Modern Aldol Reactions

R. Mahrwald (Ed.) Modern Aldol Reactions Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis ...

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R. Mahrwald (Ed.) Modern Aldol Reactions Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis

Modern Aldol Reactions. Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

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Rainer Mahrwald (Ed.)

Modern Aldol Reactions Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis

PD Dr. Rainer Mahrwald Department of Organic Chemistry Humboldt University Brook-Taylor-Str. 2 12489 Berlin Germany

9 This book was carefully produced. Nevertheless, editor, authors and publisher do not warrant the information contained therein 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 British Library Cataloguing-inPublication Data: A catalogue record for this book is available from the British Library. Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at http://dnb.ddb.de ( 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation in 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 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. Typesetting Asco Typesetters, Hong Kong Printing Strauss Gmbh, M€ orlenbach Bookbinding Litges & Dopf Buchbinderei GmbH, Heppenheim ISBN 3-527-30714-1

v

Foreword Historically, the stimulus for the development of a particular reaction has been interconnected with a class of natural products whose synthesis would be greatly facilitated by the use of that particular bond construction. For example, the steroid synthesis challenges proved instrumental in the development of the Diels–Alder reaction. So too the synthesis challenges associated with the macrolide antibiotics have provided the motivation for the development of the full potential of the aldol addition reaction. R. B. Woodward’s 1956 quote on the ‘‘hopelessly complex’’ architecture of the erythromycins was probably stimulated, in part, by the fact that the aldol reaction existed in a completely underdeveloped state five decades ago. O Me

Me Me

OH

Me

OH Me

OH

O

The erythromycin-A structure, as viewed by Woodward in the ’50s

Me O

Et

O

H

O

O Me Me

H

O Me

MeO OH

NMe2 OH

‘‘Erythromycin, with all of our advantages, looks at present quite hopelessly complex, particularly in view of its plethora of asymmetric centers.’’ R. B. Woodward in Perspectives in Organic Chemistry; Todd, A. Ed.; WileyInterscience, New York, 1956, page 160.

The challenges associated with the development of this reaction are also embodied in the more general goals of acyclic stereocontrol that have been under active investigation for nearly twenty-five years. In these studies, the goal of understanding pi-face selectivity at trigonal carbon centers for a multitude of organic transformations has been the ultimate objective. From these research activities, a host of stereochemical models have evolved, such as the Felkin–Anh model for carbonyl addition and the Zimmermann– Traxler aldol stereochemical model for aldol diastereoselection.

vi

Foreword

The development of modern aldol reaction methods has evolved through a succession of pivotal discoveries that have advanced the whole field of stereoselective synthesis: A. Development of enolization strategies for the formation of (E) and (Z) enolates. B. Development of kinetic diastereoselective aldol addition variants through the discovery of optimal metal architectures [B(III), Ti(IV), Sn(II)]. C. Discovery of aldol reaction variants such as the Lewis acid catalyzed addition of enolsilanes to aldehydes (Mukaiyama aldol variant). D. Development of chiral enolates exhibiting exceptional pi-face selectivities. E. Development of chiral metal complexes as Lewis acid aldol catalysts. This two-volume series on aldol addition reaction methodology brings together an up-to-date discussion of all aspects of this versatile process. The reader will gain an appreciation for the role of metal enolate architecture in aldol diastereoselectivities (Vol. I; Chapters 1–3) and for the utility of chiral metal complexes in the catalysis of the Mukaiyama aldol reaction (Vol. II; Chapters 1–3, 5). In Vol. II; Chapter 6, enantioselective catalytic processes incorporating both enolization and addition are surveyed, as is the exciting progress being made in the use of chiral amines as aldol catalysts (Vol. I; Chapter 4). This highly active area of research will continue to develop ever more versatile chiral catalysts and stereochemical control concepts. Students and researchers in the field of asymmetric synthesis will greatly profit from the contributions of this distinguished group of authors who have so insightfully reviewed this topic. May 2004

David A. Evans Harvard University

vii

Contents Volume 1 Preface

xvii

List of Contributors 1

1.1 1.2 1.3 1.4 1.4.1 1.4.1.1 1.4.1.2 1.4.2 1.4.3 1.4.4 1.5

2

2.1 2.2 2.3 2.3.1 2.3.2

xix

Fundamentals and Transition-state Models. Aldol Additions of Group 1 and 2 Enolates 1 Manfred Braun Introduction 1 The Acid or Base-mediated ‘‘Traditional’’ Aldol Reaction 2

The Aldol Addition of Preformed Enolates – Stereoselectivity and Transition-state Models 9 Stereoselective Aldol Addition of Lithium, Magnesium and Sodium Enolates 25 Addition of Chiral Enolates to Achiral Carbonyl Compounds 26 a-Substituted Enolates 26 a-Unsubstituted Enolates 32 Addition of Achiral Enolates to Chiral Carbonyl Compounds 41 Addition of Chiral Enolates to Chiral Carbonyl Compounds 49 Addition of Achiral Enolates to Achiral Carbonyl Compounds in the Presence of Chiral Additives and Catalysts 51 Conclusion 52 References 53 The Development of Titanium Enolate-based Aldol Reactions Arun K. Ghosh, M. Shevlin Introduction 63 Additions of Enolates to Ketones 65

63

Addition of Enolates Without a-Substituents to Aldehydes 66 Stereoselective Acetate Aldol Reactions Using Chiral Auxiliaries 67 Stereoselective Acetate Aldol Reactions Involving Chiral Titanium Ligands 69

viii

Contents

2.3.3 2.4 2.4.1 2.4.1.1 2.4.1.1.1 2.4.1.1.2 2.4.1.1.3 2.4.1.2 2.4.1.2.1 2.4.1.2.2 2.4.1.2.3 2.4.1.2.4 2.4.1.3 2.4.1.4 2.4.2 2.4.2.1 2.4.2.2 2.4.2.2.1 2.4.2.2.2 2.4.2.3 2.5 2.5.1 2.5.1.1 2.5.1.2 2.5.1.3 2.5.1.4 2.5.2 2.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2.5.2.5 2.5.3 2.5.3.1 2.5.3.2 2.5.3.3 2.5.3.4 2.5.3.5 2.6 2.6.1

Alternative Approaches to Acetate Aldol Adducts 70 Addition of Enolates with a-Substituents to Aldehydes 72 Syn Diastereoselectivity 74 Synthesis of syn Aldols in Racemic Form 75 Reactions of Ketones 75 Reactions of Esters and Thiol Esters 77 Aldol Reactions of Aldehyde Hydrazones 78 Synthesis of Optically Active syn Aldols Using Chiral Auxiliaries 80 Amino Acid-derived Oxazolidinone and Related Auxiliaries 80 Camphor-derived Chiral Auxiliaries 84 Aminoindanol and Amino Acid-derived Chiral Auxiliaries 87 Other Chiral Auxiliaries 90 Synthesis of Optically Active syn Aldols Using Chiral Titanium Ligands 92 Synthesis of Optically Active syn Aldols with Chiral Enolates 95 Anti Diastereoselectivity 98 Synthesis of anti Aldols in Racemic Form 98 Synthesis of Optically Active anti Aldols by Use of Chiral Auxiliaries 99 Aminoindanol and Related Chiral Auxiliaries 99 Oxazolidinethione and Oxazolidineselone Chiral Auxiliaries 103 Synthesis of Optically Active anti Aldols by Use of Chiral Titanium Ligands 104 Natural Product Synthesis via Titanium Enolate Aldol Reactions 105 Lactone Natural Products 105 Tetrahydrolipstatin 106 Myxopyronins A and B 106 Callystatin A 107 AI-77-B 108 Macrolide Natural Products 110 Epothilone 490 110 Cryptophycin B 110 Amphidinolide T1 111 Rapamycin 112 Spongistatins 1 and 2 113 Miscellaneous Natural Products 114 Tautomycin 114 Crocacin C 115 Stigmatellin A 116 Denticulatin B 117 Membrenone C 119 Typical Experimental Procedures for Generation of Titanium Enolates 120 Experimental Procedures 120

Contents

2.6.2 2.7

Alternative Approaches to Titanium Enolate Generation Conclusion 121 References 122

3

Boron and Silicon Enolates in Crossed Aldol Reaction Teruaki Mukaiyama and Jun-ichi Matsuo Introduction 127

3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.3.6.1 3.3.6.2

4

4.1 4.2 4.2.1 4.2.1.1 4.2.1.2 4.2.2 4.2.2.1 4.2.2.2 4.3 4.3.1 4.3.1.1 4.3.1.2 4.3.2 4.3.2.1

121

127

Crossed Aldol Reactions Using Boron Enolates 127 Discovery of Aldol Reaction Mediated by Boron Enolates 127 New Method for Direct Generation of Boron Enolates 129 Regioselectivity on Generation of Boron Enolates 130 Stereoselective Formation of (E) or (Z) Boron Enolates 131 syn-Selective Asymmetric Boron Aldol Reactions 134 anti-Selective Asymmetric Aldol Reaction 135 Crossed Aldol Reactions Using Silicon Enolates 137 Discovery of Silicon Enolate-mediated Crossed Aldol Reactions 137 Lewis Acid-catalyzed Aldol Reactions of Silicon Enolates 143 Non-catalyzed Aldol Reactions of Silicon Enolates 147 Lewis Base-catalyzed Aldol Reactions of Trimethylsilyl Enolates 148 Diastereoselective Synthesis of Polyoxygenated Compounds 149 Asymmetric Aldol Reactions Using Chiral Tin(II) Lewis Acid Catalysts 150 Stoichiometric Enantioselective Aldol Reaction 151 Catalytic Enantioselective Aldol Reaction 154 References 155 Amine-catalyzed Aldol Reactions Benjamin List Introduction 161

161

Aminocatalysis of the Aldol Reaction 162 Intermolecular Aldolizations 163 Aldehyde Donors 164 Ketone Donors 166 Intramolecular Aldolizations 167 Enolexo Aldolizations 167 Enolendo Aldolizations 171 Asymmetric Aminocatalysis of the Aldol Reaction Intramolecular Aldolizations 173 Enolendo Aldolizations 173 Enolexo Aldolizations 177 Intermolecular Aldolizations 179 Ketone Donors 179

173

ix

x

Contents

4.3.2.2

Aldehyde Donors References 196

5

Enzyme-catalyzed Aldol Additions Wolf-Dieter Fessner Introduction 201 General Aspects 202 Classification of Lyases 202

5.1 5.2 5.2.1 5.2.2 5.2.3 5.3 5.3.1 5.3.2 5.3.3 5.3.4 5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.4.6 5.5 5.6 5.7 5.8 5.9

6

6.1 6.2 6.2.1 6.2.2 6.2.2.1 6.2.2.2 6.2.2.3 6.3 6.3.1 6.3.2

193

201

Enzyme Structure and Mechanism 204 Practical Considerations 207 Pyruvate Aldolases 208 N-Acetylneuraminic Acid Aldolase 208 KDO Aldolase 216 DAHP Synthase 217 KDPG Aldolase and Related Enzymes 218 Dihydroxyacetone Phosphate Aldolases 221 FruA 222 TagA 224 RhuA and FucA 224 DHAP Synthesis 227 Applications 230 Aldol Transfer Enzymes 246 Transketolase and Related Enzymes 247 2-Deoxy-D-ribose 5-Phosphate Aldolase 250 Glycine Aldolases 254 Recent Developments 257 Summary and Conclusion 258 References 260 Antibody-catalyzed Aldol Reactions 273 Fujie Tanaka and Carlos F. Barbas, III Introduction 273 Generation of Aldolase Antibodies 273 Antibody as Catalyst Scaffold 273

Generation of Aldolase Antibodies that Operate via an Enamine Mechanism 274 Reactive Immunization with the Simple Diketone Derivative 275 Combining Reactive Immunization with Transition-state Analogs 277 Reactive Immunization with other Diketones 279 Aldolase Antibody-catalyzed Aldol and Retro-aldol Reactions 279 Antibody 38C2-catalyzed Aldol Reactions 280 Antibody 38C2-Catalyzed Retro-aldol Reactions and their Application to Kinetic Resolution 283

Contents

6.3.3 6.3.4 6.3.5 6.3.6 6.4 6.5 6.6 6.7 6.8 6.9 6.10

Aldol and Retro-aldol Reactions Catalyzed by Antibodies 93F3 and 84G3 285 Preparative-scale Kinetic Resolution Using Aldolase Antibodies in a Biphasic Aqueous–Organic Solvent System 288 Aldolase Antibody-catalyzed Reactions in Natural Product Synthesis 290 Retro-aldol Reactions in Human Therapy: Prodrug Activation by Aldolase Antibody 291 Aldolase Antibodies for Reactions Related to an Enamine Mechanism and the Nucleophilic Lysine e-Amino Group 293 Concise Catalytic Assays for Aldolase Antibody-catalyzed Reactions 297 Structures of Aldolase Antibodies and Reaction Mechanism of Nucleophilic Lysine e-Amino Group 298 Evolution of Aldolase Antibodies In Vitro 302 Cofactor-mediated Antibody-catalyzed Aldol and/or Retro-aldol Reactions 305 Summary and Conclusion 305 Experimental Procedures 306 Acknowledgments 307 References 307

7

The Aldol Reaction in Natural Product Synthesis: The Epothilone Story 311 Dieter Schinzer

7.1

History of Epothilones: Biological Source, Isolation, and Structural Elucidation 311 History of Epothilones: The Total Synthesis Race 311 Different Strategies with Aldol Reactions: The Danishefsky Synthesis of Epothilone A Relying on Intramolecular Aldol Reaction 312 Different Strategies with Aldol Reactions: The Nicolaou Synthesis of Epothilone A Using an Unselective Aldol Reaction 313 Different Strategies with Aldol Reactions: The Schinzer Synthesis of Epothilone A with Complete Stereocontrol in the Aldol Reaction 314 Model Study via Chelation Control in the Aldol Reaction by Kalesse 319 Different Aldol Strategies: Mulzer’s Total Syntheses of Epothilones B and D 320 Long-range Structural Effects on the Stereochemistry of Aldol Reactions 322 Summary and Conclusion 326 References 326

7.2 7.2.1

7.2.2 7.2.3

7.3 7.3.1 7.4 7.5

Index

329

xi

xii

Contents

Volume 2 Preface

xvii

List of Contributors 1

1.1 1.2 1.3 1.4 1.5

2

2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.2 2.2.1 2.2.2 2.2.3 2.3 2.3.1 2.3.2 2.3.3 2.3.4

3

3.1 3.2 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.2 3.3.2.1 3.3.2.2

xix

Silver, Gold, and Palladium Lewis Acids Akira Yanagisawa Introduction 1

1

Mukaiyama Aldol Reaction and Related Reactions 1 Asymmetric Aldol Reactions of a-Isocyanocarboxylates Summary and Conclusions 15 Experimental Procedures 18 References 21

8

Boron and Silicon Lewis Acids for Mukaiyama Aldol Reactions Kazuaki Ishihara and Hisashi Yamamoto Achiral Boron Lewis Acids 25 Introduction 25 BF3 Et2 O 26 B(C6 F5 )3 29 Ar2 BOH 30 Chiral Boron Lewis Acids 33 Introduction 33 Chiral Boron Lewis Acids as Stoichiometric Reagents 33 Chiral Boron Lewis Acids as Catalytic Reagents 40 Silicon Lewis Acids 53 Introduction 53 Lewis Acidity of Silicon Derivatives 54 Silicon Lewis Acids as Catalytic Reagents 55

25

Activation of Silicon Lewis Acids by Combination with Other Lewis Acids 60 References 65 Copper Lewis Acids 69 Jeffrey S. Johnson and David A. Nicewicz Introduction 69 Early Examples 69

Mukaiyama Aldol Reactions with Cu(II) Complexes 70 Enolsilane Additions to (Benzyloxy)acetaldehyde 70 Scope and Application 70 Mechanism and Stereochemistry 75 Enolsilane Additions to a-Keto Esters 80 Scope and Application 80 Mechanism and Stereochemistry 85

Contents

3.3.3 3.4 3.4.1 3.4.2 3.4.3 3.4.4 3.4.4.1 3.4.4.2 3.4.5 3.5

4

4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.3 4.3.1 4.3.2 4.4 4.4.1 4.4.2 4.4.3 4.4.4 4.4.5 4.4.6

Enolsilane Additions to Unfunctionalized Aldehydes 88 Additions Involving In-Situ Enolate Formation 90 Pyruvate Ester Dimerization 90 Addition of Nitromethane to a-Keto Esters 91 Malonic Acid Half Thioester Additions to Aldehydes 94 Dienolate Additions to Aldehydes 96 Scope and Application 96 Mechanistic Considerations 97 Enantioselective Cu(II) Enolate-Catalyzed Vinylogous Aldol Reactions 99 Conclusions 101 References 102 Tin-promoted Aldol Reactions and their Application to Total Syntheses of Natural Products 105 Isamu Shiina Introduction 105 Tin-promoted Intermolecular Aldol Reactions 105 Achiral Aldol Reactions 105 The Reaction of Silyl Enolates with Aldehydes or Ketones 108 The Reaction of Silyl Enolates with Acetals 117 Reaction of Dienol Silyl Ethers 120 Tin-promoted Intramolecular Aldol Reactions 121 The Intramolecular Aldol Reaction of Silyl Enolates 121 Reaction of Dienol Silyl Ethers or g-Silyl-a,b-enones 123 Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions 124 Asymmetric Aldol and Related Reactions of Sn(II) Enolates 125 Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions 128 Asymmetric Aldol Reaction of Silyl Enolates 129 Catalytic Asymmetric Aldol Reaction 131 Asymmetric Synthesis of syn- and anti-1,2-Diol Groups 135

Enantioselective Synthesis of Both Enantiomers of Aldols Using Similar Diamines Derived from L-Proline 139 4.5 Asymmetric Total Syntheses of Complex Molecules Using Chiral Diamine–Sn(II) Catalysts 140 4.5.1 Monosaccharides 140 4.5.2 Leinamycin and a Part of Rapamycin 142 4.5.3 Sphingosine, Sphingofungins, and Khafrefungin 145 4.5.4 Febrifugine and Isofebrifugine 147 4.5.5 Altohyrtin C (Spongistatin 2) and Phorboxazole B 148 4.5.6 Paclitaxel (Taxol) 149 4.5.7 Cephalosporolide D 153 4.5.8 Buergerinin F 153 4.5.9 Octalactins A and B 154 4.5.10 Oudemansin-antibiotic Analog 155

xiii

xiv

Contents

4.6 4.7

Conclusions 157 Experimental 158 References 159

5

Zirconium Alkoxides as Lewis Acids 167 Yasuhiro Yamashita and Shu¯ Kobayashi Introduction 167

5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8

6

6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8

7

The Asymmetric Mukaiyama Aldol Reaction 169 Asymmetric Hetero Diels–Alder Reaction 175 Reaction Mechanism 180 Structure of the Chiral Zirconium Catalyst 184 Air-stable and Storable Chiral Zirconium Catalyst 187 Conclusion 190 Experimental 191 References 192 Direct Catalytic Asymmetric Aldol Reaction Using Chiral Metal Complexes 197 Masakatsu Shibasaki, Shigeki Matsunaga, and Naoya Kumagai Introduction 197 Direct Aldol Reactions with Methyl Ketones 198 Direct Aldol Reactions with Methylene Ketones 208 Direct Aldol Reaction with a-Hydroxyketones 210 Direct Aldol Reaction with Glycine Schiff Bases 219 Other Examples 221 Conclusion 224 Experimental Section 225 References and Notes 226

Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases Scott E. Denmark and Shinji Fujimori 7.1 Introduction 229 7.1.1 Enantioselective Aldol Additions 229 7.1.1.1 Background 230 7.1.2 Lewis Base Catalysis 233 7.1.3 Organization of this Chapter 235 7.2 Preparation of Enoxytrichlorosilanes 236 7.2.1 General Considerations 238 7.2.2 Preparation of Ketone-derived Trichlorosilyl Enolates 240 7.2.3 Preparation of Aldehyde-derived Trichlorosilyl Enolates 246 7.2.4 Preparation of Trichlorosilyl Ketene Acetals 248 7.3 Preparation of Chiral Lewis Bases 249 7.3.1 Preparation of Chiral Phosphoramides 250 7.3.2 Synthesis of Chiral bis-N-Oxides 251

229

Contents

7.4 7.4.1 7.4.2 7.4.3 7.5 7.5.1 7.5.1.1 7.5.1.2 7.5.2 7.5.2.1 7.5.2.2 7.5.3 7.6 7.7 7.8 7.9 7.9.1 7.9.2 7.9.3 7.10 7.11 7.11.1 7.11.2

8

8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.3

Enantioselective Aldol Addition of Achiral Enoxytrichlorosilanes 253 Aldol Additions of Achiral Methyl Ketone-derived Enolates 254 Aldol Additions of Cyclic Trichlorosilyl Enolates 263 Addition of Acyclic Ethyl Ketone-derived Enolates 267 Diastereoselective Additions of Chiral Enoxytrichlorosilanes 272 Aldol Addition of Lactate-derived Enoxytrichlorosilanes 273 Methyl Ketone-derived Enolates 273 Ethyl Ketone-derived Enolates 277 Aldol Addition of b-Hydroxy-a-Methyl Ketone-derived Enoxytrichlorosilanes 280 Methyl Ketone-derived Enolates 280 Ethyl Ketone-derived Enolates 282 Addition of Enoxytrichlorosilanes with a b-Stereogenic Center 283 Aldol Additions of Aldehyde-derived Enoxytrichlorosilanes 288 Aldol Addition of Trichlorosilyl Ketene Acetal to Aldehydes and Ketones 294 Lewis Base Activation of Lewis Acids – Aldol Additions of Silyl Enol Ethers to Aldehydes 298 Toward a Unified Mechanistic Scheme 305 Cationic Silicon Species and the Dual-pathway Hypothesis 306 Unified Mechanistic Scheme 310 Structural Insights and Modifications 312 Conclusions and Outlook 315 Representative Procedures 316 Preparation of Enoxytrichlorosilanes 316 Aldol Addition of Ketone-derived Enoxytrichlorosilane 317 References 319 The Aldol–Tishchenko Reaction R. Mahrwald Introduction 327

327

The Aldol–Tishchenko Reaction 327 The Aldol–Tishchenko Reaction with Enolizable Aldehydes 327 The Aldol–Tishchenko Reaction with Ketones and Aldehydes 329 The Evans–Tishchenko Reduction 334 Related Reactions 339 Representative Procedures 341 References 342 Index

345

xv

xvii

Preface The aldol reaction was first described by Kane in 1848. Thus it is high time to provide a comprehensive overview of the different developments in aldol chemistry, especially those of the past few decades. Demands for this important method of CaCabond formation came and continue to come from every field of synthetic chemistry, particularly from natural product synthesis. Here, challenging problems in regioselectivity, chemoselectivity, diastereoselectivity and enantioselectivity frequently arise, many of which are still awaiting a solution. Symptomatically the word ‘‘selectivity’’ in its various connotations occurs no fewer than 1,100 times in both volumes, i.e. an average of twice a page. This book examines the enormous variety of aldol chemistry from the view of both organic as well as inorganic and bioorganic chemistry. It presents a wide range of potent syntheses based on the discoveries from enolate chemistry or the catalysis of Lewis acids and Lewis bases, for instance. The important role of metal catalysis, organocatalysis and direct aldol addition is described, along with enzymatic methods. However, it was not our intention to simply list all existing publications about aldol chemistry. Instead, we wanted to point out fundamental and at the same time efficient ways leading to defined configured aldol products. Two of these are depicted on the cover: the metal catalysis and the enzymatic method. It is now my pleasure to express my profound gratitude to the 22 authors and co-authors, all belonging to the elite of aldol chemistry, for their outstanding contributions and their professional cooperation. Special thanks are due to Wiley-VCH, especially Elke Maase and Rainer Mu¨nz, for their fine work in turning the manuscript into the finished book. Finally, I am indebted to my wife and my son for countless hours of assistance. Last but not least, this book is also a tribute to the works of Teruaki Mukaiyama, who has done tremendous work in the field of aldol reaction and now celebrates his 77th birthday. Berlin, Germany May 2004

Rainer Mahrwald

xix

List of Contributors Editor PD Dr. Rainer Mahrwald Institut fu¨r Organische und Bioorganische Chemie der Humboldt-Universita¨t zu Berlin Brook-Taylor-Str. 2 12489 Berlin Germany Authors Prof. Dr. Carlos F. Barbas, III The Skaggs Institute for Chemical Biology and the Department of Molecular Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 USA Prof. Dr. Manfred Braun Institut fu¨r Organische Chemie und Makromolekulare Chemie I Heinrich-Heine-Universita¨t Du¨sseldorf Universita¨tsstr. 1 40225 Du¨sseldorf Germany Prof. Dr. Scott E. Denmark 245 Roger Adams Laboratory, Box 18 Department of Chemistry University of Illinois 600 S. Mathews Avenue Urbana, IL 61801 USA Prof. Dr. Wolf-Dieter Fessner TU Darmstadt Department of Organic Chemistry and Biochemistry Petersenstr. 22 64287 Darmstadt Germany

Shinji Fujimori 236 Roger Adams Laboratory, Box 91-5 Department of Chemistry University of Illinois 600 S. Mathews Avenue Urbana, IL 61801 USA

Prof. Dr. Arun K. Ghosh Department of Chemistry University of Illinois at Chicago 845 West Taylor Street Chicago, IL 60607 USA

Prof. Dr. Kazuaki Ishihara Graduate School of Engineering Nagoya University Chikusa Nagoya, 464-8603 Japan

Prof. Dr. Jeffrey S. Johnson Department of Chemistry University of North Carolina at Chapel Hill Chapel Hill, NC 27599-3290 USA

Prof. Dr. Shu¯ Kobayashi Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo, Bunkyo-ku Tokyo 113-0033 Japan

xx

List of Contributors Naoya Kumagai Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo 7-3-1, Bunkyo-ku Tokyo, 113-0033 Japan

Michael Shevlin Department of Chemistry University of Illinois at Chicago 845 West Taylor Street Chicago, IL 60607 USA

Prof. Dr. Benjamin List Max-Planck-Institut fu¨r Kohlenforschung Kaiser-Wilhelm-Platz 1 45470 Mu¨lheim an der Ruhr Germany

Prof. Dr. Masakatsu Shibasaki Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo 7-3-1, Bunkyo-ku Tokyo, 113-0033 Japan

PD Dr. Rainer Mahrwald Institut fu¨r Organische und Bioorganische Chemie der Humboldt-Universita¨t zu Berlin Brook-Taylor-Str. 2 12489 Berlin Germany Prof. Dr. Shigeki Matsunaga Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo 7-3-1, Bunkyo-ku Tokyo, 113-0033 Japan Dr. Jun-ichi Matsuo The Kitasato Institute Center for Basic Research (TCI) 6-15-5 Toshima Kita-ku, Tokyo 114-003 Japan Prof. Dr. Teruaki Mukaiyama The Kitasato Institute Center for Basic Research (TCI) 6-15-5 Toshima Kita-ku, Tokyo 114-003 Japan David A. Nicewicz Department of Chemistry University of North Carolina at Chapel Hill Chapel Hill, NC 27599-3290 USA Prof. Dr. Dieter Schinzer Otto-von-Guericke-Universita¨t Magdeburg Chemisches Institut Universita¨tsplatz 2 39106 Magdeburg Germany

Prof. Dr. Isamu Shiina Department of Applied Chemistry Faculty of Science Tokyo University of Science Kagurazaka, Shinjuku-ku Tokyo 162-8601 Japan Prof. Dr. Fujie Tanaka Department of Molecular Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 USA Prof. Dr. Hisashi Yamamoto Department of Chemistry The University of Chicago 5735 S. Ellis Avenue Chicago, IL 60637 USA Dr. Yasuhiro Yamashita Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo, Bunkyo-ku Tokyo 113-0033 Japan Prof. Dr. Akira Yanagisawa Department of Chemistry Faculty of Science Chiba University Inage, Chiba 263-8522 Japan

1

1

Fundamentals and Transition-state Models. Aldol Additions of Group 1 and 2 Enolates* Manfred Braun 1.1

Introduction

In an aldol reaction, an enolizable carbonyl compound reacts with another carbonyl compound that is either an aldehyde or a ketone. The enolizable carbonyl compound, which must have at least one acidic proton in its aposition, acts as a nucleophile, whereas the carbonyl active component has electrophilic reactivity. In its classical meaning the aldol reaction is restricted to aldehydes and ketones and can occur between identical or nonidentical carbonyl compounds. The term ‘‘aldol reaction’’, in a more advanced sense, is applied to any enolizable carbonyl compounds, for example carboxylic esters, amides, and carboxylates, that add to aldehydes or ketones. The primary products are always b-hydroxycarbonyl compounds, which can undergo an elimination of water to form a,b-unsaturated carbonyl compounds. The reaction that ends with the b-hydroxycarbonyl compound is usually termed ‘‘aldol addition’’ whereas the reaction that includes the elimination process is denoted ‘‘aldol condensation’’. The ‘‘traditional’’ aldol reaction [1] proceeds under thermodynamic control, as a reversible reaction, mediated either by acids or bases. In contrast, modern aldol methods rely on the irreversible formation of ‘‘preformed enolates’’ which are added to aldehydes or ketones. In any case, the aldol reaction has proven itself by a plethora of applications to be one of the most reliable methods for carbon–carbon bond-formation yielding either carbon chains, with oxygen functionality in 1,3-positions, or alkenes, by a carbonyl olefination process [2, 3]. The first example of this reaction, the acid-catalyzed self-condensation of acetone to give mesityl oxide, was reported more than one and a half centuries ago by Kane [4]. The condensation of an aromatic aldehyde with an aliphatic aldehyde or ketone, obviously the first example of an aldol condensation under basic conditions, was reported by Schmidt [5] and by *

This chapter is dedicated to the memory of Ulrike Mahler (deceased 1995) and Ralf Devant (deceased 2002).

Modern Aldol Reactions. Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

2

1 Fundamentals and Transition-state Models. Aldol Additions of Group 1 and 2 Enolates

Claisen and Clapare`de [6], and named after the inventors (‘‘Claisen– Schmidt condensation’’) [2]. Obviously, Wurtz first recognized [7] the simultaneous presence of aldehyde and alcohol moieties in the ‘‘aldol’’ 1 resulting from the acid-induced reaction of acetaldehyde, and the reaction was named after the product it leads to later on (Eq. (1)). O H

H 3C

OH

HCl, H2O

O

ð1Þ

H

H 3C 1

1.2

The Acid or Base-mediated ‘‘Traditional’’ Aldol Reaction

Several reaction conditions feature in this ‘‘traditional’’ transformation. First, the reaction is run in protic solvents and can be mediated either by acid or by base. Second, the reaction is reversible, particularly under these conditions. Finally, the enol or the enolate, which acts as a nucleophile, is inevitably generated in the presence of the aldehyde or ketone that functions as an electrophile. The aldol reaction performed under these conditions (Scheme 1.1) was ‘‘the state of the art’’ until the early nineteenseventies, when the chemistry of ‘‘preformed enolates’’ emerged. The ‘‘traditional’’ aldol reaction has been the subject of several reviews, among which the summary by Nielsen and Houlihan in ‘‘Organic Reactions’’ in 1968 is a classical contribution and a very valuable survey [1]. The subject has also been treated in House’s monograph [2] and, more recently, by Heathcock [3]. Thus, only general features and few representative examples of ‘‘traditional’’ aldol addition will be given here; the reader is referred to the above-mentioned surveys for more details. Synthetically the reversibility of the aldol addition can cause substantial problems. Investigations performed in order to determine the relative energies of an enolate and an aldehyde on the one hand and the aldolate on the other revealed the outcome of the aldol reaction to be slightly exergonic [8]. The aldol formed by either acid- or base-catalyzed reaction is significantly stabilized by a strong OH bond in the aldol 2 which arises either directly from acid-mediated addition or on protonation of the aldolate 3 in the base-catalyzed variant, as shown in Scheme 1.1. Alternatively, chelation of the counter-ion in aldolates resulting from preformed enolates in non-protic media serves as the driving force [9]. As a general rule, applicable for protic solvents, the equilibrium in an aldol addition is located on the product side when aldehydes react with each other (Eq. (2)), but on the side of the starting materials for ketones (Eq. (3)). OH

O 2

R

O

R H

H R

ð2Þ

1.2 The Acid or Base-mediated ‘‘Traditional’’ Aldol Reaction

acid catalysis H

O H

O +

R

O

R

R

H

H

O

H

H R

H (cat)

2

O

H2O

R

OH

H OH H2O +

R

O

O

O H

R

O

R

H

H

R 3

basic catalysis Scheme 1.1

Aldol addition: general acidic and basic catalysis.

OH O 2

R

O

R

R

R R

ð3Þ

R

As a consequence, self-addition of enolizable aldehydes is usually readily accomplished in aqueous basic media if sufficient solubility is not prevented by the extended length of the carbon chain. The aldol addition (Eq. (4)) and condensation (Eq. (5)) of butanal giving 2-ethyl-3-hydroxyhexanal [10] and 2ethylhexenal [11], respectively, can serve as illustrative examples. The selfaddition of enolizable ketones, on the other hand, does not, per se, lead to substantial amounts of the aldol product, because of the unfavorable equilibrium mentioned above. This equilibrium can, however, often be shifted by a subsequent elimination step, so the aldol condensation of ketones is more frequently applied than addition. There are also special procedures that enable shifting of the equilibrium in the aldol reaction of ketones towards the products. Among these the formation of ‘‘diacetone’’ 4 by heating acetone under reflux in a Soxhlet apparatus filled with calcium or barium hydroxide is a well-known procedure which avoids contact of the base with the non-volatile hydroxy ketone 4 thus preventing a retro aldol reaction from occurring (Eq. (6)) [12, 13].

3

4


OH O

O

KOH, H2O 75%

H

86%

H

Ba(OH)2 Soxhlet, reflux

O

ð4Þ

H

ð5Þ

O

NaOH, H2O 80°C

O

H

OH

O

ð6Þ

75% 4

Mixed aldol reactions between different aldehydes or ketones are usually plagued by formation of a mixture of products, because each component can function as a CH-acidic and carbonyl-active compound. Whereas the ‘‘directed aldol reaction’’ [14–16] is a rather general solution to this problem, the traditional aldol addition of non-identical carbonyl compounds is only successful when applied within the framework of a limited substitution pattern. Thus, a fruitful combination in mixed aldol reactions is that of an aldehyde with an enolizable ketone. Obviously, the aldehyde, having higher carbonyl reactivity, reacts as the electrophilic component, whereas the ketone, with comparatively lower carbonyl reactivity, serves as the CH-acidic counterpart. Because the self-aldolization of ketones is endothermic, this type of side reaction does not occur to a significant extent, so the product of the mixed aldol condensation is obtained in fair yield, as illustrated by the formation of ketone 6 from citral 5 and acetone, a key step in the synthesis of b-ionone (Eq. (7)) [17]. O

O + H

5

O

NaOEt 45-49% 6

ð7Þ The most efficient variant of this combination is based on reaction of an enolizable ketone with a non-enolizable aldehyde, so that self-condensation of the latter cannot occur. Several examples of this type of combination in aldol reactions are given in Scheme 1.2. Usually in situ elimination occurs, so a,b-unsaturated ketones result, in particular when aromatic aldehydes are condensed with ketones (‘‘Claisen–Schmidt reaction’’) [18–21]. The intramolecular aldol condensation of dialdehydes, ketoaldehydes, and


NaOH, H2O, EtOH 20–25°C

O

O +

2 Ph

H3C

H

H O

+

+ Ph

H

ref. [18] Ph

Ph

CH3 O

ref. [19]

O

NaOH, H2O, EtOH 15–30°C

O

O

60–66%

CH3

H3C

O

1. NaOH, H2O 2. H

O

O

Ph

90-94%

CH3

5

85%

CH3

O ref. [20] Ph

Ph

OCH3 OCH3

CH3

H3C

CH3

H + O

NaOH, H2O, EtOH 25°C

CH3 CH3 ref. [21]

88% O O

Scheme 1.2

Illustrative examples of the condensation of aromatic aldehydes with enolizable ketones (‘‘Claisen–Schmidt reaction’’).

diketones is one of the most efficient means of synthesizing five, six, and seven-membered rings. There are numerous applications of this variant of the aldol reaction, in particular in the context of the Robinson annelation reaction, described in the literature for decades. Because this topic has been reviewed comprehensively [22, 23], a few illustrative examples only will be given here. An early and rather prominent example of the intramolecular aldol condensation is found in Woodward’s synthesis of cholesterol [24]. Because the precursor 7 is an unsymmetrical dialdehyde, the problem of regioselectivity arises. Nevertheless, the a,b-unsaturated aldehyde 8 is formed in excess and only minor amounts of the regioisomer 9 are obtained (Eq. (8)). Complete regioselectivity was observed, however, when dialdehyde 10 was submitted to an intramolecular aldol condensation. Thus, the enal 11 was obtained exclusively in the first synthesis of genipin described by Bu¨chi and coworkers (Eq. (9)) [25].


6

H

H

piperidine, AcOH, benzene 60°C

CHO CHO

66%

H O 7

CHO H

H

H

H

+ H

H

CHO

O

O 8

9

ð8Þ MeO2C

MeO2C

H

O OH

CHO

piperidine, AcOH

CHO

68%

H

ð9Þ

O

H

OH

10

H

CHO

11

When ketoaldehydes, compounds that are unsymmetrical per se, are submitted to intramolecular aldol condensation the ketone usually acts as the CH-acidic component whereas the aldehyde plays the role of the carbonyl active counterpart. This regiochemical outcome is also favored when the conditions of a thermodynamic control are used. Again, this type of aldol condensation has been used in a variety of natural products synthesis. A steroid synthesis, the aldolization step of which is given in Eq. (10), is an illustrative example [26]. O O H H

O

CHO

KOH, H2O 50–80°C

H

73%

H

O O

O

ð10Þ When this type of stereochemical outcome is prevented by steric hindrance, the two carbonyl groups can play opposite roles in the sense that the aldehyde, deprotonated in its a-position, functions as nucleophile whereas


the ketone acts as the carbonyl-active compound, as shown in the example given in Eq. (11) [27]. OCH2Ph

OCH2Ph O

Na2CO3, EtOH, H2O

ð11Þ

46% H

O

CHO

Although problems of regiochemistry are inherent, the aldol condensation of diketones has found wide application. Typical examples are syntheses of cyclopentenones and cyclohexenones from 1,4- and 1,5-diketones, respectively. The concept is illustrated by a synthesis of jasmone 12 (Eq. (12)) [28] and of the homosteroid derivative 13, the latter arising under thermodynamic control in a Robinson annelation reaction (Eq. (13)) [29]. O

O

ð12Þ

O 12 OMe MeO

+ O O OMe

OMe

O

O

O 13

ð13Þ Intramolecular aldol condensations also serve as the key step in ‘‘biomimetic’’ syntheses of polyketides, synthetic strategies that try to imitate in vitro a proven or an assumed biosynthetic pathway [30]. Although the first attempts in this direction go back to the early 20th century [31], practical and efficient syntheses based on this concept were elaborated much later.

7

8


O O

OEt O

O

+

O

O

O O

O

O

2

O

O OEt

O

O

14

15

O

OH

16

OH

O

O O

O

O

OH

39%

O

O

OH 17 OH

OH

O

94%

OH

1. HCl 2. HI, HOAc

KOH, MeOH

O

OH

78%

O

OH

OH

HO 18

OH

O

OH

70% HO O 19 Scheme 1.3

Biomimetic synthesis of emocline 19 involving intramolecular aldol reactions.

The concept is illustrated in Scheme 1.3 – when intermediate 16 containing a carbon chain with six free keto groups and one protected keto group has been generated by twofold Claisen condensation of the diester 14 with the highly reactive dianion 15, it undergoes spontaneous aldol condensation followed by aromatization to give the naphthalene derivative 17. A further aldol addition, which leads to the formation of a third six-membered ring, needs treatment with potassium hydroxide. Finally, dehydration and deprotection lead to the anthrone 18, which is readily oxidized to the natural product emodine 19 [32]. Similar approaches based on intramolecular aldol reactions have been applied to the synthesis of naturally occurring anthracyclinones [33] and isoquinolines [34]; the biosynthesis of these is known to involve polyketone intermediates. The problem of stereochemistry has very rarely been addressed by tra-

1.3 The Aldol Addition of Preformed Enolates – Stereoselectivity and Transition-state Models

ditional aldol addition. The question of relative stereochemistry has been studied occasionally in the context of intramolecular, in particular transannular, aldolizations. There were, however, few diastereoselective variants. Control of enantioselectivity was achieved to a remarkable extent in the cyclization of 1,3-cyclopentanediones. Independent work by research groups at Hoffmann LaRoche and Schering AG in the early nineteen seventies revealed that highly enantioselective cyclization of triketones 20a, b can be accomplished by treatment with catalytic amounts of l-proline, as shown in Eq. (14) [35, 36]. Thus, the products 21a and 21b are obtained from the Hajos–Parrish–Eder–Sauer–Wiechert reaction, the intramolecular aldol condensation, in 93 and 99% ee, respectively. The method has been applied successfully to enantioselective steroid syntheses, and provided a route to the skeleton of several other natural products [37]. The source of stereoselectivity in this cyclization has been investigated carefully [38]. Very recently, proline catalysis has also been applied to enantioselective intermolecular aldol additions [39]. This promising approach will be discussed in detail in Chapter 4 of Part I. O N H

R

O

R

CO2H , DMF

O O

20a: R = Me 20b: R = Et

O

OH

21a: 93.4% ee 21b: 99.5% ee

ð14Þ Although the number of applications of the ‘‘traditional’’ aldol reaction ‘‘is legion’’, and despite its undoubted versatility, the reaction suffers from general lack of control of stereochemistry and from the difficulty of reliable determination of the carbonyl-active and CH-acidic components. Both problems have been solved by the technique of directed aldol addition based on preformed enolates.

1.3

The Aldol Addition of Preformed Enolates – Stereoselectivity and Transitionstate Models

The chemistry of preformed enolates emerged in temporal and causal coherence with the ‘‘LDA area’’. Although lithium and magnesium salts of diisopropylamine were first developed in the nineteen-fifties [40], lithium diisopropylamide (LDA) has been a widely used reagent since 1970, because of its behavior as a soluble, strong, and non-nucleophilic base [14]. LDA and related bases, for example lithium hexamethyldisilazane (LIHMDS) [41], lithium N-isopropylcyclohexylamide (LICA) [42], and lithium 2,2,6,6-

9

10


tetramethylpiperidide (LITMP) [43] turned out to be the reagents of choice for conversion of a variety of carbonyl compounds into their enolates in an irreversible reaction which also enabled control of regiochemistry. This is illustrated in the kinetically controlled deprotonation of 2-methylcyclohexanone, 22, which leads to the formation of the enolate 23 with remarkable regioselectivity (Eq. (15)) [44]. Complementary routes that lead to the formation of the regioisomeric enolate 24 with a more substituted double bond have also been elaborated; they are based on a deprotonation under thermodynamic control or use of enol acetates, silyl enol ethers, or a,bunsaturated carbonyl compounds as precursors. In addition, procedures for formation of (E) and (Z) enolates were elaborated. The formation of preformed enolates has been reviewed comprehensively [45, 46]. In addition, the determination of enolate structures by crystal structure analyses, pioneered by the research groups of Seebach, Boche, and Williard, and NMR spectroscopic investigations and theoretical calculations led to insight into their reactivity [47]. O

22

LiN(iPr2), MeOCH2CH2OMe, -78°C

OLi

OLi +

23 99

24 :

1

ð15Þ Preformed enolates can be obtained not only from aldehydes and ketones, but also from carboxylic esters, amides, and the acids themselves. The corresponding carbonyl compound always acts irreversibly as the CH-acidic component. Thus, the term aldol reaction is no longer restricted to aldehydes and ketones but extended to all additions of preformed enolates to an aldehyde or a ketone. In contrast with the ‘‘traditional’’ aldol reaction, this novel approach is based on a three-step procedure (usually, however, performed as a one-pot reaction). First, the metal enolate 25 is generated irreversibly, with proton sources excluded, and, second, the compound serving as the carbonyl active, electrophilic component is added. The metal aldolate 26 thus formed is finally protonated, usually by addition of water or dilute acidic solutions, to give the aldol 27 (Scheme 1.4) [45, 46]. The principal aim in the development of the ‘‘modern’’ aldol reaction was stereochemical control, a field that has been treated in a series of review articles [46, 48–60]. In stereochemical terminology, the topic is discussed in the terms of ‘‘simple diastereoselectivity’’ and ‘‘induced stereoselectivity’’ [61]. Except for relatively rare examples when R1 is identical with R2 and R3 is identical with R 4 , all aldol additions are stereogenic. If the carbonyl-active compound is either an aldehyde (except formaldehyde – R 4 ¼ H) or a prochiral ketone (R 3 0 R 4 ), addition of the enolate leads to formation of either


O R

1

R2

R1

a

α

O

M

C C

X

R2

H

X 25

O

M

O

O

R4

R3 b

R4

R3

X R1

R2

26

OH H3O c

R4

R3

O X

R2 R 27

1

R1, R2: H, alkyl, aryl, OR, NR2 R3, R4: H, alkyl X: H, alkyl, aryl, OR, NR2, OM Scheme 1.4

Aldol reaction of preformed enolates. (a) irreversible enolate formation; (b) addition of the preformed enolate to aldehydes or ketones; (c) protonation.

one or two stereogenic centers. This depends on whether an enolate with identical a-substituents (mostly R1 ¼ R2 ¼ H) or an enolate with different asubstituents is used. Under the latter conditions one of the substituents R1 and R2 is usually a hydrogen atom (Scheme 1.4). A general stereochemical pattern of the aldol addition is shown in Scheme 1.5. When a carbonyl compound 28 with an a-substituent R2 (which can be an alkyl or an aryl group, or a hetero substituent, for example alkoxy, or a protected amino group, but which is not identical with hydrogen) is converted into the ‘‘preformed’’ enolate 29 and added to an aldehyde, four stereoisomeric products 30a, 30b, 31a, 31b can result. When neither the enolate 29 nor the aldehyde contains stereogenic units, both reactants have enantiotopic faces and 30a and 30b are enantiomers. The same is true for the pair 31a and 31b. However, 30 and 31 form a pair of diastereomers. When an aldol addition leads to an excess of one of these diastereomers 30 or 31, it is said to exhibit simple diastereoselectivity. Several notations that assign descriptors to diastereomeric aldols are found in the literature. The classical erythro/threo nomenclature, which is based on Fischer projection formulas [62], will not be used in this chapter, because it can cause considerable confusion with branched carbon chains. Among the

11

12


OH

O

OH R3

R1

R3

R1

R2 30b OH

R2 31a

O

OH R3

R1

O R3

R1

R2

R2

30a

31b R1CHO

R2 =/ H

O R2

O

CH2

C

O R2

CH

M

C R3

R3

28

29

R1CHO

OH

O

OH R3

R1

R2 = H

32a

O R3

R1 32b

Scheme 1.5

Stereochemical pattern of aldol addition.

different alternatives proposed in the literature, the Prelog–Seebach notation deserves mention: their l (like) and u (unlike) descriptors are systematic and unambiguous, because they correlate strictly with Cahn–Ingold–Prelog nomenclature [63]. For practical reasons, however, the syn/anti notation, introduced by Masamune [64], will be used in this chapter. Thus, the carbon chain that contains the two stereogenic centers is drawn in a zigzag fashion. In the syn diastereomers both substituents at the stereocenters are directed either toward or away from the viewer. In the anti isomers one of the substituents is directed toward the viewer, the other one away from the viewer, or vice versa. According to this notation the stereoisomers 30a and 30b are termed syn whereas 31a and 31b are defined as the anti isomers. When the topicity of an aldol addition is of interest the lk (like) and ul (unlike) notation [63] will be used in this chapter to describe the pathway by which the enolate approaches the carbonyl compound (aldehyde or ketone). The problem of simple diastereoselectivity does not arise in aldol additions when an a-unsubstituted enolate 29 (R2 ¼ H) or an enolate with two identical a-substituents reacts with an aldehyde or a prochiral ketone. The products 32a and 32b obtained from this combination are enantiomers, if neither the aldehyde nor the enolate is a chiral molecule.


If an aldol addition is performed using either an enolate with stereogenic units, which can be located in the a-substituent R2 or in the ipso substituent R3 , or if a chiral aldehyde is used as the electrophilic component, the aldol products 30a, 31a, and 32a are diastereomers of 30b, 31b, and 32b. In these combinations not only is simple diasteroselectivity has to be achieved (except for the a-unsubstituted case leading to 32a/b) but also induced stereoselectivity. In detail, induced stereoselectivity is postulated for the following combinations of reactants: 1. reaction of chiral enolates with achiral or chiral aldehydes; 2. reaction of achiral enolates with chiral aldehydes; and 3. reaction of achiral enolates with achiral aldehydes, if they are mediated by use of a chiral catalyst (including enzymes or antibodies), chiral ligands at the metal M, or all kinds of chiral solvents. When, in reactions 1–3, the enolate does not have an a-substituent, e.g. 29 (R2 ¼ H), induced stereoselectivity is highly desirable. In addition, the corresponding reaction of a-substituted enolates 29 (R2 0 H) should not only provide induced stereoselectivity but also simple diastereoselectivity. In this chapter we will not use ‘‘induced diastereoselectivity’’ as a subdivision applicable to reactions 1 and 2 and ‘‘induced enantioselectivity’’ for reaction 3 (leading to enantiomeric aldol products), because, irrespective of the stereochemical relationship of the products (diastereomers or enantiomers), the transition states leading to the different stereoisomeric compounds are always diastereotopic, even if the products are enantiomers (reaction 3). The term ‘‘induced stereoselectivity’’, which includes the different variants 1–3, is therefore used here [57, 61]. Most aldol additions of preformed enolates are run under kinetic control. In some such kinetically controlled aldol reactions simple diastereoselectivity is related to the configuration of the enolate. The seminal investigations of Dubois [65], then intensive studies by the research groups of OM R2

R3

1. R1CHO 2. H3O

OH

R3

R1 R2

H (Z )-enolate

OM H

R3 R

O

syn aldol

1. R1CHO 2. H3O

OH

R3

R1 R2

2

(E )-enolate

O

anti aldol

Scheme 1.6

Correlation between enolate geometry and aldol configuration.

13

14


House, Heathcock, and Ireland [48–51], revealed that (Z)-configured enolates furnish mainly syn-aldols whereas anti-b-hydrocarbonyl compounds arise predominantly from (E) enolates. In this context, the descriptors E and Z refer to the relative position of the a-substituent R2 and the oxygen–metal bond (Scheme 1.6). Because procedures for the selective generation of (Z) and (E) enolates have been elaborated for a variety of carbonyl compounds [45], the kinetically controlled aldol addition offers a solution to the problem of simple diastereoselectivity. Representative examples of the Z/syn and E/anti correlation are given in Eqs. (16) and (17) [66, 67].

OLi Me

OH

O

Ph

R

H (Z )-enolate

OH

1. PhCHO THF, -78°C

R

2. H3O

+

O

Ph

R Me

Me syn

anti

syn

R

: anti

98.7 : 1.3

CMe3 Et

90

: 10

ð16Þ OLi H

O

Ph

X Me

OH

1. PhCHO THF, -78°C

OH X

2. H3O

+

Ph

X

Me

Me

syn

(E )-enolate

O

anti

syn : anti

X OMe

62

:

38

OCMe3 Me

51

:

49

12

:

88

2

:

98

O Me Me3C O

Me

Me3C

ð17Þ


As shown by Eq. (16), (Z) lithium ketone enolates yield syn aldols, if the substituent R at the carbonyl group is sterically demanding. Because carboxylic amides and thioamides, like ketones, form (Z) enolates predominantly, their aldol addition also leads to the predominant formation of syn-b-hydroxycarboxylic acids (or their corresponding derivatives). In general, Z-configured boron and titanium enolates result in higher simple diastereoselectivity in favor of syn aldols than the corresponding lithium or magnesium enolates. Also, with regard to the induced stereoselectivity boron enolates are usually more selective than lithium enolates [49, 52]. This might be because the boron–oxygen bond in enolates is shorter than the lithium–oxygen bond, so cyclic transition states involving boron as the metal are tighter, and steric repulsion is more effective and chiral information is transferred more efficiently (for chiral auxiliary groups or ligands). On the other hand, carboxylic esters and thioesters, which form predominantly (E) enolates, react with aldehydes with substantial anti selectivity. As shown in Eq. (18), this selectivity is, however, restricted to reactions in which bulky aromatic substituents form the alcoholic moiety of the ester. The anti diastereoselectivity of (E) enolates is usually lower then the syn selectivity of comparable (Z) enolates. One must also take into account the effect of the asubstituent. As shown in Eq. (18) the Z–syn correlation can be completely reversed for a-substituents that are bulky, sterically demanding alkyl groups [68]. OLi R

CMe3 H

1. Me3CCHO Et2O, 20°C 2. H3O

OH

O

OH

O

CMe3 + Me3C

Me3C

CMe3

R

R

syn

anti R

syn : anti 100 : 100 :

0

Et n-Pr

98 :

2

CHMe2

29 :

71

Me

CMe3

0

0

: 100

ð18Þ In the Mukaiyama addition of the aldol reaction [16], silyl ketene acetals or silyl enol ethers are added to aldehydes in a reaction mediated by Lewis acids or fluoride. Here again the Z–syn correlation is sometimes not observed [69, 70]. Thus, the Z–syn, E–anti correlation seems to be a rule with several exceptions [71]. The stereochemical outcome of the different aldol additions of preformed enolates calls for plausible transition state models. Two kinds of explanation seem suitable for rationalizing the different stereochemical results, which

15

16


even seem to contradict each other: Thus, in a single type of transition state model a different substitution pattern might cause the reactants to have different orientations to each other so that formation of different stereoisomers results. On the other hand, different reaction conditions and reactants can be used, even if the way the aldol reaction is run is restricted to the use of preformed enolates. Thus, the latter might have very different counter-ions, and the solvents might also be different. It seems plausible that this can cause the reaction to occur via completely different types of transition state. The most widely accepted transition state hypothesis for aldol additions is the Zimmerman–Traxler model. This was originally developed to explain the stereochemical outcome of the Ivanoff reaction – addition of the dianion of carboxylic acids with magnesium counter-ions to aldehydes and ketones [72]. On the basis of investigation of the stereochemical outcome of the reaction of doubly deprotonated phenyl acetic acid to benzaldehyde (Eq. (19)), Zimmerman and Traxler proposed in a seminal paper a transition state model that involves a six-membered chair-like assembly of the reactants [73]. i-PrMgBr, Et2O

O Ph

OMgBr Ph

OH

OMgBr H

ð19Þ OH

OH

O

1. PhCHO Ph 2. H3O

OH Ph 69%

+

Ph

O OH

Ph 22%

This model offers a plausible explanation of the (Z)–syn, (E)–anti correlation, as shown in Scheme 1.7. The diasteromeric transition states 33a and 33b, which emerge from addition of a (Z) enolate to an aldehyde, differ in the position of the substituent R1 , which is equatorial in 33a and axial in 33b. By analogy with conformational analysis of the cyclohexane system [62], the transition state 33a is expected to have a lower energy than the diastereomeric alternative 33b. As a consequence the predominant formation of syn aldolates results from this kinetically controlled reaction. When the (E) enolate is chosen as the starting material, the analogous argument indicates the transition state 34a with R1 in an equatorial position to be favored compared with the alternative 34b, in which the substituent R1 occupies an axial position. Accordingly, the anti aldolate is expected to be the predominant product. Although first developed for a magnesium enolate, the Zimmerman– Traxler model could be used very successfully to explain the stereochemical


R2 O R1

O

M

R1

OM R2

R1

H

OH O

H H

H

O

17

33a

R3

R1

H

R2

R3 syn aldolate

R3

O

syn aldol

R2 OM

H

R3 (Z )-enolaye H

R2

O

O

M

O

H

R1

R1 R1

H

R3

33b

O

M

R1 R

H H

OH O

H

O

R2 anti aldol

OH O

H

2

R3

R2

O R3

R1 R2

R3

anti aldol

anti aldolate

34a

R3

R3

OM H

R1

O

R1

anti aldolate

H O R1

OM R2

H

H OM

R2 R3

(E )-enolate

H H

O

O R1

M

O

H R1

R2 34b

OM H

H R1

R3

OH O

R2

R3 syn aldolate

Scheme 1.7

Zimmerman–Traxler transition state models in the aldol additions of (Z ) and (E ) enolates.

outcome of aldol additions of boron and titanium enolates. This might be because they are monomeric, in contrast with the enolates of lithium and magnesium, known to form aggregates. Not only is (Z)–syn [49, 52] and (E)–anti [74, 75] correlation better for boron enolates, they also usually result in greater induced stereoselectivity. This also is easily explained by the Zimmerman–Traxler model if it is assumed that for boron and titanium enolates, stronger Lewis acids than lithium and magnesium, the sixmembered transition state is tighter, so steric effects are maximized.

O R3

R1 R2 syn aldol

18


The validity of the Zimmerman–Traxler model for alkali metal or magnesium enolates could be questioned, because these strongly electropositive metals might form ionic rather than covalent bonds to the enolate/aldolate oxygen atom. Even if there was a contact ion-pair of metal cation and oxygen anion, however, the geometry of a six-membered chair in the transition state would be very similar to that shown in Scheme 1.7. Even the aggregation of lithium enolates, well recognized today [47], does not severely contradict the Zimmerman–Traxler model – indeed, a six-membered transition state, postulated to occur at a tetrameric lithium pinacolone enolate [76], is very compatible with the ‘‘closed’’ model proposed by Zimmerman and Traxler. The Zimmerman–Traxler model has, however, been challenged by the frequent observation that (Z) enolates result in higher simple diastereoselectivity, giving syn aldols, compared with the lower anti selectivity of (E) enolates [49–51, 68]. Assuming the classical chair transition state, it has been remarked that for (E) enolates models 34a and 34b might both be plagued by unfavorable steric repulsion. Thus, the equatorial orientation of R1 in 34a avoids repulsion by R3 , but at the expense of a steric hindrance between R1 and R2 , which is enhanced because the torsional angle at the forming carbon–carbon bond is less than 60 . This has been postulated in skewed transition state models, proposed by Dubois [68] and Heathcock [51], in which the dihedral angle between the enolate double bond and the carbonyl group approaches 90 , as shown in Scheme 1.8 for the E–syn and E–anti correlation. The alternative, 34b, takes advantage of minimizing the R1 –R2 repulsion, but on the other hand, is disfavored by the axial R1 –R3 hindrance. As a result, both transition states 34a and 34b become similar in energy, so stereoselectivity is reduced. An important modification of the classical Zimmerman–Traxler model, which still relies on the idea of a ‘‘pericyclic-like’’ transition state, considers H R

O

M

1

O

R2 H

OH

R2

R3

O

H

anti

M O

R2

R3

R1

(E )-enolate H

O

R1

R3 (E )-enolate Scheme 1.8

Skewed transition state model for (E) enolates.

OH

O R3

R1 R2 syn


R3 H

OH

O

O M

H

O R2

R3

R1 R2

R1

(Z )-enolate

syn

R3 R1

OH

O

O M

H

O R2

H

(Z )-enolate

R3

R1 R2 anti

Scheme 1.9

Boat transition state models for (Z ) enolates.

boat conformations as alternatives. Thus, Evans [49, 77] has suggested boat transition states when there is substantial steric hindrance between groups R1 and R2 on the forming carbon–carbon bond. The model plausibly explains the results given in Eq. (18), which show that an increase of the asubstituent R2 in a (Z) enolate leads to a higher proportion of the anti aldol. The alternative orientations outlined in Scheme 1.9 for the Z–syn and Z– anti correlation show the latter to be a reasonable alternative for large substituents R2 . Hoffmann, Cremer and co-workers have proposed a transition state model for addition of enol borates to aldehydes [78]. The authors pointed out that a twist-boat 36b could easily be formed from the U-conformation of the boron enolate (E)-35b whereas the intermediate with the W-orientation, (Z)-35a, is a suitable precursor of the chair-type transition state 36a. The consequence of the assumption that (Z) enolates react via a chair transition state whereas (E) enolates react via a boat conformation is that syn aldols are formed irrespective of enolate geometry, as shown in Scheme 1.10 [79]. This type of stereochemical outcome has been observed in various examples of the Mukaiyama-type aldol addition [80] and in aldolizations of enol stannanes and zirconium enolates [81, 82]. In contrast, a clear (Z)–syn, (E)–anti correlation has been observed in the addition of allylboronates to aldehydes [83], a reaction that is closely related to the aldol addition. The stereochemical hypothesis shown in Scheme 1.10 has been underscored by the semi-empirical calculations of Gennari and coworkers [84] which show that, starting from (Z) enolates, the half-chair transition state leading to syn aldols is preferred. For (E) enolates, a preference for either syn or anti aldols is predicted, depending on whether or not the metal carries a bulky substituent. The diminished simple diastereoselectivity in aldol additions of (E) enolates can be interpreted as a result of competition between the chair

19

20


R3

R3 O 1

M

H

O R

H

R

M

O H

O

2

R1

35a

O R3

R1 R

M

R1

H H

R

36a

OH

O

2

2

H H R2

O R3

R1

M O O

R2

35b

R3 36b

Scheme 1.10

Different transition state models (chair and twist-boat) for (Z ) and (E ) enolates (M ¼ BL2 ).

and twist-boat transition states [85]. More recently, six-membered transition state hypotheses have also been proposed for ‘‘direct’’ aldol additions [86] and for the phosphoramide-catalyzed addition of trichlorosilyl enolates to aldehydes [87]. A different cyclic transition state model which does, however, not incorporate the metal, has been proposed by Mulzer and coworkers. It was developed to explain the observation that in the addition of doubly deprotonated phenyl acetic acid to pivaldehyde the highest anti selectivity is obtained with the most ‘‘naked’’ enolate anions (e.g. K/18-crown-6). The hypothesis, which might explain this stereochemical result, assumes that the approach of the enolate to the aldehyde is dominated by the interaction of the enolate HOMO and the p orbital of the aldehyde that functions as the LUMO. The favored approach of the reactants occurs when the substituents of the enolate (phenyl) and the aldehyde (t-butyl) are oriented in a trans orientation at the forming carbon bond, so that their mutual steric repulsion is minimized (Scheme 1.11). The expected transition state 37 has some similarity to that of a 1,3-dipolar cycloaddition, although the corresponding cycloadduct 38 does not form, because of the weakness of the oxygen–oxygen bond. Instead, the doubly metalated aldol adduct 39 results [88]. In a similar


H Me3C

OH OM

CHO + Ph

O OH + Me3C

Me3C

OM

OH

Ph syn M

anti

:

syn

58 70 97

: : :

42 30 3

R1 O

H

O R1

H

LUMO

O

R2

H O M

H HOMO R2

R1 H

O M

M 38

R2

OM

OM OM

H

37

O OH

Ph anti

½ Mg Li K/18-crown-6

21

O 39

R1 = C(CH3)3; R2 = C6H5 Scheme 1.11

Anti selectivity in the aldol addition of doubly deprotonated phenylacetic acid and 1,3-dipolar cycloaddition transition state model.

way, Anh and Thanh emphasized that frontier orbital interactions played an essential role in determining the stereochemical outcome of the aldol reaction [89]. A completely different rationale for the stereochemical outcome of aldol additions relies on open-transition-state models. These involve antiperiplanar orientation of enolate and carbonyl group, in contrast with their syn-clinal conformation assumed in the six-membered cyclic transition states. Open-transition-state structures have been proposed to offer a rationale for those aldol additions that give predominantly syn products, irrespective of enolate geometry [90]. This outcome has been observed in aldol reactions of tin and zirconium enolates and of ‘‘naked’’ enolates generated from enolsilanes by treatment with tris(diethylamino)sulfonium difluoromethylsiliconate [70]. As shown in Scheme 1.12, the driving force for the

22


O + R1

R2

OSiMe3 CH

(Et2N)3S

C

Me3SiF2

R3

H

Me3SiO

O

Me3SiO R3

R1

+

O R3

R1

R2

R2

syn

anti

enolate (Z ) : (E ) 99 : 9 :

1 91

product ratio syn : anti 95 94

: :

5 6

R1 = R3 = Ph; R2 = Me

δ− O R1

O R2

R3 H

O

H

δ−

O R2

H 41a (Z )

O δ−

δ−

δ− O R1 R1

R2 syn favored

O

R2 40b (E )

OH

R3

H

R3 R1

R2 anti disfavored

δ− O H

R1

R1

R3

40a (Z )

R3

δ− O H

OH

H

R3 H

R2

O δ−

41b (E )

Scheme 1.12

Formation of syn aldols irrespective of enolate geometry. Open-transition-state models.

open-transition-state model is the tendency of the negatively charged oxygen atoms to be as far apart from each other as possible. It is assumed that both transition states that lead to the formation of the anti aldol, i.e. 40a formed from the (Z) enolate and 40b from the (E) enolate, are disfavored, because of the steric repulsion of substituents R1 and R2 , which are oriented in a gauche conformation. This type of steric hindrance is avoided in the transition state structures 41a and 41b, so both (Z) and (E) enolates give the syn aldol predominantly. The basic assumption of open-chain transition-state models is the antiperiplanar orientation of the enolate and the carbonyl double bond. This


H

C

H

H

O

Li +

O C C

H

H

C

H

Li O

O

C C

H

H

H

H 40

=/

Li O

O 106.9°

C H

H

O

C

H

41

O

C H

C H

Li

H

C C

H

H

H H 42

Scheme 1.13

Calculated reaction pathway for addition of acetaldehyde lithium enolate to formaldehyde.

type of model has also been used to explain the stereochemical outcome observed in aldol additions of thioester silylketene acetals [84]. An open transition has also been proposed in additions of silyl ketene acetals to aldehydes, mediated by chiral copper complexes [91]. Even if a particular enolate with a distinct geometry is reacted with an aldehyde, the question whether the transition state is ‘‘closed’’ or ‘‘open’’ cannot be answered by simple ‘‘either–or’’. More recent discussions have, instead, led to an ‘‘as well as’’, because the role of the counter-ion becomes more evident. Thus, ab-initio calculations of Houk and coworkers [92] predict an open-transition-state structure for metal-free, ‘‘naked’’ enolates and closed transition states for lithium enolates. For addition of acetaldehyde lithium enolate to formaldehyde, the lowest-energy reaction pathway (shown in Scheme 1.13) has been studied on the basis of on ab-initio (3–21 G) calculations [93]. The reactants first reach the coordination complex 40, a local minimum on the energy hypersurface [94]. In this complex the OaLiaO angle can vary from 145 to 180 . The transition state of carbon–carbon bond formation is calculated to have the half-chair conformation 41. The angle of nucleophilic attack on the carbonyl group is 106.9 , consistent with the Bu¨rgi–Dunitz trajectory [95] and in accordance with calculations of Houk and coworkers [92]. The transition state structure 41 finally collapses to the aldolate 42 with the lithium atom coordinating the two oxygen atoms. The activation barrier of the reaction is calculated to be 1.9 kcal mol1 and the overall exothermicity is 40.2 kcal mol1 . Concerning the question of the conformation of the six-membered cyclic transition state, the different possibilities, for example chair, half-chair, or

23

24


twist boat, seem to be quite close in relative energy so the particular substitution pattern is assumed to determine the favored conformation. The key role of the counter-ion has been confirmed by experimental results obtained from the intramolecular aldol addition of bicyclic keto aldehydes. Here again, enolates with a strongly coordinating metal counter-ion, for example Mg 2þ , have strong preference for a reaction via a closed transition state in which the metal counter-ion is coordinated both to the enolate and to the carbonyl oxygen atom. ‘‘Naked’’ enolates, on the other hand, have a pronounced tendency to react through an open transition structure with an anti-periplanar conformation of the enolate and the carbonyl moiety [96]. It is self-evident that the transition state hypotheses discussed above are exclusively relevant to kinetically controlled aldol additions. Although this type of reaction control is the rule when preformed enolates are used, one should be aware that the reversibility of aldol additions cannot be excluded a priori and in any instance. In aldol reactions of preformed enolates, reversibility becomes noticeable in equilibration of syn aldolates with anti aldolates rather than in an overall low yield as found in the traditional aldol reaction. Considering the chair conformations of the syn and the anti aldolates, the former seem to be thermodynamically less stable, because of the axial position of the a-substituent R2 . This situation is avoided in the anti adduct (Eq. (20)). Indeed, the anti diastereoisomer is favored in most aldol additions run under thermodynamic control. This has been observed, for example, in aldolates syn-43 and anti-43, which arise from addition of doubly lithiated phenylacetic acid to pivalaldehyde. Whereas the kinetically controlled reaction gives a syn/anti ratio of 1.9:1, equilibration occurring after several hours in tetrahydrofuran at 25 C leads to a 1:49 in favor of the anti products (Eq. (21)) [88]. R2

O

O

M

R1

R

OLi CO2Li Ph syn-43

O

M

ð20Þ

R2

3

H

syn

Me3C

H

R1

H H

O

R

3

anti Ph

OLi

H

OLi +

Me3C

OLi CO2Li

Me3C CHO

Ph anti-43

ð21Þ The enolate counter-ion has an important effect on the rate of the reverse aldol reaction. Boron enolates usually undergo completely irreversible addition to aldehydes. The more ‘‘ionic’’ of the alkali metals, for example

1.4 Stereoselective Aldol Addition of Lithium, Magnesium and Sodium Enolates

sodium and potassium, have a greater tendency to undergo retro aldol reactions than lithium. Thus the potassium aldolate anti-44 formed from deprotonated ethyl mesityl ketone and benzaldehyde undergoes equilibration to syn-44 even at 78 C, whereas the corresponding lithium aldolate isomerizes at 0 C (Eq. (22)) [66]. That, in this reaction, the syn-aldolate is thermodynamically favored is possibly explained by the steric hindrance between the a substituent (methyl) and the bulky ipso substituent (mesityl) in the anti isomer. OM

O

Me

OM

Ph

O

Me

Ph Me Me syn-44

Me

Me Me

Me

anti-44

ð22Þ The influence of further counter-ions like ammonium, magnesium and zinc on the reversibility has been studied [65, 71]. Another influence comes from the stability of the enolate. As a rule, the rate of the retroaldol reaction correlates with the stability of the enolate. In stereoselective aldol addition, the reversibility is, in general, rather considered as a complication than a tool to obtain high selectivity. In particular, thermodynamically controlled aldol additions are usually not suitable to obtain non-racemic aldols.

1.4

Stereoselective Aldol Addition of Lithium, Magnesium and Sodium Enolates

Modern synthetic methods in organic chemistry are aimed at obtaining chiral products in a non-racemic, if at all possible, enantiomerically pure form. In addition, the products should be accessible as pure diastereomers. This section therefore focuses on aldol additions that provide pure stereoisomers. Amongst the enolate counter-ions of groups 1 and 2, only magnesium, sodium, and, particularly, lithium are important for this synthetic purpose. Although it should be remarked that most aldol additions leading to enantiomerically pure products rely on boron, tin, titanium, and zirconium enolates, topics that will be discussed in Chapters 1 and 3 of Part I of this book and Chapters 3–5 of Part II, there are also advantages of the more polar lithium and magnesium enolates. They are, in particular, highly reactive and can be added to aldehydes under mild conditions at low temperatures. Furthermore, their handling is easy, and they can be used on a large scale. As a consequence, a variety of useful aldol additions that rely on lithium and magnesium enolates have been developed and are applied fairly frequently.

25

26


1.4.1

Addition of Chiral Enolates to Achiral Carbonyl Compounds a-Substituted Enolates A variety of carbohydrate-derived ketones have been converted into their corresponding lithium enolates and used as chiral nucleophiles in additions to aldehydes. Induced diastereoselectivity was, however, found to be moderate only. Chiral ketones, oxazolidinones, amides, and esters, on the other hand, performed amazingly well when used as boron, titanium, or tin enolates in aldol additions [49, 52, 55, 57]. The corresponding lithium enolates, however, resulted in substantially lower stereoselectivity. Interestingly, the lithium enolate generated from a-siloxy ketone 45 leads, stereoselectively, to the syn aldol 46a; the diastereomeric ratio (dr) exceeds 95:5, defined as the ratio of the major isomer to the sum of all other isomers. In contrast, the corresponding boron enolate furnishes the diastereomeric syn aldol 46b, which results from the opposite induced stereoselectivity (Scheme 1.14). The different behavior of the enolates is explained by a transition state model 48a with a chelated lithium counter-ion and a non-chelating boron atom in 48b. When ketone 45 is deprotonated by treatment with bromomagnesium tetramethylpiperidide, the anti diastereomer 47a is obtained in substantial excess relative to the minor product, the anti stereoisomer 47b. It turns out that the enolates with the different counter-ions lithium, boron, and magnesium are, in a sense, complementary. The anti selectivity of the magnesium enolate is rationalized by assuming that it has the (E) configuration (Scheme 1.14) [45, 97–100]. 1.4.1.1

Procedure: 6-Hydroxy-3-trimethylsilyloxy-4-alkanones 47a by Magnesiummediated Addition of (S)-5,5-Dimethyl-4-trimethylsiloxy-3-hexanone to Aldehydes [100]. An oven-dried 5-mL Wheaton vial is flushed with nitrogen and 2,2,6,6-tetramethylpiperidine (0.26 mL, 1.5 mmol), dry THF (0.5 mL) and ethylmagnesium bromide (1.2 m in THF, 1.16 mL, 1.4 mmol) are added. The vial is capped securely and heated with stirring at 70 C for 24 h. The resulting solution is cooled to 0 C, and (S)-5,5-dimethyl-4-trimethylsiloxy-3hexanone (0.10 mL, 0.08 g, 0.50 mmol) in THF (0.25 mL) is added over 30– 60 min with a syringe pump. The solution is stirred for 1.5 h at 0 C after addition is complete. The enolate solution is then cooled to 78 C and the aldehyde (2 mmol) is added dropwise. After 30 min the reaction is quenched by pouring the mixture into satd aq. NaHCO3 (5 mL). The layers are separated, and the aqueous phase is extracted with diethyl ether (5 10 mL). The combined organic layers are washed with cold HCl (1%, 10 mL) and satd aq. NaHCO3 (10 mL). After drying, the solution is concentrated to yield the product as a clear oil. Ratios of diastereomers are determined by integration of the relevant peaks in the 1 H NMR spectra of the crude products. Purification is accomplished by flash chromatography (diethyl


1. LiN(i-Pr)2/THF -78°C 2. TMEDA 3. RCHO

OH

O

R

d.r. > 95 : 5 Me3SiO 46a 1. Bu2BOTf/(i-Pr)2NEt 2. RCHO 3. H2O2, OH

O

OH R

d.r. > 95 : 5 Me3SiO

O

46b

Me3SiO

1.

NMgBr

45

OH

O 2. RCHO

R

d.r. > 92 : 8 Me3SiO 47a NMgBr

1.

O

2. HMPA/ClTi(Oi-Pr)3 3. RCHO

OH R

d.r. > 95 : 5 Me3SiO 47b SiMe3

Me3C H

H

H O Li O

46a

R Me 48a

Me3SiO

H

O

CMe3 H H BBu2 O O

46b

R Me 48b

Scheme 1.14

Stereodivergent aldol addition of (S )-5,5-dimethyl-4-(trimethylsilyloxy)-3-hexanone (45).

27


28

ether:hexanes, 5:95). The products 47a are thus obtained: R ¼ i-Pr, 70%; R ¼ t-Bu, 80%; R ¼ Ph, 80%. Because the titanium enolate of the ketone 45 affords the stereoisomeric product 47b this completes a method of stereodivergent aldol addition. Starting from the identical chiral ketone 45 they lead to all of the different stereoisomeric products in a controlled manner [45]. The chiral a-benzoyloxyketone 49, accessible from mandelic acid, also reacts stereoselectively with aldehydes to give the syn aldols 50a/b. Both the lithium [101] and the titanium [102] enolates lead to the predominant formation of the diastereomer 50a. However, the stereoselectivity obtained by use of the titanium enolate surpasses that of the lithium analog (Eq. (23)). O O

Ph

1. LiN(i-Pr)2 2. ClTi(Oi-Pr)3 3. RCHO

O

O

1. LiN(i-Pr)2/THF 2. RCHO or

O Ph

O

O +

R OH

49

O

Ph

R OH

O

50a

50b

Enolate counterion

R

Li Li Ti Ti

Et Me2CH Et Me2CH

ratio 50a : 50b 96 96 97 97.7

: : : :

4 4 3 2.3

ð23Þ Remarkably high stereoselectivity is obtained by means of the sodium enolate of a-N,N-dibenzylamino-substituted ketone 51, a counter-ion not very frequently used in stereoselective aldol additions. In this instance, however, the sodium enolate turned out to be more efficient than the lithium analog. The predominant formation of the main diastereomeric product 52a rather than 52b is explained by an open transition state, assumed to be strongly favored over the cyclic transition state, when the more ‘‘ionic’’ sodium enolate is used rather than the corresponding lithium reagent (Eq. (24)) [103]. A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as


1. LiN(i-Pr)2/THF or NaN(SiMe3)2

O R

O R Bn2N

51

OH

R

+

R'

2. R'CHO Bn2N

O

OH

R'

Bn2N 52a

52b

enolate counter ion

R

R'

Li Na

Me Me

Ph Ph

Li

CHMe2

Ph

63

: 11 : 6 : 37

Na

CHMe2

Ph

>95

: 5

ratio 52a : 52b 89 94

ð24Þ outlined in Chapter 2 and in Chapter 3 of Part I. The aldol additions of the chiral propanoate 53, generated from triphenylglycol, serve as an illustrative example. Whereas the lithium enolate 54 (M ¼ Li) gives the diastereomers 55a, b and 56a, b in a more or less stereo-random manner, acceptable simple diastereoselectivity in favor of the anti product combined with high induced stereoselectivity was obtained only after transmetalation of the lithium enolate into the zirconium species (Eq. (25)) [104, 105]. O Me

OM

Ph Me

OSiMe3

O Ph 53

Ph

Ph OSiMe3

O Ph

H

Ph

54

OH

OH

O

PhCHO Ph

OR*

+

OH OR*

+

ð25Þ

O

Ph

56a

OR* 56b

ratio enolate counterion anti-55 : syn-56 Li Cp2ZrCl

OR* 55b

O

Ph

O

Ph

55a OH

29

70 : 30 90 : 10

ratio 55a : 55b 68 : 32 >97 :

3

30


The aldol reaction of chiral lactones, developed in the context of ‘‘selfreproduction of chirality’’ [106], takes advantage of the easy generation and high reactivity of lithium enolates. When the chiral cis dioxolanone 57, readily available from (S)-lactic acid and pivalaldehyde, is treated with LDA, the lactone enolate 58 is generated. Although the stereogenic center originating from lactic acid has vanished, because of enolate formation, the acetal carbon atom maintains the chiral information and the t-butyl residue directs the topicity in the addition to aldehydes and unsymmetrical ketones, so high stereoselectivity is achieved (Eq. (26)) [107]. H CMe3 LiN(i-Pr) 2 THF; -78°C O O H

O

57

Ph

O

O

H CMe3

O

H CMe3

Me

Ph

O

O O

OLi

HO

58

ð26Þ By analogy, a series of heterocyclic compounds 59 have been deprotonated to give the corresponding a-hetero-substituted cyclic enolates 60. On addition to aldehydes they are found to react with both high simple diastereoselectivity and induced stereoselectivity (Eq. (27)) [106–108]. H CMe3 X

Y

R

O

H CMe3 X

Y OLi

R

59

ð27Þ

60

X = O, NR', S; Y = O, NR'; R = H, Alkyl

The concept has also been extended to a six-membered homolog, the dioxanone 61, which furnishes the enolate 62 by deprotonation. Here again, subsequent aldol addition proceeds with high stereoselectivity and the diastereomer 63a results predominantly or almost exclusively (Eq. (28)) [109, 110]. With all heterocyclic enolates 58, 60, and 62 stereocontrol is relatively easily accomplished, because of the rigid structure of the heterocycle. Procedure: Aldol Addition of 2-tert-Butyl-6-methyl-one-1,3-dioxan-4-one to Propanal [110]. An ice-cold solution of (i-Pr)2 NH (11.13 mL, 79.4 mmol, 1.14 equiv.) in THF (160 mL) is treated with a solution of n-butyllithium in hexane (1.4 m, 53 mL, 79.4 mmol, 1.14 equiv.), kept at 0 C for 15 min, then cooled to 78 C. To this solution of LDA is added the dioxanone 61 (12.0 g, 69.7 mmol) in THF (80 mL) at such a rate that the temperature never ex-


CMe3 O

CMe3

LiN(i-Pr)2 THF; -78°C

O

RCHO

O

O

O

OLi

61

62

O

H

O

O

O

H

+

O

O R

ð28Þ

CMe3

CMe3

R

OH

OH 63b

63a

ceeds 70 C; the mixture is then maintained at 78 C for 45 min. To the resulting enolate solution are added (7.15 mL, 99 mmol, 1.42 equiv.) propanal in THF (80 mL), the temperature never being allowed to rise above 70 C. The reaction mixture is stirred at 78 C for 3 h then quenched at 78 C by the addition of satd aq. NH4 Cl (200 mL) then diethyl ether (200 mL). The two phases are separated, and the aqueous phase is extracted with diethyl ether (2 200 mL). The combined organic extracts are dried (MgSO4 ) and the volatile compounds removed by rotary evaporation and then with a high-vacuum pump. The crude product obtained, a 7:1 ratio of epimers at C(1 0 ), is (1 0 S,2R,5R,6R)-2-t-butyl-5-(1-hydroxypropyl)-6-methyl1,3-dioxan-4-one 63a (R ¼ Et), yield 9.6 g (60%). Efficient stereochemical control is also provided by the chiral lithium ketone enolate 64, addition of which to a variety of aldehydes leads to the formation of the corresponding b-hydroxy ketones 65, usually as single products (Eq. (29)) [111]. O

Ph

O

H

N

H

LiN(i-Pr)2 THF Ph

Tos

O

LiO H

N

H

Tos 64 HO O

RCHO

Ph

O

H

N

H

R H

Tos 65 R = CHMe2, (CH2)3Me, CH=C(Me)-CO2Et

ð29Þ

31

32


The deprotonation of chiral iron acyl complexes, which can be obtained as enantiomerically pure compounds, leads to the corresponding enolates, as shown by the research groups of Davies and Liebeskind [112–115]. The lithium enolate 67a, however, which originates from propanoate 66a, reacts stereoselectively with aldehydes or ketones only if it has been transmetalated into the corresponding copper or aluminum enolate (Eq. (30)) [116]. PPh3 OC

n-BuLi THF, -78°C

Fe

R

PPh3 OC

Fe

Me

R = Me OLi

O 66a: R = Me 66b: R = OBn

67a

n-BuLi R = OBn THF, -78°C

ð30Þ

PPh3 OC

Fe

OBn O

67b

PPh3

O

Li

OC

OBn

Fe

40% O

OH

68

Stereoselective aldol addition to the lithium enolates themselves has been achieved by reaction of the deprotonated benzyloxy-substituted iron complex 66b and subsequent reaction with symmetrical ketones. The enolate involved in this procedure is assumed to exist as a chelated species 67b. The aldol 68 is obtained in a diastereomeric ratio higher than 99:1. The reaction is, nevertheless, plagued by low chemical yield, because of deprotonation of acetone. Because a symmetric ketone is used as an electrophile, the reaction leads to the formation of just one new stereogenic center [117, 118]. a-Unsubstituted Enolates When, instead of an a-substituted enolate 29 (R2 0 H), the a-unsubstituted enolate 29 (R2 ¼ H) is used in an aldol addition, the stereochemistry is, at first glance, simplified, as outlined in Scheme 1.5. Formation of the aldol products 32a and 32b shows that now only one new stereogenic center is formed. Nevertheless, aldol addition of a-unsubstituted chiral enolates (or achiral enolates, mediated by chiral ligands or additives) has been a problem, because of insufficient induced stereoselectivity [53]. In fact, using the same chiral auxiliary group R3 transition from an a-substituted to an aunsubstituted enolate is often accompanied by complete loss of the ability to discriminate between the enantiotopic faces of an aldehyde, so that more or less equal amounts of the stereoisomers 32a and 32b result (cf. Scheme 1.4.1.2


1.5). The problem occurs in aldol additions of methyl ketones and all kind of acetic acid derivative, esters, amides, and thioamides [53, 54]. In a pioneering investigation, the lithium enolate derived from 3-methyl2-pentanone was added to aldehydes. Only moderate diastereoselectivity was obtained, however [119]. Exceptionally high induced stereoselectivity was observed when camphor-derived ketone 69 was converted into the lithium enolathe and subsequently added to aldehydes. a-Cleavage at the carbonyl group enabled the formation of b-hydroxy aldehydes and acids in high enantiomeric excess (Eq. (31)) [60]. The work on the aldol addition of methyl ketones led to a variety of stereoselective variants which rely mainly on boron enolates and will be discussed in Chapter 3 of Part I of this book. On the other hand, the transition from lithium to boron enolates did not significantly improve the induced stereoselectivity of chiral acetamides [53]. Several highly stereoselective procedures based on tin and titanium enolates have been developed, however.

(31) Many attempts have been made to add chiral acetates to aldehydes or prochiral ketones, to obtain non-racemic b-hydroxycarboxylic esters. Here again, several variants based on boron and titanium enolates and on Mukaiyama aldol additions of silyl ketene acetals have been developed, and will be described in Chapter 2 (titanium enolates), Chapter 3 (boron enolates) and in Part II (Mukaiyama reaction). For enolates of group 1 and 2 elements the following fruitful approaches were elaborated. First, sulfinyl acetates 70 [120, 121], carrying their chiral information in the sulfoxide moiety were efficiently deprotonated with t-butylmagnesium bromide and added to aldehydes to give the aldol adducts 71. Removal of the sulfinyl residue is accomplished – in an immolative manner – by reduction with aluminum amalgam to furnish t-butyl b-hydroxycarboxylic esters 72. Remarkably, the method developed by Solladie´ and Mioskowski is not restricted to aldehydes as electrophilic components, but has been extended to prochiral ketones also (Scheme 1.15) [122]. The transition-state model 73, in which the magnesium atom is chelated by the enolate, sulfoxide, and carbonyl oxygen atoms, serves to explain the stereochemical outcome of the reaction. It is plausible that the aldehyde approaches the enolate from the side of the non-bonding electron pair of the sulfoxide (opposite to the aryl residue) and that the larger group R occupies a position anti to the sulfinyl substituent.

33

34


1. t-BuMgBr THF, -78°C 2. O O Tol

O

S

OH R1 R2

R2

R1

O

OCMe3

OCMe3 S

O

Tol 70

71 OH

Al/Hg

O

R1

OCMe3

R2 72

Starting Material R1

R2

H

CH3

t-Butyl 3-Hydroxy Ester 72 e.e. (%)

Yield (%)

C7H15

86

80

C CC3H7

80

73

C CC6H13

70

53

C6H5

91

85

C7H15

95

88

C CC3H7

48

60

C CC6H13

36

72

8

80

C2H4OCOCH3

40

90

C6H5

68

75

CF3

20

75

COOC2H5

C6H5

L L Mg O O

70 Tol

S

O

RCHO Tol

S

L L Mg

O 71

O OCMe3

OCMe3 R

H 73 Scheme 1.15

Aldol addition of (R)-tolylsulfinylacetate 70 to aldehydes and prochiral ketones. Transition state model 73 (reaction of the magnesium enolate of 70 with RCHO).


Procedure: 3-Hydroxy carboxylic esters by addition of tert-butyl (B)-(R)-2-(4methylphenylsulfinyl)acetate to carbonyl compounds [123]. A solution of tBuMgBr (40 mL; prepared from 3 g Mg, 20 g t-BuBr, and 50 mL Et2 O) is added to a solution of sulfinyl ester 70 (1.5 g, 5.9 mmol) in THF (400 mL), at 78 C, over a period of 20 min, under argon. The mixture is then stirred for 30 min and the carbonyl compound (2 g) in THF (30 mL) is added. After 12 h at 78 C the mixture is hydrolyzed by addition of satd aq. NH4 Cl (50 mL) and extracted with CHCl3 (2 50 mL). The extract is dried with Na2 SO4 and concentrated. The residue, the b-hydroxy-a-sulfinyl ester, is diluted with THF (400 mL) and water (40 mL) and then treated with aluminum amalgam (4 5-g portions) while maintaining the temperature at 15–20 C. The solvent is evaporated and the residue, the b-hydroxy ester 72, is purified by column chromatography (silica gel; Et2 O–petroleum ether 20:80). The Solladie´ procedure has been successfully applied in a synthesis of maytansin [124]. In an analogous manner, chiral sulfinyl acetamides 70 (NMe2 instead of OCMe3 ) can be added to aldehydes and deliver b-hydroxy amides in high enantiomeric excess, again after reductive removal of the chiral auxiliary group [125]. More recently, the lithium enolate derived from the acetate 74 with axial chirality has been found to react with aldehydes in a highly stereoselective manner to give b-hydroxy esters 75 that can be converted into the corresponding carboxylic acids by alkaline hydrolysis (Eq. (32)) [126].

(32) Chiral acetyl iron complexes 76 also seem predestined to serve as reagents that enable introduction of a chiral acetate unit into aldehydes. In contrast with the benzyloxy-substituted derivative 66b (Eq. (30)), however, only marginal induced stereoselectivity is achieved when the lithium enolate of 76 is added to aldehydes, and the diastereomer 77a is formed in low preference compared with 77b (Eq. (33)). High diastereoselectivity is obtained only after transmetalation [112, 114, 115]. A significant improvement – as far as chiral lithium enolates of acetyl iron complexes are concerned – came from the complex 78, which carries a (pentafluorophenyl)diphenylphosphane ligand instead of the usual triphenylphosphane. Thus, the enolate 79, generated by treatment with LDA, gives the diastereomeric adducts 80a and 80b in a diastereomeric ratio of 98.5:1.5 on treatment with benzaldehyde. A donor–acceptor interaction between the enolate oxygen atom and the fluorinated aromatic ring, supported

35

36


PPh3 OC

1. n-BuLi THF, -78°C

Fe

2. PhCHO O 76

ð33Þ PPh3 OC

PPh3

Fe

Ph O

+

OC

Fe

OH

O

77a d.r.

Ph OH

77b :

57

43

by spectroscopic studies, in the boat like transition state model 81 is assumed to be responsible for the observed lk-topicity (i.e. the (S)-enolate 79 approaches the aldehyde from its Si face) of the reaction (Scheme 1.16) [127]. Despite the elegance of the concept of Davies–Liebeskind enolates, one should be aware that preparation of the acyl iron complexes definitely needs resolution. It is somewhat typical that a series of procedures has been elaborated by using the racemic iron complexes [115]. It is highly desirable that chiral a-unsubstituted enolates should be available by simple methods from enantiomerically pure starting materials that are inexpensive and readily accessible in both enantiomeric forms. This postulate seems to be fulfilled to a reasonable extent by (R)- and (S)-2hydroxy-1,1,2-triphenylethyl acetate 83 (‘‘HYTRA’’) [53, 128, 129]. It is readily prepared from methyl mandelate which is first converted into triphenylglycol 82 and subsequently converted into the acetic ester 83 by treatment with acetyl chloride (Eq. (34)). Both enantiomers of the reagent are readily accessible, because both (R)- and (S)-mandelic acid are industrial products [130]. Diol 82 and acetate 83 are commercially available. PhMgBr Et2O, reflux

Ph HO

OMe

Ph OH

HO

77%

Ph

O (R)-methyl mandelate

Ph

82

ð34Þ

O Cl pyridine 92%

O

Ph O

OH

Ph Ph (R)-83


P(C6F5)(C6H5)2 OC

P(C6F5)(C6H5)2

LDA (2 equiv) THF; -42°C

Fe

OC

Fe

CH2

O

OLi

78

79 P(C6F5)(C6H5)2 OC

Fe

P(C6F5)(C6H5)2

C6H5 O

C6H5CHO THF; -78°C

+

Fe

OC

OH

C6H5 O

80a

OH

80b

F

F

F F

Ph Ph OC

F

P

O Fe Li O

H C6H5

81 Scheme 1.16

Diastereoselective aldol addition of lithiated (pentafluorophenyl)diphenyl-substituted acetyl iron complexes 78. Transition state model 81.

Double deprotonation of the chiral acetate (R)-83 by treatment with 2 equiv. LDA enables generation of the enolate 84. Remarkably, the dilithiated reagent 84 dissolves in THF whereas the ester 83 is fairly insoluble. Bridging of the oxygen anions by the lithium cations in the enolate 84 might explain the enhanced solubility. When the lithium enolate is added to aldehydes at 78 C, the diastereomeric aldol adducts 85a are formed predominantly, the ratio of diastereomers 85a:85b ranging between 10:1 and 12:1. Enhancement of the induced stereoselectivity can be accomplished by transmetalation to the corresponding magnesium enolate and by performing the addition to the aldehyde at lower temperatures (110 C to 135 C, using 2-methylbutane as co-solvent). Thus diastereomeric ratios up to 50:1 can be achieved. A single recrystallization of the crude product mixture

37

38


O

2 LiN(i-Pr)2 THF; -78°C to 0°C

Ph OH

O Ph 83

Ph

O 84

Ph

Ph

OH

O

Ph

1. MX 2. RCHO

LiO OLi

O

R

OH OH +

Ph

R

O

Ph OH

O Ph

Ph

85a

Ph

Ph

85b

Ph OH

− HO

NaOH

Ph Ph 82 OH

O

R

OH 86

Scheme 1.17

Stereoselective aldol additions of the chiral acetate 83.

usually gives the major diastereomer 85a in the pure form. Mild alkaline hydrolysis of the aldol adducts 85 furnishes the b-hydroxycarboxylic acids 86 and triphenylglycol 82, which is easily separated and can be reused (Scheme 1.17) [131]. When the lithium enolate 84 is added to propenal (without transmetalation), the diastereomeric esters 87a and 87b are formed in the ratio 92:8. In this reaction the crude mixture 87a/87b was hydrolyzed to give the carboxylic acid (R)-88 in 83.5% ee. To obtain the enantiomerically pure 3-hydroxy4-pentenoic acid, enrichment was performed by single recrystallization of the ammonium salt, formed from (S)-1-phenylethylamine. When the amine has been liberated from the salt the carboxylic acid (R)-88 is obtained in >99.8% ee and 41% overall yield (Scheme 1.18) [132]. The (S) enantiomer, but not the (R) enantiomer, of 3-hydroxy-4-pentenoic acid 88 (both prepared according to this procedure) has been shown to be a substrate for the enzyme 3-hydroxybutanoate dehydrogenase – another example of the different biological activity of enantiomeric compounds [133]. Procedure: (R)-3-Hydroxy-4-pentenoic acid (88) by aldol addition of doubly deprotonated (R)-HYTRA (83) [132]. A 250-mL, two-necked, round-bottomed flask is equipped with a magnetic stirrer, a septum, and a connection to a combined vacuum and nitrogen line. The air in the flask is replaced by nitrogen and dry THF (100 mL) and diisopropylamine (37.7 mL, 0.264 mol)


1. 2 LiN(i-Pr)2 O 2. O

Ph

Ph 83 O

OH

H

OH

O

Ph

Ph

OH OH

O Ph

+

O

Ph OH

O Ph

Ph

Ph

87b

87a KOH MeOH, H2O

OH

O

Ph

OH OH

− HO

88 83.5% e.e.

Ph Ph 82 1.

NH2

Ph Me 2. recrystallization 3. NaOH

OH

O OH

88 99.8% e.e. Scheme 1.18

Synthesis of (R)-3-hydroxy-4-pentenoic acid 88 by stereoselective aldol addition of the chiral acetate (R)-83.

are injected via syringes via the septum. The mixture is cooled to 78 C and treated, while stirring, with a solution of n-butyllithium (15%, 168 mL, 0.269 mol) in hexane. The dry ice–acetone bath is replaced with an ice bath and stirring is continued for 30 min. A 2-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a septum, and a connection to a combined vacuum and nitrogen line is charged with (R)-83 (40.0 g, 0.120 mol). The air in the flask is replaced by nitrogen and dry THF (400 mL) is added through a cannula of 2 mm i.d., during which the flask is slightly evacuated. The suspension is stirred at 78 C in a dry ice–acetone bath. The ice-cold solution of LDA is added via a cannula, with vigorous stirring, during which the 2-L flask is slightly evacuated. The mixture is stirred at 0 C for 30 min to complete double de-

39

40


protonation. A clear, orange solution forms. This is subsequently cooled to below 70 C (dry ice/acetone bath). The septum is removed cautiously (overpressure) and dry 2-methylbutane (900 mL) is poured into the flask (alternatively, a low-boiling (30–37 C) fraction of petroleum ether can be used) during which a vigorous stream of nitrogen is maintained. The flask is immediately closed with a septum and a thermocouple, connected to a resistance thermometer, is introduced via the septum. The reaction flask is plunged into a liquid-nitrogen bath, the depth of immersion being 2–3 cm. When the temperature of the suspension has reached 125 C, a solution of propenal (acrolein; 19.2 mL, 0.285 mol) in dry THF (30 mL) is added dropwise via a syringe through the septum at such a rate that the temperature does not exceed 120 C. Stirring is continued for 30 min at 120 to –125 C, during which time the yellowish color turns to pale blue. The mixture is treated with satd aq NH4 Cl (250 mL) and left to warm to r.t. The organic solvents are removed in vacuo. The precipitate in the aqueous suspension is separated by suction filtration, washed with several portions of water (total 400 mL), and transferred to a 4-L, round-bottomed flask equipped with a magnetic stirrer and a condenser. Methanol (2.4 L), water (1 L), and potassium hydroxide (72 g) are added, and the mixture is heated under reflux for 3 h. After cooling to r.t. the organic solvent is removed in vacuo. The residual aqueous alkaline suspension is shaken with 200-mL portions of CH2 Cl2 . The aqueous solution is transferred to a 2-L, roundbottomed flask, immersed in an ice bath, and acidified to pH 3 by cautious addition of hydrochloric acid (6 mol L1 ); the mixture is stirred vigorously with a magnetic stirrer and the pH is controlled carefully in order to avoid over-acidification. The clear solution is saturated with NaCl and extracted with ethyl acetate (8 200 mL), during which the pH of the aqueous layer is monitored and, if necessary, readjusted to pH 3 by the addition of hydrochloric acid (6 mol L1 ). The combined organic layers are dried with MgSO4 , concentrated, and the oily residue is distilled under reduced pressure in a short-path distillation apparatus to afford the colorless acid 88; yield 8.32 g (59.6%); b.p. 69 C/0.04 Torr (5.3 Pa); [a]D 17 21.7 (c ¼ 1.95% aq. ethanol); 83.5% ee. A solution of the acid (8.32 g, 0.072 mol; 83.5% ee) in dry diethyl ether (300 mL) at r.t. is placed in a 500-mL, round-bottomed flask equipped with a magnetic stirrer. ()-(S)-1-Phenylethylamine (20 mL, 0.157 mol) is added in one portion with vigorous stirring. A white precipitate forms immediately and the flask is closed with a drying tube filled with calcium chloride. After stirring for 30 min at 25 C the precipitate is separated by suction filtration and washed with ice-cold diethyl ether (2 50-mL). Recrystallization from dry THF (240 mL) affords 13.80 g of a colorless salt, m.p. 127 C; [a]D 20 9.7 (c ¼ 1.998, deionized water). The salt is treated with aq. sodium hydroxide (2%, 400 mL) and the mixture is washed with CHCl3 (3 70 mL). The acidified aqueous solution is extracted with ethyl acetate (as described above) and the combined organic extract is dried with MgSO4 and con-


centrated. To remove remaining traces of solvent the flask containing the product is connected via a short, curved glass tube to a two-necked, liquidnitrogen-cooled flask, which is connected to an efficient oil pump; yield 5.77 g (69.4%, 41.4% relative to (R)-2-hydroxy-1,2,2-triphenylethyl acetate); [a]D 17 26 (c ¼ 0.996, 95% aqueous ethanol); >99.8% ee (determined by 1 H NMR measurement of the methyl ester in the presence of Eu(hfc)3 , no signals of the (S) enantiomer are detected). Since the first report of stereoselective aldol additions of the chiral acetate 83, the reagent has been applied frequently in syntheses of natural products and biologically active compounds. Among these are g-amino-b-hydroxybutanoic acid (‘‘GABOB’’) [134], the enantiomeric naphthoquinones shikonin and alkannin [135], d- and l-digitoxose [136], desoxy and aminodesoxy furanosides [132], detoxinine [137], tetrahydrolipstatin and related pancreatic lipase inhibitors [138], statin [139] and statin analogs [140], compactin and mevinolin [141], fluoroolefin peptide isoesters [142], the HMG-CoA synthase inhibitor F-(244) [143], epothilone A [144], the A-ring building block of 1a,25-dihydroxyvitamin D3 [145], intermediates for (23S)-hydroxyvitamin D3 derivatives [146], building blocks of lankacidin C [147], the synthetic statin NK-104 [148], the C1aC9 segment of bryostatin [149], the C20aC34 segment of the immunosuppressant FK-506 [150], and pyranoyl steroids having hypocholesterolemic properties [151]. Selected examples are shown in Scheme 1.19. Furthermore, a large variety of synthetic inhibitors of HMG-CoA reductase have been synthesized by including the HYTRA aldol procedure as one of the key steps [152–158]. The enzyme is responsible for reduction of hydroxymethylglutaryl CoA to mevalonic acid, a key step in cholesterol biosynthesis. HMG CoA reductase inhibitors contain a b,ddihydroxycarboxylic ester or carboxylate moiety or the corresponding dlactone. Several of these compounds, which can be regarded as synthetic analogs of compactin and mevinolin, have found their way to the marketplace, because of their hypocholesterolemic activity. Selected examples of the structures of these drugs are given in Scheme 1.20. As in the previous scheme, the stereogenic center generated by aldol addition of the chiral acetate 83 is marked with an asterisk. The (R)-configured reagent 83 always attacks the aldehyde predominantly from the Re side, the (S) acetate 83 correspondingly from the Si side. Thus, there is a predictable lk topicity in HYTRA aldol additions (Scheme 1.21). It has been reported that the induced stereoselectivity in aldol additions of the chiral lactate 83 can be improved by using an excess of base (LDA or lithium hexamethyldisilazane) in the deprotonation step [159]. 1.4.2

Addition of Achiral Enolates to Chiral Carbonyl Compounds

In a chiral aldehyde or ketone the two carbonyl faces are diastereotopic and the products resulting from either Re or Si face attack of the enolate are

41

42


HO

O

HO

O

OH H3N

COO

*

* HO

O OH (R)-Shikonin

(R)-GABOB

OH

H N

* HO

O

O

* H

O OH (S)-Alkannin

O

O

OH HCO NH C11H23

OH

O *

*

H Tetrahydrolipstatin

Detoxinine

O

O NH3

HN

OCMe3

HN

OH

* OH

O

OH

R

CO2

OH O R = C6H11, Ph Statine analogs

epi-N-Boc-statine

O

*

OH

*

N-Boc-statine

OH O

O

OCMe3

*

CH2Ph

H O

pyroGluPheN

O LeuMetNH2

F R R = H: Compactin R = Me: Mevinolin Scheme 1.19

Natural products and biologically active compounds synthesized by use of the HYTRA aldol method.

Fluoroolefin peptide mimic


43

O S *

HO

O

OH

N

O

O

O

HMG-CoA synthase inhibitor

*

O OH Epothilone A

OR' *

R

*

CHCO2R

Me3CMe2SiO

O

O

OSiMe2CMe3 OR''

Vitamin D3 A-ring building block

23-Hydroxy vitamin D3 building blocks

Scheme 1.19 (continued)

diastereomers. The question of the stereochemistry of nucleophilic addition to chiral aldehydes or ketones has been addressed by the seminal studies of Cram and co-workers [160–162]. Indeed, the stereochemical outcome of this type of reaction is best rationalized by either the ‘‘Cram–Felkin–Anh model’’ [163] or ‘‘Cram’s cyclic model’’ when the carbonyl group is substituted by ether or amino residues. The latter type of stereochemical result has also been termed ‘‘chelation control’’, the former type of reaction accordingly as ‘‘non chelation control’’ [164]. Most of these investigations have been performed on racemic substrates. In view of the tendency towards enantiomerically pure products, emphasis is given here to those procedures that start from non-racemic aldehydes or ketones. In the aldol reaction ‘‘chelation control’’ is usually provided by those variants that use strong Lewis acidic enolate metals, for example boron, titanium, and tin. In particular, ‘‘chelation control’’ results very frequently in Mukaiyama aldol additions to a-oxygen- and a-nitrogen-substituted aldehydes [165]. Lithium enolates, in contrast, either give predominantly the product predicted by the ‘‘Cram–Felkin–Anh model’’ or react more or less nonstereoselectively. Thus, the favored formation of the syn-aldol product in the reaction of 2-phenylpropanal with the lithium enolates of acetone, pinacolone, methyl acetate, or N,N-dimethylacetamide is in accordance with Cram’s rule or the Felkin–Anh model (Eq. (35)). However, a rather moderate syn:anti ratio of 3:1 is typical of this type of reaction [51, 67].

44


HO

F

O O

*

H

F

OH

OH

O

* N

OCMe3 F

N F ref. [141]

ref. [152]

OH

OH

CO2H

CO2Na

*

N

HO *

O

OH

O

N

F ref. [154]

ref. [153]

HO

HO

O *

O O

O

O

*

F

N R

H

H

R N

OH

N N Ph

HO

R

CONHPh

ref. [155]

ref. [157]

ref. [156]

R

R

OH *

N

N

R

R ref. [158] Scheme 1.20

Hypocholesterolemic-active drugs (HMGCoA reductase inhibitors) prepared by use of the HYTRA aldol method (selected examples).

*

OH CO2H

O


O

Ph

Ph OH

O

HO

Ph Ph (R)-83

MO MO

Ph Ph

O

Ph

O R

Si

O

O Ph (S)-83

Ph

Re

45

Ph Ph

OM OM

Ph

O

H

(R)-84

(S)-84

Scheme 1.21

Lk-topicity in aldol additions of (R) and (S ) acetate 83.

H

Ph

R

R

+ Ph

+ OLi

O

OH

O

OH

syn

O

anti 25

:

75

R

Ph

ð35Þ When the a-substituted (E) enolate 89 is added to 2-phenylpropanal, control of simple diastereoselectivity is provided in as far as the products with the 2,3-anti configuration result exclusively. Induced stereoselectivity is lower, however, as indicated by the 80:20 ratio of diastereomeric b-hydroxy esters 90a and 90b (Eq. (36)) [51]. OLi + Ph

CHO 89

O

Ph OH

+

O 90a 80

O

Ph OH

:

O 90b 20

ð36Þ

46


A single diastereomer 93, however, results from addition of the lithium enolate 92 derived of t-butyl thiopropanoate to the chiral, enantiomerically pure aldehyde 91. The transformation is a key carbon-chain-elongation step in Woodward’s synthesis of erythromycin A (Eq. (37)) [166]. Somewhat lower diastereoselectivity is observed in the aldol reaction between the lithium enolate 95 and the chiral aldehyde 94, a transformation used in a synthesis of maytansin (Eq. (38)). The diastereomeric adducts 96a and 96b result in a ratio of 90:10 [167].

H MeO

O

O

O

O

OAc

O

O

SCMe3

+

OLi 91

92

ð37Þ SCMe3 MeO

O

O

O

O

OAc

O

OH

O

93

O

H

O

Me3SiO

SLi +

H

SEt

94

O

95

H

OH

S

O SEt

Me3SiO 96a

+

:

H

OH

S SEt

Me3SiO 96b

ð38Þ A variety of a-alkoxy-substituted aldehydes have been submitted to aldol addition of lithium enolates. ‘‘Cram–Felkin–Anh’’ selectivity is usually observed, although often with rather low stereoselectivity. Exceptionally high diastereoselectivity results from the aldol reaction between the lithium enolate of pinacolone and isopropylidene glyceraldehyde. Thus, the b-hydroxy ketone 97 is obtained as a single product (Eq. (39)). Distinctly lower selectivity is observed when the same aldehyde is submitted to aldol additions of ester enolates, however [168].


O

O

CMe3

O

O

+

H

CMe3

OLi O

OH

O

97

ð39Þ The N-dibenzyl protecting group has been developed as a tool to provide non-chelate-controlled additions to a-amino aldehydes. Thus, anticonfigured aldol adducts are obtained predominantly when a-N-dibenzylprotected aldehydes 98 are submitted to aldol additions of lithium enolates as shown in Eqs. (40) and (41) [169, 170]. O R1

OLi R2

+

H

OMe R2

(PhCH2)2N 98 OH

O

1

R

OH OMe

(PhCH2)2N

R

+

R2 R 2

OMe

(PhCH2)2N

ð40Þ

R 2 R2 syn

anti

R1

R2

diastereomeric ratio anti : syn

yield

Me

H

95 : 5 90 : 10

82

97 :

84

PhCH2

H

Me

Me

(PhCH2)2N

O

1

83

3

O OLi H

+ OMe

O

O

(PhCH2)2N

(PhCH2)2N OMe OH

82%

d. r.:

>96

OMe

+

:

OH

99:1b

a Product b anti:syn

stereochemistry not assigned

2.3 Addition of Enolates Without a-Substituents to Aldehydes Tab. 2.3

Asymmetric acetate aldol reactions. R

O

R

O

OH

R

O

OH

a) BuLi, THF, 0° Ph

N H

16

b) Lewis acid c) PhCHO

Ph

Ph

N H

+

Ph

17

Ph

N H

18

R

Lewis Acid

7:8

Me CH2 OH

Ti(Oi-Pr)3 Cl TiCl 4

83:17 72:28

2.3.1

Stereoselective Acetate Aldol Reactions Using Chiral Auxiliaries

The early work in the field of titanium enolate acetate aldol reactions was conducted by Braun in a general investigation of acetate aldol reactions [12]. The enolates were generated from chiral acetamide 16 by transmetalation of the lithium enolate with triisopropoxytitanium chloride or titanium tetrachloride, as shown in Table 2.3. They reported moderate selectivity for the reaction with benzaldehyde. Yan and coworkers developed titanium enolate acetate aldol reactions as an extension of their boron acetate enolate methodology [13, 14]. Good yields and diastereoselectivity were reported when using camphor-derived N-acyloxazolidinethione 19 (Scheme 2.3, Table 2.4, entries 1–7, and Figure 2.1). The high selectivities were attributed to additional chelation afforded by the thiocarbonyl of the chiral auxiliary in transition state assembly 20, shown in Scheme 2.3. The corresponding camphor-derived oxazolidinone acetate imide provided no stereocontrol, supporting the chelation control hypothesis. Shortly thereafter, acetate aldol reactions using camphor-derived imidazolidinone 27 were reported by Palomo and coworkers [15]. They reported moderate yields and enantioselectivity for a variety of unsaturated and aliphatic aldehydes (Table 2.4, entries 8–12). Interestingly, enantioselectivity for unsaturated aldehydes was opposite that for aliphatic aldehydes. Also, enantioselectivity reported for titanium was completely opposite that of the corresponding lithium enolate reactions. Recently, Phillips and Guz reported a titanium enolate acetate aldol reaction based on a valine-derived N-acyloxazolidinethione 30 [16]. The titanium enolate is directly generated from TiCl 4 , ()-sparteine, and Nmethylpyrrolidone by use of Crimmins’ procedure, as discussed in Section 2.4.1.2.1. Their highly hindered chiral auxiliary can be synthesized in three steps from commercially available starting material. They reported good yields and good to excellent diastereoselectivity for a range of aldehydes,

67

68

2 The Development of Titanium Enolate-based Aldol Reactions Tab. 2.4

Survey of acetate aldol reactions employing chiral auxiliaries. O

O

Lewis acid

R1

R2CHO

O

OH

R1

R2

+

R1

24

23

OH R2

25

Entry

R1

R2

Lewis Acid

Yield (%)

24:25

Ref.

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

26 26 26 26 26 26 26 27 27 27 27 27 28 29

n-Pr i-Pr (E)-CH3 CHbCH Ph (E)-PrCHbCH (E)-Me3 SiCHbCH (E)-PhSCHbCH Ph (E)-PhCHbCH i-Pr t-Bu PhCH2 CH2 Ph Ph

TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 TiCl 4 Ti(Oi-Pr)3 Cl Ti(Oi-Pr)3 Cl

85 86 86 91 87 80 77 65 70 85 74 37 89 62

95:5 94:6 93:7 91:9 90:10 90:10 90:10 88:12 86:14 17:83 47:53 42:58 35:65 70:30

13 13 13 13 14 14 14 15 15 15 15 15 19 19

as shown in Table 2.5. Once again, the extra chelation afforded by the thiocarbonyl moiety might be responsible for their excellent results. It has, furthermore, been noted that diastereoselectivity depends critically on the exact stoichiometry of the reagents. The stereochemical outcome has been rationalized on the basis of the coordinated chair model 33 or dipole-minimized boat transition model 34, shown in Figure 2.2.

Ph N O

O

N

N S

27

26

O

28

O

29

Fig. 2.1

Chiral auxiliaries used in the asymmetric acetate aldol reactions described in Table 2.4.

2.3 Addition of Enolates Without a-Substituents to Aldehydes

O

O TiCl4, CH2Cl2 i-Pr2NEt N O

S then RCHO

R

O O

H

OH

X

S

N H

O

R

L L

Ti

O

21 +

OH

L R

X

H

20

19

22

Scheme 2.3

Camphor-derived asymmetric acetate aldol reactions.

Urpı´ and Vilarassa investigated an asymmetric acetate aldol reaction in conjunction with the synthesis of Macrolactin A [17]. They reported good yield and excellent stereoselectivity for a handful of unsaturated aldehydes using a valine-derived thiazolidinethione chiral auxiliary. 2.3.2

Stereoselective Acetate Aldol Reactions Involving Chiral Titanium Ligands

Duthaler and coworkers demonstrated that stereoselectivity in the titanium enolate acetate aldol reaction could also be induced by chiral ligands on titanium [18]. Their cyclopentadienylbis(1,2:5,6-di-O-isopropylidene-a-dTab. 2.5

Sterically hindered oxazolidinethione-derived asymmetric acetate aldol reactions. S O

S

O N

TiCl4, (-)-sparteine NMP, CH2Cl2

Ph Ph

O

O

OH

S R

N

30

O

+

Ph

then RCHO

69

O

OH R

N

Ph Ph

Ph

32

31

Entry

R

Yield (%)

31:32

1 2 3 4 5 6 7 8 9 10 11

PhCH2 CH2 n-Pr Et n-Bu (CH3 )2 CHCH2 i-Pr n-C6 H13 (E)-CH3 CHbCH PMBOCH2 TBDPSOCH2 CH2 Ph

83 78 90 77 82 83 78 85 55 56 86

95:5 95:5 93:7 95:5 96:4 92:8 95:5 99:1 97:3 99:1 85:15

70

2 The Development of Titanium Enolate-based Aldol Reactions Ph

Ph Ph

O

H

S Cl Cl

Ph

O S

N

H N

H Ti

Cl

O O

R

H R

O

O

Cl Ti

H

H

34

33

S O

O

Cl Cl

Cl

OH R

N

Ph Ph

35 Fig. 2.2

Transition-state models of the asymmetric acetate aldol reaction.

glucofuranose-3-O-yl)chlorotitanate Lewis acid provided excellent enantioselectivity and moderate to good yields with tert-butyl acetate reacting with a wide range of aliphatic and unsaturated aldehydes (Table 2.6, entries 1–7, and Figure 2.3). The chiral ligands are, furthermore, commercially available and can be recovered after the reaction. This work was extended by Rutledge to an investigation of the effects of the double stereodifferentiation of chiral ligands on titanium and a chiral auxiliary derived from (þ)- or ()-menthol (45 and 46). (Table 2.6, entries 8–11, and Figure 2.4) [19]. Similar work by Fringuielli examined the effects of chiral ligands [20] and auxiliaries [21] on the basis of (þ)-2-carane 43 and (þ)-3-carane 44 (Table 2.6, entries 12–17, and Figure 2.3). Although double stereodifferentiation can result in impressive stereoselectivity, these methods suffer from requiring stoichiometric amounts of both chiral auxiliary and chiral ligands and yields are usually modest. 2.3.3

Alternative Approaches to Acetate Aldol Adducts

Because of the inherent difficulty of inducing chirality in the acetate enolate reaction, alternative approaches have been developed. A general approach is to synthesize a-substituted aldols and then reductively remove the asubstituent. Yan reported a one-step bromination–aldolization which provided a-bromo aldols in excellent yield and diastereoselectivity (Scheme 2.4) [22]. They then demonstrated that the a-bromo substituent could be reduc-

2.3 Addition of Enolates Without a-Substituents to Aldehydes Tab. 2.6

Stereoselective acetate aldol reactions involving chiral titanium Lewis acids.

37 Ti

OLi

O

Cl

BuLi

OR* OR*

R1

R1

36

Ti O

OR* OR*

R2CHO O

O

OH

R1

R2

+

R1

39

R1

OH

38

R2

40

Entry

R1

R2

OR*

Yield (%)

39:40

Ref.

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

t-BuO t-BuO t-BuO t-BuO t-BuO t-BuO t-BuO 45 46 45 46 HO HO t-BuO t-BuO 45 47

n-Pr n-C7 H15 i-Pr t-Bu CH2 bCMe Ph 2-furyl Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

41 41 41 41 41 41 41 41 41 42 42 43 44 43 44 44 44

51 87 66 80 81 69 62 51 54 40 40 54 52 68 70 76 70

97:3 98:2 98:2 96:4 98:2 98:2 95:5 96:4 98:2 30:70 21:79 82:18 83:17 81:19 75:25 90:10 96:4

18 18 18 18 18 18 18 19 19 19 19 20 20 20 20 21 21

tively removed under mild conditions using aluminum amalgam to provide acetate aldols in good yield and enantioselectivity [23]. Urpı´ and co-workers reported aldol-like reactions of titanium enolates with acetals by use of a valine-derived N-acetylthiazolidinethione 52 [24]. They reported moderate to good stereoselectivity and moderate yield for a variety of aliphatic and unsaturated acetals, as shown in Table 2.7. In these reactions, the enolate presumably reacts with the oxycarbenium ion generated by Lewis acid activation of the acetals. Recently, Ghosh and Kim developed an alternative procedure for acetate aldol reactions utilizing ester-derived titanium enolate aldol reactions [25]. As shown in Scheme 2.5, reaction of chloroacetate 55 with TiCl 4 and diisopropylethylamine provided the titanium enolate, which upon reaction with monodentate aldehydes gave a highly anti-diastereoselective aldol product

71

72

2 The Development of Titanium Enolate-based Aldol Reactions

O O

Ph H

O

Ph

OO

Ph

Ph O

O

O O

41

O

42

O

O

H

H H

H

43

44

Fig. 2.3

Chiral ligands used in the stereoselective acetate aldol reactions described in Table 2.6.

56 in excellent yield. Addition of 2 equiv. acetonitrile is critical to the observed diastereoselectivity. Interestingly, when the aldol reaction is conducted with bidentate aldehydes, a variety of anti aldolates are obtained in excellent diastereoselectivity and yield. The reason for this reversal of diastereoselectivity will be discussed in Section 2.4.2.2.1. Reductive removal of chlorine provided convenient access to acetate aldol products. Representative aldol reactions with mono- and bidentate aldehydes are shown in Table 2.8.

2.4

Addition of Enolates with a-Substituents to Aldehydes

As described previously, when enolates have a-substituents, new a- and bchiral centers are formed. Thus, it is possible to form aldol products in which the a- and b-substituents are in a syn or anti relationship to each SiMe3O O H

O

O H

45

46

Fig. 2.4

Chiral auxiliaries used in the stereoselective acetate aldol reactions described in Table 2.6.

47

2.4 Addition of Enolates with a-Substituents to Aldehydes

O

O

b) Br2, i-Pr2NEt

N

R

L

Ti L

Br

O 48

OH

L

O O

H

c) RCHO

S

S

N H

a) TiCl4, i-Pr2NEt

49

O

OH

51 R

OH

a) Et3N, H2O, CH2Cl2

O

R

X

50

Br

b) Al / Hg

R

yield

R

yield

MeCH=CH

87%

MeCH=CH

90%

Ph

96%

Ph

94%

i-Pr

92%

i-Pr

91%

Scheme 2.4

Bromination–aldol reaction and reductive debromination–deprotection.

Tab. 2.7

Acetate aldol adducts from acetals. O

S S

N

O

S 1) TiCl4, i-Pr2NEt

S

N

OMe R

O

S

+

S

N

OMe R

2) RCH(OMe)2, LA

53

52

54

Entry

R

Lewis Acid

Yield (%)

53:54

1 2 3 4 5 6 7 8 9

Ph 4-MeOC6 H4 3-MeOC6 H4 4-ClC6 H4 (E)-PhCHbCH Me n-Pr i-Bu i-Pr

BF3 Et2 O BF3 Et2 O BF3 Et2 O BF3 Et2 O BF3 Et2 O SnCl 4 SnCl 4 SnCl 4 SnCl 4

77 87 75 81 77 57 62 70 60

88:12 93:7 88:12 88:12 82:18 76:24 73:27 79:21 71:29

73


74

TsNH

TsNH

O

O

HO

RCHO

Cl

55

56

(monodentate)

OH

1) HCO2NH4, Pd/C

O

O

O

OH

TiCl4, i-Pr 2NEt

R

2) LiOH, H2O2

Cl

57

TiCl4, i-Pr 2NEt RCHO (bidentate) TsNH

O

OH

O

OH

1) HCO2NH4, Pd/C O

HO Cl

58

R

2) LiOH, H2O2

59

Scheme 2.5

Asymmetric chloroacetate aldol reactions.

other. Methods have been developed to provide both diastereoselectivity and enantioselectivity in the aldol products. These developments are not mere extensions of previous methods. In fact, many titanium enolate-based asymmetric transformations provide stereoselectivity and efficiency which cannot be obtained by use of other methods. 2.4.1

Syn Diastereoselectivity

In general, most enolates are formed in the Z configuration. When the metal involved in the reaction is acidic enough to coordinate to both the enolate and the aldehyde of the aldol reaction, syn adducts result via a sixmembered cyclic Zimmerman–Traxler [3] transition state. This results in inherent preference for titanium enolate aldol reactions to form syn aldols,

Tab. 2.8

Chloroacetate aldol reactions. Entry

Aldehyde

Additive

Yield (%)

58:56

1 2 3 4 5 6 7 8

i-PrCHO i-PrCHO i-PrCHO i-BuCHO i-BuCHO PhCHO BnOCH2 CHO BnO(CH2 )2 CHO

– MeCN (2.2 equiv.) NMP (2.2 equiv.) MeCN (2.2 equiv.) NMP (2.2 equiv.) NMP (2.2 equiv.) – –

82 66 71 88 90 47 86 79

25:75 2:98 6:94 98:2 95:5 >98:2 >98:2 >98:2 >98:2 96:4 93:7 94:6 >98:2 >98:2

29 29 29 29 29 29 30 30 30 30 30 31 31 31 31 31 31 31 31 31

a-sulfur substituent and b-hydroxyl group are syn to each other. This might indicate additional chelation to titanium. Reactions of a-selenoacetate enolates have been reported to give excellent selectivity and yield in the presence of triphenylphosphine or triphenylphosphine oxide, as shown in Table 2.12 (entries 7–11) [30]. This work was extended to a-selenopropionate esters (Table 2.12, entries 12 and 13) and aselenoketones (Table 2.12, entries 14–20) [31]. As for a-sulfur substituents, the a-selenopropionate ester enolates gave excellent yield and selectivity for aldols in which the a-heteroatom and b-hydroxyl group were syn to each other. These papers highlighted the importance of the presence of 1 equiv. bulky phosphine or amine to coordinate to titanium to improve the yield and the selectivity. Aldol Reactions of Aldehyde Hydrazones In contrast with the aldol reactions of ketones or carboxylic acid derivatives, those of aldehyde enolates typically proceed with little to no selectivity. This 2.4.1.1.3

2.4 Addition of Enolates with a-Substituents to Aldehydes Tab. 2.13

syn-Selective aldol-like reactions of hydrazones with aldehydes. Me2NN

LDA

Me2NN

Li Ti(Oi-Pr)3Cl or

Me2NN

Ti(NEt2)3Br

H

H

H

R1

R1

TiL 3

R1 R2CHO

79 Me2NN

Me2NN

OH

H

R2

+

OH

H

R2

R1

R1

80

81

Entry

R1

R2

Lewis Acid

Yield (%)

80:81

1 2 3 4 5 6 7 8 9 10

Me Me Ph Ph Ph Ph Ph i-Pr Me Me

Ph Ph Ph p-NO2 C6 H4 Me Me i-Pr Ph Me t-Bu

Ti(Oi-Pr)3 Cl Ti(NEt2 )3 Br Ti(Oi-Pr)3 Cl Ti(Oi-Pr)3 Cl Ti(Oi-Pr)3 Cl Ti(NEt2 )3 Br Ti(Oi-Pr)3 Cl Ti(Oi-Pr)3 Cl Ti(Oi-Pr)3 Cl Ti(Oi-Pr)3 Cl

80 61 95 40 95 50 78 78 61 70

91:9 85:15 98:2 98:2 98:2 90:10 98:2 94:6 95:5 93:7

could be because of lack of steric bulk to influence the cyclic six-membered Zimmerman–Traxler transition state. For this reason there are few useful reactions that directly utilize aldehyde enolates, even though the term aldol originally referred to a b-hydroxyaldehyde. This issue was resolved by using titanium enolates generated from N,N-dimethylhydrazones by transmetalation with Ti(Oi-Pr)3 Cl or Ti(NEt2 )3 Br [32]. The reaction furnished racemic syn aldols with excellent selectivity and moderate to excellent yield, as shown in Table 2.13. Reactions with cyclic ketone hydrazones also provided excellent syn diastereoselectivity and yields, as shown in Scheme 2.8.

Me2NN

OH

Me2NN

Ph

>98:2 syn/anti 82

83

Scheme 2.8

syn-Selective aldol-like reaction of cyclic hydrazone.

79

80


Synthesis of Optically Active syn Aldols Using Chiral Auxiliaries Asymmetric aldol reactions utilizing chiral auxiliaries or templates have emerged as one of the most reliable methods in organic synthesis. Both synand anti-selective aldol reactions have been developed over the years. The field of asymmetric syn aldol reactions has been largely advanced by Evans since his development of dibutylboron enolate aldol chemistry based on amino acid-derived chiral oxazolidinones. This method requires expensive dibutylboron triflate, however, and the amino acid-derived chiral auxiliary is only readily available in one enantiomer and thus only provides one enantiomer of the syn aldol. Several methods developed on the basis of titanium enolates provide convenient access to both ‘‘Evans’’ and ‘‘non-Evans’’ syn aldol products. 2.4.1.2

Amino Acid-derived Oxazolidinone and Related Auxiliaries Oxazolidinone-, oxazolidinethione-, oxazolidineselone-, and thiazolidinethione-based enolates react with aldehydes via the well-established sixmembered Zimmerman–Traxler [3] chair-like transition state. Exhaustive studies and analysis by Crimmins have established the theoretical basis of these reactions [33]. These transition states can proceed without chelation between carbonyl or thiocarbonyl (84) or with an additional chelation to titanium (85), as shown in Scheme 2.9. To proceed via the chelated transition structure 85, one of the ligands on titanium (typically chloride) must be displaced by the carbonyl or thiocarbonyl group. Although these groups are not sufficiently nucleophilic to completely displace this ligand on their own, 2.4.1.2.1

Y R1 LnTi

Y X

N H

R3 H

O O

R1

+L

Y

R2

OH R3

N

O O

H

84

O

L

R3

R2

X

X

N H

-L

O

"Evans" syn 86 Scheme 2.9

Asymmetric syn aldol transition-state models.

OH R3

N R2

R2 R1

L

85

X Y

L

Ti

R1

"non-Evans" syn 87

2.4 Addition of Enolates with a-Substituents to Aldehydes O

O

Ti(Oi-Pr) 3

R = i-Pr

PhCHO

N

O

O

O

Ph

N

O

O

O

OH

+

OH Ph

N

O

a) LDA

89

90

b) Ti(Oi-Pr)3Cl

89 : 90

eq. Ti(Oi-Pr)3Cl O

O O

N

3

3 : 92

1

77 : 16

OH

O

R

88 a) TiCl4

R = Bn

O

O

b) base O

N Bn

TiCl 3

O

O i-PrCHO

O

+

N Bn

O

OH

N

O

Bn

91 base

91 : 92

yield

i-Pr2NEt

94 : 6

84

TMEDA

98 : 2

83

92

Scheme 2.10

syn-Selective aldol reactions involving oxazolidinone chiral auxiliaries.

the ligand can be easily abstracted with a second equivalent of titanium. A consequence of this is that these substrates will occasionally give mixtures of products resulting from incomplete conversion of 84 to 85. Also, addition of chelating ligands, extra equivalents of amine bases, or even some solvent molecules tend to disfavor transition state 85, because of their preferential chelation to the titanium enolate. The initial adaptation of amino acid-derived oxazolidinone chiral auxiliaries to titanium enolate aldol reactions was conducted by Thornton [34– 36]. The procedure involved transmetalation of the lithium enolate with Ti(Oi-Pr)3 Cl in THF or ether. By varying the amount of titanium, the ratio of products 89:90 could be varied, as shown in Scheme 2.10. They attributed this observation to quenching of lithium interference, but it could also be a matter of switching between chelated and non-chelated transition structures with excess titanium. They observed that a stoichiometric amount of THF gave rise to titanium chelation [35]. By choosing the more powerfully chelating THF they could favor formation of the syn product 89 whereas the weakly chelating ether favored syn product 90. Because both ethereal solvents can chelate to titanium, however, their products were always complex mixtures of both syn and anti aldols. The ethereal solvents were necessary because of solubility problems. These complications were alleviated when Evans demonstrated that titanium enolates could be directly generated in dichloromethane with amine

81

82


bases [28]. Stereoselection and reaction yields are comparable with those of boron enolate-based syn aldol reactions. Amine bases seemed to have a noticeable effect on stereoselectivity. As shown in Scheme 2.10, the use of TMEDA improved selectivity compared with i-Pr2 NEt; this suggests the reaction proceeded through non-chelated transition state 84. Furthermore, stoichiometry of aldehydes (2 equiv.) is also critical for complete conversion. Crimmins et al. developed amino acid-derived oxazolidinethione [37] and thiazolidinethione [38] chiral auxiliaries and demonstrated their utility in titanium enolate aldol reactions. Depending upon the amount and nature of amine bases and the stoichiometry of TiCl 4 , ‘‘Evans’’ or ‘‘non-Evans’’ syn aldol products can be provided with excellent diastereoselectivity and isolated yields. Reactions involving oxazolidinethione auxiliaries led to ‘‘Evans’’ syn aldol product 94 when 1.0 equiv. TiCl 4 , 1.1 equiv. aldehyde, and 2.5 equiv. ()-sparteine were used, as shown in Table 2.14, entries 1–3. Rationalizing that the extra amine base or excess aldehyde could be acting as a ligand on titanium, they demonstrated that 1.05 equiv. TiCl 4 , 1.1 equiv. aldehyde, 1.0 equiv. ()-sparteine, and 1.0 equiv. N-methylpyrrolidinone also gave product 94, the latter conditions being more economical and simpler to work up. ()-Sparteine was discovered to have a dramatic rate-enhancement effect on these aldol reactions, but it was demonstrated that its chiral architecture did not lead to significant asymmetric induction. Using oxazolidinethione auxiliaries, the chelation-controlled ‘‘non-Evans’’ product 95

Tab. 2.14

Oxazolidinethione based syn aldol reactions. O

O a) 1.0 eq. TiCl4

R

N

S

OH

b) 2.5 eq. (-)-sparteine O

O S

A

c) RCHO

B

a) 2 eq. TiCl4

Bn

94 +

N

O

O Bn

93

S

OH R

N

b) 1.1 eq. i-Pr2NEt Bn

c) RCHO

95

Entry

Method

R

Yield (%)

94:95:anti

1 2 3 4 5 6

A A A B B B

i-Pr Ph MeCHbCH i-Pr Ph MeCHbCH

70 89 65 87 88 81

99:1:0 97:2:1 97:2:1 0:95:5 1:98:1 0:95:5

2.4 Addition of Enolates with a-Substituents to Aldehydes O MeNHOMe

MeO

N

OH R

imidazole O

O S

OH

(90%)

97

R

N

OH Bn

NaBH4

96

HO

R

EtOH (85%)

98

Scheme 2.11

Conversion of oxazolidinethione auxiliary to other functionality.

could be formed by using 2 equiv. TiCl 4 and only 1 equiv. diisopropylethylamine, as shown in Table 2.14, entries 4–6. In a typical procedure, 2 mmol TiCl 4 was added dropwise to a solution of 1 mmol oxazolidinethione 93 in 6 mL CH2 Cl2 at 0 C and stirred for 5 min. i-Pr2 NEt (1.1 mmol) was added dropwise and the dark red solution stirred for 20 min at 0 C and then cooled to 78 C. Aldehyde (1.1 mmol) was added dropwise and stirred for 1 h. One intrinsic feature of oxazolidinethiones is that the chiral auxiliary could be readily converted to Weinreb amide 97 by reaction with imidazole and methoxylamine salt, as shown in Scheme 2.11. Similarly, sodium borohydride reduction gave alcohol 98 and DIBALH reduction provided the corresponding aldehyde in excellent yield. To demonstrate the full utility of the ()-sparteine-mediated enolization, they also showed that oxazolidinone chiral auxiliaries could be reacted with either 1.1 equiv. TiCl 4 and 2.5 equiv. ()-sparteine or 1.05 equiv. TiCl 4 , 1.0 equiv. ()-sparteine, and 1.0 equiv. N-methylpyrrolidinone to yield product 94. Thiazolidinethione-derived chiral auxiliaries have similar reactivity and selectivity, as shown in Table 2.15. Because of the increased nucleophilicity of the thiazolidinethione ring, chelation-controlled reaction through transition state 85 enabled preferential formation of the ‘‘non-Evans’’ syn product 101. One equivalent of i-Pr2 NEt, TMEDA, or ()-sparteine and 1 equiv. TiCl 4 provided 101 diastereoselectively. Interestingly, when the reaction was performed with 2 equiv. of TMEDA or ()-sparteine, ‘‘Evans’’ syn aldol adduct 100 was obtained diastereoselectively. These aldol products can be converted to a variety of other functionality under mild conditions. Other oxazolidinethiones and thiazolidinethiones have resulted in comparable diastereoselectivity and yields. Similar reactions utilizing oxazolidineselone chiral auxiliaries were developed by Silks and coworkers [39]. They demonstrated good to excellent

83

84


Thiazolidinethione-based syn aldol reactions. O

S S

a) 1 eq. TiCl4

S

A

Bn

100 +

c) RCHO

N

O

S

Bn

B

99

R

N

b) 1 eq. (-)-sparteine O

S

OH

a) 1 eq. TiCl4

S

OH R

N

b) 2 eq. (-)-sparteine Bn

c) RCHO

101

Entry

Method

R

Yield (%)

100:101

1 2 3 4

A A B B

i-Pr Ph i-Pr Ph

60 52 75 62

2:98 99:1

yields and excellent stereoselectivity in reactions of N-propionyl- and Nbenzyloxyacetyloxazolidineselone with a variety of aldehydes, as shown in Table 2.16. The acylated oxazolidineselone can be prepared in a one-pot procedure from oxazoline 102 via lithiation, addition of elemental selenium, and quenching with the appropriate acyl chloride. The selenocarbonyl also has utility as a chiral probe via 77 Se NMR. The selone chiral auxiliary can also be converted to other functionality similar to oxazolidinethione 96 and thiazolidinethione 99. Camphor-derived Chiral Auxiliaries After adaptation of amino acid-derived oxazolidinone chiral auxiliaries to titanium enolate aldol reactions, Thornton and coworkers went on to develop a camphor-derived chiral auxiliary [40]. Moderate to good selectivity was observed for reactions with a variety of aldehydes using camphorquinonederived N-propionyl oxazolidinone 106, as shown in Table 2.17. The carbonyl of the oxazolidinone is not a good enough nucleophile to completely displace chloride to form chelated transition structure 107, so the nonchelated transition state assembly 108 is always a competing pathway. Stereodifferentiation experiments with (R)- and (S)-2-benzyloxypropanal were also investigated. syn Diastereoselectivity was, however, moderate (53% de) compared with lithium enolate-based reactions which provided high selectivity (85% de) for the (R) isomer. Reactions with (S)-benzyloxypropanal resulted in mismatched aldehyde and enolate selectivity and a 42:52 ratio of syn adducts. 2.4.1.2.2


85

Tab. 2.16

Oxazolidineselone-based syn aldol reactions. O

Se

OH R3

N

O

R2 1) LiHMDS N

O

a) TiCl4

O

Se

R1

104 +

b) i-Pr2NEt

2) Se N

O

3) EtCOCl R1

R1

102

O

Se

c) R3CHO

R2

R3

N

O

103

OH

R2 R1

105 Entry

R1

R2

R3

Yield (%)

104:105

1 2 3 4

i-Pr Bn Bn Bn

BnO Me Me Me

i-Pr i-Pr MeCHbCH Ph

72 86 86 91

75:25 >99:1 >99:1 >99:1

Tab. 2.17

Camphor-derived syn aldol reactions.

O

O a) LDA N O O

b) Ti(Oi-Pr)3Cl

O

L L

Ti

c) RCHO L

O O

N H R

O O

R

H -L

106

N H

+L

O

R

109

L

108

O

OH

X

L

Ti

O O

H

107

L

L

+

OH R

X

110

Entry

R

109:110:anti

1 2 3 4

Et Ph i-Pr MeCHbCH

76:13:11 79:2:19 86:2:12 49:4:49

86


Camphor-derived syn-selective aldol reactions.

O

O O

a) LDA

O

L N O

b) Ti(Oi-Pr)3Cl

L

c) RCHO

Ti L

O

N H

H

R

O O

N

+L H

-L

R

O O

H

O

111

O

OH

X

L

Ti L

113

112

O

L

L

R

+

OH

X

R

115

114 Entry

R

Yield (%)

114:115

1 2 3 4

Me i-Pr Ph MeCHbCH

84 70 79 70

>99:1 >99:1 >99:1 99:1

To improve the p-facial and syn selectivity of the camphor-derived chiral auxiliary, Ahn et al. developed a chiral oxazinone derived from ketopinic acid (111) [41]. The explanation for the low diastereoselectivity of camphorderived auxiliary 106 was that the steric influence of the proximal bridgehead methyl group was insufficient for p-facial selectivity. It seemed that the syn-7-methyl group was too far away from the acyl moiety. In oxazinonebased chiral auxiliary 111 one enolate face is in proximity to the camphor skeleton and, as a result, steric bias was significantly enhanced over the 106-derived system. Moderate to good yields and near complete syn diastereoselectivity for a range of aldehydes have been reported, as shown in Table 2.18. The steric influence of their auxiliary is apparently strong enough to overcome inherent weakness in titanium chelation; near complete selectivity for chelation-controlled product 114 arising from transition state assembly 112 was reported. Yan et al. developed camphor-derived oxazolidinethione chiral auxiliary 116 from ketopinic acid [42, 43]. The opposing location of the N-acyl group in this auxiliary when compared with 106 and 111 leads to formation of the other syn product 120 via chelation control. Good yields and excellent selectivity were reported for a range of aldehydes, as shown in Table 2.19. Be-


87

Tab. 2.19

Camphor-derived syn-selective aldol reactions.

O a) TiCl4 O N

c) RCHO

L

Ti L

S

O

N H

L

L

b) i-Pr2NEt

O S

R

O O

H

116

R +L

H

L

Ti L

118

OH

X

L

O O

117

O

S

N H

-L

O

R

119

+

OH

X

R

120

Entry

R

Yield (%)

119:120

1 2 3

i-Pr Ph MeCHbCH

85 84 86

2:98 3:97 98 99 >96 >96

with excellent diastereoselectivity. The E enolate presumably reacted with aldehydes via a cyclic transition state to form anti aldol adducts 151. Transmetalation of the lithium enolate of 150 with 146 and reaction with a variety of aldehydes provided syn aldols in moderate to good yield and excellent stereoselectivity, as shown in Table 2.26. It was observed that the kinetically generated E enolates were responsible for the observed stereoselectivity. Equilibration to the more stable Z-enolates gave anti products, as discussed in Section 2.4.2.3. To rationalize the stereochemical outcome of these syn aldol products, boat-like transition state 152 was proposed. There are also other examples of syn aldol product formation from titanium E-enolates [53]. Mahrwald reported aldol reactions of ketone enolates with aldehydes in which the reaction was conducted with equimolar amounts of titanium(IV) alkoxides and a-hydroxy acids [54]. This provided aldol products with high syn diastereoselectivity, as shown in Table 2.27. Among a variety of alkoxides and a-hydroxy acids examined, the use of Ti(Ot-Bu)2 -BINOL and (R)mandelic acid resulted in high syn diastereoselectivity and aldol products were obtained in enantiomerically enriched form. Other a-hydroxy acids such as tartaric acid or lactic acid resulted in very low enantioselectivity (18–24%). The influence of the chirality of BINOL

93


94

Tab. 2.26

syn Aldol reactions using chiral titanium enolates. O

OLi

LDA

O

RCHO O

O

O

OH R

151

150 146 H H

TiLn

R

Ti

O

RCHO

O

O

OR* OR*

H 3C

O O

152

O

OH

O

R

153 Entry

R

Yield (%)

153:151

1 2 3 4

i-Pr CH2 bCMe Ph Pr

76 61 82 87

94:6 96:4 96:4 92:8

Tab. 2.27

syn-Selective aldol reactions. O RCHO

O

OH

BINOL=Ti(Ot-Bu)2

+

R (R)-mandelic acid

154 Entry

R

Yield (%)

syn:anti

ee (syn) (%)

1 2 3 4

Ph t-Bu PhCcC i-Pr

71 55 72 48

95:5 85:15 73:27 89:11

93 87 94 83


95

Tab. 2.28

syn-Selective aldol reactions of chiral a-silyloxyketones. O

OH

R1 O

R1 H

H

R2

O O

155

OTBS

L

L

R1 OTBS

R2

H

TBSO

157

L

Ti

O L

+

OH

R1

R2 OTBS

156

158 Entry

R1

R2

Methoda

Yield (%)

157:158

Ref.

1 2 3 4 5 6

Cyclohexyl Cyclohexyl Cyclohexyl Cyclohexyl Me Bn

Ph i-Pr Ph i-Pr i-Pr i-Pr

A A B B C C

– – – – 90 85

99:1 >99:1 99:1 99:1 97:3 97:3

55 55 56 56 57 57

a Method

A: LDA, Ti(Oi-Pr)3 Cl, R2 CHO; Method B: LDA, Ti(Oi-Pr)4 , R2 CHO; Method C: TiCl 4 , i-Pr2 NEt, R2 CHO

was insignificant. Although the mechanism of this reaction is unclear, ligand exchange between t-BuOH and a-hydroxy acids is evident from NMR analysis and might be necessary for the syn diastereoselectivity and enantioselectivity observed. Synthesis of Optically Active syn Aldols with Chiral Enolates Thornton and Siegel have reported that reactions of the titanium enolates of chiral a-silyloxyketones resulted in excellent syn diastereoselectivity, as shown in Table 2.28, entries 1–4 [55, 56]. Use of tetrakisisopropoxytitanium enolates also afforded excellent syn diastereoselectivity. In work similar to that with oxazolidinone chiral auxiliaries, these enolates were generated as lithium enolates then transmetalated with the appropriate titanium Lewis acid. Large excesses of titanium were necessary for good stereoselectivity. They also noted that carboxylic acid derivatives could be obtained by deprotection and oxidative cleavage. Chiral auxiliary methods are, however, more efficient at providing adducts of this nature. Urpı´ and coworkers demonstrated that a variety of directly generated titanium enolates of a-silyloxyketones reacted with aldehydes to give syn aldols with excellent yield and selectivity, as shown in Table 2.28, entries 5–6 [57]. The selectivity of these reactions can be explained by the transition state assembly 156. Between the O-benzyl derivative and the OTBS protected ketones, the latter provided excellent yield and syn–syn diastereoselectivity. 2.4.1.4


96

Tab. 2.29

Reactions of b-ketoimide enolates. O

O

O

OH

X O

Me O

O

O

O

H

b) i-Pr2NEt O

N

R

a) TiCl4

c) RCHO H

Bn

159

R Me

O O

Bn

L

H

N

161 L

Ti

O

O

+

O

OH

L O

160

R

N Bn

162 Entry

R

Yield (%)

161:162

1 2 3 4

i-Pr CH2 bCMe Et Ph

86 64 86 81

>99:1 95:5 >99:1 96:4

The steric bulk of the silyloxy group prohibits it from effectively chelating titanium, so the products arise from the non-chelated transition state. Much work in the field of aldol reactions of ketones was performed by Evans to enable the synthesis of polypropionate natural products. They demonstrated that b-ketoimides like 159 were selectively and completely enolized at the C4 position rather than the potentially labile methyl-bearing C2 position, most probably because steric factors prohibited alignment of the carbonyl groups necessary to activate the C2 proton. As shown in Table 2.29, it was demonstrated that these compounds would react with aldehydes to provide syn–syn product 161, via titanium enolates, with good yield and excellent selectivity, and the corresponding syn–anti product 162 could be favored by use of a tin enolate reaction [58]. They invoked the chelated transition state assembly 160 to explain the product stereochemistry observed, in which the C2 -methyl group directs diastereofacial selectivity. Interestingly, reduction with Zn(BH4 )2 provided the syn diol diastereoselectively. Evans also investigated the stereochemical influence of two adjacent stereogenic centers in the titanium enolate-based aldol reaction [28]. As shown in Scheme 2.13, asymmetric induction of the enolate resulted from the influence of the a-stereocenter; the b-stereogenic center has very little effect. Subsequently, Evans examined double-stereodifferentiating titanium enolate aldol reactions [59]. Both the aldehyde and the enolate contained a and b stereogenic centers. In aldol reactions between these substrates the enolate can adopt either a matched or mismatched relationship with the aldehyde. Several possible scenarios were investigated. As shown in Scheme

2.4 Addition of Enolates with a-Substituents to Aldehydes OTBS O

OTBS O

Ti Ln

OTBS O

i-PrCHO

a) TiCl4

97

OH

b) i-Pr2NEt

163

164 96 : 4 dr (96%)

OTBS O

OTBS O a) TiCl4

Ti Ln

OTBS O

i-PrCHO

OH

b) i-Pr2NEt

166 95 : 5 dr (82%)

165 Scheme 2.13

syn-Selective aldol reactions of chiral ketones.

2.14, when the ketone enolate and aldehyde were chirally fully matched (168) or partially mismatched (169 and 170), syn diastereoselectivity was quite good. The diastereoselectivity was poor only in the completely mismatched case (171). O

OPMB OTBS O

OTBS O

OH

OPMB

H

167

O

a) TiCl 4

OPMB

168

89 : 11 dr (86%)

OTBS O

OH

OPMB

H

b) i-Pr2NEt OTBS O

TiLn O

OPMB

169

87 : 13 dr (81%)

OTBS O

OH

H

170 O

OPMB

92 : 8 dr (85%)

OPMB OTBS O

OH

OPMB

H

171 Scheme 2.14

Double stereodifferentiation in syn aldol reaction. ( a 28% of an anti diastereomer also isolated.)

37 : 35 : 28 dra (79%)

98


2.4.2

Anti Diastereoselectivity

As can be seen from the developments described above, the control of both relative and absolute acyclic stereochemistry in a variety of syn aldol reactions can now be achieved highly stereoselectively. Both boron and titanium enolate-based syn aldol reactions have gained widespread popularity and are frequently used in synthesis. Whereas anti-a-alkyl-b-hydroxycarbonyl units are inherent to numerous bioactive natural products, there are relatively few effective synthetic processes that are convenient, operationally simple, and afford high diastereoselectivity for a wide range of aldehydes. Early examples of anti-selective aldol reactions, reported by Meyers in 1984, were based upon oxazoline-derived boron enolates [60]. Several other methods based upon metal enolates other than titanium have subsequently been developed. In this chapter, however, we will focus on titanium enolate-based methods. Synthesis of anti Aldols in Racemic Form Procter et al. reported a novel anti-selective aldol process using titanium enolates of N-propionylpyrrolidine [61]. The aldol products were obtained in good yield and anti diastereoselectivity. The aldolates were produced in racemic form, however. As shown in Table 2.30, formation of the titanium enolate of 172 was achieved by transmetalation of the lithium enolate with Cp2 TiCl2 in THF. The resulting titanium enolate reacted with a range of aldehydes. Interestingly, the lithium enolate of 172 has stereoselectivity and the corresponding zirconium enolate afforded syn diastereoselectivity. 2.4.2.1

Tab. 2.30

anti-Selective aldol reactions of N-propionylpyrrolidine. O

OH

N

R

OTiCp 2Cl

O a) LDA N

N

173 RCHO

+

b) Cp2TiCl 2

O

172

OH

N

R

174 Entry

R

Yield (%)

173:174

1 2 3 4

Et i-Pr Ph MeCHbCH

65 64 68 77

79:21 87:13 98:2 90:10

2.4 Addition of Enolates with a-Substituents to Aldehydes Tab. 2.31

anti Aldol reactions of phenyl benzyloxythioacetate with respective aldehydes. OH

O H Bn OBn

177

O Ti O

L

175

OBn

SPh

O

PhS

L

R

PhS

R

O

+ OH

O

L

176

R

PhS OBn

178

Entry

R

Yield (%)

177:178

1 2 3 4

Me n-Pr t-Bu Ph

99 97 81 99

97:3 98:2 98:2 98:2

Cinquini and Cozzi reported the synthesis of racemic anti-a,b-dihydroxy thiolesters by aldol reaction of aldehydes with a-benzyloxythiolester-derived chlorotitanium enolates [62]. The thiolester was enolized by treatment with TiCl 4 and Et3 N in CH2 Cl2 at 78 C and the resulting enolate was reacted with a variety of aldehydes at 78 C providing anti aldol products with good to excellent anti diastereoselectivity, as shown in Table 2.31. The stereochemical outcome can be explained by boat-like model 176 in which the thiolester formed an E enolate presumably by chelation through the benzyloxy group. Kazmaier reported the synthesis of several racemic a-aminoaldols in which the a-amino group and the b-hydroxyl group are anti [63]. Reactions of N-benzyloxycarbonyl amino acid ester enolates with a variety of aldehydes afforded moderate to good yields and good to excellent diastereoselectivity, as shown in Table 2.32. Titanium enolates were generated by deprotonation of 179 with LDA in THF followed by the addition of 2 equiv. Ti(Oi-Pr)3 Cl in THF at 78 C. 2.4.2.2

Synthesis of Optically Active anti Aldols by Use of Chiral Auxiliaries

Aminoindanol and Related Chiral Auxiliaries Ghosh and coworkers developed novel highly diastereoselective anti aldol methods based on ester-derived titanium enolate aldol reactions [64–66]. The utility of the cis-1-toluenesulfonamido-2-indanol-derived chiral auxiliary was demonstrated. This chiral auxiliary is readily prepared from commercially available enantiomerically pure cis-1-amino-2-indanol. Both enantio2.4.2.2.1

99

100


Synthesis of sterically demanding a-aminoaldols. a) LDA

O

O t-BuO

OH

O

OH

b) Ti(Oi-Pr)3Cl

NHCO2Bn

t-BuO c) R2CHO

R1

R2 R1

t-BuO

NHCO2Bn

R2 R1

180

179

NHCO 2Bn

181

Entry

R1

R2

Yield (%)

180:181

1 2 3 4

i-Pr i-Pr Me Et

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

70 87 87 85

97:3 92:8 92:8 95:5

mers of the chiral auxiliary are, furthermore, readily available, enabling synthesis of either enantiomer of the anti aldol. As shown in Scheme 2.15, ester 183 was readily enolized with titanium tetrachloride and diisopropylethylamine. First it was treated with TiCl 4 in CH2 Cl2 at 0 C. After stirring at 23 C for 15 min, i-Pr2 NEt was added. Evans reported that alkyl esters cannot be enolized with TiCl 4 and amine bases [28]. Smooth enolization of sulfonamidoesters is presumably because of internal chelation with the sulfonamido group, as was recently documented by Xiang et al. [48].

TsNH

NH2

O 1) TsCl OH

2) EtCOCl

182

O

183 a) TiCl4 b) i-Pr2NEt

H3 C L L

L O Ti L O

H H O H

N

L L

L O

S

O

CH3

L O Ti

O H

N S

O

184 Scheme 2.15

Enolization of N-tosylaminoindanol esters.

185


101

TsNH L L O

L

184

Ti

Ti

L

L O

i-BuCHO

O

TiCl 4

L

N

O

O

OH

O

OH

O

L

187

L

+

S TsNH

O

O

186 188 Scheme 2.16

Aminoindanol-derived anti aldol reaction.

Although treatment of enolate 184 with isovaleraldehyde produced no reaction, addition of the enolate to a solution of isovaleraldehyde precomplexed with TiCl 4 provided the anti aldol product 187 in 97% yield as a single isomer (by HPLC and 1 H NMR) as shown in Scheme 2.16. Reaction with several other aldehydes also produced the anti isomer as the major product. It should be noted that of four possible diastereomers, only one syn and one anti product were observed in this reaction. The anti:syn selectivity ranged from 85:15 to >99:1 and yields ranged from 41–97%, as shown in Table 2.33. Whereas benzaldehyde resulted in very little to no selectivity under these conditions, in the presence of an additive there was a dramatic improvement in anti diastereoselectivity. Thus, aldol reaction of the enolate of 189 with benzaldehyde (2 equiv.) precomplexed with TiCl 4 (2.2 equiv.) in the presence of CH3 CN additive (2.2 equiv.) afforded anti alTab. 2.33

anti-Selective asymmetric aldol reactions. TsNH O

a) TiCl4

TsNH

TsNH

O

O

OH

OH

b) i-Pr2NEt O

189

c) RCHO TiCl4

R +

O

190

O

191

Entry

R

Yield (%)

190:191

1 2 3 4 5 6 7

i-Bu Me Pr i-Pr MeCHbCH PhCHbCH Ph

97 50 74 91 41 63 85

>99:1 85:15 95:5 85:15 95:5 99:1 45:55

R

102

2 The Development of Titanium Enolate-based Aldol Reactions a) TiCl4

TsNH

TsNH

O

O

OH

b) i-Pr2NEt O

TiCl 4

192

a) TiCl4

TsNH

O

c) i-BuCHO

193 (20.5 : 5.8 : 1 dr) TsNH O

O

OH

b) i-Pr2NEt O

O

c) i-BuCHO TiCl4

194

a) TiCl4

MsNH

195 (1 : 1 dr) MsNH O

O

OH

b) i-Pr2NEt O

196

c) i-BuCHO TiCl4

O

197 (70 : 30 dr)

Scheme 2.17

Structure–reactivity relationship studies in anti aldol reactions.

dol product stereoselectively (96:4) in good yield. These conditions, however, did not improve the yield or selectivity for reactions with aliphatic aldehydes. The anti selectivity can be rationalized by using a novel Zimmerman– Traxler type transition state 186. In this transition state, both the methyl group of the enolate and the alkyl group of the aldehyde adopt pseudoequatorial positions, leading to the anti product. Several structural features have been shown to be critical for the high selectivities observed. First, reaction of dimethylphenylglycinol-derived auxiliary 192 with isovaleraldehyde provided a 20.5:5.8:1 ratio of isomers, as shown in Scheme 2.17. The major isomers are thought to be the two anti diastereomers. Removal of the indane aromatic ring resulted in complete loss of diastereoselectivity. Thus, reaction of the corresponding 1,2aminocyclopentanol derivative 194 with isovaleraldehyde resulted in a 1:1 mixture of syn and anti diastereomers. The use of the mesylate derivative 196 also resulted in a large loss of selectivity. The reaction of N-mesylaminoindanol derivative 196 with isovaleraldehyde provided a 70:30 mixture of anti and syn diastereomers. These results suggest a possible p-stacking interaction between the two aromatic rings. The result of this interaction would be to help stabilize the conformation shown in enolate 184, although this interaction has not been rigorously established. Double stereodifferentiation experiments with matched chiral aldehyde 199 provided anti aldol 200 as a single diastereomer, as shown in Scheme 2.18 [67].

2.4 Addition of Enolates with a-Substituents to Aldehydes a) TiCl 4

TsNH O

TsNH

O

OH

b) i-Pr2NEt O

O c) TiCl4, O

198

200 (>99 : 1 dr)

H

199 Scheme 2.18

Double stereodifferentiation in aminoindanol-derived anti aldol reaction.

On the basis of these structure–reactivity studies, Ghosh and Kim subsequently speculated that the planarity of the acenaphthene ring in conjunction with its aromaticity might further enhance p-stacking interactions with the arylsulfonamide functionality [68]. In this context, an effective synthesis of both enantiomers of cis-2-amino-1-acenaphthenol from acenaphthylene was developed. Enolization of 202 using TiCl 4 and i-Pr2 NEt provided a single enolate, presumably the Z enolate. Reaction of this enolate with isovaleraldehyde precomplexed with TiCl 4 resulted in significantly reduced anti diastereoselectivity (78:22), however. Similar to the aminoindanol chiral auxiliary, reactions with the acenaphthene-derived auxiliary produced only one anti and one syn diastereomer. Interestingly, aldol reaction of the enolate of 202 with aldehydes (2 equiv.) precomplexed with TiCl 4 (2.2 equiv.) in the presence of CH3 CN (2.2 equiv.) resulted in excellent anti diastereoselectivity and yield for a wide range of aldehydes, as shown in Table 2.34. Oxazolidinethione and Oxazolidineselone Chiral Auxiliaries Silks and coworkers reported anti-selective aldol reactions in conjunction with their investigations on chiral selenium compounds [39]. They discovered that bidentate oxyaldehydes precomplexed with TiCl 4 led to anti aldol products in good yield and with excellent stereoselectivity, as shown in Table 2.35, entries 1 and 2. Presumably, this chelation-controlled reversal of syn/anti selectivity is a phenomenon similar to that which Ghosh and coworkers exploited to produce syn aldols from aminoindanol chiral auxiliaries. Both benzyl and isopropyl oxazolidineselone chiral auxiliaries have comparable anti diastereoselectivity. Crimmins and McDougall demonstrated that protected glycolyloxazolidinethiones underwent aldol reactions with aldehydes to provide anti aldol products [69]. Moderate to good yields and good to excellent anti selectivity were observed for a wide range of reactions, as shown in Table 2.35, entries 3–8. To achieve anti selectivity, it is necessary to complex the aldehydes with TiCl 4 before addition of the enolate. Comparing their results with those of Silks, it seems that the a-oxy substituent on the enolate is a less powerful anti director than an oxygen substituent on the aldehyde. 2.4.2.2.2

103

104


Acenaphthene-derived anti aldol reactions with respective aldehydes. TsNH OH

O TsNH O

a) TiCl 4

R

O

b) i-Pr2NEt

203

O c) RCHO, TiCl4, TsNH CH3CN

201

OH

O

202

R

O

204 Entry

R

Yield (%)

203:204

1 2 3 4 5 6

i-Bu Et i-Pr cyclohexyl Ph PhCH2 CH2

95 92 95 84 93 97

97:3 92:8 96:4 99:1 93:7 95:5

Synthesis of Optically Active anti Aldols by Use of Chiral Titanium Ligands Duthaler reported the synthesis of optically active anti aldols by use of the chiral CpTi(DAGO)2 complex [70]. They reported moderate yields and 2.4.2.3

Tab. 2.35

anti-Selective aldol reactions involving oxazolidinethione and oxazolidineselone auxiliaries. X O

O

X R2CHO

N

O

OH

O

R2 + O

N

R1

X

OH

O

R2

N R1

R1 Bn

Bn

Bn

205

R2 + O

N

R1

Bn

X

OH

O

206

207

208

Entry

X

R1

R2

Yield (%)

206:207:208

Ref.

1 2 3 4 5 6 7 8

Se Se S S S S S S

Me Me OCH2 CHbCH2 OCH2 CHbCH2 OCH2 CHbCH2 OBn OBn OMe

BnOCH2 BuOCH2 Me i-Pr Ph CH3 (CH2 )4 CHbCH2 Me

100 81 84 61 56 64 48 62

>99:0:1 >99:0:1 94:6:0 87:13:0 65:24:11 88:12:0 74:26:0 86:4:10

39 39 69 69 69 69 69 69

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions Tab. 2.36

Stereoselective synthesis of anti aldols using chiral titanium Lewis acids. O

a) LDA

O

O

OH

O

b) CpTi(DAGO) 2Cl O

R

+

O

OH R

c) RCHO

209

211

210

Entry

R2

Yield (%)

210:211

1 2 3 4

Pr t-Bu CH2 bCMe Ph

74 59 50 73

89:11 83:17 54:46 23:77

good diastereoselectivity for a range of aldehydes when reacted with 2,6dimethylphenyl propionate derived titanium enolate, as shown in Table 2.36, entries 1 and 2. The method provided no selectivity (entry 3) or syn selectivity (entry 4), however, when the aldehyde was unsaturated and substituted. The corresponding N-propionyl-1,3-oxazolidin-2-one provided good selectivity with isobutyraldehyde (88:12 anti/syn) but poor yield, because of the formation of byproducts.

2.5

Natural Product Synthesis via Titanium Enolate Aldol Reactions

Numerous applications of titanium enolate aldol reactions have been reported for the synthesis of natural products and bioactive compounds of pharmaceutical interest. These syntheses were performed by utilizing the titanium enolate methods described above as key steps. There are many transformations that simply cannot be achieved by use of conventional aldol chemistry. Furthermore, the use of inexpensive titanium reagents, operational simplicity, and functional group tolerance make this chemistry very attractive in synthesis. The following applications in synthesis further exemplify the increasing importance of titanium aldol chemistry. 2.5.1

Lactone Natural Products

Asymmetric syn and anti aldol reactions have been used for synthesis of the following natural products containing lactone moieties. A titanium enolatebased aldol reaction has also been utilized in the aldol dehydration sequence during the synthesis of pyrone natural products mxyopyronin A and B. The following syntheses of lactone-containing natural products highlight the variety of aldol transformations.

105

106


Tetrahydrolipstatin Ghosh and Fidanze reported a synthesis of tetrahydrolipstatin (217) in which the anti stereochemistry of the b-lactone moiety is set by using asymmetric anti aldol methodology, discussed in Section 2.4.2.2.1 [71]. Tetrahydrolipstatin is a saturated analog of the natural product lipstatin, isolated from Streptomyces toxytricini. It is a potent and irreversible inhibitor of pancreatic lipase and has been marketed in several countries as an anti-obesity agent under the trade name Xenical. Aldol reaction between the enolate of 212, generated with TiCl 4 and i-Pr2 NEt, and cinnamaldehyde precomplexed with Bu2 BOTf gave 213 in 60% yield as a 6.1:1 mixture of anti and syn diastereomers, as shown in Scheme 2.19. Aldol adduct 213 was converted to the benzyl ester 214, which was reduced selectively to the anti 1,3-diol by use of Evans’ procedure [72] and protected as the triisopropylsilyl ether 215. Hydrogenation of the O-benzyl group over Pearlman’s catalyst and lactonization with phenylsulfonyl chloride in pyridine gave the b-lactone 216 which, on deprotection and reaction with N-formyl-l-leucine under Mitsunobu conditions, afforded ()-tetrahydrolipstatin. 2.5.1.1

Myxopyronins A and B Panek and coworkers developed syntheses of myxopyronin A (220a) and myxopyronin B (220b) in which an aldol reaction was used to append the 2.5.1.2

TsNH

TsNH

O

O

OH

i

TiCl 4, Pr2NEt O

O

212

C6H13

Bu2BOTf, PhCH=CHCHO

Ph C6H13

213

(60%) ref. 71

OH

O

OTIPS C11H23

BnO C6H13

215

OH

O

C11H23

BnO 2) TIPSOTf, 2,6-lutidine (96%)

C6H13

1) H2/Pd(OH)2 (99%)

O

O OTIPS

1) Bu4NF(70%)

O

O

2) PPh3, DIAD, N-formyl-L-leucine

216 Scheme 2.19

Synthesis of ()-tetrahydrolipstatin.

(90%)

214

H N

H

2) PhSO2Cl, pyr (74%) O

O

1) Me4NHB(OAc)3 (94%)

217

O

O

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions O

OH

O

O

CO2Me

218 TiCl4, ,i-Pr 2NEt,

CHO

R

R = Pr : 58% R = Bu: 61% O

OH

O

O

R CO 2Me

219 ref. 73

O

OH

O

O

R

H N

CO 2Me

220a: R = Pr 220b: R = Bu Scheme 2.20

Myxopyronin A and B synthesis.

hydrophobic side chain [73]. The myxopyronins are natural products isolated from the gliding bacterium Myxococcus fulvus MX f50. These molecules are bacterial growth inhibitors, because of their capacity to selectively inhibit bacterial RNA polymerase. Aldol condensation of ketone 218-derived titanium enolate and subsequent elimination provided diene 219, as shown in Scheme 2.20. Attachment of the other side chain provided myxopyronins A and B. Callystatin A Crimmins and King reported a total synthesis of callystatin A (228) using their aldol methodology (as discussed in Section 2.4.1.2.1) to construct three of the four chiral centers in the molecule [74]. Callystatin A is a natural product, isolated from the marine sponge Callyspongia truncata, which has potent in-vitro toxicity against KB cell lines (IC50 ¼ 0.01 ng mL1 ). Phenylalanine-derived N-propionyloxazolidethione 221 was subjected to enolization with TiCl 4 and ()-sparteine using Crimmins’ procedure and reacted with (S)-2-methylbutanal to provide syn aldol adduct 222 in 83% yield with 98% selectivity, as shown in Scheme 2.21. Protection of the alco2.5.1.3

107

108


Bn

1) TBSOTf

Bn TiCl4, (-)-sparteine

O

N

2) LiBH4 O

H

N 3) Swern ox.

O

S

221

H

S

O

OH

O

OTBS

(83%)

223

222

O (83%, 98:2)

TiCl4,(-)-sparteine

Oi-Pr

221 O

(81%, 98:2)

226

KOt-Bu

Bn

ref. 74

CHO BrBu3P

O TMSO

(90%) Oi-Pr

OTBS

N S

O

OH

OTBS

224

225

O

TMSO O

OTBS 1) PPTS, H2O

227

2) TPAP O

3) HF-pyr (43%)

228

O

OH

Scheme 2.21

Synthesis of ()-callystatin A.

hol as the TBS ether, reductive removal of the chiral auxiliary, and Swern oxidation furnished aldehyde 223. Aldol reaction under similar conditions with oxazolidethione 221 gave the all-syn product 224 in 81% yield with 98% selectivity; this was then converted to 225. Wittig olefination with fragment 226 (synthesized from (S)-glycidol) gave olefin 227 which, on removal of the OTMS and isopropyl acetal protecting groups, perruthenate oxidation, and deprotection of the OTBS group gave ()-callystatin A. AI-77-B Ghosh and coworkers developed a convergent synthesis of ()-AI-77-B (237) in which all five stereogenic centers were set by asymmetric synthesis [75]. 2.5.1.4

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions

109

As in their previous work [76], four of those chiral centers were set using the aminoindanol-based syn and anti aldol methods discussed in Sections 2.4.1.2.3 and 2.4.2.2.1, respectively. AI-77-B is a natural product isolated from Bacillus pumilus with potent antiulcerogenic and anti-inflammatory properties. Anti aldol reaction of 229-derived titanium enolate with 4,4,4trichlorobutryaldehyde gave adduct 230 in 90% yield with 90% de; this was subsequently transformed to isocoumarin fragment 231, as shown in Scheme 2.22. Aldol reaction of 232-derived titanium enolate with benzyloxyacetaldehyde

OMe O TsNH

TsNH

O

O

OH

TiCl4, i-Pr2NEt O

O

OH

TiCl4, i-Pr2NEt O

231

230 TsNH

O

OBn OBn

O

ref. 75 HO 2C

BnOCH2CHO

232

Boc

ref. 75

(90%, 90%de)

TsNH

H N

O

Cl3(CH2)2CHO

229

O

CCl3

233

(97%)

NBoc O

234 a) TFA

b) 231, EDCI, DMAP (72%) OMe O

OMe O O

OBn

H N

CO 2Bn

NBoc

2) H2 / Pd-C DOWEX 50-X8 (75%)

O O

OH

H N O

Scheme 2.22

AI-77B synthesis.

NH2 CO 2H

237

OH

3) CsCO3, BnBr (90%)

OBn

H N

NBoc O

O

235

236 1) MgI2 (93%)

OH

O 2) NaClO2 (99%)

O

O

1) O3, PPh3 (98%)

110


provided syn adduct 233 in 97% yield as a single product; this was transformed into carboxylic acid 234 via Curtius rearrangement, stereoselective homologation after Dondoni’s procedure [77] and functional group manipulation. Deprotection of 231 and coupling with EDCI and DMAP gave amide 235. The allyl group was converted to benzyl ester 236 which, on demethylation with MgI2 and concomitant hydrogenolysis of the O-benzyl groups and isopropylidine deprotection, gave AI-77B. Key steps included stereoselective ester-derived asymmetric syn and anti aldol reactions, a regioselective Diels–Alder reaction, and Dondoni homologation. 2.5.2

Macrolide Natural Products

Titanium enolate aldol reactions have been used in the syntheses of several of important antitumor macrolides and of the immunosuppressive macrolide rapamycin. Duthaler’s titanium enolate acetate aldol reaction was used in the synthesis of epothilone 490. A variety of titanium enolate-based syn aldol reactions highlight the scope and utility of this technique. Epothilone 490 Danishefsky and coworkers reported a concise, convergent synthesis of epothilone 490 (243) with a key late-stage acetate aldol reaction [78]. Epothilone 490 is a natural product isolated from the cellulose-degrading bacterium Sorangium cellulosum which has potent Taxol-like microtubule-stabilizing induced cancer cytotoxicity. Known vinyl iodide 238 [79] was subjected to Stille coupling and acetylation to give acetate ester 239. Reaction with previously synthesized aldehyde 240 [80] using to Duthaler’s titanium enolate aldol method (discussed in Section 2.3.2) gave aldol 241 in 85% yield as a single diastereomer (Scheme 2.23). Deprotection of the OTroc group using zinc in acetic acid followed by ring closing metathesis using the Grubbs second generation catalyst 242 yielded epothilone 490 in 64% yield. 2.5.2.1

Cryptophycin B Ghosh and Bischoff reported an efficient and convergent synthesis of cryptophycin B (249) using their aminoindanol-derived syn aldol methodology (discussed in Section 2.4.1.2.3) [81]. Cryptophycin B (249), a marine natural product isolated from Nostoc sp. GSV 224, has potency at the picogram level against KB cells. Unsaturated ester 244-derived titanium enolate was subjected to an aldol reaction with 3-benzyloxypropionaldehyde to give syn product 245 in 98% yield as a single diastereomer, as shown in Scheme 2.24. Reductive removal of the chiral auxiliary then deoxygenation of the primary alcohol and protection of the remaining secondary alcohol furnished silyl ether 246. Conversion of the benzyloxy functionality to the a,bunsaturated ester moiety was accomplished by selective OBn deprotection, PCC oxidation, and Horner–Emmons olefination to yield ester 247 which 2.5.2.2

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions 1) Pd2dba3, PPh3 S

S O

CH2=CHSnBu3 (96%)

OTES N

111

N O

2) Bu4NF (92%)

238

239

3) Ac2O, Et 3N, DMAP (98%) I

a) LDA, Et2O b) CpTi(OR)2Cl c) O

O

OTroc

H

240

(85%) O

O

S

OH

1) Zn, AcOH (86%) 2) MesN

N

Cl O OH

243

Cl

(64%) NMes Ru PCy3

O S

OH N

242 O

Ph

OTroc

241

Scheme 2.23

Epothilone 490 synthesis.

was converted to compound 249. Exposure to trifluoroacetic acid to remove the N-Boc and O-tert-butyl protecting groups, then Yamaguchi cycloamidation gave the macrocycle which, on selective epoxidation with dimethyldioxirane, gave cryptophycin B in 22% overall yield over fourteen steps. Amphidinolide T1 Ghosh and Liu reported the first total synthesis of amphidinolide T1 (258), setting four of the seven stereogenic centers with their asymmetric aldol methodology (discussed in Section 2.4.1.2.3) [82]. Amphidinolide T1 is a marine natural product isolated from Amphidinium sp. with significant antitumor properties against a variety of cell lines. Aldol reaction of ester 250 with 3-benzyloxypropionaldehyde gave syn adduct 251 in 90% yield as a single diastereomer, as shown in Scheme 2.25. Ester 251 was then converted into tetrahydrofuran derivative 252 via Wittig olefination and olefin cross-metathesis. Aldol reaction of ester 253 with benzyloxyacetaldehyde gave exclusively syn aldol adduct 254 in 93% yield; this was transformed into alkene 255. Subsequent transformation yielded tetrahydrofuran derivative 256. This cyclic bromoether serves as masked functionality for the labile exocyclic 2.5.2.3

O


112 TsNH

TsNH

O

OH

O TiCl4, i-Pr2NEt

O 98%

244

OBn

O

BnO(CH2)2CHO

245

Ph

Ph

1) LiAlH4 (92%) 2) PhLi, TsCl, LiAlH4 (96%) 3) TIPSOTf, 2,6-lutidine (99%) 1) K2CO3, BBr3 (83%) 2) PCC (98%) Ph

CO 2Et

3)

OTIPS

O

(EtO) 3PC

247

OBn

Ph OTIPS

CO 2Et

246

NaH (92%) ref. 81

Ph

O

Ph O

O

1) TFA

O

t-BuO HN

O

O

2) Yamaguchi

HN

O

O O

O

248

3) O OMe

O

(87%, 3:1)

HN

O

O

N H

O

OMe

249

Boc

Scheme 2.24

Cryptophycin B synthesis.

methylene group in the final product. Stereoselective oxocarbenium ionmediated alkylation using a modification of Ley’s procedure [83] with DTBMP and AlCl3 gave coupled product 257 in 73% yield as a single diastereomer. Deprotection of the alcohol and ester moieties followed by Yamaguchi macrolactonization, and treatment with zinc and ammonium chloride afforded amphidinolide T1. Key steps included stereoselective aminoindanol-derived asymmetric aldol reactions, efficient olefin crossmetathesis, stereoselective oxocarbenium ion-mediated anomeric alkylation, and the use of the cyclic bromomethyl ether as a novel exo-methylene group surrogate. Rapamycin Danishefsky and coworkers published a total synthesis of rapamycin (260) using a novel aldol macrocyclization reaction as the key step [84]. Rapamycin is a natural product with immunosuppresive properties. The conclusion 2.5.2.4

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions

SO2Ph

TsNH

TsNH

O

O

OH

TiCl4, i-Pr2NEt BnO(CH2)2CHO (90%)

250

O

O O

TiCl4, i-Pr2NEt

OTBS

OBn

OH ref. 82 BnO

255

254

(93%)

CO2Bn

252

O

BnOCH2CHO

253

BnO

251 TsNH

TsNH

O

ref. 82

O

O

113

OTIPS

ref. 81 Br Br

DTBMP O O

O 1) HF-pyr (87%)

TBSO

OTBS

AlCl3, 252 O

(73%) OTBS

CO2Bn 257

2) H2/Pd-C 3) Yamaguchi (71%) OH 4) Zn, NH4Cl (61%) O

O O

O

258 Scheme 2.25

Amphidinolide T1 synthesis.

of the synthesis treats late-stage intermediate aldehyde 259 with isopropoxytitanium trichloride in the presence of triethylamine to generate the cyclized product in 11% yield, with 22% of another isomer (possibly the syn aldol product), as shown in Scheme 2.26. Deprotection of the TIPS ether afforded rapamycin. Spongistatins 1 and 2 Crimmins and coworkers published a convergent synthesis of spongistatin 1 (263a) and spongistatin 2 (263b), employing their phenylalanine-derived asymmetric aldol methodology (discussed in Section 2.4.1.2.1) to set one of the stereocenters [85]. Spongistatins 1 and 2 are natural products with subnanomolar growth inhibition of several NCI chemoresistant tumor types 2.5.2.5

256

114

2 The Development of Titanium Enolate-based Aldol Reactions OMe

OMe OTIPS

OH

H

N O

O H O

HO

H O

1) Ti(Oi-Pr)Cl3,

CHO

O MeO

N O

Et3N (11%) 2) HF-pyr (85%)

O

OMe

O

O

HO O

H

O H

O

O

OH MeO

O

OMe

H

259

260

Scheme 2.26

Rapamycin synthesis.

including human melanoma, lung, brain, and colon cancers. Aldol reaction of aldehyde 261 with N-propionyloxazolidinethione then reductive removal of the chiral auxiliary furnished diol 262 in 74% yield as a 96:4 ratio of stereoisomers, as shown in Scheme 2.27. This fragment was then incorporated into synthetic spongistatins 1 and 2. 2.5.3

Miscellaneous Natural Products

Several other natural products have been synthesized by using titanium enolate-based aldol methods. Many of these syntheses utilize ketone enolate aldol reactions to establish syn stereochemistry. Duthaler’s anti aldol reaction was used in the synthesis of tautomycin. Use of Evan’s ketone–aldol reaction was nicely exemplified in syntheses of denticulatin B and membrenone C. Tautomycin Chamberlin and coworkers reported a convergent synthesis of tautomycin (270), employing Duthaler’s anti aldol methodology, as discussed in Section 2.4.2.3, to set four of its stereogenic centers [86]. Tautomycin, a serine/ threonine selective protein pyrophosphatase inhibitor is selective for PP1 over PP2A. Reaction of aldehyde 265 with the enolate of 264, generated with LDA and transmetalated with Duthaler’s reagent (R ¼ diacetoneglucose) afforded compound 266 in 80% yield as an 8:1 mixture of anti and syn aldols, as shown in Scheme 2.28. Protection of the alcohol as the silyl ether and conversion of the ester gave iodide 267, which was converted to spirocyclic aldehyde 268. Aldehyde 268 which was reacted with the titanium 2.5.3.1

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions Bn N

O BnO

BnO O

O S 1) TiCl4, (-)-sparteine

O

CHO

TESO

O

O

TESO

2) LiBH4

OH

(74% 96:4)

OH

OTES

OTES

262

261

ref. 85 OH HO HO H

O

H

H

O

O HO

O OH O

X

O H

H O

OH

OMe

O

O

H

AcO OAc OH

263a: X = CI 263b: X = H Scheme 2.27

Spongistatin 1 and 2 synthesis.

enolate of ester 264 using Duthaler’s procedure to give anti aldol adduct 269 in 67% yield as a 7:1 mixture of the anti and syn isomers. Reaction of 269 provided synthetic tautomycin. Crocacin C Chakraborty and coworkers reported a synthesis of crocacin C (276) using asymmetric aldol methodology developed by Crimmins (Section 2.4.1.2.1) to set two of the four chiral centers [87]. Crocacin C is a natural product isolated from myxobacterium Chondromyces crocatus with potent growth inhibition of Gram-positive bacteria, fungi, and yeasts. Titanium enolate aldol reaction of phenylalanine-derived N-propionyloxazolidinethione 271 with cinnamaldehyde gave the syn aldol adduct 272 in 89% yield as a single dia2.5.3.2

115

116

2 The Development of Titanium Enolate-based Aldol Reactions O

O

LDA, CpTi(OR)2Cl

O

O

OHC

266

265

264

OH

(80%, 8:1)

1) TBSOTf, 2,6-lutidine (94%) 2) DIBALH 3) I2, PPh3 (85%) OTBS

O

OHC H

ref. 86

H

I

O

268

267

LDA, CpTi(OR)2Cl

264 (67%, 7:1) O

OH

O

O H

H

O

269 ref. 86 O

OH

O

O O

O

OH

OMe

O

OH

O H

O

H O

270

Scheme 2.28

Tautomycin synthesis.

stereomer; this was converted to allylic alcohol 273, as shown in Scheme 2.29. Sharpless asymmetric epoxidation provided epoxide 274 which was opened regio- and stereoselectively with lithium dimethylcuprate to provide diol 275 in 86% yield. Diol 275 was then transformed to the final product crocacin C. Stigmatellin A Enders and coworkers developed a synthesis stigmatellin A (281) using aldol reactions to set two of the four chiral centers [88]. Stigmatellin A is a natural product isolated from bacterium Stigmatella aurantica and is one 2.5.3.3

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions Bn

117

Bn TiCl4, i-Pr 2NEt

N O

Ph

O

N

PhCH=CHCHO

S

OH

(89%)

O

O S

272

271

ref. 87 Ti(Oi-Pr)4, (-)-DIPT, Ph

OH OMe

t-BuOOH

O

Ph

OH OMe

(93%)

274

273

Me2CuLi (86%)

Ph

OH OMe OH

275

ref. 87

Ph

CONH2 OMe OH

276

Scheme 2.29

Crocacin C synthesis.

of the most powerful electron-transport inhibitors in chloroplasts and mitochondria. Hydrazone 277 was alkylated with 3-( p-methoxyphenoxy)propyl iodide using their previously developed SAMP/RAMP methodology to provide hydrazone 278 in 80% yield with 98% de, as shown in Scheme 2.30 [89]. The chiral auxiliary was removed and the resulting ketone was subjected to an aldol reaction with benzyloxyacetaldehyde to give syn aldol adduct 279 in 64% yield as a 2:1 mixture of isomers. Ketone 279 was subjected to selective anti reduction using Evans’ procedure [72] and methylated to yield compound 280, which upon removal of the p-methoxyphenyl and benzyloxy groups gave stigmatellin A. Denticulatin B Paterson and Perkins developed a synthesis of denticulatin B (285) and its isomer denticulatin A using a late-stage aldol reaction [90]. Denticulatin B is a marine natural product isolated from the mollusk Siphoneria denticulata. Aldol coupling of ketone 282 and aldehyde 283 provided the syn aldol adduct 284 in 90% yield as a mixture of diastereomers, as shown in Scheme 2.31. Swern oxidation of the hydroxyl groups and deprotection and cyclization with HF–pyridine afforded denticulatin B in 20% overall yield over nine steps. 2.5.3.4

118

2 The Development of Titanium Enolate-based Aldol Reactions OMe N

OMe LDA

N

PMPO(CH2)3I

N PMP O

N

(80%, 98%de)

277

278

1) MMPP (87%) 2) TiCl4, i-PrNEt2 BnOCH2CHO (64%, 2:1)

OMe OMe

PMP O

O

1) Me4NHB(OAc)3 PMP O OBn (99%)

OH OBn

2) KH, MeI (77%)

280

279 ref. 88

OMe O OMe OMe MeO

O OH

281 Scheme 2.30

Stigmatellin A synthesis.

TiCl4, i-Pr2NEt

O

O

Si

t-Bu

O

H

OH

OH

283

t-Bu

282

O

284

O (90%, 83 : 17)

O t-Bu

Si

O t-Bu

1) Swern (100%) 2) HF-pyr (57%) OH H O O

O

285 OH Scheme 2.31

Denticulatin B synthesis.

OH

2.5 Natural Product Synthesis via Titanium Enolate Aldol Reactions TiCl 4, i-Pr2NEt BnO

OBn

BnO H

O

OBn O

286

O

287

OH

288 a) c-Hex 2BCl, Et3N

(70%, 95%de)

b) LiBH4 c) H2O2, pH 7 (88%, 95%de)

1) t-Bu2Si(OTf)2 2,6-lutidine (72%) H

H O

O

Si

t-Bu

O

O

t-Bu

290

2) H2/Pd-C (85%)

BnO

3) PCC (61%)

OBn OH

OH

289

TiCl 4, i-Pr2NEt 3-pentanone (90%, 90%de) O

1) Swern (100%) O 2) HF-pyr O

OH

O t-Bu

Si

O

OH

291 t-Bu

O

O

O

3) TFA (52%)

292

Scheme 2.32

Membrenone C synthesis.

Membrenone C Perkins and Sampson developed syntheses of membrenone C (292) and its isomers to establish the absolute configuration of the natural product [91]. Membrenone C is a natural product isolated from the skin of a Mediterranean mollusk. Aldol reaction of the stereochemically matched chiral ketone 286 and protected (R)-3-hydroxy-2-methylpropionaldehyde 287 gave aldol adduct 288 in 70% yield and 95% de, as shown in Scheme 2.32. Synselective reduction of the ketone was accomplished by using a modification of Narasaka’s procedure [92] to give diol 289 in 88% yield and 95% de. Protection of the diol as the cyclic silyl acetal followed by hydrogenolysis of the O-benzyl groups and PCC oxidation afforded dialdehyde 290. Double aldol reaction with 3-pentanone gave compound 291 with nine contiguous chiral centers in 90% yield and 90% de. The synthesis was completed by Swern oxidation of the free hydroxyl groups, removal of the silyl protecting group, and cyclization in the presence of trifluoroacetic acid. 2.5.3.5

119

120


2.6

Typical Experimental Procedures for Generation of Titanium Enolates 2.6.1

Experimental Procedures Titanium Enolate Formation by Transmetalation, Synthesis of syn Aldols (Thornton’s Procedure, Section 2.4.1.2.1). The lithium enolate was generated at 78 C with LDA in ether. Ti(Oi-Pr)3 Cl (1–3 equiv.) was added dropwise with stirring. The clear solution became brown–orange and was left to warm to 40 C over 1 h and then cooled to 78 C. Aldehyde (1.1 equiv.) was added rapidly by syringe and the reaction was left to warm to 40 C over 3 h. The reaction was quenched with saturated NH4 F and the layers were separated. The aqueous layer was extracted three times with ether. All organic layers were combined and dried over MgSO4 , followed by vacuum filtration and rotary evaporation to dryness. Purification by flash chromatography provided the major product. Ester-derived Titanium Enolate by Transmetalation, Synthesis of syn Aldols (Duthaler’s Procedure, Section 2.4.1.2.2). BuLi (6.2 mmol) is added at 20 C to a solution of i-Pr2 NH (1 mL, 7.07 mmol) in 30 mL of ether under argon. After 15 min the reaction mixture is cooled to 78 C and a solution of 2,6-dimethylphenyl propionate (1.0 g, 5.61 mmol) in 10 mL ether is added dropwise and stirred for 1.5 h. An ethereal solution of chlorocyclopentadienylbis(1,2:5,6-di-O-isopropylidene-a-d-glucofuranos-3O-yl)titanium (0.088 m, 80 mL; 7.04 mmol, 1.25 equiv.) is added carefully via a cannula under argon pressure. After stirring for 24 h the aldehyde (7.29 mmol, 1.3 equiv.) is added and the reaction is monitored by TLC. The reaction mixture is quenched with 2 g NH4 Cl and 10 mL 1:1 THFaH2 O. After stirring for 2 h at 0 C the precipitated titanium salts are separated by filtration and washed with ether. The filtrate is washed with 20 mL 1 m HCl, 10 mL satd NaHCO3 , and brine. The aqueous washings are re-extracted with 2 50 mL EtOAc. The combined organic extracts are dried over MgSO4 and the solvent is removed. The crude products are either separated directly by chromatography or by first stirring for 1 h with 200 mL 0.1 m HCl, extracted with ether (3 100 mL), and washed with sat. NaHCO3 and brine, removing glucose as the water soluble 1,2-acetonide. Ester-derived Titanium Enolate for anti Aldol Reactions (Ghosh’s Procedure, Section 2.4.2.2.1). N-tosylaminoindanol ester was reacted with TiCl 4 in CH2 Cl2 at 0–23 C for 15 min followed by addition of i-Pr2 NEt (4 equiv.) at 23 C and stirring of the resulting brown solution for 2 h. The titanium enolate was then added to the representative aldehyde (2 equiv.) precomplexed with TiCl 4 (2.2 equiv.) at 78 C and the mixture was stirred at 78 C for 2 h before quenching with aqueous NH4 Cl. The aqueous layer

2.7 Conclusion

was extracted with CH2 Cl2 . The combined organic extracts were washed with brine, dried over Na2 SO4 , and concentrated under reduced pressure. The crude products were purified by flash chromatography on silica gel. Oxazolidinethione-derived Titanium Enolate for syn Aldol Reactions (Crimmins’s Procedure, Section 2.4.1.2.1). To a dry round-bottomed flask under nitrogen was added 0.250 g (1.0 mmol) oxazolidinethione in 6 mL CH2 Cl2 . The solution was cooled to 0 C and TiCl 4 (1.05 mmol, 0.115 mL) was added dropwise and the solution was stirred for 5 min. To the yellow slurry or suspension was added ()-sparteine (2.5 mmol). The dark red enolate was stirred for 20 min at 0 C. Freshly distilled aldehyde (1.1 mmol) was added dropwise and the reaction stirred for 1 h at 0 C. The reaction was quenched with half-saturated NH4 Cl and the layers were separated. The organic layer was dried over Na2 SO4 , filtered, and concentrated. Purification of the crude material by column chromatography afforded the main diastereomer. 2.6.2

Alternative Approaches to Titanium Enolate Generation

Although the direct generation of titanium enolates is typically the most useful method of generating titanium enolates for aldol reactions, other methods have been described. Grubbs and Stille reported that titanium enolates could be generated by reaction of biscyclopentadienyltitanium alkylidene complexes and acyl halides [93]. Oshima and coworkers reported the formation of titanium enolates from a-iodoketones with allylsilane and titanium tetrachloride [94]. Mukaiyama and coworkers reported the generation of titanium enolates from a-bromoketones on treatment with TiCl2 and copper powder [95].

2.7

Conclusion

Titanium enolate aldol reactions have been shown to be very effective for control of relative and absolute stereochemistry in acetate aldol and both syn and anti aldol reactions. The use of readily available and inexpensive titanium reagents make these methods convenient for large-scale synthesis. The synthetic potential of a variety of aldol reactions has been demonstrated by highlighting the synthesis of numerous bioactive complex natural products. The significance of enantio- and diastereoselection in synthesis, particularly in this pharmaceutical age, ensures that titanium enolate aldol reactions will remain an important part of organic synthesis for years to come. There is no doubt that unprecedented success has been achieved in the development of a variety of titanium enolate aldol reactions in the past decade. Much new potential and other exciting possibilities remain to be

121

122


explored, however. We hope this chapter will stimulate further research and developments in titanium enolate-based aldol reactions and their use in organic synthesis. References 1 Lim, B.-M.; Williams, S. F.; Masamune, S. Comprehensive

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

20 21 22

23

Organic Synthesis; Trost, B. M.; Fleming, I. Eds; Pergamon Press: Oxford, 1991, Vol. 2, Heathcock, C. H., ed., Chapter 1.7, 239. The term ‘chiral auxiliary’ was first introduced by Eliel. Eliel, E. L.; Tetrahedron 1974, 30, 1503 and references cited therein. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chem. Int. Ed. Engl. 1977, 16, 585. Westley, J. W. Adv. Appl. Microbiol. 1977, 22, 177. Masamune, S.; Choy, W.; Petereson, J. S.; Sita, L. R. Angew. Chem. Int. Ed. Engl. 1985, 24, 1. Verhe´, R.; De Kimpe, N.; De Buyck, L.; Thierie, R.; Schamp, N. Bull. Soc. Chim. Belg. 1980, 89, 563. Yoshida, Y.; Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron Lett. 1997, 38, 8727. Yoshida, Y.; Matsumoto, N.; Hamasaki, R.; Tanabe, Y. Tetrahedron Lett. 1999, 40, 4227. Tanabe, Y.; Matsumoto, N.; Funakoshi, S.; Manta, N. Synlett 2001, 12, 1959. Yachi, K.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 1999, 121, 9465. Devant, R.; Braun, M. Chem. Ber. 1986, 119, 2191. Yan, T.; Hung, A.; Lee, H.; Chang, C.; Liu, W. J. Org. Chem. 1995, 60, 3301. Yan, T.; Hung, A.; Lee, H.; Liu, W.; Chang, C. J. Chinese Chem. Soc. 1995, 42, 691. Palomo, C.; Oiarbide, M.; Gonza´les, A.; Garcıá, J.; Berreé, F.; Linden, A. Tetrahedron Lett. 1996, 37, 6931. Phillips, A. J.; Guz, N. R. Org. Lett. 2002, 4, 2253. Gonza´lez, A´.; Aiguade´, J.; Urpı´, F.; Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker, M. Angew. Chem. Int. Ed. Engl. 1989, 28, 495. Cambie, R. C.; Coddington, J. M.; Milbank, J. B. J.; Pausler, M. G.; Rustenhover, J. J.; Rutledge, P. S.; Shaw, G. L.; Sinkovich, P. I. Australian J. Chem. 1993, 46, 583. Fringuelli, F.; Martinetti, E.; Piermatti, O.; Pizzo, F. Gazz. Chim. Ital. 1993, 123, 637. Fringuelli, F.; Piermatte, O.; Pizzo, F.; Scappini, A. M. Gazz. Chim. Ital. 1995, 125, 195. (a) Wang, Y.; Su, D.; Lin, C.; Tseng, H.; Li, C.; Yan, T. Tetrahedron Lett. 1999, 40, 3577. (b) Wang, Y.; Su, D.; Lin, C.; Tseng, H.; Li, C.; Yan, T. J. Org. Chem. 1999, 64, 6495. Wang, Y.; Yan, T. J. Org. Chem. 2000, 65, 6752.

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Illinois–Chicago. 26 Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691. 27 Harrison, C. Tetrahedron Lett. 1987, 28, 4135. 28 Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpı´, F. J. Am.

Chem. Soc. 1991, 113, 1047. 29 Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.;

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Phosphorus, Sulphur, and Silicon 1998, 136–138, 653. 31 Nakamura, S.; Hayakawa, T.; Nishi, T.; Watanabe, Y.; Toru,

T. Tetrahedron 2001, 57, 6703. 32 Reetz, M. T.; Steinbach, R.; Kesseler, K. Angew. Chem. Int.

Ed. Engl. 1982, 21, 864. 33 Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.

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27, 897. 35 Shirodkar, S.; Nerz-Stormes, M.; Thornton, E. R.

Tetrahedron Lett. 1990, 31, 4699. 36 Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56,

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1997, 119, 7883. 38 Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. 39 Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J. D.;

Silks, L. A. III. J. Am. Chem. Soc. 2000, 122, 386. 40 Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,

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457. 49 Ahn, K. H.; Yoo, D. J.; Kim, J. S. Tetrahedron Lett. 1992, 22,

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M. Helv. Chim. Acta 1990, 73, 659. 53 (a) Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691.

(b) Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135. (c) Panek, J. S.; Bula, O. A. Tetrahedron Lett. 1988, 29, 1661.

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2 The Development of Titanium Enolate-based Aldol Reactions 54 Mahrwald, R. Org. Lett. 2000, 2, 4011. 55 Siegel, C.; Thornton, E. R. Tetrahedron Lett. 1986, 27, 457. 56 Siegel, C.; Thornton, E. R. J. Am. Chem. Soc. 1989, 111,

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Tetrahedron Lett. 1997, 38, 1637. 58 Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.;

Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866. 59 Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am.

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1987, 28, 2037. 62 Annunziata, R.; Cinquini, M.; Cozzi, F.; Borgia, A. L.

J. Org. Chem. 1992, 57, 6339. 63 Kazmaier, U.; Grandel, R. Synlett 1995, 945. 64 Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527. 65 Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. 66 67 68 69 70 71 72

73

74 75 76 77

78

79 80

81 82

Tetrahedron Lett. 1997, 38, 7171. Fidanze, S. Ph.D. Thesis. University of Illinois–Chicago, 2000. Ghosh, A. K.; Kim, J. Unpublished results. Ghosh, A. K.; Kim, J. Org. Lett. 2003, 5, 1063. Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591. Duthaler, R. O.; Herlold, P.; Wyler-Helfer, S.; Riediker, M. Helv. Chim. Acta 1990, 73, 659. Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2, 2405. (a) Evans, D. A.; Chapman, K. T.; Carriera, E. M. J. Org. Chem. 1988, 53, 3560. (b) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939. Hu, T.; Schaus, J. V.; Lam, K.; Palfreyman, M. G.; Wuonola, M.; Gustafson, G.; Pankek, J. S. J. Org. Chem. 1998, 63, 2401. Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084. Ghosh, A. K.; Bischoff, A.; Cappiello, J. Eur. J. Org. Chem. 2003, 821. Ghosh, A. K.; Bischoff, A.; Cappiello, J. Org. Lett. 2001, 3, 2677. (a) Dondoni, A.; Perrone, D.; Semola, T. J. Org. Chem. 1995, 60, 7927. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. Synthesis 1988, 685. (c) Dondoni, A.; Fogagnolo, M.; Medici, A.; Pedrini, P. Tetrahedron Lett. 1985, 26, 5477. Biswas, K.; Lin, H.; Njardarson, J. T.; Chappel, M. D.; Chou, T.; Guan, Y.; Tong, W. P.; He, Lifeng; Horwitz, S. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9825. Chappell, M. D.; Stachel, S. J.; Lee, C. B.; Danishefsky, S. J. Org. Lett. 2000, 2, 1633. (a) Lee, C. B.; Wu, Z.; Zhang, F.; Chappell, M. D.; Stachel, S. J.; Chou, T. C.; Guan, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 5249. (b) Wu, Z.; Zhang, F.; Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 2000, 39, 4505. Ghosh, A. K.; Bischoff, A. Org. Lett. 2000, 2, 1753. Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374.

References 83 Ley, S. V.; Lygo, B.; Wonnacott, A. Tetrahedron Lett. 1989, 26,

535. 84 Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am.

Chem. Soc. 1993, 115, 9345. 85 Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein,

S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661. 86 Sheppeck, J. E. II; Liu, W.; Chamerlin, A. R. J. Org. Chem.

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2001, 57, 9461. 88 Enders, D.; Geibel, G.; Osborne, S. Chem. Eur. J. 2000, 6,

1302. 89 (a) Enders, D. in Asymmetric Synthesis, Vol 3 (J. D. Morrison,

90 91 92

93 94 95

Ed.), Academic Press, Orlando, 1984, 275. (b) Enders, D. Chem. Scripta 1985, 65, 139. (c) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173, 183. Paterson, I.; Perkins, M. V. Tetrahedron, 1996, 52, 1811. Perkins, M. V.; Sampson, R. A. Org. Lett. 2001, 3, 123. (a) Narasaka, K.; Pai, F. Tetrahedron 1984, 40, 2233. (b) Patterson, I.; Donghi, M.; Gerlach, K. Angew. Chem. Int. Ed. Engl. 2000, 39, 3315. Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1983, 105, 1664. Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 4558. Mukaiyama, T.; Kagayama, A.; Igarashi, K.; Shiina, I. Chem. Lett. 1999, 1157.

125

127

3

Boron and Silicon Enolates in Crossed Aldol Reaction Teruaki Mukaiyama and Jun-ichi Matsuo 3.1

Introduction

Metal enolates play an important role in organic synthesis and metal enolate-mediated aldol type reactions, in particular, are very useful synthetic tools in stereoselective and asymmetric carbon–carbon bond formation. Generation and reactions of different metal enolates have been extensively studied and successful applications to the controlled formation of carbon– carbon bonds have been realized under mild conditions. The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in which basic media are usually employed, dimers, polymers, self-condensation products, or a,b-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the well-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon–carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates– Lewis acids (1973), and tin(II) enolates (1982). Here we describe the first two topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 3.2

Crossed Aldol Reactions Using Boron Enolates 3.2.1

Discovery of Aldol Reaction Mediated by Boron Enolates

First, the background of how we first conceived the idea of using boron enolate (vinyloxyboranes) in aldol reactions is described. At the beginning of the 1970s, several reactions were being screened by utilizing characteristics of alkylthioboranes based on the concept of elements in combination, i.e. two elements in combination, create a novel reactivity different from when Modern Aldol Reactions. Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

128

3 Boron and Silicon Enolates in Crossed Aldol Reaction

(CH3)2CO hν

OH O

H 2O

H2C C O + Bu2B SBu 1 2

SBu 4

SBu H2C C 3

SBu

Scheme 3.1

Unexpected formation of b-hydroxy thioester 4 on reaction of ketene 1 with thioborane 2.

they are used separately. When ketene 1 was mixed with two moles of butylthioborane 2, which we assumed would result in the formation of ketene thioacetal 3, S-butyl 3-hydroxy-3-methylbutanethiolate 4 was unexpectedly obtained (Scheme 3.1). It was difficult at first to discover the mechanism of this reaction, but the product soon indicated the participation of acetone in this reaction. In the experiment, ketene 1 is generated by degradation of acetone under irradiation; a small amount of acetone is, therefore, introduced into the reaction mixture. Thus b-hydroxy thioester 4 is afforded by reaction of the three components acetone, ketene 1, and alkylthioborane 2. When a gaseous ketene 1, free form acetone, is introduced into the mixture of alkylthioborane 2 and carbonyl compound, the expected b-hydroxy thioesters 5 are obtained in high yield (Eq. (1)) [1].

RCHO +

1

OH O

H2O

H2C C O + Bu2B SBu

R

2

SBu

ð1Þ

5

Investigation of this mechanism reveals that the key intermediate of this reaction is vinyloxyborane (boron enolate) 7 generated from ketene 1 and alkylthioborane 6 (Eq. (2)) [2]. Thus, our original study on organothioboranes led us, unexpectedly, to discover the widely utilized aldol reactions via boron enolates [3]. OBBu2 Bu2B SPh + H2C C O 6 1

H 2C SPh vinyloxyborane 7

ð2Þ Me2CO

O

Bu Bu B O SPh

OH O SPh

3.2 Crossed Aldol Reactions Using Boron Enolates

3.2.2

New Method for Direct Generation of Boron Enolates

Direct generation of boron enolates from parent carbonyl compounds had been desired to expand the synthetic utility of the boron enolate-mediated aldol reaction. Although several synthetic methods to generate vinyloxyboranes (boron enolates) were reported [3–5] no useful ones for direct generation of boron enolates from parent carbonyl compounds were known until 1976. After discovering the above-mentioned aldol reaction via boron enolates we had been exploring a useful method for direct generation of boron enolates from parent carbonyl compounds. It was then thought that increasing the Lewis acidity of boron by introducing an excellent leaving group on to boron would result in an increase in acidity of the carbonyl compounds by coordination of a carbonyl group to the boron compound; the corresponding boron enolate would then be formed by abstraction of the a-proton of the carbonyl compound with a weak base such as tertiary amine. The trifluoromethanesulfonyloxy (triflate, TfO) group was chosen as the leaving group, and dibutylboryl triflate 8 was found to generate boron enolates 9 by the reaction with ketones in the presence of a weak base such as N-diisopropylethylamine or 2,6-lutidine (Eq. (3)) [6]. This is the first example of the use of a metal triflate in synthetic chemistry; a variety of metal triflates are now known to be versatile Lewis acids in organic synthesis. Subsequent addition of aldehydes afforded the corresponding aldols 10 in good yields. Thus, the crossed aldol reaction which starts from ketone and aldehyde is performed easily by applying dialkylboryl triflate under mild reaction conditions.

O R1

Bu2BOTf 8 i-Pr2NEt

OBBu2

O

R2CHO

OH

R1

R1 9

R2

ð3Þ

10

After our first report, this aldol reaction has been investigated in detail by many research groups [3]. It is currently understood that the boron enolatemediated aldol reaction proceeds via a more rigid chair-like six-membered transition state (12 or 15) than those of alkali metal enolates, because of a shorter bond length between boron and oxygen (Figure 3.1), that is, dialkylboron enolates have relatively short metal–ligand and metal–oxygen bonds, which are suited to maximizing 1,3-diaxial (R3 –L) interactions in the transition states. This facilitates the formation of more stable transition states (12 and 15), where R3 occupies a pseudoequatorial position, when vinyloxyboranes (11 and 14) react with aldehydes to afford aldol adducts (13 and 16) stereoselectively. Therefore, aldol reactions via boron enolates give aldol adducts more stereoselectively than those via alkali metal enolates such as lithium enolates. This stereoselective aldol reaction is thus an outstanding method for the stereoselective synthesis of acyclic compounds.

129

130

3 Boron and Silicon Enolates in Crossed Aldol Reaction

O OBL2 R

R1

2

H

H R

R

L O

R1 O

3 3

B

L

R2

R3

R1

O

11 (Z )-enolate

OH R2 13 syn

12

O OBL2

H

H

R3

R1 R2

2

R 14 (E )-enolate

R3

L R1 O

B

O L

OH R3

R1

O

R2 16 anti

15

Fig. 3.1

Stereoselective aldol reaction of (Z) or (E) boron enolates and aldehydes.

3.2.3

Regioselectivity on Generation of Boron Enolates

Regioselective formation of boron enolates is conducted by using a-halo[3–5], a-diazo- [3], or a,b-unsaturated ketones [3] but their direct generation from parent carbonyl compounds is a more important and synthetically useful method. The regioselectivity on generation of the boron enolate is controlled by the reaction conditions. The kinetic boron enolate of 2-pentanone 17 is formed by use of dibutylboryl triflate 8 and N-diisopropylethylamine at 78 C in a short reaction time [6a], whereas the thermodynamic enolate 18 is predominantly generated by the use of 9-BBNOTf 19 and 2,6lutidine at 78 C in a long reaction time (Figure 3.2) [6b]. Subsequent aldol reactions of boron enolates with aldehydes proceed without loss of regiochemical integrity, but the reactions with ketones proceed slowly and the regiochemical integrity of an aldol product does not reflect that of an enolate. Preparation of Dibutylboryl Triflate 8 (Eq. (4)) [6c, 7] Bu3B + TfOH

OB

18

Bu2BOTf 8

BOTf 19

ð4Þ

O

2,6-lutidine –78 °C, 16 h

Fig. 3.2

Regioselective generation of boron enolates.

Bu2BOTf 8 i-Pr2NEt –78 °C, 15 min

OBBu2

17

3.2 Crossed Aldol Reactions Using Boron Enolates

A small amount of trifluoromethanesulfonic acid (1.0 g) was added to tributylborane (15.16 g, 83.3 mmol) at room temperature under argon. The mixture was stirred and warmed to 50 C until evolution of butane began (there is an induction period). After cooling of the mixture to 25 C the remaining trifluoromethanesulfonic acid (11.51 g, total 83.3 mmol) was added dropwise at such a rate as to maintain a temperature between 25 and 50 C. The mixture was then stirred for further 3 h at 25 C. Distillation under reduced pressure gave pure dibutylboryl triflate 8 (19.15 g, 84%; bp 60 C/ 2 mmHg). Preparation of 9-BBN Triflate 19 (Eq. (5)) [6c] BH + TfOH

BOTf

ð5Þ

19

Trifluoromethanesulfonic acid (18.75 g, 125 mmol) was added to 9-BBN (15.33 g, 127 mmol) in hexane (100 mL) under argon. After overnight stirring the reaction mixture was concentrated and distilled in vacuo to afford 9-BBNOTf 19 (38 C/0.03 mmHg, 28.84 g, 85%). 3.2.4

Stereoselective Formation of (E) or (Z) Boron Enolates

To obtain either syn or anti aldol adducts selectively it is important to generate boron enolates with the appropriate geometry (E or Z), that is, (Z) enolates 11 react with a variety of aldehydes to yield predominantly syn aldols 13, whereas (E) enolates 14 react somewhat less stereoselectively to give anti aldol adducts 16 as the major products (Figure 3.1 and Table 3.1). (E) Boron ketone enolates 20 are generated from a hindered dialkylboryl triflate (e.g. dicyclohexyl) and diisopropylethylamine at 0 C whereas the (Z) isomer 21 is prepared by using a less hindered boryl triflate (e.g. dibutyl) at 78 C (Figure 3.3) [8]. (Z) Ester boron enolates 22 [9] are selectively generated by using Bu2 BOTf and i-Pr2 NEt when the methyl or ethyl esters are employed, whereas (E) ester boron enolates 23 [9] are also selectively generated by using cHex2 BOTf and Et3 N when the tert-butyl ester is employed (Figure 3.4) [10]. Preparation of Dicyclohexylboryl Triflate (Eq. (6)) [11] c-Hex2BH + TfOH

c-Hex2BOTf

ð6Þ

A 250-mL round-bottomed flask capped with a rubber septum, containing a magnetic stirring bar and a connecting tube attached to a mercury bubbler was kept at 0 C and charged with hexane (100 mL) and c-Hex2 BH (26.7 g,

131

132

3 Boron and Silicon Enolates in Crossed Aldol Reaction Tab. 3.1

Stereoselective formation of syn and anti aldols via (Z) and (E) boron enolates. O

OBBu2 R2

+

R1

Ph

OH O H

Ph

OH O R

1

+

R1

Ph

2

R2

R syn

Boron Enolate

syn/anti

Ref.

>95:5

7a

OBBu2 Me

Boron Enolate a

syn/anti

Ref.

>97:3

8a

>97:3

8a

OBBu2

Z OBBu2 Me

anti

t-Bu Z:E = >99:1 OBBu2

25:75

7a

Ph Z:E = 99:1

E OBBu2 OBBu2 Et Z :E = >97:3

8a

98:2

7c

O

Bu2BO

18:82

8a

Z:E = 19:81

N

O

Z:E = >97:3

OB(c-C5H9)2 c-Hex

10:90

Z:E = 97:3

a The

14:86

7b

highest priority designation is assigned to the OBR2 group with enolate substituents.

Z:E = 12:88

150 mmol). Trifluoromethanesulfonic acid (13.3 mL, 150 mmol) was added dropwise using a syringe with constant stirring. Hydrogen is rapidly evolved and should be safely vented. The stirring was continued at 0 C for 2–3 h. All the suspended solid c-Hex2 BH dissolved and the homogeneous reaction mixture was left at 0 C for 1–2 h without stirring. Two layers were obtained and the top layer was transferred into a dry 250-mL round-bottomed flask

OB(c-Hex)2 c-Hex2BOTf R (E )-20 R = i-Pr E:Z = 81:19

i-Pr2NEt 0 °C, 30 min

O R

Bu2BOTf i-Pr2NEt –78 °C, 30 min

Fig. 3.3

Stereoselective formation of (Z) or (E) boron enolates of ketones.

OBBu2 R (Z )-21 R = Et E:Z = 20:1

77

3:1

62

>20:1

38

1.7:1

95

1.5:1

OH

147b 20% ee O

OH

OH

148a >99% ee OH

85

146b OH

OH

O

dr (anti/syn)

OH

O

147a 95% ee O

Yield %

145b 89% ee

OH

146a 97% ee OH

R' R 144-150

144b 76% ee O OH

145a 86% ee O

R

OH

148b O

OH

OH 149b 84% ee OH Cl O

OH

OH

150a 67% ee

150b 32% ee

Scheme 4.29

Examples of proline-catalyzed intermolecular aldolization with ketone donors other than acetone.

183

184

4 Amine-catalyzed Aldol Reactions

(anti)-diastereoselectivity can be achieved in such reactions (Scheme 4.29) [30, 31, 125]. Interestingly, the stereoselectivity of reactions of cyclohexanone with isobutyraldehyde and benzaldehyde were first predicted by using density functional theory calculations on models based on Houk’s calculated transition state of the Hajos–Parrish–Eder–Sauer–Wiechert reaction [125]. The transition states of inter- and intramolecular aldol reactions are almost superimposable and readily explain the observed enantiofacial selectivity. Relative transition state energies were then used to predict the diastereo- and enantioselectivity of the proline-catalyzed reactions of cyclohexanone with isobutyraldehyde and benzaldehyde. The predictions are compared with the experimental results in Scheme 4.30. The good agreement clearly validates the theoretical studies, and provides support for the proposed mechanism. Additional density functional theory calculation also support a similar mechanism [126, 127]. The exceptionally high stereoselectivity found in proline-catalyzed aldol reactions involving hydroxyacetone has recently been used in a total synthesis of brassinolide (156), a steroidal plant-growth regulator [128]. Readily available aldehyde 151 underwent proline-catalyzed aldolization with hyO H

H O

NO O H R

H

O

OH

H O

O

HO N O OH R

R

OH

R

R

R = i-Pr

98.5% (>99%)

87%) were obtained in good yields (46–76%). Acceptance of the non-natural N-levulinoyl d-mannosamine 22, containing a ketone moiety in the N-acyl group, by the cellular machinery in vivo has been used to produce cell-surface oligosaccharides modified in their neuraminic acid constituents (Figure 5.15) [106, 107]. The reactive ketone groups thus produced on the cell surface could then be used for versatile covalent cell redecoration under physiological conditions, for example by

O

cell

216

5 Enzyme-catalyzed Aldol Additions

O OH OH

O OH

HO

23

HO

HO HO

O CO2H

HO OH

F

HO

O CO2H

HO

25

OH

OH

O CO2H

R

OH

2

OH

24

HO

CO2H

OH OH

OH

KdoA

+

OH

HO OH O CO2H

HO

ent-5

OH

Fig. 5.16

Natural substrates of the 2-keto-3-deoxymanno-octosonic acid aldolase, and nonnatural sialic acids obtained by KdoA catalysis.

attaching functional nucleophiles (Nu*) such as fluorescent hydrazine markers or toxin conjugates. 5.3.2

KDO Aldolase

The functionally related 2-keto-3-deoxy-manno-octosonate (KDO) aldolase (KdoA; correctly termed 3-deoxy-d-manno-octulosonic acid aldolase, EC 4.1.2.23) is involved in the catabolism of the eight-carbon sugar d-KDO ent5, a core constituent of the capsular polysaccharides (K-antigens) and outer membrane lipopolysaccharides (LPS, endotoxin) of Gram-negative bacteria [108], and of the cell wall of algae and a variety of plants [109]. The aldolase, which reversibly degrades ent-5 to d-arabinose 23 and pyruvate (Figure 5.16), has been isolated from Aerobacter cloacae, E. coli, and an Aureobacterium barkerei strain in which the enzyme seems to be located in the cell wall or membrane fraction [110]. Partially purified KdoA preparations have been studied for synthetic applications [101, 111]; these studies have shown that, similar to NeuA, the enzyme has a broad substrate specificity for aldoses (Table 5.2) whereas pyruvate was found to be irreplaceable. As a notable distinction, KdoA was also active on smaller acceptors such as glyceraldehyde. Preparative applications, e.g. that for the synthesis of KDO (ent-5) and its homologs or analogs 24/25, suffer from a less attractive equilibrium constant of 13 m1 in direction of synthesis [56]. The stereochemical course of aldol additions generally seems to adhere to re-face attack on the aldehyde carbonyl which is complementary to that of NeuA. On the basis of the results published so far it can be concluded that a (3R) configuration is necessary (but not sufficient), and that stereochemical requirements at C-2 are less stringent

5.3 Pyruvate Aldolases Tab. 5.2

Substrate tolerance of 2-keto-3-deoxy-manno-octosonic acid aldolase [101]. OH

O

R3

H R

2

R

R1 R3

KdoA

R2 HO

pyruvate

1

O CO2H OH

Substrate

R1

R2

R3

Yield [%]

Rel. Rate [%]

d-Altrose l-Mannose d-Arabinose d-Ribose 2-Deoxy-2-fluoro-d-ribose 2-Deoxy-d-ribose 5-Azido-2,5-dideoxy-d-ribose d-Threose d-Erythrose d-Glyceraldehyde l-Glyceraldehyde

OH H OH H F H H OH H H OH

H OH H OH H H H H OH OH H

(RR)-(CHOH)2 aCH2 OH (SS)-(CHOH)2 aCH2 OH (R)-CHOHaCH2 OH (R)-CHOHaCH2 OH (R)-CHOHaCH2 OH (R)-CHOHaCH2 OH (R)-CHOHaCH2 N3 CH2 OH CH2 OH H H

– 61 67 57 19 47 – – 39 11 –

25 15 100 72 46 71 15 128 93 23 36

[101]. For simple product recovery excess pyruvate can be decomposed with pyruvate decarboxylase. 5.3.3

DAHP Synthase

In the biosynthesis of aromatic amino acids in microorganisms and plants, 3-deoxy-d-arabino-heptulosonic acid 7-phosphate synthase (DAHP synthase or AroS; EC 4.1.2.15) is a pivotal enzyme for carbon framework construction. The enzyme transfers a pyruvate moiety from phosphoenolpyruvate (PEP) to d-erythrose-4-phosphate (Ery4P) in an aldol-like reaction [112, 113]. Use of the activated donor renders formation of DAHP (26), the key metabolic intermediate, practically irreversible (Figure 5.17). The AroS enzyme has been purified from E. coli [114] and Streptomyces rimosus [115] and has been cloned from E. coli, Salmonella typhimurium, and potato [116, 117]. The structure of an E. coli isozyme has been determined in a complex with PEP at high resolution [118]. The cytosolic AroS isoenzyme prevalent in higher plants has been reported to be remarkably highly tolerant of acceptor substrates, including glyoxalate, glycolaldehyde, and most 3–5-carbon sugars or their phosphates [119]. For synthesis of 26 (Figure 5.17), an immobilized enzyme system was set up to generate the labile acceptor aldehyde in situ by ketol transfer from dfructose 6-phosphate [120]. The twofold driving force from PEP used in the integrated scheme as both a phosphoryl and aldol donor secured complete

217

218


D-fructose 6-phosphate

D-sedoheptulose 7-phosphate

transketolase

OH

D-ribose 5-phosphate

=O

3PO

H

OPO3=

Pi

PEP

O

HO HO

AroS

O

OH

OH

D-erythrose 4-phosphate

CO2H

HO CO2H

HO

OH OH

27

HO

26, DAHP

85%

CO2H

OH OH

CO2H

28

OH

OH

OH

OH

OH

29

30

Fig. 5.17

Multi-enzymatic scheme for synthesis of 3-deoxy-arabinoheptulosonic acid 7-phosphate based on the catalysis of DAHP synthase, and products generated consecutively in vivo by advanced microbial pathway engineering.

conversion of the starting material. Generally, synthesis of 26 on a larger scale is more efficient and economical by using engineered whole cells that contain a plasmid coding for AroS [121]; thereby necessary substrates and enzymes are intrinsically provided by regular cell metabolism. Similar elaborate schemes have been designed to produce quinic acid (27) [122], shikimic acid (28) [123], cyclohexadiene trans-diols, for example 29 [208], or phenols such as 30 [124–126] by engineered microbial biosynthesis. Purified enzyme from Escherichia coli has been studied for its reactivity with homologous five-carbon phosphosugars to yield KDO derivatives, and with modified nucleophiles. Thus, the stereochemically distinct fluoro-analogs of PEP (Z)- and (E)-31 could be separately condensed with d-erythrose 4-phosphate to yield, stereospecifically, the corresponding (3S)and (3R)-configured, fluoro-substituted DAHP derivatives 32 and 33, respectively (Figure 5.18) [127]. This provides direct evidence that the enzyme catalyzes si face addition of the C-3 of PEP to the re face of the acceptor aldehyde. 5.3.4

KDPG Aldolase and Related Enzymes

An aldolase specific for cleavage of 2-keto-3-deoxy-6-phospho-d-gluconate (35) (KDPGlc aldolase or KdgA; EC 4.1.2.14) is produced by many species of bacteria for degradation of 6-phosphogluconate to give pyruvate and d-

5.3 Pyruvate Aldolases

OPO3=

HO

OPO3=

OPO3= F O

CO2H

HO

CO2H

F

F

HO

O

F

CO2H

OPO3=

E-31

(3R)-32

Z-31

219

OH

CO2H

HO

OH

(3S)-33

Fig. 5.18

Stereospecific conversion of 3-fluoro-labeled PEP analogs to substituted DAHP derivatives by use of DAHP synthase.

KDPGlc aldolase

OH =

=O

3PO

CO2H

S

+

3PO

O

HO

2 OH

OH =O

KDPGal aldolase

3PO

R

OH

=

O CO2H

O3PO HO

35 O

Aldol reactions catalyzed in vivo by the 2-keto-3-deoxy-6-phospho-d-gluconate and 2-keto-3-deoxy-6-phospho-d-galactonate aldolases.

glyceraldehyde 3-phosphate 34 (Figure 5.19). The equilibrium constant favors synthesis (10 3 m1 ) [128]. Enzymes belonging to class I aldolases have been isolated [129–131] and cloned [132–135] from a variety of microbial sources. Genome sequencing of E. coli revealed that the enzyme is identical with 2-keto-4-hydroxyglutarate aldolase (KHG aldolase or KhgA; EC 4.1.3.16), which is involved in the catabolism of hydroxyproline [136, 137]. This activity is responsible for the retroaldolization of 4-hydroxy-2-oxoglutaric acid to pyruvate 2 and glyoxalate. In both cases, the enzyme recognizes an identical (4S) configuration. Enzyme preparations from liver or microbial sources were reported to have rather high substrate specificity [138] for the natural phosphorylated acceptor d-34 and, but at much reduced reaction rates, to have rather broad substrate tolerance for polar, short-chain aldehydes (Table 5.3) [139–141]. Simple aliphatic or aromatic aldehydes are not converted. High stereoselectivity of the enzyme has been used in the preparation of compounds 39 and 40 and in a two-step enzymatic synthesis of 38, the N-terminal amino acid portion of nikkomycin antibiotics (Figure 5.20) [142]. Thermophilic KdgA from Thermotoga maritima has been shown to have substrate tolerance with

OH CO2H

R

Fig. 5.19

OH CO2H

S

OH

O H

34

O3PO

=O

O

36


220

Tab. 5.3

Substrate tolerance of 2-keto-3-deoxy-6-phospho-d-gluconate aldolase [140]. O R

H

O COOH

Substrate

R

Rel. Rate [%]

d-Glyceraldehyde 3-phosphate 3-Nitropropanal Chloroethanal d-Glyceraldehyde d-Lactaldehyde d-Ribose 5-phosphate Erythrose Glycolaldehyde

d-CH2 OHaCH2 OPO3 ¼ CH2 aCH2 NO2 CH2 Cl d-CHOHaCH2 OH d-CHOHaCH3 d-ribo-(CHOH)3 aCH2 OPO3 ¼ erythro-(CHOH)2 aCH2 OH CH2 OH

100.0 1.6 1.0 0.8 0.2 0.04 0.01 0.01

H

NH3

pyruvate

CO2H

N

O

37

R

pyruvate

KDPGlc aldolase N

OH

KDPGlc aldolase

OH

O

NADH

CO2H

N

PheDH NAD+

38

OH

NH2

ee >99.7% CO2 OH O

CO2H

S

HO

OH

H 3C S

HO

39

O

formate DH HCO2–

OH CO2H

40

Fig. 5.20

Stereoselective synthesis of the amino acid portion of nikkomycin antibiotics and hexulosonic acids using KDPGlc aldolase.

a breadth that seems comparable to, but qualitatively distinct from, that of mesophilic enzymes, although with diminished stereoselectivity [135]. The aldolase from E. coli has been mutated for improved acceptance of non-phosphorylated and enantiomeric substrates towards facilitated enzymatic syntheses of both d and l sugars [143, 144]. Comparable with the situation for the sialic acid and KDO lyases (vide supra), a class I lyase complementary to the KDPGlc aldolase is known that has a stereopreference for the (4S) configuration (Figure 5.19). The aldolase, which acts on 2-keto-3-deoxy-6-phospho-d-galactonate (36) (KDPGal aldolase; EC 4.1.2.21) and is less abundant [145, 146], has recently been studied for synthetic applications [147].

5.4 Dihydroxyacetone Phosphate Aldolases

O X

O

H

OPO3=

OH OH

=O

3PO

OH

O OPO3=

HO

HO

FruA

RhuA

3S,4R 3R,4S

3PO

OH

O

HO

O OPO3=

HO

OPO3= HO

OH H 3C

42

D-fructose 1,6-bisphosphate

=O

41

HO

43

L-rhamnulose 1-phosphate

TagA

FucA

OH

3S,4S 3R,4R

44

D-tagatose 1,6-bisphosphate

O OPO3=

H 3C HO

HO

45

L-fuculose 1-phosphate

Fig. 5.21

Aldol reactions catalyzed in vivo by the four stereo-complementary dihydroxyacetone phosphate-dependent aldolases.

5.4

Dihydroxyacetone Phosphate Aldolases

Whereas pyruvate aldolases form only a single stereogenic center, the aldolases specific for dihydroxyacetone phosphate (DHAP, 41) as a nucleophile create two new asymmetric centers at the termini of the new CaC bond. Particularly useful for synthetic applications is that Nature has evolved a full set of four unique aldolases (Figure 5.21) to cleave all possible stereochemical permutations of the vicinal diol at C-3/C-4 of ketose 1-phosphates 42–45 during the retro-aldol cleavage [26]. These aldolases have proved to be exceptionally powerful tools for asymmetric synthesis, particularly stereocontrolled synthesis of polyoxygenated compounds, because of their relaxed substrate specificity, high level of stereocontrol, and commercial availability. In the direction of synthesis this situation formally enables generation of all four possible stereoisomers of a desired product in building-block fashion [22, 25, 26]. In this manner the deliberate preparation of a specific target molecule can be addressed simply by choosing the corresponding enzyme and suitable starting material, affording full control over constitution and absolute and relative configuration of the desired product. Alternatively, the stereocomplementary nature of enzymes also enables a combinatorial, stereodivergent approach (Figure 5.1) to the generation of all stereoisomers in a

221

222 =

O3PO


O HO HO

OH OPO3=

42

OH

O

FruA

OPO3=

HO

+

41

OPO3=

O

34

Fig. 5.22

Natural glycolytic substrates of fructose 1,6-bisphosphate aldolases.

small parallel library of diastereoisomers, e.g. for bioactivity screening [25]. Properties of the individual enzymes are therefore discussed separately from more general treatment of their preparative applications. The DHAP aldolases are quite specific for the phosphorylated nucleophile 41, which must therefore be prepared independently or generated in situ (cf. Section 5.4.4). Initial aldol products will thus contain a phosphate ester moiety, which facilitates product isolation, for example by barium salt precipitation or by use of ion-exchange techniques. The corresponding phosphate free compounds can be easily obtained by mild enzymatic hydrolysis using an inexpensive alkaline phosphatase at pH 8–9 [148], whereas baselabile compounds might require working at pH 5–6 using a more expensive acid phosphatase [149]. 5.4.1

FruA

The d-fructose 1,6-bisphosphate aldolase (FruA; EC 4.1.2.13) catalyzes, in vivo, the equilibrium addition of 41 to d-glyceraldehyde 3-phosphate (GA3P, 34) to give d-fructose 1,6-bisphosphate (42). The equilibrium constant for this reaction of 10 4 m1 strongly favors synthesis [56]. The enzyme occurs ubiquitously and has been isolated from a variety of prokaryotic and eukaryotic sources, both as class I and class II forms [29]. Corresponding FruA genes have been cloned from a variety of sources and overexpressed [25]. Typically, class I FruA enzymes are tetrameric whereas the class II FruA are dimers, with subunits of @40 kDa. The microbial class II aldolases are usually much more stable in solution (half-lives of several weeks to months) than their mammalian counterparts of class I (a few days) [149–151]. The class I FruA isolated from rabbit muscle (‘‘RAMA’’) is the aldolase used for preparative synthesis in the widest sense, because of its commercial availability and useful specific activity of @20 U mg1 . Its operating stability in solution is limiting, but recently more robust homologous enzymes have been cloned, e.g. from Staphylococcus carnosus [152] or from the extremophilic Thermus aquaticus [153], which promise to be unusually stable in synthetic applications [154]. Attempts at catalyst immobilization have been performed with rabbit muscle FruA, which has been covalently attached to microcarrier beads [58], cross-linked in enzyme crystals (CLEC) [59], or enclosed in a dialysis membrane [73]. It was recently shown that

5.4 Dihydroxyacetone Phosphate Aldolases Tab. 5.4

Substrate tolerance of fructose 1,6-bisphosphate aldolase. O R

OH

FruA H

DHAP

O OPO3=

R OH

R

Rel. Rate [%]

Yield [%]

Ref.

d-CHOHaCH2 OPO3 ¼ H CH3 CH2 Cl CH2 aCH3 CH2 aCH2 aCOOH CH2 OCH2 C6 H5 d-CH(OCH3 )aCH2 OH CH2 OH d-CHOHaCH3 l-CHOHaCH3 dl-CHOHaC2 H5 CH2 aCH2 OH CH2 aC(CH3 )2 OH dl-CHOHaCH2 F dl-CHOHaCH2 Cl dl-CHOHaCH2 aCHbCH2

100 105 120 340 105 – 25 22 33 10 10 10 – – – – –

95 – – 50 73 81 75 56 84 87 80 82 83 50 95 90 85

149, 177 149 149 149, 212 149 177 149 149 149, 177 149, 207 149 149 206, 207 205 207 206 206

less polar substrates can be converted as highly concentrated water-in-oil emulsions [63]. Literally hundreds of aldehydes have so far been tested successfully by enzymatic assay and preparative experiments as a replacement for 34 in rabbit muscle FruA catalyzed aldol additions [18, 25], and most of the corresponding aldol products have been isolated and characterized. A compilation of selected typical substrates and their reaction products is provided in Table 5.4, and further examples are indicated in Section 5.4.5. In comparison, metal dependant FruA enzymes are more specific for phosphorylated substrates and accept non-phosphorylated substrate analogs only with much reduced activity (< 1%). For chiral substituted aldehydes, racemic precursors are most often more readily available than enantiomerically pure material, but must be resolved either before or during the aldol step. Rabbit FruA discriminates between the enantiomers of its natural substrate with a 20:1 preference for d-GA3P (34) over its l antipode [149]. Assistance from anionic binding was revealed by a study on a homologous series of carboxylated 2-hydroxyaldehydes for which enantioselectivity was optimum when the distance of the charged group equaled that of 34 (Figure 5.23) [155]. The resolution of racemic substrates is not, however, generally useful, because the kinetic enantiose-

223

224


O

O

O –O

–O

P

–O

OH

46 E > 10

O O OH

34 E > 10

Fig. 5.23

Kinetic enantiopreference of rabbit muscle FruA.

lectivity for non-ionic aldehydes is rather low [149]. 3-Azido substituents (95) can lead to up to ninefold preference for enantiomers in kinetically controlled experiments [156] whereas hydroxyl (usually some preference for the d antipodes) and derived functionality, or chiral centers at a larger distance, rarely enable more than statistical diastereomer formation. 5.4.2

TagA

The d-tagatose 1,6-bisphosphate aldolase (TagA; EC 4.1.2.n) is involved in the catabolism of d-galacto-configured carbohydrates and catalyzes the reversible cleavage of d-tagatose 1,6-bisphosphate (44) to d-glyceraldehyde 3phosphate (34) and dihydroxyacetone phosphate (41). Enzymes of class I that occur in a variety of Coccus species seem to have apparently no stereochemical selectivity with regard to distinction between 42 and 44 [157], whereas class II aldolases from Gram-positive microorganisms are highly stereoselective for the natural substrate in both cleavage and synthesis directions [158, 159]. The genes coding for TagA have been cloned from Coccus strains [160] and from E. coli [53, 161]. The reverse, synthetic reaction can be used to prepare ketose bisphosphates, as has been demonstrated by an expeditious multienzymatic synthesis of the all-cis (3S,4S)-configured d-tagatose 1,6-bisphosphate 44 from dihydroxyacetone including its cofactor-dependent phosphorylation, using the purified TagA from E. coli (Figure 5.24) [158, 159]. The aldolase also accepts a range of unphosphorylated aldehydes as substrates but produces diastereomeric mixtures only. This lack of stereoselectivity with generic substrate analogs, which makes native TagA enzymes synthetically less useful, has stimulated recent X-ray structure determination and protein engineering to improve its properties [53, 54, 162]. 5.4.3

RhuA and FucA

The l-rhamnulose 1-phosphate aldolase (RhuA; EC 4.1.2.19) and the lfuculose 1-phosphate aldolase (FucA; EC 4.1.2.17) are found in many microorganisms where they are responsible for the degradation of deoxysugars l-rhamnose and l-fucose to give 41 and l-lactaldehyde (Figure 5.25). RhuA is specific for cleavage and synthesis of a l-threo diol unit whereas FucA

5.4 Dihydroxyacetone Phosphate Aldolases

glycerol kinase

O HO

OH

O OPO3=

HO

47

41 ATP

=O PO 3

ADP

TagA

TPI pyruvate pyruvate kinase PEP

225

HO

O HO

OH

44

OH OPO3=

O

34

H Fig. 5.24

Enzymatic one-pot synthesis of tagatose 1,6-bisphosphate based on the stereoselective TagA from E. coli.

OPO3=

O

HO

OH

H 3C

OH

RhuA

DHAP

FucA

O H 3C

H OH

43

OPO3=

O

DHAP

OH

H 3C HO

OH

45

Fig. 5.25

Natural substrates of microbial deoxysugar phosphate aldolases.

recognizes the corresponding d-erythro configuration. Both enzymes have been isolated from several sources [163–165], and the proteins from E. coli have been shown to be homotetrameric Zn 2þ -dependent aldolases with subunit molecular weights of @25 kDa and @30 kDa, respectively [150]. Cloning of RhuA [166, 167] and FucA [168] enzymes from several microorganisms has been reported. Efficient overexpression [150, 160, 169] has set the stage for X-ray structure determinations of both E. coli proteins [48, 49]. Like a number of other aldolases, both the RhuA and FucA enzymes are commercially available. Overall practical features make the RhuA and FucA enzymes quite similar for synthetic applications. Both metalloproteins have very high stability in the presence of low Zn 2þ concentrations with half-lives in the range of months at room temperature, and the enzymes even tolerate the presence of large proportions of organic cosolvents (b30%) [150]. Both have very broad substrate tolerance for variously substituted aldehydes, which is very similar to that of the FruA enzymes, with conversion rates generally being usefully high (Table 5.5). Characteristically, of all the DHAP aldolases yet investigated the RhuA has the greatest tolerance of sterically congested acceptor substrates, as exemplified by the conversion of the tertiary aldehyde 2,2-dimethyl-3-hydroxypropanal 48 (Figure 5.26) [25]. Aldehydes carrying an anionically charged group close to the carbonyl group, for example gly-

OPO3=

226

5 Enzyme-catalyzed Aldol Additions Tab. 5.5

Substrate tolerance of l-rhamnulose 1-phosphate and l-fuculose 1-phosphate aldolases [150, 170]. O R

H

DHAP

O

OH

aldolase

OH

O

OPO3= + R

R

OPO3= OH

OH

R

Rel. Rate [%]

RhuA Selectivity threo:erythro

Yield [%]

Rel. Rate [%]

FucA Selectivity threo:erythro

Yield [%]

l-CH2 OHaCH3 CH2 OH d-CHOHaCH2 OH l-CHOHaCH2 OH CH2 aCH2 OH CHOHaCH2 OCH3 CHOHaCH2 N3 CHOHaCH2 F H CH3 CH(CH3 )2

100 43 42 41 29 – – – 22 32 22

>97:3 >97:3 >97:3 >97:3 >97:3 >97:3 >97:3 >97:3 – 69:31 97:3

95 82 84 91 73 77 97 95 81 84 88

100 38 28 17 11 – – – 44 14 20

95% enantiomeric excess (ee). With hydroxyacetone as the donor substrate, the Z-enamine of hydroxyacetone reacts on the re face of the aldehyde. The antibody-catalyzed reactions of hydroxyacetone as the donor provided only the single regioisomer as shown in the formation of 16, 18, 20, 24, and 25 (Table 6.1). Lower enantioselectivity was achieved with acceptor aldehydes containing an sp 3 center in the a-position, for example the reaction with 12, although reactions with hydroxyacetone as the donor increased the enantioselectivity (for example, formation of 24 and 25 in Table 6.1). In the antibody-catalyzed reactions of 2-butanone with aldehydes, a mixture of both possible regioisomers of aldol products was formed with moderate selectivity by preferential bond formation at the most substituted carbon atom of the ketone. Although a variety of secondary aldols can be prepared by aldolase antibody 38C2-catalyzed cross-aldol reactions, tertiary aldols are typically not accessible via intermolecular cross-aldol reactions. For preparation of enantiomerically enriched tertiary aldols, aldolase antibody 38C2-catalyzed retroaldol reactions can be used (Section 6.3.2). Antibodies 38C2 and 33F12 also catalyzed self-aldol condensations of propionaldehyde and provided the aldol-elimination product 26, and the antibodies did not catalyze the consecutive aldol reaction of 26 with propionaldehyde (Scheme 6.3). The antibodies did not catalyze the self-aldol reactions of aldehydes bearing a longer alkyl chain (bvaleraldehyde, for example, aldehydes 3, 12, and 13). It might not be possible for the antibody to accept two

6.3 Aldolase Antibody-catalyzed Aldol and Retro-aldol Reactions Tab. 6.1

Antibody 38C2-catalyzed cross-aldol reactions. Acceptor

Donor

Product

O O

ee (%) OH O

O

H

O

98

(S)-14

N H

N H

8

OH O O O 15

N H

OH O O

O OH

OH

N H

16

O O

OH O O

H

O (S)-17

N H

>99

N H

9

OH O O

O OH

OH

N H O

18

OH O O

H

98 (S)-19

O2N

O 2N

10

OH O O OH O 2N

20

O

OH O O

H O2N

O

O

99 (S)-21

O 2N

11 H N

OH

H N

O

OH O

O

H

(R)-22

12 H N

O

OH O

O 23

20

281

282

6 Antibody-catalyzed Aldol Reactions Tab. 6.1 (continued)

Acceptor

Donor

Product

ee (%)

H N

OH O

O OH

O 24

77 (de >99)

OH

OH O

O

O H

98

OH

13

25 OH

Substrates

Product

kcat (minC1 )

Km (mM)

8 þ acetone 8 þ hydroxyacetone 9 þ acetone 9 þ hydroxyacetone 10 þ acetone 12 þ acetone

14 16 17 18 19 22

0.048 0.11 0.21 1.1 0.04 0.11

204 348 123 184 27 256

molecules of aldehyde with a larger substituent in the active-site cavity. Selfaldol reactions of acetone or cyclopentanone were also catalyzed by the antibodies in the absence of acceptor aldehyde for a cross-aldol reaction. In this instance the aldol product was also converted to the elimination product by the antibodies (for example, formation of 27). Antibodies 38C2 and 33F12 also catalyzed intramolecular aldol reactions and Robinson annulation (Scheme 6.4); 1,5-diketones 28 and 30 were converted into 29 and 31, respectively [15]. To explore the scope of Baldwin’s rules in antibody-catalyzed intramolecular aldol reactions, 38C2 was incubated with three different aliphatic diketones – 2,4-hexanedione, 2,5-heptanedione and 2,6-octanedione. No catalysis was observed in the

O

O

H

H 26 O

O

O OH 27

Scheme 6.3

Antibody 38C2-catalyzed self-aldol reactions.

6.3 Aldolase Antibody-catalyzed Aldol and Retro-aldol Reactions

O

O (S)-28

O

O (R)-28

O

(S)-29

O

O

(R)-29 O

O

O 30

O (S)-31 >95% ee

Substrate

Product

kcat (min-1 )

K m (mM)

(S)-28

(S)-29

0.186

12.4

(R)-28

(R)-29

0.126

2.45

30

31

0.086

2.34

Scheme 6.4

Antibody 38C2-catalyzed intramolecular aldol reactions.

reaction pathway from 2,4-hexanedione to 3-methylcyclopent-2-enone, presumably because of the Baldwin disfavored 5(enolendo-trig) process involved in the attack of the enamine at C2 in 2,4-hexanedione. Although the corresponding ring closure (followed by water elimination) of 2,6-octanedione to give 3-methylcyclohept-2-enone is Baldwin favored (a 7(enolendo-trig) process) in this instance also no product formation was observed. In contrast, the Baldwin favored ring closure reaction of 2,5-heptanedione, (a 6(enolendotrig) process) followed by elimination of water and giving 3-methylcyclohex2-enone was catalyzed by antibody 38C2 [8]. 6.3.2

Antibody 38C2-Catalyzed Retro-aldol Reactions and their Application to Kinetic Resolution

The antibodies also catalyzed retro-aldol reactions of secondary [9, 11, 16] and tertiary aldols [10]. In these retro-aldol reactions antibodies 38C2 and 33F12 processed hydroxyketones whose stereochemistry was the same as that of the aldol reaction product. Kinetic resolution by the retro-aldol reaction therefore provided the opposite enantiomer from the forward aldol reaction (Scheme 6.5 and Table 6.2). For example, (R)-14 (> 99% ee) was obtained by the 38C2-catalyzed kinetic resolution of (G)-14 (Table 6.2) whereas

283

284

6 Antibody-catalyzed Aldol Reactions O

O +

R

H OH

38C2 or 33F12 Enantioselective aldol reaction

O

R Racemic

O

OH

O

R

38C2 or 33F12 Enantioselective retro -aldol reaction (Kinetic resolution)

OH

R

Scheme 6.5

Stereochemistry of antibody 38C2-catalyzed aldol reactions and kinetic resolution.

(S)-14 (98% ee) was formed in the 38C2-catalyzed forward-aldol reaction (Table 6.1). The recovered aldols were highly enantiomerically enriched by the aldolase antibody-catalyzed kinetic resolution; examples include secondary aldols 14, 17, 21, and 32–35, and tertiary aldols 36–40 (Tables 6.2 and 6.3). Kinetic resolution with antibody 38C2 usually afforded higher enantiomeric excess for the recovered aldols than the forward aldol reactions, because one enantiomer was completely consumed in the resolution. For example, (S)-32 was obtained in >99% ee by 38C2-catalyzed kinetic resolution after 67% conversion whereas in the 38C2-catalyzed forward aldol reaction (R)-32 was obtained in 58% ee. In the aldol reactions to form secondary aldols the equilibrium constants favor the aldol product. For example, the aldol reaction of acetone with benzaldehyde has an equilibrium constant of 12 m1 [17]. Aqueous solutions containing 1 m acetone and 1 mm benzaldehyde reached equilibrium when 92% of the benzaldehyde had reacted to form the aldol. In the retroaldol reaction of a 1 mm solution of the aldol, equilibrium was reached at 99% conversion to benzaldehyde. Aldolase antibodies 38C2 and 33F12 efficiently provided enantiomerically enriched secondary aldols via aldol reactions or retro-aldol reactions, i.e. kinetic resolution of racemic aldols. The concentration of the substrates determined the reaction direction, aldol or retro-aldol, with these aldolase antibodies. In the aldol reaction of acetone and acetophenone, the equilibrium constant is 0.002 m1 [18]. A 1 mm solution of acetophenone would require the concentration of acetone to be 10,000 m (neat acetone ¼ 13.6 m) to reach 95% conversion. In the retro-aldol reaction, a 1 mm solution of this tertiary aldol would be converted almost completely to its constituent ketones at equilibrium. This is consistent with the fact that aldolase antibodies 38C2 and 33F12 can be used for kinetic resolution of tertiary aldols, but not for the forward aldol reactions to form tertiary aldols. While general access to optically active tertiary aldols is not available by traditional synthetic methods, a variety of enantiomerically enriched tertiary aldols can be prepared by aldolase antibody-catalyzed kinetic resolution. Significantly, the aldolase antibodies process not only keto-aldols but also aldehyde-aldols for example, the reaction to provide (S)-40.


Secondary aldols prepared by antibody 38C2-catalyzed kinetic resolution. Product

Conversion

ee (%)

52%

>99

52%

>99

51%

>99

67%

>99

50%

95

54%

98

OH O O N H

(R )-14 OH O

O N H

(R)-17 OH O

(R)-21

O2 N

OH O O N H

(S)-32 OH O

MeO

(R )-33 OH O

MeO

(4S,5R)-34 OH O

MeO

(R)-35

Substrate

kcat (minC1 Þ

Km (mM)

kcat /kuncat

kcat /Km /kuncat (MC1 )

(S)-17 (G)-33 (G)-anti-34 (G)-35

1.4 2.2 1.4 1.0

270 16 93 14

1.7 10 7 1.0 10 5 1.9 10 4 1.0 10 6

6.2 10 10 6.3 10 9 2.1 10 8 7.1 10 10

6.3.3

Aldol and Retro-aldol Reactions Catalyzed by Antibodies 93F3 and 84G3

Aldolase antibodies 93F3 and 84G3 also have promiscuous active sites and catalyze reactions of a variety of substrates [12, 19]. These antibodies pro-

285

286

6 Antibody-catalyzed Aldol Reactions Tab. 6.3

Tertiary aldols prepared by antibody 38C2-catalyzed kinetic resolution. Product

Conversion (%)

ee (%)

50

>99

52

80

50

94

50

>99

50

95

OH O

MeO

(R)-36 OH O

O (S)-37

N H

OH O

(R)-38

MeO

OH O

MeO

(R)-39

O 2N

O N

OH O O

H (S)-40

Substrate

kcat (minC1 )

Km (mM)

kcat / kuncat


(S)-36 (G)-37 (G)-38 (G)-40

1.8 4.6 0.15 0.02

0.12 0.11 1.62 0.13

1.2 10 6 8.4 10 5

1.3 10 10 7.7 10 9

vide the opposite enantioselectivity to the 38C2 and 33F12-catalyzed reactions. Examples of antibody 93F3-catalyzed aldol reactions are shown in Table 6.4. Antibodies 93F3 and 84G3 provided (R)-17, (R)-19, and (R)-21 in the aldol reactions of acetone and aldehydes 9, 10, and 11, respectively, whereas antibodies 38C2 and 33F12 provided the corresponding (S) enantiomers in the aldol reactions (Table 6.1). When unsymmetrical ketones were used in antibody 84G3-catalyzed cross-aldol reactions with aldehydes the reactions occurred exclusively at the less substituted carbon atom of the ketones, irrespective of the presence of heteroatoms in the ketones: Aldol products (R)-41–44 were regioselectively and enantioselectively obtained. This is a notable feature, because antibodies 28C2 and 33F12 gave the corresponding regioisomer mixtures and because the background reaction fa-


Aldol reactions catalyzed by antibodies 93F3 and 84G3. Acceptor

Donor

Product

O O

OH O H

N H

O

O N H

9 O

O 2N

10

93F3

95

93F3

98

(R)-19 OH O

H

O

11

O2N

O

(R)-21 OH O

H O2N

>99

OH O

O

O2N

93F3 (R)-17

O

H O2N

Antibody ee (%)

O O 2N

10

84G3

95 (dr 100:1)

84G3

95 (dr 99:1)

84G3

95 (dr 100:1)

84G3

95 (dr 98:2)

(R)-41 OH O

O O2N

(R)-42 OH O

O

OMe OMe O2N

(R)-43 OH O

O

SMe SMe O2N

(R)-44

vored the formation of the other regioisomers. In contrast with antibodies 38C2 and 33F12, aldolase antibodies 93F3 and 84G3 were very poor catalysts for aldol reactions involving hydroxyacetone as donor with aldehydes as acceptors. When kinetic resolution of aldol (G)-17 was performed with antibody 93F3, (S)-17 (>99% ee) was obtained at 52% conversion (Table 6.5), whereas antibody 38C2 provided (R)-17 in the kinetic resolution (Table 6.2). The catalytic proficiency of antibodies 93F3 and 84G3 usually exceeded that of antibody 38C2, especially for retro-aldol reactions of 3-keto-5-hydroxy-type substrates (for example, 45 and 46). In contrast with antibodies 38C2 and

287

288

6 Antibody-catalyzed Aldol Reactions Tab. 6.5

Examples of kinetic resolution catalyzed by antibodies 93F3 and 84G3. Product

Conversion

ee (%)

52%

>99

50%

99

50%

>99

50%

96

OH O O N H

(S)-17 OH O

MeO

(S)-35 OH O

MeO

(S)-45 OH O

MeS

(S)-46 OH O

MeO

(S)-33

Substrate

Antibody

kcat (minC1 )

Km (mM)

kcat /kuncat


(G)-35

93F3 84G3 93F3 84G3 93F3 84G3

2.63 3.5 43.3 46.8 69.6 81.4

15 23 6.5 10.3 2.6 4.2

2.7 10 6 3.6 10 6 4.9 10 7 5.2 10 7 1.9 10 8 2.3 10 8

1.8 10 11 1.6 10 11 7.4 10 12 5.0 10 12 7.4 10 13 5.4 10 13

(G)-45 (R)-46

33F12, antibodies 93F3 and 84G3 cannot process retro-aldol reactions of tertiary aldols. 6.3.4

Preparative-scale Kinetic Resolution Using Aldolase Antibodies in a Biphasic Aqueous–Organic Solvent System

Antibody-catalyzed reactions are typically performed in aqueous buffer, because catalytic antibodies function ideally in an aqueous environment. Many organic molecules of interest are, however, poorly soluble in water. For the transformation of such molecules by aldolase antibodies, a biphasic


Preparative scale kinetic resolution in biphasic system. Product

Antibody

Time

Recovery (%)

ee (%)

1.55 g (49)

>97

OH O

N

(R)-47

38C2 (255 mg, 0.025 mol%)

88 h

84G3 (16 mg, 0.015 mol%)

340 h

154 mg (48)

95

38C2 (15.4 mg, 0.10 mol%)

144 h

25 mg (50)

97

91 h

469 mg (47)

97

172 h 259 h

441 mg (42) 458 mg (43)

97 97

193 h

22 mg (44)

99

OH O

N

(S)-47

OH O

MeO

(R)-35 OH O

MeO

(S)-35 OH O

MeO

84G3 (210 mg, 0.065 mol%) reuse (2nd round) reuse (3rd round) 38C2 (18 mg, 0.12 mol%)

(R)-36 OH O

84G3 (500 mg, 0.0086 mol%) MeO

65 h

10 g (50)

>99

(S)-45

aqueous–organic solvent system was especially useful in a large-scale reaction [20]. Although water-miscible solvents can be used to increase the solubility of the substrates, antibody 38C2-catalyzed kinetic resolution of (G)-47 in 20% CH3 CN–buffer resulted in reduced reactivity and a lower enantioselectivity than the reaction in 2–5% CH3 CN–buffer. The same reaction in toluene–phosphate buffer yielded (R)-47 in >97% ee with 49% recovery. Examples of kinetic resolution in biphasic systems are given in Table 6.6. In the biphasic system, racemic substrate (50–100 mm) in toluene or chlorobenzene is mixed with an antibody solution in buffer, for example, a 20-gscale reaction is performed in a reaction volume of @700 mL. After completion of the reaction (determined by monitoring the ee of the substrate by HPLC) the mixture is cooled (20 C) and the organic phase is easily separated from the frozen aqueous antibody solution. The product is purified by conventional column chromatography. The antibody solution is thawed and can be reused. Although the activity of the recycled catalysts was lower

289

290

6 Antibody-catalyzed Aldol Reactions

than on first use and longer reaction time was necessary for reactions using recycling catalysts, the enantioselectivity of the reaction with the recycling catalysts was retained. 6.3.5

Aldolase Antibody-catalyzed Reactions in Natural Product Synthesis

Aldolase antibody-catalyzed aldol reactions and kinetic resolution are an efficient means of synthesis of highly enantiomerically pure aldols. These processes have been used for the total synthesis of cytotoxic natural products epothilone A (48) and C (49) (Scheme 6.6) [21]. These compounds have

Scheme 6.6

Syntheses of epothilones using aldolase antibody-catalyzed reactions.

6.3 Aldolase Antibody-catalyzed Aldol and Retro-aldol Reactions

OH

OH N

N HO

S

O 55 99% ee (50% conversion) by 84G3 99% ee (50% conversion) by 93F3

S

MeO

O 56 95% ee (51% conversion) by 84G3 95% ee (51% conversion) by 93F3

OH

OH

N MeS

N

S

O 57

99% ee (55% conversion) by 84G3 99% ee (54% conversion) by 93F3

S

O F 96% ee (54% conversion) by 84G3 98% ee (52% conversion) by 93F3 58

Fig. 6.3

Chiral precursors for syntheses of epothilones and their derivatives, which were prepared by aldolase antibodycatalyzed reactions.

a taxol-like mode of action, functioning by stabilization of cellular microtubules. The structural moieties (þ)-syn-50 and ()-51 were prepared by antibody 38C2-catalyzed reactions and converted to the intermediates 52 and 53, respectively. The key compound ()-51 (98% ee) was also obtained by kinetic resolution using antibodies 93F3 and 84G3 [22]. Chiral precursors 55–58 (Figure 6.3) for the syntheses of other epothilones and their derivatives were also prepared by the aldolase antibody-catalyzed kinetic resolution [22]. Other syntheses of natural products have capitalized on the 38C2catalyzed aldol addition of hydroxyacetone to install 1,2-syn-diol functionality. Aldolase antibody 38C2 was also used for synthesis of brevicomins 59– 61 (Scheme 6.7) [23] and 1-deoxy-l-xylulose (62) (Scheme 6.8) [24]. Antibody 38C2-catalyzed kinetic resolution of a tertiary aldol was used for the synthesis of (þ)-frontalin (63) (Scheme 6.9) [10]. 6.3.6

Retro-aldol Reactions in Human Therapy : Prodrug Activation by Aldolase Antibody

An important application of aldolase antibodies is prodrug activation in chemotherapeutic strategies. Activation of a prodrug into an active drug at the tumor site enables selective destruction of those tumor cells. This type of site-specific targeting is known as antibody-directed enzyme prodrug therapy (ADEPT) [25]. The ADEPT complex serves two functions. The antibody portion of the complex enables delivery of the drug directly to the tu-

291


292

O OH

O

38C2 O

O

CHO

55%, >99% ee

OH O

O

O

+ HO O

O O

60

OH O O

OH 38C2

O

O 59

OH

CHO

O

HO

O

O

OH

>99% ee

O O

HO

O

+ O

61

O

HO Scheme 6.7

Syntheses of brevicomins using aldolase antibody-catalyzed reactions.

O OH O O

H2 Pd(OH)2/C

OH O

38C2

OH HO

O

H 32%, 97% ee

OH

O

OH

1-Deoxy-L-xylulose (62) Scheme 6.8

Synthesis of 1-deoxy-l-xylulose using aldolase antibody-catalyzed reaction.

mor by recognition of antigen on the tumor cell surfaces. The enzyme part of the conjugate catalyzes the prodrug activation reaction at the tumor site. This system enhances the efficiency of anti-cancer drugs and reduces peripheral cytotoxicity because of the prodrug’s low toxicity. Most ADEPT sysOH O O

H

AcNH

44%, >99% ee (~50% conversion)

O OH

PO(OEt)2 O

LiOH

OH O

38C2 O

H

AcNH O

O H2 Pd(OH)2/C

AcNH Scheme 6.9

Synthesis of (þ)-frontalin using aldolase antibody-catalyzed reaction.

O (+)-Frontalin (63)

6.4 Aldolase Antibodies for Reactions Related to an Enamine Mechanism

tems incorporate a bacterial enzyme, and the problems of this system are: (1) identification of an enzyme not already present in humans, and (2) the immunogenicity of such a bacterial enzyme. These problems can be circumvented by use of a humanized catalytic antibody which catalyzes the activation reaction of the prodrug selectively, in place of the foreign enzyme [26]. Immunogenicity of the enzyme component of ADEPT can therefore be solved using humanized catalytic antibodies. Antibody 38C2 catalyzes the activation reactions of prodrugs that incorporate a trigger portion designed to be released by sequential retro-aldolretro-Michael reactions (Scheme 6.10) [27, 28]. The retro-Michael step is also catalyzed by antibody 38C2, although this step occurs spontaneously in buffer. Because the retro-aldol reaction of the tertiary aldol in this reaction cascade is not catalyzed by any known natural enzymes, this masking of the anti-cancer drugs substantially reduces their toxicity. Combination of doxorubicin-prodrug 64 and antibody 38C2 strongly inhibited cell growth of cancer cell lines, whereas the same concentration of 64 alone was far less potent [27]. Camptothecin- and etoposide-prodrugs 65 and 66 were also activated by 38C2. The aldolase antibody-prodrug system has also proven to be efficient in an animal model of cancer [28]. Incorporation of an additional 8.4-A˚ linker, as shown in prodrugs 65 and 66, enables a diverse group of drugs to be used for application of aldolase antibody-catalyzed prodrug activation. Aldolase antibody 33F12 has an active site lysine e-amino group at @10 A˚ depth in a narrow pocket (Section 6.6). The reaction sites of the masking linkers of 65 and 66 reach into the active site whereas the bulky drug molecules remain outside the active-site cavity. The prodrug activation strategy has also been demonstrated in the context of protein activation. Native insulin modified with aldol-terminated linkers at the primary amines crippled the biological activity of insulin (Scheme 6.11). The modified insulin was defective with regard to receptor binding and stimulation of glucose transport. Antibody 38C2 cleaved the linker, released insulin, and restored insulin activity in an animal model [29]. Antibody 38C2 was also used for the retro-aldol or retro-aldol-retro-Michael reactions of aldol functionality on dendrimers and polymers that have potential for drug encapsulation and delivery [30, 31].

6.4

Aldolase Antibodies for Reactions Related to an Enamine Mechanism and the Nucleophilic Lysine e-Amino Group

Because aldolase antibodies operate by an enamine mechanism, they also catalyze other reactions that proceed by a similar mechanism. For example, as described in the section on prodrug activation reactions, antibodies 38C2 and 33F12 catalyze b-elimination (retro-Michael) reactions (Section 6.3.6). These antibodies also catalyze decarboxylation of b-keto acids (Scheme 6.12)

293

N

OH

O

O

O

O

O

O

O

65

HO

N

66

8.4 Å

OCH3

O

O

O

O

64

O

O

OH

O

N O

HO

CO2

O

38C2

CO2

O

38C2

O

O

OH

OH

HOHN

O

O

N

O

O

O

O

O

N

N

O

OH

O

N

O

CH3O

Etoposide

OH

O

O

O

OCH3

O

O

NH

spontaneous

OH

O

O

O

CO2

O

38C2

CH3O

O

O

O O HO

OH

additional linker arm to enable efficient catalysis of drug release.

O

O

CH3O

HO

O

3.7 Å

O

38C2

O

O

N

O

OH

Prodrug activation via a tandem retro-aldolretro-Michael reaction catalyzed by antibody 38C2. Prodrugs 65 and 66 incorporate an

Scheme 6.10

N

O

HOHN

O

OH

O

CH3O

O

O

O O HO

CH3O

OH

O

O

OH O

OH

O N

N

O

O

OH

OH O

OH

O

Camptothecin

N

Doxorubicin

HO NH2

O

O

294


6.4 Aldolase Antibodies for Reactions Related to an Enamine Mechanism

295

NH2 Insulin

H 2N

NH2 O2N

O

38C2 O

OH O O

O O

O

OH O

O

NH Insulin

N H

OH O

O

HN

OH O O

Scheme 6.11

Modification of insulin with retro-aldol-retroMichael linkers and its reactivation by aldolase antibody 38C2.

[32], allylic rearrangement of steroids (Scheme 6.13) [33], and deuteriumexchange reactions (Table 6.7) [34]. In the antibody 38C2-catalyzed decarboxylation of 67, incorporation of 18 O into product 68 was observed in the presence of H2 18 O, consistent with decarboxylation proceeding via an enamine intermediate [32]. Antibody 38C2 catalyzed deuterium-exchange reactions at the a-position of a variety of ketones and aldehydes (Table 6.7) [34]. Because aldehydes bearing a longer alkyl chain (bvaleraldehyde) were not substrates for the

O O N H

O

67

OH Lys Ab

H H2N Lys Ab

N O

O N H

O 18O

18

H2 O

O N H

68

Scheme 6.12

Antibody 38C2-catalyzed decarboxylation.

O–

Lys Ab

H

N+

CO2

N H

296


38C2 O

O 38C2 O

O O

O 38C2

O

O

Scheme 6.13

Antibody 38C2-catalyzed allylic rearrangements.

38C2-catalyzed self-aldol reactions (Section 6.3.1), deuterium-exchanged aldehydes accumulated in the presence of 38C2 in D2 O. Aldolase antibodies can be covalently modified with cofactor derivatives at the active site lysine residue to enable catalysis of cofactor-dependent reactions [35, 36]. A variety of 1-acyl b-lactam derivatives formed the stable amide linkages to active site lysine, whereas 1,3-diketones bound reversibly (Scheme 6.14) [35]. Antibody 38C2 was modified with lactam 69, and the modified antibody catalyzed thiazolium-dependent decarboxylation of PhCOCOOH. Antibody 38C2 was also covalently modified with the succinic anhydride derivative bearing a bis-imidazole functionality that chelates Cu(II), and the modified antibody was used for Cu(II)-dependent ester hydrolysis [36]. The reactions of the active site lysine e-amino group of aldolase antibodies depend on the substrates – the catalytic lysine residue of antibody 38C2 did not react with polymer p-nitrophenyl ester [37]. An effect of metal-cofactors on antibody 38C2-catalyzed aldol reactions has also been reported [38]. The active site lysine e-amino group of antibody 38C2 also functioned as general base for the Kemp elimination [39]. Over the years, we have studied a wide-variety of enamine based chemistries using aldolase antibodies. Several key synthetic reactions have been explored using aldolase antibodies. These include investigation of antibodycatalyzed additions to imines, i.e. antibody-based Mannich reactions that operate through an enamine intermediate, and the analogous reaction with nitrostyrene-derived electrophiles (Michael reactions) and Diels–Alder reactions wherein the antibody either generates an enamine derived diene or activates a dienophile through an iminium intermediate. With the exception of the Michael reaction, only recently shown to proceed exclusively with a maleimide electrophile [40], all other reactions failed, presumably because of steric constraints imposed by what is otherwise a promiscuous active site. Significantly, these exploratory studies with catalytic antibodies set the stage

6.5 Concise Catalytic Assays for Aldolase Antibody-catalyzed Reactions Tab. 6.7

Antibody 38C2-catalyzed deuterium-exchange at the a-position. Substrate

kcat (minC1 )

O

kcat /kuncat

79

1.1 10 8

105

9.7 10 7

29.9

25

3.0 10 8

84.9

5

5.9 10 8

13.5

9.5 10 6

10.7

O

Km (mM)

9.7 3:5 ðCH2 Þ 0:6 ðCH3 Þ

O

O

O

0.95

O

19.0

0.7

27.6

0.6

H O H O

127

1

H O H

5.8

0.5

for application of these principles in the area of organocatalysis by our laboratory and former members of the laboratory familiar with these studies [41].

6.5

Concise Catalytic Assays for Aldolase Antibody-catalyzed Reactions

Spectroscopic or visible detection of antibody-catalyzed reactions enhances rapid characterization of catalysts on a small scale. Such detection systems are also useful for high-throughput screening for new aldolase antibody

297

298


O

H2N Lys Ab

O

R

O

H

N

Lys Ab

R

R

O

O

O O H2N Lys Ab

N

Lys Ab R

N H

N H

O O

N S + Br –

N 69 Scheme 6.14

Cofactor introduction at a unique active site lysine of aldolase antibodies.

catalysts and for evolution of aldolase antibodies in vitro. Examples of substrates for spectroscopic or visible detection of the antibody-catalyzed reactions are shown in Scheme 6.15. Substrate 47 was the first UV–visible-active aldol substrate designed for following retro-aldol reactions. Reaction results in liberation of the yellow product 70 [9] and this reagent served as the basis for the development of fluorescent versions when fluorescent aldehydes and ketones were later identified [42]. Substrates 35, 36, 71, and 72 liberate the fluorescent products 73, 74, 75, and 76, respectively, by aldolase antibodycatalyzed retro-aldol reaction [42]. Thus the progress of the reactions with these fluorogenic substrates can be followed by fluorescence. Substrates 77– 79 are used for analysis of retro-aldol-retro-Michael reactions. Substrates 77 and 78 generate fluorescent compounds resolufin (80) and umbelliferone (81), respectively, after the reactions [42, 43]. Substrate 79 generates a 2naphthol derivative 82 that forms a visible colored azo dye with diazonium salts [44]. Maleimide derivative 83 is useful for detection of the carbon– carbon bond-formation catalyzed by aldolase antibodies [40]. It should be noted that all the other systems monitor carbon–carbon bond cleavage, not formation. The reaction of 83 with acetone provides 84, the fluorescence of which is much greater than that of 83.

6.6

Structures of Aldolase Antibodies and Reaction Mechanism of Nucleophilic Lysine e-Amino Group

Antibodies 38C2 and 33F12, generated with diketone 1, are highly homologous with regard to sequence and have an essential lysine catalytic residue at the same position (H93) [11, 45]. Aldolase antibodies 40F12 and 42F1, generated with hapten 5, have the same enantio-preference as antibodies 38C2 and 33F12. They are also highly similar to 38C2 and 33F12 in their

O

OH O

N

N

47

H

fluorescence

λex 330 nm, λem 452 nm

fluorescence


fluorescence


MeO

fluorescence


73 O

OH O

MeO

36

74 O

OH O

H N

71

N

75 O

OH O

N

N

72

N O

76

N

OH O O

O

λmax 400 nm

O

35

MeO

UV/VIS

70

OH O

MeO

H

O

N

O O

O

O fluorescence

OH

O 80

77


OH O λex 360 nm, λem 460 nm

fluorescence O

O

O

O

O

78

OH 81

Br

CH3 N2 Br O

HO

1/2 ZnCl2

Br Cl

OH O

+Cl-

HO

N N CH3

82

79

Cl bright red dye precipitate O

H N

N N

+

O

O

H N

N N

83

O

84 fluorescence

O

O


Scheme 6.15

Substrates for fluorescent and visible detection of aldolase antibody-catalyzed reactions.

300


amino acid sequences and have an essential lysine catalytic residue at the same position (H93) [16]. On the other hand, aldolase antibodies 93F3 and 84G3, generated with hapten 5, have antipodal reactivity to antibodies 38C2 and 33F12 and have different amino acid sequences from antibodies 38C2, 33F12, 40F12, and 42F12. The essential lysine residue is at position L89. X-ray crystal structures of the Fab fragments of 33F12 [11] and 93F3 [1d] are shown for comparison in Figures 6.4 and 6.5.

(a)

(b)

Fig. 6.4

X-ray structure of aldolase antibody 33F12. (a) Top view. Residues within 5 A˚ of the eamino group of the catalytic lysine (H93) are indicated. (b) Side view.

6.6 Structures of Aldolase Antibodies

Fig. 6.5

X-ray structure of aldolase antibody 93F3. The essential lysine residue (L89) is indicated.

The structure of 33F12 shows that the entrance of the antigen binding site of 33F12 is a narrow elongated cleft. The binding pocket is more than 11 A˚ deep and is comparable with combining sites of antibodies raised against other small haptenic molecules. At the bottom of the pocket LysH93 is found within a hydrophobic environment. Within this pocket, only one charged residue is within an 8-A˚ radius of the nitrogen of e-amino group of LysH93. No salt bridges or hydrogen bonds can be formed between LysH93 and any other residues in 33F12. A Hansch plot, a study of the free energy relationship for substrate partitioning into n-octanol and kcat =Km of the retro-aldol reactions, shows that the active site in 33F12 is 1.1 times more hydrophobic than n-octanol [11]. This environment perturbs the pK a of LysH93 and enables it to exist in its uncharged form, facilitating its function as a strong nucleophile. The hydrophobic environment used by these aldolase antibodies to tune the pK a of the e-amino group of the active site lysine residue is in contrast with the mechanism used by most natural class I aldolase enzymes; in the natural aldolases an electrostatic mechanism perturbs the pK a of the e-amino group of the lysine [2, 16, 46]. Notably, with the exception of a single residue, the residues in van der Waals contact with LysH93 are conserved in both antibodies and are encoded in the germline gene segments used by these antibodies. This conservation suggests that LysH93 appeared early in the process of antibody evolution in a germline antibody. The insertion of this residue into this hydrophobic microenvironment resulted in chemical reactivity that was efficient enough to be selected. Once this covalent process appeared the

301

302


binding pocket did not further evolve toward high specificity as would be indicated by the selection of somatic variants of the germline sequence. The broad substrate specificity of aldolase antibodies prepared by reactive immunization is likely to be the result of the special ontogeny of antibodies induced by immunogens that form covalent bonds within the binding pocket during the induction. Although all aldolase antibodies generated with 1,3-diketones use an enamine mechanism in their aldol and retro-aldol reactions, the micromechanisms of the reactions might differ among these aldolase antibodies as they do among aldolase enzymes [2, 47]. In the 38C2-catalyzed retro-aldol reactions of a series of aldols prepared from acetone and p-substituted cinnamaldehyde, correlation between log kcat and the Hammett substituent s is not linear [13, 48]. A positive linear correlation between log kcat and s was, on the other hand, obtained for aldolase antibody 24H6, generated with a mixture of haptens 6 and 7; this indicates 38C2 and 24H6 differ in their micromechanisms, including the rate-limiting steps. However, similar amino acid sequences of the aldolase antibodies reflect the broad similarity in substrate specificity, enantioselectivity, and micromechanism.

6.7

Evolution of Aldolase Antibodies In Vitro

Although aldolase antibodies are broad in scope, the efficiency with which any given aldol is processed can vary significantly. To create aldolase antibodies with altered substrate specificity and turnover, phage libraries were screened using different diketone derivatives [49]. In this approach, libraries were prepared by recombining the catalytic machinery of well-characterized aldolase antibodies with a naive V gene repertoire. In vitro selection systems enabled the use of multiple haptens without animal re-immunization and enabled the experimenter to combine insights gained by the study of existing catalytic antibodies with the diversity of the immune repertoire. This strategy was used to prepare catalysts that would efficiently process cyclohexanone-aldols 85, because retro-aldol reactions of 85 were relatively slow compared with those involving acetone-aldols using existing aldolase antibodies 38C2 and 33F12 (Scheme 6.16). The phage libraries [50] prepared by combination of active site residues of 38C2 and 33F12 with a naive V gene repertoire were selected with 86 and 1 as reactants. Fab 28 obtained from this selection catalyzed the retro-aldol reactions of anti-87, syn-87, and 35. The kcat values of Fab 28 were superior to those of parental antibodies for cyclohexanone-aldols anti-87 and syn-87 by approximately three- to tenfold [49]. In addition, Fab 28 catalyzed the reaction of acetone-aldol 35 with a kcat value similar to that of antibody 33F12. The stereochemistries of the preferred substrate enantiomers of Fab 28 were the same as those of the parental antibodies 38C2 and 33F12. On the basis of on the design of

6.6 Structures of Aldolase Antibodies O

OH

303

O retro-aldol

R

+ RCHO

85 O

O

O O

O

OH

O

O

N H

86

N H

O

carrier

OH

O

O

O

OMe 35

O Ph

Ph 88

N H

OH

OMe syn-87

O

N H

1

OMe anti-87 O

O

89

Scheme 6.16

Reactions and compounds for in vitro evolution of aldolase antibodies.

the library, Fab 28 retained specific sequence elements of the parental antibodies and the essential LysH93 of the catalytic mechanism. The remaining primary sequence of Fab 28 is not related to the parental antibodies. In addition, because a naive V gene library was generated using human bone marrow cDNA, Fab 28 is a human aldolase antibody. This strategy will be useful for providing human antibodies for catalytic antibodymediated prodrug activation described in Section 6.3.6 without the need for re-immunization and selection. A correlation was observed between the kcat of the antibody-catalyzed retro-aldol reaction and the apparent K d of the corresponding diketones (i.e. the reactivity to the diketones) within the family of aldolase antibodies 38C2, 33F12, Fab 28, and antibodies selected with Fab 28 in vitro. Stronger binding (lower K d value) to acetone-diketone 88 (i.e. higher reactivity with acetone-diketone 88) correlated with a higher kcat value for the reaction of acetone-aldol 35, and stronger binding to cyclohexanone-diketone 89 correlated with a higher kcat value for the reaction of cyclohexanone-aldol anti87 (Figure 6.6) [51]. Selection using a structure-altered diketone provided catalytic antibodies that had altered substrate specificity as directed by the structure of the selecting diketone. The correlation indicates that antibodies 38C2, 33F12, and the in vitro evolved aldolase antibodies share a similar micromechanism including the rate-limiting step in their catalyzed reactions. 1,3-Diketones have also been used for phage selections of small peptides that catalyze aldol and retro-aldol reactions via an enamine mecha-

carrier

304


10

1

1 Fab 28 33F12

0.1

0.1

Fab 9 Fab 22 L87Phe

Fab 28

Fab 22 L87Phe

kcat (min-1)

kcat (min-1)

38C2

0.01

38C2

Fab 9

33F12

Fab 3

0.01

Fab 3

0.001 Fab 10

0.001

0.0001 0.1

1

(a)

10

100

0.1

1

(b)

K d (µM)

10

100

K d (µM)

Fig. 6.6

(a) Plot of k cat for the retro-aldol reaction of 35 against K d of diketone 88. (b) Plot of k cat for the retro-aldol reaction of anti-87 versus K d of diketone 89.

nism [52]. Selection with 1,3-diketones seems to be a general and effective route to catalysts that operate via an enamine mechanism. Although in vitro selection strategies using 1,3-diketones can be used to obtain access to aldolase antibodies, direct selection of catalysis resulted in improved catalysts. Fluorogenic and chromogenic substrates described in Section 6.5 might be useful for the catalytic selection. Genetic selection is also useful for the selection of catalysts. Antibody-catalyzed reaction of substrate 90, a prodrug, generates p-aminobenzoic acid (PABA), an essential metabolite for E. coli. When an E. coli strain that cannot synthesize PABA, because of a genetic defect was provided with the gene for an aldolase antibody, expression of the aldolase antibody provided the E. coli with the ability to metabolize 90 and survive. Such a genetic selection has been shown in preliminary experiments to provide a growth advantage to a strain expressing aldolase antibody 38C2 (Scheme 6.17) [53]. Ideally, such a system will be used in the future to rapidly evolve aldolase antibodies based on both turnover efficiency and substrate specificity.

O HO CH3 O 90

COOH

COOH

O N H

H2N O

PABA

O CO2

Scheme 6.17

Reaction for genetic selection of aldolase antibodies.

6.9 Summary and Conclusion

305

O N H

linker

N+ H N

OH

O 91

H2 N

H N

O O H +

O

94 O

OH O

OH O

72D4 N H

92

N H

93

Scheme 6.18

Antibody-catalyzed reaction using cofactor primary amine.

6.8

Cofactor-mediated Antibody-catalyzed Aldol and/or Retro-aldol Reactions

Antibody 72D4, generated by immunization with 91, catalyzed the aldol reaction of acetone and aldehyde 92 and the retro-aldol reaction of 93, with some enantioselectivity, in the presence of a primary amine cofactor 94 (Scheme 6.18) [54]. The antibody did not catalyze the reactions in the absence amine 94, and evidence supported an enamine mechanism (enamine formation with 94) for this cofactor amine-mediated antibody-catalyzed reaction. An antibody that mimics threonine aldolase, which uses pyridoxal as the cofactor to catalyze the aldol reaction of glycine with aldehydes, has also been reported. Antibody 10H2 catalyzed the retro-aldol reaction of bhydroxy-a-amino acid in the presence of pyridoxal [55].

6.9

Summary and Conclusion

Class I aldolases function as Nature’s most fundamental carbon–carbon bond forming enzymes. Designer catalysts – aldolase antibodies – that mimic the aldolases have been created by using a reaction-based selection strategy with 1,3-diketones. The covalent reaction mechanism is a fundamental part of the selection. Broad scope, enhanced catalytic activity, and defined chemical mechanism are three features of these aldolase antibodies that distinguish them from traditional antibody catalysts. The substrate specificities of aldolase antibodies are different from those of naturally existing

306


enzymes. Thus, applications of aldolase antibody-catalyzed reactions are very wide, from asymmetric synthesis to chemical transformations in cancer therapy [56, 57].

6.10

Experimental Procedures

Aldolase antibodies 38C2 and 84G3 are commercially available from Aldrich. Example 1. Kinetic Resolution in a Biphasic System [20]. A solution of antibody 84G3 (500 mg, 6.67 mmol active site, 0.0086 mol%) in phosphate buffered saline (PBS; pH 7.4, 87.5 mL) at room temperature was added to a solution of (G)-45 (20 g, 77.4 mmol) in toluene (600 mL) in a Teflon tube. The mixture was shaken at 250 rpm. under argon at the same temperature and the ee was monitored by chiral-phase HPLC. When ee > 99% was reached (65 h) the mixture was cooled to 20 C for several hours to enable the aqueous phase to freeze. The organic phase was decanted. The frozen aqueous phase was left to thaw and extracted with toluene (3 3 vol. equiv.) and 1:1 EtOAc–toluene (3 3 vol. equiv.). The combined organic phase was dried over Na2 SO4 , concentrated in vacuo, and purified by silica gel column chromatography (1:3 EtOAc–hexane) to afford (S)-45 (10 g, 50%). Example 2. Kinetic Resolution [22]. A solution of antibody 84G3 (0.34 g, 0.00227 mmol) in PBS (27.2 mL) was added to a degassed solution of (G)-51 (16.8 g, 75 mmol) in PBS (1.55 L)–CH3 CN (140 mL). The mixture was incubated under an argon atmosphere at 37 C for 5 days. After consumption of more than 98% of one enantiomer, as judged by HPLC analysis, the mixture was dialyzed using Amicon membranes to recover the antibody and the filtrate was passed through a reversed-phase column (C18 ). The column was first washed with water and then the desired compounds were eluted with MeOH. The solvents were removed under vacuum and the residue was purified by silica gel column chromatography (EtOAc–hexanes, 9:1 to 2:1) to afford ()-51 (7.6 g, 45%, >98% ee). Example 3. Aldol Reaction [8]. Antibody 38C2 (120 mm in PBS, 8.0 mL) was added at room temperature to a mixture of 11 (110 mg, 0.61 mmol) in DMF (15 mL), acetone (31 mL), and degassed PBS (571 mL). The final concentrations were: 11, 1.0 mm; 38C2, 1.9 mm; and acetone, 5% (v/v). The reaction mixture was kept under argon at room temperature in the dark for 7 days. The reaction mixture was saturated with NaCl and extracted with EtOAc (3 150 mL). The organic phase was dried over MgSO4 , concentrated in vacuo, and purified by silica gel column chromatography (EtOAc–hexane, 1:2) to afford (S)-21 (96 mg, 67%, 91% ee).

References

Acknowledgments

We would like to thank Richard A. Lerner, our long-term collaborator in the aldolase antibody projects performed at the Scripps Research Institute, for his contributions.

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Angew. Chem. Int. Ed. 2003, 42, 327. 32 Bjornestedt, R.; Zhong, G.; Lerner, R. A.; Barbas, C. F., III

J. Am. Chem. Soc. 1996, 118, 11720. 33 Lin, C.-H.; Hoffman, T. Z.; Wirshing, P.; Barbas, C. F., III;

34 35 36

37 38 39 40 41

42 43

44 45

46 47

48 49 50

51 52

Janda, K. D.; Lerner, R. A. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 11773. Shulman, A.; Sitry, D.; Shulman, H.; Keinan, E. Chem. Eur. J. 2002, 8, 229. Tanaka, F.; Lerner, R. A.; Barbas, C. F., III Chem. Commun. 1999, 1383. Nicholas, K. M.; Wentworth, P. Jr.; Harwig, C. W.; Wentworth, A. D.; Shafton, A.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2648. Satchi-Fainaro, R.; Wrasidlo, W.; Lode, H. N.; Shabat, D. Bioorg. Med. Chem. 2002, 10, 3023. Finn, M. G.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 1998, 120, 2963. James, L. C.; Tawfik, D. S. Protein Science 2001, 10, 2600. Tanaka, F.; Thayumanavan, R.; Barbas, C. F., III J. Am. Chem. Soc. 2003, 125, 8523. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260. Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866. Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem. Int. Ed. 2003, 42, 2785. List, B.; Barbas, C. F., III; Lerner, R. A. Proc. Natl. Sci. Acad. U.S.A. 1998, 95, 15351. Jourdain, N.; Carlon, R. P.; Reymond, J.-L. Tetrahedron Lett. 1998, 39, 9415. Carlon, R. P.; Jourdain, N.; Reymond, J.-L. Chem. Eur. J. 2000, 6, 4154. Tanaka, F.; Kerwin, L.; Kubitz, D.; Lerner, R. A.; Barbas, C. F., III Bioorg. Med. Chem. Lett. 2001, 11, 2983. The GenBank accession numbers are following: 33F12 VL, AF242212; 33F12 VH, AF242213; 38C2 VL, AF242214; 38C2 VH, AF242215; 40F12 VL, AF242216; 40F12 VH, AF242217; 42F1 VL, AF242218; 42F1 VH, AF242219. Westheimer, F. H. Tetrahedron 1995, 51, 3. Littlechild, J. A.; Watson, H. C. Trends Biochem. Sci. 1993, 18, 36. Morris, A. J.; Davenport, R. C.; Tolan, D. R. Protein Engineering 1996, 9, 61. Shulman, H.; Keinan, E. Bioorg. Med. Chem. Lett. 1999, 9, 1745. Tanaka, F.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 4835. Barbas III, C. F., Burton, D. R., Scott, J. K., and Silverman, G. J. Eds. Phage Display: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001. Tanaka, F.; Fuller, R.; Shim, H.; Lerner, R. A.; Barbas, C. F., III J. Mol. Biol. 2004, 335, 1007. Tanaka, F.; Barbas, C. F., III Chem Commun. 2001, 769. Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 3510.

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6 Antibody-catalyzed Aldol Reactions 53 Gildersleeve, J.; Janes, J.; Ulrich, H.; Yang, P.; Turner, J.;

54

55 56 57

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7

The Aldol Reaction in Natural Product Synthesis: The Epothilone Story Dieter Schinzer Dedicated to Clayton H. Heathcock, one of the pioneers of modern aldol reactions who figured out many of the import stereochemical principles of this fascinating chemistry

7.1

History of Epothilones: Biological Source, Isolation, and Structural Elucidation

The epothilones, a new class of macrocyclic compounds which show cytotoxic activity, have been isolated as secondary metabolites by Ho¨fle and Reichenbach from myxo bacteria [1]. These are so-called gliding bacteria which cruise on slime tracks forming swarms. They grow preferentially on rodded material, like dung. Their morphogenetic potential is quite interesting, forming cylindrical vegetative cells, which under starvation conditions turn into fruiting bodies with solid walls, that further differentiate into myxo spores [2]. Besides the epothilones – which were isolated from a strain of Sorangium cellulosum – many other structural diverse natural products have been isolated from myxo bacteria [3].

7.2

History of Epothilones: The Total Synthesis Race

The publication of the structures of epothilone A and B in 1996 by Ho¨fle et al. [4] in connection with the biological data of the tubulin assay was of great interest for the chemical community. The epothilones were identified by the Merck group in 1995 as tubulin-polymerizing natural products as a single active structural type out of a compound library of more than 60.000 molecules [5]. The cytotoxic effect of Taxol2 via binding to tubulin and thus stabilizing the assembly, combined with the scope of its clinical application, prompted major activities around the world. Taxol2 is far from being an ideal drug: low water solubility requires formulation vehicles, such as Modern Aldol Reactions. Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

312

7 The Aldol Reaction in Natural Product Synthesis: The Epothilone Story

Cremophore2 which create allergic side effects and other risks [6]. Two different types of resistance arise during cancer therapy with Taxol2 ; an overexpression of the P-glycoprotein (P-gp) efflux system and tubulin mutation which both cause major drawbacks. Furthermore, the remarkable efficacy of epothilone against MDR (multiple drug resistante) cell lines makes these compounds superior in comparison to known anticancer agents [7]. This started a race for the first total synthesis in which many world leading chemists got involved. In addition, biologists, medicinal chemists, and clinicians started many efforts along these lines. Besides various total syntheses, many partial solutions, a large variety of synthetic analogues have been synthesized and have created a tremendous number of publications and patent applications around the world [8]. Finally, different large (and small) pharmaceutical companies took over the project and started clinical trials of epothilones or of their synthetic analogues in order to replace Taxol2 as a therapeutic anticancer agent [9]. The first total synthesis was published by Danishefsky et al. [10], shortly followed by independent routes from Nicolaou et al. [11] and Schinzer et al. [12].

O S N

R 12

13 8

15

OH

7

O 1

3

5

OH

O

6

O

1 Scheme 7.1

Epothilone A: R¼H; epothilone B: R¼Me

7.2.1

Different Strategies with Aldol Reactions: The Danishefsky Synthesis of Epothilone A Relying on Intramolecular Aldol Reaction

The first total synthesis of epothilone A combines the two halves of the molecule via a B-alkyl Suzuki coupling [13] yielding the desired cyclization precursor. The critical cyclization was achieved by an intramolecular aldol reaction, utilizing KHMDS as base providing the natural configuration with a 6:1 ratio, 51% yield. The selectivity of the macro condensation was best at 78 C and work-up of the potassium alkoxide at 0 C. Protonation at lower temperature yielded in more of (R)-configured material. Under special conditions, even the (R)isomer predominated over the ‘‘natural’’ configuration. The reason for this surprising behavior is still unknown and under investigation.

7.2 History of Epothilones: The Total Synthesis Race

313

OTBS OTIPS

S

I

8

15

+

6

1. 9-BBN, THF, RT;

CH(OMe)2

7

N

PdCl2(dppf)2, CsCO3,

OAc

Ph3As, H2O, DMF; 71%

2

3

2. TsOH 3. KHMDS, THF, - 78 oC 51%

12

12

S

S

13

13

8 8

N 15

N

OTBS

15

7

O

5

O OK

O

5

1

6

3

1

3

OH

O

OTIPS

5

4 Scheme 7.2

First total synthesis of epothilone A by Danishefsky et al.

7.2.2

Different Strategies with Aldol Reactions: The Nicolaou Synthesis of Epothilone A Using an Unselective Aldol Reaction

The Nicolaou strategy is based on RCM [14] as the final ring closing step in order to establish the 16-membered macrolide. The linear subunit of C1aC12 was obtained by an intermolecular aldol reaction, in which an a-chiral aldehyde was coupled with an achiral enolate, yielding the desired aldol product as a 2:3 ratio of diastereomers 8 and 9. 2.3 eq. LDA, THF, - 78 oC

HO +

O

6

O

8

O

HO

7

+

O

O

OH

7

HO 6

O

8 Scheme 7.3

Model study for the total synthesis of epothilone A by Nicolaou et al.

O 9

OTBS

7

8

OH

6

OTIPS


314

2.3 eq. LDA, THF, - 78 oC

HO

3

+

O

8

OTBS O

O 7

10 HO

HO

7

3

O

OTBS O

+

8

6

O

OH

11

OTBS O

OH

12 S

1. EDC, 4-DMAP, 12 h; 52%

11 + 15

N

2. RuCl2(=CHPh)(PCy3)2, CH2Cl2, 20 h 79%

OH

13

12

S

13 8

N

15

OTBS

7

O 1

3

5 6

O

OTBS O 14

Scheme 7.4

Second total synthesis of epothilone A by Nicolaou et al.

This result is not surprising because only one chiral element was used in that reaction. A second chiral element should improve the selectivity. For that reason Nicolaou introduced a chiral enolate, which is shown in Scheme 7.4. In his second synthesis, Nicolaou used a chiral enolate of type 10 which contained the (S)-configuration at C3 and the required oxidation level at C1. However, again almost no selectivity was observed in the aldol coupling [15]. 7.2.3

Different Strategies with Aldol Reactions: The Schinzer Synthesis of Epothilone A with Complete Stereocontrol in the Aldol Reaction

The Schinzer synthesis of epothilone A is also based on a convergent strategy using three key fragments [16]. The 16-membered macrolide is closed via RCM to provide the key intermediate for the final epoxidation.


S N olefin metathesis, OH

13

O

epoxidation 7 O

S

12

13 8

N

OH aldol reaction

O esterification

7

15 1

3

O 1

O

5

OH

O

O

O

6

15 Scheme 7.5

Third total synthesis of epothilone A by Schinzer et al.

As shown before, the major stereochemical issue in epothilone chemistry is the absolute stereocontrol of the triad C6aC7aC8. In the Schinzer synthesis, a six-membered chiral acetonide of type 15 containing the (S)configuration at C3 was used. Addition of a-chiral aldehyde 7 (X ¼ C) to the preformed enolate (generated with LDA in THF at 78 C) resulted in the formation of the (6R,7S)-diastereomer 16 as a the major isomer in ratio of 25:1 in 76% yield [17]. In a synthesis of oxa-epothilones, Schinzer used aldehyde 7 (X ¼ O) in a diastereoselective aldol reaction which exclusively yielded aldol product 16 (X ¼ O) [18]. Schinzer then performed the same reaction with a-chiral aldehyde 17. Remarkably, this reaction provided again a single isomer 18 with the ‘‘natural’’ epothilone configuration in 49% yield [19]. The fully functionalized aldehyde 19 from Schinzer’s epothilone B synthesis was also used in the same aldol process. However, a 10:1 mixture of diastereomers was obtained with the ‘‘correct’’ stereochemistry as the major product 20 [20]. In the meantime, Schinzer’s chiral enolate 15 has been used extensively by other groups in academia [21] and in the pharmaceutical industry to synthesize a large number of analogues [22]. Most of the examples with highly func-

315

316


X

3

+

O

O

6

O

O

O

3

LDA, THF, - 78 oC

8

15

O

7

X

7 8

OH

O 16

X = C; O 3

7

LDA, THF, - 78 oC

15

+

O

OTBS

8

O

O

O

8

OTBS

OH

18

17

S 15

6

LDA, THF, - 78 oC

8

+

15

N

O

OTBS 19

7

3 6

O

O

O

S

8 15

OH

N 20

OTBS

Scheme 7.6

Selective double stereodifferentiating aldol reactions

tionalized chiral aldehydes generated single isomers in high chemical yields. These outstanding results are connected to the nature of the acetonide, because the lithium counter ion attached to the enolate oxygen can chelate to one oxygen of the acetonide, as shown in Scheme 7.7. The chelated structure 21 was calculated with force field (MMþ) and quantum mechanics (PM3) methods, both methods showed minima in favor of the chelated enolate 21 [19]. Thus, with these results he was able to explain the stereochemical results. There are two aspects to understanding these remarkable observations. The simple diastereoselectivity of the aldol reaction can be explained based on Heathcock’s studies [23], in which the enolate geometry is governed by the bulkiness of the group next to the ketone (in the Schinzer case a modified tbutyl group bearing an extra oxygen). This should result in the generation of a (Z)-lithium enolate, further stabilized by the oxygen at C3, forming a


LDA, THF, - 78 oC

3

3

R

+ O

O

O

O

O

O

Li

8

O

Z-Enolate

15

22

21

R

H O

O Li

7

3

H

O H

6

H O

S

O

O

O

R 8

OH

24

S

317

Zimmerman-Traxler TS

23 Scheme 7.7

Chelated nucleophile 21 with Zimmerman-Traxler TS.

rigid bicyclic structure 21. The diastereofacial selectivity to explain the stereochemical outcome in aldol condensations with a-chiral aldehydes was first proposed by Cram [24] and later on by Felkin [25]. Both models give the same products even though totally different reactive conformations are used. In Schinzer’s case, the aldol addition occurred with the opposite sense of diastereofacial addition to the theoretical models predicted. Intrigued by these results the Schinzer group decided to study this particular aldol reaction in detail. First, they conducted experiments with socalled simple aldehydes containing no chiral center to check the inherent selectivity of the chiral enolate. The reaction generated only the two syn-type diastereomeric aldol products 26 and 27, as shown in table 1 and no anti-

Tab. 7.1

Aldol reactions with achiral aldehydes R

26

:

27

Yield [%]

Ph Pr i-Pr t-Bu 1-Heptenyl

4 5 5 3 5

: : : : :

1 1 1 1 1

81 63 59 49 74

318

R 15 +


7

3

LDA, THF, - 78 oC

R

R

6

O

O

O

+

O

25

O

OH

O

O

26

OH

27

Scheme 7.8

Inherent selectivity of nucleophile 15

aldol product was observed at all. In all cases studied, the 6(R),7(S)-isomer 26 was the predominant diastereomer. The inherent selectivity of the chiral enolate is in the range of about 4:1 [26]. Next, the double-stereodifferentiating [27] aldol process with a-chiral aldehydes was examined, seperate experiments using both enantiomeric forms of phenyl propionaldehyde were undertaken. Use of (S)-phenylpropionaldehyde 28 gave two diastereomers 29 and 30 in a ratio of 2.5:1 and 68% yield. The major one is still the anti-Cram/Felkin compound 29, which is quite unusual because 28 usually provides high selectivity in favor of the Cram/ Felkin adduct 30 [28].

LDA, THF, - 78 oC

15 +

Ph

8

7

3 6

O

O

O

8

Ph

+

Ph

O

OH

O

O

OH

30

29

28

O

Scheme 7.9

Aldol reaction with (S)-phenylpropionaldehyde

This is a very good example where the inherent selectivity of the enolate overrides the inherent selectivity of the aldehyde with the 6(R),7(S)configuration resulting from double stereodifferentiation using the aldehyde with the (S)-configuration. On the other hand, the same reaction with (R)phenylpropionaldehyde 31 yielded two diastereomers 32 and 33 in a ratio of 40:1 and 77% yield as shown in Scheme 7.10 [26].

3

LDA, THF, - 78 oC

15 +

8

Ph

7 6

O

O

O

8

OH

Ph

+

Ph O

O

O

O 31

32

Scheme 7.10

Aldol reaction with (R)-phenylpropionaldehyde

33

OH

7.3 Model Study via Chelation Control in the Aldol Reaction by Kalesse

319

8

O

O

O

6

O

LDA, THF, - 78 oC

3

7

3

35

O

O

36

8

OH

O 7

3 6

34

O 8

O

Ph

O

O

8

OH 37

28

Scheme 7.11

Double stereodifferentiating aldol reactions with (R)-nucleophile 34

The major isomer was the Cram/Felkin product 32 with the 6(R),7(S),8(R)-configuration which clearly indicated that in the (S),(R)combination of chirality both effects work in the same direction and produce a matching case with very high selectivity. The same holds for the use of the (R)-enolate system as shown in Scheme 7.11 [26]. In contrast, a-chiral aldehydes of type 7 show the opposite behavior, favoring the anti-Cram/Felkin product as the major isomer. In these cases, the matched case is the (S),(S)- or (R),(R)-combination of chirality benefiting of both chiral elements. These correlation studies indicate a dominating influence of the chiral enolate 15 versus the chirality of the aldehyde. In the case of (S)-phenylpropionaldehyde 28 the chirality of enolate 15 overrides the directing effect of the aldehyde chirality, still producing a 2.5:1 ratio in favor of the 6(R),7(S),8(R)-stereochemical triad. The use of the (R)-phenylpropionaldehyde 31 forms exclusively the 6(R),7(S),8(R)-stereo chemical triad in a 40:1 ratio. In this case the matched pair is the (S)/(R)-combination of chirality. The (R)-enantiomer of the enolate reverses the stereochemical outcome. In connection with a synthesis of 6-desmethyl-epothilones Schinzer used methyl ketone 38 instead of the ethyl ketone 15 to study the influence of the missing methyl group. As seen in Scheme 7.12, the selectivity dropped to 1.7:1 still favoring diastereomer 39 with the (S)-configuration at C7 [29]. The lower selectivity can be easily explained by the lack of 1,3-diaxial interactions in the chair-like Zimmerman-Traxler transition state model [30].

7.3

Model Study via Chelation Control in the Aldol Reaction by Kalesse

Kalesse et al. [31] described an aldol reaction where a silyloxy protected ethyl ketone 41 is coupled to an b-oxa-aldehyde 41 based on Roche acid [32] (Scheme

Ph

320

7 The Aldol Reaction in Natural Product Synthesis: The Epothilone Story LDA, THF, - 78 oC 3

+

O

O

O

67%

7

38

3

7

+

8

O

8

O

O

O

O

OH

O

O

OH 40

39 Scheme 7.12

Double stereodifferentiating aldol reactions with methyl ketone 37

7.13). This is a very useful example in connection with the model studies to approach the epothilones. As a result of a chelation-controlled aldol reaction exclusive formation of compound 43 with the desired 6(R),7(S),8(R)-triad was observed. The structure has been confirmed by X-ray analysis after transformation to a crystalline six-membered lactone. In their macro-lactonizsation strategy to synthesize epothilone B Nicolaou et al. used the same ketone 41 in an aldol reaction with aldehyde 19. The diastereoselectivity in the aldol addition was only moderate, giving a ratio of 3:1 in favor of the ‘‘natural’’ epothilone configuration [33].

OBzl

3

+

LDA, THF, - 78 oC

8

O

OTBS OTBS O

42

41

3

OBzl

7 6

8

OH

OTBS OTBS O 43

Scheme 7.13

Chelation-controlled aldol reaction by Kalesse et al.

7.3.1

Different Aldol Strategies: Mulzer’s Total Syntheses of Epothilones B and D

A series of similar aldol reactions were carried out in Mulzer’s lab. In his study towards the total synthesis of epothilone B and D Mulzer et al. used first an achiral ethyl ketone of type 44 in an aldol reaction with the known (S)-aldehyde 45. In this particular case only the chiral element at 44 directed the addition giving a 4:1 mixture of diastereomers 46 and 47. The major di-

7.3 Model Study via Chelation Control in the Aldol Reaction by Kalesse

LDA, THF, - 78 oC

O

OPMB

7

OPMB +

321

8

6

8

+

OH

O

O

44

46

45

OPMB OH

O 47 Scheme 7.14

Chelation-controlled aldol reaction by Mulzer et al.

astereomer with the (R)-configuration at C6 and the (S)-configuration at C7 is formed as a result of a chelated Cram-type aldol reaction. In a later study Mulzer presented examples of double stereodifferentiating aldol reactions with (S)-C3 protected nucleophiles [35]. The same double TBSO-protected (S)-ethyl ketone 41 used before by Kalesse et al. gave 6:1 ratio in an aldol reaction with an a-(S)-chiral aldehyde 48 as a result of matching chirality (70% yield). Again, the major isomer 49 had the ‘‘natural’’ epothilone configuration at C6 and C7. A further modification of the nucleophile 50 yielded the almost exclusive formation (19:1; 92% yield) of the ‘‘correct’’ diastereomer 52 in the presence of the sensitive epoxide function [36]. Both examples shown in Schemes 7.15 and 7.16 are aldol reactions with

O O

S

3

12

+

15

N

OTBS OTBS O

O

OTBS 48

41

O 6

OTBS OTBS O

O

7

3

12

8

15

OH 49

LDA, THF, - 78 oC

8

OTBS

Scheme 7.15

Double stereodifferentiating aldol reactions by Mulzer et al.

S N

322


O S

3

13

+

LDA, THF, - 78 oC

8

O

15

N

OTBS O

12

OTBS 51

50

O

3

7 6

OTBS O

12

8

13 15

OH 52

S N

OTBS

Scheme 7.16

Double stereodifferentiating aldol reactions in the presence of the epoxide functionality by Mulzer et al.

(S)-chiral nucleophiles protected at C3. The stereochemical outcome can most likely be explained by the cyclic transition states discussed in Scheme 7.7. All types of nucleophiles protected at C3 show a predominant effect in driving the aldol reaction in the direction of favoring the anti-Cram/Felkin product. This characteristic seems to be independent of the nature of the aldehyde. The best selectivities were obtained with nucleophile 50 and even superior to that, nucleophile 15 protected as an acetonide. The final part of this chapter will focus on a special type of aldehyde where a long range effect improves the stereochemical outcome of the aldol reaction.

7.4

Long-range Structural Effects on the Stereochemistry of Aldol Reactions

In a study connected with an improved synthesis of epothilone B and deoxyepothilone F, Danishefsky et al. conducted aldol reactions with functionalized ethyl ketones and an g,d-unsaturated aldehyde. Two major studies were carried out in Danishefsky’s lab: One with an achiral system [37] and one with a chiral enolate bearing the correct oxidation level at C1 and a TBSprotected alcohol at C3 [38]. First, in a model study Danishefsky et al. investigated the reaction of a new type of enolate 53 with several aldehydes. The typical Cram/Felkindirecting (S)-phenyl-propionaldehyde 28 gave the expected all-syn orientated compound 54 (Scheme 7.17, 54/55 ¼ 11:1).

7.4 Long-range Structural Effects on the Stereochemistry of Aldol Reactions LDA, THF, - 78 oC

t-BuO +

O

OTES O

8

t-BuO

Ph

Ph O

O

53

OTES O

+

OH

54

28

t-BuO

323

7 6

O

OTES O

8

Ph

OH

55

Scheme 7.17

Model study from Danishefsky et al.

A quite interesting trend was observed with other a-chiral aldehydes. (S)Methyl pentane aldehyde 56 (R ¼ ethyl) behaved only slightly more selectively generating a diastereomeric mixture 57 and 58 of 1:1.3. Unsaturated groups improved the selectivity to about 1:2–1:5.5 (see Scheme 7.18). Danishefsky explained these results by a special long range effect connected to the distance between the formyl and the terminal olefin group via a nonbonding interaction of the carbonyl group of the enolate and the olefin group. The maximum effect can be obtained with a g,d-unsaturated aldehyde 56 (R ¼ allyl; 1:5.5).

t-BuO

R +

O

OTES O

7

OTES O

OTES O 57

R 8

6

O

R + O

56

t-BuO

t-BuO

8

O

53

LDA, THF, - 78 oC

OH

58 R = ethyl, Ph, allyl, dimethylvinyl, OBzl

Scheme 7.18

Aldol reactions of 53 with various aldehydes

In a further series of experiments Danishefsky employed chiral ketones of type 59. Both enantiomers were available with high optical purity and could be involved in investigations in the double stereodifferentiating aldol reaction. However, the lithium anion of 59 (R ¼ TBS) could not be effected in useful yield due to the sensitivity of the b-silyloxy system to elimination. The less basic titanium enolate of 59 gave mixtures of diastereomers in moderate yields. The stereochemical outcome of these reactions showed that the configuration at C3 rather than C8 had a larger effect on the newly

OH

324


t-BuO

LDA, THF, - 78 oC

3

+

O

OR

O

O 60

59

t-BuO

3

t-BuO

6

O

8

OR 61

O

7 8

OH

+ O

OR

O

OH

62

Scheme 7.19

Double stereodifferentiating aldol reaction by Danishefsky et al.

formed centers at C6 and C7. However, the selectivity of about 3.5:1 was quite low (even lower than the result shown in Scheme 7.18), indicating that neither of the enantiomers of 59 and 60 benefited from matching chirality. The difficulty in the lithium series of these aldol reactions caused Danishefsky to investigate the lithium dianion 59 (R ¼ H) as the nucleophile. Indeed, these reactions did not induce b-elimination and provided quite unexpected results with a high level of stereoselectivity [38]. When the lithium dianion of (S)-59 (R ¼ H) was treated with (S)-60 a 2:3 mixture of diastereomers 61 and 62 was obtained in 53% yield, corresponding to the (S)-configuration at C6 and the (R)-configuration at C7 as the major diastereomer. Thus, the major isomer 62 corresponded to the ‘‘unnatural’’ stereochemistry of the epothilones. The minor isomer presented the required ‘‘natural’’ configuration of the epothilones. When the same reaction was then performed with the lithium dianion of (R)-63 (R ¼ H) and the (S)-configurated aldehyde 60 it gave rise to a single diastereomer 64 that contained the ‘‘natural’’ configuration of the epothilones at C6 and C7. This is a result of the matching chirality of the two chiral reaction partners, but represented a major drawback because the center at C3 proved to be (R)configurated. Therefore, it could not be used as a precursor for epothilone syntheses without a troublesome inversion at C3. Despite that, these undesired results from the dianion aldol reactions can be used to understand some principles of the double stereodifferentiating reactions. The C3 protected series, such as Schinzer-type aldol reactions described before required the (S)-configuration at C3 to establish the (R)configuration at C6 and the (S)-configuration at C7 with a similar a-chiral (S)-aldehyde. The matching chirality in the protected series corresponds to the mismatched case in the unprotected series of these double stereodifferentiating aldol reactions. This disparity could be a result of different transition states. Danishefsky proposed five factors governing such aldol reactions: (i) the chair-like transition state leading to a syn-aldol, (ii) chelation of the lithium counter ion by the b-oxygen at C3, (iii) a syn-relationship of the a-proton of the aldehyde and the methyl group at C6 of the enolate, (iv) anti-attack of

7.4 Long-range Structural Effects on the Stereochemistry of Aldol Reactions 3

t-BuO

LDA, THF, - 78 oC +

O

OR

8

O

O 60

63

3

t-BuO

7 6

O

325

OR

8

OH

O

64 Scheme 7.20

Double stereodifferentiating aldol reaction by Danishefsky et al.

H R

O R

O Li O

R

H

O

Li

R

L Me

O Li O

R

O O Li O

O Li O H

H

(i) chair

(ii) chelation

(iii) avoid syn

(iv) aldehde

(v) pentenyl

pentane interactions

attacks anti to R

aldehyde effect

Scheme 7.21

Factors governing the aldol reaction

the aldehyde versus the large group of the enolate, and (v) the special g,dunsaturated aldehyde effect [38]. As a result of all these energy-lowering factors, Danishefsky came up with the following transition state model leading to 64 [38]. A final experiment was designed to check the possibility of an internal kinetic resolution. For this purpose, a racemic mixture of the nucleophile

Ot-Bu H O O

t-BuO

3

7 6

O Li O H

O

OR 64

65 Scheme 7.22

Transition state of Danishefsky-type aldol reaction

O

8

OH

326


59 (R ¼ H) was reacted with homochiral (S)-60. The reaction generated only diastereomer 64 which supported the concept of matching and mismatching issues at the kinetic level [38]. 7.5

Summary and Conclusion

This short chapter gave some insight in the troublesome and quite complicated aldol reaction in the context of epothilone chemistry. All the examples presented were related to the major stereochemical issue around this fascinating class of natural products that is the absolute control of the stereochemical triad C6aC7aC8. Many groups have contributed to that particular stereochemical problem because of the importance of this class of natural products an and optimal solution to this problem obviously is highly desirable. In the meantime, many analogues of the natural epothilones have been synthesized by academic groups and pharmaceutical companies – some of these are even more potent in biological systems than the natural compounds. This could lead to important developments for new anti-cancer drugs in the near future. To our knowledge, the simple acetonide-protected ethyl ketone is the backbone of many industry-based analog programs to achieve the central aldol coupling. This ketone is known as a simple and robust coupling partner yielding exclusively the desired stereochemical outcome with a large number of chiral aldehydes – even on multi kilogram scale. Typical procedure [17]: Synthesis of (4R,5S,6S,4OS)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one 16: A solution of ethyl ketone 15 (1.17 g, 5.45 mmol) in THF (1.0 mL) was added to a freshly prepared solution of LDA [nBuLi (3.34 mL, 1.6 m solution in hexanes, 5.35 mmol, 0.98 equiv) was added to a solution of diisopropylamine (749 mL, 5.35 mmol) in THF (4.0 mL) at 0 C] dropwise at 78 C. The solution was stirred for 1 h at 78 C. Aldehyde 7 (688 mg, 5.45 mmol, 1.0 equiv) was added dropwise and stirring was continued for 45 min at 78 C. The reaction mixture was quenched by dropwise addition of saturated aqueous NH4 Cl solution at 78 C. The organic layer was separated and the aqueous layer was extracted with Et2 O. The combined extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography (pentane/Et2 O ¼ 10:1) of the residue afforded antiCram aldol product 16 (1.36 g, 73%) and Cram aldol product (57 mg, 3%) as colorless oils. References ¨ fle, N. Bedorf, H. Reichenbach, (GBF), DE-4138042, 1 G. Ho 1993 [Chem. Abstr. 1993, 120, 52841].

References ¨ fle, H. Irschik, H. 2 K. Gerth, N. Bedorf, G. Ho Reichenbach, J. Antibiot. 1996, 49, 560–563. ¨ fle, in: Biotechnical Advances, 1993, 3 H. Reichenbach, G. Ho 11, 219–277. ¨ fle, N. Bedorf, H. Steinmetz, D. Schomburg, K. 4 G. Ho

5

6 7 8

9

10

11

12

13 14

15

16 17 18 19 20

21

Gerth, H. Reichenbach, Angew. Chem. 1996, 108, 1671– 1673; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567–1569. a) D. M. Bollag, P. A. McQueney, J. Zhu, O. Jensens, L. Koupal, J. Liesch, M. E. Goetz, C. Lazarides, M. Woods, Cancer Res. 1995, 55, 2325–2333; b) R. J. Kowalski, P. Giannakakou, E. Hamel, J. Biol. Chem. 1997, 272, 2534– 2541. Moos, P. J.; Fitzpatrick, F. A. Proc. Natl. Acad. Sci. USA 1998, 95, 3896–3901. Pratt, W. B.; Buddon, R. W.; Ensminger, W. D.; Maybaum, J. The Anticancer Drugs, Oxford University Press, Oxford, 1994. D. Schinzer, Eur. Chem. Chron. 1996, 1, 7–10; b) M. Kalesse, Eur. Chem. Chron. 1997, 2, 7–11; c) L. Wessjohann, Angew. Chem. 1997, 109, 739–742; Angew. Chem. Int. Ed. Engl. 1997, 36, 739–742; d) K. C. Nicolaou, F. Roschangar, D. Vourloumis, Angew. Chem. 1998, 110, 2120–2153; Angew. Chem. Int. Ed. Engl. 1998, 37, 2014–2045. Wartmann, M.; Altmann, K.-H. Curr. Med. Chem. 2002, 2, 123; b) Harris, C. R.; Kuduk, S. D.; Danishefsky, S. J. Chemistry for the 21st Century 2001, 8. A. Balog, D. Meng, T. Kamenecka, P. Bertinato, D.-S. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976–2978; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801–2803. Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem. 1997, 109, 170–172; Angew. Chem. Int. Ed. Engl. 1997, 36, 166–168. D. Schinzer, A. Limberg, A. Bauer, O. M. Bo¨hm, M. Cordes, Angew. Chem. 1997, 109, 543–544; Angew. Chem. Int. Ed. Engl. 1997, 36, 523–524. N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457. K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, Z. Yang, Angew. Chem. 1996, 108, 2554–2556; Angew. Chem. Int. Ed. Engl. 1996, 35, 2399–2401. K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, F. Roschangar, F. Sarabia, S. Ninkovic, Z. Zang, J. I. Trujillo, J. Am. Chem. Soc. 1997, 119, 7960–7973. D. Schinzer, A. Limberg, O. M. Bo¨hm, Chem. Eur. J. 1996, 2, 1477–1482. D. Schinzer, A. Limberg, A. Bauer, O. M. Bo¨hm, Chem. Eur. J. 1999, 5, 2483–2491. F. Stuhlmann, unpublished results, University of Magdeburg. A. Limberg, PhD thesis, Technical University of Braunschweig, 1998. a) D. Schinzer, A. Bauer, J. Schieber, Chem. Eur. J. 1999, 9, 2492–2500; b) D. Schinzer, A. Bauer, J. Schieber, Synlett. 1998, 861–864. a) R. E. Taylor, Y. Chen, Org. Lett. 2001, 3, 2221–2224; b) R. E. Taylor, G. M. Galvin, K. A. Hilfiker, Y. Chen, J. Org.

327

328


22

23

24

25 26 27

28 29 30 31 32 33

34 35 36 37

38

Chem. 1998, 63, 9580–9583; c) R. E. Taylor, J. D. Haley, Tetrahedron Lett. 1997, 38, 2061–2064; d) N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1999, 121, 4168–4178; e) D. Sawada, M. Shibasaki, Angew. Chem. 2000, 112, 215–219; Angew. Chem. Int. Ed. Engl. 2000, 39, 209–213; f ) D. Sawada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 10521–10532. a) K.-H. Altmann, Mini-Reviews in Medicinal Chemistry 2003, 3, 149; b) U. Klar, W. Skuballa, B. Buchmann, W. Schwede, T. Bunte, J. Hoffmann, R. B. Lichtner, ACS Symposium Series 2001, 796, 131. a) C. H. Heathcock, Science, 1981, 214, 395; b) C. H. Heathcock, C. T. White, J. Am. Chem. Soc. 1979, 101, 7076– 7077; c) C. H. Heathcock, M. C. Pirrung, C. T. Buse, J. P. Hagen, D. S. Young, J. E. Sohn, J. Am. Chem. Soc. 1979, 101, 7077–7079; d) C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, J. Lampe, J. Org. Chem. 1980, 45, 1066–1081. a) D. J. Cram, F. A. Abd Elhafez, J. Am. Chem. Soc. 1952, 74, 5828–5835; b) D. J. Cram, K. R. Kopecky, J. Am. Chem. Soc. 1959, 81, 2748–2755. a) M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968, 2199; b) N. T. Anh, O. Eisenstein, Nouv. J. Chem. 1977, 1, 61. Muharram, planned PhD thesis, University of Magdeburg, 2004. a) S. Masamune, W. Choy, F. A. J. Kerdesky, B. Imperiali, J. Am. Chem. Soc. 1981, 103, 1566–1568; b) C. H. Heathcock, C. T. White, J. Am. Chem. Soc. 1979, 101, 7076–7077; c) S. Masamune, W. Choy, J. S. Petersen, R. L. Sita, Angew. Chem. 1985, 97, 1–31. C. H. Heathcock in Asymmetric Synthesis, Vol 3 (Ed. J. D. Morrison), Academic Press, New York, 1984, 111. O. M. Bo¨hm, University of Magdeburg, unpublished results. H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79, 1920–1923. E. Claus, A. Pahl, P. G. Jones, H. M. Meyer, M. Kalesse, Tetrahedron Lett. 1997, 38, 1359–1362. K. Gerlach, M. Quitschalle, M. Kalesse, Tetrahedron Lett. 1999, 40, 3553. K. C. Nicolaou, S. Nincovic, F. Sarabia, D. Vourloumis, Y. He, H. Vallberg, M. R. V. Finlay, Z. Yang, J. Am. Chem. Soc. 1997, 119, 7974–7991. ¨ hler, Tetrahedron Lett. 1998, J. Mulzer, A. Mantoulidis, E. O 39, 8633–8636. J. Mulzer, G. Karig, P. Pojarliev, Tetrahedron Lett. 2000, 41, 7635–7638. H. J. Martin, M. Drescher, J. Mulzer, Angew. Chem. 2000, 112, 591–593; Angew. Chem. Int. Ed. Engl. 2000, 39, 581–583. A. Balog, C. Harris, K. Savin, X.-G. Zhang, T.-C. Chou, S. J. Danishefsky, Angew. Chem. 1998, 110, 2821–2824; Angew. Chem. Int. Ed. Engl. 1998, 37, 2675–2678. C. B. Lee, Z. Wu, F. Zhang, M. D. Chappel, S. J. Stachel, T.-C. Chou, Y. Guan, S. J. Danishefsky, J. Am. Chem. Soc. 2001, 123, 5249–5259

1

1

Silver, Gold, and Palladium Lewis Acids Akira Yanagisawa 1.1

Introduction

Silver(I), gold(I), and palladium(II) salts have moderate Lewis acidity and have been exploited as catalysts in organic reactions in recent years. Among these salts, Pd(II) compounds are the most well-known reagents for catalyzing a variety of carbon–carbon bond-forming reactions such as allylic alkylations [1]. Ag(I) salts are also popular reagents for promoting transformations, including glycosylation, cycloadditions, and rearrangements, which make use of their halophilicity or thiophilicity [2]. There are, however, few examples of organic reactions employing Au(I) or Au(III) compounds as Lewis acid catalysts. This chapter focuses on aldol reactions catalyzed by silver(I), gold(I), or palladium(II) Lewis acids. The Mukaiyama aldol reaction of silyl enol ethers or ketene silyl acetals and related reactions using silver(I) and palladium(II) compounds are reviewed in Section 1.2. The next section covers the diastereo- and enantioselective aldol-type reactions of activated isocyanides with aldehydes.

1.2

Mukaiyama Aldol Reaction and Related Reactions

Silver(I) compounds are known to promote the aldol condensation between silyl enol ethers or ketene silyl acetals and aldehydes (the Mukaiyama aldol reaction). For example, the adduct 3 is obtained in 72% yield when ketene silyl acetal 1 is treated with a,b-unsaturated aldehyde 2 in the presence of a catalytic amount of Ag(fod) (Scheme 1.1). Eu(fod)3 or Yb(fod)3 catalyzes a hetero-Diels–Alder reaction of 1 and 2 [3]. A [2þ2] cycloaddition followed by a ring opening of the resulting oxetane is an alternative possible route to the adduct 3. A BINAP-silver(I) complex is a superior asymmetric catalyst for allylation of aldehydes with allylic stannanes [4]. The chiral phosphine-silver(I) Modern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

2

1 Silver, Gold, and Palladium Lewis Acids

OSiMe3

O +

MeO

OSiMe3

Ag(fod) (5 mol%)

OHC

Ph 2

OMe

Ph

MeO

CH2Cl2, r.t.

OMe 3 (dr 60:40)

72% yield

1 Scheme 1.1

Ag(fod)-catalyzed Mukaiyama aldol reaction of ketene silyl acetal.

catalyst is prepared simply by stirring a 1:1 mixture of BINAP and silver(I) compound in THF at room temperature. The BINAP-silver(I) complex can be also used as a chiral catalyst of asymmetric aldol reaction. Although a variety of beneficial methods have been developed for catalytic asymmetric aldol reaction, most of these are chiral Lewis acid-catalyzed Mukaiyama aldol reactions using ketene silyl acetals or silyl enol ethers [5] and there has been no example on enol stannanes. Yanagisawa, Yamamoto, and their colleagues first reported the enantioselective aldol addition of tributyltin enolates 4 to aldehydes catalyzed by a BINAP-silver(I) complex (Scheme 1.2) [6]. OSnBu3 2

R + R4CHO

R1 R

(R)-BINAP·AgOTf (10 mol%) THF, -20 °C, 8 h

3

4

O

OH

R1

R4 R2

R

3

5

Scheme 1.2

Enantioselective aldol reaction of tributyltin enolates catalyzed by BINAPsilver(I) complex.

The tributyltin enolates 4 are easily generated from the corresponding enol acetates and tributyltin methoxide without any solvent [7]. The tin compounds thus prepared exist in the O-Sn form and/or the C-Sn form. Although the tin reagents themselves have sufficient reactivity toward aldehydes [7c], under the influence of the BINAP-silver(I) catalyst the reaction advances faster even at 20 C. The results employing optimum conditions in the catalytic enantioselective aldol reaction of a variety of tributyltin enolates or a-tributylstannylketones with aromatic, a,b-unsaturated, and aliphatic aldehydes are summarized in Table 1.1. The characteristic features are: (i) all reactions occur to provide the corresponding aldol adducts 5 in moderate to high yield in the presence of 10 mol% (R)-BINAP-AgOTf complex at 20 C, and no dehydrated aldol adduct is formed; (ii) with an a,bunsaturated aldehyde, the 1,2-addition reaction is predominant (entry 3); (iii) use of a sterically hindered tin enolate results in an increase in the

1.2 Mukaiyama Aldol Reaction and Related Reactions

3

Tab. 1.1

Diastereo- and enantioselective aldol addition of tin compounds to aldehydes in the presence of 10 mol% of (R)-BINAPAgOTf complex in THF at 20 C. Entry Tin Compound

Aldehyde

O

O

1d

SnBu3

Ph

5a O

O t-Bu

OH

PhCHO

6

2d

Yield (%)a anti:syn b ee (%)c

Product

SnBu3

PhCHO

t-Bu

7

Ph

* Ph

5b

Ph

t-Bu

t-Bu

69

86

75

94

OH

t-Bu

4a

Ph

81

99:1. g The syn isomer: 25% ee. h 1 mol% catalyst was used. i The syn isomer: 33% ee. b Determined

enantioselectivity of the aldol reaction. For example, ee higher than 90% are observed when pinacolone and tert-butyl ethyl ketone-derived tin compounds 7 and 4a are treated with aldehydes (entries 2 and 4–6); (iv) addition of the enol tributylstannane 4b derived from cyclohexanone ((E)-enolate) to

4


P

H R R2

O

E

R

Ag+

O

R3

P SnBu3

P

H

*

1

H

*

1

Ag+

O

R3

O

Z

P SnBu3

R2

H A

anti

B

syn

Fig. 1.1

Probable structures of cyclic transition states.

benzaldehyde in the presence of 10 mol% (R)-BINAP-AgOTf in THF at 20 C yields the non-racemic anti aldol adduct 5g selectively with an anti:syn ratio of 92:8, in contrast with the syn selectivity afforded by representative chiral Lewis acid catalysts [5]. The anti isomer indicates 93% ee (entry 7). The amount of catalyst can be reduced to 1 mol% without losing the isolated yield or diastereo- and enantioselectivity (entry 8). In contrast, the (Z) enolate generated from tert-butyl ethyl ketone 4a produces the synaldol adducts 5e and 5f almost exclusively with 95% ee in the reaction with benzaldehyde and hydrocinnamaldehyde (entries 5 and 6). These results reveal unambiguously that the diastereoselectivity relies on the geometry of tin enolate, and that cyclic transition-state structures (A and B, Figure 1.1) are plausible models. Accordingly, from the (E) enolate, the anti-aldol product forms via a model A, and another model B for the (Z) enolate leads to the syn product. Analogous six-membered cyclic models including a BINAP-coordinated silver atom in place of a tributylstannyl group are also probable substitutes when the transmetalation to silver enolate is sufficiently rapid. Although the above-mentioned reaction is a superior asymmetric aldol process with regard to enantioselectivity and diastereoselectivity, it has a disadvantage of requiring the stoichiometric use of toxic trialkyltin compounds. The same group has shown that the amount of trialkyltin compounds can be reduced to a catalytic amount when an enol trichloroacetate is employed as a substrate for the reaction [8]. For example, treatment of benzaldehyde with the enol trichloroacetate of cyclohexanone 8 under the influence of (R)BINAP-AgOTf complex (5 mol%), tributyltin methoxide (5 mol%), and MeOH (200 mol%) in dry THF at 20 C to room temperature for 20 h provides a 92:8 mixture of non-racemic anti and syn aldol adduct, 5g-anti and 5g-syn respectively, in 82% yield (Scheme 1.3). The anti isomer 5g-anti affords 95% ee, a grade of enantiomeric excess similar to that obtained from a BINAP-silver(I)-catalyzed aldol reaction with enol tributylstannanes [6]. A suggested catalytic cycle of this asymmetric aldol reaction is shown in Figure 1.2. To start with, Bu3 SnOMe reacts with enol trichloroacetate 9 to yield trialkyltin enolate 4 and methyl trichloroacetate. The tin enolate 4 then adds enantioselectively to an aldehyde under the influence of BINAP-AgOTf


(R)-BINAP·AgOTf (5 mol%) Bu3SnOMe (5 mol%) MeOH (200 mol%)

OCOCCl3 +

PhCHO

O

5

OH

O Ph +

Ph

THF, -20 °C (8 h) ~ r.t. (12 h) 82% yield

8

5g-anti (2S,1'R)

5g-syn (2R,1'R)

anti:syn = 92 (95% ee):8 Scheme 1.3

Enantioselective aldol reaction catalyzed by tin methoxide and BINAPsilver(I) complex.

as an asymmetric catalyst to furnish the tin alkoxide of non-racemic aldol adduct 10. Last, protonolysis of 10 by MeOH produces the optically active aldol product 5 and regenerates the tin methoxide. The rate of methanolysis is considered to be the key to success in the catalytic cycle. The BINAP-Ag(I)-catalyzed asymmetric Mukaiyama aldol reaction using trimethylsilyl enol ethers was first developed by Yamagishi and co-workers, who found that the reaction was accelerated by BINAP-AgPF6 in DMF containing a small amount of water, to give the aldol product with high enantioselectivity [9] (Scheme 1.4). In the reaction with BINAP-AgOAc, much higher catalytic activity and opposite absolute configuration of the aldol adduct were observed and ee was low [9]. Yanagisawa, Yamamoto, and their colleagues independently examined different combinations of BINAP-Ag(I) catalysts and silyl enol ethers and found that high enantioselectivity and chemical yields were obtained in the p-Tol-BINAP-AgF-catalyzed aldol reaction of trimethoxysilyl enol ethers in

O

(R)-BINAP·AgOTf R

OSnBu3

1

R4 R2 R 3 10

R4CHO

R1

OH

MeOH

OSnBu3 R2

O

3 4 R

Bu3SnOMe

MeOCOCCl3 R1

OCOCCl3 R2 9 R3

Fig. 1.2

A proposed catalytic mechanism for the asymmetric aldol reaction catalyzed by (R)-BINAPAgOTf and tin methoxide.

OH

R1

R4 R2 R 3 5


6

OSiMe3

O

(S)-BINAP·AgPF6 (2 mol%)

+ Ph

Ph

H

O

HCl

DMF + 2% H2O, 25 °C, 2 h

THF

OH

Ph

11

Ph

12, 69% ee (S)

100% yield Scheme 1.4

BINAPsilver(I)-catalyzed asymmetric Mukaiyama aldol reaction.

methanol [10]. In addition, remarkable syn selectivity was observed for the reaction irrespective of the E:Z stereochemistry of the silyl enol ethers. For example, when the (Z)-trimethoxysilyl enol ether of t-butyl ethyl ketone 13 was treated with benzaldehyde the reaction proceeded smoothly at 78 to 20 C and syn-aldol adduct 5e was obtained almost exclusively with 97% ee (Scheme 1.5). In contrast, cyclohexanone-derived (E)-silyl enol ether gave the aldol adduct with an anti:syn ratio of 84:16 [10]. Use of a 1:1 mixture of MeOH and acetone as a solvent in the reaction of the trimethoxysilyl enol ethers resulted in higher enantioselectivity [10b]. O

OSi(OMe)3 +

OH

(R)-p-Tol-BINAP·AgF (10 mol%) PhCHO

t-Bu

MeOH, -78 ~ -20 °C, 6 h

13

84% yield

t-Bu

Ph

5e, syn:anti > 99 (97% ee):1

Scheme 1.5

Enantioselective aldol reaction of trimethoxysilyl enol ether catalyzed by p-Tol-BINAPAgF complex.

The BINAP-silver(I) complex was further applied to asymmetric Mannich-type reactions by Lectka and coworkers [11]. Treatment of silyl enol ether 11 with a solution of a-imino ester 14 in the presence of 10 mol% (R)-BINAP-AgSbF6 at 80 C leads the corresponding a-amino acid derivative 15 in 95% yield with 90% ee (Scheme 1.6). They showed that (R)BINAP-Pd(ClO4 )2 was also an effective chiral Lewis acid for the reaction though it gave lower ee (80%). Asymmetric Mukaiyama aldol reactions can also be catalyzed by cationic BINAP-Pd(II) complexes. In 1995 Sodeoka, Shibasaki et al. first reported Ts

OSiMe3

N

+ H

Ph 11

O

(R)-BINAP·AgSbF6 (10 mol%) CO2Et 14

THF, -80 °C, 24 h 95% yield

Ph

N

Ts

CO2Et 15, 90% ee

Scheme 1.6

Enantioselective Mannich-type reaction catalyzed by BINAPsilver(I) complex.


(R)-BINAP·PdCl2 (5 mol%) AgOTf (5 mol%)

OSiMe3 + OHC

Ph

Ph 16

11

O

H+

7

OH

Ph

MS 4A, DMF-H2O, 23 °C

Ph 17, 73% ee (S)

86% yield Ar P

Ar

OH2 Pd2+ 2BF4– OH2 P Ar Ar 22, Ar = Ph 23, Ar = p-Tol

Ar P

H Ar

O

Ar

Ar P

Pd+ Pd+ O P P Ar Ar H Ar Ar 24, Ar = Ph 25, Ar = p-Tol

Scheme 1.7

Asymmetric Mukaiyama aldol reaction catalyzed by cationic BINAPPd(II) complexes.

that (R)-BINAP-PdClþ , prepared from a 1:1 mixture of (R)-BINAP-PdCl2 and AgOTf in wet DMF is an effective chiral catalyst for asymmetric aldol condensation of silyl enol ethers and aldehydes [12]. For instance, when hydrocinnamaldehyde (16) is treated with trimethylsilyl enol ether of acetophenone 11 under the influence of 5 mol% of this catalyst followed by desilylation the desired aldol adduct 17 is obtained in 86% yield with 73% ee as shown in Scheme 1.7. Some examples of the aldol reaction are summarized in Table 1.2. The same group subsequently succeeded in generating chiral palladium diaquo complexes 22 and 23 from (R)-BINAP-PdCl2 and (R)- pTol-BINAP-PdCl2 , respectively, by treatment with 2 equiv. AgBF4 in wet acetone [13]. These complexes are inert toward air and moisture, and have similar reactivity and enantioselectivity in the aldol reaction of 11 with the aliphatic aldehyde 16. Sodeoka et al. have further developed catalytic asymmetric Mannich-type reactions of silyl enol ethers with imines employing binuclear m-hydroxo palladium(II) catalysts 24 and 25 generated from the diaquo complexes 22 and 23, respectively [14]. In the reaction, a chiral palladium(II) enolate is assumed to be formed from the corresponding silyl enol ether. They later developed palladium complexes with polymer-supported BINAP ligands and showed that these reusable complexes are good catalysts for the asymmetric aldol reactions and Mannich-type reactions mentioned above [15]. Doucet and coworkers have shown that the complex dppe-Pd(OAc)2 is an efficient catalyst for Mukaiyama aldol addition of ketene silyl acetals to aldehydes and ketones under neutral conditions [16]. The reaction proceeds smoothly, even in the presence of 0.1 mol% of the catalyst. [Bis(diphenylphosphino)alkane]bis(propenyl)ruthenium complexes also catalyze the aldol addition, furnishing a variety of 3-hydroxymethyl esters in good yields, as do other late transition metal complexes; platinum(II) cationic complexes are known to act as Lewis acids. Fujimura reported the first

2BF4–

8

1 Silver, Gold, and Palladium Lewis Acids Tab. 1.2

Catalytic asymmetric aldol reaction of silyl enol ethers with benzaldehyde in the presence of 5 mol% (R)-BINAPPdCl2 aAgOTf in wet DMF. Entry

Silyl Enol Ether

Product

OSiMe3

1c

O

Ph

ee (%)b

87d

71

80

73

58e

72f

OSiMe3

Ph 11

Yield (%)a

Ph 18

OSiMe3

O

OH Ph

2 20

19 OSiMe3

O

OH

3

Ph 21

5g

a Isolated

yield. by HPLC analysis with chiral columns. c Desilylation with acid was not done. d Desilylated product was formed in 9% yield with 73% ee. e The syn:anti ratio was 74:26. f The value corresponds to the major diastereomer. b Determined

example of platinum-catalyzed enantioselective aldol reaction of ketene silyl acetals with aldehydes [17]. The chiral catalysts are prepared by treatment of chiral bisphosphine-Pt acyl complexes with triflic acid. In the aldol reaction, a C-bound platinum enolate is assumed to be an intermediate, on the basis of on 31 P NMR and IR studies.

1.3

Asymmetric Aldol Reactions of a-Isocyanocarboxylates

In 1986, Ito, Sawamura, and Hayashi showed that chiral ferrocenylphosphine 26-gold(I) complexes catalyzed the aldol-type reaction of isocyanoacetate with aldehydes to provide optically active 5-alkyl-2-oxazoline-4carboxylate (Scheme 1.8) [18]. Since then, they have extensively studied the chiral gold(I)-catalyzed reaction [19] as have Pastor and Togni [20]. The gold complexes can be generated in situ by mixing bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate and (R)-N-methyl-N-[2-(dialkylamino)ethyl]-1-[(S)-1 0 ,2-bis(diphenylphosphino)ferrocenyl]ethylamine (26). Examples of the reaction of methyl isocyanoacetate (27) and different aldehydes in the presence of 1 mol% of 26c-Au(I) complex are summarized in

1.3 Asymmetric Aldol Reactions of a-Isocyanocarboxylates

Me

H N

Fe

NR'2 + [Au(c-HexNC)2]BF4

PPh2

Me PPh2 26

26·Au(I) complex

CH2Cl2

26a: NR'2 = NMe2 26b: NR'2 = N 26c: NR'2 = N

CO2Me + RCHO

O

26·Au(I) complex (1 mol%)

R

CH2Cl2, 25 °C

O

NC

CO2Me R

CO 2Me

+

27

N

O

trans-28

N

cis-28

H3O+ NH2 R

CO2H OH syn-29

NH2

NH2 OH

n-C13H27 OH D-syn-sphingosine

OH

n-C13H27 OH

(30)

D-anti-sphingosine

(31)

NHMe CO2H OH MeBmt [(4R)-4-((E)-But-2-enyl)-4,N-dimethyl-L-threonine, 32] Scheme 1.8

Asymmetric aldol reaction of methyl isocyanoacetate with aldehydes catalyzed by chiral ferrocenylphosphine 26–gold(I) complexes.

Table 1.3. Benzaldehyde and substituted aromatic aldehydes, except 4nitrobenzaldehyde, are transformed into the corresponding trans-oxazolines 28 with high enantio- and diastereoselectivity (entries 1–6). Secondary and tertiary alkyl aldehydes give trans-28 nearly exclusively with high ee (entries 9 and 10). The trans-oxazolines 28 can be readily hydrolyzed to threo-b-

9


10 Tab. 1.3

Diastereo- and enantioselective aldol reaction of methyl isocyanoacetate (27) with aldehydes catalyzed by chiral ferrocenylphosphine 26cgold(I) complex. Entry Aldehyde

Yield, %a trans:cis b % ee c

Product Ph

1

CO2Me

Ph

PhCHO

O

N

O

trans-28a

N

CO2Me 2-MeC6H4

O Me

O

N

trans-28b 2-MeOC6H4

CHO

trans-28c CO2Me

O

4-ClC6H4

N

CO2Me 4-O2NC6H4

O

O

N

N

CO2Me

O CHO

O

+

N

O

83:17

86

86

95:5

96

85

87:13

92

99

89:11

89

99

96:4

87

N

CO2Me +

CHO

Me

O

N

CO2Me

N

cis-28g Me

CO2Me

+ O

N

O

trans-28h i-Bu i-BuCHO

80

cis-28f

trans-28g

9

94

n-Pr

O

MeCHO

94:6

CO2Me

O

CO2Me

8d

97

O

n-Pr n-Pr

92

cis-28e

trans-28f

7

92:8

CO2Me

+ O

O O

98

cis-28d

trans-28e

6

95

CO2Me

O

N

4-O2NC6H4 CHO

96:4

cis-28c

trans-28d

O 2N

N

+

CHO

98

CO2Me

O

N

4-ClC6H4 Cl

95

cis-28b

CO2Me 2-MeOC6H4

O OMe

5

N

+

3

95:5

CO2Me

+

2

93

cis-28a

2-MeC6H4

CHO

4

CO2Me

+

N cis-28h

CO2Me

i-Bu

CO 2Me

+ O

N

trans-28i

O

N cis-28i


11

Tab. 1.3

(continued) Entry Aldehyde

CO2Me

t-Bu

10

Yield, %a trans:cis b % ee c

Product CO2Me

t-Bu +

t-BuCHO

O

N

O

trans-28j

N

94

cis-28j

a Isolated

yield. by 1 H NMR analysis. c Determined by 1 H NMR analysis with chiral shift reagent Eu(dcm) . 3 d 0.2 mol% of the catalyst was used. b Determined

hydroxy a-amino acids 29. The gold-catalyzed aldol reaction has been applied to the asymmetric synthesis of the biologically important compounds d-threo-sphingosine (30) [21], d-erythro-sphingosine (31) [21], and MeBmt (32) [22]. The enantioselective synthesis of ()-a-kainic acid has also been achieved using this aldol reaction [23]. A proposed transition-state model for the reaction is shown in Figure 1.3. The presence of the 2-(dialkylamino)ethylamino group in 26 is necessary to obtain high selectivity [24]. The terminal amino group abstracts one of the a-protons of isocyanoacetate coordinated with gold, and the resulting ion pair causes advantageous arrangement of the enolate and aldehyde around the gold. In contrast, Togni and Pastor proposed an alternative acyclic transition-state model [20d]. The chiral ferrocenylphosphine-gold(I)-catalyzed aldol reaction of a-alkyl a-isocyanocarboxylates 33 with paraformaldehyde gives optically active 4alkyl-2-oxazoline-4-carboxylates 34 with moderate to good enantioselectivity [25]. The absolute configuration (S) of the product indicates that the reaction proceeds selectively at the si face of the enolate, as illustrated in Figure 1.3. These oxazolines 34 can be converted into a-alkylserine derivatives 35 (Scheme 1.9).

H

Ph Ph P

+ Au

Fe P

Ph

Me Me

Ph

O C

R N

O– OMe

+ NHR'2 H

N

Fig. 1.3

Transition-state assembly in the gold-catalyzed asymmetric aldol reaction.

>99:1

97

12


CO2Me + (CH2O)n

R

L*·[Au(c-HexNC)2]BF4 (1 mol%) CH2Cl2, 25 °C

NC

MeO2C R O

33 R = Me, Et, i-Pr, Ph L* = 26a or 26b

N

(S)-34 63~81% ee H 3O + MeO2C R NH2 HO (S)-35

Scheme 1.9

Catalytic asymmetric synthesis of a-alkylserines.

This enantioselective aldol reaction using isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes, as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R ¼ Me) in the aldol reaction with N,N-dimethyl-a-isocyanoacetamide (36) (Scheme 1.10) [26]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90% ee [27]. The same group also developed an asymmetric aldol reaction of Nmethoxy-N-methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Scheme 1.10). For instance, reaction of the Weinreb amide 37 with acetaldehyde in the presence of 26c-Au(I) catalyst gives the optically active trans-oxazoline 39 (E ¼ CON(Me)OMe; R ¼ Me) with high diastereoand enantioselectivity similar to those of 36 [28]. The oxazoline can be transformed into N,O-protected b-hydroxy-a-amino aldehydes or ketones. (Isocyanomethyl)phosphonate 38 is also a beneficial pronucleophile that leads to optically active (1-aminoalkyl)phosphonic acids, which are

E +

RCHO

NC 36~38

L*·[Au(c-HexNC)2]BF4 (1 mol%)

R O

N

O

trans-39 E

R

L*

CONMe2 (36) CON(Me)OMe (37) PO(OPh)2 (38)

Me Me Ph

26b 26c 26b

Gold(I)-catalyzed asymmetric aldol reaction of isocyanoacetamides and (isocyanomethyl)phosphonate.

E

+

CH2Cl2, 25 °C

Scheme 1.10

R

E

N

cis-39

trans (% ee) : cis 91 (99) : 9 95 (97) : 5 >98 (96) : 2


E +

R

E

O

N

26b·Ag(I) (1~2 mol%)

E

+

RCHO solvent, 25~30 °C

NC 27 or 40

R O

trans-39

E

R

Ag(I)

Solvent

CO2Me (27)a CO2Me (27)a SO2(p-Tol) (40) SO2(p-Tol) (40)

Ph i-Pr Ph i-Pr

AgOTf AgClO4 AgOTf AgOTf

ClCH2CH2Cl ClCH2CH2Cl CH2Cl2 CH2Cl2

N

cis-39

trans (% ee) : cis 96 (80) : 4 99 (90) : 1 >99 (77) : 1 >99 (86) : 1

a) slow addition of 27 over 1 h. Scheme 1.11

Asymmetric aldol reaction of methyl isocyanoacetate and tosylmethylisocyanide catalyzed by chiral ferrocenylphosphinesilver(I) complex.

phosphonic acid analogs of a-amino acids, via trans-5-alkyl-2-oxazoline-4phosphonates 39 (E ¼ PO(OPh)2 , Scheme 1.10) [29]. Ito and coworkers found that chiral ferrocenylphosphine-silver(I) complexes also catalyze the asymmetric aldol reaction of isocyanoacetate with aldehydes (Scheme 1.11) [30]. It is essential to keep isocyanoacetate at a low concentration to obtain a product with high optical purity. They performed IR studies on the structures of gold(I) and silver(I) complexes with chiral ferrocenylphosphine 26a in the presence of methyl isocyanoacetate (27) and found a significant difference between the coordination numbers of the isocyanoacetate to the metal in these metal complexes (Scheme 1.12). The P 26a Au+ CNCH2CO2Me P

41 RCHO high ee

low ee

RCHO

RCHO P

P 26a Ag

+

+27 CNCH2CO2Me

P

42

-27

Scheme 1.12

A difference in the coordination number of methyl isocyanoacetate to metal between gold(I) and silver(I) complexes.

26a Ag+ P

CNCH2CO2Me CNCH2CO2Me 43

13

14


gold(I) complex has a tricoordinated structure 41, which results in high ee, whereas the silver(I) complex is in equilibrium between tricoordinated structure 42 and tetracoordinated structure 43, which results in low enantioselectivity. Slow addition of isocyanoacetate 27 to a solution of the silver(I) catalyst and aldehyde effectively reduces the undesirable tetracoordinated species and results in high enantioselectivity. The asymmetric aldol-type addition of tosylmethyl isocyanide (40) to aldehydes can also be catalyzed by the chiral silver(I) complex giving, almost exclusively, trans-5-alkyl-4-tosyl-2-oxazolines 39 [E ¼ SO2 ( p-Tol)] with up to 86% ee, as shown in Scheme 1.11 [31]. The slow addition method described above is not necessary for this reaction system. Soloshonok and Hayashi used chiral ferrocenylphosphine-gold(I) complexes in asymmetric aldol-type reactions of fluorinated benzaldehydes with methyl isocyanoacetate (27) and N,N-dimethyl-a-isocyanoacetamide (36). Interestingly, successive substitution of hydrogen atoms by fluorine in the phenyl ring of benzaldehyde causes a gradual increase in both the cis selectivity and the ee of cis oxazolines [32]. Cationic chiral palladium complexes are known to catalyze the aldol reaction of methyl isocyanoacetate (27) and aldehydes. For example, Richards et al. prepared cationic 2,6-bis(2-oxazolinyl)phenylpalladium(II) complex 44 from the corresponding bromopalladium(II) complex and AgSbF6 in wet CH2 Cl2 and showed that an increase in rate was observed for the aldol reaction of 27 with benzaldehyde in the presence of 1 mol% 44 and 10 mol% Hu¨nigs base [33]. Zhang and coworkers developed a palladium(II) complex of PCP-type chiral ligand 46 (PCP is the monoanionic ‘‘pincer’’ ligand [C6 H3 (CHMePPh2 )2 -2,6] ). Removal of the chloride with AgOTf produces an active cationic chiral Pd(II) catalyst for the asymmetric aldol reaction of aldehydes (Scheme 1.13) [34]. Several examples of the reaction under the influence of 1 mol% of catalyst 46 are summarized in Table 1.4. When the effects of solvent on enantioselectivity were examined in the reaction with benzaldehyde, THF was found to be solvent of choice (trans-47a: 24% ee, cis47a: 67% ee, entry 1). The trans isomers were usually obtained as major products though with lower ee. In the reaction with aromatic aldehydes the enantioselectivity is almost constant (entries 1–5) and the trisubstituted aromatic aldehyde gives the highest ee (entry 5). It is noteworthy that higher enantioselectivity is observed with aliphatic aldehydes than with aromatic aldehydes with regard to their cis product (entries 6 and 7). l-Valine-derived NCN-type Pd(II) complex 48 (NCN is the monoanionic, para-functionalized ‘‘pincer’’ ligand [C6 H2 (CH2 NMe 2 )2 -2,6] ) synthesized by van Koten and coworkers is also an active catalyst for the aldol reaction after conversion into the corresponding cationic complex by treatment with AgBF4 in wet acetone [35]. Motoyama and Nishiyama have shown that excellent trans diastereoselectivity (> 99% trans) and moderate enantioselectivity (57% ee) was obtained in the asymmetric aldol-type condensation of tosylmethyl isocyanide with benzaldehyde employing cationic Pd(II) aqua complex 45 [36].

1.4 Summary and Conclusions

+ X– O

O N i-Pr

Pd

Ph2P

N

H H2O i-Pr 44 (X = SbF6) 45 (X = BF4)

CO2Me + RCHO

PPh2

46

46/AgOTf (1 mol%) (i-Pr)2NEt (10 mol%)

R

THF, 23 °C

O

NC

Pd Cl

H

27

CO2Me R

CO2Me

+ N

trans-47

O

N

cis-47

NMe2 Pd Br NH NMe2

HO2C 48 Scheme 1.13

Asymmetric aldol reaction of methyl isocyanoacetate with aldehydes catalyzed by cationic chiral palladium(II) complexes.

Other notable examples of the aldol-type reaction using a variety of palladium complexes have also appeared [37–41].

1.4

Summary and Conclusions

Described herein are examples of aldol reactions using silver(I), gold(I), or palladium(II) Lewis acids. The BINAP-silver(I) catalyst has made possible the aldol reaction of silyl enol ethers or trialkyltin enolates with high enantio- and diastereoselectivity. This silver catalyst is also effective in Mannich-type reactions of silyl enol ethers with a-imino esters. The remarkable affinity of the silver ion for halides is useful for accelerating chiral palladium-catalyzed asymmetric Mukaiyama aldol reactions. Isolated chiral palladium diaquo complexes and binuclear m-hydroxo palladium(II) complexes can catalyze asymmetric Mannich-type reactions and the aldol reaction. The chiral ferrocenylphosphine gold(I)-catalyzed asymmetric aldol reaction results in high stereoselectivity, although the substrates are restricted to a-isocyanocarboxylates and their derivatives, and has proven to be an excellent method for synthesizing optically active a-amino acid derivatives and

15

PhCHO

1

CH3

O 2N

3

4

2

Aldehyde

Entry

CHO

CHO

CHO

N

N

+

N

+

N

N

CO2Me

cis-47d

O

N

CO2Me

cis-47b

O

CO2Me

cis-47c

O

CO2Me 4-O2NC6H4

trans-47d

O

4-O2NC6H4

+

CO2Me 4-MeC6H4

trans-47c

O

4-MeC6H4

N

CO2Me

cis-47a

O

Ph

CO2Me N

+

trans-47b

O

CO2Me

trans-47a

O

Ph

Product

60

80

81

85

Yield, %a

74:26

82:18

81:19

78:22

trans:cis b

21

11

23

24

trans

% ee c

Asymmetric aldol reaction of methyl isocyanoacetate (27) with aldehydes catalyzed by a cationic Pd(II) complex generated from 46 and AgOTf.

Tab. 1.4

57

61

66

67

cis

16


EtCHO

CHO

CHO

b Determined

yield. by 1 H NMR analysis. c Determined by GC analysis.

a Isolated

7

6

5

N

CO2Me

trans-47g

O

Et

N

+

CO2Me

trans-47f

O

c-C6H11

N

+

N

CO2Me

cis-47g

O

Et

N

N

CO2Me

cis-47e

O

CO2Me

cis-47f

O

c-C6H11

+

CO2Me 2,4,6-Me3C6H2

trans-47e

O

2,4,6-Me3C6H2

91

97

84

91:9

72:28

86:14

30

11

26

70

74

71

1.4 Summary and Conclusions 17

18


amino alcohols. The examples given here unambiguously indicate that silver(I), gold(I), and palladium(II) compounds in combination with chiral ligands are chiral Lewis acid catalysts of great promise for asymmetric synthesis.

1.5

Experimental Procedures Typical Procedure for Asymmetric Aldol Reaction of Benzaldehyde with 3,3Dimethyl-1-tributylstannyl-2-butanone (7) Catalyzed by BINAP-AgOTf Complex. Synthesis of (R)-4,4-Dimethyl-1-hydroxy-1-phenyl-3-pentanone (5b, entry 2 in Table 1.1) [6]. A mixture of AgOTf (26.7 mg, 0.104 mmol) and (R)BINAP (64.0 mg, 0.103 mmol) was dissolved in dry THF (3 mL) under argon atmosphere and with direct light excluded and stirred at 20 C for 10 min. To the resulting solution was added dropwise a THF solution (3 mL) of benzaldehyde (100 mL, 0.98 mmol), and then 3,3-dimethyl-1tributylstannyl-2-butanone (7, 428.1 mg, 1.10 mmol) was added over a period of 4 h with a syringe pump at 20 C. The mixture was stirred for 4 h at this temperature and treated with MeOH (2 mL). After warming to room temperature, the mixture was treated with brine (2 mL) and solid KF (ca. 1 g). The resulting precipitate was removed by filtration and the filtrate was dried over Na2 SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford the aldol adduct 5b (161.7 mg, 78% yield as a colorless oil). TLC RF 0.22 (1:5 ethyl acetate–hexane); IR (neat) 3625–3130, 3063, 3033, 2971, 2907, 2872, 1701, 1605, 1495, 1478, 1455, 1395, 1368, 1073, 1057, 1011, 984, 914, 878, 760, 747, 700 cm1 ; 1 H NMR (CDCl3 ) d (ppm) 1.14 (s, 9 H, 3 CH3 ), 2.89 (d, 2 H, J ¼ 5.7 Hz, CH2 ), 3.59 (d, 1 H, J ¼ 3.0 Hz, OH), 5.13 (m, 1 H, CH), 7.29–7.39 (m, 5 H, aromatic); [a] 30 D þ61.5 (c 1.3, CHCl3 ). The enantioselectivity was determined to be 95% ee by HPLC analysis using a chiral column (Chiralcel OD-H, Daicel Chemical Industries, hexane–i-PrOH, 20:1, flow rate 0.5 mL min1 ); t minor ¼ 17.7 min, t major ¼ 20.2 min. Typical Procedure for Silver(I)-catalyzed Asymmetric Mukaiyama Aldol Reaction of Benzaldehyde with Acetophenone Silyl Enol Ether 11. Synthesis of (S)-1Hydroxy-1,3-diphenyl-3-propanone (12, Scheme 1.4) [9]. Wet DMF containing 2% H2 O (206 mL) was added under nitrogen atmosphere to a mixture of AgPF6 (4.0 mg, 0.013 mmol) and (S)-BINAP (8.4 mg, 0.013 mmol) and the solution was stirred at room temperature for 10 min. Benzaldehyde (69 mL, 0.67 mmol) was added and stirring was continued for 10 min. Acetophenone silyl enol ether 11 (276 mL, 1.35 mmol) was added and the mixture was stirred for 2 h at 25 C. It was filtered through a short silica gel column, concentrated in vacuo, and clear oil was obtained. The oil was hydrolyzed

1.5 Experimental Procedures

with 1 m HCl THF/H2 O (1:1) solution, extracted with ether, dried over anhydrous sodium sulfate, concentrated in vacuo to afford a pale clear oil. This oil was purified by column chromatography on silica gel (1:1 ethyl acetate– hexane) to give the (S)-enriched aldol adduct 12 (100% yield, 69% ee). 1 H NMR (CDCl3 ) d (ppm) 3.38 (d, 2 H, J ¼ 5.9 Hz, CH2 ), 3.56 (d, 1 H, J ¼ 3.0 Hz, OH), 5.35 (dt, 1 H, J ¼ 3.0, 5.9 Hz, CH), 7.26–7.62 (m, 8 H, aromatic), 7.95 (d, 2 H, J ¼ 7.3 Hz, aromatic); FAB-MS calcd. for C15 H14 O2 , 226 (Mþ ); found 227 ((M þ 1)þ ), 209 ((M-OH)þ ); HPLC analysis using a chiral column (Chiralcel OB-H, Daicel Chemical Industries, hexane–i-PrOH, 9:1, flow rate 0.9 mL min1 ); t minor ¼ 22.5 min (R), t major ¼ 33.5 min (S). Typical Procedure for Asymmetric Aldol Reaction of Trimethoxysilyl Enol Ether 13 with Benzaldehyde Catalyzed by (R)- p-Tol-BINAP-AgF Complex. Synthesis of 1-Hydroxy-2,4,4-trimethyl-1-phenyl-3-pentanone (5e, Scheme 1.5) [10]. A mixture of AgF (13.0 mg, 0.102 mmol) and (R)- p-Tol-BINAP (67.9 mg, 0.100 mmol) was dissolved in dry MeOH (6 mL) under an argon atmosphere and with direct light excluded, and stirred at 20 C for 10 min. Benzaldehyde (100 mL, 0.98 mmol) and t-butyl ethyl ketone-derived trimethoxysilyl enol ether 13 (236.9 mg, 1.01 mmol) were successively added dropwise, at 78 C, to the resulting solution. The mixture was stirred at this temperature for 2 h, then at 40 C for 2 h, and finally at 20 C for 2 h. It was then treated with brine (2 mL) and solid KF (ca. 1 g) at ambient temperature for 30 min. The resulting precipitate was removed by filtration through a glass filter funnel filled with Celite and silica gel. The filtrate was dried over Na2 SO4 and concentrated in vacuo after filtration. The crude product was purified by column chromatography on silica gel (1:5 ethyl acetate–hexane as eluent) to afford a mixture of the aldol adduct 5e (181.2 mg, 84% yield). The syn/anti ratio was determined to be >99/1 by 1 H NMR analysis. The enantioselectivity of the syn isomer was determined to be 97% ee by HPLC analysis using a chiral column (Chiralcel OD-H, Daicel Chemical Industries, hexane–i-PrOH, 40:1, flow rate 0.5 mL min1 ); tsyn-minor ¼ 17.1 min, tsyn-major ¼ 18.0 min. Specific rotation of the syn isomer (95% ee) [a] 30 D 67.1 (c 1.3, CHCl3 ). Other spectral data (IR and 1 H NMR) of the syn isomer were in good agreement with reported data [6]. Typical Procedure for Asymmetric Mukaiyama Aldol Reaction of Silyl Enol Ethers with Aldehydes Catalyzed by Cationic BINAP-Pd(II) Complexes. Synthesis of (R)-1,3-Diphenyl-1-trimethylsiloxy-3-propanone (18, Scheme 1.7, and entry 1 in Table 1.2) [12, 13]. Wet DMF (8 mL dry DMF with 144 mL H2 O) was added to a mixture of (R)-BINAP-PdCl2 (160 mg, 0.20 mmol), AgOTf (51 mg, 0.20 mmol), and MS 4 A˚ (powder, 1.2 g) and the suspension was stirred at 23 C for 20 min. After cannula filtration, benzaldehyde (410 mL, 4.0 mmol) and acetophenone silyl enol ether 11 (1.23 mL, 6.0 mmol) were added to the resulting orange solution and the mixture was stirred for 13 h at 23 C. Dilution of the reaction mixture with diethyl ether, filtration

19

20


through a short silica gel column, and concentration afforded pale yellow oil. This crude product was purified by column chromatography on silica gel to give the (R)-enriched silylated aldol adduct 18 (1.04 g, 87% yield, 71% ee) and its desilylated product (82 mg, 9% yield, 73% ee). The enantioselectivity of the silylated product 18 was determined by HPLC analysis using Chiralcel OJ (hexane–i-PrOH, 9:1) after conversion to the corresponding desilylated product (1 m HClaTHF, 1:2). Specific rotation of the desilylated aldol adduct (70% ee) [a]D þ32.4 (c 0.74, MeOH). General Procedure for Asymmetric Aldol Reaction of Methyl Isocyanoacetate (27) with Aldehydes Catalyzed by Chiral Ferrocenylbisphosphine-Gold(I) Complexes (Scheme 1.8 and Table 1.3) [18]. Methyl isocyanoacetate (27, 5.0 mmol) was added to a solution of bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (0.050 mmol), chiral ferrocenylbisphosphine 26 (0.050–0.055 mmol), and aldehyde (5.0–5.5 mmol) in CH2 Cl2 (5 mL) and the mixture was stirred under nitrogen at 25 C until 27 was not detected by silica gel TLC (hexane–ethyl acetate, 2:1) or IR. Evaporation of the solvent followed by bulb-to-bulb distillation gave oxazoline 28. The trans/cis ratio was determined by 1 H NMR spectroscopy and the enantiomeric purity of trans-28 and cis-28, readily separated by MPLC (hexane–ethyl acetate), were determined by 1 H NMR studies using Eu(dcm)3 . The OCH3 singlet of the major enantiomer of trans-28 always appeared at a higher field than that of the minor enantiomer. General Procedure for Asymmetric Aldol Reaction of Tosylmethyl Isocyanide (40) with Aldehydes Catalyzed by Chiral Ferrocenylbisphosphine-Silver(I) Complexes (Scheme 1.11) [31]. Aldehyde (1.5 mmol) was added to a solution of silver(I) triflate (0.011 mmol), chiral ferrocenylbisphosphine 26 (0.010 mmol), and tosylmethyl isocyanide (40, 1.0 mmol) in dry CH2 Cl2 (5 mL). The mixture was stirred under nitrogen at 25 C for 2 h. The catalyst was removed by passing the mixture through a bed of Florisil (17 mm 30 mm, EtOAc), and MPLC purification (silica gel, CH2 Cl2 aEtOAc, 15:1) gave oxazoline 39. The trans/cis ratio was determined by 1 H NMR spectroscopy and the enantiomeric excess of trans-39 was determined by HPLC analysis with a chiral stationary phase after conversion to the corresponding anaphthylurea derivative of amino alcohol (1. LiAlH4 , 2. a-naphthyl isocyanate). Experimental Procedure for Pd(II)-Catalyzed Asymmetric Aldol Reaction of Methyl Isocyanoacetate (27) with Aldehydes (Scheme 1.13 and Table 1.4) [34]. Preparation of [(1R,1OR)-2,6-bis[1-(diphenylphosphino)ethyl]phenyl]chloropalladium(II) (46). PdCl2 (PhCN)2 (383 mg, 1.0 mmol) was added to a solution of (1R,1 0 R)-1,3-bis[1-(diphenylphosphino)ethyl]benzene (502 mg, 1.0 mmol) in CH2 Cl2 (15 mL). The resulting orange solution was stirred at room tem-

References

perature for 24 h. The reaction mixture was then reduced to one-third of its volume and absolute ethanol was added to precipitate the product. Filtration gave the desired product 46 as a yellow powder (418 mg, 85%), mp 249–252 C; [a]D 323.6 (c 1.0, CHCl3 ). 1 H NMR (360 MHz, CDCl3 ) d (ppm) 1.19 (m, 6H, CH3 ), 4.04 (m, 2H, CH), 7.10 (m, 3H), 7.34–7.45 (m, 12H), 7.70– 7.74 (m, 4H), 7.95–7.97 (m, 4H); 13 C NMR (90 MHz, CDCl3 ) d (ppm) 22.1 (s, 2C, CH3 ), 46.7 (m, 2C, CH), 122.5–156.8 (twelve different aromatic carbon atoms); 31 P NMR (145 MHz, CDCl3 ) d (ppm) 46.5. HRMS calculated for C34 H31 P2 PdCl (Mþ ) 642.0624; found 642.0634. General Procedure for the Aldol Reaction. A solution of Pd complex 46 (7 mg, 0.011 mmol, 1.0 mol%) and AgOTf (3 mg, 0.011 mmol) in CH2 Cl2 (2 mL) was stirred for ca. 30 min at room temperature. The resulting cloudy solution was filtered through Celite and the solvent was removed under reduced pressure to give the active catalyst. The catalyst was then dissolved in EtOAc and passed through a plug of silica gel to remove excess AgOTf. After removal of EtOAc the catalyst was dissolved in THF (6 mL), and methyl isocyanoacetate (27, 110 mL, 1.1 mmol) was added followed by introduction of diisopropylethylamine (19 mL, 0.11 mmol) and aldehyde (1.1 mmol). The reaction was monitored by TLC (EtOAc–hexane, 1:1, visualized with KMnO4 ). After removal of solvent, the pure product 47 was obtained by bulb-to-bulb distillation under reduced pressure (0.1 mmHg). The trans/cis ratio was determined by 1 H NMR spectroscopy by integration of the methyl ester protons and the enantiomeric excess for trans-47 and cis-47 were determined by GC analysis. References 1 (a) B. M. Trost, in Comprehensive Organometallic Chemistry,

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21 22 23 24 25

26 27 28 29

30 31 32

33 34 35 36 37 38 39

40 41

A. Togni, J. Am. Chem. Soc. 1989, 111, 2333; (c) A. Togni, S. D. Pastor, Helv. Chim. Acta 1989, 72, 1038; (d) A. Togni, S. D. Pastor, J. Org. Chem. 1990, 55, 1649; (e) A. Togni, R. Haüsel, Synlett 1990, 633; (f ) S. D. Pastor, A. Togni, Tetrahedron Lett. 1990, 31, 839; (g) A. Togni, S. D. Pastor, G. Rihs, J. Organomet. Chem. 1990, 381, C21; (h) S. D. Pastor, A. Togni, Helv. Chim. Acta 1991, 74, 905. Y. Ito, M. Sawamura, T. Hayashi, Tetrahedron Lett. 1988, 29, 239. A. Togni, S. D. Pastor, G. Rihs, Helv. Chim. Acta 1989, 72, 1471. M. D. Bachi, A. Melman, J. Org. Chem. 1997, 62, 1896. M. Sawamura, Y. Ito, T. Hayashi, Tetrahedron Lett. 1990, 31, 2723. (a) Y. Ito, M. Sawamura, E. Shirakawa, K. Hayashizaki, T. Hayashi, Tetrahedron Lett. 1988, 29, 235. See also: (b) Y. Ito, M. Sawamura, E. Shirakawa, K. Hayashizaki, T. Hayashi, Tetrahedron 1988, 44, 5253. Y. Ito, M. Sawamura, M. Kobayashi, T. Hayashi, Tetrahedron Lett. 1988, 29, 6321. Y. Ito, M. Sawamura, H. Hamashima, T. Emura, T. Hayashi, Tetrahedron Lett. 1989, 30, 4681. M. Sawamura, Y. Nakayama, T. Kato, Y. Ito, J. Org. Chem. 1995, 60, 1727. (a) A. Togni, S. D. Pastor, Tetrahedron Lett. 1989, 30, 1071; (b) M. Sawamura, Y. Ito, T. Hayashi, Tetrahedron Lett. 1989, 30, 2247. T. Hayashi, Y. Uozumi, A. Yamazaki, M. Sawamura, H. Hamashima, Y. Ito, Tetrahedron Lett. 1991, 32, 2799. M. Sawamura, H. Hamashima, Y. Ito, J. Org. Chem. 1990, 55, 5935. (a) V. A. Soloshonok, T. Hayashi, Tetrahedron Lett. 1994, 35, 2713; (b) V. A. Soloshonok, T. Hayashi, Tetrahedron: Asymmetry 1994, 5, 1091; (c) V. A. Soloshonok, A. D. Kacharov, T. Hayashi, Tetrahedron 1996, 52, 245. M. A. Stark, C. J. Richards, Tetrahedron Lett. 1997, 38, 5881. J. M. Longmire, X. Zhang, M. Shang, Organometallics 1998, 17, 4374. G. Guillena, G. Rodrı´guez, G. van Koten, Tetrahedron Lett. 2002, 43, 3895. Y. Motoyama, H. Kawakami, K. Shimozono, K. Aoki, H. Nishiyama, Organometallics 2002, 21, 3408. ¨ntener, M. Wo¨rle, Helv. R. Nesper, P. S. Pregosin, K. Pu Chim. Acta 1993, 76, 2239. C. Schlenk, A. W. Kleij, H. Frey, G. van Koten, Angew. Chem. Int. Ed. 2000, 39, 3445. A. W. Kleij, R. J. M. Klein Gebbink, P. A. J. van den Nieuwenhuijzen, H. Kooijman, M. Lutz, A. L. Spek, G. van Koten, Organometallics 2001, 20, 634. M. D. Meijer, N. Ronde, D. Vogt, G. P. M. van Klink, G. van Koten, Organometallics 2001, 20, 3993. G. Rodriguez, M. Lutz, A. L. Spek, G. van Koten, Chem. Eur. J. 2002, 8, 45.

23

25

2

Boron and Silicon Lewis Acids for Mukaiyama Aldol Reactions Kazuaki Ishihara and Hisashi Yamamoto 2.1

Achiral Boron Lewis Acids 2.1.1

Introduction

The classical boron Lewis acids, BX3 , RBX2 and R2 BX (X ¼ F, Cl, Br, I, OTf ) are now popular tools in organic synthesis. B(III) can act as a Lewis acid because there is an empty p-orbital on the boron. Enthalpy values indicate that when pyridine is the reference base, the Lewis acidities of Group IIIB halides increase in the order AlX3 > BX3 > GaX3 . The Lewis acidity of BX3 generally increases in the order fluoride < chloride < bromide < iodide, i.e. the exact reverse of the order expected on the basis of relative sdonor strengths of the halide anions. The main reason for this anomaly is that in these BX3 compounds the BaX bonds contain a p-component which is formed by overlap of a filled p-orbital on the halogen with the empty porbital on the boron. Because the latter orbital is used to form a s-bond when BX3 coordinates with a Lewis base, this p-component is completely destroyed by complex formation. The strength of the p-component now increases in the order iodide < bromide < chloride < fluoride, i.e. the amount of p-bond energy that is lost on complex formation increases as the atomic weight of the halogen decreases. Evidently, as far as the extent of complex formation is concerned, this is a more important factor than the corresponding decrease in the s-donor strength of the halogen. The BF3 and BCl3 complexes of diethyl ether are less stable than those of dimethyl ether, and the same order of stability is observed for complexes of diethyl and dimethyl sulfides. As expected, steric interaction decreases as the distance between the metal and ligand atom is increased. Thus, it decreases when the metal atom is changed from boron to aluminum, and when the ligand atom is changed from oxygen to sulfur. The classical boron Lewis acids are used stoichiometrically in Mukaiyama Modern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

26

2 Boron and Silicon Lewis Acids for Mukaiyama Aldol Reactions

aldol reactions under anhydrous conditions, because the presence of even a small amount of water causes rapid decomposition or deactivation of the promoters. To obviate some of these inherent problems, the potential of arylboron compounds, Arn B(OH)n3 (n ¼ 1–3), bearing electron-withdrawing aromatic groups as a new class of boron catalyst has recently been demonstrated. For example, tris(pentafluorophenyl)borane, B(C6 F5 )3 , is a convenient, commercially available Lewis acid of strength comparable with that of BF3 , but without the problems associated with reactive BaF bonds. Although its primary commercial application is as a co-catalyst in metallocenemediated olefin polymerization, its potential as a Lewis acid catalyst for Mukaiyama aldol reactions is now recognized as being much more extensive. Diarylborinic acids and arylboronic acids bearing electron-withdrawing aromatic groups are also highly effective Lewis acid catalysts [1]. 2.1.2

BF3 .Et2 O

Although TiCl 4 is a better Lewis acid at effecting aldol reactions of aldehydes, acetals, and silyl enol ethers, BF3 .Et2 O is more effective for aldol reactions with anions generated from transition metal carbenes and with tetrasubstituted enol ethers such as (Z)- and (E)-3-methyl-2-(trimethylsilyloxy)-2-pentane [2, 3]. One exception is the preparation of substituted cyclopentanediones from acetals by aldol condensation of protected fourmembered acyloin derivatives with BF3 .Et2 O rather than TiCl 4 (Eq. (1)) [2, 4]. Use of the latter catalyst results in some loss of the silyl protecting group. The pinacol rearrangement is driven by the release of ring strain in the four-membered ring and is controlled by an acyl group adjacent to the diol moiety.

O + R

R'

Me3SiO

OSiMe3

BF3•Et2O 89% yield

SiMe3 HO O O R R' O

(1)

R R' O

This reagent is the best promoter of the aldol reaction of 2-(trimethylsiloxy)acrylate esters, prepared by the silylation of pyruvate esters, to afford galkoxy-a-keto esters (Eq. (2)) [5] These esters occur in a variety of important natural products.

2.1 Achiral Boron Lewis Acids

OSiMe3 OEt

OMe + Ph

27

OMe

O

ð2Þ

OMe O

BF3•Et2O

OEt

Ph

CH2Cl2 –78 °C to 0 °C 86% yield

O

BF3 .Et2 O can improve or reverse aldehyde diastereofacial selectivity in the aldol reaction of silyl enol ethers with aldehydes, to give syn adducts. For example, Heathcock and Flippin have reported that the reaction of the silyl enol ether of pinacolone with 2-phenylpropanal using BF3 .Et2 O results in enhanced Felkin selectivity (up to 36:1) compared with addition of the corresponding lithium enolate [6, 7]. When the a-substituents are more subtly differentiated, however, it is still difficult to achieve acceptable levels of selectivity. Davis et al. have reported that use of triisopropylsilyl enol ether and i-Pr3 SiB(OTf )4 results in selectivity of ca. 100:1 with 2-phenylpropanal and a useful level of 7:1 with 2-benzylpropanal (Eq. (3)) [8]. Control experiments employing BF3 .Et2 O catalysis and 2-benzylpropanal as substrate results in lower selectivity (ca. 3:1) that does not depend substantially on the bulk of the silyl group in the enolate (Eq. (3)). In contrast, both levels of 1,2asymmetric induction in the i-Pr3 SiB(OTf )4 (5 mol%)- and the BF3 .Et2 O (1 equiv.)-promoted additions of silyl ketene thioacetals to a-asymmetric aldehydes are affected by the bulk of the silyl group (Eqs. (4) and (5)) [8].

OTIPS + Bn

CHO

X

X=Me, t-Bu, OMe, Ot-Bu

Lewis acid

X

Bn TIPSO

i-Pr3SiB(OTf)4 BF3•Et2O

+

O

Cram 7 3

X

Bn TIPSO

: :

O

anti-Cram 1 1

ð3Þ

OR + Bn

CHO

i-Pr3SiB(OTf)4

St-Bu (5 mol%)

St-Bu + Bn

Bn

R=TIPS R=TBDMS

RO

O

Cram 5.5 3.6

St -Bu RO

:

O

anti-Cram 1 1

ð4Þ

28


OR

BF3•Et2O

+ Bn

CHO

St-Bu

(1 equiv)

St-Bu + Bn

Bn HO

R=TIPS R=TBDMS

St-Bu

O

Cram 13 5.8

HO

O

anti-Cram 1 1

:

ð5Þ

Addition of the tetrasubstituted selenoketene silyl acetal to b-benzyloxy aldehyde in the presence of Et2 BOTf leads to good yields and high ratios of products with 3,4-anti relative stereochemistry (Cram chelate model) (Eq. (6)). In contrast, reversed diastereoselectivity and a synthetically interesting ratio of 1:11 in favor of the 3,4-syn products is obtained when the bulky bsilyloxy aldehyde is used in the presence of the monodentate Lewis acid BF3 .OEt2 (Felkin–Anh model) (Eq. (7)) [9].

BnO

OSiMe3

O +

H

OMe SePh

Et2BOTf (1.2 equiv) CH2Cl2, –78 °C

BnO

OH O

OMe SePh 86% yield, syn:anti=99%

>99% OH O Ph

O

97% OH O

O Ph

syn:anti=71:29

Ph

Ph

35%

+

Ph

Ph

65% (>99% syn)

Diphenylborinic acid (10 mol%), which is stable in water, is an effective catalyst for the Mukaiyama aldol reaction in the presence of benzoic acid (1

31

32


mol%) as a co-catalyst and sodium dodecyl sulfate (10 mol%) as a surfactant (Eq. (13)) [15]. Use of water as solvent is essential in this reaction. The reaction proceeds sluggishly in organic solvents such as dichloromethane and diethyl ether. Much lower yield than in water is obtained under neat conditions. Not only aromatic aldehydes but also a,b-unsaturated and aliphatic aldehydes give high syn selectivity. Although lower diastereoselectivity is observed when E enolates are used, reverse diastereoselectivity is observed when both stereoisomers of the silyl enolate derived from tert-butyl thiopropionate are used. Ph2BOH (10 mol%) C12H25SO3Na (10 mol%) PhCO2H (1 mol%)

OSiMe3

PhCHO +

H2O, 30 °C 99% ee

20% yield, >99% ee

OTMS + Ph

CHO

OEt

(R)-2a (1 equiv) CH2Cl2, -78 °C, 3 h

Ph

CO2Et OH

18% yield, >99% ee

+

Ph

CO2Et OH

(22)

41% yield, >99% ee

The reaction of b-chiral aldehydes with ketene silyl acetals gives both syn and anti aldols in similar yields without any Cram selectivity (Eq. (23)) [17d].

2.2 Chiral Boron Lewis Acids

OTMS CHO +

OEt

OBn

ð23Þ

(S)-2a (1 equiv) CH2Cl2, -78 °C, 3 h

CO2Et

+

OBn OH 46% yield, 98% ee

CO2Et OBn OH 42% yield, 82% ee

In Kiyooka’s approach to acetate aldols using a stoichiometric amount of 2a, a serious reduction (ca. 10–20%) in enantiomeric excess was observed in the reaction with silyl ketene acetals derived from a-unsubstituted acetates, compared with the high level of enantioselectivity (> 98% ee) in the reaction with 1-ethoxy-2-methyl-1-(trimethylsiloxy)-1-propene. Introduction of an eliminable substituent, e.g. a methylthio or bromo substituent, after aldol reaction at the a-position of chiral esters resolves this problem [17e]. Asymmetric synthesis of dithiolane aldols has been achieved in good yields by using the silyl ketene acetal derived from 1,3-dithiolane-2-carboxylate in the 2a-promoted aldol reaction; desulfurization of the dithiolane aldols produces the acetate aldols in high enantiomeric purity (Eq. (24)).

PhCHO +

S

OTMS

S

OEt

OH O

2a (1 equiv) Ph CH2Cl2, -78 °C, 3 h

S

S

OEt

88% yield Ni2B-H2

(24)

OH O Ph

OEt

85% yield, 98% ee (S)

A very short asymmetric synthesis of the bryostatin C1 aC9 segment has been achieved using three sequential 2a-promoted aldol reactions under reagent control [17f ]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Scheme 2.1). The 2a-promoted asymmetric aldol reaction of a variety of aldehydes with a silyl nucleophile derived from phenyl propionate (E isomer 98%) results in moderate anti diastereoselectivity with relatively low enantioselectivity. On the other hand, with pivalaldehyde and the silyl nucleophile derived from ethyl propionate (E/Z ¼ 85:15), the syn isomer is obtained as a major product (22:1) with 96% ee (Eq. (25)) [17g]. This unexpected switching of diastereoselectivity observed in the reaction of the bulky aldehyde can be explained by merging Corey’s hydrogen-bond model between the aldehyde hydrogen and the catalyst borane-ring oxygen [18e] and Yamamoto’s ex-

37

38


HO MeO2C

OAc

9

O

OH OH OH O

7

1

O

BnO OH

OH O

OEt

O O

AcO

OH CO2Me Bryostatin

CHO +

BnO

S

OTMS

1. (R)-2a (1 equiv) CH2Cl2, -78 °C, 8 h

S

OEt

2. Ni2B-H2

OH CO2Et

BnO >98% ee OTMS

S 1.

OTBDMS CHO

1. TBDMACl 2. DIBAH

BnO

TBDMSO

OH O

BnO

S OEt (S)-2a (1 equiv) CH2Cl2, -78 °C, 8 h 2. Ni2B-H2

TBDMSO

1. TBDMACl OEt

2. DIBAH

BnO

OTBDMS CHO

~100% de OTMS 1. OEt (R)-2a (1 equiv) CH2Cl2, -78 °C, 3 h 2. Ni2B-H2

TBDMSO

TBDMS O OH O

BnO

OEt ~100% de

Scheme 2.1

tended transition model 3 (see also Figure 2.4) [19] as depicted in Figure 2.2, where 4 is destabilized by gauche interaction between the methyl and tert-butyl groups. Important limitations have been observed with regard to reagent control in reactions with highly sterically hindered aldehydes involving a chiral hydroxy function at the b-position (Eq. (26)) [17g]. When (S)-2a is used for 5, the diastereo- and enantioselectivity are less satisfactory. When (R)-2a,


Ts

BH O O Me H

H t-Bu O

Ts

i-Pr

N

O

>>

N

i-Pr

BH O O H H

Me t-Bu

O

O

O

O 4

3 Fig. 2.2

Kiyooka’s transition-state models.

OTMS t-BuCHO + OEt OH O

(S)-2a (1 equiv) CH2Cl2 –78 °C, 3 h

t-Bu

OH O OEt

+

ð25Þ

t-Bu

OEt

22:1 96% ee

95% ee

is used, however, the reaction proceeds more smoothly to give the corresponding aldols with moderate syn selectivity in 87% yield. Each of the isomers obtained is almost enantiomerically pure. The spatial orientation of the siloxy group at C-3, which is presumably fixed by introduction of two methyl groups at C-2, affects the entire conformation of the aldehydes, and when the chiral borane coordinates to the aldehyde an adequate fit might be needed between the stereocenters of the reagent and the substrate (at C3) for the stereochemical outcome expected from reagent control. Reaction with (S)-2a loses reagent control because of stereochemically mismatched interactions. Even in such complex circumstances, however, the reaction with (R)-2a gives products with stereochemistry at C-3 similar to that expected on the basis of reagent control. Effective approach of the silyl nucleophile might occur via a path similar to 11 in Figure 2.3.

Me TMSO Blocking

Me TMSO

Me H

O H B O 10

Fig. 2.3

Kiyooka’s transition-state models.

2a part

Me H

O H B O 11

Nu

39

40


TBDMSO

OTMS 2 CHO 3

2a (1 equiv)

OTMS +

1

OEt

CH2Cl2 –78 °C, 24 h

5 TMSO

OH O

TBDMSO

TMSO OEt

+

TBDMSO

OEt 7

6 TMSO +

OH O

TBDMSO

OH O

TMSO OEt

+

OH O

TBDMSO

8

OEt 9

(S)-2a

34% yield, syn(6+8):anti(7+9)=2:1, 6:8=7:5, 7:9=5:3

(R)-2a

87% yield, syn(6+8):anti(7+9)=4:1, 6:8=>50:1, 7:9=>50:1

ð26Þ

2.2.3

Chiral Boron Lewis Acids as Catalytic Reagents

CAB 12, R ¼ H, derived from monoacyloxytartaric acid and diborane, is an excellent catalyst (20 mol%) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with a variety of aldehydes. The reactivity of aldol-type reactions can be improved without reducing enantioselectivity by using 10–20 mol% 12, R ¼ 3,5-(CF3 )2 C6 H3 , prepared from 3,5-bis(trifluoromethyl)phenylboronic acid (13) and a chiral tartaric acid derivative. Enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol% 12, R ¼ o-PhOC6 H4 , prepared from o-phenoxyphenylboronic acid and a chiral tartaric acid derivative. The 12-catalyzed aldol process enables preparation of adducts highly diastereo- and enantioselectively (up to 99% ee) under mild reaction conditions [19a,c]. These reactions are catalytic, and the chiral source is recoverable and reusable (Eq. (27)). The relative stereochemistry of the major adducts is assigned to be syn, and the predominant re-face attack of enol ethers at the aldehyde carbonyl carbon has been confirmed when a natural tartaric acid derivative is used as Lewis acid ligand. The use of an unnatural form of tartaric acid as a chiral source gives the other enantiomer, as expected. Almost perfect asymmetric induction is achieved with the syn adducts, reaching 99% ee, although a slight reduction in both enantio- and diastereoselectivity is observed in reactions with saturated aldehydes. Irrespective of the stereochemistry of the starting enol silyl ethers generated from ethyl ketone, syn aldols are obtained with high selectivity in these reactions. The observed high syn selectivity, and its lack of dependence on the stereoselectivity of the silyl enol ethers, in 12-catalyzed reactions are fully consistent with Noyori’s TMSOTf-


Oi-Pr O 1)

OTMS R1CHO + R2

HO

R3

O O B Oi-Pr 12 (10~20 mol%) R HO EtCN, -78 °C

HO Ph

(99%), 88% ee (12 (10 mol%), R=3,5-(CF3)2C6H3) HO

O

Ph

HO

Ph

Ph

O Et

(99%), 96% ee syn syn:anti=94:6 (12 (20 mol%), R=H)

O

Pr

(83%), 97% ee syn syn:anti=>95:5 (12 (20 mol%), R=3,5-(CF3)2C6H3)

HO

(92%), 96% ee syn syn:anti=99:1 (12 (10 mol%), R=3,5-(CF3)2C6H3)

O

R3 R2

O

Ph

O

R1

2) 1N HCl

O

Ph

CO2H O

HO Et

(27)

O Et

(61%), 88% ee syn syn:anti=80:20 (12 (20 mol%), R=H)

(95%), 93% ee syn syn:anti =94:6 (12 (20 mol%), R=3,5-(CF3)2C6H3)

catalyzed aldol reactions of acetals, and thus might reflect the acyclic extended transition state mechanism postulated in the latter reactions (Figure 2.4). Judging from the product configurations, 12 (from natural tartaric acid) should effectively cover the si face of the carbonyl after its coordination, and selective approach of nucleophiles from the re face should result. This behavior is totally systematic and in good agreement with the results from previously described 12-catalyzed reactions for all of the aldehydes examined. A catalytic enantioselective aldol-type reaction of ketene silyl acetals with achiral aldehydes also proceeds smoothly with 12, R ¼ H; this can furnish erythro b-hydroxy esters with high optical purity (Eq. (28) [19b,c]. R2

TMSO

H H

TMSO

R

R1

O

CAB

94% for addition of the tert-butyl thioacetate silylketene acetal to methyl pyruvate in all of these solvents. Catalyst loadings down to 1 mol% are feasible. The temperature–enantioselectivity profile has been studied and shown to be relatively flat (99% ee at 78 C; 92% ee at þ20 C). Interestingly, the catalytic reaction in THF, a relatively good donor solvent, is significantly faster than the identical reaction in CH2 Cl2 . Control experiments with stoichiometric quantities of (t-Bu-box)Cu(OTf )2 demonstrate that the actual addition step is faster in CH2 Cl2 , a fact consistent with the predicted deactivation of the Lewis acidic center in THF via solvent coordination. Accordingly, THF must play a role in promoting catalyst turnover. One postulated role of THF in the catalytic cycle is to act as a silicon shuttle, forming a more reactive silylating species (e.g. [THF-SiMe3 ]OTf ). The ‘‘silicon shuttle’’ hypothesis predicts significant intermolecular crossover, which is experimentally borne out by double-labeling experiments in analogy to those described above for benzyloxyacetaldehyde additions. Silylation of the putative metal aldolate by an exogenous Si(þ) source results in significant rate accelerations. For example, a catalyzed pyruvate addition that requires 14 h in the absence of an additive is complete in 0.5 h in the presence of 1.0 equiv. TMSOTf (Eq. (7)). The presence of stoichiometric quantities of this Lewis acid does not erode the selectivity of the reaction. The Cu(II) complex again reacts to complete exclusion of the achiral complex. Me

Me

N

N

O

O

OTMS Me3CS

O Me

6

CO2Me 37

Cu Me3C TfO OTf CMe3 5 2 mol % n equiv TMSOTf CH2Cl2, -78 °C; then aq. HCl;

O HO Me Me3CS

CO2Me 38 n = 0; reaction time = 14 h; 97% ee n = 1; reaction time = 0.5 h; 97% ee

ð7Þ The scope of the reaction with regard to the carboalkoxy and acyl moieties (electrophile) includes a range of substituents (Figure 3.7). a-Branched substrates (e.g. i-PrC(O)CO2 Me) result in low p-facial selectivity (39e) but comprise the only subset of poorly selective a-keto esters. Enolsilanes derived from acetone and acetophenone are effective and selective nucleophiles in additions to methyl pyruvate (39g–h). Propionate silylketene acetals are also usually effective (39i). As in the [(pybox)Cu](SbF6)2 -catalyzed additions to benzyloxyacetaldehyde, good syn diastereoselectivity is observed. The only

3 Copper Lewis Acids

82

O HO Me Me3CS

39a

CO2Bn

95%, 99% ee O HO

Me3CS

39b

CO2CMe3

Me3CS

i

O HO Me

Pr

CO2Me 39e 36%, 36% ee

CO2Me 39f 97%, 97% ee

Ph

CO2Me 39g 77%, 99% ee

O HO Me

CO2Me

O HO Me

CO2Me

EtS

i

Bu 39j 88%, 93% ee syn:anti 90:10

Pr 39k 80%, 99% ee syn:anti 90:10

Et

39d

Bu CO2Me

94%, 94% ee O HO Me Me

CO2Me 39h 81%, 94% ee HO Me

CO2Me O 39l O 99%, 99% ee syn:anti 5:95

Et

Me

Me O 39m 85% yield syn:anti 93:7 97% ee

Me3CS

i

O

O HO Me EtS

CO2Me

EtS

i

Me 39i 88%, 99% ee syn:anti 97:3

O HO

O HO Me

EtS

O HO Me

39c

CO2Me

84%, 94% ee

91%, 99% ee

Me3CS

Me3CS

O HO Et

O HO Me

O

regioselectivity 98:2

Fig. 3.7

Aldol products derived from enantioselective additions catalyzed by (t-Bu-box) Cu(OTf )2 (5).

exception to this trend is again 2-trimethylsilyloxyfuran, for which anti diastereoselectivity is high (39l). 2,3-Pentanedione also participates in selective aldol reactions with silylketene acetals. In addition to diastereo- and enantioselectivity issues faced in other examples this electrophile contains a subtle regiochemical issue between two nominally similar carbonyl groups. In practice, the (t-Bu-box)Cu(OTf )2 complex performs the subtle discrimination between the two groups and effects a highly regio- and stereoselective aldol reaction with the acetyl group to give 39m. Verdine has described the application of this aldol methodology to the enantio- and diastereocontrolled synthesis of a-hydroxy-a-methyl-b-amino acids (40) in a sequence that uses the carbothioalkoxy group as an amine surrogate via a Curtius rearrangement (Scheme 3.7) [15]. Thus, the desired protected b-amino acid can be obtained in four steps with the needed stereochemical relationships established in the (t-Bu-box)Cu(OTf )2 -catalyzed aldol addition. The asymmetric pyruvate addition can be effected with a complex derived

3.3 Representative Experimental Procedures

Me

83

Me O

O N

O

OTMS

OEt

Me

EtS

O

Me

N Cu Me3C TfO OTf CMe3 5 THF, -78 °C 48 h, 85%

O Me OH EtS

CO2Et Me Me

Me

dr = 10-15:1; >91% ee Me OH

4 steps BocHN

CO2H Me Me 40

Scheme 3.7

Synthesis of a-hydroxy-a-alkyl-b-amino acids from enantioselective pyruvate aldol reactions catalyzed by (t-Bu-box)Cu(OTf )2 (5).

from Cu(OTf )2 and a polystyrene-bound bis(oxazoline) ligand (41) with selectivity approaching that of the solution reaction (Eq. (8)) [16]. As with many solid-supported complexes, catalytic activity was significantly less than the soluble variant. Nonetheless, Salvadori and co-workers demonstrated that the ligand could be reused in multiple reaction cycles with no loss of activity provided that additional Cu(OTf )2 was added to the reaction mixture. In the absence of additional Cu(OTf )2 , recycling is still possible, with

O

Me O

O N Me3C O

OTMS

OMe

Me

Me3CS 6

O 37

N

ð8Þ

41 CMe3 12 mol %

O Me OR

Cu(OTf)2 (7 mol %) THF, 0 °C MS 3Å

Me3CS

CO2Me

38 R = H, TMS

7 cycles; reaction time = 1-4 h, ee = 88-93%

84


the consequence of extended reaction times in subsequent cycles. It is interesting to note that the relative amounts of the silylated and unsilylated aldol products vary from run to run, but the enantioselectivity is relatively constant. A post-catalytic cycle desilylation seems most reasonable. Jørgenson and co-workers have extended the a-keto ester additions to keto malonate substrates (Eq. (9)) [17]. In these asymmetric additions, the tertiary carbinol is not a stereogenic center; in essence the chiral complex induces asymmetry on the nucleophile. For a range of enolsilane nucleophiles, enantiocontrol in the addition step is moderate to excellent. The optimal promoter for these additions is the (Ph-box)Cu(OTf )2 complex (42). In all instances but one the (E)-enolsilane was employed; the (Z)-enolsilane derived from propiophenone gave excellent results (43e). Me

Me O

O N

O

OTMS EtO2C

R

N Cu Ph TfO OTf Ph 42 10 mol % CO2Et

O

O

43a 82% 58% ee O Ph

OH CO2Et CO2Et

OH CO2Et CO2Et Me 43e 95% 90% ee

R'

OH CO2Et CO2Et

OH CO2Et CO2Et

O

OH CO2Et CO2Et

43b 91% 86% ee O

R

Et2O

R'

OH CO2Et CO2Et

O

43c 88% 93% ee O

O

OH CO2Et CO2Et

43d 90% 85% ee

OH CO2Et CO2Et

ð9Þ 43f 80% 60% ee

43g 26% 36% ee

Dalko and Cossy have employed the Danishefsky diene in additions to ethyl pyruvate catalyzed by an uncharacterized complex prepared by mixing enantiopure stilbene diamine 44 and cyclobutanone 45 (1:1), followed by complexation with Cu(OTf )2 (Eq. (10)) [18]. Cyclobutanone was optimal with regard to yield and enantioselectivity for the ketones and aldehydes surveyed. Reactant stoichiometry and premixing time were found to have a significant effect on enantioselectivity and reaction efficiency. The reaction affords a mixture of both the silylated and desilylated acyclic aldol product

3.3 Representative Experimental Procedures

(48), in addition to the cyclized dihydropyrone (47). Whether the dihydropyrone is formed by a concerted or stepwise mechanism is yet to be determined. In practice, the acyclic aldols are easily cyclized to the dihydropyrone in the presence of trifluoroacetic acid for the purpose of determining the enantiomeric excess. This catalyst system is noteworthy for the simplicity with which the active catalyst is assembled (in situ). OMe

O OEt

Me TMSO

O 46

Ph Ph 44

37

NH2

O

NH2 (1:1)

45

OMe O

Cu(OTf)2 (10 mol %), MS 4Å THF, -72 °C

O

(10)

OH(TMS)

CO2Et Me

47 85%, >98% ee

O

CO2Et Me 48

F3CCO2H

Mechanism and Stereochemistry The mechanism of Cu(II)-catalyzed additions to a-keto esters is thought to proceed via a Mukaiyama aldol pathway, with the difunctional electrophile undergoing bidentate activation by the Cu(II) Lewis acid (49). This coordination event lowers the LUMO of the ketone to a point that facilitates addition of the silylketene acetal (49 ! 50). Silylation of the Cu(II) aldolate via an intra- or intermolecular silicon transfer gives the neutral metalcoordinated adduct (52) that decomplexes to regenerate the catalytically active Lewis acid and release the product, 53 (Scheme 3.8) [13]. A distorted square-planar metal center is implicated in all reactions involving (t-Bu-box)CuL n [19]. This is suggested both by X-ray crystallographic studies of the hydrated complex [(t-Bu-box)Cu(OH2 )2 ](SbF6 )2 and by PM3 calculations designed to probe the structure of activated intermediates. The X-ray structure reveals that the coordinated water molecules are tilted out of the ligand plane by approximately 30 (Figure 3.8). This is a steric effect, as water molecules in the corresponding [(i-Pr-box)Cu(OH2 )](SbF6 )2 complex are nearly coplanar with the ligand (approximately 7 out of plane). By inspection, replacing the water molecules with the oxygen atoms of the pyruvate ester should result in a complex in which the enantiotopic faces of the carbonyl are significantly differentiated. This has been con3.3.2.2

85

86

3 Copper Lewis Acids O

Me3CS

O R OTMS O

N

N Cu TfO OTf 5

OMe

53

O R OTMS N O Cu N Me3CS L 52 OMe

L TMS

Me3CS

N

N O R O Cu O 51

OMe 37

R

N O Cu O

49 OMe

N TMS

-L

2+ 2 OTf

N

2+ 2 OTf

2+ 2 OTf

O

R

N O R O Cu O

2+ 2 OTf

OTMS Me3CS 6

Me3CS +L 50 OMe OMe Scheme 3.8 Proposed mechanism for (t-Bu-box)Cu(OTf )2 -catalyzed enantioselective aldol reactions.

firmed by PM3 calculations. The pyruvate ester additions are all consistent with the stereochemical model shown in Figure 3.9. The bulky t-butyl group effectively shields the re face of the ketone, directing nucleophilic addition to the si face. This complexation mode is now well established with this family of catalysts. The diastereoselectivity in additions of substituted enolsilanes to a-keto esters can be rationalized by an open, antiperiplanar transition structure that minimizes steric interactions between the enolsilane substituent and

Me

2+

Me O

O N

N

2 SbF6

Cu Me3CH O OH CMe3 2 2

Fig. 3.8

X-ray crystal structure of [(t-Bu-box)Cu(H2 O)2 ](SbF6 )2 .

3.3 General Experimental Procedure

Me O

O CMe3 N N Cu O O

Me

H CMe3 OMe

H

R

OTMS SR Fig. 3.9

Model for enantioselective addition to a-keto esters catalyzed by (t-Bu-box)Cu(OTf )2 .

the pendant ligand substituent (Figure 3.10). The disposition of the aOTMS and aSR groups are less important in this model, a point that is supported by the relative insensitivity of reaction diastereoselectivity as a function of enolsilane geometry.

General Experimental Procedure

In an inert atmosphere box, (S,S)-bis(tert-butyloxazoline) (15 mg, 0.050 mmol) and Cu(OTf )2 (18 mg, 0.050 mmol) were placed in an oven-dried

Me

Me

Me

2+ O

O N

N Cu CMe3 Me3C O Me O H Me

Me

N

N Cu CMe3 Me3C O H O Me Me

OMe R'

2+ O

O

R

OMe R' R

R,R' = OTMS, SR

O HO Me Me3CS

CO2Me

O HO Me Me3CS

CO2Me

Me

Me

anti disfavored

syn favored

Fig. 3.10

Stereochemical models for syn-selective aldol reactions catalyzed by (t-Bu-box)Cu(OTf )2 .

87

88


10-mL round-bottomed flask containing a magnetic stirring bar. The flask was fitted with a serum cap, removed from the inert atmosphere box, and charged with solvent (1.5–3.0 mL). The resulting suspension was stirred rapidly for 4 h with CH2 Cl2 to give a slightly cloudy bright green solution or 1 h with THF to give a clear dark green solution. The catalyst was cooled to 78 C, and the pyruvate (0.50 mmol) was added, followed by the silylketene acetal (0.60 mmol). The resulting solution was stirred at 78 C until the pyruvate was completely consumed (0.5 to 24 h) as determined by TLC (2.5% Et2 OaCH2 Cl2 ). The reaction mixture was then filtered through a 2 cm 4 cm plug of silica gel with Et2 O (60 mL). Concentration of the Et2 O solution gave the crude silyl ether which was dissolved in THF (5 mL) and treated with 1 m HCl (1 mL). After being stirred at room temperature for 1–5 h this solution was poured into a separatory funnel and diluted with Et2 O (20 mL) and H2 O (10 mL). After mixing the aqueous layer was discarded and the ether layer was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The resulting ether layer was dried over anhydrous Na2 SO4 , filtered, and concentrated to provide the hydroxy esters. Purification was achieved by flash chromatography. 3.3.3

Enolsilane Additions to Unfunctionalized Aldehydes

In 1998, Kobayashi made the counterintuitive observation that the Lewis acid-catalyzed addition of enolsilanes to aldehydes could be conducted in wet organic solvents (e.g. 10% H2 O in THF) [20]. The initial study documented that a wide range of metal salts are effective in promoting Mukaiyama aldol reactions in an aqueous environment. It is particularly relevant to this chapter that Cu(ClO4 )2 acts as a catalyst (Eq. (11)), but is not particularly efficient (one turnover in 12 h at ambient temperature). The carbonyl addition pathway is clearly faster than Lewis or Brønsted acidcatalyzed decomposition of the enolsilane.

Ph

OTMS Me

O H

O

Cu(ClO 4)2 (20 mol %) h Ph

OH

Ph H2O/THF (1:9) 25 °C, 12 h

Ph

ð11Þ

Me 47%

This discovery led to the development of an enantioselective variant. Implicit requirements for aqueous enantioselective Mukaiyama aldol reactions include a strong association between the chiral ligand and the metal center that is not disrupted by water, and/or a ligand–metal complex that is considerably more active than the corresponding hydrated complex, M m (OH2 )n Xm . Given the documented activity of Cu(ClO4 )2 in water, attention was directed to bis(oxazoline) ligands, known to have strong affinity for Cu(II). The optimal catalyst with regard to both chemical and optical yield was the (i-Pr-


box)Cu(OTf )2 complex; H2 OaEtOH (1:9) was identified as the best solvent. Under the optimized reaction conditions a range of substituted enolsilanes underwent asymmetric catalyzed addition to aromatic, heteroaromatic, alkenyl, and aliphatic aldehydes with moderate to good enantioselectivity (Eq. (12)) [21]. The absolute stereochemistry of these aldol adducts is unfortunately not known, so speculation about the mechanism of asymmetric induction is premature at this time. Me

Me

N

N

O

O

CHMe2 53 24 mol % Cu(OTf)2 (20 mol %)

Me2HC

1

R

OTMS Me

O H

R

O

2

R

H2O/EtOH (1:9)

R

OH

O

Me 54a 74%, syn/anti = 3.2/1 67% ee (syn) O

OH

O iPr

Me 54b 81%, syn/anti = 3.5/1 81% ee (syn)

Me 54c 95%, syn/anti = 4.0/1 77% ee (syn)

O

O

OH

Et

Et Me 54d 91%, syn/anti = 4.0/1 79% ee (syn) O

Me

Cl 54e 88%, syn/anti = 2.6/1 76% ee (syn) O

iPr

54f 87%, syn/anti = 2.9/1 75% ee (syn) O

OH

O

Me

OH

S Me

54j 78%, syn/anti = 5.7/1 75% ee (syn)

54i 86%, syn/anti = 4.0/1 76% ee (syn)

54h 97%, syn/anti = 4.0/1 81% ee (syn) O

OH

Et

O

Me

54g 77%, syn/anti = 4.6/1 42% ee (syn)

OH

Et

iPr Me

OH OMe

Et Me

OH

OH

Et

OH

ð12Þ

Me

-10 °C, 20 h O

OH

1

2

O

OH

Et Me 54k 56%, syn/anti = 1.6/1 67% ee (syn)

Cl

Me 54l 94%, syn/anti = 2.3/1 57% ee (syn)

Subsequent experiments demonstrated that pure H2 O, rather than mixtures of H2 O and organic solvent could be used as the solvent, either by the

89

90


use of an additive (Triton-X100, Eq. (13)) or a lipophilic Cu(II) salt in conjunction with a fatty acid additive (Eq. (14)) [22, 23]. Me

Me

N

N

O

O

MeO

OTMS Me

53 Me2HC (20 mol %) CHMe2 Cu(OTf) 2 (20 mol %)

OHC

Triton X-100 (3 mol %) H2O

Me

O

OH

MeO Me Me 54m

0 °C, 24 h

86%, 53% ee

ð13Þ Me

Me O

O

N 53 Me2HC 24 mol % CHMe2 Cu(O 3SOC12H25)2 (20 mol %) N

Me

OTMS Me

OHC

CH3(CH2)9CO2H (10 mol %) H2O

O

OH

Me Me

54b 23 ° C, 20 h 76%, syn/anti = 74/26, 69% ee (syn)

ð14Þ

3.4

Additions Involving In-Situ Enolate Formation

A continuing goal of organic chemists is the development of ‘‘direct’’ reactions in which the compounds undergoing reaction are activated in situ. The Mukaiyama aldol reaction, despite its broad utility, is not an example of a direct reaction, because preformation of an enolsilane in a separate step is a necessary requirement. Direct enolization and subsequent aldol reaction have been achieved in a handful of asymmetric Cu(II)-catalyzed reactions. 3.4.1

Pyruvate Ester Dimerization

Additions to pyruvate esters without pre-activation of the nucleophilic reactant have been explored by Jørgenson and co-workers. Ethyl pyruvate is enantioselectively dimerized in the presence of a chiral Cu(II) Lewis acid and catalytic quantities of a trialkylamine base to afford diethyl 2-hydroxy-2-

3.4 Additions Involving In-Situ Enolate Formation

methyl-4-oxoglutarate, 55 (Eq. (15)) [24]. Formation of the aldol was achieved with good enantiocontrol by use of (t-Bu-box)Cu(OTf )2 as catalyst in conjunction with a dialkylaniline base. Subtle interplay between the identity of the solvent, the counter-anion, and base were observed. The initial aldol adduct cyclizes in the presence of base and TBS-Cl to afford a highly substituted g-lactone 56 in moderate yield and with high enantioselectivity (Eq. (16)). The scope of this reaction beyond use of ethyl pyruvate was not described. Me

Me O

O N

N Cu Me3C TfO OTf CMe3 5 10 mol %

O 2 Me

CO2Et 37

PhNBn2 (10 mol %) Et2O

O Me OH EtO2C

(15)

CO2Et 55

>80% conversion, 93% ee Me

Me O

O N

N Cu 1) Me3C TfO OTf CMe3 5 10 mol %

O 2 Me

CO2Et

PhNMe2 (5 mol %)

37 2) Et3N, TBSCl

O

O

Me

(16)

CO2Et TBSO

56 48%, 96% ee

3.4.2

Addition of Nitromethane to a-Keto Esters

The enantioselective addition of nitroalkanes to carbonyl compounds (Henry reaction) has been documented by Jørgenson and co-workers [25]. With nitromethane as solvent, a combination of the (t-Bu-box)Cu(OTf )2 complex 5 (20 mol%) and Et3 N (20 mol%) effect room-temperature aldol reactions with a range of a-keto esters (Eq. (17)). The reaction is especially enantioselective with alkyl and aromatic groups on the ketone moiety. b,gUnsaturated-a-keto esters react with nitromethane to afford aldol products in good yield, but enantiocontrol is significantly lower than for aromatic or aliphatic substrates. Product partitioning is completely selective, however, for the 1,2-mode of addition compared with 1,4-conjugate addition. This selectivity is not observed when the reaction is conducted in the absence of (t-Bu-box)Cu(OTf )2 , leading the authors to propose that the nitronate anion might be coordinated to the metal center during the catalytic reaction. Triethylamine is uniquely suited as catalytic base in this reaction: N-

91

92


methylmorpholine, dimethylaniline, tribenzylamine, pyridine, ethyl diisopropylamine, and potassium carbonate are all inferior with regard to both yield and enantiocontrol. Enantioselectivity is optimal for the t-Bu-box ligand and triflate counter-ion (as compared with hexafluoroantimonate). Me

Me O

O N

N Cu Me3C TfO OTf CMe3 5 20 mol %

O CO2Et

R

Et3N (20 mol %) CH3NO2 25 °C

HO Me

HO Et

O2N

CO2Et 57a 95%, 92% ee

HO R O2N

CO2Et

Ph HO C6H13

HO

O2N

CO2Et 57b 46%, 90% ee

ð17Þ

57

O2N

O2N

CO2Et 57c 47%, 77% ee

CO2Et 57d 91%, 93% ee

Me Me

Me HO

HO O2N

CO2Et

57e 97%, 94% ee

O2N

HO CO2Et

57f 92%, 94% ee

O2N

CO2Et

57g 90%, 94% ee

Cl

HO CO2Et 57i 81%, 86% ee

O2N

CO2Et 57j 91%, 88% ee

CO2Me 57m 95%, 35% ee

OMe

HO

HO

O2N

CO2Et 57k 99%, 93% ee

Ph

O2N

CO2Et 57l 68%, 57% ee

Me

HO O2N

Me CO2Et 57h 99%, 92% ee

O2N

NO2

HO

O2N

HO

HO O2N

CO2Me 57n 95%, 30% ee

HO O2N

CO2Et 57o >96%, 60% ee

Reactant stoichiometry is critical in the catalyzed Henry reaction. With a 20% loading of (t-Bu-box)Cu(OTf )2 catalyst optimum enantiocontrol (92% ee for the reaction of nitromethane with ethyl pyruvate) is realized by use of 20 mol% Et3 N. In contrast, using 15 mol% Et3 N under otherwise identical conditions leads to a product enantiomeric excess of only 56%. Use

3.4 Additions Involving In-Situ Enolate Formation

of 25 mol% Et3 N leads to a product with 73% ee. The diminished enantioselectivity when employing excess base relative to Lewis acid can be accounted for by a racemic pathway – Et3 N alone catalyzes non-selective nitroaldol addition. The reason for reduced selectivity in the presence of excess Lewis acid (relative to base) is less clear. Another distinctive feature of the (t-Bu-box)Cu(OTf )2 -catalyzed Henry reaction is reversed p-facial selectivity relative to that normally obtained with this catalyst (vide supra). Indeed, the usual distorted square-planar arrangement (cf. Figures 3.8 and 3.9) cannot correctly account for the stereochemistry observed (the absolute stereochemistry of 57j was determined by X-ray crystallography). Jørgenson and co-workers instead propose that the ketone carbonyl and the nitronate anion coordinate to the Cu(II) center in the ligand plane, with the carboethoxy group bound in the axial position to complete the square pyramidal complex (Figure 3.11). The Zimmerman– Traxler chair-like transition structure is proposed on the basis of the observation of complete 1,2-selectivity in additions to b,g-unsaturated-a-keto Me

Me O

O

Me

CMe3 N N Cu O OO

H

O

N

O

H

Me3C

CMe3 Me

EtO

Me H O N Cu N O H OO Me CMe3 N O EtO

Me O

Me O

O

Me

H CMe3 N N Cu O CMe3 O R O N H O OEt

Me3C H R

O EtO

R OH O2N

CO 2Et

disfavored Fig. 3.11

Proposed stereochemical model for enantioselective Henry reactions catalyzed by (t-Bu-box)Cu(OTf )2 .

H N

N O Cu

O N O

Me

CMe3

HO R O2N

CO 2Et favored

O

93

94


esters. One possible explanation of this selectivity is that the electropositive metal center directs addition to the carbonyl, rather than the CbC p bond. The strong preference for one of the two diastereomeric transition structures illustrated is less clear, because both require interaction of one reaction component (either a-keto ester or nitronate) with the bulky tert-butyl group of the ligand. 3.4.3

Malonic Acid Half Thioester Additions to Aldehydes

Shair and coworkers have developed a mild aldol addition based on the decarboxylative Claisen condensation that is the key step in polyketide biosynthesis [26]. Malonic acid half thioesters (MAHT) are employed as enolate equivalents in addition reactions with aldehydes catalyzed by Cu(2-ethylhexanoate)2 and 5-methoxybenzimidazole. This metal salt and additive were optimized after initial screening experiments that identified Cu(OAc)2 and imidazole as promising leads for the desired transformation. The decarboxylative aldol addition is performed at ambient temperature under ambient atmosphere in wet solvent to afford moderate to excellent yields of the b-hydroxy thioesters (Figure 3.12). The substrate scope is good with regard to the electrophile. A common problem with direct aldol reactions is self-condensation of enolizable aldehydes; the reaction is not observed in this instance, demonstrating the mildness of the reaction. Good levels of diastereocontrol are observed when a-methyl MAHT are used. These diastereomer ratios are kinetic values, not thermodynamic, as judged by resubmission experiments. In the absence of aldehyde, no decarboxylation is observed, suggesting that a Cu(II)-thioacetate enolate is not on the reaction pathway. The authors propose that enolization of the MAHT by the amine base might be required for the reaction to proceed. No incorporation of a second aldehyde into an isolated aldol adduct is observed under the catalyzed reaction conditions – retro-aldol reactions do not occur.

General Experimental Procedure

5-Methoxybenzimidazole (0.11 mmol, 0.22 equiv.) and Cu(2-ethylhexanoate)2 (0.1 mmol, 0.2 equiv.) were added to a stirred solution of malonic acid half benzylthioester (0.5 mmol, 1.0 equiv.) in THF (5 mL; solvent stored in a vial without protection from the air before use) at 23 C. After the reaction became homogeneous (ca. 1 min) aldehyde (0.5 mmol, 1.0 equiv.) was added. The solution was stirred at 23 C for the prescribed time and quenched with 0.5 m HCl solution. The resulting solution was diluted with EtOAc and washed successively with 0.5 m HCl, saturated aq. NaHCO3 , and brine. The organic layer was dried over Na2 SO4 , filtered through cotton,

H

Cu O

Cu O

Et 59

N H (22 mol %) wet THF

N

(20 mol %)

O

N H (22 mol %) wet THF

N

Et 59 (20 mol %)

OMe

2

2

BnS

BnS

O

R

OH

R

OH

Me

60

O

O

CO2Et

Me

Me

70%

81%

97%

85%

Ph 82%

61a R = (CH2)2Ph: 52%, 7:1 syn/anti 82%, 8:1 syn/anti 61b R = CO2Et:

Me

OMe

Me

Direct aldol additions of MAHT catalyzed by Cu(II) complexes.

O R

CO2H

R

CO2H

Me 58b

O

H

O

58a

Fig. 3.12

BnS

BnS

O

O

Ph

Ph OMOM

NO2

74%

22%

82%

65%

3.4 General Experimental Procedure 95

96


and concentrated under reduced pressure. The product was purified by continuous gradient flash column chromatography. 3.4.4

Dienolate Additions to Aldehydes Scope and Application Activation of silyl enolates toward aldol additions can be achieved by desilylation. Carreira and coworkers developed this approach in highly enantioselective additions of silyl dienolates to aromatic, heteroaromatic, and a,b-unsaturated aldehydes in the presence of an (S-Tol-BINAP)CuF2 catalyst [27]. The copper fluoride catalyst is generated in situ by treatment of S-Tol-BINAP with Cu(OTf )2 , followed by addition of a crystalline, anhydrous fluoride source, (Bu 4 N)Ph3 SiF2 (TBAT). When as little as 2 mol% is used, (S-Tol-BINAP)CuF2 (63) catalyzes enantioselective addition of a silyl dioxolanone-derived dienolate to a range of aldehydes at 78 C (Eq. (18)). Selectivity ranged from good to excellent (83–95% ee) for all substrates except a-methylcinnamaldehyde, for which the level of enantioinduction was somewhat lower (65% ee). Aliphatic aldehydes are also selective electrophiles, but alkylnals suffered from low yields (< 40%). 3.4.4.1

(pTol)2 P CuF2 P (pTol)2

RCHO

Me

Me

O

O

63 2 mol %

+

THF, -78 °C; then CF3CO2H

OSiMe3 62

Me

Me

O

O

OH R

O 64a-j

CHO

CHO

S

CHO

O

CHO

ð18Þ a: 92%, 94% ee

b: 86%, 93% ee

c: 98%, 95% ee

CHO

CHO

CHO OMe

MeO e: 93%, 94% ee

Me

d: 91%, 94% ee

f: 83%, 85% ee

Me

CHO

h: 48%, 91% ee

Me

CHO

i: 81%, 83% ee

g: 82%, 90% ee

Ph

CHO Me

j: 74%, 65% ee


(S-Tol-BINAP)CuF2 -catalyzed addition of silyl dienolates to aldehydes has found synthetic utility in the construction of the polyol subunit of amphotericin B (Scheme 3.9) [28]. Both key fragments of the polyol chain (C1 aC13 ) were derived from the same aldol reaction of furfural and the trimethylsilyl dienolate, differing only in the antipode of (Tol-BINAP)CuF2 catalyst used. It is noteworthy that the furfural aldol adduct can be obtained in >99% ee after a single recrystallization of the aldol product. Chiral copper enolate methodology has also been employed for the total synthesis of leucascandrolide A [29]. Crotonaldehyde reacts with the aforementioned trimethylsilyl dienolate in the presence of 2 mol% (R-TolBINAP)CuF2 to afford the allyl alcohol adduct in 91% ee and 42% yield (Scheme 3.10). Yields were hampered in this instance because of crotonaldehyde polymerization, as noted by the authors. Further elaboration of this aldol product furnished a highly convergent synthesis of leucascandrolide A. Mechanistic Considerations [30] The hard fluoride anion is an effective desilylating agent. When mismatched with a soft Cu(II) cation the fluoride anion is designed to serve as an in-situ means of enolate formation. This is achieved by desilylation of the enolsilane, then by metalation. Supporting evidence for copper enolate formation was obtained by independent synthesis – when silyldienolate 62 is subjected to MeLi (10 mol%) followed by (S-BINAP)Cu(OTf )2 and benzaldehyde the expected aldol adduct is obtained in good yield and enantioselectivity. Similar results are obtained by employing (Bu 4 N)Ph3 SiF2 as the desilylating reagent. Mechanistic studies by Carreira and coworkers have concluded that the catalytically active species is the Cu(I) dienolate depicted in Scheme 3.11. Cu(II) complexes are known to undergo a one-electron reduction in the presence of enolsilanes. Thus desilylation of the silyl enolate via the hard fluoride anion of the copper complex followed by copper metalation gives the putative Cu(I) dienolate 66. The same (S-Tol BINAP)Cu(dienolate) has been observed independently via desilylation of the trimethylsilyl dienolate by (Bu 4 N)Ph3 SiF2 , followed by treatment with (S-Tol-BINAP)Cu(ClO4 ). Formation of the (S-Tol BINAP)Cu(dienolate) species and its disappearance after addition of benzaldehyde was closely monitored by IR spectroscopy (ReactIR). Regeneration of the catalytically active species is achieved by desilylation of another molecule of silyldienolate by the resulting Cu(I) alkoxide complex (68 ! 69 þ 66). Reactivity is also observed in the presence of catalytic quantities of (S-Tol-BINAP)Cu(O t Bu), with identical yields and selectivity as with the corresponding Cu(I) or Cu(II) fluoride catalysts, providing corroborating evidence for the proposed mechanism. 3.4.4.2

General Procedure. A mixture of Cu(OTf )2 (3.6 mg, 0.010 mmol, 2 mol%) and (S)-Tol-BINAP (7.5 mg, 0.011 mmol, 2.2 mol%) in 2 mL THF was stirred at 23 C in an inert gas atmosphere for 10 min to yield a clear yellow

97

Me

HO

Me

O

Me

THF, -78 °C

ent-63 2 mol%

Application of (S-Tol-BINAP)CuF2 -catalyzed additions of silyl dienolates to the polyol subunits of amphotericin B.

*

O

Me

O

Me BuPh2SiO

Scheme 3.9

t

O

*

OH

ent-64d

O

O O

Me

Me

1

O


O

+

OSiMe3

* OH

THF, -78 °C

63 2 mol%

OH

13

OH

CO2H

OMycosamine

OH OH O

CHO

O

Me

amphotericin B

*

OH OH

O

Me


H O

*

O

Me

O

Me

O

Me

O

Me t OSi BuMe2

O 64d 95%, > 99% ee *

OH O

98



Me

Me

O

O

(pTol) 2 P CuF 2 P (pTol) 2 OTMS

62 +

OH O

Me O

*

Me

THF, -78 °C

O Me

Me ent-63 2 mol%

O

ent-64h 42%, 91% ee

H Me *

O

OM O

O

O

O

N O

HN

O

MeO

Me

O Me leucascandrolide A

Scheme 3.10

Application of an (S-Tol-BINAP)CuF2 catalyzed addition of a silyl dienolate to the leucascandrolide A.

solution. A solution of Ph3 SiF2 (Bu 4 N) (10.8 mg, 0.02 mmol, 4 mol%) in 0.5 mL THF was added via a cannula and stirring was continued for 10 min. The mixture was cooled to 78 C and the dioxenone-derived dienolate (0.16 mL, 0.75 mmol) was added dropwise, followed by a solution of the aldehyde (0.50 mmol) in 0.5 mL THF. The progress of the reaction was monitored by TLC (reaction times 0.5–8 h). On completion trifluoroacetic acid (0.2 mL) was added at 78 C and the solution was left to warm to 23 C. Stirring was continued an another hour. The reaction mixture was diluted with ether (5 mL) and a saturated aqueous solution of NaHCO3 was added dropwise until evolution of gas ceased. The organic layer was washed with brine (3 mL), dried over Na2 SO4 , and concentrated in vacuo. Purification of the crude material by chromatography on silica gel with 3:1 ether– hexanes afforded the aldol adduct. The enantiomeric excess of the alcohol products was determined by HPLC analysis using a racemic sample as reference. 3.4.5

Enantioselective Cu(II) Enolate-Catalyzed Vinylogous Aldol Reactions

The traditional challenge associated with vinylogous aldol reactions is competition between reactivity at the a or g positions of the vinyl enolate. For-

99

OSiMe3

-FSiMe3

62

O

O

Proposed catalytic cycle for (S-TolBINAP)CuF2 -catalyzed additions of silyl dienolates to aldehydes.

(pTol) 2 P Cu(OTf) 2 P (pTol) 2

Ph3SiF 2(NBu4)

Scheme 3.11

65

63

(pTol) 2 P CuF2 P (pTol) 2

Me

Me

O

Me

OCu

R

Me3SiO

66

O

Me

RCHO

69

O

Me

P

P

62

O

O O

R

Cu O

O

Me

68

OSiMe3

P

P

Me

Me

Me

O H 67

Me O O

Me

O

P R Cu O P

O

Me

O

100


3.5 Conclusions

mation of the a-aldolate product has been suppressed by employing bulky Lewis acids such as aluminum tris(2,6-diphenyl)phenoxide (ATPH). Campagne and Bluet also discouraged a-aldolate formation and rendered the vinylogous aldol enantioselective by use of Carreira’s catalyst system (Eq. (19)) [31]. In the presence of 10 mol% (S-Tol-BINAP)CuF2 (63), the authors observed only the g-aldol products 70 in moderate enantioselectivity at ambient temperature. The authors propose that the catalytic cycle is analogous to that of the Carriera system, although no mechanistic studies of this system have yet been reported.

(pTol)2 P CuF2 P (pTol)2 63 10 mol%

OSiEt3 RCHO

+

OEt

OH R

THF, RT

OEt

Me OH

70a-d Me OH

O

O OEt

OEt 70a

O

Me

70b

80%, 70% ee

Me

OH

O

OH

O

OEt 70c

ð19Þ

70%, 48% ee

Me

35%, 56% ee

OEt 70d Me 68%, 77% ee

3.5

Conclusions

Copper complexes enable mechanistically diverse and synthetically useful approaches to the synthesis of b-hydroxy ketones. The Cu(II)-catalyzed asymmetric Mukaiyama aldol reaction developed by Evans provides facile stereocontrolled access to a range of aldol adducts derived from chelating electrophiles. Subsequent extension of this system in the context of ‘‘green’’ chemistry, described by Kobayashi, enabled access to aldols from unfunctionalized aldehydes. Recent efforts have focused on the use of copper complexes to effect direct aldol unions by way of in-situ enolization. Under this general mechanistic umbrella, reports of addition of nitromethane to pyr-

101

102


uvate esters, malonic half thioester additions to aldehydes, and desilylative dienolate additions have been described. It is both remarkable and exciting that these mechanistically dissimilar reactions are all catalyzed by the same metal. Given that nearly all of the examples from this chapter were reported after 1995 it is reasonable to expect continued interest and development in these fundamental bond constructions.

References 1 M. Iwata, S. Emoto, Chem. Lett. 1974, 959–960. 2 K. Irie, K.-i. Watanabe, Chem. Lett. 1978, 539–540. 3 Y. Ito, T. Matsuura, T. Saegusa, Tetrahedron Lett. 1985, 26,

5781–5784. 4 D. A. Evans, J. A. Murry, M. C. Kozlowski, J. Am. Chem.

Soc. 1996, 118, 5814–5815. 5 D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey,

6 7

8 9 10 11 12 13 14

15 16 17 18 19 20

K. R. Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999, 121, 669–685. D. A. Evans, D. M. Fitch, T. E. Smith, V. J. Cee, J. Am. Chem. Soc. 2000, 122, 10033–10046. D. A. Evans, P. H. Carter, E. M. Carreira, A. B. Charette, J. A. Prunet, M. Lautens, J. Am. Chem. Soc. 1999, 121, 7540– 7552. D. A. Evans, E. Hu, J. D. Burch, G. Jaeschke, J. Am. Chem. Soc. 2002, 124, 5654–5655. H. Matsunaga, Y. Yamada, T. Ide, T. Ishizuka, T. Kunieda, Tetrahedron: Asymmetry 1999, 10, 3095–3098. T. K. Hollis, B. Bosnich, J. Am. Chem. Soc. 1995, 117, 4570– 4581. C. Girard, H. B. Kagan, Angew. Chem. Int. Ed. 1998, 37, 2923–2959. D. A. Evans, M. C. Kozlowski, C. S. Burgey, D. W. C. MacMillan, J. Am. Chem. Soc. 1997, 119, 7893–7894. D. A. Evans, C. S. Burgey, M. C. Kozlowski, S. W. Tregay, J. Am. Chem. Soc. 1999, 121, 686–699. For recent modifications to the bis(oxazoline) ligand and application to the pyruvate addition, see: H. L. van Lingen, J. K. W. van de Mortel, K. F. W. Hekking, F. L. van Delft, T. Sonke, F. P. J. T. Rutjes, Eur. J. Org. Chem. 2003, 317–324. R. Roers, G. L. Verdine, Tetrahedron Lett. 2001, 42, 3563– 3565. S. Orlandi, A. Mandoli, D. Pini, P. Salvadori, Angew. Chem. Int. Ed. 2001, 40, 2519–2521. F. Reichel, X. M. Fang, S. L. Yao, M. Ricci, K. A. Jorgensen, Chem. Commun. 1999, 1505–1506. P. I. Dalko, L. Moisan, J. Cossy, Angew. Chem. Int. Ed. 2002, 41, 625–628. J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325– 335. S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc. 1998, 120, 8287–8288.

References 21 S. Kobayashi, S. Nagayama, T. Busujima, Tetrahedron 1999,

55, 8739–8746. 22 K. Manabe, S. Kobayashi, Chem. Eur. J. 2002, 8, 4095–4101. 23 S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209–217. 24 K. Juhl, N. Gathergood, K. A. Jorgensen, Chem. Commun.

2000, 2211–2212. 25 C. Christensen, K. Juhl, R. G. Hazell, K. A. Jorgensen, J.

Org. Chem. 2002, 67, 4875–4881. 26 G. Lalic, A. D. Aloise, M. S. Shair, J. Am. Chem. Soc. 2003,

125, 2852–2853. 27 J. Krueger, E. M. Carreira, J. Am. Chem. Soc. 1998, 120,

837–838. 28 J. Kruger, E. M. Carreira, Tetrahedron Lett. 1998, 39, 7013–

7016. 29 A. Fettes, E. M. Carreira, Angew. Chem. Int. Ed. 2002, 41,

4098–4101. 30 B. L. Pagenkopf, J. Kruger, A. Stojanovic, E. M. Carreira,

Angew. Chem. Int. Ed. 1998, 37, 3124–3126. 31 G. Bluet, J. M. Campagne, J. Org. Chem. 2001, 66, 4293–

4298.

103

105

4

Tin-promoted Aldol Reactions and their Application to Total Syntheses of Natural Products Isamu Shiina 4.1

Introduction

Stereoselective aldol reactions are frequently used for synthesis of complicated natural and unnatural oxygenated products, because b-hydroxy carbonyl groups are now easily prepared by several effective methods. Among the three stable valences of tin, the stannic and stannous species are generally used for effective formation of the desired aldol adducts from two starting materials. These tin-promoted reactions are divided into two types according to the principles: (i) directed Mukaiyama aldol reaction of silyl enolates with carbonyl compounds promoted by Sn(IV) or Sn(II) Lewis acids, and (ii) the crossed aldol addition of C- or O-enolates with Sn(IV) or Sn(II) to other carbonyl components. This review first covers Sn(IV)mediated aldol reactions of enol silyl ethers (ESE) or ketene silyl acetals (KSA) with carbonyl compounds or acetals, which have been developed as powerful tools for stereoselective synthesis of b-hydroxy or b-alkoxy carbonyl groups. Chiral diamine–Sn(II) complex-promoted aldol and related addition reactions for preparation of a variety of optically active polyoxy compounds will be the second subject discussed. Finally, recent applications of the reactions to highly enantioselective syntheses of optically active natural products will be described.

4.2

Tin-promoted Intermolecular Aldol Reactions 4.2.1

Achiral Aldol Reactions

In 1973, Mukaiyama and Narasaka developed an acid-catalyzed aldol reaction of silyl enolates with electrophiles and revealed that Lewis acids such as TiCl 4 , SnCl 4 , AlCl3 , BF3 OEt2 , and ZnCl2 promoted the reaction quite Modern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

106

4 Tin-promoted Aldol Reactions and their Application to Total Syntheses of Natural Products

effectively, affording a variety of b-hydroxy ketones from ESE and carbonyl compounds (Eq. (1)) [1]. The synthetic capacity of KSA in the new aldol reaction was also reported in 1975, and the corresponding b-hydroxy- and b-siloxycarboxylic esters were obtained in good combined yields by use of TiCl 4 (Eq. (2)). OTMS

O + Ph

Ph

H

(1)

CH2Cl 2, -78 °C 83% OTMS

O + R

OH O

SnCl 4

H

R1

OR' O

TiCl 4

OR3

CH2Cl 2, -78 °C 84~99%

R2

OR3

R

(2)

R1 R2 R' = H or TMS

Although it is mentioned in their reports that TiCl 4 seems to be superior to other Lewis acids with regard to yield, SnCl 4 was also a popular reagent because of its mild activity and good chelation ability. For example, Wissner applied the SnCl 4 -mediated aldol reaction of tris(trimethylsiloxy)ethene with several aldehydes to the synthesis of a,b-dihydroxycarboxylic acids (Eq. (3)) [2] and Ricci and Taddai prepared a bicyclic g-lactone in good yield by aldol addition of 2,5-disiloxyfuran to two molar amounts of acetone using SnCl 4 (Eq. (4)) [3].

O R

2

OTMS

+

TMSO

H

O

+

TMSO

OTMS

O

OTMS

OH O

SnCl4 R

OH

58~82%

SnCl 4

(3)

OH O

O

(4) CH2Cl 2, -78 °C 70%

O

O

In 1983, Kuwajima and Nakamura reported a novel method for generation of a-stannylketones from ESE and SnCl 4 and studied the properties of the new metallic species in the reaction with carbonyl compounds giving aldol adducts (Eq. (5)) [4]. This facile method for preparing trichlorostannyl enolates was successfully employed in the regioselective synthesis of aldols, as shown in Eq. (6) [5]. Interestingly, syn selectivity was observed in this alternative method, in contrast with the anti selectivity obtained in the direct SnCl 4 -promoted aldol reaction of ESE with the electrophiles (Eqs. (5) and (7)) [1]. Therefore, dif-

4.2 Tin-promoted Intermolecular Aldol Reactions

O OTMS

O

SnCl 4

Ph

CI3Sn

α-stannylketone O + Ph

ð5Þ

Ph CH2Cl 2, -70 °C 80%

CH 2Cl 2, 20 °C

O

OH O

H

OH O

SnCl 4

TMS

syn/anti =93/7

Ph

H

CH2 Cl2 -78 to -50 ˚C 81%

Ph

(6)

Ph

ferent mechanisms were proposed for these reactions, and it was assumed that the silyl nucleophiles could directly attack the carbonyl compounds activated by the Lewis acid at low temperature. OTMS

SnCl4

O Ph

H

O

OH O

SnCl 4

(7) Ph

CH2Cl 2, -78 °C

Ph

H

activated aldehyde

CH2Cl 2, -78 °C 83%

syn/anti = 24/76

Structural features and reactivity of the Sn(IV) C- or O-enolates have been investigated [6, 7]. Yamamoto and Stille independently studied the aldol reaction of stannyl enolates derived from ketones with aldehydes, and showed that stereoselectivity depended on the substituents on the tin and the reaction temperature (Eqs. (8) and (9)) [8, 9]. O OLi

Ph3SnCl

OSnPh3

Ph

OH O

H Ph

rt Sn(IV) enolate

THF -70 °C 80%

(8)

syn/anti = 71/29

O OAc

Bu3SnOMe

OSnBu3

rt isolated Sn(IV) enolate

Ph

H

OH O

Ph ð9Þ THF -78 °C; 78% -78 °C; syn/anti = 20/80 45 °C; 86% 45 °C; syn/anti = 77/23

107

108


Mukaiyama and Iwasawa developed a facile method for the generation of Sn(II) enolates in situ from the corresponding carbonyl compounds with Sn(OTf )2 and a tertiary amine (Eqs. (10) and (11)) [10], and excellent syn selectivity of the aldol reaction was observed in the course of their studies of Sn(II) enolate chemistry (described in a later section). O O

OSnOTf

Sn(OTf) 2

Ph

OH O

H Ph

-78 °C 41%

NEt Sn(II) enolate

syn/anti =>95/5

CH2 Cl2, -78 °C

S

O N

(10) O

OTf Sn S O

Sn(OTf) 2

Ph

S N

NEt CH2Cl 2, -78 °C

S

-78 °C 94%

S

OH O

H Ph

N

S

syn/anti =97/3

Sn(II) enolate

ð11Þ

4.2.2

The Reaction of Silyl Enolates with Aldehydes or Ketones

Diastereoselective addition of ESE and KSA to aldehydes using SnCl 4 were systematically studied by Heathcock, Reetz, and Gennari, who produced a variety of synthetic intermediates. As shown in Eqs. (12)–(15), Heathcock and Reetz independently examined the stereoselectivity of the Mukaiyama aldol reaction of ESE with many kinds of aldehyde, promoted by SnCl 4 [11, 12]. Their results can be summarized: 1. good 2,3-anti or 2,3-syn asymmetric induction was observed in the reaction between achiral simple or a-heteroatom-substituted aliphatic aldehydes and ESE derived from ethyl ketones (Eqs. (12) and (13)); OTMS

O + R

Bu

OTMS

O BnO

t

H

Ph

(12)

syn/anti = 5/>95 OH O

SnCl 4 BnO CH2Cl 2, -78 °C >95% (conversion)

t Bu

R

CH2Cl 2, -78 °C 60~72%

+ H

OH O

SnCl 4

Ph

syn/anti = >95/5 [TiCl4 ; 90/10]

(13)


2. high 3,4-syn asymmetric induction was observed in the reaction between a-heteroatom-substituted aliphatic aldehydes and ESE derived from methyl ketones (Eq. (14)); and O

OH O

SnCl 4

OTMS +

H

Ph

OBn

Ph CH2Cl 2, -78 °C 68%

(14)

OBn syn/anti =>99/1

3. good 2,3-syn and high 3,4-syn asymmetric induction was observed in the reaction between a-heteroatom-substituted aliphatic aldehydes and ESE derived from ethyl ketones (Eq. (15)). O

OH O

SnCl 4

OTMS +

H

Ph

OBn

Ph CH2Cl 2, -78 °C 85%

BnO 2,3-syn/anti = 95/5 3,4-syn exclusively

(15)

The observed excellent 3,4-syn selectivity for the a-branched aldehyde was explained by the formation of a Lewis acid–aldehyde complex (so-called chelation model, Scheme 4.1). Good stereoselectivity was not achieved, however, when KSA was employed, even in the reaction with a-benzyloxypropionaldehyde, except when tetrasubstituted KSA were used (Eqs. (16)– (18)).

M O BnO

Nu-TMS

OH

β-face attack

H H Chelation Model

Nu BnO 3,4-syn selection

Me

M BnO Me

O

H R'

H TMSO

R' BnO R 2,3-syn-3,4-syn selection

OTMS

M O BnO R Me

OH O

favorable R H

OH O

unfavorable H R'

R' BnO R 2,3-anti-3,4-syn selection

Scheme 4.1

Chelation model for producing 3,4-syn aldols.

109

110


O H

O t Bu

OBn

O

CH2Cl 2, -78 °C 65%

OTMS +

H

CH2Cl 2, -78 °C >85%

OTMS +

H

syn/anti = 65/35

OH O

CH2Cl 2, -78 °C 93%

(17)

BnO syn/anti = >97/3

OH O

SnCl 4

OTMS

OBn

(16)

OBn

OMe

OMe

MeO

O t Bu

SnCl 4

OBn

O

OH O

SnCl 4

OTBS

+

OH OMe

BnO

(18)

2,3-syn/anti = 5/95 3,4-syn/anti =>99/1

Gennari further studied the Mukaiyama aldol addition of KSA to aldehydes and found that S- t Bu propanethioate or ethanethioate is a quite suitable precursor of the required KSA for stereoselective reactions [13]. Although the reaction of KSA derived from S- t Bu propanethioate with simple achiral aliphatic aldehydes gave poor 2,3-diastereoselectivity (Eq. (19)), it reacted with a-alkoxy aldehydes highly stereoselectively to afford 2,3-syn-3,4syn isomers as shown in Eq. (20). O

OTMS +

H

St Bu

SnCl 4

OH O

S t Bu CH2Cl 2, -78 °C E/Z=93/7; 86% E/Z=93/7; syn/anti = 42/58 E/Z=10/90; 80% E/Z=10/90; syn/anti =42/ 58

ð19Þ O

OTBS H

OBn

SnCl 4

+ St Bu

CH2Cl 2, -78 °C

OH O S t Bu

OBn E/Z = >95/5; 89% E/Z=>95/5; 2,3-syn/anti = 97/3 E/Z = 5/>95; 90% 3,4-syn exclusively E/Z=5/>95; 2,3-syn/anti = 76/24 3,4-syn exclusively

ð20Þ Furthermore, KSA derived from S- t Bu ethanethioate also gave a 3,4-syn adduct preferentially in good yield (Eq. (21)). The highly 3,4-syn asymmetric induction by chelation control using SnCl 4 is quite effective for the con-


111

struction of natural complex molecules (as is described at the end of this section). O H OBn

St Bu

OH O

SnCl4

OTBS +

CH2Cl 2, -80 °C 70%

St Bu

(21)

OBn syn/anti =>98/2

It is worthy of note that a-stannylthioesters, instantly generated from KSA by treatment with SnCl 4 , also react with aldehydes to afford the corresponding aldol adducts, but the stereoselectivity of this reaction is sometimes very different from that in the reaction involving KSA and an SnCl 4 – aldehyde complex (compare Eqs. (19) and (22), and Eqs. (20) and (23)). The order of addition of KSA and aldehydes to a solution of Lewis acid catalysts such as SnCl 4 should therefore be selected carefully in accordance with the stereoselectivity desired. O H

OTMS

O

SnCl4

S tBu CH2Cl 2, -78 °C

CH2 Cl2 -78 to 0 °C 45%

CI3Sn

St Bu

OH O St Bu syn/anti =>98/2

ð22Þ O H

α-stannylthioester OBn

OH O St Bu

CH2 Cl2 OBn -78 to -20 °C 2,3-syn/anti =10/90 75% 3,4-syn exclusively

(23) Further examples of the construction of multi-functional b-hydroxy carbonyl compounds using SnCl 4 are given in Eqs. (24)–(28). Although sulfursubstituted ESE derived from methylthioacetone reacted with a-alkoxy aldehyde to give a 3,4-syn adduct preferentially (Eq. (24)) [14], the reaction of KSA prepared from methyl a-methylthiopropionate afforded an almost equimolar mixture of the corresponding 3,4-syn and anti diol groups (Eq. (25)) [15]. A 2,3-anti-3,4-syn a-amino carboxylic ester was stereoselectively prepared by reaction of amino-substituted KSA with a-benzyloxypropionaldehyde (Eq. (26)), and the adduct was converted to the corresponding g-lactone which is known as a synthetic intermediate of l-daunosamine and l-vancosamine [16].

112


O

OTMS H

OH O

SnCl4

+

OBn

CH2Cl 2, -78 °C OBn SMe E/Z =80/20; 58% E/Z =17/83; 53% E/Z=80/20; 3,4-syn/anti =80/20 E/Z=17/83; 3,4-syn/anti =82/18

SMe

(24) O

OTMS H

+ MeS

OBn

OMe

OH O

SnCl4 CH2Cl 2, -78 °C

OMe SMe

BnO

E/Z=25/75

(25)

OH O

i) NaIO 4

OMe

ii) ∆

BnO 65%, syn/anti =52/48

O

OTMS H

OBn

+

Bn 2N

OtBu

OH O

SnCl4

OtBu CH2 Cl2 -78 to -40 °C 50%

OBn NBn2 2,3-syn/anti =16/84 3,4-syn/anti =>98/2 HO

NHZ O

ð26Þ

O

a known intermediate in the synthesis of aminosugars NH2

NH2

HO

HO O

OH

L-Daunosamine

O

OH

L-Vancosamine

It is notable that the reaction of KSA derived from ethyl acetate with an a-amino aldehyde in the presence of SnCl 4 gave a 3,4-syn amino alcohol under chelation-control conditions (Eq. (27)) [17] whereas the opposite diastereoselectivity was observed when an a-phenylthio aldehyde was used as the electrophile (Eq. (28)) [18] and a 3,4-syn aldol adduct was obtained when TiCl 4 was employed for the latter reaction instead of SnCl 4 . The 3,4-anti selectivity in the reaction promoted by SnCl 4 was therefore explained, as an exception, by the non-chelation model.


O

OH O

SnCl4

OTMS +

H NHBoc

OEt

OEt

CH2Cl 2, -78 °C 60%

NHBoc syn/anti =91/9

ð27Þ O

OH O

SnCl4

OTMS +

H

OMe

CH2Cl 2, -78 °C 78%

SPh

OMe PhS syn/anti = 2/>98 (non chelation) [TiCl 4; 86%, 80/20 (chelation)]

ð28Þ The SnCl 4 -promoted diastereoselective aldol reaction has been applied to the synthesis of some parts of complex molecules such as oligopeptides, oligosugars, and polyoxyamides (Eqs. (29)–(36)). Joullie´ obtained a 2,3-syn3,4-syn thioester by reaction of KSA derived from S- t Bu propanethioate with an a-alkoxy aldehyde, as shown in Eq. (29) [19]. The prepared intermediate was successfully converted to the macrocyclic peptides didemnin A, B, and C in 1990. O H

+

OH O

SnCl4

OTBS

St Bu

St Bu CH2Cl 2, -78 °C 74%

OBn

OBn exclusively

O Me N

N

ð29Þ PMP O

O O

O

NH

R=

O

Me N

OH

O O O

O

HO

O

NHR NH

Didemnin C

Danishefsky employed a trisubstituted butadiene for reaction with an aldehyde connected to a ribonucleoside, with promotion by SnCl 4 (Eq. (30)); subsequent desilylation of the adduct afforded the corresponding dihydropyran which was transformed to tunicamycins [20]. Cox and Gallagher employed a cyclic ESE as a nucleophile for reaction with ribosyl aldehyde, as depicted in Eq. (31); the aldol isomers formed could be used as precursors of tetracyclic hemiketals [21]. Akiyama and

113

114


OTBS BzO O

PMB N O N

MOMO O

O

PMB N O

OMe O

O SnCl 4

H

MOM TBS O O

O

N

OBz

CH2Cl 2, -78 °C

O

O

O

PMB N O

O HF

OMe

O

N

MeCN, 0 °C 61% (2 steps)

MOMO O

O

O

Bz O

5 4

O

O

with another 4,5-cis isomer

O

H N

O N HO

HO

OH

H O

O

O

H N

R O

O

NHAc

O

OH HO

OH OH

Tunicamycins, R = unsaturated alkyl chains

ð30Þ Ozaki developed a new chiral auxiliary group in the diastereoselective synthesis of optically active aldols with a tertiary hydroxyl group (Eq. (32)) [22]. For example, (R)-dimethyl citramalate was synthesized from an adduct produced by the SnCl 4 -accelerated aldol reaction of KSA derived from ethyl acetate with the chiral pyruvate. O O

O O

OTBS H

OBn

OH O SnCl4

O

O

+ O

CH2Cl 2, -78 °C 35%

O OBn syn/anti = 50/50 O

(31) H

H 2, Pd/C 50%

H O

O

H

O

O O

H

O

OH


115

OTBS O

OTBS O

O

OEt SnCl 4

O

O

OTBS HO O

O

OEt

O

O

O

O

CH2Cl 2, -20 °C 80%

O

O

O

>98% de O

HO MeO

OMe

O (R)-Dimethyl citramalate

ð32Þ Mukai and Hanaoka reported the formal synthesis of AI-77B in which they successfully used the stereoselective direct aldol reaction of KSA derived from S- t Bu ethanethioate with an a-alkoxy aldehyde (Eq. (33)) [23].

TBSO

O

Ph

OTBS H

OBn

+

S t Bu

SnCl 4

TBSO

OH O St Bu

Ph CH2Cl 2, -78 °C 53% (2 steps, from the corresponding thiol ester)

OBn

O O

OH NH2 O

H N

OH O

OH

AI-77B

ð33Þ

They also used an a-trichlorostannyl thioester generated from KSA with SnCl 4 in a reaction with an a-alkoxy aldehyde to produce a 2,3-anti-3,4-syn aldol group which was employed as an intermediate in the total synthesis of bengamide E, as shown in Eq. (34) [24]. Recently, Boeckman re-applied this methodology for the practical preparation of bengamide B, E, and Z (Eq. (35)) [25]. Mukai and Hanaoka also used SnCl 4 as catalyst in the reaction of the KSA derived from S- t Bu ethanethioate with an a,b-dibenzyloxy aldehyde possessing a Co complex part, to produce a new synthetic intermediate of

116


OTMS MeO

TBSO

O

SnCl 4 Cl 3Sn

St Bu CH Cl , -78 °C 2 2

St Bu

O H

+ OBn

OMe

E/Z=75/25 TBSO

OH O StBu

CH 2Cl2, -78 to 0 °C 73% (2 steps, from the corresponding thiol ester)

OBn OMe 2,3-syn/anti =8/92 3,4-syn exclusively OH OH O

OH OMe

NH

N H

O

ð34Þ

Bengamide E

OTMS MeO

SnCl 4

SPh CH Cl , -78 °C 2 2

TBSO

O Cl 3Sn

SPh

O

+

H OR

OMe TBSO

OH O

SPh CH2Cl 2, -78 °C OR OMe R = Bn; 73% R = Bn; 2,3-syn/anti =8/92 R = 2-naphthylmethyl; 73% R = 2-naphthylmethyl; 2,3-syn/anti =11/89 R2 OH OH O

OH OMe

N H

Bengamide B, E, Z

NR1 O

ð35Þ

bengamide E under direct Mukaiyama aldol-reaction conditions (Eq. (36)) [26]. In contrast, non-metalated a,b-dibenzyloxy aldehyde stereorandomly reacted with the same KSA to give a mixture of isomers, and a similar result was also observed in Liu’s recent research (Eq. (37)) [27].


BnO

BnO

O + MeO

OH O

SnCl 4

OTMS

H OBn Co(CO)3 Co (CO) 3

St Bu

E/Z =75/25

117

St Bu OBn OMe Co(CO)3 Co (CO) 3

CH2 Cl 2 -78 to 0 °C

BnO

CAN

OH O St Bu

MeOH, 0 °C 47% (3 steps, from the corresponding alcohol)

OBn OMe exclusively

OH OH O NH

N H

O

OH OMe Bengamide E

ð36Þ BnO

O H + MeO

SPh

OBn

BnO

SnCl 4

OTMS

OH O SPh

any Lewis Acid

OBn OMe no selectivity

ð37Þ 4.2.3

The Reaction of Silyl Enolates with Acetals

Mukaiyama reported that acetals are also activated by Lewis-acid catalysts and are effectively coupled with nucleophilic ESE and KSA to give the desired b-alkoxy carbonyl compounds in high yields (Eq. (38)) [28]. Kuwajima showed that trichlorostannyl C- or O-enolates could be used as nucleophiles in reactions with acetals and aldehydes (Eq. (39)) [5]. OTMS

OEt + Ph

CH2Cl 2, -78 °C 95% O

CI

(38)

Ph

OEt

OMe

OEt O

TiCl 4

+

TMS

OMe Ph

SnCl 4 CH2 Cl2 -78 to -40 °C 72%

OMe O CI

(39) Ph

118


Some examples of reactions using ESE and KSA with acetals to produce the corresponding b-alkoxy carbonyl compounds are given in Eqs. (40)–(43) [29–32]. This method is useful for the synthesis of protected aldols directly from the silyl enolates and acetals. OMe +

OMe

N SO2Ph

OMe O

SnCl 4

OTMS Ph

Ph

N SO2Ph

CH2Cl 2, -70 °C 93%

(40)

Ph

N H

TMS

SnCl 4

OTMS

TMS

O

+ C5H 11

F F Br

O

OMe

Ph

OTMS

OEt

O

Ph

(41)

F F

SnCl 4

+

OEt O

Br

OEt

CH2Cl 2, -78 °C 83%

AcO + O

C5H 11

CH2Cl 2, -78 °C 92%

OEt

OTMS

SnCl 4 CH2Cl 2, -78 °C 87%

(42)

AcO

O O

ð43Þ Although little systematic research has been performed on the stereoselectivity of this reaction, some approaches to the use of chiral acetal parts for asymmetric synthesis have been reported. Kishi successfully accomplished the preparation of an optically active synthetic intermediate of aklavinone by reaction of a-stannylketone with a chiral aromatic aldehyde acetal as depicted in Eq. (44) [33]. A similar achiral acetal was also used for synthesis of racemic 4-demethoxydaunomycinone by Rutledge in 1986 (Eq. (45)) [34]. Rutledge’s and Yamamoto’s approaches are noteworthy for the stereoselective synthesis of optically active b-alkoxy carbonyl compounds in SnCl 4 promoted aldol reactions (Eqs. (46) and (47)) [35, 36].


OH O

OH

O

O O

OH O

OH O

+ MeCN, -20 °C 83%, ds 10/1

TMS O

OH O

SnCl 4

119

CO2Me

CO2Me

O OH O

OH OH OH

O

CO2Me

Aklavinone

ð44Þ O

OH OMe OMe

O

O OTMS

SnCl 4

O

MeCN, -23 °C 70%

OH OMe O

+

OMe CO2Me

O O

OMe CO2Me

O

OH OH OH

O OH O rac-4-demethoxydaunomycinone

ð45Þ MeO O Ph O OTMS

SnCl 4

O

MeO

MeO

H O

Cl 3Sn

MeCN, -23 °C

MeCN, -23 °C 73%

Ph

O

O MeO 3α/3β=64/36

ð46Þ TMS TMS

OTMS O O

O O

1 + R

R3 R2

O

SnCl 4 TMS

CH2 Cl2 -78, -97 or -125 °C 55~91%

R3

O R1 R2 64~94% ee

ð47Þ

120


Otera discovered that Sn(IV) Lewis acids such as Bu2 Sn(OTf )2 , Bu2 Sn(ClO4 )2 , Bu3 SnClO4 , and (C6 F5 )2 SnBr2 are suitable activators for the aldol reaction of ESE and KSA with aldehydes [37]. Interestingly, it was proved by elaborate research that reactions of ESE with ketones and of KSA with acetals do not proceed under the influence of these catalysts. It was also shown that a,b-unsaturated aldehydes are much more reactive than aromatic and saturated aliphatic aldehydes. They expanded this concept to ‘‘parallel recognition’’, in which some reaction patterns proceed exclusively, affording the desired adducts only, on treatment of several different nucleophiles and electrophiles in one pot. When an ambident electrophile is used in this new strategy ESE and KSA, respectively, react with one of the electrophilic points in the substrate to produce a single adduct in high yield with perfect selectivity (Eqs. (48) and (49)). TMSO t

OMe O

+

+

OTBS

MeO

Bu

TBS

(C 6F5 )2SnBr2

O MeO

O

O

OEt CH Cl , -78 °C t 2 2 Bu 73%

OEt

ð48Þ OTMS

OH O

+

O

Ph

(C 6F5 )2SnBr2

Ph

H OTBS +

O

OEt

CH2Cl 2, -78 °C 58%

CO2Et OTBS

ð49Þ

4.2.4

Reaction of Dienol Silyl Ethers

Siloxyheteroaromatic compounds function as nucleophilic dienol silyl ethers with carbonyl compounds or acetals under the influence of a Lewis acid catalyst. For example, Takei showed that 2-siloxyfurans react with aldehydes and acetals to give the corresponding g-substituted g-lactones in high yields (Eqs. (50) and (51)) [38]. O + R1

OTMS

R2

MeO OMe R1

O

R2

SnCl 4 CH2Cl 2, -78 °C 70~96%

+

O

OTMS

SnCl 4 CH2Cl 2, -78 °C 66~92%

R1 R2

OH

R1 R2

O

O

(50)

OMe O

O

(51)

4.3 Tin-promoted Intramolecular Aldol Reactions

2-Siloxypyrrole has also been used as a suitable nucleophile in the SnCl 4 promoted aldol reaction with aldehydes shown in Eq. (52). Several polyoxy a-amino acids and carbocyclic amines were synthesized by Rassu and Casiraghi using a stereoselective aldol reaction of 2-siloxypyrrole with protected glyceraldehyde in the presence of SnCl 4 [39]. O H

O

Boc N OTBS

+

O

OH Boc N O

SnCl 4 O O

Et 2O, -80 °C 80% >95% ds OH O

HO

NH2

HO OH

OH

NH2

(52) NH2

HO OH

HO

HO

OH

OH

Baldwin successfully used the reaction of functionalized 2-siloxypyrrole with 2-methylpropionaldehyde for synthesis of an intermediate of lactacystin, a natural g-lactam (Eq. (53)) [40]. Ph

Ph O

O H

+

O

SnCl4 N

OTBS

N

HO

Et 2O, -78 °C 61%

O

5

5α/5β=9/1

(53) AcHN O HO2C

S HO

H N

O

OH Lactacystin

4.3

Tin-promoted Intramolecular Aldol Reactions 4.3.1

The Intramolecular Aldol Reaction of Silyl Enolates

Not only intermolecular additions of ESE and KSA to acetals, but intramolecular reactions of acetals with a silyl enolate moiety are also quite

121

122


effective, especially for synthesis of strained cyclic compounds. Kocienski fully studied the intramolecular reaction of ESE to give medium-sized compounds (Eq. (54)), and this method was even found to be applicable to the synthesis of an eight-membered carbocycle (Eq. (55)) [41]. Paquette also succeeded in preparing a bicyclic eight-membered ring compound as shown in Eq. (56) [42]. OSiMe 2Ph O

SnCl 4

(54) O

CH2Cl 2, -78 °C 30%

O

OH

O

cis/trans=50/50 OTMS O

O

SnCl 4

O

HO

O

(55)

CH2Cl 2, -40 °C 35% OSiMe 2Ph

O

SnCl 4 proton sponge

(56) O

CH2Cl 2, -78 °C 69%

O MeO

Tatsuta recently reported a total synthesis of pyralomicin 1c in which SnCl 4 -catalyzed cyclization was effectively employed for formation of a 6membered ring core as shown in Eq. (57) [43].

O

TBS TBS O OMe

PhO2S TBSO

O SnCl 4

PhO2S

OTBS

OMe CH2Cl 2, -78 °C OTBS 71%

OTBS OTBS OH OH

HO

N

(57)

OH O

Cl Cl O

OH

Pyralomicin 1c

4.3 Tin-promoted Intramolecular Aldol Reactions

[1,3] rearrangement of ESE with anomeric carbon was developed by Ley in 1998, and several 6- and 5-membered C-glycosides have been prepared by SnCl 4 acceleration (Eqs. (58) and (59)) [44]. OTMS C6H13

O

R = Ph, C

O

CPh, tBu

CH2Cl 2, -30 °C 79~86%

SnCl 4 O

C6H13

R

OTMS O

OH

SnCl 4

C7H 15

O

R

(58)

O α/β=75/25 O

HO

O

CH2 Cl2 56%

(59)

C7H 15

4.3.2

Reaction of Dienol Silyl Ethers or g-Silyl-a,b-enones

In 1986, Kuwajima established a method for generation of g-stannyl-a,benones as nucleophilic species. It was found that these reactions with acetals proceeded smoothly to afford the corresponding coupling products in good yields (Eq. (60)) [45].

O

O

SnCl 4 CH 2Cl2 , 0 °C

TMS

Cl 3Sn γ-stannylenone

O

OMe

γ-stannylenone O

OMe

(60) O

OMe

CH 2Cl2 , 0 °C 71%

Remarkable results from SnCl 4 -induced aldol cyclization using dienol silyl ethers have been observed in synthetic studies on taxane diterpenoids [46]. In the initial approach for construction of the basic skeleton of a taxane ring using a g-stannyl-a,b-enone generated from a g-silyl-a,b-enone by SiaSn metal exchange, the yield of the desired tricyclic compound was unsatisfactory (Eq. (61)). Cyclization of acetals with a dienol silyl ether moiety promoted by SnCl 4 occurred rapidly, however, to afford the aromatic taxanes in high yields (Eqs. (62) and (63)). Kuwajima recently accomplished the total synthesis of paclitaxel (taxol), using this intermediate as the main component with the eight-membered ring core.

123

124


TMS

O

TIPSO H

OBn OBn

TIPSO HO

SnCl4

OMe

MeO

PhS

OMe

OMe OMe

OH

E/Z=60/40

CH2 Cl2, rt 15~17% [SnCl 4/TiCl 4; -23 °C; 73%]

OMe OMe

OH OMe

(61)

O

OMe

H

MeO

OMe

SnCl4

(62)

CH2Cl 2, -45 °C Z ; 77% E ; 66%

(MeBO)3 pyridine benzene, rt 90%

O H

i) SnCl4 CH2Cl2 -78 to -45 °C

OH OMe

PhS

ii) pinacol DMAP benzene, rt 76% (2 steps)

O HO

OBn

OH

AcO O Ph

NH

O

OH

O

Ph

O

OH

H O O Ac Bz Paclitaxel (Taxol®)

O

HO

ð63Þ

4.4

Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions

Enantioselective aldol addition is one of the most powerful tools for construction of new carbon–carbon bonds with control of the absolute configurations of new chiral centers, and the utility of this reaction has been demonstrated by several applications to the synthesis of natural products such as carbohydrates, macrolide and polyether antibiotics, etc. In the asymmetric aldol reactions reported chiral auxiliary groups are usually attached to the reacting ketone-equivalent molecules. Until the early 1980s there had been no example of an aldol-type reaction in which two achiral carbonyl compounds were used to form a chiral molecule with the aid of a chiral ligand.

4.4 Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions

Chiral auxiliaries derived from (S)-proline seemed to be particularly attractive, because they have conformationally rigid pyrrolidine rings. Chiral diamines derived from (S)-proline, especially, are successfully employed for creation of an efficient chiral environment because almost all the main and transition metals having vacant d orbitals are capable of accepting a bidentate ligand. An intermediate derived from the chiral ligand and an organometallic reagent would have a conformationally restricted cis-fused five-membered ring chelate and would afford optically active organic compounds by reaction with appropriate substrates. 4.4.1

Asymmetric Aldol and Related Reactions of Sn(II) Enolates

Enantioselective aldol reaction via Sn(II) enolates coordinated with chiral diamines was explored by Mukaiyama and Iwasawa in 1982 [10c, 47]. In the presence of chiral diamine 1a, various optically active aldol adducts were produced by reactions between aromatic ketones and aldehydes (Eqs. (64) and (65)). This is the first example of the formation of crossed aldol products in high optical purity, using chiral diamines as chelating agents, starting from two achiral carbonyl compounds.

N

N Me Sn(OTf) 2

O

1a

OSnOTf

N N Me Sn O OTf

Ph

Ph NEt

Ph chiral Sn(II) enolate

CH2 Cl2, -78 °C

O R

OH O

H

-95 °C 57~78%

R * *

Ph

syn/anti=80/20~100/0 75~90% ee (syn)

ð64Þ O Sn(OTf) 2

O Ph

NEt CH2 Cl2, -78 °C

diamine 1a

Ph

H

-95 °C 35%

OH O Ph

Ph 75% ee

(65)

125

126


This procedure is successfully applied to the reactions of carboxylic acid derivatives such as thioamides and thione esters (Eqs. (66) and (67)) [48]. 3-Acetylthiazolidine-2-thiones are quite suitable substrates for the Sn(II) enolate-mediated asymmetric aldol reaction, and various optically active bhydroxy 3-acylthiazolidine-2-thiones are obtained by use of chiral diamine 1a (Eq. (68)) [49]. O LDA / THF

S NMe2

diamine 1a

Ph

OH S

H Ph

Sn(OTf) 2 -78 °C

CH2 Cl2 -20 °C 93%

NMe2

(66)

syn/anti =92/8 85% ee (syn)

O diamine 1a

Sn(OTf) 2

S

Ph

OH S

H Ph

OMe

OMe

(67)

73%

NEt


CH2Cl 2, -78 °C O S

O N

diamine 1a

Sn(OTf) 2

R

S

-95 °C 63~81%

NEt

S

OH O

H R

N

S

(68)

65~>90% ee

CH2Cl 2, -78 °C

A complex formed from chiral diamine 2a with the Sn(II) enolate of 3acetylthiazolidine-2-thione reacts with some a-keto esters to afford aldol adducts with tertiary hydroxyl groups and high ee, as shown in Eq. (69) [50].

N Me

S

O N

Sn(OTf) 2

N H

S

R

O

NEt

OMe

R CH2Cl 2, -78 °C

S

MeO2C OH O

2a

N

S

(69)

85~>95% ee

O 65~80%

When 3-(2-benzyloxyacetyl)thiazolidine-2-thione is treated under these reaction conditions the corresponding anti-diol groups are produced with


good diastereoselectivity and high enantioselectivity by addition of chiral diamine 1a (Eq. (70)) [51]. O S

O BnO

N

Sn(OTf) 2

diamine 1a

S

R

OH O

H R

N S OBn syn/anti =19/81~7/93 87~94% ee (anti )

68~93%

NEt

S

CH2Cl 2, -78 °C

ð70Þ Because Sn(II) enolates of thioesters are generated by the reaction of Sn(II) thiolates with ketenes, the optically active b-hydroxy thioesters are also readily synthesized by way of an aldol reaction with aldehydes in the presence of Sn(OTf )2 and chiral diamine 1a (Eq. (71)) [52]. O O

Sn(StBu)2

Sn(OTf) 2

diamine 1a

CH2Cl2, -78 °C

R

OH O

H

-100 ˚C 55~70%

StBu

R

(71)

58~80% ee

Mukaiyama and Iwasawa also developed an enantioselective Michael Addition reaction using Sn(OTf )2 with chiral diamines [48, 53]. For example, Sn(II) enolate of methyl ethanedithioate reacts with benzalacetone in the presence of chiral diamine 2a and trimethylsilyl trifluoromethanesulfonate (TMSOTf ) to give the corresponding Michael adduct in 82% yield with good enantioselectivity (Eq. (72)). Sn(OTf) 2

S SMe

NEt

diamine 2a

TMSOTf

O

O

SMe * (72) 82%, 70% ee (after hydrolysis)

Ph CH2 Cl2, -78 °C

Ph

S

The Michael adducts were obtained from trimethylsilyl enethioate and a,b-unsaturated ketones in high yields with moderate to good enantioselectivity by use of a catalytic amount of chiral diamine–Sn(OTf )2 complex (Eq. (73)) [48, 54]. As shown in Scheme 4.2, SiaSn metal exchange occurs rapidly to generate chiral Sn(II) enolate and TMSOTf in situ, because the silicon–sulfur bond is rather weak and tin has high affinity for sulfur. Activation of the a,b-unsaturated ketone by TMSOTf would lead to the Michael reaction, affording the silyl enolate of the Michael adduct and regeneration of the chiral diamine–Sn(II) complex. To preclude the competitive

127

128


N NRR' Me Sn TfO OTf

STMS SMe

R2

TMSO

chiral Sn(II) complex

1

R

S SMe

* O R1

R2

N NRR' Me Sn S OTf SMe + TMSOTf Scheme 4.2

Catalytic asymmetric Michael reaction using chiral Sn(II) enolate.

direct reaction of KSA with a,b-unsaturated ketone under the influence of TMSOTf, the concentration of the KSA is kept low by slow addition of a solution of the KSA to the reaction mixture.

O

STMS

diamine 2a (0.11 eq) Sn(OTf) 2 (0.1 eq)

R2

O

S

+ R1

R2

SMe

CH2Cl 2, -78 °C 79~82% (after hydrolysis)

R1

SMe * 40~70% ee

(73)

These chiral enolate preparations and reactions with several electrophiles giving the optically active aldols have been applied to the synthesis of natural compounds such as b-lactam antibiotics. References in reviews by Mukaiyama et al. [10c, 48, 55] describe advanced studies on Sn(II) enolate chemistry. 4.4.2

Chiral Diamine–Sn(II) Complex-promoted Aldol Reactions

Chiral Sn(II) Lewis acids prepared in situ by coordination of chiral pyrrolidine derivatives to Sn(OTf )2 were developed by Mukaiyama and Kobayashi in 1989 to promote the asymmetric aldol reaction of ESE or KSA with carbonyl compounds. Some chiral Lewis acids had already been reported and fruitful results were observed in the field of the Diels–Alder and related reactions, in particular, in the late 1980s. The chiral Lewis acids employed for


Sn(OTf) 2 N

N Me

N N Me Sn TfO OTf

CH2 Cl2, rt 1a

chiral Sn(II) complex 1a-Sn Sn(OTf) 2

N H

N Me

N N Me Sn H TfO OTf

CH2 Cl2, rt

2a

chiral Sn(II) complex 2a-Sn

Scheme 4.3

Chiral Sn(II) Lewis acids generated from Sn(OTf )2 with diamines.

these reactions were rather strong and hard acidic metals such as aluminum and titanium. Chiral Sn(II) Lewis acids prepared in situ by chelation of a chiral diamine to Sn(OTf )2 , might, on the other hand, be effective because Sn(II) is a soft metal and the complex has one vacant d orbital to be coordinated with oxygen in the carbonyl group of an aldehyde without losing the favorable asymmetric environment (Scheme 4.3). On this basis a variety of efficient asymmetric aldol reactions between achiral silyl enolates and achiral carbonyl compounds have been developed. Some chiral diamines used in the asymmetric aldol reaction of KSA with carbonyl compounds promoted by Sn(OTf )2 are listed in Scheme 4.4. 4.4.3

Asymmetric Aldol Reaction of Silyl Enolates

Asymmetric aldol reaction of a KSA derived from S-Et ethanethioate with aldehydes achieves high ee by employing a chiral promoter, the combined use of Sn(OTf )2 coordinated with the chiral diamine (1a or 2a), and tributyltin fluoride (Eq. (74)) [56]. diamine 1a or 2a Sn(OTf) 2 OTMS

O R

OH O

+ H

SEt

Bu3SnF CH2Cl 2, -78 °C 50~90%

R

SEt

(74)

78~>98% ee

The complex consisting of Sn(OTf )2 with 2a is quite effective for reaction of KSA generated from S-Et propanethioate with aldehydes to afford the corresponding syn aldol adducts with excellent diastereoselectivity and enantioselectivity (Eq. (75)) [56b, 57]. A highly enantioselective aldol reac-

129

130


N

N Me

N H

N Me 1a

2a N

N Et 1b

N Me 3a

N

N 6

N

N Et

1d

N

5 N

N Me

1c

N Pent

N Me

2b N

N

4

N H

N Me

N Pr

N Pr

N Me

N 7

3b

Scheme 4.4

Useful chiral diamines for asymmetric aldol reaction.

tion of the KSA of benzyl acetate with achiral aldehydes can be conducted using the chiral promoter formed from Sn(OTf )2 with 1b (Eq. (76)) [58].

OTMS

O + R

H

O + R

H

SEt

OTBS OBn

diamine 2a Sn(OTf) 2 Bu3 SnF [Bu 2Sn(OAc)2 ] CH2Cl 2, -78 °C 48~91% [70~96%]

OH O R

(75) syn/anti =>99/1 >98% ee (syn)

diamine 1b Sn(OTf) 2 Bu3SnF mesitylene CH2Cl 2, -95 °C 51~79%

SEt

OH O R

OBn

(76)

89~>98% ee

In the presence of a promoter including the chiral diamine 1d, the KSA of a thioester reacts with a-ketoesters to afford the corresponding aldol-type adducts, 2-substituted malates, in good yields with excellent ee (Eq. (77)) [59].


O

OTMS

diamine 1d Sn(OTf) 2

MeO 2C OH O

+ R

CO2Me

SEt

R = Me, iPr, Ph

R SEt 92~>98% ee

Bu3SnF CH2Cl 2, -78 °C 74~81%

(77)

In the course of developments in asymmetric synthesis using Sn(OTf )2 it has also been revealed that a tetrahydrothiophene ligand, an analog of the chiral diamine, also affords an asymmetric environment around the Sn(II) metal suitable for promoting the enantioselective aldol reaction giving the desired adducts with high selectivity (Eq. (78)) [60].

S OTMS

O + R

H

SEt

N H OH O

Sn(OTf) 2 Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 48~98%

R

(78) SEt

syn/anti =86/14~100/0 63~93% ee (syn)

4.4.4

Catalytic Asymmetric Aldol Reaction

Catalytic asymmetric synthesis is an extremely desirable method for producing optically active compounds from achiral substrates. If asymmetric amplification could be realized by employing a catalytic amount of a chiral source, substantial amounts of optically active compounds could be synthesized in a convenient and rational way. The promoter, consisting of a chiral diamine and Sn(OTf )2 , has mild acidity which accelerates the asymmetric aldol reaction of KSA with aldehydes; these reactions always required a stoichiometric amount of the chiral diamines, however. From experimental examination of the mechanism of the stoichiometric asymmetric aldol reaction, Mukaiyama and Kobayashi considered the possibility of catalytic use of the chiral diamine–Sn(OTf )2 complex. Their hypothesis was:

. the reaction first produces Sn(II) alkoxides and TMSOTf (Scheme 4.5); . if the substrates (KSA and aldehyde) are added quickly to a solution of .

the chiral diamine–Sn(OTf )2 complex, the initially formed TMSOTf promotes the achiral asymmetric process to produce the racemic aldol from the remaining substrates; and if the substrates are added slowly to a solution of the chiral diamine– Sn(OTf )2 complex, in accordance with the reaction rate of KSA with aldehyde, transmetalation from Sn(II) on the formed Sn(II) alkoxide to Si would occur by sequential reaction with TMSOTf in situ.

131


132

O R

N NRR' Me Sn TfO OTf

H +

TMSO

chiral Sn(II) complex

R

OTMS

O SEt

SEt

N NRR' Me Sn TfO O O R

SEt

+ TMSOTf Scheme 4.5

Catalytic asymmetric aldol reaction using chiral Sn(II) complex.

Actually, an optically active trimethylsilyl ether of the aldol was obtained by the reaction of KSA derived from S-Et propanethioate with aldehydes by slow addition of a mixture of substrates to a solution including a catalytic amount of the chiral diamine–Sn(OTf )2 complex (Eq. (79)) [61].

OTMS

O + R

H

SEt

diamine 2a or 2b (0.22 eq) Sn(OTf) 2 (0.2 eq)

OH O

R SEt CH2Cl 2, -78 °C 64~86% syn/anti =93/7~100/0 (after hydrolysis) 91~>98% ee (syn)

(79)

The rate of this transmetalation is affected by the conditions, particularly the solvent. Propionitrile was found to be a suitable reaction medium for the catalytic process, and a variety of the optically active aldol adducts were prepared with high ee when a solution of aldehydes and KSA derived from S-Et propane- or ethanethioate was added to the catalyst consisting of a chiral diamine and Sn(OTf )2 in propionitrile (Eqs. (80) and (81)) [61, 62].

OTMS

O + R

H

SEt

diamine 2a (0.11~0.22 eq) Sn(OTf) 2 (0.1~0.2 eq)

OH O R

(80) SEt

EtCN, -78 °C 65~80% syn/anti = 89/11~100/0 (after hydrolysis) 89~>98% ee (syn)


O

OTMS


OH O

(81)

+ R

H

SEt

EtCN, -78 °C 48~90% (after hydrolysis)

R

SEt 68~93% ee

A novel combined catalyst generated from SnO and TMSOTf was also developed for catalytic synthesis of the desired compounds, as shown in Eq. (82) [63]. Although the exact structure of the complex is unclear, SnO interacted with TMSOTf and formed an acidic species which functions as a chiral catalyst in this reaction. Kobayashi employed SnO as an effective additive for aldol reaction of KSA with aldehydes, promoted by the chiral diamine–Sn(OTf )2 complex, that is, the optically active aldol adducts were synthesized with high stereoselectivity by using a new combination, a chiral diamine–Sn(OTf )2 aSnO (Eq. (83)) [64].

OTMS

O R

+

+ H

SEt R' R' = H, Me

OH O

R SEt CH2Cl 2, -78 °C 58~82% syn/anti = 91/9~98/2 (after hydrolysis) 67~94% ee (syn)

diamine 2a (0.22 eq) Sn(OTf) 2 (0.2 eq) OTMS SnO (0.2~0.4 eq)

O R

SEt

H

diamine 2a (0.5 eq) SnO (1.0 eq) TMSOTf (0.65 eq)

(82)

OH O

R SEt EtCN, -78 °C R' 50~85% syn/anti = 95/5~100/0 (after hydrolysis) 84~>98% ee (syn)

(83)

Evans recently designed an original chiral Sn(II) catalyst generated from bis(oxazoline) and Sn(OTf )2 [65]. Bis(oxazoline) functions as a bidentate ligand to Sn(OTf )2 and the complex formed might have a rigid C2 -symmetric structure creating an excellent asymmetric environment. This asymmetric aldol reaction proceeds with high diastereoselectivity and enantioselectivity to give the corresponding adducts when bis-functionalized electrophiles such as alkyl glyoxylates, a-ketoesters, and a-diketones are used, because of the formation of suitable complexes with bis(oxazoline) and Sn(OTf )2 . For example, the desired optically active anti aldols were obtained by reaction of KSA derived from thiol esters with ethyl glyoxylate using a catalytic amount

133

134


of the Bn/Box–Sn(II) complex. Anti-(2R,3S) selectivity is also observed in the construction of b-hydroxy-a,b-dimethyl thioesters by aldol addition of the KSA of S-Et propanethioate to an a-ketoester in the presence of a Bn/ Box–Sn(II) complex. A distinctive feature of this asymmetric aldol reaction is that an anti-(2S,3R) adduct, corresponding to the optical antipode of the above anti-(2R,3S) adduct, was produced on use of a Ph/PyBox–Sn(II) complex with the same chirality at the C4 position in the oxazoline moiety of Bn/Box (Eqs. (84) and (85)).

O

O N

N

Sn Bn TfO OTf Bn O R3O

OTMS 2

R

+

SR R1

O

OTMS

MeO

+

N

Ph

N Sn N TfO OTf

O

Ph

(85)

OH O

(0.1 eq) MeO

SR CH2Cl 2, -78 °C 81~94% (after hydrolysis)

R1

O

(84)

R3O

SR CH2Cl 2, -78 °C O R1 72~90% syn/anti =10/90~4/96 (after hydrolysis) 92~98% ee (anti )

O

O

HO R2 O

(0.1 eq)

SR O

R1

syn/anti =5/95~1/99 92~99% ee (anti )

KSA prepared from acetic acid and a,a-dialkyl-substituted acetic acid derivatives also reacted with ethyl glyoxylate to produced the desired aldol adducts with high enantioselectivity, as shown in Eqs. (86) and (87) [65, 66].

O

Bn O EtO

OTMS H

O

+

O N N Sn TfO OTf Bn (0.1 eq)

SPh CH2Cl 2, -78 °C 90% (after hydrolysis)

(86)

OH O EtO

SPh O 98% ee


O

O N

Bn O EtO

OTMS +

H

N Sn TfO OTf Bn (0.1 eq)

OH O EtO

SEt

SEt CH2Cl 2, -78 °C 89% (after hydrolysis)

O

(87)

O 95% ee

4.4.5

Asymmetric Synthesis of syn- and anti-1,2-Diol Groups

Optically active 1,2-diol groups are often observed in nature as carbohydrates, macrolides, or polyethers, etc. Several excellent asymmetric dihydroxylation reactions of olefins using osmium tetroxide with chiral ligands have been developed to give the optically active 1,2-diol groups with high enantioselectivity. Some problems remain, however, for example, preparation of the optically active anti-1,2-diols, etc. The asymmetric aldol reaction of a KSA derived from an a-benzyloxy thioester with aldehydes has been developed by Mukaiyama et al. to introduce two hydroxyl groups simultaneously with stereoselective carbon–carbon bond-formation using the chiral Sn(II) Lewis acid. First, a variety of optically active anti-a,b-dihydroxy thioester derivatives were obtained in good yield with excellent diastereoselectivity and enantioselectivity when the chiral diamine 1a or 1b, Sn(OTf )2 , and dibutyltin diacetate were employed together (Eq. (88)) [67]. By means of current aldol methodology, two hydroxyl groups can be stereoselectively introduced at the 1,2-position during formation of the new carbon–carbon bond.

OTMS

O + R

H

diamine 1a or 1b Sn(OTf) 2

SEt OBn

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 59~88%

SEt OBn

(88)

syn/anti = 2/98~1/99 95~98% ee (anti )

On the other hand, several syn-aldol adducts are obtained under the same reaction conditions, i.e. in the presence of chiral diamine 1a, Sn(OTf )2 , and dibutyltin diacetate. The reaction of a KSA with a t-butyldimethylsiloxy group at the 2-position with achiral aldehydes smoothly proceeds to give the corresponding syn-a,b-dihydroxy thioester derivatives in high yield with good stereoselectivity. When a chiral diamine 1c, which is similar to 1a in possessing a propyl group on the nitrogen of the pyrrolidine ring, is used

135

136


the ee increases up to 94% (Eq. (89)) [68, 67b]. Now it becomes possible to control the enantiofacial selectivity of the KSA derived from a-hydroxy thioester derivatives just by choosing the appropriate protective groups of the hydroxy parts of the KSA, and the two diastereomers of the optically active a,b-dihydroxy thioesters can be synthesized. OTMS

O + R

H

SEt OTBS

diamine 1c Sn(OTf) 2

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 46~93%

SEt OTBS

(89)

syn/anti = 88/12~97/3 82~94% ee (syn)

Kobayashi also introduced several new types of chiral diamine, for example 4 and 5, to obtain rather higher selectivity for the synthesis of syn-a,bdihydroxy thioester derivatives, as shown in Eq. (90) [69, 70]. OTMS

O + R

H

SEt OTBS

diamine 4 or 5 Sn(OTf) 2

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 4; 69~89% 5; 61~86%

SEt OTBS

(90)

4; syn/anti = 94/6~99/1 86~96% ee (syn) 5; syn/anti = 98/2~>99/1 96~99% ee (syn)

Diastereoselective and enantioselective synthesis of both stereoisomers of a,b-dihydroxy-b-methyl thioester derivatives has also been achieved by reaction of KSA with a benzyloxy or t-butyldimethylsiloxy group at the 2position, promoted by an Sn(II) Lewis acid including chiral diamine 1c or 4 (Eqs. (91) and (92)) [69, 71].

OTMS

O + R

CO2Me

R = Me, Ph

OTMS +

R

CO2Me

R = Me, Ph

SEt OTBS

MeO 2C OH O R

SEt OBn

O

diamine 1c Sn(OTf) 2 Bu3SnF CH2Cl 2, -78 °C 66~93%

diamine 4 Sn(OTf) 2

(91)

syn/anti =13/87~7/93 91% ee (anti)

MeO 2C OH O R

Bu3SnF CH2Cl 2, -78 °C 76~89%

SEt OBn

SEt OTBS syn/anti = 84/16~94/6 87~88% ee (syn)

(92)


KSA derived from phenyl esters have a unique capacity to promote remarkable stereoselectivity in asymmetric aldol reactions involving a chiral diamine–Sn(II) complex [72–74]. For instance, Kobayashi found that (E)KSA derived from p-methoxyphenyl (t-butyldimethylsiloxy)acetates reacts with aldehydes to afford the corresponding anti-1,2-diol derivatives with high diastereoselectivity and enantioselectivity when promoted by an Sn(II) Lewis acid complexed with chiral diamine 1a (Eq. (93)) [74].

OTMS

O + R

H

OPMP OTBS

diamine 1a Sn(OTf) 2

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 31~95%

OPMP OTBS

(93)

syn/anti = 31/69~2/98 84~95% ee (anti )

Reaction of (Z)-KSA derived from phenyl benzyloxyacetate with aldehydes, using chiral diamine 3b, also affords the optically active anti-1,2aldols preferentially (Eq. (94)). However, the corresponding syn aldols were formed when the reaction was conducted in the presence of chiral diamine 6 (Eq. (95)) [75]. The latter reaction also proceeded when accelerated by a catalytic amount of chiral diamine 2a or 2b under Kobayashi conditions (Eq. (96)) [76].

O

OTMS +

R

H

+ H

BnO

OPh

OTMS

O R

OPh

OTMS

O R

BnO

+ H

BnO

OPh

diamine 3b Sn(OTf) 2

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 51~80%

OPh OBn syn/anti =12/88~7/93 90~94% ee (anti )

diamine 6 Sn(OTf) 2

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 85~90%


(94)

OPh

(95)

OBn syn/anti =94/6~>99/1 91~98% ee (syn)

OH

O

R OPh SnO (0.2 eq) OBn EtCN, -78 °C syn/anti =90/10~>98/2 68~87% 80~96% ee (syn) (after hydrolysis)

(96)

137

138


This method of producing chiral aldols is also applicable to the construction of an asymmetric quarternary carbon included in the 1,2-diol groups. In the presence of a chiral promoter consisting of the chiral diamine 1a, Sn(OTf )2 , and dibutyltin diacetate, optically active anti-a,b-dihydroxy-amethyl thioester and phenyl ester derivatives were synthesized in good yields with high stereoselectivity (Eqs. (97) and (98)) [72, 73].

OTMS

O + Ph

H

E/Z =12/88

OTMS +

Ar

H

OH O

SEt OBn

O

diamine 1a Sn(OTf) 2 Ph Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 58% diamine 1a Sn(OTf) 2

OH O Ar

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 44~72%

(97)

syn/anti = 2/98 97% ee (anti )

OPh OBn E/Z =58/42

SEt OBn

OPh OBn

(98)

syn/anti = 26/74~8/92 73~95% ee (anti)

Another interesting phenomenon in which the corresponding syn-a,bdihydroxy-a-methyl ester derivatives were produced from similar KSA using a stoichiometric or catalytic amount of the chiral catalyst containing diamine 2a as shown in Eqs. (99) and (100) [73].

OTMS

O + R

H

OR OBn

R = Et, iPr, Ph E/Z =58/42~71/29

OTMS

O Ph

+ H

diamine 2a Sn(OTf) 2 Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 52%~quant.

R OR BnO syn/anti = 81/19~98/2 80~97% ee (syn)

diamine 2a (0.24 eq) Sn(OTf) 2 (0.2 eq)

Oi Pr OBn E/Z =71/29

OH O

EtCN, -78 °C 60% (after hydrolysis)

(99)

OH O Ph BnO

Oi Pr

(100)

syn/anti = 90/10 96% ee (syn)

Similarly, it was found that KSA (E=Z ¼ 38 to 62) derived from p-methoxyphenyl a-benzyloxypropionate reacted with aldehydes in the presence of a Sn(II) catalyst containing diamine 3a to give the corresponding anti-aldol groups (Eq. (101)), whereas asymmetric aldol reaction of (E)-KSA, derived from p-methoxyphenyl a-benzyloxypropionate with a variety of aldehydes,


promoted by Sn(OTf )2 coordinated by chiral diamine 2a, afforded the stereoisomeric syn compounds with high ee (Eq. (102)) [77]. Tetrasubstituted KSA with an alkylthio group also reacted with aldehydes to produce the syn-aldol compounds preferentially [78]; these were used as synthetic intermediates of anti-b-hydroxy-a-methyl groups in the total synthesis of octalactins, described in a later section (Eq. (103)).

OTMS

O + R

H

BnO

OPMP

E/Z=38/62

O

OTMS +

R

H

OPMP OBn

OTMS

O + R

H

MeS

OEt

E/Z=12/88


OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 53~69%


OPMP OBn syn/anti = 6/94~3/97 88~92% ee (anti )

OH O

R OPMP Bu 2Sn(OAc)2 BnO CH2Cl 2, -78 °C syn/anti = 93/7~>99/1 64~79% 95~97% ee (syn) diamine 2a Sn(OTf) 2 Bu 2Sn(OAc)2 [Bu3SnF] CH2Cl 2, -78 °C 52~87%

(101)

(102)

OH O R MeS

OEt

(103)

syn/anti = 91/9~99/1 90~95% ee (syn)

4.4.6

Enantioselective Synthesis of Both Enantiomers of Aldols Using Similar Diamines Derived from L-Proline

Kobayashi recently reported remarkable results in the synthesis of optically active aldol compounds using new chiral diamine–Sn(II) complexes as promoters. Reaction of KSA derived from S-Et (t-butyldimethylsiloxy)ethanethioate with aldehydes using chiral diamine 6 mainly yielded the syn-(2R,3S) compounds which are optical antipodes of aldol adducts (syn(2S,3R)) prepared by the reaction using chiral diamine 1c (Eqs. (89) and (104)) [70, 79]. Optically active syn-(2R,3R) aldols were also prepared from propionic acid derivatives and promotion with an Sn(II) complex with chiral diamine 7, whereas syn-(2S,3S) aldols were produced if chiral diamine 2a was used in the same reaction (Eqs. (75) and (105)) [80]. Chiral diamines 1c, 2a, 6, and 7 were all prepared starting from l-proline and have identical chirality at the C2 position. Artificial switching of the enantiofacial selectiv-

139

140


ity of the aldol reaction by using only one chiral source could therefore be achieved by use of these methods.

OTMS

O + R

H

SEt OTBS

OTMS

O + R

H

SEt

diamine 6 Sn(OTf) 2

OH O R

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 63~86%

(104)

syn/anti =>99/1 98~>99% ee (syn)

diamine 7 Sn(OTf) 2 Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 67~83%

SEt OTBS

OH O R

SEt

(105)

syn/anti =>99/1 80~92% ee (syn)

4.5

Asymmetric Total Syntheses of Complex Molecules Using Chiral Diamine–Sn(II) Catalysts

Enantioselective aldol reactions can be powerful tools for the stereoselective synthesis of complex molecules, especially for construction of optically active 1,2-diol groups in the carbon backbones of the target compounds. Recent progress in this area will be illustrated by means of successful methods for stereoselective synthesis of natural and unnatural polyoxy compounds. 4.5.1

Monosaccharides

In the last decade chemical synthesis of monosaccharides has made a great advance as a result of stereoselective addition reactions of 2,3-Oisopropylidene-d- or -l-glyceraldehyde or 4-O-benzyl-2,3-O-isopropylidene-lthreose with enolate components or allyl nucleophiles, and many examples of the effective synthesis of sugars, both natural and unnatural, have been demonstrated [81]. In these syntheses one of the starting materials, glyceraldehyde or a threose derivative, is prepared from a natural chiral pool, mannitol and tartaric acid, respectively. In contrast, a general method has been developed for synthesis of a variety of sugars starting from both achiral KSA and a,b-unsaturated aldehydes (Scheme 4.6). Chiral induction can be accomplished by means of an asymmetric aldol reaction using a complex consisting of Sn(OTf )2 and an appropriate chiral diamine. Subsequent dihydroxylation or epoxidation of the double bond in the aldol adducts affords several tetrahydroxy thioester derivatives which can be useful precursors for the syntheses of a variety of monosaccharides, including rare sugars.

4.5 Asymmetric Total Syntheses of Complex Molecules Using Chiral Diamine–Sn(II) Catalysts

R2

OSiMe 3

O

R1

H

+

R3

N N R Sn TfO OTf

SEt

R2 R1

OP

R2

OH O or

SEt OTBS

R3

2,3-syn

R1

HO R2 OH O

SEt R3

HO R2 OH O 2,3-anti

R1

HO R2 OH O H R1

R1

HO R2 OH O

H R1 H HO R3 OTBS HO R3 OTBS

HO R2 OH O H

OBn

2,3-anti

HO R2 OH O

H R1 H HO R3 OTBS HO R3 OTBS

OH O

R1

2,3-syn HO R2 OH O

141

R1

HO R2 OH O H R1

H

HO R3 OBn

HO R3 OBn

HO R3 OBn

HO R3 OBn

4,5-syn-3,4-anti

4,5-anti-3,4-anti

4,5-anti-3,4-syn

4,5-syn-3,4-syn

Scheme 4.6

Synthesis of monosaccharides by use of the asymmetric aldol reaction.

One example, synthesis of 6-deoxy-l-talose, is shown in Scheme 4.7 [82]. The asymmetric aldol reaction between crotonaldehyde and the KSA of a-benzyloxy thioester was carried out in the presence of Sn(OTf )2 , chiral diamine 1a, and dibutyltin diacetate, and the corresponding aldol adduct was obtained in 85% yield with >97% enantiomeric excess. Dihydroxylation of this chiral synthon, subsequent reduction of the resulted lactone, and deprotection of the benzyl group gave the desired 6-deoxy-l-talose in good yield.

OSiMe 3

O H

+

N N Me Sn TfO OTf

OH O

SEt OBn

SEt Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 85%

OBn syn/anti=2/>98 >97%ee (anti ) O HO

OH OH

OH 6-Deoxy- L-talose Scheme 4.7

Synthesis of 6-deoxy-l-talose.


142

O

OH

4-C-Methy-D-ribose H

O

HO

OBn

R

OH

O

HO

OH

SEt

OH

HO

HO

OH O

D-Ribose

R = H, Me HO

OH O

OH

OH

H

O

OH

SEt OBn

HO NHAc N-Acetyl-L -fucosamine

AcHN

H

HO

O

AcHN OH 3-Acetamido-3,6-dideoxy-L -idose

OH OH

5-Acetamido-5,6-dideoxy-D-allose Scheme 4.8

Synthesis of d-ribose, 4-C-methyl-d-ribose and several amino sugars.

By use of this universal methodology, several monosaccharides including branched and amino sugars were synthesized as shown in Scheme 4.8 (d-ribose and 4-C-methyl-d-ribose (1990) [82], N-acetyl-l-fucosamine, 3acetamide-3,6-dideoxy-l-idose and 5-acetamide-5,6-dideoxy-d-allose (1993) [83]). Scheme 4.9 shows the syntheses of two stereoisomers of 6-deoxy-l-talose from the corresponding intermediates generated via asymmetric aldol reaction (6-deoxy-d-allose (1992) [84] and l-fucose (1993) [76]). Several 2-branched saccharine acid g-lactones, 2-C-methyl-d- or l-threono1,4-lactones and 2-C-methyl-d-erythrono-1,4-lactone have been effectively prepared using this strategy, by enantioselective construction of asymmetric quaternary carbons developed in the former section (Schemes 4.10 and 4.11) [72, 73, 69]. Because the key asymmetric aldol reaction has wide flexibility in controlling newly created chiral centers, these methods are expected to provide useful routes to the synthesis of a variety of monosaccharides from achiral KSA and aldehydes. 4.5.2

Leinamycin and a Part of Rapamycin

Fukuyama used the asymmetric formation of a 1,2-diol group for the total synthesis of leinamycin in which it was shown that KSA with a p-methoxybenzyloxy group at the C2 position functions as a suitable nucleophile for the multifunctional aldehyde (Scheme 4.12) [85]. White also reported that


N N Me Sn TfO OTf

OTMS

O +

H

SEt OBn

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 82%

143

OH O SEt OBn syn/anti=6/94 92% ee (anti) O

OH

HO

OH OH

6-Deoxy-D-allose

N N Me Sn H TfO OTf OTMS

O

BnO

+ H

OH O

(0.2 eq)

OPh

OPh SnO (0.2 eq) EtCN, -78 °C 87% (after hydrolysis)

OBn syn/anti=97/3 92% ee (syn) O

OH

HO

OH OH L-Fucose

Scheme 4.9

Synthesis of 6-deoxy-d-allose and l-fucose.

OTMS

O TIPSO

+ H

N N Me Sn H TfO OTf

O iPr OBn E/Z=71/29

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 45%

OH O TIPSO

OiPr BnO

syn/anti=91/9 90% ee (syn) O

O

OH HO 2-C-Methyl- D-threono-1,4-lactone Scheme 4.10

Synthesis of 2-C-methyl-d-threono-1,4-lactone.

144


N N Pr Sn TfO OTf

OTMS

O + CO 2Me

MeO2C OH O

SEt

SEt Bu3SnF CH2Cl 2, -78 °C 93%

OBn

OBn syn/anti=13/87 91% ee (anti ) O

O

HO OH 2-C-Methyl-L -threono-1,4-lactone

N N Pr Sn TfO OTf

OTMS

O + CO 2Me

SEt OTBS

MeO2C OH O SEt OTBS syn/anti=94/6 88% ee (syn)

Bu3SnF CH2Cl 2, -78 °C 89%

O HO

O

OH

2-C-Methyl-D-erythrono-1,4-lactone Scheme 4.11

Synthesis of 2-C-methyl-l-threono- and d-erythrono-1,4-lactones.

tBu

O

O

O

OTMS

H +

O O O

OMe O

N N Me Sn TfO OTf

SEt OPMB

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 92%

tBu

O

OH O

O

SEt OPMB

O O

OMe

O

O HO

H O O S

H N

S O O

Leinamycin Scheme 4.12

Synthesis of leinamycin.

O

N S


OTMS

OH O N N Me Sn TfO OTf

SEt O

O

SEt O

+

H

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 80%

OMe OMe

OMe OMe syn/anti =5/95 92% ee (anti )

OTMS

OTBS N N Me Sn TfO OTf

SEt OTBS

O

O H

OH O SEt O

+ Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 80%

OMe OMe

HO O N

OMe OMe syn/anti =8/92 H

O O MeO

O MeO HO

H

O OH O O OMe Rapamycin

Scheme 4.13

Synthesis of a part of rapamycin.

reaction of the KSA generated from S-Et (3,4-dimethoxybenzyloxy)ethanethioate with a,b-unsaturated aldehydes proceeded smoothly to afford the corresponding diol groups in high yields with excellent stereoselectivity, as shown in Scheme 4.13 [86]. 4.5.3

Sphingosine, Sphingofungins, and Khafrefungin

Kobayashi used asymmetric reactions for stereoselective synthesis of a variety of polyoxygenated natural compounds. Initially, a new method for the preparation of sphingosine was developed using the catalytic asymmetric aldol reaction of KSA with a,b-eynal as a key step (Scheme 4.14) [87].

145

146


N N Me Sn H TfO OTf O H

+

BnO

OPh

TMS

OH O

(0.2 eq)

OTMS

OPh SnO (0.2 eq) TMS OBn EtCN, -78 °C syn/anti =97/3 87% 91% ee (syn) (after hydrolysis) OH C13H 27

OH NH2

Sphingosine Scheme 4.14

Synthesis of sphingosine.

Sphingofungins B and F were also totally synthesized from small molecules by the asymmetric aldol strategy as shown in Scheme 4.15 [87b, 88]. Here the optically active polyol part was obtained by reaction of trisubstituted KSA using a chiral diamine ent-2a, and the sole asymmetric center in the side chain was synthesized by the reaction of KSA derived from an acetic acid derivative using the chiral diamine 2a. These segments were coupled to form the basic skeleton of sphingofungins in the total synthesis. A diastereoselective aldol reaction using an a-alkoxyaldehyde was also mentioned in this research (Eq. (106)) [88c]. TBSO

O

C13H 27

OTMS H

+

OBn

SEt TBSO

SnCl 4 C13H 27 CH2Cl 2, -78 ˚C 82% ds 100/0

ð106Þ

OH O SEt OBn

Total synthesis of khafrefungin and the determination of its stereochemistry was recently achieved by Kobayashi, who used chiral induction technology to give the optically active aldol compounds (Scheme 4.16) [89]. The asymmetric aldol reaction of KSA derived from S-Et propanethioate with aldehydes was applied not only to the first step to afford the corresponding thioester with high ee but also to the following stage to give the multifunctional linear thioester with excellent diastereoselectivity.


N N Me Sn H TfO OTf O H

+

BnO

OPh

TMS

OH O

(0.2 eq)

OTMS

OPh SnO (0.2 eq) TMS OBn CH 3CN, -78 °C syn/anti =97/3 87% 91% ee (syn) (after hydrolysis)

N N Me Sn H TfO OTf C6H 13CHO

+

(0.2 eq)

OTMS SEt

OH O

SnO (0.2 eq) CH2Cl 2, -78 °C 87% (after hydrolysis)

HO C6H 13

C6H 13

SEt

94% ee

OH OH O (CH2)6

OH HO

NH2

Sphingofungin B O C6H 13

OH OH O (CH2)6 HO

OH NH2

Sphingofungin F Scheme 4.15

Synthesis of sphingofungins B and F.

4.5.4

Febrifugine and Isofebrifugine

Kobayashi also reported the enantioselective total synthesis of febrifugine and isofebrifugine using the Sn(II)-mediated catalytic asymmetric aldol reaction giving the optically active diol groups (Scheme 4.17) [90]. The correct absolute stereochemistries of natural febrifugine and isofebrifugine were shown by comparison with spectral data and the sense of the optical rotations of four synthetic samples, including enantiomorphs.

147

148


N N Me Sn H TfO OTf OTMS C9H 19CHO

+

SEt

OPMB

O

C10H 21

H

OH O

(0.2 eq) SnO (0.2 eq) CH2Cl 2, -78 °C 83% (after hydrolysis)

C9H 19

SEt


N N Me Sn H TfO OTf

OPMB

OH O

C10H 21 OTMS +

SEt

SEt

Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 90% >98% ds OH

O

C10H 21

OH OH

O

OH

O OH O Khafrefungin

Scheme 4.16

Synthesis of khafrefungin.

4.5.5

Altohyrtin C (Spongistatin 2) and Phorboxazole B

Asymmetric aldol reaction accelerated by the chiral bis(oxazoline)– Sn(OTf )2 complex also provides a powerful means of construction of polyfunctionalized natural compounds. Evans succeeded in the total synthesis of altohyrtin C (spongistatin 2), a macrocyclic compound with many oxygenated functional groups (Scheme 4.18) [91]. Part of the tetrahydropyran segment (F ring) in altohyrtin C was stereoselectively obtained from the corresponding anti-b-hydroxy-a-methyl thioester generated by the asymmetric aldol reaction using the Ph/Box–Sn(II) complex catalyst. This asymmetric aldol reaction is effective when using chelating electrophiles such as ethyl glyoxylate; therefore, a-oxazole aldehyde might be employed in the preparation of an optically active oxazole derivative. Indeed, the reaction of KSA generated from S- t Bu ethanethioate with a-oxazole al-


149

N N Me Sn H TfO OTf O TBSO

H

OPh

OH O

(0.2 eq)

OTMS

+ BnO

TBSO SnO (0.2 eq) EtCN, -78 °C 70% (after hydrolysis)

OPh OBn

syn/anti =95/5 >96% ee (syn) O TBSO

H OBn

OH O N H

N

O

N

N O Febrifugine

N

H O

N H

O Isofebrifugine

Scheme 4.17

Synthesis of febrifugine and isofebrifugine.

dehyde took place as expected to afford the corresponding aldol with high ee, and the total synthesis of phorboxazole B was successfully achieved using the adduct as a part of the complex structure (Scheme 4.19) [92]. 4.5.6

Paclitaxel (Taxol)

Mukaiyama and Shiina accomplished the total synthesis of paclitaxel (taxol) by the strategy shown in Scheme 4.20, i.e. synthesis of the eight-membered B ring first, starting from an optically active polyoxy precursor generated by the highly controlled enantioselective aldol reaction and subsequent construction of the fused A and C ring systems on to the B ring [93]. The optically active diol unit 9 was prepared by the asymmetric aldol reaction of a KSA with a benzyloxy group at the C2 position with an achiral aldehyde 8 using a chiral diamine–Sn(II) complex (Scheme 4.21). Synthesis of the eight-membered ring aldols from an optically active polyoxy-group 10 containing all the functionality necessary for the construction of taxol was performed by the intramolecular aldol cyclization using SmI2 . Subsequent acetylation of this mixture of isomeric alcohols and treatment with DBU gave the desired eight-membered enone 11 in good yield.

150


O

O N

Ph O EtO

OTMS H

+

OH O EtO

SPh

CH2Cl 2, -78 °C 97% (after hydrolysis)

O

TESO EtO

N Sn TfO OTf Ph (0.1 eq)

SPh O syn/anti=4/96 94% ee (anti ) O H O

OH O SEt

OMe

O

OTES OH

HO H O

O OH H O

F HO

O HO

HO

OMe

O

O

O O

O

AcO

OAc

OH Altohyrtin C (Spongistatin 2) Scheme 4.18

Synthesis of altohyrtin C (spongistatin 2).

As shown in Scheme 4.22, fully functionalized BC ring system 12 was then synthesized from the optically active eight-membered ring compound 11 by successive Michael addition and intramolecular aldol cyclization of ketoaldehyde. Intramolecular pinacol coupling of the diketone derived from the above BC ring system using a low-valent titanium reagent resulted in the formation of ABC ring system 13, a new taxoid, in good yield. 7-Triethylsilylbaccatin III was prepared from the above new taxoid 13 by oxygenation at the C13 position and construction of the oxetane ring. It was also shown that the asymmetric aldol reaction is useful for preparation of the chiral side chains of taxol (Scheme 4.23). Because reaction of the KSA derived from S-Et benzyloxyethanethioate with benzaldehyde afforded the corresponding aldol adduct 14 in high yield with excellent selectivity, as shown in the last section, this adduct was successfully con-


O

O N

O H

O N

OTMS

+

StBu

Ph

N Sn Ph TfO OTf (0.1 eq)

OH O

Ph

StBu

O N

CH2Cl 2, -78 °C 91% (after hydrolysis)

Ph

94% ee

OH

O O

N

O

Br O

OMe O

HO

O

O

OH N O

OMe Phorboxazole B Scheme 4.19

Synthesis of phorboxazole B.

AcO

O

OH

B RO

A HO

TBS O O

BnO

C

H O O Ac Bz

PMBO

OBn

Scheme 4.20

Retrosynthesis of taxol.

OBn

OTBS OTBS

BnO

B

DO

OPMB

MeO

O

TBSO

+

MeO BnO

O H

OTBS

O H

+

OMe OBn

151

152


MeO MeO

N N Me Sn TfO OTf

OTBS

O +

H

MeO

OMe

MeO

OMe OBn syn/anti =20/80 9; 93% ee (anti )

Bu 2Sn(OAc)2 CH2Cl 2, -23 °C 68%

OBn 8

OH O

BnO

TBS O O

OTBS Br BnO

TBSO

1) SmI2 (70%)

OPMB

OBn 10

O

2) Ac2 O (87%) 3) DBU (91%)

PMBO

OBn 11

Scheme 4.21

Synthesis of the B ring of taxol.

BnO

O

BnO

TBSO

O

AcO

OH

O

OTES

TBSO

PMBO

OBn

PMBO

11

H O

O

OBn 12

O

Scheme 4.22

Synthesis of the ABC ring system of taxol.

O

OTMS H

+

N N Et Sn TfO OTf

OH O SEt

SEt Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 96%

OBn

BzHN

OBn syn/anti=1/99 14; 96% ee (anti) Ph

O SEt OBn

Scheme 4.23

Synthesis of the side chain of taxol.

OH

BzN O PMP

O

15

13


AcO

HO HO

O

OTES

HO O H Bz

O

7-Triethylsilylbaccatin III

1) 15, DPTC DMAP (95%) 2) TFA (93%)

AcO BzHN

O

OH

O

Ph

O OH

HO

HO O H Bz

O

Paclitaxel (Taxol ®)

Scheme 4.24

Synthesis of taxol.

verted into the targeted b-amino acid 15 in good yield, with inversion of chirality at the b-position, by use of the Mitsunobu reaction. Introduction of N-benzoylphenylisoserine 15 to 7-triethylsilylbaccatin III was further studied, and dehydration condensation was found to proceed smoothly using DPTC (O,O-di(2-pyridyl)thiocarbonate) as a novel coupling reagent in the presence of DMAP to afford the desired ester in 95% yield at 93% conversion (Scheme 4.24) [93e, 94]. Finally, deprotection of the intermediate gave the final target molecule taxol in excellent yield. This established a new method for asymmetric synthesis of baccatin III by way of B to BC to ABC to ABCD ring construction and completion of the total synthesis of taxol by preparation of the side chain by asymmetric aldol reaction and subsequent dehydration condensation with 7-TES baccatin III using DPTC. This synthetic route would be widely applicable to the preparation of a variety of derivatives of taxol and related taxoids. 4.5.7

Cephalosporolide D

Shiina developed a method for preparation of cephalosporolide D, a natural eight-membered ring lactone, and the exact stereochemistry of this compound was determined through the first total synthesis (Scheme 4.25) [95]. In this synthetic strategy two asymmetric carbon atoms were constructed by the asymmetric aldol reaction using the KSA derived from S-Et ethanethioate. It is also mentioned that the second diastereoselective aldol reaction afforded the desired compound in 3:97 ratio when using the chiral diamine ent-2a–Sn(II) complex and that the ratio ranges from 97:3 to 59:41 when the 2a–Sn(II) complex or SnCl 4 was used as a catalyst. The desired eightmembered ring lactone moiety was constructed by cyclization of the seco acid via a novel mixed-anhydride method using (4-trifluoromethyl)benzoic anhydride (TFBA) with Hf(OTf )4 [96]. 4.5.8

Buergerinin F

The synthesis of buergerinin F, a natural compound consisting of a unique tricyclic skeleton, was achieved in the course of synthetic studies by Shiina

153

154


N N Me Sn H TfO OTf

OTMS

O

OH O

+ SEt

H

OTBS

O

SEt 96%ee

Bu3SnF CH2Cl 2, -95 °C 78%

N N Me Sn H TfO OTf

OTMS

OTBS

OH O

+ H

OH

SEt

Bu3SnF CH2Cl 2, -78 °C 89%

TFBA Hf(OTf) 4

OBn O OH

SEt ent-2a-Sn(OTf)2 ; syn/anti =3/97 2a-Sn(OTf)2; 62%, syn/anti =97/3 SnCl4; 62%, syn/anti =59/41

H2, Pd/C

O O

OH

MeCN reflux Chephalosporolide D

Scheme 4.25

Synthesis of cephalosporolide D.

on the utilization of the asymmetric aldol strategy [97]. The first key step is producing the optically active a,b,g 0 -trioxy ester including an asymmetric quaternary carbon at the C2 position as shown in Scheme 4.26. It was also revealed that enantioselective aldol reaction of tetrasubstituted KSA with four oxygenated functional groups is quite effective for preparation of this complex synthetic intermediate. Successive intramolecular Wacker-type ketalization and one-carbon elongation of the intermediate afforded the optically active buergerinin F. On completion of the total synthesis using the asymmetric aldol reaction promoted by chiral diamine–Sn(OTf )2 as catalyst, the absolute stereochemistry of natural buergerinin F was determined. 4.5.9

Octalactins A and B

Shiina recently developed a new method for synthesis of octalactin A, an antitumor agent consisting of an eight-membered ring lactone (Scheme 4.29) [98]. Because the lactone moiety includes two pairs of anti-b-hydroxya-methyl groups, enantioselective addition of the KSA derived from ethyl 2methylthiopropanoate was efficiently used for construction of the required


OTMS

O

+

TBSO

H

OMe OBn 84/16

N N Me Sn H TfO OTf

O TBSO BnO

Bu 2Sn(OAc)2 EtCN, -78 °C 62%

OAc

HO H

OSiMe 2CMe 2Ph

OMe

OH H syn/anti =98/2 93% ee (syn)

PdCl2

HO

155

OAc

O O CuCl, O2

H

OSiMe 2CMe 2Ph

O O O H Buergerinin F Scheme 4.26

Synthesis of buergerinin F.

components, i.e. asymmetric aldol reaction of the tetrasubstituted KSA with aldehydes [78] and subsequent treatment of the optically active adducts formed with Guidon’s reduction [99] afforded the desired two chiral segments 16 and 17 (Scheme 4.27). The optically active side chain 18 was also produced by means of the asymmetric aldol reaction of the KSA derived from S-Et ethanethioate with 2-methylpropionaldehyde (Scheme 4.28). A chiral linear precursor having repeated anti-b-hydroxy-a-methyl units was obtained by coupling segments 16 and 17, and the resulting seco acid was eventually cyclized to form the eight-membered ring lactone by a new quite effective mixed-anhydride method using 2-methyl-6-nitrobenzoic anhydride (MNBA) with DMAP, as shown in Scheme 4.29 [100, 98b]. Finally, the side chain 18 was introduced to the eight-membered ring lactone moiety to afford the targeted multioxygenated compounds, octalactins A and B. 4.5.10

Oudemansin-antibiotic Analog

Uchiro and Kobayashi recently reported the synthesis of b-methoxyacrylate antibiotics (MOA) and their analogs (Scheme 4.30) [101]. In accordance with their strategy for preparation of the related compounds, asymmetric aldol reaction of the KSA generated from S-Et propanethioate with cinnamyl aldehyde was used for stereoselective synthesis of the intermediate of an MOA analog, as shown in Scheme 4.30.

156


O +

MeS

OEt

H

TIPSO

N N Me Sn H TfO OTf

OTMS

E/Z=12/88

Bu3SnF CH2Cl 2, -78 °C 56%

OH O OEt

TIPSO MeS syn/anti =96/4 87% ee (syn) OBn TBSO

PPh 3I 16

O +

TIPSO

N N Me Sn H TfO OTf

OTMS MeS

OEt

H

E/Z=12/88

Bu3SnF CH2Cl 2, -78 °C 50%

OH O TIPSO

OEt SMe

syn/anti =87/13 69% ee (syn) PMP O

O

H O 17 Scheme 4.27

Synthesis of two chiral segments of octalactins A and B.

N N Me Sn H TfO OTf O

OTMS H

(0.2 eq.)

OH O

+ SEt

EtCN, -78 °C 48% (after hydrolysis)

SEt 90% ee OTBS I 18

Scheme 4.28

Synthesis of the side chain of octalactins A and B.

4.6 Conclusions

157

O O

OH

OBn

HO

MNBA OTBDPS

DMAP CH2 Cl2 rt, 13 h

TBDPSO

O

O 18 OH

O

OBn

O

O

OH

OH

O

O

O Octalactin A

Octalactin B Scheme 4.29

Synthesis of octalactin A and B.

4.6

Conclusions

In this chapter a variety of Sn(IV) or Sn(II) metallic species-promoted aldol reactions have been presented, with their application in syntheses of complicated molecules with high stereoselectivity. Alkoxy aldehydes were effectively activated by SnCl 4 , and reactions with particular ESE or KSA are highly applicable to the generation of 3,4-syn aldol compounds with high diastereoselectivity. Intramolecular reaction of ESE and KSA with an acetal moiety is also quite attractive for preparation of medium-sized compounds which are generally not available by other methods. Sn(II)-promoted asymmetric aldol reaction could be now used as a general and powerful method for the construction of not only optically active small molecules but highly

OTMS

O + Ph

H

SEt

N N Me Sn H TfO OTf Bu 2Sn(OAc)2 CH2Cl 2, -78 °C 92%

OH O Ph

SEt 98% ee OMe O MeO

OMe

Oudemansin-type Analog Scheme 4.30

Synthesis of oudemansin-antibiotic analog.

OH

158


advanced multifunctional compounds. Progress in aldol reactions using tin reagents has contributed greatly to the syntheses of many useful substrates in the last decade, and this fruitful history might provide valuable information to organic and organometallic chemistry in the future.

4.7

Experimental Typical Procedure for Catalytic Asymmetric Aldol Reaction of a KSA with Simple Achiral Aldehydes (Eqs. (80) and (81)) [61d]. A solution of 2a (21.1 mg, 0.088 mmol) in EtCN (1 mL) was added to a solution of Sn(OTf )2 (33.4 mg, 0.080 mmol, 20 mol%) in EtCN (1 mL). The mixture was cooled to 78 C and a mixture of KSA (0.40 mmol) and an aldehyde (0.40 mmol) in EtCN (1.5 mL) was then added slowly over 3–4.5 h by means of a mechanical syringe. The mixture was further stirred for 2 h, and then quenched with saturated aqueous NaHCO3 . The organic layer was isolated and the aqueous layer was extracted with CH2 Cl2 (three times). The organic solutions were combined, washed with H2 O and brine, then dried over Na2 SO4 . After evaporation of the solvent the crude product was purified by preparative TLC on silica gel to afford an aldol-type adduct as the corresponding trimethylsilyl ether. The trimethylsilyl ether was treated with THF–1 m HCl (20:1) at 0 C to give the corresponding alcohol. Typical Procedure for Catalytic Asymmetric Aldol Reaction of a KSA with Ethyl Glyoxylate (Eqs. (84) and (86)) [65a]. (S,S)-bis(Benzyloxazoline) (19.9 mg, 0.055 mmol) and Sn(OTf )2 (20.8 mg, 0.050 mmol) were placed, within an inert atmosphere box, in an oven-dried 8-mL vial containing a magnetic stirring bar. The flask was fitted with a serum cap, removed from the inert atmosphere box, and charged with CH2 Cl2 (0.8 mL). The resulting suspension was stirred rapidly for 1 h to give a cloudy solution. The catalyst was cooled to 78 C and the KSA (0.50 mmol) was added followed by distilled ethyl glyoxylate–toluene solution (8:2 mixture, 100 mL, 0.75 mmol). The resulting solution was stirred at 78 C until the KSA was completely consumed (0.1–2 h), as determined by TLC. The reaction mixture was then filtered through a 0.3 cm 5 cm plug of silica gel, which was then washed with Et2 O (8 mL). Concentration of the ether solution gave the crude silyl ether which was dissolved in THF (2 mL) and 1 m HCl (0.2 mL). After standing at room temperature for 0.5 h this solution was poured into a separatory funnel and diluted with Et2 O (20 mL) and H2 O (10 mL). After mixing the aqueous layer was discarded and the ether layer was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The resulting ether layer was dried over anhydrous Na2 SO4 , filtered, and concentrated to furnish the hydroxy esters. Purification by flash chromatography provided the desired aldols.

References

Typical Procedure for Synthesis of an Optically Active Diol Group by Asymmetric Aldol Reaction (Eq. (88)) [67b, 93f ]. A solution of 1a or 1b (0.405 mmol) in CH2 Cl2 (0.5 mL), then a solution of Bu2 Sn(OAc)2 (131.1 mg, 0.373 mmol) in CH2 Cl2 (0.5 mL), were added successively to a suspension of Sn(OTf )2 (141.8 mg, 0.340 mmol) in CH2 Cl2 (1 mL). The mixture was stirred for 30 min at room temperature, then cooled to 78 C. A solution of 2-benzyloxy-1-ethylthio-1-(trimethylsiloxy)ethene (96.1 mg, 0.340 mmol) (Z=E ¼ 9:1, the E isomer has no reactivity) in CH2 Cl2 (0.5 mL), and a solution of aldehyde (0.228 mmol) in CH2 Cl2 (0.5 mL) at 78 C, were then added successively to the reaction mixture. The mixture was further stirred for 20 h then quenched with saturated aqueous NaHCO3 . The organic layer was isolated and the aqueous layer was extracted with CH2 Cl2 (three times). The organic solutions were combined, washed with H2 O and brine, then dried over Na2 SO4 . After evaporation of the solvent the crude product was purified by preparative TLC on silica gel to afford the corresponding antia,b-dihydroxy thioester derivatives. References 1 (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,

2 3

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25 26 27 28 29 30

31 32 33

34 35 36

37

38

39

40

1994, 35, 6899. (b) Mukai, C.; Kataoka, O.; Hanaoka, M. J. Org. Chem. 1995, 60, 5910. Boeckman Jr., R. K.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4, 2109. Mukai, C.; Moharram, S. M.; Kataoka, O.; Hanaoka, M. J. Chem. Soc. Perkin Trans. 1 1995, 2849. Liu, W.; Szewczyk, J. M.; Waykole, L.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2002, 43, 1373. Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15. Muratake, H.; Natsume, M. Heterocycles 1990, 31, 691. Linderman, R. J.; Graves, D. M.; Kwochka, W. R.; Ghannam, A. F.; Anklekar, T. V. J. Am. Chem. Soc. 1990, 112, 7438. Peng, S.; Qing, F.-L. J. Fluorine Chem. 2000, 103, 135. Cossy, J.; Rakotoarisoa, H.; Kahn, P.; Desmurs, J.-R. Tetrahedron Lett. 2000, 41, 7203. (a) Pearlman, B. A.; McNamara, J. M.; Hasan, I.; Hatakeyama, S.; Sekizaki, H.; Kishi, Y. J. Am. Chem. Soc. 1981, 103, 4248. (b) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7371. (c) Sekizaki, H.; Jung, M.; McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7372. Cambie, R. C.; Larsen, D. S.; Rickard, C. E. F.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1986, 39, 487. Cambie, R. C.; Rutledge, P. S.; Watson, P. A.; Woodgate, P. D. Aust. J. Chem. 1989, 42, 1939. (a) Ishihara, K.; Nakamura, H.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 7720. (b) Nakamura, H.; Ishihara, K.; Yamamoto, H. J. Org. Chem. 2002, 67, 5124. (a) Otera, J.; Chen, J. Synlett 1996, 321. (b) Chen, J.; Sakamoto, K.; Orita, A.; Otera, J. Synlett 1996, 877. (c) Chen, J.; Otera, J. Synlett 1997, 29. (d) Chen, J.; Otera, J. Tetrahedron 1997, 53, 14275. (e) Chen, J.; Otera, J. Angew. Chem. Int. Ed. Engl. 1998, 37, 91. (f ) Chen, J.; Otera, J. Tetrahedron Lett. 1998, 39, 1767. (g) Chen, J.; Sakamoto, K.; Orita, A.; Otera, J. Tetrahedron 1998, 54, 8411. (h) Shirakawa, S.; Maruoka, K. Tetrahedron Lett. 2002, 43, 1469. (a) Asaoka, M.; Sugimura, N.; Takei, H. Bull. Chem. Soc. Jpn. 1979, 52, 1953. (b) Asaoka, M.; Yanagida, N.; Ishibashi, K.; Takei, H. Tetrahedron Lett. 1981, 22, 4269. (a) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J. Org. Chem. 1992, 57, 3760. (b) Rassu, G.; Casiraghi, G.; Spanu, P.; Pinna, L.; Fava, G. G.; Ferrari, M. B.; Pelosi, G. Tetrahedron: Asymmetry 1992, 3, 1035. (c) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. Tetrahedron Lett. 1994, 35, 2423. (d) Rassu, G.; Zanardi, F.; Cornia, M.; Casiraghi, G. J. Chem. Soc. Perkin. Trans. 1 1994, 2431. (e) Zanardi, F.; Battistini, L.; Rassu, G.; Cornia, M.; Casiraghi, G. J. Chem. Soc. Perkin. Trans. 1 1995, 2471. (f ) Rassu, G.; Auzzas, L.; Pinna, L.; Battistini, L.; Zanardi, F. J. Org. Chem. 2000, 65, 6307. (g) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.; Battistini, L.; Marzocchi, L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2002, 67, 5338. Uno, H.; Baldwin, J. E.; Russell, A. T. J. Am. Chem. Soc. 1994, 116, 2139.

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4 Tin-promoted Aldol Reactions and their Application to Total Syntheses of Natural Products 41 (a) Cockerill, G. S.; Kocienski, P. J. Chem. Soc. Chem.

42 43 44 45 46

47 48 49 50 51 52 53 54 55 56

57

58

59 60 61

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63 64 65

66 67

68 69 70 71 72 73 74

75 76 77 78 79

80 81

82 83 84 85

86 87

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4 Tin-promoted Aldol Reactions and their Application to Total Syntheses of Natural Products 88 (a) Kobayashi, S.; Hayashi, T.; Iwamoto, S.; Furuta, T.;

89 90

91

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93

94 95

96

97

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99

Matsumura, M. Synlett 1996, 672. (b) Kobayashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett 1997, 301. (c) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908. Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 1372. (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett. 1999, 40, 2175. (b) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833. (c) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2000, 66, 809. Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671. (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem. Int. Ed. Engl. 2000, 39, 2533. (b) Evans, D. A.; Fitch, D. M. Angew. Chem. Int. Ed. Engl. 2000, 39, 2536. (c) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033. (a) Mukaiyama, T.; Shiina, I.; Sakata, K.; Emura, T.; Seto, K.; Saitoh, M. Chem. Lett. 1995, 179. (b) Shiina, I.; Uoto, K.; Mori, N.; Kosugi, T.; Mukaiyama, T. Chem. Lett. 1995, 181. (c) Shiina, I.; Iwadare, H.; Sakoh, H.; Tani, Y.; Hasegawa, M.; Saitoh, K.; Mukaiyama, T. Chem. Lett. 1997, 1139. (d) Shiina, I.; Iwadare, H.; Sakoh, H.; Hasegawa, M.; Tani, Y.; Mukaiyama, T. Chem. Lett. 1998, 1. (e) Shiina, I.; Saitoh, K.; Frećhard-Ortuno, I.; Mukaiyama, T. Chem. Lett. 1998, 3. (f ) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem. Eur. J. 1999, 5, 121. Saitoh, K.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1998, 679. (a) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 1998, 831. (b) Shiina, I.; Fujisawa, H.; Ishii, T.; Fukuda, Y. Heterocycles 2000, 52, 1105. (a) Shiina, I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T. Chem. Lett. 1994, 515. (b) Shiina, I.; Miyashita, M.; Mukaiyama, T. Chem. Lett. 1994, 677. (c) Shiina, I. Tetrahedron 2004, 59, 1587. Shiina, I.; Kawakita, Y.; Ibuka, R. Abstracts of Papers, 83rd National Meeting of the Chemical Society of Japan, Tokyo, 2003, Vol. 2, 2C401; Ibuka, R. Ph.D. Thesis, Tokyo University of Science, Tokyo, Japan, 2003. (a) Shiina, I.; Oshiumi, H.; Hashizume, M.; Yamai, Y.; Ibuka, R. Tetrahedron Lett. 2004, 45, 543. (b) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822. (a) Guindon, Y.; Faucher, A.-M.; Bourque, E´.; Caron, V.; Jung, G.; Landry, S. R. J. Org. Chem. 1997, 63, 9276. (b) Guindon, Y.; Jung, G.; Gue´rin, B.; Ogilvie, W. W. Synlett 1998, 213. (c) Hena, M. A.; Terauchi, S.; Kim, C.-S.;

References Horiike, M.; Kiyooka, S. Tetrahedron: Asymmetry 1998, 9, 1883. 100 (a) Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 286. (b) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535. 101 Uchiro, H.; Nagasawa, K.; Kotake, T.; Hasegawa, D.; Tomita, A.; Kobayashi, S. Bioorg. Med. Chem. Lett. 2002, 12, 2821.

165

167

5

Zirconium Alkoxides as Lewis Acids ¯ Kobayashi Yasuhiro Yamashita and Shu 5.1

Introduction

Zirconium is a group 4 element, and its low cost and low toxicity are advantageous compared with other metals used in industry. The usefulness of zirconium is well known in organic chemistry. Zirconium compounds promote some organic reactions efficiently and play important roles resulting in interesting selectivity [1]. In aldol reactions zirconium compounds have often been used to realize high and unique selectivity by forming zirconium enolates [2, 3]. Bis(cyclopentadienyl) zirconium compounds, which form zirconium enolates via metal exchange from lithium enolates, have been successfully used in stereoselective aldol reactions, and high syn selectivity was obtained. Both (E) and (Z) enolates gave the same syn adducts predominantly. This methodology was also applied to highly diastereoselective asymmetric aldol reactions to afford aldol adducts with excellent selectivity (Scheme 5.1) [3]. Zirconium alkoxides, especially zirconium tetra-t-butoxide, have been known to act as bases and directly deprotonate the a-hydrogen atoms of ketones to form zirconium enolates [4]. The enolates reacted with aldehydes to give aldol adducts (Scheme 5.2) [4c]. Following this report, asymmetric aldol and related reactions using chiral zirconium alkoxides as bases were investigated. Aldol–Tishchenko reactions are an efficient method for synthesizing 1,3-diol derivatives from aldehydes and enolates. It was recently shown that a zirconium enolate generated by retro-aldol reaction of a b-keto-tert-alcohol and a catalytic amount of a zirconium t-butoxide–TADDOL complex, reacted with an aldehyde to afford the corresponding 1,3-anti-diol via domino aldol–Tishchenko process in good yield with moderate enantioselectivity (Scheme 5.3) [5]. Similar to the aldol reaction of zirconium enolates, zirconium Lewis acidmediated aldol reactions of silicon enolates with aldehydes (Mukaiyama aldol reaction) have also been well explored [6]. Zirconium Lewis acids are comparatively mild and have been employed in several stereoselective reModern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

168

5 Zirconium Alkoxides as Lewis Acids

O

R1

LDA Cp2ZrCl2

R1 R2

OZr(Cl)Cp2 R2 O

(Z )-form

R3CHO

+

THF, –78 °C

R3

R1

R2 (E )-form

OH R3 R2

syn

R1

anti

syn/anti =52/48 to 98/2

MEMO

OZr(Cl)Cp2

RCHO +

O + R1

R2

OZr(Cl)Cp2

MEMO

OH

O

N

R

N

THF-hexane –78-0 °C

OH

69-77% > 96% de

Scheme 5.1

Stereoselective aldol reactions using zirconium enolates.

O

O

O +

H

OH

Zr(Ot Bu)4 (2.6 eq.) Ph

Ph

THF, –30 °C

(2.0 eq.)

77%

Scheme 5.2

Direct aldol reaction using a zirconium alkoxide.

Ph Ph O Zr(Ot Bu)4 + O

OH O H

+

(10 mol%) t Bu

OH OH

O

Ph Ph

O

CH2Cl2, 0 °C, 3 h

O

OH tBu

84%, 57% ee Scheme 5.3

Asymmetric aldol-Tishchenko reaction using a chiral zirconium catalyst.

actions. Among these, zirconium alkoxides have served as mild and stereoselective Lewis acids, especially in asymmetric catalysis. Several catalytic asymmetric reactions using chiral zirconium alkoxides as Lewis acids have been developed [4c]. In chiral modification of zirconium catalysts, chiral alcohol derivatives or chiral phenol derivatives, especially 1,1 0 -binaphthalene2,2 0 -diol (BINOL) derivatives, have often been employed. In this chapter,

5.2 The Asymmetric Mukaiyama Aldol Reaction

aldol and related reactions catalyzed by zirconium alkoxides as chiral Lewis acids are discussed.

5.2

The Asymmetric Mukaiyama Aldol Reaction

A chiral zirconium catalyst prepared from zirconium alkoxide and BINOL derivatives has been successfully applied to the catalytic asymmetric Mukaiyama aldol reaction [7]. Among several types of zirconium catalyst, a catalyst prepared from zirconium tetra-t-butoxide and 3,3 0 -dihalogeno-1,1 0 bi-2-naphthol (3,3 0 -X2 BINOL) [8] was found to be effective. The aldol reactions of benzaldehyde 1a with ketene silyl acetals proceeded smoothly in toluene at 0 C in the presence of an additional alcohol. It was found that the additional alcohol played important roles in this reaction (vide infra) [9]. Among the catalysts screened, a Zr catalyst containing 3,3 0 -I2 BINOL was the most effective, and high level of enantiocontrol was achieved. The reproducibility of the reaction was not as good, however, and the enantioselectivity was sometimes poor. After several investigations to address this issue it was finally revealed that a small amount of water had an important effect on enantioselectivity [10]. The effect of water was significant. Under strictly anhydrous conditions enantioselectivity was occasionally quite low. It was revealed that the presence of a small amount of water was essential to realize high enantioselectivity (Table 5.1). The effect of alcohol additives was investigated in the reaction of benzaldehyde 1a with the ketene silyl acetal of S-ethyl ethanethioate (2a) (Table 5.2). In the presence of water reactions using normal primary alcohols such as ethanol (EtOH), propanol (PrOH), and butanol (BuOH) gave high yields and high enantioselectivity (entries 1–3). Other primary alcohols such as benzyl alcohol (BnOH) and 2,2,2-trifluoroethanol (CF3 CH2 OH) gave lower yields and selectivity (entries 4 and 5). Secondary and tertiary alcohols such as isopropanol ( i PrOH) and tert-butyl alcohol ( t BuOH) resulted in reduced yields and selectivity (entries 6 and 7). Phenol also resulted in lower yield and selectivity (entry 8). The best yields and enantioselectivity were obtained when 80–120 mol% PrOH was used (entries 9–12) and similar yields and selectivity were obtained when zirconium tetrapropoxide–propanol complex (Zr(OPr)4 aPrOH) was employed instead of Zr(O t Bu)4 (entry 14). The use of Zr(OPr)4 aPrOH is desirable economically. Other substrates were then examined; the results are shown in Table 5.3. The ketene silyl acetal derived from methyl isobutyrate (2b) also worked well. For aldehydes, whereas aromatic and a,b-unsaturated aldehydes gave excellent yields and selectivity, aliphatic aldehydes resulted in high yields but somewhat lower selectivity. Diastereoselective aldol reactions using this chiral zirconium catalyst were then examined (Table 5.4). First, the ketene silyl acetal derived from methyl

169

170

5 Zirconium Alkoxides as Lewis Acids Tab. 5.1

Effect of water in asymmetric Mukaiyama aldol reactions using a chiral zirconium catalyst. OSiMe3

O Ph

H

R1

+

XR2 R1

Silicon Enolate

1a 2 3 4

Product

OSiMe3 SEt

Ph

ee (%)

SEt

0 0 10 20

28 42 86 94

16 3 83 88

OMe

0 20

94 88

10b 94

OH O

OSiMe3

2b

R 1 R1 4

Yield (%)

4aa

OMe

XR2

Ph

H2 O (mol%)

OH O

2a

5 6

OH O

toluene, 0°C, 14-18 h

2

1a

Entry

Zr(Ot Bu)4 (10 mol%) (R)-3,3'-I2BINOL (3a) (12 mol%) PrOH (50 mol%), H2O

Ph 4ab

a PrOH b The

was not used. product obtained was the opposite enantiomer. I OH OH I (R)-3,3'-I2BINOL (3a)

propionate (2c) was employed in the reaction with benzaldehyde. The reaction proceeded smoothly to afford the desired anti-aldol adduct in high yield with high diastereo- and enantioselectivity when ethanol was used as a primary alcohol. The selectivity was further improved by use of the ketene silyl acetal derived from phenyl propionate (2d). Other aldehydes such as p-anisaldehyde (1b), p-chlorobenzaldehyde (1g), cinnamaldehyde (1d), and 3-phenylpropionealdehyde (1e), etc., were tested, and all the reactions proceeded smoothly, and the desired anti-aldol adducts were obtained in high yield with high diastereo- and enantioselectivity. In the reactions of the ketene silyl acetals derived from propionate derivatives, most chiral Lewis acids led to syn diastereoselectivity. Few catalyst systems giving anti-aldol adducts with high selectivity are known, so the general anti selectivity was a remarkable feature of the zirconium aldol reaction [11]. Although the high anti selectivity observed in these reactions is remarkable, examination of the effect of the geometry of the ketene silyl acetals revealed further important information on the selectivity – when the (E) and (Z) ketene silyl acetals (2e and 2f ) derived from methyl propionate were employed in reactions with benzaldehyde, high anti selectivity was obtained for both, and it was confirmed that selectivity was independent of the ge-

5.2 The Asymmetric Mukaiyama Aldol Reaction Tab. 5.2

Effect of alcohol (additive). OSiMe3

O H +

Ph

SEt 2a

1a

Entry

Zr(Ot Bu)4 (10 mol%) (R)-3,3'-I2BINOL (3a) (12 mol%) PrOH , H2O (20 mol%)

OH O Ph

toluene, 0°C, 14 h

SEt 4aa

ROH (mol%)

Yield (%)

ee (%)

1 2 3 4 5

EtOH (50) PrOH (50) BuOH (50) BnOH (50) CF3 CH2 OH (50)

85 94 92 76 47

87 88 86 76 62

6 7 8

i

t

PrOH (50) BuOH (50) PhOH (50)

87 39 36

85 44 54

9 10 11 12 13

PrOH (30) PrOH (80) PrOH (100) PrOH (120) PrOH (160)

68 91 95 94 95

74 95 95 95 91

14a

PrOH (60)

98

92

a Zr(OPr)

4 -PrOH

was used instead of Zr(O t Bu)4 .

Tab. 5.3

Asymmetric aldol reactions (1). O R1

H 1

+

R3

Zr(Ot Bu)4 (10 mol%) OH O OSiMe3 (R)-3,3'-I BINOL (3a) (12 mol%) 2 1 XR2 XR2 PrOH (80 mol%), H2O (20 mol%) R R3 R 3 R3 toluene, 0°C, 18 h 2 4

Entry

Aldehyde (R1 )

Silicon Enolate

Yield (%)

ee (%)

1 2 3 4 5 6 7

Ph (1a) Ph (1a) p-MeOC6 H4 (1b) (E)-CH3 CHbCH (1c) (E)-PhCHbCH (1d) PhCH2 CH2 (1e) CH3 (CH2 )4 ð1f Þ

2a 2b 2b 2b 2b 2a 2a

91 95 92 76 94 92 93 (93)a

95 98 96 97 95 80 84 (87)a

a The

reaction was performed at 20 C. OSiMe3 SEt 2a

OSiMe3 OMe 2b

171

172


Asymmetric aldol reactions (2). OSiMe3

O R1

+

OR

H

2

Zr(Ot Bu)4 (10 mol%) (R)-3,3'-I2BINOL (3a) (12 mol%) ROH (80 mol%), H2O (20 mol%) toluene, 0°C, 18 h

2

1

OH O OR2

R1 4

Entry

Aldehyde (R1 )

Silicon Enolate

ROH

Yield (%)

syn/ anti

ee (%)

1 2 3 4 5 6 7 8 9

Ph (1a) Ph (1a) Ph (1a) Ph (1a) p-MeOC6 H4 (1b) p-ClC6 H4 (1g) (E)-CH3 CHbCH (1c) (E)-PhCHbCH (1d) PhCH2 CH2 (1e)

2c 2c 2d 2d 2d 2d 2d 2d 2d

PrOH EtOH PrOH EtOH PrOH PrOH PrOH PrOH PrOH

79 87 94 90 89 96 65 92 61

7/93 7/93 5/95 4/96 7/93 9/91 11/89 15/85 14/86

96 97 99 99 98 96 92 98 89

OSiMe3 OMe 2c

OSiMe3 OPh 2d

ometry of the ketene silyl acetals (Scheme 5.4). For the transition states of these reactions, acyclic pathways are assumed (details are discussed below). Further investigation of the effect of the aldehyde structure was conducted (Table 5.5). Reactions of other aliphatic aldehydes were examined O

OSiEtMe2 H +

E/Z = 88/12 2e

1a

63% Yield syn/anti = 9/91 95% ee (Anti)

OMe

Zr(OtBu)4 (10 mol%) (R)-3,3'-I2BINOL (3a) (12 mol%) EtOH (80 mol%) H2O (20 mol%) toluene, 0 °C, 18 h

O H

+

OSiEtMe2 OMe E/Z = 7/93

1a

2f

Scheme 5.4

Effect of geometry of the silicon enolates.

OH

O OMe

4ac

77% Yield syn/anti = 7/93 98% ee (Anti )

5.2 The Asymmetric Mukaiyama Aldol Reaction Tab. 5.5

Effect of structures of aliphatic aldehydes. OSiMe3

O + R

OPh

H

Entry

Aldehyde

1

3 4

CHO Ph

CHO CHO CHO

OH O R

toluene, 0°C, 18 h

2d

1

2

Zr(Ot Bu)4 (20 mol%) (R)-3,3'-I2BINOL (3a) (24 mol%) PrOH (160 mol%), H2O (20 mol%)

OPh 4

Yield (%)

syn/anti

ee (%) (anti)

(1f )

64

12/88

85

(1e)

71

10/90

82

(1h)

71

15/85

81

(1i)

56

12/88

89

(1j)

52

14/86

78

(1k)

16

17/83

28

(1l)

14

21/79

31

(1m)

Trace

–

–

CHO

5 6 7 8

CHO

CHO CHO

using a chiral zirconium catalyst consisting of Zr(O t Bu)4 , (R)-3,3 0 -I2 BINOL (3a), PrOH, and water. For normal linear aliphatic aldehydes, for example hexanal and butanal, the reactions proceeded with high selectivity. gBranched aldehydes also reacted smoothly to afford the desired anti adducts in good yield and with high diastereo- and enantioselectivity. The catalyst did not, however, work well in reactions of a-branched and b-branched aliphatic aldehydes, possibly because of by steric interaction between the BINOL parts (especially large di-iodo atoms at the 3,3 0 -positions) of the catalysts and the alkyl moieties of the aldehydes. These results indicated that the environment around the zirconium of the catalyst was crowded and that the catalyst recognized the structure of the aldehydes strictly. To create more effective catalyst systems, improvement of catalyst activity is important. It has recently been revealed that introduction of stronger electron-withdrawing groups at the 6,6 0 -positions of the binaphthyl rings effectively improved the Lewis acidity of the zirconium catalyst system [12]. The effect of stronger electron-withdrawing groups at the 6,6 0 -positions of (R)-3,3 0 -I2 BINOL in this aldol system was therefore examined. Bromo, iodo, and pentafluoroethyl groups were selected as the electron-withdrawing

173

174


Improvement of catalyst activity in the aldol reaction. OSiMe3

O + Ph

H 1a

SEt

Zr(Ot Bu)4 (5 mol%) (R)-BINOL 3 ROH (50 mol%), H2O (10 mol%)

OH O Ph

toluene, 0°C, 3 h

2g

SEt 4ag

Entry

BINOL Derivatives

Yield (%)

syn/anti

ee (%) (anti)

1

(R)-3,3 0 -I2 BINOL (3a) (6 mol%) (R)-3,3 0 -I2 -6,6 0 -Br2 BINOL (3b) (7.5 mol%) (R)-3,3 0 -I2 -6,6 0 -(C2 F5 )2 BINOL (3c) (7.5 mol%) (R)-3,3 0 ,6,6 0 -I4 BINOL (3d) (7.5 mol%)

38

5/95

96

61

4/96

98

71

7/93

96

70

4/96

98

2 3 4

X

I OH OH

X

I

X: H, Br, I, C2F5

(R)-3,3'-I2-6,6'-X2BINOL (3)

groups. In the aldol reaction of benzaldehyde with the ketene silyl acetal derived from S-ethyl propanethioate (2g), the new catalysts prepared from 6,6 0 -disubstituted-3,3 0 -I2 BINOL (3b–d) had greater activity and the reaction proceeded much faster than with the catalyst prepared from 3,3 0 -I2 BINOL. In particular, iodo and pentafluoroethyl groups at the 6,6 0 -positions led to better results, giving the desired anti adducts in high yields with high diastereo- and enantioselectivity (Table 5.6). The new catalyst system was successfully applied to the reactions of aliphatic aldehydes. In the reactions of hexanealdehyde with the ketene silyl acetals derived from phenyl propionate (2d) and S-ethyl propanethioate (2g), the best results were obtained when (R)-3,3 0 ,6,6 0 -I4 BINOL (3d) was employed (Table 5.7). The electronwithdrawing substituents at the 3,3 0 - and 6,6 0 -positions of the BINOL derivatives were assumed to increase the Lewis acidity of the zirconium catalysts. By changing the chiral ligands, chemical yields were improved (38% to 71% in Table 5.6, entries 1 and 3; 9% to 92% in Table 5.7, entries 4 and 6) much more than enantioselectivity (80% ee to 87% ee in Table 5.7, entries 1 and 3). A chiral zirconium complex prepared from zirconium tetra-t-butoxide, 2.2 equiv. 6,6 0 -dibromo-1,1 0 -binaphthalene-2,2 0 -diol (6,6 0 -Br2 BINOL), and a small amount of water, which was originally developed in asymmetric Mannich-type reactions [12], was found to be an effective catalyst in asymmetric aldol-type reactions using ethyl diazoacetate [13]. The chiral zirco-

5.3 Asymmetric Hetero Diels–Alder Reaction Tab. 5.7

Effect of new BINOLs in the aldol reactions of hexanaldehyde 1f. OSiMe3

O H

C5H11

+

R

1f

Zr(Ot Bu)4 (10 mol%) OH O (R)-3,3'-I2-6,6'-X2BINOL (3) (12-15 mol%) ROH (80 mol%), H2O (20 mol%) R C5H11 toluene, 0°C, 18 h

2

Entry

X

Silicon Enolate

1 2 3

H (3a) C2 F5 (3c) I (3d)

OSiMe3

4 5 6

H (3a) C2 F5 (3c) I (3d)

OSiMe3

OPh 2d

SEt 2g X

4

Yield (%)

syn/anti

ee (%) (anti)

53 39 66

16/84 11/89 12/88

80 84 87

9 80 92

12/88 17/83 11/89

93 93 93

I OH OH

X

I

(R)-3,3'-I2-6,6'-X2BINOL (3)

nium complex deprotonates the a-hydrogen atom of the diazo ester directly (Scheme 5.5). Zr(OtBu)4 + 2(S)-6,6'-Br2BINOL O

O H

+

H

OEt N2

(20 mol%) H2O (20 mol%) DME, –35 °C, 72 h

OH O OEt N2 65%, 87% ee

Scheme 5.5

Asymmetric aldol reaction of an azoester.

5.3

Asymmetric Hetero Diels–Alder Reaction

Hetero Diels–Alder (HDA) reactions of aldehydes with 1-methoxy-3trimethylsiloxy-1,3-butadiene (Danishefsky’s diene) also proceeded in the presence of the chiral zirconium catalyst [14]. HDA reactions of aldehydes with Danishefsky’s dienes [15] mediated by Lewis acids, which provide 2,3dihydro-4H-pyran-4-one derivatives, are promising tools for construction of pyran ring systems [16]. Because Danishefsky’s dienes contain a silicon enolate moiety, an aldol-type reaction and subsequent cyclization process

175

176


Asymmetric hetero Diels–Alder reactions of benzaldehyde (1a) using a chiral zirconium catalyst. OSiR23

O Ph

H

+

OR1

1a

Zr(Ot Bu)4 (10 mol%) (R)-3,3'-I2BINOL (3a) (12 mol%) PrOH, H2O (20 mol%) TFA Ph

toluene, 18 h

2

O

O 5ah

Entry

Diene

PrOH (mol%)

Temp. (˚C)

Yield (%)

ee (%)

1 2 3 4 5 6 7 8 9 10a

2h 2h 2i 2i 2i 2i 2i 2j 2k 2j

50 80 50 80 120 80 80 80 80 80

0 0 0 0 0 20 45 20 20 20

39 35 50 65 44 70 Trace 80 24 Quant.

22 62 91 94 94 97 – 97 89 97

a Toluene/tBuOMe

(2:1) was used as solvent. OSiR3

OSiMe3 OMe 2h

Ot Bu 2i: SiR3 = SiMe3 2j: SiR3 = SiEtMe2 2k: SiR3 = Sit BuMe2

are a possible pathway in HDA reactions using Danishefsky’s dienes [17]. It was therefore assumed that the chiral zirconium catalyst effective in aldol reactions might work well in HDA reactions of aldehydes with Danishefsky’s dienes. On the basis of this assumption a model HDA reaction of benzaldehyde with 1-methoxy-3-trimethylsiloxy-1,3-butadiene (2h) using a chiral zirconium catalyst prepared from Zr(O t Bu)4 , (R)-3,3 0 -I2 BINOL, PrOH, and water was examined (Table 5.8). The initial result was rather disappointing, however, and the corresponding pyranone derivative was obtained in lower yield and selectivity (Table 5.8, entry 1). The selectivity was improved to 62% ee by increasing the amount of PrOH, but the yield was even lower (entry 2). According to the reaction pathway the product was formed with elimination of methanol. It was suspected that this methanol might decompose the diene, reducing the yield, and that the selectivity might be reduced by interaction of the methanol with the zirconium catalyst. To prevent production of methanol, 1-tert-butoxy-3-trimethylsiloxy-1,3butadiene (2i) was used instead of 2h. As expected, yield and selectivity were improved, and the desired adduct was obtained in 50% yield with 91% ee (entry 3). Yield and selectivity were also found to be affected by the amount of PrOH and the reaction temperature, and the desired product was ob-

5.3 Asymmetric Hetero Diels–Alder Reaction Tab. 5.9

Asymmetric hetero Diels–Alder reactions (1). O R

OSiEtMe2 H

+

Ot Bu 2j

1

Zr(Ot Bu)4 (10 mol%) (R)-3,3'-I2BINOL (3a) (12 mol%) PrOH (80 mol%), H2O (20 mol%)

O TFA R

solvent, –20°C, 18 h

O 5

Entry

Aldehyde; R

Solvent

Yield (%)

ee (%)

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

Ph (1a) Ph (1a) p-MeC6 H4 (1n) p-MeC6 H4 (1n) p-ClC6 H4 (1g) p-ClC6 H4 (1g) PhCH2 CH2 (1e) PhCH2 CH2 (1e) CH3 (CH2 )4 (1f ) CH3 (CH2 )4 (1f ) (E)-PhCHbCH (1d)

Toluene Toluene- t BuOMea Toluene Toluene- t BuOMea Toluene Toluene- t BuOMea Toluene Toluene- t BuOMea Toluene Toluene- t BuOMea Toluene- t BuOMea

80 Quant. 63 95 65 90 84 Quant. 69 98 97

97 97 95 95 84 84 90 90 91 93 90

a Toluene/ t BuOMe b Sc(OTf )

3

(2:1) was used. (10 mol%) was used instead of TFA.

tained in 70% yield with 97% ee when the reaction was performed using 80 mol% PrOH at 20 C (entry 6). The effects of substituents on the silicon atoms of Danishefsky’s dienes and of the solvents in this HDA reaction were further examined. When diene 2j, with an ethyldimethylsilyloxy group, was employed the desired product was obtained in 80% yield with 97% ee (entry 8), although the more stable diene 2k, with a tert-butyldimethylsilyloxy group, did not work well under these conditions (entry 9). Finally, the desired pyranone derivative was obtained quantitatively with 97% ee by use of the mixed solvent system toluene– t BuOMe, 2:1 (entry 10) [18]. The reactions of different aldehydes with diene 2j in toluene or toluene– t BuOMe, 2:1, were then tested (Table 5.9). Aromatic, a,b-unsaturated, and even aliphatic aldehydes reacted with the Danishefsky diene to afford the desired HDA adducts in good to high yields with high enantioselectivity. It was noted that high stereocontrol was achieved even in reactions of aliphatic aldehydes. With regard to solvents, use of the toluene– t BuOMe system always resulted in higher yields than use of toluene. In these HDA pathways the reaction was quenched by adding saturated aqueous NaHCO3 , and after usual work-up the crude adduct was treated with trifluoroacetic acid (TFA) to accelerate formation of the pyranone derivative. In the reaction with cinnamaldehyde, however, the desired cyclic product was not obtained in good yield after treatment with TFA, because side-reactions occurred. When other work-up conditions were investigated it was found that treatment with a

177

178


Asymmetric hetero Diels–Alder reactions (2). Zr(Ot Bu)4 (10 mol%) OSiMe3

O R

H 1

+

Ot Bu

(R)-BINOL 3 (12-15 mol%) PrOH (80 mol%), H2O (20 mol%)

O TFA

Conditions

R

2l

O 5

Entry Aldehyde; R

BINOL Conditions

1 2 3 4 5 6 7 8a 9b 10b 11c 12c 13c

Ph (1a) Ph (1a) Ph (1a) p-MeC6 H4 (1n) p-MeC6 H4 (1n) p-ClC6 H4 (1g) p-ClC6 H4 (1g) p-ClC6 H4 (1g) (E)-PhCHbCH (1d) (E)-PhCHbCH (1d) PhCH2 CH2 (1e) PhCH2 CH2 (1e) PhCH2 CH2 (1e)

3a 3c 3c 3c 3c 3c 3c 3c 3c 3c 3c 3d 3d

14c 15c

CH3 (CH2 )4 (1f ) CH3 (CH2 )4 (1f )

3d 3d

Toluene, 0 C, 18 h Toluene, 20 C, 18 h Toluene, 40 C, 24 h Toluene, 20 C, 18 h Toluene, 40 C, 24 h Toluene, 20 C, 18 h Toluene, 40 C, 24 h Toluene, 40 C, 168 h Toluene, 10 C, 18 h Toluene, 20 C, 60 h Toluene, 0 C, 48 h Toluene, 20 C, 48 h Toluene/ t BuOMe (2:1), 20 C, 72 h Toluene, 20 C, 48 h Toluene/ t BuOMe (2:1), 20 C, 72 h

Yield (%)

cis/ trans

ee (%) (trans)

Trace Quant. 99 93 99 99 99 90 78 96 23 68 97

– 8/92 4/96 13/87 6/94 10/90 4/96 6/94 12/88 10/90 15/85 10/90 10/90

– 98 97 90 93 97 98 97 87 90 79 87 90

63 94

9/91 9/91

88 95

a2

mol% Zr catalyst. PrOH (80 mol%). b Sc(OTf )3 (10 mol%) was used instead of TFA. c PrOH (120 mol%). X

I OH (R)-3a: X=H (R)-3c: X=C2F5 OH (R)-3d: X=I

X

I

catalytic amount of scandium triflate (Sc(OTf )3 ) [19] gave a high yield of the desired product. The HDA reactions of 4-methyl-substituted Danishefsky’s diene, which include diastereo- and enantiofacial selectivity issues, were then investigated. 1-tert-Butoxy-2-methyl-3-trimethylsiloxy-1,3-pentadiene (2l) was selected as a model, and was reacted with benzaldehyde using a chiral zirconium catalyst with an (R)-3,3 0 -I2 BINOL moiety under the conditions shown in Table 5.9 (toluene was used as solvent). Unexpectedly, the reaction proceeded sluggishly (Table 5.10, entry 1), a result which clearly showed that 4substituted diene 2l was less reactive than 4-unsubstituted dienes 2h–2k. To increase the Lewis acidity of the zirconium catalyst, introduction of electronwithdrawing groups at the 6,6 0 -positions of the BINOL derivatives was

5.3 Asymmetric Hetero Diels–Alder Reaction

investigated. (R)-3,3 0 -I2 -6,6 0 -(C2 F5 )2 BINOL (3c) was chosen as chiral ligand and a chiral zirconium catalyst was prepared from Zr(O t Bu)4 , (R)-3c, PrOH, and water. It was remarkable that in the presence of 10 mol% of this chiral zirconium catalyst the reaction of benzaldehyde (1a) with 2l proceeded smoothly in toluene at 20 C to afford the desired HDA adduct quantitatively. It was also of interest that the stereochemistry of the product was 2,3trans, and that the enantiomeric excess of the trans adduct was proved to be 98% (Table 5.10, entry 2). The trans selectivity was further improved when the reaction was performed at 40 C (entry 3). The reactions of other aldehydes, including aromatic, a,b-unsaturated, and aliphatic aldehydes, using this new chiral zirconium catalyst were examined. With aromatic and a,b-unsaturated aldehydes the reactions proceeded smoothly to give the desired pyranone derivatives in high yield with high trans selectivity; the enantiomeric excesses of the trans adducts were also high. Yield and selectivity were, however, lower in the reaction of an aliphatic aldehyde (entry 11). They were finally improved when (R)-3,3 0 ,6,6 0 -I4 BINOL ((R)-3d) was used instead of (R)-3c and the reaction was conducted in toluene– t BuOMe, 2:1, as a solvent; the desired products were obtained in high yield with high diastereo- and enantioselectivity. It should be noted this was the first example of catalytic asymmetric trans-selective HDA reactions of aldehydes, and that a wide variety of aldehydes react with high yields and selectivity. HDA reactions using more functionalized Danishefsky’s dienes were also investigated. 3-Oxygenated 2-alkyl-2,3-dihydro-4H-pyran-4-one derivatives are important synthetic intermediates, affording hexose derivatives [20]. As a new approach to hexose derivatives, an HDA reaction of an aldehyde with a Danishefsky’s diene having an oxy-substituent at the 4-position has already been developed [21]. As a catalytic asymmetric HDA reaction using this type of diene the reaction of benzaldehyde (1a) with 1-tert-butyldimethylsilyloxy-4-tert-butoxy-2-trimethylsilyloxy-1,3-butadiene (2m) was conducted using the Zr-3,3 0 ,6,6 0 -I4 BINOL catalyst system. The reaction proceeded sluggishly and it was speculated that the bulky substituent at the 4-position prevented the smooth progress of the reaction. Next, the reaction employing 1-benzyloxy-4-tert-butoxy-2-trimethylsilyloxy-1,3-butadiene (2n) as diene component was investigated. The HDA reactions of aldehydes with diene 2n using the zirconium catalyst were conducted under optimized conditions (Table 5.11). The reactions proceeded smoothly in toluene–tert-butyl methyl ether, 2:1, to afford the desired cycloadducts in high yield with high diastereo- and enantioselectivity. It should be noted that the stereochemistry of the adduct obtained was 2,3-cis, completely opposite to the 2,3-trans selectivity obtained in the reaction with diene 2l (details of the selectivity are discussed in Section 5.4). In the reaction of other aldehydes, aromatic aldehydes and a,bunsaturated and aliphatic aldehydes reacted with the diene smoothly to afford the desired products in high yield with high cis selectivity; the enantiomeric excess of the cis adducts was also high.

179

180


Asymmetric hetero Diels–Alder reactions (3). Zr(Ot Bu)4 (10 mol%) OSiMe3

O R

H 1

+ BnO

OtBu

(R)-3,3',6,6'-I4BINOL (3d) (12 mol%) PrOH (160 mol%), H2O (20 mol%) Sc(OTf)3

O BnO

toluene/t BuOMe (2:1) –20 °C, 96 h

2n

R

O 5

Entry

Aldehyde; R

Yield (%)

cis/trans

ee (%) (cis)

1 2 3 4 5 6

Ph (1a) p-MeC6 H4 (1n) p-ClC6 H4 (1g) p-NO2 C6 H4 (1o) (E)-PhCHbCH (1d) PhCH2 CH2 (1e)

95 90 Quant. 85 Quant. 54

97/3 95/5 97/3 93/7 85/15 92/8

97 94 97 90 92 81

OSiMe3 t

BuMe2SiO

Ot Bu 2m

5.4

Reaction Mechanism

In asymmetric aldol reactions the zirconium catalyst had anti selectivity irrespective of enolate geometry. This remarkable feature was in contrast with most syn-selective aldol reactions mediated by known chiral Lewis acids [22]. In the usual reactions affording syn-aldol adducts the selectivity was explained in terms of steric repulsion between the alkyl groups of the aldehydes and the a-methyl groups of enolates in acyclic transition state models. In the zirconium-catalyzed reactions, anti-aldol adducts were obtained from both (E) and (Z) enolates, showing that acyclic transition states were most likely. It was speculated that the origin of the anti selectivity was steric interaction between the a-methyl groups of enolates and not the alkyl groups of aldehydes but chiral Lewis acids coordinated to carbonyl oxygen atoms (Figure 5.1) [23]. The asymmetric environment around the zirconium center seemed to be very crowded, because of the bulky iodo groups at the 3,3 0 -positions of the BINOL derivatives. Experiments in which this zirconium complex strictly recognized the structures of aliphatic aldehydes also seemed to be indicative of highly steric hindrance around the active site of the catalyst. Two mechanistic pathways have, on the other hand, been considered for HDA reactions of carbonyl compounds with Danishefsky’s diene catalyzed by Lewis acids (Scheme 5.6) [17]. One is a concerted [4þ2] cycloaddition pathway, the other a stepwise cycloaddition pathway (Mukaiyama-aldol reaction and cyclization). In most reports of HDA reactions of aldehydes with 4-substituted Danishefsky’s dienes catalyzed by chiral Lewis acids, fa-

5.4 Reaction Mechanism

L.A.

L.A. O

O

H

R2

R2

R1

H

R3

Me3SiO

OH

R1

R3

O R3

R1 R2

OSiMe3

Syn-adduct

L.A.

L.A. O

O

R2

R2

R3

R1

H

R1

H

O R3

R1

R3

Me3SiO

OSiMe3

OH

R2 Anti-adduct

Fig. 5.1

Origin of the anti-selectivity.

vored products were 2,3-cis-disubstituted pyranones [24]. In reactions with 4-methyl Danishefsky’s diene using the chiral zirconium complex, however, remarkable 2,3-trans selectivity was observed. This unique selectivity is difficult to explain on the basis of the concerted [4þ2] cycloaddition mechanism, because of the disadvantage of the exo-type transition state. In almost

R2

OSiMe3 R3

R1

O

OR4

Lewis Acid H+

Concerted Pathway O R

1

O

H +

OSiMe3 R2

R3

R2 R1 OR4

R3

Stepwise Pathway

Lewis Acid

Me3SiO

H+

O OR4

R1 R

2

R

3

Scheme 5.6

Proposed reaction pathways in HDA reaction.

O

181

182


OSiMe3

O Ph

H

+

1a

Ot Bu

Chiral Zr Catalyst

HO

O

Ph

2l

Ot Bu

I syn/anti = 8/92 O TFA Ph

O 5al cis/trans = 8/92 98% ee (trans)

Scheme 5.7

Isolation of an intermediate of the HDA reaction.

all HDA reactions using the zirconium catalyst, it has been reported that the reaction mixture was simple, and that only one new product was observed by TLC analysis. In the reaction of benzaldehyde (1a) with 1-tertbutoxy-2-methyl-3-trimethylsiloxy-1,3-pentadiene (2l), the product was carefully isolated by use of deactivated silica gel column chromatography before treatment with TFA. It was revealed that the product isolated was the corresponding anti-aldol adduct (I) as a hydroxy-free form, and that high anti selectivity was observed (syn/anti ¼ 8:92), as shown in Scheme 5.7. In addition, the aldol adduct (I) readily cyclized quantitatively under acidic conditions to afford the product with high selectivity (cis/trans ¼ 8:92, 98% ee (trans)). These facts, the observed 2,3-trans selectivity, and the isolation of the anti-aldol intermediate, indicate that the HDA reaction catalyzed by the chiral zirconium complex proceeds via a stepwise (Mukaiyama-aldol reaction and cyclization) pathway. This unique 2,3-trans selectivity can therefore be explained by the remarkable anti-selective Mukaiyama aldol reactions using the chiral zirconium catalyst system, which proceeded with anti preference irrespective of the E and Z geometry of the silicon enolates, as already mentioned. On this basis the lower reactivity of diene 2k would be understood by considering the greater stability of the tert-butyldimethylsilyloxy group than that of the trimethylsilyloxy or ethyldimethylsilyloxy group. The effect of the tert-butoxy group of the dienes on the enantioselectivity could, moreover, be explained in terms of steric hindrance effectively preventing the [4þ2] cycloaddition pathway. Remarkable cis selectivity obtained in the reaction with 1-benzyloxy-4-tert-butoxy-2-trimethylsilyloxy-1,3butadiene (2n) could also be accounted for by interaction of the benzyloxy group with the zirconium center of the catalyst. In the mechanism of zirconium-catalyzed aldol reactions steric repulsion between the methyl

5.4 Reaction Mechanism

Zr Me H

Zr O

O R1

OH O Me R1

H

Me anti-adduct

OSiMe3

Me3SiO

OR2

R1

O Me O R1 trans-product Zr

Zr O H

OBn R1 OSiMe3

Bn

O H

O

OH R1

Me3SiO

O OR2

R1 OBn syn-adduct O BnO

O R1 cis-product Fig. 5.2

origin of the trans- and cis-selectivity.

group of the enolate and the zirconium catalyst seemed to be an important factor explaining anti selectivity in an open-chain transition-state model. In reactions of the diene 2n coordination of the oxygen atom of the benzyloxy group would be more favored than steric repulsion, and the stereochemical outcome results in cis selectivity (Figure 5.2) [25]. An assumed catalytic cycle for this aldol and HDA reaction is shown in Scheme 5.8. First, the zirconium catalyst A is produced by mixing Zr(O t Bu)4 , (R)-3,3 0 -I2 BINOL, a primary alcohol, and H2 O. At this stage, the remaining t-butoxide groups are exchanged for the primary alcohols or H2 O. An aldehyde coordinated to this catalyst and a silicon enolate attack the carbonyl carbon of the aldehyde to generate intermediate B. The silyl group on the carbonyl oxygen is then removed by the primary alcohol, directly generating the aldol product and the original catalyst again, or moves to the most anionic atom in the same complex, the oxygen of the binaphthol, to form intermediate C. The SiaO and ZraO bonds of the intermediate C are also cleaved by the primary alcohols to form the aldol adduct and the catalyst again. This mechanism is supported by the observation that aldol adducts are obtained with free hydroxyl groups and that the trimethylsilyl ether of the alcohol and the mono trimethylsilyl ether of 3,3 0 -I2 BINOL are observed in the reaction system.

183

184


Zr(Ot Bu)4 + I

* O Zr

OSiMe3

O

R3

O OROR

OH OH

R1

R2 R4

H

I

+ ROH

* O I O

-

OR

RO O RO

OR

R1

Zr O

O

Zr

+O

SiMe3 R2

R3 R4

I

B

A OH

O R2

R1

ROH

R3 R 4 + ROSiMe3

* Me3SiO Zr

R1

O

O OROR COR2 R3 R4 C

Scheme 5.8

Assumed catalytic cycle of the aldol reaction.

5.5

Structure of the Chiral Zirconium Catalyst

NMR experiments were performed to clarify the structure of the chiral zirconium catalyst. The catalyst was prepared from 1 equiv. Zr(OPr)4 aPrOH, 1 equiv. 3,3 0 -I2 BINOL, and 1 equiv. H2 O in toluene-d8 . 1 H and 13 C NMR spectra were acquired at room temperature, and clear and simple signals were observed (Figure 5.3). It was revealed that this catalyst was stable in the presence of excess PrOH at room temperature and that almost the same spectra were obtained after one day. In the 13 C NMR spectrum two new kinds of signal corresponding to the naphthyl rings and two kinds of signal corresponding to the propoxide groups were observed in addition to the signals corresponding to the free BINOL. The presence of these two kinds of sharp signal suggested that the catalyst formed a dimeric structure. We

5.5 Structure of the Chiral Zirconium Catalyst

ppm

∗

∗

∗

ppm

a

The complex was prepared from Zr(OPr) 4-PrOH (1.0 equiv.), (R)-3,3'-I2BINOL (3a) (1.0 equiv.), and H2O (1.0 equiv.). ∗ : free 3,3'-I 2BINOL Fig. 5.3 1

H and

13

C NMR spectra of the zirconium complexa.

also observed characteristic signals of propoxide protons connected directly to the carbon atoms attached to the oxygen atoms at 3.8, 4.0, 4.8, and 5.2 ppm in the 1 H NMR spectrum (OaCH2 a). Integration of the proton signals indicated the presence of two kinds of propoxide moiety (one pair observed at 3.8 and 4.0 ppm and the other at 4.8 and 5.2 ppm) in the catalyst; the ratio was 2:1. The role of a small amount of water in this catalyst system was also revealed by NMR analysis [10, 26]. In the absence of PrOH and water a clear 13 C NMR spectrum was obtained from the combination of Zr(O t Bu)4 and 3,3 0 -I2 BINOL (Figure 5.4a). When PrOH was added to this system, rather complicated signals were observed (Figure 5.4b). Clear signals appeared once again when water was added to the catalyst system consisting of Zr(O t Bu)4 , 3,3 0 -I2 BINOL, and PrOH (Figure 5.4c). From these results, it was assumed that the role of water in this catalyst system was to arrange the structure of the catalyst, i.e. the desired structure was formed from the oligomeric structure by adding water.

185

186


a)

b) ∗

∗

∗

c) ∗

∗

∗

a) Zr(Ot Bu)4 (1.0 equiv.) + (R)-3,3'-I2BINOL (3a) (1.0 equiv.) b) Zr(Ot Bu)4 (1.0 equiv.) + (R)-3,3'-I2BINOL (3a) (1.0 equiv.) + PrOH (5.0 equiv.) c) Sample b) +PrOH (2.0 equiv.) + H 2O (1.0 equiv.) ∗ : free 3,3'-I 2BINOL

Fig. 5.4

Effect of water.

Because of the dimeric structure of the catalyst, the possibility of a nonlinear effect in the asymmetric aldol reaction was examined [27]. The reaction of benzaldehyde with the ketene silyl acetal derived from S-ethyl ethanethioate (2a) was chosen as a model, and the chiral Zr catalysts prepared from 3,3 0 -I2 BINOLs with lower enantiomeric excess were employed. It was found that a remarkable positive non-linear effect was observed, as illustrated in Figure 5.5. After preparation of the chiral Zr catalysts from (R)3,3 0 -I2 BINOL and (S)-3,3 0 -I2 BINOL, respectively, they were combined and correlation between the ee of the zirconium catalyst and the ee of the product was investigated. A linear correlation between them was observed (Figure 5.6) [28]. These results also supported the dimeric structure of the cata-

5.6 Air-stable and Storable Chiral Zirconium Catalyst

Fig. 5.5

Correlation between the ee of the product and the ee of (R)-3,3 0 -I2 BINOL (3a) in the aldol reaction using the catalyst prepared from (R)-3,3 0 -I2 BINOLs with low ee.

lyst; on the basis of these experiments it was assumed the catalyst structure was as shown in Figure 5.7.

5.6

Air-stable and Storable Chiral Zirconium Catalyst

Although fruitful results have been obtained by use of chiral Lewis acids as catalysts in asymmetric synthesis, it has been known that Lewis acid catalysts are often sensitive to moisture and/or oxygen, even in air, and decompose rapidly in the presence of a small amount of water. Accordingly, most chiral Lewis acids must be prepared in situ under strictly anhydrous conditions just before use, often with tedious handling, and they cannot be stored for extended periods. This is also true for chiral zirconium catalysts. Development of air-stable and storable chiral Lewis acid catalysts is therefore desirable [29]. To address this issue, an air-stable, storable chiral zirconium catalyst (ZrMS) has been developed in catalytic asymmetric Mannich-type reactions [30]. This catalyst is stable in air at room temperature and is easy to handle

187

188


Fig. 5.6

Correlation between the ee of the product and the ee of the catalyst in the aldol reaction using the catalyst prepared by mixing (R)- and (S)-catalyst.

I O Zr O

I

H O

O

O Zr

O

O

O I

I

A Fig. 5.7

Assumed catalyst structure.

without requiring strict attention to levels of moisture and oxygen, etc. The key to this stability was combination of the catalyst and zeolite (5-A˚ molecular sieves (MS 5A)). This method should be generally applicable to zirconium catalysts. The zirconium catalyst with MS (3I-ZrMS) was prepared simply by combining the already prepared zirconium catalyst and MS 5A [31]. In the course of development of 3I-ZrMS, the amount of water in MS 5A was found to be important to achieving high enantioselectivity in the reaction

5.6 Air-stable and Storable Chiral Zirconium Catalyst Tab. 5.12

Effect of storage time of 3I-ZrMS. OSiMe3

O Ph

(R)-3I-ZrMS (5 mol%)

OH O

PrOH (80 mol%) H

1a

+

OPh 2d

toluene, 0 °C, 18 h

Ph

OPh 4ad

Entry

Storage Time (weeks)

Yield (%)

syn/anti

ee (%) (anti)

1 2 3 4

0 2 6 13

Quant. Quant. Quant. Quant.

5/95 5/95 5/95 5/95

99 99 99 99

[10]. In practice 3I-ZrMS was prepared by first combining a zirconium propoxide propanol complex (Zr(OPr)4 aPrOH) and 3,3 0 -I2 BINOL in toluene at room temperature for 3 h. MS 5A (2.5 g mmol1 ) containing 10% (w/w) H2 O was then added and the mixture was stirred for 5 min. After removal of the solvents under reduced pressure at room temperature for 1 h the 3I-ZrMS catalyst was formed. Compared with zirconium tert-butoxide Zr(OPr)4 aPrOH is an economical source of zirconium alkoxide. The aldol reaction of benzaldehyde (1a) with ketene silyl acetal 2d was then conducted using 5 mol% 3I-ZrMS catalyst in toluene at 0 C in the presence of PrOH (80 mol%). The reaction proceeded smoothly to afford the desired product in high yield with high selectivity (quantitative yield, syn/anti ¼ 5/95, anti 99% ee). The result obtained by use of 3I-ZrMS was almost comparable with that obtained by use of the zirconium catalyst prepared in situ. It is worthy of note that this 3I-ZrMS catalyst was remarkably stable in air and moisture, and that the catalyst could be stored for at least 13 weeks at room temperature without loss of reactivity and selectivity (Table 5.12). The 3I-ZrMS catalyst was successfully applied to asymmetric aldol reactions of a variety of substrates; the results are summarized in Table 5.13. In reactions of benzaldehyde (1a) with other silicon enolates (2a and 2b) the 3I-ZrMS catalyst worked well and excellent yields and enantioselectivity were obtained (entries 1–3). In reactions with the ketene silyl acetal derived from phenyl propionate (2d), anti-aldol adducts were obtained with high diastereo- and enantioselectivity (entry 4). The reactions of p-methoxy- and p-chlorobenzaldehyde (1b, 1n) and a,b-unsaturated aldehyde with 2d also occurred with high diastereo- and enantioselectivity (entries 5–7). With 3phenylpropionaldehyde (1e), slight decreases of yield and selectivity were observed (entry 8). It is noted that high stereocontrol was achieved in reactions of several aldehydes and that anti-aldol adducts were obtained with excellent diastereo- and enantioselectivity. It was also found that the hetero Diels–Alder reaction of benzaldehyde (1a) with Danishefsky’s diene 2j proceeded smoothly in the presence of

189

190


Asymmetric aldol reactions using 3I-ZrMS. OSiMe3

O R1

1

+

R2

H

XR4 R3 2

OH O (R)-3I-ZrMS (5 mol%) PrOH (80 mol%) XR4 R1 R2 R 3 toluene, 0 °C, 18 h 4

Entry

Aldehyde; R1

Silicon Enolate

Yield (%)

syn/anti

ee (%) (anti)

1 2a 3 4 5 6 7 8

Ph (1a) Ph (1a) Ph (1a) Ph (1a) p-MeOC6 H4 (1b) p-ClC6 H4 (1n) PhCHbCH (1d) PhCH2 CH2 (1e)

2a 2a 2b 2d 2d 2d 2d 2d

Quant. 97 92 Quant. 80 Quant. 94 65

– – – 5/95 5/95 8/92 16/84 15/85

92 94 94 99 94 95 98 87

a 10

mol% catalyst. OSiMe3 SEt 2a

O Ph

OSiEtMe2 H

+

1a

Ot Bu 2j

OSiMe3

OSiMe3

OMe

OPh

2b

2d

(R)-3I-ZrMS (10 mol%) PrOH (80 mol%) toluene-tBuOMe

(2:1)

–20 °C, 18 h

O TFA Ph

O

5ah 96%, 96% ee

Scheme 5.9

Asymmetric hetero Diels–Alder reaction using 3I-ZrMS.

3I-ZrMS to afford the desired product in high yield with high enantioselectivity (Scheme 5.9).

5.7

Conclusion

Asymmetric aldol reactions and hetero Diels–Alder reactions via the Mukaiyama aldol process using chiral zirconium alkoxides as Lewis acids have been discussed. Both reactions proceeded under milder conditions to afford b-hydroxy esters and 2,3-dihydro-4H-pyran-4-one derivatives in high yield with high diastereo- and enantioselectivity. Addition of primary alcohols played an important role in catalyst turnover. It was discovered that a small amount of water affected the structure of the catalyst and that the presence of water was essential for high enantioselectivity. The remarkable stereo-

5.8 Experimental

selectivity obtained would be ascribed to the unique steric features of the zirconium complex. Zirconium catalysts can be stored for a long time without loss of activity after stabilization on molecular sieves 5A. This methodology will contribute to practical asymmetric aldol chemistry.

5.8

Experimental Typical Experimental Procedure for Asymmetric Aldol Reactions Using Chiral Zirconium Catalyst Prepared from 3,3O-I2 BINOL (3a). Zr(O t Bu)4 (0.040 mmol) in toluene (1.0 mL) was added at room temperature to a suspension of (R)-3,3 0 -diiodo-1,1 0 -binaphthalene-2,2 0 -diol ((R)-3,3 0 -I2 BINOL, 0.048 mmol) in toluene (1.0 mL) and the solution was stirred for 30 min. Propanol (0.32 mmol) and H2 O (0.080 mmol) in toluene (0.5 mL) were then added and the mixture was stirred for 3 h at room temperature. After cooling to 0 C aldehyde 1 (0.40 mmol) in toluene (0.75 mL) and silicon enolate 2 (0.48 mmol) in toluene (0.75 mL) were successively added. The mixture was stirred for 18 h and saturated aqueous NaHCO3 (10 mL) was added to quench the reaction. After addition of dichloromethane (10 mL) the organic layer was isolated and the aqueous layer was extracted with dichloromethane (2 10 mL). The organic layers were combined and dried over anhydrous Na2 SO4 . After filtration and concentration under reduced pressure the residue was treated with THF–1 m HCl (20:1) for 1 h at 0 C. The solution was then made alkaline with saturated aqueous NaHCO3 and extracted with dichloromethane. The organic layers were combined and dried over anhydrous Na2 SO4 . After filtration and concentration under reduced pressure the crude product was purified by preparative thin-layer chromatography (benzene–ethyl acetate, 20:1) to afford the desired aldol adduct 4. The optical purity was determined by HPLC analysis on a chiral column. For some compounds optical purity was determined after acetylation or benzoylation of the hydroxy group. Typical Experimental Procedure for Asymmetric Hetero Diels–Alder Reactions Using a Chiral Zirconium Catalyst Prepared from (R)-3,3O-I2 -6,6O-X2 BINOL (X: C2 F5 (3c), I (3d)). Zr(O t Bu)4 (0.040 mmol) in toluene (0.5 mL) was added at room temperature to a suspension of (R)-3,3 0 -diiodo-6,6 0 -disubstituted-1,1 0 binaphthalene-2,2 0 -diol ((R)-3,3 0 -I2 -6,6 0 -X2 BINOL (X: I, C2 F5 ), 0.048 mmol) in toluene (0.5 mL) and the solution was stirred for 3 h. A mixture of propanol (0.32 mmol) and H2 O (0.080 mmol) in toluene (0.3 mL) was added and the mixture was stirred for 30 min at room temperature. After cooling to 78 C, aldehyde 1 (0.40 mmol) in toluene (0.35 mL) and diene 2 (0.48 mmol) in toluene (0.35 mL) were successively added. The mixture was warmed to 20 C and stirred for 18 h. Saturated aqueous NaHCO3 (10 mL) was then added to quench the reaction. After addition of CH2 Cl2 (10

191

192


mL) the organic layer was isolated and the aqueous layer was extracted with CH2 Cl2 (2 10 mL). The organic layers were combined and dried over anhydrous Na2 SO4 . After filtration and concentration under reduced pressure the residue was treated with TFA (0.5 mL) in CH2 Cl2 (8 mL) for 1 h at 0 C. For reactions of a,b-unsaturated aldehydes and reactions with diene 2n, scandium triflate (Sc(OTf )3 , 0.040 mmol, 10 mol% relative to the employed aldehyde) was used instead of TFA in CH2 Cl2 at room temperature for 12 h. The solution was made alkaline with saturated aqueous NaHCO3 (20 mL), the organic layer was isolated, and the aqueous layer was extracted with CH2 Cl2 (2 10 mL). The organic layers were combined and dried over anhydrous Na2 SO4 . After filtration and concentration under reduced pressure, the trans and cis isomers were separated and purified by preparative thinlayer chromatography (benzene–ethyl acetate, 20:1). The optical purity of trans and cis isomers were determined by HPLC analysis on a chiral column (see following analytical data). For reactions with diene 2n diastereoselectivity was determined by 1 H NMR analysis of the diastereomixtures and enantioselectivity was determined by HPLC analysis of the diastereomixtures. Typical Experimental Procedure for Asymmetric Aldol Reactions Using 3IZrMS. PrOH (19.2 mg, 0.32 mmol) in toluene (0.3 mL) was added at room temperature to a suspension of 3I-ZrMS (74.5 mg, 5 mol%) in toluene (0.9 mL) and the mixture was stirred for 1 h at the same temperature. After cooling to 0 C aldehyde 1 (42.5 mg, 0.4 mmol) in toluene (0.4 mL) and silicon enolate 2 (107 mg, 0.48 mmol) in toluene (0.4 mL) were successively added and the mixture was stirred for 18 h at the same temperature. The reaction was quenched with saturated aqueous NaHCO3 , and dichloromethane (CH2 Cl2 ) was added. The organic layer was isolated, and the aqueous layer was extracted with CH2 Cl2 . The organic extracts were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure the crude mixture was purified by preparative thin-layer chromatography (SiO2 , benzene–ethylacetate) to afford the desired aldol adduct. The diastereomer ratio was determined by 1 H NMR analysis, and the optical purity was determined by HPLC analysis on a chiral column directly or after acetylation.

References 1 (a) Cardin, D. J.; Lappert, M. F.; Raston, C. L.; Riley, P. I.

In Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W. Eds.; Pergamon, New York, 1982, Vol. 3, 549; (b) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 72, 2591; (c) Takahashi, T.; Kotora, M.; Hara, R.; Xi, Z. Bull. Chem. Soc. Jpn. 1999, 72; for review of zirconium alkoxide in catalysis see: (d) Yamasaki, S.; Kanai, M.;

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193

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5 Zirconium Alkoxides as Lewis Acids 10 In some metal catalyzed asymmetric reactions, water affected

11

12

13 14

15 16

17 18

19

20

the yields and selectivities, Ribe, S.; Wipf, P. Chem. Commun. 2001, 299. Posner et al. and Mikami et al. also reported that a small amount of water affected catalytic enantioselective ene reactions using a Ti–BINOL complex. See, (a) Posner, G. H.; Dai, H.; Bull, D. S.; Lee, J.-K.; Eydoux, F.; Ishihara, Y.; Welsh, W.; Pryor, N.; Petr Jr., S. J. Org. Chem. 1996, 61, 671; (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Chem. Commun. 1997, 281. (c) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. J. Molecular Catalysis A: Chemical 1998, 132, 165. (d) Mikami, K.; Terada, M.; Matsumoto, Y.; Tanaka, M.; Nakamura, Y. Microporous and Mesoporous Materials 1998, 21, 461. (e) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg. Chim. Acta 1999, 296, 267. Recent examples of anti-selective aldol reactions, (a) Parmee, E. R.; Hong, Y.; Tempkin, O.; Masamune, S. Tetrahedron Lett. 1992, 33, 1729; (b) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077; (c) Evans, D. A.; MacMillan, W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859; (d) Yanagisawa, A.; Matsumoto, Y., Nakashima, H.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319; (e) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333; (f ) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798; (g) Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.; Yamamoto, H. Tetrahedron 2002, 58, 8331; (h) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405; (i) Wadamoto, M.; Ozawa, N.; Yanagisawa, A.; Yamamoto, H. J. Org. Chem. 2003, 68, 5593. (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 7153; (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180. Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527. (a) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. Org. Lett. 2002, 4, 1221; (b) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807. (a) Danishefsky, S. J. Chemtracts: Org. Chem. 1989, 273; (b) Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59; (c) Boger, D. L. in Comprehensive Organic Synthesis; Trost, B. M. Ed.; Pergamon Press: Oxford, 1991; Vol. 5, 451; (d) Waldmann, H. Synthesis 1994, 535. Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am. Chem. Soc. 1985, 107, 1246. tert-Butyl methyl ether was used as an efficient solvent in asymmetric HDA reactions previously. See: Schaus, S. E.; Bra˚nalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403. (a) Kobayashi, S. Synlett 1994, 689; (b) Kobayashi, S. Eur. J. Org. Chem. 1999, 15; (c) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227. Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, 1269.

References 21 (a) Danishefsky, S. J.; Webb II, R. R. J. Org. Chem. 1984, 49,

22

23

24

25 26

27 28 29

30 31

1955; (b) Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, 1269. Reviews of catalytic asymmetric aldol reactions, (a) Bach, T. Angew. Chem. Int. Ed. Engl. 1994, 33, 417; (b) Nelson, S. G. Tetrahedron: Asymmetry. 1998, 9, 357; (c) Groger, H.; Vogel, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137; (d) Mahrwald, R. Chem. Rev. 1999, 99, 1095; (e) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325; (f ) Machajewski, T. D.; Wong, C.-H. Angew. Chem. Int. Ed. 2000, 39, 1352; (g) List, B. Tetrahedron 2002, 58, 5573; (h) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595; (i) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Eur. J. 2002, 8, 37; ( j) Carreira, E. M. in Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds.; Springer: Heidelberg, 1999. Vol. 3, p 998; (k) Carreira, E. M. in Catalytic Asymmetric Synthesis 2 nd Edition, I. Ojima Ed.; Wiley–VCH, New York, 2000, p 513; (l) Sawamura, M.; Ito, Y. in Catalytic Asymmetric Synthesis 2 nd Edition, I. Ojima Ed.; Wiley–VCH, New York, 2000, p 493. (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1985, 447. (b) Gennari, C.; Beretta, M. G.; Bernardi, A.; Moro, G.; Scolastico, C.; Todeschini, R. Tetrahedron 1986, 42, 893. Reviews of catalytic asymmetric hetero Diels–Alder reactions, (a) Ooi, T.; Maruoka, K. in Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds.; Springer: Heidelberg, 1999. Vol. 3, p 1237; (b) Jørgensen, K. A. Angew. Chem. Int. Ed. Engl. 2000, 39, 3558. See also references in ref. 14b. Kobayashi, S.; Ueno, M.; Ishitani, H. J. Am. Chem. Soc. 1998, 120, 431. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708; (b) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K. Chem. Eur. J. 2003, 9, 4405. Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37, 2922. Mikami, K.; Motoyama, T.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812. A stable chiral La catalyst has been reported: Y. S. Kim, S. Matsunaga, J. Das, A. Sekine, T. Ohshima and M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 6506. M. Ueno, H. Ishitani and S. Kobayashi, Org, Lett, 2002, 4, 3395. Kobayashi, S.; Saito, S.; Ueno, M.; Yamashita, Y. Chem. Commun. 2003, 2016.

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6

Direct Catalytic Asymmetric Aldol Reaction Using Chiral Metal Complexes Masakatsu Shibasaki*, Shigeki Matsunaga, and Naoya Kumagai 6.1

Introduction

The aldol reaction has established a position in organic chemistry as a remarkably useful synthetic tool which provides access to b-hydroxy carbonyl compounds and related building blocks. Intensive efforts have raised this classic process to a highly enantioselective transformation employing only catalytic amounts of chiral promoters, as reviewed in this handbook [1]. Although many effective applications have been reported, most methods necessarily involve the preformation of latent enolates such as ketene silyl acetals, by use of less than stoichiometric amounts of base and silylating reagents (Scheme 6.1, top). Because of an increasing demand for environmentally benign and atom-efficient processes, such stoichiometric amounts of reagents, which inevitably result in waste, for example salts, should be excluded from the procedure. Thus, the development of a direct catalytic asymmetric aldol reaction (Scheme 6.1, bottom), which employs unmodified ketone as a donor, is desired. The clue for success in achieving the direct enolization of unmodified ketone with a catalytic amount of reagent is found in enzymatic reactions. (a) Mukaiyama-type reactions A: SiR3 or CH3

O

base (1 equiv.)

R2 (b) Direct reactions O R2

O

A

AO

chiral catalyst

R2

R1CHO

R2

R1

HO

chiral catalyst R1CHO

O

O

R1

Scheme 6.1

(a) Mukaiyama-type reactions and (b) direct reactions. Modern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

R2

198

6 Direct Catalytic Asymmetric Aldol Reaction Using Chiral Metal Complexes

O HO

OH

O

aldolase

OPO32-

OPO32OH

OH Tyr O H

H Glu

O

CO2–

H

O

His Zn His His O

H O

His Zn His O– His

OH O

OPO32HO OH

OH

Ser Thr

Ser

O

NH2

OPO32-

O HO

Asn

OH OH

NH2

OH

Asn

Ser Thr

Ser

Fig. 6.1

Mechanism of action of the class II aldolase fructose-1-phosphate aldolase.

Aldolases efficiently promote the direct aldol reaction under mild in-vivo conditions – fructose-1,6-bisphosphate and dihydroxyacetone phosphate aldolases are typical examples. Such enzymes function as a bifunctional catalyst, activating a donor (ketone) with Brønsted basic functionality and an acceptor (aldehyde) with an acidic functionality. As shown in Figure 6.1, the mechanism of class II aldolases (e.g. fructose-1-phosphate aldolase) is thought to involve co-catalysis by a Zn 2þ cation and a basic functional group in the enzyme’s active site [2]. The Zn 2þ functions as a Lewis acid to activate a carbonyl group, and the basic part abstracts an a-proton to form a Znenolate. Synthetic organic chemists regarded this bifunctional mechanism of the aldolases as a very promising strategy for achieving direct catalytic asymmetric aldol reactions with an artificial small molecular catalyst. This chapter focuses on notable advances recently achieved by use of metallic catalysis. This catalysis mimics that of the class II aldolases [3]. Important early contributions on direct catalytic asymmetric aldol reactions using Au as catalyst by Ito, Hayashi, and their coworkers [4] are described in Chapter 1 of Part II of this book. The other type of the direct aldol reaction, the organocatalysis as mimics of class I aldolases (amino acid based mechanism) [5] is discussed in Chapter 4 of Part I of this book.

6.2

Direct Aldol Reactions with Methyl Ketones

A possible catalytic cycle for achieving direct catalytic asymmetric aldol reaction by means of bifunctional metallic catalysis is shown in Scheme 6.2,

6.2 Direct Aldol Reactions with Methyl Ketones

R2

R2

O R1

H

II

R2

*

*

O M O LA I

O M O H O LA O

*

OH O R1

R2

O O M H O O LA

H R1

R2

LA : Lewis acid M : Metal of Brønsted base III

O : Chiral ligand

*

*

O

O M O H O LA

O

R1

IV

Scheme 6.2

Possible catalytic cycle for direct catalytic asymmetric aldol reactions.

which involves synergistic action of the Brønsted basic and the Lewis acidic moieties in the catalyst. The Brønsted base functionality (OM) in the catalyst I deprotonates an a-proton of a ketone to generate the metal enolate II. Lewis acid functionality activates an aldehyde to give III. The activated aldehyde then reacts with the metal enolate in a chelation-controlled asymmetric environment to afford a b-keto metal alkoxide IV. Proton exchange between the metal alkoxide moiety and an aromatic hydroxy proton or an

La(O-i-Pr)3 +

3

OH OH

+

3 BuLi

(S)-BINOL Li O O O Li La O O O Li

Fig. 6.2

The structure of LaLi3 tris((S)-binaphthoxide) ((S)-LLB).

199

200


O

R1CHO

+

R2 2 (1.5–50 equiv.)

1

(S)-LLB (20 mol %) THF, -20 °C

OH O R2 3 y. 28-90% 44-94% ee

R1

Scheme 6.3

Direct catalytic asymmetric aldol reactions of methyl ketone 2 promoted by (S)-LLB.

a-proton of a ketone leads to the optically active aldol adduct, and at the same time leads to regeneration of the catalyst. In 1997, Shibasaki reported that a heterobimetallic (S)-LaLi3 tris(binaphthoxide) complex (Figure 6.2, (S)-LLB), prepared from La(O-i-Pr)3 , BINOL and BuLi, was effective in the direct catalytic asymmetric aldol reaction of unmodified ketones (Scheme 6.3) [6]. As shown in Table 6.1, the LLB catalyst was effective for methyl aryl ketones (2a and 2b) and methyl alkyl ketones

Tab. 6.1

Direct catalytic asymmetric aldol reactions of methyl ketone 2 promoted by (S)-LLBa. Entry

Aldehyde

Ketone (equiv.)

Product

1a

-Ph

2a (5)

3aa

2 3

1a 1a

-Ph -Ph

2a (1.5) 2a (10)

4

1a

5

1a

CHO

1

6

Ph

CHO

7b 8 CHO

9

CHO

10 11

Ph

Yield (%)

ee (%)

88

76

88

3aa 3aa

135 91

43 81

87 91

2b (8)

3ab

253

55

76

-CH3

2c (10)

3ac

100

53

73

1b

-Ph

2a (7.4)

3ba

87

90

69

1b 1b

-CH3 -CH2 CH3

2c (10) 2d (50)

3bc 3bd

185 185

82 71

74 94

1c

-Ph

2a (8)

3ca

169

72

44

1d

-Ph

2a (8)

3da

277

59

54

1e

-Ph

2a (10)

3ea

72

28

52

conditions: (S)-LLB (20 mol%), THF, 20 C. reaction was carried out at 30 C.

a Reaction b The

CHO

Time (h)


O

O

H Me OMOM 4 (>99% ee)

O

+

OH O

(S)-LLB (10 mol %)

O

THF, –20 °C, 16 h TMS 5 (6 equiv.)

TBS OH O

Me OMOM 6 y. 65% α/β = 3.6/1

OTBDPS

O Me OTES

7

Scheme 6.4

Application of (S)-LLB to the formal total synthesis of fostriecin.

(2c and 2d). Excess ketone was necessary to achieve good yield (entries 1–3). Although the reactivity was moderate even using 20 mol% catalyst, the enantiomeric excess reached 94% ee. The results demonstrated that the concept shown in Scheme 6.2 was possible. As shown in Scheme 6.4, LLB was applicable to optically active functionalized aldehyde 4 and acetylenic ketone 5. The aldol reaction of 4 and 5 proceeded smoothly with 10 mol% (S)-LLB at 20 C to afford 6 in 65% yield. Diastereoselectivity was 3.6:1 and the desired a-OH 6 was obtained as a major product. Compound 6 was successfully converted into known intermediate, 7, of fostriecin [7]. It is worthy of note that the aldol reaction did not proceed when a standard base, for example LDA, was used.

R1CHO

(S)-LLB (8 mol %) KHMDS (7.2 mol %) H2O (16 mol %)

O + 2

THF

R 2 (3–15 equiv.)

1

OH O R

1

R2 3 y. 50-91% 30-93% ee

KOH

(S)-LLB 1 equiv.

+

KHMDS 0.9 equiv.

+

H 2O

2 equiv.

Li O O O La Li O O O Li

(S)-LLB•KOH complex Scheme 6.5

Direct catalytic asymmetric aldol reactions of methyl ketone 2 promoted by (S)-LLB– KOH.

201

TMS

202


Tab. 6.2

Direct catalytic asymmetric aldol reactions of methyl ketone 2 promoted by (S)-LLB–KOHa. Entry

Aldehyde

Ketone (equiv.)

CHO

1 2 3 4 5

CHO

Ph

6b 7

CHO

BnO

8 CHO

9 10

CHO

11

CHO

12 13

2

Ph

CHO

Product

Temp (˚C)

Time (h)

Yield (%)

ee (%)

1a

-Ph

2a (5)

3aa

20

15

75

88

1b 1b 1b

-Ph -CH3 -CH2 CH3

2a (5) 2c (10) 2d (15)

3ba 3bc 3bd

20 20 20

28 20 95

85 62 72

89 76 88

1b

-Ph

2a (5)

3ba

20

18

83

85

1b

-Ph

2a (5)

3ba

20

33

71

85

1f

-Ph

2a (5)

3fa

20

36

91

90

1f

-Ph

2a (5)

3fa

20

24

70

93

1d

-Ph

2a (5)

3da

30

15

90

33

1d

-m-NO2 -C6 H4

2e (3)

3de

50

70

68

70

1g

-m-NO2 -C6 H4

2e (3)

3ge

45

96

60

80

1h

-m-NO2 -C6 H4

2e (5)

3he

50

96

55

42

1e

-m-NO2 -C6 H4

2e (3)

3ee

40

31

50

30

a Reaction

conditions: (S)-LLB (8 mol%), KHMDS (7.2 mol%), H2 O (16 mol%), THF, unless otherwise noted. b (S)-LLB (3 mol%), KHMDS (2.7 mol%), H O (6 mol%), THF. 2

Substantial acceleration of this reaction was achieved using a (S)-LLB– KOH catalyst prepared from (S)-LLB, KHMDS, and H2 O; this enabled reduction of the catalyst loading from 20 to 3–8 mol% with a shorter reaction time (Scheme 6.5) [8]. The results are summarized in Table 6.2. Aldol adducts were obtained in good yield and in moderate to good enantioselectivity (30–93% ee). The LLB–KOH complex was also applicable to the reaction between cyclopentanone and aldehyde 1b, affording the aldol adduct 3bf syn selectively (syn/anti ¼ 93:7, syn:76% ee, anti:88% ee) in 95% yield (Scheme 6.6). Kinetic studies, including initial rate kinetics and isotope effects, indicated that the rate-determining step was deprotonation of the ketone. Additional KOH is supposed to accelerate the rate-determining enolization step. Because high ee was achieved in the presence of additional KOH, self-assembly of the LLB complex and KOH was assumed. On the basis of mechanistic studies a working model was proposed for the direct

6.2 Direct Aldol Reactions with Methyl Ketones (S)-LLB (8 mol %) KHMDS (7.2 mol %) H2O (16 mol %) THF, 99 h, –20 °C

O CHO

Ph

+

1

2f (5 equiv.)

OH O Ph

3bf y. 95%, syn/anti = 93/7 syn: 76% ee, anti: 88% ee

Scheme 6.6

Direct catalytic asymmetric aldol reactions of cyclopentanone (2f ) promoted by (S)-LLB–KOH.

O

* O Li

O

Li O

O

La

O R1

Li

2

R

O

O Li K H

R2

O O

La

O O

O

*

O

O

Li

O

O

La

*

O

O

Li

*

K

*

R2

O

O

O La

1

H

R

O

R1

Li

*

proposed intermediate

* O Li O K R1

O

R1

O

Li O

*

H

O

H H

Li

H

* *

rate-determining step

Li

* H

R2

*

O

O KOH

H

O Li H H O

Li O O

La O

R2

O

*

O

O

H

*

Li K O

R2

Fig. 6.3

Working model for direct catalytic asymmetric aldol reactions promoted by the (S)-LLB–KOH complex.

catalytic asymmetric aldol reaction promoted by the LLB–KOH complex (Figure 6.3). KOH functions as a Brønsted base, generating an enolate from the ketone (rate-determining step); the lanthanum ion acts as a Lewis acid to activate the aldehyde. 1,2-Addition and the protonation of an alkoxide leads to the aldol adduct and regenerates the catalyst. As shown in Scheme 6.7, a key-intermediate of bryostatin 7 was synthesized by using the LLB– KOH complex twice. 3fa was prepared by the aldol reaction using (R)LLB–KOH. Baeyer–Villiger oxidation, followed by functional group manipulation, afforded aldehyde 9. The aldol reaction of 9 with (S)-LLB–KOH proceeded in a catalyst-controlled manner and the anti adduct was obtained (anti/syn ¼ 7:1). The LLB–KOH complex was also applied to the total synthesis of epothilones; the LLB–KOH complex was effectively applied for

203

204


OH O

OH O a

Ph

BnO

O

OPh

BnO

3fa

TBSO b

H

BnO

8

9 TBSO

O OH

BnO

O

(S)-LLB•KOH (20 mol %) ketone 2a (5 equiv.)

OH O

THF, –20 °C

Ph

BnO

10 y. 90% (anti/syn = 7/1)

11

(a) mCPBA, NaH2PO4, ClCH2CH2Cl, y. 73%; (b) i)TBSOTf, Hünig base; ii) DIBAL; iii) PCC y. 87% (3 steps). Scheme 6.7

Application to the synthesis of intermediate to bryostatin 7.

O RCHO

1

+

Ph 2a (2 equiv.)

OCH3 + Ba(O-i-Pr)2 OH

12

(R)-Ba-12 (5 mol %) DME, -20 °C

DME

OH O Ph 3 y. 77-99% 50-70% ee

R

CH3 O O Ba O O H3C

Ba-12 (proposed structure)

Scheme 6.8

Direct catalytic asymmetric aldol reactions of acetophenone (2a) promoted by (R)-Ba-12.

resolution of the racemic aldehyde [9]. Further details are given in Chapter 7 in Vol. 1. To reduce the amount of ketone Shibasaki prepared a Ba-12 complex from Ba(O-i-Pr)2 and 12 [10]. As shown in Scheme 6.8, the Ba-12 complex afforded aldol adducts in good yield (77–99%) from as little as 2 equiv. ketone 2a, although ee was modest (50–70% ee). In 2000 Trost reported a dinuclear Zn complex prepared from Et2 Zn and 13 [11]. 13 was easily synthesized from p-cresol in four steps. On the basis of ethane gas emission measurement and ESI-MS analysis the dinuclear complex Zn2 -13 was proposed (Scheme 6.9). As shown in Table 6.3, the Zn complex was effective in direct catalytic asymmetric aldol reactions with a variety of methyl aryl ketones (2a, 2g–2j; 10 equiv.). Excellent enantioselectivity (up to 99% ee) was achieved by use of 5 mol% 13, although excess ketone was used and yields were occasionally moderate. It is worthy of note that high ee was achieved at relatively high reaction temperature


205

Tab. 6.3

Direct catalytic asymmetric aldol reactions of methyl ketone 2 promoted by dinuclear Zn2 -13 complexa. Entry

Aldehyde

1

Ketone (Equiv.)

CHO

2 3

CHO CHO

4

CHO

5

6

Ph

CHO

Product

Temp (˚C)

Time (h)

Yield (%)

ee (%)

1i

-Ph

2a (10)

3ia

5

48

33

56

1i

-Ph

2a (10)

3ia

15

48

24

74

1j

-Ph

2a (10)

3ja

5

48

49

68

1d

-Ph

2a (10)

3da

5

48

62

98

1c

-Ph

2a (10)

3ca

5

48

60

98

1k

-Ph

2a (10)

3ka

5

48

79

99

1l

-Ph

2a (10)

3la

5

48

67 (dr: 2/1)

94

1m

-Ph

2a (10)

3ma

5

96

61

93

2g (10)

3dg

5

48

66

97

2h (10)

3dh

5

48

48

97

2i (5)

3di

5

48

36

98

2j (5)

3dj

5

48

40

96

Ph

7

8

Ph

CHO

TBSO

9

CHO

CHO

1d

O

OMe

10

1d

11

1d OMe

12

1d

a Reaction

conditions: ligand 13 (5 mol%), Et2 Zn (10 mol%), Ph3 PbS (15 mol%), THF.

(5 C). Bifunctional Zn catalysis is proposed, with one Zn acting as Lewis acid and another Zn-alkoxide functioning as a Brønsted base to generate a Zn-enolate (Figure 6.4). Trost also reported that modification of the ligand occasionally led to better results. When ligand 14 was used instead of 13 the direct aldol reaction of acetone (10–15 equiv.) proceeded smoothly with good enantioselectivity (Scheme 6.10) [12]. The results are summarized in Table 6.4. Aldol adducts were obtained in good yield (59–89%) and ee (78–94%). In

206


O

R1CHO

+

HO

OH N

OH

Ph Ph

O

Ar 3 y. 24-79% 56-99% ee

Ph Ph

N

H O R1

MS 4A, THF

Ar 2 (5–10 equiv.)

1

Ph Ph

ligand 13 (5 mol %) Et2Zn (10 mol %) Ph3P=S (15 mol %)

Et O O Zn Zn N N O

Ph Ph

Et2Zn (2 equiv.)

THF CH3 13

CH3 Zn2-13 (proposed structure)

Scheme 6.9

Direct catalytic asymmetric aldol reactions of methyl ketone 2 promoted by dinuclear Zn2 -13 complex.

R

Ar O Ph Ph

Zn Zn N

H

O

O O

O

Ph Ph

N

CH3 Fig. 6.4

Proposed transition state for the direct aldol reaction of methyl ketone 2.

general, self-condensation of aldehydes should be suppressed to achieve good yield by using a-unsubstituted aldehydes. It is worthy of note that good yield and high ee were achieved even with a-unsubstituted aldehydes (entries 5–7, yield 59–76%, 82–89% ee). Noyori prepared a highly active Ca-15 complex from Ca[N{Si(CH3 )3 }2 ]2 and 15 (Scheme 6.11) [13]. As shown in Table 6.5, aldol adducts were obtained in good yield (75–88%) in moderate to good ee (66–91% ee) by using as little as 1–3 mol% catalyst loading. The reactivity of the Ca catalyst is higher than those of other catalysts. The enhanced reactivity is ascribed to the high basicity of the calcium alkoxide. Even with this active Ca-15 catalyst, however, excess ketone was essential to achieve good yield and ee. This problem would be solved in future research.


ligand 14 (x mol %) Et2Zn (2x mol %)

O RCHO

1

+

2c (10-15 equiv.) MS 4A, THF, 5 °C, 48 h (x = 5-10 mol %)

OH O

HO

OH

Ph Ph

N

OH

3 y. 59-89% 78-94% ee

H3C

14

Direct catalytic asymmetric aldol reactions of acetone (2c) promoted by dinuclear Zn2 -14 complex.

Tab. 6.4

Direct catalytic asymmetric aldol reactions of acetone (2c) promoted by dinuclear Zn2 -14 complexa. Aldehyde

CHO

1

CHO

2

CHO

3

4

Ph

CHO

Product

Catalyst (mol%)

Yield (%)

ee (%)

1c

3cc

10

89

92

1d

3dc

10

89

91

1a

3ac

10

72

94

1k

3kc

10

84

91

1j

3jc

10

59

84

1e

3ec

10

76

82

1i

3ic

10

69

89

1n

3nc

5

78

83

1o

3oc

5

62

78

Ph

5 6

CHO Ph

7

CHO CHO CHO

8

CHO

9 O 2N a Reaction

N

R

Scheme 6.10

Entry

207

conditions: ligand 14 ( mol%), Et2 Zn (2 mol%), THF, MS 4A, 5 C, 48 h.

CH3

Ph Ph

208


O RCHO

+

C2H5CN/THF, –20 °C

Ph 2 (10 equiv.)

1

H O

(S,S)-Ca-15 (x mol %)

R

Ph 3 y. 75-88% 66-91% ee

(x = 1-3 mol %)

[(CH3)3Si]2N

O

OH Ca(thf)2

+

+

[(CH3)3Si]2N

Ca-15 complex

KSCN

OH

1 equiv.

15 3 equiv.

1 equiv.

Scheme 6.11

Direct catalytic asymmetric aldol reactions of acetophenone (2a) promoted by Ca-15 complex.

6.3

Direct Aldol Reactions with Methylene Ketones

The aldol reaction between aldehydes and methylene ketones or propionates should provide a powerful tool for construction of two continuous chiral centers and for formation of carbon–carbon bonds. Catalytic asymmetric syntheses of syn and anti aldols from latent enolates have already been well investigated [1]. In contrast, diastereo- and enantioselective synthesis of aldols, starting from methylene ketones, by means of the direct catalytic asymmetric aldol reaction is still immature. The bulkiness of methylene ketones was expected to make it more difficult for the catalysts to abstract an a-hydrogen from the ketones. Shibasaki reported a strongly basic La-Li-16 complex with an Li alkoxide Tab. 6.5

Direct catalytic asymmetric aldol reactions of acetophenone (2a) promoted by Ca-15 complexa. Entry

Aldehyde

CHO

1 2 3

Ph

4

BnO

5

a Reaction

CHO

CHO

CHO

Product

Catalyst (mol%)

Time (h)

Yield (%)

ee (%)

1a

3aa

3

22

87

86

1a

3aa

1

20

79

82

1b

3ba

3

24

75

87

1f

3fa

3

24

76

91

1c

3ca

3

20

88

66

conditions: (S,S)-Ca-15 ( mol%), C2 H5 CN/THF, 20 C.

6.3 Direct Aldol Reactions with Methylene Ketones

CHO

BnO

O

+

1f (1.5 equiv.)

La-Li-16 complex (20 mol %) LiI (0–60 mol %)

2k (5 equiv.)

O OH OH

HO

toluene –20 °C, 6 d

OH O BnO

La(O-i-Pr)3 (1 equiv.) BuLi (3 equiv.)

HO HO

y. 5-38% 4-51% ee

3fk

O O La O O O Li LiO OLi La-Li-16 complex (proposed structure)

OH

16

209

Scheme 6.12

Direct catalytic asymmetric aldol reactions of 3-pentanone (2k) promoted by La-Li-16 complex.

moiety. The catalyst promoted the direct aldol reaction of 3-pentanone antiselectively; yield and ee were only modest, however (Scheme 6.12) [14]. A notable advance in the direct aldol reaction of methylene ketone was reported by Mahrwald in 2002 [15]. As shown in Scheme 6.13, a catalytic amount (10 mol%) of Ti-17-rac-BINOL complex was suitable for promoting the direct asymmetric aldol reaction of 3-pentanone with a variety of aldehydes. Interestingly, combination of chiral mandelic acid (17) and racBINOL afforded a good chiral Ti-catalyst. As summarized in Table 6.6, aldol adducts were obtained syn-selectively (syn/anti up to 91:9) in moderate to good yield (43–85%) and with good ee (71–93%). Good selectivity was achieved at room temperature. The aldehyde/ketone ratio in this reaction is

rac-BINOL2Ti2(O-i-Pr)3 /(R)-17

O RCHO

1 (1.5 equiv.)

room temperature

2k(1 equiv.)

OH

+ Ph

R

3

y. 43-85% syn/anti =72/28–91/9 71-93% ee

OH OH

OH O

(10 mol %)

+

OH

+ Ti(O-i-Pr)4

O (R)-mandelic acid (17)

rac-BINOL Scheme 6.13

Direct catalytic asymmetric aldol reactions of 3-pentanone (2k) promoted by racBINOL2Ti2 (O-i-Pr)3 /(R)-17 complex.

rac-BINOL2Ti2(O-i-Pr)3 /(R)-17 complex

210

6 Direct Catalytic Asymmetric Aldol Reaction Using Chiral Metal Complexes Tab. 6.6

Direct catalytic asymmetric aldol reactions of 3-pentanone (2k) promoted by rac-BINOL2Ti 2 (O-i-Pr)3 /(R)-17 complexa. Entry

Aldehyde

1

PhCHO CHO

2 3 4 5

Ph

CHO CHO

CHO

Product

Catalyst (mol%)

dr (syn/ anti)

Yield (%)

ee (%)

1n

3nk

10

91/9

85

91

1a

3ak

10

88/12

71

93

1p

3qk

10

73/27

68

78

1d

3dk

10

79/21

43

71

1q

3qk

10

72/28

78

74

a Reaction

conditions: rac-BINOL2Ti 2 (O-i-Pr)3 /(R)-17 (10 mol%), room temperature.

also worthy of note. The aldol reaction proceeded smoothly with 1 equiv. ketone and 1.5 equiv. aldehyde.

6.4

Direct Aldol Reaction with a-Hydroxyketones

a-Hydroxyketones also serve as aldol donors in the direct catalytic asymmetric aldol reaction. In contrast with conventional Lewis acid-catalyzed aldol reactions, protection of the OH group is not necessary. The versatility of the resulting chiral 1,2-diols as building blocks makes this process attractive. The first successful result was reported by List and Barbas with proline catalysis [16]. l-Proline catalyzed a highly chemo-, diastereo- and enantioselective aldol reaction between hydroxyacetone and aldehydes to provide chiral anti-1,2-diols. Trost and Shibasaki have made important contributions to metallic catalysis. Trost reported a direct aldol reaction with 2-hydroxyacetophenone and 2-hydroxyacetylfuran using the dinuclear Zn2 -13 catalyst [17] (Scheme 6.14). The aldol reaction between a variety of aldehydes and 1.5 equiv. ketone proceeded smoothly at 35 C with 2.5–5 mol% of catalyst, in the presence of MS 4A, to afford the products syn-selectively (syn/anti ¼ 3:1 to 100:0) in 62–98% yield and 81–98% ee (Table 6.7). Strikingly, the absolute configuration of the stereocenter derived from the aldehyde is opposite to that obtained with acetophenone (2a, Scheme 6.9) and acetone (2c, Scheme 6.10) as donors, possibly because of the bidendate coordination of a-hydroxyketone to the catalyst, as depicted in Figure 6.5. Occasionally the

6.4 Direct Aldol Reaction with a-Hydroxyketones

+

RCHO

Ar

MS 4A, THF, –35 °C

OH (x = 2.5–5 mol %) 18a: Ar = Ph 18b: Ar = 2-furyl (1.1-1.5 equiv.)

1

H O

ligand 13 (x mol %) Et2Zn (2x mol %)

O

Ph Ph

O

R

211

HO

OH N

OH

N

Ar

O H 19 y. 65-97% syn/anti = 4/1–100/0 86-98% ee

CH3 13

Scheme 6.14

Direct catalytic asymmetric aldol reaction of hydroxyketone 18 promoted by Zn2 -13 complex.

Tab. 6.7

Direct catalytic asymmetric aldol reaction of hydroxyketone 18 promoted by dinuclear Zn2 -13 complexa. Entry

Aldehyde

CHO

1 2 3 4

CHO

5 6 7

Ph

CHO

Ketone (Equiv.)

Product

Catalyst (Dmol%)

Yield (%)

dr (syn/ anti)

ee (%) (syn)

1c

18a (1.5)

19ca

2.5

83

30/1

92

1c 1c 1c

18a (1.5) 18b (1.3) 18b (1.1)

19ca 19cb 19cb

5 5 5

97 90 77

5/1 6/1 6/1

90 96 98

1d

18a (1.5)

19da

2.5

89

13/1

93

1d

18a (1.1)

19da

5

72

6/1

93

1k

18a (1.5)

19ka

2.5

74

100/0

96

1j

18a (1.5)

19ja

2.5

65

35/1

94

1j

18a (1.1)

19ja

5

79

4/1

93

1e

18a (1.5)

19ea

2.5

78

9/1

91

1r

18a (1.5)

19ra

5

89

5/1

86

1s

18a (1.5)

19sa

5

91

5/1

87

Ph

8

CHO

9 10

CHO

Ph

11 12 a Reaction

CHO 4

CHO 6

conditions: ligand 13 ( mol%), Et2 Zn (2 mol%), THF, MS 4A, 35 C, 24 h.

Ph Ph

212


Ar Ph Ph

R H O OH O Zn

O O Zn N

O

Ph Ph

N

CH3 Fig. 6.5

Proposed transition state for the direct aldol reaction of hydroxyketone 18.

reaction has been performed with a ketone/aldehyde ratio of 1.1:1.0 albeit at the expense of conversion, which comes closest in reaching the ideal atom economical process. The reaction with 18b resulted in higher ee and, moreover, the furan moiety is suitable for further conversion of the resulting chiral 1,2-diol. Oxidative cleavage of the furan ring was successfully used for asymmetric synthesis of (þ)-boronolide, as shown in Scheme 6.15 [18]. Shibasaki developed direct catalytic asymmetric aldol reactions of 2hydroxyacetophenones, providing either anti or syn chiral 1,2-diols, by using two types of multifunctional catalyst, (S)-LLB–KOH and an Et2 Zn/(S,S)linked-BINOL 20 complex [19]. (S)-LLB–KOH (5–10 mol%) promoted the direct aldol reaction of 2-hydroxyacetophenones 18 to afford anti-1,2-diols in good yields and ee (up to 98% ee), although anti-selectivity was occasionally modest. (Scheme 6.16 and Table 6.8) [19, 20]. Enolizable aldehydes were successfully utilized without any self-condensation. The absolute configuration was identical at the a-position of both anti and syn products, suggesting that the enantioface of the enolates derived from 2-hydroxyacetophenones

O +

H

18b 1.1 eq

1h: 16 mmol scale OAc OAc

O

a(a)

a

OH

OAc (+)-boronolide

TBSO O

O OH

OH

O

O

O

O

3

O 20

19bh TBSO MeO O

O

O b

O 21

3

5 mol % of Zn catalyst, MS 4A, THF, –35 °C, 12 h, 93% (syn/anti = 4.2/1, syn = 96% ee);

(b) RuCl3 (cat.), NaIO4, CCl4, CH3CN, H2O; CH2N2, Et2O, 70%. Scheme 6.15

Stereocontrolled total synthesis of (þ)-boronolide.

3


213

KOH

(S)-LLB•KOH (5-10 mol %)

O R

RCHO +

THF, –40 or –50 °C

OH 1

Li O O O La Li O O O Li

OH O R

R OH

19 y. 50-96% anti/syn = 65/35–84/16

18 (2 equiv.)

anti : 84-97% ee

(S)-LLB•KOH

Scheme 6.16

Direct catalytic asymmetric aldol reaction of hydroxyketone 18 promoted by (S)-LLB–KOH.

18 was well differentiated. The configuration at the b-position of the major anti diastereomer was opposite to that of the aldol product from the methyl ketone (Scheme 6.5) possibly because of bidendate coordination of a-hydroxyketone 18 to the catalyst. Proposed transition state models are depicted in Figure 6.6. Hydroxyketones would coordinate to La in a bidentate fashion, resulting in efficient Si-face shielding of the Z enolate (Figure 6.6, a and b). In addition, this preferential bidentate coordination of 18 is supposed to suppress the self-condensation of aldehydes. Shibasaki reported another approach to the direct asymmetric aldol reac-

Tab. 6.8

Direct catalytic asymmetric aldol reaction of hydroxyketone 18 promoted by (S)-LLB–KOHa. Entry

Aldehyde

1

Ph

CHO

2 3 4 5 6

a Reaction

Product

Catalyst (mol%)

Temp (˚C)

Time (h)

Yield (%)

dr (anti/ syn)

ee (%) (anti/syn)

1t

H-

18a

19ta

10

50

24

84

84/16

95/74

1t 1t 1t 1t

H4-MeO2-Me4-Me-

18a 18c 18d 18e

19ta 19tc 19td 19te

5 10 10 10

50 40 40 40

40 35 35 35

78 50 90 90

78/22 81/19 77/23 83/17

92/70 98/79 84/57 97/85

4-Me-

18e

19ue

10

40

12

96

75/25

96/89

1v

H-

18a

19va

10

50

28

90

72/28

94/83

1j

H-

18a

19ja

10

50

24

86

65/35

90/83

CHO 1u CHO

7

8

Ketone (R-)

CHO

conditions: (S)-LLB ( mol%), KHMDS (0.9 mol%), H2 O (2 mol%), THF.

214


R

H

O H

Li H

O

H O

K

O Li H R

O

H O

La

K

La O

O

O

O Li

Li

a

b

OH O

OH O

R

Ph OH anti-19 (αR,βR)-dihydroxy ketone

R

Ph OH syn-19 (αR,βS)-dihydroxy ketone

(favored)

(disfavored)

Fig. 6.6

Transition states postulated for formation of anti diol and syn diol.

tion of 2-hydroxyacetophenones 18. The Et2 Zn/(S,S)-linked-BINOL 20 complex promoted the aldol reaction of 2-hydroxyacetophenones 18 to afford syn-1,2-diols in good yield (Scheme 6.17) [19, 21, 22]. Reactivity and stereoselectivity depended on the substituent on the aromatic ring of the 2-hydroxyacetophenones 18. 2-Hydroxy-2 0 -methoxyacetophenone (18f ) gave the best result to afford the product in 94% yield and high stereoselectivity (syn/anti ¼ 89:11, syn ¼ 92% ee, anti ¼ 89% ee) with as little as 1 mol% catalyst. The catalyst was applicable to a variety of aldehydes including aunsubstituted aldehydes (Scheme 6.17). As summarized in Table 6.9, the reaction reached completion within 24 h with 1 mol% catalyst to give syn-

O R1CHO +

(S,S)-linked-BINOL 20 (x mol %) 2 R Et2Zn (2x mol %)

OH 1

THF, –30 °C

O OH O R

R

OH OH

HO HO

OH

18 (2 equiv.)

19

(S,S)-linked-BINOL 20

R1 = PhCH2CH2, R2 = H (18a), X = 10: 48 h, y. 81%, syn/anti = 67/33, 78% ee(syn) R1 = PhCH2CH2, R2 = 2-MeO (18f), X = 3: 4 h, y. 94%, syn/anti = 90/10, 90% ee(syn) R1 = PhCH2CH2, R2 = 2-MeO (18f), X = 1: 16 h, y. 94%, syn/anti = 87/13, 93% ee(syn)

Scheme 6.17

Direct catalytic asymmetric aldol reactions of hydroxyketone 18 promoted by Et2 Zn/ (S,S)-linked-BINOL 20 complex.

6.4 Direct Aldol Reaction with a-Hydroxyketones Tab. 6.9

Direct catalytic asymmetric aldol reaction of hydroxyketone 18f promoted by Et2 Zn/ (S,S)-linked-BINOL 20 complexa. Entry

1

Aldehyde

CHO

Ph

2

CHO

3

CHO CHO

4

Product

Time (h)

Yield (%)

dr (syn/ anti)

ee (%) (syn/anti)

1e

19ef

20

94

89/11

92/89

1u

19uf

18

88

88/12

95/91

1j

19jf

18

84

84/16

93/87

1w

19wf

12

91

93/7

95/–

1v

19vf

24

94

86/14

87/92

1x

19xf

18

81

86/14

95/90

1y

19yf

16

84

72/28

96/93

1z

19zf

14

93

84/16

90/84

d

19df

24

83

97/3

98/–

1g

19gf

16

92

96/4

99/–

1c

19cf

18

95

97/3

98/–

O CHO

5

CHO

6

BnO

7

BnO

8

BOMO

9

10

11

CHO CHO

CHO

CHO

CHO

a Reaction

conditions: (S,S)-linked-BINOL 20 (1 mol%), Et2 Zn (2 mol%), 30 C, THF.

1,2-diols in excellent yield and stereoselectivity (yield 81–95%, syn/anti ¼ 72:28 to 97:3, syn ¼ 87–99% ee). Mechanistic investigations by kinetic studies, X-ray crystallography, 1 H NMR, and cold-spray ionization mass spectrometry (CSI-MS) analyses shed light on the reaction mechanism and the structure of the active species [22]. X-ray analysis of a crystal obtained from a 2:1 solution of Et2 Zn/(S,S)linked-BINOL 20 in THF revealed the complex consisted of Zn and ligand 20 in a ratio of 3:2 [trinuclear Zn3 (linked-BINOL)2 thf3 ] with C2 symmetry (Figure 6.7, 21). The CSI-MS analysis and kinetic studies revealed that the complex 21 was a precatalyst and that a oligomeric Zn-20-18f complex would work as the actual active species. The proposed catalytic cycle is shown in Figure 6.8. The product dissociation step is rate-determining.

215

216


Zn(1) Zn(3) Zn(2)

Zn3(linked-binol)2thf3 21 Fig. 6.7

X-ray structure of preformed complex Zn3 (linked-BINOL)2 thf3 21.

O

OMe

Zn3(linked-binol)2 preformed complex Et2Zn

OR

O

enolate formation oligomeric Zn-rich species –H+ (Ar*OZn-20) (I) Ar*OH = ligand 20

OMe

OR R = Zn or H OH O

MeO

slow

OMe

O O Zn

Zn Ar*OH/Zn-enolate (II)

exchange

+H+ protonation

R

Re face RCHO OH 19 H O

H HR

H

O Zn Zn Ar*OH/Zn-alkoxide (IV) MeO

R

1,2-addition Ar

O

Fig. 6.8

Postulated catalytic cycle for the direct aldol reaction with Et2Zn/(S,S)-linked-BINOL 20 complex.

fast

O Zn O (III)

O Zn


aldehyde

(A)

OH O

favored

Re

R

OH (2R,3S)-syn-19 (major)

O O

Zn

OH O

O Zn Si

S

OMe

R

R

disfavored

OMe

R R

OH (2R,3R)-anti-19 (minor)

aldehyde

(B) H

H H

R

R

Ar O Zn O

O

Zn a (favored)

syn-19 (2R,3S)

H

Ar O Zn O

O

anti-19 (2R,3R)

Zn b (disfavored)

Fig. 6.9

Stereochemical course of direct aldol reaction of hydroxyketone 18f.

The identical absolute configuration (R) was obtained at the a-position of both the syn- and anti-aldol products (Figure 6.9), suggesting that the catalyst differentiates the enantioface of the enolate well and aldehydes come from the Re face of the zinc enolate (Figure 6.9A). Syn selectivity is explained by the transition state shown in Figure 6.9B. The positive effects of the ortho MeO group suggested the MeO group coordinated with one of the Zn centers in the oligomeric Zn complex affecting the stereoselection step. The electron-donating MeO group has a beneficial effect on further conversion of the products into esters and amides via regioselective rearrangement as shown in Scheme 6.18 [21, 22]. Mechanistic studies suggested that additional Et2 Zn and MS 3A would accelerate the reaction rate. In the presence of MS 3A the second generation Zn catalyst, prepared from Et2 Zn/linked-BINOL 20 in a ratio of 4:1, promoted the direct aldol reaction of hydrocinnamaldehyde (1e) and 1.1 equiv. ketone 18f, smoothly and with reduced catalyst loading (0.25–0.1 mol%, Scheme 6.19) [22]. The practical utility of the reaction was demonstrated by a large-scale reaction performed on the 200-mmol scale by using 0.25 mol% 1 (0.5 mmol, 307 mg) to afford 53.7 g product 19cf (yield 96%) in high dr (syn/anti ¼ 98:2) and ee (94% ee) after 12 h (Scheme 6.19). Considering that the standard catalyst loading for the direct catalytic asymmetric aldol reaction is 2.5 to 20 mol% the exceptionally low catalyst loading in this asymmetric zinc catalysis is remarkable.

217


218

O

O OH O

OMe O

R

Ph

S

O

O b

O

O

Baeyer-Villiger Ph OMe oxidation

Ph

OH 19ef

O y. 93%

Beckmann rearrangement y. 97% O O

H N

OMe

O

O

a

OH

OMe c

N OH H y. 94% a (a) mCPBA, NaH PO , CICH CH CI, 50 °C, 2h; (b) O-mesitylenesulfonylhydroxylamime, 2 4 2 2 CH2CI, rt, 4 h; (c) DIBAL, –78 °C to rt, 2h. Ph

Ph

O

OMe

Scheme 6.18

Transformations of aldol adduct via regioselective rearrangementa.

Et2 Zn/linked-BINOL 20, 4:1, with MS 3A enabled the direct aldol reaction of 2-hydroxy-2 0 -methoxypropiopheneone (23), leading to construction of a chiral tetrasubstituted carbon stereocenter (Scheme 6.20) [22]. Although a higher catalyst loading and 5 equiv. ketone 23 were required, a variety of a-unsubstituted aldehydes afforded the product syn-selectively (syn/anti ¼ 59:41 to 71:29) in moderate to good yield and ee (yield 72–97%, syn ¼ 72– 87% ee, anti ¼ 86–97% ee) with (S,S)-linked-BINOL 20 (Table 6.10). Interestingly, the reaction using (S,S)-sulfur-linked-BINOL 22, a linked-BINOL analog including sulfur in the linker, instead of oxygen, resulted in the opO CHO

Ph

OMe

+

OH 1e

O

OMe

+

OH 1c 200 mmol

OH O Ph

OMe

R S

OH

MS 3A, THF, –20 °C

18f (1.1 equiv.)

CHO

Et2Zn (4x mol %) (S,S)-linked-BINOL 20 (x mol %)

19ef x = 0.25 mol %, 18 h yield: 90%, syn/anti = 89/11, syn = 96% ee x = 0.1 mol %, 36 h yield: 84%, syn/anti = 89/11, syn = 92% ee

Et2Zn (1 mol %) (S,S)-linked-BINOL 20 (0.25 mol %) MS 3A, THF, –20 °C, 12 h

18f (1.1 equiv.)

yield: 96%, syn/anti = 98/2, syn = 94% ee

Scheme 6.19

Direct catalytic asymmetric aldol reactions of hydroxyketone 18f promoted by Et2 Zn/ (S,S)-linked-BINOL 20 ¼ 4:1 complex with MS 3A.

OH O R S

OH 19cf 53.7 g

OMe

6.5 Direct Aldol Reaction with Glycine Schiff Bases

O RCHO 1

OMe

+

Et2Zn (20 mol %) ligand 20 or 22 (5 mol %)

OH 23 (5 equiv.)

MS 3A, THF, – 30°C

OMe

R OH 24

X=O: (S,S)-linked-BINOL 20 y. 72-97% syn/anti = 59/41–71/29 syn: 68-87% ee, anti: 86–97% ee

X OH HO OH HO

X = O: 20, X = S: 22

OH O

219

X=S: (S,S)-sulfur-linked-BINOL 22 y. 56-82% syn/anti= 41/59–35/65 syn: 45-60% ee, anti: 81–93% ee

Scheme 6.20

Direct catalytic asymmetric aldol reactions of 2-hydroxy-2 0 -methoxypropiophenone (23) promoted by Et2 Zn/(S,S)-linked-BINOL complex.

posite diastereoselectivity (Scheme 6.20). Reactivity with 22 was somewhat lower than that with 20, and aldol adducts were obtained in moderate to good yield (56–82%) on use of 10 equiv. ketone 23. Major anti isomers were obtained in high ee (81–93% ee), although ee of minor syn isomers was rather low (48–60% ee) (Table 6.10).

6.5

Direct Aldol Reaction with Glycine Schiff Bases

Catalytic asymmetric aldol reactions of glycine equivalents with aldehydes afford efficient and direct access to b-hydroxy-a-amino acid derivatives, which serve as useful chiral building blocks, especially in the pharmaceutical industry. A partially successful catalytic asymmetric aldol reaction of a glycine Schiff base was reported by Miller in 1991 [23]. When Nbenzylcinchoninium chloride 26 was used as chiral phase-transfer catalyst, aldol reaction of Schiff base 25 with aldehydes afforded products synselectively (14–56% de) in good yield (46–92%) although ee was at most 12% ee (Scheme 6.21). After that work no efficient artificial catalyst was reported for a decade, except for the chemoenzymatic process with glycinedependent aldolases [2]. In 2002 Shibasaki reported use of the heterobimetallic asymmetric catalyst La3 Li3 (binaphthoxide)3 .LiOH (LLB.LiOH) for anti-selective direct aldol reaction of glycine Schiff bases with aldehydes (Scheme 6.22) [24]. Use of 20 mol% of the catalyst, Schiff base 25b, and aldehydes (3 equiv.) gave the products anti-selectively (anti/syn ¼ 59:41 to 86:14) in moderate to good yield (71–93%) and with moderate ee (anti ¼ 19–76% ee).


220 Tab. 6.10

Direct catalytic asymmetric aldol reaction with 2-hydroxy-2 0 -methoxypropiophenone (23) promoted by Et2 Zn/ (S,S)-linked-BINOL complexa. Entry

1

Aldehyde

Ketone 23 (Equiv.) CHO

Ph

2 3

Ph

CHO

4

Product

Catalyst (Dmol%)

Temp. (˚C)

Yield (%)

dr (anti/ syn)

ee (%) (anti/syn)

1e

5

24e

20 (5)

30

97

62/38

87/96

1e

10

24e

22 (10)

20

82

35/65

60/92

1t

5

24t

20 (5)

30

72

64/36

78/90

10

24t

22 (10)

20

63

41/59

45/86

20 (5)

30

88

71/29

68/86

22 (10)

20

56

41/59

48/87

20 (5)

30

89

59/41

86/95

1t 0

5

24a

6

1a 0

10

24a 0

7

0

5

24b

0

1b 0

10

24b 0

22 (10)

20

73

41/59

58/93

1z

5

24z

20 (5)

30

92

69/31

87/97

1z

10

24z

22 (10)

20

72

39/61

52/81

1j

5

24j

20 (5)

30

80

68/32

72/87

1y

5

24y

20 (5)

30

80

65/35

85/92

5

1a

CHO

CHO

PMBO

8 9

CHO

BOMO

10 11 12

CHO BnO

a Reaction

CHO

1b

0

conditions: Et2 Zn (4 mol%), ligand ( mol%), MS 3A,

THF.

Maruoka recently developed an efficient direct aldol reaction of glycine Schiff base 25a using phase-transfer catalyst (R,R)-29 [25]. The aldol reaction of Schiff base 25a with aldehydes was efficiently promoted by 2 mol% of 29 in toluene–aqueous NaOH (1%) at 0 C to give anti-b-hydroxy-a-amino acids in excellent ee (91–98% ee), moderate to good dr (anti/syn ¼ 1.2:1 to H HO N N N

Ph

CO2-t-Bu

+

Ph 25a

RCHO

1 (5 equiv.)

+ Cl

–

H

OH 26 10 mol %

CH2Cl2/NaOH (2 equiv., 5% w/v) yield: 46-92% de: 14-56% de ee: up to 12% ee

CO2-t-Bu

R N

Ph

27 Ph

Scheme 6.21

Direct catalytic asymmetric aldol reaction of 25a promoted by phase-transfer catalyst 26.

6.6 Other Examples

N

Ar Ar

CO2-t-Bu

i) (S)-LLB (20 mol %) LiOH (18 mol %) H2O (22 mol %), THF, –50 °C + RCHO

25b

1

ii) citric acid, THF-H2O 40 °C 2

221

OH R

CO2-t-Bu NH2

8 R = t-Bu: y. 71% anti/syn = 86/14 anti: 76% ee

Ar = 4-Cl-C6H4 Scheme 6.22

Direct catalytic asymmetric aldol reaction of 25b promoted by heterobimetallic catalyst (S)-LLB.LiOH.

20:1), and in good yield (58–78%) (Scheme 6.23 and Table 6.11). Low catalyst loading, operationally easy reaction conditions (0 C, two-phase reaction), and high ee are noteworthy. Use of (R,R)-29b as catalyst occasionally significantly enhanced both diastereo- and enantioselectivity in this system.

6.6

Other Examples

Morken reported a catalytic asymmetric reductive aldol reaction in which aldehydes and acrylate 30 were converted into chiral syn-a-methyl-b-hydroxy esters under the catalysis of transition metal (Rh and Ir) complexes (Scheme 6.24) [26]. The method provided a means of catalytic synthesis of active

Ph

N Ph

CO2-t-Bu

+ RCHO 1

25a

i) 29a or 29b (2 mol %) toluene/aqueous NaOH (1%), 0 °C, 2 h ii) HCl (1 M)/THF

OH R

CO2-t-Bu

28 NH2 y. 40-78% anti/syn = 1.2/1–20/1 anti: 80-96% ee CF3

F3C

Ar Br–

+ N

CF3 Ar = CF3

CF3 Ar 29a Scheme 6.23

Direct catalytic asymmetric aldol reaction of 25a promoted by chiral phase-transfer catalyst 29 promoted by chiral phasetransfer catalyst 29a.

29b

CF3

222

6 Direct Catalytic Asymmetric Aldol Reaction Using Chiral Metal Complexes Tab. 6.11

Direct catalytic asymmetric aldol reaction of 25aa. Entry

Aldehyde

Product

Catalyst

Yield (%)

dr (anti/ syn)

ee (%) (anti)

1

Ph

1e

28e

29a

76

3.3/1

91

1e

28e

29b

71

12/1

96

1t

28t

29b

65

10/1

91

CHO

1c 0

28c 0

29b

72

20/1

98

CHO

1d 0

28d 0

29b

62

6.3/1

80

6

1d 0

28d 0

29a

71

2.4/1

90

7

1e 0

28e 0

29a

58

2.3/1

92

1c

28c

29a

40

2.8/1

95

1c

28c

29a

78

1.2/1

93

CHO

2 3

CHO

4

TIPSO

5

CH3CHO CHO

8 9b a Reaction

conditions: catalyst 29 (2 mol%), toluene/aqueous NaOH (1%), 0 C, 2 h. b Use of dibutyl ether as solvent.

[(cod)RhCl]2 (2.5 mol %) (R)-BINAP (6.5 mol %) Et2MeSiH (1.2 equiv.)

O 1

R CHO + 1

OPh

CHO + 1

OR2 30 (1.2 equiv.)

dichloroethane rt, 24 h

PPh2 PPh2

OPh

31 yield: 48-82% (R)-BINAP syn/anti = 1.8/1-5.1/1 syn = 45-88% ee, anti = 7-99% ee

[(cod)IrCl]2 (2.5 mol %) indane-pybox 32 (7.5 mol %) Et2MeSiH (1.2 equiv.)

O R1

R

dichloroethane rt, 24 h

30 (1.2 equiv.)

OH O

OH O O R

OR'

31 yield: 47-68% syn/anti = 2.7/1-9.9/1 syn = 82-96% ee

Scheme 6.24

Catalytic asymmetric reductive aldol reactions promoted by Rh–(R)-BINAP complex and Ir-32 complex.

O

N N

N 32

6.6 Other Examples Tab. 6.12

Catalytic asymmetric reductive aldol reaction promoted by Ir-32 complexa. Entry

Aldehyde

1b

PhCHO

2

BnO

CHO

3c 4

TBSO

5

BnO

CHO CHO

RO

Yield (%)

dr (syn/ anti)

ee (%) (syn)

1n

Et

68

6.6/1

94

1y

Me

49

9.9/1

96

1y

Me

59

9.5/1

96

1f 0

Me

47

8.2/1

96

1x

Me

65

2.7/1

82

a Reaction

conditions: [(cod)lrCl]2 (2.5 mol%), 32 (7.5 mol%), Et2 MeSiH (2 equiv.), rt, 24 h. b [(coe)lrCl] was used instead of [(cod)lrCl] . 2 2 c Reaction carried out on 35 mmol scale with 1 mol% [(cod)lrCl] and 2 3 mol% of 32.

enolate species from unmodified substrates. Combination of 2.5 mol% [(cod)RhCl]2 and 6.5 mol% (R)-BINAP promoted the reductive aldol reaction between aldehydes 1 and phenyl acrylate (30) in the presence of Et2 MeSiH at room temperature to afford a diastereomixture (syn/anti ¼ 1.7:1 to 5.1:1) of b-hydroxy esters 31 in good to moderate yield (48–82%) and ee (45–88% ee) [26a]. The stereoselectivity was improved by using the Ir complex derived from [(cod)IrCl]2 and indane-pybox 32, affording the product synselectively (up to 9.9:1) in high ee (up to 96% ee). The results obtained with Ir-32 are summarized in Table 6.12 [26b]. Use of H2 gas as reducing reagent instead of silanes was recently reported by Krische in an achiral reductive aldol reaction [27]. Evans reported a direct catalytic diastereoselective aldol reaction of Nacyloxazolidinones 33. In the presence of a catalytic amount of Mg salt (10 mol%) stoichiometric amounts of Et3 N (2 equiv.) and (CH3 )3 SiCl (1.5 equiv.) the enolate species was generated in situ and anti-aldol adducts were obtained in excellent stereoselectivity (yield 36–92%, dr 3.5:1 to 32:1; Scheme 6.25) [28a]. Stoichiometric amounts of silylating regents were essential to achieve efficient catalyst turnover. Because mechanistic study revealed that the reaction does not involve an enol silyl ether as an intermediate, a Mukaiyama-type reaction pathway was reasonably excluded. By using N-acylthiazolidinethiones 35 instead of 33 the aldol adducts were obtained with different stereoselectivity [28b]. MgBr2 aOEt2 (10 mol%) afforded the best results for 35 (Scheme 6.25). anti-Aldol adducts were obtained in excellent selectivity (yield 56–93%, dr 7:1 to 19:1). Catalytic asymmetric variants of these reactions on the basis of the Mg catalysis seem promising.

223


224

O O

O N R1 Bn 33

S S

+ R2CHO (1.1 equiv.) 1

O N R1 Bn 35

+ R2CHO (1.1 equiv.) 1

1) MgCl2 (10 mol %) (CH3)3SiCl (1.5 equiv.) Et3N (2 equiv.)

O O

OH

O

R2

N R1

EtOAc, 23 °C, 24 h 2) H+

34 Bn y. 36-94%, dr 3.5/1-32/1 dr ratio = (desired isomer)/Σ other isomers

1) MgBr2•OEt2 (10 mol %) (CH3)3SiCl (1.5 equiv.) Et3N (2 equiv.)

O O

EtOAc, 23 °C, 24 h 2) H+

OH

O

R2

N R1

36 Bn y. 56-93%, dr 7/1-19/1 dr ratio = (desired isomer)/Σ other isomers

Scheme 6.25

Direct catalytic diastereoselective aldol reactions promoted by Mg salts.

Shair recently reported an achiral direct aldol reaction starting from malonic acid half thioester 37 (Scheme 6.26). The active enolate species were generated under extremely mild conditions with Cu catalysis. Development of a direct catalytic asymmetric aldol reaction on the basis of this strategy is also promising [29].

6.7

Conclusion

Representative examples of direct catalytic asymmetric aldol reactions promoted by metal catalysis have been summarized. The field has grown rapidly during past five years and many researchers have started to investigate this ‘‘classical’’ yet new field using metal catalysts and organocatalysts. Application of these systems to direct Mannich reactions and Michael reactions has also been studied intensively recently. Further investigations will be needed to overcome problems remaining with regard to substrate generality, reaction time, catalyst loading, volumetric productivity, etc. The development of a direct catalytic asymmetric aldol reaction with unmodified esters as a donor is particularly required. O

O

BnS OH 37 (1 equiv.)

+ RCHO 1 (1 equiv.)

Cu(2-ethylhexanoate)2 (20 mol %) N

OMe

N (22 mol %) H wet THF, air, 23 °C, 2-24 h Scheme 6.26

Catalytic thioester aldol reactions prompted by Cu(II) salt.

O BnS

OH R

38 y. 22-97%

+ CO2

6.8 Experimental Section

6.8

Experimental Section Procedure for the Preparation of (S)-LLB Complex. A solution of La(O-i-Pr)3 (20.4 mL, 4.07 mmol, 0.2 m in THF, freshly prepared from La(O-i-Pr)3 powder and dry THF) was added to a stirred solution of (S)-binaphthol (3.50 g, 12.2 mmol) in THF (39.7 mL) at 0 C. (La(O-i-Pr)3 was purchased from Kojundo Chemical Laboratory, 5-1-28 Chiyoda, Sakado-shi, Saitama 350-0214, Japan; Fax: þ81-492-84-1351). The solution was stirred for 30 min at room temperature and the solvent was then evaporated under reduced pressure. The resulting residue was dried for 1 h under reduced pressure (ca. 5 mmHg) and dissolved in THF (60.5 mL). The solution was cooled to 0 C and n-BuLi (7.45 mL, 12.2 mmol, 1.64 m in hexane) was added. The mixture was stirred for 12 h at room temperature to give a 0.06 m solution of (R)-LLB which was used to prepare (S)-LLB–KOH catalyst. General Procedure for Direct Catalytic Asymmetric Aldol Reactions of Methyl Ketone 2 Using (S)-LLB–KOH. A solution of water in THF (48.0 mL, 0.048 mmol, 1.0 m) was added to a stirred solution of potassium bis(trimethylsilyl)amide (KHMDS, 43.2 mL, 0.0216 mmol, 0.5 m) in toluene at 0 C. The solution was stirred for 20 min at 0 C and then (S)-LLB (400 mL, 0.024 mmol, 0.06 m in THF, prepared as described above) was added and the mixture was stirred at 0 C for 30 min. The resulting pale yellow solution was cooled to 20 C and acetophenone (2a) (175 mL, 1.5 mmol) was added. The solution was stirred for 20 min at this temperature then 2,2-dimethyl-3-phenylpropanal (1b) (49.9 mL, 0.3 mmol) was added and the reaction mixture was stirred for 28 h at 20 C. The mixture was then quenched by addition of 1 m HCl (1 mL) and the aqueous layer was extracted with ether (2 10 mL). The combined organic layers were washed with brine and dried over Na2 SO4 . The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2 , ether–hexane 1:12) to give 3ba (72 mg, 85%, 89% ee). General Procedure for Direct Catalytic Asymmetric Aldol Reaction of Methyl Ketone 2 Using Dinuclear Zn2 -13. The prepare the catalyst a solution of diethyl zinc (1 m in hexane, 0.2 mL, 0.2 mmol) was added to a solution of ligand 13 (64 mg, 0.1 mmol) in THF (1 mL) at room temperature under an argon atmosphere. After stirring for 30 min at the same temperature, with evolution of ethane gas, the resulting solution (ca. 0.09 m) was used as catalyst for the aldol reaction. To perform the aldol reaction a solution of the catalyst (0.025 mmol) was added, at 0 C, to a suspension of aldehyde (0.5 mmol), triphenylphosphine sulfide (22.1 mg, 0.075 mmol), powdered 4 A˚ molecular sieves (100 mg, dried at 150 C under vacuum overnight), and ketone 2 (2.5 or 5 mmol) in THF (0.8 mL). The mixture was stirred at 5 C for 2 days then poured on to

225

226


1 m HCl and extracted with ether. After normal work-up, the crude product was purified by silica gel column chromatography. General Procedure for Catalytic Asymmetric Aldol Reaction of Hydroxyketone 18f Promoted by Et2 Zn/(S,S)-linked-BINOL, 4:1, with MS 3A. MS 3A (200 mg) in a test tube was activated before use under reduced pressure (ca. 0.7 kPa) at 160 C for 3 h. After cooling, a solution of (S,S)-linked-BINOL (1.53 mg, 0.0025 mmol) in THF (0.6 mL) was added under Ar. The mixture was cooled to 20 C and Et2 Zn (10 mL, 0.01 mmol, 1.0 m in hexanes) was added to the mixture at this temperature. After stirring for 10 min at 20 C, a solution of 18f (182.8 mg, 1.1 mmol) in THF (1.1 mL) was added. Aldehyde 1e (1.0 mmol) was added and the mixture was stirred at 20 C for 18 h and then quenched by addition of 1 m HCl (2 mL). The mixture was extracted with ethyl acetate and the combined organic extracts were washed with sat. aqueous NaHCO3 and brine and dried over MgSO4 . Evaporation of the solvent gave a crude mixture of the aldol products. The diastereomeric ratios of the aldol products were determined by 1 H NMR of the crude product. After purification by silica gel flash column chromatography (hexane– acetone 8:1 to 4:1), 19ef was obtained (269.6 mg, 0.898 mmol, yield 90%, dr syn/anti ¼ 89:11, 96% ee (syn)). General Procedure for Catalytic Asymmetric Aldol Reaction of Glycine Schiff Base 25a Promoted by Phase-transfer Catalyst 29. Aqueous NaOH (1%, 2.4 mL) was added at 0 C, under Ar, to a solution of Schiff base 25a (88.6 mg, 0.3 mmol) and (R,R)-29b (9.9 mg, 2 mol%) in toluene (3 mL). Aldehyde 1e (79 mL, 0.6 mmol) was then introduced dropwise. The whole mixture was stirred for 2 h at 0 C, and water and diethyl ether were then added. The ether phase was isolated, washed with brine, dried over Na2 SO4 , and concentrated. The crude product was dissolved in THF (8 mL) and treated with HCl (1 m, 1 mL) at 0 C for 1 h. After removal of THF in vacuo the aqueous solution was washed three times with diethyl ether and neutralized with NaHCO3 . The mixture was then extracted three times with CH2 Cl2 . The combined extracts were dried over MgSO4 and concentrated. After purification by silica gel column chromatography (CH2 Cl2 aMeOH 15:1) 28e was obtained (56.8 mg, 0.214 mmol, yield 71%, dr anti/syn ¼ 12:1, 96% ee (anti)).

References and Notes 1 Recent review: C. Palomo, M. Oiarbide, J. M. Garcıá, Chem.

Eur. J. 2002, 8, 37. 2 Review: T. D. Machajewski, C.-H. Wong, Angew. Chem. Int.

Ed. 2000, 39, 1352. 3 Recent review for the direct catalytic asymmetric aldol

References and Notes

4 5 6 7 8 9

10 11 12 13

14 15 16

17 18 19

20 21 22

23 24 25 26

27 28

29

reactions: B. Alcaide, P. Almendros, Eur. J. Org. Chem. 2002, 1595. Review: M. Sawamura, Y. Ito, Chem. Rev. 1992, 92, 857. Review: B. List, Tetrahedron 2002, 58, 5573. Y. M. A. Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Angew. Chem. Int. Ed. Engl. 1997, 36, 1871. K. Fujii, K. Maki, M. Kanai, M. Shibasaki, Org. Lett. 2003, 5, 733. N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1999, 121, 4168. (a) D. Sawada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 10521; (b) D. Sawada, M. Shibasaki, Angew. Chem. Int. Ed. 2000, 39, 209. Y. M. A. Yamada, M. Shibasaki, Tetrahedron Lett. 1998, 39, 5561. B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003. B. M. Trost, E. R. Silcoff, H. Ito, Org. Lett. 2001, 3, 2497. T. Suzuki, N. Yamagiwa, Y. Matsuo, S. Sakamoto, K. Yamaguchi, M. Shibasaki, R. Noyori, Tetrahedron Lett. 2001, 42, 4669. N. Yoshikawa, M. Shibasaki, Tetrahedron 2001, 57, 2569. R. Mahrwald, B. Ziemer, Tetrahedron Lett. 2002, 43, 4459. (a) W. Notz, B. List, J. Am. Chem. Soc. 2000, 122, 7368; (b) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas, III, J. Am. Chem. Soc. 2001, 123, 5260. B. M. Trost, H. Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123, 3367. B. M. Trost, V. S. C. Yeh, Org. Lett. 2002, 4, 3513. N. Yoshikawa, N. Kumagai, S. Matsunaga, G. Moll, T. Ohshima, T. Suzuki, M. Shibasaki, J. Am. Chem. Soc. 2001, 123, 2466. N. Yoshikawa, T. Suzuki, M. Shibasaki, J. Org. Chem. 2002, 67, 2556. N. Kumagai, S. Matsunaga, N. Yoshikawa, T. Ohshima, M. Shibasaki, Org. Lett. 2001, 3, 1539. N. Kumagai, S. Matsunaga, T. Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 2169. C. M. Gasparski, M. J. Miller, Tetrahedron 1991, 47, 5367. N. Yoshikawa, M. Shibasaki, Tetrahedron 2002, 58, 8289. T. Ooi, M. Taniguchi, M. Kameda, K. Maruoka, Angew. Chem. Int. Ed. 2002, 41, 4542. (a) S. J. Taylor, M. O. Duffey, J. P. Morken, J. Am. Chem. Soc. 2000, 122, 4528. (b) C.-X. Zhao, M. O. Duffey, S. J. Taylor, J. P. Morken, Org. Lett. 2001, 3, 1829. Achiral reaction: (c) S. J. Taylor, J. P. Morken, J. Am. Chem. Soc. 1999, 121, 12202. H.-Y. Jang, R. R. Huddleston, M. J. Krische, J. Am. Chem. Soc. 2002, 124, 15156. (a) D. A. Evans, J. S. Tedrow, J. T. Shaw, C. W. Downey, J. Am. Chem. Soc. 2002, 124, 392. (b) D. A. Evans, C. W. Downey, J. T. Shaw, J. S. Tedrow, Org. Lett. 2002, 4, 1127. G. Lalic, A. D. Aloise, M. D. Shair, J. Am. Chem. Soc. 2003, 125, 2852.

227

229

7

Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases Scott E. Denmark and Shinji Fujimori 7.1

Introduction 7.1.1

Enantioselective Aldol Additions

The aldol addition reaction is one of the most powerful carbon–carbon bond-construction methods in organic synthesis and has achieved the exalted status of a ‘‘strategy-level reaction’’. The generality, versatility, selectivity, and predictability associated with this process have inspired many reviews and authoritative summaries and constitute the theme of this treatise [1]. The primary objective in the evolution of the aldol addition is the striving for exquisite diastereo- and enantioselectivity from readily available enolate precursors. The ideal aldol reaction would provide selective access for all four isomers of the stereochemical dyad that make up the aldol products. This has given way to more ambitious investigation of the triads and tetrads that accrue from double and triple diastereoselection processes [2]. The solutions to these challenges have been imaginative and diverse, and have pioneered the contemporaneous development of asymmetric synthesis as a core discipline. A secondary and more recent objective is the development of ‘‘direct aldol additions’’ that mimic enzymatic processes (aldolases) and obviate the independent activation of the nucleophilic partner. The number and variety of inspired and elegant solutions for perfecting the aldol addition are expertly described in the accompanying chapters of this volume. This chapter differs somewhat, however, in that it describes a conceptually distinct process that has been designed to address some of the shortcomings inherent in the more classic approaches involving chiral Lewis acid catalysis of aldol addition in its many incarnations. Thus, to assist the reader in understanding the distinctions and to provide the conceptual framework for invention of Lewis-base-catalyzed addition, the introduction will outline briefly the stereocontrolling features of the main families Modern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

230

7 Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases

Ph

O Me

O HO

Ph Ph

OH

1. LDA / THF / −78 °C 2. MgBr2 3. Aryl

CO2Me

Aryl 94% ee

CHO

4. NaOMe Me

Me

Me O N

S O2

Me O

1. LICA / THF −78 °C Me 2. PhCHO

N S O2

O

OH Ph

OH

+ Χ∗N

Ph Me

Me 85 / 8 / 7 (anti)

Scheme 7.1

Aldol additions with chirally modified lithium enolates.

of enantioselective aldol additions and thus, the basis for inventing a new process. Background Early examples of asymmetric aldol addition reactions involved lithium enolates of chiral carbonyl compounds that reacted with aldehydes to give good diastereoselectivity [3]. The chirality of the enolate translated to enantiomerically enriched products when the auxiliaries were destroyed or removed. Thus, using enolates of modified ketones [3a], esters [3b], and sulfonamides [3c], high enantioselectivity and diastereoselectivity can be achieved if enolates are generated in geometrically defined form (Scheme 7.1). Although high selectivity is obtained, these reactions are not practical because they require stoichiometric amounts of covalently bound auxiliaries. In addition, the high reactivity of the lithium enolates did not ensure reaction via closed, organized transition structures, a feature crucial for stereochemical information transfer. A revolutionary advance in aldol technology was the use of less reactive metalloenolates (boron [4a], titanium [4b–d], and zirconium [4d]) that organize the aldehyde, enolate, and auxiliary in a closed transition structure (Scheme 7.2). Although these reagents are similar to those described above in that an auxiliary is needed in stoichiometric amounts, the use of boron and titanium enolates enable attachment of the modifier by an acyl linkage or directly around the metal of the enolate. Geometrically defined enolates react with aldehydes to give the syn or anti diastereomers with high enantiomeric excess. This variant is best exemplified by the acyl oxazolidinone boron enolates [1a], the diazaborolidine derived enolates [5], titanium enolates derived from diacetone glucose [6], the diisiopinylcampheyl boron enolates for ketone aldolizations [2c], and proline-derived silanes for N,Oketene acetals [7]. 7.1.1.1

7.1 Introduction

O

O

Ln*M

MLn

R1CHO

O

or

H 3C

X R*

X

R

O

OH R1 or

RX

OH

RX

R1

CH3

CH3

231

syn

CH3

anti

Ph

n-Bu O H 3C

n-Bu B N

O O

Bn

SO2Aryl N Ph B diacetone glucoseO Ti N O O diacetone glucoseO ArylO2S RO XR CH3

CH3

CH3 B R

N

O CH3

CH3

O O Si

CH3

Scheme 7.2

Chirally modified boron, titanium, and silicon enolates.

The key stereocontrolling features common to these agents are:

. the organizational role of the metal center; . the close proximity of the electrophile, nucleophile and asymmetric mod.

ifier in coordination sphere of the metal assuring high stereochemical information transfer, and the high stereochemical influence of enolate geometry on product diastereoselectivity.

The major disadvantage of these variants is the inability to operate catalytically. Indeed, it is the high metal affinity of the aldehyde, enolate, and chiral auxiliary that interferes with the turnover. Catalytic processes have, over the past decade, dominated the development of enantioselective aldol addition reactions [1j,k]. This category can be subdivided into five main classes:

. chiral-Lewis-acid-catalyzed aldol additions of silicon or tin enol ethers aldol addition); . (Mukaiyama in-situ generated metalloenolates from silicon or tin enol ethers; . in-situ generated metalloenolates directly from ketones; . in-situ generated enolate equivalents (enamines) directly from carbonyl and . compounds; enzyme- and antibody-catalyzed aldol additions.


232

Me3SiO CH3 +

RX

R1

O

MXn*

O

R1

RX H

NH

O

Me Aryl N OH

O

MeO

Fe

N

H PPh2

Me

NMe2 Me O N

OMe PPh2

[Sn(OTf)2 / n-Bu3SnF]

R1 CH3

CO2H

HO2C

OH

+ RX

CH3

OH N Me

O

OH

[BH3]

[Ti(Oi-Pr)4]

[Au(I)]

Me O N t--Bu

t--Bu

[Cu(II)]

Scheme 7.3

Representative metal-based chiral Lewis acids.

The first three only will be discussed in the context of the origins of stereoinduction. The use of chiral Lewis acids [8] has received by far the most attention and is amply discussed in the many chapters dedicated to various metals in this volume. Some of the more commonly used and selective chiral Lewis acids are shown here, for example diamine complexes of tin(II) triflate [9], borane complexes of a monoester of tartaric acid (CAB catalysts) [10], sulfonamido amino acid borane complexes [11], titanium binaphthol [12] and binaphthylimine complexes [13], ferrocenylphosphine–gold [5d] and BINAP– silver [14] complexes, and copper(II) bisoxazoline and pyridyl(bisoxazoline) complexes [15], (Scheme 7.3). These variants of the aldol reaction have several key features in common:

. the additions have been demonstrated for aldehydes and enol metal dewith sub-stoichiometric loading of the chiral Lewis acid; . rivatives the diastereo- and enantioselectivity are variable although they can be and . high; these reactions are not responsive to prostereogenic features – when the configuration of the enolsilane nucleophile changes, the diastereoselectivity of the product does not change [16]. In these reactions, the metal center is believed to activate the aldehyde to addition and the enol addition subject primarily to steric approach control, i.e. it is lacking the pre-organization associated with the stoichiometric aldol addition reactions of the boron and titanium enolates. This problem has been addressed in part by the recently developed class of aldol additions that involve the use of chirally modified metalloids in a catalytic process [17]. In these reactions it is proposed a metal–phosphine

7.1 Introduction

complex undergoes transmetalation with TMS enol ethers or tributylstannyl ketones to provide chiral metalloid enolates in situ. The aldol addition then proceeds, with turnover of the metalloid species to another latent enol donor. In addition, in the third class the metalloenolate is generated in situ from either heterobimetallic (lanthanide/alkali metals) or chiral zinc phenoxide complexes and promotes the addition of unmodified ketones to aldehydes [18]. In these reactions it is postulated that the aldehyde is coordinated to the metal after generation of the metalloenolate. However, because the enolates are generated in situ, the enolate geometry is not known and geometry has not been correlated with product configuration. Despite the power and clear synthetic applicability of these families, deficiencies are still apparent:

. lack of a catalytic variant of the boron or titanium enolate family; and . lack of controllable selectivity in the chiral Lewis acid family. Lewis base-activation provides a mechanism enabling devising of a class of aldol addition that addresses these concerns. This chapter describes, in detail, the formulation, development, and understanding of a Lewis-basecatalyzed aldol reaction process that embodies both the selectivity and versatility of the stoichiometric reactions in combination with the efficiency of the catalytic methods. 7.1.2

Lewis Base Catalysis

The design criteria for Lewis basic catalysis of the aldol addition are outlined in Figure 7.1. This approach differs from Lewis acid catalysis of aldol addition in that it postulates activation of the enoxymetal derivative by preassociation with a chiral Lewis basic (LB) group bearing a non-bonding pair of electrons. This complex must be more reactive than the free enolate for ligand accelerated catalysis to be observed [19]. Next, association of this -ate complex with the Lewis basic carbonyl oxygen of the aldehyde produces a hyper-reactive complex in which the metal has expanded its valence by two. It is expected that this association complex between enolate, aldehyde, and the chiral Lewis basic group reacts through a closed-type transition structure to produce the metal aldolate product. For turnover to be achieved the aldolate must undergo the expulsion of the LB group with formation of the chelated metal aldolate product. Thus, Lewis base-catalysis involves simultaneous activation of the nucleophile and the electrophile within the coordination sphere of the metal. The reaction must occur in a closed array and be capable of releasing the activating group by chelation or change in the Lewis acidity. To realize this process selection of the appropriate enoxymetal and activator moieties is crucial. For the metal, the MXn subunit must be able expand

233

234


O

Xn M *

O

O

MXn

LB (Lewis basic promoter)

* R

turnover event rapid

LB

LB MXn O O * * R

O

MXn

more reactive than free enolate

LB reaction through closed TS

O

MXn O H

O R

H

R

Fig. 7.1

Hypothetical catalytic cycle for Lewis-base-catalyzed aldol addition.

its valence by two and balance the nucleophilicity of the enolate with electrophilicity to coordinate both the Lewis basic aldehyde and the chiral LB group. To impart sufficient Lewis acidity to that metal group and accommodate the valence expansion such that two Lewis basic atoms may associate, the ligands (X) should be small and strongly electron-withdrawing. The criteria necessary for the chiral Lewis basic group LB are that it must be able to activate the addition without cleaving the OaMXn linkage and provide an effective asymmetric environment. Candidates for the Lewis basic group include species with high donicity properties as reflected in solvent basicity scales [20]. The inspiration to propose the possibility of nucleophilic catalysis of aldol additions and guide selection of the appropriate reaction partners is found in the cognate allylation process by allyl- and 2-butenyltrichlorosilanes. Inspired by the pioneering observations of Sakurai [21] and Kobayashi [22] that allyltrihalosilanes can be induced to add to aldehydes in the presence of nucleophilic activators (fluoride ion or DMF solvent) it was first shown in 1994 that chiral Lewis bases (phosphoramides) are capable of catalyzing the addition of allyltrichlorosilanes [23]. Thus, by analogy, reducing this plan to practice required the invention of a new class of aldol reagent, trichlorosilyl enolates, in conjunction with one of the most Lewis basic neutral functional groups, the phosphoramide group, Figure 7.2. Trichlorosilyl enolates of esters had been reported in the literature [24] and (because of the electronwithdrawing chloride ligands on silicon) were expected to be highly electro-

7.1 Introduction

LB MXn O O

H

O

SiCl3

R1

R1 N O P R2 N N 2 R1 R

Fig. 7.2

Reaction components required for chiral Lewis-base-catalyzed aldol addition.

philic and thus able to stabilize the hypercoordinate silicon species necessary in such a process. The phosphoramides can be seen as chiral analogs of HMPA the Lewis basicity of which is well documented [20], especially toward silicon-based Lewis acids [25]. 7.1.3

Organization of this Chapter

On the basis of the design criteria outlined above, the first, chiral-Lewisbase-catalyzed, enantioselective aldol addition was reported in 1996 [26]. This disclosure, which reported the reaction of the trichlorosilyl enolate of methyl acetate with a variety of aldehydes in the presence of several chiral phosphoramides, was significant not so much for the results obtained (enantioselectivity was modest 20 to 62% ee) but rather as a proof of principle for this conceptually new approach to the aldol addition reaction (Scheme 7.4). This early success launched a broad-ranging program on the scope, synthetic application, and mechanistic understanding of chiral Lewis base catalysis of the aldol addition. A chronological recounting of the evolution of this program has already appeared [27]. For this chapter, a more comprehensive treatment of the various components of the process is presented, and thus, a more structurally based organization is employed. The main section begins with the preparation of the two new reaction components, namely the enoxytrichlorosilanes of ester, ketones, and aldehydes and the chiral Lewis basic catalysts (phosphoramides and N-oxides). Me N O P N N Ph Me 10 mol % Ph

OSiCl3 OMe

O + R

H

CH2Cl2, −78 °C 30 min - 3 h

HO R

O OMe

R = Ph, 87%, er 2.0/1 R = t-Bu, 78%, er 2.3/1

Scheme 7.4

The first enantioselective, chiral-Lewis-base-catalyzed aldol addition.

235

236


The bulk of the chapter is dedicated to describing the diversity of enolate structural subtypes in order of increasing structural complexity. Beginning with trichlorosilyl enolates of simple achiral methyl, ethyl, and cyclic ketones the survey then addresses chirally modified enolates of ketones and the phenomenon of double (1,n)-diastereoinduction. The next sections outline the use of trichlorosilyl enolates derived from aldehydes and esters and the features unique to these structures. The final preparative section is dedicated to the newest variation on the theme, namely, the use of chiral Lewis bases to activate simple, achiral Lewis acids for enantioselective aldolization. To facilitate more fundamental understanding of the development of the reaction variants, the chapter ends with an overview of the current mechanistic picture. Although this aspect is still evolving, the basic features are well in hand and enable integrated understanding of the behavior of trichlorosilyl enolates under these conditions. Representative procedures for all the asymmetric processes described herein are provided at the end of the chapter.

7.2

Preparation of Enoxytrichlorosilanes

Silyl enol ethers (enoxysilanes) derived from carbonyl compounds are among the most important reagents in synthetic organic chemistry, because of their ability to form carbon–carbon bonds when combined with a myriad of carbon electrophiles [28]. The first silyl enol ethers, reported in 1958, were obtained by hydrosilylation of unsaturated carbonyl compounds (Scheme 7.5) [29]. Since then silyl enol ethers have become particularly versatile synthetic intermediates, and a number of reviews on preparation and reactions of these compounds have appeared [30]. The synthetic utility of enoxysilanes was not fully recognized until pioneering work by Mukaiyama on Lewis acid-catalyzed aldol additions of trimethylsilyl enol ethers to different carbonyl compounds (Scheme 7.6) [31]. The physical properties of simple enoxytrialkylsilanes were thoroughly investigated by Baukov and Lutsenko [30d]. Unlike conventional metal enolates, enoxytrialkylsilanes are stable and isolable covalent species. These

O + H

Et3SiH

cat. H2PtCl6 i -PrOH, reflux

O SiEt3

Me H

1 (62%) Scheme 7.5

First reported synthesis of a silyl enol ether.

7.2 Preparation of Enoxytrichlorosilanes

OTMS +

PhCHO

1. TiCl4 (1.1 equiv) CH2Cl2, −78oC 2. H2O

O

O

OH Ph

syn-2 (69%)

+

OH Ph

anti-2 (23%)

Scheme 7.6

Application of a silyl enol ether in a directed aldol addition.

species can be stored under non-acidic conditions for a long period of time but can also can be readily hydrolyzed to the parent carbonyl compounds under acidic conditions. Trialkylsilyl enol ethers were originally introduced as precursors for regioisomerically-defined metal enolates. As enol derivatives they have reasonable nucleophilicity, although the most common use of these reagents involved regeneration of the metal enolate under basic conditions followed by reaction with electrophiles [30]. The nucleophilicities of a variety of enoxytrialkylsilanes have recently been correlated with other nucleophiles by Mayr [32]. The established order indicates that the nucleophilicity of enoxytrialkylsilanes is greater than that of allylic trialkylsilanes and less than that of commonly used enamines. Mayr also showed that silyl ketene acetals are much more nucleophilic than silyl enol ethers. Trialkylsilyl enol ethers are extensively utilized in chiral Lewis acidcatalyzed stereoselective aldol additions [33]. On the other hand, silyl enol ethers with other groups on the silicon have been less widely applied in synthesis [34]. Heteroatom-functionalized silyl enol ethers can be prepared by methods similar to those used to prepare their trialkylsilyl counterparts (Scheme 7.7). Walkup and coworkers reported a convenient procedure for syntheses of a variety of non-alkyl-substituted enoxysilanes such as 4 and 5 [34a]. Hydrosilylation of a,b-unsaturated carbonyl compounds is also a viable method for preparation of such enoxysilanes [35]. Although a variety of silicon-functionalized silyl enol ethers have appeared in the literature, their application in synthetically useful reactions is still limited. A recent exception disclosed by Yamamoto and coworkers is a Lewis-acid-catalyzed enantioselective aldol reaction of an enoxy(trimethoxy)silane (Scheme 7.8) [36]. Because development of an effective Lewis-base-catalyzed aldol addition required access to electrophilic enolates, the preparation, properties and reactivity of enoxytrichlorosilanes became important areas of investigation. Pioneering studies by Baukov et al. ensured the possibility of generating trichlorosilyl ketene acetals, but it was subsequent studies by Denmark et al. that elevated these and related species to the status of useful synthetic reagents [30d, 37].

237

238


O

Me Me Si O Cl

Li Me2SiCl2

t-Bu

Et2O

t-Bu

Me Me Si O OEt

EtOH, Et3N t-Bu

Et2O 4

3

O +

HSi(OEt)3

5 (79%) OSi(OEt)3

[Rh(OH)(cod)]2 (0.15 mol%) THF

6 (>99%) Scheme 7.7

Preparation of silicon-functionalized silyl enol ethers.

7.2.1

General Considerations

Trichlorosilyl enolates (enoxytrichlorosilanes) are typically viscous oils and can be obtained in the pure form by simple distillation. These silyl enolates can be stored under anhydrous conditions at low temperature for an appreciable time without decomposition. Exclusion of moisture is essential when working with trichlorosilyl enolates. Trace amounts of water leads to hydrolysis of the chlorosilane unit, and the resulting HCl is deleterious to the trichlorosilyl enolate. Degradation of the trichlorosilyl enolates can also be initiated by trace impurities such as metal salts and ammonium salts which promote formation of di- and polyenoxysilane species [37]. The thermal stability of trichlorosilyl enolates depends on their structure. For ketone- and aldehyde-derived trichlorosilyl enolates the O-silyl and Csilyl isomerism strongly favors the O-silyl species [37]. Although ketoneand aldehyde-derived trichlorosilyl enolates can be heated to 140 C, trichlorosilyl enolates can disproportionate into dienoxysilanes and silicon tetrachloride at higher temperatures [37]. On the other hand, trichlorosilyl ketene acetals are not as thermally stable as the other trichlorosilyl enolates O

OSi(OMe)3 8 (10 mol %) +

PhCHO

OH Ph 8=

MeOH, −78 oC 7

2 (78%) syn/anti , 5.3/1 er(syn), 14/1 Scheme 7.8

Asymmetric aldol addition of a trialkoxysilyl enol ether.

Ar Ar P Ag F P Ar Ar Ar = p-tolyl


IR (C=C): 1659 cm-1 H NMR (ppm) E-HC(2): 4.42 (s) Z-HC(2): 4.55 (d) 13 C NMR (ppm) C(1): 152.62 C(2): 96.94

1

Cl3Si Me

O HZ

1

2

HE

9

Cl3Si Et

1

O Me

1

2

H (Z )-11

H NMR (ppm) HC(2): 5.01 (qt) 13 C NMR (ppm) C(1): 150.54 C(2): 105.18

Cl3Si

O

MeO

HZ

1

2

HE 10

Cl3Si Et

1

O 1

H 2

Me (E )-11

1

Cl3Si

O

H

1

Me 2

H (Z )-12

H NMR (ppm) HC(1): 6.25 (qd) HC(2): 4.95 (dq) 13 C NMR (ppm) C(1): 136 C(2): 112

IR (C=C): 1672 cm-1 NMR (ppm) E-HC(2): 3.41 (s) Z-HC(2): 3.65 (s) 13 C NMR (ppm) C(1): 152.62 C(2): 96.94

1H

H NMR (ppm) HC(2): 5.13 (qt) 13 C NMR (ppm) C(1): 150.54 C(2): 105.90 1

Cl3Si H

O 1

H 2

Me (E )-12

H NMR (ppm) HC(1): 6.27 (qd) HC(2): 5.40 (dq) 13 C NMR (ppm) C(1): 135 C(2): 111

Fig. 7.3

Spectroscopic properties of enoxytrichlorosilanes.

and tend to isomerize to the corresponding carbon-bound, a-trichlorosilyl esters upon heating [37]. Distillation of these reagents should therefore be performed under vacuum at a temperature as low as possible. The spectroscopic properties of several enoxytrichlorosilanes are summarized in Figure 7.3 [37, 38]. The 1 H NMR chemical shifts of the vinylic protons in enoxytrichlorosilanes are usually higher than those of the corresponding trimethylsilyl enol ethers. The vinylic protons for (E)- and (Z)-11 derived from ethyl ketones are sufficiently different that the E/Z ratios for these enolates are readily obtained by 1 H NMR analysis. The vinylic proton for the E enolate is typically found at lower field than for the corresponding Z enolate. In the aldehyde-derived enoxytrichlorosilane the former aldehydic proton appears above 6 ppm. The IR stretching frequencies for the enol double bonds appear between 1630 and 1660 cm1 for ketone-derived enoxytrichlorosilanes and at 1677 cm1 for the acetate-derived trichlorosilyl ketene acetal. One of the major differences between trialkylsilyl enol ethers and trichlorosilyl enolates is their reactivity toward aldehydes. Trialkylsilyl enol ethers usually do not react with aldehydes in the absence of nucleophilic or electrophilic activators [39]. On the other hand, trichlorosilyl enolates undergo aldol additions spontaneously with aldehydes at or below ambient

239

240


(1) Direct enolization: O R

SiCl4 Lewis base Et3N

O

SiCl3

R

(2) Metal exchange: OLi (a)

O SiCl4

R

R

OSnBu3 (b)

OTMS (c)

R

O SiCl4

R

SiCl4 MXn

SiCl3

SiCl3

R

O

SiCl3

R

Fig. 7.4

General methods for preparation of enoxytrichlorosilanes.

temperature to afford aldol adducts in good yields. More importantly, trichlorosilyl enolates are susceptible to ligand-accelerated catalysis in the presence of Lewis bases [26]. The development, scope, utility, and mechanism of this process will be covered in subsequent sections. In this section, the preparation and properties of trichlorosilyl enolates, classified by enolate structure, are described. Preparations of enoxytrichlorosilanes can be generalized to several categories: direct enolization of parent carbonyl compounds, trapping of corresponding metal (lithium) enolates, and metathesis of tin(IV) or trialkylsilyl enol ether with silicon tetrachloride (Figure 7.4). The optimum method for a given different class depends on the structure of the enolate. Synthetically viable methods only are discussed herein; other approaches are found in earlier review articles [30d]. 7.2.2

Preparation of Ketone-derived Trichlorosilyl Enolates

One of the earliest reports on the synthesis of a trichlorosilyl enolate described the reduction of an a-chloroketone using trichlorosilane and a tertiary amine. Benkeser employed a combination of trichlorosilane and tri-nbutylamine for reduction of polyhalogenated organic compounds [40]. For example, a-chloroketone 13 is smoothly converted to trichlorosilyl enolate 14 in good yield by use of this procedure (Scheme 7.9). Under similar con-


O Cl Cl

THF Me + HSiCl3 + n-Bu3N

reflux,1 h

Cl

13

Cl

SiCl3 Me

Cl 14 (80%)

O

THF + HSiCl3 + n-Bu3N

Cl

O

Me

10 - 25 oC, 1 h

15

O

SiCl3 Me

9 (72%)

Scheme 7.9

Reductive silylation of a-chloroketones.

ditions the monochloro ketone 15 provides the corresponding trichlorosilyl enolate 9 in good yield. Surprisingly, the reaction cannot be effected by triethylamine or diisopropylethylamine in place of tri(n-butyl)amine. The use of pentane as solvent was found to be superior to use of tetrahydrofuran because it enabled easier removal of solvent from these volatile trichlorosilyl enolates. These enolates are purified first by vacuum-transfer of the reaction mixture to separate them from ammonium salt and then by redistillation to remove solvent. Despite the operational simplicity and high yields obtained by use of this procedure, the scope of the reaction is somewhat limited by the availability of the corresponding a-chloro ketone and the volatility of the resulting enolate, which is necessary for vacuum-transfer. For the acetone-derived enolate 9, however, this is the method of choice. Another useful method of preparation of trichlorosilyl enolates involves metathesis of the corresponding enol stannane with silicon tetrachloride (Scheme 7.10) [37, 41]. Enol stannanes can be prepared by treatment of enol acetates with tributylmethoxystannane at elevated temperature [42]. Reaction of enol stannanes with silicon tetrachloride at low temperature provides trichlorosilyl enolates in modest to good yield. Excess silicon tetrachloride is recommended to prevent formation of polyenoxysilanes. These two steps can be performed without purification of the intermediate enol stannane, and this makes the method more practical. Trichlorosilyl enolates are efficiently generated from methyl and cyclic ketones by this method. For the propiophenone-derived enolate 18, excellent geometric selectivity for the Z isomer is observed. Although this method is general for the preparation of ketone-derived trichlorosilyl enolates, the use of a stoichiometric amount of the tin reagent and the limited availability of structurally homogeneous enol acetates make this procedure less practical. Distillation of the trichlorosilyl enolate in the presence of tin residues and excess chlorosilane during purification is sometimes difficult.

241

242


OSiCl3

OSnBu3

OAc Bu3SnOMe

SiCl4

o

100 C

0 oC OSiCl3

OSiCl3 Me

OSiCl3 Me

Me Me 17 (67%)

18 (83%) Z/E >50/1

OSiCl3

OSiCl3

OSiCl3

19 (27%)

20 (78%)

16 (54%)

21 (63%)

Scheme 7.10

Preparation of enoxytrichlorosilanes from enoxystannanes.

To avoid the use of tin reagents several other methods have been developed for preparation of trichlorosilyl enolates. Among these the most general method for ketone-derived trichlorosilyl enolates is the metal-catalyzed trans-silylation of trimethylsilyl enol ethers. It is known that mercury(II) and tin(IV) salts react with trimethylsilyl enol ethers to generate a-mercurioand a-stannyl-ketones [43, 44]. Also, as shown previously, tin enolates can be readily converted into trichlorosilyl enolates by the action of silicon tetrachloride. From these observations, a metal-catalyzed process for conversion from trimethylsilyl enol ethers to trichlorosilyl enolates could be devised (Figure 7.5) [37]. A survey of different metal salts revealed that soft Lewis acids such as Hg(OAc)2 and Pd(OAc)2 are effective catalysts of this transformation [37]. Optimization studies indicated that the stoichiometry of the reagents and the reaction concentration are critical to the rate of trans-silylation and to control the amount of bisenoxysilane species formed. A bis(enoxy)dichlorosilane is a common impurity associated with many aspects of enoxytrichlorosilane chemistry. The formation of a bis(enoxy)dichlorosilane can be explained by disproportionation of a monoenoxytrichlorosilane. At

O

OTMS MXn - TMSX Fig. 7.5

Metal-catalyzed transsilylation.

OSiCl3 MXn-1

- MXn SiCl4


243

the end of the reaction the crude reaction mixture usually contains 10–15% bis(enoxy)dichlorosilane species. The amount of bis(enoxy)silane depends on the metal catalyst used, and mercury(II) acetate is the most selective for production of enoxytrichlorosilanes. Although a slight excess of silicon tetrachloride can reduce the amount of bis(enoxy)dichlorosilane formed, use of a large excess (more than 3 equiv.) leads a significant rate deceleration owing to catalyst deactivation. Optimum conditions are use of 2–3 equiv. of silicon tetrachloride and a concentration below 1.0 m in dichloromethane [37]. The loading of the metal catalyst can be as low as 0.25 mol%, but usually 1–5 mol% of the metal salt can be employed. Several trichlorosilyl enolates have been prepared by this method (Scheme 7.11). This transformation is general for a variety of enolate structures and it is synthetically appealing, because the precursor trimethylsilyl enol ether can be readily prepared in regiochemically pure form. This transformation is extremely facile, especially for preparation of methyl ketone-derived trichlorosilyl enolates, and enables complete conversion in less than 2 h with 1 mol% Hg(OAc)2 . The cyclic ketone-derived enol ethers require longer reaction times ranging from 18 to 24 h [37].

OTMS

OSiCl3

Hg(OAc)2 (1-5 mol %) SiCl4 (2 equiv) CH2Cl2, rt

OSiCl3

OSiCl3

OSiCl3

OSiHCl2

OSiCl3

OSiCl3

Me

n-Bu Me

19 (73%)

20 (68%)

OSiCl3

22 (59%) w/ HSiCl3 OSiCl3

Me

i-Bu

23 (83%)

21 (78%)

OSiCl3

24 (83%) OSiCl3

OSiCl3

TBSO

Me Me

25 (74%) OSiPhCl2 i-Bu 28 (45%) w/ PhSiCl3

26 (61%)

16 (81%)

27 (69%) OSiCl3

OSiCl3 Me

Me OTBS 29 (71%)

17 (71%) OSiCl3

Me OPiv 30 (78%)

Scheme 7.11

Preparation of enoxytrichlorosilanes by Hg(II)-catalyzed metathesis.

OBn 31 (60%)

244

7 Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases Tab. 7.1

Metal-catalyzed transsilylation of 3-pentanone-derived trimethylsilyl ether 32. Me

OTMS SiCl4 (2 equiv) MX2 (5 mol %) 32

Me

Me

CH2Cl2, rt

OSiCl3 Me 11

Entry

MX2

32, E/ Z

Time, h

Yield, %a

11, E/Z b

1 2 3 4 5 6

Hg(OAc)2 Hg(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 Pd(TFA)2

3/1 1/4 3/1 1/4 3/1 1/4

5 5 5 5 15 15

72 60 76 69 70 43

1/2 1/2 1/6 1/6 1/7 1/6

a Yield

of distilled material. b Determined by 1 H NMR analysis.

Common functional and protecting groups can be tolerated under the reaction conditions and the resulting trichlorosilyl enolates are sufficiently pure for use in the phosphoramide-catalyzed aldol addition (vide infra). The use of other chlorosilanes enables the preparation of different classes of chlorosilyl enolate. For example, when trichlorosilane is used in place of silicon tetrachloride, dichlorohydridosilyl enolate 22 can be obtained. A major drawback to the metal-catalyzed trans-silylation is lack of control over the geometry of the resulting trichlorosilyl enolate. Starting from either E- or Z-enriched trimethylsilyl enol ether 32, the E/Z ratio of the enoxytrichlorosilane 11 is always 1:2 when Hg(OAc)2 is used as the catalyst (Table 7.1) [45]. Use of Pd(II) salts results in slightly higher Z selectivity, but again the E/Z ratio of the enoxytrichlorosilane does not mirror the E/Z ratio of the trimethylsilyl enol ether. The E/Z ratio also depends on the structure of enolates (Table 7.2). ZTrichlorosilyl enolates are always selectively formed. The general trend of Z/E selectivity is related to the size of the R group. For larger R groups, higher Z selectivity is observed. These trends are also observed in the transsilylation catalyzed by Pd(OAc)2 and Pd(TFA)2 . These observations can be rationalized by the following mechanism (Figure 7.6). The overall process consists of electrophilic attack of the metal salt to afford a-metalloketone 34. Coordination of silicon tetrachloride to the carbonyl group of 34 and loss of metal salt gives the enoxytrichlorosilane. The initial formation of 34 is presumably reversible, and this event can account for the randomization of enolate geometry. The E/Z ratio of the resulting trichlorosilyl enolate is determined by the relative rate of breakdown of the two limiting conformers i and ii. The avoidance of steric interaction between Me and R in i makes this conformer more favorable, leading to the preferred formation of the Z enoxytrichlorosilane. This explanation is consistent with the trend observed in the relationship between steric


245

Tab. 7.2

Hg(II)-catalyzed transsilylation of a variety of trimethylsilyl enol ethers. OTMS

SiCl4 (2 equiv) Hg(OAc)2 (5 mol %)

R

R

CH2Cl2, rt

Me

OSiCl3

OSiCl3 Me

+

R

Me (E )-33

(Z )-33

Entry

R

Time, h

Yield, %a

33, E/Z b

1 2 3 4 5 6c

H Me Et i-Pr t-Bu Ph

16 16.5 5 18 24 18

50 58 72 65 55 66

1/8 1/2 1/2 1/8 1/>20 1/99

of distilled material. b Determined by 1 H NMR analysis. mol% of Hg(OAc)2 was used.

a Yield c 10

demand of R and the E/Z ratio. In fact, the presence of bulky R groups enables highly selective preparation of Z enolates under these conditions. E-Configured trichlorosilyl enolates cannot, however, be obtained selectively by this method. A method has been developed that avoids the use of a metal catalyst to prepare geometrically defined trichlorosilyl enolates. It involves generation of a lithium enolate, by treatment of an isomerically enriched trimethylsilyl enol ether with methyllithium, and subsequent capture of the configurationally defined lithium enolate with silicon tetrachloride [46]. Both E and Z trichlorosilyl enolates can be prepared by means of this method, without loss of geometrical purity (Scheme 7.12). Addition of methyllithium to a trimethylsilyl enol ether leads to smooth conversion to the lithium enolate [46]. The E/Z ratio of the trichlorosilyl enolates mirrors the E/Z ratio of the starting trimethylsilyl enol ether.

MLn-1 SiCl4 R H

R

OTMS Me

MLn

O

MLn-1 34

(Z )-33

O Me SiCl3 i: favored

Me

-TMSL R

Cl

-MLn-1Cl

Cl SiCl4

Me R

H SiCl3 O MLn-1

ii: less favored Fig. 7.6

Proposed mechanism for metal-catalyzed transsilylation.

(E )-33 -MLn-1Cl

246


1. MeLi 2. SiCl4

OTMS RZ

R

Et2O

RE OSiCl3 Me

TBSO

Me

OSiCl3 RZ

OSiCl3 Me

R RE

TIPSO Me

OSiCl3 Me

(Z )-35 (81%) Z/E, 50/1

OSiCl3

Me Me

Me

(E )-11 (34%) E/Z, 99/1

TIPSO

(Z )-36 (53%) Z/E, 32/1

(E )-36 (23%) E/Z, 15/1

Scheme 7.12

Preparation of geometrically defined enoxytrichlorosilanes.

Numerous methods are used to prepare geometrically defined trimethylsilyl enol ethers. For example, Z trimethylsilyl enol ethers can be prepared by using dibutylboron triflate and subsequent treatment of the boron enolate with trimethylsilyl chloride [47]. The E isomers are typically prepared by use of lithium tetramethylpiperidide as described by Collum [48]. The geometrically defined trimethylsilyl enol ethers are converted into the corresponding trichlorosilyl enolates by the above-mentioned procedure. Unfortunately, the resulting enolate is often contaminated with the bis(enoxy)dichlorosilane thus reducing the overall yield of the process. Nonetheless, the ability to prepare geometrically defined enoxytrichlorosilanes makes the metal-exchange method synthetically attractive. 7.2.3

Preparation of Aldehyde-derived Trichlorosilyl Enolates

In this section, three methods used to generate aldehyde-derived enoxytrichlorosilanes are described [49]. The first is the metathetical route from the corresponding trimethylsilyl enol ether using a catalytic amount of Pd(OAc)2 and excess silicon tetrachloride (Scheme 7.13). In this method, the geometry of the resulting trichlorosilyl enolate is not dependent on the trimethylsilyl enol ether for the same reason as discussed above (Figure 7.6). Thus, only unsubstituted or symmetrically substituted enolates are suitable.

SiCl4 (2 equiv) Pd(OAc)2 (1 mol %)

n-C5H11 OTMS

n-C5H11

CH2Cl2

OSiCl3 37 (79%) Z/E, 3.5/1

Scheme 7.13

Preparation of an aldehyde-derived enoxytrichlorosilane.


H

n-C5H11

Ph N O P N N

+

O

CDCl3

OSiCl3 38 (72%)

SiCl4 (i-Pr)2NEt

+ Me

O

Cl

n-C5H11

Ph

H

n-C5H11

SiCl4

247

N O

Me

n-C5H11

CH2Cl2

OSiCl3 37 (79%) Z/E, 3.5/1

Scheme 7.14

Direct silylation of aldehydes using SiCl4 and a Lewis base.

The second procedure is direct silylation from an aldehyde with phosphoramides or N-oxides and a base (Scheme 7.14). In the presence of silicon tetrachloride and a catalytic amount of a Lewis base aldehydes are rapidly transformed into a-chloro trichlorosilyl ethers. The formation of such intermediates has recently been documented and observed by means of 1 H NMR spectroscopic analysis [50]. Addition of an amine base promotes elimination of HCl to yield the trichlorosilyl enolate. Before use the resulting trichlorosilyl enolate must be distilled from the ammonium salt generated by the reaction. Although this procedure provides the trichlorosilyl enolate directly from a given aldehyde, the enol geometry cannot be controlled, thus limiting the utility of this process. Generation of stereodefined trichlorosilyl enolates of aldehydes can also be accomplished by the direct O-to-O trans-silylation via lithium enolates (Scheme 7.15). The geometrically-defined trimethylsilyl enol ethers of heptanal react with methyllithium to yield the configurationally stable lithium enolates. After trapping with a large excess of silicon tetrachloride the geometrically enriched trichlorosilyl enolates of aldehydes are prepared in good yield.

OTMS RZ

1. MeLi 2. SiCl4 Et2O

RE n-C5H11

OSiCl3 RZ

n-C5H11

OSiCl3

RE Me OSiCl3

OSiCl3 (Z )-37 (53%) Z/E, 99/1

(E )-37 (71%) E/Z, 30/1

(Z )-12 (29%) Z/E, 98/2

Scheme 7.15

Preparation of geometrically defined enoxytrichlorosilanes.

Me

OSiCl3

(E )-12 (34%) E/Z, 99/1

248


O SnBu3

MeO

0 oC

39 OSiCl2H MeO 40 (48%)

MeO

OSiCl3 MeO

OSiCl2Me MeO

10 (65%)

OSiCl2Ph MeO

OSiClRR'

RR'SiCl2

41 (57%)

OSiMe2Cl O

MeO

Si

Cl

MeO 42 (23%)

43 (18%)

44 (19%)

Scheme 7.16

Preparation of acetate-derived trichlorosilyl ketene acetals.

7.2.4

Preparation of Trichlorosilyl Ketene Acetals

The first reported enoxytrichlorosilanes were derived from esters [38]. Those ketene acetals are prepared by reaction of a chlorosilane and an a-stannyl ester (Scheme 7.16). This method is still the most general preparation of acetate-derived trichlorosilyl ketene acetals. In the presence of excess silicon tetrachloride the stannyl ester 39 is smoothly converted to the ketene acetal 10. The ketene acetal can be distilled at ambient temperature under reduced pressure. These species cannot be heated because isomerization to a Ctrichlorosilyl ester occurs at higher temperatures [51]. This isomerization is also a problem when these ketene acetals are stored for a long time, because even at room temperature isomerization occurs in a month. Unlike the trichlorosilyl enolates derived from ketones and aldehydes, which exist exclusively as the O-silyl isomers, trichlorosilyl ketene acetals can isomerize to the thermodynamically more stable C-silyl isomer [38]. The C-silyl esters are not reactive in phosphoramide-catalyzed aldol reactions and these species do not revert to the corresponding trichlorosilyl ketene acetal under common reaction conditions. The use of different chlorosilanes enables preparation of structurally diverse chlorosilyl ketene acetals (Scheme 7.16). Although this procedure is relatively simple, the method suffers from low yields because of the difficulty of separating the trichlorosilyl ketene acetal from tributylchlorostannane and from the C-trichlorosilylacetate. The purity of the chlorosilyl ketene acetal is critical because tin residues from the reaction promote oligomerization of the ketene acetal. In the reaction with tributylstannylpropanoates under similar conditions the major products obtained are, unfortunately, the C-trichlorosilyl prop-

7.3 Preparation of Chiral Lewis Bases

anoate derivatives. Thus, so far only acetate-derived trichlorosilyl ketene acetals have been prepared by this method. In summary, practical and efficient methods are now available for preparation of enoxytrichlorosilanes. The most general method is the transition metal-catalyzed trans-silylation of trimethylsilyl enol ethers with silicon tetrachloride. Geometrically defined enoxytrichlorosilanes are best prepared by silylation of lithium enolates. The configuration of the lithium enolate precursor is preserved in this process. The metathesis of methyl tributylstannylacetate with silicon tetrachloride is the most efficient route for preparation of trichlorosilyl ketene acetals.

7.3

Preparation of Chiral Lewis Bases

The structure of the Lewis base greatly affects its catalytic activity and selectivity in the aldol addition. Moreover, different types of trichlorosilyl nucleophile require different types of chiral Lewis base catalyst. To examine a wide range of structures, general methods are needed for synthesis of phosphoramides and N-oxides [52]. The four most commonly used Lewis-base catalysts are shown in Chart 7.1. The phosphoramide 45 is the most general and selective catalyst for aldol addition of ketone-derived trichlorosilyl enol ethers to aldehydes [53]. In MeMe Me N O P N N

N

t-Bu

Me 45: addition of ketone-derived trichlorosilyl enol ethers

H H

O P N N Me

t-Bu

46: addition of trichlorosilyl ketene acetals to ketones

Me N O P N N Me Me

N

CH2

2

47: addition of allylic trichlorosilanes

N O O On-Bu n-BuO

CH2

2

48: addition of aldehyde-derived trichlorosilyl enol ether and addition of TMS enol ethers

Chart 7.1

Commonly used chiral Lewis bases for aldol additions.

249

250


recent studies dimeric phosphoramide catalysts such as 47 and 48 have been shown to be highly selective in additions of allyltrichlorosilane and allyltributylstannane (with silicon tetrachloride) to aldehydes [54]. These catalysts are also effective in the addition of aldehyde-derived trichlorosilyl enolates and in additions of trialkylsilyl ketene acetals and enol ethers to aldehydes [49, 50]. For addition of trichlorosilyl ketene acetal to ketones the bis-N-oxide 46 has proven to be the most selective catalyst [55]. Syntheses of these Lewis base catalysts are briefly described in the following sections. 7.3.1

Preparation of Chiral Phosphoramides

The basic strategy for synthesis of chiral cyclic phosphoramides is to couple a chiral 1,2-, 1,3-, or 1,4-diamine to either a phosphorus(V) or phosphorus(III) reagent. There are three general routes (Scheme 7.17). Method A is the most straightforward strategy for preparation of chiral cyclic phosphoramides. A chiral diamine is combined with an aminophosphoric dichloride in the presence of triethylamine [56]. The reaction is typically conducted in a halogenated solvent under reflux. This method works well for preparation of sterically less bulky phosphoramides and for coupling aliphatic diamines. For sterically demanding coupling partners, elevated temperatures and longer reaction times are required. For example, phosphoramide 45 is obtained in good yield from (R,R)-N,N 0 -dimethyl-1,2-diphenylethylenediamine [57] by method A (Scheme 7.18). For less reactive diamines a more electrophilic phosphorus(III) reagent is needed to enhance the reaction rate (Methods B and C, Scheme 7.17) [58]. In these methods the diamine is first lithiated by use of n-BuLi at low temperature. The lithiated diamine is combined with the mono-

NHR

A:

+

[G]* NHR

O Cl P NR12 Cl

+

[G]* NHR

CH2Cl2, reflux 1. n-BuLi 2. [O]

NHR

B:

Et3N

Cl P NR12 Cl 1. n-BuLi

C:

2. R12NH

NHR [G]*

+ NHR

Cl P Cl Cl

3. [O]

Scheme 7.17

General preparations of chiral phosphoramides.

R O N P NR12 N [G]* R R O N P NR12 N [G]* R R O N P NR12 N [G]* R

7.3 Preparation of Chiral Lewis Bases

Me NH + NH Me

O Cl P N Cl

Et3N CH2Cl2, reflux

251

Me N O P N N Me (R,R)-45 (50%)

Scheme 7.18

Preparation of monophosphoramide 45.

aminophosphorus(III) dichloride reagent (Method B, Scheme 7.17) or with phosphorus(III) chloride followed by treatment with an amine (Method C, Scheme 7.17). The resulting phosphorus(III) triamine species is oxidized with m-CPBA to give the desired phosphoramide. For example, the bisphosphoramide 48 is prepared in good yield from N,N 0 -dimethyl-1,1 0 binaphthyl-2,2 0 -diamine by a three-step sequence [59] (Scheme 7.19). In this example, the N,N 0 -dimethylpentanediamine (49) is used as the linker [60].

Me NH NH Me

Me N 49, Et3N P Cl N Me 49 = MeHN

1. n-BuLi 2. PCl3 THF

Me N P N N Me Me

m-CPBA CH2

NHMe

Me N O P N N Me Me

CH2

2

2

(R,R)-48 (72%, 3 steps) Scheme 7.19

Preparation of bisphosphoramide 48.

The bisphosphoramide 47 can be prepared from 2,2 0 -bispyrrolidine (Scheme 7.20) [61]. In the presence of triethylamine, enantiomerically pure bispyrrolidine reacts with phosphorus oxychloride to provide diaminophosphoryl chloride 50. The lithiated linker 49 is combined with (R,R)-50 to afford the bisphosphoramide 47 in excellent yield.

252


NH H H

+ POCl3 NH

Et3N

O P Cl N N

H H

Et2O

49, n-BuLi THF

O P N N Me N

H H

CH2 2

(R,R)-50 (67%)

R-(l,l )-47 (93%)

Scheme 7.20

Preparation of bisphosphoramide R-(l,l)-47.

7.3.2

Synthesis of Chiral bis-N-Oxides

N-Oxides are readily obtained by oxidation of tertiary amines [62]. Accordingly, chiral N-oxides are usually prepared by oxidation of chiral tertiary amines. Several axially chiral bis-N-oxides have been synthesized; these are known to promote addition reactions of chlorosilane species [62]. The chiral bis-N-oxide 46 contains both central and axial elements of chirality (Scheme 7.21). These two features are essential for the stereoselectivity observed in promoted aldol reactions and are also helpful in enantio- and diastereoselective synthesis of the catalysts. Introduction of the stereogenic center is achieved by reduction of the tert-butyl ketone by (Ipc)2 BCl [63]. The N-oxide obtained after etherification and oxidation undergoes diastereoselective oxidative dimerization to afford (P)-46 [55].

Me Br

1. n-BuLi 2. pivaloyl chloride (2 equiv) t-Bu

Et2O

N

Me

1. (-)-(Ipc)2BCl 2. (HOC2H4)2NH t-Bu

THF/ Et2O

N

Me

90% KOH, 18-c-6 n-BuBr DMF

N OH

O

84% (R/S = 97.8/2.2)

Me

Me m-CPBA

t-Bu

N On-Bu

CH2Cl2

n-BuO

84%

N O 84%

MeMe LiTMP; I2 THF, −73 oC - rt t-Bu n-BuO

t-Bu

N O

N O n-BuO

P-(R,R )-46 : 48% Scheme 7.21

Preparation of chiral bis-N-oxide P-(R,R)-46.

t-Bu

7.4 Enantioselective Aldol Addition of Achiral Enoxytrichlorosilanes

7.4

Enantioselective Aldol Addition of Achiral Enoxytrichlorosilanes

Trichlorosilyl enolates (enoxytrichlorosilanes) derived from ketones undergo additions to aldehydes spontaneously at or below ambient temperature without external activation [53]. The intrinsic reactivity of these reagents contrasts with that of trialkylsilyl enol ethers in the aldol addition, for which a promoter is usually required [64]. The reactivity of trichlorosilyl enolates is not because of the inherent nucleophilicity of the enolate but rather the high electrophilicity of the silicon atom [27]. The silicon atom of a trichlorosilyl enolate is highly electropositive, because of the effect of chlorine ligands. Lewis basic functions, including aldehydes, can bind to the Lewis acidic silicon and form a hypercoordinate complex. On binding of an aldehyde to the Lewis-acidic silicon atom the aldehyde is electrophilically activated (Figure 7.7, iii). The enolate moiety is concurrently activated by increased polarization of the enolate SiaO bond. This dual activation results in the high reactivity of trichlorosilyl enolates. A similar rationale is also proposed for the aldol reaction of boron enolates [2c] and strained-ring alkyl silyl enolates [65]. Aldol additions of trichlorosilyl enolates are catalyzed by Lewis bases, most notably phosphoramides (Figure 7.8). It is believed that binding of a phosphoramide to a trichlorosilyl enolate leads to ionization of a chloride, forming a cationic silicon–phosphoramide complex [66]. The binding of an aldehyde to the silicon complex leads to aldolization through a closed transition structure. There are two catalyzed pathways – one involves the intermediacy of a pentacoordinate, cationic silicon complex in which only one phosphoramide is bound to silicon and the other involves a hexacoordinate, cationic silicon complex in which two phosphoramide molecules are bound to the silicon [66]. In the former pathway aldolization occurs through a boatlike transition structure, whereas in the latter pathway, the transition structure is chair-like (Figure 7.8, iv and v). This mechanistic duality in the catalyzed process is analyzed in more detail in Section 7.9.

nucleophilic activation OSiCl3

Cl O

+ RCHO

electrophilic activation

Cl Si

Cl

O

H

Cl3 Si O O

R iii: boat transition structure Fig. 7.7

Hypothetical assembly for uncatalyzed aldol addition of a trichlorosilyl enolate.

R

253

254


Cl Cl O

OP(NR2)3 Si

Cl

O

Cl3 Si O

O HH one-phosphoramide pathway OSiCl3

(R2N)3PO

R'

R' iv: cationic, trigonal bipyramid boat

+ R'CHO Cl Cl two-phosphoramide pathway

HR'

O Si OP(NR2)3 OP(NR2)3 O H Cl

O

Cl3 Si O R'

v: cationic, octahedron chair Fig. 7.8

Divergent pathways for catalyzed aldol addition of a trichlorosilyl enolate.

The appeal of aldol additions of trichlorosilyl enolates is the selective and predictable diastereocontrol that probably arises from a closed transition structure. For substituted enolates the diastereomeric ratio of aldol products can be directly correlated with the enolate geometry as predicted by the Zimmerman–Traxler model [67]. Thus, the dominant reaction pathway in the catalyzed reactions of trichlorosilyl enolates involves a chair-like transition structure organized around the silicon. By employing chiral phosphoramides, enantioselection can be controlled. Thus highly stereocontrolled aldol addition can be envisaged in Lewis-base-catalyzed aldol addition of trichlorosilyl enolates. In this section aldol additions of achiral trichlorosilyl enolates derived from ketones are described. The inherent reactivity of these species and their potential use in asymmetric, catalytic processes will be discussed. 7.4.1

Aldol Additions of Achiral Methyl Ketone-derived Enolates

Trichlorosilyl enolates derived from methyl ketones are reactive toward aldehydes in the absence of Lewis base catalysts at ambient temperature (Scheme 7.22) [68]. Trichlorosilyl enolates bearing a broad range of non-participating substituents react with benzaldehyde to give excellent yields of the aldol


OSiCl3

O

OH

Me

OH

n-Bu

Ph

O

Ph

O

Ph

OH Ph

OH

TBSO

OH

i-Pr

Ph 54 (93%)

O

OH

Ph

Ph

56 (93%)

55 (91%)

O

53 (94%)

O

OH

Ph

i-Bu

52 (95%)

51 (92%)

OH

R

rt, 4 - 6 h

R O

O

CH2Cl2

PhCHO

+

57 (97%)

Scheme 7.22

Uncatalyzed aldol addition of methyl ketone-derived trichlorosilyl enolates.

products in several hours. The steric and electronic properties of the enolates do not have a large influence on the rate of aldol addition. Under similar conditions the trichlorosilyl enolate 24 undergoes aldol addition to a wide range of aldehydes at room temperature with excellent yields (Scheme 7.23). Aromatic and conjugated aldehydes are typically more reactive than aliphatic aldehydes, presumably because of their smaller size and higher Lewis basicity [69]. The structure of the aldehyde significantly affects the rate of aldol addition, however. Reactions with bulky aldehydes

OSiCl3

+

n-Bu

O

CH2Cl2

RCHO

rt, 4 - 14 h

OH

n-Bu

R

24 O

OH

n-Bu

Ph

O n-Bu

52 (95%) O

Ph

O n-Bu

Ph Me 59 (92%)

OH

O

Me MeMe

60 (93%)

OH

n-Bu

58 (91%)

OH

n-Bu

O

OH

61 (trace) (86%, w/ 10 mol % HMPA)

Scheme 7.23

Uncatalyzed aldol additions of 62 to a variety of aldehydes.

OH

n-Bu

Ph 62 (84%)

255


256

OSiCl3

O

OHC

CH2Cl2

+

OH

n-Bu

+ 63 (95%)

−78oC, 2 h

n-Bu 24

64 (4%)

63 Scheme 7.24

Uncatalyzed aldol addition of 24 at 78 C.

are slower, as is evidenced by the reaction of pivalaldehyde. Addition of 10 mol% HMPA leads to a dramatic increase in the rate of addition, enabling isolation of 61 in good yield. The rate of reaction of trichlorosilyl enolates with aldehydes is greatly attenuated at low temperature. For example, in the addition of 24 to 4biphenylcarboxaldehyde, only 4% of 64 was isolated and 95% of unreacted aldehyde was recovered after 2 h (Scheme 7.24). This behavior is crucial for optimization of the asymmetric process, because suppression of the achiral background reaction is important for achieving high enantioselectivity in the catalyzed reaction. In the presence of several structurally diverse chiral phosphoramides the aldol addition proceeds smoothly at low temperature (Scheme 7.25). Although all of the phosphoramides are effective in promoting the aldol addition of 24 to benzaldehyde, the stilbene-1,2-diamine-derived phosphoramide 45 is the most active and selective catalyst. The structure of the chiral diamine backbone clearly has a large effect on the enantioselectivity of the process. Also, substitution of a diisopropylamino group for the piperdinyl group in 63 leads to dramatic drop in enantioselectivity. Correct choice of solvent is a critical aspect of obtaining high enantioselectivity in the aldol addition of trichlorosilyl enolates [68]. Dichloromethane is the most suitable solvent for the reaction, in terms of both reactivity and selectivity (Table 7.3). Other halogenated solvents such as trichloroethylene or the more polar propionitrile are good solvents for this reaction and proOSiCl3 n-Bu

PhCHO CH2Cl2, −78oC 2h

24

Ph Ph

Me N O P N N Me

45 (92%); er 12.5/1

O

cat. (10 mol %) +

Ph Ph

Me N O P i-Pr N N Me i-Pr

63 (79%); er 1.70/1

n-Bu

Me N O P N N Me 64 (76%); er 1/3.31

Scheme 7.25

Catalyzed aldol additions of 24 to benzaldehyde.

OH Ph

52 Me N O P N N Me 65 (71%); er 4.29/1

7.4 Enantioselective Aldol Addition of Achiral Enoxytrichlorosilanes Tab. 7.3

Effect of solvent on aldol addition of 24 to benzaldehyde. OSiCl3

O

(S,S)-45 (10 mol %) +

PhCHO

n-Bu

solvent, −78 oC

OH

n-Bu

24

Ph

52

Entry

Solvent

ea

er

Yield, %

1 2 3 4 5 6b

CH2 Cl2 trichloroethylene Et2 O toluene THF EtCN

9.08 3.4 4.34 2.38 7.52 27.7

12.5/1 4.03/1 2.25/1 1.85/1 3.37/1 1/8.71

92 88 37 48 59 88

a Ref.

20a. b Performed with 10 mol% (R,R)-45.

vide good yield of the aldol product. Coordinating solvents such as ether and THF give low yields and attenuated selectivities. In ethereal solvents coordination of the Lewis basic oxygen with the silicon species might compete with binding of 45 or benzaldehyde, thus accounting for the lower yields and attenuated selectivity observed. In a non-polar medium such as toluene, the aldol product is formed in significantly lower yield with only marginal enantioselectivity. The lack of reactivity observed in the non-polar solvent might reflect difficulties in generating the kinetically relevant, ionized silyl cation. Catalyst loading also has a large effect on selectivity. Although high catalyst loadings (more than 10 mol%) do not improve enantioselectivity significantly, reducing the catalyst loading to less than 3 mol% leads to a slower rate of reaction and attenuated selectivity. At low catalyst loadings the one-phosphoramide pathway that involves a poorly selective boat-like transition structure becomes competitive with the highly selective, twophosphoramide pathway that involves a chair-like transition structure (c.f. Scheme 7.6). Thus, a catalyst loading of 5 mol% or more is necessary for optimum enantioselectivity. The scope of the enolate structure in this aldol reaction is significant (Scheme 7.26). Catalyzed reactions with benzaldehyde proceed in excellent yield with modest to good selectivity. The enolate structure does not have a significant effect on the rate of the reaction but greatly affects the enantioselectivity of the process. Enolates with larger substituents on the nonparticipating side, for example phenyl and tert-butyl, result in significantly lower enantioselectivity than those bearing smaller substituents such as methyl and n-butyl. In these reactions the lower enantioselectivity can be attributed to a lack of facial selectivity at the aldehyde. For this aldolization to be synthetically useful it is important for highly functionalized enolates to tolerate the reaction conditions. For example, ad-

257

258

7 Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases OSiCl3 R

O

O

OH

Me

n-Bu

Ph

O

OH

O

Ph

OH

t-Bu

Ph

Ph O

OH

i-Bu

OH

Ph

O

Ph

Ph

54 (97%); er 9.75/1 OH

TBSO

55 (93%); er 2.92/1

OH

i-Pr

Ph

53 (95%); er 10.1/1

O

66 (95%); er 3.17/1

OH

R

0.5 M in CH2Cl2 −78oC, 2 h

52 (98%); er 12.0/1

51 (98%); er 14.6/1

O

(S,S)-45 (5 mol %) + PhCHO

Ph

56 (94%); er 13.5/1

Scheme 7.26

Addition of different trichlorosilyl enolates to benzaldehyde.

dition of enolate bearing a TBSO group results in an excellent yield of 56 with high enantioselectivity. The scope of the reaction with regard to the aldehyde component is also broad. Good to high enantioselectivity can be achieved in the addition of 24 to a variety of aldehydes using 45 (Scheme 7.27). Under these reaction conditions uniformly excellent yields and good enantioselectivity are obtained OSiCl3 n-Bu

O

OH

n-Bu

O

Ph

O

OH

n-Bu

OH

n-Bu

OH

n-Bu

Ph Me 59 (95%); er 21.7/1

OH

n-Bu

67 (92%); er 13.1/1 O

O

58 (94%); er 11.5/1

52 (98%); er 12.0/1

R

OH

n-Bu

Ph

OH

n-Bu

0.5 M in CH2Cl2 −78oC, 2 - 6 h

24 O

O

(S,S)-45 (5-10 mol %) + RCHO

64 (95%); er 12.7/1 O

OH

O

OH

Me

n-Bu

n-Bu Me Me

60 (79%); er 17.5/1

61 (81%); er 24.0/1

Scheme 7.27

Catalyzed addition of 24 to a variety of aldehydes.

62, no reaction

Ph


259

Cl O Ph H

O

Cl Si

OP(NR2)3 OP(NR2)3

Cl n-Bu

vi

aldolization

Cl

O

Ph H

O

Cl Si

OP(NR2)3 OP(NR2)3

Cl vii n-Bu

no aldolization

Fig. 7.9

Reaction of aliphatic aldehydes under the action of phosphoramide catalysis.

from aromatic and unsaturated aldehydes. Aliphatic aldehydes, on the other hand, react significantly more slowly than their unsaturated counterparts. When hydrocinnamaldehyde is used as acceptor no aldol product is isolated under standard conditions. Aldehyde structure clearly has a significant effect on enantioselectivity. Interestingly, sterically congested aldehydes, especially those with a-branching, result in higher enantioselectivity than unbranched substrates. Although the origin of this effect is unclear, sterically bulky aldehydes presumably increase the energy difference between the competing chair- and boat-like transition structures. Several explanations have been proposed for the relatively low reactivity of aliphatic aldehydes. This behavior was originally rationalized by considering the low Lewis basicity of these aldehydes compared with related unsaturated aldehydes [69]. Another consideration was the competitive enolization of these substrates in the presence of phosphoramide catalysts [68b]. It has, however, now been shown that aliphatic aldehydes rapidly form a-chloro trichlorosilyl ethers under the reaction conditions and these species are unreactive towards nucleophiles (Figure 7.9) [50]. In the mechanism of phosphoramide-catalyzed aldol additions the cationic hexacoordinate silicon complex has a chloride counterion. When the aldehyde carbonyl is activated in this complex chloride is a potential nucleophile that competes with the enolate. Aldolization of aliphatic aldehydes is, apparently, slow compared with addition of chloride, resulting in formation of the a-chloro silyl ether. The role of ionized chloride in suppressing the aldolization is in agreement with the observation that aliphatic aldehydes are reactive under conditions without phosphoramide. Because these uncatalyzed reactions do not involve ionization, the formation of a-chlorosilyl ether is no longer competitive. Efforts to construct a stereochemical model of absolute stereoselection in these aldol additions have so far been unsuccessful. The absolute configuration of aldol adduct 52 has been determined by formation of the corresponding bromobenzoate then single-crystal X-ray analysis and the absolute

260


configurations of other aldol products have been assigned by analogy. In aldol additions catalyzed by phosphoramide (S,S)-45, the nucleophile attacks the Si face of the complexed aldehyde, usually forming the S configuration at the hydroxy-bearing carbon. The solution and solid-state structures of several Sn(IV)–phosphoramide complexes have been examined to obtain better understanding of the stereochemical environment crafted by the chiral phosphoramide [70]. Despite this effort no transition structure has yet been proposed that can rationalize the absolute configuration observed in these catalyzed aldol additions. One major concern in development of a model is understanding the mode of ligand binding around silicon. Among the challenges facing the formulation of reasonable transition structures are:

. multiple configurational possibilities with two phosphoramides around . silicon; conformational flexibility of the phosphoramides; and . the deducing the reactive conformations of the ternary complex from the vast number of potential configurations and conformations. Computational solution of these problems is currently untenable. Because of the number of heavy atoms and rotatable bonds present in the complex, prediction of the reactive conformation in the ternary complex is difficult at the current level of understanding. In general, performing aldol addition of a trichlorosilyl enolate involves two discrete steps – generation and isolation of the trichlorosilyl enolate then aldolization. In an effort to streamline the process, a method for in situ formation of the reactive enolate has been developed (Scheme 7.28). As described in Section 7.2, trichlorosilyl enolates can be prepared from the corresponding trimethylsilyl enol ethers by use of silicon tetrachloride and a catalytic amount of transition metal salt. In this procedure the trichlorosilyl enolates generated in situ from trimethylsilyl enol ethers by Hg(OAc)2 catalyzed metathesis can, after removal of Me3 SiCl and excess SiCl 4 , be used directly in the subsequent aldol addition. The yield and enantioselectivity of the aldol reaction are not affected by the presence of the mercury salt. This procedure obviates purification and handling of the moisturesensitive trichlorosilyl enolate and enables use of shelf-stable trimethylsilyl

OTMS n-Bu

Hg(OAc)2 (1 mol %) SiCl4 (2.0 equiv) CH2Cl2, rt

OSiCl3 n-Bu

(S,S)-45 (5 mol %) RCHO CH2Cl2, −78oC

24

O

OH

n-Bu

Ph Me

59 (89%, 2 steps); er 23.4/1 Scheme 7.28

Aldol addition of 24 generated in situ.


O

OSiCl3 +

n-Bu

Me

H

O

CH2Cl2 rt

Me

n-Bu

OTBS

OTBS

24

68

+

n-Bu

69 (95%); syn/anti, 1/2.4

O

OSiCl3

Me

H

O

CH2Cl2 rt

OBn

24

OH

70

n-Bu

OH Me OBn

71 (92%); syn/anti, 1/2.7

Scheme 7.29

Uncatalyzed aldol additions to chiral aldehydes.

enol ethers. This in situ generation of trichlorosilyl enolates and their use has enhanced the synthetic utility of the phosphoramide-catalyzed aldol reaction. The possibility of substrate-controlled aldol additions of trichlorosilyl enolates has been investigated using lactate-derived chiral aldehydes [68b]. Uncatalyzed reactions of 24 with chiral aldehydes 68 and 70 proceed in high yield at room temperature (Scheme 7.29). The compatibility of common protecting groups on the aldehyde with trichlorosilyl enolates has been demonstrated in these examples. The internal diastereoselection (Section 7.5, Figure 7.13) exerted by the chiral aldehyde slightly favors the anti isomer, although the diastereomeric ratio obtained in this reaction is not synthetically useful [71]. The intrinsic selectivity can be rationalized by use of the Felkin–Ahn model, if boat-like transition structures are considered (Figure 7.10) [72]. The two possible approaches of the nucleophile can be envisaged with the oxygen anti to the incoming nucleophile, as suggested in the Heathcock model [73]. These two conformers viii and ix lead to the two diastereomeric transition structures. Addition of the nucleophile would occur on the sterically less hindered face (H rather than Me), which leads to the observed major anti diastereomer. The nature of the group on the a-oxygen seems to have little effect on the selectivity of the aldolization. This indicates that stereoelectronic factors control the orientation of the oxygen atom in the stereochemistrydetermining step [74]. This observation is also consistent with Heathcock’s analysis of non-chelation-controlled additions to simple a-oxygenated aldehydes [73]. The aldol reaction of an achiral enolate with a chiral aldehyde in the presence of a chiral phosphoramide is an interesting opportunity for double diastereoselection [75]. Diastereoselectivity in aldol additions to chiral aldehydes can be significantly enhanced when the sense of internal and external

261

262


Cl

Cl

Si Cl O Me O RO H H viii: favored O

OSiCl3 +

n-Bu

Me

H

Cl Cl

OR

24

n-Bu

68 (R = TBS)

O n-Bu

n-Bu Me OR O H O Si Cl H Cl Cl

anti-69

Cl Si H O OR

Me H ix: disfavored

n-Bu RO H O Me O Cl Si H Cl Cl

syn-69

Fig. 7.10

Diastereoselection for addition of 24 to 68.

diastereoselection are matched (Scheme 7.30). When (S,S)-45 is used in the addition of 24 to 68, the aldol product obtained is the syn diastereomer, albeit with low selectivity. Use of (R,R)-45, on the other hand, provides anti-69 with good diastereoselectivity. In catalyzed additions to the chiral aldehyde 68 the configuration of the catalyst dominates the stereochemical course of the addition. The inherent selectivity in the catalyzed pathway can be examined by employing an achiral catalyst. Modest anti selectivity is observed when 72 is used. The anti selectivity observed with phosphoramide (R,R)-45 is therefore a result of matching internal (from the chiral aldehyde) and external stereoinduction (from chiral catalyst) [71]. O

OSiCl3 +

n-Bu

Me

H

O

cat. (10 mol %)

OH Me

CH2Cl2, −78oC n-Bu

OTBS

OTBS

24

68 Me N O P N N Me

(S,S)-45 (47%) syn/anti, 2.7/1

69 Me N O P N N Me (R,R)-45 (50%) syn/anti, 1/15.6

Scheme 7.30

Catalyzed aldol additions to chiral aldehydes.

Me N O P N N Me 72 (37%) syn/anti, 1/6.7


OSiCl3

O

OH

CH2Cl2 Ph

+ PhCHO

0 oC n-5

n-5

O

OH

73 (90%) syn/anti, 22/1

O

OH

74 (92%) syn/anti, 49/1

n =5, 6, 7 O

OH

75 (90%) syn/anti, 19/1

Scheme 7.31

Uncatalyzed aldol additions of cyclic trichlorosilyl enolates.

7.4.2

Aldol Additions of Cyclic Trichlorosilyl Enolates

In the absence of a Lewis base catalyst, cycloalkanone-derived trichlorosilyl enolates undergo aldol additions to benzaldehyde even at 0 C (Scheme 7.31) [53, 76, 77]. Excellent yields of syn aldol products can be obtained under these conditions. The syn selectivity derived from the E-configured enolate suggests that the reaction proceeds through a closed, boat-like transition structure. The generality of uncatalyzed aldol additions with 20 has been demonstrated in reactions with a variety of aldehydes (Scheme 7.32). Additions with 20 provide high yields of aldol products with modest to high syn selectivity [76]. The rate of the reaction can be correlated with aldehyde structure. The reactions are significantly slower for bulky aldehydes than for smaller ones. Aliphatic aldehydes are less reactive, presumably because of their attenuated Lewis basicity. The aldehyde structure also affects the diastereoselectivity of the aldol reaction. The steric bulk around the aldehyde carbonyl group has a deleterious effect on diastereoselectivity, as is illustrated by comparison of cinnamaldehyde and a-methylcinnamaldehyde. Aliphatic aldehydes are also poorly selective, as is exemplified by aldol addition to cyclohexane carboxaldehyde. In such reactions the energy difference between the boat- and chair-like transition structures is assumed to be small (vide supra). From simple analysis of the transition structure model for the uncatalyzed process it is clear that the steric bulk of the aldehyde increases steric congestion in the favored boat transition structure (Figure 7.8, iv). The reactivity of 20 has been examined at low temperature to assess the rate of the background reaction in the context of the asymmetric, catalytic process. Aldol addition of 20 to benzaldehyde at 78 C results in 19% conversion after 2 h, indicating that 20 is more reactive than the methyl ketone-derived enolates (c.f. Scheme 7.24). Although the background reac-

263

264


OSiCl3

O

OH

CH2Cl2 R

+ RCHO

0 oC, 1 - 36 h

20 O

O

OH

OH

O

OH

Ph Ph 74 (92%); syn/anti, 49/1 O

76 (83%); syn/anti, 49/1 O

OH

OH

Ph

77 (91%); syn/anti, 36/1 O

OH Ph

Me 78 (86%); syn/anti, 6/1

79 (92%); syn/anti, 1/1

80 (82%); syn/anti, 5.3/1

Scheme 7.32

Uncatalyzed addition of 20 to different aldehydes.

tion is rather significant in the aldol addition of 20 at low temperature, in the presence of a phosphoramide the catalyzed pathway becomes dominant. An extensive survey of catalysts for the addition of 20 to benzaldehyde showed that several chiral phosphoramides catalyzed the reaction efficiently (Scheme 7.33). The stereoselectivity was highly dependent on catalyst structure. Among the catalysts shown below, the stilbene-1,2-diamine-derived catalyst 45 is the most enantioselective. For other catalysts diastereo- and enantioselectivity were lower. The N,N 0 -diphenylphosphoramide 81 results in remarkably high syn diastereoselectivity, albeit with modest enantioselectivity. As shown in the reactions using 82, the phosphorus stereogenic center has no significant effect on stereoselectivity. The strong dependence of the diastereomeric ratio on catalyst structure again implies competition between chair- and boat-like transition structures. As discussed in Section 7.9, the primary pathway in the catalyzed aldol addition of trichlorosilyl enolates using 45 involves a chair-like transition structure organized around a cationic, hexacoordinate silicon atom bound by two phosphoramide molecules. Thus for an E-configured enolate the corresponding anti aldol product is expected. From this diastereoselectivity it is clear that in the reaction catalyzed by 45 the two-phosphoramide pathway is favored, because the anti product is obtained from the E enolate. The reaction with 81, on the other hand, proceeds predominantly through a boat-like transition structure involving one phosphoramide, enabling formation of the syn aldol product from the E enolate. For other catalysts the energy difference between the two transition structures is very small and so poor diastereoselectivity is obtained.


O

OSiCl3

OH

cat. (10 mol %) Ph

+ PhCHO CH2Cl2, −78oC 2h

20 Ph Ph

Me N O P N N

74 Me N O P N N Me

Me N O P N N

Me

Me

(S,S)-45 (94%) syn/anti, 1/50 er (anti), 27.6/1

(R,R)-64 (91%) syn/anti, 1/2.0 er (syn), 1.00/1 er (anti), 1/3.00

(R)-65 (87%) syn/anti, 3.2/1 er (syn), 1/3.00 er (anti), 3.55/1 Me

Ph Ph

Ph N O P N N Ph

(S,S)-81 (95%) syn/anti, 97/1 er (syn), 3.08/1

N N P O N

Me

(S,S)-82 (94%) syn/anti, 1/1.1 er (syn), 1.08/1 er (anti), 1/1.22

Me N N P N O

Me

(S,R)-82 (96%) syn/anti, 1/3.1 er (syn), 1.06/1 er (anti), 1/1.15

Scheme 7.33

Catalysts for the addition of 20 to benzaldehyde.

Analysis of the absolute configurations of the products enables construction of a crude transition state model that explains the overall arrangement of the components. The absolute configuration of the aldol product 74 from the reaction using (S,S)-45 has been established to be (2R,1 0 S) by singlecrystal X-ray analysis of the corresponding 4-bromobenzoate. This observation, in conjunction with the results obtained for acyclic Z enolates, offers important insights into the arrangement of the aldehyde relative to the enolate in the transition structure, and into factors that determine the absolute configuration of the aldol adduct (Figure 7.11). The configuration of the chiral phosphoramide determines the face of enolate that undergoes aldolization. On the other hand, the chair or boat transition structure determines the face of aldehyde to be attacked. For example, when (S,S)-45 is used as catalyst, the Si face of the enolate is blocked (Figure 7.11). Placement of aldehyde in a chair-like transition structure will then correctly predict the absolute configuration of the major diastereomer. The phosphoramide 45 is also an effective catalyst for the additions of other cyclic ketone-derived enolates (Scheme 7.34) [77]. Both cyclopentanoneand cycloheptanone-derived enolates provide anti products with good

265

266


configuration of phosphoramide

chair or boat transition structure

Si-C(2) R

phosphoramide configuration O

Si

R

O H

Cl3SiO

OH

Re

Re-C(2)

chair or boat transition structure

Fig. 7.11

Factors leading to the observed configuration.

enantioselectivity. It is interesting to note that diastereoselectivity for these reactions is sensitive to the rate of mixing; slow addition of aldehyde is therefore necessary to obtain reproducible and high diastereoselectivity. The synthetic utility of the aldol addition of 20 has been expanded by examining a wide range of aldehydes of different structure (Scheme 7.35). Enantioselectivity is usually good to excellent for the anti diastereomers. For addition of 20 to different aldehydes excellent anti selectivity is always obtained except for use of phenylpropargyl aldehyde. In this particular system there is no obvious relationship between stereoselectivity and aldehyde structure. Steric bulk around the aldehyde carbonyl seems to enhance diastereoselectivity and enantioselectivity in additions to benzaldehyde and to 1-naphthaldehyde. The lower diastereoselectivity observed in the addition to phenylpropargyl aldehyde can be attributed to the lack of facial differentiation for the aldehyde, because the substituents (H and acetylenic groups) are similar in size. Addition of 20 to aliphatic aldehydes does not, unfortunately, furnish the corresponding aldol products under catalysis by chiral phosphoramides. This may be caused by competitive enolization of the aldehyde by the basic O

OSiCl3

OH

(S,S)-45 (10 mol %) + PhCHO n-5

O

OH

74 (95%) syn/anti, 1/61 er (anti), 27.6/1

Ph

CH2Cl2, −78oC

n = 5, 6, 7

n-5

O

OH

73 (98%) syn/anti, 1/22 er (anti), 7.13/1

O

OH

75 (91%) syn/anti, 1/17 er (anti), 9.87/1

Scheme 7.34

Catalyzed aldol additions of a variety of cyclic enolates to benzaldehyde.


OSiCl3

O

OH

(S,S)-45 (10 mol %) R

+ RCHO CH2Cl2, −78oC

20

O

O

OH

O

OH

OH

Ph Ph 74 (95%) syn/anti, 1/61 er (anti), 27.6/1

O

76 (94%) syn/anti, OPiv > OBn. This order suggests that a pathway involving chelation of the cationic silicon might become possible with more coordinating oxygen functions (vide infra) [81]. The use of (R,R)-45 represents the matched case in which the sense of external stereoinduction is the same as that of internal stereoinduction, whereas in the use of (S,S)-45 the sense of stereoinduction is opposite, leading to attenuated selectivity. The predominant syn selectivity is rationalized by the model depicted in Figure 7.15. The preferred conformation of the resident stereogenic center again places the oxygen substituent in the plane of the enol double bond as explained above. The enolate faces are discriminated not only by the chiral phosphoramide but also by the substituents on the resident stereogenic center. In the chair-like transition structure xvi attack of the enolate on the Re face of the aldehyde leads to the syn diastereomer observed. In this model (R,R)-45 blocks the more sterically hindered face (syn to the methyl group) of the enolate, thus matching the internal and external stereoinduction. On the other hand (S,S)-45 prevents approach of the aldehyde from sterically less hindered face (anti to the methyl group) of the enolate (xvii, Figure 7.15). In this case, the internal and external stereoinductions oppose each other, resulting in significantly attenuated diastereoselectivity.

7.5 Diastereoselective Additions of Chiral Enoxytrichlorosilanes

277

Cl OP(NR"2)3 OSiCl3 Me

OP(NR"2)3

Cl Cl

Si

O O

O Me

RO Me H H R'

+ R'CHO OR

OH R'

OR

xviii

anti

Fig. 7.16

Competitive, chelated transition structure for catalyzed aldol addition of lactate-derived trichlorosilyl enolates.

The attenuated diastereoselectivity when protecting groups other than OTBS are used might indicate the intervention of a competitive chelated transition structure (Figure 7.16). In the transition structure xviii, the oxygen on the non-participating side is coordinated to the Lewis acidic silicon. As the coordinating capacity of oxygen increases, the transition structure xviii might be favorable, and attenuated diastereoselectivity is observed. Catalyzed additions of 29 to olefinic aldehydes have also been demonstrated. For example, addition of 29 to crotonaldehyde catalyzed by 45 gives the corresponding aldol product in good yield (Scheme 7.45). Although the diastereoselectivity obtained in these reactions is lower, the stereochemical trend remains the same. The (R,R)-45 catalyst is the matched case providing syn-102 with good diastereoselectivity. Ethyl Ketone-derived Enolates The stereochemical course of addition of the corresponding ethyl ketonederived enolates incorporates all three forms of stereoselection [82]. Aldol addition of (Z)-103 under the action of phosphoramide catalysis provides the syn,syn (relative, internal) aldol product with high selectivity (Scheme 7.46). A survey of chiral and achiral phosphoramides shows a remarkable 7.5.1.2

OTMS Me OTBS 99

Hg(OAc)2 SiCl4 CH2Cl2

Me

CHO OSiCl3 Me 45 (5 mol %) Me OTBS 29

Scheme 7.45

Catalyzed addition of 29 to crotonaldehyde.

−78 oC, 4.5 h

O

OH Me

OTBS

(S,S)-45

102 (80%) syn/anti, 1.2/1

(R,R)-45

102 (81%) syn/anti, 6.2/1

278


OSiCl3 Me +

Me

O

cat. (15 mol %) PhCHO CH2Cl2, −78oC 2-8h

OTBS

Ph

Me N O P N N Me

(R,R)-45 (87%) rel. syn/anti, 16/1 int. syn/anti, >50/1

Ph

TBSO

Me

(syn,syn)-104

(Z )-103 Ph

OH

Me

Ph Ph

Me N O P N N Me

(S,S)-45 (80%) rel. syn/anti, 15/1 int. syn/anti, 30/1

Ph Ph

Ph N O P N N Ph

(R,R)-81 (65%) rel. syn/anti, 15/1 int. syn/anti, 3/1

Me N O Me P Me N N Me Me Me HMPA (79%) rel. syn/anti, 15/1 int. syn/anti, 30/1

Scheme 7.46

Aldol additions of (Z)-103 to benzaldehyde catalyzed by different phosphoramides.

trend. All the phosphoramides yield the syn relative aldol product with perfect Z/E to syn/anti correlation, indicating that a chair-like transition structure is maintained. These results are intriguing considering that bulky phosphoramides such as (R,R)-81 favor the boat-like transition state in the addition of the cyclohexanone-derived trichlorosilyl enolate [76]. Internal stereoselectivity varies for different catalyst structures. For the stilbene-1,2-diamine derived catalyst, (R,R)-45, excellent internal syn selectivity is obtained. Use of the enantiomeric catalyst (S,S)-45 does not reverse the sense of internal diastereoselection and the aldol product is again obtained with good internal syn selectivity. These observations indicate the overwhelming influence of the resident stereogenic center and the stereochemical course of the aldol addition is determined solely by this factor. To support this explanation, additions using a variety of achiral phosphoramides including HMPA demonstrate that the internal syn aldol product is preferentially formed under catalyzed conditions, irrespective of catalyst configuration. Bulky phosphoramides such as (R,R)-81 result in attenuated internal diastereoselectivity compared with that resulting from other phosphoramides. The observed stereochemical outcome can be explained by the nonchelation model that places the OTBS substituent in the enolate in plane with the enolate double bond to minimize the dipole moment (Figure 7.17) [73, 80, 82]. The two enolate faces are differentiated by the size of the groups on the stereogenic center (H compared with Me), and the aldehyde approaches from the less hindered Si face of the Z enolate. The chair-like arrangement of the aldehyde in the transition structure leads to the formation of the observed syn,syn diastereomer. The low selectivity observed when bulky phosphoramides are used can be rationalized by the intervention of another transition structure, xx [82]. These phosphoramides are known to


H H Cl OP(NR2)3 Me Si OP(NR2)3 O Ph O Cl

OSiCl3 Me

Me

O

TBSO

OTBS (Z )-103

279

OH

Me

Ph

TBSO

Me

Me

(R2N)3PO

(syn,syn)-104

xix

+ PhCHO

TBS O Cl H OP(NR2)3 O Si O Cl Ph Me

Me H

O

OH

Me

Ph

TBSO

Me

(syn,anti )-104

xx Fig. 7.17

Proposed transition structures for aldol addition of (Z)-103.

favor boat-like transition structures via a mechanism that involves only one phosphoramide in the stereodetermining step [66]. In this pentacoordinate species, it is possible that the silyloxy group could coordinate the Lewis acidic silicon to form an octahedral, cationic silicon intermediate. This internal coordination might favor the chair-like arrangement over the usual boat-like transition structure for these phosphoramides. Although the coordinating capacity of the TBS ether is modest at best [81], the proximity of the silyloxy group to the cationic silicon is believed to enhance the possibility of this type of chelation [83]. In this model, the aldehyde now approaches from the Re face of the enolate leading to the syn,anti diastereomer. The aldol additions of (Z)-103 to different aldehydes illustrate the generality of this process (Scheme 7.47). The in-situ generation of trichlorosilyl enolate (Z)-103 from the corresponding TMS enol ether further demonstrates not only the synthetic utility of this reagent but also the improved OTMS Me

Me

Hg(OAc)2 SiCl4 CH2Cl2 rt

OTBS (Z )-103 O

TBSO

O

OH

CH2Cl2, −78oC

104 (87%) rel. syn/anti, 15/1 int. syn/anti, >50/1

TBSO

OH R

TBSO

Me O

O

Ph Me

O Me

syn,syn

OH

Me

Me

(R,R)-45 (5 mol %) RCHO

Me


Scheme 7.47

Aldol addition of (Z)-103 to different aldehydes.

O

OH

Me

Me TBSO

TBSO

OH

Me Me

Me



Ph

280


yield and selectivity of the overall process. The addition can be catalyzed by either (R,R)-45 or HMPA, and syn,syn-aldol products can always be obtained selectively. The relative and internal diastereoselectivities are all perfect when (R,R)-45 is used as the catalyst. The diastereoselectivity and yield are slightly attenuated under the action of catalysis by HMPA. 7.5.2

Aldol Addition of b-Hydroxy-a-Methyl Ketone-derived Enoxytrichlorosilanes Methyl Ketone-derived Enolates The effects of a-methyl and b-hydroxy groups on the stereochemical course of aldol additions with trichlorosilyl enolates have been investigated. This type of enolate structure is synthetically important because the resulting aldol product resembles the highly oxygenated structural motif for a variety of polypropionate natural products. Not surprisingly, diastereoselective aldol additions of this type of enolate have already been demonstrated for lithium, boron, and tin enolate aldol additions [1d, 79, 84]. The effect of the a-methyl stereogenic center has been determined in aldol additions of the methyl ketone-derived trichlorosilyl enolate (S)-108 (Scheme 7.48) [85]. The addition of 108 using (R,R)-45 as catalyst provides the syn aldol product selectively. The use of (S,S)-45 enables formation of anti-109, albeit with attenuated selectivity. The intrinsic internal selectivity arising from an a-methyl stereogenic center is determined by examining the diastereoselectivity of the aldol addition using the achiral phosphoramide 72. The internal selectivity is low but slightly favors the 1,4-syn diastereomer. The inherent selectivity is rationalized by means of a transition structure model in which transition structure xxi (Figure 7.18) involves octahedral, cationic silicon in a chair-like arrangement of groups. To avoid steric interaction between the phosphoramide-bound silicon and the non-participating substituent on the enolate the least sterically demanding substituent (hydrogen) is placed in plane with the enolate CaO bond. This model predicts 7.5.2.1

TBSO

OSiCl3

cat. (5 mol %) + PhCHO

CH2Cl2, −78 oC

Me (S)-108

Ph Ph

Me N O P N N Me

(R,R)-45 (79%) syn/anti, 10/1

Ph Ph

TBSO

O

Ph Me syn -109

Me N O P N N

Me N O P N N

Me

Me

(S,S)-45 (76%) syn/anti, 1/6

OH

72 (51%) syn/anti, 5/1

Scheme 7.48

Aldol addition of 108 to benzaldehyde catalyzed by phosphoramides.

OH

+

Ph

anti-109


TBSO

OSiCl3

H H Cl Me OP(NR2)3 RL Si OP(NR2)3 O Ph O Cl

72 + PhCHO

Me (S)-108

TBSO

281

O

OH Ph

Me

RL = CH2OTBS xxi

syn-109

Fig. 7.18

Stereochemical course of aldol addition of (S)-108 to benzaldehyde.

approach of benzaldehyde from the less sterically demanding methyl group side, leading to the syn diastereomer. The generality of this aldol addition has been investigated with a wide variety of aldehydes (Scheme 7.49). The trichlorosilyl enolate 108 generated in situ (from TMS enol ether 110) reacts with aromatic, conjugated, and TBSO

SiCl4 Hg(OAc)2

OTMS

CH2Cl2

Me (S)-110

OSiCl3

TBSO

RCHO TBSO 45 (10 mol %)

O

R

CH2Cl2, −78oC

Me

OH

OH

108

O

OH

TBSO

syn

O

OH

Ph

anti

TBSO

O

112 (34%) syn/anti, 10.1/1 TBSO

OH

Me Me

OH

Me

111 (81%) syn/anti, 8.0/1

OH

O

O

Ph

Me

109 (80%) syn/anti, 19.0/1 TBSO

TBSO Ph

Me

O

OH Me

Me

Me

Me

113 (78%) syn/anti, 24.0/1

Me

114 (85%) syn/anti, 4.9/1

Me Me

115 (73%) syn/anti, 27.9/1

Using (S,S)-45 TBSO

O

OH

TBSO

O

Ph Me

109 (75%) syn/anti, 1/7.3 O

TBSO

O

Me

113 (75%) syn/anti, 1/4.6

Ph 112 (22%) syn/anti, 1/2.5 TBSO

OH

Me Me

OH

Me

111 (82%) syn/anti, 1/4.3

OH

O

Ph

Me

TBSO

TBSO

OH

O

OH Me

Me Me 114 (83%) syn/anti, 1/2.9

Scheme 7.49

Aldol addition of 108 to different aldehydes catalyzed by 45.

R

Me

Using (R,R)-45 TBSO

+

Me

Me Me

115 (78%) syn/anti, 1/6.5

282


Catalyzed aldol additions of 35 and 116 to benzaldehyde. relative RO

OSiCl3 Me +

O H

cat. (10 mol %) Ph

Me 35 : R = TBS 116: R = TIPS

RO

CH2Cl2, −78 ˚C

OH

O

Ph Me

Me 117: R = TBS

internal 118: R = TIPS

Entry

Enolate

Z/E

Catalyst

Yield

Relative dr (syn/anti)

Internal dr a (syn/anti)

1 2 3 4 5 6 7

(Z)-35 (Z)-35 (E)-35 (E)-35 (Z)-116 (Z)-116 (Z)-116

50/1 50/1 1/50 1/50 50/1 50/1 50/1

(R,R)-45 (S,S)-45 (R,R)-45 (S,S)-45 (R,R)-45 (S,S)-45 72

72 82 72 72 84 82 81

9/1 12/1 1/4 1/2 53/1 32/1 27/1

10/1 1/7 6/1 2/1 24/1 1/8 5/1

a Ratio

of major relative diastereomer.

aliphatic aldehydes. Additions to aromatic aldehydes result in high yields and good diastereoselectivity. Additions to the olefinic aldehydes always result in good yields, but selectivity is quite variable. Interestingly, steric bulk around the carbonyl group has a beneficial effect on diastereoselectivity. Unhindered aliphatic aldehydes are significantly less reactive, resulting n only modest yields of the aldol products. Ethyl Ketone-derived Enolates When the corresponding ethyl ketone enolate reacts with aldehydes, an additional stereogenic center is formed (Table 7.4) [86]. The reactions of both (Z)-35 and (E)-35 have been examined, enabling the effect of enolate geometry on diastereoselectivity to be probed. Several interesting trends can be noted from aldol additions of 35 and 116 to benzaldehyde. Additions of (Z)35 are generally syn (relative) selective, indicating that a chair-like transition structure is involved in the dominant pathway (Table 7.4, entries 1 and 2). The diastereoselectivity observed for (E)-35 is only marginal, however, and the anti (relative) diastereomer is preferred (Table 7.4, entries 3 and 4). In both reactions the E/Z ratio of the enolate does not translate strictly into the relative syn/anti ratio. This observation can be accounted for by the presence of competitive boat-like transition structures that lead to the minor diastereomers. Fortunately, the relative diastereoselectivity can be significantly improved by changing the protecting group from TBS to the TIPS (Table 7.4, entries 5–7). The intrinsic selectivity has been determined using the achiral catalyst 72, and small preference for the internal syn diastereomer was observed (Table 7.4, entry 7). The internal diastereoselectivity is also largely determined by 7.5.2.2


catalyst configuration in the addition of Z enolates. Reactions with (R,R)-45 corresponds to matched cases wherein the sense of internal and external diastereoselection is the same. Thus, higher internal selectivity is obtained with (R,R)-45 than with (S,S)-45. In additions of (E)-35, internal selectivity is modest, and there is no dependence on catalyst configuration. Additions of (Z)-116 to a variety of aldehydes furnish the syn (relative) diastereomers in good yields with good to excellent selectivity (Scheme 7.50). The structure of the aldehyde makes an important contribution to the relative diastereoselectivity. Bulky aldehydes such as 1-naphthaldehyde and tiglic aldehyde result in significantly lower diastereoselectivity. The internal selectivity also depends on the aldehyde structure. Selectivity is significantly higher for aromatic aldehydes than for olefinic aldehydes. The internal diastereoselection is always determined by catalyst configuration. When (R,R)45 is used high syn (internal) selectivity can be achieved, and anti (internal) diastereomers can be obtained by use of (S,S)-45, albeit with attenuated selectivity. The dramatic difference between the behavior of acyclic Z and E enolates in these aldol additions has already been discussed above (Figure 7.12, Section 7.4). Here again, addition of (Z)-35 results in good syn relative selectivity and addition of (E)-35 is only slightly anti relative selective. In the addition of (Z)-35 the diastereoselectivity observed can be better rationalized by the chair-like transition structure xxii (Figure 7.19). The transition structure xxii is consistent with the small internal diastereoselection exerted by the stereogenic center on the enolate. The conformation of the stereogenic center in xxii minimizes steric interaction between the substituents on the non-participating side of the enolate and the bulky ligands on the hypercoordinate silicon. This transition state model leads to the observed (syn,syn)-117. The poor selectivity observed for addition of (E)-35 is explained by the competitive transition structure models chair-xxiii and boat-xxiv. In chair-xxiii A 1; 3 strain between the equatorial methyl group and the nonparticipating substituent of the enolate is minimized [2c]; the disposition of the a-methyl and CH2 OTIPS groups toward the bulky silicon center can, however, cause severe steric congestion. This interaction can be significant enough to make the boat-xxiv transition structure more favorable. The boatxxiv is easily accessed simply by placing the silicon group in the least crowded quadrant. The anti coordination of silicon to the aldehyde places the phenyl group of benzaldehyde in the pseudo-axial position, leading to the syn (relative) diastereomer. 7.5.3

Addition of Enoxytrichlorosilanes with a b-Stereogenic Center

Thus far the effect of an a-stereogenic center on the stereochemical course of aldol additions of trichlorosilyl enolates has been described. Diastereo-

283


284

TIPSO

RCHO 45 (10 mol %)

OSiCl3 Me + RCHO

TIPSO

OH R + diastereomers

CH2Cl2, −78oC

Me (Z )-116

O

Me Me syn,syn

Using (R,R)-45 TIPSO

O

OH

TIPSO

O

OH

TIPSO

OH

O

Ph Me

Ph

Me

Me

118 (84%) rel. syn/anti, 53/1 int. syn/anti, 24/1

Me


TIPSO

O


TIPSO

OH

O

OH Me

Me Me

Me

Me

Me

Me

121 (90%) rel. syn/anti, >50/1 int. syn/anti, 15/1

Me

Me


Using (S,S)-45 TIPSO

O

OH

TIPSO

O

OH

TIPSO

O

OH

Ph Me

Ph

Me

Me

118 (82%) rel. syn/anti, 32/1 int. syn/anti, 1/8 TIPSO

Me

Me

119 (79%) rel. syn/anti, 14/1 int. syn/anti, 1/17 O


TIPSO

OH

O

OH Me

Me Me

Me

121 (85%) rel. syn/anti, >50/1 int. syn/anti, 1/5

Me

Me

Me

Me


Scheme 7.50

Aldol additions of (Z)-116 to different aldehydes catalyzed by 45.

selectivity clearly depends on the nature of the a-substituent. The a-oxygen substituent of lactate-derived enolates has a strong effect on the diastereoselectivity of the catalyzed aldol addition whereas the a-hydroxymethyl stereogenic center of hydroxybutyrate-derived enolates plays a minor role only in the diastereoselection, and catalyst configuration primarily determines the stereochemical course of the aldol addition.


L L L H Si O L O

H

(Z )-35 + PhCHO

(R2N)3PO

Me TBSOCH2 Ph H Me

Cl (syn,syn)-117

L = Cl, (R2N)3PO

xxii

OTBS H

H (E )-35 + PhCHO

(R2N)3PO

Cl

Me SiLn O O

Ph Me

(anti,anti )-117

H chair-xxiii

Me Ph H

OTBS Cl (syn,anti )-117

O O

H Me H

Si Ln

boat-xxiv Fig. 7.19

Proposed transition structures for addition of (Z)- and (E)-35.

The effect of a remote stereogenic center on diastereoselection in aldol additions is also worth investigation. In the aldol addition of boron enolates it has been demonstrated that a b-oxygen stereogenic center can strongly influence the stereochemical course of the reaction [87]. This class of enolate is also important because these aldol products have a 1,3,5-oxygenated carbon chain, a common motif in a variety of natural products [2c]. The aldol reactions of 123 under phosphoramide catalysis are summarized in Table 7.5 [88]. The intrinsic selectivity determined using 72 is almost negligible, indicating that the b-stereogenic center does not exert significant stereoinduction during addition of this enolate. Interestingly, use of chiral phosphoramides affords only marginal improvement in diastereoselectivity. Additions of ethyl ketone-derived enolates (Z)- and (E)-36 are also catalyzed by 45 (Table 7.6). Good relative syn diastereoselectivity is observed for addition of (Z)-125. As previously observed for addition of (Z)-35, changing from the TBS protecting group to TIPS has a beneficial effect on the dia-

285

286


Catalyzed aldol addition of 123 to benzaldehyde. TBSO

OSiCl3 + PhCHO

Me

cat. (10 mol %) CH2Cl2, −78 ˚C

(S)-123

TBSO

O

OH

Me

Ph 124

Entry

Catalyst

Yield, %

syn/anti

1 2 3

(R,R)-45 (S,S)-45 72

72 75 55

1/2.5 1.3/1 1/1.4

stereoselectivity and additions of (Z)-36 result in significantly higher relative diastereoselectivity. Addition of (E)-36 is again unselective and, surprisingly, syn (relative) selective. The intrinsic internal diastereoselection is again almost negligible (Table 7.6, entry 6). Thus, internal diastereoselectivity is primarily controlled by catalyst configuration. The match/mismatch effect in these aldol additions is not significant. This observation is in contrast to the strong 1,5-anti stereoinduction observed for boron enolate aldol additions [87]. The stereochemical model in this reaction should be analogous to that proposed for achiral enolate additions (Figure 7.11, Section 7.4). Aldol additions of (Z)-36 to a variety of aldehydes provide syn (relative) diastereomers selectively (Scheme 7.51). Excellent syn (relative) selectivity is obtained in the reaction with cinnamaldehyde. The internal selectivity is controlled by catalyst configuration, enabling selective preparation of both syn (relative) diastereomers. Tab. 7.6

Catalyzed aldol additions of (Z)-125, (Z)-36, and (E)-36 to benzaldehyde. relative RO

OSiCl3 Me + PhCHO

Me 125: R = TBS 36: R = TIPS

cat. (10 mol %) CH2Cl2, −78 ˚C

RO

O

OH

Me

Ph Me 126: R = TBS 127: R = TIPS

internal

Entry

Enolate

Z/E

Catalyst

Yield, %

Relative dr (syn/anti)

Internal dr a (syn/anti)

1 2 3 4 5 6

(Z)-125 (Z)-125 (Z)-36 (Z)-36 (E)-36 (Z)-36

12/1 12/1 16/1 16/1 1/15 30/1

(R,R)-45 (S,S)-45 (R,R)-45 (S,S)-45 (S,S)-45 72

59 60 84 86 80 83

6/1 12/1 30/1 26/1 3/1 29/1

14/1 1/14 16/1 1/10 1/1 1.4/1

a Ratio

of major relative diastereomer.


287

relative TIPSO

OSiCl3 Me + RCHO

TIPSO

cat. (10 mol %)

Me 36 (Z/E, 32/1)

O

OH

Me

CH2Cl2, −78 ˚C

R Me

internal

Using (R,R)-45 TIPSO

O

OH

Me

Ph

TIPSO

OH

O

Me

TIPSO Me

Me

O

Me

Ph

Me


OH

Me 129 (80%) rel. syn/anti, >50/1 int. syn/anti, 1/9.6


Using (S,S)-45 TIPSO

O

OH

Me

Ph Me


TIPSO

O

OH

Me

TIPSO Me

Me 128 (83%) rel. syn/anti, 37/1 int. syn/anti, 6/1

O

OH

Me

Ph Me 129 (75%) rel. syn/anti, >50/1 int. syn/anti, 7.5/1

Scheme 7.51

Catalyzed aldol addition of (Z)-36 to different aldehydes.

These aldol additions using three different classes of chiral trichlorosilyl enolates are interesting examples of double stereodifferentiating aldol additions. In the matched cases, high diastereoselectivity is obtained with the appropriate chiral phosphoramide catalyst. In aldol additions of lactate-derived enolates strong internal stereoinduction dominates the stereochemical course of the reaction. For the other two types of enolate, diastereoselection is primarily determined by catalyst configuration (external diastereoselection), enabling access to two diastereomers. The effect of the a and b stereogenic centers described above would be very important in the construction of a stereodyad or triad in a predictable manner. The compatibility of common protecting groups with trichlorosilyl reagents is clearly established, and the in-situ generation of trichlorosilyl enolate from the corresponding TMS enol ether further enhances the synthetic utility of this process. In the addition of the substituted enolates, the syn (relative) diastereomers can be obtained with high selectivity starting with Z enolates, although, because E enolates do not undergo selective aldol addition, the corresponding anti (relative) diastereomers cannot be accessed by these methods.

288


7.6

Aldol Additions of Aldehyde-derived Enoxytrichlorosilanes

In the previous section the aldol addition of ketone-derived enolates was discussed and illustrated examples were used to document the synthetic utility of these reactions. This section deals with aldol additions of trichlorosilyl enolates derived from aldehydes. This type of aldol addition would be a particularly useful and practical approach to the construction of poly-propionate-derived natural products. The stereoselective aldol addition of an aldehyde-derived enolate and an aldehyde remains a challenging topic [3a]. The difficulties associated with this process arise from complications inherent in the self-aldol reaction of aldehydes:

. polyaldolization resulting from multiple additions to the aldol products; . Tischenko-type processes among the products; and . oligomerization of the aldol products. Only recently several approaches have been developed to address these problems [89]. Denmark et al. have achieved the first catalytic, enantioselective crossed-aldol reaction of aldehydes utilizing the Lewis-base-catalyzed aldol addition of trichlorosilyl enolates [49]. More recent developments have been made in direct, catalytic crossed-aldol reactions of aldehydes using proline, although an excess of one component is needed [90]. In the Lewis base catalysis approach, the immediate aldol adduct obtained by addition of an aldehyde-derived trichlorosilyl enolate is protected as its a-chlorosilyl ether, which is less prone to further additions. The concept is illustrated in the addition of heptanal-derived enolate (Z)-37 to benzaldehyde in the presence of phosphoramide (S,S)-45 (Scheme 7.52). Low-temperature NMR analysis of this adduct revealed it exists in the form of the a-chlorosilyl ether 130. Because the aldolate occurs as a chelate complex, further reactions leading to a variety of side products are prevented. The chlorosilyl ether intermediate can be hydrolyzed to obtain either its aldehyde or acetal (Scheme 7.53). When 130 is quenched in a mixture of aqueous THF and triethylamine (basic conditions), the corresponding aldehyde is obtained in excellent yield. When dry methanol is used for quench-

(S,S)-45 (10 mol %)

OSiCl3 n-Pent

H

+ PhCHO CDCl3, −60oC

Cl H H Si O Ph Cl O Cl n-Pent

(Z )-37 Scheme 7.52

Catalyzed aldol addition of (Z)-37 to benzaldehyde.

130

7.6 Aldol Additions of Aldehyde-derived Enoxytrichlorosilanes

THF/H2O/Et3N (9/0.5/0.5)

OH

O

Ph (S,S)-45 (10 mol %)

OSiCl3 n-Pent

H

+ PhCHO

289

H n-Pent

Cl

Cl Si O O

131 (95%)

H Cl

CHCl3, −65 oC Ph n -Pent

(Z )-37

130 OH

OMe

Ph

MeOH

OMe n-Pent

132 (89%) Scheme 7.53

Quenching of the chlorosilyl ether intermediate 130.

ing, the chlorosilyl ether is converted to its dimethyl acetal 132 which can be isolated in excellent yield. High diastereoselectivity is observed in additions of geometrically defined enolates (Z)- and (E)-37 (Scheme 7.54). The diastereomeric composition of the aldol product strictly mirrors the E/Z ratio of the enolate, suggesting the reaction proceeds exclusively via a closed transition structure. From the correlation of Z enolate with syn diastereomer and E enolate with anti diastereomer, a chair-like transition structure can be inferred. Although nearly perfect correlation is achieved between the E/Z ratio of the enolate and the syn/anti ratio of the aldol product, the enantiose-

OSiCl3 n-Pent

H

(S,S)-45 (10 mol %)

HCl

CHCl3, −65 oC

MeOH

+ PhCHO

(S,S)-45 (10 mol %)

H OSiCl3

OMe

Ph

OMe n-Pent

132 (89%) syn/anti, 99/1 er (syn), 1.7/1

37 (Z/E, 99/1)

n-Pent

OH

+ PhCHO CHCl3, −65 oC

OH

HCl MeOH

OMe

Ph

OMe n-Pent

37 (E/Z, 24/1) 132 (90%) syn/anti, 1/24 er (anti), 1.7/1 Scheme 7.54

Dependence of enolate geometry of aldol additions of 37.

290


OSiCl3 n-Pent

H

(R,R)-48 (10 mol %)

HCl

CHCl3, −65 oC

MeOH

+ PhCHO

H OSiCl3

OMe

Ph

OMe n-Pent

(2S,3S)-132 (92%) syn/anti, 99/1 er (syn), 19/1

37 (Z/E, 99/1)

n-Pent

OH

(R,R)-48 (10 mol %)

HCl

CHCl3, − 65 oC

MeOH

+ PhCHO

OH

OMe

Ph

OMe n-Pent

37 (E/Z, 32/1) (2R,3S)-132 (91%) syn/anti, 1/32 er (anti), 10/1

(R,R)-48 =

Me N O P N N Me Me

CH2 2

Scheme 7.55

Aldol addition of 37 to benzaldehyde catalyzed by (R,R)-48.

lectivity obtained by the use of 45 is rather poor. Despite an extensive catalyst survey, no significant improvement was achieved with a wide variety of monophosphoramides. A significant improvement in the enantioselectivity is achieved by using dimeric phosphoramides. Among these catalysts the binaphthyldiamine-derived dimer 48 affords the highest enantioselectivity for this transformation (Scheme 7.55). Additions of (Z)-12 to a variety of aldehydes in the presence of only 5 mol% (R,R)-48 provide the corresponding aldol products in excellent yield and with exclusive syn selectivity (Scheme 7.56). Enantioselectivity varies significantly, good selectivity being observed for aromatic aldehydes only. There is no obvious correlation between aldehyde structure and enantioselectivity. It seems that the asymmetric induction provided by the catalyst (R,R)-48 is most effectively transferred for benzaldehyde-like acceptors, and any structural change leads to erosion of enantioselectivity. Aliphatic aldehydes can also be used for aldol addition of (Z)-12. Additions to aliphatic aldehydes are, however, very slow at 65 C, so increased temperature (20 C) and longer reaction times are required for complete reaction. The absolute configuration of syn-133 was assigned by conversion to the corresponding methyl ester, which was unambiguously assigned as the (2S,3S) isomer [91]. The corresponding E enolate also reacts with a variety of aldehydes to give anti b-hydroxy acetals (Scheme 7.57). This high relative diastereoselectivity


(R,R)-48 (10 mol %)

OSiCl3 Me

H

OH

HCl

+ RCHO

R

MeOH

CHCl3, −65 oC 6h

OMe OMe

Me

(Z )-12 (Z/E, 99/1) OH

OMe

Ph

OH

OMe

OMe

Ph

Me

OMe Me

133 (95%) syn/anti, 49/1 er (syn), 9.5/1

134 (86%) syn/anti, 99/1 er (syn), 2.4/1

OH

OH

OMe OMe Ph

Ph

Me 136 (98%) syn/anti, 49/1 er (syn), 1.2/1

OMe

OMe Me (−20 oC, 20 h) 137 (47%) syn/anti, 19/1 er (syn), 1.2/1

OH

OMe

Ph

OMe Me

Me

135 (91%) syn/anti, 32/1 er (syn), 5.3/1 OH

OMe OMe

Me (−20 oC, 20 h) 138 (42%) syn/anti, 32/1 er (syn), 2.6/1

Scheme 7.56

Catalyzed addition of (Z)-12 to different aldehydes.

contrast with the poor diastereoselectivity obtained from addition of E enolates derived from acyclic ketones. These trends in enantioselectivity are also different from those observed for additions of (Z)-12. The highest enantioselectivity is obtained for addition to a-methylcinnamaldehyde whereas addition to benzaldehyde provides only modest enantioselectivity. Markedly higher yields are obtained for addition of (E)-12 to aliphatic aldehydes than for addition of (Z)-12, indicating that (E)-12 is more reactive than (Z)-12. The absolute configuration of anti-133 was established by chemically by correlation with the TBS-protected aldehyde, which has been unambiguously assigned as the (2R,3S) isomer [92]. On the basis of the individual effects of mono-substitution at the Z and E position it was envisaged that higher selectivity might be achieved by employing a disubstituted enolate. Aldol addition to benzaldehyde of adisubstituted trichlorosilyl enolate derived from isobutyraldehyde has been examined using 10 mol% of (R,R)-48 (Scheme 7.58) [93]. The enantiomer ratio of 140 is surprisingly low when compared with the results obtained from addition of (E)- and (Z)-12. For electron-rich aromatic aldehydes and electron-deficient aromatic aldehydes, however, enantioselectivity improves significantly (Scheme 7.59). Important mechanistic insights have been obtained from these observations [93]. It has been suggested that the divergence of enantioselectivity is because of the two different factors determining enantioselectivity for electron-rich and electron-

291

292


(R,R)-48 (10 mol %)

H Me

OSiCl3

OH

HCl

+ RCHO

R

MeOH

CHCl3, −65 oC 6h

OMe OMe

Me

(E )-12 (E/Z, 99/1) OH

OH

OMe

Ph

OMe

OMe

Ph

OMe

133 (97%) syn/anti, 1/99 er (anti), 3.9/1

134 (88%) syn/anti, 1/99 er (anti), 1.7/1

OH

OH

OMe OMe

Me 136 (99%) syn/anti, 1/49 er (anti), 7.3/1

Ph

OMe

Ph

Me

Me

Ph

OH

OMe Me

Me

135 (89%) syn/anti, 1/99 er (anti), 19/1 OH

OMe

OMe

OMe Me (−20 oC, 20 h)

OMe Me (−20 oC, 20 h)

137 (79%) syn/anti, 1/99 er (anti), 4.9/1

138 (69%) syn/anti, 1/99 er (anti), 1.5/1

Scheme 7.57

Catalyzed addition of (E)-12 to different aldehydes.

deficient aldehydes. For electron-poor aldehydes the event determining the stereochemistry is most probably the aldehyde binding process. For electron rich aldehydes, on the other hand, the stereocontrolling step is the aldolization. In both mechanistic extremes, high selectivity can be achieved. The different electronic nature of the aldehydes not only affects enantioselectivity but also reactivity. Additions of 139 to a variety of aldehydes result in modest to good enantioselectivity, albeit with no distinct trend (Scheme 7.60). Additions to aliphatic aldehydes also proceed with good yields and moderate selectivity although elevated temperatures and long reaction times are required. Problems associated with crossed-aldol reactions are successfully overcome by the Lewis-base-catalysis approach, and catalytic, enantioselective (R,R)-48 (10 mol %)

OSiCl3 Me

H Me 139

OH

OMe

HCl OMe

+ PhCHO CHCl3, −65 oC

Scheme 7.58

Catalyzed aldol addition of 139 to benzaldehyde.

MeOH

Me Me 140 (86%) er, 2.3/1


(R,R)-48 (10 mol %)

HCl

CHCl3, − 65 oC

MeOH

OSiCl3 Me

+ RCHO

H Me 139 OH

OH

OMe

OMe Me Me

MeO OMe

OH

142 (80%) er, 7.0/1 OMe

OH

OMe

OMe

OMe Cl

OMe

MeO

Me Me

OMe

Me Me

OMe Me Me

141 (92%) er, 3.1/1

140 (86%) er, 2.3/1 OH

R

OMe MeO

OMe

OH

OMe

OMe Me Me

OH

F3C

143 (85%) er, 8.1/1

OMe

Me Me

Me Me

O2N

144 (86%) er, 9.0/1

145 (89%) er, 10/1

Scheme 7.59

Catalyzed addition of 139 to substituted benzaldehydes.

(R,R)-48 (10 mol %)

HCl

CHCl3, −65 oC

MeOH

OSiCl3 Me

+ RCHO

H Me 139

OH

OMe OMe

OMe Me Me

OH

OMe OMe

OMe

148 (85%) er, 4.4/1

OMe

147 (90%) er, 2.1/1

OMe

Me Me

OMe Me Me

Ph

146 (90%) er, 4.9/1

n-Bu

OMe

R

OH

Me Me

OH

OH

Ph

OH

OMe

Me

OMe

Me Me

Me Me

149 (82%) er, 1.3/1

150 (80%) er, 10/1

Scheme 7.60

Catalyzed aldol addition of 139 to a variety of aldehydes.

293

294


crossed-aldol reactions of aldehydes have been achieved by use of dimeric phosphoramide 48. High diastereoselectivity can be achieved under the conditions described above by using geometrically defined trichlorosilyl enolates. When the chiral bisphosphoramide 48 is used a variety of crossedaldol products are obtained with moderate to good enantioselectivity. The immediate aldol adduct can be recovered as the aldehyde or the acetal, depending on the quenching conditions. Thus the method discussed above will be extremely useful in enantioselective construction of a polypropionate chain.

7.7

Aldol Addition of Trichlorosilyl Ketene Acetal to Aldehydes and Ketones

For trichlorosilyl ketene acetals, enhanced nucleophilicity is expected, because of the additional oxygen substituent compared with ketone-derived enolates [32]. Trichlorosilyl ketene acetal 10 is, indeed, an extremely reactive nucleophile and reactions with a variety of aldehydes occur even at 80 C. Aromatic, conjugated and aliphatic aldehydes all afford excellent yields of the aldol products within 30 min (Scheme 7.61). The compatibility with enolizable and sterically demanding aldehydes attests to the generality of this aldol addition. Several chiral phosphoramides from different structural families have been examined for their capacity to induce enantioselectivity (Scheme 7.62). With 10 mol% of these phosphoramides aldol additions of 10 proceed rapidly at 78 C to give good to excellent yields of the aldol products. Unfortunately, the enantioselectivity obtained in these reactions is poor. Modification of the reaction conditions did not significantly improve enan-

OSiCl3

O

CH2Cl2

+

OMe

R

H

0

oC,

30 min

HO

O

R

OMe

10 HO Ph

HO

O OMe

151 (98%)

HO OMe

O

HO OMe

OMe 154 (96%)

OMe 153 (89%)

O

Ph

O

Ph

152 (94%) HO

HO

O

Ph

O

Me

OMe

Me Me 155 (96%)

Scheme 7.61

Uncatalyzed addition of 10 to a variety of aldehydes.

156 (99%)

7.7 Aldol Addition of Trichlorosilyl Ketene Acetal to Aldehydes and Ketones

OSiCl3

O

OMe 10

R

H

Me N O P N N Me

Ph Ph

(R,R)-64 R = Ph (88%); er 1/1.5 R = t-Bu (76%); er 1/1.8

HO

cat. (10 mol %)

+

CH2Cl2, −78 oC 30 min - 3 h

O

R

OMe

Me N O P N N Me

Me N O P N N Me

(S,S)-45 R = Ph (87%); er 2.0/1 R = t-Bu (78%); er 2.3/1

(R)-65 R = Ph (91%); er 1.6/1 R = t-Bu (91%); er 2.9/1

Scheme 7.62

Catalyzed additions of 10 to benzaldehyde and pivaldehyde.

tioselectivity. The poor enantioselectivity observed can be explained by the competitive, rapid background reaction between 10 and aldehydes. Although the addition of 10 to aldehydes gives modest enantioselectivity only, the extraordinary reactivity of 10 enables aldol addition to ketones. In the absence of Lewis basic promoters, ketene acetal 10 reacts with acetophenone sluggishly at 0 C; this background reaction can, however, be completely suppressed by reducing the temperature to 50 C. With 10 mol% HMPA the reaction gives almost quantitative yields of 157 [55]. In a survey of a variety of Lewis bases amine-N-oxides were found to be superior in promoting addition of 10 to acetophenone (Table 7.7) [55]. A variety of amine-N-oxides can promote this reaction and, among all the Lewis bases

Tab. 7.7

Survey of N-oxide promoters for addition of 10 to acetophenone. OSiCl3 OMe

promoter (100 mol %)

O + Ph

Me

CH2Cl2

HO

O

Ph Me

OMe 157

10

Entry

Promoter

Temp, ˚C

Time, min

Conv., %

1 2 3 4 5 6 7 8

none Me3 NO Me3 NO NMOa quinuclidine N-oxide pyridine N-oxide pyridine N-oxide pyridine N-oxideb

50 78 20 78 78 78 50 rt

240 240 50 70 70 70 50 120

0 10 76 25 35 37 97 100

a N-methymorpholine-N-oxide. b 10

mol% of promoter was used.

295


296

10 mol % pyridine-N -oxide

O

OSiCl3

+

R1

CH2Cl2, rt

R2

R1

OMe

OH

O

R2

OMe

10 OH Ph

OH

O OMe

Me

Ph

157 (94%) OH

O

Me

OH

O OMe

Me

Ph

158 (92%)

O

OH OMe

161 (91%)

t-Bu

Me

O

OH OMe Ph

Me 159 (92%) OH

O OMe

162 (93%)

O

O OMe

Me 160 (94%) OH

O

OMe 163 (94%)

OMe 164 (45%)

Scheme 7.63

Addition of 10 to a variety of ketones, catalyzed by pyridine-N-oxide.

surveyed, pyridine-N-oxide resulted in the highest conversion in the aldol addition. With a catalytic amount of pyridine-N-oxide, complete conversion can be achieved within 2 h at room temperature. With catalytic amounts of pyridine-N-oxide addition of 10 to a variety of ketones has been achieved (Scheme 7.63). Excellent yields are obtained for a wide range of substrates, including highly enolizable ketones. Aldol addition to 2-tetralone is the only instance in which the reaction does not produce the expected aldol product in high yield. To provide enantiomerically enriched aldol products the use of structurally diverse chiral N-oxides has been studied (Scheme 7.64). In this process enantioselection is clearly enhanced by use of dimeric N-oxides with 6,6 0 stereogenic centers. Among these, the highest enantioselectivity is obtained by use of bis-pyridine-derived P-(R,R)-46. Interestingly, the M-(R,R)-46 is equally capable of catalyzing the aldol addition, although this reaction affords the enantiomeric product with slightly attenuated enantioselectivity. The generality of this catalyst system has been demonstrated in additions of 10 to a variety of ketones (Scheme 7.65). The enantiomeric ratio of the product ranged from modest to good, depending on the ketone structure. The crucial factor in obtaining high selectivity seems to be the size differential between the two substituents on the ketones. Catalytic, asymmetric aldol additions to ketones have been achieved by means of the extraordinary reactivity of trichlorosilyl ketene acetal combined with Lewis-base-catalysis. The axially chiral bipyridine-N-oxide bearing stereogenic centers at the 6,6 0 -positions has excellent catalytic properties and results in synthetically useful enantioselectivity. This process provides access to enantiomerically enriched tertiary alcohols catalytically. Enantio-

7.7 Aldol Addition of Trichlorosilyl Ketene Acetal to Aldehydes and Ketones OSiCl3

O

OMe

+

Ph

−20 oC, 12 h

N

N

Me O Me O

O O

N

(R)-165 er, 2.6/1

(S)-166 er, 1.7/1

t-Bu t-Bu

(R,R)-167 (92%) er, 3.4/1

N N O O On-Bu n-BuO

N N O O On-Bu n-BuO

MeMe

N N O O On-Bu n-BuO

CMe2Ph t-Bu

N N O O On-Bu n-BuO

t-Bu t-Bu

P-(R,R)-46 (94%) er, 12/1

P-(R,R)-169 (90%) er, 9.0/1

t-Bu

(R,R)-168 (94%) er, 4.6/1

MeMe

MeMe

PhMe2C

OMe 157

N N O O OMe MeO

t-Bu

O

Ph Me

CH2Cl2

Me

10

N

HO

cat. (10 mol %)

297

t-Bu

M-(R,R)-46 (89%) er, 1/2.5

Scheme 7.64

Catalyst survey for addition of 10 to acetophenone.

OSiCl3

P-(R,R)-46 (10 mol %)

O +

10 OH Ph

Me

OH

O

157 (96%) er, 10/1 OH

O

161 (87%) er, 2.9/1

OH OMe

170 (89%) er, 13/1

O

Me

O

Ph

OMe

OH OMe

Ph

R1

CH2Cl2, −20 oC 12 - 32 h

R2

R1

OMe

OH

160 (97%) er, 2.1/1

OMe

O

OH

Me

OH OMe

OMe 172 (90%) er, 9.1/1

O

Me 173 (91%) er, 1.9/1

Scheme 7.65

Addition of 10 to different ketones catalyzed by P-(R,R)-46.

O

OMe

171 (89%) er, 3.5/1

O

Me

R2

O

OH OMe

t-Bu

Me

O OMe

162 (87%) er, 2.5/1

298


selectivity, however, is not consistently high for different substrates, so catalyst optimization is still needed if this reaction is to be truly practical.

7.8

Lewis Base Activation of Lewis Acids – Aldol Additions of Silyl Enol Ethers to Aldehydes

The aldol reactions of enoxytrichlorosilanes described in preceding sections all involve the use of a chiral Lewis base (phosphoramide or N-oxide) to activate the nucleophile and provide the chiral environment for CaC bond-formation [53, 55, 94]. These reactions all proceed by a common mechanistic pathway that involves a cationic, hypercoordinate silicon as an organizational center for the reactants and catalyst (Section 7.9). The ability of certain Lewis bases to induce the ionization of silicon Lewis acids has intriguing potential for a new concept in Lewis-acid catalysis of organic reactions. The possibility of activating a weak Lewis acid, for example silicon tetrachloride, with a chiral Lewis base and using the resulting complex as a chiral Lewis acid for a variety of reactions has recently been demonstrated [54b]. The Lewis acidity of SiCl 4 is relatively weak compared with typical Lewis acids such as TiCl 4 or BF3 [8]; in the presence of several different Lewis bases, however, a highly Lewis acidic silyl cation is produced (Scheme 7.66) [95]. Formation of a cationic silicon complex has been experimentally demonstrated by Bassindale and coworkers in heterolysis of halosilanes with Lewis bases [95a]. For example, 1 H, 13 C, and 29Si NMR spectroscopic evidence suggested the formation of a cationic silicon complex from silyl halides and triflate in DMF. Although enhancement of Lewis acidity by Lewis bases is counter-intuitive, it can be explained by a set of empirical bond-length and charge-variation rules formulated by Gutmann [96]. Activation of silicon by ionization of a ligand has been proposed in several other systems [97]. The concept of Lewis base activation leads to an ideal opportunity for ligand-accelerated catalysis. Because the Lewis acid is active only when coordinated to the Lewis base, a stoichiometric amount of silicon tetrachloride can be used to assist rate and turnover [19]. The use of the [Lewis base–SiCl3 ]þ complex as a chiral Lewis acid was first demonstrated in the opening of meso epoxides to obtain enantioenriched chlorohydrins [98]. A more relevant application of this concept has

SiCl4

+

O Me2N P NMe2 NMe2

Cl

OP(NMe2)3 Cl Si Cl OP(NMe2)3

Scheme 7.66

Formation of HMPA–trichlorosilyl cation complex.

Cl

7.8 Lewis Base Activation of Lewis Acids – Aldol Additions of Silyl Enol Ethers to Aldehydes

(R,R)-48 (5 mol %) SiCl4 (110 mol %) SnBu3 + PhCHO

CH2Cl2, −78 oC

299

OH Ph 174 (91%) er, 32/1

Scheme 7.67

Allylation of aldehydes using SiCl4 –bisphosphoramide complex.

been illustrated in asymmetric allylation of aldehydes (Scheme 7.67) [54b]. With allyltributyltin as an external nucleophile, the allylation of a variety of aldehydes proceeds in excellent yield; excellent enantioselectivity is obtained with the dimeric phosphoramide (R,R)-48. This reaction system can be applied to aldol additions of silyl ketene acetals (Scheme 7.68) [50]. Although the aldol addition of ketene acetal 175 to aldehydes does not proceed in the absence of the Lewis base catalyst, with 5 mol% (R,R)-48, the aldol products are obtained in excellent yields within 15 min. This behavior is strikingly different from the addition of trichlorosilyl ketene acetal, which reacted spontaneously with aldehydes (Section 7.7). Not surprisingly, the enantioselectivity observed in these reactions is significantly better than that obtained from the reaction of trichlorosilyl ketene acetal with aldehydes, which suffers from competitive background reaction. Excellent enantioselectivity was observed for most of the aldehydes surveyed. Sterically bulky aldehydes seem to afford lower enantioselectivity, (R,R)-48 (5 mol %) SiCl4 (110 mol %)

OTBS OMe 175

OH

+ RCHO

O

OH

CH2Cl2, −78oC

O

OMe

OH OMe

151 (97%) er, 28/1

OH

O

O

R

OMe

OH

O

O

153 (95%) er, 32/1 OH

O

Me 178 (98%) er, 2.7/1

155 (98%) er, 2.7/1

O OMe

OMe

OMe

154 (94%) er, 14/1

Scheme 7.68

Aldol addition of 175 to a variety of aldehydes catalyzed by SiCl4 -(R,R)-48.

O OMe

OMe 177 (94%) er, 14/1

176 (98%) er, 9.0/1 OH

OH

300


and there is no significant electronic effect. Additions to aliphatic aldehydes are slow, but good yields of the aldol products can be obtained after 6 h with good enantioselectivity. These observations are remarkable considering that addition of trichlorosilyl nucleophiles to aliphatic aldehydes have been problematic. The absolute configuration of the benzaldehyde aldol product is R, which is consistent with the sense of asymmetric induction observed for the allylation. Aldol additions with substituted ketene acetals introduce the issue of relative diastereoselection. Unlike the reactions with trichlorosilyl nucleophiles which involve closed transition structures, the mechanism of Lewisacid-catalyzed aldol reactions usually involves an open transition structure. Under such conditions control of relative diastereoselection cannot be achieved simply by adjustment of enolate geometry. Interestingly, the reactions of propanoate-derived ketene acetals with benzaldehyde produce the anti aldol products with high diastereoselectivity (Scheme 7.69). A survey of ketene acetal structures indicated that larger ester groups afford higher enantioselectivity. For the t-butyl propanoatederived ketene acetal, enantioselectivity is significantly higher than for the addition of other ketene acetals. It is also important to note that the geometry of the ketene acetal does not affect the stereochemical outcome of the reaction. Starting from either the E- or Z-enriched ketene acetal 183, the anti aldol product is obtained exclusively with excellent enantioselectivity. This suggests that these aldol additions do not proceed via a cyclic transition structure as alluded to above – an open transition structure can better account for the stereoconvergent aldol addition. This type of stereoconvergent anti aldol process is rare [16c] and the selectivity observed promises great synthetic utility for this aldol reaction. The broad scope of this reaction has been demonstrated with a variety of aldehydes (Scheme 7.70). Aromatic and conjugated aldehydes afford high yields of the anti aldol product with excellent diastereoselectivity and mod-

(R,R)-48 (1 mol %) SiCl4 (110 mol%)

OTBS Me

OR

OH

+ PhCHO

OH

O

O

OMe Ph

Ph

CH2Cl2, −78 oC OH

OH

O

Ph

OR

Me OH

O

O

OPh Ph

OEt Ph

Ot-Bu

Me

Me

Me

Me

179 (98%) dr, 99/1 er, 6.1/1

180 (78%) dr, 49/1 er, 7.3/1

181 (98%) dr, 16/1 er, 16/1

182 (93%) dr, 99/1 er, >99/1

Scheme 7.69

Aldol addition of a variety of propionate-derived ketene acetals.


SiCl4 (110 mol%) (R,R)-48 (1 mol %)

OTBS Ot-Bu + RCHO Me 183 OH

OH

Ot-Bu Me OH

O

Ot-Bu

O Ot-Bu

Ot-Bu

Me

Me

Me

182 (93%) dr, 99/1 er, >99/1 OH

O

R

CH2Cl2, −78 oC 3h

O

OH

185 (95%) dr, >99/1 er, >99/1

184 (98%) dr, 24/1 er, 32/1 O

OH

O

Ot-Bu

OH

O

Ot-Bu

Me

Me

Me

Ot-Bu Ph

Me

187 (90%) dr, >99/1 er, 24/1

186 (98%) dr, >99/1 er, >99/1

188 (92%) dr, 24/1 er, 5.3/1

Scheme 7.70

Aldol addition of 183 to a variety of aldehydes.

est to excellent enantioselectivity. Unfortunately, aliphatic aldehydes do not react with this particular ketene acetal under these conditions. The use of less sterically demanding ethyl ketene acetal 189 enables reactions with aliphatic aldehydes, however (Scheme 7.71). For example, combining 189 with hydrocinnamaldehyde affords 190 in 71% yield with good

OTBS OEt

SiCl4 (110 mol %) (R,R)-48 (5 mol %) TBAI (10 mol %)

O +

Ph

H

Me

189

OEt Me

+

CH2Cl2, −78 oC 24 h

SiCl4 (110 mol %) (R,R)-48 (10 mol %) TBAI (10 mol %)

O

OTBS

H CH2Cl2, −40 C 24 h

189

Scheme 7.71

Aldol addition of 189 to aliphatic aldehydes.

o

301

OH

O OEt

Me 190 (71%) dr, 10/1 er, 16/1 OH

O OEt

Me 191 (49%) dr, 8.1/1 er, 2.1/1

302


SiCl4 (150 mol %) (R,R)-48 (5 mol %) TBAOTf (10 mol %) i-Pr2EtN (10 mol %)

OTMS R O

OH Ph n-Bu

Me 51 (97%) er, 49/1

+ PhCHO

O

OH

CH2Cl2, −78 oC 3h O OH

Ph i-Bu 52 (99%) er, >99/1

O

OH

R O

Ph OH Ph Ph

Ph i-Pr 53 (98%) er, 99/1

54 (95%) er, >99/1

O

OH Ph

55 (98%) er, >99/1

Scheme 7.72

Catalyzed aldol additions of TMS enol ethers to benzaldehyde.

selectivity. The yield can be significantly improved by addition of tetrabutylammonium iodide and extending the reaction time. In the addition to cyclohexanecarboxaldehyde a higher reaction temperature is also needed to achieve good conversion. The same catalyst system can effect aldol additions of TMS enol ethers of ketones [99]. Additions of methyl ketone-derived TMS enol ethers to aldehydes proceed smoothly to afford the corresponding aldol products in excellent yield and with excellent enantioselectivity (Scheme 7.72). The use of a catalytic amount of a tetraalkylammonium salt is important for achieving complete conversion in these reactions. These studies also revealed the compatibility of the reaction system with a small amount of diisopropylethylamine to scavenge adventitious HCl present in silicon tetrachloride. This modification obviates distillation of silicon tetrachloride and makes the process more practical. The generality of this aldol addition is illustrated by the addition of 2hexanone-derived TMS enol ether 192 to a variety of aldehydes (Scheme 7.73). Aromatic aldehydes are among the best substrates in this reaction, affording both high yields and high enantioselectivity. Heteroaromatic aldehydes are also compatible, and good yields and excellent enantioselectivity can be obtained. Sterically encumbered aldehydes react more slowly and less selectively. This effect is most evident in the reaction with a-methylcinnamaldehyde. Unfortunately, aliphatic aldehydes are not reactive under these conditions. A highly regioselective vinylogous aldol reaction has also been achieved by use of the SiCl 4 –bisphosphoramide system [100]. Vinylogous ketene acetals have two nucleophilic sites, i.e. the C(2)- and C(4)-positions, and reaction at the C(2)-position is usually favored, owing to the higher electron density [101]. It has been a challenge to control the reactivity of these two sites to obtain the g-aldol adduct selectively [102]. In the presence of


SiCl4 (150 mol %) (R,R)-48 (5 mol %) i-Pr2NEt (10 mol %)

OTMS + RCHO

n-Bu

CH2Cl2, −78 oC 3 -24 h

192 O

OH

O

n-Bu

O n-Bu

R

OH

O n-Bu

52 (99%) er, >99/1

193 (88%) er, 19/1

67 (95%) er, 24/1 O

OH S

n-Bu

OH O

n-Bu

O

OH

OH

n-Bu

O

OH

n-Bu Me 59 (54%) er, 3.5/1

194 (79%) er, 99/1

58 (98%) er, >99/1

Scheme 7.73

Aldol addition of 192 to different aldehydes.

the bisphosphoramide (R,R)-48, crotonate-derived silyl ketene acetal 195 reacts with benzaldehyde to yield the g-aldol adduct exclusively in good yield with excellent enantioselectivity (Scheme 7.74). The exclusive g-selectivity is attributed to the steric differentiation between the a- and g-positions (substituted compared with unsubstituted). In this catalyst system the reaction occurs preferentially at less sterically demanding site. Under similar reaction conditions a variety of simple enoate-derived silyl ketene acetals undergo vinylogous aldol additions (Scheme 7.75). In the 2-pentenoate derived silyl ketene acetal a sterically bulky ester group is necessary for high regioselectivity. For example, reaction of the t-butyl esterderived dienol ether yields the g adduct 199 in good yield. The high re-

OH OTBS OEt

195

SiCl4 (110 mol %) (R,R)-48 (5 mol %)

O +

Ph

H

CH2Cl2, −78 oC 3h

Scheme 7.74

Aldol addition of dienol silyl ether 195 to benzaldehyde.

O OEt

196 (89%) γ / α, >99/1 er, 99/1

303

304


R4

OTBS

R5

SiCl4 (110 mol %) (R,R)-48 (5 mol %)

O

OR2

+

R1

H

OH R

O OR2

1

CH2Cl2, −78 oC 3 - 24 h

R3

R4

R5

R3

Me Me O

OH Ph

OH O OMe

O

OH O

Ph

Ph

Me

Ot-Bu

Me

197 (93%) γ / α, >99/1 er, >99/1

OH

O

198 (92%) γ / α, >99/1 er, 6.7/1

O

Ph

OH OEt

199 (92%) γ / α, >99/1 dr (anti/syn), >99/1 er, 17/1

OH

O

Ph

OEt

Ph

O Ot-Bu

Me 200 (84%) γ / α, >99/1 er, 49/1

201 (68%) γ / α, >99/1 er, 19/1

202 (71%) γ / α, 99/1 dr (anti/syn), >99/1 er, 10/1

Scheme 7.75

Catalyzed aldol addition of a variety of dienol silyl ethers.

gioselectivity is complemented by high anti diastereoselectivity and excellent enantioselectivity. In terms of aldehyde scope, good yields and selectivity are obtained with aromatic and olefinic aldehydes, and even aliphatic aldehydes can be employed in this reaction, although longer reaction times are needed. It is important to mention that the aldol products obtained by use of bisphosphoramide (R,R)-48 reveal the commonality of absolute configuration at the hydroxyl center (Figure 7.20). When (R,R)-48 is used, nucleophiles attack the aldehyde Re face in xxv. Although stereochemical models need to be developed, the catalyst has created a highly defined environment for the aldehyde acceptor. The bisphosphoramide–SiCl 4 complex has been successfully used as a chiral Lewis acid in highly efficient catalytic, enantioselective aldol additions of silyl ketene acetals and silyl enol ethers. Compared with aldol additions of trichlorosilyl reagents, these systems are superior in terms of preparation and handling of the nucleophiles. In particular, additions of propanoate-derived ketene acetals are one of the most stereoselective anti aldol additions reported to date.

7.9 Toward a Unified Mechanistic Scheme

Nucleophilic attack OSiR3

Cl LB

O Si

LB

Cl H

Ph

Cl

X

OH O

R1

Ph R

Cl xxv

LB

X R1

OH

OH

O

O

= (R,R)-48

Ot -Bu

OMe

LB

Me 182

151 OH

O

OH n-Bu

52

Ph

174

Fig. 7.20

Commonality of absolute configuration in a variety of aldol products.

7.9

Toward a Unified Mechanistic Scheme

Detailed discussion of the extensive kinetic, spectroscopic, and structural investigations that have provided the current mechanistic picture is beyond the scope of this chapter, the primary focus of which is preparative aspects of chiral Lewis base-catalyzed aldol reactions. Instead a summary of the important studies that have led to the current level of understanding will be presented, with the implications for catalyst design and reaction engineering. As originally formulated, the foundation of Lewis base activation of the aldol addition (and subsequent stereoinduction) was based on hypothetical ternary assembly of enolate, aldehyde, and chiral catalyst in a hexacoordinate arrangement about the silicon atom (Figure 7.21) [103]. When catalysis was successfully demonstrated, the hypothesis seemed correct – i.e. that the rate acceleration arose from dual activation of the enol and the aldehyde in close proximity. Two important aspects of the reactions seemed at odds with this picture, however – rate and stereoselectivity were both difficult to rationalize. Although polarization of electron density away from the silicon atom was expected from the Gutmann analysis [96a], there was no basis for estimation of the magnitude of this effect. From analysis of simple molecular models it was, furthermore, not at all clear how single-point binding could provide the highly dissymmetric environment that induced such high facial selectivity.

305

306


R 2N

OSiCl3 R

RCHO

1

R2 (R2N)3P=O

R R

1

H

2

HR

NR2 P NR2

OSiCl3

O

O

R1

O Si Cl Cl O Cl

R R2

Fig. 7.21

Original hypothetical transition structure assembly.

7.9.1

Cationic Silicon Species and the Dual-pathway Hypothesis

The first experimental evidence against the simple mechanistic picture in Figure 7.21 was the observation that the diastereoselectivity of aldolization of cyclohexanone-derived enolate 20 with benzaldehyde depended on catalyst loading (Scheme 7.76). The appearance of syn isomers from Econfigured enolates (at low catalyst loading) implied intervention of boat-like transition structures. Curiously, although the diastereomeric ratio changes dramatically the enantiomeric ratio of the anti isomer remains unchanged. This suggested that two independent pathways could be operating, one favoring the anti diastereomer (with high facial selectivity) and one favoring the syn isomer (with low facial selectivity). Quantitative support of this hypothesis was obtained from several studies. First, the diastereoselectivity of reactions promoted by the achiral phosphoramide 203 (Figure 7.22) is dramatically dependent on catalyst loading. Figure 7.22 depicts graphically the change in syn/anti ratio from 1.3:1 at 200 mol% loading to 130:1 at 2 mol% loading. The excellent correlation of diastereoselectivity with inverse phosphoramide concentration provided quantitative support for the dual pathway hypothesis, namely, one phosphoramide leads to syn and two phosphoramides lead to anti [66]. The second source of quantitative evidence is the divergent behavior of chiral catalysts (S,S)-45 and (S,S)-81 in studies of the dependence of enantioselectivity on catalyst composition. In contrast with the highly antiselective reactions promoted by (S,S)-45, diphenylphosphoramide catalyst

OSiCl3

1. (S,S)-45 (x mol %) PhCHO, –78 ˚C

O

OH

O

OH

Ph +

Ph

2. sat. aq. NaHCO3 (–)-syn

20

(–)-anti

10 mol % cat (94%) syn/anti, 1/50 (er anti, 21/1) 0.5 mol % cat (53%) syn/anti, 1/5 (er anti, 21/1) Scheme 7.76

Catalyst loading-dependent diastereoselectivity.


Ph N O P N N Ph 203

Fig. 7.22

Dependence on loading of selectivity with catalyst 203.

(S,S)-81 provided the syn aldol product in excellent diastereoselectivity (97:1), albeit with modest enantioselectivity (3.25:1 er) (Scheme 7.77) [66, 76]. With enantioselective catalysts now available for both syn and anti pathways, an important link between the steric demand of the catalyst and the resulting diastereoselectivity could be forged. According to the dual pathway hypothesis one (to syn) or two (to anti) catalyst molecules can be present in the stereochemistry determining transition structures, and that these different pathways are also stereochemically divergent. This hypothesis could be tested by making use of non-linear effects and asymmetric amplification as pioneered by Kagan [104]. The dependence of enantiomeric excess (ee) of the aldol products on the enantiomer composition of the cata-

Ph Ph

Ph N O P N N Ph

OSiCl3

10 mol% (S,S)-81 +

PhCHO

O

OH Ph +

O

OH Ph

CH2Cl2, –78 ˚C 20

(94%) syn/anti 97/1 er (syn) 3.25/1

Scheme 7.77

syn-Selective aldolization catalyzed by (S,S)-81.

(+)-syn

(–)-anti

307


Ph

Ph N O P N N

Ph Ph

Ph (S,S)-81 (

Me N O P N N Me

)

(S,S)-45 (

)

% ee of syn-adduct ( )

Ph

% ee of anti-adduct ( )

308

% ee of catalyst Fig. 7.23

Correlation of product and catalyst ee for (S,S)-45 (f) and (S,S)-81 (n).

lysts is illustrated in Figure 7.23. The linear relationship between catalyst ee and syn-adduct ee with phosphoramide (S,S)-81 (Figure 7.23, n) suggests this product arises from a transition structure involving only one chiral phosphoramide. In contrast, the obvious non-linear relationship between catalyst ee and anti-adduct ee with phosphoramide (S,S)-45 (Figure 7.23, f) suggests the participation of two phosphoramide molecules in the transition structure for aldolization [66]. The most compelling and direct evidence for the operation of dual pathways is provided by establishment of the order of the reaction in catalyst for (S,S)-45 and (S,S)-81 [66b]. The rate and sensitivity of these reactions required use of in-situ monitoring techniques such as ReactIR and rapid injection NMR (RINMR). First-order dependence on (S,S)-81 (R 2 ¼ 1.000) is observed for catalyzed aldol addition of 20 to benzaldehyde with typical catalyst loadings at 35 C. Importantly, the rate of reaction at very low catalyst loadings has pronounced curvature, indicative of a change in mechanism between the promoted and unpromoted pathways. RINMR analysis of the reaction catalyzed by (S,S)-45 at 80 C reveals aldol addition to have second order dependence on phosphoramide (plot of log kobs against log [catalyst]; m ¼ 2.113, R 2 ¼ 0.992). For Lewis-base-catalyzed aldol addition involving trichlorosilyl enolates the rate equations are rate ¼ k[cat][enolate][aldehyde] for catalyst (S,S)-81 and rate ¼ k[cat] 2 [enolate][aldehyde] for catalyst (S,S)-45. The experimentally determined reaction order is consistent with turnover-limiting com-


(a) O

1.000 OH (assumed)

Me

(b) O

1.000 OH (assumed)

Me 1.000 1.003 0.997 1.038 52

0.998 1.032 0.990 1.005 52

Fig. 7.24

(a) 13 C KIEs (k12 C /k13 C ) for a reaction taken to 5% conversion using limited aldehyde. (b) 13 C KIEs (k12 C / k13 C ) for a reaction taken to 5% conversion using limited enol ether.

plexation or aldolization, and whereas Arrhenius activation data suggest complexation is rate-limiting they do not discount the possibility that aldolization is the turnover-limiting step. Natural abundance 13 C kinetic isotope effects (KIE) as pioneered by Singleton [105] provide a clear answer. 13 C NMR analysis of aldol product 52 from reaction of enolate 24 and benzaldehyde at 5% conversion afforded excellent results (Figure 7.24). If binding or any other pre-equilibrium process not involving the reactive centers were turnover limiting, no isotope enrichment would be expected in the aldol product. The presence of significant (1.038 and 1.032) [106] k12 C / k13C kinetic isotope effects at the enolate carbon and the aldehyde carbonyl carbon clearly show, however, that rehybridization is occurring at both reactive centers in this transformation [107, 108]. These data, with results from the non-linear effect studies above clearly support the conclusion that the aldolization step is both stereochemistry-determining and turnover-limiting. With evidence from a variety of sources that two phosphoramide molecules can be bound to the silicon atom of the enolate in the transition structure, formulating a picture of this assembly could be undertaken. It was reasonable to postulate that the aldehyde is also coordinated to silicon, because the stereochemical consequences of changing enolate geometry are strongly reflected in changing diastereoselectivity of the process. Thus, given the likelihood of a closed, silicon-centered transition structure, one of two possibilities arises:

. formation of a heptacoordinate silicon group; or . ionization of a chloride, forming a cationic, hexacoordinate silicon moiety. Support for the intermediacy of cationic silicon species is available from the effects of ionic additives on the rate and selectivity of the reaction [66a]. For reactions with catalyst (S,S)-81 a clear trend emerges (Scheme 7.78). Addition of 1.2 equiv. tetrabutylammonium chloride causes marked deceleration and a diminution in enantioselectivity. Addition of 1.2 equiv. tetra-

309

310


Ph N O P N N

Ph Ph

OSiCl3 +

PhCHO

Ph 10 mol% (S,S)-81

O

OH Ph

CH2Cl2, –78 ˚C 8 min

(+)-syn

44% conv. 8% conv. 92% conv.

er 3.26/1 er 1.70/1 er 3.44/1

20 no additive 1.2 equiv Bu4N+ Cl1.2 equiv Bu4N+ TfOScheme 7.78

Effects of salts on the rate and selectivity of catalyzed aldolization.

butylammonium triflate results in moderate rate acceleration and an increase in the enantioselectivity of the overall process. The decrease in rate is consistent with a common-ion effect wherein ionization of chloride precedes the rate-determining step. The corresponding increase in rate and selectivity with tetrabutylammonium triflate, which increases the ionic strength of the medium, confirms the notion of ionization. 7.9.2

Unified Mechanistic Scheme

The available evidence from measurements of kinetics, additive effects, nonlinear studies, and stereochemical information supports a revised picture of the mechanism of phosphoramide-catalyzed aldol additions. As originally proposed, ternary association of enolate, aldehyde, and Lewis base was believed to be sufficient for activation and selectivity. Whereas unpromoted additions of trichlorosilyl enolates to aldehydes probably involve simple combination of the two reactants in a trigonal bipyramidal assembly, the catalyzed process is clearly much more complex (Figure 7.25). On binding the Lewis basic phosphoramide the trichlorosilyl enolate undergoes ionization of chloride. Depending on the size and concentration of the phosphoramide two scenarios are possible [109]. With a bulky phosphoramide, or in the limit of insufficient catalyst, aldehyde coordination and aldolization through a boat-like transition structure (with low facial selectivity) provides the syn aldol product (bottom pathway). Alternatively, with smaller phosphoramides or higher catalyst loading, a second molecule of catalyst can be bound to the cationic dichlorosilyl enolate to form an octahedral silicon cation [110]. On binding the aldehyde this intermediate undergoes aldolization through a chair-like transition structure organized around a hexacoordinate silicon atom (top pathway). This process occurs with a high level of facial selectivity, most probably because of the greater stereochemical influence of two chiral moieties in the assembly.

N

Ph

P N

O

N

O

O

Si Cl Cl

O +

P(NR2)3

coordination of phosphoramide displaces chloride

+

PhCHO

aldolization

Cl–

PhCHO

aldolization

(R2N)3P=O

Cl

–

O P(NR2)3

Cl Cl

O Si

O

P(NR2)3

Unified mechanistic scheme for phosphoramide-promoted aldolizations.

Fig. 7.25

N

Ph

P

Ph

N

Ph

Ph

one phosphoramide pathway

(R2N)3P=O

OSiCl3

2 (R2N)3P=O

two phosphoramide pathway

Me

N

Me

cationic tbp boat

Cl NR2 H O Si O P O Cl NR2 R2N

H

cationic octahedron chair

H

‡

‡ NR2 NR2 P O L O Si Cl O Cl H R2N

+

+

Ph

syn

O

anti

O

Ph

OSiCl3

Ph

OSiCl3

7.9 Toward a Unified Mechanistic Scheme 311

312


7.9.3

Structural Insights and Modifications

The revised mechanistic picture provides a clearer understanding of the remarkable change in diastereoselectivity with catalyst size and loading, and of the origin of rate enhancement. The reasons for the high enantioselectivity observed remain obscure, however. Insights into the stereochemical consequences of catalyst binding are provided by the solution and solid-state structures of chiral phosphoramide complexes of tin(IV) Lewis acids [70, 111]. The unified mechanistic scheme suggests a preference for 2:1 complexation with (S,S)-45 and a preference for 1:1 complexation with (S,S)-81. Both scenarios are confirmed crystallographically. Single-crystal X-ray structural analysis of the 2:1 complex, ((S,S)-45)2 aSnCl 4 reveals interesting features (Figure 7.26):

. 2:1 complexation is confirmed, . cis geometry of the complex is preferred, . the piperidino nitrogen is planar and oriented orthogonal to the phospholidine ring

N

N

Cl P

Sn

Cl

Cl Cl

O P N

Fig. 7.26

X-ray crystal structure of ((S,S)-45)2 aSnCl4 .


Cl Cl

Cl Sn

Cl

O

O P N

N N

Fig. 7.27

X-ray crystal structure of (S,S)-81aSnCl4 aH2 O.

. the phospholidine nitrogen atoms are pyramidal, with the methyl groups away from the stilbene phenyl groups, and . disposed the PaOaSn unit is non-linear such that the tin moiety is oriented over the phospholidine ring. 119

Sn-solution NMR studies and analysis of 1JPaSn coupling constants corroborate the observation of 2:1 complexes (hexacoordinate chemical shift regime) favoring the cis configuration. Crystallization of (S,S)-81 with SnCl 4 afforded a 1:1:1 complex of (S,S)81aSnCl 4 with one molecule of water filling the sixth coordination site on the tin octahedron (Figure 7.27). This complexation stoichiometry is also obtained in solution, as verified by 119 Sn NMR studies that clearly show a doublet with ( 1JPaSn ) in the pentacoordinate chemical-shift region. The availability of an open coordination site in (S,S)-81aSnCl 4 suggested the possibility of incorporating a molecule of the substrate. Indeed, cocrystallization of (S,S)-81 with SnCl 4 and benzaldehyde afforded a ternary complex, PhCHOa(S,S)-81aSnCl 4 (Figure 7.28). Both of these complexes had the same basic structural features as are found in the 2:1 complex ((S,S)-45)2 aSnCl 4 . Although these studies do indeed provide structural clues to the arrangement of groups around the central group 14 atom, there are still far too

313

314


Fig. 7.28

X-ray crystal structure of PhCHO–(S,S)-81aSnCl4 .

many degrees of freedom to enable compelling depiction of the most favorable placement of reactive groups and alignment of combining faces. The structural insights available from these studies have, nevertheless, enabled important trends to emerge that facilitate the invention of new and better catalysts such as those that can enforce 2:1 binding by tethering and still accommodate the preferred arrangement of groups around the central atom. Such tethered dimeric phosphoramides have been prepared from several different diamine subunits, for example those shown in Chart 7.3. In these cases the diamine subunits have been linked by aliphatic 1,n-diamines and have served admirably in a number reactions, for example catalytic enantioselective allylation with allylic trichlorosilanes [54c, 112] and activation of silicon tetrachloride for aldol and related reactions of trimethylsilyl enol ethers (Section 7.8). In the aldol addition of enoxytrichlorosilanes, the best results have been obtained from the use of the dimeric bis(phosphoramide) 48 for addition of aldehyde trichlorosilyl enolates (Section 7.6). A dimeric catalyst that promotes a highly enantioselective addition of trichlorosilyl enolates in general is still lacking [113].

7.10 Conclusions and Outlook

CH3 CH3 N O O N P P (CH2)n N N N N CH3CH3 CH3CH3

CH3 CH3 N O O N P P (CH2)n N N N N CH3 CH CH3 CH3 3 (R,R)-205: n = 3-6

(R)-(l,l )-204: n = 2-6

H H

N

O P

N

O

N

P (CH2)n N N N CH3 CH3

(R)-(l,l )-206: n = 4-6

315

H H

Ph Ph

CH3 CH3 N O O N P P (CH2)n N N N N CH3 CH3 CH3 CH3 (R)-(l,l )-207, n = 4-8

Chart 7.3

Tethered bisphosphoramides.

7.10

Conclusions and Outlook

The phenomenon of chiral Lewis base catalysis has been successfully demonstrated for a wide variety of aldol addition reactions. This represents a fundamentally new class of reactions that embody a conceptually novel and preparatively useful addition to the growing number catalytic, enantioselective processes. Design criteria for the invention of this new variant have been formulated and documented experimentally. Enoxytrichlorosilanes are a new class of aldolization reagents that are highly susceptible to catalysis by Lewis basic phosphoramides and N-oxides. A wide range of enolates have been prepared from simple cyclic and acyclic ketones, chiral ketones, esters, unsaturated esters, and aldehydes. Each of these classes of reagent has proven viable in aldol additions. The reactions are characterized by high yields, good functional group compatibility, excellent (and predictable) diastereoselectivity, and high enantioselectivity. There are, nevertheless, clearly identifiable limitations and shortcomings. For example, aliphatic aldehydes are a very important class of aldol partners that do not give generally acceptable results. In addition, the ability to generate substituted enolates with defined geometry (both E and Z) is still limited. The concepts developed in this field are also applicable (and have been applied) to other reactions such as allylation [112], imine addition, Michael addition, and epoxide opening [98]. Development of chiral Lewis base activation of Lewis acids is, furthermore, a powerful extension of these concepts that has enabled a broader range of carbon–carbon bond-forming processes to be executed under the action of enantioselective catalysis (e.g. the Passerini reaction [114]). In addition, Lewis base catalysis should find applica-

Ph Ph

316


tion in activation of processes associated with other main group elements capable of structural changes similar to silicon. Extensive kinetic and spectroscopic studies have revealed an unexpected mechanism involving the intermediacy of cationic silicon species. Elucidation of dual pathways proceeding via one or two-catalyst molecules has opened the door to the development of new dimeric catalysts that have proven useful in promoting faster, more selective reactions, but which have yet to find application in the aldol process specifically. The synergistic evolution of synthetic utility and mechanistic understanding illustrates the fruitful interplay of synthesis, reactivity, and structure. These central activities constitute a chemical evergreen that will continue to address the challenges of the invention and development of new catalytic processes for years to come.

7.11

Representative Procedures 7.11.1

Preparation of Enoxytrichlorosilanes Transition Metal Catalyzed trans Silylation (Section 7.2, Scheme 7.11) – Preparation of Trichloro[(1-butylethenyl)oxy]silane (24). Silicon tetrachloride (9.18 mL, 80.0 mmol, 2.0 equiv.) was added quickly to a suspension of Hg(OAc)2 (127 mg, 0.40 mmol, 0.01 equiv.) in CH2 Cl2 (40 mL). During the addition the mercury salt dissolved. Trimethyl[(1-butylethenyl)oxy]silane (6.89 g, 40.0 mmol) was then added to the solution dropwise over 10 min and the solution was stirred at room temperature for an additional 50 min. During this time the reaction mixture became somewhat cloudy once again. Removal of a sample and 1 H NMR analysis indicated the reaction was complete. The mixture was concentrated at reduced pressure (100 mmHg) and the resulting oil was distilled twice through a 7.5 cm Vigreux column to give 7.76 g (83%) of the trichlorosilyl enolate 24 as a clear colorless oil. Metal Exchange via Lithium Enolate (Section 7.2, Scheme 7.11) – Preparation of (2Z,4S)-5-(tert-Butyl-dimethylsilyloxy)-4-methyl-3-trichlorosilyloxy-2-pentene ((Z)-35). (2Z,4S)-5-(tert-Butyl-dimethylsilyloxy)-4-methyl-3-trimethylsilyloxy2-pentene (908 mg, 3.00 mmol) was dissolved in 6 mL ether at 0 C. To this solution was slowly added MeLi (3.00 mL, 4.50 mmol, 1.5 equiv., 1.5 m in ether). The reaction mixture was stirred for 4.5 h at room temperature and then cooled to 78 C. The reaction mixture was transferred to a cold solution of silicon tetrachloride (3.45 mL, 30.0 mmol, 10 equiv.) in 6 mL ether by use of a cannula. The reaction mixture was stirred at 78 C for 1 h and then gradually warmed to room temp. The precipitate was left to settle at the bottom of the flask and the supernatant was transferred to an-

7.11 Representative Procedures

other flask by means of a cannula. The volatile compounds were removed under reduced pressure and the residue was distilled by means of a Kugelrohr apparatus to afford 901 mg (2.48 mmol, 81%) (Z)-35 as a clear colorless oil. 7.11.2

Aldol Addition of Ketone-derived Enoxytrichlorosilane Aldol Addition of Achiral Enoxytrichlorosilane (Section 7.4, Scheme 7.26) – Preparation of (C)-S-1-Hydroxy-1-phenyl-3-heptanone (52). Trichlorosilyl enolate 24 (514 mg, 2.2 mmol, 1.1 equiv.) was added quickly to a cold (74 C) solution of (S,S)-45 (37.1 mg, 0.1 mmol, 0.05 equiv.) in CH2 Cl2 (2 mL). A solution of benzaldehyde (203 mL, 2.0 mmol) in CH2 Cl2 (2 mL) was cooled to 78 C and added quickly, via a short cannula, to the first solution. During the addition the temperature rose to 68 C. The reaction mixture was stirred at 75 C for 2 h then quickly poured into cold (0 C) sat. aq. NaHCO3 solution. The slurry obtained was stirred for 15 min. The two-phase mixture was filtered through Celite, the phases were separated, and the aqueous phase was extracted with CH2 Cl2 (3 50 mL). The organic extracts were combined, dried over Na2 SO4 , filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2 , pentane–Et2 O, 4:1) to give 402.0 mg (98%) of ()-52 as a clear colorless oil. Aldol Addition of in-situ-generated Enoxytrichlorosilane (Section 7.5, Scheme 7.44) – Preparation of (1R,4S)-1-Hydroxy-4-[((dimethyl)-(1,1-dimethyl)silyl)oxy]1-phenyl-3-pentanone (syn-96). Trimethylsilyl enol ether 99 (548 mg, 2.0 mmol) was added dropwise over 2 min to a stirred solution of SiCl 4 (460 mL, 4.0 mmol, 2.0 equiv.) and Hg(OAc)2 (3.1 mg, 0.010 mmol, 0.005 equiv.) in CH2 Cl2 at room temperature. After complete addition the reaction mixture was stirred at room temperature for 1 h; volatile compounds were then removed under reduced pressure (0.3 mmHg) to give a cloudy residue. Dichloromethane (2.0 mL) was added and the mixture was cooled to 75 C. A solution of (R,R)-45 (37.0 mg, 0.1 mmol, 0.05 equiv., dried at 0.1 mmHg for 12 h) in CH2 Cl2 was then added over 1 min via a cannula. A solution of benzaldehyde (203 mL, 2.0 mmol) in CH2 Cl2 (1.0 mL) was then added over 1 min and the reaction mixture was stirred at 75 C for 3 h. The reaction mixture was then rapidly poured into cold (0 C) sat. aq. NaHCO3 solution (15 mL) and the mixture was stirred for 15 min. The heterogeneous mixture was filtered through Celite, the organic phase was separated, and the aqueous phase was extracted with CH2 Cl2 (3 50 mL). The organic extracts were combined, dried over Na2 SO4 , filtered, and concentrated to give a crude oil. Purification by column chromatography (SiO2 , hexane–EtOAc, 8:1) afforded 524.4 mg (85%) of a mixture of diastereomers 96 as a clear colorless oil. The diastereomeric ratio was determined by SFC analysis to be syn/anti 73:1.

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Aldol Addition of Aldehyde-derived Enoxytrichlorosilane (Section 7.6, Scheme 7.55) – Preparation of (1S,2S)-3,3-Dimethoxy-2-pentyl-1-phenyl-1-propanol (syn132). Trichlorosilyl enolate (Z)-37 (496 mg, 2.0 mmol, 1.0 equiv.) was added to a cold (78 C) solution of the bisphosphoramide (R,R)-48 (84 mg, 0.1 mmol, 0.05 equiv.) in CHCl3 aCH2 Cl2 , 4:1 (8 mL) and the mixture was stirred for 10 min. Freshly distilled benzaldehyde (0.205 mL, 2.0 mmol, 1.0 equiv.) was then added. After 6 h at 78 C, MeOH (32 mL) was added and the mixture was stirred at that temperature for 45 min. The cold bath was removed and reaction mixture was left to warm to room temperature (total time 0.5 h), then was poured into cold (0 C) sat. aq. NaHCO3 solution and the mixture was stirred for 4 h. The reaction mixture was filtered through Celite and then washed with pentane–Et2 O, 1:1 (20 mL). The organic layer was separated and the aqueous layer was extracted once with pentane–Et2 O, 1:1 (20 mL). The combined extracts were dried over MgSO4 and then concentrated in vacuo. Column chromatography (SiO2 , hexane–EtOAc, 85:15) then bulb-to-bulb distillation gave 491 mg (92%) syn-132 as a clear, colorless, viscous liquid. Aldol Addition of Trichlorosilyl Ketene Acetal (Section 7.7, Scheme 7.65) – Preparation of Methyl 3-Hydroxy-3-phenylbutanoate (157). Trichlorosilyl ketene acetal 10 (380 mL, 2.4 mmol, 1.2 equiv.) was added to a solution of acetophenone (240 mL, 2.0 mmol) and chiral bis-N-oxide (P)-(R,R)-46 (101 mg, 0.20 mmol, 0.1 equiv.) in CH2 Cl2 (10 mL) at 20 C under nitrogen in a flame-dried, round-bottomed flask with magnetic stirrer. After stirring for 12 h at 20 C the reaction mixture was transferred dropwise to a cold (0 C) sat. aq. NaHCO3 solution (20 mL) with vigorous stirring. The mixture was further stirred for 30 min at room temperature. The silicate precipitate was removed by filtration through Celite and the filtrate was extracted with CH2 Cl2 (4 20 mL). The combined organic extracts were dried over MgSO4 and then were concentrated under reduced pressure. The crude aldol product was separated from the catalyst by distillation and was further purified by silica gel chromatography. Analytically pure 157 (364 mg, 94%) was obtained as a colorless liquid after bulb-to-bulb distillation. Aldol Addition of Propionate-derived Silyl Ketene Acetal (Section 7.8, Scheme 7.70) – Preparation of tert-Butyl (2S,3R)-3-Hydroxy-2-Methyl-3-Phenylpropanate (anti-182). A flame-dried, 10-mL, 2-neck flask containing a solution of bisphosphoramide (R,R)-48 (8.4 mg, 0.01 mmol, 0.01 equiv.) in CH2 Cl2 (5 mL) was cooled to 78 C under nitrogen and benzaldehyde (102 mL, 1.0 mmol, 1.0 equiv.) was then added. Silicon tetrachloride (123 mL, 1.1 mmol, 1.1 equiv.) was added to the resulting solution and the reaction mixture was stirred at 78 C for 5 min. (E)-1-[(tert-Butoxy)propenyl]-tert-butyldimethylsilane ((E)-183) (293 mg, 1.2 mmol, 1.2 equiv.) was then added dropwise to the reaction mixture over 5 min. The resulting mixture was stirred at 78 C (bath temperature) for 3 h whereupon the cold reaction mixture

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88 89 90

91

(b) Gung, B. W.; Zhu, Z.; Fouch, R. A. J. Org. Chem. 1995, 60, 2860–2864. Lodge, E., P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353–3361. (a) Reetz, M. T. Angew. Chem. Int. Ed. 1984, 23, 556–569. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462–468. (c) Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162. For reviews on diastereoselective aldol additions using chiral aldehydes, see: (a) Gennari, C. In Comprehensive Organic Synthesis, Vol. 2, Additions to CaX p Bonds, Part 2; Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991; pp. 639–647. (b) Ref. 1(k), pp 1713–1722. Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333–2334. Denmark, S. E.; Stavenger, R. A.; Wong, K.-T. Tetrahedron 1998, 54, 10389–10402. Seebach, D.; Prelog, V. Angew. Chem. 1982, 21, 654–660. Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121–7124. Denmark, S. E.; Stavenger, R. A. J. Org. Chem. 1998, 63, 9524–9527. For a discussion of the coordinating abilities of various ether substituents, see: (a) Ref. 74(b). (b) Chen, X.; Hortellano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1990, 112, 6130– 6131. (c) Mori, S.; Nakamura, M.; Nakamura, E.; Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1995, 117, 5055–5065. Denmark, S. E.; Pham, S. M. Org. Lett. 2001, 3, 2201–2204. For a discussion of chelation as a stereocontrol element in lactate-derived stannous enolate, see: Paterson, I.; Tillyer, R. Tetrahedron Lett. 1992, 33, 4233–4236. (a) Martin, V. A.; Murray, D. H.; Pratt, N. E.; Zhao, Y.; Albizati, K. F. J. Am. Chem. Soc. 1990, 112, 6965–6978. (b) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241– 8244. (c) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett. 2002, 4, 525–527. Denmark, S. E.; Fujimori, S. Synlett 2001, 1024–1029. Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3473– 3476. (a) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585–8588. (b) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187–1191. (c) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996, 37, 8581–8584. (d) Evans, D. A.; Coleman, P. J.; Cote, B. J. Org. Chem. 1997, 62, 788–789. Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3477–3480. Alcaide, B.; Almendros, P. Angew. Chem. Int. Ed. 2003, 42, 858–860. (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799. (b) Kandasamy, S.; Notz, W.; Bui, T.; Barbas, C. F. III, J. Am. Chem. Soc. 2001, 123, 5260–5267. (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.Y. J. Am. Chem. Soc. 1993, 115, 2613–2621. (b) Heathcock, C. H.; White, C. T.; Morrison, J. J.; Van Derveer, D. J. Org. Chem. 1981, 46, 1296–1309.

References 92 Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998,

639–652. 93 Denmark, S. E.; Bui, T. Proc. Nat. Acad. Sci. 2004, 101, 5439–

5444. 94 Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021–

12022. 95 (a) Bassindale, A. R.; Stout, T. J. Organomet. Chem. 1982,

96

97

98 99 100 101

102

103

104

105 106

238, C41–C45. (b) Bassindale, A. R.; Glynn, S. J.; Taylor, P. G. In The Chemistry of Organic Silicon Compounds; Rappoport, Z.; Apeloig, Y., Eds.; Wiley: Chichester, 1998; Vol. 2, pp 495– 511. (a) Gutmann, V. The Donor–Acceptor Approach to Molecular Interactions; Plenum Press: New York, 1978. (b) Jensen, W. B. The Lewis Acid–Base Concepts; Wiley Interscience: New York, 1980; Chapter 4. (a) Chojnowski, J.; Cypryk, M.; Michalski, J.; Wozniak, J. J. Organomet. Chem. 1985, 288, 275–282. (b) Corriu, R. J. P.; Dabosi, G.; Martineau, M. J. Organomet. Chem. 1980, 186, 25–37. (c) Bassindale, A. R.; Lau, J. C.-Y.; Taylor, P. G. J. Organomet. Chem. 1995, 499, 137–141. Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. J. Org. Chem. 1998, 63, 2428–2429. Denmark, S. E.; Heemstra, J. R. Jr. Org. Lett. 2003, 5, 2303– 2306. Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800–7801. (a) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley–Interscience: New York, 1996; p. 40–47. (b) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H. Tetrahedron Lett. 1973, 14, 2433–2436. For examples of stereoselective vinylogous aldol reactions see: (a) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 813–814. (b) Ref. 13(b). (c) Bluet, G.; Campagne, J.-M. J. Org. Chem. 2001, 66, 4293–4298. (d) De Rosa, M.; Soriente, A.; Scettri, A. Tetrahedron Asymmetry 2000, 11, 2255–2258. (e) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connel, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669–685. For a general discussion of this position see: Denmark, S. E.; Stavenger, R. A.; Su, X.; Wong, K.-T.; Nishigaichi, Y. Pure & Appl. Chem. 1998, 70, 1469–1476. (a) Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. Nonlinear Effects in Asymmetric Catalysis. J. Am. Chem. Soc. 1994, 116, 9430–9439. (b) Kagan, H. B.; Fenwick, D. Asymmetric Amplification. Top. Stereochem. 1999, 22, 257–296. (c) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Nonlinear Stereochemical Effects in Asymmetric Reactions. Tetrahedron: Asymmetry 1997, 8, 2997–3017. Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357–9358. For a detailed discussion involving the determination of 13 C KIE from NMR integration and error analysis; Ref. 105.

325

326

7 Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases 107 Pham, S. M. Ph.D. Thesis, University of Illinois, Urbana–

Champaign, 2002. 108 A similar study has been completed in the addition of

109 110

111

112 113 114

isobutyraldehyde trichlorosilyl enolate to benzaldehyde. Here as well, the aldolization step is shown to be rate-limiting; Ref. 93. The importance of the ordering of the subsequent steps is at present unknown. The configuration around the octahedral silicon cation is unknown. Moreover, given the divergent criteria for which would be more stable and which more reactive, a definitive answer must await computational analysis. Attempts to identify stable complexes with silicon(IV) Lewis acids and phosphoramides have as yet been unsuccessful. However, a stable complex of bis(N-oxide) 46 with silicon tetrachloride has been analyzed crystallographically, Fan, Y. unpublished results from these laboratories. Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2003, 125, 2208– 2216. For recent studies on linked phosphoramides in the aldol addition of ethyl ketone trichlorosilyl enolates; Ref. 45. Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825– 7827.

327

8

The Aldol–Tishchenko Reaction R. Mahrwald 8.1

Introduction

The Tishchenko reaction has been known for almost 100 years [1]. The importance of catalysis in this reaction – dimerization of aldehydes to the corresponding esters and the polymerization of dialdehydes to the expected polyesters – has grown in the last 50 years. This reaction has great potential in stereoselective synthesis of defined stereocenters. Depending on the nature of substrates, reaction conditions, and catalysts, defined diastereoselective and enantioselective stereogenic centers can be created.

8.2

The Aldol–Tishchenko Reaction

The aldol–Tishchenko reaction was first studied at the beginning of the last century [2]. Although in many Tishchenko reactions the aldol–Tishchenko reaction is a competitive transformation, by use of the right reaction conditions and catalysts one can affect which pathway is taken. In recent years interest in this area has increased substantially. This reaction can be performed either with enolizable aldehydes (resulting in trimerization of aldehydes) or with ketones (resulting in formation of 1,3-diol monoesters). 8.2.1

The Aldol–Tishchenko Reaction with Enolizable Aldehydes

The classic aldol–Tishchenko reaction is used to obtain 1,3-diol monoesters by self-addition of aldehydes with at least one a-hydrogen [3]. In the first step of this reaction two molecules of aldehyde react by reversible aldol addition to give the expected aldol adduct; this is further reduced by a third molecule of aldehyde to give the 1,3-diol monoesters, 1 and 2 (Eq. (1)). Modern Aldol Reactions. Vol. 2: Metal Catalysis. Edited by Rainer Mahrwald Copyright 8 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30714-1

328

8 The Aldol–Tishchenko Reaction

3 R - CH2 - CHO catalyst

R OH

R O

R O 1 +

R O

R OH

R O 2

Equation 1

Catalysts: magnesium-2,4,6trimethylphenoxide [4], Cp2 Sm(THF)2 [5], SmI2 [6], LiO-iPr [7], BINOL-Li [8], Y2 O(OiPr)13 [9].

Merger et al. [10] reacted aldol adducts with aldehydes and isolated the 1,3-diol monoesters. These aldol–Tishchenko reactions were performed in the presence of metal alkoxides or without catalysts at higher temperatures. They showed that:

. the ester functionality does not come from the intermolecular combinaof two aldehydes; . tion hydride shift occurs in an intermediate equilibrium of hemiacetals and (Scheme 8.1); . dioxanolen aldols are hydride acceptors – the carbonyl function will be reduced; and . primary 1,3-diol monoesters are the thermodynamically stable products and they are formed by an acyl migration during the reaction. Results from mechanistic study of the stereoselective aldol–Tishchenko reaction support the mechanism depicted in Scheme 8.1. First, a rapid aldol reaction occurs and by reaction with a further molecule of aldehyde the hemiacetal 4 is formed. Subsequent hydride transfer (in the intermediate equilibrium of hemiacetals and dioxanolen) yields the 1,3-diol monoester 5. There are only two examples of enantioselective execution of the aldol– Tishchenko reaction of aldehydes. Loog and Maëorg used chiral binaph-

8.2 The Aldol–Tishchenko Reaction

R2

H

R1

H

R1 3

O OH

O

R2

H

H

OM

O

R2 - CHO

OM

329

R2

R2 - CHO

R1 R2

O

5 H

R1 H

R1

O R2

H

O

M

O

O OM

O H

H

OM H R2

O

R2

O

R1

R1 R2 MO

R1 H

O

O

R2 R2

H

4

R2 H

Scheme 8.1

tholate catalysts to investigate the stereochemistry of the self-addition of 2-methylpropanal [8]. 1,3-Diol monoesters were obtained with low enantioselectivity (ee > 30%). Morken et al. recently published details of an asymmetric mixed aldol–Tishchenko reaction of aromatic aldehydes with 2methylpropanal catalyzed by salen complexes of yttrium [9]. The results are shown in Table 8.1. These are the first examples of enantioselective catalytic aldol–Tishchenko reactions of two different aldehydes. 8.2.2

The Aldol–Tishchenko Reaction with Ketones and Aldehydes

Ketones and aldehydes also undergo an aldol–Tishchenko reaction. Three adjacent stereogenic centers can be created by use of these reactants in the aldol–Tishchenko reaction whereas only two stereogenic centers can be formally produced by reacting enolizable aldehydes with aldehydes (Eq. (1)). This is a very effective reaction sequence in terms of chiral economy [11]. The nomenclature used in Eq. (2) and Scheme 8.2 is used throughout the following sections.

330

8 The Aldol–Tishchenko Reaction Tab. 8.1

Enantioselective aldol–Tishchenko reaction in the presence of chiral yttrium complexes. Ph H

Ph H

N

N R - adamantyl

OH

HO R

R

2 mol% Y2O(OiPr)13 R - CHO +

CHO

13 mol% ligand

OH

OCOiPr

R

Entry

Substrate

Yield [%]

e.r. (Configuration)

1 2 3 4 5

Phenyl 4-Bromphenyl Naphthyl 4-Methoxyphenyl 3-Phenyl-2-propenyl

70 55 50 21 50

87:13 (S) 85:15 (S) 82:18 86:14 55:45

O R'

O

2 R' - CHO +

R''

OH

O

O R'

OH

2 1

3

O

R'

2

R''

R'

1

3

R''

+ 6 1,3-diol 1-monoester

7 1,3-diol 3-monoester

Equation 2

Catalysts: nickel enolates [12], SmI2 [6, 13], zinc enolates [14], titanium ate complexes [15], LDA [16–18], Ti(OiPr)4 [19].

The 1,3-diol 1-monoester 6 and the corresponding 3-monoester 7 were prepared with high simple stereoselectivity. Only one of the four possible diastereoisomers has been formed in all examples described in the literature. On the basis of the transition state shown in Scheme 8.1 the 1,3-diol 1-monoester 6 was formed in the 1,2-anti, 1,3-anti configuration (Scheme 8.2). The diol 3-monoester 7 was again formed by acyl migration during reaction. The extent of this migration usually depends on the steric bulkiness of the starting aldehydes. Heathcock et al. showed that isolated nickel ketone enolates react with


O R1 2 R1 - CHO +

O

O

OH 6

R1

1,2-anti, 1,3-anti 1,3-diol 1-monoester R1

O R1

H O

O

R1

M OH R1

O

O 7

1,2-anti, 1,3-anti 1,3-diol 3-monoester

Entry

R1

Diastereoselectivity

1

Ph

99 : 1

2

tBu

98 : 2

3

iPr

98 : 2

4

nPr

97 : 3

Scheme 8.2

Reaction conditions: titanium ate complexes [15].

benzaldehyde to furnish products resulting from an aldol–Tishchenko reaction [12]. They also established the 1,2-anti, 1,3-anti configuration of the isolated 1,3-diol monoester. These are the first examples of an aldol– Tishchenko reaction of ketones with aldehydes. Later we found that 1,3-diol monoesters 6 and 7 were formed with high stereoselectivity by an one-pot aldol–Tishchenko reaction of ketones with aldehydes in the presence of substoichiometric amounts of titanium ate complexes [15]. An instructive example for the direction of stereochemistry during the aldol–Tishchenko reaction is the observation that the 1,2-anti, 1,3-anti configuration of the isolated diol monoesters 6 and 7 is independent of the configuration of the assumed starting aldol. To demonstrate this, we have reacted the pure syn aldol 8 of benzaldehyde and diethylketone with one equivalent of benzaldehyde in the presence of catalytic amounts of titanium ate complexes (Eq.

331

332


(3)). Under these conditions the 1,2-anti, 1,3-anti configured diol monoesters 9 and 10 were formed exclusively. OH

O

Ph - CHO + Ph

8

Ph OH

O

O

Ph 9 + Ph O

O

OH

Ph 10 Equation 3

Reaction conditions: 10 mol% BuTi(OiPr)4 Li.

Other authors have also described achieving the same stereodirection by use of catalytic amounts of metal alkoxides [7] or LDA [16–18] (Eq. (2)). Three applications of this reaction are shown in Eqs. (4)–(6). A samarium ion-catalyzed aldol–Tishchenko reaction combined with a reductive cyclization process was reported by Curran and Wolin [13]. Only one isomer was detected during this transformation (Eq. (4)). The configuration of the 1,3diol monoester 12 (1,2-anti, 1,3-anti) was the same as that shown in Scheme 8.2 and Eq. (3). O O

OH

O

Ph Ph

I 11 Equation 4

SmI2 , Ph(CH2 )2 CHO, 81%.

12


333

Ph

Ph Ph O

O

O

OH

Ph 14

13 Equation 5

LDA, PhCHO, 56%.

O Br

OH

CHO Br

OH

Br

OTIPS

OTIPS

+ 15

16

17

Equation 6

1. SmI2 , MeCHO; 2. K2 CO3 , MeOH, 96%.

In another example, the keto epoxide 13 was reacted with LDA and benzaldehyde to give the hydroxyester 14 as a single isomer (Eq. (5)) [16]. Because of the missing stereogenic center in the epoxide 13 only one new stereogenic center was created. In terms of the stereochemistry only this example seems to lie between the Evans–Tishchenko reduction and the aldol–Tishchenko reaction. A samarium-catalyzed aldol–Tishchenko reaction has been used to synthesize the intermediate 17 in a highly convergent synthesis of luminacin D [20]. The diol 17 was obtained as a single isomer (Eq. (6)). The aldol–Tishchenko reaction has also been used in the synthesis of 1 0 branched chain sugar nucleosides. The 1 0 -hydroxymethyl group was introduced by an Sm2 -promoted aldol–Tishchenko reaction of 1 0 -phenylseleno2 0 -ketouridine 18 with aldehydes (Eq. (7)). This is the first example of generation of an enolate by reductive cleavage of a CaSe bond by SmI2 [21].

O

N

O

NBOM

NBOM

NBOM RO

O

O

O

RO O

SmJ2

N

RO

O

O HO

R' - CHO

SePh RO

O 18

Equation 7

Synthesis of 10 -branched nucleosides.

RO

OSm3+

N

O R

OCOR'

RO 20

334


O OH

OSiMe3

OH

OH

O

i

20

21 O

OH

OSiMe3

OH

OH

O

ii

22

23

Scheme 8.3

Reaction condition: (i)10 mol% Ti(OiPr)4 , EtCHO, 0 C, 91%; (ii) 10 mol% Ti(OiPr)4 , EtCHO, 0 C, 90%.

An interesting reaction was reported by Delas et al. [19]. They described aldol–Tishchenko reactions of enolsilanes (activated ketones) with aldehydes in the presence of Ti(OiPr)4 – a variation of the classic aldol– Tishchenko reaction (Scheme 8.3). They were able to obtain the stereosixtades 21 and 23 – compounds with six defined adjacent stereogenic centers – in one reaction step. The diastereoselectivity observed was very high and the stereosixtades were obtained as single isomers. This example indicates that the stereodirection of the aldol–Tishchenko reaction can be affected. Oxygen-containing functionality in the starting enolsilanes 20 and 22 has a useful stereodirecting effect on this transformation and on the configuration of the stereosixtades 21 and 23. This paper pioneered the field of stereoselective aldol–Tishchenko reactions. The two examples given in Scheme 8.3 show the stereochemical potential of this process. Schneider et al. recently published an enantioselective approach to chiral 1,3-anti-diol monoesters. Although at first glance this transformation seems to be a Tishchenko reduction of an acetate aldol (Section 8.2.3) inspection of the mechanism furnishes evidence of a retro-aldol/aldol–Tishchenko reaction. By using 10 mol% Zr(OtBu)4 -TADDOL the 1,3-diol monoesters were obtained with moderate enantioselectivity (Table 8.2) [22]. 8.2.3

The Evans–Tishchenko Reduction

The Evans–Tishchenko reduction is a special case of the aldol–Tishchenko reaction. The starting material is an aldol adduct, usually an acetate aldol. During the reaction the keto functionality of the starting aldol is reduced by

8.2 The Aldol–Tishchenko Reaction Tab. 8.2

Enantioselective aldol–Tishchenko reaction of aldehydes and ketones. R1 OH

10 mol% Zr(OtBu)4 TADDOL

O

R1 - CHO +

O

O

OH

R1

R2

R2

R1 - CHO

OZr(OtBu)3

R1 - CHO

OH

R2

O

R1

R2

Entry

R1

R2

Yield [%]

ee [%]

1 2 3 4

tBu tBu tBu tBu

nHex iPr cHex 2-ethylpropyl

88 84 75 69

42 57 50 47

reaction with an aldehyde in the presence of a Lewis acid. This reaction was first described and elaborated on by Evans and Hoyveyda [23]. The reaction was performed in the presence of substoichiometric amounts of SmI2 . The 1,3-diols were isolated in excellent yields with high anti stereoselectivity (> 99:1). The transition structure proposed for the samarium-catalyzed reduction is given in Scheme 8.4. It is very close to those described in previous sections. R1 OH R1

O

R2 R2 +

O R3

H

R3 - CHO

O

O Sm

O R3

O O

OH

OH

O

R3

+ R1 Scheme 8.4

Catalysts: SmI2 [24–29] BuLi [30, 31], zirconocene complexes [32], Sc(OTf )3 [33], ArMgBr [34].

R2

R1

R2

335

336


Several other metal compounds were subsequently found to induce this reduction (Scheme 8.4). Few authors have described the acyl migration as a result of this reduction that one could expect from the reaction mechanism [30, 34]. This is an unusual result. Five applications of the SmI2 -mediated reduction of hydroxy ketones in natural product synthesis are given in Scheme 8.5.

OH

O O

Ph

OAc

O O

Ph

O i

OH

C14H29

C14H29

24 OH TBSO ( ) 5

25

O

OBz OH ii

TBSO

( )5

27

26 OSEM O

iii

OSEM

OH

OH

OBz 29

28 iiii

PMBO O

PMBO OH

OH

OCOEt

30 OH

31 O

OTBS

OBz OH

Ph

v O

O

OTBDPS

32 Scheme 8.5

(i) CH3 CHO, SmI2 , 80% [25]; (ii) PhCHO, SmI2 , 70% [26]; (iii) PhCHO, SmI2 , 85% [27]; (iv) EtCHO, SmI2 , 97% [29]; (v) SmI2 , PhCHO, 95% [35].

OTBS

Ph O

O

OTBDPS

33


The broad variety of functional groups which can be used in this reaction are represented in these substrates. An interesting example is reduction of the hydroxyketone 32 to the hydroxybenzoate 33. The authors obtained a single 1,2-syn, 1,3-anti-configured diastereoisomer [35]. Exclusive formation of the 1,2-syn, 1,3-anti-configured hydroxybenzoate 33 is observed, irrespective of the 1,2-anti configuration of the starting hydroxyketone 32. This reaction could offer an approach to natural products containing a 1,2-syn configuration; these have previously been unattainable by contemporary aldol additions. Two spectacular examples of the use of the Evans–Tishchenko reduction in natural product synthesis are given in Scheme 8.6. In 1993 Schreiber et

OTBS PMBO

ODEIPS

O

OH

H

MeO 34

OMe

OTIPS CHO i,

NBoc

BocN H ODEIPS

OTBS PMBO

OH

O

O H

MeO 35

OMe

OTIPS

J

PMBO

36 OH

O

OTBS

ii PMBO

J OH

O

O

OTBS

Et Scheme 8.6

(i) SmI2 aPhCHO complex, 95%; (ii) SmI2 , EtCHO, 92%.

37

337

338


al. used this reaction in the total synthesis of rapamycin to obtain the intermediate 35 [24]. This 1,3-diol monoester 35 was obtained with the correct and required stereochemistry as a single isomer by a Tishchenko reduction of ketone 34 in the presence of 30 mol% (PhCHO)SmIaSmI3 (Scheme 8.6). The formation of this complex was described by Evans and Hoyveyda [23]. Paterson et al. used the Tishchenko reduction successfully for several total syntheses. In the synthesis of callipeltoside they needed the intermediate 37 for the synthesis of the aglycone [28]. Again, Tishchenko reduction of ketone 36 with propionaldehyde in the presence of SmI2 yielded the diol monoester 37 with the required 1,2-anti, 1,3-anti configuration (Scheme 8.6). Evans et al. [36] used this procedure in the total synthesis of bryostatin 2. Starting from the corresponding ketone 38 they obtained the ketone 39, with the required configuration of the hydroxy group, by samariumcatalyzed Tishchenko reduction (Eq. (8)). These examples show the broad application of this highly stereoselective Tishchenko reduction process.

O PhO2S

OH

O

( )3 OPMB 38

O PhO2S

OR

OH

( )3 OPMB 39

Equation 8

Reaction conditions: SmI2 , p-NO2 C6 H4 CHO; ds > 95:5, 76%.

The Evans–Tishchenko reduction also provides an efficient and practical solution for the oxidation of aldehydes containing sensitive electron-rich heteroatoms (e.g. aldehyde 40, Eq. (9)). Careful selection of the sacrificial b-hydroxy ketone subsequently provides very flexible access to the desired carboxylic acid 41 (Eq. (9)). This methodology was used in total synthesis of (þ)-13-deoxytedanolide [37].


O

OH O

R S OHC

339

i

OH

S S

O

S

R

40 S ii HOOC

S

Equation 9

Reaction conditions: (i) 20 mol% SmI2 , THF, 10 C; (ii) LiOH, aqueous MeOH.

8.2.4

Related Reactions

The samarium-mediated coupling reaction of vinyl esters with aldehydes has been described [38]. These reactions were performed with enolizable and aromatic aldehydes. Unsymmetrical diesters such as 42 were formed by means of this transformation (Scheme 8.7). On the basis of labeling studies (reaction of vinyl acetate with PhCOD) the mechanism given in Scheme 8.7 seems plausible. An eight-membered alkoxy samarium species might be the key intermediate in this reaction. Subsequent intramolecular hydride shift, as known from the Tishchenko reaction, produces the diester. The pinacol–Tishchenko reaction has recently been described (Eq. (10)), Figure 8.1) [39]. a-Hydroxy epoxides 43 were reacted with SmI2 , efficiently forming the 2-quaternary 1,3-diol monoesters 44 and 45 with high diaster-

O R1

O + R2 - CHO

O

R1

O

R2 O

R2

O 42

Ph O D D O

O

D

Ph

O

Ph O

Sm O Scheme 8.7

Reaction conditions: 10 mol% Cp2 Sm(THF)2 .

O

D

O

Ph

41

340


HO R2 O

R2 i

R1

2

OH R2 R1

1

R1

+

3

OCOR3

OH

1,2-anti, 1.3-anti-diol 1-monoester 44

43

OCOR3

1,2-anti,1.2-anti-diol 3-monoester 45

Equation 10

Reaction conditions: (i) 10–30 mol% SmI2 ; R1 ¼ R2 ¼ Ph, 95%; R1 ¼ Me, R2 ¼ Ph, 96%; R1 ¼ Et, R2 ¼ Ph, 92%; R1 ¼ iPr, R2 ¼ Ph, 92%.

eoselectivity. The reaction is similar to those already described. Rearrangement of the starting a-hydroxy epoxide 43 occurs under the reaction conditions described. Insertion into the MaO bond occurs on addition of the aldehyde R3 CHO, and as a consequence the hemiacetal is formed (Figure 8.1). Hydride transfer results in the formation of the 1,3-diol monoesters 44 and 45. Only the 1,2-anti, 1,3-anti configured diol monoester is formed. This configuration is again independent of the configuration of the starting ahydroxy epoxides. The corresponding 1,2-syn configured products were not detected.

O M R2

OH R1

R1

M

O

OH

R2 R3 - CHO

H R3

O O R2

R1 OH

R1

H R3

O R2

OH O M

Fig. 8.1

8.3 Representative Procedures

It is clear that the Tishchenko reaction and its variations are valuable additions to the repertoire of the chemist interested in stereoselective synthesis. The exceptionally high stereoselectivity obtained in this reaction is fascinating (de > 95:5 for all the examples described). Only one diastereoisomer was formed during the reaction in all other examples. Although much has been achieved there still is a need for control of the remaining directions of stereochemistry. This is true not only for the diastereoselectivity but also for the control of enantioselectivity. 8.3

Representative Procedures Typical Procedure for the Aldol–Tishchenko Reaction: rac(1S,2S,3R)-3-Hydroxy2-methyl-1-phenylpent-3-yl benzoate (9) and rac(1S,2R,3S)-1-Hydroxy-2-methyl1-phenylpent-1-yl benzoate (10) [15]. BuLi (0.64 mL, 1.0 mmol in hexane) was carefully added, under inert conditions, to a solution of titanium(IV) iso-propoxide (0.32 mL, 1.0 mmol) in 1-tert-butoxy-2-methoxyethane (1.5 mL). After stirring for 30 min at room temperature pentan-3-one (0.5 mL, 5 mmol) and then benzaldehyde (1.0 mL, 10 mmol) were added. The solution was stirred for further 24 h at room temperature. Diethyl ether (50 mL) was added and the organic phase was extracted with water until neutral. The organic layer was isolated, dried (Na2 SO4 ), filtered, and evaporated under vacuum. The pure products 9 and 10 were separated by flash chromatography with hexane–isoPrOH as eluent (95:5). Yield 63% (ratio of 9/10 ¼ 95:5). Typical Procedure for the Tishchenko Reduction: (7S,9R,10R)-1-Benzenesulfonyl-2,2-dimethyl-9-hydroxy-10-(para-methoxybenzyloxy)-7-(para-nitrobenzoyloxy)-undecan-3-one (39) [36]. Freshly prepared samarium diiodide (0.1 m in THF, 38 mL, 38 mmol, 0.24 equiv.) was added dropwise to a cooled (0 C) solution of ketone 38 (7.86 g, 15.6 mmol) and p-nitrobenzaldehyde (23.6 g, 156 mmol. 10 equiv.) in 200 mL THF. The reaction was stirred in the dark under an argon atmosphere for 5.5 h then quenched with 150 mL sat. aqueous NaHCO3 . The mixture was partitioned between 250 mL EtOAc and 250 mL aqueous sat. NaHCO3 and the aqueous phase was extracted with EtOAc (3 100 mL). The organic extracts were combined, washed with brine (1 75 mL), dried (MgSO4 ), filtered, and evaporated in vacuo. A small sample was removed and filtered through a plug of silica gel with 50% EtOAc–hexane as eluent. All the fractions containing the product were combined and assayed by HPLC (Zorbax silica gel, 0.7% EtOHaCH2 CL2 , 1.0 mL min1 , 254 nm UV cut-off ) to reveal the product was a 93:7 mixture of diastereoisomers (retention time major product 23.9 min; retention time minor product 32.7 min) which were shown to be from the previous aldol addition. The other diastereomer from the Tishchenko reduction could not be isolated and the only other compound visible in the HPLC chromatogram was present at

Modern Aldol Reactions

Modern Aldol Reactions

Modern Aldol Reactions

Aldol Reactions

Aldol Reactions