Trends in Synthetic Carbohydrate Chemistry 9780841215634, 9780841212381, 0-8412-1563-4

Citation preview

Trends i Synthetic Carbohydrate Chemistry

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

ACS

SYMPOSIUM

SERIES

Trends in Synthetic Carbohydrate Chemistry Derek Horton, EDITOR The Ohio State University

Lyn

,

Eisai Research Institute of Boston, Inc.

Glenn J. McGarvey,

EDITOR University of Virginia

Developed from symposia sponsored by the Divisions of Organic Chemistry and of Carbohydrate Chemistry at the 191st National Meeting of the American Chemical Society, New York, New York, April 13-18, 1986, and the 194th National Meeting of the American Chemical Society, New Orleans, Louisiana, August 30-September 4, 1987

American Chemical Society, Washington, DC 1989

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

386

Library of Congress Cataloging-in-Publication Data Trends in synthetic carbohydrate chemistry. Derek Horton, Lynn D. Hawkins, Glenn J. McGarvey, editors. p.

cm.—(ACS Symposium Series, 0097-6156; 386).

"Developed from a symposium sponsored by the Divisions of Organic Chemistryandof Carbohydrate Chemistry at the 191st National Meeting of the American Chemical Society, New York, New York, April 13-18, 1986, and the 194th National Meeting of the American Chemical Society, New Orleans, Louisiana, August 30-September 4, 1987." Includes bibliographies an ISBN 0-8412-1563-4 1. Carbohydrates—Congresses. I. Horton, Derek, 1932- . II. Hawkins, Lynn D., 1954- . III. McGarvey, Glenn J., 1951- . IV. American Chemical Society. Division of Organic Chemistry. V. American Chemical Society. Division of Carbohydrate Chemistry. VI. American Chemical Society. Meeting (191st: 1986: New York. N.Y.). VII. American Chemical Society. Meeting (194th: 1987: New Orleans, La.) VIII. Series. QD320.T74 1989 547.7'8—dc19

88-39237 CIP

Copyright ©1989 American Chemical Society All Rights Reserved. The appearance of the code at the bottom of the first page of each chapter in this volume indicates the copyright owner's consent that reprographic copies of the chapter 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., 27 Congress Street, Salem, MA 01970, 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, tor creating a new collective work, for resale, or for information storage and retrieval systems. The copying fee for each chapter is indicated in the code at the bottom of the first page of the chapter. 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 anyrightor permission to the holder, reader, or any other person or corporation, to manufacture, reproduce, use, or sell any patented invention or copyrighted work that may in any way be related thereto. Registered names, trademarks, etc., used in this publication, even without specific indication thereof, are not to be considered unprotected by law. PRINTED IN THE UNITED STATES OF AMERICA

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

ACS Symposium Series M. Joan Comstock, Series Editor 1988 ACS Books Advisory Board Paul S. Anderson

Vincent D. McGinniss

Merck Sharp & Dohme Research Laboratories

Battelle Columbus Laboratories

Harvey W. Blanch University of California—Berkeley

Malcolm H. Chisholm Indiana University

Quin University of Iowa

James C. Randall Exxon Chemical Company

Alan Elzerman

E. Reichmanis

Clemson University

AT&T Bell Laboratories

John W. Finley Nabisco Brands, Inc.

Natalie Foster Lehigh University

C. M. Roland U.S. Naval Research Laboratory

W. D. Shults Oak Ridge National Laboratory

Marye Anne Fox The University of Texas—Austin

Geoffrey K. Smith Rohm & Haas Co.

Roland F. Hirsch U.S. Department of Energy

G. Wayne Ivie USDA, Agricultural Research Service

Douglas B. Walters National Institute of Environmental Health

Michael R. Ladisch

Wendy A. Warr

Purdue University

Imperial Chemical Industries

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Foreword The ACS SYMPOSIUM SERIES was founded in 1974 to provide a medium for publishin format of the Serie IN CHEMISTRY 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 pub­ lished papers are not accepted. Both reviews and reports of research are acceptable, because symposia may embrace both types of presentation.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Preface C A R B O H Y D R A T E S , C H I R A L O R G A N I C M O L E C U L E S found naturally or obtained by synthetic transformations, currently comprise a quarter of a million or so known compounds. The rich structural diversity of this group and the multifaceted importance of carbohydrates in biochemistry, medicinal chemistry, microbiology, technology, and many other areas have long challenged synthetic chemists toward a multitude of objectives. The potential of sugars as starting points for highly efficient, stereochemically designed syntheses of noncarbohydrate targets is now increasingly recognize hydrates also serve as excellen stereochemical influence and control of chemical transformations in multifunctional, three-dimensional matrices. Trends in Synthetic Carbohydrate Chemistry is divided into two sections, each of which may be further subdivided into three themes. The first section, "Synthetic Transformations in Carbohydrate Chemistry", surveys a variety of synthetic methodologies useful for transformation of natural saccharides into desired target molecules. The initial three chapters focus on functional-group transformations and protective-group strategy, with special emphasis on aminodeoxy, deoxyfluoro, and deoxynitro sugars and cyclitols, as well as the formation and cleavage of cyclic acetals. Examples of applications to specific synthetic aims are given in Chapters 4-6, including the synthesis of bicyclic nucleosides, the Wittig approach to long-chain sugars, and the transformation of sugar precursors into chiral pyrrolidine alkaloids. The last three chapters of the first section address the ever-significant problem of high-yielding, stereoselective glycosidic coupling procedures, first from the standpoint of basic methodology, next in glycosylations directed toward antibiotics containing deoxy sugars, and finally in the notable applications that have provided practical syntheses of cyclodextrins and complex oligo­ saccharides. The second section of the book, entitled "Total Synthesis of Carbohydrates", focuses on strategies for the generation of monomeric carbohydrates, with major emphasis on the use of nonchiral, acyclic precursors. The contributors do not "reinvent the wheel" by providing tedious synthetic access to abundant natural sugars. Rather, they show

xi

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

the potential of synthetic design for controlled access to molecules containing multiple chiral centers that are not readily accessible from natural precursors. Chapters 10-13 illustrate from a variety of viewpoints the great utility of Diels-Alder reactions for the direct and indirect formation of chirally functionalized tetrahydropyrans and tetrahydrofurans. Chapters 14-16 address the aldol reaction and its control, the use of boron and tin enolates, and the use of chiral auxiliaries in the stereocontrolled formation of carbon-carbon bonds generating new chiral centers. Finally, the last two chapters describe the harnessing of enzymes as synthetic tools for chiral precursors and target products, both by use of isolated enzymes and by reactions brought about by living cultures of microorganisms. Trends in Synthetic Carbohydrate Chemistry offers the reader a wealth of contemporary ideas for the construction of complex natural molecules and their analogs, from conceptualization to practical realization. The rich legacy of the carbohydrate literature in conjunction with newer concepts in general organi provides some of the most exciting challenges for today's chemist. As the molecular basis of biological concepts opens up new vistas of understanding, the synthetic chemist is presented with unique opportunities for exercising creative talent toward significant objectives of ever-increasing complexity. Emulation of the virtuosity of nature in synthesis provides an ever-present challenge for the chemist. We hope that the efforts of those who have created this book will bring broader awareness of the role of carbohydrates in modern synthetic work and stimulate others in the pursuit of great intellectual satisfaction and worthy objectives for their creative efforts in the laboratory. This book is an international collaborative effort, with authors from Canada, France, the Federal Republic of Germany, Great Britain, Italy, Japan, Sweden, Switzerland, and the United States. It is not possible to cover all aspects of this subject in a single volume, but the contributions here are broadly representative of innovative work in the field. The order of the chapters is developed from the relationship of the topics and is not necessarily related to the sequence of contributions at the two symposia from which much of the initial material was derived.

Acknowledgments The editors deeply appreciate the excellent work of the contributing authors that has made this book possible. We also thank the many other colleagues in the field who have given of their time to review the chapters and offer constructive criticism. Excellent support by the American Chemical Society Divisions of Carbohydrate Chemistry and xii

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Organic Chemistry helped to make possible the original ACS symposia that provided the impetus for this book. Additional support for the symposia came from Burroughs Wellcome Company, Ciba-Geigy, ICI Americas, The Upjohn Company, Merck & Company, Sandoz Research Institute, SmithKline Beckman, Syntex Research, and Warner Lambert Company. The support and patience of Joan Comstock and Robin Giroux of the A C S Books Department is recognized. We particularly appreciate the fine support and consultation of David C. Baker at all stages of the development of this book. DEREK HORTON

Department of Chemistry The Ohio State University Columbus, OH 43210 LYNN D. HAWKINS

Eisai Research Institute of Boston, Inc. Lexington, MA 02173 September 3, 1988

xiii

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Chapter 1

New Synthetic Methods Emphasizing Deoxyfluoro Sugars and Protective-Group Strategy Walter A. Szarek Department of Chemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada The selective introduction of fluorine is of continuing interest not onl but also becaus change in biological activity. The fluoride-ion dis­ placement of carbohydrate trifluoromethanesulfonates using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) provides a convenient route to deoxyfluoro sugars. Partially protected mono­ saccharides, having the anomeric hydroxyl underiva­ tized, react with pyridinium poly(hydrogen fluoride) to yield the corresponding glycosyl fluorides. Two new developments in protective-group strategy are also described. These are (i) a method for the selective silylation of primary hydroxyl groups in carbohydrates involving the use of N-trimethylsilyl- or N-tertbutyldimethylsilyl-phthalimide and (ii) a method for acetal cleavage in carbohydrate derivatives using the simple reagent system, iodine in methanol. The search for new methods of synthesis of halogenated carbohydrates continues to be an active area of investigation. The compounds are of u t i l i t y as synthetic intermediates, and many of them are of i n t r i n s i c value i n biochemistry and pharmacology. In the present Chapter methods for the synthesis of deoxyfluoro sugars and glycosyl fluorides are discussed. Because of the polyfunctional nature of carbohydrates, protective-group strategy plays an important role i n synthetic methodology involving t h i s class of compounds. In the present Chapter, results are described from a study of the u t i l i t y of Nt r i m e t h y l s i l y l - and N-tert-butyldimethylsilyl-phthalimide for the selective s i l y l a t i o n of primary hydroxyl groups i n carbohydrates. Also described, i s a new, f a c i l e method for cleavage of acetals and dithioacetals i n carbohydrate derivatives; the method involves treatment of the derivatives with a d i l u t e solution of iodine i n methanol. c

0097-6156/89/0386-0002$06.00/0 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1.

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy

3

Synthesis of Deoxyfluoro Sugars The expanding application of deoxyfluoro sugars f o r the study of carbohydrate metabolism and transport i n both normal and pathological states has stimulated interest i n t h e i r chemical (.1,2) and b i o l o g i c a l ( 3 — 5 ) properties. Furthermore, i t has actuated intensive e f f o r t s to develop improved methods of synthesis, and especially procedures suitable f o r the preparation of F - l a b e l e d carbohydrates f o r use i n medical imaging (6,7). Included i n the approaches taken to t h i s end are addition reactions of such reagents as molecular fluorine ( 8 — 1 1 ) , xenon d i f l u o r i d e (12—14), and acetyl hypofluorite (15—20), reaction of free hydroxyl groups with (diethylamino)sulfur t r i f l u o r i d e (21—23), nucleophilic ring-openings with potassium hydrogenfluoride (24—27), and nucleophilic displacement of good leaving groups by a range of f l u o r i d e s a l t s (28—35). We recently described (36,37) th rapid fluoride-io d i s placement of carbohydrat tris(dimethylamino)sulfoniu (38), a reagent which previously had been u t i l i z e d (39) f o r the synthesis of 1-deoxy-l-fluoro-D-fructose. TASF i s a hygroscopic s o l i d which i s f r e e l y soluble i n a variety of organic solvents i n which i t acts as an e f f e c t i v e fluoride-ion donor when employed under rigorously anhydrous conditions; the r e l a t i v e l y b r i e f reaction times (36,37) are such that i t may be of interest f o r the potential synthesis of F - l a b e l e d radiopharmaceuticals f o r positron emission tomography. Examples of the u t i l i t y of the reagent are described i n the present Chapter; TASF has been used to e f f e c t the displacement, with inversion of configuration, of t r i f l a t e groups at each of C-2, C-3, C-4, and C-6 of suitably protected aldohexopyranosides, at C-6 of 1,2:3,4-di-0isopropylidene-a-D-galactose, and at C-3 of l,2:5,6-di-0isopropylidene-ot-D-allofuranose. The synthetic results have been summarized i n Table I. In most cases the displacement of t r i f l a t e anion occurred rapidly (^30 min) at or below reflux temperature; however, i n two examples (see Table I, compounds 4 and 13) an elimination reaction was found to predominate. The reaction of methyl 4,6-0-benzylidene-3-0-methyl-2-0trifluoromethanesulfonyl-p-D-mannopyranoside (1) with TASF (an approximately 3-fold molar excess of reagent was employed per mole of t r i f l y l group i n each case) i n dichloromethane occurred rapidly (35) under conditions which decreased the ease of nucleophilic substitution (33,43,44). 18

18

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

4

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

Table I.

Substrate

R e a c t i o n s o f TASF w i t h D e r i v a t i v e s (R= S 0 C F ) o f Aldohexo-pyranoses and - f u r a n o s e s 2

Reaction Reaction Time Temperature (min) (°C)

Product

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

3

Yield (%)

1.

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy Table I.

Substrate

Reaction Time (min)

5

Continued

Reaction Temperature (°C)

Product

Yield (%)

C o n t i n u e d on next page.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

6

Table I. Substrate

Reaction

Continued

Reaction

Product

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1.

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy

1

The reaction of benzyl 3,4,6-tri-0-benzyl-2-0-trifluoromethanesulfonyl-p-D-mannopyranoside (3) with TASF was complete i n less than 5 min below room temperature, to give a low (11%) y i e l d of benzyl 3,4,6-tr i-0-benzyl-2-deoxy-2-fluorο-β-D-glucopyranos ide (16), whereas the isomeric α-D-mannopyranoside reacted r e l a t i v e l y slowly with TASF at room temperature to give a product tentatively assigned the structure of 17. The reactions of the β-D-glucopyranosides j>, £, and 2. with TASF yielded results which were very d i f f e r e n t i n each case, but which were f u l l y consistent with the current understanding of nucleophilic displacements i n carbohydrates (41,A3—46). The less rapid and e f f i c i e n t displacement of t r i f l a t e anion from as compared with that from J>, may be attributable to the increased s t e r i c hinderance occasioned by the introduction of benzyl and 2,2,2-trichloroethyl groups i n place of methyl groups. Furthermore, the f a c i l e displacement of t r i f late from C-3 of 1^ r e f l e c t s the diminution of the s t e r i c and electronic effects which render the displacemen much more d i f f i c u l t (44) the r e l a t i v e l y d i f f i c u l t reaction of TASF with £ was found to contain, i n addition to 19, two unidentified components, a result which indicates the r e l a t i v e increase i n competing reactions as nucleophilic substitution i s impeded. The reaction of methyl 2,3,6-tri-0-benzyl-4-0-trifluoromethanesulfonyl^-D-glucopyranoside (j8) with TASF i n dichloromethane at reflux temperature gave within 20 min methyl 2,3,6-tri-0-benzyl-4-deoxy-4-f luoro-β-Ι)galactopyranoside (21) i n 77% y i e l d . Methyl 2,3,6-tri-0-benzyl-4-0trifluoromethanesulfonyl-a-D-galactopyranoside (9) reacted with TASF much more rapidly than did j i ; the conversion was complete within 10 min after the addition of TASF to a cold solution of ^9 to afford methyl 2,3,6-tri-0-benzyl-4-deoxy-4-fluoro-α-D-glucopyranoside (22) in 67% y i e l d . The enhanced ease of displacement of the a x i a l l y oriented t r i f l o x y group of j), as compared to that of the equatorially oriented one of JS, i s consistent with the suggestion (45) that a galacto isomer has a higher ground-state energy than the corresponding gluco compound. The nucleophilic displacement by TASF of a t r i f l o x y group located on a primary carbon atom occurred with great r a p i d i t y under mild conditions. Thus, the reaction of l,2:3,4-di-0isopropylidene-6-0-trifluoromethanesulfonyl-a-D-galactopyranose (10) with TASF was complete i n less than 10 min at 0—20°C and afforded a 71% y i e l d of 6-deoxy-6-fluoro-1,2:3,4-di-0isopropylidene-a-D-galactopyranose (23)· In a similar manner, methyl 2,3-d i-0-benzyl-4,6-b i s-0-(trifluoromethanesulfony1)-β-Dglucopyranoside (11) reacted rapidly with TASF at reflux temperature to give a 39% y i e l d of methyl 2,3-di-0-benzyl-4,6dideoxy-4,6-difluoro-β-D-galactopyranoside (24); t h i s , however, was accompanied by the formation of a s l i g h t l y smaller amount of a lesspolar, unidentified compound. The selective introduction of f l u o r i n e into a furanose ring was demonstrated by the reaction of TASF with l,2:5,6-di-0isopropylidene-3-0-trifluoromethanesulfonyl-a-D-allofuranose (12) which gave a 66% y i e l d of 3-deoxy-3-fluoro-1,2:5,6-di-0isopropylidene-a-D-glucofuranose (£5)· The isomeric t r i f l a t e 13,

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

8

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY having the D-gluco configuration, reacted with TASF under the same conditions to give an 83% y i e l d of the elimination product, 3-deoxy-l,2:5,6-di-0-isopropylidene-q-D-erythro-hex-3-enofuranose (26), but no fluorine-containing product was detected. Very recently, there have been reports of the u t i l i t y of TASF for the synthesis of 2 -deoxy-2 -fluoroinosine (47) and of the β-6 ^luoro analog of (i)-aristeromycin (48). !

1

!

Synthesis of Glycosyl Fluorides The u t i l i t y of glycosyl fluorides i n enzymology (49—51) and as glycosylating agents (52—64) has stimulated interest i n t h e i r preparation and chemistry (2,52,65). The o r i g i n a l synthesis (66) of glycosyl fluorides employed the reaction of peracetylated aldoses with hydrogen f l u o r i d e . In addition, glycosyl fluorides have been obtained by treatment of an acylated glycosyl bromide or chloride with s i l v e r f l u o r i d e (67,68) or with s i l v e r tetrafluoroborate (69,70) f l u o r i d e (71). Two recentl 1-0-acetylated sugar derivatives with pyridinium poly(hydrogen f l u o r i d e ) (72) and treatment of phenyl 1-thioglycosides with diethylaminosulfur t r i f l u o r i d e (DAST) and N-bromosuccinimide (59). Also, glycosyl fluorides have been obtained by substitution of a free, anomeric hydroxyl group by f l u o r i n e using 2 - f l u o r o - l methylpyridinium tosylate (54), or d i e t h y l 1,1,2,3,3,3hexafluoropropylamine (56,73), or diethylaminosulfur t r i f l u o r i d e (74,75). We recently described (76) a method for the synthesis of glycosyl fluorides involving treatment of p a r t i a l l y protected monosaccharides, having the anomeric hydroxyl group underivatized, with pyridinium poly(hydrogen f l u o r i d e ) , a reagent introduced by Olah et a l . (77). Examples which i l l u s t r a t e the scope of the reaction are given i n Table I I . The u t i l i z a t i o n of Olah s reagent for the f l u o r i n a t i o n of carbohydrates at s i t e s other than the anomeric carbon f a i l e d i n a series of experiments with methyl hexopyranosides or t h e i r p a r t i a l l y protected derivatives (see Ref. 78). In the case of 2,3,5-tri-O-benzoyl-D-ribofuranose (27) pyridinium poly(hydrogen f l u o r i d e ) was added to a solution of 27 in anhydrous dichloromethane and the solution was shaken at room temperature for 10 h i n an atmosphere of dry argon. Anhydrous acetone was found to be equally e f f e c t i v e i n most reactions. The reaction of compound 28 with Olah s reagent required the use of anhydrous acetone or anhydrous dichloromethane—collidine [1:1 (v/v)]; i n the case of compound 30 the addition of c o l l i d i n e was disadvantageous, whereas i n the case of compound 31 best results were obtained using anhydrous a c e t o n e — c o l l i d i n e [1:1 (v/v)] as the solvent. Compounds 32 and 33 were treated using pyridinium poly(hydrogen f l u o r i d e ) as the only solvent. Reaction times varied from 2 h f o r compound 31 to more than 12 h f o r 32 and 33. The action of pyridinium poly(hydrogen f l u o r i d e ) on compounds 29—33 resembles that of anhydrous hydrogen f l u o r i d e on peracetylated D-glucopyranose (2,66), and of s i l v e r tetrafluoroborate i n d i e t h y l ether (when prolonged) on 1

1

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1.

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy Table I I .

Substrate

Synthesis of Glycosyl Product

Fluorides Yield

(%)

29

37 C o n t i n u e d on next page.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

9

10

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

Table I I . Substrate

Continued

Product

Yield (%)

CH 0Ac

CH 0Ac

2

2

53

OAc

38

Ch^OBn OBn

OH

BnO

82^

BnO OBn

31

CH 0Ac

CH 0Ac

2

2

69

AcO

32

CH 0Ac AcOl

F

40

2

Ad 62

33 1

- H-NMR d a t a

OAc indicated

that

t h e r a t i o o f a - and β-isomers was ^ 1 : 1 . 1

— A t r a c e o f t h e β-isomer was i n d i c a t e d by t h eH-NMR spectrum.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1.

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy

11

peracetylated α-D-glucopyranosyl chloride (69) i n that i t gives r i s e to the thermodynamically stable isomer. Moreover, with compounds 30, 32, and 33, Olah s reagent contrasts with both 2,4,6trimethylpyridinium f l u o r i d e (_71) and s i l v e r f l u o r i d e (68) i n affording the α-glycosyl f l u o r i d e from a p a r t i a l l y acetylated aldose regardless of whether the p a r t i c i p a t i n g group at C-2 i s c i s - or trans-related to the f l u o r i n e atom. 1

Reactions of N-Trimethylsilyl- or Ν-tert-ButyIdimethyIs i l y 1 phthalimide with Carbohydrate Derivatives N-Trimethylsilylphthalimide (42) (79) i s a poor donor of the t r i m e t h y l s i l y l group, and, hence, i t s application i n organic chemistry has been limited to only special cases (80,81^), not involving hydroxyl groups. However, we have found that 42 i n the presence of weak bases as catalysts provides a reagent system capable of performing selective t r i m e t h y l s i l y l a t i o n of primary hydroxyl groups. As catalysts triphenylphosphine, tri-n-butylphosphine methyldiphenylphosphine, and 4-N,N-dimethylaminopyridine are suitable; the use of triethylamine affords mono- and highertrimethyIs i l y l a t e d products. The s i l y l a t i o n reactions were performed by treatment of a solution of the substrate (1 mol. equiv.) i n oxolane [or a 4:1 (v/v) mixture of oxolane—dimethyl sulfoxide for substrates insoluble i n oxolane] with £2 (1.4—1.5 mol. equiv.) and triphenylphosphine (0.5 mol. equiv.). The structures of the substrates employed and of the products obtained, and y i e l d s , are shown i n Figure 1. Under the p a r t i c u l a r reaction conditions employed secondary hydroxyl groups are either not s i l y l a t e d or are s i l y l a t e d d i s t i n c t l y slower. Although a t r i m e t h y l s i l y l group blocking a primary hydroxyl group i s not very stable (82,83) and can be readily removed, f o r example, under acetylation conditions (84), nevertheless, we have been able to perform a s i g n i f i c a n t reaction at a secondary hydroxyl group leaving the (trimethyIsilyloxy)methy1 group intact. Thus, ethyl 2,3-dideoxy-q-D-erythro-hex-2-enopyranoside (48) reacted r e a d i l y with 42 and triphenylphosphine to afford £9 and phthalimide; t h i s mixture, on treatment i n s i t u with d i e t h y l azodicarboxylate, gave ethyl 2,3,4-trideoxy-4-phthalimido-6-0t r imethy Is i l y 1 - ot-D - thr eo -hex - 2 - enopyr anos ide (50) i n 71.4% o v e r a l l y i e l d (see Figure 2). A s a l i e n t feature of t h i s synthetic process i s that two of the reagents required i n the Mitsunobu amination (85) step, namely triphenylphosphine and phthalimide, are present already from the f i r s t step. The tert-butyldimethyIsily1 group i s known to be a p a r t i c u l a r l y useful blocking group, and Ogilvie and Hakimelahi (86) have described a method for the introduction of t h i s group s e l e c t i v e l y at primary hydroxyl groups. We have examined the u t i l i t y of N-tert-butyId imethyIs ilylphthalimide for t h i s purpose. Using conditions similar to those employed i n the case of Ntrimethylsilylphthalimide did not lead to the transfer of the tert-butyId imethyIs i l y 1 group; even heating at reflux temperature for several hours was not successful. I f the solvent system was

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

χ: -Ρ •Η

χ ω U I a: cr

ο

*5

OQ a* 2

Σ

(λ

5

u u ii a: cucc

II

II

II

Q: Q:

σ .ο ο

Ν — ο

ο

ΙΛ Σ U II

i j

Σ

J

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

φ «Μ Ό 0 •Η

4J υ χ: (0 φ ι Μ ιΗ >1 φ ιΗ χ : •Η -Ρ W ι—I u >1 0 χ: Μ-Ι Φ ΙΛ ε •Η υ Ό D rH Ό >1 0 4J u D eu χ ι Ό -Μ C

•Η 1-1 4-> 0 (0

4-> (Ω I XI ι Η >1 ιΗ •Η ω ιΗ >1 • XJ ι Η 4J Φ Φ ε Μ •Η D Μ CP -Ρ •Η I 21

fa

> •Η Μ Φ Ό Φ -Ρ to Ό

χ: 0 u to υ

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy

Et0 CN=NC0 Et 2

2

50 (71.4V.) Figure 2. Synthesis of ethyl 2,3,4-trideoxy-4-phthalimido6-0-trimethylsilyl-a-D-threo-hex-2-enopyranoside.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

14

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY changed to 4:1 (v/v) oxolane—hexamethylphosphoric triamide, then 43a and £4a at room temperature gave products having the primary hydroxyl group s i l y l a t e d i n 41 and 44% y i e l d , respectively, and 46a at reflux temperature gave the corresponding product i n 40% y i e l d . The non-carcinogenic solvent, 1,3-dimethyl-3,4,5,6tetrahydro-2(lH)-pyrimidinone (87), could not be employed as a substitute for hexamethylphosphoric triamide. Cleavage of Acetals and Dithioacetals i n Carbohydrate Derivatives Using Iodine i n Methanol The reagent system, iodine and methanol, has been reported (88,89) to open oxirane rings to afford β-methoxy alcohols. We have found (90) that t h i s reagent system i s a highly e f f i c i e n t one for the cleavage of acetal and d i t h i o a c e t a l groupings i n carbohydrate derivatives, groupings which find wide application i n synthetic carbohydrate chemistry (91,92) Benzylidine ethylidene and isopropylidene acetal by heating at reflux temperatur acetal groupings are present i n the molecule, one of them can be removed s e l e c t i v e l y . Simple glycosides and disaccharides do not undergo cleavage of their glycosidic linkages under the conditions employed. Also, acetyl groups survive the reaction conditions. However, i f the reaction mixture i s heated at reflux temperature for a prolonged period, carbohydrates having a free hydroxyl group at the anomeric center are converted into methyl glycosides. I t i s noteworthy that methyl glycofuranosides preponderate i n the mixtures of glycosides that are formed, a result that resembles that generally observed i n the case of the acid-catalyzed, Fischer glycoside synthesis (93). The results obtained using a variety of carbohydrate acetals are shown i n Table I I I . The o v e r a l l yields are usually high. Recently, we were able to cleave the isopropylidene acetal i n 6-chloro-9-(3-deoxy-5,6-0-isopropylideneq-D-threo-hexofuranosyl-2-ulose)purine and the β-D-erythro isomer by treatment with a d i l u t e solution of iodine i n methanol to afford the corresponding, parent 3 -deoxy-2 -ketonucleosides, i n each case i n 65% y i e l d ; these results are p a r t i c u l a r l y s i g n i f i c a n t , since both of the protected ketonucleoside derivatives were found to be l a b i l e under a c i d i c conditions normally required for the removal of an 0-isopropylidene group. 1

1

The acetal-cleavage reactions presumably involve i n i t i a l l y a complexation of an iodine species with one of the oxygen atoms; a subsequent reaction with methanol would lead to the free alcohols. On t h i s basis i t would be expected that dithioacetals should undergo f a c i l e cleavage, since the soft acid, iodine, would be expected to complex readily with the soft sulfur s i t e . Indeed, treatment of D-arabinose d i e t h y l d i t h i o a c e t a l with a 1% solution of iodine i n methanol afforded, after ^2 days at room temperature, methyl α-D-arabinofuranoside i n 70% y i e l d . Other examples of the removal of d i t h i o a c e t a l groupings under mild conditions are given in Table I I I . I t was found that cleavage of the d i t h i o a c e t a l grouping i n D-glucose ethylene d i t h i o a c e t a l required heating at reflux temperature; i t i s known that mercury(II) chloridecatalyzed hydrolysis of ethylene dithioacetals occurs slowly (94).

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1.

SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy

Table I I I .

Substrate

15

C l e a v a g e o f C a r b o h y d r a t e A c e t a l s and D i t h i o a c e t a l s U s i n g I o d i n e and Methanol Reaction Conditions-

Compounds Obtained

Overall Yield (%)

>90

C o n t i n u e d on next page

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

16

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY Table

III.

Continued

Reaction a Conditions-

Substrate

tMe /

MOCH2.O A 2

r

o

o

Overall Yield (%)

Compounds Obtained

,OMe CH OH

m

' temp, 14 h or r e f l u x , 7 h

HÇ

90—95

2

OH

3(α) :7(β) •CMe

2

35

A, H2OH HÔ Γ

CHjOH

H0CH?_.0 A, room temp, 14 h or r e f l u x , 6 h

,0Me HO

90

CH 0H 2

OH

H(^ ^CMe N

A 2

'

r

o

o

m

r

o

o

m

temp, 6 h

HOCHo^O HQJ j\

CMe? 1

A

' temp, 24 h or reflux, 6 h

HÇ

,0Me CH 0H 2

90

OH

A, room temp, 24 h or r e f l u x , 2.5 h

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

85—90

1. SZAREK

Deoxyfluoro Sugars and Protective-Group Strategy Table I I I .

ÇH(SEt)2 HÇOH HOÇH HÇOH HÇOH CH2OH

HÇOH HOÇH HÇOH HÇOH CH2OH

Continued

HO(jH

2

HOCH >-0 A, room temp, 32 h

74

A, r e f l u x , 18 h

90

ÇH(SCH Ph) HOÇH HOÇH A, room temp, 24 h HÇOH HÇOH CH^H 2

17

2

S o l u t i o n A: 1% i o d i n e i n methanol i n methanol (w/v).

HO_

Me (w/v); s o l u t i o n B: 0.5% i o d i n e

- I s o l a t e d as the p e r - O - a c e t y l a t e d d e r i v a t i v e .

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

18

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY Developments i n protective-group strategy, including the formation and cleavage of acetals, continue to be of interest i n synthetic carbohydrate chemistry (95,96). The attractiveness of the reagent system described here stems from i t s s i m p l i c i t y , convenience, v e r s a t i l i t y , and the high yields of the cleavage products. Acknowledgments I t i s a pleasure to acknowledge the f i n a n c i a l support of the Natural Sciences and Engineering Research Council of Canada and the Medical Research Council of Canada, and the dedicated e f f o r t s of the following participants i n the research: Dr. Bogdan Doboszewski, Dr. Grzegorz Grynkiewicz, Professor George W. Hay, Dr. Edward R. Ison, Dr. Ramesh K. Sood, Dr. Kamal N. Tiwari, and Professor Aleksander Zamojski.

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

11. 12. 13. 14. 15.

Kent, P.W. In Carbon—Fluorine Compounds. Chemistry, Biochemistry and Biological Activities; Ciba Found. Symp.; Elsevier: Amsterdam, 1972; pp 169—213. Penglis, A.A.E. Adv. Carbohydr. Chem. Biochem. 1981, 38, 195—285. Taylor, N.F. In Carbon—Fluorine Compounds. Chemistry, Biochemistry and Biological Activities; Ciba Found. Symp.; Elsevier: Amsterdam, 1972; pp 215—238. Schwartz, R.T.; Datema, R. Trends Biochem. Sci. 1980, 5, 65—67. Schwartz, R.T.; Datema, R. Adv. Carbohydr. Chem. Biochem. 1982, 40, 287—379. De Kleijn, J.P. J. Fluorine Chem. 1977, 10, 341—350. Fowler, J.S.; Wolf, A.P. Brookhaven National Laboratory, Report 1981 BNL 31222 (U.S. Department of Energy Order. No. DE82012799). Ido, T.; Wan, C.-N.; Fowler, J.S.; Wolf, A.P. J. Org. Chem. 1977, 42, 2341—2342. Ido, T.; Wan, C.-N.; Casella, V.; Fowler, J.S.; Wolf, A.P.; Reivich, M.; Kuhl, D.E. J. Labelled Compd. Radiopharm. 1978, 14, 175—183. Takahashi, T.; Ido, T.; Shinohara, M.; Iwata, R.; Fukuda, H.; Matsuzawa, T.; Tada, M.; Orui, H. J. Labelled Compd. Radiopharm. 1984, 21, 1215—1217, and references cited therein. Bida, G.T.; Satyamurthy, N.; Barrio, J.R. J. Nucl. Med. 1984, 25, 1327—1334. Korytnyk, W.; Valentekovic-Horvat, S. Tetrahedron Lett. 1980, 21, 1493—1496. Shiue, C.-Y.; To, K.C.; Wolf, A.P. J. Labelled Compd. Radiopharm. 1983, 20, 157—162. Sood, S.; Firnau, G.; Garnett, E.S. Int. J. Appl. Radiat. Isot. 1983, 34, 743—745. Shiue, C.-Y.; Salvadori, P.A.; Wolf, A.P.; Fowler, J.S.; MacGregor, R.R. J. Nucl. Med. 1982, 23, 899—903.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1. SZAREK Deoxyfluoro Sugars and Protective-Group Strategy 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

19

Adam, M.J. J. Chem. Soc., Chem. Commun. 1982, 730—731. Adam, M.J.; Ruth, T . J . ; Jivan, S.; Pate, B.D. Int. J. Appl. Radiat. Isot. 1984, 35, 985—986. Diksic, M.; Jolly, D. Int. J. Appl. Radiat. Isot. 1983, 34, 893—896. Ehrenkaufer, R.E.; Potocki, J.F.; Jewett, D.M. J. Nucl. Med. 1984, 25, 333—337. Van Rijn, C.J.S.; Herscheid, J.D.M.; Visser, G.W.M.; Hoekstra, A. Int. J. Appl. Radiat. Isot. 1985, 36, 111—115. Straatmann, M.G.; Welch, M.J. J. Labelled Compd. Radiopharm. 1977, 13, 210. Card, P.J.; Reddy, G.S. J. Org. Chem. 1983, 48, 4734—4743. Somawardhana, C.W.; Brunngraber, E.G. Carbohydr. Res. 1983, 121, 51—60, and references cited therein. Pacák, J.; Točík, Z.; Cerný, M. Chem. Commun. 1969, 77. Barford, A.D.; Foster A.B.; Westwood J.H.; Hall L.D.; Johnson, R.N. Carbohydr Beeley, Ρ.Α.; Szarek J. Chem. 1984, 62, 2709—2711. Szarek, W.A.; Hay, G.W.; Doboszewski, B.; Perlmutter, M.M. Carbohydr. Res. 1986, 155, 107—118. Christman, D.R.; Orhanovic, Z.; Wolf, A.P. J. Labelled Compd. Radiopharm. 1977, 13, 283. Levy, S.; Elmaleh, D.R.; Livni, E. J. Nucl. Med. 1982, 23, 918—922. Olesker, Α.; Dessinges, Α.; Thang, T.T.; Lukacs, G. C.R. Acad. Sci. Ser. 2 1982, 295, 575—577. Tewson, T.J. J. Org. Chem. 1983, 48, 3507—3510. Dessinges, Α.; Olesker, Α.; Lukacs, G.; Thang, T.T. Carbohydr. Res. 1984, 126, C6—C8. Haradihara, T.; Maeda, M.; Yano, Y.; Kojima, M. Chem. Pharm. Bull. 1984, 32, 3317—3319. Haradihara, T.; Maeda, M.; Omae, M.; Yano, Y.; Kojima, M. Chem. Pharm. Bull. 1984, 32, 4758—4766. Haradihara, T.; Maeda, M.; Kai, Y.; Omae, H.; Kojima, M. Chem. Pharm. Bull. 1985, 33, 165—172. Szarek, W.A.; Hay, G.W.; Doboszewski, Β. J. Chem. Soc., Chem. Commun. 1985, 663—664. Doboszewski, Β.; Hay, G.W.; Szarek, W.A. Can. J. Chem. 1987, 65, 412—419. Middleton, W.J. U.S. Patent 3 940 402, 1976. Card, P.J.; Hitz, W.D. J. Am. Chem. Soc. 1984, 106, 5348—5350. Binkley,, R.W.; Ambrose, M.G.; Hehemann, D.G. J. Org. Chem. 1980, 45, 4387—4391. Binkley,, R.W.; Ambrose, M.G. J. Carbohydr. Chem. 1984, 3, 1—49. Su, T.L.; Klein, R.S.; Fox, J.J. J. Org. Chem. 1981, 46, 1790—1792. Richardson, A.C. Carbohydr. Res. 1969, 10, 395—402. Miljković, M.; Gligorijević, M.; Glišin, D. J. Org. Chem. 1974, 39, 3223—3226.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

20 TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72.

Stevens, C.L.; Taylor, K.G.; Valicenti, J.A. J. Am. Chem. Soc. 1965, 87, 4579—4584. Szarek, W.A. Adv. Carbohydr. Chem. Biochem. 1973, 28, 225—306. Pankiewicz, K.W.; Nawrot, B.; Watanabe, K.A. Abstr. Pap. 193rd ACS Natl. Meeting, Denver, April 5—10, 1987, Carb-14. Madhavan, G.V.B.; Prisbe, E.J.; Verheyden, J.P.H.; Martin, J.C. Abstr. Pap. 193rd ACS Natl. Meeting, Denver, April 5—10, 1987, Carb-11. Barnett, J.E.G.; Jarvis, W.T.S.; Munday, K.A. Biochem. J. 1967, 105, 669—704. Ariki, M.; Fukui, T. J. Biochem. (Tokyo) 1975, 788, 1191—1199. Palm, D.; Blumenauer, G.; Klein, H.W.; Blanc-Muesser, M. Biochem. Biophys. Res. Commun. 1983, 111, 530—536. Micheel, F.; Klemer, A. Adv. Carbohydr. Chem. 1961, 16, 85—103. Mukaiyama, T.; 431—432. Mukaiyama, T.; Hashimoto, Y.; Shoda, S. Chem. Lett. 1983, 935—938. Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984, 25, 1379—1382. Araki, Y.; Watanabe, K.; Kuan, F.-H; Itoh, K.; Kobayashi, N.; Ishido, Y. Carbohydr. Res. 1984, 127, C5—C9. Nicolaou, K.C.; Dolle, R.E.; Chucholowski, Α.; Randall, J.L. J.. Chem. Soc., Chem. Commun. 1984, 1153—1154. Nicolaou, K.C.; Chucholowski, Α.; Dolle, R.E.; Randall, J.L. J. Chem. Soc., Chem. Commun. 1984, 1155—1156. Nicolaou, K.C.; Dolle, R.E.; Papahatjis, D.P.; Randall, J.L. J. Am. Chem. Soc. 1984, 106, 4189—4192. Voznyi, Ya. V.; Kalicheva, I.S.; Galoyan, A.A. Bioorg. Khim. 1984, 10, 1256—1259; Chem. Abstr. 1985, 102, 95930q. Dolle, R.E.; Nicolaou, K.C. J. Am. Chem. Soc. 1985, 107, 1695—1698. Nicolaou, K.C.; Randall, J.L.; Furst, G.T. J. Am. Chem. Soc. 1985, 107, 5556—5558. Kunz, H.; Sager, W. Helv. Chim. Acta 1985, 68, 283—287. Voznyi, Ya. V.; Galoyan, Α.Α.; Chizhov, O.S. Bioorg. Khim. 1985, 11, 276—278; Chem. Abstr. 1985, 102, 167047q. Paulsen, H. Adv. Carbohydr. Chem. Biochem. 1971, 26, 127—195. Brauns, D.H. J. Am. Chem. Soc. 1923, 45, 833—835. Helferich, B.; Gootz, R. Ber. 1929, 62, 2505—2507. Hall, L.D.; Manville, J.F.; Bhacca, N.S. Can. J. Chem. 1969, 47, 1—17. Igarashi, K.; Honma, T.; Irisawa, J. Carbohydr. Res. 1969, 11, 577—578. Igarashi, K.; Honma, T.; Irisawa, J. Carbohydr. Res. 1970, 13, 49—55. Voznyi, Ya. V.; Kalicheva, I.S.; Galoyan, A.A. Bioorg. Khim. 1981, 7, 406—409; Chem. Abstr. 1981, 95, 43491q. Hayashi, M.; Hashimoto, S.; Noyori, R. Chem. Lett. 1984, 1747—1750.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

1. SZAREK Deoxyfluoro Sugars and Protective-Group Strategy 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.

21

Takaoka, Α.; Iwakiri, H.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1979, 52, 3377—3380. Rosenbrook, W., Jr.; Riley, D.A.; Lartey, P.A. Tetrahedron Lett. 1985, 26, 3—4. Posner, G.H.; Haines, S.R. Tetrahedron Lett. 1985, 26, 5—8. Szarek, W.A.; Grynkiewicz, G.; Doboszewski, B.; Hay, G.W. Chem. Lett. 1984, 1751—1754. Olah, G.A.; Welch, J.T.; Vankar, Y.D.; Nojima, M.; Kerekes, I.; Olah, J.A. J. Org. Chem. 1979, 44, 3872—3881. Olah, G.A.; Welch, J. Synthesis 1974, 653—654. Janzen, A.F.; Kramer, E.A. Can. J. Chem. 1971, 49, 1011—1018. Dickopp, H. Ph.D. Thesis, University of Cologne, 1966; cited in: Pierce, A.E. Silylation of Organic Compounds; Pierce Chem. Co.: Rockford, 1968; p 23. Kozyukov, V.P.; Kozyukov, V.P.; Mironov, V.F. Zh. Obshch. Khim. 1983, 53, 2091—2097; Chem Abstr 1984 100 22696s Hurst, D.T.; McInnes 2004—2011. Hengstenberg, W.; Morse, M.L. Carbohydr. Res. 1968, 7, 180—183. Fuchs, E.-F.; Lehmann, J. Chem. Ber. 1974, 107, 721—724. Mitsunobu,, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94, 679—680. Ogilvie, K.K.; Hakimelahi, G.H. Carbohydr. Res. 1983, 115, 234—239. Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385—391. Jewell, J.S.; Szarek, W.A. Carbohydr. Res. 1971, 16, 248—250. Kocór, M.; Kurek, Α.; Tomaszewska, L. Abstr. Pap. 11th IUPAC Int. Symp. Chem. Nat. Prod., Golden Sands, Bulgaria, 1978, 2, 136—138; Chem. Abstr. 1979, 91, 211651e. Szarek, W.A.; Zamojski, Α.; Tiwari, K.N.; Ison, E.R. Tetrahedron Lett. 1986, 27, 3827—3830. De Belder, A.N. Adv. Carbohydr. Chem. Biochem. 1977, 34, 179—242. Wander, J.D.; Horton, D. Adv. Carbohydr. Chem. Biochem. 1976, 32, 15—124. Capon, B. Chem. Rev. 1969, 69, 407—498. Zimmer, H.; Brandner, H.; Rembarz, G. Chem. Ber. 1956, 89, 800—813. Guindon, Y.; Yoakim, C.; Morton, H.E. J. Org. Chem. 1984, 49, 3912—3919, and references cited therein. Albert, R.; Dax, K.; Pleschko, R.; Stütz, A.E. Carbohydr. Res. 1985, 137, 282—290.

RECEIVED May 31, 1988

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Chapter 2

New Approaches to the Synthesis of Nitrogenous and Deoxy Sugars and Cyclitols Hans H. Baer Department of Chemistry, University of Ottawa, Ottawa, Ontario K1N 9B4 Canada

Chiral syntheses based on nitroalkane cyclization, of 3amino-2,3-dideoxy-D-myo- and D-epi-inositol and of some asymmetrically substituted derivatives and preparative precursors of 2-deoxystreptamine are reported. A new mode of formation of carbohydrate nitrocyclopropane derivatives by an internal, cyclizing displacement is disclosed, with a discussion of the potential of such compounds in chiral synthesis. Methods for the preparation of amino and deoxy analogs of α,α-trehalose are outlined, including nitro­ methane cyclization, oxyamination, selective triflate dis­ placement, reductive anination and desulfonyloxylation, palladium-catalyzed allylic substitution, and iron carbonyl­ -mediated chain elongation. Ongoing c o n c e r n s i n t h i s l a b o r a t o r y i n c l u d e t h e study o f methods f o r f u n c t i o n a l and s t e r e o c h e m i c a l m o d i f i c a t i o n o f c a r b o h y d r a t e s , t h e adaptation o f s y n t h e t i c t o o l s l a r g e l y developed o u t s i d e the f i e l d t o the s p e c i a l r e q u i r e m e n t s i n c a r b o h y d r a t e c h e m i s t r y , and t h e s y n t h e s i s of sugar d e r i v a t i v e s o f p o t e n t i a l value i n b i o c h e m i c a l r e s e a r c h . F o r t h e advancement o f b i o l o g i c a l and m e d i c i n a l r e s e a r c h t h e r e i s a need not o n l y f o r e f f i c i e n t s y n t h e s e s o f n a t u r a l p r o d u c t s o f r e c o g n i z e d s i g n i f i c a n c e , but a l s o f o r a steady supply o f s y n t h e t i c d e r i v a t i v e s , s t e r e o i s o m e r s and o t h e r a n a l o g s which may, p o t e n t i a l l y , d i s p l a y b i o a c t i v i t i e s o f t h e i r own o r may s e r v e a s p r o b e s f o r u n r a v e l i n g mecha­ nisms o f b i o l o g i c a l a c t i o n . A m i n o c y c l i t o l s , because o f t h e i r c e n t r a l standing i n the f i e l d o f a n t i b i o t i c s , c o n s t i t u t e a p a r t i c u l a r l y i m p o r t a n t case i n p o i n t . The p r e s e n t a r t i c l e d e s c r i b e s (a) c h i r a l s y n t h e s e s o f m o l e c u l e s r e l a t e d t o 2 - d e o x y s t r e p t a m i n e , a p i v o t a l com­ ponent o f a m i n o c y c l i t o l a n t i b i o t i c s ; (b) d i s c l o s e s a new, p r e p a r a t i v e route t o carbohydrate nitrocyclopropane d e r i v a t i v e s having p o t e n t i a l f o r c o n v e r s i o n i n t o v a r i o u s c h i r a l , b r a n c h e d - c h a i n s y n t h o n s ; and (c) o u t l i n e s s e v e r a l c u r r e n t methods b e i n g d e v e l o p e d f o r t h e s y n t h e s i s o f amino and deoxy a n a l o g s o f t h e b i o l o g i c a l l y i m p o r t a n t d i s a c c h a r i d e , o< eC-trehalose. f

c

0097-6156/89/0386-0022$06.50/0 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

2. BAER

Nitrogenous and Deoxy Sugars and Cyclitols

Chemical Synthesis streptamine

o f an I n t e r m e d i a t e

i n t h e B i o s y n t h e s i s o f 2-Deoxy-

2-Deoxystreptamine (^1) i s a c e n t r a l b u i l d i n g b l o c k i n t h e s t r u c t u r e s o f many i m p o r t a n t a m i n o c y c l i t o l a n t i b i o t i c s , i n c l u d i n g t h e neomycins, kanamycins, and g e n t a m i c i n s ( 1 ) . The pathway f o r i t s b i o s y n t h e s i s from g - g l u c o s e has been p r o p o s e d by R i n e h a r t (2^3) t o i n v o l v e an aminoc y c l o h e x a n e t e t r o l , most p r o b a b l y 1 L - ( 1 , 3 , 5 / 2 , 4 ) - 5 - a m i n o - l , 2 , 3 , 4 - c y c l o h e x a n e t e t r o l , a l s o d e s i g n a t e d as 3 - a m i n o - 2 , 3 - d i d e o x y - D - m y o - i n o s i t o l ( 2 ) , which was t h e n unknown. T h i s assumption was s u b s e q u e n t l y p r o v e d c o r r e c t when 2 was i s o l a t e d from c u l t u r e media o f c e r t a i n m i c r o o r g a n isms (4), i t s s t r u c t u r e c o n f i r m e d t h r o u g h comparison w i t h a s e m i s y n t h e t i c sample o b t a i n e d from d e g r a d a t i o n o f c h e m i c a l l y m o d i f i e d kanamycin-A ( 5 ) , and i t s b i o c o n v e r s i o n i n t o ^1 d e m o n s t r a t e d ( 6 ) .

2

R = OH

C o n v e n i e n t p r e p a r a t i v e a c c e s s t o such c h i r a l a m i n o c y c l i t o l s as j2 s h o u l d f a c i l i t a t e c h e m i c a l a n a l o g s y n t h e s i s and b i o c h e m i c a l mutas y n t h e s i s i n t h e f i e l d o f a m i n o c y c l i t o l a n t i b i o t i c s , A s h o r t and e c o n o m i c a l s y n t h e s i s o f 2 and i t s h i t h e r t o unknown 1L-(1,3,4,5/2), o r D - e p i , s t e r e o i s o m e r £ was t h e r e f o r e d e v i s e d ( 7 ) . I t i s based on t h e n i t r o a l k a n e c y c l i z a t i o n method ( 8 ) , and i s d e l i n e a t e d i n F i g u r e 1. The n i t r o s u g a r 4, a v a i l a b l e (£,10) from D - g l u c o s e i n f o u r s t e p s w i t h h i g h y i e l d s , g i v e s i n a s i n g l e o p e r a t i o n (AC2O—NaOAc; 84%) t h e n i t r o a l k e n i c a c e t a t e 2> i n t e r m e d i a r y d i a c e t a t e 5 (10). R e d u c t i o n o f 2 kv sodium b o r o h y d r i d e had been r e p o r t e d (11) t o f u r n i s h t h e n i t r o a l k a n o l 9 d i r e c t l y , b u t o n l y i n 49% y i e l d , on a s m a l l s c a l e . S c a l e d - u p o p e r a t i o n under c a r e f u l l y c o n t r o l l e d c o n d i t i o n s , w i t h i s o l a t i o n o f t h e i n t e r m e d i a t e 8, now gave 9 i n 92% y i e l d from^7. V a r i o u s a t t e m p t s t o p r e p a r e 9 d i r e c t l y from t h e 3 , 5 - d i a c e t a t e 5, by r e d u c t i v e d e h y d r o a c e t o x y l a t i o n and O - d e a c e t y l a t i o n w i t h sodium b o r o h y d r i d e , p r o v e d u n s a t i s f a c t o r y . The same was t r u e when t h e 3 , 5 - b i s ( t r i f l u o r o a c e t a t e ) Jo was used i n s t e a d ; a l t h o u g h some 9 c o u l d be i s o l a t e d , a major (and u n d e s i r e d ) b y - p r o d u c t was i n t h i s c a s e i d e n t i f i e d a s t h e t r i f l u o r o e t h y l i d e n e a c e t a l 11. v

i

a

t

n

e

H y d r o l y t i c removal o f t h e i s o p r o p y l i d e n e group i n 9 then gave 5,6-dideoxy-6-nitro-g-glucose (10, n o t i s o l a t e d ) , which was c a u s e d t o c y c l i z e i m m e d i a t e l y by r e n d e r i n g i t s aqueous s o l u t i o n s l i g h t l y b a s i c . The m i x t u r e o f 4 - e p i m e r i c , 2 , 3 - d i d e o x y - 3 - n i t r o i n o s i t o l s (12) c o u l d n o t be s e p a r a t e d b u t t h e i r t e t r a a c e t a t e s 1 J and 14 c o u l d be i s o l a t e d p u r e by 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 (29 and 2 3 % ) . S t a n d a r d , c a t a l y t i c hydrogénation f o l l o w e d by d e a c e t y l a t i o n p r o c e d u r e s f i n a l l y f u r n i s h e d the t a r g e t compounds £ and ^3 v i a t h e i r a c e t y l a t e d d e r i v a t i v e s 15-18· Hydrogénation o f t h e m i x t u r e 12, f o l l o w e d by s e q u e n t i a l N- and 0a c e t y l a t i o n o f t h e amines p r o d u c e d , p r o v e d t o be more e c o n o m i c a l f o r l a r g e r - s c a l e preparations. This permitted clean separation o f the e p i m e r s by v i r t u e o f a h i g h t e n d e n c y f o r 18 and 15 to c r y s t a l l i z e .

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

23

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

CH N0 2

CH N0

CHNOp II CH

2

2

CH M0 z

2

2

2

o-c a

λ

i R = H R = Ac 6 R = C0CF

2

Me

ο-ανΐθ

CH2,

CH ,

o-CMe^

7 R = Ac

5

£ R = Ac ^ 9 R = Η — ^ ( 7 R = COCF3) - < a

3

OH

2

AG*

2

^CH

~100%

HO a. b. c. d. e. f. g. h. i.

NaBH -EtOH -25° K C0 -MeOH 22° Ο.025 M H S 0 1 0 0 Ba(OH)~, pH 8.5-8.9 A c 0 - B F , 0-25° Fractional cryst. H -Pt NaQMe-MeOH Ba(OH) ,98° 4

2

11

/

3

H O - ^ ^ ^ ^ O H

f

o

2

2

4 #

3

2

2

AcO

AcO AcO'T"

Μτ^κOAc

A c O ^ ^ - ^ ^ O A c iNOo AcO

NOj> 13 |g,h,i

14

g,h,i

RO

NHR

D-myo

15 R = R'= Ac 16 R = Ac,R'= Η 2 R = R'= Η

17 R = R'= Ac 18 R = Ac,R'= Η ^ R = R'= Η

Figure 1. Synthesis of 3-amino-2,3-dideoxy-D-myo- and D-epi-inositols (2 and 3).

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

2. BAER

Nitrogenous and Deoxy Sugars and Cyclitols

25

A C h i r a l S y n t h e s i s o f 2-Deoxystreptamine A l t h o u g h 2-deoxystreptamine (1) i s i t s e l f a c h i r a l (meso), i t i s r e n ­ d e r e d c h i r a l by m o n o s u b s t i t u t i o n a t e i t h e r o f the e n a n t i o t o p i c OH-4 or OH-6 groups, o r a t e i t h e r amino g r o u p , o r by unequal d i s u b s t i t u t i o n a t t h e s e s i t e s . Such p a t t e r n s a r e t y p i c a l f o r a m i n o c y c l i t o l a n t i b i o t i c s . F o r i n s t a n c e , the neomycins and r i b o s t a m y c i n s p o s s e s s a g l y c o s y l a t e d OH-4 (and OH-5) group, whereas OH-6 i s u n s u b s t i t u t e d ; i n the s e l d o m y c i n s , kanamycins, and g e n t a m i c i n s , both e n a n t i o t o p i c p o s i ­ t i o n s a r e o c c u p i e d b u t u n e q u a l l y so. The s t e r e o i s o m e r s destomycin A and hygromycin Β d i f f e r s o l e l y by b e i n g N-monomethylated i n p o s i t i o n s 1 and 3, r e s p e c t i v e l y . T o t a l s y n t h e s e s t h a t employ, as b u i l d i n g b l o c k s , u n s y m m e t r i c a l l y m o d i f i e d but r a c e m i c d e r i v a t i v e s o f 1, must r e l y on d i a s t e r e o s e l e c t i v i t i e s which may be modest, and on d i a s t e r e o m e r s e p a ­ r a t i o n a t an advanced s t a g e , which may be cumbersome and i n e f f i c i e n t . I t would c l e a r l y be advantageous t o have a v a i l a b l e , as s y n t h o n s , some c h i r a l d e r i v a t i v e s o f 1, (or s u i t a b l e , p r e p a r a t i v e p r e c u r s o r s ) i n p u r e e n a n t i o m e r i c form t o 1, was t h e r e f o r e d e s i g n e d e n t i r e l y t h r o u g h c h i r a l s t a g e s , t h e r e b y p r o v i d i n g a number o f o p t i c a l l y a c t i v e i n t e r m e d i a t e s o f t h e t y p e d e s i r e d ( F i g u r e s 2-4) (12). The known l - d e o x y - l - n i t r o - D - g l y c e r o - D - g a l a c t o - h e p t i t o l hexaa c e t a t e (19), o b t a i n e d from g-mannose by the n i t r o m e t h a n e method (13), was r e d u c t i v e l y d e h y d r o a c e t o x y l a t e d , and t h e p r o d u c t (20) Od e a c e t y l a t e d . The r e s u l t a n t d i d e o x y n i t r o p e n t o l 21 was a c e t o n a t e d under thermodynamic c o n t r o l t o g i v e , e x c l u s i v e l y , t h e 4 , 5 ; 6 , 7 - d i i s o p r o p y l i d e n e a c e t a l 22. The l a t t e r i s t h e f a v o r e d r e g i o i s o m e r as i t i n c o r p o r a t e s a t r a n s - d i s u b s t i t u t e d d i o x o l a n e s t r u c t u r e . The m e s y l a t e 23 and t r i f l a t e 24 then p r e p a r e d were the k e y s t o n e s f o r l a t e r i n t r o ­ d u c t i o n o f a second n i t r o g e n o u s f u n c t i o n ( F i g u r e 2 ) . From t h i s p o i n t onward, two a l t e r n a t i v e r o u t e s l e a d i n g t o t h e same t a r g e t s were p u r s u e d . They d i f f e r e d i n the sequence whereby t h e c a r b o c y c l i c system was e s t a b l i s h e d and t h e second n i t r o g e n group i n ­ c o r p o r a t e d . In t h e f i r s t v a r i a n t ( F i g u r e 3 ) , compound 23 was s e l e c ­ t i v e l y d e a c e t o n a t e d w i t h 90% t r i f l u o r o a c e t i c a c i d i n t o l u e n e a t -20° t o f u r n i s h t h e 6 , 7 - d i o l j£5, w h i c h was c l e a v e d by p e r i o d a t e t o g i v e the s u b s t i t u t e d , 5,6-dideoxy~6-nitro-aldehydo-Q-arabino-hexose 26. B a s e - c a t a l y z e d c y c l i z a t i o n o f t h i s n i t r o sugar l e d t o a s e p a r a b l e m i x t u r e o f e p i m e r i c c y c l i t o l s , 27 and £ 8 , w i t h t h e l a t t e r s l i g h t l y p r e p o n d e r a t i n g . When the m i x t u r e was f r a c t i o n a l l y c r y s t a l l i z e d from e t h a n o l i n the p r e s e n c e o f a t r a c e o f a l k a l i , p a r t o f t h e l e s s s t a b l e (and more s o l u b l e ) 27 p r e s e n t was c o n v e r t e d i n t o t h e d e s i r e d , l e s s s o l u b l e epimer 28, which c r y s t a l l i z e d i n 70% y i e l d . Compounds £1 and 28 were r e a d i l y h y d r o l y z e d t o t h e r e s p e c t i v e t r i o l s ^0 and £ 2 , c h a r ­ a c t e r i z e d as h i g h l y c r y s t a l l i n e t r i a c e t a t e s (31 and 33). Next, b o t h 28 and i t s progeny 32 were s u b j e c t e d t o d i s p l a c e m e n t r e a c t i o n s w i t h a z i d e i o n , which gave h i g h y i e l d s o f a z i d o n i t r o c y c l i t o l s . However, b o t h p r o d u c t s had l o s t t h e i r s t e r e o c h e m i c a l i n t e g r i t y , as p a r t i a l e p i m e r i z a t i o n a t t h e c a r b i n o l p o s i t i o n v i c i n a l t o the n i t r o qroup o c c u r r e d d u r i n g t h e p r o c e s s , v i t i a t i n g t h e p r e c e d i n g epimer s e p a r a ­ t i o n . N e v e r t h e l e s s , pure t r i o l 34 was i s o l a t e d i n 72% y i e l d , and p u r i f i c a t i o n o f the i s o p r o p y l i d e n e d e r i v a t i v e 29 was a l s o p o s s i b l e (see l a t e r ) . In t h e second approach, t h e sequence o f r i n g c l o s u r e and a z i d e

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

26

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

CHoNOo

CH N0 2

I

CH

HCOAc I AcOCH

2

2

I ROCH

I

I

NaBH.—MeCN

AcOCH I HCOAc I HCOAc I

Me C(OMe) 2

ROCH

0°; 85%

Me C0, H+

a/

2

1

25"; 81%

I

HCOR I HCOR

I

CH OR 2

CH 0Ac 2

=

22 R H 23 R = Ms (76%) 24 R = Tf (>67%)

NaOMefSS * = Ac 80% U21 R = H

19

Figure 2. Synthesi

CH N0 I 2

CH

23

CH N0 I CH I MsOCH NaQMe I „OCH Me0H,25° M e C — h HCO I CHO 2

2

2

2

2

2

2

IY180CH 90% TFA I • OCH PhMe,-20ft C ^ - h HCO I HCOH 25 CI H O H

2

e

26

2

OMs 0

2

0 N^^\

N ^ \ ^ \

H

^

OMs

0 N^\

Z

Z

O—CMe*

28

t

OMs

- ^ W - A

X ^ ^ O R

0

2

3

z

29 (+ epimer) epimer 29

OMs

W ^ ^ ^ - ^ A

R o \ ^ N ^

LiN O

R

3 >

0 Ι\Κ^· ^ r - N a 2

H 0 \ ^ ^ HO

RO

20 R = Η 31 R = Ac

N

00 —— C CM f e

O—CMej.

27

•

^ T

32 R = Η 33 R = Ac

34 (+ epimer)

Figure 3. Synthesis of azidonitrocyclitols 29 and 34.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

0

H

2. BAER

Nitrogenous and Deoxy Sugars and Cyclitols

27

d i s p l a c e m e n t were r e v e r s e d ( F i g u r e 4). F i r s t e x p e r i m e n t s t o d i s p l a c e the mesyloxy group i n 23 under c o n v e n t i o n a l c o n d i t i o n s gave the p r o t e c t e d a z i d o n i t r o h e p t a n e t e t r o l 35 i n low y i e l d s o n l y , as an unexpect e d s i d e - r e a c t i o n i n t e r v e n e d (to be d i s c u s s e d i n t h e next s e c t i o n ) . A l t h o u g h p a s e - t r a n s f e r c o n d i t i o n s were e v e n t u a l l y found t h a t p r o d u c e d 35 from 23 i n 76% y i e l d , the r e a c t i o n was i n o r d i n a t e l y slow (6 days a t 56°). The 3 - t r i f l a t e 24, on the o t h e r hand, p r o v e d f a r s u p e r i o r i n t h a t r e g a r d , a f f o r d i n g 35 (> 85%) w i t h i n 6 h a t 25°. S e l e c t i v e 6,7d e a c e t o n a t i o n , f o l l o w e d by p e r i o d a t e o x i d a t i o n o f the d i o l 36, gave the a l d e h y d o - a z i d o n i t r o h e x o s e 37, which was c y c l i z e d by base c a t a l y s i s t o p r o v i d e a m i x t u r e o f 29 and epimer £8. A g a i n , 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 under e p i m e r i z i n g c o n d i t i o n s (as f o r 21 + 28) a l l o w e d the l e s s - s o l u b l e 29 t o be i s o l a t e d i n ~ 7 0 % y i e l d . F i n a l l y , p l a t i n u m c a t a l y z e d hydrogénation c o n v e r t e d the t r i o l £4 i n t o 2-deoxystreptamine (1), and the a c e t a l 29 i n t o t h e o p t i c a l l y a c t i v e 4 , 5 - 0 - i s o p r o p y l i d e n e d e r i v a t i v e (39) o f 1, i s o l a t e d as the c r y s t a l l i n e d i a c e t a m i d e £0. Compounds 29, 34, 39 d 40 c o n s t i t u t c h i r a l synthon suitabl f o r use i n s t e r e o s p e c i f i appropriately N-protecte s t e r e o s p e c i f i c s u b s t i t u t i o n a t OH-6; a l t e r n a t i v e l y , a f t e r temporary p r o t e c t i o n o f OH-6 f o l l o w e d by removal o f the a c e t a l , the m o l e c u l e s h o u l d be amenable t o m a n i p u l a t i o n a t OH-4. In £9 and JJ4, the two unequal n i t r o g e n o u s f u n c t i o n s may be r e d u c e d s t e p w i s e t o amino g r o u p s , t h u s o f f e r i n g p o s s i b i l i t i e s f o r s t e r e o s p e c i f i c i n t r o d u c t i o n o f an Ns u b s t i t u e n t a t e i t h e r p o s i t i o n . In o r d e r t o demonstrate t h a t s u c h a s t r a t e g y i s f e a s i b l e , r e a c t i o n sequences l e a d i n g t o the e n a n t i o m e r s o f mono-N-methyl-2-deoxystreptamine were p e r f o r m e d , as i l l u s t r a t e d i n F i g u r e 5. F o r m a t i o n and

P o t e n t i a l U t i l i t y of Carbohydrate

Nitrocyclopropanes_

As mentioned i n t h e f o r e g o i n g s e c t i o n , an unexpected s i d e - r e a c t i o n was o b s e r v e d when v a r i o u s c o n d i t i o n s f o r a z i d e d i s p l a c e m e n t i n the m e s y l a t e 23 were s t u d i e d . Homogeneous-phase r e a c t i o n w i t h t e t r a b u t y l ammonium a z i d e i n b o i l i n g t o l u e n e consumed c o m p l e t e l y w i t h i n 1 h, but gave o n l y 46% o f 35. Three b y p r o d u c t s , i s o l a t e d i n y i e l d s o f 25, 4.5 and 3%, were e l u c i d a t e d (14) as the 1-epimeric n i t r o c y c l o p r o p a n e s 41 and 42, and the b r a n c h e d - c h a i n a z i d o n i t r o compound £3 ( F i g u r e 6). E v i d e n t l y , 41 and 42 a r o s e from i n t e r n a l d i s p l a c e m e n t i n i t i a t e d by p r o t o n a b s t r a c t i o n from the n i t r o m e t h y l e n e group, c a u s e d by the b a s i c i t y o f a z i d e i o n ( E q u a t i o n 1), and 43 seems t o stem from a slow, subsequent n u c l e o p h i l i c s u b s t i t u t i o n on the r i n g , w i t h n i t r o n a t e a n i o n f u n c t i o n i n g as the l e a v i n g group. The r e s u l t s o f u s i n g phaset r a n s f e r c o n d i t i o n s a r e a l s o shown i n F i g u r e 6. ,CHN0

2

(1)

W i t h s o l i d sodium h y d r o g e n c a r b o n a t e i n s t e a d o f t h e a z i d e , compound j£3 gave 41 as the main p r o d u c t (85%) , t o g e t h e r w i t h a t r a c e o f 42 (14) T h i s r e c a l l s a r e l a t e d p r e c e d e n t , namely, ^ r - e l i m i n a t i o n o f

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

28

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY 23 or 24 Ν*

phase transfer

CHoNOo I

CH0NO0 , 2 2

CH

CH

2

H(^N

90% TFA ^

3

^OÇH

^

Me C

pv HCO

2

I

HCOv^ I ^CMe H C0^

^ Ν

Η

CH0NO0 !2 2 ^^2

2

NaI0 ^

δ

NaQMe

4

^OCH

π HCO

M

^OCH

e C

h HCO

2

I

I

HCOH I CH 0H

2

2

CHO 37

2

35

36

H N

°2 "~V^-^V 3 N

0

^ H (

^

MeOH,25°*

J

0-CMe

2

Ν - Λ ^ ^ Λ Γ Ν

H

R N - ^ ^ - ^ N R

3

HOX^V^/

H o V - ^ / ° 0—CMe^

2

J9 H+T

38 ~

34

0

0—CMej. R• Η 40R = Ac

22

H

H

,-Pt ?

-

»

J.

Figure 4. Synthesis of chiral acetals 39 and 40 derived from 2-deoxystreptamine.

0 ^N -- ^^ ^^ ^^ -SNTH 2

m

A

09N 0 Ν - ^ ^ ^ Λ Γ ·VΝNΗH 2

c

A C

Η Ο Λ ^ ^ / —CMe C—CMe

2

2

0—CMe

-Ι

0—th

2

a

•I

CHNMe N—^^-^T-NHAc ^· ^ X

0—CMe

2

9

H N---W^^^NHI H N—>^ _-^-NHMe 2

9

OH

a. Pd-cyclohexadiene. b. A c 0 — MeOH. 2

g. Me NCH(OMe) . 2

4

MeNH--^^^—NH ^ --NH

2

2

h. HC1.

2

-Ί 0—CMe

2

4

—

22

0—CMe

f. L i A l H .

HO 0

2

0

1

2

MI HH C( 0Ο ,N, -Ν- — ^^ ^^ ^^ - -- II \

2

H O ^ ^ ^ / 6—CMe Ο-—CMe

0

c. AcOCHO r~ MeOH.

OH d. H -» P t . e. DHP — TsOH. 2

i . MeOTf.

Figure 5. Synthesis of the enantiomeric mono-N-methyl-2-deoxystreptamines from 29.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

2. BAER

Nitrogenous and Deoxy Sugars and Cyclitols

29

hydrogen bromide by t h e a c t i o n o f p o t a s s i u m a c e t a t e from ( c * - a l k y l - o r a r y l - / 3 - n i t r o e t h y l ) b r o m o m a l o n a t e s (L5,16) ; see E q u a t i o n 2. Our r e a c t i o i took p l a c e under c o n d i t i o n s s i m i l a r t o t h o s e o f t h e well-known, n i t r o a l k e n e - f o r m i n g d e h y d r o a c e t o x y l a t i o n o f / ^ - n i t r o e s t e r s (the Schmidt —

S p u r r e d by t h e s e o b s e r v a t i o n s , we examined a r e l e v a n t a p p l i c a t i o n o f t h e method f o r n i t r o c y c l o p r o p a n e s y n t h e s i s from n i t r o a l k e n e s and d i m e t h y l s u l f o x o n i u m m e t h y l i d e (17), E q u a t i o n 3. I t had p r e v i o u s l y been employed f o r t h e s y n t h e s i s o f a 2 , 3 - d i d e o x v - 2 , 3 - C - m e t h y l e n e - 3 - n i t r o h e x o p y r a n o s i d e , t h e f i r s t one o f t h e s m a l l number o f c a r b o h v d r a t e s c o n t a i n i n g t h e n i t r o c y c l o p r o p a n e s t r u c t u r e thus f a r known (18).

Treatment o f t h e known n i t r o a l k e n e 44 w i t h t h e y l i d e i n d e e d gave 41, b u t i t was accompanied by a s m a l l p r o p o r t i o n o f t h e s t e r e o i s o m e r 45 (1£) . A l t h o u g h t h e p r e p a r a t i v e y i e l d was low ( ^ 3 0 % ) , t h e h i q h d i a s t e r e o f a c i a l s e l e c t i v i t y o f t h e methylene a d d i t i o n was r e m a r k a b l e . I t becomes p l a u s i b l e on i n s p e c t i o n o f a m o l e c u l a r model, which p o i n t s to h i n d e r e d a p p r o a c h from one f a c e , and u n h i n d e r e d a p p r o a c h from t h e other (Figure 7 ) . A n o t h e r mode o f f o r m a t i o n o f c a r b o h y d r a t e n i t r o c y c l o p r o p a n e s , s t u d i e d by us e a r l i e r (19), c o n s i s t s o f n i t r o g e n e x t r u s i o n from p y r a n o s i d i c , 2 , 3 - d i d e o x y - 3 - n i t r o sugars b e a r i n g a methyleneazo b r i d g e i n t h e 2 , 3 - p o s i t i o n s . Such f u s e d - r i n q 1 - p y r a z o l i n e s had been o b t a i n e d (19) by 1 , 3 - d i p o l a r c y c l o a d d i t i o n o f diazomethane t o 3 - n i t r o - 2 - e n o p y r a n o s i d e s ( F i q u r e 8 ) . In o r d e r t o e x p l o r e a p o s s i b l e a p p l i c a t i o n t o c a r b o h y d r a t e s p o s s e s s i n g a t e r m i n a l n i t r o a l k e n e q r o u p i n g , t h e compounds 7, 44, and 46 were t r e a t e d w i t h e t h e r e a l diazomethane. They r e a c t e d r a p i d l y a t low t e m p e r a t u r e s , b u t n o t i n a l t o g e t h e r c l e a r ways. (More than 1 m o l a r e q u i v a l e n t o f CH2N2 was consumed.) C r y s t a l l i n e , y e l l o w p r o d u c t s i s o l a t e d i n moderate y i e l d s were determined t o be 4 - s u b s t i t u t e d , 3 - n i t r o - 2 - p y r a z o l i n e s (48), p r o b a b l y formed by t a u t o m e r i z a t i o n o f t h e 1 - p y r a z o l i n e s e x p e c t e d as the p r i m a r y adducts ( 2 0 ) ; see F i q u r e 9. In t h e r e a d i l y a v a i l a b l e c y c l o p r o p a n e 41, C-2 comprises a c e n t e r o f c h a i n b r a n c h i n q whose c o n f i q u r a t i o n i s r i q o r o u s l v d e f i n e d (as R) thanks t o t h e manner i n which i t was enqendered. I t s h o u l d be p o s s i b l e to t a k e advantage o f t h i s c i r c u m s t a n c e f o r g e n e r a t i n g , by s c i s s i o n o f the 3-membered r i n g , some s t e r e o s p e c i f i c a l l v f u n c t i o n a l i z e d m o l e c u l e s w h i c h , a f t e r a p p r o p r i a t e m a n i p u l a t i o n s i n t h e suqar m o i e t y , c o u l d s e r v e as u s e f u l synthons f o r q e n e r a l p u r p o s e s . Compound £ 3 , a p p a r e n t l y o r i q i n a t i n q from r i n q o p e n i n g a f t e r azide-promoted f o r m a t i o n o f £1 (or 4 2 ) , o f f e r s i t s e l f as a f i r s t c a n d i d a t e f o r such t r a n s f o r m a t i o n s , p r o v i d e d i t c a n be p r e p a r e d i n an a c c e p t a b l e y i e l d . Thus, s e q u e n t i a l r e d u c t i o n s o f t h e two n i t r o g e n o u s f u n c t i o n s , each f o l l o w e d by i n d i v i d u a l N - s u b s t i t u t i o n as d e s i r e d — i n a n a l o q y t o t h e t r a n s f o r m a t i o n s o f 29 i l l u s t r a t e d i n F i g u r e 5 — would p r o v i d e avenues t o compounds o f type 49, i n which t h e r e s i d u e Z, o r i g i n a l l y r e p r e s e n t i n g t h e p o l y o l

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

30

CHoNOo I CHo I MsOCH I OCH Me C HCO I

CHoNOo I CH I HCNx 2

Me C' 2

HC0>

I

2

2

/

2

N CH -CH 3

Me C

2

M9 C—f-) HCO I

2

H6O I HCO>

'CMe

H CO

2

2

2

^OÇH

2

CH IM0 I

HC I

Z

HCO.

:CMe«

:CMe

9

H C0'

24

2

35 Reaction c o n d i t i o n s a. b. c. d.

Product r a t i o 35: (41+42+43) 1.4 -0.5 ~0.2 10

Bu N+N " — PhMe; 100°, 1 h NaN — Bu NHS0 , H o O — PhMe; 100°, 2 d as i n b, but a t 80° as i n b, but a t 56° 4

3

3

4

4

Figure 6. Formation of nitrocyclopropanes 41 and 42 from mesylate 24.

H X - N 0 H

2

C

2

HC I

J

^OCH Me^C—π HCO I T > e HgCO^ M

41,

.0ÇH

Me C2

"HCO

I I

2

H

44,

p-manno

D-arabino

a:

Re,Re face

attack

b:

Si , S i face

attack

2

j;CMe

C O ^

45,

p-gluco

Ratio 41:45 =20:1

Figure 7. Formation of nitrocyclopropanes from nitroalkene 44.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

2

2

2. BAER

Nitrogenous and Deoxy Sugars and Cyclitols

31

Ph

Me

0 N 2

Figure 8. Formation of a carbohydrate nitrocyclopropane from a nitroalkenic sugar via a pyrazoline.

HC-NOII CH I

CH N -^' 2

2

s L

NwN=0

J -—Of,

\X

R

7,44,46

^ N ^ N ^

"Ol

— 48

47

(C-4 configuration unknown) R for 7:

From 7: 17%; mp 167-169° From 44: 54%; two 4-epimers, ~" mp 174-176°, 125-130°

VOAc

J t ,Me,

?rom 46: 29%; mp 152-156° dec. • OÇH M* C ~HÇO 2

H CO 2

x

Z

I AcOCH AcOCH HCOAc I HCOAc CH OAc R f o r 46 2

R for 44

Figure 9. Preparation of some carbohydrate pyrazolines by cycloaddition of diazomethane to nitroalkenic sugars.

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

32

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

chain, may be modified by degradation to comprise f u n c t i o n a l i t i e s (e.g., —CHO, —CH Br) suitable for carbon — carbon bond formation. Furthermore, conversion of the nitromethyl group into a formyl, hydroxymethyl, or carboxyl group by e x i s t i n g procedures (21) , deamination of a selectively-formed amino group, and other functional modifica­ tions may be contemplated, which should make 43 an exceedingly versa­ t i l e stepping stone i n syntheses of c h i r a l ,fc>,«o'-disubstitutedi s o a l k y l structures. We have not yet achieved a preparative conversion of 41 into 43 by azide, but sodium thiophenoxide i n b o i l i n g oxolane reacted r e a d i l y with 41 to give the thioether 50a and, i n t e r e s t i n g l y , the t h i o hydroximic phenyl ester 50b (R as for 44 i n Figure 9). Both products were desulfurized and reduced with Raney n i c k e l , y i e l d i n g the same amine (J^Oc) , i s o l a t e d as a c r y s t a l l i n e N-acetyl derivative (Baer,H.H. , Williams, U., Radatus, B., Carbohydr. Res., i n press). Oxidative de­ gradation of the (deprotected) sugar chain then led to (~)-(R)-3amino-2-methylpropanoic acid, a compound of considerable importance (22) i n thymine metabolism and elsewhere i n biochemistry I t s carbo­ hydrate-based, stereospecifi propounded. 2

1

CH NR R

2

CH N0

2

3

4 4

I AA>

2

PhS^^JOH

'

'

R R NCIL—C—H 49

2

Ζ

PhSCH„—C — H 50a

CH.—OH

0

50b

3

I R

2

'

PhSCH — O H

I R

2

1

2 2

H CNH

I

50c R

«N*o»

In general, however, f i s s i o n of the nitrocyclopropane ring i n 41 appears to be unusually d i f f i c u l t . A number of reaqents known to open cyclopropane rings were found i n e f f e c t i v e under the conditions t r i e d ; they included hydrochloric and hydrobromic acids, bromine, and catal y t i c a l l y activated hydrogen. Hydroaenation over palladium-on-carbon readilv reduced the amino group but f a i l e d to cleave the r i n q . The exploitation of c h i r a l nitrocyclopropanes for purposes of stereospec i f i c synthesis therefore remains a challenqing problem. Methods for_ the Synthesis o f Aminodeoxy and Deoxy Disaccharides Related to oc,oc-Trehalose The disaccharide Λ,β2 (52, with OH-2' inverted) occur as actinomycetal metabolites, reported to show (modest) a n t i b i o t i c a c t i v i t y (24-27). The chemical synthesis of derivatives and analogs has long commanded much i n t e r e s t , as such compounds are required for the study of struc- . t u r e — a c t i v i t y relationships i n the action o f trehalases (23^28), may serve as substitutes for 51 i n the synthesis o f cord-factor analogs to be used as probes i n the f i e l d of mycobacterial biochemistry (29, 30), and could possibly prove to possess i n t e r e s t i n g properties as enzyme i n h i b i t o r s or a n t i b i o t i c agents. Several groups o f investigators have reported syntheses o f numer­ ous, aminated rt-D-hexopyranosyl , 6 ~ d i - 0 - i s of » ro ρ y 1 i d e n e - Γ ) - m a un i t ο 1 on mort: than a lOO-gram h a s i s f o l l o w i n g r e f .16, iiotwi t h s t a η d i n g s orne d i f f i c u 1 t i e s a p p a r e n t l y e x p e r i e n c e d bv some a u t h o r s ( 2 4 . 2 b ) Ί . 0097-6156/89/0386-0045$06.00/0 ° 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

46

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

Having a t hand t h i s s t r a t e g y f o r s p e c i f i c acetalation of sugars, we c o n s i d e r e d the use o f ketene acet a I s instead o f e-iol e t h e r s m i g h t a f f o r d a g o o d mean o f access to orthoesters under k i n e t i c - a l l y controlled conditions ( F i g u r e 2) . A t t h e t i m e we i n i t i a t e d t h i s work, at least two r e a c t i o n s o f k e t e n e a c e t a l s w i t h an a l c o h o l were known (Figure 2). The f i r s t one d e s c r i b e d the intramolecular addition of the primary hydroxyl group at p o s i t i o n 4 of 4 - h y d r o x y m e t h y l - 2 - m e t h y 1eηe- 1 , 3 - d i o x o l a n e (26); the second one was t h e p r o d u c t i o n (27) of a b i c y c l i c orthoester of the bicyclo[2.2.21 octane s e r i e s from dehydrohalogenation of a bifunctionna] 1,3-dioxane (probably through the i n termediacy of the (non-isolated) methylene dioxane gene­ rated by B - e l i m i n a t i o n o f HC1 a n d s u b s e q u e n t intramole­ cular addition of the hydroxyl group]. 1

Ry analogy with the r e a c t i o n using enol ethers (which g e n e r a l l y doe group at the anomeri tion using ketene a c e t a l s would lead t o o r t h o e s t e r s at the non-anorne r i c p o s i t i o n s . Although 1,2-orthoest.ers of sugar are well-known (28-30) and widely used, e s p e c i a l l y f o r glycoside synthesis (31-34) , f e w o r t h o e s t e r s are; know i n which the anomeric center i s not involved. Four different examples are given i n Figure 3, respectively i n the nucleoside s e r i e s (35-37) ( e t h a n o l y s i s of the 2,3-orthoester gave a mixture of regioisomers of formates), f o r methyl α-D-arabinopyranoside ( 3 8 ) ( r e d u c t i o n o f t h e 3,4orthoester provided an unusual approach to ethylidene derivatives), f o r a D-galacto d e r i v a t i v e (39) ( h y d r o l y s i s o f t h e 3 , 4 - o r t h o e s t e r was régiospecific, giving the axial ester, a f f o r d i n g OH-3 f r e e f o r g l y c o s y l a t i o n i n t h e synthesis of blood-group substances) and, f i n a l l y , f o r t h e 30-methyl-1 ,2-0-isopropylidene-a-D-glucofuranose(40) ( thermal dégradation o f t h e 5 , 6 - o r t h o e s t e r l e d t o an e t h y l e n i c sugar). V e r y f e w o t h e r e x a m p l e s caη be f o u n d i n t h e l i t e ­ rature: they concern ( i ) the h y d r o l y s i s of the 3,4-orthoacetate of methyl 2 , 6-d i d e ο χ y-ot-D-1 y χ o - h e χop v r a no s i de C ii") the formation of the 2 , 3 : 5 , 6-d i o r t h o f o r m a t e derivative of methyl a-D-mannofuranoside (42): and f i i i ) the i s o l a t i o n o f the 4 , 6 - o r t h o a c e t a t e of D-idopyranose i n t h e r e a c t i o n o f a n t i m o n y n e η t a ο h 1 οri d e w i t h β-D-g1ucopyranose pentaacetate (43) ORTHOFSTFRJFICAT1ON

OF

PYRANOSFS

AND

PYRANOSIDFS

The reagent chosen f o r t h i s study was 1,1-dimethoxyethene prepared by d e h y d r o c h l o r i n a t i o n o f chloroacetaldehyde dimethyl acetal according to Met)vain (44). The dry r e a g e n t c a n be s t o r e d f o r s e v e r a l w e e k s o r m o n t h s i n s m a l l v i a l s , w i t h fncilcou) a r s i e v e s , i n a r e f r i g e r a t o r . A magnetically stirred s o l u t i o n of methyl a-Dg 1 u c o p y r a n o s i d e 1 ( F i g u r e 4) i n d r y Ν,N-dimeth y 1 f o r m a m i d e

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Orthoesterification Under Kinetic Control

BOUCHRA ET A L

HCONMe

/Me

2

CoH

+

Φ

θ θ ι Y© -ROH

KINETI

C> Figure

/-OH

e

1. Synthesis of acetals from enol ethers and d i o l s .

/OR "-Me OR

/OR

0^

"OR

ν_0^

N^le

CH OH 2

CH OH 2

Figure diols.

HOCH,

/°~Λ^

2. Synthesis of orthoesters from ketene acetals and

American Chemical Society Library 1155 15th St., N.W. Washington, D.C. 20036

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

48

YOCHj ο

Β

YOCHj Ο Β (^N

_EtOH

HO

(HO)

HCOMe

HO,

Q

OH

OEt

°

CHjOAc

HOCH HOÇH

H

ÔH

CHjOAc

OAc

/

CHPAc

ÔAc

OAc

2

HCfoEJ^ Ms,

Figure

HOÇH

(OCHO)

3. Orthoesters at non-anomeric p o s i t i o n .

n

2

H

O-0Me

O-CM».

MeO

M e

OCH2

C =

' C,

HCdNMejJtsOH 0°

OH

Ac 0 2

Pyridine AcOÇHj

HOÇH2

MeO ,H Q*

le 6

r

•Me

H