheno, S. Cabrera, J. C. Carretero, J. Org. Chem. 2002, 67, 1346. 33 (a) B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem. Res. 2006, 39, 747; (b) M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921. 34 For P-N ligands, see: (a) P. Von Matt, A. Pfaltz, Angew. Chem., Int. Ed. Engl. 1993, 32, 566; (b) J. Springs, G. Helmchen, Tetrahedron Lett. 1993, 34, 1769; (c) G. J. Dawson, C. G. Frost, J. M. J. Williams, Tetrahedron Lett. 1993, 34, 3149. 35 Some representative P/S ligands: (a) G. Molander, J. Burke, P. J. Carrol, J. Org. Chem. 2004, 69, 8062; ˜ o, R. Gomez Arrayas, (b) O. G. Manchen J. C. Carretero, J. Am. Chem. Soc. 2004, 126, 456; (c) D. A. Evans, K. R. Campos, J. S. Tedrow, F. E. Michael, M. R. Gagne, J. Am. Chem. Soc. 2000, 122, 7905; (d) Y. Y. Yan, T. V. Rajan Babu, Org. Lett. 2000, 2, 199; (e) A. Albinati, P. S. Pregosin, K. Wick, Organometallics 1996, 15, 2419. 36 P. R. Auburn, P. B. Mackenzie, B. Bosnich, J. Am. Chem. Soc. 1985, 107, 2033. 37 R. Tokunoh, M. Sodeoka, K. Abe, M. Shibasaki, Tetrahedron Lett. 1995, 36, 803.

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9 Sulfones in Asymmetric Catalysis Juan Carlos Carretero, Ramoń Go´mez Arraya´s, and Javier Adrio

Abstract

Despite the great chemical versatility of the sulfonyl group, only recently have the sulfones begun to be incorporated systematically into the arsenal of highly valuable asymmetric catalytic methodologies. In this revision, it is shown that functionalized sulfones, especially vinyl sulfones and b-keto sulfones, have become very appealing substrates in asymmetric catalysis, both in metal-mediated and in organocatalysis procedures. Due to the great chemical versatility of the sulfones in the formation of CaC and CbC bonds, after the asymmetric catalytic step the resulting enantioenriched chiral sulfones constitute very interesting synthetic intermediates in the enantioselective synthesis of complex compounds.

9.1 Introduction

Asymmetric catalysis is one of the most fundamental and growing fields in current organic synthesis. During the past twenty years, vast progress has been achieved in the development of new chiral ligands and organocatalysts, as well as in the discovery of highly efficient enantioselective variants of an extremely wide variety of synthetically important CaC and CaX bond-forming reactions [1]. In accord with the key role of carbonyl compounds and alkenes in organic synthesis, the majority of the asymmetric catalytic processes developed to date deal with these functional groups or the combination of both (especially a,bunsaturated carbonyl compounds). In contrast, in spite of the chemical versatility of the sulfonyl group, the sulfones have only recently begun to be systematically incorporated to the arsenal of highly valuable asymmetric catalytic methodologies. Within this context, the aim of this chapter is to highlight the undoubted interest of readily available achiral sulfones in the preparation of synthetically useful,


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9 Sulfones in Asymmetric Catalysis

highly enantioenriched compounds by means of asymmetric catalytic procedures. Not surprisingly (as will be described in detail in the main two sections of the chapter), most of the reported procedures involve the use of either alkenyl sulfones or ketosulfones in a variety of addition and cycloaddition processes. Due to the great versatility of the sulfonyl group in the further formation of CaC and CbC bonds, the resulting chiral sulfone products constitute very interesting intermediates in asymmetric synthesis. (The results described in this chapter cover the literature up to January 2007.)

9.2 Alkenyl Sulfones in Asymmetric Catalysis

Alkenyl sulfones – especially vinyl sulfones – have long been recognized as one the most useful types of electron-deficient alkenes in organic synthesis. The strong electron-withdrawing nature of the sulfonyl group determines the unique utility of vinyl sulfones as Michael acceptors and radical acceptors, and as 2pelectron donors in cycloaddition reactions, particularly in [4 þ 2], [3 þ 2], and [2 þ 2] processes [2, 3]. From a synthetic strategy point of view it is important to note that, unlike the typical carbonyl-based Michael acceptors, a,b-unsaturated sulfones act as two-carbon atom synthons, allowing the sulfone’s electronwithdrawing capability to be used temporarily. The varied and reliable methods for the synthesis of vinyl sulfones have been recently reviewed in detail [4], as well as its broad reactivity in organic synthesis [5, 6]. With regard to the use of vinyl sulfones in asymmetric catalysis, most precedents involve its participation in conjugate additions and cycloadditions. Within this context, it should also be noted that in the majority of cases the study of the reactivity has been limited to either benzenesulfonyl or toluenesulfonyl (tosyl) compounds. However, several recent lines of research developed independently by the groups of Carretero and Toru (see Sections 9.2.2 to 9.2.4) have shown that the use of (heteroaryl)sulfonyl groups with metal-coordinating capability can dramatically affect the reactivity of the vinyl sulfone moiety, thus allowing reactions that are not feasible with the traditional phenylsulfonyl or tosyl groups. Another key advantage of such heteroarylsulfones is that they undergo easy desulfonylation under mild reaction conditions. 9.2.1 Asymmetric Catalytic Conjugate Addition

In accordance with the paramount importance of conjugate addition as one of the most powerful and widely used synthetic tools for CaC bond construction, the development of enantioselective catalytic procedures for this cornerstone reaction has attracted a great deal of attention in recent years [7]. However, in contrast to the considerable efforts devoted to the development of chiral auxiliary-based stra-


tegies [8], the realization of enantioselective catalytic conjugate addition reactions to a,b-unsaturated sulfones has remained elusive until very recently. In 2003, Hayashi et al. reported that a,b-unsaturated phenyl sulfones were unreactive substrates towards the rhodium-catalyzed 1,4-addition of organoboron reagents [9]. The use of the more reactive aryltitanium triisopropoxide reagents led to the discovery of an unprecedented type of catalytic cine-substitution reaction of vinyl sulfones, affording allylarenes with excellent enantiocontrol from a,b-dialkyl substituted substrates (e.g. cylclohexenyl phenyl sulfone; Scheme 9.1). The results of deuterium-labeling studies suggested that, after coordination of the alkene to the chiral aryl–rhodium complex and subsequent olefin insertion, the resulting intermediate A undergoes b-hydrogen elimination of the synhydrogen on the neighboring carbon to give B. Subsequent syn hydrorhodation, followed by anti elimination of the sulfone from the resulting complex C, would produce the corresponding allylic arene [9].

Scheme 9.1 Asymmetric Rh-catalyzed cine-substitution of vinyl sulfones with aryltitanium reagents.

The first catalytic procedure for the enantioselective conjugate addition of carbon nucleophiles to a,b-unsaturated sulfones was reported in 2004. As a dramatic example of the influence of the arylsulfonyl group on the outcome of the reaction, by using metal-chelating heteroarylsulfones as substrates Carretero et al. developed a general methodology for the rhodium-catalyzed conjugate addition of organoboronic acids to a,b-unsaturated sulfones (Scheme 9.2) [10]. The methodology features broad scope, with regard to both the aryl- or alkenyl boronic acid and the sulfone substrate, excellent yields (typically above 90%), and high enantioselectivity ranging from 76% to 92% enantiomeric excess (ee). The success of the reaction relies heavily on the use of the (2-pyridyl)sulfonyl group as rhodium-coordinating unit and chiraphos as the optimal chiral ligand. Other

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Scheme 9.2 Rh-catalyzed conjugate addition of organoboronic acids to 2-pyridyl vinyl sulfones.

combinations of aryl- or heteroarylsulfonyl groups and chiral ligands led typically to an absence of reaction, or poorer reactivity and/or enantioselectivity profile. The 2-pyridylsulfonyl group also greatly facilitates its elimination through a modified Julia–Kocienski olefination reaction, providing a novel route to optically active allyl substituted alkenes. In a further study, this methodology was extended to the enantioselective construction of all-carbon stereogenic quaternary centers (Scheme 9.3) [11]. The known reluctance of b,b-disubstituted a,b-unsaturated sulfones to undergo intermolecular conjugate addition was overcome by combining the chelation-assisted effect of the 2-pyridylsulfonyl group with the use of a sterically low-hindered nucleophile, such as alkenylboronic acids. The reaction combines very high asymmetric induction and great stereochemical fidelity, in all cases the enantioselectivity being within the range of 88% to 499% ee. By taking advantage of the versatility of the sulfonyl group, the resulting adducts can be easily transformed into other synthetically useful functional groups such as alkenes, ketones or esters having quaternary stereogenic centers. The high efficiency of organocatalysis in asymmetric synthesis has also had a significant impact on the field of conjugate addition to vinyl sulfones. Alexakis and coworkers have pioneered the direct Michael addition of aliphatic aldehydes to vinyl sulfones using a new class of amine catalysts derived from 2,2 0 bipyrrolidine (i-PBP; Scheme 9.4) [12]. In the presence of 25 mol.% of catalyst loading, the transient chiral nucleophilic enamine intermediate leads to the corresponding 1,4-adducts in good yields (59–78%) and moderate to good enantioselectivities (53–80% ee). The reaction requires the highly electrophilic 1,1-bis(benzenesulfonyl)ethylene as the Michael acceptor, no conversion being observed with the simple phenyl vinyl sulfone even after prolonged reaction times. With regard to the nucleophile, best results were obtained with hindered


Scheme 9.3 Generation of quaternary stereogenic centers via asymmetric Rh-catalyzed conjugate addition to b,b-disubstituted a,b-unsaturated 2-pyridyl sulfones.

aldehydes such as isovaleraldehyde (75% ee) and 3,3-dimethylbutyraldehyde (80% ee), while smaller substrates such as acetaldehyde or the use of a,a-dialkylsubstituted aldehydes to generate quaternary carbon centers resulted in very low enantiocontrol (0–12% ee).

Scheme 9.4 Organocatalyzed asymmetric Michael addition of aldehydes to 1,1-bis(benzenesulfonyl)ethylene.

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The observed absolute configuration and strong dependence of the asymmetric induction with the steric hindrance of the nucleophile was rationalized by means of the acyclic synclinal models shown in Scheme 9.5. Here, it is assumed that there are favorable electrostatic interactions between the enamine nitrogen and the sulfone group. According to this model the less-hindered Si,Si transition state, affording the product with the observed (R)-configuration, would be more stable than that corresponding to the Re,Re approach.

Scheme 9.5 Proposed transition state models for diamine-catalyzed Michael addition.

Having discovered the excellent performance of cinchona alkaloid derivatives as catalysts for asymmetric conjugate additions to a,b-unsaturated carbonyl compounds [13] and nitroalkenes [14], the group of Deng has recently devised a highly enantioselective protocol for the Michael addition of a-substituted cyanoacetates to vinyl sulfones (Scheme 9.6) [15]. The prochiral nature of the nucleoplile renders this method a new and valuable catalytic entry for the enantioselective construction of all-carbon quaternary stereocenters. After an extensive screening of a variety of cinchona alkaloid derivatives, compound I (20 mol.%) was found to catalyze the Michael addition of a range of a-aryl a-cyanoacetates to phenyl vinyl sulfone at room temperature, providing the

Scheme 9.6 Asymmetric organocatalytic addition of a-substituted cyanoacetates to vinyl sulfones.


1,4-adduct in good to excellent yields (89–96%) and enantioselectivities in the range of 93 to 97% ee. The poor reactivity observed in the case of a-alkyl cyanoacetate nucleophiles (up to 17% conversion after 17 h) was compensated by enhancing the electrophilicity of the vinyl sulfone via the introduction of electronwithdrawing substituents on the aromatic ring. Thus, the conjugate addition of a-allyl- or a-methyl cyanoacetates to 3,5-bis(trifluoromethyl)phenylvinyl sulfone with I at 0 8C led to the sulfone adducts in good yields and 94% ee and 92% ee, respectively. The synthetic utility of the optically active chiral sulfone products has been demonstrated in the development of a versatile catalytic enantioselective approach to a,a-disubstituted amino acids, in which the sulfonyl group is removed by Julia-like olefination. More recently, a bifunctional thiourea–tertiary amine organocatalyst (IIa) proved also to be an efficient promoter for the conjugate addition of a-aryl acyanoacetates to phenyl vinyl sulfone, providing high levels of asymmetric induction (91–96% ee) at 40 8C (Scheme 9.6) [16]. In this case, the reaction of the less-reactive a-alkyl cyanoacetates was only achieved by employing the highly electrophilic bis(sulfonyl)ethylene as the Michael acceptor in combination with the more rigid catalyst IIb (72–96% ee; Scheme 9.7). The possibility of hydrogen-bonding interactions between the NH of the thiourea and the sulfone functionality has been hypothesized by the authors to explain the catalyst activity [17, 18].

Scheme 9.7 Asymmetric thiourea-catalyzed addition of a-substituted cyanoacetates to vinyl sulfones.

9.2.2 Asymmetric Catalytic Conjugate Reduction

Since the first protocol reported by Buchwald and coworkers in 1999, the enantioselective copper-catalyzed conjugate reduction of b,b-disubstituted a,b-unsaturated carbonyl compounds has experienced a dramatic growth and development [19], including the recently achieved extension of this methodology to other Michaeltype acceptors such as a,b-unsaturated nitriles and nitro compounds. Owing to the high levels of efficiency and asymmetric induction typically obtained, this methodology currently rivals the catalytic asymmetric conjugate addition of organometallic species to b-substituted Michael acceptors. As in other catalytic asymmetric processes, vinyl sulfones have lately been incorporated into the arsenal of

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electrophiles that participate in this important reaction, most likely due to the lower reactivity of vinyl sulfones compared to that of a,b-unsaturated carbonyl compounds. Recently, Carretero et al. have developed a general protocol for the copper-catalyzed enantioselective conjugate reduction of b,b-disubstituteda,b-unsaturated sulfones that solves this reactivity problem by using a metalcoordinating (2-pyridyl)sulfonyl group instead of the typically used (yet unreactive in this transformation) phenylsulfonyl or tosyl groups (Scheme 9.8) [20]. This reaction nicely complements the catalytic asymmetric conjugate addition of boronic acids to b-substituted a,b-unsaturated 2-pyridyl sulfones (see Schemes 9.2 and 9.3). In the presence of CuCl/t-BuONa/Binap as the catalytic system (5 mol.%) and PhSiH3 as hydride source, a wide variety of b-aryl-b-alkyl- and b,b-dialkyl-a,bunsaturated 2-pyridyl sulfones were reduced in excellent chemical yields and enantiomeric excesses (both typically above 90%). The 2-pyridyl unit proved to be essential for the success of the reaction, as the analogous phenyl vinyl sulfones proved to be inert under the optimal reaction conditions. The synthetic potential of this methodology has been demonstrated by the easy transformation of one of the resulting chiral b-substituted 2-pyridyl sulfone into a variety of functionalized chiral compounds.

Scheme 9.8 Asymmetric conjugate reduction of b,b-disubstituted-a,bunsaturated 2-pyridyl sulfones.

9.2.3 Asymmetric Catalytic Radical Addition

Toru and colleagues have shown that the correct choice of a metal-coordinating (heteroaryl)sulfonyl group enables the development of asymmetric radical reactions of vinyl sulfones. Here, the discriminative coordination of a chiral Lewis acid to one of the two enantiotopic sulfonyl oxygens is proposed as the origin of


asymmetric induction. The enantioselective allylation of the a-sulfonyl-stabilized radical derived from N-benzylbenzimidazolyl vinyl sulfone, generated by treatment with tert-butyliodide and triethylborane as radical initiator, with diallyldibutyltin took place with 80% yield and 84% ee in the presence of stoichiometric amounts of Zn (OTf )2/Ph-BOX as chiral Lewis acid (Scheme 9.9) [21]. Calculations of simplified radical structures (MOPAC/PM3 and MM/DREIDING 2.21) showed that coordination of zinc complex to the pro-(R) oxygen of the sulfone moiety in the s-trans radical intermediate provides the lowest energy alternative. In the plausible transition state the pro-(R) oxygen of the sulfone and the nitrogen atom of the benzimidazolyl group are coordinated with the tetrahedral Zn, so that the diallyldibutyltin approaches the less-hindered Si face to give the product with (S)-configuration through an SH2 0 pathway. The higher performance of the N-benzyl-2-benzimidazolyl group over the 2-benzimidazolyl or 2-pyridyl units was attributed to its more sterically demanding nature.

Scheme 9.9 Enantioselective allylation of a-sulfonyl radicals controlled by a chiral Lewis acid.

This strategy was later extended to the Zn (OTf ) 2/Ph-BOX-promoted hydrogen atom transfer to a-sulfonyl radicals generated from the alkyl radical addition to substituted benzimidazolyl vinyl sulfones (Scheme 9.10) [22], and the radical cyclization of benzimidazolyl iodoalkenyl or iodoalkadienyl sulfones (Scheme 9.10)

Scheme 9.10 Asymmetric radical addition to benzimidazolyl vinyl sulfones.

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[23]. In both cases, moderate to good enantioselectivities were typically obtained. The stereochemical course of these reactions were discussed in similar terms as in the previous case. 9.2.4 Asymmetric Catalytic Cycloadditions

Driven by the wide-ranging significance of chiral non-racemic pyrrolidine derivatives both for pharmacological purposes and as synthetic intermediates, the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient alkenes catalyzed by substoichiometric amounts of chiral Lewis acids has been the subject of intense research activity since it was first reported in 2002 [24]. In 1995, Grigg described the reaction of phenyl vinyl sulfone with (e)-alanine methyl ester 2-naphthaldehyde Schiff base in the presence of stoichiometric amounts of AgOTf and a chiral diphosphine; this produced the corresponding endo-pyrrolidine cycloadduct in 70% ee (Scheme 9.11) [25]. This scattered example represents the first report on the participation of a vinyl sulfone in an enantioselective Lewis acid-promoted 1,3-dipolar cycloaddition of azomethine ylides.

Scheme 9.11 The first asymmetric 1,3-dipolar cycloaddition of an azomethine ylide with a vinyl sulfone catalyzed by a chiral Lewis acid.

Very recently, in 2006, the authors’ group described a general protocol for the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides to a,bunsaturated sulfones [26]. Good yields, complete exo-selectivities, and high enantioselectivities (typically in the rage of 65–86% ee) were attained with CuClO4/ Taniaphos (5 mol.%) as the optimal catalyst system (Scheme 9.12). This procedure features wide substitution tolerance at the azomethine ylide, both at the iminic carbon (R1) and at the a-position (R2), although the reaction proved to be rather sensitive to steric hindrance. Thus, b-substituted vinyl sulfones resulted in being very low reactives, except for those substituted with electron-withdrawing groups (e.g. a CF3 moiety). Interestingly, the enantiopurity of the resulting 3sulfonylpyrrolidines can be enhanced to 499% ee after a single recrystallization. Following N-methylation and further reductive desulfonylation with Na (Hg), these cycloadducts are readily transformed in good yields into optically pure 2,5disubstituted pyrrolidines. It should be noted that, in the global sequence cycloaddition þ desulfonylation, the vinyl sulfone acts as a synthetic equivalent of ethylene, a type of unactivated olefin unsuitable for the reaction with azomethine ylides.


Scheme 9.12 Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides to vinyl sulfones.

Allyl sulfones have also shown to participate in catalytic asymmetric [3 þ 2] cycloadditions. Using the Tsuji approach [27] for the generation of sulfonesubstituted Pd-trimethylenemethane (TMM) complexes, Yamamoto and coworkers developed the first catalytic enantioselective variant [28] of Trost’s palladiumcatalyzed [3 þ 2] cycloaddition of TMM synthons with electron-deficient olefins [29] to produce exo-methylenecyclopentanes (Scheme 9.13). The cycloaddition of 2-(phenylsulfonylmethyl)-2-propenyl carbonate with methyl acrylate or methyl vinyl ketone in the presence of a combination of Pd2(dba) 3CHCl3 (1.5 mol.%) and a chiral ferrocenyl diphosphine amine (3.3 mol.%) as catalyst led to inseparable mixtures of pyrrolidines with moderate diastereoselectivities and up to 78% ee.

Scheme 9.13 Pd-catalyzed asymmetric [3 þ 2] cycloadditions of a sulfonyl trimethylenemethane synthon.

9.2.5 Asymmetric Catalytic Dihydroxylation and Epoxidation Reactions

Because of its high reliability and functional group tolerance, the asymmetric dihydroxylation (AD) reaction has become an essential step in the enantioselec-

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tive introduction of a vicinal diol moiety in organic molecules [30]. Sharpless and coworkers have also developed a modified process for the osmium (VIII)catalyzed dihydroxylation of olefins under acidic conditions that allows electrondeficient substrates to be converted into the corresponding diols much more efficiently than under the standard mildly basic process [31]. The b,g-unsaturated sulfones are among those olefins bearing an electron-withdrawing functionality that benefits most from acidifying the reaction medium with 25 mol.% citric acid as additive. As an example, the yield of the dihydroxylation of allyl phenyl sulfone was increased from less than 40% to 78% under these new reaction conditions. Despite the AD being an ‘‘old’’ process, its application to a,b-unsaturated sulfones was not reported until 2003 [32]. Under the standard Sharpless conditions, this reaction afforded enantioenriched a-hydroxyaldehydes, as well as their dimeric species, as a result of the spontaneous 1,2-elimination of arylsulfinic acid from the initially formed diol. These mixtures of a-hydroxyaldehydes and homodimeric species were directly transformed into g-hydroxy-a,b-unsaturated esters in moderate yields and high enantioselectivities via Horner–Wadsworth– Emmons (HWE) olefination (Scheme 9.14). Alternatively, optically active furan2(5H)-ones are also accessible, albeit in low yield, through the cis-selective Still– Gennari variant of the HWE reaction.

Scheme 9.14 The asymmetric dihydroxylation (AD) reaction of vinyl sulfones and its application to the synthesis of g-hydroxy-a,b-unsaturated esters and furan-2(5H)-ones.

This strategy for the generation of enantioenriched a-hydroxy aldehydes has recently been applied to the preparation of unsaturated anti-1,2-amino alcohols in high enantiomeric purity (83–95% ee) through a borono-Mannich reaction with b-styryl boronic acids in the presence of primary amines (Scheme 9.15) [33]. The synthetic potential of these valuable chiral building blocks has been demonstrated in the development of a formal synthesis of the natural product ()swainsonine. Owing to its electron-poor nature, the double bond of a vinyl sulfone does not undergo facile epoxidation when treated with electrophilic peracid reagents (e.g.


Scheme 9.15 The AD reaction of vinyl sulfones and applications to the enantioselective synthesis of amino alcohols.

MCPBA). Like typical electron-deficient olefins, nucleophilic reagents are generally needed to epoxidize vinyl sulfones. Ba¨ckvall et al. elegantly demonstrated the chemoselective epoxidation of dienyl sulfones with two electronically dissimilar double bonds, such as the 2-phenylsulfonyl-1,3-cyclohexadiene. MCPBA led to the highly selective epoxidation of the b,g-unsaturation (80% isolated yield) while alkaline hydrogen peroxide (H2O2/NaOH) afforded (with complete regiocontrol) the a,b-epoxy sulfone (97% yield) [34]. The nucleophilic combination t-BuOOH/ n-BuLi is often used in the epoxidation of a,b-unsaturated sulfones [35]. Within a research program oriented towards the synthesis of polypropionatecontaining natural products, Fuchs and coworkers have elegantly exploited the potential of the asymmetric epoxidation of 2-sulfonyl-1,3-cycloalkadienes under Jacobsen conditions (Scheme 9.16). In 1997, the group found that the asymmetric epoxidation of cyclohexadienyl [36] and cycloheptadienyl [36a, 37] sulfones

Scheme 9.16 Asymmetric catalytic epoxidation of cyclic dienyl sulfones.

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gave rise to the corresponding b,g-epoxy sulfones in good yields (72–80%) and high enantioselectivity (495% ee). Both enantiomeric antipodes of the product are readily accessible by application of the appropriate commercially available chiral catalyst. A double stereoselection was also achieved in the epoxidation of chiral dienyl sulfones with Jacobsen’s catalyst, to afford highly functionalized epoxy cyclohexenyl- [36b] and cycloheptenyl [37, 38] sulfones (Scheme 9.16). More recently, an optimized procedure suitable for large-scale synthesis (up to 1 mol) has been developed for the epoxidation reaction of cycloheptadienyl sulfone, with outstanding enantiocontrol (499% ee) [39]. The synthesis of optically active a,b-epoxy sulfones by direct catalytic asymmetric epoxidation of a,b-unsaturated sulfones was accomplished in 2004 by Roberts and colleagues [40] by applying a modified Julia–Colonna procedure (Scheme 9.17) [41]. Under phase-transfer catalysis, poly-(L)-leucine was found to sequester hydrogen peroxide from a basic aqueous solution, resulting in a polyleucine/ peroxide-containing gel that can epoxidize a small range of aryl vinyl sulfones in good to excellent enantioselectivity (70–95% ee). Alternatively, the asymmetric epoxidation of a,b-unsaturated sulfones can be carried out with potassium hypochlorite in the presence of N-9-anthracenylmethyl cinchonidinium salts as asymmetric phase-transfer catalysts [42], following a modified procedure similar to that previously reported for a,b-unsaturated ketones [43]. After extensive catalyst and reaction conditions optimization, the epoxidation of (E )-phenyl styrylsulfone could be achieved with 96% conversion and 83% ee after three days. A much lower enantioselectivity was observed in the reaction of phenyl vinyl sulfone (48% ee) and (Z)-phenyl styrylsulfone (16% ee), the latter affording exclusively the cis epoxide. In contrast, cis a,b-unsaturated ketones yielded trans epoxides under identical reaction conditions.

Scheme 9.17 Asymmetric catalytic epoxidation of vinyl sulfones.

9.3 Ketosulfones

9.3 Ketosulfones 9.3.1 Asymmetric Reduction of Ketosulfones

The asymmetric metal-catalyzed reduction of ketones has been a central topic in asymmetric catalysis over the past two decades, and today represents one of the most effective methods for preparing optically active secondary alcohols. Several approaches based on asymmetric hydrogenation [44], transfer hydrogenation [45] or metal hydride asymmetric reductions [46] have been successfully applied in the reduction of a wide range of differently substituted ketones. Optically active b-hydroxy sulfones have found widespread use as building blocks for organic synthesis, being effectively applied to the synthesis of lactones [47], tetrahydrofurans [48], allylic alcohols [49] or epoxides [48]. Owing to the importance of these chiral synthons, a variety of methods for their preparation have been reported, among which the enantioselective reduction of b-ketosulfones is the most convenient. Several groups have reported the preparation and application of tartaric acid– NaBr–modified Raney nickel (TA–NaBr–MRNi) for the enantioselective hydrogenation of ketones [50]. The first example of the asymmetric hydrogenation of a bketosulfone, using this catalyst system, was reported in 1981 [51]. The reduction occurred in quantitative yield, although the enantioselectivity was only moderate (67–71% ee) (Scheme 9.18).

Scheme 9.18 TA–NaBr–MRNi-catalyzed enantioselective hydrogenation of b-ketosulfones.

Chiral ruthenium complexes are among the most effective catalysts for the enantioselective hydrogenation of ketones. In 1999, Genet and coworkers described the synthesis of chiral b-hydroxysulfones via an enantioselective rutheniumcatalyzed hydrogenation [52]. The chiral Ru (II) catalyst was prepared in situ from the commercially available (COD)Ru (methylallyl)2 and a chiral diphosphine in the presence of HBr [53]. The optimal ligand (S)-MeO-BIPHEP provided quantitative yields and excellent asymmetric inductions (495% ee) for a variety of aliphatic and aromatic b-ketosulfones, allowing the reaction to be conducted at relatively low catalyst loadings (1 mol.%). Whilst for aliphatic b-

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ketosulfones the reaction proceeded smoothly in refluxing methanol at atmospheric pressure of hydrogen, in the case of aromatic ketones the reduction required higher pressures (Scheme 9.19).

Scheme 9.19 Ru-catalyzed enantioselective hydrogenation of b-ketosulfones.

Very recently, the highly enantioselective Rh-catalyzed hydrogenation of aromatic b-ketosulfones has been described using a new type of biferrocene diphosphine ligand (Scheme 9.20) [54]. The hydrogenation was performed using 1 mol.% of Rh (COD) 2SbF6 as metal source and 1.1 mol.% of ligand, in isopropanol at 40 8C, and hydrogen pressure (85 bar). Under these conditions enantioselectivities ranging from 72.4 to 97.9% ee were achieved for a variety of substrates, with the aromatic rings substituted with electron-withdrawing groups providing the best results.

Scheme 9.20 Biferrocene diphosphine Rh-catalyzed asymmetric hydrogenation of b-ketosulfones.

The asymmetric reduction of ketosulfones with chiral boron reagents is also a very useful method for the preparation of enantiomerically enriched hydroxysulfones. In 1990, Corey and colleagues described the catalytic reduction of a g-keto-a, b-unsaturated sulfone using a modification of the previously described oxazaborolidine-catalyzed asymmetric protocol [55]. The asymmetric reduction of the g-ketosulfone employing catecholborane as stoichiometric reductant and a chiral oxaazoborolidine as catalyst in toluene at 78 8C gave rise to the corresponding alcohol with 495% yield and 91% ee (Scheme 9.21). The optical purity of this alcohol was improved to 498% ee by a single recrystallization. g-Hydroxya,b-unsaturated sulfones and derivatives represent very useful compounds in

9.3 Ketosulfones

stereoselective conjugate additions of nucleophiles and radicals [56]. Other alternatives for the preparation of these versatile intermediates in optically pure form are the dehydration of chiral b,g-dihydroxy sulfones [57], and the kinetic lipasemediated resolution of racemic g-hydroxy-a,b-unsaturated sulfones [58].

Scheme 9.21 Oxazaborolidine-catalyzed borane asymmetric reduction of a g-keto-a,b-unsaturated sulfone.

By applying the oxazaborolidine-catalyzed asymmetric reduction of ketones, Cho and coworkers have reported an efficient synthesis of optically active bhydroxysulfones by the reduction of b-ketosulfones, employing N-ethyl-Nisopropylaniline as the borane source (Scheme 9.22) [59]. With this catalyst system the reduction of aromatic b-ketosulfones afforded the corresponding bhydroxysulfones with almost complete enantioselectivity (498% ee). Lower asymmetric inductions were obtained in the reduction of the aliphatic analogues (73–87%), except for the case of very bulky aliphatic ketones (i.e. tert-butyl ketone analogue).

Scheme 9.22 Oxazaborolidine-catalyzed borane asymmetric reduction of b-ketosulfones.

In order to make the chemical process more environmentally friendly, one important goal in asymmetric catalysis is to prepare recyclable chiral catalysts by immobilizing the ligand on an insoluble support [60]. In this area, Zhao and colleagues have reported the enantioselective reduction of prochiral ketones with BH3SMe2 or NaBH4/Me3SiCl in the presence of a chiral polymer-supported sulfonamide (Scheme 9.23) [61]. The application of this procedure to the reduction of

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b-ketosulfones, using 25 mol.% of polymer-supported sulfonamide (200–400 mesh, 2% DVB, 2.29 mmol g1 N) as catalyst, in refluxing tetrahydrofuran (THF), provided the corresponding b-hydroxysulfones in excellent chemical yields and high enantioselectivities, especially from aromatic and bulky aliphatic b-ketosulfones [62]. Interestingly, in a model reaction it was proved that the polymer-supported sulfonamide could be recovered by filtration and reused at least five times with little or no loss of reactivity and enantioselectivity.

Scheme 9.23 Asymmetric reduction of b-ketosulfones catalyzed by a polymer-supported chiral sulfonamide.

Finally, among other interesting methods for the enantioselective preparation of b-hydroxysulfones, mention should be made of the asymmetric reduction of b-ketosulfones, using baker’s yeast [63], and the kinetic resolution of racemic b-hydroxysulfones [64]. 9.3.2 Diels–Alder Reactions

The combination of a bidentate dienophile (i.e. acryloyl oxazolidinones) and a chiral Lewis acid has provided excellent results in asymmetric catalytic Diels– Alder reactions [65]. In this area, some interesting precedents have been set involving the use of alkenyl b-ketosulfones as bidentate dienophiles. Furthermore, the complexation of one oxygen of the sulfonyl group to the metal center generates a new chiral center which may amplify the selectivity of the reaction [66]. Wade and Kanemasa have applied this principle to the titanium-promoted asymmetric hetero Diels–Alder reaction of alkenyl b-ketosulfones with vinyl ethers [67]. Thus, the reaction of these b-ketosulfones with an excess of a vinyl ether in the presence of 10 mol.% of a titanium TADDOL complex afforded the cis dihydropyran adduct in good yields and moderate to high asymmetric induction. The enantioselectivity of the process was highly dependent on the substitution at the metal atom, the titanium bromide catalyst being more effective than the corresponding chloride catalyst (Scheme 9.24). The participation of the complex intermediate III in which the carbonyl group and one of the oxygens at sulfur coordinate the titanium atom has been tentatively postulated.

9.3 Ketosulfones

Scheme 9.24 Asymmetric hetero Diels–Alder reaction of alkenyl b-ketosulfones with vinyl ethers.

In a later study the same research group extended the use of these sulfonylfunctionalized chelating enones to the asymmetric Diels–Alder reaction with cyclopentadiene [68]. The reaction between (E )-1-phenylsulfonyl-3-penten-2-one and cyclopentadiene, catalyzed by the different titanium–TADDOL complexes IV, occurred with excellent chemical yield and endo-selectivity, but with very poor enantiocontrol (16% ee). Interestingly, when using much bulkier titanium– TADDOL complexes (especially the naphthyl analogues IVc and IVd) the cycloadditions took place with complete enantioselectivity (Scheme 9.25).

Scheme 9.25 Asymmetric Diels–Alder reaction of alkenyl b-ketosulfones with cyclopentadiene.

9.3.3 Michael–Aldol Reactions

Today, organocatalysis is a fundamental and growing field in asymmetric catalysis [69], and in this respect Jorgensen and coworkers have described the organo-

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Scheme 9.26 Asymmetric organocatalytic Michael–aldol reaction of b-aryl a,b-unsaturated ketones with 2-phenylsulfonylacetophenone.

catalytic asymmetric Michael reaction of soft nucleophiles to a,b-unsaturated ketones catalyzed by chiral imidazoline catalysts [70]. Interestingly, optically active cyclohexanones (with up to four chiral carbon centers) were stereoselectively formed through a domino Michael–aldol reaction using b-ketoesters as nucleophiles [71]. This methodology was successfully extended to other nucleophiles, such as b-diketones and b-ketosulfones [72]. Some examples of the addition of 2-phenylsulfonylacetophenone to 4-aryl-3-butenones catalyzed by a chiral imidazoline catalyst are shown in Scheme 9.26. Here, in all cases a single cyclohexanone diastereomer was formed, with excellent enantioselectivity (86–99% ee).

Scheme 9.27 A working model for the asymmetric organocatalytic Michael–aldol reaction.

9.4 a-Diazo-b-Ketosulfones

Jorgensen et al. also suggested that the catalyst plays three functions during the reaction: (1) formation of the chiral iminium salt of the Michael acceptor; (2) deprotonation of the nucleophile precursor; and (3) behavior as a base in the intramolecular aldol reaction (Scheme 9.27).


The importance of a-diazocarbonyl reagents has been clearly shown during recent years and, in fact, these reagents are ideal carbene precursors for several transition metal-catalyzed processes including cyclopropanations and CaH insertion reactions [73]. The first examples of the use of a-diazo-b-ketosulfones in asymmetric catalysis were reported in 1990 [74]. In these pioneering studies the rhodium (II) carboxylates derived from mandelic acid and proline were used as chiral catalysts. Starting from model alkyl and alkenyl substrates, both the intramolecular CaH insertion and the cyclopropanation occurred with very high yield, but very low enantioselectivity (Scheme 9.28).

Scheme 9.28 First precedents on the enantioselective intramolecular CaH insertion and cyclopropanation of a-diazo-b-ketosulfones.

Surprisingly, no further applications of a-diazo-b-ketosulfones in asymmetric catalysis were reported until 2003, when Nakada and colleagues described the copper-catalyzed intramolecular cyclopropanation [75]. Nakada’s group found that the use of a chiral copper catalyst formed in situ by mixing CuOTf and an enantiomerically pure bisoxazoline provided excellent enantioselectivities in the intramolecular cyclopropanation of a-diazo-b-ketosulfones, especially using the

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very bulky mesityl sulfones. With this type of bulky substrate the asymmetric inductions were higher than those encountered with a-diazo-b-keto esters, showing the beneficial role exerted by the sulfonyl group. Some relevant examples, showing the great structural scope and high enantiocontrol of this process of synthesis of bicyclo [3.1.0]hexanes, are shown in Scheme 9.29. This approach was later extended to the enantioselective preparation of bicyclo [4.1.0]heptanes, although the yields were moderate due to the competing intramolecular CaH insertion reaction [76].

Scheme 9.29 Cu-catalyzed asymmetric intramolecular cyclopropanation of a-diazo-b-ketosulfones.

The 2,5-cyclohexadiene derivatives are other interesting type of substrates, affording tricycle[4.3.0.0]nonenone compounds [75]. As revealed by the previous examples, the appropriate choice of bisoxazoline ligand and sulfone substitution were crucial to achieving a high stereocontrol. The best results were obtained with the combination of the mesityl sulfone and the ligand Vd (Scheme 9.30).


Scheme 9.30 Enantioselective formation of tricyclic compounds.

In order to develop an efficient access to the synthesis of a family of natural products possessing a stereogenic quaternary carbon bearing an aromatic group, the catalytic asymmetric intramolecular cyclopropanation reaction of aryl substituted a-diazo-b-ketosulfones was examined under the usual conditions [77]. The enantioselectivity of the reaction proved to be highly dependent on the substitution at the aryl group. Thus, while a racemic product was obtained from the substrate having a p-methoxyphenyl moiety, the asymmetric induction was moderate with methylenedioxy or tert-butyldimethylsilyloxy aryl groups, and a high enantiocontrol was observed when benzoate groups were present (Scheme 9.31).

Scheme 9.31 Cu-catalyzed asymmetric cyclopropanation of aryl substituted a-diazo-b-keto mesitylsulfones.

The synthetic potential of this methodology has been clearly demonstrated by the synthesis of several natural products. As shown in Scheme 9.32, some easily available sulfonyl cyclopropanes were efficiently converted into enantiopure methyl jasmonate [78], allocyathin [79], and malyngolide [80] by applying relatively short synthetic sequences.

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Scheme 9.32 Applications in enantioselective natural product synthesis.

9.5 Miscellaneous: Other Substituted Sulfones

The Darzens reaction is a very useful tool for the preparation of epoxides substituted with electron-withdrawing groups [81]. Besides a-haloesters and ahaloketones, a-halosulfones are also appropriate substrates for this reaction [82]. The first examples of a catalytic asymmetric Darzens reaction between chloromethyl phenyl sulfone and carbonyl compounds were described by Arai and coworkers, who used a chiral quaternary ammonium salt as the phase-transfer catalyst [83]. The reaction proceeds smoothly in the presence of KOH as base and 10 mol.% of a chiral quaternary salt, derived from quinine, to afford the epoxides in high yields. Among the tested quaternary ammonium salts, those having a trifluoromethyl group at C-4 provided the best enantioselectivity. Under these optimized reaction conditions, the reaction of a variety of aromatic aldehydes led selectively to the trans a,b-epoxysulfone with enantioselectivities up to 81% ee. This catalyst system has also been applied to ketones, although in this case a cis/trans mixture of epoxysulfones was usually obtained in moderate yield and enantioselectivity (Scheme 9.33) [84]. Among other a-functionalized sulfones used in asymmetric catalytic processes, the a-amido sulfones are worthy of note [85]. These compounds are bench-stable solids that can be readily obtained by the condensation of carbamates and aryl sulfinates with the appropriate aldehyde [86]. In their applications in asymmetric catalysis, the sulfonyl group does not participate directly in the asymmetric step since, under basic conditions, the sulfone moiety simply acts as a leaving group, providing a very convenient approach for the in-situ generation of N-acyl imines, including the highly labile aliphatic a-enolizable substrates. These acyl imine

9.6 Summary

Scheme 9.33 Asymmetric Darzens reaction of chloromethyl phenyl sulfone under phase-transfer-catalyzed conditions.

synthons have been broadly used in asymmetric catalytic additions of stabilized nucleophiles, such as enolates and their synthetic equivalents (asymmetric Mannich reaction) [87], cyanide (Strecker reaction) [88], nitroalkanes (aza-Henry reaction) [89], acyl-anion equivalents [90], and organozinc reagents [91]. Some representative examples of these asymmetric reactions are shown in Scheme 9.34.

9.6 Summary

In conclusion, during recent years functionalized sulfones – and especially vinyl sulfones and b-keto sulfones – have become highly appealing types of substrates in asymmetric catalysis. A wide variety of synthetically useful processes has been developed, including asymmetric epoxidations, cycloadditions, conjugate additions and reductions of vinyl sulfones, the asymmetric reduction of keto sulfones, and the asymmetric cyclopropanation of a-diazo-b-keto sulfones. In some of these metal-catalyzed processes the presence of a metal-coordinating sulfone (e.g. a 2-pyridylsulfone), instead of the typical phenyl or p-tolyl sulfones, has allowed a dramatic increase in the reactivity of the process and in the control of stereoselectivity. Due to the very wide chemical versatility of the sulfones in the formation of CaC bonds (through a-sulfonyl carbanion) and CbC bonds (through Julia-type reactions), following the asymmetric catalytic step the resultant enantioenriched chiral sulfones constitute very interesting synthetic intermediates in the enantioselective synthesis of complex compounds.

315

316


Scheme 9.34 a-Amido sulfones in asymmetric catalysis.

References

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9 Sulfones in Asymmetric Catalysis J. W. Kampf, J. Am. Chem. Soc. 1993, 115, 2622. 87 For some recent studies, see: (a) F. Fini, L. Bernardi, R. P. Herrera, D. Pettersen, A. Ricci, V. Sgarzani, Adv. Synth. Catal. 2006, 348, 2043; (b) T. Ollevier, E. Nadeau, J.-C. Eguillon, Adv. Synth. Catal. 2006, 348, 2080; (c) J. Song, H.-W. Shih, L. Deng, Org. Lett. 2007, 9, 603. 88 (a) R. P. Herrera, V. Sgarzani, L. Bernardi, F. Fini, D. Pettersen, A. Ricci, J. Org. Chem. 2006, 71, 9869; (b) T. Ooi, Y. Uematsu, J. Fujimoto, K. Fukumoto, K. Maruoka, Tetrahedron Lett. 2007, 48, 2007. 89 (a) F. Fini, V. Sgarzani, D. Pettersen, R. P. Herrera, L. Bernardi, A. Ricci,

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10 Asymmetric Reaction of a-Sulfenyl Carbanions Shuichi Nakamura and Takeshi Toru

Abstract

This chapter describes electrophilic carbon–carbon bond formations utilizing a-sulfenyl carbanions. Sulfides have synthetically interesting aspects, such as easy formation of the a-sulfenyl carbanion, high reactivity of the carbanion toward various electrophiles, and facile cleavage of the sulfenyl group from the product. As a result, a-sulfenyl carbanions have been considered in several synthetic strategies and thus employed in the preparation of both functionalized products and biologically active compounds, notably in enantioselective syntheses. The configurational stability of a-sulfenyl carbanions and the reaction pathway of their reactions are discussed to elucidate the chiral induction mechanism in enantioselective reactions. Enantioselective reactions of configurationally labile a-carbanions of sulfides and thiocarbamates in the presence of a stoichiometric quantity of chiral ligands are described in detail. The enantioselective reactions of a-carbanions of thioacetals are also included.

10.1 Asymmetric Reactions of a-Sulfenyl Carbanions 10.1.1 Introduction

The significant property that the sulfenyl group stabilizes negative charges on the a-carbon, has made a-sulfenyl carbanions the targets of intensive studies to develop methods forming carbon–carbon bonds. a-Sulfenyl carbanions react with a wide range of electrophiles to produce new sulfenyl compounds which, when obtained, are generally stable towards heat, acids, bases, and reducing reagents. An easy cleavage of the CaS bond removes the sulfenyl group after the reaction. The oxidation of sulfides to sulfoxides, followed by thermal b-elimination of the sulfinyl group, affords olefins. The sulfur in sulfides can be easily alkylated using Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

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10 Asymmetric Reaction of a-Sulfenyl Carbanions

Figure 10.1 Biologically active compounds and chiral ligands.

the Meerwein reagent to afford sulfonium salts, which are then subjected to substitution by an intramolecular or an intermolecular nucleophilic attack. In this way, sulfides have been employed not only in a number of synthetic strategies but also in the preparation of many functionalized products and biologically active compounds. In addition to the above-mentioned synthetic utility of sulfides, pharmaceutically important compounds which have a chirality a to the sulfenyl group are known (e.g. PNU-142721, diltiazem, and montelukast sodium). During recent years, several chiral ligand templates having a-chirality of sulfides have undergone intensive study (see Figure 10.1). The a-sulfenyl carbanions are generated by treatment with alkyllithium in an aprotic solvent with an appropriate ligand. Corey and Seebach reported the first

Scheme 10.1 Lithiation of thioanisole and the stabilization effect of the a-sulfenyl carbanion.

10.2 Racemization Mechanism and Configurational Stability of a-Sulfenyl Carbanions

straightforward preparation of the a-sulfenyl carbanion of thioanisole 2 with BuLi and 1,4-diazabicyclo [2.2.2]octane (DABCO) in tetrahydrofuran (THF) at 0 8C (Scheme 10.1) [1]. The stabilization effect of substitution of the phenylsulfenyl group is estimated to be about 2–10 pK a units [2]. Today, it has been generally accepted that this stabilizing effect is derived from the interaction with negative hyperconjugation between the non-bonding orbital and s* orbital for the SaC bond [3], as well as the sulfur’s polarizability (Scheme 10.1) [4]. A further important point demonstrated by both calculated and crystallographic results is that the SaC bond in all cases is shorter in the lithiated species than in the non-lithiated parent compounds by the n-s* hyperconjugation [3b,d, 5]. Therefore, the a-proton acidity of sulfides is generally higher than that of ethers (see Table 10.1) [6, 7], although the electron negativity of oxygen is stronger than that of sulfides (electron negativity: oxygen: 3.5; sulfur: 2.5; carbon: 2.5). Although the a-proton of sulfides is less acidic than that of sulfoxides and sulfones, the a-proton of sulfides can be easily deprotonated by alkyllithiums or aryllithiums. In general, aryl sulfides show higher acidity in comparison with alkyl sulfides due to their strong n-s* hyperconjugation. Thioacetals are definitely more acidic than thioethers.

Table 10.1 Equilibrium acidities in dimethylsulfoxide.

Parent acid

pKa

Parent acid

pKa

Parent acid

pKa

PhSCH3 CH4 PhSCH2Ph PhSCHPh2 (PhS)2CHPh

42.0 56.0 30.8 26.7 23.0

PhOCH3 PhH PhSOCH2Ph PhSCH2SPh (PhS)3CH

49.0 43.0 27.2 30.8 22.8

CH3SCH3 (CH3)2CH2 PhSO2CH2Ph 1,3-Dithiane (PrS)3CH

45.0 51.0 23.4 39.0 31.3


Carbanions a to the sulfur are configurationally rather labile in comparison with a-oxy carbanions. The racemization mechanism of a-sulfenyl carbanions is essentially different from that of a-oxy carbanions. Sulfur, in being less electronegative than oxygen, ensures that a-sulfenyl carbanions have a higher s character than a-oxy carbanions [8], and the negative charge of a-sulfenyl carbanions is partially stabilized by the n-sS-C* negative hyperconjugation [3]. Therefore, a-sulfenyl carbanions may have more sp2-like orbitals, which is closer to the stereochemistry at the transition state of inversion for carbanionic centers in comparison with a-oxy carbanions. Thus, the inversion of a-sulfenyl carbanions occurs more easily than does that of a-oxy carbanions. However, the activation energy of racemization of

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Figure 10.2 Racemization mechanism of a-sulfenyl carbanions.

a-sulfenyl carbanions does not correspond to that of the transition state of the inversion process. Hoffmann and coworkers have studied in detail the mechanism of racemization of a-lithiated sulfides by using dynamic NMR [9] and molecular calculation [10]. These carbanions adopt an antiperiplanar arrangement of the CaLi and SaR bonds in order to maximize delocalization by the n-sS-C* negative hyperconjugation. Their racemization process is composed of several distinct steps: (a) dissociation of a lithium cation from the carbanionic center to form a separated or a contact ion pair; (b) inversion of configuration of the carbanion; (c) subsequent rotation about the CaS bond (or vice versa (c) first, rotation and (b) second, inversion); and finally (d) recombination of the carbanion with the Li cation (Figure 10.2).Hoffmann and coworkers have observed that the racemization rate of a-lithiated sulfides having bulkier substituents on the heteroatom increases the configurational stability (Figure 10.3) [9b, 10, 11]. These results imply that the rotation about the CaS bond (Figure 10.2, step c) should be the rate-determining step of racemization [10]. Reich and Dykstra have obtained the experimental data on the racemization mechanism of a-sulfenyl carbanions by surveying dynamic NMR in the coalescence of the diastereotopic methylene groups of the a-silyl-a-sulfenyl carbanion [12]. A barrier to racemization of the a-silyl-a-sulfenyl carbanion was estimated to be 7.9 kcal mol1 in THF at 100 8C (Figure 10.4). The addition of hexamethylphosphoramide (HMPA) to the formed organolithium compound generates a solvent-separated ion pair, increasing the barrier to racemization to 9.1 kcal mol1. From these data, the authors concluded that the racemization rate of the sepa-

Figure 10.3 Racemization barriers for substituted a-sulfenyl carbanions.


Figure 10.4 Racemization barriers for the a-sulfenyl carbanions.

rated ion pair of a-sulfenyl carbanions was slower than that of the non-separated ion pair [13]. Intramolecular coordination to the lithium cation also enhances the value of DGA [9a, 13], though is due apparently to the enhanced negative hyperconjugation which is related to the increase of the barrier to rotation about the CaS bond. Hoffmann and coworkers have examined the configurational stability of asulfenyl carbanions on the reaction time scale by using the so-called Hoffmann test [14], performing two reactions of the racemic a-sulfenyl carbanions with either a racemic or a chiral aldehyde at 78 8C in THF (Scheme 10.2) [15]. These authors found that both reactions afforded the anti- and syn-diastereomers in an identical diastereomeric ratio. Based on these results, it was concluded that the sulfur-stabilized benzyllithium compound 4 epimerizes faster than it reacts with the aldehyde – that is, the carbanion is configurationally labile in THF at 78 8C. On the other hand, the reaction of the a-sulfenyl carbanion of the butyl phenyl sulfide with the same chiral aldehyde as above in 2-methyl-THF at 120 8C gives the product in an almost 1 : 1 ratio of the anti- and syn-isomers. This result shows

Scheme 10.2 Hoffmann test for the a-sulfenyl carbanion.

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Figure 10.5 Configurational stability for the a-thio carbanions for various thiocarbamates.

the lithiated butyl sulfide to be configurationally stable at 120 8C during the reaction time scale [16]. Although the a-sulfenyl carbanion derived from butyl phenyl sulfide is configurationally stable at very low temperature, a-sulfenyl carbanions are in general configurationally labile. On the other hand, a-thio carbanions of thiocarbamates can be configurationally stable by the effect of a neighboring carbonyl group. Hoppe and coworkers have shown that the lithiated (S)-1-phenylethylthiocarbamate 6 (Figure 10.5) maintains its configuration as a tertiary dipole-stabilized carbanion for over 12 min at 1 8C in Et2O [17]. The configuration of a-silyl-stabilized a-thio carbanion 7 can be retained at 78 8C in Et2O for several hours, whereas the secondary analogue 8 is configurationally unstable at 78 8C. The dilithiated (S)-cyclohex-2-enylthiocarbamate 9 and the lithiated thiocarbamate 10 [18] are configurationally stable even at 0 8C in THF. The latter results can be ascribed to the pronounced tendency of these resonance-stabilized tertiary carbanions to form solvent-separated ion pairs in THF [19].

10.3 Diastereoselective Reaction of a-Sulfenyl Carbanions

Generally, the reaction of simple a-lithiated sulfides with aldehydes affords the products with low diastereoselectivity (Scheme 10.3) [20, 21]. On the other hand,

Scheme 10.3 1,2-Asymmetric induction in reaction of the a-sulfenyl carbanion.

10.3 Diastereoselective Reaction of a-Sulfenyl Carbanions

reaction of the a-sulfenyl Grignard reagent 13 with benzaldehyde occurs with excellent diastereoselectivity in comparison with the corresponding a-lithiated sulfide 11 [22]. McDougal and colleagues have reported high 1,2-asymmetric induction of the a-sulfenyl carbanion derived from sulfide 15 with BuLi (98 : 2; Scheme 10.4) [23]. Lithiated syn-16 and anti-16 are thought to be formed diastereoselectively through the tin–lithium exchange reaction of the respective (R*,R*)-18 and (S*,R*)-18, but both silylations of syn-16 and anti-16 give the same ratio of diastereomers, due possibly to their rapid epimerization on a macroscopic time scale. A similar diastereomeric ratio is obtained by the reductive lithiation and silylation of 19. However, in-situ quenching by TMSCl in this reaction affords 17 in a diastereomeric ratio (dr) of 61 : 39, indicating that two diastereomeric organolithiums do not reach the thermodynamic equilibrium on a reaction time scale. These results show that the a-sulfenyl carbanions rapidly epimerize and produce a thermodynamically equilibrated mixture of the diastereomeric lithiated intermediates which, on addition of electrophiles, affords the products with the corresponding diastereoselectivity.

Scheme 10.4 1,2-Asymmetric induction of secondary a-sulfenyl carbanions.

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a-Sulfenyl carbanions derived from a-stannyl allyl sulfides 20 by metal exchange undergo [2,3]-thia-Wittig rearrangement stereospecifically at 78 8C over a period of 30 min in THF (Scheme 10.5) [24]. This rearrangement proceeds with complete inversion of the carbanionic center. In the case of benzylic [2,3]-thia-Wittig rearrangement of 23, on the other hand, the reaction proceeds with loss of the aromaticity. Due to the disadvantage in the thermodynamic stability of the lithiated sulfides syn- and anti-24, the rearrangement proceeds slowly with a loss of stereospecificity, indicating that the a-alkylthio organolithium 24 is configurationally stable only for a few minutes at 78 8C.

Scheme 10.5 Stereospecific [2,3]-thia-Wittig rearrangement of a-sulfenyl carbanions.

Although tertiary a-sulfenyl carbanions are known to be configurationally more stable than the secondary a-sulfenyl carbanions, the tertiary carbanion also shows a reaction feature similar to that of the secondary carbanion. Reactions of the a-sulfenyl carbanions (R*,S*)-26 and (R*,R*)-26 with s-BuLi, followed by the addition of MeOD at 78 8C, both provide the deuterated products (R*,S*)-27 and (R*,R*)-27 in similar ratios (Scheme 10.6) [25].

10.4 Enantioselective Reaction of a-Sulfenyl Carbanions

Scheme 10.6 1,2-Asymmetric induction of tertiary a-sulfenyl carbanions.

The reaction of a-methylthiocyclohexyllithium 29 with propanoic acid proceeds with epimerization into a more stable axial carbanion within 1 min at 78 8C to produce the epimeric sulfide 30 (Scheme 10.7) [26].

Scheme 10.7 Epimerization of tertiary a-sulfenyl carbanion.

10.4 Enantioselective Reaction of a-Sulfenyl Carbanions 10.4.1 Reaction Pathway of Enantioselective Reaction of a-Sulfenyl Carbanions

Enantioselective reactions of prochiral compounds having a sufficiently acidic CaH bond are of major importance to access enantiomerically pure compounds. The sulfides are deprotonated by organolithium reagents in the presence of chiral tertiary amines, and the resultant complexes react with electrophiles to give enantioenriched products [27]. Asymmetric induction occurs on the prochiral methylene carbon or on the methine carbon. Recently, asymmetric induction on prochiral methylene carbons has been extensively studied in the reactions of a-sulfenyl as well as a-oxy and a-amino carbanions. These reactions consist of two consecutive reactions: a prochiral proton is replaced by lithium to give an organolithium species (a), which subsequently react with electrophiles to give enantiomeric products (b) (Scheme 10.8). Asymmetric induction in these reactions occurs either in the first deprotonation step [Scheme 10.8, step (a)] or in a post-deprotonation step [Scheme 10.8, step (b)] [28]. When the enantioselection occurs in the deprotonation step, a

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Scheme 10.8 Enantioselective reaction on the prochiral methylene group.

proton of a prochiral substrate is stereoselectively abstracted by a chiral base to provide a configurationally stable enantioenriched carbanion, which reacts with an electrophile giving an enantioenriched product. This enantiodetermining pathway is termed ‘‘asymmetric deprotonation’’ (Figure 10.6). In fact, the reactions of dipole-stabilized a-oxy and a-amino carbanions are often controlled through an asymmetric deprotonation pathway [28, 29]. Enantioselectivity through an asymmetric deprotonation pathway depends on the difference in the stability of the transition state of deprotonation by a chiral base. The carbanions a to the sulfenyl group often epimerize quite rapidly (as described in Chapter 9). In addition, the configurational stability of carbanions is required in this asymmetric deprotonation pathway. Therefore, the asymmetric deprotonation pathway generally does not meet with the enantioselective reaction of the a-sulfenyl carbanion. The enantioselective pathway is termed asymmetric substitution, when the deprotonation gives the racemic carbanion and the enantioenriched product is formed in the reaction with an electrophile [28]. Enantioselection through an

Figure 10.6 Reaction pathway and energy diagrams for asymmetric deprotonation.


asymmetric substitution pathway is strongly related either to the stability of the carbanion–chiral ligand complexes or to the activation energy in the transition state of the reaction with an electrophile. The former is the dynamic thermodynamic resolution pathway [30] and the latter the dynamic kinetic resolution pathway [31]. The reaction proceeds through a dynamic thermodynamic resolution pathway, when the complexes are configurationally stable enough to react with an electrophile. In the dynamic thermodynamic resolution pathway, the enantioselectivity is determined by the diastereomeric ratio of the lithium carbanion–chiral ligand complexes, where the enantioselectivity must be established before the reaction with an electrophile takes place (Figure 10.7). In dynamic kinetic resolution, following the Curtin–Hammett principle, the enantioselectivity is determined by the difference in activation energy between the diastereomeric transition states in the reaction with an electrophile (Figure 10.8). In this case, the diastereomeric complexes should be configurationally labile so as to allow the carbanionic center to undergo epimerization much faster than its reaction with an electrophile, and one of the complexes preferentially reacts with an electrophile to give the enantioenriched product. The enantioselective reaction on a methine carbon is apparently different from that on a methylene carbon. Deprotonation of a racemic methine proton always affords the racemic carbanion, which gives the racemic product when the carbanion is configurationally stable. Some reports have been made which state that the enantiopurity of chiral sulfides remains through the configurationally stable chiral tertiary carbanions, as shown in Figure 10.5.

Figure 10.7 Reaction pathway and energy diagram for dynamic thermodynamic resolution.

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Figure 10.8 Reaction pathway and energy diagram for dynamic kinetic resolution.

10.4.2 Enantioselective Reactions of a-Sulfenyl Carbanions

Takei and coworkers have reported the enantioselective reaction of arylthiostabilized amide-homoenolates with aldehydes in the presence of ()-sparteine, through a dianionic cyclic intermediate Li-31 which gives anti- and syn-32 with good diastereoselectivity but low enantioselectivity (36% enantiomeric excess (ee); Scheme 10.9) [32]. Since the reaction at 100 8C showed even lower enantioselectivity (30% ee), it has been concluded that the reaction of the dianionic intermediate Li-31 proceeds through a dynamic thermodynamic resolution pathway at 78 8C. Toru and coworkers have reported a highly enantioselective reaction of alithiated benzyl phenyl sulfide 34, generated by the metal exchange reaction, with various electrophiles such as aldehydes, ketones, alkyl halides and carbon dioxide in the presence of bis(oxazoline)s as the most efficient chiral ligand (Scheme 10.10) [33]. Higher enantioselectivity was obtained when the reaction was performed with ketones as electrophiles at lower temperature. Cumene is the choice as a solvent to show a high ee-value, whereas toluene slightly lowers the enantioselectivity. The reaction with ketones at lower temperature (98 8C) leads to higher enantioselectivity (499% ee). The chiral b-hydroxy sulfides obtained can be converted to chiral epoxides using the Meerwein reagent under basic conditions.


Scheme 10.9 Enantioselective reaction of the carbanion of b-arylthio amides.

The reaction proceeds through a dynamic kinetic resolution pathway, which is verified by the Hoffman test using 2-(N,N-dibenzylamino)-3-phenylpropanal with either tetramethylethylenediamine (TMEDA) or the enantiopure bis(oxazoline). It has shown by ab initio calculations that the CaLi bond prefers the conformation antiperiplanar to the SaCips bond due to the n-s* negative hyperconjugation of a-lithiated benzyl phenyl sulfide (Figure 10.9). Thus, this enantioselective reaction is assumed to proceed through a four-membered cyclic transition state (TS-1) stabilized by the negative hyperconjugation.

Scheme 10.10 Enantioselective reaction of a-sulfenyl carbanion of benzyl phenyl sulfide.

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Figure 10.9 Preferred transition state for the reaction of benzyl phenyl sulfide.

Interestingly, the stereochemical outcome in the reaction of a-lithiated benzyl phenyl sulfide was found to differ from that in the reaction of a-lithiated benzyl methyl ether, which proceeds through a dynamic thermodynamic resolution pathway (Scheme 10.11) [34]. Taking into account Wiberg’s results that the aoxy carbanion derived from dimethyl ether places the lone pair of carbanion syn to the methyl group by the electron repulsive effect [3d], the difference in the stereochemical outcome between a-sulfenyl and a-oxy carbanions would be ascribed to their different preferred conformations. A similar change in the stereochemical outcome has been observed in reactions of dipole-stabilized a-thio and a-oxy organolithium compounds (see Scheme 10.17). Since the SE2 reaction on the sp2-like hybridized carbanion tends to proceed with inversion of the stereochemistry, it is reasonable that a-thio carbanions having a higher s character than


Scheme 10.11 Enantioselective reaction of the a-oxy carbanion.

a-oxy carbanions, more frequently invert the stereochemistry on the anionic carbon in the reaction with electrophiles. The reaction of a-sulfenyl carbanion of benzyl phenyl sulfides with 4-substituted cyclohexanones affords the products 38 and 40 with only moderate to good dia-

Scheme 10.12 Enantioselective synthesis for axially chiral olefins using a-sulfenyl carbanions.

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stereoselectivity but excellent enantioselectivity (Scheme 10.12). Following the separation of diastereomers, the stereospecific elimination of the sulfenyl and hydroxyl groups on treatment with methanesulfonyl chloride and triethylamine gives the axially chiral olefins 39 and 41, which may be key intermediates for the synthesis of biologically active compounds such as carbacyclines [35]. Allyl sulfides are widely used as synthetically important reagents or precursors of homoenolates and chiral allyl alcohols. The reaction of the a-sulfenyl carbanion of allylic sulfides 42 with ketones in the presence of bis(oxazoline)-t-Bu shows good enantioselectivity with low regioselectivity. This reaction also proceeds through a dynamic kinetic resolution pathway via a boat-form, six-membered cyclic transition state (Scheme 10.13) [36].

Scheme 10.13 Enantioselective reaction of a-sulfenyl carbanion of allylic sulfides.

The change of the phenyl substituent of benzyl phenyl sulfide 32 to a pyridyl group causes a drastic change in the reaction feature. Thus, the proton a to the pyridyl sulfide is abstracted without a ligand due to the enhanced acidity by intramolecular coordination of the pyridyl nitrogen to lithium. In addition, the enantioselective reaction of a-lithiated benzyl 2-pyridyl sulfide 46 with electrophiles gives 47 with reversed stereochemistry to that obtained in the reaction of the alithiated benzyl phenyl sulfide 34 (Scheme 10.14). The reaction of a-lithiated benzyl 2-pyridyl sulfide 46 was proved to proceed through a dynamic thermodynamic resolution pathway by experiments using a substoichiometric amount of an electrophile (0.2 equiv. benzophenone at 78 8C, 50% ee), as well as by warm–cool experiments [37]. Thus, a-lithiated benzyl 2-pyridyl sulfide 46 reacts with an electrophile before interconversion between the diastereomeric lithium carbanion–chiral ligand complexes. The (R)-diastereomeric complex (R)-46 was shown to be more stable than the (S)complex (S)-46 by ab initio and semiempirical calculations (Figure 10.10). In this complex, the pyridyl nitrogen plays an important role in determining the direction of approach of an electrophile. All electrophiles, including carbonyl com-


Scheme 10.14 Enantioselective reaction of a-sulfenyl carbanion of benzyl 2-pyridyl sulfide.

Figure 10.10 Geometry optimization of complexes of a-pyridylsulfenyl carbanion.

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pounds, attack the carbanion without coordination to the cationic lithium, which is fully coordinated with three nitrogens – that is, two of the bis(oxazoline) and one of the pyridine – giving (R)-products, where the reaction proceeds with inversion of the carbanionic center. The inversion of configuration in the above reaction is in sharp contrast to the retention of stereochemistry generally observed in the enantioselective reaction with carbonyl compounds. A few reports have been made on the SE2 reaction with a carbonyl compound proceeding with inversion [17, 38]. As in the case of a-lithiated benzyl 2-pyridyl sulfide, the reaction of a-lithiated benzyl 2-quinolyl sulfide 49 also proceeds through a dynamic thermodynamic resolution pathway. The quinolyl group is an excellent protecting group of thiols, and may be removed to yield the corresponding chiral thiols 51, without racemization (Scheme 10.15) [39].

Scheme 10.15 Enantioselective synthesis of chiral thiols using a-carbanion of the quinolyl sulfide.

Although most a-sulfenyl carbanions are configurationally labile and racemize rapidly even at low temperature, Hoffmann and coworkers have reported the preparation of enantioenriched a-lithio sulfides 53 by retrocarbolithiation of the cyclopropyl group [11]. The lithiated intermediate can be trapped with methyl iodide or stannylating agents to provide products 54 with retention of configuration (Scheme 10.16). The ring opening occurs with a retention of configuration


to provide a lithiated intermediate, which is configurationally stable at 108 8C but racemizes at 78 8C (half-life ¼ 90 min). The inversion barrier of the asulfenyl carbanion is estimated to be 15.0 kcal mol1, which is similar to that measured for other lithiated duryl sulfides [9b].

Scheme 10.16 Reaction of configurationally stable a-sulfenyl carbanion.

Hoppe and coworkers have reported the asymmetric reaction of a-lithiated thiocarbamates as a dipole-stabilized carbanion with moderate enantioselectivity [19], in contrast to the reaction of similar dipole-stabilized a-oxy organolithium compounds which shows excellent enantioselectivity (Scheme 10.17) [29, 40]. It should be noted that the stereochemistry of the products 56 obtained from alithiated thiocarbamates is different from that obtained in the a-lithiated carbamate [41].

Scheme 10.17 Enantioselective reactions of a-carbanions derived from thiocarbamates and carbamates.

The enantioselective silylation and alkylation of the secondary carbanion of allylic thiocarbamate 57 in the presence of bis(oxazoline)-Ph yield 58 with excellent enantioselectivity (Scheme 10.18) [42]. The reaction is assumed to proceed through a dynamic thermodynamic resolution pathway, with inversion of configuration.

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Scheme 10.18 Enantioselective reaction of a-thio carbanion of allylic thiocarbamate.

The lithiation of propargylic thiocarbamate 59 in the presence of ()-sparteine in pentane affords precipitates of the complex 60 (Scheme 10.19) [43]. The precipitates were shown by X-ray crystallography to consist of the (S)-60 complex, the reaction of which with trimethylsilyl trifluoromethanesulfonate (TMSOTf ) gives the enantiomerically pure propargylsilane 61 through a dynamic thermodynamic resolution pathway with inversion of stereochemistry, where the crystallization induces the dynamic resolution [31c]. Transmetallation with ClTi (Oi-Pr)3, and subsequent reaction with benzaldehyde afford the axially chiral allene 63 with excellent stereochemistry.

Scheme 10.19 Enantioselective reaction of a-thio carbanion of propargylic thiocarbamate.

To date, no reports have been made concerning the enantioselective reaction of tertiary a-sulfenyl carbanions; in contrast, a number of reactions of chiral tertiary carbanions of a-thiocarbamates, which are relatively configurationally more stable


than secondary carbanions of a-thiocarbamates, have been reported. The racemization of dilithiated thiocarbamate 9 depends on the solvent used, and occurs readily at 78 8C either in diethyl ether or in toluene, but the compound is configurationally stable in THF (Scheme 10.20). Lithiated thiocarbamate 10, on the other hand, is configurationally stable in THF, diethyl ether, and toluene [18]. Due to the stability of carbanions, the reaction of chiral lithiated thiocarbamate 10 starting from chiral thiocarbamate 67 with some electrophiles affords 68 with complete retention of stereochemistry and with a-selectivity. In contrast, the reaction of chiral dilithiated thiocarbamate 9 affords the non-regioselective products with a certain loss of enantiopurity.

Scheme 10.20 Configurationally stable dilithiated and lithiated thiocarbamates.

The configurationally stable chiral a-thio carbanion 8 derived from chiral thiocarbamate 70 reacts with carbonyl compounds to create a quaternary center with complete inversion of the carbanionic center [17], whereas reaction of the corresponding a-oxy carbanion derived from chiral carbamate proceeds with retention of configuration (Scheme 10.21) [44]. These reactions show a sharp contrast in stereochemical outcome between a-thio and a-oxy carbanions, although the detailed stereochemistry depends on the electrophiles, as shown in Scheme 10.21. The lithiated a-silylthiocarbamate prepared from 73 with s-BuLi/TMEDA has been also proved to be configurationally stable at 78 8C. Standing for 2.5 h in the lithiated carbanion form, followed by deuterolysis with MeOD, leads to formation of the optically active deuterated compound 74 with retention of configuration, but without changing the enantiopurity of the starting 73 (Scheme 10.22) [19]. Successful symmetric reaction of sulfides bearing a tricarbonyl (h 6-arene)chromium complex has been reported by Gibson and Simpkins [45, 46]. The benzylic methylene groups in tricarbonyl (h 6-phenylmethyl alkyl sulfide)chromium (0) 76 and tricarbonyl (h 6-1,3-dihydroisobenzothiophene)chromium (0) 78 are highly asymmetrically functionalized by deprotonation with the chiral bis-lithium amide and subsequent electrophilic reactions (Scheme 10.23).

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Scheme 10.21 Stereochemistry of the reaction with various electrophiles.

Gibson and coworkers pointed out an interesting reaction feature of these reactions; the reaction of a-lithiated sulfides derived from the chromium complexes of benzyl sulfides gives 76 having a configuration opposite that obtained in the reaction of the corresponding ethers 79 (Scheme 10.24) [47]. In contrast, this type of stereochemical reversibility has not been observed in enantioselective reactions of chromium complexes of 1,3-dihydroisobenzothiophene and 1,3dihydroisobenzofuran [48]. The reaction of the chromium complexes of benzyl ethers has been assumed to proceed through a selective deprotonation to give the configurationally stable intermediates, which then react with electrophiles from their exo face (Scheme

Scheme 10.22 Enantioselective reaction of a-silyl-a-sulfenyl carbanion.


Scheme 10.23 Enantioselective reaction of a-sulfenyl carbanion of chromium complex.

Scheme 10.24 Enantioselective reaction of a-oxy carbanions of the chromium complex.

Scheme 10.25 Stereoselective deprotonation of the chromium complex.

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10.25) [49]. Provided that the reaction of benzyl sulfides proceeds through a similar intermediate, the different stereochemical outcome in benzyl sulfides from that in ethers might be rationalized by the difference in the deprotonation pattern. 10.4.3 Enantioselective Reactions of a-Lithiated Dithioacetals

Metallated dithioacetals are known to be useful as acyl anion equivalents, and successful diastereoselective reactions have led to many applications of dithioacetals [50]. However, only a few enantioselective reactions of dithioacetals have been reported. One example is the enantioface-selective conjugate addition of lithiated phenyldithiane 82 to a,b-unsaturated esters. The reaction was carried out in the presence of a chiral ligand derived from l-phenylalanine to afford the addition product 83 with moderate enantioselectivity (Scheme 10.26) [51].

Scheme 10.26 Enantioselective Michael addition of a-carbanion of 2-phenyl-1,3-dithiane.

Scheme 10.27 Enantioselective reaction of a-carbanion of 1,3-dithiane.


The enantioface-selective reaction of benzaldehyde with 2-lithio-1,3-dithiane in the presence of ()-a-isosparteine, prepared from ()-sparteine in several steps, gives the addition product 85 with 70% ee, whereas the reaction with ()sparteine exhibits almost no selectivity (Scheme 10.27) [52]. The assumed transition state for this reaction is illustrated in Scheme 10.27. The reaction with aliphatic aldehydes, however, does not proceed with high enantioface-selection. It is more difficult to achieve high enantioselection in the reaction of acyclic dithioacetals than that of dithianes. The reaction of acyclic symmetric dithioacetals 86 using various chiral ligands with benzaldehydes affords the products 87 with low carbonyl face selectivity. On the other hand, acyclic unsymmetrical dithioacetals 88 having a coordinative pyridyl group and a bulky t-butyl substituent can control the stereochemistry of the products 89 in the presence of chiral bis(oxazoline) (Scheme 10.28) [53]. The warm–cool procedure and an experiment using a deficient amount of the electrophile showed that the reaction proceeds through a dynamic thermodynamic resolution pathway. The obtained products can be converted to chiral diols 90 and a-hydroxy carboxylic acids 91.

Scheme 10.28 Enantioselective reaction of acyclic dithioacetals.

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The chiral N,S-acetal structure is a very important functional group as a privileged structural element in biologically active penicillin and cephalosporin compounds. Only one report has been made on the enantioselective reaction of a-carbanion of N,S-acetals, whereas the diastereoselective reactions of N,S-acetals have been extensively studied [54]. The reaction of a-carbanion of simple N,Sacetals with aldehydes in the presence of ()-sparteine afforded the products with good enantioselectivity but with low diastereoselectivity (Scheme 10.29) [55]. Recrystallization of the N,S-acetals obtained from hexane and subsequent deprotection and reduction affords the chiral diols, without loss of enantiopurity.

Scheme 10.29 Enantioselective reaction of a-carbanion of N,S-acetals.

10.5 Conclusions

The enantioselective reaction of configurationally labile a-sulfenyl carbanions in the presence of stoichiometric quantities of chiral ligands represents an efficient method for the stereoselective formation of carbon–carbon bonds. Clearly, any future challenge will be to develop a catalytic system for the enantioselective reaction of a-sulfenyl carbanions.

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1997, 2189–2190; (b) R. W. Hoffmann, R. Koberstein, Chem. Commun. 1999, 33–34; (c) R. W. Hoffmann, R. Koberstein, J. Chem. Soc., Perkin Trans. 2 2000, 2, 595–602. H. J. Reich, R. R. Dykstra, Angew. Chem. Int. Ed. Engl. 1993, 32, 1469–1470. T. Ruhland, R. W. Hoffmann, S. Schade, G. Boche, Chem. Ber. 1995, 128, 551–556. (a) R. Hirsch, R. W. Hoffmann, Chem. Ber. 1992, 125, 975–982; (b) R. W. Hoffmann, T. Ru¨hl, F. Chemla, T. Zahneisen, Liebigs Ann. Chem. 1992, 719–724. R. W. Hoffmann, T. Ru¨hl, J. Harbach, Liebigs Ann. Chem. 1992, 725–730. R. W. Hoffmann, M. Julius, F. Chemla, T. Ruhland, G. Frenzen, Tetrahedron 1994, 50, 6049–6060. (a) D. Hoppe, B. Kaiser, O. Stratmann, R. Fro¨hlich, Angew. Chem. Int. Ed. Engl. 1997, 36, 2784–2786; (b) O. Stratmann, B. Kaiser, R. Fro¨hlich, O. Meyer, D. Hoppe, Chem. Eur. J. 2001, 7, 423–435. (a) F. Marr, R. Fro¨hlich, D. Hoppe, Org. Lett. 1999, 1, 2081–2083; (b) F. Marr, R. Fro¨hlich, B. Wibbeling, C. Diedrich, D. Hoppe, Eur. J. Org. Chem. 2002, 2970–2988; (c) F. Marr, D. Hoppe, Org. Lett. 2002, 4, 4217–4220. B. Kaiser, D. Hoppe, Angew. Chem. Int. Ed. Engl. 1995, 34, 323–325. For a review; K. Ogura, in: Comprehensive Organic Synthesis, Pergamon, 1991, Vol. 1, Chapter 2.3. C. A. Kingsbury, J. Org. Chem. 1972, 37, 102–106. V. Schulze, P. G. Nell, A. Burton, R. W. Hofmann, J. Org. Chem. 2003, 68, 4546–4548. P. G. McDougal, B. D. Condon, M. D. Lafosse, Jr., A. M. Lauro, D. Van Derveer, Tetrahedron Lett. 1988, 29, 2547–2550. K. Brickmann, R. Bru¨ckner, Chem. Ber. 1993, 126, 1227–1239. G. P. Lutz, A. P. Wallin, S. T. Kerrick, P. Beak, J. Org. Chem. 1991, 56, 4938–4943. H. J. Reich, M. D. Bowe, J. Am. Chem. Soc. 1990, 112, 8994–8995.

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10 Asymmetric Reaction of a-Sulfenyl Carbanions 27 For review; T. Toru, S. Nakamura, Top. Organomet. Chem. 2003, 5, 177–216. 28 (a) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res. 1996, 29, 552–560; (b) A. Basu, S. Thayumanavan, Angew. Chem. Int. Ed. Engl. 2002, 41, 716–738. 29 D. Hoppe, T. Hense, Angew. Chem. Int. Ed. Engl. 1997, 36, 2282–2316. 30 P. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer, D. J. Pippel, G. A. Weisenburger, Acc. Chem. Res. 2000, 33, 715–727. 31 For reviews: (a) R. Noyori, M. Tokunaga, M. Kitamura, Bull. Chem. Soc. Jpn. 1995, 68, 36–56; (b) R. S. Ward, Tetrahedron: Asymmetry 1995, 6, 1475–1490; (c) S. Caddick, K. Jenkins, Chem. Soc. Rev. 1996, 447–456; (d) H. Pellissier, Tetrahedron 2003, 59, 8291–8327. 32 T. Shinozuka, Y. Kikori, M. Asaoka, H. Takei, J. Chem. Soc., Perkin Trans. 1, 1996, 119–120. 33 (a) S. Nakamura, R. Nakagawa, Y. Watanabe, T. Toru, Angew. Chem. Int. Ed. 2000, 39, 353–355; (b) S. Nakamura, R. Nakagawa, Y. Watanabe, T. Toru, J. Am. Chem. Soc. 2000, 122, 11340–11347; (c) S. Nakamura, T. Aoki, T. Ogura, L. Wang, T. Toru, J. Org. Chem. 2004, 69, 8916–8923. 34 (a) N. Komine, L. F. Wang, K. Tomooka, T. Nakai, Tetrahedron Lett. 1999, 40, 6809–6812; (b) K. Tomooka, L. F. Wang, N. Komine, T. Nakai, Tetrahedron Lett. 1999, 40, 6813–6816. 35 (a) S. Nakamura, T. Ogura, L. Wang, T. Toru, Tetrahedron Lett. 2004, 45, 2399–2402; (b) L. Wang, S. Nakamura, N. Shibata, T. Toru, Chem. Lett. 2005, 34, 76–77. 36 S. Nakamura, T. Kato, H. Nishimura, T. Toru, Chirality 2004, 16, 86–89. 37 (a) D. J. Gallagher, H. Du, S. A. Long, P. Beak, J. Am. Chem. Soc. 1996, 118, 11391; (b) S. Thayumanavan, A. Basu, P. Beak, J. Am. Chem. Soc. 1997, 119, 8209–8216; (c) N. C. Faibish, Y. S. Park, S. Lee, P. Beak, J. Am. Chem. Soc. 1997, 119, 11561–11570. 38 A. Basu, P. Beak, J. Am. Chem. Soc. 1996, 118, 1575–1576.

39 S. Nakamura, A. Furutani, T. Toru, Eur. J. Org. Chem. 2002, 1690–1695. 40 D. Hoppe, F. Hintze, P. Tebben, Angew. Chem. Int. Ed. Engl. 1990, 29, 1422–1424. 41 M. Capo´, J. M. Saa´, J. Am. Chem. Soc. 2004, 126, 16738–16739. 42 R. P. Sonawane, R. Fro¨hlich, D. Hoppe, Adv. Synth. Catal. 2006, 348, 1847–1854. 43 R. Otte, R. F. Fro¨hlich, B. Wibbeling, D. Hoppe, Angew. Chem. Int. Ed. 2005, 44, 5492–5496. 44 C. Derwing, H. Frank, D. Hoppe, Eur. J. Org. Chem. 1999, 3519–3524. 45 (a) S. E. Gibson (neé Thomas), P. Ham, G. R. Jefferson, M. H. Smith, J. Chem. Soc., Perkin Trans. 1 1997, 2161–2162; (b) S. E. Gibson (neé Thomas), E. G. Reddington, Chem. Commun. 2000, 989–996. 46 A. Ariffin, A. J. Blake, R. A. Ewin, N. S. Simpkins, Tetrahedron: Asymmetry 1998, 9, 2563–2566. 47 (a) E. L. M. Cowton, S. E. Gibson (neé Thomas), M. J. Schneider, M. H. Smith, Chem. Commun. 1996, 839–840; (b) A. Ariffin, A. J. Blake, R. A. Ewin, W. Li, N. S. Simpkins, J. Chem. Soc., Perkin Trans. 1 1999, 3177–3189. 48 R. A. Ewin, A. M. MacLeod, D. A. Price, N. S. Simpkins, A. P. Watt, J. Chem. Soc., Perkin Trans. 1 1997, 401–415. 49 S. E. Gibson, P. C. V. Potter, M. H. Smith, Chem. Commun. 1996, 2757–2758. 50 (a) L. Colombo, C. Gennari, G. Resnati, C. Scolastico, J. Chem. Soc., Perkin Trans. 1 1981, 1284–1286; (b) G. Solladie´, F. Colobert, P. Ruiz, C. Hamdouchi, M. C. Carreno, J. L. G. Ruano, Tetrahedron Lett. 1991, 32, 3695–3698; (c) G. Delogu, O. D. Lucchi, P. Maglioli, J. Org. Chem. 1991, 56, 4467–4473; (d) V. K. Aggarwal, S. Schade, H. Adams, J. Org. Chem. 1997, 62, 1139–1145; (e) B. Delouvrie´, L. Fensterbank, F. Na´jera, M. Malacria, Eur. J. Org. Chem. 2002, 3507–3525. 51 K. Tomioka, M. Sudani, Y. Shinmi, K. Koga, Chem. Lett. 1985, 329–332. 52 J. Kang, J. I. Kim, J. H. Lee, Bull. Korean. Chem. Soc. 1994, 15, 865–868. 53 S. Nakamura, Y. Ito, L. Wang, T. Toru, J. Org. Chem. 2004, 69, 1581–1589.

References 54 (a) C. Gaul, D. Seebach, Org. Lett. 2000, 2, 1501–1504; (b) R. E. Gawley, Q. Zhang, A. T. McPhail, Tetrahedron: Asymmetry 2000, 11, 2093–2106; (c) C. Gaul, K. Scha¨rer, D. Seebach, J. Org. Chem. 2001, 66, 3059–3073; (d) C. Gaul, P. I. Arvidsson, W. Bauer, R. E. Gawley, D. Seebach, Chem. Eur. J. 2001, 7, 4117–4125; (e) C. Gaul,

D. Seebach, Helv. Chim. Acta 2002, 85, 772–787; (f ) R. E. Gawley, S. A. Campagna, M. Santiago, T. Ren, Tetrahedron: Asymmetry 2002, 13, 29–36. 55 (a) L. Wang, S. Nakamura, T. Toru, Org. Biomol. Chem. 2004, 2, 2168–2169; (b) L. Wang, S. Nakamura, Y. Ito, T. Toru, Tetrahedron: Asymmetry 2004, 15, 3059–3072.

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11 Stereoselective Reactions with a-Sulfinyl Carbanions Alessandro Volonterio and Matteo Zanda

Abstract

a-Sulfinyl carbanions are useful chiral intermediates which have been used extensively to achieve stereoselective CaC bond-forming reactions. This chapter reviews the use of a-sulfinyl carbanions in organic synthesis from the seminal studies to the most recent applications, with special emphasis on: (1) the stereochemistry of these intermediates; (2) the alkylation with suitable electrophiles; (3) Michael-type additions to a,b-unsaturated systems; (4) additions to the CbO bonds of aldehydes and ketones; and (5) additions to the CbN bonds of imines. Relevant examples of a-sulfinyl carbanions in the synthesis of biologically important targets are provided.

11.1 Introduction

a-Sulfinyl carbanions are versatile synthetic intermediates that have a number of applications in asymmetric synthesis. Since several and exhaustive reviews on this topic have been recently published [1], this chapter is not intended as a further (and probably superfluous) update of the literature. Rather, an attempt will be made to define the underlying concepts and principles, as well as the essential chemical features and the role of stereogenic a-sulfinyl carbanions in the arena of organic synthesis.


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11 Stereoselective Reactions with a-Sulfinyl Carbanions

Figure 11.1 pK a values of CaH bonds in phenyl benzyl sulfoxide and related structures.

11.2 Stereochemistry of a-Sulfinyl Carbanions

The a-proton of a sulfoxide is moderately acidic (see Figure 11.1), and can be removed by the action of a base such as NaH, or by stronger bases such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), Grignard reagents, MeLi, or n-BuLi. With the latter base (and also tert-BuLi) it is possible to observe cleavage of the CaS bond owing to a nucleophilic displacement by the organolithium; therefore, these nucleophilic bases must be used with care. a-Sulfinyl carbanions are inherently diastereomeric, because the carbanion center is attached to the stereogenic sulfinyl function. The geometry of an asulfinyl carbanion can be either pyramidal or planar (Figure 11.2). If the energy barrier of the pyramidal structure or the rotational barrier around the CaS bond of the planar structure are sufficiently high, then the configuration of the carbanion will be retained.

Figure 11.2 (a) Pyramidal and planar geometries of a-sulfinyl carbanions in one of the possible conformations. (b) Structure of lithiated a-sulfinyl carbanion.

11.2 Stereochemistry of a-Sulfinyl Carbanions

Different research groups have shown independently that lithium salts of asulfinyl carbanions may be satisfactorily described by a sp2 planar structure with the Liþ ion chelating both carbon and oxygen (Figure 11.2b) [2]. During the 1960s a series of landmark reports were published which, in effect, gave birth to the modern chemistry of a-sulfinyl carbanions. In 1962, Corey and Chaykovsky reported for the first time the use of the methylsulfinyl carbanion in organic synthesis [3], thus paving the way for the generation and use of other a-sulfinyl carbanions. In a second report, Wolfe and coworkers showed that the hydrogen exchange in benzyl methyl sulfoxide occurs in a stereospecific manner [4], thus posing the bases for the use of a-sulfinyl carbanions in stereoselective synthesis. These seminal studies provided the basis for the ongoing investigations of Durst who, during the following years, described the first true stereoselective reactions involving a-sulfinyl carbanions. First, chloromethyl phenyl sulfoxide was reported to undergo a stereospecific Darzens-type reaction with ketones, such as cyclohexanone and acetone, affording the corresponding sulfinyl-epoxides as single diastereomers (Scheme 11.1) [5]. Extensive studies on achloro-a-sulfinyl carbanions were later developed by Satoh and coworkers, who exploited these intermediates for a huge variety of synthetic processes [6].

Scheme 11.1 Durst’s stereospecific Darzens-type reaction.

Durst subsequently showed that the sense of stereocontrol for the reaction of a-sulfinyl carbanions with electrophiles may depend heavily on the nature of the latter [7]. Indeed, different lithiated sulfoxides reacted with the same sense of high stereoselectivity with electrophiles that can be coordinated by the lithium cation, such as D2O and ketones (cyclohexanone, acetone and benzophenone), but gave the opposite stereoselectivity with a poorly electron-donating electrophile such as MeI (Scheme 11.2). Analogous observations were made several years later by Nishihata and Nishio [8], who showed that the stereoselectivity of the carboxylation of a-sulfinyl carbanions was strongly influenced by the concentration and availability of lithium cations in the reaction environment. Thus, lower stereoselectivities were observed in the presence of higher amounts of Liþ in the reaction mixture, but complexation of the lithium countercation by hexamethylphosphoramide (HMPA) also produced a reduction in stereocontrol.

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Scheme 11.2 Reaction of lithiated sulfoxides with different electrophiles.

11.3 Alkylation of a-Sulfinyl Carbanions

The methylation of a-sulfinyl carbanions has recently been carried out with good to excellent stereocontrol by the use of (MeO)3PO as an electrophile (Scheme 11.3) [9], which resulted in a remarkable improvement with respect to MeI (see above). The best degrees of stereocontrol were observed with b-silyl-a-sulfinyl carbanions, possibly owing to stabilizing interactions between the silyl atom and the PbO oxygen in the transition state. Analogous observations were made with a cyclic equatorial sulfoxide (Scheme 11.4), which gave the equatorial methyl derivative upon lithiation with n-BuLi followed by treatment with MeI, and the axial methylation product when reacted

11.3 Alkylation of a-Sulfinyl Carbanions

Scheme 11.3 Methylation of a-sulfinyl carbanions with (MeO) 3PO.

with (MeO)3PO [10]. It is likely that the axial-lithiated intermediate is formed, after which MeI reacts with inversion without coordination by Liþ, whereas (MeO) 3PO is coordinated by Liþ and reacts with a retention of configuration. Not surprisingly, the presence of a large excess of LiClO4 restored the axial stereocontrol in the reaction with (MeO) 3PO. Interestingly, the axial sulfoxide reacted with MeI affording exclusively the axial derivative, thus showing that the configuration of the sulfinyl group dictates the stereochemistry of the lithiation.

Scheme 11.4 Methylation of a cyclic sulfoxide.

The base is another important factor that can play a key role in the stereocontrol of the alkylation of a-sulfinyl carbanions. This was clearly shown by Bravo et al. for the alkylation of ethyl p-tolyl sulfoxide with bromo-methacrylate [11]. In this process, the highly hindered base lithium tetramethylpiperidide (LTMP) afforded considerably higher diastereoselectivity than LDA (Scheme 11.5), although the effect was less pronounced with other sulfoxides. The methodology was subsequently used to prepare a-methylene-g-lactones.

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Scheme 11.5 Influence of the base on the stereocontrol of a reaction of a-sulfinyl carbanions with bromo-methacrylate.

b-Hydroxy-sulfoxides can be alkylated in a-position by means of 2 equiv. of base (MeLi, n-BuLi or LDA), and the resulting stereoselectivity is generally high and mainly dependent on the configuration of the b-carbinolic center [12]. This methodology was used to synthesize both enantiomers of the pheromone disparlure [13], using the two carbinolic epimers as substrates (Scheme 11.6).

Scheme 11.6 Synthesis of both enantiomers of the pheromone, disparlure.

Good diastereoselectivity was also obtained in the alkylation of b-phenylsulfinylethanol (ca. 7 : 1) [14], although clearly in that case the stereocontrol must be ascribed exclusively to the sulfinyl group. Metallated methylene active sulfoxides, such as b-keto- and b-carboxy-sulfoxides, feature a generally low stereoselectivity and reactivity in alkylation reactions [15]. This is true both under kinetic and thermodynamic conditions, the latter often being predominant owing to the liability of the C-stereogenic center, which has strong proclivity to epimerize via enolization. Vinyl sulfoxides can also be lithiated in the a-position, and subsequently alkylated. However, the a-sulfinyl carbanions derived from vinyl sulfoxides are geometrically unstable and cis/trans isomerization occurs even at 100 8C. As an example, Posner has shown that a-alkylation of (E )- and (Z)-alkenyl sulfoxides leads almost exclusively to (E )-isomers [16], independently of the starting geometry (Scheme 11.7).

11.4 Conjugated Additions with a-Sulfinyl Carbanions

Scheme 11.7 Alkylation of vinyl sulfoxides.

A thorough study on the a-alkylation of lithiated vinyl sulfoxides with alkyl iodides, in total agreement with the above findings, was also reported [17]. A peculiar example of alkylation of a lithiated vinyl sulfoxide was reported by Chou and Liang [18] (Scheme 11.8), whereby the presence of an endocyclic sulfonyl moiety directed the metallation, and also the subsequent alkylation, on the sp3 carbon at C2. Moderate to excellent (in the case of allyl bromide) diastereocontrol was observed.

Scheme 11.8 Alkylation of a cyclic sulfonyl sulfoxide.


a-Sulfinyl carbanions are effective nucleophiles for conjugated additions to Michael acceptors. One of the first reports on this topic was made by Solladie´, who described the reaction of the enantiopure sodium salt of a-sulfinyl tert-butyl acetate with ethyl crotonate (Scheme 11.9) [19]. The process occurred with modest stereocontrol, and eventually afforded a d-lactone as final product in 12% enantiomeric excess (ee). Low stereocontrol was observed also with ethylidene and benzylidene malonates as Michael acceptors (524%).

Scheme 11.9 Synthesis of a d-lactone via conjugate addition of an a-sulfinyl carbanion.

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Later, Scolastico et al. reported a highly diastereoselective synthesis of prostaglandin intermediates using the carbanion of (S)-p-tolyl-p-tolylthiomethyl sulfoxide with cyclopentenones (Scheme 11.10) [20].

Scheme 11.10 Synthesis of prostaglandin intermediates.

In 1988, Casey and colleagues were the first to demonstrate the feasibility of simple a-sulfinyl carbanions as nucleophiles in conjugate additions [21]. The group showed that lithiated alkyl tert-butyl-sulfoxides added to crotonates and other a,b-unsaturated esters with a high stereocontrol (Scheme 11.11), which was much superior to that featured by the corresponding p-tolyl sulfoxides.

Scheme 11.11 Conjugated additions of simple a-sulfinyl carbanions.

This process was subsequently improved by the group of Toru, who applied b-silyl a-sulfinyl carbanions (see also Scheme 11.3) to achieve an extremely high stereocontrol, even with p-tolylsulfinyl derivatives [22]. In addition, it was possible to trap the intermediate enolate resulting from the conjugate addition by quenching with electrophiles, thus obtaining a doubly stereoselective process with complete stereocontrol (Scheme 11.12).

Scheme 11.12 Stereoselective conjugated additions of b-silyl a-sulfinyl carbanions and subsequent trapping of the enolate intermediate with electrophiles.


The proposed transition state for this highly stereoselective process is, according to the authors, a bicyclic structure with the silyl atom interacting with the carbonyl oxygen of the Michael acceptor, and the lithium atom coordinating the same CbO and the sulfinyl oxygen (Figure 11.3).

Figure 11.3 Proposed intermediate for the reaction in Scheme 11.12.

A related, highly stereoselective process involving a-carbanions derived from vinyl-sulfoxides was described by Tanaka et al. [23]. In the case of (Z)-a,bunsaturated esters, this tandem intramolecular Michael addition/enolate alkylation occurred with near-complete stereocontrol, thus providing access to functionalized cyclopentenes (Scheme 11.13). When benzaldehyde was used as the trapping electrophile, the process generated three new stereogenic centers in a spectacularly selective manner. Much lower stereocontrol was observed with the corresponding (E )-a,b-unsaturated esters.

Scheme 11.13 Intramolecular Michael addition of a lithiated vinyl sulfoxide with trapping of the intermediate enolate by external electrophiles.

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Another remarkably stereoselective application of a-sulfinyl carbanions (in this case stabilized) was reported by Alvarez-Ibarra et al. [24]. The main drawback of this process – a tandem Michael addition/cyclization (Scheme 11.14) – was the rather modest yield of formation of the target 5,6-dehydropiperidin-2-ones.

Scheme 11.14 Michael addition of b-imino-sulfoxides to a,b-unsaturated esters.

11.5 Additions of a-Sulfinyl Carbanions to Carbonyl Compounds

The very large body of literature on this topic pays witness to the synthetic importance of the reaction between a-sulfinyl carbanions and aldehydes or ketones to afford the corresponding carbinols. The stereocontrol of the reaction can involve the newly formed carbinolic center and/or the a-sulfinyl carbon, the latter being generally higher. One of the very first reports on this methodology showed simply its viability, but did not provide information about the stereocontrol (Scheme 11.15) [25].

Scheme 11.15 Addition of lithiated methyl n-butyl sulfoxide to benzaldehyde.

Soon afterwards, a Japanese group showed that the addition of lithiated methyl p-tolyl sulfoxide both to ketones and aldehydes takes place with low stereocontrol (Scheme 11.16) [26]. The possibility of achieving very high stereocontrol in the reaction between a-sulfinyl carbanions and carbonyl compounds was demonstrated by Sakuraba and Ushiki [27], who reported that (S)-lithiomethyl 1-naphthyl sulfoxide adds to phenyl n-alkyl ketones with total diastereocontrol (Scheme 11.17). A lower stereocontrol was observed when the alkyl group of the ketone was sterically hindered.


Scheme 11.16 Addition of lithiated methyl p-tolyl sulfoxide to benzaldehyde and tetralone.

The high stereocontrol observed in this process was ascribed to a stabilizing pstacking interaction between the naphthyl and the phenyl groups in the chelated transition state. In agreement with this hypothesis, a low stereocontrol was achieved with bis-alkyl ketones.

Scheme 11.17 Stereoselective reaction of (S)-lithiomethyl 1-naphthyl sulfoxide with phenyl n-alkyl ketones.

A stereoselective addition of methyl aryl sulfoxides to benzaldehyde was described by Braun and Hild, who showed that the use of the Zn (II) derivative of p-tolyl methyl sulfoxide is essential in order to achieve high diastereocontrol (Scheme 11.18) [28]. Indeed, it was shown previously that the lithium derivative undergoes scarcely stereoselective addition [diastereomeric ratio (dr) from 7 : 3 to 1 : 1] to several different carbonyl compounds [26, 29].

Scheme 11.18 Addition of zinc (II) derivative of p-tolyl methyl sulfoxide to benzaldehyde.

The formation of a stereogenic center at the a-sulfinyl carbon has been also widely investigated. The pioneer in this process was once again Durst and colleagues [30], who showed that lithiated methyl benzyl sulfoxide reacts with acetone affording the corresponding product (Scheme 11.19) with a dr of 15 : 1, which can vary depending on the amount of lithium salts in the reaction environment.

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Scheme 11.19 Stereoselective generation of an a-sulfinyl stereocenter with acetone.

In analogy with the reaction in Scheme 11.18, Pyne and Boche showed that high diastereofacial stereocontrol in the reaction of benzyl sulfoxides to aldehydes can be achieved by using zinc (II) derivatives [31]. Thus, starting from tert-butyl benzyl sulfoxide and aryl or alkyl aldehydes (Scheme 11.20), the reaction afforded – with moderate to good simple diastereocontrol – the corresponding anti carbinols, whereas total diastereofacial control at the a-sulfinyl carbon was obtained. As the reaction was under kinetic control, the observed outcome was rationalized on the basis of a Zimmerman–Traxler chair-like transition state.

Scheme 11.20 Stereoselective reaction of Zn(II) benzyl sulfoxide derivative with aldehydes.

Similar results were obtained for the reactions of benzyl p-tolylsulfoxide with long-chain aliphatic aldehydes, when the reaction was used as a key stereocontrolled step to prepare intermediates of the pheromone disparlure [32]. The carboxylation of a prostereogenic a-sulfinyl carbon with CO2 (Scheme 11.21) occurred with moderate stereoselectivity under kinetic control (reaction time about 1 min) [33]. Upon longer reaction times thermodynamic control was achieved, due to the high acidity of the residual a-sulfinyl proton. As observed already for other reactions involving a-sulfinyl carbanions (see above), the stereoselectivity was strongly dependent on the quantity of lithium salts in the reaction medium. Under kinetic control, the stereoselectivity was higher in the presence of lower amounts of Liþ.

Scheme 11.21 Carboxylation of a prostereogenic a-sulfinyl carbon.


Additional stereogenic centers on the a-sulfinyl carbon framework may have a profound influence on the stereocontrol. In the synthesis of juvabiol [34], different stereoisomers of the starting a-sulfinyl carbanion (Scheme 11.22) gave a totally different sense of stereocontrol with 3-methylbutanal, depending on the configuration of the neighboring carbon center. In both cases, however, a 3 : 2 ratio in favor of the 1,3-anti stereoisomer was obtained.

Scheme 11.22 Influence of additional stereogenic centers on the a-sulfinyl carbon framework.

More recently, Toru and colleagues reported the stereoselective addition of b-silyl-a-sulfinyl carbanions (see Scheme 11.3) to symmetric ketones (dr up to 98 : 2) [9]. Lithiated vinyl sulfoxides were also reacted with aldehydes. In general, the stereocontrol was satisfactory only with highly hindered aldehydes, such as pivalic aldehyde, whereas the stereocontrol was negligible with less bulky aldehydes (Scheme 11.23) [35]. Even starting from a mixture of (E ) and (Z) vinyl sulfoxides the products were obtained as homogeneously (E )-configured molecules.

Scheme 11.23 Stereo-convergent reaction of lithiated vinyl sulfoxide with pivalic aldehyde.

The carboxylation of a-lithiated vinyl sulfoxides is also highly stereoconvergent, leading to the corresponding (E )-a-sulfinyl-esters [36]. One useful application of the reaction of a-sulfinyl carbanions derived from vinyl sulfoxides and aldehydes is in the stereocontrolled synthesis of a vitamin E intermediate [37]. In that case, stereocontrol was ensured by the intramolecular

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Scheme 11.24 Synthesis of a vitamin E intermediate via a vinyl sulfoxide-derived carbanion.

chelation of an acetal oxygen by the lithium atom (Scheme 11.24), and the corresponding b-hydroxy sulfoxide was formed as a sole diastereomer. Among the most important reactions of a-sulfinyl carbanions with carbonyl compounds, mention should certainly be made of the additions of magnesium derivatives of a-sulfinyl acetates to aldehydes and ketones. The use of a suitable Grignard reagent (e.g. tert-butyl magnesium bromide) as the base is essential for the success of the methodology [38]. Thus, a-sulfinyl acetates have been used successfully as chiral equivalents of acetates to generate, with high stereocontrol, a carbinol center in the reaction with aldehydes (mainly) and ketones. Solladie´ applied this methodology to the synthesis of g- and d-lactones, with high stereochemical purity [39]. In general, the a-sulfinyl stereocenter was reductively cleaved after the condensation step (Scheme 11.25), and the resulting carbinols generally had a high enantiopurity.

Scheme 11.25 Reaction of a-sulfinyl acetates with carbonyl compounds.

Another important application of this methodology was reported by Corey and coworkers [40], who exploited it for a key-step in the synthesis of the potent tubu-

Scheme 11.26 a-Sulfinyl acetate in Corey’s synthesis of maytansine.


Figure 11.4 Proposed transition state for the stereoselective reaction of magnesium-a-sulfinyl acetates with aldehydes.

lyin binder maytansine (Scheme 11.26). The target b-hydroxyacid precursor was obtained with high stereocontrol after reductive desulfinylation. Sulfinylacetamide anions were also reported to undergo reaction with aldehydes with a very high degree of stereoselectivity [41]. The above-described reactions can be rationalized through a cyclic chelated transition state in which the magnesium cation coordinates at the same time: (1) the sulfinyl; (2) a carboxyl; and (3) the carbonyl oxygens (Figure 11.4). The aldehyde approaches the sulfinyl nucleophile from the sulfur lone-pair site, and assumes the orientation that allows for the minimal steric and electronic interactions between the carbonyl substituents and the sulfinyl nucleophile. a-Sulfinyl a-methyl acetates were also exploited as chiral a-propanoate equivalents in the reaction with aldehydes [42]. In that case, the stereocontrol was generally higher with alkyl rather than with aryl aldehydes (Scheme 11.27).

Scheme 11.27 Reaction of a-sulfinyl a-methyl acetates with aldehydes.

Masked a-sulfinyl acetates such as 2-(arylsulfinylmethyl)oxazoles have also been used as chiral equivalents of acetates in the reaction with aldehydes [43]. In general, the observed stereocontrol was rather modest, both with Mgþþ and Liþ as counterions (Scheme 11.28). An interesting use of a-chloro-a-sulfinyl carbanions in the synthesis of cyclic quaternary amino acids was recently reported by Satoh and coworkers [44]. The intermediate chlorhydrines obtained by reaction with b-tetralone were directly converted into the corresponding oxiranes, obtained as a 3 : 1 mixture of diastereomers (Scheme 11.29).

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Scheme 11.28 Reaction of 2-(arylsulfinylmethyl)oxazoles with aldehydes.

Scheme 11.29 Enantiopure cyclic a-amino-acids from a-chloro-a-sulfinyl carbanions.

Other attempts to achieve high stereocontrol in the addition of a-sulfinyl carbanions to carbonyl compounds were based on the use of C2-symmetric bis(sulfoxides) [45]. In that case, the degree of stereocontrol was indeed high both with alkyl and aryl aldehydes (Scheme 11.30).

Scheme 11.30 Reaction of a C2-symmetric bis(sulfoxide) with aldehydes.

The methodology was next extended to cyclic C2-symmetric bis(sulfoxides) [46], thus achieving near-total stereocontrol in the reaction with benzaldehyde (Scheme 11.31).

Scheme 11.31 Reaction of a cyclic C2-symmetric bis(sulfoxide) with benzaldehyde.

11.6 Additions of a-Sulfinyl Carbanions to Imines and Related Compounds


The CbN bond is generally less electrophilic than the CbO bond, and therefore the reactivity of a-sulfinyl carbanions with imines and related compounds is somewhat lower. It can, nonetheless, be increased by the use of electron-withdrawing substituents on the nitrogen. However, better results in terms of stereocontrol have been achieved with additions to CbN bonds rather than with CbO bonds. In 1973, Tsuchihashi et al. reported that the reaction between N-(benzylidene)aniline and a lithium derivative of p-tolyl methyl sulfoxide occurred with excellent diastereoselectivity to afford the corresponding b-sulfinylethylamine as a sole reaction product (Scheme 11.32) [47]. Unfortunately, in this report the reaction temperature – which is a critically important factor (see below) – was not clearly mentioned.

Scheme 11.32 The first report by Tsuchihashi on the addition of a-sulfinyl carbanions to imines.

However, some 15 years later these data were substantially challenged by Kagan and colleagues, who failed to reproduce the reported diastereoselectivity [48]. Indeed, under the conditions reported by Tsuchihashi the diastereomers were observed in a ratio of 75 : 25. Moreover, Kagan et al. found that the stereochemical outcome of the reaction was affected in a surprisingly important manner by the temperature of formation of the lithiated sulfoxide. The typical reaction temperature with the imine electrophiles was reported to be 78 8C. On the other hand, a systematic study conducted by Pyne and coworkers [49] revealed that the diastereoselectivity of the reactions of various chiral a-sulfinyl carbanions with imines was subject to kinetic-thermodynamic control, and the addition reaction was reversible at a temperature of about 0 8C (Scheme 11.33).

Scheme 11.33 Pyne’s kinetic/thermodynamic addition of a-sulfinyl carbanions to imines.

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In general, a remarkably lower diastereoselection was achieved under equilibrium control. The observed kinetic stereocontrol was interpreted with a classical chair-like Zimmerman–Traxler transition state (see Scheme 11.33). As an application of the methodology, Pyne and Dikic reported the stereoselective synthesis of tetrahydropalmatine (Scheme 11.34) [50].

Scheme 11.34 Synthesis of (þ)-tetrahydropalmatine.

Some years later, the present authors’ group reinvestigated the reaction of a-sulfinyl carbanions to arylimines having different electronic densities (Scheme 11.35) [51]. The results confirmed the findings of Pyne, namely that the reaction is stereoselective under kinetic control at lower temperatures, but becomes thermodynamically controlled at temperatures close or above 0 8C. No meaningful effect of the temperature of formation of the lithium sulfoxide on the degree of stereocontrol was detected. Interestingly, the diastereocontrol was also found to decrease when increasing the electron-density on the arylidene ring, with the lower stereocontrol values being observed for imines derived from more electron-deficient aldehydes.

Scheme 11.35 Effect of the electron-density of the arylidene ring of imines on the diastereoselectivity of the reaction with a-sulfinyl carbanions.

These results were further confirmed a few years later by Tanner et al. (Scheme 11.36) [52], who also showed that the use of external ligands, such as C2-symmetric bis-sulfonamides, could remarkably improve the stereocontrol of these kinetically controlled processes.


Scheme 11.36 Effect of an external ligand on the stereoselectivity of a-sulfinyl carbanions to imines.

Another strategy to improve the stereoselectivity of the addition of a-sulfinyl carbanions to arylimines was proposed by Garcia-Ruano and coworkers, who employed chiral sulfinimines as electrophiles, thus exploiting a double stereodifferentiation process (Scheme 11.37) [53]. A match was observed between (S)sulfinimine and lithiated (R)-ethyl-p-tolyl-sulfoxide, whereas mismatch and mixtures of diastereomeric products were observed with the (S)-sulfoxide. In the former case, excellent stereocontrol was observed by allowing the reaction to take place under thermodynamic control at 0 8C. The reasons for the observed outcome are unclear and rather surprising, given the acyclic nature of the products; however, the authors reported a lower (albeit still good) stereocontrol under kinetic conditions at 78 8C. Very remarkably, in this study the a-sulfinyl carbanions could be used as chiral a-hydroxy-carbanion equivalents. This was possible as a result of using the ‘‘Non-Oxidative Pummerer Reaction’’ (NOPR), a process discovered a few years earlier by Zanda and coworkers [54]. This can be used to displace the sulfinyl group of b-sulfinylamines with a hydroxy group with total stereoselectivity and inversion of configuration at the carbon stereocenter, thus affording b-amino-alcohols.

Scheme 11.37 Stereoselective synthesis of b-amino-alcohols using lithiated alkyl sulfoxides and sulfinimines.

Later, Bravo and colleagues also investigated the stereoselective reaction of a-sulfinyl carbanions to non-enolizable N-PMP-imines derived from fluoroalkyl aldehydes, as a means of preparing the corresponding fluoroalkyl-glycinols and fluoroalanines in enantiopure form (Scheme 11.38) [55]. In contrast, the additions of a-sulfinyl carbanions to N-Cbz imines of trifluoropyruvate (Scheme

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11.38) proceeded with generally low stereocontrol, thus providing a synthetically useful entry to stereochemically pure a-trifluoromethyl a-amino acids in both enantiomeric forms [56]. The low stereocontrol was ascribed to the poor Lewis basicity of the imine nitrogen, that could not be effectively chelated by the lithium counterion, thus leading to an acyclic, scarcely stereodirecting transition state.

Scheme 11.38 The addition of a-sulfinyl carbanions to fluoroalkyl imines.

In order to achieve the reaction of a-sulfinyl carbanions with enolizable alkylimines, Zanda and coworkers exploited the potential of a-amino sulfones as insitu precursors of activated N-Cbz imines. In a first application, the synthesis of the stereochemically pure amino acid statine was obtained (Scheme 11.39) [57]. In the key reaction, lithiated p-tolyl-homoallylic sulfoxide was reacted with a NCbz-imine generated in situ from an a-amino-sulfone, affording the correct diastereomeric statine precursor with good stereocontrol. An analogous synthetic strategy was employed to synthesize a trifluoromethyl analogue of statine, which was incorporated into a bis-trifluoromethylated pepstatin A analogue [58]. Next, by a closely related process which made use of b-amino-a-sulfinyl carbanions as nucleophiles, different hydroxyethylamine dipeptide isosteres – including an epimer of the anti-HIV drug saquinavir – were synthesized in stereocontrolled manner [59].

Scheme 11.39 The synthesis of statine.

11.7 Conclusions

Strongly activated N-sulfonyl imines were also successfully reacted with asulfinyl carbanions. One of the most interesting reports was made by Bhat and colleagues [60], who described the stereoselective synthesis of b-aminophenylpropionic acid through a stereoselective addition of t-butyl (R)-p-tolylsulfinyl acetate to N-p-toluenesulfonyl imines (Scheme 11.40). The high diastereocontrol was rationalized once again through a cyclic chelated Zimmerman–Traxler-like transition state. Unsaturated N-sulfonylimines were also used as electrophiles in a stereoselective reaction with methyl p-tolylsulfoxide [61].

Scheme 11.40 Synthesis of enantiopure b-aminophenylpropionic acid.

The addition of a-sulfinyl carbanions to the CbN bond of nitrones was applied to the stereocontrolled synthesis of the tetrahydroisoquinoline framework [62]. Although the addition reaction was scarcely stereoselective with phenyl-, methyland tert-butyl-benzyl sulfoxides, a dramatic increase in stereoselectivity was achieved with 2-methoxy-1-naphthyl-benzyl sulfoxide (Scheme 11.41).

Scheme 11.41 Addition of a-sulfinyl carbanions to nitrones.

11.7 Conclusions

The results of more than 40 years’ of synthetic research in the field of a-sulfinyl carbanions have demonstrated the importance and versatility of these intermediates in a number of reactions. Typically, the most common conjugate additions of a-sulfinyl carbanions consist of reactions with alkylating agents, or carbonyl

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compounds (aldehydes and ketones), or CbN compounds (imines and nitrones). Among these reactions, the latter are probably the most efficient in terms of stereocontrol. Moreover, the conjugate additions to Michael acceptors have also demonstrated their value and potential in asymmetric synthesis. As a final comment, it is likely that the synthetic power of a-sulfinyl carbanions in synthesis will be fully expressed only when it is possible to displace, stereoselectively, the sulfinyl auxiliary by means of general and straightforward processes. Hopefully, it will then be possible to produce sulfur-free stereochemically pure compounds of biomedicinal and pharmaceutical interest.

References 1 For very recent reviews see: (a) H. Pellissier, Tetrahedron 2006, 62, 5559–5601 and references therein; (b) C. H. Senanayake, D. Krishnamurthy, Z.-H. Lu, Z. Han, I. Gallou, Aldrichim. Acta 2005, 38, 93–104. 2 (a) J. F. Biellmann, J. Vicens, Tetrahedron Lett. 1974, 15, 2915–2918; (b) G. Chassaing, R. Lett, A. Marquet, Tetrahedron Lett. 1978, 19, 471–474. 3 (a) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1962, 84, 866–867; (b) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1345–1353. 4 A. Rauk, E. Buncel, R. Y. Moir, S. Wolfe, J. Am. Chem. Soc. 1965, 87, 5498–5500. 5 T. Durst, J. Am. Chem. Soc. 1969, 91, 1034–1035. 6 T. Satoh, M. Hirano, A. Kuroiwa, Y. Kaneko, Tetrahedron 2006, 62, 9268–9279 and references therein. 7 T. Durst, R. Viau, M. R. McCrory, J. Am. Chem. Soc. 1971, 93, 3077–3078. 8 K. Nishihata, M. Nishio, Tetrahedron Lett. 1976, 17, 1695–1698. 9 S. Nakamura, H. Takemoto, Y. Ueno, T. Toru, T. Kakumoto, T. Hagiwara, J. Org. Chem. 2000, 65, 469–474. 10 (a) S. Bory, R. Lett, B. Moreau, A. Marquet, Tetrahedron Lett. 1972, 13, 4921–4924; (b) S. Bory, A. Marquet, Tetrahedron Lett. 1973, 14, 4155–4158. 11 P. Bravo, G. Resnati, F. Viani, Tetrahedron Lett. 1985, 26, 2913–2916. 12 R. Tanikaja, K. Hosoya, K. Hamamura, A. Kaji, Tetrahedron Lett. 1987, 28, 3705–3706.

13 T. Sato, T. Itoh, T. Fujisawa, Tetrahedron Lett. 1987, 28, 5677–5680. 14 H. Ohta, S. Matsumoto, T. Sugai, Tetrahedron Lett. 1990, 31, 2895–2898. 15 (a) G. Solladie´, F. Matloubi-Moghadam, C. Luttmann, C. Mioskowski, Helv. Chim. Acta 1982, 65, 1602–1606; (b) P. A. Bartlett, J. Am. Chem. Soc. 1976, 98, 3305–3312. 16 G. H. Posner, P.-W. Tang, J. P. Mallamo, Tetrahedron Lett. 1978, 19, 3995–3998. 17 H. Takei, H. Sugimura, M. Miura, H. Okamura, Chem. Lett. 1982, 1209–1212 and references therein. 18 S.-S. P. Chou, P.-W. Liang, Tetrahedron Lett. 2002, 43, 4865–4870. 19 F. Matloubi, G. Solladie´, Tetrahedron Lett. 1979, 20, 2141–2144. 20 L. Colombo, C. Gennari, G. Resnati, C. Scolastico, J. Chem. Soc., Perkin Trans. 1, 1981, 1284–1286. 21 M. Casey, A. C. Manage, L. Nezhat, Tetrahedron Lett. 1988, 29, 5821–5824. 22 S. Nakamura, Y. Watanabe, T. Toru, J. Org. Chem. 2000, 65, 1758–1766. 23 N. Maezaki, H. Sawamoto, S. Yuyama, R. Yoshigami, T. Suzuki, M. Izumi, H. Ohishi, T. Tanaka, J. Org. Chem. 2004, 69, 6335–6340. 24 H. Acherki, C. Alvarez-Ibarra, A. de Dios, M. Gutie´rrez, M. L. Quiroga, Tetrahedron: Asymmetry 2001, 12, 3173–3183. 25 C. R. Johnson, C. W. Schroeck, J. Am. Chem. Soc. 1971, 93, 5303–5305. 26 G. Tsuchihashi, S. Iriuchijima, M. Ishibashi, Tetrahedron Lett. 1972, 13, 4605–4608.

References 27 H. Sakuraba, S. Ushiki, Tetrahedron Lett. 1990, 31, 5349–5352. 28 M. Braun, W. Hild, Chem. Ber. 1984, 117, 413–414. 29 N. Kunieda, M. Kinoshita, J. Nokami, Chem. Lett. 1977, 289–292. 30 T. Durst, M. Molin, Tetrahedron Lett. 1975, 16, 63–66. 31 S. Pyne, G. Boche, J. Org. Chem. 1989, 54, 2663–2667. 32 D. G. Farnum, T. Veysoglu, A. M. Carde´, B. Duhl-Emswiler, T. A. Pancoast, T. J. Reitz, R. T. Carde´, Tetrahedron Lett. 1977, 18, 4009–4012. 33 K. Nishihata, M. Nishio, Tetrahedron Lett. 1976, 17, 1695–1698. 34 D. R. Williams, J. G. Phillips, J. Org. Chem. 1981, 46, 5452–5454. 35 S. House, P. R. Jenkins, J. Fawcett, D. R. Russell, J. Chem. Soc., Chem. Commun. 1987, 1844–1845. 36 H. Kosugi, M. Kitaoka, A. Takahashi, H. Uda, J. Chem. Soc., Chem. Commun. 1986, 1268–1269. 37 G. Solladie´, G. Moine, J. Am. Chem. Soc. 1984, 106, 6097–6098. 38 C. Mioskowski, G. Solladie´, Tetrahedron 1980, 36, 227–236. 39 G. Solladie´, F. Matloubi-Moghadam, J. Org. Chem. 1982, 47, 91–94. 40 E. J. Corey, L. O. Weigel, A. R. Chamberlin, H. Cho, D. H. Hua, J. Am. Chem. Soc. 1980, 102, 6613–6615. 41 R. Annunziata, M. Cinquini, F. Cozzi, F. Montanari, A. Restelli, Tetrahedron 1984, 40, 3815–3822 and references therein. 42 (a) G. Solladie´, F. Matloubi-Moghadam, C. Luttmann, C. Mioskowski, Helv. Chim. Acta 1982, 65, 1602–1606; (b) C. Papageorgiou, C. Benezra, Tetrahedron Lett. 1984, 25, 1303–1306. 43 R. Annunziata, M. Cinquini, A. Gilardi, Synthesis 1983, 1016–1018. 44 T. Satoh, M. Hirano, A. Kuroiwa, Tetrahedron Lett. 2005, 46, 2659–2662. 45 B. Delouvrie´, L. Fensterbank, F. Najera, M. Malacria, Eur. J. Org. Chem. 2002, 3507–3525. 46 M. E. Vargas-Diaz, S. Lagunas-Rivera, P. Joseph-Nathan, J. Tamariz, L. G. Zepeda, Tetrahedron Lett. 2005, 46, 3297–3300.

47 G. Tsuchihashi, S. Iriuchijima, K. Maniwa, Tetrahedron Lett. 1973, 14, 3389–3392. 48 B. Ronan, S. Marchalin, O. Samuel, H. B. Kagan, Tetrahedron Lett. 1988, 29, 6101–6104. 49 S. G. Pyne, B. Dikic, J. Chem. Soc., Chem. Commun. 1989, 826–827. 50 S. G. Pyne, B. Dikic, J. Org. Chem. 1990, 55, 1932–1936. 51 P. Bravo, S. Capelli, M. Crucianelli, M. Guidetti, A. L. Markovsky, S. V. Meille, V. A. Soloshonok, A. E. Sorochinsky, F. Viani, M. Zanda, Tetrahedron 1999, 55, 3025–3040. 52 B. Pedersen, T. Rein, I. Sotofte, P.-O. Norrby, D. Tanner, Collect. Czech. Chem. Commun. 2003, 68, 885–898. 53 J. L. Garcia Ruano, A. Alcudia, M. del Prado, D. Barros, M. C. Maestro, I. Fernandez, J. Org. Chem. 2000, 65, 2856–2862. 54 (a) A. Arnone, P. Bravo, L. Bruche´, M. Crucianelli, L. Vichi, M. Zanda, Tetrahedron Lett. 1995, 36, 7301–7304; (b) P. Bravo, M. Zanda, C. Zappala`, Tetrahedron Lett. 1996, 37, 6005–6006. 55 P. Bravo, M. Guidetti, F. Viani, M. Zanda, A. L. Markovsky, A. E. Sorochinsky, I. V. Soloshonok, V. A. Soloshonok, Tetrahedron 1998, 54, 12789–12806. 56 P. Bravo, S. Capelli, V. P. Kukhar, S. V. Meille, V. A. Soloshonok, F. Viani, M. Zanda, Tetrahedron: Asymmetry 1994, 5, 2009–2018. 57 C. Pesenti, P. Bravo, E. Corradi, M. Frigerio, S. V. Meille, W. Panzeri, F. Viani, M. Zanda, J. Org. Chem. 2001, 66, 5637–5640. 58 (a) C. Pesenti, A. Arnone, S. Bellosta, P. Bravo, M. Canavesi, E. Corradi, M. Frigerio, S. V. Meille, M. Monetti, W. Panzeri, F. Viani, R. Venturini, M. Zanda, Tetrahedron 2001, 57, 6511–6522; (b) C. Binkert, M. Frigerio, A. Jones, S. Meyer, C. Pesenti, L. Prade, F. Viani, M. Zanda, ChemBioChem 2006, 7, 181–186. 59 C. Pesenti, A. Arnone, P. Arosio, M. Frigerio, S. V. Meille, W. Panzeri, F. Viani, M. Zanda, Tetrahedron Lett. 2004, 45, 5125–5129.

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11 Stereoselective Reactions with a-Sulfinyl Carbanions 60 A. V. Sivakumar, G. S. Babu, S. V. Bhat, Tetrahedron: Asymmetry 2001, 12, 1095–1099. 61 S. Raghavan, A. Rajender, Tetrahedron 2004, 60, 5059–5067.

62 (a) S. G. Pyne, A. R. Hajipour, K. Prabakaran, Tetrahedron Lett. 1994, 35, 645–648; (b) for a pioneering use of a-sulfinyl carbanions with nitrones, see: R. Annunziata, M. Cinquini, F. Cozzi, Synthesis 1982, 929–931.

375

12 Asymmetric Reactions of a-Sulfonyl Carbanions Hans-Joachim Gais

Abstract

This chapter deals with the structure, dynamics, configurational stability and asymmetric reactions of a-sulfonyl carbanions. Asymmetric reactions of asulfonyl carbanions can be performed either by the generation of: (1) a configurationally labile chiral a-sulfonyl carbanion containing an additional stable stereogenic center in its backbone and its subsequent reaction with an electrophile (external quench); (2) a configurationally labile chiral a-sulfonyl carbanion carrying a chiral ligand at the Li-atom from a racemic or prochiral sulfone and its subsequent reaction with an electrophile (external quench); (3) a configurationally labile chiral a-sulfonyl carbanion in the presence of a reactive electrophile (internal quench) through enantioselective deprotonation of a prochiral sulfone with a chiral base; or (4) a configurationally stable chiral a-sulfonyl carbanion through deprotonation of an enantiomerically pure sulfone and its subsequent reaction with an electrophile (external quench). Examples of all four strategies are discussed.

12.1 Introduction

According to a number of studies, including X-ray crystal structure analysis [1], ab initio calculations [2], NMR spectroscopy [1f,g,j,l, 3], acidity measurement [4], reactions with electrophiles [5], polarimetry [1f ], and cryoscopy [1f,g,j], the acyclic a-sulfonyl carbanions 1 and 2 carrying two different substituents at the Caatom adopt a chiral CaaS conformation in which the lone pair orbital at the Ca-atom approximately bisects the OaSaO angle (Figure 12.1) [6, 7]. While the aryl-alkyl-substituted a-sulfonyl carbanions 1 have a planar Ca-atom [1f,g], that of the dialkyl-substituted carbanions 2 is strongly pyramidalized [1h,j,l]. The planar a-sulfonyl carbanion 1 exhibits axial chirality, and the pyramidalized a-sulfonyl carbanion 2 possesses both axial and central chirality. The Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

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12 Asymmetric Reactions of a-Sulfonyl Carbanions

Figure 12.1 Structure of the lithium salts of chiral a-sulfonyl carbanions.

lithium salts of a-sulfonyl carbanions exist in tetrahydrofuran (THF) solution mainly as monomeric contact ion pairs of type 3, 4 or/and 5, the Li-atom of which is coordinated to the O-atom (s) [1f,g,j, 4a]. Besides the monomeric contact-ion pairs, dimeric OaLi contact-ion pairs of type 7 also exist in THF solution [1j,l]. Monomeric and dimeric OaLi (K) contact-ion pairs of the lithium and potassium salts of a-sulfonyl carbanion of types 3, 4, 5 and 7 carrying the various ligands L at the metal atom have been prepared and their crystal structure determined using X-ray analysis [1]. The use of [2.1.1]-cryptand as ligand allowed the isolation and structure determination of an inclusion complex of the lithium salt of the a-sulfonyl carbanion 2 (R1 ¼ R2 ¼ Me, R3 ¼ Ph), which may be regarded as a solvent-separated contact-ion pair [1h]. Recently, the crystal structure of the lithium a-sulfonyl carbanion salt 6 (R1 ¼ H, R2 ¼ Me, R3 ¼ Ph), the Li-atom of which is coordinated to the Ca-atom, has been described [1p]. Interestingly, the CaaLi-coordinated carbanion 6 adopts the same chiral CaaS conformation as the OaLi-coordinated carbanions 3, 4, 5 and 7. These results show that monomeric

12.1 Introduction

Figure 12.2 Enantiomerization of a-sulfonyl carbanion salts. (Priority sequence R1 4R2 and [S]4R1 4R2 ).

and dimeric CaLi contact-ion pairs of type 6 could also exist in THF solution. According to ab initio calculations [2] and acidity measurements [4], a-sulfonyl carbanions are predominantly stabilized by electrostatic interaction between the negatively charged Ca-atom and the positively charged S-atom. A second important mechanism of stabilization is negative hyperconjugation through nC –s*SR3 interaction. Stabilization of the a-sulfonyl carbanion by a pC –dS-interaction plays no role, and a pO –dS-interaction in a-sulfonyl carbanions and sulfones with the formation of SbO double bonds is of no relevance [8]. The enantiomerization of the a-sulfonyl carbanion 1, either free or Li-coordinated, to give ent-1 requires a rotation around the CaaS bond, while that of 2 necessitates an inversion of the Ca-atom with formation of diastereomer 8 followed by a rotation around the CaaS bond, or vice versa, to give ent-2 (Figure 12.2). Ab initio calculations of a-sulfonyl carbanions revealed a low barrier towards inversion of the Ca-atom and a much higher barrier towards rotation around the CaaS bond [2b,h]. The rotational barrier is mainly caused by steric effects and negative hyperconjugation which is most significantly expressed in the case of the S-trifluoromethylsulfonyl carbanions [2h]. Dynamic 1H NMR spectroscopy of the lithium salts of the racemic alkyl-aryl- and dialkyl-substituted S-phenylsulfonyl carbanions rac-9 and rac-11, respectively, which were prepared from the corresponding sulfones, in THF revealed barriers of enantiomerization DGA of 9.6 kcal mol1 and 9.7 kcal mol1 at the given temperatures (Figure 12.3) [1f ]. The barrier of the hexamethylphosphoramide (HMPA)-coordinated salt rac-10 is slightly higher than that of the THF-coordinated salt rac-9. The similar barriers of rac-9 (the Ca-atom of which is planar) and of rac-11 (the Ca-atom of which is strongly pyramidalized) show that rotation around the CaaS bond and not inversion of the Ca-atom is rate-determining. The low enantiomerization barriers of rac-9, rac-10, and rac-11 preclude the successive synthesis of chiral Ca-monoand Ca-disubstituted S-phenylsulfonyl carbanions in enantiomerically highly enriched form and asymmetric reaction with electrophiles. An increase in steric hindrance around the CaaS bond of a a-sulfonyl carbanion should lead to an increase of its enantiomerization barrier. This was de-

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Figure 12.3 Enantiomerization of a-sulfonyl carbanions.

monstrated in the case of the lithium salt of the S-tert-butylsulfonyl carbanion rac-12 by using dynamic 1H NMR spectroscopy which revealed a barrier for enantiomerization DGA of 13.5 kcal mol1. Dynamic 1H NMR spectroscopy of the S-trifluoromethyl-substituted lithium salt rac-13 in THF, potassium salt rac-14 in dimethylsulfoxide (DMSO) and ammonium salt rac-15 in DMSO, all of which were generated from the corresponding sulfone, gave enantiomerization barriers DGA of 16.0, 15.7, and 15.7 kcal mol1, respectively [1g]. Thus, S-trifluoromethylsulfonyl carbanions exhibit a higher configurational stability than the corresponding S-tert-butylsulfonyl carbanions, despite the smaller steric size of the trifluoromethyl group. The higher configurational stability of the Strifluoromethylsulfonyl carbanions as compared to their S-tert-butyl analogues is mainly due to the much stronger negative hyperconjugative nC –s*SR interaction in the fluorinated carbanions [2h]. The kinetic results obtained with rac-13, rac-14 and rac-15 also show that the counter-ion and structure of the contact-ion pair have only small effects on the height of the enantiomerization barrier. While

12.1 Introduction

the lithium salt rac-13 is a monomeric OaLi contact-ion pair in THF, the potassium salt rac-14 exists in DMSO solution as free solvated ions and the ammonium salt rac-15 forms in DMSO solution most likely contact-ion pairs with an ion pair interaction being much different from that of the lithium salt rac-13. A polarimetric determination of the racemization of the enantiomerically highly enriched S-tert-butyl substituted lithium salt 18, which was prepared from the corresponding enantiomerically pure sulfone (vide infra), in THF in the presence of dimethylpropylurea (DMPU), revealed a pseudo first-order kinetics with a free energy of activation for racemization DGA of 13.0 kcal mol1 and an extrapolated half-life of approximately 3 h at 105 8C (Figure 12.4) [1g,f ]. The polarimetric determination of the racemization kinetics of the enantiomerically highly enriched S-trifluoromethyl-substituted lithium salt 17, which was obtained from the corresponding enantiomerically pure sulfone (vide infra), in THF gave an activation energy for racemization DGA of 17.2 kcal mol1 and an extrapolated half-life of approximately 30 days at 78 8C. A comparison of Figures 12.3 and 12.4 shows that there is a good correlation between the enantiomerization barrier DGA of rac-17 as determined by dynamic 1H NMR spectroscopy and the racemization barrier DGA of 17 as deduced by polarimetry. In summary, while the configurational stability of the lithium salts of S-tertbutyl- and S-trifluoromethylsulfonyl carbanions carrying two alkyl groups or an alkyl and an aryl group at the Ca-atom is relatively high, that of the corresponding S-phenylsulfonyl carbanions is relatively low. Because of a reduced steric hindrance of CaaS bond rotation, monosubstituted S-phenyl-, S-tert-butyl-

Figure 12.4 Activation parameters fort the racemization of the lithium salts of a-sulfonyl carbanions.

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and S-trifluoromethylsulfonyl carbanions are expected to have a significantly lower enantiomerization barrier than their Ca-disubstituted analogues. Taken together, these results suggest that asymmetric reactions of chiral a-sulfonyl carbanions can be realized under one of the following conditions:

• • • •

The generation of a configurationally labile chiral a-sulfonyl carbanion containing an additional stable stereogenic center in its backbone and its subsequent reaction with an electrophile (external quench). The generation of a configurationally labile chiral a-sulfonyl carbanion carrying a chiral ligand at the Li-atom from a racemic or prochiral sulfone and its subsequent reaction with an electrophile (external quench). The generation of a configurationally labile chiral a-sulfonyl carbanion in the presence of a reactive electrophile (internal quench) through enantioselective deprotonation of a prochiral sulfone with a chiral base. The generation of a configurationally stable chiral a-sulfonyl carbanion through deprotonation of an enantiomerically pure sulfone and its subsequent reaction with an electrophile (external quench).

12.2 Configurationally Stable a-Sulfonyl Carbanions

The relatively high configurational stability of the S-trifluoromethyl and S-tertbutyl carbanion salts 17 and 18, respectively, suggested their enantioselective synthesis from the corresponding enantiomerically pure sulfones and a study of the enantioselectivity and stereochemistry of their formation and reaction with electrophiles [1f, 5j]. Treatment of the enantiomerically pure sulfone 19 with n-BuLi led to the formation of the chiral non-racemic carbanion salt 17, the protonation of which either with CF3CO2H or HBF4 gave sulfone 19, in both cases with 82% enantiomeric excess (ee) (Figure 12.5). Deuteration of carbanion 17 showed the complete deprotonation of sulfone 19 under the conditions applied. Thus, deprotonation of sulfone 19 and protonation of carbanion 17 both proceeded with high enantioselectivity under overall retention of configuration. Similar results were recorded in the deprotonation of the enantiomerically pure sulfone 20 and the protonation of carbanion 18, which gave sulfone 20 with 90% ee. The application of t-BuLi in the deprotonation of sulfones 19 and 20 under otherwise identical conditions gave sulfones 19 and 20, respectively, with slightly higher ee-values. It is reasonable to assume that the deprotonation of sulfones 19 and 20 with n-BuLi occurs after a prior coordination of the base to the O-atom (s) in a CaaS conformation in which the Ca-H-atom and the O-atom (s) of the sulfone are in syn position. Similarly, protonation of carbanions 17 and 18 should preferentially take place syn to the O-atoms because of the pyramidalization of the Ca-atom and a shielding of the anti attack of the electrophile at the Ca-atom by the trifluoromethyl and tertbutyl group, respectively. The higher ee-values of sulfones 19 and 20 in the case

12.2 Configurationally Stable a-Sulfonyl Carbanions

Figure 12.5 Enantioselective generation and protonation of a-sulfonyl carbanions.

of the use of t-BuLi indicate that with this base the enantioselectivity of the deprotonation is slightly higher than with n-BuLi. It should be pointed out that deprotonation of sulfones 19 and 20 in a CaaS conformation in which the Ca-H-atom is anti to the O-atom (s) would give the enantiomeric carbanion salts ent-17 and ent-18, respectively. Deprotonation of the enantiomerically pure sulfone 19 with t-BuLi and the treatment of carbanion 17 with allyl iodide gave the tertiary sulfone 21 with 95% ee (Figure 12.6). A similar deprotonation of sulfone 20 and allylation of carbanion 18 afforded sulfone 22 with 92% ee. Thus, deprotonation and allylation had both occurred with very high enantioselectivity, and the allylation of carbanions 17 and 18 proceeded with higher enantioselectivity than the protonation. The treatment of carbanion 18, which was generated from sulfone 20 by using t-BuLi, with PhCHO furnished a 3 : 2-mixture of the b-hydroxy sulfones 23 and 24, both having an ee-value of 92% (Figure 12.7). In summary, the deprotonation of enantiomerically pure Ca-disubstituted Stert-butyl and S-trifluoromethyl sulfones with RLi allows the generation of chiral a-sulfonyl carbanions with high enantioselectivity. The Ca-atom of theses carbanions is attacked by electrophiles with high enantioselectivity syn to the O-atoms and anti to the substituent at the S-atom.

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Figure 12.6 Enantioselective generation and allylation of a-sulfonyl carbanions.

Figure 12.7 Enantioselective generation and hydroxyalkylation of a-sulfonyl carbanions.

12.3 Configurationally Labile a-Sulfonyl Carbanions

Convincing evidence for the chirality of the a-sulfonyl carbanion 27 was provided for the first time through base-mediated H/D-exchange experiments of the optically pure sulfone 25, which gave sulfone 26 of high optical purity (Figure 12.8). The exchange proceeded with retention of configuration, and the ratios of the second-order rate constants for exchange to the corresponding constants for racemization ranged from 10 to 1980 [5b–5h]. Thus, both deprotonation and deuteration had occurred with high enantioselectivity. It was proposed that the H/D-exchange of 25 occurs via a mechanism whereby the base and alcohol are both coordinated to the sulfone [5d]. Thus, deprotonation of sulfone 25 selectively gives a a-sulfonyl carbanion 27, which is coordinated by the potassium ion and the alcohol, the intramolecular deuteration of which then affords sulfone 26. The H/D-exchange of sulfone 25 with the intermediate formation of carbanion 27 is an example of the enantioselective generation and reaction of a configurationally labile a-sulfonyl carbanion in the presence of the electrophile (internal quench). Alternatively, carbanion 27 was generated through the base-mediated decarboxylation of the optically pure acid 28. The internal pro-


Figure 12.8 Generation and in-situ trapping of chiral a-sulfonyl carbanions.

tonation of 28 with HOt-Bu gave sulfone 25 of high optical purity [5a,g,i]. Thus, the decarboxylation of acid 28 with formation of carbanion 27 and protonation of the latter had both occurred with high enantioselectivity. Similarly, basemediated cleavage of the optically pure hydroxy sulfone 29 in the presence of HOt-Bu furnished sulfone 25 with high optical purity [5g]. The series of generation and internal quench experiments of chiral a-sulfonyl carbanions was concluded with the base-mediated decarboxylation of acid 30 in the presence of the quenching reagent HOt-Bu, which gave sulfone 31 of high optical purity. These results show that, also in the case of the cleavage of sulfones 28, 29 and 30, the internal protonation of the corresponding carbanions 27 and 32 is much faster than their racemization. While carbanion 27 has a pyramidalized Ca-atom, that of carbanion 32 is planar. Thus, the similar results obtained in the decarboxylation of sulfones 28 and 30 show that the observation of the chirality of carbanions 27 and 32 is due to restricted CaaS rotation and not to Ca-inversion.

383

384


Figure 12.9 Generation and in-situ as well as external trapping of chiral a-sulfonyl carbanions.

An interesting set of quenching experiments had been conducted with the enantiomerically pure sulfone ent-25 (Figure 12.9) [6b]. While treatment of ent-25 with lithium diisopropylamide (LDA) in the presence of ClSiMe3 afforded the non-racemic sulfone 33 (the configuration and ee-value of which are, however, not known), the two-step sequence involving the deprotonation of ent-25 with LDA followed by treatment of the carbanion ent-34 with ClSiMe3 gave only the racemic sulfone rac-33. These results are in accordance with the low configurational stability of S-phenylsulfonyl carbanions, and demonstrate the value of internal quench for the realization of asymmetric reactions of a-sulfonyl carbanions. All the examples described thus far for the generation of chiral, non-racemic a-sulfonyl carbanions have involved the application of the corresponding chiral, non-racemic sulfones as starting material. The alternative utilization of prochiral sulfones as starting material would be synthetically of high interest. Treatment of the prochiral sulfone 35 with the enantiomerically pure lithium amide 36 in the presence of ClSiMe3 gave sulfone 37, the configuration of which is, however, not known, with 67% ee (Figure 12.10) [9]. The interpretation of the stereochemical course of the reaction sequence leading from sulfone 35 to the silylated sulfone 37 is difficult at present because of a lack of structural information. Further experiments would be required in order to differentiate between the following two mechanistic schemes. The deprotonation of sulfone 35 could be enantioselective with the preferential formation of either carbanion 38 or ent-38 followed by its trapping with ClSiMe3 before a racemization had occurred to give 37. Alternatively, sulfone 35 could either be selectively or non-selectively deprotonated by the base 36 to give the diastereomeric aminecoordinated carbanion salts 39 and/or 40, which are in rapid equilibrium because of the low configurational stability of a Ca-monosubstituted S-phenylsulfonyl carbanion. The rapid equilibration of the diastereomeric carbanion salts would be followed by a slower but selective silylation of 39 or 40 because of the chiral amine ligand.


Figure 12.10 Generation of chiral a-sulfonyl carbanions from prochiral sulfones with a chiral base.

In a different, but related, approach sulfone 35 was first treated with 2 equiv. of EtMgBr in the presence of the chiral diamine 41 and then with acetone, which afforded sulfone 42 with 33% ee (Figure 12.11) [10]. Here, the formation of the magnesium salts 43 and 44 can be envisioned in which the diamine and the carbanion are coordinated to the Mg-atom. Furthermore, the establishment of an equilibrium between salts 43 and 44 of unknown composition can be assumed because of the rapid enantiomerization of the corresponding Li-coordinated asulfonyl carbanion at the temperature used in the deprotonation step. According to this scheme, the formation of sulfone 42 would imply a preferential reaction of carbanion salt 44 with acetone at low temperatures. However, this mechanistic scheme is speculative as neither the structure nor the dynamics of the magnesium carbanion salts 43 and 44 are known. A higher enantioselectivity was observed in the case of the prochiral allyl sulfone 45, the successive treatment of which with EtMgBr, diamine 41 and acetone furnished sulfone 46 with 80% ee. Here, the formation of a mixture of the carbanion salts 47 and 48 can be assumed. The preferential reaction of 48 with acetone at 100 8C would furnish the hydroxy sulfone 46. Because of the lack of information on the structure and dynamics of structure of salts 47 and 48, the assumption of a Curtin–Hammett situation – that is, a rapid isomerization of the salts and their slower reaction with acetone – is, as in the case discussed above, only speculative.

385

386


Figure 12.11 Generation of chiral a-sulfonyl carbanions from prochiral sulfones in the presence of a stereogenic diamine.

Utilization of the configurationally labile a-sulfonyl carbanion 43 in combination with the chiral ligand 41 and magnesium as the counterion resulted in only low enantioselectivities. A dramatic improvement of the enantioselectivity in the substitution of a prochiral sulfone by the application of a chiral ligand was attained by using the trifluoromethyl sulfone 49 as substrate and the bis(oxazoline)


Figure 12.12 Generation of chiral a-sulfonyl carbanions from prochiral sulfones in the presence of a stereogenic bis(oxazoline).

50 as ligand (Figure 12.12) [11]. Remarkably, high enantioselectivities were recorded by using as little as 2 mol.% of the ligand 50. Treatment of the trifluoromethyl sulfone 49 with n-BuLi in the presence of 2–30 mol.% of the bis(oxazoline) 50, followed by the successive addition of an aromatic aldehyde

387

388


and Me3SiCl, afforded a mixture of the alcohols 51 and 52 with high enantio- and diastereoselectivity in good yields. The addition of Me3SiCl served to trap the lithium alcoholates of 51 and 52, thereby rendering the reaction irreversible. Interestingly, the treatment of racemic 51 with n-BuLi in the presence of 30 mol.% of 50, followed by successive addition of the aromatic aldehyde and Me3SiCl, gave 51 with similar high enantio- and diastereoselectivity. These results may be interpreted as follows because the hydroxyalkylation of sulfone 49 was carried out in toluene at 30 8C. Under the conditions employed, the corresponding carbanion lithium salt derived from 49 is expected to exist as a highly aggregated contact ion pair of low reactivity towards the aldehyde. The addition of 2–30 mol.% of the bidentate ligand 50 is expected to cause to a similar extent a disaggregation with the formation of monomeric contact ion pairs of types 53–58 which should have a higher reactivity than the aggregates. Although S-trifluoromethyl-substituted a-sulfonyl carbanions have a higher configurational stability than the corresponding S-phenyl and S-tert-butyl derivatives (cf . Figures 12.3 and 12.4), carbanions 53–58 bearing a H-atom and a phenyl group at the Ca-atom are expected to have a significantly lower barrier towards CaaS bond rotation than rac13. Thus, because of the lower barrier and the temperature chosen, the lithium carbanion salts 53–58 most likely engage in a rapid diastereomerization. On the basis of these considerations, the selective formation of 51 could, thus, be rationalized by assuming a higher reactivity of 53, 55 and 57 as compared to 54, 56 and 58, respectively, because of less steric interference between the phenyl group at the Ca-atom and the substituent R1 of the ligand 50 in the former three species. However, this interpretation requires a cautionary note because of the following experimental observations. Application of the protocol shown in Figure 12.12 to the S-phenyl and S-tert-butyl derivatives of 49 gave the corresponding bhydroxy sulfones only with very low enantio- and diastereoselectivities. The Sphenyl and S-tert-butyl analogues of 53–58 should have an even lower configurational stability than the latter compounds.

12.4 Configurationally Labile a-Sulfonyl Carbanions with an Additional Stereogenic Center

An asymmetric reaction of the lithium salt of a configurationally labile a-sulfonyl carbanion can be induced by coordination of a chiral ligand to the Li-atom of the contact-ion pair (cf . Figures 12.10 and 12.12). Alternatively, the backbone of the a-sulfonyl carbanion can be furnished with an additional but stable element of chirality. A particularly interesting example for this strategy is depicted in Figure 12.13 [12]. Treatment of the dibenzylamino-substituted sulfones 59 (the Cb-atom of which carries different alkyl groups) with LDA in the presence of tetramethylethylenediamine (TMEDA), followed by the treatment of the corresponding a-sulfonyl carbanion salts with alkyl halides gave preferentially the (R,R)configured sulfones 60 with medium to high diastereoselectivities. The stereo-


Figure 12.13 Dialkylamino-substituted chiral a-sulfonyl carbanions with an additional stereogenic center.

chemical course of the alkylation may be rationalized as follows. Deprotonation of sulfone 59, either diastereoselectively or unselectively, gives the diastereomeric lithium carbanion salts 61 or/and 62. The carbanion salts are characterized by an intramolecular coordination of the Li-atom by the amino group leading to a sixmembered cyclic structure with the typical energy-minimum CaaS conformation. Cleavage of the NaLi bond, rotation around the CaaS bond, inversion of the Ca-atom and formation of the NaLi bond would convert 61 to its diastereomer 62. The equilibration of the diastereomeric carbanion salts should be rapid at 78 8C. Reaction of the carbanion salt 61 with the alkylating agent, which gives sulfones 60, should be faster than that of 62 because of less steric hindrance in the attack of R2X at the Ca-atom by the R1 group. It should be emphasized, however, that neither the structures of the carbanion salts 61 and 62, nor their dynamics, are known. In particular, the effect of TMEDA upon the proposed structure of 61/62 is difficult to predict. For example, the Li-atom could be coordinated by TMEDA leading to a disruption of the intramolecular coordination of the Li-atom by the amino group because of a steric interference between the TMEDA molecule and the benzyl groups. Interestingly, the application of a similar deprotonation/lithiation/methylation sequence to the corresponding Cb-phenyl- and dimethylamino-substituted sulfone rac-63, but using n-BuLi as base and omitting TMEDA, afforded preferentially the (R,S)-configured sulfone rac-64 (Figure 12.14) [13]. In analogy to the carbanion salts 61 and 62, one would have to propose the formation of the diastereomeric carbanion salts rac-65 and rac-66 having similar structures and dynamics as 61 and 62. This would imply, however, that diastereomer rac-66, the Ca-atom of which is sterically more shielded than that of rac-65, is the one which reacts faster with MeI. This contradictory situation is complicated even more by the observation that the treatment of sulfone rac-67, which carries only one methyl group at the N-atom, first with 1 equiv. of n-BuLi and then with MeI, gave the diastereomerically pure (R,R)-configured sulfone rac-68. Here, the assumption of the formation of a mixture of the rapidly equilibrating

389

390


Figure 12.14 Dimethylamino- and methylamino-substituted chiral a-sulfonyl carbanions with an additional stereogenic center.

diastereomeric carbanion salts rac-69 and rac-70, having similar structures as 61 and 62, would be consistent with the stereochemical course observed in the case of the deprotonation/methylation of sulfone 59. Attack of MeI at the Ca-atom of rac-69 should be sterically less hindered than that at the Ca-atom of rac-70. A further interesting example for the asymmetric reaction of a a-sulfonyl carbanion containing both an additional stereogenic center and a potentially chelating N-atom is shown in Figure 12.15 [14]. Successive treatment of the (R)-configured S-tert-butyl sulfone 71 carrying an oxazoline ring with n-BuLi and an alkyl iodide at low temperatures gave sulfone 72 with high diastereoselectivity. Application of the same reaction sequence to the chiral sulfones 75 and 79 by using EtI in the first and MeI in the second case afforded sulfones 76 and 80, respectively, also with very high diastereoselectivities. A consistent stereochemical model for the rationalization of the high stereoselectivities observed in the alkylation of sulfones 71, 75 and 79 can be developed by postulating the formation of rapidly equilibrating mixtures of the carbanion salts 73/74, 77/78, and 81/82, the bicyclic structures of which are characterized by an intramolecular coordination of the N-atom to the Li-atom. The salts 73, 77 and 81 should exhibit a higher reactivity towards the alkylation reagents because of less steric hindrance in the attack of the electrophile from the exo side at their Ca-atoms. The reactivity of the diastereomers 74, 78 and 82


Figure 12.15 Oxazoline-substituted chiral a-sulfonyl carbanions with an additional stereogenic center.

391

392


Figure 12.16 Diastereoselective synthesis and reactions of a-sulfonyl carbanions.

should be lower because of the attack of the electrophile from the sterically more hindered endo side. It should be emphasized, however, that neither the structures of 73/74, 77/78, and 81/82 nor their dynamics are known. It seems interesting to note that the models proposed in Figures 12.13 to 12.15 allow a consistent rationalization of the sense of asymmetric induction observed in the alkylation of the a-sulfonyl carbanions derived from sulfones 59, rac-67, 71, 75 and 79, with the exception of the deprotonation/alkylation of sulfone rac-63, which does not fit into this picture. An example of a diastereoselective deprotonation of a chiral sulfone and the external trapping of the corresponding a-sulfonyl carbanion before equilibrium has been reached is shown in Figure 12.16 [1l].


Treatment of the endo-configured S-tert-butyl sulfone rac-83 with n-BuLi at 105 8C in THF followed by the addition of MeOCH2I at 105 8C after 5 min had elapsed since the end of the addition of the base (termed as the endo-exo isomerization time, t) gave quantitatively a mixture of the sulfones rac-91, rac-89 and rac-90 in a ratio of 13 : 72 : 15, the major isomer being the exo-configured sulfone (Table 12.1, entry 1). With increasing tisn the ratio of rac-91, rac-89 and rac90 changed from mainly exo sulfone to mainly endo sulfone and converged after tisn ¼ 30 min at a ratio of 43 : 30 : 27 (Table 12.1, entry 2). In a final experiment the solution of the carbanion salt rac-88 was maintained for 2 h at room temperature in order to ensure a complete endo–exo isomerization before the iodide was added at 105 8C. Here, the sulfones rac-91, rac-89 and rac-90 were isolated in a ratio of 44 : 22 : 34 (entry 3). A similar series of experiments was carried out starting with the exo-configured sulfone rac-84 Reaction of rac-84 with n-BuLi at 105 8C, followed by the addition of the iodide at 105 8C after t ¼ 5 min gave the sulfones rac-91, rac-89 and rac-90 in a ratio of 59 : 14 : 27, the major isomer being now the endo-configured sulfone (entry 4). In the final experiment, the solution of the carbanion salt rac-87 was maintained for 2 h at room temperature in order to ensure a complete endo–exo isomerization before the iodide was added at 105 8C. Here, the sulfones rac-91, rac-89 and rac-90 were isolated in a ratio of 43 : 22 : 35 (Table 12.1, entry 6). The variation of the regio- and stereoselectivities of the methoxymethylation of rac-88 and rac-87 with increasing tisn can be taken as an indication that, at 105 8C, reaction with the electrophile and endo–exo isomerization approaches kinetic quenching. The data in Table 12.1 show that the deprotonation–quenching sequence starting with the endo-configured sulfone rac-83 gives with high selectively the exo sulfone rac-89, while that of the exoconfigured sulfone rac-84 affords highly selectively the endo sulfone rac-91. Thus, the selective formation of rac-89 and rac-91 from rac-83 and rac-84, respectively, could be rationalized by assuming that: (1) the deprotonation of rac-83 and rac84 with n-BuLi at 105 8C in THF is highly selective to give rac-87 and rac-88, respectively; (2) rac-87 reacts with the electrophile at the anionic C-atom with high selectivity from the endo side and anti to the tert-butyl group to furnish rac-89, while rac-88 reacts with equal high selectivity from the exo side and anti to the

Table 12.1 Generation and reaction of the carbanion salts rac-87 and rac-88

with MeOCH2I at 105 8C in THF.

Entry

Sulfone

t [min]

rac-91 : rac-89 : rac-90

Yield [%]

1 2 3 4 5 6

83 83 83 84 84 84

5 30 120 5 30 120

13 : 72 : 15 43 : 30 : 27 44 : 22 : 34 59 : 14 : 27 50 : 22 : 28 43 : 22 : 35

b98 b98 b98 b98 b98 b98

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Figure 12.17 Structure of the monomeric lithium a-sulfonyl carbanion salt 92 in the crystal.

tert-butyl group to yield rac-91; and (3) the asymmetric induction provided by the bicyclic ring system is negligible as compared to that exerted the sulfonyl group. The proposed selective deprotonation of rac-83 and rac-84 under formation of rac87 and rac-88, respectively, could be rationalized by assuming: (1) an intramolecular deprotonation following the coordination of n-BuLi by the sulfone in a monodentate fashion; (2) the attainment of transition states TS-85 and TS-86, in which the tert-butyl group occupies the sterically least encumbered position being gauche to 1-H and approximately anti to C-3; and (3) a preferential clockwise rotation of the sulfonyl group around the C2aS bond in TS-85 and a counterclockwise rotation around this bond in TS-86, together with a planarization of C-2 following proton transfer to give rac-87 and rac-88, respectively. According to NMR spectroscopy rac-88 and rac-87 exist in THF as an equilibrium mixture in a ratio of 2.5 : 1. The free energy of activation for the endo–exo isomerization of rac-87/88 was determined as DGA210 ¼ 13.1 e 0.1 kcal mol1. This corresponds well with the barrier determined for the acyclic a-sulfonyl carbanion 18. NMR spectroscopy furthermore revealed that, in THF solution at low temperatures, rac-87/88 forms an equilibrium mixture of monomeric and dimeric OaLi contact-ion pairs having the endo and exo configuration. The structures of the exo-configured lithium carbanion salt 92 [1l] (Figure 12.17) and of the endo-configured lithium carbanion salt 93 [1j] (Figure 12.18) can be taken as models for the monomeric and dimeric OaLi contact-ion pairs. An interesting example for a dynamic kinetic resolution of a a-sulfonyl carbanion through reaction with a chiral electrophile is shown in Figure 12.19 [15].


Figure 12.18 Structure of the dimeric lithium a-sulfonyl carbanion salt 93 in the crystal.

Deprotonation of the prochiral sulfone 94 with n-BuLi at 78 8C gave the racemic carbanion salt rac-95. Treatment of this with the chiral alkene 96 resulted in both a highly enantioselective dynamic kinetic resolution and a highly diastereoselective Michael-addition, and gave sulfone 97 of b92% diastereomeric excess (de). Obviously, the (R,M)-configured carbanion 95 reacted much more rapidly in the conjugate addition than the (S,P)-configured carbanion ent-95, and the racemization of ent-95 was faster than its reaction with the alkene. A kinetic resolution was observed in the reaction of the racemic carbanion salt rac-38 with aldehyde 98 (Figure 12.20) [16]. Deprotonation of the prochiral sulfone 35 with n-BuLi gave rac-38 which, upon treatment with the racemic aldehyde rac-98, afforded a mixture of the diastereomeric sulfones rac-99 and rac-100 (the configuration of which was not determined) in a ratio of 27 : 73. The application of the enantiomerically pure aldehyde 98 gave sulfones 99 and 100, the ratio of which was time-dependent. It was concluded from these results that the rate of enantiomerization of 38/ent-38 is slower than that of its reaction with aldehyde 98.

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Figure 12.19 Dynamic kinetic resolution of a chiral a-sulfonyl carbanion.

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Figure 12.20 Kinetic resolution of a chiral a-sulfonyl carbanion.

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Z. Rappoport (Eds.), Supplement S: The chemistry of sulphur-containing functional groups, Wiley, New York, 1993, pp. 339–362; (h) G. Raabe, H.-J. Gais, J. Fleischhauer, J. Am. Chem. Soc. 1996, 118, 4622–4630. 3 S. Bradamante, G. A. Pagani, Adv. Carbanion Chem. 1996, 2, 189–263. 4 (a) M. J. Kaufmann, S. Bronert, D. A. Bors, A. Streitwieser, Jr., J. Am. Chem. Soc. 1987, 109, 602–603; (b) F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456–463; (c) S. Wodzinski, J. W. Bunting, J. Am. Chem. Soc. 1994, 116, 6910–6915; (d) A. Streitwieser, G. Peng Wang, D. A. Bors, Tetrahedron 1997, 53, 10103–10112; (e) F. Terrier, E. Kizilian, R. Goumont, N. Faucher,

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12 Asymmetric Reactions of a-Sulfonyl Carbanions C. Wakselman, J. Am. Chem. Soc. 1998, 120, 9496–9503; (f ) C. F. Bernasconi, K. W. Kittredge, J. Org. Chem. 1998, 63, 1944–1953; (g) A. Facchetti, Y.-J. Kim, A. Streitwieser, J. Org. Chem. 2000, 65, 4195–4197. 5 (a) J. E. Taylor, F. H. Verhoek, J. Am. Chem. Soc. 1959, 81, 4537–4540; (b) D. J. Cram, W. D. Nielsen, B. Rickborn, J. Am. Chem. Soc. 1960, 82, 6415–6416; (c) E. J. Corey, E. T. Kaiser, J. Am. Chem. Soc. 1961, 83, 490–491; (d) D. J. Cram, D. A. Scott, W. D. Nielsen, J. Am. Chem. Soc. 1961, 83, 3696–3707; (e) D. J. Cram, R. D. Partos, S. H. Pine, H. Ja¨ger, J. Am. Chem. Soc. 1962, 84, 1742–1743; (f ) H. L. Goering, D. L. Towns, B. Dittmar, J. Org. Chem. 1962, 736–739; (g) D. J. Cram, A. S. Wingrove, J. Am. Chem. Soc. 1963, 85, 1100–1107; (h) E. J. Corey, T. H. Lowry, Tetrahedron Lett. 1965, 13, 803–809; (i) E. J. Corey, T. H. Lowry, Tetrahedron Lett. 1965, 13, 793–801; (j) H.-J. Gais, G. Hellmann, J. Am. Chem. Soc. 1992, 114, 4439–4440. 6 For reviews, see: (a) G. Boche, Angew. Chem. 1989, 28, 286–306; Angew. Chem. Int. Ed. Engl. 1989, 28, 277–297; (b) N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon Press, Oxford, 1993; (c) A. Batsu, S. Thayumanavan, Angew. Chem. 2002, 114, 740–763; Angew. Chem. Int. Ed. 2002, 41, 716–738; (d) T. Toru, S. Nakamura, Top. Organomet. Chem. 2003, 5, 177–216.

7 The stereodescriptors M and P are used for the designation of the chiral Ca–S conformation of the a-sulfonyl carbanions according to: G. Helmchen, in: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann (Eds.), Stereoselective Synthesis, Thieme, Stuttgart, 1996, Vol. E21, pp. 1–74. 8 (a) D. B. Chesnut, L. D. Quin, J. Comp. Chem. 2003, 25, 734–738; (b) E. D. Glending, A. L. Shrout, J. Phys. Chem. A 2005, 109, 4966–4972; (c) L. Vandermeeren, T. Leyssens, D. Peeters, Theochem 2007, 804, 1–8. 9 (a) N. S. Simpkins, Chem. Ind. 1988, 387–389; (b) P. J. Cox, N. S. Simpkins, Tetrahedron: Asymmetry 1991, 2, 1–26. 10 T. Akiyama, M. Shimizu, T. Mukaiyama, Chem. Lett. 1984, 611–614. 11 S. Nakamura, N. Hirata, T. Kita, R. Yamada, D. Nakane, N. Shibata, T. Toru, Angew. Chem. 2007, 118, 7792–7794. 12 D. Enders, S. F. Mu¨ller, G. Raabe, J. Runsink, Eur. J. Org. Chem. 2000, 879–892. 13 J. J. Eisch, J. E. Galle, J. Org. Chem. 1980, 45, 4536–4538. 14 E. V. Dehmlow, S. Pieper, B. Neumann, H.-G. Stammler, Liebigs Ann./Recueil 1997, 1013–1018. 15 L. F. Basil, A. I. Meyers, A. Hassner, Tetrahedron 2002, 58, 207–213. 16 (a) R. W. Hoffmann, T. Ru¨hl, J. Harbach, Liebigs Ann. Chem. 1992, 725–730; (b) R. Hirsch, R. W. Hoffmann, Chem. Ber. 1992, 125, 975–982.

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13 Computational Studies on Asymmetric Reactions with Sulfur Reagents David Balcells and Feliu Maseras

Abstract

The contribution of theoretical chemistry to the understanding of the role of asymmetric sulfur centers in chirality issues is reviewed through the description of selected examples. In particular, results are presented on the application of density functional theory (DFT) and density functional theory/molecular mechanics (DFT/MM) methods on the directing effect of sulfinyl substituents, the reactivity of sulfur ylides, and the synthesis of chiral sulfoxides from either prochiral sulfides or racemic sulfinyl chlorides. Computational chemistry is shown to be successful in the clarification of the reaction mechanism of these processes.

13.1 Introduction

During recent years computational chemistry has undergone a spectacular progress [1], as can be measured by the number of publications and their impact on experimental research. Calculations of thermodynamic stabilities and energy barriers have been accurate enough to help in mechanism determination for more than a decade, in particular in the field of organic chemistry [2]. The more complicated topic of homogeneous catalysis by transition metal complexes has also become tractable more recently [3]. Chirality is a complex issue for computational study. After all, enantiomers have the same energy, and asymmetric synthesis from prochiral reactants relies on the introduction of diastereomeric differences at some point of the reaction pathway, which must be thus understood in detail. The energy differences involved in enantioselection are small – an energy difference of only 3 kcal mol1 at room temperature is associated with an enantiomeric excess (ee) above 99.5%, and this requires accurate calculations. In spite of that, computational chemistry has been successfully applied to improve the understanding of a number of processes in asymmetric synthesis [4], as proline-catalyzed aldol reactions [5] and Organosulfur Chemistry in Asymmetric Synthesis. Takeshi Toru and Carsten Bolm Copyright 6 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31854-4

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transition metal catalysis, as dihydroxylation [6], and hydrogenation [7]. The usual approach to translate computed energy barriers into enantiomeric excesses is quite simple. It is assumed that the final S/R ratio is given, at a certain temperature, by the Boltzmann distribution of the transition states leading to each enantiomer: DG‡ R=S ½S ¼ e RT ½R

ð13:1Þ

Sulfur reagents are extremely useful in chiral reactions, as demonstrated in other chapters in this book. However, it is impossible to speak of a specific field of theoretical calculations on asymmetric reactions involving sulfur. Among the cases where computational chemistry has been applied to asymmetric reactions, there are some where asymmetry is associated with sulfur centers, but the cases are not necessarily related among them. These studies will be reviewed in this chapter, with special focus on selected representative examples. The chapter contains six sections; following the Introduction, Section 13.2 deals with sulfur auxiliary substituents (mostly sulfoxides), while Section 13.2 discusses sulfur transient intermediates, in particular sulfur ylides. Sections 13.3 and 13.4 discuss the preparation of chiral sulfoxide species, either by oxidation of prochiral sulfides or by resolution of racemic sulfinyl chlorides; Section 13.6 includes other, more specific studies, while Section 13.7 presents conclusions and perspectives. No detailed discussion will be made on the particular computational methods used in each case, because they correspond to the current standards in computational chemistry. Quantum mechanical (QM) calculations are based on density functional theory (DFT) [8], and make use of functionals based on the generalized gradient approach (GGA), often B3LYP. Hybrid quantum mechanical/ molecular mechanical (QM/MM) calculations use approaches of the ONIOM type [9, 10], with the same GGA DFT functionals for the QM part, and standard force fields as MM3 [11] and UFF [12] for the MM part.

13.2 Directing Effect of Chiral Sulfur Substituents

One of the main roles of sulfur-based functional groups in modern organic chemistry is that of chiral auxiliaries. In a number of examples, an asymmetric sulfur center forms part of a substituent which is introduced at a certain position in a given step of the reaction; it then controls the stereoselectivity of the overall process in the key enantiodetermining step, and is removed afterwards. The analysis of how the auxiliary group directs the enantioselectivity was among the first applications of computational chemistry to the area of sulfur-based chirality. The general concept can be well illustrated by the case of sulfoxides.

13.2 Directing Effect of Chiral Sulfur Substituents

The first question in the computational study of the enantioselective reactivity of chiral sulfoxides is the nature of the most stable conformers, and their relative stabilities. This topic was analyzed from an early stage for the case of methyl vinyl sulfoxide and its derivatives (Figure 13.1). Vinyl sulfoxides constitute one of the simplest examples of chiral sulfoxide, and can undergo stereospecific Diels–Alder and diastereoselective Michael reactions. The study with a restricted Hartree– Fock (RHF) method published by Kahn and Hehre in 1986 [13] found that the parent molecule R1 ¼ R2 ¼ R3 ¼ H exists in the two different conformations shown in Figure 13.1. In the most stable conformation, the SaO bond is in a syn coplanar arrangement with the CbC bond. In the second available conformation, 1.6 kcal mol1 above, this syn coplanar position is occupied by the sulfur lone pair. The nature of the most stable conformers of vinyl sulfoxide has subsequently been confirmed by other authors using more sophisticated computational methods [14, 15]. In particular, Tietze and coworkers [15] have shown that the RHF result is closely reproduced by MP2 and B3LYP calculations, but not by semi-empirical methods such as PM3 and AM1. These semi-empirical approaches are thus of limited application to this type of system. There is a successful example of application of PM3 to explain the reaction of nitrile oxides with chiral sultams [16], but this system seems to be quite particular. The nature of the most stable conformer in vinyl sulfoxides is dictated by electronic effects. The preferred arrangement maximizes the interaction between the sS-CH3 orbital and the sulfur lone pair with the p*CbC orbital, as well as the interaction of the pCbC orbital with the s*S-CH3 orbital and a Rydberg orbital at sulfur. The energy barrier between the two conformers is quite low, the transition state being 4.4 kcal mol1 above the most stable one at the B3LYP level. The stability of the conformers of vinyl sulfoxide, and their nature itself, is strongly affected by the presence of substituents (see Figure 13.1). Substitution at the R2 position, in the b-carbon and trans to sulfur, has little effect, but the situation is different for positions R1 and R3. Replacement of hydrogen by a bulkier substituent in the cis position R1 destabilizes the conformer with a syn coplanar SaO, which the presence of methyl alone in this position pushes 0.4 kcal mol1 above the alternative conformer. Electron-withdrawing substituents at the R3 position, in the a-carbon, have the contrary effect, destabilizing the least-stable con-

Figure 13.1 The two stable conformations of vinyl sulfoxide.

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former. The presence of a cyano group increases the energy difference between both conformers from 1.7 to 3.6 kcal mol1. Knowledge of the structure and energies of the available conformers of the reactants is a necessary step in any study of reactivity, but it is not sufficient to identify the stereochemical outcome, because this depends on the transition states, not on the reactants. The complexity of the problem is nicely illustrated ˜ as and coworkers by a computational study with a B3LYP method by Mascaren on sulfinyl-directed [5C þ 2C] intramolecular cycloadditions [17]. The reaction is experimentally known to proceed through the cyclic oxidopyrylium ylide species shown in the left part of Figure 13.2. This intermediate contains a chiral sulfinyl group attached to a carbon–carbon double bond, and the compound can thus exist in two different conformers. The most stable conformer is found to be that with the oxygen coplanar to the double bond, in this case favored by an energy difference of 2.1 kcal mol1.

Figure 13.2 The reaction path for the sulfinyl-directed [5C þ 2C] intramolecular cycloaddition as computed by Mascarenãs and coworkers.

13.3 Sulfur Centers in Chiral Intermediates

This intermediate undergoes the intramolecular cycloaddition, the step where the regioselectivity of the product is decided. Four different transition states can be envisaged for this process, depending on the nature of the starting conformer, and on the face of the oxidopyrylium ring to which the double bond approaches. Calculations indicate that the choice of the face is ruled by sterics, it takes place from the less-hindered face of the double bond, which is that opposite to the phenyl group, as shown in Figure 13.2. Due to the stereochemistry of the system, each conformer of the reactant leads to a different stereoisomer of the product. The most remarkable result is however that the lowest overall barrier (12.5 kcal mol1) corresponds to the path emerging from the least stable conformer. The difference between the two energy barriers (more than 3 kcal mol1 between 12.5 and 15.9 kcal mol1) is sufficiently large to allow for a very high selectivity, in good agreement with the experimental result. This behavior seems to be associated with the dipolar interactions between sulfoxide and ylide, and it clearly exemplifies the importance of the calculation of transition states. The same computational work is also able to reproduce the experimental observation of a reversal of stereoselectivity when switching from sulfoxide to sulfoximine. A similar B3LYP analysis was also carried out by Garcıá-Ruano and coworkers [18] on the sterocontrol of the asymmetric 1,3-dipolar reactions of 5-ethoxy-3p(S)-tolylsulfinylfuran-2(5H)-ones with diazoalkanes. The calculations, including in this case also solvent effects with a polarized continuum model (PCM), were able to reproduce the experimental result, and hinted in this case to the potential role of a CaHO hydrogen bond. The general model for the study of the directing effect of chiral sulfur substituents seems to be well defined. First, the conformational space of the reactants must be systematically studied, after which the study must be extended to the transition states. Reliable results can be obtained with currently common DFT methods, but the systematic conformational studies can be troublesome. There is, however, an important prize for the computational analysis in the form of allowing the explanation of unexpected results that may be in contradiction with established trends based on empirical analysis of results.

13.3 Sulfur Centers in Chiral Intermediates

Chiral sulfur compounds play a key role in the enantioselectivity of a number of processes where they exist mainly as transient intermediates. Significant examples of this role are provided by the reactivity of sulfur ylides and of betaines (Figure 13.3). Both types of compound have a formal charge on the sulfur center, which has a sp3 hybridation and four substituents, one of them a lone pair. Sulfur ylides are a highly versatile class of organic reactants that can undergo a variety of interesting reactions such as olefination, epoxidation of aldehydes, cyclopropanation, and aziridination [19]. Ylides can be generated in situ under mild conditions, for instance from diazocompounds and sulfides, and with a cor-

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Figure 13.3 Schematic structure of a sulfur ylide and a betaine.

rect choice of substituents they are chiral. The subsequent reactions can achieve high enantioselectivity, and their study has been the subject of intense computational study, notably by Harvey, Aggarwal and coworkers [20–24], with significant contributions also having been made by other groups [25–27]. All of these calculations have been carried out with a DFT description (often B3LYP), and solvation effects have been in general introduced through a PCM. The epoxidation of aryl aldehydes by sulfonium ylides has been the subject of mechanistic controversy, and is a representative example of the contribution of computational chemistry in this field. Early studies on the topic had used geometry optimizations at the Hartree–Fock level. These succeeded in clarifying the different behaviors of sulfur and phosphorus ylides [28], as well as the importance of solvation effects [29], but the computational approach was not sufficient for the quantitative description of the reactivity in these types of system. The first systematic study [20] conducted with a B3LYP method on a non-chiral model system R2Sþ-CHR 0 plus R 00 -CHO (R ¼ Me, R 0 ¼ R 00 ¼ Ph) characterized the general mechanism depicted in Scheme 13.1. The reaction starts with the electrophilic addition of the aldehyde on the sulfonium ylide, that produces a betaine. This betaine is in a cisoid conformation with the negatively charged oxygen and the positively charged sulfur close to each other. The presence of charge separation between different regions of the betaine system is responsible for the critical role of solvation in the proper description of the systems. The cisoid betaine is not properly arranged for the reaction to proceed, because the sulfide must depart anti to the closing oxygen group. Because of this, a rotation must take place around the central CaC bond of betaine. The final step is the ring closure. The barriers for the betaine rotation step were found to be competitive with those of the other steps, and in fact, the betaine rotation was the rate-determining step for the path leading to the cis stilbene epoxide. The key role of rotation around a single bond, was the main conclusion of this initial analysis. Later studies have unearthed a subtly more complicated picture. The ordering of the relative height of the barriers for the different steps has been found to be not always the same. The calculations mentioned above, with R2SþCHPh as ylide, are representative of the behavior of semi-stabilized ylides, with aryl substituents, but not of all sulfur ylides. For instance, amide-stabilized ylides, such as R2SþCHCONEt2, have a different behavior and their rate-limiting step is ring

13.4 Synthesis of Chiral Sulfoxides from Prochiral Sulfides

Scheme 13.1 General scheme for the epoxidation reaction between a sulfur ylide and an aldehyde.

closure [22]. In fact, examples have been reported where the rate-limiting step can be either the electrophilic addition, the betaine rotation, or the ring closure. A similar mechanistic picture, with its own subtleties, is obtained for the case of aziridination [24] and cyclopropanation [27] processes. The current understanding of these complex mechanisms could have hardly been accomplished without the help of computational chemistry.


Enantiomerically pure sulfoxides are probably the most frequently used chiral sulfur compounds because of their existence as natural products and drugs, and because of their role in asymmetric synthesis as chiral auxiliaries and ligands [30, 31]. One of the major methods for the preparation of chiral sulfoxides is the oxidation of prochiral sulfides, in the process labeled sulfoxidation: SRR 0 prochiral þ oxidant ! SORR 0 optically active Any sulfide with two different substituents is prochiral, and its reaction with an oxygen donor will produce the corresponding sulfoxide, in principle in a racemic form. This process can be enantioselective if a chiral oxygen donor is used or, in a more efficient variation, if the reaction is catalyzed by a chiral catalyst. The

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vanadium-catalyzed sulfoxidation with hydrogen peroxide originally proposed by Bolm [32] is among the most efficient methods for sulfoxidation. An interesting example of this synthetic approach is the asymmetric oxidation of 1,2-bis(tert-butyl) disulfide reported by Ellman and coworkers, which is shown in Scheme 13.2 [33]. The nature of the catalyst and the reaction mechanism of this catalytic system were essentially unknown. The mechanism was particularly puzzling because it had to explain the dependence of the enantiomeric excess on the nature of the R1, R2, R3 substituents. The ee-value was 82% when R1 ¼ R2 ¼ R3 ¼ t-Bu, and it was practically unchanged (83%) when a hydrogen was placed in the R2 position. However, it was far more sensitive to the nature of R1 and R3. For the system with R1 ¼ R2 ¼ t-Bu, R3 ¼ i-Pr, the ee-value fell to 60%, and for the case with R1 ¼ R2 ¼ H, R3 ¼ t-Bu, it fell to 46%.

Scheme 13.2 Vanadium-catalyzed asymmetric sulfoxidation of 1,2-bis(tert-butyl) disulfide with hydrogen peroxide.

The origin of enantioselectivity in this particular reaction was computationally analyzed by the present authors’ group. The first part of the investigation [34] consisted of a study of the overall features of the reaction through a B3LYP calculation on a model system, where the bulky tert-butyl substituents were replaced by hydrogen atoms. Experimental mechanistic studies on related systems [35] had highlighted that the catalyst is a neutral oxo complex of vanadium (þV) characterized by a metal : ligand : peroxide ratio of 1 : 1 : 1. Nevertheless, such studies did not clarify whether hydrogen peroxide is bound to the metal as a hydroperoxo (HOO) or peroxo (OO) ligand. The results of these studies, which are summarized in Scheme 13.3, were that the hydroperoxo complex is the active form of the catalyst and that the reaction follows a direct oxygen transfer mechanism, without coordination of sulfur to vanadium. The presence of a hydroperoxo ligand in the catalyst represents a significant difference with the results obtained for molybdenum species active in sulfoxidation, where the ligand is in a peroxo form [36, 37]. This difference seems to be associated with the nature of the metal. In any case, the catalytic role of the vanadium species in this system was confirmed by the calculations, the barrier for the catalyzed process being 26.7 kcal mol1, compared to the value of 40.4 kcal mol1 computed for the uncatalyzed reaction.


Scheme 13.3 Direct oxygen transfer mechanism with the hydroperoxo catalyst in the sulfoxidation process.

Once the nature of the catalyst and the reaction mechanism had been established, the origin of enantioselectivity was explored considering the real systems in a QM/MM study with the IMOMM(B3LYP:MM3) method [38]. The key to the simultaneous influence of the R1 and R3 substituents of the ligand happens to be in the existence of two diastereomeric forms of the catalyst in equilibrium. The pentacoordinate vanadium atom of the catalyst is stereogenic in the square-base pyramidal structure, and its combination with the fixed configuration of the chiral Schiff base ligand originates a pair of diastereomers, which can be arbitrarily labeled as A and B; these are shown in Figure 13.4. Calculations indicate that isomer A is more stable than isomer B by 1.9 kcal mol1 when R1, R2, R3 are t-Bu. The main structural difference between both species is given by the relative

Figure 13.4 Diastereomeric forms A and B of the vanadium catalyst.

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Scheme 13.4 Steric model for the vanadium-catalyzed asymmetric sulfoxidation.

position of substituent R3 which occupies the oxo face of the catalyst in B and the opposite side in A. Both, the A and B forms of the complex catalyze the oxidation of bis(tert-butyl) disulfide, but they lead to opposite enantioselectivities. Diastereomeric form A is pro-R, while diastereomeric form B is pro-S. The overall result is that the product is R for the four R1, R2, R3 sets considered in the calculations, in full agreement with the experimental data [33]. Computational results indicate, however, a subtle dependence on the nature of the path leading to the minor S enantiomer with respect to the particular set of substituents. In some cases, it comes from the A form of the catalyst, while in the other cases it comes from the B form. On the basis of these QM/MM calculations it was possible to build the steric model represented in Scheme 13.4. This model is able to explain the strong dependence of enantioselectivity with respect to the nature of both R1 and R3. For each isolated isomer, the selectivity is controlled by the energy gap between the

13.5 Synthesis of Chiral Sulfoxides from Racemic Precursors

pro-R and pro-S transition states: DEA for A and DEB for B. Both DEA and DEB are controlled by substituent R1, which discriminates the pro-R and pro-S pathways, within the same form of the catalyst, by introducing repulsive steric interactions with the tert-butyl group of the substrate. The reduction in steric bulk associated to the replacement of t-Bu by H in this position implies a reduction of DEA from 2.4 kcal mol1 (97% ee) to 0.3 kcal mol1 (21% ee), in good agreement with the experimental data. On the other hand, enantioselectivity can also be affected by the energy gap between the most stable pro-R transition state, which is connected to A, and the pro-S transition state connected to B. This energy gap, labeled as DEAB, depends mostly on R3, which gives the main structural difference between the A and B diastereomers of the catalyst. The steric bulk reduction given by the replacement of t-Bu by i-Pr in this position implies a reduction of DEAB from 1.8 kcal mol1 (90% ee) to 1.1 kcal mol1 (74% ee), again in good agreement with the experimental observation. Computational chemistry has been also applied by Zampella and coworkers to study the reactivity of another family of vanadium catalysts active in sulfoxidation: the biomimetic models of vanadate-dependent haloperoxidases [39, 40]. Complex K [VO(O2)Hheida] (Hheida2 ¼ 2,2 0 -[(2-hydroxyethyl)imino]diacetate) is a representative example of this class of species. The overall mechanism is similar to that mentioned above. Here, the starting species is an anionic peroxo complex, but its reactivity is largely accelerated upon protonation, thus reaching the hydroperoxo state. Enantiomeric excesses are modest, and this seems related to the particular binding of the chelating ligand.


A second procedure for the preparation of enantiomerically pure sulfur compounds is the resolution of racemic precursors [41]. A relevant example of this type of approach is the dynamic kinetic resolution (DKR) of sulfinyl chloride racemates that is part of the DAG method [42–44]. This synthetic approach consists of two steps: (1) the preparation of enantiomerically pure sulfinate esters; and (2) their reaction with Grignard reagents. From the point of view of enantioselectivity, the key step of the process consists of the formation of a sulfinate ester from the sulfinyl chloride: SOClR 0 racemic þ DAGOH ! SO(DAGO)R 0 optically active þ HCl The reaction is fundamentally different from sulfoxidation in the sense that there is no change in the oxidation state of sulfur [it stays always as S(IV)], and that the starting product is already chiral, although in a racemic form. The chiral alcohol DAGOH (diacetone-d-glucose) (Scheme 13.5) is added to a sulfinyl chloride racemate, and the chloride from the substrate is displaced by the DAGO alkoxide, the reaction taking place in the presence of an organic nitrogenated

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base. The high yield and enantioselectivity of the reaction are certainly remarkable, but there are two features that make its mechanism especially puzzling, and attracted the present authors’ interest as computational chemists. The first of these is the existence of DKR, which requires the transformation from the minor to the major enantiomer at some point in the process. The second remarkable feature consists of the possibility of reversing the final absolute configuration of sulfur, changing only the nature of the base, without any modification of the chiral source (DAGOH). Certainly, the major reaction product is R when pyridine is used as base, while it is S when collidine (2,4,6-trimethylpyridine) is used, in spite of the electronic similarity between these two bases. This reversal of selectivity induced by the base is very convenient because whereas the different organic bases used in the synthesis are cheap and easily accessible, the other enantiomer of DAGOH is very expensive.

Scheme 13.5 The DAG synthetic method.

The reaction mechanism of the DAG method was initially explored [45, 46] in model systems at the DFT level with the B3LYP functional. The mechanism for the DKR was explained through the study of the energy barrier for racemization in different SO(X)(Me) systems [45]. Two different X substituents were considered, Cl and OMe. The barrier was computed for the isolated system and with the presence of trimethylamine NMe3. When no nitrogenated base is introduced, the barrier to inversion is high, and similar for both systems: 63.4 kcal mol1 for SO(Cl)Me, 64.1 kcal mol1 for SO(OMe)Me. This agrees with the experimentally observed chiral stability of these compounds. When the base is introduced, it coordinates to the sulfur center, the transition state keeping otherwise the same general pyramidal form. However, the effect on the energy barrier is very sub-


Scheme 13.6 Reaction mechanism of the DAG synthetic method.

stantial. For the SO(Cl)Me þ NMe3 system the barrier is as low as 22.9 kcal mol1, with an intermediate value of 42.7 kcal mol1 for the case of SO(OMe)Me þ NMe3. The barrier for the sulfinyl chloride system (22.9 kcal mol1) is sufficiently low to allow the inversion to take place under the experimental conditions. The base is thus able to catalyze the chiral inversion of sulfinyl chloride systems. On the basis of this catalytic effect, the two enantiomeric forms of the reactant are in equilibrium, and this ultimately explains the overall dynamic kinetic resolution accomplished by the DAG method. On the other hand, the barrier for the system with the alkoxy substituents (42.7 kcal mol1) is still sufficiently high to allow for the chiral product to be optically stable at room temperature.

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A subsequent study on the nucleophilic addition of DAGOH (modeled as methanol) to SO(Cl)(Me) showed that this reaction follows a step-wise addition/ elimination pathway [46], as previously proposed by Bachrach for similar systems [47]. The key step of the mechanism, which determines the overall rate and selectivity of the reaction, consists of direct addition of the alcohol to SO(Cl)(Me). In this step, formation of the SaOMe bond and cleavage of the SaCl bond are simultaneous and coupled with a hydrogen transfer from the alcohol to the sulfinyl chloride (see Scheme 13.6). The base assists this process, reducing its energy barrier from 26.8 to 12.2 kcal mol1, and makes the reaction more exergonic by 11.8 kcal mol1. The origin of enantioselectivity was determined considering the real system in a QM/MM study [48] at the ONIOM(B3LYP:UFF) level. The large conformational complexity of this system was explored with a MCMM (Monte Carlo Multiple Minima) approach. The four most stable pro-R and pro-S transition states of the addition step were optimized for both pyridine and collidine. The results showed that pyridine is pro-R, with DE ¼ 1.0 kcal mol1 (85% de). In contrast with this, collidine was found to be pro-S, with DE ¼ þ2.2 kcal mol1 (99% de). Hence, this computational study was able to reproduce the influence of the base upon the sense of selectivity of the reaction. The analysis of the optimized transition states gave rise to the steric model represented in Scheme 13.7. All saddle points have a trigonal bipyramid geometry centered on sulfur in which the axial positions occupied by DAGOH and Cl are fixed. The OH group bound to the base and the methyl attached to sulfur lie on the equatorial plane, and their relative positions are exchanged in the pro-R and pro-S transition states. The analysis is more clear if the transition state structures are divided into two blocks. The first block consists of the DAG substituent, while the second, centered at sulfur, consists of the remainder of the system, including the base. The two blocks are obviously connected by a single OaC bond. The diastereomeric interactions of the methyl and the base with DAG rule the stereoselectivity. The DAG block can be divided in turn into two parts, namely the single cycle (SC) and the fused bicycle (BC). The BC fragment is more sterically demanding than SC, because of its size and, mostly, because of its rigidity. In the transition-state structures presented in Scheme 13.7, DAGOH is oriented in such a manner that the single cycle SC lies on the left-hand side and the fused bicycle BC stands on the right-hand side. Hence, the most stable transition state is that one having the less bulky fragment in the sulfur side on the left-hand side. In the case of pyridine, the most sterically active group is methyl, because the base stands coplanar with the HaOaSaO plane of the hydrogen transfer, far from DAGOH. Thus, the less-stable transition state with pyridine is the pro-S due to the repulsive interactions between the methyl and BC. In contrast to this, in the case of collidine, the most sterically active group is the base itself due to its perpendicular arrangement with respect to the HaOaSaO plane, induced by the presence of methyl substituents in the positions ortho to nitrogen. Hence, the less-stable transition state is the pro-R due to the repulsive interactions between collidine and BC.

13.6 Other Systems Involving Chiral Sulfur Centers

Scheme 13.7 Steric model for the DAG synthetic method.

The study revealed that the identity of the most sterically active fragment around sulfur (the methyl or the base) depends on the nature of the base. The combination of this phenomenon with the exchange of the relative positions of these substituents in the pro-R and pro-S transition states originates the reversal of stereoselectivity. Furthermore, the steric model of Scheme 13.7 can be used to formulate a strategy to improve selectivity. Regardless of the base, selectivity would increase by amplifying the steric hindrance introduced by the BC fragment of DAGOH. In the particular case of non-bulky pro-R bases such as pyridine or imidazole, stereoselectivity would be higher with bulkier substituents in the sulfinyl chloride substrate. In the case of bulky pro-S bases such as collidine or triethylamine, selectivity can be improved by increasing the steric hindrance introduced by the base itself .

13.6 Other Systems Involving Chiral Sulfur Centers

A notable omission in the list of systems discussed above is that of chiral sulfurcontaining ligands. This is certainly an important topic in the overall chemistry

413

414


of chiral sulfur species [49], but to the present authors’ knowledge it has not been yet analyzed in detail from a computational point of view. Calligaris and coworkers have analyzed the topic of the coordination of sulfoxides to transition metal systems [50], and have reported B3LYP calculations on the linkage isomerism of dimethyl sulfoxide to ruthenium and rhodium complexes [51, 52]. Coordination through sulfur seems to be preferred with respect to coordination through oxygen in most cases, with the latter being preferred only for metal centers with high positive electronegativity. However, the studies have concentrated on non-chiral sulfoxides (typically dimethylsulfoxide), and no direct insight into chirality issues has been obtained. A different family of sulfur-related coordinating systems is that of chiral chelating ligands, coordinating through two (S/S) or one sulfur center (S/P, S/N). The role of sulfur as a coordinating atom has been investigated recently with a B3LYP method in related complexes, but not yet on chiral systems [53]. Finally, DFT calculations have been also applied to analyze the role of bridging sulfur atoms in dimetallic species [54], and to a variety of issues concerning sulfur coordination to metals [55, 56], but the potential chirality issues have not been addressed. Computational chemistry has been also applied to the study of chiral sulfur species in topics not directly related to chemical reactivity. The drug omeprazole, a chiral sulfoxide, is still the subject of computational studies with quantum mechanics and molecular mechanics methods on its conformational stability and tautomerism [57, 58]. Chiral sulfur compounds have been often the subject of the application of quantitative structure–enantioselectivity retention relationship (QSERR) techniques [59, 60], which are applied to an understanding of the mechanism of enantiomer separation by chromatography. Sulfoxides have been also used as prototypical chiral molecules in computational discussions of the role of chiral substituents in the overall molecule chirality [61], and for the calibration of novel theoretical techniques aiming to the calculation of vibrational circular dichroism spectra [62].

13.7 Conclusions and Perspectives

The theoretical study of asymmetric reactions with sulfur reagents is an active field of research, reflecting both the growing importance of computational chemistry and the chemical relevance of sulfur-based chirality. Calculations have made significant contributions to the understanding of the directing effect of sulfinyl substituents, the reactivity of sulfur ylides, and on the synthesis of chiral sulfoxides from either prochiral sulfides or racemic sulfinyl chlorides. Currently available DFT and DFT/MM methods are sufficiently accurate to describe the key issues concerning reactivity in this field, and the future will likely see an increasing contribution of computational chemistry as a useful tool for the solution of specific mechanistic controversies.

References

Acknowledgments

Financial support is acknowledged from the ICIQ foundation, from the Spanish MEC through projects CTQ2005-09000-CO1-02 and Consolider Ingenio 2010 CSD2006-003, and from the Catalan DIUE through project 2005SGR00715.

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417

Index a

N,S-acetal structure 346 a-acetoxy thioderivative 138 acidity 323, 351f., 362, 377 acyclic synclinal model 296 acyl anion equivalent 161f. – sulfur-stabilized 162 N-acyl imine 314f. acylation 212f. 1-adamentylsulfinamide 239 ADC, see asymmetric dipolar cycloaddition 1,4-addition 90, 125 addition-elimination-isomerization (AEI) reaction 219 1,4-adduct 294 alcohol 33f., 38, 203, 210 – anti-1,2-amino 302 – homoallylic 219f., 286 – homopropargylic 220f. – secondary 203, 272, 305 – sulfinylation using cinchona alkaloid/ arenesulfinyl chloride system 38 – b-sulfonimidoyl-substituted 219f. – d-sulfonimidoyl-substituted 219 aldehyde 131, 133, 187, 279, 295, 302, 363, 365f. – cyanosilylation 279 – a,a-heterodisubstituted 142 – a-hydroxy 302 – Zn-promoted allylation 131 aldol reaction, see also Michael-aldol reaction 73, 169f., 227 – Cu(I)-catalyzed 74 alkaloid 36 alkane sulfinate 37, 46 alkanesulfinyl chloride 49 alkenyl sulfone 292ff., 309 alkenyl sulfoxide 88 2-alkenyl sulfoxime, titanated N-methylated 219

alkoxide addition 88 – diastereoselective C-O formation b-alkoxy vinyl sulfoxide 95 alkoxy-lithium aluminium hydride 57 O-alkyl alkane sulfinate 33f. O-alkyl arene sulfinate 37 O-alkyl p-toluenesulfinate 39 O-alkyl tert-butanesulfinate 39 alkyl carbinol 62 alkyl carrier 225 alkyl ferrocenyl sulfoxide 286 alkyl sulfinamide 237 – ketimine 240 – sulfinyl aldemine 240 – tertiary 237 a-alkyl-b-ketosulfoxide 61f., 71 – reduction 71 alkylation 70ff., 136, 287, 354ff., 357, 389f. – base influence 356 – cyclic sulfonyl sulfoxide 357 – Pd-catalyzed 287 – b-phenylsulfinylethanol 356 – solvent influence 70 – stereochemical course 389 – stereocontrol 354ff. – vinyl sulfoxide 356f. alkylidencylopentane 96 alkylidene transfer 214 alkylsulfinyl group 236 alkyne 201 all-carbon stereogenic quarternary center 294ff. allenic derivative 202 allocyathin 313f. p-allyl complex 278f. allyl cyclopropane 94 g-allyl intermediate 279 – M-type 279 – W-type 279


418

Index allyl sulfide 336 allyl sulfone 301 allyl sulfoximine 216 g-allyl system 279 allyl transfer 216 allylation 286, 299, 381f. – aldehyde 286 – a-sulfonyl carbanion 381f. – a-sulfonyl-stabilized 299 – sulfoxide-promoted 286 allylic alcohol 62f. allylic alkylation reaction 254, 273, 276 – 1,3-diphenyl propenyl acetate 273 – Pd-catalyzed 254, 273f. allylic amination 276 – Pd-catalyzed 276 allylic substitution 273ff., 278 – enantioselectivity model 278 – mechanism 276ff. – Pd-catalyzed 273f., 278 allyltitanium(IV) complex 203 – in-situ-formed sulfonimidoyl-substituted 203 aluminium (salalen) complex 20 AM1 calculation 401 amide 130 – a,b-unsaturated 130 amide enolate addition 248 a-amido sulfone 315 amine 203, 233, 235, 241 – primary 241 – secondary 203 – stereoselective 233 – synthesis 233, 241 amino acid 89, 246f., 259, 297 – a,a-disubstituted 297 a-amino acid 89, 246, 259, 366 – cyclic 366 – substituted 246 – a-trifluoromethyl 370 amino acid ester 221 amino alcohol 39, 90, 303 – anti-1,2-disubstituted 1,2-amino alcohol 133 1,2-amino alcohol 242f. 1,3-amino alcohol 244f. – Nelson’s asymmetric synthesis 245 1,4-amino alcohol 244f. – mechanism 246 – synthesis 244 a-amino alcohol 243 b-amino alcohol 90, 140, 369 g-amino alcohol 140 amino compound 189

– b-functionalized 189 b-amino ester 244, 258 a-amino ketone 246 b-amino ketone 244, 248 – syn-a-substituted 248 a-amino nitrile 246 amino sulfoxide 80 (6R,7S)-7-amino-7,8-dihydro-a-bisabolene 257 b-aminophenylpropionic acid 371 1,2-aminothioether 134 Andersen method 3f., 237 Andersen reagent 235f. anion-stabilization effect 163 anthracyclinone 78, 139 – precursor 139 l-arabinitol 59 arene sulfinate 37, 46 arenesulfinyl chloride 49 aromatic aldehyde 183 aromatic sulfoxide 131 – ortho-directed metallation 131 O-aryl alkane sulfinate 33f. O-aryl arene sulfinate 33f. aryl carrier 225 aryl methyl sulfoxide 20 aryl sulfinamide 237, 240 – ketimine 240 – sulfinyl aldemine 240 – tertiary 237 arylation 21 N-arylation 213, 222 – Buchwald-Hartwig-type 213 – metal-catalyzed 213 arylboronic acid addition 246f. – rhodium-catalyzed 246f. – rhodium(I)-phosphine-catalyzed 246 trans-arylcyclopropane carboxylate 195 arylimine 134, 368f. O-arylmethyl tert-butanesulfinate 35 a-arylpropionic acid 174f. arylsulfinamide 237 – biocatalytic route 237 arylsulfinyl group 236 2-(arylsulfinylmethyl)oxazole 366 arylsulfonyl group 293 a-arylthio amide 332 aryltitanium reagent 293 asymmetric dihydroxylation (AD), see dihydroxylation asymmetric dipolar cycloaddition (ADC) 111ff., 115 – 1,3-ADC 113, 115, 117, 118 – p-facial selectivity 111

Index – non-functionalized vinyl sulfoxide 111 asymmetric substitution 275, 277 – Pd-catalyzed 275, 277 asymmetric transformation, see transformation aza-Darzens reaction 190, 249f. aza-Darzens-type chemistry 249f. aza-Wittig reaction 81 azabicycle 219 azaheterocycle, functionalized 217 azapolycycle 217 aziridination 189ff., 192f., 249ff., 252, 405 – catalytic 192 – diastereoselectivity 190 – mechanism 190f. – stereoselectivity 250f. – stoichiometric 190 aziridine 92, 134, 180, 189ff., 192f., 214, 249ff., 252 – application 249 – aza-Darzens-type chemistry 249f. – formation 191 – ring-opening 189 – synthesis via methylide 251 aziridine-2-phosphate 249f. aziridinyl carboxamide 190 azomethine ylide 115ff., 119, 300f. – heteroatomic 117 axially chiral olefin 335f.

b B3LYP calculation 400ff., 403f., 410, 414 benzaldehyde 126, 183ff., 272f., 360f. – diethylzinc addition 272f. benzenesulfenate 51f. – oxidation 52f. – ortho-phosphonate group bearing 52 benzenesulfinate 51ff. – ortho-phosphonate group bearing 51f. benzimidazolyl vinyl sulfone 299 O-benzyl tert-butanesulfinate 35f. – synthesis 36 benzyl tert-butyl sulfinate 6f., 35f. benzyl tert-butyl sulfoxide 23 benzyl phenyl sulfide 333ff. – a-lithiated 334 – transition state 334 benzyl 2-pyridyl sulfide 336ff. benzyl sulfide 342, 344 N-benzyl a-sulfinyl imine 80 benzylamine 85 benzylic alcohol 141 benzylic carbanion 133, 135f., 141 benzylic chiral center 136

benzylidenation 183ff. N-benzyloxycarbonyl b-(fluoroalkyl) b-enamino sulfoxide 82 betaine 183, 186f., 191f., 196f., 403f. – cisoid 191f. – formation 183, 187, 191, 196 – reactivity 403 – rotation 404f. – structure 404 – transoid 191f. bicyclo[4.1.0]heptanes 312 bicyclo[2.2.2]octene 108 binaphthol 15 biologically active compound 176, 256ff., 322, 336 – synthesis 256ff. biomimetic model 409 Bolm catalyst 19 bond strength 237 borane 203 – tetrasubstituted 203 borohydride 57, 67, 69 boschnialactone 103 Brook-type rearrangement 164 bryostatin 176 Buchwald-Hartwig conditions 222 tert-butanesulfinamide (t-BSA) 236f., 239, 242, 248, 250f. – enantiomerically pure synthesis 239 – synthesis 237, 239 tert-butanesulfinate 51 N-tert-butanesulfinyl aziridine 251f. tert-butanesulfinyl imine 243 tert-butyl alkyl sulfoxide 6 tert-butyl arylsulfinate 6f., 35 1,2-bis(tert-butyl) disulfide 406f. tert-butyldimethylsilylcyanide (TBDMSCN) 82 tert-butylsulfinamide 256 tert-butylsulfinate 9 tert-butylsulfinyl group 236

c C-a control 77 C3 triethanolamine ligand 15 CaC bond formation 225, 227 – metal-catalyzed 225, 227 cage compound, heterocyclic 125 calyculin 176 carbacycline 336 carbamate 339 carbanion 163, 214, 321ff., 330f., 351ff. – configurational stability 330f. – (R,M)-configured 395

419

420

Index carbanion (cont.) – (S,P)-configured 395 – conformation 334, 352, 375f. – SE2 reaction 334 – sp2-like hybridized 334 – stabilization 163, 214, 326, 339 – sulfonimidoyl-stabilized 214 carbinol 59, 61f., 72, 110, 269f., 273, 360, 364 – cyclic 63 carbocycle 96 (–)-N-carbomethoxypelletierine 112 carbonyl ylide 121 carboxylation 362f. – prostereogenic a-sulfinyl carbon 362 carboxylic acid 88, 345 – b-alkyl-substituted 88 – a-hydroxy 345 catalyst 12, 16, 18f., 225ff., 252ff., 255f., 267ff., 270f., 276, 281, 283, 285, 287f. – bifunctional 279 – dual Lewis-acid-Lewis-base 288 – heterogeneous 285 – reusable 285 – P,N-sulfinimine-based 256 (–)-centrolobine 66 cetirizine 259ff. – synthesis 259ff. (S)-cetirizineHCl 260f. chair transition state 165, 362, 368 chalcone 224f. chelation control method 171 a-chloro-a-sulfinyl carbanion 365f. chlorosulfite 49f. O-cholesteryl 1-alkenesulfinate 44f. O-cholesteryl methanesulfinate 44 – synthesis 44 chromium complex 341ff. – deprotonation 343 cinchona alkaloid 36ff., 296 cinchona ester 37 cisoid 191f. (–)-cispentacin 115 CMO, see cyclohexanone mono-oxygenase collidine 412f. computational chemistry 399f. computational study 399ff. condensation 41ff., 240f. condensing reagent 42 configuration 323ff., 326, 330, 352 – inversion 338ff., 341 – retention 338, 341, 380 conformation 98, 182, 352, 375f. conformer 401ff.

– energy 402 – stability 401 – structure 401f. conjugate addition 56, 83ff., 86ff., 125, 132, 167, 224, 292ff., 295f., 307, 344, 357ff. – 1,4-conjugate addition 132 – benzylamine 85 – enantioface-selective 344 – general principle 83f. – Grignard reagent 88 – intramolecular 86f. – intramolecular one-pot deprotection process 86 – malonate 357 – Ni-catalyzed 84, 224 – nucleophilic 84, 86 – radical-promoted 83, 95 – Rh-catalyzed 294f. – stereocontrol 357f. – a-sulfinyl carbanion 357ff. – thiolate 85 – a,b-unsaturated carbonyl compound 296 – a,b-unsaturated ester 358 – a,b-unsaturated sulfoxide 83ff. – vinyl sulfone 294 conjugate reduction 297f. – Cu-catalyzed 298 – b,b-disubstituted a,b-unsaturated carbonyl compound 297 – b,b-disubstituted a,b-unsaturated sulfone 298 contact-ion pair 376ff., 379, 388, 394 – configuration 394 – structure 394 copper, see Cu CP-293,019 281 cross-coupling 221f., 226f. – metal-catalyzed 221f., 226 – Ni-catalyzed 221 – Pd-catalyzed 222, 226f. crossed-aldol reaction 169f. – mechanism 169 – l-proline-catalyzed 170 crotylation 286 – benzoyl hydrazone 286 Cu catalyst 74, 200ff., 227, 252ff., 298, 301, 311f. Cu complex 200f. Cu(MeCN)4PF6/bis(oxazoline) 201 Cu(SbF6)2-SIAM 252ff. Cu(II)-SIAM catalyst 252ff. curcuphenol 89 Curtin-Hammett principle 204, 331 Curtin-Hammett situation 385

Index N-cyano sulfoximine 212 cyanoacetate 296f. – thiourea-catalyzed addition 297 cyanohydrin 128 cyanosilylation 279 – Ti-catalyzed 279 b-cyanosulfoxide 85 cyclization 95f. – 5-exo-trig 95f. cycloaddition 56, 96, 103ff., 106, 122f., 270f., 292 – [2 þ 2] 292 – [2 þ 2 þ 1] 123 – [3 þ 2] 292, 301 – [4 þ 2] 292 – [4 þ 3] 122 – catalytic 270f. – 1,3-dipolar 300 – 5-exo-trig 96 – 6-exo-trig 96 – formal [2 þ 2 þ 1] 123 – [5 þ 2] intramolecular 122] – intramolecular radical 96 – Lewis acid-catalyzed 300 – Pd-catalyzed 301 – sulfinyl-directed [5C þ 2C] intramolecular 402 cycloalkanone 72f. cyclobutane adduct 169 cycloheptenone 132 cyclohexadiene 104 cyclohexane 125 cyclohexanone 310 cyclohexanone mono-oxygenase (CMO) 172ff. cyclohexene 125 cyclohexenol 63, 108 cyclohexenone 125, 132 cyclohexylamine 241f. – a-substituted 241f. – synthesis 241f. cyclopentadiene 98ff., 102ff., 105, 309 cyclopentane 122 – functionalized 122 2-cyclopentanone 91 cyclopentene 359 – functionalized 359 cyclopentenone 89, 91, 132 – substituted 89 cyclopropanation 93f., 179f., 194ff., 197f., 281f., 311ff., 405 – alkene 194 – Cu-catalyzed 311ff. – cycle 283

– intramolecular 311f. – mechanism 196f. – stoichiometric 195ff. – styrene 282 cyclopropane 94, 120f., 180, 194ff., 198, 214, 282 – synthesis 282 – trans 198 cyclopropyl ester 283

d DAG (diacetone-d-glucose) 5, 45ff., 409ff., 412f. – stereoselectivity 412 DAG alkylsulfinate 5 DAG arylsulfinate 5 DAG method 5, 409ff. – mechanism 411 – model system 410, 412 – steric model 412f. DAGOH 409f., 412f. Dane’s diene 99f., 106 Darzens reaction 314f., 353 Davis’ method 237 Davis’ protocol 246 DCG (dicyclohexylidene-O-glucose) 45ff. decarboxylation 382f. 5,6-dehydropiperidin-2-one 360 3,4-dehydroproline 222 density functional theory (DFT) 399f., 404 density functional theory/molecular mechanics (DFT/MM) 399 deprotonation 330f., 343, 381, 383ff., 393 deprotonation-quenching sequence 393 desulfinylation 116f. DET (R,R-diethyl tartrate) 12ff. diacetone-d-glucose, see DAG a,a’-dialkyl-b-ketosulfoxide 62 diamine 242 – C2-symmetrical vicinal 242 a,b-diamino acid 246 a,b-diamino ester 242 diarylamine 247 a-diazo-b-keto ester 312 a-diazo-b-ketosulfone 311ff. diazoacetamide 202 – substituted 202 diazoalkane 118ff. diazocompound 188, 190, 201f. diazoester 200ff. DIBAL (diisobutylaluminium hydride) 57ff., 60ff., 63ff., 66ff., 69f., 76, 79, 81, 124, 128f., 132

421

422

Index DIBAL/ZnCl2 59f., 62ff., 65ff., 68ff., 71, 79, 129, 132 – reduction 59ff., 62ff., 65ff., 71, 76, 132 – reduction mechanism 61 – stereoselectivity 63ff., 66ff. DIBAL/ZnX2 59ff. dicyclohexylidene-O-glucose, see DCG Diels-Alder reaction 55, 96, 98ff., 101, 103ff., 109ff., 127, 130, 175, 227, 252ff., 270ff., 308f., 401 – [4 þ 2] 175 – asymmetric hetero 109ff., 308 – catalytic 271 – chiral Lewis acid-catalyzed 252, 271 – Cu(SbF6)2-SIAM-catalyzed 252ff. – endo-attack model 272 – hetero 127f., 227 – intramolecular 108f. – Ti-promoted 308 diene 96, 98ff., 102ff., 106ff., 128, 252ff. – acyclic 253f. – cyclic 99, 252f. – 4-methyl-substituted 128 dienophile 96ff., 99ff., 102ff., 107, 254, 308 – bidentate 308 – cyclic 100 – reactivity 97, 107 – stereoselectivity 97 – sulfinyl ethylene 97 – vinyl sulfoxide 96 diester 227 R,R-diethyl tartrate, see DET 2,3-dihydrofuran 220f. dihydroxylation 301ff. – a,b-unsaturated sulfone 302 – vinyl sulfone 302f. diisobutylaluminium hydride, see DIBAL b,d-diketosulfoxide 64 (R)-(–)-2,6-dimethylheptanoic acid 174 diol 63, 64f., 129, 168, 302, 345f. – synthesis 63 1,2-diol 65 1,3-diol 64, 129 1,3-dipolar reaction 55, 110, 117, 300f., 403 – calculation 403 – Cu-catalyzed 301 – cycloaddition 111, 117, 300f. – stereocontrol 403 dipolarophile 111ff., 120 – activated vinyl sulfoxide 113 – acylic sulfinyl acrylonitrile 120 dipole 111, 121 directing effect study 400, 403

disparlure 356 dithiane 161, 167, 169ff., 172, 344f. – conversion 161 – crossed-aldol product 169f. – 2-hydroxy 164 – lithiated 162ff. 1,3-dithiane 161ff., 170, 344 – 2-anion 161 – a-carbanion 344 dithiane oxide 171, 175 1,3-dithiane ring introduction 162 1,3-dithiane-1-oxide 171f., 174 dithioacetal 161ff., 167f., 171, 176f., 344f. – application 175 – a-lithiated 167f., 344 – natural product 175 double stereodifferentiation process 369 Doyle-Kirmse reaction 199 dual activation 279, 281 dynamic kinetic resolution (DKR) 35, 331ff., 334, 336, 394ff., 409ff. – energy diagram 332 – reaction pathway 332 – sulfinyl chloride racemate 409 dynamic thermodynamic resolution 331, 333f., 336, 338ff., 345 – energy diagram 331 – reaction pathway 331

e electron-density effect 369 electron-withdrawing group 88, 97, 102f., 107, 121, 136, 236f., 292, 297, 300, 302, 314, 367, 401 electronic approach control 98 electrophile 72f., 131, 135ff., 139, 180ff., 203, 336ff., 342f., 353, 369, 371 – activation 279 – b-ketosulfoxide 73 – prochiral 182 – N-sulfinylimine 133, 135 electrophilic addition 96 enaminonitrile 92 b-enaminosulfoxide 79ff. – synthesis 79 enantiodetermining step 400 enantioface-selection 344f. enantiomerization barrier 377ff., 380 enantioselection 399 – energy difference 399 endo approach 112 endo mode 98 endo/exo isomerization 393f. – free activation energy 394 endo/exo isomerization time 393f.

Index endo/exo selectivity 103, 105, 107, 111, 113f., 116f., 120, 124, 238, 300 energy barrier 400, 403, 410ff. – translation into enantiomeric excess 400 enolate 248, 358f. – addition 248 – trapping with electrophile 358f. ephedrine 9 epoxidation 181, 183, 186, 188f., 301, 303f., 404f. – aryl aldehyde 404 – dienyl sulfone 303 – general scheme 405 – mechanism 404 – rate-determining step 404 – 2-sulfonyl-1,2-cycloalkadiene 303 – a,b-unsaturated 303 – vinyl sulfone 303f. epoxide 58, 68, 74, 76, 163, 183, 186, 214, 314f., 353 – aliphatic 186 – functional 187f. – ring-opening 163 – terminal 187 – unsaturated 186 a,b-epoxy sulfoxide 91 epoxysulfone 314 (þ)-erythro-roccellic acid 90 esomeprazole 14 ester 302, 359f. – g-hydroxy-a,b-unsaturated 302 – a,b-unsaturated 358ff. Et2AlCN 76f., 83, 85, 125, 128 – pentacoordinated 77 ethane 1,2-bis-sulfinyl chloride 48 Evans auxiliary 11 Evans oxazolidinone 12 exo approach 113, 115 exo mode 98 external quench 380

f

p-facial selectivity 97ff., 100, 103f., 106f., 109ff., 112ff., 117ff., 120ff. – control 106 fenoprofen 90 ferrocene 131 ferrocenyl p-tolyl sulfoxide 12 flavone 89 O-(9-fluorenyl) tert-butanesulfinate 35 g-fluoro-b-iminosulfoxide 81 fluoroalkyl imine 370 formyl anion equivalent 167f. free ylide pathway 202 furan-2(5H)-one 302

furanone 113f. furyl imine 193

g generalized gradient approach (GGA) 400 glycidic acid 78 glycidic derivative 187 Grignard reagent 4, 6f., 9ff., 12, 70, 72, 88, 94, 126, 171, 242, 244f., 261, 327, 364 – dithiane oxide addition stereoselectivity 171 guanacastepene 216f.

h H/D exchange experiment 382 – mechanism 382 (–)-halosaline 243 a-halosulfone 314f. Heck reaction 223 helicenequinone 106 heteroarylsulfone 292f. Hoffmann test 325, 333 homaline 94 Horner-Wadsworth-Emmons (HWE) olefination 302 hybrid quantum mechanical/molecular mechanical calculation (QM/MM) 400, 412 hydrocyanation reaction 76ff., 82f., 85, 125, 128 – mechanism 77 – a-sulfinyl ketone 77 hydrogenation 228, 255f., 267f., 270, 305f. – biferrocene diphosphine Rh-catalyzed 306 – chemoselective 228 – imine 228 – ketone 305 – b-ketosulfone 305f. – olefin 255f. – reactivity 228 – Rh-catalyzed 268 – Ru-catalyzed 305f. hydroperoxide 22 hydroperoxo complex 406f. b-hydroxide ketone 132 a-hydroxy acid 90 b-hydroxy acid 90 b-hydroxy sulfide 201, 333 b-hydroxy sulfone 305, 381, 388 a-hydroxy-carbanion equivalent 369 b-hydroxy-g-ketoester 73 – a-substituted 73 (2S,3R)-(–)-3-hydroxy-methylproline 166 (E)-g-hydroxy-a,b-unsaturated sulfoxide 85 g-hydroxyalkylation 216f., 219 a-hydroxyester 227

423

424

Index b-hydroxyester 58, 73 hydroxyethylamine dipeptide isostere 370 a-hydroxyketone 68, 175 hydroxysulfone 306ff., 381 hydroxysulfoxide 57f., 70 b-hydroxysulfoxide 58f., 63, 272f., 356, 364 – a-alkylation 256 – bidentate ligand 272f. – homoallylic 59 b-hydroxysulfoximine 215, 224f. hygroline 112 hyperconjugation 163, 323ff., 333, 377f. hypervalent iodo compound 24

i imination 212 – agent 212 – metal-catalyzed 212 imine 81ff., 190, 192, 212, 228, 236, 240, 367ff. – diastereofacial selectivity 236 – electronic nature 192 – hydrogenation 228 – nitrogen substitution 236 – protected 193 – substituent 193 – a-sulfinyl carbanion addition 367ff. b-iminosulfoxide 79ff., 82, 360 – arylation 82 – reduction 79 – synthesis 79 indolizidine 79, 86 (R)-indolizidine 79 induction 57, 283 – 1,2-induction 77, 326f., 329 – 1,3-induction 62f., 77, 80 – 1,4-induction 92, 124ff., 130, 167 – 1,5-induction 128, 130 – 1,6-induction 129 – 1,n-induction 57 – enantiodetermining pathway 330 – energy diagram 330 – mechanism 283, 321, 329f. – reaction pathway 330 intermolecular b-addition 95 internal quench 380 intramolecular C-H insertion 311 intramolecular hydride transfer 61, 70, 124 intramolecular nucleophilic substitution 179 iron complex 19 isomerization time 393 isoxazolidine 115 – 5,5-disubstituted 115 isoxazolopyridazinone 118

j Jacobsen conditions 303 Jacobsen’s catalyst 303f. Julia-Colonna procedure 304 Julia-Kocienski olefination 294 Julia-like olefination 297 Julia-type reaction 291, 315

k Kagan oxidation 13 b-keto g-sulfinyl ester 65 – stereoselective reduction 65 ketone 73, 183, 215f., 305, 307, 363 ketosulfone 305ff., 308ff., 315 b-ketosulfoxide 57ff., 60f., 63ff., 66ff., 69ff., 73f., 77f., 80f., 117, 124f., 128f. – (SR)-a-alkyl-g-fluoro-ketosulfoxide 75 – electronegative substituent influencing chemo- and stereoselectivity 76 – fluorinated 69, 74 – hydrocyanation reaction 76, 125 – (S)-g-monofluorinated 74 – perfluorinated a-alkyl(aryl) 76 – polyhalogenated 69 – reduction 57ff., 60, 63, 124f., 129 – a-sulfenyl group influence 67 – g,d-unsaturated 59f. (1R, SR)-ketosulfoxide 75 kinetic conditions 113 kinetic control 368 kinetic resolution 395, 397

l lactam 169 b-lactam 127, 139, 194 lactone 59ff., 62, 65 – macrocyclic 60 g-lactone 61f., 364 d-lactone 62, 357, 364 lactone enolate 73 Lewis acid 252, 271, 279, 300 Lewis acid-Lewis base bifunctional asymmetric catalysis 279f. ligand 14ff., 228, 252ff., 255, 265ff., 268ff., 271, 273ff., 276, 279, 281, 283f., 287f., 305, 307, 312, 322, 368, 376, 386f., 413 – bidentate 273f. – C1-symmetric 274f. – C2-symmetric 1,2-diol 14 – C3-triethanolamine 15 – carbohydrate-tethered sulfur 270 – chiral chelating 414 – coordination mode 266f. – enantioselectivity 275f., 279

Index ligand (cont.) – external ligand effect on stereoselectivity 369 – hydroxysulfoxide 284 – immobilizing 307 – N-based 267 – phosphine-based 267 – S,N 271, 275 – sulfinamide-based P,N 255 – sulfoxide bonding mode 267 – sulfoxide-based 265ff., 274, 279, 287 – sulfoxide/nitrogen 275 – sulfoxide/phosphine 276f., 279 – sulfoxime 228 – sulfur coordinating role 414 – thioether-based 288 – thioether/phosphorus 288 lithiated dithiane 162ff. lithiated N-methyl sulfoximine 215 lithiation 322, 324 d-lithiation 220 2-lithio-1,3-dithiane 162ff., 167 – aldehyde/ketone addition 164 2-lithio-2-methyl-1,3-dithiane 166 2-lithio-2-phenyl-1,3-dithiane 165 lithium complex 73f. – tricoordinated 73f. lithium enolate 73

m malyngolide 313f. manganese catalyst 17 manganese complex 17 manostatin 63 maytansine 364f. menthol 3, 24, 41ff., 44 – condensation with p-toluenesulfinic acid 41f. menthyl alkylsulfinate 4, 8, 42, 44 menthyl arene sulfinate 42f. menthyl sulfinate 4, 8, 42f., 44, 288 – synthesis 4 O-menthyl p-toluenesulfinate 40 (MeO)3PO 354f. metal-catalyzed asymmetric catalysis 267ff. metalloenamine 243, 257 methanesulfinate 5 methyl alkyl sulfoxide 4 methyl o-bromophenyl sulfoxide 17 methyl tert-butyl sulfoxide 23 methyl carbinol 61 methyl enol ether 75 methyl jasmonate 313f. methyl phenyl sulfoxide 16, 18, 23

methyl phenyl sulfoximine 211, 224 – preparation 211 O-methyl sulfinate 40 – steroidal 40 – synthesis 40 methyl p-tolyl sulfoxide 11f., 15 methylating reagent 70 methylation 354f. – cyclic sulfoxide 355 – stereocontrol 355 – a-sulfinyl carbanion 355 a-methylene-g-lactone 355 exo-methylenecyclopropane 301 methylenedithiolane 169 – cycloaddition with chiral lactam 169 methylidenation 187 Metzner epoxidation 189 Michael acceptor 292, 294, 357, 359 Michael addition 86, 89, 91ff., 94, 219, 222, 294ff., 344, 360, 395 – diamine-catalyzed 296 – intramolecular 86, 91 – mechanism 92 – organocatalyzed 295 – a-substituted cyanoacetate to vinyl sulfone 296 – transition state model 296 Michael reaction 21, 86, 89, 91ff., 94, 219, 222, 294ff., 309ff., 344, 360, 395, 401 Michael-aldol reaction 309ff. – b-aryl a,b-unsaturated ketone 310 – catalyst function 310 – organocatalytic 310 – working model 310 Mitsunobu reaction 69 Modena system 13 molybdenum complex 19 MP2 calculation 401 Mukaiyama reaction 127, 129, 227 – aldol 127, 129, 227 – vinylogous aldol 227 multicomponent coupling 164

n NaBH4 68, 79, 81 naphthaldehyde 126 – remote asymmetric nucleophilic trifluoromethylation 128 1-naphthyl methyl sulfoxide 19 nelfinavir 85f. neutral coordinate-organocatalyst 284 nitrile oxide 117f. nitro group reduction 226 nitrogen-activating group 237 nitrone 111ff., 114f., 119, 175, 371

425

426

Index [3 þ 2] nitrone cycloaddition 175 nucleophile 130, 137, 285 – activation 279 – silicon-based 285 – sulfinated 130 – ortho-sulfinated benzylcarbanion 132 nucleophilic addition 56ff., 84, 90, 133 – intramolecular 133 – Ni-catalyzed 84 – a-sulfinyl group-mediated 57ff. nucleophilic epoxidation 91, 175 nucleophilic process 123ff. nucleophilic substitution 137

o Oppolzer’s camphor sultam auxiliary 201 orbital 323 organoaluminium reagent 125 organoborane 203 organocatalysis 285, 288, 295 organocatalyst 285, 288, 295, 297 – bifunctional thiourea-tertiary amine 297 organometallic reagent 49ff., 89, 125f. organozinc reagent 225 organozincate 84 oxabicyclo[3.2.1]octane 122 oxacycle 216 oxathiazolidine oxide 9f., 25, 233ff., 238f., 260 – N-activated 235 – endo/exo selectivity 238 – precursor 239 1,2,3-oxathiazolidine-2-oxide 9f., 25, 234, 261 oxathiazolidine-S-oxide 233 oxaziridine 22ff. oxazolidinone 12, 308 oxazoline 74, 78, 167, 271f., 386f. – chiral (bis) 167f., 387 oxidant 24 oxidation 2, 12, 14, 22, 171ff., 237 – catalytic 12 – sulfide 173f. oxirane 75f., 91, 179, 183, 186f., 189, 365 – spirocyclic bis-sulfinyl 91 a-oxoester 167 oxosulfonium salt 136f. a-oxy carbanion 323, 329f., 334f., 341, 343 oxygen donor 22 oxygen transfer mechanism 406f.

p palladium catalyst 222, 226f., 254f., 273ff., 276f., 278 palladium-catalyzed asymmetric allylic alkylation (Pd AAA) 273ff., 276 (–)-pateamine 258f. – synthesis 258f. Pauson-Kahn reaction 123 – intramolecular 123 Pd AAA, see palladium-catalyzed asymmetric allylic alkylation Pd(p)-olefin p–complex 278 Pd-trimethylenemethane (TMM) 301 – sulfone-substituted 301 (S)-pentafluoro-g-caprolactone 70 phaclofen 94 phase transfer catalyst 304, 314f. phenyl benzyl sulfoxide 352 – pKa value 352 phenyl tert-butyl sulfoxide 6 phenyl sulfone 293 – a,b-unsaturated 293 4-phenyl-1,5-diazacyclooctan-2-one 94 trans-2-phenylcyclohexanol 49 (þ)-(R)-phenylethanol 215 phenyloxirane 180 N-phosphinooxaziridine 23 a-phosphorylvinyl sulfoxide 90 (2S,3S,4R)-phytosphingosine 164 Pictet-Spengler reaction 82 piperidine 86, 134, 188, 280 PM3 calculation 401 polarizability 163 polarized continuum model (PCM) 403f. polymeric chiral metalloporphyrin complex 20 polyoxamic acid lactone 258f. pre-catalyst 200 l-proline 169f. a-propanoate equivalent 365 propargyl carbinol 59 prostaglandine intermediate 358 pseudopteroxazole 222ff. Pummerer intermediate 78 Pummerer reaction 57, 63, 136ff., 139f. – additive 137f., 142 – chiral center 138f. – interrupted 137, 140 – mechanism 140f. – non-oxidative (NOPR) 69, 140, 369 – non-oxidative, mechanism 140 – normal 136f. – stereoselectivity 138 – vinylogous 137f., 141 Pummerer rearrangement 69, 76, 136, 141f.

Index pyrazoline 120f. pyridine 130, 412f. – ortho-directed metallation 130 2-pyridyl group 294 2-pyridyl sulfone 295, 298, 315 – b-aryl-b-alkyl 298 – b,b-dialkyl-a,b-unsaturated 298 – b-disubstituted a,b-unsaturated 298 2-pyridyl vinyl sulfone 293f. (2-pyridyl)sulfonyl group 298 – b,b-disubstituted a,b-unsaturated 295 1-(4-pyridyl)-1-p-tolylsulfinyl ethylene 84 a-pyridylsulfenyl carbanion complex 337 – geometry optimization 337 pyronesulfinylalkene 122 pyrrolidine 134, 188, 300 – 2,5-disubstituted 300 – endo-pyrrolidine cycloadduct 300 pyrroloazepine 113

q quantum mechanical (QM) calculation 400 quenching 380, 383f. – kinetic 393 quinine 6f. quinolyl sulfide 338 quinone 106

r racemization 323ff., 379 – activation parameters 379 – barrier 324f., 379 – kinetics 379 – polarimetric determination 379 – pseudo first order 379 – rate-determining step 324 radical 95f., 283f., 298f. -structure calculation 299 radical addition 298 radical allylation 283f. – mechanism 284 – sulfonamide/hydroxysulfoxide 284 rate-determining step 186 (R)-recifeiolide 59f. recyclability 222, 307 reducing agent 124, 248f. reduction 56ff., 59ff., 62ff., 65ff., 71, 79, 124f., 128f., 228, 248f., 260, 305ff., 308 – oxaborolidine-catalyzed 307 – transition metal-catalyzed 228 reductive alkylation 226 Reformatzky reagent 12 Reissert reaction 280 remote stereocontrol 123, 126f.

remote sulfinyl group 127 – stereocontrol 127 remote sulfoxide 123ff. d-p p-resonance 163 restricted Hartree-Fock (RHF) method 401 retro-Michael reaction 21 rhodium catalyst 267f., 293f. rhodium complex 200f., 246f., 270, 311 – cationic disymmetrically P,C-chelated 270 ring-opening reaction 50f., 68, 76, 78, 163, 189 – nucleophilic 76, 78 – oxirane ring 76, 78 – thiane ring 68 rotational barrier 325, 352, 377, 388 rubiginone A2 106f., 125 – retrosynthesis 107 rubiginone C2 106f., 125 – retrosynthesis 107 ruthenium catalyst 267f., 281f., 305 Rydberg orbital 401

s SaN bond 237ff. SaO bond 237f. Salen ligand 16 Salen manganese(III) complex 17 SC-53116 256f. – synthesis 256f. Schiff base 18f. – tridentate ligand 18 sedridine 112 l-Selectride 81, 86, 124, 128 N-SES aziridine 192 seudenol 72 Sharpless epoxidation 172 shikimic acid 99 SIAM (bis(sulfinyl)imidoamidine) ligand 252ff. sibutramine 259f. – synthesis 259f. [2,3]-sigmatropic rearrangement 108, 110, 179f., 196, 199ff., 203 – catalytic 200 – mechanism 199ff. – sulfonium ylide-mediated 199 a-silyl-a-sulfenyl carbanion 324, 342 b-silyl-a-sulfinyl carbanion 354, 358, 363 a-silylamine 247f. – silyl anion addition 248 Simmons-Smith reaction 184 – sulfonium ylide-mediated 179 solvent influence 76, 333

427

428

Index Sonogashira coupling 222 spiroacetal 170 spiroketal 110 spirolic derivative 142 spongistatin 176 stabilized ylide 1921f. – mechanism 192 p,p-stacking interaction 135 stanna-Pummerer rearrangement product 141 statine 370 steric approach control 98, 112 steric effect 135 stilbene oxide 180, 183ff., 188f. – synthesis 183 b-stiryl p-tolyl sulfoxide 85 Strecker reaction 259 – sulfinyl imine-based 259 substitution 330f. sugar alcohol 45f., 48 sugar sulfinate 6 – diastereoselective formation 6 sulfenate ester 33 – oxidation 33 sulfenic ester 52 a-sulfenyl carbanion 321ff. – configurational stability 323ff., 326 – diastereoselective reaction 326ff. – enantioselective reaction 329, 332ff. – 1,2-induction 326f. – preparation 322f. – properties 321f. – racemization mechanism 323ff. – secondary 327 – stabilization 322f. – a-stannyl allyl sulfide-derived 328 – tertiary 328f., 340 sulfenyl group 321ff. – properties 321f. a-sulfenyl-b-ketosulfoxide 67 sulfenylation 73 sulfenylketosulfoxide 67 – reduction 67 sulfide 12, 14, 22, 182ff., 185ff., 191, 321f., 324 – C2 symmetric 183, 186 – catalytic use 188f. – a-chirality 322 – CMO-catalyzed oxidation 173f. – formation 183 – a,b-functionalized 137 – a-lithiated 324, 326f., 336ff., 342 – oxidation 12, 14, 22 – structure 183

– synthetic utility 321f. – tricarbonyl(h6-arene)chromium complex bearing 341 sulfinamide 9ff., 12, 233ff., 241, 252, 255f., 260f. – aliphatic 260 – application 233ff., 241, 256 – aromatic 260 – background 234f. – biologically active molecule 256 – enantiopure 240 – endo/exo selectivity 238 – ether-functionalized 240 – Grignard addition 261 – ligand 252, 254 – modular asymmetric synthesis 240 – precursor 235 – sulfinyl auxiliary 241 – synthesis 233ff., 236ff., 240 – transformation into enantiopure sulfoxide 9 – tunable chiral 261 b-sulfinamine 369 sulfinate 3ff., 6ff., 10, 36ff., 49f. – Andersen method 3f. – diastereoselective formation 5ff., 49f. – precursor 8 – synthesis 4, 33 – synthesis using alkaloid 7 – synthesis using 2-phenylcyclohexanol 5 – synthesis using sulfite 7ff. sulfinate ester 48 – C2-symmetric bis- 48 sulfinate ketimine 260 – reduction 260 sulfinated electrophile 123ff. sulfinated nucleophile 130 sulfinic acid ester, see sulfinic ester sulfinic ester 31ff., 39f., 42, 52 – asymmetric oxidation 32 – catalytic 35 – chiral ester functionality 40 – diastereomeric 31, 40ff. – enantiomeric 31ff. – structure 31 – synthesis 32ff., 40 – synthesis using optically active tertiary amine 33, 35 – synthesis using sulfinyl chloride with achiral alcohol 33ff. – synthetic method 32 – a,b-unsaturated 44 sulfinimine 241 – synthesis via condensation 241

Index a-sulfinyl acetate 364f. – masked 365 (Z)-sulfinyl acrylonitrile 103 a-sulfinyl aldehyde 77 N-sulfinyl a-amino 1,3-dithioketal 246 N-sulfinyl a-amino ketone 246 ortho-sulfinyl benzylcarbanion 135 a-sulfinyl carbanion 351ff., 354ff., 357ff., 360f. – alkylation 354ff. – carbonyl addition 360 – configuration 352, 395 – conformation 352 – conjugated addition 357ff. – geometry 352 – imine addition 367ff. – lithium salt 352 – properties 351f. – stereochemistry 351ff., 360 – stereogenic center formation 361f. a-sulfinyl carbon 362f. sulfinyl chloride 33ff., 37f., 41f., 44, 46ff., 49, 411 – rapid racemization 35 – a,b-unsaturated 44 sulfinyl cyanohydrin 78 a-sulfinyl cycloalkanone 77 sulfinyl diazine 130 – ortho-directed metallation 130 sulfinyl diene 107ff. – p-facial selectivity 108 – reactivity 108 – 1-sulfinyl diene 107f., 110 – 2-sulfinyl diene 108ff. sulfinyl dienophile 96ff. – cyclic 100 – geminal 99 sulfinyl enamine 79 – endocyclic 79 – reduction 79 sulfinyl epoxide 59, 74, 353 (E)-a-sulfinyl ester 363 sulfinyl ethylene 97, 111, 121 – dipolarophile 111 – reactivity 111 sulfinyl furanone 114 sulfinyl group 55ff., 107, 111, 118f., 123, 128, 130, 132, 140, 236, 288 – a-C 57 – chiral auxiliary 57 – electron-withdrawing 236 – p-facial selectivity control 119 – nucleophilic substitution 137 – regioselectivity control 118

– stereoselective SN2 displacement 140 – stereoselectivity control 71f., 111, 119, 123, 130, 132 sulfinyl imine 236, 241f., 244, 246f., 250, 254, 256, 259 – ligand 254 a-sulfinyl imine 80 – cyclic 80 N-sulfinyl imine 165, 241ff., 244 1,3-sulfinyl induction 75 4-sulfinyl isoxazole 117 sulfinyl ketimine 248f., 257 – reduction 248f. sulfinyl quinone 105f. 2-sulfinyl quinone 105 sulfinyl sulfur 56 sulfinyl transfer agent 234f., 237 – cyclic 237 N-sulfinyl-a-amino-1,3-dithiane 166 sulfinyl-directed [5C þ 2C] intramolecular cycloaddition 402 – reaction path 402 bis(sulfinyl)imidoamidine (SIAM) ligand 252ff. a-sulfinyl-a,b-unsaturated ester 88 – nucleophile approach 88 sulfinylation 6, 37f. – catalytic 37 sulfinylbenzylcarbanion 132ff. b-sulfinylethylamine 367 1-sulfinylethylene 83 sulfinylimine 234ff., 240 – background 234 – synthesis 234ff., 240 a-sulfinylketimine 82f. N-sulfinylketimine 134 sulfite 7ff., 38f., 50f. – C2-symmetric transformation 8 – cyclic 50f. – cyclic, derived from C2-symmetric alcohol 8 – dissymmetrical 7 – prochiral 38 – ring-opening reaction 51 sulfonamide 307f. – polymer-supported 307f. sulfonate ion 21 – catalytic arylation 21 sulfondiimide 209 sulfone 291ff., 293, 300, 302, 304ff., 307ff., 314ff., 380ff., 383ff., 386ff., 389f., 392ff., 395 – alkylation 390, 392 – a-amido 314

429

430

Index sulfone (cont.) – base-mediated H/D exchange experiment 382 – (R,R)-configured 388f. – (R,S)-configured 389 – deprotonation 381f., 384f., 389, 392ff., 395 – deuteration 382 – enantiomerization 385 – epoxidation 304 – a,b-epoxy 304 – b,g-epoxy 304 – formation 385f., 389 – a-functionalized 314f. – heteroaryl 292f. – g-hydroxy-a,b-unsaturated 306 – hydroxyalkylation 388 – g-keto-a,b-unsaturated 306f. – metal-coordinating 315 – prochiral 384ff. – reduction 306f. – silylated 384 – substituted 314f. – a,b-unsaturated 292f., 300, 302 – b,g-unsaturated 302 sulfonimidamide 209 sulfonium salt 137, 181ff., 187, 190, 195ff., 198f. – aziridination 190 – camphor-derived 190 – deprotonation 181 – formation 182 sulfonium ylide 179ff., 187, 191, 194, 197, 203, 404 – conformation 191 – preparation method 180ff. – reaction 179ff. – stereocontrol conditions 182 – stereogenic element introduction 182 – sub-stoichiometric formation 197 – theoretical investigation 182 a-sulfonyl carbanion 291, 315, 375ff., 378ff., 381ff., 384ff., 387ff., 390f. – alkylamino-substituted 390 – alkylation 392 – allylation 381f. – aryl-alkyl-substituted 375 – asymmetric reaction conditions 380 – chirality 375, 382f. – configurational labile 382ff., 388 – configurational stability 378ff., 388 – (R,M)-configured 395 – (S,P)-configured 395 – conformation 375, 389

– dialkylamino-substituted 389f. – dynamic kinetic resolution 396 – enantiomerization 377f. – external trapping 383 – hydroxyalkylation 382 – in-situ trapping 383f. – lithium salt 375f. – oxazolidine-substituted 391 – protonation 381, 383 – reaction 392 – stabilization mechanism 377 – stereogenic center addition 388ff., 391 – structure 375f., 389f., 395 – synthesis 392 a-sulfonyl carbanion salt 376, 389f., 393ff. – monomeric 394 – racemization 379 – structure 376, 389f., 394f. sulfonyl chloride 43 sulfonyl cyclopropane 313 sulfonyl group 292ff., 298, 394 – heteroaryl 292f., 298 – metal-coordinating 291f., 298, 315 – rotation 394 N-sulfonyl imine 371 a-sulfonyl radical 299 sulfonyl trimethylenemethane synthon 301 N-sulfonyloxaziridine 23 3-sulfonylpyrrolidine 300 sulfoxidation 13f., 16, 23, 172, 405ff., 408ff. – Al-catalyzed 21 – B3LYP calculation 406 – 1,2-bis(tert-butyl) disulfide 406f. – iron-catalyzed 20 – manganese-catalyzed 17 – mechanism 406, 409f. – steric model 408 – Ti(Salen)-catalyzed 16 – using Ti/binaphthol complex 15 – using Ti/1,2-diol complex 14 – vanadium-catalyzed 18, 406ff., 409 sulfoxide 1ff., 6, 9ff., 13f., 55ff., 123, 172, 234f., 237f., 265ff., 268ff., 274ff., 279, 281, 283, 285ff., 288, 353f., 400, 403, 405, 409, 414 – application 281, 283f. – bonding mode 267 – C2-symmetric bis- 274, 283, 366 – coordinating transition metal 414 – coordination mode 266f. – cyclic equatorial 354 – ligand 265ff., 274, 283f., 287f. – lithiated 353f. – main synthetic routes 2

Index – neutral coordinate-organocatalyst 284 – non-enzymatic asymmetric synthesis 2ff. – stereoselectivity control 123 – structure-activity study 286 – switching to sulfoximine 403 – synthesis 1ff., 9f., 238 – synthesis using Evans auxiliary 11 – synthesis using 1,2,3-oxathiazolidine2-oxide 9f. – synthesis using prochiral sulfide 405 – synthesis using racemic precursor 409ff. sulfoxide-metal complex 267 sulfoximine 209ff., 212ff., 224, 227 – application 209ff., 213 – biological activity 210 – C2-symmetric bis- 212, 226 – chiral auxiliary 214 – chiral ligand 224 – enzyme inhibition 210 – general preparation process 211 – herbicidal activity 210 – insecticidal activity 210 – lithiated N-methyl 215 – N,N-type 227 – N,O-chelating 227 – P,N-type 227f. – structural modification 211ff. – structure 209ff. – N-substituted 212 – synthesis 209ff., 212f. sulfoxonium ylide 194 sulfur center 403ff. – directing effect 403 sulfur derivative, a-substituted 136f. sulfur function 55, 400 – directing effect 400, 403 – stabilizing mechanism 163 sulfur precursor 3ff. – use 3ff. sulfur ylide 93f., 179ff., 182, 400, 403f. – application 179ff. – conformation 182 – epoxidation 405 – reactivity 403f. – stereocontrol conditions 182 – theoretical investigation 182 – structure 404 – synthesis 179ff. sulindac ester 14 (–)-swainsonine 302 swinholide 176 (–)-sydowic acid 71

t tandem reaction 91ff. – intramolecular Michael addition/enolate alkylation 359 – involving Michael-type addition 91, 93 tartaric acid diester 12f. tertiary amine 33, 35 tetrahydrofuran 66, 69, 95, 163, 216f. – bicyclic 220 – derivative 216, 220 – trans-2,5-disubstituted 167 – formation 95 – substituted 217 – 2,3,5-trisubstituted 163 tetrahydroisoquinoline 371 tetrahydropalmatine 368 tetrahydropyran 66 tetrahydropyrrole 117 tetralone 361 thermodynamic conditions 113f. thermodynamic control 368f. [2,3]-thia-Wittig rearrangement 328 a-thio carbanion 326, 334, 340f. thioacetalization 162 thioanisole lithiation 322 thiocarbamate 321, 326, 334, 339ff. – lithiated 341 thiolane 189 Ti/binaphthol complex 15 Ti/DET complex 12f. Ti/DET methodology 13 – industrial application 13 Ti(Salen) catalyst 16 Ti/triethanolamine complex 15 titanating agent 219f. titanation 219f. titanium complex 12ff., 15, 308f. titanium TADDOL complex 308f. TMPOO (N-toluenesulfonyl-4-methyl-5phenyl-1,2,3-oxathiazolidine-2-oxide) 239 – S-N bond 239 p-toluenesulfinamide (p-TSA) 235ff., 240 – synthesis 236f. p-toluenesulfinate 46ff., 237 – cellulose-derived 47 – b-cyclodextrin-derived 47 p-toluenesulfinic acid 41 – condensation with menthol 41f. p-toluenesulfinimine 235f. – synthesis 236 p-toluenesulfinyl chloride 41 p-toluenesulfinyl imine 259 N-toluenesulfonyl-4-methyl-5-phenyl-1,2,3oxathiazolidine-2-oxide, see TMPOO

431

432

Index p-tolyl group 236 p-tolyl methyl sulfoxide 19, 367 p-tolyl sulfoxide 3, 361 (R)-a-(p-tolylsulfinyl) ketoxime 81 – reduction using l-Selectride 81 (R)-a-(p-tolylsulfinyl)acetophenone 70 p-tolylsulfoxide 371 N-tosylnorephedrine 11 total synthesis 222, 257 – (6R,7S)-7-amino-7,8-dihydro-a-bisabolene 257 transfer hydrogenation 268ff. – Ir-catalyzed 269f. – Rh-catalyzed 268 transformation 55 – sulfinyl group-mediated 55ff. transient chiral metal-complexed carbene, selective transfer 199 transition state 278f., 334, 362, 368, 402f., 412f. – calculation 403, 412f. – pro-R 408f., 412f. – pro-S 408f., 412f. transoid 191f. tricycle[4.3.0.0]nonenone 312 tricyclic compound 312f. triisopropylphenylsulfinamide (TIPP sulfinamide) 248 trimethylsilylcyanide (TMSCN) 82 TS-cisoid addition 192 TS-transoid addition 192 tungsten catalyst 20

u umpolung synthon 161f., 177 urea hydrogen peroxide adduct (UHP) 16

v vanadium catalyst 18, 406ff. – diastereomeric forms 407f. – Schiff base-derived 18 vinyl aziridine 194, 251 vinyl cyclopropane 196, 198 vinyl epoxide 186 vinyl ether 309f. vinyl sulfinyl allene 108 vinyl sulfone 292ff., 296ff., 300f., 315 – conjugate addition 294 – rhodium-catalyzed cine-substitution 293

– b-substituted 300 vinyl sulfoxide 83ff., 86, 88, 91, 95, 97f., 107, 109, 111f., 115f., 121ff., 137, 220, 356f., 363, 401 – ADC substrate 111 – b-alkoxy 95 – alkylation 356f. – conformation 401 – dienophilic feature 97 – electron-withdrawing group influencing reactivity and stereoselectivity 88, 97 – functionalized 221 – gem-disubstituted 99f. – lithiated 357, 363 – reactivity 97, 100 – selectivity 97 – stable conformer 401 – 1-substituted 88ff. – 2-substituted 84 – trans-substituted 98, 100 vinyl thioether 137 – g-substituted 137 vinyl p-tolyl sulfoxide 101 – (Z)-substituted 101 vitamin E intermediate synthesis 363f.

w Wittig reaction 223, 328

y ylide 181, 197f., 200, 203, 403f. – amide-stabilized 404 – chirality transfer 200 – conformation 203 – ester-stabilized 197 – facial selectivity 182, 198 – formation 181f., 197, 199f. – mechanistic model 197 – metal-associated 200 – precursor 192, 194, 196, 198 – prochiral 182 – semi-stabilized 404 – structure influence 200

z Zimmerman-Traxler chair-like transition state 362, 368 zinc alkoxide 225 zinc complex 299, 361f.

Organosulfur Chemistry in Asymmetric Synthesis

Catalysis in Asymmetric Synthesis (Postgraduate Chemistry Series)

Organosulfur Chemistry II

Asymmetric Catalysis In Organic Synthesis