Asymmetric Synthesis of Nitrogen Heterocycles

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Asymmetric Synthesis of Nitrogen Heterocycles Edited by Jacques Royer

Further Reading Cornils, B., Herrmann, W. A., Muhler, M., Wong, C.-H. (eds.)

Catalysis from A to Z A Concise Encyclopedia 2007 Hardcover

Hiersemann, M., Nubbemeyer, U. (eds.)

The Claisen Rearrangement Methods and Applications 2007 Hardcover ISBN: 978-3-527-30825-5

ISBN: 978-3-527-31438-6

Dalko, P. I. (ed.) Knipe, C., Watts, W. E. (eds.)

Enantioselective Organocatalysis

Organic Reaction Mechanisms, 2005

Reactions and Experimental Procedures

Hardcover ISBN: 978-0-470-03403-3 Online Buch Wiley Interscience ISBN: 978-0-470-06661-4

2007 Hardcover ISBN: 978-3-527-31522-2

Roberts, S. M. Mikami, K., Lautens, M. (eds.)

New Frontiers in Asymmetric Catalysis

Catalysts for Fine Chemical Synthesis Volume 5: Regio- and Stereo-Controlled Oxidations and Reductions

2007 Hardcover

2007 Hardcover

ISBN: 978-0-471-68026-0

ISBN: 978-0-470-09022-0

Sheldon, R. A., Arends, I., Hanefeld, U.

Wyatt, P., Warren, S.

Green Chemistry and Catalysis

Organic Synthesis

2007 Hardcover ISBN: 978-3-527-30715-9

Strategy and Control 2007 E-Book ISBN: 978-0-470-06120-6

Asymmetric Synthesis of Nitrogen Heterocycles Edited by Jacques Royer

The Editor Prof. Dr. Jacques Royer Universit´e Paris Descartes Facult´e de Pharmacie Laboratoire de Chimie CNRS/UMR 8638 4, Avenue de l Observatoire 75270 Paris Cedex 06 France

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliograﬁe; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microﬁlm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not speciﬁcally marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany Printed on acid-free paper Typesetting Laserwords Private Limited, Chennai, India Printing betz-druck GmbH, Darmstadt Binding Litges & Dopf Buchbinderei GmbH, Heppenheim Cover Design Graﬁk-Design Schulz, Fußg¨onheim ISBN: 978-3-527-32036-3

V

Foreword It is a great pleasure to see a new volume of Asymmetric Synthesis of Nitrogen Heterocycles going to press. Since the nineteenth century, the study of nitrogen-containing products, especially alkaloids, has often provided the impetus for great advances in organic chemistry. On one hand, the unceasing proliferation of alkaloid literature accounts for the interest in this class of natural products. On the other hand, heterocyclic chemistry, in general, represents a special topic in medicinal chemistry. Moreover, optically active amines constitute an important class of compounds that ﬁnd a wide range of interest as chiral building blocks and as part of many pharmaceutical products. Indeed, asymmetric synthesis is more than an academic specialty. It is the goal of this book to bring all these aspects up to date and to extend the scope of asymmetric synthesis of nitrogen heterocycles to a large variety of structures, that is, with respect to ring size and number of heteroatoms. The objective of the Editor, who is also contributor of a chapter, has been reached in receiving the collaboration of leaders in this ﬁeld from Europe, China and Japan. This volume is divided into two parts. Part One describes in four chapters asymmetric synthesis of nitrogen heterocycles containing only one heteroatom in 3-,4-,5-,6-,7- (and more) membered rings. Part Two consists of four chapters covering the asymmetric synthesis of nitrogen heterocycles with more than one heteroatom. I am sure that this treatise, which highlights an important ﬁeld of enantioselective chemistry, should be of value to both academic and pharmaceutical chemists as well as PhD students. Paris, October 2008

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

Professor H.-P. Husson

VII

Contents Preface

XIII

List of Contributors

XV

Part One Asymmetric Synthesis of Nitrogen Heterocycles Containing Only One Heteroatom 1 1

1.1 1.1.1 1.1.2 1.1.2.1 1.1.2.2 1.1.3 1.1.3.1 1.1.3.2 1.1.4 1.1.4.1 1.1.4.2 1.1.5 1.1.6 1.1.6.1 1.1.6.2 1.1.6.3 1.1.6.4 1.1.6.5 1.2 1.2.1 1.2.2

Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles 3 Giuliana Cardillo, Luca Gentilucci and Alessandra Tolomelli Substituted Aziridines 3 Generalities 3 Asymmetric Aziridination via Cyclization Methods 6 Cyclization of a Nucleophilic N on an Electrophilic C (Pathway A) 7 Cyclization of a Stabilized Anion on an Electrophilic N (Pathway B) 9 Asymmetric Aziridination via Cycloaddition Methods 12 Addition of Nitrenes to Alkenes 12 Reaction between Carbenes and Imines 16 Ring Transformation Methods 27 Aziridines from Epoxides 27 Aziridines from Other Heterocycles 30 Racemate Resolution 31 Asymmetric Synthesis of Azirines 33 The Neber Reaction 33 Thermal or Photochemical Treatment of Vinyl Azides 34 Elimination from Aziridines 34 Resolution of Racemic Azirines 35 Oxidation of Aziridines 36 Substituted Monocyclic Azetidines and Carbocyclic-Fused systems 36 Generalities 36 Cyclization Methods: Introduction 38

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

VIII

Contents

1.2.2.1 1.2.2.2 1.2.3 1.2.4

2 2.1 2.1.1 2.1.2 2.1.2.1 2.1.2.2 2.1.2.3 2.1.3 2.1.3.1 2.1.3.2 2.1.4 2.1.4.1 2.1.4.2 2.1.5 2.1.5.1 2.1.5.2 2.1.5.3 2.1.5.4 2.1.5.5 2.1.5.6 2.2 2.2.1 2.2.2 2.3 2.3.1 2.3.1.1 2.3.1.2 2.3.1.3 2.4

3 3.1 3.2

Cyclization methods: Enantiopure Azetidines via Formation of C–N Bond 39 Cyclization Methods: Enantiopure Azetidines via Formation of C–C Bond 40 Azetidines by Resolution of Racemates 42 Azetidines by Ring Transformation 44 References 45 Asymmetric Synthesis of Five-Membered Ring Heterocycles 51 Pei-Qiang Huang Monocyclic Pyrrolidines and Pyrrolidinones 51 Generalities 51 Cyclization Methods 52 Cyclization via C1 /C5 –N Bond Formation 52 Cyclization via C2 –C3 Bond Formation 61 Cyclization Involving C3 –C4 Bond Formation 62 Cycloaddition Methods 64 Cycloaddition Approach 64 Annulation Approach 66 Ring Transformation Methods 67 Ring Expansion Methods 67 Ring Contraction Methods 68 Substitution of Already Formed Heterocycle 68 By Nucleophilic Reaction of Pyrrolidinium Ions 71 By Nucleophilic Reaction of Cyclic Imides 72 By Nucleophilic Addition/Cycloaddition of Pyrrolidine Nitrones 74 By Functionalization of 2-Pyrrolines 76 By Enantioselective Reactions 77 By Functionalization at C3 /C4 Positions of Pyrrolidines 77 Pyrrolines 79 Synthesis of Pyrrolines by Cyclization and Annulation Reactions 79 Synthesis of Pyrrolines by Substitution of Already Formed Heterocycles 80 Fused Bicyclic Systems with Bridgehead Nitrogen 82 Pyrrolizidines 82 Through Extension of Methods for the Synthesis of Pyrrolidines 82 Other Methods for the Synthesis of Pyrrolizidines 83 Asymmetric Synthesis of Polyhydroxylated Pyrrolizidines 85 Acknowledgments 87 References 87 Asymmetric Synthesis of Six-Membered Ring Heterocycles Naoki Toyooka Introduction 95 Dihydropyridines 95

95

Contents

3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.4 3.4.1 3.4.2 3.4.2.1 3.4.2.2 3.4.3 3.4.3.1 3.4.3.2 3.4.3.3 3.4.4 3.4.4.1 3.4.4.2 3.4.4.3 3.4.5 3.4.5.1 3.4.5.2 3.4.5.3 3.4.5.4 3.4.5.5 3.5

Tetrahydropyridines 98 Ring-Closing Metathesis (RCM) 98 Reduction of Pyridine Derivatives 101 Deracemization Processes 101 Michael Addition Followed by Elimination 102 Enamine Reaction 102 Electrocyclization 105 Monocyclic Piperidines and Carbocyclic Fused Systems 107 Generalities 107 Cyclization Methods 107 Nitrogen as a Nucleophile 108 C–C Bond Formation 113 Cycloaddition Methods 117 [4 + 2] Azadiene Cycloaddition 117 [4 + 2] Acylnitroso Cycloaddition 117 [3 + 2] Cycloaddition 119 Ring Transformation Methods 119 Ring Enlargement of Pyrrolidines to Substituted Piperidines 120 Ring Transformation of Lactones to 2-Piperidones 121 Ring Enlargement of γ -Lactam to 2-Piperidones 122 Substitution of Already Formed Heterocycle 123 Phenylglycinol-Derived Oxazolidine 123 Asymmetric Michael Addition 125 Nitrone Cycloaddition 127 Iminium Strategies 128 Oxidative Methods 131 Fused Tri- or Bicyclic System with Bridgehead Nitrogen 132 References 135

4

Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles 139 Yves Troin and Marie-Eve Sinibaldi Substituted Azepines 139 Generalities 139 Cyclization Methods 142 Lactamization: C–N Bond Formation 142 Radical Cyclization 146 Intramolecular Cyclization 149 Oxidative Phenol Coupling Reaction 155 The Ring Closure Metathesis 155 Cycloaddition Methods 161 [5 + 2] Cycloaddition 162 [4 + 3] Cycloaddition 162 Nitrone Cycloaddition 162

4.1 4.1.1 4.1.2 4.1.2.1 4.1.2.2 4.1.2.3 4.1.2.4 4.1.2.5 4.1.3 4.1.3.1 4.1.3.2 4.1.3.3

IX

X

Contents

4.1.3.4 4.1.4 4.1.4.1 4.1.4.2 4.1.4.3 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.3

Intramolecular Diels–Alder Reactions (IMDA) – [4 + 2] Cycloaddition 163 Ring Transformation Methods 163 Classical Methods 164 Ring Expansion 166 Substitution of Already Formed Heterocycles 169 Substituted Azocines 171 Azocines from Intramolecular Nucleophilic Substitution 172 Ring Transformations Methods 173 Cycloaddition Approaches to Azocines 174 Ring-Closing Metathesis 175 Substituted Large Nitrogen-Containing Rings 177 References 181

Part Two Asymmetric Synthesis of Nitrogen Heterocycles with More Than One Heteroatom 187 5

5.1 5.2 5.2.1 5.2.1.1 5.2.1.2 5.2.2 5.2.3 5.2.3.1 5.2.3.2 5.2.3.3 5.3 5.3.1 5.3.2 5.3.2.1 5.4

6

6.1 6.1.1

Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles with More Than One Heteroatom 189 Steve Lanners and Gilles Hanquet Introduction 189 Three-Membered N-Heterocycles with Two Heteroatoms 189 Diaziridines 190 Substrate-Controlled Diastereoselective Diaziridination Using Chiral Enantiomerically Pure Amines 191 Substrate-Controlled Diastereoselective Diaziridination Using Chiral Enantiomerically Pure Ketones 192 Diazirines 193 Oxaziridines 194 Chiral Peracidic Oxidation of Achiral Imines 195 Achiral Peracidic Oxidation of Chiral Nonracemic Imines 196 Photocyclization of Nitrones 207 Four-Membered N-Heterocycles with Two Heteroatoms 208 Diazetidines 208 Oxazetidines 210 Thiazetidines 212 Conclusions 217 References 217 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom 223 Catherine Kadouri-Puchot and Claude Agami Five-Membered Heterocycles with N and O Atoms 223 Oxazolidines 223

Contents

6.1.1.1 6.1.1.2 6.1.2 6.1.3 6.1.3.1 6.1.3.2 6.1.4 6.1.4.1 6.1.4.2 6.2 6.2.1 6.2.1.1 6.2.1.2 6.2.2 6.2.2.1 6.2.2.2 6.2.3 6.3 6.3.1 6.3.1.1 6.3.1.2 6.3.1.3 6.3.2 6.3.2.1 6.3.2.2 6.3.3

N-Alkyloxazolidines 224 N-Tosyl and N-Boc Oxazolidines 228 Oxazolines (4,5-dihydrooxazoles) 230 Oxazolidinones 235 Oxazolidin-2-ones 235 Oxazolidin-4-ones and 5-ones 242 Isoxazolines and Isoxazolidines 243 Isoxazolidines 244 Isoxazolines 246 Five-Membered Heterocycles with Two N Atoms 249 Imidazolidines and Imidazolidinones 249 Imidazolidines 249 Imidazolidinones 252 Pyrazolidines and Pyrazolines 255 Pyrazolidines 255 Pyrazolines 257 Pyrazolidinones 260 Five-Membered Heterocycles with N and S Atoms 263 Thiazolidines 263 Iminothiazolidines 267 Thiazolidinethiones 268 Thiazolidinones 269 Thiazolines 270 2-Thiazolines 270 3-Thiazolines 275 Sultams 276 References 281

7

Asymmetric Synthesis of Six-Membered Ring Nitrogen Heterocycles with More Than One Heteroatom 293 P´eter M´atyus and P´al Tapolcs´anyi Six-Membered Rings with Another Heteroatom in the Same Ring 293 Pyridazines 293 Ring Closure of Optically Active Precursors 294 Diels–Alder Reactions 299 Pyrimidines 302 Formation of the Pyrimidine Ring 302 Stereoselective Transformation by the Involvement of the Pyrimidine Ring 307 Piperazines 311 Formation of the Piperazine Ring 311 Stereoselective Transformation of the Piperazine Ring 327 Oxadiazines 332 1,2,5-Oxadiazines 332 1,3,4-Oxadiazines 332

7.1 7.1.1 7.1.1.1 7.1.1.2 7.1.2 7.1.2.1 7.1.2.2 7.1.3 7.1.3.1 7.1.3.2 7.1.4 7.1.4.1 7.1.4.2

XI

XII

Contents

7.1.5 7.1.5.1 7.1.5.2

Morpholines 335 Formation of the Morpholine Ring 335 Asymmetric Transformations with the Involvement of the Morpholine Ring 352 References 359

8

Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom 367 Jacques Royer Diazepines 367 1,2-Diazepines 367 1,3-Diazepines 368 1,4-Diazepines 371 1,4-Benzodiazepines 371 Other 1,4-Diazepines 376 Oxazepines 378 1,2-Oxazepine 378 Diels–Alder Cycloaddition 378 Intramolecular 3 + 2 Cycloaddition 379 Pd-Catalyzed 4 + 3 Cycloaddition 379 Rearrangements 379 1,3-Oxazepines 380 N,O-Acetals 380 1,4-Oxazepines 383 Amino Alcohol Double Condensation 383 Other Cyclization Methods 383 Pd-Catalyzed Allene Cyclization 384 Radical Cyclization 385 Ring Enlargement 385 Cycloaddition 386 Thiazepines 386 1,2-Thiazepines 387 1,3-Thiazepines 387 1,4-Thiazepines 388 From Mercaptopropionic Acid Derivatives 388 From Amino Thiols 390 Others 391 References 392

8.1 8.1.1 8.1.2 8.1.3 8.1.3.1 8.1.3.2 8.2 8.2.1 8.2.1.1 8.2.1.2 8.2.1.3 8.2.1.4 8.2.2 8.2.2.1 8.2.3 8.2.3.1 8.2.3.2 8.2.3.3 8.2.3.4 8.2.3.5 8.2.3.6 8.3 8.3.1 8.3.2 8.3.3 8.3.3.1 8.3.3.2 8.3.3.3

Index 399

XIII

Preface Nitrogen heterocycles are a huge family of compounds. Among them, numerous natural products as well as synthetic derivatives exhibiting some interesting biological activities can be found. Chirality is often encountered in such products since bioorganic substances such as receptors and enzymes are essentially asymmetric and thus their ligands are better to be asymmetric in order to ﬁt with this asymmetric environment. On the other hand, natural nitrogen compounds are also mainly asymmetric. Thus, the asymmetric synthesis of nitrogen heterocycles is a frequent preoccupation of organic chemists from both the academic and industrial areas. While the synthesis of nitrogen heterocycles uses several types of known classical reactions, it also has its own speciﬁcity shown through various strategies. In this context, I had been keen on editing a book dealing with the ‘‘asymmetric synthesis of nitrogen heterocycles’’. While several books dealing with nitrogen heterocycles already exist, no book or review article proposes an overview of the different methods used in their preparation in the asymmetric form according to their structure. It then appeared that there would be a need to have a review gathering such information. I requested some colleagues to contribute the chapters in this book. They were all approached on the basis of their experience in and authoritative knowledge of speciﬁc nitrogen heterocycles. In an attempt to cover most of the classical nitrogen heterocycles, the book has been divided into two parts. The ﬁrst part deals with heterocycles bearing only one heteroatom in their ring; it is organized into chapters according to the size of the ring: aziridine, azetidine, pyrrolidine, piperidine, azepine and larger rings. The second part deals with heterocycles that contain at least two heteroatoms (one being nitrogen), here again, the chapters correspond to the size of the ring: from three to seven-membered rings. Each chapter is also carefully organized with the aim to provide easy access to information about the different heterocyclic structures. In summary, the main idea of this book is to furnish a comprehensive handbook giving ﬁrsthand information to researchers wanting to prepare chiral nitrogen heterocycles. Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

XIV

Preface

This book would be useful for organic chemists interested in the asymmetric synthesis of heterocyclic compounds including natural products and to those working in pharmaceutical companies or in academic institutions as well. It would also be helpful for graduate students. I am deeply indebted to my colleagues who, knowing the time-consuming nature of this important piece of work, have contributed the articles for this book. Paris, October, 2008

Jacques Royer

XV

List of Contributors Claude Agami University Pierre et Marie Curie Paris France

Steve Lanners University of Namur Namur Belgium

Giuliana Cardillo University of Bologna Bologna Italy

P´eter M´atyus University of Budapest Budapest Hungary

Luca Gentilucci University of Bologna Bologna Italy

Jacques Royer CNRS-University Paris Descartes Paris France

Gilles Hanquet CNRS-University of Strasbourg Strasbourg France

Marie-Eve Sinibaldi Clermont Universit´e UBP, CNRS (UMR 6504) Laboratoire SEESIB ` Cedex 63177 Aubiere France

Pei-Qiang Huang Xiamen University Xiamen China Catherine Kadouri-Puchot University Pierre et Marie Curie Paris France

P´al Tapolcs´anyi Semmelweis University Budapest Hungary

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

XVI

List of Contributors

Alessandra Tolomelli University of Bologna Bologna Italy Naoki Toyooka University of Toyama Toyama Japan

Yves Troin Clermont Universit´e ENSCCF Laboratoire de Chimie des H´et´erocycles et des Glucides EA 987 ` Cedex 63174 Aubiere France

Part One Asymmetric Synthesis of Nitrogen Heterocycles Containing Only One Heteroatom

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

3

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles Giuliana Cardillo, Luca Gentilucci and Alessandra Tolomelli

1.1 Substituted Aziridines 1.1.1 Generalities

Small heterocyclic rings constitute systems of central importance in theoretical, synthetic organic, bioorganic, and medicinal chemistry, and in particular aziridines and azirines are very useful and interesting systems as they occur in a number of natural and biologically active substances and as they are useful building blocks and versatile synthetic intermediates. Therefore, the development of efﬁcient and stereoselective methods for synthesis and elaboration of aziridines is an inviting ongoing challenge [1]. Very often, stereogenic centers within such strained heterocycles can be used to direct the stereochemical outcome of subsequent transformations. Aziridines and their dehydro derivatives, 2H-azirines, can be regarded as representatives of the ﬁrst and most simple heterocyclic systems [2].

H H N H

Aziridine

C – C 1.48 Å C – N 1.49 Å Endocyclic angle 60° Exocyclic angle 153–160° Nitrogen inversion barrier 64.8 kJ mol−1 Nitrogen deviation from planarity 69.7°

H H N

C – C 1.46 Å C =N 1.23–1.28 Å C – N 1.59 Å Endocyclic angle 48 – 60° Exocyclic angle 142 – 160°

Azirine

While numerous members of the aziridine ring systems are known and have been fully characterized, derivatives of the azirine ring system are mainly known as useful intermediates and only few examples of naturally occurring azirine derivatives have been reported. Aziridines are present as structural motifs in a variety of strongly biologically active compounds such as azinomycins A and B [3]. which are potent antitumors as well as antibiotic agents against both Gram-positive and Gram-negative bacteria Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

4

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

and have been isolated from the fermentation broth of Streptomyces griseofuscus S42227. O MeO

O

OH N O AcO

O

O MeO

N H

O

O

N

OH N O AcO

HO

OH

O N H N

O

HO

Azinomycin A

Azinomycin B

The antineoplastic activity of mitomycins A, B, and C [4], produced by Streptomyces caespitosus, is associated with the high reactivity of the strained heterocycle. Furthermore, some synthetic aziridines show strong activity as enzyme inhibitors [5], or are versatile intermediates for bioactive compounds. O O MeO N

NH2 O OMe NH

NH2

O O MeO N

O

O OH N

O

Mitomycin A

Mitomycin B

NH2

O O H2N N

O OMe NH

O Mitomycin C

The ﬁrst example of azirine-ring-containing natural compound was azirinomycin [6], an unstable antibacterial agent isolated from Streptomyces aureus fermentation broth in 1971. Only several years later, the cytotoxic compound dysidazine [7], the second structure showing the azirine motif, was extracted from Dysidea fragilis, a sponge collected in Fiji islands. Since their discovery by Gabriel [8], aziridines have attracted attention as starting materials for further transformations in organic synthesis. The ring strain of aziridines, which amounts to 26–27 kcal mol−1 , renders these compounds susceptible to ring opening with excellent stereo- and regiocontrol and allows their use as precursors of a variety of nitrogen-containing compounds such as amino acids, aminoalcohols, and β-lactams. The main transformations of three-membered ring [9] are reported below: 1. Hydrogenolysis: this allows chiral amine derivatives to be obtained via the regiospeciﬁc cleavage of a C–N bond. The process induces ring opening usually with inversion of the reacting stereocenter and without any modiﬁcation of the stereochemistry at the unaffected carbon. R1 R2

N H

H CO2R3

Pd(OH)2 H2

R2 R1

CO2R3 NH2

1.1 Substituted Aziridines

2. Hetero- and carbon nucleophile ring opening: this gives access to a variety of optically active ramiﬁed amines or amino alcohols, amino thiols, diamines, etc. While the reactivity of N-unsubstituted aziridines is relatively low, high reactivity is associated with aziridines incorporating an electron-withdrawing group on the nitrogen atom. For instance, the presence of an acyl group strongly activates the ring toward opening by a nucleophile. This reaction is generally favored by the presence of Lewis acids and proceeds with inversion of conﬁguration at the stereogenic center of the aziridine. Unlike their acyclic amide counterparts, acylaziridines are highly pyramidalized at nitrogen, which makes the acyl-aziridine nitrogen more basic. The stereoselectivity is usually high and the regioselectivity depends upon the ring substituents and the nature of the nucleophile. Nu

GWE

Nu R1 H H N R2 EWG

R

R2

1

EWG

+

NH2

1

R

R2 Nu

NH2

3. Ring expansion: this is another important reaction characteristic of N-acylaziridines, which represents the isomerization to the corresponding oxazolines, protected form of chiral amino alcohols. This reaction generally occurs in the presence of a Lewis acid and leads to the ﬁve-membered ring with retention of conﬁguration. R1

O R

R1

R2

O N

R2

R Acid

SNi

R1

O

OH

N Acid or

R2

R1

R

HN

Acid N

O

or

R

NH R1

R2 OH

R R2

O

4. aza-Payne reaction: this is the rearrangement of aziridine-2-methanols under basic conditions to the corresponding epoxide-2-amines. These last compounds can be further transformed by reaction with nucleophiles. R1 N Ts

OH

O

R1 Base

Ts

NH

5. 1,3-dipolar cycloaddition of aziridine-2,2-dicarboxylates: this is an interesting reaction that involves generation of 1,3-dipoles from three-membered rings and π systems, giving access to larger size heterocycles.

5

6

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Ar N Ar

Ar

CO2R

OR1

Ar N

⊕

CO2R

+

CO2R

CO2R

Ar

Ar N

R2 R2

CO2R CO2R OR1

6. Carbonylation: this allows the formation of β-lactams via insertion of the carbonyl group and inversion of conﬁguration at the reacting carbon terminal. R2

R1 N

R2

Co(CO)8 CO -500 psi or

N

O

Fe2(CO)9 Sonication

Bn

R1 Bn

7. Formation and reactivity of aziridinyl anions: these are stable species at low temperature, which may react with a variety of electrophiles allowing introduction of functionalized chains on the heterocycle. R2 N

R2

R1 M

+ E⊕

N R3

− M⊕

R3 M = Li, Mg, Zn, Zr

R1 E

1.1.2 Asymmetric Aziridination via Cyclization Methods

General approaches to the asymmetric synthesis of aziridines through cyclization methods can be divided into two main categories: (A) nitrogen nucleophilic cyclization on the adjacent position bearing a leaving group and (B) ring closure to three-membered ring via attack of a stabilized carbanion on the electrophilic nitrogen bearing a leaving group. The last approach is particularly suitable for the preparation of aziridine-2-carboxylates. R1

H N:

R1

(A) R2

R

N R2

R

X X

R1 (B)

N R

R3

R3 = Carboxylate

R1 N R

R3

1.1 Substituted Aziridines

In both cases, the asymmetric induction may be exerted by the chirality of the substrate, by the introduction of a chiral auxiliary, by the presence of a chiral metal catalyst, or by the application of organocatalytic processes. 1.1.2.1 Cyclization of a Nucleophilic N on an Electrophilic C (Pathway A) Cyclization of Amino Alcohols The most general and conceptually simple method for the synthesis of optically active aziridines is the cyclization of amino alcohols and amino halides. The availability of enantiopure amino alcohols directly from the chiral pool or by simple reduction of amino acids makes this approach extensively exploited. Protection of the amino function is sometimes required, and in these cases sulfonyl or phosphinyl groups are usually preferred to carbamates or acyl groups, to avoid competitive formation of larger heterocycles such as oxazolines or oxazolidinones. Thus, conversion of the hydroxyl moiety into a good leaving group such as tosyl [10], mesyl, nosyl, tetrahydropyranyl (THP) [11], diphenylphosphinyl (Dpp) [12], t butyldimethylsilyloxy (TBS) [2] allowed the preparation of an activated intermediate to be easily converted to aziridine under basic conditions through an intramolecular SN 2 reaction. O Ph2P(O)Cl

R

OH NH2

PPh2 N

NaH

R

OP(O)Ph2 51–86% NHP(O)Ph2

(2 equiv.)

R

BF3Et2O

H N

MeOH 80–92%

R

When reduction of the carboxylic function is needed to produce the proper aminoalcohol, N-tosyl amino acids have been used as reagents of choice to avoid difﬁculties in the isolation of water-soluble amino alcohols [10]. Ts R

CO2H NHTs

LiAlH4

TsCl, TEA

R

81–100%

N

OH NHTs

DMAP

79–90%

R

Activation of the hydroxyl function may be preformed also under Mitsunobu conditions. Treatment of N-Boc-amino alcohols, easily obtained by reduction of the corresponding amino acids, with triphenylphosphine and Diethyl azodicarboxylate (DEAD) afforded optically active N-Boc-aziridines in good yields [13].

R

CO2H NHBOC

NaBH4 82–98%

R

OH NHBOC

BOC N

PPh3 DEAD

73 – 86%

R

Aziridine-2-carboxylates have been successfully obtained starting from serine or threonine. Starting from d-threonine, Rapoport and coworkers [14] synthesized enantiopure N-benzyl-aziridine-2-esters by treatment with triphenylphosphine. On

7

8

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

the other hand, ring closure of N-protected-serine esters with diethoxyphenylphosphorane (DTPP) gave aziridines-2-tert-butylate in satisfactory yield [15].

NHBn OCH3

PPh3

H

Bn N

H OCH3

89%

OH O

O

NHP HO

P N

DTPP

OR

H OR

Toluene

O

O

P = Boc, Trt R = tBu, Bn

Generally, enantiopure aziridine-2-carboxylates are synthesized as precursors of α- or β-amino acids in a multistep sequence directed to the preparation of bioactive peptides and peptidomimetics. To this purpose, Palomo and coworkers reported the easy formation of the aziridine ring by treatment of the dipeptide serine–glycine benzyl ester via nosylation of the oxygen atom under basic conditions. This procedure allowed the authors to reduce protection/deprotection steps, directly performing the reaction on glycine benzylester derivative [16].

H2N O

Ns

R

NsCl KHCO3

OMe

N

R

OH

O

OMe

85 – 89%

R = Me, Bn Ph H2N O

Ns NsCl

OH N H

OBn

KHCO3 86%

O

N

Ph O

N H

OBn O

Asymmetric Synthesis of Aziridines via Gabriel-Cromwell Reaction The GabrielCromwell reaction is a general and convenient method for aziridination of α, β-unsaturated compounds. Since its introduction in 1952 [17]. many variations on the standard procedure have been explored to broaden the ﬁeld of application. The reaction occurs via addition of bromine to the double bond followed by treatment with an amine. The mechanism proceeds with the formation of a dibromo derivative that converts to a α-bromo-alkene through elimination of bromhydric acid. The conjugate addition of a second molecule of amine, followed by nucleophilic displacement of the bromine, leads to aziridine-carboxylate formation.

1.1 Substituted Aziridines

O

O

Br2

X

R

Br

X

O

R′NH2

R

X

-HBr

Br

Br O

R′

O

N R

X

R

NHR′

X

R′NH2

R Br

The asymmetric version of this reaction has been described using chiral auxiliaries such as camphor sultam [18]. Stereodeﬁned 3-unsubstituted-aziridine-2carboxylic acid may be prepared starting from acryloyl camphor sultam derivatives and by removal of the chiral auxiliary in a nondestructive manner in the ﬁnal step. Repetition of aziridination protocol with N-crotonyl-camphor sultam resulted in the formation of 1:1 mixtures of easily separable aziridines. O

Br2

N O2S

Br

R

O RNH2

N Br O2S

O N N H O2S ds > 9:1

Mg(OMe)2

R

O

R = Bn (86%) PMP (89%) H (60%)

N OMe

MeOH, rt

H

79%

The asymmetric induction controlled by means of ephedrine-derived Helmchen’s auxiliary gave better results [19]. Gabriel-Cromwell reaction on chiral imides in DMSO afforded via diastereoselective and high yielding procedure, optically active trans-aziridines, easily puriﬁed by ﬂash chromatography. The nondestructive cleavage of the chiral auxiliary with lithium benzyloxide gave the corresponding enantiopure benzyl aziridine-2-carboxylates.

O N

O N

R

CuBr2, CH2Cl2

O

O

Br2

N

O

Br

NH3

R

N Br

dry DMSO

N

R = Me, Et, nPr O Ph

O

H N

N

R

Ph dr 90:10

Ph

Ph

O

H N

PhCH2OLi

R

THF

1.1.2.2 Cyclization of a Stabilized Anion on an Electrophilic N (Pathway B) Starting from the unsaturated derivatives reported above, the same authors performed the diastereoselective synthesis of aziridine-2-imides via conjugate addition

9

10

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

of O-benzylhydroxylamine followed by cyclization to three-membered rings [20]. This second step was induced through the formation of the stabilized aluminum enolate of the addition product that spontaneously attacked the electrophilic nitrogen bearing the O-benzyl leaving group. Removal and recovery of the chiral auxiliary were performed as reported above.

O

O AlMe2Cl O N

N

NH2OBn

O

Ph

O

O TiCl4

R = Me, Et, nPr, iPr, Ph

R

N

N

NH2OBn

TEA 65 –75%

N

O

H N R

N Ph

>99% de

NHOBn R

N

O

AlMe2Cl

Ph Up to 90:10

R

N

NHOBn

TEA 65–75%

Ph Up to 90:10

Me O

O N

O

AlMe2Cl

N

H N R

N Ph

>99% de

Me Al

N

O

NOBn R

Ph

In a similar way, optically active 1H-α-keto aziridines were synthesized from conjugated enones via Sc[(R)-BNP]3 -catalyzed enantioselective Michael addition of O-methylhydroxylamine, followed by La(OiPr)3 -catalyzed ring closure [21]. MeO

O R′

NH O

MeONH2

R′′

10% Sc[(R )BNP]3 Yield 39 – 97%

R′

10% La(Oipr)3

R′′

40–84% ee

THF Yield 59–99%

H O N Ph

Ph

The products obtained by addition of chiral hydroxylamine to acrylates have been transformed into 2- and 2,3-disubstituted-N-alkylaziridinecarboxylate through an efﬁcient diastereoselective 3-exo-tet ring closure induced by O-acylation of the diastereomeric adduct followed by enolization. This two-step protocol afforded optically active aziridines with excellent diastereoselectivity (93:7). Attempts to perform a one-pot two-step reaction resulted in a lower stereoselectivity (67:33) [22]. A further development of the same synthetic approach is represented by the synthesis of 3 -unsubstituted-N-Boc-aziridines, which has been carried out in one step by conjugate addition of sodium or lithium anion of N-Boc-O-benzoylhydroxylamine to chiral acryloyl-imides [23].

1.1 Substituted Aziridines

N H

OH +

⊕ OH N + H2 O HO

N

CO2R

OH (1) Acylation

CO2R

(2) Acylation

O

N

+

N

N

CO2R

PhOCO _ O O NBoc

BocNOCOPh M

O N

N

M = Li, Na

CO2R

One pot

(3) LHMDS

−

N

CO2R 93:7

(1) TEA

O

O

+

N

(2) LHMDS, THF CO2R

N

M

+ O N

91%

O

Boc N

N Ph

Ph

Ph

67:33 CO2R

dr (2′R )/(2′S ) = 80:20

The Michael-type addition of (+)-(R)-o-methoxyphenylsulfonylethylsulﬁmide to unsaturated carbonyl compounds afforded optically active trans-acylaziridines with modest stereoselectivity by displacement of the diphenylsulﬁde group from the intermediate enolates [24]. o -MeOPh

Ph S

R

Ph

H N

Ph

H S N o -MeOPh ⊕

NH

O

Ph R

COPh

R

O

Optical purity up to 30%

The addition of N, O-bis(trimethylsilyl)hydroxylamine to alkylidene malonates in the presence of a catalytic amount of Cu(OTf)2 and chiral bisoxazoline as ligand, followed by base-induced cyclization, represents a useful route to enantiomerically enriched aziridine-2,2-dicarboxylates. This two-step protocol afforded the three-membered rings with good yield and enantiomeric excesses up to 80%, depending on the substituent on the alkylidene double bond [25]. NH COOMe COOMe

TMSNHOTMS O

O N

N Cu Ph Ph

OTMS COOMe

COOMe

tBuOk, CH2Cl2 rt

H

H N

COOMe

COOMe 80% ee

In general, the conjugate addition of hydroxylamines to unsaturated carbonyl derivatives is one of the most convenient methods for the stereoselective synthesis of β-hydroxylamino-carbonyl building blocks, which are useful intermediates in the preparation of enantiopure aziridines. Asymmetric methods dealing with stoichiometric use of chiral auxiliaries in the presence of Lewis acids or with the use of catalytic amount of chiral metal complexes have been exhaustively reviewed [26].

11

12

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

The organocatalytic version of the aza-Michael addition was less explored. MacMillan and coworkers reported the ﬁrst organocatalytic addition of N-silyloxycarbamates to unsaturated aldehydes, giving access to aziridine precursors [27]. N

O

N H

H

+

GP

R

N H

OTBS

O

O

Ph

GP OTBS N

H 20% mmol

R

Up to 97% ee

In a recent report, the conjugate addition of O-benzylhydroxylamine to chalcones was performed in the presence of thiourea-derived catalysts. Although a screening of solvents, O-substituted hydroxylamines, and chiral ligands was performed, moderate enantiomeric excesses up to 60% could be observed [28]. F3C O

O

NHOBn

H2N

R

OBn

R

Ph

HN

Cat.* =

Cat.* 20% mmol

Ph

CF3

HN

60% ee

S H

N

O N

The organocatalysis may be applied to aziridination when the substrate to be transformed is an aldehyde. In fact, the highly chemo- and enantioselective organocatalytic aziridination of a variety of α, β-unsaturated aldehydes with acetyloxy carbamates was developed. The reaction was catalyzed by chiral pyrrolidine derivatives and gave Boc- or Cbz-2-formylaziridines in yields ranging from 60 to 70%, with dr 4:1–19:1 and 84–99% ee [29].

O H

+ R

R′

N H

OAc

R

Ph N Ph H TMSO

R′ O N R

H

20% mmol

BzO

Me Et nPr nBu

R′

Yield

dr

ee

Boc Cbz Cbz Cbz Boc

54% 60% 62% 70% 60%

6:1 5:1 10:1 5:1 5:1

94% 97% 99% 96% 98%

1.1.3 Asymmetric Aziridination via Cycloaddition Methods 1.1.3.1 Addition of Nitrenes to Alkenes One of the most important pathways to aziridines is the addition of a nitrene to an alkene; however, this reaction may not be well controlled stereochemically owing to the rapid interconversion of the singlet and triplet nitrene states. Anyway,

1.1 Substituted Aziridines

several methods for nitrene generation have been successfully developed with the aim to obtain stereospeciﬁc aziridination. The most common involve photolysis, thermolysis, or chemical modiﬁcation of nitrogen derivatives. Many chiral metal catalysts have been used to induce nitrene formation from N-substituted iminoiodinanes, although this method produces stoichiometric amount of iodobenzene and yields N-protected aziridines. The use of azide precursors gives some advantage in terms of atom efﬁciency and environmental impact since molecular nitrogen is the only side product. Nosyloxycarbamates and N-aminophtalimides are also alternative sources of nitrene. KOH

(a) TsNH2 + PhI(OAc)2

MeOH

⊕ L*Cu PF6

PhI NTs

PhI NTs ⊕

*LCu NTs

O

PF6

+ PhI

O Pb(OAc)4

(b)

N NH2

N N

O

O

RO2CN3

hn or ∆

(c)

N-CO2R NsONHCO2R

Base

N-(p-toluenesulfonyl)iminophenyliodinane (PhI = NTs) [30] (source a) proved to be superior to other imido group donor as precursor and yielded excellent stereoselectivity. In 1991, Evans and coworkers disclosed that low-valent copper complexes catalyze the aziridination of several different oleﬁns by this reagent. Development of the enantioselective process consists in the use of chiral bisoxazoline catalysts. Some selected results are reported in Table 1.1. 5–10% Cu-ligand

R2 R

1

+ R

3

PhI NTs CH3CN

R2 R1

Ts N

+ PhI R3

Aryl-substituted oleﬁns have been found as good substrates, which can be efﬁciently transformed into N-tosyl-aziridines with enantioselectivities up to 97% ee (entries 1–4) [31]. The reactions have been carried out with 5% of chiral catalyst derived from copper(I) triﬂate and bisoxazoline as ligand. Unfortunately, tartrate-derived bisoxazoline gave only low enantiomeric excess (2–49% ee). A complete study on the effect of bisoxazoline substituents and reaction conditions on this reaction has been reported by Page and coworkers [32]. Some improvements of both enantioselectivity and chemical yields were obtained when [N-(4-nitrobenzenesulfonyl)imino]phenyliodinane was employed instead of the

13

14

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles Table 1.1 Enantioselective aziridination with N-aryliminophenyliodinane and chiral metal complexes

Entry

Chiral ligand

Oleﬁn

1

Ph

2 O

3

N

Ph

N

R

4

(α)Nap

O R

Ph

a: R = Ph b: R = CMe3

5

Ph

6

Ph

7

Ph

CO2Ph

Catalyst

Nitrene precursor

Yield

ee

a

PhI = NTs

64

97

CO2Me

a

PhI = NTs

76

95

Me

b

PhI = NTs

62

70

H

b

PhI = NTs

89

63

Me

b

p-NO2 -PhI = Ts

83

80

H

b

p-NO2 -PhI = Ts

94

66

PhI = NTs

79

66

PhI = NTs

75

>98

PhI = NTs

70

87

PhI = NTs

76

94

H

O H

8 Cl

N Cl

H N

Cl

NC

Cl

9 N

10

N

OH HO Ph Ph

Ph

H

Mn

commonly used p-tolyl analog (entries 5–6) [33]. In a similar way, Jacobsen and coworkers [34] obtained excellent results in the aziridination of benzylidene derivatives with chiral copper complexes deriving from bis(benzylidene)imine of 1,2-diaminocyclohexane (entries 7–9). The asymmetric aziridination of styrene derivatives has also been successfully performed with Salen-Mn(III) complexes (entry 10) [35]. Phtalimidonitrene (source b), generated from N-aminophatalimide by oxidation with lead tetraacetate, reacted with N-enoylbornane[10,2]sultams (Oppolzer auxiliary) to give the corresponding N-phtalimidoaziridine adducts in 12–94% yield and diastereofacial selectivity up to >95% [36]. In a similar way, excellent diastereoselection could be obtained by the addition of phtalimidonitrene to sugar-derived α, β-unsaturated esters [37].

1.1 Substituted Aziridines

R1

O N SO2

O R1

PhtNNH2

R2

Pb(OAc)4

R3

Xc

R2

N NPth Major

+

R3

Yield 12–94%

Xc

O R1 R2 Xc

N NPth Minor R3

de up to >95% O

RO

O

H

O

PhtNNH2

O

NPth H N

H

H

RO

Pb(OAc)4 Yield 12–60%

O O

de up to >99%

Chen and coworkers applied this methodology to the diastereoselective aziridination of α, β-unsaturated amides linked to a camphor pyrazolidinone-derived chiral auxiliary [38]. The reactions carried out in 5 min afforded excellent yield (86–95%) of diastereomeric aziridines with high selectivity (up to >90% de). In pursuing this work, the same author reported the enantioselective version of this protocol, by performing the lead tetraacetate oxidative addition on N-enoyl oxazolidinones in the presence of camphor-derived chiral ligands [39]. R2

O

R3

N N Ph

O

Pb(OAc)4

R1

O R2

PhtNNH2

Yc R1

Yield 88–95%

O

N NPth

+

O R2 R3 Yc

Major

N NPth Minor R1

de up to >90%

Yc O

R3

O

R3

N

O R2

R1

O

PhtNNH2 Pb(OAc)4, L* Yield 85–99%

O

N

R2 R3 N R1 NPth

ee Up to 95% L* =

HO O N N O OH

Besides the use of a chiral auxiliary linked to the alkene reagent or of chiral complexes of lead tetraacetate, another possibility is the use of chiral aziridinating agents. Atkinson and coworkers [40] reported that enantiopure 3-acetoxyaminoquinazolinones react with β-trimethylsilylstyrene affording 11:1 ratio of diastereomeric aziridines.

15

16

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Q*

N

+ Me N NH2 OSiMe2tBu

O

Ph

Q* N H

Ph

SiMe3

H

SiMe3 dr 11:1

Organic azides (source b) may be considered as ideal sources of nitrenes although they are not very reactive and harsh conditions, such as heating or UV irradiation, are generally needed for molecular nitrogen dissociation. Initial attempts to perform asymmetric aziridination using azides and chiral metal catalysts have been reported by Jacobsen with Cu-diimine complexes and by M¨uller and co-workers using chiral Rh-complexes. In both cases, the nitrene generation was induced by UV irradiation. On the other hand, excellent yields (up to 99%) and enantioselectivities (up to >99% ee) have been obtained by Katsuki and coworkers in the presence of ruthenium(CO)(salen) complexes and tosyl azide. Under these conditions, neither heating nor irradiation was required for nitrene formation. The method is of general application since it has been successfully applied to a number of different oleﬁns, changing the substituent of the chiral ligand and generating the nitrene reagent starting from different organic azides. R2

+

R1

R2

N3

R1 = Ph, BrPh, C10H7, n C6H13, indene

N

Ru(salen)(CO) Yield Up to 99%

R1

N

Up to 99% ee

CO N

Ru

O O Ar Ar ′

R2 = Ts, Ns, SES

Finally, nitrenes may be formed from N-protected nosyloxycarbamate by treatment with a base such as CaO. Pallacani and Tardella applied this method to the synthesis of a variety of substituted N-protected aziridines [41]. Recently, excellent diastereoselectivity was observed in the aziridination of 2-L-α-aminoacyl-(E)-acrylonitriles under parallel solution-phase conditions [42]. O NC R′

O

R N H

OMe O

NsONH-Boc CaO Yield 82–93%

NC Boc N R′

R N H

OMe O

dr up to 16:1

1.1.3.2 Reaction between Carbenes and Imines Among several synthetic routes, the classic methods involving imines have been upgraded to their asymmetric version inducing enantiocontrol by the use of chiral imines, chiral nucleophiles, or chiral catalysts. All these approaches share as

1.1 Substituted Aziridines

common feature the addition of a nucleophile on the electrophilic imine carbon, followed by cyclization to the three-membered heterocycle. X R4

N R1

R5

N2

R3 R

4

R

5

R2

R

1

R3 N R4

R2

R5

⊕

SR2

5 R4 − R

aza-Darzens-Type Reactions Involving α-Haloenolates The aza-Darzens reaction between a α-haloenolate and an imine can be considered a not fully investigated tool for the asymmetric synthesis of aziridines. Davis and coworkers obtained excellent results in the synthesis of N-sulﬁnylaziridine-2-carboxylates by reacting enantiopure chiral sulﬁnimines with α-bromoenolates. The method is general for aliphatic, aromatic as well as α, β-unsaturated imines, giving good yields and de up to 98%, N-sulﬁnyl-heterocycles, which are easily transformable into activated N-tosyl-aziridines [43]. O R

1S

H N

X

+ R2

H

OR3

OM X = Cl, Br R1 = p-Tolyl, 2-Methoxynaphtyl R2 = Ph, n-pr, i-pr, naphtyl R3 = Me, tBu M = Li, Na

−78 °C, THF Yields up to 93% de up to 98%

R2 CO2R3 H N H + S 1 O R Major isomer

H CO2R3 2 R N H S O R1

m-CPBA 94–98% R2 CO2R3 H N H Ts

Following the same procedure, enantiopure aziridine-2-phosphonates were obtained from sulﬁnimines and halomethylphosphonates. A further improvement could be obtained employing N(2,4,6-trimethylphenylsulﬁnyl)imines and lithium diethyliodophosphonate [44]. Despite the excellent results obtained with chiral sulﬁnimines, development of new chiral imines could overcome shortcomings as sensitivity to oxidative conditions and destructive chiral auxiliary removal. The reaction between chiral N-phosphonimines and α-bromo-enolates gave N-phosphonylaziridines with excellent yield and high stereocontrol. The electrophilicity of the imine can be controlled by introducing electron-donating or electron-withdrawing groups onto phosphonate chiral auxiliary [45].

17

18

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

R

O 1 S

H N

Z

+

P(OEt)2 O

Ph-X

Base, −78°C, THF

R1 = p-Tolyl, tBu X = H, 4-OMe, 4-NO2, 4-CF3 Z = Cl, Br, I

O S

H N

I

+

P(OEt)2 O

Ph-X

O H H P(OEt)2 N P(OEt)2 + X-Ph N H O S 1 S 1 O R O R Mixtures

H X-Ph

Base, −78°C, THF

H X-Ph

Yields up to 78% O

H

H NH

HN

+

OLi

Br

P N

THF, −78°C

P N

O

R

R R = Ph, 2-Cl-Ph, 2-Me-Ph, 2-thienyl, 4-halo-Ph, 4-MeO-Ph

H P(OEt)2 O de > 99% Mes

H NH

HN

59–82%

OCH3

O

H

N S

CO2Me

de 80 to >99%

Chiral heterosubstituted aziridines have been obtained by the coupling of lithium enolates derived from (α-chloroalkyl)heterocycles with various enantiopure imines, which are obtained from nonracemic phenylethylamine. The reaction afforded chiral aziridines with complete stereocontrol. The steric hindrance and the coordination power of the alkyl group linked to the iminic nitrogen are responsible for the stereochemistry of the ﬁnal product [46]. PH R1

Cl R

H

LDA

Ph

R3

Ph

N

+

2

R3

THF, −78 °C Yields up to 90%

R1 = thiazolyl, oxazolinyl, pyridyl R2 = H, CH3

R2 R1

N

H Ph

dr > 98:2

R3 = CH3, OCH3

In a similar way, the addition of chloromethyllithium to the imine derived from 2-pyridinecarboxaldehyde and chiral aminoalcohol or aminoesters gave disubstituted aziridines with good yields and excellent diastereoselectivity. In the latter case, double addition of the organometallic reagent occurred, affording aziridines having a keto function in the side chain [47].

1.1 Substituted Aziridines (1) CH2ICl, LiBr (2) MeLi

R R′

N N

OTMS

R R′

N

(3) NH4F 44 – 58%

N

OTMS

dr up to 99:1 R OMe

N N

O

R

(1) CH2ICl, LiBr

Cl

N

(2) MeLi

N

(3) NH4F 97 – 98%

O

dr up to 99:1

Enantiopure N-acylaziridines have been obtained starting from aldimine bearing the chiral auxiliary into the carbon side chain. Under these conditions, complete inversion of diastereocontrol was induced by changing the metal counterion of the bromoenolate from lithium to zinc [48]. O

M = Li

N

Ar

X

O O

OCH3

35–49%

OCH3

O

OCH3

N Ar

OtBu

OCH3

H

OM

O

ButO

de 82– 99%

THF, −78 °C to rt O M = Zn

O

OCH3

ButO O

9–59%

OCH3

N Ar

de 99%

Similarly to aza-Darzens mechanism, the addition of organometallics as Grignards to chiral sulﬁnylimines bearing a α-halogen leaving group followed by treatment with a base represents a high yielding route to optically active N-sulﬁnylaziridines. In this reaction, spontaneous or base-induced cyclization of the nonisolated intermediate β-halo-N-sulﬁnamides affords the three-membered rings in high yield and excellent diastereomeric ratio [49]. t-Bu

t-Bu

R

R

N

S H

Cl

O

R1MgX CH2Cl2 −78 °C

R = Et, Pent R1 = Et, Ph, allyl, vinyl

HN S O R R R1 Cl

t-Bu

−78 °C rt or KOH Yield 8–90%

S N R

O R1

R dr up to 96:4

An application of aza-Darzens-type reaction has been performed to obtain polyfunctionalized aziridines through the base-induced dimerization of oxiranylaldimines. This highly diastereoselective process is noteworthy since both nucleophile and electrophile originate from the same precursor. The nucleophilic moiety

19

20

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

is the 1-aza-allylanion having the epoxide at the β carbon and the leaving group is represented by the oxirane oxygen atom [50]. O LDA

O

2X

HO N iPr

N iPr

iPr

N iPr

54%

O

N iPr

N

OH

Asymmetric induction in the condensation between imine and haloacetates may be also obtained introducing chiral auxiliaries into the α-haloacetate counterpart. For instance, (+)-8-phenylmenthyl esters gave aziridine-2-carboxylates only in 40% yield and as diastereomeric mixtures of cis/trans heterocycles. Anyway, the diastereomeric excess of the trans isomer reached 85% [51]. N

OR*

Cl

+

O

Ph

Ph Base

H

CH2Cl2

Ph Ph Ph N H Ph N CO R* 2 + H CO2R* H H

40%

cis:trans 3.2 cis de 41% trans de > 85%

R* =

Ph

On the other hand, camphorsultam-derived α-bromoenolates reacted with N-Dpp-imine to afford a single cis diastereoisomer in high yield. Removal of the chiral auxiliary was simply performed with LiOH at room temperature. The method was successfully applied to aromatic, para-substituted aromatic, unsaturated, and aliphatic enolates. The introduction of an ortho substituent into the aromatic ring determined the stereoselectivity inversion, often giving exclusively trans products [52]. Dpp

R = tBu, Ph, 4-X-Ph, 4-MeO-Ph MHMDS THF N S O

O

Br O

H R

NP Ph

N S O O

H N O

H R

Dpp H N LiOH H THF/H2O HO2C R

dr > 99:1

O

Dpp H N N H

Ph R = 2-Halo-Ph, 2-NO2-Ph, 2-OMe-Ph

S O O

O

R

dr From >99:1 to <1:99

Dpp LiOH

H N

THF/H2O HO2C

H R

1.1 Substituted Aziridines

Finally, enantiopure cis N-alkoxy-aziridine-carboxylates have been obtained via aza-Darzens like reaction between the anion of optically pure chloroallyl phosphonamide and oximes. The reaction occurred in good to excellent yields through the approach of the oxime on the less hindered left cleft of the phosphonamide anion, giving a single diastereoisomer [53]. OR2 N

N

N

O P

Cl

+

N

P

NaHMDS

R1O

N

THF, −78 °C

O

OR2 O N OR1

Yield 46 – 78 % de > 99:1 Na

R1 = iPr, tBu R2 = Bn, PMB, Trt

O

O P

O

Cl

OR1 N OR2

aza-Darzens-Type Reactions Involving Diazo Compounds This methodology, involving the formation of a metal–carbene intermediate complex that adds to an imine, shows several advantages of other synthetic approaches since the reagents are synthetically accessible and highly reactive and the only by-product is represented by molecular nitrogen. The asymmetric version of this reaction has been successfully developed using enantiopure starting materials, stoichiometric amounts of chiral auxiliaries linked to the reagent backbone, or by catalyzing the reaction with chiral Lewis acids. The protocol recently reported by Johnston and coworkers, based on the Bronsted acid-catalyzed annulation, afforded enantiopure aziridine-2-carboxylates by using glyceraldehyde as chiral auxiliary. The diazocompound reacted as enolate synthon without any decomposition, giving the product in 83% yield and complete diastereoselectivity [54].

N2 CO2Et

N

+

CHPh2 H

O O

H

0.25 TfOH 83%

O O

CHPh2 N H CO2Et

ds > 95:5

The asymmetric metal-catalyzed transfer of diazocarbonyl-derived carbene to imines represents the most explored approach. To this purpose, Jacobsen and coworkers investigated copper(II) complexes catalyzed aziridination of N-benzylidene aniline and diazoacetate [55]. Although cis-aziridines were obtained only in modest yields (5–65%) and stereoselectivities (2–67% ee), a deep exploration of the reaction mechanism allowed to suggest the generation of a transient bis(dihydrooxazole)copper carbene complex that reacts with the imine to form a

21

22

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

metal-complexed azomethine ylide. This intermediate may undergo intramolecular ring closure to optically active aziridine or it may dissociate to free azomethine ylide, precursor of the formation of racemic aziridine. This investigation outlined the inﬂuence of the chiral ligand on the metal-complexed azomethine ylide evolution, thus providing useful information for enantioselectivity enhancement. ⊕ L2Cu X

CO2Et

L2CuI

+

H

H

N2CHCO2Et

Ar

Ar

N

Ar

CO2Et

H CO2Et

H

CO2Et H N Ar Ar ⊕ X H

L2CuI

H

N Ar

H N Ar ⊕

Ar

Ar

H

Racemic

H CO2Et N Ar

Optically active

On the other hand, Jørgensen and coworkers explored the reaction of imines with diazoacetate. In the course of this study, they proposed a second possible mechanism involving the coordination of the Lewis acid to the nitrogen atom of the imine, followed by the nucleophilic attack of diazoacetate on the C=N double bond and by the ring closure on the carbon bearing N2 leaving group [56]. ⊕ N2 R1

N

R2

R3 N2CHR

L.A.

⊕ N2 H

H

R1

N

R2

L.A.

R3 R1

N

R2 −

R2 N

- N2 - L.A.

R3

R1

L.A.

Extension of this approach to the reaction of α-imino esters in the presence of chiral ligands allowed the development of a catalytic diastereo- and enantioselective aziridination of imines derived from α-ethylglyoxylate. Bisoxazolines, phosphinoxazolines, and bis(phosphino)-binaphtyl ligands were tested in combination with AgSbF6 or CuClO4 . High diastereoselectivity in cis-aziridine formation was observed using (R)-Tol-BINAP (cis/trans 19:1) with a good enantiomeric excess (72%), while the trans isomer was obtained as major product in the presence of (4R, 5S)-Ph-BOX [57].

1.1 Substituted Aziridines

Ts

+

N

TMS H

N2

Ts N

CuClO4

EtO2C

L*

Ts N

+ TMS

EtO2C

TMS

CO2Et L* =

Ph

PTol2

cis / trans 19:1

O

O

L* =

PTol2

N Ph

72% ee

Ph

N

cis / trans 1:10

Ph 8% ee

One of the best generally applicable method for the catalytic asymmetric aziridination was presented by Wulff and Antilla, using a catalyst prepared from VAPOL and borane-tetrahydrofurane. Under these conditions, excellent yields and high asymmetric induction were obtained in the reaction of benzhydrylimines with ethyl diazoacetate using 1% mol of the chiral catalyst [58]. A further enhancement of cis/trans selectivities (up to >50:1), yields (up to 91%), and enantiomeric excesses (90–98%) could be obtained using VAPOL or VANOL ligands in the presence of triphenylborate [59].

t-Bu N

+

EtO2C H

N2

L* (1% mol)

R R = Ph, p -X-Ph, alkyl

Bn N

MX3 = BH3-THF

R

MX3

cis/trans from 3:1 to >50:1

L* = S-VAPOL

91–99% ee

MX3 = B(OPh)3

cis/trans > 50:1

L* = S -VAPOL or S-VANOL

Ph Ph

S -VAPOL

CO2Et

OH OH

Ph Ph

91–98% ee

OH OH

S -VANOL

Aziridination by Reaction of Imines with Ylides Besides α-halo derivatives and diazo compounds, also ylides were reacted with imines in the asymmetric ring-closure to aziridine. The initial attack of the ylide to the electrophilic imine carbon affords a betaine, which evolves to aziridine via intramolecular ring closure and elimination of ylide heteroatom.

23

24

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

R′ R

N

N R′′

Het

R

−

H

−

R′

⊕ Het

R′ N

⊕ R

R′′

R′′

Betaine

This methodology has been mainly applied to the preparation of enantiopure terminal-, alkyl-, aryl-, propargyl-, and vinyl-substituted heterocycles, by using methylene sulfur ylides as reagents. The asymmetric induction in this reaction has been obtained introducing a stereocenter on the nitrogen imine side chain or generating sulfur ylides from chiral sulﬁdes. Following the ﬁrst approach, Garcia Ruano and coworkers performed the reaction between enantiopure N-tolylsulﬁnylimines and dimethyloxosulfonium methylides and dimethylsulfonium methylides [60]. Optically active imines were easily generated by applying the ‘‘DAG methodology’’, where diacetone-d-glucose was used as an inducer of chirality [61]. Under these conditions, the formation of terminal aziridines occurred with good to excellent diastereoselectivities (up to 95:5) and the enhancement of the stereocontrol was obtained by increasing the bulkiness of substituents. The opposite diastereoselectivity observed in the aziridination of dimethyloxosulfonium methylides and dimethylsulfonium methylides was explained by the authors, who suggested a thermodynamic control for the reaction of the ﬁrst reagent and a kinetic control for the second one. O R1 S CH2 =SMe2

H N

R2 (R)

NaH

R

1

O S

Up to 90% de

H N

R2

CH2 =S(O)Me2 NaH

O R1 S

H N (S )

R2

Up to 90% de

In a similar way, vinyl aziridines were obtained by Stockman and coworkers by treatment of chiral tert-butylsulﬁnylimines with the ylide generated by deprotonation of S-allyl tetrahydrothiophenium bromide. Using these methodologies, good yields (44–82%) and satisfactory cis/trans selectivities, always around 20/80, could be observed. On the other hand, aziridines were always obtained in excellent diastereoselectivity (up to >95%), thus demonstrating the efﬁciency of tert-butylsulﬁnyl group as activating and directing group [62].

1.1 Substituted Aziridines ⊕

S

O S

Br

H N

−

H R

tBuOLi 44–82%

S N

O

S N

H

R

O H

R

H

cis/trans 20/80 Up to >95% de

Dai and coworkers [63] were able to perform the enantioselective synthesis of acetylenylaziridines owing to the introduction of chirality on ylides. Propargylic sulfonium ylides, generated in situ under phase transfer conditions, reacted with N-sulfonylimines to give acetylenylaziridines in excellent yields (80–98%). In most cases complete diastereoselectivity could be achieved to give exclusively cis heterocycles, although with enantiomeric excesses not higher than 85%.

R

N

Ts

+

OH Br

SiMe3

SiMe3

Me ⊕ S

H

R H

CsCO3

−

CH2Cl2

N Ts

H

Yields 80 – 98% Up to 85% ee

In a similar way, Corey-Chaykovsky reaction between N-sulfonylimine, arylmethylbromide, chiral sulﬁde, and a base by solid–liquid phase transfer conditions allowed Saito and coworkers [64] to synthesize enantiopure aziridines. The reaction occurs via the formation of a sulfonium ylide from the coupling of the sulﬁde with the halide, followed by deprotonation with the inorganic base. Excellent yields were obtained with imines bearing electron-withdrawing substituents on nitrogen atom. p -Tol

R1

N

R

2

R3

H S H

Br K2CO3

OH

R1 H

R2 N

H R3

Yield 53 –>99% trans-cis up to 79:21 trans 85 – 98% ee

On the basis of the excellent results reported for oxathianes as precursors of ` enantiopure ylides in asymmetric synthesis, Solladie-Cavallo and coworkers [65] developed a two-step asymmetric process for the preparation of enantiopure disubstituted N-tosyl-aziridines using a phosphazene base to generate the ylide. Although stechiometric amounts of oxathiane are required in this reaction, complete recovery and recycle of this reagent are possible. Furthermore, no unstable or hazardous reagents are involved. Under these conditions, complete conversion of the starting

25

26

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

material into cis/trans mixtures of aziridines was observed. Both diastereoisomers have exceptionally high enantiomeric purities (98.7–99.9%).

O

S⊕

O

S

OTf

−

EtP2 Ts N R

⊕

Ts N

+ Ph

R

−

R

EtP2H OTf

N Ts

Ph

Yield 60– 88 % cis /trans up to 100/0 98.7– 99.9% ee

Generation of the two reagents for aziridination was also carried out by treatment of an aminosulfoxonium-substituted β, γ -unsaturated α-amino acid with a base. Fragmentation of the anion indeed affords a conjugated allyl aminosulfonium ylide and an N-tert-butylsulfonyl-imino ester. Recombination of these two molecules gave cis-vinyl aziridine in almost quantitative yield and excellent diastereoselectivity and enantioselectivity [66]. −

H

Bus N

−

H O NMe2 S ⊕ Ph

EtO2C R

⊕

X

Bus N

DBU

+

R

EtO2C

O NMe2 S ⊕ Ph − ⊕

−

Bus N Yield 65 – 94% cis/trans up to 93:7 47 to >98% ee EtO2C

R

+ EtO2C

Bus N R

The asymmetric aziridination involving addition of sulfur ylides to imines normally requires stoichiometric amounts of enantiopure reagents. The ﬁrst catalytic asymmetric application of this reaction was reported by Aggarwal and coworkers, wherein imines bearing an electron-withdrawing group on the nitrogen atom reacted with diazocompounds in the presence of chiral sulﬁde (20 mol%) and rhodium or copper salts (1 mol) [67]. The reaction proceeds following the catalytic cycle as reported in the ﬁgure below, affording optically active aziridines in excellent yields. A complete study on the relevant factors governing stereocontrol allowed to establish that the origin of diastereoselectivity lies for semistabilized ylides (benzylic) in the nature of transition states leading to betaines, while for stabilized ylides (ester/amide) in the nature of the transition states leading to ring closure [68]. On the other hand, the enantioselectivity is always very high and may be attributed to

1.1 Substituted Aziridines

⊕ − SH CHPh

H R

P

N

Rh2(OAc)4

N2CHPh

P N Ph

N2

R

Chiral sulfide

Rh CHPh

both steric and electronic factors in ylide preferred conformation (trimethylsilylethanesulfonyl (SES)). It is noteworthy that the parallel reaction of diazocompounds with imines is very limited and does not signiﬁcatively affect yield and stereocontrol. Although higher yields could be obtained using stoichiometric amount of chiral sulﬁde, reduction to catalytic amount did not result in lower stereoselectivity. To overcome potential problems due to hazardousness of large-scale reactions, the diazo compound was generated in situ and a new class of sulﬁdes, compatible with reaction conditions, was developed [69].

20% mmol

SES + N

R

Ph

Sulfide * =

N2

+

Ph

N

N

Ts

S Sulfide* =

Ph

90 – 95% ee Na⊕

N

R

Yields 47– 91% cis/trans 3:1 to 5:1

H P

Rh2(OAc)4 1% mmol

O

S

R

SES N

Sulfide*

H

O

P N

Sulfide* 20% mmol Rh2(OAc)4 1% mmol

R

Ph

Yields 50 – 82% cis/trans 2:1 to 8:1 73 – 98% ee

1.1.4 Ring Transformation Methods 1.1.4.1 Aziridines from Epoxides The transformation of oxiranes to aziridines through a Staudinger-type reaction [70] represents a useful and well-known method for synthesis of these nitrogen-containing heterocycles. The reaction occurs via the regioselective ring opening of the oxirane moiety by means of an azide followed by closure to aziridine by treatment with triphenylphosphine. Overall, both carbons of the initial epoxide are inverted.

27

28

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

R

NaN3

O CO2Me

R N3

OH

R

+

N3 CO2Me

HO

CO2Me

PPh3

R

R

H N

N CO2Me

CO2Me

R

+

OH PPh3

CO2Me

HO N Ph3P

The absolute stereocontrol of this methodology suggests that starting from enantiopure oxiranes, enantiopure aziridines can be obtained. In particular, epoxides deriving from allylic alcohols, which are readily available in optically active form employing Sharpless epoxidation technique, can be considered excellent starting materials. The initial introduction of chirality may be guided by simple variation of the starting allylic alcohol (Z or E) and tartrate (d or l) geometries. The excellent regio- and stereospeciﬁcity of the following Staudinger reaction allows to obtain only one enantiomer of the aziridine by choosing the proper precursors. This methodology has been successfully applied to the preparation of aziridine-2-carboxylates [71], which represent an interesting class of compounds for their potential application as mimetics and precursors of both α- and β-amino acids. In a similar way, the same authors applied this methodology to the preparation of enantiopure 2,3-dicarboxylic acid, the only example of naturally occurring aziridine-carboxylic acid, isolated as metabolite of Streptomyces MD398-A1 [72].

EtO2C

OH

TMSN3

O CO2Et

EtO2C

CO2Et N3

(2R, 3R)

72%

EtO2C

OH +

EtO2C

CO2Et N3

PPh3

8%

EtO2C N H

CO2Et

(2R, 3R)

CO2Et N H

(2S, 3S)

95% ee

This methodology has been successfully applied to the preparation of building blocks for the synthesis of bioactive derivatives as carbapenems [73] or lipooxygenase pathway intermediates [74]. Enantiopure azides, useful starting material for the preparation of bicyclic analog of aziridine-2-carboxylates, have been obtained using readily available carbohydrates as a source of chirality. Thus, ring opening of 2,3-sulﬁte-furanoside by an azide group, followed by tosylation of the resulting hydroxyl moiety, gave

1.1 Substituted Aziridines

29

a reactive substrate for a Staudinger-type reaction, leading to carbohydrate-fused aziridines [75].

H3CO

O

O

S O

H3CO

OR NaN3 DMF

O

O N3

H3CO

OR

OH

O OR H N

(1) TsCl (2) PPh3 58%

In general, the presence of an azido moiety vicinal to a good oxygenated leaving group is a sufﬁcient requirement for the synthesis of aziridine rings via Staudinger-type mechanism. Recently, the preparation of polyfunctionalized azetidin-2-ones, bearing an aziridine ring and an hydroxyl moiety on the side chain, has been reported via aza-Payne displacement induced by triethylphosphine [76]. O N3

OH Ph

Ph Et3P

N O

N H

THF, 40°C 50 – 80%

R

N R

O

The direct conversion of chiral epoxides to aziridines can be also performed using a cyclic guanidine derivative as nitrogen source. The reaction involves the formation of a spiro intermediate, which undergoes acid catalysis fragmentation to aziridine and urea. Application of this procedure to (R)-styrene oxide gave (S)-aziridine in 41% yield [77]. O

MeN

NMe

Ph Ph

Bn N

Bn Ph

+

O

TsOH

N

MeN ⊕ NMe

Bn

N

MeN

O NMe

O 41% MeN

Bn NMe + N

(R )

Following a very close mechanism, aziridine-2-esters have been obtained from enantiopure guanidine ylides and a variety of aryl aldehydes. This method afforded trans-aziridines as major diastereoisomers in excellent yields (up to 95%) and high enantiomeric excess (72–97%). An efﬁcient and practical route to enantiopure aminoalcohols starting from racemic terminal oxiranes via enantioselective ring opening with trimethylsilylazide in the presence of chromium-salen was presented by Jacobsen and coworkers. This kinetic resolution allowed the preparation of azido-alcohols with excellent enantiomeric excesses (80–98% ee) [78].

Ph

(S ) 96% ee

30

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Bn ⊕ N

Br

−

CO2R

MeN

NMe

Ph

Ph

Bn

Ar +

Base

H

O

O

Ar

N

CO2R

RO2C Bn

MeN ⊕ NMe Ph

N

Ar O

MeN

NMe

Ph

Ph

Ph

(R,R ) or (S,S ) O Up to 75%

Bn MeN

NMe

Ph

Ph

+

CO2R N Ar

72–97% ee

OTMS TMSN3

O

N3

R

5% cat.

R

H N

Cat. =

ee 80 – 98%

R = Me, Et, n-But, CH2Cl, CH2OTBDMS, CH2CN, etc.

H N

Cr O N O 3

t-Bu

t-Bu

t-Bu

t-Bu

The same group explored the possibility to identify alternative nitrogen sources to overcome azide practical concerns and reported a general catalytic method for the preparation of enantiomerically enriched aziridines starting from racemic epoxides and N-Boc-2-nitrobenzenesulfonamide. The reaction, promoted by (S,S)[(salen)Co-Ac], provided in few steps enantiopure N-nosylaziridines in yields ranging from 58 to 86% and enantiomeric excesses always higher than 99%. Moreover, the presence of the N-nosyl protecting group imparts to the heterocycle a particular reactivity toward nucleophilic addition [79]. Ns

Boc N H 2% cat.

N

(2) Ms2O, Py (3) Base

ee > 99%

(1) O R

Ns

Cat. =

R

R = n Bu, CO2Me, CH2Cl, Ph, 2-Cl-Ph, etc.

H

H N

N Co

But

O

O OAc tBu But

tBu

1.1.4.2 Aziridines from Other Heterocycles 4-Isoxazolines are useful sinthons for the preparation of 2-acylaziridines through thermal rearrangement. This transformation was ﬁrst reported by Baldwin and coworkers but its application to asymmetric synthetic purposes was scarcely developed. In order to accelerate this rearrangement, catalysts for N–O bond cleavage have been tested and CO2 (CO)8 in anhydrous acetonitrile gave excellent

1.1 Substituted Aziridines

results. The transformation proceeds with complete diastereoselectivity when a stereogenic center is present in the substituent on the N atom [80]. Me

Ph

Ph

Co2(CO)8

BuLi, THF

Ph

N

O

O

Ph

N

MsCl, TEA

O

Bu

Me

Me

CH3CN 75°C

Ph H

Ph N

COBu H

64%

1.1.5 Racemate Resolution

Starting from racemic mixtures, mono- and disubstituted enantiomerically pure aziridines can be obtained by chemical or enzymatic resolution. Concerning chemical methods, an efﬁcient resolution of N-alkyl-aziridine-2-carboxylates has been carried out by host–guest molecular association with optically active host compounds derived from tartaric acid [81]. Ph Ph

Ph Ph O

HO HO

O

HO HO

O

Ph Ph

O

Ph Ph Tartaric acid derivatives R N

R N

R N

H N

CO2R′ R = Et, nPr R′ = Me, Et

CO2Me

CONHR R = Et, nPr

R = nPr, i Pr

Efﬁcient methods for the kinetic resolution of aziridines have also been obtained with the use of biocatalysts. Racemic substituted aziridine-methanol, aziridine-carboxylate, and aziridine-carboxamide derivatives have been easily separated. Enzymatic hydrolysis catalyzed by Candida Cylindracea Lipase (CCL) [82] has been performed both on N-unsubstituted aziridine-carboxylates and on more reactive N-chloro, N-acyl, or N-sulfonyl derivatives. R N R′

(±)

CCL

CO2Me

R′ = H, CO2Me R = H, Cl, Ac, COPr SO2Me, SO2Tol-p

Phosphate buffer pH 7.5, rt

R N

R N

+ R′ CO2Me R′ CO2H (+) or (−) (−) or (+)

31

32

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

In a similar way Lipase PS-C II, immobilized on porous ceramic particles, has been reported to catalyze the resolution of (2R*,3S*) and (2R*,3R*)-3-methyl3-phenyl-2-aziridinemethanol [83]. The temperature control on alcohol acetylation by means of vinylacetate suggests that enantioselectivity of this lipase-catalyzed kinetic resolution is favored by low temperature [84].

Ph Me

H N

Lipase PS-C II

H OH

(2R *,3S *)

Me Ph

H N

(2S )-Selective

Low temperature Lipase PS-C II

H OH

(2R )-Selective

Me Ph

H N H

OAc +

Ph Me

(2S,3R )

Me Ph

H N

H

H OH

(2R,3S )

+ Ph OAc Me

(2R,3R )

(2R *,3R *)

H N

H N H

OH

(2S,3S )

Biotransformation of racemic 1,2-trans-N-substituted-aziridine-2-carboxamides were carried out with a standard cell concentration of Rhodococcus rhodochrous IFO15564, an amidase-containing commercially available bacterium. Owing to the concomitant presence of a nitrile hydratase in these bacterial strains, the biotransformation was also successfully performed on trans-N-substituted-aziridine-2carbonitriles [85].

R N

Rhodococcus rhodochrous IFO15564

R N

or

(±) CONH2

(±) CN

Phosphate buffer pH 7.0, 28 °C

R N

+

R H N⊕ −

CONH2 (1R,2S ) Enantiopure

CO2

In a similar way, enantiopure (2R,3S)-3-aryl-aziridine-2-carboxamides were obtained from racemic 2,3-trans-aziridine-2-carbonitriles and amides under the catalysis of Rhodococcus erythropolis AJ270 whole cells. This highly efﬁcient and enantioselective hydrolysis occurred under very mild conditions in aqueous phosphate buffer at pH 7.0 at 30 ◦ C [86].

Ar

R N

or

(±) CONH2 R = H, Me

Ar

R N (±) CN

Rhodococcus erytropolis AJ270 Phosphate buffer pH 7.0, 30 °C

Ar

R N

+

CONH2 (2R,3S ) amide

Ar

R N

CO2H (2S,3R ) acid

1.1 Substituted Aziridines

1.1.6 Asymmetric Synthesis of Azirines 1.1.6.1 The Neber Reaction 2H-Azirines have been ﬁrst reported by Neber et al. in 1932 [87]. The Neber reaction possibly occurs either through an internal concerted nucleophilic displacement (route a) or via a electrocyclization of a vinylnitrene (route b), a reactive species formed by base-promoted loss of the leaving group on the nitrogen atom of oxime sulfonates and hydrazonium halides [88]. LG

N R2

R1

LG

N

Base (b)

R3

R2

R1

Base

R1

(a)

R3

N

N

− R2

R1

R3

R2 R3

The ﬁrst optically active 2H-azirine was synthesized by Neber reaction starting from the O-mesyl amidoxime derivative carrying a chiral phenylglycine (Phg) ester as a chiral auxiliary. Treatment of this derivative with base gave the 3-amino-2H-azirine in good yield and 96:4 stereoselectivity [89]. MeSO2

N

O

H2N

N

NaOMe

O

H2N

Phg-OEt

Phg-OEt

A remarkable asymmetric synthesis of azirine 2-carboxylates has been performed with a stoichiometric amount of dihydroquinidine or quinine as chiral tertiary base. The enantiomeric excess obtained ranged between 44 and 82%. Good results were also obtained when a catalytic amount (10 mol%) of quinidine was used. The hydroxy group of the base proved to be fundamental for a good stereoselectivity. Indeed, other chiral tertiary bases deprived of such hydroxy group, sparteine, brucine, and strychnine, did not provide any optically active azirine [90]. Later, this strategy has also been applied to the ﬁrst synthesis of enantiomerically enriched 2-phosphinyl-2H-azirines [91].

TsO

N

O

N

10% Base

R

OR1

R

N

HO

O OR1

Base =

OMe N

Finally, optically active 2H-azirines substituted in the 3-position with a phosphine oxide group or a phosphonate in the 2-position have been obtained with moderate enantiomeric excess by Neber reaction, starting from easily available oximes, and using chiral polymer-bound amines [92].

33

34

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

TsO

N

R

O P Ph Ph

N

Base

R

O P

Ph Ph

Base =

N OMe

1.1.6.2 Thermal or Photochemical Treatment of Vinyl Azides The thermal and/or photochemical treatment of vinyl azides has become a general method for the synthesis of 2H-azirines. In a similar way as for the Neber reaction, 4π-electron vinylnitrenes are thought to be the intermediates, which would then undergo electrocyclization to 2H-azirines. N3

R1

R

∆ or hn

R2

N R

R1 R2

Optically active 3-amino 2H-azirines can be obtained starting from mono- or disubstituted thioamides with a chiral substituent at the amino group, by treatment with phosgene/triethylamine and sodium azide [93]. This reaction is based on a previously reported synthetic protocol that likely proceeds through α-chloro enamine and vinyl azide intermediates, which are not isolated [94]. S PhSO2

N

Ph

COCl2 base

PhSO2

+

N

NaN3

G

N

N

PhSO2

N

Ph

Ph

The highly toxic phosgene can be substituted by diphenyl phosphorochloridate (DPPCl), (route a) [95]. Further, diphenyl phosphorazidate (DPPA) has been used as an alternative azide source allowing to obtain the azirines in a single step with very good yields (route b) [96]. (a)

O R1

N R2

R4 R3

LDA DPPCl

Cl R1 N R2

R4 R3

NaN3

N3

R4

R1 N R2

R3

R1

N N R2

R1 R2

LDA

(b)

DPPA

1.1.6.3 Elimination from Aziridines Aziridines carrying a leaving group at the nitrogen (N-chloro, N-sulfonyl, and N-acyl groups) are prone to elimination when treated with a base, giving 2H-azirines. This strategy has also been used for the asymmetric synthesis of azirine-carboxylates by the elimination of N-haloaziridines [97].

1.1 Substituted Aziridines

R

LG N R1 R2

N

Base

R1 R2

R

An alternative approach was based on the elimination of the SiMe3 and the N-quinazolinone substituents from a chiral aziridine promoted by cesium ﬂuoride. The resulting optically active azirines were not isolated, but directly treated with nucleophiles to yield aziridines in high enantiomeric excess. Q N NC

F

Ph

−

N

H N

Ph

NC

KCN

Ph

Q = Quinazolinone

On the other hand, the treatment of chiral N-sulﬁnylaziridines with TMSCl followed by LDA gave 2H-azirine-2-carboxylates under complete regioselectivity. This procedure has been applied to the ﬁrst asymmetric synthesis of the marine cytotoxic antibiotic (R)-(−)-dysidazirine and its (S)-(+) epimer [98]. p-Tolyl

O S O N OMe

Ph

N

(1) TMS-Cl (2) LDA −95 °C - rt

O

Ph

OMe

Most methods developed for the preparation of azirines cannot be utilized for the asymmetric synthesis of 2H-azirine-3-carboxylates. On the contrary, the dehydrochlorination of methyl 2-chloroaziridine 2-carboxylates provided the ﬁrst examples of enantiopure 2-substituted 2H-azirine 3-carboxylates [99]. H N

Ph 4

COOMe Cl

i -Pr2NEt

N

Ph 4

COOMe

1.1.6.4 Resolution of Racemic Azirines Enantiomerically, pure 2H-azirines have been recently obtained by enzymatic methods. Thus, the kinetic resolution of the racemic 2H-azirinemethanol with Amano lipase at low temperature gave optically pure (S)-(1)-phenyl-2H-azirine-2-methanol and the (R)-(2)-acetate derivative [100]. N Ph Rac

N

Amano PS

OH OAc

Ph

OH (S )-

+

N Ph

OAc (R )-

35

36

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

1.1.6.5 Oxidation of Aziridines One of the ﬁrst asymmetric syntheses of 2H-azirine-2-carboxylates described in the literature is the Swern oxidation of 3-alkylaziridine-2-carboxylates to the corresponding 2H-azirines. The oxidation of either the (Z) or the (E) isomers with COCl2 /DMSO, followed by NEt3 , proceeded with complete regioselectivity, in good yields and with retention of conﬁguration of the surviving stereogenic center [101]. H N R

COOMe

N

Swern

R

H N

COOMe Swern

R

COOMe

Z

E

The Swern oxidation has been later utilized for the efﬁcient synthesis of (+)-2H-azirine 3-phosphonate. This compound represents a new kind of chiral iminodienophile that on reaction with dienes such as trans-piperylene affords bicyclic aziridine adducts [102].

p-MeOPh

H O N P OMe OMe

Swern

N

p -MeOPh

O P OMe OMe

1.2 Substituted Monocyclic Azetidines and Carbocyclic-Fused systems 1.2.1 Generalities

Azetidines are four-membered nitrogen-containing analogs of cyclobutane whose nonplanar cyclic structure has been elucidated by electron diffraction and X-ray christallographic studies. Unsaturated derivatives of azetidine are also known as 1-azetines, 2-azetines, and azetes. Considerable attention has been paid in particular to the well-known amide derivatives azetidin-2-ones (β-lactams) that constitute systems of central importance due to their antibacterial properties. They have been the subject of many exhaustive reviews and books of bioorganic and medicinal chemistry owing to the widespread interest shown by scientists [103]. For this reason, in this chapter, their asymmetric synthesis are not treated. On the other hand, some azetidinones have been reported as starting materials for the preparation of enantiopure azetidines.

NH Azetidine

N 1-Azetine

NH 2-Azetine

N Azete

1.2 Substituted Monocyclic Azetidines and Carbocyclic-Fused systems

In comparison with strained highly reactive three-membered aziridines, the four-membered rings are more stable, unreactive toward reduction and susceptible of ring cleavage only at high temperature. Nevertheless, azetidines are unstable toward mineral acids and ring cleavage by nucleophiles may be performed on protonated rings or in the presence of Lewis acid activation. Azetidines are typical cyclic amines, appreciably more basic than both smaller and larger rings, showing in aqueous solution a pK a = 11.29. Naturally occurring azetidine derivatives are rare, and only in 1991 biologically active sphingosine-like compounds from marine origins, penaresidin A and B, were isolated as mixture of isomers. Tested as the mixture, they induced activation of myoﬁbrils from rabbit skeletal muscle elevating the ATPase activity. After few years, a related compound, penazetidine A, was isolated from Indopaciﬁc marine sponge Penares sollasi, which possesses potent protein kinase C inhibitory activity. OH

OH

HO

CH3 N

CH3

(15S,16S) : Penaresidin A

H OH

(15R,16R) : allo-Penaresidin A OH

CH3

HO N

CH3

Penaresidin B

H OH HO

CH3 N

CH3

Penazetidin A

H

The isolation and characterization of the polyoxin group nucleosides have been reported by Isono and coworkers [104]. Nucleoside polyoxins A, F, H, and K represent a class of antifungal antibiotics. An unusual common feature is the presence of an unsaturated azetidine-containing amino acid peptidically linked to polyoxin C. CO2H

CO2H

NH

N

cis-Polyoximic acid HO H2N

O

H N

O O

OH O

O H2N O

O OH

NH2

N H

O O

HO OH N

HO OH Polyoxin C

CH2OH

H N

O

Polyoxin A

N

O CH2OH

37

38

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Finally, azetidine 2-carboxylic acids and 2-phosphonic acids have been recently proposed as conformationally constrained analogs of α –amino acids in peptide chemistry [105]. Moreover, chiral C2 -symmetric 2,4-disubstituted azetidine derivatives showed excellent catalytic ability in the asymmetric addition of organozinc to carbonyl compounds. 1.2.2 Cyclization Methods: Introduction

General synthetic methods for the preparation of azetidine ring are based on intramolecular displacement of a leaving group on carbon by a γ -amino function. Aminoalcohols and aminohalo-derivatives are among the most important classes of starting materials for heterocycle formation. Halo-alkyloxiranes have also been converted to 3-hydroxy-azetidines via epoxide ring opening by an amine followed by intramolecular nucleophilic displacement. R1 R2

R1

R3 X

Z

NH

R2

X = Halogen, OTs OSO3−

R3 N

Z

Z=H Ts Bn OH

O X

H2N

X

OH HN

In a similar way, reaction of an amine or a sulfonamide with a 1,3-dihalogeno derivative results in the dialkylation of the nitrogen atom, providing a useful method for the preparation of NH, N-alkyl, or N-tosyl azetidines. Br RNH2

Br

RN

COOMe R = H, Ts, Bz

COOMe

A general enantioselective synthesis of this class of four-membered rings is still lacking and the stereoselective methodologies presented so far suffer from indirect and lengthy procedures such as reduction of enatiopure β-lactams, bis-alkylation of 1,3-sulfonates with primary amines, or intramolecular N-alkylation involving 1,3-amino alcohols. Anyway, the transformation of these methodologies into asymmetric procedures has been performed mainly by cyclization of optically active precursors or by resolution of racemic azetidine mixtures. In the following sections, some selected examples are reported.

1.2 Substituted Monocyclic Azetidines and Carbocyclic-Fused systems

1.2.2.1 Cyclization methods: Enantiopure Azetidines via Formation of C–N Bond The most important and easy synthetic pathway to azetidines involves the ring closure of aminoalcohols induced by transformation of the hydroxyl moiety into a good leaving group. Many optically active amino alcohols are commercially available; nevertheless, they can also be easily obtained by asymmetric reduction of β-aminoketones or β-amino acids [106]. This approach has also been applied to the synthesis of bioactive alkaloids core and fused-azetidine rings present in bridged nucleosides [107]. R′

R′ Red

O R3

NHR2

R3

R′

MeSO2Cl

OH

TEA 65–76%

NHR2

R3

N

R2

When the reacting hydroxy derivative was obtained by reduction of hydroxyaspartate [108], the presence of two possible leaving groups generated a competition between three-membered and four-membered rings. A strong effect of the starting aminoalcohol stereochemistry on the regioselectivity of the process was demonstrated. OH MeOOC

NHR

OMs

(1) BH3SMe2 NaBH4

COOMe

MsO

COOMe

MsO

73%

NHR

(2) MsCl, Py 70% Overall yield

TEA

COOMe N

R

On polyfunctionalized amino alcohols, precursors of sphingosine-derived alkaloids named penaresidins, crucial cyclization has been induced under mild Mitsunobu conditions to yield enantiopure azetidines [109]. Under the same conditions, enantiopure ethynylazetidines were obtained in high yields from 2-ethynyl-1,3aminoalcohols [110]. OBn

OBn BnO Ts

OTBS NH OH

PPh3

BnO

OTBS N Ts

DEAD 60% 60%

R Ts

R′ NH OH

PPh3 DEAD 9–87%

R N Ts

R′

Enantiopure 1,3-diols, obtained by hydrogenation of 1,3-diketones in the presence of chiral ligands, have been successfully used as 2,4-disubstituted azetidine precursors. Treatment with methanesulfonyl chloride followed by reaction with an

39

40

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

excess of benzylamine afforded N-benzyl heterocycles in yields ranging form 60 to 85% [111]. O

O

R

OH

H2, (R )-Binap

Bn

OH (1) MsCl, TEA

R

R

R N

R

Ruthenium salt

R

(2) BnNH2

Iodomethylation of enantiopure α-(dibenzyl)aminoaldehydes by means of samarium/diiodomethane under mild conditions gave optically active aminoiodohydrins, as precursors of azetidinium tetraﬂuroborate salts. These salts are versatile building blocks that can be transformed into aminoepoxides, 1,3-oxazolidines, or turned into N-benzyl-hydroxyazetidines by simple hydrogenolysis [112]. HCO2H O R Bn2N

Sm/CH2I2 H

H3O+

H

R

H OH

R I

AgBF4

Bn2N H de 80%

Bn2N ⊕

OH

BF4

R

Pd/MeOH Bn

R′NH2

OH N

H O R

CH2Cl2 Bn2N

N R′ H 50–62%

Ring closure of aminoallenes has attracted much attention in the development of stereoselective processes to ﬁve- or six-membered nitrogen-containing heterocycles. In a similar way, allenes bearing shorter carbon chain may lead to small size rings. Treatment of β-aminoallene and iodobenzene in the presence of palladium afforded exclusively 2,4-cis-azetidines in excellent yield [113]. H R Mts

C NH

H

R′ Cat. Pd (0) R′-I, K2CO3 DMF

R H

N H Mts

Yield 22–91% de 64 – >99%

1.2.2.2 Cyclization Methods: Enantiopure Azetidines via Formation of C–C Bond Considerable attention has been paid to the synthesis of enantiopure azetidines bearing a nitrile or a phosphonic acid linked to the α position of the ring, owing to the potential application of these molecules as precursors or mimics of cyclic amino acids. To this purpose, Couty and coworkers [114] developed an easy three-step methodology starting from readily available β-amino alcohols. N-cyanomethylation or N-phosphomethylation of the starting material was followed by substitution of the alcoholic moiety by thionyl chloride. Stereoselective 4-exo-tet ring closure through intramolecular alkylation of the methylene group gave enantiopure azetidines.

1.2 Substituted Monocyclic Azetidines and Carbocyclic-Fused systems

CO2Et EWG

R1 R2

N

Cl R1

R3

R′

OH

R

NH R

EWG

−

N

BrCH2CN K2CO3 >99%

HCOH (EtO)2P(O)H

CO2Et

EWG

R2

EWG

−

R3

R2

R1

OH

R2

N R3 H

R′

OH

R

N R

R′

OH

R

N R

N

R3

SOCl2 K2CO3 92–97%

CN

R2

R′

Cl

R

N R

R′ K2CO3 70–92%

N

R3

LiHMDS R′ CN

80–90%

LiHMDS

R

N R

CN

N R R dr 7/3

Cl

SOCl2 O P OEt OEt

O P OEt 30–75% OEt

R′

Ph PhLi, chromatography

O 77%

N Me Ph

CN

OH HCl

N Me

Me

Me

Ph

O

Dowex

Me (1) H2SO4 (2) LiAlH4

Ph

(3) MsCl, TEA (4) CHCL3, ∆

Me

N

97% Me

OMs N

Ph Me

Me

OMs N Me

75%

O

P

OEt OEt

N R R de > 99%

2-Cyano azetidines are versatile building blocks that can be easily transformed into functionalized heterocycles. In fact, treatment of cyano azetidines with phenyllithium cleanly afforded 2-acyl azetidines. Unfortunately, under these conditions, complete epimerization at C2 could not be avoided. On the other hand, hydrolysis of the cyano derivatives into carboxylic acids required harsh conditions, and prolonged heating in concentrated acid was necessary to completely hydrolyze the intermediate amide. Although drastic conditions were applied, neither ring opening nor epimerization was observed. These derivatives were successfully introduced into peptidic sequences as constrained mimetics of natural amino acids. Finally, reduction of the nitrile to alcohol followed by mesylation allowed the expansion of enantiopure azetidines to 3-mesyloxy pyrrolidines. Ph

41

42

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Starting from the same N-cyanomethylated intermediates, the same authors reported the preparation of a new class of functionalized heterocycles via Wittig oleﬁnation of a transient amino-aldehyde followed by intramolecular Michael addition of the deprotonated methylene position. Unfortunately, low diastereoselectivity could be observed because of the base-catalyzed equilibration between stereoisomers [115]. CO2Et OH R

N Bn

CN

EtO2C

LiHMDS

Swern oxidation Wittig olefination 73%

R

N Bn

CN

CN N R Bn dr 56/44

58 – 73%

1.2.3 Azetidines by Resolution of Racemates

Azetidines can be obtained in enantiomerically pure form through enzymatic or chemical resolution of racemic mixtures. Starting from the Baldwin’s adaptation of Cromwell general method of preparation of azetidine from 1,3-dihalogeno compounds, racemic azetidine-2-carboxylates were obtained in 96% by reaction with benzhydrylamine under microwave irradiation in CH3 CN. The resolution [116] was conveniently carried out by using l-tyrosine hydrazide as a resolving agent. Enantiomerically pure azetidines have been converted into (R)- or (S)-oxazaborolines, useful for the enantioselective reduction of prochiral ketones. H H

Br Br

COOBn

H N

COOBn 1. PhMgBr R

COOBn

RNH2

2. Pd/MeOH

N

H N

Ph OH

H

N R H COOBn

L-tyrosine

hydrazide

R

N

Ph

BH3

H

COOBn

R

Ph

N B

Ph O H

(S)-1-Phenylethylamine has been used as a chiral auxiliary as well as a nitrogen atom donor in the synthesis of an enantiomeric pair of azetidine-2,4-dicarboxylic acids from racemic dibromoderivatives; the absolute conﬁguration of one of which has been assigned on the basis of the X-ray structure and the known absolute conﬁguration of the (S)-1-phenylethylamine moiety [117]. These C2 -symmetric disubstituted heterocycles have been successfully exploited as rigid core for the preparation of chiral ligands in the asymmetric addition of diethylzinc to aldehydes.

1.2 Substituted Monocyclic Azetidines and Carbocyclic-Fused systems Br

Br

+ CO2Me

MeO2C

NH2 H Ph Me

K2CO3

MeO2C

88%

CO2Me

N

Ph

43

Diastereomeric mixture

H Me

(1) LiAlH4

MeO2C

N

CO2Me (2) MeI/NaH

H Ph Me (S, S, S )

MeO

(3) H2 /Pd (4) BrCH2CO2Et, K2CO3

N Ph

(5) PhMgBr

OMe OH

C2-symmetric chiral ligand

Ph

The application of hydroxy-azetidines as chiral ligands for zinc-catalyzed enantioselective additions was also previously reported by Martens and coworkers. Starting form (S)-azetidinecarboxylic acid, a constituent of the natural mugineic acid and one of the few commercially available azetidines, the chiral catalyst was prepared by enantioselective catalytic reduction of ketone moiety in the presence of oxazaborolidines [118]. Resolution of racemic trans-azetidine-2,4-dicarboxylic acids, synthesized following the same procedure, was achieved by transesteriﬁcation of N-substituted dimethylesters with (-)-8-phenylmenthol and chromatographic separation of the resulting diastereoisomers [119].

MeLi MeO2C

N R

RO2C

Chromatography

CO2Me + OH Ph

RO2C R=

N R + N R

CO2R

NaOH HO2C

CO2R

NaOH HO C 2

Ph

Starting from dicarboxylic derivatives, cis- and trans-dihydroxy-substituted heterocycles were obtained by reduction with LiAlH4 , followed by treatment with benzylamine. The dihydroxy-meso compound was desymmetrized and transformed into monoacetate by the immobilized mammalian lipase from Porcine pancreas (S-PPL). The best results were obtained when diisopropylether was used as cosolvent in the presence of vinyl acetate. Optimized procedure allowed to obtain enantiomeric excess higher than 98% by stopping the reaction at conversion around 55%. Longer reaction times showed the formation of a signiﬁcative amount of meso-diacetate derivative. Using the same enzyme, the trans isomer was resolved by a double kinetic resolution, stopping the reaction at moderate degree of conversion. In this case, the diacetate was isolated by the higher enantiomeric excess, while the starting dihydroxyderivative was isolated with 94.5% ee after recrystallization [120].

N R

N R

CO2H

CO2H

44

1 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles EtO2C

EtO2C

CO2Et

N Bn

CO2Et

N

S-PPL

LiAlH4 HO

N Bn

OH

N Bn

OH

Vinyl acetate AcO

N

OH

Bn

ee > 99.5%

S-PPL

LiAlH4 HO

Bn

Vinyl acetate AcO

N Bn

rac

OAc ee > 99.5%

Enzymatic resolution of N-alkyl-azetidine-2-carboxylates could be accomplished via transacylation of ammonia catalyzed by Candida Antarctica lipase. Treatment of racemic azetidine-esters with an alcoholic saturated solution of ammonia afforded enantiopure unreacted (R)-esters and highly enriched (S) amides [121].

Br Br

CO2Me

RNH2

N R

K2CO3

CO2Me

R = Bn, Allyl, PMB

Candida Antarctica Lipase

CO2Me

N R

ee > 99% +

NH3, t BuOH Conv 50 – 56%

N R

CONH2 ee 80 – 97%

1.2.4 Azetidines by Ring Transformation

Transformation of heterocyclic precursors represents a further possibility for the synthesis of this class of compounds. One of the most important features is the ring expansion of activated aziridines. ⊕ − R1

R H

N H

E E

Me2S

R2

E = COOMe

R

R1 R2

HN E

E

Azetidine derivatives carrying a carbonyl group on the ring backbone occupy a special place in heterocyclic chemistry. Besides the well-known natural and synthetic azetidin-2-one derivatives, whose asymmetric synthesis has been extensively reviewed in the past, much less attention has been paid to azetidin-3-ones. Recently, a useful protocol for the synthesis of these heterocycles has been reported by De Kimpe and coworkers [122], starting from readily accessible N-alkylidene-tribromopropylamines. Anyway, both classes of compounds represent starting materials for the preparation of azetidine derivatives. Optimization of the conditions for chiral nonracemic azetidinones reduction with metal hydrides allowed to identify DIBAL-H or AlH2 Cl as the reagents of choice [123].

References BnO

BnO

Ar N

O

DIBAL-H

Ph

N

THF

Ar = Ph, p -F-Ph, furanyl, thiophenyl BnO N

BnO

Ar

AlH2Cl

Ph

Ph

54 – 85%

Ar

O

Ar

N

Et2O

Ph 53 – 95%

Natural-cis and unnatural-trans polyoximic acids have been synthesized starting from d-serine through l-3-azetidinone-2-hydroxymethyl chiron using a rhodiummediated diazoketene insertion reaction. By choosing the proper reagents, the following Horner-Wadsworth-Emmons and Wittig reactions were suited to exclusively obtain the cis or the trans isomer [124]. O

O N2

HO

OTBDPS NHBoc

OH NHBoc

Rh2(OAc)4 MeO

N

OTBDPS NBoc

O O

COOH NBoc

OTBDPS NBoc MeO

N

O OTBDPS NBoc

COOH NBoc

References 1 For reviews on aziridine syn-

thesis see: (a) Yudin, A. K. (ed) (2006) Aziridines and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH, Weinheim; (b) Osborn, H. M. I. and Sweeney, J. (1997) Tetrahedron: Asymmetry, 8, 1693–715; (c) Tanner, D. (1994) Angew. Chem. Int. Ed. Engl., 33, 599–619; (d) Atkinson, R. S. (1999) Tetrahedron, 55, 1519–59; (e) Osborn, H. M. I. and Sweeney, J. (1997) Tetrahedron: Asymmetry, 8,

1693–715; (f) Kemp, J. G. (1991) Comprehensive Organic Synthesis (eds B. M. Trost and I. Fleming), Pergamon, Oxford, Vol. 7, Chapter 3.5; (g) Watson, I. D. G., Yu, L. and Yudin, A. K. (2006) Acc. Chem. Res., 39, 194–206; (h) Singh, G. S., D’hooghe, M. and De Kimpe, N. (2007) Chem. Rev., 107, 2080–135. 2 Katritzky, A., Ramsden, C., Scriven E. and Taylor R. (eds) (2008) Comprehensive Organic Chemistry, Vol. 1, Elsevier.

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46

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M. (2001) Tetrahedron, 57, 4467. Kasai, M. and Kono, M. (1992) Synlett, 778. Schirmeister, T. (1999) Biopolymers, 51, 87. Stapley, E. D., Hendlin, D., Jackson, M., Miller, A. K., Hernandez, S. and Mata, J. M. (1971) J. Antibiot., 24, 42–47. Molinski, T. F. and Ireland, C. M. (1988) J. Org. Chem., 53, 2103–5. Gabriel, S. (1888) Chem. Ber., 21, 1049. For reviews on the reactivity of aziridines see: (a) Cardillo, G., Gentilucci, L. and Tolomelli, A. (2003) Aldrichimica Acta, 36, 39–50; (b) Lee, W. K. and Ha, H. J. (2003) Aldrichimica Acta, 36, 57–63; (c) McCoull, W. and Davis, F. A. (2000) Synthesis, 10, 1347–65; (d) Kulkarni, Y. S. (1999) Aldrichimica Acta, 32, 18–27; (e) Padwa, A. (1991) Comprehensive Organic Synthesis, (eds B. M. Trost and I. Fleming), Pergamon, Oxford, Vol. 4, Chapter 4.9; (f) Righi, G. and Bonini, C. (2000) Targets in Heter. Syst., 4, 139–65. Berry, M. B. and Craig, D. (1992) Synlett, 41–44. Kim, B. M., Bae, S. J., So, S. M., Yoo, H. T., Chang, S. K., Lee, J. H. and Kang, J. (2001) Org. Lett., 3, 2349–51. (a) Osborn, H. M. I., Cantrill, A. A., Sweeney, J. B. and Howson, W. (1994) Tetrahedron, 35, 3159–62; (b) Osborn, H. M. I. and Sweeney, J. B. (1994) Synlett, 145–47. Ho, M.,Chung, J. K. K. and Tang, N. (1993) Tetrahedron Lett., 34, 6513–16. Shaw, K. J., Luly, J. R. and Rapoport, H. (1985) J. Org. Chem., 50, 4515–23. (a) Kuyl-Yeheskiely, E., Lodder, M., van der Marel, G. A. and van Boom, J. H. (1992) Tetrahedron Lett., 33, 3013–16; (b) Baldwin, J. E., Farthing, C. N., Russell, A. T., Schonﬁeld, C. J. and Spivey, A. C. (1996) Tetrahedron Lett., 37, 3761–64. Palomo, C., Aizpurua, J. M., Balentova, E., Jimenez, A., Oyarbide,

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J., Fratila, R. M. and Miranda, J. I. (2007) Org. Lett., 9, 101–4. (a) Nagel, D. L., Woller, P. B. and Cromwell, N. H. (1971) J. Org. Chem., 36, 3911–17; (b) Tarburton, P., Woller, P. B., Badger, R. C., Doomes, E. and Cromwell, N. H. (1977) J. Heterocycl. Chem., 14, 459–64. Garner, P., Dogan, O. and Pillai, S. (1994) Tetrahedron Lett., 35, 1653. Cardillo, G., Gentilucci, L., Tomasini, C. and Visa Castejon-Bordas, M. P. (1996) Tetrahedron: Asymmetry, 3, 755–62. Cardillo, G., Casolari, S., Gentilucci, L. and Tomasini, C. (1996) Angew. Chem. Int. Ed. Engl., 35, 1848–49. Sugihara, H., Daikai, K., Lin, X. L., Furuno, H. and Inanaga, J. (2002) Tetrahedron Lett., 43, 2735–39. Bew, S. P., Hughes, D. L., Savic, V., Soapi, K. M. and Wilson, M. A. (2006) Chem. Commun., 3513–15. Cardillo, G., Gentilucci, L., Ratera Bastardas, I. and Tolomelli, A. (1998) Tetrahedron, 54, 8217–22. (a) Fukurawa, N., Yoshimura, T., Ohtsu, M., Akasaka, T. and Oae, S. (1980) Tetrahedron, 36, 73–80; (b) Fukurawa, N. and Oae, S. (1975) Synthesis, 30–32. Cardillo, G., Fabbroni, S., Gentilucci, L., Gianotti, M., Percacciante, R. and Tomelli, A. (2002) Tetrahedron: Asymmetry, 13, 1407–10. (a) Sibi, M. P. and Manyem, S. (2000) Tetrahedron, 56, 8033–61; (b) Almasi, D., Alonso, D. A. and Najera, C. (2007) Tetrahedron: Asymmetry, 18, 299–365. Chen, Y. K., Yoshida, M. and MacMillan, D. W. C. (2006) J. Am. Chem. Soc., 128, 9328–29. Pettersen, D., Piana, F., Bernardi, L., Fini, F., Fochi, M., Sgarzani, V. and Ricci, A. (2007) Tetrahedron Lett., 48, 7805–8. Vesely, J., Ibrahem, I., Zhao, G. L., Rios, R. and Cordova, A. (2007) Angew. Chem. Int. Ed. Engl., 46, 778–81.

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31

32

33

34

35 36

37

38 39 40

41

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51

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles Pei-Qiang Huang

2.1 Monocyclic Pyrrolidines and Pyrrolidinones 2.1.1 Generalities

The pyrrolidine structural unit is one of the most commonly occurring structural cores in a large number of biologically active alkaloids [1]. For example, since its ﬁrst isolation in 1954 [2a], anisomycin (1) has become a valuable tool in molecular biology, having been used for the treatment of Trichomonas vaginitis and amoebic dysentery, and also as an agricultural fungicide. Recent investigation showed that anisomycin and its higher homolog 3097-B1 (1a) as well as 3097-B2 and 3097-C2 exhibited in vitro anticytotoxic activity (Figure 2.1) [2b]. The role of the naturally occurring excitatory amino acid (R)-α-kainic acid (2) in mediating synaptic responses has made it an important reagent for investigations into Alzheimer’s disease, epilepsy, and other neurological disorders [3]. It has also been used as an antiworming agent to eliminate parasites from humans and animals. (+)-Lactacystin (3) is a potent and selective proteasome inhibitor that was isolated from Streptomyces sp [4]. Recently, a more potent proteasome inhibitor, (−)-salinosporamide A (4), was isolated from a marine actinomycete [5] and it inhibits proteasomal proteolytic activity with an IC50 value of 1.3 nM. Moreover, compound 4 has potent in vitro cytotoxicity (LC50 < 10 nM against four different cancer cell lines). On the other hand, pyrrolidine is also a motif for designing pharmaceuticals. For example, nemonapride (YM-09151-2) (5) was marketed in 1991 as a potent antipsychotic drug [6]. Recently, A-315675 (6) was developed by scientists at Abbott laboratories as a potent inﬂuenza neuraminidase inhibitor and is a candidate for development as an anti-inﬂuenza drug [7]. In addition to their underexplored medicinal importance, functionalized pyrrolidines have found wide applications as chiral ligands [8], chiral auxiliaries [9], and organocatalysts [10] in asymmetric synthesis. Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

52

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

ROCO

MeO

OH N H

(−)-Anisomycin (1), R = CH3 3097-B1 (1a), R = C2H5 Cl

O Me

HO

HO2C HO2C

(+)-a-Kainic acid (2) MeHN

N H

O

H (−)-Salinosporamide A (4)

N H O

O

(+)-Lactacystin (3) Me

Me

H N MeO

AcHN

S

Me

Cl

O HO

HO2C

N H

HO

O Me

HN N Bn

Me

Nemonapride (5)

O CO2H N H H OMe Me A-315675 (6)

Fig. 2.1 Selected examples of bioactive pyrrolidines/pyrrolidin-2-ones.

Consequently, signiﬁcant efforts have been devoted to the development of efﬁcient routes to substituted pyrrolidines. 2.1.2 Cyclization Methods

Formation of the pyrrolidine/pyrrolidinone ring by cyclization is a widely used approach. Almost all disconnections around pyrrolidine/pyrrolidine-2-one ring are viable, including C1 /C5 –N bond, C2 –C3 bond, and C3 –C4 bond disconnections, as well as C1 –N/C5 –N double disconnections. 2.1.2.1 Cyclization via C1 /C5 –N Bond Formation Many methods have been reported for the synthesis of pyrrolidines and pyrrolidin-2ones by intramolecular amination or amidation of chiral nonracemic alicyclic amines or amides. They will be classiﬁed according to the methods used to synthesize the chiral nonracemic alicyclic precursors. Naturally Occurring Chiron Approach Enantiomerically pure α-amino acids are cheap and easily available chirons [11]. A three-step synthesis of 5-alkyltetramic acids 7, developed by Jouin and Castro [12], provides a ﬂexible approach to cis-4-hydroxy-5-alkylpyrrolidin-2-ones 8 after a highly stereoselective reduction with NaBH4 , and to 2,5-disubstituted pyrrolidin-4-ols after further transformations (Scheme 2.1). Sugars provide a rich source of chirons for the synthesis of enantiomeric pure hydroxylated pyrrolidines/pyrrolidin-2-ones. Nicotra developed a four-step method for the synthesis of 4,5-cis-substituted pyrrolidine-2-ones (11) and pyrrolidines (12) starting from 2,3,5-tri-O-benzyl-d-arabinofuranose (9) (Scheme 2.2) [13]. This provided a basis for the asymmetric synthesis of antibiotic anisomycin (1) [14a] and the antifungal agent (+)-preussin (15) [14b], as well as pyrrolizidine alkaloid

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

R

R

H2N

CO2H + Meldrum's acid

O

O

O

HN Boc O

HO

O

AcOEt reflux

NaBH4

O N Boc (7)

R

O

O N Boc (8)

R

Scheme 2.1 An α-amino acid–based approach to tetramic acids and cis-4-hydroxy-5-alkylpyrrolidin-2-ones. BnO

OBn OH

O

R′MgX 88–100% de

OBn (9)

R

Tf2O, Py R′

N

RNH R R′ HO R′ PCC OH O OBn N BnO H Bn n C9H19 N OBn OBn CH 3 (10) (11) (+)-Preussin (15) R = CH2Ph C-3 Deoxygenation

RNH2; BnO

Boc Bn OTBS

OBn O

(a) C9H19MgBr, −78 °C, THF; (b) Et3SiH, BF3 OEt2

N

BnO

n C9H19

Boc Bn OTBS

N

67% (2 steps)

OBn (12)

(13)

(14)

Scheme 2.2 Nicotra’s approach to hydroxylated pyrrolidin-2-ones/pyrrolidines (TBS = tert-butyl-dimethylsilyl).

(+)-alexine [14c]. To introduce the C-5 side chain of (+)-preussin, Yoda et al. developed a reductive alkylation method (13 → 14), which allows the establishment of C2 /C5 cis stereochemistry with high diastereoselectivity [14d,e]. Scheme 2.3 shows three approaches for the rapid transformation of sugars into pyrrolidine/1-pyrroline derivatives [15–17]. In Ganem’s approach (Scheme 2.3a) [15], upon treatment of bromobenzoate 16 with Zn-NaBH3 CN, reductive ring opening and reductive amination occurred to give 17, which was followed by a spontaneous intramolecular displacement of the benzoate in 17, leading to pyrrolidine 18 in 70% yield from 16.

(a)

Br BzO BnO

Zn, NaBH3CN PrOH/H2O (19:1)

O OBn OCH

3

(16)

Reflux, 7 h

(b) Suárez’s approach[16] NHBoc O

O

Boc N

OH PhIO, I2 O

21 h 73%

HO2C

OBn

(17)

Bn N

H2C BnO

NHBn

BzO BnO

BnO (18)

70%

(c) Moriarty’s approach[17] OH

H O O

O

O

MsO

N

(a) CH3MgBr

O

O

Scheme 2.3 Three rapid approaches for the transformation of sugars to pyrrolidine/1-pyrroline derivatives.

(b) NH3

CH3

H O

O

53

54

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

O CO2Li

O

+

O

N3 Thiamine pyrophosphate

HO

OH

MgCl2, transketolase

H

71%

OH

OH

OH

Pd /C 80 bar, H2

N OH H LAB-1 (19)

76%

OH OH N3

Scheme 2.4 Enzymatic synthesis of azasugar LAB-1.

Enzymatic Approach Among various routes to azasugars, an enzymatic route should be quite efﬁcient, because such approaches are generally free of deprotection–protection procedures. Effenberger et al. developed an enzymatic synthesis of 5-azido-5-deoxy-d-xylose, which led to the synthesis of azasugar LAB-1 (19, Scheme 2.4) [18]. Wong et al. undertook a systematic study on chemo-enzymatic synthesis, which led to the synthesis of many polyhydroxylated pyrrolidines [19]. Catalytic Asymmetric and Chiral Auxiliary-Induced Approaches The efﬁcient enantioselective synthesis of polyhydroxypyrrolidine 21 shown in Scheme 2.5 involves a sequential Sharpless asymmetric dihydroxylation and asymmetric epoxidation in the presence of the Mizuno’s dinuclear peroxotungstate catalyst. Final treatment of 20 with 10% NH3 in water gave azasugar 21 in 88% yield [20] via a tandem nucleophilic substitution–intramolecular ring opening of the epoxide. A recent synthesis of (−)-codonopsinine (22) illustrates a new approach to substituted pyrrolidines. It involves a highly trans-diastereoselective intramolecular SN 1 reaction via a resonance-stabilized benzylic carbacation intermediate derived from 23, which was synthesized via the Sharpless asymmetric dihydroxylation reaction (dr = 91:9) (Scheme 2.6) [21]. On the basis of iterative asymmetric Ti-mediated allylations, Cossy and coworkers developed an asymmetric approach to (+)-preussin (15). The two titanium-complex(a) AD-mix a MeSO2NH2 (70%)

Br

Br

10% NH3 /H2O

(b) H2O, 50 °C (98%) 1.2 H2O2 Br 0.02K2[ W2O3(O2)4(H2O2)] 99%

OH

HO

OH O

OH

OH (20) ds = 92%; 97% ee

OH N H H (21)

4h 88%

OH

Scheme 2.5 A concise enantioselective synthesis of polyhydroxypyrrolidine.

AcO OAc Me

TFA, CH2Cl2

Ar NH OAc Cbz (23)

0 °C, to rt, 4 h 81%

(Ar = C6H4OMe-p)

OH

HO

OAc

AcO

LiAlH4, THF

Me

N

Ar 0 – 60 °C, 5 h Me 74%

Cbz dr = 100:0

N Me

OMe

(−)-Codonopsinine (22)

Scheme 2.6 Rao’s enantioselective synthesis of polyhydroxypyrrolidine.

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

MOM O OH

OMOM Bn Bn CHO 63%

Bn

OH ds = 91:9 90% ee

RO MsCl, Et3N; aq. MeNH2

n C9H19

n C9H19 N Me R = MOM R = H, preussin (15) Bn

48%

OH

Scheme 2.7 Cossy’s Ti-mediated asymmetric allylation approach to (+)-preussin.

CO2Me

N

Bn

Li

Bn

N Bn

Bn N Bn

Bn CO2Me

THF, −78 °C, 2 h; N BnBr,16 h Bn 94%

Bn (24)

N

Pd(PPh3)4, CH2Cl2 rt, 16 h, then SiO2

Bn

92%

(25) 94% de

Bn N

O

Bn (26) 96% de

Scheme 2.8 Davies’ diastereoselective approach to 3-substituted 4-aminopyrrolidines.

catalyzed asymmetric allylation reactions proceeded with 91:9 and 96:4 diastereoselectivities respectively, which established all three stereogenic centers of the target molecule (Scheme 2.7) [22]. As an application of their chiral lithium amide conjugate addition methodology (24 → 25), Davies et al. developed a highly diastereoselective and enantioselective approach to 3,4-trans- and 3,4-cis-substituted aminopyrrolidines (Scheme 2.8) [23]. Catalytic enantioselective and diastereoselective addition of enecarbamates with α-oxo aldehydes provides a one-step synthesis of γ -amino acid derivative 27, which was converted subsequently into substituted 3-hydroxypyrrolidin-2-one 28 and 3-hydroxy-4-methylproline (HMP, 29, Scheme 2.9) [24]. Recently, two catalytic enantioselective Michael addition–based approaches to β-aryl-γ -lactams 30 have been developed by Kanemasan [25] and Barnes [26] (Scheme 2.10a and b respectively), with the latter being used in the synthesis of the antidepressant rolipram. The same product can also be obtained via Ley’s butane-2,3-diacetal (BDA) derivative 31-based Michael addition (Scheme 2.10c) [27]. In Shibasaki’s catalytic asymmetric total synthesis of (+)-lactacystin, the lactam intermediate 32 was made by subsequent oxidative cleavage, oxidation, and lactamization of the chiral cyclopentene derivative 33, obtained via an enantioselective Strecker reaction of ketoimine 34 (Scheme 2.11) [28]. Cbz HN EtO2C

H + O (E )-

TBSO CuClO4 4MeCN (1 mol%) Chiral ligand CH2Cl2, 0 °C; Sc(OTf)3

HO

OEt

EtO2C

OH NHCbz (27)

O

N N HOOC H Bn (28) HMP (29)

Scheme 2.9 Enantioselective Stork-type approach to substituted 3-hydroxypyrrolidin-2-one.

55

56

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

(a)

Ar

Chiral catalyst MeNO2 Ar

Ar

N

b

N

91%

O

O2N

N H (30)

72%

O 98% ee

O (c)

(b) CO2Et Chiral ligand (5.5 mol%)

EtO2C

Mg(OTf)2 (5 mol%)

+

NO2

Ar

Ar ′ EtO2C

O O

H NO 2

EtO2C

95%

R = Ph, 96% dr = 34:1

O

+ R O

O

96% ee

LiHMDS

NO2

(31)

Scheme 2.10 Three enantioselective approaches to β-aryl-γ -lactams.

NP(O)Ph2

i -Pr

NC

P(O)Ph2 NH

i -Pr (34)

3 steps

Boc EtO2C

i -Pr (33)

98% ee

NH

(a) O3: Me2S (b) NaClO2 (c) H2SO4 EtOH

EtO2C O

N Pr-i H

O

(32)

Scheme 2.11 Shibasaki’s catalytic asymmetric approach to (+)-lactacystin.

O Bn

H

2-Undecanone LiHMDS, ZnCl2

NHCO2Me

72% dr = 10:1

OR O Bn

BF3 OEt2 Et3GeH

HO

n C9H19 n C9H19 Bn N 88% NHCO2Me ds = 100% X X = CO2Me (36) → R=H→ X = Me (+)-Preussin (15) R = OTBS, (35)

Scheme 2.12 Kitahara’s intramolecular reductive amidoalkylation approach to (+)-preussin.

A combination of chelation-controlled syn-selective aldol reaction of α-amino aldehyde and zinc enolate of 2-undecanone, with Lewis acid-promoted intramolecular reductive amidoalkylation (35 → 36), establishes a concise and highly diastereoselective approach to (+)-preussin (15) (Scheme 2.12) [29]. Synthesis of substituted pyrrolidines by both substrate [30] and chiral auxiliary [31]-induced asymmetric intramolecular aza-Michael addition was reported. As shown in Scheme 2.13, reaction of hemiaminal 37 with the carbanion generated from trimethyl phosphonoacetate led, via a tandem Wittig-aza-Michael reaction, to the formation of all-cis-trisubstituted pyrrolidine 38 in 5.6:1 diastereoselectivity [30]. Remarkably, starting from methylated hemiaminal 40, all-cis-tetrasubstituted pyrrolidine 41 was formed as a single diastereomer in 75% yield. Metal and halogen-mediated intramolecular cyclizations of amido/amino-oleﬁns/ allenes/alkynes constitute another versatile strategy for pyrrolidine formation. Pd(0) complex, Hg(II) salt, and Ag(I) salt are the most frequently used metal catalysts.

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

R

O

O (MeO)2P

O

OH N SO2Ph

N

CO2Me

N SO2Ph

SO2Ph (38) R = H (41) R = Me

88% 75%

R

O + O CO2Me

O

NaH, −15 °C, 96 h

(37) R = H (40) R = Me

R

O CO2Me

dr = 5.6/1 dr = 100/0

(39) R = H (42) R = Me

Scheme 2.13 Synthesis of polysubstituted pyrrolidines by intramolecular aza-Michael addition.

The seminal work of Harding established that pyrrolidine ring systems can be formed via intramolecular amidomercuration, and 2,5-trans-disubstituted pyrrolidines can be obtained under kinetically controlled conditions, while thermodynamically controlled conditions allow access to 2,5-cis-disubstituted pyrrolidines [32]. Starting from this reaction, Momose and coworkers accomplished the asymmetric synthesis of several alkaloids [33]. The mercury(II)-mediated amidomercuration-oxidative demercuration reaction of the δ-alkenylamide 43, prepared from achiral 4-(p-methoxy)phenoxylated α,β-unsaturated ester via a regio- and enantioselective Sharpless aminohydroxylation, was shown to be highly trans-diastereoselective. On the basis of these reactions, a six-step enantioselective synthesis of polyhydroxylated pyrrolidines 44 was developed (Scheme 2.14) [34]. The concise ﬁve-step synthesis of the antifungal agent (+)-preussin (15) is an excellent demonstration of the power of Hg(II)-mediated ring closure of ynone 45 (Scheme 2.15) [35]. The advantages of Pd-catalyzed amination of alkenes/alkynes reside on the usefulness of the Pd-intermediate formed, which in turn can be used for carboxylation or arylation. This was demonstrated by the concise syntheses of (+)-preussin, 3-epi-preussin, and its analogs shown partially in Scheme 2.16a [36]. In addition, OPMP

PMBO HO

HN Ac

Hg(OAc)2; NaHCO3, KBr

HO

OPMB

44% (two steps)

N HgBr Ac OPMP dr > 15:1

(43)

OH

HO

O2, NaBH4 DMF

X

N H HCl

OH

(44a) X = OH (44b) X = H

Scheme 2.14 Han’s asymmetric synthesis of azasugars by mercury(II)-mediated amidomercuration.

O BocHN

O Hg(OAc)2 NaCl

n C9H19

Bn (45)

HO

X NaBH4, MeOH

n C9H19 LiAlH , THF N 4 Boc 100% de X = HgCl → X = H > 95% ee

Bn

Bn

N

n C9H19

CH3 (+)-Preussin (15)

Scheme 2.15 Hecht’s Hg(II)-mediated ring closure approach to (+)-preussin.

57

58

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

(a) Boc NH OTBS R (R = C9H19-n)

Pd(OAc)2 DPE-Phos

R

(b)

Boc N Bn

Me

Me O

Pd(0)

CO2Et

NH

PhBr, NaOt Bu toluene, 90 °C 62%

OTBS

CO2Et

N

Z (46)

dr > 20:1

OH

Z (47)

Scheme 2.16 Wolfe’s Pd-catalyzed carboamination approach to preussin and Pd(0)-catalyzed amidation of allylic epoxide.

Pd(0)-catalyzed ring opening of allylic epoxide 46 yielded 47 and its diastereomer in 90:10 ratio (Scheme 2.16b) [37]. The intramolecular iodosulfonamidation of 48 was achieved by treating with Na2 CO3 and I2 under biphasic conditions, which afforded 2,5-trans-pyrrolidine derivative 50 as the major diastereomer (Scheme 2.17) [30]. This approach complements that by intramolecular aza-Michael reaction (Scheme 2.13) [30] in terms of diastereoselection. Taking advantages of the 5-endo-trig iodoamidation reaction developed by Knight [38], ﬂexible approaches to 2,5-dialkylpyrrolidines [39] and anisomycin (1) [40] were developed [40]. In the synthesis of anisomycin (1), the 4-iodopyrrolidine 53 was converted efﬁciently to pyrrolidinediol 54 by a Woodward–Pr´evost reaction (Scheme 2.18). The osmium-catalyzed oxidative cyclization of aminoalkenes developed by Donohoe exhibits notable stereospeciﬁcity (syn-addition across the tethered alkene) and stereoselectivity with exclusive formation of cis-2,5-disubstituted pyrrolidines (Scheme 2.19) [41]. Borhan and coworkers developed a tandem aza-Payne/hydroamination reaction– based approach to tetrasubstituted pyrrolidines. The starting material was synthesized by addition of alkynyl Grignard reagent to 2,3-aziridinal, which gave the aziridinol 55 in high syn-selectivity. Treatment of the syn-aziridinol 55 with base led, O

O

I2, K2CO3 Et2O, H2O

O NH

CO Me SO2Ph 2 (48)

O

71%

Ni2B 86%

O

O OMe + N SO2Ph X 4:96 (49) X = I (51) X = H

O

O

OMe N SO2Ph X (50) X = I (52) X = H

Scheme 2.17 Intramolecular iodosulfonamidation approach to 2,5-trans-pyrrolidines.

O PMP Pf

NH

BH3 SMe2 91%; Ac2O

AcO

PMP OR

I

I2 Pf

NH

90%

HO

OH

AgBF4

N PMP Pf

LiAlH4

(53) Scheme 2.18 Park’s approach to anisomycin (PMP = para-methoxyphenyl).

N PMP Pf (54)

2.1 Monocyclic Pyrrolidines and Pyrrolidinones O

5 mol% K2OsO2(OH)4 0.75 equiv. citric acid

HO

HO PNO, TFA, H2O acetone, 40 °C 90%

BnO2CHN H > 95% ee

O

H

N

H OH CO2Bn

> 95% ee

Scheme 2.19 Synthesis of cis-2,5-disubstituted pyrrolidines by osmium-catalyzed oxidative cyclization of aminoalkenes.

Ts N

BnO

OH −

Ts − N

O + S

BnO

BnO O

DMSO

Me (55)

Ts N

Me

Me

O (56)

Scheme 2.20 Borhan’s tandem aza-Payne/hydroamination reaction–based approach to tetrasubstituted pyrrolidines. DBU (PhO)2P(O)N3

Ar

OH (57)

90%

Ar

B(C6H11)2

N3 Ar (58)

85%

R N B− + N R N

Ar

N H (R )-Nornicotine

(Ar = 3-Pyridinyl; R = Cyclohexyl)

Scheme 2.21 Synthesis of pyrrolidines by intramolecular hydroboration–cycloalkylation.

via successive aza-Payne rearrangement and hydroamination, to epoxypyrrolidine 56 (Scheme 2.20) [42]. The intramolecular hydroboration–cycloalkylation of azido-oleﬁns affords an attractive method for the synthesis of pyrrolidines [43, 44] because of the easy availability of the precursor. As shown in Scheme 2.21, the unnatural (R)-nicotine was synthesized in four steps with an overall yield of 51%. The starting (S)-homoallylic alcohol was obtained in 86% yield with 94% ee by asymmetric allylation. Scheme 2.22a shows a general method for the synthesis of ketimine-type iminosugars, based on the tandem Grignard reagent addition/cyclization reaction of methanesulfonyl glycononitriles, which are easily available from sugars [45]. In recent years, several catalytic asymmetric hydroamination methods have been developed. For example, chiral phosphoric acid diesters [46] and binaphthylamido ytterbium ate complexes [47] were shown to be effective catalysts for the intramolecular hydroaminations of nonactivated alkenes (Scheme 2.22b). (a) BnO NC MsO

OBn OBn

CH3MgBr PhMe, 70 °C 55%

BnO H3C

OBn N

(b) R

OBn

Scheme 2.22 Synthesis of ketimine-type iminosugars and catalytic asymmetric intramolecular hydroamination.

R NHR′

R

Chiral catalysts

R Me

N R′

59

60

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

(a) Boc

NH

O

O

O

Rh2(OAc)4

P(OMe)2

R N2

CH2Cl2, 35 °C R 65–88% from (59)

Boc (60)

(59) X = P(O)(OMe)2

O

R′

N Boc

(61) (b)

(c)

(61) X = CO2Me O hv, PhH Oallyl R

P(OMe)2

N

O

LiCl, DBU R′-CHO; 69–70% R Pd/C, H2 85%

O

N

Pd(PPh3)4

R

Morpholine THF, rt

Boc

OH

(a) [RuCl2(p -cymene)]2 (1 mol%), MeOH, rt, O

N

(b) NaBH4, MeOH; (c) TFA, rt 87%

Boc (63) (94–99% ee)

Ph

CO2Me

N H (62)

Scheme 2.23 Synthesis of 3-oxopyrrolidines via N–H insertion and 2-oxopyrrolidines via the Wolff rearrangement.

Metal carbenoid N–H insertion constitutes a particular method for the formation of 3-oxopyrrolidine rings (Scheme 2.23). Treatment of the α-diazo compound 59 with 4 mol% of Rh2 (OAc)4 resulted in the formation of 3-oxopyrrolidine phosphate 60, which can be converted into cis-2,5-disubstituted 3-oxopyrrolidines, and cis-2,5-disubstituted pyrrolidines (Scheme 2.23a) [48]. Che reported that [RuCl2 (p-cymene)2 ] is also an effective catalyst for the N–H insertion reaction which, in tandem with sodium borohydride reduction, afforded 5-substituted 3-hydroxyprolinates 62 with good chemical yield and stereoselectivity (Scheme 2.23b) [49]. Wang et al. showed that the reactions of α-diazo compound 61 can lead to either 2-oxo or 3-oxo-pyrrolidine derivatives (Scheme 2.23c) [50]. Under photoinduced conditions, a Wolff rearrangement reaction occurred, leading to the formation of 2-oxopyrrolidine derivatives (63) after subsequent decarboxylation. Divinylcarbinol 64 is a usual prochiral building block for the asymmetric synthesis of pyrrolidines via Sharpless asymmetric epoxidation [51–53]. Aminolysis followed by the reverse-Cope cyclization [54] afford an easy access to substituted pyrrolidine N-oxides 65 (Scheme 2.24) [53]. Denmark developed a chiral auxiliary-induced regioselective asymmetric [4 + 2] cycloaddition of 2-(acetoxy)vinyl ethers with nitroalkenes, which provides an efﬁcient approach to pyrrolidines with a quaternary chiral center (Scheme 2.25) [55a]. Extension of this strategy to asymmetric tandem [4 + 2]/[3 + 2] cycloadditions OH

(64)

D-(−)-DiPT Ti(Oi Pr)4

t-BuOOH, CH2Cl2 −30 °C 51%

OH

BnNHOH HC NaOMe

O MeOH, rt, 72 h 72%

HO

H O

OH N

Bn

HO H3C_

OH + N

O Bn (65)

Scheme 2.24 Synthesis of substituted pyrrolidine N-oxides by the reverse-Cope cyclization.

2.1 Monocyclic Pyrrolidines and Pyrrolidinones −

−

O + O N

H Et + H

Ar (66)

OXc*

O + O N

OXc*

(a) PtO2, H2 160 psl

OAc

(b) TsCl, DBU (c) NaOH

SnCl4

OAc −78 °C 90% (67)

Ar Et (68) (97:3)

Ar

HO

Et Ph

75%

Ph

Xc* =

N Ts 96% ee

OH

Scheme 2.25 Denmark’s approach to 3-hydroxypyrrolidines. Ar = 3,4-dimethoxyphenyl; Ac = acetyl; Ts = p-toluenesulfonyl.

provides a powerful methodology for the synthesis of pyrrolizidine alkaloids such as (+)-macronecine, (+)-petasinecine, and (−)-hastanecine [55b]. 2.1.2.2 Cyclization via C2 –C3 Bond Formation Several methods for the construction of pyrrolidine ring by forming the C2 –C3 bond have been reported. The highly enantioselective SN i cyclization reactions reported independently by Kawabata [56] and Kolaczkowski [57] (69, Scheme 2.26a) involve the extension of the concept of memory of chirality developed by Fuji and coworkers. In Tian’s asymmetric synthesis of dehydroclausenamide, a highly diastereoselective nucleophilic epoxide-opening reaction was used as the key step. When using a 1:1 CH2 Cl2 :H2 O mixture as the biphase solvent, the reaction of 70 provided the lactam 71 as a single product (Scheme 2.26b) [58]. In Fukuyama’s synthesis of (−)-α-kainic acid, a highly stereoselective intramolecular Michael addition reaction was used as the key step (Scheme 2.27a) [59]. The amino-zinc-ene-enolate cyclization developed by Karoyan and coworkers [60] turned out to be a stereoselective method for the synthesis of cis-3-substituted prolinate. The zinc intermediate 73 formed during the reaction can be further (a)

(b) Ph O

Br

EtO2C Bn

KOH EtO2C DMSO

H N Boc (69)

20 °C 90%

Bn

Ph N O

Boc

N Me

Ph 1% Me4NOH CH2Cl2:H2O Ph = 1:1 O 79%

O

N Me

O

(71) (dr = 100:0)

(70)

99% ee

OH

Scheme 2.26 Synthesis of pyrrolidines by SN i reactions.

(a)

O O

Me

O LHMDS, DMF, −60 °C, base 89%

(b)

O Me H

CO2Et ds = 94:6 N Boc

CuCN/2LiCl

H H N CO Et 2 Boc

N

X

LDA, −78 °C; ZnBr2

CO2t-Bu TsCN

Bn (72)

Scheme 2.27 Synthesis of pyrrolidines by intramolecular Michael addition and the amino-zinc-ene-enolate cyclization.

68%

N Bn

CO2t-Bu

(73) X = ZnBr (74) X = CN

61

62

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

functionalized. For example, tandem cyclization–cyanation of 72 gave 74 in good overall yield (Scheme 2.27b) [60]. Recently, Szymoniak reported a novel method for the construction of the pyrrolidine ring via a tandem hydrozirconation-stereoselective Lewis acid–mediated cyclization [61]. By using N-3-alkenylcarbamates as the starting material and replacing Lewis acid by n-butyllithium the above-mentioned concept was applied to the asymmetric synthesis of pyrrolidin-2-ones (Scheme 2.28). 2.1.2.3 Cyclization Involving C3 –C4 Bond Formation Dieckmann reaction of the chiral β-amino ester, prepared by Davies’ asymmetric aza-Michael addition method, was shown to give good regioselectivity through the β-aminoenolate. The use of Weinreb amide served as a better electrophilic component. Similarly, intramolecular Thorpe reaction of a chiral dicyanide also gave good regioselectivity (Scheme 2.29a) [62]. In a synthesis of kainoic acid, the reaction of methylvinyl ketone (MVK) with the Michael donor–acceptor α-amino-α,β-unsaturated eater 75 proceeded smoothly to give the tandem Michael addition product 76 in 90% yield (Scheme 2.29b) [63]. In the synthesis of salinosporamide A (4), an even more effective proteasome inhibitor than omuralide, Corey and coworkers developed two highly diastereoselective syntheses of the highly substituted lactam intermediates via an internal Kulinkovich reaction (Scheme 2.30a) [64], and an internal Baylis–Hilman–aldol reaction (Scheme 2.30b) [65]. In the synthesis of the amino acid moiety of polyoxypeptins A/B, the SmI2 mediated Barbier-type cyclization of iodoketone 77 led to the desired diastereomer in 97:3 (Scheme 2.31a) [66].

R1

Cp2Zr(H)Cl

R2

N

Ph

R1 BF3⋅OEt2 OH (R2 = Ar)

R2

N

O

Ph

Boc ;

Me

Ph O

Cp2ZrCl2 n -BuLi;

N Bn

Ph O

O

H 2O

dr = 4.5:1

N Bn

Scheme 2.28 Synthesis of pyrrolidines/pyrrolidin-2-ones by tandem hydrozirconation–cyclization.

(a)

(b) O

OMe

Me N

O

CO2Me

Bu-n N Boc

O KHMDS, THF −78 °C, 2 min 89%

CO2Me Bu-n N Boc

CO2Et

+ Ph

N H (75)

Scheme 2.29 Synthesis of pyrrolidine derivatives by Dieckmann reaction and tandem Michael addition (KHMDS = potassium hexamethyldisilylamide).

O

CO2Et

TMG, rt

OTBS

N Bn OTBS (76)

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

(a) OH

Me

(b) (a) Ti(Oi-Pr)4 c - C5H9MgCl; I2, −40 °C, 2 h;

TBSO i -Pr MeO2C

N PMB ds > 99:1

O

63

Me H OP

(b) NEt3, CH2Cl2 R MeO2C 85%

RO

O

Quinuclidine Me DMF BnO

O N PMB

(R = TBS, P = Pr-i )

O N MeO2C PMB (R = Bn, P = H) ds > 90:10 90%

Scheme 2.30 Corey’s approaches to the intermediates for the synthesis of salinosporamide A.

(a) I

(b) O

SmI2 HMPA/THF

N

N2 Bn

OH

Ts

OH

Ph

Cat. Rh2(OAc)4

N

N

75%

Ts OH ds = 97:3 (77)

SO2Ph O

CH2Cl2 Reflux, 12 h 91%

O (78)

SO2Ph

H O

N O

(79)

Scheme 2.31 Synthesis of pyrrolidine/pyrrolidin-2-one by radical cyclization and carbene insertion.

Rh-Catalyzed intramolecular carbene C–H insertion of diazo compound 78, derived from α-amino acid in six steps, gave the chiral γ -lactam 79 with high regioand diastereoselectivity (Scheme 2.31b) [67]. In association with the synthesis of kainoids, several useful methods have been developed for the construction of pyrrolidine ring by C3 –C4 bond formation. They include, among others, Oppolzer’s intramolecular thermal type I Ene reaction (Scheme 2.32a) [68], Hoppe’s (−)-sparteine-mediated asymmetric deprotonation–cycloalkylation (Scheme 2.33b) [69], and Ganem’s catalytic enantioselective metallo-ene reaction (Scheme 2.32c) [70].

(a) CO2Et

EtO2C Toluene 130 °C, 40 h 75%

N Boc

Me

(c)

n -BuLi

Boc

OTBS

O N

N

OTBS

Bn

OTBS

L-1

EtO2C

Mg(ClO4)2 rt, CH2Cl2, 2 h O

Ph

Ph

N

N Bn

Me

O

OC(O)NPr i 2

(−)-Sparteine N

OTBS

(b)

OC(O)NPr i 2

Cl

N COPh

72% ds > 20:1

L-1

Scheme 2.32 Three typical approaches to kainoic acid skeleton.

EtO2C

Me O

N COPh

64

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

2.1.3 Cycloaddition Methods 2.1.3.1 Cycloaddition Approach Imidotitanium-alkyne [2 + 2] cycloaddition of aminoalkynes provides an approach to cyclic imines, as used in the asymmetric synthesis of (+)-preussin (15) (Scheme 2.33) [71]. An interesting highly diastereoselective approach to C2/C3 trans-pyrrolidines was developed by Lautens, consisting of a magnesium iodide–mediated ring expansion of methylenecyclopropane 80 in the presence of a chiral sulﬁmine (Scheme 2.34a) [72]. This reaction was applied to a total synthesis of (−)-α-kainic acid (2). Kerr and coworkers reported another one-step synthesis of polysubstituted pyrrolidines by Yb(OTf)3 -catalyzed reaction of oxime ethers with cyclopropane diesters in an inter- or intramolecular manner. By using the oxime ether–tethered cyclopropane diesters, the highly stereospeciﬁc annulation reaction was extended to a wider range of substrates (81, Scheme 2.34b) [73]. The reaction of Z-oxime ethers produce 2,5-trans-pyrrolo-isoxazolidines, whereas E-oxime ethers lead to 2,5-cis adducts. Starting with N-unsubstituted oxime ethers, cis adducts can be obtained in high diastereoselectivity via a three-component reaction. 1,3-Dipolar cycloaddition of azomethines ylides with electron-deﬁcient alkenes (dipolarophile) constitutes a direct approach to 3,4-disubstituted pyrrolidines (Scheme 2.35) [74]. Several molecular motifs can be used to generate the dipoles. For example, aziridines (82) is a class of synthetic equivalents of azomethine ylides, which upon thermolysis, undergo a ring-opening reaction to produce the corresponding N-substituted azomethine ylides (83) [75]. Azomethine ylides, generated in situ from imino esters, are another class of chiral 1,3-dipoles that can react with electron-deﬁcient alkenes with good diastereomeric control (Scheme 2.36). In Scheme 2.36, a large-scale catalytic asymmetric CpTi(CH3)2Cl n- C7H15 25 °C;

OBn

Bn n-C7H15COCN

H 2N

THF, 25 °C

NC

OBn

OBn (a) CH3OTf

Bn (b) NaBH3CN

N

n- C7H15 Bn N Me

NC

81%

Scheme 2.33 Imidotitanium-alkyne [2 + 2] cycloaddition approach to (+)-preussin. (a) Tol

N +

(80)

(b)

O

O S

Ar O

THF, reflux 78%

N S

ds > 20:1 Ar = p -MeOC6H4

O

NPh2

N

NPh2

MgI2

Ar Tol

O

Yb(OTf)3 81–99%

trans:cis = 8:1 to 100:0

R MeO2C (81)

CO2Me

Scheme 2.34 MgI2 -mediated ring expansion of methylenecyclopropane and annulation of oxime ethers with cyclopropane diesters.

O N R

H

MeO2C CO2Me

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

(a)

(b)

R5

R1

R4

R5

R4

Bn N

+ + − R3 N R2

R1

N R2

R3

O

Bn

X NX

∆

+N

O S (82) O

X X

O

N O S O (83)

−

Scheme 2.35 1,3-Dipolar cycloaddition approach to pyrrolidines and the generation of an azomethine ylide from a chiral aziridine.

Pr-i N

t-BuO

N S

O

t-BuO

−

Pr-i

+

i -Pr t-BuO O

OMe N

N H

OMe N

i -Pr HO

S

dr > 99:1; er = 87:13

S

M

O

CO2Me

N

N O

Hydroquinine (6 mol%) AgOAc (3 mol%)

N

O

S

O

(84) er = 99.9:0.1

Bu-t OMe

Scheme 2.36 1,3-Dipolar cycloaddition of the α-amino azomethine ylides generated from α-amino imines.

[3 + 2] cycloaddition of methyl acrylate and the N-metalated azomethine ylide for an asymmetric synthesis of an inhibitor of HCV polymerase (84) are outlined [76]. The alkaloid plays the roles of both a chiral ligand and as a base for the formation of the azomethine ylide or 1,3-dipole. Starting from the chiral auxiliary-induced asymmetric [3 + 2] cycloaddition, Garner and coworkers developed an imaginative [C+NC+CC] reaction, which provides a highly efﬁcient and ﬂexible approach to highly functionalized pyrrolidines in a single operation and under mild conditions. In this context, Ag+ -catalyzed asymmetric three-component reaction using Oppolzer’s L-camphor sultam as a chiral auxiliary provides a reliable means to control the endo-selective [3 + 2] cycloaddition, leading to 4,5-cis disubstituted pyrrolidines (Scheme 2.37) [77], while CuI -catalyzed reaction allows an access to 4,5-trans disubstituted pyrrolidines [78]. The methods involve a cascade imine formation, azomethine ylide formation, and 1,3-dipolar cycloaddition sequence. EWG XLOC

N H

R

Cat. Ag1 THF, rt R

+ CHO "C"

H2N

I H Cat. Cu + ligand COXL/D H DMSO, rt C C C + H H2 EWG XLOC

"NC"

"CC"

(XL = Oppolzer’s L-camphorsultam)

Scheme 2.37 Garner’s stereocomplementary asymmetric ‘‘2 + 2 + 1’’ approaches to proline derivatives.

EWG N H

R

65

66

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

Recently, this concept was extended to an organocatalytic version. The protected diphenylprolinol-catalyzed, enantioselective, three-component coupling between aldehydes, dialkyl 2-aminomalonates, and α,β-unsaturated aldehydes gives access to highly substituted pyrrolidines in good yield with >10:1 diastereoselectivity and 90–98% ee (Scheme 2.38) [79]. 2.1.3.2 Annulation Approach Pyrrolidines and pyrrolidine-2-ones can be synthesized by nucleophilic ring opening of optically active aziridines in a [3 + 2] annulation manner [80]. Reaction of conﬁgurationally stable alkoxy allenylzinc reagent 85 with the imine derived from (S)-malic acid furnished a route to pyrrolidin-2-one 86 with anti–anti stereochemistry (Scheme 2.39) [81]. A novel [4 + 1] annulation method for the efﬁcient synthesis of diastereomerically and enantiomerically pure 2,3-disubstituted pyrrolidines is shown in Scheme 2.40. The method involves a sulfoxoniumylide-based aza-Payne rearrangement of the 2,3-aziridin-1-ols and the subsequent [1 + 4] annulation reaction [82]. Lewis acid–catalyzed [3 + 2] annulation [83] of optically active N-Ts-α-amino aldehydes and 1,3-bis(silyl)propenes opens another one-step access to polysubstituted pyrrolidines in excellent diastereoselectivity (98:2). The conversion of the silyl group into a hydroxyl group by Tamao oxidation allows the total synthesis of polyhydroxylated alkaloids (Scheme 2.41) [84].

O

Ph Ph EtO C 2 OTMS

N H

CO2Et NH2

Cat.2

R1

+

+ R

Cat.2 (20 mol%)

O

H

H

O R

H

CO2Et CO2Et N H dr = 4:1 to >10:1 90 – 98% ee

Tol. or CHCl3, rt Et3N (1 equiv.) 51–63% yield

R1

Scheme 2.38 Organocatalytic, three-component synthesis of highly substituted pyrrolidines.

TBSO H

ZnBr SiMe3

MOMO

+

(85)

MeO2C

OMOM

OTBS H 86%

0.25 equiv. NBn

SiMe3 N Bn (86) dr > 40:1; ee > 95% O

Scheme 2.39 Normant’s [3 + 2]-annulation approach to substituted pyrrolidin-2-ones.

Ts N R

Base Aza-Payne OH rearrangement

TsHN R

−

O

O S

NTs

O

HO

S +

R OH

R

Scheme 2.40 Borhan’s [4 + 1] annulation approach to 2,3-disubstituted pyrrolidines.

N Ts

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

O SiMe2Ph

R

+ SiMe2Ph

H NHTs

HO

MeAlCl2 CH2Cl2

R

−78 °C

HO

SiMe2Ph

OH

N

N

dr > 98:2

SiMe2Ph

Ts

OH

OH

Ts

Scheme 2.41 Synthesis of substituted pyrrolidines via a Lewis acid–catalyzed [3 + 2] annulation.

2.1.4 Ring Transformation Methods 2.1.4.1 Ring Expansion Methods In a formal synthesis of (−)-anisomycin (1), Somfai et al. showed that microwaveassisted rearrangement of vinylaziridines provides an easy access to 3-pyrrolines (Scheme 2.42) [85]. The β-lactam skeleton has been recognized as a valuable precursor for the synthesis of pyrrolidine-2-ones via ring expansion [86]. For example, upon treatment of N-unsubstituted 4-(α-aminoalkyl) β-lactam with methanolic HCl at 60 ◦ C for 2–24 h, the expected rearrangement occurred smoothly to give the pyrrolidine-2-one bearing four contiguous chiral centers in almost quantitative yield. The starting β-lactams are easy available via the Staudinger reaction (Scheme 2.43) [87]. Using Tamura’s Beckmann reagent, O-(mesitylenesulfonyl) hydroxylamine (MSH), Greene et al. developed a chiral auxiliary-induced, regio-controlled cyclobutanone → pyrrolidinone ring expansion reaction. This, after dechlorination with zinc–copper coupling, led to cis-pyrrolidin-2-ones in high yields (Scheme 2.44). Using this strategy, they accomplished the total syntheses of pyrrolidine alkaloids (+)-preussin (15) [88a], (−)-anisomycin (1) [88b], and (−)-detoxinine [88c].

OH

CHO Ar

NTs Ar

NH2

Ar

LiI, MW 200 °C 10 min 92%

N Ar

Ts

O

NIS, HClO4 THF-H2O 50%

Ar

(Ar = p -MeOC6H4)

N Ts

Scheme 2.42 Microwave-assisted rearrangement of vinylaziridines to 3-pyrrolines en route to (−)-anisomycin.

Boc

Boc BnOCH2COCl + Bn

N

N

O Ph

BnO H H O

N

N

O Ph

Bn

3 M HCl in MeOH BnO 60 °C, 24 h 99%

O

NHBn OH N H

Scheme 2.43 Ring expansion of β-lactam derivatives to pyrrolidine-2-one derivative.

Ph

67

68

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

Cl

H R* =

CH3

Cl

• O

Cl + *RO

O

Cl *RO

R

*RO

Tamura's reagent

R

Zn/Cu, H+

R

O

N H

Scheme 2.44 Greene’s synthesis of cis-4,5-disubstituted pyrrolidin-2-ones by cyclobutanone ring expansion.

2.1.4.2 Ring Contraction Methods Although rarely used in pyrrolidine syntheses, the carbene ring contraction– decarboxylation of (2R,3S)- and (2S,3R)-6-diazo-3,4-dimethyl-2-phenyloxazepane5,7-diones opens an easy regiospeciﬁc entrance to (S)- and (R)-1,5-dimethyl-1-4phenyl-1,5-dihydro-2H-pyrrol-2-ones in enantiomeric pure forms (Scheme 2.45) [89]. Chiral auxiliary-induced, diastereoselective hetero-Diels-Alder reaction of nitroso derivatives and the subsequent reductive ring contraction of the resulting 1,2-oxazines under catalytic hydrogenolytic conditions constitutes a useful approach to dihydroxypyrrolidines (Scheme 2.46) [90]. 2.1.5 Substitution of Already Formed Heterocycle

A number of approaches are available for the functionalization of a pyrrolidine/ pyrrolidin-2-one ring at C-2 because of its presence in many alkaloids, including pyrrolidines, pyrrolizidines, and indolizidines alkaloids. Hence, the synthesis of 2-alkyl and 2,5-dialkyl pyrrolidines has attracted much attention [91]. Ph

Ph

O

O

Me H

TsN3, NEt3 MeCN, rt, 24 h 85%

N

Me

O Me H

N

CH2Cl2, rt

N2

Me

O

Cu(OTf)2 or Rh2(OAc)4

O

- N2

O

Ph H Me

- CO2

O

N

Me 100% ee

95%

Scheme 2.45 Regiospeciﬁc ring contraction of oxazepane-5,7-dione to α,β-unsaturated pyrrolidin-2-one derivatives.

Xc*

Xc*

+ 1

R

Xc*

O

N

O N

CO2Bn R

1

O CO2Bn

O 1

O

H2, Pd/C

N

or H2, Ra-Ni

CO2Bn

R

O

O R1

N CO2Bn

Scheme 2.46 Stereoselective access to dihydroxylated pyrrolidines by reductive ring contraction of 1,2-oxazines.

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

69

With Seebach’s SRS methodology (self-regeneration of stereochemistry), singleenantiomer proline and pyroglutamate may serve as reliable chirons for the generation and reaction of pyrrolidine α-carbanions [92]. It was shown that the alkylation of the enolate proceeds cis with respect to the tert-butyl group (‘‘cis rule’’), with overall retention of conﬁguration. For example, in the ﬁrst total synthesis of kaitocephalin, the condensation of 87 with 89 led only to cis adducts 90 (Scheme 2.47) [93]. In contrast, the MgBr2 •OEt2 -mediated conjugate addition of the silyl enol ether, formed in situ from the N,N-acetal 88, with a nitrooleﬁn resulted in a 10:1 mixture of two trans diastereomers 91. The major diastereomer 91 was used as a key intermediate for the synthesis of the marine alkaloid (−)-amathaspiramide F [94]. tert-Butoxycarbonyl (Boc) is an efﬁcient group for the stabilization of α-amino carbanions. The deprotonation of N-Boc-pyrrolidin-3-ol 92 occurred regioselectively at C-5. The reaction of the resulting dianion with electrophiles yielded a 1:1 diastereomeric mixture in each case tested except with methyl iodide (dr = 5:1) (Scheme 2.48) [95, 96]. The SmI2 -mediated reaction of the N,O-diprotected 2-pyridyl 3-pyrrolidinol-2-yl sulﬁde 94 with carbonyl compounds affords the protected N-α-hydroxyalkyl-3-pyrrolidines 95 with excellent diastereoselectivity at the newly formed chiral center in the pyrrolidine ring [97]. Asymmetric alkylation of the β-hydroxyproline ethyl ester N-carbamate, prepared by enantioselective reduction of 96 with Baker’s yeast, was shown to proceed with net retention of conﬁguration. By developing this method, Williams et al. achieved a total asymmetric synthesis of paraherquamide A (Scheme 2.49a) [98].

Cbz

N

O dr = 2:3

LDA, THF −78 °C Cbz

OH O

N

X t-Bu (87) X = O (88) X = NMe

N O

OHC

(89)

O (90)

t-Bu

O

N

51%

dr = 10:1

t-BuLi, HMPA THF, −78 °C to rt TBSCl, 0 °C;

H

Ar

O

Ar MgBr2 OEt2

S

N

72% (Ar = 2,4-2Br-5-MeOC6H2)

NMe

t-Bu (91)

Scheme 2.47 Syntheses of proline derivatives with Seebach’s SRS methodology. HMPA = hexamethylphosphoramide and TBSCl = tert-butyldimethylsilyl chloride.

OH

N Boc (92)

OH

s -BuLi (2.2 equiv.) THF-TMEDA −78 to −46 °C, 2 h; electrophile 37–65%

E

N Boc (93)

TBSO 2-PyrS

NO2

NO2

R1R2CO SmI2 /THF rt, 10 min 50–92%

TBSO OH

N N R2 Boc Boc (S )-(94) (95) ca. 100% trans -selectivity

Scheme 2.48 Synthesis of 5- or 3-substituted pyrrolidin-3-ols via the pyrrolidine C-2 carbanion intermediates. TMEDA = N,N,N , N -tetramethyl-1,2-diaminoethane.

R1

70

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles (a)

HO

EtO2C

R

O

Baker's yeast 80%; >90% ee;

N Boc

LDA, THF, RX 49–73% (from 96)

(>90% ee)

R2 OH

Chiral catalyst (1 mol%) R1Br (1.2 equiv.)

N

R′O2C

Sat. K2CO3, o -xylene 84–99% (from 97); R2M

Boc (96) R′ = Et, bH; (97) R′ = Bu-t

(b)

CO2Bu-t R1 Boc (87 – 95% ee) N

Scheme 2.49 Syntheses of substituted 3-hydroxyproline derivatives by alkylation.

A phase-transfer-catalyzed alkylation strategy developed by Maruoka provides an efﬁcient and high-yielding approach to another diastereomer and its derivatives (Scheme 2.49b) [99]. Beak and coworkers showed that enantioselective deprotonation (lithiation) of N-Boc-pyrrolidine (98) can be achieved using sec-BuLi/(−)-sparteine (L-2). The carbanion thus generated (100, α-Li) reacts with electrophiles to give 2-substituted pyrrolidines with high enantioselectivities (Scheme 2.50) [95, 100]. The unnatural ligand L-3 developed by O’Brien allows access to another enantiomer of the 2-substituted pyrrolidines [101]. Coldham’s ligands L-4/L-5 afford a highly enantioselective dynamic kinetic resolution pathway of the racemic organolithium 100, derived from 98 or 99 by deprotonation or by tin–lithium exchange [102]. Gawley showed that the tin–lithium exchange of enantioenriched 2-stannylpyrrolidine 99 affords conﬁgurationally stable 2-lithiopyrrolidine 100 with retention of conﬁguration [103]. Through the reaction sequence displayed in Scheme 2.51, tetramate derivative 101 turned out to be a valuable synthetic equivalent of the 4-hydroxypyrrolidin-2-one 2-carbanion synthon, which is used for the synthesis of pyrrolidin-2-ones 102 [104]. Me

H

N

N

s-BuLi E (−)-Sparteine (L-2) N Et2O, −78 °C Boc Boc E+ (98) X = H 83–100% yield; er = 95–98% (99) X = SnBu3 (100) X = Li

OH

N

H H N

N

Me (−)-Sparteine (L-2) 96 – 97% ee (S )

X

N

N

(L-3) L-4. a-H 90 – 94% ee (R ) L-5. b-H

E+ = TMSCl, Me2SO4, Bu3SnCl, Ph2CO

Scheme 2.50 Methods for the generation and reaction of conﬁgurationally stable enantioenriched N-Boc 2-lithiopyrrolidine. HO t-BuLi, THF, HMPA, −78 °C;

N

Et Et

O

Me (S )-101

N PMB

O

RX 69–85%

Et Et Me

H+;

N

NaBH4

O

R

> 97% de

N

R

O

PMB

Scheme 2.51 A ﬂexible approach to cis-5-alkyl-4-hydroxypyrrolidin-2-ones.

N PMB (102)

O

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

2.1.5.1 By Nucleophilic Reaction of Pyrrolidinium Ions Because of its double functionality and easy availability, (S)-pyroglutamic acid is a versatile useful chiron (Scheme 2.52) [105] for the asymmetric synthesis of 2,5-disubstituted pyrrolidines [106], pyrrolizidines [107], and indolizidines [108]. Both the lactam carbonyl and carboxyl groups in pyroglutamic acid can be employed to introduce side chains. Elongation of the carboxyl group can be achieved by reduction to a hydroxymethyl group followed by tosylation and coupling with an organocopper reagent [106, 107], or by transformation into a formyl group, followed by Kocienski’s modiﬁcation of Julia oleﬁn synthesis [108]. The amide carbonyl can be used to install a second alkyl group via the corresponding thiolactam by Eschenmoser sulﬁde contraction reaction [109], via enamino diester derivative [106, 107], or via thioimidate derivative [106]. A more versatile method for the activation of lactams consists in converting lactams into the corresponding N-carbamates (imides). After their regioselective partial reduction with diisobutyl aluminium hydride (DIBAL-H) or Super hydride, they are converted into N,O-acetals and subjected to Lewis acid–promoted α-amidoalkylation with lower order organocuprates (107 → 112, Scheme 2.53) [110] or with Si-nucleophiles (110 → 113) [111]. The latter reaction can also be achieved by Ley’s sulfone chemistry [112] (108 → 112) [113]. Martin’s improvements over the stepwise reductive alkylation method [114] provides a general and highly chemoand diastereoselective reductive alkylation (114 → 115, Scheme 2.54) [115]. It is well recognized that the α-aminoalkylation passes through N-acyliminium ion intermediates [116]. H H Reductive alkylation O

Depprotonation O

H N

CO2H

H Pyroglutamic acid (103)

CO2Me/Et

N

Reduction Chain elongation LiBHEt3 or DIBAL-H 95%

RO

N O

Boc (105a) (105b), ∆

O (109a) (109b)

TFAA, DIPEA cat. DMAP

Alkylative S -contraction X S

O

N

CO2Bu-t

Bn (104)

N

CO2Me/Et

N

N O O (110) R = Me, Et

CO2Me

Boc (111)

Boc (106) X = OH (107) X = OMe, OEt (108) X = SO2Ph

Scheme 2.52 Conversion of pyroglutamic acid into useful synthetic intermediates. 89%

(107) (108)

TiCl4, CH2Cl2, −78 °C Allyltrimethylsilane;

MeCu F3B · OEt2 15–93% MeZnCl

R

CO2Me N Boc (112)

(110)

trans:cis = 9:1 (from 107) 100% trans (from 108)

or TMSOTf for TMSCN, (113) Silyl enol ether 43–95%

Scheme 2.53 Summary of the stereoselective α-amidoalkylation of the N,O-acetals derived from (S)-pyroglutamic acid.

Nu

N O O

trans:cis = 93:3 to ca.100:0

71

72

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

O

N Cbz

CO2Me

CO2Me BF3 OEt2, Ph3SiH

C4H7MgBr TMEDA

CH2Cl2, −78 °C→rt

THF, −78 °C 73%

O

NH Cbz

CO2Me

N

99%

Cbz

(114)

(115)

Scheme 2.54 Martin’s modiﬁed reductive alkylation method.

R

LiAlH4, AlCl3 75 – 95% (from 116);

N

HO Ph (118)

H O

N

Me (121)

O

TiCl4 Nucleophile

R O

LiBHEt3 (from 117); ds = 100%

X

N

85 –94% (from 116)

Ph (116) X = O (117) X = 2H

SiMe3

p -Xylene, TiCl4 92% dr = 8.7:1

O

N

Me HO

R O

R Nu HO

N

O Li /NH3(l )

65 – 93% Ph (Nu = H; allyl, 5:1) (119) SiMe3 or N N

(122)

Silyl enol ether OMe

R

O N H (120)

R

N

O

N

Nu

dr = 80:20 to 96:4

Scheme 2.55 The α-amidoalkylation reactions of Meyers’ and Kibayashi’s chiral N,O-acetals.

A simple asymmetric synthesis of 2-substituted pyrrolidines (116 → 118, Scheme 2.55) [117] and 5-substituted pyrrolidin-2-ones (116 → 119) [118] starting form γ -keto acid and (R)-phenylglycinol was developed by Meyers et al. [119]. This method was extended to the (R)-phenylglycinol-derived bicyclic 1,3-oxazolidine 117 [120]. The N,O-acetals bearing easily cleavable chiral auxiliaries 121 [117] and 122 [121] were developed by Kibayashi et al. and were shown to give good stereoselectivities in the α-amidoalkylation. Except one case [122], retention of conﬁguration was observed in the above-mentioned reactions. The α-amidoalkylation of N,O-acetals 123 [123], 125 [124] and 126 [125] with trimethylallylsilane and silyl enol ether give the corresponding products with excellent trans diastereoselection (Scheme 2.56). By contrast, the reactions of O-TBS-protected N,O-acetals derived from tartaric acid (124) [126], malic acid [127], and related compounds [128] were shown to give good-to-excellent cis diastereoselectivities. The α-amidoalkylation of N,O-acetals 127 [129], 128 [130], and 129 [131] and also the borono-Mannich reaction of 131 [132] with more ﬂexible carbon nucleophiles are trans-diastereoselective (Scheme 2.57). By contrast, reactions of O-acetyl-protected N,O-acetals derived from tartaric acid (130) [133] give cis diastereomers as major products. 2.1.5.2 By Nucleophilic Reaction of Cyclic Imides Results from Yoda’s laboratory [134] show that the reductive alkylation of the C2 -symmetrical tartarimides is a better alternative to the α-amidoalkylation reaction displayed in Schemes 2.56 and 2.57 both in terms of chemical yields and in trans-diastereoselectivities (Scheme 2.58a) [134a]. They applied this method to the

2.1 Monocyclic Pyrrolidines and Pyrrolidinones AcO

R Me3Si

AcO

O

N Bn (123)

O

TBSO

AcO

TBSO SnBu3

OTBS

R O O

N

CH2Cl2

Bn R = H, BF3 OEt2, dr = 71:29 R = Me, BF3 OEt2, dr = 11:1, 95% HO

OCOH

OAc

N

O

OCOH

Bn

N

CO2Bn

BF3 OEt2 CH2Cl2

Bn

N

Bn dr = 21:1

O

O

t-Bu

MeO

BF3 OEt2 CH2Cl2, 20 h

O

N

CO2Bn

PMB

dr > 95:5

(125)

N

OSiMe3

O

Me3Si O

O

MgBr2 100%

Bn (124)

OTBS

O N PMB COBu-t

70% Single diastereomer

(126)

Scheme 2.56 α-Amidoalkylation reactions of the chiral pool-derived N,O-acetals. MOMO

OMOM

MOMO

P2O

P2O

OMOM

RMgBr

ArCH2MgCl MeO

N

Ph O (127) AcO O

Et2O, reflux 90% Ar = p-MeOC6H4

Bn (130)

Ar H dr = 65:1

PhO2S

N

O

1

ZnCl2 65%

P (128) P1 = i- Pr, P2 = Ac (129) P1 = P2 = Bn

OAc

N

N

BF3 OEt2

AcO

OAc

RBF3K O R N 65–87% Bn R = Ar, alkynyl dr = 70:30–90:10

OAc

BnO R

Bn

45% BF3 OEt2 Et3SiH

(131)

83%

N

O

O

N

P1 dr = 80:20 dr = 67:33 – 83:17

RB(OH)2 BF3 OEt2;

BnO HO

R

N

O

Bn dr = 91:9

Scheme 2.57 α-Amidoalkylation reactions of chiral pool-derived N,O-acetals with organometallic compounds.

asymmetric synthesis of the pyrrolidine alkaloid codonopsinine (22) [134b]. Pilli et al. showed that the Grignard addition products, N,O-acetals 133, can undergo an α-amidoallylation with allyltributyltin leading to the formation of a quaternary stereocenter [135a]. Regioselectivity in the reductive alkylation of the protected malimides [136] was shown to be dependent on the protecting group [136b]. Moreover, the reaction of the O-benzyl-protected malimides with Grignard reagents gives excellent C-2 regioselectivity [136], while addition of organocerium reagents affords C-5 adducts as the major products (Scheme 2.58b) [135b]. In both cases, subsequent reductive dehydroxylation reactions give excellent trans diastereoselectivities. Unexpectedly, the reaction of malimides with organotitanium reagents gives only modest regioselectivity [137]. The intramolecular Wittig reaction of a malimide derivative followed by stereoselective hydrogenation was used as key steps in a highly regio- and diastereoselective synthesis of the Geissman–Waiss lactone (Scheme 2.59) [138].

73

74

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

(a) TBSO

TBSO

OTBS

OTBS F B · OEt 3 2 OH Et3SiH or

R1Li or

O

O N Bn (132)

O

R1MgX

R1

N Bn

TBSO

OTBS

TBSO

R1

O

+

O

Bu3Sn

N Bn

R2 N R1 Bn (R2 = allyl) (R2 = H)

X

(133)

(b)

O

BnO

BnO

BnO O N P (S )-134

HO R

RM

N P (135)

RMgX or ArLi or Li-enolates n -BuLi, THF RMgX, ClTi(Oi -Pr)3 RMgX, CeCl3 (OBn/OTBS)

O

+

R O

N P

Et3SiH BnO F3B ·OEt2

BnO +

OH −78 °C -r.t. R

R N P (4S,5S )-138

O

O N P (4S,5R )-137

(136) C2:C5 adducts ≥ 94:6 C2:C5 adducts = 58:42 C2:C5 adducts = 1:2 C2:C5 adducts = 1:2.7 – 0:100

OTBS

trans:cis = ≥94.5:5.5

trans:cis = 60:20–97.5:2.5

(P = Bn, PMB, PMB: p -Methoxybenzyl) Scheme 2.58 The stepwise reductive alkylation of tartarimides and malimides.

O

O O

N

O OPiv

PPh3

O O

O

O H2, Rh/Al2O3

N OPiv

EtOAc 99%

O

O

N OPiv

Scheme 2.59 A highly regio- and diastereoselective synthesis of the Geissman–Waiss lactone.

2.1.5.3 By Nucleophilic Addition/Cycloaddition of Pyrrolidine Nitrones Enantioenriched pyrrolidine nitrones [139] are versatile building blocks for the asymmetric synthesis of pyrrolidines, pyrrolizidines, and indolizidines through nucleophilic addition [140] and 1,3-dipolar cycloaddition [141]. Pyrrolidine nitrones can be prepared by intramolecular condensation of a hydroxylamine with a carbonyl group or by oxidation of cyclic hydroxyamines, amines, and imines available from chiral pools such as tartaric acid, malic acid, and sugars. For the synthesis of nitrones from unsymmetric N-hydroxypyrrolidines, such as those derived from malic acid, regioselectivity may be a problem. Fortunately, oxidation with yellow HgO was reported to give good regioselectivities (Scheme 2.60a) [142]. The environmentally friendly oxidant, bleach, gives only modest regioselectivities [143]. Catalytic oxidation of preformed imines by methyl trioxorhenium/urea hydrogen peroxide (Scheme 2.60b) eliminates the problem of regioselectivity [144], which is also the case by decarboxylative oxidation of α-amino acids (Scheme 2.60c) [145].

2.1 Monocyclic Pyrrolidines and Pyrrolidinones X

(a)

X

X +

N

N+ O−

OH

(b)

N+ O−

OTBS

(c) OTBS

Urea–H2O2 N

a. X = OCH2CH=CH2, C2/C5 ratio = 9:1 b. X = OBu-t, C2/C5 ratio = 9:1 c. X = OTBS, C2/C5 ratio = 12:1 d. X = OCOPh, C2/C5 ratio = >20:1 e. X = NBn2, C2/C5 ratio = 4:1

CH3ReO3 (cat.) 97% OTBS

N+ O−

H N H

OTBS

CO2H

H2O2, Na2WO4 (cat.) Et4NCl (cat.), K2CO3 CH2Cl2-H2O

+ N O−

Scheme 2.60 Regioselective synthesis of chiral, nonracemic, unsymmetric nitrones.

(a)

X

X N+ O−

N OH

X +

N+ O−

(b) CH3ReO3 (cat.) 97%

OTBS

OTBS

(c) OTBS

Urea–H2O2

N

a. X = OCH2CH=CH2, C2/C5 ratio = 9:1 b. X = OBu-t, C2/C5 ratio = 9:1 c. X = OTBS, C2/C5 ratio = 12:1 d. X = OCOPh, C2/C5 ratio = >20:1 e. X = NBn2, C2/C5 ratio = 4:1

N+ O−

H OTBS

N H

CO2H

H2O2, Na2WO4 (cat.) Et4NCl (cat.), K2CO3 CH2Cl2-H2O

+

N O−

Scheme 2.61 Stereoselective Grignard addition to nitrones.

Stereoselection in Grignard additions to nitrones is substrate and reagent dependent. While the addition of benzylic Grignard reagents to nitrone 139 gave a 3:2 trans/cis selectivity, a 3:7 ratio was obtained by using magnesium bromide etherate as an additive (Scheme 2.61) [146]. The vinylation of nitrone 140 was shown to be entropy-controlled: a 93:7 trans/cis diastereomeric ratio was obtained independent of the reaction temperature [147]. Similarly, ZnI2 -promoted reactions of ketene t-butyldimethylsilyl methyl/t-butyl acetals with nitrone 141 gave excellent trans diastereoselectivities [148]. The structural similarity between nitrone 142 and alkaloids radicamine A (143), radicamine B (144), as well as codonopsine and codonopsinine (22) justiﬁes consideration of the former as the chiron for the synthesis of radicamines A and B. Indeed, starting from nitrone 142, derived in seven steps from d-xylose, the antipodes of (+)-radicamine A and (+)-radicamine B were synthesized as the sole diastereomers respectively (Scheme 2.62) [149]. Similarly, (−)-codonopsine was synthesized from l-xylose [150]. Nitrones are excellent 1,3-dipoles for cycloaddition and, after cleavage of the N–O bond, can be used to introduce side chains at C-2 of pyrrolidine ring. The asymmetric total synthesis of marine natural product crambescidin 359 (145) nicely demonstrates the value of nitrone cycloaddition methodology for the asymmetric synthesis of pyrrolidines (Scheme 2.63) [151].

75

76

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles BnO

OBn

BnO

N+ − O

OBn

THF, 0 °C 89% 80%

H2

Ar

OH

HO

OBn

ArMgBr

ent -143 ent -144

Y

N OH OBn

N Me

X

OH

(X = OMe, Y = OH) (−)-radicamine A (143) (X = OH, Y = H) (−)-radicamine B (144)

(142)

Scheme 2.62 Asymmetric syntheses of radicamines A and B via nitrone intermediates.

(3) Regioselective nitrone formation (4) Diastereoselective reduction H

HO H +

N O−

HO

OTBS

H

H

N O

H

Toluene, 110 °C 67%

H N N + N H O H

OTBS

Me H (1) Regioselective nitrone formation (2) Diastereoselective 1,3-dipolar cycloaddition

X Me Me Crambescidin 359 (145)

Scheme 2.63 Asymmetric synthesis of crambescidin 359 via iterative selective nitrones formation-1,3-dipolar cycloaddition.

2.1.5.4 By Functionalization of 2-Pyrrolines Three approaches are available for the functionalization of endocyclic enecarbamates (cf. Scheme 2.79). Ketene [2 + 2] cycloaddition with endocyclic enecarbamate 146, developed by Correia showed a 1:4 diastereoselectivity. An meta-chloroperoxybenzoic acid (CPBA)-mediated, regioselective Baeyer–Villiger oxidation led to the synthesis of the Geissman–Waiss lactone (147) (Scheme 2.64a) [152]. ` uchi reaction to the chiral 2-substituted 2-pyrroline By applying the Paterno-B¨ 148 derived from pyroglutamic acid, Bach et al. developed a stereoselective

(a) Cl Xc* =

O • O

Cl m -CPBA Cl

Cl

Ph O

N Cyclohexane CO-Xc* Et3N, 40 °C 88% (146)

N CO-Xc*

CH2Cl2 63%

dr = 1:4

(b) C9H19-n N COOMe (148)

H

PhCHO, hn MeCN 53%

O Ph

H

O

Zn-Cu NH4Cl;

H2, Pd(OH)2/C

C9H19-n 81% N COOMe

Scheme 2.64 Synthesis of substituted pyrrolidines via [2 + 2] cycloaddition reactions of endocyclic enecarbamates.

O

N X X = COXc* Geissman–Waiss lactone (X = H) (147) HO

Ph

C9H19-n N COOMe

2.1 Monocyclic Pyrrolidines and Pyrrolidinones

cis-3-hydroxy-2-benzylation of 2-pyrroline 148. The key [2 + 2] photocycloaddition was shown to exhibit an unprecedented facial diastereoselectivity. Taking advantage of this reaction, a short total synthesis of (+)-preussin (15) was achieved (Scheme 2.64b) [153]. 2.1.5.5 By Enantioselective Reactions Catalytic hydrogenation of substituted pyrrole derivatives is a classical method for the synthesis of all-cis-substituted pyrrolidines. A catalytic enantioselective synthesis version of this method has recently been shown to give high enantioselectivities (Scheme 2.65) [154]. Direct asymmetric α-substitution of pyrrolidine carbamates can be achieved by highly regio-, diastereo-, and enantioselective C–H insertion of methyl aryldiazoacetates. Using this method, both monosubstituted and C2 -symmetric 2,5-transdisubstituted pyrrolidines can be synthesized with high enantioselectivities (Scheme 2.66) [155a]. A Rh(II)–Carbenoid mediated, intramolecular C–H insertion reaction affords a short approach to both Geissman–Waiss lactone and the necine base (−)-turneforcidine [155b]. Katsuki found that asymmetric desymmetrization of N-t-butoxycarbonyl-meso-3, 4-isopropylidenedioxy-pyrrolidine 149 can be effected through an enantiotropic selective oxidation using an (R,R)-(salen)manganese(III) complex as catalyst (Scheme 2.67) [156]. 2.1.5.6 By Functionalization at C3 /C4 Positions of Pyrrolidines As shown in Scheme 2.52, pyroglutamic acid is not only suitable for the introduction of substituents at C2 and C5 positions but it has also been widely used to synthesize 3/4-substituted pyrrolidines/pyrrolidin-2-ones [105]. This can be done by deprotonation–substitution at α-position of the lactam carbonyl group [157]. Through the formation of an α,β-unsaturated lactam system (105b and 109b, Scheme 2.52), a number of reactions can be realized in the oleﬁn portion, including R2

R2

R2

Ru(h3-methallyl)(cod)(2.5%) (S,S )-(R,R )-PhTRAP (2.8%)

R3

N

R1

Et3N (25%), H2 (50 atm)

Boc

R3

N Boc

EtOAc, 80 °C, 24 h

R1

+

R3

[Ru] cat. H2

N

R1

Boc 91–99.7% ee

Scheme 2.65 Synthesis of all-cis-substituted pyrrolidines by catalytic enantioselective hydrogenation. H O Rh N O Rh SO2Ar 4

N2 Ph

+ CO2Me

(6 equiv.)

N Boc

(a) Cat. 2 2,3-DiMebutane hex, −50 to 58 °C; (b) TFA 78%

H Ph MeO2C

H Ph N H CO2Me 97% ee

Cat. 2 Ar = p -(C12H25)C6H4

Scheme 2.66 α-Substitution of pyrrolidine carbamates by enantioselective C–H insertion.

77

78

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

conjugate addition [158], tandem conjugate addition-trapping of enolate intermediates [159], epoxidation [160], and [2 + 3] dipolar cycloaddition reactions [160]. Trans-4-Hydroxyproline (152) constitutes another useful chiron for the synthesis of 3,4-dihydroxyprolinol derivatives. For example, it was converted into 153 [161], 154 [162], 155 [163], and 156 [164] (Scheme 2.68). Compounds 155 and 156 were used in a total synthesis of α –kainic acid [162, 163]. Meyers’ chiral bicyclic lactams 158 are versatile building blocks for highly endo-selective α-alkylations, α,α-dialkylations, cyclopropanations, and so forth (Scheme 2.69) [119].

O

O

−25 °C, 25 h

N

O

O

Mn–salen complex PhIO, C6H5Cl

H

H

O

O

PCC, CH2Cl2 rt, 8 h

H

H

H

H

56% (from 149)

HO

O

N

Boc (149)

N

Boc (151) (71% ee)

Boc (150)

Scheme 2.67 Enantioselective α-oxidation of pyrrolidine carbamates. O

HO 82%

CO2H

N H

LHMDS O MoOPh CO2Me

N

(152) CO2Me

82%

N

HO

CO2Me

91%

CO2Me

Pf (155)

CH2OH

N Pf (154)

MeO2C Pd(PPh3)4 CO, THF/ H2O

TfO N

Pf

CO2Me

Pf

OH N

OH

LiEt3BH

Pf (153)

O

HO

OH

CO2Me

N Boc (156)

CO2Me

N

94%; CH2N2 94%

Boc (157)

Scheme 2.68 Some pyrrolidine derivatives derived from trans-4-hydroxyproline. OBn

O

AlH3

HO

OH OH

NMO 80% (R = CH2OBn) R

Ph O

N R

Cat. OsO4

13:87

R1

N

N 1 N R

O Ph

O

R

Ph O N

R, R = alkyl 1

Ph O

Me O

CH2 SMe2

N

N

(R = Me) R' O (158) R′ = H, CO2Me, Ph

R

O

endo 96– 99%

R

Ph O

Et3SiH, TiCl4 N O

R HO

Scheme 2.69 Selected transformations of the Meyers’chiral bicyclic lactams.

O

N Ph

2.2 Pyrrolines

2.2 Pyrrolines 2.2.1 Synthesis of Pyrrolines by Cyclization and Annulation Reactions

Several ‘‘2 + 3’’ annulation approaches to 2-pyrrolines have been reported. Gor´e [164] and Reißig [165] independently developed a one-pot ‘‘3 + 2’’ annulation approach to 2-pyrroline derivatives (Scheme 2.70). The chiral inducer may be a part of the molecule or introduced as a chiral auxiliary on either imines or alkoxyallenes. Using this method, a straightforward synthesis of (−)-detoxinine was achieved from the adduct 162 in ﬁve steps. Recently, a catalytic enantioselective three-component synthesis of 4-arylated dehydroprolines was reported. In the presence of 10 mol% of [Cu(MeCN)4 ]ClO4 /(R)Ti(BINAP) (cat. 3), the ‘‘3 + 2’’ annulation of allenylstannane with an α-imino ester, followed by a tandem Stille coupling of the resulting 4-stannyl dehydroprolinate, gave 4-arylated dehydroprolinates (Scheme 2.71) [166]. A tandem aza-Michael-type-reaction–Wittig reaction between α-amide ketones and vinylphosphonium salts was reported to give 3-pyrrolines 164 and pyrrolizidines in high yields. The stereochemistry of the starting α-amido ketone is retained during this process (Scheme 2.71) [167]. Nucleophilic addition of lithio propiolate to nitrones derived from d-glyceraldehyde and α-amino aldehydes has been shown to give excellent diastereoselectivity. This opens a ready access to enantiopure 5-substituted-3-pyrrolin-2-ones [168]. After further reﬁnement, Hanessian and coworkers applied this methodology to the total synthesis of A-315675 (6), a potent neuraminidase inhibitor (Scheme 2.72) [169]. Several ring-closing oleﬁn metathesis (RCM) reaction based approaches to pyrrolines have been reported [170]. Sharpless asymmetric epoxidation [171],

Ar H

Bn N

OMe

N N

(159a) +

N N

(160)

Ar

MeO de > 95%

OMe + Li

H

(160)

+

O

OR

(159a) R = Me (159b) R = Bn

O

OBn

(159b) + (161) THF 50% (3 steps)

O N Bn

Ph

Ph O

(162) syn: anti ≥ 97:3

(161)

Scheme 2.70 Gor´e’s and Reißig’s one-pot ‘‘3 + 2’’ annulation approaches to 3-pyrrolines.

Ar

Sn(n-Bu)3 +

R'

NTs

Pd(PPh3)4, PhX reflux, 5 h

CO2Et 34–80%

(1) NaH

O

Cat. 3

CO2Et R N Ts (163) 74– 93% ee

NH Y

+

(2)

PPh3 X

X = H, SPh Y = COPh, SO2R

Scheme 2.71 Two ‘‘3 + 2’’ annulation approaches to pyrrolines.

R' R

X N Y (164)

79

80

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles CO2Me BocHN

+ Bn N O− OTBDPS

BocHN

a

N

BocHN

Bn

BocHN O N Bn OTBDPS

H OH OTBDPS

b

N R OMe

H

H

n -Pr

Me

O

Scheme 2.72 Hanessian’s synthesis of 5-substituted-3-pyrrolin-2-ones. OCO2Me

H2N

N

CbzN

HN

2% [Ir(COD)Cl]2 4% L-2, 8% TBD THF, rt, 1 d 78%

Grubbs II cat. 92%

N

N 96% ee

Scheme 2.73 Helmchen’s enantioselective synthesis of (R)- and (S)-nicotine.

regioselective rhodium-catalyzed allylic amination [172], palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of vinyl epoxides [173], and Ir-catalyzed enantioselective allylic amination [174] (Scheme 2.73) have all been used to form the bis-allylic alicyclic precursors. Hayes et al. developed a KHMDS-promoted stereospeciﬁc alkylidene carbene 1,5-CH insertion for the synthesis of substituted 3-pyrrolines (Scheme 2.74). This was used as a key step in an enantioselective total syntheses of omuralide, of its C7 -epimer, and of (+)-lactacystin (3) [175]. OTBS TBSO

N H

Br

KHMDS Et2O

H N H

OTBS OTBS

1,5 – CH Insertion 49%

N H

OTBS OTBS

Scheme 2.74 Synthesis of substituted 3-pyrrolines by base-promoted stereospeciﬁc alkylidene carbene 1,5-CH insertion.

2.2.2 Synthesis of Pyrrolines by Substitution of Already Formed Heterocycles

Chiral auxiliary-induced, tandem Birch-type reduction–protonation/alkylation of N-Boc-pyrrole carboxylic ester/amide [176a,b] 165 gives rise to nonalkylated/ alkylated 3,4-dehydroprolines with good diastereoselectivities (Scheme 2.75) [176]. More interestingly, and through chiral protonation, enantioselective partial reduction of pyrrole 2,5-dicarboxylate can be achieved with good diastereo- and enantioselectivities following recrystallization [177]. Alkylation of a chiral, nonracemic formamidine developed by Meyers et al. affords a highly enantioselective entrance to 2-alkyl-3-pyrrolines (95–96% ee, Scheme 2.76a) [178], while Royer et al. showed that chiral nonracemic α,β-

2.2 Pyrrolines R OXc*

N

Li / NH3 (l ) THF, −78 °C;

Boc O

X

Boc (165) Ph

Isoprene; RX 91– 97%

R = Me (dr = 8:1) R = Et (dr = 13:1) X = H, Y = CO2Xc*

Y

N

81

Li, (cat) DBB; BrCH2CH2Br

MeO2C CO2Me N H H −78 °C Boc (−)-Ephedrine 74% ee Recrystallization > 94% ee 84% X = Y = CO2Me

Xc* =

Scheme 2.75 Donohoe’s approaches to proline derivatives.

(b)

(a)

N

t-BuO

N

H

−100 °C; RX

Pr-i (166)

Ph

R

n -BuLi

N

N

(b) LDA, R X 45–68%

N

t-BuO

Pr-i C2 /C4 Regioselectivity = 92:8

Ph

1 OH (a) LDA, R X 47–80% O 2

(167)

OH N

R2 R1 de = 73 – 99%

Scheme 2.76 Diastereoselective approaches to 2-alkyl-3-pyrrolines and to β,γ -unsaturated lactams.

unsaturated γ -lactam 167 is a useful building block for the construction of β,γ -unsaturated lactams bearing a chiral quaternary center (Scheme 2.76b) [179]. The vinylogous Mukaiyama-type aldol addition methodology, originally developed by Rassu/Casiraghi et al., affords a versatile approach to chiral nonracemic α,β-unsaturated γ -lactams [180]. For example, in the presence of SnCl4 , the reaction of 2,3-O-isopropylidene-d-glyceraldehyde (169) with N-(tert-butoxy carbonyl)-2-(tert-butyldimethylsiloxy) pyrrole (TBSOP) 168 gave d-arabino α,β-unsaturated γ -lactam 170 as the sole product (Scheme 2.77) [180a]. However, BF3 etherate–mediated reaction led to d-ribo-epimer 171. Moreover, a clean and almost quantitative epimerization at C-5 can be achieved by stirring lactam 170 with Et3 N/DMAP, which provides a good alternative preparation of the thermodynamically more stable d-ribo-lactam 171. The reactions of chiral 2-(tert-butyldimethylsiloxy) pyrroles 172 and 173 with achiral aldehydes were investigated independently by Baldwin and Royer and used in the syntheses of (+)-lactacystin (3) [181] and cephalotaxine [182] respectively. The Rassu/Casiraghi methodology is applicable to imines, which constitutes a vinylogous Mannich-type reaction [183]. The reaction of TBSOP (168) with chiral imines was used as a key step in the total synthesis of an inﬂuenza H OHC

O

Et2O, −85 °C

O

SnCl4 (to 170) BF3 OEt2 (to 171)

TBSO

N + Boc (168) (TBSOP)

(169)

OR

N

O

O Boc O (170) b-H (171) a-H

O

NEt3/DMAP CH2Cl2, rt

Scheme 2.77 Rassu/Casiraghi vinylogous Mukaiyama-type aldol addition methodology.

82

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles

Me

Ar OMe

TBSO

N

TBSO

N O

(172) Ph

(173)

SCPh3 N

OMe

TBSOP (168) TfOH, THF −40 °C 90 – 95%

Ph3CS HN H

N

O

Boc

OMe 174 (dr = 19:1)

Scheme 2.78 Two chiral 2-(tert-butyldimethylsiloxy) pyrroles and a vinylogous Mannich-type reaction.

N CO2Me

Pd2(dba)3 (1–2% mol%) p -MeOC6H4N2BF4 OTr

(175)

NaOAc 90–95%

MeO

OH

HO OTr N CO2Me (176) (dr = 90:10)

6 steps MeO

N Me

Me

(−)-codonopsinine (22)

Scheme 2.79 Correia’s synthesis of (−)-codonopsinine.

neuraminidase inhibitor. It was found that the use of TfOH as a catalyst gave excellent diastereoselectivity and chemical yield (Scheme 2.78) [184]. Heck reaction of enecarbamates 175 derived from pyroglutamic acid with p-methoxybenzenediazonium tetraﬂuoroborate was shown to give 2,5-disubstituted 3-pyrroline 176 with good regio- and trans-diastereoselectivity. The product was converted into (−)-codonopsinine (22) in six steps (Scheme 2.79) [185].

2.3 Fused Bicyclic Systems with Bridgehead Nitrogen 2.3.1 Pyrrolizidines 2.3.1.1 Through Extension of Methods for the Synthesis of Pyrrolidines Because a pyrrolizidine can be viewed as a fused pyrrolidine, many methods developed for the asymmetric synthesis of pyrrolidines can be extended to pyrrolizidines [167,186–189]. Thus methods employed for the formation of pyrrolidine rings can be used to construct the pyrrolizidine ring system starting from pyrrolidine derivatives. For example, the palladium-catalyzed cyclization of proline-derived allylic carbonates, initially developed for the synthesis of 4,5-cis-disubstituted γ -lactams, was extended to the synthesis of pyrrolizidinone, which led to a stereoselective synthesis of (−)-trachelanthamidie (177) (Scheme 2.80) [190]. Intramolecular reductive alkylation is a useful method widely used for the synthesis of pyrrolidines [116], and has also found widespread applications in the synthesis of pyrrolizidines and indolizidines. In the ﬁrst enantioselective synthesis

2.3 Fused Bicyclic Systems with Bridgehead Nitrogen

H

Pd2(dba)3 (5 mol%)

N OCO2Me

P(Oi-Pr)3 (0.5 mol%)

O Ts

Ts

N

MeCN, 12 h, rt 72%

OH

H

N (−)-Trachelanthamidine (177)

O dr = 94:6

Scheme 2.80 Synthesis of pyrrolizidinones by palladium-catalyzed cyclization of proline-derived allylic carbonate.

X

X

H HClO4

N H O

O

B

H N

H

H N

H

NaBH3CN

X = CN X=H

OH

Me NaBH4 100%

H

C7H15-n

Me (+)-Xenovenine (178)

Scheme 2.81 Takano’s intramolecular reductive alkylation approach to xenovenine.

of the ant venom alkaloid xenovenine (178, Scheme 2.81) [191], double intramolecular reductive alkylation was employed to form the pyrrolizidine ring in high stereoselectivity. Later, this became a standard procedure for the synthesis of this alkaloid [192], as well as of other pyrrolizidine alkaloids such as the pyrrolizidines 239K , 265H , 267H [193], epohelmin B [194a], as well as hyacinthacines A2 and A3 [194b]. Husson’s synthesis of trans-2,5-dialkylpyrrolidines [192a] and xenovenine (178) [192b] is another demonstration of such an approach (Scheme 2.82) [192c]. Similarly, Greene’s methodology [88] was extended to the synthesis of (+)-hyacinthacine A1 [189a], (+)-amphorogynines A and D, and (+)-retronecine [189b]. The cumulated ylide Ph3 PCCO is a useful C2 a, d component. Its reaction with α-amino esters can lead to tetramates [195a]. The reaction with (R)-prolinate gave, via a domino addition–Wittig reaction, bicyclic tetramate, which was converted into (−)-pyrrolam A (179) in four steps from prolinate (Scheme 2.83) [195b]. 2.3.1.2 Other Methods for the Synthesis of Pyrrolizidines Formation of the pyrrolizidine ring system by intramolecular α-amidoalkylation is a widely adopted strategy [116]. Ketene dithioacetal (180, Scheme 2.84) [196] and allyl tin (181) [197] were shown to be excellent nucleophiles for intramolecular α-amidoalkylation. Using acetoxy-directed N-acyliminium ion-ketene dithioacetal cationic cyclization (of 180) as the key step, Chamberlin et al. established a versatile Ph NC

Ph N

O

LDA, RX Li, NH3 (I)

R

Ph N

O

R2MgBr

OH R

N

R

H N

R2

H

Scheme 2.82 Husson’s approach to pyrrolidines and pyrrolizidine.

(178)

R2

83

84

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles H N H

PS-3 THF, 60 °C, 16 h

H

- PS-Ph3PO 80%

N

CO2Bn

NaBH4 CH2Cl2-AcOH

H

53% dr = 93:7

N

OBn

N

99%

O

O H

OH

O

H

Pd/C, H2 (1 bar) MeOH, rt, 2 h

Polystyrene resin cross-linked with 2% divinylbenzene

N Ph

O Pyrrolam A (179) 95% ee

O

PS-3 = PS

P C C C Ph

Scheme 2.83 Schobert’s synthesis of (−)-pyrrolam A.

OAc

OAc O

N

S

MsCl Et3N

OH S

AcO

S

H

OH

N

75–80%

S

MsCl AcO Et3N 73%

N (180)

O

(181)

N O

Bu3Sn

O

H

Scheme 2.84 Synthesis of pyrrolizidinones by cyclization involving N-acyliminium ion intermediates.

entrance to six pyrrolizidine alkaloids [196], while cyclization of 181 led to the synthesis of (+)-heliotridine [197]. SmI2 -mediated intramolecular reductive alkylation of tartarimide derivative 182 affords an easy approach to dihydroxylated pyrrolizidinone (Scheme 2.85) [198]. A similar product can be obtained through silylative Dieckmann-like cyclizations of ester-imides 183 (Scheme 2.85) [199]. A general 1,3-thiazolidine-2-thione-induced asymmetric α-amidoalkylation-type reaction affords a two-step approach to (−)-trachelantamidine (177, Scheme 2.86) [200]. Using this strategy, Pilli et al. established a synthesis of (+)-hastanecine [201]. ‘‘Cp2 Zr’’-Mediated ring contraction of vinylmorpholine derivatives 184 was used to synthesize pyrrolidines and pyrrolizidine derivative 185. The latter was further transformed into (−)-macronocine (Scheme 2.87a) [202]. In White’s total synthesis of (+)-australine (186), a transannular cyclization was used to build the pyrrolizidine ring (Scheme 2.87b) [203]. TBSO TBSO O X = OH X=H

OH N

SmI2, Fe(DBM)3 77% X=I Et3SiH 87% CF3CO2H

X TBSO

O N

TBSO

O (182) X = I (183) X = CO2Me

Scheme 2.85 Nucleophilic cyclizations leading to dihydroxylated pyrrolizidinone derivatives. (Fe(DBM)3 ) = tris(dibenzoylmethido)iron(III).

MeOTf Et3N CDCl3, rt 72% X = CO2Me

TBSO

OTMS CO2Me

TBSO

N O dr = 33:1

2.3 Fused Bicyclic Systems with Bridgehead Nitrogen S

O N

S S

+

Cl

H

O

Pr-i

Sn(OSO2CF3)2 N-Ethylpiperidine

O

THF, −5 to 0 °C, 3–4 h 64% de ≥ 97%

OAc

N H

OH H

S LiAlH4, THF

N

H

0 °C, 5 min N reflux (−)-Trachelantamidine 44% (177) Optical purity ≥99%

H NH

O

Cl

Scheme 2.86 Nagao’s approach to (−)-trachelantamidine. (a)

(b) H O N

OH

57% − ds = 95:5 BF3

(184)

HO OBn

N+

OMe

O

H

"Cp2Zr"/THF; BF3 · OEt2

OBn

N O

(185)

H2, Pd(OH)2/C

H

OH OH

N

100%

OH (+)-Australine (186)

O

Scheme 2.87 Synthesis of pyrrolizidine by ring contraction and transannular cyclization reactions.

2.3.1.3 Asymmetric Synthesis of Polyhydroxylated Pyrrolizidines By a combination of Nicotra’s highly stereoselective vinylation, Ganem’s pyrrolidine formation procedure [15], and the RCM reaction, Martin achieved the ﬁrst synthesis of (+)-hyacinthacine A2 (187) in six steps starting from protected d-arabinofuranose (9) (Scheme 2.88) [204]. Reductive double cyclization is an efﬁcient strategy for the synthesis of polyhydroxylated pyrrolizidines [53, 205, 206], as was demonstrated by Pearson et al. in their synthesis of (+)-australine (186) and (−)-7-epi-alexine (Scheme 2.89a) [205]. Another nice demonstration of the efﬁciency of the reductive double cyclization strategy was made by Wong and coworkers, in which a skillful combination of an improved Sharpless asymmetric epoxidation of divinylcarbinol (64) with Payne rearrangement, an enzymatic aldol reaction, and an intramolecular bis-reductive amination led to a concise synthesis of australine (186) (Scheme 2.89b) [53]. The Cope–House cyclization is a useful method for the construction of pyrrolidine rings. This strategy was used for the synthesis of pyrrolizidines 5-epi-hyachinthacine A3 and 5-epi-hyacinthacine A5 (Scheme 2.90) [207]. Besides serving as electrophiles in the nucleophilic addition with Grignard reagents, the umpolung of nitrones can be achieved by a samarium diiodide– induced coupling of nitrones with electron-deﬁcient oleﬁns. This paved the route for a very concise synthesis of (+)-hyacinthacine A2 (187) (Scheme 2.91) [208].

OBz BnO BnO

O OBz

BnO 78%

N

OBn BnO dr = 3:1

Grubb's catalyst 30% (75%)

HO

BnO BnO

Scheme 2.88 Martin’s synthesis of (+)-hyacinthacine A2 .

BnO

N H

HO

N

HO H (+)-Hyacinthacine A2

85

86

2 Asymmetric Synthesis of Five-Membered Ring Heterocycles (a)

OBn

BnO

(b) K2CO3, EtOH

N3

O a:b = 2:1

BnO

(a) H2 10% Pd/C

OTs

BnO

H

BnO BnO

OH

HO H2, Pd/C HO

87%

N

N

HO (+)-Australine (186)

(2:1)

OH

(b) OH

OH O

OH

NaIO4, H2 DHAP, FDPA then pase

OH

O3, −78 °C; H2 Pd/C;HCl; H2 Pd/C 70%

OH O OHC NH

NHCHO

OH

H

OH

OH

Scheme 2.89 Pearson’s and Wong’s syntheses of (+)-australine. DHAP = dihydroxyacetone phosphate; FDPA = fructose-1,6-diphosphate aldolase; and Pase = acid phosphatase.

BnO +

−

N

BnO

BnO O

MgBr THF. −78 °C

BnO BnO

BnO

BnO

O H

+

CHCl3, 24 h

N:

BnO

99% Two steps

H

−

O

BnO

N H

Scheme 2.90 Py’s synthesis of (+)-hyacinthacine A2 .

O BnO

N

− +

CO2Et SmI2 (3 equiv.)

HO

OH BnO

N

CO2Et

HO

N

H2O (8 equiv.)

BnO

OBn THF, −78 °C, 3 h 64%

BnO OBn (dr = 90:10)

HO H (+)-Hyacinthacine A3

Scheme 2.91 Py’s synthesis of (+)-hyacinthacine A3 .

By regio- and diastereoselective 1,3-dipolar cycloaddition of functionalized dipolarphiles with pyrrolidine nitrones, several pyrrolizidines and indolizidines have been synthesized. For example, the 1,3-dipolar cycloaddition of nitrone 188 with ethyl 4-bromocrotonate provided a highly selective and concise synthesis of (+)-heliotridine (Scheme 2.92) [209]. A similar strategy was also used in the synthesis of hyacinthacine A2 and 7-deoxycasuarine [210]. Blechert’s enantiospeciﬁc synthesis of (+)-hyacinthacine A2 (187) exhibits the efﬁciency of a convergent synthesis. Indeed, after synthesizing fragments A and B respectively, it needs only three steps to combine the two fragments and convert the coupled product into the target molecule hyacinthacine A2 , in which two rings and three chiral centers have been formed stereoselectively (Scheme 2.93) [211].

References t-BuO

EtO2C

N+ − O (188)

Toluene 0 °C to rt

+

t-BuO

H

CO2Et

N O

Br

(a) H2, Ra-Ni (b) Ambersep 900 −OH

t-BuO

CO2Et OH

N

46%

Br

H

Scheme 2.92 Brandi’s synthesis of (+)-heliotridine.

O

O

Cat. [Ru]

CbzHN

CH2Cl2, 40 °C

+ TBSO

CbzHN

O

73%

TBSO

O

O O

AD-Mix-b 67%;

H

Pd/C H2, 4 bar;

N

OH

(187)

OH OH

88% de (+)-Hyacinthacine A2 Scheme 2.93 Blechert’s enantiospeciﬁc convergent synthesis (+)-hyacinthacine A2 .

2.4 Acknowledgments

The author thanks Ms Yan-Jiao Gao and Ms Jing-Wei Chen for technical assistance in preparing this manuscript. We are indebted to Professor G. Michael Blackburn for valuable discussions and help during the preparation of this manuscript. References 1 (a) Liddell, J.R. (1999) Nat. Prod.

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95

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles Naoki Toyooka

3.1 Introduction

The functionalized six-membered heterocycles with one nitrogen (piperidine ring systems) have been found in many biologically and medicinally important natural and nonnatural products. Among the nitrogen heterocycles, the piperidine ring probably represents the more frequently encountered substructure of natural or unnatural products. Indeed, many methodologies for the asymmetric construction of this ring system have been developed. This chapter gathers the most recent methods described so far for the asymmetric access of these products, and is divided into four sections: dihydropyridines, tetrahydropyridines, monocyclic and carbocyclic fused piperidines and ﬁnally fused tri- or bicyclic systems with bridgehead nitrogen. The ﬁrst two sections describe the preparation of unsaturated systems that are often used as intermediates in the syntheses of piperidines, thus the methods reported in these two sections may also be useful for the synthesis of piperidines. Owing to the very important literature and several available reviews [1] on this topic, only the recent literature from 2000 to 2007 is reviewed.

3.2 Dihydropyridines

The main interest of dihydropyridine compounds is their reactivity. They can be transformed to yield highly functionalized and substituted piperidines. Indeed, there are quite unstable products and, of course, there are, in most of the cases, intermediates in the asymmetric synthesis of piperidine derivatives. Thus, the preparation of dihydropyridines should be considered as supplementary methods to attain the saturated piperidine compounds. Direct addition of nucleophile on pyridine ring in an enantioselective manner is one of the most effective methods for the construction of chiral six-membered Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

96

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

ring system. The pioneering work on this area was reported from Comins’ group [2]. This was the method that Charette used to elaborate a practical and highly regio- and stereoselective synthesis of 2-substituted dihydropyridine. The strategy involved the addition of Grignard reagents to chiral pyridinium salt prepared from 1 and pyridine in the presence of Tf2 O to yield the 2-substituted dihydropyridines. These compounds are valuable synthetic intermediates since an enantioselective synthesis of ()-coniine was obtained by this methodology in very few steps [3]. Owing to the other application of this method to natural product synthesis, the expedient asymmetric synthesis of (C)-juliﬂoridine in four steps was achieved from 2 (RDC12 H24 OBn) by monohydrogenation followed by a one-pot, highly diastereoselective epoxidation–nucleophilic addition of Me2 Zn. On the other hand, synthesis of the nonracemic 2,5-cis-disubstituted piperidine 3 has also been accomplished (Scheme 3.1) [4]. The ﬁrst catalytic asymmetric addition reaction of nucleophile to N-acylpyridinium ion was reported by Shibasaki and Kanai using Lewis acid–Lewis base bifunctional asymmetric catalyst. Thus, the catalytic enantioselective Reissert reaction of pyridine was achieved in the presence of chiral ligand 4 (10 mol%) and Et2 AlCl (5 mol%) to yield the adduct 5 (98% yield with 91% ee). Interestingly, the use of 4, which is not C2 symmetric, showed best regio- (1,6- vs. 1,2-; 12:1–50:1) and enantioselectivity (up to 96% ee) on this reaction. Adduct 5 was converted to the key intermediate 6 for the synthesis of dopamine D4 receptor-selective antagonist CP-293,019 (Scheme 3.2) [5]. Ma’s group also reported the catalytic enantioselective addition of activated terminal alkynes to 1-acylpyridinium salts using Cu-bis(oxazoline) complexes. Among the chiral bis(oxazoline) catalysts, use of less bulky ligand 7 showed best results, and two adducts 8 and 9 were obtained with 94% and 91% ee, respectively. Both adducts were converted to poison-frog alkaloids 167B and 223AB, respectively, as shown in Scheme 3.3 [6]. Yamada reported the synthesis of chiral 1,4-dihydropyridines by face-selective addition to a cation-π complex of a pyridinium salt. The addition reaction of ketene HO

O Ph

(1) Tf2O, pyridine

NH OMe

i -Pr (1)

(2) RMgX, −78 °C (89 – 65%, >90% de)

N Ph

R

H2, Pd(OH)2 then add cyclohexene and AcOH, 100 °C (60%) R = propenyl

OH 12

N H

Me

R = C12H24OBn

N

i -Pr (2)

Steps

(+)-Julifloridine Ph

OMe

Steps N

R = Ph

Ph N

Ph

i -Pr N H (−)-Coniine

Scheme 3.1

(3) OMe

3.2 Dihydropyridines O NMe2 6

N 1

2

O

Et2 AlCl (5 mol%) ligand 4 (10 mol%)

NMe2

TMSCN (2 equiv) NC MeOCOCl (1.4 equiv) CH2Cl2, −60 °C S OH OH

OH

Steps N

N

BocN

CO2Me (5)

(6)

Ph Steps

O–

F O–

S

O

Ph Ligand 4

N N F

N N

CP-293,019

Scheme 3.2

H

+ N CO2Me

From 8

CuI, ligand 1 i -Pr2Nn-Pr CH2Cl2, −78 °C

O

O N

N

N CO2Me

N (223AB)

R

8: R = CO(CH2)3CH3 (70% 91% ee) 9: R = CO2Et (72%, 94% ee)

H From 9

N (167B)

Ligand 7 Scheme 3.3

silyl acetals to the pyridinium salt of nicotinic amide derivatives proceeded in good diastereoselectivity to yield the 1,4-dihydropyridine derivatives. The nucleophile attacked on more stable conformer 10 (from ab initio calculations) from less hindered top face to yield the product (Scheme 3.4) [7]. The strategy of Comins was broadened by his author with the highly regio- and diastereoselective addition of several nucleophiles such as Grignard reagents, lithium acetylide, and metallo enolates to chiral N-acylpyridinium salts to give enantiopure N-acyl-2,3-dihydro-4-pyridones. According to this methodology, the ﬁrst asymmetric synthesis of natural (C)-cannabisativine [8] from 11, a concise asymmetric synthesis of (C)-allopumiliotoxin 267A [9] from 12, the asymmetric synthesis of (C)-β-conhydrine [10] from 13, and synthetic studies toward ()-FR901483 [11] from 14 have been reported as shown in Scheme 3.5.

97

98

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles R1 R2 O

MeO2C

O N

O

(1) ClCO2Me

N

(2) nucleophile

N Ph

R1 R2

O

N

OTMS OMe

CO2Me Ph

R1, R2 = Me R1 = H, R2 = Ph

Solvent Yield (1,4 : 1,6-) CH2Cl2 94% 86:14 CHCl3 93:7 90% 87:13 THF 56% 97:3 Toluene 70% CH3CN 80% >99:1 CH2Cl2 61% 93:7

de% >99% >99% >99% >99% >99% >99%

R1, R2 R1, R2 = Me R1, R2 = Me R1, R2 = Me R1, R2 = Me R1 = H, R2 = Ph R1 = H, R2 = Ph

Nu–

+ MeO2C N

N

O

MeO2C N +

O

N

O

O

(10)

Scheme 3.4

3.3 Tetrahydropyridines

Tetrahydropyridines are more stable compounds than dihydropyridines, but, as dihydropyridines, are mainly prepared as intermediates in the synthesis of piperidines. The position where the unsaturation takes place is important: the 1,2,3,4-tetrahydropyridines are enamines that can react at the C-3 position with electrophiles giving access to more substituted compounds. Though several methods were described for the construction of substituted tetrahydropyridines, the most versatile methodology is probably the ring-closing metathesis (RCM), which has emerged as one of the most powerful tools in organic synthesis. The total synthesis of piperidine and pyrrolidine natural alkaloids with RCM as a key step has been reviewed by Lebreton in 2003 [12]. 3.3.1 Ring-Closing Metathesis (RCM)

Davis reported the asymmetric synthesis of (C)-CP-99,994 by using the RCM reaction of diene 19, derived from sulﬁnimine-derived 2,3-diamino ester 17. Thus, the addition reaction of enolate of 15 to chiral sulﬁnamide 16 yielded the differentially N-protected diamino ester 17. The latter was converted to alcohol 18, which was then transformed into 19. The RCM reaction of 19 using Grubbs–Hoveyda catalyst

3.3 Tetrahydropyridines

99

OMe R

TIPS

OZnCl

N CO2R*

O Li

Ph

R∗ = (+)-TCC:

+ O then H3O (85%, 95% de) Et or Et

O

CO2Et then H O+ (70%, 96% de) 3 or MgBr then H3O+ (97% de) or p -MeOBnMgCl then H3O+ (89%, 90% de)

X=

R H X

O

N CO2R*

R=H (11)

O

O

TIPS

R = Me (R, X = cis) (12) R=H OMe (13)

CO2Et

R=H (14) HO

H

H N

C5H11

O NH

OH

(OH)2OPO

OH HO

N H

NH (+)-Cannabisativine

N HO

H N

(+)-Allopumiliotoxin (267A)

OMe

OH (+)-β-Conhydrine

NHMe (−)-FR901483

Scheme 3.5

yielded tetrahydropyridine 20 in high yield, which was converted to (C)-CP-99,994 in four-step sequence (Scheme 3.6) [13]. Lebreton achieved the chiral synthesis of ()-3-epi-deoxoprosopinine by using chiral imino alcohol 21 and compound 23. The diastereoselective allylation of 21 yielded the trans-adduct 22 as the major product and subsequent RCM reaction of O LDA, −78 °C

CO2Et

(Bn)2N

O

(15)

p -Tolyl

Ph

(2) Modified Julia Ph olefination (88%)

Grubbs – Hovyda catalyst

N

N

N(Bn)2

OH

Ph

CO2Et

Ph

N(Bn)2 (18) H N

Steps

(94%)

N(Bn)2 (19)

Scheme 3.6

Boc

N(Bn)2 (17)

(16)

Boc

Steps

NH

H

p -Tolyl S N

(1) Dess – Martin periodinane

S

N Ph Boc (20)

N H

Ph

OMe

(+)-CP-99,994

100

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

BrMg −

H

N

O

n -C12H25

Mg Br

BrMg

Fig. 3.1 Stereochemical course of Grignard addition to 21.

H

n -C12H25

O

MgSO4

+

AllylMgBr

H

THF

H2N

OH

N

n -C12H25

OH

−78 – 0 °C (56%) trans :cis = 87:13

(21)

N H

n -C12H25

2) Grubbs’ 2nd catalyst CH2Cl2, reflux (99%)

OH

Steps

1) (Imd)2CO

n-C12H25

OH

N O

O

OH N H (−)-3-epi-Deoxoprosopinine

n -C12H25

(23)

(22)

Scheme 3.7

oxazolizinone yielded 23. The diastereoselectivity of the above addition is explained by the chelation-controlled model shown in Figure 3.1. Epoxidation of 23, reductive opening of the epoxide followed by alkaline hydrolysis of the oxazolizinone ring, yielded ()-3-epi-deoxoprosopinine (Scheme 3.7) [14]. In the Lee’s chiral synthesis of tetrahydropyridines, the dienes required for the RCM were prepared via the regioselective opening of the chiral aziridine ring systems as the key step. Both chiral aziridines 24 and 25 were treated with PhSH to yield the amino alcohol 26 or 27 in highly regioselective manner, which was converted to tetrahydropyridines 30 or 31 via dienes 28 or 29, respectively (Scheme 3.8) [15]. Ph

Ph Me

N

OH H (24)

PhSH, CH2Cl2 (95%)

NH

Me PhS

(26) OH

N

OH H (25)

PhSH, CH2Cl2 (83%)

Me PhS

NH (27) OH

Scheme 3.8

N (28) OH

Ph

Ph Me

Ph Me PhS

Ph Me PhS

N

(29) OH

Grubbs’ 1st catalyst (10 mol%) Toluene, reflux (91%)

Grubbs’ 1st catalyst (10 mol%) Toluene, reflux (74%)

Ph N

Me PhS

(30) OH Ph Me PhS

N (31) OH

3.3 Tetrahydropyridines o -Ns

OH NH + (32)

o -Ns

Ph3P, DIAD THF, 0 °C (83%)

(33)

(1) n -BuLi, Cp2 ZrCl2 THF, −78 °C

1. K2CO3 thiophenol DMF, 80 °C

CH2Cl2, 50 °C (96%, 98% ee)

Me H

Me H Pd/C, H2

H (35): R = o -Ns (36): R = Bn

Grubbs I catalyst ethylene

(34)

(2) HCl, rt (74%)

N R

N

101

N Bn

(37)

MeOH, rt (90%)

N H (+)-Trans -195A H

2.TBAI, BnBr 80 °C (95%)

Scheme 3.9

An interesting ring-rearrangement metathesis was developed by Blechert in the total synthesis of poison-frog alkaloid (C)-trans-195A. Thus, the Mitsunobu reaction of the chiral sulfonamide 32 with chiral cyclohexenol 33 yielded the secondary amide 34, which was subjected to ring-rearrangement metathesis using Grubbs I catalyst to yield 35. The protecting group on nitrogen in 35 was crucial to achieve the next Negishi-coupling reaction. Negishi-coupling reaction of the N-benzyl derivative 36 proceeded smoothly to yield 37, which was converted to (C)-trans-195A (Scheme 3.9) [16]. 3.3.2 Reduction of Pyridine Derivatives

The chiral Brønsted acid-catalyzed reduction of pyridine derivatives is also an efﬁcient method to prepare tetrahydropyridines or octahydroquinolinones in good ee. Thus, the reduction of several pyridine derivatives, shown below, in the presence of chiral Brønsted acid 38 (5 mol%) and Hantzsch diethyl ester (4 equiv) as the hydride source yielded the reduction products in good ee. This methodology was applied to formal enantioselective synthesis of di-epi-pumiliotoxin C (Scheme 3.10) [17]. 3.3.3 Deracemization Processes

Takahata reported the asymmetric synthesis of tetrahydropiperidinol chiral building block 39 using the palladium-catalyzed deracemization of corresponding carbonate (Scheme 3.11) [18]. Thus, the reaction was performed using 8 mol% of phosphine ligand ((R)-BPA) developed by Trost and 2 mol% of Pd2 (dba)3 in CH2 Cl2 /H2 O (9:1) to yield 39 (88–94% yield and 87–99% ee), which is the key chiral building block for the synthesis of biologically important alkaloids such as 1-azasugars [19].

102

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles EtO2C

O

Me

N

CO2Et N Me H

N H

OP O O OH Ar (5 mol%)

(38): Ar = anthracenyl benzene, 60 °C

H

R = n -Pr

Ar

R

Me

O

(4 equiv)

N H di-epi-Pumiliotoxin C

R

H

R = n -Pr (69%, 89% ee) R = n-Bu (72%, 91% ee) R = n-C5H11 (84%, 91% ee) R = 3-nonenyl (83%, 87% ee) R = n-C10H21 (73%, 92% ee) R = phenetyl (66%, 92% ee)

Scheme 3.10

OCOOCH3

(R )-BPA (8 mol%) Pd2(dba)3-CHCl3 (2 mol%) CH2Cl2 /H2O (9:1)

N

OH N

P

P = Boc

Isofagomine, homoisofagomine 5-deoxyisofagomine

P O

O NH HN

(39) P = Ts: 93% 99% ee Boc: 94% 94% ee Cbz: 88% 87% ee COOMe: 90% 99% ee

PPh2Ph2P (R )-BPA Scheme 3.11

3.3.4 Michael Addition Followed by Elimination

The synthesis of tetrahydropyridines using the diastereoselective intramolecular Michael cyclization of vinylsulﬁnyl-containing amino alcohol as the key step, as shown in Scheme 3.12, was described by Delgado. The authors designed a ‘‘one-pot’’ procedure based on the removal of N-Boc followed by neutralization with excess Et3 N and ‘‘in situ’’ cyclization under high-dilution conditions at 50 Ž C to yield the piperidine 40 or indolizidine 41 with high diastereoselectivity. Elimination of the sulfoxide group yielded the tetrahydropyridines 42 or 43, respectively [20]. Davis used the intramolecular Michael-type addition reaction followed by retro-Michael elimination reaction of the N-sulﬁnyl δ -amino β-keto phosphonate to yield dihydropyridone 44 (Scheme 3.13). The conjugate addition reaction of 44 resulted in the selective formation of 2,6-trans-disubstituted tetrahydropyridine 45, which was used for asymmetric synthesis of ()-myrtine [21]. 3.3.5 Enamine Reaction

The intramolecular enamine reaction in the electrophilic center was used by several groups to prepare the piperidine ring through the C3–C4 bond formation. In the

3.3 Tetrahydropyridines p -Tol

S

p -Tol

O

S

OH

O

OH CH3

CH3 Boc

N

103

H

Bn

N

Bn

AcCl (4 equiv) MeOH

p -Tol

S

O

p -Tol

OH

S

O

OH

N

N

Boc

H

O

p -Tol

S

OH N

OH

CH3

Bn (40) (dr >97:3)

Et3N

p -Tol

CH3

Bn (42) (78%)

DABCO

O

MeOH (0.01 M solution) (68 – 70%)

N

Mesitylene

S

OH

OH N

N

(43)

(41) (dr 97:3)

(60%)

Scheme 3.12

p -Tolyl

O S NH O

Me2NCH(OMe)2 O P(OEt)2

O p -Tolyl S NH O

OBn

OBn O

Boc2O

OBn

N Boc (44)

O P(OEt)2 NMe2

O P(OEt)2

N H

OBn

O P(OEt)2

Et3N /DMAP (90%)

O 4 N HCl

O Steps

Steps

OBn

N Me Boc (45)

N

Me

(−)-Myrtine

Scheme 3.13

synthesis of indolizidine alkaloid, Ma reported the efﬁcient construction of the functionalized cyclic enamines by the Michael addition of enantiopure amino alcohols to alkynones followed by intramolecular cyclization reaction. On the basis of this methodology, the asymmetric syntheses of poison-frog alkaloid ()-223A and its 6-epimer [22], ()-deoxoprosophylline [23], and ()-deoxocassine and (C)-azimic acid [24] have been achieved. The enantiopure amino alcohols 46 and 47 were prepared by Davies’ method [25], and were added to alkynone 48 by Michael

104

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles NH2 Steps

O

N

Ph Ph

OBu-t R R = H or Et

Bn

OH

(R = H)

O

NHBn

(46) OBu-t

n-BuLi, −78 °C

R R = H (85%) R = Et (67%) OH

Steps

(R = Et)

NH2 OH

O (47)

O

K2CO3

(48)

OBn

N H

OBn

(88%)

(1) I2 /Ph3P/ imidazole CH2Cl2, rt

(49)

MeCN /H2O, rt

OH

N H

(2) MeCN, Et3N, reflux

O

OBn (88%) (50)

O

O

OBn

N H

N

N

Steps

Steps

6-epi-223A O

N H

O

OBn

N

N (−)-223A

Scheme 3.14

addition reaction to yield the enamines 49 and 50, respectively. The key two-step cyclization of 49 or 50 yielded the cyclic enaminones, which were converted to 6-epi-223A (originally proposed structure for natural 223A) [26] and ()-223A by modiﬁcations on the side chain, reduction of the ketone moiety, and indolizidine formation reaction (Scheme 3.14). This methodology was developed to one-pot procedure, and then the enantioselective total synthesis of the poison-frog alkaloid ()-209I has been achieved. The key one-pot reaction was performed by the reaction of chloride 51 with conjugated alkynone to yield the piperidine (52) after hydrogenation and epimerization at the 3-position, which was converted to ()-209I in some steps (Scheme 3.15) [27]. The total synthesis of lepadins B, D, E, and H and determination of the absolute conﬁguration of lepadins D, E, and H were also achieved by Ma using the same methodology. The key feature of Ma’s synthesis was the construction of octahydro

3.3 Tetrahydropyridines

105

O NBn

Ph

NH3Cl

3 steps

CO2Me

EtOC

Cl

(CH2)3OBn

Na2CO3 / NaI/i -PrOH reflux (64%)

n -C3H7

(51)

N H

(CH2)3OBn

O (1) PtO2 /H2 AcOH (82%)

Steps

(2) NaOMe/MeOH reflux (75%)

n -C3H7

N H (52)

(CH2)3OBn

N

n -C3H7

(−)-209I

Scheme 3.15

(1) HCO2H/CH2Cl2 then NaHCO3 (aq) (80%)

OTBS Br NHBoc

(2) 1,3-Cyclohexanedione benzene, reflux (65%)

O

Br

O OTBS Et N, NaI 3

N Me H (53)

OTBS

DMF, 110 °C (98%)

N Me H (54)

Pt /C, H2, 80 atm Dry AcOH, 50 °C (85%)

OH OH H

OTBS

N Me HH (55)

Steps

H

OH

H

N Me H Lepadin B

H

H

OR N H

Me

Lepadin D: R = H Lepadin E: R = (E )-C(O)CH CH-n-C5H11 Lepadin H: R = (2E,4E )-C(O)CH

CHCH CH-n -C3H7

Scheme 3.16

quinolinone ring system by alkylative cyclization of 53. The diastereoselective hydrogenation of 54 was performed in the presence of Pt/C catalyst by a stereoelectronically controlled axial addition of hydrogen to yield the common intermediate 55 for the synthesis of lepadins after Boc protection and oxidation of the hydroxyl group of the resulting amino alcohol. Elaborations on 55 yielded lepadins B, D, E, and H. The absolute conﬁguration of later three alkaloids was determined by these total syntheses (Scheme 3.16) [28, 29]. 3.3.6 Electrocyclization

Katsumura reported the asymmetric 6π-azaelectrocyclization utilizing the 7-alkyl substituted cis-1-amino-2-indanols 56 as the novel chiral auxiliary. Then the method

106

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

Chiral auxiliary

Chiral auxiliary

N

N

R ∗

CO2Et

R

CO2Et

O

OH

i-Pr NH2 (56)

CHO

N

CO2Et

(1) LiAlH4 (83%)

N

i -Pr

CHCl3, rt (99%, 10:1)

CO2Et

Ts

(2) MnO2 (74%)

N H

Ts N OH

Steps

20-Epiuleine N Ts

Scheme 3.17

OHC

OH

O Pd2(dba)3, P(2-furyl)3

+

i -Pr

NH2

I

TBSO

CO2Et SnBu3

LiCl, MS 4A DMF, 80 °C ′(78%)

N

i -Pr TBSO

CO2Et 20:1 (57)

OH Me

Steps

Me Steps N

N

i -Pr TBSO

OH

Me H (−)-Dendroprimine

Scheme 3.18

was successfully applied to the asymmetric formal synthesis of 20-epiuleine (Scheme 3.17) [30]. Furthermore, efﬁcient one-pot process of the above reaction has been developed by the same author [31]. Thus, the unsaturated ester 57 was synthesized by this method, and the asymmetric synthesis of ()-dendroprimine was achieved via the stereoselective opening of the N, O-acetal as shown in Scheme 3.18 [32]. Fu achieved the elegant catalytic asymmetric [4 C 2] annulation of imines with allenes in the presence of the catalytic amounts of binaphthyl-based C2 -symmetric phosphine 58 (5–10 mol%) to yield 2,6-cis-disubstituted piperidine derivatives in good ee (Scheme 3.19). This methodology was applied to the synthesis of a framework (59) common to an array of important natural products such as the indole alkaloids of 6-oxoalstophyllal and 6-oxoalstophylline [33].

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

R1

N

R2 Ts

+ R3

H

Cat. (R )-58 R1

Ts N

CH2Cl2, rt

R2 R3

P t-Bu

(R )-(58) (1) H2NTs (99%)

N Me

O (2)

CO2Et CO2Et

H

10 mol% (R ) (58) CH2Cl2, rt

N Me

Ts N

CO2Et CO2Et

(99%) 93 : 7 dr, 97% ee O

O

(1) MeSO3H

H

(2) Boc2O (86%)

N Me

RN

R = Boc (59)

CO2Et

MeN MeO

N Me

O

H O R1 R = Me, R1 = H: 6-oxoalstophllal R = H, R1 = Me: 6-oxoalstophlline

R

Scheme 3.19

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems 3.4.1 Generalities

In this section, the asymmetric synthesis of piperidines and their corresponding carbocyclic fused systems are described. Of course, most of the methods described above for the preparation of di- and tetrahydropyridines could be applied to piperidines after functionalization or reduction. The following section deals with different cyclization methods, cycloaddition, ring transformation, and substitution of already formed heterocycles. 3.4.2 Cyclization Methods

Several types of substituted monocyclic piperidines have been synthesized. The more classic cyclization method and more often used is nitrogen intramolecular substitution reaction of appropriate precursors to form the cyclized products in chiral form. Nevertheless, other methods forming the C–C bonds are also reported and described below.

107

108

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles Cp Ti O Ph O Ph Ph O Ph O

O O

H

O

(S,S )-60 Et2O, −78 °C (86%)

O

Steps

OH

O

OH

OH

O

OBn

O N H (61)

OTBDPS

O

Steps

Et

(1) Swern oxidn (2) (R,R )-(60), Et2O −78 °C (81%)

OBn

Steps

OBn

O

O

OH

OH 9 N H (−)-Prosophylline

Scheme 3.20

3.4.2.1 Nitrogen as a Nucleophile SN 2 Reactions The nucleophilic substitution with nitrogen as the nucleophile is probably the most obvious method to achieve cyclization; the leaving group may be an activated ester (tosylate), epoxide, or a halogen as illustrated in the following examples. Cossy reported the sequential use of enantioselective allyltitanation using the both enantiomers of 60 to form the chiral homo-allylalcohol, which was converted to the chiral 2,3,6-trisubstituted piperidine 61 by intramolecular cyclization reaction of the chiral allylamine. Construction of the side chain by Grubbs 2nd catalyst-catalyzed cross-metathesis reaction yielded ()-prosophylline (Scheme 3.20) [34]. The double nucleophilic attack of nitrogen on a bis-tosylate or a bis-epoxide was also described. Takahata reported the synthesis of a novel C2 -symmetric 2,6-diallylpiperidine building block for the synthesis of several alkaloids using the double asymmetric allylation under the Brown procedure and cyclization by interand intramolecular substitution with benzylamine to yield the key piperidine 62. Desymmetrization of 62, crucial step for further elaboration of this building block, was achieved by the intramolecular iodocarbamation to yield the oxazolizinone 63 in high yield. This oxazolizinone is a versatile chiral building block for the synthesis of several alkaloids such as ()-solenopsin A and ()-porantheridine, as shown in Scheme 3.21 [35]. Concellon and Rivero achieved the chiral synthesis of 3,4,5-trisubstituted piperidine by sequential inter- and intramolecular ring opening reaction of epoxyaziridine with primary amines as the key step (Scheme 3.22). The aminoketone 64, derived from l-serine, was converted to aziridine 65 in three steps. The aziridine was transformed into desired epoxyaziridine 66 in three-step sequence, and the key opening reaction of 66 with several primary amines in the presence of lithium perchlorate yielded the 3,4,5-trisubstituted piperidines as the sole product [36]. Gallagher reported [3 C 3] annulation using the 1,3-cyclic sulfate as a double electrophile in the asymmetric synthesis of piperidine. The chiral 1,3-diol was converted to cyclic sulfate, which was treated with dianion of 67 to yield the

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

109

B 2

OH

CHO

OHC

OH

(1) TsCl, Et3N (2) BnNH2

N

+ meso

Bn (61%) (62)

Steps

Me

N 10 H (−)-Solenopsin A

(1) ClCO2Me (93%)

N

(2) I2 (98%)

O

I

O (63)

Steps

N O

Me (−)-Porantheridine Scheme 3.21

O TBSO

NBn

3 steps

Cl

RHN

R

NBn

NBn2 (66)

H

R N

N

HO

HO NBn2

RNH2 LiClO4 MeCN, rt

NBn2 (65)

NBn NBn2

NBn

TBSO

NBn2 (64)

OH

O

3 steps

R = n -Pr : 60% allyl: 78% benzyl: 66% NHBn cyclohexyl: 70% NBn (S )-Ph(Me)CH: 65%

Scheme 3.22

piperidone 69 directly or via sulfate 68. This piperidone was transformed into (S)-coniine in several steps (Scheme 3.23) [37]. Reductive Alkylation Efﬁcient cyclization reactions via the formation of iminium ion followed by its reduction to form the substituted piperidines have been achieved. Mori described the chiral synthesis of (C)-carpamic acid by stereoselective hydrogenation of the iminium, generated from an acyclic amino ketone, to give 2,6-cis-disubstituted 3-piperidinol derivative. The key substrate 70 was synthesized from (S)-alanine methyl ester involving the diastereoselective addition of the acetylene unit to the corresponding aldehyde. Treatment of 70 with Pearlman’s Pd(OH)2 in methanol yielded the piperidine 71, which was converted to (C)-carpamic acid (Scheme 3.24) [38].

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

110

O O

S

(1) NaH, O TolO2S N SO Tol 2 H DMF, rt

O O

O TolO2S

(2) H2SO4, H2O / THF (85%)

Steps

Boc

N H

DEAD, Ph3P

TolO2S

SO2Tol

N

(42%) (69)

OSO3H (68)

NaH, O TolO2S N SO2Tol H (67)

N

O SO2Tol

Dimethyl acetoamide rt then reflux (34%)

(S )-N -Boc-connine

Scheme 3.23 O NH3Cl Me

Steps

(2) Dess – Martin oxidn (90%)

H2, Pd(OH)2 /C, MeOH then AcOH (78%)

CO2Me

(1) CbzCl, NaHCO3 (84%)

(CH2)7CO2Me

BnO Me

Me

Me

NBn2 (70) (1) NaBH4 (quant)

O

(2) Ba(OH)2•8H2O N (CH2)7CO2Me Cbz

(3) H2, Pd(OH)2 /C

HO N H (71)

(CH2)7CO2Me

HO Me

N (CH2)7CO2H H (+)-Carpamic acid

Scheme 3.24

Kumar’s [39], Ghosh’s [40], and Hum’s [41] groups also used the similar iminium cyclization–reduction process to yield 2,6-cis-disubstituted 3-piperidinol derivatives for the chiral synthesis of ()-deoxocassine, (C)-carpamic acid, and (C)-spectaline. Enders’ group reported the asymmetric total synthesis of (C)-2-epi-deoxoprosopinine by using his original SAMP/RAMP hydrazone method as the key step. The α-alkylation of SAMP hydrazone 72 with iodide 73, which was also prepared by SAMP method, yielded the product 74 with high diastereoselectivity (de D 95%). Hydrolytic cleavage of the auxiliary followed by hydrogenolysis of Cbz-group and subsequent reductive amination resulted in an attack of hydrogen from sterically less hindered si face of resulting imine 75 to yield the piperidine 76. Finally, deprotection of acetonide group yielded (C)-2-epi-deoxyprosopinine, as shown in Scheme 3.25 [42]. π-Allyl Substitution The metal-catalyzed cyclization reactions involving a π-allyl metal have also been used by several groups to form the six-membered nitrogen heterocycles. For instance, Hirai achieved the enantioselective synthesis of azasugars of 1-deoxymannojirimycin [43] and fagomine [44] using his original Pd(II)-catalyzed cyclization of urethanes 77 to form the functionalized piperidine ring systems 78 as the key step. Interestingly, the use of the bulky pivaloyl ester

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

N

O Me

H CbzN

Then HMPA OMe O Me (72)

N

Acid

N

O Me

I

O Me

O

(75)

Me

Me

N Me

Me

O

(74)

″H″

O O

H2, 10% Pd /C EtOH (88%)

O

n -C12H25

(73)

n - C12H25

O

n -C12H25

H CbzN

n-C12H25

H CbzN

OMe

t-BuLi, THF −78 °C

N

n -C12H25

Me

N H (76)

O

OH

Lewatit S 100

Me

MeOH, reflux (87%)

OH N H (+)-2-epi-Deoxoprosopinine

n -C12H25

Scheme 3.25 OH HO

OBn R

OBn NH Boc (77)

OH

15 mol% PdCl2L2 R THF, rt (86%) L = MeCN (>26 :1)

N Boc (78)

NH Boc (79)

R=H

OH OH

OBn OBn

20 mol% PdCl2L2 MOMO

OPiv

THF, rt (36%) L = MeCN (9:2)

OH

OH N H OBn R = OMOM 1-Deoxymannojirimycin OBn

OBn MOMO

111

OBn

OH N H (+)-Fagomine

N Boc (80)

Scheme 3.26

79, instead of allylic alcohol 77, for the cyclization reaction resulted in the selective formation of the diastereomer 80 (9:2) (Scheme 3.26). Makabe used the Pd(II)-catalyzed cyclization of amino allylic alcohol, originally developed by Hirai [45], to obtain 2,6-cis-disubstituted 3-piperidinol derivative (Scheme 3.27). Thus, the treatment of allylic alcohol 81 with 5 mol% of PdCl2 yielded the 2,6-cis-disubstituted 3-piperidinol 82 in a highly diastereoselective manner, which was transformed into ()-cassine [46]. Palladium was not the only used metal for such transformation; Helmchen’s group developed the highly enantioselective synthesis of α-vinyl substituted piperidine 83 by Ir-catalyzed allylic amination. This methodology was extended to sequential reaction to yield the C2 -symmetric 2,6-trans-divinylpiperidine 84 with an excellent ee (Scheme 3.28) [47].

112

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles Steps

BnO

OH

OMOM

(81)

MOMO

THF (69%) (>49:1)

NHBoc

HO

Steps

Me

5 mol% PdCl2

HO

N

Me

N H (−)-Cassine

Boc (82)

O

Scheme 3.27 [Ir(COD)Cl]2 (2 mol%) ligand (4 mol%), TBD (8 mol%) OCO2Me

BnNH

THF (1 M), rt (92%, 96% ee)

N Bn (83)

7 O P N O

Ligand:

OMe

N

TBD: N

[Ir(COD)Cl]2 (4 mol%) ligand (8 mol%), TBD (16 mol%) BnNH2 (1.3 equiv)

2 MeO2CO

N H

OCO2Me

THF (0.5 M), rt (73%, dr : 97 : 3, >99% ee)

N Bn (84)

OMe

Ligand:

O P N O OMe

Scheme 3.28

Hydroamination of Allenes The gold(I)-catalyzed intramolecular hydroamination of allenes 85 was used by Toste for the preparation of chiral piperidines. Chiral ligands allowed the reaction to occur with good enantioselectivity (74–98% ee), as shown in Scheme 3.29. A dramatic ampliﬁcation of enantioselectivity was observed when benzoate counterions were employed in this cyclization reaction [48]. R2 R2

NHTs (85)

R1 (R )-ClMeOBiPHEP(AuOPNB)2 (5 mol%) R1

0.3 M in MeNO2, 50 °C

R2

NTs

R2

R1 = Me, R2 = H R1 = Et, R2 = H R1 = Me, R2 = Me R1 = Me, R2 = Ph R1 = Me, R2 = −CH2(CH2)3CH2−

Scheme 3.29

R1 R1 88%, 81% ee 41%, 74% ee 70%, 98% ee 70%, 88% ee 66%, 97% ee

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems O Cbz

BF3 • Et2O

Ph

Cbz

CH2Cl2 (30%)

N Cbz (87) NH

(96%)

Ph

Ph (86)

O

O

p -TsOH, (CH2OH)2 CH(OMe)3

Ph

O

p -TsOH, (CH2OH)2 CH(OMe)3

NH O

(quant), (9 :1)

(89)

Ph

(Z )-15 or (E )-15 or (Z )-15 + (E )-15

O

N Cbz (88)

O

N Me Cbz (90)

Scheme 3.30

Michael Addition Chalard and Troin studied the 6-endo-Michael-type cyclization to yield 2-mono- and 2,6-disubstituted piperidines with 2,6-trans selectivity. The intramolecular Michael reaction of 86 in the presence of BF3 žEt2 O yielded the product 87 (only 30% yield). On the other hand, this type of cyclization reaction was achieved by using p-TsOH and ethylene glycol in the presence of CH(OMe)3 to yield the corresponding acetal 88 from 86 and 90 from 89 in 96% and quantitative yield, respectively. The 2,6-trans adduct 90 was obtained as the major isomer (9:1) starting from either E- or Z-oleﬁns (Scheme 3.30) [49]. 3.4.2.2 C–C Bond Formation Nitrogen α–Carbanion Kawabata’s group succeeded in the asymmetric cyclization of α-amino acids to yield the six-membered cyclic amino acid with a quaternary stereocenter on the basis of his original concept of memory of chirality (Scheme 3.31). Thus, the amino acid bearing the bromobutyl on the nitrogen was treated with potassium hexa-methyldisilazane (KHMDs) in dimethylformamide (DMF) at 60 Ž C to yield the cyclic compound 91 (84% yield with high enantioselectivity 97% ee). This methodology can be applied to construct the ﬁve-membered ring system too [50]. Iminium Addition The intramolecular Mannich-type cyclization is also a powerful tool for the construction of functionalized piperidine ring system. Davis reported the efﬁcient asymmetric synthesis of β-amino ketones from sulﬁnimines followed by the Mannich-type cyclization to give functionalized 4-piperidone ring systems. These piperidones are very versatile building blocks for CO2Et Boc

N

(CH2)4Br

CO2Et KHMDS DMF, −60 °C, 30 min (84%, 97% ee)

Boc

N (91)

Scheme 3.31

113

114

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

O S

O

p -Tolyl

O S

H

p -Tolyl Pr-n

N

LiHMDS ether, −78 °C

NH

O

N

(1) TFA/MeOH (2)

n-Pr (92)

O MgSO4 (93%)

O

(93)

(78%) + 8% of anti-isomer O Steps

TsOH /Ph-H 40 h, rt (58%)

N H

N (−)-(223A)

Scheme 3.32

the synthesis of several alkaloids, and the asymmetric syntheses of ()-223A [51], ()-nupharamine [52], and (C)-241D [53] have been achieved. The ﬁrst key reaction was the syn-selective addition of the enolate to chiral sulﬁnimine to yield the α-substituted β-amino ketone 92. The second key step was the acid-catalyzed Mannich cyclization of 93, derived from 92, to yield the functionalized 4-piperidone, which was converted to ()-223A by indolizidine formation followed by the reduction of the ketone moiety (Scheme 3.32). The intramolecular attack of allylsilane on iminium ion or imine is also effective to construct the chiral piperidine ring system by cyclization reaction. Remuson described a new asymmetric synthesis of 2,6-cis-disubstituted 4-methylenepiperidine 95 based upon a Mannich-type intramolecular cyclization of an allylsilane on an iminium ion 94. According to this strategy, the poison-frog alkaloid 241D was synthesized, as shown in Scheme 3.33 [54]. Hiemstra and Rutjes investigated the amidopalladation of alkoxyallenes to yield the α-alkoxycarbamates or amides. The formal enantioselective synthesis of poison-frog alkaloid 233A has been achieved by using the above key reaction followed by acyliminium cyclization of the resulting α-alkoxycarbamate. Treatment of 96 with Hoveyda–Grubbs catalyst (5 mol%) resulted in unusual double bond Me Me HN

O

n -C9H19

TFA

H

SiMe3

Me

+ N

H SiMe3

n -C9H19

SiMe3

H

80% AcOH (68%)

n -C9H19

n -C9H19

(94)

(53%, 78% de, 76% ee) (95) Me

Me OsO4, Na3H3IO6

N

NaBH4 N

H

MeOH O

Me H

N OH

n -C9H19

N OH

n -C9H19

(241D) 83

Scheme 3.33

:

17

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

115

TMS (1) Hoveyda-Grubbs cat. (5 mol%) TMS, CH2Cl2, reflux (87%)

HN Ns

CO2Me

(2) Benzyl propadienyl ether Pd(OAc)2 / dppp (5 mol%) Et3N, MeCN, rt (80%)

Sn(OTf)2 (2 mol%)

BnO

Steps

Steps

(98)

CO2Me

CH2Cl2, 0 °C to rt (82%)

CO2Me

Ns (97)

(96)

N Ns

N

N (99)

OH

N (233A)

Scheme 3.34

isomerization followed by cross-metathesis with allyltrimethylsilane to give the product, which was subjected to key amidopalladation with benzyl propadienyl ether to yield 97. Sn(OTf)2 -catalyzed cyclization of 97 via acyliminium salt yielded the trisubstituted piperidine 98 as a 86:14 mixture of trans/cis-isomers. The major trans-isomer was converted to quinolizidine 99, which is a key intermediate for the synthesis of poison-frog alkaloid 233A (Scheme 3.34) [55]. The divergent synthesis of both 2,6-cis- and trans-3-trans-trisubstituted tetrahydropyridines from chiral organosilanes was reported by Panek. The ﬁrst enantioselective total synthesis and determination of absolute stereochemistry of poison-frog alkaloid ()-217A were achieved by this methodology via the quinolizidine 100, as shown in Scheme 3.35. Treatment of preformed imine with TiCl4 at low temperature yielded the desired product with good-to-excellent diastereoselectivity (8:1 to >30:1). Interestingly, the cis–trans selectivity depended upon the chirality of organosilane. Use of the 2,3-anti-organosilanes yielded the 2,6-trans products as the major isomer (9:1 to >30:1); on the other hand, use of the 2,3-syn-organosilanes yielded the 2,6-cis products (8:1 to >30:1) selectively [56]. Troin’s group investigated very actively on the intramolecular Mannich-type cyclization reaction of chiral imine 101 to yield the 2,6-cis-disubstituted piperidine ring systems. This reaction was applied to the syntheses of highly substituted piperidines [57], pipecolic acid derivatives [58], and (š)-alkaloid 241D (Scheme 3.36) [59]. Radical Cyclization The construction of chiral piperidines by means of radical cyclization reaction is a very interesting method, although very rarely used. Snaith proposed a novel approach to 2,4-trans-disubstituted piperidines by the radical cyclization of 7-substituted 6-aza-8-bromooct-2-enoates 101 (Scheme 3.37) [60]. The use of tris(trimethylsilylsilane) instead of tributyltin hydride as the radical source enhanced the diastereoselectivity (>99:1). The trans selectivity is explained by the proposed transition state, as shown in Figure 3.2 involving a pseudo-A1,3 allylic strain.

SiMe2Ph +

OAc

CO2Me

NH2

Scheme 3.35

H

O

2 CO Me 2

NH2

SiMe2Ph

3

R H

(2) TiCl4, CH2Cl2 (3) CbzCl, Na2CO3 (60%)

N

H

Cbz

H MeO2C

(CH2)4OAc

CO2Me

Me

(3) TFAA, pyridine CH2Cl2

(2) TiCl4, −78 °C to rt

(1) MgSO4, CH2Cl2

(1) MgSO4, CH2Cl2

+

O N

R CF3

(3) CBr4, Ph3P Et3N, CH2Cl2 (93%)

N

H

(100)

CO2Me

Me Steps N

H

(−)-(217A)

Me

R = 2-furyl: 75%, cis : trans = 8 : 1

R = 4-BrPh: 82%, cis : trans = >30: 1

R = (trans)PhCHCH: 64%, cis : trans = 1: 9 From 2,3-syn : R = C6H12: 78%, cis : trans = 10:1

R = 2-furyl: 89%, cis : trans = 1 :12

From 2,3-anti : R = i-Pr: 73%, cis : trans = 1:13 R = m-NO2Ph: 90%, cis : trans = <1:30

(2) H2, Pd/C, K2CO3 MeOH

(1) H2, PtO2 MeOH

O

H

Me

116

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems R2 H2N

O

N

R1

O

+

R1 O

R1– CHO

H N

R2

R2

Steps

n -C9H19

H N

Me

O O

(100)

O

OH (241D)

de > 95%

Scheme 3.36 Ts R

N

Br

Ts (Me3Si)3SiH, AIBN

R

Ts

N

R

N

+

Toluene, 90 °C

CO2R′

R′O2C (101)

R = Me, R′ = Me R = Bn, R′ = Me R = i -Pr, R′ = Me R = i -Pr, R′ = t -Bu R = sec -Bu, R′ = t -Bu

CO2R′

73:27 (90%) 92:8 (76%) 97:3 (73%) 99:1 (75%) >99:1 (60%)

Scheme 3.37 CO2R′ N Ts R pseudo A1,3 strain

Ts N CO2R′ R

Fig. 3.2 Preferential conformer on the radical cyclization of 101.

3.4.3 Cycloaddition Methods 3.4.3.1 [4 + 2] Azadiene Cycloaddition The construction of chiral piperidines by using the aza[4 C 2] cycloaddition reaction as the key steps has been reported. Hall’s group achieved a new entry to palustrine alkaloids using the three-component sequential, aza[4 C 2] cycloaddition/allylboration/retro-sulﬁnyl-ene, reaction (Scheme 3.38). This approach was then applied to enantioselective synthesis of ()-methyl dihydropalustramate. The key three-component sequential reaction smoothly proceeded to yield the product 102, which was converted to ()-methyl dihydropalustramate via oxazolizinone 103 [61]. 3.4.3.2 [4 + 2] Acylnitroso Cycloaddition The formation of bicyclic- or tricyclic-nitrogen heterocycles has been reported by using [4 C 2] or formal [3 C 3] cycloaddition reaction as the key step. Kibayashi and Aoyagi studied the stereocontrolled intramolecular acylnitrosoDiels–Alder reaction to yield the bicyclic oxazino lactam. Oxidation of hydroxamic acid 104 with Pr4 NIO4 in aqueous media (water–DMF D 50:1) yielded the

117

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

118

O

B

O– S N

O +

Ph O (1 equiv)

N NBn2 (1 equiv)

O− S+ N

(1) Toluene, 80 °C

N OH NBn2 O

(2) NaHCO3 (aq), rt (62%)

EtCHO (5 equiv)

Ph

O + O− S

N OH NBn2 O

NH Ph

(102)

(1) NaOH H2O/acetone (3:1) (2) HCl (aq) then NaHCO3 (aq) up to pH 6.5

H

Steps

Steps N OH NBn2 O

N

NH O

Ph

CO2H

CO2Me

N OH H

O (103)

(−)-Methyl dihydropalustramate

(3) CHCl3, reflux (77%)

Scheme 3.38

cycloadduct 106 selectively (6.6:1) via acylnitroso compound 105. Elaboration of 106 (stereoselective introduction of methyl substituent, construction of decahydroquinoline skeleton, and installation of the dienyl side chain) yielded the marine alkaloids ()-lepadins A, B, and C [62, 63]. According to this method, the macrocyclic dilactones containing a 2,3,6-trisubstituted piperidine of (C)-azimine and (C)-carpaine have also been synthesized (Scheme 3.39) [64]. The Diels–Alder reaction of chiral 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridine to yield the octahydroquinoline ring systems was achieved by Craig. Thus, the cycloaddition reaction of 107 with maleic anhydride or acrolein yielded the cycloadduct 108 or 109, respectively. Formation of 108 or 109 indicated preferred endo approach of the dienophile toward the α-face of 107 (Scheme 3.40) [65]. BnO Steps

OH OH

HO

OMOM

OBn NHOH

n O (104)

N O

O

n OMOM

Pr4IO4 or NaIO4 H2O-DMF (50:1) 0 °C

(105) H N

X

Me

BnO N O

O From n = 1

H

O OR

N Me H (−)-Lepadin A: X = H2, R = COCH2OH B: X = H2, R = H n = 1: 6.6:1 (90%) n OMOM (106)

n = 2: 6.4:1 (69%)

Scheme 3.39

From n = 2

n O

O

n

O

H

C: X = O, R = COCH2OH

Me

N H

(+)-Azimine: n = 1 (+)-Carpaine: n = 3

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems Ts

Ts (1) N -Iodosuccinimide, PhI(OH)(OTs) (2) n -Bu3SnCH=CH2, Pd2dba3 i -Pr (2-furyl)3P, DMF, 70 °C (67%)

N

N

i -Pr

Ts (107)

Ts Ts (1) Maleic anhydride 65 °C (2) TMSCHN2 (74%)

N MeO2C i -Pr H Ts MeO2C (108)

(1) Acrolein 53 °C

Ts

(2) LiAlH4 (40%)

N Ts (109)

H HO

i -Pr

Scheme 3.40

3.4.3.3 [3 + 2] Cycloaddition The [3 C 2] 1,3-dipolar cycloaddition reaction of nitrone is also an efﬁcient methodology for the construction of chiral piperidine building blocks. Indeed, in this methodology, the cycloaddition allowed the formation of the C2–C3 bond of the piperidine ring along with the formation of the ﬁve-membered oxazolidine ring. Poison-frog alkaloid (C)-allopumiliotoxin 323Bž has been synthesized by Holmes employing the intramolecular [3 C 2]-cycloaddition reaction of Z-N-alkenylnitrone to yield the precursor of 2,3,4-trisubstituted piperidine (Scheme 3.41). The key cycloaddition of 110 was conducted by heating at 70 Ž C in toluene to yield four isoxazolidine cycloadduct (32:5:8:8). The major isomer 111 was converted to 2,3,4-trisubstituted piperidine 112, which was transformed into the ketone 113. The stereoselective addition of Grignard reagent to 113 was performed to yield the desired diol 114 as the sole product. The selectivity on this addition reaction was explained by A1,3 -strain and Cieplak hypothesis (Figure 3.3). The diol 114 was converted to (C)-allopumiliotoxin 323Bž by the construction of the exo-oleﬁn side chain [66]. 3.4.4 Ring Transformation Methods

The construction of the piperidine ring can result from ring transformation and particularly from ring enlargement. The ring enlargement of ﬁve-membered ring systems such as pyrrolidine, lactone, or γ -lactam is also an effective method for the construction of six-membered nitrogen heterocycles. According to these

119

120

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles OBz

HO

NaBH3CN MeOH /HCl

OTBS

N

HO

OBz NH

O H CH2Cl2

OTBS

MeOH

–

O + N

OTBS

(110) OTBS 70 °C

OTBS H2, 10% Pd/C then

N

Toluene O (111) (53% from oxime (32:5:8:8)) BzO

OTBS

Cbz (112) Me Me

MeMgBr OBz

N

O

Steps

OH

THF (90%)

OH

OH

N

Cbz (113)

OBz

N

OTBS O

Steps

OH

CbzCl NaHCO3 (aq) (90%)

Cbz (114)

Me

Me OH H

N

(+)-Allopumiliotoxin 323B′

Scheme 3.41

OTBS N O OBn A1,3 -strain

O OBz

Nu– TBSO

O

N O

H OBn OBz

Fig. 3.3 Preferential conformer on Grignard-addition to 113.

enlargement methodologies, functionalized piperidine or 2-piperidone chiral building blocks are elaborated in highly stereoselective manner. 3.4.4.1 Ring Enlargement of Pyrrolidines to Substituted Piperidines A powerful method for the construction of piperidines is the ring transformation of prolinol derivatives. Cossy and Pardo described the ring expansion reaction of derivative 115, derived from l-pyroglutamic acid, by treatment with MsCl followed by Et3 N to yield the 3,4,5-trisubstituted piperidine 116, which was used for asymmetric formal synthesis of ()-paroxetine (Scheme 3.42) [67]. The asymmetric synthesis of cis-2,3-disubstituted 3-piperidinol 120, which is the useful intermediate for the synthesis of medicinally important neurokinin-1 receptor antagonists, has been reported by Lee [68] following a similar strategy. Thus, treatment of the prolinol derivative 118, prepared by the Jacobsen’s asymmetric epoxidation of oleﬁn 117 as the key step, with MsCl followed by n-Bu4 NOAc

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems F

121

F

F Steps

CO2i -Bu

O

HO2C

N H L-Pyroglutamic acid

HO

(1) MsCl (1.1 equiv) 0 °C to rt (2) Et3N (3.1 equiv) reflux (84%)

N

Steps CO2i -Bu

Cl

Ph

Ph

(115)

O N H

N

O O (−)-Paroxetine

(116)

Scheme 3.42 PhCH2NH2 NaHCO3, NaI

Jacobsen Cl

Epoxidation Cl (94% ee, 75%)

Ph

O Ph

(1) MsCl, Et3N

H OH

(65%)

N Ph

(117)

(2) n -Bu4NOAc (85%)

Ph (118) OAc

(95%)

N P Pd/C, H2 Boc2O (95%)

OH

NaOH

(119): P = Bn P = Boc

O

Moffat oxidn (86%)

N

N

Boc

Boc

(120)

(121)

Scheme 3.43 TBDMSO (1) TFAA N Ph

OH

TBDMSO

(2) DIPEA

OH N

Ph (122)

(123)

Steps

NHBoc

T N

COOH T = thymine

Scheme 3.44

yielded 119 with high enantiomeric purity. This piperidine was also converted to 3-piperidone 121 by Moffat oxidation with no racemization (Scheme 3.43). In the synthesis of chiral piperidine peptide nucleic acid (PNA), the ring enlargement of prolinol 122 yielded the key intermediate trans-3,5-disubstituted piperidine 123 (Scheme 3.44) [69]. An original ring enlargement reaction of functionalized pyrrolidine 124 to piperidone 125 was proposed by Honda through a unique samarium-promoted C–N bond cleavage of 124 and simultaneous cyclization of the resulting amino ester to yield 125 (Scheme 3.45). The presence of pivalic acid as a proton source is essential in this transformation, and enantiospeciﬁc total synthesis of ()-adalinine was also achieved. [70]. 3.4.4.2 Ring Transformation of Lactones to 2-Piperidones The lactones bearing a nitrogen functionality such as an amino or azide group on the γ -substituent are suitable substrates for this transformation.

122

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles TBDMSO SmI2, pivalic acid

Steps EtO2C

N

O

EtO2C

H

THF–HMPA (7:1) (70%)

N H (124)

TBDMSO

O Steps

O

N H (125)

O

N H (−)-Adalinine

Scheme 3.45 HO

Microwave-assisted hydrogenation

O

N3 MeOH, Pd – C, H, 15 bar, 90 °C, 25 min

O

O

N

(90%)

H (127)

(126)

Scheme 3.46

Holzgrabe described the microwave-enhanced hydrogenation of azide-lactone 126 at the medium pressure to yield the 2-piperidone 127 in only 25 min with good yield (Scheme 3.46) [71]. 3.4.4.3 Ring Enlargement of γ-Lactam to 2-Piperidones Langlois described the synthesis of cis-4,5-disubstituted 2-piperidone 130 as a key intermediate for pseudodistomin C synthesis by ring expansion of aminomethylsubstituted γ -lactam 129 (Scheme 3.47). Thus, treatment of 129, derived from (S)-pyroglutaminol via secondary alcohol 128, in methanol at 65 Ž C for 24 h yielded transamidation product 130 with good yield, which was transformed into the marine alkaloid of pseudodistomin C [72]. OH

Steps

OH

Steps

(S )-Pyroglutaminol O

N

O O

Ph (128)

N Boc

NaN3 (90%) 10% Pd – C, H2 (quant)

OH

Scheme 3.47

R = OMs R = N3 (129) R = NH2

NH2

Steps

N H (130)

MeOH, 65 °C

OH NHBoc

O

R

Pseudodistomin C

N H

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

123

3.4.5 Substitution of Already Formed Heterocycle

One strategy used in the asymmetric synthesis of piperidine was the preparation of a chiral and versatile building block that possesses the six-membered ring and can be further diversely substituted. This building block should be easily prepared with high yield and selectivity offering large possibilities of substitution. The substitutions should be stereocontrolled. The use of chiral auxiliaries is still the main strategy used, although some reactions using asymmetric catalysts were also reported. 3.4.5.1 Phenylglycinol-Derived Oxazolidine Enantiomerically pure phenylglycinol is frequently used for the induction of the chiral center on piperidine ring system. Involved in an oxazolidine ring, it allowed various diastereomerically controlled reactions that were exploited by several research groups in the preparation of piperidine derivatives. Husson reported the reductive decyanation of the 3-phenylhexahydro-5H-[1,3] oxazolo[3,2-a]pyridine-5-carbonitrile building block 86, the key element of his elegant CN(R,S) strategy, with Raney nickel and its further application to other derivatives. This new piperidine scaffolds serve as stable 2-piperideine (enamine) equivalent in the rapid and efﬁcient construction of 3-substituted piperidines 132 [73]. On the other hand, regioselective oxidative transformations of the N-(cyanomethyl)-oxazolidine system with potassium permanganate leading to enantiopure lactams have also been reported. Oxidation of 131 yielded the lactam 133, which is a very versatile chiral building block for the synthesis of several alkaloids. This methodology can be applied to the conversion of 134 to chiral lactam 135 and piperidine 136, as shown in Scheme 3.48 [74]. A unique approach to the synthesis of chiral nonracemic substituted [5,6]and [6,6]-spiropiperidines was also described by the use of the CN(R, S) method Ph NC

Ph N

OH O

KMnO4 (7 equiv)

NC

Ph

Ph Raney nickel

O

N

Acetone/H2O (8:2) (80%)

N

O

N

O

MeOH, reflux (92% de)

THF, reflux (79%)

(133)

MVK (1 equiv)

(131) (132) (1) LDA (3 equiv) MeI (2 equiv), −78 °C (95%) (2) Raney nickel (quant)

Ph OH H3C

N

O

Ph

Ph

KMnO4 (4 equiv) H3C

N

Scheme 3.48

H3C

N

MeOH (92%)

Acetone/H2O (7:3) (90%) (135)

O

NaBH4 (5 equiv)

(134)

(136)

OH

O

124

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles Ph

Ph NC

N

LDA, THF, −78 °C

O

X

n Y

X NC

N

O

Li, naphthalene THF, −78 °C or

H2 N

t -BuLi, pentane/Et2O −78 °C

n

n = 1, X = Cl

Ph

O N n

n = 2, X = Cl

Steps Me Ph

HO

N

OTBS

Steps

NC Ph

OTBS

H

Steps

OH N

CO2Et

OTBS Ph

OH (137)

N

Scheme 3.49

(Scheme 3.49) [75]. Owing to the valuable application of this methodology to natural product synthesis, the advanced intermediate 137 in pinnaic acid series was achieved [76]. Lhommet developed the synthesis of chiral bicyclic β-enaminoester 138 by condensation of (S)-phenylglycinol on oxo alkynoate. The diastereoselective reduction of 138 was performed by hydrogenation of Pd(OH)2 to yield the 2,6-cis-disubstituted piperidine 139 with an excellent enantioselectivity (>98%), which was a key intermediate previously reported in the total synthesis of (C)-calvine [77]. The construction of chiral bicyclic β-enaminoketone 140 by the same condensation procedure using the triketone instead of oxo alkynoate was also reported. The bicyclic β-enaminoketone 140 was converted to 2,3,6-trisubstituted piperidine 141 by hydrogenation of PtO2 followed by hydrogenolysis of Pd(OH)2 in highly stereoselective manner. The piperidine 141 was transformed into ()-deoxocassine. On the other hand, the trisubstituted piperidine 142, derived from 140, was converted to (C)-isodeoxocassine via the epimerization on the 3-position (Scheme 3.50) [78]. Substitution reactions on the already formed heterocycle using the acyliminium ion strategy have been widely studied, and constitute an effective method for the construction of chiral piperidine ring. Such strategy was the basis of Amat and Bosch enantioselective syntheses of piperidine alkaloids. Mono-substituted piperidine (R)-coniine, 2,6-cis-disubstituted piperidine alkaloid (2R,6S)-dihydropinidine, 2,6-trans-substituted piperidine alkaloids (2R, 6R)-lupetidine and (2R,6R)-solenopsin A, and indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I were prepared starting from both enantiomers of a common Meyers’ type lactam, (3R,8aS)-5-oxo-3-phenyl2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine. Addition of allyl moiety on 143 in the presence of TiCl4 yielded the product in a diastereoselective manner. The selectivity observed here was rationalized by the nucleophilic attack upon the less hindered Re face on the iminium ion, whose conformation is restricted by the chelation, as shown in Figure 3.4. Thus, the mono-substituted piperidine alkaloid

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

n -Pent O

CO2Me

N

H2, Pd(OH)2 MeOH (66%)

Ph (138)

CO2Me

N H

n -Pent

(2) H2, Pd(OH)2

O (+)-Calvine

n -C12H25

n-C12H25

O

OH Steps

n -C12H25 N

Me

N

Me

H

COMe (141) N

N

O

(3) Ac2O, Et3N, DMAP (82%)

O

n -Pent

(139)

(1) H2, PtO2

O

Known

(−)-Deoxocassine

Me O

Ph (140) (1) H2, PtO2 (2) H2, Pd(OH)2 (3) Boc2O (76%)

OH Steps

n -C12H25

N Boc (142)

Me

n -C12H25

N

Me

H (+)-Isodeoxocassine

Scheme 3.50

of ()-coniine was synthesized from 144 in several steps. Similarly, the addition of higher-order cyanocuprate to 143 in the presence of BF3 žEt2 O yielded the adduct 145 in highly diastereoselective manner. Partial reduction of 145 with Red-Al yielded the masked iminium ion 146, which was made to react with Grignard reagent to yield 147 as the only isolated product with good yield. This stereoselectivity was explained by stereoelectronic effects. Further reactions on 147 yielded 2,6-cis-disubstituted piperidine alkaloid of ()-dihydropinidine. Likewise, the syntheses of ()-indolizidine 167B and (C)-monomorine I have also been achieved. On the other hand, the iminium reduction of 149 (R D Me or C11 H23 ) derived from 148 with NaBH4 yielded the 2,6-trans-disubstituted piperidines, which was converted to lupetidine and solenopsin A, respectively (Scheme 3.51) [79]. This methodology was extended to the synthesis of 3,5-cis- and trans-disubstituted, 2,5-disubstituted, and 2,3,5-trisubstituted enantiopure piperidines, and the indole alkaloids 20R- and 20S-dihydrocleavamine [80]. 3.4.5.2 Asymmetric Michael Addition Toyooka disclosed the stereodivergent construction of 2,3,5,6-tetrasubstituted piperidine ring system by sequential use of key Michael-type conjugate addition reaction of the enaminoesters 150 and 151 (Scheme 3.52). Thus, the ﬁrst enantioselective synthesis of poison-frog alkaloid 223A and the structural revision were achieved [81]. On the other hand, the ﬁrst enantioselective synthesis of unique tricyclic poison-frog alkaloid ent-205B [82, 83] was also achieved. The observed remarkable stereoselectivity of key conjugate addition reaction can be rationalized by the stereoelectronic effect and is also consistent with Cieplak’s hypothesis, as shown in Figures 3.5 and 3.6.

125

126

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

Ph

Ti O

O N+

H

Nu Fig. 3.4 Diastereoselective addition to 143 controlled by chelation. Ph H

OH O

Steps

N

N

TMS (−)-Coniine

(144) TiCl4 (9:1) (91%) Ph

Ph O

N

O

Me2Cu(CN)Li2 BF3•Et2O

O

Ph N

OH Me

(70%) (97:3)

Red-Al

O

Me n-PrMgBr

(70%)

Me

(146)

Steps

Ph

Ph

H

OH N

Me

H2, Pd(OH)2

N

(+)-Dihydropinidine

(147)

(148) Me2CuLi or C11H23MgBr, CuI

Ph

Ph R

N +

OTBS Me

(149) H

Steps R

N

Me

R = Me: (+)-lupetidine R = C11H23: (−)-solenopsin A

Scheme 3.51

Me

(65%)

OTBS Me

N +

OX N +

(80%)

(145)

(143)

MeS

N

Ph

NaBH4 (55%)

R

N

OTBS Me

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

H MeO2C

OTBDPS

N CO2Me

R1

(vinyl)2CuLi or

H MeO2C

Me2CuLi

H

R1

Steps

H

OTBDPS

N CO2Me

RaO

H

H N

(150)

(vinyl)2CuLi

RaO

H

R1 H

H

H

R2 H N CO2Me CO2Me

Steps

H

H

H H

N

H

H

H N

Proposed for 223A

R1 = Et, R2 = vinyl

(151)

CO2Me

CO2Rb (151)

Revised for 223A

Ra = protective group Rb = Me (acyclic carbamate)

Me2CuLi

R1 H

H

H

N O

R2 H CO2Me

Me H

Steps

H

H

Me H

N

O

H Me ent-(205B)

R1 = Me, R2 = Me Ra, Rb = cyclic carbamate

Scheme 3.52

N CO2Me CO2Me

H N CO2Me CO2Me Nu

Stereoelectronically favored axial attack

Cieplak’s hypothesis

Fig. 3.5 Stereochemical course of Michael-type addition to 151 (acyclic carbamate). Stereoelectronically favored axial attack Nu

Me

CO2Me N O O

Me

CO2Me N O

H

O Cieplak’s hypothesis

Fig. 3.6 Stereochemical course of Michael-type addition to 151 (cyclic carbamate).

3.4.5.3 Nitrone Cycloaddition The 1,3-dipolar cycloaddition reaction of chiral six-membered ring of nitrone 153 was the key step in a convergent enantioselective synthesis of (C)-febrifugine.

127

128

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

O

O

CO2H

Steps

OBn

CH2Cl2, 0°C (88%), 7:1

N OH (152) OBn

N O (154)

OH O

N

N O

N

+

+ N O− (153)

Steps

Toluene, reflux (48%)

OBn

MnO2

N H

N

N N

O (+)-Febrifugine

O (155) Scheme 3.53

Thus, the oxidation of piperidine 152, which was derived from l-glutamic acid, with MnO2 yielded a 7:1 mixture of separable regioisomeric nitorones. Key 1,3-dipolar cycloaddition reaction of 153 with quinazolone 154 yielded the adduct 155 as the major isomer. This isoxazolidine was converted to (C)-febrifugine in several steps, as shown in Scheme 3.53 [84]. 3.4.5.4 Iminium Strategies Yamazaki and Kibayashi described the construction of the quaternary center at the α-position of the piperidine ring using the acyliminium addition reaction on similar tricyclic N-acyl-N,O-acetal 156. This method was applied to the asymmetric synthesis of ()-adaline. Lewis acid promotes C–O bond cleavage to form the N-acyliminium ion, which preferably conforms with the hydrogen atom in the

O

N

TMS

O

O

TiCl4 (76%) (16:1)

Me

(1) LiH2NBH3 (88%)

N

H O

(2) TPAP, NMO (80%)

Me

Me

OH (158)

(156)

Cl3Ti

O O

(157)

Me

+ N H

(159)

Pentyl

Figure 7 Nu

HC ≡ CLi•H2NCH2CH2NH2 (5 equiv) (88%)

O Steps

Steps N H (160)

Scheme 3.54

N

N

N CHO

(161)

H

(−)-Adaline

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

inside position to minimize the 1,3-allylic strain. Subsequent nucleophilic addition to 157 is expected to occur from the less hindered bottom face leading to the R conﬁguration in the piperidone to give 158 (Figure 3.7). Reduction of 158, and then tetrapropyl-ammonium perrathenate (TPAP) oxidation of the resulting alcohol yielded 159. Upon treatment of 159 with lithium acetylide ethylenediamine complex, the nucleophilic alkynylation proceeded with complete inversion of conﬁguration at the reaction center with concomitant removal of the 1-(2-hydroxyphenyl)ethyl function via C–N bond cleav-to yield 160 as the sole diastereomer. Further elaborations on 160 via 161 yielded the ()-adaline (Scheme 3.54) [85]. The asymmetric Morita–Baylis–Hillman type reaction of six-membered N, O-acetal with cyclic enones was reported by Aggarwal. In the presence of chiral sulﬁde 162 derived from camphor sulfonic acid and TMSOTf, high enantioselectivity was achieved (Scheme 3.55). In this reaction, the use of piperidine-based N, O-acetal yielded the adducts with improved enantioselectivity values compared to the pyrrolidine series. When the acyclic enone methyl vinyl ketone (MVK) was employed, the enantioselectivity value of the corresponding adduct was very low [86]. Blaauw reported the total synthesis of (C)-epiquinamide by using a highly diastereoselective N-acyliminium ion allylation, and RCM to yield a quinolinone skeleton. The N-acyliminium allylation of 163 yielded the 2,3,6-trisubstituted piperidine 164, which was converted to acrylamide 165. The RCM reaction of 165 using Grubbs 2nd catalyst yielded the quinolinone 166, which was transformed into (C)-epiquinamide in several steps, as shown in Scheme 3.56 [87]. In the following example, the synthesis of new six-membered multifunctional chiral building block 167 was obtained through the ring transformation of an optically active butenolide (as already illustrated in Section 3.4.4). Imide 167 is a very versatile chiral building block for the synthesis of natural alkaloids such as epiquinamide [88], homopumiliotoxin 223G [88], deoxocassine [89], and biologically important molecules such as L-733,060 [90], L-733,061 [89], and CP-99,994 [90]. The key feature of Huang’s approach is regio- and diastereoselective installation of the nucleophile on the 2-position of 167. On treatment of piperidinol, derived from regioselective reduction of 167 with NaBH4 and then with BF3 žEt2 O, the phenyl

S O (1.5 equiv)

O

O

(162)

N

OMe

Cbz

n

TMSOTf (2.5 equiv) CH2Cl2, −60 °C

H N Cbz

n

n = 1: 88%, 94% ee n = 2: 49%, 98% ee

Scheme 3.55

129

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

130

O

(1) HBr, AcOH O

TMS BF3•Et2O

HO

Steps

MeO NH2

CO2Me −30 °C to rt (95%)

N

CO2H

N

CO2Me

Cl Et3N, 65 °C

Cbz (164)

(1) Grubbs 2nd cat. (10 mol%)

HO Steps

H N

(2) H2, Pd/C (63%)

AcHN H

CO2Me

N

O (166)

O (165)

O

CO2Me (3)

N

Cbz (163)

HO

(2) K2CO3 MeOH (85%)

HO

(+)-Epiquinamide

Scheme 3.56

migration from the tert-butyldiphenylsilyl (TBDPS) protective group smoothly proceeded to yield 168 in 80% isolated yield with high cis (>95%) selectivity. Reduction of lactam moiety and deprotection of para-methoxy-benzyl (PMB)-group followed by protection with (Boc)2 O yielded 169. Further two-step treatment of 169 yielded (C)-L-733,060. On the other hand, the Boc-derivative 169 was transformed into the amino-derivative 171 via the reduction of the corresponding oxime 170. Further elaboration yielded (C)-CP-99,994 (Scheme 3.57).

O

−78 to 40°C (90%)

CONPNB

O

OR

t -BuOK, THF

H H

O

OH N

O

PNB TBDPSC limid., CH2Cl2 (94%)

Steps

N

Ph

(1) NaBH4 MeOH, −20 °C (94%) (2) BF3•Et2O CH2Cl2, rt (80%)

OH O

N

R=H (167): R = TBDPS CF3

(1) NaH, DMF, rt 3,5-(CF3)2C6H4CH2Br (75%) (2) TFA, CH2Cl2, rt (93%)

Boc (169)

Ph

PNB (168)

O N

Ph

CF3

H (+)-L-733,060

2 steps NOH N Boc (170)

Scheme 3.57

Ph

Ac2O

NH2

BH3•SMe2

THF, rt THF, 55 °C (65%) (86%)

N Boc (171)

Ph

H N

Steps N

Ph

OMe

Boc (+)-CP-99,994

3.4 Monocyclic Piperidines and Carbocyclic Fused Systems

131

3.4.5.5 Oxidative Methods Oxidative methods, and particularly electrochemical process, proved to be valuable in the asymmetric synthesis of nitrogen compounds and piperidine derivatives. For example, the stereoselective synthesis of azasugars was obtained by Matsumura through the electrochemical oxidation of chiral piperidine derivatives. The enaminoester 100 was synthesized by anodic oxidation of 172 or 173 in 80% and 66% yield, respectively. After conversion of 174 to 175, the latter was subjected again to electrochemical oxidation to yield 176. The reduction of 176 with Et3 SiH yielded 177 as the major isomer. On the other hand, electrochemical oxidation of 178 or 179 yielded 180 in 62% and 51% yield, respectively, which was then converted to 181. The electrochemical oxidation of 182 yielded 183, whose α-acetoxy moiety was reduced with Et3 SiH to give 184 (Scheme 3.58) [91]. The sulﬁnyliminium salt instead of acyliminium ion is also effective for the enantioselective nucleophilic substitution on the six-membered ring system. Royer reported the asymmetric synthesis of mono-substituted piperidine using the nucleophilic addition to the chiral N-sulﬁnyliminium salts. The ﬁrst example −2e OAc

N CO2Me (172)

(1) Br2, MeOH, Et3N

Heat

MeOH (80%)

MeO

OAc

N

NH4Cl

N CO2Me (174)

CO2Me

−2e

OAc

MeOH-AcOH (66%) HN

HN

AcO

OAc MeO

OAc

N

CO2Me

MeO2C

CO2Me

MeOH (62%)

MeO

N

−2e

N

HN

O (181)

OAc AcO −2e

HN

CO2Me CO2Me

(2) DBU, DMF (68%)

O

(180)

MeOH –AcOH (51%)

MeO2C

MeO

AcOH/AcOK

N

R

N

O

(179)

O O

O (182)

Scheme 3.58

(176): R = OAc (177): R = H

(1) Br2, NaOMe MeOH

DME/MeOH (80%)

CO2Me

OAc

N

Et3SiH (1.2 equiv) MeSO3H (1.5 equiv) 0 °C (53%)

NaBH4

CO2Me

(178)

R

CO2Me

(175)

−2e CO2Me

−2e AcOH/AcOK

CO2Me

(173)

N

OAc (2) DBU, DMF (56%)

Et3SiH (1.2 equiv) MeSO3H (1.5 equiv) 0 °C (57%)

(183): R = OAc (184): R = H

132

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles H N

O MeMgBr then menthyl arylsulfinate

S N

Ar

O

S

Ar OMe

N

Anodic oxidation

+

O

S

Ar

OMe Ar = p -Tol (84%, 98% ee) o -Tol (82%, 94% ee) Ph (88%, 98% ee) o -CF3-C6H4 (87%, 99% ee)

(138)

(185a) (185b) (185c) (185d)

Me

OTMS

TMSOTf (0.4 equiv) −78 °C O

S

Ar

N O CF3 TMSOTf (1.2 equiv) (185d)

Alkynylalanes (2 equiv) −78 °C

O

(1) 3 M HCl (88%) S

R

N

H N

(2) H2, Pd/C (90%) (3) IR 120H (R = n-Pr)

(187)

(186) (R = n -Pr)

Scheme 3.59

was the anodic oxidation of chiral sulﬁnylpiperidines, which was prepared from piperidine and menthyl arylsulﬁnates in high yields (82–88%) and enantioselectivity (94–99% ee). The anodic oxidation of 185 yielded α-methoxylated sulﬁnylamines along with the N–S bond cleavage products (¾15%). Diastereoselective addition of trimethylsilylpropene to the corresponding iminium salts, derived from 185 d with TMSOTf, proceeded to yield the adducts in acceptable diastereoselectivities (64–84% de). α-Alkynylation, as a further application of the chiral sulﬁnyliminium salt to the synthesis of mono-substituted piperidine, was also investigated. In this reaction, o-triﬂuoromethylsulﬁnylpiperidine showed best result, and the α-alkynylated products were obtained with high diastereoselectivities (92–97% de). The absolute conﬁguration of the adduct was assigned by conversion of 186 to known 187 (Scheme 3.59) [92].

3.5 Fused Tri- or Bicyclic System with Bridgehead Nitrogen

Several syntheses of bicyclic systems with bridgehead nitrogen have already been described in the above sections as an illustration of synthetic methods used in the asymmetric synthesis of piperidines (see Sections 3.2, 3.3.4, 3.3.5, Nitrogen α –Carbanion, Iminium Addition, 3.3.2.3, 3.4.5.1, and 3.4.5.4). Some examples reported in the present section could also be considered as piperidines synthesis, though, in general, they are more speciﬁc methods directed toward the preparation of polycyclic systems.

3.5 Fused Tri- or Bicyclic System with Bridgehead Nitrogen (1) t-BuLi, Et2O −78 ∼ −45 °C OBPS OBPS

(2)

O Me (1 equiv) Et2O, −78~−20 °C

S

S

(1) TBAF, THF (98%)

S OTBS NHTs

S NTs O (1.3 equiv)

(3) O

TBS (188)

(3) K2CO3, MeOH 5% Na-Hg, Na2HPO4 (70% for 22 steps)

O O

(189)

THF/ DME, −78~0 °C (53%) H

S

N

H

H

Me

O (190)

N H Me

H Me

S Steps N

(2) LiHMDS, TMSCl THF, −78 °C

H O

H Me

(3) Grubbs’ catalyst (2 nd) benzene, 65 °C (81%) Toyooka endgame sequence

H

H

S

(1) 2 M HCl acetone, reflux (83%)

S

O

(2) MsCl, Et3N, CH2Cl2

Me

H

Me

N H Me

H

H

Me (−)-(205B)

N

(−)-(223AB)

Scheme 3.60

A stereocontrolled total synthesis of natural enantiomer of poison-frog alkaloid ()-205B has been achieved employing a one-pot construction of the embedded indolizidine skeleton as a key step. Thus, the dithiane three-component linchpin coupling reaction of 140 with aziridine and epoxide yielded the desired compound 141. The one-pot construction of the indolizidine ring system was achieved by the removal of the silyl groups, bismesylation of the resulting diol, and treatment of the bismesylate with potassium carbonate in MeOH, followed by the addition of sodium amalgam to yield the indolizidine 142 (69% yield). This indolizidine was transformed into the natural enantiomer of ()-205B. The indolizidine ()-223AB was also synthesized by this convergent strategy (Scheme 3.60) [93, 94]. A highly diastereoselective quinolizidine ring closure reaction allowed Ma’s group to achieve the total synthesis of marine alkaloids clavepictines A and B, and pictamine. Thus, the reaction of β-keto sulfone with chiral amine yielded the enamine sulfone 191, which was then converted to alcohol 192 by iminium reduction and to precursor for the key intramolecular conjugate addition reaction. The key cyclization was performed by treatment of 193 with AlCl3 followed by exposure of the liberated amine to aqueous NaHCO3 to yield 195 via the most stable conformer 194. After installation of the dienyl side chain by Julia coupling reaction, the total syntheses of clavepictines A and B, and pictamine were completed, as shown in Scheme 3.61 [95]. Angle’s group reported the general synthesis of pyrroloquinolizidines using m¨unchnone 1,3-dipolar cycloaddition as the key step. The strategy was applied to the

133

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

134

(1) AlCl3, CH2Cl2

OTBS

(2) PhO2S

Br

O

MgSO4

SO2Ph

OBn 3

Steps

(3) Et3N, NaI DMF, 120 °C (75%)

NHBoc

N

TBSO

H

N

TBSO OBn

Me (191) AlCl3, CH2Cl2 then NaHCO3 (aq)

2 steps

N

TBSO

H

SO2Ph

(193)

SO2Ph

N

Boc

Me

OH (192)

TBSO Me

(80%)

Boc

Me

(194)

Steps

N

TBSO

N

RO Me

Me

SO2Ph (195) n Clavepictine A: R = Ac, n = 4 Clavepictine B: R = H, n = 4 Pictamine: R = Ac, n = 2

Scheme 3.61

synthesis of unnatural homolog of the ant-alkaloid mymicarin 215B. The chiral bicyclic lactam 197, prepared from 196, was subjected to 1,3-dipolar cycloaddition reaction with disubstituted alkyne 198 to yield the adduct 200, which was then transformed into 201, a homolog of mymicarin 215B. This is the ﬁrst example of the

N

H2O, MeOH (72%)

O CN (196)

O

(198)

KOH N

H

O

H

H I 2 steps

N O CO2H (197)

Me Ac2O, t-Bu

N

t -Bu

Toluene, 100 °C (74%) H + N

H

H Steps

N

N

−

O O (199)

Scheme 3.62

O

(200)

(201)

References (1) EtOAc/EtOH Na2SO4 piperidinium acetate 100 °C

O

(•93:7) H

(2) 5% Pd/C, H2 (50%)

R

NH

O

N

HO

HO

MnO2 (30 equiv) MeOH / CH2Cl2 (60 – 80%)

(203)

R = CH2OH (202): R = CHO O

(1) Toluene/EtOH, Na2SO4 piperidinium acetate 150 °C

TBDPSCl imidazole (202)

(50%)

NH

O

(2) 5% Pd/C, H2 (60%)

TBDPSO (204) O

H

(6:4) H

Known

H

N TBDPSO

H

N

HO (205)

(+)-Gephyrotoxin

Scheme 3.63

1,3-dipolar cycloaddition using the tricyclic m¨unchnone such as 199 (Scheme 3.62) [96]. A novel and highly stereoselective intramolecular formal [3 C 3] cycloaddition reaction of vinylogous amides tethered with α,β-unsaturated aldehydes allowed straightforward access to indolizidine skeleton. This methodology was extended to efﬁcient formal synthesis of gephyrotoxin. Thus, the cycloaddition of 202 yielded the tricyclic compound 203 with high stereoselectivity. This ring system was key intermediate for the synthesis of gephyrotoxin; however, the stereochemistry of the newly formed position was opposite for gephyrotoxin synthesis. On the other hand, the cycloaddition of 204 yielded the desired cycloadduct 205, which is the key intermediate of the Kishi’s gephyrotoxin synthesis, although the stereoselectivity on the key cycloaddition reaction was low (Scheme 3.63) [97]. References 1 (a) Bailey, P. D., Millwood,

P. A. and Smith, P. D. (1998) Chem. Commun., 633–40; (b) Weinstraub, P. M., Sabol, J. S.,

Kane, J. M. and Borcherding, D. R. (2003) Tetrahedron, 59, 2953–89; (c) Buffat, M. G. P. (2004) Tetrahedron, 60, 1701–29;

135

136

3 Asymmetric Synthesis of Six-Membered Ring Heterocycles

2

3

4 5

6

7 8

9

10

11 12 13

14

15 16

17

18

19

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139

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles Yves Troin and Marie-Eve Sinibaldi

Seven-membered ring nitrogen heterocycles (azepines) together with moremembered substrates, in particular azocines (eight-membered azacycles) and sometimes azonines (nine-membered azacycles), are important classes of compounds occurring in a range of natural and synthetic products with interesting biological activities leading to application in pharmaceutical research [1a,b,c]. However, the generation of these medium-sized ring molecules, in particular of the eight or moremembered ring compounds, constitutes always a challenge in organic synthesis. We summarize herein the different asymmetric methods described for the elaboration of these skeletons. 4.1 Substituted Azepines 4.1.1 Generalities

The azepine (azacycloheptatriene system) exists in four tautomeric forms with the relative stability, 3H->1H->2H->4H-(Scheme 4.1). Dihydro- and tetrahydroazepines are the most common azepine substrates forming the pharmacophores of many biologically active compounds [1d]. For example, simple N-substituted hexahydroazepines are interesting substrates which are recognized as antitussives, mydriatics, antispasmodics and oral hypoglycemics, and, azepan-2-one (ε-caprolactam) which has been industrially used in the production of perlon constitutes the cornerstone starting material in the preparation of more elaborated azepanes. Moreover, variously substituted hexahydroazepines are compounds of particular interest. Thus, hexahydro-azepin-4-ol derivatives possess most often analgesic properties; for example, proheptazine is recognized to have twice the analgesic effect of morphine without addictive effects. Balanol, a bisubstituted hexahydro-azepine is an antineoplastic inhibitor of protein kinase C and plays an important role in cellular growth control, regulation and differentiation (Scheme 4.2) [1e]. Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

140

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

NH 1H-azepine

2H-azepine

N

N

N

3H-azepine

4H-azepine

Scheme 4.1 Azepine systems.

Ph OCOEt Me N Me

Me Me

OH

O HO

O

O O

Proheptazine

OH OMe H N

HO CO2H

HN

OH (−)-Balanol

NH

O

R

NR2

OH OH O Bengamides

N H

O HS

R1

N H

N O

OR

HCl NH

Iminohomopiperidinium salts

R1 = H, OCO(CH2)12CH3 R2 = H, Me

Vasopeptidase inhibitors

Scheme 4.2 Azepanes with biological activities.

Imino-homopiperidinium salts are known to be selective inhibitors of inducible nitric oxide synthase and could be therefore considered as therapeutic agents in arthritis (Scheme 4.2) [1f]. Seven-membered lactams are also of considerable interest in drug discovery and pharmaceutical research. For example, the bengamides, a family of marine natural products differing only in their lactam moiety, show anthelmintic and antitumor activities [1g]. Hydroxamic acid–derived azepinones are depicted as vasopeptidase inhibitors having selective angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition (Scheme 4.2) [1h]. Moreover, the aza-seven-membered ring could be also found fused with other rings leading to structures with various interesting properties. In particular, benzazepines constitute a core scaffold of many active compounds including integrin antagonists [1i], selective 5HT2C receptors agonists [1j] or oxytocin (OT) receptors [1k]. Dihydrobenzoazepines are components of a series of psychopharmaceuticals such as desipramine [1l] (Scheme 4.3). Benzazepine-3-one and its derivatives have been used as adrenaline antagonists, inﬂammation inhibitors, drugs with cholesterol-lowering properties, or mediators in cellular adhesion events. Phenylbenzazepines possess selective dopamine D1 agonist or antagonist properties, like SCH23390 or Fenoldopam (Scheme 4.3) [1m]. Recently, fused azepine like thieno[3,2-b] azepine derivatives which acted as arginine vasopressin antagonists were also synthesized (Scheme 4.3) [1n]. Many polycyclic complex alkaloids, including an azepine ring in their skeleton, also exhibited interesting properties and were therefore suitable targets for total synthesis.

4.1 Substituted Azepines OMe

Me2N

H N N

S

N

O O Arginine vasopressin antagonist

N H

Desipramine

Cl

NH

NCH3

Cl

HO HO

Fenoldopam

HO SCH23390 OH

Scheme 4.3 Fused-azepine derivatives.

Among them, we found the Stemona alkaloids [1o] with a pyrrolo[1,2-a]azepine core like stemoninoamide, neotuberostemonine, and so on, the extracts of which have been used for years in China and Japan as human cough remedies and also as an antihelminthic in domestic animals. More recently, insecticidal properties also have been recognized (Scheme 4.4) [1p]. We can also mention the Amaryllidacae family with the well-known alkaloid (−)-galanthamine possessing a seven-membered aza nucleus fused with a 2,3-dihydrobenzo[b]furan. This compound commercially available as Razadyne acts as a selective acetylcholinesterase inhibitor and is in clinical use for the symptomatic treatment of Alzheimer’s disease [1q]. Lycoramine a member of galanthamine type alkaloid family has similar but albeit less potent activity (Scheme 4.4).

O

H OH H

O

O

O

O

O

H

H

H

O

N

H

O H

H

H

N

H

O

N

Sessilifoliamide B

Stemoninoamide Neotuberostemonol OMe RO

N 8

H

7

O N O R = H (Cephalotaxine) OH R= (CH2)2C(OH)Me2 (Harringtonine)

O

MeO

O

OH H (−)-Galanthamine (∆7,8) (−)-Lycoramine

O CH2CO2Me

Scheme 4.4 Polycyclic complex alkaloids with azepine ring.

141

142

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

Finally, but without being exhaustive, alkaloids from Cephalotaxus genus owning a spiro-fused benzazepine core are of considerable current interest, in particular the well-known naturally occurring ester derivative homoharringtonine (HHT) which exhibits antitumor activities [1r,s]. The different methods related to prepare the seven-membered heterocyclic ring of azepine derivatives are classiﬁed in four concepts: cyclization, cycloaddition reactions, ring transformation processes, or substitution of a preformed seven-membered ring. 4.1.2 Cyclization Methods 4.1.2.1 Lactamization: C–N Bond Formation The intramolecular reaction of an ω-aminoester is the most current route to prepare azepanes but provided in most cases low yields of the desired seven-membered lactams. Activation of either the carboxyl or the amino function together with the use of coupling reagents (catecholborane, carbodiimide, (Benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexaﬂuorophosphate (BOP), Diphenylphosphoryl azide (DPPA), etc.) allowed to increase the yield of the reaction [2]. Thus, an efﬁcient asymmetric synthesis of the vasopeptidase inhibitor BMS189921 was reported starting from 1, prepared in four steps from 2-nitropropane using an enantioselective hydrogenation with (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)-benzene (cyclooctadiene) thodium(1)triﬂuoromethanesulfonate([(COD) Rh-(S,S)-EtDuPHOS]OTf) followed by a Zn, HCl/MeOH reduction of the nitro group [3]. Alkylation and selective saponiﬁcation of the methyl ester gave the azepine precursor 2 in 88% yield. Formation of the seven-membered ring was performed by lactamization of the amino acid using N-(3-Dimethylaminopropyl)-N -ethylcarbodiimide (EDC)/1-hydroxybenzotriazole (HOBt)/diisopropylethylamine (DIPEA) in dichloromethane providing the azepinone 3 in a 90% yield with less than 2% epimerization (Scheme 4.5). (1) Acroleine, Et3N (2) DBU, CH2Cl2, 90%, 92% (Z) H N Cbz O2N

NH2 ButO2C

PO(OMe)2 CO2Me

(3) H2, MeOH, 40 psi

Cbz

(1) BrCH2CO2tBu, DIPEA, CH3CN, 90%

H N

(2) Saponification 98%

CO2Me

[(COD)Rh-S,S-EtDuPHOS]-OTf 90%, ee 99%, then Zn, HCl

(1) EDC, HOBT

CO2H

O H2N

Ph

N O

H N

(2)

(1)

DIPEA, CH2Cl2, 90% (2) H2, Pd(OH)2 MeOH, 92%, ee 97%

Cbz

H N

CO2tBu

(3)

Scheme 4.5 Synthesis of BMS-189921 azepine ring.

SH

N

N H O

BMS-189921

CO2tBu

4.1 Substituted Azepines

OH

(1) HMDS/xylene ∆

O

H2N

NH2

HO

OH (2) 2-Propanol

(50%, 2 steps)

NH

NH2 (4)

NH2

HO

BH3·THF THF, ∆

O

(5)

NH (6)

Scheme 4.6 Synthesis of azepine fragment of (−)-balanol.

The lactam ring cyclization process has been applied to prepare the azepine frameworks of other simple seven-membered lactams such as 6 or 10, precursors of (−)-balanol [4] and bengamides, respectively [5]. Thus diamine 4 obtained in 82% ee from 4-chloro-1-butanol via an asymmetric amino-hydroxylation step underwent a basic intramolecular cyclization affording the ε-caprolactam 5 which could be further transformed by reduction into the expected azepine fragment of (−)-balanol 6 (50% in two steps, Scheme 4.6). Similar methodology has been applied to the synthesis of bengamide B [5]. Iodoepoxide 7, prepared from (D)-aspartic acid was treated with the commercially available imine 8 to give the glycinate 9 in 83% yield as a single diastereomer. After ring opening of the epoxide with benzylmethylamine followed by imine hydrolysis of the amino-alcohol intermediate, the seven-membered ring closure was effected in a sealed tube in basic medium leading to 10 in 86% yield from 9 (Scheme 4.7). Extension of the lactamization reaction allowed also the preparation of bicyclic 5,7-fused lactam. For example, condensation of (S)-valinol and 2 -formylbiphenyl-2carboxylic acid 11, available in two steps from diphenylanhydride, provided under dehydrating conditions lactams 12 as a mixture of two epimers in 96% yield with a 75% de (Scheme 4.8) [6]. In a similar way, stereoselective formation of the 5,7-fused bicyclic lactam 16 has been realized under the classical dehydrating conditions developed by Meyers [7]. Keto-acid 15 (R = H) obtained via the Suzuki cross-coupling reaction of commercially available boronic acid 13 with aryl halides 14 led, efﬁciently, to lactam 16 in the presence of (R)-phenylglycinol with good diastereoselectivity. Treating the

Ph

N

Ph

I O (7)

Ot Bu

(8)

CsOH/CH2Cl2 −60 °C, 18 h, 83%

O H2N

N

CH3

Ph

4 steps

OtBu

OCH3

H3C OH

(3) H2, Pd(OH)2 (4) NaOCH3, CH3OH sealed tube, 80 °C 86%

O

OH

OH OH (10)

(2) 10% aq. citric acid

N

(9)

CH3

(1) BnNHMe, CH3OH

O

Ph

O

H N

O N

CH3

O

Bengamide B

OCOnC3H27

Scheme 4.7 Synthesis of the seven-membered lactam ring of bengamide B.

143

144

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles O

O CO2H CHO

(S)-Valinol

aR

S

Pri S

N H

Pri

+

N

O

H

(aR,S,S)-(12a), major

(11)

O

(aS,R,S)-(12b), minor

Scheme 4.8 Lactamization to bicyclic 5,7-fused lactam.

CO2Et

COMe + B(OH)2 (13)

Y

CO2R

Pd(PPh3)4 (8%) K2CO3/toluene:H2O/∆ 48 h

X

Y MeOC

(14) X = Br, I, Cl

(15) O Me

O Me (1) Aqueous NaOH/EtOH, rt, 48 h (2) (R)-Phenylglycinol/toluene, ∆ Y = CH R = H, de = 86%, yield = 88% R = Et, de > 95%, yield = 95% Y=N R = Et, de > 95%, yield (16d) = 81%

H

R N S

Ph

H +

N

Ph

aS

O

Y

Major Y = CH, (aR,3R,13bS)-(16a) Y = N, (aR,3R,13bS)-(16c)

O Y Minor Y = CH, (aS,3R,13bR)-(16b) Y = N, (aS,3R,13bR)-(16d)

Scheme 4.9 Use of phenylglycinol in the synthesis of bicyclic 5,7-fused lactam.

ester of 15 (R = Et) under the same conditions furnished the lactam 16b as a single isomer in more than 90% yield (de > 95%). A successful application concerned the preparation of the lactams 16c,d incorporating now a heterocyclic ring (Scheme 4.9) [8]. Pyrroloazepinone aminoacid (7R)-18 or (7S)-18 was prepared in 11 steps and 13% overall yield from pyrrolidine 17, easily obtained from pyroglutamic acid. The seven-membered ring cyclization was realized using, either O-(7-azabenzotriazol1-yl)-N,N,N ,N -tetramethyluroniumhexa-ﬂuorophosphate (HATU), or O-benzotriazol-1-yl-N,N,N ,N -tetra-methyluroniumtetraﬂuoroborate (TBTU) with DIEPA in yields ranging 50 and 60%. For example, conversion with HATU gave 18 as a 2:1 mixture of diastereomers easily separated by chromatography on silica gel (Scheme 4.10) [9a]. Moreover, this convenient method allowed an access to the two ring-fusion isomers with good yields. Another application has been reported for the synthesis of Stemona alkaloids [9b]. The synthesis of ‘‘trans’’- or ‘‘cis’’-7,5-fused lactams 20a–d was also efﬁciently achieved starting from the ‘‘trans’’- or ‘‘cis’’-5-allylproline derivatives 19a or 19b, respectively. The crucial ﬁnal ring closure was performed using, for 19a, a EDC/HOBt-promoted lactam formation and for 19b a thermal basic lactam ring formation leading, in each case, to a mixture of the two possible epimers which were then easily separated by ﬂash chromatography (Scheme 4.11) [9c].

4.1 Substituted Azepines 10 steps

O

N H

CO2H

O N H.HCl O NHFmoc (17)

26%

HO2C Pyroglutamic acid

H

H HATU

60%

+

N

Et(iPr)2N, CH2Cl2

FmocHN

O O (7S)-(18)

O

N FmocHN

O

O O (7R)-(18)

Scheme 4.10 Synthesis of (7R)- or (7S)-pyrroloazepinone amino acid.

N

BocHN (1) Boc2O, DMAP, THF then H2, Pd/C, MeOH

3 steps,75% CO2tBu N CBz

CO2t Bu

N H (19a)

MeO2C NHCBz

79% (2) NaOH, MeOH, 84% (3) EDC, DMAP, HOBt, NEt3, CH2Cl2, 72% (20a/20b) = 1:1

(20a)

O

CO2tBu

+

N

BocHN (20b)

O

CO2tBu

N NaOH, MeOH H2,Pd/C

4 steps, 71% CO2tBu N CBz

N H

40% (20c/20d) = 85:15

NCBz

CO2tBu

N

(19b) Z:E = 6:1

MeO2C Boc

CO2t Bu

BocHN (20c) O +

BocHN O (20d)

CO2tBu

Scheme 4.11 ‘‘Cis’’- or ‘‘trans’’- allyl-prolines as precursor of 5,7-fused lactams.

During the diastereoselective formal synthesis of benazepril•HCl [10], an antihypertensive drug, Yang et al. used an in situ intramolecular cyclization of an amino group with an ester function to create the bicyclic 6,7-fused skeleton. The precursor 22 was obtained by an asymmetric aza-Michael addition reaction of the l-homophenylalanine ethyl ester with the nitro compound 21 as a diastereoisomeric mixture. The diastereoselectivity of the 1,4-addition reaction depended upon the solvent, the temperature and the stoichiometry. Compound 22 was then reduced by a catalyzed Pd/C hydrogenation to its amino derivative which, under acidic treatment in toluene, led to the attempted (2S, 3 S)-caprolactam 23 easily transformed to benazepril (Scheme 4.12).

145

146

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

CO2Et

NH2 O

CO2Et +

O

OCH3

rt, 90%

OCH3

(21)

HN

CH2Cl2

NO2

O

NO2

(1) H2, 150 psi, Pd/C

3′

40 °C, THF (1N HCl) (2) AcOH/toluene, 90 °C 40%

O (22) (S,S)/(R,S) = 4.5:1

2

H N

N O CO2Et R (23) R = H Benazepril R = CH2CO2H

Scheme 4.12 Diastereoselective formal synthesis of benazepril.

4.1.2.2 Radical Cyclization Numerous reports illustrated the construction of ﬁve- and six-membered heterocyclic rings by radical cyclization processes [11]. By contrast, less favorable cyclization to seven-membered ring has been less studied. During their work devoted toward the total synthesis of (−)-balanol, Naito et al. [12a] described the radical cyclization of aldehyde 24a with SmI2 in the presence of Hexamethylphosphoric triamide (HMPA) leading preferentially to the trans seven-membered ring 25a in 46% yield (Scheme 4.13). Selectivity has been explained by chelation between the Sm(III)(HMPA)n cation to the carbonyl and the oxime ether moieties. By the same way, Skrydstrup et al. [12b] synthesized the hexahydro-azepine 27 with high trans selectivity (10:1) by a Sm(II)iodide/HMPA induced pinacol-type cyclization of the corresponding acyclic hydrazone precursor 26. Upon treatment with tributyltin hydride and 2,2 -azobis(2-methylpropionitrile (AIBN), oxime ether 24b underwent stannyl radical addition–cyclization with high selectivity to the major trans-hexahydro-azepine fragment 25b in an exo-trig reaction pathway (Scheme 4.13) [12c]. Finally, the enantiomerically pure hexahydro-azepine framework (3R, 4R)-29a,b, precursors of (−)-balanol, was obtained (i) after chemical optical resolution of the diastereomeric esters of the racemic alcohols 28 derived from 25 or (ii) by enzymatic optical resolution of 28 using the immobilized lipase Pseudomonas sp. (Scheme 4.14) [13]. HO

NHOR2

O R1

N

N

NOR2

(24a) R = Boc, 1

R = Bn 2

(24b) R1 = Z, R2 = Me

SmI2/HMPA

t-BuOH Bu3SnH AIBN

O R1

(25a) R = Boc, 1

TsN

N NPh2

R = Bn 2

(25b) R1 = Z

(26)

SmI2 /HMPA THF, Ar 20 °C 59%

HO

H N NPh2 NTs

(27) trans :cis >10:1

R2 = Me

Scheme 4.13 Use of radical cyclization processes to azepine fragment of (−)-balanol.

4.1 Substituted Azepines

O *ROCO

HN

OBn

(1) NEt3, DMAP, CH2Cl2 rt, 7.5h

OH

NBoc

(2) Separation 95%, ee > 99%

NHR

(3R,4R)-(29a)

O N Boc Immobilized lipase (±)-(25a) R = OBn (±)-(28) R = COp -PhOBn vinylacetate, t-BuOMe,

HN

AcO

20 h, 42%, ee 96%

OBn (3R,4R)-(29b)

NBoc

Scheme 4.14 Chemical or enzymatic optical resolution of ester (±)-28.

H OMe OMe

OMe OMe H

O

12

N

N

H OMe OMe

O +

H

H

O

N

N

H

O

H

H

H

Br (30)

(31a)

(32)

(31b)

Scheme 4.15 Radical cyclization to azepino-indoline of Stemona alkaloids.

The azepino-indoline skeletons of the Stemona alkaloids have been efﬁciently prepared by radical cyclization [14] of hydroindolone 30 (Scheme 4.15). Thus, azepinoindolines 31a and 32 were obtained in a 5:1 ratio and 85% overall yield using Ph3 SnH/AIBN in reﬂuxing benzene under slow addition. The major formation of 31 arose from a 7-endo-trig radical cyclization process. Reduction of the lactam moiety followed by C-12 equilibration in acidic medium, permitted an access to 31b owning another ring-fusion type of the Stemona compounds. In 2000, Evans et al. [15] related the ﬁrst examples of the intramolecular addition of acyl and alkyl radicals to oxauracil for the diastereoselective construction of trans-disubstituted-6,7-azabicycles 33 (Scheme 4.16). Octahydrocyclopenta[b]azepines were obtained with excellent stereoselectivity by a 7-endo cyclization of various chiral vinylogous amides as reported by Cordes and Franke [16] in 2004. By this way, 34 was N-acylated with (S)-(−)-2-acetoxypropionyl chloride to give chiral enaminone 35 in 82% yield. Treatment of 35 with Bu3 SnH in the presence of the radical initiator 1,1 -azo-bis(cyclohexanecarbonitrile) (ACN) O (TMS)3SiH Et3B, O2

O Y X

O

N R

X = O, Y = SePh X = H2, Y = Br R = Me, Ph

X

X

H N

O

+

N R

R

Scheme 4.16 trans-Disubstituted 6,7-azabicycles.

H

(33a)

ds > 19:1

(33b)

O

147

148

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

O

O

Bu3SnH, ACN toluene (0.01 M) reflux, 21 h

SePh N R O (34) R = H (35) R = H2C O

O

H

H

+

47%

H

N

H

O O

N O

O

(36a)

(36b)

Scheme 4.17 Diastereoselective synthesis of octahydrocyclopenta[b]azepines.

afforded the enantiopure azabicycles 36a,b via a 7-endo ring closure in 47% yield (2:1 ratio). Changing the chiral appendage on the nitrogen atom of 35 (use of (1S)-(−)-camphanic chloride) permitted the formation of a single trans-fused octahydrocyclopenta[b]azepine in 44% yield with the relative stereochemistry of 36a (Scheme 4.17). An original and efﬁcient approach to chiral 1,3-perhydrobenzoxazines 39 precursors of 3-substituted hexahydroazepines has been described. Thus, compounds 38, generated in two steps from 37, were engaged in an intramolecular radical addition promoted by Bu3 SnH affording a nearly quantitative mixture of 7-endo 39a,b and 6-exo 39c,d cyclized compounds in a ratio depending upon the substituents at the α-position of the double bond (Scheme 4.18). When R2 = Me and R1 = H, the cyclization step delivered a mixture of three products40a–c in favor of the 7-endo cyclization (75, 12, and 13% yields, respectively). The major one 40a was further transformed into the enantiopure chlorhydrate (S)-3-methylperhydroazepine 41 in 70% yield [17].

OH NH2

O N

SePh

O (37) 8-Aminomenthol

O N

H

O R2 R1 (39a)

(38)

O

R2

N

R1 Bu3SnH/AIBN C6H6, ∆

R2

R1

O N

+

O H R1 (39b)

O R2 N

O (39c)

R2

7-endo cyclization

(39d)

O

6-exo cyclization O N O 1

H

H

CH3 2

(40a) R = H, R = Me

Me

+ N

70%

Cl− H

(41)

Scheme 4.18 Asymmetric approach to 3-substituted perhydroazepines.

R1

4.1 Substituted Azepines

H

O GPHN

+

10 mol%

N

O

R2

OR1 (43)

(42)

O

O OR1

R

2

(44) O

Deprotection 7-endo-dig cyclization/isomerization 82 – 97%

GP

PhCH3, 23 °C, 24 h 76 – 86%

R N

CO2R

R2

N R

GP = protective group

1

Me

(45) Scheme 4.19 Azepine from 7-endo-dig cyclization of allenoate esters.

Vinyl ketones 42 derived from N-protected amino acids were coupled to allenoate esters 43 to furnish 44 which, after amine deprotection followed by 7-endo-dig addition of nitrogen to the electron-deﬁcient sp-carbon of the allene and isomerization, afforded the azepines 45 in excellent yields (Scheme 4.19) [18]. 4.1.2.3 Intramolecular Cyclization Pyne et al. [19] developed a convergent preparation of the tricyclic B,C,D-ring core structure of croomine, a natural product possessing a pyrrolo[1,2-a]azepine skeleton. The key precursor 48 was prepared by a tandem chiral vinyl epoxide aminolysis/ring-closing metathesis (RCM) sequence starting from amine 46 and epoxide 47 and was then engaged in an intramolecular SN 2 process to generate the 1H-pyrrolo[1,2-a]azepine 49 in a good yield of 68 % (Scheme 4.20). Beak and Lee [20] reported an efﬁcient asymmetric synthesis of 3,4,5- and 3,4,5,6-substituted hexahydroazepines 54 and 55 starting from enantio-enriched ene-carbamates 51 themselves obtained via a (−)-sparteine-mediated asymmetric lithiation of allylamines 50 (Scheme 4.21).

H OTBDPS

TBDPSO

TBSO H

NH2

(46)

N H H

H +

O

H

TBDPSO

OTBS (47)

OPMB

OH (48) Me

HO PPh3, CBr4 NEt3, 0 °C, 81% then HCl, MeOH, CHCl3 90 °C, 3 days, 84%

O H

H

N

O

H H

OH (49)

OH

H N

H

Croomine

O O

Scheme 4.20 Diastereoselective access to 1H-pyrrolo[1,2-a]azepine framework.

149

150

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

R

(1) nBuLi/L*, toluene, −78 °C R2

1

(2)

Ar

NBoc (50)

Br

R

CO2Et

(3) Me3Al/RNH2 CH2Cl2 76 – 91%

(51) O

HCl (aq), CHCl3

R1

R

N

R2 (52)

R2 R1

N R Ar

2

(1) LDA, THF, −78 °C (2) Electrophiles

N R (53)

O

73–92%

Boc NHR

96–98%

R O

Ar

LAH, THF

R1

EtOH, H2, Pd(OH)2

Ar

N

Ar

Ar or Raney-Ni 93 – 99% dr = 96:4 to 99:1

R2 1

−78 °C to rt 71–96% dr 95:5 to 99:1

(54) H3C

CH3

Ar R

N (55) Ar

Scheme 4.21 Asymmetric synthesis of 4,5,6- and 3,4,5,6-substituted azepanes.

Acid hydrolysis of enamide 51 to aldehyde and subsequent cyclization led to the expected seven-membered ring system 52. Hydrogenation of 52 afforded 53 possessing a trans stereochemistry at the C-6 position. Reduction of lactam with LiAlH4 gave efﬁciently trisubstituted compounds 54, whereas substitution at the C-3 position of 53 (for example, R1 = R2 = CH3 , R = Ar) by selected electrophiles provided tetrasubstituted azepanes 55 in good yields and high diastereoselectivity (dr >95:5) (Scheme 4.21). Optically active ω-bromocyanohydrin 56 easily synthesized through an enantioselective (R)-oxynitrilase-catalyzed reaction from its corresponding ω-bromoaldehyde was used as starting material to prepare azepan-3-ol 58 in a high enantiomeric excess. The crucial ring closure took place quantitatively using tBuOK on the (R)-protected bromoamino alcohol 57 with ee of 91% (Scheme 4.22) [21a]. Similar annelation process has been applied to the synthesis of the azepine core of (−)-galanthamine via the mesylate derivative of 59 but in modest yield (Scheme 4.23) [21b]. Williams et al. [22] reported in 2003 an enantioselective synthesis of (−)-stemonine in which, the aza-seven-membered ring is formed by a Staudinger-aza-Wittig cascade reaction of an aldehyde-azide 61 followed by NaBH4 reduction. The chiral azide precursor 61 was itself easily prepared from the optically pure butyrolactone 60 through classical transformations. Cbz Br

CN

( )3

H OH (56)

Br

( )3

NHCbz H OTBDMS

t BuOK, THF

(57)

Scheme 4.22 Enantioselective synthesis of 3-hydroxyazepanes.

N

(58)

OTBDMS

4.1 Substituted Azepines

BocN

HO

N (1) MsCl, NEt3 CH2Cl2, rt

OH

(2) TFA then NaHCO3

OH

O

O

H3CO (59)

H3CO (−)-Galanthamine (23%)

Scheme 4.23 Synthesis of (−)-galanthamine. OTBS O

TBSO 10 steps

BnO

H

H 3C

MeOH 70%

TBSO

N3 O

OTBS CH3 H H

OCH3

CH3

(60)

(1) EtPPh2, benzene rt, 18 h TBSO (2) THF, NaBH4

H

H3C

O H

O

CH3 (61)

H

H 3C

N

CH3

NH H3CO (62)

H

H

O

O

H O

O

O

(−)-Stemonine H

Scheme 4.24 Staudinger-aza-Wittig formation of the azepine ring.

Finally, iodine-induced cyclization of 62 led in a single step to the pyrrolidinobutyrolactone framework with good stereoselectivity which was then further transformed efﬁciently to the tricyclic fused (−)-stemonine (Scheme 4.24). Reductive aminocyclization has been successfully adapted to the elaboration of seven-membered azacycles and we depict below some examples. Palladium-catalyzed asymmetric allylic alkylation of halophenol 63 and α, β-unsaturated ester 64 led to intermediate 65 which was further transformed using a Heck cyclization process to the tricyclic compound 66. Standard transformations afforded then compound 67 which underwent after Boc deprotection a ﬁnal reductive intramolecular amination reaction to give (−)-3-deoxygalanthamine [23] in a good yield (Scheme 4.25). Tri- and tetrahydroxyazepanes which were known as potent glycosidase inhibitors, were obtained in good yields from d-(−)-quinic acid. Oxidative cleavage of alcohols 68 or 69 afforded the corresponding dialdehydes which underwent a subsequent reductive aminocyclization using BnNH2 and NaBH(OAc)3 . Hydrogenation gave azepanes 70 and 71, which were in fact prepared in 10 steps with 17–34% yields from d-(−) -quinic acid (Scheme 4.26) [24]. Chiral nitrogen-containing seven-membered rings have been also efﬁciently prepared using 7-endo cyclization of oleﬁns on N-acyliminium [25]. Thus, enamide 72 was obtained in three steps in a 1:1 ratio of two isomers from N-protected l-phenylalanine used as a chiral template. After separation by preparative high performance liquid chromatography (HPLC), isomer 72a (R1 = CO2 Me, R2 = H) was efﬁciently cyclized by acidic treatment to the optically active azepine

151

152

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles X OHC

OH

CO2CH3 Br

OMe (63) CO2CH3 OTroc

OCH3

Heck reaction O

TBDMSO O OCH3

(65) (64)

TBDMSO

CHO

BocN

(66) NCH3

OCH3 O

MeO

(67)

(1) TFA, CH2Cl2, rt (2) molecular sieves, MeOH, 60 °C (3) NaBH3CN, MeOH, 0 °C 53%

O H3CO (−)-3-Deoxygalanthamine

Scheme 4.25 Azepine ring from reductive intramolecular amination.

derivative 73 possessing the 5-7-6 tricyclic system of cephalotaxine alkaloid. The stereoselectivity of the reaction was excellent and was due to the equatorial conformation adopted by the phthalimide moiety in the acyliminium intermediate structure (Scheme 4.27) [26]. An asymmetric construction of the same 5-7-6 tricyclic core was reported through a Pictet–Spengler reaction [27]. Thus, conversion of the amido-alcohol 74 easily obtained from (S)-malic acid, to the lactams 75a,b was realized in 70% yield with a good regioselectivity using triﬂic acid via an acyliminium cyclization process (Scheme 4.28). The Pictet–Spengler reaction was also efﬁciently applied by Chida et al. [28] to the stereoselective synthesis of (+)-galanthamine starting from d-glucose which allowed the formation of the optically pure cyclohexene ring of the amide precursor 76. Upon treatment with para-formaldehyde in the presence of triﬂuoroacetic acid (TFA), 76 generated the known seven-membered tetracyclic derivative 77, precursor of the alkaloid in 67% yield (Scheme 4.29). Using the same methodology, the azepine ring of (−)-lycoramine was elaborated by Malachowski et al. [29] in 2007 in the ﬁrst enantioselective synthesis of this alkaloid. Even if the Pummerer-cyclization applied to seven-membered ring systems is less efﬁcient than for the six-membered analogs, benzazepine derivatives that are difﬁcult to obtain by others methods have been synthesized using this reaction and a review discussed their preparation [30]. Others cyclization processes have been adapted to the ediﬁcation of azepane framework. For example, Hayes et al. [31a] created the azepine ring of the tetracyclic core of (−)-cephalotaxine [31b], using an intramolecular Heck cyclization. Thus, cyclization of 78, prepared from N-Boc-l-proline ester in seven steps and 7% overall yield, mediated by Pd catalyst afforded the sole formation of the endocyclic oleﬁn 79 in 62% yield (Scheme 4.30).

O

MeO

O

BnO H

MeO

OH

OMe (69)

O

BnO

OMe (68)

O

NaBH(OAc)3 65%

(1) O3, PPh3 (2) BnNH2

NaBH(OAc)3 80%

(1) NaIO4, MeOH (2) BnNH2

Scheme 4.26 Asymmetric synthesis of trihydroxy- and tetrahydroxyazepanes.

D-(−)-Quinic acid

D-(−)-Quinic acid

H OBn OH

Bn

H

O

(71)

N

O

OBn

O

OMe

OMe

H (70) OBn

N

O

MeO BnO

Bn

MeO

H2, Pd/C

2N HCl, MeOH quant

H2, Pd/C

2N HCl, MeOH 99%

HN

HN

HO

HO

OH

OH

OH

OH

OH

4.1 Substituted Azepines 153

154

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

H

CF3SO3H

N

OH

PhtN O N-Phthaloyl-L-phenylalanine PhtN

O

R1

77%

PhtN

R2

(72)

(73)

N O HO2C

Scheme 4.27 Cyclization of oleﬁns on N-acyliminium.

O

O

OH

OMe

OAc

OH 5 steps

OH

27%

OH N

O

(S)-Malic acid

(74) CO2Me

70%

OMe AcO

H

(75a)

MeO AcO H

+

N O

5% CF3SO3H CH2Cl2

N

3:1

O

CO2Me

(75b)

CO2Me

Scheme 4.28 Pictet–Spengler approach to the azepane ring.

8 steps 38%

D-Glucose

O

OBn

MeO OTBS

MeO

NHMe

O O OTBS (76)

H N

(CH2O)n TFA, CH2Cl2 67%

OH

NMe

O O

O H OMe

OTBS (77)

(+)-Galanthamine

Scheme 4.29 Asymmetric synthesis of (+)-galanthamine via a Pictet–Spengler cyclization.

Azaspiro[4.4]nonane framework which constitutes the C/D ring moiety of cephalotaxine has received particular interest. Thus, compound 80, prepared in an enantiomerically pure form using an original semipinacolic rearrangement of an α-hydroxyiminium ion by Royer et al. [32], was chosen as a pivotal compound in

4.1 Substituted Azepines

O

O 7 steps

Dioxane, 100 °C

N N Boc

CO2t Bu

N

Pd(Pt Bu3)2, NMeCy3

Br

H (79)

(78) Scheme 4.30 Heck cyclization to seven-membered lactam.

a-Naph

Me N

O

OTBS +

(1) BF3·Et2O CH2Cl2, −78 °C

a-Naph O N

(2) HCl, CH2Cl2 (3) Purification 66% in 3 steps

O

Me O 6 steps

(80) (1 dia)

O O

OH N

(81)

O

SnCl4 CH2Cl2 CH3NO2

N

O

O

(−)-Cephalotaxine H

−78 °C

Scheme 4.31 Lewis acid cyclization to seven-membered azepane.

the preparation of (−)-cephalotaxine and analogs; the ﬁnal azepine ring closure of 81 precursor was then performed using Lewis acid (Scheme 4.31). 4.1.2.4 Oxidative Phenol Coupling Reaction Optically active (−)-galanthamine has been efﬁciently prepared from l-tyrosine methyl ester and 3,5-dibenzyloxy-4-methoxybenzaldehyde using as key step a phenolic oxidative coupling to create the seven-membered ring [33a]. An improved synthesis of the same alkaloid has been also depicted [33b,c] starting from the protected substrate 82, issued from (R)-N-Boc-d-phenylalanine, and using, in this case, phenyliodine(III)bis-(triﬂuoroacetate) as the oxidant instead of Mn(acac)3 for the oxidative coupling. In this case, the spirodienone 83 was obtained in 61% yield and was then further transformed into (−)-galanthamine. Formation of the last stereocenters of the ﬁnal tetracycle is controlled by the chirality of the (R)-N-Boc-d-phenylalanine which, in fact, promotes a total asymmetric induction (Scheme 4.32). 4.1.2.5 The Ring Closure Metathesis Because of increasing strain in the transition state and entropic inﬂuences, medium-sized rings, for example, 8–10 membered rings are the most difﬁcult to prepare. Among all the cyclization reactions developed to obtain these

155

156

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles HO

O O

HO2C

Bn

3 steps

N

H BocHN

BnO

69%

Bn N

H H3CO OBn

O

PIFA CF3CH2OH

N

61%

H

COCF3 (82) dr > 99.5:0.5

BnO

Bn N

H

H COCF3

H3CO OBn

(83)

(−)-Galanthamine

Scheme 4.32 Phenolic oxidative coupling to aza-seven-membered nucleus.

structures, the RCM provided an alternative efﬁcient pathway to form heterocyclic systems, in particular nitrogen-containing compounds and even to prepare fused-nitrogen subunits present in the natural product area. Therefore, this method has been extensively developed these last years. In fact, numerous syntheses of the seven-membered ring of azepine-compounds using RCM [34] have also been investigated, all the approaches varying only on the strategy developed to prepare the diene and the enyne precursors 84 and 85 and on the type of catalysts used (Scheme 4.33). To facilitate the cyclization, several features were installed in the substrates 84 or 85 providing conformational constraint. These steric hindrances were generally obtained by using preexisting rings (like oxazolidine ring) or acyclic conformational constraints. We introduce here, different routes developed for the RCM cyclization leading to the azepine precursors 84 and 85. Chiral 2-substituted azepines 88 were prepared from bis-oleﬁnated oxazolidines 86 via the [5,3,0]-bicyclic lactam scaffold 87 [35]. These chiral templates were obtained by azeotropic condensation of 5-hexene-2-one with (R)-phenylglycinol followed by treatment with acryloyl chloride. An RCM ring closure of the major 2-(R)-N-acroyl oxazolidine 86 using 5 mol% of Grubbs ruthenium catalyst followed by reduction of the resulting double bond afforded the 5,7-bicyclic lactam 87b in 98% yield as a single product (61% from (R)-phenylglycinol). Stereoselective reduction followed by hydrogenolytic cleavage of the N-benzyl moiety gave ﬁnally the perhydroazepine (S)-88b in 80% yield. The same procedure applied to the syn epimer gave the (R)-88a in 85% yield (Scheme 4.34). Chiral aldoxime ether (S)-89 acted as chiral precursor of allylamine 91 in the RCM approach of 2-substituted tetrahydroazepines. Conversion of 89 to the hydroxylamine 90 followed by N-allylation using allylbromide in the presence of K2 CO3 led to 91 which underwent an RCM reaction by heating in the presence of

N R (84)

ene RCM

NR

enyne RCM N R (85)

Scheme 4.33 RCM applied to azepine derivatives.

NR

4.1 Substituted Azepines

OH H2N

O +

Me

(1) ∆, toluene (2) Acryloyl chloride NEt3, DCM

Ph

(2) H2, Pd(OH)2

Me N

Ph

O Ph N

O (86) (major diastereomer)

Me

O (1) RCM

Me

NH.HCl

O (87b) anti

(S)-(88b) (80%)

Me O Ph N

Me

(1) H−

NH.HCl

(2) Pd(OH)2 H2, EtOH

O (87a) syn

(R)-(88a) 85%

Scheme 4.34 Asymmetric synthesis of perhydroazepine starting from chiral oxazolidines.

Ph

PhLi Ph

Ph N

HN O

(89)

Ph

Ph

Ph

K2CO3, CH3CN

Ph

Allylbromide

Grubbs’ catalyst N

*RO

O (90)

CH2Cl2, heat Ph

N OR*

(91)

Scheme 4.35 Azepines from chiral aldoxime ether.

Grubbs catalyst giving the expected seven-membered heterocycle but in only 9% yield (Scheme 4.35) [36]. F¨urstner and Thiel reported in 2000 [37] a short (eight steps) enantioselective route for the hexahydro-azepine moiety of (−)-balanol with an excellent overall yield. The approach needed the preparation of the diene 92 which was obtained through a four-step sequence starting with a Sharpless epoxidation of divinylcarbinol. RCM reaction of 92 was then conducted in the presence of the ruthenium indenylidene complex 93 giving the tetrahydroazepine 94 in 87% yield (Scheme 4.36). The ﬁrst total synthesis of the complex polycyclic Stemona alkaloid (−)-tuberostemonine, known for its properties against pulmonary tuberculosis and bronchitis, was reported by Wipf et al. [38] The synthesis of its [1,2-a]azepine core was on the basis of an RCM reaction of 96 to form the azepane skeleton. Pivotal intermediate 96 was formed by selective transformations of the building block 95, while the latter was prepared from Cbz-l-tyrosine which served as a scaffold for the installation of nine of the 10 stereogenic carbons of tuberostemonine. Heating a solution of 96 in the presence of the ruthenium catalyst 97 led to the tricyclic precursor 98 of the alkaloid in 92% yield (Scheme 4.37). Intramolecular Grubbs’ oleﬁn metathesis has also been used to obtain chiral fused 7-5- or 5-7-bicyclolactams in good yields [39a]. For example, the pyrrolo[1,2-a]azepine core of (−)-stemoamide was prepared either by an ene [39b]

157

158

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

BnO OH

Sharpless epoxydation

OH

OH

2 steps

O

NBoc

89%

(92)

Cl

O

PCy3

Cl

OH

BnO

Ru

HN

HO

Ph PCy3 (93)

3 steps

NBoc

(5 mol% 93, 24 h) CH2Cl2, ∆

NBoc

50%

OBn

(94)

Azepine fragment of (−)-balanol

Scheme 4.36 Access to azepine fragment of (−)-balanol using chiral divinylcarbinol and RCM.

H

OBz H

3 steps

Cbz-L-tyrosine

N CO2Me H Cbz (95)

HO MesN Cl Cl

H

NMes

Ru PCy3

(97) Ph

H

7 steps

CO2Me

N H (96)

O

H O H

CH2Cl2, ∆, 92%

N

CO2Me

(−)-Tuberostemonine

(98)

Scheme 4.37 Synthesis of [1,2-a]azepine core of (−)-tuberostemonine by RCM.

MeO2C

Cl Cl

H O

N

CO2Me

PCy3 Ru PCy3

Ph H

CH2Cl2, rt, 87% O N OH H (S)-Pyroglutaminol

EtO2C H N

O

CH2Cl2, 40 °C

N O

(−)-Stemoamide

EtO2C

Second generation catalyst 92%

H

N O

Scheme 4.38 Pyrrolo[1,2-a]azepine core of (−)-stemoamide.

or an enyne RCM [40a] reaction starting from protected (S)-pyroglutaminol, which introduced the chirality (Scheme 4.38). Others successful applications of intramolecular enyne metathesis have been reported. Among them, we can mention the enantiospeciﬁc access to the 9-azabicyclo [4.2.1] skeleton core of (+)-anatoxin-a [40b] starting from d-methyl pyroglutamate and using, in this case, as the key enyne a cis-2,5-disubstituted pyrrolidine (Scheme 4.39).

4.1 Substituted Azepines

O

CO2H

N H

BzC

MesN NMes Cl Ru Ph Cl (97) PCy3

N Bz

CH2Cl2, rt 87%

N

9-Azabicyclo[4.2.1] skeleton core of (+)-anatoxin-a

Scheme 4.39 Enantiospeciﬁc synthesis of (+)-anatoxine-a.

(1) Cp2ZrHCl (2) Me2Zn (3) NP(O)Ph2 Ar

R

Ar (4) Zn(CH2I)2.DME (5) NaH, HMPA, allyl iodide, THF, 70 °C

R

MesN NMes Cl Ru Cl Ph (97) PCy3

Ar

(99)

R

H

CH2Cl2, ∆

NP(O)Ph2

N (100)

P(O)Ph2

Scheme 4.40 Diastereoselective approach toward spiroazepines.

ω-Unsaturated dicyclopropylmethylamines obtained by multicomponent condensation of N-diphenylphosphinoylimines, alkynes, zirconocene hydrochloride, and diiodomethane constitutes interesting building block in the synthesis of spiro-azaheterocycles [41]. Thus, the N-alkylated C,C-dicyclopropylmethylamines 99 underwent a ring-closing reaction using second-generation Grubbs catalyst (10 mol%) leading to 1H-azepines 100 in 63–84% yield (Scheme 4.40). Chiral alcohols 101 prepared in good diastereoselectivity (de > 90) from (−)-8-aminomenthol underwent RCM reaction with Grubbs’ catalyst to afford 2-benzoylperhydro-1,3-benzoxazines 102. The mol% of the catalyst used (4–15 mol%) together with the temperature of the reaction (20 ◦ C to reﬂux) and its duration (20–240 h) depended of the nature of the substituent of the double bond [42]. The ﬁnal transformation of 102 into the enantiopure 2,3,4,7-tetrahydro-1H-azepin-3-ols 103 was performed in three steps and 44–56% yield by (i) reductive ring opening of the N,O-acetal moiety with aluminum hydride, (ii) oxidation with pyridinium chloro-chromate (PCC) of the menthol, and (iii) basic cleavage (KOH, tetrahydrofuran (THF)/methanol) (Scheme 4.41).

R1

N

R1 OH R 4 O

CH2Cl2 Cl Cl

R2 R3 (101)

N

PCy3 Ru PCy3

R1 O

OH

OH

HN R4

Ph

R2

R4 (102)

Scheme 4.41 Asymmetric synthesis of 2-benzoylperhydro-1,3-benzoxazines.

R2 (103)

159

160

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

R1 Ph

O O

Cbz N

5 steps

R1

(104) R1 R2

N Cbz (107)

R2

(106) DCE, ∆, 5 h 68–88%

(105)

50 psi, H2, Pd/C AcOH, 20 °C 73–100%

R1 R2

NH

Mst N N Mst Cl Ru Ph Cl PCy3 (106)

(108)

Scheme 4.42 Chiral 4-mono and 4,4 -disubstituted tetrahydroazepines.

A general strategy for the preparation of 4-mono and 4,4 -disubstituted tetrahydroazepines 108 was developed by Merschaert et al. [43] starting with chiral, commercially available or easy to prepare lactones 104. The key aza derivatives 105 issued from 104 underwent then an RCM reaction using Grubbs’ catalyst 106, leading to the unstable seven-membered heterocycles 107 (68–88%) (Scheme 4.42). Hydrogenolysis and concomitant reduction of the double bond furnished the tetrahydroazepines 108 in nearly quantitative yields (Scheme 4.42). 1,2,3,6-Tetrahydro-1H-azepin-3-ols are intermediates in the asymmetric synthesis of azasugars. A method for their stereoselective preparation was reported by Lee et al. [44a] starting from optically pure aziridine 109 and using, as the ﬁnal ring closure pathway, an RCM reaction. Thus, the (2R)-aziridine 109, generated by reaction between (R)-(+)-α-methylbenzylamine and ethyl 2,3-dibromopropionate, was transformed in 73% yield to the allyl ketone 110 using an Horner–Wadsworth–Emmons oleﬁnation. A stereoselective reduction of the ketone function led to the erythro alcohol (2R, 3S)-111 in 96% yield using NaBH4 /ZnCl2 in MeOH and to the threo (2R, 3R)-112 exclusively by treatment with l-Selectride. The N-allylamine 113 was then obtained after regioselective ring opening of the chiral aziridine with a thiolate anion at the less sterically hindered C-1 position followed by alkylation with allylbromide. Subsequent RCM reaction of the resulting bis-oleﬁn with second-generation Grubbs catalyst afforded enantiomerically pure (2S, 3S)- and (2S, 3R)-azepinols 114 and 115 from (2R, 3S)- and (2R, 3R)-alcohols 111 and 112, respectively (Scheme 4.43). Another tetrahydro-(1-H)-azepine-3-ol of similar structure has been also described using a similar methodology, the unique difference being in the synthesis of the chiral precursor which was here obtained through an Evans aldol reaction [44b]. Gmeiner et al. [45] developed a useful synthesis of (2S)-7-membered cyclic dipeptides mimics 119 using an RCM cyclization promoted by ruthenium catalyst of precursors 118. The metathesis precursor 118 was readily available through a N,N -dicyclohexylcarbodiimide (DCC)/HOBt-promoted peptide coupling of glycine derivative 116 with the secondary amine 117, which was in turn prepared from glycine or alanine esters (Scheme 4.44).

4.1 Substituted Azepines Ph

NaBH4, ZnCl2 Me Ph Me N

CO2Et H (109)

OH N

(1) nBuLi CH3PO(OMe)2, −78 °C, 88%

H

Ph Me N

(2) CH3CHO, K2CO3, CH3CN, rt, 75%

(2R,3S)-(111)

H

O Ph

H (110)

Me

H N

OH (2R,3R)-(112)

L-selectride H Ph

Ph (1) PhSH, CH2Cl2 rt, 85% (2) Allylbromide, NaH THF, cat(n -Bu4)NI, ∆, 90%

Me

(2R,3S)-(111)

PhS

Me

Toluene, ∆, 90%

N

PhS HO

OH Ph

(2S,3S)-(114)

(2S,3S)-(113) N

Me

(2R,3R)-(112)

Grubbs’ catalyst (10 mol%)

N

PhS HO (2S,3R)-(115)

Scheme 4.43 Chiral azepines from ring opening of aziridines followed by RCM reaction.

R2 NH2·HCl ClH·HN

R1

CO2 R R = H, R1 = Et or R = R1 = Me

1

R

+ BocHN

DCC/HOBt, DIEA

OH

CH2Cl2

CO2R O (116) R2 = H, Me (117) R2

BocHN

N

R2 CO2R1

O R (118)

42–89% PCy3 Cl Ru CHPh Cl PCy3

BocHN

N O (119)

R

O OR1

Scheme 4.44 Chiral 2-amino seven-membered lactams from aminoacids.

4.1.3 Cycloaddition Methods

Just a few cycloaddition methods were depicted to generate aza-seven-membered ring. The most commonly developed was the [4 + 3] cycloadditions which took place with moderate to high yields with complete regio and diastereoselectivity. Others attractive approaches exploited either 1,3-dipolar cycloaddition of nitrone or intramolecular Diels–Alder reactions (IMDA).

161

162

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

4.1.3.1 [5 + 2] Cycloaddition A concise approach to the C-D-E part 121 of HHT, was reported in 2001 by Booker-Milburn et al. [46a] Intramolecular [5 + 2] photocycloaddition of substituted maleimide 120 led, after reopening of the four-membered ring, to azepine framework which was obtained as a mixture of two diastereoisomers (yield 75%, de 3.5:1) (Scheme 4.45). The same cyclization process was applied also with success to the synthesis of the tetracyclic core of neotuberostemonine [46b] and of oxetanol-fused azepines [46c]. 4.1.3.2 [4 + 3] Cycloaddition Thermal cycloaddition reaction of alkenyl Fischer chiral carbene 122 derived from (−)-menthol with oxime 123 resulted in the formation of diastereomers 124 and 125 in 87% yield and a 7:3 ratio. Changing for (+)-menthol afforded the same diastereomers in 80% yield and a reverse 3:7 ratio. Crystallization of the major one followed by acid hydrolysis allowed the isolation of enantiomerically pure azepinones (Scheme 4.46) [47]. 4.1.3.3 Nitrone Cycloaddition Formation of azepane skeleton has been also envisaged through intramolecular 1,3-dipolar cycloaddition of nitrone to oleﬁne, followed by N–O reductive cleavage processes. An example of this method [48a] consists in the preparation of the pyrrolo[1,2-a]azepine framework 130 by N-allylcarbohydrate nitrone cycloaddition. The precursor 126 was classically obtained in six steps from the 1,2,5,6-di-O-isopropylidene-α-d-glucofurannose and was then transformed to the furanoside-fused pyrrolidine 127 as a 2:1 anomeric mixture in 73% yield using standard reactions. On treatment with N-methylhydroxylamine hydrochloride/K2 CO3

Me O

Me

−

Me

OH

Me

O

H

O

N

Me

N+ O

hn pyrex HO

Me

O

Me

H

N O H HO

H (120)

O

Me N

+ 3.5:1 (121)

O H HO

Scheme 4.45 Diastereoselective access to azepines derivatives by [5 + 2] photocycloaddition.

Ph

Me THF, ∆

+ *RO

M

N

(122)

OH (123)

− OR* M HON +

Me

M = (CO)5Cr, R* = (−)-menthyl

Ph

+

Ph Me

Me

Ph

N

OR*

(124) (50%)

N

OR*

(125) (45%)

Scheme 4.46 Enantiomerically pure azepinone using [4 + 3] cycloaddition process.

4.1 Substituted Azepines 1,2,5,6-Di-O-isopropylidene-a-D-glucofuranose 6 steps O

H

H

BnO O

N

HN H

OH

O

O

O

(126)

H OH OH

BnO

O

OH

MeNHOH, HCl NaHCO3, 80% then aq. EtOH reflux, 20 h, 71%

+ Me N O−

N (128)

(127) Me

HO HO H BnO

N

NMe O

(129)

(1) Mo(CO)6 aq. MeCN, ∆, 5 h (2) Ac2O, DMAP, pyridine, 12 h, 35%

AcO AcO H BnO

N (130)

N Ac

OAc

Scheme 4.47 Nitrone cycloaddition to azepine ring.

127 gave exclusively the bridged isoxazolidine 129 via the nitrone 128 in a 71% yield. Cleavage of this isoxazolidine ring was realized using Mo(CO)6 in aqueous acetonitrile and led to the azabicyclic ring in 35% yield (Scheme 4.47). Intramolecular nitrone cycloaddition allowed also an access to aminohydroxyazepines starting from amino acids as chiral pool [48b]. 4.1.3.4 Intramolecular Diels–Alder Reactions (IMDA) – [4 + 2] Cycloaddition The intramolecular version of the Diels–Alder reaction [49] has been applied with success to the elaboration of the seven-membered ring of the Stemona alkaloids. Thus, Jacobi and Lee [50a] described an original concise synthesis of (−)-stemoamide using an IMDA-retro-Diels-Alder (DA) reaction of the propyne derivative 132 obtained in three steps from (S)-oxazole lactam 131 easily prepared on multigram scales with no racemization from (S)-l-pyroglutamic acid. Thermolysis of (S)-132 in diethylbenzene at reﬂux gave the tricyclic azepine compound 134 owning the natural conﬁgurations and issued from rearrangement of tetracyclic derivative 133. Subsequent selective reduction with NaBH4 /NiCl2 afforded ﬁnally (−)-stemoamide (Scheme 4.48). This cyclization mode has been applied with success to the synthesis of (−)-stenine, another member of the Stemona alkaloids [50b]. 4.1.4 Ring Transformation Methods

Much attention has been focused upon the preparation of seven-membered rings incorporating one nitrogen atom using (i) rearrangement of cyclohexanones (Beckmann, Schmidt reactions or its intramolecular version, the Boyer reaction) or (ii) expansion of preexisting smaller rings. Sometimes, thermal and photochemical rearrangements are also combined with retro-aldol reaction. We report in this section the asymmetric syntheses of azepines framework on the basis of all these methods [51], and, for better understanding, we present here

163

164

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles O Cl HO

O NH

O

MeO +

N

N

Me 2 steps

O

MeO

N

44%

Me CO2H (S)-L-Pyroglutamic acid

N Me

Me (131)

Me

retro DA ∆ − MeCN

O N

Me

O

O

N

Me MeO

(132)

O

H IMDA ∆ Diethylbenzene 182 °C

O

5 Steps MeO

O

N

Me

O

O

(2) NaBH4/NiCl2 73%

O

H

(−)-Stemoamide 4% overall yield

(134)

(133)

N H

+

(1) H , 53% MeO

H

N

H

Scheme 4.48 Azepine ring from an IMDA reaction.

the literature results in two parts; the ﬁrst one describing ‘‘classical reactions’’ of rearrangement and the second part introducing an access to seven-membered aza nucleus by enlargement of nitrogenous cycle of variable size. 4.1.4.1 Classical Methods Aub´e et al. [52a,b] converted ketone 135 to lactams 137a,b in good yield and stereoselectivity (for example, when R1 = Ph and R2 = H, 137a/137b = 7.2:1) via an ‘‘in situ-tethering’’ strategy using hydroxyalkyl azides 136 and a Lewis acid. The stereoselectivity may be explained by the equatorial attack of azide on the oxonium ion followed by migration of the pseudo-axial bond antiperiplanar to the leaving N2 substituent (Scheme 4.49). In a further study, the authors [52c] showed that the stereoselectivity of the reaction could be modulated by electronic and conformational effects. The ratio of isomers 137a,b depended upon the nature (alkyl or aryl) of the R2 -substituents of the hydroxyl-azide 136 and even upon the electronic nature of the R2 -aryl group. Effective enhancement of selectivity was also detected using a linker containing a quaternary carbon like 138 (Scheme 4.50). + N O 2 N

O

R 1 R2

+ N

t Bu

R1

t Bu (135) (1) BF3·OEt N3 (2) NaHCO3

R2 OH (136)

+ N

O N

1 2 +N R R 2

t Bu

R1

OH R2

R

R2

O

t Bu

N

1

t Bu

R1

O

R2

O

t Bu (137a) major O R1 N HO

R2 (137b) minor

Scheme 4.49 Chiral caprolactam by asymmetric nitrogen insertion process.

t Bu

4.1 Substituted Azepines

N3

HO

OH R2

N3

H

(136) R1 = H (138) Yield of (137) = 85%, (137a) : (137b) = 77 : 23

R2 = Me (137a) : (137b) = 74 : 26 R2 = i-Pr (137a) : (137b) = 88 : 12 R2 = Ph (137a) : (137b) = 64 : 36

R2 = 4-nitrophenyl (137a) : (137b) = 76 : 24 R2 = 4-methoxyphenyl (137a) : (137b) = 47 : 53 Scheme 4.50 Inﬂuence of the azide in the formation of the caprolactams.

This method allowed the stereoselective synthesis of substituted caprolactams by ring expansion of chiral ketones in a one-pot procedure with only one work-up providing diastereomers which were easy to separate. Moreover, the removal of the chiral group on the nitrogen could be accomplished efﬁciently and depended only upon the structure. A systematic study of this asymmetric Schmidt reaction has been published in 2003 by Aub´e et al. [52d] During their work devoted to the synthesis of a series of Gly–Gly-derived macrocycles containing a cis-aminocaproic acid (Aca) tether, Aub´e et al. [52e] needed to prepare several linkers 141 which could be easily obtained by acid hydrolysis followed by esteriﬁcation of chiral caprolactams. An example is depicted below: the caprolactam 140 resulted in excellent yield from light induced ring opening (photo-Beckmann rearrangement) of the chiral oxaziridines mixture 139. The mixture of lactams thus obtained could be easily separated and the major one, 140, afforded linker 141 with an excellent enantiomeric excess of 98% (Scheme 4.51). Thermal regioselective Beckmann rearrangement (microwave 100 ◦ C) [53a] of separated p-toluenesulfonyloximes 143 obtained from ketone 142 led to isomeric lactams 144 (Scheme 4.52). An asymmetric Beckmann rearrangement/allylsilane-terminated cation cyclization cascade was used to elaborate the seven-membered ring of cephalotaxine framework (Scheme 4.53) [53b].

Me Me Ph

N Ph

O

O

N

(1) hn

3 steps 82%

O ClH·H2N

OCH3

(2) Separate 79%

Ph (139) + isomers

Ph (140)

Ph

Scheme 4.51 Photolysis of oxazolidines to chiral caprolactams.

(141)

165

166

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles CF3

CF3

CF3

CF3

CF3

O

O O

pTolSO2 O

RN

N

CF3

(1) NH2OH·HCl, NaOH, EtOH-H2O, reflux (2) p-TolSO2Cl, DMAP

O

F

F

(144a), 76%

(143a) CF3

CH2Cl2 (3) Separation

THF, H2O 100 °C microwave

F

CF3

(142) CF3

CF3

O

O RN

N O

pTolSO2

F (143b)

(144b), 64%

F

Scheme 4.52 Modiﬁed Schmidt rearrangement to caprolactams.

MeO

MeO DIBAL-H

MeO

N OMs

CH2Cl2 −78 °C to 0 °C 55%

NH MeO

PhMe2Si Scheme 4.53 Asymmetric Beckmann rearrangement.

4.1.4.2 Ring Expansion The synthesis of azepines derivatives has been efﬁciently envisaged by ring expansion of preexisting smaller rings in particular piperidine, pyrrolidine, azetidinium salts, and pyranoside. During their study toward the synthesis of balanol, Kato and Morie [54] developed the ring expansion of a cis-aziridinium cation 145 to form, together with the normal displacement piperidine derivative, the aza-seven-membered ring via an SN 2-type attack of the azide anion at the methyne carbon (Scheme 4.54). Using the same approach starting from the symmetrical piperidine 146, Brechbiel et al. [55] synthesized diastereomerically azepanes in about 90% yield by ring expansion using NaN3 in Dimethyl-sulfoxyde (DMSO) with good stereoselectivity; only the cis isomer was obtained via a backside attack at the methine carbon (Scheme 4.55). It is well known that azidolactols underwent reductive ring enlargement in the presence of hydrogen to yield azepanes [56]. Applied to chiral lactol 147 and lactone 148, obtained from the transformation of l-ascorbic acid, this reaction allowed the preparation of 3,4-disubstituted azepanes 149 and (5S, 6S)-caprolactam 150, precursors of (+)- and (−)-balanol in excellent yields (Scheme 4.56) [57].

4.1 Substituted Azepines OMOM OMOM N

NaN3 CH3CN

CH2OMs

+ N Bn

∆

CH2Ph

N3

OMOM − N3

(−)-Balanol

N Bn OMOM

(145)

(2R, 3S)-Piperidine

N Bn

CH2N3

Scheme 4.54 Chiral azepine fragment of balanol via piperidine ring expansion.

NaN3,DMSO

X

N Bn

X

X

+ N Bn

H

N3

N

N3

Bn

(146) X = Cl, Br Scheme 4.55 Piperidine ring expansion to azepanes. N3 L-Ascorbic acid

OX

H2,10% Pd/C, MeOH

O

OY

OH N H

TBDMSO N3

(147)

(149a) X = H, Y = TBDMS (149b) X = TBDMS, Y = H OH

O TBDMSO (148)

H2,10% O Pd/C MeOH/H2O O 9:1, 16 – 24 h, 85%

OTBDMS N H (150)

Scheme 4.56 Chiral lactones to substituted caprolactam.

Polyhydroxyazepanes (seven-membered iminocyclitols) [58], have been synthesized using an analogous method. For example, iminocyclitol 152 could be obtained starting from chiral azidolactol 151 derived from α-d-glucopyranoside, by a tandem Staudinger intramolecular aza-Wittig ring expansion with triphenyl phosphine in 87% yield (Scheme 4.57) [58c]. Chemo-enzymatic synthesis starting from benzylpyranoside produced polyhydroxyazepane 153 in only two steps using aqueous media and proceeding on a gram scale (Scheme 4.58) [58d]. In 2003 [59a], a simple and versatile method for the enantio- and diastereoselective synthesis of 2-substituted- and 2,7-disubstituted-3-aminoazepanes 156 and 157 was reported using a tandem ring enlargement/alkylation or reduction process starting from 2-cyano 6-oxazolopiperidine154 (Scheme 4.59). Bicyclic aminal 155, derived from 154 by standard reactions, could be then transformed into the trans-azepane 156 in yields between 80% and 96%. This method permitted the stereoselective preparation of the indolyldiamine 156 (R1 = N-methyl indole), carba-analog precursor of the tetracyclic azepane eudistomine, an antiviral and antitumoral compound (Scheme 4.58) [59b].

167

168

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

N3 OH

O

N PPh3, THF

HO BnO

OBn

BnO

OBn (151)

H N

NaBH3CN 1M HCl in CH3OH

HO

87%

OBn

OBn

BnO

OBn

OBn (152)

Scheme 4.57 Seven-membered iminosugar. Galactose oxidase catalase OH OH CuSO4·5H2O O HO OBn 50 mM Phosphate buffer pH 7.0 OH

OH N OR O HO OBn OH

OH O NH2OR O MeOH/pyridine HO OBn OH H N

H2, (5% w/w), Pd(OH)2/C Degussa type 4 : 4 : 1, MeOH : H2O : THF 60 psi /2 days 90 – 98%

OH

HO OH

HO

(153) Scheme 4.58 Chemo-enzymatic synthesis of seven-membered iminocyclitol. Ph NC

1 O (1) R Li

N

(2) NaH, TBDMSCl

(3) Li/NH3 or LAH

(154)

H R1

R1 Ph OTBDMS NH H N + (155a) minor

Ph N

OTBDMS NH

(1) LAH (2) H2, Pd/C

(1) R2MgX, Et2O, ∆

(155b) major

(2) BF3·OEt2 (3) H2, Pc/C

H R1

62 < de < 90 H2N

Ph

OTBDMS NH

(155b) major

R1 NH

H2N

N

(156)

R1 NH

(157)

R2

Scheme 4.59 Enantioselective synthesis of 2-substituted- or 2,7-disubstituted-3-aminoazepanes.

On the other hand, treatment of 154 with iso-butyl or benzyl Grignards, which act as nucleophilic reagents, led to 2,7-disubstituted-3-aminoazepanes 157 in good yields and excellent diastereoselectivity (de > 95%) (Scheme 4.59). The chiral hexahydro-azepine 161 constitutes an interesting potential azepine derivative for the synthesis of more functionalized compounds. It could be rapidly prepared by ring opening of γ -aminoaldehyde 158 with (R)-tert-butylsulﬁnamide followed by reaction with diphenyl vinyl sulfonium 160. Derivative 161 existed as a 3:1 mixture of diastereomers easily separated by ﬂash chromatography (Scheme 4.60). Further deprotection of the major aziridine has permitted, for example, the synthesis of the known precursor of (−)-balanol [60].

4.1 Substituted Azepines O

O S NH N

S N OH Ts (158)

N H

N Ts

Ts

(159)

O

Ph + Ph TfO − S (160)

S N TsN

NaH (1.2 eq.) DMF (0.018 M) 4 h, 0 °C, 68%

(161)

(−)-Balanol

Scheme 4.60 Vinyl sulfonium salt in asymmetric synthesis of aziridine fused azepine.

The two-carbon ring expansion of heterocyclic compounds is an original method to elaborate azepine derivatives, which has been successfully used in the preparation of 3-oxo-pyrrolidine and azetidine substrates (vide infra). Thus, a Michael Aldol Retro-Dieckmann (MARDi) sequence was used in converting 3-oxo-pyrrolidine 162 and acrolein in the presence of MeOH into a mixture of hydroxyazepane 163 (dr = 1.6:1) and tetrahydro-azepine 164 in 36% overall yield (Scheme 4.61) [61]. Ring expansion of enantiomerically pure 2-alkenylazetidinium triﬂuoromethanesulfonate salts 165 under basic condition permitted a clean access to enantiomerically pure substituted azepanes 166a and 166b with variable diastereoselectivity at the C-2 position through a [2,3] sigmatropic shift (Stevens rearrangement) of the ylide generated after selective deprotonation α to the ester group (Scheme 4.62) [62]. 4.1.4.3 Substitution of Already Formed Heterocycles Most of the syntheses of complex azepines derivatives associated with pharmaceutically important activities depicted in the literature have, as a corner stone, an already formed aza-seven-membered ring which has been formed from caprolactam derivatives [51b]. For example, asymmetric synthesis of fused seven-membered lactams 168 was reported employing an asymmetric hydrogenation of the caprolactam derivative 167 with [Rh(COD)-(+)-(2S, 5S)-Et-DUPHOS]OTf. This approach allowed O

O CO2Me

Ar

N

+

Base, MeOH

H MARDi cascade

Ar N

MeO2C

MeO2C + CO2Me

HO

(162)

Ar N CO2H (164)

(163)

Scheme 4.61 Diastereoselective MARDi cascade to azepine ring.

Ph

KHMDS

+ − TfO

N

CO2Et

Bn (165)

93% de = 80%

Ph

(R)

Ph (R) CO2Et

N Bn (166a)

(R)

+

9:1

N Bn

(S) CO2Et (166b)

Scheme 4.62 Ring expansion of chiral 2-alkenylazetidinium triﬂuoromethanesulfonate salts.

169

170

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

CO2H

O 3 steps

NBoc

NH 19%

CO2H Catalyst* H2, 1000 psi

NBoc

N O ( )n

(167)

(166)

(168) n = 1 85% (169) n = 2 58% Scheme 4.63 Fused chiral seven-membered lactams from caprolactam.

the preparation of the (S)-N-protected-homopipecolic acid 168 in 98% yield and 90% ee. Acid 168 is then further transformed into the azabicyclic compounds 169a,b in a four-step sequence using as a key reaction an RCM ring formation (Scheme 4.63) [63]. Construction of the azaspiro[5.6]dodec-9-ene 172, a part of pinnatoxin A, a marine toxin of shellﬁsh and dinoﬂagellate, has been efﬁciently elaborated by an asymmetric Diels–Alder reaction of the α-methylene caprolactam 170 with the diene 171 using chiral Lewis acid. The precursor 170 was readily obtained in ﬁve steps and 54% overall yield from caprolactam itself (Scheme 4.64) The enantioselectivity observed in this synthesis arose from the chirality of the copper complex formed and the exo selectivity was due to the unfavorable steric interactions between the substituent in the diene and the chiral ligand of copper complex in the endo-transition state [64]. The ongoing interest in bengamides and analogs as clinical candidates for cancer chemotherapy has prompted the preparation of a lot of various original 2-N-substituted-aminocaprolactams by introducing the polyfunctional substituent either on the commercially available (2S)-aminocaprolactam, or, on the readily accessible chiral 4-hydroxy-2-aminocaprolactam [51b], [65a]. Thus, for example, synthesis of (+)-bengamide E relied on ring opening of substituted acetylenic β-lactone 174 by (S)-3-aminocaprolactam 173. Subsequent stereoselective reduction of the acetylenic moiety led to (+)-bengamide E. A similar approach was also reported starting with γ -lactone 175 (Scheme 4.65) [65b,c,d,e]. The meso epoxide azepine compound 176 prepared by an RCM reaction of N-Teoc-N, N-bishomoallylamine constitutes a versatile substrate for the synthesis of hexahydro-disubstituted azepines. When treated with trimethylsilyl azide in the presence of the Jacobsen Cr(salen) catalyst epoxide176 furnished, after cleavage of the silyl ether, the hydroxyazide 177 in 98% yield and 87% ee in two steps. Epoxide opening of 176 with i-butanol under the same reaction conditions led to O

O NH

5 steps

O N

OBn

OBn (171) TBSO CH2Cl2, 25 °C, 144 h 2+

54%

(170)

TBSO

O NCBz

−

[Cu ((S,S)-t-Bu-BOX)](AsF6 )2 82%, exo/endo 99:1, ee = 96%

BnO (172)

Scheme 4.64 α-Methylene caprolactam, precursor of the azaspirocyclic part of pinnatoxin A.

4.2 Substituted Azocines

OBn OMe

OBn O

H2 N

O

(174)

BnO or

O

(173)

OH OMe

O OMe

(175) OMOMOBn

O

H N

O

NH

OBn OH O

OMe

NH O

H N

MOMO

(+)-Bengamide E NH

OBn O

Scheme 4.65 Use of (S)-2-aminocaprolactam for the synthesis of azepine derivatives.

N

(1) CH2Cl2, ∆, 90% PCy3 Cl Ru Ph Cl PCy3 O (2) mCPBA, CH2Cl2 84%

Teoc

(1) (S,S)-Jacobsen Cr(salen)catalyst TMSN3, Et2O N3 (2) CSA, MeOH 98%, 87%ee, 2 steps HO NTeoc

NTeoc (177) HO

(176) (S,S)-Jacobsen Cr(salen)catalyst i-butanol, 63%, 25% ee

NTeoc

O (178)

Scheme 4.66 Epoxide ring opening to chiral 4-hydroxy azepines.

the alcohol 178 in 63% yield but in this case with a modest enantiomeric excess (25%) (Scheme 4.66) [66].

4.2 Substituted Azocines

The commonly encountered azocines (π-equivalent heterocyclic analogues of cycloocta-tetraenes), fully or partly reduced, constitute a part of the skeleton of natural products with complex structures like apparicine, magallanesine, nakadomarin A and manzamine A, an indole alkaloid isolated from marine sponges with antitumor and antibiotic activities (Scheme 4.67) [67a]. Many of the synthetic azocine derivatives have found application as therapeutic agents because of their broad spectrum of properties [1d] together with the favorable ﬂexibility of their ring which allow binding with species. In particular azocin-2-ones have been used as sedatives, anticonvulsant, antihypertensive agents and the disubstituted ones ﬁnd application as peptide analogues to mimic the type VI β-turn conformation of natural polypeptides [67b,c]. Fused-azocines like benzofuroazocines possess important activity in the central nervous system [67d] and the pyrrolido- and piperidino-azocines could serve as intermediates in alkaloids synthesis [67e]. The preparation of this aza-eight-membered ring, especially in highly functionalized form, using classical cyclization from an alicyclic chain by intramolecular

171

172

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

N

O

N H H Apparicine

O

O

H N O

N N H O H

O

H

H

OMe O Magallanesine

Azocinones as constrained dipeptides

N H

O

N

N H OH

N

N

OMe

N

H

N

Nakadomarin A

Manzamine A

Scheme 4.67 Azocine compounds.

nucleophilic substitution remains very speciﬁc and is often slow and hampered by unfavorable enthalpies and entropies of the reaction [68]. Diverse other synthetic methodologies have been developed on the basis of intramolecular substitution, ring contraction or enlargement such as fragmentation of fused 5/5-ring system, [2 + 2] photochemical, or thermal cycloaddition reactions, and most recently by powerful RCM reaction that sometimes requires high dilution conditions for successful conversion. 4.2.1 Azocines from Intramolecular Nucleophilic Substitution

For example, azocine 181 has been efﬁciently synthezized in 76% yield by intramolecular basic substitution of the oxazolidinone iodide 180 easily obtained by exposure of the Sharpless epoxide 179 to sodium hydride and benzoylisocyanate [69] (Scheme 4.68). Recently, fused indolo-azocines have been prepared by an intramolecular cyclization of alkyne derivatives of trytamine catalyzed by AuCl3 in an 8-endo-dig process (Scheme 4.69) [70].

OTBDMS O

(1) NaH, PhCONCO 97%

HO H N H

(2) TBAF, 80% (3) PPh3, I2, 74%

(179)

HO H

O

I (180)

Scheme 4.68 Intramolecular cyclization to azocine.

O

NaH, 76%

O N

(181)

O

4.2 Substituted Azocines

CO2Me CO2Me N DNBS

N DNBS

AuCl3, 0.5 h 75%

N H

N H

DNBS = dinitrobenzenesulfonyl group Scheme 4.69 Cyclization to azocines catalyzed by gold.

Asymmetric synthesis of benzazocine framework 184, an advanced intermediate in the synthesis of FR900482, has been achieved by Pd-catalyzed carbonylationinsertion-cyclization of an arylhydroxylamine with a tethered vinyl iodide 183. Compound 183 was easily prepared from commercially available 3,5-dinitro-p-toluic acid in seven steps and 57% yield via the enantiomerically pure secondary alcohol 182 (ee > 99%). The best parameters for this reaction were a temperature ranging 65–80 ◦ C, N, N-dimethylacetamide as solvent and Pd(PPh3 )2 Cl2 as catalyst. By this way, eight-membered rings were obtained in 64–78% yield (Scheme 4.70) [71]. 4.2.2 Ring Transformations Methods

Formation of substituted eight-membered lactams by intramolecular rearrangement of 5,6-dehydro-2-oxocanone 187 provided an access to either trans-3,8-disubstituted or 3-substituted eight-membered lactams 188 and 189, from acids 185 or 186 in 89% and 85% yields, respectively (Scheme 4.71) [72]. Cope rearrangement of enantiomerically pure 2-azetidinone-tethered dienes 190, prepared as single cis-diastereomers from cinnamylideneimine derived from R-(+)-α-methylbenzylamine, allowed the preparation of optically pure eightmembered lactams 191 in good yields (Scheme 4.72) [73].

NO2

HO2C

OBn

OBn

SiMe3

2 steps 78%

NO2

MeO2C

NO2

OH NO2

MeO2C

5 steps 73%

(182) ee > 99% OTBDMS

OBn

OTBDMS

OBn

OH

OCONH2 OH

5%Pd(0), CO Et3N, DMA

MeO2 C

65 – 80 °C

NH I RO

MeO2C

N RO

(183)

O (184)

Scheme 4.70 Asymmetric approach to FR900482 benzazocine.

OHC

O N FR900482 O

NH

173

174

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles O OH NHBoc

(2) DMAP, toluene reflux 89 – 96%

R

OH

(1) TFA, CH2Cl2 (2) Et3N, toluene

(1) 2,4,6-Trichlorobenzoylchloride Et3N, THF, rt O

BocHN

R

89 –100%

(185) R = H (186) R = NHZ

R

N OH H

O (187)

O (188) R = H (189) R = NHZ

Scheme 4.71 2-Azocanones by lactone-to-lactam ring contraction of 2-oxonanones.

Ph H N Me

Ph

Ph

Ph COCl

R N R Ph Me H

S

Et3N, CH2Cl2 ∆

O

+

N

Ph Me H (190b)

O

(190a) Toluene, ∆ 75%

Toluene, ∆ 83%

Ph

Ph Me

Me N

N

PH H

O H3C (191a)

O H3C (191b)

Ph H

Scheme 4.72 Eight-membered lactams via [3,3] sigmatropic rearrangement of azetidinones.

4.2.3 Cycloaddition Approaches to Azocines

Thermal [2 + 2] cycloaddition reaction between 1,4-dihydropyridine 192 and diethylacetylenedicarboxylate in the presence of Al2 O3 , afforded a cyclobutene intermediate which underwent an electrocyclic ring opening resulting in the formation of the two diastereomers 193a and 193b in 30 and 44% yields, respectively (Scheme 4.73) [74]. Ph

Ph NC

N

O

H3C

Ph N

N + OH − CN

H3C

OH

H3C Ph OH EtO2C H3C N + − CN EtO2C

(192)

Ph

Ph H3C

EtO2C

N

EtO2C

H3C O

+

EtO2C

N

O

EtO2C (193a)

(193b)

Scheme 4.73 Synthesis of tetrahydro-azocines by cycloaddition of latent 1,4-dihydropyridines.

4.2 Substituted Azocines

Another cycloaddition process allowing the stereoselective synthesis of 3,7-disubstituted azocin-2-one has been developed by Shea et al. [75]. Thus bridged bicyclic oxazinolactam 195b was obtained as a single diastereomer in 85% yield (100% ds) by a type 2 intramolecular N-acylnitroso Diels–Alder reaction of the hydroxamic acid 194 (R2 = H, R1 = Bn) in the presence of n-Bu4 NIO4 . For example, bicycle[5.3.1]oxazinolactam 195a could be transformed to the trans-azocinone 196 by alkylation followed by cleavage of the N–O bond, whereas oxazinolactam 195b was converted to the cis-compound 197. In the case of (R)-C-4 substituted hydroxamic acid 194 (R1 = H, R2 = Bn), Diels–Alder oxidation with n-Bu4 NIO4 provided in 84% yield two diastereomers 195 d and 195e in a 3.7:1 ratio in favor of the syn compound 195e (Scheme 4.74). 4.2.4 Ring-Closing Metathesis

Synthesis of medium-ring cyclic amines has been reported by Schrock et al. [76a] using an asymmetric ring-closing metathesis (ARCM) reaction catalyzed by Mo catalysts in the absence of solvent. Thus, compound 198 in the presence of 5 mol% 199 delivered optically pure amine 200 (ee > 98%) in 93% yield (Scheme 4.75). Enantioselective syntheses of benzaocine compounds (e.g. (+)-FR900482) have been completed with this method using Grubbs’ catalyst [76b]. A library of constrained chiral eight-membered ring lactams has been prepared in high yields from two l-allylglycine residues 201 (Agy) employing an RCM reaction with ﬁrst generation benzylidene ruthenium catalyst [77] (Scheme 4.76). R1

O

R2 R1 (194)

1 O (195a) R = H, 80% (195b) R1 = Bn, 85%

n-Bu4NIO4 CHCl3, 0 °C, R2 = H

N H

N

OH

(195c) R1 = Allyl, 87%

O OBn

BnO

O

O n-Bu4NIO4 R1 = H CHCl3, 0 °C, R2 = OBn

+

N

O

O (195d) anti (195a)

(1) LDA, THF, −78 °C

(1) H2, 10% Pd/C, MeOH

(195e) syn

HO

(2) BnBr then Na(Hg), Na2HPO4, EtOH

N

Ph (196), 77% N H

O

HO

(195b) (2) Na(Hg), Na2HPO4, EtOH

Ph HN O

Scheme 4.74 Medium-ring lactams by diastereoselective intramolecular N-acylnitroso Diels–Alder reaction.

(197), 64%

175

176

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

H3C

Cl

Cl N

5 mol% (199)

N Ph

H

CH2Cl2, 22 °C 20 min

Mo O

PhN

(198)

O

(200)

(199)

Scheme 4.75 Mo-Catalyzed asymmetric ring-closing metathesis to eight-membered amines.

O H2N

O

NHBoc OMe

O

Cl2Ru(PCy3)2 CHPh DCM, ∆

NDMB

(0.003 M substrate) 1 day, 80%

DMB O N

BocHN

OMe

O MeO (201) Scheme 4.76 Synthesis of eight-membered ring lactam by RCM reaction.

In view of the high potential of iminosugars for drug discovery and considering the increase of conformational ﬂexibility that the eight-membered ring has brought, a synthesis of iminoalditols 203 has been developed from aminoheptenitols 202 using an RCM reaction. The chirality at C-3, C-4 and C-5 came from the commercially available starting material, 2,3,4,6-tetra-O-benzyl-d-glucopyranose precursor of 202. The epimer mixture at C-2 was easily separated by ion-exchange chromatography (Scheme 4.77) [78]. Enantiopure 1,2,3,4,5,8-hexahydroazocin-3-ols have been prepared by distereoselective addition (de > 95) of Grignard reagents to chiral perhydrobenzoxazines followed by an RCM reaction of the 1,9-azadienes thus obtained [42]. Moreover, the RCM reaction was adapted successfully to the synthesis of the eight-membered rings of more complex compounds, namely the alkaloids Manzamine A, Ircinal and Nakadomarin A in moderate to good yields [79].

CBz BnO

N

BnO BnO OBn (202)

MesN NMes Cl Ru Ph Cl PCy3 (1) CH2Cl2, 40 °C, 30 h 73% (2) H2, Pd/C, MeOH/HCl 1N 24 h, 82%

BnO

H N

BnO

BnO +

BnO BnO

BnO

Scheme 4.77 Synthesis of eight-membered iminoalditols.

H N

OBn

OBn (203)

4.3 Substituted Large Nitrogen-Containing Rings

4.3 Substituted Large Nitrogen-Containing Rings

Among the large nitrogen-containing rings, the substituted nine-membered derivatives deserve particular attention. In fact, these nitrogen heterocycles, well known as azonine derivatives, are found as subunits in natural and pharmaceutically important molecules [1c,d], [51b] like rhazinilam, which interfere with tubulin polymerization, tuberostemonone, and cleavamine (Scheme 4.78). Moreover, these medium-sized constrained ring systems, in particular the azocinones, serve as key intermediates in the synthesis of bicyclic amino compounds like indolizidines or quinolizidines [80] by selective transannular ring contractions. The easiest way to generate a nine-membered nitrogen ring, for example lactam azocinones, consists of an intramolecular reaction of ω-amino esters. But, even using activating groups either at the carboxyl or amino functions the cyclization was often low yielding (Scheme 4.79) [81]. This process has been also used in indole series and allowed the synthesis of cleavamine [81c] and 5a-homo-vinblastine [81d]. Because of the interesting biological properties of rhazinilam, a lot of methods have been devoted to the synthesis of its skeleton. Among them, palladium-catalyzed intramolecular coupling [82a] and carbon homologation to macrolactam via palladium-catalyzed carbonylation [82b] were the more efﬁcient and afforded the nine-membered aza ring in good yields (Scheme 4.80). N

N

O O

O

H

O N H Cleavamine

NH

O O

N

H Tuberostemonone

O Rhazinilam Scheme 4.78 Substituted Azonines.

R1 = H, R2 = CHO

NHR1 MeO2C

(1) KOH (100 mol equiv) EtOH, 18 °C, 3 h, then aq HCl (2) EDCI, DMAP, 18 °C, 3 h (3) Chlorotris(triphenylphosphine)rhodium 1,4-dioxane, 100 °C, 2 h

O NH

68%, ee 74%

N

R2

R1 = Boc, R2 = CO2Me (1) Ba(OH)2, TFA 71%, ee 94% (2) HATU, iPr2NEt (3) 50% NaOH, then aq HCl

Scheme 4.79 Enantioselective synthesis of (−)-rhazinilam.

N

177

178

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

CO2Me N

N

(1) Pd/C (5 mol%) dppb, HCO2H, DME CO (10 atm), 150 °C, 58% (2) NaOH, MeOH then HCl, 50 °C, 90%

NH2

N H NaOH, MeOH HCl, 85%

MeO2C

CO2Me NMe2

N

O

Rhazinilam

CO2Me

N

N

Pd Cy3P 10 mol% 10 mol% Pd(OAc)2 O K2CO3, 47%

MOM

N

N MOM

N

O

MOM

O

I Scheme 4.80 Palladium-catalyzed coupling to rhazinilam skeleton.

Others methodologies have been developed to elaborate azocine derivatives in particular the ring enlargement of a smaller ring by N or C atoms insertion using fragmentation or rearrangement reactions. For example, oxidative cyclization of Cbz-tyrosine permitted the preparation of the hydroindole 204, which when exposed to a mixture of iodobenzene diacetate and iodine, provided the azonane 205 as a single isomer in 72% yield via a radical-fragmentation-oxidation reaction (Scheme 4.81) [83]. Insertion of a nitrogen atom could also be realized by classical Beckmann rearrangement (Scheme 4.82) [84] Applied to a more-membered ring, the photoinduced Beckmann ring expansion allowed, for example, the synthesis of the 10-membered framework of isohalichlorensin. Thus, photolysis at 254 nm in benzene of the chiral spirooxaziridine (1) PhI(OAc)2, CF3CH2OH (2) NaHCO3, MeOH (3) NaBH4, CeCl3·7H2O (4) TBSCl, Imidazole (5) H2, Pt/C TBSO

OH

H COOH

OH

O PhI(OAc)2 CO2Me I2, CH2Cl2

N H H CBz (204)

CO2Me

O

NHCBz

O CO2Me

TBSO

N I

N H H CBz

TBSO

H CBz

Scheme 4.81 Ring expansion of 4-hydroxyindoles.

72%

TBSO

CO2Me N H OAc CBz (205)

4.3 Substituted Large Nitrogen-Containing Rings NH2OH·HCl NaOAC, MeOH

TsCl, SiO2

+

CH3 ∆, 48 h 75%

CH3

CH3 69%

N

O

N OH

H N O

HO 1:2

Scheme 4.82 Nine-membered ring lactam by Beckmann rearrangement.

Ph

O

O N OCH3

hn, benzene 254 nM

(206)

O Ph

N OCH3

N

HN (207)

(208)

Isohalichlorensin NH2

Scheme 4.83 Enantioselective access to 10-membered amine.

206 prepared from commercially available cyclononanone and (R)-(−)-1-amino1-phenyl-2-methoxyethane, afforded the 10-membered lactam 207 in 57% yield, which could be further transformed in 54% yield to the (3R)-3-methylazacyclodecane 208, precursor of the natural alkaloid isohalichlorensin (Scheme 4.83) [85]. Strained azocinones bearing an E-double bond within their skeletons are of particular interest because they constitute the key intermediates for the synthesis of diverse natural products. An original access to these compounds has been developed by zwitterionic aza-Claisen rearrangement of vinyl pyrrolidines with carboxylic acid ﬂuorides [86]. This reaction led to enantiomerically pure azocinones with (i) exclusive generation of the E-double bond in the ring (ii) yields ranging 35–92% depending on the acid used (better yields were observed with phenylacetyl and chloroacetyl ﬂuoride), and (iii) 3,4-syn/anti diastereoselectivity [86a] strongly inﬂuenced by the nature of the substituent (R2 ) in the starting vinyl pyrrolidine. For example, unsubstituted vinyl pyrrolidine 210a obtained from 209a led to a mixture 211a with almost no distereoselectivity. In contrast, when the bulky tert-butylsilyloxy (TBSO) group was used, 1,4-chirality transfer was nearly complete. Thus, pyrrolidine 210b, easily prepared from trans-4-hydroxy-l-(−)-proline 209b, reacted with various carboxylic acids (R3 = Cl, F) leading, after a Lewis acid activation of the resulting acyclic precursor followed by a base induced deprotonation of the acylimmonium salt, to a zwitterion which could exist in two transition states (TS), a chairlike and a boatlike TS. The ﬁnal rearrangement proceeded then diastereoselectively via a preferred boatlike transition state affording predominantly (anti/syn: 10/1) the 3,4-syn-disubstituted (E)-azocinone 211b with a trans relative conﬁguration of the stereogenic centers C-3 and C-8 (Scheme 4.84) [86b].

179

180

4 Asymmetric Synthesis of Seven- and More-Membered Ring Heterocycles

R1

R1

CO2H N H (209a) R1 = H, L-(−)-proline (209b) R1 = OTBS Bn R

1

CHCl3, R3-CH2COF 70 – 95%

H

[3,3] 4 R2

N Bn

3

R3

R1

(211a) R1 = H, R3 = Cl, R2 = H, 3,8-anti: 3,8-syn = 1.4:1, 77%

2

R3 R2

N + Bn

H H Boat-like transition state

(211b) R1 = OTBS, R3 = Cl, R2 = H, 3,8-anti: 3,8-syn = 10:1, 92% R1 (211c) R1 = H, R2 = CO Et, 3,4-anti > 3,4-syn

H

− O

R3 H

−O H Chair-like transition state

8

Me3Al, K2CO3

R2

N +

R1

R2

N Bn

(210a) R1 = R2 = H (210b) R1 = OTBS, R2 = H (210c) R1 = H, R2 = CO2Et

[3,3]

R2 N Bn

R3

O (E)-3,8-anti (211)

O (E)-3,8-syn (211)

Scheme 4.84 Aza-Claisen rearrangement of TBSO-substituted vinyl pyrrolidines.

In contrario, when the vinylic group of the pyrrolidine was substituted (210c) a change in the diastereoselectivity was observed and the 3,4-anti substituted azoninone 211c arising from the preference for a chairlike transition state was majoritary formed as a result of the repulsive interactions between the substituent and the ester group detected in the boatlike transition state [86c]. Enantioselective aza-Claisen rearrangement has been applied to the synthesis of 10-membered lactam starting from trans-2,3-disubstituted acyl piperidine 212. The diastereoselectivity of this reaction induced by an amide enolate is due to (i) the favorable chair–chair like TS and (ii) the formation of the preferred amide (Z)-enolate. The lactam 213, formed in 74% yield as the sole product, was further converted into the aglycone part of the macrolactam antibiotic ﬂuvirucinine A1 in 10 steps and 16% yield by standard transformations (Scheme 4.85) [87a].

OLi

LiHMDS, toluene

N

O

∆, 74%

N

Aza-Claisen rearrangement

(212) O N O H (213)

N H

Scheme 4.85 Asymmetric aza-Claisen rearrangement.

Aglycone part of Fluvirucinine A1 OH

References

Ph

O O

N

(R ) N

LiHMDS, Toluene ∆, 10 min 75%

N H

Husson’s oxazolidine

N

O H2N

Isohalichlorensin Scheme 4.86 Ring expansion to large-membered amine.

H

H

O O

Bs

N

DCM, (0.5 mM) reflux

HN

O

First generationRu cat. (30 mol%)

O

O Bs

N HN

O

Z:E = 64:23 Scheme 4.87 Formation of the C ring of Manzamine B by RCM reaction.

The same method, starting from (R)-N-propionyl-2-vinyl piperidine obtained from Husson’s oxazolopiperidine, allowed also the synthesis of the 10-membered diamine isohalichlorensin [87b] (Scheme 4.86). More recently, the applicability of the RCM reaction in the synthesis of medium-sized rings [34], which permits high yields and tolerates many functional groups, has been reported for the synthesis of 10-membered [88] and larger azacycles. For example, the 11 aza ring of manzamine B and the 15-membered azacycle of (+)-nakadamorin A were elaborated by this method (Scheme 4.87). References 1 (a) Smalley, R. K. (1984) in Compre-

hensive Heterocyclic Chemistry, (ed W. Lwowski), Pergamon press, Bristol, Vol. 7, pp. 545–46; (b) Devon, T. K. and Scott, A. I. (1972) Handbook of Naturally Occuring Compounds, Academic Press, New York and London, Vol. II; (c) Meigh, J.-P. K. (2004) Science of Synthesis, (ed S. M. Weinreb), Thieme, Stuttgart, New York, Vol. 17, pp. 829–30; (d) Evans, P. A. and Holmes, A. B. (1991) Tetrahedron, 47, 9131–66 and references cited therein; (e) O’Hagan, O. (1997) Nat. Prod. Rep., 637–52; (f) Nishizuka, Y. (1992) Science, 258, 607–14; (g) Hansen

Jr, D. W., Peterson, K. B., Trivedi, M., Kramer, S. W., Webber, R. K., Tjoeng, F. S., Moore, W. M., Jerome, G. M., Kornmeier, C. M., Manning, P. T., Connor, J. R., Misko, T. P., Currie, M. G. and Pitzele, B. S. (1998) J. Med. Chem., 41, 1361–66; (h) Thale, Z., Kinder, F. R., Bair, K. W., Bontempo, J., Czuchta, A. M., Versace, R. W., Phillips, P. E., Sanders, M. L., Wattanasin, S. and Crews, P. (2001) J. Org. Chem., 66, 1733–41; (i) Walz, A. J. and Miller, M. J. Org. Lett., 2002, 4, 2047–50; (j) Miller, W. H., Alberts, D. P., Bhatnagar, P. K., Bondinell, W. E., Callahan, J. F., Calvo, R. R., Cousins,

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182

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Part Two Asymmetric Synthesis of Nitrogen Heterocycles With More Than One Heteroatom

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

189

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles with More Than One Heteroatom Steve Lanners and Gilles Hanquet

5.1 Introduction

Three- and four-membered N-containing heterocycles are invested with a special allure that is derived from their apparent simplicity and spartan architecture. Thus, these systems are multifaceted, and the literature continues to provide evidence of their diversity, both in terms of preparative routes and subsequent transformations. Among them, those containing two or more heteroatoms have, for the most part, only been synthesized in the second half of the twentieth century, even though some of them exhibit a synthetically useful balance between stability and reactivity. They are often used as versatile and selective reagents and in some cases, as synthetic intermediates or for their biological properties. While syntheses of such racemic small heterocycles have already been reviewed [1], only few papers were devoted to their stereoselective preparation. This chapter highlights the stereoselective preparation of three- and fourmembered N-heterocycles, both containing two or more heteroatoms, from the recent literature. We will generally focus on stereoselective transformations that lead to enantiomerically enriched N-heterocycles.

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

Three-membered N-heterocycles with two heteroatoms were discovered only after 1950. A great number of them have been synthesized since then, using generally simple procedures familiar to synthetic chemists decades before. The saturated C–N–N rings (diaziridines) and their dehydrogenation products (diazirines) play the most important role in this ﬁeld together with the C–N–O rings (oxaziridines). The latter are the most widely represented family in enantiomerically pure form as a result of their important applications in asymmetric synthesis [2]. Three-membered Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

190

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

N-heterocycles containing sulfur or phosphorus atoms are less common, because of their fewer applications and their difﬁcult syntheses. The stereochemistry of these small rings has received considerable attention mainly because of the chirality of the nitrogen atom and the generally appreciable barrier to its inversion (Equation 5.1) [3].

R′

R N C O R″

R′

R N C O R″

(5.1)

Enantioselective preparations of these small rings are mainly based on substratecontrolled diastereoselective ring construction starting from enantiomerically pure precursors. In many cases, this strategy is mainly based on nitrogen-heteroatom ring closure as depicted in Equation 5.2 [1e]. R N- Het X

R N Het

C R′

C R″

R′

R″

(5.2)

Some examples of photoisomerization of open chain 1,3 dipoles such as nitrones, azomethinimines and linear diazo compounds have also been employed but are less common. 5.2.1 Diaziridines

In general, the conﬁguration at the nitrogen atom of trialkylamines (NR1 R2 R3 ) is invertible at room temperature, and they are impossible to isolate in optically active form. However, inversion of the N-atom in a three-membered ring system becomes remarkably slow [4]. The inversion barriers (108–113 kJ mol−1 ) have been determined by Mannschreck et al. in 1969 by means of NMR studies [5]. Generally, monocyclic diaziridines in solution and in the solid or gaseous state exist as 1,2-trans-isomers because the 1,2-cis-form is destabilized by n–n interactions of the nitrogen lone pairs and nonbonded interactions of N-substituents [6]. The ﬁrst optically active diaziridines were reported in 1974 [7], and their absolute conﬁgurations were established by X-ray diffraction analysis. Chiroptical properties [8] and conﬁgurational stability were studied by racemization kinetics [9]. In 1979, Mannschreck et al. applied chiral chromatography to the optical resolution of diaziridines and also measured the inversion barriers by racemization kinetics [10]. In all known examples, the inversion barriers of diaziridines did not exceed 117 kJ mol−1 and are related to the substitution pattern of the three-membered ring [2, 11]. Most enantiomerically pure diaziridines described in the literature result from optical resolution of a racemic mixture using chiral chromatography or crystallization [12]. Syntheses of racemic diaziridines almost always proceed by N–N bond

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

formation, using Schmitz’s methodology, which consists of mixing an aldehyde or a ketone with an amine and an electrophilic amination agent [13]. The latter can be a chloramine, hydroxylamine-O-sulfonic acid (HOSA), or an O-sulfonylated hydroxylamine. As enantioselective electrophilic amination reagents remain unusual, the most interesting route to chiral nonracemic diaziridines is based on diastereoselective preparations starting from enantiomerically pure amines or ketones. 5.2.1.1 Substrate-Controlled Diastereoselective Diaziridination Using Chiral Enantiomerically Pure Amines H N N

N R*

R*

Ito et al. have studied the enantioselective N-atom transfer from chiral diaziridine 1 to α,β-unsaturated amides leading to chiral aziridines with good diastereo- and enantioselection (ee 96%, trans maj.). Diaziridine 1 was prepared (under Schmitz’s conditions) [13b] with (1R)-1-phenylethylamine from cyclohexanecarboxaldehyde as a mixture of two diastereomers 1/1 (7:3) separable after column chromatography [14]. The conﬁgurations of 1 and 1 were assigned by analogy to the diastereoselectivity reported for the preparation of 2, bearing two methyl substituents on the endocyclic carbon, and its diastereoisomer 2 [15]. While 2 gradually isomerized to its diastereoisomer at room temperature, 1 was found to be stable and could be used as enantioselective nitrogen-atom transfer reagent (Scheme 5.1). The presence of the cis-methyl group in 2 probably facilitates the isomerization. Chiral nonracemic diaziridines have also been prepared from imines bearing chiral substituents on nitrogen using an [(arenesulfonyl)oxy]carbamate as aminating agent (Scheme 5.2) [16].

O H2N

Me

H H N

EtOH, NEt3

+

Ph

NH2OSO3H 0 °C

H

Me

N Ph

At rt

7/3 Stable at rt

Me Me

Ph

Me N

Me (2)

Scheme 5.1

Isomerization

Ph N N H

Me (1)

H N

H Me

N Ph

Me

+

(2′)

N H

(1′)

191

192

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Ph R1

H

Ph

N

NsONHCO2Et

R2

R1

H

N

CH2Cl2 de = 40%

Yield of 4 N CO2Et

a. R1 = R2 = H b. R1 = Me, R2 = H c. R1 = R2 = Me

R2

(3a–c)

31% 46% 42%

(4a–c)

Scheme 5.2

The yields were modest but the diastereoisomeric mixtures of 4b and 4c are easily separated by ﬂash chromatography and spirodiaziridines 4b and 4c were obtained as pure diastereoisomers. 5.2.1.2 Substrate-Controlled Diastereoselective Diaziridination Using Chiral Enantiomerically Pure Ketones H N HN

N

(*)

X

(*)

Vasella et al. have prepared glycosylidene diaziridines 5 as precursors of the corresponding diazirines [17]. The starting ketone was converted to (glycosylidene)amino sulfonate 6 [18] and ﬁnally treated with ammonia under pressure (Scheme 5.3). These diaziridines are mixtures of trans-conﬁgurated diastereoisomers. The main (S,S)-conﬁgured isomer 5S is stabilized by a weak intramolecular H-bond from pseudoaxial N–H to RO-C(2) [19]. This study suggests that the addition of the amine to lactone oxime sulfonate is kinetically controlled. Vasella et al. showed later that the Schmitz conditions [13] could be applied directly on the corresponding ketone (validone) if a persilylated pyranoside nucleus was used [20]. The trimethylsilyl protecting group plays a crucial role for the formation of the diaziridine increasing the yields from 28% (for deprotected validone) [21] to 50%. OBn OBn

OBn N (6)

OSO2CH3

6 bar

95

OBn BnO BnO

OH N 5 BnO (5R )

Scheme 5.3

H N

BnO N (5S ) H

NH3

O

BnO BnO

O

BnO BnO

N H

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

NH2OH

(1) NaNO2 / H2SO4

90%

(2) NH3 (3) HCl

O

NOH

(+)-Camphor

(8)

(1) HOSA

Cl−

NH2+

(9)

(2) NH3

N H (7)

NH

Scheme 5.4

2-Hydrazicamphane (7), which is also a precursor of the corresponding diazirine, was synthesized in enantiomerically pure form starting from (+)-camphor (Scheme 5.4) [22]. (+)-Camphor was converted to the corresponding oxime 8, which after a nitrosation/rearrangement sequence followed by aminolysis afforded the imine hydrochloride 9 in good yields. Treatment of imine 9 with HOSA and NH3 delivered enantiomerically pure 2-hydrazicamphane 7. Schmitz’s conditions [13b] ave been applied to 14-hydroxydihydromorphinones to prepare the corresponding diaziridines with interesting opioid activity [23]. 5.2.2 Diazirines N N

(*)

H N HN

(*)

The recent emergence of diazirines as popular carbene precursors can be attributed to their relative stabilities with regard to acids, bases, and heat when compared with other sources [24]. The chiroptical properties of enantiomerically pure diazirines are of particular interest because the diazirine chromophore is very well suited for circular dichroism (CD) studies [25]. This was applied recently in studies dealing with the induced CD as a probe for structural analysis of supramolecular complexes [26]. Furthermore, the fact that diazirines are easily photoactivated by long-wave UV light makes them suitable for biochemical applications [27]. As diazirines are the dehydrogenation products of diaziridines, their synthesis is simple when the corresponding diaziridines are available. The preparation of 2-azicamphane 10, which represents one of the very few examples of chiral enantiomerically pure diazirines, is performed by oxidation of 2-hydrazicamphane 7 (Scheme 5.5) [28].

I2, Et3N

NH N H (7) Scheme 5.5

N N (10)

193

194

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

N

OH

OBn

CH2 N

R

O

BnO BnO

H

N

N

N BnO

N

N OH

(11)

(12)

(13)

Fig. 5.1 Structures of diazirines 11, 12 and 13.

The chiral nonracemic diazirines 11 [29], 12 [17] and 13 [22] depicted in Figure 5.1 were also prepared by oxidation of the corresponding diaziridines. 5.2.3 Oxaziridines

The oxaziridines, three-membered rings containing nitrogen, oxygen, and carbon, have been of mechanistic and structural interest since their introduction in a classic paper by Emmons in 1957 [30]. This paper not only describes the preparation and structural proof of a new heterocycle but also contains the basis for most oxaziridine chemistry known so far, including rearrangement chemistry and decomposition of oxaziridines by low-valent metal salts [31]. During the following decade, oxaziridine chemistry remained conﬁdential and this heterocycle became of interest for stereochemists in the 1970s because of the chirality of the nitrogen atom and the appreciable barrier to its inversion. This barrier to inversion was determined to be 105–130 kJ mol−1 [32]. It turns out that the combination of placing a nitrogen in a three-membered ring (which destabilizes the 120◦ angle of the sp2 -like transition state involved in pyramidal inversion) with attaching the electron-withdrawing oxygen atom (which opposes the increased s-orbital character of nitrogen during inversion) makes simple oxaziridines the most interesting class of compounds containing a bona ﬁde nitrogen stereogenic center [33]. Oxaziridines have also been shown to epimerize photochemically through a nitrone intermediate [34]. While the inversion barrier is considerable in N-alkyl oxaziridines [35] and N-halogenated oxaziridines [36], it is smaller when the N-substituent is capable of π-conjugation (or hyperconjugation). N-aryl as well as N-acyl oxaziridines both have inversion barriers around 90 kJ mol−1 [37, 38]. N-sulfonyl and N-phosphinoyl oxaziridines also exhibit a lower barrier to inversion as a result of hyperconjugation present in the system [39]. Synthetic applications of chiral oxaziridines concern photochemical rearrangement reactions affording chiral amides or lactams with high levels of enantio- or regioelectivity [40], and asymmetric heteroatom transfer reactions. Oxaziridines can be used as both electrophilic aminating and oxygenating agents in their reactions with a wide variety of nucleophiles. In spite of this dual reactivity, the predominance of one process over another can be affected by varying the substitution pattern on nitrogen. In general, oxaziridines with small groups on nitrogen (H, Me) [41, 42] or

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

aryl, acyl, carboxyamido [43], alkoxycarbonyl [44] groups act as aminating agents, whereas those with bulky [45] or strongly electron-withdrawing groups on nitrogen such as sulfonyl, sulfamyl, or phosphinoyl [46] groups preferentially transfer the oxygen atom [47]. Perﬂuoroalkyl oxaziridines [48] and oxaziridinium salts [49, 50] are highly reactive electrophilic oxygen-atom transfer reagents. The epoxidation of double bonds mediated by oxaziridinium salts are generally performed in situ via an organocatalytic process using the corresponding chiral iminium salts in substoichiometric amounts and Oxone as oxygen source [31, 51]. Enantioselective oxygen-atom transfer reactions onto nucleophiles, such as oleﬁns, enolates or sulﬁdes [52] represent the essential part of the applications of chiral oxaziridines in asymmetric synthesis. Chiral oxaziridines can be produced via oxidation of chiral nonracemic imines, oxidation of achiral imines with a chiral nonracemic peracid, via separation of diastereoisomeric oxaziridines produced from achiral peracid oxidation using chromatography [53] or enzymatic resolution [54]. A few resolutions of racemic oxaziridines using complexation or inclusion with chiral host complexes have also been reported [55]. Several nonoxidative methods have been also developed but are less general: photocyclization of nitrones carrying a chiral substituent and photocyclization of achiral nitrones in an optically active environment. Finally, derivatization at the nitrogen atom of chiral nonracemic stable N–H oxaziridines can therefore provide a useful alternative method to peracidic oxidation of chiral nonracemic imines, for the preparation of N-functionalized oxaziridines. The electrophilic amination of ketones [13b] and the double 1,4 conjugate addition of hydroxamic acids to propiolates [56] to give racemic oxaziridines have been described but no asymmetric versions of these methods have been developed so far. 5.2.3.1 Chiral Peracidic Oxidation of Achiral Imines O (*) N

N

The ﬁrst preparation of an oxaziridine, and still the most widespread method today, was the oxidation of an imine with a peracid. Rapidly, attempts to obtain enantiomerically enriched oxaziridines using chiral nonracemic peracids have been performed. The most commonly used oxidizing agent is (S)-(+)-peroxycamphoric acid (monoperoxycamphoric acid (MPCA) 14) [57]. In most instances, the degree of asymmetric induction afforded by MPCA is rather low [35, 58]. Nevertheless, the use of crystalline MPCA at −78 ◦ C in a carefully selected solvent system can give optical purities of up to 60% for oxaziridine 15 [59]. (Scheme 5.6) Modest enantioselectivities (5–33% optical yield) have been observed when mixing different imines with meta-chloroperbenzoic acid (m-CPBA) in the presence of optically active carbinols [60]. The better selectivities were observed with chiral acyclic or aromatic triﬂuoromethyl-carbinols and are correlated with the reaction temperature and the relative amount of chiral solvent [61]. As one has to consider

195

196

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles O

CH2Cl2 /CHCl3 1:4 −78 °C

Br

O

14

N

OOH COO−

N

(16)

Br

(−)-15 60% o.p.

Scheme 5.6

that in the presence of chiral alcohols the peracid can be hydrogen-bonded to the solvent to produce a chiral peracid form, the authors proposed a chiral carbinol-imine solvation via hydrogen bonding between the imine nitrogen and the chiral protic solvent. 5.2.3.2 Achiral Peracidic Oxidation of Chiral Nonracemic Imines Diastereoselection of substrate-controlled peracidic oxidations of chiral nonracemic imines is generally excellent. The mechanism of oxidation of imines has been studied and found to proceed through a two-step sequence, through cleavage of π bonding followed by the elimination of one molecule of carboxylic acid, rather than a concerted oxygen transfer [62–64]. This method is the most widely used for preparation of chiral oxaziridines of high optical purities, starting from enantiomerically pure imines. In the same manner as that in diaziridines, the stereogenic center of the imine can come either from the ketone or the amine part. In the latter case, α –methylbenzylamine is widely used because of its low cost and ease of removal under dissolving metal conditions. This methodology will be illustrated by the most representative examples for each kind of N-substituted oxaziridines. N-Unsubstituted Oxaziridines O HN

(*)

HN

(*)

Although the ﬁrst N–H oxaziridine was reported in the 1960s [65], because of their general instability, only a few N–H oxaziridines have been prepared and utilized for their ability to transfer an amino group to various nucleophiles [41, 66]. The preparation of the ﬁrst stable enantiomerically pure chiral N–H oxaziridines has been accomplished only very recently by Page et al. [67]. These N–H oxaziridines 17 and 18, derived from (1R)-(+)-camphor and (1R)-(+)-fenchone were remarkably stable and used as asymmetric electrophilic nitrogen-atom transfer reagents on various ester- and nitrile-containing carbon nucleophiles [24]. Classical treatment of ketones with HOSA or a precursor of a chloramine to prepare N–H oxaziridines [13] were totally ineffective on camphor or fenchone. Thus, Page et al. decided to oxidize the primary (N–H) imines 19 and 20, which were prepared from the corresponding oximes 21 and 22 via the nitrimines 23 and 24, with m-CPBA (Scheme 5.7). The N–H oxaziridines 17 and 18 were obtained with good overall

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

NOH (21)

NNO2

Nitrosation Rearrangement

(23)

NH

NH

Ammonolysis

(19)

m- CPBA

O (17)

O NOH

NNO2

(22)

NH

(24)

(20)

N H (18)

Scheme 5.7

yields in enantiomerically pure form as diastereoisomeric mixture (6/4) at the pyramidal nitrogen atom. The diastereoisomers observed arise from the two conﬁgurations at the nitrogen atom resulting from endo attack of the oxidant on the imine 19 and exo attack of the oxidant on the imine 20. N-Alkyl Oxaziridines O N

N

(*)

(*)

The pioneering work concerning diastereoselective peracidic oxidation of imines has been performed on Schiff bases [68] bearing a chiral substituent on nitrogen, namely, (S) or (R)-α-phenylethylamine. In the case of acyclic imines, the conﬁguration of the C–N double bond inﬂuences the stereochemical outcome of the reaction. Using imines such as 26 derived from symmetrical ketones, a mixture of N-epimers 25a,b is obtained (Scheme 5.8) [69]. When aldimines or imines derived from unsymmetrical ketones are employed, four oxaziridines are obtained [70]. A pro-S attack of the peracid is proposed to account for the observed absolute conﬁgurations of oxaziridines 28 (Scheme 5.9). A stereospeciﬁc oxidation of chiral trans-aldimines leading to the corresponding (E)-oxaziridines has been described when a nitrile–hydrogen peroxide system was used as oxygen source instead of m-CPBA [71]. Ph R N

Ph H Me

m- CPBA

R (26) R = Me R = [CH2]4 R = [CH2]5

Scheme 5.8

R N R O (25a) 82 87 97

H Me

Ph +

R N R O (25b) 18 13 3

H Me

197

198

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles Ph

H Me

R

Br

N H

R=

(27) m-CPBA

R N

H O

Ph

Me H (28a) 58%

H

R H O Me N H Ph

Trans

N

R O

Ph

Me H

(28b)

(28c)

21%

16%

H R O Me N H Ph

Cis

(28d) 5%

PRO S

N H

Me H Ph

Scheme 5.9

Chiral nonracemic spirocyclic oxaziridines are important compounds in stereoselective synthesis as a result of their possible stereospeciﬁc photorearrangement leading to chiral lactams [72]. Stereospeciﬁc cyclic expansion occurs generally in which the group syn to the chiral N-substituent of the oxaziridine undergoes preferential migration to nitrogen upon photolysis. By use of chiral nitrogen substituents (typically α-methylbenzyl) on symmetrical cyclic imines, it is possible to control the absolute stereochemistry of the oxaziridine nitrogen atom [73]. Oxaziridines derived from six-membered cyclic imines tend to form via equatorial attack [74] and are also subject to control by a chiral group on nitrogen substituent (Scheme 5.10) [22]. Condensation of a 4-substituted cyclohexanone generates a mixture of diastereomeric imines 29a–b. Addition of the peracid to either imine can afford products of equatorial attack or axial attack, with the former being favored. Finally, N–O bond closure occurs such that the newly generated nitrogen stereogenic center emerges preferentially with the unlike [75] relative conﬁguration when α-methylbenzylamine was used for imine formation. The selectivity toward the equatorial/unlike product increases as the bulkiness of the peracid and of the substituent of the cyclic imine become more important [76]. Imines prepared from cyclohexanones containing bulky substituents, presumably have a superior ability to prejudice the six-membered ring into one chairlike conformation over the other. If a stereogenic center is located on the cyclohexane skeleton such as in the case of (R)-(+)-3-methylcyclohexanone 31, the overall stereochemical control results from a matched effect between this stereogenic center and the benzylic stereocenter on the nitrogen [77]. (Scheme 5.11)

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

199

Me N

O Unlike

O

O

83

Me Ar Ph

Equatorial attack

(30a)

Ph

Ph Me

Me

Me Ph

O O HN

N

N

Ph

O 12

Like Unlike

O Ph

Ph Me

(30b)

Me Ar

(29a)

N

Ph

Ph MPCA

Ph

Ph

(29b)

O O HN

Ph

N

O

Ph

3

Axial attack

(30c) Ph Me

Ph Like

N

O

Ph 2 (30d)

Ph Scheme 5.10

Me

Me N

O

Ph

N (+)-MPCA

Me

Me (32a)

Ph

Me

Me O (R )-aMBA

N

(S )-aMBA

Me

N

Ph

O

Ph

(+)-MPCA

Me

Me

(31)

de > 80%

Scheme 5.11

Condensation of (R)-α-methylbenzylamine and (S)-α-methylbenzylamine on (R)-(+)-3-methylcyclohexanone 31 followed by peracidic oxidation using (+)-MPCA delivers the oxaziridines 32a and 32b with an excellent diastereoselectivity. In each case, attack of the oxidizing agent takes place from an equatorial direction, leading to the cis relationship between the C-3 methyl group and the oxaziridine oxygen. In addition, oxidation affords products in which the benzylic stereogenic center and the oxaziridine nitrogen have unlike [75] relative stereochemistry [78]. (+)-MPCA is used only for its steric hindrance as any given stereocenter of this peracid is too far away from the forming bonds to have an effect on the face selectivity of the

(32b) de > 80%

200

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

oxygen addition. Interestingly, photorearreangment of oxaziridines 32a–b affords the corresponding regioisomeric lactams stereospeciﬁcally. The peracid oxidation of imines derived from 2-alkyl-substituted cyclohexanones gives more complex mixtures because of partial epimerization at C-2 position during imine formation and oxidation of the enamine tautomer [79]. The stereoselection of the reaction drops dramatically leading to a number of very minor oxaziridines accompanying one or two major isomers in the reaction mixture [72]. The effect of polar substituents at the C-2 position on the stereoselectivity of oxaziridine formation [80] has also been recently studied on the same substrates [81]. In contrast, the general equatorial attack by m-CPBA observed onto 4- and 3-alkylsubstituted cyclohexylimines or 2-methoxy-substituted cyclohexylimines can be changed into axial attack for 2-hydroxylated cyclohexylimines in favorable circumstances. A syn hydroxyl-directed approach of the peracid in the same manner as syn-directed epoxidation of allylic alcohols is proposed to take into account this unusual stereoselectivity. N-Alkyl Oxaziridines as Precursors of N-Quaternarized Oxaziridines + N

N

+O N

O N

N-alkyl oxaziridines are sluggish for epoxidation of alkenes and even for sulfoxidations but quaternarization of their nitrogen atom signiﬁcantly enhances the oxygen transfer reactivity [49, 50]. N-Alkylation leads to oxaziridinium salts that are among the most efﬁcient agents for oxygen transfer onto nucleophilic substrates. It has also been demonstrated that oxygen-atom transfer from N-alkyl oxaziridines could be promoted by Brønsted or Lewis acids [82, 83]. Since the ﬁrst report of steroidal oxaziridinium salt 33 by Lusinchi and coworkers in 1976 [84] and the establishment that such N-quaternarized oxaziridines are powerful electrophilic reagents for oxyfunctionalization of organic substrates [49, 50], their potential as asymmetric epoxidating agents has been intensively pursued (Figure 5.2) [85]. Chiral nonracemic oxaziridinium salts are generally generated in situ by peracidic oxidation of the corresponding enantiomerically pure iminium salts which are used for epoxidations in substoichiometric amounts in a catalytic cycle [50, 51, 85]. Only few optically active oxaziridinium salts have been isolated so far and most of them result from N-methylation of the corresponding enantiomerically pure oxaziridines. This alkylation reaction does not affect the conﬁguration of the three-membered ring. The peracidic oxidation of iminium salts also leads to optically active oxaziridinium salts, but generally their isolation via this pathway is

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

Me + O N Me FSO3− H Me

H H

H

(33)

Fig. 5.2 Structure of the ﬁrst isolated oxaziridinium salt.

more difﬁcult. We only focus on the preparation of oxaziridinium salts that have been isolated or clearly detected in solution. Steroid-Based N-alkyl Oxaziridines Enantiomerically pure steroid-based oxaziridines 34 [86] and 37 [87] have been obtained by a stereoselective peracid oxidation of the corresponding imines 36 and 38. A total selectivity of the peracid attack for the α face of 36 and the β face of 38 was observed (Scheme 5.12). Peracidic oxidation of O

Me

N

N

Me H

H Me

p -Nitroperbenzoic acid

H H

Me

H

CH2Cl2

(36)

H

FSO3 Me

(34)

H

FSO3Me

−

H

FSO3Me

Me + N

Me H

H H

p -Nitroperbenzoic acid

Me + O Me FSO3− N H H H

(35)

H

Me

CH2Cl2

H (33) Me C6H17 H

C H Me 6 17 H Me H N

R 2O

Me

m-CPBA

H

MeOH

H

R 2O

(38)

Me C6H17 H Me

Me3O+BF4− CH2Cl2

R 2O

Scheme 5.12

H

H H N + BF4− O Me (39)

O

H N

H H (37)

201

202

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

iminium salt 35 afforded oxaziridinium salt 33 with the same complete α-selectivity [84]. Oxaziridine 34 can also be prepared by treatment of the corresponding nitrone by p-tolylsulfonyl chloride in basic medium [88]. Oxaziridinium salts 33 and 39 result from methylation of the corresponding enantiomerically pure oxaziridines 34 and 37. Dihydroisoquinoline-based N-alkyl oxaziridines In 1993, the enantiomerically pure oxaziridinium salt 40 was isolated by crystallization and fully characterized including X-ray diffraction [89, 90]. It was conveniently prepared from benzaldehyde and (1S, 2R)-(+)-norephedrine via enantiomerically pure dihydroisoquinoline 41 following two possible stereoselective pathways already described for oxaziridinium 33 (Scheme 5.13). While the peracidic oxidation of the iminium 42 was fully stereoselective at room temperature, that of the parent imine 41 had to be performed at low temperature (−45 ◦ C) [82b, 91]. At room temperature, the peracidic oxidation of the dihydroisoquinoline 41 was not stereoselective and even not chemoselective as the corresponding nitrone was detected as side product. The cis relative conﬁguration observed between the oxygen of the oxaziridine ring and the methyl substituent of oxaziridine 43 and oxaziridinium 40 can result from minimization of torsional strain during the formation of the three-membered ring [92]. Catalytic asymmetric epoxidations mediated by the dihydroisoquinolinium salt 44 derived from a chiral amine delivered good level of enantioselectivity for various oleﬁns [93]. Nonaqueous conditions developed by Page et al. have allowed NMR spectroscopy to be carried out on the reaction mixture and show the stereoselective formation of the corresponding oxaziridinium salt 45 (Scheme 5.14) [94]. Binaphtyl-based N-alkyl Oxaziridines Recently, enantiomerically pure oxaziridines 46 and 47 have been prepared as acid-promoted asymmetric sulfoxidation reagents [95]. They resulted from a stereospeciﬁc oxidation of the corresponding enantiomerically pure imine by m-CPBA in methanol, leading to single enantiomers (Figure 5.3). The formation of the SC , RN isomer can be interpreted as a result of a steric Ph

Ph Me

Me

Me3O+BF4−

N

CH2Cl2

N (41) m- CPBA −45 °C CH2Cl2

m- CPBA 20 °C CH2Cl2

Ph

Ph Me

(43)

N O

Scheme 5.13

BF4− Me (42)

+

Me

Me3O+BF4−

+

CH2Cl2

(40)

N Me − O BF4

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

N+ BPh4−

N+ O

Ph4P+HSO5−

O

BPh4− O

+

O

O

O (44)

(45)

BPh4−

N+

O O

100/0

Scheme 5.14

H

Ph

N

N

O

O

H

Ph

(S )-46

(S )-47

Fig. 5.3 Structures of oxaziridines 46 and 47.

Me N

BF4−

+

Me m- CPBA

N

CH2Cl2

+

O Me

Me (S )-48

BF4−

(S )-49

Scheme 5.15

repulsion between the arene hydrogen and an oxygen of the perester of the minor intermediate [92]. Binaphtyl-based iminium salt 48 with C2 -symmetry has been transformed by peracidic oxidation into the enantiomerically pure oxaziridinium salt 49 that has been clearly characterized in solution by NMR spectroscopy (Scheme 5.15). A dichloromethane solution of the oxaziridinium salt 49 was used at low temperature to epoxidize various oleﬁns with enantioselectivities up to 75% [96]. N-Acyl and N-Alkoxycarbonyl Oxaziridines O N O

N O

N-acyl and mostly N-alkoxycarbonyl oxaziridines have found extensive use as a source of electrophilic nitrogen [43, 97, 98]. An asymmetric variant of this methodology would be useful as the development of efﬁcient chiral nonracemic

203

204

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

O O

N

Ph N

O

Me O

Ph

Me

N Ph

Cl

Ph N

Me Me

Cl (50a)

(50b)

O

O

O

N

O

O

N

O

H

H

CN

CN (51a)

(51b)

Fig. 5.4 Examples of chiral N-substituted oxaziridines.

reagents for asymmetric transfer of electrophilic nitrogen to organic substrates is an important contemporary goal. Only two chiral N-protected oxaziridines 50 [99] and 51 [100] have been prepared so far, both by the same group. The stereogenic center of the starting imines is located on the amine part for all of them (Figure 5.4). N-Carboxamido oxaziridines 50 were prepared by biphasic basic m-CPBA oxidation of the corresponding N-carboxamidoimines as a mixture of two diastereoisomers which are trans isomers with opposite conﬁguration at the ring carbon. They have been used as the ﬁrst asymmetric sulﬁmidation reagents [82] of thioethers and aziridination reagents of oleﬁns [101] giving interesting enantiomeric excesses. N-Alkoxycarbonyl oxaziridines 51 were prepared using the m-CPBA/BuLi system [43] as oxidant. The compounds were single diastereoisomers at the ring carbon disclosing a high diastereoselectivity with respect to facial attack on the imine carbon. Asymmetric lithium enolate amination was performed with oxaziridines 51 with modest enantiomeric excesses [83]. N-Sulfonyl Oxaziridines O N SO2

N SO2

The development of reagents for the reagent-controlled asymmetric oxygen-atom transfer onto prochiral nucleophiles with high enantioselectivity is an important synthetic goal. To date, N-sulfonyl oxaziridines represent the most versatile and general active oxygen compounds able to oxidize many prochiral nucleophiles with high enantioselection [31, 47].

5.2 Three-Membered N-Heterocycles with Two Heteroatoms

N-Sulfonyl oxaziridines 52 were the ﬁrst examples of oxaziridines to have a substituent other than carbon or hydrogen attached to nitrogen. These stable oxaziridines are readily prepared by biphasic-buffered oxidation of chiral sulfonimines 53 with m-CPBA or potassium peroxymonosulfate [102]. The latter resulted from condensation of enantiomerically pure sulfonamides with the diethylacetal of an aromatic aldehyde. Since oxidation of sulfonimines give only (E)-2-sulfonyl oxaziridines [103], just two oxaziridine diastereoisomers having the S,S and R,R conﬁgurations at the three-membered ring are obtained upon oxidation of 53. The best ratio of 52 (S,S/R,R) obtained reached 65/35 and was improved by fractional crystallizations to give optical yields (30–100%) depending on the nature of the aromatic substituent (Scheme 5.16) [104]. In order to increase the efﬁciencies of chiral 2-sulfonyl oxaziridines 52, Davis et al. decided to vary the groups attached to the oxaziridine N and C atoms in a systematic manner. They found that chiral 2-sulfamyl oxaziridines 54 could be prepared by oxidation of the corresponding chiral 2-sulfamylimines, in enantiomerically pure form after separation of diastereoisomers by chromatography [105]. These oxaziridines were particularly efﬁcient as enantioselective epoxidation reagents (ee up to 80%) when the aromatic substituent were perﬂuorinated (Figure 5.5). 3-Substituted 1,2-benzisothiazole-1,1-dioxide 55a-b has been also developed as new N-sulfonyl oxaziridine [106]. It was obtained by biphasic oxidation of the corresponding imines in a 85/15 mixture of diastereoisomers. Several crystallizations from ethanol gave pure (+)-55a and (+)-55b, which were less effective than N-sulfamyl oxaziridines 54 in their asymmetric oxidations (Figure 5.6). The camphor-derived oxaziridines 56–62 are of particular interest for two reasons: ﬁrst, they are derived from materials readily available from the chiral pool with a rigid structure, thus reducing the problem of separation of isomers during the synthesis as observed for oxaziridines 52, 54, and 55. Secondly, these oxaziridines ArCH(OEt)2

R*-SO2NH2

Ar

[O]

R*-SO2N=CHAr

N *R S O2

(53)

O

S,S O

R* =

O

or

Br Scheme 5.16

Ar N Z* S O2

O

C O

S,S

N H

Ar C

Z* S O2 (54)

H

Me Z* = Ph

R,R

Fig. 5.5 Structure of N-sulfamyloxaziridines 54.

N Ph

O

C

N H

Ar C

*R S O2 (52)

H

R,R

205

206

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

*R

*R O

R* =

or

a

O

N

O

N

S O2

S O2 55a–b (+)-(2S,3R ) (+)-(2R,3S )

b

Fig. 5.6 Structure of N-sulfonyloxaziridines 55.

O N

N

N

S O2 O

S O O2

S O2 O

(56)

(57)

(58)

X O

Cl

X N

O N

Cl N SO2Ph

S O2 O

S O2 O

O

(60) X = Hal (61) X = OMe

(59)

(62)

Fig. 5.7 Structure of camphoryl N-sulfonyloxaziridines.

are among the most efﬁcient reagents, specially 60 and 62, for enantioselective sulfoxidations of thioethers and enantioselective α-hydroxylation of carbonyl compounds. Not only is the product stereochemistry predictable, but the enantiomeric excesses often exceed 90% (Figure 5.7) [31, 47], [107, 108]. An important advantage of the camphorylsulfonyl oxaziridines is that upon oxidation of the corresponding imines, they are obtained as single isomers because the exo face of the C–N double bond is blocked by the methyl group of the methylene bridge. Some exo-camphorylsulfonyl oxaziridines have been also described. For example, exo-oxaziridne 63 has been prepared by m-CPBA oxidation of camphor imines 64 [109]. This unexpected result is probably due to the conformation of the imine which prevents attack of the peracid from the endo direction (Scheme 5.17). Amberlyst A-15

Cl

O

SO2NH2

Cl

N (64)

Scheme 5.17

Cl

m -CPBA

SO2 aq. K2CO3

O SO2 N (63)

5.3 Three-Membered N-Heterocycles with Two Heteroatoms

N-Phosphinoyl Oxaziridines O N

N P* O

P * O

N-Phosphinoyl oxaziridines, like their better established N-sulfonyl analogs are generally prepared by peracidic oxidation of the corresponding imines [110]. Optically active N-phosphinoyl oxaziridines 65 and 66 containing a chiral phosphorus center have been prepared and evaluated as enantioselective oxygen-atom transfer reagents onto thioethers (Scheme 5.18) [111]. Oxidation of N-Phosphinoylimine 67 (75% ee) prepared from scalemic R-Pmesityl-P-phenylphosphinic amide (75% ee) with anhydrous m-CPBA/potassium ﬂuoride complex [110] afforded a mixture of diastereoisomeric oxaziridines 65 and 66 (2.6:1) with total retention of the conﬁguration at the phosphorus atom (75% ee). 5.2.3.3 Photocyclization of Nitrones Photocyclization of Achiral Nitrones in Optically Active Environment Optically active oxaziridines can be obtained with generally modest enantioselectivity (optical purity 35%) by photoisomerization of achiral aldo- and keto-nitrones in the presence of a chiral solvent [112]. The best selectivities were obtained with (+)-(S) or (−)-(R)-2,2,2-triﬂuoro-1-phenylethanol [113]. More interesting is the irradiation of complexes of nitrones 68 and 69 in a crystalline inclusion with optically active (−)-1,6-di(o-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-1,6-diol that affords the corresponding oxaziridines with high enantioselectivity (>95% ee) (Figure 5.8) [114]. Photocyclization of Chiral Nitrones Photorearrangment of chiral nitrones to optically active oxaziridines has been found to occur in achiral solvents with optimum diastereoisomeric excess of 20% [113]. Because of low stereoselectivities observed, this method remained conﬁdential. Ar H Ar TiCl4

H2N

P

Ph

Et3N, ArCHO

N O H P Ph

KF-m -CPBA

Ph

(67) Ar = 2-Chloro-5-nitrophenyl

O P

(65) O N O H P Ph

Ar

O

Scheme 5.18

O N

(66)

207

208

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

Cl O− N+

O− N+ H

H (68)

(69)

Fig. 5.8 Structure of nitrones 68 and 69.

5.3 Four-Membered N-Heterocycles with Two Heteroatoms

Compared to the three-membered heterocycles mentioned above, their fourmembered homologs give rise to a larger variety of structures as for each combination of heteroelements there are two possible constitutional isomers (i.e. the 1,2- and 1,3-di-X-cyclobutanes). In addition, a wide variety of synthetic methods, centered mostly around [2 + 2]-cycloadditions and similar processes have been developed for their synthesis, and have been comprehensively reviewed [1]. As previously, we only cover recent methods that stereoselectively access enantiomerically enriched heterocycles. Despite their structural diversity, the four-membered N-heterocycles containing two (or more) heteroatoms have received much less attention than their smaller-ring congeners as far as their use as reagents or biologically active substrates is concerned. There are, however, a few notable exceptions. There is, for example, a fundamental interest in the electronic structure of some of the unsaturated four-membered ring structures in order to elucidate to what extent the presence of the heteroatoms renders these systems aromatic or antiaromatic [115, 116]. On the other hand, 1,2-diazetidine-3-ones, 1,3-diazetidine-2-ones (both often referred to as aza-β-lactams), 1,2-thiazetidine-1,1-dioxides (β-sultams) and azaphosphetidines (β-phospholactams) have received more attention from the synthetic community as analogs of β-lactams and thus potential antibiotics [117]. Not surprisingly, more general strategies for the synthesis of the latter structures have been sought, but their asymmetric synthesis remains underdeveloped. 5.3.1 Diazetidines

Diazetidines, the four-membered N-heterocycles, containing a second nitrogen atom comprise two isomeric types of structures, namely, 1,2-diazetidines 70 and 1,3-diazetidines 71 (Figure 5.9). N N

N

(70)

(71)

N

Fig. 5.9 General structures of diazetidine isomers.

5.3 Four-Membered N-Heterocycles with Two Heteroatoms

Despite the fact that 1,2-diazetidines have been described as early as 1931 [118] and that the most general method for the construction of the more prominent aza-β-lactams, namely, the reaction of azostilbenes with ketenes, dates back to 1941 [119], reports on chiral nonracemic diazetidines are scarce. Even the more recent and general strategies for the construction of these β-lactam analogs have not been developed to deliver enantiomerically enriched products [120]. The ﬁrst report concerning the synthesis of a scalemic 1,2-diazetidine-3-one was made in the context of the synthesis of dipeptides of l-proline with unnatural amino acids [121]. In an Ugi-type multicomponent reaction, N-amino-l-proline was reacted with an aldehyde and cyclohexylisonitrile to afford, presumably via the seven-membered intermediates 72, the enantiomerically enriched diazetidines 73 in modest optical purities ranging from 22 to 35%. The latter were converted to the corresponding dipeptides by reductive cleavage of the N–N bond (Scheme 5.19). More recently, a diastereoselective addition of hydrazine to the uridine-derived phenylselenones 74 was described as part of the synthesis effort toward nucleoside analogs [122]. 1,2-Diazetidines 75 were obtained in good yield as single diastereoisomers (Scheme 5.20). A simple procedure for the synthesis of chiral nonracemic 3-substituted 1,2diazetidines has been published recently by Ma et al. [123]. The authors describe an approach based on the proline-catalyzed α-hydrazination of aldehydes followed by aldehyde reduction and cyclization under Mitsunobu conditions or via the corresponding mesylate. Although most of their study was conducted with racemic proline, as a proof of principle 3-phenylpropanal 76 was reacted in the presence of (R)-proline and reduced in situ to afford 2-hydrazinoalcohol 77, which was then cyclized to the diazetidine 78 in a one-pot procedure using methanesulfonyl

O (1) RCHO

COOH N NH2

(2) C6H11NC

N HN

N

O N C6H11

R

(72)

O

RO

N O

RO

Ura

N2H4

O

O HN

NH

PhO2Se 74a: R = MMTr 74b: R = H Scheme 5.20

R

CONHC6H11 (73)

Scheme 5.19

NH

O

N

75a: R = MMTr, 60% 75b: R = H, 62%

209

210

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles N Cbz N Cbz (R )-Proline

Ph

O Then NaBH4

(76)

Ph

OH

Cbz

N

NH Cbz

(77) 98% ee

MsCl, DBU

Ph N Cbz

N Cbz

(78) 98% ee

Scheme 5.21

chloride and DBU (Scheme 5.21). Both 77 and 78 were obtained with an excellent enantiomeric excess of 98%. While these few methods are available for the synthesis of 1,2-diazetidines, their 1,3-isomers are even less studied. In particular, to our knowledge, there are no general methods described for the stereoselective synthesis of enantiomerically enriched 1,3-diazetidines. There are two reports on the synthesis of amino acid-derived diazetidinones by the reactions of tryptophan derivatives with alkyl isocyanates [124]; however, their structural assignments have later been questioned [125]. 5.3.2 Oxazetidines

Oxazetidines are the four-membered heterocycles containing one nitrogen and one oxygen atom. As for their diazetidine counterparts, two possible constitutional isomers, i.e. the 1,2- 79 and 1,3-diazetidines 80, are possible (Figure 5.10). While the chemistry of these compounds has been comprehensively reviewed on several occasions [1], there are only scattered reports on their asymmetric synthesis – a characteristic they share with their diazetidine analogs (see Section 5.3.1). One might argue that the limited availability of stereoselective synthetic methods is due to the poor stability of many oxazetidines. However, the scarcity of target molecules containing the oxazetidine motif can also be regarded as a reason for the apparent lack of interest from the synthetic community. Symptomatically, the isolation and ﬁrst structural assignment of the halipeptins [126] – cyclic depsipeptides that were thought to contain a 1,2-oxazetidine moiety – immediately triggered studies toward the synthesis of this unusual fragment [127]. However, these studies only conﬁrmed the structural revision that had been published in the meantime and supported the hypothesis that halipeptin contains a thiazole ring instead [128], an assumption that was later ascertained by total synthesis [129].

HN O (79)

HN O (80)

Fig. 5.10 General structures of oxazetidine isomers.

5.3 Four-Membered N-Heterocycles with Two Heteroatoms

Recently, two methods for the synthesis of enantiomerically enriched 1,2oxazetidines have been reported by Florio et al. Their interest in these structures arose when, during the course of studies aimed toward the synthesis of α,β-unsaturated oxazolines, they discovered that 1,2-oxazetidines were formed during the reaction of α-lithiated oxazolines with nitrones [130]. Careful optimization of the reaction conditions allowed the highly diastereoselective synthesis of 1,2-oxazetidines 81a,b from readily accessible α-chloro-oxazoline 82 via lithiation and addition to nitrones 83a,b (Scheme 5.22) [131]. The reaction was found to be limited to the use of aromatic nitrones and enantiomerically pure oxazetidines 84a,c,d and ent-84a,c could be obtained from the valinol-derived α-chloro-oxazolines 85 and ent-85. The same authors recently reported a similar synthesis of enantiomerically enriched oxazetidines on the basis of the diastereoselective addition of lithiated aryloxiranes to nitrones [132]. Having established the excellent diastereoselection of this process, they demonstrated its applicability to the synthesis of optically enriched substrates. Indeed, optically active oxiranyllithium reagents 86 and ent-86 add to nitrones 83c and 87a,b to afford hydroxylamines 88a–c, which upon treatment with NaOH in i-PrOH undergo an intramolecular epoxide opening to form oxazetidines 89a–c with er of 98:2 (Scheme 5.23). −

Cl N

Cl LDA

CH3

Li CH3

N

O Ar N+ t -Bu 83a,b

H3C N

O

O

O N

t- Bu Ar H

O

(82)

81a: Ar = p -CF3C6H4, 60% 81b: Ar = p -MeOC6H4, 85% Cl (1) LDA

N

CH3 O

(2) −O

N+ t - Bu

Ar

(83a,c,d)

(85)

O N

H3C N

t- Bu Ar H

O 84a: Ar = p -CF3C6H4, 93% 84c: Ar = C6H5, 90% 84d: Ar = p -ClC6H4, 90%

Cl (1) LDA

N

CH3 O

ent- 85

Scheme 5.22

(2) −O Ar N+ t-Bu

(83a,c,d)

N O H3C

O N

t-Bu H Ar

ent- 84a: Ar = p -CF3C6H4, 90% ent- 84c: Ar = C6H5, 72%

211

212

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

H

Ph

O

N O

Ar

Ar H

Li H

R

N

H

O

Ph

Ph

R

R

ent -86

N

OH

ent -88a, 88c −

O N+ R

Ph

HO (89a,b)

NaOH, i -PrOH

Ar

Li O

OH

(88a,b)

(86)

H

R

Ph

O

83c, 87a

H Ar

N O OH Ph

ent -89a, 89c 89a: R = t- Bu, Ar = Ph 89b: R = cumyl, Ar = p -ClC6H4 89c: R = cumyl, Ar = 2-furyl

Ar

83c: R = t- Bu, Ar = Ph 87a: R = cumyl, Ar = p -ClC6H4 87b: R = cumyl, Ar = 2-furyl Scheme 5.23

O

Me HH

O Me

Me

H

H H

O

N H

O

O

Sessilifoline A (90) Fig. 5.11 Structure of sessilifoline A.

As was the case for 1,3-diazetidines, there are, to our knowledge, no methods described for the asymmetric synthesis of 1,3-oxazetidines. Again, it has to be emphasized that the strained bis-aminal functionality of these heterocycles makes them particularly reactive and unstable. However, the natural product sessilifoline A (90, Figure 5.11) was recently assigned a structure containing a 1,3-oxazetidine [133]. Hopefully, interesting natural product targets such as this one will rekindle the interest of the synthetic community in these rare heterocycles. 5.3.2.1 Thiazetidines Thiazetidines are the four-membered heterocycles containing one nitrogen and one sulfur atom. Again, two types of constitutional isomers are possible: the 1,2- 91 and 1,3-thiazetidines 92 (Figure 5.12). In addition, the sulfur atom may be oxidized, and thus give rise to thiazetidine-1-oxides 93 and thiazetidine-1,1-dioxides 94, 95. The chemistry of this family of heterocycles has been comprehensively reviewed [1]. Again, our focus will be on the stereoselective synthesis of enantiomerically enriched products, and in this area there are, to our knowledge no reports concerning compound types 91, 92, 93 and 94. As suggested for the oxazetidines

5.3 Four-Membered N-Heterocycles with Two Heteroatoms

O

S NH

S

(91)

NH (92)

O S NH O S NH (93)

O O S NH (95)

(94)

Fig. 5.12 General structures of thiazetidines.

(vide supra), one might argue that it is the lack of attractive target structures that has prevented a more vivid interest in these structurally intriguing compounds. On the other hand, 1,2-thiazetidine-1,1-dioxides (β-sultams) of general structure 94 have received far more attention. We have mentioned the fundamental interest in the latter as more reactive analogs of β-lactam antibiotics [117]. This has been the main motivation of synthetic chemists to successfully develop approaches for their stereoselective preparation. In the following, we will distinguish between chiral β-sultams bearing stereogenic elements within or outside the four-membered ring and subdivide the synthetic methods accordingly. A simple and general synthesis of enantiomerically pure chiral β-sultams has been reported recently by Page et al. [134]. They report the reaction of (chlorosulfonyl)dimethylacetyl chloride 96 with a series of amino acids to afford the corresponding enantiomerically enriched β-sultams 97 (Scheme 5.24). Otto et al. have recently described the synthesis of β-sultams bearing stereogenic centers on and outside the four-membered ring. While their ﬁrst approach used only racemic β-sultam 98 that was derivatized on nitrogen by the use of chiral acid chlorides and on the carboxylate end with amino acids [135], they later developed an asymmetric approach to the same types of compounds (Scheme 5.25) [136]. Starting from orthogonally protected aspartic acid 99, chemoselective reduction of the carboxylate group afforded amino alcohol 100. The latter was transformed into bromide 101 and nucleophilic displacement produced sulﬁde 102. The hydrochloride 103 was obtained after Boc deprotection, and was cyclized to (S)-98 via a one-pot oxidative chlorination-base induced ring-closure sequence. Several other examples of cyclization strategies starting from amino acids have been reported [137]. In particular, β-sultam 104, obtained from (R)-cysteine, has been used to prepare oxazaborolidine catalyst 105 in situ by reaction with borane (Scheme 5.26) [138]. The latter was able to promote the enantioselective reduction

Cl

O O O S

Cl

+

H2N

O S O N

R COOH

O

R

HOOC (96) Scheme 5.24

R or S

R- or S -97 R = i -Pr, i -Bu, Ph

213

214

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles

HOOC

NHBoc BH3-THF COOBn HO (99)

NHBoc CBr4, PPh3 Br COOBn (100)

BnSH, NaH

BnS

NHBoc COOBn (102)

(1) Cl2, EtOH

(101) Cl−

(1) TFA (2) HCl

NHBoc COOBn

+

NH3

BnS

COOBn (103)

O2S NH

(2) NH3

COOBn (S )-98

Scheme 5.25

OH Ph Ph

2 BH3

H

NH SO2

(104)

Ph Ph H

O

BH N+ BH3− SO2

(105)

Scheme 5.26

of acetophenone with a good enantiomeric excess (81%), even though the reaction was run at an unusually high temperature (66 ◦ C). The same ring closure of open-chain β-amino sulfonates featured in the previous examples has also been put to proﬁt by the Enders group. Their efforts in this area were initially seen as an extension of the conjugate addition methodology of chiral amines to α,β-unsaturated sulfonates that had been developed in order to prepare taurine derivatives [139]. The best results were obtained with the RAMBO chiral hydrazine 106, which was used in a three-step sequence involving Lewis acid-catalyzed conjugate addition to sulfonates 107, followed by N–N bond cleavage and Cbz protection to afford β-amino sulfonates 108 with enantiomeric excesses in excess of 96% (Scheme 5.27) [140]. Subsequent sulfonate hydrolysis and chlorination afforded sulfonyl chlorides 109. Cbz removal and base-induced cyclization afforded the desired β-sultams 110 that displayed no erosion of enantiomeric purity. In a second approach by the Enders group, 3,4-disubstituted β-sultams were targeted, and the general strategy modiﬁed in order to include a diastereoselective alkylation of SAMP-hydrazone 111 [141]. The latter was transformed into β-amino sulﬁde 112 by a known sequence. Removal of the benzyl group afforded 113, which was oxidized and chlorinated to obtain 114 (Scheme 5.28). The same deprotection and cyclization conditions used previously ﬁnished the synthesis of the cis-3,4-disubstituted β-sultams 115. An interesting synthesis of β-sultams, on the basis of a ring opening-ring closing strategy starting from isoxazolidines 116, was recently described by Caddick et al. [142]. Although this strategy has been applied successfully to the diastereoselective

5.3 Four-Membered N-Heterocycles with Two Heteroatoms

OMe N NH2 O

c -HexO

O

c -HexO

R 3 steps (107) R = Et, Pr, i -Pr, Bu, CH2CH2Ph (1) EtOH, reflux, then NaOAc (2) COCl2

62 –74%

O NHCbz

O

RAMBO (106)

S

S

R

(108) ee > 96% (1) HBr-HOAc

O NHCbz (2) Et3N

O S

Cl

R

29–78%

(109) ee > 96%

O2S NH R (110) ee > 96%

Scheme 5.27 O

MeO N

HN

4 steps

N

OMe

R1

R2 SBn (112) de, ee > 96% R1 = i -Bu, Bn, (CH2)2Ph, CH2c -Hex R2 = Me, Bu, Hex

25 –73%

SBn (111)

O Li/NH3

HN R1

68–99%

OMe 2

R

(1) H2O2, (NH4)6Mo7O21 (2) NaOAc (3) COCl2 44 – 99%

SH (113) de, ee > 96% O HN

OMe

1

(1) HBr-HOAc (2) Et3N

R

R2 SO2Cl (114) de, ee > 96%

39 – 83%

O2S NH R1

R2 (115) de, ee > 96%

Scheme 5.28

synthesis of the sultams 117 bearing a large variety of aryl substituents, no asymmetric version is available yet (Scheme 5.29). All the previously described methods proceed by cyclization involving S–N bond formation. There is only one example of a stereoselective synthesis of β-sultams by a C–N bond formation. Del Buttero et al. used chiral (tricarbonyl)chromium arene

215

216

5 Asymmetric Synthesis of Three- and Four-Membered Ring Heterocycles O2 S

C6 F 5 O

OH Mo(CO)6

O N H

Ar

SO2 NH Ar

(116)

(117)

Scheme 5.29 R

R CHO +

O2 S

SO2 NHt -Bu

BuLi

NHt- Bu

OH Cr(CO)3

Cr(CO)3 (118) R = Me, OMe, Cl

(119)

R SO2 NHt -Bu

hn

MsCl, Et3N

R SO2 NHt -Bu OMs

OH (120)

NaH

(121)

t -Bu N SO2

R (122)

Scheme 5.30

complexes 118 as starting point for their approach (Scheme 5.30) [143]. Diastereoselective addition of the dianion of tert-butyl methanesulfonamide afforded alcohols 119, which were deprotected under photochemical conditions and the resulting alcohols 120 transformed into their corresponding mesylates 121. Deprotonation of the sulfonamide nitrogen by NaH effected the intramolecular SN 2 ring closure to afford β-sultams 122. Another appealing strategy for the formation of β-sultams is the [2 + 2] cycloaddition of sulfenes with imines. Despite the fact that this type of methodology had been known for several years [144], and that attempts at diastereoselective versions had been reported in solution [145] and on solid phase [146] with moderate success, there was no general asymmetric version available until the recent report by the Peters group [147]. A variety of sulfonyl chlorides 123 were used as sulfene precursors and reacted with electron-poor imines 124 in the presence of quinine as chiral catalyst. cis-β-Sultams 125 were obtained in good yields and diastereo- and enantioselectivities (Scheme 5.31).

References

NTs R

SO2Cl (123)

R = Me, Et, Pr, CH2Ph CH2OC6H4OMe, (CH2)2Cl

+

Quinine (10 mol%) i -PrNEt2

EWG (124) EWG = CCl3, CO2Et

O2S NTs R

EWG (125)

Up to 95% ee up to 94% dr up to 21:1

Scheme 5.31

5.4 Conclusions

As illustrated above, three- and four-membered N-heterocycles with two heteroatoms are prepared by a wide variety of synthetic methods. There are several methods to synthesize certain ring systems in enantiomerically enriched form and, in many cases, as a result of its high inversion barrier, their nitrogen atom is stereogenic. Whereas the three-membered rings, and mainly enantiomerically pure oxaziridines, have been used as chiral substrates or chiral reagents in a variety of unique stereoselective transformations, their four-membered congeners, such as β-sultams, have been mainly prepared for their potential biological applications. Despite these diverse applications and the efforts outlined above, the enantioselective synthesis of these heterocycles remains underdeveloped. Especially in the area of the hetero-azetidines, many subclasses lack preparative methods of general scope, and certain constitutional isomers have never been synthesized asymmetrically. Undoubtedly, because of their growing interest, the chemistry of three- and four-membered N-heterocycles will provide synthetic challenges for some time to come. References 1 (a) Maitland, D. J. (1975) Three-

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223

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom Catherine Kadouri-Puchot and Claude Agami

Asymmetric syntheses of chiral ﬁve-membered heterocycles containing two heteroatoms, one of which being nitrogen, have been the subject of several studies. Such compounds indeed are of manifold signiﬁcance. First, they are intrinsically interesting owing to their various biological properties: anti-inﬂammatory ability (2 -pyrazolines), antibacterial activity (oxazolidinones and pyrazolidinones), ligands for dopamine receptors and platelet glycoprotein antagonists (isoxazolines), and anti-inﬂammatory drugs (thiazolines) can be quoted as very fragmentary examples. In the second place, these heterocycles are extraordinary and useful reagents for the synthesis of a great variety of optically active molecules and most of them are the basis of new methodologies that are now widely used. In this context, many distinguished chemists have linked their names to processes that embody exceptional versatility in building elaborate optically active molecules often obtained in an enantiopure form. Last but not least, many members of this family (especially, oxazolines and isoxazolines) are used as chiral ligands in metal-catalyzed enantioselective transformations; this property might appear as the most promising one and research in that direction is fast expanding. Owing to these outstanding features, as can be expected, many reviews pertinent to this area are available and they will be cited in due course below. Therefore, the present review will focus on the more recent outcomes, and the most widely known results of the last 15 years will be described. 6.1 Five-Membered Heterocycles with N and O Atoms 6.1.1 Oxazolidines

Chiral oxazolidines may be viewed as masked forms of aldehydes, and as such are widely employed as chiral auxiliaries in asymmetric synthesis. Since the Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

224

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom R4 R3

R4 OH

+

O R1

OHC-R1 N R2

R3

2

NHR

Scheme 6.1

stereoselective construction of this type of ﬁve-membered heterocycle is especially straightforward, this property has allowed numerous applications [1]. Basically, oxazolidines are easily formed by an acid-catalyzed reaction between an aldehyde (or an acetal) and a suitable 1,2-amino alcohol derived from an α-amino acid or belonging to the ephedrine family (Scheme 6.1). This transformation involves the prior formation of an iminium ion, which undergoes an intramolecular nucleophilic addition from the hydroxy group. This cyclization, which is the main pathway leading to such heterocycles [2], is nevertheless a disfavored 5-endo-trig process [3], and is unmanageable in the case of an unsubstituted amino group (R2 = H in Scheme 6.1) reacting with aromatic aldehydes. Actually, in that case, the condensation (Scheme 6.2 R = Ar) leads to a mixture of the oxazolidine 1 (as an epimeric mixture) and its tautomeric hydroxyimine 2, the ratio between them being dependent on many experimental features [4]; however, oxazolidine is always produced as the minor tautomer in this case. When the aldehyde is not an aromatic one, the imine tautomer 2 (R = Ar) appears as a trace product but the created oxazolidine still appears as two epimers in nearly equal amounts. On the other hand, the fact that the cyclization goes to completion with all N-substituted amino alcohols (Scheme 6.1) can be viewed as a consequence of the classical Thorpe–Ingold effect. As stated above, the case of oxazolidine formation from N-substituted amino alcohol does not show any of these inconveniencies: yields and stereoselectivities are excellent. However, the formation of N-alkyloxazolidines has to be treated separately from that of N-tosyl and N-Boc oxazolidines. 6.1.1.1 N-Alkyloxazolidines Considerable confusion about the structure of these heterocycles prevailed in the early stages, since an X-ray analysis published in 1971 [5] speciﬁed that condensation of ephedrine and p-bromobenzaldehyde led to a 2,4-trans-oxazolidine conﬁguration. Many subsequent works [6, 7] have contributed to correct this assertion; it is now unambiguously established that, in all cases, the major oxazolidine isomer shows a relative 2,4-cis-conﬁguration (the single crystal studied by Neelakantan [5] should not be representative of the dissolved material). Actually this cis conﬁguration is OH Ph

NH2

Scheme 6.2

O +

R

OHC-R Ph

N H (1)

OH

+ Ph

N (2)

R

6.1 Five-Membered Heterocycles with N and O Atoms

Ph

OH

Me

NHMe

Ph

OH

Me

NHMe

Ph +

+

OHC-C6H4-p -X

O C6H4-p -X

Me

N Me

Ph

O

Me

N Me

OHC-C6H4-p -X

C6H4-p -X

Scheme 6.3

the result of a thermodynamic control and the less stable trans structure may, in some cases, appear solely as a transient species depending on the reaction medium [8]. Scheme 6.3 depicts two representative examples of oxazolidine formations from (−)-ephedrine [7] and from (+)-pseudoephedrine [8], respectively. The fact that the 2,4-cis conﬁguration is more stable that the trans one can be ascribed to the favorable trans/trans array between substituents on the C-2, N-3 and C-4 centers. This also explains why both C-2 epimers are equally stable when N-unsubstituted amino alcohols are involved. The most used chiral amino alcohols are ephedrine [7, 9], pseudoephedrine [4], valinol [10], phenylglycinol [11], and their N-substituted derivatives. Recently [12], amino alcohols prepared from l-methionine and S-methyl-l-cysteine were employed for the synthesis of oxazolidines which were later used in the actively explored ﬁeld [13] of asymmetric palladium-catalyzed allylations. Oxazolidines are also valuable tools in the most challenging ﬁeld of organoﬂuorine compounds. A large array of amino alcohols was reacted with triﬂuoromethyl aldehyde, which afforded oxazolidines 3 in excellent yields but as an epimeric mixture (Scheme 6.4); this last fact is unimportant since these oxazolidines were transformed into their corresponding imine counterparts 4, which exist as unique stereoisomers [14]. A highly diastereoselective organometallic addition to these imines affords the interesting chiral amino alcohols 5. Analogous triﬂuoromethyl-substituted oxazolidines also served as chiral auxiliaries for the alkylation of amides and for the synthesis of various β-amino acids, β-amino alcohols, and γ -amino alcohols via Reformatsky- and Mannich-type reactions [15]. Recently, it has been reported [16] that the oxazolidine formed from ephedrine and salicylaldehyde can be used as a catalytic ligand in the addition of diethylzinc to a variety of aldehydes. An original methodology arose when a dialdehyde (namely glutaraldehyde) instead of an aldehyde was treated with phenylglycinol (R1 = C6 H5 , R2 = H) or

R

OH + OHC-CF3 NH2

O R

N H (3)

Scheme 6.4

OH R

N (4)

CF3 R

PhLi

CF3 CF3

OH

Ph (5)

225

226

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

R2

R1 H2N

KCN

+ CHO

CHO

CN

O

pH 3.0

R1 R2

OH

N (6)

Scheme 6.5

norephedrine (R1 = CH3 , R2 = C6 H5 ) as the amino alcohol counterpart, in the presence of potassium cyanide (Scheme 6.5); this led to the bicyclic oxazolidine 6 as a single isomer in which the classical 2,4-cis structure is still present (in that case, however, the favored trans junction of the bicyclic system should be taken into account to explain the stereoselectivity) [17a]. On the other hand, an anomeric effect explains the axial position of the cyano group, and this geometry is a crucial element for the numerous syntheses that were developed from this compound as starting material. This methodology, which permits the synthesis of many natural and unnatural derivatives containing either the piperidine or the pyrrolidine moieties, was dubbed the CN(R, S) method by its authors, Husson et al. [18]. Some years after the preceding reports, Katritzky et al. described a similar condensation that also involves dialdehydes: glutaraldehyde [19a] and succinaldehyde [19b] which were made to react with phenylglycinol in the presence of benzotriazole (instead of potassium cyanide). Whereas the condensation product 7 formed from glutaraldehyde was obtained as a mixture of epimers and regioisomers [19c], this was not the case when succinaldehyde was the starting material; in this last case, the pyrrolidine homolog 8 was obtained as the single, more stable trans isomer (Scheme 6.6). Another occurrence of this 2,4-cis structure in a bicyclic oxazolidine was found in the oxazolopiperidine 10, which results from the highly stereoselective intramolecular cyclization (Scheme 6.7) of the pyridinium salt 9 [20]. The cyclization depicted in Scheme 6.8 shows a cyclization that is related to the preceding one: oxazolidine 12 was synthesized from β-hydroxy tertiary amine N-oxides 11 [21]. Here again, the product shows the usual 2,4-cis geometry. N N N

N N

O

(7)

N N

N

(8)

Scheme 6.6

Ph

Ph N+

OH Cl−

( 9) Scheme 6.7

RMgX

R

N

(10)

O

O

6.1 Five-Membered Heterocycles with N and O Atoms

Me

Me O−

N+

Me

Me

OH

BuLi

O

N

THF, −78 °C

(11)

(12)

Scheme 6.8

A moderate diastereoselectivity, favoring now the 2,4-trans geometry in compound 13, was reported during the iodocyclization of 1,4-dihydropyridines 14 [22]. It should be noted that an iminium ion does not come into play (as in the preceding reactions): cyclization occurs on an iodonium ion and the reaction product may not be thermodynamically controlled (Scheme 6.9). Intermediate iminium ions are also involved during the partial reduction of δ-lactams whose intramolecular cyclization (Scheme 6.10) leads oxazolopiperines. Thus, compound 16 was obtained from the readily available bicyclic lactam 15 and eventually cyclohexenone 17 was produced in >99% ee [23]. δ-Lactam 18 can be converted into oxazolopiperidine 19 through addition of a Grignard reagent (Scheme 6.11). The cis conﬁguration observed in the product was attributed to an A1, 2 allylic strain. [24] Other chiral bicyclic compounds analogous to the preceding ones were recently synthesized by an original method: 2-pyrrolidino-1-ethanol was oxidatively cyclized to the corresponding oxazolopyrrolidines by treatment with Me3 NO [25]. This reaction is catalyzed by an iron carbonyl complex, which led to a 2,4-trans geometry of the oxazolidine moiety since, owing to the preferred cis ring junction of this [3.3.0] system, this structure is the more stable. Though the mechanism of this process is not fully elucidated, an iminium ion seems to be a likely intermediate (Scheme 6.12). Ph

Ph OH

N

O

N

NIS, THF

R

R (R = CN, OAc) (13)

I (14)

Scheme 6.9

Me O

Me N

Red-Al

O

Me

N O

(15) Scheme 6.10

O

Me

O HO

(16)

H3O+

HO

Me (17)

227

228

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom Ph

Ph

OH N

(1) NaH (2) MeMgCl

O

O

N

Me Bn

Bn (18)

(19)

Scheme 6.11 R

R

R N

OH

Me3NO, catalyst

+

N

OH

N

O

Scheme 6.12

6.1.1.2 N-Tosyl and N-Boc Oxazolidines Scolastico et al. [26] made use of ketals, instead of aldehydes, as substrates for the synthesis of oxazolidines 20, which present a very interesting distinctive feature: the heterocycle nitrogen is substituted by various electron-withdrawing groups (EWGs; Cbz, Ts, CO2 -t-Bu, CO2 Me, etc.). However, the tosyl N-substituent proved to be the most productive since it allows the formation of the 2,4-cis epimer in a totally stereoselective mode (Scheme 6.13). A structural study [27] showed that, when substituted by this group, the nitrogen is no longer planar (as with the other groups) and, as described above, results in the formation of this thermodynamically favored geometry. A great deal of work has been published that reports the various applications of such oxazolidines as chiral inductors in asymmetric synthesis [1]; most applications concern stereoselective transformations on an unsaturated moiety attached on the C-2 center of the oxazolidine (see an example in Scheme 6.13). Subsequently, the same authors [28], concurrently with Hoppe’s group [29], reported a new stereoselective method of producing stereoisomerically pure N-tosyl oxazolidines (Scheme 6.14) via the formation of an intermediate oxocarbenium 21, reacting with a nucleophile such as an enoxysilane or an allylstanane. Ph

OH +

Me

NH EWG

MeO MeO

CO2Me

Ph

O

Me

N EWG

CO2Me (20)

[RCu]

OHC

CO2Me R

Scheme 6.13

Ph

O

Me

N EWG

H CO2Me R

6.1 Five-Membered Heterocycles with N and O Atoms

Ph

O OMe

Me

Lewis acid

N Ts

Ph

O

+

SnBu3

Me

N Ts

Me

R

Ph

O

Me

N Ts

(21)

Me

OSiMe3

Ph

O

Me

N Ts O

Scheme 6.14

O OMe Ph

N Ts

O

TMSCN

CN

TMSOTf

RMgBr

N Ts

Ph

Ph

O

R

N Ts (22)

O

Scheme 6.15

These various methodologies led the way to the synthesis of some of the most useful oxazolidine derivatives: that is, the N-tosyl and N-Boc-2-acyloxazolidines. Actually, Hoppe [30] published the synthesis (Scheme 6.15) of the N-tosyl derivative via the addition the Lewis acid–catalyzed addition of a cyanide ion to an oxocarbenium ion analogous to 21 (Scheme 6.14), and shortly thereafter Colombo [31] described a synthesis of N-Boc-2-acyloxazolidine by an organometallic method (Scheme 6.16). Both methods afford very conveniently 2-acyloxazolidines 22 or 23. The use of such 2-acyloxazolidines as chiral substrates for many asymmetric transformations was extensively studied by Couty et al. [1]. These authors described a new method that affords such synthons (Scheme 6.17) via a condensation between ethylglyoxylate and phenylglycinol or norephedrine [32]. The produced oxazolidines 24, once saponiﬁed, were transformed into their corresponding Weinreb amides 25, which were, in turn, treated with Grignard reagents in order to produce the required 2-acyloxazolidines 26 in a totally stereoselective way. Such a methodology allows the formation of a great variety of substrates, which undergo many asymmetric transformatons. One example [33] of such a process is given in Scheme 6.18. Before closing this paragraph, it is worth mentioning that chiral oxazolidines produced from ketones, instead of aldehydes, have been scarcely described. Besides O SnBu3 Ph

N Boc

Scheme 6.16

(1) BuLi, −78 °C (2) PhCHO

O

OH

O

PDC

Ph

N Ph Boc

Ph

O

N Ph Boc (23)

229

230

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

OH Ph

(1) OHCCO2Et (2) Boc2O

NH2

O

Ph

N Boc

N(Me)OMe

O

N O Boc

Ph

(24)

R

O

CO2Et RMgX

Ph

(25)

N O Boc (26)

Scheme 6.17

O 24

NaH / THF Ph

N

R

AL−O Lewis acid

O

Ph

O

+ N

R

HO

R

AllylTMS

N O

Ph

O

O

O

Scheme 6.18

HN O

HCl, MeOH reflux

O HO

Cl−

N

+N O HO

(27)

Scheme 6.19

the well-known fact that ketones are much less reactive than aldehydes as regards this type of ketalization, it may be emphasized that in such oxazolidine derivatives the essential control of the geometry of the quaternary C-2 center would be very enigmatic. Clearly, there is no such a problem when this center is not a stereogenic one as in the special case of the oxazolidine derived from acetone, which was recently synthesized by using ﬂuoroalkanesulfonyl azides [34a]. On the other hand, the structural constraints inherent to the tricyclic nature of oxazolidine 27 explain why it was formed as a single diastereoisomer in the reaction depicted in Scheme 6.19 [34b,c]. Interestingly, this cyclization involves the addition on an anti-Bredt iminium ion. 6.1.2 Oxazolines (4,5-dihydrooxazoles)

In the ﬁeld of asymmetric synthesis, oxazolines hold a preeminent position, since they come into play as chiral auxiliaries as well as ligands in catalytic systems. Asymmetric carbon–carbon bond formation is of great signiﬁcance for the synthesis of enantiopure compounds; in this respect, Meyers’ methodology, which makes use of such moieties in order to create deﬁnite stereogenic centers in carboxylic derivatives, is considered as one of the most fruitful methods in this area [35]. This process was extended with equal success to aromatic substitutions and aryl couplings [36, 37]. On the other hand, oxazoline and, especially, bisoxazolines are recognized as very fruitful ligands for asymmetric catalysis and are concerned with

6.1 Five-Membered Heterocycles with N and O Atoms

OEt RCH2

NH+ Cl−

(28) +

or RCH2(OEt)3

HO

Ph

Ph O

H2 N HO (30)

(29)

Ph

OH N

RCH2

OMe

t-BuOK, MeI

O (31)

N

RCH2 (32)

Scheme 6.20

Ph O

Ph

OMe N

CH3CH2

BuLi

MeI

CO2H

OMe +

O

CH3CH2

N CH3

H3O

HO +

78% ee 84% overall yield

Ph

H2N MeO

Scheme 6.21

a very impressive array of important reactions, such as for example, aldol reactions, homo- and hetero-Diels–Alder reactions, cyclopropanations, allylic substitutions, and so on [38]. The popularity of these compounds is mainly due to their ease of preparation, which rests on a relatively few but very efﬁcient methods. As regards the preparation of these versatile heterocycles, it should be underscored that they are masked forms of carboxylic acids; however, carboxylic acids themselves are sometimes inadequate to synthesize oxazolines owing to the weakness of their electrophilic reactivity. Meyers [39] showed that it would be worthwhile to convert them into much more reactive derivatives: that is, imidates of nitriles 28 or orthoesters 29. These substrates react very smoothly with various enantiopure amino alcohols, and the oxazolines 31 are obtained, maintaining the conﬁguration of the initial stereocenters (Scheme 6.20). The ﬁrst amino alcohol that was used in this way was (+)-(1S,2S)-1-phenyl-2-amino-1,3-propanediol 30 (this enantiomer is commercially available since it was a basic material during the industrial synthesis of chloramphenicol). The CH2 OMe polar appendage in reagent 32 was thought to play a crucial role during the asymmetric transformations that were operated on the carboxylic moiety. Indeed, it can act as a ligand, which, jointly with a nitrogen atom, chelates a metal cation (in the most cases Li+ ), thereby forcing the attacking nucleophile to enter from a speciﬁc side of the molecule. Once the subsequent asymmetric transformation is realized, the amino alcohol is easily recovered from the acidic hydrolysis of the product (see Scheme 6.21 for an example). Since then, many other amino alcohols have been employed in order to synthesize such chiral oxazolines [40]. Among them, the usual reduced derivatives of α-amino acids and derivatives of the ephedrine family frequently reported as substrates (Scheme 6.22) are phenylalaninol 33, valinol 34, phenylglycinol 35, ephedrine 36, pseudoephedrine 37, and so on. Special mention may be made to a camphor-derived amino alcohol 38, which leads to oxazolines whose carboxylic moiety was alkylated with excellent diastereoselectivity without the need for any polar appendage [41].

231

232

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom PhCH2

Ph

O

N

O

N

Ph

O

N

Me

O

Ph

Me

O

N

N

RCH2

RCH2

RCH2

SiH3

RCH2

(33)

(34)

(35)

(36)

(37)

O N CH2R (38)

Scheme 6.22

O R

HO N H

O R

NHR′

NHR′

N

O

O

(39) Scheme 6.23

OMs TrO

K2CO3

R N

CF3

O F 3C

OTr

N

O Scheme 6.24

Actually, Meyers has observed that such extra ligands may not always be necessary in order to achieve highly stereoselective synthesis [37]. Apart from their outstanding involvement in asymmetric synthesis, enantiopure oxazolines are found as elements of miscellaneous natural products and biologically active molecules [42]. Therefore, it is understandable that a great deal of work has been devoted to their preparation. The most expeditious way of synthesizing 1,2-oxazolines is the reaction of 1,2-amino alcohols (belonging to or simply derived from the chiral pool) with acid derivatives as presented by Meyers (see above). Intramolecular substitution has also contributed to such syntheses. Thus, various dehydrating catalysts have been reported as being effective in the dehydrative cyclizations of N-acyl-β-hydroxy-α-amino acid amides 39 (Scheme 6.23), and a catalytic procedure using molybdenum oxide has recently been reported for the corresponding reaction applied to N-acylserine and N-acylthreonine derivatives [43]. Another type of a related intramolecular cyclization involves the amide group as the nucleophile (Scheme 6.24). In this case, the hydroxy moiety has to be converted into mesylate and the ring closure occurs stereospeciﬁcally with inversion [44]. This procedure has the advantage of allowing the formation of oxazolines substituted only on the C-5 center; these compounds are otherwise difﬁcult to obtain owing to the lack of accessibility of the corresponding amino alcohols. To the best of our knowledge, there is only one work reporting a genuine enantioselective synthesis of enantiopure oxazolines (all the other cases actually are mostly diastereoselective processes). Komatsu et al. [45] described the transformation of styrene (Scheme 6.25) derivatives into optically active oxazolines when they are reacted with acyl chlorides in the presence of the salen complex 40.

6.1 Five-Membered Heterocycles with N and O Atoms

N Mn O O N N

R

R′

(40)

+ R′COCl

O

N

Pyridine N -oxide, CH2Cl2, 0 °C

Ph

R

Ph

80 – 86% ee’s 80 – 90% overall yields Scheme 6.25

O

O

O

N

N N R

(41)

O

R

R

O

N (42)

N R

O

O

R

N

N R

(43)

O

Ph

N (44)

Ph

R = CHMe2, CMe3 Scheme 6.26

O

O Cl

Cl

OH

+ Ph

NH2

Et3N

SOCl2

Cl

O

O NH HN

Ph

Cl

NaOH

44

Ph

Scheme 6.27

The ﬁrst report of chiral oxazolines as ligands for catalytic asymmetric transformations goes back to 1986 [46]. Since then, much works has been devoted to the preparation and application of these compounds, and, as mentioned before, a number of reviews have covered this topic [38]. However, the seminal studies by both Evans [47a] and Corey [47b] (Scheme 6.26) should not be overlooked because they introduced the exceptionally fruitful C2 -symmetric bisoxazoline ligands 41–43 [47a] and 44 [47b] in this ﬁeld (Box ligands). The procedure that was used to prepare these ﬁrst Box ligands is univocal: the spacer comes from a symmetrically disubstituted malonic acid derivative, and the cyclization from the chiral aminoalcohol moiety is somewhat trivial (Scheme 6.27). This procedure still is the most used one, and many variants have been presented, in particular by Denmark [48] and Hanessian [49]: sulfonates as leaving group, various dehydrating agents, malononitrile instead of malonyl chloride, and so on. All these interesting variants have been extensively described in Desimoni and Jorgensen’s review [38d]. The second general procedure can be viewed as an extension of the preceding one; it is based on the substitution of the methylene hydrogens of the malonyl moiety and has led to numerous other Box ligands (see Scheme 6.28 for a representative example [50] of this method).

233

234

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

O

O

MeLi

RO O

CH2Br

O

N

N

N

O N

t-Bu

t-Bu

t-Bu

t-Bu

OR

R = CH2C6H4OCH2CH CH2 Scheme 6.28

O

O CO2Me

N N O

N N

PhMgBr

Ph Ph OH

O

CO2Me

Ph Ph OH

Scheme 6.29

R2 HO

NHFmoc O R1

R

OH

R1

O

R2

R

N

NH2

R1 R

O

R2

N

N R3 R4

NH2 O O N Ph

N H Boc (45)

N

Ph Ph

O

CH2Ph

N

HN SO2

OH O (46)

Scheme 6.30

Another procedure consists in the manipulation of groups already present in the ligand or in the spacer as depicted in Scheme 6.29 [51]. Recently, nonsymmetric Box-containing ligands appeared to be very promising in the asymmetric catalysis of various reactions. Thus, Sigman exploited a modular approach to ligands (for example 45 and 46) composed of both oxazoline and another basic moiety (Scheme 6.30) acting as templates during the catalysis of enantioselective Diels–Alder reaction [52a], addition of allylic halides to aldehydes [52b] as well as addition of allyl bromide to ketones [52c]. Very recently, another set of 16 nonsymmetrical Box ligands were tested in the chromium-catalyzed Nozaki–Hiyama–Kishi allylation of benzaldehyde [53]. Compounds 47 and 48 are the most promising in this respect (Scheme 6.31). Now, we cannot overemphasize the remarkable creativity that is still displayed in this ﬁeld, and a large number of various ligands have been prepared and tested in

6.1 Five-Membered Heterocycles with N and O Atoms

S O NH

N R2

N

R1

47: R1 = t-Bu, R2 = Bn 48: R1 = Bn, R2 = t-Bu

O Scheme 6.31 Et O N O

Et O N

O N

N

(49)

(50) O

O

Scheme 6.32

a variety of metal-catalyzed enantioselective reactions (see for instance compounds 49 [54] and 50 [55] in Scheme 6.32). Extensive research is still ongoing in this very fruitful ﬁeld, and recently the use of such ligands supported on poly(ethylene glycol) has been reported [56]; enantioselective catalysis can thus be envisioned in aqueous solution. 6.1.3 Oxazolidinones 6.1.3.1 Oxazolidin-2-ones Oxazolidin-2-ones constitute an important class of oxazolidine derivatives. Since the ﬁrst report in 1981 [57], chiral oxazolidin-2-ones (namely, Evans auxiliaries) have been widely used as chiral auxiliaries in numerous asymmetric organic reactions [58, 59], such as aldol condensations [60], Diels–Alder reactions [61], 1,3-dipolar cycloadditions [62], and radical reactions [63]. Moreover, since the 1980s, oxazolidinones represent an exciting new class of synthetic antibacterial agents [64]. Given the high synthetic utility of these heterocycles, asymmetric synthesis of oxazolidinones has attracted much attention. As the oxazolidines described above, one of the important chiral sources for the preparation of enantiopure 1,3-oxazolidin-2-ones is β-amino alcohols [65]. Reactions of amino alcohols with carbonyl derivatives such as phosgene [66], trichloromethylchloroformate (diphosgene) [67, 68], triphosgene [69], carbonyldiimidazole [70], and diethylcarbonate [71] have led to oxazolidinones in which the conﬁgurations of the stereocenters of the starting amino alcohols are retained. The construction of oxazolidinones from N-carbamate derivatives of

235

236

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

R2 R1

OH

R2

X2C O

O

Base

O N H

R1

NH2

R2

OH

R2

OH

R1

NH2

O R1

N H

OR3

Scheme 6.33

Ph Me

Ph

OH NBoc R R = H, Me

TsCl 70%

O O N R

Me

NHBoc MsCl

H N

76%

O

OH

O

Scheme 6.34

(1) R1

OH

R2

NH2

Et4N+ N

O

(2) CO2; TsCl

R1

OH OTs

R2

N H

O

R1

O

O N H 65% < yield < 95% R2

Scheme 6.35

1,2-aminoalcohols occurred also without changes in the conﬁguration of the carbon bearing the hydroxyl group, when the carbamate was treated by a base, as shown in Scheme 6.33 [72, 73]. In contrast, an inversion of conﬁguration, as depicted in Scheme 6.34, was observed via an SN 2 pathway from N-Boc derivatives of 1,2-amino alcohols, when the hydroxyl group was transformed into a good leaving group (reaction with TsCl [74], MsCl [75]). With the aim of ﬁnding methodologies involving the use of harmless materials in place of toxic reagents such as phosgene, Feroci et al. used carbon dioxide in the presence of 2-pyrrolidone electrogenerated base and tosyl chloride (Scheme 6.35) [76]. In this methodology, the absolute conﬁguration of all chiral atoms is retained; this result excludes the tosylation of the hydroxyl group. Carboxylation followed by a Mitsunobu reaction has been investigated [77]. These reactions occurred with high yields. The stereochemical course of the Mitsunobu reaction is dependent on the N-substituent: primary amines gave oxazolidinones 51 with retention of conﬁguration at the oxygen-bearing center, while secondary amines led to oxazolidinones 52 with inversion of conﬁguration at the oxygen-bearing center (Scheme 6.36). Experiments with 18 O-labeled carbon dioxide evidenced two distinct mechanisms during the cyclization step [77b]. Chiral oxazolidinones were synthesized by using the selenium-catalyzed carbonylation of the corresponding 2-amino alcohols by bubbling CO at atmospheric pressure without racemization (Scheme 6.37) [78]. An alternative strategy involves the intramolecular displacement of a leaving group by the nitrogen atom of a N-benzoyl or N-tosyl carbamate (Scheme 6.38). The leaving group can be a bromine [79], a phenylselenide substituent [80]. The

6.1 Five-Membered Heterocycles with N and O Atoms R1 R2

OH

R1

CO2

NHR

R2

OH N H

R1

Mitsunobu

OH

R1

O

O

O R2

O

O N R (52) (R # H)

N R2 R (51)(R = H)

Scheme 6.36 OH

O

CO, Secat

NH2

O

CH3CN

N H

96%

Scheme 6.37

O

NHR

R1

O

R1

O

X

R2

R2

N R

O

Scheme 6.38 R (Boc)2N

Br

NBS

CO2Me

CCl4

(Boc)2N

R

R

R MeO2C O + O BocN BocN O trans O cis (54) major (55) minor

AgNO3 MeO2C

CO2Me Acetone H 70% (53)

Scheme 6.39

O R1 R2

OH R3

OH

(PhO)2P(O)N3 NEt3, Tol, 80 °C

R1 R2

N

R3

C

OH

O R1

O

72–88% R2

N R3 H

O

(56) Scheme 6.40

oxazolidinone ring was also generated by a similar intramolecular nucleophilic addition, in basic media, to a vinyl sulfoxide moiety [81] or an epoxide [82]. Crich and Banerjee reported an expedient synthesis of oxazolidinones from α-amino acids, as precursors of β-hydroxy-α-amino acids (Scheme 6.39). [83] The N-bromosuccinimide (NBS)-mediated radical bromination of N, N-di-tert-butoxycarbonyl-protected α-amino acids afforded a 1:1 mixture of the diastereoisomeric bromide 53, which was treated with silver nitrate to give predominantly the trans-oxazolidinones 54. Formation of acyl azide from chiral β-hydroxy-α-amino acids, Curtius rearrangement and internal cyclization afforded 4-substituted and 4,5-disubstituted oxazolidin-2-ones 56 in good yields and with complete stereochemical control, as described in Scheme 6.40 [84].

237

238

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

Ar

R

Ar

HN

OH OEt

Ar R

+

O

NaOH

R

HO EtO

NH O

Ar

R

HN

O

R +

Ar

HN

O O

O Scheme 6.41 R R

O +

NH2COOEt

(R,R)-XX

p -Nitrobenzoic acid TBME, rt, in air

O

HO EtO

(57)

(58)

N Co

t-Bu

O

NH

Base

O

NH

R

O

(59) R = Et 99.9% ee 94% yield

N O

t-Bu

t-Bu t-Bu (60) (R,R)

Scheme 6.42

In the following approach, the authors envisioned the use of the Sharpless asymmetric amino hydroxylation of a styrene derivative followed by a base-mediated selective ring closure of the resulting carbamate to afford oxazolidinones in a single step (Scheme 6.41). The optimized aminohydroxylation conditions were used on several β-substituted styrene derivatives [85]. Bartoli et al. reported a methodology that provided a simple and practical tool for synthesizing a collection of varied 5-substituted oxazolidinones in almost enantiomerically pure form from racemic terminal epoxides [86]. The asymmetric carbamate-based aminolytic kinetic resolution (AKR) of racemic epoxides 57 catalyzed by Jacobsen’s (salen)-CoIII chiral complex 60, which was generated in situ by oxidation of the catalytically inactive (salen)-CoII complex, gave N-protected 1-amino-2-ol 58 in almost enantiomerically pure form (Scheme 6.42). The best base to promote the subsequent cyclization step was sodium hydride. This one-pot reaction sequence appeared as an easy and very convenient protocol to access a wide range of enantiopure 5-substituted oxazolidinones 59. 5-Functionalized enantiomerically pure oxazolidin-2-ones 64 were also prepared in one pot from commercially available chiral aziridines 61 bearing an EWG at C-2 (R = ester, vinyl or acyl, Scheme 6.43) [87]. The reaction was performed with methyl chloroformate to give a high yield (up to 85%) of the 5-functionalized oxazolidinones. This reaction occurred with retention of the conﬁguration through an SN 2-type double inversion process: acylation on the nitrogen to form the

6.1 Five-Membered Heterocycles with N and O Atoms Ph (R ) Me

Ph O (R ) N Me O

ClCO2Me

N

239

R (S ) H (61)

R (S ) H (64) Ph O

Me

O Me

Ph OMe

+ N

R

Me

N

O

H R Cl (63)

H

−

Cl

(62)

Scheme 6.43 Ph Me

N

R1 R2 OH H

(65)

(1) NaH, THF, 0 °C (2) Phosgene, −78 °C

Ph Me Cl

O N

O R2 R1

O Anisole, MeSO3H Hexane, ∆ when R1 = R2 = H

(66)

HN

Cl

O

Ar

R2 R1 (67)

R1 and R2 = alk 80% < yield < 92%

Scheme 6.44

activated aziridinium species 62, which was regioselectively cleaved by chloride ion via an SN 2 process, followed by intramolecular cyclization by the carbamate moiety. The same authors reported a novel and efﬁcient pathway to oxazolidinones from aziridines 65 [88]. Treatment of these compounds with sodium hydride and phosgene led to enantiopure (chloromethyl)-5-substituted-oxazolidin-2-ones 66. Phosgene was selected as the intramolecular cyclizing agent of the amino alcohol moiety in order to form the cyclic carbamate with regioselective ring opening of the aziridine by the chloride ion (Scheme 6.44). The oxazolidinone 67 (R1 = R2 = H) was then transformed into enantiopure (L)-homophenylalanilol derivatives. Trost and coworkers have investigated the palladium-catalyzed desymmetrization of meso biscarbamates. [89] The oxazolidinone-forming reaction was easily carried out by preparing the biscarbamate substrate in situ from the cis-diol 68, and the biscarbamate solution was added to a solution of 5 mol% catalyst, prepared by stirring a mixture of ligand (L) and tris(dibenzylideneacetone)dipalladium–chloroform complex. The best yields and enantiomeric excesses (84% yield and >99% ee for n = 1) were obtained by using L* with R = R1 = H and by adding triethylamine to the mixture (Scheme 6.45). The origin of the enantioselectivity was explained by a model suggesting that the difference in diastereotopic transition states (ionization of the pro-S leaving group vs. ionization of the pro-R leaving group) was the result of steric interactions between the chiral ligand and the cycloalkene. Larksarp and Alper reported a highly enantioselective method for the synthesis of oxazolidinones by palladium(0) catalyzed cycloaddition of vinyloxiranes with heterocumulenes such as carbodiimides or isocyanates by using chiral phosphine ligands [90]. Oxidative addition of the chiral phosphine–palladium complex

OH NH2

240

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

OH

O

(2) dba3Pd2CHCl3 L*

(68)

O

O

n

(1) TsN=C=O

n

HO

NH

N

O

Ts

PPh2 R

HN Ph2P

R1

L*

Scheme 6.45

+

R

X=C=Y

3 mol% Pd2(dba)3·CHCl3 6 mol% TolBINAP THF, N2

O

O

X = O, Y = C6H4N R=H R = CH3 X = Y = C6H4N X O

X O ⊕

+

Pd R L L (69)

via η3–η1–η3 pathway

L

X

X = O, Y = N-R′ X = Y = NR″

−

Y

Y

R

−

Y

Pd R L (70)

Scheme 6.46 O

t-Bu O NHSO2Ar

O

O OR2

O (71)

NSO2Ar H (72)

O N Pd X

SiMe3

Fe

O

2 Pd

X=I X = OCOCF3

N

Co Ph O

2

Ph

(73) FOD

Ph Ph (74) COD

Scheme 6.47

to racemic vinyl oxirane followed by heterocumulene complexation led to a diastereoisomeric π-allyl palladium complexes 69 and 70, which are equilibrated via an η3 –η1 –η3 mechanism (Scheme 6.46). This equilibrium is much faster than the nucleophilic addition of the nitrogen. Cyclization of the allylic N-arylsulfonylcarbamates 71 (prepared from allylic alcohol and arylsulfonylisocyanate) catalyzed by ferrocenyloxazoline palladacycles (FOP) afforded 4-vinyloxazolidin-2-ones in high yields and enantioselectivities. A better catalyst was recently found by the same authors: the cobalt oxazoline palladacyclic complex 74 that does not require preactivation like the FOD complexes (Scheme 6.47) [91]. Lespino and Du Bois described the catalytic oxidative cyclization of various carbamates to oxazolidinones [92]. The reactions were performed optimally using [Rh2 (OAc)4 ] as catalyst, PhI(OAc)2 as oxidant and MgO as base additive

6.1 Five-Membered Heterocycles with N and O Atoms

O

Me O

(S )

NH2

[Rh2(O2CR)4]

HN

O

PhI(OAc)2, MgO

O Scheme 6.48

O R1

H

+

R3O2C N R2SH + N

OTMS N H Ar Ar

(1) NaBH4 EtO2C (2) NaOH

CO2R3

H N

O N

R2S R1

O 38% < yields < 72% 68% < dr < 90% 97% < ee < 99%

Scheme 6.49

O N O

OH N

H

F

N

O

O (+)-Streptazolin

Linezolid

O NHAc

Scheme 6.50

(Scheme 6.48). The authors showed that the C–N bond formation is totally stereoselective and postulated a metal-directed N-atom insertion process. This method is signiﬁcant because it gives access to quaternary α-amino acids. A very efﬁcient asymmetric multicomponent reaction [93] involving both enamine and iminium activation gave access to highly functionalized oxazolidinones (Scheme 6.49). The domino-conjugated nucleophilic addition of thiols to α-βunsaturated aldehydes in the presence of 2-[bis(3,5-bistriﬂuoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine as catalyst, followed by electrophilic amination reaction to the enamine intermediate, resulted in the formation of nearly enantiopure oxazolidinones. Many recent works have reported the asymmetric synthesis of oxazolidinones via asymmetric desymmetrization of prochiral diols. Serinol derivatives were used to give enantiomerically enriched monoacetates, which were transformed by appropriate reactions into oxazolidinones [94]. Besides the importance of oxazolidinones as chiral auxiliaries, these compounds also constitute a new class of antimicrobial compounds, which were discovered by researchers at Dupont in the 1980s [95]. The oxazolidinone moiety was found in the structure of few biologically active natural products such as (−)-cytoxazone [96] or (+)-streptazolin [97], and much effort has been devoted to the development of analogs (Scheme 6.50). Actually, these compounds exert potent in vitro and in vivo antibacterial activity against multiple antibiotic-resistant strains of Gram-positive bacteria. Linezolid [98] was the ﬁrst oxazolidinone that was introduced into clinical trials and approved

241

242

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom O

(1) R1NH2 OH OH

R

TBSO

EDCI, DMAP (2) R2COOH EDCI, DMAP

O

R2

O

H N

R

TBSOTf R1 2,6-lutidine

O

R2 R1 N +

R2 O

OTBS R1 N

O R (75) major 99

O R (76) minor 1

Yield = 89%

R = Ph, R1=CH2=CHCH2, R2 = PhSeCH2

84

16

Yield = 88%

R = Ph, R1=CH2=CHCH2, R2 = BrCH2

63

37

Yield = 97%

O

R = Ph, R1= Bn, R2 = Me

Scheme 6.51

O O R

R1 N H

(CH2O)n, C6H6

CO2H

TsOH (cat)

R

R1 N

O O

41– 81% Scheme 6.52

in 2000 by the Food and Drug Administration. Many enantioselective syntheses of these products and their analogs have been described by using the classical reactions, cited above, to generate the oxazolidinone ring. 6.1.3.2 Oxazolidin-4-ones and 5-ones Only a few reports are devoted to the asymmetric synthesis of 4-oxazolidinones. Kamimura et al. [99] described in 2002 the synthesis of a new type of heterocycles: the oxyoxazolidinones 75 and 76 (Scheme 6.51), which are readily prepared from O-acylmandelamides on treatment with TBSOTf. These compounds were used by the same authors as chiral auxiliaries for heterocyclic synthesis [100]. Although much less used than the oxazolidin-2-ones, 5-oxazolidinones are attractive precursors for the synthesis of various substituted amino acids [101]. Ben-Ishai [102] was the ﬁrst to describe the reaction between N-Cbz-amino acids with paraformaldehyde, under acid catalysis, that led to 5-oxazolidinones via an intramolecular cyclization. With a view to synthesizing N-methyl amino acids, several chemists extended the range of substrates that can be transformed into 5-oxazolidinones, and different protecting groups (N-Fmoc [103], N-Cbz, N-Boc [104] were used to develop this methodology (Scheme 6.52). Recently, Hughes et al. [105] described the syntheses of N-methyl amino acids of the common 20 amino acids in high yields and without racemization via 5-oxazolidinone intermediates. The synthesis of α,α -disubstituted amino acids from a bicyclic oxazolidinone was ﬁrst developed by Seebach and coworkers [106]. Reaction between proline and pivalaldehyde under acidic catalysis gave the single product 77, in which the tert-butyl group is on the exo face, in a cis relationship with the bridgehead hydrogen. No epimerization occurred during this condensation. Deprotonation and alkylation led to the products 78 in moderate to excellent yields and with essentially complete diastereoselection (Scheme 6.53). Recently, Vartak et al. [107] described a stereoselective synthesis of α,α -biprolines by using this procedure.

6.1 Five-Membered Heterocycles with N and O Atoms

CO2H

t-BuCHO

N

H+

N H

R O

H O

H

(1) LDA

N

(2) RX

O

H (78)

t-Bu (77)

O

t-Bu

Scheme 6.53

BnO

ArCHO

CO2H

N H

Ph

O

Ph

O

BnO

N

TsOH (cat) 40%

O + O

Ar

Ph

O

9:1

BnO

N Ar

O O

Scheme 6.54

This methodology has been applied to acyclic amino acids with moderate yields. The procedure involves an aromatic aldehyde [108, 109] or pivalaldehyde [110] and afforded a separable mixture of oxazolidinones, whose major isomer showed a cis conﬁguration, as depicted in Scheme 6.54. Most of the syntheses described here are based on stereoselective synthesis using chiral precursors (amino alcohols, amino acids, hydroxy acids, aziridines, etc.). But, during the last few years, new strategies using asymmetric catalysis to obtain enantioenriched oxazolidinones have emerged. They have contributed to widening the ﬁeld of application of these compounds as chiral auxiliaries and as biologically active compounds. 6.1.4 Isoxazolines and Isoxazolidines

As clearly suggested by the presence of their N–O bond, isoxazolidines 79 and isoxazolines 80 are commonly prepared (Scheme 6.55) through 1,3-dipolar cycloaddition reactions [62, 111] from alkenes and nitrones 81 or nitrile oxides 82, respectively. As it will be detailed below, isoxazolidines 79 are especially valuable reagents for synthetic purposes, whereas isoxazolines 80 essentially constitute the basis

+ R2

R3

⊕ R4 N O

−

(81)

R3 R1

R4 N

O

(79)

R2

R1

+

− ⊕ R3 C N O

(82) Scheme 6.55

R3 R1

N

O

(80)

R2

243

244

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom O N * * 1 R * (79) R2

R1 R3

R3

HO * * * NH2 R2 R1

O *

R

1

R2 *

O N * *

(80)

N Metal

R1

R2

HO * * R2

O

Scheme 6.56

for meaningful ligands that are used during various metal-catalyzed reactions (Scheme 6.56). 6.1.4.1 Isoxazolidines Chiral isoxazolidines are known for a long time as valuable intermediates in the synthesis of many important classes of molecules: alkaloids, β-amino acids, β-lactams, amino sugars, and so on. This is due to the labile nature of their N–O bond; isoxazolidines can be viewed as masked forms of γ -amino alcohols and they are easily prepared in an enantiopure form from chiral nitrones or chiral alkenes or also, to a lesser extent, from both chiral nitrones and alkenes [112]. Intermolecular as well as intramolecular [3 + 2] cycloadditions have been performed and the recent use of metal catalysis was especially examined [62, 111, 113]. First, it should be underscored that such reaction creates up to three stereogenic centers and, irrespective of the enantioselectivity issue, this fact requires that regioand diastereoselectivities are controlled [114]. The classical endo/exo problem adding further to these difﬁculties, much work has been devoted to circumvent these points [111, 115]. For instance, MacMillan [116] (Scheme 6.57) described an example of remarkable control of all these selectivities by using crotonaldehyde 83 (the presence of the EWG on the alkene clearly directs the regioselectivity on the dipolarophile) reacting with nitrone 84 in the presence of the imidazolidinone salt 85, which acts as the chiral organocatalyst. Me (83) +

C6H11

⊕ Bn N O

(84) Scheme 6.57

O

−

Me O HClO4 . N Me Bn N Me (85) H −10 °C , CH3NO2 – H2O 70% yield

Cy OHC

Bn N O Me

endo (99%) 99% ee

+

Bn N O

Cy OHC

Me

exo (1%)

6.1 Five-Membered Heterocycles with N and O Atoms O +

O

Ph N O

−

N N Cu(OTf)2

O

O

O

(88) +

Me

N

(86)

O CH2Cl2, rt 90% yield

(87)

Ph N O O

Ph N O

Me N

+

Me

O

O

N

O

O

O

endo 91% 96% ee

exo 9% 99% ee

Scheme 6.58 O

O Me

N

O

+ Ph

+ Ph

Bn

Rf

N − O

Me O O N Ph

Ph

Me O

O N

O

Bn

Rf

endo (major isomer)

+

O N Ph

Ph

O N

O

Bn

Rf

exo

Scheme 6.59

The improvement of the diastereofacial selectivity provoked by the presence of a Lewis acid is common in the cycloaddition ﬁeld. This can be also substantiated in the present case as shown in Scheme 6.58, which depicts the enantioselective reaction of nitrone 86 with dipolarophile 87 under the catalytic effect of a chiral bisoxazoline/Lewis acid complex 88 [117a]. Nitrone cycloaddition of a ﬂuorous oxazolidinone chiral auxiliary catalyzed by Yb(Otf)3 or Sc(Otf)3 was reported [118] to give cycloadducts with excellent yields and stereoselectivities (Scheme 6.59). This initial work stimulated intensive research in the ﬁeld of ﬂuorous-supported auxiliaries [119] in order to make use of such reactions for speciﬁc synthesis purposes [73, 120] or for elaborating combinatorial libraries [121]. Interestingly, N-oxide derivative 90 was produced via a reverse-Cope elimination from hydroxylamine 89 [122]; on the other hand, after being oxidized by air, hydroxylamine 89 reacted intramolecularly to afford the spiro tricyclic isoxazolidine 91 with excellent diastereoselectivity. Eventually, the N–O bond was cleaved with zinc, yielding a hydroxylamine, as shown in Scheme 6.60. Similar strategies were described by others later on [123]. As might be anticipated, nitrones derived from natural products have given rise to numerous studies. Two of these (Scheme 6.61) may serve as examples of this fruitful area. First, highly regio- and stereoselective cycloaddition of methyl acrylate

245

246

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom ⊕

O Me

MeOH, ∆

N O (90)

N OH

O

⊕

Air

N

O

N H

N O

O

− O

O

(89)

OH

(91)

Scheme 6.60

+

R

Bn N O

−

+

CO2Me

R = Gal

O Bn N

CO2Me H O

O O

(R = Gal or Glu)

O O

(92) Scheme 6.61 Ph O

OH HO

OH

H

+

N O

OBn −

OBn (93)

N

O

O H

H

H N O H

N

OBn OBn

O (94)

Scheme 6.62

to nitrones 92 derived from d-galactose and d-glucose afforded starting material for the synthesis of complex molecules [124]. The second example [125] is related to nitrone 93, synthesized from a d-glyceraldehyde derivative, which shows complete regio- and stereoselectivities when it reacts with a large range of dipolarophiles. For instance (Scheme 6.62), its reaction with N-phenyl succinimide produced compound 94 in an exclusive exo/anti cyclization mode. An attractive organocatalytic synthesis of 5-hydroxyisoxazolidines has been described by Cordova et al. [126]. These authors made use of a tandem reaction involving hydroxylamines and α, β-ethylenic aldehydes as reagents (Scheme 6.63); the target compounds offer a versatile entry to the synthesis of different β-amino acids and γ -amino alcohol derivatives. 6.1.4.2 Isoxazolines 2-Isoxazolines are also prepared from a [3 + 2] cycloaddition reaction to alkenes, the reagents here being nitrile oxides (Scheme 6.55) [127]. They can be prepared as single stereoisomers when the chiral allylic alcohol is a dipolarophile [128]. Synthesis of such heterocycles as well as their applications have been intensively reviewed [62, 111] and this can be easily understood given the usefulness of such compounds, in particular, as starting material for the synthesis of amino acids [129] and as chiral ligands in metal-catalyzed reactions [130].

6.1 Five-Membered Heterocycles with N and O Atoms

O Boc

OH

N H

+

Catalyst, CH2Cl2, 4 °C

R

O

Catalyst : N H

HO

Ph Ph OTMS

N R Boc

75 – 99% ee’s O Boc N 75 – 94% yields

OH

R Scheme 6.63 Boc

Boc N O R

(1) LiAlH4, THF

1

(2) Boc2O R2

NH R1

HN O R

NH

NaIO4, RuCl3 R

R2

OH

OH

OH

CO2H

1

R

2

(96)

1

OH R2 (95)

Scheme 6.64

It could be ﬁrst mentioned that isoxazoline can be transformed into their saturated homologs, namely, the isoxazolidines (see above), with advantageous control of the created stereogenic center at the C-3 position. For instance, Mapp et al. [129] reported stereoselective hydride addition to the C-3 C=N bond of the unsaturated heterocycle in order to obtain intermediate isoxazolidines 95, which were then transformed into β-amino acids 96 (Scheme 6.64). Similar reactions were also described by using Grignard and organolithium reagents. Though enantiopure isoxazolidines are commonly produced when starting from either chiral reagents or chiral catalyst, racemic isoxazolidine can be resolved by using lipases. In this way, condensation of achiral nitrile oxide 97 and isobutyl vinylacetate 98 afforded racemic isoxazoline 99. However, enzymatic hydrolysis with lipase PS30 operates smoothly a kinetic resolution, yielding the enantiopure isoxazoline acid 100 (Scheme 6.65) [131]. The effect of Lewis acids linked to a bisoxazoline ligand gave rise to a recent, interesting study about the control of regioselectivity which can be crucial during the nitrile oxide cycloaddition. Sibi et al. [132] recently made a careful examination of the different factors that affect this selectivity and delineated the role of various Z templates and Lewis acids in the relative production of the C-adduct and the O-adduct (Scheme 6.66). The higher regioselectivity as well as the best enantioselectivity was obtained by using MgI2 linked to the ligand 101 and the achiral pyrazolidinone template 102.

247

248

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom O

+

−

+

N O

NC

NC

O

(97)

O

N O

O

(99)

(98)

Lipase

OH NC

N O

O

(100)

Scheme 6.65

O Chiral LA

Z

R

N

R′ +

Z

+

R′

O

R

O

O

−

O N

R′

O N

O N

Z

C-adduct

O

R

O-adduct

O

N

N N Bn

(101)

(102)

Scheme 6.66

O

N H

+ Ph-CHO + Ph-NH-OH Ph N O

Ph N O

Ph O

Ph

N Ph

(103)

+ Ph-NH-OH

O Scheme 6.67

Actually, very enantioselective processes have been described as the outcome of the 1,3-dipolar cycloaddition reactions that lead to isoxazolidines when mediated by a chiral Lewis acid, and it meaningful to note that Box ligands (see above) appear as the most appealing ones [133]. Apart from these processes involving chiral catalysts, the most common ones are deﬁnitely the use of chiral nitrile oxides or chiral alkenes; both processes have been extensively reviewed [111]. Recently, it has been reported [134] that a supported proline catalyst can be used for a three-component intermolecular [3 + 2] cycloaddition, which is displayed in Scheme 6.67. Tricyclic bis-isoxazoline 103 was thus obtained with an outstanding

6.2 Five-Membered Heterocycles with Two N Atoms

N

CO2R2 R1

NO2 (104)

+

Br

−

CO2Et OMe

+ N

(105)

Cs2CO3 THF, 0 °C

O

EtO2C R1

+

N O

−

CO2R2 (106)

Scheme 6.68

stereocontrol (>25:1 dr and 99% ee) during the formation six new bonds and ﬁve new stereocenters. In conclusion, it is interesting to note that a recent preliminary report describes a very stereoselective synthesis of isoxazoline N-oxides [135]. In the presence of cesium carbonate, nitrooleﬁns 104 reacted with the ammonium salt 105 of cinchonidine to afford nitrile oxides 106 with utmost dia- and enantioselectivities (Scheme 6.68).

6.2 Five-Membered Heterocycles with Two N Atoms 6.2.1 Imidazolidines and Imidazolidinones 6.2.1.1 Imidazolidines At the end of the 1970s, Mukaiyama [136] reported the ﬁrst efﬁcient asymmetric synthesis, which was based on the use of chiral diamino ligands (including heterocyclic ones), and since then this ﬁeld is continuously growing [137]. As will be developed below, preparations of imidazolidine derivatives and oxazolidine (see above) are similar; however, it should be noted at the onset that the chiral pool does not furnish diamines as abundantly as the amino alcohols, which are the starting material for the synthesis of oxazolidines. Actually, the condensation of chiral diamines with aldehydes produces imidazolidines smoothly, which are rather fragile compounds (as every aminal is), and care is needed during the hydrolysis process. Scheme 6.69 shows Mukaiyama’s preparation of compounds 108–111 from diamine 107 derived from (S)-N-benzyloxycarbonylproline. These N-acylimidazolidines were reported to be very efﬁcient chiral auxiliaries for remarkably enantioselective Grignard 1,2 or 1,4 additions. The 2R conﬁguration of the aminals was produced exclusively, and this has been explained by its less crowded structure compared to that of its 2S epimer [138]. As mentioned above, enantiopure 1,2-diamines are not very commonly obtained from the chiral pool, and an original way for supplying for these heterocycles was reported (Scheme 6.70) [139]. It consists of asymmetric deprotonation of an achiral imidazolidine 112 carried out by butyl lithium in the presence of sparteine, and the resulting anion was then reacted with an alkyl halide, the eventual ring opening

249

250

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom CHO

RMgX + PhCOCHO

R OH 94–95% ee

Ph

N NPh (108)

Ph O + N H

MeO

O

R′MgX

N

NHPh (107)

N

NPh THF, −70 °C

OMe HO

MeO

NPh R

(109)

O

(110)

O R″ MgBr

+ OHC

OHC

N

CO2Me

H

NPh

CO2Me R″

(111)

MeO2C

Scheme 6.69

NH

(CH2O)3

N

NH2

then Boc2O

N Boc

H 3O +

N

s-BuLi (−)-Sparteine the RX

R

N Boc

NH R

(112)

NH2 (113)

Scheme 6.70 TiCl4

Ph 2

N

Mg /Hg

Ph MeNH

Ph

+

NHMe

Ph

Ph

(±)

MeNH

NHMe (−)-Tartaric acid

Ph (114) MeNH

Ph NHMe

100% ee Scheme 6.71

and deprotection of the amino group allowing the synthesis of many optically active 2-alkyl diamines 113. The fact that such diamines are not easily attainable is also illustrated by the formation of N, N -dimethyl-1,2-diphenylethylenediamine in the racemic form via a reductive coupling reaction with low-valent titanium species (Scheme 6.71). Flash chromatography allowed the separation of the chiral isomers from the meso isomers. This very attractive synthesis was reported by Normant’s groups [140], who resolved the racemic mixture with (+)-tartaric acid and obtained large amounts R, R-N, N -dimethyl-1,2-diphenylethylenediamine (DMPEDA) 114. The imidazolidines that result from the condensation of an aldehyde (ketones are much less reactive) with such a chiral diamine show the remarkable C2 symmetry,

6.2 Five-Membered Heterocycles with Two N Atoms Me O 114 + OHC-CHO

Ph

N

N (115) Me

Me

(1) n-Pent-Li (2) Ac2O, DMAP

AcO

n-Pent

Ph

N

Ph

N

Ph

H3O+

AcO

n-Pent

Me

Scheme 6.72

OHC-CHO +

Me NH +

N Me (116)

NHMe

OH

NHMe

NHMe

Me N O

N Me

O

O

OH

N Me

SPh

+ OHC-CHO

OH +

N Me

O

(117)

Scheme 6.73

whose interest since the pioneering work by Kagan [141] is widely recognized [142]. In the present case, it should be noted that, in imidazolidine 115, the created C-2 center is nonstereogenic and this avoids the necessity of controlling the stereochemistry of this center (as was the case with oxazolidines, see above). Alexakis and Mangeney took advantage of this fact when they developed the use of such aminals as chiral auxiliaries for an impressive number of very original syntheses [143]. An example of such transformation is depicted in Scheme 6.72 [144]. Incidentally, Scheme 6.73 reveals another interesting feature: while condensation of glyoxal with 1,2-amino alcohols leads to a morpholine structure (see above) [17b], an analogous reaction leads to imidazolidines when 1,2-diamines come into play. Yet, both condensations involve iminium ions (116 and 117) as the key intermediate (Scheme 6.73), but its intramolecular cyclization affects either the C=N or the C=O bond according to the hydroxyl or amino nature of the nucleophile. To our knowledge, no explanation has been given to this opposite behavior. As mentioned above, enantiopure, C2 -symmetric 1,2-diamines are not simply available. Corey et al. [145] have described another way for their production. It consists in condensing benzil with cyclohexanone and reducing the formed bis-imine 118 as shown in Scheme 6.74; the enantiopure diamine 119 was then obtained via optical resolution with tartaric acid. This method was taken up many a time afterwards [146]. In particular, Kanemasa and Onimura [147] made use of such diamines to prepare new chirality-controlling auxiliaries such as imidazolidine and made an exhaustive conformational analysis in order to understand their behavior during dipolar cycloadditions and Diels–Alder reactions. Aiming to synthesize isoindolones, which present many interesting biological activities, Katritzki et al. [148] realized the ingenious transformation depicted in

251

252

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

Ph

O Ph

Ph O

AcO−NH4+

+

Ph

N

Li, THF/NH3

N

EtOH

AcOH

O

Resolution

Ph

Ph

H2N

NH2

(119)

(118) Scheme 6.74 R2 HO2C

R2 H2N

NHR

1

CHO

N HO2C

+

(120)

(121)

R2 NHR1

O

N

H

(122)

N R1 H

(123)

Scheme 6.75

Scheme 6.75. Condensation of enantiopure diamines 120 with 2-formylbenzoic acid 121 afforded, with both high yields and stereoselectivities, various tetrahydro-5Himidazo[2,1-a]isoindol-5-one 123. Imine 122 is a likely intermediate in which the addition of the amino moiety onto the imine bond occurs on the less crowded re diastereoface of the imine double bond. Actually, imidazolidine and imidazolidinone heterocycles take part in many fruitful ligands for various metal-catalyzed reactions or for organocatalyzed reactions [149]. 6.2.1.2 Imidazolidinones 4-Imidazolidinones Lithium enolates of 4-imidazolinones are the basis of the classical asymmetric transformation proposed by Seebach who founded the famous concept of ‘‘Self-generation of stereocenters’’ [150]. Imidazolidinones 125 were prepared in racemic form (Scheme 6.76) either by condensing the glycine-derived salt 124 with pivalaldehyde or via an indirect route from bromoacetyl bromide; mandelic acid was used in order to resolve the racemic mixtures and produce the

O

O MeO2C

MeHN NH3+Cl−

H+

+ t-Bu-CHO

N H

NH3+Cl−

(124) Bn

BrCH2COBr

BnNH2

NH3

HN N

R N

O

H+

O

(125a) (R = Me)

R N

O

N H (125b) (R = Bn)

Scheme 6.76

6.2 Five-Membered Heterocycles with Two N Atoms

HO HO2C

HO

Bn BocHN (126)

NH

N NH2 Bn

O

BnO

Bn NH

MeO BnO

OH

(−)-Galanthamine

O

O

N Me

MeO Scheme 6.77

O

+

EtO2C

CO2Et

O Me

N H

Me

Me (128)

(127) Me N N H (130)

(125a), TFA salt

Me

(129)

91% yield 93% ee

O Ph

Scheme 6.78

enantiopure imidazolidinones [151]. Numerous other imidazolidinones were prepared in this way and these works mark out a new method for the enantioselective syntheses of many amino acids from such an asymmetric derivatization of glycine [152]. Clearly, every α-amino acid, other than glycine, can be used, and in such a case the produced imidazolidinone shows one more stereocenter. In this fashion, the synthesis of (−)-galanthamine, performed by Node et al. [153], made use, as a starting material, of the imidazolidinone 126 formed from Boc-d-alanine (Scheme 6.77). MacMillan recently introduced a new concept in the realm of organocatalysis: the lowest unﬁlled molecular orbital (LUMO) lowering iminium activation which has found many rewarding applications for various transformations [154]. For instance ( Scheme 6.78), imidazolidine 125a catalyzes an enantioselective transfer hydrogenation from Hantzsch ester 128, and enal 127 was reduced to the optically active aldehyde 129. Imidazolidinone 130 was also tested but the enantioselectivities thus obtained were lower than with 125a. An original route to chiral oxazolidin-2-ones has been described by Kunieda et al. [155] through the smooth cycloaddition of 1,3-diacetyl-2-imidazolone 131 and

253

254

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

+ Ac N

Ac N N Ac

O

H N

N

O

(131)

N

O

Ac (132)

Ac (−)-(133)

Scheme 6.79

Me

O

O

O Me N Me

NH Ph (134)

Me N Me

PhMgCl

N

Ph (135)

O

AlMe2Cl

Me N Me

O N

Ph Me

Ph (136)

Scheme 6.80

anthracene (Scheme 6.79). This reaction leads to a meso adduct 132, which was enantioselectively N-deacylated by reaction with an enantiopure amino alcohol. Compound 133 was used as an exceptionally rigid and congested chiral auxiliary for various asymmetric syntheses such as Diels–Alder reactions and enolate methylations [156]. 2-Imidazolidinones 2-Imidazolidinone 134 is easily prepared following a Helmchen procedure [157] from ephedrine and urea. The chiral α, β-unsaturated imide 135, which was derived from the heterocycle 134, was submitted (Scheme 6.80) to an asymmetric 1,4-addition in the presence of Lewis acids and this led to the formation of the adduct 136 [158]. Another original application of a 4-imidazolidinone derivative in catalysis was found in the metallocarbene ﬁeld. Complex 138, which is formed from imidazolidinone 137 (Scheme 6.81), has been used for an original ‘‘aldol reaction’’ that affords the N-acyl imidazolidinone 139 with excellent stereoselectivity, as shown in Scheme 6.82 [159]. 2-Imidazolidinones can also be prepared from an original cycloaddition to phenyl isocyanate [160]. As a matter of fact, Alper reported (Scheme 6.82) that this isocyanate adds to (S)-(+)-n-butyl-2-phenylaziridine in the presence of a PdII catalyst. It is worth noting that the conﬁguration of the aziridine stereogenic center is retained during this process. It can be concluded that, owing to their straightforward availability, imidazolidines as well as imidazolidinones play an important role in the asymmetric synthesis as chiral auxiliaries, a ﬁeld whose expansion has been at lightning speed. However, it seems that their use as chiral ligands in metal-catalyzed reactions or as organocatalysts constitutes at the present time a major subject of research in this area.

6.2 Five-Membered Heterocycles with Two N Atoms O−

M(CO)6 + MeLi

AcBr

Me

N

Ph

O

(CO)5M OMe

M = Cr or W

Me N

Me O

Me

N

(CO)4M

N Ph H

(137) M = Cr

KOH, MeOH

R

Me (1) n-BuLi (2) RCHO (3) AcOH (4) CeIV

O

OH O OH O

(138)

N

N Me

OMe

R

(139)

Me

Ph

Scheme 6.81 Ph Ph N R

Ph N

(PhCN)2PdCl2

+ O C N-Ph

120 °C

N R

O

Scheme 6.82

6.2.2 Pyrazolidines and Pyrazolines 6.2.2.1 Pyrazolidines As was commonly observed in this series, pyrazolidines exhibit very interesting biological properties [161]. On the other hand, from a purely chemical point of view, chiral pyrazolidines can be used for the synthesis of optically active 1,3-diamines by the N–N bond cleavage [162]. Here again, as in the aforementioned case of oxazines, most synthetic methods resort to dipolar cycloadditions to various dipolarophiles. For instance, the azomethine imine dipole 142 is an intermediate during the totally regio- and diastereoselective reaction (Scheme 6.83) of the substituted hydrazine 141 to the substrate140, which gave pyrazolidine 143 [163]. Kobayashi et al. described an enantioselective approach to such structures. They made use of a chiral zirconium catalyst to perform the [3 + 2] cycloaddition of

O + CO2Et (140)

Scheme 6.83

HN HN

Bn

Et3N

CO2Et

(141)

Bn + N CO Et N− 2 CO2Et (142)

H

Bn N N CO2Et

H CO Et 2 (143)

255

256

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

O

O

Ph

Ph

NH MeS + N

HN N

Zr(OPr)4, PrOH

SMe

SMe SMe 97% ee

Ph

(R )-3,3′,6,6′-I4BINOL

Ph

SmI2

(145)

(144)

(1) LIAlH4 (2) Ac2O

AcHN AcN (146)

Ph

Ph

Scheme 6.84

CF3

CF3

O

OTMS NH

+ Me

N

Me

Me

C6H13

O

Zr(Ot-Bu)4

SmI2, THF

BINOL

NH HN COMe

C6H13

H N HN

O

Me C6H13 Me (147)

Me Me Scheme 6.85

Ph CO2Bn

HN N CO Bn + Ph – I 2 CO2Et O

Ligand*, Pd(OAc)2 THF, Ag3PO4

O

CO2Bn N N CO Bn 2 CO2Et

Scheme 6.86

acylhydrazones onto achiral substrates (Scheme 6.84). With tetraiodo-(R)-4-binaphtol (BINOL) as the enantiopure ligand, they were able to synthesize, for instance, pyrazolidine 145, whose N–N bond cleavage mediated by SmI2 allowed the formation of the diamino compound 146 [164]. The observed enantioselectivity enabled the authors to discard a possible stepwise pathway in favor of a concerted one. Acylhydrazones were also used [165] as imine equivalents during a chiral-zirconium-catalyzed Mannich-type reaction (Scheme 6.85). Here again, a BINOL derivative (3,3 -BrBINOL) was chosen as the chiral ligand. The produced hydrazide treated by SmI2 eventually gave pyrazolidine 147. In the same way, a palladium-based chiral catalyst was reported to allow the cyclization between optically active allenylic hydrazines and organic halides: that is, with a double asymmetric induction process (Scheme 6.86). Many asymmetric ligands were tested, and ﬁnally the (R, R)-box ligand ent-43 (R = Bn) gave the best results [166].

6.2 Five-Membered Heterocycles with Two N Atoms PhSe

Me (149)

Me

30

−

°C

HN

R1

Me

N

N

N H

SePh Me

H

20

°C

HN

(148)

Me N COMe

(150)

O

RCHO

HN

O

HN

O

HN

R1

R2

SePh R2 (152)

N

COMe

Me

(151) a: R1 = Me, R2 = Ph b: R1 = R2 = Me

Scheme 6.87 Ph

O

HN

N H (153)

Ph

R-CHO O

N

R1

Ph

Ph N

N

O

+

N−

O

MeO2C CO2Me O

R1

O

80 –100 °C, 3d

1

R

MeO2C

R1

O N

N

CO2Me (154)

COPh PhCONH R (155) MeO2C

NHCOPh CO2Me

R MeO2C

N

N

O

COPh

CO2Me

(1) H2, Pd(OH)2, MeOH, H2SO4 (2) PhCOCl, DBU

Scheme 6.88

Organoselenium-induced intramolecular cyclization of N-allyl acetylhydrazide 148 affords either oxadiazine 149 or pyrazolidine 150 (Scheme 6.87). It was shown that the ﬁve-membered heterocycle was the result of a thermodynamic control, whereas its six-membered isomer was formed under kinetically controlled conditions. Interestingly, substrates 151a–b were cyclized to produce compounds 152a–b as the sole diastereomers [167]. Husson et al. [162, 168] described the formation of pyrazolidines 154 via a tandem process from carbazate 153. The last step in Scheme 6.88 involves a cycloreversion–cycloaddition process; various dipolarophiles (methyl maleate, fumarate and crotonate) were successfully employed. A chemoselective electroreduction of the functionalized pyrazolidines allowed the synthesis of enantiopure 1,3-diamines such as 155, which was obtained when dimethyl maleate was chosen as the dipolarophile. Carreira [169] described the asymmetric synthesis of 2 -pyrazolines 157 from dipolar cycloaddition reaction of trimethylsilyl diazomethane and camphorsultamderived acrylates and showed afterwards that various Lewis acid-catalyzed additions to these pyrazolines afforded very smoothly the corresponding pyrazolidines. TiCl4 proved to be the optimal Lewis acid and the adducts were isolated in many cases as single diastereomers. 6.2.2.2 Pyrazolines The preceding report initiates here a section devoted to the synthesis of chiral pyrazolines. In the ﬁeld of the scarcely explored dipolar cycloadditions with metal carbene complexes, Barluenga and coworkers [170] described the reaction of

257

258

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom OR*

R2CHN2

(CO)5Cr

THF, rt

OR* R1

(CO)5Cr

(156) R1

N

R*OH = (−)-8-phenylmenthol

R2

N H

(Boc)2O −78 °C

OR* R1

O N

N Boc

OR*

PNO, rt

R1

(CO)5Cr

R2

N

(157)

N Boc

R2

Scheme 6.89

MeO2C

CO2Me

Cl N

Base

N ⊕

NH

N −

Tol

Tol

O R*

MeO2C

R*

MeO2C +

R*

Tol

N N Tol

64% yield

16% yield

N N

O

O

(158)

R* =

N S O

O

Scheme 6.90

diazo compounds with alkenyl Fischer carbenes 156 derived from chiral alcohols (Scheme 6.89). In this way, enantiopure 2 -pyrazolines 157 were obtained. The process displayed in Scheme 6.89 can be still improved because the formation of 2 -pyrazolines 157 can be performed in a one-pot reaction. It is worth noting that stereoselectivity was excellent, whereas an analogous reaction from menthyl trans-cinnamate alone (that is, the ligand linked to Cr in 156) showed a much lesser stereoselectivity when directly condensed with TMSCHN2 . Barluenga also showed that treatment of such pyrazolines with LiBEt3 H leads to pyrazolidines (see above). Barluenga also described a similar reaction in which metal carbene complexes reacted with nitrile oxides; however, in this case, the stereoselectivity was not so high as in the preceding case [171]. Apart from this single use, 2 -pyrazolines were examined for their physical applications [172a] and their pharmacological activity [172b]. Cycloadditions with nitrile imine intermediates 158 were studied by Molteni et al. (Scheme 6.90), who tested various chiral auxiliaries R* in such condensations [173]. Intramolecular cycloadditions with nitrile imine intermediates 159 were also described [174], but in this case too the stereoselectivity was rather poor as shown in Scheme 6.91; however, the resulting diastereomers can be easily separated through column chromatography and appeared to be enantiomerically pure.

6.2 Five-Membered Heterocycles with Two N Atoms

Ph-NH-N

O

−

OH Cl Me

CO2Me

Me

H

Me

CO2Me (159)

O N

+

Ph N

CO2Me

Me

O

Me

O

CO2Me

O N Ph N

O

PhN N

Ag2CO3

O

+

259

44% yield

O H

CO2Me

22% yield

Scheme 6.91

O Ph

N

N

Me2CN2

N N

Me Me O

Me Ph

N

N

Me

Scheme 6.92 (1) MeZnBr (2) LDA/THF, −78 °C (3) CbzN=NCbz

OH MeO

CO2Me OMe

CO2Me

MeO OMe

CbzN=NCbz (160)

OH

(1) H2, Pd/C

OH

(2) TFA, rt

N

N H (161)

Scheme 6.93

Actually, it was already shown by Stanovnick and Svete [175] that dipolarophiles can be the substrates of such cycloaddition: Scheme 6.92 displays one example of such reaction with diazomethane as the dipolar constituent. Another intramolecular cycloaddition leading to 2 -pyrazolines 161 was described by Genet and Greck [176]. The hyrazino derivative 160 was ﬁrst obtained (Scheme 6.93) from the zinc enolate of the hydroxyester by treatment with dibenzylazodicarboxylate, and it was then N-deprotected and cyclized in the presence of triﬂuoroacetic acid. A cooperative chirality control was observed by Kanemasa [177] during a Lewis acid-catalyzed cycloaddition of a diazoalkane (Scheme 6.94). Thus, several chiral catalysts were screened, and ligand 162 was found to be the most effective to perform the cycloaddition that led to 2 –pyrazolines 163 with excellent yields and enantioselectivity. Unsaturated pyrazolidinone imides, though less reactive than the usual dipolarophiles, were found to be efﬁcient substrates for cycloadditions involving diazoacetates [178]. The produced pyrazoline 165 was obtained in an enantiopure form, and Sibi took advantage of this reaction in order to synthesize (−)-manzazidin

CO2Me

260

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

N N-Ac

O

O TMSCHN2 + R

N

O

(162) Ac2O

O

N N-Ac

Mg(OMe)2

COMe

N

O

O O N

O

Ph

M

M = aqua complexes of Zn, Ni, or Mg

N

O

(163)

(162) Ph

Scheme 6.94 O

O

O

O +

N N Bn

164/MgX2

EtO N2

O

N N HN N Bn (165)

H N

O

O CO2H

O

OEt

HN Br

N

(166)

O

O N

N (164)

Scheme 6.95

A 166 (Scheme 6.95). In this case, as in many others reviewed above, a chiral Box ligand 164 was used in the catalyst system. 6.2.3 Pyrazolidinones

One of the ﬁrst preparations of a chiral pyrazolidinone was performed by Elly’s group [179]; it concerns compound 168, a key intermediate for the synthesis of carbapenem analogs that have useful antibacterial properties [180]. The Mitsunobu reaction (Scheme 6.96) applied to the serine-derivative 167 allowed the preparation of large quantities of pyrazolidinone 168. An interesting synthesis was described by Matsuyama [181], who showed that the conjugate addition of pyrazolidine 169 to optically active vinylsulfoxide 170 led to OH BocNH

NH O

O N H

(167) Scheme 6.96

DEAD/Ph3P

CF3

NH NH

BocNH O

(168)

6.2 Five-Membered Heterocycles with Two N Atoms

HN HN

+

Na (3 equiv)/Na

N N

Ph

87% ee

(170)

NH HN

(171)

Ph

Ph (169)

O

O

p -Tol O O SR O-t -Bu

(172)

Scheme 6.97

CO2H

(1) PhCHO, Ac2O (2) N2H4/H2O

NHCOPh

HN Ph

H N

Ar O

+

ArCHO

NHCOPh

N N

Ph

−

O

(±)-(173)

NHCOPh MeO2C

CO2Me

CO2Me CO2Me N Ph

O NHCOPh

Scheme 6.98

pyrazolidinone 171 with a high level of enantioselectivity (Scheme 6.97). Breaking the N–N bond with Na/NH3 furnishes diazacyclooctanone 172. Another strategy was used by Svete’s group [182]; however, this method affords pyrazolidinones but only as racemic mixtures. Scheme 6.98 depicts this process, which furnishes an heterocycle that can be conveniently transformed into azomethine imine 173. This dipole reagent is clearly very reactive toward various cycloadditions; one of these reactions with dimethylacetylenedicarboxylate is illustrated here. Actually, the fact that pyrazolidinones can be easily transformed into such dipolar reagents is known from the pioneering work by Dorn [183], and Oppolzer already made use of the resourceful reactivity of azomethine imines [184]. Sharpless [185] described a versatile access to these heterocycles from an enantiopure oxirane as shown in Scheme 6.99, improving greatly the above-reported Svete’s approach since nonracemic compounds are now obtained. Transformation of the oxirane into the aziridinium structure 174 is the key step of this process, and it should be noted that pyrazolidinone 175 could be converted into azomethines 176 which were used as starting materials for cycloadditions leading to more complex pyrazolidinones. During his studies on the effect of pyrazolidinones as chiral templates on the reactivity and selectivity of many enantioselective reactions [186], Sibi described recently [187] the condensation of benzylhydrazine 177 to various benzimides 178

261

262

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

O

(1) NHR2

O OEt

Ph

−

Cl

(2) MsCl, Et3N

+

RR O N

Ph

Cl

O

Ph

OEt

OEt NR2

(174)

NH2NH2, K2CO3

Ar +

N N

HN NH

−

ArCHO

Ph

Ph

O

O NR2

NR2

(175)

(176) Scheme 6.99

O Ph

O

+ R1

N H

H2N

R2 NH

O

Ligand 164 Mg(ClO4)2 30 mol%

NH N (178) R2

R1

(177)

(R1 = Me , R2 = i -Pr : 87% ee)

Scheme 6.100

Me N

O

O +

R

Ar

N

N

O

Ph

N

N Mes N 180

O

Me

R1

(179) Ph

− + BF4

DBU, 0 °C

R

N N Ar

R1 O (180)

(181) N − N + BF4 Mes

Scheme 6.101

in the presence of a catalytic system composed by a Lewis acid linked to the Box ligand 164 (Scheme 6.100). In this way, many pyrazolidinones (for instance 179) were stereoselectively obtained. A new method that looks very promising has been described by Chan and Scheidt [188]. The heterocyclic carbene derived from the triazolium salt is an excellent catalyst for a completely regioselective cycloaddition (Scheme 6.101) between enones and acylaryldiazenes 179 in order to produce various pyrazolidinones 180. Moreover, these authors reported also that the chiral carbene formed from the triazolium salt 181 produces enantioselectively pyrazolidinones. The mechanism of

6.3 Five-Membered Heterocycles with N and S Atoms

263

these transformations involves the addition of the carbene to the α, β-unsaturated aldehyde to give a homoenolate intermediate, which then undergoes a formal [3 + 2] cycloaddition with the diazene.

6.3 Five-Membered Heterocycles with N and S Atoms 6.3.1 Thiazolidines

Thiazolidines have received particular attention owing to their pharmacological activity. Among the large number of compounds containing a thiazolidine ring, penicillins are the most popular ones (Scheme 6.102). The thiazolidine ring in these structures was commonly introduced from d-penicillamine hydrochloride, which was cyclized in the presence of an aldehyde [189]. In this manner, a countless number of penicillin derivatives have been prepared [190]. l-Cysteine (and 1,2-aminothiols in general) reacts with simple aromatic aldehydes in a nonstereoselective way to produce mixtures of the two epimers at C-2. Under speciﬁc conditions, N-acetylation of the diastereoisomeric mixture leads to either 2-4-cis- or 2-4-trans-2-aryl-3-acetyl-1,3-thiazolidine-4-carboxylic acids [191]. For instance, the acylation of a diastereoisomeric mixture of (2S, 4R) and (2R, 4R)-2-phenyl-4-carbomethoxy-1,3-thiazolidine with chloroacetylchloride in the presence of potassium carbonate led to the selective formation of the cis isomer 183 [192], which was used to synthesize the chiral thiazolopyrazine 184 (Scheme 6.103). R H H

O

S

HN

COOH

N O

HS NH2·HCl

COOH Penicillins

Penicillamine

Scheme 6.102 SH MeO2C

NH2

PhCHO

MeO2C

L-Cysteine

S N H (182)

S

S

ClCH2COCl

Ph

Ph

K2CO3

MeO2C Cl

N

Ph

H O

N N

O (183)

O (184)

R

Scheme 6.103

MeO2C

S

HCOONa

N H

HCOOH (185)

Scheme 6.104

S MeO2C

N CHO (186)

LDA DMPU MeO2C RX R

S N CHO

SH

H+

NH2·HCl

HOOC R

(187)

264

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

N-Formylation of the thiazolidine 185, derived from (R)-cysteine methyl ester hydrochloride and pivalaldehyde, led only to the syn diastereoisomer of the compound 186. Alkylation of compound 186 in a basic medium with alkyl bromide occurred exclusively anti to the bulky t-butyl substituent (Scheme 6.104). This method was applied to the synthesis of enantiopure 2-alkyl cysteines 187 [193]. Baldwin and coworkers [194] synthesized several γ -lactam analogs of penems possessing antibacterial activity (Scheme 6.105). Condensation of aspartic acid semialdehyde with l-cysteine methyl ester 188 in pyridine afforded a 1:1 mixture of the diastereoisomeric thiazolidines 189, which was reﬂuxed in pyridine to give the bicyclic lactam 190 (45% yield). An analogous approach was reported to synthesize spiro bicyclic thiazolidine lactams 191 [195] and 192 [196] (Scheme 6.106), which are β-turn mimetics and therefore valuable tools in order to study the bioactive conformation of biologically active peptides. Geyer and Moser [197] prepared the ﬁrst bicyclic peptidomimetic, the thiazolidine lactam 195 derived from the carbohydrate precursor 193 (Scheme 6.107). After deprotection, the amino group of 195 was elongated with a glycine derivative. Several chiral catalysts containing a thiazolidine ring have been reported [198]. Natural l-cysteine and derivatives were often used in this way. For example, chiral thiazolidines were easily prepared from the condensation of l-cysteine ester with aldehydes or ketones; they were used as starting materials for the synthesis of a wide range of ligands 196, which catalyzed an enantioselective addition of diethylzinc to aldehydes [199] and an arylation of aldehydes using aryl boronic acids [200], as shown in Scheme 6.108. CHO

Pyridine

CO2Bn

ZHN

H

HCl·H-L-Cys-OMe

H S

N H CO2Bn

ZHN

(188)

Reflux CO2Me

ZHN

S N

Pyridine O

(189)

(190) CO2Me

Scheme 6.105 H

H

S

Ph N N CO2Me Boc O (192)

N S N O N O H (191) H N 2 O

Scheme 6.106 NHZ O

OH OH

NHZ O

O

TFA

O O (193)

Scheme 6.107

HCl·H-L-Cys-OMe

O

O

OH

O OH (194)

H2O-pyridine

HO S ZHN

N O CO2Me (195)

6.3 Five-Membered Heterocycles with N and S Atoms SH

S

R1OOC

R2

R1 = Me, Et, i -Pr R2 = H, Me, Et, n -Bu, CH2(CH2)3CH2

N R2 R1OOC H Ligands (196)

NH2 HCl

OH (1) ∆

PhB(OH)2 + Et2Zn

265

R′CHO + Et2Zn

(2) Ligand, p -TolCHO yield > 90%; 0 < ee < 81% ee = 0% for R1 = R2 = Me ee = 81% for R1 = i -Pr, R2 = Bu

OH

(1) Ligand

R′ Et (2) HCl 45% < yield < 99% 52% < ee < 88% ee = 88% for R1 = i -Pr, R2 = Et

Scheme 6.108 SH

NH2

HOOC

S

ArCHO

Ar

(1) NaBH4, I2

N H

HOOC

(2) O2

HO

HCHO

S HN Ar (197)

2

O

N

S Ar 2

NaBH4

S N

Ar (198)

Scheme 6.109

Ph

Ph OH

S

R2

NH R1 R1

Ph

S (199)

Ph

R2

OH NH R1 R1

OH

(200)

Scheme 6.110

From these works, it appears that the thiazolidine derivatives have higher enantioselectivity when they have a larger steric bulk in the thiazolidine rings. Braga et al. [201] synthesized the new thiazolidine ligand 198 derived from disulﬁde 197, obtained in an easy three-step synthesis from l-cysteine, as described in Scheme 6.109. This ligand was used in asymmetric palladium-catalyzed allylations and provided the allylation product in high yield and with high enantiomeric excess (80%). The chiral 2,2-disubstituted thiaprolinol derivatives 199 [202] and 200 [203] were used as ligands for diethylzinc addition to aldehydes and for borane reduction of aromatic ketones. These catalysts led to alcohols with moderate to good enantioselectivities (Scheme 6.110). Thiazolidines were also used as new chiral formyl anion equivalents. Several silylated thiazolidines were synthesized, generally as a mixture of the cis and trans diastereoisomers 201 and 202, which could be separated by chromatography to give enantiopure compounds [204]. Diastereoselectivity was not observed during the reaction with aldehydes in the presence of ﬂuoride ion; however, functionalization occurred with a total retention of conﬁguration of the starting C–Si bond (Scheme 6.111).

266

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

SH NH2

+

MeO

SiMe3

+

SiMe3

B−

Br

S

S

Boc2O

SiMe3 N Boc (202)

N Boc (201)

RCHO F−

RCHO F− R S N Boc

OH

S

R

N Boc

OH

Scheme 6.111

NH2·HCl CHO + COOH SH

Boc2O NEt3

Boc N CO2H

Ph C N CH2Ph H

S Cl

N+ I−

N

, NEt3

Boc O

S N Ph

(203)

(204)

CH2Ph

Scheme 6.112

Boc N S

OH Ph Ph

(1) n-BuLi (2) (−)-Sparteine (3) Benzophenone

(1) n-BuLi Boc (2) (−)-Sparteine N (3) RCHO S (205)

Boc N

OH

S

R

syn

+

Boc OH N S anti

R

Scheme 6.113

A Staudinger reaction between chiral ketenes and imines was reported to afford enantiopure spiro-β-lactams derived from 1,3-thiazolidines [205]. The best result, as regards diastereoselectivity, was obtained with the 4-iso-propyl-1,3-thiazolidine-2carboxylicacid 203, which led to only one enantiomerically pure spiro-β-lactam 204 in 46% yield (Scheme 6.112). The authors stressed the importance of the C-4 substitution of the thiazolidine ring on the stereochemical outcome of this reaction. Toru and coworkers used the simple N-Boc-thiazolidine 205 as a formyl anion equivalent [206]. As shown in Scheme 6.113, the reaction of the lithiated 205 with benzophenone in the presence of (−)-sparteine afforded the products with up to 93% ee. This reaction was expanded to various aromatic and aliphatic aldehydes to afford the products of addition with high enantioselectivity but moderate diastereoselectivity (syn/anti = 55/45). Recently, Kwon and coworkers [207] prepared functionalized thiazolidines and oxazolidines with a high yield, one-step biphosphine-catalyzed mixed double-Michael reaction. Diphenylphosphinopentane (DPPP) was the best catalyst used for this reaction compared to diphenylphosphinomethane (DPPM), diphenylphosphinoethane (DPPE), and diphenylphosphonobutane (DPPB). The importance of the tether length between the two phosphine moieties was explained by invoking the stabilization of the intermediate phosphonium ion 207, as represented in Scheme 6.114.

6.3 Five-Membered Heterocycles with N and S Atoms

SH NHTs

Ph Ph P

S

DPPP (10%)

+

Ts

N Ts (206)

Ts

267

X

P PhPh

N E (207) Ts X = O, S

yield = 89% cis:trans = 96:4 Scheme 6.114

N

(R )-YbPB (5 –20 mol%)

S

(H3CO)2PHO

O CH3O P CH3O

H NH S

(208)

(R )-(209) yield = 86% ee = 98%

Scheme 6.115

An efﬁcient enantioselective approach to the pharmaceutically interesting 4thiazolidinephosphonate (R)-209 was described [208] using 2,2,5,5-tetramethyl-3thiazoline 208 and various heterobimetallic lanthanoid catalysts (Scheme 6.115). The best results were obtained with (R)-YbKB as catalyst (where B = (R)-(+)binaphtol). 6.3.1.1 Iminothiazolidines Being present in a large variety of biologically active compounds, 2-iminothiazolidines have been intensively studied [209]. Ring expansion of aziridines, which leads to ﬁve-membered heterocycles, appears to be a powerful tool for the construction of iminothiazolidines. Palladium-catalyzed ring expansions of aziridines have thus been described by Alper et al., who reported an enantioselective version of this reaction (Scheme 6.116) [210]. Treatment of aziridines 210 with isocyanates in the presence of bis(acetonitrile)palladium dichloride afforded thiazolidines 211 in both regio- and stereoselective manner. The enantioselectivity of the palladium-catalyzed cycloaddition was unequivocally demonstrated; consequently, the relative and absolute stereochemistry was conserved throughout this cycloaddition reaction. An analogous ring expansion of thiiranes with carbodiimide catalyzed p -ClC6H5 N C N p-ClC6H5

R′ R′N=C=S 10 mol% PdCl2(PhCN)2

N ROOC

120 °C, 20 h, 5 psi N2

(210)

R = Me, Et R′ = 4-ClC6H4, 4-NO2C6H4

Scheme 6.116

N N

PdCl2(dba)3·CHCl3

S COOR (211)

S (212)

L*, 5 psi N2

Cl

*

N N S (213)

Cl

268

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom +

+

Cl

NH2

NHMe

Ph R R (214)

NaSCN −

NH

−

SCN N

NaOH

S

EtOH

N

H2O/CHCl3

R R Ph (215)

Ph

Cl

S

Scheme 6.117

R1

NH2

R1

NHBoc

R1

NCS

R1

4

N

R2

OH

R2

OMs

R2

OMs

R2

5

S

(216)

NH

(217)

Scheme 6.118

by palladium with 2,2 -bis(diphenylphosphino)-1,1 -binaphtyl (BINAP)-type ligands afforded iminothiazolidines 213 in good yields (up to 68% ee) [211]. The ephedrine derivative 214 was converted into a 2-iminium derivative upon treatment with sodium thiocyanate. This salt was neutralized and gave the enantiopure 2-iminothiazolidine 215, preserving the relative and absolute conﬁguration of the starting material (Scheme 6.117) [212]. Enantiopure 4,5-dialkyl-2-imino-1,3-thiazolidines have been synthesized from commercially available β-amino alcohols or β-amino acids. The cyclization of the resulting isothiocyanates 216 was performed in the presence of ammonia and it occurred with inversion of conﬁguration at C-5 [213]. The compounds 217 are potent inducible nitric oxide (NO) synthase inhibitors (Scheme 6.118). 6.3.1.2 Thiazolidinethiones Chiral thiazolidinethiones constitute a class of versatile auxiliaries for asymmetric synthesis [214]. They are easily synthesized from β-amino alcohols and carbon disulﬁde in a basic medium. Le Corre and coworkers [215] studied the reaction between amino alcohols and carbon disulﬁde. According to the experimental conditions, either oxazolidinethiones 218 or thiazolidinethiones 219 could be obtained. The authors reported that the preparation of oxazolidinethiones required mild conditions, whereas thiazolidinethiones were isolated under more drastic conditions (excess of CS2 , very alkaline KOH medium and long reaction time). The formation of thiazolidinethiones occurred with an inversion of conﬁguration of the oxygen-bearing carbon, as depicted in Scheme 6.119. Thiazolidinethiones have been used in a wide variety of transformations, mainly for the asymmetric aldol condensation, but also in order to differentiate the enantiotopic groups in molecules bearing prochiral centers and for other applications. All the thiazolidinethiones 220–226 depicted in the Scheme 6.120 undergo highly efﬁcient and selective aldol condensation.

6.3 Five-Membered Heterocycles with N and S Atoms

R2 R1

R3 R4 O

RN

R2

CS2

R1 RHN

K2CO3

R3 R4 OH

CS2

R2 R1

KOH

RN

S (218)

R3 R4 S S

(219)

S R3 R4 OH

R2 R1 RN

R2 R1 RN

SH

R3 R4 OH S

S

R2 R1 RN

−

O SH R3 R4 S

S

S

Scheme 6.119

S S

S

O X

N

(220) Ref (216) S S

O

S

N

S

S

N

S

O N

(222)

(223)

Ref (218) S

O

S

N

Ph Me Ph Me (221) Ref (217)

O

Ref (219)

O

O

N

S

N S

OTES (224) Ref (220)

(225) Ref (221)

(226) Ref (222)

Scheme 6.120

6.3.1.3 Thiazolidinones Thiazolidinones (carbonyl group located at position C-2, C-4 or C-5) have received much attention, owing to their uses as intermediates and to their diverse biological activities [223, 224]. Reaction between l-cysteine and N, N-carbonyldiimidazole [225] or triphosgene [226] afforded the corresponding thiazolidin-2-one. In a practical synthesis of (+)-biotin, Seki et al. reported a one-pot preparation of N-benzyl-2-thiazolidinone-4carboxylic acid 228 from l-cysteine. Treatment with phenyl chloroformate and NaOH, followed by reaction with benzyl chloride, afforded product 227 in high yield [227] (Scheme 6.121).

269

270

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

COOH COOH

PhOCOCl, NaOH

S

N Bn

then PhCH2Cl

HS

O (227)

COOH

Triphosgene or N,N -Carbonyldiimide NaOH

NH2

S

NH

(228)O

Scheme 6.121

COOH HS

NH2

COOH

OH

(1) N,N -Carbonyldiimide (2) PMBCl, K2CO3

S

O

Latrunculin A

O

N PMB

OR

H PMBN O

S

(229)

Scheme 6.122

Compound 229, possessing a thiazolidine moiety, is a key building block for the synthesis of latrunculin A. It was synthesized from cysteine in a classical way (Scheme 6.122) [228]. 6.3.2 Thiazolines 6.3.2.1 2-Thiazolines Chiral thiazolines are mainly known as subunits of biologically active macromolecules, which exhibit antitumor and anti-HIV activities, but they are less familiar than their oxygenated analogs, namely the oxazolines. As a matter of fact, the 2-aminothiols, which can be viewed as the most obvious precursors, are not easily available compared to the corresponding amino alcohols. Nevertheless, the asymmetric synthesis of thiazolines has received renewed attention because thiazolines and bis-thiazolines have been proved to possess great potential as a new class of ligands in enantioselective synthesis. Until 1990, desferrithiocyn 230, a natural ferric ion chelator isolated from Streptomyces antibioticus, was the only example of a naturally occurring 4-methyl substituted 2-thiazoline; since then, a very wide range of new and biologically active linear and cyclic peptides containing at least one thiazoline ring have been isolated and characterized. For example, thiangazole B 231, isolated from blue green algae, is a linear, fused 2,4-disubstituted poly-thiazoline/oxazole ring, and lissoclinamide 232 is a marine cyclopeptide alkaloid with two thiazolidine rings, as shown in Scheme 6.123. In structures 230 and 231, the thiazoline rings are derived from 2-methylcysteine, and different authors have developed different strategies for the elaboration of this thiazoline ring. With the aim of synthesizing desferrithiocyn, Pattenden

6.3 Five-Membered Heterocycles with N and S Atoms O

MeHN

O

N

O

S

N

O N

N

N

N

N

O

N

(231) Ph Thiangazole

S O

Ph

Ph

N

H N

O

S

Desferrithiocyn

S

HN

N

(230)

N H

S

COOH

S

271

(232)

Lissoclinamide

Scheme 6.123

OH

SH

OH

+ MeO2C

N

NH2, HCl Me

CN

N

N S

(233)

CO2Me Me

Scheme 6.124

SH PhHC=CHCN Me NH2, HCl MeO2C

Me MeO2C

S N (234)

S Ph

Me NC

N (235)

XX Ph NEt3

S Me N S N (236) Me CO Me 2

Ph

Scheme 6.125

and coworkers elaborated ﬁrst the thiazoline ring from the hydrochloride of (S)-(2)-methylcysteine methyl ester [193], which reacted with the pyridine nitrile derivative 233 to give the (S)-desferrithiocyn 230 in high yield (Scheme 6.124). To synthesize thiangazole, the same authors synthesized the thiazoline ring as described above. The resulting ester 234 was converted into the nitrile 235, and a second cyclocondensation reaction produced the bis-thiazoline 236 as shown in the Scheme 6.125 [229]. Thiazolines containing amino acids 238 could be obtained efﬁciently in an optically pure form from simple condensation reactions between cysteine derivatives and N-protected imino ethers 237, which are derived from natural amino acids (Scheme 6.126) [230]. Chiral centers attached to the C-2 position of thiazolines are prone to epimerization; therefore racemization-free methods have been developed. The Mitsunobu reaction [231a] or treatment with Burgess’ reagent (methyl N-(triethylammoniosulfonyl)carbamate) [231b] applied to thiopeptides were efﬁciently used to introduce thiazolines in the peptide backbone and proceeded without loss of stereochemical integrity.

231

272

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

RO2C

RO2C

NH

NH2

N

NHR″

+

EtO

SH

NHR″

S

R′ H (237)

R′ (238)

H

Scheme 6.126 SBn H N

Ph O

O Me

Me SBn

N H

Me O

H N O

(239)

N Me H SBn

(1) Na, NH3

OBn

OH

(2) NH4Cl

NHMe

Me

(3) TiCl4

O

Me H N

S Me

S

S N

O

MeHN

Me

N

N

O

68%

Ph (240)

Scheme 6.127

H Cbz

N H

N H CO2Me O

NEt3, MeOH H2S

Cbz

N H

H

O H H H N

H Burgess reagent OMe

S

Cbz

N H

S

N H CO2Me H

H OH

Scheme 6.128 O R

CO2Me

S N3 (241)

Me

S

PPh3

R

Me CO2Me N 67– 88% yield (242)

Scheme 6.129

As shown in Scheme 6.127, Heathcock and Parsons [232] made use of the tetrapeptide 239 that was reductively debenzylated and was cyclized by treatment with TiCl4 in order to provide the tris-thiazoline 240, a precursor of thangazole 231. Wipf and coworkers [233] used also Burgess’reagent in a general method for the oxazoline–thiazoline conversion. This reaction was stereoselective and essentially free of racemization (Scheme 6.128). A one-pot Staudinger reduction/aza-Wittig reaction was used as a mild and versatile process for the conversion of azido-thiolesters 241 into enantiopure 2,4-disubstituted thiazolines 242 (Scheme 6.129) [234]. Recently, the dehydrative cyclization of N-acylcysteine derivatives was carried out in the presence of a molybdenum oxide catalyst to afford thiazolines in high yield, as shown in Scheme 6.130 [235]. Xu and Ye [236] used amino alcohols to synthesize 2,4,5-trisubstituted thiazolines 246 with high diastereoselectivity via the intramolecular conjugate reaction described in Scheme 6.131. The unstable intermediate thioamide 245 readily undergoes an intramolecular conjugate addition reaction in a weak acidic medium (silica gel).

6.3 Five-Membered Heterocycles with N and S Atoms

SH

O N H

R

S

MoO2(acac)2

273

CO2Me N

CO2Me

R Yield = 81% ee = 98.7%

Scheme 6.130

O

O OH

O2N

O OH

O HN

DIPEA

+

NH2HCl O

N

O

t-Bu

N

N

OH HN

S (244)

(243)

Chromatography on silica gel

O

S N H

NH

O (245)

S

t -Bu

O (246)

Scheme 6.131 R1 R2 R3

R4

OH

SF3NEt2/CH2Cl2

S N H

R1

R5 Et2NF2SO

X R5

R3

(247)

R2

N R4 (248)

R1 R2

R3 R4 N H

S R5

Scheme 6.132

Diethylamidosulfur triﬂuoride (DAST) was used as a powerful hydroxyl activating agent for the intramolecular cyclization of (1,2)-thioamidoalcohols to 2-thiazolines, as shown in Scheme 6.132; this reaction was totally diastereoselective with the inversion of conﬁguration at C-5 [237]. The amino sugar 249 was allowed to react with para-substituted phenyl isothiocyanates, and thiazoline derivatives 250 were thus obtained (Scheme 6.133) [238]. O O H2N

OBn

HN O (249)

S

OH

(250) R

Scheme 6.133

OBn

N

RC6H4N C S

274

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

Me

R2

Me R2

N

N

S P2S5

BzCl R2

NH2

(251)

R3

R3 OH

OH

R3

P2S5

Me

OEt

R2

S

O

NH2+Cl−

R3

t-BuCOCl

N

(252)

R3 S

OH

P2S5

O R2

Ph R2

NHBz

N R3 H

R2

t-Bu (253)

N R3

t-Bu

Scheme 6.134 R N

CO2t -Bu

S

Chiral PTC, RX

N

KOH, PhMe

S

X

CO2t -Bu R

N+

X 67% < ee < 99% 46% < yield < 99%

R (254) Chiral PTC R = 3′,4′,5′-trifluorophenyl

Scheme 6.135 S Me BocHN

BocNH Me CO2Me TFA O

Me O PhCOSH O

K2CO3

Ph

(255)

S

N

Me CO2Me

Ph S (256)

Me S Me S

N

S Me N

N

N N

Me S

S Me

N

N

N

S

Me

N S

Me S Me

(257)

Scheme 6.136

With the aim to study the oxidation of thiazolines into thiazolines dioxide, thiazolines 251–253 have been prepared from β-amino alcohols in two steps (Scheme 6.134); the cyclization occurred in the presence of the simple reagent phosphorus pentasulﬁde [239]. Park et al. described an enantioselective synthesis of alkylcysteines via phasetransfer catalytic alkylation of 2-aryl-2-thiazoline-4-carboxylate ester, by using the chiral catalyst 254. This methodology seems very efﬁcient, given the mild reaction conditions and the high enantioselectivity obtained in the most cases (Scheme 6.135) [240]. In a very elegant synthesis of cyclic oligothiazolines, Fukuyama and coworkers [241] have built the thiazolidine ring from β-lactone 255 with thiobenzoic ester to provide in two steps the monothiazoline unit 256, which was submitted to repetitive elongation to give ultimately the cyclic oligothiazoline 257 (Scheme 6.136).

6.3 Five-Membered Heterocycles with N and S Atoms

R′

S

R′ S

S N

PPh2

N

S

AcO

O

N OAc

R (259)

AcO

OAc

(260)

Ph

Fe

N

S

S

N H S

N

S

OAc

N

N

R

(258)

S

N

O

275

Fe

N

N S

Fe

S

pTol

Fe R

R

N (263)

(262)

(261)

Scheme 6.137

S SMe +

H2N

OH

(1) NEt3

S

(2) MeSO2Cl, NEt3

N

(2) Anion exchange

X− = PF6− X− = BF4− N − − R (264) X = NTf2 S

(1) RI

X

−

+

Scheme 6.138

The ﬁrst application of a chiral bis(thiazoline) ligand for an asymmetric hydrosilylation reaction was reported by Helmchen et al. [242]. Since then, a few promising examples have been reported for asymmetric catalytic reactions with thiazolines or bis-thiazolines as ligands, such as Diels–Alder reactions (with ligands 258 and 259) [243], cyclopropanation (in the presence of the carbohydrate-derived pyridyl bis(thiazoline) 260) [244] and allylic substitution (with ligands 259) [245] (Scheme 6.137). C2 -symmetric tridentate bis(thiazoline) ligands 261 were used in catalytic asymmetric Henri reaction (nitroaldol reaction); an interesting metal-controlled reversal of enantioselectivity was obtained by replacing Cu(II) with Zn(II) [246]. In order to use them as ligands for asymmetric catalysis, new chiral ferrocene-thiazolines with (ligand 262) [247] and without (ligand 263) [248] C2 symmetry have been synthesized. A novel class of chiral ionic liquids based on the thiazolium cation 264 was prepared from amino alcohols in a multigram scale, as shown in Scheme 6.138. Their properties (low melting point, water tolerance and stable under acidic or basic conditions) make them interesting potential candidates for new chiral solvents [249]. 6.3.2.2 3-Thiazolines Very few enantioselective syntheses of 3-thiazolines have been reported in the literature. The ﬁrst synthesis of enantiopure 3-thiazolines via an Asinger reaction was described by Martens and coworkers [250]. The easily accessible galactose

276

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

OH

NH3 O

O O

O 0 °C, 12 h

+

O

O

Cl NaSH

N

H O SH

O

O

(265)

O

O (266)

Scheme 6.139

derivative 265 reacted under Asinger conditions to give 3-thiazolines 266 in good yields and in a highly diastereoselective way (Scheme 6.139). 6.3.3 Sultams

Chiral γ -sultams are useful heterocycles for asymmetric synthesis and medicinal chemistry. The most important application concerned the use of these sultam derivatives as chiral auxiliaries. In 1984, Oppolzer described the synthesis of the camphor-derived sultam 269 (named Oppolzer’s camphor sultam auxiliary), which was easily prepared from (+)-camphor-10-sulfonyl chloride 267, as shown in Scheme 6.140 [251]. Many asymmetric syntheses of chiral sultams that are not derived from camphor have been developed [252]. Oppolzer and coworkers [253] have performed the synthesis of compounds 272a and 272b, which are structurally simpler than the compound 269 (Scheme 6.141). The product 272a was obtained in two steps from saccharine 270. The key step was the asymmetric hydrogenation of imine 271 catalyzed by Ru2 Cl4 [(R)-(+)-BINAP]2 (NEt3 ). While the reduction of 271a furnished, after crystallization, the enantiomerically pure sultam 272a, reaction from imine 271b gave only traces of the racemic 272b. An alternative approach consisted in the resolution of the racemic 272b.

LiAlH4

(1) NH3 (2) EtONa

NH S H O2 (269)

S N O2 (268)

O SO2Cl (267) Scheme 6.140

O NH S O2 (270)

Scheme 6.141

R

R RLi

H2

N S O2

Ru2Cl4R*2NEt3 R* = (R )-(+)-BINAP

(271a) R = Me (271b) R = t -Bu

NH S O2 (272a) R = Me (272b) R = t -Bu

6.3 Five-Membered Heterocycles with N and S Atoms

O2 N S BnO

O2 HN S

Pd(CF3CO2)2

(273)

(S )-SegPhos H2, 4A MS

BnO

(274)

ee: 86%, yield: 93% Scheme 6.142 R

R RuCl(TsDPEN)(benzene)

N S O2 (271a) R = Me (271b) R = t -Bu (271c) R = CH2Ph

NH S O2

Ph

H N SO Ph 2

Ph

NH2

TsDPEN =

ent -(272a) R = Me ent -(272b) R = t -Bu ent -(272c) R = CH2Ph

Scheme 6.143

271a

RMgX

O2 S Resolution (+)-275 F2 / He NH and (−)-(275) R (275)

O2 S N F * R (276)

Scheme 6.144

The Pd/phosphine complexes were found to be valuable catalysts for the asymmetric hydrogenation of a series of cyclic sulfonamides 271 [254]. For example, Scheme 6.142 shows the ﬁrst enantioselective synthesis of the chiral sultam 274 from the sulfonamide 273. The asymmetric transfer hydrogenation of imines 271 catalyzed by ruthenium and rhodium complexes led to the corresponding sultams in good to excellent enantiomeric excesses (Scheme 6.143) [255]. Ahn et al. reported a practical synthesis of the sultams ent-272a–c by using Noyori’s RuCl(N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN))(benzene) catalyst as hydrogen donor. The sultam auxiliaries ent-272 were obtained in high enantiomeric excess (93%> ee >91%) [256]. All these sultams have been shown to be highly selective chiral auxiliaries in asymmetric alkylations [257], aldol reactions [258], radical additions [259], Diels–Alder reactions [260], addition reactions [261], cyclopropanation [262], epoxidation [263], azidation [264], ene-reaction [265], asymmetric Bayliss – Hillman reaction [266], and so on. With a view to synthesizing new chiral ﬂuorinating agents, some authors reported the synthesis of chiral sultams with a stable but reactive N–F bond [267], such as compound 276 obtained by the ﬂuorination of enantiopure compound 275 (Scheme 6.144). Chiral β-amino alcohols were used as precursors for the synthesis of chiral halosulfonamides and sultams [268]. In the case of the cis-aminoindanol 277, the hydroxyl group was converted to the trans-β-halosulﬁnamide 278 with inversion

277

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

278

NH2

O O N S CH 2

NHSO2Me MeSO2Cl

OH

DIPA

Cl

NEt3 85%

277

H N SO 2

Cl

n -BuLi

(278)

70%

(279)

(280)

Scheme 6.145 X

OH ROC

O

(1) HCl

AcSH, DIAD

NHBoc

ROC

(281)

(282) X = SAc (283) X = SO2Cl

S

(2) NEt3

NHBoc

K2CO3

N O H (284)

ROC

R′X

O

S

N O R′ (285)

ROC

Scheme 6.146 Ph

Ph

Ph Cbz-L-Phe CbzHN

X

(1) Boc2O

NH

S

Ph

(2) LDA, BnBr O (286) (3) TFA

O

S O

NH O

(287)

Scheme 6.147 R1

R1 R2

N H

R2

N

O

OH

R1 R3NOH

CHO

R2

Ph

O (288)

O

N

N − + O

N

NEt3

S

O

R2 N 70 – 87%

S Ph (289)

R3

R1

R3

O

O S O

Ph (290)

Scheme 6.148

of conﬁguration. Sultam 180 was obtained via the intramolecular sulfonamide dianion 279 alkylation, as shown in Scheme 6.145. The synthesis of enantiopure sultam 285, a potential anti-inﬂammatory agent [269, 270], was accomplished from chiral alcohols 281 that were converted to the thioacetate 282. Chlorine oxidation followed by selective N-Boc removal and cyclization gave 284, which is a precursor of the target compound 285 (Scheme 6.146). A novel series of HIV protease inhibitors containing the sultam scaffold 287 has been synthesized from the enantiopure Cbz-l-phenylalanine [271]. Alkylation of sultam 286 led to the trans isomer 287 as the sole isomer (Scheme 6.147). Bicyclic sultams 290, including an isoxazoline or isoxazolidine moiety, have been synthesized by intramolecular cycloaddition of sulfonamide oxime 289 [272]. This occurs with a complete diastereoselectivity: the stereochemical information present in the dipolarophile was completely preserved in the cycloadducts and the stereochemistry was predetermined by the alkene geometry, as outlined in Scheme 6.148.

6.3 Five-Membered Heterocycles with N and S Atoms H

H R−C N O +

−

O

Me

+

N C

Me

N

H S O Ph O (291)

N C

H Ph

O

+

N

S O R H O (292)

Me N C

H S O Ph H R O (293)

Scheme 6.149

O

O

13 kbar

O2S N

CH2Cl2, rt 94%

O

N

Ph

S

O O

Ph

(294)

+

O S O N Ph

66%

34%

Scheme 6.150

Ph

O O S N R1

RCM

R1 O N O S H

O O S N R1

H

Et2AlCl 85%

(295)

(296)

(297)

Scheme 6.151

Scheme 6.149 describes an intermolecular version of this 1,3-dipolar cycloaddition by using the chiral sultam 291 and nitrile oxide as starting materials. The reaction led to a separable 1:1 diastereoisomeric mixture of the bicyclic sultams 292 and 293 [273]. Enantiopure sultams have been readily prepared by intramolecular Diels–Alder reaction of the furan-containing vinylsulfonamides 294, but with a relatively low diastereoselectivity, as shown in Scheme 6.150 [274]. α-β-Unsaturated-γ -sultams 296 were generated via ring-closing metathesis (RCM) [275]; these sultams reacted with cyclopentadiene under Lewis acid catalysis to yield the tricyclic sulfonamides 297 with complete facial and endo selectivity (Scheme 6.151). With the aim of synthesizing a new class of nucleoside analogs with a speciﬁc inhibition against the HIV-1, Postel and coworkers reported the synthesis and the treatment of new cyanomethanesulfonamides of monosaccharidic and nucleosidic substrates under carbanion-mediated sulphonamide intermolecular coupling (CSIC) conditions [276]. This reaction, depicted in Scheme 6.152, led to the dihydroisothiazole 1,1-dioxide 299 in good yields. Recently, Combs and coworkers [277] described the ﬁrst asymmetric synthesis of compound 302 from the enantiopure sulfoxide 300. The key step of this synthesis was the reduction of the heterocycle with excellent regiochemical and stereochemical controls (Scheme 6.153). The hydride attacked the ethylenic double

279

280

6 Asymmetric Synthesis of Five-Membered Ring Heterocycles with More Than One Heteroatom

O

O BnO

N Boc

N

O

O

NC NH

S

BnO

LDA 67%

OTBMS

NH

S

(298)

N BOC O

H2N

OTBMS

O O

N

O

(299)

O O

Scheme 6.152 R

R

R H

O

S N

NaBH4

O

O (300)

> 98% ee

S N

H H + H B H Na O

H O (1) m CPBA (2) TFA

> 98% de

(301)

O

O S N O H > 98% ee

PH

(302)

N S O (303)

Scheme 6.153

H3CO N

c -HexO O

Cbz NH HN

N (1) RM/CeCl3

S O

H + (304)

c -HexO

(2) BH3 (3) CbzCl, K2CO3

R

S O

O2 HN S

O

R (305)

(306)

Scheme 6.154

bond adjacent to the sulfonamide on the opposite face of the heterocycle that bears the sulfonamide oxygen, as depicted on model 303. Enders and coworkers [278] have developed an efﬁcient asymmetric synthesis of 3-substituted γ -lactams through the diastereoselective nucleophilic 1,2-addition of various organocerium compounds to the CN double bond of ω-S-1-amino-2-methoxymethylpyrrolidine (SAMP)-hydrazonosulfonates 304. Compounds 306 were obtained in good overall yields and with high enantiomeric excesses (Scheme 6.154). As can be seen from the above discussion, ﬁve-membered heterocycles with N, O and S atoms constitute a large category of highly valuable reagents. Their value is clearly noticeable in the ﬁeld of asymmetric synthesis as well as biologically active compounds. As a matter of fact, these compounds not only act as chiral auxiliaries (some of them even belonging to very classical stereoselective reactions) but also as chiral ligands linked to metal catalysts, which allow various remarkable enantioselective transformations in many diverse topics. Though revealed more recently as important pharmaceutical tools, their usefulness in this area cannot be underestimated and the ongoing extensive research should lead to still more promising results.

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293

7 Asymmetric Synthesis of Six-Membered Ring Nitrogen Heterocycles with More Than One Heteroatom P´eter M´atyus and P´al T´apolcsanyi

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

This chapter covers the synthesis of chiral partially or fully saturated substituted pyridazines, pyrimidines, piperazines, oxadiazines, and morpholines with deﬁned conﬁguration of the substituents. Methods considering the formation of the heterocyclic ring are discussed separately from the stereoselective transformations by the involvement of the already existing ring. A literature search was performed using the SciFinder program by using both keyword search (combination of the name of the corresponding ring with the keyword ‘‘asymmetric synthesis’’) and structure search. In the latter case, for the corresponding ring given as ‘‘product’’, unlimited substitution was allowed, but ring tools were locked out. The hits were reﬁned (i) by omitting patents, (ii) by selecting the stereoselective reactions, and (iii) by the keyword ‘‘asymmetric synthesis’’. The literature is surveyed covering the period from 1957 till 2007. 7.1.1 Pyridazines

Partially saturated pyridazine derivatives with deﬁned chirality have so far been obtained via two different routes. In the ﬁrst, most frequently employed pathway, the key step is the ring closure of enantiomerically pure precursors to pyridazines. Such precursors have generally been (i) a lactone or lactam, (ii) a hydroxy ester or acid, (iii) an amino acid, (iv) a protected hydroxy aldehyde, (v) keto ester, or (vi) a chiral heterocycle. The second route, which may be considered an important variant of the ﬁrst, is based on the Diels–Alder reaction, which involves the cycloaddition of a chiral diene and azodicarboxylic ester or triazolo derivative as dienophile.

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

294

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

O O

O NH

O +

Br

(a) O

Br (b)

(3)

O

O N

Ph

Ph (2)

O

Boc

Cl

Ph (R)-(1)

N

O

O

O

N

NH Br Boc

O

N Boc

N

Ph (5)

(4)

N Boc

(c, d) Reagents and conditions:

(a) n BuLi/THF (80–91%), (b) 1. LDA/DBAD/CH2Cl2, 2. DMPU (55–63%), (c) LiOH/THF/H2O (89%), (d) TFA/CH2Cl2 (94%).

LDA: lithium diisopropylamide, DBAD: di-tert -butylazodicarboxylate,

HO

O NH NH

CF3COOH

(R)-(6)

DMPU: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H )-pyrimidinone

Scheme 7.1

7.1.1.1 Ring Closure of Optically Active Precursors Piperazic acid (hexahydropyridazine-3-carboxylic acid) is a typical building block for a number of pharmacologically active compounds. Moreover, one of its enantiomers (3S) has been found to exert γ -aminobutyric acid (GABA) uptake inhibitory activity in rat cerebral cortex slices. Subsequently, enantioselective syntheses of such compounds have been thoroughly studied. Hale and coworkers described the synthesis of both enantiomers. The synthesis of (3R)-piperazic acid ((R)-6) starts with the N-acylation of (4R)-phenylmethyl-2-oxazolidinone (1) with 5-bromovaleryl chloride (2), followed by diastereoselective α-hydrazination of 3 with di-tert-butylazodicarboxylate and LiNiPr2 . When the reaction was carried out in the presence of DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone), the cyclized product 5 could be obtained directly without isolation of the intermediate bromovaleryl hydrazide 4. Interestingly, without the addition of DMPU, 4 was isolated as the major product. These ﬁndings were explained by the formation of a highly aggregated lithium-aza anion, which is transformed to a more reactive species in the presence of DMPU. After removal of the protecting groups from 5, (3R)-piperazic acid ((R)-6) was obtained as triﬂuoroacetate salt with 96% ee [1, 2]. The method has also been used for the preparation of (S)-piperazic acid [3, 4]. An analogous, convenient procedure was developed for the preparation of the S-enantiomer of 6 by Hale’s group, starting from an oxazolidinone precursor derived from norephedrine. The product in this case was obtained with a lower enantiomeric excess (88–93%). Three other pathways for the synthesis of enantiomerically pure pyridazinecarboxylic acid derivatives have been described by Schmidt’s group, which are based on cyclocondensation with hydrazone formation or cyclization with alkylation of α- or δ-hydrazinocarboxylic acids. In method I, as the key step, asymmetric hydrogenation of dehydro amino acid derivative 7 in the presence of a chiral rhodium catalyst ((R,R)-(Rh(1,5-COD) (DIPAMP)+ BF4 − ) afforded amino ester 8 with high enantioselectivity. By treatment with NaNO2 in acetic acid, 8 was transformed into hydrazine derivative 9, in which

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring O

O

COOMe (a)

O

O

NHCbz

COOMe (d)

O

NHCbz

(7)

COOMe

O

COOMe (b)

RHN

(8)

295

NCbz N

NHCbz

(9): R = Ac (10): R = Boc

COOMe (e)

(11)

(c)

NCbz NH (S )-(12)

Reagents and conditions: (a) (R,R)-(R)h(1,5-COD)(DIPAMP)+ BF4−/H2/MeOH (100%, 97% ee), (b) 1. NaNO2/ Ac2O/AcOH, 2. Zn/Ac2O/AcOH (50%), (c) 1. Boc2O/DMAP/MeCN, 2. K2CO3/MeOH (84%), (d) 6 N HCl/dioxane (87%), (e) NaCNBH3/AcOH (81%). COD: cyclooctadiene DIPAMP: (R,R)-1,2-bis[2-(methoxyphenyl)phenylphosphanyl]ethane Cbz: benzyloxycarbonyl

Scheme 7.2

the protecting group was replaced to obtain 10. Its ring closure to 11 was achieved with HCl/dioxane; 11 could then be smoothly reduced to (S)-12 [5]. Methods II and III used enantiomerically pure (2S)-pyroglutamic acid isopropyl ester or (2R)-5-oxotetrahydrofuran-2-carboxylic acid tert-butyl ester, respectively, which were transformed to properly protected α-hydrazino-δ-hydroxy or δ-hydrazino-α-hydroxy ester, and subsequently cyclized via intramolecular nucleophilic substitution of the corresponding mesylate or triﬂate to pyridazinecarboxylic ester [5]. Tetrahydropyridazine derivative 16, which can be regarded as a useful intermediate for synthesis of the luzopeptins (natural products possessing inhibitory activity against reverse transcriptase), was prepared from β-hydroxy ester 13. The Gennari–Evans–Vederas reaction of 13 with dibenzyl azodicarboxylate afforded an 18:1 mixture of the anti (14) and syn diastereomers of the corresponding α-hydrazino ester. Sequential O-acetylation and catalytic debenzylation in the presence of di-tert-butyl dicarbonate, followed by acylation of the mono-Boc-protected derivative thus formed with (4R)-3-acetyl-2-oxo-1,3-oxazolidine-4-carbonyl chloride, resulted in 15, which could be smoothly cyclized with triﬂuoroacetic acid to 16 [6]. Enzyme-assisted synthetic methods have been described for the preparation of tetrahydropyridazines. Lipase Triacylglycerol lipase (TL)-mediated kinetic O O

O

OH COOi Bu

O

(a)

OH

COOi Bu

O COOi Bu (b –c – d)

O

BocHN CbzHN

OAc

OAc

N

COOi Bu

(e)

O

N

O O

O

Reagents and conditions:

(14)

(15)

(a) CbzN NCbz/LDA/THF (61%, anti :syn = 18:1), (b) Ac2O/pyridine (95%), (c) Boc2O/H2/Pd–C/MeOH (97%), (d) sym-collidine/(4R )-3-acetyl-2-oxo1,3-oxazolidine-4-carbonyl chloride/CH2Cl2 (60%), (e) TFA/H2O (97%).

Scheme 7.3

O NAc

NAc O

(13)

N

NCbz

(16)

296

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

resolution of protected alcohol 17 gave the (R)-acetate (R)-18 and the corresponding (S)-alcohol with high enantiomeric purity. The reaction conditions were thoroughly studied: application of n-hexane as solvent led to the best chemical yields and enantiomeric ratios, whereas basic additives such as pyridine, 4-N,N-dimethylaminopyridine, 2,4- and 2,6-lutidine were found to increase reaction rates considerably. Compound (R)-18 was debenzylated and subsequently oxidized to aldehyde (R)-19 with Dess–Martin reagent. Treatment of (R)-19 with tert-butyl carbazate and NaBH3 CN, and then protection with benzyloxycarbonyl group, led to compound (R)-20. For its cyclization to (S)-21, an intramolecular Mitsunobu reaction was carried out. (S)-33 was transformed to piperazic acid derivative (S)-22 with 98% ee [7]. Four possible stereoisomers of 5-hydroxypiperazic acid were synthesized starting from chiral compounds 23 and 27, which were transformed to the corresponding O-protected 3-butyraldehyde derivatives 24 and 28, respectively, possessing a good leaving group at position 4. Ring closure with hydrazine hydrate and subsequent N-protection with benzoyl chloride gave tetrahydropyridazine derivatives (S)-25 and (R)-25. Their diastereoselective Strecker reaction was investigated with trimethylsilyl cyanide in the presence of a Lewis acid. Interestingly, when Zn(OTf)2 was used as Lewis acid, together with NaOAc/AcOH as additives, the syn cyano products (3S,5S)-26 or (3R,5R)-26 were formed in higher amounts. However, when Mg(OAc)2 was used in combination with acetic acid, the anti isomers (3R,5S)-26 or (3S,5R)-26, respectively, were obtained as the major product [8]. Another series of dihydropyridazines, the 6-aryl-5-methyl-4,5-dihydropyridazin3(2H)-ones (R)-33 could be obtained in four steps from the respective arene. Friedel–Crafts acylation of arenes 29 with (2R)-2-chloropropanoyl chloride to 30, followed by their SN 2 reactions with benzyl methyl malonate in the presence of NaH, afforded 31. The reason for using benzyl methyl malonate instead of dimethyl malonate was to suppress possible epimerization in the subsequent step, in which removal of one of the ester groups was needed. Debenzylation of 31 and

BnO

OTBS

(a)

BnO

OH (17)

BocHN

N Cbz

OTBS OH

(R )-(20)

(g)

OTBS

(b,c)

OHC

OTBS

OAc

OAc

(R )-(18)

(R )-(19)

OTBS NBoc

N Cbz

(S )-(21)

(d – f)

COOMe (h–j) NH

N Cbz

(S )-(22)

Reagents and conditions: (a) Lipase TL/CH2CHOAc/solvent/additive (11– 62%, 82– 98% ee), b) H2/Pd– C/MeOH (quant), (c) Dess – Martin periodinane/CHCl3 (99%), (d) 1. BocNHNH2/EtOH/AcOH, 2. NaCNBH4 (67%), (e) CbzCl/NaHCO3/CHCl3 (97%), (f) K2CO3/MeOH (73%), (g) DEAD/PPh3/THF (86%), (h) 1. TBAF/THF, 2. Jones reagent/acetone, (i) TMSCHN2/MeOH (81%), (j) TFA/CH2Cl2 (84%).

Scheme 7.4

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

O

O

OH

TsO

4 steps

O

H

(a)

Bz

N

N

(b or c)

Bz

N

H N

Bz

CN

N

297

H N

CN

+

HO OH

OTBS

(23)

(24)

OTBS

OTBS (S )-(25)

OTBS

(3S,5S )-(26)

(3R,5S )-(26)

(b) syn:anti = 75:25-87:13 (c) syn:anti = 7:93-3:97 O

Cl

OEt

2 steps

Cl

O

H

Bz

(a)

N

N

Bz

(b or c)

N

H N

Bz

CN

H N

N

CN

+ OH

OTBS

(27)

(28)

OTBS

OTBS

OTBS

(R )-(25)

(3S,5R )-(26)

(3R,5R )-(26)

(b) syn:anti = 81:19 (c) syn:anti = 3:97 Reagents and conditions: (a) 1. NH2NH2.H2O/EtOH, 2. BzCl/pyridine (89 – 93%), (b) Me3SiCN/Zn(OTf)2/AcOH/NaOAc/ CH2Cl2 (42–70%), (c) Me3SiCN/Mg(OAc)2/CH2Cl2 (75– 99%).

Scheme 7.5

O

(a) ArH

O

(b)

Ar

COOBn

Ar

COOMe

O

(c) Ar

(d) COOMe

Cl (29)

(30)

(31)

N

H N

O

Ar

(32)

(R)-(33)

ArH: acetanilide, 2-isopropylpyrazolo[1,5-a]pyridine Reagents and conditions: (a) (2R )-2-chloropropanoyl chloride/AlCl3/1,2,4-trichlorobenzene (59–80%), (b) NaH/CH2(COOMe)(COOBn)/DMF (81–84%), (c) 1. Pd– C/H2/EtOAc, 2. diglyme/rfx (55–84%), (e) N2H4·H2O/AcOH/MeOH/H2O (69–91%, 84–90.2% ee).

Scheme 7.6

subsequent decarboxylation gave monoesters 32, which cyclized to pyridazinones (R)-33 in 84–90.2% ee on treatment with hydrazine hydrate [9, 10]. Diastereoselective synthesis of tetrahydropyridazinone 40 as a precursor of β-strand mimetics has been described starting from (S)-phenylalanine (34), which was ﬁrst transformed to phenyloxazolidinone 35. Alkylation of 35 with allyl bromide in the presence of lithium hexamethyl-disilazide (LiHMDS) selectively furnished allyl derivative 36 as the single isomer. Subsequent hydrolytic ring opening, followed by treatment with diazomethane, gave the α, α-dialkylated ester 37. Ozonolysis of the double bond and the subsequent ring closure of aldehyde 38 led to dihydropyridazinone 39, which could be hydrogenated to tetrahydroderivative 40 upon treatment with NaBH3 CN [11].

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

298

Ph Ph

3 steps

Bz N

COOH

H2N

(b) Bz N

O

Bz

Bz

NH

NH

COOMe

Bz NH

(36)

Ph

(e)

N

(d)

Ph Bz NH

COOMe

Ph (35)

Ph

(c)

Ph

O O

Ph (34)

O

Ph (a)

O

(37)

(38)

NH NH

NH O

O (39)

(40)

Reagents and conditions:

(a) LiHMDS/allyl bromide/THF (93%, 95% ee), (b) 1. NaOH/MeOH, 2. CH2N2 (99%), (c) O3/CH2Cl2/MeOH (96%), (d) N2H4 (85%), (e) NaCNBH3 /MeOH (73%).

Scheme 7.7

Asymmetric γ -alkylation of α, β-unsaturated glutamic acid derivatives 42 possessing a chiral auxiliary was the key step in the synthesis of 4-substituted 4,5-dihydropyridazinones 44. Compounds 42 were obtained by selective Me3 Almediated acylation of methyl ester 41 with (2R)-bornane-10,2-sultam or 8-phenylmenthol. Alkylation of 42 was carried out under phase transfer-catalyzed conditions with various electrophiles, affording 43 with high diastereomeric excess (70–100% de) in favor of the 2R isomer. Reaction of the alkylated derivatives 43 with hydrazines afforded dihydropyridazinones 44 via N-deprotection and cyclization in one pot, with recovery of the chiral auxiliary [12]. Chiral pyridazine derivatives were synthesized by Young’s group. They applied a ‘‘ring switching’’ method, starting from another optically active heterocyclic compound. Reaction of the β-lactam 45, bearing a formylmethyl group, with hydrazine hydrate in methanol at room temperature gave a mixture of hydroxypyrrolidinones 46 (62%) and tetrahydropyridazine 47 (17%). Interestingly, reaction of the aldehyde t BuOOC

N

t BuOOC

Ph

N

Ph

Ph

(a) Ph O

OMe

(41)

(b)

Ph O

N

t BuOOC

Ph

(c)

t BuOOC

N

R1

R2 N O

R1

R*

O

(42)

R*

(43)

R1X = MeI, BnBr, EtO2CCH2Br, p -NO2C6H4CH2Br, CH2CHCH2Br R = H, Me, Bn 2

R∗ H =

(44)

Ph OH

or

NH S O O

Reagents and conditions:

Scheme 7.8

(a) Me3Al/R∗H (80%), (b) R X/NaOH/n Bu4NCl/MeCN (30 – 90%, 70 –100% de), (c) R2NHNH2/EtOH (90 –95%). 1

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

O

H H

H COOt Bu

COOt Bu

(a)

N NH2

Boc (45)

+

O

H

H

(b)

NHBoc HO

N O

H

(46)

(47)

COOt Bu NHBoc

N

N H

O

(47)

(c)

(a) NH2NH2/MeOH/rt (46: 62%, 47: 17%), (b) heating, (c) NH2NH2/benzene/rfx (65%).

Reagents and conditions: Scheme 7.9 H O

CHO H

N Boc

OTBDPS

(48)

Reagents and conditions:

H (a)

N RN

299

OTBDPS NHBoc

O (49) R = H, Me

(a) RNHNH2/MeOH/rt (41–65%).

Scheme 7.10

with hydrazine hydrate in reﬂuxing benzene afforded 47 in 65% yield as the sole product [13]. The ring switching method could also be successfully applied to functionalized pyrrolidinone derivative 48, when dihydropyridazinones 49 were obtained in moderate to good yields [14]. An elegant one-pot method was recently described for the enantioselective synthesis of 3-substituted tetrahydropyridazines from achiral starting materials, using a chiral organocatalyst. In the ﬁrst step, asymmetric catalytic α-amination of aldehydes 50 with azodicarboxylates 51 in the presence of (S)-proline or 5[(2S)-pyrrolidin-2-yl]-5H-tetrazole as catalyst gave intermediates 52. Base-promoted addition of the secondary nitrogen in 52 to vinylphosphonium bromide led to the ylide intermediate 53, which could be cyclized to the product 54 in 69–99% ee [15]. 7.1.1.2 Diels–Alder Reactions In stereoselective hetero-Diels–Alder reactions, the stereochemical outcome of the reaction could be determined by chiral auxiliaries present either on the diene or on the dienophile, or as a further possibility, asymmetric catalysis could be employed. The 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl unit displayed an Re-face reactivity in the cycloaddition reactions of dienes 55 with azodicarboxylates 51, furnishing cycloadducts 56 with high stereoselectivity. On removal of the protective groups, 56 can be transformed to tetrahydropyridazine ester (S)-57. The benzyl ester of 56

300

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

O

COOR2

+ R1

O

(a)

N N COOR2

Ph3P

COOR2

HN N COOR2

O

1

R

(50)

(51)

N N

COOR2 COOR2

R1

(52)

(53)

N N

COOR2 COOR2

R1 (54)

R = i Pr, t Bu, allyl, Bn R2 = Et, t Bu, Bn 1

(a) 1. Proline or 5-[(2S )-pyrrolidin-2-yl]-5H-tetrazole/CH2Cl2, 2. CH2CHPPh3Br/NaH/DMSO or THF (63–89%, 69–99% ee).

Reagents and conditions:

Scheme 7.11 COOR1 +

COOR1 N N

COOR2 COOR2

(a)

R2OOC

N 2 R OOC N

COOMe (b)

OR*

HN N

OR*

(55)

(51)

R1 = Me, t Bu, Bn, R2 = Et, Bn, Cl3CH2, i Pr, t Bu

(c)

COOR1 R2OOC

R∗ =

OAc

O

OAc

(d)

N R2OOC N

OAc

AcO

(S )-(57)

(56)

(S )-(57)

OR* (58)

Reagents and conditions: (a) EtOAc/70 °C or toluene/100 °C (57–87%), (b) H2/Pd – C/EtOAc (R1 = Me, R2 = Bn) (37%, 98% ee), (c) H2/Pd – C/EtOAc (R2 not Bn) (82–93%), (d) TFA (R1 = Me, R2 = t Bu) (57%).

Scheme 7.12

furnished (S)-57 directly, while hydrogenolysis of tert-butyl esters afforded saturated derivatives 58, which were then treated with triﬂuoro-acetic acid (TFA) to yield (S)-57 [16]. Oxazolidinethione moiety was applied as chiral auxiliary in an analogous Diels–Alder reactions of (4R)-3-[(1E)-buta-1,3-dien-1-yl]-4-phenyl-1,3-oxazolidine-2thione with diethyl azodicarboxylate to furnish the product in moderate stereoselectivity (50% de) [17]. (3S,4R,5R)-4,5-Dihydroxy-3-methyl-2,3,4,5-tetrahydropyridazine 66 has been prepared from triazolocarbinol 63 derived from [(S)R]-(1E,3E)-1-p-tolylsulﬁnyl-1,3pentadiene (59) and 4-methyl-1,2,4-triazoline-3,5-dione (60) in an asymmetric tandem hetero-Diels–Alder cycloaddition [2, 3] – sigmatropic rearrangement – sulfenate trapping reaction. After protection of the hydroxy group of 63, the

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring S*OTol

TolO*S

O N N

+

(a)

O (59)

HO

Me

TolSO O

Me

(61) OH

O HO

(b, c)

N N

N N

N Me

Me

(60)

O

O N N

N Me

N Me TBDMSO O

Me

(63)

Reagents and conditions:

N N

(64)

N Me O

(62) Me Me

O (d)

O

TBDMSO

Me

O

O

N Me O

301

N N Me (65)

(e) N CH3

H

H HN N

OH OH H

O

(66)

(a) P(OMe)3 (b) TBDMSOTf/Et3N (57%), (c) OsO4–NMO/acetone – H2O (54%, 80% de), or (trifluoromethyl)methyldioxirane (64%, 98% de), (d) DMP/TsOH/acetone (75%), (e) NH2NH2 (quant).

TBDMS: tert-butyldimethylsilyl

Scheme 7.13

tert-butyldimethylsilyl derivative was dihydroxylated in the presence of OsO4 , yielding 64 with 80% de and 54% yield. When (triﬂuoromethyl)methyldioxirane was the oxidizing agent, 98% de and 64% yield were attained. Transformation of cis diol 64 to acetonide 65 and subsequent hydrazinolysis resulted in pyridazine derivative 66 [18]. The cycloadduct from the analogous diastereoselective aza-hetero-Diels–Alder reaction of 4-phenyl-1,2,4-triazoline-3,5-dione with (4S)-4-benzyl-3-[(2E)-penta-2,4dienoyl]-1,3-oxazolidin-2-one in the presence of titanium tetrachloride (dr: 97:3) could be transformed to the triﬂuoroacetate of S-piperazic acid (S)-6 via a series of steps [19]. According to the other approach, a chiral auxiliary was built in the dienophile. Thus, the asymmetric synthesis of piperidazine-3-phosphonic acid enantiomers was performed via a one-pot process of hetero-Diels–Alder reaction and subsequent phosphonylation. The reaction of diene 67 with dimenthyl azodicarboxylate in the presence of trimethyl phosphite and trimethylsilyl triﬂate as Lewis acid gave an isomeric mixture of 3-(dimethoxyphosphoryl)-3,6-dihydropyridazine-1,2-dicarboxylate 68. After catalytic hydrogenation, the saturated derivatives could be separated by chromatography, affording (S)-69 and (R)-69 in the ratio of 66:34. Subsequent hydrolysis gave (S)-70 and (R)-70, respectively [20]. The reactions of variously functionalized dienes 71 with azopyridine 72 have been investigated in the presence of chiral catalysts. A combination of (R)-2,2 -Bis(diphenylphosphino)-1,1 -binaphthalene (BINAP) and AgOTf as catalyst and propionitrile as solvent provided the most effective reaction conditions, affording products 73 in good yields and high enantiomeric purity for most substrates [21].

302

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

OTMS +

N N

COOR

(a)

COOR

PO(OMe)2 COOR N N COOR

(67)

PO(OMe)2 (b)

N N

PO(OMe)2

COOR

N N

+ COOR

(S )-(69)

(68)

R = (−)-menthyl

COOR COOR

(R )-(69) (c)

(c)

PO(OMe)2

PO(OMe)2 NH NH

NH NH

(S )-(70)

(R )-(70)

Reagents and conditions: (a) P(OMe)3 / TMSOTf/CH2Cl2, (b) H2/Pd – C/MeOH (99%, 66:34 dr), (c) 1. 6 N HCl/AcOH, 2. propylene oxide (64 – 67%). Scheme 7.14

TIPSO OTIPS R1

(a)

R2 (71)

+

N

N

N

(72)

Troc

R1

R2 N N

Py

Troc (73)

R1 = Me, Bn, 4-MOMO-Bn, (CH2)3OTBS R2 = Me, Ph, i Bu, i Pr, BOM, 2-furyl Reagents and conditions: (a) 5 mol% (R )-BINAP/10 mol% AgOTf/EtCN (65 – 87%, 55 – 99% ee). Scheme 7.15

7.1.2 Pyrimidines

For the synthesis of substituted pyrimidines with deﬁned stereochemistry, condensation of an enantiomerically pure β-amino acid amide derivative with an aldehyde followed by the intramolecular addition of the amino nitrogen to the imine bond formed, in one pot or via separate steps, is a frequently applied method. The other most frequently used approach involves an intramolecular nucleophilic substitution as the ring closure step. Besides, stereoselective transformation such as alkylation, halogenation, or hydroxylation of the pyrimidine ring could also be employed. 7.1.2.1 Formation of the Pyrimidine Ring Ring Formation by Addition to Imine Bond [5 + 1] Types Synthesis of (2R, 4S)-2-tert-butyl-6-oxohexahydropyrimidine-4-carboxylic acid and its protected derivatives (2R,4S)-3 has been reported in several papers. Thus, treatment of

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

303

(S)-asparagine (1) with pivaldehyde in the presence of KOH resulted in pyrimidinone 2 with cis orientation of the substituents as the single isomer. Protection of the amine nitrogen in 2 with benzyl chloroformate gave compound 3 [22–28]. In an analogous way, (6S)-1-benzoyl-3,6-dimethyltetrahydropyrimidin-4(1H)-one ((S)-6) was prepared from methyl (S)-3-aminobutanoate (4) by conversion to amide with methylamine and subsequent Schiff’s base formation to 5 followed by ring closure and subsequent benzylation [29]. The same method was applied for the synthesis of the phenyl derivative (S)-10 by amide formation of methyl (S)-3-amino-3-phenylpropionate (9) with methylamine, followed by cyclization with formaldehyde. Compound (S)-9 was prepared via diastereoselective addition of lithium (R)-benzyl(α-methylbenzyl)amide to tert-butyl cinnamate (7), followed by hydrogenolysis of 8 and subsequent esteriﬁcation [30].

NH2 NH2 O

(a)

HN

COOH

O

(S )-(1)

(b)

NH

HN

COOK

O

N

R COOH

(2S,4S )-(3)

(2)

R = Cbz, MeO2C, Bz (a) KOH/t BuCHO, (b) RCl/NaHCO3 /H2O (67– 80% from 1).

Reagents and conditions:

Scheme 7.16 O

O

O

MeO H2N

N

(b)

MeHN

(a)

N

H2C N

(S )-(4)

Bz (S )-(6)

(5)

(a) 1. MeNH2/MeOH, 2. (CH2O)n (79%), (b) BzCl/DMAP/ benzene (92%).

Reagents and conditions:

Scheme 7.17

O

Ph O

(a)

Ph

N

Ph

(7) Reagents and conditions:

OMe

Ot Bu

Ph (8)

N Bz

(S )-(9)

(a) Li (R )-benzyl(a-methylbenzyl)amide, (b) H2/Pd-C/AcOH, (c) Me3SiCl/MeOH (69% from 7), (d) 1. MeNH2/MeOH, 2. (CH2O)n, (e) BzCl/DMAP/benzene (82% from 9).

Scheme 7.18

N

(d, e)

O

Ot Bu

Ph

NH2 O

(b, c)

Ph (S )-(10)

304

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

Optically active oxazoline 11 derived from d-valinol could be stereoselectively transformed to β-aminoalkanamide 15 and its substituted derivatives by addition of the lithium salt of 11 to N-cumyl nitrone 12. The addition afforded a mixture of the equilibrating spirocycle 13 and hydroxylamine 14. Hydrogenation of the mixture gave 15 in a highly enantioselective way (dr: 93:7), which was subsequently converted to tetrahydropyrimidinone 16 by treatment with paraformaldehyde [31]. Ring Closure by Intramolecular Nucleophilic Displacement 1,3,6-Trisubstituted 2,4-dioxohexahydropyrimidines (S)-21 could be synthesized via intramolecular nucleophilic attack of the terminal amino group to methyl ester in anilinocarbonylamino diester intermediate (S)-20, which was prepared from partially protected aspartic acid (S)-17. Its activation with isobutyl chloroformate in the presence of N-methylmorpholine and the subsequent reaction of the mixed anhydride with diazomethane gave diazo compound (S)-18, which underwent the Arndt–Eistert rearrangement upon treatment with silver benzoate with methanol, leading to the homoaspartic acid derivative (S)-19. Hydrogenolysis, followed by addition to phenyl isocyanate, afforded the linear urea intermediate (S)-20, which, under basic conditions, cyclized regioselectively through the methyl ester and subsequently alkylated on the nitrogen, providing the 2,4-dioxohexahydropyrimidine derivative (S)-21 [32]. (S)-1-tert-Butyl-4-methyl 2-aminobutanedioate ((S)-22) was reacted with diphenyl cyanocarbonimidate (23) to give (S)-24, which was then treated with benzylamine, affording a 1:1 mixture of pyrimidine (S)-25 and imidazole 26. The latter showed little optical activity, but (S)-25 was obtained with 80% ee. The same reaction sequence starting from (R)-1-tert-butyl-4-methyl 2-aminobutanedioate gave the enantiomeric (R)-25 with 90% ee [33]. Dihydropyrimidinone derivative (S)-30, a precursor of the antibiotics TAN-1057A, has been synthesized from N-protected diamino acid (S)-27, which was coupled with S-methylisothiobiuret (28). Removal of the Boc-protecting group from (S)-29, followed by ring closure and subsequent hydrogenolysis, gave (S)-30 in 87% ee [34].

NH O N O Ph N

+

O

(a)

+

−N

Ph O

Ph

(b)

(13)

O

H N

H2 N Ph H O

Ph

(4R,1′S )/(4R,1′R ) (11)

(12)

N HO O

(15)

N

(c) OH

N H Ph N H (R,R,R ) (16)

Ph Ph (14)

Reagents and conditions: (a) s BuLi/THF, (b) H2/Pd – C/MeOH (98%, 93:7 dr), (c) (CH2O)n /MeOH (60%).

Scheme 7.19

OH

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring COOt Bu

COOt Bu Cbz

(a) N H

COOH

Cbz

+

N

N H

O

(S )-(17)

COOt Bu (b) −

Cbz

N

(S )-(18)

(c, d) COOMe

N H

COOt Bu

O Ph

O

305

N H

N H

(S )-(19)

COOMe O

(S )-(20) (e, f) O R

N

Ph

N

O COOt Bu R = Me, Bn, MeCO2CH2 (S )-(21) Reagents and conditions:

(a) i BuOCOCl/NMM/(THF)/CH2N2/Et2O, (b) PhCOOAg/Et3N/MeOH, (c) H2/Pd–C/MeOH, (d) PhNCO/THF, (e) KOt Bu/THF (70%), (f) RX/KOt Bu/THF (80–93%).

NNM: N-methylmorpholine

Scheme 7.20 NCN NCN COOt Bu (b) COOMe PhO N HH

COOt Bu NCN (a) COOMe + H2N PhO OPh H (S )-(22)

Bn

NH

NCN

+ COOt Bu H

O

(S )-(24)

(23)

N

Bn N

NH COOMe

O

(S)-(25)

(26)

(a) i PrOH (84%, 100% ee), (b) BnNH2 /i PrOH (68% 1:1 mixture of (S )-25 and 26, 80% ee for (S )-25).

Reagents and conditions:

Scheme 7.21

NH Cbz

N

NHBoc + COOH

MeS

N H

O

(a) NH2

Cbz

HI

N

NHBoc NH

O MeS

(S )-(27) Reagents and conditions:

(28)

N

(S )-(29)

(b, c)

O

HN O

NH2

N N H

O N H

NH2

(S )-(30)

(a) HOBt, EDC, DIEA (100%), (b) 1. TFA/anisole/CH2Cl2, 2. Et3N/AcOH (55%, 92% ee), (c) H2/Pd–C/DMA (96%, 87% ee).

HOBt: 1-hydroxybenzotriazole EDC: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride DIEA: N,N -diisopropylethylamine

Scheme 7.22

For the asymmetric synthesis of (2S,3R)-capreomycidine (35) as a structural unit of pentapeptides possessing tuberculostatic properties, the pyrimidine ring was elaborated by intramolecular Mitsunobu reaction. The synthesis started with the

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

306

preparation of the aluminum enolate of chiral morpholinone 31 by treatment with LiHMDS and subsequent transmetalation with MeAl2 Cl. Addition of O-protected N-benzyl-3-hydroxypropylidene amine to the aluminum enolate gave a mixture of two diastereomers 32, in which the imine is situated on the opposite face of the morpholine ring rather than the phenyls. Guanidinylation of 32 with N,N -di-tert-butoxycarbonyl-S-methylisothiourea in the presence of HgCl2 afforded a single diastereomer, which was deprotected to 33. Formation of the pyrimidine ring was achieved by Mitsunobu reaction. Hydrogenolysis of the cyclized product 34 and subsequent acidic hydrolysis resulted in (2S,3R)-capreomycidine (35) in over 99% ee [35]. Further Ring Closure Methods 1,2-Dihydropyrimidines 38 were synthesized by the reaction of 3-aminoalkyl-2-enimines 36 with chiral aldehydes 37 in the presence of zinc chloride. Subsequent stereoselective reduction of 38 gave tetrahydroderivatives 39 in 99% de [36, 37]. Three-component Biginelli reactions between glycosylated aldehydes 40, keto esters 41, and urea (42) have been carried out in the presence of a mixture of CuCl, acetic acid and BF3 •OEt2 as additives for the synthesis of mono- and bis-C-glycosylated chiral dihydropyrimidinones 43 (due to asymmetric induction of the sugar moiety) with moderate to good (35–80%) stereoselectivities [38]. Ph

Ph Ph Ph (a)

Ph Cbz

Ph

O Cbz

N

Ph

O

(b, c) Cbz

N

Ph

O N

(d) Cbz N

O

O NHBn

TBSO

BocHN (31)

(32)

H2N

O

(e)

O

NH

NBn

NBn

HO

O

OH

O

N H

N NBoc Boc

NBoc

(33)

(34)

2 HCl

NH

(35)

Reagents and conditions: (a) 1. LiHMDS, 2. Me2AlCl, 3. TBSOCH2CH2CH NBn (60%, 3.3:1 dr), (b) N,N '-di-tert-butoxycarbonyl-S-methylisothiourea /HgCl2 /Et3N/DMF (67%), (c) HF/MeCN (81–91%), (d) DIAD/PPh3 / THF (87%), (e) 1. H2/PdCl2, 2. HCl (95%).

Scheme 7.23

Ph R1 R

2

O NHPh +

H

H

NH (36)

R

3

(a)

Ph

Ph N N

R1 R2

(37)

(38)

R3 (b)

H

Ph R1

Ph N

R3 NH

H

R2 (39)

R1 = Me, Bn, CH2CHCH2 R2 = Me, Ph, p-Tol R3 = Ph, BnO Reagents and conditions: Scheme 7.24

(a) ZnCl2/THF (91%, 88 – 97% de), (b) NaBH4/MeOH (quant, 99% de).

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

307

R1 EtOOC R1 CHO

+

R

(40)

H 2N

2

O

O

+

(a)

EtOOC R2

H 2N

(41)

(42)

* NH N H (43)

O

R1 = ribosyl, galactosyl, mannosyl, Ph, 2-(CF3)-C6H4 R2 = Me, ribosyl, galactosyl, mannosyl Reagents and conditions: (a) CuCl/AcOH/BF3·Et2O (35 – 92%, 35 – 80% de).

Scheme 7.25

(R)-N-Boc-2,2-dimethyloxazolidine-4-carbaldehyde was subjected to the Biginelli reaction with ethyl acetoacetate and urea, with Yb(OTf)3 as Lewis acid, furnishing the corresponding pyrimidinones as a 5:1 mixture of 4R,4 S and 4S,4 S diastereomers [39]. Asymmetric Biginelli reactions could also be performed starting from achiral components (benzaldehyde, ethyl acetoacete, and urea) in the presence of CeCl3 or InCl3 as Lewis acid, using chiral diamine or amide ligands as additives. In this way, 4-phenyldihydropyrimidinone derivative 43 (R1 = Ph, R2 = Me) could be obtained with moderate enantioselectivity (8–40%) [40]. 7.1.2.2 Stereoselective Transformation by the Involvement of the Pyrimidine Ring Stereoselective Alkylations In the presence of chiral amines, achiral pyrimidinone 44 was enantioselectively alkylated at 5-position in good yields with moderate (47:53–70:30) enantiomeric ratio. Lithium amides of the chiral amines were prepared with nBuLi, and the pyrimidinone 44 was treated with the chiral base obtained in this way, affording the lithium enolate of the heterocycle (45), which was then reacted with the corresponding electrophile. The enantioselectivity of the alkylation was the highest when (−)-sparteine was used as chiral amine, in toluene or tetrahydrofuran (THF) as solvent, and could be increased by the addition of LiBr. Moreover, a racemic mixture of alkylated pyrimidinones 46 could be enantiomerically enriched by deprotonation with lithium diisopropylamide (LDA), and subsequently reprotonated with a chiral proton source, achieving 53–68% ee [41]. A substituent with deﬁnite stereochemistry can determine the position of the entering electrophile in the C-alkylation of chiral substituted pyrimidinones. Compounds (S)-6 could be stereoselectively alkylated at position 5 by deprotonation with O N

O

O Li N

(a)

HNR2*

N

N

(b)

Me or Bn N

N

Bz

Bz

Bz (44)

Reagents and conditions:

Scheme 7.26

(45)

(46)

(a) LiNR2*/toluene, (b) MeI or BnBr (70 – 92%, er (S:R ) = 47:53 to 70:30).

308

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles O

O

O

N

N

(a)

N R

R

+

N

N

N Bz

Bz

Bz (S )-(6)

(5S,6S )-(47)

(5R,6S )-(47)

R = Me, Bn Reagents and conditions: (a) LDA/THF/MeI or BnBr/–75 °C (71–91%, dr trans:cis = 4:1).

Scheme 7.27

LDA and subsequent treatment with alkyl halides, furnishing a 4:1 mixture of the trans and cis diastereomers 47 [29]. Alkylation of (2S)-1-benzoyl-2-isopropyl-3-methyltetrahydropyrimidin-4(1H)-one was carried out in an analogous way, affording the products with the same stereoselectivity [27]. Considerably higher stereoselectivity (de > 95%) could be achieved in the C-alkylation of 5-alkyl-1-benzoyl-2(S)-tert-butyl-3-methylpyrimidinone at position 5 with various alkyl halogenides. Again, addition of the electrophile to the corresponding enolate preferably took place from the face opposite the tert-butyl group, leading to the 5-dialkylated product with the entering group trans to the tert-butyl group [42]. Asymmetric alkylation of the pyrimidine ring of 48 could be achieved under SAMP ((2S)-1-amino-2-(methoxymethyl)pyrrolidine) control as a temporary chiral auxiliary providing 50 via SAMP-hydrazone intermediates 49. The hydrazone moiety was cleaved off, and the alkylated ketones 51 were then reduced to the corresponding 5-hydroxypyrimidin-2-ones 52 as potential HIV protease inhibitors [43]. Asymmetric induction via 1,5-radical translocation is used for the highly diastereoselective transformation of racemic and enantiomerically pure N-(o-bromo- and iodobenzoyl)-2-tert-butylperhydropyrimidinones 53 with electron-deﬁcient alkenes O

O O Bn

N

Bn N

Bn

(a)

N

N

Bn

Bn

N

N

(b)

(c)

R N

O

N

N

(49)

Bn

N

O N

Bn (d)

Bn

N

O

Bn

N

R

N

R OH

OMe

OMe (48)

O

Bn

(50)

(51)

(52)

R = Me, Bu, CH2CHCH2, Bn, BnCH2

Reagents and conditions: (a) SAMP/CH2Cl2/MS (3A) (93%), (b) 2,2,6,6-tetramethylpiperidine/nBuLi/THF/RX, (c) dimethyldioxirane/acetone/MeCN/H2O or CuCl2/THF/H2O (44–59%, 2 steps), (d) LiAlH4/Et2O (76–84%, 96% de, 76–96% ee). SAMP: (2S )-1-amino-2-(methoxymethyl)pyrrolidine.

Scheme 7.28

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring O

O N

(a)

N

N HC

O

X

O

O N

309

N

N

O

N

+

O

O Y

(53)

(54)

(55)

(56)

X = Br, I Y = COOMe, CN, SO2Ph Reagents and conditions: (a) nBu3NCl/NaCNBH3/AIBN/CH2 CH–Y/tBuOH (27 – 64% for 55, 16–70% for 56, over 95:5 dr). AIBN: azobisisobutyronitrile.

Scheme 7.29

to substituted derivatives 55. Thus, reaction of racemic bromo- or iodoperhydropyrimidinone 53 with methyl acrylate, acrylonitrile or phenyl vinyl sulfone in the presence of a catalytic amount of nBu3 SnCl, NaCNBH4 , and AIBN (azobisisobutyronitrile) resulted in a mixture of addition product 55 and reduced derivative 56, in moderate yields and high stereoselectivity. With bromo derivatives as starting material, the expected product 55 is obtained as the major product, whereas reduced derivative 56 is formed in higher amount from the iodo compound. From enantiomerically pure 53, products 55 are obtained in similar yields and high enantiomeric excess [44]. The palladium-catalyzed asymmetric allylic alkylation of barbituric acid derivatives with chiral ligands has been described. The reaction of 1,5-dimethylbarbituric acid (57) with allyl acetate (58) resulted in the 5-allyl substituted product 59 in moderate enantiomeric excess in the presence of Pd(acac)2 as catalyst and 60 as phosphine ligand [45]. Low enantioselectivities (0–37% ee) were achieved in the reaction of barbiturate 61 with allyl acetate (58) in the presence of chiral phosphine ligands 65 or 66. Using cyclopentenyl carbonate as the allylating agent, the product 64 was obtained in higher yields and enantioselectivities; however, the diastereomeric ratio was low [45]. Asymmetric allylic alkylation was also used for preparation of stereoisomeric mixtures enriched with one of the isomers of the narcotic methohexital, when

HN

OH t Bu

O

O N

O

+

(a)

(58)

Reagents and conditions: Scheme 7.30

HN O

O

(57)

N N

OAc O

(59)

Ligand:

N

Ph2P

H

(60)

(a) Pd(acac)2 / DBU / toluene / CH2Cl2 / ligand (77%, 34% ee).

310

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles O O HN HN

N

(a)

+

O

O

OAc

(61)

O

O

(58)

Reagents and conditions:

N

(62)

(a) h3C3H5PdCl2./CH2Cl2 or DMSO/ligand (42–72%, 0–37% ee).

Scheme 7.31 O

O HN O

HN

N

OCOOMe

+

O

(a)

N

O

O H

(61)

(63)

Reagents and conditions:

(64)

(a) Pd2dba3·CHCl3/CH2Cl2 or DMSO/ligand/54–93%, dr :1.1:1 to 2.51, 43–90% ee. PPh2 Ph2P

PPh2 Ph2P Ligand:

NH HN O

(65)

NH HN

or O

O

O

(66)

Scheme 7.32

reactions of 5-allyl-5-(2 -hex-3 -ynyl)-1-methylbarbituric acid with allyl acetate were performed under various conditions. Ratio of the isomers mainly depended on the phosphine ligands used [46]. Halogenation, Hydroxylation Perhydropyrimidinone 67 could be halogenated via its enolate, formed by treatment with LiHMDS, using tosyl chloride, benzenesulfonyl bromide, or iodine as the halogenating agent. The chlorination reaction proved to be more selective than the bromination. Shorter reaction times (15 min) generally, favored the formation of the cis products 69, while after longer reaction times (hours) a reversal of the stereoselectivity was observed for both chlorination and bromination. The cis adducts 69 are the kinetically preferred products, and the trans derivatives 68 are the thermodynamically preferred compounds. In contrast, iodination led to the trans isomer as the major product even after a short reaction time [47].

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring X O Ph

(a) N

N

X O

O Ph

Cbz

N

(67)

N

+ Cbz

Ph

N

N

Cbz

(69)

(68)

X = Cl, Br, I Reagents and conditions: (a) LiHMDS/THF/TsCl or PhSO2Br or I2 (74–98%, dr = 10:90 to 85:15).

Scheme 7.33

O N

O N

(a)

OH

N Bz

N Ph

(S )-(10)

Bz

Ph

(5R,6R )-(70)

N S O O O (71)

Reagents and conditions: (a) 1. LDA, 2. oxaziridine 71.

Scheme 7.34

Enolization of pyrimidinone (S)-10 with LDA followed by hydroxylation with oxaziridine 71 resulted in the exclusive formation of hydroxy compound (5R,6R)-72 [30]. 7.1.3 Piperazines

Substituted piperazines with deﬁned conﬁguration of the substituents are synthesized in most cases starting from enantiomerically pure starting materials. A method quite frequently applied for synthesis of piperazine ring is intramolecular amide coupling between amino and carboxylic acid ester moieties, resulting in ketopiperazines, which can be further functionalized. Further widely employed reactions for cyclization are intramolecular nucleophilic substitution, imine formation or cycloaddition. Asymmetric transformations of the piperazine ring could also be accomplished by alkylations with various electrophilic or nucleophilic reactants. 7.1.3.1 Formation of the Piperazine Ring Ring Closure by Lactam Formation The following scheme presents three approaches for the synthesis of diketopiperazines (DKPs) via key intermediates N-monobenzylglutamate 2 (prepared from dimethyl glutamate 1) and chloroacetamide 5. In the ﬁrst approach, N-benzyl-protected derivative 2 was transformed to dipeptide 3, and subsequently cyclized to piperazine derivative 4. As an alternative pathway to 4, compound 2 was acylated with chloroacetyl chloride to 5, which was

311

312

H2N

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

COOMe H HCl

COOMe

(a)

COOMe (b) NH H Bn COOMe

(1)

Cbz NH

H N

(c)

COOMe N H Bn COOMe (3)

O

(2)

O

N Bn (4)

O H COOMe

(d) (c)

R:

Cl

– CH3, – C4H9,

O

– CH2C6H4– 4OCH3, – CH2CH2Ph, cyclohexyl, phenyl,

N3

N Bn (5)

COOMe H

(e)

COOMe

O N Bn

COOMe H COOMe

(6)

(f)

R N

– C(CH3)3 O

N Bn

O H COOMe

(7) Reagents and conditions: (a) 1.C6H5CHO/NEt3/pentane/Na2SO4/rt, (91%), 2. NaBH4/MeOH/ 0 °C (93%), (b) Cbz-glycine/DCC/THF/CH2Cl2/rt, (c) H2/Pd–C/MeOH/rt (84% from 3, 87% from 6), (d) ClCH2COCl/NaHCO3/CH2Cl2/rt (73%), (e) NaN3/acetone/rfx (99%), (f) RNH2/CH3CN in case of cyclohexylamine: CH3CN/48 h/reflux, in case of aniline: DMF/16 h / 155 °C (52–97%). Scheme 7.35

reacted with NaN3 , and the azide 6 formed was hydrogenated to afford piperazine 4. According to the third approach, the chloroacetyl derivative 5 was treated with various primary amines, resulting in the cyclized products 7 in one pot [48]. Principally in the same way as in the ﬁrst approach above, a series of (2R,5S)- and (2S,5S)-2-hydroxymethyl-5-alkylpiperazines can be prepared starting from enantiomerically pure serine without any racemization. Commercial amino acids were converted into the corresponding N-benzyloxycarbonyl derivatives 8, which were treated with (S)- or (R)-serine methyl ester hydrochloride (9) to give dipeptides 10 via the mixed anhydride coupling method. After deblocking of the benzyloxycarbonyl group, DKPs were formed in dry methanol by heating (65 ◦ C) for ﬁve days. DKPs 11 were reduced to piperazines 12 with an excess of LiAlH4 in reﬂuxing THF [49]. DKP 18 was synthesized from N-sulﬁnyldiamino ester 13 via dipeptide 17, which was prepared by coupling of the differently protected derivatives 15 and 16 of the same amino acid [50]. Dilactim ethers 22, known as Sch¨ollkopf chiral auxiliaries widely used for asymmetric synthesis of amino acids, were prepared from amio acids 19 in

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring OH R1 (a) + Cbz N * COOH HCl.H2N COOMe 2 R (8) = Cbz-Sar-OH, Cbz-Val-OH Cbz-Leu-OH Cbz-Ile-OH

OH

R1 Cbz

(9)

N CO NH R2

* COOMe

(b, c)

313

H N *

O

OH

R1 N O R2 (11)

(10)

(d)

H N

R1 = H, i Pr, i Bu, (S )-sBu R2 = H, Me Reagents and conditions: (a) EtOCOCl/4-methylmorpholine/EtOAc (43–88%), (b) 10%Pd–C/cyclohexene/MeOH, (c) MeOH/65 °C/110 h (36 – 93%), (d) LiAlH4/65 °C/72 h/THF (48 – 85%).

OH

R1 N R2 (12)

Scheme 7.36

N

p-Tol

O S

NH

COOMe ( )4 OTS NHCbz (13)

(a, b)

Boc N NHCbz

COOH

(c)

COOMe (d) (14)

Boc NHCbz

(15)

N

Boc NH2 COOMe

(e, f)

Boc N NH2

COOMe NH N Boc

O

(17) g

(16) Boc H N N

O

N N O H Boc (18) Reagents and conditions: (a) 1. H3PO4/MeOH/H2O, 2. K2CO3, (b) Boc2O/Et3N/dioxane/H2O (82%), (c) LiOH/THF/H2O (100%), (d) Pd–C/H2 (100%), (e) BOP/DIPEA/CH2Cl2, (f) Pd–C/H2 (85% 2 steps), (g) DMF/rfx/40 h (22%) or KCN/DMF/80 °C/4 d (29%).

Scheme 7.37

three steps. Reaction with triphosgene was followed by treatment of the resulting oxazolinedione 20 with ethyl glycinate to give piperazinedione 21, which was subsequently transformed to dilactim ether 22 [51, 52]. The enantiomer of 22 could also be prepared via the same route starting from the enantiomer of the corresponding amino acid [53–55]. Synthesis of the naturally occurring DKPs (−)-phenylhistine (28, R = Bn) and (−)-aurantiamine (28, R = iPr) begins with the coupling of amino acid 23 and phosphinyl glycine 24. Phosphinyl ester dipeptide 25 was then reacted with formylimidazole 26 under Horner–Emmons coupling conditions. Finally, in situ

314

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles O

NH2 R1

O

(a)

COOH

O

(19)

(b) R1

N H

O

(20)

H N

O

N H

R1

(c) R2O

N

OR2

N

R1

(S )-(22)

(21)

R1 = i Pr,t Bu R2 = Me, Et Reagents and conditions: (a) triphosgene/THF (99%), (b) 1. NH2CH2CO2Et/CHCl3/EtN3/THF/−70°C, 2. tolueneor xylene/rfx (70%), (c) R23OBF4/CH2Cl2 (90%).

Scheme 7.38

O R

N

OH NHBoc + (23) MeO

R NH2 PO3Me2 O

(a)

NHBoc

O MeO

NH PO3Me2 O

(24)

N Ts

OHC (26)

NHBoc

R

NH N

O MeO

NH

O

(b)

(25)

(27) (c)

R = Bn,i Pr

O R

Reagents and conditions: (a) HOBT/EDC/HCl/CH2Cl2 (80–87%), (b) DBU/CH2Cl2 (51–52%), (c) 1.TFA/CH2Cl2 (90–92%).

NH N

HN

NH

O (28)

Scheme 7.39

ring closure of 27, during hydrolysis of the Boc-protecting group, resulted in the products 28 [56]. Analogous to the second approach shown in Scheme 7.35, ethyl or menthyl (2S)-5,6-dioxo-4-[(1R)-1-phenylethyl]piperazine-2-carboxylates were synthesized starting with ring opening of ethyl or menthyl (2R)-1-[(1R)-1-phenylethyl]aziridine2-carboxylate with azide as nucleophile in aqueous acidic media in the presence of a catalytic amount of AlCl3 • 6H2 O, furnishing stereoselectively the corresponding (2S)-2-azido-3-[(1R)-1-phenylethyl]aminopropanoates, which were made to react with methyl oxalyl chloride, followed by catalytic hydrogenation. The absolute conﬁguration, determined by X-ray crystallography, showed that the ring opening proceeded with complete inversion at the reaction center [57]. Monolactim ether 33, widely used by Sandri et al. as a chiral auxiliary in syntheses of amino acids, was prepared according to the third approach shown in Scheme 7.35. L-Valine methyl ester (29) was benzylated to 30, followed by N-acylation with chloroacetyl chloride. Ester hydrolysis of 31 and cyclization with ammonia gave 33 after treatment of 32 with Et3 OBF4 [58].

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring OMe

OMe

O

OMe (a)

O

O

(b) N Ph

(29)

(30)

OEt NH

(d)

N

N

Cl

NH2 Ph

(c)

O

NH

315

O

Ph

N O

Ph

(32)

(31)

O (33)

Reagents and conditions: (a) PhCH2Br /pyridine /CH2Cl2 (85%), (b) ClCH2COCl/TEA /CH2Cl2 (96%), (c) 10 M NH3 in EtOH (> 98%), (d) EtO3BF4 /CH2Cl2 (75%).

Scheme 7.40

Applying the third approach shown in Scheme 7.35, piperazino-piperidine-based CCR5 antagonists were synthesized via reductive amination of 4-triﬂuoromethylacetophenone with various l-amino acids, followed by N-acylation with chloroacetyl chloride, and subsequent cyclization in the presence of 1-Boc-protected-4substituted-4-aminopiperidines [59]. By the same strategy, the four possible stereoisomers of the N-acetyl derivative of the natural marine compound Etzionin were synthesized to carry out a stereochemical analysis by comparing the natural compound and the stereoisomers synthesized from enantiomerically pure starting materials. Thus, for synthesis of the (S,R) diastereomer, methyl (2S)-2-[(bromoacetyl)amino]-3-phenylpropanoate was submitted to nucleophilic displacement with methyl (3R)-3-aminododecanoate to give the corresponding peptide and subsequently cyclized [60]. DKPs 37 were prepared from protected amino acid amides 34 by the addition to methyl 3,3,3-triﬂuoropiruvate (35). The adduct dipeptides 36 were then converted to the corresponding 3-hydroxy-3-triﬂuoromethyl-2,5-diketopiperazines 37, which are used as homochiral electrophilic synthons for α-triﬂuoromethyl amino acids [61]. The last step in the total synthesis of the cyclotryptophan alkaloid asperazine (39) is the formation of two DKP rings. A series of ﬁve reactions could be accomplished in a single step by heating 38 at 200 ◦ C under argon. The reaction gave 39 and two stereoisomers in 70:3:2 ratio; after separation, 39 was obtained in 34% yield. However, the conversion of 38 to 39 was more efﬁcient when two separate steps were applied. First, removal of the Boc-protecting groups, followed by heating of the crude deprotected reaction mixture in butanol in the presence of acetic acid, gave 39 in 59% yield [62].

R

H

NH2

O + NCbz (34)

COOMe

F3C O

(35)

(a)

F3C OH HN COOMe (b) H R O NCbz (36)

H

R H N

O

N H

O OH CF3

(37)

R = Me, i Pr, i Bu, Bzl Reagents and conditions: (a) CH2Cl2, (b) H2 /Pd–C/ MeOH (69 – 86%).

Scheme 7.41

316

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles Ph

H Ph O

MeOOC

Boc N

H

Boc N H

N

O

H N H

H H N

(a or b)

H N BocHN

H

O

HN

O

H N

COOMe

H Ph

HN NH

O

H

Ph

(38)

O

(39)

Reagents and conditions: (a) 200 °C, 4h (34%), (b) 1. HCOOH, 2. AcOH, n BuOH, 120 °C (59%).

Scheme 7.42

Analogous to DKP formation, monoketopiperazines are synthesized via intramolecular amide coupling of N-aminoethyl substituted amino acids. Thus, enantiomerically pure 2,6-dimethylpiperazin-5-ones 45 were synthesized by employing a diastereoselective triﬂate alkylation to set the required stereochemistry. The reaction sequence started with the conversion of N-Boc-l-alanine (40) to dibenzylamide (41) through the mixed anhydride. Removal of the Boc group, followed by borane-methyl sulﬁde reduction, gave diamine 42, which was alkylated with the triﬂate (43) of methyl (R)-lactate. The alkylation proceeded with inversion to afford ester 44. Hydrogenolysis of 44 in the presence of HCl resulted in monodebenzylation and partial cyclization, which was completed by heating in the presence of p-toluenesulfonic acid to ketopiperazine 45. Reduction of the oxo group with LiAlH4 , followed by debenzylation with Pearlman’s catalyst, gave O BocHN

(a)

COOH

(b)

BocHN

(40)

NBn2

H2N

(41)

NBn2 (42)

MeOOC

(d)

NBn2

(44)

N

O

H N

(e)

N H

N H

(45)

(46)

Reagents and conditions: (a) 1. ClCOOi Bu //Et3N / THF, 2. Bn2NH (82%), (b) 1. TFA/CH2Cl2, 2. BH3·DMS / THF (84% for 2 steps, 98% ee), (c) CH2Cl2 / Et3N (94%), (d) 1. Pd–C / H2 / HCl / EtOH, 2. TsOH / EtOH / rfx (81%), (e) LiAlH4 / THF (93%, 98% ee), (f) Pd(OH)2 / H2 / MeOH (91%, 98% ee).

Scheme 7.43

COOMe

(43)

Ph H N

(c) TfO

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

317

(2S,6S)-2,6-dimethylpiperazine (46). The (R,R) enantiomer was prepared in an analogous way from N-Boc-d-alanine and methyl (S)-lactate [63, 64]. N-(2-Diallylamino-3-hydroxyalkyl)-substituted amino acid esters were deallylated to primary amines under mild conditions with (PPh3 )3 RhCl. While tert-butyl esters could be easily deprotected to the corresponding primary amine, methyl esters such as 47 spontaneously cyclized to piperazine 48 after deprotection [65]. As a building block for the synthesis of natural products TAN1251C and D, disubstituted piperazine 32 was synthesized from carbamate 49 obtained from l-tyrosine. Reduction of 49 with LiAlH4 , followed by Boc protection and subsequent Swern oxidation of the corresponding primary alcohol, gave aldehyde 50, which was condensed with O-benzyl-l-tyrosine under reductive conditions. After deprotection of the Boc group, amine 51 was cyclized with NaOMe to piperazinone 52 [66]. Piperazine-2-carboxylic acid ester enantiomers 57 were prepared from l- or d-serine ester 53 via the azide intermediate 54, obtained by Mitsunobu reaction. After deprotection of 54, the amino compound was alkylated with the triﬂate (55) of dimethyl-d-malate to afford l-aspartic acid derivative 56 via an SN 2 reaction. Reduction of the azido group in 70 resulted in spontaneous lactam formation to piperazine derivative 57 [67]. O N nPr

(a)

H N

HN NH

nPr

COOMe

OH

OH (47)

(48)

Reagents and conditions: (a) (PPh3)3RhCl/MeCN/H2O (47%). Scheme 7.44

EtOOC

N CHO Boc

NH COOMe (49)

(50)

NH

(f)

MPMO

(d – e)

(a – c)

L-tyrosine

OMPM

OMPM

OMPM

N H

NH COOMe

OBn

(51)

OBn

N O (52)

Reagents and conditions: (a) LiAlH4 /THF (82%), (b) Boc2O/THF–H2O (99%), (c) (COCl)2 /DMSO/Et3N, (d) O -Bn-L-tyrosine methyl ester / NaBH3CN /DMF (90%), (e) ZnBr2 /CH2Cl2 (99%), (f) NaOMe/THF (85%).

Scheme 7.45

318

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles COOMe COOMe TfO

NH2 X

Y

NHBoc N3 X Y

(53)

(54)

(a)

OH

COOMe

COOMe HN

(55) (b)

COOMe N3

X

O

HN

(c)

NH

X Y (57)

Y (56)

X = Cbz, Y = H or X = H, Y = Cbz Reagents and conditions: (a) 1. Boc2O/H2O/dioxane, 2. HN3 /(i PrNOOC)2 /PPh3 (39–67%), (b) 1. TFA/CH2Cl2, 2. 55/CH2Cl2 /2,6-lutidine (61–73%), (c) PPh3 /THF (49–85%).

Scheme 7.46

Viso et al. employed chiral sulﬁnamides for the synthesis of enantiomerically pure substituted piperazines. 1-Benzyl-2,3-disubstituted piperazines 61 were obtained by treatment of N-sulﬁnyl-N-benzylamino alcohols 58 with diethyl oxalate and NaOMe, followed by borane reduction. Ring closure of 58 gave morpholine derivative 60 as a side-product, which could be transformed to piperazine 59 by NaOMe treatment [68, 69]. (2S,3S)-2,3-bis[(benzyloxy)methyl]piperazine was prepared from (S,S)-threitol1,4-dibenzyl ether also via a 1,2-diamino intermediate by a ﬁve-step reaction (c)

pTol

O S

O NH

NHBn

(a or b)

OH

R

O pTol

HN

N Bn OH

R

(58)

+

(59)

R1 = Et, (CH2)2Ph, i Pr, Ph, 1-Naph

O S R

NH

Bn N

O O (60)

(d)

HN R

N Bn OH (61)

Reagents and conditions: (a) (COOEt)2 / NaOMe/CH2Cl2/MeOH, (b) 1. (COOEt)2 / CH2Cl2 2. NaOMe/MeOH (77 –90% for 59, 10–15% for 60), (c) NaOMe /MeOH, (d) BH3·DMS/THF (60 –84%).

Scheme 7.47

O

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

sequence: (i) mesylation, (ii) nuclephilic displacement with azide, (iii) LiAlH4 reduction, (iv) cyclization with diethyl oxalate, and ﬁnally (v) reduction of the oxo groups [70]. 2,5-Diketopiperazine derivatives 65 were synthesized through Ugi four-center three-component reactions from commercially available dipeptides 62, aldehydes 63, and isocyanides 64 in 2,2,2-triﬂuoroethanol as solvent in moderate to good yields. A new chiral center was created at the carbon originating from the aldehyde; the relative stereochemistry of the resulting diastereomers was not determined. The best observed diastereomeric ratio was 6:1. The reaction time and yield could be improved by the application of microwave irradiation [71]. Trisubstituted DKPs were synthesized by intramolecular amidation of dipeptide esters, obtained in four-component Ugi reactions. Thus, the imine intermediate 67 formed in situ from (R)-leucine methyl ester (66) and benzaldehyde was reacted with tert-butylisonitrile and (R)-indanyl glycine 68. The dipeptide ester 69 formed was then treated with 4 N HCl in dioxane, which resulted in removal of the Boc-protecting group and partial cyclization, which was completed by addition of triethylamine to give a 1:3 mixture of diastereomers 70 and 71. The partial stereocontrol originates from the attack of the isonitrile on the less hindered face of the imine [72]. As an alternative route to isomeric DKPs, secondary amine 95 was prepared ﬁrst via a four-center three-component Ugi reaction and subsequent hydrolysis. Then it was acylated with (R)-Boc-indanyl glycine 91 through mixed anhydride 96. Dipeptide intermediate 97 was then cyclized to 98 [73]. Ring Closure by Intramolecular Nucleophilic Substitution O-protected N-sulﬁnyl diaminoalcohols 76 were acylated with chloroacetyl chloride to 77 and subsequently cyclized to N-sulﬁnylpiperazines 78. The sulﬁnyl group was eliminated by treatment with NaH, affording unsaturated derivative 79 [69].

O R

H N

R2

N

O

1

H N

H2N O

COOH +

R3 CHO

+

R4 NC

Gly-L-Leu L-Ala-L-Ala L-Ala-L-Pro L-Leu-Gly L-Phe-L-Ala

R1

O

R3

R2

(62):

(a or b)

(63)

(64)

(65)

HN

R4

R3 = Ph, 4-F-Ph, i Pr R4 = t Bu, Bn, TsCH2

Reagents and conditions: (a) −40 °C to rt / CF3CH2OH / 33 – 52 h (24 – 87%, dr 2:1 to 6:1) or (b) MW (30 W) 100 °C /CF3CH2OH-BmimPF6 / 15 min (42–58%, dr 2 : 1 to 3 : 1).

Scheme 7.48

319

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

320

Ph NH2

+

MeOOC

(a)

Ph CHO

MeOOC

i Pr

COOH

i Pr

(R )-(66)

(R )-(68)

O R

(b)

NHt Bu

N BocHN MeOOC

NHBoc

(67)

Ph

O

t BuNC

N

NHt Bu

N R

HN

O

Ph

O

Ph R

+

O

O R

R O

i Pr

(69)

NHt Bu

N S

HN O

i Pr

(70)

i Pr

(71)

Reagents and conditions: (a) Et3N / MeOH, (b) 1. 4 N HCl/dioxane, 2. Et3N/dioxane.

Scheme 7.49 Ph NH2 MeOOC

PhCHO +

+

t BuNC

(a)

O HOOC

i Pr

i Pr (72)

(R )-(66)

COOH

NHt Bu

HN

O

O

(b)

O NHBoc

NHBoc (R )-(68)

Ph

O

(72)

NHt Bu

N

Ot Bu BocHN MeOOC

(73)

Ph

O

(c)

R HN

O

NHt Bu

NS O

S O

i Pr (74)

i Pr

(75)

Reagents and conditions: (a) MeOH/−30 °C to rt, (b) i PrOCOCl/N-Me-morpholine/THF, (c) 1.4 N HCl/dioxane, 2. HCl/MeOH (57%).

Scheme 7.50 O pTol

S

O NH R

NHBn

(a)

pTol

S

Cl NH

OTBDMS R

(76)

(77)

O

O NBn

(b)

OTBDMS

O

O S N pTol R

N Bn

(78)

OTBDMS

(c)

N

N Bn OTBDMS

R (79)

R1 = Et, (CH2)2Ph, i Pr, Ph, 1-Naph Reagents and conditions: (a) ClCH2COCl / EtOAc:NaHCO3 (1:1) satd, (52 – 90%), (b) Cs2CO3 / DMF (74 – 92%), (c) NaH / THF (73 – 87%).

Scheme 7.51

1-Benzyl 2-methyl (2S,3R)-3-alkyl-5-oxopiperazine-1,2-dicarboxylates were prepared in an analogous way from 1N-p-tolylsulﬁnyl derivative of methyl (2R, 5R)-5-methyl-2-phenylimidazolidine-4-carboxylate [50].

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

321

A diamino derivative was cyclized to piperazine in an unexpected way in the following reaction. The treatment of bistosylamide 80 with ethylene glycol ditosylate did not give the expected Richman–Atkins cyclization. Instead, chiral piperazine 81 was formed as a result of nucleophilic attack of the central benzylic amine on the electrophilic tosylate in ethylene glycol ditosylate, followed with expulsion of the C-3 tosamide unit either before or during the cyclization [73]. Although, generally, Mitsunobu reactions involving a nitrogen nucleophile require an acidic hydrogen (pK a < 13), there are examples of intramolecular Mitsunobu reactions of amino alcohols to obtain heterocycles. Accordingly, cyclization of 85 by treatment with PPh3 /diethyl azodicarboxylate (DEAD) resulted in benzylated piperazine 86. Amino alcohol 85 was prepared from (R)-1-aminopropan-2-ol (82) by reductive alkylation and the subsequent coupling of 83 with N-Boc-l-alanine providing 84, which was reduced to 85 [63]. The method could be extended to the preparation of monomethylpiperazines. The ﬁrst step was the coupling of N-Boc-d-alanine (87) with N-benzylethanolamine to amide 88. Subsequent hydrolysis of the Boc group followed by the Mitsunobu reaction gave methylpiperazinone 89, which was reduced to methylpiperazine 90 [63]. Cyclization via Imine/Enamine Formation The synthesis of tetrahydropyrazinone 93 was based on the coupling of α-aminoketone 91 with N-Boc-l-alanine pivalic acid mixed anhydride to 92. Compound 91 was obtained from (R)-valine in a three-step reaction sequence (i) N-protection with Boc, (ii) transformation of the carboxylic group to dimethyl amide, followed by (iii) reaction with phenylmagnesium bromide. After acidic deprotection of 92, the pyrazine ring was formed by intramolecular

NHTs NHTs

BnN

(a)

BnN

(80)

NTs

(81)

Reagents and conditions: (a) 1. NaH/THF/∆, 2. (CH2OTs)2 /DMF/120 °C (32%).

Scheme 7.52 Ph Ph (a)

H2N

OH

Ph

H N

OH

(b)

N

BocHN

Ph (c) OH

H 2N

N

OH

O (82)

(83)

(84)

(d)

(85)

N N H (86)

Reagents and conditions: (a) 1. PhCHO/MgSO4 / THF, 2. NaBH4 / EtOH (57%), (b) CDI/CH2Cl2 / N-Boc-L-Alanine (80%), (c) 1. TFA/CH2Cl2, 2. BH3·DMS / THF (76%, 2 steps), (d) DEAD / PPh3 / THF (66%).

Scheme 7.53

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

322

O O

(a)

Bn N

(b)

NHBoc

(87)

(88)

(c)

OH

Bn N

NH

Bn N

NHBoc

HO

O

(89)

NH (90)

Reagents and conditions: (a) CDI/CH2Cl2 /N-benzyl-ethanolamine (81%), (b) 1. TFA/CH2Cl2, 2. DEAD/PPh3 /THF (62%), (c) LiAlH4 /THF (88%). Scheme 7.54

NH2

NHBoc

(a)

OO

HO

O

O

Ph

(R )-valine

NH O

(b) O

NHBoc

Ph

(91)

O NHBoc (92)

Boc O N

(c, d)

Ph

N (93)

Reagents and conditions: (a) 1. (Boc)2O, 2. Me2NH·HCl/TBTU, 3. PhMgBr (78%), (b) HClg /EtOAc (95%), (c) 1. HClg /EtOAc, 2. K2CO3 (86%), (d) (Boc)2O/0 °C/THF (84%, trans :cis = 20:1).

Scheme 7.55

condensation between the oxo and amino groups, which was transformed to Boc-protected derivative 93 as a 20:1 mixture of the trans and cis diastereomers [74, 75]. In an analogous way, a derivative of 121 without methyl substituent was also prepared using N-Boc-glycine pivalic acid mixed anhydride instead of alanine derivative as the coupling partner of 119 [76]. Synthesis of piperazinecarboxylic ester 98 was achieved by starting with the coupling of protected l-tyrosine 94 and 2-amino-3,3-diethoxypropionate (95). The dipeptide 96 obtained was then cyclized to unsaturated piperazine 97 by treatment with TFA. Subsequent catalytic hydrogenation under acidic conditions resulted selectively in the single diastereomer 98. When the acid was omitted, no reduction of the double bond occurred, and 99 was isolated, which could be reduced to 98 with NaCNBH3 in the presence of HCl [77]. Reaction of the primary amino moiety in 100 with aldehydes and subsequent reduction of the imine intermediate with NaBH4 gave alkylamino derivatives 101. Reductive cyclization of 101 with aqueous glyoxal solution in the presence of NaCNBH3 as reducing agent provided 2-substituted-1,4-piperazines 102 [78]. Diastereomeric 3,5-disubstituted piperazines 104 and 105 were formed in high yields but in moderate ratios when the corresponding β-keto esters 103 were hydrogenated at 45 ◦ C and 45 psi with Pd/C as catalyst. Removal of the Cbz protecting group and reductive amination took place in a one-pot reaction. Although in slightly lower yield, the piperazine ring was also formed in two steps involving

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring O CbzHN

OH

OEt

O

+

CbzHN

OEt OEt

H2N

Ar

O

(a)

(94)

H HN

OEt OEt

N H

Ar

(95)

Ar = p -HOC6H4CH2

OEt

O

(96)

COOEt

(c)

(b)

NH

Ar

H O (98)

Cbz

NH

Ar

(e)

H O (97)

COOEt

HN

COOEt

N

(d)

NH

Ar H O (99)

Reagents and conditions: (a) DCC / HOBT/CH2Cl2 (100%), (b) TFA / H2O (70%), (c) Pd(OH)2 / H2 / HCl then neutr. (70%), (d) Pd(OH)2 / H2 / EtOH, (e) NaCNBH3 / HCl / MeOH (70%).

Scheme 7.56 Ph N H

Ph Ph NH2 (100)

Ph

(a)

N H

Ph HN

(b)

R

(101)

Ph

N N

R

(S )-(102)

R = Ph, pentyl Reagents and conditions: (a) 1. RCHO/MgSO4 / MeOH, 2. NaBH4 (83 – 94%), (b) (CHO)2 / NaCNBH3 / MeOH (85 – 87%).

Scheme 7.57

removal of the Cbz group, by catalytic hydrogenation and reduction of the resulting intermediates with NaBH3 CN in the presence of ZnCl2 [79]. The enantioselective synthesis of the antipode (111) of the pyrazinone alkaloid hamacanthin A was based on Sharpless asymmetric dihydroxylation of vinylindole 106 with asymmetric dihydroxylation (AD)-mix-α to give (S)-indolyl-1,2-ethanediol 107, which was then transformed to 3-indolylazidoethylamine 108 in seven steps. Compound 108 was coupled with 6-bromo-3-indolyl-α-oxoacetyl chloride to azide

323

324

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles R1

R1 Cbz

O

O

NH

NH

O OR2

R1 NH

HN

COOR2

+

O

NH

HN

COOR2

O (103)

(105)

(104)

R1 = Me, Bn R2 = Me, Et Reagents and conditions: Method A: H2 /Pd-C, 45 psi, 45 °C, 48–72 h (89–97%); Method B: 1. H2 /Pd–C/25 °C/2 h, 2. NaBH3CN/ZnCl2 /25 °C/3 h (64–80%) (dr 1.7:1 to 5.7:1).

Scheme 7.58

109, followed by an intramolecular Staudinger-aza-Wittig cyclization through intermediate 110 [80]. For the synthesis of the related alkaloids hamacanthin A [81], hamacanthin B [81, 82], antipode of cis-dihydrohamachantin B [81, 83], and the antipode of cis- and trans-dihydrohamachantin A [84], a similar approach was applied. OH

Br

N Ts

Br

O

Br

Br

Ts N O

(c)

N3 Br

(109)

(d)

N-P(Bu)3

N H (110)

H N O

Br

NH O

N H

(b)

N Ts (108)

Br

NH O

N3

7 steps

N Ts (107)

(106)

H N

NH2 OH

(a)

Br

H N N

Br

N H

(111)

Reagents and conditions: (a) AD-mix-a(92%), (b) 6-bromo-3-indolyl-a-oxoacetyl chloride/Et3N /DMF (74%), (c) 1.n Bu3P/ toluene/rfx, 2. reflux (97%), (d) NaOH /MeOH /rfx (88%).

Scheme 7.59

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

325

Piperazine-2-carboxylic acid is a conformationally restricted nonproteinogenic amino acid with medicinal applications. It is widely used as a building block in a number of bioactive compounds [85–87]. Synthesis of orthogonally protected (S)-piperazine-2-carboxylic acid 118 has been achieved in four steps from N-Boc-l-serine β-lactone 113, obtained from protected l-serine 112 via a Mitsunobu reaction, by utilizing an extension of the Vederas’ serine lactone ring-opening methodology. Thus, treatment of lactone 113 with allylamine gave a mixture of amino acid 114 and amide 115. Cbz protection of 114 to 116 and subsequent ozonolysis gave piperazine 117 via the corresponding formyl intermediate. Compound 117 was then reduced chemoselectively to (S)-piperazinecarboxylic acid derivative 118 [88]. Cycloaddition The key step for the synthesis of the piperazinone ring system of pseudotheonamide A1 (123) and A2 (124) was intramolecular [3 + 2] cycloaddition of the appropriately oriented azido group and the α,β-unsaturated ester moiety in compound 121, which was obtained from (R)-α-azido acid 119 and p-aminophenylalaninol 120 in three steps. The target molecules were then obtained as a 3:7 mixture of the corresponding diastereomers by reduction of 122 [89]. Similarly, enantiomerically pure piperazines were prepared via intermolecular [3 + 2] cycloaddition of an azide to a C–C double bond in N-allyl-1,2-azidoamines, which were prepared from 1,2-amino alcohols. The corresponding cycloadduct triazolopyrazine derivative was then reacted with acyl chlorides, carbamoyl chlorides, or alkyl halides to obtain halomethylpiperazines [90, 91].

NH

OH O

(a)

Boc

NH COOH (112)

Boc NH

(b)

Boc

O

(113)

NH COOH

OH NH + Boc NH CO

(114)

(115)

52%

41%

(c)

Cbz N Boc

NH COOH

Cbz N

(d)

HO

(116)

N COOH Boc (117)

Reagents and conditions: (a) DEAD/Ph3P/ THF, (b) CH2=CHCH2NH2 /MeCN, (c) CbzCl/NaHCO3 /H2O/acetone (97%), (d) 1. O3, 2. Me2S, (e) Et3SiH/BF3(OEt)2 (80%).

Scheme 7.60

(e)

Cbz N COOH N Boc (118)

326

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles OMe

COOH N3

OH

+ MeO

(119)

COOEt

HN O

O

NH

(121) OMe

(b)

OMe

H COOEt

HN O

(a)

N3

(120) OMe

COOEt

HN

3 steps

NH2

NH

H +

COOEt

HN O

NH

(3:7) (122)

(123)

(124)

Reagents and conditions: (a) Et3N (catalytic) / toluene/rfx (56%) (b) NaCNBH3 /MeOH / 5% HCl (90%).

Scheme 7.61

Miscellaneous Methods for Ring Closure The asymmetric synthesis of 2-vinylpiperazines 127 has been described from oleﬁns 125 and 1,2-bis[benzylamino] ethane 126 in the presence of a chiral Pd(0) complex. On using Pd2 (dba)3 as the Pd source and [bicyclo[2.2.1]heptane-2,3-diylbis(methylene)]bis(diphenylphosphine) (BHMP) as chiral phosphine ligand, moderate yields (28–68%) and enantioselectivities (22–42% ee) were achieved [92]. The cyclized product was obtained in 87% yield and 60% ee by the application of BINAP as ligand [93], while the combination of [PdCl(η3 -C3 H5 )]2 and phosphinooxazinane 162 gave vinylpiperazine 161 in 50% yield and 70% ee [94]. Kukula’s method for synthesis of piperazine-(2S)-carboxylic acid 135 consists of three simple steps: (i) coupling of the precursor 129 with (S)-proline methyl ester (130) as a chiral auxiliary, (ii) heterogeneous diastereoselective hydrogenation of amide 131 via intermediate 132 to give diastereomers 133 and 134 in a ratio of 4:1, and (iii) acidic hydrolysis of the tricyclic amide 133. The diastereoselectivity obtained in the hydrogenation of the substrate over a Pd catalyst was considerably higher than over Rh, Ru or Pt catalysts. Separation of the two diastereomers from the hydrogenation product by crystallization is possible [95]. With (R)-phenylglycinol (137) as the chiral inductor, 2,3-dialkyl-substituted piperazines were synthesized via hydroxyethylenediamine precursor 139, which was obtained by reduction of oxazino-oxazine 138. Compound 139 was condensed with α-dicarbonyl compounds (glyoxal or 1-phenyl-1,2-propanedienone), which afforded bisoxazolidine 140 or 143 as single diastereomers, while the reaction with

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

327

X Ph P R2

R1

R1

HN R2

R2 N * N R2

(125)

(126)

(127)

HN

(a)

+

M

P

Ph

Ph

Ph BHMP-7X OCH2CON(CH3)CH2COOH, X = H, OCH2COOH, OCH2CONHCH2COOH, OCH2CONH(CH2)2COOH, OCH2CH2OCH2COOH

R1 = OAc, OCOOMe R2 = Bn, Ts

Ph

Reagents and conditions: (a) Pd(0)/L/THF

Ph2P

L: BHBP-7X or BINAP or 128

O

N

O H

O

H

O

(128)

Scheme 7.62 O

COOH

N N

HN

+ MeOOC

(129)

(a)

N

(130)

N N MeOOC

O 5 4a 3a 3 6 4 N HN 2 N 9 7 9a 1 8 8a O

(b)

(131) N

HN N

O (133)

(b) HN

(c)

N N

+

(133)

H N N H

COOH

+

(135)

N H

N

HN

O (4aS, 9aS )

(132)

O

O

O

COOH

(136)

Reagents and conditions: (a) DCC/HOBT/CHCl3 (85%), (b) H2 /Pd–C/MeOH (95%, 67% de), (c) 6 M HCl, rfx (96%).

Scheme 7.63

2,3-butanedienone gave a 1:1 diastereomeric mixture of 141 and 142. The bisoxazolidines 140–143 obtained were reduced to give piperazine derivatives 144–147, respectively [96]. 7.1.3.2 Stereoselective Transformation of the Piperazine Ring Alkylations Metalated bislactim ethers (known as Sch¨ollkopf chiral auxiliaries) derived from DKPs are widely used as homochiral nucleophilic templates (homochiral glycine anion equivalents) for the synthesis of nonproteogenic α-amino acids. In this approach, enantiomerically pure bislactim ethers such as (S)-22 can be deprotonated with nBuLi and the aza-enolate anions 148 formed are alkylated with an alkyl halogenide as electrophile. The alkyl group R3 enters trans to the R1

N O (4aR, 9aS ) (134)

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

328 OH NH2

Ph

O

(a) Ph

(137)

H H N

OH HO

(b) Ph

O N H H (138)

Reagents and conditions:

NH

O R O

(c/d/e)

HN Ph

Ph

N R′ N

Ph

(f) Ph

R2 R3 N

R1 N

R4

HO

OH

Ph

(140): R = R′ = H (144): R1 = R2 = R3 = R4 = H (141+ 142): R = R′ = Me (145): R1 = R3 = H, R2 = R4 = Me (143): R = Ph, R′ = Me (146): R1 = R3 = Me, R2 = R4 = H

(139)

(147): R1 = R4 = H, R2 = Ph, R3 = Me

(a) glyoxal/H2O /EtOH (70%), (b) BF3·THF (97%), (c) glyoxal /H2O/EtOH (68%), (d) 2,3-butanedione/toluene (84%, 1:1 mixture), (e) 1-phenyl-1,2-propanedienone/benzene (70%), (f) BF3·THF (70 – 99%).

Scheme 7.64

substituent of the piperazine ring, affording trans-alkylated bislactim ether 149 in high diastereomeric excess, which can be hydrolyzed to the mixture of l-valine or tert-l-leucine ester 150 and the target enantiomerically pure α-amino acid 151 [51, 97–113]. N,N-Bis(p-methoxybenzyl)piperazinedione derivative 152 was developed and used as chiral auxiliary for synthesis of enantiomerically pure amino acids. The methoxybenzyl derivative has the advantage over the dilactim ether Sch¨ollkopf chiral auxiliaries in that it is crystalline and therefore easier to handle, and the p-methoxybenzyl (PMB) group can be removed under mild conditions. Thus, alkylation of the piperazine core with alkyl halides via the lithium or potassium enolate 152 afforded 153 with high diastereoselectivities, which could be deprotected to 154 [114–117]. Besides Sch¨ollkopf chiral auxiliaries 22 and PMB derivative 152, other piperazine precursors, such as monolactim ether 63 or piperazinones 155, with a chiral N-substituent, can also be stereoselectively alkylated in essentially the same way [118–126]. It is not necessary to use a strong base for alkylation of the piperazine ring in all cases. Mild phase transfer catalysis (PTC) conditions in the presence of a weak base have been successfully employed for the diastereoselective alkylation R1 R2O

N

OR2

(a)

R1 R2O

N

(S )-(22)

N

OR2

N

+

Li

R1 N

(b)

R2O

(148)

N (149)

R1 = i Pr, t Bu R2 = Me, Et R3X = alkyl halogenide Reagents and conditions: (a) BuLi/ THF/−78 °C, (b) R3X, (c) 0.1 M HCl(aq) / MeCN.

Scheme 7.65

OR2 R3

(c)

R1 R2O (150)

NH2 O

O +

H2N (151)

OR2 R3

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring OMe

OMe

N

i Pr

i Pr

O (a)

O

O

N

N N

O (b)

R

i Pr O

H N N H

O R

MeO

MeO (152)

(153)

(154)

Reagents and conditions: (a) LiHMDS or KHMDS / THF/R-X, (b) Ce(NH4)2(NO3)6 / MeCN/ H2O.

Scheme 7.66 OEt

i Pr Ph

N

R N

O R:

N O

N Boc

(33)

(155)

Ph

OH

HO

OTBDMS

Scheme 7.67 Boc N O Ph

N (93)

Boc N O

(a or b)

Ph

N

R

(156)

R = allyl, propargyl, Bn, EtCOOCCH2 Reagents and conditions: (a) R-X /K2CO3 /Bu4NBr/ MeCN or CH2Cl2 /rt (75 – 86%, >94% de) (b) Allyl carbonates/Pd(OAc)2 / PPh3 / THF (75 – 85%, >96% de).

Scheme 7.68

of piperazinones 93 with activated halides, affording alkylated products 156. Pd-catalyzed allylation of the same substrate was also performed by reacting 93 with allyl carbonates in the presence of Pd(OAc)2 and PPh3 [74, 75]. Reaction of the Piperazine Ring with Electrophiles Different from Alkyl Halides Not only alkyl halides but also other electrophiles, such as aldehydes, ketones, epoxides [127–129], and acyl halogenides [130], can react with enolate anions 148 to afford the corresponding alcohol. Further possibilities include Michael conjugate addition of 148 to α,β-unsaturated esters [131–134], oxo compounds [135], or nitro compounds [136, 137] to result in the corresponding substituted piperazines. Even stereoselective arylation

329

330

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

of the piperazine ring is possible by the reaction of lithium enolates 182 with arene-Mn(CO)3 cations [138–140]. When aldehydes are reacted with 148 as such, the diastereoselectivity with regard to the heterocyclic carbon is high, whereas formation of the second chiral center at the secondary carbon in 157 (R4 = H) proceeds with low stereoselectivity [141–145]. However, replacement of the lithium ion in complex 148 with another metal complex (trisdimethylaminotitanium group is used in most cases) leads to a strong increase in stereoselectivity as regards the formation of the alcoholic moiety. The predominant formation of one diastereomer can be rationalized on the basis of the two six-membered pericyclic transition states A and B. Transition state A is lower in energy because of the quasi-diaxial repulsion between the R moiety, the methoxy group and the ligands on the metal in transition state B [146–149]. Reaction of the Piperazine Ring with Nucleophiles As revealed by the previous examples, the Sch¨ollkopf chiral auxiliary itself serves as a nucleophilic synthon, and therefore it can be attacked by electrophiles. Its chloro derivative 158, however, has been used as an electrophilic synthon, and the chloride in 158 could be stereoselectively replaced by malonate anions as nucleophiles, furnishing the product 159 [150]. Another example of diastereoselective nucleophilic reactions on the piperazine ring is the reaction of organomagnesium or organocadmium reagents with cyclic acyl imines 161 in situ generated from the corresponding acetates 160, resulting in 162 as the major and 163 as the minor diastereomer [61].

R1 R2O

N

OR2

R1

(a)

N

R2O

N

(S )-(22)

N

OR2 -

R1

(b)

Li+

R2O

OR2

N N

R3

(157)

(148)

R1 = i Pr, t Bu R2 = Me, Et (a) BuLi/ THF/−78 °C,

Reagents and conditions:

(b) R3-COR4 or 1. Cl(TiNMe2)3, 2. R3-COR4. L L Ti O L C H R

O

L L Ti L C R

H N

N MeO N i Pr

OMe H A

Scheme 7.69

MeO

i Pr

OMe N H B

OH R4

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

i Pr MeO

N

OMe

N

Cl

(a)

i Pr

N

OMe

MeO

N

CH(COOR)2

331

(159)

(158) R = Me, i Pr, t Bu Reagents and conditions:

(a) NaHC(COOR)2 /THF/18-crown-6 (65%, dr 25:1 to 60:1).

Scheme 7.70

R1 H N H O

O

(a)

OAc CF3

N H

R1 H N H

O

R1 H N H

O

CF3

O

(160)

N (161)

N H (162)

O CF3 R2

+

R1 H N H O

N H

(a) R2MgX/THF or R22Cd/THF (40–62%, de 54–99%).

Scheme 7.71 MeOOC

MeOOC

O NH

O

(a)

NH AcN

AcN O (164)

R

O

R2 CF3

(163)

R1 = Me, i Pr, i Bu, Bzl R2 = Me, Bz, Reagents and conditions:

O

R

(165)

Reagents and conditions: (a) H2 /Pd–C (44–97%, >97% de).

Scheme 7.72

Asymmetric Hydrogenations Dehydropiperazines 164 could be stereoselectively hydrogenated by using Pd/C as the catalyst giving the cis saturated product 165 with high diastereoselectivity [151]. The highly diastereoselective conjugate reduction of benzylidene DKPs 166 by treatment with SmI2 in THF and subsequent addition of deoxygenated water led to the cis 3,6-disubstituted derivative 167 on starting from either the E or the Z stereoisomer. Dideutero derivatives could also be synthesized using D2 O instead of H2 O [152, 153]. Tetrahydropyrazinecarboxamide 168 was reduced to the corresponding piperazine derivative 169 with moderate stereoselectivity (57% ee) by the application of rhodium catalysis using ferrocene-based phosphine ligand with planar chirality [154].

332

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles OMe

OMe

i Pr

N

O

N

O

(a)

i Pr

N

O

N

O

Ph

Ph MeO

MeO (166)

(167)

Reagents and conditions: (a) SmI2 / THF/ H2O (89 – 93%, 95 – 96% de).

Scheme 7.73 COOPh N N Boc O (168)

(a)

NHt Bu

COOPh N N Boc O

NHt Bu

(169)

Reagents and conditions: (a) [Rh(nbd)2]PF6 /(S,S)-EtTRAP-H / H2 / Cl(CH2)2Cl (92%, 57% ee). nbd: norbornadiene (S,S )-EtTRAP-H: (S,S )-2,2″-bis[(diethylphosphino)methyl]-1,1″-biferrocene.

Scheme 7.74

7.1.4 Oxadiazines

Asymmetric syntheses of oxadiazines have been far less explored than those of other rings discussed in the previous sections. The methods will be classiﬁed according to the type of the oxadiazine ring: 1,2,5-oxadiazines and 1,3,4-oxadiazines. 7.1.4.1 1,2,5-Oxadiazines 1,2,5-Oxadiazines 4 were prepared from N-(benzotriazolylcarbonyl)-l-alanine or phenylalanine 1, which was converted to the corresponding acyl chloride 2. Its reaction with N-phenylhydroxylamine gave hydroxamic acid 3, which readily underwent cyclization under basic conditions [155]. 7.1.4.2 1,3,4-Oxadiazines Synthesis of 1,3,4-oxadiazines 8 and 9 started from ethyl (S)-3-hydroxybutyrate (5). Diastereoselective amination with di-tert-butylazodicarboxylate gave an 84:16 mixture of hydrazino ester epimers 6 and 7. Treatment of 6 with 2,2-dimethoxypropane afforded oxadiazine 8, which underwent base-catalyzed equilibration to give the more stable trans product 9 (trans/cis ratio = 98:2). The latter compound

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

N

N

O N

R O

N H

(a)

N

N

O N

O

N H

OH

(1)

R N

(b)

N

O

R

R

N

N H N HO

Cl

(2)

O

(c)

O

(3)

(c) Na2CO3 /H2O / acetone (28%).

Scheme 7.75

(a)

OH

OH COOEt

(5)

BocHN

NBoc

(6)

COOEt

+ BocHN

b

O

NBoc NBoc

(b)

(c)

O

COOEt (8) d

O

Reagents and conditions:

NBoc NBoc

NBoc (7)

84:16

NBoc NBoc COOEt (9)

(e)

(d)

O

O

N

(4)

Reagents and conditions: (a) SOCl2, (b) PhNHOH /N-methylmorpholine / toluene (15 – 31%),

COOEt

O

HN

R = Me, Bn

OH

333

NBoc NBoc

CH2OH

CH2OH

(10)

(11)

(a) LDA / CbzNNCBz, (b) (MeO)2CMe2 /pTsOH/ benzene/ rfx (75% for 8, 61% for (9), (c) NaH/ EtOH/ THF/ rt / 1d (78%), (d) Ca(BH4)2 (from 3.5 equiv CaCl2 and 6 equiv NaBH4), EtOH / THF (91–92%), (e) Ca(BH4)2 (from 3 equiv CaCl2 and 6.5 equiv NaBH4) NaOEt / EtOH/ THF (86%).

Scheme 7.76

could also be obtained from the syn hydrazino derivative 7. The esters 8 and 9 were reduced to the corresponding hydroxymethyl derivative 10 and 11 by Ca(BH4 )2 in situ formed from CaCl2 and NaBH4 . However, the cis isomer was sensitive to the conditions of the reduction: when CaCl2 was used in a slight excess compared to NaBH4 , no epimerization took place; on the contrary, employing NaBH4 in excess resulted in nearly complete conversion to the more stable trans alcohol 11 [156, 157].

334

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

Another method was applied by Hitchcock et al. for the synthesis of the 1,3,4-oxadiazine ring. They synthesized 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2ones 16 starting from enantiomerically pure natural amino alcohols such as ephedrine, norephedrine or their stereoisomers. Introduction of alkyl moiety to the primary amino group in 12 could be carried out by condensation with a suitable oxocompound under reductive conditions. Subsequent treatment of 13 with NaNO2 /HCl gave N-nitrosamines 14, which were reduced to β-hydrazinoalcohols 15. Cyclization of 15 could be performed either by using 1,1 -carbonyldiimidazole or diethyl carbonate to afford oxadiazinones 16 (Scheme 7.77) [158–162]. Oxadiazines 17 and 18 could also be prepared principally by the same way starting from the corresponding amino alcohol [162–164]. 3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones 36 were used as chiral auxiliaries. Asymmetric aldol reactions of acylated oxadiazinone 19 with various aldehydes via titanium enolate afforded adducts 20. When aldehydes without an α-hydrogen were employed, the products were obtained in high yields and diastereoselectivities; in contrast to this ﬁnding, by employment of aldehydes bearing an α-hydrogen, moderate diastereoselectivities were achieved. The observed stereoselectivity could be explained by the conformation of the oxadiazinone ring, in which the N-4 substituent blocks the si face of the N-3 acyl substituent (see scheme) [165–169].

OH NH2

Ph

OH

(a)

Ph

(12)

H N

OH

(b)

R1

Ph

(13)

NO N 1 R

(c)

(14)

(1R,2S )-Norephedrine O OH Ph

NH2 N 1 R

O

(d)

Ph (15)

NH N 1 R

(16)

R = i Pr, n Bn, Me R2 = Me, Bn, bornyl 1

Reagents and conditions: (a) Me2CO or PhCHO / NaBH4, (b) NaNO2 / HCl / THF (95 – 97%), (c) LiAlH4 / THF, (d) (EtO)2CO / LiH / hexane or CDI / pTsOH (74%), (e) LiH / RCOCl / CH2Cl2 (43 – 95%). O

O O

Scheme 7.77

NH N Bn Ph (17)

O

NH N Bn (18)

i Pr

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring O

O O Ph

N N

O R2

1

R

(a)

O Ph

(19)

N N

H C O

OH R3

R

R2 1

(20)

R1 = Me, i Pr, bornyl R2 = Me, PhSCH2, MeO, BnO, PhO R3 = aryl, t Bu, alkyl Reagents and conditions:

O

335

Me Ph H

O

N N H Me

O O

Ti L

H C O

(a) 1. R3CHO / THF, 2. Et3N, 3. TiCl4 (62 – 97%, dr 75:25 to 99:1 for aldehyde without a-hydrogen, 8:1 to 38:1 with a-hydrogen).

Scheme 7.78

7.1.5 Morpholines

Morpholine derivatives with deﬁned conﬁguration of the substituents can be obtained either by cyclization of enantiomerically pure starting material or by asymmetric transformation of the morpholine ring. A review appeared in Synthesis in 2004 summarizing syntheses of C-substituted morpholine derivatives. It classiﬁes the methods according to the type of starting material or reaction type; thus syntheses from amino alcohols, epoxides, oleﬁns, and carboxylic acid derivatives and via organometallic reactions are described [170]. In the ﬁrst part of this section, we follow a classiﬁcation of the ring closures according to the method of cyclization: lactone or lactam formation, imine bond formation, nucleophilic substitution, conjugate addition, and by the involvement of organometallics. In the second part, asymmetric alkylations, arylations, radical additions, and hydrogenations on the morpholine ring are discussed. 7.1.5.1 Formation of the Morpholine Ring Ring Closure by Lactone or Lactam Formation A frequent route to the synthesis of enantiomerically pure morpholinone derivatives is the cyclization of a suitably substituted enantiomerically pure N-(2-hydroxyethyl)-α-amino acid or ester by lactone formation. Thus, (1R,2S)-2-amino-1,2-diphenyl ethanol (1) was N-alkylated with ethyl bromoacetate in the presence of a weak base to afford 2; subsequent N-protection and acidic cyclization gave 4-protected-5,6-diphenylmorpholin-2-ones 4 via intermediates 3 [171]. In the same pathway, differently substituted morpholinone derivatives were also synthesized [172–176]. Similar to the previous example, the hydroxy ester suitable for lactonization was prepared by N-alkylation of an amino alcohol; diastereoselective coupling between racemic α-halo acids 5 and N-benzylethanolamine (6) was performed in the presence of Bu4 NI, and 7 obtained with high diastereoselectivity was then cyclized to oxazinones 8 upon treatment with pTsOH [177].

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

336

Ph

Ph

Ph (a)

Ph

(b)

Ph

OH NH2

OH COOEt

HN

(1)

Ph R

OH COOEt

N

(2)

Ph (c)

Ph R

O N

(3)

O (4)

R = Boc, Cbz Reagents and conditions:

(a) BrCH2COOEt / Et3N / THF, (b) Boc2O/ toluene or CbzCl / CH2Cl2 / NaHCO3 (aq), (c) p TsOH / toluene (75 – 86% overall).

Scheme 7.79 OH X

O O

Ar

+

N

(a)

OH

BnHN

Ph

N

N

Ph

O

Ar

O

Ar

O

(b)

O N

O

O (5)

(6)

(7)

(8)

Reagents and conditions: (a) Et3N /THF /Bu4NI (84–90%, 76–96% de), (b) toluene/ p TsOH (82%, 86–91% ee).

Scheme 7.80

Diphenylmorpholine (2R,3S)-4a was prepared in enantiomerically pure form in six steps starting from benzaldehyde. Enzymatic stereoselective HCN addition to the aldehyde was followed by O-protection to 9, which was then converted to 11 via a one-pot Grignard addition–transamidation–reduction sequence. The reduction proceeded with complete diastereoselectivity to 11, which upon O-deprotection gave 12. Subsequent N-protection and acidic cyclization resulted in morpholine (2R,3S)-4a [178]. Asymmetric Strecker reaction of various aldehydes and (R)-2-phenylglycinol (13) gave nitriles 14, which were esteriﬁed with methanolic HCl. The esters were cyclized O Ph

OTHP

(a–b)

H

Ph

THPO

(c)

Ph

CN (9)

THPO

NH Ph

OH Ph

Cbz N

Ph (12)

COOMe

COOMe

Ph (11)

(10)

(d–e)

H N

Ph

Ph

O

Ph

N Cbz

O

(f)

(2R,3S )-(4a)

Reagents and conditions: (a) HCN / oxynitrilase (99% ee), (b) p TsOH / Et2O / dihydropyran, (c) 1. PhMgBr / Et2O, 2. MeOH, 3. NH2CH2COOMe, 4. NaBH4, (d) p TsOH / MeOH, (e) CbzCl, (f) p TsOH / cyclohexane (48% overall). Scheme 7.81

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

Ph RCHO +

(a)

Bn

H N

R

Ph

(b)

OH

H2N

CN

(R )-(13)

337

OH

R

N

O

O (15)

(14)

Ph

R = Me, Bn, n Pr, BnO(CH2)2 Reagents and conditions: (a) NaCN / NH4Cl / MeOH / H2O, (b) 1. HCl / MeOH, 2. toluene / p TsOH, 3. BnBr / K2CO3 / DMF (overall: 33 – 48%, 66 – 80% de). Scheme 7.82

in the presence of pTsOH, and the intermediates obtained were N-benzylated to compounds 15. Good diastereoselectivities were achieved [179]. The 3R,5S-disubstituted morpholinone 19 was elegantly obtained in the following pathway. A highly stereoselective (dr: 95:5) conjugate addition of amino alcohol (S)-17 to unsaturated oxocarboxylic acid 16 in combination with crystallizationinduced dynamic resolution (CIDR) provided the hydroxyethylamino carboxylic acid derivative (R,S)-18 in high diastereoselectivity, which, by lactonization, led to (3R,5S)-19. In the CIDR process, the solvent plays an important role: the solubility of the arising amino acid should be as low as possible, but high enough to permit the equilibration processes [180]. Lactone formation for synthesis of compound (S)-22 could be carried out either by cyclization between a hydroxy function and a carboxylic amide moiety in (S)-21 derived from amino acid amide (S)-20 or by reacting amino acid (S)-23 with 1,2-dibromoethane [181]. Reacting ephedrine 24 with α-oxocarboxylic acid chlorides results in lactol formation, giving compounds 25 after N-acylation [182].

O Ph

Bn COOH

(16)

+

OH

Bn

O

(a)

Bn COO− NH+3

Ph

NH2

Ph

COOH

(S )-(17)

+

O HN O O

OH

O H2N

(b)

Ph

Bn

Bn

Bn

COO−

Ph

O H2N+

+ Ph

(R,S )-(18)

(S,S )-(18)

Reagents and conditions: (a) EtOH or CH2Cl2 /25 – 30 °C/7d (for (R,S )-18: 81%, dr 95:5), (b) THF / H2SO4 /rt (60%).

OH

COO−

Less soluble

(3R,5S )-(19)

Scheme 7.83

OH

O HN

OH

338

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles OH

H N

Ph

N

Ph

CONH2

CONH2

(a)

F

F (S )-(20)

(S )-(21)

(b)

H N

Ph

O

COOH (c)

N

Ph

F

O

F

(S )-(23) Reagents and conditions:

(S )-(22) (a) BrCH2CH2OH /i Pr2NEt / DMF (75%), (b) AcOH / 60 °C (95%), (c) Br(CH)2Br /i Pr2NEt.

Scheme 7.84

+

Cl−

N H2

Ph OH

(24)

Ph

N

(a)

O

O R OH (25)

R = Me, Et, n Pr, i Pr Reagents and conditions: (a) RCOCOCl/Et3N/DMAP/CH2Cl2 (65–71%). Scheme 7.85

Lactone and lactam formation took place by reacting ephedrine 24 with oxalyl chloride, affording morpholine-2,3-dione (5S,6R)-26 [183–185]. Reaction of amino alcohols with an α-halo ester in the presence of weak base results in N-alkylation (see above), while treatment of amino alcohols 27 with a strong base as NaH followed by addition of ethyl chloroacetate gave O-alkylated derivative of 27, which spontaneously cyclized to form lactam 28 [186]. Morpholine-2,5-diones can be considered as lactones and lactams in the same ring. Two different approaches could be applied for their synthesis: (i) ﬁrst ester formation of the hydroxy moiety of an α-hydroxy acid with an amino acid, followed by intramolecular amide formation as the ring closure step give the product or (ii) the amide formed in the ﬁrst step is cyclized via lactonization.

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

Ph

+

N Cl− H2

(a)

Ph

N

OH

O

O

O (5S,6R )-(26)

(24)

Reagents and conditions: (a) (COCl)2 / Et3N/ DMAP/ CH2Cl2 (65–71%).

Scheme 7.86 R

(a)

H N

O

R

OH

H2N

O (27)

(28)

R = Me, Bn, i Bu, t Bu, s Bu Reagents and conditions: (a) NaH/ClCH2COOEt / THF (69–88%).

Scheme 7.87

According to the ﬁrst approach, synthesis of (S)-32 started from hydroxy acid (S)-29, which was coupled with 1,1 -carbonyldiimidazole (CDI)-activated Cbz-glycine yielding amino acid (S)-30 after deprotection. Cyclization of (S)-30 took place upon treatment with Mukaiyama reagent. The lactam (S)-31 could be transformed to lactim (S)-32 using Me3 OBF4 [187]. Employing the second approach, depending on the reaction conditions, two different stereoisomeric products were formed starting from the acid 33. By treatment with diethyl azodicarboxylate and triphenyl phosphine, intramolecular Mitsunobu reaction with inversion of the conﬁguration led to (6R)-34, while heating 33 under reduced pressure resulted in (6S)-34 via spontaneous cyclization with retention [170–188]. The N-benzyl-protected amino alcohol 6 was cyclized with glyoxylic acid (35), then the product 36 activated with Tf2 O and reacted with the alcohol 37 followed by crystallization driven epimerization, affording (2R,1 R)-38 in 99% diastereomeric excess [170, 189].

t Bu

COOH OH

(a–b)

t Bu O

(S )-(29)

COOH O NH2

(S )-(30)

O (c)

t Bu

H N

(d)

O

t Bu

OMe N O

O (S )-(31)

O (S )-(32)

Reagents and conditions: (a) Cbz-glycine/ CDI / THF (86%), (b) H2 / Pd – C/ EtOH (96%), (c) 2-chloro-1-methylpyridinium iodide/i Pr2NEt / CH2Cl2 (84%), (d) Me3OBF4 / CH2Cl2 (89%).

Scheme 7.88

339

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

340

(a)

OH NH

i Pr O

i Pr

O

O

O

N H

OMe

(6R )-(34)

COOH

OMe

i Pr

O

O

O

N H

OMe

(b)

(33)

(6S )-(34) Reagents and conditions: (a) DEAD / PPh3 (30%), (b) 65 °C / 0.2 bar (95%).

Scheme 7.89

CF3 Crystallization driven epimerization

(1) Tf2O

OH +

HO

OH

THF / H2O

O

OH

76%

N Bn

O

COOH

NH Bn

(2) BF3Et2O CF3

F3C

84%, 99% de

F3C OH

(6)

(35)

(36)

O

O

N Bn

O

(2R,1′R )-(38)

(37)

Scheme 7.90

Ring Closure via Imine/Enamine Bond Formation Intramolecular condensation of an oxo group with an amino moiety is also a suitable way of morpholine ring formation. Thus, for the synthesis of 43, ketones 39 halogenated at α-position and potassium salts 40 of N-protected α-amino acids were condensed to give esters 41, which were then deprotected to 42. Cyclization to morpholinones 43 could be performed in acetate buffer to avoid pH decrease during the reaction, which would cause hydrolysis and slow down the cyclization [190].

Br R1

O

(39)

+

O

O

KO HN Cbz

R2

(40)

O

O

(a)

O

(b)

R1

O HN

R2

(c) 1

R

Cbz (41)

O

N H2

R2 HBr

(42)

R1 = aryl, R2 = Me, Bz, i Pr Reagents and conditions: (a) DMF / rt (74–100%), (b) HBr/AcOH/rt (80–99%), (c) 0.2 M acetate buffer/rt (65–90%).

Scheme 7.91

R1

O

O

N

R2

(43)

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

341

Via the corresponding ester intermediate analogous to 42 possessing oxo and amino group in proper position, synthesis of (6S)-6-isopropyl-5-phenyl-3,6-dihydro2H-1,4-oxazin-2-one [191, 192], as well as (6R)-6-isopropyl-3-methyl-5-phenyl-3,6dihydro-2H-1,4-oxazin-2-one diastereomers [193] were reported in similar way as above. Principally the same method was applied for the synthesis of (3S,5R)-3,5diphenylmorpholin-2-one ((3S,5R)-46) from (S)-44 via (S)-45: esteriﬁcation of an N-protected amino acid by reacting its potassium salt with an α-halogenated ketone, followed by N-deprotection of the formed ester and subsequent cyclization by imine formation. Finally, stereoselective hydrogenation of the imine bond gave the product [194]. Asymmetric Strecker reaction of the α-acyloxy ketone 48 afforded cyanomorpholine (3S,5S)-50 as the major diastereomer through the iminium intermediate 49. The stereochemistry is controlled by the conﬁguration of the acyloxy amino chiral center: the relative conﬁguration of the nitrile group is usually anti to that of the amino side chain. The Strecker precursor 48 was prepared from methyl 3-(chlorocarbonyl)propanoate (47) by addition of diazomethane followed by insertion of the resulting diazoketone to Boc-l-valine [195]. Enantiomerically pure morpholinone (5S,1 S)-52 was prepared by condensation of amino alcohol (2S,1 S)-51 with glyoxal [196]. When the 2-aminoethanol derivative (R)-53 possessing N-homoallyl substituent was reacted with glyoxal in aqueous media, morpholine (3R,5R)-56 was obtained from an aza-Cope rearrangement of the iminium intermediate 54, directly formed by the condensation of amino alcohol (R)-53 and glyoxal, followed by hydrolysis of intermediate 55. In this reaction sequence, stereoselective formation of the new

H2N

Ph H COOH

(a–c)

BocHN

Ph H

O

O

Ph

H Ph O

O

O (S )-(45)

(S )-(44)

H N

H Ph

(d–f)

(3S,5R )-(46)

Reagents and conditions: (a) Boc2O/NaOH/ H2O/dioxane (89%), (b) KOH / MeOH (quant), (c) PhCOCH2Br/DMF (74%), (d) HBr / AcOH (81%), (e) NaOAc/AcOH buffer (89%), (f) H2 /Pd – C / EtOAc (86%).

Scheme 7.92 (a – b)

O Cl

MeOOC

(47)

O O

MeOOC (48)

H + N

(c)

BocHN O

MeOOC

MeOOC

CN−

O

(49)

Reagents and conditions: (a) CH2N2 (90%), (b) Boc-L-valine/Cu(acac)2 /toluene (40%), (c) 1. TFA/CH2Cl2, 2. NaCN/ i PrOH (64%, dr 18:1).

Scheme 7.93

H N O

O NC

O

(3S,5S )-(50)

342

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles OH

O

O

(a)

NH

N

Ph

Ph

(2S,1′S )-(51)

(5S,1′S )-(52)

Reagents and conditions: (a) OHC–CHO/THF/rfx (86%).

Scheme 7.94 OH

O (a)

Ph

NH

Ph

(R )-(53)

O

OH

+ N

O

OH

+

N

Ph

(54)

Ph

OH

N H

(3R,5R )-(56)

(55)

Reagents and conditions: (a) OHC – CHO / H2O (54%).

Scheme 7.95

chiral center at 3 position was observed giving exclusively the 3R stereoisomer [197–199]. Reaction of amino alcohol (R)-57 with 4-ﬂuorophenylglyoxal 58 yielded a mixture (1:2) of the diastereomers 59. However, the newly formed chiral center was labile under acidic conditions, and when the diastereomeric mixture was treated with HCl in isopropyl alcohol, the 3R isomer crystallized preferentially and nearly all of the other diastereomer was converted into the 3R isomer leading to formation of (3R,1 R)-60 in excellent yield and stereoselectivity (98% de) [170, 200]. Ring Closure via Nucleophilic Substitution with C–O Bond Formation Intramolecular deplacement of a halogen with a hydroxy group in a suitable haloacetylaminoethanol derivative can be used for morpholine ring formation. Thus, compound (S,S)-62 prepared by acylation of amino alcohol (S,S)-61 with chloroacetyl chloride was treated with KOtBu to give morpholinone (S,S)-63 [201, 202]. Optically active 2-hydroxymethylmorpholine derivatives (S)-67 and (R)-69 could be prepared from precursors possessing the stereogenic center from natural origin. Namely, the protected d-mannitol derivative 64 was cleaved with sodium

Me Ph

N H

O

O

OH

OH

+

N Ph (58)

HCl

N Me (59)

F

Ph

Me (3R,1′R )-(60)

Reagents and conditions: (a) AcOH, (b) HCl /i PrOAc (90%, 98% de).

Scheme 7.96

O

O (b)

OH

F

(R )-(57)

O

(a)

F

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

343

O OH

OH OH HN

(a)

(b)

NH2

NH

Cl

OH

O OH

(S,S )-(61)

(S,S )-(62)

O

(S,S )-(63)

Reagents and conditions: (a) ClCH2COCl/Et3N /CH2Cl2 (70%), (b) KOt Bu / BuOH (80%).

Scheme 7.97

metaperiodate to aldehyde (R)-65, and reductive amination with benzyl amine followed by acylation with chloroacetyl chloride and subsequent deprotection gave (S)-66, which was then cyclized to the product (S)-67 with S conﬁguration by treatment with NaOEt. Since the enantiomer of (S)-67 could not be prepared in a stereochemically pure form by inversion of the conﬁguration of (S)-66 as the key step, another route was applied. Treatment of the epoxide (R)-68 prepared from (R)-65 in ﬁve steps with aminoethyl hydrogensulfate gave the cyclized product, which was then debenzylated to (R)-69 [203]. Enantiomerically pure starting material, (S)-3-amino-1,2-propanediol ((S)-70), was also used for the preparation of (S)-2-hydroxymethylmorpholine ((S)-72) as a key intermediate for the synthesis of the selective norepinephrine inhibitor reboxetine. After N-acylation of (S)-70 with chloroacetyl chloride, (S)-71 could be cyclized to morpholine (S)-72 with KOtBu [204].

O O HO H H

H H OH O

(a)

HO

O O

(b)

H

HO

H CHO

N Bn

O (64)

(R )-(65)

Cl O

(S )-(66)

(c)

HO

H

O N Bn

(S )-(67)

5 steps

O

H

OBn (R )-(68)

(d – e)

HO

O H

N Boc (R )-(69)

Reagents and conditions: (a) NaIO4 / H2O, (b) 1. BnNH2 /EtOH /H2O/Raney-Ni/H2 (quant), 2. ClCH2COCl/Et3N /CH2Cl2, (86%), 3. 20% aq AcOH (quant), (c) NaOEt / EtOH (88%), (d) 1. H2N(CH2)OSO3H /NaOH /H2O (62%), 2. Boc2O / Et3N /CH2Cl2, (88%), (e) Pd – C /H2 /MeOH (quant).

Scheme 7.98

O

344

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles OH

OH

OH O

(a)

OH

HO

(b)

H

N H

HN

NH2

Cl

(S )-(70)

O

(S )-(71)

(S )-(72)

Reagents and conditions: (a) ClCH2COCl/Et3N/MeCN/MeOH (94%), (b) KOt Bu/t AmOH (92%).

Scheme 7.99

H Cl +

H

O

NH2

(a)

Cl

O

Cl

OH (b)

N

O

NH

F

F F (R )-(73)

(R )-(75)

(74)

(R )-(76)

Reagents and conditions: (a) cyclohexane / rt (70%, 98% ee), (b) BrCH2COBr / NaOH / H2O / CHCl3 (86%). Scheme 7.100

Synthesis of the morpholine derivative (R)-76 as an intermediate for the gastroprotecting agent mosapride started from (R)-(−)-epichlorohydrin ((R)-73). Using hydrocarbons as cyclohexane as the solvent proved to be more efﬁcient over other solvents in the reaction of (R)-73 with 4-ﬂuorobenzylamine (74) furnishing the product (R)-75 in good yield and high enantiomeric purity. Reaction of (R)-75 with bromoacetyl bromide in a mixture of chloroform and 30% aqueous NaOH solution resulted in the ring-closed product (R)-76 without isolation of the bromoacetamide intermediate [205]. Enzymatic synthesis of enantiomerically pure morpholine (R)-81 could be achieved through an epoxide intermediate, where the key step is the asymmetric reduction of the bromoaldehyde 77 to bromo alcohol (S)-78 using baker’s yeast. OSO3Na Br O

Ph

(a)

Br Ph

OH

(b)

O Ph

OH

(c)

(d)

NH

Ph

O N H

H (77)

Ph

(S )-(78)

(R )-(79)

(R )-(80)

(R )-(81)

Reagents and conditions: (a) Baker's yeast / XAD1180 resin (100%, 98,6% ee), (b) NaOH / H2O (73%), (c) H2N(CH2)2OSO3Na / NaOH / MeOH, (d) NaOH / toluene (66%).

Scheme 7.101

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

345

Ring opening of the epoxide (R)-79 with ethanolaminesulfonate to (R)-80 and subsequent basic cyclization gave (R)-81 [170]. For the synthesis of N,N -dibenzyl derivative of (2S,2 S)-2, 2 -bimorpholine (2S,2 S)-84, tetraol 83 prepared from tartaric acid derivative 82 was cyclized in a one-step procedure with NaH and p-toluenesulfonyl imidazole [206]. trans-2,5-Disubstituted morpholine derivative (2S,5R)-88 was prepared starting from enantiomerically pure epoxide (S)-85 and d-alaninol (R)-86 via diol 87 applying the same cyclization method. Thus, reﬂuxing (S)-85 and (R)-86 in n-propanol and subsequent N-tosylation yielded selectively diol 87, which was then cyclized via deprotonation with NaH in the presence of p-toluenesulfonyl imidazole. Removal of the tosyl group with sodium in ethanolic ammonia provided (2S,5R)-88 in pure form [207]. However, adaptation of the method bearing larger substituents was not unambiguous. When attempting the same reaction sequence for synthesis of analogous morpholine derivatives with larger 5-substituents (e.g. phenyl and benzyl), ring opening proceeded smoothly, but instead of selective N-tosylation, O-tosylation occurred as a result of sterical hindrance. For the preparation of the N-tosylated diol (analog of 87), ﬁrst, transient protection of hydroxy groups was necessary with trimethylsilyl groups. Ring closure of the phenyl analog of diol 87 was also unsuccessful using the same procedure (NaH/TsIm) as used for 87, but O-tosylation and subsequent treatment with K2 CO3 in tBuOH resulted in the cyclized product [207]. An enantioselective route to reboxetine analog (S,S)-94 with S,S conﬁguration was described, where the key step was the Sharpless asymmetric epoxidation of the cinnamyl alcohol derivative 89 to epoxide (R,R)-90 in 85% ee. The stereochemical outcome was highly dependent on the oxidating agent: the best enantiomeric excess was achieved by using cumene hydroperoxide. The (R,R) enantiomer of the product O

Bn

O

OMe

O

OMe

HO

4 steps

N N

HO

O

Bn

OH

(a)

Bn N

OH

O

Bn

(82)

N O

(2S,2′S )-(84)

(83)

Reagents and conditions: (a) NaH / THF/ TsIm (82%, 50% overall, 99% ee).

Scheme 7.102 NH2

TBDMSO ( ) 3 H

O +

(a)

TBDMSO ( ) 3

N

Ts

(b)

TBDMSO ( ) 3

OH

NH O

OH OH

(S )-(85)

(R )-(86)

(87)

Reagents and conditions: (a) 1.n PrOH/rfx (99%), 2. TsCl/Et3N/CH2Cl2 (77%), (b) 1. NaH / THF/TsIm (99%), 2. Na/NH3 / EtOH (100%).

Scheme 7.103

(2S,5R )-(88)

346

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles MeO OH

O

(a)

OH

MeO

O

(b)

O

(c)

OH Cl

Cl

Cl (S,R )-(91)

(R,R )-(90)

(89)

O

OH

Cl (S,S )-(92) (d)

MeO

MeO

O

O

(e)

NH

NBoc OH

O Cl (S,S )-(94)

OH

Cl

(S,S )-(93)

Reagents and conditions: (a) Ti(Oi Pr)4 /cumene hydroperoxide / D-DET / CH2Cl2 / mol. sieves (72%, 85% ee), (b) guaiacol / NaOH / CH2Cl2, (c) 1. TMSCl / Et3N / EtOAc, 2. MsCl/Et3N/ EtOAc, 3. 1N HCl, 4. NaOH / toluene / MeBu3NCl (60%), (d) 1. etanolamine / i PrOH, 2. Boc2O / CH2Cl2 (83%), (e) 1. NaH/TsIm / THF (61%), 2. TFA / CH2Cl2 (93%).

Scheme 7.104

could be obtained using l-diethyl tartrate (DET) instead of d-DET as the additive. Ring opening of (R,R)-90 with guaiacol gave diol (S,R)-91, which was then transformed to epoxide (S,S)-92 in four steps. Reaction of (S,S)-92 with ethanolamine, and the subsequent N-protection and cyclization of (S,S)-93 with tosylimidazol gave (S,S)-94 [208]. Starting from oleﬁn 95, Sharpless dihydroxylation was performed affording diol 96 in 98% ee. Selective tosylation on the primary hydroxy group, followed by nucleophilic substitution with ethanolamine and N-protection gave compound 97, which was cyclized under Mitsunobu conditions, and then deprotected to morpholine derivative (R)-98 [170, 209]. Ring Closure via Nucleophilic Substitution with C–N Bond Formation Another pathway for the synthesis of (S)-2-hydroxymethylmorpholine (72) from enantiomerically pure starting material involved the alkylation of the protected amino alcohol 99 derived from l-serine with tert-butyl bromoacetate to ester 100, which was then reduced in two stages to the corresponding alcohol. Subsequent mesylation to 101 and base-mediated cyclization followed by deprotection gave (S)-72 [210]. Using (R)-1-benzylglycerol ((R)-102), S- and R-hydroxymethylmorpholine derivatives (S)-105 and (R)-108, respectively, could be prepared selectively via the key intermediate 103 by varying the removal of the applied protecting groups. Thus, the

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring Ar (a)

HO

Ar OH

HO

(b)

Ar

OH NBoc

347

OH (c)

Ar O

OTBDMS

OTBDMS

OTBDMS

NH

Ar = 3,4-dichlorophenyl (95)

(96)

(R )-(98)

(97)

Reagents and conditions: (a) AD-mix-b/tBuOH /H2O (94%, 98% ee), (b) 1. TsCl/pyridine, 2. etanolamine /LiClO4 / MeCN, 3. Boc2O/Et3N / CH2Cl2 (86%), (c) 1. DEAD/PPh3 /toluene, 2. 4 N HCl/dioxane, 3. 5% NaOH.

Scheme 7.105 OH

O

COOtBu

(a)

TBDPSO

NHBoc (99)

O (b)

TBDPSO

NHBoc (100)

TBDPSO

OMs (c)

HO

NHBoc (101)

Reagents and conditions: (a) BrCH2COOt-Bu/aq NaOH/toluene/BuN4I (87%), (b) 1. DIBAL-H/CH2Cl2, 2. LiBH4/Et2O (85%), 3. MsCl/Et3N/CH2Cl2 (93%), (c) 1. TFA/CH2Cl2 , 2. DIEA/MeOH, 3. nBu4NF/THF (87%).

Scheme 7.106

ﬁrst debenzylation of 103 to 104 followed by ditosylation and subsequent treatment with benzylamine gave (S)-N-benzyl-2-tert-butyldiphenylsilyloxymethylmorpholine ((S)-105). On the contrary, when the tert-butyldiphenylsilyl (TBDPS) group of 103 was removed followed by ditosylation of 106, then ring closure of 107 in the presence of benzylamine was performed, and (R)-N-benzyl-2-benzyloxymethylmorpholine ((R)-108) could be obtained [211]. Synthesis of (2R,6R)-dimethylmorpholine ((2R,6R)-113) was carried out by a reaction sequence starting with SN 2 reaction of (R)-ethyl lactate ((R)-109) on the triﬂate of (S)-ethyl lactate ((S)-110). The conditions, particularly the used solvent, had great inﬂuence on the stereochemistry of the reaction. Complete inversion could be achieved by using a 4:1 mixture of n-pentane and 1,2-dichloroethane as the solvent and K2 CO3 as base. Reduction of diester (R,R)-111 to diol and subsequent mesylation gave dimesylate (R,R)-112, which could be cyclized with ninefold excess of benzylamine and then debenzylated to (2R,6R)-113 [212]. Iodination of 114 using N-iodosuccinimide, and subsequent reaction with N-Boc-ethanolamine gave compound 115. Ring closure with base, deprotection and subsequent recrystallization with d-(−)-tartaric acid provided the stereochemically pure product (R)-116 [170, 213]. (2S,2 S)-2, 2 -Bimorpholine ((2S,2 S)-119) could be synthesized from diazido diol 117 via NaH-induced double cyclization of intermediate 118 by intramolecular displacements of the mesyloxy groups with the Boc-protected nitrogens. In an analogous way, the isomeric (3S,3 S)-3, 3 -bimorpholine ((3S,3 S)-122) was prepared

H

O N H (S)-(72)

348

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles OH

OH

OH 5 steps

(a)

OH

O TBDPSO

OBn (R )-(102)

O

TBDPSO

(b)

O OBn

(103)

N Bn

OH

TBDPSO

(S )-(105)

(104)

(c)

OTs

OH (d)

O

O OBn

HO

O

BnO

(e)

(106)

N Bn

OBn

TsO

(R )-(108)

(107)

Reagents and conditions: (a) H2/Pd–C (98%), (b) 1. TsCl/pyridine (57%), 2. BnNH2 (84%), (c) HF/MeCN (87%), (d) TsCl/pyridine (56%), (e) BnNH2/Na2CO3/MeCN (85%).

Scheme 7.107

HO

(a) OTf COOEt

H H COOEt +

(R )-(109)

O EtOOC

(S)-(110)

O

(b)

COOEt

MsO MsO

(R,R )-(111)

O

(c)

N H (2R,6R )-(113)

(R,R )-(112)

Reagents and conditions: (a) K2CO3 /npentane-1,2-dichloroethane (4:1) (89%), (b) 1. LiAlH4 /Et2O, 2. MsCl/pyridine (94%), (c) 1. BnNH2 /dioxane (85%), 2. H2 /Pd–C/AcOH/MeOH. Scheme 7.108 (a)

Ar

I

Ar = 3,4-dichlorophenyl (114)

NHBoc O

OTr

OTr

Ar (115)

(b)

HN O Ar

OH

(R )-(116)

Reagents and conditions: (a) N -Boc-etanolamine/NIS/MeCN (72%), (b) 1. NaH/DMF (77%), 2. 4 N HCl/dioxane/EtOH, 3. recryst. with D-(−)-tartaric acid, 4. 1 N NaOH (82%, 99% ee).

Scheme 7.109

from 120 via the intermediate 121. In both cases, an enantiomeric excess of over 98% was achieved [214].

Ring Closure by Intramolecular Michael Addition Intramolecular conjugate addition of either nitrogen or oxygen to α,β-unsaturated ester was employed to morpholine ring formation. Thus, N-alkylation of 123 with 124 and subsequent intramolecular

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring NH HO

N3 N3

HO

5 steps

O

MsO MsO

NHBoc NHBoc

O

O

(a–b)

O NH

(117)

(2S,2′S)-(119)

(118)

O O

8 steps

OH OH

O

BocHN BocHN

O O

OMs

(a–b)

HN

OMs

HN O

(120)

(3S,3′S)-(122)

(121)

Reagents and conditions: (a) NaH/THF (91 – 99%), (b) 1. TFA/CH2Cl2, 2. 3 M NaOH / Et2O (29 – 47%, >98% ee).

Scheme 7.110 COOMe H N

OH OH

+

Br (a)

COOMe

OH

N

OH

O

O +

N

COOMe (123)

(124)

(2S,6S )-(125)

(2R,6S )-(125)

Reagents and conditions: (a) K2CO3 /Et2O/MeOH (100%, dr 6:1).

Scheme 7.111

Michael addition afforded a 6:1 mixture of (2S,6S)-125 and (2R,6S)-125, which could be separated by ﬂash chromatography [170, 215]. Selenium-promoted addition of (R)-phenylglycinol to alkene 126 bearing an electron-withdrawing group gave selenides 128 and 132, which after separation were oxidized to unsaturated nitrile derivatives 129 or 133, respectively. Intramolecular Michael addition of the trans isomer 129 gave a 1:1 diastereomeric mixture of 130 and 131, while the cis Michael acceptor 133 resulted in a 7:3 mixture of 134 and 135 [216]. Miscellaneous Methods for Ring Closure Morpholines 138 and 139 could be synthesized in excellent regio- and stereoselectivities (dr: 22.7:1 to 1:14.4) by opening the epoxide 136 in the presence of enantiomerically pure palladium complexes using ligands 140, and subsequent ring closure with KCN [170, 217]. Three-component boro-Mannich reaction between N-protected ethanolamines 141, glyoxal derivatives 142, and boronic acids 143 via a tetracoordinated intermediate (144) provided 2-hydroxymorpholines 145 in various stereoselectivities (10–75% de) depending on the nature of the substituents [170, 218]. The stereoisomer lactols are interconvertible through the ring-opened form, and in some cases, the facile equilibration of the isomers in solution in combination with the crystallization

349

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

350

R

R

O

PhSe R

(126)

HN Ph CN Boc

(128)

O

R

N Ph + CN Boc

(129)

(130)

(a)

+ BocHN

R (c)

Ph HN CN Boc

CN

O

(b)

O

N Ph CN Boc (131)

1:1

OH R

Ph (127)

R

O

(b)

PhSe

O

(c)

HN Ph CN Boc

HN Ph CN Boc (132)

R

R

O

O

N Ph + CN Boc

N Ph CN Boc

(134)

(135)

(133)

7:3

R = Me, Ph N-PSP = N-(phenylseleno)phthalimide.

Reagents and conditions: (a) N-PSP/BF3·OEt2 (20 – 20%), (b) H2O2 /CH2Cl2 (86 – 93%), (c) NaH / THF (92 – 95%).

Scheme 7.112

O

O

(136) + Cl

−

(a)

R

R

O O

HN

R +

O

R

NH

NH

O

HN

H3N+

COOMe (137)

R O

(138)

(139)

PPh3 Ph3P (140)

Reagents and conditions: (a) 1. [h3-CH3H5PdCl]2 /Et3N/CH2Cl2 /140, 2. KCN/THF/MeCN (39–91%, 22.7:1 to 1:14.4). Scheme 7.113

R1 R2

OH

O

R5

O

H

+ NH

+

OH EtOH/rt R B OH 4

R3 (141)

R1 R2

O +N 3

R5 O OH B OH 4 R

R

(142)

(143)

(144)

R1 50–92% 10–75% de

R2

O

OH 5 R

N R3

R4

(145)

Scheme 7.114

of the desired diastereomer could lead to a crystallization-induced transformation resulting in a single isomer from a complex mixture [219]. Employing a similar method, alkenyl moiety deriving from boronic acid 146 could be introduced to the morpholine ring by reacting with glyoxylic acid and amino alcohol 147. From the obtained diastereomeric mixture, compound (3S,5S)-148 could be transformed to (3R,5S)-148 by treatment with triethyl amine, increasing the diastereoselectivity to 100% in this way [170, 220]. Oleﬁns 149 and N-protected ethanolamines 150 reacted via palladium-catalyzed allylic substitution in the presence of a chiral palladium(0) complex to give

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

Ph OHC COOH +

B(OH)2

(a)

NH

+

H

Ph

(146)

O

O O

+

(3R,5S)-(148)

(147)

H

Ph

N

OH

Ph

O

351

N (3S,5S)-(148)

Et3N Reagents and conditions: (a) CH2Cl2 (87%, 1.5:1 or 1:0).

Scheme 7.115 X HO

O

(a)

+ HN R

X (149)

N R

(150)

(151)

Reagents and conditions: (a) Pd(0)/L/THF(20–80%, 16–90% ee). X = AcO, MeOOCO, t BuOOCO.

Scheme 7.116

R1

O

O N

(a)

R2

(152)

R1

LA+

LA O

O N

O R2

(153)

R1

+

N

(154)

O R2

+

R1

LA O N

R2

(155)

O

O

R1

N

(156)

R1= H, Me, i Pr, t Bu, Ph, napth R2 =(S)-i Pr, (S)-i Pr, (R)-Ph, (R )-BnOCH2 Reagents and conditions: (a) SeO2 /dioxane/D (22 – 93%).

Scheme 7.117

2-vinylmorpholines 151 with moderate to good (16–90%) enantioselectivities [92–94,170, 221, 222]. A SeO2 -promoted oxidative rearrangement of 2-alkyl and 2-(arylmethyl)oxazolines 152 to unsaturated morpholinones 156 was reported. The proposed mechanism as follows: α-keto carbonyl derivative 153 formed by SeO2 oxidation of 152 undergoes Lewis acid-catalyzed ring opening to nitrilium ion 154, which rearranges to acylium ion 155 followed by a ring closure to 156 [223]. Morpholine N-oxides could be stereoselectively prepared from (1S,2S)-pseudoephedrine ((S,S)-157). Reaction of (S,S)-157 with acrylonitrile gave the N-cyanoethyl derivative 158, which was then O-alkylated with allyl bromide to 159. Treatment of 159 with m-chloroperbenzoic acid yielded the N-oxide 160, which underwent in situ Cope elimination to hydroxylamine 161 and subsequent reverse Cope elimination by heating in dichloromethane, providing morpholine N-oxide (4R)-162 as the

R2

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

352

OH

OH (a)

Ph

Ph

NH (S,S )-(157)

+

N

O

(4R)-(162)

NC

(159) Ph

O

Ph

N

NC (158)

Ph

(c)

Ph

N

NC

O

O (b)

O (d or e) +

N O (160)

Ph HO

N

(161)

O

+

+

N

O

(4S)-(162)

Reagents and conditions: (a) CH2CHCN/MeOH (100%), (b) 1. NaH/THF, 2. CH2CHCH2Br, (c) m-CPBA/CH2Cl2/K2CO3, (d) CH2Cl2/D (32%, dr 1:0), (e) MeOH/D (82%, dr 3:2).

Scheme 7.118

single diastereomer. However, heating 161 in methanol gave a 3:2 mixture of the diastereomers (4R)-162 and (4S)-162 [224]. Aminodiazoacetoacetates 165 prepared from amino alcohols 163 by treatment with ketene 164 followed by diazotransfer with MsN3 underwent cyclization to morpholinones 166 via copper-catalyzed carbene-transfer reaction with limited diastereoselectivity (dr: 1:1 to 3:3) [225]. 7.1.5.2 Asymmetric Transformations with the Involvement of the Morpholine Ring C-Alkylations of Morpholinones Asymmetric C-alkylation of a stereochemically pure substituted morpholine derivative and subsequent hydrolysis is a widely used strategy for the synthesis of enantiomerically pure amino acids. Thus, enantiomerically pure 5,6-diphenylmorpholin-2-ones 167 (called Williams chiral auxiliaries) can be stereoselectively alkylated on the ring carbon α-position to the oxo group by reacting the corresponding enolates 168 with alkylhalogenides, thereby providing the products 169 with the newly entered alkyl group trans to the phenyl groups. In most cases, high diastereoselectivity was obtained. Alkylated O

Bn

R1 N

R3 OH

R2 (163)

O

(164) (a)

Bn

R1 N

R3

O

O

R2

O

R2 (165)

R3 (b)

N2

O

O

Ac N Bn 1 R (166)

R1 = Me R2 = Me, Ph, Bn R3 = H, Ph, Reagents and conditions: (a) 1. 164/Et3N/CH2Cl2, 2. MeSO2N3/Et3N/aq MeCN (64–83%), (b) Cu-powder/toluene/rfx (70–71%, dr 1:1 to 3:1). Scheme 7.119

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring

Ph PG

N

Ph

(a)

O

N

PG

Ph

N

(5R,6S)-(167)

N

OH H 2N

O

O

R

R (169a)

(170a)

Ph (b)

O

PG

O

(c)

O

Ph (a)

O N

OLi (or Na, K)

Ph

(5S,6R)-(168)

Ph

PG

(b)

O

PG

O

(5S,6R)-(167)

Ph

Ph

Ph

Ph

353

OLi (or Na, K)

Ph PG

N R (169b)

(5R,6S)-(168)

(c)

O O

OH H2N

O R

(170b)

PG = Cbz, Boc R = various alkyl Reagents and conditions: (a) LiHMDS or NaHMDS or KHMDS/THF (crown ether), (b) RX (>90% de), (c) H2/Pd – C or PdCl2. Scheme 7.120

morpholinones, after hydrogenolysis, could be transformed to the corresponding amino acids 170 [175, 226–237]. Other differently substituted, optically active morpholinones could also be alkylated at the α-position with various stereoselectivities [196, 238, 239]. Dialkylation at 2-position could be diastereoselectively achieved by deprotonation of monoalkylated derivative 169 and subsequent reaction with various nucleophiles affording 171 [240, 241]. Najera et al. used mild PTC conditions in the presence of a weak base for diastereoselective alkylation of morpholinones 172 with activated halides. Pd-catalyzed allylation of the same substrate was also performed by reacting 172 with allyl carbonates in the presence of Pd(PPh3 )4 and 1,2-bis(diphenylphosphino)ethane (dppe) to give the product 173 [242]. However, in the alkylation reactions of 172 with inactivated alkyl halide, the PTC conditions were not suitable; instead, 2-tert-butylimino-2-diethylamino-1,3dimethylperhydro-1,3,2-diazaphosphorine (BEMP) or 1,8-diazabicyclo(5.4.0)undec7ene (DBU) was used as the base. In this case, a competitive O-alkylation was observed, which could be suppressed by adding LiI [243]. Ph Ph PG

Ph O

N

(a)

O

R1 (169) Reagents and conditions: (a)

Scheme 7.121

Ph PG

O N R2 R1

O

(171) KHMDS/R2X/THF

(80–90%, 100% de).

354

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles

O Ph

O

O

(a or b or c)

Ph

N (172)

N

O R

(173)

R = for (a) or (b): (subst)allyl, propargyl, Bn, EtCOOCCH2 for (c): Et, i Pr, nBu, i Bu. Reagents and conditions: (a) RX/K2CO3 /nBu4NBr/MeCN or CH2Cl2 /rt (60 – 75%, >92% de), (b) allyl carbonates/Pd(PPh3)4/dppe/THF/rt (53 – 65%, >91% de), (c) RX/BEMP or DBU/ (LiI)/NMP (28 – 65%, >96% de). dppe: 1,2-bis(diphenylphosphino)ethane. BEMP: 2-tert-butylimino -2- diethylamino-1,3-dimethylperhydro -1,3,2-diazaphosphorine. DBU: 1,8- diazabicyclo(5.4.0)undec -7-ene.

Scheme 7.122

Besides halogenides, allyl silanes are also suitable reagents for allylation of the morpholine ring. Reaction of acetoxy hemiacetals 174 or acetals 176 with allyltrimethylsilane in the presence of BF3 •OEt2 or TiCl4 , gave allylated products 175 or 177 as single diastereomers, respectively [244, 245]. The same methods were applied to chiral morpholines substituted in a different way [246, 247]. Titanium, aluminum, or boron enolates of diphenylmorpholinone 167 could be reacted with orthoester, aldimine, or aldehyde, affording stereoselectively the corresponding alkylated product 178, 179, or 180, respectively, with the entering group trans to the phenyl groups. In case of compounds 179 and 180, a 3.1:1 or 8:1 diastereomeric mixture was obtained, respectively, with regard to the newly formed chiral center in the side chain [248–250]. Ph

Ph Cbz

Cbz Ph

N

Ph

N

(a)

O

O

H

OAc (174)

(175)

Reagents and conditions: (a) allyltrimethylsilane/BF3·Et2O/MeCN (98%). Ph

Ph Cbz

Ph

N O R

OH

(176)

(a)

Cbz

Ph

N O R

(177)

R = alkyl Reagents and conditions: (a) allyltrimethylsilane/TiCl4/CH2Cl2 (65–67%).

Scheme 7.123

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring Ph

Ph Ph PG

(a)

O N

355

Ph PG

O

O N

O

MeO

(5S,6R )-(167)

OMe

(178) Ph Ph

O

(b)

(5S,6R )-(167)

N

PG

O

TBSO

NHBn (179) Ph Ph

(c)

(5S,6R )-(167)

PG

O N

CbzHN

O OH

(180) Reagents and conditions: (a) 1. TiCl4/Et3N, 2. (MeO)3CH/CH2Cl2 (94%), (b) 1. LiHMDS/THF, 2. Me2AlCl, 3. TBSO(CH2)2CH NBn (60%, dr 3.1:1), (c) 1. Bu2BOTf/Et3N/CH2Cl2, 2. Cbz(CH2)2CHO (69%, dr 8:1).

Scheme 7.124

Alkyl radicals generated from alkyl iodides were added to the imine bond in unsaturated morpholinones (S)-156a and (5R,6S)-182 in the presence of Bu3 SnH/AIBN. In the reaction of disubstituted morpholinone (5R,6S)-182 higher diastereoselectivity than that of (S)-156a was observed, affording the products 181 and 183, respectively, by preferential attack anti with respect to the substituents. Complete stereoselectivity, but lower yield, was obtained by alkylating compound (5R,6S)-182 at low temperature with Et3 B as complexing agent and a radical initiator [251]. Radical addition to morpholines 184 was performed in the presence of BF3 •OEt as Lewis acid using triethyl borane as the radical initiator providing the ethylated product 185 (R = Et) and ethylated imine 186 (R = iPr). Isopropyl radical addition proceeded smoothly in the presence of isopropyl iodide [252]. Under the same conditions, except using Lewis acid, radical addition to unsaturated 5,6-diphenylmorpholinone N-oxides were carried out in high (95%) diastereoselectivity [253]. Arylations Stereoselective introduction of aryl groups to position 3 was performed on substrate 187 in two alternative ways. Reaction of 187 with various aromatic compounds possessing bromine, methoxy or hydroxy groups as the substituents in the presence of TFA or reaction of boronic acid gave the corresponding substituted products 188 in 60–90% de [170, 254].

356

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles O

O

O

(a)

N

i Pr

R

(S )-(156a)

O

O

Ph

(a or b)

N

O

i Pr N H (181)

O

O

R

N H

(5R,6S )-(182)

Ph

(183)

R = n Bu, t Bu, c Hex Reagents and conditions: (a) RI/nBu3SnH/AIBN/benzene/80 °C (41– 62%, dr 55:45 to 60:40 for 181, 75:25 to 87:13 for 183), (b) RI/Et3B/CH2Cl2/−40 °C (25 – 27%, dr 90:10 to 100:0).

Scheme 7.125 Ph

Ph

Ph N

N

NH

(a or b)

O

O

R

+

O

R

O

O

O

(184)

(185)

(186)

Reagents and conditions: (a) BF3·OEt2/Et3B/hexane/CH2Cl2/0 °C-rfx (42 – 74%, 81– 87% de, 185:186=10:6 to 10:1), (b) BF3·OEt2/i PrI/Et3B/hexane/CH2Cl2/rfx (185: 61%, 82% de, 186: 15%).

Scheme 7.126

Arylation of oxazinones 189 was achieved by treatment of the corresponding enolates with (arene)Mn(CO)3 complexes, followed by oxidative demetalation of the intermediate substituted cyclohexadienyl-Mn(CO)3 complex 190 to afford arylmorpholinones 191 in 75–99% de [255]. Stereoselective Reductions Reduction of alkylidene substituents in compounds 192 or 194 to the alkyl ones could be carried out either by hydrogen gas in the O Ph

N (187)

O

O

(a or b)

Ph

O

N Ar H (188)

Reagents and conditions: (a) TFA/CH2Cl2/ArH (83 – 98%, 60 –100% de), (b) 4-MeOC6H4B(OH)2/Cl(CH2)2Cl/TFA (85%, 90% de).

Scheme 7.127

7.1 Six-Membered Rings with Another Heteroatom in the Same Ring Ph Ph PG

N

PG

(a)

O O

O N

O

Ph

(b)

R

PG

O N

O Ar

Mn(CO)3 (190)

(189)

(191)

PG = Boc, Cbz Reagents and conditions: (a) 1. NaHMDS/THF, 2. (arene)Mn(CO)3+PF6−, (b) NBS/Et2O (44–65%, 75–99% de).

Scheme 7.128

O

PMB N R

O

PMB R N

(a)

O

O Ph

Ph (192)

(193)

R = i Bu, s Bu Reagents and conditions: (a) H2/Pd – C (97–98%, dr 8:1 to 10:1). Scheme 7.129 O

O

O

O

Ph

N R

(a or b)

Ph

N R

( )n

(194)

COOEt

( )n

COOEt

(195)

R = H, Bn n = 0, 1, 2 Reagents and conditions: (a) BH3·THF/MeCN (76 – 80%, 90 – 92% de), (b) NaBH4/AcOH/MeCN/TFA (71%, 94% de).

Scheme 7.130

presence of a Pd–C catalyst or with NaBH4 , or using the borane–THF complex as the reducing agent, providing the cis products 193 or195, respectively, in good stereoselectivity [186, 256]. Iridium complex-catalyzed asymmetric hydrogenation of achiral exocyclic double bond in 196 allowed the introduction of a chiral center on an achiral structure. The reaction was performed in the presence of chiral phosphine ligands and afforded the corresponding saturated derivatives (S)-197 in good (79–85.5%) enantiomeric excesses [257].

357

358

7 Asymmetric Synthesis of Ring Nitrogen Heterocycles O

O COOEt

N

(a)

O

RO

COOEt

N RO

(196)

O (S )-(197)

R = Me, t Bu Reagents and conditions: (a) 40 – 50 bar H2/((COD)Ir(Cl))2/(S )-BINAP or (S )-TolBINAP (100% conv, 79 – 85.5% ee).

Scheme 7.131

Both endo- and exocyclic double bond in 198 was saturated using PtO2 as the catalyst to 199 in excellent stereoselectivities (dr: 96:4 to 97:3). In the presence of formaldehyde, N-methylated derivative 200 was obtained with diastereomeric ratios of 91:9 to 98:2 [192, 193]. Diastereoselective reductions of chiral unsaturated morpholinones 201 to 202 were carried out by three different methods. PtO2 /H2 , NaBH(OAc)3 , or BH3 proved to be the suitable reducing agent [256, 258]. For saturation of 203 to 204 or205 to 206, respectively, either PdCl2 or Pd–C was applied successfully as hydrogenation catalyst [183, 259, 260].

O Ph

O

O

O

N X

R

(a or b)

Ph

N R

(199) X = H (200) X = Me

(198) R = Me, Ph, i Pr, i Bu X = H, Me

Reagents and conditions: (a) PtO2/H2/MeOH (62–95%, dr 96:4 to 97:3), (b) PtO2/H2/CH2O/MeOH (63–75%, dr 91:9 to 98:2).

Scheme 7.132

O

O

O

O

N H

Ph

(a or b or c)

R

N (201)

Ph

R

(202)

R = Me, Et, i Pr, n Bu, t Bu Reagents and conditions: (a) H2/PtO2/MeOH (73–89%, cis:trans = 83:17 to 93:7), (b) NaBH(OAc)3/TMSCl (73–83%, 60–86% de), (c) BH3·THF/MeCN (71–93%, 84–98% de).

Scheme 7.133

References Ph

Ph Cbz

Ph

N

(a)

Ph

HCl HN O

O ROOC

ROOC (203)

(204)

R = Me, Et Ph

N

(b)

Ph

N O

O

COOEt

COOEt (205)

(206)

Reagents and conditions: (a) H2/PdCl2/EtOH/HCl (99%, dr 96:4), (b) H2/Pd – C/EtOAc (quant).

Scheme 7.134

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8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom Jacques Royer

8.1 Diazepines

The diazepines represent a large class of compounds for which many syntheses were described in the literature. They are natural and synthetic products with interesting biological activity. Among diazepines, the 1,2-diazepine are rare while 1,4-diazepines are the most often reported isomers. The 1,3-diazepines are urea or amine derivatives and their preparation was on the basis of the access to these functional groups. Concerning the 1,4-diazepines, many methods of preparation were reported but most of them were derived from amino acids, which furthermore allowed the introduction of chirality. 8.1.1 1,2-Diazepines

Asymmetric synthesis of chiral 1,2-diazepine is rarely reported in the literature though some of them are known as biologically active compounds. For example, talampanel was found to possess potential antiepilectic, neuroprotectant and skeletal muscle relaxant activities [1] and cilazapril (Figure 8.1) is effective in the treatment of hypertension and other cardiovascular disorders [2]. A very few methods were reported and were classical ones on the basis of a unique strategy. They are mainly prepared through the bis-condensation of a hydrazine to a 1,5-dicarbonyl derivative. The latter is thus the chiral part of the molecule and no new chiral center is formed during the process. The bis-condensation may be attained during a one-pot reaction; for example, the pyrrolodiazepine 3, a potential acetylcholine esterase (ACE) inhibitor, was prepared through the reaction of a monosubstituted unprotected hydrazine with the cetoacide derivative 1 [3] to give the required heterocycle 2 in modest yield (Scheme 8.1).

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

368

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom O N N

O

O N N

O EtO NH

O

OH

O Ph

H2N

Cilazapril

(−)-Talampanel

Fig. 8.1 Biologically active 1,2-diazepines. O O H H2N N

Cbz

O

N O

O O

CO2Et

Cbz N

O EtO2C

(1)

N N

HCl

N N O

EtO2C

Cbz N H

O

OH

(2)

(3)

Scheme 8.1

Indeed, a two-step process seemed more efﬁcient and is currently used. The 1,5-dicarbonyl compound may be a suitably protected glutamic acid or a synthetic product. The hydrazine part may also be chiral as in the following two examples. In these cases, devoted to the preparation of interleukin-1β converting enzyme (ICE) inhibitors the condensation is sequential and ends up by lactamization [4, 5] or by reductive alkylation [6] ( Scheme 8.2). In the preparation of 9, a sugar (d-xylose) was the starting material, which was treated with a monoprotected hydrazine (Scheme 8.3). The basic treatment of mesitylsulfonate 7 gave in good yield and without loss of optical purity, the seven-membered ring 8 probably via the intermediate formation of an epoxide [7]. 8.1.2 1,3-Diazepines

These heterocycles are widely represented by compounds found as potent HIV protease inhibitors. This is particularly the case for cyclic ureas such as DMP 323 CO2Bn

Cbz

Cbz

N HN

Phth N

CO2tBu

COCl

BnO2C

NaHCO3 aq. (92%)

N Phth

(4)

(5)

Scheme 8.2

O N N O CO2tBu

N N

(1) H2, Pd/C, MeOH (2) PCl5, N-Et-morpholine

Phth=N

O (6)

CO2tBu

8.1 Diazepines Bz Ac N N

O O SO2 OH

N NHBz Ac

O

MeONa

HO

(77%)

H H N N

HCl

HO

OH

OH

HO (7)

369

HO

(8)

(9)

Scheme 8.3

and DMP 450. The main characteristics of their structures are the seven-membered ring, the cyclic urea functionality, and a C2 symmetry. The synthesis of these compounds and their analogs is, in most cases, the same and consists of the preparation of a chiral 1,4-diamine, which is transformed into a cyclic urea with a suitable reagent, such as carbonyldiimidazole, [8] phosgene [9], trialkylorthocarbonate [10], or dimethylcyanodithioiminocarbonate via the cyanoguanidine [11]. The following sequence [8c] (Scheme 8.4) is representative of the published syntheses. In this example, the chiral diamine 11 was obtained through the low valent vanadium pinacol coupling with the aldehyde 10 derived from phenylalanine. Several examples are also reported on the preparation of analogous diamines from tartaric acid or sugars. The preparation of structurally related C2-symmetric guanidines was also reported. These compounds are potent glycosidase inhibitors. Diamine 13 (Scheme 8.5), derived from mannitol, when treated with carbon disulﬁde in pyridine gave thiourea 14, which could be transformed to guanidine 15 [12]. O O CbzHN

CbzHN

VCl3 (THF)3, Zn

H

Ph

Ph

THF, rt

Ph

(1) SEMCl, Hunig's base

NHCbz

HO (10)

OH

HN

(2) H2, Pd/C (3) CDI, CH2Cl2

Ph

SEMO

(11)

N

O N

Ph

N

OH Ph

or

H 2N

DMP 323

N

Ph

NH2

Ph HO

OH

HO

OSEM (12)

O

HO

NH

Ph

OH

, 2 CH3SO3H

DMP 450

Scheme 8.4 NBn

S NH2

NH2

BnO

HN OBn

O

O

(13)

Scheme 8.5

CS2 Py (86%)

HN

NH

BnO

OBn O

O

(14)

BnNH2, HgCl2 Et3N, CH2Cl2 (91%)

NH

BnO

OBn O

O

(15)

370

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

Fused diazepine–pyrrolidine compounds have been obtained by Wasserman by the use of the vinyl tricarbonyl reagent he introduced some years ago (Scheme 8.6). Hence, the amide derived from glutamic acid was condensed with this tricarbonyl reagent 17 to give a bicyclic compound in a fair 33% yield [13]. A single stereomer was obtained but its conﬁguration not reported. A Pd-catalyzed cyclization process of 2-vinylpyrrolidine 19 and aryl isocyanate or carbodiimide was recently proposed [14] and gave a vinyl 1,3-diazepine 20 (Scheme 8.7). This interesting reaction, which formally implied the insertion of the carbodiimide in the pyrrolidine ring, was also conducted in the presence of chiral phophine ligands such as (R,R)-NORPHOS; unfortunately, only a modest chiral induction was observed. A much more classical reaction was described in 2005 to achieve the asymmetric synthesis of a 1,3-diazepine system. The synthesis was conducted in solid phase and the cyclization to form the azepine ring was the result of the trapping of an in situ formed acyliminium (Scheme 8.8). Acidic deprotection of oxazidine A gave an aldehyde that could condense with the amide to form an acyliminium, which slowly cyclized in TFA to form the bicyclic heterocycle in high yield and as a unique stereomer [15]. CO2Me

NH2

MeO2C

O

NH2

OtBu

+ O

O

CH2Cl2 /MeOH

N

rt (33%)

O

O CO2tBu

NH O (18)

(17)

(16)

Scheme 8.6 10 mol% Pd2(dba)3 CHCl3 Ph P Ph

20 mol%

N R R = Bu, Cy (19)

+ Ar N

NAr

Ph P Ph

N Ar

NAr

rt, THF (6–65%)

NR

Ar = o, m, p Cl-C6H4 (20) (6–41% ee)

Scheme 8.7 O

(1) TFA aq. (10%) 1h

NH

Boc N

NHTrt O O (21)

Scheme 8.8

O

O

O

GlyPheGly

HOGlyPheGly N

(2) TFA, 20h (3) 0.1M NaOH aq. then 0.1M HCl aq.

NH H O

(93% purity) (22)

8.1 Diazepines O

R2 N

O CONH2

N N H

Me OH

H OH

R1

O MeO HO

Anthramycin

N

N

N

O

H

N

371

Circumdatin F (R1 = R2 = H)

Tomaymycin

Benzomalvin A (R1 = Ph; R2 = CH3) Asperlicin (R1= indole; R2= H)

Fig. 8.2 Natural benzodiazepines.

8.1.3 1,4-Diazepines

These heterocycles are of great importance as a very impressive number of 1,4-diazepines are biologically active products. Among them, the benzodiazepine series is a very well known series and has been proved to exhibit important activities ranging from those of central nervous system (CNS) to those of anticancer agents, while antibiotics, anti-HIV, or cardiovascular agents were also reported. Several natural products were also known and some of them are depicted in Figure 8.2. Because of the huge importance of this series of products, a very rich literature exists describing numerous asymmetric syntheses. Indeed, compared to the number of papers dealing with 1,4-diazepines, the number of available methods of preparation is not so large; the more general and recent ones are gathered below. Because of their paramount importance, the benzodiazepine products are described separately. 8.1.3.1 1,4-Benzodiazepines Via 2-Nitrobenzoic Acid Derivatives or Isatoic Anhydride Formally, a benzodiazepine is the result of the condensation between anthranilic acid and an α-amino acid. This O

O

NO2

N

R1

L-Pro-OMe

O (24)

(23) O

R1

H N N O (25)

Scheme 8.9

O

CO2Me SnCl2 2H2O, DMF, H2O

CO2Me (2) DCC, DMAP

R1

NO2

(1) NaOH, dioxan

HO

R2

O

N N

R1 O (26)

R1 = H, OCH3 R2 = H, CH3, allyl

372

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom CH(SEt)2

RO

NO2 CO2H

MeO

RO

HN

(COCl)2, DMF, THF Et3N, CH2Cl2

NHFmoc CH(SEt)2 N

MeO

O

CH(SEt)2

N

MeO

Fmoc OH N H

RO

HgCl2 CaCO3 CH3CN-H2O

N

MeO

(29)

(1) SnCl2 2H2O, MeOH, ∆ (2) Fmoc-Cl, Na2CO3-H2O, dioxane

O (28)

(27)

RO

NO2

O

R = CH2CH2CH2CO2Me

(30)

Scheme 8.10

methodology is not directly used but derived methods were more often described. A 2-nitrobenzoic acid (or ester or acyl chloride) [16] is usually condensed with an amino acid through classical coupling methods as in the recent example depicted in Scheme 8.9 showing the possible use of a solid phase synthesis. The reduction of the nitro group then allowed cyclization by lactamization [16b]. The same type of reaction was also described starting from an o-azido benzoic acid [17]. The use of isatoic anhydride (substituted or not) as a more activated starting material has been reported [18]. The condensation with an α-amino acid may be conducted in a single step in reﬂuxing pyridine [19]. The preparation of anthramycin, tomaymycin, and analogs and more generally of antitumor- and gene-targeted drugs possessing an imine or N, O-acetal (or hemiacetal) function [20] requires the use of a chiral aminoaldehyde instead of the parent amino acid. The strategy remained the same and is illustrated in Scheme 8.10 [20d]. The nitrobenzoic acid 27 was ﬁrst coupled with a protected aldehyde derived from proline and the nitro group was reduced to a primary amino group. The Fmoc protection, followed by the selective aldehyde regeneration allowed the cyclization to occur with formation of the benzodiazepine ring. Via an SN Ar Reaction Some authors described the synthesis of benzodiazepines through an SN Ar reaction. The attachment of the appropriate amino acid to a benzoic acid derivative was followed by the SN Ar reaction. This reaction usually necessitated the presence of a ﬂuorine atom and a nitro activating group. This may Ot-Bu

F

N (MeO)2HC

H N

(1) DBU, THF

NHFmoc

O2N

O Ot-Bu

(2) Et3N, DMSO, H2O

N

O2N

O (31)

Scheme 8.11

CH(OMe)2 (32)

8.1 Diazepines

373

allow the speciﬁc substituents on the aromatic ring to be suitably positioned. The SN Ar reaction could occur for the cyclization step or for the introduction of the amino acid moiety onto the aromatic ring. The sequence described in Scheme 8.11 used the SN Ar reaction as the ﬁnal cyclization step and furnished a benzodiazepine as a mimetic of type-II β-turn [21]. To achieve the cyclization, an intramolecular CuI-catalyzed arylamination according to the Ullmann reaction has also been described [22]. For instance, 1,5-benzodiazepines 34 (Scheme 8.12) has been prepared as a peptidomimetic with caspase-1 inhibitor properties. Along with this synthesis the SN Ar reaction of 1-ﬂuoro-2-nitrobenzene with Boc-(l)-2,3-diamino propionic acid afforded amino acid 33 [23]. The latter was reduced and then cyclized to give 34. Via a Strecker Reaction R. Herranz proposed an original strategy of preparation of 1,4-benzodiazepines using an aminonitrile route. Methyl anthranilate was condensed with a chiral N-Boc-amino aldehyde in the presence of TMSCN to give the aminonitrile 35 in good yield but as a 2 : 1 mixture of stereomers (Scheme 8.13). Reduction (Raney Ni) and cyclization allowed the isolation of the desired benzodiazepines 36, which were chromatographically resolved to both epimers [24]. Ugi Reaction In a series of papers devoted to the enantioselective preparation of 1,4-benzodiazepine-2,5-diones as Hdm2 antagonist, Lu and coworkers [25] reported the use of a Ugi reaction according to the process established by Amstrong [26], which used 1-cyclohexyl isocyanide. The Ugi reaction was followed by in situ cyclization to the diaza heterocycle. Chiral amine 37, benzaldehyde 38, and acid 39 were condensed with isocyanocyclohexene 40 for two days at room temperature and followed by cyclization with acetyl chloride to give the expected diazepine 41 in good yield but as a 1 : 1 mixture of epimers, which could be separated by chromatography (Scheme 8.14). H2N

NO2

Boc

F

NaHCO3, DMF (83%)

N H

CO2H

NO2 CO H 2 NH Boc

N H (33)

H N

(1) H2, Pd/C (2) EDC, DMF (71%)

N H

O NH Boc

(34)

Scheme 8.12 Bn

Bn

NH2

OHC

H N

N Boc H

CN CO2Me

CO2Me ZnCl2, TMSCN (81%)

(35)

Scheme 8.13

Bn N Boc (1) Raney-Ni (94%) H (2) NaOMe/MeOH (87%)

H N NH O (36)

N Boc H

374

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom Cl NO2

Cl

Cl +

+

I

CO2H

N +

(37)

(38)

N

(2) AcCl, rt to 60 °C (73%)

CHO

H2N

I

(1) MeOH, rt

NHBoc

NO2

O

(39)

N H

(40)

Cl O (41)

Scheme 8.14

Diastereoselective Alkylation Carlier reported the enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepine -2-one 43 by alkylation of chiral diazepine 42 following the concept of memory of chirality deﬁned by K. Fuji. The use of the di-(p-anisyl)methyl (DAM) group on the lactam nitrogen was proved to provide quaternary benzodiazepines in higher enantioselectivities and yields upon the deprotonation/alkylation sequence as ee > 99% was obtained as in the following example (Scheme 8.15) [27]. Photocyclization The same concept of memory of chirality was invoked in a photochemical process that may involve a 1,7-triplet biradical. The proline derived potassium salt 44 gave the pyrrolobenzodiazepine 45 upon a decarboxylative photocyclization (Scheme 8.16). A high degree of chirality was retained as compound 45 was obtained with 86% ee [28]. Ph N

O

Ph Cl

Bn

BnBr (80%)

N

O

OMe MeO

MeO

(42)

COOK N HO hv

N O

(44) Scheme 8.16

Acetone-H2O (45%)

N OMe

Scheme 8.15

O O

Cl

N

KHMDS, HMPA, THF, −78 °C

N H

N

O

O

(45) 86% ee

(43) 99% ee

8.1 Diazepines

375

1,3-Dipolar Cycloaddition Homochiral N-alkenoyl azide 46 (Scheme 8.17), easily obtained from the corresponding amines via diazotation, underwent an intramolecular 3+2 cycloaddition to furnish original triazol-benzodiazepine-4-ones 47a,b. Under very mild conditions, and thanks to the presence of a chiral appendage on nitrogen, diastereomers were obtained and could be separated. Though the method was somewhat hampered by a modest diastereoselectivity, it offered an original and straightforward approach to this type of compounds [29]. Meyers’ Bicyclic Lactam Strategy In efforts toward the asymmetric synthesis of natural products of the circumdatin series, the Meyers’ bicyclic lactam strategy was used to attain the benzodiazepine skeleton in very good diastereoselectivity albeit low yield. The methyl-quinazoline 48 was easily prepared by the condensation of two molecules of anthranilic acid and then oxidized to the aldehyde 49 with selenium oxide (Scheme 8.18). Then aldehyde 49 was condensed with phenylglycinol to afford the quinazolone–benzodiazepine 50 in a modest 25% yield but an excellent 95% de [30]. Importantly, the conditions allowed the formation of the natural product biaryl aS conﬁguration. Nitrilium Insertion An original new approach to pyrrolobenzodiazepines (PDB) known as antitumor compounds and their heterocycle-fused pyrrolodiazepine analogs appeared in 2005 [31]. In this approach, the cyclization process consisted in intramolecularly trapping of a nitrilium species by an electron-enriched aromatic group. Proline derivative 51 was readily obtained by classical amino acid coupling and transformed to the methoxyamide 52. Hypervalent iodine (phenyliodine bis(triﬂuoroacetate) (PIFA) (Scheme 8.19) oxidation was found to be effective

N3

N N

Et2O, rt

N

O

N H O N

Ph (46)

N N

N H O

+ N

Ph

(47a) (61%)

Ph

(47b) (28%)

Scheme 8.17

Ph O CO2Et CO2Et NH2

HC(OEt)3 Sealed tube, 180 °C

N

(48) Scheme 8.18

CHO

SeO2

N O

CO2Et N N

O

(49)

Ph NH2

N OH

CH2Cl2 MgSO4

O

aS N

H N

O

(50)

376

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

O N

O N

MeO

O

N

N

MeOHN

O

(51)

PIFA

N

CH2Cl2 (60%)

O

N N O

MeO

(52)

(53)

Scheme 8.19

to form the positively charged N-acetyl nitrenium species that was trapped in situ to form the pyrrolo benzodiazepine (PBD) analog 53. 8.1.3.2 Other 1,4-Diazepines Amino Acid Strategies The methods already described in the benzodiazepine series could be used in the preparation of diazepines in general. The more general and obvious method is the condensation of a β-amino acid with an α-amino acid; both of them could be asymmetric [32] but more frequently only the α-amino acid is the chiral partner with no formation of a new chiral center [33]. In the following example (Scheme 8.20), the preparation of a novel µ-opiod receptor antagonist was on the basis of the asymmetric access to the highly substituted pipecolic acid 54, coupled with 3-amino propionic acid and cyclized to form the diazepine skeleton [34]. The amino acid could be condensed with a 3-haloamine or 3-acrylonitrile [35] giving rise after function manipulations to intermediary derivatives ready to cyclize into the diazepine ring. The ﬁnal cyclization is generally a lactamization, as described above, but a Mitsunobu reaction with a serine hydroxyl was reported [36]. OTBDMS

OTBDMS

OH

Bn NH EtO2C

HO2C

N Boc

(1) 4M HCl

Bn N

TBTU, i-Pr2NEt (60%)

O

EtO2C

(54)

N Boc

(2) o-Xylene (23%, 2 steps)

O N O

Bn N

(55)

(56)

Scheme 8.20

H N

O O

S O (57)

Scheme 8.21

R

NH2

NH2

COOH H2O, 40 °C

S

NH O

O OH R

H N

AcOH 100 °C

S

O

NH O (58)

R

8.1 Diazepines

377

In a recent paper, Martinez [37] described the reaction of various amino acids with thiaisatoic anhydride (Scheme 8.21). This two-step, one-pot procedure allowed an expeditive and efﬁcient access to thienodiazepines. Cyclization through a Nitrogen Nucleophilic Displacement Several diazepines were prepared through a non–amino acid route. In most of these cases, the formation of a carbon–nitrogen bond was the ultimate cyclization step giving rise to the diazepine skeleton [38]. In the following example (Scheme 8.22), 1,4-diazepane annulated β-lactam was obtained by construction of the diazepine ring on the β-lactam. The (R)-glyceraldehyde acetonide (59) was the starting material for the β-lactam ring formation through the Staudinger reaction. The oxidative cleavage of the diol and alkylation of the nitrogen of the lactam allowed the formation of a bromo aldehyde and then the bromo imine 61. The latter was reduced with NaBH4 to allow the cyclization and furnish the optically active bicyclic β-lactam 62 [39]. Cyclization through a Strecker type reaction was used in the total synthesis of manzacidin A and C reported in 2000 by Ohfune [40]. In the synthesis of liposidomycins, a new class of complex nucleoside-type antibiotics, the construction of the diazepinone ring was attained by the double opening of bis-epoxide 63 by methylamine as shown in Scheme 8.23 [41]. Paal–Knorr Cyclization Lubell has described the synthesis of pyrrolodiazepinone via an intramolecular Paal–Knorr condensation [42]. The synthesis started by the condensation of an α- and a β-amino acid to 65 (Scheme 8.24), which was transformed to the homoallylic ketone 66 precursor of 4-keto aldehyde or 1,4

O H

O

H H

O

O

BnO

NaBH4

BnO N

O

N

H H

O

(59)

N

Br

(60)

MeOH

Br

O (61)

O

O

O

O

O

N

HN

PMB O

N

(67%)

O O

O

N

HN N

O

O

HO (63)

Scheme 8.23

OH

O

MeNH2

N O (62)

Scheme 8.22

N

H H BnO

(64)

O

PMB O

N

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

378

O

Bn

N H NHBoc

O CO2Me

Bn

O H

N H NHBoc

(65)

Bn

(1) TFA / CH2Cl2

N

HN

(2) Et3N / CH2Cl2 (3) TsOH / CH2Cl2

O

O

(66)

(67)

Scheme 8.24

diketone through oxidative processes. Deprotection of the nitrogen allowed the Paal–Knorr condensation to occur in good yield.

8.2 Oxazepines

Oxazepines constitute a large family of compounds while not so large as the diazepine ones. Their preparations are interesting and basically different from those of diazepine derivatives. 8.2.1 1,2-Oxazepine

This type of compounds has mainly been prepared by cycloaddition: 4+2, 3+2 and 3+4 cycloadditions were found to be used to give bicyclic derivatives with good diastereoselectivities. 8.2.1.1 Diels–Alder Cycloaddition Several workers reported that Diels–Alder cycloaddition of cycloheptatriene with chiral acyl- or chloronitroso derivatives afforded oxaza-bicyclo[3.2.2] nonanes in good yields and stereoselectivities. Lallemand [43] investigated various acylnitroso compounds (derived from alanine, mandelic acid, and ribose). The hydroxamic acid 69, derived from alanine (Scheme 8.25), was reported to be oxidized under Swern conditions and in situ cyclized with cycloheptatriene to give the bicycloadduct 70 as a 3 : 1 mixture of stereomers [44]. Recrystallization of the mixture allowed the diastereomeric ratio to be raised to 50 : 1, and was followed by deprotection and oxidative cleavage of the double bond to furnish the diester 71. During the preparation of the same type of oxaza-bicyclo compounds, Wang [45] reported that both the acylnitroso and the chloronitroso compounds derived from O + Boc NH

(68)

(69)

Scheme 8.25

O

(COCl)2, DMSO

NH OH

BocHN −78 °C, Py

N O (70)

MeO2C R

N

O

(71)

CO2Me

8.2 Oxazepines

379

OBn

BzO

Toluene

+

NHOH BzO

BnO

CHO

N

OBz

OBz O

MS, 4A 110 °C, 20 h

OBz H

(72)

OBz (73)

Scheme 8.26

the same ketopinic acid added to cycloheptadiene to give the desired compounds in good yield and excellent but inverted diastereoselectivity. 8.2.1.2 Intramolecular 3+2 Cycloaddition Several papers reported the intramolecular 3+2 cycloaddition between a nitrone and an oleﬁne [46]. The condensation of hydroxylamine 72, derived from methyl α-d-glucopyranose, with 2-(benzyloxy)-acetaldehyde in dry toluene gave cycloadduct 73 as the only isolable product (Scheme 8.26). 8.2.1.3 Pd-Catalyzed 4+3 Cycloaddition Inspired by the cycloaddition of the Palladium trimethylenemethane complexes reported by B. Trost, R. Shintani, and T. Hayashi [47] described the cycloaddition of nitrones with γ -methylene-δ-valerolactone 74. The use of chiral ligands such as 77 furnished the oxazepine 76 in excellent yield, as well as dia- and enantioselectivity (Scheme 8.27). 8.2.1.4 Rearrangements Some rearrangements, in natural product series, have been found to provide the 1,2-oxazepines in good preparative yields and deserve to be noticed herein [48]. Thus, (+)-nupharidine (78) (Scheme 8.28) furnished 1,2-oxazepine 79 in 65% yield O

−

O + CO2Me

O + Ar1 N

Ar2

Ar

H

PdCp(h3-C3H5)

(75)

H

N

Scheme 8.28

CO2Me (76)

O

H

(78)

Ar1

L*, CH2Cl2

Scheme 8.27

O

Ph

Ar2 L* =

N

∆, 1.5 h

O O (79)

Me

O O

P N Me Ph

Ar

(74)

N

O N

(77)

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

380

upon simple heating in dimethyl acetamide (DMA) for 1.5 h. A stereoselective reaction was observed but the conﬁguration of the new formed chiral center was not determined [49]. 8.2.2 1,3-Oxazepines

The two heteroatoms in this type of compounds can form a N,O-acetal or a carbamate function. This would dictate the mode of formation of the heterocycle. 8.2.2.1 N,O-Acetals Iminium Cyclization The formation of a N,O-acetal was classically obtained through an iminium cyclization. The iminium ion can be classically formed by oxidative or reductive methods or by in situ condensation of a secondary amine with an aldehyde. This is illustrated herein in the preparation of similar peptidomimetic derivatives. In the synthesis of peptidomimetic 80 described by Moeller [50], the iminium was formed by the anodic oxidation of the proline-homoserine dipeptide 81 and trapped in situ to give regio- and stereoselectively the pyrrolooxazepine (Scheme 8.29). The same product was obtained by Zhang [51] in 2001, but in this case the partial and selective reduction of the lactam function of a pyroglutamic-homoserine derivative 82 furnished the iminium. A similar compound was recently prepared through the Rh catalyzed hydroformylation of the dipeptide 83 (Scheme 8.30). The so-formed intermediate aldehyde 84 allowed the formation of the N,O-acetal of the piperidinooxazepine 85 derivative with complete stereoselectivity [52]. In the synthesis of alkaloid (+)-tacamonine, an interesting insertion of two formaldehyde units were reported to occur in high yield to give the pentacycle 87, O

O

CO2R

BocHN

Pt anode

N

nBu4NBF4 iPrOH/CH3CN 48%

HO (81) R = Me

O

CO2R

BocHN

(1) LiBEt3H

N

N

THF, −78 °C

O

(2) TFA cat. CH2Cl2 35%

H (80)

CO2R

BocHN O HO

(82) R = Et

Scheme 8.29

BocHN

O

CO2Me

N H OH (83)

Scheme 8.30

H2, CO PTSA, Tol. Rh(Acac)(CO)2 BIPHEPHOS

BocHN

O

CO2Me

N H OH

O

CO2Me N

O CHO

(84)

BocHN

H (85)

8.2 Oxazepines N N

H N

N

(CH2O)3, ∆

OAc

HCO2H, THF

OAc

N

Boc

OAc

N H

O

(86)

O (+)-Tacamonine

(87)

Scheme 8.31

which was stereoselectively reduced to the indoloquinolizidinooxazepine allowing the introduction of two of the stereogenic centers of natural tacamonine (Scheme 8.31) [53]. Formaldehyde was also used to attain the oxazepine skeleton in the synthesis of analogs of quinocarcin [54]. The treatment of the amino alcohol, resulting from the Cbz deprotection of 88, with formol furnished the tricyclic compound 89 in 52% overall yield and >95% ee (Scheme 8.32). An interesting while undesired cyclization to an oxazepine was observed in the course of the synthesis of pinnaic acid. This was obtained during the trimethylsilyliodide (TMSI) cleavage of the O-benzyl group of intermediate 90 to give 91 in 83% yield [55] (Scheme 8.33). This reaction may constitute an interesting access to oxazepine derivatives and, moreover, shows the high electrophilicity of the triﬂuoroacetyl group. Nucleophilic Displacement The 1,3-oxazepine skeleton has been formed in very good yield by an intramolecular nitrogen alkylation of β-lactam 92 (Scheme 8.34) [56]. Only very minor amount (3%) of the expected six-membered ring 94 was found in this process while the seven-membered ring 93 was isolated in 80% yield.

OH

OMe

OMe (1) H2, Pd/C, AcOEt

NHCbz

O N

(2) 35% HCHO, MeOH 52% 2 steps

(89) >95% ee

(88) Scheme 8.32

MeO2C

MeO2C

H F3C

TMSI, CH2Cl2

N

O BnO

rt (83%)

Scheme 8.33

H F3C HO

N

O H CH3

H

CH3 (90)

381

(91)

382

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom O

TsO TsO H O

O

NH

CH3CN, ∆

O

O

O

H O

Bu4NBr, Na2CO3

H

H N

+

H OTs

O

O

H

O

O

O

N

(92)

O

O H OTs

O

(93) (80%)

(94) (3%)

Scheme 8.34

Radical Cyclization A tandem radical cyclization was observed when the phenyselenium derivative 95 was treated with Bu3 SnH and AIBN in benzene. The second cyclization gave the seven-membered ring compound 96, which upon Tamao conditions furnished the cyclonucleoside 97 in 35% overall yield (Scheme 8.35) [57]. Carbamates The nitrogen and the oxygen of the 1,3-oxazepine may be linked in a carbamate function. This function can be classically obtained from the corresponding amino alcohol. Indeed, in the examples found in the literature, the oxazepine was an undesired by-product obtained by the nucleophilic attack of an alcohol on the amide or carbamate protecting group [58]. Similarly, the photolysis of azido derivative 98 gave rise to the oleﬁne aziridination in 85% yield, instead of the expected nitrene insertion at the allylic position (Scheme 8.36) [59]. Others In sugar series, the thermal treatment of diazides such as 100 led to the formation of a tetrazole ring with enlargement of the sugar ring to a 1,3-oxazepine skeleton in a very good yield (Scheme 8.37) [60]. The reaction was also reported through photolysis giving 1,3- and 1,2-oxazepines [61]. NBz2

NBz2 N

N

N

N

N

PhSe O O

Bu3SnH, AIBN

Ph Si Ph BzO (95)

N Ph Si Ph O

NBz2 N

N N

O

N

H2O2, KF

RO

KHCO3

RO

BzO

BzO

(96)

(97)

Scheme 8.35

O

O H O

O

O O H (98)

Scheme 8.36

H

N3

hn, 254 nm CH2Cl2 −40 °C

O

O

OH

O

O O O

N H

(99)

N N

8.2 Oxazepines

BnO

OBn O

BnO

BnO N3

o -Xylene, ∆

N3

(82%)

OBn O N

OBn

BnO

N N N

OBn

(100)

(101)

Scheme 8.37

8.2.3 1,4-Oxazepines 8.2.3.1 Amino Alcohol Double Condensation Formally, the condensation of a β-amino-alcohol with a 1,3-bis-electrophilic derivative should lead to the 1,4-oxazepine skeleton. This strategy was classically used with different electrophilic functions. In the following example (Scheme 8.38), ephedrine (102) was condensed with dimethyl malonate to construct the oxazepine skeleton in a sequential three-step reaction. The ﬁrst two steps were the amide formation and the saponiﬁcation to the acid 103. The latter was eventually lactonized through the use of 2-chloro-1-methylpyridinium tosylate to give the optically pure oxazepinedione 104 in 55% overall yield [62]. The double condensation of a β-amino alcohol with a α-haloacetate was also reported. The reaction could be conducted in one step and necessitated the use of a base reagent such as NaH [63]. A more sophisticated and interesting synthesis was also reported by Bartlett [64] starting from alaninol. The condensation of the D-amino alcohol with aldehydo-α,β-unsaturated amide 105 was catalyzed by tin triﬂate and furnished the bicyclic pyrrolidino-oxazepine 106 in very good yield and diastereoselectivity (Scheme 8.39). In this synthesis, a thermodynamic control allowed the reaction to occur stereoselectively with formation two new chiral centers. Interestingly, condensation of the same compound with l-alaninol led to the enantiomer 109 of the target compound as the result of a difﬁcult cyclization of 107, which equilibrated to 108 after ring opening to the iminium intermediate. 8.2.3.2 Other Cyclization Methods Lactamization, lactonization, and transacetalization are classical reactions allowing cyclization to 1,4-oxazepines. HOOC HO

HN (1)

COOMe

HO

O

O

COOMe

N

N

Cl + TsO−

O O

(2) LiOH

(102) Scheme 8.38

(103)

(104)

N

383

384

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

O OMe

N

MeO O

HH N

H PMP

O

Sn(OTf)2 CH3CN

MeO

DMB O

(106) Bn N

DMB

OH Ibid

N

OH

(105)

NH2

Bn

HH N

NH2

OH + H PMP

H + N

Bn N

HH N

DMB

O OH

Bn N

OH + H PMP

O

PMP (107)

(108)

DMB

HH N

O O

Bn N H PMP

DMB O

(109)

Scheme 8.39

Lactamization of chiral aminoesters was often used to attain the oxazepinone skeleton. The chirality was already installed on the framework of the amino esters [65]. In the following scheme (Scheme 8.40) [66], upon reduction of the nitro group of the chiral nitroketal 110 derived from dimethyl tartrate, spontaneous lactamization occurred to give almost quantitatively the optically active bicyclic oxazepinone 111. Similarly, the ﬁnal cyclization may be the result of lactonization [67] or transacetalization [68, 69]. In all cases, the chirality was brought from chiral amino alcohol which was or not protected. Intramolecular opening of a chiral epoxide by an amino group was also reported to give the oxazepine in good yield [70]. 8.2.3.3 Pd-Catalyzed Allene Cyclization Tanaka et al. [71] have investigated the reaction of a bromoallene, which can act as a dication equivalent in the presence of Pd catalyst. When the bromoallene also bore an amino alcohol group, a cyclization could occur to give a ring containing a nitrogen and an oxygen. Following this methodology, the preparation of oxazepine was reported. Thus, (S,aS)-bromoallene 112, in the presence of sodium methylate in methanol and of 5 mol% of Pd(PPh3 )4 , was transformed into oxazepine 113 in 73% yield, which represented the major regioisomer (9% of isomer 114 was also isolated) (Scheme 8.41).

CO2Me

MeO2C O

H2 Raney-Ni

O NO2 (110)

Scheme 8.40

O

MeO2C O

O

MeOH (99%)

(111)

NH

8.2 Oxazepines

MeO Br H

Ts N OH

OMe

Pd(PPh3)4 MeONa MeOH

Ts

O

N

(112)

+

(113) (73%)

Ts

N (114)

O

(9%)

Scheme 8.41

8.2.3.4 Radical Cyclization The intramolecular nucleophilic carbonyl trapping of an α-ketenyl radical by an amino group allowed Ryu [72] to propose an original and efﬁcient preparation method of nitrogen heterocycles. This method is general enough to be used for the access of oxazepines. Alkynylamine 115, prepared from prolinol, was treated in benzene at 90 ◦ C for 3 h with tributyltin hydride under CO pressure of 75 atm using AIBN as initiator, to give the α-methylene-oxazepinone 116 in 52% yield after protodestannylation (TMSCl, MeOH) (Scheme 8.42). 8.2.3.5 Ring Enlargement Several papers reported on the preparation of asymmetric 1,4-oxazepine via the ring enlargement of a six-membered ring. One way to this ring transformation was the Baeyer–Villiger oxidation of a piperidinone to the oxazepine. Thus, the m-chloroperbenzoic acid (MCPBA) oxidation of the piperidine-4-one 117, in the presence of sulfuric acid (to protect the basic nitrogen), gave a 64% yield of oxazepine 118 as a unique regio- and stereomer [73] (Scheme 8.43). The [1,2]-Stevens rearrangement was also reported to perform a six- to sevenmembered ring enlargement. In the following example (Scheme 8.44), the rearrangement of a cyclic ammonium ylide offered a simple and efﬁcient route to chiral nonracemic cyclic amines. The key intermediate 121 was obtained in 80% yield by H N O

O (1) Bu3SnH, AIBN CO, C6H6

N

O

(2) TMSCl, MeOH

(115)

(116)

Scheme 8.42

O

O

O MCPBA, CH2Cl2

Ph

N H (117)

Scheme 8.43

Ph

H2SO4 (64%)

Ph

N H (118)

Ph

385

386

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

O

Ph

N2

(120)

Ph

N

O

O

O

CO2Et

O

O

O

NH

O

||

Cu Acac

N2

N

CO2Et (119)

O

O

(121)

(122)

Ph CO2Et O

Ph CO2Et O

N

(33%)

(123) (66%)

Scheme 8.44

the conjugate addition of (R)-5-phenylmorpholin-2-one 119 to the diazo compound 120. The copper(II) acetyl acetonate (ACAC) catalyzed reaction of the diazo intermediate 121 in boiling toluene provided quantitatively the easily separable bicyclic rearranged diastereomers 122 and 123 [74]. 8.2.3.6 Cycloaddition The cycloaddition of azides with an unsaturated bond (Huysgens condensation) to give rise to triazol derivatives also offers an efﬁcient method to access various heterocycles when it proceeds in an intramolecular fashion. In particular, performing the 1,3-dipolar cycloaddition reaction on carbohydrate-derived azido-alkynes (or alkene [75]) should offer good opportunity to the construction of bicyclic chiral triazolo-oxazepines. Starting from xylofuranosyl diol 124, the primary alcohol function was transformed to the azido derivative via a classical sequence and the secondary alcohol function then converted to the propargyl ether 125 (Scheme 8.45). The cycloaddition was obtained by simple heating of 125 in toluene at 100 ◦ C for 2 h resulting in the formation of 126 in 95% yield [76].

8.3 Thiazepines

Few works have been reported on the asymmetric preparation of chiral thiazepines probably because sulfur-containing starting materials are rare. Most of the thiazepines described so far are 1,4-thiazepines. Despite the similarity with oxazepines, most of the preparations are different.

O O O

HO

O

N3

HO

(124) Scheme 8.45

O (125)

Toluene, ∆

O O

N N

O

N O (126)

O O

8.3 Thiazepines

387

8.3.1 1,2-Thiazepines

The 1,2-thiazepines are only represented by cyclic sulfonamides and their preparation methods are classical ones, the chiral pool being used in order to introduce the chirality. In the synthesis of bicyclic sulfonamide 129 reported by S. Hannessian [77] as a constrained proline analog, 2-propenyl derivative 127 was prepared from proline and treated with but-3-ene-1-sulfonyl chloride to give 128 in 55% yield. An ring closure metathesis (RCM) with ﬁrst generation Grubbs catalyst furnished the bicyclic sulfonamide 129 in 81% yield. A cyclic sulfonamide was described in the synthesis of enantiopure 4-phenyl pyrrolidine-2-yl-methanol. In this synthesis (Scheme 8.47), the sulfonamide 130 obtained in two steps from hydroxyproline was transformed to the 2,5-dihydropyrrole 131, which was subjected to a Heck reaction furnishing a 1 : 1 mixture of benzosulfonamides 132. Interestingly, protection of the primary alcohol as a bulky pivaloyl ester gave a stereoselective Heck reaction. 8.3.2 1,3-Thiazepines

Bicyclic thiazepinone was prepared as dipeptide mimetics with metalloprotease inhibitor properties [78]. The synthesis, in this case, parallels the synthesis of oxazepine via the cyclization into iminium ions (cf Section on Iminium Cyclization). Homocysteine derivative 135 was resolved from racemic material and condensed with hydroxylnorleucine 134 (enzymatically resolved) and the dipeptide was oxidized to aldehyde 136 (Scheme 8.48). The deprotection of the thiol was followed by the acid promoted cyclization and Cbz removal to 137. RSO2Cl

N H

CO2Bn

Grubbs I

CO2Bn N 6%, CH2Cl2 S O O

Et3N, CH2Cl2

(127)

(128)

H CO2Bn N S O O

(129)

Scheme 8.46

HO Br

CO2Bn N S O O (130)

Scheme 8.47

Br

N S O O

(131)

OR

RO

Pd(OAc)2 PPh3, K2CO3 DMF

S N O2

OR

+

(132) R = H 55% 1:1 (133) R = Piv 96% 4:1

N S O2

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

388

OH SAc + H2N

SAc OHC (1) WSC, HOBt, CH2Cl2, DMF

CO2Me CbzHN

CO2H (2) Swern

CbzHN O

(134)

(135)

S H

(1) NaOMe, MeOH

H N

N

(2) TFA (cat.)CH2Cl2

H2N

CO2Me

(136)

O CO2 Me (137)

Scheme 8.48

8.3.3 1,4-Thiazepines

The 1,4-thiazepines are the most frequently described thiazepines. Several asymmetric syntheses are available. In most of the cases, the chirality was introduced as a fragment arising from the chiral pool; cysteine and penicillamine are the most common. Curiously, the syntheses are speciﬁc ones and very few follow the strategy encountered with 1,4-diazepine or oxazepine counterparts. 8.3.3.1 From Mercaptopropionic Acid Derivatives We will ﬁnd in this category the achiral mercapto acids as well as cysteine or penicillamine. The two last compounds react at the thiol and acidic functions of the mercapto acids; thus the acids react with a 3-atom fragment possessing a nitrogen and an electrophilic function. Condensation with Haloethylamine, β-Amino Alcohol, and Derivatives The condensation of cysteine with haloethylamine has been used recently in a one-pot process to prepare thiazepine with ICE (interleukin converting enzyme) inhibitor properties. A simple reﬂux in methanol, in the presence of NEt3 , of l-cysteine methyl ester hydrochloride and 2-chloroethylamine hydrochloride allowed the condensation to occur furnishing 1,4-thiazepine 138 [79] (Scheme 8.49). This reaction illustrates a type of condensation that was used with various reagents and generally in a multistep process. The condensation of cysteine with a chiral β-haloamine, for example, allowed the introduction of new chiral centers on the seven-membered ring. The ﬁrst step of the sequence was the sulfur alkylation, which was followed by a peptide coupling [80]. Reaction of cysteine with a chiral amino alcohol was also reported; in this case the ﬁnal cyclization was obtained after activation of the OH function as a mesylate [81]. Zhu [82] recently reported on the N-carbamate-assisted stereoselective substitution SH ClH H2N O

+ Cl OMe

MeOH, Et3N

NH2 HCl

Reflux

H2N O

S N H (138)

Scheme 8.49

8.3 Thiazepines

389

NHCbz NHCbz

CO2Me NHCbz

OMe OH OH

OMe S

OH

OMe S

O

CO2Me

NHBoc

O

NH

(1) LiOH

SH Toluene-TFA

NHBoc O

(2) EDCI

O

O (139)

O

OH O

(140)

(141)

Scheme 8.50

of benzylic hydroxyl group by thiol. Simple treatment of a benzylic alcohol having a neighboring carbamate function with a thiol in the presence of TFA led to the introduction of the thiol with retention of conﬁguration. This was applied to compound 139 and cysteine, which gave 140 with complete stereocontrol and the latter was cyclized with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to furnish the thiazepine 141. Reactions with achiral mercaptopropionic acid were also reported; chiral aziridine [83] or amino acid [84] was used as the 3-atom fragment. In the preparation of thiazepanes as inhibitors of nitric oxide synthase, the amino alcohol 142 was the precursor of the aziridine 143 via a Mitsunobu reaction (Scheme 8.51). Addition of β-mercaptopropionic acid furnished the amino acid 144, which was cyclized to 145 via conventional methods. Condensation with Nitro Oleﬁne The research of new active inhibitors of ACE led Japanese researchers to propose an interesting access to thiazepine through the Michael addition of cysteine onto a nitro oleﬁne [85]. In this sequence a new chiral center was formed. Unfortunately, there is no report of the diastereoselectivity of the Michael addition. The reduction of the nitro group into a primary amine allowed the ﬁnal cyclization through lactamization. The ﬁnal product was obtained in enantiomerically pure form after recrystallization. OH

(1) HS

PPh3, DIAD

NHBoc

nPr

CO2H

S

CO2H

NBoc nPr

(142)

(2) HCl

(143)

nPr

S EDC NMM

NH2

Prn

(144)

N H

O

(145)

Scheme 8.51 AcO AcO AcO

AcO OAc NAc cysteine AcO AcO BF3 OEt2 NPhth

O

CH2Cl2

(146)

Scheme 8.52

O S NPhth HNAc (147)

(1) H2N

NH2

(2) EDCI, HOBt

CO2H (3) Ac2O, Py

AcO AcO AcO

O S HN O (148)

NHAc

390

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom

Condensation with Amino Sugar Fused bicyclic glycosides–thiazepines have been prepared by the reaction of the phthalimido-protected sugar 146, used as donor, with N-acetylated l-cysteine [86] (Scheme 8.52). This ensured the introduction of cysteine at the anomeric center as the desired β-thioglycoside. Selective removal of the N-phthalimido group was obtained by treatment with ethylenediamine in methanol and the free amino group was reacted with EDCI/hydroxybenzotriazole (HOBt) to give the bicyclic product in 50% yield. Cysteine in SN Ar Reaction Benzothiazepine compounds have been prepared in the search of new effective inhibitors of ACE. One of these syntheses paralleled the synthesis of benzodiazepine (cf Section on Via an SN Ar Reaction) starting with a SN Ar reaction of N-Ac cysteine on 2-ﬂuoronitrobenzene. The reduction of the nitro group into primary amine was followed by lactamization to give the required benzothiazepine [87]. 8.3.3.2 From Amino Thiols Aminothiols were also broadly used as sulfur reagents in the preparation of thiazepines. Since the aminothiol is a bis-nucleophile derivative, the counterpart in this condensation should possess two electrophilic functions. Aminothiols and Acrylic Acid Derivatives The most frequently used reactants were acrylic acid and its analogs [88]. Thus, as illustrated in Scheme 8.53, d-penicillamine was reacted with α-phenylacetamidoacrylate (149) in the presence of Et3 N to give the expected thiazepine 150, unfortunately as a mixture of stereomers without indication of the ratio [89]. Aminothiols and Other Dielectrophilic Compounds Diltiazem, a calcium channel blocker, is probably the most representative compound of thiazepines. Several syntheses were published but very few were asymmetric ones. Researchers from Hoffmann-La Roche published an efﬁcient synthesis [90] in which the condensation of 2-aminobenzenethiol to an enantiomerically pure epoxy ester 152 allowed the preparation of diltiazem in asymmetric form (Scheme 8.54). The synthesis was based on the lipase-catalyzed kinetic resolution of trans-2-phenylcyclohexanol to give the pure (−)-1R,2S enantiomer 151. This compound was the chiral source to attain pure glycidic ester 152 via a Darzens reaction. 2-Aminobenzenethiol reacted with 152 in reﬂuxing toluene to give 153 with the expected conﬁguration. Deprotection of 153 was followed by acidic treatment, which allowed cyclization to occur. H N

Ph

HS +

O O (149)

Scheme 8.53

OMe

H2N

MeOH, Et3N

CO2H

H N

Ph O

O

S N H

(150)

CO2H

8.3 Thiazepines Ar

H Ar

Ph

Ph

NH2

H

O

S

SH

O

O

OH

391

OH H O

NH2 O Ph

(151)

(152)

(153) OMe

OMe

(1) NaOH/EtOH (2) TsOH, xylene

S

S OAc

OH N H

N O

O N

(154)

Diltiazem

Scheme 8.54

Dihalopropan and halopropanol were also used in the condensation of aminothiols. A one-step reaction was claimed to occur by condensation of 3-chlorobromopropane with penicillamine [91]. In the following example (Scheme 8.55) [92], the ﬁrst step was the sulfur alkylation of cysteine with bromopropanol, which was followed by N-sulfonylation to give 155. The ﬁnal cyclization was achieved by a Mitsunobu reaction to give the thiazepine 156 as depicted in Scheme 8.55. 8.3.3.3 Others Recently, Gleason [93] reported a study devoted to the asymmetric construction of quaternary centers on the basis of the use of the 5,7-bicyclic thioglycolate 159. An interesting, short and straightforward preparation of 159 was proposed, which was like the Meyer’s lactam synthesis. In the present preparation, achiral methyl thioglycolate was alkylated with 2-bromoethyl dioxolane and the obtained ester 157 used to N-acylate S-valinol (Scheme 8.56). The resulting amide 158 underwent a O O

O HO

NH2

SH

(1) Br(CH2)3OH (2) ArSO2Cl, Et3N

t-BuO

O2S

O

NH

PPh3, DEAD

t-BuO S

(3) t-BuBr, DMA

(155)

Scheme 8.55

O

OH

O2S N

THF

S (156)

392

8 Asymmetric Synthesis of Seven-Membered Rings with More Than One Heteroatom O

O N H

O S

n -BuLi

OH

O S

BF3 OEt2

S -Valinol

CH2Cl2

O

O O

O

(157)

(158)

N

S

O H (159)

Scheme 8.56

transacetalization to give the expected bicyclic compound 159, in an excellent 71% overall yield and as a single stereoisomer. References 1 Srinivasan, S. and Argade, N. P. Z.

2

3

4

5

6

7

8

(2003) Tetrahedron: Asymmetry, 14, 333–37. Attwood, M. R., Francis, R. J., HassaIl, C. H., KrGhn, A., Lawton, G., Natoff, I. L., Nixon, J. S., Redshaw, S. and Thomas, W. A. (1984) FEBS Lett., 165, 201–6. ` J., Perez, A., Gubert, S., Bolos, Anglada, L., Sacrista` n, A. and Ortiz, J. A. (1992) J. Org. Chem., 57, 3535–39. Attwood, M. R., Hassall, C. H., Krohn, A., Lawton, G. and Redshaw, S. (1986) J. Chem. Soc. Perkin Trans. 1, 1011–19. Chen, M. H., Goel, O. P., Hyun, J.-W., Magano, J. and Rubin, J. R. (1999) Bioorg. Med. Chem. Lett., 9, 1587–92. Liu, B., Brandt, J. D. and Moeller, K. D. (2003) Tetrahedron, 59, 8515–23. Ernholt, B. V., Thomsen, B., Lohse, A., Plesner, I. W., Jensen, K. B., Hazell, R. G., Liang, X., Jakobsen, A. and Bols, M. (2000) Chem. Eur. J., 6, 278–87. (a) Nugiel, D. A., Jacobs, K., Worley, T., Patel, M., Kaltenbach, III, R. F., Meyer, D. T., Jadhav, P. K., De Lucca, G. V., Smyser, T. E., Klabe, R. M., Bacheler, L. T., Rayner, M. M. and Seitz, S. P. (1996) J. Med. Chem., 39, 2156–69; (b) Hult´en, J., Bonham, N. M., Nillroth, U.,

Hansson, T., Zuccarello, G., Bouzide, A., Aqvist, J., Classon, B., Danielson, U. H., Karl´en, A., Kvarnstr¨om, I., Samuelsson, B. and Hallberg, A. (1997) J. Med. Chem., 40, 885–97; (c) Lam, P. Y. S., Ru, Y., Jadhav, P. K., Aldrich, P. E., DeLucca, G. V., Eyermann, C. J., Chang, C.-H., Emmett, G., Holler, E. R., Daneker, W. F., Li, L., Confalone, P. N., McHugh, R. J., Han, Q., Li, R., Markwalder, J. A., Seitz, S. P., Sharpe, T. R., Bacheler, L. T., Rayner, M. M., Klabe, R. M., Shum, L., Winslow, D. L., Kornhauser, D. M., Jackson, D. A., Erickson-Viitanaen, S. and Hodge, C. N. (1996) J. Med. Chem., 39, 3514–25; (d) De Lucca, G. V., Liang, J., Aldrich, P. E., Calabrese, J., Cordova, B., Klabe, R. M., Rayner, M. M. and Chang, C.-H. (1997) J. Med. Chem., 40, 1707–19; (e) Kalmtenbach R. F. III, Patel, M., Waltermire, R. E., Harris, G. D., Stone, B. R. P., Klabe, R. M., Garber, S., Bacheler, L. T., Cordova, B. C., Logue, K., Wright, M. R., Erickson-Viitanen, S. and Trainor, G. L. (2003) Bioorg. Med. Chem. Lett., 13, 605–8; (f) Han, W., Pelletier, J. C. and Hodge, C. N. (1998) Bioorg. Med. Chem. Lett., 8, 3615–20; (g) Patel, M., Bacheler, T., Rayner, M. M., Cordova, B. C., Klabe, R. M., Erickson-Viitanen, S. and Seitz,

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10

11

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13

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397

399

Index a acylation 342f. N-acylaziridine 5 acyliminium 131 – addition reaction 128 – N- acyliminium allylation 129 aldimine 19 aldol reactions 277 alkaloids – marine 118, 122, 133 – poison-frog 96, 103f., 114f., 119, 126, 133 – polycyclic complex 140f. – Stemona 141, 147, 157, 163 alkene 12, 59 alkylation 69f., 80, 242, 337f., 348, 352ff. – allylic 309 – asymmetric 277, 298, 309 – amido- 73 – deprotonation/alkylation sequence 374 – dialkylation 353 – diastereoselective 328, 374 – phase-transfer catalyzed 70 – piperazine ring 327f. – protected amino alcohol 346f. – reaction 200 – reductive 53, 71f., 74, 83, 108f., 368 – stereoselective 307f. alkylidene malonates 11 alkynes 96 allylic – alcohol 28, 110, 115 – alkylation 309 – strain 115 – substitution 110, 231, 350 Alzheimer’s desease 51, 141 amination – catalytic asymmetric hydro- 58f., 112 – diastereoselective 332 – Pd-catalyzed 57f.

– reductive 53, 110, 315, 322, 343 amino alcohol 38, 105 – β-amino alcohol 7, 40 – camphor-derived 231 – enantiopure 7 – N-substituted 224 – polyfunctionalized 39 aminohalo-derivatives 38 aminothiols 390f. ammonolysis 197 angiotensin-converting enzyme (ACE) 140, 389f. anisomycin 51f., 58 annulation approach 66f., 108 – imines 106 – pyrrolines 79f. antibacterial activity 4, 223, 241, 264 antibiotics 3, 51f., 171 anticytotoxic activity 51 antidepressant 55 antifungal 37, 57 anti-HIV activity 270, 279 – protease inhibitors 278, 368 anti-inﬂammatory 223 antineoplastic activity 4 antitumor activity 3, 142, 170, 270 antiworming 51 asymmetric allylation reaction 55, 108, 225 asymmetric aziridination 6ff. – benzylidene derivatives 14 – catalytic 22f. – cycloaddition methods 12ff. – protocol 9 – stereospeziﬁc 13 – styrene derivatives 14 asymmetric desymmetrization 241 asymmetric induction 20, 23f., 123, 308 asymmetric reduction 39 asymmetric synthesis of azirines 33ff.

Asymmetric Synthesis of Nitrogen Heterocycles. Edited by Jacques Royer Copyright  2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32036-3

400

Index azabicycles 148 aza-Claisen rearrangement 179f. azacycloheptatriene, see azepine aza-Darzens-type reaction 17, 19ff. – diazo compounds 21ff. – α-haloenolate 17ff. aza-Payne – displacement 29 – /hydroamination 58f. – reaction 5 – rearrangement 66 azasugar 54, 110 – stereoselective synthesis 131 azepanes 130f. – 3-hydroxy- 150, 153 – 4-hydroxy- 153 – substituted 150, 166ff. azepines 139ff. – dihydro- 139 – fragment 143, 146, 158 – hexahydro- 139, 148f., 157 – perhydro- 157 – ring closure metathesis (RCM) 155ff. – spiro- 159 – substituted 139ff. – tetrahydro- 139, 160, 171 – trans-hexahydro- 146 azepino-indoline 147 azetidines – 2-Cyano 41 – cyclization methods 38ff. – hydroxy- 43 – monocyclic 36 – precursor 39 – unsaturated derivatives 36f. azinomycin 3f. aziridine – N-benzyl-aziridine-2-esters 7 – N-Boc- 7 – -2-carboxylates 6ff. – cis- 21f. – cis-vinyl- 26 – elemination 34f. – -2-esters 29 – -2,2-dicarboxylate 5, 11 – N-halo- 34 – -2-imides 9 – N-substituted 5 – oxidation 36 – -2-phosphonates 17 – polyfunctionalized 18f. – precursors 12 – N-protected 13, 16 – ring systems 3f.

– -2-tert-butylate 8 – N-tosyl- 13, 17 – trans- 29 – transformations 4f. – 3’-unsubstituted-N-Boc- 10 azirines 3f., 33ff. – -carboxylates 34 – 2H- 33f. – motif 4 – 2-phosphinyl-2H- 33 azirinomycin 4 azocines 171ff.

b bacterial strains 32 Baeyer-Villiger oxidation 385 Baldwin’s adaptation 42 barbiturate 309f. Baylis-Hillman-aldol reaction 62, 277 Beckmann rearrangement 178 – asymmetric 165f. – thermal regioselective 165 benzazocine 173 benzodiazepine, see diazepine Biginelli reaction 306 bioactive 4, 325 – alkaloids 39 – derivatives 28 – peptides 8 – peptidomimetics 8 biocatalysts 31 biological activity – alkaloids 51 – diazepine 367ff. – peptides 264 biotransformation 32 bisoxazoline 13 Boc – deprotection 151, 213 – oxidation 105 – protection 105, 314f. bond formation – C-C bond formation 40f., 107, 113ff. – C1 /C5 bond formation 52ff. – C2 -C3 bond formation 61, 119 – C3 -C4 bond formation 62, 102 – C-N bond formation 39, 142 α-bromo-alkene 8 Brønsted – acid-catalyzed annulation 21 – acid-catalyzed reduction 101 building blocks 3, 28, 81 – β-hydroxylamino-carbonyl 11 – piperacic acid 294

Index – prochiral 60 – versatile 40f., 78, 108, 113, 123, 129 Burgess’ reagent 271f.

c camphor-derived chiral ligands 15 camphor sultam 9, 20, 276 – α-bromoenolates 20 – N-crotonyl- 9 – Oppolzer’s L- 65 Candida Cylindracea Lipase (CCL) 31 carbamates 382 – pyrrolidine 77f. carbanion-mediated sulphonamide intermolecular coupling (CSIC) 279 carbenes 16, 21 – chiral 262f. – heterocyclic 262 – insertion 63 carbocyclic-fused systems 36, 107 carbonylation 6, 11 carboxylation 236 catalyst – chiral 13, 16, 43, 244 – Grubbs 2nd 129f., 133, 156f., 159f., 175, 387 – Grubbs-Hoveyda catalyst 98, 114 – organocatalyst 244 – Pearlman’s 316 cation-π complex 96 cellular growth control 139 chain – carbon side 18 – functionalized 6 – nitrogen imine 24 chelation 124, 146 – -controlled model 100 chemical resolution 42 chemoselective 12 chiral – auxiliary 9ff. – bisoxazoline catalyst 13 – center 123, 367, 376 – copper complexes 14 – epoxides 29 – heterosubstituted aziridines 18 – imides 9 – imines 16f., 115 – metal catalyst 13 – metal complexes 11, 14, 16 – morpholinone 306 – nonracemic alicyclic precursor 52 – nonracemic azetidinones reduction 44 – nucleophiles 16

– organosilanes 115 – piperidines 112, 117 – polymer-bound amines 33 – pool-derived N,O-acetals 72f. – pyridinium salt 96f. – pyrrolidine derivatives 12 – sulﬁnamide 98 – sulﬁnimines 17, 114 chirality 7, 24, 28 – ylides 25 chiron 52, 69 chiroptical properties 193 chromatographic separation 43 chromatography – chiral 190 – column 258 – ﬂash 9, 144, 168, 250 – high performance liquid (HPLC) 151 – ion-exchange 176 Cieplak hypothesis 119, 126f. circular dichroism (CD) 193 CN(R,S) method 123, 226 condensation – β-amino alcohol double 383, 388f. – amino sugar 390 – bis- 367f. – haloethylamine 388 – Huysgens 386 – in situ 380 – intramollecular 340 – nitro oleﬁne 389 – Paal-Knorr 377f. conﬁguration 70, 72 – retention 72 conformation 124 conjugate addition 9ff. – O-benzylhydroxylamine 12 – hydroxylamines 11 conversion 29, 43, 333 Cope elimination 245, 351 Corey-Chaykovsky reaction 25 Cromwell general method 42 cross-metathesis reaction 108, 114 crystallization 190, 276, 339 – -induced dynamic resolution (CIDR) 337 – -induced transformation 349 Curtius rearrangement 237 cyclization – alkylative 105 – amino alcohols 7 – amino halides 7 – azetidines 38ff. – Barbier-type 62 – catalytic-oxidative 240

401

402

Index cyclization (contd.) – electro- 105 – endo 147f., 170 – 7-endo-dig 149 – exo/anti 246 – Heck 151f., 387 – hydrozirconation- 62 – imine/enamine formation 321ff. – iminium 380f. – in situ 144 – intramolecular 103, 144, 149, 172, 227, 232, 239, 251 – iodine-induced 151 – Lewis-acid 155 – meta-catalyzed 110 – nitrogen nucleophilic displacement 8, 33, 304f., 319, 377, 381 – nucleophilic 84 – Paal-Knorr 377 – partial 316, 319 – Pd-catalyzed 83, 370, 384 – Pictet-Spengler 154 – pinacol-type 146 – piperidines 107ff. – pyrrolidine 52ff. – pyrrolines 79 – radical 115f., 145f., 382f., 384 – reductive amino- 151f. – reverse-Cope 60 – Richman-Atkins 321 – transannular 84f. – two-step 104 cycloaddition 5 12f., 107, 117ff. – [3 + 2] 119, 375, 378f. – [4 + 2] 163, 378 – [4 + 3] 162, 378f. – [5 + 2] 162 – acylnitroso 117f. – azadiene 117 – azides 386 – azocines 174f. – 1,3-dipolar 5, 128, 134f., 161, 235, 248, 279, 375 – intermolecular 244, 248, 325 – intramolecular 244, 259, 278, 325 – Lewis-acid catalyzed 259 – nitrile oxide 247 – nitrone 161ff. – photo- 162 – piperazinone 325f. – pyrrolidines 64ff. – regioelective 245, 262 – stereoselective 245 cycloadduct 118

cyclocondensation reaction 271, 294 cyclopropanation 277 cycloreversion-cycloaddition process 257 cytotoxic compound 4, 35

d DAG methodology 24 Darzens reaction 390 decarboxylative 60 – oxidation 74 dehydroxylation reaction 73 deprotection/protection 8, 54, 110, 130, 317, 336, 340f. deprotonation 25, 70, 242, 345, 353 – achiral imidazolidine 249 – cycloalkylation 63 – deprotonation/alkylation sequence 374 – selective 169 – -substitution 77 – sulfonamide nitrogen 216 deracemization processes 101f. Dess-Martin periodinane 99, 296 desymmetrization 108 dialkylation 38 diastereofacial selectivity 14, 245 diastereoisomer 20, 26, 43, 263, 279 – cis 20, 265 – oxaziridine 205 – separation 205 – single 21, 56 – thiazolidines 263f. – trans 265 diastereomer 69f., 129, 319 – adduct 10 – cis 173, 322 – (S,R) 315 – single 257 – trans 69 diastereomeric – aziridines 15 – esters 146 – excess 20 – mixture 20, 69 – ratio 19, 309, 319, 358, 378 diastereoselective – addition 109, 216 – allylation 99 – amination 332 – aziridination 15 – conjugate reduction 331 – coupling 335 – epoxidation-nucleophilic addition 96 – 3-exo-tet ring closure 10 – hydrogenation 105

Index – intramolecular Michael cyclation 102 – nucleophilic 1,2-addition 280 – reduction 358 – synthesis 9f., 19 – trans- 54, 57 diastereoselectivity 10, 16, 21, 24, 56, 66, 69, 77, 97, 115, 378 diazepines 367ff. – 1,4 benzodiazepines 371ff. – 1,2-diazepines 367f. – 1,3-diazepines 368ff. – 1,4-diazepines 367, 371ff. – fused diazepine-pyrrolidine 370 – pyrrolobenzodiazepines (PDB) 375f. – pyrrolodiazepine 375 diazeridination 191ff. diazeridines 189ff. – chiral nonracemic 191 – monocyclic 190 diazetidines 208f. diazirines 193f. diazocompounds 21f., 26f. diazoketene insertion reaction 45 diazotation 375 Dieckmann reaction 62 Diels-Adler reaction 117f., 234f., 251, 254, 277, 293, 378f. – asymmetric 170 – homo- 231 – intramolecular (IMDA) 161, 163f., 175, 279 – stereoselective hetero- 231, 301, 299 – pyridazine 299ff. diethoxyphenylphosphorane (DTTP) 8 diketopiperazines (DKPs) 311ff, 319 dipolarophile 244, 246, 259, 278

e electrochemical oxidation 131 electrocyclization 33, 105 electron – -donating 17 – -enriched aromatic group 375 – -withdrawing group (EWG) 17, 25f., 194f., 228, 238, 244 electrophilic 6, 383, 388 – amination 191, 195 – center 102 – dielectrophilic 390 – imine carbon 17 – nitrogen 10 electrophiles 6, 98, 150, 298, 327 electrophilic – imine carbon 23 – reactants 311

electrophilicity 17, 381 enamine 102ff. – functionalized cyclic 103 – intramolecular 102 – reaction 102f. enantiocontrol 16 enantiomer 28, 108 – natural 133 – (R,R) 317 – single 69 enantiomeric 11 – excess 11ff. – purity 26, 121, 214, 344 – ratio 307 enantiopure – N-acylaziridine 19 – amino alcohol 7 – azetidines 36, 39ff. – azides 28 – aziridine-2-carboxylates 21 – aziridine-2-phosphonates 17 – benzyl aziridine-2-carboxylates 9 – N-benzyl-aziridine-2-esters 7 – -2-carboxylates 8 – diamines 252 – ethynylazetidines 39 – imidazolidinones 253 – imines 18 – oxiranes 28, 261 – solfoxide 279 – sultam 276, 278f. – ylides 25 enantioselective – addition 264 – allyltitanation 108 – aziridination 12ff. – catalytic reduction 43 – hydrogenation 142 – hydrolysis 32 – nucleophilic substitution 131 – reactions 77 – reduction 69, 213 – synthesis 110 – transformations 280 enantioselectivity 112, 239f., 249, 253, 256 enantiospeciﬁc synthesis 159 endocyclic enecarbamates 76 endo-selective 78 ene-reaction 277 enolate 69, 329 – aza-enolate anion 327 – aliphatic 20 – amination 204 – intermediate 11

403

404

Index Helmchen’s auxiliaries 9 enolate (contd.) homochiral nucleophilic templates 327 – lithium 18, 330 Horner-Wadsworth-Emmons reaction 45, enolization 10 160, 313 enones hydrazine 367f. – acyclic 129 hydrazone formation 294 – cyclic 129 hydroformylation 380 enzymatic resolution 31, 42, 44, 195 hydrogenation 39, 73, 104f., 142, 150 enzymatic synthesis 54 – asymmetric 169, 276f., 294 – azasugar 54 – asymmetric transfer 277 – chemo- 54, 167f. – catalyzed Pd/C 144, 301, 314, 322f., 358 – morpholine 344 hydrogenolysis 4, 110, 160, 303f. enzyme inhibitors 4 hydrolysis 41 environmental impact 13 – alkaline 100 epimerization 41, 104, 124, 142, 242, – enzymatic 31 333, 339 – ester 314 epoxidation 277 hydrolytic cleavage 110 epoxide 27f., 54, 345f. hydropyridines – racemic 30 – chiral 1,4- 96f. – reductive opening 100 – dihydropyridines 95ff. – ring opening 345 Eschenmoser sulﬁde contraction reaction 71 – tetrahydropyridines 98ff. – substituted 96 esteriﬁcation 303 hydroxylation Evans aldol reaction 160 – amino 143 exo-trig reaction pathway 146 – pyrimidinone 310f.

f Food and Drug Administration (FDA) formaldehyde 380f. Friedel-Crafts acylation 296

242

g Gabriel-Cromwell reaction 8f. Ganem’s approach 53, 63 Garner’s stereocomplementary asymmetric approach 65 Geissman-Waiss lactone synthesis 73, 77 Gennari-Evans-Vederas reaction 295 Gly-Gly-derived macrocycles 165 Grignard – addition/cyclization reaction 59 – addition to nitrones 75 – addition-transamidation-reduction sequence 336 – reagent 19, 58f., 73, 75, 96f., 119, 125, 227, 247 guanidine – cyclic derivative 29 – C2-symmetric 369

h haloacetates 20 halogenation 310f. Hantzsch diethyl ester 101, 253 Heck reaction 151f., 387

i imidazolidines 249ff. imidazolidinones 249, 252ff. imine 16f., 19, 21ff. – annulation 106 – chiral 16, 115 – imine/enamine formation 321ff. – formation 311 iminium 251, 380f., 383 – addition 113 – reduction 133 – strategies 128 – sulﬁnyliminium salt 131f. imino – eight-membered iminoalditols 176 – α-imino esters 22 – iminothiazolidines 267 – sugar 168 inhibitor – glycosidase 151, 369 – neutral endopeptidase (NEP) 140 – selective 140 – vasopeptidase 140, 142 inhibitory acitvity 37, 139 interconversion 12 intramolecular – alkylation 40 – amidation 52, 319

Index – amination 52 – condensation 74 – conjugate addition reaction 133, 272, 348f. – displacement 38, 53, 236, 342 – hydroboration-cycloalkylation 59 – nucleophilic substitution 172 – Pd-catalyzed coupling 177f. – substitution 232 inversion barriers 190, 194, 217 iodocarbamation 108 iodocyclation 227 isatoic anhydride 371f. isomer 128, 131 – chiral 250 – constitutional 212, 217 – diazetidine 208 – DKPs (diketopiperazines) 319 – meso 250 – oxazolidine 224f. – six-membered 257 – thiazetidines 212f. isomerization 5, 114, 149, 191 – photo- 190 isoxazolidines 243ff. – chiral 244 isoxazolines 243, 246ff. – N-oxides 248

j Jacobsen’s asymmetric epoxidation of oleﬁn 120 Jacobsen’s (salen)-CoIII chiral comples Julia – coupling reaction 133 – oleﬁn synthesis 71, 99

238

lactam – chiral bicyclic 134, 227 – chiral caprolactams 164ff. – eight-membered 173f., 176 – enantiopure 123 – formation 311f., 317, 338f. – β-lactams 266 – δ-lactams 227 – γ -lactam 122 – Meyers’-bicyclic lactam strategy 124, 375 – ring enlargement 122 – ring formation 335, 338f. – seven-membered 140, 142ff. – ten-membered 179 lactone – chiral 167 – formation 337 – ring transformation 121, 335, 338 lactonization 368, 383f. Lee’s chiral synthesis 100 Lewis acid 11, 22 – activation 37 – catalyzed annulation 67 – -Lewis base bifunctional asymmetric catalyst 96 Ley’s sulfone chemistry 71 ligands 11f. – BINAP-type 268 – Box 233f., 248, 256, 260, 262 – chiral diamine 249 – VANOL 23 – VAPOL 23 lowest unﬁlled molecular orbital (LUMO) 253

m k keto function 18 ketones – moiety 43, 104, 114 – prochiral 42 kinase C 37, 139 kinetic – aminolytic kinetic resolution (AKR) 238 – asymmetric transformation 80 – control 24 – racemization 190 – resolution 29, 31f., 35, 43, 70, 247, 296, 390 Kulinkovich reaction 62

l lactamization 383f., 389

142f., 368, 372, 376,

Ma’s synthesis 104 Mannich-type – boro- 349 – cyclization 113f.f. – reaction 82, 256 mercaptopropionic acid derivatives 388f. mesylation 319 metal-carbene intermediate complex 21 methylvinyl ketone (MVK) 62 Meyer’s chiral bicyclic lactams 78 Michael – addition 11., 55, 101ff. – Aldol Retro-Dieckmann (MARDi) sequence 169 – aza- 12, 56ff. – enantioselective Michael addition 10 – intramolecular 42, 102 – retro-Michael elimination reaction 102

405

406

Index microwave irradiation 42, 67, 319 – hydrogenation 122 – rearrangement 67 Mitsunobu – condition 7, 39 – intramolecular reaction 101, 236, 271, 296, 305, 317, 321, 339, 376, 391 Mizuno’s dinuclear peroxotungstate catalyst 54 Moffat oxidation 121 monoperoxycamphoric acid (MPCA) 195, 199 Morita-Baylis-Hillman type reaction 129 morpholines 335ff. – asymmetric transformations 352ff. – ring formation 335ff. morpholinone 335, 337, 340ff. – C-alkylations 352 Mukaiyama – reagent 339 – -type aldol addition metholodogy 81

n Neber reaction 33 Negishi-coupling reaction 101 nitrene – formation 12f., 16 – insertion 382 – singlet state 12 – triplet state 12 nitrilium insertion 375f. nitrogen – α-carbanion 113 – insertion process 164 – inversion barrier 3 nitrones 74ff. – cycloaddition 127f., 161 – photocyclation 207f. – regioisomeric 128 nitrosation rearrangement 197 NMR spectroscopy 203 nosylation 8 Nozaki-Hiyama-Kishi allylation 234 nucleophile 5 – addition 17 – chiral 16 – nitrogen 108 – piperazine ring 330f. – prochiral 204 nucleophilic – addition 30, 131, 237 – addition/cycloaddition 74 – attack 22, 124, 382

– substitution 54, 108, 311 – nucleophilic reaction 71f.

o oleﬁn 120 – aryl-substituted oleﬁn substrate 13 – endocyclic 152 – Grubb’s oleﬁn metathesis 157 – Horner-Wadsworth-Emmons 160 – Jacobsen’s asymmetric epoxidation 120 – Julia oleﬁn synthesis 71, 99 – ring-closing metathesis reaction 79 oleﬁnation 42 one-pot – construction 133 – procedure 102, 104, 106, 165, 209, 301, 322 optically active – 2-alkyl diamines 250 – aminoalcohols 39 – azepine 151 – aziridine 7, 10, 66 – azirines 33, 35 – imines 24 – morpholinones 353 – oxazepinone 384 – oxazilines 232 – oxaziridine 207 – oxaziridinium salt 200ff. – oxazoline 304 – pyrimidine 304 – trans-aziridine 9, 11 – N-sulﬁnyl-aziridine 19 organocatalytic processes 7, 12 organolithium reagent 247 organometallic reagent 18f., 73 organosilanes 115 oxadiazines 332ff. oxadiazinones 334 oxathianes 25 oxazepines 378ff. – 1,2-oxazepines 378f. – 1,3-oxazepines 380f. – 1,4-oxazepines 383 oxazetidines 210ff. oxazidine 370 oxaziridines 194ff. – chiral nonracemic spirocyclic 198, 200 – N- acyl 203f. – N-alkoxycarbonyl 203f. – N-alkyl 197ff. – N-phosphinoyl 207 – N-quaternarized 200 – N-sulfonyl 204f. – N-unsubstituted 196f.

Index – photorearrangement 200 – preparation 195f. oxazolidine 123, 165, 223ff. – N-alkyl- 224 – N-Boc 228 – N-Tosyl 228 – oxazolidin-2-ones 235ff. – oxazolidin-4-ones 242f. – oxazolidin-5-ones 242f. – photolysis 165 oxazolidinone 7, 235ff. – bicyclic 242 – trans- 237 oxazolines 5, 7, 230ff oxazolizinone ring 100 oxidative methods 131 – anodic 132 – electrochemical 131f. – phenol coupling reaction 155f. oxyfunctionalization 200 ozonolysis 297

p ` uchi reaction 76 Paterno-B¨ penicillin derivates 263 pharmacological activity 263 pharmacophores 139 phase transfer – -catalyzed conditions 298 – solid-liquid 25 phenylglycinol 123 photochemical rearrangement 194 photocyclation 207, 374 – chiral nitrones 207f. photolysis 165, 382 Pictet-Spengler reaction 152, 154 piperazine 311ff. – asymmetric hydrogenation 331ff. – DKPs (diketopiperazines) 311ff. – ring formation 311ff. – stereoselective ring transformations – substituted 322f. piperazinone ring system 325 piperidine 95, 104, 107ff. – alkaloids 124 – enantiopure 125 – functionalized 95, 110, 120 – monocyclic 107 – ring system 102, 123 – saturated 95 – substituted 95f., 109, 115, 123f. piperidones 121f. polyoxin C 37 pyrazolidines 255ff.

– chiral 255 – conjugate addition 260 pyrazolidinones 260ff. pyrazolines 255, 257ff. pyridazines 293ff. – dihydropyridazine derivates 298 – tetrahydropyridazine derivates 295ff. pyridine 264 pyridinium salt 96f. pyrimidines 302ff. – ring formation 302, 304ff. pyrimidinones 306f. – halogenation 310f. – hydroxylation 310f. pyrrolidine – amino- 55 – bioactive 52 – carbamates 77f. – cyclization methods 52ff. – dihydroxylated 68 – functionalized 51, 121 – nitrones 74 – -2-ones 52f. – polyhydroxylated 54, 57 – polysubstituted 57ff. – pyrrolidine-2-ones 66ff. – pyrrolidine-2-ones/pyrrolidine 52f., 62f., 68 – pyrrolidine/1-pyrrolidine derivatives 52 – vinyl 179f. pyrrolidinones 51 pyrrolines synthesis 79f. pyrrolizidines 82ff. – polyhydroxylated 85f.

r racemate resolution 31, 42 racemic – alcohols 146 327ff. – azetidine mixtures 38, 43f. – aziridine 22 – azirines 35f. – biotransformation 32 – chiral non- 123 – epoxides 238 – isoxazoline 247 – mixture 31 radical – addition 277, 355 – alkyl 355 radicamine alkaloids 75f. radicamization free-methods 121 Raney nickel 123, 373

407

408

Index receptor – antagonist 120 – oxytocin (OT) 140 – selective antagonist 96 – selective 5HT2C 140 recrystallization 43, 378, 389 reduction – concomitant 160 – stereoselective 52, 160, 380 regiocontrol 4, 279 regioselective – nitrone formation 76 – oxidative transformation 123 – reduction 76, 129 regioselectivity 5, 35f., 39, 62, 74f., 380 Reissert reaction 96 resolution – chemical optical 146f. – enzymatic optical 146f. rhazinilam synthesis 177f. ring – aromatic 20 – backbone 44 – cleavage 37 – -closing metathesis (RCM) 98ff. – contraction 68, 85, 177 – enlargement 120f., 385 – 4-exo-tet 40 – expansion 5, 44, 67, 166ff. – fused-azetidine 39 – morpholine 306 – piperazine 311ff. – α-position 40, 77, 128 – protonated 37 – pyrimidine 306ff. – rearrangement metathesis 101 – transformation 27f. 44f., 67ff. ring heterocycles – bicyclic 117 – cis 25 – eight-membered azacycles 139 – ﬁve-membered 40, 113, 223f., 249f., 263ff. – four-membered 37f., 208ff. – functionalized 41f. – nine-membered azacycles 139 – seven-membered 139f., 367ff. – six-membered 40, 95f., 293ff. – substitution 68f., 80f., 123f. – C2 -symmetric disubstituted 42 – three-membered 10f., 17, 19, 37, 39, 117, 189ff. ring closure 6f., 10, 133 – aminoalcohols 39 – aminoallenes 40

– asymmetric ring-closing metathesis (ARCM) 23, 175 – base-mediated selective 238 – imine/enamine bond formation 340ff. – intramolecular Michael addition 348f. – intramolecular nucleophilic displacement 304ff. – intramolecular nucleophilic substitution 319ff. – lactam formation 335, 338 – lactone formation 335, 338 – methods 306, 326f., 349f. – nucleophilic substitution with C-N bond 346ff. – nucleophilic substitution with C-O bond 342ff. – oleﬁn ring-closing metathesis (RCM) reaction 79 ring opening – carbon nucleophile 4f. – epoxide 38, 171 – hetero-nucleophile 5 – intermolecular 108 – intramolecular 54, 108 – Lewis acid-catalyzed 351 – nucleophilic 66 – reductive 53 – regioselective 27 – Vederas’ serine lactone 325

s SAMP – -hydrazone 214, 308 – -hydrazonosulfonates 280 – method 110 saponiﬁcation 142 Schmidt rearrangement 165f. Sch¨ollkopf chiral auxiliaries 312, 327f., 330 Seebach’s SRS (self-regeneration of stereochemistry) metholodogy 69 selectivity – cis/trans 24 – endo 279 – facial 279 – syn- 58 – trans 146 Sharpless asymmetric – amino hydroxylation 57, 238 – dihydroxylation 54, 323 – epoxidation 28, 54, 60, 79, 157, 345 SN 2 reactions 7, 108, 236 SN Ar reactions 372f., 390 Staudinger reaction 28f., 67, 266 Staudinger-aza-Wittig formation 151, 324

Index stereochemistry 4, 12, 18, 148 – aminalcohol 39 – C2 /C5 cis 53 – trans 150 stereocontrol 4, 17f., 24, 26, 279, 341 – partial 319 – total synthesis 133 stereodivergent construction 126 stereoelectronic 127 stereogenic centers 3, 5, 24, 31, 36, 55, 247, 342, 381 – aziridune 5 – benzylic 199 – carboxylic derivates 230 – nitrogen 179, 194 – β-sultams 213 stereoisomer 42, 309, 342 – N-acetyl derivate 315 – single 246 stereoselective – alkylation 307f. – arylation 329, 355f. – conjugate addition 337 – hydrogenation 73, 109, 341 – Grinard addition to nitrones 75 – reduction 52, 160, 356f. – synthesis 3, 11, 131, 215 – transformation 189, 302, 307f., 327f. stereoselectivity 5, 11, 13, 20, 26f., 378, 380 stereospeciﬁc 58 – oxidation 197 Stevens rearrangement 169, 385 Stork-type approach 55 Strecker reaction 55, 296, 336, 341, 373 sulfonamides 387 sultams 276ff. – bicyclic 278f. – chiral γ -sultams 276f. – cis 216 – Oppolzer’s camphor sultam auxiliary 276 – β-sultams 213ff. Suzuki cross-coupling reaction 143

t Tamao oxidation 66 Tamura’s Beckmann reagent tautomer 139 – enamine 200 – imine 224 thiazepines 386ff. – 1,2 thiazepines 387 – 1,3 thiazepines 387 – 1,4 thiazepines 386, 388 thiazetidines 212ff.

thiazolidines 263ff. thiazolidinethiones 268 thiazolidinones 269f. thiazolines 270ff. – cyclic oligo- 274 – mono- 274 – 2-thiazolines 270 – 3-thiazolines 275f Thorpe reaction 62 Thorpe-Ingold effect 224 N-tosyl amino acids 7 Toyooka endgame sequence trans isomer 20 transacetalization 383f. transacylation 44 transamidation 122 transesteriﬁcation 43 transmetalation 306

u Ugi-type multicomponent reaction 209, 319, 373 Ullmann reaction 373 UV irradiation 16

v vinyl – azide 34 – aziridine 24 – 1,3-diazipine 370 – tricarbonyl 370

w Weinreb amide 62 Wittig reaction 45, 73 – -aza Michael 56 – domino addition- 83 – oleﬁnation 42 Wolff rearrangement reaction 60 Woodward-Prevost reaction 58

x X-ray diffraction analysis

y 67

133

ylides – chirality 25 – guanidine 29 – heteroatom 23 – methylene sulfur 24 – semistabilized 26 – sulfonium 25f.

z zwitterionic

179

190, 224, 314

409