Preparative Carbohydrate Chemistry

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Hanessian, Stephen. . Preparative earbohydrarechemistry I Stephen Hanessum. p. em. Includes index. ISBN 0-8247-9802-3 (alk. paper) 1. Carbohydrates-Derivatives. 1. Title. QD321.H288 1996 547'.780459-DC21 96-39338 CIP

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Carbohydratechemistry has been an important and vital subdisciplineof org1mic chemistry ever since the pioneering discoveries of Emil Fischer. Stereochemical features, conformational aspects, and stereoelectronicprinciples dealt with in organic chemistryin general are deeply rooted in molecules we generally refer to as sugars. Over the years, carbohydrate chemistry has served as an important link between organic chemistry,medicinal chemistry, and biology. In recent years, the general areas of carbohydrate chemistry and biochemistry have enjoyed unprecedented popularity. A clear indication of this resurgence of interest is the large contingent of "noncarbohydrate" chemists by training, who have flocked to the area with new ideas and exciting applications.This, coupled with the increasinglyimportantrole that sugar molecules are playing in glycobiology; in anti-infective therapy as components of antibiotics, antitumor,and antiviralagents;and in relatedbiomedicalareas, makesthis old subdiscipline of organic chemistry a vibrant and rejuvenated area in which to work. What has been sorely missing,however,is an authoritativemonographthat describes the preparation of some of the more importantcarbohydratederivatives and related moleculesin an upto-date and concise manner. This volume, written by authorities on the subject, is a compendium of classic procedures for the synthesisand utilization of carbohydrate-relatedmolecules. Representative, state-of-the-art procedures provide even newcomers to the field with ready access to commonly used carbohydrate derivatives for a variety of applications. A total of 28 chapters'have been grouped under 7 themes. Each chapter consists of introduction, discussion, and experimental sections that cover the particular "method" in a thorough manner. The reader will thus be introduced to the subject matter pertaining to a general method, a -specific reaction, or type of derivative, as well as to the experimental procedures performed in the author's laboratory and described in the literature, whenever pertinent. The first four chapters, which come under the general theme of sugar derivatives. represent methods for the transformation of sugar molecules into synthetically useful derivatives, such as aeetals,dithioacetals.ethers. and related compounds.The following sb chapters explore selected reactions of sugar derivatives. in which some of the most important bond-fonning reactions in the modifications of sugars are discussed. The third theme is concerned with the chemical synthesis of 0- and N-glycosy. compounds, and of oligoseccharides, and is the subject of ten chapters. The most widel) used methods for glycoside synthesis are discussed, together with the inclusion of conceptually new approaches to anomeric activation and glycoside synthesis. II

Preface

chapters on 'The use of enzymes in carbohydrate chemistry is covered in two

-

and oligosac l.Z)'D1lllic synthesis of sialic acid, KDO, and related deoxyulosonic acids, aarides,

cal- and The theme of C-glycosylcompouridsis covered by two chapters on freel'lldi carbon of ynthesis ntrolleds .ewisacid-mediated transformationsthat address the stereoeo . cposition ubstituents at the anomeri Iized cyThe sixth theme, carbocycles from carbohydrates,explores how functiona thereby rs, precurso rate carbohyd from prepared be can lopentanes and cyclohexanes compounds. :xtending the usefulness of sugars for the synthesis of mainstream organic thatare The last theme,total synthesis of sugars from nonsugars,groupstwo chapters syntliesized :oncemed with how amino sugars, deoxy sugars, and sugars in general are . rom amino acids and related compounds, as well as by de novo methods some In shortintroductorycommentarieson each theme, I have attempted to provide entsin developm recent put and years. the nover nsight into the topic,reflecton its evolutio perspective, preThe foregoing themes and the specific chapters represent some of the most coverage is reh Althoug y. chemistr rate carbohyd modern in methods useful y parativel carbohydrate stricted to a selection of topics, the most important aspects of preparative my hope that is ence,it consequ a As manner. expert an in with dealt been have y chemistr this volume will have lasting value. sm to I am greatly indebted to all the authors, who responded with great enthusia expert the edge acknowl to like also my initial proposal by providing chapters. I would ionof my own assistance of Carol St-Vmcent Major and Michelle Piche in the prepanrt for producing chapters, and Gurljala V. Reddy, Olivier Rogel, and Benoit Larouche artworlc for them. be of Finally, I hope the preparative methods described in this monograph will al individu their of pursuit the torsin investiga of ns generatio service to present and future research objectives;

Contents

Preface Contributors PART I SUGAR DERIVATIVES ,Commentary by Stephen Hanessian 1. S~thesJs?f Isopropylldene, Benzylldene, and Related Acetals Pierre Calinaud and Jacques Gelas I. Introduction 11. Methods 11. EXperimental Procedures References 2.

Stephen Hanessian

3.

iii

xi 1

3

3 6 15 28

Dlalkyl Ditbioacetals of Sugars Derek Horton and Peter Norris

3S

I. Introduction Il Methods m. Experimental Procedures References

36 39 43 50

Regiose.IecCfve Cleavage of O-BenzyUdene Acetals to Benzyl Ethers . Per J. Garegg tion Introduc I. 11. Re!ioselective Reductive Cleavage of O-Benzylidene Acetals to Benzyl Ethers m. Mechanistic Considerations IV. Experimental Procedures References

S3

4. Selective O-Substitution and Oxidation Using StannyIene AcetaIs and Stannyl Ethers Serge David

I.

Introduction

n. Methods

54

57 61

62 65

69

69 70

v

Contents

vi

m.

Experimental Procedures ReferenceS

75 82

10. Selected Methods for Synthesis of Branched-Chain Sugars l\Ies Chapleur and Francoise Chretien I.

PART n SELECTED REACTIONS IN CARBOHYDRATE CHEMISTRY Commentary by Stephen Hanessian

5.

L

Tritlate Synthesis and Reactivity Introducing Azido and HalegenoGroups by Tritlate Displacement m Reactions of carbohydrate Tritlates IV. carbohydrate Imidazo1ylsulfonates V. Experimental Procedures References

n.

Direct Halogenation of Carbohydrate Derivatives Walter A Szarek and Xianqi Kong

I. Introduction

n.

m. 7.

General Methods for the Direct Halogenation of Alcohols Experimental Procedures References

NudeophDic Displacement Reactions of Imidazole-I-Sulfonate Esten Jean-Michel Vat~le and Stephen Hanessian

I. Introduction

n.

m. 8.

Methods Experimental Procedures References

Free Radical Deoxygenation of Thiocarbonyi Derivatives of Alcohols D. H. R. Barton, J. A. Ferreira, and J. C. Jaszbereny; . I.

n. m. 9.

n.

85

m.

Introduction Methods Experimental Procedures References

207

207 211

240 252

Srt2-Type B8logenation and Azidation Reacfions with Carbohydrate Tri8ates Edith R. Binkley and Roger W. Binkley

6.

vII

Introduction

Methods ExperimentalProcedures Notes and References

'lbiazole-Based One-Carbon ExtensIon of Carbohydrate Derivatives Alessandro Dondoniand Alberto Marra I.

n. m.

Introduction Methods Experimental Procedures References

87

88 90

PART m CHEMICAL SYNTHESIS OF 0- AND N-GLYCOSYL COMPOUNDS, AND OF OLIGOSACCHARIDES Commentary by Stephen Hanessian

93 96 97

11. 0- and N-Glycopeptides: Synthesis of Selectively Deprotected Building Blocks Horst Kunz

102

I.

105

n.

m. 106 107 116

123

12. Oligosac:charide Synthesis with Trichloroacetimidates I. Introduction

n.

m.

127 130 136 145

I.

n.

m.

168

174

174 188 196

The Trichloroacetimidate Method Experimental Procedures References and Notes

13. OUgosaccharide Synthesis from Glycosyl Fluorides and Sulfides K. C. Nicolaou and Hiroa/ci Ueno

151 153 157 173

265

268 273 279

283

Richard R. Schmidt and Karl-Heinz Jung

127

151

Introduction Methods Experimental Procedures References

265

14.

Introduction Methods Experimental Procedures References

Oligosaccharide Synthesis by n-Pentenyl Glycosides Bert Fraser-Reid and Robert Madsen

I.

n. m.

Introduction Methods Experimental Procedures References and Notes

283 289 296

308

313

314 314 329 336 339

339 341 348

354

Content s

viII

15. Chemical Synthesis of Sialyl Glycosides AkiTaHasegawa and MaJcoto Kiso Introduction Regio- and a-Stereoselective Sialyl Glycoside Syntheses Using Tbioglycosides of Sialic AcidS in Acetonitrile Applications to Systematic Synthesis of Gangliosides and Sialyloligosaccharides IV. Experimental Procedures References I.

n. m.

An 16. Glycoside Synthesis Based on the Remote Activation Concept: Overview Stephen Hanessian I. Introduction The Challenges of the Glycosidic Bond m. The Remote Activation Concept Iv. New Generations of Glycosyl Donors References

n.

l 17. Glycoside and Ollgosaccharlde Synthesis with Unprotected Glycosy Concept on Donors Based on the Remote Activati Boliang Lou, Gurijala V. Reddy, Heng Wang, and Stephen Hanessian

I. Introduction n. Glycoside and Oligosaccharide Synthesis Using 3-Methoxy-2pyridyloxy (MOp) O-Unprotected Glycosyl Donors m. Experimental Procedures References 18. OUgosaceharlde Synthesis by Remote Activation: O-Protected 3-Methcmy-2-pyrldylcmy (MOP) Glycosyl Donors Boliang Lou, Hoan Khai Huynh, and Stephen Hanessian

I. Introduction n. O-Protected 3-Methoxy-2-pyridyloxy Glycosyl Donors m. Applications to the Synthesis of T Antigen and Sialyll..e" IV. Experimental Procedures References l 19. OUgosaccharide Synthesis by Remote Activation: O-Protected Glycosy Donors bonate rldylcar 2-thiopy Boliang Lou, Hoan Khai Huynh, and Stephen Hanessian 1

n. m.

Introduction Methods: Glycosyl 2-thiopyridylcarbonates (TOPCAT) as Glycosyl Donors Experimental Procedures References

357 358

Content s

MOP20. OUgosaccluuide Synthesis by Selective Anomer lc Activation with and TOPCAT-LeaviDg Groups 449 Boliang Lou, Elisabeth EckharrJt, and Stephen Hanessian 1

359 364 370 375

Ix

n.

Introduction Experimental Procedures References

450 451 464

PART IV ENZVMATIC SYNTIIESIS OF SIALIC ACID lIDO AND uunES RELATED DEOXYULOSONIC ACIDS, AND OF OLiOO SACciL Commentary by Stephen Hanessian

381 381 382 383 386 387

389 390 391 398 410

413 414 415 419 422 427

431 432

21. Enzymatic SynthesJs of Carbohy drates ClaudineAuge and Christine Gautheron-Le Narvor 1

n.

m.

46~

471 471 48:

22. OUgosaceharide Synthesis by Enzyma tic Glycosidation Wolfgang Fitz and Chi-Huey Wong

I.

n.

m.

Introduction Enzymatic Glycosidation Experimental Procedures References

481 481 4950:

PART V SYNTHESIS OF C-GLYCOSYL COMPOUNDS Commentary by Stephen Hanessian

SO;

23. C-Glycosyl Compounds from Free Radical Reactions Bernd Giese and Heinz-Georg Zeitz

SO'

I. Introduction Intermolecular Methods m. Intramolecular Methods IV. Experimental Procedures References

n.

24. Synthesis of Glycosylarenes KeisuJce Suzuki and Takoshi Matsumoto 1

434 439 447

Introduction Methods Experimental Procedures References

46S

Introduction

n. Methods

m.

Experimental Procedures References

50 51 51 51 52

52 52 53 53 54

Contents

x

PART VI

CARBOCYCLES FROM CARBOHYDRATES

Commentary by Stephen Hanessian

25.

Functiona1ized Carboeylic Derivatives from Carbohydrates: Free Radical and Organometallic Methods T. V. RajanBabu I.

Introduction n. Cyclopentanes ill. Cyclohexanes Iv. Functiona1ized Carbocylic Compounds via Organometallic Methods V. Experimental Procedures References and Notes

26. The Conversion of Carbohydrates to Cydohexane Derivatives Robert J. Ferrier I.

n.

m.

Introduction Methods Experimental Procedures References

PART VB TOTAL SYNTHESIS OF SUGARS FROM NONSUGARS Commentary by Stephen Hanessian 27.

Total Synthesis of Amino Sugars

545 546 554 555 558 565

569 570 571 585

I.

28.

Introduction Methods Experimental Procedures References

Total Synthesis of Sugars

Claudine Aug6 France

Institut de Cbimie Mol6culaire d'Orsay, Universiti Paris-Sud, Orsay,

D. B. R. Barton Department of Chemistry, Texas A&M University, College Station. Texas

Edith R. Binkley Center for Carbohydrate Study, Ober-lin, Ohio

590 Roger W. Binkley Center for Carbohydrate Study, Oberlin, andDepartment of Chemistry, Cleveland State University. Cleveland, Ohio

593 Pierre Calinaud Ecole Nationale Sup6rieure de Cbimie de Clermont-Ferrand, Aubim:, France

59S

Janusz Jurczak

n. m.

Contributors

S46

595 596 601 611

615

Yves Chapleur Institut Nanc6ien de Chimie Molkulaire, URA CNRS 486, Henri Poincare-Nancy I, Vandoeuvre, France

Universite

Fran~ise Chritien Institut Nan~ien de Chimie Molkulaire, URA CNRS 486, versiti Henri Poincare-Nancy I, Vandoeuvre, France

Uni-

Serge David I.C.M.O., Laboratoire de Chimie Organique Multifunctionelle, Universite Paris-Sud, Orsay, France

AleksanderZamojski I.

n.

m. Index

Introduction Methods Experimental Procedures References and Notes

Dipartimento di Chimica, Universita di Ferrara, Ferrara, Italy

615 617

Alessandro Dondonl

622

Elisabeth Eckhardt Boehringer Mannheim GmbH, Penzberg, Germany

634

637

J. A. Ferreira

Department of Chemistry, Texas A&M University, College Station, Texa:

Robert J. Ferrier Department of Chemistry, Victoria University ofWelliilgton, Welling ton, New Zealand Wolfgang Fltz Department of Chemistry, The Scripps Research Institute, La Jolla California Bert Fraser-Reid Department of Chemistry. Duke University, Durham, North Carolin

xII

Contributors

xIII

Per J. Garegg Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden

Peter Norris Ohio

Department of Chemistry, Youngstown State University, Youngstown,

Christine Gautheron-Le Narvor Paris-Sud, Orsay, France Jacques Gelas France Bernd Giese

Institut

dC Cbimie Moleculaire d'Orsay, Universite

Ecole Nationale Superieure de Chimie de Clermont-Ferrand, Aubim,

Department of Chemistry, University of Basel, Basel, Switzerland

Stephen Hanessian Quebec, Canada AkJra Hasegawa Japan

Derek Horton

Department of Chemistry, University of Montreal, Montreal,

Department of Applied Bioorganic Chemistry, Gifu University, Gifu,

Hoan Kbai Huynh Quebec, Canada

Department of Chemistry, University of Montreal, Montreal,

J. C. Jaszberenyi Department of Organic Chemical Technology, Technical University of Budapest, Budapest, Hungary Fakultiit fUr Chemie, Universitlit Konstanz, Konstanz,

Germany

Janusz Jurczak Department of Chemistry, Warsaw University and Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Makoto Kiso Japan

Department of Applied Bioorganic Chemistry, Gifu University, Gifu,

Xianqi Kong

Department of Chemistry, Queen's University, Kingston, Ontario, Canada

Hont Kunz Institut fUr Organische Chemie, Johannes Gutenberg-Universitiit Mainz, Mainz, Germany Boliang Lou

Department of Chemistry, Cytel Corporation, San Diego, California

Robert Madsen Department of Chemistry, Duke University, Durham, North Carolina Alberto Marra

Department OfChemistry, TheOhio State University, Columbus, Ohio

Gurijala V, Reddy Quebec, Canada

Department of Chemistry, University of Montreal, Montreal,

Richard R. Schmidt Fakultlit fUr Chemie, Universitlit Konstanz, Konstanz, Germany Keisuke Suzuki

Department of Chemistry, Tokyo Institute ofTechnology, Tokyo, Japan

Walter A. Szarek Department of Chemistry, Queen's University, Kingston, Ontario, Canada

Hiroaki Ueno The Scripps Research Institute and University of California at San Diego,

Department of Chemistry, The American University, Washington, D.C.

Karl-Heinz Jung

T. V. ~anBabu

Dipartimento di Chimica, Universita di Ferrara, Ferrara, Italy

'Thk8sm Matsumoto

Department of Chemistry, Tokyo Institute of Technology, Tokyo,

Japan

K. C. Nicolaou The Scripps Research Institute and University ofCalifornia at San Diego, La Jolla, California

La Jolla, California Jean-Michel VaQle Department of Chemistry, Universite Claude Bernard, Villeurbanne, France Heng Wang

Department of Chemistry, University ofMontreal, Montreal, Quebec, Canada

Chl-Huey Wong California

Department of Chemistry,

A1eksander Zamojski Warsaw, Poland Heinz-Georg Zeitz

The Scripps Research Institute, La Jolla,

Institute of Organic Chemistry, Polish Academy of Sciences,

Department of Chemistry, University of Basel, Basel, Switzerland

I Sugar Derivatives THEMES: Aceta/s, Dithioacetals, Ethers, Site-Selective Oxidations

Because of their abundance and their endowment with unique stereochemical and functional features, carbohydrates can be considered as one of nature's better gifts to the synthetic organic chemist. Although this personalopinion was appreciated and shared by a few sugar chemistry aficionados 30 years ago, there was reluctance on the part of the general community of synthetic organic chemists to venture into the field as explorers or exploiters. Today this is no longer true, One of the main deterrents to thispractice was a combination of "sugarophobia" and conservatism on the part of the noncarbohydrate chemists, who preferred to tread along the charted waters of terpenes and related traditional natural products. Indeed, what better carbon frameworks to study mechanistic organic chemistry and to advance the state of the art of synthesis? Major insights, roles, and theories were being advanced throughout the 19608 and 19708. Meanwhile the carbohydrate chemist, born and bred on a sugar-rich diet, had become a bit of an isolationist, content to work in and around the periphery of a sugar molecul~, and with good reason. In fact, a large number of natural products with antibiotic, antitumor, and antiviral properties contained unusual sugar moieties that had to be isolated, their structures elucidated and synthesized. Who would be better suited for such a task but the carbohydrate chemist? The notion that sugar molecules need not be just sugar molecules was popularized in the mid-19608 and early 19708. In recent years, this school of thought has had a large following from the community of synthetic organic chemists in general. I do not think: that chemists label themselves as sugar, terpene, or alkaloid people any longer. Much of this has had to do with changing attitudes in the classroom with revised curricula, in the laboratory with the need to synthesize enantiomerically pure molecules, and in people's psyches in general. A major operational problem in working with polyhydroxylated molecules, is their derivatization in ways that render them synthetically useful as starting materials or as intermediates in synthesis. Thus, the availability of sugars, with a plethora of stereochemical and functional features, can be an amenity as well as a problem, Fortunately, the roles of chemical reactivity and conformational analysis, coupled with the laws of thermodynamics, join forces to allow us to functionalize polyhydroxy aldehydes and ketones (aldoses and alduloses) in a selective and predictable fashion. Water-soluble sugars disguised as hemiacetals, become organic-solvent-soluble as

1

2

Part I

O-protected cyclic or acyclic carbon frameworks. The choice of acetals or ethers as derivatives allows a systematic manipulation of diols and polyols. Kinetic control and a lesser affinityfor protonation on sulfur compared with oxygen allows the transformation of cyclic hemiacetals into acyclic dialkyl dithioacetals. Acetal, ether, and dithioacetal derivatives are some of the pivotal intermediates needed to explore various applications of carbohydrates in synthesis. Selectivity can be an overriding commodity in cases where reactivity is dictated by logic and accepted concepts. Such is the case with stannylene acetals of diols and trialkylstannyl ethers of alcohols. Enhanced nucleopbilicity of oxygen attached to tin and welldocumented stereoelectronic effects associated with methine carbon atoms of trialkyltin ethers lead to remarkably selective reactions of O-substitution and oxidation in polyhydroxy compounds. The following four chapters offer insight and experimental details in the selective derivatization of sugar molecules.

1 Synthesis of Isopropylidene, Benzylidene, and Related Acetals Pierre Calinaud and Jacques Gelas Ecole Nationale Superieure de Chimie de Clermont-Ferrand, Aubiere, France .

Stephen Hanessian I. Introduction II. Methods for Preparation of Acetals in Carbohydrate Chemistry A. General methods B. Mechanistic and structural aspects m. Experimental Procedures A. Acyclic sugars B. Pentoses C. Hexoses D. Aminosugars E. Deoxysugars F. Oligosaccharides G. Acetalation of trans-vicinal diols References

3 6 6 11 15 15 16 18 23 24 25 27 28

I. INTRODUCTION The condensation of aldehydes and ketones with alcohols and polyols is one of the first reactions of the organic chemistry. Following the pioneering work by Wurtz [I] (acetaldehyde and ethylene glycol), and by Meunier [2] (catalysis witil acids), Emil Fischer [3] described as early as 1895 theformation of acetals* of glycoses (first from o-fructose and acetone). Since then. thisprotecting group has been extensively used in organic chemistry, in general, and in carbohydrate chemistry, in particular. These developments concern not ·F911owing the recommendation of illPAC (rule C-331.1) the term ocetal should be given to the compounds obtained throughthereactionof a carbonylgroupof an altkhyde as well as from a ketone.

3

4

C8l1naud and Gelas

only acyclic and cyclic acetals, but also analogues in which the oxygen atoms have been replaced by other heteroatoms, the sulfut atom being of particular importance (thio- and dithio-acetals). This chapter will consider only the most popular and useful acetals, with some comments concerning related acetals and extension to oligosaccharides. The case where the acetal involves the anomeric center (glycosides) falls outside the scope of this chapter.A later chapter deals with acyclic dithioacetals, and these can be found elsewhere in this monograph. Several reviewshave already been published on the subject,for example, the acetalation of alditols [4], of aldoses and aldosides [5,6], and of ketoses [7]. Some aspects of the stereochemistry of cyclic acetals have been discussed in a review dealing with cyclic derivativesof carbohydrates [8], also in a general article [9] and, morerecently, in a chapter of a monograph devoted to the stereochemistry and the conformationalanalysis of sugars [10].Aspects on predicting reactions patterns of alditol-aldehyde reactions are reviewed within a general series of books on carbohydrates [11]. The formation and migration of cyclic acetals of carbohydrates have also been reviewed [12,13]. The evident success of the transformation of polyols into cyclic acetals as a method for temporary protection, is mainly due to the following features: (1) accessibility and cheapnessof the reagents; (2) ease of the procedure leading quickly and in high yield to the protected derivatives; (3) inertness of the protecting group to a large variety of reagents used in the structural modifications of the substrate; (4) ease and high-yielding step for deprotection.Usually, reagents for acetalation are quite common chemicals that are essentially nontoxic; their uses are well established and straightforward. Some representative procedures of the various methods will be presented here, especiallyfor the most important derivatives; namely, O-isopropylidene and O-benzylidene sugars. For example, 1,2:5,6di-O-isopropylidene-o-glucofuranose 1,1,2:3,4-di-O-isopropylidene-o-galactopyranose 2, and methyI4,6-0-benzylidene-a-o-glucopyranoside 3, continue to be used extensively by sugar chemists.

3

Only short comments will be given for other acetal derivatives that are less popular.' Chart 1 presents a list of formulae of cyclic acetals, mainly, those with five- and sixmemberedrings (1,3-dioxolanes and 1,3-dioxanes).Seven-membered ring acetals are omitted because they are scarcely represented in carbohydrate chemistry. The special case of spiroacetals and cyclohexane-1,2-diacetal-protecting groups, which have been reported recently, will be presented in Part Il. The essential justifications for the choice of one type of acetal among the various possibilities are probably (1)the structure of the acetal obtained (i.e., dioxolane or dioxane type; with or without involvement of the anomerichydroxyl group; obtention of a furanoid or a pyranoid protected form of the sugar, especially when one starts from a free one); (2) the respective reactivity of these acetals as far as the deprotecting step is concerned. A brief discussion of the point (1)will be given in the next paragraph. Relative to the deprotection of cyclic acetals, generallytheir cleavage,regeneratinga diol, is obtainedusing very similaracidic aqueous conditions [4-7]. However, a selective removal of one acetal in the presence of the same (or different) functions, at distinct positions in the same molecule,

lsopropylldene, Benzylidene, and Related Acetals

j

5

- 0 " /R __ o/c",,-~,

R

R'

O-methylene

H

H

O-ethylidene

Me

H

O-cycloalkylidenes 0=4 cyclopcnt,ylidene o=S cyclohexylidene O-isopropylidene

Me

Me

O-benzylidene

Ph

H

Y-C6H4 O-benzylidene substituted y~ o-N0 2, p -OMe, P- NMe 2

H

Chart 1 Most common cyclic acetaIs used in carbohydrate chemistry

is possible and has been quite often observed. As examples, one can recall that generally a 1,2-0-isopropylidene group is more resistant to acid hydrolysis than the same group at any other position. trans-Fused 4,6-0-benzylidene acetals of hexopyranosides are hydrolyzed faster than the corresponding cis-fused acetals and a para-anisylidene group can be removed without loss of a benzylidenegroup in the same molecule by graded acid hydrolysis. A list of representative examples of this kind of selective removal within a multifunctional carbohydrate derivative can be found in a review partly devoted to acetals [14]. Finally, it should be emphasized, even if it is paradoxical, that this excellent protecting group can, under special conditions, behave as a real functional group with its own reactivity. During these last 20 years, reactions have opened the way for the developmentof strategies for structural modifications, thereby amplifying the interest for acetals. Among these reactions one can briefly recall: (1) oxidation (ozonolysis, action of potassium permanganate); (2) photolysis; (3) halogenation (N-bromosuccinimide, triphenylmethylfluoroborate, and halide ions; hydrogen bromide in acetic acid; dibromomethylmethylether; miscellaneous reagents); (4) hydrogenolysis (mixed hydride reagents); (5) action of strong bases (ring opening with butyllithium, other strong bases); (6) formation of esters induced by peroxides and (7) cleavage with Grignard reagents. This reactivity has been the subject of a review [15] that demonstrated the versatility of acetals Chart2 shows some protective groups closely related to cyclic acetals, and it may be useful to comment briefly about them as they will not be discussed further here. The first example corresponds to the O-cyanoalkylidene group, especially the O-eyanoethylidene group, which actually has been introduced in carbohydrate chemistry as a method for activation of the anomericcenter in oligosaccharidesynthesis [16].Other examples are less closely related to acetals and result from the substitution of the acetal carbon atom by an heteroatom (Si, So, or B) or correspond to the presence of three heteroatoms (0 or N) on this center. Thus, use of 1,3-dichloro-l,1,3,3-tetraisopropyldisiloxane in basic medium has been introduced for the simultaneous protection of the 3'- and the 5'- OH groups in nucleosides [17];this strategy has been extended to the monosaccharides and the migration

C8l1naud and Gelu

6

l80propylldene, Benzylidene, and Related Acetale

7

Acetalation in Acidic or Neutral Conditions O-cyanoalkylidene

--0 --0

Ph

"8/ /1

O-silylene

\.ph

O-alkylboron

DIred Condensation of a Carbonyl Derivative. Historically, this is the first procedure and generally the sugar and an aldehyde (or a ketone) are simply mixed either directly (the reagent,for instance propanone,used in a large excess, also being the solvent) or in solution in a solvent (~N-dimethylformamide is the most frequently used, dimethylsulfoxidebeing encounteredfar less) and eventually in the presenceof a catalyst.The latter can be either a soluble acid (practicallyall kinds of organic and inorganic acids have been tested, and the most frequently used are sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, or hydrogen chloride)or an insoluble one (Amberlystresins, Montmorillonite KIO). An idealizedrepresentationof the mechanismof the reactionis given in SchemeI, but it does not necessarilygive the exact nature of all possibleintermediates(see Sec. II.B).

O-(dimethylaminoalkylidene)

Chart 2

Derivatives related to acetals used in carbohydrate chemistry

of the silyl-protectinggroup hasbeen studied [18]. A slightly different silyl group has also been suggestedfor the selective protection of sucrose, even if the interosidic acetals (1',2silylene and 1',2:6,6'-disilylene derivatives), resulting from the action of dimethoxydiphenylsilanein the presence of acid, are obtained in low yield [19].More interesting from the preparativepoint of viewis the introductionin carbohydratechemistryof the reactionof dibutyltinoxide giving dibutylstannylenederivatives(or stannoxane)[20]. Their reactivity with electrophiles gives predominantly monosubstituted products, usually with a high regioselectivity[21],as exemplifiedby a monoalkylation [22]. Anotherexample is offered by cyclic boronates,whichhave been used to a limitedextent owingto their high sensitivity to hydrolyticconditions [23]. However,the O-ethylboronderivativeshave been especially developed to give special assistance in various controlled reactions of monosaccharides [24]. The last example is concerned with protecting groups closer to ortho-esters than to aceta1s. The selectiveformationof ortho-esters at nonanomericpositions hasbeen recently described[25]. Amide acetalshave been used particularlyin carbohydratechemistryin the a-(dimethylarnino)-ethylidene and -benzylideneacetal series [26].Their general properties have been considered,especiallythe acid hydrolysisto monoesters,which is of valuein the ribofuranoside series for oligonucleotide synthesis. II.

METHODS FOR PREPARATION OF ACETALS IN CARBOHYDRATE CHEMISTRY

A. General Methods Fundamentally,we can classifythe differentmethodsinto two categories,dependingon the experimentalconditions: (1) acid or neutral medium; (2) basic conditions. Less common procedures will be presented in a third section.

The use of a Lewis acid (e.g., triethyl1luoroborate, zinc chloride, stannous chloride, titanium chloride, iron(ITI)chloride) and other reagents (e.g., iodine, trimethylsilane, triftuoromethane-sulfonylsilane) have also been recommended. Exhaustive lists of catalysts and conditionscan be found in reviews devoted to carbohydrates[5-7], or to general organic chemistry [27,28]. However, one can add the new catalyst, which has been introduced for the smooth formation of p-methoxybenzylidene acetals and p-methoxyphenylmethyl methyl ether [29], namely 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), andhas been applied very recently [30] to the synthesis of isopropylidenemixed acetals. Obviously,the condensationof a carbonyl group with a diol produces 1 mol of water and because of the reversibilityof the reaction(hydrolysisof the acetal),yields are lowered if this by-productis not removed.For such a purpose,there are essentiallytwo possibilities: (1) the continuous removal of water by an azeotropic distillation with a solvent mainly chosen for its boilingyoint (petroleumether,benzene,toluene,xylene, for instance);(2) the presence of a desiccant (the most commonly taken is copper(Il)sulfate,but sodium sulfate or molecular sieveshave been also used); moleculesknown to be water scavengers,such as ortha-esters or dialkylsulfites, have also been suggested, even if they are seldom used in carbohydrate chemistry. Important in this quite general strategy is that, for practically all instances, the reaction is underthermodynamiccontrol, and the control of the stoichiometryis extremely difficolt.lt follows that only the more stableacetals are produced(see Sec. II.B) and usually multiacetals are obtained if several hydroxyl groups are available within the same molecule. This has been a major concern in acetalation reactions in neutral conditions. For instance, use of copper(II)sulfate either in acetone alone or in ~N-dimethylformamide without any additional catalyst, leads to acetals with structures that differ from those resultingfromreactionsin the presenceof an acid; The reactiondependson the temperature [31];however, the strict neutrality of a medium in which copper(Il)sulfateand polyols are interacting can be questioned.

Callnaud and GeIa8

8

Tnmsacetalation. This strategy, based on an acetal exchange in acid conditions, has been introduced more recently in carbohydrate chemistry [32-34]. It offers several advantages over the direct condensation of the corresponding free carbonyl group: (1) anhydrous conditions can be strictly followed, as the only by-product is 2 mol of the alcohol (e.g., MeOH) used to prepare the reagent (Scheme 2); this alcohol can even be removed by

9

l80propylldene, Benzylidene, and Related Acetal.

molecular addition of an hydroxyl group on monovinylethers of 1,2-diols [48]; and its application to the synthesis of 1,2-0-isopropylidene-a-n-galactose [49], this strategy was underestimated until it was shown that the use of 2-aIkoxypropene in N,N-dimethylformamide was a simple and efficient method of acetonation under exclusive kinetically controlled conditions. In many instances, the products differed from those prepared under thermodynanrlc control [50]. The reaction (Scheme 3) is characterized mainly by the .c----....~c ....--.... ,\I\,__ ~, H+ OH + C-OR+ ~

COH

,0.... / ,r:.. / "o,.C, ~ '0""-H+

I

c< -w

H

SCheme 2 diminished pressure to displace the equilibrium if necessary; (2) the stoichiometric of the reaction can be controlled; (3) in some instances, it is possible to obtain acetal(s) under kinetically controlled conditions, even if many sugars (especially free sugars) still react to give the more stable structures (see Sec. II.B); (4) also th~ is a possibility .of obtaining strained acetals, such as those resulting from the acetalation of 2,3-trans-diols of pyranosides, although yields are generally low. Thus, the formation of O-isopropylidene derivatives using 2,2-dimethoxy-propane~N-dimethylformamide-p"toluenesulfonicacid has become one of the .most pop~ar w~ys to protect diols. This strategy has been applied to many sugars and IS ~~~tible With aminosugars [35] and oligosaccharides such as sucrose [36], maltose,laminanbiose, cellobiose, and gentobiose [37]. It has been extended to O-benzylidene derivatives for which the use of a a-dimethoxytoluene can advantageously replace benzaldehyde [38,39]. Its application to oligosaccharides is also .possible and has been described, for instance, for ~~ oligosaccharides [40]. A slight modification of the classic procedure (the ~tion 1S followed by a partial hydrolysis of the crude mixture to remove unstabl~ acyclic acetals) offers a convenient route to an interosidic, eight-membered. cyclic benzylidene acetals [41]. can ~~ the Once again, efforts have been made to find neutral conditions course of the reaction. For instance, use of 2,2-dimethoxypropane m solution in 1,2,dimethoxyethane (which probably plays a role through its interaction with polyols) ~ been suggested as a reagent for acetalation in neutral conditions (no catalyst) of n-mannitol [42] and n-glucitol [43]. . For transacetalation reactions, it is worth noting here the recent strategy mtroduced for selective protection of vicinal diols (and especially with. a trans confi~tion) in carbohydrates: a double exchange involving the acetal functio~ of l,1,2,~~ethoxy­ cyclohexane gave a dispiroacetal, structurally related to a 1,4-dioxane, stab~zed by ~e axial position of the methoxyl groups [44]. This method completes th~ preced;ing one usmg enol ethers, leading to an analogue of 1,4-dioxane [45] (see followmg section). Acetalation with Enol Ethen Under KlneticaDy Controlled Conditions. The first mentio~ of the use of an enol ether to protect the hydroxyl group of an alcohol was developed by Paul [46], who introduced the reaction ~th lIibydrop~ to give tetrahydroyranyl ethers, which is still used 60 years later. In spite of some no~ceable developmen~, ~uch as the preparation of2',3'-O-alk.ylidene derivatives ofnucl~S1des [33]; the syn~es1s of 4,6-0-ethylidene-a-n-glucopyranoside with use of methylvmylether [47]; the mtra-

th:tt

q;-oMe •

Q

0 OH

17

Mll2c"-O OH To a solution of o-ribose (7.5 g, 50 mmol) in dry DMF (30 mL) containing 1 g of Drierite and maintained below 5°C with an ice bath, 2-methoxypropene(100 mmol) andp-toluenesulfonic acid (20 mg) were added. The mixture was stirred magnetically at 0-5°e until monitoringby TLC indicated that all starting material had disappeared (3-4 h), whereupon anhydrous sodium carbonate (5 g) was added and the cooling mixture was stirred vigorously for 1 h more. In subsequent experiments, 3,4-0-isopropylidene-o-ribopyranose 17 was obtained directly by evaporating the neutralized reaction mixture to remove DMF, extracting the residue with ethyl acetate, adding ether to the extract and nucleating; yields were in the range 40-50%. 3,4-0-Isopropylidene-o-ribopyranose 17 obtained by this procedure had an mp of 115-117°e (from ethyl acetate), [ale -85° initial ~ -82° (final 24 h; c 1.1, water).

Methyl 2,a-o-isopropylldene-f>-o-ribofuranoslde [1DO} a,4.Q-isopropylidene-p-o-arabinopyranose'[54}

A solution of 50g (330 mmol) of dry o-ribose in 1.0L of acetone, 100 mL of 2,2dimethoxypropane, and 200 mL of methaiJ.ol containing20 mL of methanol saturated with hydrogen chloride at ooe was stirred at 25°C overnight. The resulting orange solution was neutralized with pyridine and evaporated to a yellow oil. This oil was partitioned between 500 mL of water and 200 mL of ether. The water layer was extracted twice with 200-mL portions of ether, and the combined ether extracts were dried. Evaporation yielded a pale yellow oil, whiclt was distilled at 0.3 mm and 75°C to give 47 g (70%) of the colorless, protected glycoside: "n 1.4507, [a]D -82.2° (c 2, chloroform).

To a solution of o-arabinose (7.5 g, 50 mmol) in dry DMF (150 mL; the slightly turbid mixture became clear after 1 min of reaction) containing 1 g of Drierite, and maintained below 5°C with an ice-bath,2-methoxypropene (100 mmol) and p-toluenesulfonic acid (20 mg) were added. The mixture was stirred magnetically at 0-5°e until monitoring by TLe indicated that all starting material had disappeared (3-4 h), whereupon anhydrous sodium carbonate (5 g) was added, and the cooling mixture was stirred vigorously for 1 h more. The mixture was filtered, poured into ice water (50 mL), and extracted with

Calln aud and Gelas

18 wash ed with wate r the com bine d organic extracts were dichloromethane (3 x 30 mL) , and were freeze-dried. and the com bine d aque ous extra cts (3 x 20 mL). The aque ous phas e gave pure 2; yield iol) ethaJ telm 150 g; 4:1 ethy l aceta Colu mn chromatography (silic a gel ixture was evap orate d ion-m react ed raliz neut nal origi the 4.8 g (63%). In a direc t procedure, ition of ethe r and a syru p disso lved in ethy l acetate. Add directly in vacu o and the resu ltant . yield 0% 60-7 crystal nucleus affored solid 2 in . of 75-7 6°C. yran ose 18 thus obta ined had am.p 3,4-0 -Isop ropy liden e-a-o -arab inop e crystals, mp 82whit gave nol etha ate-m acet l 1:1 ethy Slow evaporation of a solu tion in (final, 24 h; ted) 4 -128 ° (10- 12 min) 4 -IW 84°C, [aID -156 ° (initial. extrapola e i.i, water).

C. Hexosea

Furanoses furanose [95J 1,2:5,6-Di'()-isopropy}idene-o-gluco

D-GhJcose

Related Acet als Isop ropy flden e, Benzytldene, and oc~

?~H

M~ ,I

~~HOa