Asymmetric Reactions and Processes in Chemistry 9780841207172, 9780841208780, 0-8412-0717-8

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Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.fw001

Asymmetric Reactions and Processes in Chemistry

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.fw001

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Asymmetric Reactions and Processes in Chemistry Ernest L . Eliel,

EDITOR

University of North at Chapel Hill Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.fw001

Sei Otsuka,

Carolina

EDITOR

Osaka University

Based on a U.S.-Japan seminar cosponsored by the Japan Society for the Promotion of Science and the National Science Foundation and held at Stanford University, Stanford, California, July 7-11, 1981.

ACS

SYMPOSIUM AMERICAN

CHEMICAL

WASHINGTON, D. C.

SERIES

185

SOCIETY

1982

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.fw001

Library of CongressCIPData Asymmetric reactions and processes in chemistry. (ACS symposium series, ISSN 0097-6156; 185) Includes index. 1. Chemistry, Organic—Synthesis—Congresses. 2. Stereochemistry—Congresses. I. Eliel, Ernest Ludwig, 1921- . II. Otsuka, Sei. III. Nippon Gakujutsu Shinkokai. IV. National Sci­ ence Foundation (U.S.). V. Series. QD262.A78 547'.2 82-3908 ASCMC8 185 1-300 ISBN 0-8412-0717-8 AACR2 1982

Copyright © 1982 American Chemical Society All Rights Reserved. The appearance of the code at the bottom of thefirstpage of each article in this volume indicates the copyright owner's consent that reprographic copies of the article may be made for personal or internal use or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc. for copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Law. This consent does not extend to copying or transmission by any means—graphic or electronic—for any other purpose, such as for general distribution, for advertising or promotional purposes, for creating new collective work, for resale, or for information storage and retrieval systems. The citation of trade names and/or names of manufacturers in this publication is not to be construed as an endorsement or as approval by ACS of the commercial products or services referenced herein; nor should the mere reference herein to any drawing, specification, chemical process, or other data be regarded as a license or as a conveyance of any right or permission, to the holder, reader, or any other person or corporation, to manufacture, repro­ duce, use, or sell any patented invention or copyrighted work that may in any way be related thereto.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.fw001

ACS Symposium Series M. Joan C o m s t o c k , Series Editor

Advisory Board David L. Allara

Marvin Margoshes

Robert Baker

Robert Ory

Donald D. Dollberg

Leon Petrakis

Robert E. Feeney

Theodore Provder

Brian M. Harney

Charles N. Satterfield

W. Jeffrey Howe

Dennis Schuetzle

James D. Idol, Jr.

Davis L. Temple, Jr.

Herbert D. Kaesz

Gunter Zweig

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.fw001

FOREWORD The ACS S Y M P O S I U M SERIES was founded in 1 9 7 4 to provide a medium for publishing symposia quickly in book form. The format of the Series parallels that of the continuing A D V A N C E S I N C H E M I S T R Y SERIES except that in order to save time the papers are not typeset but are reproduced as they are submitted by the authors in camera-ready form. Papers are reviewed under the supervision of the Editors with the assistance of the Series Advisory Board and are selected to maintain the integrity of the symposia; however, verbatim reproductions of previously published papers are not accepted. Both reviews and reports of research are acceptable since symposia may embrace both types of presentation.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

PREFACE The

possibility of an asymmetric synthesis was foreseen in L e

Bel's

pioneering 1874 paper on the asymmetric carbon atom and the idea was reduced to practice by E m i l Fischer, W. Marckwald, and A . McKenzie around the turn of the century. Although there seems to have been a long lasting air of mystery about asymmetric induction, the process was put on a firm mechanistic basis by the classical studies of W. Doering, L . M . Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.pr001

Jackman, H . S. Mosher, V . Prelog, and D . J . Cram around 1950. However, it was only in 1961 that a practical asymmetric synthesis proceeding in high optical yield—the hydroboration-oxidation of cw-2-butene by tetrapinanyldiborane—was achieved by H . C . Brown and G . Zweifel. 1971, when the definitive book in the area, Asymmetric

By

Organic Reactions

by J . D. Morrison and H . S. Mosher appeared, innumerable asymmetric reactions were on record and the mechanism of a number of them was quite well understood, but optical yields much in excess of 40-50 percent were surprisingly rare. Perhaps as a result of the publication of the Morrison-Mosher book or simply because the time was ripe, the situation has changed drastically in the last ten years.

Recent reviews by H . B. Kagan and J . C . Fiaud,

D . Valentine and J . W. Scott, and J . W. ApSimon and R. P. Seguin, as well as the current literature indicate large numbers of methods, probably now well over a hundred, by which chiral products may be obtained with enantiomeric excess in the 80- to 90-percent region.

Although such

methods have been reported from all over the chemically active world, a substantial number have originated either in Japan or in the United States. It therefore seemed timely to arrange a joint U.S.-Japan Seminar on the topic of asymmetric reactions and processes—the title including not only asymmetric syntheses, both conventional chemical and enzymatic, but also certain separation methods involving the same kind of diastereomeric interactions that are involved in asymmetric synthesis. The seminar was held July 7-11, 1981, at Stanford University with the editors and Professor Harry S. Mosher as co-organizers.

It was supported jointly by

the Japan Society for the Promotion of Science and the National Science Foundation and featured 19 plenary speakers: nine from Japan and ten from the United States. The names and brief biographies of all but one of these speakers are given on pp. xi-xiii, and their subjects are listed in the Table of Contents. ix

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.pr001

Approximately half the chapters (1-10) deal with what might be termed "classical asymmetric synthesis": a chiral adjuvant is combined with a prochiral reagent, thus producing diastereotropic ligands or faces. Stereoselective replacement of the ligands or addition to the faces followed by removal of the chiral adjuvant leads to chiral products. T h e second largest block of chapters (11-13 plus parts of 7 and 8) deals with asym­ metric catalysis, involving, in several instances, chiral organometallic reagents. It is remarkable that, not only in the stoichiometric but also in the catalytic reactions presented, optical yields frequently exceed 9 0 % . Chapters 14 and 15 are concerned with large-scale commercial applica­ tions of asymmetric enzymatic synthesis and Chapters 16 and 17 deal with biochemical applications of enzyme chemistry. Despite the fascination of asymmetric synthesis, separation methods for enantiomers even today compete, often successfully, with direct syn­ thetic routes. Thus it is appropriate that the topic of separation was included in the seminar. Chapter 18 is concerned with this topic, as was a paper presented by D . J . Cram on host-guest complexation [J. A m . Chem. Soc., 103, 3929 (1981); J . Org. Chem., 46, 393 (1981); and J . Chem. S o c , Chem. Comm., 625 (1981)]. Substantial parts of Chapters 1 and 10 also deal with the role of resolution and separation methods in the synthesis of chiral compounds, including enantioconvergent syntheses. In addition to the 19 main papers, two short papers and nine posters (preceded by short oral presentations) were featured at the Seminar. Nine of these eleven short communications are summarized in the form of abstracts on pages 261-286. The titles of these communications are listed in the Table of Contents. Abstracts of two communications are not i n ­ cluded: that of D. Valentine, Jr. (Catalytica Associates, Inc.) on phosphines having both chiral phosphorus and chiral ligands has been published in J . Org. Chem., 45, 3691 (1980) and that by B. Sharpless (MIT), on kinetic resolution, has appeared in J . A m . Chem. S o c , 103, 6237 (1981). B y the judgement of most of the participants, the Seminar was a success in that it brought together information on a wide variety of diverse, although often fundamentally related, methods for efficient synthesis of chiral organic compounds. We hope that this written record will prove of equal interest to the reader.

ERNEST L. ELIEL

University of North Carolina Department of Chemistry Chapel Hill, North Carolina 17514 SEI OTSUKA

Osaka University Department of Chemistry Toyonaka, Osaka, Japan 560 χ

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

CONTRIBUTING A U T H O R S

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.pr001

ICHIRO CHIBATA is Director of the Research Laboratory of Applied Biochemistry, Tanabe Seiyaku, Co., Ltd. Born Osaka, Japan, 1926; B.S., 1948, Ph.D, 1959, Kyoto University. With Research Laboratories, Tanabe Seiyaku, Co., Ltd. since 1948, Director since 1971. ERNEST L. ELIEL is W. R. Kenan, Jr. Professor of Chemistry, Univer­ sity of North Carolina, Chapel Hill. Born Cologne, Germany, 1921, D.Phys.-Chem.Sci., University of Havana, Cuba, 1946; Ph.D. University of Illinois, 1948. University of Notre Dame, 1948-72; University of North Carolina since 1972. HEINZ G. FLOSS is Lilly Professor of Medicinal Chemistry at Purdue University, West Lafayette, Indiana. Born Berlin, Germany, 1934. Diplom., Technical University, Berlin, 1959; Ph.D., Technical University, Munich, 1961; Postdoctoral, University of California at Davis (Conn) 1964-65. At Purdue University since 1966. KAORU HARADA is Professor of Chemistry, University of Tsukuba, Ibarati. Born Toyonaka, Osaka, Japan, 1927, B.S., 1952, Ph.D., 1961, Osaka University. Research Associate, Florida State University, 1956-64. University of Miami, 1964-74; The University of Tsukuba since 1974. TAMIO HAYASHI is Instructor, Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University. Born Gifu, Japan, 1948. B.Eng., 1970, Ph.D., 1975, Kyoto University; Postdoctoral, Colorado State University (Hegedus), 1976-77. At Kyoto University since 1975. CLAYTON HEATHCOCK is Professor of Chemistry, University of Cali­ fornia at Berkeley. Born San Antonio, Texas, 1936. B.S. Abilene Chris­ tian College, 1958; Ph.D., University of Colorado, 1963; Postdoctoral, Columbia University (Stork), 1963-64. At University of California at Berkeley since 1964. xi

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

KENJI KOGA is Professor, Faculty of Pharmaceutical Sciences, Univer­ sity of Tokyo. Born Aichi, Japan, 1938; B.S., 1960, Ph.D., 1966, Univer­ sity of Tokyo; Postdoctoral, University of California at Los Angeles (Cram), 1971-73. At University of Tokyo since 1976.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.pr001

ALBERT I. MEYERS is Professor of Chemistry, Colorado State Uni­ versity, Fort Collins. Born New York City, New York, 1937. A.B., 1954, Ph.D., 1957, New York University. With Cities Service Research & Development, 1957-58; Louisiana State University, 1958-70; Wayne State University, 1970-72; Colorado State University since 1972. TERUAKI MUKAIYAMA is Professor, Department of Chemistry, University of Tokyo. Born Nagano prefecture, Japan, 1927. B.S., Tokyo Institute of Technology, 1948; D.Sc, University of Tokyo, 1956. Assistant Professor, Gakushuin University, 1952-58; Professor, Tokyo Institute of Technology, 1962-73; University of Tokyo since 1974. HITOSI NOZAKI is Professor, Department of Industrial Chemistry, Kyoto University. Born Okayama prefecture, Japan, 1922. B.Eng., 1943, Dr.Eng., 1949, Kyoto University; Postdoctoral, Cornell University (Meinwald), 1956-57. At Kyoto University since 1963. ATSUYOSHI OHNO is Associate Professor, Institute for Chemical Re­ search, Kyoto University. Born Kure, Hiroshima, Japan, 1936. B.S., Kyoto University, 1958; Ph.D., Osaka City University, 1963; Postdoctoral, Massachusetts Institute of Technology (Swain), 1963-65; Purdue Uni­ versity (Davis) 1965-66. At Kyoto University since 1974. IWAO OJIMA is Senior Research Fellow and Group Leader, Sagami Chemical Research Center, Sagamihara. Born Yokohama, Japan, 1945. B.S., 1968, M.S., 1970, Ph.D., 1973, University of Tokyo. At Sagami Research Laboratories since 1970. SEI OTSUKA is Professor, Department of Chemistry, Osaka University. Born Tchingtao, China, 1918. B.S., 1941, D.Sc., 1955, Osaka University; Postdoctoral, Ohio State University (Newman), 1955-57; Max-Planck Institut fur Kohleforschung, Mulheim (Wilke), 1958. With Japan Syn­ thetic Rubber, Co. Ltd, 1957-1964. At Osaka University since 1964. xii

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

WILLIAM H. PIRKLE is Professor, School of Chemical Sciences, Uni­ versity of Illinois, Urbana. Born Shreeveport, Louisiana, 1934. B.S., University of California, Berkeley, 1959; Ph.D., University of Rochester, 1963; Postdoctoral, Harvard University (Corey), 1964. At University of Illinois since 1964.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.pr001

GARY H. POSNER is Professor, Department of Chemistry, Johns Hop­ kins University. Born New York City, New York, 1943; B.S., Brandeis University, 1965; Ph.D., Harvard University, 1968; Postdoctoral, Uni­ versity of California at Berkeley (Dauben), 1969. At Johns Hopkins since 1969. GABRIEL SAUCY is Associate Director, Chemical Research Department, Hoffmann-La Roche, Incorporated, Nutley, New Jersey. Born Schaffhausen, Switzerland, 1927; Diplom, 1951; Ph.D., 1954, Federal Institute of Technology, Zurich, Switzerland. With Hoffmann-La Roche, Basle, 1954-64, Nutley since 1964. BARRY M. TROST is Evan P. and Marion Helfaer Professor of Chem­ istry, University of Wisconsin, Madison. Born Philadelphia, Pennsylvania, 1941. B.A., University of Pennsylvania, 1962; Ph.D., Massachusetts Institute of Technology, 1965. At University of Wisconsin since 1965. GEORGE M. WHITESIDES is Professor of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts. Born Louisville, Ken­ tucky, 1939. A.B., Harvard University, 1960; Ph.D., California Institute of Technology, 1964. At Massachusetts Institute of Technology since 1963.

xiii

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

1 Approaches for Asymmetric Synthesis as Directed Toward Natural Products BARRY M . TROST

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

University of Wisconsin, Department of Chemistry, McElvain Laboratories of Organic Chemistry, Madison, WI 53706

Asymmetric synthesis of natural products embraces one of four different strategies - 1) resolution of a con­ venient intermediate or final product, 2) utilization of enantiomerically pure starting materials, 3) asym­ metric induction at the stage of an achiral intermedi­ ate, and 4) enantioconvergency. Each of these is illustrated. A new type of enantioconvergency embody­ ing a [3.3] sigmatropic rearrangement is employed for the synthesis of prostanoids. Asymmetric induction strategy is examined in the context of a model for asymmetric induction in the Diels-Alder reaction. The enantiomerically pure and partially pure adducts are employed in the synthesis of iboga alkaloids and pil­ laromycinone. Erythrynolides are the framework for strategies embodying resolution and enantiomerically pure building blocks. For the former, both enantio­ mers of a key building block are utilized to synthe­ size different halves of the molecule. In the latter, a single enantiomerically pure intermediate is util­ ized for the synthesis of the two halves of the mole­ cule in a convergent approach. Emphasis is placed on the general utility of O-methylmandelic acid as 1) an enantiomeric inducing agent, 2) a resolution agent via HPLC, 3) an analytical tool to determine % ee, and 4) a tool for deducing absolute configuration. The t o t a l s y n t h e s i s o f complex n a t u r a l p r o d u c t s o f f e r s c h a l l e n g e s i n t h e c o n s t r u c t i o n o f t h e c a r b o n framework, a d j u s t ment o f t h e o x i d a t i o n p a t t e r n , c o n t r o l o f r e l a t i v e s t e r e o c h e m i s t r y and c o n t r o l o f a b s o l u t e s t e r e o c h e m i s t r y . W h i l e a l l o f t h e s e a r e a s o f f e r e x c i t i n g o p p o r t u n i t i e s , the l a s t remains the l e a s t c o n s i d e r e d and most p e r p l e x i n g i n d e v e l o p i n g p a r t i c u l a r s y n t h e t i c strategy. To a very l a r g e extent, total synthesis of natural products s t i l l implies the s y n t h e s i s o f a racemate which, by d e f i n i t i o n , c o n t a i n s o n l y 50% o f t h e n a t u r a l p r o d u c t and may be r e s o l v e d a t t h e end o r a l o n g t h e way. 0097-6156/82/0185-0003$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

4

ASYMMETRIC

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Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

In a t t e m p t i n g t o s p e c i f i c a l l y c o n s i d e r t h e p r o b l e m o f absolute stereochemistry i n developing strategy, four options emerge. F i r s t and most common i s t h e r e s o l u t i o n o f some c o n v e n ­ i e n t i n t e r m e d i a t e o r f i n a l p r o d u c t . S e c o n d and i n c r e a s i n g l y popular i s t h e u t i l i z a t i o n o f o p t i c a l l y pure s t a r t i n g m a t e r i a l s . Third i s the d i s s e c t i o n o f the t a r g e t molecule i n t o an a c h i r a l i n t e r m e d i a t e i n w h i c h asymmetry c a n be i n d u c e d i n a s u b s e q u e n t step. Fourth i s t h e design o f an intermediate which allows easy i n t e r c o n v e r s i o n o f two e n a n t i o m e r s ( e n a n t i o c o n v e r g e n c y ) . I n t h i s p r e s e n t a t i o n , I w i s h t o c o n s i d e r some a s p e c t s o f each o f these s t r a t e g i e s i n t h e context o f s e v e r a l problems i n t h e t o t a l synthesis o f natural products. Enantioconvergence

Strategy

The c o n c e p t o f e n a n t i o c o n v e r g e n t s y n t h e s i s has h e r e t o f o r e been v i r t u a l l y r e s t r i c t e d t o c a s e s i n w h i c h t h e c h i r a l c e n t e r i s d i r e c t l y e p i m e r i z a b l e s u c h a s i n α-amino a c i d s . I n a n a l t e r n a t i v e v i e w , t h e s e p a r a t e t r a n s f o r m a t i o n o f two e n a n t i o m e r s v i a s t e r e o ­ c h e m i c a l l y c o m p l e m e n t a r y pathways i n t o a s i n g l e e n a n t i o m e r i c s e r i e s r e p r e s e n t s a c a s e o f enantioconvergence.(1_) F o r e x a m p l e , c o n v e r s i o n o f t h e e n a n t i o m e r i c a l c o h o l s l a a n d l b t o 1c v i a t h e 1 and Ε o l e f i n s r e s p e c t i v e l y c o n v e r g e t o ~ t h e same e n a r i t i o m e r o f the product d e r i v e d v i a a C l a i s e n ortho e s t e r rearrangement ( e q u a t i o n 1). (£,3) (1)

lb

An a l t e r n a t i v e c o n c e p t u a l a p p r o a c h t o e n a n t i o c o n v e r g e n t s y n t h e s i s i n v o l v e s i n t e r m e d i a t e s whose e n a n t i o m e r s may be r e a d i l y i n t e r c o n v e r t e d by s i m p l e c h e m i c a l r e a c t i o n s . Compound 2 p o t e n ­ t i a l l y r e p r e s e n t s s u c h a s p e c i e s s i n c e i t c a n be r e a s o n e d t h a t a [3.3] s i g m a t r o p i c r e a r r a n g e m e n t commutes t h e S,S i s o m e r 2a i n t o

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

1.

Asymmetric Synthesis of Natural Products

TROST

t h e R,R i s o m e r 2b ( e q u a t i o n 2 ) . { ] )

A t t e m p t s t o e q u i l i b r a t e 2a C0 CH 2

C0 CH 2

(2)

2

R,R CH 0 C 3

PhCH NH 0

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

3

2

NHCH Ph

||

«

'

2

HgOCCF

0

X

NHCH Ph 2

2b

3

0

( 5 6 % e e , [ a ] n + 1 6 . 3 ° ( c 5.25 (CHC13)) t h e r m a l l y l e d t o r e c o v e r e d 2a w i t h no c h a n g e i n r o t a t i o n . However, a d d i t i o n o f 0.2 e q u i v . o f m e r c u r i c t r i f l u o r o a c e t a t e t o a r e f l u x i n g dioxane o r THF s o l u t i o n o f 2a f o r 6-10 h o u r s l e a d s t o c o m p l e t e r a c e m i z a t i o n and no c o m p e t i n c T c i ^ - t r a n s i s o m e r i z a t i o n . A mechanism i n v o k i n g t h e intermediacy o f 3 rationalizes this observation. A l t h o u g h i n i t s s i m p l e s t form t h i s p r o c e s s would seem m e r e l y t o l e a d t o r a c e m i z a t i o n , i t c a n , i n f a c t , be a d a p t e d t o o p t i c a l enrichment. Thus, use o f an o p t i c a l l y a c t i v e urethane such a s 4 combined w i t h f r a c t i o n a l c r y s t a l l i z a t i o n o f one d i a s t e r e o m e r c r e a t e s a " r e s o l v i n g m a c h i n e . " Not o n l y o p t i c a l r o t a t i o n , b u t NMR a n a l y s i s a s w e l l a l l o w s d e t e r m i n a t i o n o f o p t i c a l p u r i t y w i t h Cp CH 2

C0 CH

3

2

3

S,S,S

t h e S,S,S i s o m e r 4 a s h o w i n g t h e m e t h y l e s t e r a b s o r p t i o n u p f i e l d (63.58 t o t h a t i n t h e R,R,S i s o m e r 4fc ( 6 3 . 6 8 ) ) . I n d e e d , r e a c t i n g the racemate o f the hydroxy e s t e r with the i s o c y a n a t e d e r i v e d f r o m i - a - n a p h t h e t h y l a m i n e gave t h e u r e t h a n e 4 a s a 1:1 m i x t u r e o f 4a and 4 b w i t h [ a ] £ f - 1 3 . 2 ° ( c 2.46, PhH) arid two s i n g l e t s o f e q u a l i n t e n s i t y i n t h e NMR s p e c t r u m a t 63.68 and 3.58. Mercury catalyzed e q u i l i b r a t i o n converts t h i s mixture t o an approximately 1:2 r a t i o o f 4a t o 4 b a s d e t e r m i n e d b y t h e NMR s p e c t r u m , w i t h t h e s i g n a l a t 63.$8 l a r g e r t h a n t h a t a t 6 3 . 5 8 , and a r o t a t i o n 6

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

6

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A N D PROCESSES IN

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Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

[a]516 - 1 1 . 8 ° ( c 1.95, PhH). To v e r i f y that the urethanes could be s u c c e s f u l l y employed i n s y n t h e s i s , t h e i r c o n v e r s i o n t o t h e c o r r e s p o n d i n g h y d r o x y e s t e r s w i t h o u t r a c e m i z a t i o n must be demons t r a t e d . I n f a c t , t r e a t m e n t w i t h t r i c h l o r o s i l a n e 1n hot b e n z e n e c o n t a i n i n g t r i e t h y l a m i n e c o n v e r t s o p t i c a l l y a c t i v e 4a back t o i t s h y d r o x y e s t e r w i t h no l o s s o f o p t i c a l a c t i v i t y . W i t h t h e phenomenon e s t a b l i s h e d , a s t r a t e g y f o r p r o s t a n o i d s y n t h e s i s emerges a s shown i n e q u a t i o n 3. I n t h e m a j o r s i m p l i f i -

c a t i o n , two key p o i n t s must be r e c o g n i z e d 1) t h e a b i l i t y o f a n a , e unsaturated aldehyde t o lead t o i n t r o d u c t i o n o f both s i d e chains and 2 ) t h e a b i l i t y o f a c a r b o x y g r o u p t o s e r v e a s a p r e c u r s o r t o an a l c o h o l b y a c a r b o x y i n v e r s i o n p r o c e d u r e . T h e r e a d y a c c e s s i b i l i t y o f a cyclopentene-l-carboxaldehyde by a d i r e c t e d a l d o l c o n d e n s a t i o n and t h e g e n e r a t i o n o f a d i a l d e h y d e b y t h e o x i d a t i v e c l e a v a g e o f a n o l e f i n l e a d s t o t h e a l c o h o l 5 w h i c h r e l a t e s t o 4. T h i s approach a l s o i n t r i n s i c a l l y d i f f e r e n t i a t e s the C(9) and c ( l l ) o x y g e n s t o p r o v i d e a n e n t r y i n t o a number o f PG compounds. Scheme 1 i l l u s t r a t e s t h e u t i l i z a t i o n o f t h i s s t r a t e g y f o r a n analogue. Asymmetric Induction

Strategy

W h i l e a g r e a t d e a l o f e m p h a s i s h a s been p l a c e d upon s e a r c h ing f o r asymmetric i n d u c t i o n , s t r i k i n g l y s u c c e s s f u l r e s u l t s r e m a i n e d e l u s i v e u n t i l v e r y r e c e n t l y . One o f t h e m o s t p o w e r f u l a p p r o a c h e s f o r t h e s y n t h e s i s o f n a t u r a l p r o d u c t s has been t h e D i e l s - A l d e r r e a c t i o n but a s y m m e t r i c i n d u c t i o n i n t h i s r e a c t i o n r e m a i n e d d i s a p p o i n t i n g . (4) T h i s r e a c t i o n i s p a r t i c u l a r l y i m p o r tant since the c y c l o a d d i t i o n normally creates c h i r a l products from a c h i r a l r e a c t a n t s . A w o r k i n g model f o r i n d u c i n g c h i r a l i t y c o u l d g r e a t l y e n h a n c e t h e power o f t h e a p p r o a c h . A l t h o u g h t h e mechanism o f t h e D i e l s - A l d e r r e a c t i o n i s s t i l l controversial, i t i s p r a c t i c a l l y useful t o envision a r e l a t i o n s h i p between i t s t r a n s i t i o n s t a t e ( t . s . ) and a c h a r g e t r a n s f e r c o m p l e x . (J>) I n i t s s i m p l e s t v e r s i o n , t h e two e n a n t i o m e r i c t . s . ' s 6a a n d 6b become d i a s t e r e o m e r i c t . s . ' s i f a c h i r a l " s o l v a t o r " i s p r e s e n t ^ P r e f e r e n t i a l s o l v a t i o n o f one o f t h e t w o e n a n t i o t o p i c

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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1.

7

SCHEME 1. A n E n a n t i o c o n v e r g e n t A p p r o a c h t o P r o s t a n o i d s

C 0

C H C H C0 6

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C0 CH

C H 3

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3

2

c

C H C H C0 6

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6

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g

,

d

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(d 1.5, C H 0Ac) 2

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( a ) 1) 1 m o l * OsO.,, N a C 1 0 , H 0 ; 11) N a l O * . THF, H 0 ; 3

2

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i l l ) C H N H 0 A c , PhH, 5 0 ° . ( b ) HMPA, THF, e t h e r , - 7 8 ° ( l h ) , - 2 0 ° ( 3 h ) . 5

9

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( c ) o C ^ t K C H s h . HOAc, CH CN; 1 i ) LAH, THF, 0 ° ; 111) T s C l , 3

C5H5N, 0 ° ; 1v) NaH, DMF, r t .

(d) 1 ) C H C 0 C 0 H , THF, B F - e t h e r ; 11) C H 0 C H = C H , P 0 C 1 , ( C H ) N ; 111) P h P C H 0 C H C l , t - C » H L 1 , THF, 0 ° ; i v ) H g ( 0 A c ) , THF, H 0 then KI, H 0 . 3

2

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s

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( e ) 1 ) P h P C H ( C H ) C 0 , C H S 0 C H N a , DMS0; 11) HOAc, THF, H 0 . 3

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faces o f t h e dlene w i l l then lead t o p r e f e r e n t i a l r e a c t i o n v i a | a o r 6b, I . e . t o a s y m m e t r i c I n d u c t i o n . R e a s o n i n g t h a t a π - s t a c k 1ng t y p e o f I n t e r a c t i o n m i g h t be a n e f f e c t i v e " s o l v a t o r , " t h a t s u c h a n I n t e r a c t i o n would be more f a v o r a b l e w i t h t h e d i e n e t h a n

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

Chiral Solvator

6b

Chiral Solvator

t h e d i e n o p h i l e ( f o r e l e c t r o n i c r e a s o n s ) , and t h a t i n t e r n a l s o l v a t i o n would be more f a v o r a b l e t h a n e x t e r n a l s o l v a t i o n l e d u s t o explore i n c o r p o r a t i o n o f a mandelic a c i d group i n t o the diene. In s u c h a m a n d e l a t e s y s t e m , a l a r g e s u b s t i t u e n t either projects t o w a r d ( i . e . 7a) o r away ( i . e . 7b) from t h e d i e n e and would t h u s b i a s t h e s e n s e ' o f s t a c k i n g o f t B e s y s t e m t o want t h e l a t t e r i n t e r D1enoph1le

a c t i o n . C h o i c e o f L=0CH and S=H has t h e a d v a n t a g e s t h a t t h e c h i r a l inducing agent i s r e a d i l y a v a i l a b l e i n o p t i c a l l y pure form and o f f e r s a d i r e c t method f o r a n a l y z i n g t h e d e g r e e o f a s y m m e t r i c i n d u c t i o n b y NMR s p e c t r o s c o p y . In a d d i t i o n , i t o f f e r s a method f o r t h e d i r e c t d e t e r m i n a t i o n o f a b s o l u t e c o n f i g u r a t i o n . Mosher s u g g e s t e d a m o d e l , r e p r e s e n t e d i n 8 a and 8b, i n w h i c h t h e e x t e n d e d d i h e d r a l a n g l e o f 0° between R and Ph i n 8 a and R and Ph i n 8 b l e a d s t o s h i e l d i n g o f R' i n 8 a and R i n 8 b ( i n t h e s e e x t e n d e d Newman p r o j e c t i o n s , t h e c i r c l e r e p r e s e n t s ~ t h e C 0 g r o u p ) ( 6 ) . A n a l t e r n a t i v e model d e p i c t e d i n S ô and 9b s u g g e s t s a d i h e d r a l a n g l e o f a b o u t 60° between R and Ph i n " 9 a and R and Ph 3

1

2

1

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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i n 9b w h i c h s h o u l d l e a d t o d e s h i e l d i n g o f R i n 9a and o f R* i n 9b due t o t h e a n i s o t r o p y o f t h e p h e n y l r i n g . D i p o l a r e f f e c t s and e x t e n d e d e c l i p s i n g i n t e r a c t i o n s t e n d t o f a v o r c o n f o r m a t i o n s 9a and 9b w h i l e e c l i p s i n g i n t e r a c t i o n s a r o u n d t h e c a r b o x y l a t e f u n c t i o n H t e n d t o f a v o r 8 a and 8b. F o r t u n a t e l y , b o t h c o n f o r m a t i o n a l m o d e l s p r e d i c t t h e same t r e n d - t h e S - m a n d e l a t e e s t e r o f e n a n t i o mer 10a s h o u l d e x h i b i t t h e NMR s i g n a T f o r R d o w n f i e l d o f t h e c o r r e s p o n d i n g s i g n a l f o r t h e S - m a n d e l a t e e s t e r o f e n a n t i o m e r 10b H

H

L

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10a

1-

-R

10b 1

and t h e c o n v e r s e s i t u a t i o n h o l d s f o r t h e s i g n a l s f o r R . We have f o u n d t h a t t h i s l i t t l e u s e d method nas c o r r e c t l y p r e d i c t e d e v e r y a b s o l u t e c o n f i g u r a t i o n we were a b l e t o v e r i f y i n d e p e n d e n t l y . C h a r t 1 e x e m p l i f i e s some o f t h e m o l e c u l e s w i t h key NMR a b s o r p ­ tions. D i e l s - A l d e r c o n d e n s a t i o n o f d i e n e "Π w i t h a c r o l e i n and j u g l o n e , c a t a l y z e d b y B F - e t h e r and BfOAclU r e s p e c t i v e l y , l e d t o a d d u c t s 12 and 13 ( 5 ) . F o r 12, t h e r a t i o o f t h e a b s o r p t i o n s f o r t h e a l d e l i y d i c p r o t o n s a t 69.65 and 9.20 o f 82:18 r e p r e s e n t s t h e d e g r e e o f a s y m m e t r i c i n d u c t i o n and a s s i g n s t h e 1R,2R c o n f i g u r a ­ t i o n to the major product - an i n t e r p r e t a t i o n confirmed by c o r ­ r e l a t i o n w i t h t h e known lR,2R-2-hydroxymethylcyclohexanol. 3

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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0

The 64% e e r i s e s t o ^100% e e f o r t h e j u g l o n e a d d u c t 13 whose e n a n t i o m e r i c p u r i t y and a b s o l u t e s t e r e o c h e m i s t r y w e r î T a s s i g n e d by t h e NMR method ( s e e C h a r t 1 ) . B o t h r e s u l t s a g r e e w i t h a t . s . i n v o k i n g f o l d i n g a s r e p r e s e n t e d i n 7b - i n good a c c o r d w i t h t h e m o d e l . Most i n t e r e s t i n g i s t h e enhancement o f t h e e e a s a f u n c t i o n o f d i e n o p h l l e . A g a i n t h e model p r e s e n t e d accommodates t h i s o b s e r v a t i o n . For j u g l o n e , charge t r a n s f e r i n t e r a c t i o n s i n t h e t . s . f o r c y c l o a d d i t i o n s h o u l d be more i m p o r t a n t t h a n f o r a c r o l e i n - a f a c t t h a t s h o u l d l e a d t o t i g h t e r complex f o r m a t i o n a t the t . s . and thus enhanced c h i r a l r e c o g n i t i o n . A s t r a t e g y f o r s y n t h e s i s o f i b o g a a l k a l o i d s e v o l v e s from the a c r o l e i n c y c l o a d d i t i o n (9,11). Focusing on the s i m p l e s t conceptual approach t o iboga a l k a l o i d s v i a D i e l s - A l d e r chemistry, a d o u b l e bond must be i n t r o d u c e d i n t o t h e e x i s t i n g c y c l o h e x y l r i n g . Such a r e t r o s y n t h e t i c a n a l y s i s , r e p r e s e n t e d i n e q u a t i o n 4, r a p i d l y d i s s e c t s the problem t o the c y c l o a d d i t i o n o f a c r o l e i n t o a 1-acyloxy-l,3-hexadiene. Scheme 2 summarizes t h e s y n t h e s i s t o

g i v e 80% o f 3R,4S,6R-ibogamine and 20% o f t h e 3S,4R,6S i s o m e r ( 9 ) .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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1.

Chart 1. figurations

Determination of absolute configuration using mandelate esters. Condenoted refer only to carbinol carbon atom. Key: A, Ref. 7; B, Ref. 8; C, Ref. 9; D, Ref. 10; and E, Ref. 5. Continued on next page.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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A S Y M M E T R I C REACTIONS A N D PROCESSES IN

Chart 1. Continued. esters. Configurations

Determination of absolute configuration denoted refer only to carbinol carbon page 11.

using atom.

mandelate Key: see

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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Ibogamine

(a) a c r o l e i n , B F - e t h e r , (b) t r y p t a m i n e , MgSO*, PhCH t h e n add ( c ) 3 % ( P h P K P d , CH CN. NaBH*, C H 0 H . (d) ( C H C N ) P d C l , AgBF*, ( C H ) N , CH CN t h e n add NaBHi*. 3

3

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The e e and a b s o l u t e c o n f i g u r a t i o n o f t h e i n i t i a l a d d u c t 14 a s s i g n e d b y t h e NMR method ( s e e C h a r t 1 ) was v e r i f i e d b y ~ c o m p a r i son o f t h e f i n a l p r o d u c t w i t h a n a u t h e n t i c s a m p l e . A s i m i l a r s t r a t e g y was employed f o r t h e s y n t h e s i s o f c a t h a r a n t h i n e 15 O p .

15 An a p p r o a c h toward a n t h r a c y c l i n o n e a n t i t u m o r a g e n t s emerges from t h e j u g l o n e a d d u c t 13 (1_2). P i l l a r o m y c i n o n e 16 has a l l o f i t s c h i r a l c e n t e r s i n r i n g D, and t h e y c a n e m a n a t e T f r o m a c y c l o hexenone 17 i n w h i c h t h e c i s ^ r i n g j u n c t u r e would d i r e c t t h e stereochemical i n t r o d u c t i o n o f the remaining s u b s t i t u e n t s (see e q u a t i o n 5 ) . The c i s r i n g j u n c t u r e o f 17 c a n r e a d i l y d e r i v e f r o m a D i e l s - A l d e r r e a c t i o n s t a r t i n g from a c y c l o h e x e n o n e 18. T h i s r e q u i r e s p a r t i a l s a t u r a t i o n o f t h e Β r i n g b u t i n s u c l T a manner a s to f a c i l i t a t e r e a r o m a t i z a t i o n , thus u t i l i z i n g the presence o f the two o x y g e n s u b s t i t u e n t s . F u r t h e r m o r e , t h e c i s B/C r i n g j u n c t u r e o f 18 w i l l d i r e c t a n i n c o m i n g d i e n e s o a s t o c r e a t e t h e c o r r e c t

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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s t e r e o c h e m i s t r y o f J 7 . T h e s t e r e o c h e m i s t r y o f 18 a n d , b y extrapolation, that'of J 6 i s established i n t h e ~ f i r s t step o f s y n t h e s i s , t h e D i e l s - A l d e r r e a c t i o n , even t h o u g h t h e p e r t i n e n t c h i r a l c e n t e r s ( i n r i n g B) d i s a p p e a r i n t h e f i n a l p r o d u c t . T h e y r e p r e s e n t s t e r e o c h e m i c a l r e l a y c e n t e r s w h i c h a r e t o be d i s c h a r g e d o n c e t h e y s e r v e d t h e i r f u n c t i o n . Scheme 3 o u t l i n e s t h e a p p r o a c h . P r e l i m i n a r y e x p e r i m e n t s s u g g e s t t h a t t r e a t m e n t o f 19 w i t h B F « e t h e r i n m e t h a n o l does p r o d u c e t h e a c e t o n i d e o f d e o x y p i l l a r o m y cinone. 3

Resolution Strategy The m a n d e l a t e e s t e r s s e r v e y e t a n a d d i t i o n a l r o l e i n c h i r a l s y n t h e s i s - f a c i l i t a t i o n o f r e s o l u t i o n by h p l c . The d i a s t e r e o mers i n e n t r i e s 1,2, and 4 o f C h a r t 1 a r e a l l r e a d i l y r e s o l v e d on a W a t e r s P r e p 500 c o l u m n u t i l i z i n g 2-10% e t h y l a c e t a t e 1n hexane ( 7 , 8 , 1 0 , 1 3 ) . The d i a s t e r e o m e r l a b e l l e d S o f e n t r y 2, C h a r t 1, may be u s e d f o r a s y n t h e s i s o f v e r r u c a r i n i c a c i d 21 a s o u t l i n e d i n e q u a t i o n 6; t h e a c i d i s p r o d u c e d a s i t s b i s t - b u t y l dimethylsilyl ether f o r incorporation into verrucarin A T 8 ) . 1) H

l)Mg(0CHj 3'2

2

2) 1)BH , 11) H 0 3

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3)t-C H (CH ) S1Cl 4

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(6) The m a c r o l i d e e r y t h r y n o l i d e B, 22, o f f e r s a p a r t i c u l a r l y s t r i k i n g strategy u t i l i z i n g t h i s type~of r e s o l u t i o n (equation 7 ) . In p a r t i c u l a r u t i l i z i n g 23 a s a key i n t e r m e d i a t e w h i c h f o c u s e s o n an a l l y l i c a l k y l a t i o n f o ? ~ t h e c r u c i a l r i n g f o r m a t i o n , t h e a l c o h o l 24 a n d a c i d 25 become s i m p l e p r e c u r s o r s c o n t a i n i n g a l l t h e c r i t i c a l centers. Straightforward analysis r a p i d l y converts

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SCHEME 3. A n A p p r o a c h t o P l l l a r o r a y c i n o n e

( a ) 1 ) B F - e t h e r , C H C 1 2 5 ° ; 1 i ) NaBH*, C H 0 H , P h C H ; l i t ) ( t - C H ) ? . S i C l , 1 - h y d r o x y b e n z t r i a z o l e , ( C H ) N , CH CN; i v ) L i B H * , T H F , 0 ° ; ν ) t - C , H ( C H ) S i C l , i m i d a z o l e , DMF, 5 0 ° ; v i ) DIBAL-H, P h C H , - 7 8 ° ; v i i ) A c 0 , DMSO, P h C H . ( b ) B C 1 , C H C 1 , 0 ° . ( c ) i ) ( C H ) C ( C H 0 H ) , TsOH, PhH; i i ) MCPBA, C H C 1 , - 7 8 ° ; i i i ) C H L i , e t h e r ; i v ) P h C H , r e f l u x . (d) ? Ρ i ) P h P C H 0 C H , n - C * H L i , THF, - 7 8 ° ; i i ) 0 , h v , s e n s i t i z e r , CH^ CI 2 ( e ) i ) C H 5 N ( H F ) , C H N , THF; i i ) M n 0 , ( C H ) C 0 . 3

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In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

A S Y M M E T R I C REACTIONS A N D PROCESSES IN

16

CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

0

h y d r o x y k e t o n e £ 4 t o a l c o h o l 26 and a c i d 25 t o a l c o h o l 2 7 . However, 26 and 27 a r e s i m p l y m i r r o r i m a g e s . T h u s ^ i n t h i s s t r a t e g y , b o t h e n a n t i o m e r s a r e needed - t h e 5R,6g i s o m e r 26 f o r t h e n o r t h w e s t e r n h a l f and t h e 5S,6S i s o m e r 27 f o r t h e s o u t h e a s t e r n h a l f . P r e p a r a t i v e hplc o f the mandelate e s t e r o f the racemate r e a d i l y l e a d s t o t h e i r e p i m e r i c a l l y p u r e d i a s t e r e o m e r s whose o p t i c a l p u r i t i e s and c o n f i g u r a t i o n s were a s s i g n e d b y NMR s p e c t r o s c o p y ( s e e C h a r t 1, e n t r y 4 ) and c o n f i r m e d b y p o t a s s i u m c a r b o n a t e h y d r o l y s i s t o e n a n t i o m e r i c a l l y p u r e 26 and £ 7 ; t h e c o n f i g u r a t i o n s s o deduced were i n a g r e e m e n t w i t h t h e l i t e r a t u r e a s s i g n m e n t ( 1 0 ) . T h e r e c o v e r e d O - m e t h y l m a n d e l 1 c a c i d was s u i t a b l e f o r r e c y c l i n g . E q u a t i o n s 8 and 9 show t h e a p p r o a c h e s t o 24 (10) and 25 (14) respectively.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Asymmetric Synthesis of Natural Products

TROST

1.

17

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

26

29

( a ) i ) c o n e HC1, Δ ; ϋ ) NaH, P h C H B r , OMF, r t . ( b ) HC1, H 0 , CH CN, r t . ( c ) i ) 2 , 4 , 6 - ( i - C H ) C H S 0 C l , C H N , r t ; i i i ) L i ( C H ) C u , e t h e r , - 7 8 ° . (d) i ) t-C»H C0Cl, C H N; i i ) 1 0 % Pd/C, C H 0 A c , r t ; i i i ) ( C 0 C 1 ) , DMSO, ( C H ) N , C H C 1 , - 6 0 ° . ( e ) i ) LDA, C H C H C ( 0 ) C H ( C H ) S 0 P h , THF, - 7 8 ° ; i i ) S 0 C 1 , C H N, -50°. 2

3

3

3

2

3

e

2

2

2

5

5

s

2

5

2

3

5

7

2

3

2

5

5

5

3

2

2

2

5

(9)

( a ) S t e p s a and b i n e q u a t i o n 8. ( b ) i ) 2 , 4 , 6 ( C H ) C H C 0 C 1 , H , 10X Pd/C, C H 0 H , HOAc, r t ; i i i ) ( C H ) C ( 0 C H ) TsOH, r t . ( c ) i ) N a 0 C H , C H 0 H , 6 5 ° ; i i ) DMSO, ( C 0 C 1 ) , C H C 1 ,

C5H5N, - 4 0 ° ; i i )

3

2

3

6

2

3

3

3

3

2

2

3

2

2

Continued on p . 18.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2

18

ASYMMETRIC

REACTIONS

A N D PROCESSES IN

CHEMISTRY

O p t i c a l l y A c t i v e B u i l d i n g Blocks

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

An e v e n more e f f i c i e n t s t r a t e g y m i g h t be based upon t h e u t i l i z a t i o n o f t h e same c h i r a l b u i l d i n g b l o c k f o r a l l t h e asym­ m e t r i c c e n t e r s p r o v i d e d s u c h a b u i l d i n g b l o c k 1s r e a d i l y a v a i l a b l e i n e n a n t i o m e r i c a l l y pure f o r m . T h e b e n z y l e t h e r o f 21 ( s e e e q u a t i o n 10) i s t h e i n t e r m e d i a t e i n t h e c u p r a t e c o u p l i n g o f 28

i n e q u a t i o n 8, s t e p c . T h u s , t h e r e l a t i o n s h i p o f 31 t o 24 i s a p p a r e n t . On t h e o t h e r hand, whereas t h e two o r i g i n a l c h i r a l c e n t e r s o f 27 ( e q u a t i o n 7 ) c o r r e s p o n d t o C ( 2 ) and C ( 3 ) o f e r y t h r y n o l i d e B, t h e two c h i r a l c e n t e r s o f 31 c o r r e s p o n d t o C ( 3 ) and C(4) ( e q u a t i o n 1 0 ) . I n t h i s a p p r o a c h , t h e s e two c e n t e r s assume r e s p o n s i b i l i t y f o r c r e a t i n g C ( 2 ) o f a n a p p r o p r i a t e c o n f i g ­ u r a t i o n . T h u s , 31 r e p r e s e n t s a s i n g l e e n a n t i o m e r from w h i c h a l l the c h i r a l centers o f e r y t h r y n o l i d e Β w i l l s p r i n g . The f a c t t h a t 31 i s a f o u r c a r b o n c h a i n i n w h i c h e v e r y c a r b o n b e a r s a s u b s t i t u e n t , t h r e e o f them oxygen and one a m e t h y l g r o u p , s u g g e s t s R , R - t a r t a r i c a d d a s a l o g i c a l p r e c u r s o r (15,16). Scheme 4 o u t l i n e s in e x t r a o r d i n a r i l y e f f i c i e n t r o u t e from R,Rt a r t a r i c a c i d t o 31 i n a n o v e r a l l y i e l d o f 64%. C o r r e l a t i o n " o f 31 v i a c u p r a t e c o u p l i n g and s e l e c t i v e f o r m a t i o n o f t h e p i v a l a t e a t t h e s e c o n d a r y a l c o h o l g i v e s 32 w h i c h was p r e v i o u s l y d e r i v e d from 2 9 . OH

32

footnotes t o equation 9 contd... ( C * H ) N , - 6 0 ° . (d) P h C H 0 C H P P h C l " , ΐ-0«>Η 0Κ, THF, - 7 8 ° . ( e ) CH2I2, Z n ( A g ) , DME, r t . ( f ) i ) HOAc, C H 0 H , r t ; i i ) A c 0 , CsHsN, r t ; i i i ) H , Pd, CHsOH. (g) i ) H g ( 0 A c ) , r t ; i i ) NaBHi», CH 0H. 5

3

2

2

3

9

3

2

2

2

3

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

1.

Asymmetric Synthesis of Natural Products

TROST

19

SCHEME 4. S y n t h e s i s o f a Key S y n t h o n f o r E r y t h r y n o l i d e Β Ç 0

2 2 5 C

ι

H

0

'Ph

Ph^

"0 · 0

"OH

a

I

OCPh

c

HO — C0 C H 2

2

P K ^ O

5

—J

Ph

HO—I

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

Ph' OH

-OTS

d

Ph

OH

HO

1

[οΐβ

1

- 4 " (c 1.14, CHC1 ) 3

31

( a ) i ) PhCHO, H C ( 0 C H ) 3 , TsOH, r t ; i i ) LAH, e t h e r , Δ ; i i i ) NaH, P h C H B r , THF. ( b ) NBS, C C I » , Δ . ( c ) L i ( C H ) C u , e t h e r , 0 ° . ( d ) i ) T s C l , C 5 H 5 N , r t ; i i ) Η , 105SPd/C, CH3OH, HOAc. ( e ) NaOH, CH 0H. 2

5

2

3

2

3

T h i s c o r r e l a t i o n a l s o p r o v i d e s unambiguous c o n f i r m a t i o n o f t h e a b s o l u t e s t e r e o c h e m i s t r y o f 2 9 . F u r t h e r m o r e , 31 c a n be c o n v e r t e d t o a l d e h y d e s 33 a n d 34 w h i c h ~ i r e r e l a t e d t o 30~"( e q u a t i o n 9) a s shown i n e q u a t i o n 11~~

• OCHjPh

HO—I

31

ΟΙ) ^ H

>—osi -Ι­ ( a ) PhCH 0Na, P h C H 0 H , r t . ( b ) i ) A c 0 , C 5 H 5 N , r t ; i i ) H , 102 Pd/C, CH3OH, HOAc; i i i ) PCC, C H C 1 , 0 ° . ( c ) i ) t - C ^ H ( C H ) S i C l , i m i d a z o l e , DMF, r t ; i i ) MEM-C1, ( i - C H 7 ) N C H , C H C 1 ; i i i ) step i i and i i i o f b. 2

2

2

2

2

9

3

3

2

2

2

2

5

2

2

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

20

REACTIONS

A N D PROCESSES I N CHEMISTRY

The c r e a t i o n o f t h e f i n a l c h i r a l c e n t e r c a n be e n v i s i o n e d a n a l o g o u s t o e q u a t i o n 9 b u t r e m a i n s y e t t o be a c c o m p l i s h e d . W h i l e t h e c o m p l e t i o n o f t h e s y n t h e s i s a w a i t s t h e outcome o f t h e a b o v e s t u d i e s , t h e c r i t i c a l m a c r o c y c l i z a t i o n s t e p has been d e m o n s t r a t e d i n a m o d e l . T h u s , t h i s a p p r o a c h p r o v i d e s much promise o f e f f i c i e n t l y c r e a t i n g the m a c r o l i d e a n t i b i o t i c s . Acknow!edgment

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch001

I am i n d e b t e d t o a t a l e n t e d g r o u p o f c o l l a b o r a t o r s who t r a n s f o r m e d t h e s e i d e a s from dreams t o r e a l i t y . T h e y a r e i n d i v i d u a l l y recognized i n the references. Financial support was g e n e r o u s l y p r o v i d e d b y t h e N a t i o n a l S c i e n c e F o u n d a t i o n , t h e G e n e r a l M e d i c a l S c i e n c e s I n s t i t u t e and t h e N a t i o n a l C a n c e r I n s t i t u t e o f the National I n s t i t u t e s o f Health, and the U n i v e r s i t y of Wisconsin. Literature Cited 1.

Trost, B.M.; Timko, J.M.; Stanton, J.L. Chem. Commun. 1978, 436. 2. Cohen, N.; Lopresti, R . J . ; Neukom, C . ; Saucy, G. J. Org. Chem. 1980, 45, 482 and references therein. 3. Saddler, J.C.; Donaldson, R.E.; Fuchs, P.L. J. Am. Chem. Soc. 1981, 103, 2110. 4. Mukaiyama, T . ; Iwasara, N. Chem. Lett. 1981, 29. David, S.; Eustache, J.; Lubineau, A. J. Chem. Soc. Perkin I, 1971, 1795. Corey, E.J.; Ensley, H.E. J. Am. Chem. Soc. 1975, 97, 6908. 5. Trost, B.M.; O'Krongly, D.; Belletire, J.L. J. Am. Chem. Soc. 1980, 102, 7595. 6. Dale, J.A.; Mosher, H.S. J. Am. Chem. Soc. 1973, 95, 512. 7. Schmuff, N., unpublished work in these laboratories. 8. McDougal, P.G., unpublished work in these laboratories. 9. Trost, B.M.; Godleski, S.A.; Genet, J.P. J. Am. Chem. Soc. 1978, 100, 3930. 10. Belletire, J., unpublished work in these laboratories. 11. Trost, B.M.; Godleski, S.A.; Belletire, J. J. Org. Chem. 1979, 44, 2052. 12. Caldwell, C . , unpublished work in these laboratories. 13. Cf. Bandi, P.C.; Schmid, H.H.O. Chem. Phys. Lipids, 1976, 17, 267. 14. Nishimura, Y . , unpublished work in these laboratories. 15. Lubineau, Α., unpublished work in these laboratories. 16. For an independent investigation on the use of tartaric acid derivatives as chiral building blocks, see Hüngerbühler, E.; Seebach, D.; Helv. Chim. Acta, 1981, 64, 687. R E C E I V E D December 14, 1 9 8 1 .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2 Synthetic Control Leading to Natural Products TERUAKI M U K A I Y A M A

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

University of Tokyo, Department of Chemistry, Faculty of Science, Tokyo, Japan 113

New and useful asymmetric reactions have been developed based on the concept of "Synthetic Control". The concept of "Synthetic Control" is characterized by the utilization of common metal chelates for inter-or intramolecular interactions leading to highly stereospecific or entropically advantageous reactions. A variety of optically active compounds are obtained in much higher enantiomeric purities, compared with conventional methods, by utilizing chiral heterocyclic compounds such as chiral pyrrolidine or oxazepine derivatives, which have strong interactions with organometallic compounds to form tight complexes as intermediates. Similarly, asymmetric intramolecular Diels-Alder reactions are realized by the utilization of effective intramolecular metal chelation. Various natural products are successfully synthesized by the appli­ cation of these reactions.

In t h i s a r t i c l e , we summarize a v a r i e t y of asymmetric syntheses guided by the p r i n c i p l e of " S y n t h e t i c C o n t r o l " d e s c r i b e d i n the a b s t r a c t .

0097-6156/82/0185-0021 $05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

22

REACTIONS

A N D PROCESSES IN

Asymmetric syntheses based on c h i r a l diamines.

CHEMISTRY

Optically

a c t i v e secondary a l c o h o l s are obtained by r e d u c t i o n of p r o c h i r a l ketones with the c h i r a l hydride reagent 1^ prepared from l i t h i u m aluminium hydride and

(S)-2-(N-substituted aminomethyl)-

p y r r o l i d i n e s , d e r i v e d e a s i l y i n four steps from available

(S)-proline.^

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

0

0 L

J A Κ

commercially

i

A >

2 Π

N

R

OH

1

J* ^ 2

T

C

1

0

ϋ) HjO

R

The diamine 2^ (R=»Ph) was

Κ

PhCOEt 96% ee a-Tetralone 86% ee

a l s o a p p l i e d to the s y n t h e s i s of

o p t i c a l l y a c t i v e α-hydroxyaldehydes.

Treatment

of the aminal,

prepared from the c h i r a l diamine and p h e n y l g l y o x a l , with Grignard reagents a f f o r d s

hydroxyanimals,which,

i n t u r n , are hydrolyzed 2a to y i e l d α-alkyl-a-hydroxyphenylacetaldehydes.

1. R M g X 2.aq.NtyCl

O^Ph •Λ 1MgCI ^ VNPh — Î * 2

MeoX

2. R MgBr

2.Me S 2

(-) 84% ee

(+) 100% ee

Frontalin 1

2

(-):. R — ( Œ ) C ( C H ) - C H , R = Me 2

1

3

3

2

2

(+): R » Me, R =-(CH > C(CH >=CH 2

Furthermore a new marine a n t i b i o t i c ,

3

3

(-)-Malyngolide,

discovered i n the marine blue green a l g a Lyngbya

majuscula

Gomont, was synthesized i n high o p t i c a l y i e l d by way o f another 2d a p p l i c a t i o n o f t h i s asymmetric r e a c t i o n .

The sequence i s out-

l i n e d i n Scheme 1. O p t i c a l l y a c t i v e 3-formyl-3-hydroxycarboxylic

esters are

obtained by employing e i t h e r the l i t h i u m or z i n c enolate of e t h y l acetate i n p l a c e of Grignard reagents i n the above mentioned reaction.

N V

NR

O^R

1

2

CHfC %

0Et.

CHO

2%HCI R T0" M CH C0 Et 1

2

2

R

C^CC^Et

'J

84-92% ee

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

24

03

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2.

MUKAIYAMA

Synthetic Control

25

Asymmetric syntheses based on c h i r a l aminoalcohols.

Various

c h i r a l aminoalcohols 3^ 4_, 5^ b_ were synthesized s t a r t i n g from ( S ) - p r o l i n e , and the e n a n t i o s e l e c t i v e a d d i t i o n of organometallic compounds to aldehydes i n the presence of these aminoalcohols was investigated.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

HO

R

The e n a n t i o s e l e c t i v e a d d i t i o n of a l k y l l i t h i u m reagents to aldehydes i n the presence of the l i t h i u m s a l t of aminoalcohol 5^ y i e l d s o p t i c a l l y a c t i v e secondary a l c o h o l s .

High o p t i c a l y i e l d s

are achieved when the r e a c t i o n i s c a r r i e d out i n dimethyl ether 3 and dimethoxymethane a t low temperature.

CH

R* Li +

RXHO

'3

OH *CH

0 L i

>

2

R

1h

R

54-94% ee I t i s of i n t e r e s t that the a l c o h o l s which possess the R c o n f i g u r a t i o n are produced by the r e a c t i o n of diaIkylmagneslums with aldehydes, whereas the a l c o h o l s obtained by the s i m i l a r r e a c t i o n o f a l k y l l i t h i u m s possess the S o r R c o n f i g u r a t i o n , 3 depending on the s i z e of the a l k y l l i t h i u m .

^Jy ι

2

R Mg +• RCHO 2

2

*

C H

3

0

L

OH *ΓΗ

I

; —

i^" «2

toluene.-110 C,1h R

1

(R)-(+)

R 22-92% ee

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

26

ASYMMETRIC

REACTIONS

A N D PROCESSES IN

CHEMISTRY

By extending the above mentioned asymmetric a d d i t i o n of a l k y l l i t h i u m to other organolithium reagents such as l i t h i u m s a l t s of methyl phenyl s u l f i d e , 2 - m e t h y l t h i o t h i a z o l i n e , a c e t o n i t r i l e , N-nitrosodimethylamine, and t r i a l k y l s i l y l a c e t y l e n e s ,

optically

a c t i v e oxiranes, t h i i r a n e s , aminoalcohols, and a c e t y l e n i c a l c o h o l s 4 5 are r e a d i l y obtained. *

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

RCHO

RC=CLi

*

R _ ^

u n

3

—R' K

OH

C^£)

ru

^

H

R'-H.

^

-SiMe

3

e t c

OLi

40-80% ee

Some of the o p t i c a l l y a c t i v e a c e t y l e n i c a l c o h o l s were suc­ c e s s f u l l y converted t o , e.g., γ-ethyΙ-γ-butyrolactone, the i n s e c t pheromone of Trogoderma, and important intermediates f o r the s y n t h e s i s of substances with a n t i b a c t e r i a l a c t i v i t i e s . ^

RCHO

MejSiC=CLi — - ~ * CH

3

R

* Y

SiMe

3

OLi

Et Trogoderma . _ , i n s e c t pheromone

ι canadensolide

^ avenaciolide

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2.

27

Synthetic Control

MUKAIYAMA

A c h i r a l aminoalcohol _7, derived from 4-4-hydroxyproline,

is

found to be a s u p e r i o r c a t a l y s t f o r the e n a n t i o s e l e c t i v e 1,4-add i t i o n of a r y l t h i o l s to 2-cyclohexen-l-orie to y i e l d

3-arylthio-

cyclohexanones i n high o p t i c a l p u r i t i e s . ^

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

HO

RSH

€>

+

R « l - B u O -

Κ * XJjPh tt H

2 mol»/.

= £> *

0

88% ee (2R, 3 S ) -

Asymmetric s y n t h e s i s based on a c h i r a l oxazepine. 3,4-Dimethyl-2-phenylperhydro-l,4-oxazepine-5,7-dione

(8) was

prepared from the h a l f e s t e r of malonic a c i d and JL -ephedrine and syntheses of v a r i o u s o p t i c a l l y a c t i v e c a r b o x y l i c a c i d s s t a r t i n g from t h i s c h i r a l oxazepine 8^ were i n v e s t i g a t e d .

% C H

3

VOH

" O y H ^ i ^ ^ W

+

CH,N "CH, A

ru ri

6

Λ./

λ

VN-^Cph ^CH 3

LiOH THF-HjO

^ C H J

Ο ψ

2

. 64%

0

>^;

C

H

3

8 i ) Synthesis o f β-substituted c a r b o x y l i c a c i d s . O p t i c a l l y a c t i v e 3 - s u b s t i t u t e d a l k a n o i c a c i d s are obtained by the r e a c t i o n of the 6 - a l k y l i d e n e d e r i v a t i v e s o f

( 9 ) , which

are e a s i l y prepared from 8^ and aldehydes, with Grignard reagents i n the presence of a c a t a l y t i c amount of n i c k e l c h l o r i d e , followed by h y d r o l y s i s .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

28

RCHO +

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

8 PyH-THF

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

RMgX,NiCl

2

H3O

R Ο OH

THF,-78°C

82- >99% ee

9

The a n t i b i o t i c indolmycin was synthesized i n high o p t i c a l p u r i t y as one a p p l i c a t i o n o f t h i s c h i r a l reagent

(Scheme 2 ) .

i i ) Synthesis of o p t i c a l l y a c t i v e c y c l o p r o p a n e d i c a r b o x y l i c a c i d s . The r e a c t i o n o f dimethylsulfoxonium

methylide with 6-

alkylideneoxazepine 9_ followed by h y d r o l y s i s gives almost o p t i c a l l y pure c y c l o p r o p a n e d i c a r b o x y l i c a c i d s i n good y i e l d s .

OCH3 OCH3

iii)

Synthesis of o p t i c a l l y a c t i v e 3 - s u b s t i t u t e d γ-butyrolactones. Almost o p t i c a l l y pure 3 - s u b s t i t u t e d γ-butyrolactones were

obtained by the f o l l o w i n g sequence; i ) the r e a c t i o n of 6-alkylideneoxazepine

9_ with p h e n y l t h i o m e t h y l l i t h i u m i n the

presence of a c a t a l y t i c amount of n i c k e l c h l o r i d e , i i ) the transformation of the adduct 10 to the dihydrofuran d e r i v a t i v e s 11 by trimethyloxonium

t e t r a f l u o r o b o r a t e , i i i ) a c i d h y d r o l y s i s of

the dihydrofuran d e r i v a t i v e 11.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

MUKAIYAMA

Synthetic Control

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

2.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

29

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

υ

H

83

β

H

?HH

75·/.

/ο

β

2 )

T

67 /·

U ^jj J

h

§ Η

ΤΗΡΤΗΡ

H

g

H

M

0

e

H

N

H

Ç

S

NH

Scheme 2.

3

! L _ Î

3

/ Et N

CH CN

2

Η

'"·μ

H

§* Η

Η

Ô*"

H

H

A

N

H

M

e

U

3 "

J ,

O N H

M

e

(sa./.ee)

AcOH-THF-H 0

^

(5§,6R)-indolmycin

s.

THPTHP 1 5 · / .

(continued)

1

M-N '

N

2

(95·/·ββ)

(2S,3R)-indolmycenic acid 6θ7·

^ J k X

2) recrystallization

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

*

J ^ - O^y P h

R

PhSCH Li, N i C l 2

Vfrl "CH3 0 ^ C ^H

31

Synthetic Control

MUKAIYAMA

2.

0

THF-toluene, -78°C

PhS 0 li^>OyPh R

u

3

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

y, H CH C

0

V Ή "'CKh Ο CH

4

CH C1 0

2

^

0

2

10

Ογ»ΡΙΐ ^

3

3

9

n

. Me OBF -

6

N

R S0 -Ac0H 2

4

0-0

3

3

> 90% ee

11 D i e l s - A l d e r r e a c t i o n a s s i s t e d by i n t r a m o l e c u l a r

interactions.

The D i e l s - A l d e r r e a c t i o n i s one of the most important i n organic

reactions

synthesis and has been a p p l i e d to the s y n t h e s i s o f

v a r i o u s n a t u r a l products which possess a six-membered r i n g system. Unfortunately,

however, there are some l i m i t a t i o n s to the

s t r u c t u r e s of dienes and dienophiles

that can be used s u c c e s s f u l l y .

For example, the D i e l s - A l d e r adducts between furan d e r i v a t i v e and β,β-dimethylacrylic a c i d d e r i v a t i v e s have not y e t been i s o l a t e d . The adducts of some s t e r i c a l l y hindered d i e n o p h i l e and furan d e r i v a t i v e s are s u c c e s s f u l l y obtained i n good y i e l d s by the intramolecular

D i e l s - A l d e r r e a c t i o n of the diene and d i e n o p h i l e

a c t i v a t e d by an alkoxymagnesium s a l t coordinated cule.

to the same mole­

The a c c e l e r a t i o n o f the r e a c t i o n i s apparently

c o o r d i n a t i o n of the d i e n o p h i l e and a proximity 12 the r e a c t i o n e n t r o p i c a l l y advantageous.

due to the

e f f e c t which makes

7 6 %

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

32

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

13 This process was applied to the synthesis of the Karahana ether. v/H 0 OH w H 0 AT\ 60% HNO. i) KOH/ EtOH U AcOH, SO'C.l^h ^>L,N-N=0 > 82%

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

^Z j %

12

The adduct 13 is transformed into (+)-Farneciferol C

Na Pd/C

liq.NH^-THF

A

14

i)NaN0 AcOH NH ' ^ ii)K0H EtOH 2

iii) H 0 3

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

+

2.

33

Synthetic Control

MUKAIYAMA 0

i)LiAlH /Et 0

0

"Ο J ^ J

0 E t

i

-OH

)

C

B

r

4

,

p

p

h

3

/

Ï

H

4

j

i i ) CI

T s C 1

iii)PhSK/EtOH iv)MCPBA/CH A/CH C Cl I

ii)Ph SnH,AIBN/ benzene r e f l u x

•>n ι ' ^ Ρ Η

i

J )

2

3

0

+

^

2

TO:.

i v ) 5%Na-Hg Na HP0,/Me0H,HMPA 2 4' o

i ) CBr ,PPh /CH CN Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

4

3

3

ii) KO Χ

κ>« (+)-Farneciferol C

This methodology, i . e . , the i n t r o d u c t i o n of an i n t r a m o l e c u l a r c h e l a t e e f f e c t f o r h i g h l y s e l e c t i v e r e a c t i o n , has been f u r t h e r extended to the asymmetric Michael r e a c t i o n .

The r e a c t i o n of N-

c r o t y l e p h e d r i n e 14 with Grignard reagents, followed by a c i d h y d r o l y s i s , c o n s t i t u t e s a simple procedure f o r o b t a i n i n g o p t i c a l l y pure c a r b o x y l i c

highly

acids.

H C» H

0 CH

3

3

R'ïf^ t N

Ho4*Ph H

'Br^

y

C H 3

H

14 C

, W l

H

N

n

i 3H ^ 3 H

C

H

° H 0 ^

H S04-ACOH ^ 2

R

OH

R'YT 85- >99% ee

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

34

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

Stereospecific reactions derivatives.

l e a d i n g t o o p t i c a l l y a c t i v e sugar

The cadmium s a l t o f the

d e r i v a t i v e 15 r e a c t s with various

2-allyloxybenzimidazole

aldehydes to a f f o r d adduct 16^

i n high r e g i o - and s t e r e o s e l e c t i v i t y , Adducts 1 Y 16

THF,

57-98%

/

reflux

RV(CH CH 0) Me 2

2

3

*

Q 17

(α/γ=75/25-90/10)

60-91% the m i l d a l l y l a t i o n of carbonyl compounds with

Further,

a l l y l t i n d i h a l o i o d i d e , formed i n s i t u by the o x i d a t i v e

addition

of stannous f l u o r i d e to a l l y l i o d i d e , has been a p p l i e d to the synthesis

of 2-deoxy-D-ribose s t a r t i n g from 2,3-0-isopropylidene18

D-glyceraldehyde.

1)

ο \m ^CHO

SnF

OCOCH^Ph

2

2) Ph0CH C0Cl 2

DMI/DMF

Q-y^

74%

(erythro:threo=81:19)

NH 0H erythro-18 >

OH

4

OH

AcOH/H 0 2

_ 0 0-^ 71%

OH 95%

2 ) M e

2

S

oTT 75%

2-deoxy-D-ribose

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

MUKAIYAMA

Synthetic Control

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

2.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

35

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch002

36

ASYMMETRIC

REACTIONS

A N D PROCESSES IN

CHEMISTRY

Literature Cited 1) a) Mukaiyama, T.; Asami, M.; Hanna, J.; Kobayashi, S. Chem. Lett. 1977, 783. b) Asami, M.; Ohno, H.; Kobayashi, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1978, 51, 1869. c) Asami, M.; Mukaiyama, T. Heterocycles 1979, 12, 499. 2) a) Mukaiyama, T.; Sakito, Y.; Asami, M. Chem. Lett. 1978, 1253. b) Mukaiyama, T.; Sakito, Y.; Asami, M. ibid. 1979, 705. c) Sakito, Y.; Mukaiyama, T. ibid. 1979, 1027. d) Sakito, Y.; Tanaka, S.; Asami, M.; Mukaiyama, T. ibid. 1980, 1223. e) Sakito, Y.; Asami, M.; Mukaiyama, T. ibid. 1980, 455. 3) a) Mukaiyama, T.; Soai, K.; Kobayashi, S. ibid. 1978, 219. b) Soai, K.; Mukaiyama, T. ibid. 1978, 491. c) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455. d) Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978, 601. 4) Mukaiayama, T.; Suzuki, K.; Soai, K.; Sato, T. ibid. 1979, 447. 5) Soai, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979, 52, 3371. 6) Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255. 7) Mukaiyama, T.; Ikegawa, Α.; Suzuki, K. ibid. 1981, 165. 8) a) Mukaiyama, T.; Takeda, T.: Osaki, M. ibid. 1977, 1165. b) Mukaiyama, T.; Takeda, T.; Fujimoto, K. Bull. Chem. Soc. Jpn. 1978, 51, 3368. 9) Takeda, T.; Mukaiyama, T. Chem. Lett. 1980, 163. 10) Mukaiyama, T.; Fujimoto, K.; Takeda, T. ibid. 1979, 1207. 11) Mukaiyama, T.; Fujimoto, K.; Hirose, T.; Takeda, T. ibid, 1980, 635. 12) Mukaiyama, T.; Tsuji, T.; Iwasawa, N. ibid. 1979, 697. 13) Mukaiyama, T.; Iwasawa, N.; Tsuji, T.; Narasaka, K. ibid. 1979, 1117. 14) Mukaiyama, T.; Iwasawa, N. ibid. 1981, 29. 15) Mukaiyama, T.; Iwasawa, N. ibid. 1981, 913. 16) Yamaguchi, M.; Mukaiyama, T. ibid. 1979, 1279. 17) Yamaguchi, M.; Mukaiyama, T. ibid. 1981, 1005. 18) Harada, T.; Mukaiyama, T. ibid. 1981, 1109. RECEIVEDDecember 21, 1981. In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

3 Asymmetric Synthesis of Chiral Tertiary Alcohols in High Enantiomeric Excess ERNEST L . ELIEL, JORMA K. KOSKIMIES, BRUNO LOHRI, W. JACK FRAZEE, SUSAN MORRIS-NATSCHKE, JOSEPH E . L Y N C H , and KENSO SOAI

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch003

University of North Carolina, Department of Chemistry, Chapel Hill, NC 27514

Chiral 1,3-oxathianes have been used as adjuvants for highly stereoselective asymmetric syntheses. Acylation (direct or via an intermediate carbinol) proceeds to give exclusively equatorial products in which the chirality has been transferred to C(2) of the 1,3-oxathiane. Reaction of the acyl com­ pounds with Grignard reagents gives predominantly one diastereomer of a 2-oxathianylcarbinol bearing two different alkyl groups on the carbinol carbon, following Cram's rule. Conditions for maximum stereoselectivity have been worked out. Cleavage of the oxathiane (NCS/AgNO) leads to α-hydroxy­ aldehydes, RR'C(OH)CHO, from which glycols, RR'C­ (OH)CHOH, tertiary alcohols, RR'C(OH)CH and other derivatives can be prepared, generally in enantiomeric purity exceeding 90%. Suitable chiral 1,3-oxathianes can be conveniently derived from camphor (either enantiomer) or (+)-pulegone. 3

2

3

In 1971 we d i s c o v e r e d (1) t h a t the r e a c t i o n o f conforma­ t i o n a l ^ l o c k e d 2 - d i t h i a n y l l i t h i u m compounds with e l e c t r o p h i l e s (Corey-Seebach r e a c t i o n ) proceeds with remarkable s t e r e o s e l e c ­ t i v i t y , g i v i n g v i r t u a l l y e x c l u s i v e l y the e q u a t o r i a l s u b s t i t u t i o n products, as e x e m p l i f i e d i n Scheme 1 (R=H). The preference f o r the l , 3 - d i t h i a n y l - 2 - c a r b a n i o n t o undergo e l e c t r o p h i l i c s u b s t i t u ­ t i o n from the e q u a t o r i a l s i d e amounts t o over 6 kcal/mol ( 2 ) , corresponding t o a s e l e c t i v i t y f a c t o r i n excess o f 10,000. This high preference was subsequently shown (3) t o be due t o s t e r e o e l e c t r o n i c f a c t o r s , i n accord with t h e o r e t i c a l p r e d i c t i o n s (4, 5_, 6 ) . S t e r e o s e l e c t i v i t i e s o f such magnitudes resemble those found i n enzymatic r e a c t i o n s and we r e s o l v e d t o t r y t o apply the high

0097-6156/82/0185-0037$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

38

REACTIONS

A N D PROCESSES IN

CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch003

Scheme 1 s e l e c t i v i t y t o the design o f a v e r y e f f i c i e n t asymmetric s y n t h e s i s . Before e n t e r i n g i n t o d e t a i l s , we wish t o s t a t e here the c o n d i t i o n s of an e f f e c t i v e asymmetric s y n t h e s i s i n g e n e r a l terms (7 ) :

1)

The s y n t h e s i s must be h i g h l y s t e r e o s e l e c t i v e .

2)

I f a c h i r a l adjuvant ( c h i r a l a u x i l i a r y reagent) i s b u i l t i n t o the s t a r t i n g m a t e r i a l , the c h i r a l center (or other c h i r a l element) c r e a t e d i n the asymmetric s y n t h e s i s must be r e a d i l y separable from the c h i r a l adjuvant without r a c e m i z a t i o n .

3)

The c h i r a l adjuvant i t s e l f must be r e c o v e r a b l e i n good y i e l d and without l o s s o f enantiomeric p u r i t y .

4)

The c h i r a l adjuvant should be r e a d i l y (cheaply) a v a i l a b l e i n e n a n t i o m e r i c a l l y pure form.

In a d d i t i o n , o f course, the s y n t h e s i s must proceed i n acceptable o v e r a l l chemical y i e l d . Statement 1) i s q u a l i t a t i v e and i t s t r a n s l a t i o n i n t o q u a n t i t a t i v e terms i s a matter o f t a s t e . Syntheses producing 85-90% enantiomeric excess (e.e.) u s u a l l y allow p u r i f i c a t i o n o f the c h i r a l product (or an intermediate on the way) t o enantiomeric p u r i t y by simple r e c r y s t a l l i z a t i o n . However, higher demands may be made i n cases o f syntheses of c h i r a l l i q u i d s when c r y s t a l l i n e intermediates are not a c c e s s i b l e . With r e s p e c t t o statements 2) and 3 ) , these c o n d i t i o n s are p a r t i c u l a r l y easy t o f u l f i l l i n c a t a l y t i c asymmetric s y n t h e s i s where 2) simply demands s e p a r a t i o n o f the c h i r a l product from the c h i r a l c a t a l y s t and 3) i s superseded by a requirement of reasona b l e turnover. (A turnover number of 100, modest by the standards of many c a t a l y t i c r e a c t i o n s , i s e q u i v a l e n t to a 99% recovery o f c h i r a l a u x i l i a r y reagent, which i s r a r e l y achieved!) Catalytic asymmetric syntheses are t h e r e f o r e p a r t i c u l a r l y a t t r a c t i v e , but, of course, they a r e o f t e n not a v a i l a b l e . Statement 3) may not apply when the c h i r a l a u x i l i a r y reagent i s v e r y cheap (e.g. sucrose). Contemplation o f Scheme 1 suggests t h a t i t s a p p l i c a t i o n t o asymmetric s y n t h e s i s should be f a c i l e i f R = CH. and the s t a r t i n g

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch003

3.

ELiEL E T AL.

39

Chiral Tertiary Alcohols

d i t h i o l i s r e s o l v e d . However, s e p a r a t i o n o f the new c h i r a l center (C-2) from the o r i g i n a l one (C-6) would appear t o be unachievable. We f e l t t h a t t h i s dilemma c o u l d be overcome by the use o f 1,3oxathianes i n s t e a d o f 1,3-dithianes and, indeed, i t was found t h a t the e l e c t r o p h i l i c r e a c t i o n s o f 2 - l i t h i o - l , 3 - o x a t h i a n e s are o f the same order o f s t e r e o s e l e c t i v i t y as those o f the corresponding d i t h i a n e s (8). However, an asymmetric s y n t h e s i s based on the s t e r e o s e l e c t i v e cleavage o f t h e C(2)-S bond f o l l o w e d by s c i s s i o n of the C(6)-0 l i n k a g e i n 2-alkyl-4,6,6-trimethyl-l,3-oxathianes gave d i s a p p o i n t i n g l y low o p t i c a l y i e l d s (9). A chance d i s c o v e r y p o i n t e d us toward the s u c c e s s f u l s y n t h e t i c approach. 2-Acyl-l,3-oxathianes can be obtained with e x c l u s i v e l y e q u a t o r i a l a c y l groups by a c y l a t i o n o f c o n f o r m a t i o n a l l y b i a s s e d 2 - l i t h i o - 1 , 3 - o x a t h i a n e s o r ( i n b e t t e r y i e l d ) by r e a c t i o n with aldehydes followed by Swern o x i d a t i o n (10). We d i s c o v e r e d (8) t h a t r e a c t i o n o f these ketones with Grignard reagents once again proceeds h i g h l y s t e r e o s e l e c t i v e l y g i v i n g one o f the two p o s s i b l e t e r t i a r y a l c o h o l s i n l a r g e excess over the other. The sequence of t h e two h i g h l y s t e r e o s e l e c t i v e steps i s shown i n Scheme 2. I t i s c l e a r t h a t s t a r t i n g from a c h i r a l 1,3-oxathiane such as ^, ^ T ^

s

^ 7

ι\ Bu L i - /7 Γ ^ T/ ^ ç U 1) 2) RCHO L ^ ^ D ' Ο 3) DMSO-TFAA' Et^N only isomer

^ r ^ ^ s - ^ T ^ c —

s

R l

— T ^ —

2

s

D R'MgX > 2° H

^ 7 — c

minor CrVu

61

•Λν.

Λ ν

(10/1)

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch004

Also suppose t h a t we have a c h i r a l enolate which r e a c t s w i t h a c h i r a l aldehydes t o g i v e the two e r y t h r o - a l d o l s i n a 10:1 r a t i o :

(10/1)

Now suppose t h a t we a l l o w one enantiomer o f the c h i r a l aldehyde t o r e a c t i n t u r n w i t h the two enantiomers o f the c h i r a l e n o l a t e . I n one case the two r e a c t a n t s w i l l both promote the same absolute con­ f i g u r a t i o n ( c h i r a l i t y ) a t the two new c h i r a l c e n t e r s . In t h i s case, the e f f e c t i v e "Cram's r u l e s e l e c t i v i t y " shown by the aldehyde w i l l be g r e a t e r than i n i t s r e a c t i o n s with r e p r e s e n t a t i v e a c h i r a l e n o l a t e s . For the s e l e c t i v i t i e s chosen i n t h i s example, t h e "Cram:anti-Cram r a t i o " should be on the order o f 100:1.

good

good

ΙΟχΙΟ«ΙΟΟ

bod bod I χI «I

Of course, i n the other combination, n e i t h e r r e a c t a n t gets i t s way. In t h i s case, the e f f e c t i v e d i a s t e r e o f a c e s e l e c t i v i t y shown by the aldehyde should be poorer than i s seen i n r e a c t i o n s o f t h e same aldehyde w i t h r e p r e s e n t a t i v e a c h i r a l e n o l a t e s .

good

bad

10 χ I - 10

bod

good

I χ 10 « 10

In order t o t e s t t h i s concept as a way o f c o n t r o l l i n g t h e problem o f d i a s t e r e o f a c e s e l e c t i v i t y i n a l d o l condensations i n v o l v ­ ing c h i r a l aldehydes, we prepared the c h i r a l e t h y l ketone shown below, which i s a v a i l a b l e i n four s t r a i g h t f o r w a r d steps from Dfruetose. T h i s compound shows modest inherent diastereoface

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

62

REACTIONS

A N D PROCESSES IN

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s e l e c t i v i t y , r e a c t i n g w i t h benzaldehyde to g i v e the two e r y t h r o a l d o l s i n a r a t i o o f 4:1, w i t h the jt,Il diastereomer predominating* As a r e a c t i o n p a r t n e r , we chose the acetonide o f g l y c e r a l d e h y d e , s i n c e both enantiomers a r e r e a d i l y a v a i l a b l e . T h i s aldehyde also shows modest i n h e r e n t d i a s t e r e o f a c e s e l e c t i v i t y i n i t s r e a c t i o n s w i t h a c h i r a l e n o l a t e s — on the order o f 4.5:1. The sense o f the s t e r e o s e l e c t i v i t y i s such t h a t Il-glyceraldehyde acetonide g i v e s predominantly the a l d o l w i t h the S,S c o n f i g u r a t i o n a t the two new HO.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch004

*CHO

80%

20%

0, T M S *O ^

O H C ^ ^

TMSO^N

TMS< 82%

18%

centers. Thus, the f r u c t o s e - d e r i v e d ketone and the acetonide o f ^ - g l y c e r a l d e h y d e show unproductive double s t e r e o d i f f e r e n t i a t i o n and g i v e an almost equal mixture o f the two e r y t h r o - a l d o l s . However, the other combination i s r e i n f o r c i n g , and o n l y a s i n g l e e r y t h r o a l d o l r e s u l t s . (1_1)

5?

OHC

0

-V '

\

97%

ό

-C H -

>95%

90%

which a f t e r h y d r o l y s i s a f f o r d s the 2 , 3 - d i s u b s t i t u t e d acids 6^ i n 77-82% diastereomeric p u r i t y . HPLC examination of the d i a s t e r e o meric oxazolines _5 p r i o r to h y d r o l y s i s i n d i c a t e s that the a l k y l a ­ t i o n o f 2: occurred with >99% s t e r e o s e l e c t i v i t y . Thus, v i r t u a l l y no presence of diastereomeric i m p u r i t i e s was observed. I t may, t h e r e f o r e , be concluded that t h e observed diastereomeric p u r i t y f o r 6_ was the r e s u l t o f p a r t i a l racemization during the h y d r o l y s i s 0097-6156/82/0185-0083$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

84

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

R

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

Me

Ph

OMe

(-)-3 Figure

1.

Formation

of 2,3-disubstituted alkanoic acids by conjugate addition alkylation of α,β-unsaturated oxazolines.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

and

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

6.

Chiral Oxazolines

MEYERS

85

o f J5. S e v e r a l examples of t h i s tandem d i a l k y l a t i o n are given i n Table I . With regard to the absolute c o n f i g u r a t i o n of the acids J6, they are assigned on the b a s i s of both known compounds and previous p r e d i c t i o n s described i n e a r l i e r work (1). I t i s i n t e r ­ e s t i n g to note that quenching adduct 2^ to give the 2-alkyloxazol i n e 4^ and then metalation back to _2 followed by a l k y l a t i o n gave the 2 , 3 - d i s u b s t i t u t e d acids j3 o f the same c o n f i g u r a t i o n as that obtained from 1_ i n the s e q u e n t i a l d i a l k y l a t i o n process. This confirms that the same l i t h i o azaenolate 2^ i s formed both by con­ jugate a d d i t i o n (1^2) and metalation (4*2). Since both processes have been performed as separate methods, l e a d i n g e i t h e r to c h i r a l 2 - s u b s t i t u t e d c a r b o x y l i c a c i d s or 3 - s u b s t i t u t e d c h i r a l a c i d s , the absolute c o n f i g u r a t i o n of the 2 , 3 - d i s u b s t i t u t e d acids 6^ i s c o n s i s ­ tent with these e a r l i e r f i n d i n g s .

Table I.

R ( i n 1)

2,3-Disubstituted C a r b o x y l i c Acids 6^

f

R Li

Diastereomeric Ratio .5

Yield 5

a-C

Diastereomeric R a t i o , 6^

%

e-c

Me

Et

99

65

77

(R)

99

(R)

Me

n-Bu

99

80

82

(R)

99

(R)

t-Bu

n-Bu

99

82

80

(S)

99

(R)

n-Bu

t-Bu

99

75

79

(R)

99

(R)

A l d o l Products

v i a Boron

Azaenolate

The use of c h i r a l oxazolines as reagents f o r a l d o l type products ( F i g . 2) r i c h i n e r y t h r o or threo β-hydroxy a c i d s has a l s o been accomplished. In e a r l i e r work i n our l a b o r a t o r y (8) we described the formation of β-hydroxyesters _7 from l i t h i o oxazo­ l i n e s and v a r i o u s aldehydes i n 20-25% ee. The absence of an aa l k y l group was considered the major reason f o r the poor ee's of the product which lacked s t r i n g e n t stereochemical requirements i n the t r a n s i t i o n s t a t e . The process was repeated with the 2 - e t h y l o x a z o l i n e and gave 8^ i n much h i g h e r s e l e c t i v i t y mainly as the threo-isomer and i n 75% enantiomeric p u r i t y (7). We have now i n v e s t i g a t e d t h i s a l d o l process u s i n g the boron " e n o l a t e s " of oxazolines £-and'10 ( F i g . 3) ( 9 ) . I t should be noted that boron azaenolate 9. contains the c h i r a l center on the organoborane, whereas 10 contains the c h i r a l center on the o x a z o l i n e .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

86

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OH

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

7 (^20% e e )

8 {82% t h r e o , 75% e e ) Figure

2.

Chiral

oxazolines used as reagents for aldol-type erythro or threo β-hydroxy acids.

products

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

rich

in

6.

MEYERS

Chiral Oxazolines

Me

87

Λ

Ph

M û

I

Me

''.

I

ι

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

A

OMe

10

1) RCHO 2) H 0

1) RCHO I 2) H 0 3) C H N

+

+

3

3

3) C H N 2

2

2

Me

Me

Ok

C0 Me

11 ( 9 0 - 9 5 %

k

2

C0 Me 2

HO

HO

Figure 3.

2

threo)

12 ( 9 7 - 9 8 %

erythro)

Formation of β-hydroxyesters with an a-alkyl group by the aldol using boron enolates of oxazolines 9 and 10.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

process

88

ASYMMETRIC

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Treatment o f with v a r i o u s aldehydes gave the threo-β-hydroxye s t e r JL1 a f t e r h y d r o l y s i s and e s t e r i f i c a t i o n , i n 90-95% d i a s t e r e o s e l e c t i v i t y with enantiomeric excess o f 77-85% (Table I I ) . On the other hand, the boron enolate 10, when t r e a t e d s i m i l a r l y with aldehydes now gave the e r y t h r o β-hydroxy e s t e r s 12 i n 97-98% d i a s t e r e o s e l e c t i v i t y though i n somewhat poorer e e s (40-60%, Table I I I ) . C NMR spectroscopy employing £ and 10 with C enriched methyl groups confirmed that only a s i n g l e enolate was fomp.d a t -78° under the c o n d i t i o n s o f k i n e t i c c o n t r o l . Equili­ b r a t i o n o f 9 or 10 took p l a c e by warming t h e i r ether s o l u t i o n s t o -25° showing a steady i n c r e a s e i n a second methyl s i g n a l u n t i l e q u i l i b r i u m was reached a t 2:1. Unfortunately, which enolate i s formed a t -78° i s not known a t t h i s time. When the condensation f

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

1 3

Table I I .

1 3

C h i r a l threo-hydroxyesters 11 from £

RCHO

% threo-erythro

% ee

Conf'n. Major Isomer [ a ]

(CHCl^)

D

EtCHO

92:8

77

2R,3R

-9.9

PrCHO

91:9

77

2R,3R

-2.5

n-PentCHO

90:10

77

2R,3R

-3.1

Me CHCH0

91:9

85

2R,3R

-12.5

CyclohexCHO

95:5

84

2R,3R

-8.1

t-BuCHO

94:6

79

2R,3S

-21.2

2

Table I I I .

RCHO

Chiral

erythro-hydroxyesters 12 from 10

% erythro-threo

Conf'n. % ee Major Isomer [ot] (CHC1 ) D

1.4

98:2

40

2S,3R

Me CHCH0

98:2

41

2S,3R

-2.3

t-BuCHO

97:3

60

2S,3S.

-6.6

EtCHO 2

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

3

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6.

MEYERS

Chiral Oxazolines

89

with aldehydes was c a r r i e d out w i t h e q u i l i b r a t e d 9_ or 10, the d i a s t e r e o s e l e c t i v i t y i n 11 and 12 decreased, as expected, to ^80:20. Since the stereochemistry of the boron enolates 9_ and 10 i s not known, i t i s d i f f i c u l t to advance a reasonable mechanism except to p o s t u l a t e a c h a i r - t y p e six-membered t r a n s i t i o n s t a t e based on the Zimmerman model (10). This c o r r e c t l y p r e d i c t s the stereochemistry of the product provided the Ζ boron enolates of 9_ and 10 are employed ( F i g . 4) . A v a r i e t y o f other oxazolines was i n v e s t i g a t e d ( F i g . 5) to probe the nature of s t r u c t u r a l parameters i n determining the e r y t h r o threo r a t i o s of 3-hydroxy e s t e r s . Thus, r e a c t i o n of boron enolates of 13-16 and 9-BBN a l s o gave h i g h e r y t h r o s e l e c t i v i t y of JL2 (R = i - P r ) when t r e a t e d with isobutyraldehyde. It i s interest­ i n g to note that JL3 gave high threo s e l e c t i v i t y (Table I I ) when diisopinocampheyl borane enolate 9_ was employed while g i v i n g high e r y t h r o s e l e c t i v i t y o f _12 (R = i - P r ) u s i n g 9-BBN enolate. This i m p l i e s a major e f f e c t on the product due to the nature of the boron s u b s t i t u e n t s . F u r t h e r work should help c l a r i f y t h i s p o i n t .

C h i r a l Phthalides Aromatic oxazolines have a l s o been u t i l i z e d ( F i g . 6) as v e h i c l e s f o r asymmetric s y n t h e s i s . Thus the c h i r a l oxazoline 17, used as i t s l i t h i o or magnesiohalide d e r i v a t i v e 17b (from the bromo compound 17a) was t r e a t e d w i t h s e v e r a l carbonyl compounds to give the adducts 18, whose diastereomer r a t i o s were assessed by ^H-nmr or HPLC (Table IV). The extent of s t e r e o s e l e c t i o n was r a t h e r poor i n d i c a t i n g a s t e r i c a l l y undemanding t r a n s i t i o n s t a t e .

Table

IV. % Yield

Diast. Ratio

PhCOMe

71

64:31

PhCHO

60

57:43

o-MeOPhCHO

63

59:41

n-BuCHO

64

51:49

a) Assessed

on

a

18

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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min'm. l , 3 - 1 n t ' n . MeO Ρ

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I

Me

/

L

Ην 0-° " ^ < ^ ^
c o n f i g u r a t i o n ) . Pure enantiomers of 1£ were obtained by MPLCa s s i s t e d r e s o l u t i o n s o f JL8 followed by h y d r o l y s i s with a c i d . We next turned to r e v e r s a l of the n u c l e o p h i l e - e l e c t r o p h i l e combination by p r e p a r i n g o_-acylaryl oxazolines 21 and t r e a t i n g them with οrganometallies ( F i g . 8). A d d i t i o n of o r g a n o l i t h i u m or Grignard reagent gave the adducts 22. which smoothly rearranged to the iminolactones T5. HPLC analyses of 23. showed the r a t i o of diastereomers to be r a t h e r low again suggesting that a d d i t i o n o f organolithium reagents to 21 was perhaps too f a s t with a low ΔΔ(?*\ However, when methylmagnesium c h l o r i d e was t r e a t e d with the Qr benzoyloxazoline 24, the r e a c t i o n proceeded more slowly and, a f t e r h y d r o l y s i s , the p h t h a l i d e 2j> was recovered almost e n a n t i o m e r i c a l l y pure ( F i g . 9) (12). Future e f f o r t s w i l l now be d i r e c t e d to Grignard a d d i t i o n s to ketooxazolines i n the hope that the above r e a c t i o n possesses some g e n e r a l i t y . The complexities o f t h i s system and f a c t o r s a f f e c t ­ i n g the t r a n s i t i o n s t a t e w i l l have to be more c a r e f u l l y addressed b e f o r e a general s y n t h e t i c approach to c h i r a l p h t h a l i d e s can be achieved.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

f

C h i r a l Binaphthyls An asymmetric s y n t h e s i s of c h i r a l binaphthyls has been accom­ p l i s h e d u t i l i z i n g naphthyloxazolines. The method i s based on the f a c i l e displacement o f an o-methoxyl group i n a r y l o x a z o l i n e s by v a r i o u s n u c l e o p h i l e s (13). The aromatic s u b s t i t u t i o n process has now a l s o been found to proceed with o-methoxynaphthyloxazolines ( F i g . 10). A number o f n u c l e o p h i l i c reagents smoothly d i s p l a c e d the methoxyl group to 26 and a f t e r h y d r o l y s i s l e d to 1-substituted2-naphthoic a c i d s 27^. U t i l i z a t i o n of t h i s e f f i c i e n t coupling r e a c t i o n with c h i r a l oxazolines was examined i n an attempt to reach c h i r a l b i n a p h t h y l s . Thus, 28 was t r e a t e d with the Grignard reagent of l-bromo-2-methoxynaphthalene at room temperature i n THF to give the b i n a p h t h y l adduct 29_ ( F i g . 11) . Nmr a n a l y s i s showed that the r a t i o o f diastereomers i n 2£ was greater than 95:5 i n d i ­ c a t i n g a high degree of s t e r e o s e l e c t i o n i n the coupling r e a c t i o n . H y d r o l y s i s o f 29 followed by hydride r e d u c t i o n of the intermediate e s t e r gave the c h i r a l b i n a p h t h y l 30 i n VL00% ee (confirmed by LISR-nmr techniques). Two a d d i t i o n a l naphthyl Grignard reagents were examined ( F i g . 12) which l e d to products whose r a t i o s were not as high as i n the methoxy naphthyl system, but,nevertheless, were s t i l l formed i n 60-70% ee. The c r y s t a l l i n e nature of 29

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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ASYMMETRIC

20 Figure

88% e e 7.

Asymmetric

synthesis using proline

derivative

20.

(11)

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

6.

Chiral Oxazolines

MEYERS

OMe

93

R'L1 -78°

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

22

D i a s t e r e o m e r i c R a t i o s o f 23 R

R' L i

* Yield

Ratio

t-Bu

Ph

94

2:1

Ph

Me

85

2:1

Ph

n-Bu

86

1.2:1 23

Figure 8. Synthesis of iminolactones, 23, by reaction of o-acylaryloxazolines with organolithium or Grignard reagent and rearrangement of product, 22.

1) MeMgCl, - 4 5 ° , T H F ir

\ OMe 2) O x a l i c A c i d

25, S, 24 Figure

[a]

D

+68.4°

99% ee 9.

Preparation of phthalide, 25, by treatment of o-benzoyloxazoline, with Grignard reagent followed by hydrolysis.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

24,

94

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ASYMMETRIC

Figure

10.

Synthesis of l-substituted-2-naphthoic acids by aromatic of o-methoxynaphthyloxazolines followed by hydrolysis.

substitution

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

Chiral Oxazolines

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

95

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Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

Ph

CH

3

68.0

75:25 (PMR)

0CH

3

71.0

>95:5 (PMR)

Figure

12.

Asymmetric synthesis of chiral binaphthyls, 29, by reaction naphthyl Grignard reagents. Ratios of diastereomers are given.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

with

6.

MEYERS

Chiral

97

Oxazolines

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch006

(R = H, Me, MeO) r e s u l t e d i n very easy p u r i f i c a t i o n to s i n g l e diastereomers by simple c r y s t a l l i z a t i o n . However, s i n c e t h i s was not the current aim o f the study, care was taken to avoid inadvertent r e s o l u t i o n during the workup and p u r i f i c a t i o n o f _29. The most convenient method to reach c h i r a l binaphthyls was to c a r r y out a tandem h y d r o l y s i s - r e d u c t i o n to the hydroxymethyl group ( F i g . 13). Thus, the b i n a p h t h y l o x a z o l i n e s 29 were only p a r t i a l l y hydrol y z e d to the aminoesters 31 and then subjected to hydride reduct i o n to the a l c o h o l 30. The absolute c o n f i g u r a t i o n o f the c h i r a l binaphthyls was determined by c o r r e l a t i o n methods to known d e r i v a t i v e s as w e l l as CD s p e c t r a l c h a r a c t e r i s t i c s .

Figure

13.

Hydrolysis of binaphthyloxazolines, 29, to aminoesters, reduction to alcohol producing chiral binaphthyls.

31,

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

and

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Literature Cited 1. Meyers, A. I. Accounts of Chem. Res., 1978, 11, 375. 2. Meyers, A. I. Pure & Appl. Chem., 1979, 51, 1255. 3. Meyers, A. I.; Smith, R. K.; Whitten, C. E. J. Org. Chem., 1979, 44, 2250. 4. Meyers, A. I.; Smith, R. K. Tet. Lett., 1979, 2749. 5. Meyers, A. I.; Slade, J.; J. Org. Chem., 1980, 45, 2785. 6. Meyers, A. I.; Yamamoto, Y.; Mihelich. E. D.; Bell, R. A. J. Org. Chem., 1980, 45, 2792. 7. Meyers, A. I.; Reider, P. J. J. Am. Chem. Soc., 1979, 101, 2501. 8. Meyers, A. I.; Knaus, G. Tet. Letters, 1974, 1333. 9. Meyers, A. I.; Yamamoto, Y. J. Am. Chem. Soc., 1981, 103, 4278. 10. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc., 1957, 79, 1920. 11. Asami, M. and Mukaiyama, T. Chem. Lett., 1980, 17. 12. Meyers, A. I.; Hanagan, Μ. Α., research in progress. 13. Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem., 1978, 43, 1372. RECEIVED December 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

7 Highly Selective Synthesis with Novel Metallic Reagents HITOSI NOZAKI, TAMEJIRO HIYAMA, KOICHIRO OSHIMA, and KAZUHIKO TAKAI

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

Kyoto University, Department of Industrial Chemistry, Kyoto, 606, Japan

Allylchromium reagents as produced from allylic bromides and Cr(II) salts in anhydrous THF or DMF react with carbonyl components to form homo­ allylic alcohols. The aldehyde adducts, RCH(OH)­ -CHMeCH=CH, are oxidized with various recently described reagents to produce epoxy alcohols with different ways of steric control.--Alkylation of cyclopropane derivatives with R Al proceeds from preliminary heterolysis in one case, whereas the reaction introduces alkyl carbanions with S 2like inversion in other cases.--Catalysis with Pd(O) makes possible the substitution of an -ΟΡΟ(OR) group on an sp carbon and finds a number of synthetic applications.--Finally, the aliphatic Claisen rearrangement is smoothly per­ formed at room temperature by means of R2AlX reagents (where X = R, H, or SPh etc.) involving "combined acid-base" attack. 2

3

N

2

2

T h i s paper w i l l d e a l with f o u r t o p i c s : t h e f i r s t one i s r e ­ l a t e d t o allylchromium reagents, while the l a t t e r three r e f e r t o the behavior o f t r i a l k y l a l u m i n u m o r r e l a t e d species i n d i f f e r e n t s i t u a t i o n s . The authors' main concern here i s t o d e s c r i b e new reactions useful for selective synthesis. Allylchromium Reagents i n Homoallyl A l c o h o l Synthesis Organochromium compounds prepared from h a l i d e s and C r ( I I ) species i n anhydrous, a p r o t i c , p o l a r s o l v e n t s provide means o f s e l e c t i v e s y n t h e s i s as has been d e s c r i b e d p r e v i o u s l y U , 2 ) . In p a r t i c u l a r , the Grignard type carbonyl a d d i t i o n o f allylchromium reagents proceeds much more slowly and s e l e c t i v e l y than t h a t o f organomagnesium compounds. Scheme 1 i n d i c a t e s threo s e l e c t i v i t y i n the r e a c t i o n o f

0097-6156/82/0185-0099$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

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Scheme 1 . RCHO + M e ^ ^ B r ι1 mol ™i mni 29 mol R

Solvent

Ph Ph

b

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Ph

CrCl (4mol) LAH ( 2 m o l )

R Y

3

1

. V

I 0 H

3

Y i e l d (%)

L V

R +

V I 0 H

t h r e o (%) 0

THF

96

100

THF

87

100

0

92

75

25 7

DMF

D-Pr

THF

59

93

i-Pr

THF

55

95

5

i-Pr

DMF

78

66

34

û-Am

THF

70

97

3

η-Am

DMF

77

68

32

a

T h e r e a c t i o n was c a r r i e d o u t a t room temp f o r 2 h . The c i s - i s o m e r o f c r o t y l bromide was u s e d .

Scheme 2 P h

J L

^

Ph

OH

t-Bu00H/Al(0Bu-t) mCPBA

.

Y i e l d (%) 2

3

52

I

Ph

OH

Oxidant $-Bu00H/V0(acac)

I

.

OH Isomer R a t i o (%) 76 : 2 4

51

1 8 : 82

69

55 : 45

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

7.

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c r o t y l bromide (3) as reported a l s o by Heathcock (4). Tetrahydrofuran (THF) as s o l v e n t gives higher s e l e c t i v i t i e s but somewhat poorer y i e l d s than dimethylformamide (DMF). Epoxidation o f the r e s u l t i n g h o m o a l l y l i c a l c o h o l s has been i n v e s t i g a t e d (Scheme 2 ) . The Sharpless and r e l a t e d epoxidation techniques (5_,6) provide a way to c o n t r o l the stereochemistry o f three neighboring carbons. The C r ( I I ) mediated r e a c t i o n has been extended f u r t h e r t o systems i n v o l v i n g aldehydes and 2,2-diiodopropane (with HI l o s s ) as w e l l as v i n y l i o d i d e s and bromides, a l l a f f o r d i n g a l l y l i c a l c o h o l s (7).

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

A l k y l a t i o n o f an sp3 Carbon with Trialkylaluminum The r e a c t i o n o f d i e t h y l geranyl phosphate with R3AI produces q u a n t i t a t i v e l y a mixture of geranyl-R and l i n a l y l - R products i n 9:1 r a t i o , while the corresponding n e r y l phosphate a f f o r d s 4-RCMe2~ s u b s t i t u t e d 1-methylcyclohexenes e x c l u s i v e l y (8). Evidence f o r the intermediacy o f a c a r b o c a t i o n species i n the r e l a t e d r e a c t i o n shown i n Scheme 3 i s d e r i v e d from the f a c t t h a t the o p t i c a l act i v i t y o f the s t a r t i n g acetate substrate i s completely l o s t i n the r i n g cleavage r e a c t i o n product (9,10). A p o s s i b l e e x p l a n a t i o n i s given i n Scheme 4. Throughout these and subsequent r e a c t i o n s we use no l e s s than a 2:1 mol r a t i o o f aluminum reagents which are mostly d i m e r i c . We p o s t u l a t e t h a t the l e a v i n g acetate group i s s u b s t a n t i a l l y reduced i n n u c l e o p h i l i c i t y by double complexation with R 3 A I , so t h a t the c a t i o n i c p a r t i s almost naked even i n the e a r l y i o n - p a i r stage. The cyclopropylmethyl c a t i o n i s isomerized to the more s t a b l e b e n z y l i c one which i s then slowly a l k y l a t e d by the complex anion p a r t . I t should be noted t h a t the a n i o n i c comp l e x , but not the Lewis a c i d i t s e l f , p a r t i c i p a t e s i n t h i s key step. Thus the R3AI reagent may be c a l l e d a "combined acid-base." In sharp c o n t r a s t , however, Scheme 5 gives an instance o f a methyl carbanion being introduced l a r g e l y i n an SN2-type i n v e r s i o n stereochemistry. Note t h a t the substrate c a r r i e s a cyclopropane carbon doubly a c t i v a t e d by 1,3-dicarbonyl groups. A p o s s i b l e exp l a n a t i o n i s given i n Scheme 6. The r e a c t i o n can be u t i l i z e d i n the s e l e c t i v e s y n t h e s i s o f dl-neonepetalactone and i t s epimer. The sequence i n v o l v e s (1) e n o l i z a t i o n (NaH) and p h o s p h o r y l a t i o n ( C l P O ( 0 E t ) ) , (2) methylation (Me2CuLi), (3) o z o n o l y s i s (MeOH, -78°) and r e d u c t i o n , and (4) the f i n a l l a c t o n i z a t i o n (PyH.OTs). 2

2 A l k y l a t i o n o f an sp

Carbon with the R3A1-Pd(0) System

The methylation [step (2)] i n the above sequence proceeds smoothly due to the presence o f an ethoxycarbonyl a c t i v a t i n g group. A new technique (11) i s based on the c a t a l y s i s by a Pd(0) complex and provides a methodology o f a l k y l s u b s t i t u t i o n o f an enol phosphate moiety i n the absence o f such an a c t i v a t i n g group. The r e s u l t s are given i n Table 1. As the e n o l i z a t i o n o f ketones can be performed regi©selectively, the technique f u r n i s h e s an approach t o r e g i o s e l e c t i v e o l e f i n formation from ketones.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

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102

Scheme 6

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

NOZAKI

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

7.

ET

AL.

Metallic

103

Reagents

T a b l e 1. C o u p l i n g on an s p ^ C a r b o n Product Substrate

Reagent

Time ( h )

Y (%)

Me Al

2

91

Et Al

3

71

3

47

b

2

82

b

(Ej-l-heptenylAIBu ^

4

66

C

Me Al Et Al

2

94

d

2

80

3

67

5

72

6

70

Me(CH ) C(=CH )-0P0(0Ph) 2

a

9

2

2

3

3

Me(CH2)4C=CAlEt2 PhC=CAlEt 2

1

PhC(=CH )-0P0(0Ph) 2

2

3

3

PhC=CAlEt 4-t-Bu-l-cyclohexenyl< >2 0 P 0

a

Me;jAl PhC=CAlEt

0 P h

Pd(PPh ) 3

4

0.1/C1CH CH C1 a t 2 5 ° . 2

2

2

Enyne p r o d u c t e x c l u s i v e l y .

2

C

(E)-Diene G.l.p.c.

product yield.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

b

b

only.

104

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2

In c o n t r a s t t o the analogous s p carbon a l k y l a t i o n procedures (12,13), the present method does not a f f e c t c o e x i s t i n g v i n y l s u l ­ f i d e groups as shown i n Scheme 7 (14). T h i s r e a c t i o n p r o v i d e s ac­ cess t o ketones R'C^COR s t a r t i n g from R'O^COOH. Y i e l d s i n pa­ rentheses i n d i c a t e the formation o f e t h y l a t e d (R = Et) p l u s hydrogenated (R = H) products i n the r e a c t i o n o f E t 3 A l . In benzene s o l v e n t the r a t i o o f these two products i s roughly 2:1. In hexane the hydrogenated products are predominant. Scheme 8 shows the s y n t h e s i s o f 1 , 3 - d i a l k y l a t e d cyclohexenes from 2-cyclohexenones c o n s i s t i n g o f 1,4-addition o f organocuprates, enol phosphorylation, and the f i n a l a l k y l a t i o n o f the sp2 carbon. Scheme 9 provides a novel a d d i t i o n t o the technique o f 1 , 2 - t r a n s p o s i t i o n o f a carbonyl moiety accompanied by a l k y l a ­ t i o n i n tandem (15) . The d e s u l f u r i z a t i o n i s best performed by Mukaiyama's T1CI4 method (16). Treatment o f an enone, PhCOCH=CHMe, with RSLi (R = Ph, Et) and subsequent phosphorylation with ClPO(OPh) give PhC[OPO(OPh)2]=CH-CHSR-Me. The phosphate group i s s u b s t i t u t e d by methyl by means o f the present technique t o produce PhCMe=CH-CHSR-Me, the transformation o f which i n t o PhCMe=CHCOMe i s known (17). In e f f e c t the sequence f u r n i s h e s a new route o f 1.3- carbonyl t r a n s p o s i t i o n cum a l k y l a t i o n . 2

A l i p h a t i c C l a i s e n Rearrangement a t Room Temperature Sigmatropic rearrangement o f a l l y l v i n y l ether substrates u s u a l l y r e q u i r e s heating a t around 200°. A l l y l phenyl ether rearranges a t room temperature i n the presence o f Lewis a c i d r e a ­ gents, which have, however, turned out to be i n e f f e c t i v e with a l i ­ p h a t i c e t h e r s . The concept o f "combined acid-base a t t a c k " pre­ v i o u s l y mentioned (18,19) has motivated s e v e r a l s u c c e s s f u l e x p e r i ­ ments as shown i n Schemes 10 through 12 (20). A s o l u t i o n o f ΜββΑΐ i n hexane (1 M, 4.0 mmol) was added t o a s o l u t i o n o f l - b u t y l - 2 - p r o p e n y l v i n y l e t h e r (2.0 mmol, Scheme 10) i n 1,2-dichloroethane (15 ml) a t 25° under an A r atmosphere and the mixture was s t i r r e d f o r 15 min. Workup and TLC (S1O2) p u r i f i c a t i o n gave the o l e f i n i c a l c o h o l (0.28 g, 91% y i e l d ) , the E/Z r a t i o being almost 1:1. As shown i n Scheme 10 (b,c) an a l k y n y l o r a l k e n y l group i s introduced i n preference t o an a l k y l group. Examples o f r e d u c t i v e rearrangement are found i n Scheme 11. With exception o f a s i n g l e instance producing a 2-phenylethenyl system, the r e s u l t i n g o l e ­ f i n i c l i n k a g e has shown p r a c t i c a l l y no s t e r e o s e l e c t i v i t y . The r e g u l a r C l a i s e n products, o r γ,6-unsaturated aldehydes, have been produced i n the r e a c t i o n with R2AlSPh as summarized i n Scheme 12. A combination o f a c i d (Et2AlCl) and base (PPh ) has turned out t o be e f f e c t i v e . I t i s i n t r i g u i n g t o note that the rearrangement o f 3.4- dihydro-2-vinyl-2H-pyran a f f o r d i n g 3-cyclonexenecarbaldenyde (60% y i e l d ) takes p l a c e i n the presence o f t h i s couple a t room temperature w i t h i n one hour. The p y r o l y t i c procedure without 3

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

7.

Metallic Reagents

NOZAKi E T A L .

105

Scheme 7 0P0(0Ph)

R

2

R'CH=C

>R'CH=C

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

N

N

SPh

SPh

R'

R

Ph

Me

1

64

Et

2

(55)

n-Pr

Time ( h ) Y (%)

Me

1

83

Et

2

(82)

PhC=C-

2

83

a

a

A mixture o f e t h y l a t i o n and hydrogénation product ( s e e t e x t ) .

Scheme 8 0 D

1. B u C u L i , 2

2. C l P 0 ( 0 P h ) 0P0(0Ph)

.à Q

Bu

2

à

^ Pd(PPh ) °Bu 82% 3

84%

2

2 5 0 j

3

4

h

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

106

ASYMMETRIC

REACTIONS

AND

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IN

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a) 1. LDA/PhSSPh ( Y 7 8 Î Î , 2. NaH, C l P 0 ( 0 P h ) ( Y 8 2 X ) . 2

b) M e A l , P d ( P P h )

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

3

3

4

(Y80X).

c) T i C l , aq, CH C1 4

2

(Y78X).

2

Scheme 10 . 0 ^

BiA ^

ί y

^0H ^ B i r

^ \ j f

-

m

4 7 / 5 3

Ph C H 6

c k

] 3

J

_

3

b) Et AlC=CPh ( Y 8 2 * ) . c ) ^ A l C H - C H C g H j - ( E ) 2

3

Scheme 11

Scheme 12

1

O^R

H0>

R '}

R

Bu

Η

Reagent A

R

38/62

Bu

Η

Β

81

43/57

Bu

Me

A

77

52/48

Ph H

Η Ph

A

67

100/0

A

86

AD

A

78

— —

40/60

°Bu

Me

A

89

45/55

D

Ph

Η

A

93

100/0

H

Ph

A

91

—

A

90

...

Β: B u A l H ( 2 . 5 ) . 2

Υ ( ί ) E/Z 39/61

80

]

Reagent

84

Β

(2.6).

R

A

Η

Ί

R 2

Η

Bu

Α : -Βιι,Α1

1

1

-Bu a

( ° Ό

U O / R

R

Y ( % ) E/Z 82

1

/O^R

J$

R 2

^ OH

a) M e A l ( Υ 9 Ί % ) .

D

^

OH OH

^

D

b

A: E t A l S P h ( 2 . 5 ) 2

B: E t A l C l (2) + P P h 2

3

(2.2).

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

7.

NOZAKi E T A L .

Metallic

Reagents

107

such a reagent r e q u i r e s h e a t i n g a t 410°. The Et2AlCl/PPh3 system can be compared with Mukaiyama's R2BOSO2CF3/NR'3 system (21) o r with T s u j i ' s R A10R /NR 3 system (22) . The p o s s i b i l i t y o f an Et2AlP Ph3 species being the a c t i v e reagent i n our r e a c t i o n w i l l be i n v e s t i g a t e d . ,

,,

2

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

+

Acknowledgments Thanks are given f o r h e l p f u l d i s c u s ­ sions with P r o f . E . L. E l i e l on h i s occasion o f v i s i t i n g Japan i n 1978 as w e l l as f o r v a l u a b l e c o n t r i b u t i o n s by e n t h u s i a s t i c students o f t h i s research group, whose names are found i n the r e f e r e n c e s . F i n a n c i a l support by the M i n i s t r y o f Education, Sciences, and C u l t u r e , Japanese Government, through S c i e n t i f i c Research Grants (510202, 56430027 etc.) i s g r a t e f u l l y acknow­ ledged .

Literature Cited 1. Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3175. 2. Okude, Y.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1977, 3829. 3. Hiyama, T.; Kimura, K.; Nozaki, H. ibid. 1981, 22, 1037. 4. Buse, C.T.; Heathcock, C. H. ibid. 1978, 1635. 5. Takai, K.; Oshima, K.; Nozaki, H. ibid. 1980, 21, 1657. 6. Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. ibid. 1980, 21, 4843. 7. Hiyama, T.; Kimura, K.; Takai, K.; Nozaki, H. The 44th Fall Meeting of Chem. Soc. Jpn. at Okayama, 2D12, Oct. 13, 1981. 8. Yamamoto, H.; Nozaki, H. Angew. Chem. Int. Ed. Engl. 1978, 17, 169. 9. Itoh, Α.; Ozawa, S.; Oshima, K.; Sasaki, S.; Yamamoto, H.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc. Jpn. 1980, 53, 2367. 10. Hiyama, T.; Morizawa, T.; Yamamoto, H.; Nozaki, H. ibid. in press. 11. Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 2531. 12. Hayashi, T.; Katsuro, Y.; Kumada, M. ibid. 1980, 21, 3915. 13. Okamura, H.; Miura, M.; Takei, H. ibid. 1979, 43. 14. Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. ibid. 1981, 22, 1609. 15. Fristad, W. E.; Bailey, T. R.; Paquette, L. A. J . Org. Chem. 1980, 45, 3028 and ref. cited. 16. Mukaiyama, T.; Kamio, K.; Kobayashi, S.; Takei, H. Bull. Chem. Soc. Jpn. 1972, 45, 3723. 17. Trost, Β. M.; Stanton, J. L. J. Am. Chem. Soc. 1975, 97, 4018. 18. Trost, Β. M.; Hutchinson, C. R. (ed.); "Organic Synthesis Today and Tomorrow (IUPAC)"; Pergamon Press: Oxford, New York, 1981; p. 241.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

108

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

19. Oshima, K.; Nozaki, H. Yuki-Gosei-Kagaku (J. Synth. Org. Chem. Jpn.) 1980, 38, 460. 20. Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett. in press. 21. Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, 53, 174. 22. Tsuji, J . ; Yamada, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1979, 2257; Bull. Chem. Soc. Jpn. 1980, 53, 1417.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch007

RECEIVED December 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

8 Novel Approaches to the Asymmetric Synthesis of Peptides IWAO OJIMA

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

Sagami Chemical Research Center, Nishi-Ohnuma 4-4-1, Sagamihara, Kanagawa 229, Japan

A variety of dehydrodipeptides (N-protected free acids or methyl esters) have been hydrogenated with homogeneous rhodium catalysts bearing a variety of chiral diphosphine ligands. Diastereomer excess is frequently above 95%. The stereoselectivity of the reaction is, in a number of instances, quite dif­ ferent from that in hydrogenation of N-acyldehydro­ amino acids. The synthesis of acylphenylalanyl-α,β­ -d -alanine methyl ester as a nearly pure diastereomer (and enantiomer) is described. 2

Dipeptides have also been synthesized by cyclo­ -addition of azidoketene (formed in situ from azido­ acetyl chloride) to t-butyl esters of α-amino acids to give β-lactams which are then chromatographically resolved into diastereomers and cleaved by mild hy­ drogenolysis over palladium. By an extension of this method, t r i - , tetra- and higher oligopeptides can be obtained. A salient feature is the high solubility of the β-lactam intermediates in common organic solvents which facilitates chromatographic purifica­ tion. By an adaptation of this method, Leucine­ -Enkephalin (Tyr-Gly-Gly-Phe-Leu) t-butyl ester hydro­ chloride and its analog have been synthesized. Peptide linkages are g e n e r a l l y formed by the c o u p l i n g o f two o p t i c a l l y a c t i v e amino a c i d components through a c y l c h l o r i d e , a c y l a z i d e , mixed anhydride, carbodiimide, o r enzymatic methods. These methods have been developed f o r the s y n t h e s i s of n a t u r a l l y o c c u r ­ r i n g p o l y p e p t i d e s w i t h minimum racemization. Recently, i t has been shown that s i g n i f i c a n t m o d i f i c a t i o n s of b i o l o g i c a l a c t i v i t i e s can be e f f e c t e d through i n v e r s i o n o f c o n f i g u r a t i o n a t one or more c h i r a l centers, o r through replacement o f one o r more " n a t u r a l " amino a c i d residues by " u n n a t u r a l " amino a c i d components i n a b i o 0097-6156/82/0185-0109$07.50/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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l o g i c a l l y a c t i v e polypeptide such as Enkephalin, Vasopressin, A n g i o t e n s i n I I , Gonadoliberin and other hormones (1). I n order t o o b t a i n such s y n t h e t i c polypeptides by the conventional methods mentioned above, i t i s indispensable t o prepare c h i r a l amino a c i d s with "unnatural" c o n f i g u r a t i o n or "unnatural" s u b s t i t u e n t s . As an approach to the s y n t h e s i s of c h i r a l o l i g o - and polypeptides with d e s i r e d s t r u c t u r e s , we have been t r y i n g t o develop f a c i l e approaches to o b t a i n i n g c h i r a l b u i l d i n g b l o c k s . We w i l l d e s c r i b e here such approaches i n v o l v i n g i ) c a t a l y t i c asymmetric hydrogénation, and i i ) the use of β-lactams as s y n t h e t i c intermediates.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

Synthesis o f C h i r a l Dipeptides by Means of Asymmetric Hydrogénation of Dehydrodipeptides As precursors of modified peptides, n a t u r a l l y o c c u r r i n g dehydropeptides may be i n t e r e s t i n g candidates s i n c e c a t a l y t i c asymmetric hydrogénation can, i n p r i n c i p l e , convert the dehydroamino a c i d residue i n t o an amino a c i d r e s i d u e with e i t h e r R o r S c o n f i g u r a t i o n . Indeed, the homogeneous asymmetric hydrogénation of dehydro-a-amino a c i d s c a t a l y z e d by rhodium complexes with c h i r a l d i phosphine l i g a n d s has turned out t o be q u i t e e f f e c t i v e f o r the synt h e s i s of c h i r a l α-amino a c i d s (2). An i n t e r e s t i n g p o i n t i n t h i s r e a c t i o n i s whether the c h i r a l center of the dehydrodipeptide ex­ e r t s a strong i n f l u e n c e on the asymmetric i n d u c t i o n , i . e . , whether the o p t i c a l p u r i t y of the newly formed c h i r a l center i s or i s not a f f e c t e d by the already e x i s t i n g c h i r a l center, and whether, i n f a c t , we can synthesize d i p e p t i d e s having the d e s i r e d c o n f i g u r a ­ tions. N-acyldehydrodipeptides were r e a d i l y prepared e i t h e r by the condensation of N.-acyldehydro-a-amino a c i d s with α-amino a c i d e s t e r s or by the r e a c t i o n of the azlactones o f dehydro-a-amino a c i d with α-amino a c i d e s t e r s (eq. 1 ) . Asymmetric hydrogénation o f the N-acyldehydrodipeptides thus obtained (eq. 2) was c a r r i e d out by u s i n g rhodium complexes with a v a r i e t y of c h i r a l diphosphines such as £-Br-Phenyl-CAPP (3), Ph-CAPP (3), (-)BPPM (4_), (+)BPPM (4), (-)DIOP (5), (+)DI0P (5), diPAMP (6), Chiraphos (7), Prophos (8), BPPFA (9) and CBZ-Phe-PPM ( F i g . 1)(10). The c h i r a l c a t a l y s t s were prepared i n s i t u from c h i r a l diphosphine l i g a n d with [ R h ( N B D ) ] (NBD = norbornadiene). T y p i c a l r e s u l t s a r e summarized i n Tables I-V. As Table I shows, the e f f i c i e n c y of each c h i r a l diphosphine l i g a n d e x h i b i t e d i n the asymmetric hydrogénation of dehydrodipept i d e s i s c o n s i d e r a b l y d i f f e r e n t from that reported f o r the r e a c t i o n of N-acyldehydroamino a c i d s , e s p e c i a l l y i n the case o f Chiraphos and BPPFA, which a r e known to l e a d t o much b e t t e r e n a n t i o s e l e c t i v i t y than DIOP i n the dehydroamino a c i d case (2, 7_ 9 ) . When AcAPhe-(S)Phe-0H was employed as s u b s t r a t e , Chiraphos induced S^ conf i g u r a t i o n (Entry 17) and BPPFA l e d t o R c o n f i g u r a t i o n (Entry 19) with low s t e r e o s e l e c t i v i t i e s ; i n both cases, the d i r e c t i o n s o f asymmetric i n d u c t i o n are opposite t o those observed f o r a - a c e t +

CIO4"

2

9

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

8.

Asymmetric Synthesis of Peptides

OJIMA

tf NHCOR H^COOH 2

111

P MzN-CH-COOR^-! 3

w

+

R Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

2

+ H N-CH-COOR^-J 2

.1

Η

X

NHCORR3

CONH-CH-COOR* 1

Equation

R

W

N

H

C

O

R

R 3

H

1.

2

H^TONH-CH-COOR L*-Rh A

ÇH2R

1

R

3

R^ONH-CH-CONH-CH-COOR

4

Equation

2.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

112

ASYMMETRIC

REACTIONS

" V · " C=0

H

Mey04^-PPh Μ β ^ Ο φ — PPh Η

(+)DIOP

(-)BPPM H

2

2

Mey04^~PPh

Me^O^v-pPh, Η

MeyPPh,

j ^ ^ ^ P h

Me^PPh

diPAMP

Chiraphos

2

Prophos Figure 1.

2

(-)DIOP

OMe

PPh

CHEMISTRY

COO^Bu

(+)BPPM

Ι*θ(.·

IN

V " V * COO^u

Ph-CAPP Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

A N D PROCESSES

Typical

2

^>-PPh

2

^ ^ - P P h

2

BPPFA chiral diphosphine

ligands.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Bz-APhe-(S)Phe-OMe

Ac-APhe-(SI)Phe-0H

1 2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20

1 1 1 5 5 10 5 5 5 1 5 10 10 5 5 5 10 10 50 10

Ph-CAPP (-)BPPM (+)BPPM (-)DIOP (+)DI0P diPAMP Chiraphos Prophos BPPFA dppb

40°C, 40°C, 40°C, 25°C, 25°C, 50°C, 40°C, 40°C, 40°C, 40°C, 40°C, 50°C, 50°C, 40°C, 40°C, 50°C, 50°C, 50°C, 50°C, 50°C,

atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm, atm,

20h 20h 20h 20h 20h 20h 20h 20h 20h 20h

3h lh lh 18h 18h 15h lOh 10b 10b 5h 98.0/2.0 96.2/3.8 0.6/99.4 81.8/18.2 5.9/94.1 1.4/98.6 39.1/60.9 18.8/81.2 61.2/38.8 34.1/65.9 100 100 97 100 89 86 96 95 23 99 6

99.2/0.8 98.7/1.3 0.9/99.1 84.1/15.9 15.0/85.0 2.2/97.8 85.1/14.9 4.1/95.9 18.7/81.3 37.8/62.2

Dipeptide (R,S)/(S,S)*

100 100 100 100 100 100 82 99 51 85

b

Conversion Conditions (%) (H2 p r e s s . , Temp., Time)

p-Br-phenyl-CAPP (-)BPPM (+)BPPM (-)DIOP (+)DI0P diPAMP Chiraphos Prophos BPPFA dppb

Ligand

-4 of the s u b s t r a t e and 5.0 x 10" mol of the c a t a l y s t a A l l r e a c t i o n were run with 5.0 x 10 mol b Determined by HPLC.

Substrate

a

E f f i c i e n c y of C h i r a l Diphosphine Ligands i n the Asymmetric Hydrogénation o f T y p i c a l Dehydrodipeptides

Entry

Table I.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

114

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

amidocinnamic a c i d . Prophos induced high s t e r e o s e l e c t i v i t y with Bz-APhe-(S)Phe-OMe (Entry 8) whereas i t was no longer a very good c h i r a l l i g a n d f o r Ac-APhe-(S)Phe-OH (Entry 18). Pyrrolidinodiphosphines and diPAMP achieved extremely high s t e r e o s e l e c t i v i ­ ties. There seems to be a trend that the c h i r a l l i g a n d s which form seven membered r i n g c h e l a t e s w i t h rhodium give r i s e to much b e t t e r r e s u l t s than those forming r i g i d f i v e membered r i n g c h e l a t e s or q u a s i f i v e membered r i n g c h e l a t e s except diPAMP. The r e s u l t s may imply that the seven membered r i n g c h e l a t e has f l e x i b i l i t y f o r " i n d u c e d - f i t " a c t i o n l i k e an enzyme, which i s q u i t e an important f a c t o r f o r a c h i r a l complex c a t a l y s t when the s u b s t r a t e i s p o l y f u n c t i o n a l (11). As f o r the i n f l u e n c e of the c h i r a l center i n the s u b s t r a t e on asymmetric i n d u c t i o n , c o n s i d e r a b l e double asymmetric i n d u c t i o n was observed on u s i n g a dehydrodipeptide bearing a f r e e a c i d terminus such as Ac-APhe-(S)Phe-OH (see Entry 12, 13, and 14, 15). To r e ­ a l i z e the extent of double asymmetric i n d u c t i o n i n a q u a n t i t a t i v e manner, one has to look not a t the d i f f e r e n c e of the r e l a t i v e amounts of diastereomers i n percent but a t the r a t i o of two d i a s t e ­ reomers, which i s r e l a t e d to MG*: For BPPM, (R,S)/(S,S) =25.3 (Entry 12, (-)BPPM), (S,S)/(R,S) = 165.7 (Entry 13, (+)BPPM); f o r DIOP, (R,S)/(£,S) = 4.49 (Entry 14, (-)DIOP), (S^S)/(R,S.) = 15-9 (Entry 15, (+)DIOP). Thus, the extent of double asymmetric induc­ t i o n turns out to be more pronounced f o r BPPM than f o r DIOP a l ­ though the apparent d i f f e r e n c e i n o p t i c a l p u r i t y i s much s m a l l e r f o r BPPM compared with that f o r DIOP. The r e s u l t s concerning the double asymmetric i n d u c t i o n i n d i c a t e t h a t the formation of the (]L,S)-isomer i s p r e f e r r e d i n these systems. An experiment u s i n g an a c h i r a l diphosphine l i g a n d , bis(diphenylphosphino)butane (dppb), gave a c o n s i s t e n t r e s u l t (Entry 20), i . e . 31.8% asymmetric induc­ t i o n f a v o r i n g the formation of the (S,S)-isomer o f Ac-Phe-Phe-OH was observed. On the other hand, when dehydrodipeptide methyl e s t e r s were employed, o n l y a s l i g h t e f f e c t of the e x i s t i n g c h i r a l center was observed as f a r as DIOPs were concerned, e.g., Bz-PhePhe-OMe: (+)DI0P, (R,S)/(£,S) = 16.4/83.6, (-)DIOP, (R,S)/(S,,S) - 84.1/15.9; Ac-Phe-Phe-OMe: (+)DI0P, (R,S)/(£,S) = 19.4/80.6, (-)DIOP, (R,S)/(£,S) * 81.6/18.4; Bz-Phe-Val-OMe: (+)DI0P, (R,S)/ (S,S) = '20.6/79.4, (-)DIOP, (R,£)/(S_,S) = 83.0/17.0. The r e s u l t s could be i n t e r p r e t e d by assuming e x c l u s i v e coor­ d i n a t i o n of the N-acyldehydroamino a c i d moiety w i t h the rhodium com­ p l e x i n which the r e s t of the molecule, i . e . the α-amino e s t e r moie­ t y , i s l o c a t e d i n the outer sphere of the c h i r a l c o o r d i n a t i o n s i t e : t h i s may be the reason why v i r t u a l l y no double asymmetric i n d u c t i o n was observed. However, a simple asymmetric hydrogénation u s i n g dppb as a c h i r a l l i g a n d (Entry 10) d i s c l o s e d p r e f e r e n t i a l formation of Bz-(S)Phe-(S)Phe-OMe with 24.4% asymmetric i n d u c t i o n , which i s c o n s i s t e n t with the r e s u l t u s i n g Ac-APhe-(S)Phe-0H as s u b s t r a t e (Entry 20). A c c o r d i n g l y , i t seems t h a t the r e s u l t s of u s i n g DIOPs are r a t h e r e x c e p t i o n a l . In t h i s context, we f u r t h e r looked a t the e f f e c t of the c h i r a l center on the c a t a l y t i c asymmetric i n d u c t i o n

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

8.

OJIMA

Asymmetric

Synthesis

of

Peptides

115

by using Ac-APhe-(R)Phe-OMe and Ac-APhe-(S)Phe-OMe as s u b s t r a t e s , and CBZ-(S)Phe-PPM (3^), CBZ-(S)Val-PPM Q £ ) and CBZ-(S)Pro-PPM (M) as c h i r a l l i g a n d s f o r the c a t i o n i c rhodium complex. The r e s u l t s are l i s t e d i n Table I I . As Table I I shows, there i s only a s l i g h t d i f f e r e n c e between the two s u b s t r a t e s i n percent asymmetric i n d u c t i o n from a s y n t h e t i c p o i n t of view, s i n c e the r e a c t i o n s achieve q u i t e high s t e r e o s e l e c t i v i t i e s , yet there i s a s i g n i f i c a n t d i f f e r e n c e i n MG* s i n c e i t i s observed that the (R,R)/(S,R) r a t i o i s three to four times l a r g e r than the (R,S!)/ CS,S) r a t i o i n every case examined. Moreover, s i m i l a r r e s u l t s were obtained i n the asymmetric hydrogénation of Ac-APhe-(R)Phe-OMe by using (-)BPPM and (+)BPPM as shown i n Table I I I . Thus, the r e a c t i o n using (-)BPPM l e d to 99.6% production of Ac-(R)Phe-(R)Phe-OMe while that using (+)BPPM produced 98.5% of the (S,R)-isomer: (R,R)/(S,R) = 249 f o r (-)BPPM: (S^R)/(R,R) = 65.7 f o r (+)BPPM. Consequently, i t may be s a i d that there i s a s i g n i f i c a n t extent of double asymmetric i n d u c t i o n f o r the r e a c t i o n of dehydrodipeptide methyl e s t e r s , too, and the case of DIOP i s r a t h e r e x c e p t i o n a l . Table I I I summarizes t y p i c a l r e s u l t s f o r the asymmetric hydrogénation of a v a r i e t y of N-acyldehydrodipeptides with p y r r o l i d i n o diphosphines and diPAMP. As Table I I I shows, (R,S), (S,S.), (S,R) or (R,R)-dipeptides i n high o p t i c a l p u r i t i e s can be r e a d i l y synt h e s i z e d by using these c h i r a l l i g a n d s , and, i n one r e c r y s t a l l i z a tion, e a s i l y lead to o p t i c a l l y pure d i p e p t i d e s . Since c a t a l y t i c asymmetric hydrogénation can generate e i t h e r S or R c o n f i g u r a t i o n at the p o s i t i o n of the dehydroamino a c i d r e s i d u e , t h i s method could be p o t e n t i a l l y u s e f u l f o r the s p e c i f i c l a b e l i n g of c e r t a i n amino a c i d residues i n a p o l y p e p t i d e . The r e g i o s p e c i f i c and s t e r e o s e l e c t i v e l a b e l i n g of an amino a c i d r e s i due i s d i f f i c u l t to achieve with the conventional stepwise peptide s y n t h e s i s . We c a r r i e d out the d i d e u t e r a t i o n of Ac-APhe-(S)Ala-0Me with the use of the c a t i o n i c rhodium complexes w i t h (-)BPPM and (+)BPPM (Scheme 1 ) , which gave Ac-(R,R)Phe(d2)-(S)Ala-0Me [(R,R,S)/ (S,£,S) = 98.7/1.3] and Ac-(S,£)Phe(^)-(S)Ala-OMe [ (R,R,S1)/(S,S,£) «0.5/99.5], r e s p e c t i v e l y , without any scrambling of deuterium. As i t has been shown that the i n t r o d u c t i o n of deuterium a t the c h i r a l center of c e r t a i n amino a c i d s , e.g., 3 - f l u o r o - 2 - d e u t e r i o (R)-alanine, changes b i o l o g i c a l a c t i v i t y remarkably (12), t h i s s t e r e o s e l e c t i v e d i d e u t e r a t i o n may provide a convenient device f o r t h i s kind of m o d i f i c a t i o n of b i o l o g i c a l a c t i v i t y . Since p y r r o l i d i n o d i p h o s p h i n e s , e.g., Ph-CAPP, 2,-Br-Phenyl-CAPP and BPPM, gave e x c e l l e n t s t e r e o s e l e c t i v i t i e s , we prepared a s e r i e s of new c h i r a l p y r r o l i d i n o d i p h o s p h i n e s , i n which the n i t r o g e n atom of PPM (4, 11) i s l i n k e d up with a v a r i e t y of α-aminoacyl groups. The rhodium complexes with these l i g a n d s may serve as good b i o mimetic models of reductase when they are anchored on polymers e s p e c i a l l y polyamides. α-Aminoacyl-PPMs Q ) were prepared by the condensation o f PPM with an N-CBZ-α-amino a c i d or an N-CBZ-dipept i d e i n the presence of d i c y c l o h e x y l c a r b o d i i m i d e (DCC) and 1-hyd r o x y b e n z t r i a z o l e (HOBT)(eq. 3 ) .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

b

a

Ac-APhe- (S) Phe-OMe Ac-APhe- (R) Phe-OMe Ac-APhe- (S)Phe-OMe Ac-APhe- (R) Phe-OMe

CBZ- (S)Pro-PPM(^J)

CBZ- (S)Pro-PPM(^J)

CBZ- (S)Val-PPM(^)

CBZ- (S)Val-PPM(^)

3

4

5

6

98.9/1.1

98.1/1.9

98.0/2.0

96.2/3.8

99.5/0.5

99.5/0.5

Ac-Phe-Phe-OMe ( R , S ) / ( S , S ) * or ( R , R ) / ( S , R ) *

on S t e r e o s e l e c t i v i t y

A l l r e a c t i o n s were run with 5.0 * 10 mol the s u b s t r a t e and 5.0 x 10 mol Of the c a t a l y s t a t 40°C and 1 atm of hydrogen f o r 2h. Conversion was 100% f o r every case examined. Determined by HPLC.

Ac-APhe- (R) Phe-OMe

CBZ- (S)Phe-PPM(^)

2

fc

, ^ Substrate

Ac-APhe- (S) Phe-OMe

0

CBZ- (S)Phe-PPM(^.)

, Ligand

E f f e c t of C h i r a l Center i n Dehydrodipeptides

1

Entry

Table I I .

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

d

40°C, 40°C,

10 atm, 10 atm, 1 atm, 1 atm, 1 atm, 1 atm, 5 atm, 10 atm, 1 atm, 5 atm, 5 atm, 5 atm,

Ph-CAPP diPAMP (-)BPPM (+)BPPM (-)BPPM (+)BPPM (-)BPPM diPAMP CBZ-(S)Phe-PPM Ph-CAPP Ph-CAPP (+)BPPM

Ac-APhe-(£)Val-OH

Bz-ALeu- (S) Phe-OMe

Ac-APhe-(R)Phe-OMe

Ac-APhe- (R)Phy-0Me

Bz-APhe- (R) Phe-OMe

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982. r

64h

24h

24h

lh

24h 24h

2h 2h

24h 16h

20h 20h

20h 20h

46h lh

20h 24h

3h lh

100

100

100

100

100 100

100 100

100 100

100 100

100 100

100 100

100 100

100 100

fc

h

0.9/99.1

99.4/0.6

99.8/0.2^

99.5/0.5

h

h

95.7/4.3 2.6/97.4°

99.6/0.4 , 1.5/98.5°

fc

95.3/4.7 3.6/96.4

96.3/3.7 3.0/97.0

98.0/2.0 0.6/99.4

99.0/1.0 0.6/99.4

98.0/2.0 1.0/99.0

99.2/0.8 0.9/99.1

a Determined by HPLC. (R,S)/(S,S) unless otherwise noted, b (R,R)/(S,R). a (Ac)Tyr = 4-acetoxyt y r o s y l . d (AcO)(MeO)Phe = 3-methoxy-4-acetoxyphenylalanyl. e (F)Phe = 4 - f l u o r o p h e n y l a l a n y l .

Ac-A(F)Phe-(S)Leu-0Me

6

Ac-A(AcO) (MeO)Phe-(R)Ala-OMe

40 °C,

40°C,

40°C, 40°C,

40°C, 40°C,

40°C, 40°C,

50°C, 50°C,

40 °C, 40°C,

5 atm, 10 atm,

Ph-CAPP (+)BPPM

Ac-APhe-(S)Phe-OH

40°C, 40°C,

1 atm, 1 atm,

40°C, 40°C,

Ph-CAPP (+)BPPM

10 atm, 10 atm,

£-Br-phenyl-CAPP diPAMP

Bz-APhe-(S)Val-OMe

40°C, 40°C,

Ac-APhe- (S) Phe-OMe

1 atm, 1 atm,

2-Br-phenyl-CAPP (+)BPPM

Ac-A (Ac) T y r - (R) Ala-OMe^

n

Dipeptide Conditions Conversion Ph-^^NH^CO^Bul

-122.6*(MeOH)

B

7g

° *

s

rj^^Me

N 4 - f - P h H /10«/.Pd-C ^ N ^ - f o h H /10*/.Pd-C J-N υ MeOH, r.t. * J - N f _MeOH(Haaq), 50*C O' vple ry vp< C02BU CO2B1A 7b 8b

3

N -H-Ph

2

Chbci * -78-C-r.t.

3

2

* Et N

3

N CH Coa

2

(S)-PhCH°N^CQ Bui

3

H H N 4-f-Ph

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

OJIMA

8.

N

Asymmetric

3 W

A

Synthesis

Y

131

Peptides

ο

r

Jr-W C0 R Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

of

Ho

2

2

HSUc*

Dipeptide

" V > "

Tripeptide

A

r 1

R X-NH-^CONH^^Ar Υ1* ^ C 0 3

Γ

v

R

2

2

P P d

c

Β

N ^Ar 3

P^CONHy-jAr' 0

Ri

"2 > Tetrapeptide

P C0 R v

Ο ^ Υ ^ ' J-N C0 Y

K

3

P d

2

2

"

C

- ρ ϊ Τ

T r i

P*P

t i d

2

D Scheme 9.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

*

132

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ω ο ι Ο < ι

X

2 LO

I φ α. ι

CN CN

I

Χ ο Σ Ο CO

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch008

CM Q I

s

α

CSI I




I acetone

mp

121-122"

ta]J (

c

0

Λ

2

1

+ >

141.7° one)

a c e t

(S)-(+)-10

Me 11

(S)-(+)-10

MeMgl

% Yield

% e.e.

77

80 (11)

Me CuLi 2

(S)-(+)-10

Al/Hg

91

80

To preform a strong enone s u l f o x i d e - m e t a l i o n complex and thus p o s s i b l y t o i n c r e a s e the amount o f asymmetric i n d u c t i o n , s e v e r a l metal dibromides were added t o cyclopentenone s u l f o x i d e (S)-(+)-10. As shown i n eq. 12, only z i n c dibromide was h i g h l y e f f e c t i v e i n r a i s i n g the extent o f asymmetric i n d u c t i o n during methyl Grignard conjugate a d d i t i o n .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

POSNER

9.

»

M

ET

Br P

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

(s)-io

Vinylic

AL.

^

147

Sulfoxides

Me \

MeMgX^ Al-Hg

2

^ (12) % Yield 96e.e.

Ni Co Pd Mg Zn

Br Br Br I

53 73 58 81

70 70 71 73

I

99

87

The best stereochemical r e s u l t s , however, were obtained with the new and bulky m e t h y l m e t a l l i c reagent, methyl t r i i s o p r o p o x y t i t a n i u m , (12) and with methylmagnesium c h l o r i d e (eq. 13). Pre­ sumably, the more e l e c t r o p h i l i c chloromagnesium s p e c i e s formed a stronger complex with the bidendate enone s u l f o x i d e than d i d the bromo or the iodomagnesium species (13) and thus forced the β a d d i t i o n to proceed e n t i r e l y through the chelated and t h e r e f o r e locked conformation shown i n model 9.

=\

Me-M % Yield %e,e. MeTi(0Pr-i)

3

MeMgCl

90

90

91

95-100

American Chemical Society Library 1155 16th st. N. nr. In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical WttMogton, 0. C. Society: 2009·Washington, DC, 1982.

ASYMMETRIC

148

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

We have a l s o prepared (R)-(+)-3-methylcyclohexanone (13) v i a m e t h y l m e t a l l i c conjugate a d d i t i o n to e n a n t i o m e r i c a l l y pure c y c l o hexenone s u l f o x i d e (S)-(+)-12 (eq. 14). Equations 13 and 14 represent h i g h l y s u c c e s s f u l asymmetric syntheses of 3-methylcyclopentanone and 3-methylcyclohexanone and i l l u s t r a t e a general new method f o r p r e p a r a t i o n of 3 - a l k y l c a r bocycles of h i g h or v i r t u a l l y complete enantiomeric p u r i t y (14).

(CH ) CuLi Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

3

2

AL-H

>

(SM+H2

90% /ield 72% e.e. 1. ZnBr

AHHg^

2

2. CH M Br 3

g

ioo % Yield 83% e.e.

Besides conjugate a d d i t i o n of the small methyl group, c y c l o pentenone s u l f o x i d e (S)-(+)-lû a l s o underwent conjugate a d d i t i o n of a l a r g e naphthyl group. As shown i n scheme I , we have a p p l i e d t h i s r e a c t i o n which proceeds with complete asymmetric i n d u c t i o n to e f f i c i e n t c o n s t r u c t i o n of 3-naphthylcyclopentanone 1£ having the n a t u r a l absolute s t e r o i d c o n f i g u r a t i o n at carbon 14 ( s t e r o i d numbering). Reductive cleavage of the s u l f i n y l group using dimethylcopperlithium allowed r e g i o s p e c i f i c formation of enolate i o n 15 which underwent carbon a l k y l a t i o n to g i v e only 9,11-seco s t e r o i d 1É having the d e s i r e d 13S-14J5 absolute stereochemistry! Synthetic seco s t e r o i d 16 was i d e n t i c a l by HPLC, NMR, IR, mass spectrometry, m e l t i n g point (116.5-118°C), mixed m e l t i n g p o i n t and o p t i c a l r o t a t i o n [ [ a ] ^ 5 = +168° (ς 0.36, CHCl3)]to a sample of 16 prepared by degradation of n a t u r a l e s t r a d i o l (5a). Because we have p r e v i o u s l y converted racemic 16 i n t o the racemic s t e r o i d e q u i l e n i n 17, (15) p r e p a r a t i o n of e n a n t i o m e r i c a l l y pure 1$ amounts to a formal t o t a l s y n t h e s i s of e n a n t i o m e r i c a l l y pure e q u i l e n i n 12. 3-Vinylcyclopentanone lg and the corresponding enol s i l y l ether 12 have been used r e c e n t l y i n some elegant, c r e a t i v e , and e f f i c i e n t c o n s t r u c t i o n s of estrones v i a i n t r a m o l e c u l a r D i e l s A l d e r c y c l o a d d i t i o n r e a c t i o n s of intermediate O-quinodimethanes (Scheme II) (16-18). Only one r e p o r t , however, has appeared t

0

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

POSNER

ET

AL.

Vinylic

149

Sulfoxides

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

9.

16, 8 9 % >98 %

17 e.e. Scheme L

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

Scheme

IL

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

9.

POSNER

ET

AL.

Vinylic

Sulfoxides

151

i n v o l v i n g asymmetric s y n t h e s i s of o p t i c a l l y a c t i v e s t e r o i d i n t e r mediate 18 used i n p r e p a r a t i o n of o p t i c a l l y a c t i v e estrones v i a g e n e r a l i z e d scheme I I ( 1 6 i ) . We found that e n a n t i o m e r i c a l l y pure cyclopentenone s u l f o x i d e (S)-(+)~lû reacted with vinylmagnesium bromide i n the presence of a c a t a l y t i c amount of cuprous bromide and then with methyl i o d i d e to g i v e 2 , 2 , 3 - t r i s u b s t i t u t e d cyclopentanone 20 (Scheme I I I ) . T r i s u b s t i t u t e d cyclopentanone 20, however, could be formed i n b e t t e r y i e l d (^75%) v i a the corresponding sodio enolate. Aluminum amalgam r e d u c t i v e cleavage produced 3-vinylcyclopentanone (S)-l§ i n 80% enantiomeric p u r i t y . The amount of asymmetric i n d u c t i o n was improved d r a m a t i c a l l y , however, by f i r s t complexing cyclopentenone s u l f o x i d e (S)-10 with z i n c dibromide and then adding v i n y l magnesium bromide. In t h i s way, f o l l o w i n g scheme I I I , 3 - v i n y l cyclopentanone (S)-18 was formed i n >98% enantiomeric p u r i t y and i n 55-60% o v e r a l T y i e l d ! Reductive cleavage of α-sulfinylcyclopentanone 2g using dimethylcopperlithium followed by a d d i t i o n of t r i m e t h y l s i l y l c h l o r i d e gave e n a n t i o m e r i c a l l y pure enol s i l y l ether (S)-(+)-19 i n 54% o v e r a l l y i e l d (5b). T h i s complete asym­ metric i n d u c t i o n i n s y n t h e s i s of s t e r o i d intermediates (S)-18 and and (S)-19 amounts to a formal t o t a l s y n t h e s i s of e n a n t i o m e r i c a l l y pure estrone! I t i s c l e a r from the r e s u l t s summarized here that some very s u c c e s s f u l , general, and h i g h l y u s e f u l asymmetric syntheses of carbon-carbon bonds can be performed u s i n g e n a n t i o m e r i c a l l y pure 1-carbonyl 1-alkenyl s u l f o x i d e s and v a r i o u s organometallic r e ­ agents. These r e s u l t s add s i g n i f i c a n t l y to the r a p i d l y growing number of new, r a t i o n a l l y designed, and h i g h l y s t e r e o c o n t r o l l e d C-C bond-forming s y n t h e t i c methods and should be e s p e c i a l l y use­ f u l i n asymmetric s y n t h e s i s of e n a n t i o m e r i c a l l y pure 3-substituted carbocycles.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

152

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IN

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Toi

(§)-(+)-! 0 1)

ZnBr-

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

2)

1)

N^CuLi

2)

CI Si M e , Si Me

:

(SH8

(S)-(+)-l9 Scheme

III.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

9.

POSNER E TA L .

Vinylic

Sulfoxides

153

Acknowled gement We g r a t e f u l l y acknowledge f i n a n c i a l support from the N a t i o n a l Science Foundation (CHE 79-15161), from the Donors o f the P e t r o ­ leum Research Fund, administered by the American Chemical S o c i e t y , from G. D. Searle and Co., and from Merck, Sharp, and Dohme. We warmly acknowledge experimental help from P-W. Tang and A. Y. Black.

Literature Cited

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

1.

2.

3. 4.

5.

6. 7. 8. 9. 10. 11.

(a) Morrison, J.D.; Mosher, H.S. "Asymmetric Organic Reac­ tions"; Prentice-Hall; Engelwood Cliffs, N.J.; 1971. (b) Scott, J.W.; Valentine, D., Jr. Science 1974, 184, 943. (c) Valentine, D., Jr.; Scott, J.W. Synthesis 1978, 329. (d) Meyers, A.I. Accts. Chem. Res. 1978, 11, 375. (a) Knowles, W.S.; Sabacky, M.J.; Vineyard, B.D.; Weinkauf, D. J. Amer. Chem. Soc. 1975, 97, 2569. (b) Kagan, H.B; Dang, T.P. ibid., 1972, 94, 6429. (c) Gelbard, G.; Kagan, H.B.; Stern, R. Tetrahedron, 1976, 32, 233. (d) Fryzuk, M.D.; Bosnich, B. J. Amer. Chem. Soc. 1977, 99, 6262. Cohen, N. Accts. Chem. Res. 1976, 9, 412. (a) Hashimoto, S.I.; Yamada, S.I.; Koga, K. J. Amer. Chem. Soc. 1978, 98, 7450. (b) Mukaiyama, T.; Takeda, T.; Osaki, Chem. Lett. 1977, 1165. (c) Meyers, A.I.; Smith, R.K.; Whitten, C . E . J. Org. Chem. 1979, 44, 2250. (d) Hashimoto, S.; Komeshima, N.; Yamada, S.; Koga, K. Chem. Pharm. Bull. 1979, 27, 2437. (e) Isobe, M.; Kitamura, M.; Goto, T. Tetrahedron Lett. 1981, 22, 239. (a) Posner, G.H.; Mallamo, J.P.; Miura, K. J. Amer. Chem. Soc. 1981, 103, 2886. (b) Posner, G. H.; Hulce, M.; Mallamo, J. P.; Drexler, S. Α.; Clardy, J; J. Org. Chem. 1982, 47, 000. Abbott, D.J.; Colonna, S.; Stirling, C.J.M. Chem. Comm. 1971, 471. Tsuchihashi, G.; Mitamura, S.; Inoue, S.; Ogura, K. Tetra­ hedron Lett. 1973, 323. Posner, G.H.; Brunelle, D.J. J. Org. Chem. 1973, 38, 2747. Posner, G.H.; Tang, P-W.; Mallamo, J.P. Tetrahedron Lett. 1978, 3995. Langer, W.; Seebach, D. Helv. Chim. Acta 1979, 62, 1710. (a) Gustafson, B.; Hallnemo, G.; Ullenius, C. Acta Chem. Scand. 1980, B34, 433. (b) Zweig, J.S.; Luche, J.L.; Barreiro, Ε.; Crabbe, P. Tetrahedron Lett. 1975, 2355.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch009

154

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

12. (a) Weidmann, B.; Wildler, L . ; Olivero, A.G.; Maycock, C.D.; Seebach, D. Helv. Chim. Acta 1981, 64, 357. (b) Reetz, M.T.; Steinbach, R.; Westermann, J.; Peter, R. Angew. Chem. Inst. Ed. Engl. 1980, 19, 1011. 13. Ashby, E.C.; Laemmle, J.; Newmann, H.M. Accts. Chem. Res. 1974, 7, 272, and references therein. 14. For a recent synthetic approach to optically active 3-alkylated cyclopentanones and cyclohexanones, see Taber, D.F.; Saleh, S.A.; Korsmeyer, T.W. J. Org. Chem. 1980, 45, 4699. 15. Posner, G.H.; Chapdelaine, M.J.; Lentz, C.M. J. Org. Chem. 1979, 44, 3661. 16. (a) Oppolzer, W.; Petrzilka, M.; Battig, K. Helv. Chim. Acta 1977, 60, 2965. (b) Kametani, T.; Nemoto, H.; Fukumoto, K. J. Amer. Chem. Soc. 1977, 99, 3461. (c) Funk, R.L; Vollhardt, K.P.C. J. Amer. Chem. Soc. 1977, 99, 5483 and 1979, 101, 215. (d) Oppolzer, W.; Battig, K.; Petrzilka, M. Helv. Chim. Acta 1978, 61, 1945. (e) Nicolaou, K.C.; Barnette, W.E.; Ma, P. J. Org. Chem. 1980, 45, 1463. (f) Djuric, S.; Sarkan, T.; Magnus, P. J. Amer. Chem. Soc. 1980, 102, 6885. (g) Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Amer. Chem. Soc. 1981, 103, 476. (h) Quinkert, G.; Weber, W-D.; Schwartz, U.; Durner, G. Angew. Chem. Int. Ed. Engl. 1980, 19, 1027. (i) Quinkert, G.; Schwartz, U.; Stark, H.; Weber, W-D.; Baier, H.; Adam, F.; Durner, G. Angew. Chem. Int. Ed. Engl. 1980, 19, 1029. 17. For a review, see Oppolzer, W. Synthesis 1978, 793. 18. A resolved cyclopentanone acetic acid has been used in syn­ thesis of two optically pure estrone derivatives: Oppolzer, W.; Roberts, D.A. Helv. Chim. Acta 1980, 63, 1703. RECEIVED December 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

10 Asymmetric Reactions: A Challenge to the Industrial Chemist GABRIEL SAUCY and N O A L COHEN

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

Hoffmann-La Roche Incorporated, Chemical Research Department, Nutley, NJ 07110

A variety of established industrial processes for the manufacture of and new synthetic approaches to certain optically active compounds such as pharmaceuticals, vitamins, and fine chemicals are surveyed. Among the techniques for obtaining optically pure intermediates covered in this review are classical or modified optical resolutions, the utilization of starting materials from the chiral pool, as well as stoichiometric and catalytic asymmetric transformations. The development o f p r a c t i c a l and economical processes f o r l a r g e s c a l e i n d u s t r i a l p r e p a r a t i o n of c e r t a i n o p t i c a l l y a c t i v e compounds such as pharmaceuticals, f i n e chemicals, and vitamins has been and continues to be a major challenge. H i s t o r i c a l l y , a number of e f f i c i e n t i n d u s t r i a l processes have evolved which are based on c l a s s i c a l r e s o l u t i o n (e.g. D - b i o t i n (1,2) and D-pantothenic a c i d (3)) o r the use of o p t i c a l l y a c t i v e s t a r t i n g m a t e r i a l s (e.g., v i t a m i n C (4)). More r e c e n t l y , a t t r a c t i v e processes utilizing asymmetric r e a c t i o n s have been designed (5). From an i n d u s t r i a l p o i n t o f view, the use o f c h i r a l c a t a l y s t s to generate asymmetry i s p a r t i c u l a r l y advantageous. Unfortunately, our l a c k of understanding o f the q u a n t i t a t i v e aspects which govern the degree o f asymmetry created i s a s e r i o u s problem. The development of c h i r a l c a t a l y s t s u s e f u l to i n d u s t r y i s p r e s e n t l y very much dependent on the e m p i r i c a l approach. New i n s i g h t and knowledge are needed to design r a t i o n a l approaches i n asymmetric s y n t h e s i s . T h i s review i s intended to show how i n d u s t r y has solved o r , at l e a s t , confronted the problem of producing c e r t a i n o p t i c a l l y a c t i v e t a r g e t compounds i n a p r a c t i c a l and economical manner, u s i n g s e l e c t e d examples from the area of pharmaceuticals, vitamins, and f i n e chemicals.

0097-6156/82/0185-0155$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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L-Dopa

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

P r i o r to the p i o n e e r i n g development of the asymmetric hydrogénation process f o r producing L-Dopa by Knowles and coworkers at Monsanto (5), we had i n v e s t i g a t e d an a l t e r n a t i v e approach i n v o l v i n g hydrogénation of the c h i r a l s u b s t r a t e 1 using an a c h i r a l c a t a l y s t ( 6 ) . T h i s produced the mixture of epimeric amides 2 and 3 which could be converted, i n 89% o v e r a l l y i e l d , to the clesired isomer 3 v i a simultaneous base c a t a l y z e d e q u i l i b r a t i o n - c r y s t a l l i z a t i o n . Unfortunately, h y d r o l y s i s of ^ to L-Dopa gave unacceptably low y i e l d s , of the order of only 50%. 19-Norsteroids Very s u b s t a n t i a l asymmetric i n d u c t i o n at C-13 was found to take p l a c e upon condensation of the o p t i c a l l y a c t i v e hydroxy v i n y l ketone 4 (R=CsH5) with 2-methylcyclopentane-l,3-dione (5) g i v i n g predominantly the d i e n o l ether 6 (7). The e x p l o i t a t i o n of t h i s f o r t u i t o u s r e s u l t enabled us Ύο design s e v e r a l e f f i c i e n t routes to o p t i c a l l y a c t i v e 19-norsteroids and estrone (8). The key c h i r a l annulating agents 4 were secured by v a r i o u s schemes r e l y i n g on c l a s s i c a l r e s o l u t i o n s or microbio­ l o g i c a l r e d u c t i o n of δ-keto a c i d s g i v i n g o p t i c a l l y a c t i v e ό-lactones . Of p a r t i c u l a r i n t e r e s t i s the r e g i o - and e n a n t i o s p e c i f i c r e d u c t i o n of d i k e t o a c i d ^ with Margarinomyces bubaki a f f o r d i n g the keto l a c t o n e 8. The l a t t e r serves as the c h i r a l s t a r t i n g p o i n t i n an asymmetric t o t a l s y n t h e s i s (+)-estr-4-ene-3,17dione v i a key intermediate 9 (9). A most impressive example of c a t a l y t i c asymmetric s y n t h e s i s forms the b a s i s f o r s t i l l another and very e f f i c i e n t approach to 19-norsteroids (10,11). The exact mechanism r e s p o n s i b l e for the extremely high asymmetric i n d u c t i o n noted i n the c r u c i a l conversion of p r o c h i r a l to k e t o l 11 and (S)-enedione 12 s t i l l needs to be c l a r i f i e d (12,13). Nonetheless, these ôftlral a l d o l products serve very e f f e c t i v e l y as s t e r o i d CDr i n g synthons (8,14-21). Zeaxanthin Zeaxanthin, which occurs i n corn and many other p l a n t s , i s an important carotenoid. I t s s y n t h e s i s i n o p t i c a l l y a c t i v e form can be achieved on the b a s i s of the three approaches depicted. In the f i r s t case (22), o p t i c a l a c t i v i t y i s introduced by asymmetric r e d u c t i o n of the enedione ^ with yeast, g i v i n g dione Stereo- and r e g i o s e l e c t i v e r e d u c t i o n then produced the key k e t o l J ^ . In the second approach (23), the cyclohexa-

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

10.

SAUCY

Asymmetric

AND COHEN

157

Reactions

COOH NH H 2

CNHR

L-DOPA

H NHCCH, 9

II

CNHR H

CH 03

Ο 2

NoOt-Bu

NHCCH 'Pd/C

CH 03

Ο

3

II

0

0

CNHR

L 3° CH

(R*

*

H

0^ ")

CH3O

Η

NHCCH, u

3

Ο

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

0

158

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

ASYMMETRIC

^NJA.

L-Proline

u— 10

6

catalytic °"

(prochiral) \ \

I' A ' X ο/ ~ ~ 9 3%e.e. Y =100% L-Proline/HCI0

. # /

/

'2 8 7 % e.e. Y=87%

4

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

SAUCY A N D COHEN

Asymmetric

Reactions

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

10.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

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REACTIONS

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CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

diene 16, a v a i l a b l e from s a f r a n a l , i s subjected to an asymmetric hydroboration with (+)-diisopinocampheylborane g i v i n g i n t e r ­ mediate Γ7. In t h i s context, i t should be noted that asym­ metric hydroboration of dienes has a l s o been a p p l i e d at HoffmannLa Roche i n a s y n t h e s i s of p r o s t a g l a n d i n intermediates having i n d u s t r i a l p o t e n t i a l (24). The t h i r d approach to zeaxanthin (25) e x p l o i t s the s p e c i a l f e a t u r e s of keto a c e t a l which i s t h e o r e t i c a l l y a v a i l a b l e i n q u a n t i t a t i v e y i e l d s t a r t i n g from the diketone ^ and (2R,3R)2,3-butanediol. F o r t u n a t e l y , 19b i s c r y s t a l l i n e and l e s s s o l u b l e than i t s epimer 19a. E q u i l i b r a t i o n with sodium hydroxide thus favors the d e s i r e d epimer. Diastereomer )£b i s then transformed i n t o the d i o l 20 i n two s t e r e o s p e c i r i c steps. Pantothenic A c i d The present i n d u s t r i a l processes used to produce the c r u c i a l intermediate (R)-(-)-pantolactone (22) are based on r e s o l u t i o n of racemic m a t e r i a l ( 3 ) . A d i f f e r e n t and very promising approach has been reported by a Japanese group (26). Independently, Roche workers a l s o i n v e s t i g a t e d t h i s approach which i n v o l v e s asymmetric r e d u c t i o n of ketolactone %1 u s i n g rhodium c a t a l y s t s d e r i v e d from c h i r a l phosphines (27;. In t h i s manner, 22 can be obtained i n very high chemical and optical yie l d ^ D-Biotin The o r i g i n a l s y n t h e s i s of D - b i o t i n , which i n v o l v e s a c l a s s i c a l r e s o l u t i o n w i t h e f f i c i e n t r e c y c l i n g of the unwanted enantiomer (1), has r e c e n t l y been advantageously modified (28). The key. f e a t u r e of the new Sumitomo route i n v o l v e s p r e p a r a t i o n of the c h i r a l imide 24 from symmetrical d i a c i d 23. Hydride r e d u c t i o n of 24 occurs wî€h h i g h asymmetric i n d u c t i o n , generating hydroxy amîâe 25 having e x c e l l e n t o p t i c a l p u r i t y , i n 65% y i e l d . Treatment with HC1 converts ^ to the corresponding γ-lactone and u l t i m a t e l y D - b i o t i n by the e s t a b l i s h e d route. The c h i r a l aminopropanediol (R*) i s recovered and r e c y c l e d . Other novel approaches to D - b i o t i n have been s t u d i e d at Hoffmann-La Roche i n recent years (29,30). f

Vitamin Ε ((2R,4'R,8 R)-α-Tocopherol) The development of a p r a c t i c a l t o t a l s y n t h e s i s of n a t u r a l (2R,4 R,8'R)-α-tocopherol (^) i s a major c h a l l e n g e . While much progress has been made i n t h i s area, a t e c h n i c a l l y f e a s i b l e s y n t h e t i c approach to t h i s form of v i t a m i n Ε remains an e l u s i v e goal and i s o l a t i o n from soybean o i l continues to be the major source of 26 (31). f

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

10.

SAUCY A N D COHEN

Asymmetric

Reactions

161

QH H

H

υπ ft ^ v | 4 y K k ^ '0

0

C

0

0

H

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

PANTOTHENIC ACID

21

22

Ketoloctone

(R)-H-Pontoloctone

D-BIOTIN

tf^A^tf HOOC

COOH

23

tf-^T^NT^j!

NoBH

4

o^N^O 1

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

162

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

Much of our s y n t h e t i c work aimed at has been summarized i n a recent review (32) and w i l l not be covered i n d e t a i l here. The two homologous s t r a t e g i e s employed are depicted by the bond d i s s e c t i o n s "a" and "b". In the former, a C14chroman u n i t i s coupled with a C i s - s i d e chain intermediate i n the penultimate step while i n the l a t t e r , Cis-chroman and C 1 4 s i d e chain synthons are u n i t e d . Regarding the s i d e chain, recent developments i n our l a b o r a t o r i e s i n v o l v e a p p l i c a t i o n s of asymmetric hydride reductions (e.g., 27 + 29 and 31) to provide c h i r a l C l a i s e n rearrangement substrates ^ ^ , a n d ^ which, i n turn, a f f o r d o p t i c a l l y a c t i v e e s t e r ^ or i t s enantiomer ^ with e s s e n t i a l l y complete c h i r a l i t y t r a n s f e r (33). In another approach, c a t a l y t i c asymmetric hydrogénation of geranic a c i d (38) y i e l d s the C 1 0 intermediate ^ i n 70% e.e. (34). Man$%ther, o f t e n q u i t e ingenious routes to c h i r a l s i d e chain precursors have been reported r e c e n t l y by v a r i o u s groups (35-39). Progress has a l s o been made with regard to the a c c e s s i b i l i t y of key chroman intermediates. Thus methods were developed which allow u t i l i z a t i o n of the unwanted enantiomers of chroman2 - c a r b o x y l i c and chroman-2-acetic a c i d s ( 4 $ ^ 42c) obtained along with the d e s i r e d antipodes (41b, 42b) by'^cî'assical r e s o l u t i o n of the racemic forms ({flffl* (enantioconvergence 40, 41). For example, a four s t a g e l n v e r s i o n sequence provides a route f o r transforming 41c i n t o the (S)-enantiomer required for synthesis (42). S i m i l a r l y , the homologous, unwanted (R)-chroman-2-acet"îc a c i d 42c can be u t i l i z e d by means of a r a c e m i z a t i o n - r e c y c l i n g process (43). While these approaches s t i l l r e l y on c l a s s i c a l r e s o l u t i o n s , the m o d i f i c a t i o n s incorporated s u b s t a n t i a l l y improve the o v e r a l l e f f i c i e n c y i n terms of o b t a i n i n g o p t i c a l l y pure intermediates. A s i g n i f i c a n t o f f s h o o t of our s y n t h e t i c s t u d i e s aimed at 26 has been the e x p l o i t a t i o n of the r e s u l t i n g methodology f o r preparing a l l seven stereoisomers of 26 (44). Employing a v a r i a t i o n of a gas chromatographic metnod r e c e n t l y developed f o r separating the diastereomers of α-tocopherol (45), we were able to demonstrate that a l l of our s y n t h e t i c stereoisomers were of high (93-99%) diastereomeric p u r i t y (44). The a v a i l ­ a b i l i t y of these compounds i n pure form w i l l now allow a p r e c i s e determination of the r e l a t i o n s h i p between s t e r e o ­ chemistry and v i t a m i n Ε biopotency i n the α-tocopherol molecule. During the course of t h i s work, i t was e s t a b l i s h e d f o r the f i r s t time that n a t u r a l l y o c c u r r i n g d-a-tocopherol from soybean o i l i s a s i n g l e enantiomer (2R,4 R,8'R), that s y n t h e t i c d.,JL-atocopherol i s an equimolar mixture of four racemates, and that n a t u r a l ( E ) - ( 7 R , l l R ) - p h y t o l i s e n a n t i o m e r i c a l l y homogeneous (44). f

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

SAUCY A N D C O H E N

Asymmetric

Reactions

(2R,4'R,8'R) - c c - Tocopherol

X

LiAIH, "CH

1

27

3

HC

,

H

>P

H

H

3

~P h~C h v ^f * l

OH

2

N(CH ) 3

9

®

2

28

Li A I H

^

4

HO,

H

H C 3

R

Γ^Ί

HO

N(CH3)

Η

31 (S) 2

3 0 (R)

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

3

AND

PROCESSES

IN

CHEMISTRY

H \ OH

pH

H C

REACTIONS

33

(S-E)

EtO

34

HO

H

ÇH

3

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

31

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

10.

SAUCY

AND

COHEN

Asymmetric

Reactions

165

410j R ' , R » C H , C 0 H ( ± ) 2

3

4lb

2

R' » C H , R « C 0 H ( S ) 2

;

41C;

3

2

R' » C O H , R « C H ( R ) 2

2

3

42ÛÎ R',R «CH ,CH CO H(±) 2

3

2

2

42b;

R'»CH ;

42C;

R'»CH C0 H; R »CH (R)

3

R «CH C0 H(S) 2

2

2

2

2

2

3

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

166

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

Conclusions

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

For many reasons, the pharmaceutical i n d u s t r y w i l l continue to r e q u i r e f a c i l e s y n t h e t i c routes to d i a s t e r e o i s o m e r i c a l l y and e n a n t i o m e r i c a l l y pure c h i r a l molecules. In order t o achieve these goals, new asymmetric processes, e s p e c i a l l y c a t a l y t i c asymmetric r e a c t i o n s , w i l l be needed. A l t e r n a t i v e l y , there i s great p o t e n t i a l f o r the development of i n d u s t r i a l l y u s e f u l b i o t r a n s f o r m a t i o n s to produce complex o p t i c a l l y a c t i v e compounds. Genetic engineering w i l l probably p l a y an important r o l e i n such approaches. Nonetheless, the challenge to the organic chemist w i l l remain. Acknowledgment We a r e g r a t e f u l to the Research Management of Hoffmann-La Roche Inc. f o r the opportunity to prepare t h i s review which covers the m u l t i d i s c i p l i n a r y e f f o r t s of v a r i o u s research groups i n the U.S.A. (Nutley, N. J.) and Switzerland ( B a s l e ) .

Literature Cited 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14.

Sternbach, L. H. in "Comprehensive Biochemistry"; Vol. 11, Florkin, M.; Stotz, Ε. H.; Elsevier: New York, 1963; p. 66. Gerecke, M.; Zimmermann, J.-P.; Aschwanden, W. Helv. Chim. Acta 1970, 53, 991. Robinson, F. A. "The Vitamin Co-factors of Enzyme Systems", Pergamon Press: London, 1966, p. 415; Paust, J.; Pfohl, S.; Reif, W.; Schmidt, W. Ann. Chem. 1978, 1024. Reichstein T.; Grüssner, A. Helv. Chim. Acta 1934, 17, 311. Koenig, K. E.; Sabacky, M. J.; Bachman, G. L . ; Christopfel, W. C.; Barnstorff, H. D.; Friedman, R. B.; Knowles, W. S.; Stults, B. R.; Vineyard, B. D.; Weinkauff, D. J. Ann. N. Y. Acad. Sci. 1980, 333, 16 and references cited therein. Perry, C.; Saucy, G. unpublished results. Saucy, G.; Borer, R. Helv. Chim. Acta 1971, 54, 2517. Cohen, N. Acc. Chem. Res. 1976, 9, 412 and references cited therein. Rosenberger, M.; Borer, R.; Saucy, G. J. Org. Chem. 1978, 43, 1550. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496. Buchschacher, P.; Cassal, J.-M.; Fürst, Α.; Meier, W. Helv. Chim. Acta 1977, 60, 2747. Brown, K. L . ; Damm, L . ; Dunitz, J. D.; Eschenmoser, Α.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108. Eder, U. J. Steroid Biochem. 1979, 11, 55 and references cited therein.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

10.

15. 16. 17. 18. 19. 20. Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

SAUCY

AND

COHEN

Asymmetric

Reactions

167

Neef, G.; Eder, U.; Haffer, G., Sauer, G.; Wiechert, R. Chem. Ber. 1977, 110, 3377. Eder, U.; Cleve, G.; Haffer, G.; Neef, G.; Sauer, G.; Wiechert, R.; Fürst, A.; Meier, W. Chem. Ber. 1980, 113, 2249. Pandit, U. K.; Bieräugel, H. Rec. Trav. Chim. 1976, 95, 223. Kametani, T.; Matsumoto, H.; Nemoto, H.; Fukumoto, K. J. Am. Chem. Soc. 1978, 100, 6218. Crabbé, P.; Bieber, L . ; Nassim, B. J.C.S. Chem. Comm. 1980, 472. Tsuji, J.; Shimizu, I.; Suzuki, H.; Naito, Y. J. Am. Chem. Soc. 1979, 101, 5070. Shimizu, I.; Naito, Y.; Tsuji, J. Tetrahedron Lett. 1980, 21, 487. Leuenberger, H. G. W.; Boguth, W.; Widmer, E . ; Zell, R. Helv. Chim. Acta 1976, 59, 1832. Rütimann, Α.; Mayer H. Helv. Chim. Acta 1980, 63, 1456. Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. J. Am. Chem. Soc. 1973, 95, 7171. Saucy, G.; Weber G. Paper presented at the ACS/CSJ Chemical Congress, Honolulu, Hawaii, April 1-6, 1979; Abstr. ORGN 200. Ojima, I.; Kogure, T.; Terasaki, T.; Achiwa, K. J. Org. Chem. 1978, 43, 3444. Townsend,J; Valentine, D., Jr. unpublished results; Valentine, D., Jr.; Sun, R. C.; Toth, K. J. Org. Chem. 1980, 45, 3703. Aoki, Y.; Suzuki, H.; Akiyama, H.; Okano, S. Chem. Abstr. 1974, 80, 95951z (U. S. Patent no. 3,876,656 - Sumitomo). Confalone, P. N.; Pizzolato, G.; Baggiolini, E. G.; Lollar, D.; Uskokovic, M. R. J. Am. Chem. Soc. 1975, 97, 5936. Vasilevskis, J.; Gualtieri, J. S.; Hutchings, S. D.; West, R. C.; Scott, J. W.; Parrish, D. R.; Bizzarro, F. T.; Field, G. F. J. Am. Chem. Soc. 1978, 100, 7423. Rubel, T., "Vitamin Ε Manufacture", Noyes Development Corp.: Park Ridge, N. J. 1969. Saucy, G.; Cohen, N. in "New Synthetic Methodology and Biologically Active Substances"; Yoshida, Z. Ed.; Kodansha (Tokyo); Elsevier (New York), 1981; Ch. 9, p. 155. Cohen, N.; Lopresti, R. J.; Neukom, C.; Saucy, G. J. Org. Chem. 1980, 45, 582. Valentine, D. Jr.; Johnson, Κ. K.; Priester, W.; Sun, R. C.; Toth, K; Saucy, G. J. Org. Chem. 1980, 45, 3698. Takahashi, J.; Mori, K.; Matsui, M. Agric. Biol. Chem. 1979, 43, 1605. Bödeker, C.; de Waard, E. R.; Huisman, H. O. Tetrahedron 1981, 37, 1233. Sato, T.; Kawara, T.; Nishizawa, Α.; Fujisawa, T. Tetra­ hedron Lett. 1980, 3377.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

168

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch010

38. Fujisawa, T.; Sato, T.; Kawara, T.; Ohashi, K. Tetrahedron Lett. 1981, 22, 4823. 39. Trost, B. M.; Klun, T. J. Am. Chem. Soc. 1981, 103, 1864. 40. Trost, B. M.; Timko, J. M.; Stanton, J. L. J.C.S. Chem. Commun. 1978, 436. 41. Fischli, A. Chimia 1976, 30, 4. 42. Cohen, N.; Lopresti, R. J.; Neukom, C. J. Org. Chem. 1981, 46, 2445. 43. Cohen, N.; Banner, B. L . ; Neukom, C. Synthetic Commun., in press. 44. Cohen, N.; Scott, C. G.; Neukom, C.; Lopresti, R. J.; Weber, G.; Saucy, G. Helv. Chim. Acta 1981, 64, 1158. 45. Slover, H. T.; Thompson, R. Η., Jr. Lipids 1981, 16, 268. RECEIVED December 28, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

11 Stereochemistry of Heterogeneous Asymmetric Catalytic Hydrogenation KAORU HARADA

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

University of Tsukuba, Department of Chemistry, Ibaraki 305, Japan

In this paper, the stereochemistry of heterogeneous catalytic hydrogenation of C=N- and C=O double bonds of the derivatives of α-keto acids, keto alco­ hols and diketones is described. The steric course could be explained by the chelation hypothesis. In 1961, H i s k e y e t a l . ( 1 ) r e p o r t e d t h e s u c c e s s f u l asymmetric s y n t h e s e s o f α-amïho a c i d s . They demons t r a t e d t h e s y n t h e s i s o f amino a c i d s i n 45-70% e n a n t i o m e r i c p u r i t y by c a t a l y t i c hydrogénation o f t h e S c h i f f bases p r e p a r e d from α-keto a c i d s and o p t i c a l l y a c t i v e α-methylbenzylamine f o l l o w e d by h y d r o g e n o l y s i s (Scheme 1 ) . When (S)-amine was used, (S)-α-amino a c i d r e s u l t e d . This i s a highly stereoselective reaction. However, the a u t h o r s d i d n o t d i s c u s s t h e s t e r i c c o u r s e o f t h e asymmetric hydrogénation p r o c e s s . Scheme 1 R-C-COOH " Ν C H -CH-CH (S) 6

5

3

n

R-CH-COOH L NH

H 2

Pd/C ' C H - C H - C H 6

5

3

n

Pd

(S) R-CH-COOH I

H 2

(OH)'

2

L a t e r M i t s u i e t al.(2) r e p o r t e d t h e asymmetric s y n t h e s e s o f p h e n y l g l y c i n e by t h e H i s k e y t y p e r e a c t i o n and p r o p o s e d a s t e r i c c o u r s e f o r t h e asymmetric s y n ­ t h e s i s as shown i n Scheme 2. I f i t i s a p p l i c a b l e t o a l l o f t h e H i s k e y t y p e r e a c t i o n s , t h e f o l l o w i n g may be e x p e c t e d : (a) an i n c r e a s e i n o p t i c a l y i e l d upon s u b s t i ­ t u t i o n o f α-methylbenzylamine by α-ethylbenzylamine and (b) a comparable o p t i c a l y i e l d upon s u b s t i t u t i o n o f α-methylbenzylamine by a - ( 1 - n a p h t h y 1 ) e t h y l a m i n e . 0097-6156/82/0185-0169$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

170

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

Scheme 2 C,H 6 5

COOH /

C

X

CH

3

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

N

0

.

(S) C

C.H . COOH 6 5 / C H I NH ^

N

C if Ν

;C

H

C.H,. COOH 6 5 / C H II 2 Ν >^(S)

H

C

6 5

H

6 5

C H

3

9 2 r

H

C

H

6 5

C H

COOH I Η,Ν-j-H

3

In o r d e r t o examine t h e s t e r i c c o u r s e proposed by M i t s u i e t a l . , we have performed asymmetric s y n t h e s e s o f a l a n i n e , α-aminobutyric a c i d , p h e n y l g l y c i n e , p h e n y l ­ a l a n i n e and g l u t a m i c a c i d from t h e c o r r e s p o n d i n g a-keto a c i d s u s i n g (S) -α-methylbenzylamine [Me (-) ] , (S) - a ethylbenzylamine [ E t ( - ) ] and ( R ) - a - ( 1 - n a p h t h y l ) e t h y l amine [Naph(-)] as t h e c h i r a l a d j u v a n t . The r e s u l t s a r e shown i n T a b l e 1(3^,4). The r e s u l t s i n d i c a t e t h a t a) t h e o p t i c a l p u r i t y o f amino a c i d s o b t a i n e d w i t h α-methylbenzylamine i s always h i g h e r than when α-ethylbenzylamine i s used, b) t h e o p t i c a l p u r i t y o f t h e amino a c i d s d e c r e a s e s s t e a d i l y as t h e b u l k o f t h e a l k y l group o f t h e α-keto a c i d s i n ­ c r e a s e s , and c) t h e o p t i c a l p u r i t y i n c r e a s e s when ( R ) a-(1-naphthyl)ethylamine i s used(£) . These f i n d i n g s show c l e a r l y t h a t t h e s t e r i c c o u r s e proposed p r e v i o u s l y does n o t e x p l a i n any o f t h e e x p e r ­ imental r e s u l t s . Based on m o l e c u l a r models we p r o ­ posed a d i f f e r e n t s t e r i c c o u r s e c o n s i s t e n t w i t h t h e experiments. S t r u c t u r e I (Scheme 3) r e p r e s e n t s a con­ f o r m a t i o n o f t h e s u b s t r a t e which s a t i s f i e s a l l o f t h e Table I

Asymmetric S y n t h e s i s o f Amino A c i d s

α-Keto a c i d R-CO-COOH R= C H

2

C

5

H

6 5

C H

C

H

2" 6 5

(CH ) COOH 2

2

Solvent:EtOH

Amino

acid

Optical purity(%)

Alanine Alanine Alanine

67 52 83

Butyrine Butyrine

44 33

Me (-) E t (-)

(S) (S) (R) (S) (S)

Me (-) E t (-)

(S) P h e n y l g l y c i n e (S) P h e n y l g l y c i n e

30 24

Me (-) E t (-)

(S) P h e n y l a l a n i n e (S.) P h e n y l a l a n i n e

14 10

Me (-) E t (-)

(S) G l u t a m i c (S.) G l u t a m i c

12 6

Me (-) E t (-) Naph(+)

3

C H

Optically a c t i v e amine

acid acid

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

HARADA

11.

Heterogeneous

Asymmetric

Catalytic

Hydrogénation

Scheme 3 H R (S) ι \ I

C

H

R I

0

6 5

HN

( I )

C

0

0

H

2

^(S)

2

Scheme 4 H

R

C

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

C C

H

6 5

N

^

CH

0

y° (Pd)'n

H

(ID

-C

3

R

Ρ

C

C

V "(Pdfn

(III

—

c o n d i t i o n s r e q u i r e d by the e x p e r i m e n t a l f i n d i n g s (_3) · The s t r u c t u r e I might be c o n s i d e r e d t o form a sub­ s t r a t e - c a t a l y s t complex as shown i n s t r u c t u r e I I (Scheme 4 ) . A m o l e c u l a r model o f s t r u c t u r e I I f i t s v e r y w e l l on the s u r f a c e o f the p a l l a d i u m c a t a l y s t . The p l a n e c o m p r i s i n g the S c h i f f base o f the α-keto a c i d i s assumed t o be p e r p e n d i c u l a r t o the p a l l a d i u m s u r ­ f a c e , w i t h the p h e n y l group l y i n g on the p a l l a d i u m s u r ­ f a c e as shown i n s t r u c t u r e I I . I f the p h e n y l group was p l a c e d as shown i n s t r u c t u r e I I I (Scheme 4 ) , the a l k y l group o f the asymmetric m o i e t y and t h a t o f the k e t o a c i d would i n t e r f e r e w i t h each o t h e r , and the s t r u c t u r e I I I would be u n s t a b l e . Thus we assume (A) the sub­ s t r a t e i n i t i a l l y i n t e r a c t s w i t h the c a t a l y s t , t o form a s u b s t r a t e - c a t a l y s t complex as shown i n s t r u c t u r e I I b e f o r e the c a t a l y t i c hydrogénation t a k e s p l a c e , and t h e n (B) the s t r u c t u r e I I i s adsorbed on the c a t a l y s t from the l e s s b u l k y s i d e o f the m o l e c u l e , and c a t a l y t i c hydrogénation t a k e s p l a c e . We have c a l l e d t h i s hydrogénation p r o c e s s "the c h e l a t i o n h y p o t h e s i s " ( 3 ) / and f u r t h e r s t u d i e s were u n d e r t a k e n t o t e s t t h i s hypothesis. T a b l e I I shows s o l v e n t e f f e c t s i n t h e asymmetric s y n t h e s i s o f a l a n i n e from p y r u v i c a c i d and ( S ) - a methylbenzylamine(A). The o p t i c a l p u r i t y o f a l a n i n e decreases with i n c r e a s i n g p o l a r i t y of the s o l v e n t . In the c a s e o f t h e asymmetric s y n t h e s i s o f g l u t a m i c a c i d from α-keto-glutaric a c i d and (S)-α-methylbenzylamine, the c o n f i g u r a t i o n o f t h e r e s u l t i n g g l u t a m i c a c i d was a c t u a l l y i n v e r t e d by the use o f p o l a r s o l v e n t s . The s u b s t r a t e appears t o i n t e r a c t w i t h the c a t a l y s t more s t r o n g l y i n a l e s s p o l a r t h a n i n a more p o l a r s o l v e n t . Thus, the p o p u l a t i o n o f the c h e l a t e d s u b s t r a t e i s

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

172 Table

II

A N D PROCESSES

S o l v e n t E f f e c t i n t h e Asymmetric of Alanine

Solvent

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

REACTIONS

Yield(%)

CHEMISTRY

Synthesis

Optical purity(%)

Hexane

75

75

AcOEt

49

60

DMFA

47

50

i-PrOH

56

46

MeOH

61

38

MeOH:H 0(l:2) 2

75

35

MeOH:H 0(l:4)

76

29

2

IN

l a r g e r i n t h e l e s s p o l a r s o l v e n t than i n t h e more p o l a r one. The u n c h e l a t e d s p e c i e s , which has a s t a b l e conf o r m a t i o n IV (Scheme 5 ) i n s o l u t i o n , c o u l d be adsorbed on t h e l e s s b u l k y f r o n t -C=N- f a c e o f t h e m o l e c u l e (Scheme 5 ) r e s u l t i n g i n an a l a n i n e d e r i v a t i v e which has the c o n f i g u r a t i o n o p p o s i t e t o t h a t o b t a i n e d from t h e chelated species. Asymmetric c a t a l y t i c hydrogénation o f t h e S c h i f f base p r e p a r e d from e t h y l p y r u v a t e and an o p t i c a l l y a c t i v e amine i n d i f f e r e n t s o l v e n t s was c a r r i e d o u t and supports the c h e l a t i o n hypothesis. F i g u r e 1 shows s o l v e n t e f f e c t s i n t h e s y n t h e s i s o f a l a n i n e and a a m i n o b u t y r i c a c i d (5^) . When (£) - b e n z y l i c amine was used as t h e asymmetric m o i e t y , t h e o p t i c a l p u r i t y o f t h e r e s u l t i n g amino a c i d i n c r e a s e d w i t h a d e c r e a s e i n s o l vent p o l a r i t y ( £ , 7 J · temperature e f f e c t was a l s o o b s e r v e d , and t h e o p t i c a l p u r i t y o f t h e amino a c i d s i n c r e a s e d upon l o w e r i n g t h e r e a c t i o n t e m p e r a t u r e ( £ , 9 ^ A

10 ) . The c h e l a t i o n h y p o t h e s i s c o u l d a l s o be a p p l i e d t o the c a t a l y t i c hydrogénation o f α-keto a c i d amides c a r r i e d o u t i n i t i a l l y by H i s k e y e t a l . , who e x p l a i n e d the s t e r i c c o u r s e assuming i n t e r m e d i a t e s t r u c t u r e V ( 1 1 ) (Scheme 6 ) . Scheme 5 H 1

C H> 6

5

R \ N

%

Ο polar solvent

c

^0 (Pd)n—

(S) amino a c i d

less polar solvent

υ R'^ C H 6 5

R £ N

,0 0~

(IV)

(R) amino a c i d

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

HARADA

11.

Figure

Heterogeneous

Asymmetric

Catalytic

Hydrogénation

173

S o l v e n t E f f e c t i n t h e Asymmetric S y n t h e s i s o f Amino A c i d s from E t h y l P y r u v a t e ( 5 )

1

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

Amine (R)-(+) - a - M e t h y l b e n z y l (SM-) -a-Methylbenzyl (RM+) - a - E t h y l b e n z y l (R)-(+) -1- (a-Naphthyl) ethyl (S)-(-) - a - M e t h y l b e n z y l (S)-(-) - a - M e t h y l b e n z y l (a)-(e), Alanine ( f ) , a-Aminobutyric acid

Product

Catalyst:

(a)-(d) , P d ( 0 H ) / C (e) (f) , Pd/C 9

z

Dielectric of Solvent

Constant

Scheme 6 R-N CH

34Ο

Η

R-N

\

*C/

NH

„„f

NH

i C 3

0

J Η CH3

(V)

Pd/C

-o-cCH

/

CHo

N 2

/ \

•c

COOH /

c-..„ 0

CH^

3

The change i n c o n f i g u r a t i o n o f t h e r e s u l t i n g amino a c i d w i t h t h e use o f d i f f e r e n t asymmetric m o i e t i e s i s a l s o e x p l a i n e d by the c h e l a t i o n h y p o t h e s i s ( 1 2 ) (Scheme 7 ) . I n t h e s e q u e l , we w i l l d i s c u s s a g e n e r a l i z a t i o n o f the c h e l a t i o n h y p o t h e s i s as i t a p p l i e s t o r e a c t i o n s o t h e r t h a n hydrogénation o f S c h i f f bases o f α-keto a c i d s w i t h c h i r a l amines. The c a t a l y t i c hydrogénation o f p y r u v i c a c i d amide r e s u l t e d i n the f o r m a t i o n o f l a c t a m i d e i n h i g h o p t i c a l p u r i t y (75-99% d i a s t e r e o m e r i c excess)(13). T h i s might be e x p l a i n e d by the c h e l a t e c o n f o r m a t i o n o f the s u b s t r a t e - c a t a l y s t complex shown i n Scheme 8. The c a t a l y t i c hydrogénation o f o p t i c a l l y a c t i v e b e n z o i n oxime r e s u l t e d i n t h e s t e r e o s e l e c t i v e f o r m a t i o n of o p t i c a l l y a c t i v e erythro diphenylethanolamine in

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

174

REACTIONS

Scheme 7 ?3 /? .COOiBu

CH

C

,

C

/~ \/\-CH

Bzl-N^ ,NH \ * 'n~"

— H

3

A N D PROCESSES

C

N - f "

Η

N

λ

Ν

(pdi

3

2

3

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

Z

2

H

t

N

H

2

CH (R)64%ee 3

Scheme 8 CH\ _ • 0 R I (§)

2N

H

H

H

3

5

c

2

n

Ο

H

CH Ο ,C H ÇOOH 2 \ c _ ' /-icSoiBu H I — «g V \ — - 3 (S)41%ee

5

C 0 0 l B u H

C

COOH

A - C H 3 —

H

CH Ο CH >- f c^B 1-/ > \ — (Pd) —

CHEMISTRY

Ο COOiBu

3

2

IN

3

CHo

2

^Ο R, (,„ S) x

.NH \ H / (S) V \ H (Pd),η 75 - 99%(§-S) high optical and diastereomeric purity(14) (Scheme 9). Benzil monoxime was similarly hydrogenated using a palladium catalyst to form erythro diphenylethanolamine (15). If the conformation of the substrate in the reaction is planar, as expected from steric and elec­ tric considerations, the resulting hydrogénation product should be the threo isomer(16) (Scheme 10). In Scheme 9 C H^ 6

E

χ

#

6

( § )

C *5

/

\

6

2

H

/N-OH

(Pd) n

H 0

Ç H

6

""/~\ H 0

P d / C

5

Ρα/C'

6

5

5

H-C-OH (S) erythro H-C-NH (R) 85 - 90 % (S-R) I 2

65 H

Scheme 10 Ç H 6

5

HO-C-H + I H-C-NH CH racemic threo isomer 2

6

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

5

HARADA

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

11.

Heterogeneous

Asymmetric

Catalytic

Hydrogénation

175

f a c t , however, the r e s u l t i n g d i p h e n y l e t h a n o l a m i n e was found t o be p r e d o m i n a n t l y the e r y t h r o form. S i m i l a r r e s u l t s have been r e p o r t e d i n the s y n t h e s i s o f t h r e o n i n e , p h e n y l s e r i n e and ephedrine(17-21) (Scheme 11). I n 1953 Chang and Hartung p r o p o s e d a mechanism f o r the hydrogénation o f d i k e t o n e monoxime which e x p l a i n s the f o r m a t i o n o f a s i n g l e racemic m o d i f i c a t i o n ( e r y t h r o form) by the f o r m a t i o n o f a r i g i d r i n g - l i k e s t r u c t u r e w i t h the c a t a l y s t (22) . The e x p l a n a t i o n c o u l d be r e g a r d e d as a c h e l a t i o n h y p o t h e s i s p r e c e d i n g t h e present generalized c h e l a t i o n hypothesis i n c a t a l y t i c hydrogénation. R e c e n t l y , s u p p o r t f o r the c h e l a t i o n h y p o t h e s i s was o b t a i n e d by examining the i n f r a r e d d i c h r o i s m o f t h e s u b s t r a t e a d s o r b e d on a m e t a l s u r f a c e u s i n g t h e h i g h s e n s i t i v i t y r e f l e c t i o n method(23-26). I n t h e s e i n v e s t i g a t i o n s the o r i e n t a t i o n o f the s u b s t r a t e on the m e t a l s u r f a c e i s j u s t as assumed by the c h e l a t i o n h y p o t h e s i s . I t was found t h a t the OH, C=0, NH~, =NOH groups i n t e r a c t w i t h the m e t a l s u r f a c e and the s u b s t r a t e s s t a n d on the c a t a l y s t s u r f a c e v e r t i c a l l y . The o b s e r v a t i o n o f the i n f r a r e d d i c h r o i s m i s c o n s i d e r e d t o be a d i r e c t p h y s i c a l e v i d e n c e f o r the c h e l a t i o n h y p o t h e s i s (Scheme 12). Scheme 11 C*H 6 5 rt

C

CH

H

, 6 5 •C

COOEt /

3

HO-N

•c w

C//

w

6

6

N-OH

,0 M

C H

n

65

C »5

M

M

CH

5

CH-

3

F^COOEt

->c—c'

C H5

.COOEt -C \ NH-Ac

6

H

HO

/

\

0

N-CH,

NH-Ac M

M

M Scheme 12 C

H 6

5 S

CH, CH

OH

2

H-^C-C

7

,0

H.V,•C—C J +/ H N^

\ .0'

3

HO

7

\ (Ni) C Hc "COOEt fi

(Ni), CH-

C—c

C—C

// 0

OEt

% ,ΝΟΗ *(Pd)'

//

% ,0

HON^ N

(Pdf'-

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch011

176

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

Literature Cited 1. Hiskey,R.G.; Northrop,R.C. J. Am. Chem. Soc. 1961, 83, 4798. 2. Kanai,A.; Mitsui,S. J. Chem. Soc. Jpn. (Pure Chem. Sec.) 1966, 89, 183. 3. Harada,K.; Matsumoto,K. J. Org. Chem. 1967, 32, 1794. 4. Harada,K.; Matsumoto,K. J. Org. Chem. 1968, 33, 4467. 5. Harada,K.; Yoshida,T. B u l l . Chem. Soc. Jpn. 1970, 43, 921. 6. Harada,K.; Kataoka,Y. Tetrahedron Lett. 1978, 2103. 7. Harada,K.; Tamura,M. B u l l . Chem. Soc. Jpn. 1979, 52, 1227. 8. Harada,K.; Yoshida,T. J. Chem. Soc. Chem. Commun. 1970, 1071. 9. Harada,K.; Yoshida,T. J. Org. Chem. 1972, 37, 4366. 10. Harada,K.; Kataoka,Y. Chem. Lett. 1978, 791. 11. Hiskey,R.G.; Northrop,R.C. J. Am. Chem. Soc. 1965, 87, 1753. 12. Harada,K.; Matsumoto,K. B u l l . Chem. Soc. Jpn. 1971, 44, 1068. 13. Harada,Κ.; Munegumi,Τ.; Nomoto,S. Tetrahedron Lett. 1981, 22, 111. 14. Harada,Κ.; Shiono,S.; Nomoto,S. unpublished result. 15. Ishimaru,T. J. Chem. Soc. Jpn. (Pure Chem. Sec.) 1960, 81, 643. 16. Harada,K. In "The Chemistry of the Carbon-nitrogen Double Bond"; Patai,S., E d . ; Interscience Publishers: London, 1970; pp 255-298. 17. Albertson,N.F.; T u l l a r , B . F . ; King,J.A. J. Am. Chem. Soc. 1948, 70, 1150. 18. Pfister,K.; Robinson,C.A.; Schabica,A.C.; Tishler, M. J. Am. Chem. Soc. 1948, 70, 2297. 19. Pfister,K.; Robinson,C.A.; Schabica,A.C.; Tishler, M. J. Am. Chem. Soc. 1949, 71, 1101. 20. Bolhofer,W.A. J. Am. Chem. Soc. 1952, 74, 5459. 21. Freudenberg,K.; S c h ö f f e l , E . ; Braun,E. J. Am. Chem. Soc. 1932, 54, 234. 22. Chang,Y.; Hartung,W.H. J. Am. Chem. Soc. 1953, 75, 89. 23. Hatta,A.; Suëtaka,W. B u l l . Chem. Soc. Jpn. 1975, 48, 2428. 24. Hatta,A.; Moriya,Y.; Suëtaka,W. B u l l . Chem. Soc. Jpn. 1975, 48, 3441. 25. Osawa,M.; Hatta,A.; Harada,K.; Suëtaka,W. B u l l . Chem. Soc. Jpn. 1976, 49, 1512. 26. Suëtaka,W.; Harada,Κ. unpublished result. RECEIVEDJanuary 4, 1982.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

12 Asymmetric Grignard Cross-Coupling Catalyzed by Chiral Phosphine-Nickel

and

Phosphine—Palladium Complexes TAMIO HAYASHI

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch012

Kyoto University, Department of Synthetic Chemistry, Faculty of Engineering, Yoshida, Kyoto, Japan 606

A process of kinetic resolution in the coupling of Grignard reagents R*MgX (having a chiral center at the point of attachment to the metal) with various alkenyl halides under the influence of chiral phosphine-nickel or -palladium complexes is described. Enantiomeric excess of the coupling products depends strongly on the phosphine ligand and ranges up to 94% with e.e.'s in the 60-70% range common. Synthetic applications of the procedure are described. We have prepared various kinds o f o p t i c a l l y a c t i v e phos1

phines, »

2

e.g., ferrocenylphosphines and

8-aminoalkylphosphines,

u s e f u l f o r s e v e r a l c a t a l y t i c asymmetric r e a c t i o n s , v i z . , hydrogénation o f o l e f i n s ,

3

ketones,^

and i m i n e s

5

c a t a l y z e d by rhodium

complexes, h y d r o s i l y l a t i o n o f ketones by rhodium complexes and o f o l e f i n s by a palladium complex, 2

c r o s s - c o u p l i n g by n i c k e l complexes. *®

7

6

as well as Grignard Here, we d e s c r i b e the

asymmetric c r o s s - c o u p l i n g o f Grignard and organozinc

reagents

with organic h a l i d e s c a t a l y z e d by c h i r a l phosphine-nickel and -palladium complexes. Phosphine-nickel and -palladium complexes have been used as c a t a l y s t s f o r the r e a c t i o n o f Grignard reagents

(RMgX) with v i n y l

1

or a r y l h a l i d e s (R'X ) to produce, s e l e c t i v e l y , c r o s s - c o u p l i n g products

(R-R').

The c a t a l y t i c c y c l e o f the r e a c t i o n has been

proposed t o c o n s i s t o f a sequence o f steps i n v o l v i n g a diorganometal complex (L M(R)R') as a key intermediate (Scheme I ) . n

0097-6156/82/0185-0177$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

178

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

Scheme I

R'

R'-X'

R-R'

/ MgXX'

Ν R-MgX

Grignard reagents c a r r y i n g the magnesium atom attached to a

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch012

c h i r a l carbon center o r d i n a r i l y undergo racemization because of the stereochemical i n s t a b i l i t y of the magnesium-carbon bond.

Should

the i n v e r s i o n a t t h i s c h i r a l carbon be much f a s t e r than the c r o s s coupling r e a c t i o n , however, k i n e t i c r e s o l u t i o n of the racemic Grignard reagent under the i n f l u e n c e of c h i r a l

phosphine-metal

complexes might occur, l e a d i n g to a constant o p t i c a l y i e l d f o r the coupling product throughout the r e a c t i o n (Scheme I I ) .

Scheme I I

R^X' ML*

R3"

optically

active

The r e a c t i o n of 1-phenylethyl-, 2 - o c t y l - , and 2 - b u t y l magnesium c h l o r i d e ( l a , b , C ) with v i n y l bromide ( 2 a ) ,

(£)-8-bromo-

styrene ( 2 b ) , 2-bromopropene ( 2 c ) , and bromobenzene ( 2 d ) was c a r r i e d out i n the presence of 0,5 mol% of a n i c k e l c a t a l y s t prepared i n s i t u from n i c k e l c h l o r i d e and a c h i r a l l i g a n d , or a c h i r a l palladium-phosphine complex (eq. 1 ) . The c h i r a l phosphines used are shown i n F i g u r e 1 and r e p r e ­ s e n t a t i v e r e s u l t s are summarized i n Table I.

Among the f e r r o -

cenylphosphines, (5)-(/?)-PPFA was one of the most e f f e c t i v e ligands g i v i n g the c o u p l i n g product, 3-phenyl-l-butene ( 3 a ) , i n up to 68% ee i n the r e a c t i o n of l a with 2 a .

The ferrocene planar

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

HAYASHi

12.

Phosphine

Table I.

179

Asymmetric Cross-Coupling of 1 with 2 Producing 3

Entry

Chiral

No

catalyst

Product

% ee

1

-(7?)-PPFA/NiCl

2

-(/?)-PPFA/NiCl ^

2

2

3 (5)-- ( 7 ? ) - P P F A / N i C l

2

Chiral

No

catalyst

% ee

3a 63(i?)

24 (5)-(7?)-PPFA/NiCl

3a

25 P d C l

2

[(5)-(7?)-BPPFA] 3b 46(7?)

26 P d C l

2

[(5)-(7?)-BPPFA] 3C

56(R)

3a 66(7?)

c

27 (5)-(7?)-PPFA/NiCl

5 P d C l [(£)-(i?)-PPFA]^

3a 61(7?)

6 (7?) -(/?)-PPFA/NiCl

3a 54(7?)

29 (7?)-(5)-PPFA/NiCl

2

2

2

3b 52(7?)

2

28 (5)-(7?)-BPPFA/NiCl

c

a

Product

Entry

3a 68(5)

4 (/?)•- ( 5 ) - P P F A / N i C l Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch012

Complexes

5(5)

3d 37(5)

2

3d 24(5)

2

3e 30(7?)

2

7 (5)·-FcPN/NiCl

2

3a 65(5)

30 PdCl [(7?)-(5)-BPPFA]

3 f 12(7?)

8 (*) -PPEF/NiCl

2

3a

31 PdCl [(5)-(7?)-BPPFA]

3g 22(7?)

3a 38(5)

5(5)

2

2

9 (5) - ( / ? ) - 4 a / N i C l

2

3a 33(7?)

32 ( 5 ) - A l a p h o s / N i C l

10 (5) - ( i ? ) - 4 b / N i C l

2

3a 65(7?)

33 (5)-Leuphos/NiCl

11 (5) - ( / ? ) - 4 c / N i C l

2

3a 65(7?)

34 (5)-Phephos/NiCl

12 (5) - ( i ? ) - 4 d / N i C l

2

3a 57(7?)

35 (7?)-PhGlyphos/NiCl

13 (5) - ( / ? ) - 5 a / N i C l

2

3a 35(7?)

36 ( 5 ) - V a l p h o s / N i C l

2

3a 81(5)

14 (S) - ( / ? ) - 5 b / N i C l

2

3a

37 ( 5 ) - I l e p h o s / N i C l

2

3a 81(5)

7(5)

2

3a 57(5)

2

3a 71(5)

2

15 (5) - ( / ? ) - 5 c / N i C l

2

3a 15(5)

38 (7?)-ChGlyphos/NiCl

16 (5) - ( 7 ? ) - 5 d / N i C l

2

3a 62(7?)

39 (7?) -t-Leuphos/NiCl

17 (5) - ( i ? ) - 5 e / N i C l

2

3a 42(5)

18 (5) - ( / ? ) - 5 f / N i C l

2

3a 17(7?) 40 ( 5 ) - 8 / N i C l

19 (5) - ( / ? ) - 5 g / N i C l 20 (5) - ( i ? ) - 6 / N i C l

a

2

f o r 60 h.

e

(94)* 3a 25(7?)*

2

3a

3a 57(7?) 42 ( 5 ) - 9 / N i C l

2

3a 50(5)

2

3a 65(7?) 43 ( 5 ) - 9 / N i C l

2

44 ( 5 ) - 1 0 / N i C l

(reused)

ο

3a 48(5) 3a 53(5)

2

3a 17(7?)

2

The r e a c t i o n was

otherwise noted.

3 a 83(7?)

2

3a 65(7?) 41 N i C l [(5)-prophos]

22 P d C l 2 [ ( s ) - ( R ) - B P P F A ] ^ 3 a 61(7?) 23 (7?) - ( 5 ) - 7 / N i C l

3 a 77(7?)

2

2

2

21 (5) - ( f l ) - B P P F A / N i C l

3a 70(7?)

2

c a r r i e d out i n ether at 0°C f o r 24 h unless

1/2=2-4.

* 1/2 = 1.

0

At - 2 0 ° C

d

At 25°C

Corrected f o r the o p t i c a l p u r i t y of the phosphine

ligand.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

180

REACTIONS

A N D PROCESSES IN

CHEMISTRY

H jje

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch012

^^Jc—NMe ^-^C—NMe H Me (s)-(i?)-PPFA

,PPh

(Sx

2

^-^PPhz

2

2

^^N:—NMe

2

Me \\

(i?)-(S)-PPFA

(i?)-(i?)-PPFA

&

/-^/CH NMe 2

^>

f ^ l iyjL.C0 Me ^ j f 0 9

2

c

2

M e

H ^ ^ Or H

2 OH

Η

lyJL.C0.Me ^ T X 2

H

0

H

100 100 100

97.6 (i?) 96.5(5) 94.7(5)

100

52.5 (i?)

9

9

>

9

9

100 92.0(7?) 100 92.0(5) 68 71.3(7?) 66 41.4(5)

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

REACTIONS A N D PROCESSES IN

CHEMISTRY

Table 4 Continued

MeO. RR"'

CF, '^3

V

97 "

|^1 ^CF. ^ *>< 3 S

>

>

H

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

C F

3

x OT

F

S 3

9 5

S

7 5 C

)

iiff

CF

H

^

©

99

RR

C)

3

O\^

74

ffî

OH

3

RR

77

3

*K

C )

99

SS

85

3

-

Î

O.N

100

> 9 5

( 5 )

52.5 82.2(i?)

OH

C F

C F

95 (Λ)

55.3 82.5(if)

B r - ^ Î X 3

100

90

(i?)

OH

C F

% < 3

58.0 85.9(i?)

OH

J• ^ Se^ Su^ ' Η

RR

0

C F

Η

CF3

0

n

Η

C F

80.2(Λ)

4

33.6 76.4(Λ)

1

Η

C F

·

100

CF

'^'^^X 3

100

8

OH

^ " 3 -^ „ Η OH

u

7

C F

CF

3

1

0

0

> 9 9

( 5 )

OH

^ J ^ X ^ 50.1 62.8(Λ) H OH

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

16.

OHNO

Biomimetic

Asymmetric

Reductions

223

Table 4 Continued

45.2 52.1(i?)

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

78.3

-0

40.3 43.4(i?)

43.3 53.5(5)

39.4 30.3(5)

35.7 16.5(5)

See Note 5 f o r the n o t a t i o n .

Amount of substrate consumed.

Reaction without magnesium p e r c h l o r a t e .

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

A S Y M M E T R I C REACTIONS A N D PROCESSES

224

IN CHEMISTRY

The r e s u l t s show s e v e r a l i n t e r e s t i n g c h a r a c t e r i s t i c s ; 1. I n t r o d u c t i o n of two methyl groups on the d i h y d r o p y r i d i n e r i n g (Me2PNPH) enhances the r e a c t i v i t y compared to PNPH, as e x h i b i t e d by the r e d u c t i o n o f α,α,α-trifluoroacetophenone without magnesium ion. 2. The predominant enantiomer of the product i s determined by the c o n f i g u r a t i o n a t the C ^ - p o s i t i o n of Me2?NPH i n the presence of M g . However, i n the absence of magnesium i o n , the c o n f i g u r a t i o n a t the b e n z y l i c carbon exerts a secondary e f f e c t on the s t e r e o ­ chemistry. For enzymic r e a c t i o n s , i t was proposed that the carbonyl oxygen o f the substrate points toward the d i h y d r o p y r i d i n e r i n g n i t r o g e n of NAD(P)H i n the t r a n s i t i o n s t a t e ( 6 ) . Based on the same assumption the stereochemistry of the product i n the mimetic r e d u c t i o n can be p r e d i c t e d as shown i n 1_.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

2+

HC 3

.H

R : polar substituent R: n

nonpolar s u b s t i t u e n t

R CONHR

HC"

C

J

κ

R p

\S Π δ

The r e l a t i v e bulk of the s u b s t i t u e n t s i n the substrate exerts no c o n t r i b u t i o n , a t l e a s t not a primary one. In order to o b t a i n i n f o r m a t i o n on the t r a n s i t i o n - s t a t e stereochemistry, we s t u d i e d the r e d u c t i o n o f camphoroquinone (CQ) with Me PNPH. Products from the r e d u c t i o n of (-)- and (+)-CQ s are shown i n Scheme 2 and the r e s u l t s are l i s t e d i n Table 5. ,

2

Scheme 2

OH D-2a

OH Z>-3a

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

16.

OHNO

Biomimetic

Asymmetric

Reductions

225

OH X-3b

£-3b

Scheme 3

D-2

X-2


b

2

Product Yield, %>

Product Ratio

X-2a

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

c)

c

D-2a

*-3a

Z?-3a

(-)-CQ

RR

57.7

40.6

8

19

68

5

(-)-CQ

SS

36.2

67.6

20

16

6

58

X-2b

D-2b_

X-3b

Z?-3b

(+)-CQ

RR

53.1

47.3

21

14

7

58

(+)-CQ

SS

50.9

58.7

7

21

62

10

X-2 (±)-CQ

SS

d)

X-3

e)

e)

D-3

e)

43

27

16

14

54.1

46.0

Z)-2

e)

' Reaction was run f o r 52 h r w i t h each 1 mmol o f reagent. b

)

C

Isolated y i e l d s .

^

^ R e l a t i v e i n t e n s i t i e s o f ^"H-NMR s i g n a l s .

Racemic camphoroquinone.

e

^ A mixture o f a^ and b^.

Table 6.

Reduction of Camphoroquinone w i t h

Substrate

Model

ν T, h r * '

,, C

7

Product f$> Y i e

NAD(P)H-Models ν Product Ratio

X-2a

Z?-2a

X-3a

D-3a

(-)-CQ

BNAH

235

42.3

7.3

14

13

16

57

(-)-CQ

PNAH

48

65.6

4.3

13

11

24

52

9

14

62

(-)-CQ

(+)-CQ a )

i?-PNPH

91

i?-PNPH

Reaction time. of ^-H-NMR s i g n a l s .

91 b

)

50.2

61.6 Isolated y i e l d s .

15

8.6

6.8 C

)

X-2b

D-2b

X-3b

Z?-3b

8

10

20

62

Relative i n t e n s i t i e s

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

16.

OHNO

Biomimetic Asymmetric Reductions

227

Based on the above r e s u l t s , s t e r i c and e l e c t r o n i c e f f e c t s of the s u b s t i t u e n t s of a substrate have been s t u d i e d f u r t h e r . Results from the r e d u c t i o n of a s e r i e s of 2 - f l u o r o a c y l p y r i d i n e s and 2 - a c y l p y r i d i n e s i n d i c a t e that s u b s t i t u e n t e f f e c t s are such that the s t e r e o s p e c i f i c i t y of the r e d u c t i o n i s mainly governed by electronic effects. However, the s t e r i c bulk of the s u b s t i t u e n t s exerts a c e r t a i n e f f e c t on the conformation of these substrates(7

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

" U). The s t e r e o s p e c i f i c i t y remains almost constant (>90% e.e.) f o r the r e d u c t i o n of s u b s t i t u t e d and unsubstituted α,α,α-trifluoroacetophenones i n the presence of magnesium i o n . On the other hand, the s p e c i f i c i t y changes with a change i n e l e c t r o n i c e f f e c t of the s u b s t i t u e n t f o r the r e d u c t i o n without magnesium i o n . Both e l e c t r o n - r e l e a s i n g and -withdrawing s u b s t i t u e n t s increase the specificity. The r e s u l t s cannot be accounted f o r by simple s t e r i c or e l e c t r o n i c s u b s t i t u e n t e f f e c t s i n a one-step r e a c t i o n . However, a m u l t i - s t e p mechanism with an i n i t i a l e l e c t r o n - t r a n s f e r process(12, 13) e x p l a i n s the v a r i a t i o n of the s p e c i f i c i t y . An e l e c t r o n - r e l e a s i n g s u b s t i t u e n t reduces the e l e c t r o n - a f f i n i t y of a substrate and the e l e c t r o n - t r a n s f e r to a substrate of t h i s s o r t r e q u i r e s a high a c t i v a t i o n energy, as i l l u s t r a t e d i n Scheme 4a. A substrate i n t h i s category would form an e l e c t r o n - t r a n s f e r complex with Me2PNPH, which i s unstable. The subsequent protont r a n s f e r takes place almost spontaneously. The stereochemistry of the net r e d u c t i o n w i l l be d e f i n e d i n the i n i t i a l e l e c t r o n t r a n s f e r step. The s e l e c t i v i t y - r e a c t i v i t y r e l a t i o n s h i p p r e d i c t s that the l e s s the e l e c t r o n - r e l e a s i n g power o f a s u b s t i t u e n t on the subst­ r a t e , or the l e s s the a c t i v a t i o n energy f o r the e l e c t r o n - t r a n s f e r process, the l e s s the d i f f e r e n c e i n energy between p r e f e r r e d and other conformations. Consequently, the r e d u c t i o n becomes l e s s stereospecific. With a s t r o n g l y electron-withdrawing s u b s t i t u e n t on a subst­ r a t e , on the other hand, the e l e c t r o n - t r a n s f e r takes place q u i t e r a p i d l y and the intermediate e l e c t r o n - t r a n s f e r complex becomes more s t a b l e than the reactant system as shown i n Scheme 4c. The p r e f e r e n t i a l course of r e d u c t i o n i n t h i s category i s , t h e r e f o r e , c o n t r o l l e d by the thermodynamic s t a b i l i t y of the intermediate, which makes s t r o n g l y electron-demanding substrates more s t e r e o s p e c i f i c than weakly electron-demanding ones. The s t e r e o ­ chemistry of the net r e d u c t i o n i s now d e f i n e d i n the second step. Scheme 4b represents the intermediate category, i n which both the i n i t i a l and second steps a f f e c t the s t e r e o s p e c i f i c i t y of the reduction. In Scheme 4, f u l l l i n e s i n d i c a t e the r e d u c t i o n without magnesium i o n and dotted l i n e s represent the r e d u c t i o n with magnesium i o n . Since magnesium i o n c a t a l y z e s the i n i t i a l e l e c t r o n - t r a n s f e r process, the stereochemistry of the net reduc­ t i o n i n the presence of magnesium i o n i s c o n t r o l l e d by e n e r g e t i c s of-the second step.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

228

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

Scheme 4

\ I I

(a)

(b)

(c)

Literature Cited 1. Ohnishi, Y.; Kagami, M.; Ohno, A. J. Am. Chem. Soc. 1975, 97, 4766 2. Ohnishi, Y.; Numakunai, T.; Ohno, A. Tetrahedron Lett. 1975, 3813. 3. Ohnishi, Y.; Numakunai, T.; Kimura, T.; Ohno, A. Tetrahedron Lett. 1976, 2699. 4. Ohno, Α.; Yamamoto, H.; Kimura, T.; Oka, S. Tetrahedron Lett. 1977, 4585. 5. Bentley, R. "Molecular Asymmetry in Biology", Vol2, Academic Press, New York, 1970; pp 36 - 39. 6. Ohno, Α.; Yasui, S.; Oka, S. Bull. Chem. Soc. Jpn. 1980, 53, 2651. 7. Barassin, J . ; Queguiner, G.; Lumbroso, H. Bull. Soc. Chim. Fr. 1967, 4707. 8. Osborne, R. R.; McWhinnie, W. R. J. Chem. Soc., A 1967, 2075. 9. Kidani, Y.; Noji, M.; Koike, H. Bull. Chem. Soc. Jpn. 1975, 48, 239. 10. Gase, R. Α.; Pandit, U. K. J . Am. Chem. Soc. 1979, 101, 7059. 11. Ohno, Α.; Yamamoto, H.; Oka, S. J. Am. Chem. Soc. 1981, 103, 2041. 12. Ohno, Α.; Shio, T.; Yamamoto, H.; Oka, S. J. Am. Chem. Soc. 1981, 103, 2044. RECEIVED December 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

17 Stereochemistry of One-Carbon Transfer Reactions HEINZ G. FLOSS

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

Purdue University, Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, West Lafayette, IN 47907

The steric course of a number of biological one-carbon transfer reactions has been studied by means of stereo­ specifically isotope-labeled substrates. These reactions in­ clude the transfer of the methylene group of serine to tetra­ hydrofolate catalyzed by serine transhydroxymethylase, the fur­ ther utilization of the methylene group of methylene-tetrahydro­ folate for the generation of the methyl group of thymidylic acid catalyzed by thymidylate synthetase, the transfer of the S-meth­ yl group of S-adenosylmethionine to various acceptors catalyzed by a number of different methyl transferases, and the transfer of a methyl group from dimethylnitrosamine to DNA or model nucleo­ philes, a process thought to initiate carcinogenic cell trans­ formation. As part of a broader interest in stereochemical aspects of biological processes, our laboratory has recently carried out a variety of studies on the stereochemistry of biological one­ -carbon transfer reactions. Since biologically important single carbon units, like methyl groups, are not per se chiral, this work has required the use of one-carbon centers made chiral by virtue of isotopic substitution; for example, methyl groups which are chiral by virtue of the presence of normal hydrogen, deuterium and tritium. The synthesis of such species is not particularly difficult; it can be accomplished essentially by an extension of methods used widely to generate stereospecifically labeled prochiral centers. However, the configurational analy­ sis, i.e., the determination whether an unknown sample represents a methyl group of R- or S- configuration presented a conceptually new problem. This was solved by the pioneering work carried out in the laboratories of Cornforth (1) and Arigoni (2). These au­ thors developed a method which involves conversion of the methyl group in the form of acetic acid into acetyl-CoA followed by con­ densation with glyoxylate, catalyzed by malate synthase, to give malate, and equilibration with fumarase. Based on an isotope ef­ fect in the malate synthase reaction, the percentage tritium re­ tention in the fumarase reaction, called the F value, indicates 0097-6156/82/0185-0229$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

230

ASYMMETRIC

REACTIONS A N D

PROCESSES IN

CHEMISTRY

t h e c o n f i g u r a t i o n a n d d e g r e e o f p u r i t y o f t h e a c e t a t e methyl g r o u p . An F v a l u e o f 79 c o r r e s p o n d s t o an o p t i c a l l y pure R_methy l g r o u p , a n F v a l u e o f 21 i s shown b y a c h i r a l l y pure methyl g r o u p ( 3 ) . T h i s a n a l y t i c a l m e t h o d o l o g y was e m p l o y e d i n most o f the s t u d i e s t o be r e p o r t e d here. Our f i r s t s t u d y o f a n e n z y m a t i c o n e - c a r b o n t r a n s f e r r e a c t i o n a c t u a l l y i n v o l v e d n o t t h e t r a n s f e r o f a methyl g r o u p b u t r a t h e r o f a m e t h y l e n e g r o u p a n d was c a r r i e d o u t i n c o l l a b o r a t i o n w i t h t h e l a b o r a t o r y o f B e n k o v i c ( 4 ) . T h e p y r i d o x a l p h o s p h a t e enzyme serine transhydroxymethylase catalyzes the conversion o f serine and t e t r a h y d r o f o l a t e i n t o g l y c i n e and m e t h y l e n e - t e t r a h y d r o f o l a t e as shown i n Scheme I . M e c h a n i s t i c c o n s i d e r a t i o n s s u g g e s t e d t h a t f r e e o r enzyme-bound f o r m a l d e h y d e must b e a r e a c t i o n i n t e r m e d i a t e . T o p r o b e t h i s q u e s t i o n , we c a r r i e d o u t t h e r e a c t i o n w i t h s e r i n e s t e r e o s p e c i f i c a l l y t r i t i a t e d i n t h e 3 p o s i t i o n and t r a p p e d t h e m e t h y l e n e - t e t r a h y d r o f o l a t e g e n e r a t e d i m m e d i a t e l y by f u r t h e r dehydrogenation t o m e t h e n y l - t e t r a h y d r o f o l a t e c a t a l y z e d by methylene t e t r a h y d r o f o l a t e dehydrogenase. The s t e r e o s p e c i f i c removal o f one h y d r o g e n f r o m t h e m e t h y l e n e g r o u p b y t h i s enzyme simultaneously served t o determine the t r i t i u m d i s t r i b u t i o n between t h e two m e t h y l e n e h y d r o g e n s o f m e t h y l e n e - t e t r a h y d r o f o l a t e . S t a r t i n g f r o m s e r i n e c a r r y i n g 100% o f i t s t r i t i u m i n o n e d i a s t e r e o t o p i c h y d r o g e n we o b t a i n e d , u n d e r s i n g l e t u r n o v e r c o n d i t i o n s , m e t h y l e n e - t e t r a h y d r o f o l a t e c o n t a i n i n g 76% o f i t s t r i t i u m i n one m e t h y l e n e h y d r o g e n a n d 2 4 % i n t h e o t h e r . I f t h e l a b e l i n s e r i n e was i n t h e o t h e r d i a s t e r e o t o p i c h y d r o g e n , t h e m i r r o r image t r i t i u m d i s t r i b u t i o n i n m e t h y l e n e - t e t r a h y d r o f o l a t e was g e n e r a t e d . I f t h e r e a c t i o n was a l l o w e d t o go b a c k and f o r t h s e v e r a l t i m e s , t h e m e t h y l e n e g r o u p was r a n d o m l y l a b e l e d . T h i s c h a r a c t e r i s t i c r e a c t i o n - d e p e n d e n t s c r a m b l i n g c a n be e x p l a i n e d i n e i t h e r o f two ways. F o r m a l d e h y d e may be a r e a c t i o n i n t e r m e d i a t e w h i c h r e m a i n s enzyme bound d u r i n g i t s t r a n s i e n t e x i s t e n c e e x c e p t f o r a few m o l e c u l e s w h i c h d i s s o c i a t e f r o m t h e enzyme a n d r e b i n d b e f o r e r e a c t i n g w i t h t e t r a h y d r o f o l a t e . A l t e r n a t i v e l y , t h e enzyme may b i n d s e r i n e i n two c o n f o r m a t i o n s a r o u n d t h e a,3 bond w i t h each c o n f o r m a t i o n r e a c t i n g s t e r e o s p e c i f i c a l l y a s i l l u s t r a t e d i n Scheme I I . I t i s n o t p o s s i b l e a t t h e moment t o d i s t i n g u i s h between t h e s e two a l t e r n a t i v e s , a l t h o u g h c i r c u m s t a n c i a l e v i d e n c e f a v o r s the second p o s s i b i l i t y . The a b s o l u t e s t e r i c course o f the r e a c t i o n was n o t a p p a r e n t a t t h e t i m e b u t c a n now b e w r i t t e n a s shown i n Scheme I I I b a s e d on t h e r e c e n t d e t e r m i n a t i o n o f t h e a b s o l u t e c o n f i g u r a t i o n o f t e t r a h y d r o f o l a t e and a d d i t i o n a l s t u d i e s in the l a b o r a t o r y o f Benkovic. Scheme I I I shows t h e e x p e r i m e n t a l a r r a n g e m e n t t o s t u d y t h e s e c o n d o n e - c a r b o n t r a n s f e r r e a c t i o n we i n v e s t i g a t e d , t h e f o r m a t i o n o f t h y m i d y l i c a c i d from u r i d y l i c a c i d c a t a l y z e d by thymidyl a t e s y n t h e t a s e . I n t h i s r e a c t i o n , t h e methyl g r o u p o f t h y m i d y l a t e i s d e r i v e d f r o m t h e c a r b o n and t h e two h y d r o g e n s o f t h e m e t h y l e n e b r i d g e p l u s H-6 o f m e t h y l e n e - t e t r a h y d r o f o l a t e . T o s t u d y t h e s t e r e o c h e m i s t r y o f t h i s r e a c t i o n , we ( 5 ) s y n t h e s i z e d s e r i n e s t e r e o s p e c i f i c a l l y l a b e l e d w i t h t r i t i u m and d e u t e r i u m a t

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

FLOSS

One-Carbon

Transfer

231

Reactions

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

17.

Scheme I.

Serine

transhydroxymethylase mechanism stereochemical analysis.

and experimental

setup

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

for

232

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

S

\ / Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

E

=

N

\

/ -

c

(?)

\

±

L-serine

/ E = N

\

^ S

H

L-serine

F ^ J ^ F ^ Ï fllllllllllllllllllllir

ΤΤΤΤΤΤΤΤΤΤΤΠΤΤΤΤΤΤΤΤΓ

H - folate

^

4

Η S

^ C - H - folate 4

Η R

^C-H -folate 4

5,10-methylenetetra- 5,10-methylenetetrahydrofolate hydrofolate Scheme II.

Stereochemical

mechanism of serine

transhydroxymethylase.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

One-Carbon

Transfer

Reactions

233

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

FLOSS

Scheme

111. Stereochemistry

of

serine transhydroxymethylase synthetase.

and

thymidylate

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

234

ASYMMETRIC

REACTIONS

A N D PROCESSES IN

CHEMISTRY

C-3 a n d c o n v e r t e d i t i n a c o u p l e d r e a c t i o n s e q u e n c e i n t o t h y m i d y l i c a c i d w h i c h was t h e n d e g r a d e d t o r e c o v e r t h e m e t h y l g r o u p a s a c e t i c a c i d . C h i r a l i t y a n a l y s i s o f t h e a c e t i c a c i d showed t h a t i t was i n d e e d c h i r a l a n d had t h e c o n f i g u r a t i o n shown i n Scheme I I I . G e n e r a t i o n o f t h e m e t h y l g r o u p o f t h y m i d y l a t e f r o m methyl e n e - t e t r a h y d r o f o l a t e i n v o l v e s f o u r s e q u e n t i a l bond b r e a k i n g and forming steps a t the s t e r e o s p e c i f i c a l l y l a b e l e d one-carbon u n i t ; t h e r e s u l t s show t h a t e a c h o f t h e s e s t e p s o c c u r s i n a h i g h l y s t e r e o s p e c i f i c manner. However, b e c a u s e o f t h e m u l t i t u d e o f s t e p s i n v o l v e d , t h e r e s u l t does n o t y e t a l l o w us t o d e s c r i b e t h e s t e r i c course o f each i n d i v i d u a l s t e p . The mode o f f o r m a t i o n o f a m e t h y l g r o u p s e e n i n t h y m i d y l a t e i s e x c e p t i o n a l ; most m e t h y l g r o u p s i n b i o l o g i c a l m o l e c u l e s a r i s e f r o m t h e S-methyl g r o u p o f m e t h i o n i n e . O u r n e x t g o a l was t o d e termine the s t e r i c c o u r s e o f the t r a n s f e r o f a methyl group from m e t h i o n i n e o r S - a d e n o s y l m e t h i o n i n e (AdoMet) t o v a r i o u s C-, N-, o r 0-atoms i n b i o l o g i c a l m o l e c u l e s c a t a l y z e d by m e t h y l t r a n s f e r a s e enzymes. P u r s u i t o f t h i s g o a l i n v o l v e d t h e f o l l o w i n g t a s k s : 1) S y n t h e s i s o f m e t h i o n i n e and AdoMet c a r r y i n g a c h i r a l m e t h y l g r o u p o f known c o n f i g u r a t i o n . 2) E n z y m a t i c t r a n s f e r o f t h e m e t h y l g r o u p t o t h e s u b s t r a t e . 3) D e g r a d a t i o n o f t h e p r o d u c t t o c a r v e o u t t h e c h i r a l methy l g r o u p and c o n v e r t i t i n t o a compound s u i t a b l e f o r c o n f i g u r a t i o n a l a n a l y s i s , u s i n g o n l y s t e r e o s p e c i f i c r e a c t i o n s o f known steric course. 4) C o n f i g u r a t i o n a l a n a l y s i s o f the methyl group. The s y n t h e s i s o f m e t h i o n i n e and AdoMet c a r r y i n g a c h i r a l m e t h y l g r o u p s t a r t e d f r o m c h i r a l a c e t a t e , w h i c h had been p r e p a r e d as shown i n Scheme IV ( 6 ) . T h e c o n v e r s i o n i n t o m e t h i o n i n e (Scheme V) i n v o l v e d a S c h m i d t r e a c t i o n , known t o p r o c e e d w i t h r e t e n t i o n o f c o n f i g u r a t i o n , t o g i v e methylamine, which, i n the f o r m o f i t s d i t o s y l i m i d e , was t h e n u s e d t o a l k y l a t e t h e S - a n i o n o f h o m o c y s t e i n e ( 6 ) . T h e l a t t e r r e a c t i o n was e x p e c t e d t o p r o c e e d w i t h i n v e r s i o n o f c o n f i g u r a t i o n o f the methyl group; the o n l y p l a u s i b l e a l t e r n a t i v e , r a c e m i z a t i o n due t o a n S*.l mechanism, i s r u l e d o u t b y t h e s u b s e q u e n t f i n d i n g t h a t t h e m e t h y l g r o u p was i n deed s t i l l c h i r a l . E n z y m a t i c a c t i v a t i o n o f t h e two samples o f m e t h i o n i n e ( 7 ) t h e n gave AdoMet. The f i r s t t r a n s m e t h y l a t i o n s t u d i e d was t h a t c a t a l y z e d b y c a t e c h o l - 0 - m e t h y l t r a n s f e r a s e (COMT) u s i n g e i t h e r e p i n e p h r i n e ( l a ) or 3,4-dihydroxybenzoic a c i d ( l b ) as s u b s t r a t e . The products,~~ m e t a n e p h r i n e ( 2 a ) a n d 4 - h y d r o x y - 3 - m e t h o x y b e n z o i c a c i d (2fe)> were d e g r a d e d b y t h e ~ s t e r e o s p e c i f i c r e a c t i o n s e q u e n c e shown i n Scheme VI t o g i v e a c e t i c a c i d c a r r y i n g t h e c h i r a l m e t h y l g r o u p . I t w i l l be n o t e d t h a t t h e d e g r a d a t i o n s e q u e n c e i n v o l v e s o n e i n v e r s i o n o f the c o n f i g u r a t i o n o f the methyl group i n the c y a n i d e d i s p l a c e m e n t step ( 8 ) . C o n f i g u r a t i o n a l a n a l y s i s o f t h e v a r i o u s a c e t i c a c i d samples showed t h a t AdoMet s y n t h e s i z e d f r o m a c e t a t e o f F=28 gave 2a and 2b w h i c h , upon d e g r a d a t i o n , p r o d u c e d a c e t a t e o f F=68 and 5 7 , r e s p e c t i v e l y . I n t h e o t h e r e n a n t i o m e r i c s e r i e s , t h e v a l u e s were

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

•

Λ

xX

Scheme IV.

1

M

E

R

E

2

2

© h

COOH

acetate.

2

Τ

3 |

COOH H(D)

.„ (H)D3

D(H)

\ HQI γ_|ΟΗ OH

N

C*

sN

Cr0 pyruvate (H)D kinose,excess 'OH H ® dehydro- H(D) Ilactate I U \ # I U I C uciiyuiw-

Q

,

Jgenose,H 0(D20)

Γ\/Ι_Ι\ D(H,

O

U

; —• phosphofructokinase, D 0(H 0)

S

U

Synthesis of chiral

X

COOH

(OH V T O H HO\_/ (DH

2

CH 0 ®

COOH phosphogly- ® 0 aldolase, \P*^ cerate mutaseJ triose phosphate (H)D enolose isomerase, glyceraldehyde Η 3- phosphate 0® dehydrogenase, orsenate

( O H VT.OH ΗΟγ_γ OH

UA

2

CH 0H

®0

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

236

D

H,J

*"C

N0N3

R

COONo

H S0 2

Hj •

4

d)-S-CH CH CHC00H, I NH 2

\

NaOH

NH,

y \

NH-Ts

2

H

2

N

2+ ATP, Mg;

Νο,ΗΜΡΑ INVERSION

H N. 9

H Scheme

V.

COOH

Synthesis of chiral

H

(S)-adenosylmethionine

COOH from

chiral

acetate.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Ts

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

17.

FLOSS

One-Carbon

Transfer

237

Reactions

°«Js "Γ

OH

S-Ad

OH

OH

COMT

H N2

H

COOH

I ^a:X=

-C0 H 2

Ce(NH ) (N0 )

= - CH O H - C H 2 N H C H 3

NaH /

(J

4

a

3

6

S-CI > 5 . OH

KCN/HMPA

1. HoOo/OH^ CN

Scheme VI.

2

H2O

— • 2. NaN0fc/H S0 2

4

Degradation of the products from the COMT chiral methyl group as acetic acid.

D///JS /^C0 H ?

reaction

to recover the

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

238

REACTIONS

AND

PROCESSES IN

CHEMISTRY

F=68 f o r t h e s t a r t i n g a c e t a t e , a n d F=39 and 44 f o r t h e a c e t a t e s a m p l e s f r o m t h e d e g r a d a t i o n o f £ a and £ b , r e s p e c t i v e l y . T h u s , t h e r e i s a n odd number o f i n v e r s i o n s i n g o i n g f r o m t h e s t a r t i n g a c e t a t e (Scheme V , u p p e r l e f t ) t o t h e f i n a l p r o d u c t (Scheme V , l o w e r r i g h t ) . S i n c e b o t h t h e s y n t h e s i s and t h e d e g r a d a t i o n e a c h i n v o l v e one i n v e r s i o n , i t f o l l o w s t h a t the enzymatic t r a n s f e r o f t h e m e t h y l g r o u p c a t a l y z e d b y COMT must have o c c u r r e d w i t h i n v e r sion o f configuration (8). The same s t e r e o c h e m i c a l c o u r s e was a l s o o b s e r v e d f o r a n o t h e r methyl t r a n s f e r t o oxygen, the m e t h y l a t i o n o f the p o l y g a l a c t u r o n i c a c i d c a r b o x y l g r o u p s o f p e c t i n c a t a l y z e d b y a n enzyme p r e p a r a t i o n f r o m mung bean s h o o t s . The m e t h y l g r o u p i n t h i s c a s e was r e c o v e r e d by d i r e c t c y a n o l y s i s o f t h e p e c t i n t o g i v e a c e t o n i t r i l e ( w i t h i n v e r s i o n ) , w h i c h was t h e n c o n v e r t e d t o a c e t a t e f o r a n a l y s i s . A g a i n , t h e s t a r t i n g and t h e f i n a l a c e t a t e s a m p l e s had o p p o s i t e c o n f i g u r a t i o n s (F=28 + F=62; F=68 -> F=32) ( 9 ) . In a m i c r o b i a l s y s t e m , S t r e p t o m y c e s g r i s e u s , we s t u d i e d s i m u l t a n e o u s l y two m e t h y l t r a n s f e r s , o n e t o c a r b o n and one t o n i t r o g e n , which are i n v o l v e d i n the b i o s y n t h e s i s o f the a n t i b i o t i c i n d o l m y c i n ( 1 0 ) . I n t h i s c a s e , c h i r a l m e t h i o n i n e was added d i r e c t l y t o t h e c u l t u r e s and t h e r e s u l t i n g i n d o l m y c i n and i n d o l m y c e n i c a c i d were d e g r a d e d a s shown i n Scheme V I I . T h e r e s u l t s again i n d i c a t e d enzymatic t r a n s f e r o f the methyl group, both t o c a r b o n and t o n i t r o g e n , w i t h i n v e r s i o n o f c o n f i g u r a t i o n ( 6 ) . E a r l i e r work f r o m o u r l a b o r a t o r y had shown t h a t , i n t h e C-methyl a t i o n r e a c t i o n l e a d i n g t o i n d o l m y c i n , a h y d r o g e n a t C-3 o f i n d o l e - p v r u v a t e i s r e p l a c e d by the methyl group i n a r e t e n t i o n mode ( 1 1 ) . Thus t h e s t e r e o c h e m i s t r y o f i n d o l m y c i n b i o s y n t h e s i s i n S t r e p t o m y c e s g r i s e u s can be summarized a s shown i n Scheme V I I I . In c o n c l u s i o n , a l l e n z y m a t i c m e t h y l t r a n s f e r r e a c t i o n s s t u d i e d s o f a r proceed with net i n v e r s i o n o f c o n f i g u r a t i o n o f the m e t h y l g r o u p . A l l t h e s e m e t h y l t r a n s f e r a s e s t h e r e f o r e i n v o l v e an uneven number o f t r a n s f e r s o f t h e m e t h y l g r o u p , most l i k e l y a s i n g l e , d i r e c t t r a n s f e r f r o m t h e s u l f u r o f AdoMet t o t h e a c c e p t o r atom i n a n S 2 - t y p e r e a c t i o n . P i n g - p o n g mechanisms i n w h i c h a g r o u p i n t h e enzyme a c t i v e s i t e i s t r a n s i e n t l y m e t h y l a t e d can be e x c l u d e d . T h e two s u b s t r a t e s must be o r i e n t e d i n t h e enzyme a c t i v e s i t e such t h a t i n the t r a n s i t i o n s t a t e the s u l f u r , the m e t h y l c a r b o n and t h e a c c e p t o r atom f o r m a l i n e a r a r r a y . Methyl t r a n s f e r a s e s are not o n l y important i n v a r i o u s metab o l i c p r o c e s s e s , b u t a l s o i n t h e p r o c e s s i n g o f i n f o r m a t i o n a l macr o m o l e c u l e s ; f o r e x a m p l e , DNA b y r e s t r i c t i o n m e t h y l a s e s . Aberrat i o n s i n t h i s p r o c e s s i n g , a s o c c u r i n t h e m e t h y l a t i o n by c a r c i n o gens l i k e d i m e t h y l n i t r o s a m i n e , a r e p r o b a b l y i n v o l v e d i n t h e t r a n s f o r m a t i o n o f t h e c e l l i n t o a tumor c e l l . T h i s p r o c e s s i n v o l v e s m e t a b o l i c a c t i v a t i o n o f d i m e t h y l n i t r o s a m i n e , i n t h e manner shown i n Scheme IX, t o g e n e r a t e t h e u l t i m a t e c a r c i n o g e n , a methyldiazoniurn i o n which then t r a n s f e r s i t s methyl group t o v a r i o u s n u c l e o p h i l i c s i t e s on DNA. T h i s l a t t e r p r o c e s s i s p r e sumably n o t e n z y m e - c o n t r o l l e d and s h o u l d t h e r e f o r e f o l l o w t h e same r u l e s a s t h e same p r o c e s s i n a n a b i o l o g i c a l s y s t e m . K e e p i n g N

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

17.

FLOSS

One-Carbon

Transfer

D NaOH

239

Reactions

D l)NoOH/TsCl%

H

""'c

w

*

\ 1

2)NaH/TsCI V MU.

c

\

I

/

ν

d

T

s

N

Ts

KCN/HMPA

Η

"r

\OOH

D

% D Scheme

VIL

ι

C=N

>

NaN0 ,

/NaOH

2

COOH

Z

*

Degradation of indolmycin and indolmycenic chiral methyl groups as acetic acid.

D

CONH

5

acid to recover

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

the

ASYMMETRIC

REACTIONS

AND

PROCESSES IN

CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

240

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

17.

FLOSS

One-Carbon

Transfer

241

Reactions

a l l o t h e r f a c t o r s c o n s t a n t , t h e s t e r e o c h e m i s t r y o f t h i s methyl t r a n s f e r should be s e n s i t i v e t o the p o l a r i t y o f the r e a c t i o n environment. T h e r e f o r e , a c o m p a r i s o n o f t h e i n v i t r o and t h e i n v i v o process s h o u l d enable us t o probe whether the r e a c t i o n i n the i n t a c t c e l l takes p l a c e i n a hydrophobic environment, l i k e t h e n u c l e a r membrane, o r i n an aqueous s u r r o u n d i n g . T o l a y t h e groundwork f o r e x p e r i m e n t s p r o b i n g t h i s q u e s t i o n , we s y n t h e s i z e d d i m e t h y l n i t r o s a m i n e c a r r y i n g a c h i r a l methyl group by the r e a c t i o n sequence shown i n Scheme X. Methods f o r t h e a l k y l a t i o n o f DNA and f o r t h e r e c o v e r y o f t h e methyl g r o u p f r o m t h e most p r o m i n e n t m o d i f i e d b a s e , 7 - m e t h y l g u a n i n e , have been worked o u t , b u t r e s u l t s f r o m t h e s t e r e o c h e m i c a l a n a l y s i s o f t h e s e samples a r e n o t y e t a v a i l a b l e . We h a v e , however, c o m p l e t e d t h e s t e r e o c h e m i c a l a n a l y s i s o f t h e a l k y l a t i o n o f a model n u c l e o p h i l e , 3,4d i c h l o r o t h i o p h e n o l , by d i m e t h y l n i t r o s a m i n e a c t i v a t e d w i t h r a t l i v e r m i c r o s o m e s ( 1 2 ) . The r e a c t i o n sequence i s shown i n Scheme X I . Based on t h e s t r u c t u r e o f t h e a l k y l group i n t h i s r e a c t i o n and t h e n a t u r e o f t h e n u c l e o p h i l e , we e x p e c t e d t o s s e t r a n s f e r o f t h e methyl g r o u p w i t h a h i g h d e g r e e o f i n v e r s i o n o f c o n f i g u r a t i o n . However, t h e f i r s t s e t o f a n a l y s e s o f t h e a c e t a t e samples f r o m t h e d e g r a d a t i o n o f t h e a l k y l a t e d m a t e r i a l shown i n T a b l e I s u g g e s t s t r a n s f e r o f t h e methyl g r o u p w i t h c o m p l e t e r e t e n t i o n o f c o n f i g u r a t i o n . T h i s s u r p r i s i n g r e s u l t may i n d i c a t e t h a t even i n t h i s i n v i t r o s y s t e m , t h e r e a c t i o n t a k e s p l a c e e n t i r e l y /in t h e l i p o p h i l i c m i c r o s o m e s and t h e r e f o r e p r o c e e d s e x c l u s i v e l y b y an i o n p a i r mechanism w i t h i n t e r n a l r e t u r n . A l t e r n a t i v e l y , t h e mechanism o f d i m e t h y l n i t r o s a m i n e a c t i v a t i o n and a l k y l t r a n s f e r may be more complex than i s c u r r e n t l y e n v i s i o n e d and may, f o r example, i n v o l v e a double displacement p r o c e s s . F u r t h e r e x p e r i ments a r e under way t o v e r i f y t h e i n i t i a l r e s u l t and t o s t u d y t h i s problem f u r t h e r . Table I.

S t e r e o c h e m i c a l a n a l y s i s o f t h e a l k y l a t i o n o f 3,4dichlorothiophenol by m e t a b o l i c a l l y a c t i v a t e d dimethylnitrosamine. F-VALUE

STARTING ACETATE

28

CONFIGURATION S

F-VALUE 68

CONFIGURATION R

DIMETHYLNITROSAMINE

S

R

3,4-DICHLOROTHIOPHENOL METHYL ETHER

S

R

ACETATE FROM DEGRADATION

R

33

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

242

NaN /H S0 3

CHDT-COONa

2

4

• CHDT-NH

TsCI ^ CH I ^ » CHDT-NH-Ts 2.5 Ν Ν 2.5NNaOH Steam 3

2

g

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

ά

CHDT \ . N

T

s

CHDT V

3 I % H Ç ^

/

CHDT \

/

CH3

HOAc

CH3

Scheme X.

Synthesis

CN® HMPA Q Scheme XL

D

»

H

Alkylation

of dimethylnitrosamine

\

7

Ι)Η 0 /0Η 2

C

-

C

N

carrying

Θ

2

of 3 4-dichlorothiophenol f

D

2

2)HN0

CH3

»

H

a chiral

M

.

M

-

0

/

methyl

group.

\

7 /

C

"

C

by chiral

0

0

H

dimethylnitrosamine.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

17.

FLOSS

One-Carbon

Transfer

Reactions

243

Acknowledgements T h i s work was s u p p o r t e d b y t h e N a t i o n a l I n s t i t u t e s o f H e a l t h I wish t o acknowledge w i t h g r a t i t u d e the e n t h u s i a s t i c c o n t r i b u t i o n s o f numerous c o w o r k e r s and c o l l a b o r a t o r s whose names a p p e a r on t h e p u b l i c a t i o n s l i s t e d .

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch017

Literature Cited 1 Cornforth, J.W.; Redmond, J.W.; Eggerer, H.; Buckel, W.; Gutschow, C. Eur. J. Biochem., 1970, 14, 1. 2 Lüthy, J.; Rétey, J.; Arigoni, D. Nature (Lond.), 1969, 221, 1213. 3 For a review see: Floss, H.G.,; Tsai, M.D. Adv. Enzymol., 1979, 50, 243. 4 Tatum, C.M.; Benkovic, P.Α.; Benkovic, S.J.; Potts, R.; Schleicher, E.; Floss, H.G. Biochemistry, 1977, 16, 1093. 5 Tatum, C.; Vederas, J.; Schleicher, E.; Benkovic, S.J.; Floss, H.G. J. Chem. Soc. Chem. Commun., 1977, 218. 6 Woodard, R.W.; Mascaro, L . ; Hörhammer, R.; Ei,senstein, S.; Floss, H.G. J. Amer. Chem. Soc., 1980, 102, 6314. 7 Cantoni, G.L. Biochem. Prep., 1957, 5, 58. 8 Woodard, R.W.; Tsai, M.D.; Floss, H.G.; Crooks, P.Α.; Coward, J.K. J. Biol. Chem., 1980, 255, 9124. 9 Woodard, R.W.; Weaver, J.; Floss, H.G. Arch. Biochem. Biophys., 1981, 207, 51. 10 Hornemann, U.; Hurley, L.H.; Speedie, M.K.; Floss, H.G. J. Amer. Chem. Soc., 1971, 93, 3029. 11 Zee, L . ; Hornemann, U.; Floss, H.G. Biochem. Physiol. Pflanzen (Jena), 1975, 168, 19. 12 Shen, S.J.; Tsai, M.D.; Floss, H.G., unpublished results. RECEIVEDDecember 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

18 A Useful and Conveniently Accessible Chiral Stationary Phase for the Liquid Chromatographic Separation of Enantiomers WILLIAM H. PIRKLE, JOHN M. FINN, BRUCE C. HAMPER, JAMES SCHREINER, and JAMES R. PRIBISH

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

University of Illinois, School of Chemical Sciences, Urbana, IL 61801

The use of a simply prepared high efficiency chiral HPLC column capable of separating the enantiomers of thousands of compounds is described, documentation being provided by more than 120 specific examples covering 19 classes of compounds. Chiral recognition models are presented to account for elution orders of the enantiomers. Practical applications of the chiral column, including preparative separations, are described. I t has long been perceived that chromatography of enantiomers upon a c h i r a l s t a t i o n a r y phase (CSP) might, i n p r i n c i p l e , r e s u l t i n s e p a r a t i o n of the enantiomers. Owing to the p o t e n t i a l u t i l i t y o f such a r e s o l u t i o n procedure, a great many workers have attempted to so e f f e c t r e s o l u t i o n s . Most e a r l y attempts i n v o l v e e m p i r i c a l l y chosen, r e a d i l y a c c e s s i b l e CSP s (e.&., starches, modified c e l l u l o s e s , wool) with v a r y i n g degrees o f success. More r e c e n t l y , s y n t h e t i c CSP s (coupled with modern HPLC technology) have begun to a f f o r d impressive examples of chromâtographically e f f e c t e d r e s o l u t i o n s . Several recent reviews of t h i s work are a v a i l a b l e (1-4)· The development o f CSP s f o r the d i r e c t chromatographic s e p a r a t i o n o f enantiomers i s r e v o l u t i o n i z i n g stereochemical a n a l y s i s and w i l l c o n s i d e r a b l y a l t e r f u t u r e s y n t h e t i c approaches to c h i r a l compounds. From the a n a l y t i c a l standpoint, an e f f e c t i v e c h i r a l HPLC column makes p o s s i b l e the accurate determination o f enantiomeric p u r i t y upon as l i t t l e as nanogram q u a n t i t i e s o f sample, absolute c o n f i g u r a t i o n s being obtained simultaneously. From the p r e p a r a t i v e standpoint, multigram q u a n t i t i e s of racemate can be r e s o l v e d per pass through l a r g e c h i r a l columns. Automation of t h i s process w i l l enable hundreds of grams of racemate t o be r e s o l v e d d a i l y . Hence, a wide v a r i e t y of c h i r a l precursors w i l l be a v a i l a b l e f o r the s y n t h e s i s 1

1

1

0097-6156/82/0185-0245$05.O0/O © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

246

ASYMMETRIC

REACTIONS

AND

PROCESSES IN

CHEMISTRY

of more complex c h i r a l m a t e r i a l s . In many cases, the f i n a l products w i l l themselves be chromatographically r e s o l v a b l e . F i n a l l y , chromatographic r e s o l u t i o n conveniently provides both enantiomers f o r b i o l o g i c a l e v a l u a t i o n . The c r i t i c a l p o i n t i n the preceding Utopian p r e d i c t i o n i s whether or not c h i r a l columns can be devised which w i l l indeed e f f i c i e n t l y and p r e d i c t a b l y separate the enantiomers of a wide array of s o l u t e s . Work conducted i n our l a b o r a t o r y i n Urbana leads us to b e l i e v e that such "Broad Spectrum" CSP's are c l e a r l y p o s s i b l e , that t h e i r c h i r a l r e c o g n i t i o n mechanisms can be discerned, and that an understanding of these mechanisms can be used f o r the r a t i o n a l design of s t i l l more e f f e c t i v e CSP's (5-10). To support t h i s b e l i e f , l e t us d e s c r i b e a simply prepared c h i r a l chromatography column capable of s e p a r a t i n g the enantiomers of thousands of compounds of d i v e r s e f u n c t i o n a l types. Results and D i s c u s s i o n Treatment of γ-aminopropylsilanized s i l i c a with a THF s o l u t i o n of R-N-3,5-dinitrobenzoylphenylglycine a f f o r d s CSP 1, a CSP i n which the c h i r a l moiety i s i o n i c a l l y bonded to the a c h i r a l support. T h i s treatment may be performed e i t h e r upon a prepacked HPLC column or upon bulk m a t e r i a l (8, 9).

CSP

1

For a n a l y t i c a l (and small s c a l e p r e p a r a t i v e ) a p p l i c a t i o n s , we modified a Regis 4.6 mm χ 250 mm 5 μ Spherisorb NH2 column. Using hexane-isopropyl a l c o h o l as a mobile phase, we have been able to r e s o l v e the enantiomers of the types of compounds i n d i c a t e d i n Tables I-IV. I t can be seen from F i g u r e 1 that t h i s column i s of high e f f i c i e n c y , enabling one to a c c u r a t e l y determine enantiomeric p u r i t y (by peak area comparison) f o r compounds having an enantiomeric s e p a r a b i l i t y f a c t o r of 1.05 or greater (the enantiomeric s e p a r a b i l i t y f a c t o r , a, i s simply the r a t i o of r e t e n t i o n times of the enantiomers measured, not from i n j e c t i o n , but from the e l u t i o n point of a non-retained compound.) For compounds having an α value between u n i t y and 1.05, m u l t i p l e column or r e c y c l e techniques may have to be

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

18.

PiRKLE E T A L .

Liquid

Chromatographic

Separation

247

Table I . R e s o l u t i o n o f Some A l c o h o l s Upon CSP 1 Using 1-10% 2-Propanol i n Hexane. PROPANOLOL ANALOGS

BENZYL ALCOHOLS

(AS N-LAUROYL DERIVATIVE) CH

/ 3

Ar—CMIIR OH

I

CH /

\ CH

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

ArO-CH — C — C H — Ν H

Ar

R

α

Ph

Me

1.05*

Ph

t-Butyl

1.08*

a-Naph

Me

1.14*

a-Naph

CF

H

Ar

ni

1.08

1.08*

3

/v. o-

9-Anth

1.08

1.33*

9-Anth

n-Butyl

9-Anth

CH COOC H 2

1.48 2

5

a-Naph

1.07

1.27

CYCLIC ALCOHOLS R 1.04* H

1.17

Me

1.37

n-Butyl

1.73

H

1.17

Me

1.39

n-Butyl

1.50

1.11

American Chemical Society Library 1155 t e a st. N. w. In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; 0. C. Society: 20036Washington, DC, 1982. ACS Symposium Series; American Chemical

ASYMMETRIC

248

REACTIONS

A N D PROCESSES I N

CHEMISTRY

Table I . (continued)

HYDROXY SULFIDES R

ARYL-SUBSTITUTED HYDROXY PHOSPHONATES

OH

1

1 1 II

OH 0

Ph-S-CH-CM'R,

h

I II

2

H

R

R

i

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

H

Ar—C—P(0R)

2

Me

H

C

H

^- 12 25

Me

Me C

n-C H 1 2

1 0

2 5

H

α

Ar

1.03

Ph

Ph

1.07

1.04

a-Naph

Et

1.19

p-Anisyl

Et

1.12

1.03

n-C H

H

*- 6 13

2 1

1.07/1.10

H

1.06

Ph

1.06 (first?)

Table I I

o

0

R e s o l u t i o n of Some Bi-g-naphthols Upon CSP 1 Using 10-20% 2-Propanol i n Hexane. ΒI-β-NAPHTHOLS

R

α

Η

1.45*

Η

CH

6,7-(Me),

2.40*

Η

C H

6- Br

1.41*

6,7-(Me),

CH

7- 0CH„

1.51

1.75*

3

2

3

5

1.23* 3.67*

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

18.

PIRKLE E T A L .

Table I I I

249

Liquid Chromatographic Separation

R e s o l u t i o n o f Some S u l f o x i d e s Upon CSP 1 Using 5-20% 2-Propanol i n Hexane.

0

ARYL ALKYL SULFOXIDES

DIARYL SULFOXIDES 0

0 II

II » Ar—S'"'iAr

II

II

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

Ar—SMMR

Ar

R

α

Ar

Ar'

α

Ph

Me

1.05*

£-Tolyl

Ph

1.09

Ph

t-Butyl

1.09*

£-Tolyl

o-Tolyl

1.04

£-Tolyl

i-Propyl

1.10*

9-Anth

Ph

1.59

a-Naph

Me

1.09*

9-Anth

£-Anisyl

1.57

9-Anth

Me

1.19*

9-Anth

£-N0 -C H

9-Anth

i-Propyl

1.22*

9-Anth

2,4-(N0 ) C H

9-Anth

CH COOC H 2

2

5

2

6

2

1.40

4

2

6

3

1.20

1.20 SPIRO-2,2-DITHI0LANE-1-0XIDES

1.33

1.15

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

250

ASYMMETRIC

Table I I I

REACTIONS

0

β-HYDROXY SULFOXIDES

A N D PROCESSES IN

CHEMISTRY

(continued) β-HYDROXY SULFOXIDES CONTINUED

OH

I

9-Anth—SimR

Ar—g*iMCH —CHR 2

Ar Ph

9-Anth

H

1.31

9-Anth

Me

1.38/1.22

9-Anth Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

C

H

^ 18 37 9-Anth

Ph

OH

1.42, 1.22, 1.13

1.52/1.28

1.15/?

1.18/1.04

1.22, 1.26, 1.07,

l-ARYL-l-ALKYL-2,2-DITHI0LANE-1-0XIDES Ar

R

Ph

Et

_α

Note:

ΓΛ s

xT°

Ar

1.06/NS C

H

*- ll 23

ου

entries

f o r α a r e those of

R

Ph

Multiple

diastereomers.

1.10/NS

If i n

parentheses, α values r e f e r to other 1.13/1.04 positional

isomers.

1.10/si.01

m

1.24/NS

Table IV. R e s o l u t i o n of Some Amides Upon CSP 1. ARYL-SINSTITUTED SUCCINIMIDES

ARYL ACETAMIDES γ I

Ar-C-CONH

2

Ar

R

α

Ar

Y

α

Ph

Η

1.13

Ph

i-Propyl

1.08

Ph

Me

1.07

Ph

Methoxy

1.13

Ph

Et

1.13

Ph

i-Propoxy

1.30

p-Anisyl

H

1.24

Ph

SPh

1.03

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

18.

PiRKLE E T A L .

Liquid

Chromatographic

Table IV.

251

Separation

(continued) DIELS-ALDER ADDUCTS OF

ARYL-SUBSTITUTED LACTAMS

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

ACRYLAMIDES AND ANTHRACENES

Ar

R

Ph

H I

£-Anisyl

Η

1 1.33*

α-Naph

Η

l

p-Anisyl

Η

2 1.30

α-Naph

Η

2 1.23

1.18* (1.02) (1.03)

1.14

PHTHALIDES

Ar

R

α

Ph

H

1.03

Ph

Et

1.03*

p-Anisyl

H

1.07

Β

c

α

Η

Η

Η

H

1.13

Me

Η

Η

H

1.40

Me

Η

Ph

H

1.42

Me

Η

Cl

H

1.56

Me

Η

Br

H

1.80

Me

Η

Br

Br

1.96

si Y

X α

H

H

0

1.13

Ph

Et

H

0

1.26

p-Anisyl

i-Propyl

H

0

1.50

α-Naph

Me

H

0

1.35

α-Naph

(CH ) CH=CH

H

0

1.48

β-Naph

CH

H

0 1.39

β-Naph

H

1.13

a-Naph

Me

1.37

Ph

9-Anth

CF

OXAZOLIDONES

A

ο

a-Naph

1.20

R

ARYL-SUBSTITUTED HYDANTOINS

Ar

3

to

0

η α

0

II

2

2

2

3

A

B

α

H

Ph

1.05*

H

a-Naph

1.04

Ph

0 1.33 H (CHJ CH=CH ζ ζ ζ C0CH s 1.27 H

Ph

Ph

1.02*

β-Naph

CH

9

9

3

3

CH

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

3

0

1.53

H

3 1

W W

00

8

>

δ

m

H

H

Ο

w

to

LA

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

18.

PIRKLE

ET AL.

Liquid

Chromatographic

Separation

253

employed. Each Table i n d i c a t e s the magnitude of α noted upon the c h i r a l a n a l y t i c a l column f o r the i n d i c a t e d s o l u t e . As a r u l e , many more compounds have been r e s o l v e d w i t h i n each c l a s s than are presented, great g e n e r a l i t y being encountered. E l u t i o n order from the column i s d i a g n o s t i c of the absolute c o n f i g u r a t i o n of the enantiomers. When a stereochemical r e p r e s e n t a t i o n i s shown f o r a g e n e r a l i z e d s o l u t e type, that enantiomer i s e i t h e r known ( i n d i c a t e d by an a s t e r i s k ) or b e l i e v e d ( f o r mechanistic reasons) to be l a s t e l u t e d . Elution orders were determined e i t h e r by chromatographing enriched samples of known c o n f i g u r a t i o n or through use of a p o l a r i m e t r i c d e t e c t o r (Figure 2), the s i g n of r o t a t i o n a f f o r d e d by each enantiomer being noted as i t e l u t e d . These r o t a t i o n a l signs were then compared to l i t e r a t u r e assignments of stereochemistry. C h i r a l Recognition

Mechanisms

The conformation depicted i n CSP 1 i s analogous to the s o l u t i o n conformations p r e f e r e n t i a l l y populated by amides of primary amines having a s i n g l e α-hydrogen. This conformation i s used i n our present c h i r a l r e c o g n i t i o n mechanisms. A minimum of three simultaneous i n t e r a c t i o n s , at l e a s t one of which must be stereochemically dependent, i s r e q u i r e d f o r c h i r a l r e c o g n i t i o n . CSP 1 uses the f o l l o w i n g types of i n t e r a c t i o n s . The DNB group i s used to π-complex to a π-base ( u s u a l l y an a r y l group) i n the s o l u t e , the amide hydrogen bonds to a b a s i c s i t e i n the s o l u t e , the t h i r d stereochemically dependent i n t e r a c t i o n being e i t h e r hy­ drogen bonding of the carboxylate group by an a c i d i c s o l u t e s i t e or s t e r i c r e p u l s i o n between the phenyl of CSP 1 with a " s t e r i c b a r r i e r " contained w i t h i n the s o l u t e . S t e r i c r e p u l s i o n s are notably l e s s e f f e c t i v e f o r c h i r a l r e c o g n i t i o n than are bonding i n t e r a c t i o n s i n v o l v i n g the carboxylate group. Solutes c o n t a i n i n g two a c i d i c s i t e s (and a π-base) but no s u i t a b l e b a s i c s i t e can s u b s t i t u t e a hydrogen bond to the DNB carbonyl oxygen f o r the hydrogen bond from the amide hydrogen. Figures 3-8 i l l u s t r a t e these m u l t i p l e i n t e r a c t i o n s between R-CSP 1 and the most s t r o n g l y r e t a i n e d enantiomer f o r s e v e r a l s o l u t e types. For benzyl a l c o h o l s , one can see from Figure 3 the simultaneous occurrence of a ττ-π i n t e r a c t i o n , a conventional hydrogen bond, and a weaker " c a r b i n y l hydrogen bond" ( 8 , 11) to the carbonyl oxygen of the DNB group. A l t e r i n g the c o n f i g u r a t i o n of e i t h e r c h i r a l center breaks one of these bonding i n t e r a c t i o n s , hence a s t a b i l i t y d i f f e r e n c e occurs f o r the diastereomeric s o l v a t e s . Figure 4 shows recognizably s i m i l a r i n t e r a c t i o n s between bi-g-naphthol and CSP 1. Increasing the π-basicity of the naphthol system or i n c r e a s i n g the b a s i c i t y of one of the oxygens by methylation increases the magnitude of α (Table I I ) . Two of the i n t e r a c t i o n s shown i n F i g u r e 5 are analogous to those j u s t discussed. The t h i r d s t e r e o c h e m i c a l l y dependent i n t e r a c t i o n seems to be r e p u l s i o n between the s t e r i c

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

254

Figure

2.

Separation on (R)-CSP 1 of the enantiomers of 5-anisylhydantoin employing UV (254 nm) and polarimetric (589 nm) detectors.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

18.

PIRKLE E T A L .

Liquid Chromatographic Separation

255

Figure 3. Chiral recognition model showing the relative arrangement for three simultaneous bonding interactions between (R)-CSP 1 and the most retained enantiomer of an alkyl aryl carbinol.

Figure 4. Chiral recognition model showing the relative arrangement for three simultaneous bonding interactions between (R)-CSP 1 and the most retained enantiomer of bi-fi-naphthol.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

A S Y M M E T R I C REACTIONS A N D

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

256

PROCESSES IN

CHEMISTRY

b a r r i e r of the a l i c y c l i c r i n g and e i t h e r the carboxylate or phenyl group of CSP 1, depending upon r e l a t i v e c o n f i g u r a t i o n . The i n t e r a c t i o n w i t h phenyl i s the most severe. Figure 6 shows r a t h e r s i m i l a r i n t e r a c t i o n s with a r y l a l k y l s u l f o x i d e s , the stereochemically dependent i n t e r a c t i o n being, at l e a s t i n p a r t , s t e r i c r e p u l s i o n with the a l k y l group. A s i m i l a r model accounts f o r the r e s o l u t i o n of d i a r y l s u l f o x i d e s , the π-π i n t e r a c t i o n o c c u r r i n g at the most π-basic a r y l group, the s t e r i c b a r r i e r being the l e a s t π-basic a r y l group. Note from the data i n Table I I I that i n c o r p o r a t i o n of a hydroxyl group i n t o the a l k y l group of 9-anthryl a l k y l s u l f o x i d e s can enhance α by a l l o w i n g hydrogen bonding to the carboxylate group to augment s t e r i c r e p u l s i o n with the phenyl group. Consequently, SN2 r i n g opening of an epoxide w i t h 9-anthryl t h i o l followed by o x i d a t i o n to the s u l f o x i d e appears to o f f e r promise i n terms of HPLC enantiomeric p u r i t y determinations of epoxides. Figure 9 shows separation of the eight e n t i t i e s so derived from racemic d i s p a r l u r e , the Gypsy moth sex a t t r a c t a n t . Figures 7 and 8 show that c h i r a l r e c o g n i t i o n of hydantoins and lactams by CSP 1 u t i l i z e s the same, now f a m i l i a r , three bonding i n t e r a c t i o n s . Table IV shows r e s o l u t i o n data f o r these and other amide-like compounds. The foregoing d i s c u s s i o n makes c l e a r that CSP 1 r e q u i r e s that s o l u t e s c o n t a i n s t r u c t u r a l subunits capable of undergoing the r e q u i r e d m u l t i p l e simultaneous i n t e r a c t i o n s employed by CSP 1 i n e f f e c t i n g enantiomer s e p a r a t i o n . I t should be obvious that not only must appropriate "complementary f u n c t i o n a l i t y " be present but that i t must be arrayed so that i t can e f f e c t i v e l y c o n t r i b u t e to t h e c h i r a l r e c o g n i t i o n process. Because HPLC can e f f e c t i v e l y r e v e a l q u i t e small s t a b i l i t y d i f f e r e n c e s between diastereomeric " s o l v a t e s " , the conformational behavior of both s o l u t e and s t a t i o n a r y phase must be considered i n advancing c h i r a l r e c o g n i t i o n models to account f o r observed chromatographic behavior. One i s seldom i n a p o s i t i o n to f u l l y describe the conformations assumed by conformâtionally mobile molecules. Nevertheless, our work i n d i c a t e s that c h i r a l r e c o g n i t i o n r a t i o n a l e s of r a t h e r broad scope can be formulated and can be used i n a s s i g n i n g absolute c o n f i g u r a t i o n s to a v a r i e t y of compounds. Moreover, the r a t i o n a l e s can be used to formulate s t i l l more e f f e c t i v e c h i r a l chromatography columns. Preparative

Resolutions

Larger s c a l e r e s o l u t i o n s have been accomplished using a 2" χ 30" column f i l l e d w i t h CSP 1 d e r i v e d from J . T. Baker 40 μ i r r e g u l a r "amino" s i l i c a . T h i s column i s considerably l e s s e f f i c i e n t ( i n terms of t o t a l p l a t e s ) than the a n a l y t i c a l column but a f f o r d s somewhat l a r g e r α values owing to the use of a d i f f e r e n t type of s i l i c a . Used i n conjunction w i t h a homemade automated prep chromatography system, we have been able to

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

18.

Ρ IRK L E E T A L .

Liquid

Chromatographic

Separation

257

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

S'-OCjjHj;

Figure 5. Chiral recognition model showing the relative arrangement for two simultaneous bonding and one (least) repulsive interaction between (R)-CSP 1 and the most retained enantiomer of l,2,3,4-tetrahydrobenz[a]anthracen-l-ol.

Figure 6. Chiral recognition model showing the relative arrangement between (R)-CSP 1 and the most retained enantiomer of an alkyl aryl sulfoxide.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

258

A S Y M M E T R I C REACTIONS A N D PROCESSES IN CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

3T

Figure 7. Chiral recognition model showing the relative arrangement for three simultaneous bonding interactions between (R)-CSP 1 and the most retained enantiomer of a 3-aryllactam.

Figure 8. Chiral recognition model showing the relative arrangement for three simultaneous bonding interactions between (R)-CSP 1 and a 5-arylhydantoin.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Liquid

Chromatographic

Separation

259

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

PiRKLE E T A L .

Figure 9. Chromatogram showing the separation on CSP 1 of the eight possible β-hydroxy sulfoxides derived from racemic disparlure. Bands bearing the same letter designation arise from enantiomers. A and Β differ in relative stereochemistry from C and D. A and Β (and C and D) are identical stereochemically but are regioisomers.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

A S Y M M E T R I C REACTIONS A N D PROCESSES I N CHEMISTRY

260

e f f e c t e s s e n t i a l l y t o t a l r e s o l u t i o n of multigram samples of racemates having an α value o f 1.4 or g r e a t e r . For example, 4.0 g samples of racemic 2 , 2 , 2 - t r i f l u o r o - 1 - [ 9 - ( 1 0 - m e t h y l ) a n t h r y l ] e t h a n o l [the precursor o f another type of CSP (6, 7)] have been so separated i n t o " f i r s t " and "second" chromatographic bands, the enantiomeric p u r i t i e s being 99 and 86%, r e s p e c t i v e l y . Eight-gram samples o f t h i s racemate have been s i m i l a r l y r e s o l v e d with o n l y s l i g h t l y poorer r e s u l t s . For samples having α values of 1.05 t o 1.25, a more e f f i c i e n t prep column d e r i v e d from 5 μ p a r t i c l e s would be d e s i r a b l e .

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch018

Acknowledgement T h i s work has been supported by a grant from the N a t i o n a l Science Foundation. A number of the samples used i n these s t u d i e s have been provided by c o l l e a g u e s throughout the world.

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Krull, I. S. Advan. Chromatogr. 1978, 16, 175. Audebert, R. J. Liq. Chromatogr. 1979, 2, 1063. Blaschke, G. Angew. Chem., Int. Ed. Engl. 1980, 19, 13. Davankov, . Advan. Chromatogr. 1980, 18, 139. Pirkle, W. H.; Sikkenga, D. L. J. Chromatogr. 1976, 123, 440. Pirkle, W. H.; House, D. W. J . Org. Chem. 1979, 44, 1957. Pirkle, W. H.; House, D. W.; Finn, J . M. J. Chromatogr. 1980, 192, 143. Pirkle, W. H.; Finn, J. M. J. Org. Chem. 1981, 46, 2935. Pirkle, W. H.; Finn, J. M.; Schreiner, J. L.; Hamper, B. C. J. Am. Chem. Soc. 1981, 103, 3964. Pirkle, W. H.; Schreiner, J. L. J. Org. Chem. 1981, 46, 4988. Pirkle, W. H.; Hauske, J . R. J. Org. Chem. 1976, 41, 801.

RECEIVED December 21, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

New Asymmetric Reactions Using (S)-2-Aminomethylpyrrolidine Derivatives MASATOSHI ASAMI

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch019

University of Tokyo, Department of Chemistry, Faculty of Science, Tokyo, Japan 113

A new chiral auxiliary reagent, (S)-2-substituted-amino­ -methylpyrrolidine 1, has been designed based on the fundamental assumption that a conformationally restricted cis-fused five­ -membered bicyclic structure would be effective for asymmetric in­ duction. The effectiveness of the new reagent was realized in the following highly stereoselective reaction: Asymmetric reduction of prochiral ketones. A chiral hydride reagent formed by treating the chiral diamine 1 with LiAlH was postulated to assume a cis-fused five-membered bicyclic ring structure 2. Highly enantiomerically pure alcohols were obtained when the reaction was carried out in ether at low temperature (-100°C) by employing diamines 1 having 2,6-xylyl or phenyl substituents on nitrogen. 4

1

α-Tetralone 0097-6156/82/0185-0263$05.00/0 © 1982 American Chemical Society

86% ee

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

264

ASYMMETRIC REACTIONS AND

PROCESSES IN CHEMISTRY

Asymmetric synthesis of optically active aldehydes.

The

idea was extended to the synthsis of various synthetically useful optically active aldehydes utilizing aminals having a similar rigid structure as 2. The f i r s t example is an asymmetric

1,2-

addition of Grignard reagents to a chiral keto aminal leading to various

α-hydroxyaldehydes.

The u t i l i t y of the aminal structure

was also shown in an asymmetric 1,4-addition of Grignard reagents to an aminal 3, prepared from the diamine 1 (R=Ph) and fumarPublication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch019

aldehydic acid methyl ester.

Various 3-alkylsuccinaldehydic acid

methyl esters were thus obtained with high optical yields.3

Another highly enantioselective addition was achieved by using the chiral aryllithium derived from 4. lithium compound assumes structure 5.

Presumably the

Highly optically pure

lactols 6 were obtained by i t s reaction with aldehydes.

The

resulting lactols 6 were successfully converted to optically active 3-alkylphthalide, e.g., (S)-3-butylphthalide, an essential o i l of celery.4

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASAMi

(S)-2-Aminomethylpyrrolidine

Derivatives

265

(S)-3-Butylphthalide

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch019

88% ee

Literature Cited 1. a) Mukaiyama, T., Asami, M., Hanna, J., Kobayashi, S. Chem. Lett., 1977, 783. b) Asami, Μ., Ohno, H., Kobayashi, S., Mukaiyama, T. Bull. Chem. Soc. Jpn., 1978, 51, 1864. c) Asami, M., Mukaiyama, T. Heterocycles, 1979, 12, 499. 2. See Mukaiyama, T., article in this volume. 3. Asami, M., Mukaiyama, T. Chem. Lett., 1979, 569. 4. Asami, M., Mukaiyama, T. ibid., 1980, 17. RECEIVED December 21, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Liquid Chromatographic Resolution of Enantiomeric α-Amino Acid Derivatives Employing a Chiral Diamide Phase SHOJI HARA, AKIRA DOBASHI, and MASAKATZU EGUCHI

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch020

Tokyo College of Pharmacy, Horinouchi, Hachioji, Tokyo 192-03, Japan

Liquid chromatographic resolutions based on highly selective host-guest, metal chelate and charge-transfer com­ plexations have been described (1,2). Recently, a chiral diamide-bonded stationary phase (I) has been prepared, which relies entirely on hydrogen bond associations for the material to be resolved. Despite the weak and flexible interaction in this system, direct resolution of enantiomeric N-acyl-α­ -amino acid esters (II) was accomplished with the advent of a highly efficient column technology (2-4). Amide derivatives of α-amino acid solutes (III) were tested for resolution. An increase in the bulkiness of the N-alkyl moiety R' improved the separation factors (α), i.e., the enantioselectivity. The highest α value (1.43; 2(v/v)% 2-propanol in n-hexane) was obtained for N-tert-butylamides. Thus, enantiomeric N-tert-butylamide derivatives of N-acyl­ -α-amino acids were separated with larger α values than corre­ sponding 0-alkyl ester derivatives.

HCONH-CH-CONH

CH3CONH-CH-COXR

R X= 0, (I)

(II)

X=NH (III)

0097-6156/82/0185-0266$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch020

HARA E T A L .

Enantiomeric α-Amino Acid Derivatives

267

For characterization and exploitation of the diamide-phase system, a c h i r a l diamide, e.g., (III) was examined as a modi­ f i e r i n the mobile phase (solvent) in conjunction with a nonbonded (bare) silica. Such a c h i r a l c a r r i e r separated enantiomeric N-acyl-α-amino acid esters and amides with sepa­ ration factors comparable to those f o r bonded stationary phase systems. The resolution can be ascribed to diastereomeric complexation through amide-amide hydrogen bonding between the amide additive and enantiomeric solute molecules i n the c a r r i e r solvent, followed by separation of the diastereomeric com­ plexes by the (achiral) silica phase. This process should be applicable as widely as that involving c h i r a l diamide-bonded stationary phase systems. Analytical high resolution of enantiomers was achieved with high s e n s i t i v i t y by using glass c a p i l l a r y micro-column technology based on these diamide-phase systems. The amide phase systems are also applicable to preparative scale separations. A semi-preparative bonded column (10 mm i . d . x 25 cm) was prepared, y i e l d i n g a loading capacity of ca. 1 mg per 1 g packing material. Enantiomeric and diastereo­ meric pairs of benzyloxycarbonyl and tert-butyloxycarbonyl protected di- and tri-peptides were resolved successfully using this c h i r a l amide-bonded column system.

Literature Cited 1. Audebert,R. J. Liq. Chromatogr., Special Issues on Liquid Chromatographic Separation of Enantiomers, Diastereomers, and Configurational Isomers, Marcel Dekker, New York 1979, 2, 1063. 2. Dobashi, Α.; Hara, S. Kagaku no Ryoiki, Special Issue on Biomedical Chromatography, Nanko-do, Tokyo 1981, 132, 171. 3. Hara, S.; Dobashi, A. J . Chromatogr. 1979, 186, 543. 4. Dobashi, Α.; Oka, K.; Hara, S. J . Am. Chem. Soc., 1980, 102, 7122. RECEIVED December 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Asymmetric Reduction with Chiral N A D H Model Compounds YUZO INOUYE

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch021

Kyoto University, Institute for Chemical Research, Uji, Kyoto, Japan 611

Novel chiral bis(l,4-dihydronicotinamide) derivatives bear­ ing an S-prolinamide moiety were prepared and used to reduce ethyl phenylglyoxylate and other substrates. High optical yields of the reduction product R-mandelate (95.6-98.1%) were obtained with the p-xylylene- and hexamethylene-bridged bis(NAH) reductants. The e.e. was unaffected by an excess of Mg and also did not change at all during the course of reduction. Upon addition of Mg to bis(NAH), the carbonyl absorption band at 1680 shifted to lower frequency,whereas the C-N band at 1605 moved to a higher value. This shows that Mg ion complexes to the primary amide carbonyl oxygen of prolinamide. The mole ratio method showed the formation of a 1:1 complex between the bis(NAH) and Mg. The Table shows the outcome of this reaction and the related ones. The spectral evidence, when combined with the stereochemical outcome that the e.e. was at a maximum when equimolar quantities of bis(NAH) and Mg were employed, shows that the present reduction with bis(NAH) is a single kinetically controlled process in con­ trast to that with the mono-derivatives. The stereochemical requirements are well accommodated in a stoichiometric intramolec­ ular chelation complex which assumes a C -conformation (I) with one specific diastereotopic face of the dihydropyridine moiety disposed toward the outside for the attack on substrates. The chiral bis(NAH) reductants were easily regenerated by re­ duction of the resulting oxidized forms with aqueous solutions of 1

c m -

c m -

32 ,

4

5,6,7

2

0097-6156/82/0185-0268$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Chiral

INOUYE

Table.

NADH

Asymmetric

Model

269

Compounds

Reductions w i t h C h i r a l

NADH Model Compounds

H

H^CONH

2

2

H

N

0

C

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch021

bis-NAH

Product

Reaction

Substrate

-X-

Temp.(°C)

Period(hr)

% Yield

25 Config. [a]£V)

% ee

o-xylylene

PhCOCOOEt

25

23

69.5

-38.0

R

36.4

m-xylylene

PhCOCOOEt

25

23

61.5

-35.4

R

34.0

' PhCOCOOEt

25

1

66.6

-102.4

R

98.1

PhCOCOOEt

50

2

79.8

-97.8

R

93.5

QcOMe

60

16

66.9

+50.8

R

89.7

Q c O P h

50

100

71.5

-123.3

-

99.7

25

192

16.8

+4.1

R

23.2

25

67

-19.3

R

38.1

p-xylylene

Ph(Me)C=C(CN)

2

I

100

0

-(CH ) -

PhCOCOOEt

20

19

50.4

-41.7

R

39.9

-(CH ) -

PhCOCOOEt

20

17

73.4

R

43.0

" PhCOCOOEt

20

17

63.5

-44.9 -99.8

R

95.6

QcOMe

50

23

84.3

-37.8

R

66.7

Q c O P h

50

23

67.0

-114.6

-

92.7

50

96

59.2

+4.3

R

24.5

50

23

65.7

-17.2

R

33.9

0 PhCOCOOEt PhCOCOOEt

20

15

57.9

-61.3

R

58.7

20

15

63.2

-84.8

R

81.2

mesitylylene PhCOCOOEt (tris-NAH)

20

16

16.5

+18.3

5

17.6

2

2

4

5

-(CH ) 2

6

Ph(Me)C=C(CN)

2

II

-(CH ) -(CH ) 2

2

7

8

^

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

ASYMMETRIC

REACTIONS

A N D PROCESSES IN

CHEMISTRY

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch021

270

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

INOUYE

Chiral

NADH

Model

Compounds

111

sodium h y d r o s u l f i t e i n 42-60% recovery and can be r e c y c l e d with the o p t i c a l y i e l d s remaining unchanged. The m e s i t y l y l e n e - b r i d g e d tris(NAH) d e r i v a t i v e o f S - p r o l i n amide and the p - x y l y l e n e - b r i d g e d bis(NAH) d e r i v a t i v e o f 5 - p r o l i n o l switched the s t e r i c course of r e d u c t i o n so as to give the enantio-

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch021

meric 5-mandelate i n lower e.e.

Literature Cited 1. Seki,M;Baba,N.;Oda,J.;Inouye,Y.J.Amer.Chem.Soc., 1981, 103, 4613. 2. Hughes,M;Prince,R.H.;Weyth,P. J.Inorg.Nucl.Chem., 1978,40,713. 3. Kanzaki,M.;Nonoyama,M.;Yamazaki,K. Kagaku,1971, 27, 1182. 4. Yoe,J.H.;Jones,A.L. Ind.Eng.Chem. Anal.Ed.,1944, 16, 111. 5. Makino,T.;Nunozawa,T.;Baba,N.;Oda,J.;Inouye,Y. J.Chem.Soc. Perkin I, 1980,7. 6. Makino,T.;Nunozawa,T.;Baba,N.;Oda,J.;Inouye,Y.Tetrahedron Lett. 1979, 1683. 7. Baba,N;Oda,J.;Inouye,Y. J.Chem.Soc., Chem.Commun.,1980,815. RECEIVEDJanuary 4, 1982.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Asymmetric Hydrogenation of Cyclic Dipeptides Containing α,β-Dehydroamino Acid Residues and Subsequent Preparation of Optically Pure α-Amino Acids

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch022

NOBUO IZUMIYA Kyushu University, Laboratory of Biochemistry, Faculty of Science, Higashi-ku, Fukuoka 812, Japan

AM-Toxin I (I, Scheme 1) is a host specific phytotoxin. To elucidate the role of the double bond in the ∆Ala residue, we planned to prepare [L-Ala ]- or [D-Ala ]-AM-toxin I (II) by hydro­ genation of AM-toxin I. By way of a preliminary study we hydro­ genated cyclo(∆Ala-L-Leu) (III) and observed unexpectedly high asymmetric induction, affording pure cyclo(L-Ala-L-Leu) (IV). 2

2

2

Cyclo(L-Ser-L-AA) (AA=Ala, Val, Phe or Lys(ε-Ac)) was con­ verted by the Photaki method (1) into the corresponding cyclo (∆Ala-L-AA) and subsequently hydrogenated with Pd black in metha­ nol at 25°C affording cyclo(Ala-L-AA) (2). Generally high chiral inductions defined as %L-Ala minus %D-Ala in the cyclo(Ala-L-AA) were observed, ranging from 92 to 98% with yields of 63-75%. Similarly high chiral inductions (96-99%) were observed for 0097-6156/82/0185-0272$05.00/0 © 1982 American Chemical Society

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch022

IZUMIYA

Cyclic Dipeptides

273

hydrogenation of a series of cyclo(∆AA'-L-AA) (∆AA'=∆Aba, ∆val or ∆Leu) prepared from cyclo(Gly-L-AA) and appropriate aldehydes (3). Hydrogenation of ∆Phe or ∆Trp i n cyclo(∆Phe or ∆Trp-L-AA) resulted in a slightly lower asymmetric induction at 25°C (3). Hydrogenation of a series of its higher homologs (e.g. cyclo(∆Homophe-LAla)), however, afforded high induction (4). Cyclo(∆Phe-L-Ala) was hydrogenated with high chiral induction at a low temperature, 0°C (4). Optically pure α-amino acids can be prepared by this route. For example, pure cyclo(L-Aba-L-Lys(ε-Ac)) obtained from cyclo (∆Aba-L-Lys(ε-Ac)) was hydrolyzed by 6 M HCl to give pure L-Aba (L-2-aminobutanoic acid) (3). Pure L-App (L-2-amino-5-phenylpentanoic acid) was prepared from cyclo(ΔΑρρ-L-Ala) and used for the synthesis of AM-toxin II (5). H -D-Phe was prepared from cyclo(∆Phe-D-Lys(ε-Ac)) and deuterium at 0°C, and synthesis of [ H2-D-Phe ']-gramicidin S (cyclic decapeptide) for NMR investi­ gation i s under study. The mechanism of the chiral inductions has been discussed (2^ 4). In cyclo(AAla or ALeu-L-AA), the r i g i d and planar structure of the diketopiperazine ring and the side chain containing the double bond i s an important factor inducing high asymmetry. In cyclo(APhe or ATrp-L-AA), however, the diketopiperazine ring and the aromatic ring cannot be coplanar; a somewhat poorer stereo­ selectivity i n the adsorption of the diketopiperazine ring on Pd i s assumed to lower the degree of asymmetric hydrogénation. 2

2

2

4,4

Acknowledgments The author thanks Drs. S. Lee, T. Kanmera, H. Aoyagi, and Y . Hashimoto in his laboratory for their experimental assistance.

Literature cited 1. Photaki, I. J. Am. Chem. Soc. 1963, 85, 1123. 2. Lee, S.; Kanmera, T.; Aoyagi, H.; Izumiya, N. Int. J. Pept. Protein Res. 1979, 13, 207. 3. Kanmera, T.; Lee, S.; Aoyagi, H.; Izumiya, N. Int. J. Pept. Protein Res. 1980, 16, 280. 4. Hashimoto, Y.; Aoyagi, H.; Izumiya, N. Int. J. Pept. Protein Res. in preparation. 5. Shimohigashi, Y.; Izumiya, N. Int. J. Pept. Protein Res. 1978, 12, 7. RECEIVED December 14, 1981.

In Asymmetric Reactions and Processes in Chemistry; Eliel, E., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.