Six-Membered Transition States in Organic Synthesis

SIX-MEMBERED TRANSITION STATES IN ORGANIC SYNTHESIS Jaemoon Yang Montana State University Department of Chemistry A J...

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SIX-MEMBERED TRANSITION STATES IN ORGANIC SYNTHESIS

Jaemoon Yang Montana State University Department of Chemistry

A JOHN WILEY & SONS, INC., PUBLICATION

SIX-MEMBERED TRANSITION STATES IN ORGANIC SYNTHESIS

SIX-MEMBERED TRANSITION STATES IN ORGANIC SYNTHESIS

Jaemoon Yang Montana State University Department of Chemistry

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright  2008 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and speciﬁcally disclaim any implied warranties of merchantability or ﬁtness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of proﬁt or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data: Yang, Jaemoon Six-membered transition states in organic synthesis / by Jaemoon Yang. p. cm. Includes index. ISBN 978-0-470-17883-6 (cloth) 1. Reaction mechanisms (Chemistry) 2. Stereochemistry 3. Organic compounds—Synthesis. I. Title. QD502.5.Y36 2008 547 .2—dc22 2007019896 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

To my sons, Walt and Larry

CONTENTS

Preface

ix

Introduction

1

1

[3,3]-Sigmatropic Rearrangements

5

General Considerations, 5 Reactions, 13 1.1 Claisen Rearrangement, 13 1.2 Johnson–Claisen Rearrangement, 20 1.3 Ireland–Claisen Rearrangement, 27 1.4 Cope Rearrangement, 32 1.5 Anionic Oxy-Cope Rearrangement, 36 1.6 Aza-Cope–Mannich Reaction, 43 2

Aldol Reactions

49

General Considerations, 49 Reactions, 57 2.1 Asymmetric Syn-Aldol Reaction, 57 2.2 Asymmetric Anti-Aldol Reaction, 78 2.3 Proline-Catalyzed Asymmetric Aldol Reaction, 91 3

Metal Allylation Reactions

97

General Considerations, 97 Reactions, 102 3.1 Boron Allylation Reaction, 102 3.2 Silicon Allylation Reaction, 127 4

Stereoselective Reductions

147

General Considerations, 147 Reactions, 151 4.1 Diastereoselective Syn-Reduction of β-Hydroxy Ketones, 151 vii

viii

CONTENTS

4.2 4.3

Diastereoselective Anti-Reduction of β-Hydroxy Ketones, 161 Asymmetric Reduction, 173

List of Copyrighted Materials

197

Abbreviations

199

Subject Index

201

Scheme Index of Natural Products

209

PREFACE When I was a graduate student in the Department of Chemistry at the University of Pittsburgh, I took organic chemistry courses taught by Professors Craig S. Wilcox and Dennis P. Curran. One of the most amazing topics that I learned about from their lectures was stereoselective synthesis in organic chemistry. Stereochemistry is a concept of paramount importance in chemistry. Stereoselective reactions, be they diastereoselective or enantioselective, are therefore a valuable tool in producing compounds of the desired stereochemistry. Every stereoselective reaction has an energetically preferred transition state that can explain the formation of the major stereoisomer. A reasonable transition state is very important not only in rationalizing the experimental results, but also in further advancing the chemical system that one is studying. Since the seminal proposal in 1957 by Howard E. Zimmerman and Marjorie D. Traxler regarding the stereoselective Ivanov reaction, six-membered chairlike transition states have been recognized as one of the most convincing methods used in organic chemistry to describe the course of reactions that have a well-organized molecular ensemble geometry. In this book I describe organic reactions that go through well-deﬁned six-membered transition states. The reactions are classiﬁed into four categories: [3,3]-sigmatropic rearrangements, aldol reactions, metal allylation reactions, and stereoselective reductions. Each chapter begins with a section on general considerations in which I gather all the computational studies known to me that support the proposal of a six-membered transition state. Each reaction has a brief introduction, a description of the six-membered chairlike transition state, and applications selected from natural product synthesis. In presenting reactions and transition states, I have tried to deliver the arguments and conclusions exactly the way they are outlined in the original references. When questions arise or further information on a transition state is sought, readers are strongly encouraged to study the references listed at the end of each section. This book will serve as a starting point in learning the amazing features of six-membered chairlike transition states in stereoselective organic reactions. With this book, I hope that students and practitioners alike will be able to propose reasonable transition states for the description of newly discovered stereoselective reactions. Comments and suggestions from readers are always welcome. I can be reached by email at [email protected].

ix

x

PREFACE

Acknowledgments I would like to thank the American Chemical Society and Elsevier for their generous permission to use materials for this book. A list of copyrighted materials is included. Without the many people who have helped me, this book could not have appeared. I would like to thank Professor Tom Livinghouse of Montana State University for his critical reading of the entire manuscript. Drs. Rohan Beckwith, Xing Dai, Tim Peelen, and Janelle Thompson each read portions of the manuscript and provided a number of helpful comments. Thanks are also due to graduate students Elisa Leonardo and Bryce Sunsdahl at the Livinghouse Laboratory for their invaluable editorial assistance. Thanks also to the anonymous reviewers who read sample chapters and gave me invaluable suggestions. I have one very special person to whom I would like to express my sincere gratitude: Walt Harris, head football coach at the University of Pittsburgh between 1996 and 2005. Not only has coach Harris been a constant source of inspiration to me, he has also been a big part of my family’s life, and I truly thank him for that. Finally, I would like to thank my wife, Wenjing Xu, for her criticisms, encouragement, and suggestions over the course of writing the book.

Jaemoon Yang Bozeman, Montana

INTRODUCTION In 1957, Zimmerman and Traxler published their study on the reaction of benzaldehyde with the magnesium enolate of phenylacetic acid: namely, the Ivanov reaction 1 (Scheme I). The major product from the reaction is an anti - or threo-isomer of 2,3-diphenyl-3-hydroxypropionic acid, and the minor product is a syn- or erythro-isomer.2 Although in 1957 the Ivanov reaction had been known for quite some time, no reasonable proposal had been put forward to explain the stereochemical outcome observed for the reaction. In explaining the ratio of the two stereoisomers, the authors made a seminal proposal that the condensation reaction would go through a six-membered transition state (Scheme II). The coordination of benzaldehyde carbonyl group with magnesium brings the two reactants in close contact in both chairlike transition state A and boatlike transition state B. The authors speculated that the particular spatial arrangement of the four substituents in the transition state could determine the stereochemistry of the products. For the Ivanov reaction of benzaldehyde, transition state A would be favored over B because transition state A involves a lower-energy approach to bonding than that of the alternative transition state B, which experiences an energetically unfavorable gauche interaction between the two phenyl substituents1 (Scheme III).

Ph

OMgBr

Et2O, reflux, 5 h

O

OMgBr +

Ph

H

Ph Ph

(91%)

CO2H OH 1-anti + Ph

Ph

CO2H OH

1-syn anti/syn = 76:24

Scheme I

Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

1

2

INTRODUCTION

R3

R3

O

O

R2

R1

R4

O

BrMg

vs.

R4 O

Mg Br

OMgBr R1

O MgBr

R2

TS B: boatlike transition structure

TS A: chairlike transition structure

Scheme II

favored

O Ph

OMgBr

H

OMgBr

OMgBr

H

BrMg

Ph Ph

BrMg O

Ph

O

MAJOR

OMgBr

H

Ph Ph

O H

Ph

CO2H OH

H TS A

PhCHO

disfavored

Ph

Ph

CO2H OH minor

TS B

Scheme III

Due to its simplicity and outstanding prediction power, the Zimmerman–Traxler transition state has frequently been used in explaining the stereochemical outcome of certain stereoselective reactions. The characteristics of the Zimmerman– Traxler transition state can be summarized as follows: 1. The transition state is for a six-atom system and thus is six-membered. 2. The transition state involves six electrons and thus exhibits the aromatic character of benzene.3 3. A chairlike transition state is favored over a boatlike transition state. There are, however, exceptions.

INTRODUCTION

CO2

−

CO2 Claisen rearrangement

O

CO2

−

O

−

−

CO2 −

CO2

−

O

or

CO2

OH 2

OH

OH TS A

TS B

−

−

O 2C

CO2 O OH 3

Scheme IV TABLE 1 Conformational Energies of Monosubstituted Cyclohexanes R ∆G25

R AX R Me Et i-Pr t-Bu C6H5 OMe

EQ −∆G (kcal/mol) 1.74 1.79 2.21 4.7 2.8 0.55

EQ/AX 19 :1 19:1 42:1 >99:1 >99:1 2.5:1

3

4

INTRODUCTION

4. When two chairlike transition states compete, the transition state in which a bulky substituent occupies an equatorial position is favored over the state that has the same substituent in an axial position. The free-energy difference between the two potential transition states can be approximated by using the ∆G or A-values of the monosubstituted cyclohexanes4 (Table 1). In the following four chapters, readers will ﬁnd some of the most frequently cited and most synthetically relevant examples of the Zimmerman–Traxler or six-membered transition state. In presenting reactions that go through a sixmembered chairlike transition state, I pay special attention to including computational studies, in an effort to prove the existence of a six-membered chairlike transition state. Although not all six-membered transition states have been studied computationally, recent interest in using computers in studies of stereoselective reactions would certainly conﬁrm the legitimacy of Zimmerman–Traxler transition states for many more reactions.5 Before we embark on our journey into the world of six-membered transition states, I would like to speak brieﬂy about one reaction, to illustrate how a transition state is drawn throughout the book. The enzyme-catalyzed transformation of chorsimate (2) to prephenate (3) is a classic example of a [3,3]-sigmatropic Claisen rearrangement 6 (Scheme IV). As an old bond is being broken and at the same time a new bond is formed in the transition state, the transition state for the Claisen rearrangement of chorismate to prephenate would look more like transistion state A than like B. Still, for the convenience of following the bond connection event clearly, I prefer to draw the transition state like B. REFERENCES 1. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79 , 1920. 2. For deﬁnitions of syn and anti , see Masamune, S.; Ali, S. A.; Snitman, D. L.; Garvey, D. S. Angew. Chem. Int. Ed. 1980, 19 , 557. 3. (a) Day, A. C. J. Am. Chem. Soc. 1975, 97 , 2431; (b) Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry, Part A, 3rd ed.; Plenum Press: New York, 1990; Chap. 11. 4. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994; Chap. 11. 5. Lipkowitz, K. B.; Kozlowski, M. C. Synlett 2003, 1547. 6. (a) Andrews, P. R.; Haddon, R. C. Aust. J. Chem. 1979, 32 , 1921; (b) Copley, S. D.; Knowles, J. R. J. Am. Chem. Soc. 1985, 107 , 5306.

1

[3,3]-Sigmatropic Rearrangements

GENERAL CONSIDERATIONS The Claisen and Cope rearrangements are two of the best known sigmatropic rearrangements in organic chemistry1 (Scheme 1.I). As the rearrangement involves six electrons in a six-atom system, these two reactions serve as excellent examples of the ubiquitous existence of a six-membered transition state in organic chemistry. In 1912, Ludwig Claisen discovered that the allyl ether 1 of ethyl acetoacetate underwent a reaction to afford 2 upon heating in the presence of ammonium chloride2 (Scheme 1.II). Similarly, the allyl naphthyl ether 3 transformed into ◦ 1-allyl-2-naphthol (4) in 82% yield at 210 C. The reaction, now known as the Claisen rearrangement , is general for a variety of aliphatic and aromatic ethers and is recognized as one of the most synthetically useful reactions in organic chemistry.3 The Claisen rearrangement is a thermally induced [3,3]-sigmatropic rearrangement of allyl vinyl ethers to form γ,δ-unsaturated carbonyl compounds.4 Due to the concerted nature and synthetic utilities of the Claisen rearrangement, much effort has been devoted to understanding the mechanism of the reaction.5 Although the extent of delocalization of the six electrons involved in the transition state may depend on the nature of the substrates, it is believed that the rearrangement goes through a six-membered aromatic transition state6 (Scheme 1.III). To uncover the transition-state structures for Claisen rearrangement of the parent allyl vinyl ether,7 Vance et al. performed ab initio quantum mechanical calculations8 (Scheme 1.IV). When the transition structures were calculated using ˚ and the the 6-31G* basis set, the partially formed C1 –C6 bond length is 2.26 A ˚ in chairlike transition structure A. partially broken C4 –O bond length is 1.92 A These two bond lengths were conﬁrmed by Meyer et al. in a later study employing different-level calculations.9 Another important ﬁnding in Vance et al.’s study is that chairlike transition structure A is more stable than boatlike structure B, by 6.6 kcal/mol. The conclusion thus supports the proposals of chairlike transition structures for the stereoselectivities observed for the Claisen rearrangement reactions of substituted molecules. Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

5

6

[3,3]-SIGMATROPIC REARRANGEMENTS

O

Claisen rearrangement

O

Cope rearrangement

Scheme 1.I O

O

heating, NH4Cl

H3C

H3C

CO2Et

CO2Et 1

2

O

OH

210°C (82%)

3

4

Scheme 1.II

O

O

O

Scheme 1.III 1.92 Å favored

2.26 Å

2

TS A: 0.0 kcal/mol

1

O 4 5

O

6 disfavored

O TS B: 6.6 kcal/mol

Scheme 1.IV

O

GENERAL CONSIDERATIONS

7

One classic example that conﬁrms the preference of Claisen rearrangement for a chairlike transition state was provided by Hansen and others. In 1968, they investigated the Claisen rearrangement of the crotyl propenyl ethers 5a and◦ 5b to examine the stereochemistry of the rearrangement in the gas phase at 160 C10 (Scheme 1.V). Both the E ,E - and Z ,Z -isomers rearrange to afford a syn-isomer as the major product. The stereochemical outcome of the reaction can be explained

Me

Me

O 5a

O

160°C

Me

Me

O +

H

H

Me 6-syn

O Me

Me

Me 6-anti

5b Ether

syn/anti

Rel. Rate

5a 5b

95.9:4.1 94.7:5.3

9 1

Scheme 1.V

O

H Me

H

O

Me H

Me

O

Me

Me

favored

MAJOR

TS A

Me

5a disfavored

Me

O

O H

H

Me

H TS B

Me

Me favored

O Me

5b

Me

Me

minor

H

H O Me TS C

Scheme 1.VI

reaction

Me

O

slower

H Me

8

[3,3]-SIGMATROPIC REARRANGEMENTS

in terms of a six-membered transition state10 (Scheme 1.VI). Between the two transition states for 5a, chairlike transition state A is favored over boatlike state B to afford a syn-isomer as the major product. Chairlike transition state C can explain the formation of the syn-isomer that is enantiomeric to 6-syn. Other indirect evidence for the existence of a chairlike transition state is the fact that the E ,E -isomer 5a reacts nine times faster than the Z ,Z -isomer 5b. This difference in the reaction rate can be understood by examining transition states A and C: Transition state C for 5b is of higher energy than transition state A for 5a, due presumably to the 1,3-diaxial interactions arising from the axial methyl groups in transition state C.

OTBS

OTBS Me

H

O

O Me

+

H

1. 60°C

7E

+

HO2C

2. 2 N NaOH 3. 6 N HCl

HO2C H Me

H Me 8a

7Z

8b

7E/7Z

8a/8b

Yield, %

83:17 4:96

84:16 72:28

79 91

Scheme 1.VII

favored

OMe

O H

OMe Me

O

MeO2C H Me MAJOR

Me

TS A: 0 kcal/mol

H

7Z(OMe) disfavored

H

MeO2C

O

H Me

H MeO

Me

TS B: 1.0 kcal/mol

Scheme 1.VIII

minor

GENERAL CONSIDERATIONS

favored

MeO2C H Me

O Me

OMe H

MeO

O

9

H

MAJOR

TS A: 0 kcal/mol

Me

7E(OMe) disfavored

O

OMe

Me

H TS B: 1.4 kcal/mol

MeO2C H Me minor

Scheme 1.IX

Although a chairlike transition state is favored for the Claisen rearrangement reactions of acyclic substrates, this is not always the case with cyclic systems. For example, Bartlett and Ireland independently studied the rearrangement reactions of cyclohexenyl silylketeneacetals and found that there was competition between the chairlike and boatlike transition states11 (Scheme 1.VII). Clearly, the E -isomer 7E gives 8a via a chairlike transition state, whereas the Z -isomer 7Z affords the same product (8a) via a boatlike transition state. To quantitatively understand the preference for the chairlike and boatlike transition states of the Claisen rearrangement, Houk et al. carried out a computational study12 (Scheme 1.VIII). In the theoretical treatment two methyl acetals, 7Z (OMe) and 7E (OMe), were used as a model system instead of the tert-butyldimethylsilyl (TBS) ketene acetal. Calculations locate four transition states for the rearrangement of 7Z (OMe), among which boatlike transition state A is of the lowest energy that leads to the formation of the major isomer observed experimentally. Chairlike transition state B is disfavored, due to steric repulsion between the axial hydrogen of the cyclohexenyl unit and the methoxy substituent of the alkene. For the reaction of 7E (OMe), chairlike transition state A is favored over boatlike transition state B12 (Scheme 1.IX). These computational results provide a solid theoretical rationalization of the original proposal by Bartlett and Ireland that the boatlike transition state is favored for the Claisen rearrangement of 7Z , and the chairlike transition state is preferred for 7E . Another important [3,3]-sigmatropic rearrangement is the Cope rearrangement, a carbon analog of the Claisen rearrangement. At the eighth National Organic Chemistry Symposium in 1939, Arthur C. Cope and Elizabeth M. Hardy presented their exciting discovery of this new reaction in which an allyl group

10

[3,3]-SIGMATROPIC REARRANGEMENTS

Me

Me CN CO2Et

Me Me

150–160°C (18 mmHg), 4 h (67%)

CO2Et CN

9

10

Scheme 1.X

H

H H 40 ° C

H 11a TS A: 0 kcal/mol

12

H H 240 ° C

H

H

11b TS B: 14.9 kcal/mol

Scheme 1.XI

migrated in a three-carbon system13 (Scheme 1.X). The discovery of the reaction was made possible by careful analysis of the product (10) that formed during vacuum distillation of the diene 9. The Cope rearrangement, which is the conversion of a 1,5-hexadiene derivative to an isomeric 1,5-hexadiene by the [3,3]-sigmatropic mechanism, has been studied extensively.14 As is the case for the Claisen rearrangement, the Cope rearrangement prefers to go through a six-membered chairlike transition state. Shea et al. demonstrated elegantly the preference for the chairlike over the boatlike transition state by carrying out Cope rearrangements of racemic (11a) and meso (11b) naphthalenes15 (Scheme 1.XI). It was determined that the racemic 1,5-diene 11a underwent Cope rearrangement 7 million times faster than the meso diene 11b. The energy difference between transition states A and B is calculated to be 14.9 kcal/mol.

GENERAL CONSIDERATIONS

favored

1.97 Å

2

TS A: 0 kcal/mol

1

3 4 5

6 disfavored

TS B: 7.8 kcal/mol

Scheme 1.XII Me

Me

Me

180°C, 18 h (97%)

Me

Me Me Me

13

14EE

14ZZ

14EZ

Me

14EE/14ZZ/14EZ = 90:9:<1

Scheme 1.XIII

H favored

Me

Me

Me Me

H TS A

Me

MAJOR

Me

Me disfavored

H

H Me Me TS B

least

Me

favored

H

Me minor Me

H Me TS C

Scheme 1.XIV

trace

Me

11

12

[3,3]-SIGMATROPIC REARRANGEMENTS

A number of theoretical studies have been conducted to understand the mechanism of the Cope rearrangement.16 According to calculations by Houk and co-workers, the chairlike transition state is more stable than the boatlike transition state by 7.8 kcal/mol (Scheme 1.XII). When Schleyer and colleagues performed calculations to compute the magnetic properties of the transition-state structures, transition states A and B had a magnetic susceptibility of −55.0 and −56.6, respectively. These values are comparable to that of benezene (−62.9), conﬁrming the existence of an aromatic transition state in the Cope rearrangement. One classic example is an experiment reported by Doering and Roth in 196217 (Scheme 1.XIII). Upon heating, racemic 3,4-dimethylhexa-1,5-diene (13) rearranged to a mixture of (2E ,6E )-octa-2,6-diene (90%), (2Z ,6Z )-octa-2,6-diene (9%), and a trace amount of (2E ,6Z )-isomer. The experimental results are explained in terms of a six-membered transition state17 (Scheme 1.XIV). Chairlike transition state A is favored over transition state B based on the conformational analysis of 1,2-dimethylcyclohexane, in which the methyl substituents prefer to be in an equatorial position. The observation that 14EZ was formed in only trace amounts indicates that boatlike transition state C is of signiﬁcantly higher energy than transition state A or B. REFERENCES 1. Hoffmann, R.; Woodward, R. B. Acc. Chem. Res. 1968, 1 , 17. 2. Claisen, L. Chem. Ber. 1912, 45 , 3157. 3. (a) Tarbell, D. S. Org. React. 1942, 2 , 1; (b) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22 , 1. (c) Hiersemann, M.; Nubbemeyer, U. Eds. The Claisen Rearrangement: Methods and Applications; Wiley-VCH: New York 2007. 4. For reviews, see (a) Ziegler, F. E. Acc. Chem. Res. 1977, 10 , 227; (b) Ziegler, F. E. Chem. Rev . 1988, 88 , 1423; (c) Castro, A. M. M. Chem. Rev . 2004, 104 , 2939. 5. (a) Houk, K. N.; Gonz´alez, J.; Li, Y. Acc. Chem. Res. 1995, 28 , 81; (b) Gajewski, J. J. Acc. Chem. Res. 1997, 30 , 219. 6. Dewar, M. J. S. Angew. Chem. Int. Ed . 1971, 10 , 761. 7. Hurd, C. D.; Pollack, M. A. J. Am. Chem. Soc. 1938, 60 , 1905. 8. Vance, R. L.; Rondan, N. G.; Houk, K. N.; Jensen, F.; Borden, W. T.; Komornicki, A.; Wimmer, E. J. Am. Chem. Soc. 1988, 110 , 2314. 9. Meyer, M. P.; DelMonte, A. J.; Singleton, D. A. J. Am. Chem. Soc. 1999, 121 , 10865. 10. (a) Vittorelli, P.; Winkler, T.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta 1968, 51 , 1457; (b) Hansen, H.-J.; Schmid, H. Tetrahedron 1974, 30 , 1959. 11. (a) Bartlett, P. A.; Pizzo, C. F. J. Org. Chem. 1981, 46 , 3896; (b) Ireland, R. E.; Wipf, P.; Xiang, J. J. Org. Chem. 1991, 56 , 3572. 12. Khaledy, M. M.; Kalani, M. Y. S.; Khong, K. S.; Houk, K. N.; Aviyente, V.; Neier, R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68 , 572. 13. Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62 , 441. 14. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 2nd ed., Part B; p. 316. 15. Shea, K. J.; Stoddard, G. J.; England, W. P.; Haffner, C. D. J. Am. Chem. Soc. 1992, 114 , 2635.

REACTIONS

13

16. For theoretical studies, see (a) Wiest, O.; Black, K. A.; Houk, K. N. J. Am. Chem. Soc. 1994, 116 , 10336; (b) Jiao, H.; Schleyer, P. v. R. Angew. Chem. Int. Ed . 1995, 34 , 334; (c) Hrovat, D. A.; Beno, B. R.; Lange, H.; Yoo, H.-Y.; Houk, K. N.; Borden, W. T. J. Am. Chem. Soc. 1999, 121 , 10529; (d) Staroverov, V. N.; Davidson, E. R. J. Am. Chem. Soc. 2000, 122 , 186; (e) Hrovat, D. A.; Borden, W. T. J. Am. Chem. Soc. 2001, 123 , 4069. 17. Doering, W. v. E.; Roth, W. R. Tetrahedron 1962, 18 , 67.

REACTIONS 1.1. Claisen Rearrangement A very interesting stereochemical outcome is noted for the Claisen rearrangement of substituted allyl vinyl ethers. For example, the allyl vinyl ethers 1 underwent Claisen rearrangement to afford the unsaturated aldehydes 2 in quantitative yields and with high levels of stereoselectivity, which depend largely on the steric bulkiness of the R group1 (Scheme 1.1a). To explain the stereochemical outcome of the rearrangement, Perrin and Faulkner proposed a six-membered chairlike transition state1 (Scheme 1.1b). Transition state A, leading to formation of the major product, is favored over B, in which the bulky alkyl group (R) occupies an axial position, resulting in energetically unfavorable 1,3-diaxial interactions. The methyl substituent in 2-methyltetrahydropyran prefers to be in an equatorial position2 (Scheme 1.1c). The formation of 2E (R = Et) as a major isomer in the rearrangement can be understood qualitatively when 2-methyltetrahydropyran is employed as a model system to estimate the energy difference between transition states A and B.3 As the Claisen rearrangement is a concerted reaction, the chirality in the starting material is translated directly to the product without loss of optical purity. For example, upon heating the allyl vinyl ethers 3R and 3S both gave the γ,δ-unsaturated aldehyde 44 (Scheme 1.1d). The degree of chirality transfer was calculated to be 98% after correcting the optical purities of the starting materials. The high level of chirality transfer in the foregoing reactions supports the notion that the reaction goes through a six-membered transition

O

R

110°C

CHO

R

R Me 1

+

Me 2E R Et i-Pr

Scheme 1.1a

CHO Me 2Z

E/Z

Yield, %

90 :10 93 : 7

100 100

14

[3,3]-SIGMATROPIC REARRANGEMENTS

Me O

favored

CHO

R

R

Me H

O

MAJOR TS A

R Me 1

Me

R

O

disfavored

CHO

H Me

HH

R

minor

TS B

Scheme 1.1b

∆G = −2.86 kcal/mol

O

EQ

O

>99 =

Me

AX

<1

Me

Scheme 1.1c

Me

O

H

H

or

O

H

Me 3R (93.0% ee)

O 80°C

3S (95.6% ee)

4 (89.8% ee from 3R; 91.6% ee from 3S)

Scheme 1.1d

state4 (Scheme 1.1e). The isobutyl group in transition states A and B occupies an equatorial position in the six-membered chairlike conformation. The Claisen rearrangement was used in the asymmetric total synthesis of (+)-9(11)-dehydroestrone methyl ether (5), a versatile intermediate in the synthesis of estrogens5 (Scheme 1.1f). The key feature of the synthesis is the successful development of the asymmetric tandem Claisen-ene sequence. Thus, a solution ◦ of the cyclic enol ether 6 in toluene was heated in a sealed tube at 180 C for 60 hours to afford the product 9 in 76% isolated yield after deprotection of the silyl enol ether. The Claisen rearrangement of the allyl vinyl ether 6 occurred stereoselectively to give an intermediate (7), in which the 8,14-conﬁguration was 90% syn. The stereoselectivity in the Claisen rearrangement can be explained

REACTIONS

Me

O favored

H 3R

Me O

15

H

H TS A

O H 4

H

O

H favored

H O

Me 3S

Me TS B

Scheme 1.1e

by the chairlike transition state 6TS, which has minimal 1,3-diaxial interactions. Therefore, the S-Z chirality of the enol ether 6 is transmitted completely to the 14S chirality in the Claisen product 7, along with a high 8,14-syn selectivity. Another application of the Claisen rearrangement is given in Boeckman et al.’s synthesis of (+)-saudin (10), a natural product that has been shown to possess in vivo non-insulin-dependent hypoglycemic activity6 (Scheme 1.1g). The allyl vinyl ether 13 was synthesized by O-alkylation of the thermodynamic enolate of 11 with the allylic triﬂate 12. The Claisen rearrangement of 13 occurred ◦ at −65 C with excess TiCl4 in the presence of Me3 Al as a proton scavenger to afford 14 as the major product. The facial selectivity was rationalized by invoking a six-membered chairlike transition state 13TS, in which titanium(IV) metal coordinates with oxygens of both the vinyl ether and the ester. In the total synthesis of the tetrodotoxin 15, Isobe et al. used the Claisen rearrangement to obtain the highly functionalized intermediate 187 (Scheme 1.1h). The alcohol 16 was treated with 2-methoxypropene and a catalytic amount of pyridinium p-toluenesulfonate (PPTS) in tetrahydrofuran (THF) to afford the allyl vinyl ether 17. Heating 17 in 1,2-dichlorobenzene in the presence of base affected a smooth Claisen rearrangement to provide the ketone 18 in high yield. The Claisen rearrangement was used to prepare an α-allyl carbonyl compound in the total synthesis of garsubellin A (19), a polyprenylated phloroglucin natural product with highly potent neurotrophic activity8 (Scheme 1.1i). O-Allylation of ˚ molecular sieves the 1,3-diketone 20 with allyl iodide in the presence of 4-A gave the enol ether 21. The Claisen rearrangement of 21 with the use of sodium acetate went smoothly to afford the key intermediate (22) in excellent yield. Metal-catalyzed isomerization of unsymmetrical diallyl ethers is a unique route to synthesize allyl vinyl ethers for the Claisen rearrangement. In 1977, Reuter and Salomon reported that heating the diallyl ether 23 in the presence of a catalytic amount of tris(triphenylphosphine)ruthenium(II) dichloride resulted in the

16

[3,3]-SIGMATROPIC REARRANGEMENTS

CO2Me

Si O

MeO 180°C, 60 h

O

H

toluene

CO2Me

H Me H 6TS

6

R3SiO O

OSiR3

O

MeO

MeO2C R3SiO

CO2Me ene H

O

reaction H

H 14 8

MeO

H

MeO 8

7

(76% from 6) 1 N HCI, THF

CHO O

CO2Me

O

H

H H

MeO

H MeO

9

5, (+)-9(11)-dehydroestrone methyl ether

Scheme 1.1f

formation of the γ,δ-unsaturated aldehyde 259 (Scheme 1.1j). The Claisen rearrangement presumably occurred through the intermediate 24, which was produced via a highly regioselective isomerization of the monosubstituted alkene. In accessing chiral allyl vinyl ethers for Claisen rearrangement reactions, Nelson et al. employed the iridium-mediated isomerization strategy. Thus, the requisite enantioenriched diallyl ether substrate 28 was synthesized via a highly enantioselective diethylzinc–aldehyde addition protocol10 (Scheme 1.1k). The enantioselective addition of Et2 Zn to cinnamaldehyde catalyzed by (−)-3-exomorpholinoisoborneol (MIB; 26)11 provided an intermediate zinc alkoxide (27). Treatment of 27 with acetic acid followed by O-allylation in the presence of palladium acetate delivered the 28 in 73% yield and 93% ee. Isomerization of 28 with a catalytic amount of the iridium complex afforded the allyl vinyl ether

REACTIONS

17

TBDPSO O

O t-Bu O Si Ph Ph

TfO

+ Me CO2Me 11

KHMDS, THF/HMPA (65%)

Me CO2Me 13

12

(65%)

O

Me

H

TiCl4, Me3Al, CH2Cl2, −65°C

Ti

OTBDPS O

Me O

O Me

Me Me CO2Me

H 13TS

14

OTBDPS

O O

H

O O O

O

O 10, (+)-saudin Scheme 1.1g

29, which then underwent Claisen rearrangement to produce the γ,δ-unsaturated aldehyde 30 (syn/anti = 95 : 5) without loss of optical purity. Nelson and Wang completed an enantioselective synthesis of (+)-calopin dimethyl ether (31), highlighting the potential utility of the oleﬁn isomerization– Claisen rearrangement strategy in asymmetric synthesis12 (Scheme 1.1l). Reaction of 2,3-dimethoxy-4-methylbenzaldehyde (32) with Meyers’s lithio enaminophosphonate reagent gave the enal 33, which was then subjected to the (−)-MIB (26)-catalyzed addition of Et2 Zn, acetic acid treatment, and palladium-catalyzed O-allylation to afford the diallyl ether 34 in high enantioselectivity. Isomerization– Claisen rearrangement of 34 and the in situ reduction of the intermediate aldehyde generated the 2,3-syn-disubstituted 4-heptenol (35) (90% ee, syn/anti = 94 : 6).

18

[3,3]-SIGMATROPIC REARRANGEMENTS

O

TBSO

O-i-Pr

TBSO

O

O-i-Pr

OMe PPTS (cat.), THF (89%)

OH

O K2CO3, 150°C (94%) 1,2-dichlorobenzene

TMS

TMS

16

17 −

O + H 2N

H

H

N N HO H

O-i-Pr

O

TBSO

HO O O O

O OH

TMS

OH

15, tetrodotoxin

18

Scheme 1.1h

O

O

O

CO(i-Pr) O

NaHMDS, 4-Å MS, ethylene carbonate;

O

allyl iodide (82%)

O

O

O

O

O O

O 20

21 (92%) NaOAc, 200°C

HO

O

O

O

O O O

O

O O O

19, (±)-garsubellin A

Scheme 1.1i

22

O

REACTIONS

O

Ru(PPh3)3Cl2 (0.1 mol %)

O

19

O

200°C, 1 h (92%)

23

H

24

25

Scheme 1.1j

26 (2 mol %) Et2Zn, pentane

O Ph

H Me

Me

0°C

O

1. AcOH 2. Pd(OAc)2, PPh3

ZnX

Et

Ph

Ph

Et

27

O

28 (93% ee)

N

PPh3 (3 mol %), 40°C [Ir(PCy3)3]+ −BPh4 (82%) (1 mol %)

OH 26

Me

O

allyl acetate (73%, 3 steps)

O Me

H

Et

Ph

Et

Me

O

Ph

30 (92% ee)

29

Scheme 1.1k

CHO OMe OMe

O t-BuN

CHCH2PO(OEt)2, LDA

H

1. Et2Zn, 26 (2 mol %) 2. AcOH 3. Pd(OAc)2 (5 mol %), PPh3, allyl acetate (90%)

(65%)

Ar

Me 32

Ar

Et

34 (90% ee)

33

O

O

[Ir(PCy3)3]+ −BPh4 NaBH4 (80%) (1 mol %) PPh3 (3 mol %), 80°C;

O

HO

OH

Me OMe OMe Me

31, (+)-calopin dimethyl ether

Scheme 1.1l

Me Et

Ar 35 (90% ee)

20

[3,3]-SIGMATROPIC REARRANGEMENTS

REFERENCES 1. Perrin, C. L.; Faulkner, D. J. Tetrahedron Lett. 1969, 10 , 2783. 2. Eliel, E. L.; Hargrave, K. D.; Pietrusiewicz, K. M.; Manoharan, M. J. Am. Chem. Soc. 1982, 104 , 3635. 3. Wilcox, C. S.; Babston, R. E. J. Am. Chem. Soc. 1986, 108 , 6636. 4. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41 , 3497. 5. Mikami, K.; Takahashi, K.; Nakai, T. J. Am. Chem. Soc. 1990, 112 , 4035. 6. Boeckman, R. K., Jr.; Ferreira, M. R. R.; Mitchell, L. H.; Shao, P. J. Am. Chem. Soc. 2002, 124 , 190. 7. Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125 , 8798. 8. Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127 , 14200. 9. Reuter, J. M.; Salomon, R. G. J. Org. Chem. 1977, 42 , 3360. 10. Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003, 125 , 13000. 11. Nugent, W. A. J. Chem. Soc. Chem. Commun. 1999, 1369. 12. Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128 , 4232.

1.2. Johnson–Claisen Rearrangement In 1970, Johnson and others reported a highly stereoselective synthesis of trans-trisubstituted oleﬁnic bonds via the Claisen rearrangement. The alcohol 1, on heating with 7 equivalents of ethyl orthoacetate and a catalytic amount ◦ of propionic acid at 138 C for 1 hour while distilling ethanol, was converted to the diene ester 2 in 92% yield and with more than 98% (E )-isomer1 (Scheme 1.2a). Heating a mixture of allylic alcohol and ethyl orthoacetate in the presence of a small amount of propionic acid gives a mixed orthoacetate that loses ethanol to form the ketene acetal, which then undergoes a [3,3]-sigmatropic rearrangement1 (Scheme 1.2b). The outstanding stereoselectivity observed in the Johnson–Claisen rearrangement can be explained by a six-membered transition state where the nonbonded interaction between the ethoxy and R groups is a determining factor2 (Scheme 1.2b). Other indirect evidence for the existence of a six-membered transition state in the Johnson–Claisen rearrangement is found in Daub et al.’s experiments3 (Scheme 1.2c). When cinnamyl alcohol was heated with triethylorthopropionate in the presence of an acid catalyst, the products were obtained

+

Me

EtCO2H (0.06 equiv), 138°C, 1 h

Me CH3C(OEt)3

(92%)

EtO2C

HO E/Z = >98:< 2 2

Me 1

Scheme 1.2a

Me

21

REACTIONS

Me

Me CH3C(OEt)3 EtCO2H

HO

Me − EtOH

EtO EtO

R

O

EtO

R

O

Me

EtO H

Me

favored

O

R

Me EtO

O

EtO2C Me TS A

R

MAJOR

R EtO R

Me

disfavored

O

H

EtO2C Me TS B

R

minor

Scheme 1.2b

R Ph

OH

CH3CH2C(OEt)3, EtCO2H (0.06 equiv)

R

R CO2Et

125°C, 2 h

+

Ph

CO2Et Ph

4-syn

3 R

H CH3

4-anti syn/anti

Yield, %

60:40 85:15

72 65

Scheme 1.2c

in 60 : 40 selectivity, slightly favoring the syn-isomer. The syn-selectivity improved to 85 : 15 for the rearrangement reaction of the ketene acetal of (E )-2-methyl-3-phenyl-2-propen-1-ol (Scheme 1.2c). The increased syn/anti selectivity observed in the Johnson–Claisen rearrangement of the ketene acetal from the trisubstituted alkene is an indication that the reaction goes through a six-membered chairlike transition state4 (Scheme 1.2d). Transition state B is disfavored compared to state A, due to the developing 1,3-diaxial interactions between the two methyl groups in the transition state.

22

[3,3]-SIGMATROPIC REARRANGEMENTS

OEt

Me

favored

H Ph

O

Ph

EtO

Ph

H

Me

CO2Et MAJOR

Me TS A

O OEt OEt

H

disfavored

H CO2Et

Ph O

Ph

Me Me

minor

TS B

Scheme 1.2d

favored

O

OMe OMe

OMe TS A: 0.0 kcal/mol

O

O

OMe disfavored

O TS B: 2.3 kcal/mol

Scheme 1.2e

The preference for a chairlike transition state in the Johnson–Claisen rearrangement is supported by further Houk et al.’s computational studies (Scheme 1.2e).5 For the rearrangement of the parent methyl ketene acetal, chairlike transition state A is favored over boatlike transition state B by 2.3 kcal/mol. Johnson et al. used their newly developed orthoester Claisen reaction to achieve a highly stereoselective total synthesis of all-trans squalene (5)1 (Scheme 1.2f). The diene diol 6 underwent Johnson–Claisen rearrangement when it was ◦ heated with ethyl orthoacetate in the presence of propionic acid for 3 h at 138 C. The diene dialdehyde 7, obtained by treatment of the resulting ester with lithium aluminum hydride followed by oxidation with Collins reagent, reacted with 2-propenyllithium to give the tetraene diol 8. The tetraene dialdehyde 9, which

23

REACTIONS 1. CH3C(OEt)3, C2H5CO2H (cat.) 2. LiAlH4

OH

H

3. CrO3•py2 (65%, 3 steps)

OH

2

O

6

7 (97% E) CH2

C(CH3)Li

1. CH3C(OEt)3, C2H5CO2H (cat.) 2. LiAlH4

H

3. CrO3•py2 (60% from 7)

2

O

9

2

OH

8

(36%) Ph3P C(CH3)2

5, squalene (95% all E)

Scheme 1.2f

O

HO H

H

2. ClCO2Me, pyridine (90%)

O

O

OH

1. CH2=CHMgBr (3 equiv), THF, CH2Cl2, 0°C (96%)

H O

O

11

OCO2Me H

CH3(OMe)3, 140°C, 3 h EtCO2H (0.1 equiv) (83%)

12 CO2Me

CO2Me 1. 25% aq. AcOH 2. Et3N

O HO

CO2Me

xylene, 160°C, 1h (59% from 13)

H O

C(OMe)3

CO2Me

dr 1:1

O

O

O

14

15

OCO2Me H

H

13

O

CO2Me

CO2H

8

MeO2C

12

16

O

O

OH 10, prostaglandin A2

O

Scheme 1.2g

24

[3,3]-SIGMATROPIC REARRANGEMENTS

O O

110°C, 24 h (99%)

OH

TBSO

(E)-isomer

O

CH3C(OMe)3, C2H5CO2H (cat.)

O MeO2C

TBSO

18

19 (70%) AD-mix β

O

O

O

O

1. TBAF, THF (84%) 2. MsCl, pyridine (90%)

O

TBSO 21

HO HO

O

3. NaN3, DMSO (75%)

OMs

N3

H

O

O

OH 20

OH

N

17, (−)-swainsonine

Scheme 1.2h

was accessed by the same reaction sequence as that for the conversion of 6 to 7, afforded squalene upon treatment with isopropylidenetriphenylphosphorane in 36% yield. In the total synthesis of prostaglandin A2 (PGA2 ; 10), Stork and Raucher used two Johnson–Claisen rearrangements to obtain the key intermediates6 (Scheme 1.2g). The ﬁrst Johnson–Claisen rearrangement was carried out by heating the allylic alcohol 12, derived from 2,3-isopropylidene-L-erythrose (11), with trimethyl orthoacetate to afford the unsaturated ester 13 with an (E )-geometry. Hydrolysis of the acetonide followed by treatment with triethylamine afforded the allylic alcohol 14. The second Johnson–Claisen rearrangement of the allylic alcohol 14 with the orthoester 15 produced 16 in good yield. The chirality at the C12 center in 16 was secured by virtue of chirality transfer of a carbon–oxygen bond in 14 through a six-membered chairlike transition state in the rearrangement. The formation of a 1 : 1 mixture at the C8 center is due to the nonstereoselective generation of the ketene acetal precursor of the rearrangement. Pearson and Hembre synthesized a key intermediate (19) using the Johnson–Claisen rearrangement protocol in the total synthesis of the indolizidine

REACTIONS

25

SmI2, EtCHO, THF, −10οC (96%)

PMBO

OH

PMBO

OH

O 23

OCOEt

24 1. K2CO3, MeOH 2. PhSeCH2CH(OEt)2

(93%, 2 steps)

PMBO

O

O Ph

NaIO4, NaHCO3, MeOH/H2O

O PhSe

26

25

xylenes, reflux (82% from 25) CH2

O

DBU, C(OMe)OTBS

PMBO

HO 9

PMBO

Se O

16

9

11

O O 27

O 16

O 1

11

OH

O

OH OH

NH2 O

22, discodermolide

Scheme 1.2i

alkaloid (−)-swainsonine (17), a potent anticancer drug as an inhibitor of many mannosidases7 (Scheme 1.2h). When the allylic alcohol 18 was heated in toluene with trimethyl orthoacetate in the presence of a catalytic amount of propionic acid with the constant removal of methanol, the γ,δ-unsaturated ester desired (19) was obtained in nearly quantitative yield with the (E )-alkene geometry. Oxidative lactonization via Sharpless dihydroxylation8 of the alkene 19 provided the lactone desired (20) in 70% yield along with the other diastereomer in 9% isolated yield. Deprotection of the silyl ether, mesylation, and selective substitution of the less hindered primary mesylate of the diol produced the monoazide 21. Further synthetic manipulations to the azide 21 provided 4.5 g of target molecule 17, successfully demonstrating a practical synthesis of (−)-swainsonine. In the total synthesis of a polyketide natural product, (+)-discodermolide (22), Paterson and co-workers synthesized the C9 –C16 fragment 27 using a JohnsonClaisen rearrangement9 (Scheme 1.2i). Evans–Tishchenko reduction10 of

26

[3,3]-SIGMATROPIC REARRANGEMENTS

OTBDPS

O

Br

TBDPSO

30

H

OH

NiCl2, CrCl2, DMF, rt, 2 h (100%)

29

31 CH3C(OEt)3, 100°C, 12 h (88%) C2H5CO2H (cat.)

HO2C

TBDPSO

O

EtO2C 16:1 (Z/E)

32

28, (+)-hippospongic acid A

Scheme 1.2j

the β-hydroxy ketone 23 gave the anti -1,3-diol monoester 24 (see Chapter 4). Methanolysis followed by transacetalization afforded the selenide 25. Oxidation of 25 with NaIO4 resulted in the formation of the selenoxide 26, which underwent β-elimination upon treatment with DBU. The ketene acetal thus generated underwent a highly stereoselective Johnson–Claisen rearrangement, via a six-membered chairlike transition state, to provide the eight-membered lactone 27 in excellent yield. The natural product (+)-hippospongic acid A (28) shows a variety of biological activities, such as inhibition of gastrulation in starﬁsh embryos and induction of apotosis in the human gastric cancer cell line. In the synthesis of 28, Trost et al. prepared a key intermediate via a Johnson–Claisen rearrangement reaction11 (Scheme 1.2j). The Nozaki–Hiyama–Kishi reaction12 of the aldehyde 29 with the vinyl bromide 30 gave the allylic alcohol 31 in quantitative yield under mild reaction conditions. When the alcohol 31 was subjected to a Johnson–Claisen ◦ rearrangement at 100 C, the product desired (32) was obtained in excellent yield with high stereoselectivity around the newly formed double bond. The stereochemical outcome of the rearrangement reaction is rationalized by a sixmembered transition state.

REACTIONS

27

REFERENCES 1. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brockson, T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92 , 741. 2. Perrin, C. L.; Faulkner, D. J. Tetrahedron Lett. 1969, 2783. 3. Daub, G. W.; Shanklin, P. L.; Tata, C. J. Org. Chem. 1986, 51 , 3402. 4. Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.; Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M. J.; Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunningham, P. S.; Berliner, M. A. J. Org. Chem. 1997, 62 , 1976. 5. Khaledy, M. M.; Kalani, M. Y. S.; Khong, K. S.; Houk, K. N.; Aviyente, V.; Neier, R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68 , 572. 6. Stork, G.; Raucher, S. J. Am. Chem. Soc. 1976, 98 , 1583. 7. Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61 , 7217. 8. Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992, 33 , 6407. 9. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123 , 9535. 10. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112 , 6447. 11. Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005, 127 , 7014. 12. (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24 , 5281; (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108 , 5644.

1.3. Ireland–Claisen Rearrangement In 1976, Ireland et al. reported that [3,3]-sigmatropic rearrangement of allylic esters as enolate anions or corresponding silylketene acetals produces the γ,δ- unsaturated acids in good yields and with excellent levels of diastereoselectivity. For example, rearrangement of the ester 1 afforded (E )-4-decenoic acid (2) with greater than 99% stereoselectivity and in high yield1 (Scheme 1.3a). The tert-butyldimethylsilylketeneacetal 1OTBS, generated by successive treatment of 1 with lithium diisopropylamide (LDA) and tert-butyldimethylsilyl chloride at ◦ −78 C, undergoes rearrangement via a six-membered chairlike transition state2 (Scheme 1.3b). An examination of nonbonded interactions readily indicates which of the two possible transition states will be favored. The equatorial disposition of the R group puts transition state A at lower energy, which results in predominant formation of the E -isomer. n-C5H11

LDA, THF/HMPA (10:1), −78°C, TBSCl;

O

Me

then 25°C, 2 h (83%)

n-C5H11 O OH

O 1

2 (>99.5% E)

Scheme 1.3a

28

[3,3]-SIGMATROPIC REARRANGEMENTS

n-C5H11

O

favored

HO2C

H

TBSO n-C5H11

n-C5H11

MAJOR

TS A O OTBS

1OTBS

H

O

disfavored

n-C5H11

n-C5H11

TBSO

CO2H

minor TS B

Scheme 1.3b Me O

Me

Me

Me

LDA, solvent, −78°C, TBSCl;

+

CO2H

then 25°C

Me 4-anti

O 3

Solvent THF THF/HMPA (77:23)

CO2H Me 4-syn

anti/syn

Yield, %

87:13 19:81

79 73

Scheme 1.3c O

favored

TBSO

H

Me

O

CO2H Me MAJOR

TS A

LDA

Me

Me Me

in THF

O

CH3

TBSCl

3

O

disfavored

H

Me Me

in THF

TBSO

CH3 TS B

Scheme 1.3d

CO2H Me minor

REACTIONS

Et

Me

H

THF

+

O

O

BnO

OMOM n-BuLi,

O

BnO

Me

Et

OH

Cl

O

H

−78°C

Me

O

O

OMOM O

6

29

7

Me

8 1. LDA, −78°C 4. CH2N2 (50%, 5 steps) 2. TMSCl 3. NaOH

Et

Me

OH

BnO H

O

Et H

O

1. H2, Raney-Ni 2. DIBAL-H 3. Ph3P=CH2 4. H2, Raney-Ni 5. 10% HCl (68%, 5 steps)

Me

Me

Et

Me

OMOM

BnO H

O

E H

O

Me

OH

Me

Et

HO Me

Me

9 (E = CO2Me)

10

CO2H

Et

OH

O

H

O

Et H

O

Me

5, lasalocid A

Scheme 1.3e

As the Ireland–Claisen rearrangement proceeds through a six-membered chairlike transition state, the stereochemistry about the newly formed carbon–carbon single bond can be predicted from the geometries of the double bonds in the starting 1,5-dienes.1 For example, the stereochemical outcome of the rearrangement of (E )-crotyl propanoate (3) depends on the solvents used. The anti -isomer is obtained as a major isomer in THF, whereas the syn-isomer is the major product when the reaction was carried out with hexamethylphosphoramide (HMPA) as a cosolvent (Scheme 1.3c). Again, these results can be explained via a six-membered transition state (Scheme 1.3d). In THF, the (E )-enol ether is formed preferentially and subsequently undergoes a [3,3]-sigmatropic rearrangement via transition state A. When HMPA is used as a cosolvent along with THF, the (Z)-enol ether becomes a major isomer, resulting in the formation of 4-syn.1 Claisen rearrangements of silylketene acetals have been used in numerous organic syntheses of natural products.3 Ireland used his newly developed ester enolate Claisen rearrangement in the total synthesis of lasalocid A (X537A) (5), a polyether ionophore antibiotic natural product with a broad range of biological potency (Scheme 1.3e).4 The ester 8, which was prepared by the reaction

30

[3,3]-SIGMATROPIC REARRANGEMENTS

Me

Me

1. LDA, THF, −45°C 2. TESCl, −45°C

O Me

3. Toluene, reflux, 20 min 4. Me2SO4, K2CO3 (42%, 4 steps)

N

CO2TES

Me

O 12

13 1. KOH, MeOH/H2O 2. KI3, NaHCO3, H2O

Me

Me

DBU, THF 25°C, 1.5 h (73% from 13)

Me

O

Me

O 11, rac-frullanolide

I

O O

14

Scheme 1.3f

of the acyl chloride 6 from α-D-glucosaccharinic acid lactone and the glycal 7 from 6-deoxy-L-glucose, underwent Ireland–Claisen rearrangement to provide the tetrahydrofuran 9 in 50% yield after hydrolysis and esteriﬁcation. The tetrahydrofuran 10 was eventually utilized as a key intermediate in Ireland’s total synthesis of lasalocid A.5

1. LDA, −78°C; then TBDMSCl, HMPA

1. t-BuPh2SiCl, Et3N, DMAP, CH2Cl2 2. C2H5COCl, pyridine (90%, 2 steps)

OH

OH

O

TBDPSO

16

17

Et

2. KOH 3. CH2N2 (90%, 3 steps)

O

O CO2Me TBDPSO 18

O H

O O NH

Scheme 1.3g

N

NHMe CO2H

15, calcimycin

REACTIONS

O

O CH3O

KHMDS, TMSCl, THF

O

CH3O

+ PPh3 − Br

OH Ph

(81%)

OMe 20

21

22

O BocHN

O O

1. LDA, ZnCl2, THF

O

BocHN

OMe H

2. CH2N2, Et2O (72%, 2 steps)

24

23

1. n-BuLi, THF, 0°C, 3 h

22 + 25

31

2. NaOH, MeOH (48%, 2 steps)

N-Boc-Adda

CO2Me NHBoc 25

Ph

CO2H OMe

NH2 19, Adda

Scheme 1.3h

Still and Schneider employed Ireland–Claisen rearrangement in the total synthesis of (±)-frullanolide (11)6 (Scheme 1.3f). The key step of the synthesis is efﬁcient Ireland–Claisen rearrangement of the β-pyrrolidinopropionate ester 12. The triethylsilylketene acetal rearranged in toluene at reﬂux and the pyrrolidine moiety was eliminated after stirring with a mixture of dimethyl sulfate and potassium carbonate in methanol to afford the α-substituted acrylic ester (13). Saponiﬁcation followed by iodolactonization gave the iodolactone 14, which upon treatment with DBU led to (±)-frullanolide. In total synthesis of the structurally unique natural product calcimycin (15), Grieco and others used Ireland–Claisen rearrangement of the ester 17 to synthesize the key intermediate (18)7 (Scheme 1.3g). Monosilylation of the diol 16 followed by treatment with propionyl chloride in pyridine ◦gave rise to the ester 17 in 90% yield. Treatment of 17 with LDA in THF at −78 C, subsequent addition of tert-butyldimethylsilyl chloride in HMPA, and brief heating of the resulting silylketene acetal provided the corresponding silyl ester. Subsequent hydrolysis of the silyl ester and esteriﬁcation with diazomethane gave 18 in 90% yield from 17. The C20 amino acid (2S ,3S ,8S ,9S ,4E ,6E )-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid (Adda; 19) is a molecule of interest to biologists and organic chemists as a component of the hepatotoxic cyclic peptides called microcystins. Kim and Toogood used Ireland–Claisen rearrangement in their successful synthesis of Adda8 (Scheme 1.3h). The ester 20 underwent highly diastereoselective Ireland–Claisen rearrangement to provide the acid 21. Conversion of this acid to the phosphonium bromide 22 was achieved in nine

32

[3,3]-SIGMATROPIC REARRANGEMENTS

steps. Another Ireland–Claisen rearrangement of 23 in the presence of ZnCl2 9 efﬁciently afforded the ester 24. Wittig reaction of the two fragments 22 and 25, followed by saponiﬁcation, provided N -Boc-protected Adda. REFERENCES 1. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98 , 2868. 2. (a) Wipf, P. in Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991: Vol. 5 , Chap. 7.2; (b) Ireland, R. E.; Wipf, P.; Xiang, J.-N. J. Org. Chem. 1991, 56 , 3572. 3. For a review of the synthetic applications of Ireland–Claisen rearrangement, see Pereira, S.; Srebnick, M. Aldrichimica Acta 1993, 26, 17. 4. Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1980, 102 , 1155. 5. Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983, 105 , 1988. 6. Still, W. C.; Schneider, M. J. J. Am. Chem. Soc. 1977, 99 , 948. 7. (a) Grieco, P. A.; Williams, E.; Tanaka, H.; Gilman, S. J. Org. Chem. 1980, 45 , 3537; (b) Martinez, G. R.; Grieco, P. A.; Williams, E.; Kanai, K.-I.; Srinivasan, C. V. J. Am. Chem. Soc. 1982, 104 , 1436. 8. Kim, H. Y.; Toogood, P. L. Tetrahedron Lett. 1996, 37 , 2349. 9. Kazmaier, U. Angew. Chem. Int. Ed. 1994, 33 , 998.

1.4. Cope Rearrangement Because of the concerted nature of the mechanism of Cope rearrangement, chirality at C3 in the starting material leads to enantiospeciﬁc formation of the new chiral center in the product. For example,◦ Cope rearrangement of (3R,5E )-3-methyl-3-phenyl-1,5-heptadiene (1) at 250 C resulted in an 87 : 13 mixture of trans- and cis-3-methyl-6-phenyl-1,5-heptadiene in quantitative yield1 (Scheme 1.4a). The optical purity of the starting material is 95% ee, and those of the products are 91% ee for 2E and 89% ee for 2Z . Thus, the optical integrity of the starting material is preserved during thermal rearrangement, suggesting that the rearrangement is concerted. The stereochemical outcome of the above reaction is explained in terms of a six-membered chairlike transition state1 (Scheme 1.4b). The 87 : 13 preference for

Ph 250°C

Me

(100%)

Ph

Me +

Me

Me

Me 1

2E

Me 2Z

2E/2Z = 87:13

Scheme 1.4a

Ph

REACTIONS

H

33

Ph

favored

Me

Ph

Me

Me

Me

Ph

MAJOR

TS A

Me Me Ph

1

Me

disfavored

Me

Ph

Me

Me

H minor

TS B

Scheme 1.4b

2E corresponds to a free-energy difference of about 2 kcal/mol between transition states A and B. Based on the A-values of the monosubstituted cyclohexanes, it was understood that transition state A in which the phenyl subsitituent group occupies an equatorial position would be favored over B. Raucher et al. used a tandem Cope–Claisen rearrangement during total synthesis of the germacrane sesquiterpene (+)-dihydrocostunolide (3)2 (Scheme 1.4c).

Cope

Ireland–Claisen

200°C

OTIPS

OTIPS

OTIPS

H

O

O

O

5

4

1. KF, HMPA (30% from 4) 2. CH N 2 2

H O O 3, (+)-dihydrocostunolide

Scheme 1.4c

H

O OMe 6

34

[3,3]-SIGMATROPIC REARRANGEMENTS t-BuLi, Et2O, −78°C

O I

O

OSi(i-Pr)3

8

O

O MeO then

N Me

O

O 9

OTIPS 10

(70%) TMSCl, −78 to 0°C LDA, −78°C

R (74% from 10)

O

O

H

O

R

TMSO

TMSO

Me

Me

HCl–H2O

OTIPS 13

12

11

O H

HOOC HO

H

OBz

7, (−)-scopadulcic acid A

Scheme 1.4d

A solution of the silylketene acetal 4 in dodecane was subjected to thermolysis ◦ at 200 C for 140 minutes. The Cope–Claisen rearrangement product 5 was then treated with KF in HMPA followed by esteriﬁcation to afford the methyl ester 6. Fox et al. used the Cope rearrangement in total synthesis of the structurally unique tetracyclic diterpene acid ( − )-scopadulcic acid A (7), which exhibits a broad range of pharmacological activities3 (Scheme 1.4d). Lithiation of the optically active iodide 8 with t-BuLi followed by condensation of the resulting organolithium species with the amide 9 afforded the cyclopropyl ketone 10. Compound 10 was then treated sequentially with LDA and TMSCl to provide a silyl enol ether intermediate (11), which underwent Cope rearrangement to furnish the silyloxy cycloheptadiene 12. Hydrolysis of 12 then resulted in the cycloheptenone 13 as a single stereoisomer in 74% overall yield.

35

REACTIONS

H Me

Me

H

catalyst 16 CH2 CH2

Me

Cope

Me

rearrangement

C6H6, 50–80°C (79%)

Me

Me

Me

Me

O

O

15

17

Me O 18

O Mes N Cl Cl

Me

N Mes Me Ru

Me

PCy3

Ph

O O 14, (−)-asteriscanolide

catalyst 16

Scheme 1.4e

The Cope rearrangement was used in the total synthesis of (−)-asteriscanolide (14), a novel sesquiterpene natural product4 (Scheme 1.4e). Ring-opening metathesis of the cyclobutene 15 with ethylene in the presence of the ruthenium catalyst 165 proceeded smoothly to provide the cyclooctadiene 18 via Cope rearrangement of the intermediate dialkenyl cyclobutane (17). When the vinyldiazoacetate 19, which can be prepared from benzaldehyde in a one-pot process,6 was treated in 2,2-dimethylbutane (DMB) with dirhodium tetrakis[(S )-N -(dodecylbenzenesulfonyl)prolinate] [Rh2 (S -DOSP)4 ] in the presence of 4-methyl or 4-trimethylsilyloxy-1,2-dihydronaphthalene (20), the product 21 was obtained with exceptionally high levels of enantio- and diastereo selectivity7 (Scheme 1.4f).

R N2

Ph

R Rh2(S-DOSP)4 (1 mol %)

+

23°C, DMB

CO2Me

Ph H

19

20

21 R

ee, %

Me OTMS

99 98

Scheme 1.4f

CO2Me

de, %

Yield, %

>98 >98

92 55

36

[3,3]-SIGMATROPIC REARRANGEMENTS

H Ph R

H

Rh

H CO2Me H

C-H/Cope

Ph R

H CO2Me

Ph R

Cope

20a

TS A

H CO2Me H

21

Scheme 1.4g

The highly enantioselective reaction is explained in terms of a double Cope rearrangement event7 (Scheme 1.4g). The substrate 20 is approaching from the front side, due to the chiral environment posed by the D 2 -symmetric rhodium catalyst.8 The Cope rearrangement then presumably occurs to form 20a through chairlike transition state A. Another Cope rearrangement of the 1,5-diene 20a affords the product 21 in a highly stereoselective manner. REFERENCES 1. Hill, R. K.; Gilman, N. W. J. Chem. Soc. Chem. Commun. 1967, 619. 2. Raucher, S.; Chi, K.-W.; Hwang, K.-J.; Burks, J. E., Jr. J. Org. Chem. 1986, 51 , 5503. 3. Fox, M. E.; Li, C.; Marino, J. P., Jr.; Overman, L. E. J. Am. Chem. Soc. 1999, 121 , 5467. 4. Limanto, J.; Snapper, M. L. J. Am. Chem. Soc. 2000, 122 , 8071. 5. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1 , 953; (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34 , 18; (c) Schrock, R. R. Chem. Rev. 2002, 102 , 145. 6. Davies, H. M. L.; Yang, J.; Manning, J. R. Tetrahedron: Asymmetry 2006, 17 , 665. 7. Davies, H. M. L.; Jin, Q. J. Am. Chem. Soc. 2004, 126 , 10862. 8. Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J. Am. Chem. Soc. 2003, 125 , 15902.

1.5. Anionic Oxy-Cope Rearrangement ◦

In 1964, Berson and Jones reported that heating 1 in the gas phase at 320 C gave cis-2-octalone (2) in 50% yield1 (Scheme 1.5a).

H OH

O

320°C (50%)

H 1

2

Scheme 1.5a

REACTIONS

HO

HO 1

R

37

O

[3,3]

3

R

R

5

Scheme 1.5b

H OH

66°C several minutes (98%)

MeO

O

KH, THF

OK MeO

MeO

H 4

3

3K

Scheme 1.5c

HO

OMe

O 110°C, 24 h

Me

+ H Me

OMe H

7E (96%)

OMe

8Z (4%)

O KH, diglyme

Me 6

H Me

OMe

H

5

HO

O

KH, diglyme

110°C, 24 h

H Me

OMe H 7Z (77%)

O + H Me

H

OMe 8E (23%)

Scheme 1.5d

Berson proposed the term oxy-Cope rearrangement for the reaction, as the reaction is a [3,3]-sigmatropic Cope rearrangement of 3-hydroxy-1,5-hexadiene1 (Scheme 1.5b). The oxy-Cope rearrangement would be a synthetically useful route to access δ,ε-unsaturated carbonyl compounds from the corresponding secondary or tertiary alcohols if the reaction conditions were mild. In 1975, Evans and Golob discovered that the Cope rearrangement of 3-hydroxy-1,5-hexadienes proceeds extremely fast in the presence ◦of potassium hydride. For example, heating the potassium alkoxide 3K at 66 C for several minutes in anhydrous THF completed the Cope rearrangement to afford the methoxy ketone in superb ◦ yield2 (Scheme 1.5c). From kinetic experiments it was determined that at 25 C rearrangement of 3K occurred 1012 times faster than 3 in the presence of 1.1 equivalents of 18-crown-6.

38

[3,3]-SIGMATROPIC REARRANGEMENTS

H favored

HO

H

MeO −O

O Me H Me

OMe TS A

KH

Me

H

5 disfavored

−

MAJOR O

Me

MeO O

OMe

H

H H Me

OMe H minor

TS B

Scheme 1.5e

OMe favored

HO

−

H

H

O Me

O

H Me

OMe

OMe H MAJOR

TS C

KH

Me MeO

6 disfavored

−

O

Me

H

H

O

H Me TS D

H

OMe minor

Scheme 1.5f

To gain insights into the possible transition-state geometry of the sigmatropic process, Evans et al. rearranged the diastereomeric dienols 5 and◦ 63 (Scheme 1.5d). When a mixture of 5 and KH was heated in diglyme at 110 C for a day, the rearranged products were obtained in 78% yield and with high diastereoselectivity. Under similar reaction conditions, the dienol 6 also underwent anionic oxy-Cope rearrangement, but with poor diastereoselectivity. The striking difference in the stereoselectivity observed in the rearrangement of 5 and 6 suggests that a six-membered transition state is operating in these reactions. In the rearrangement of 5, the major product 7E is formed via chairlike transition state A,

REACTIONS

Bond Energy, kcal/mol

Molecules H CH2OH

90.7

H CH2OK

79.0

3

OH

39

OK

3

vs. 4

4

bond weakening

Scheme 1.5g

O−

O−

3.28 Å

H

O− H 2.33 Å TS A

Scheme 1.5h

and the minor product 8Z is produced via the boatlike transition state B (Scheme 1.5e). The 96 : 4 selectivity indicates that transition state A is more stable than B by 2.2 kcal/mol. For the rearrangement of 6, the major isomer is once again formed through six-membered chairlike transition state C3 (Scheme 1.5f). Because the methoxy substituent in transition state C is now in an axial position, the free-energy gap between transition states C and D becomes narrow, resulting in diminished 3 : 1 diastereoselectivity. To explain the marked rate enhancement in the anionic oxy-Cope rearrangement, Evans and others conducted theoretical calculations of the carbon–hydrogen bond strengths for methanol and potassium methoxide4 (Scheme 1.5g). The computations indicate that the carbon–hydrogen bond in KOMe is significantly weaker than that in MeOH. From these studies, it is concluded that weakening of the C3 –C4 bond is responsible for the rate acceleration in the anionic oxy-Cope rearrangement. Houk and others performed a computational study with density functional and ab initio calculations to better understand the reaction mechanism of the

40

[3,3]-SIGMATROPIC REARRANGEMENTS

Me

O

KH, 18-crown-6 110°C, 2.5 h

Me

OH diglyme (99%)

Me

Me 11

Me

Me H 10

3. (CH2OH)2 1. m-CPBA (89%, 3 steps) 2. BF3•OEt2

O O

Me Me

Me

OH

Me

Me

O O

O

HO

O

9, rac-pleuromutilin

Me

Me 12

Scheme 1.5i

anionic oxy-Cope rearrangement5 (Scheme 1.5h). The reaction proceeds via a concerted reaction pathway with an activation energy of 9.9 kcal/mol. Although the six-membered transition-state structure is dissociative, no intermediate is found over the entire course of the rearrangement. Anionic oxy-Cope rearrangement has been used extensively in the total synthesis of natural products.6 For example, Boeckman et al. employed a remarkably facile anionic oxy-Cope rearrangement in the total synthesis of (±)-pleuromutilin (9), which is utilized as an animal food additive to control dysentery in swine and poultry7 (Scheme 1.5i). The crucial anionic oxy-Cope rearrangement of the ◦ β,β-disubstituted alcohol 10 proceeded cleanly at 110 C on exposure to potassium hydride and 18-crown-6 ether to afford the ketone 11 in 99% yield. Epoxidation of cyclopentene ring and rearrangement of the resulting epoxide followed by selective ketalization gave the ketal 12. The anionic oxy-Cope rearrangement was the key step in Lee et al.’s synthesis of (+)-dihydromayurone (13)8 (Scheme 1.5j). When the allylic alcohol 14 was treated with potassium hydride and 18-crown-6 ether to effect the crucial anionic oxy-Cope rearrangement, the aldehyde 15 was obtained in high enantioselectivity. The highly efﬁcient transfer of chirality from the secondary allylic alcohol center to the quaternary carbon center in 15 is indicative of transition state 14TS, in which the carbon–oxygen bond adopts an equatorial position in the chairlike transition state. The aldehyde 15 was oxidized to the corresponding carboxylic acid, which was in turn converted to the diazo ketone 16 via the corresponding acyl chloride. The target molecule (13) was then obtained readily in high yield when the diazo ketone 16 was treated with a catalytic amount of rhodium acetate in benzene. In the total synthesis of (−)-salsolene oxide (17), an architecturally unusual sesquiterpene with an unsaturated bicyclo[5.3.1]undecane core and trisubstituted

41

REACTIONS

OH

KH, 18-crown-6, DME, reflux, 3 h

O−

CHO

(75%)

H

14

15

14TS

1. Ag2O 3. CH2N2 (51%) 2. (COCl)2

O H

(86%)

O

N2

Rh2(OAc)4, benzene, rt

13, (+)-dihydromayurone

16

Scheme 1.5j

H

O H

H H2C

Me

SPh Me H

H

THF −78°C

18

Me

H OLi

OLi

CHLi,

SPh Me H

Me

SPh Me H 20

19

(87%) CH3I

H H

H O H H Me Me

Me

Me 17, (−)-salsolene oxide

Me H 21

Me H O SPh

Scheme 1.5k

oxirane, Paquette and co-workers utilized the anionic oxy-Cope rearrangement to synthesize a key intermediate (21)9 (Scheme 1.5k). The thiophenyl substituent in the bicyclo ketone 18 directed the 1,2-addition of vinyllithium to the exo-face of 18. The ring strain in 1,2-divinylcyclobutanoxide (19) was sufﬁcient to promote a facile [3,3]-sigmatropic rearrangement under the reaction conditions. The enolate anion 20 was therefore generated stereoselectively via a six-membered chairlike transition state. Direct methylation of 20 with excess methyl iodide furnished 21.

42

[3,3]-SIGMATROPIC REARRANGEMENTS

O

Me 5

CO2Me OPMB 23 O

toluene, −78 to 23°C, dilute to 0.01 M (53%)

O

BrMg

Me OMOM

24

Me O

MeO

Me

O

O

2

O

MeO

OMOM Me

O

O

2

OMOM Me

5

5

O BrMg

O

OPMB

BrMg

OPMB

25

26 Me

O O

O

O

O

O

Me O

O

H

2

OMOM Me

Me

O

O

5

5

O HO2C

22, (+)-CP-263,114

OPMB 27

Scheme 1.5l

Shair et al. employed anionic oxy-Cope rearrangement in their synthesis of (+)-CP-263,114 (22), a fungal metabolite with the ability to inhibit squalene synthase and Ras farnesyltransferase10 (Scheme 1.5l). The addition of the Grignard reagent 24 into the cyclopentanone (+)-23 provided a bromomagnesium alkoxide 25, that underwent anionic oxy-Cope rearrangement to furnish the cyclononadiene 26. An in situ transannular cyclization of 26 delivered 27. REFERENCES 1. Berson, J. A.; Jones, M., Jr. J. Am. Chem. Soc. 1964, 86 , 5019. 2. Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97 , 4765.

43

REACTIONS

3. Evans, D. A.; Balliargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978, 100 , 2242. 4. (a) Evans, D. A.; Baillargeon, D. J. Tetrahedron Lett. 1978, 19 , 3315; (b) Evans, D. A.; Baillargeon, D. J. Tetrahedron Lett. 1978, 19 , 3319; (c) Steigerwald, M. L.; Goddard, W. A., III; Evans, D. A. J. Am. Chem. Soc. 1979, 101 , 1994. 5. (a) Yoo, H.-Y.; Houk, K. N.; Lee, J. K.; Scialdone, M. A.; Meyers, A. I. J. Am. Chem. Soc. 1998, 120 , 205; (b) Haeffner, F.; Houk, K. N.; Reddy, R.; Paquette, L. A. J. Am. Chem. Soc. 1999, 121 , 11880; (c) Haeffner, F.; Houk, K. N.; Schulze, S. M.; Lee, J. K. J. Org. Chem. 2003, 68 , 2310. 6. For reviews, see (a) Paquette, L. A. Tetrahedron 1997, 53 , 13971. (b) Paquette, L. A. Angew. Chem. Int. Ed. 1990, 29 , 609. 7. Boeckman, R. K., Jr.; Springer, D. M.; Alessi, T. R. J. Am. Chem. Soc. 1989, 111 , 8284. 8. Lee, E.; Shin, I.-J.; Kim, T.-S. J. Am. Chem. Soc. 1990, 112 , 260. 9. Paquette, L. A.; Sun, L.-Q.; Watson, T. J. N.; Friedrich, D.; Freeman, B. T. J. Am. Chem. Soc. 1997, 119 , 2767. 10. Chen, C.; Layton, M. E.; Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122 , 7424.

1.6. Aza-Cope–Mannich Reaction The cationic aza-Cope rearrangement was discovered in 1950 when the α-allylbenzylamine 1 was treated with formaldehyde and formic acid to give two unexpected products, 1-dimethylamino-3-butene (2) and benzaldehyde1 (Scheme 1.6a). It was postulated that the cleavage reaction presumably occurred via a pathway similar to that in the Cope rearrangement. The iminium ion 3 would undergo [3,3]-sigmatropic rearrangement to another iminium ion (4), which upon hydrolysis produces homoallylamine and benzaldehyde. The aza-Cope rearrangement is synthetically useful because the rearrangement occurs under mild reaction conditions, and [3,3]-sigmatropic rearrangement typically proceeds with a high level of stereocontrol.

CH2O, HCO2H

Ph

NH2

40°C (70–81%)

N Me Me 2

1

Ph

+ N H 3

O

+ Ph

H

hydrolysis

[3,3]

Ph

N H 4

Scheme 1.6a

O

+ NH2

Ph

H

44

[3,3]-SIGMATROPIC REARRANGEMENTS

O Me

O +

HO NH Bn

Me

CSA (0.9 equiv)

Ph

H

Ph

C6H6, 24°C, 24 h (94%)

5a

N Bn

6a (dr = 2:1) O

Me

O

Me

CSA (0.9 equiv)

+

HO

H

NH Me 5b

C6H6, 80°C, 24 h (84%)

N Me

N

N 6b (dr = 1:1)

Scheme 1.6b Me

O

Me [3,3]

RCHO

HO

HO

+

NH

N

R1

R1

HO

−

Me

+

R

N

H+

Me

R

N

R1

R1

5

6

Scheme 1.6c O

O O

O

HO

HO

Ar

O

AgNO3 (1.1 equiv)

HO

EtOH, 50°C, 1 h (94%)

CN

N Bn 7

N

N Bn

H

Bn

8

Ph

O + H

N Me

CH3CHO

Ph

CSA (0.95 equiv) EtOH, 80°C (81%)

9

Me N H Me 10

Scheme 1.6d

R

45

REACTIONS

Ar

H

Ar

H

H

O Ar

H

[3,3]

R

+ N

N

N

OH R R1 TS A

H

OH R R1

R1

Scheme 1.6e

Ar

O O OH

formalin (2 equiv) CSA (0.2 equiv) Na2SO4, CH2Cl2 23°C (81%)

H N Bn 12

O N Bn

H 13

CH2Cl2, BF3•OEt2 −23 to 23°C (2.4 equiv) (97%)

O

O H

1. H2, Pd/C 2. formalin, Et3N

O O

3. HCl, MeOH (65%, 3 steps)

N H 15

H

Ar

N H Bn 14

OH O O

OH N H

11, rac-pancracine

Scheme 1.6f

To control the equilibrium position of the rearrangement, Overman and others introduced a nucleophilic hydroxyl group at the C2 position to capture the rearranged iminium ion2 (Scheme 1.6b). Although the levels of diastereoselectivity for the formation of pyrrolidines 6a and 6b are low, the tandem cationic aza-Cope–Mannich cyclization provides a variety of substituted 3-acylpyrrolidines in high yields under mild reaction conditions. The ﬁrst step in the reaction is the

46

[3,3]-SIGMATROPIC REARRANGEMENTS

formation of the iminium ion, which undergoes a facile [3,3]-sigmatropic rearrangement to provide an enol iminium intermediate2 (Scheme 1.6c). Intramolecular attack of the enol on the rearranged iminium ion then produces pyrrolidine. The chemistry can be extended to the construction of more complex ring systems.3 When cyclic amino alcohols are subjected to the tandem cationic aza-Cope–Mannich reaction, pyrrolidine-annulated bicyclic products are formed in which the starting ring is now expanded by one number4 (Scheme 1.6d). For example, when the tandem aza-Cope–Mannich cyclization reactions were performed on the cyclopentanols 7 and 9, the cis-octahydroindoles 8 and 10 were formed, respectively, in high yields as a single diastereomer (Scheme 1.6d). The exclusive formation of a single diastereomer is rationalized in terms of chairlike transition state A, in which the E -iminium ion isomer rapidly undergoes [3,3]-sigmatropic rearrangement (Scheme 1.6e). The highly diastereoselective intramolecular aza-Cope–Mannich reaction was used in the total synthesis of (±)-pancracine (11), an alkaloid natural product5

NHCOCF3

OH

O R2N

1. NaH, C6H6 2. KOH, EtOH (62%, 2 steps)

OtBu

OAc 17 18

Ot-Bu

N CH3CN, 80°C (98%)

R2N

(CH2O)n, Na2SO4

O

N H

Me N

HO

Ot-Bu

N

20 19 N H N

H

O

O H 16, (−)-strychnine

Scheme 1.6g

O NMe

REACTIONS

HO Bn

Me

Me O

decanal

H 22

47

NH2

C9H19

−H2O

N H

Bn 23

CF3CH2OH, 23°C CSA (0.9 equiv)

O

AcO Bn

C9H19 N CO2Et 25

(94%)

1. ClCO2Et (61% from 22) 2. CF3CO3H, 0 to 23°C (31%)

Me Bn

N H

C9H19

24

LiAlH4, Et2O

HO Bn

C9H19 N Me 21, (+)-preussin

Scheme 1.6h

(Scheme 1.6f). Reaction of the E -allylic alcohol 12 with formaldehyde in the presence of acid catalyst and sodium sulfate gave the oxazolidine 13. Exposure of 13 to 2.4 equivalents of BF3 · OEt2 provided a key intermediate hydroindolone (14) in 97% yield as a single diastereomer. Hydrogenolysis of 14 followed by Pictet–Spengler cyclization afforded the methanomorphanthridine ketone 15 in 65% yield. (−)-Strychnine (16), an alkaloid natural product isolated in 1818 from Strychnos ignatii , represents one of the most challenging target molecules in organic synthesis. In 1993, Overman used his highly efﬁcient cationic aza-Cope–Mannich cyclization reaction to accomplish the total synthesis of (−)-strychnine6 (Scheme 1.6g). Treatment of 18, prepared from (1R,4S )-(+)-4-hydroxy-2-cyclopentenyl acetate (17), with NaH, followed by removal of the triﬂuoroacetyl group, provided the azabicyclooctane 19. The crucial aza-Cope–Mannich cyclization was accomplished in essentially quantitative yield in an 800-mg scale reaction to afford the diamine 20. Further elaboration of the intermediate 20 led to the ﬁrst asymmetric synthesis of (−)-strychnine (16).7 Deng and Overman employed the aza-Cope–Mannich reaction in the enantioselective total synthesis of (+)-preussin (21), a potent antifungal agent possessing a pyrrolidine skeleton8 (Scheme 1.6h). Conversion of the amino alcohol 22 to the oxazolidine derivative 23 was readily accomplished by reacting with decanal in hot benzene with removal of water using a Dean–Stark trap. Treatment of

48

[3,3]-SIGMATROPIC REARRANGEMENTS ◦

23 with 0.9 equivalent of camphorsulfonic acid (CSA) in CF3 CH2 OH at 23 C yielded the desired all-cis pyrrolidine 24 as the major product. Compound 24 was treated directly with ethyl chloroformate followed by Baeyer–Villiger oxidation with triﬂuoroperoxyacetic acid to afford the product 25. Finally, reduction of 25 with LiAlH4 in Et2 O provided (+)-preussin (21) in 94% yield. REFERENCES 1. Morowitz, R. M.; Geissman, T. A. J. Am. Chem. Soc. 1950, 72 , 1518. 2. Overman, L. E.; Kakimoto, M.-A.; Okazaki, M. E.; Meier, G. P. J. Am. Chem. Soc. 1983, 105 , 6622. 3. (a) Overman, L. E. Acc. Chem. Res. 1992, 25 , 352; (b) Overman, L. E. Aldrichimica Acta 1995, 28 , 107. 4. Overman, L. E.; Mendelson, L. T.; Jacobsen, E. J. J. Am. Chem. Soc. 1983, 105 , 6629. 5. Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56 , 5005. 6. Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115 , 9293. 7. Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117 , 5776. 8. Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116 , 11241.

2

Aldol Reactions

GENERAL CONSIDERATIONS The aldol reaction is an addition of metal enolates to aldehydes or ketones to form β-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.I). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2 The aldol reaction is one of the most synthetically useful methods in organic synthesis to form a carbon– carbon bond in a stereoselective and predictable manner.3 In general, the Z -enolates react with aldehydes to give syn-products preferentially, whereas the E -enolates produce anti -adducts as a major diastereomer (Scheme 2.II). One of the simplest explanations for this diastereoselectivity would be the Zimmerman– Traxler six-membered chairlike transition-state model, in which the metal cation is chelated by the two oxygens of the reacting molecules, and the alkyl (R) group of the aldehyde prefers to be equatorial4 (Scheme 2.III). In transition-state Z -chair B, the R group occupies an axial position, resulting in an unfavorable 1,3-diaxial interaction5 with the R1 group of the enolate. This model clearly explains the fact that low stereoselectivity is observed when R1 is a small group. E -Enolates often react with lower stereoselectivity than those of the corresponding Z -enolates. A classic example to illustrate this point is a study carried out by Heathcock et al.6 (Scheme 2.IV). When the carbonyl compounds 1 were deprotonated with lithium diisopropylamide (LDA) and the resulting enolates were subsequently treated with benzaldehyde at –72◦ C, the aldol products desired (2) were obtained in 83 to 99% yield. The Z -enolates derived from t-butyl and 1-adamantyl ethyl ketones afforded syn-products in excellent levels of diastereoselectivity. The fact that the syn/anti ratios directly reﬂect the isomeric purity of the reacting enolates hints that the Z -enolates in these cases undergo aldol reaction through a chairlike six-membered transition state (Scheme 2.III, Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

49

50

ALDOL REACTIONS

O

Li

Li +

H

O

O H

O

Li

O

H

O

OH

O

workup

H

H

Scheme 2.I

R2

+

1

H

R Z-enolates

R

R

2

R1

R

H

R

OH

O

O M

+

1

R E-enolates

R

R1 R

2

anti (minor)

OH

O R1

R

H

O

+ R

2

syn (MAJOR)

[M = Li, B(alkyl)2]

H

OH

O

OH

O

O M

O

+ R

R1 2

R2

R

syn (minor)

anti (MAJOR)

Scheme 2.II

R1H favored

H R2 R

2

H

O M

+ R R1 Z-enolates

O

OH

R

O

M

O

R1

R

O

R2 MAJOR

TS: Z-chair A H R1R disfavored

H

OH M

O O

H R2 TS: Z-chair B

O R1

R R

2

minor

Scheme 2.III

TS: Z-chair A). On the other hand, the E -enolates of 3-pentanone and methyl propanoate gave products slightly favoring a syn-diastereomer. If chairlike transition state TS: E -chair A were the highly favored state for the aldol reaction of the lithium E -enolate of methyl propanoate, we would expect an anti -isomer as a major product (Scheme 2.V). To accommodate situations

51

GENERAL CONSIDERATIONS

OH

(Z) Me O LDA, THF

Me

R

O Li

H

R

H

O Li

Ph

OH

then aq. NH4Cl

Me

R Me

PhCHO, −72°C;

−72°C, 20 min

1

O

2-syn O

Ph

R Me

R (E) R t-C4H9 1-adamantyl 2,4,6-(CH3)3C6H2 C2H5 OCH3

Z/E >98:2 >98:2 5:95 30:70 5:95

2-anti

syn/anti >98:2 >98:2 8:92 64:36 62:38

Scheme 2.IV

R1H O

R2 H H

O Li

R2

R1

+

O R

OH Li

R

O R1

R

O

R2 anti

TS: E-chair A H H H

E-enolates R2

OH O

Li O R1 TS: E-boat A

R

O R1

R R2 syn

Scheme 2.V

where a signiﬁcant amount of syn-isomer is formed from the E -enolate, many alternative stereochemical models, including a boatlike transition state, have been proposed.7 To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K¨oster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9

52

ALDOL REACTIONS

OH

O

Ph O

O

R2BOTf, i-Pr2NEt

BR2 Me

Cy Me

O

H

Cy

H

3

n-Bu2BOTf

—

(9-BBN)OTf

>95:<5

(c-C5H9)2BOTf

Me OH

12:88

4-syn O

Ph

(E)

Z/E

Cy

PhCHO

Me

(Z)

R2BOTf

BR2

Cy Me

syn/anti

Yield, %

43:57

—

>97:3 14:86

4-anti

79 88

Scheme 2.VI

(Scheme 2.VI). When the cyclohexyl ethyl ketone 3 was converted into the corresponding enol borinate by using dibutylboron triﬂuoromethanesulfonate (triﬂate) and N,N -diisopropylethylamine (DIPEA, H¨unig’s base) according to Mukaiyama and Inoue’s protocol,10 and the resulting enolate was allowed to react with benzaldehyde, the aldol products were obtained with little selectivity. The situation changed dramatically when different dialkylboron triﬂates were employed. With the use of 9-borabicyclo[3.3.1]nonyl (9-BBN) triﬂate, the syn-isomer was obtained with superior (syn/anti = 97 : 3) selectivity. The anti -isomer, on the other hand, was readily accessible by the use of dicyclopentylboron triﬂate, although the stereoselectivity in this case was not as high as that observed in the syn-isomer. Thus, Masamune demonstrated elegantly that by a proper selection of reagents, a ﬂexible synthesis of either syn- or anti -aldol products is possible in a highly stereoselective manner starting from the same ketone (3). In 1979, Evans and others independently disclosed a highly diastereoselective aldol reaction employing a boron enolate to improve the kinetic diastereoselectivity in the aldol reaction.11 A variety of boron enolates, generated from the ethyl ketone 5 by using an equimolar quantity of di-n-butylboron triﬂate (n-Bu2 BOTf) and H¨unig’s base, undergo aldol condensation to give product 6 in excellent levels of diastereoselectivity (Scheme 2.VII). The high level of diastereoselection observed with Z -boron enolates can be explained in terms of six-membered chairlike transition states11 (Scheme 2.VIII). Transition state B is destabilized relative to A due to two distinct energetically unfavorable 1,3-diaxial interactions: one between the phenyl and R groups and the other between the phenyl and boron butyl groups. One major reason for the huge improvement with boron enolates over lithium enolates is the creative exploitation of metal-centered steric effects. Thus, the inherent 1,3-diaxial interactions in transition state B are maximized by

GENERAL CONSIDERATIONS

OH

O R

Ph O Me

R

O

n-Bu2BOTf, i-Pr2NEt

BBu2 Me + R

R 5

O

H (Z)

RCOCH2CH3 O

O

BBu2 H

53

Me

6-syn

PhCHO

OH

Me (E)

O

Ph

R Me

6-anti

Enolate Formation

Z/E

syn/anti

Yield, %

−78°C, 30 min

>99:1

>97:3

77

−78°C, 30 min; 0°C, 30 min

>99:1

>97:3

82

O −78°C, 30 min; 0°C, 60 min

45:55

44:56

92

O 35°C, 120 min

>99:1

>97:1

65

25°C, 60 min

>99:1

>97:3

82

O Ph

Scheme 2.VII

˚ shortening the metal–oxygen bond lengths, as the boron–oxygen bond (1.4 A) ˚ is much shorter than the lithium– oxygen bond11 (1.9 to 2.2 A). To quantify the energy difference between various transition-state structures of the aldol reactions, theoretical studies have been performed. In an attempt to discover the working models of stereoselectivity, in 1988 Houk and others performed a computational study of the transition structures for aldol reactions12 (Scheme 2.IX). As a model system, calculations were carried out on the hypothetical reaction of propanal dihydroborinate and formaldehyde. The Z -enol dihydroborinate 7Z prefers chairlike transition structure A over twist-boat transition structure B by 4.0 kcal/mol because of the destabilizing interactions between the methyl and the hydrogen on boron in twist-boat transition structure B. Introduction of alkyl groups larger than the methyl in the Z -enol borinate 7Z or replacement of the hydrogens on boron by alkyl groups should favor chairlike transition structure A even more. On the other hand, interaction between the pseudoaxial hydrogen of the enolate and the hydrogen of the boron in transition state B is relatively small for E -enolate

54

ALDOL REACTIONS

RH favored

H Me

Bu2B O R

Me

Bu B Bu

O

OH O Ph

O

Ph

TS A

PhCHO

R Me MAJOR

H

(Z)

R Ph

disfavored

Bu B Bu

O

H

Ph

O

H

Me

OH O R Me minor

TS B

Scheme 2.VIII

HH favored

O

H

H

O BH2

H

H

O

H CH3

O

H 3C

H B

TS A: 0 kcal/mol

H

H 7Z

H H

H H

disfavored

O H

CH3 O

H H

OH

O CH3

B H

H

TS B: 4.0 kcal/mol

Scheme 2.IX

7E , so that E -enolate prefers the chair conformation less and there should be strong competition between transition structures A and B. Consequently, the E -enolates give lower stereoselectivity because the minor product can be formed through a twist-boat structure of comparable energy (Scheme 2.X). Gennari et al. developed a computational model to reproduce the experimental syn/anti setereoselectivity for the aldol reactions of Z and E enol borinates of butanone with acetaldehyde.13 For the reaction of Z -enol borinate 8Z , the chair transition state TS: Z -chair A dominates over other three-transition states (Scheme 2.XI). When a Boltzmann distribution was calculated for the competing transition structures, a complete syn/anti selectivity of 99 : 1 was predicted. The aldol reaction of E -enol borinate 8E with acetaldehyde is, however, calculated to have four transition structures of similar energy (Scheme 2.XII). Although

55

GENERAL CONSIDERATIONS

HH

H B

equally favored

H H3C

TS A: 0.1 kcal/mol

H

H

H

O

H

H

O

O BH2

O

H3C

H H

H 7E

OH

H equally

H3C

favored

H

H CH3

O O

H

O

B H

H

H

TS B: 0.0 kcal/mol

Scheme 2.X

H3C H

OH O

O

O BMe2

+

CH3

H3C

8Z

O

Me H B Me H

O Me Me TS: Z-chair A 0 kcal/mol most favored

Me Me H

CH3

MAJOR

minor

O

O H Me TS: Z-chair B 1.93 kcal/mol

O Me B Me

O

Me Me TS: Z-boat A 5.35 kcal/mol

syn

least favored

Me Me H B Me Me H

CH3

CH3

Me

Me H H

CH3 + H3C

H3C

H

OH O

O Me

O Me B Me

TS: Z-boat B 2.74 kcal/mol

anti

Scheme 2.XI

56

ALDOL REACTIONS

H H3C

O BMe2

+ H3C

CH3

Me Me O

O H H TS: E-chair B 1.28 kcal/mol

H 3C

CH3

CH3

CH3

minor

MAJOR

Me Me Me B Me Me H

O Me B Me

O H

TS: E-boat B 0.79 kcal/mol

similarly

similarly

syn

disfavored

disfavored

Me

Me H Me

CH3 +

H3C

H

8E

Me

OH O

OH O

O

O

O Me H TS: E-chair A 0 kcal/mol more favored

Me B Me

Me H

O

O Me B Me

H Me TS: E-boat A 1.60 kcal/mol

anti

less favored

Scheme 2.XII

chairlike transition state TS: E -chair A has the lowest energy, twist-boat transition state TS: E -boat B is only 0.79 kcal/mol higher than TS: E -chair A and can be a competitive transition structure. The overall outcome is a reduced diastereoselectivity (syn/anti = 14 : 86) for the E -enol borinate. REFERENCES 1. For a general introduction to the aldol reaction, see March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp. 937–944. 2. Kleschick, W. A.; Buse, C. T.; Heathcock, C. H. J. Am. Chem. Soc. 1977, 99 , 247. 3. For reviews of the aldol reaction, see (a) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev . 2004, 33 , 65; (b) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 10 , 1595; (c) Mahrwald, R. Chem. Rev . 1999, 99 , 1095; (d) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9 , 357; (e) Cowden, C. J.; Paterson, I. Org.

REACTIONS

4. 5. 6. 7.

8. 9. 10. 11.

12. 13.

57

React. 1997, 51 , 1; (f) Heathcock, C. H. in Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2 , p. 181; (g) Evans, D. A.; Nelson, J. V.; Taber, T. in Topics in Stereochemistry, Wiley: New York, 1982; Vol. 13 , p. 1. Juaristi, E. Introduction to Stereochemistry and Conformational Analysis, Wiley: New York, 1991; Chap. 13. Eliel, E. L.; Willen, S. H. Stereochemistry of Organic Compounds, Wiley: New York, 1994; Chap. 11. Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45 , 1066. (a) For an insightful description of the differences among many different types of transition states, see Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1991, 113 , 2177; (b) Evans, D. A.; McGee, C. R. Tetrahedron Lett. 1980, 21 , 3975. (a) Mukaiyama, T.; Inomata, K.; Muraki, M. J. Am. Chem. Soc. 1973, 95 , 967; (b) Fenzl, W.; K¨oster, R. Liebigs Ann. Chem. 1975, 1322. Masamune, S.; Mori, S.; Horn, D. V.; Brooks, D. W. Tetrahedron Lett. 1979, 20 , 2229. Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 559. (a) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101 , 6120; (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103 , 3099. (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1988, 110 , 3684; (b) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55 , 481. Bernardi, A.; Capelli, A. M.; Gennari, C.; Goodman, J. M.; Paterson, I. J. Org. Chem. 1990, 55 , 3576.

REACTIONS 2.1. Asymmetric Syn-Aldol Reaction When Evans and others in 1979 carried out the reaction of the boron enolate of the chiral ethyl ketone 1, synthesized from (S )-proline, to study the reaction of chiral enolate in the aldol reaction, the syn-diastereomers were formed in high stereoselectivity1 (Scheme 2.1a). Another signiﬁcant observation was that the diastereoselectivity (i.e., the ratio of 2-syn to 2 -syn), of the reaction is high. This experiment is signiﬁcant, as it was one of the ﬁrst enantioselective aldol reactions to afford optically active products starting from chiral enolates. To explain the results, two diastereomeric six-membered chairlike transition states, A and B, are compared (Scheme 2.1b). One expects transition state A to be preferred over B as a consequence of the inﬂuence of metal-center steric parameters. In other words, the steric repulsion between RS and the butyl group is less than that between RL and the butyl group. Asymmetric syn-aldol condensation reactions employing chiral auxiliaries were reported in 1981 by both Masamune et al.2 and Evans et al.3 Masamune et al. introduced boron enolates obtained from (S )-mandelic acid, which underwent

58

ALDOL REACTIONS

a highly diastereoselective syn-aldol reaction2 (Scheme 2.1c). There are several salient features of Masamune et al.’s auxiliary. First, no trace of anti -aldol products was found in the reaction mixture, meaning that an exclusive formation of Z -enolates occurred. Second, the ratios of 5a to 5b are impressively high and depend largely on the size of the ligands attached to the boron. Third, in the case of α-branched aldehydes such as isobutyraldehyde, the use of either 4a or 4b is

Me N Ts N Ts

Me O

O

1. n-Bu2BOTf, i-Pr2NEt 2. i-C3H7CHO

Me N Ts

OH

2-syn

−78οC, CH2Cl2

O OH 2′-syn Me

Me

1

N Ts

O

N Ts

OH

2-anti

O OH 2′-anti

syn/anti = 91:9 2-syn/2′-syn >97:3

Scheme 2.1a

N Ts

N Ts

Me O

RS

H

n-Bu2BOTf, i-Pr2NEt

Me OBBu2

H Me OBBu2

(Z)-enolate

1

H RL favored

H

H

R

H N Ts

H RL

Me OBBu2

Me

RCHO

RS

H

disfavored

H Me

RS Bu B O Bu O TS A

RL H O

R

Scheme 2.1b

Bu B

RS RL

Me R

H

O

MAJOR RS

Bu

O TS B

OH

RL

Me R

H

O minor

OH

REACTIONS

OTBDMS

OTBDMS

OTBDMS

R′CHO

R2BOTf, i-Pr2NEt 0οC,

−78 to CH2Cl2

O 3

R2B

R′ OH

O

R′ OH

R′

HO2C (S)-mandelic acid

O 5a OTBDMS

4a, R = 9-BBN 4b, R = n-C4H9 4c, R = c-C5H11

OH

59

O 5b

5a:5b (4a)

5a:5b (4b)

5a:5b (4c)

17:1 C2H5 >100:1 i-C3H7 14:1 C6H5 16:1 BnO(CH2)2

50:1 >100:1 40:1 28:1

>100:1 no reaction 75:1 100:1

Scheme 2.1c

Me favored

OTBDMS

O

H R′

O

R′ BR2

OH

H TBDMSO

O MAJOR

OTBDMS TS A

R′CHO

R 2B

O

Me R′

OTBDMS

O

H

O

disfavored

H TBDMSO

BR2

R′ OH

O minor

TS B

Scheme 2.1d

recommended to achieve excellent levels of diastereoselection, as the aldol reaction does not proceed with 4c, due possibly to steric congestion in the transition state (Scheme 2.1d). Masamune et al. used this aldol strategy to achieve the total synthesis of 6-deoxyerythronolide B (6), a common biosynthetic precursor leading to all the erythromycins presently known4 (Scheme 2.1e). The highlight of the synthesis is

60

ALDOL REACTIONS

MeO2C OTBDMS MeO2C

CHO

0°C, 1.5 h

+ (9-BBN)B

7

hexane (85%)

O 4a

OH O OTBS 8 (dr 40:1) (100%) 1. HF, CH3CN 2. NaIO4

O

O 1. 4a, CH2Cl2 2. TBAF

O

OH HO2C

3. NaIO4 (71%)

O OHC

1. (COCl)2 2. H2 (95%)

10

11 (dr 14:1)

O O HO2C 9

O

OH O O

OH OH

6, 6-deoxyerythronolide B

Scheme 2.1e

the iterative use of the highly efﬁcient diastereoselective aldol condensation with the chiral boron reagent (S )-4a. Thus, the aldol condensation of the aldehyde 7 with the chiral reagent 4a provided the syn-aldol product 8 in 85% yield and 40 : 1 stereoselectivity. Successive treatment of 8 with hydrogen ﬂuoride and sodium metaperiodate gave the Prelog–Djerassi lactonic acid 9. Another aldol reaction of the aldehyde 10 with 4a once again proceeded smoothly to afford 11 after treatment of the aldol product with tetra-n-butylammonium ﬂuoride followed by sodium metaperiodate. In the same year that Masamune et al. published their chiral auxiliary-based stereoselective aldol reaction, Evans et al. synthesized two recyclable chiral

61

REACTIONS

O

O

O

NH

O

O

1. n-Bu2BOTf, i-Pr2NEt; RCHO, −78οC

N Me

2. MoOPH; 1 N NaOH

O

O

O

OH

N

R O

N

O

O

OH

R Me

Me

XV 13a

12 O O

O NH

O

O

O

1. n-Bu2BOTf, i-Pr2NEt; RCHO, −78οC

N

2. MoOPH; 1 N NaOH

O

O

Me

Ph

R O

Ph

R Me

Ph

Me

13a/13b 497:1 141:1 >500:1

Yield, % 69 68 81

OH

N Me 15b

15a R i-C3H7 n-C4H9 C6H5

O

Me

Me 14

XN

O

OH

N

Me Ph

13b

Yield, % 78 71 60

15a/15b <1:500 <1:500 <1:500

Scheme 2.1f

O O

O O

O

BBu2

H

H

BBu2

O

H

Me

N

O

N

favored

Me

O

Me

O

R

MAJOR

O

O

H

R

O

O

N

disfavored

R

N

O

TS A

RCHO

OH

BBu2

O O

Me

O

OH R

N Me minor

TS B

Scheme 2.1g

oxazolidinones, XV and XN , prepared from (S )-valinol or (1S ,2R)-norephedrine, which served as efﬁcient chiral auxiliaries for highly diasteroselective syn-aldol condensations via the boron enolates3 (Scheme 2.1f). The diastereoselectivity is exceptionally high and the substrate scope is quite general; both alkyl and aryl aldehydes give satisfactory results.5 To explain the enantiofacial stereoselectivity,

62

ALDOL REACTIONS

O O

O

N

favored

H O

H O O

O

BMe2 Me

N

O

OH Me

N

O

Me

O

Me Me MeCHO

Me B Me

MAJOR

TS A (0 kcal/mol)

H O O

12BMe2 disfavored

O

N

H

O

O O

Me Me

B Me Me

H

O

OH Me

N Me minor

TS B (3.0 kcal/mol)

Scheme 2.1h

the dipole alignment in two diastereoisomeric chairlike six-membered transition states were compared6 (Scheme 2.1g). Transition state A, in which the two carbonyl dipoles of aldehyde and oxazolidinone are opposed to each other, would be a conformer of lower energy than transition state B, where two dipoles are in the same direction. Makino and others carried out a computational study on the Evans aldol reaction of dimethylborinate 12BMe2 with acetaldehyde7 (Scheme 2.1h). The AM1 semiempirical calculations indicate that six-membered chairlike transition state A, which would lead to formation of the major syn-isomer, is more stable than B by 3.0 kcal/mol, providing a theoretical conﬁrmation of the experimental observations. In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired syn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 : 1 mixture of diastereomers, which was puriﬁed to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9 –C14 subunit of the TBS ether of (+)-trienomycinol.

REACTIONS

O O

O N

O

(80%)

Me Ph

O

n-Bu2BOTf, methacrolein

Me 14

O

OH

N Me

Ph

Me 17 3. CDI, Me(MeO)NH•HCl (95%) 4. DIBAL (90%)

1. TBSCl, imidazole (99%) 2. LiOOH (98%)

OH

63

OTBS

O

OTBS

(88%) dIpc B(allyl) 2

Me 19 (93%, 2 steps)

O

9

H Me 18

1. TBAF, THF 2. Me2C(OMe)2, p-TsOH

OTBS

14

O 14

10

Me 20

HO

9

HO

O OMe

10

16, (+)-trienomycinol TBS ether

Scheme 2.1i

Glucolipsin A (21) is a macrocyclic dilactone natural product that exhibits glucokinase-activating properties. F¨urstner et al. employed an Evans aldol strategy to synthesize the syn-aldol intermediate 2310 (Scheme 2.1j). The aldol reaction of the boron enolate of 14 with 14-methylpentadecanal (22) delivered the syn-aldol product 23 in essentially diastereomerically pure form (99% de) after puriﬁcation. Subsequent glycosidation of the alcohol 23 with trichloroacetimidate (24) was facilitated by catalytic amounts of TMSOTf (20 mol %) to afford the key intermediate (25) in moderate yield. Gage and Evans later introduced another oxazolidinone, XP , derived from (S )-phenylalanine11 (Scheme 2.1k). The new chiral auxiliary, readily prepared in either enantiomeric form from the corresponding phenylalanine, is more convenient than the valine-derived oxazolidinone XV because the oxazolidinone XP can be puriﬁed easily by direct crystallization.11 Another practical advantage of XP over the valine-derived oxazolidinone XV is that the oxazolidinone XP contains an ultraviolet chromophore, which facilitates thin-layer chromatographic or high-performance liquid chromatographic analysis when it is employed as a chiral auxiliary. The aldol reaction of N -propionyloxazolidinone (26S ) with benzaldehyde proceeds in an extremely stereoselective manner12 to provide the β-hydroxy

64

ALDOL REACTIONS

acid 28 as a single diastereomer in high yield after removal of chiral auxiliary using the lithium hydroperoxide protocol. Evans and others used this methodology to complete numerous total syntheses of natural products. For example, they built the spiroketal subunit 29 in the asymmetric synthesis of the macrolide antibiotic rutamycin B13 (Scheme 2.1l). The

O

O

O

N

O

O

(63%)

Me

H

22

14

N

Ph

11

11

Me O

O

AcO

23 NH

CCl3 OBn

BnO

OH HO

OH

O

Me Ph

O

n-Bu2BOTf, Et3N, aldehyde 22

OBn

OH

TMSOTf, CH3CN (45%)

24

11

O O

O O

O O

O

O

O

O

O

HO

XN

AcO

OH

BnO

11

OH

11

OBn OBn 25

21, glucolipsin A

Scheme 2.1j

O

O HO

NH2

BF3• OEt2, BH3• SMe2

HO

NH2

THF, reflux, 6 h (75%)

O Ph

OH Ph

HO

O

30% H2O2, LiOH

NH

n-BuLi, EtCOCl

O

N Me

(96%)

135°C (79%)

Ph

O

CO(OEt)2, K2CO3

O

Ph 26S

Ph XP O

OH

XP

Ph Me

Me 28 (90%) + XP (89%)

27

Scheme 2.1k

(93%) n-Bu2BOTf, Et3N, PhCHO, −65οC

REACTIONS

O N

O

O

n-Bu2BOTf, Et3N, CH2Cl2, −78 to 0°C

O

OH

N

O

26R

Me

CHO

Me

Bn

65

CHO

Et

Bn

26R

n-Bu2BOTf, Et3N, CH2Cl2, −78 to 0°C

OPMB

30

31 Me Me

O

TBSO

O

OH O

OH OPMB

N

O

Me

O

Me

Et

Bn OPMB

Et

32

29

Scheme 2.1l

O O

OH

O

O

O

n-Bu2BOTf, Et3N, CH2Cl2, RCHO

N Me

−78 to 0°C (96%)

Bn

N O

Me Bn

OTBS

26S

OH

O

O

1. Me3Al, MeNH(OMe)• HCl, CH2Cl2 (86%) 2.

MgBr (82%)

34

OH

dr = 30:1 OH

OH

DIBAL-H, THF, −78°C

O

Me

OTBS

(85%)

H O

OH H

Me O HO

OTBS 35

OH

36

OH

33, phorbol

Scheme 2.1m

propionamide 26R, prepared from the (R)-phenylalanine-derived imide chiral auxiliary, underwent highly diastereoselective aldol reactions with crotonaldehyde and p-methoxybenzl (PMB)-protected aldehyde 31 to furnish the aldol adducts 30 and 32, respectively, which were then assembled to afford a spiroketal 29 in the synthesis of rutamycin B. The phorbol 33 is a tigliane diterpene whose 12, 13-diesters play a principal role in efforts to understand biological activities such as carcinogenesis and

66

ALDOL REACTIONS

O O

O

p-(TBSO)-Ph

N Et

O

1. n-Bu2BOTf, i-Pr2NEt, RCHO, CH2Cl2, −78°C

O

TrO

Bn 38

Et

HO

O XP 39

HO O P HO O

O TrO

OH O

Et

2. TESCl, imidazole 3. LiSEt, THF

p-(TBSO)-Ph OH

H2N

O

(72%, 3 steps)

O

O O

Et

TESO

37, leustroducsin B

O

SEt 40

Scheme 2.1n

signal transduction. In the synthesis of 33, Wender et al. used an Evans aldol reaction protocol to prepare the furan-containing compound 3414 (Scheme 2.1m). The highly diastereoselective aldol reaction between N -propionyloxazolidinone (26S ) and 5-substituted furaldehyde occurred in 96% yield with 98% de stereoselectivity to provide the alcohol 34 as a single diastereomer. Formation of Weinreb amide followed by addition of 3-butenylmagnesium bromide afforded the hydroxy ketone 35. A highly diastereoselective (30 : 1) reduction with diisobutylaluminum hydride, consistent with the formation of a six-membered aluminum chelate, provided the diol 36. Fukuyama et al. synthesized the alcohol 39 using Evans’s chiral auxiliary in the total synthesis of leustroducsin B (37), a potent colony-stimulating factor inducer via NF-κB activation at the transcription level15 (Scheme 2.1n). The asymmetric aldol reaction between 38 and the requisite aldehyde proceeded smoothly to afford 39. Protection of the secondary alcohol as the TES ether and removal of the chiral auxiliary with LiSEt furnished the thioester 40. In an industrial synthesis of the microtuble-stabilizing agent (+)-discodermolide (41), Novartis scientists used an Evans asymmetric aldol reaction method to stereoselectively synthesize a C15 –C21 fragment16 (Scheme 2.1o). Reaction of the boron enolate of 26R with the chiral aldehyde 42 gave the corresponding alcohol 43 in 55% yield on a scale of 20 to 25 kg. Transamidation using N, O-dimethylhydroxylamine/triisobutylaluminum complex, DDQ-mediated p-methoxybenzylidene acetal formation, and LiAlH4 reduction provided the

67

REACTIONS O O

MeO

O N Me

O

H O

42

26R

MeO

Bn

O

n-Bu2BOTf, Et3N (55%)

OH

15

21

O

O

43 3. LiAlH4, THF (91%)

O

XP

OH

1. Me(MeO)NH• HCl, Al(i-Bu)3 (80%) 2. DDQ, 4-Å MS, toluene (61%)

XP

H (85%)

O

O

26R, n-Bu2BOTf, Et3N

O

O

44 OMe

OMe 45

HO O

O

OH

O

OH OH

O NH2

41, (+)-discodermolide

Scheme 2.1o

aldehyde 44. Another asymmetric aldol reaction between 26R and 44 afforded the aldol product desired (45) in 85% yield with no unwanted diastereoisomers detected. Oppolzer et al. used (2R)-bornane-10, 2-sultam as an effective chiral auxiliary to achieve a highly enantioselective syn-aldol reaction17 (Scheme 2.1p). Treatment of N -propionylsultam (46) with dibutylboron triﬂate and H¨unig’s base at –5◦ C in CH2 Cl2 followed by addition of aldehydes at –78◦ C provided, after a simple crystallization, the pure syn-aldols 47a. It is noteworthy that no anti -aldol product was observed in the aldol reactions with any of the aldehydes. From the1 H nuclear magnetic resonance (NMR) study, it was conﬁrmed that the boron

68

ALDOL REACTIONS

O Bu2BOTf, i-Pr2NEt; then RCHO

O N O S O

O

OH

Me

Me Me

R

XS

R

XS

OH

47b

47a

46 R Yield, %b Me 69 Eta 80 i-C3H7 71 C6H5 80 (E)-MeCH CH 54

NaH, EtCOCl

dr (47a/47b)c >99:<1 98:2 97:3 99:1 98:2

ded >99 >99 >99 >99 >99

a

NH O S O

Et2BOTf was used. Yields after crystallization. c Diastereomeric ratio (dr) of the crude products. d Diastereomeric excess (de) after crystallization. b

(2R)-bornane-10,2-sultam

Scheme 2.1p

O

H OBBu2 N O S O

Me H

Z-enolate

favored RCHO

N

O S O

O r

H H

B

workup

r

Me O

OH R

XS Me 47a

(r = Bu)

R TS A

Scheme 2.1q

enolate had a Z -conﬁguration. The aldol reaction is considered to proceed via a Zimmerman–Traxler type of six-membered transition state in which aldehyde approaches from the bottom face of the boron enolate17 (Scheme 2.1q). Oppolzer et al. completed an asymmetric synthesis of (–)-denticulatin A (48) by using a syn-aldol methodology as a key feature18 (Scheme 2.1r). The diethylboron enolate of N -propionylbornanesultam (46-ent) obtained from diethylboron triﬂate and H¨unig’s base underwent a highly stereoselective aldol reaction with the meso-dialdehyde 49 to furnish the lactols 50 in 74% yield as a 2 : 1 epimeric mixture. When the lactols 50 were treated with 1, 2-ethanedithiol in the presence

REACTIONS

69

OTBS Et2BOTf, i-Pr2NEt; then aldehyde 49 (74%)

O N Me

S O2

O

OTBS CHO

OHC

XS

2:1 H

O

OH (92%) ZnI2, 1,2-ethanedithiol

50

46-ent

49 OH

O

O

O H

O

OH

OH

S S

XS

OH

51

48, denticulatin A

Scheme 2.1r

Bu2BOTf, i-Pr2NEt; then RCHO (82%)

O

O

OH

O

O

XS

N O S O 46

O

Me

O

O

54

H

53 3. LiOH, H2O2 1. Dowex, MeOH (95%) 4. TsOH, CH2Cl2 (85%, 2 steps) 2. t-BuPh2SiCl, imidazole, DMAP (91%)

HO

OH O O

O 52, lasonolide A

O O

OTBDPS

O 55

OH O O OH

Scheme 2.1s

of ZnI2 , the pure dithiolane 51 was obtained in excellent yield via a desilylation/ ring-opening sequence. In an effort toward the enantioselective synthesis of the natural product lasonolide A (52), Shishido et al. used Oppolzer et al.’s syn-aldol method to access a key intermediate (55)19 (Scheme 2.1s). Aldol reaction of the boron enolate of 46 with

70

ALDOL REACTIONS

O N O S O

Bu2BOTf, i-Pr2NEt; then RCHO (95%) O

Me

H

O

OH OBn

XS 57

OBn

2. DIBAL-H 1. TBSOTf, 2,6-lutidine

46 TBSO

OH

Bu2BOTf, i-Pr2NEt −78°C, 16 h (70% from 57)

O X S′

OBn 58

O

59

N Me

TBSO

OTBS

H

OBn

(65%, 2 steps)

O

S O2 46-ent

1. TBSOTf, 2,6-lutidine 2. LiOH, H2O2

OTBS CO2H

HO

O

O

O

OH

OH

OMe

OBn 60

OH 56, FD-891

Scheme 2.1t

the aldehyde 53 gave the aldol product desired (54) in good yield. Acidic hydrolysis, regioselective protection of the primary alcohol as the tert-butyldiphenylsilyl (TBDPS) ether, removal of the chiral auxiliary, and treatment of the resulting acid with p-toluenesulfonic acid furnished the lactone 55. In the stereoselective synthesis of the cytotoxic macrolide FD-891 (56), which exhibits antitumor activity, Oppolozer et al.’s asymmetric syn-aldol reaction protocol was used to synthesize a key fragment (60)20 (Scheme 2.1t). Thus, the asymmetric aldol reaction of the boron enolate of sultam propionate (46) with 3-benzyloxypropanal provided the aldol product 57 as a single isomer in excellent yield. Silylation followed by reductive cleavage of the sultam chiral auxiliary using DIBAL-H afforded the aldehyde 58, which was subjected to another syn-aldol reaction with the reagent 46-ent to give a single aldol product (59) in good yield. Silylation of 59 with TBSOTf followed by removal of the chiral auxiliary with LiOOH hydrolysis furnished the carboxylic acid 60. Having noticed certain limitations of chlorotitanium aldol reactions on Evans et al.’s chiral auxiliary,21 in 1997 Crimmins and others developed a brilliant protocol to achieve a highly diastereoselective aldol reaction.22 Asymmetric aldol

71

REACTIONS

S

S

O TiCl4, (−)-sparteine;

N

O

then RCHO, −78°C

Me

O

R

N

O

S

OH O

O

R

N

Me

Bn

Me

Bn

61

OH

Bn

62a

62b

R i-C3H7 C2H5 C6H5

Yield, %b 62a/62ba Yield, %a 62a/62bb 70 98.8:1.0 0:95.5 79 69 97.5:1.0 6.4:93.6 72 89 98.7:1.3 0.7:97.6c 88c a 1.0 equiv of TiCl and 2.5 equiv of (−)-sparteine were used. 4 b 2.0 equiv of TiCl and 1.1 equiv of (−)-sparteine were used. 4 c i-Pr NEt was used instead of (−)-sparteine. 2

Scheme 2.1u

O Bn LxTi

S

N O

R

O

TiCl4 (1 equiv)

LxTi

O

R

H

S

O

O

OH

workup

R

N

O

XC

Me

Me

Bn

Me TS A O Bn R H

S Cl

N

Ti

O O

Cl Cl

Cl3Ti TiCl4 (2 equiv)

S O

O

R

workup

XC Me

O

O

OH R

N Me Bn

Me TS B

Scheme 2.1v

reactions using chlorotitanium enolates of the N-oxazolidinethione propionates 61 proceed with high diastereoselectivity to produce syn-aldol products. Whereas the syn-aldol 62a is the major isomer with the use of 1 equivalent of titanium chloride (TiCl4 ) and 2.5 equivalents of (–)-sparteine, a pseudoenantiomeric (62b) becomes a major syn-aldol product when 2 equivalents of TiCl4 are employed22 (Scheme 2.1u). The change in facial selectivity in the aldol additions is proposed to be the result of switching mechanistic pathways between chelating and nonchelating transition states (Scheme 2.1v). In the presence of 2.5 equivalents

72

ALDOL REACTIONS TiCl4, (−)-sparteine

Bn O

Me

Me

N S

Bn

H

O

O

N

Et

Et (83%)

H

3. Swern [O] (83%)

64 (de > 98%)

61

65

(81%)

Me

Me

H O

O

Me

Et OTBS

O

OH

O

S

O

Me

1. TBSOTf 2. LiBH4

Me

TiCl4, 61 (−)-sparteine

Bn

Me

1. TMSOTf 2. LiBH4

Et OTBS TMS

3. Swern [O] (71%)

Me O

Me

N S

O

OH

Me

Et OTBS

66 (dr 98:2)

67

O 63, (−)-callystatin A

O Me

Me

Me

Me

Me

Me

Me O

OH

Scheme 2.1w

of (–)-sparteine, nonchelating transition state A is operative, possibly due to the coordination of the second equivalent of base to the titanium, resulting in formation of the syn-aldol product 62a. The formation of 62b can be explained in terms of the highly ordered chelated transition state B.23 Crimmins and King exploited a highly efﬁcient aldol methodology to complete the asymmetric total synthesis of (–)-callystatin A (63), a natural product that exhibits a remarkable in vitro cytotoxicity24 (Scheme 2.1w). The synthesis of propionate fragment in (–)-callystatin A was achieved by two consecutive asymmetric aldol additions using chlorotitanium enolates of acyloxazolidinethiones. Thus, treatment of N -propionyloxazolidinethione (61) with titanium chloride and (–)-sparteine followed by addition of (S )-2-methylbutanal resulted in formation of the syn-aldol adduct 64 in greater than 98% de and 83% yield. For the second aldol reaction, the requisite aldehyde (65) was prepared under standard conditions. Execution of the second asymmetric aldol reaction under conditions identical to

73

REACTIONS

TBSO

OPMB

Me

(COCl)2, DMSO, Et3N

OH

(99%)

TBSO

OPMB CHO

Me

BnO Me Me

BnO Me Me

69

70

O

O N

TiCl4, (−)-sparteine (94%)

O

Me 26R

Bn

OH HO

TBSO

OH OH O O

O

PMB OH

Me

N BnO Me Me

OH

O

O

O

Me Bn

OH

71

68, (9S)-dihydroerythronolide A

Scheme 2.1x

the ﬁrst afforded the aldol product 66 in excellent diastereoselectivity. Alcohol protection, removal of chiral auxiliary, and Swern oxidation gave the aldehyde 67. Crimmins’s TiCl4 -mediated asymmetric aldol condensation protocol was used in the enantioselective total synthesis of (9S )-dihydroerythronolide A (68)25 (Scheme 2.1x). Swern oxidation of the primary alcohol 69 provided the aldehyde 70 in almost quantitative yield, which underwent asymmetric aldol condensation with the titanium enolate of (R)-4-benzyl-3-propionyloxazolidin-2-one (26R) in the presence of (–)-sparteine to afford the aldol adduct desired (71) as a single diastereomer. Wu and Sun utilized the Crimmins’s aldol method in the total synthesis of valilactone (72), which shows promising inhibitory activity toward an esterase and pancreas lipase26 (Scheme 2.1y). The synthesis began with the TiCl4 mediated asymmetric Crimmins aldol condensation between 73 and 74. The syn-aldol 75 was obtained as the only detectable product in 78% yield. The chiral auxiliary in 75 was then removed with concurrent protection of the carboxylic group as a benzyl ester. The thiane protecting group in 76 was removed and the stereoselective reduction of β-hydroxy ketone in 77 using an Evans–Chapman– Carreira reagent27 (see Chapter 4) generated the 1, 3-anti -diol 78. In 1995, Boeckman et al. disclosed a highly diastereoselective aldol reaction using the ligand 79 derived from chiral bicyclic lactam28 (Scheme 2.1z). The imide 80, readily prepared from bicyclic lactam 79 and propionyl chloride, was converted to the boron Z -enolate, which was then treated with a representative series of aldehydes at –40◦ C for 48 hours. The levels of diastereoselectivity observed in reactions of boron enolate derived from 80 are comparable to those

74

ALDOL REACTIONS

S O

S

O S

+

N C6H13

S

TiCl4, TMEDA

CHO C4H9

Bn 73

O

O

HO

S

S

N

CH2Cl2, 0°C, 2 h (78%)

C6H13

C 4 H9

Bn 75

74

(75%) BnOH, DMAP

O

OH

O

O (87%)

BnO

S

S

BnO

I2, NaHCO3

C6H13

HO

C6H13

C 4H 9

C 4 H9

76

77 (97%) Me4NBH(OAc)3

O

OH

OH

O O O

BnO C6H13

C 4H 9

O

NHCHO

H H

78

72, valilactone

Scheme 2.1y

O

O

1. Et2BOTf, i-Pr2NEt 2. RCHO

N

3. H2O2, CH3OH

O

N

Me N

R O

80

O Me

OH

O

81a

O N H 79

R n-C3H7 i-C3H7 c-C6H11 t-C4H9 C6H5

Scheme 2.1z

R OH

81b 81a/81b >98:2 >98:2 >98:2 >98:2 >98:2

Yield, % 80 75 74 90 95

75

REACTIONS

Me

Me

Et

N

Et B

XL

favored

O

H O

R O

O

O R

H2O2

XL

R O

BEt2

OH

MAJOR

Me

TS A

Scheme 2.1aa

O O BnO

1. Et2BOTf, i-Pr2NEt; RCHO, CH2Cl2, −50οC

N

OBn XL′

2. TBSCl, imidazole (80%, 2 steps)

TBSO 84

83 OH

OH

OMe

OH

H N

O

1. LiSEt, THF (95%) 2. DIBAL-H, −78οC 10 min (91%)

OBn

O

H NH

O

82, (+)-bengamide E

TBSO

O 85

Scheme 2.1bb

obtained by employing the Evans auxiliary. The six-membered transition-state structure A is responsible for the high level of diastereoselectivity obtained by the imide 80. In transition state A, the two carbonyl (C = O) dipoles are pointing opposite to each other to minimize the electrostatic repulsion, and the steric congestion is avoided28 (Scheme 2.1aa). Using a lactam chiral auxiliary, Boeckman et al. completed the synthesis of (+)-bengamide E (82), a member of the natural bengamides family that shows potentially useful antiproliferative activity29 (Scheme 2.1bb). The imide 83 underwent a highly diastereoselective aldol condensation reaction with (E )-4-methyl-2pentenal to afford the syn-aldol adduct expected (84) in > 24 : 1 diastereomeric ratio. The chiral auxiliary was removed efﬁciently with LiSEt, and the resulting thioester was reduced to give the corresponding aldehyde (85). Ghosh et al. reported that the chiral oxazolidinone 87, derived from (1S ,2R)-cis-1-amino-2-indanol (86), underwent a highly diastereoselective syn-aldol reaction with a variety of aldehydes30 (Scheme 2.1cc). Reaction of the indanolamine 86 with disuccinyl carbonate in acetonitrile gave the oxazolidinone 87, which was deprotonated with n-BuLi and reacted with propionyl chloride to provide the N -propionyl derivative 88. Reaction of 88 with n-Bu2 BOTf and

76

ALDOL REACTIONS

O HO

O

NH2 +

N O

O

O

O

O N

(88%)

O

O 86

O

Yield,% O 71 73 64 62

(85%) n-BuLi, EtCOCl

87

O

R de, % Me >99 i-C3H7 >99 Ph >99 PhCH CH >99

NH

Et3N, CH3CN, rt, 12 h

O

OH R

N

O

O N

n-Bu2BOTf, Et3N; then RCHO

Me

Me

−78 to 0°C, CH2Cl2

89

88

Scheme 2.1cc

O

O Ph

N

OH O

n-Bu2BOTf, Et3N, CH2Cl2, 0οC; then O , BnO H −78 to 23οC (88%)

BnO

N

N H

O

O

92

NH2 O NH

N Ph

91

O

O

O

H OH N Ph

O

H

NH

OH BnO

NHBoc Ph 93

90, saquinavir

Scheme 2.1dd

triethyl amine at –78◦ C for 30 minutes and then warming up to 0◦ C for an hour afforded the boron enolate. Condensation of the enolate with various aldehydes resulted in the formation of a single syn-diastereomer (89). The exceptionally high diastereoselectivity is probably due to the conﬁgurational rigidity of the tricyclic ring system of the chiral auxiliary.31 The transition state for the foregoing reaction has yet to be published but is assumed to be similar to those for the asymmetric reactions with the Evans and Boeckman chiral auxiliaries.

REACTIONS

77

Ghosh et al. utilized an asymmetric syn-aldol reaction methodology to synthesize the core structure of saquinavir (90), a protease inhibitor recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of AIDS32 (Scheme 2.1dd). Aldol reaction of the boron enolate of 91 with benzyloxyacetaldehyde in CH2 Cl2 at –78◦ C provided the syn-aldol product 92 as a single diastereomer in 88% yield. After removal of the chiral auxiliary and several more manipulations, there was obtained a key intermediate amino alcohol (93), from which saquinavir can be synthesized according to known protocol.33 REFERENCES 1. (a) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101 , 6120; (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103 , 3099. 2. Masamune, S.; Choy, W.; Kerdesky, F. A.; Imperiali, B. J. Am. Chem. Soc. 1981, 103 , 1566. 3. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103 , 2127. 4. Masamune, S.; Hirama, M.; Mori, S.; Ali, S. A.; Garvey, D. S. J. Am. Chem. Soc. 1981, 103 , 1568. 5. Evans, D. A. Aldrichimica Acta 1982, 15 , 23. 6. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53 , 1109. 7. Makino, Y.; Iseki, K.; Fujii, K.; Oishi, S.; Hirano, T.; Kobayashi, Y. Tetrahedron Lett. 1995, 36 , 6527. 8. Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1995, 117 , 10777. 9. Brown, H. C.; Bhat, K. S.; Randad, R.S. J. Org. Chem. 1987, 52 , 320. 10. F¨urstner, A.; Ruiz-Caro, J.; Prinz, H.; Waldmann, H. J. Org. Chem. 2004, 69 , 459. 11. Gage, J. R.; Evans, D. A. Org. Synth. Coll . Vol. 8 , 1990, 528. 12. Gage, J. R.; Evans, D. A. Org. Synth. Coll . Vol. 8 , 1990, 339. 13. Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115 , 11446. 14. Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119 , 7897. 15. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125 , 4048. 16. (a) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Daefﬂer, R.; Osmani, A.; Schreiner, K.; Seeger-Weibel, M.; B´erod, B.; Schaer, K.; Gamboni, R.; Chen, S.; Chen, W.; Jagoe, C. T.; Kinder, F. R., Jr.; Loo, M.; Prasad, K.; Repic, O.; Shieh, W.-C.; Wang, R.-M.; Waykole, L.; Xu, D. D.; Xue, S. Org. Proc. Res. Dev . 2004, 8 , 92; (b) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.; Daefﬂer, R.; Osmani, A.; Seeger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer, K.; Gamboni, R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.; Kinder, F. R., Jr.; Lee, G. T.; McKenna, J.; Ramsey, T. M.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole, L. Org. Proc. Res. Dev . 2004, 8 , 107. 17. Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112 , 2767. 18. Oppolzer, W.; De Brabander, J.; Walther, E.; Bernardinelli, G. Tetrahedron Lett. 1995, 36 , 4413.

78

ALDOL REACTIONS

19. Deba, T.; Yakushiji, F.; Shindo, M.; Shishido, K. Synlett 2003, 1500. 20. Garcia-Fortanet, J.; Murga, J.; Carda, M.; Marco, J. A. Org. Lett. 2006, 8 , 2695. 21. (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113 , 1047; (b) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112 , 866. 22. (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119 , 7883; (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66 , 894; (c) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2 , 775. 23. (a) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51 , 2391; (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113 , 1047. 24. Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120 , 9084. 25. Peng, Z.-H.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125 , 6018. 26. Wu, Y.; Sun, Y.-P. J. Org. Chem. 2006, 71 , 5748. 27. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110 , 3560. 28. (a) Boeckman, R. K., Jr.; Connell, B. T. J. Am. Chem. Soc. 1995, 117 , 12368; (b) Boeckman, R. K., Jr.; Johnson, A. T.; Musselman, R. A. Tetrahedron Lett. 1994, 35 , 8521. 29. Boeckman, R. K., Jr.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4 , 2109. 30. Ghosh, A. K.; Duong, T. T.; McKee, S. P. Chem. Commun. 1992, 1673. 31. Senanayake, C. H. Aldrichimica Acta 1998, 31 , 3. 32. Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J. Org. Chem. 1997, 62 , 6080. 33. Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J. J. Org. Chem. 1994, 59 , 3656.

2.2. Asymmetric Anti -Aldol Reaction The synthetic methodology for the efﬁcient construction of anti -aldol has also been explored. In 1986, Masamune and others reported a new asymmetric aldol reaction that afforded an aldol product in greater than 98% de favoring anti -isomer1 (Scheme 2.2a). The chiral E -enolates 1, derived from S -3-(3-ethyl)pentylpropanethioate and (2S,5S )-dimethylborolane triﬂoromethanesulfonate, underwent aldol reactions smoothly at –78◦ C, and anti -aldol products were obtained for a variety of aldehydes with greater than 30 : 1 anti /syn stereoselectivity. More important, the anti -aldol products were of greater than 97% optical purity. In explaining the results, Masamune et al. invoked a six-membered chairlike transition-state model (Scheme 2.2b). In transition state A, the methyl group in the enolate steers the 3-ethyl-3-pentanethiol group toward the borolane moiety, thus forcing the enolate to attack aldehyde on its si -face. In 1997, Masamune et al. disclosed another anti -selective aldol reaction method, using a readily available chiral ligand, norephedrine2 (Scheme 2.2c). The ester 3 was treated with 2 equivalents of dicyclohexylboron triﬂate (Cy2 BOTf) and 2.4 equivalents of triethylamine at –78◦ C for 2 hours. When aldehyde was

79

REACTIONS

Me Et

O B

RCHO −78οC

S

pentane

Et 1

OH

O

OH

R

SCEt3

R

Me 2-anti

Et

R n-C3H7 i-C3H7 t-C4H9 c-C6H11 C6H5 BnO(CH2)2

CF3SO3 B

O SCEt3

Me 2-syn

anti/syn 33:1 30:1 30:1 32:1 33:1 >30:1

ee, % (2-anti) 97.9 99.5 99.9 98.0 99.8 97.1

Yield, % 91 85 95 82 71 93

Scheme 2.2a

H

R O S

L2B

O

Me H

B

O

OH

O

favored

workup

SCEt3

R Me

O SCEt3

R Me MAJOR

TS A

Scheme 2.2b

added and the aldol reaction was conducted at –78◦ C for 1 hour and then 0◦ C for another hour, the anti -aldol product 4-anti was obtained in high yield with superb anti -selectivity (anti /syn = 98 : 2) and high diastereofacial selectivity ( > 95 : 5) for all of the aliphatic, aromatic, and α,β-unsaturated aldehydes. As the boron enolate from dicyclohexylboron triﬂate and triethylamine at –78◦ C was determined to be an E -isomer, the predominant formation of anti aldol product can be explained via the classic Zimmerman–Traxler six-membered chairlike transition state3 (Scheme 2.2d). In transition state A, the norephedrine unit of the boron enolate presumably arranges itself in such a way that the phenyl group directs the approach of the aldehyde.4 Masamune et al. applied the newly developed enantioselective anti -aldol reaction to the syntheses of two key fragments of miyakolide 5, a bryostatin-like marine metabolite5 (Scheme 2.2e). The readily synthesized aldehyde 8 was treated with chiral enol borinate generated from the ester 3 to give the aldol 9 in 85%

80

ALDOL REACTIONS

Ph Me

Ph Me Bn

O O

N

Bn

OH

O N

Cy2BOTf, Et3N −78οC, 2 h;

R

SO2Mes 4-anti

Ph Me Bn

then RCHO

Ph Me Bn

O O

3

Ph

N

OH R

SO2Mes

R Et n-C3H7 i-C3H7 c-C6H11 t-C4H9 C 6H 5 (E)-MeCH=CH BnO(CH2)2

NH2 (−)-(1R,2S)-norephedrine

a

OH

O N

R

SO2Mes

Ph Me Bn

O

OH

O N

R

SO2Mes 4′-syn

4′-anti OH

O

4-syn

SO2Mes

Me

O

Yield, %a 90 95 98 91 96 93 96 94

dr (4-anti / 4′-anti) 96.1:3.9 95.2:4.8 97.7:2.3 95.2:4.8 99.4:0.6 94.7:5.3 98.0:2.0 94.8:5.2

Yields of syn-isomers were less than 2%.

Scheme 2.2c

yield with high selectivity (15 : 1), eventually furnishing the C6 –C13 fragment 6. The synthesis of the fragment 7 started with the chiral aldehyde 10 and featured a double asymmetric anti -aldol reaction. Thus, 10 reacted with enol borinate from the ester 3-ent to provide the aldol 11 as the major isomer in the ratio 15 : 1. The norephedrine-derived Masamune asymmetric aldol reaction was utilized in the total synthesis of (+)-testudinariol A (12), a triterpene marine natural product that possesses a highly functionalized cyclopentanol framework with four contiguous stereocenters appended to a central 3-alkylidene tetrahydropyran6 (Scheme 2.2f). The norephedrine-derived ester 13 was enolized with dicyclohexylboron triﬂate and triethylamine in dichloromethane and then treated with 3-benzyloxypropanal to afford the aldol adduct (14) as a 97 : 3 mixture of anti /syn diastereomers in 72% yield. Diastereoselectivity within the anti -manifold was 90 : 10. Protection of alcohol as the methoxyethoxymethyl (MEM) ether followed by conversion of the ester to an aldehyde by LiAlH4 reduction and subsequent Swern oxidation gave the aldehyde 16 in 64% yield over three steps. Masamune’s norephedrine-based anti -aldol methodology was again employed successfully in the total synthesis of the antitumor macrolide natural product rhizoxin D (17)7 (Scheme 2.2g). The synthesis began with an anti -aldol addition of boron enolate of 3-ent to the aldehyde 18. The addition proceeded with

REACTIONS

Ph Me Bn

O O

N

Ph Cy2BOTf, Et3N; then RCHO

Me

−78 to 0 C

N

Bn

3

Bn

MesO2S

OBCy2 O

N

SO2Mes

30% H2O2

favored

Me

R

4-anti

Cy2BOTf, Et3N, −78οC, 2 h

Ph

OH

O

ο

SO2Mes

O

81

Bn N Ph

RCHO

SO2Mes

O

Cy B

H O

Me R H TS A

Cy

O

Scheme 2.2d

excellent diastereoselectivity (90% de) and in good yield to afford the anti aldol 19. Silylation and reductive cleavage of the chiral auxiliary then provided the alcohol 20. Perhaps Walker and Heathcock were the ﬁrst to accomplish an asymmetric anti -aldol reaction using acyloxazolidinone chiral auxiliary8 (Scheme 2.2h). An aldehyde was precomplexed with Et2 AlCl in CH2 Cl2 at –78◦ C and the dibutylboron enolate was added to the cold solution. The anti /syn selectivity is satisfactory for aliphatic aldehydes, with the anti /syn ratios ranging from 86 : 14 to 95 : 5. With benzaldehyde, however, the ratio is only 74 : 26, leaving room for improvement. As the reaction was mediated by Lewis acid and the predominant product was an anti -diastereomer, Heathcock proposed open transition states to explain the stereochemical outcome of the aldol reactions.9 Two decades after the discovery of a powerful syn-diastereoselective aldol reaction, Evans and colleagues reported a highly diastereoselective anti -aldol reaction with chiral acyloxazolidinones promoted by catalytic amounts of magnesium chloride (MgCl2 ) in the presence of triethylamine and chlorotrimethylsilane10 (Scheme 2.2i). Ethyl acetate (EtOAc) is the optimal solvent in promoting the reaction of 23S with benzaldehyde to afford aldol product in 91% yield and with 32 : 1 diastereoselectivity. Variation of the aldehyde reaction component results in large changes in diastereoselectivity, providing moderate-to-high selectivity of anti -aldol products. One limitation to this aldol procedure is that aliphatic aldehydes such as hydrocinnamaldehyde are relatively unreactive, resulting in low conversion. Because the major product is an anti -diastereomer and the Z -enolate is involved, it is unlikely that a traditional Zimmerman–Traxler transition state

82

ALDOL REACTIONS

O

Ph Me

H

O

3, Cy2BOTf, Et3N (85%)

8

Bn

OH

O

N

OTBDPS

SO2Mes OTBDPS

9 (dr 15:1)

O

O

O

13 6 28

O O

14

20

H

6, C6

O

OH O

O

OH 28

5, miyakolide

OH

OTBS C13 fragment

O

6

OH

OBn

CO2Me

19

EtO

O

7, C19 C28 fragment Ph O

O O

H 10

3-ent, Cy2BOTf, Et3N (90%)

Bn

O

OH

O O

Me

O N

SO2Mes 11 (dr 15:1)

Scheme 2.2e

is operating here. To gain solid ground to explain the unusual result, semiempirical calculations were carried out on the two possible transition states where the magnesium metals are six-coordinated. This study suggests that in this case, twist-boat transition state A is more stable than corresponding chair transition state B by 2.5 kcal/mol11 (Scheme 2.2j). Chiral acylthiazolidinethiones such as 26 can readily be prepared from commercially available amino acids in three steps12 (Scheme 2.2k). They have been employed as a synthetically useful auxiliary in diastereoselective aldol reactions.13 The magnesium-catalyzed aldol reaction of the thiazolidinethione 26S with cinnamaldehyde afforded 27 as a major diastereomer in 87% yield. Interestingly, compound 27 is the opposite anti -aldol diastereomer to that seen with the oxazolidinone 23S . Because the acylthiazolidinethione-derived magnesium-enolate exhibits the opposite face selection to that of its oxazolidinone counterpart, it is necessary to assume that the thione C = S moiety is not coordinating to the Mg center in

REACTIONS

Ph Me Bn

Ph

O

Cy2BOTf, Et3N;

O N

C

CH2

SO2Mes

Me

OBn

Bn

OH

O

O H

O

N

OBn

SO2Mes

C

(72%)

13

83

CH2

14 (dr 9:1) MEM-Cl, i-Pr2NEt (79%)

OMEM

O H

OBn C 16

1. LiAlH4 (87%) 2. (COCl)2, DMSO (93%)

Ph Me Bn

CH2

OMEM

O O

N

OBn

SO2Mes 15

H

C

CH2

H H

O

O

OH

H HO

12, testudinariol A

Scheme 2.2f

the aldol reaction transition state11 (Scheme 2.2l). The enolate and benzaldehyde would then be arranged so as to minimize the electrostatic interactions of the two dipoles, C = O and C = S. Between the two possible transition states, calculations found that a boatlike transition state is favored over a chairlike six-membered transition state, in good agreement with the experimental result. In the total synthesis of the migrastatin 28, an anti -selective aldol reaction of N -propionyl oxazolidinone (23R) with the aldehyde 29 was employed successfully to furnish the key intermediate (30) as a single isomer14 (Scheme 2.2m). Protection of the alcohol as a TES ether and reductive cleavage of the chiral auxiliary with LiBH4 gave the alcohol 31. Evans et al. employed anti -aldol methodology during synthesis of the C8 –C18 ketone fragment 32 of the (–)-aﬂastatin A C9 –C27 degradation polyol15 (Scheme 2.2n). The synthesis began with MgCl2 -catalyzed directed aldol addition to provide the anti -aldol adduct 33 (dr > 20 : 1). The imide 33 was converted into the Weinreb amide 34, protected as a p-methoxybenzyl ether and then reduced to afford the C8 –C11 aldehyde 35 in high yield. (–)-Stemoamide (36), isolated from the roots and rhizomes of Stemona tuberosa in 1992, is one of the structurally simplest members of the Stemona family and has shown many biological activities. Olivo and others used a highly

84

ALDOL REACTIONS

Ph Me Bn

O

Ph

Cy2BOTf, Et3N; add 18

+ H

O N

OTIPS

O

Me

(81%)

Bn

SO2Mes

3-ent

O

OH

O N

SO2Mes

OTBS

18

OTIPS

OTBS

19

(86%, 2 steps) 1. TMSCl, imidazole 2. DIBAL

O

O

OTBS

17, rhizoxin D

TIPSO HO

OTMS O

O

HO O

N

20

OMe

Scheme 2.2g

O O

O

Bu2BOTf, i-Pr2NEt, CH2Cl2, 0οC, 45 min;

N Me

21S

RCHO (1.5 equiv), Et2AlCl (3 equiv), −78οC, 3–5 h

O O

O

O

OH R

N

O

Me

OH R

N Me

22-anti RCHO i-BuCHO C2H5CHO i-PrCHO t-BuCHO methacrolein C6H5CHO

O

22-syn anti/syn 86:14 88:12 95:5 95:5 90:10 74:26

Yield, % 86 81 63 65 67 62

Scheme 2.2h

diastereoselective anti -aldol reaction to prepare the aldol product 3816 (Scheme 2.2o). When the thiazolidinethione 37, derived from (R)-phenylglycine, was subjected to an anti -aldol reaction with cinnamaldehyde in the presence of a catalytic amount of magnesium bromide, the aldol product expected (38) was obtained in 74% yield with the stereochemistry desired for the synthesis of (–)-stemoamide. The chiral auxiliary was removed by NaBH4 reduction and the resulting alcohol was oxidized using Ley’s reagent17 to furnish the aldehyde 39.

85

REACTIONS

O O

O

1. MgCl2 (10 mol %), Et3N, TMSCl, EtOAc, 23οC, 24 h

O +

N Me

R

O O

H

O

OH R

N

2. MeOH, TFA

Me

Bn

Bn 24

23S dra 32:1 24:1 32:1 7:1 21:1 14:1 6:1 16:1

RCHO C6H5CHO p-MeC6H4CHO p-OMeC6H4CHO p-NO2C6H4CHO cinnamaldehyde α-naphthaldehyde furfural methacrolein

Yield, % 91 — 91 71 92 91 80 77

a

dr, diastereomeric ratio reported as major isomer/ sum of other diastereomers.

Scheme 2.2i

H Br

Me

OH2 Mg

H2O

Ph

O

H

favored

O

O

O

N

O

N

O

Bn MAJOR

O

O MgBr2

N

Ph Me

Bn O

OH

O

TS A: 0 kcal/mol

PhCHO

Me

Me Bn 23S

H 2O disfavored

Br Mg H2O O

Ph

O

O

H

O H N

O

TS B: 2.5 kcal/mol

Scheme 2.2j

OH Ph

N Me

Bn O

O

Bn minor

86

ALDOL REACTIONS

S HO

NH2

NaBH4, I2

HO

NH2

S

O

(90%) EtCOCl, Et3N, CH2Cl2

Ph 25

Ph

Ph

S

NH

(80%)

(85%)

O

S

CS2, 1 M KOH

OH

1. MgCl2 (10 mol %) Et3N, TMSCl, cinnamaldehyde

Ph

N

2. HCl, THF (87%, 2 steps)

Me Bn 27 (dr 10:1)

S S

O N Me Bn 26S

Scheme 2.2k

H Me

H2O

Ph

O

Br

Mg

OH2

H O

favored

N

S S S

S OH2

N

Ph Me

Bn MAJOR

S TS A: 0 kcal/mol

PhCHO

OH

N

S

Bn

O MgBr2

O

Me Bn 26S

Me Ph

disfavored

H

O H

S

N

S

OH2

O

OH2 Mg OH2 Bn

S Br

O

OH

N

Ph Me

Bn minor

S TS B: 2.8 kcal/mol

Scheme 2.2l

(–)-Talaumidin (40) exhibits signiﬁcant neurite outgrowth-promoting and neuroprotective activities in the biological assays and is a promising agent for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. In the synthesis of (–)-talaumidin (40), Fukuyama et al. used the recently disclosed Evans magnesium-catalyzed anti -aldol methodology18 (Scheme 2.2p).

87

REACTIONS

O O

XP O

O

H +

1. MgCl2, Et3N, TMSCl, EtOAc

N

O

Me OTBS

HO

2. MeOH, TFA (67%, 2 steps)

Bn

OTBS

OMe

OMe

29

30

23R

O OH 1. TESCl, imidazole 2. LiBH4, MeOH, THF

NH

O

TESO

O

(83%, 2 steps)

O O

OTBS OMe OH

31 OMe

28, migrastatin

Scheme 2.2m

N Me Bn

TMSO

MgCl2 (10 mol %) NaSbF6 (20 mol %)

O

O

O

O XP

TMSCl, Et3N, cinnamaldehyde (92%)

OH O

1. LiSEt 2. Me(MeO)NMgCl

Ph

Me N OMe

(80%)

Ph 34

33 (dr > 20:1)

23S

(91%)

PMBO Ph

O

O

OTBS O

PMBO

8 11

17

32

1. NaH, PMB-Br 2. DIBAL-H

Ph

8

O 11

H

35

Scheme 2.2n

The reaction of 4-benzyloxy-3-methoxybenzaldehyde (41) with N -propionyl oxazolidinone (23S ) in the presence of chlorotrimethylsilane along with a catalytic amount of MgCl2 provided the aldol adduct 42 in modest yield with a high

88

ALDOL REACTIONS

S S

O N

S

H

1. MgBr2• OEt2(10 mol %), Et3N, TMSCl, cinnamaldehyde (74 %)

O

N

OTES Ph

N

S

2. TESOTf, 2,6-lutidine, 0°C, CH2Cl2 (99%)

Me

Ph

O

H N

Ph

Me

O 38

37 O 1. NaBH4, EtOH, −15 to 4°C (96%)

OTES

H

Me Ph

O

H N

2. TPAP, NMO, CH2Cl2 (90%)

H H

O

O

N

H Me

O 39

36, stemoamide

Scheme 2.2o

O

O MeO

CHO +

N

O

Me

BnO 41

MeO

2. HF, pyridine, CH3CN (68%, 2 steps)

Bn

O

OH O

1. MgCl2, Et3N TMSCl, EtOAc

N

O

Me

BnO

Bn 42 (98% de)

23S

2. LiBH4, MeOH 1. TBSOTf, 2,6-lutidine CH2Cl2, rt, 5 min (91%, 2 steps)

OTBS MeO

O

O O

HO

MeO

OH Me

BnO 43

40, (-)-talaumidin

Scheme 2.2p

diastereoselectivity of 98% de. Protection of the hydroxyl group as a TBS ether and removal of the chiral auxiliary using LiBH4 efﬁciently furnished the primary alcohol 43. The chiral sulfonamide 45, which can be prepared in two steps from commercially available (1R,2S )-cis-1-amino-2-indanol (44), was introduced by Ghosh and Onishi for the synthesis of enantiomerically pure anti -aldol products via titanium enolate19a (Scheme 2.2q).

89

REACTIONS

p-Tol-O2S

NH

O

O O Me

OH

Ind

TiCl4, i-Pr2NEt;

O

then RCHO, CH2Cl2, −78°C

R

O +

O

R

Me

45

Me 46-syn

46-anti

1. p-TsCl, Et3N 2. EtCOCl, Et3N

R CH3 C 2H 5 i-C3H7 i-C4H9 C 6H 5

NH2 OH

OH

Ind

anti/syn 85 : 15 85 : 15 85 : 15 >99 : 1 45 : 55

Yield, % 50 50 91 97 85

44

Scheme 2.2q

+ +

H Me O LnTi N p-Tol-O2S

R O H

p-Tol-O2S

O

TiLn

favored

NH

O

OH

O

R Me

TS A

Scheme 2.2r

The aldol reactions of the titanium Z -enolates proceeded smoothly with various aldehydes precomplexed with titanium chloride at –78◦ C. The diastereoselectivity is high to excellent, with the single exception of benzaldehyde. The high degree of diastereoselection associated with this current asymmetric anti -aldol process can be rationalized by a Zimmerman–Traxler type of six-membered chairlike transition state A19a (Scheme 2.2r). The model is based on the assumptions that the titanium enolate is a seven-membered metallocycle with a chairlike conformation, and a second titanium metal is involved in the transition state, where it is chelated to indanolyloxy oxygen as well as to the aldehyde carbonyl in a six-membered chairlike transition-state structure. Ghosh and Kim recently disclosed a new chiral auxiliary (47) that exhibits an enhanced diastereoselectivity over the previously utilized auxiliary (44) in the anti -aldol reaction19b (Scheme 2.2s). Based on this anti -aldol strategy, Ghosh and Fidanze achieved an asymmetric synthesis of (–)-tetrahydrolipstatin (50), which was isolated from Streptomyces toxytricini 20 (Scheme 2.2t). (–)-Tetrahydrolipstatin is a potent inhibitor of pancreatic protease and has been

90

ALDOL REACTIONS

p-Tol-O2S

NH

O

O TiCl4, i-Pr2NEt;

O Me

Ace

then RCHO CH2Cl2, −78°C

48

O

OH

O

R

+ Ace

OH

O

R

Me

Me

49-anti

49-syn

R CH3 C2H5 BnCH2CH2 i-C3H7 c-C6H11 C6H5

NH2

OH

anti/syn 80 : 20 92 : 8 95 : 5 96 : 4 99 : 1 93 : 7

Yield, % 71 92 97 95 84 93

47

Scheme 2.2s

p-Tol-O2S

p-Tol-O2S NH

O

NH

TiCl4, i-Pr2NEt; cinnamaldehyde

O

O

OH

O

CH2Cl2, −78°C (38%)

Ph n-C6H13

52 (single diastereomer)

51

O O O

LiOOH (92%)

H N H

O O

OH

O HO

Ph n-C6H13

H H

53 50, (-)-tetrahydrolipstatin

Scheme 2.2t

marketed in several countries as an antiobesity drug under the trade name Xenical. The key step of the synthesis is the diastereoselective anti -aldol reaction of the titanium enolate of the ester 51. When the titanium enolate of 51 was reacted with trans-cinnamaldehyde, an anti -aldol product (52) was obtained as a single diastereomer in 38% yield. Hydrolytic cleavage of the chiral auxiliary with LiOOH then provided the acid 53.

REACTIONS

91

REFERENCES 1. Masamune, S.; Sato, T.; Kim, B.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108 , 8279. 2. Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119 , 2586. 3. Andrus, M. B.; Sekhar, B. B. V. S.; Turner, T. M.; Meredith, E. L. Tetrahedron Lett. 2001, 42 , 7197. 4. (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119 , 6496; (b) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116 , 9361. 5. Yoshimitsu, T.; Song, J. J.; Wang, G.-Q.; Masamune, S. J. Org. Chem. 1997, 62 , 8978. 6. Amarasinghe, K. K. D.; Montgomery, J. J. Am. Chem. Soc. 2002, 124 , 9366. 7. Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. Tetrahedron Lett. 1999, 40 , 4145. 8. Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56 , 5747. 9. (a) Mahrwald, R. Chem. Rev . 1999, 99 , 1095; (b) Gennari, C. in Stereoselectivities in Lewis Acid Promoted Reactions; Schinzer, D., Ed.; Kluwer Academic Publishers: Dordrecht, the Netherlands, 1989; Chap. 4; (c) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980, 102 , 3248; (d) Mulzer, J.; Bruntrup, G.; Finke, J.; Zippel, M. J. Am. Chem. Soc. 1979, 101 , 7723. 10. Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124 , 392. 11. Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4 , 1127. 12. (a) Nagao, Y.; Yamada, S,; Kumagai, T.; Ochiai, M.; Fujita, E. J. Chem. Soc., Chem. Commun. 1985, 1418; (b) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2 , 775. 13. Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119 , 7883. 14. Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125 , 6042. 15. Evans, D. A.; Trenkle, W. C.; Zhang, J.; Burch, J. D. Org. Lett. 2005, 7 , 3335. 16. Olivo, H. F.; Tovar-Miranda, R.; Barragan, E. J. Org. Chem. 2006, 71 , 3287. 17. Grifﬁth, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625. 18. Esumi, T.; Hojyo, D.; Zhai, H.; Fukuyama, Y. Tetrahedron Lett. 2006, 47 , 3979. 19. (a) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118 , 2527; (b) Ghosh, A. K.; Kim, J.-H. Org. Lett. 2003, 5 , 1063. 20. Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2 , 2405.

2.3. Proline-Catalyzed Asymmetric Aldol Reaction An approach has recently been made in which asymmetric aldol reactions are performed without the need for preformed metal enolates.1 In 2000, List and co-workers reported that the cyclic amino acid l-proline is an effective catalyst for the asymmetric aldol reaction of acetone with a variety of aromatic and aliphatic aldehydes2 (Scheme 2.3a). When l-proline was mixed with acetone

92

ALDOL REACTIONS

O + RCHO +

Product O

CO2H N H (30 mol %)

Yield, %

OH

O

NO2

O

O 74

ee, %

94

69

54

77

97

96

OH

60

OH

Yield, % Cl

OH

76

62 O

R 1

Product

OH

O

OH

rt

ee, %

68

O

DMSO

OH

65

Br

Scheme 2.3a

O +

RCHO

− H2O

N H

CO2H

CO2H

N

R H

enamine

OH

O

+ L-proline

H Me

N O

H O

TS A

+ H2O

R

O

R

N OH

CO2

Scheme 2.3b

and 4-nitrobenzaldehyde in anhydrous dimethylsulfoxide (DMSO) solvent, the aldol product was obtained in 68% yield and 76% ee. Other aromatic aldehydes provided products with similar enantiomeric excess. Although α-unbranched aldehydes such as pentanal did not yield any signiﬁcant amount of the desired aldol products, the reaction of isobutyraldehyde gave the corresponding aldol product in 97% yield and 96% ee. The reaction is considered to proceed via an enamine mechanism. The enantioselectivity of the reaction can be explained in terms of a metal-free version of a six-membered transition state

REACTIONS

O

O +

CO2H N H (35 mol %)

O

H

DMSO, rt, 24 h (75%)

3

O

OH

93

O

4 (>99% ee) (76%)

pyrrolidine (0.1 equiv), CH2Cl2, rt, 3 h

O O

TBS O O

1. TBSCl, imidazole (81%) 2. RuCl3 (0.03 equiv), NaIO4 (5.5 equiv) (67%)

HO

HO

Et 5

6

O S OH

N O 2, epothilone A

O

OH

O

Scheme 2.3c

in which the tricyclic hydrogen-bonded framework provides a solid ground for enantiofacial selectivity3 (Scheme 2.3b). Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1 –C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of d-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). Not only does acetone undergo a highly enantioselective aldol reaction, but hydroxy acetone exhibits excellent stereoselectivity to produce the anti -aldol products 75 (Scheme 2.3d). For example, l-proline catalyzed the aldol reaction between hydroxy acetone and cyclohexanecarbaldehyde to furnish the anti -diol in 60% yield with a greater than 20 : 1 diastereomeric ratio. The enantiofacial selectivity of the anti -isomer was higher than > 99%. Diastereoselectivities are very high with α-substituted aldehydes, whereas low selectivities are recorded in reactions with aromatic aldehydes and with α-unsubstituted aliphatic aldehydes. It is noteworthy that the levels of enantiofacial selectivity for the anti -aldol products

94

ALDOL REACTIONS

O

O +

R

H

+

OH

ee, % (anti/syn)

Product O

OH

>99 (>20:1)

ee, % (anti/syn)

O

60

Yield, %

OH >97 (1.7:1)

38

67 (1.5:1)

95

OH

OH

>99 (>20:1)

62

O

51

O

OH

OH O

OH 7

Product

Yield, %

OH R

N H (20 mol %)

OH O

O

DMSO

CO2H

Cl

OH

OH

>95 (>20:1)

Ph OH

OH

62

79 (3:1) OH

(2:1)

Scheme 2.3d

H favored

O

OH +

N H

HO R

O

H

CO2H

H

H Me

disfavored

H

O

R

O

R

N O

H O Me

TS B

OH MAJOR

H

HO

OH

H

TS A

O R

O N

O

OH

H O

R OH minor

Scheme 2.3e

from both α-substituted and α-unsubstituted aliphatic aldehydes are exception ally high. Based on the presumption that the enamine double bond would possess an (E )-conﬁguration, the diastereofacial selectivity can be explained by comparing two potential transition states A and B5 (Scheme 2.3e). Thus, anti -diol products

95

REACTIONS

CO2H N H (20 mol %)

O OR

H

O

OH OR

H

DMF, rt, 24–48 h

OR 8 ee, % (anti/syn)

Yield, %

OBn

98 (4:1)

73

OMOM

96 (4:1)

42

OTBDPS

96 (9:1)

61

Product O

OH

H OBn O

OH

H OMOM O

OH

H

OTBDPS

Scheme 2.3f

OTIPS

H

TIPSO

O

OH OAc

OH mannose 13 (95% ee; dr >19:1)

OH 95% ee (anti) anti/syn = 4:1

OTIPS

H

DMF, rt, 24 h (92%)

9

TIPSO

O

CO2H N H (10 mol %)

O

OTIPS 10 H

OTMS OAc 11

H

OTMS OAc

MgBr2•OEt2, −20 to 4οC, CH2Cl2 (87%)

11 MgBr2•OEt2, −20 to 4οC, Et2O (79%)

TIPSO

O

TIPSO

OH OAc

OH glucose 12 (95% ee; dr 10:1)

Scheme 2.3g

are formed via a six-membered chairlike transition state A in which the alkyl (R) group occupies an equatorial position. The formation of syn-diol products can be rationalized by a boatlike transition state B, where the facial selectivity of the aldehyde is reversed. When α-alkoxyaldehyde substrates were subjected to organocatalytic conditions, a highly enantioselective aldol dimerization reaction occurred6 (Scheme 2.3f). Substrates bearing relatively electron-rich alkoxy groups provide dimers

96

ALDOL REACTIONS

with synthetically useful levels of enantioselectivity and reactivity. Moreover, the aldehyde with bulky α-silyloxy substituent can readily be utilized to produce anti -diol with moderate levels of diastereoselectivity. Northrup and MacMillan reported an elegant two-step carbohydrate synthesis using the method described above7 (Scheme 2.3g). The ﬁrst step of the synthesis was an l-proline-catalyzed enantioselective dimerization of triisopropylsilyl (TIPS)-protected α-hydroxyaldehyde (9), which afforded α,γ-oxy-protected l-erythrose (10) in excellent yield and with high enantioselectivity. A Mukaiyama aldol reaction in ether between the TIPS-protected aldehyde 10 and the α-acetoxy enolsilane 11 in the presence of MgBr2 ·OEt2 afforded the glucose 12, whereas the analogous reaction in dichloromethane provided the mannose 13 with high selectivity. REFERENCES 1. For reviews, see (a) Gr¨oger, H.; Wilken, J. Angew. Chem. Int. Ed . 2001, 40 , 529. (b) List, B. Chem. Commun., 2006, 819. 2. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122 , 2395. 3. Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123 , 11273. 4. Zheng, Y.; Avery, M. A. Tetrahedron 2004, 60 , 2091. 5. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123 , 5260. 6. Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed . 2004, 43 , 2152. 7. Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305 , 1752.

3

Metal Allylation Reactions

GENERAL CONSIDERATIONS The addition of allylic organometallic reagents to carbonyl compounds gives homoallylic alcohols1 (Scheme 3.I). The homoallylic alcohol products are often obtained with high stereoselectivity and can be further manipulated to access synthetically valuable intermediates such as β-hydroxy carbonyl compounds. As a result, the addition reaction of allylic metal reagents to carbonyl compounds has been a subject of great interest to synthetic organic chemists. Over the last three decades, numerous allylic boron and silicon reagents have been invented that participate in highly stereoselective syntheses of homoallylic alcohols.2 The boron and silicon reagents are popular not only because they afford products with high stereoselectivity, but also because the stereochemical outcome of the addition reaction is predictable. Due to the high Lewis acidity of boron, the allylic boron reagents tend to undergo addition to aldehydes and ketones through a six-membered cyclic transition state. Unlike their boron counterparts, only certain types of allylic silicon reagents can have a closed six-membered chairlike transition state, due to the low Lewis acidity of silicon. Allylic boron reagents have allowed organic chemists a great deal of control over stereochemistry in carbon–carbon bond-forming reactions. Hoffmann et al. discovered that crotylboronates and their derivatives add to aldehydes with high diastereoselectivity.3 For example, when the crotylboronates 1E or 1Z were treated with an equimolar amount of aldehydes at –78◦ C, the homoallylic alcohols 2 were obtained in almost quantitative yields after workup. More signiﬁcantly, the diastereoselectivity of the reaction was always greater than 93 : 7, with E -boronate 1E affording anti -isomer and Z -boronate 1Z yielding syn-isomer4 (Scheme 3.II). In a related study, Hoffmann and Kemper also synthesized the γmethoxyallylboronates 3E and 3Z and performed addition reactions into a variety of aldehydes to explore the possibility of a stereoselective synthesis of vicinal diols5 (Scheme 3.III). Once again, the reaction is highly diastereoselective, affording an anti -isomer from the E -boronate and a syn-isomer from the Z -boronate. The nearly perfect diastereoselectivity observed in the reaction of crotylboronates Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

97

98

METAL ALLYLATION REACTIONS

M

M + H

M

O

O

O

OH

workup

H

M = B, Si

Scheme 3.I

O B

Me

O

1E or

+ O B

OH

O R

−78°C to rt, Et2O;

H

R

N(CH2CH2OH)3

O

1Z

R Ph Me Et i-Pr a b

R Me 2-anti

Me

OH

Me 2-syn

anti/syn w/1Z b w/1E a 94:6 4:96 93:7 3:97 93:7 3:97 96:4 6:94

E/Z = 93:7. E/Z = <5:>95.

Scheme 3.II

with aldehydes is explained in terms of a six-membered chairlike transition state4 (Scheme 3.IV). In the favored six-membered chairlike transition state A, the residue R of the aldehyde prefers to occupy an equatorial position. To explain the stereochemical outcome of the reaction of allylic boron reagents with carbonyl compounds, Houk and Li carried out calculations on the transition structures of the model reaction of formaldehyde and allylboronic acid6 (Scheme 3.V). The bimolecular complex formed initially between allylboronic acid and formaldehyde would rearrange via a six-membered transition state to form an intermediate. Calculations show that chair transition state A is 8.2 kcal/ mol more stable than twist-boat transition structure B, clearly conﬁrming that the six-membered chairlike transition-state model is a legitimate scheme to predict the stereochemical outcome of the boron allylation reaction. Houk and Li also performed calculations on the reaction between allylboronic acid and acetaldehyde6 (Scheme 3.VI). Transition state A, in which the methyl group of acetaldehyde occupies an equatorial position is more stable than transition state B by 5.5 kcal/mol. Thus, the theoretical studies support the transitionstate models in Scheme 3.IV proposed by Hoffmann and others.

GENERAL CONSIDERATIONS

O B

MeO

O

3E

+

or

O B

OH

O R

99

OH

25 or 40°C*

H

N(CH2CH2OH)3

R

R OMe

OMe

4-anti

O

4-syn

OMe 3Z

anti/syn w/3E 95:5 95:5 93:7 95:5

R Ph Me Et i-Pr

* 25°C with 3E and 40°C with 3Z.

a

w/3Zb <5:>95 7:93 8:92 11:89

E/Z = 89:11. E/Z = <5:>95.

a b

Scheme 3.III

Me

Me

O B

O B

H

favored

H

OH O

R Me

O

R

MAJOR

RCHO

TS A

O O B

R

disfavored

Me H

H

O

OH O

R Me minor

TS B

Scheme 3.IV

An interesting diastereoselectivity pattern was observed when α-halogen-sub stituted allylboronates were added to aldehydes. In this reaction, (Z )-alkenes were obtained as the major products7 (Scheme 3.VII). Hoffmann and Landmann explained the results by examining two competing six-membered chairlike transition states (Scheme 3.VIII). Among the possible factors that favor the transition state A, they pointed out that dipole–dipole interactions could play a dominant

100

METAL ALLYLATION REACTIONS

favored

OH B OH

H

O H TS A: 0 kcal/mol

H2C O B(OH)2

OB(OH)2

complex disfavored

H

O

H

B OH HO

TS B: 8.2 kcal/mol Scheme 3.V

O

H3C B(OH)2

OH B OH

H

favored

TS A: 0 kcal/mol

CH3CHO

OH H3C

OH B OH

CH3

disfavored

H

O

TS B: 5.5 kcal/mol Scheme 3.VI

role: The dipoles of the C–X and the B–O bonds in transition state A run opposite to each other, to render it a minimum net dipole moment.8 Theoretical support was obtained to explain the experimental results observed with α-chloro- or α-bromo-substituted pinacolboronates (5)6 (Scheme 3.IX). When calculations were performed on the reaction between the α-ﬂuoro-substituted allylboronic acid and formaldehyde, transition state A, in which ﬂuorine atom occupies an axial position, was found to be more stable than transition state B by 3.5 kcal/mol. In the next two sections we examine a number of stereoselective addition reactions of boron and silicon allylic reagents to carbonyl compounds.

101

GENERAL CONSIDERATIONS

O B

OH

O O

+

OH X

0°C, 15 h;

H

R

R

N(CH2CH2OH)3

X

R X 6a

5

6b

X = Cl R Ph Me Et i-Pr

6a/6b 95:5 93:7 94:6 96:4

X = Br 6a/6b 97:3 93:7 94:6 96:4

Yield, % 82 63 86 83

Yield, % 80 78 82 83

Scheme 3.VII

X R

O

RCHO

R

B O O

H O B

OH H

favored

X MAJOR

TS A

O

X

H disfavored

OH X

R

O H

X

R

B O O

minor

TS B

Scheme 3.VIII

H

favored

H

OH B OH

O F TS A: 0 kcal/mol

OH F

H

B(OH)2

CH2O

MAJOR

F disfavored

H H

F

OH B OH

O

H TS B: 3.5 kcal/mol

Scheme 3.IX

F

OH minor

102

METAL ALLYLATION REACTIONS

REFERENCES 1. (a) Bartlett, P. A. Tetrahedron 1980, 36 , 3; (b) Hoffmann, R. W. Angew. Chem. Int. Ed . 1982, 21 , 555; (c) Yamamoto, Y.; Asao, N. Chem. Rev . 1993, 93 , 2207. 2. Kennedy, J. W. J.; Hall, D. G. Angew. Chem. Int. Ed . 2003, 42 , 4732. 3. Hoffmann, R. W.; Niel, G.; Schlapbach, A. Pure Appl. Chem. 1990, 62 , 1993. 4. (a) Hoffmann, R. W.; Zeiβ, H.-J. J. Org. Chem. 1981, 46 , 1309; (b) Hoffmann, R. W.; Kemper, B. Tetrahedron 1984, 40 , 2219. 5. (a) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1981, 22 , 5263; (b) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1982, 23 , 845. 6. Houk, K. N.; Li, Y. J. Am. Chem. Soc. 1989, 111 , 1236. 7. Hoffmann, R. W.; Landmann, B. Tetrahedron Lett. 1983, 24 , 3209. 8. Hoffmann, R. W.; Landmann, B. Chem. Ber . 1986, 119 , 1039.

REACTIONS 3.1. Boron Allylation Reaction In 1978, Herold and Hoffmann reported their ﬁnding that the chiral allylboronate 1, derived from (+)-camphor, added to a variety of aldehydes to give the homoallylic alcohol 2 with moderate to good levels of enantioselectivity1 (Scheme 3.1a). Presumably, the reaction proceeds via a six-membered chairlike transition structure2 (Scheme 3.1b). The major enantiomer would be formed through transition state A, where the allyl group is delivered on the si -face of the aldehyde, which is activated by an internal coordination of boron atom to the carbonyl oxygen. Transition state B would be disfavored over A, due to the possible steric

O

O O Ph 1

B

+

R

OH

hexane, −40°C

R

H

2

O (+)-camphor

R CH3 C 2H 5 n-C3H7 i-C3H7 t-C4H9 C 6H 5

Scheme 3.1a

ee, % 65 77 72 70 45 36

Yield, % 92 91 93 88 85 90

REACTIONS

O

si-face

H H

O O Ph

R

O

MAJOR R

TS A

RCHO

B

OH

B

O Ph

favored

103

OH O disfavored

O Ph

re-face

B H R

R minor

O H

TS B

Scheme 3.1b

O O

R1

B R2

Ph

O +

R

Sc(OTf)3 (10 mol %)

H

CH2Cl2, −78°C

3

OH R

R1

R2 4

R1, R2 H, H

Me, H

H, Me

R PhCH2CH2 TBDMSOCH2 C6H5 PhCH2CH2 TBDMSOCH2 C6H5 PhCH2CH2 TBDMSOCH2 C6H5

ee, % 97 90 92 96 95 97 96 96 59

Yield, % 97 76 85 71 74 60 52 57 53

Scheme 3.1c

interactions between the alkyl (R) group of aldehyde and the hydrogen and phenyl substituents of the camphor frame. Computational study to support the foregoing hypothesis has yet to be done. In 2003, Hall et al. made an impressive improvement in enantioselectivity by employing a scandium catalyst3 (Scheme 3.1c). When a catalytic amount

104

METAL ALLYLATION REACTIONS

Sc3+ O

O O

R

R2 R1

favored re-face

B H

Ph

R

O

OH

R2 workup

R

R1

(RO)2B

R1

R2

H

TS A

Scheme 3.1d

OH MgBr 2B(OMe)

RCHO

2B

−78°C

−78 to 25°C

R 6

5, dIpc2B(allyl) d

Ipc2BOMe or (−)-Ipc2BOMe

ee, %a 93 (>99) 86 (—) 87 (96) 90 (96) 83 (>99) 96 (96)

R CH3 C2H5 n-C3H7 i-C3H7 t-C4H9 C6H5

1. BH3•SMe2 2. CH3OH

Yield, % 74 71 72 86 88 81

a

The %ee values in parentheses were obtained when allylboration reaction was conducted. at –100°C after the removal of MgBr(OMe) salt.

(+)-α-pinene or dpinene

Scheme 3.1e

OH RCHO,

MgBr, 2B(OCH3)

−78°C

2B

−78 to 25°C

R 8

7 (100% ee) 1. BH3•SMe2 2. CH3OH

R CH3 C2H5 n-C3H7 i-C3H7 t-C4H9 C6H5

(+)-2-carene

Scheme 3.1f

ee, % 98 94 94 94 99 95

105

REACTIONS

OH

Me

O

favored

H

TS A: 0.0 kcal/mol

O Me

Me R MAJOR

B dIpc

si-face

2B

dIpc

(R/S) Prediction Experiment 98.8:1.2 96.5:3.5

H

5, dIpc2B(allyl)

dIpc

H disfavored

Me

O

re-face

B

OH

dIpc

Me S minor

TS B: 2.12 kcal/mol

Scheme 3.1g

TBDPSO 10 1. Cp2ZrHCl, 20°C, CH2Cl2 2. n-BuNC, 0°C (54%, 2 steps)

O

TBDPSO H 11 d

(63%)

Ipc2B(allyl) (5), −78°C, Et2O

OMe OH

TBDPSO

N S 9, (+)-curacin A

12 (93% ee)

Scheme 3.1h

of the Lewis acid Sc(OTf)3 is used in the allylboration reaction with Hoffmann’s camphor-based reagent (3), there is not only a reaction rate increase but also a dramatic improvement in enantioselectivity. Both aliphatic and aromatic aldehydes are excellent substrates for allylation with allyl- and (E )-crotylboronates to afford

106

METAL ALLYLATION REACTIONS

O O H

TBDPSO

1. lIpc2B(allyl) (88%) 2. TESOTf, 2,6-lutidine (90%) 3. O3, CH2Cl2, PPh3 (80%)

TESO

7H

TBDPSO 3

14

15

39

1. O3, Ph3P (95%) 2. MeOH, PPTS (cat.) (87%) 3. TBSCl, imidazole (78%)

1. dIpc2B(allyl)

TBSO

O

2. NaH, MeI (79%, 2 steps)

O 17

OH

O 13, phorboxazole A Br MeO

O O

OMe

33 OMe

O OH 18

TBSO 16

OMe TBSO

H

O

OMe

39 O OH

N

O

33

N

OH

O

O O

O O

7 3

Scheme 3.1i

corresponding homoallylic alcohols of synthetically useful levels of enantioselectivity. The only system yet to be improved is the combination of Z -crotylboronate with benzaldehyde. The allylboration is proposed to proceed via a six-membered chairlike transition state in which the Lewis acidic scandium metal coordinates to the boronate oxygen4 (Scheme 3.1d). Five years after Hoffmann’s disclosure of the enantioselective allylation reaction, Brown reported in 1983 a new chiral allylborane reagent, B -allyldiisopinocampheylborane [5; d Ipc2 B(allyl) or (+)-Ipc2 B(allyl)]. d Ipc2 B(allyl) is readily prepared in three steps from commercially available (+)-α-pinene (Scheme 3.1e). Thus, hydroboration of (+)-α-pinene (d pinene) with borane–dimethyl sulﬁde followed by methanolysis of the Ipc2 BH gives B -methoxydiisopinocampheylborane [d Ipc2 BOMe or (–)-Ipc2 BOMe]. The reaction of Ipc2 BOMe with allylmagnesium bromide then generates the allylborane reagent 5. d Ipc2 B(allyl) has been utilized successfully for asymmetric carbon–carbon bond formation reaction to furnish secondary homoallylic alcohols (6) with optical purities in the range 83 to 96%5 (Scheme 3.1e).

107

REACTIONS

OH Me Me

Me

1. n-BuLi, KO-t-Bu 2. dIpc2BOMe

R −78°C

2B

3. BF3•OEt2

Me

RCHO

d19Z

20a

OH R Me

20b

OH R 1. n-BuLi, KO-t-Bu 2. dIpc2BOMe

Me Me

Me

2B

3. BF3•OEt2

Me 20c OH

RCHO −78˚C

d19E

R Me R CH3 C2H5 CH2 CH C6H5

(w/d19Z) 20a/20b Yield, % 95:5 75 95:5 70 95:5 63 94:6 72

(w/d19E) 20c/20d Yield, % 95:5 78 95:5 70 95:5 65 94:6 79

20d

Scheme 3.1j

The reaction provides a uniformly high level of enantioselectivity regardless of the nature of the aldehydes used. The new chiral reagent, B -allyldiisopinocampheylborane, therefore has one signiﬁcant advantage over Hoffmann’s reagent, as even aromatic aldehydes are good substrates to access homoallylic alcohols with high enantioselectivity. Later, Racherla and Brown discovered that the enantioselectivity dramatically improved when the reaction was ◦ conducted at –100 C after the removal of MgBr(OMe) salt.6 An even more efﬁcient reagent than B -allyldiisopinocampheylborane (5) is B -allylbis(2-isocaranyl) borane [7; 2-d Icr2 B(allyl)], which undergoes a highly efﬁcient asymmetric allylboration with a variety of aldehydes to afford the homoallylic alcohol 8 in 94 to 99% ee7 (Scheme 3.1f). Although Brown and co-workers proposed a six-membered transition state for the asymmetric allylboration reaction in which the aldedyde oxygen initially coordinates to boron followed by an internal transfer of the allyl group from boron to the carbonyl carbon,8 a quantitative analysis to explain the enantioselectivity was not available until 1993, when Gennari et al. conducted a computational study to rationalize the enantiofacial selectivity of Brown allylation9 (Scheme 3.1g). Calculation predicts that transition state A, in which the allyl group attacks the si -face of the aldehyde, is favored over transition state B by 2.12 kcal/mol.

108

METAL ALLYLATION REACTIONS

O O

2. TBDPSCl, im. DMAP, DMF (82%, 2 steps)

Me +

2B

O

1. THF, −78°C; H2O2, NaOH

O

Me

TBDPSO

d19E

O

H 22 (96% ee) O , CH2Cl2, (84%) MeOH,3 −78°C; Me2S

O O HO

Me

OH 21, nikkomycin B

O

− CO2

+ N H H NH3 HO

O O

N

NH O

OH

Me

TBDPSO H

O

23

Scheme 3.1k

The enantioselectivity calculated from this energy difference agrees well with the experimental value. The Brown allylation protocol was used successfully in the total synthesis of (+)-curacin A (9), a structurally novel antimitotic agent10 (Scheme 3.1h). Hydrozirconation11 of the triene 10 at the terminal vinyl group followed by quenching the zirconium intermediate with n-butyl isocyanide gave the aldehyde 11 after acidic aqueous workup. Asymmetric Brown allylation of 11 with d Ipc2 B(allyl) (5) gave the homoallylic alcohol 12 in 93% ee. In the total synthesis of phorboxazole A (13), one of the most potent cytotoxic natural products discovered to date, the Brown asymmetric allylation method, was employed repeatedly to access a variety of homoallylic alcohols12 (Scheme 3.1i). Construction of the C3 –C7 fragment began with Brown allylation of the aldehyde 14 with l Ipc2 B(allyl) to acquire the corresponding homoallylic alcohol, which was subsequently protected as a TES ether. Upon ozonolysis of the alkene, the aldehyde 15 was obtained in good yield. Another asymmetric Brown allylation was performed to construct the C33 –C39 subunit of phorboxazole A. Treatment

109

REACTIONS

O

19Z

H

( Ipc)2B

TBSO

O H

2. O3; PPh3 (90%)

(82%)

TES

1. TBSOTf, 2,6-lutidine (97%)

OH

d

d

TES

TES

27 26

25

OH HO

O O

MeO

24, apoptolidin

O

OH MeO HO

O OH H O

OMe O

O OH

OH

O O

OMe

HO

Scheme 3.1l

1.

(lIpc)2B l

O

OBn

19E

OBn

2. Ac2O, pyridine (80%, 2 steps)

1. O3; PPh3, NaBH4 2. K2CO3, MeOH (61%, 2 steps)

OAc

H 29 (98% ee, dr > 99%)

O O HO

NH HN

OBn OH

NH2

O

30

NH HN O

Scheme 3.1m

O

28, azumamide A

110

METAL ALLYLATION REACTIONS

OH OMe

OMe 2B(OMe)

s-BuLi, −78°C;

OMe

RCHO

2B

32a

−78°C

then BF3•OEt2 dIpc

R

OH

d31

2BOMe

R OMe 32b R

32a/32b

Yield, %

CH3

95:5

57

C2H5 (CH3)2CH C6H5

94:6

65

94:6

57

95:5

72

CH2 CH

94:6

63

Scheme 3.1n

OMEM O

B(dIpc)2

OH

d

OMEM

O

HO

35

O

O

(87%)

O

OH

1. TBSCl, imidazole 2. PhCOCl, pyridine, DMAP 3. TBAF 4. (COCl)2, DMSO, Et3N 5. NH2OH•HCl, NaOAc (98% from 36)

36 (95% ee, de > 98%)

34

O OMEM

H HON

NHCO2Me O

O

O

OBz

aq. NaOCl

O O

(65%)

BzO 37

HO

N H OMEM 38

OH MeSSS 33, (−)-calicheamicinone

Scheme 3.1o

of the aldehyde 16 with d Ipc2 B(allyl) resulted in the corresponding homoallylic alcohol, which was then converted to its methyl ether (17). Cleavage of the double bond via ozonolysis, acidic methanolysis to generate the cyclic acetal, and reprotection of the primary hydroxyl group as a TBS ether afforded 18.

111

REACTIONS B(lIpc)2

C12H25CHO

OMEM

35

OMEM

OMEM

l

1. Ph3P, DIAD

C12H25

C12H25

2. NaOH, MeOH

(81%)

OH

OH

(S,S)-40 (95% ee, dr > 98:2)

(R,S)-40

OH O

C12H25

O OH

OH

O

39, murisolin

Scheme 3.1p

CO2-i-Pr O B

O (S,S)-41

O CO2-i-Pr

+

R

toluene, 4-Å MS −78°C

H

OH R 42

R

ee, %

Yield, %

CH3(CH2)8

79

86

c-C6H11

87

72

t-C4H9

82

—

C6H5

71

78

Scheme 3.1q

Brown and Bhat also developed highly stereoselective crotylation reactions using Z - and E -crotyldiisopinocampheylborane reagents8a,13 (Scheme 3.1j). The reagents are prepared from cis- and trans-2-butene, respectively. The 2-butenes are metalated with potassium tert-butoxide and n-butyllithium in THF at –45o C. Treatment of the resulting crotylpotassiums with B -methoxydiisopinocampheylborane at –78o C followed by boron triﬂuoride etherate affords the crotylborane reagents d 19Z and d 19E , respectively. Reaction of d 19Z and d 19E with aliphatic and aromatic aldehydes provides β-methylhomoallylic alcohols in good yields and with high enantioselectivity. Barrett and Lebold used the Brown asymmetric crotylation to prepare the homoallylic alcohol 22 in the total synthesis of nikkomycin B 21, a natural product that exhibits fungicidal, insecticidal, and acaricidal activities14 (Scheme 3.1k).

112

METAL ALLYLATION REACTIONS

O H

favored

R

re-face

O B

O

O-i-Pr OH O-i-Pr

O O

MAJOR

O

O

B

i-PrO2C

R

O

TS A

H

O

CO2-i-Pr (S,S)-41

R

disfavored

O B

H

si-face

OH O-i-Pr

O

R

O

O

R

O-i-Pr

minor

coulombic repulsion TS B

Scheme 3.1r

O d

O B

H

favored si-face

O MeO2C

B

O

Me

δ+

H

O

d O

H3C H

Me

O

disfavored re-face

OCH3

MAJOR

TS A: 0 kcal/mol (d = 3.28 Å)

CO2Me

(R,R)-41Me2

OH

O

H3C

O

OCH3

O O

Me

B O

δ+

OH

OCH3 OCH3

minor

O

TS B: 1.75 kcal/mol (d = 4.11 Å)

Scheme 3.1s

Reaction of 4-(pivaloyloxy)benzaldehyde with the E -crotyldiisopinocampheylborane d 19E gave the corresponding homoallylic alcohol 22 in a 98 : 2 enantiomeric ratio. After protection of the alcohol as a tert-butyldiphenylsilyl (TBDPS) ether, the alkene was subjected to ozonolysis to provide the β-hydroxy aldehyde 23.

113

REACTIONS

CO2-i-Pr

1. n-BuLi, KO-t-Bu 2. BF(OMe)2 3. aq. HCl

O B

Me 4. DIPT (88% yield, 4 steps)

(S,S)-43E, 4-Å MS

O

H O

Me

Me

O

Me

−78°C, toluene (80%)

OH

OH 45a

OH 45c

45b

Me

Me (S,S)-43E, 4-Å MS

O

46

Ktl

45a/45b/45c = 88:4:8

O

O

Me Ktl

Ktl

44

H

CO2-i-Pr O (S,S)-43E

−78°C, toluene (85%)

Acl

OH

OH 47a

Me Acl

Acl

47b

OH 47c

47a/47b/47c = 96:2:2

Scheme 3.1t

The Brown asymmetric crotylation method was utilized in the total synthesis of the apoptolidin 24, an attractive synthetic target with many unique biological activities, including the selective induction of apoptosis in rat glia cells15 (Scheme 3.1l). In this synthesis, the acetylenic aldehyde 25 was treated with (Z )-crotyl-d Ipc2 borane (d 19Z ) to afford the alcohol 26 selectively and in 82% yield. Protection of 26 as a TBS ether, followed by ozonolysis of the oleﬁnic bond, gave the aldehyde 27 in high yield. Brown’s crotylboration protocol was used effectively in the synthesis of azumamide A 28. Azumamides are unusual cyclic peptides that show potent inhibitory activity on histone deacetylase enzymes. A highly diastereo- and enantioselective (dr > 99%; 98% ee) crotylation of 3-benzyloxypropanal with the chiral reagent (E )-crotyl-l Ipc2 borane (l 19E ) afforded the homoallylic alcohol 29. Subsequent reductive ozonolysis and K2 CO3 -mediated hydrolysis of the acetate furnished the diol 3016 (Scheme 3.1m). Asymmetric allylboration has also been applied to γ-methoxyallyl derivatives. Isomerically pure (Z )-γ-methoxyallyldiisopinocampheylborane (d 31), prepared from d Ipc2 BOMe and the lithium anion of allyl methyl ether, reacts with various aldehydes to afford the syn-β-methoxyhomoallylic alcohol (32a) in a highly regio- and stereoselective manner17 (Scheme 3.1n). This one-pot synthesis of enantiomerically pure 1,2-diol derivatives went as smoothly as the asymmetric Brown crotylation, affording products with uniformly high diastereoselectivity.

114

METAL ALLYLATION REACTIONS

CO2-i-Pr

tBuPh2SiO

O

O B

Me

H

O

CO2-i-Pr (S,S)-43E

TBDPSO

1. Et3SiCl, Et3N

toluene, −78°C, 4-Å MS (75%)

Me

OH

Me

49

2. O3; Me2S

Me

50 (dr 88:11:1)

TBDPSO

TES TBDPSO O

OTES

1. HCl, THF 2. 2-methoxypropene 3. O3; Me2S

OH

(R,R)-43E

CHO

4. HC(OMe)3, PPTS 5. TBAF (79%, 5 steps)

(76%, 3 steps)

Me

Me

Me

51

OH

O

Me

Me

52 (dr 99:1)

OH

OMe

O

O

OMe

O

1. (COCl)2, DMSO

OMe Me

Me

OMe

2. (S,S)-43E (73%, 2 steps)

Me

Me

Me

Me

Me

54 (dr 95:5)

53

2. O3; Me2S 1. Ac2O, pyridine CO2-i-Pr

OH OAc O

O B

O (R,R)-41

OMe

O

OMe dr (91:9) Me Me Me Me

CO2-i-Pr

toluene, −78°C, 4-Å MS (70%, 3 steps)

1. KOtBu, MeI 2. p-TsOH (cat.)

OMe OAc O

O CHO

29

19

Me 48, C19

Me

Me

Me

C29 segment of rifamycin S

Scheme 3.1u

O

OMe OMe

Me Me Me Me 55

56

(67%, 2 steps)

OAc O OHC

115

REACTIONS

OHC

O

OAc

H

O

O

TBSO O H TBSO

Ph

AcO OAc

58

Tri-OAc-D-glucal CO2iPr O B

CH2Cl2, −78°C (93%)

O

CO2iPr

(S,S)-41

H HO

O

H

1. TBAF 2. NaIO4

O

TBSO O H TBSO

Ph

O

HO

3. NaBH4 (96%, 3 steps)

HO

A O

O B

O

H OH 60

59

H

H

H

H C O

O

H O D

Ph

H E O

OH

H H H H OH OBn 57, ABCDE-ring part of CTX3C H

Scheme 3.1v

The Brown allylboration was used in the enantioselective total synthesis of (–)-calicheamicinone 3318 (Scheme 3.1o). Thus the lactol 34, readily prepared from tetronic acid, was treated with the allylborane d 35 to give 36 in a highly stereoselective manner (95% ee, > 98% de). Compound 36 was converted to the aldoxime 37 by standard chemistry. Generation of the nitrile oxide with aqueous sodium hypochlorite was accompanied by spontaneous [3 + 2]-dipolar cycloaddition to afford 38 in 65% yield. In the synthesis of a library of (+)-murisolin (39) and its 15 other stereoisomers, Curran and others used Brown allylation strategy to obtain the four diastereoisomers of the homoallylic alcohol 4019 (Scheme 3.1p). Thus, the homoallylic alcohol (S,S )-40 was prepared in 95% ee from allylborane reagent l 35 and corresponding aldehyde. By using the Mitsunobu reaction, (R,S )-40 was obtained. Similarly, (R,R)-40 was synthesized via the enantiomeric borane reagent d 35

116

METAL ALLYLATION REACTIONS

OH

OH

PhCHO (3 equiv), CF3CO2H (4 equiv)

1. (COCl)2, DMSO; Et3N

O

O

2.

62

CO2-i-Pr O B

O

toluene, −20 to 0°C (82%)

O

CO2-i-Pr O (R,R)-41

63

toluene, −78°C, 4-Å MS (86%, 2 steps)

OH

OH 1. (COCl)2, DMSO; Et3N

O

O

2. (S,S)-41, toluene −78°C, 4-Å MS (77%, 2 steps)

O O

Ph

Ph 65

64 O O

O OH HO

O

O

O 61, lasonolide A

OH

Scheme 3.1w

derived from d Ipc2 BOMe, and (S,R)-40 was obtained by the Mitsunobu reaction of (R,R)-40. The four isomers thus secured were used in the total synthesis of (+)-murisolin and of its 15 isomers. Roush et al. discovered that the tartrate ester–modiﬁed allylboronates, such as diisopropyl tartrate allylboronate (S ,S )-41, react with achiral aldehydes to give the homoallylic alcohols 42 in good yields and high levels of enantioselectivity of up to ˚ molecular 87% ee when the reaction is carried out in toluene in the presence of 4-A sieves20 (Scheme 3.1q). To rationalize the asymmetric induction realized by 41, two six-membered transition states were compared (Scheme 3.1r). It was reasoned that transition state A was favored over transition state B due mainly to the nonbonded electronic repulsive interactions of the lone-pair electrons of the aldehyde oxygen and the carbonyl oxygen of the tartrate ester. In an effort to elucidate the electronic effects in the stereochemistrydetermining transition states, Gung and co-workers conducted a computational study in 2002.21 The calculations carried out on the allylation reaction between

117

REACTIONS CO2-i-Pr O B

OHC

OPMB

O

1. TBSOTf, 2,6-lutidine 2. catecholborane, (Ph3P)3RhCl

OH

CO2-i-Pr (R,R)-43E

OPMB

toluene, −78°C, 8 h (78%)

(R)-67

(86%, 2 steps)

68

OMe OTBS HO

O O

OPMB 69

HO

HO

OH

OH O OMe 66, (−)-bafilomycin A1

Scheme 3.1x

(R,R)-dimethyl tartrate allylboronate and acetaldehyde showed that transition state A is more stable than B by 1.75 kcal/mol (Scheme 3.1s). The major force for the energy difference is an attractive Coulomb interaction between the ester oxygen and the boron-complexed aldehyde carbonyl group: The distance between ˚ than in B (4.11 A). ˚ The the two interacting charges is shorter in A (3.28 A) authors concluded that the repulsive n/n interaction proposed initially might play a lesser role than speculated previously. The tartrate-based E -crotylboronate (S,S )-43E , which can readily be prepared from E -2-butene, underwent highly enantioselective crotylation reactions with the chiral aldehydes 44 and 4622 (Scheme 3.1t). Best results in both cases were ◦ ˚ obtained in reactions performed at –78 C in toluene in the presence of 4-A molecular sieves. Under these conditions, the reaction of the l-deoxythreose ketal 44 was highly selective to generate 45a in 22 : 1 diastereofacial selectivity. Similarly, the reaction of the d-glyceraldehyde acetonide 46 with (S,S )-43E showed exceptionally high 48 : 1 selectivity. In order to apply tartrate ester–modiﬁed allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19 –C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S )-43E and the chiral aldehyde (S )-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 : 11 : 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95:5 mixture

118

METAL ALLYLATION REACTIONS

O COOMe H

HO

H

H

H

TBSO OH

OMe OH

71, hyodeoxycholic acid methyl ester

OMe 72

toluene, −78°C, 4-Å MS (92%, 2 steps)

CO2-i-Pr O B

O

CO2-i-Pr (R,R)-43E

O OH H H

1. H2NNH2, H2O2 2. (COCl)2, DMSO; Et3N

TBSO

OMe OH

(83%, 2 steps)

TBSO

OMe

74

OMe OH

OMe 73

3. HF, CH3CN 1. TiCl4-Zn-CH2Br2 (50%, 3 steps) 2. LiBF4, H2O

H H H HO

OH

H CHO

70, orostanal

Scheme 3.1y

of 54 and its isomer. Acylation of 54 followed by ozonolysis provided 55, which was treated with allylboronate (R,R)-41 under standard conditions. The allylation product 56 was obtained as a 91 : 9 mixture. The Roush allylboration method was also used in the synthesis of the ABCDEring part of ciguatoxin CTX3 C 5725 (Scheme 3.1v). The aldehyde 58, which was prepared from tri-O-acetyld-glucal in six steps, was treated with the chiral allylboronate reagent (S,S )-41 to give the homoallylic alcohol 59 as the sole product. Removal of the TBS groups followed by oxidative cleavage of the

REACTIONS

119

CO2-i-Pr O B

PMBO

O H (S)-67

O

CO2-i-Pr (S,S)-43Z

PMBO

toluene, −78°C, 4-Å MS

PMBO

(71%, 2 steps)

77

(95% from 67)

OH 76

1. NMO, OsO4 2. NaIO4

PMBO

TBSOTf, 2,6-lutidine

OTBS

CHO OTBS 78

HO O

O

OH

O

OH

NH2 O

75, discodermolide

OH

Scheme 3.1z

OH

O B

+

R

Et2O −100°C, 3 h

H

R 81

SiMe3 80 R

ee, %

Yield, %

C2H5

96

80

i-C3H7

96

85

t-C4H9

97

90

CH3CH CH BnOCH2CH2

97

85

92

84

MgBr

B OMe SiMe3 79

Scheme 3.1aa

120

METAL ALLYLATION REACTIONS

R

O

favored

OH

SiMe3 R

B H

MAJOR TS A

RCHO

B SiMe3

H R

disfavored

OH

B

O

H

SiMe3

R minor

H TS B

Scheme 3.1bb

Ph N

Ts

Ph

Ph B Br

N

Bu3Sn

Ts

Ts

N

Ph B

N

OH RCHO CH2Cl2, −78°C

Ts

R 84

(R,R)-82

83

1. TsCl 2. BBr3

Ph

Ph

H2N

NH2

(R,R)-stien

R

ee, %a

n-C5H11

90 (95)

c-C6H11

93 (97)

C 6H 5

94 (95)

(E)-C6H5CH CH

98 (97)

a

The % ee values in parentheses are for reactions run in toluene.

Scheme 3.1cc

resulting 1,2-diol and the subsequent reduction afforded the triol 60 in 96% overall yield. The tartrate-based allylboronates were also used in the total synthesis of (+)-lasonolide A (61), which displays antitumor activity by inhibiting the invitro proliferation of A-549 human lung carcinoma cells26 (Scheme 3.1w). In the synthesis, the alcohol 62 was oxidized and then treated with the allylboronate (R,R)-41 to give the homoallylic alcohol 63 with 78% ee.Compound 63 was then

REACTIONS

R

O favored

Ph Ts

N

Ph B 83

N

Ts N B Ph N Ph Ts

121

OH R

H

MAJOR

RCHO

TS A

Ts

disfavored

Ts N B Ph N Ph Ts

OH O

R H

R minor

TS B

Scheme 3.1dd

treated with benzaldehyde in the presence of triﬂuoroacetic acid to furnish a separable 5 : 1 mixture favoring the benzylidene desired (64). Swern oxidation of 64 followed by a second asymmetric allylation, this time with (S,S )-41, yielded the alcohol 65 with an enhanced enantioselectivity of 91% ee. Roush et al. applied the diastereoselective crotylboration methodology in the total synthesis of baﬁlomycin A1 (66), a potent vacuolar ATPase inhibitor that displays broad antibiotic activity27 (Scheme 3.1x). In the synthesis, the known aldehyde (R)-67 was treated with (E )-crotylboronate (R,R)-43E to provide an 85 : 15 mixture of the homoallylic alcohol 68 and the undesired 3,4-anti -4,5-syn diastereomer with an isolated 78% yield of 68. Alcohol protection as a TBS ether followed by hydroboration mediated by Wilkinson’s catalyst efﬁciently provided the primary alcohol 69. Liu and Zhou applied Roush’s crotylboration to the stereoselective synthesis of the orostanal 70, a novel sterol that induces apoptosis in human acute promyelotic leukemia cells28 (Scheme 3.1y). The aldehyde 72, prepared from hyodeoxycholic acid methyl ester, underwent asymmetric reaction with crotylboronate (R,R)-43E to furnish 73. Hydrogenation of the terminal alkene followed by Swern oxidation gave the ketone 74. Methylenation of the ketone and removal of the protective groups afforded orostanal in 50% yield. Another synthetic application of Roush’s crotylboration methodology using a (Z )-crotylboronate can be found in the formal synthesis of (+)-discodermolide (75)29 (Scheme 3.1z). The aldehyde (S )-67, which was prepared from the Roche ester, reacted with (Z )-crotylboronate (S,S )-43Z to give the syn-homoallylic alcohol 76. Silylation of alcohol and oxidative cleavage of the alkene 77 provided the aldehyde 78, from which the ﬁnal product (75) can be synthesized according to a known procedure.30

122

METAL ALLYLATION REACTIONS Ph

TBSO Ts

N

MeO CHO OMOM

Ph N Ts B Br

TBSO

(S,S)-82

dr = 17:1 MeO

Bu3Sn OAc

MOMO

(92%)

OH OAc

88

87

1. TBSOTf, 2,6-lutidine (88%) 2. N-bromosuccinimide (95%)

TBSO 1. PMe2Ph, CH3CN; DBU

MeO

2.

Br

OHC (85%, 2 steps)

MOMO

O

O TBS

89 HO TBSO

33 35

33 35

MeO MeO

30

O

30

MOMO

O

N

86, C18-C35 segment of FK-506

O HO

1

18

O TBS

O HO

O

O 18

O OMe OMe

85, FK-506

Scheme 3.1ee

Short and Masamune reported that the monosubstituted C1 -symmetric borolane derivative 80, prepared by addition of allylmagnesium bromide to a solution of (S )-B -methoxy-2-(trimethylsilyl)borolane (79), was a highly efﬁcient reagent for asymmetric allylboration 31 (Scheme 3.1aa). The borolane reagent shows satisfactory reactivity and high stereoselectivity toward a variety of aldehydes at –100o C. To explain the stereochemical outcome of the reaction, a six-membered chairlike transition state was proposed31 (Scheme 3.1bb). Transition state A, in which the allyl group attacks the si -face of the aldehyde is presumably operating here based on steric interactions. Transition state B would be of higher energy than transition state A, due to the severe nonbonded repulsions between the

123

REACTIONS Ph 1. Ts

OTBS OPiv

2.

SnBu3

N

Ph B Br

N

PMBO (98%)

OTBS

O

OPiv N

N O

90

OH

Ts (R,R)-82

dr > 25 : 1

CHO

OPMB

92

91

O PMBO

OTBDPS

N

then aldehyde 93 (S,S)-82, 90, rt, 12 h; −78°C (96%)

O 93

CHO

OTBDPS OH O

13, phorboxazole A

O N

PMBO

dr = 92 : 8

OPiv

TBSO 94

Scheme 3.1ff

trimethylsilyl group and the two hydrogens of the allyl group. It is noteworthy that the allylation reaction of isobutyraldehyde with the chiral reagent bearing a butyl group on the borolane ring gave product in much reduced enantioselectivity of 72% ee. Thus, the Masamune asymmetric allylation reaction was an elegant demonstration of the effective steric role played by a trimethylsilyl group.32 In 1989, Corey et al. reported a highly enantioselective allylation of aldehydes utilizing (R,R)-1,2-diamino-1,2-diphenylethane (stilbenediamine, or stien) as an efﬁcient chiral auxiliary33 (Scheme 3.1cc). Reaction of the bis-p-toluenesulfonyl derivative of (R,R)-stien34 in CH2 Cl2 with 1 equivalent of BBr3 followed by treatment of the resulting bromoborane (82) with allyltributyltin generated the chiral allylborane 83. Reaction of 83 with aliphatic and aromatic aldehydes in ◦ CH2 Cl2 or toluene at –78 C produced the corresponding homoallylic alcohol 84 in excellent optical purities and greater than 90% yield. The absolute conﬁguration observed for the homoallylic alcohol 84 derived from the (R,R)-allylborane reagent 83 can be rationalized on the basis of a chairlike six-membered transition state33 (Scheme 3.1dd). The major enantiomer is formed via transition state A, in which the boron allyl group attacks the re-face

124

METAL ALLYLATION REACTIONS Ph

O TrO

Ts

H OAc

N

Ph N Ts B Br (R,R)-82

1. TsCl, pyridine (99%)

TrO Bu3Sn (85%)

96

OH

2. KOH (99%)

OAc dr > 99 : 1 97 O HO

TrO

O O 98

O O 95, amphidinolide T3

Scheme 3.1gg

of the aldehye. Transition state B would be disfavored, due to the nonbonded interaction between the sulfonyl group and the pseudoaxial aldehydic hydrogen. Corey and Huang used this allylation method in construction of the C18 –C35 subunit 86 of the macrocyclic immunosuppressant FK-506 (85)35 (Scheme 3.1ee). The aldehyde 87 underwent asymmetric allylation with the cyclic borane reagent generated in situ by reaction of bromoborane (S,S )-82 and 2-acetoxyallyltributylstannane. The allylation proceeded with high 17 : 1 diastereoselectivity to furnish the homoallylic alcohol 88 in 92% yield after column chromatography. Silylation of 88 followed by treatment with N -bromosuccinimide yielded the bromomethyl ketone 89, which was further elaborated via a Wittig reaction to afford the C18 –C35 fragment 86. The highly enantioselective allylation method developed by Corey was utilized iteratively during the total synthesis of phorboxazole A (13), a natural product that exhibits unprecedented cytostatic activity against all 60 cell lines of the National Cancer Institute human cancer test panel36 (Scheme 3.1ff). The ◦ stannane 90 underwent effective transmetalation from 0 C to room temperature over 12 hours with the (R,R)-bromoborane 82. The asymmetric allylation of 91 gave the homoallylic alcohol 92 with excellent diastereoselectivity. After further manipulations, the aldehyde 93 was generated, setting the stage for the second asymmetric allylation with the stannane 90 and the (S,S )-bromoborane 82 to produce the polyol derivative 94 in a 92 : 8 diastereomeric ratio.

REACTIONS

O

125

Me O HO Me

O Me n-Bu

Me

CO2H CO2H

n-Bu Me

99

OH

O Me 100

B 3

OH Ph

Me O Me

R

102R OH Ph

Ph

CHO

n-Bu O O B

S

102S

Me

O

Me

n-Bu 101

R/S Prediction

Experiment

85:15

71:29

Scheme 3.1hh

Corey’s asymmetric allylation methodology was utilized in the total synthesis of amphidinolide T3 (95), a marine natural product that exhibits signiﬁcant antitumor properties37 (Scheme 3.1gg). The asymmetric allylation of the aldehyde 96 was carried out successfully with chiral allylborane reagent generated in situ from allyltributylstannane and (R,R)-82 to furnish the homoallylic alcohol desired (97) in 85% yield with excellent diastereoselectivity. Subsequent conversion of the alcohol to the tosylate ester followed by treatment with potassium hydroxide resulted in formation of the trisubstituted tetrahydrofuran 98. To rapidly generate a structurally diverse set of chiral ligands for asymmetric reactions, a new research program using computer-aided design has recently been launched. Using this technique, Kozlowski et al. identiﬁed a structurally unique diol (100) for enantioselective boron allylation reaction. Compound 100 was synthesized from the known dioxatetracyclic compound 99, and the validity of the computational prediction was evaluated for an asymmetric boron allylation reaction38 (Scheme 3.1hh).

126

METAL ALLYLATION REACTIONS

The allyl boronate 101, prepared by treatment of the cis-decalin diol 100 with trisallylborane, underwent allylation with dihydrocinnamaldehyde to afford the corresponding homoallylic alcohols favoring the R-enantiomer, which was the major enantiomer predicted based on transition-state calculations. Although the level of enantioselectivity realized with 100 is low, further reﬁnements of the computational parameters should lead to the discovery of more efﬁcient chiral ligands.39 REFERENCES 1. Herold, T.; Hoffmann, R. W. Angew. Chem. Int. Ed . 1978, 17 , 768. 2. Herold, T.; Schrott, U.; Hoffmann, R. W.; Schnelle, v. G. E.; Ladner, W.; Steinbach, K. Chem. Ber . 1981, 114 , 359. 3. Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003, 125 , 10160. 4. Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126 , 4518. 5. (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105 , 2092; (b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S.; Perumal, T. J. Org. Chem. 1986, 51 , 432. 6. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56 , 401. 7. Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla, U. S. J. Am. Chem. Soc. 1990, 112 , 2389. 8. (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108 , 5919; (b) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990, 55 , 1868. 9. Vulpetti, A.; Gardner, M.; Gennari, C.; Bernardi, A.; Goodman, J. M.; Paterson, I. J. Org. Chem. 1993, 58 , 1711. 10. (a) Wipf, P.; Xu, W. J. Org. Chem. 1996, 61 , 6556; (b) Xu, W. Ph.D. dissertation, University of Pittsburgh, Pittsburgh, PA, 1997. 11. (a) Wipf, P.; Xu, W. J. Org. Chem. 1993, 58 , 825; (b) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35 , 5197. 12. White, J. D.; Kuntiyong, P.; Lee, T. H. Org. Lett. 2006, 8 , 6039. 13. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108 , 293. 14. Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1991, 56 , 4875. 15. Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Wei, H.-X.; Weyershausen, B. Angew. Chem. Int. Ed . 2001, 40 , 3849. 16. Izzo, I.; Maulucci, N.; Bifulco, G.; De Riccardis, F. Angew. Chem. Int. Ed . 2006, 45 , 7557. 17. Brown, H. C.; Jadhav, P. K.; Bhat, K. J. Am. Chem. Soc. 1988, 110 , 1535. 18. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114 , 3134. 19. (a) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004, 126 , 36; (b) Curran, D. O.; Zhang, Q.; Richard, C.; Lu, H.; Gudipati, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006, 128 , 9561. 20. Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107 , 8186. 21. Gung, B. W.; Xue, X.; Roush, W. J. Am. Chem. Soc. 2002, 124 , 10692. 22. Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc. 1986, 108 , 294.

REACTIONS

127

23. For a comprehensive review of synthetic applications of asymmetric boron allylation reactions, see Chemler, S. R.; Roush, W. R. in Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapt. 11. 24. Roush, W. R.; Palkowitz, A. D. J. Am. Chem. Soc. 1987, 109 , 953. 25. Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45 , 7011. 26. Kang, S. H.; Kang, S. Y.; Kim, C.; Choi, H.; Jun, H.-S.; Lee, B.; Park, C.; Jeong, J. Angew. Chem. Int. Ed . 2003, 42 , 4779. 27. Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W. R. Angew. Chem. Int. Ed . 1999, 38 , 1652. 28. Liu, B.; Zhou, W. Tetrahedron Lett. 2002, 43 , 4187. 29. Francavilla, C.; Chen, W.; Kinder, F. R. Jr. Org. Lett. 2003, 5 , 1233, 30. Kinder, F. R. (Novartis A-G, Switzerlands Novartis-Erﬁndungen Verwaltungs G mbH). Process for preparing discodermolide and analogues thereof. PCT Int. Appl. 22, CODEN: PIXXD2 WO 0212220 A2 20020214, 2002. 31. Short, R.; Masamune, S. J. Am. Chem. Soc. 1989, 111 , 1892. ˚ is signiﬁcantly longer than the C–C bond of 1.5 A. ˚ For 32. The C–Si bond of 1.9 A selected C–Si bond lengths, see (a) Sakurai, H.; Nakadaira, Y.; Tobita, H. J. Am. Chem. Soc. 1982, 104 , 300; (b) Igau, A.; Baceiredo, A.; Gr¨utzmacher, H.; Pritzkow, H.; Bertrand, G. J. Am. Chem. Soc. 1989, 111 , 6853. 33. Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111 , 5495. 34. Pikul, S.; Corey, E. J. Org. Synth. Coll. Vol . 9 , 1998, 387. 35. Corey, E. J.; Huang, H.-C. Tetrahedron Lett. 1989, 30 , 5235. 36. Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Proc. Natl. Acad. Sci. USA, 2004, 101 , 12058. 37. Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem. 2006, 71 , 4625. 38. Kozlowski, M. C.; Waters, S. P.; Skudlarek, J. W.; Evans, C. A. Org. Lett. 2002, 4 , 4391. 39. Kozlowski, M. C.; Panda, M. J. Org. Chem. 2003, 68 , 2061.

3.2. Silicon Allylation Reaction Although the addition of allylic trialkylsilanes to carbonyl compounds is analogous to the reaction of allylboranes, it occurs through an acyclic transition state.1 This is because, in contrast to the boranes, the silicon in allylic trialkylsilanes is a poor Lewis acid and would not be expected to coordinate to the carbonyl oxygen. The transition state changes, however, to a closed one when the silicon becomes sufﬁciently Lewis acidic, owing to incorporation of electronegative ligand into the silicon atom.2 Evidence for a closed transition-state model was gathered on the basis of the diastereoselectivity in reactions of pentacoordinate allylic silicates. Bis(1,2benzenediolato)allylsilicates 1a and 1b, which can be prepared via the reactions of E - and Z -crotyltrichlorosilanes with dilithium catecholate, react with aromatic aldehydes to give the corresponding homoallylic alcohols 2 in high yields3 (Scheme 3.2a). Unlike allyltrimethylsilane,4 the allylation reactions of

128

METAL ALLYLATION REACTIONS

γ OLi

SiCl3

Me +

OLi

R2

α

or

rt, 1 h

Li

O O Si O O

THF

Me

−

R1

SiCl3

+

1a, R1 = Me, R2 = H 1b, R1 = H, R2 = Me Silicate 1a (E/Z = 88:12) 1b (E/Z = 21:79)

anti/syn 88:12 22:78

Yield, % 82 91

reflux, 90 h, PhCHO THF

OH

OH

Ph

Ph Me

Me

2-anti

2-syn

Scheme 3.2a

O E-silicate

favored

H Me H

Ph

Si O O O

OH workup

Ph Me anti

O

TS A

O Z-silicate

favored

H H Me

Ph

Si O O O

OH workup

Ph Me syn

O

TS B

Scheme 3.2b

the allylsilicates 1 do not require external Lewis acids. The reactivity difference is due to the enhanced Lewis acidity of silicon in the silicates 1 over that in allyltrimethylsilane.5 The pentacoordinate allylsilicates 1 show an extremely high level of diastereoselectivity in the crotylation reaction. For instance, when the crotylsilicate 1a with an E /Z ratio of 88 : 12 was used, the corresponding

REACTIONS

OH

O +

silane

129

OH

0°C, 2 h R

H

(E/Z = 97:3)

R Me 3-syn

Me 3-anti

R

syn/anti

Yield, %

C6H5

3:97

89

PhCH2CH2

3:97

87

c-C6H11

4:96

83

C6H5

>99:1

82

PhCH2CH2

>99:1

90

97:3

85

Silane SiCl3

R

DMF

SiCl3 (E/Z = <1:>99)

c-C6H11

Scheme 3.2c

DMF SiCl3

H

RCHO DMF

Si Cl Cl O Cl

Me

E-silane

H

R

OH workup

R Me anti

TS A DMF SiCl3

DMF

Z-silane

H

RCHO

H Me

R

Si Cl Cl O Cl

OH workup

R Me syn

TS B

Scheme 3.2d

homoallylic alcohols 2 were obtained with an anti /syn ratio of 88 : 12. The crotylsilicate 1b, rich in (Z )-isomer (E /Z = 21 : 79) afforded the alcohol 2 in an anti /syn ratio of 22 : 78. Thus, the reaction is extremely stereoselective, giving anti and syn-homoallylic alcohols from the E - and Z -crotylsilicates, respectively.

130

METAL ALLYLATION REACTIONS

OH

O silane

+

OH

CsF, THF

R

H

R

R Me 5-syn

4

R

Temperature (Time)

syn/anti

Yield, %

C 6H 5

0°C (1 h)

1:99

92

n-C8H17

rt (4 h)

1:99

96

C 6H 5

0°C (1 h)

99:1

96

n-C8H17

rt (5 h)

92:2

89

Silane SiF3 (4E; E/Z = 99:1)

SiF3 (4Z; E/Z = 1:99)

Me 5-anti

Scheme 3.2e

SiF3

H

favored

Me E-silane

SiF3

H

R

favored

H

Me

OH workup

R Me anti

TS A

H Z-silane

F Si F F O F

R

F Si F F O F

OH workup

R Me syn

TS B

Scheme 3.2f

These diastereoselective reactions of pentacoordinate crotyl silicates are reminiscent of those of allylboronates.6 Consequently, the stereoselectivity of the silicon crotylation is similarly interpreted by the six-membered chairlike transition state (Scheme 3.2b). Transition state A, in which the silicon of the (E )crotylsilicate is now hexacoordinated and the phenyl group of benzaldehyde occupies an equatorial position, would give the major anti -product. Similarly, the (Z )-silicate affords the syn-product through transition state B. The silicons in transition states A and B are presumably strongly electron donating to the π-allyl system, thus enhancing the nucleophilicity of the γ-carbon of the allylsilicates. This explains the exclusive formation of the γ-adduct.

REACTIONS

F H

favored

F F

O

OH

TS A: 0 kcal/mol

CsF

SiF3

F Si

H 3C

131

H 3C

CH3CHO

F CH3

disfavored

F Si

F

F O H TS B: 18.7 kcal/mol

Scheme 3.2g

O OH

OH

OH

Et3N, THF, rt, 14 h

SiF3

HO

HO

6-anti

6-syn

(4E; E/Z = 97:3) or, SiF3 HO

Et3N, THF, reflux, 30 h

(4Z; E/Z = 5:95)

3

a b

97:3 5:95

OH

OH

7-anti

7-syn

Silane Ketonea syn/antib Yield, % (6) Silane HA HA

Ph

2

OH Ph

4E 4Z

Ph

Ph

O Ph

HO

Ph

83 87

4E 4Z

Ketonea

syn/antib

Yield, % (7)

BZ BZ

97:3 5:95

71 75

HA is α-hydroxy acetone and BZ is benzoin. The ratios of 2,3-syn to 2,3-anti. The 1,2-anti diol was not observed within the product from either 4E or 4Z.

Scheme 3.2h

Similar to crotylsilicates, crotyltrichlorosilanes react regioselectively with aldehydes in N ,N -dimethylformamide (DMF) without a catalyst to afford the corresponding homoallylic alcohols in high yields (Scheme 3.2c).7 New carbon– carbon bond formation takes place only at the γ-positions of the crotyltrichlorosilanes. In addition, syn-isomers are obtained from Z -crotyltrichlorosilanes, while

132

METAL ALLYLATION REACTIONS

HH favored

SiF3 +

O

H

Ph

Ph

H

Ph

Si F + Et3NH TS B O

MAJOR

HO

F −

O

Ph OH

F + Et3NH TS A

Ph

Ph

HO F

O

HH disfavored

F − Si

Et3N

OH

Ph

O

Ph

Ph Ph

F OH minor (not observed)

Scheme 3.2i

anti -isomers are produced from E -crotyltrichlorosilanes with near-perfect selectivity. Another synthetically useful feature of the reaction is that aromatic and aliphatic aldehydes exhibit the same degree of stereoselectivity. The intermediate and key species proposed for the reaction in Scheme 3.2c are hypervalent silicates based on the silicon NMR spectra of (Z )-crotyltrichlorosilane in DMF. This hypervalent silicate has sufﬁcient Lewis acidity based on the electron-withdrawing chlorine groups as well as nucleophilicity due to electron donation from the hypervalent silicon atom to the allyl systems, which enables the reaction to proceed smoothly. Thus, the high levels of diastereoselectivity can be explained by a six-membered cyclic transition state (Scheme 3.2d). Another successful method for the highly diastereoselective silicon allylation reaction is the allyltriﬂuorosilane– cesium ﬂuoride system discovered by Sakurai et al. in 19878 (Scheme 3.2e). After a mixture of aldehyde,the allylic triﬂuorosilane 4, and cesium ﬂuoride in a ratio of 1:2:2.3 was stirred in THF, the reaction mixture was quenched with a solution of HCl in MeOH to afford the products desired (5) in excellent yield and exceptionally high diastereoselectivity. In addition, the reaction is highly regioselective in that the carbon–carbon bond formation occurs exclusively at the γ-carbon of allylic silanes. The regioselectivity and diastereoselectivity can be interpreted in terms of a six-membered chairlike transition state8 (Scheme 3.2f). Thus, the nucleophilic attack of a ﬂuoride anion to an allyltriﬂuorosilane may afford a rather stable pentacoordinate allylsilicate, which then reacts with an aldehyde via a cyclic six-membered transition state. The high level of regioselectivity of the reaction is presumably due to the enhanced nucleophilicity of the γ-carbon of the allylsilicate. In an effort to explain the high levels of diastereoselectivity observed in the crotylation reactions, Sakurai et al. performed a computational study on the

REACTIONS

133

R H3C OH

O

TBDPSO

O

SiF3

H

4-Å MS, i-Pr2NEt (75%)

H

F Si F F

O

H CH3

9

9TS O

O

TBDPSO

O

1. 2-methoxypropene, PPTS 2. OsO4 (94%, 2 steps)

H

1. Li

OH

10

dr = 93:7

TBDPSO

3. NaIO4 (90%)

11

2. H2, Pd/C (84%) 3. BOM-Cl, i-Pr2NEt (86%)

OH

O O 12 (73%)

OH OH OH 7

O

O

H

O

TBDPSO

7

HO2C

OCH2OBn

O

13

H OH

16

O dr = 86:14

16

8, zincophorin

Scheme 3.2j

reaction of acetaldehyde with allyltriﬂuorosilane9 (Scheme 3.2g). In the transition states calculated, the geometry around the silicon atom is octahedral and the allyl group of the hexacoordinate silicate occupies the equatorial position of the octahedral geometry. The calculations indicate that transition state A, in which the methyl group occupies an equatorial position, is a lot more stable than transition state B, by 18.7 kcal/mol. The destabilization in B is presumably caused by the nonbonding interactions between the axially oriented methyl group and the Si–F bond. The computational study described above explains the extremely high diastereo selectivity observed with the (E )- and (Z )-crotylsilanes and further conﬁrms the legitimacy of the six-membered chairlike transition state in the allylation reaction with the pentacoordinate allyltriﬂuorosilane. In 1989, Sakurai et al. reported that allyltriﬂuorosilanes react with a variety of α-hydroxy ketones in the presence of stoichiometric amount of triethylamine to yield the corresponding tertiary homoallylic alcohols in an extremely high regioand diastereoselective manner10 (Scheme 3.2h). Upon reacting with α-hydroxy acetone, the (E )-crotylsilane 4E gave 6-syn as a major product in 83% yield with

134

METAL ALLYLATION REACTIONS

OH

O silane +

Ph

Silane

ligand (15 or 16)

H

+

Ph

−78°C, CH2Cl2

Major Product

OH Ph

Me 14-syn

Me 14-anti

ee, %a (syn/anti)

Yield, %a

ee, %b (syn/anti)

Yield, %b

60

81

87

85

66 (2:98)

68

86 (1:99)

82

60 (98:2)

72

OH

SiCl3 Ph

OH SiCl3 Ph

(E/Z = >99:1)

Me OH

SiCl3 Ph (E/Z = <1:>99) a b

Me

94 (99:1)

89

One equivalent of 15 was used. 5 mol% of 16 was used. Me N O P N N Me

H H

N N

N

O

O P

P N Me

(S,S)-15

N N Me

H H

(R,R)-16

Scheme 3.2k

a syn/anti ratio of 97 : 3, while the (Z )-isomer 4Z resulted in the formation of 6-anti in 87% yield with a syn/anti ratio of 5 : 95. An additional stereoselectivity was discovered when the crotylsilanes reacted with α-substituted-α-hydroxy ketones such as benzoin. The diols 7-syn and 7-anti were obtained in good yields and with perfect levels of 1,2-diastereoselectivity from the reactions of (E )- and (Z )-crotylsilanes, respectively. The stereochemical outcome of the reaction above is explained in terms of a structurally rigid 1,3-bridged six-membered chairlike transition state (Scheme 3.2i). Transition state B would be disfavored relative to transition state A because the phenyl group of benzoin is engaged in nonbonded interactions with the methyl and the hydrogen of the crotylsilane. Although β-hydroxy ketones are inert toward allyltriﬂuorosilanes under the reaction conditions mentioned above,10 β-hydroxy aldehydes do react with allylic

REACTIONS

H

H H H

H favored

N

P

Me N

N

si-face

O

N N N 5N P P N N O Cl O O Si Ph

135

OH

H Ph

MAJOR

Cl

H PhCHO

TS A Cl3Si

Me N N

O P

H

N

H

disfavored re-face

H H

H N H N N 5N P P N N O Cl O O Si Ph

(R,R)-16

Cl

OH Ph minor

H

TS B

Scheme 3.2l

OH

O

Ph + Me

H

Ph

SiCl3

ligand (S,S)-16 −78°C, CH2Cl2 (64%)

18

O

N N

OMe

Ph Ph Me 19 (94% ee; 98% de)

H H

Ph Me 17, LY426965

N N

N

O

O

P

P N Me

N N Me

H H

(S,S)-16

Scheme 3.2m

triﬂuorosilanes to afford products with high levels of diastereoselectivity. In the synthesis of the C7 –C16 segment 13 of the ionophore antibiotic zincophorin 8, Chemler and Roush performed a reaction of α-methyl-β-hydroxy aldehyde with (Z )-crotyltriﬂuorosilane to assemble an anti,anti -dipropionate stereotriad11 (Scheme 3.2j). The chiral aldehyde 9 reacted with (Z )-crotyltriﬂuorosilane to give the desired isomer (10) in 93 : 7 selectivity. The reaction presumably proceeds

136

METAL ALLYLATION REACTIONS

Ph

H N

TMSO

RCHO (2 equiv) TMSOTf (0.1 equiv);

CF3

SiMe3, −78°C

O

R

Ph O

CF3 O

21

20

Na, NH3

1. CF3CO2Me 2. TMSCl, Et3N

R

Ph HO

H N

NH2

OH 22

(1R, 2R)-norpseudoephedrine Yield, % R CH3 (CH2)7CH3 CH(C2H5)2 c-C6H11 t-C4H9 C6H5 C6H4-p-OMe a

de, % (21) >99 >99 >99 90 >99 56 96

21 52 65 71 49 55 73 80

22 —a 87 88 90 82 0 75

The yields were not reported.

Scheme 3.2n

through the bicyclic transition state 9TS, in which the β-hydroxyl group of 9 is coordinated to the silicon center of the (Z )-crotyltriﬂuorosilane, which requires that the aldehyde alkyl substituent adopt an axial position in the six-membered transition state 9TS. The crotylsilane would then attack opposite to the aldehyde α-methyl group, resulting in a highly anti -selective crotylation.12 Protection of 10 as an acetonide, dihydroxylation of the terminal oleﬁn, and oxidative cleavage of the resulting diol afforded the aldehyde 11. The reaction of compound 11 with the vinyllithium species 12 proceeded in 86 : 14 selectivity to furnish the major diastereomer, which was subjected to hydrogenation and alcohol protection to provide the known C7 –C16 segment 13 of zincophorin.13 Asymmetric allylation and crotylation reactions using allylic trichlorosilanes and chiral phosphonamides were developed by Denmark and coworkers in 1994 and further reﬁnement of the chiral ligands system was made in 200114 (Scheme 3.2k). The inﬂuence of the six-membered chairlike transition state is once again evidenced by the excellent correlation of the geometry of the reacting silanes with the diastereomeric composition of the products. Thus, anti -isomer is obtained from the E -allylic silane, and syn-isomer is produced from the Z -silane. Based on

137

REACTIONS

silane

+

R

OH

OH

O

1. 130°C, 24 – 48 h

H

R

R

2. aq. HCl

n-Pr 24-anti

n-Pr 24-syn

23 Silane

Si Ph 23a

Si Ph 23b

n-Pr

n-Pr

Si Ph 23c

R

syn/anti

Yield, %

Ph

—

85

n-C6H13

—

58

Ph

5:95

68

n-C6H13

10:90

59

Ph

95:5

66

n-C6H13

80:20

60

Scheme 3.2o

OH Si Ph

n-Pr

H

favored RCHO

Si

n-Pr

E-silane

H

workup

R

Ph

O

R

n-Pr anti

TS A OH

n-Pr

Si Ph

Z-silane

H

favored RCHO

H R n-Pr

Si O

workup

Ph

R n-Pr syn

TS B

Scheme 3.2p

experimental data,15a Denmark et al. proposed a closed six-membered chairlike transition state in rationalizing the enantioselectivity realized with the bisphosphonamide 1615b (Scheme 3.2l). Transition state B would be disfavored because the phenyl ring is experiencing a steric collision with a forward-pointing pyrrolidine

138

METAL ALLYLATION REACTIONS

Ph

OH

Ph

SiCl3 Et3N, CH2Cl2

Me

NH Me (1S,2S)-pseudoephedrine

Me

O Si N Cl Me

OH RCHO toluene, −10°C, 2 h

R 26

(S,S)-25 (dr 2:1) R Ph PhCH CH PhCH2CH2 c-C6H11 t-C4H9 BnOCH2

ee, % 81 78 88 87 96 88

Yield, % 80 59 84 70 80 85

Scheme 3.2q

p-BrC6H4

OH

O N

+

Si N

R

CH2Cl2

H

−10°C, 20 h

R 28

Cl p-BrC6H4

(R,R)-27

NH2 NH2

R PhCH2CH2 c-C6H11 BnOCH2 Ph p-MeOC6H4 PhCH CH

ee, % 98 96 97 98 96 96

Yield, % 90 93 67 69 62 75

(1R,2R)1,2-diaminocyclohexane

Scheme 3.2r

ring. In the favored transition state, A, the allyl group transfer occurs on the si -face of the benzaldehyde to deliver the major enantiomer. Denmark utilized the asymmetric allylation methodology in the synthesis of the serotonin antagonist LY426965 (17), preclinical studies of which suggest its pharmacotherapy use for smoking cessation and depression-related disorders16 (Scheme 3.2m). The key intermediate alcohol (19) was prepared in 94% ee via the asymmetric addition of the silane 18 to benzaldehyde in the presence of the chiral ligand (S ,S )-16. In 1992, Tietze et al. discovered an elegant method for the direct and simple preparation of homoallylic ethers with excellent de values ( > 99%) using the

REACTIONS

p-BrC6H4 Cl3Si

OH Me

N

Me

Si

DBU CH2Cl2, 0°C (76%)

Cl

N

139

RCHO CH2Cl2 0°C, 20 h

R Me 31-syn

p-BrC6H4 (R,R)-30Z

p-BrC6H4 NH NH 29

p-BrC6H4 p-BrC6H4 OH Cl3Si

N

Me

Me

Si

DBU CH2Cl2, 0°C (69%)

N

Cl

RCHO CH2Cl2 0°C, 20 h

R Me 31-anti

p-BrC6H4 (R,R)-30E 31-syn (w/30Z)

R PhCH2CH2 c-C6H11 Ph p-CF3C6H4 PhCH CH

31-anti (w/30E)

ee, %

Yield, %

ee, %

Yield, %

97 97 95 96 95

83 67 67 61 67

98 97 93 96 94

81 68 54 60 52

Scheme 3.2s

trimethylsilyl ether derivative 20 of (1R,2R)-N -triﬂuoroacetylnorpseudoephedrine17 (Scheme 3.2n). After aldehydes and the TMS ether 20 were stirred for an ◦ hour at –78 C in the presence of a catalytic amount of TMSOTf, the resulting ◦ mixture was treated with 2 equivalents of allyltrimethylsilane at –78 C for 48 hours. The homoallylic ethers 21 were obtained after workup with nearby perfect diastereoselectivity and in good yields. The homoallylic alcohols 22 were then obtained by reductive cleavage of the chiral auxiliary in 21 with sodium in liquid ammonia. One limitation to Tietze’s method is that 1-phenyl-3-buten-1-ol (22, R = Ph) cannot be obtained, due to the incompatibility of the reductive cleavage protocol with the corresponding ether (21, R = Ph).

140

METAL ALLYLATION REACTIONS

Cl H favored

H N

Si

H 3C

O

si-face

MAJOR H

CH3 N Si N Cl CH3

OH

N

CH3

TS A: 0 kcal/mol

CH3CHO

Cl

(R,R)-32 disfavored

H

re-face

OH

H N

Si

N

O H3C

H3C minor

H

TS B: 1.5 kcal/mol

Scheme 3.2t

The incorporation of silicon into a strained ring provides another avenue for allowing allylsilane reagents to participate in six-membered transition states. Although allyldimethylphenylsilane did not add to benzaldehyde even after heat◦ ing at 160 C for 24 hours, 1-allyl-1-phenylsilacyclobutane (23a) did react with ◦ benzaldehyde at 130 C to provide the homoallylic alcohol 24 in 85% yield18 (Scheme 3.2o). Not only do the allylic silacyclobutanes undergo allylation reactions with aldehydes, but the corresponding (E )- and (Z )-crotylsilacyclobutanes (23b, 23c) exhibit a high level of diastereoselectivity in the addition reactions. Thus, (E )-1-(2-hexenyl)silacyclobutane (23b) reacts with benzaldehyde to provide the corresponding anti -homoallylic alcohol 24-anti as a major product in high anti /syn (95 : 5) diastereoselectivity. Similarly, (Z )-1-(2-hexenyl)silacyclobutane (23c) affords a product (24-syn) with an excellent level of diastereoselectivity. The stereochemical outcome of allylic silacyclobutanes is explained in terms of a six-membered chairlike transition state18 (Scheme 3.2p). The aldehyde would coordinate to the Lewis acidic silicon19 to form a pentacoordinated complex, from which the allyl group transfer occurs subsequently to give homoallylic alcohols. In transition states A and B, the aryl or alkyl group (R) of the aldehydes prefers to occupy an equatorial position to produce anti - and syn-alcohols from the (E )and (Z )-allylic silacyclobutanes, respectively. Hinted at by Tietze’s work and based on the phenomenon that four- or ﬁve-membered cyclic silicon compounds exhibit substantial Lewis acidity for

141

REACTIONS Ph

CHO Me

MeO

O Si N Cl H (69%)

OH 35

(77%, 2 steps)

OHC

OMe

OTBS

1. 35 2. TBSOTf, 2,6-lutidine

OH

34

36 (94% ee) OMe O

OH

37 (dr 17:1)

OMe N H

OH O

AcO

OTBS O

(81%, 2 steps) 1. O3; Ph3P 2. Ac2O, Et3N, DMAP

HO OHC O OH

O

OH

38

33, psymberin

Scheme 3.2u

uncatalyzed allylation reactions, Leighton et al. designed a pseudoephedrinederived allylsilane reagent (25). Treatment of (1S,2S )-pseudoephedrine with allyltrichlorosilane afforded 25 as an inseparable 2 : 1 mixture of diastereomers in 88% ◦ yield20 (Scheme 3.2q). Reaction of 25 with benzaldehyde in toluene at –10 C generated the corresponding homoallylic alcohol with enantioselectivity of 81% ee. Although the reagent 25 is only moderately effective with aromatic and conjugated aldehydes, the levels of enantioselectivity are generally satisfactory for a range of aliphatic aldehydes. Kubota and Leighton later introduced a diamine-based strained silacycle (27) as an enatioselective allylation reagent. Upon reaction with aldehydes, 27 provides chiral homoallylic alcohols in good-to-excellent yields and, more important with uniformly excellent levels of enantioselectivity with both aliphatic and aromatic aldehydes21 (Scheme 3.2r). Leighton et al. developed two diamine-based reagents, 30E and 30Z , for aldehyde crotylation reactions22 (Scheme 3.2s). Both crotylsilane reagents are easily prepared in bulk and provide the homoallylic alcohols with excellent diastereo- and enantioselectivity. The diamine 29 reacts with cis- and trans-crotyltrichlorosilanes in the presence of 2 equivalents of DBU to generate reagents (R,R)-30Z and (R,R)-30E , respectively. When a variety of aliphatic, aromatic, and α,β-unsaturated aldehydes are treated with the crotylsilane reagent 30Z , the corresponding syn- diastereomers are obtained in good to excellent diastereoselectivities and greater than 95% ee. Similarly, the reagent 30E reacts with a wide range of aldehydes to afford anti -diastereomers with excellent enantioselectivity. Houk et al. performed a theoretical study on the asymmetric silicon allylation reaction to rationalize the high levels of enantioselectivity realized with

142

METAL ALLYLATION REACTIONS

pBrC6H4

OH

N

+

Si

O

O

CH2Cl2 −50 to 0°C (78%)

O

Cl

N

CHO

O

Br OMe

pBrC6H4 40

Br OMe 42 (96% ee)

41 Br

O O

O

TBSO

Ph

O O

OMe 43 3. 43, Pd(PPh3)4, Ph3P (72%, 2 steps)

O

O O

O O

1. TBSCl, 2,6-lutidine (98%) 2. 9-BBN

Br OMe

MeO

O O

O O 39, interiotherin A

44

Scheme 3.2v

Leighton’s silicon reagent, (R,R)-3223 (Scheme 3.2t). Calculations indicate that the reaction occurs in a single concerted step through a six-membered chairlike transition state with a pentacoordinate silicon. The two transition states, A and B, are of the lowest energies that can explain the formation of each enantiomer. Transition StateA is the lowest-energy transition state because the methyl group of the acetaldehyde occupies an equatorial position in the chairlike transition state and the lone-pair electrons of the nitrogen directly opposite the aldehyde are pointing downward to avoid electronic collision with the lone pair electrons of the chlorine atom. In Transition State A, the allyl group transfer occurs to the si -face of acetaldehyde to afford the major enantiomer observed experimentally. Transition state B which would lead to the formation of a minor enantiomer, is less stable than A by 1.5 kcal/mol, due to the unfavorable electron repulsion between the lone-pair electrons of the nitrogen and chlorine atoms. De Brabander et al. employed Leighton’s silane reagent in the synthesis of psymberin 33, which shows exceptional cell line–speciﬁc cytotoxicity24 (Scheme 3.2u). The monoprotected dialdehyde 34 underwent asymmetric allylation reaction using Leighton’s chiral silane reagent 35 with deprotection during workup to give 36 with 94% ee. A second allylation performed on the aldehyde 36 (dr 17 : 1) followed by monosilylation, furnished compound 37. Ozonolysis of 37 afforded

REACTIONS

p-BrC6H4 N Si N Cl

46, CH2Cl2, −20°C (80%)

OH

PMBO

143

O

O H

p-BrC6H4

47 (98% ee)

48

46

(S,S)-27 p-BrC6H4

O

1.

Si N

OPMB H

N

2. NaH, PMBBr (53%, 2 steps)

Cl

49 (88% ee) p-BrC6H4 (R,R)-30Z OH

OH

OAc

O

O

HO

O

OAc n-Pr

PMBO

H

O O

50

OH OH 45, dolabelide D

Scheme 3.2w

a lactol, which was then protected as an acetate (38), from which psymberin was synthesized. The total synthesis of dibenzocyclooctadiene lignan natural product interiotherin A (39) involved a novel crotylation sequence using the Leighton silane auxiliary25 (Scheme 3.2v). Thus, the addition of the chiral tiglylsilane 40 to the aldehyde 41 occurred smoothly to afford the anti -adduct 42 with complete diastereoselectivity and excellent enantioselection (96% ee). Protection of the benzylic hydroxyl group of 42 as the tert-butyldimethylsilyl ether followed by hydroboration of the alkene moiety with 9-BBN furnished the corresponding primary alkylborane, which was then without isolation subjected to a reaction with the aryl bromide 43 under the standard Suzuki–Miyaura coupling conditions to provide 1,4-diarylbutane (44). Leighton et al. used chiral allylsilane and crotylsilane reagents to synthesize two key intermediates, 48 and 50, in the total synthesis of dolabelide D (45), a 24-membered macrolide with cytotoxicity against HeLa-S3 cells26 (Scheme 3.2w). Asymmetric allylation of the aldehyde 46 with the chiral reagent (S ,S )-27

144

METAL ALLYLATION REACTIONS

proceeded smoothly to give 47 in 80% yield and 98% ee. The crotylation of methacrolein with (Z )-crotylsilane (R,R)-30Z and subsequent protection of the resulting alcohol as a p-methoxybenzyl (PMB) ether provided 49 in 53% yield and 88% ee. REFERENCES 1. Hayashi, T.; Kabeta, K.; Hamachi, I.; Kumada, M. Tetrahedron Lett. 1983, 24 , 2865. 2. For reviews on silicon allylation reactions, see (a) Hosomi, A. Acc. Chem. Res. 1988, 21 , 200, (b) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev . 1997, 97 , 2063, (c) Miura, K.; Hosomi, A. In Main Groups Metals in Organic Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, Denmark, 2004; Chapt. 10. 3. Kira, M.; Sato, K.; Sakurai, H. J. Am. Chem. Soc. 1988, 110 , 4599. 4. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17 , 1295. 5. Fleischer, H. Eur. J. Inorg. Chem. 2001, 393. 6. For reviews on the hypervalent silicon compounds, see (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev . 1993, 93 , 1371; (b) Rendler, S.; Oestreich, M. Synthesis 2005, 1727. 7. (a) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59 , 6620; (b) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34 , 3453. 8. (a) Kira, M.; Kobayashi, M.; Sakurai, H. Tetrahedron Lett. 1987, 28 , 4081; (b) Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989, 30 , 1099. 9. Kira, M.; Sato, K.; Sakurai, H.; Hada, M.; Izawa, M.; Ushio, J. Chem. Lett. 1991, 387. 10. Sato, K.; Kira, M.; Sakurai, H. J. Am. Chem. Soc. 1989, 111 , 6429. 11. Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998, 63 , 3800. 12. Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68 , 1319. 13. (a) Danishefsky, S. J.; Selnick, H. G.; DeNinno, M. P.; Zelle, R. E. J. Am. Chem. Soc. 1987, 109 , 1572; (b) Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. J . Am. Chem. Soc. 1988, 110 , 4368. 14. (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59 , 6161; (b) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123 , 9488. 15. (a) Denmark, S. E.; Fu, J.; Coe, D. M.; Su, X.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 2006, 71 , 1513; (b) Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem. 2006, 71 , 1523. 16. Denmark, S. E.; Fu, J. Org. Lett. 2002, 4 , 1951. 17. (a) Tietze, L. F.; D¨olle, A.; Schiemann, K. Angew. Chem. Int. Ed . 1992, 31 , 1372; (b) Tietze, L. F.; Wulff, C.; Wegner, C.; Schuffenhauer, A.; Schiemann, K. J. Am. Chem. Soc. 1998, 120 , 4276. 18. Matsumoto, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1994, 59 , 7152. 19. (a) Myers, A. G.; Kephart, S. E.; Chen, H. J. Am. Chem. Soc. 1992, 114 , 7922. (b) Denmark, S. E.; Griedel, B. D.; Coe, D. M. J. Org. Chem. 1993, 58 , 988. 20. Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124 , 7920. 21. Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed . 2003, 42 , 946.

REACTIONS

145

22. Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6 , 4375. 23. Zhang, X.; Houk, K. N.; Leighton, J. L. Angew. Chem. Int. Ed . 2005, 44 , 938. 24. Jiang, X.; Garcia-Fortanet, J.; De Brabander, J. K. J. Am. Chem. Soc. 2005, 127 , 11254. 25. Coleman, R. S.; Gurrala, S. R.; Mitra, S.; Raao, A. J. Org. Chem. 2005, 70 , 8932. 26. Park, P. K.; O’ Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128 , 2796.

4

Stereoselective Reductions

GENERAL CONSIDERATIONS Since the discovery of sodium borohydride (NaBH4 ) in 1942 and lithium aluminum hydride (LiAlH4 ) in 1945, the reduction of carbonyl compounds has become one of the most versatile reactions in organic synthesis.1 Many variants of these two metal hydrides have been created to provide synthetic organic chemists with a means to access organic compounds with a variety of functional groups.2 Lithium aluminum hydride is a powerful reagent for reducing ketones to alcohols.3 In 1976, Ashby and Boone conducted a series of kinetic experiments to better understand the mechanism of lithium aluminum hydride reduction of ketones. They observed that the rate of reduction depends on the type of countercation associated with aluminum hydride4 (Scheme 4.I). When the mesityl phenyl ketone 1 was treated with lithium and sodium aluminum hydrides in THF ◦ at 25 C, LiAlH4 reacted 10 times faster than NaAlH4 to produce the alcohol 2. Based on the accompanying kinetic data and an observation that lithium cation is essential in the lithium aluminum hydride reduction,5 Ashby and Boone proposed that the reduction would occur via a six-membered transition state in which the lithium cation is involved4 (Scheme 4.II). Because the aluminum in the boat transition state TS-boat is proximal to the carbonyl oxygen, the boat transition state might be of lower energy than the chairlike transition state TS-chair. Furthermore, the boatlike transition state would be a favored states as it results in direct formation of the lithium alkoxyaluminum hydride intermediate. Ashby and Boone’s proposed mechanism was not veriﬁed until 2001, when Luibrand et al. carried out a theoretical study on the lithium aluminum hydride reduction of formaldehyde6 (Scheme 4.III). Two types of complexes are possible between formaldehyde and LiAlH4 , depending on the geometry of LiAlH4 ; complex A is from tridentate η3 -LiAlH4 , and complex B is from bidentate η2 -LiAlH4 .7 Calculations indicate that the intermediate product OLiAl would be formed via six-membered transition state A, derived from complex A, which is more stable than transition state B by 2.0 kcal/mol.

Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

147

148

STEREOSELECTIVE REDUCTIONS

OH

O THF, 25°C;

+

MAlH4

then H2O

2

1 M

Rel. Rate

Li Na

10 1

Scheme 4.I

R1 H O

favored

R2 H LiAlH4

R

Li H

H

O 1

Al

R

TS-boat

Li

+

O

−

AlH3

2

R1 disfavored

O R1

H R2

R2

OH

H2O

R1

R2

H Li Al H H

TS-chair

Scheme 4.II

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were ﬁrst (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-O-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlH4 , the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantioselectivity in the reduction of acetophenone to 70% ee with an ethanol-modiﬁed lithium aluminum hydride–sugar complex.10 Since the seminal work by Tatchell’s group, many efforts have been directed to developing a highly enatioselective reduction of ketones.11 One successful

149

GENERAL CONSIDERATIONS

H H H

Li

Li Al

O

H

Al

H

H

Al

O H

H

H H

complex A

η3-LiAlH4

H

Li

H

H

H

H

H

complex B

H Li

H Al H

H η2-LiAlH4 Li O

favored via complex A

O H

H

H

H Al

H

H

H H

Li O

TS A: 0.0 kcal/mol

LiAlH4

H Al

H H Li O

disfavored

Al H

via complex B

H

H

TS B: 2.0 kcal/mol

H

H

H H

H

OLiAl

H + − Li O AlH3 H

H

H

Scheme 4.III

system is the one reported by Jacquet and Vigneron in 1974.12 The chiral complex 5, generated by reacting lithium aluminum hydride with 1 equivalent of (−)-N -methylephedrine and 2 equivalents of 3,5-dimethylphenol, has been used in the asymmetric reduction of ketones (Scheme 4.V). The chiral alcohol 6 was obtained with high levels of enantioselectivity for a variety of phenyl alkyl ketones. Further improvements have been made in the design of chiral reducing reagents incorporating lithium aluminum hydride. A highly enantioselective chiral reagent is the one developed by Noyori, discussed in Section 4.3.

150

STEREOSELECTIVE REDUCTIONS

HO LiAlH4, Et2O

O

H HO

O

O

O HO

reflux, 3 h

O

O

O Al O H H H

O Li

OH

ketone, Et2O

−

reflux, 3 h

Me

R

+

4

3 Ketone

ee, %

Yield, %

t-BuCOMe PhCOMe

5.2 14.3

52 66

Scheme 4.IV

Ph

Me

HO

NMe2

Ph

(1 equiv)

LiAlH4

+

Li HO (2 equiv)

H

O − Al

Me NMe2

O Ph

OH

R

−15°C, THF

Ph

R 6

OAr OAr 5 R CH3 C2H5 n-C3H7 n-C4H9

ee, % 83 85 89 78

Scheme 4.V

REFERENCES 1. (a) http://nobelprize.org/nobel prizes/chemistry/laureates/1979/brown-lecture.pdf; (b) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35 , 567. 2. Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd ed.; Wiley-VCH: New York, 1997. 3. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin-Cummings: Menlo Park, CA, 1972; Chap. 2. 4. Ashby, E. C.; Boone, J. R. J. Am. Chem. Soc. 1976, 98 , 5524. 5. Pierre, J. L.; Handel, M.; Perrand, R. J. Tetrahedron 1975, 31 , 2795. 6. Luibrand, R. T.; Taigounov, I. R.; Taigounov, A. A. J. Org. Chem. 2001, 66 , 7254. 7. Demachy, I.; Volatron, F. Inorg. Chem. 1994, 33 , 3965.

151

REACTIONS

8. (a) Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall: London, 1971; pp. 177–202; (b) Mosher, H. S.; Morrison, J. D. Science 1983, 221 , 1013; (c) Yoon, N. M. Pure Appl. Chem. 1996, 68 , 843; (d) Cho, B. T. Aldrichimica Acta 2002, 35 , 3. 9. Landor, S. R.; Miller, B. J.; Tatchell, A. R. Proc. Chem. Soc. 1964, 227. 10. Landor, S. R.; Miller, B. J.; Tatchell, A. R. J. Chem. Soc. (C) 1967, 197. 11. (a) Singh, V. K. Synthesis 1992, 605; (b) Kim, J.; Suri, J. T.; Corde, D. B.; Singaram, B. Org. Proc. Res. Dev. 2006, 10 , 949. 12. Jacquet, I.; Vigneron, J. P. Tetrahedron Lett. 1974, 15 , 2065.

REACTIONS 4.1. Diastereoselective Syn-Reduction of β-Hydroxy Ketones In 1984, Narasaka and Pai demonstrated that high levels of 1,3-asymmetric induction can be realized in the reduction of acyclic β-hydroxy ketones via boron chelates.1 Treatment of the β-hydroxy ketones 1 with tributylborane in the presence of a catalytic amount of air results in formation of the chelated dibutylboric ester complex 1BBu2 . Upon reaction with sodium borohydride at −78o C for 2 to 6 hours, syn-1,3-diols 2-syn are obtained after oxidative workup with good to high levels of ◦ diastereoselectivity (Scheme 4.1a). When the reaction is carried out at −100 C, excellent diastereoselectivity is obtained in the reduction to afford meso-undecane-5,7-diol. The high level of 1,3-asymmetric induction can be explained by considering the six-membered transition states in Scheme 4.1b.2 The hydride nucleophile prefers to attack the carbonyl group of the borane complex 1BBu2 from the top face following the B¨urgi–Dunitz trajectory.3 The

Bu OH R

O R

1

O

n-Bu3B, air

Bu B

OH

O

−78°C

THF, rt

R

OH

OH

NaBH4

R

R

R 2-syn

1BBu2

OH

R

R 2-anti

R

syn/anti

Yield, %

Ph n-C4H9

98:2 88:12 (96:4)a 73:27

86 91 90a 95

c-C6H11 aReaction

Scheme 4.1a

at −100°C.

152

STEREOSELECTIVE REDUCTIONS

H

−

H favored

Bu O

B

H R

Bu

H R

O

R

Bu B

O O

H

Bu B

H

R

O

Bu

OH Bu

R

O

R

OH R

MAJOR

TS A

R NaBH4 H

H disfavored

H R H R

Bu B

O O

R

O

R

O

OH B

Bu

OH

Bu R Bu

R minor

H TS B H

Scheme 4.1b

O

OH

OH

OH

OH

+ 4a-syn

OH

3b

OH

(95%) syn/anti = 100 : 0

3a

O

n-Bu3B, air; then NaBH4, −100°C

n-Bu3B, air; then NaBH4, −100°C

OH

4a-anti

OH

OH

OH

+

(90%) syn/anti = 73 : 27

4b-syn

4b-anti

Scheme 4.1c

resulting six-membered chairlike transition state A, in which both bulky R groups occupy an equatorial position, is more stable than transition state B.4 The approach of the hydride from the bottom face would be sterically disfavored due to the presence of the axial hydrogen of the α-carbon.1 Furthermore, the bottom attack would lead to a twist-boatlike transition state B, which is of higher energy than the chairlike transition state A, due to interactions between the R group and β-hydrogens.5 Therefore, the 1,3-syn-diols are formed as a major diastereomer via transition state A. To determine the effect of an α-substituent on the diastereoselectivity of the BBu3 /NaBH4 system, Narasaka and Pai carried out the reduction of α-methyl-β-hydroxy ketones1 (Scheme 4.1c). Whereas the α,β-syn-β-hydroxy

153

REACTIONS

OH

O R1

R 5

Et

Et2BOMe, THF, MeOH

O

−70°C, 15 min

Et B

OH

O

−78°C, 3 h

R1

R

OH

NaBH4

OH

OH

R1 R

R 6-syn

R1 6-anti

5BEt2 R Ph Ph n-C4H9

R1

syn/anti

Yield, %

Ph CH2CO2Et n-C4H9

99:1 98:2 99:1

95 85 99

Scheme 4.1d

ketone 3a underwent reduction in excellent yields and with very high stereoselectivity, the diastereomeric α,β-anti -β-hydroxy ketone 3b exhibited lower syn-selectivity. The interference of an α-substituent on the syn-diastereoselectivity is rationalized by considering the conformation of dibutylborinate complexes of 3a and 3b.1 Three years after Narasaka and Pai’s disclosure, Prasad et al. developed a modiﬁed procedure to improve syn-diastereoselectivity in the reduction of cerin lieu of tain β-hydroxy ketones6 (Scheme 4.1d). When methoxydiethylborane, ◦ tributylborane, reacts with β-hydroxy ketones at −70 C in anhydrous methanol, the complex 5BEt2 is formed. Subsequent treatment of the complex with sodium borohydride and quenching the reaction mixture with acetic acid affords syn-diols in excellent levels of diastereoselectivity regardless of the structure of β-hydroxy ketones. Another practical advantage of Prasad et al.’s modiﬁcation may be an enhanced safety feature, as methoxydiethylborane is generally less hazardous to handle than triethylborane.6 An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7 , which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the β-hydroxy-δ-lactone moiety in 7 is the highly diastereoselective reduction of the β-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The syn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. In the stereoselective synthesis of epothilone A (11), Carreira used a syn-reduction methodology in the synthesis of the key intermediate◦ (14)9 (Scheme 4.1f). Reduction of the isoxazoline 12 with samarium iodide at 0 C in THF gave the ketone 13. Narasaka reduction of the β-hydroxy ketone 13 using triethylborane/sodium borohydride afforded the syn-diol 14 in high yield and with high diastereoselectivity.

154

STEREOSELECTIVE REDUCTIONS

F

F Me

Me O

OH

O OMe

Me

OH

Et3B, NaBH4, −78°C

OH

O OMe

THF, MeOH (90%)

Me

Me

Me 10 (syn/anti = 100:1)

9

2. toluene, 1. NaOH, MeOH 90°C, 8 h

F Me

O

O

O

O

O

O

H

OH

OH Me

Me

Me

8, compactin

7

Scheme 4.1e N

O

O

Me

SmI2, THF

Me

S

OTBS

N

OTBS

N

OH

Me S

(76%)

Me TIPSO

TIPSO 12

Me

Me

13 −78°C, THF, MeOH Et3B, NaBH4 (90%)

S Me

OH

O N

OH OTBS

N OH

Me

Me S

Me

O TIPSO 11, epothilone A

O

OH

O

Me 14

Scheme 4.1f

REACTIONS

155

1. t-BuLi, HMPA, −78°C, O TBSO

O

S S

OTBS

OMe

OMe

OTBS

2. aq. H2SO4 (72%, 2 steps) 3. NBS, AgClO4 (90%)

16

O

O TBSO

O OBz O S O O 17

OBz OH

O

OMe

OTBS

OMe

OTBS

18 −78°C, THF n-Bu3B, NaBH4 (92%)

O

O TBSO

OBz OH

OH

OTBS

OMe

OTBS

OMe 19 OMe

O OH

OH O

OH

OH

O

O

OMe

MeO

O

O O HO

OH

OH

OH

O

OMe

Scheme 4.1g

15, swinholide A

156

STEREOSELECTIVE REDUCTIONS

Nicolaou et al. exercised the stereoselective syn-reduction of β-hydroxy ketones in the total synthesis of swinholide A (15), a marine natural product that displays a range of biological properties, including antifungal activity and potent cytotoxicity against a number of tumor cell lines10 (Scheme 4.1g). Treatment of 16 with t-BuLi in the presence of HMPA generated the lithio derivative of dithiane, which underwent a coupling reaction with the cyclic sulfate 17. After aqueous acid treatment and removal of the dithiane moiety with N -bromosuccinimide (NBS) and AgClO4 , the β-hydroxy ketone 18 was obtained, which upon reduction with the NaBH4 /n-Bu3 B system resulted in formation of the 1,3-syn-diol 19 in 92% yield. Fleming and Ghosh employed the β-hydroxy ketone syn-selective reduction method to synthesize the intermediate 23 during the synthesis of the nonactin 2011 (Scheme 4.1h). Treatment of the starting acid 21 with diazomethane followed by deprotection of the ketal in the presence of pyridinum p-toluenesulfonate (PPTS) furnished the β-hydroxy ketone 22, which was then reduced successfully by employing the reagents NaBH4 /Bu2 BOMe to give the syn-1,3-diol as a 90 : 10 mixture, of which the major diastereomer was separated from the minor isomer and protected as the acetonide to afford 23 in good yield. The syn-reduction methodology was utilized in the total synthesis of anachelin H (24), which was isolated from the freshwater cyanobacterium Anabaena cylindrical and postulated to serve as a bacterial growth factor facilitating iron uptake12 (Scheme 4.1i). The reduction of the β-hydroxy ketone 25 was carried out by precomplexing the substrate with Et2 BOMe, formed from Et3 B, pivalic SiMe2Tol 1. CH2N2

HO2C HO

O

2. PPTS

O

SiMe2Tol MeO2C OH

21

22 2. Me2C(OMe)2, PPTS 1. NaBH4, Bu2BOMe (68% from 21)

O O

H O H

H

O

O

H

O

SiMe2Tol MeO2C

H

O

O

20, nonactin H

23 O O

O

H

O

H

O O

Scheme 4.1h

O

REACTIONS

TBSO

OH

O

1. Et3B, pivalic acid, NaBH4, THF, MeOH

O OMe

HN

2. TBSOTf, 2,6-lutidine (68%, 2 steps)

CO2Bn

O

TBS TBS TBS O O O OMe

HN

CO2Bn 26 (dr > 97:3)

25 HO H H N

HO HO

N H 3C OH H 3C

Cl

157

O OH

O N H

HN

HN O

O

HO

N H

O

2. EDC, HOBt, NMM, 2-BnO-benzoic acid 1. H2, Pd/C, MeOH (58%, 2 steps)

OH

O

TBS TBS TBS O O O

OH

OMe HN

O OBn

HO 24, anachelin H

27

Scheme 4.1i

OR

O

OR

OH

OR

OH

Zn(BH4)2

R1

R1

Et2O, 0°C

29-syn

28

R H H H Me

R1 29-anti

R1

syn/anti

Yield, %

Ph CH2 C(Me) PhCH2CH2 Ph

25:1 25:1 1.3:1 33:1

95 91 97 99

Scheme 4.1j

acid, and MeOH, then reducing with NaBH4 . The resulting syn-diol compound was isolated in good yield and greater than 97 : 3 diastereoselectivity after subsequent TBS protection. Cleavage of the benzyloxycarbonyl group of 26 followed by condensation with O-benzyl salicylic acid afforded the intermediate 27. In 1984, Nakata and co-workers reported that zinc borohydride reduces the α-methyl-β-hydroxy or α-methyl-β-methoxy ketone 28 stereoselectively to afford

158

STEREOSELECTIVE REDUCTIONS

a syn-isomer as the major product13 (Scheme 4.1j). The levels of diastereoselectivity are exceptionally high when the ketones are conjugated. Based on the x-ray crystal structure of Cp2 Nb(CO)H·Zn(BH4 )2 ,14 Oishi and Nakata proposed that the zinc cation is coordinated to oxygens of both the alcohol and the carbonyl to form a structurally rigid six-membered chelated complex (28ZnB)15 (Scheme 4.1k). The hydride transfer occurs intramolecularly to form the zinc complex 28ZnO of the 1,3-diol product. Of the two possible transition states, A and B, transition state A would be the favored one in which the hydride transfer occurs opposite the α-methyl substituent. Transition state B would be less favorable than A, as the incoming hydride nucleophile experiences a steric interaction with the α-methyl group.16 Zinc borohydride has found many synthetic applications in the context of a “chelation-controlled” reduction.17 In the synthesis of the antibiotic tirandamycin 30, DeShong et al. prepared a key intermediate (32) via stereoselective reduction of a β-silyloxy ketone18 (Scheme 4.1l). Reduction of 31 with Zn(BH4 )2 gave the mono-TBS-protected 1,2-syn-2,3-anti -diol 32 stereoselectively. Oxidation of

OH

O

Zn(BH4)2

H H

Ph

B

H H Zn H H H O O

H H

B

Zn

L

intramolecular hydride delivery

H O

O

Ph 28ZnB

favored

OH

28ZnO

Ph O

H H

H Ph

B H

H

Zn

OH Ph

Me

H

O MAJOR

H

O

OH

TS A

Zn(BH4)2

Ph H H B disfavored

H H

H O

Zn

Me H TS B

Scheme 4.1k

OH

Ph

OH Ph

O minor

REACTIONS

Zn(BH4)2, Et2O, rt

OBn

O O

OBn

O

(80%)

OTBS

OTBS

OH

31

32 (90%)

O

O

O

H

O

(50%)

O

O

H

BnO 33

34

O

1. m-CPBA 2. aq. HF, CH3CN

TMSCl, NaI, CH3CN, rt

HO

O

159

H O O

O NH HO

30, tirandamycin

O

Scheme 4.1l

32 with m-chloroperbenzoic acid followed by deprotection afforded the bicyclic enone 33. Removal of the benzyl ether with trimethylsilyl iodide generated in situ from TMSCl and NaI then provided the alcohol 34. In 2005, Carreira et al. reported the total synthesis of erythonolide A (35), one of the most popular target molecules in organic synthesis19 (Scheme 4.1m). ◦ The syn-reduction of the hydroxy ketone 36 with Zn(BH4 )2 in CH2 Cl2 at −30 C produced the syn-diol 37 as a single diastereomer. Protection of the diol with benzaldehyde dimethylacetal in the presence of camphorsulfonic acid (CSA) gave 38 in good yield. (+)-Conagenin (39) is a promising anticancer natural product isolated in 1991 from the culture broths of Streptomyces roseosporus 20 (Scheme 4.1n). The chelation-controlled Zn(BH4 )2 reduction of the β-hydroxy ketone 40 produced the 1,3-syn-diol 41 in 30 : 1 diastereoselectivity. Protection of the hydroxyl groups gave the bis-acetate 42, which was then subjected to oxidative cleavage to afford the acid 43.

160

STEREOSELECTIVE REDUCTIONS

TBSO

O

OPMB

OH

TBSO

Zn(BH4)2, CH2Cl2, −30°C

OH

(60%)

O TES

O TES

36

OPMB

OH

37 toluene, rt, 1.5 h PhCH(OMe)2, CSA (10 mol%) (87%)

O Ph HO

OH

TBSO

OH O O

O

OH

OPMB

O O TES 38

OH

35, erythronolide A

Scheme 4.1m

OH O

Zn(BH4)2, Et2O, rt

Ph

OH OH

Ac2O, DMAP, pyridine

Ph

(70%)

40

41

dr 30 : 1

OAc OAc Ph

(98%)

42 RuCl3• n-H2O, H5IO6

CCl4/CH3CN/H2O (78%)

OAc OAc OH OH

H N

O

OH OH O 39, (+)-conagenin

OH O 43

Scheme 4.1n

REFERENCES 1. Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40 , 2233. 2. For examples of chelation-controlled reactions, see (a) Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90 , 4019; (b) Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21 , 1031; (c) Still, W. C.; Schneider, J. A. Tetrahedron Lett. 1980, 21 , 1035.

REACTIONS

161

3. (a) B¨urgi, H. B.; Dunitz, J. D.; Shefter, E. J. J. Am. Chem. Soc. 1973, 95 , 5065; (b) B¨urgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30 , 1563; (c) B¨urgi, H. B.; Lehn, J. M.; Wipff, G. J. Am. Chem. Soc. 1974, 96 , 1956. 4. For an example of a preferential axial attack of nucleophile on the oxonium ion of six-membered ring, see Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104 , 4976. 5. (a) Velluz, L.; Valls, J.; Nomine, G. Angew. Chem. Int. Ed. 1965, 4 , 181; (b) Hammond, G. S. J. Am. Chem. Soc. 1955, 77 , 334; (c) Corey, E. J.; Sneen, R. A. J. Am. Chem. Soc. 1956, 78 , 6269; (d) House, H. O.; Umen, M. J. J. Org. Chem. 1973, 38 , 1000. 6. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28 , 155. 7. For selected total syntheses of compactin, see (a) Robichaud, J.; Tremblay, F. Org. Lett. 2006, 8 , 597; (b) Grieco, P. A.; Zelle, R. E.; Lis, R.; Finn, J. J. Am. Chem. Soc. 1983, 105 , 1403; (c) Kozikowski, A. P.; Li, C.-S. J. Org. Chem. 1987, 52 , 3541; (d) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111 , 2599. 8. Sletzinger, M.; Verhoeven, T. R.; Volante, R. P.; McNamara, J. M. Tetrahedron Lett. 1985, 26 , 2951. 9. Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66 , 6410. 10. Nicolaou, K. C.; Ajito, K.; Patron, A. P.; Khatuya, H.; Richter, P. K.; Bertinato, P. J. Am. Chem. Soc. 1996, 118 , 3059. 11. Fleming, I.; Ghosh, S. K. J. Chem. Soc. Perkin Trans. 1 , 1998, 2733. 12. Gademann, K.; Bethuel, Y. Org. Lett. 2004, 6 , 4707. 13. Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm. Bull. 1984, 32 , 1411. 14. For the x-ray crystal structure of MeZn(BH4 ), see Aldridge, S.; Blake, A. J.; Downs, A. J.; Parsons, S.; Pulham, C. R. J. Chem. Soc. Dalton Trans. 1996, 853. 15. Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17 , 338. 16. (a) Cimarelli, C.; Palmieri, G. Tetrahedron: Asymmetry 2000, 11 , 2555; (b) Notz, W.; Hartel, C.; Waldscheck, B.; Schmidt, R. R. J. Org. Chem. 2001, 66 , 4250; (c) Ravikumar, K. S.; Sinha, S.; Chandrasekaran, S. J. Org. Chem. 1999, 64 , 5841. 17. Narasimhan, S.; Balakumar, R. Aldrichimica Acta 1998, 31 , 19. 18. DeShong, P.; Ramesh, S.; Perez, J. J. J. Org. Chem. 1983, 48 , 2117. 19. Muri, D.; Lohse-Fraefel, N.; Carreira, E. M. Angew. Chem. Int. Ed. 2005, 44 , 4036. 20. Matsukawa, Y.; Isobe, M.; Kotsuki, H.; Ichikawa, Y. J. Org. Chem. 2005, 70 , 5339.

4.2. Diastereoselective Anti -Reduction of β-Hydroxy Ketones In 1986, Evans and colleagues introduced tetramethylammonium triacetoxyborohydride, a mild reducing reagent for the highly diastereoselective synthesis of 1,3-anti -diols from acyclic β-hydroxy ketones1 (Scheme 4.2a). The reaction, commonly called the Evans–Chapman–Carreira reduction, is typically carried out in a 1 : 1 mixture of anhydrous acetic acid and acetonitrile, as the reaction needs to be run at low temperature in the presence of acetic acid. An important observation is that the anti -diastereoselectivity is realized regardless of the stereochemistry of the α-alkyl substituent: Both anti - and syn-α-methyl-β-hydroxy

162

STEREOSELECTIVE REDUCTIONS

Me4NHB(OAc)3

R1

R2 R

CH3CN/CH3CO2H, −40oC, 5 h

R1

1 Reactant

R2

2-anti

2-syn

OH OH

OH O

OH OH

OH O

anti/syn

OH OH

O

OH OH O

OR [R = (CH2)3Ph] OH O

R2 R

Product

OH O

R

1

R

OH O

a Reaction

OH OH

OH OH

OH O

Yield, %

96:4

86

98:2a

92

98:2a

84

95:5

92

83:17

—

OR

OH OH

at −20°C for 18 h.

Scheme 4.2a

ketones undergo reductions with remarkably high levels of diastereoselectivity, favoring the anti -diol diastereoisomers. When the substrate lacks a β-substituent, a diminished selectivity is observed, hinting that the β-substituent in the starting material is a key structural element in attaining high stereoselectivity. The diastereoselectivity of this reaction reﬂects competition between two chairlike transition states A and B, each of which involves intramolecular hydride delivery as well as activation by acid catalysis. The 1,3-diaxial interaction between R2 and acetoxy groups would destabilize transition state B to a greater extent than the analogous interaction between hydroxy and acetoxy groups in the favored transition state, A1 (Scheme 4.2b). The Evans–Chapman–Carreira reaction was used in the total synthesis of macrolactin A(3), one of the polyene macrolide antibiotics, which shows inhibition of HIV replication in T-lymphoblast cells in preliminary studies2 (Scheme 4.2c).

REACTIONS + +

+

favored

R2

H O H

−

R1

R2

R1

R2 MAJOR

O

R1

OH O

OH OH

OAc − B OAc

H

163

TS A

B(OAc)3H

+ +

R H

disfavored

2

O

OH OH

OAc B OAc

H H

R1

O

R1

R2 minor

TS B

Scheme 4.2b

O

O

1. Me4NBH(OAc)3, CH3CN (87%)

OH SnBu3

BuO

2. Me2C(OMe)2, PPTS (89%)

O

O

O SnBu3

BuO dr = 14:1 5

4 OTBS I

O

O

O

TBSO

BuO

6 Pd2(dba)3, CdCl2, i-Pr2NEt (69%)

7 3. Ph3PCH2I2, KHMDS 1. DIBAL (80%) 2. (COCl)2, DMSO, Et3N (78%, 2 steps)

OH I

O

O

OTBS O 8

O

HO HO 3, macrolactin A

Scheme 4.2c

164

STEREOSELECTIVE REDUCTIONS

Ph O

N O

Ph

Bu2BOTf; BnOCH2CHO

OBn

O 10

O

N

−78°C (95%)

OH O

O

11

2.

MgBr 1. Me3Al, Me(MeO)NH• HCl (90%, 2 steps)

OBn

OBn

1. Me4NBH(OAc)3, CH3CN/AcOH

O

2. Me2C(OMe)2, PPTS (93%, 2 steps)

O

OH O 12

13

H O

O

OH

O 9, (−)-ebelactone A

Scheme 4.2d

OPMB

O

O

O

TBS OH O

O

O

OBn

Me (99%)

Me Me

Me

Me4NBH(OAc)3, CH3CN/AcOH

15

OPMB

O

O

O

TBS OH OH O

O

OBn

Me

MeO

OMe

PPTS, CH2Cl2 (85% from 15)

Me Me

Me 16 (dr > 95:5) OH OH OH OH OH

O

O

O

O

OBn

Me Me

Me

O

HO

Me O

17

OH 14, roxaticin

Scheme 4.2e

Me

165

REACTIONS

The selective reduction of the δ-hydroxy-β-keto ester 4 with Me4 NBH(OAc)3 afforded the corresponding 1,3-anti -diol in 87% yield and 14 : 1 diastereoselectivity. The 1,3-anti -diol was protected as the acetonide 5, followed by a Pd-catalyzed coupling reaction with the vinyl iodide 6 to provide the diene 7 in 69% yield. Reduction of the ester, Swern oxidation, and ﬁnally, Wittig oleﬁnation afforded the (Z )-vinyl iodide 8. Mandal completed the total synthesis of (−)-ebelactone A (9), which is an inhibitor of esterases, lipases, and N -formylmethionine aminopeptidases located on the cellular membrane of various cell strains3 (Scheme 4.2d). The synthesis began with Evans’s syn-aldol reaction between N -propionyloxazolidinone (10) and benzyloxyacetaldehyde to afford the syn-aldol adduct 11 in 95% Ph

Me OPMB

Me

O H

Me O

O

O

Ph 19

O

+

O

O

BnMe2Si

Me

O

Ph 20 i-Pr2NEt Bu2BOTf (88%)

BnMe2Si O

Me OPMB

Me

Ph O

dr > 19:1

Me O

2. Me2C(OMe)2, CSA 1. Me4NBH(OAc)3 (87%, 2 steps)

O

O

Ph

O

OH O

Ph 21

BnMe2Si O

Ph O

O Me Me

OH O

Me O

O Ph

O

O

Me Me

dr > 19:1

18, RK-397 OH OH OH OH OH OH

22

Scheme 4.2f

OH

166

STEREOSELECTIVE REDUCTIONS

O

H

OPMB TBSO

O

25

24 OMe MeO

OMe

O

O

OPMB

26 2. Me2C(OMe)2, 1. Me4NBH(OAc)3, PPTS (83%) CH3CN/AcOH (95%)

TBSO

H

O O

H

OH O

O

O H

TBSO

Bu2BOTf, i-Pr2NEt (93%)

O

O

O

OPMB

27

H

O O MeO

O

23, (+)-clavosolide A

OMe OMe

Scheme 4.2g

yield as a single diastereomer. Conversion of 11 to the Weinreb amide followed by addition of 2-propenylmagnesium bromide yielded the enone 12. The Evans–Chapman–Carreira 1,3-anti -reduction of the β-hydroxy ketone 12 with Me4 NBH(OAc)3 resulted in the 1,3-anti -diol, which was then converted to the acetonide 13 in 93% yield over two steps. The 1,3-anti -reduction of β-hydroxy ketones was utilized in the total synthesis of (+)-roxaticin (14), a pentaene macrolide isolated from streptomycete X-149944 (Scheme 4.2e). The β-hydroxy ketone 15 underwent 1,3-anti -reduction to afford the diol 16 in 99% yield and greater than 95 : 5 diastereoselectivity. The resulting diol was then protected as a cyclopentylidene ketal (17) by using cyclopentylidene dimethyl ketal and pyridinium p-toluenesulfonate (PPTS). In the synthesis of RK-397 (18), Denmark and Fujimori prepared an anti -diol using the Evans–Chapman–Carreira protocol5 (Scheme 4.2f). The β-hydroxy ketone 21, obtained by a diastereoselective boron aldol reaction between 19 and 20, was reduced with tetramethylammonium triacetoxyborohydride to afford the anti -diol derivative 22 in greater than 19 : 1diastereoselectivity. The 1,3-anti -selective reduction was utilized in the total synthesis of the structurally unique compound (+)-clavosolide A (23)6 (Scheme 4.2g). The 1,5-anti -aldol reaction of a dibutylboron enolate of 24 with the aldehyde 25 proceeded smoothly to afford the β-hydroxy ketone 26 in 93% yield and > 96 : 4 diastereoselectivity. Compound 26 was subsequently treated with

REACTIONS

OH O R1

R1

R1

−10oC, 45 min

R

R

R

28

29-anti

29-syn

Reactant

Product

OH O

anti/syn

Yield, %

> 99:1

96

> 99:1

85

> 99:1a

95a

> 99: 1

85

OAc OH n-C6H13

OH O

a

OAc OH

OAc OH

CH3CHO, 15% SmI2, THF

167

n-C6H13 OAc OH

OH O

OBz OH

OH O

OAc OH

Benzaldehyde was used.

Scheme 4.2h

Me4 NBH(OAc)3 in CH3 CN–AcOH, followed by protection of the resulting 1,3-anti -diol with 2,2-dimethoxypropane to provide the acetonide 27. In 1990, Evans and Hoveyda disclosed another novel method for the synthesis of anti -1,3-diol using samarium iodide7 (Scheme 4.2h). When the β-hydroxy ketone 28 was treated with 4 to 8 equivalents of aldehyde and a catalytic ◦ amount (15 mol %) of freshly prepared SmI2 in THF at −10 C, the corresponding 1,3-anti -diol monoester 29-anti was formed in high yields and with superb levels of diastereoselectivity. The anti -diastereoselectivity is not affected by the presence of a chiral substituent at the C2 position, as the reduction of both synand anti -α-methyl-β-hydroxy ketones follows the same stereochemical course with equally high asymmetric induction. One advantage of the current samarium iodide–catalyzed Evans–Tishchenko reduction over the triacetoxyborohydride reduction is that the two alcohol functional groups are in a different protection format in the product, enabling further synthetic operations on the 1,3-anti -diol monoester. To explain the high levels of anti -selectivity, Evans and Hoveyda proposed that the reduction occurs through a hydride-bridged six-membered transition

168

STEREOSELECTIVE REDUCTIONS

OH

H

SmI2

O R1

SmI2

H O

CH3CHO

O

O

L

O Sm O

R1

R1 28Sm + +

H favored

O

R1

O

OAc OH Sm L

R1

O H H O

L

MAJOR

O Sm O

intramol.

R1

hydride delivery

TS A + +

O 28Sm disfavored

L

Sm

H R1

O

OAc OH R1

O H

minor

TS B

Scheme 4.2i

state7 (Scheme 4.2i). The samarium-catalyzed reduction may involve coordination of the hydroxy ketone to the catalyst and subsequent formation of an eight-membered samarium-containing hemiacetal (28Sm).8 The stereochemistrydetermining stage would be the intramolecular hydride delivery step. Transition state A, leading to the formation of the major isomer, would be favored because the isopropyl group adopts an equatorial position, whereas the isopropyl substituent in transition state B occupies an energetically unfavorable axial position.9 Schreiber et al. used the Evans–Tishchenko reduction in the total synthesis of (−)-rapamycin (30), which complexes with an intracellular receptor FKBP12 to interfere potently with distinct signaling components of the cell cycle10 (Scheme 4.2j). The sulfone 31 underwent oleﬁnation reaction, followed by regioselective dihydroxylation and periodate cleavage, to furnish the β-hydroxy ketone 32 in good overall yield. A 1 : 4 mixture of the ketone 32 and (S )-N -Boc-pipecolinal (33) was treated with 30 mol % of PhCHO-SmI2 , and the Evans–Tishchenko reduction product 34 was obtained in 95% yield as a mixture of > 20 : 1 anti/syn 1,3-diol monoesters.

REACTIONS

TBSO

Ph OSiEt2iPr SO2 OH

PMBO

H

OMe

OMe

OTIPS 31

3. NaIO4 1. n-BuLi; CH2I2-i-PrMgCl (69%, 3 steps) 2. OsO4, pyridine; NaHSO3

TBSO

PMBO

ODEIPS

O

OH

H

OMe

OTIPS

32 N CHO, Boc 33 SmI2, PhCHO

(95%)

TBSO

PMBO

BocN H OH O

ODEIPS

OMe

O

H

OMe

OMe OTIPS

dr > 20:1 34

O H OH OMe O

O N H O

O

O H

OH O OMe

30, (−)-rapamycin

Scheme 4.2j

OMe OH

169

170

STEREOSELECTIVE REDUCTIONS

O

TIPSO

O Bu2BOTf, i-Pr2NEt

O

N

OTIPS

Bn

Ph

Ph

2. CH2=CHCH2MgBr (92%)

OH O

CHO

37

36

1. Me3Al, MeNH(OMe)•HCl (93%)

Xp

38

(84%) 1. PMBOC(=NH)CCl3 TfOH (cat.) (70%) 2. DIBAL-H (90%) 3. TIPSOTf, i-Pr2NEt (93%)

TIPSO

TIPSO CH3CHO, SmI2

Ph

O

Ph Ph TIPSO

OH O 39

O

TIPSO

Ph

(96%)

OAc OH 40

O

O

HN

O

HN

Cl

OPMB 41 O

O

OMe

35, cryptophycin 1

Scheme 4.2k

Gardinier and Leahy employed a samarium-catalyzed anti -reduction protocol to access one of the key intermediates en route to the synthesis of cryptophycin 1 (35), which exhibits extraordinary activity against a variety of tumor cell lines11 (Scheme 4.2k). Thus, the syn-aldol reaction between N -propionyloxazolidinone (36) and the chiral aldehyde 37 proceeded smoothly to afford the adduct desired (38) as a single product in high yield. Formation of Weinreb amide and subsequent addition of allylmagnesium bromide provide the β-hydroxy ketone 39 which was then subjected to Evans–Tishchenko reduction conditions to produce the monoacetate 40 cleanly in 96% isolated yield. Protection of the alcohol as a p-methoxybenzyl (PMB) ether, DIBAL reduction of the acetate, and treatment of the resulting alcohol with triisopropylsilyl triﬂate furnished compound 41. The samarium-catalyzed reduction was utilized in the asymmetric synthesis of the marine macrolide bryostatin 2 (42) to furnish an intermediate (46)12 (Scheme 4.2l). The ketone 43 underwent an aldol reaction with the ketoaldehyde 44 via the isopinylboryl enolate to give the aldol adduct 45 in good yield and 93 : 7 diastereoselectivity. Subsequent samarium-catalyzed Evans–Tishchenko reduction of the β-hydroxy ketone 45 provided the p-nitrobenzoate 46 with excellent stereoselectivity. Silylation and saponiﬁcation readily converted compound 46 into the alcohol 47 in 88% yield over two steps.

171

REACTIONS

2BCl,

O

PhO2S

O

OH O

(−)-DIPCl, Et3N; then PhO2S

OPMB

O

O

OPMB 45 (dr 93:7)

H

43

44

(87%) (76%)

SmI2 (20 mol %), p-NO2C6H4CHO

C6H4-p-NO2 PhO2S

O

O

O

OH

OPMB 46 (dr > 95:5) 1. TBSOTf, 2,6-lutidine 2. LiOH

THF/MeOH/H2O (88%, 2 steps)

HO MeO2C O

PhO2S

O

OH

O O

OH OTBS OH H OH O O OPMB

42, bryostatin 2

47

O

OH O

CO2Me

Scheme 4.2l

Dermostatin A (48) is a 36-membered macrolide that shows potent antifungal activity against a large number of human pathogens and has been used clinically as a treatment for deep vein mycoses. During the total synthesis of dermostatin A, Sinz and Rychnovsky utilized the Evans–Tishchenko reduction methodology to furnish a 1,3-anti -diol intermediate (52)13 (Scheme 4.2m). The enol silane 49 and aldehyde 50 were subjected to Mukaiyama aldol coupling to yield the 1,3-anti adduct desired (51) with a modest 3.3 : 1 diastereomeric ratio. The Evans–Tishchenko anti -reduction of the β-hydroxy ketone 51 with isobutyraldehyde and subsequent reductive cleavage of the monoester provided the 1,3-anti -diol 52 with excellent diastereoselectivity. Desilylation under acidic condition followed by protection of the tetraol afforded the bis-acetonide 53. In the synthesis of the marine macrolide leucascandrolide A (54), Kozmin used the samarium-catalyzed diastereoselective ketone reduction method in a highly stereocontrolled synthesis of the C1 –C15 fragment 5814 (Scheme 4.2n). Generation of the dicyclohexylboron enolate of the ketone 55 followed by addition

172

STEREOSELECTIVE REDUCTIONS

H

+ Br

Br TBSO

OTMS

BF3•OEt2, −78οC, CH2Cl2

Br

(74%)

TBSO

49

TBSO

O

O

OH

Br OTBS

51 (dr 3.3:1)

50

2. DIBAL-H 1. SmI2 (cat.), i-PrCHO (75%, 2 steps)

Br

Br O

O

O

1. Dowex-H+, MeOH

Br

2. Me2C(OMe)2, CSA (cat.) (50%, 2 steps)

O

TBSO

OH

OH

Br OTBS

52 (de > 95%)

53

O

OH O

OH

OH

OH OH OH OH 48, dermostatin A

OH

OH

Scheme 4.2m

O

Cy2BCl, Et3N

O

OH

O O

CHO O 56

O

(74%)

O 15

17

O

7

OBn

O

dr > 95:5 57

55 H

H

11

OBn

9

H

O

OMe O O

CH3CHO SmI2 (30 mol %) (92%)

1

O

dr > 95:5

O

H

N

O 15

O

OAc OH

O 54, leucascandrolide A

NHCO2Me

Scheme 4.2n

OBn

O 1

58

REACTIONS

173

of the aldehyde 56 provided the aldol adduct desired (57) as a single diastereomer. Diastereoselective β-hydroxy ketone reduction of compound 57 using an Evans–Tishchenko protocol cleanly afforded the monoacetate 58 in greater than 95 : 5 diastereoselectivity.15

REFERENCES 1. (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27 , 5939; (b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110 , 3560. 2. Kim, Y.; Singer, R. A.; Carreira, E. M. Angew. Chem. Int. Ed. 1998, 37 , 1261. 3. Mandal, A. K. Org. Lett. 2002, 4 , 2043. 4. Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125 , 10899. 5. Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127 , 8971. 6. Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett. 2006, 8 , 661. 7. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112 , 6447. 8. (a) Molander, G. A.; Etter, J. B. J. Am. Chem. Soc. 1987, 109 , 6556; (b) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem. 1999, 64 , 2172. 9. Abu-Hasanayn, F.; Streitwieser, A. J. Org. Chem. 1998, 63 , 2954. 10. Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115 , 7906. 11. Gardinier, K. M.; Leahy, J. W. J. Org. Chem. 1997, 62 , 7098. 12. Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew. Chem. Int. Ed. 1998, 37 , 2354. 13. Sinz, C. J.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2001, 40 , 3224. 14. Kozmin, S. A. Org. Lett. 2001, 3 , 755. 15. Wang, Y.; Janjic, J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124 , 13670.

4.3. Asymmetric Reduction In 1979, Noyori and co-workers invented a new type of chiral aluminum hydride reagent (1), which is prepared in situ from LiAlH4 , (S )-1,1 -bi-2naphthol (BINOL), and ethanol. The reagent, called binaphthol-modiﬁed lithium aluminum hydride (BINAL-H), affects asymmetric reduction of a variety of phenyl alkyl ketones to produce the alcohols 2 with very high to perfect levels of enantioselectivity when the alkyl groups are methyl or primary1 (Scheme 4.3a). The binaphthol-modiﬁed lithium aluminum hydride reagents (BINAL-Hs) are also effective in enantioselective reduction of a variety of alkynyl and alkenyl ketones2 (Scheme 4.3b). When ◦the reaction is carried out with 3 equivalents of (S )-BINAL-H at −100 to −78 C, the corresponding propargylic alcohol 3 and allylic alcohol 4 are obtained in high chemical yields with good to excellent levels of enantioselectivity. As is the case with aryl alkyl ketones, the alcohols with (S )-conﬁguration are obtained when (S )-BINAL-H is employed.

174

STEREOSELECTIVE REDUCTIONS

O

O

R + Li +

Ph

−100οC, 2 h; −78οC, 16 h

H

Al O

−

OH

THF

Ph

R

OEt

1, (S)-BINAL-H

2

R CH3 C 2H 5 n-C3H7 n-C4H9 i-C3H7 t-C4H9

ee, % 95 98 100 100 71 44

Yield, % 61 62 92 64 68 80

Scheme 4.3a

OH

O

Li

H

ketone, THF

OEt

−100οC, 1 h; −78οC, 1 h

Al −

+

O

R2 R1

OH or

R1

3

R2 4

1, (S)-BINAL-H

Alcohol

Ketone

OH

O

O

OH

71

90 a

90a

79

47

91

91

n-C5H11

n-C5H11 n-C4H9

n-C4H9 O n-C4H9

OH CH3

n-C4H9

O

a

84 n-C5H11

n-C5H11

n-C4H9

ee, % Yield, %

CH3 OH

n-C5H11

n-C4H9

BINAL-H from methanol was used.

Scheme 4.3b

n-C5H11

175

REACTIONS

O

R

OH

favored

Al

O

Li

O Li O H Al O OEt 1, (S)-BINAL-H

O Un

Et

Un

H O

MAJOR

TS A

R

O

Un

OH

disfavored

(Un: aryl, alkynyl, alkenyl)

Al

O

R

Un

O Et

Li

H O

R

Un

R

minor

TS B

Scheme 4.3c

Noyori et al. proposed that the reaction would be initiated by complexation of the Lewis acidic lithium cation to the ketone oxygen atom; then hydride transfer occurs from aluminum to the carbonyl carbon by way of a six-membered chairlike transition state3 (Scheme 4.3c). Between the two competing six-membered chairlike transition states A and B, transition state B is disfavored, due to the substantial n/π-type electronic repulsion between the axially oriented binaphthoxyl oxygen and the unsaturated phenyl or alkenyl moiety. Although there is a 1,3-diaxial steric interaction between the Al–O and C–R bonds in transition state A, the absence of electronic repulsion would make transition state A preferred to B, giving the (S )-enantiomer as the major product. However, there is a delicate balance between electronic and steric factors. Hence, the decrease in enantioselectivity seen in the reduction of tert-butyl phenyl ketone reﬂects greater steric interactions in transition state A between the Al–O bond and the tert-butyl group. The BINAL-H reduction protocol was utilized in a highly enantioselective prostaglandin synthesis4 (Scheme 4.3d). Asymmetric reduction of the iodovinyl ketone 6 with (S )-BINAL-H proceeded well, with superb enantioselectivity and in high yield.5 Protection of the resulting alcohol gave the TBS ether 7. Conjugate addition of the cuprate reagent generated from 7 into cyclopentenone 8 followed by alkylation with 9 afforded the cyclopentanone 10. Desilylation followed by enzymatic hydrolysis then produced the natural prostaglandin E2 (PGE2) 5. Marko et al. employed an enantioselective Noyori BINAL-H reduction in the synthesis of methyl monate C (11), the methyl ester derivative of the potent antibiotic pseudomonic acid C6 (Scheme 4.3e). The α,β-unsaturated ketone 12 underwent the Noyori reduction with the (S )-BINAL-H reagent to give the product desired (13) in 70% yield and 95% ee. The chiral alcohol was then condensed

176

STEREOSELECTIVE REDUCTIONS

I

n-C5H11

1. (S)-BINAL-H 2. TBSCl

I

n-C5H11

(95%)

OTBS

O 6

7 (97% ee)

3. I (78% from 7)

9

1. t-BuLi, CuI, PBu3, HMPA 2. O TBSO

CO2Me

8

O

O CO2Me

CO2H

1. HF-pyridine 2. enzyme

HO

TBSO

OTBS 10

OH 5, prostaglandin E2

Scheme 4.3d

O

OH (S)-BINAL-H, THF, −78οC

TMS

(70%)

TMS

OTBS

OTBS 13 (95% ee)

12

BF3•OEt2, CH3CH2CN (50%) MeO

OH

OMe 14

TBSO O

O

OMe

OH

HO

O

O

O

11, methyl monate C

CO2Me

15

Scheme 4.3e

with compound 14 in the presence of BF3 ·OEt2 to provide the tetrahydropyran 15 as a single diastereomer in 50% yield. Noyori et al. demonstrated the effectiveness of the BINAL-H reduction method by synthesizing the Japanese beetle pheromone (R)-167 (Scheme 4.3f). The ◦ alkynyl ketone 17 was treated with 3 equivalents of (R)-BINAL-H at −100 C ◦ for 1 hour and then held at −78 C for 2 hours. The propargylic alcohol 18 was obtained in good yield and with moderate enantioselectivity of 84% ee. Exposure

REACTIONS

O

OH

(R)-BINAL-H (3 equiv), THF, −100 to −78°C

CO2CH3

CO2CH3

(82%)

C8H17

177

C8H17 18 (84% ee)

17

TsOH benzene

C8H17 H2, Lindlar

H

O

O

C8H17

(90%, 2 steps)

O

O

H 19

(R)-16

Scheme 4.3f

of 18 to p-toluenesulfonic acid in reﬂuxing benzene afforded the γ-lactone 19, which upon hydrogenation with Lindlar catalyst yielded the target molecule (16) in 75% ee. The BINAL-H enantioselective reduction of α,β-conjugated ketones was used in the total synthesis of (−)-lepadiformine (20), which exhibits moderate cytotoxic activities against various tumor cell lines8 (Scheme 4.3g). A solution of 21 in toluene

O

BnO HCOOH, toluene/THF

BnO NHBoc

(88%)

Boc O

H

N H

3′

C6H13

O

C6H13

21

22 1. K2CO3, MeOH/H2O (98%)

2. MnO2 (91%)

BnO

BnO Boc HO

N HO

(S)-BINAL-H, THF, −78°C

N H

C6H13

20, (−)-lepadiformine

C6H13 24 (97% de)

Scheme 4.3g

(92%)

Boc O

N H

C6H13 23

178

STEREOSELECTIVE REDUCTIONS

H NH

OH

N H

(S)-prolinol

OH

O

H

BH3•THF (1 equiv)

Ph

O B H H

Et

Ph

30°C, 60 h (99%)

26 (44% ee)

25a

H OH

O

H

BH3•THF (1 equiv)

H

NH2 (S)-valinol

N H

Et

Ph

O B H H

OH Et

Ph

30°C, 60 h (99%)

Et

26 (60% ee)

25b

Scheme 4.3h O

Ph Ph

OH 1. BH3•THF (2 equiv)

PhMgBr

OMe H NH2 • HCl

OH H NH2

(56%)

Ph

2. PhCOEt, 30°C, 2 h

26 (94% ee)

27

Scheme 4.3i

H Ar Ar

H Ar Ar O

BH3•THF

H 3B

28a, Ar = Ph, R = H 28b, Ar = Ph, R = CH3 28c, Ar = 2-Naph, R = CH3

O RL

O

N B R

OH

RS

RS

RL

N B R

29

ee, % Ketone (RLCORS)a

Et

w/28a

w/28b

w/28c

C6H5COCH3

97

96.5

97.8

C6H5COC2H5

90

96.7

97.4

α-tetralone t-BuCOCH3

89 92

86.0 97.3

94.5 92.7

Reaction temperatures: 25°C with 28a, −10°C with 28b, 23°C with 28c. RL, aromatic substituent for aromatic ketones and tertiary alkyl group for aliphatic ketones. a

Scheme 4.3j

179

REACTIONS

and THF was treated with formic acid to generate in situ an N -acyliminium species which underwent a spirocyclization reaction to provide the 1-azaspirocyclic formate ester 22 as a 1.6 : 1 mixture favoring the 3 β-formate isomer. Compound 22 was subjected to basic hydrolysis conditions to give a mixture of diastereomeric allylic alcohols, which were oxidized with MnO2 to furnish the α β-unsaturated ketone 23. Asymmetric reduction of 23 with (S )-BINAL-H then afforded the alcohol 24 in 92% yield with excellent diastereoselectivity (97% de). In 1981, Hirao and others reported that the chiral borane–amine complex 25a, derived from (S )-prolinol and 1 equivalent of BH3 · THF, enantioselectively reduced propiophenone to afford (R)-1-phenyl-1-propanol (26) in 44% ee9 (Scheme 4.3h). The chiral complex 25b was even better than 25a, affording the same secondary alcohol in 60% ee. Two years after the initial disclosure, Hirao et al. uncovered a new catalyst system that improved the previous experimental conditions dramatically10 (Scheme 4.3i). When the chiral aminoalcohol 27, prepared from (S )-valine methyl ester hydrochloride and phenylmagnesium bromide, was used along with 2 equivalents of BH3 · THF, the enantioselectivity of the alcohol 26 jumped to 94% ee. In addition, the reaction time was shortened to 2 hours. In 1987, Corey and co-workers proved that highly enantioselective reduction of ketones could be achieved by using stoichiometric borane in the presence of catalytic amounts of the oxazaborolidine 28a11 (Scheme 4.3j). Compound 28a, synthesized by heating (S )-(−)-2-(diphenylhydroxymethyl)pyrrolidine at reﬂux in THF with 3 equivalents of BH3 · THF, shows excellent catalytic activity for the asymmetric reduction of acetophenone and other ketones. The B-methylated analog 28b was later synthesized to improve the air and moisture sensitivity associated with 28a. The third analog, 28c, with a 2-naphthyl substituent on the oxazaborolidine ring, has proven to be the best to afford the alcohol 29 with superb levels of enantioselectivity.

H

Ph

Ph OH

NO

favored

H Ph Ph O N B H (R)-28a

B H B H H H

O Ph

CH3

O Ph CH3

Ph

S

CH3

MAJOR

TS A: 0 kcal/mol

BH3•THF

H disfavored

Ph NO

Ph

B H B H H H

OH O

Ph

CH3

minor Ph

TS B: 3.54 kcal/mol

Scheme 4.3k

R

CH3

180

STEREOSELECTIVE REDUCTIONS

H Ph Ph O N B Me 28b

OH

borane reagent;

R2

ketonea

R

Ketone

R1

R2

30

31

Borane

ee, %

Yield, %

OH CH3

Ph

BH3•Me2S

71

80

BH3•Me2S

98

81

BH3•Me2S

95

54

BH3•THF

90

90

BH3•THF

90

89

Catechol– borane

97b

90b

CH3 Ph

O

OH c-C6H11

c-C6H11

O

OH n-C7H15

n-C7H15

O

OH

Br

Br

OH

O Br

Br

O Ph a

or

1

Alcohol O

OH

OH CH3

Ph

CH3

For alkynyl ketones, the reaction was run with 2 equivalents of 28b and 5 equivalents of BH3•Me2S at −30οC.

b

B-n-Bu oxazaborolidine was used.

Scheme 4.3l

Numerous theoretical treatments have been carried out to understand the mode of asymmetric induction of the Corey–Bakshi–Shibata (CBS) reduction, more thoroughly.12 Liotta et al. carried out computational studies to identify the transition states for CBS reductions of various ketones13 (Scheme 4.3k).In the asymmetric reduction of acetophenone with the catalyst (R)-28a, four transition states were found. Of the lowest energy is chairlike transition state A, which would lead to formation of the major enantiomer. In transition state A, the phenyl group of acetophenone occupies an equatorial position that is free from ˚ away from one of the two phenyl groups of any steric interaction, as it is 5.5 A the diphenylprolinol ring. On the other hand, transition state B, leading to the

181

REACTIONS

formation of the minor enantiomer, is less stable than A by 3.54 kcal/mol. Two energetically unfavorable interactions are responsible for the high-energy state of B: The methyl group of acetophenone experiences a steric interaction with the phenyl substituent of the catalyst, and the phenyl group of acetophenone is engaged in additional interactions with the axial B–H bonds in transition state B. The calculations predict 98% ee in the asymmetric reduction of acetophenone, with the catalyst (R)-28a favoring an (S )-enantiomer, which is in excellent agreement with the experimental value of 97% ee. The CBS reduction has also proven to be an efﬁcient method for asymmetric reduction of α,β-unsaturated enones14 and ynones15 (Scheme 4.3l). The asymmetric reduction of alkynyl ketones affords propargylic alcohols 30 with high levels of enantioselectivity and in moderate to good yields. Optimized reaction ◦ conditions for the reduction are the use of THF at −30 C, 2 equivalents of chiral oxazaborolidine 28b, and 5 equivalents of borane methyl sulﬁde complex. The CBS reduction has been employed in numerous synthetic applications.16 The cetirizine hydrochloride 32 (Zyrtec) is an effective treatment as a secondgeneration histamine H1 antagonist for a range of allergic diseases. Zyrtec is one of the leading antihistamine drugs, with sales of $1.3 billion in 2004 in the United States alone. Corey and Helal prepared a chiral benzylic alcohol intermediate 34 en route to their enantioselective synthesis of Zyrtec17 (Scheme 4.3m). The asymmetric reduction of the ketone 33 in toluene with catecholborane in

H Ph Ph

O

(CO)3Cr

OH

O N B 28d (0.15 equiv) n-Bu

Cl 33

catecholborane (2 equiv), toluene, −40οC, 2.5 h (99%)

Cl

(CO)3Cr

34 (98% ee) O

N N H

OH

O N N

O

HBF4•Et2O OBu −60οC; then 35 (86%)

O 2 HCl

OBu

O 1. pyridine, reflux (92%)

N

2. 2 M HCl, 50οC (86%)

N

Cl 32, cetirizine hydrochloride

O

Cl

(CO)3Cr 36

Scheme 4.3m

182

STEREOSELECTIVE REDUCTIONS H Ph Ph

O

SnBu3 38

OH

O 28b N B (0.2 equiv) Me catecholborane, (1 equiv), toluene, −30°C, 2.5 h (78%)

1. 2,4,6-trimethylbenzoyl chloride, 2,6-lutidine, CH2Cl2, 20°C 2. [(E)-MeC C)]2CuLi (83%, 2 steps)

SnBu3 39 (85% ee)

OH OMe SnBu3

O

O

N

O

N

O

40

37, (−)-hennoxazole

Scheme 4.3n

the presence of a catalytic amount of 28 d afforded the alcohol 34 in 99% yield and 98% ee. Treatment of the secondary alcohol 34 with tetraﬂuoroboric acid at ◦ −60 C followed by addition of the amine 35 yielded compound 36. Removal of the chromium substituent and subsequent acidic hydrolysis produced 32 in 98% ee, demonstrating a practical application of the CBS oxazaborolidine-catalyzed reduction. In the synthesis of (−)-hennoxazole (37), Wipf and Lim used a CBS reagent to prepare the chiral allylic alcohol 3918 (Scheme 4.3n). The enantioselective reduction of the enone 38 using a catalytic amount of the oxazaborolidine 28b

H Ph Ph

AcO O

MeO

Me 42

AcO

O 28b N B (0.1 equiv) Me BH3 • Me2S, THF, −20°C, 6 h (95%)

OH

MeO

Me 43 ( > 95% ee) PPh3, DEAD (60%) TsNHCH2CH(OMe)2 (44)

OMe MeO

AcO

OMe

NH

MeO

N

MeO Me

Me

41, (1S)-(−)-salsolidine

45

Scheme 4.3o

Ts

REACTIONS

183

along with stoichiometric amount of catecholborane delivered the allylic alcohol 39 in 85% ee. Stereoselective addition of the E -propenyl cuprate reagent to the 2,4,6-trimethylbenzoate of 39 provided the 1,4-diene 40. The oxazaborolidine-catalyzed enantioselective reduction of aryl alkyl ketones was used in the asymmetric synthesis of the naturally occurring molecule (1S )-(−)-salsolidine 4119 (Scheme 4.3o). The ketone 42 underwent oxazaborolidine-mediated reduction to furnish the alcohol 43 in excellent yield and greater than 95% ee. The alcohol 43 was then coupled with the reagent 44 under Mitsunobu conditions to produce the aminoacetal 45. Corey and Roberts reported a total synthesis of the dysidiolide 46, a marine sponge metabolite with biological activities against A-549 human lung carcinoma and P388 murine leukemia cancer cell lines20 (Scheme 4.3p). The unwanted alcohol (47) was converted to the ketone 48 via Dess–Martin periodinane oxidation. The asymmetric reduction of 48 with the CBS catalyst 28b efﬁciently gave the alcohol 49, which was transformed into the dysidiolide 46 via photochemical oxidation.

AcO OAc I OAc O

H HO

O pyridine, CH2Cl2 (100%)

H O

O 47

O 48 BH3• Me2S (2 equiv) toluene, −30°C, 15 h (91%)

O2, hν, Rose Bengal i-Pr2NEt, −78°C (98%)

H 46, dysidiolide

HO HO

O

H HO O 49

O

Scheme 4.3p

H Ph Ph O 28b N B (2 equiv) Me

184

STEREOSELECTIVE REDUCTIONS H Ph Ph

O

O N B (R)-28a H

OH

1. PhN C O (93%) 2. OsO4, NMO; MeCOMe, H+ (78%)

catecholborane (93%)

51

52 ( >96% ee)

OCONHPh O 53

OH

SiMe2Ph O

n-BuLi; CuI(Ph3P)2; PhMe2SiLi (81%)

O

O

54

OH O MeN 50, (−)-morphine

Scheme 4.3q

Overman et al. exercised the CBS reduction strategy during synthesis of the natural opium alkaloid (−)-morphine (50)21 (Scheme 4.3q). Enantioselective reduction of 2-allylcyclohex-2-en-1-one (51) with catecholborane in the presence of the (R)-oxazaborolidine catalyst (R)-28a provided the corresponding (S )-cyclohexenol 52 in greater than 96% ee. Condensation of this intermediate with phenyl isocyanate, regioselective catalytic dihydroxylation of the terminal double bond, and protection of the resulting diol afforded 53 in 68% overall yield from 51. The allylic silane 54 for the upcoming iminium ion–allylsilane cyclization step was obtained in 81% yield by a stereoselective SN 2 displacement of allylic carbamate. (−)-Erinacine B (55) is the ﬁrst xylose-conjugated terpenoid possessing a cyathane core and exhibits signiﬁcant activity in stimulating nerve growth factor synthesis. In an enantioselective synthesis of 55, the stereoselective CBS reduction was utilized with excellent stereochemical outcome22 (Scheme 4.3r). Treatment of the β,γ-epoxy ketone 56 with DBU promoted a clean β-elimination reaction to provide the γ-hydroxy-α,β-unsaturated ketone, which was then converted to the benzoate 57. CBS reduction of 57 yielded the alcohol desired (58) as a single isomer. Brown et al. disclosed an asymmetric reduction protocol by using (−)-diisopinocampheylchloroborane [59; (−)-Ipc2 BCl, d Ipc2 BCl, (−)-DIP-Chloride], readily prepared from commercially available (+)-α-pinene in high optical purity of 99% ee23 (Scheme 4.3s). This reagent reduces aryl alkyl ketones to afford the alcohol 60 with excellent levels of asymmetric induction. Although the asymmetric reduction of less sterically hindered ketones, such as 3-methyl-2-butanone, gives the product in only 32% ee, α-tertiary aliphatic ketones smoothly undergo reduction to afford 60 with high enantioselectivity.24 Brown et al. proposed that

REACTIONS

185

O

O 1. DBU 2. Bz2O, pyridine, DMAP

OTBDPS

(78%, 2 steps)

O

H

OTBDPS H OBz

56

57 H Ph Ph

BH3• Me2S, CH2Cl2, −40°C (95%)

OH

O O

O N B (R)-28b Me

OH

OH O

OTBDPS H OBz

CHO H

58 55, (−)-erinacine B

Scheme 4.3r

the reduction would involve a six-membered boatlike transition state23 (Scheme 4.3t). In the preferred transition state A, the smaller group (RS ) has to face an unfavorable 1,3-diaxial interaction with the methyl group, while the larger alkyl group (RL ) assumes a pseudoequatorial position. This explains the formation of the S -enantiomer as the major product. In collaboration with Brown and others, Rogic undertook a computational study to better understand the transition states of the asymmetric reduction25 (Scheme 4.3u). In transition state A, the six-membered ring is nearly planar, with the B–Cl bond being syn to the C1 –H bond. Transition state B, on the other hand, is half-chair, the B–Cl bond being anti to the C1 –H bond. Calculations show that transition state A is more stable than B by 2.46 kcal/mol, predicting an (S )-enantiomer of 99% enantiomeric purity. Brown et al. achieved a highly enantioselective synthesis of (S )-ﬂuoxetine hydrochloride (61) (Prozac), an antidepressant medicine26 (Scheme 4.3v). Reduction of β-chloropropiophenone (62) with (+)-Ipc2 BCl provided the secondary alcohol 63 in 97% ee and greater than 99% ee after single recrystallization. Mitsunobu reaction of the alcohol with p-triﬂuoromethylphenol afforded the ether 64, which was then converted to (S )-(+)-ﬂuoxetine hydrochloride (61) after subsequent treatment with excess methylamine and a solution of hydrogen chloride in ether.

186

STEREOSELECTIVE REDUCTIONS O 2BCl

1. BH3• SMe2

RL

−25 or 25°Ca

2. HCl, Et2O

ee, % (Config.)

Ketone (Aromatic)

Yield, %

Ketone (Aliphatic)

O

RS

ee, % (Config.)

Yield, %

32 (S)

—

95 (S)

50

98 (S)

71

91 (S)

60

O 98 (S)

Me

72

Me

O Ph

RL

(S)-60

(−)-59 (99% ee)

(+)-α-pinene or dpinene

Ph

OH RS

O Et

98 (S)

62

97 (S)

62

86 (S)

70

Me

O

O

O

O

a Aromatic ketones: −25°C, 5 h, THF; aliphatic ketones: 25°C, 12 h, neat. RL, aromatic substituent for aromatic ketones and tertiary alkyl group for aliphatic ketones.

Scheme 4.3s

Ipc H

O R L

RL

RS MAJOR

CH3 R S TS A

O 2BCl RL

OH

Cl B

favored

RS

(−)-59

Ipc disfavored

B H

O R S

CH3 R L TS B

Scheme 4.3t

OH

Cl RL

RS minor

187

REACTIONS

Ipc O

1 favored

B

2

OH Ph

Ph Me

H

H

O 2BCl

Ph

Me

MAJOR

Cl Me

TS A (0.0 kcal/mol)

Me

(−)-59

Cl disfavored

B

Ipc

OH

O H Me

H

Me

Ph

minor

Me Ph

TS B (2.46 kcal/mol)

Scheme 4.3u

OH

O Cl

(+)-Ipc2BCl, −25°C, THF

62

Cl 63 (97% ee) CF3

DEAD, PPh3, THF (70%) HO

CF3 CF3

O 1. MeNH2 2. HCl, Et2O

O N H

Cl

CH3 64

HCl

61, (S)-fluoxetine hydrochloride

Scheme 4.3v

Nicolaou and Hepworth used the Ipc2 BCl reduction method in an efﬁcient synthesis of naphthoquinone alkannin (65), which exhibits many interesting biological properties, such as antibacterial, antifungal, anti-inﬂammatory, and antitumor activities27 (Scheme 4.3w). The lithium anion of the bromonaphthalene 66 underwent a coupling reaction with the Weinreb amide 67 to provide the

188

STEREOSELECTIVE REDUCTIONS

O

O

O

O

O

O

t-BuLi, −78°C, THF

Br O

O

Me

OMe N

(63%)

O

66

O

67

68

THF, −40 to −25°C (−)-Ipc2BCl (1.5 equiv) (93%)

OH

O

O

O

O

O

anodic oxidation (80%)

OH

O

OH

OH

69 ( > 98% ee)

65, alkannin

Scheme 4.3w

ketone 68 in good yield. The asymmetric reduction of 68 was carried out with (−)-Ipc2 BCl to form the alcohol 69 in greater than 98% ee and high yield. The subsequent mild anodic oxidation of the free hydroxy derivative 69 afforded the target molecule, alkannin (65). Taber and Zhang synthesized the enediol isofuran 70, which belongs to a new class of isofurans that show signiﬁcant biological activities28 (Scheme 4.3x). The Horner–Wadsworth–Emmons condensation of the aldehyde 71 with the phosphonate 72 gave the α,β-unsaturated ketone 73 in high yield. Asymmetric reduction with (−)-Ipc2 BCl proceeded well to afford the allylic alcohol 74 as a single diastereomer. Trauner et al. completed the total synthesis of (−)-heptemerone B (75), a diterpene natural product that strongly inhibits fungal germination of the plant pathogen Magnaporthe grisea 29 (Scheme 4.3y). Monolithiation of 3,4-diiodofuran at low temperature followed by addition of the resulting organolithium species to (E ) 4-methyl-4-hexenal produced the racemic alcohol ( ± )-76, which upon oxidation furnished the furyl ketone 77. The ensuing (+)-Ipc2 BCl reduction then afforded (+)-76 in 94% ee. The vinyl iodide 76 underwent intramolecular Heck coupling in the presence of tetra-n-butylammonium bromide to give a 5.1:1 mixture of the desired diastereomer (78) and its epimer. Midland and others reported that B-isopinocampheyl-9-borabicyclo[3.3.1]nonane [Alpine-Borane; (R)-79] is an effective reagent for the highly asymmetric reduction of alkynyl ketones to afford the propargylic alcohol 8030 (Scheme 4.3z). The reagent (R)-79 is prepared from (+)-α-pinene and 9-borabicyclo[3.3.1]nonane (9-BBN) and often represented as 79banana. The levels of asymmetric

189

REACTIONS

O TBSO

H OBn

O TBSO 71 O O NaH, THF P MeO n-C5H11 (90%) OMe

72 OH

O TBSO

TBSO

n-C5H11 OBn

O TBSO

n-C5H11

(−)-Ipc2BCl THF, −78°C (85%)

OBn

O TBSO

73

74

OH HO O HO

O OH

70, enediol isofuran

Scheme 4.3x

induction realized with 79 are good to excellent. Particularly noteworthy is the reduction of benzoylacetylenic ketoester, which undergoes reduction with perfect enantiofacial selectivity.31 The reduction is considered to proceed through a six-membered transition state30 (Scheme 4.3aa). In the hydride-bridged six-membered transition state A, the acetylenic unit positions itself away from the isopinocampheyl skeleton. The hydrogen β to the boron is then transferred to the carbonyl group from the bottom face of the ketone. Computational analysis on the proposed transition state of the Midland reduction has not, however, been reported.32 Midland and Graham completed a total synthesis of (−)-pestalotin (81)33 (Scheme 4.3bb). The asymmetric reduction of the ketone 82 gave the propargylic alcohol 83 with high enantioselectivity. Partial reduction of the alkyne,

190

I

STEREOSELECTIVE REDUCTIONS

I

O

n-BuLi

HO

I

Dess–Martin periodinane [O]

O

(88%)

I

OHC (62%)

O

O (±)-76

77 THF, −20°C (+)-Ipc2BCl (75%)

Me Pd(OAc)2, Et3N, n-Bu4NBr

HO

I

(75%)

HO O

O (+)-76 ( 94% ee)

78

Me

Me H

AcO O H

OAc O

75, (−)-heptemerone B

Scheme 4.3y

protection of alcohol as a MEM ether, and ozonolysis afforded the aldehyde 84. A hetero Diels–Alder reaction of 84 with Brassard’s diene (85) followed by deprotection provided 81. In the total synthesis of (−)-chlorothricolide (86), Roush and Sciotti used the Midland reduction technology34 (Scheme 4.3cc). Asymmetric reduction of the acetylenic ketone 87 with (S )-79 afforded the alcohol 88 in 94% ee. Protection of the hydroxyl group as a MOM ether, DIBAL reduction, and subsequent protection of the resulting aldehyde provided 89. Mulzer and Berger used the Midland reduction en route to the total synthesis of the boron-containing macrodiolide antibiotic tartrolon B (90), which acts

REACTIONS

9-BBN

OH

ketones

B

R1 (R)-79

Ketone

Alcohol O

80

79banana

ee, %

Yield, %

78

98

89

72

92

65

99

78

77

59

100

64

OH CH3

Ph

CH3 Ph

O

OH Ph

Ph n-C4H9

n-C4H9 O

OH n-C5H11

n-C5H11

O

OH i-C3H7

i-C3H7

O

OH CH3

EtO2C

CH3 EtO2C

O

OH Ph

EtO2C

B

R2

rt, THFa

(+)-α-pinene or dpinene

191

Ph EtO2C

a

Reaction time: 8 h for terminal ketones and acetylenic ketoesters, 1 to 4 days for internal acetylenic ketones.

Scheme 4.3z

as an active ion carrier against gram-positive bacteria35 (Scheme 4.3dd). The chiral aldehyde 91 was converted to the corresponding lithium acetylide by a Corey–Fuchs protocol, and subsequent reaction of the anion with the Weinreb amide 92 resulted in the formation of the alkynone 93. Asymmetric reduction with the boron reagent (R)-79 afforded the alcohol 94 with 80% de. The alkynol 94 was then subjected to hydrogenation to yield the 1,3-diol derivative 95.

192

STEREOSELECTIVE REDUCTIONS

B 79

R

favored

O 2

OH

R1

R2

H

H R

R

O

B 2

R1 MAJOR

Me TS A

1

Scheme 4.3aa

B (S)-79

OH

O 82

83 (83% ee) 3. O3 1. H2, Pd/BaSO4 2. MEM-Cl

O

OTMS

1. MeO

O

O 85

H OMEM

OMe

OMe OH

2. TiCl4 (50%, 2 steps)

84

81, (−)-pestalotin

Scheme 4.3bb

B

Me3Si

Me3Si (S)-79

CO2Me

CO2Me

(82%)

OH 88 (94% ee)

O 87

3. MeOH, p-TsOH, 1. MOMCl, i-Pr2NEt HC(OMe)3 2. DIBAL (84%, 3 steps)

O O

H

HO2C OH

MeO

OH O H

Me3Si

O

OMOM 89

86, chlorothricolide

Scheme 4.3cc

OMe

REACTIONS

193

O 1. CBr4, Zn, PPh3 2. n-BuLi

CHO

TBSO

OPMB

O

3. MeO

91

TBSO

N Me (73%)

OPMB

93

92

B

(82%)

(R)-79

OH OH OPMB

TBSO

H2NNH2•H2O O2, Cu(OAc)2 (95%)

94 (80% de)

95

OH O

O

O O O

O

Na+ B−

O O O O

O

OPMB TBSO

O

OH

90, tartrolon B

Scheme 4.3dd

Nakada et al. utilized the Midland asymmetric alkynone reduction as a key step in the total synthesis of (+)-phomopsidin (96), which shows strong inhibitory activities against the assembly of the microtubule proteins puriﬁed from porcine brain36 (Scheme 4.3ee). The conversion of the δ-lactone 97 to its corresponding Weinreb amide followed by protection of the resulting free alcohol as an ethoxyethyl ether provided compound 98 in excellent yield. The amide 98 was treated with lithium trimethylsilylacetylide to afford the alkynone 99. Diastereoselective reduction with (S )-79 followed by removal of the TMS group gave the alcohol 100 as a single diastereomer in 88% yield over three steps.

194

STEREOSELECTIVE REDUCTIONS

OEt OEE 1. MeNH(OMe)•HCl Me2AlCl (78%)

O

O TMSC CH

NMe(OMe)

2. ethyl vinyl ether, PPTS (95%)

O 97

n-BuLi

O O

TMS 99

98

1. 2. TBAF (88% from 98)

B

CO2H

(S)-79

OEE H HO H HO 96, (+)-phomopsidin

H 100

Scheme 4.3ee

REFERENCES 1. Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979, 101 , 3129. 2. (a) Nishizawa, M.; Yamada, M.; Noyori, R. Tetrahedron Lett. 1981, 22 , 247. (b) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106 , 6717. 3. (a) Noyori, R.; Tanimoto, T. Y.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106 , 6709; (b) Noyori, R. Pure Appl. Chem. 1981, 53 , 2315. 4. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994; pp. 311–319. 5. Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1985, 107 , 3348. 6. van Innis, L.; Plancher, J. M.; Marko, I. E. Org. Lett. 2006, 8 , 6111. 7. Nishizawa, M.; Yamada, M.; Noyori, R. Tetrahedron Lett. 1981, 22 , 247. 8. Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem. Int. Ed. 2002, 41 , 3017. 9. Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem. Soc. Chem. Commun. 1981, 315. 10. Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc. Chem. Commun. 1983, 469. 11. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109 , 5551; (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109 , 7925; (c) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30 , 6275. 12. (a) Evans, D. A.; Science 1988, 240 , 420; (b) Corey, E. J.; Link, J. O.; Bakshi, R. K. Tetrahedron Lett. 1992, 33 , 7107; (c) Quallich, G. J.; Blake, J. F.; Woodall, T. M.

REACTIONS

13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

31. 32. 33. 34. 35. 36.

195

J. Am. Chem. Soc. 1994, 116 , 8516; (d) Alagona, G.; Ghio, C.; Persico, M.; Tomasi, S. J. Am. Chem. Soc. 2003, 125 , 10027. Jones, D. K.; Liotta, D. C.; Shinkai, I.; Mathre, D. J. J. Org. Chem. 1993, 58 , 799. Corey, E. J.; Rao, K. S. Tetrahedron Lett. 1991, 32 , 4623. Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61 , 3214. (a) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed . 1998, 37 , 1986; (b) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev . 2006, 106 , 2734. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37 , 4837. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117 , 558. Ponzo, V. L.; Kaufman, T. S. Tetrahedron Lett. 1995, 50 , 9105. Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119 , 12425. Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115 , 11028. Watanabe, H.; Takano, M.; Umino, A.; Ito, T.; Ishikawa, H.; Nakada, M. Org. Lett. 2007, 9 , 359. Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem. Soc. 1988, 110 , 1539. For reviews, see (a) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25 , 16; (b) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500 , 1. Rogic, M. M.; Ramachandran, P. V.; Zinnen, H.; Brown, L. D.; Zheng, M. Tetrahedron: Asymmetry 1997, 8 , 1287. Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem. 1988, 53 , 2916. Nicolaou, K. C.; Hepworth, D. Angew. Chem. Int. Ed. 1998, 37 , 839. Taber, D. F.; Zhang, Z. J. Org. Chem. 2006, 71 , 926. Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.; Trauner, D. J. Am. Chem. Soc. 2006, 128 , 17057. (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102 , 867; (b) Midland, M. M.; McLoughlin, J. J. J. Org. Chem. 1984, 49 , 1316. Midland, M. M. Chem. Rev. 1989, 89 , 1553. Rogic, M. M. J. Org. Chem. 2000, 65 , 6868. Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984, 106 , 4294. Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120 , 7411. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69 , 891. Suzuki, T.; Usui, K.; Miyake, Y.; Namikoshi, M.; Nakada, M. Org. Lett. 2004, 6 , 553.

LIST OF COPYRIGHTED MATERIALS The following transition states were redrawn with permission from the American Chemical Society and Elsevier. The American Chemical Society owns the copyright for material in the Journal of the American Chemical Society (JACS) and the Journal of Organic Chemistry (JOC). The copyright for articles in Tetrahedron Letters (TL) belongs to Elsevier. Transition State in Scheme: II 1.1g 1.4d 1.4g 1.5j 1.5l 1.6e 2.1q 2.1v 2.1aa 2.2b 2.2r 2.3a, 2.3b 2.3e 3.IV 3.VIII 3.1r

Redrawn from: Figures on p. 1922 in: Zimmerman and Traxler, JACS , 1957, 79 , 1920. Figure 1 in: Boeckman et al., JACS , 2002, 124 , 190. Scheme 7 in: Fox et al., JACS , 1999, 121 , 5467. Scheme 1 in: Davies and Jin, JACS , 2004, 126 , 10862. Scheme X in: Lee et al., JACS , 1990, 112 , 260. Scheme 3 in: Chen et al., JACS , 2000, 122 , 7424. Equation 2 in: Overman et al., JACS , 1983, 105 , 6629. Scheme IV in: Oppolzer et al., JACS , 1990, 112 , 2767. Scheme 7 in: Crimmins et al., JOC , 2001, 66 , 894. Figure 1 in: Boeckman and Connell, JACS , 1995, 117 , 12368. Figure I in: Masamune et al., JACS , 1986, 108 , 8279. Figure 1 in: Ghosh and onishi, JACS , 1996, 118 , 2527. Table 2 and Scheme 1 in: List et al., JACS , 2000, 122 , 2395. Figure 3 in: Sakthivel et al., JACS , 2001, 123 , 5260. Figures of 17 and 18 in: Hoffmann and Zeib, JOC , 1981, 46 , 1309. Figures of 5 and 6 in: Hoffmann and Landmann, TL, 1983, 24 , 3209. Figure of A and B in: Roush et al., JACS , 1985, 107 , 8186.

Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

197

198

LIST OF COPYRIGHTED MATERIALS

Transition State in Scheme: 3.1u 3.2b 3.2i 3.2l 3.2p 4.2b 4.3c

Redrawn from: Scheme I in: Roush and Palkowitz, JACS , 1987, 109 , 953. Scheme I in: Kira et al., JACS , 1988, 110 , 4599. Figure on p. 6430 in: Sato et al., JACS , 1989, 111 , 6429. Figure 7 in: Denmark et al., JOC , 2006, 71 , 1523. Scheme 2 in: Matsumoto et al., JOC , 1994, 59 , 7152. Scheme IV in: Evans et al., JACS , 1988, 110 , 3560. Figures of 11 and 12 in: Noyon et al., JACS , 1984, 106 , 6709.

ABBREVIATIONS AD-mix-β 9-BBN Bn Boc Bz BOM CDI m-CPBA CSA Cy DBU DDQ DEAD DIAD DIBAL-H DIPT DME DMF DMAP DMSO EDC HMPA HOBT KHMDS LDA MEM MOM MoOPH NaHMDS NBS NMM NMO Piv PMB

Reagent for Sharpless asymmetric dihydroxylation 9-Borabicyclo[3.3.1]nonyl Benzyl t-Butoxycarbonyl Benzoyl Benzyloxymethyl Carbonyldiimidazole m-Chloroperoxybenzoic acid Camphorsulfonic acid Cyclohexyl 1,8-Diazabicyclo[5.4.0]undec-7-ene 2,3-Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate Diisopropyl azodicarboxylate Diisobutylaluminum hydride Diisopropyl tartrate Dimethoxyethane N ,N -Dimethylformamide 4-Dimethylaminopyridine Dimethyl sulfoxide N -(3-Dimethylaminopropyl)-N ’-ethylcarbodiimide Hexamethylphosphoramide 1-Hydroxybenzotriazole Potassium hexamethyldisilazane Lithium diisopropylamide Methoxyethoxymethyl Methoxymethyl Oxidodiperoxymolybdenum(pyridine)(hexamethylphophoramide) Sodium hexamethyldisilazane N -Bromosuccinimide N -Methylmorpholine N -Methylmorpholine N -oxide Pivaloyl p-Methoxybenzyl

Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

199

200

ABBREVIATIONS

PPTS Py TBAF TBDPS TBS TES TFA THF TIPS TMEDA TMS Tf Tol TPAP Tr Ts

Pyridinium p-toluenesulfonate Pyridine Tetra-n-butylammonium ﬂuoride t-Butyldiphenylsilyl t-Butyldimethylsilyl Triethylsilyl Triﬂuoroacetic acid Tetrahydrofuran Triisopropylsilyl N ,N ,N ’,N ’-Tetrmethylethylenediamine Trimethylsilyl Triﬂuoromethanesulfonyl Toluene Tetrapropylammonium perruthenate Trityl p-Toluenesulfonyl

SUBJECT INDEX Ab initio calculations, 39 Abbreviations, listing of, 199–200 Acetaldehyde, 49, 62, 98, 133, 142 Acetic acid, 153, 161 Acetone, 91, 93 Acetonide, 62, 136, 156, 165–167 Acetonitrile, 75, 161 Acetophenone, 148, 181 Acetoxy groups, 162 Acetylaldehyde, 54, 133 Acyclic substrates, 9 Acylation, 118 Acyl chloride, 30 Acyloxazolidinone, 81 3-Acylpyrrolidines, 45 Acylthiazolidinethiones, 82 Adda, 31–32 (−)-Aﬂastatin A, 87 AIDS, 77. See also HIV replication Alcohol(s), 26, 106–107, 110–112, 115, 117–118, 120–121, 124–126, 129, 131, 133, 139–141, 173–176, 181, 183, 188, 190–191, 193 Aldehydes, 13, 16–17, 26, 49, 61–62, 66–67, 70, 79, 84, 91–93, 95–98, 102–103, 107–108, 110–111, 113, 116–117, 123–124, 132, 134–136, 139–141, 170–171, 173, 188, 190–191 Aldol reactions: asymmetric anti-, 78–90 asymmetric syn,- 57–77 deﬁned, 49 diastereoselective, 49–52, 56, 73, 81 1,3-diaxial interactions, 52 proline-catalyzed asymmetric, 91–96 Aliphatics, 5, 79, 81, 91, 93–94, 123, 141, 178, 184, 186 Alkannin, 187–188 Alkenes, 9, 25, 121 Alkenyl groups, 175 Alkoxy groups, 95

Alkyl groups, 49, 53, 95, 173, 178, 185 3-Alkylidene tetrahydropyran, 80 Alkynone, 191, 193 Allyboration, Roush method, 118–119 Allylation, 105 2-Allylcyclohex-2-en-1-one, 184 Allyl groups, 9, 13, 123 Allyl iodide, 15 Allylboranates, 116 Allylborane, 115, 125 Allylboration, 106, 115, 122 Allylboronates, 118, 120 Allylboronic acid, 98, 100 Allyldimethylphenylsilane, 140 Allylic alcohol, 24, 26, 40 Allylmagnesium bromide, 122, 170 1-Allyl-2-naphthol, 5 1-Allyl-1-phenylsilacyclobutane, 140 Allylsilane, 140, 184 Allylsilicates, 127–128, 130 Allyltributyltin, 123 Allyltriﬂuorosilanes, 132–135 Allyltrimethylsilane, 127–128, 139 Allyl vinyl, 13–14 α-Acetoxy enolsilane, 96 α-Alkoxyaldehyde, 95 α-D-glucosaccharinic acid lactone, 30 (+)-α-Pinene, 104, 106, 184, 188, 191 α-Silyloxy, 96 Aluminum hydride, 147 Alzheimer’s Disease, 86 Amides, 193 Aminoacetal, 183 Amino acids, 31, 82, 91 Amino alcohols, 46, 77, 179 (2S, 3S, 8S, 9S, 4E, 6E)-3-Amino-9-methoxy-2,6, 8-trimethyl-10- phenyldeca-4,6y-dienoic acid, 31 Ammonium chloride, 5 Amphidinolide T3, 124–125 Anabaena cylindrical, 156

Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

201

202 Anachelin H, 156 Anionic Oxy-Cope rearrangement, 36–42 Anodic oxidation, 188 Ansamycin antibiotic group, 117 Anti-aldol products, 58 Antibiotics, 29, 64–65, 121, 158, 162, 190 Anticancer drugs, 25 Antidepressants, 185 Anti-1,3-diol monoester, 26 Anti-isomer, 1, 50 Apoptolidin, 113 Apoptosis, 121 Aromatics, 2, 5, 12, 79, 91–93, 123, 127, 141, 178, 186 (−)-Asteriscanolide, 35 Aza-Cope-Mannich rearrangement, 43, 45–48 Azide, 25 Azumamide A, 109 B-allyldiisopinocampheylborane, 106 Baeyer-Villiger oxidation, 48 Baﬁlomycin A1 , 117, 121 1BBu2 , 151 B-chloropropiophenone, 185 (+)-Bengamide E, 75 Benzaldehyde, 1, 36, 43, 49, 52, 63, 81, 83, 89, 121, 130, 138, 140–141, 159, 167 Benzene, 12, 47, 177 Benzoate, 184 Benzoic acid, 157 Benzoin, 134 Benzoylacetylenic ketoester, 189 Benzyl ester, 31 Benzyloxyacetaldehyde, 77, 165 4-Benzyloxy-3-methoxybenzaldehyde, 87 3-Benzyloxypropanal, 70, 113 β-hydroxy ketones, diastereoselective reduction: anti-, 161–173 syn, 151–160 β-pyrrolidinopropionate ester, 31 B-H bonds, 181 B-isopinocampheyl-9-borabicyclo[3.3.1]nonane, 188 Bi-2-naphthol (BINOL), 173 Binaphthol-modiﬁed lithium aluminum hydride (BINAL-H), 173–177, 179 Bisphosphonamide, 137 B-methoxydiisopinocampheylborane, 106 Boatlike transition structure, 1–2, 5, 9–10, 12, 22, 39, 83, 95, 147–148, 185 Boltzmann distribution, 54 9-Borabicyclo[3.3.1]nonane (9-BBN), 51, 143, 188

SUBJECT INDEX Borane, 106, 179–180 Borolanes, 122 Boron: allylation, 125–126 enolates, 61–63, 69, 76, 79, 97 -oxygen bonds, 53 triﬂuoride etherate, 111 Bromoborane, 123 Bromonaphthalene, 187 Brown allylation, 107–108 Bryostatin 2, 170 2-Butenes, 111 3-Butenylmagnesium bromide, 66 Butyl groups, 57–58 Calcimycin, 30–31 (−)-Calicheamicinone, 110, 115 (−)-Callystatin A, 72 (+)-Calopin dimethyl ether, 17, 19 (+)-Camphor, 102–103 Camphorsulfonic acid (CSA), 48, 159 Cancer: anticancer drugs, 25 carcinogenesis, 65 gastric, 26 leukemia, 183 tumor cell lines, 170, 177 Carbamate, allylic, 184 Carbohydrates, 96 Carbon-carbon bond, 49, 97, 106 Carbon-hydrogen bond, 39 Carbonyl: carbon, 107 compounds, 51 groups, 49, 117, 189 oxygen, 147 Carbonyldiimidazole (CDI), 62 Carbon-oxygen bond, 24, 40 Carboxylic, generally: acid, 40, 70 group, 73 Carcinogenesis, 65 (+)-2-Carene, 104, 107 Catalysis, 162 Catecholborane, 181–183 Cetirizine hydrochloride, 181 Chairlike transition state, 1–2, 5, 8–10, 15, 21–22, 26, 32, 38, 50, 53, 55, 57, 62, 78, 83, 89, 95, 98–99, 102–103, 106, 122–123, 130, 132–134, 136–137, 140, 142, 147–148, 152, 175, 162, 180 Chelation, 49, 71–72, 158–159 Chiral auxiliary, 57, 60–61, 63, 65, 67, 70, 73, 75–76, 81, 83–84, 88–90, 123, 139

203

SUBJECT INDEX Chirality transfer: Claisen rearrangements, 13, 15 Johnson-Claissen rearrangement, 24 S-Z, 15 Chlorine, 142 Chloroperbenzoic acid, 159 (−)-Chlorothricolide, 190, 192 Chlorotitanium, 70–72 Chlorotrimethylsilane, 81, 87 Chorsimate, 3 Chromatographic analysis: column, 124 high-performance liquid, 63 thin-layer, 63 Chromophores, 63 Ciguatoxin (CTX3 C), 118 Cinnamaldehyde, 16, 81, 84, 88, 90 Cinnamyl alcohol, 20 Cis-octahydroindoles, 46 Cis-3-methyl-6-phenyl-1,5-heptadiene, 32 Cis-2-octalone, 37 Claisen, Ludwig, 5 Claisen rearrangement, 3–7, 9–10, 13–19, 49 (+)-Clavosolide A, 166 Cleavage, 70, 81, 83, 90, 118, 121, 136, 139, 157, 159, 168, 171 Collins agent, 22 Colony-stimulating factor, 66 Compactin, 153 (+)-Conagenin, 159–160 Cope, Arthur C., 9 Cope-Claisen rearrangement, 34 Cope rearrangement, 5, 9–10, 32–36, 49 Copyrighted materials, list of, 197–198 Corey-Bakshi-Shibata (CBS) reduction, 180–181, 183–184 Corey-Fuchs protocol, 191 Coulombic repulsion, 112 Coulomb interaction, 117 Countercation, 147 (+)-CP-263, 114, 42 Crimmins aldol condensation, 73 Crotylation, 111–113, 128, 130, 132, 136, 141, 143–144 Crotylboration, 113, 117, 121 Crotylboronates, 97–98, 105–106, 117 Crotyldiisopinocampheylborane, 112 Crotylpotassiums, 111 Crotyl propenyl ethers, 7 Crotylsilanes, 133–134, 141, 143–144 Crotylsilicates, 128–130 Crotyltrichlorosilanes, 127, 131–132 Crotyltriﬂuorosilane, 135–136 Cryptophycin 1, 170

Crystallization, 63, 68 (+)-Curacin A, 105, 108 CTX3 C, 118 Cyclobutene, 35 Cycloheptenone, 34 Cyclohexanes, 3–4, 33, 93 Cyclohexenyl silylketeneacetals, 9 Cyclononadiene, 42 Cyclooctadiene, 36 Cyclopentanols, 46 Cyclopentene, 40 Cyclopentenone, 42, 175 Cyclopentylidene ketal, 166 Cyclopropyl ketone, l34 Cytotoxicity, 72, 142–143, 156, 177 Dean-Stark trap, 47 Decanal, 47 Deep vein mycoses, 171 (+)-9(11)-Dehydroesterone methyl ether, 14, 16 (−)-Denticulatin A, 68–69 6-Deoxyerythronolide, 59 6-Deoxy-L-glucose, 30 Depression-related disorders, 138 Deprotection, 14, 25, 156, 159, 190 Deprotonation, 49 Deprotonation, 75 Dermostatin A, 171–172 Desilylation, 62, 69, 171, 175 Dess-Martin periodinane, 183, 190 D-glyceraldehyde acetonide, 117 Dialdehydes, 22, 142 Dialkenyl cyclobutane, 36 Dialkylboron, 51–52 Diallyl ethers, 15–17 Diaminocyclohexane, 138 Diarylbutane, 143 Diastereofacial selectivity, 94 Diastereomer, 81, 90 Diastereoselectivity, 38, 45, 49, 52, 56, 73, 75–76, 81, 89, 97, 99, 113, 124, 127, 130, 132, 134–135, 140–141, 143, 158. See also β-hydroxy ketones, diastereoselective reduction Diasterofacial selectivity, 79 Diasteromer, 25, 46 Diaxial interactions, 13, 15, 21, 52 Diazomethane, 31, 156 DIBAL-H, 62, 70 DIBAL reduction, 190 Dibenzocyclooctadiene, 143 Dibutylborinate, 153 Dibutylboron triﬂuoromethanesulfonate, 52 1,2-Dichlorobenzene, 15, 18

204 Dichloromethane, 80 Dicyclohexylboron, 78, 80, 171 Dienes, 10, 12, 29, 36, 42, 165, 190 Dienols, 38 Diethylzinc-aldehyde, 16 Diglyme, 38 Dihydrocinnamaldehyde, 126 (+)-Dihdyrocostunolide, 33 (9S)-Dihydroerythronolide A, 73 (+)-Dihydromayurone, 40–41 Dihydroxylation, 136, 168, 184 3,4-Diiodofuran, 188 (−)-Diisopinocampheylchloroborane, 184 1,3-Diketone, 15 Dilithium catecholate, 127 Dimerization, 95–96 2,3-Dimethoxy-4-methylbenzaldehyde, 17 1-Dimethylamino-3-butene, 43 Dimethylborinate, 62 (2S, 5S)-Dimethylborolane triﬂoromethanesulfonate, 78 2,2-Dimethylbutane (DMB), 35 3,5-Dimethylphenol, 149 Dimethylsulfoxide (DMSO), 92 Diols, 22, 25–26, 31, 62, 95, 113, 120, 126, 134, 151–153, 156–159, 166–167, 184, 191 Dioxatetracyclic, 125 (−)-DIP-chloride, 184 2,3,-Diphenyl-3-hydroxypropionic acid, 1 Diphenylprolinol, 180 Dipole-dipole interactions, 99 Dipropionate, 135 Dirhodium tetrakis[(S)-N-(dodecylbenzenesulfonyl) prolinate, 35 (+)-Discodermolide, 15, 25, 66–67, 119, 121 Disuccinyl carbonate, 75 Dithiane, 156 Dithiolane, 69 1,2-Divinylcyclobutanoxide, 41 Dolabelide D, 143 Dysentery, 40 Dysidiolide, 183 (−)-Ebelactone A, 164–165 (E)-Crotyl propanoate, 29 (E)-4-Decenoic acid, 27 E-Enolates, 49–50, 53–54 Electron repulsion, 142, 175 Electrostatic: interactions, 83 repulsion, 75 (E)-4-Methyl-4-hexenal, 188 (E)-2-Methyl-3-phenyl-2-propen-1-ol, 21

SUBJECT INDEX Enantiofacial selectivity, 93, 189 Enantiomer, 142 Enantiomeric ratio, 112 Enantioselectivity, 16, 35–36, 40, 92, 96, 103, 105, 107–108, 121, 123, 126, 137, 141, 143, 148–149, 173, 175–176, 179, 181, 184 Enediol isofuran, 188–189 Enolates, 166 Enol borinates, 51–52 Enone, 159 Epothilone A, 93, 153–154 Epoxidation, 40 Epoxide, 40 (−)-Erinacine B, 184–185 Erythromycins, 59 Erythronolide A, 159–160 Esterases, 73, 165 Esteriﬁcation, 30–31, 34 Estrogens, 14 1,2-Ethanedithiol, 68 Ethanol, 20, 173 Ethyl: acetate, 81 acetoacetate, 5 orthoacetate, 20, 22 Ethylene, 35, 18 3-Ethyl-3-pentanethiol group, 78 Evans-Chapman-Carreira reduction, 73, 161–162, 166 Evans-Tishchenko reduction, 25, 167–168, 170–171, 173 (−)-3-Exo-morpholinoisoborneol (MIB), 16–17 FD-891, 70 FKBP12, 168 FK-506, 124 Fluoride, 132 Fluorine, 100 Formaldehyde, 49, 53, 98, 147 Formalin, 45 (±)-Frullanolide, 30–31 Furan, 66 (±)-Garsubellin A., 15, 18 Glucal, 115 Glucolipsin A, 63 Glucose, 95–96 Glycal, 30 Gram-positive bacteria, 191 Grignard reagent, 42 Half-chair transition state, 185

205

SUBJECT INDEX Hardy, Elizabeth M., 9 Hemiacetal, 168 (−)-Hennoxazole, 182 Hepatotoxic cyclic peptides, 31 (−)-Heptemerone B, 188, 190 1,5-Hexadiene derivatives, 10 Hexamethylphosphoramide (HMPA), 29, 31, 34, 156 (+)-Hippospongic acid A, 26 HIV replication, 162 Homoallylic alcohols, 97 Hydroboration, 121, 143 Hydrocinnamaldehyde, 81 Hydrogen: characterized, 53, 103 chloride, 185 ﬂuoride, 60 Hydrogenation, 121, 136, 177, 191 Hydrogenolysis, 47 Hydrolysis, 30–31, 34, 43, 70, 179, 182 Hydroxy groups, 162 3-Hydroxy-1,5-hexadienes, 37 Hydroxyl group, 45, 88, 110, 159, 190 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), 153 Hyodeoxycholic acid methyl ester, 118, 121 Hyroindolone, 47 Imidazole, 110 Iminium ion, 43, 45–46, 184 Indanolyloxy oxygen, 89 Indolizidine alkaloid, 24–25 Interiotherin A, 142–143 Iodolactone, 31 Iodolactonization, 31 Ireland-Claisen rearrrangement, 27–32 Iridium, 16 Isobutyraldehyde, 58, 92, 123, 171 Isomerization, 15–17 Isomutyl group, 14 Isopinylboryl enolate, 170 Isopropyl groups, 168 2,3-Isopropylidene-L-erythrose, 24 Isopropylidenetriphenylphosphorane, 24 Isoxazoline, 153 Ivanov reaction, 1 Japanese beetle pheromone, 176–177 Johnson-Claisen rearrangement, 20–26 Ketoacid, 93 Ketoaldehyde, 170

Ketones, 26, 40–41, 47, 52, 97, 121, 124, 131, 134, 147–1513, 156–159, 161–162, 166–168, 173–181, 183–184, 186, 188–190 KOMe, 39 Lactam, bicyclic, 73 Lactols, 68, 143 Lactone, 25–26, 30–31, 177, 193 Lactonization, 25, 31 Lasalocid A (X537A), 29–30 (+)-Lasonolide A, 69, 116, 120 L-deoxythreose ketal, 117 Leighton’s silicon reagent, 142 (−)-Lepadiformine, 177 Leucascandrolide A, 171–172 Leukemia cancer cell lines, 183 Leustroducsin B, 66 Ligands, 58, 78, 126–127, 134 Lipases, 73, 165 Lithiation, 34 Lithium: acetylide, 191 alkoxyaluminum hydride, 147 aluminum hydride, 22, 147–149 characterized, 187 diisopropylamide (LDA), 27, 34, 49, 51 enolates, 52 hydroperoxide, 62 peroxide, 64 trimethylsilylacetylide, 193 l-proline, 91 Lung carcinoma cells, 120, 183 Lutidine, 109, 119, 122, 141–142, 157, 182 LY426965, 138 Macrolactin A, 162–163 Magnaporthe grisea, 188 Magnesium: bromide, 84 chloride, 81 enolate, 1 Mannose, 96 Mannosidases, 25 Mesityl phenyl ketone, 147 Meso-dialdehyde, 68 Mesylation, 25 Metal allylation reactions: boron allylation reaction, 102–126 characterized, 97–101 silicon allylation reaction, 127–144 Metal-centered steric effects, 52 Metal enolates, 91 Metallocycle, 89

206 Metal-oxygen bonds, 53 Methacrolein, 144 Methanol, 39, 153 Methanolysis, 26, 106, 110 Methoxyallyl, 113 Methoxydiethylborane, 153 Methoxyethoxymethyl (MEM), 80 Methoxy ketone, 37 Methoxypropene, 15, 114, 133 Methyl: acetals, 9 groups, 8, 21, 35, 133, 158, 185 iodide, 41 monate C, 175–176 propanoate, 50 Methylamine, 185 Methylation, 41 3-Methyl-2-butanone, 184 Methylenation, 121 (3R,5E)-3-Methyl-3-phenyl-1,5-heptadiene, 32 2-Methyltetrahydropyran, 13 Microcystins, 31 Midland reduction, 189–190, 193 Migrastatin, 87 Mitsunobu conditions/reaction, 115–116, 183 Miyakolide, 79 Monoazide, 25 Monoesters, 171 Monolithiation, 188 Monosilyation, 31, 142 (−)-Morphine, 184 (+)-Murisolin, 111, 115–116 Naphthalenes, meso, 10, 12 2-Naphthyl, 179 Narasaka reduction, 153 N-bromosuccinimide (NBS), 122, 124, 156 Neurodegenerative diseases, 86 N-formylmethionine aminopeptidases, 165 Nikkomycin B, 108, 111 Nitrile oxide, 115 4-Nitrobenzaldehyde, 92 Nitrogen, 142 (−)-N-methylephedrine, 149 N,N-dimethylformamide (DMF), 131–132 Nonactin, 156 Norephedrine, 61, 78, 80 Norpseudoephedrine, 136 N-oxazolidinethione propionates, 71 Noyori reduction, 175 Nozaki-Hiyama-Kishi reaction, 26 N-propionylbornanesultam, 68–69 N-propionyloxazolidinone, 63, 66, 83, 87, 165, 170

SUBJECT INDEX N-propionyloxazolidinethione, 72 N-propionylsultam, 67 Nuclear magnetic resonance (NMR), 67, 132 Nucleophilicity, 132 (2E,6E)-Octa-2,6-diene, 12 (2Z,6Z)-Octa-2,6-diene, 12 Oleﬁnation reaction, 165, 168 Oleﬁns, 17, 136 Organolithium, 188 Orostanal, 121 Oxazaborolidine, 179–181, 183 Oxazolidine, 47 Oxazolidinones, 61–63, 75 Oxidation, 22, 48, 73, 80, 112, 158, 165, 183, 188 Oxidative lactonization, 25 Oxirane, 41 Oxygen, 106, 116, 158 Ozonolysis, 108, 110, 112–113, 118, 142, 190 (±)-Pancracine, 45–46 Parkinson’s Disease, 86 3-Pentanone, 50 (−)-Pestalotin, 189, 192 Pharmacotherapy, 138 Phenylacetic acid, 1 1-Phenyl-3-buten-1-ol, 139 Phenyl groups, 79, 130, 134, 175, 180–181 Phenylmagnesium bromide, 179 Phenyls, 103, 137 (+)-Phomopsidin, 193–194 Phorbol, 65 Phorboxazole A, 106, 108, 123–124 Phosphonate, 188 Phosphonium bromide, 31 Pictet-Spengler cyclization, 47 Pinacolboronates, 100 Pinacolone, 148 Pivalic acid, 156–157 4-(Pivaloyloxy)benzaldehyde, 112 (±)-Pleuromutilin, 40, 46 p-methoxybenzyl (PMB), 65, 144, 170 p-methoxybenzyl ether, 83 p-nitrobenzoate, 170 Polyols, 83, 124 Potassium: hydride, 37, 40 hydroxide, 125 methoxide, 39 Prelog-Djerassi lactonic acid, 60 (+)-Preussin, 47–48 Propanal dihydroborinate, 53 2-Propenyllithium, 22

SUBJECT INDEX 2-Propenylmagnesium bromide, 166 Propionamide, 65 Propionic acid, 20, 22, 25 Propionyl chloride, 31, 73, 75 Prostaglandin A2 , 24 Prostaglandin E2 (PGE2), 175–176 Proteases, 89 Prozac, 185 Pseudoenantiomerics, 71 Pseudoephedrine, 138, 141 Pseudomonic acid C6 , 175 Psymberin, 141–143 P388 murine leukemia cancer cell lines, 183 p-toluenesulfonic acid, 70, 177 p-triﬂuoromethylphenol, 185 Pyridine, 31, 109–110, 114, 176, 183, 185 Pyridinium p-toluenesulfonate (PPTS), 15, 156, 166 Pyrrolidines, 31, 45–46, 48, 93, 137 Quantum mechanics, 5 Quenching, 153 Racemic 3,4-dimethylhexa-1,5-diene, 12 (−)-Rapamycin, 168–169 Ras farnesyltransferase, 42 Rat glia cells, 113 (R)-4-Benzyl-3-propionyloxazolidin-2-one, 73 Recrystallization, 185 R group, 13, 27, 49, 52 Rhizoxin D, 80, 84 Rhodium, 36, 40 Rifamycin S, 114, 117 RK-397, 165–166 (+)-Roxaticin, 164, 166 (R)-Phenylglycine, 84 (R)-1-Phenyl-1-propanol, 179 (R,R)-Bromoborane, 124 (R, R)-Dimethyl tartrate allylboronate, 117 R2 , 162 Rutamycin B, 64–65 Ruthenium, 15, 35 (−)-Salsolene oxide, 40–41 (1S)-(−)-Salsolidine, 182–183 Samarium, 168, 170–171 Saponiﬁcation, 31–32, 170 Saquinavir, 76–77 (+)-Saudin, 15, 17 Scandium, 103, 106 (−)-Scopadulcic acid A, 34 (S)-Cyclohexenol, 184 (S)-(−)-2-(Diphenylhydroxymethyl)pyrrolidine, 179

207 Selenoxide, 26 Serotonin, 138 Sesquiterpenes, 40 S-3-(3-Ethyl)pentylpropanethioate, 78 (S)-Fluoxetine hydrochloride, 185, 187 Sharpless dihydroxylation, 25 [3,3]-Sigmatropic rearrangements: anionic Oxy-Cope, 36–42 aza-Cope-Mannich, 43, 45–48 Claisen, 3–7, 9–10, 13–19, 49 Cope, 5, 9–10, 32–36, 49 Ireland-Claisen, 27, 29–32 Johnson-Claisen, 20–26 Signal transduction, 66 Silacyclobutanes, allylic, 140 Silanes, 131, 136–138, 171 Silicon, 140 Silylation, 70, 81, 121, 124, 170 Silyl enol, 14 Silylketene acetals, 27, 31 Silyloxy cycloheptadiene, 34 Silyls, 25, 31 (S)-mandelic acid, 57, 59 Smoking cessation, 138 Sodium: borohydride, 147, 153 hypochlorite, 115 metaperiodate, 60 (−)-Sparteine, 71–73 (S)-Phenylalanine, 63 Spirocyclization reaction, 179 (S)-Prolinol, 178–179 Squalene, 22–23, 42 Stannane, 124 (−)-Stemoamide, 83–84, 88 Stemona, 83 Stereochemistry, 116 Stereoselective reactions: asymmetric reduction, 173–194 characterized, 147–150 diastereoselective anti-reduction of β-hydroxy ketones, 161–173 diastereoselective syn-reduction of β-hydroxy ketones, 151–160 Stereoselectivity, 14, 20, 26, 78, 93, 134 Steric repulsion, 9, 57 Stien, 123 Stilbenediamine, 123 Stoichiometric borane, 179 Streptomyces: roseosporus, 159 toxytricini, 89 (−)-Strychinine, 46–47 Sulfate, 156

208 Sulfones, 168 Sultam propionate, 70 Sumarium iodide, 153 Suzukii-Miyaura coupling, 143 (S)-Valine methyl ester hydrochloride, 179 (S)-Valinol, 61 (−)-Swainsonine, 24–25 Swern oxidation, 73, 80, 121, 165 Swinholide A, 155–156 Syn-aldol reaction: asymmetric, 57–77 characterized, 52, 57 2,3-Syn-disubstituted 4-heptenol, 17 Syn-isomer, 50–52, 62 Synlanti, 21, 49 (−)-Talaumidin, 86, 88 Tartrolon B, 190, 193 TBSOTf, 70 Terpenoids, 184 Tert-butyl-dimethylsilyl (TBS): characterized, 9, 88, 118 chloride, 27, 31 ether, 143 keteneacetal, 10, 27, 157 Tert-butyldiphenylsilyl (TBDPS) ether, 70, 112 (+)-Testudinariol A, 80, 83 Tetraﬂuoroboric acid, 182 Tetrahydrofuran (THF), 15, 27–28, 30–31, 51, 125, 179 (−)-Tetrahydrolipstatin, 89–90 Tetrahydropyran, 176 Tetramethylammonium triacetoxyborohydride, 166 Tetraol, 171 Tetrodotoxin, 15, 18 Tetronic acid, 115 Thermal rearrangement, 32 Thianes, 73 Thiazolidinethione, 81, 84 Three-carbon system, 10 Threo-isomer, 1 Tirandamycin, 158–159 Titanium, 71–72, 88–90 TMSCl, 34 Toluene, 30–31, 42, 114, 117–119, 138, 141, 181–182 Transamidation, 66 Transition state. See speciﬁc types of transition states Transmetalation, 124

SUBJECT INDEX Trans-3-methyl-6-phenyl-1,5-heptadiene, 32 Triacetoxyborohydride reduction, 167 Trialkylsilanes, 127 Trichloroacetimidate, 63 (+)-Trienomycinol TBS ether, 62–63 (+)-Trienomycins, 62 Triethylamine, 24, 76, 78, 80–81, 133 Triethyl borane/sodium borohydride, 153 Triethylsilylketene acetal, 31 Triﬂuoroacetic acid, 121 Triﬂuoroperoxyacetic acid, 48 Triisopropylsilyl triﬂate, 170 Trimethylbenzoyl chloride, 182 Trimethyl orthoacetate, 24 Trimethylsilyl, 123, 139, 159 4-Trimethylsilyloxyl-1,2-dihydronaphthalene, 35 Trisallylborane, 126 Tris(triphenylphosphine)ruthenium(II) dichloride, 15 Tumor cell lines, 170, 177 Twist boat-like transition, 53, 55, 82, 98, 152 U.S. Food and Drug Administration (FDA), 77 Valilactone, 73–74 Valinol, 178 Vinyl bromide, 26 Vinyldiazoacetate, 36 Vinyl iodide, 165, 184 Vinyllithium, 41 Weinreb amide, 62, 66, 83, 170, 187, 191, 193 Wilkinson’s catalyst, 121 Wittig oleﬁnation, 165 Wittig reaction, 32 Xenical, 90 X537A, 29–30 X-14994, 166 Xylene, 25 Z-boronate, 97 Z-enolates, 49, 52–54, 58 Zimmerman-Traxler transition state, 2–3, 49, 68, 79, 81, 89 Zinc: alkoxide, 16 borohydride, 157–158 Zincophorin, 136 Zyrtec, 181

SCHEME INDEX OF NATURAL PRODUCTS adda, 1.3 h (−)-aﬂastatin A, 2.2n alkannin, 4.3w amphidinolide T3, 3.1gg anachelin H, 4.1i apoptolidin, 3.1 l (−)-asteriscanolide, 1.4e azumamide A, 3.1 m (−)-baﬁlomycin A1 , 3.1x (+)-bengamide E, 2.1bb bryostatin 2, 4.2 l calcimycin, 1.3 g (−)-calicheamicinone, 3.1o (−)-callystatin A, 2.1w (+)-calopin dimethyl ether, 1.1 l cetirizine hydrochloride (Zyrtec), 4.3 m (−)-chlorothricolide, 4.3cc (+)-clavosolide A, 4.2 g compactin, 4.1e (+)-conagenin, 4.1n (+)-CP-263,114, 1.5 l cryptophycin 1, 4.2k CTX3 C, 3.1v (+)-curacin A, 3.1 h (+)-9(11)-dehydroestrone methyl ether, 1.1f (−)-denticulatin A, 2.1r 6-deoxyerythronolide B, 2.1e dermostatin A, 4.2 m (+)-dihydrocostunolide, 1.4c (9S )-dihydroerythronolide A, 2.1x (+)-dihydromayurone, 1.5j (+)-discodermolide, 1.2i, 2.1o, 3.1z dolabelide D, 3.2w dysidiolide, 4.3p (−)-ebelactone A, 4.2 d

enediol isofuran, 4.3x epothilone A, 2.3c, 4.1f (−)-erinacine B, 4.3r erythronolide A, 4.1 m FD-891, 2.1t FK-506, 3.1ee (S )-(+)-ﬂuoxetine hydrochloride (Prozac), 4.3v (±)-frullanolide, 1.3f (±)-garsubellin A, 1.1i glucolipsin A, 2.1j glucose, 2.3 g (−)-hennoxazole, 4.3n (−)-heptemerone B, 4.3y (+)-hippospongic acid A, 1.2j interiotherin A, 3.2v Japanese beetle pheromone, 4.3f lasalocid A (X537A), 1.3e (+)-lasonolide A, 2.1s, 3.1w (−)-lepadiformine, 4.3 g leucascandrolide A, 4.2n leustroducsin B, 2.1n LY426965, 3.2m macrolactin A, 4.2c mannose, 2.3 g methyl monate C, 4.3e migrastatin, 2.2 m miyakolide, 2.2e (−)-morphine, 4.3q (+)-murisolin, 3.1p nikkomycin B, 3.1k nonactin, 4.1 h

Six-Membered Transition States in Organic Synthesis, By Jaemoon Yang Copyright  2008 John Wiley & Sons, Inc.

209

210

SCHEME INDEX OF NATURAL PRODUCTS

orostanal, 3.1y

saquinavir, 2.1dd (+)-saudin, 1.1 g (−)-scopadulcic acid A, 1.4 d squalene, 1.2f (−)-stemoamide, 2.2o (−)-strychnine, 1.6 g (−)-swainsonine, 1.2 h swinholide A, 4.1 g

(±)-pancracine, 1.6f (−)-pestalotin, 4.3bb (+)-phomopsidin, 4.3ee phorbol, 2.1 m phorboxazole A, 3.1i, 3.1ff (±)-pleuromutilin, 1.5i (+)-preussin, 1.6 h prostaglandin A2 , 1.2 g prostaglandin E2 , 4.3 d Prozac ((S )-(+)-ﬂuoxetine hydrochloride), 4.3v psymberin, 3.2u (−)-rapamycin, 4.2j rhizoxin D, 2.2 g rifamycin S, 3.1u RK-397, 4.2f (+)-roxaticin, 4.2e rutamycin B, 2.1 l (−)-salsolene oxide, 1.5k (1S )-(−)-salsolidine, 4.3o

(−)-talaumidin, 2.2p tartrolon B, 4.3dd (+)-testudinariol A, 2.2f (−)-tetrahydrolipstatin, 2.2t tetrodotoxin, 1.1 h tirandamycin, 4.1 l (+)-trienomycinol TBS ether, 2.1i valilactone, 2.1y X537A (lasalocid A), 1.3e zincophorin, 3.2j Zyrtec (cetirizine hydrochloride), 4.3 m