Table Of Contenta-Hydraxy Acids in Enantioxlective Synthesis. Garry M. Coppola, Herbert F. Schuster
Copyright © 2002 WileyVCH Verteg GmbH & Co. KGaA
ISBNs: 3-527-29093-1 (Hardback); 3-527-60085-X (Electronic)
Gary M. Coppola
Herbert F. Schuster
a-Hydroxy Acids
in Enantioselective Syntheses
VCH
A Wiley company
Further Titles of Interest
Curran, D. P. /Porter, N. A. /Giese, B.
Stereochemistry of Radical Reactions
Softcover: ISBN 3-527-29409-1
Nicolaou, K. C. / Sorensen, E. J.
Classics in Total Synthesis
Hardcover: ISBN 3-527-29284-5
Softcover: ISBN 3-527-29231-4
Nogradi, M.
Stereoselective Synthesis. A Practical Approach
Second, Thoroughly Revised and Updated Edition
Hardcover: ISBN 3-527-29242-X
Softcover: ISBN 3-527-29243-8
Waldmann, H. (ed.)
Organic Synthesis Highlights II
Hardcover: ISBN 3-527-29200-4
Softcover: ISBN 3-527-29378-7
Gary M. Coppola
Herbert F. Schuster
a-Hydroxy Acids
in Enantioselective
Syntheses
VCH
A Wiley company
Gary M. Coppola
Dr. Herbert F. Schuster
Department of Metabolic Diseases
Novartis Pharmaceuticals Corporation
59 Route 10
East Hanover, NY 07936-1080
USA
This book was carefully produced. Nevertheless, authors and publisher do not warrant the infor-
mation contained therein to be free of errors. Readers are advised to keep in mind that statements,
data, illustrations, procedural details or other items may inadvertently be inaccurate.
Editorial Director: Dr. Gudrun Walter
Production Manager: Claudia Grossl
Cover picture: The molecule depicted on the cover is (+)-milbemycin J3s along with its electrostatic
isopotential surface. Milbemycin was chosen because the spiroketal portion of the structure was synthe-
sized from both malic and tartaric acids.
Library of Congress Card No. applied for
A catalogue record for this book is available from the British Library
Die Deutsche Bibliothek - CIP-Einheitsaufnahme
Coppola, Gary M.:
a-hydroxy acids in enantioselective syntheses /
Gary M. Coppola ; Herbert F. Schuster. - Weinheim : VCH, 1997
ISBN 3-527-29093-1
NE: Schuster, Herbert F.:
© VCH Verlagsgesellschaft mbH, D-69451 Weinheim (Federal Republic of Germany), 1997
Printed on acid-free and low-chlorine paper
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To
my wife, Maro,
and my children,
Stefan and Kristiana
H.F.S.
To
my parents,
Richard and Josephine Coppola,
my wife, Joanne,
and my children,
Matthew and Laura
G.M.C.
Preface
With the mechanical separation of the optical isomers of sodium ammonium tartrate, Louis
Pasteur, in 1848, realized that two molecules behaving differently toward polarized light,
despite the appearance of identical chemical properties, must be different. Chirality was born.
Nature produces enantiomerically and diasteromerically pure molecules with a wide range of
chiral carbon centers. Enzymes, possessing inherent chirality as a consequence of the unique
situation that all amino acids in living organisms are left-handed, provide rigid templates that
accommodate only specific spatial arrangements of atoms. Chemists, eager to imitate nature,
have developed very ingenious approaches that are capable of exploiting both steric and
electronic factors to produce chiral carbon centers with high optical purity.
The modern synthetic chemist has available a collection of asymmetric molecules from
nature's chiral pool that can be selectively transformed to incorporate their chiral centers into
a target molecule with excellent optical integrity. One important class of compounds from the
chiral pool is the amino acids, which are readily available in both S and R forms. The diversity
of functional groups present in the various amino acids allows for a range of synthetic
transformations leading to target molecules in which the initial amino acid chiral center either
remains intact or directs the formation of new chiral centers. Our book Asymmetric Synthesis:
Construction of Chiral Molecules Using Amino Acids, John Wiley & Sons, 1987, focused on
the synthetic utility of amino acids geared toward the synthesis of biologically active mole-
cules as well as natural products. The book was well received by the chemical community and
indicated to us the importance of keeping scientists aware of the availability and utility of
abundant chiral starting materials. With the pharmaceutical industry rapidly moving away
from the development of racemic drugs, it is becoming important to research and develop-
mental chemists to have access to synthetic routes that efficiently lead to each enantiomeric
form of a new drug in order to minimize potential adverse side effects from the undesired
antipode.
This prompted us to write a book focusing on the naturally occurring a-hydroxy acids,
which may be considered relatives of the amino acids since these a-hydroxy acids can be
obtained from amino acids in optically pure form. We have chosen to discuss the chemistry of
lactic, mandelic, malic, and tartaric acids, focusing on chemistry that incorporates the chiral
center of these acids into the final spatial arrangement of atoms. We also discuss how these
chiral centers can direct the creation of new chiral centers. Most of our chemical discussion is
concerned with the more abundant natural antipode of each of these acids. It should be kept in
mind that, unless otherwise noted, all the reactions employed in the transformation of the
natural antipode into a target molecule apply identically to the unnatural antipode. In fact, it is
the beauty of these chiral starting materials that identical chemical reactions can be used to
prepare all possible antipodes of a target molecule with excellent optical integrity.
Our goal is to provide chemists a concise and practical source of information regarding
asymmetric synthesis of a variety of compounds ranging from relatively simple molecules
with only one asymmetric center to exceedingly complex ones having numerous chiral
centers. Our schemes show the absolute stereochemistry of all the chiral carbon centers, and
provide detailed summaries of the reaction conditions employed. Wherever possible, we have
included both chemical and optical yields, as well as some indication of diastereomeric purity.
Our discussions focus on the important facts a chemist might need in order to undertake a
VIII Preface
synthetic challenge that utilizes a particular hydroxy acid. Tables of physical data for key
a-hydroxy acid derivatives are provided at the end of each of the chapters. Also, in the
accompanying appendices at the end of the book we include several tables of reaction con-
ditions used for the protection, deprotection, and manipulation of functional groups so one can
quickly view a menu of reagents and conditions for a particular chemical transformation.
It is our sincere hope that this book will provide you, the synthetic chemist, with new
opportunities for achieving your synthetic goals. For those students who are reading this book
in order to enhance your synthetic repertoire, we hope you will enjoy the chemistry and not be
intimidated by the sight of complex molecules. However, it is perhaps this sense of awe
evoked by the many beautiful molecules given to us by nature's laboratories that continues to
challenge chemists to recreate them for themselves.
East Hanover, New Jersey Gary M. Coppola
January 1997 Herbert F. Schuster
Contents
1 Lactic Acid 1
1.1 Reaction at the Ester Site 1
1.1.1 a-Alkylation of Lactic Acid 6
1.2 Inversion Reactions 11
1.2. Mitsunobu Reaction 13
1.2. .1 Sulfur Nucleophiles 13
1.2. .2 Oxygen Nucleophiles 14
1.2. .3 Nitrogen Nucleophiles 14
1.2. .4 Carbon Nucleophiles 15
1.2.2 O-Sulfonyl Lactates 16
1.2.2.1 O-(p-Toluenesulfonyl) L-Lactic Acid Derivatives 16
1.2.2.2 O-(Methanesulfonyl) L-Lactic Acid Derivatives 20
1.2.2.3 O-(Trifluoromethanesulfonyl) L-Lactic Acid Derivatives 25
1.3 O-Acyl Lactates 28
1.4 O-Protected Lactic Acid Derivatives 30
1.4.1 Acetyl 32
1.4.2 Benzyl 37
1.4.3 Benzyloxymethyl (BOM) 39
1.4.4 Ethoxyethyl (EE) 42
1.4.5 (Methoxyethoxy)methyl (MEM) 49
1.4.6 Methoxymethyl (MOM) 51
1.4.7 Silyl Groups 55
1.4.7.1 tert-Butyldimethylsilyl (TBS) 55
1.4.7.2 tert-Butyldiphenylsilyl (TBPS) 59
1.4.8 Tetrahydropyran (THP) 62
1.4.9 Triphenylmethyl (Trityl) 64
1.5 O-Protected Lactaldehydes 65
1.5.1 Benzyl 66
1.5.2 Benzyloxymethyl (BOM) 82
1.5.3 Ethoxyethyl (EE) 85
1.5.4 (Methoxyethoxy)methyl (MEM) 88
1.5.5 Methoxymethyl (MOM) 91
1.5.6 Silyl-Protected Lactaldehydes 95
1.5.6.1 tert-Butyldimethylsilyl (TBS) 95
1.5.6.2 tert-Butyldiphenylsilyl (TBPS) 109
1.5.7 Tetrahydropyran (THP) 111
1.5.8 Triphenylmethyl (Trityl) 118
1.6 D-Lactic Acid Derivatives 119
1.6.1 D-Lactaldehydes 122
References 132
X Contents
2 Mandelic Acid 137
References 165
3 Malic Acid 167
3.1 The Basics 167
3.1.1 Malic Acid Diesters and Amides 168
3.1.2 O-Protected Malates 168
3.2 Site-Selective Reactions of Malic Acid Derivatives 170
3.2.1 C-l Selective Reactions 170
3.2.1.1 Hydrolysis and Related Reactions 171
3.2.1.2 Reduction 175
3.2.1.3 Cyclization 189
3.2.2 C-2 Selective Reactions 192
3.2.2.1 Inversion Reactions 192
3.2.2.2 Alkylation 196
3.2.3 C-3 Selective Reactions 198
3.2.4 C-4 Selective Reactions 202
3.3 Reactions at Both Carboxylate Sites 213
3.3.1 Reduction 214
3.3.1.1 Acetals of (S)-l,2,4-Butanetriol 221
3.3.1.1.1 Five-Membered Acetals 222
3.3.1.1.2 C-2 to C-4 Six-Membered Acetals 257
3.3.2 Cyclization 263
3.4 (tf)-Malic Acid 275
3.5 Citramalic Acid 291
3.6 Addenda 298
References 308
4 Tartaric Acid 313
4.1 2,3-O-Isopropylidene Tartaric Acid Derivatives 314
4.2 2,3-O-Benzylidene Tartaric Acid Derivatives 368
4.3 Miscellaneous Diol-Protected Tartaric Acid Derivatives 386
4.3.1 Cycloalkylidenes 386
4.3.2 Orthoester Protection 394
4.3.3 Cyclic Sulfur and Carbonate Derivatives 401
4.3.4 Di-O-Alkylated Tartrates 407
4.3.5 Methoxymethyl Ether (MOM) Protection 415
4.3.6 Silyl-Protected Tartaric Acids 424
4.3.7 Vicinal Dihydroxy Ester-Protected Tartaric Acid Derivatives 430
4.3.8 Halohydrins from Tartaric Acids 446
4.3.9 Addenda 453
References 474
Appendix A Protection of Functional Groups 479
Appendix B Protective Group Removal 483
Appendix C Functional Group Manipulation 486
Appendix D Abbreviations 492
Index 495
a-Hydraxy Acids m Enantio&lective Synthesis. GmyM.Co^\a,tterbertf. Schuster
Copyright O 2002 Wiley-VCH Vertag GmbH & Co. KGaA
ISBNs: 3-527-29093-1 (Hardback); 3-527-60085-X (Electronic)
Index
Acetal exchange with benzaldehyde dimethyl Acetylene group
acetal 368 -oxidation of 284
Acetalization of (-)-(S,S)-diethyl tartrate 394 Acetylenic-vinylidene rearrangement 462
Acetal protecting group 388 (iS)-O-Acetylmandelic acid chloride
Acetate deprotection by methanolysis 43 1 , -reaction with organomanganese
432 compounds 148
Acetic anhydride/boron trifluoride 1 - Acety 1-3 -7V-(4-methoxybenzy l)hy dantoin
-dioxolane ring fission with 388 355
Acetonide group N-AcetyIneuraminic acid 119
-from carbonate group 233 Af-Acetylslaframine 299
-hydrolysis of 225, 235, 242, 247, 256, 290, (5)-2-(Acetylthio)-2-phenylacetic acid
322 -synthesis of 147
— with Amberlite IR 120 resin 251 (5)-2-(Acetylthio)propionic acid 14
— with dilute hydrochloric acid 320 (7?)-2-Acetylthiopropionic acid ethyl ester 23
-protection with 77, 186, 222, 288, 292, (7?)-2-Acetylthiopropionic acid methyl ester 17
479 L-Acosamine 85
-removal of 187, 228, 239, 483 A^-Acyliminium ion
— with Amberlyst-15 256 -alkylation of 268
-selective cleavage of 243 -cyclization 266, 270, 273
— in presence of TBPS group 230 —mechanism of 271
(S)-4-Acetoxy-3 ,6-dioxosuberate 213 0-Acyl (tf)-malates
-synthesis of 194
hexadecanolide 388 AHPBA 201
(5R,6S)-( - )-6-Acetoxy-5- (— )-Ajmalicine 114
hexadecanolide 334 D-Alanine derivatives
(S)-( — )-Acetoxypropionic acid 17 - diazotization of 119
L-2-Acetoxypropionic acid 32 L-Alanine 263
(S)-2-Acetoxypropionyl chloride - diazotization of 11
-preparation of 33 — in acetic acid 17, 32
(^)-Acetoxysuccinic anhydride 286 — in HC1 18
(2*S)-Acetoxysuccinic anhydride 173 (7?)-Alanine
(5)-3-Acetoxysuccinimides 264 -N-Eoc protected 27
(S)-( - )-2- Acetoxysuccinyl chloride 2 1 3 Alcohol
(#)-2-Acetoxy- 1 , 1 ,2-triphenylethanol 1 60 -alkylation of 186
TV- Acety 1-L-acosamine 98 -methylation of 237
TV-Acetyl-L-daunosamine - primary
-preparation of 386 — alkylation of 258
0- Acetyl (S)-isoserine 171 —benzylation of 235
Acetyl glycerol ether phosphorylcholines 371 — mesylation of 3
Acetyl group — selective silylation of 236
-introduction of 169 —tosylation of 5, 7, 236, 246, 261, 281
-protection with 31, 32, 479 -removal of
-removal of 31,34,217,266,483 — via xanthate ester 282
— by bromination 192 - secondary
— under acidic conditions 277 —benzylation of 238, 251
