[r j ferrier; regine blattner; royal society of c(bookza.org)

Carbohydrate Chemistry Volume 31

A Specialist Periodical Report

Carbohydrate Chemistry Monosaccharides, Disaccharides and Specific Oligosaccharides Volume 31

A Review of the Literature Published during 1997

Senior Reporter R.J. Ferrier, Industrial Research Limited, Lower Hutt, New Zealand

Reporters R. Blattner, Industrial Research Limited, Lower Hutt, New Zea la n d K. Clinch, Industrial Research Limited, Lower Hutt, New Zealan d R.H. Furneaux, Industrial Research Limited, Lower Hutt, New Zealand J.M. Gardiner, UMlST, Manchester, UK F?C. Tyler, Industrial Research Limited, Lower Hutt, New Zealand R.H. Wightman, Heriot Watt University, Edinburgh, UK

ROYAL SOCIETY OF CHEMISTRY

ISBN 0-85404-223-7 ISSN 0951-8428

A catalogue record of this book is available from the British Library

0 The Royal Society of Chemistry 2000

All rights reserved

Apart from any fair dealing for the purposes of research or private study, or criticism or review as permitted under the terms of the UK Copyright, Designs and Patents Act, 1988, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page.

Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 OWF, UK

For further information see our web site at www.rsc.org

Typeset by Computape (Pickering) Ltd, Pickering, North Yorkshire, UK Printed by Athenaeum Press Ltd, Gateshead, Tyne &Wear, UK

In the Preface to the preceding volume attention was drawn to the increase in the amount of research of relevance to these Reports that is appearing in the organic chemical literature. This year it is appropriate to highlight the point that very recent years have also seen major enhancement in the importance and scientific merit of much of the work described. In no area is this more evident than in the field of oligosaccharides - particularly their synthesis (Chapter 4) - the number of papers having doubled since 1990, but the quality and importance indices having increased by an appreciably larger factor.

It is, of course, the needs of scientists working in glycobiology that is driving activity in this area, the significance being notably exemplified by reports on the preparation of specific carbohydrate-based antigens - especially cancer- specific oligosaccharides and glycoconjugates. Glycomedicinal chemistry and its reliance on carbohydrate synthesis are now very well established.

Oligosaccharide synthetic methods are developing in line with demands, polymer-supported procedures now being common - several decades after analagous developments in the oligopeptide and oligonucleotide fields, and specific enzyme-dependent processes are at last in frequent use.

Concurrently, solution-phase methodology is progressing quickly with the overdue recognition that the differential reactivities of both glycosylating agents and carbohydrate acceptor alcohols can be harnessed for the opening of selective, multi-step, one-pot procedures. Startling consequences are beginning to appear, and surely herald major applications of this approach.

Other matters to catch the eye in the oligosaccharide field are the expanding use of intramolecular approaches and, inevitably, examples of the combinatorial strategy. With the sialic acids having such prominent significance in glycobiology their chemistry is being pursued with particular vigour.

I thank our unchanged team for shouldering the continuously more demanding task of surveying this field, and trust that the assistance that Prof. Rob Field and Dr Rayi Kartha, St Andrews University, will provide with future volumes will enable us to bring forward our completion dates.

R.J. Ferrier September 1999

V

Chapter 1 Introduction and General Aspects

References

Chapter 2 Free Sugars

1 Theoretical Aspects

2 Synthesis 2.1 Pentoses 2.2 Hexoses 2.3 Chain-extended Sugars

3 Physical Measurements

4 Isomerization

5 Oxidation

6 Other Aspects

References

Chapter 3 Glycosides and Disaccharides

1 0-Glycosides 1.1 Synthesis of Monosaccharide Glycosides 1.2 Synthesis of Glycosylated Natural Products and Their

Analogues 1.3 0-Glycosides Isolated from Natural Products 1.4 Synthesis of Disaccharides and Their Derivatives 1.5 Disaccharides with Anomalous Linking or Containing

Modified Rings 1.6 Reactions, Complexation and Other Features of

0-Gl y cosides

2 S-, Se- and Te-Glycosides

1

2

4

4

11

11

12

12

13

15

15 15

24 27 28

37

38

39

Carbohydrate Chemistry, Volume 31 0 The Royal Society of Chemistry, 2000

vii

... Vlll

3 C-Glycosides 3.1 Pyranoid Compounds 3.2 Furanoid Compounds

References

Chapter 4 Oligosaccharides

1

2

3

4

5

6

7

8

9

10

General

Trisaccharides 2.1 General 2.2 Linear Homotrisaccharides 2.3 Linear Heterotrisaccharides 2.4 Branched Homotrisaccharides 2.5 Branched Heterotrisaccharides 2.6 Analogues of Trisaccharides and Compounds with

Anomalous Linking

Tetrasaccharides 3. I Linear Homotetrasaccharides 3.2 Linear Heterotetrasaccharides 3.3 Branched Heterotetrasaccharides 3.4 Analogues of Tetrasaccharides

Pent asaccharides 4.1 Linear Homopentasaccharides 4.2 Linear Heteropentasaccharides 4.3 Branched Homopentasaccharides 4.4 Branched Heteropentasaccharides

Hexasaccharides 5. I Linear Hexasaccharides 5.2 Branched Hexasaccharides

Heptasaccharides 6.1 Linear Heptasaccharides 6.2 Branched Hep tasaccharides

Octasaccharides

Nonasaccharides

Higher Oligosaccharides

Cyclodextrins 10.1 10.2 Branched Cyclodextrins 10.3 Cyclodextrin Ethers

General Matters, and Synthesis of Cyclodextrins

Contents

41 41 50

51

62

62

64 64 65 65 67 67

67

68 68 69 69 71

71 71 71 72 72

73 73 74

74 74 75

76

76

78

79 79 80 80

Contents ix

10.4 Cyclodextrin Esters 10.5 Amino Derivatives 10.6 Thio- and Halogeno-Derivatives 10.7 Other Features of Cyclodextrins

80 81 82 82

83 References

92 Chapte 5 Ethers and Anhydro-sugars

92 92 92 94

1 Ethers 1.1 Methyl Ethers 1.2 Other AlkyI and Aryl Ethers 1.3 Silyl Ethers

95 95 95

2 Intramolecular Ethers (Anhydro-sugars) 2.1 Oxirans 2.2 Other Anhydrides

96 References

98 Chapter 6 Acetals

1 Methylidene, Isopropylidene and Benzylidene Acetals 98

99 2 Other Acetals

101 3 Reactions of Acetals

1 02 References

104 Chapter 7 Esters

104 104 1 08

1 Carboxylic Esters 1.1 Synthesis 1.2 Natural Products

109 2 Phosphates and Related Esters

111 3 Sulfates and Related Esters

112 4 Sulfonate Esters

113 5 Other Esters

114 References

X Contents

Chapter 8 Halogeno-sugars

1 Fluoro-sugars

2 Chloro-, Bromo- and Iodo-sugars

References

Chapter 9 Amino-sugars

1 Natural Products

2 Syntheses 2.1 By Chain Extension 2.2 By Epoxide Ring Opening 2.3 By Nucleophilic Displacement 2.4 By Amadori Reaction 2.5 From Azido-sugars 2.6 From Unsaturated Sugars 2.7 From Aldosuloses 2.8 From Aminoacids 2.9 From Chiral Non-carbohydrates 2.10 From Achiral Non-carbohydrates

3 Properties and Reactions 3,l Interconversions 3.2 N-Acyl and N-Carbamoyl Derivatives 3.3 N-Sulfonates and N-Sulfates 3.4 Imide, Isothiocyanate and Thiocarbonyl Derivatives 3.5 N-Alkyl Derivatives 3.6 Lipid A Analogues 3.7 Other References to Amino-sugars

4 Diamino-sugars

References

Chapter 10 Miscellaneous Nitrogen-containing Derivatives

1 Glycosylamines and Related Glycosyl-N-bonded Compounds 1.1 Glycosylamines 1.2 Glycosylamides Including N-Glycopeptides 1.3 N-Glycosyl-carbamates, -isothiocyanates, -thioureas and

Related Compounds

2 Azido-sugars

3 Nitro-sugars

118

118

120

121

123

123

123 123 124 125 128 128 129 130 130 131 132

133 133 134 135 136 137 137 137

137

138

142

142 142 142

144

145

148

Contents

4 Carbodiimides

5 Oximes, Hydroxylamines, Nitriles, Imines and Amidines

6 Hydrazones and Related Compounds

7 Other Heterocycles

References

Chapter 11 Thio- and Seleno- and Telluro-sugars

References

Chapter 12 Deoxy-sugars

References

Chapter 13 Unsaturated Derivatives

1 General

2 Pyranoid Derivatives 2.1

2.2 2,3-Unsaturated Cyclic Compounds 2.3 3,4-Unsaturated Cyclic Compounds 2.4 5,6-Unsaturated Cyclic Compounds

1,2-Unsaturated Cyclic Compounds and Related Derivatives

3 Furanoid Derivatives 3.1 1 ,ZUnsaturated Cyclic Compounds 3.2 2,3-, 3,4- and 5,6-Unsaturated Cyclic Compounds

4 Acyclic Derivatives

5 Miscellaneous Compounds

References

Chapter 14 Branchedchain Sugars

R I

I 1 Compounds with a C-C-C Branch-point

0

xi

148

149

151

152

154

158

164

166

170

172

172

172

172 175 177 178

178 178 178

179

180

181

183

183

xii Con tents

1.1 1.2 Branch at C-3 1.3 Branch at C-4 1.4 Branch at C-5

Branch at C-1 or C-2

R I

2 Compounds with a C-C-C Branch-point I N

2.1 Branch at C-3 or C-4 2.2 Branch at C-5 or C-6

R I

3 Compounds with a C-CH-C Branch-point 3.1 Branch at C-2 3.2 Branch at C-3 3.3 Branch at C-4

R I

R II

R I

4 Compounds with a C-C-C, C-C-C or C-C-C I Branch-point

R

References

Chapter 15 Aldosuloses and Other Dicarbonyl Compounds

1 Aldosuloses

2 Other Dicarbonyl Compounds

References

Chapter 16 Sugar Acids and Lactones

1 Aldonic and Aldaric Acids and Lactones

2 Anhydroaldonic Acids and Lactones

3 Ulosonic Acids

4 Uronic Acids

5 Ascorbic Acids

References

183 183 186 187

188

188 189

189 189 193 195

195

197

200

200

20 1

20 1

202

202

204

205

209

21 1

21 2

Contents

Chapter 17 Inorganic Derivatives

... Xl l l

216

1 Carbon-bonded Phosphorus Derivatives 216

2 Other Carbon-bonded Derivatives 217

3 Oxygen-bonded Derivatives 219

4 Nitrogen-bonded Derivatives 219

References 220

Chapter 18 Alditols and Cyclitols 222

1 Alditols and Derivatives 1.1 Alditols 1.2 Anhydro-alditols 1.3 Amino- and Imino-alditols

222 222 227 227

2 Cyclitols and Derivatives 236 2.1 Cyclopentane Derivatives , 236 2.2 Inositols and Other Cyclohexane Derivatives 240 2.3 Inositol Phosphates and Derivatives 244

References 247

Chapter 19 Antibiotics 254

1 Aminoglycosides and Aminocyclitols 254

2 Macrolide Antibiotics 256

3 Anthracyclines and Other Glycosylated Polycyclic Antibiotics 256

4 Nucleoside Antibiotics 258

5 Miscellaneous Antibiotics 262

References 264

Chapter 20 Nucleosides 267

1 General 267

2 Synthesis 267

3 Anhydro- and Cyclo-nucleosides 269

xiv

4

5

6

7

8

9

10

11

12

13

14

15

16

Contents

Deoxynucleosides 270

Halogenonucleosides 274

Nucleosides with Ni trogen-su bs ti tuted Sugars 274

Thio- and Seleno-nucleosides 275

Nucleosides with Branched-chain Sugars 277

Nucleosides of Unsaturated Sugars, Aldosuloses and Uronic Acids 280

C- Nucleosides 280

Carbocyclic Nucleosides 28 1

Nucleoside Phosphates and Phosphonates 283 12.1 Nucleoside Mono-phosphates and -phosphonates and

Their Analogues 283 12.2 Cyclic Monophosphates and Related Phosphonates 285 12.3 Nucleoside Triphosphates and Their Analogues 286 12.4 Nucleoside Mono- and Di-phosphosugars 287 12.5 Di- and Tri-nucleotides and Their Analogues 287

Oligonucleotide Analogues with Phosphorus-free Linkages 29 1

Ethers, Esters and Acetals of Nucleosides 294

Miscellaneous Nucleoside Analogues 296

Reactions 298

References 30 1

Chapter 21 NMR Spectroscopy and Conformational Features 312

General Aspects

Furanose Systems

Pyranose and Related Systems

Disaccharides

Oligosaccharides

NMR of Nuclei Other than 'H and l3C

References

312

313

315

316

317

318

318

Contents xv

Chapter 22 Other Physical Methods 322

1 IR Spectroscopy

2 Mass Spectrometry

3 X-ray and Neutron Diffraction Crystallography 3.1 Free Sugars and Simple Derivatives Thereof 3.2 Glycosides, Disaccharides and Derivatives Thereof 3.3 Higher Oligosaccharides and C-Glycosides 3.4 Anhydro-sugars 3.5 Halogen, Phosphorus, Sulfur, Selenium and Nitrogen

containing Compounds 3.6 Branched-chain Sugars 3.7 Inorganic Derivatives 3.8 Alditols and Cyclitols and Derivatives Thereof 3.9 Nucleosides and Their Analogues and Derivatives Thereof 3.10 Neutron Diffraction

4 Polarimetry, Circular Dichroism, Calorimetry and Related Studies

References

Chapter 23 Separatory and Analytical Methods

1 Chromatographic Methods 1.1 Gas-Liquid Chromatography 1.2 Thin-layer Chromatography 1.3 High-pressure Liquid Chromatography 1.4 Column Chromatography

2 Electrophoresis 2.1 Capillary Electrophoresis 2.2 Other Electrophoretic Methods

3 Other Analytical Methods

References

Chapter 24 Synthesis of Enantiomerically Pure Non-carbohydrate Compounds

1 Carbocyclic Compounds

2 Lactones

3 Macrolides, Macrocyclic Lactams, Polyether Ionophores and Their Constituent Segments

322

323

325 325 325 326 327

328 330 330 33 1 332 332

332

334

340

340 340 340 340 342

342 342 343

343

343

347

347

352

354

xvi

4 Other Oxygen Heterocycles

Con tents

356

5 N- and S-Heterocycles 362

6 Acyclic Compounds 37 1

7 Carbohydrates as Chiral Auxiliaries, Reagents and Catalysts 373 7.1 Carbohydratederived Reagents and Auxiliaries 373 7.2 Carbohydrate-derived Catalysts 379

References 38 1

Author Index 385

Abbreviations

The following abbreviations have been used:

Ac Ade AIBN All Ar Ara

. BBN Bn Boc Bu BZ CAN Cbz CD Cer CI

ASP

CP CYt Dahp DAST DBU DCC DDQ DEAD DIBALH DMAD DMAP DMF DMSO Dmtr e.e. Ee ESR Et FAB

acetyl adenin-9-yl 2,2-azobisisobutyronitrile ally1 aryl arabinose aspartic acid 9-borabicyclo[3.3.3]nonane benzyl t-but oxycar bonyl butyl benzoyl ceric ammonium nitrate benzylox ycar bonyl circular dichorism ceramide chemical ionization cyclopen tadien y 1 cytosin- 1 -yl 3-deoxy-~-arabino-2-heptulosonic acid 7-phosphate diethylaminosulfur trifluoride 1,8-diazabicyclo[5.5.0]undec-5-ene dicyclo hexy lcarbodi-imide 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone diethyl azodicarboxylate di-isobutylaluminium hydride dimethylacetylene dicarboxylate 4-(dimethylamino)pyridine N,N-dimeth y 1 formamide dimethyl sulfoxide dimethoxytrityl enantiomeric excess 1 -ethoxyethyl electron spin resonance ethyl fast-atom bombardment

xvii

xviii Abbreviations

Fmoc Fru FTIR Fuc Gal GalNAc GLC Glc GlcNAc

Gua

HMPA HMPT HPLC IDCP Ido Im IR Kdo LAH LDA Leu LTBH LYX Man mCPBA Me Mem Mmtr Mom Ms MS NAD NBS NeuNAc NIS NMNO NMR NOE ORD PCC PDC Ph Phe Piv

GlY

HeP

9-fluorenylmethylcarbony l fructose Fourier transform infrared fucose galactose 2-acetamido-2-deoxy-~-galactose gas-liquid chromatography glucose 2-acetamido-2-deoxy-~-glucose glycine guanin-9 -yl L-gbcero-D-amanno-hep tose hexamethylphosphoric triamide hexamethylphosphorous triamide high performance liquid chromatography iodonium dicollidine perchlorate idose imidazoly 1 infrared 3-deoxy-~-rnanno-2-octulosonic acid lithium aluminium hydride lithium di-isopropylamide leucine lithium triethylborohydride 1 yxose mannose rn-chloroperbenzoic acid methyl (2-me thox yethox y)methyl monomet hoxytri tyl me thoxyme thy1 methanesulfonyl (mesyl) mass spectrometry nicotinamide adenine dinucleotide N-bromosuccinimide N-acetylneuraminic acid N-iodosuccinimide N-methylmorpholine N-oxide nuclear magnetic resonance nuclear Overhauser effect optical rotatory dispersion pyridinium chlorochromate pyridinium dichromate phenyl p hen ylalanine pivalo y 1

Abbreviations xix

Pmb Pr Pro p.t.c. PL Rha Rib Ser SIMS TASF Tbdms Tbdps Tipds Tips Tf Tfa TFA THF ThP Thr Thy Tips TLC Tms TPP TPS Tr Ts Ura UDP UDPG uv XYl

p-met hox y benzy 1

proline phase transfer catalysis pyridine rhamnose ribose serine secondary-ion mass spectrometry tris(dimeth ylamino)sulfonium( trimethylsily1)difluoride t- bu t y ldimeth ylsily 1 t- butyldipheny lsilyl tetraisopropyldisilox- 1,3-diyl triisoprop ylsil y 1 triflluoromethanesulfonyl (triflyl) trifluoroacetyl trifluoroacetic acid tetrahydrofuran tetrahydrop yran yl threonine thymin- 1 -yl 1,1,3,3-tetraisopropyldisilox- 1,3-diyl thin layer chromatography trimethylsilyl triphenylphosphine tri-isopropylbenzenesulfon y 1 triphenylmethyl (trityl) toluene-p-sulfonyl (tosyl) uracil- 1 -yl uridine diphosphate uridine diphosphate glucose ultraviolet xylose

ProPYl

1 Introduction and General Aspects

The long awaited comprehensive IUPACfiUBMB paper on Nomenclature of Carbohydrates which covers all aspects of the subject has received wide dissemination. Although the contents have the formal status of ‘Recommen- dations’, they are effectively the ‘rules’ to be followed. The subject has been revisited, particularly from the Hungarian perspective.* Hanessian’s multi- authored book ‘Preparative Carbohydrate Chemistry’ deals with a wide range of practical aspects of modern synthesis. Examples, which include experimental details, cover such topics as oligosaccharide synthesis, the conversion of carbohydrates into carbocyclic compounds, free radical reactions, the use of organotin reagents in the field, selective 0-substitution and oxidation reactions applied to carbohydrates. A further book on synthesis consists of 21 chapters written by experts on various aspects of the field including methodology and the synthesis of different carbohydrate-based natural product^.^

A method for the representation of oligosaccharide structures by graphic theoretical methods has been developed for the purpose of storing and searching relevant informati~n.~

Attention is drawn to the plethora of reviews that have appeared on specific features of the subject and which are noted in relevant chapters. An extreme example is Chapter 4 which begins with a catalogue of 39 references to review material relevant to oligosaccharide chemistry and biochemistry.

Reviews of wider interest have appeared on the following topics: protecting groups of value in carbohydrate chemistry;6 protecting groups revealed in the 1997 li terat~re;~ the use of phase transfer catalyses in anomeric transformations and glycosylations; the use of sugar derivatives as phase transfer catalysts* and combinational synthesis in the field.9p10

Biologically inclined treatments have dealt with preparative biotransforma- tions of carbohydrate derivatives (survey of the 1997 literature);‘ structure- biological activity relationships of natural products; l2 the role of 1 -deoxy-D- threo-pentulose as a precursor in thiamine biosynthesis; chemo-enzymic synthesis of oligosaccharides of importance in molecular glycobiology. l4 A brief discussion of molecular recognition events involving carbohydrates and their biological consequences has been written for non-specialists.

A very interesting proposal by A.I. Scott regarding the prebiotic biosynthesis of polyketides, fatty acids and polyprenoids uses ribonucleosides 5’-linked to

Carbohydrate Chemistry, Volume 3 1 0 The Royal Society of Chemistry, 2000

1

2 Carbohydrate Chemistry

RNA as templates, the C-C bonding reactions involving monomeric units linked to 0-3’.16

A survey has been presented on the carbohydrate transformations that can be induced by hypervalent iodine reagents. Such topics as the direct oxidation of tri-0-acetyl-D-glucal to the corresponding l-en-3-one, C- 1, C-2 bond oxidation of derivatives protected at all the hydroxyl groups except the anomeric and H- 1 abstraction from C-glycosidic compounds were covered. l 7

A significant development has been made in use of sodium periodate for oxidizing carbohydrate a-diols with the reagent adsorbed on silica; oxidations are carried out in dichloromethane and can be followed by TLC; product isolation requires decanting of the solution and removal of the solvent; yields are very high.’*

Carbohydrate-containing dendrimers are attracting considerable attention (see Chapter 3) and an overview of the topic by Stoddart and colleagues has appeared. l9

The subject of dihexulose dianhydrides has been the subject of a thorough review.20

References

1

2 3

4

5

6

7 8

9

10

11 12

13 14 15 16

A.D. McNaught, Adv. Carbohydr. Chem. Biochem., 1997, 52, 43 (Chem. Abstr., 1997, 127, 234 489); Carbohydr. Res., 1997, 297, 1. Pure Appl. Chem., 1996, 68, 1919. L. Kovacs, Mugy. Kem. Fofy., 1997,103,178 (Chem. Abstr., 1997, 127,34410). Preparative Carbohydate Chemistry, 1997, Ed. S . Hanessian, Dekker, New York, N.Y. Modern Methods in Carbohydrate Synthesis, 1996, Eds. S.H. Khan and R.A. O’Neill, Harwood, Amsterdam. I.J. Bruno, N.M. Kemp, P.J. Artymiuk and P. Willett, Carbohydr. Res., 1997, 304,61. T.B. Grindley, Front. Nat. Prod Res., 1996, 1, 225 (Chem. Abstr., 1997, 127, 50 861). K. Jarowicki and P. Kocienski, J. Chem. Soc., Perkin Tram. 1, 1998,4005. R. Roy, Handb. Phase Transfer Catal., 1997, 244 (Chem. Abstr., 1997, 127, 95 457). D. Kahne, Curr. Opin. Chem. Biof., 1997, 1, 130 (Chem. Abstr., 1997, 127, 109 094). R. Liang, L. Yan, J. Loebach, M. Ge, Y. Uozumi, K. Sekanina, N. Horan, J. Gildersleeve and C. Thompson, Science, 1996, 274, 1520 (Chem. Abstr., 1997, 126,89 652). S.M. Roberts, J. Chem. SOC., Perkin Trans. I , 1999, 1. A.C. Weymouth-Wilson, Nat. Prod. Rep., 1997, 14,99 (Chem. Abstr., 1997, 127, 5248). S. David and B. Estramareix, Adv. Carbohydr. Chem. Biochem., 1997,52,268. G.J. McGarvey and C.-H. Wong, Liebigs Ann. Chem., 1997, 1059. R.J. Ferrier, Sci. Spectra, 1997,9, 32 (Chem. Abstr., 1997,127,205 763). A.I. Scott, Tetrahedron Lett., 1997,38,4961.

I : Introduction and General Aspects 3

17 18 19 20

A. Varvoglis, Tetrahedron, 1997,53, 1179. Y.-L. Zhong and T.K.M. Shing, J. Org. Chem., 1997,62,2622. N. Jayaraman, S.A. Nepogodiev and J.F. Stoddart, Chem. Eur. J., 1997,3, 1193. M. Manley-Harris and G.N. Richards, Adv. Carbohydr. Chem. Biochem., 1997, 52, 207.

2 Free Sugars

1 Theoretical Aspects

An improved method for partitioning the overall molecular charge distribution into atom-centred monopole charges has been applied to D-glucose and D- fructose.’ The influence of the em-anomeric effect on the conformations of D-

glucose, as well as simpler tetrahydropyran derivatives, in the gas phase and in aqueous solution has been investigated by use of ab initio calculations.2

2 Synthesis

The synthesis and reactions of sugars and nucleosides under conditions pertinent to early evolution have been incorporated in a review on ‘prebiotic chemistry’.

2.1 Pentoses - C-3- Modified D-erythrO- and ~-threo-2-deoxypentofuranose derivatives, such as compounds 1 and 2, useful as precursors of nucleoside analogues, have been synthesized from 2,3-O-cyclohexylidene-~-glyceraldehyde as outlined in Scheme 1; a zinc-mediated allylation was used for extending the ~arbon-chain.~ 1 -O-Acetyl-2,3,5-tri-O-benzyl-~-~-ribofuranose was obtained from 3,s-0-Tips-protected methyl L-arabinofuranoside via a 2- 0-trifluoromethanesulfonyl-intermediate.

CHO

i ___)

ii

OR

R = Tbdms or Ts R’ - H, R2R3 =

c R’ = Tbdms or Ts, R2 P H, R3 = Bz

Scheme 1 Reagents: i, AIIBr, Zn; ii, 0 3 , PPh3; iii, NaN3, DMF

BzOCHr,

iii - R-TS

2

Carbohydrate Chemistry, Volume 3 1 0 The Royal Society of Chemistry, ZOO0

4

2: Free Sugars 5

2.2 Hexoses - Trapping of dihydroxyacetone phosphate (prepared from a-L- glycerol phosphate by use of co-immobilized a-L-glycerolphosphate oxidase and catalase under anaerobic conditions) by DL-glyceraldehyde in the presence of an aldolase gave, after enzymic dephosphorylation, a mixture of D-fructose and D-sorbose.6 3,4,6-Tri-O-acetyl-2-azido-2-deoxy-~-glucopyranose (3) (or its manno-analogue) underwent fragmentation on exposure to (diacetoxyiod0)- benzene and iodine to give nitrile 6, by way of alkoxyl radical 4 and a-azido- carbinyl radical 5, as shown in Scheme 2.7

CH20Ac

ACO G O H - i P - N3 N3 AcO gEHo R

3 4 5 R = CHN3 6 R--N

Reagent: i, PhI(OAc)z, 12 Scheme 2

In a novel isomerization reaction ditosylate 7 was converted to methyl a-D- altropyranoside (8) by treatment with sodium acetate in DMF, followed by aqueous-KOH; a manno-configured epoxide-intermediate has been postulated.*

OTs OH CH208n 7 8 0

2,3,4,6-Tetra-O-qllyl- and -benzyl-D-glucose have been obtained in 77% yield by thiolysis (EtSH/BF,.OEt,) of per-O-allyl- and per-O-benzylsucrose, respectively: and hydrolysis of sucrose, maltose, cellobiose or starch by use of commercial, acidic zeolites at 80-150°C in aqueous media gave D-

glucose in >90% yield.I0 D-Fructose was available similarly by hydrolysis of inulin. lo

2.3 Chain-extended Sugars - Fructose 1,6-diphosphate aldolase-catalysed condensation of 4-benzyloxybutanal with dihydroxyacetone phosphate furnished, after enzymic dephosphorylation, the 5,6-dideoxy-~-fhreo-hept-2-ulose derivative 9; its use in the synthesis of the natural macrolactone (+)-aspicilin is referred to in Chapter 24." Molybdic acid has been found to catalyse the carbon-skeleton rearrangement of 2-C-hydroxymethyl-~-aldohexoses to D- hept-2-uloses. In agreement with the known mechanism of the molybdate- catalysed epimerization of aldoses, 2-C-hydroxymethyl-~-glucose (10) gave D-


manno-heptulose (12), and 2-C-hydroxymethyl-~-mannose (1 1) gave D - g h 0 - heptulose (13) preferentially. l2

AH 10 R’ = CH20H, R2 = OH 11 R’ = OH, R2 = CH20H

12 R’ =OH, R2 = H 13 R’ = H, R2 = OH

14 R=Me 15 R-Bn

2.3. I Chain-extension at the “on-reducing End’ - The epimeric 6-C-methyl-~- glucoses 1413 and their 6-C-butyl analogues 1514 have been synthesized by action of methyllithium and butyllithium, respectively, on 1,2-O-isopropylidene-5-O-Tbdms-oc-~-glucurono-3,6-lactone and subsequent reduction and deprotection (see Vol. 30, Chapter 2, ref. 32). Addition of propargyl groups (HC = CCH2Br/Zn) to various 5-aldehydo-pentofuranose derivatives proceeded with good erythro-selectivity; the addition products were either partially hydrogenated to alkenes, as precursors of 6-deoxyheptoses, or ozonolysed to afford 6-deoxyhepturonates; an example is given in Scheme 3. l5

CH2CH=CH2 I

Reagents: i, CH=CCH2Br, Zn; ii, Pd/BaS04, HP; iii, AcpO, Py; iv, 03, MeOH-Py, S0Cl2 Scheme 3

An improved procedure for the synthesis of D-glycero-D-manno-heptofurano- side derivative 18 from 5-aldehydopentofuranose derivative 16 by Wittig additiodcis-hydroxylation via 2-alkene 17 has been reported (see Vol. 20, Chapter 2, refs. 25-27); use of formylmethylenetriphenylphosphorane in place of (methoxycarbonylmethy1ene)triphenylphosphorane furnished mainly the E- alkene 19, which on cis-hydroxylation gave the L-glycero-isomer 20 selectively. The D-glycero isomer 18 was also available by one-carbon elongation of the mannose-derived aldehyde 21 with benzyloxymethylmagnesium chloride.

Several protected 1,6-dialdohexopyranoses have been extended by the Wittig reactionfcis-hydroxylation method (22+23, l7 24+2518) or by use of Grignard reagents (26+27,18 28+2919). Reaction of carbohydrate-derived Wittig reagents with calixarene tetra-aldehyde 30, followed by reduction of the double bonds, produced ‘ C-calixsugars’, for example compound 31 .20

2: Free Sugars 7

CHO Ho

21 R = B n O d

The nitrile oxide/oxazoline approach to higher sugars (see Vol. 27, Chapter 2, ref. 39) has now been applied to the syntheses of 7-deoxy-nonose and -decose derivatives, as illustrated in Scheme 4.*l

ex BnO

24 R' - CHO

25 R l = -{OH] R2,R2 = "xMe, X = OMe

26 R' = CHO

27 R, FzFph} R2,R2 ="r, X = SEt

28 R'=CHO

29 Rl mT} R2 = Bn, X = OMe

C'LC=NOH

Reagents: i, tzx, TEA; ii, H2, PdC; iii, NaBH4

Scheme 4

30 R'=CHO 1

ii. iii ___c

Hol H O T


Radical alkylation of 6-iodide 32 with trimethyl[(2-tributylstannylmethyl)-2- propenyllsilane (34) furnished the branched, unsaturated tetradeoxynonopyr- anose derivative 33 in 45% yield.”

R

32 R=CH21 Aco @Me OAC

33 R - CH2CH2C-CH2Tms

SiMe3 < 34 SnBu3

EH2

2.3.2 Chain-extension at the ‘Reducing End’ - A review on transition metal- catalysed functionalization at the anomeric centre of carbohydrates covered Heck-type and Pd-catalysed vinylic coupling reactions of glycals, as well as reactions of glycal-derived n-ally1 complexes.23

CH20Tr CH20Tr TrOCH2 0 OH - i @cQMe - OH

HO HO

OH OH OH 35 36 37

I TIOCHp

I

Reagents: i, [Ph&sCH2CQEt]+Br, Zn or Ph&s=CHC02Et, BuLi (see text)

Scheme 5

Partially protected free sugars reacted with arsonium ylids in toluene under neutral conditions ([Ph3AsCH2C02Et]+Br-/Zn) to give mainly E-alkenes (e.g., 35 + 36 in Scheme 5); under basic conditions (Ph3As=CHCO,Et/BuLi) fused lactones were formed via C-glycofuranosides (e.g., 36+37-+38).24 D-Mannose has been extended by 4, 6, 8 or 10 carbon atoms by reaction of the protected aldehydo-sugar 39 with the appropriate Wittig reagents, followed by hydrogenation. Two of the products 40 were then elaborated into carbon-backbone- elongated GDP-L-fucose derivatives 41 .25

It has been demonstrated that Reformatzki alkylations of protected hexos- uloses furnish 2-deoxy-4-octulosuronic acid derivatives with considerable diastereoselectivity; the methodology has been applied to the synthesis of oct-

2: Free Sugars 9

O x 0

CH20Tbdms 39 R=CHO 40 R = (CH2),,Me, n = 4,6,8, 10

OH \ 41 n=4or6 +

42 R=CHO + 43 - 2HCH2C02Me

OH

4-ulo-4,7-furanonate 43 from hexos-2-ulofuranose derivative 42.26 4-Benzo- phenone-substituted ribofuranose derivative 46 has been prepared as a precursor of novel nucleoside analogues. The key step involved treatment of 2,3- 0-isopropylidene-L-erythrose 44 with Grignard reagent 45, as shown in Scheme 6.27

HO 0

0 0 x 44 3 stepsf = 46

Reagents: i, w M g i 3 q ii, PCC; iii, Bu4NF

U 45 Schehe 6

Indium-mediated allylation of D-erythrose in aqueous media generated the trideoxyhept- 1 -enit01 47 which offered convenient access to 3-deoxy-~- arabino-2-heptulose and 3-deoxy-~-arabino-2-heptulosonic acid.28 3-Carbon elongation of 2-acetamido-2-deoxy-~-mannose by similar indium-promoted allylation and subsequent ozonolysis of the terminal double bond furnished 4- acetam~do-~,4-d~deoxy-~-glycero-~-ga~acto-octose, isolated as the a-peracetate

Allylation at the reducing end of sugars has also been effected with tetraallyltin in micellar systems, although with only moderate stereoselectivity; alkenes 49 were obtained from D-arabinose in 82% yield as a 3:7 mixture of the D-gluco- and D-manno-compounds, for example.30

Commercial D-gbcero-D-gubheptono- 1,4-lactone (50) served as the starting material in a novel multi-step synthesis of N-acetylneuraminic acid (shown as the protected derivative 54, Scheme 7). The chain-elongation was achieved by alkylation of a 2-alkoxy-2-cyanoacetate anion with the allylic bromide 51. In a further key-step, opening of an epoxide by a neighbouring trichloroacetimidate

10

tH2 FH

Carbohydrate Chemistry

Y2 FH2

CH I

HOT:: AcHNfz) AC$oAc OAc

CH20Ac

OAc OAc

CH2OH OAc 47 18 49

group was used to introduce the amino function (52+53).31 A stereospecific addition reaction of lithiated tri-0-benzyl-D-glucal to tetra-0-benzyl-D- glucono-l,5-lactone (55) has been used in the synthesis of the C-C-linked analogue 56 of a,a-trehalose (Scheme 8).32

8 steps

vi

i

NC C@Bu'

OMom

54 53 52

Reagents: i, NC-CHCO2Bu1, NaH; ii, BF3.0Et2; iii, MomCI, Pr'Et2N; iv, TsOH, Py, H20; I

OTbdms v, Bu&nH, AIBN; vi, Bu4NF

Scheme 7

0-

OBn OBn OH OH 55 56

SnBy, Buli; ii, 0 ~ 0 4 . NMNO; iii, H2, Pd/C

Scheme 8 BnO

2: Free Sugars

RO

11

r O P i v

57 R = Sip& or TWrns,

58 R = SiPt3 or TWrns, r7=2 ,

n = 1

59 R = Sip& or Tbdrns 60 R = Sip& or Tbdrns N 61 R R = < I

62 RR = a*> '0

Full details on the acid-catalysed Wagner-Meerwein type rearrangements of glycal-derived carbinols ( 5 7 4 9 , 58-60; see Vol. 27, Chapter 3, Scheme 23) have been published.33 Reaction of the pivaloylated diazirine 61 with dihydrofuran gave the sugar-spirocyclopropane derivative 62 in 70% yield. The benzylated analogue of 61 and alternative enol ethers (dihydropyran, glycals, 1 -methoxyoct- 1 -ene) reacted poorly, however.34

3 Physical Measurements

A cost efficient method for determining the free energies of the anomers of free a- (axial) and p- (equatorial) anomers of D-mannose has been Calculated by three different standard methods [i, free energy perturbation (FEP), ii, potential of mean free force (PMF) and iii, the recently described MC(JBW)/ SD simulation technique], the last of which performed best.36

The solubilities of sucrose in aqueous MeOH, aqueous EtOH and in MeOW EtOH mixtures have been measured at 25, 40 and 60°C, and three UNIQUAC-based activity coefficient models were evaluated for their ability to describe these new data, as well as older ones taken from the l i t e r a t ~ r e . ~ ~ Glass transition temperatures of aqueous glucose solutions calculated by molecular dynamics simulation were in good agreement with experimental data, in contrast to similarly calculated melting temperature^.^^

The diffusion constants of water in glassy systems of glucose and maltose syrups at various temperatures, water contents and molecular weights have been determined from the rates of desorption under reduced pressure.39

The activation energy for CAN-catalysed sucrose hydrolysis is referred to in Section 6 (ref. 45).

4 Isomerization

A study on the catalysis of mutarotation of tetramethylglucose by ribonucleosides found cytidine the most efficient, achieving a 20 fold rate increase which suggests a bifunctional mechanism.40

It has been postulated that the calcium ion-catalysed epimerization of glucose in alkaline solution proceeds via a complex of the cation with 0 -1 ,


0-2, 0-3 and 0-4 of the acyclic form of the sugar, and that the reaction, like the Bilik reaction, involves a rearrangement of the carbon skeleton.41 The glucose-mannose epimerization reaction has been carried out with the chiral nickel complexes (R, R)- and (S, S)- 1,2-bis(dimethylamin0)-1,2-diphenyl- ethane.42

5 Oxidation

Two major products, ~-a~a~ino-hex-2-ulosonic acid and ~-threo-hexo-2,5- diulose, were formed on oxidation of D-fructose with molecular oxygen over W C catalysts. Promotion of the catalyst with bismuth improved the selectivity for the former product, which, however, deactivated the cata-

A kinetic and mechanistic study of the Pd(I1)-catalysed oxidation of maltose and lactose by acidic NBS to give gluconic acid from maltose and both, gluconic and galactonic acid from lactose, has been published.44

lyst?

6 OtherAspects

The activation energy for sucrose hydrolysis by ceric ammonium nitrate at pH 7 was found to be 5.88 kJ/mol, which is much less than that for hydrolysis by 0.18 N HCl (126 kJ/mol) The hydrolysis of various other disaccharides, such as lactose, maltose and cellobiose, with the former reagent was equally eff i~ient .~~

The degradation of D-ribose in the presence of propylamine in phosphate buffer at pH 7.4 and 70 "C furnished N-propylglycine propylamide, N-propyl- alanine propylamide, glycolic acid propylamide and lactic acid propylamide. Under similar conditions, D-glucose reacted more slowly giving the same products .&

The diboronic acid-appended (R)-binaphthyl 63 showed enantiomer discri- mination in the complexation of some saccharides; L-xylose, in particular, was favoured 8.7-fold over ~ - x y l o s e . ~ ~

2: Free Sugars 13

References

1

2 3 4 5

6 7

8

9 10

11 12

13

14

15 16 17 18

19

20 21 22 23 24 25

26

27 28

29

30 31

32 33

C. Carey, L.E. Chirlian, M.M. Franc1 and D.M. Gange, Glycoconj. J. , 1997, 14, 501. C. J. Cramer, D.G. Truhlar and A.D. French, Carbohydr. Res., 1997,298, 1. J.D Sutherland and J.N. Whitfield, Tetrahedron, 1997,53, 11493. A. Chattopadhyay, Tetrahedron: Asymm., 1997,8,2727. I.P. Shnipor and A.S. Shalamai, Biopolim. Kleta, 1996, 12, 86 (Chem. Abstr., 1997,126,238 547). L. Kramer and E. Steckhan, Tetrahedron, 1997,53, 14645. R. Hernandez, E.I. Leon, P. Moreno and E. Suarez, J. Org. Chem., 1997, 62, 8974. E.A. Djurendic, S. Velimirovic, M. Popsavin, V. Popsavin and D. Miljkovic, J. Serb. Chem. SOC., 1997,62, 393 (Chem. Abstr., 1997, 127,34 417). K. Kasbeck and H. Kessler, Liebigs Ann. Chem., 1997, 169. C. Moreau, R. Durand, J. Duhamet and P. Rivalier, J. Carbohydr. Chem., 1997, 16, 709. R. Chenevert, M. Lavoie and M. Dasser, Can. J. Chem., 1997,75,68. L. Petrus, Z. Hricoviniova, M. Petrusova and M. Matulova, Chem. Pap., 1996, 50, 373 (Chem. Abstr., 1997,126,264 271). Y . Bleriot, C.F. Masaguer, J. Charlwood, B.G. Winchester, A.L. Lane, S. Crook, D.J. Watkin and G.W.J. Fleet, Tetrahedron, 1997,53, 15135. C.F. Masaguer, Y. Bleriot, J. Charlwood, B.G. Winchester and G.W.J. Fleet, Tetrahedron, 1997,53, 15 147. Z. Pakulski and A. Zamojski, Tetrahedron, 1997,53,2653. H. Stepowska and A. Zamojski, Carbohydr. Res., 1997,304, 347. S. Jarosz and M. Mach, J. Carbohydr. Chem., 1997,16, 11 1 1. N.C.R. van Straten, N.M.A.J. Kriek, C.M. Timmers, S.C.M. Wigchert, G.A. van der Mare1 and J.H. van Boom, J. Carbohydr. Chem., 1997,16,947. M. Kaneko, 0. Kanie, T. Kajimoto and C.-H. Wong, Bioorg. Med. Chem. Lett., 1997,7,2809. A. Dondoni, M. Kleban and A. Marra, Tetrahedron Lett., 1997,38, 7801. R.M. Paton and A.A. Young, J. Chem. SOC., Perkin Trans. I , 1997,629. D.L.J. Clive, C.C. Paul and 2. Wang, J. Org. Chem., 1997,62,7028. I. Frappa and D. Sinou, J. Carbohydr. Chem., 1997,16,255. C. Lievre, C. Frkchou and G. Demailly, Carbohydr. Res., 1997,303, 1. C. Vogel, C. Bergemann, A.-J. Ott, T.K. Lindhorst, J. Thiem, W.V. Dahlhoff, C. Hallgren, M.M. Palcic and 0. Hindsgaul, Liebigs Ann. Chem., 1997, 601. I. Izquierdo, M.T. Plaza, R. Robles and A. Mota, Tetrahedron: Asymm., 1997,8, 2597. T.E. Lehmann and A. Berkessel, J. Org. Chem., 1997,62, 302. R.H. Prenner and W. Schmid, Monatsh. Chemie, 1996, 127, 1045 (Chem. Abstr., 1997,126,277 695). L.A. Paquette, T.M. Mitzel, M.B. Isaac, C.F. Crasto and W.W. Schomer, J. Org. Chem., 1997,62,4293. S . Kobayashi, T. Wakabayashi and H. Oyamada, Chem. Lett., 1997,83 1. T. Takahashi, H. Tsukamoto, M. Kurosaki and H. Yamada, Synlett, 1997, 1065. T. Mochizuki and M. Shiozaki, Chem. Lett., 1997,801. L.A. Paquette, M. Kinney and U. Dullweber, J. Org. Chem., 1997,62, 1713.


34 35

36

37 38 39 40 41 42

43

44

45 46 47

C. Waldraff, B. Bernet and A. Vasella, Helv. Chim. Acta, 1997,80, 1882. I . Kolossvary, J. Phys. Chem., 1997, 101, 9900 (Chem. Abstr., 1997, 127, 331 641). H. Senderowitz and W.C. Still, J. Phys. Chem., 1997, 101, 1409 (Chem. Abstr., 1997, 126, 104 306). A.M. Peres and E.A. Macedo, Carbohydr. Res., 1997,303, 135. E.R. Caffarena and J.R. Grigera, Carbohydr. Res., 1997,300,5 1 . R.H. Tromp, R. Parker and S.G. Ring, Carbohydr. Res., 1997,303, 199. C. Melander and D.A. Home, Tetrahedron Lett., 1997,38,713. S.J. Angyal, Carbohydr. Res., 1997,300,279. H. Brunner and D. Opitz, J. Mol. Catal. A: Chem., 1997, 118, 273 (Chem. Abstr., 1997,126,317 530). A.W. Heinen, J.A. Peters and H. van Bekkum, Carbohydr. Rex, 1997, 304, 155. - D. Chopra, S. Rahmani and A.K. Singh, Oxid. Commun., 1997, 20, 450 (Chem. Abstr., 1997, 127, 307 856). H. Ishida and K. Seri, Chem. Lett., 1997, 379. U. Biittner, F. Gerum and T. Severin, Carbohydr. Res., 1997,300,265. M. Takeuchi, S. Yoda, T Imada and S. Shinkai, Tetrahedron, 1997,53, 8335.

3 Glycosides and Disaccharides

1 0-Glycosides

1.1 Synthesis of Monosaccharide Glycosides - Sinay and Mallet have presented a review on the preparation and use of glycosyl xanthates and end ethers and related derivatives as glycosyl donors,' and Voelter and colleagues have written one on the use of sugar epoxides and unsaturated sugars as intermediates in carbohydrate synthesis which contains work relevant to glycosides synthesis2 A general review (in Chinese) on glycosylation methods has a ~ p e a r e d . ~

1.1.1 Methods of synthesis of glycosides - A new approach to the synthesis of furanosides adopts pentenyl glycofuranosides as donors, these being made from 4-pentenol and glucose, mannose and galactose using FeC13 as catalyst. The acetylated furanosyl products were used in the synthesis of furanosyl disaccharides, successful 1,2-trans-linking being achieved to the 4-position and, separately, to the 4-position of g luco~e .~ A novel specific synthesis of furanosides of ADP-ribose uses the corresponding glycofuranosyl nicotinimide as donor with NAD-ase as the catalyst. Reasonable yields were obtained by transfer to simple primary alcohol^.^ A study of the effect of ultrasound on the glucosylation of butanol and octanol using the free sugar as glycosyl source and montmorillonite as catalyst has been reported?

As usual peracetylated sugars have been used commonly as glycosyl donors, and in the cases of the peracetates of glucose, mannose, galactose and an N- protected glucosamine compound, the decyl glycosides have been made in good yield in a solvent-free system with ZnCl2 as catalyst and with the aid of microwave a~tivation.~ Less commonly, 0-benzylated a-D-mannopyranosyl trichloroacetate, activated with a hindered pyridine base, has been used, and it gave good yields of a-glycosides including those of a secondary monosaccharide alcohol and of phenols.*

The glycosyl trichloroacetimidate method remains highly favoured, and a further review article on the subject and on the 0-1 alkylation approach to glycosides has been prepared by S ~ h m i d t . ~ (See also ref. 25 et seq.). Lithium triflate has been recommended as a new promoter for glycosylation using trichloroacetimidates as donors, but the results presented suggest that yields and a$-ratios are similar to those obtained with other Lewis acid promoters. l o

~-


15


The versatility of glycosyl trichloracetimidates is illustrated by the use of the 0-benzylated furanosyl glucose, mannose and galactose compounds in the synthesis of a-glycosides in good yie1ds.l' The method has also been used to prepare 4-carboxy-2,6-dimethoxyphenyl2,3,4-tri-0-benzyl-6-0-mesy~-~-~-g~u- copyranoside,'2 and the syntheses of 2,6-dideoxy-~-glucosides have best been achieved using the a-trichloroacetimidate of 4-0-acetyl-6-bromo-6-deoxy-2- phenylthio-3-0-Tbdms-~-glucose. The anomeric selectivity of the coupling, however, decreases as the steric availability of the acceptor hydroxy group decreases.13

The N-p-nitrobenzyloxycarbonyl protecting group has been used in conjuc- tion with 3,4,6-0-acetyl protection of glucosamine a-trichloroacetimidate, the compound being a donor which results in high P-selectivity when coupled to primary or secondary sugar alcohol groups. The N-protecting group can be selectively removed hydrogenolytically in the presence of N-acetyl- or 0- benzyl-groups. l4 Nicolaou and colleagues utilized a selectively 0-protected trichloroacetimidate derived from D-arabinose to introduce the sugar component of eleutherobin, a newly discovered antitumour agent with a mechanism of action similar to that of taxol."

A review has appeared on the dihalogenomethyl methyl ether / Lewis acid method for generating glycosyl halides from various mono- and oligosaccharide derivates.16 Further work has been reported on the use of glycosyl iodides, in particular tetra-O-benzyl- fh-glucopyranosyl iodide which can be made using lithium iodide and lithium perchlorate from a variety of glycosyl esters. Treated with alcohols it gives rise mainly to a-glucosides with yields just above 50% with primary sugar alcohols, and less than that figure with secondary alcohols. 2-Acetamido-3,4,6-tri- 0-acetyl-2-deoxy-a-~-glucosyl chloride activated with Hg12 has been used to make P-D-N-acetylglucosami- nides of different lipophilicities. * Tetra- 0-acetyl-a-D-galactosyl bromide has given access to the P-glycoside of 4-methylumbelliferone for use in an enzyme assay, l9 and acetobromo- and benzobromo-glucose have been used to glycosylate hydroxycali~[4]arenes,~~ and model lignins having 3-aryl-2,3-dihydroxypropyl aglycons.*' P-Xylosides were also made in the course of this latter work which was based on biosynthesis studies.

Thioglycosides are now used commonly in di- and oligo-saccharides syntheses (see below). Uchiro and Mukaiyama, using tetra-0-benzyl-S-methyl- 1 - t hio- P-D-glucopyranoside with trityl tetrakis(pen tafluorop henyl) borate and periodate as activators, have developed a highly selective P-glucoside synthesis. With methyl 2,3,6-tri-O-benzyl-ol-~-glucopyranoside as acceptor 85% yield of disaccharide was obtained with 10: 1 P-selectivity.22 Coupling of 3-(trifluoroacetamido)propanol with 0-protected ethylthio glycosides of N-acetyl- and N- glycolyl-neuraminic acid with NIS/TmsOTf activation occurred with moderate selectivity.22a By use of an 0-benzyl-protected xylofuranosyl xanthate, furanosides have been produced with the a,P-ratios dependent upon the polarity of the systems employed.23

Schmidt and co-workers have used quite a different approach starting with 2,3:5,6-di-O-isopropylidene-~-mannose and tetritol derivatives containing tri-

3: Glycosides and Disaccharides 17

flate ester leaving groups; a series of 2-O-mannofuranosyl-~-erythritol derivatives having surfactant properties were prepared.24 Mukaiyama has also used 0- 1 unprotected compounds to make glycosides, treating tetra-0-benzyl- galactose with alcohols in the presence of tin triflate, TmsCl and lithium perchlorate, and in this way producing good yields of glycosides with a, p-ratios in the region 10: 1 . a-1 ,&Linked disaccharides were reported in the course of this In related studies 2,3,4,6-tetra- 0-benzylglucose has been used as a glycosyl donor with triflic anhydride as activator in diphenyl sulfoxide. Low temperatures were used and efficient coupling to alcohols, phenols, thiols and activated benzene rings were described. Yields were high but the a,p-ratios were very variable, favouring the P-glycosides with simple alcohols but the a-compounds with thiols and phenols. In the case of 1,3,5- trimethoxybenzene only the P-C-linked compound was reported. The method was found to be applicable also to N-Tms-amides and to. carbohydrate alcohols, 88% of 1,6-linked glucobiosides being produced with a,p-ratio 1:3. When 2,3,4,6-tetrabenzoylglucose was used as alternative donor only P-products were obtained, demonstrating the expected neighbouring group effect.26 A striking stereochemical factor was discovered when tetra-~-acetyl-D-glucopyranose was coupled with ally1 bromide in the presence of sodium hydride in dichloromethane. Under these conditions the P-glycoside was produced; however, when tetrabutylammonium iodide was added the a, p-ratio swung dramatically to 98:2. In the course of this work the a-ally1 glycoside of N-acetylglucosamine was treated with the appropriate thiol in water under light and the symmetrical glycoconjugates 1 were prepared.27 It has now been shown that 0-protection of the donor is not required for the generation of glycosyl donors and that free sugars in DMF with sodium hydride present react directly with 4-substituted benzyl bromides, the glycosidic products being separated by column chromatography. The reactions were conducted with a-D-glUCOSe, a-D-N-acetylglucosamine and N-trifluoroacetylglucosamine, D-xylose, D-ribose and a range of 4-substituted benzyl bromides. Yields varied from 14 to 75% and a,p-ratios were mainly about 1:4 but, on some occasions, poorer selectivity was observed.28 In a variation of the reactions of free sugars which result in glycosides 2,3,4,6-tetra-0-acetyl-~-glucose has been applied in a Mannich reaction with formaldehyde and penta-N-methyl- melamine and, following deacetylation, compound 2 was isolated in low yield from the products.29

1 2

1,2-Anhydroaldopyranose chemistry has been exploited appreciably, mainly in the preparation of P-glucosides which are formed under basic conditions, whereas the Danishefsky method, involving the use of zinc chloride, normally


leads to the production of a-products. The method applied with 3,4,6-tri-O- acetyl- 1,2-anhydro-~-glucose and 4-substituted phenols gives modest a-selectivity when zinc chloride is used and P-selectivity up to 95% with potassium carbonate in the presence of a crown ether.30 The related starting material was then used to prepare 2-naphthyl 3,4,6-tri-0-methyl-~-glucopyranoside from which was made the 2-crotyl ester and hence chiral acids by chiral-inductive addition processes involving Grignard reagent^.^' In related work ally1 3,4,6- tri-U-benzyl-P-D-glucopyranoside was epoxidized, and the diastereomeric products were then ring opened with alcohols to give pure 1-glucosylglycerol derivative^.^^ This approach, but involving 1,2-anhydr0-3,4,6-tri-O-pivaloyl- D-glucose, has been used to give P-glucosides using terpene alcohols as nu~leophiles.~~ Closely related chemistry has been used to make compounds 3 which are spacer-linked 1 , 1'-bis-P-galactoside derivatives, and the paper also described the tris-P-glycoside having 6-O-benzyl-~-~-ga~actopyranosyloxy groups at positions 1, 3 and 5 on a benzene ring.34

Mukaiyama and colleagues have described transglycosylation from methyl glycosides to sugars derivatives, thus making disaccharides when monosaccharide derivatives were used as acceptors together with tin triflate and trimethylsilyl chloride as promoter. Good yields and moderate anomeric selectivities were reported.35

Enzymic methods have now become very important in glycoside synthesis and this year several relevant reviews have appeared. One deals with the use of glycosidases in preparing glycosidic bonds and also with the use of lipases in acylation and deacylation of carbohydrate derivative^,^^ another covers enzymic synthesis of glycosides and oligosa~charides,~~ while a further deals with glycosyl transferase acceptors, inhibitors and related corn pound^.^^ The syntheses of inhibitors of glycosidases and glycosyl transferases involved in the biosynthesis of glycoproteins have also been treated in a review.39

In the area of specific glucosides 4-hydroxybutyl-~-glucopyranoside was obtained in yields of up to 50% by use of a P-glucosidase on an inert support, the a-compound being prepared in reciprocal fashion using starch a-amylase, again held on a mineral support, as catalyst. Largely dry media were used to press the reaction in the direction of the product, and the effects of water and of the supports were particularly examined ,40 The a-glucosides derived from the aliphatic hydroxy group of diol 441 and pyridoxine (4- and 5-is0mers)~~ were made by use of a-glucosidases. P-D-Glucosidases, on the other hand, have been studied as synthesizing catalysts in dry media with microwave activation to make P-glucosides of various aliphatic d i ~ l s , ~ ~ 3-hydroxy- 1 -butene and related alcoholsM and various cyclohexylethanoid acceptors. In the last work isorengyol (5) was glycosylated at the primary and secondary positions in the ratio 9; 1, the overall yield being 44% when p-nitrophenyl P-D-glucopyranoside was used as donor.45

Some lipid-coated P-galactosidases have been found to be effective transglycosylation catalysts with lactose as donor and various alcohols, including carbohydrates, as acceptors. A two-phase system was used with the enzyme

3: Clycosides and Disaccharides 19

OH )&$’ 0 OH

3 X = (CH2)4, CH2, C=C, Q-

Me

HO

Me m I : O H Me

4

HO ,\OH

b OH

5

t

operating in the non-aqueous phase!6 The reaction of galactose with various racemic secondary alcohols was catalysed selectively by a P-galactosidase from E. coli, and proceeded with enantioselectivity to give the R-products. The e.e. for the transfer to 1-phenylethanol was 98%.47 A p-1,3-linked analogue of the T-antigen determinant was made on a preparative scale by use of a P-galact~sidase,~~ and transglycosylation of a-galactose to various simple alcohols from the p-nitrophenyl a-glycoside has been described. Transfer also occurred to the substrate itself, in which case 1,6-linked di- and t ri-saccharides resulted .49

In a broader study, lipid-coated glycosidases were used in the transfer of a-D-Man, P-D-G~cNAc, P-D-G~c and P-D-Gal to hydrophobic acceptors in dry isopropyl ether. Yields were in the range 23-71?40.~O

1.1.2 Classes of glycosides - In this section papers dealing with the synthesis of glycosides of particular categories of compounds are dealt with together.

P-D-Mannopyranosides always present a special challenge, and a Japanese paper has described the preparation of such compounds and analogues with azido-, fluoro- and deoxy-groups at C-2, all formed by double nucleophilic displacements from alky 2,4-di- 0-triflyl-galactosides. Initial inversion at C-4 with acetate gave the corresponding glucosides which were then subjected to nucleophilic displacement at C-2.51 T. Ogawa has modified his intramolecular P-mannoside synthesis such that it can be applied on polymer supports. Compound 6, on treatment with DDQ and an alcohol, gave the general type of acetal 7 which, with methyl triflate, collapsed to the corresponding R‘-2- hydroxy-P-mannopyranosides. Various primary and secondary sugar alcohols were used as well as 2-azido long-chain alcohols. The products were easily separated from by-products, and the phrase ‘gatekeeper monitored glycosylation’ was coined to describe the overall process.52 See Refs. 176-179 for other approaches to P-mannopyranosides.

Glucuronides are of special interest because of their role in many natural products and as drug metabolites. Compounds 853 and 954 were synthesized by usual methods, the latter being found to be subject to hydrolysis by P-glucuronidase to release its toxic aglycon. The analogous glucuronide of


raloxifene, an anti-osteoporosis drug, was tested for its affinity for the human estrogen receptor.55 Standard glycosylations gave the P-glucuronides of tropo- lone and several of its substituted derivative^,^^ and the p-nitrophenyl p-furanosyl derivatives of D-glucuronic acid and D-xyluronic acid were made by standard procedures and found not to be better substrates for bovine p-D- glucuronidase than was the analogous pyranosyl g lucur~nos ide .~~

In the area of ulosonic acids the a- and P-glycosides of 3-deoxy-~-lyxo-hept- 2-ulosonic acid were made by specific methods, the former by addition to the corresponding 2,3-unsaturated compound, and the latter by way of the aglycosyl chloride.58 An ingenious way of making a-glycosides of sialic acid involves the use of long range participation which generates intermediate 10 from the corresponding 2-(methy1thio)ethyl ester of the methylthio glycoside. The procedure was used to link sialic acid to 0-6, and separately to 0 - 3 , of methyl P-D-galactopyranoside, and to make other glycosides, with a,p-ratios >5:1.59 Sialylglycolipids 11 and 12 were made in stepwise fashion from the spacer group glycoside having a chloro-terminal unit.60

-0

6 A = H 0-0 7 R = O R ~

AcO-7 0

AcHN

New work has been reported in the area of deoxy-glycosides. Compound 13, activated with trimethylsilyl triflate, is a good donor yielding 80% of products with a,p-ratios approximately 20: 1 .61 Glycosylation by use of peracetylated glycals together with IDCP and followed by reduction afforded 2-deoxy- a-glycosides of triterpene alcohols and deoxycholic a ~ i d . ~ * - ~ ~ Study of the influence of substituents at C-6 and C-4 on the stereoselectivity of the addition of PhSCl and PhSeCl to D-glucal derivatives has led to increased stereoselectivity in the synthesis of 2-deoxy-P-glycosides. Electronegative hetero atoms at C-6 favour the formation of 2-thio-~-gluco-products from 0-substituted glucal derivatives.M Franck and Win have used ingeneous hetero-Diels-Alder addition reactions to confer selectivity on the production of 2-deoxy-a-glucosides in the steroid series as is exemplified in Scheme 1 .65


BnO (&

bo@17

BnO + 1 -substituted isomer

Reagents: i, 2,6-Lutidine; ii, Raney Ni Scheme 1

13 14

The ulosyl bromide compounds 14 can be applied satisfactorily to the synthesis of L-rhamnosides. Direct substitution leads to P-glycosides, and the final products are obtained by sodium borohydride reduction of the ketonic groups.66 Wong and colleagues have used Selectofluor { 1,4-diaza-l -chloro- methy-4-fluoro- bicyclo[2.2.2 Joct ane bis(tetrafluorob0rate) 1 addition to pyranoid and furanoid glycals to produce 2-deoxy-2-fluoro-sugars which were then converted into glycosides under standard condition^.^^ 2-Deoxy-3,4,6-tri-O- methyl-2-(N-methylacetamido)-~-~-glucopyranoside, -P-D-galactopyranoside and -a-D-mannopyranoside were converted into the corresponding oxazoli- nium ions with Lewis acids. The reaction of these intermediates with (+)-2- butanol has been examined in the course of work which was aimed at the study of R- and S-2-butyl glycosides formed during polysaccharide analysis.68

Glycosides with unsaturated aglycons are useful for further functionalization purposes, and Stick has reviewed the preparation of epoxyallyl glycosides and aziridine and thiirane analogues as potential inhibitors of P-D-glucosidases and P-D-ghcan hydro lase^.^^ Stick’s group has also reported the asymmetric dihydroxylation of the unsaturated glycosides 15, compound 16 being the only product readily obtained pure by this procedure. It was converted into the episulfide with inverted stereochemistry as a potential inhibitor of P-D-glucan h y d r ~ l a s e . ~ ~ In similar work the catalytic asymmetric hydroxylation of ally1 2- O-benzyl-3,4-di-O-substituted-ol-~-xylopyranosides generally gave disap-


pointing ~electivity.~' Several P-D-glycopyranosides of Glc, 3-O-Me-Glc and GlcNAc have been reported with unsaturated and otherwise functionalized aglycons which permitted potential linking to pep tide^.^^ But-3-yne-2-yl and propargyl tetra- O-benzyl- P-D-glycopyranosides, on treatment with potassium t-butoxide and DMF, rearranged in good yield to give the corresponding allenyl glycosides 17. These compounds, activated with trimethylsilyl triflate, proved to be potentially useful glycosyl donors, and with a sugar primary alcohol gave stereospecifically the 0- 176-linked disaccharide in 56% yield.73 In very different studies involving additions to glycosides with unsaturated aglycons penta- O-allyl-D-glucose has been treated with cysteamine under light in the presence of HCl and the penta-substituted compound carrying (CH&S(CH&NH2 groups resulted.74

AcO

OAc 15

OAc 16

OBn 17 R = H, Me

The p-nitrophenyl glycosides of L-rhamnose or a-( 1 -, 3)-linked rhamnobiose or the related trisaccharide were converted into the corresponding glycosyl isothiocyanates for coupling to peptides and proteins,75 and P-D-glucopyranosides have been made of a set of tetramethoxymono- and di-hydroxy-cis-and trans-~tilbenes.~~ By use of the Mitsunobu reaction 2,3:S76-di-O-isopropylidene-D-mannofuranose has been linked to several hydroxylated calix[4]arenes. A range of related compounds including diglycosyl compounds and others with P-D-galactopyranose bonded to the upper rim of calix[4]arenes were reported.77 The tetra- 0-acetyl-P-D-glucopyranoside of 4-hydroxy-3-methoxy- benzaldehyde has been elaborated by use of phosphonate technology to compound 18 which is an inhibitor of lignin p~lymerization.~~

&pGlc-o &ffi lc NAcO m16H33

MeO &oGlc NAcO xw16&3 19 18

There is considerably increased interest in complex compounds which contain more than one sugar unit, most of these being produced for biological studies. The so-called gemini neoglycolipid 19 has been made for studies of its interfacial b e h a ~ i o u r , ~ ~ and a related report has described very similar compounds having P-D-galactopyranose or its 3-sulfate or 3,4-diphosphate esters as the sugars. The sulfate was the most potent competitive inhibitor of binding of HL-60 cells to immobilized selectins.** Stoddart and colleagues have now used monosaccharide derivatives as the terminal groups on dumb-


bell molecules and have described compound 20 and its characteristics as a precursor of rotaxanes carrying ring-like polar molecules added by either the slippage procedure or by clipping.8

The trilactosyl compound 21 was made as a potential means of delivery of 2’-deoxy-Siodouridine to the liver,82 and &-D-Galp-( I +4)-~-Galp has been attached to several di-, tri- and tetra-functional compounds to produce haemaglutination inhibitors. Generally the multivalent galactobiosides were more potent.83

0

0 OH

O A N

21 OBz

Considerable attention has been given to the preparation of dendrimeric compounds, particularly by Stoddart and his colleagues. Thus core compounds such as 22 condensed with triglycosides such as 23 offer means of obtaining products with multisugar components, and an extensive series of complex products of this sort have been reported this year.84-86 Other workers in the

RNH

OAc

25 R = a-D-GalNACO-


same area have, for example, described complex compounds with structures 2487 and 25.88

Compounds called 'sugar balls' have been made by polymerizing the glycosylated L-serine N-carboxyanhydrides 26 with dendrimeric polyamido- amine~.*~ A somewhat different glycosykated polymeric compound 27 was made by polymerizing a diunsaturated cyclopentane d e r i v a t i ~ e , ~ ~ and an acrylamide homopolymer (28) having Sia LeX as part of the repeating unit had increased activity relative to the corresponding monomer in inhibiting E- selectin-mediated cell adhe~ion .~ '

Ph

n A YH~OAC

X 0

a-D-ManO-

Mt: 26 X = OAC, NHAc 27

\

0 '

S i a L e x o ( C H 2 ) 6 N H ~ ~

28 ,

1.2 Synthesis of Glycosylated Natural Products and Their Analogues - In the area of glycosylated acyclic compounds the P-D-glucosides of ethyl and butyl 3-hydroxybutanoate have been made for comparison with compounds isolated from 2,3-di- and 2,3,4-tri-O-p-~-lactosyl-D-threitol have been re- ported93 and the p-D-glucopyranoside of the primary alcohol of 2S,3S-3-O- acetyl-2-aminooctadecane- 1,3-diol has been synthesized as a model for natural cerebr~s ides .~~ Sialylphospholipids of general structure 29 have been made as potential antirotaviral agents,95 while two papers have described the synthesis of cerebrosides, for example 30, with different degrees and positions of sulfation on 2-amino-2-deoxy-~-glucose and -galactose and glucose and galactose themselves. 96997

29 30 R = H, S03H


@Protected 2-aminoethyl P-D-xylopyranoside has been coupled with a peptidomimetic to give compound 31,98 and in an extended piece of work along similar lines the 3-aminopropyl a-glycoside of D-glycero-D-manno- heptose has been linked to a solid-supported peptide and hence to a lipopep- tide to produce a synthetic vaccine targeted at Neisseria rneningitidi~?~ In parallel work glycosides carrying 4-carboxybutyl aglycons have been linked to solid-supported peptides to give complicated molecules such as 32'0° and, likewise, artificial glycolipids based on 9-D-galactose or P-D-Gal-( 1 -+ ~)-P-D- Gal (compound 33) have been made.lol

RO(CH2)4CONH I

0 (CH2)4 JJF

r>H F t O ( C H 2 ) 4 A X ~ ~ C o J d

B~QC" N Pr'

0 (YH2)4

BzO ic)' R0(CH2)4KNH 0 OBz

32 X = NH, HN(CH2)FONH (y= 1,3) R = pa-Gal, &D-GalNAc n - 0 , l

31

0 Me I1 I

@+Gal-( 1 +4)-f3-&aall-(CC~)~CNHCHCN(C~~H~)2

33 II 0

For the purposes of synthesizing glycosylated peptides 0-glycosyl-substituted serine and threonine are very popular. Coupling of acetobromoglucose with the suitably protected aminoacids gave the P-D-glucosides and also some of the glycosides derived from P-D-G~uc-( 1 + 2)-P-~-Glc, the conditions of coupling causing cleavage of the ester group at 0-2 in the donor. Similar experiments were carried out with a-D-mannosyl and a-L-rhamnosyl bromides. lo2 Related work gave protected derivatives of a-L-fucosyl-serine, -threonine and - t y r ~ s i n e ' ~ ~ and p-D-glucuronosylthreonine. Io4 Schmidt and his group have compared variously N-substituted glucosamine-based glycosylating agents to produce a range of substituted compounds with the sugar P-bonded to serine and threonine.'05 These two amino-acids, 0-substituted with ~ - D - N - acetylgalactosamine, have been used as acceptors for galactose transferred from its p-nitrophenyl P-glycoside with P-galactosidase which gave the P-( 1 -+3)-linked T-antigenic determinants in 22 and 28% yield respectively. lo6

A suitably protected threonine carrying N-protected 6-amino-6-deoxy-P-~-glucose as a glycosidic unit has been used in the synthesis of several a-helical peptides in order to study the effect of the 0-glycosylation on the conformations of the peptides.lo7 Compounds 34, each of which contains a lipid A analogue section and a sugar antigen, have been made as potential vaccines against cancer."' Syntheses of a-D-GalNAc-0-Ser-Ser-Gly and P-D-Gal- ( 1 -+ 4)-a-~-GalNAc-O-Ser-Ser-Gly-Asp-Glu-Thr, which are microbial pro-

26

0


O oY(CH2)12Me 0

34 R = a-DGalNAc, a-Neu5Ac-(2+6)-a-D-GaINAc

ducts that suppress the defence responses of plants, have been reported.lo9 Compounds 35 are examples of several diglycosylated peptides to have been reported following their synthesis by solid phase technology. lo-

Bz-IleSer-GI y-Ile-ser-GI y-Ile-Gly-OMe I I

OR' OR* 35 R' = R2 = &D-Gal

R' = R2 = P-L-Fuc R' = P-D-Gal, ~2 = B-L-FUC R' = P-L-Fuc, R2 = f3-D-Gal

a-D-Gal-( I -+ l)-L-myo-inositol (galactinol), which is a natural donor of galactose in the biosynthesis of raffinose, has been made by standard procedures, ' and 6-0-(2-am~no-2-deoxy-a-~-g~ucopyranosy~)-~~o-~nos~to~ 1 -phosphate and its corresponding 1,2-cyclic phosphate have been prepared in connection with interests in insulin secondary messenger biochemistry.[ l 2

Interest continues in the glycosylation of steroidal compounds, cholesterol having been linked to P-D-G~cNAc by way of ethyleneoxy bridges of length 1 -4.lI3 The unusual sugar 5-C-hydroxymethyl-~-galactose has been a-linked (it has the L-configuration) to cholesterol and diosgenin using the glycosyl fluoride coupling procedure, l4 and the glycosylphenyl sulfoxide method has been used to prepare a di-a-D-glucosyl derivative of a dihydroxy methyl cholate compound.' I 5 By application of the trichloroacetimidate method the p-D-glUCOSyl- and a-L-arabinofuranosyl-( 1 +6)-P-~-glucopyranosyl derivatives of the monoterpene (-)-myrtenol were made,' l 6 and in the same area diglyco- sides of neohancoside A, B and C were produced.117

In the triterpenoid field D-glucose, L-fucose and several fucosylglucoses were glycosidically bonded to diosgenin using the trichloroacetimidate procedure. I I 8 The 2-deoxy-a-~-glucosides and -a-galactoside of 18-0-glycyr- rhetic acid and several analogues have been made by additions to glycals. 199120 0-Acetylated cellobiosyl bromide121 and fluoride122 have been used in the preparation of several glycosides of tycogenin, and active inhibitors of cholesterol absorption were produced. The a-mannosides of stevioside and isosteviol were synthesized as Sia LeX mimics, the latter compound having 100 times more affinity for P-selectin than does Sia


Me 36 R=C02H 37 R-CH20H

B-D-GIc-O 38

LeX. 123 Vasella’s group, using the glycosylidene diazirine procedure, have made the mono-, di- and tri-glucosides of ginkgolide A and B, these being highly oxidized triterpene trialactones. 124

As usual, several aromatic natural products have been made by glycosylation, for example the sex pheromonal compounds of the Chlamydomonas, lurlenic acid (36)125 and lurlenol (37),126 and the diphenyl ether compound 38, which is aceroside IV, a component of the bark of a Japanese tree.127 An improved synthesis involving the use of the glucuronosyl trichloroacetimidate of the p-D-glucuronide of coumarin has been described,128 the primary hydroxy group of the hepatoprotective flavolignan compound silybin (Flavo- bionTM and LegalonTM) has been substituted to give the P-galactoside, -glucoside, -1actoside and -maltoside, some of which have increased hepatoprotective activity,129 and the related a-tocopherol which is a potent natural antioxidant has been converted into the glycosides of the following di- and higher saccharides: p-maltose, a-cellobiose, p-lactose, p-malto-triose, -tetraose, -hexaose and -heptaose. 130 Grayanoside A, which belongs to the phenylpropa- noid group of natural glycosides which have a range of biological activities, has been made. It is the 2-(4-hydroxyphenyl)ethyl P-glucoside having a substituted cinnamoyl ester group at O-6.l3l The configuration of the simple natural lactone p-D-glucoside of phyllanthurinolactone (4-hydroxy-7-oxa-8- oxo-bicyclo[4.3.0]nona-2,9-diene) has been established by synthesis. 32 Spin labelled derivatives e.g. 39 of podophyllotoxin glycoside exhibit anticancer activity. 33

As always, some nitrogenous compounds have been glycosylated to give, for example, the enantiomer of compound 40 which is a natural acetal glycoside found in maize. It was made by the unusual use of L-glucose derivatives, 34 and L-biopterin has been converted to the 2’-0-(2-acetarnido-2- deoxy- p-D-glucosyl) derivative limpterin. ’ 35 Enzymic methods were used to make the (3-glucosides 41 and 42 of calystegine B1 and B2 and other glycosides. 36

1.3 0-Glycosides Isolated from Natural Products - As always, only a selection of papers published on this aspect of glycoside chemistry are dealt with: either


f5-D-GlcOxl,0Me OH

O M e O I M e O

39 OMe 40

41 R' = H, R2 = &D-GlC, R3 = OH " " " " ~ 43 OH

42 R' = O-g-DGlc, R2 = R3 9 H

those showing interesting structural features within the carbohydrate moieties or those describing notable biological properties.

A review has been presented on the benzoxazinoid acetal glucosides which occur in the Gramineae. 37 D-Ristosamine (3-amino-2,3,6-trideoxy-~-ribo- hexose) is the sugar component of a marine streptomyces aryl glyco~ide, '~~ and a-L-Araf-( 1 +5)-~-Araf has been isolated as its 2-trans- feruloyl ester from sugar beet pulp. 139 l-O-a-( 1 -+3)-Mannobiosylglycerol has been isolated, as a derivative carrying two long-chain fatty acid ester groups at 0-6 of the disaccharide and at 0 - 3 of the glycerol moiety, from a sponge-associated Micrococcus.'40 P-~-Glcp-( 1 + 4)-~-GalA occurs as the sugar component of a marine sponge tetramic acid glycoside,141 and a group of saponins with hepatoprotective activity rely for that activity on the presence of P-D-GIC-

Amongst some biologically active glycosides to have been recorded is compound 43, an a-keto acid glycoside, which causes leaf opening in plants in the daytime as opposed to potassium D-idarate, also present in the same plants, which has the opposite effect.'43 A l-P-D-galactoside of glycerol bearing a long chain fatty acid ester group at 0 -3 and isolated from a marine sponge, is reported to have antileukemic activity.144 A similar compound, (2s)- 1 - O-(hexadeca-4,7,10,13-tetraenoyl)-3-O- P-~-galactop yranosylgl ycerol, isolated from a marine micro-algae, inhibited platelet aggregation by a thromboxane analogue at 100pg/mL and was cytotoxic in vitro at lower concentrations. 145 A galactose-based glycolipid from a further marine sponge was found to be immunosuppressive on activated T cells. *46

(1 + ~)-D-Fuc. 14*

1.4 Synthesis of Disaccharides and Their Derivatives - A review has been written on Dondoni's 1996 research into the preparation of a-linked ketodisac-


charides using thiazolylketol acetates as glycosyl donors,147 and one on chemoenzymatic methods used for the preparation of novel oligosaccharide mimetics designed for use in the study of cell adhesion includes material relevant to disaccharides. 148

In the field of non-reducing disaccharides a review has appeared on the transformation of sucrose into potentially valuable chiral synthons, 149 and several sucrose analogues have been produced following the introduction of the triflate ester group at C-2 of the glucose residue which led to the a-mannopyranosyl, the a-N-acetylmannosaminyl and the altropyranosyl com- p o u n d ~ . ' ~ ~ Other analogues have been produced by chain extension from C-6 of the glucose moiety following selective Swern oxidation at that position,151 and enzymic studies have led to the synthesis of 6-deoxy-a-~-sorbofuranosyl a-D-ghcopyranoside. 52

A review has appeared on the preparation of a,a-trehalose from dried yeast and on its production from starch by enzymic methods,153 and the digalactose analogue has been made by stereochemical inversion at both C-4 positions.'54 New crystalline and amorphous forms of a,a-trehalose have been identified. 55

In the field of reducing disaccharides, inulobiose and inulotriose have been isolated in nearly equal proportions following enzymic hydrolysis of inulin. 56

Glucobiose chemistry has always attracted much attention and has been used to further exemplify elegant means of coupling sugars by intramolecular procedures. Maltose derivatives and analogues based on N-phthaloylmaltosa- mine have been made by intramolecular S-phenyl thioglycoside coupling to the 4-hydroxy group of a second glucose unit bound between 0-2 of the former to 0 - 3 of the latter by a succinic diester linkage. High yields and high selectivity were reported. 157 Japanese workers have carried out a related glycosidic 1,6- linking of two glucoses starting with a compound having 0-1 and 0 -6 of two protected glucose derivatives linked by way of a four-carbon glycosididester bridge having a phenylethynyl substituent which was activatible by cobalt octacarbonyl. The work was repeated in the galactose and mannose series, and on judicious choice of protecting groups good yields were produced with very high a-selectivities. * 58

The glycosylation reaction exhibited in Scheme 2 shows selectivity because

BnO 0 Et+ BnO QsQ __t

OBn OBn

Reagent: i, IDCP Scheme 2 OBn


the bulky S-protecting group inhibits activation at that centre. A 40% yield was reported, and then it was intriguingly shown that this bulk factor is less potent than is the disarming influence of benzoate substituents at 0-2. This paper represents a very nice study of controlling factors in glycosylation which is leading to means of directing oligosaccharide synthesis much more precisely. To illustrate this the a- 1,6-gIucopentaose was made. Is9

By the finding that acid treatment of a mixture of the two carbonates shown in Scheme 3 gives the four illustrated products in similar proportions it is revealed that the reaction is intermolecular and not, as had been previously supposed, intramolacular. 160

I OBn - + OBn +

R20 Q O a B r / \

- OR2

R2 = Bn, R’

Reagent: i, TmsOTf Scheme 3

P-D-Glcp-( 1 -+2)-~-Glc (sophorose) has been made by standard methods,161 and the a-trichloroacetimidate of the 0-acetylated derivative of this compound having a benzyl group at 0-2 of the non-reducing unit, on treatment with BF3, formed a 1,2-internal glycoside, so the product is a 1,2’: 1’,2-dianhydro compound. 162 The coupling of glycosyl thiocyanate to trityl ether glycosylation method has been adopted to make the 1,3-a-glucobiose as a methyl P-glucoside derivative. 163

DIBALH reduction of tetra-0-benzyl-D-glucono- I $lactone ethylene acetal affords the 2-hydroxyethyl P-glycoside with high selectivity and good yield. The related acetal44, formed from the same lactone and the methyl glucoside 2,3-diether, on similar treatment, afforded the 6-hydroxycellobiose product in 92% yield, and galactose and mannose analogues likewise gave P-disaccharides in very high yields.164 Cellobiose has been P-linked, using zinc fluoride catalysis and the acetylated glycosyl bromide, to the Pfizer 14C-labelled cholesterol absorption inhibitor to give pamaqueside. 165 Cellobiose has also been linked


OBn OJ 44

by way of glycosylamine bonding to a peptide,166 and maltose by use of the 2- bromoethyl-O-acetylated glycoside has been bonded to the porphyrin benzo- chlorin. 167

Tetra-O-benzyl-glucosyl N-phenyldiethylphosphorimidate is an efficient gly- cosy1 donor which can give rise to either 1,2-cis- or 1,2-trans-glycosylated products, the anomeric ratios derived from a primary sugar alcohol being varied from 5.3:l to 1:9 by alteration in the activation and condensation conditions. 168 In closely related work a very interesting experiment was done which tested O-benzyl compounds against O-benzoyl compounds in the tetramethyl phosphoroamidate series. Thus the armed donor 45 in the presence of the disarmed acceptor 46 gave an 86% yield of the directly coupled disaccharide derivative. The benzoyl groups in the product 47 were then exchanged for benzyl to give the glycosyl donor 48 (Scheme 4). Compound 49, although nominally disarmed by virtue of the presence of the benzoyl groups, was a good enough glycosylating agent to couple with alcohol 46 and give 86% of the expected P-disa~charide.'~~ Tetrabenzyl-S-ethyl P-thioglucoside condensed with 1,2:3,4-diisopropylidene-~-galactose afforded the (1 + 6)-linked products with 15: 1 a,P-selectivity in toluene/dioxane which was much higher than the 0.7: 1 observed in dichl~romethane.'~~

OBn OBZ OBn OR 45 46 47 R = B z

48 R=Bn Scheme 4 Reagent: i, TmsOTf

OBZ 49

OH 50

~t-~-Glcp-( 1 + 3)-~-Rha, the disaccharide unit of Serratia marcescens 04 antigen, has been made by the unusual use of the glycosyl trichloroacetate as donor.'71 The adenophostins, for example 50, are full agonists of the IP3 receptor, and this has led to the synthesis of compound 52 (by coupling of


compound 51 with iodobenzene) and hence the 2,3’,4’-trisphosphate. When the coupling was repeated in the presence of 1,2,4,5tetraiodobenzene cluster analogues of 52 were produced and hence the corresponding phosphorylated cluster analogue of 50. 172 I - P-D-Glucopyranosyl-D-ribitol has been prepared by the trichloroacetimidate method to provide a compound present in the hydrolysate of a novel triterpene glycoside. In the course of the work the corresponding 1 -glucoside of L-ribitol was also made. 173 6-0-P-~-Glucofura- nosyl-D-galactose was obtained in high yield by the method outlined in Scheme 5. When the approach was applied to the corresponding a-mannofuranosyl compound, however, the yield was only 40Y0.l~~ The disaccharide analogue 53 was made by enzymic glucosylation of the product of reduction of 5-azido-5- deoxy fructose. 75

7H2OH AcOCH2

ii ___c

Reagents: i, AcCI, BF3.Et20; ii, AgOTf, Ag2C03; iii, NaOMe; iv, HgC12, H20; v, AQO, Py Scheme 5

OAc

OBn 51 R = G C H 52 R = CH2CH2Ph

OH 53

Two groups have looked at the use mannose series. In these cis-related nucleophile and therefore, on reaction

of 1,2-stannylene derivatives in the D-

P-compounds 0-1 is activated as a with glycosylating electrophiles, gives

rise to non-reducing disaccharides. For example 2- 0-acetyl- 3,4,6-tri- 0- benzyl- a-D-mannopyranosyl trichloroacetimidate generates a a, P- 1,l ’-linked mannobiose compound having potentially free C-2 hydroxyl groups, thereby making available routes to corresponding tri- and tetra-saccharides. 176 In similar fashion, 0-1 of mannose may be used to displace other good leaving groups,


and the consequent syntheses of P-D-mannopyranosyl 1,4- and 1,6-linked glucosides have been effected using a galactoside 4-triflate and a glucoside 6- triflate, respectively, this representing a novel approach to these types of compounds. 177 The glycosyl sulfoxide 54 is a further suitable P-mannosylating agent (cf. refs. 51, 52), and with an appropriately protected rhamnose compound has given rise to a P-D-Manp-( 1 -+ 4)-~-Rha derivative in 90% yield with P,a-selectivity >25: 1. 178 In parallel work P-mannosidase has been used to prepare p-D-Man-( 1 -+ 4)-~-Man and higher related saccharides, and a transferase has been employed in similar fashion to produce alkyl p-D-mannopyranosides from the above mannobiose. 179

L-Xylose was used as precursor of compound 55 which was converted into L-gulose and hence 2-0-( 3-O-carbamoy~-a-~-mannopyranosyl)-~-gulose which is the sugar of bleomycin A2.1809181 A further paper on the synthesis of the same compound gives a detailed account of work which has previously been xported (see Vol. 29, p. 33, ref. 169).182 An a-D-mannofuranosyl disaccharide has been made from 2,3: 5,6-di-O-isopropylidene-~-mannose and a 2,3-unsaturated glycoside bearing methoxycarbonyl ester groups at 0-4 and 0-6, the product (43%) being compound 56 and the coupling being effected by way of a 7c-ally1 palladium complex. 83 A set of D-aZa-mannOpyranOSyl disaccharides, made using a carbocyclic starting material for the aza sugar part, has been described in detail (cf. Vol. 28, p. 229, ref. 61).184

Considerable attention continues to be paid to galactosyl disaccharides. A review has appeared on the preparation of a-D-Galp-( 1 - + 3 ) - ~ - G a l ' ~ ~ and a transglycosylation reaction by use of a-galactosidase has given rise to the same disaccharide as its p-nitrophenyl a-glycoside. In the course of this work p-D- Gal-( 1 -+ 3)-~-GalNAc was also produced, 86 and a- and P-D-Gal-( 1 -+ 3)-D- GalNAc 3-(trifluoroacetylamino)propyl glycosides, and the corresponding di- GalNAc disaccharides, have been made by chemical synthesis. 187 The Koenigs Knorr reaction, adapted by use of IBr to make tetra-0-acetyl-a-galactosyl bromide from the corresponding S-methyl thioglycoside, has led to the 1,3- and 1,6-linked galactobioses. 188 P-D-Gal-( 1 -+3)-~-GawAc has been linked by way of a six-carbon spacer to biotin, both the a- and P-anomers having been obtained, and the amino-sugar having been developed from a disaccharide glycal. The same disaccharide has been linked enzymically to serine to give the P-glycoside. 190 The a-( 1 -+ 4)-linked 57 was prepared by formal synthesis involving the use of formaldehyde diphenyl dithioacetal as a means of locking the preferred conformation of the galactobiose. The neoglycolipid with the


trimethylsilyl group replaced by SC18H37 was also made in attempts to obtain compounds which were resistant to enzymic hydrolysis. 191 Standard enzymic methods have been applied to the preparation of p-D-Gal-( I + 6)-a-~-GalOMe and related c o m p o ~ n d s . ' ~ ~

Further enzymic work has led to p-D-Galp-( 1 -3)-~-GlcpNAc'~~ and to its p-nitrophenyl p-glycoside. 194 When p-D-GalNAc was used as the acceptor, the 1 -3- and 1 -+6-linked disaccharides were obtained in the ratio 7:3.Ig3

New chemical methods have allowed access to a range of P-glycosides of the 1 -+4-linked N-acetyllactosamine series from the acetylated lactal. Iodoacetoxy- lation, followed by treatment with azide, gave the 2-deoxy-2-iodo-glycosyl azides which were then converted into the glycosides following treatment with alcohols and Ph3P. 195 Ingenious work with lipid-coated p-D-galactosidase in a two phase system allowed the enzyme, in the aqueous phase for example, to hydrolyse lactose, whereas in the organic phase P-galactosides were produced from this sugar. In this way P-~-Galp-( I +6)-~-Glc and the non-reducing glucosyl galactoside were made by galactosylation of the corresponding tetra- 0-acetylglucoses.196 Standard glycosidase-catalysed glycosylation of 3-0- methylglucose gave the p-( 1 4)-galactosylated glucose 3-ether plus some of the p-( 1 + 6)-linked galactobiose. Five enzymes and solvent systems were investigated and yields of up to 40% were recorded. 197 Trans-galactosylation from lactose has led to a set of lactosamine compounds and also to a set of p-( 1 + 3)- and p-( 1 -6)-linked di~accharides,'~~ and the ability of an enzyme from bovine colostrum to form P-( 1 - 4)-linkages with glucose derivatives varying in substituents at C-1 has been examined. Notably, the compound with a P-hydroxymethyl substituent (2,6-anhydro-~-glycero-~-gulo-heptitol) is a substrate.198a Chemical syntheses using the glycosylating agents 58 and 59 were adopted in the preparation of D-Gal-( 1 + 3)-Glc compounds, unusually high a-selectivities being recorded. 99 Polyglutamic acids carrying lactose and di-N-acetylchitobiose residues, made from the corresponding glycosylamines, have been described.2m

CH20H

57 58 R = CI Y

59 R=OCCCI,

In the area of disaccharides based on 2-amino-2-deoxyhexoses N,N-diacetylchitobiose has been made in 43% yield by chitinase coupling of N-acetylglucosamine and the 1,2-0xazoline derivable from it.201 Structural characterization of lipid A from rough- and smooth-forms of the lipopolysaccharide of Helicobacter pylori has shown that they differ from lipid A of other bacteria.202 Synthesis of the biosynthetic precursor of lipid A 60 has been reported,203 and the analogue of lipid A with CI4 and C12 acyl groups on the


hydroxy functions of the ester and amide substituents of the non-reducing moiety has been described.2M The differentially protected disaccharide derivative 61 of lipid A and several other glucosamine disaccharides with orthogon- ally protected amino groups have been made.205

\ 0-

CI CI 61

In the field of 2-deoxyglycosides Mukaiyama has reported the synthesis of a-linked 2-deoxyglucosides made by use of 3,4,6-tri-0-benzyl-Z-deoxy- D-glucose coupled with alcohols, including carbohydrate alcohols, to give about 80% of products with a:p-ratios of the order of 9: 1 .206 The L-altrosyl carbamoate 62 was made from the corresponding glycosyl fluoride, and following deester- ification and radical reduction at C-2, gave the digitoxosyl galactose disaccharide. Using analogous compounds of the D-configuration the same authors reported the synthesis of an a-D-altrosyl-( 1 + 6)-a-~-altrose derivative.207

6-Deoxy compounds continue to attract interest, particularly fucosyl disaccharides, and compound 63 has been made, as a blocker of L- and P- selectin binding, by way of the S-phenyl thiofucoside.208 By use of 2-O-acetyl- 3,4,6-tri-O-benzyl-a-~-mannose thioglycosidically-linked to a polymer a-L- Fuc-( 1 +2)-a-~-ManOMe was made in 54% yield,209 and methyl 3-0-p-D- fucopyranosyl-P-D-quinovopyranoside and its 3'- and 2,3'-dimethyl ethers were synthesized by Helferich glycosidation.210 The S-in-the-ring compounds 5- thio-L-Fuc-( 1 -+6)-, (1 +3)- and (1 +4)-linked to GlcNAc and (1 -+2)-linked to P-D-Gal were all prepared as ally1 P-glycosides which were all active in inhibiting bovine epididymis fucosidase. Only the last of them, however, inhibited bacterial fucosidase.21

2'-Deoxy-2'-fluorocellobiose has been made and found to be a mechan-


0

OBn 64

ism-based inhibitor of retaining glycosidases which exploit aglycon specificity.*12

In the area of sugar acids sialic acids continue to attract major attention, and the glycosylating agents 64 on a polymer support have been used to link sialic acid to the 6-position of galactose. In the course of this work the a-(2+3)-sialyl galactose disaccharide was also made. Yields were in the 50-70% range.213 Further solid support work has led to a-D-NeuNAc- (2+6)-a-~-GalNAc linked to a decapeptide via a threonine unit.214 Other workers have produced building blocks comprising the same disaccharide linked to threonine for the solid phase synthesis of analogous glycopeptides which are fragments of HIV gp120.*15 Schmidt and co-workers have studied the selective acceptor reactivity at positions 7 and 8 of 7,8- dihydroxy sialic acid derivatives on glycosylation with sialic acid glycosyl phosphites and halides. Yields of up to 55% of the p- and 66% of the ct-(2+8)-linked dimers were recorded.216 The artificial glycolipid 65, containing the two (2+8)-linked dimers of sialic acid is a mimic of GQlb ganglioside. In the course of the work a compound containing one of the sialic acid dimers, which is a mimic of GD3, was reported.*17 Tri-U- benzoyl-P-D-galactofuranosiduronic acid S-ethyl thioglycoside has been used to build disaccharides involving linkages to 0-6 and 0-3 of D-

galactose and 0-4 of L-fucose.2'8

a%5H31

ococ 1 5H3 1

a-NeuNAc-(2+8)-a-NeuNAc

a-Neu NAc-(2+8)-u-Neu NAc I 0- 65

Several papers have focused on disaccharides having pentoses in the non- reducing position. A xylan has been degraded enzymically to give p-(1+4)- linked xylobiose which, by way of its hexaacetate, was converted into the p-


nitrophenyl P - g l y c ~ s i d e . ~ ~ ~ p-D-xylp-( 1 +6)-~-Glc is a relatively common disaccharide of natural products several of which have been synthesized this year, the aglycons being o-hydroxyacetophenone,220 3R-linalool and 8- hydro~y-3R-linalool~~~ and various triterpenoids.222 In the last case the derived saponins were compared biologically with triterpenoid saponins synthesized previously. Nucleosides based on the disaccharide P-D-Ribf- (1 +2)-P-~-Rib have been described223 and 1,2-anhydr0-3,5-di-O-benzyl-a-~- ribose has been used to make P-furanosides, P-linked nucleosides and a derivative of the disaccharide L-Ribfi( 1 - P ~ ) - D - X Y ~ . * ~ ~ The same workers have reported the preparation of the same type of products derived by use of 1,2- anhydro-3 ,S-di- 0- benzyl-D-ri bose. 225

1.5 Disaccharide with Anomalous Linking or Containing Modified Rings - Reference to disaccharide analogues containing carba-sugars at the non- reducing end is made in Chapter 18.

Ester-linked disaccharide analogues involving cyclic 2-hydroxyketose derivatives and uronic acids were made by nucleophilic organometallic addition to aldonolactones followed by acylation of the derived tertiary alcohol with the acids in the presence of DCC as coupling agent.226 Dehydrative condensation between a neuraminic acid derivative having a free carboxyl group and one with a 5-amino group led to the amide-linked 66,227 and a related compound with a longer bridge was made by the same researchers following condensation of a neuraminic acid carboxylic group with ethyl glycinate and then condensation between the ethyl ester group and the amino function of a second neuraminic acid. Similar work was done using serine and alanine as bridging units.228 In Chapter 7 several references are made to the linking of two sugar units by diester bridges which do not involve the anomeric centre, and reference to the intramolecular syntheses of glycosides which involve related compounds is made earlier in this chapter. The methylene acetal analogue 67 is the first tri-component bisubstrate analogue for glycosyl transferase inhibition. It showed strong inhibition of UDP-Ga1:GlcNAc p- (I -+ 4)- t ran~ferase.~~~

The ether-linked disaccharide 6-0-(5,6-anhydro- 1,2-0-isopropylidene- ~-glucos-3-~1)-3- 0-dodecyl- 1,2-O-isopropylidene-~-glucose, on treatment with KOH in toluene/DMSO, led to a disaccharide crown ether-like


compound.230 A related type of 3,6’-anhydrodisaccharide analogue was produced by nucleophilic attack by the lithio-derivative 68 on the cyclic sulfate 69 giving compound 70. Reiteration of this procedure gave the trisaccharide analogue 71 (Scheme 6), and in the course of the work a further compound containing one mannofuranose unit and two glucofura- noses was also described.231

+

6 8 ’ 69 70 R - H

7’

Scheme 6

1.6 Reactions, Complexation and Other Features of 0-Glycosides - De-0- allylation of allyl glycosides under Wacker reaction conditions (PdC12, CuC1, 0 2 , DMF, H20) leads to the formation of the desired hydrolysis products but, in addition, ketones and n-palladium vinyl complexes are formed. A variety of sugar allyl glycosides and ethers were examined.232 2-Silylethyl glycosides with a substitutent on the silicon with linking potential may be cleaved by use of acetic anhydride and BF3. This therefore affords means of releasing sugars as glycosyl acetates from silicon tethers by which they are bonded to resins.233 Ceric ammonium nitrate effectively catalyses the hydrolysis of various disaccharides such as sucrose and maltose at pH 7. Some thermodynamic data on the processes were recorded.234 In an interesting investigation involving the use of antibodies raised to a 2,5-dideoxy-2,5-iminohexitol derivative, p-nitrophenyl a-glucopyranoside and a-galactopyranoside were activated in glycosyl transfer reactions.235 The examination of enzymic hydrolysis of monoglucur- onides of vitamin D and 25-hydroxy-vitamin D has been described.236

Reactions of various alkyl and glycosyl 2,3,4,6-tetra-0-benzyl-P-~-glucopyranosides with magnesium bromide and titanium tetrabromide etherate caused highly selective anomerization with resulting a$ ratios being 9:l or larger.237 An interesting study of the cleavage of per-0-allyl- or benzyl-sucrose with ethanethiol and other nucleophiles in the presence of BF3 resulted in tetra-0-allyl- or benzyl-glucose and various fructofuranosyl derivatives. Ethanethiol gave the ethylthio furanosides, while Tms azide gave the corresponding glycosyl azido compounds and water resulted in degradation of the fructose moiety to a furanone derivative.238


OAc

72 X = H , F 73 Reagents: i, Hg(CN)*, HgBq

Scheme 7

0

74

In the Koenigs-Knorr glycosidation of the acceptor 72 with the KDN glycosyl bromide 73, ring contraction was observed and the products 74 were formed (Scheme 7). A mechanism was proposed for this reaction.239

Further observations (see Vol. 29, p. 37, ref. 216) on the use of zinc porphyrins containing both Lewis acid and Lewis base sites as molecular receptors for octyl glycosides have shown they have good affinity for gluco- and rnanno-compounds but poor affinity for galac~o-analogues.~~~

2 S-, Se and Te Glycosides

The use of thioglycosides as donors in oligosaccharide synthesis has been reviewed comprehensively by Garegg (see Chapter 1).

@Protected 1 -thiosugars retain their value as starting materials for thioglycosides and seven examples of 5-nitropyridine 2-thioglycosides have been produced from them.241 Likewise a-(aminoalky1)thio-p-D-glycopyranosides have been obtained from the 1-thiosugars by alkylation with a-(phthalimido)alkyl bromides.242 More complex compounds, however, can be made by this approach, and several S-linked disaccharides comprising glucose, galactose and 2-acetamido-2-deoxyglucose have been made using thio-nucleophilic opening of cyclic sulfates. (See for example Scheme 8). Interestingly, while the a-galactoside acceptor led to p-( 1 + 4)-linked D-glum-compounds, the corresponding p-glycoside sulfate gave predominantly p-( 1 + 3)-linked D-gulo-analogues presumably because the aglycon no longer impedes attack at C-3 which is favoured according to the Furst-Plattner generalization. 4,6-Cyclic sulfate acceptors gave (1 +6)-linked products.243 This work highlights the use of cyclic sulfates in displacement reactions. Glycosyl thiols have also been used as the precursors of such compounds as 75 which is described as a ‘pro-nucleotide’ for use in anti-HIV work.244 N-Chloroacetyl analogues have been used to obtain the thioglycosidic glycodendrimers 76,245 and in related work SiaLea- O(CH2)3NHCO(CH2)3SH has been bonded to N-chloroacetyl-polylysine to give a thiolated derivative as a handle for ELISA.246 Although the product is


OAc 0 OAc OAc Reagents: i, CsCO3, DMF

Scheme 8

not a thioglycoside it suggests opportunities for thioglycosidic linkages to polypeptides.

A considerable range of S-alkyl 1-thioglycosides have been made in standard ways from the peracetates. In one study, while BF3 etherate was a satisfactory catalyst for the glucosides and galactosides, in the mannose series ferric chloride had to be The corresponding 0-acetylated 2-deoxy-2-fluoro- a-D-glycosyl fluorides were used to obtain long chain alkyl 2-deoxy-2-fluoro- thioglycosides with the D-gluco- and D-manno-configurations. The effects of replacement of an hydroxyl group by fluorine and 0-1 by S on liquid crystal properties were discussed.248 The trichloroacetimidate method has been used to glycosylate cysteine at sulfur, the previously unknown wanomer being made by this method.249 1,2-Anhydro-3,4,6-tris-O-Tbdms-cc-~-glucose can be converted to P-thioglycosides by use of thio-nucleophiles in mild bases, the products being conveniently unprotected at 0-2, but when lithium phenylthiolate was used as nucleophile, ether migration occurred from 0 - 3 to 0 - 2 so an 0 - 3 unprotected product was isolated.250

Anomerization of methyl tetra-0-benzyl-1-thio-P-D-glucopyranoside with IDCP, somewhat surprisingly, has been shown to occur in te rm~lecular ly .~~~ Selective sulfoxide formation from S-phenyl 6-O-acetyl-3,4-O-isopropylidine- 1 -thio-P-D-galactopyranoside has allowed a study of the diastereomeric sulfoxides of the thioglycoside, the #-isomer hydrolysing twice as fast as the R- compound under acid conditions. With P-galactosidase only the S-isomer reacted, thus a means of obtaining the R-isomer pure was developed.252 S- Isopropyl 1-thio-P-D-glucopyranoside has been shown to be an inducer of the production of the P-D-glucosidase of Aspergillus niger, a process which is repressed by glucose itself.253 In Chapter 22 the crystal structure of the 5-S- oxide of a 1,5-dithio-P-~-thiopyranoside is reported as well as those of other compounds with thioglycosidic nature.

A set of methyl-, benzyl- and phenyl-seleno- and telluro-P-mglucopyrano- sides has been described,254 and the work was interestingly extended to


compare the reactivities of phenyltelluro-, phenylseleno- and phenylthio-glycosides activated with NIS/TfOH. Selective glycosylation of alcohols was possible with the tellurium compounds in the presence of the selenium analogues, and with selenium in the presence of sulfur-containing compounds.255 Other workers have described the preparation of aryltelluryl glucosides, obtaining high selectivities for the P-compounds. However, these slowly epimerized on standing.256 The preparation and use of aryltellurium furanosides in the production of C-ribofuranosides is illustrated in Scheme 9, the products 77-79 being formed by way of anomeric free radicals, carbocations and carbanions, respectively. 257

Me I

BnO R 77

B n o H 2 c ~ o M s - i kTe+ OMe - iv ,v r ! j o M e OMe -Y 78

BnO R R = H, OBn

1k7FPh Me

Reagents: i, ( V I e O e e - , NaBH4; ii, Et3B; iii, % ; iv, BF3Et20;

; vi, BunLi; vii, PhCHO

v*"'oYoMe OMe Scheme 9

CFsC02-

3 C-Glycosides

3.1 Pyranoid Compounds - Several reviews have been published on C-glycosides one describing the synthesis of such compounds including C-disaccharides,258 one on the synthesis of C-glycosidic analogues of biologicially significant O-glyco~ides,~~~ one on the synthesis of C-glycosides using anionic and free radical donors,260 another on the preparation of C-glycosides and their inhibition of N-linked glycoprotein biosynthesis,261 while another has concentrated on the preparation of C-glycosides containing unsaturation within the glycosyl components. In this last case transition metal-catalysed functionalization was involved in each example and the material covered includes the conversion of glycals into phenyl 2,3-unsaturated C-glycosides


and the replacement of various substituents on C-1 of glycals and on 2,3- unsaturated glycosyl compounds to give C-glycosidic glycals and 2,3-unsaturated compounds, respectively.262 Successful enzymic p-( 1 -+ 4)-galactosylation of hydroxymethyl P-C-glucopyranoside (2,6-anhydro-~-gZ~cero-~-guZo-heptitol) has been reported. 198a

A short synthesis of a-glycosyl cyanides of several sugars relies on the use of trimethylsilyl cyanide activated by methyl triflate and applied to O-benzylated- S-ethyl thioglycosides. The a-anomers derived from L-fucose, D-glucose, D-

galactose and D-mannose predominated, and yields were close to 70%.263 The p-glycosyl cyanide of N-acetylglucosamine, on reduction, gave the amino- methyl compound which was bonded to the aspartic acid unit of a pentapeptide. The corresponding pentapeptide derived from the analogous glycosylamine was made, and the products were tested as glycosidase inhibitors.264

The p- C-formyl glycosides of glucose, galactose, mannose and N-acetyl-glucosamine (2,6-anhydroheptoses) were derived by ozonolysis of the corresponding nitromethyl compounds and, following reaction with nitromethane, were converted into their corresponding 2-nitroethenyl and 2-nitroethyl C- glycoside~.*~~ Extended chain C-glycosides have been made from the corresponding C-formyl compounds following nucleophilic addition of the Grignard reagent of trimethylsilylacetylene, removal of the silyl group, partial reduction to give epimeric allylic alcohols which were converted to their 2,4- dichlorobenzoates. Palladium-promoted nucleophilic rearrangements involving such nucleophiles as dimethyl malonate gave a set of products, e.g. Scheme 10 illustrates the preparation of a C-glycosylglycine which was made together with several related compounds.267 Compounds 81268 and 82269 were made from analogues carrying a carboxymethyl C-1 substituent on the sugars, and were amide-bonded to give glycopeptide-like adducts. Conjugated dienes

CH~OAC I

Aco%o NH

YHpOBn

C02Me

BnO Et)-. C02Me FmocHN

0 80 81

OBn

82


ii-v 1

Reagents: i, Me&HCONEt2; ii, NaH, THF; iii, TsCI, Py; iv, NaN3, DMF; v, Ph3P. THF Scheme 10

can be made from aldonolactones as illustrated in Scheme 11.270 Carbene addition to tribenzyl-D-glucal gave an adduct which was oxidatively ring expanded to 83 and taken through, as indicated in Scheme 12, to the 2-0- formyl- C-methyl compound 84.271 Related bicyclic compounds were made by Lewis acid-catalysed rearrangement of the phenyl sulfones indicated in Scheme 1 3. An a-D-galactopyranosyl analogue reacted similarily but gave epimers about the anomeric centre.272

-WPd Reagents: i, KHMDS, HMPA, (Ph0)2POCI; ii, Bu&n

Scheme 11

CH20Bn CH20Bn (J OBn , - i. ii /hc, - iii. iv 14 - v, vi 0 OBn

BnO BnO Me

0 0 OH OCHO 83 04

Reagents: i, C13CCOCl, Zn-Cu, Et20; ii, MCPBA; iii, Zn, HOAc; iv, DIBALH; v, PhI(OAc)p, 12, hv;

Scheme 12 vi, Bu3SnH, AIBN

CQBu' 0

R = H, Bn 3 : 8 mixture, 88%

Scheme 13 Reagents: i, SnC14, 4 0 "C


BiBr3 has been used to catalyse the production of C-ally1 glycosides from 0- glycosides and allyltrimethylsilane, for example methyl tetra-0-benzyl-a-D-glucopyranoside gave the. C-ally1 analogues in 63% yield with an ccp-ratio of 8:1.273 More commonly, such products are made by use of the same ally1 source and TmsOTf as catalyst, and adaptation of this chemistry by use of 3- trimethylsilylpropyne led to the allenyl glycoside 85 in 72% yield.274 Isomeric compounds, with 1,3-dienic functionality at C-1, for example 86, were made from l-C-ally1 glycosyl chlorides by treatment with DBU. The starting materials were available from 1 -bromo- 1 -chloro compounds which were converted by radical reduction to C-ally1 chloro-anal~gues.~~~ Treatment of tetra- O-benzyl-C-ally1 glucosides with iodine gives good yields of compounds 87 which, with zinc and acetic acid were converted into the C-ally1 compounds unprotected at 0-2. From these, corresponding 2-deoxyamino derivatives were prepared by use of azide displacements, the work leading to C-glycosides in the glucosamine and mannosamine series.276

CH20Bn YH20Ac FH20Bn

BnO

OAc 0 I 05 86 87

Silyl ketene acetals offer further means of obtaining C-glycosides, tetra-0- benzyl-D-glucosyl acetate affording compounds 88 on treatment with the Tbdms enol ether of the correspoding methyl ester. Compound 89 was made in analogous fashion by use of a dihydrofuran enolsilyl ether.277 Glycal derivatives reacted as expected with trimethylsilyl ketene acetals under acidic conditions, triacetylglucal, for example, affording compound 90 with 1 - methoxy-2-methyl- 1 -Tms-oxyprop- 1 -ene. Further use of trimethylsilyl ketene acetals in the preparation of branched-chain derivatives is referred in Chapter 1 3.278

CH20Bn

BnO ($C02Me

_.

OBn OAc AcO 88 R = H , M e 89 90

Two reports have been made on the well established addition of glycosyl radicals to alkyl acrylates and a ~ r y l o n i t r i l e , ~ ~ ~ - ~ * ~ compounds such as 91 and 92 being obtainable by this approach.

Glycosyl pyridyl sulfoxides, treated with samarium diiodide, give glycosyl- samarium intermediates which may be used (effectively as glycosyl carbanions) to add to carbonyl compounds. Aldehydes and ketones may be employed, or


otherwise more complex materials such as sugar derivatives carrying formyl C- branching groups (see below).281

CH20Ac CN I

91 92 93 n - 1-3

Alkenylmagnesium bromides, added to tetrabenzylgluconolactone, have given intermediates from which the hydroxy groups may be cleaved reductively using triethylsilane/BF3, to give specific products which were debenzylated and epoxidized to afford compounds 93.282 The same gluconolactone derivative, following methylenation, was used to make 1'- and 2'-linked C-glycosidic analogues of glycerolipids, for example 94. Free radical addition of malonate was used to produce this compound, and butenyl Grignard reagent was utilized in the formation of the analogous 1-linked products.283 In related work a novel C-glucosylsphingosine was made by oxidation of a C-1 ally1 substituent followed by Wittig chemistry and elaboration of the derived alkene.284 In the field of C-analogues of glycosylamino-acids the 0-D-glucopyr- anosylserine analogue has been elaborated starting from the O-benzylated- S-lactone which was treated with vinylmangesium halide to give a C-vinyl free sugar which was converted into the (methoxycarbony1)methyl 0-glycoside prior to sigmatropic rearrangement and elaboration of the C-1 s u b ~ t i t u e n t s . ~ ~ ~ A glycosyltin reagent, added to an appropriate aldehyde, resulted in the p-D- GlcNAc analogue of an N-glucosyl asparagine,286 and a range of or-glucosyl, galactosyl and mannosyl C-analogues of glycosylserines have been built up using asymmetric additions on unsaturated a g l y ~ o n e s . ~ ~ ~

Oen

Interest continues in C-glycosyl aromatic compounds, tetrabenzylglucosyl fluoride with boron trifluoride catalysis having allowed the C-glycosylation of di- 0-benzylphloroglucinol, and a second glycosylation proceeded efficiently to allow the production of compound 95.288 Unprotected 2-deoxy-sugars can be condensed with 0-naphthol to give 1 -C-glycosides in chloroform using montmorillonite as catalyst and, much more surprisingly, this type of chemistry can


0

H O H M O M e &X \

OH ' OBn

HO OMe BnO OMe 0 96 97 X = H, CI

0 OH

98

be effected in water. For example, 2-deoxyglucose and dimethylphloroglucinol gives compound 96 in 60% yield.289 Full details of previous work (Vol. 29, p. 47, ref. 268 and Synlett, 1996, 433) on the synthesis of the C-glycosyljuglones 97 and their conversion into galtamycinone 98 have appeared, the chemistry involving an 0 -+ C glycosyl rearrangement.290 An O-protected iodomethyl a-C-glucoside was used to obtain compound 99 and the naphthaquinone analogue, both of which inhibited an a-glucosidase, and continuation of the work led to the unnatural 6-C-linked diglycosyl compound Free sugars were used to make several 2,6-dideoxy compounds, e.g. 101, TmsOTf and AgC104 being the catalysts and MeCN the solvent. In closely related cases methyl glycosides were employed in CH2C12 with TmsOTf catalysis.292

CH20Bn

100 101 0

99

An interesting 2-O-acylation of a C-glycoside, involving migration of the acyl group from the aglycon, has led to compounds 102.293

Considerable attention has been devoted to the preparation of C-linked disaccharides, and in this section the C-bonded group which replaces the oxygen atom linking the sugar units is indicated within the abbreviated names used. The following compounds were made by Wittig linking: P-D-G~c-( 1 -CH2- 6)-~-Gal, p-~-Gal-( 1 -CH2-6)-~-Glc, P-D-GalNAc-( 1 -CH2-6)-~-Glc, P-D-G~c- ( 1 -CH2-6)-~-Glc, a-D-Ribf-( 1 -CH2-6)-~-Gal and a-D-Manf( 1 -CH2-6)-D- Gal.294 A Michael addition applied to levoglucosenone has afforded an


intermediate which was reduced to P-D-G~c-( 1 -CH2-4)-3-deoxy-~-G1~.295 The intramolecular condensation of tethered species is now commonplace for synthesizing disaccharides and their C-linked analogues, and a-~-Glc-( 1 -CH2- 6)-~-Glc has been made by this approach,296 as has cc-~-GalNAc-( I-CH2-4)-P- D-GlcOMe. In the latter case the galactosamine and glucose (in the form of a 1 -em-methylene derivative) were initially bridged by way of a phosphate linkage between the amino group and 0-6 of the latter.297 Carbanion additions to formyl branched groups on monosaccharides leads to disaccharide analogues having a hydroxymethylene group between the sugar units, and by this approach ct-~-NeuNAc-( 1 -CHOH-~) -D-G~~ has been made298 as has a-D-Man- ( ~ - C H O H - ~ ) - D - M ~ ~ . ~ ~ ~

CH20Bn CH20Bn CH20Bn

BnO b S n B u 3 + BnO @O - BnO wan OBn /

OBn OBn 1 i. ii

OH OH Reagents: i, 0 ~ 0 4 , NMNO; ii, H2, Pd/C Scheme 14

Several examples of disaccharide analogues derived by direct carbon-carbon coupling of monosaccharides have been reported. For example, electrochemical reduction of tetra-0-acetylglucosyl chloride has given the l,l'-linked compound and 6-deoxy-6-halogeno-diisopropylidine-a-~-galactose, treated similarly, has given a dimer with direct C-&C-6)-b0nding.~~~ Scheme 14 illustrates the production of a different type of trehalose analogue, the compound formally being a dodeca-6,7-diulose. 300 The unusual compound 103 was derived via 104 which in turn was made from the corresponding pentodial- dose by treatment with f~ranyllithium.~~' Compound 105 is a further example of a quasi-disaccharide built on a monosaccharide template, on this occasion from 106 using ethyl vinyl ether in a hetero-Diels-Alder condensation to prepare the second pyranosyl ring.302

Ac I

OCR II 0

1 02

OMe

OH

103 A 1 04 A


Interest in acetylenic C-glycosides continues and reaction of 1,2-anhydro- 3,4,6-tri-O-benzyl-D-glucose with alkynes in the presence of n-butyllithium and zinc chloride gives a-acetylenic 2-hydroxy C-glycosidic compounds, Treated with cobalt octacarbonyl these give complexes, e.g. 107, which, on treatment with triflic acid, give anomerized p-isomers. Extension of this work has given alkyne 108 which offers further access to a-~-Glcp-( 1 - C H ~ - ~ ) - D - G I C . ~ ~ ~ Vasel- la’s team has continued its interest in macrocycles derived from carbohydrate diacetylenes, and palladium coupling of compound 109 has led to the cyclic trimer 110 and also an analogous tetramer.304 Cyclic compounds with three and four diacetylenic dipyranoid ring units have also been described.30s Palladium- catalysed addition of aryl halides to the double bonds of 2,6-anhydro-l- deoxyhept- 1 -enitols produced arylmethyl C-glycosides with the P-configuration in both the D-glUC0- and D-manno-series. Extending this reaction, for example to p-dibromobenzene, has given rise to C-linked compounds involving two sugar units joined by way of a benzene ring, such as compound 11 1 .306

BnO q BnO QMe

I OBn

108

VH~OAC

A OAll Tms

109

Several compounds having glucose C-linked to ring systems similar to pyranose rings have been described. Hetero-Diels-Alder chemistry conducted in water has allowed the formation of compound 112 from a glucosyl C- glycoside bearing a penta-l,3-dienyl group which was coupled with glyoxylic acid.307 Otherwise the C-linked glycosylcarba-sugar 113 has been made by Diels-Alder chemistry applied to a C-glucoside having a dienophile in the a g l y ~ o n . ~ ~ ~ In related studies a 2-deoxyglycosylstannyl compound was coupled

3: GIycosides and Disaccharides 49

HO

111 OBn 112 113

P1

OAC Reagents: i, CO(50 atm), Pd2(dba)3,

""h \O

CN

1 : OAc

Ph3As Schome 15

"';;;h \O

CN

1 : OAc

Ph3As Schome 15

CN 1

in the presence of butyllithium with a cyclopentyl derivative bearing a formylmethyl group to give compound 114 and a diastereomer. In the course of the work an analogue was made having the sugar similarly linked to deoxyinositol d e r i v a t i ~ e . ~ ~ Scheme 15 illustrates chemistry which has given C- linked glycosylcarba-sugars analogous to compound 1 13.310 Extension of this work by Vogel and his team has led to the azasugar derivative 115 and hence

115 114

OH

.OMe

OH 116


to the C-disaccharide analogue 116. This chemistry was described in a long, complex paper with much detail3'

Enzymic galactosylation of C-glycosides is referred to earlier in this chapter and Paquette's work on the ring expansion of particular 1,2-~nsaturated C- glycosides to give spirocyclic compounds is referred to in Chapter 2.

3.2 Furanoid Compounds - Palladium chloride-catalysed ring closure of 1,2- dideoxy-hex-l-enitols having a free hydroxyl group at C-5 leads to a new way of making methyl C-glycofuranosides. The reactions proceed by way of the 1- deoxyketofuranoses which, with triethylsilane and boron trifluoride, are dehydroxylated. The assigned configurations at the new anomeric centres in this work have to be viewed with care because they conflict with results presented in J. Chem. SOC., Perkin 1, 1995, 517, in which NOE evidence pertaining to configuration is provided.312 The functionalized branched chain C-glycosidic compound 117 was the product of treatment of a corresponding methyl a-pyranosidic compound with DAST. The starting material with the alternative configuration at C-2 reacted quite differently affording a glycopyranosyl fluoride with methoxyl now attached to (2-2. Clearly intermolecular rearrangements are proceeding in this chemistry, and the mechanisms of these are discussed. ' From the corresponding exo-difluoromethylene glycosylidene compound the phosphonates 118 were produced by free radical addition processes.314 Tri-O-benzyl-P-D-ribofuranosyl cyanide is, as expected, the product of reaction of the corresponding acetate with trimethylsilyl cyanide.3* Also in the ribofuranosyl series a- C-glycosides having acetylmethyl-, benzoyl- methyl- and cyanomethyl-a-substituents have been produced starting from the corresponding lactones which underwent nucleophilic additions to give free sugars which were reductively dehydroxylated in the normal way.316 In the 2- deoxy-ribofuranosyl series an O-substituted glycosyl acetate, treated with the appropriate O-silylated ketene acetal in the presence of a Lewis acid, gave the a-furanosyl C-glycosidic compound having (benzyloxycarbony1)methyl as the aglycon .3

118 X = O , S

TrOHzC

"q 119 0

Reaction of partially protected free sugars with arsonium ylids under neutral conditions [(Ph3As-CH2C02Et)+Br -/Zn] gave mainly E-alkenes, whereas under basic conditions [(Ph3As=CHC02Et/nBuLi)J the products were bicyclic compounds. For example, 6- O-tritylglucose afforded ultimately the bicyclic C- glycosidic 1 19.31 * The same authors then described conditions for producing the analogous O-unprotected lactone in 70% yield directly from glucose.


Galactose afforded the analogous isomeric compound in 72% yield, but the pentoses mainly gave the unsaturated intermediate^.^'^ This represents a very much more convenient approach to compounds such as 119 than does an alternative route involving 2-0-bromoacetyl y-lactones from which Wittig reagents were produced and hence the bicyclic lac tone^.^^^

Elaboration of the a-D-arabinofuranosyl C-formyl glycoside (2,5-anhydro- D-mannose), involving condensation with cyclopentadiene in the presence of benzylamine hydrochloride and Nd(OTf)3 in water led to compound 120. In the course of the work compound 121, which can be considered to be a C- glycoside of an aza-sugar derivative, was made.321

H0H2cw HO " H Q / y Me

N!-OH OH OH OH

121 122 OH 120

A review has been written on 'C-nucleosides derived from simple aromatic hydrocarbons'. i. e. aryl C-glycosides of P-D-ribofuranose and its 2-deoxy derivative.322 The heterocyclic compound 122 has been prepared starting from 2,3,5-tri-O-benzylribose to which was added a heterocyclic nucleophile. Several derivatives were made one of which was half as active as cimetidine as an anti-ulcer agent, and the paper refers to much other related medicinal chemistry.323

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4 Oligosaccharides

1 General

Following the major recent increase in activity in this field, this year has seen the production of a mass of relevant reviews. Paulsen has surveyed general developments in the chemical synthesis of oligosaccharides over the last 25 years,' and an assessment in Chinese has concentrated on the stereoselectivity of relevant reactiom2

Methods involving the use of polymer-supports are now used extensively, and Krepinsky has reviewed the production of oligosaccharides on poly(ethy1ene glyco1)monomethyl ether (MPEG).3 Solid-phase methods of synthesis of polylactosamine oligosaccharides involving orthogonal glycosylation have been ~urveyed,~ as has the use of several new p-substituted benzyl or phenyl protectingllinking groups in solid-phase oligosaccharide synthesis. p-Acyl- aminobenzyl and p-azidobenzyl groups are, as expected, more acid-stable than p-methoxybenzyl analogues, but are readily cleaved by methods involving DDQ. The p-acylaminophenyl glycosidic linkage is easily broken with CAN.5

A further review has covered the synthesis of compounds, e.g. Sia LeX mimetics, that interact with cell surface carbohydrates, and refers to the solid- phase approach and also combinatorial procedures,6 while another7 covers the latter technique applied to oligosaccharides and oligonucleotides.

Garegg has surveyed the use of thioglycosides as glycosylating agents,8 and with colleagues, their use in the making of oligosaccharides found in fungal and bacterial polymer^.^ A related review has dealt with glycosylations based on thioglycosides, sulfoxides and other S-glycosidic donors,10 and another has assessed phenylselenyl glycosides as donors and acceptors in reactions that lead to oligosaccharides. '

Glycals have particularly been exploited by Danishefsky who, with Bilo- deau, has reviewed this impressive work,** while Fraser-Reid has dealt with his n-pentenyl glycoside approach' and other workers have covered Boons's latent-active glycosylation strategy (see ref. 42 below). l4

Enzymic synthetic procedures are now of great use in specific oligosaccharide production, and several reviews have appeared. One dealt with the topic generally,15 and another reported on the optimization of methods for application on the kg scale. l6 More selective surveys covered the use of glycosyl transferases in the synthesis of unnatural oligosaccharides, and the applica-


62

4: Oligosaccharides 63

tion of a-( 1 + 4)-galactosyltransferases for the same purpose. l 8 The topic of inhibition of these enzymes has been dealt with; various mono-0-methyl UDP- Gal ethers and derivatives having acceptors bridged to UDP-Gal were discussed. Potent specific inhibitors have been discovered in this way. l 9 A further survey of the use of enzymes emphasized the production of Sia LeX antigen and dealt with the matter of inhibition of glycosidases and glycosyl transferases .20

The substrate specificity and synthetic applications of transferases have been discussed in a review that included treatment of the use of glycosyl phosphites in oligosaccharide synthesis and in the synthesis of glycopeptides,21 and enzymic approaches to these latter compounds form part of a further review.22 The variables involved in making glycoconjugate di- and tri-saccharides based on Gal, GlcNAc, Fuc and Man by enzymic approaches have been assessed,23 as have analogous procedures for making nucleotide deoxy-sugars and oligosaccharides. 24

Reviews have appeared on the chemical synthesis of cello-oligosaccharides,25 P-mannopyranoside-based compounds,26 deoxy-sugar ~ l i g o m e r s , ~ ~ thio-oligosaccharides which are recognized by proteins,28 heparan sulfate, heparin and heparinoid r n i m e t i ~ s ~ ~ and biologically active sulfated and phosphorylated oligomers. 30

The important topic of the preparation of glycocongugates by chemical and enzymic procedures has been surveyed by S~hmidt ,~ ' and several reviews have concentrated on such compounds - especially those which contain sialic acid components. 32-36

The specific topics of the synthesis of dimeric forms of the calicheamycin oligosaccharide and their docking in the minor groove of duplex DNA have been surveyed,37 and reviews have appeared on the molecular recognition of oligosaccharides by proteins3* and of oligosaccharide glycolipids in supramolecular self assemblies in aqueous media.39

Reports of new work of general importance are now dealt with. Powerful new methodologies continue to be developed to help overcome the limitations of traditional approaches to the synthesis of oligosaccharides. For example, the branched trisaccharide glycoside p-~-Glc-( 1 + 4)-[p-~-Glc-( 1 (6)]-a-~-Glc- OMe has been made by linking 0-6 of the (1 -+6)-bonded dimer to 0 -2 of a suitably protected glucosyl fluoride by a phthalic diester bridge, and activating the fluoride with silver triflate and Cp2HfCl, to give in 37% yield, the cyclic product 1 which was deprotected to give the trisaccharide.40 Further evidence that the elegant intramolecular approach to disaccharide synthesis is being extended into oligosaccharide work comes from the synthesis of the strepto- coccal capsular polysaccharide unit p-~-GlcNAc-( 1 + 3)-a-~-Gal-( 1 -+ 4)-p-L- Rha-( 1 -+ 4)-~-Glc for which the rhamnose moiety as an S-ethyl thioglycoside was succinic diester linked via 0-2 to 0 -3 of the glucose unit in such a way that activation of the thioglycoside led to the required p-( 1 + 4)-bond formation. The resulting disaccharide, still intramolecularly diester-linked, was then coupled with the GlcNAc-Gal component?

A most significant development is Boons's exploitation of the different

64 Carbohydrate Chern istry

reactivities towards glycosylation of different types of hydroxyl groups in acceptor molecules, equatorial groups being more reactive than axial, primary than secondary, and most importantly, hydroxyl groups neighboured by ether protecting groups being more reactive than those with neighbouring ester substituents. Using these differences and Fraser-Reid's armed and disarmed glycosylating agents he demonstrated high yields of selectively substituted disaccharides, and extended the principles into the preparation of the hetero- hexamer a-~-Glc-( 1 -+ 6)-P-~-Gal-( 1 +4)-P-~-Glc-( 1 +6)-P-~-Gal-( 1 +4)-p-D- Glc-( 1 3 6 ) - ~ - M a n . ~ ~

A new approach to linking sugars and peptides involves galactose oxidase oxidation of galactosyl or N-acetylgalactosaminyl-0-peptides and coupling of the aldehydic products with glycosylamines (e.g. lactosylamine) elaborated to contain the -NHCOCH20NH2 group. The products are therefore as indicated in 2.43

A specific development involves the preparation of chito-oligosaccharides on a large scale using E. coli with genes encoding for relevant glycosidases and N-deacylases. The method led particularly to the pentaoses carrying four and five acetyl groups.+'

1

ACHN I H2N-Peptide-COZH

2

2 Trisaccharides

2.1 General - Compounds in sections 2.1-2.4 are now characterized according to their non-reducing end sugars.

The combinatorial approach involving solid phase techniques on TentaGel resin has provided a library of 1200 di- and tri-saccharides which were screened against a Bauhinia purpurea 1ecti1-t.~~

In the area of non-reducing trisaccharides the enzymic syntheses of 6 - 0 - w ~ - mannopyranosyl-, 6-0-a-D-glucopyranosyl- and 6-0-a-D-galactopyranosyl- trehalose and 6-0-a-D-mannopyranosylsucrose have been ~ p t i m i z e d , ~ ~ and Nicolaou and co-workers, using a 1,2-0-stannylidene derivative of p-D-mannopyranose coupled with a mannosyl trichloroacetimidate, have produced a 2- O-unprotected a,&manno-trehalose analogue derivative and hence have made a 2-O-a-~-mannosylated-manno-trehalose. Several related compounds were


prepared, and the methods were also used to make the F-G ring system of everninomicin 13,3841 .47

2.2 Linear Homotrisaccharides - The use of n-pentenyl glycosides has been extended to the solid-support preparation of oligosaccharides with either the pentenyl donors or the acceptors bound to the resin, and the linkages to the polymers being photolabile. In the course of the work polymer-bound, fully deprotected oligomers were produced which points to the preparation of libraries of oligosaccharides. In this way a-~-Glc-( 1 +6)-u-~-Glc-( 1 +6)-~-Glc was made,48 and the a-( 1 +6),p-( 1 +@-linked analogue was produced as the glycosylamine for amide coupling to give the core structure of the nephrito- genoside glycopeptide, the glycosyl phenyl sulfoxide method of glycosylation being used.49 Thioglycosides were used in making the a-( 1 + 4)-linked trimer of D-galacturonic acid.

Hydrolysis of inulin with a bacterial endoinulase gave the P-Fru.(2-+ 1)- linked dimer and trimer in nearly equal proportions.’

2.3 Linear Heterotrisaccharides - P-D-G~c-( 1 +2)-P-~-Glc-( 1 + 4) -b~-Ga l is the sugar component of a steroidal glycoside of the plant Hosta plantaginea which shows cytostatic activity against leukaemia cells.52 Other glucosyl compounds of this set which have been synthesized are P-D-Hex-( 1 + 4)-P-D- GlcNAc-( 1 +2)-a-D-Man (where Hex = D-G~c, 4-deoxy-~-Gal and 4-deoxy-4- fluoro-~-Gal),’~ and 3-U-Me-p-~-Glc-( 1 + 3)-a-~-Rha-( 1 + 3)-a-~-Rha which was prepared as the p-isothiocyanatophenyl glycoside for coupling to pep tide^.^^

In the area of D-galactose-terminating compounds various trisaccharides were made from glucoside acceptors following the use of 4,6-O-pyruvylidine galactosyl chloride and trichloroacetimidate donors,55 and the glycosyl phosphoroamidate method, coupled with the armeddisarmed concept, were employed in making a ceramide based on a-D-Gal-( 1 + 4)-p-~-Gal-( 1 -+ 4)-p-D- Glc? The closely related a-D-Gal-( 1 + 3)-P-~-Gal-( 1 -+ 4)-p-~-Glc-NHC02 CH2CC13 was produced by enzymic methods as its S-ethyl thiogly~oside,’~ and the galactobiosyl-GlcNAc analogue was produced by chemico-enzymic procedures on an MPEG resin in the course of work on immunosuppression.58 Solid-phase work led to P-D-Gal-( 1 + 3)-P-~-Gal-( 1 -+ 3)-a-~-GalNAc 0-bonded to a peptide and to similar p-( 1 + 3), p-( 1 +.6) linked glycopeptides all of which are related to mucin core structure^.^^ p-D-Gal-( 1 -+2)-P-~-Glc- (1-+6)-~-Glucal was reported in work designed to use complex glycals as glycosylating agents.60 Modifications in the galactose unit of P-D-Gal-( 1 + 4)- P-D-G~cNAc-( 1 +2)-a-~-Man gave a set of compounds required for the study of sialyl transferase specificity,61 while a different group produced the unmodified trisaccharide and its p-D-Gal-( 1 + 4)-p-~-GlcNAc-( 1 -+6)-a-~-Man isomer by use of a P-N-acetylglucosaminidase and a P-galactosidase.62 Modification to the P-D-Gal-( 1 + 4)-p-~-GlcNAc-( 1 +2)-a-~-Man system gave several analogues terminating in moieties having modifications at C-3 of the galactose unit and with this sugar replaced by P-D-gUlOSe, a-L-altrose and P-~-galactose.~~


Solid-phase and n-pentenyl glycoside technologies were combined to afford p-D-Gal-( 1 + 2)-a-D-Man-( 1 + ~)-D-GIcNAc.~~

P-D-Man-( 1 -+ 4)-p-~-GlcNAc-( 1 -+ 4)-~-GalNAc has been prepared by use of recombinant enzymes," and an improved synthesis of ol-L-Araf( 1 -+3)-p-D- Gal-( 1 +6)-p-~-Gal has been described.65

The following compounds terminating in 2-N-acetylaminohexoses have been synthesized: P-D-G~cNAc-( 1 + 3)-p-~-Gal-( 1 -+ 4)-GlcNAc and its p-( 1 +6), p-( 1 -+ 4) linked isomer (enzymic procedure),66 P-D-G~cNAc-( 1 -+2)-a-D4- NHAc-Man-( 1 -+6)-~-Glc (as well as seven analogues with other acyl groups on the 4-amino-4-deoxy-~-mannose moiety),66 and P-D-GalNAc-( 1 + 4)-3-0- S03H-p-~-Gal-( 1 + 4)-p-~-GlcNAc and its analogue with sulfate replaced by

In the field of compounds containing L-glycero-o-manno-heptose the following trisaccharides have been made: a-~-GlcA-( 1 +2)-a-Hep-( 1 +3)-Hep6* and Hep-( 1 + 4)-Kdo-5-phosphate-(2-+ 6)-GlcNAc corresponding to the inner core region of a bacterial lipopoly~accharide.~~

Because of their biological significance considerable activity has taken place on trisaccharides terminating in a sialic acid unit, the ganglioside GM3 a-NeuNAc-(2+ 3)- p-~-Gal-( 1 + 4)-p-~-Glc- O-Cer and near analogues having been targets particularly favoured. Thioglycoside 3 has been used for the introduction of the sialic acid,70 and in another chemical approach which led to the N-glycolyl analogue, compound 4 was emp10yed.~' Mainly, however, enzymic procedures have been ~ s e d . ~ ~ - ~ ~ Lactone 5 of GM3 has been made as a possible hapten for development of an anticancer vaccine.79

glycoly1.67

I / 3Mu ACHN t)Ac

OAC 3 R=SPh 4 R = H

6 i Tms

Related work has resulted in the preparation of a-NeuNAc-(2 + 3)-p-~-Gal- (1 +3)-a-~-GalNAc linked to cysteine which is part of the B-chain of human a 2HS glycoprotein. Solid-phase procedures were used and, in the course of the work, compounds with the trisaccharide having lactone linking between the acid group and 0-4' are bonded to serine were involved.80 Use of sialyl transferases has allowed the preparation of the closely related a-NeuNAc- (2+ 3)-P-D-Gal-( 1 + 4)-~-GlcNAc and a-NeuNAc-(2+ 3)-p-~-Gal-( 1 + 3)-2-0- Ac- p-D- Gal.

The xylose-containing trisaccharide a-NeuNAc-(2 + 3)-P-~-Gal-( 1 + 4)-p-D- Xyl has been made enzymically as its p-nitrophenyl glycoside as a potential inhibitor of human skin fibroblast glycosaminoglycan biosynthesis,82 and


derivatives of the same trimer glycosidically linked to a ceramide have been made in the form of a lactone involving the acid function and 0-2 of Gal. The analogue with Gal replaced by GalNH2, and with the amino group lactam- linked to the acid group, was also de~c r ibed .~~

Trisaccharides terminating in 6-deoxyhexoses to have been synthesized are a-L-Rha-(1 + 4)-ct-~-Rha-( 1 -+2)-~-Fuc (the sugar of a resin gly~oside) ,~~ and 6-deoxy-a-~-Tal-( 1 +2)-p-~-Rhaf-( 1 + 5)-DHA (a very unusual type of rhizo- bial compound; DHA being 3-deoxy-~-lyxo-heptulosaric acid). X-Ray structural analysis was carried out on a methyl glycoside, methyl ester peracetate!

Glycal- and hence 1,2-anhydroglucofuranose-based methods were used in the preparation of a-L-Araf-( 1 +2)-p-~-Glcf-( 1 - 6 ) - ~ - G l c . ~ ~

2.4 Branched Homotrisaccharides - 4,6-Di-~-~-~-ghcopyranosyl-~-glucose has been made by an intramolecular method,40 while a solid support synthesis involving the use of a photolabile linkage was employed in the preparation of 3,6-di- 0-mannopyranosyl-D-mannose. 87

2.5 Branched Heterotrisaccharides - Compounds in this section are categor- ized according to their reducing end sugars.

Further attention has been given to the Lex-related P-D-Gal-( 1 + 4)-[a-~- Fuc-( 1 + 3)]-~-Glc: its synthesis from lactose was described,88 as were those of derivatives with sulfate groups at 0-389990 or 0-4,89 or 0 -3 and 0-4,89 or 0-3 and/or 0-691 of the galactose moiety. In the case of the 3’-sulfate dendrimers were made and their selectin-binding properties were measured.90 An analogue with a 3-carboxymethyl-3-deoxy branch in the galactose unit was also reported?2 and the Lea antigen P-D-Gal-( 1 + 3)-[a-~-Fuc-( 1 +4)]-~-Glc has been made with sulfate groups at 0-3 andor 0-6.91

LeX antigen, p-D-Gal-( I -+ 4)-[a-~-Fuc-( 1 -+ 3)]-~-GlcNAc, has been made by use of two specific glyco~idases~~ and combined chemical and enzymic procedures were employed in making analogues with the fucose moiety modified by replacement of the C-6 methyl group by n-pentyl and n-heptyl groups.94 The 3’-sulfate, esterified on 0-3 of the galactose moiety, has been produced by chemical methods,95 and several 0-3’ ethers (e.g. the S- and L-lactyl ethers) were made following molecular modelling studies aimed at the rational design of E-selectin antagonists based on Sia LeX as lead compound.96 Solid-phase work involving enzymic fucosylation of the appropriate disaccharide disulfide-bonded to Sepharose led to fi-D-Gal-( 1 + 3)-[a-~-Fuc-

In work related to core glycopeptides of mucins the following branched trisaccharides have been made: P-D-G~cNAc-( 1 +6)-[P-~-Gal-( 1 + 3)]-

a-~-NeuNAc-(2 + 6)-[ p-D-Gal-( I + 3)]-~-GalNAc, lo’ and this compound with P-D-Gal replaced by or-D-GalNAc. lo2

(1 +~)]-D-GICNAC.’~

2.6 Analogues of Trisaccharides and Compounds with Anomalous Linking - In studies of the LeX antigen and its biological function mimic molecules to have been made are the morpholine-trisaccharide model compounds 7 which


contain mimics of two sugar units and the analogue with Fuc replaced by CI-D- Man. Some of the products showed strong inhibition of leukocyte adhesion in rats.*#

Compounds 8 (twelve were made) with methylene inter-unit linkages were prepared as potential inhibitors of the synthesis of the surface proteins of Helicobacter pylori. They allowed a study of the effects of systematic variation of the central moiety which was effected by Grignard-like coupling of a 2-bromoallyl 'aglycon' on the Fuc unit and a formylmethyl C-3 substituent on the 3-deoxyglucosamine. lo5

p-~-GlcNAc-( 1 + 2)-a-D-Man-( 1 + 3)-a-~-Man-O-Me with a methylene acetal bridge between 0-6 of GlcNAc and 0-2 of the terminal Man is locked in a suitable conformation for binding with a specific lectin.lo6

The trithio-ganglioside GM3 epitope 9 has been specifically synthesi~ed.'~~

OH 8 R' = CH20H, Me; R2 = OH

CH20H qH20H

OH 9

3 Tetrasaccharides

Compounds of this set and higher oligosaccharides are classified according to whether they have linear or branched structures and then by the nature of the sugars at the reducing termini.

3.1 Linear Homotetrasacharides - Pivaloylation of maltose gave 61% of a hepta-ester which led to the 3-deoxy-analogue which was coupled with a


partially 0-protected trehalose derivative to give a-D-Glc-( 1 -+ 4)-3-deoxy-p-~- Glc-( 1 --+ 4)-a-~-Gk-( 1 --+ 1)-a-D-Glc.'O8 A 6'-O-trityl maltoside was used in the preparation of a-D-Glc-( 1 -+ 6)-P-~-Glc-( 1 + 6)-a-D-Glc-( 1 + 4)-D-Glc, lo9 and a-D-Glc-( 1 -+ 3)-a-~-Gkc-( 1 + 4)-a-~-Glc-( 1 --+ 4)-D-Glc has been produced by use of a crude enzymic preparation from an Acremonium species.' lo

a-D-Man-( 1 + 3)-a-~-Man-( 1 +2)-a-~-Man-( 1 +2)-~-Man, related to the antigen of an E. coli, has been synthesized"' and the glycosyl trichloroacetimidate of 0-benzylated ac-D-Man-( 1 -+ 4)-3-0-Me-a-~-Man-( 1 + 4)-3-0-Me- a-D-Man-( 1 --+ 4)-3-0-Me-a-~-Man has been made as a glycosylating agent together with a hexasaccharide analogue.112

3.2 Linear Heterotetrasaccharides - The non-reducing tetrasaccharide a-L-Fuc-( 1 -2)-P-~-Glc-( 1 + l)-p-D-Glc-(2+ I)-~-L-FUC (difucosyl-P,P-trehalose) has been made to mimic Leb and Ley antigens.'13 Incubation of cycloinulo- hexaose and methyl a-D-glucopyranoside in the presence of cycloinulo- oligosaccharide fructanotransferase gave, as the main product, p-~-Fm.- (2- l)-P-D-Fm.(2+ l)-P-~-Fruf-(2+6)-a-~-Glc-O-Me.' l4 The hydroxylated derivative 10 of a diastereoisomer of acarbose was made by a 2 + 2 unit strategy involving a 'carba-disaccharide' having the amino group carbonyl linked to 0-3 of the neighbouring sugar moiety.' l5 Ganglioside GT4, containing a-NeuNAc-(2 + 8)-a-NeuNAc-(2 --+ 8)-a-NeuNAc-(2 + 3)- P-D-Gal, was made as was the isomer with a-(2-+6)-bonding to the Gal component.lL6 The capsular polysaccharide of Streptococcus pneumoniae, P-D-G~cNAc-( 1 --+ 3)- a-D-Gal-( 1 + 4)-P-~-Rha-( 1 + 4)-~-Glc was made by an intramolecular reaction used to form the rhamnosyl glycosidic bond.41

a-NeuNAc-(2-+ 6)-p-~-GalNAc-( 1 -+ ~)-P-D-GIcNAc-( 1 +2)-a-~-Man, which is part of the N-linked chain of human 1utropin,ll7 and P-D-Ga1-(1+4)-p-D- GlcNH2-( 1 + 3)-P-~-Gal-( 1 -+ 4)-p-~-GlcNH2, the tetrasaccharide of the glycoprotein of laminin, * l * have also been synthesized. p-~-GlcNH2-( l --+ ~)-P-D- Glc-( 1 + d)-P-D-Glc-( 1 + 4)-b-~-GlcNAc with a long chain acyl substituent on the amino group and as the p-methoxyphenyl glycoside has been made and subjected to conformational and molecular dynamics analysis, l9 and synthesis of the sulfated chondroitin sulfate tetrasaccharide terminating (reducing end) in glucuronic acid has been described. 120

Two reports on the preparation of tricolorin A, a cytotoxin active against breast tumour cells and which is a derivative of a-L-Rha-( 1 + 3)-a-~-Rha-( 1 -2)- P-D-G~c-( 1 --+2)-P-D-Fuc have been published. The aglycon contains a branched C16 carboxylic acid chain which is lactonized with 0 - 3 of the Glc moiety.121*122

Enzymic procedures were used in the preparation of the 4-methylumbelli- feryl glycoside of P-D-GIcA-( 1 +3)-p-~-Gal-( 1 + 3)-P-~-Gal-( 1 --+ 4)-p-~-Xyl. 123

In the area of compounds containing L-glycero-D-manno-heptose (Hep), p-D- Gal-( 1 +2)-a-Hep-( 1 --+2)-a-Hep-( 1 + 3)-a-Hep and several related trisaccharides were made as their p-(trifluoroacetamido)phenyl glycosides. 23a

3.3 Branched Heterotetrasaccharides - Because of their biological importance much of the greatest interest in this category of branched compounds is found


on sialylated members and syntheses have been reported of a-NeuNAc-(2+ 3)- [P-D-GalNAc-( 1 +6)]-P-~-Gal-( 1 + 4)-p-~-Glc which is the 6'-regioisomer of ganglioside GM2,124 and of the (2-+3), (1+4), (1+4)-bonded isomer which is GM2 itself. 125

Compounds terminating in Man to have been made are a-~-Glc-( 1 + ~)-P-D- Glc-( 1 + d)-[a-D-GlcA-( I +3)]-~-Man, which is related to the repeating unit of the antigen from Klebsiellu type 2 polysaccharide,126 and a-~-Man-( 1 +3)- [p-D-Xyl-( I +2)]-a-D-Man-( I + 3)-a-~-Man, which is found in the capsular polysaccharide of a Cryptococcus. 127 In related work the Mycobacterium lipopolysaccharide component a-L-Rha-( 1 -+2)-3-O-Me-a-~-Rha-( 1 + 3)-[ p-D- Xyl-( 1 +2)]-a-~-Rha has been produced synthetically.128 Sialic acid also occurs in non-mammalian oligosaccharides, the repeating unit of a Streptococcus capsular polysaccharide P-L-Rha-( 1 + 4)-p-~-Glc-( 1 + 4)-[a-NeuNAc-(2 + 311- D-Gal having been synthesized. 129

Considerable attention has been paid to compounds terminating in GlcNAc. Chemical methods which the authors describe as 'economical' have been used to make the Sia Lex antigen a-Neu-(2 3)-p-~-Gal-( 1 + 4)-[a-~-Fuc( 1 + 3)]-~- GlcNAc and in the course of the work the isomer with the galactose unit a-linked was produced. 30 Wong and colleagues using chemo-enzymic methods and solid-phase technology have produced Sia LeX 0-bonded through threonine to an octapeptide, the product representing the mucin domain of a specific cell adhesion and also a product of bonding this carbohydrate antigen to ribonuclease B by a glycosylamine-based linkage.132 Enzymic methods have also been used to make analogues of Sia LeX having D-arabinose and L-galactose in place of the fucose moiety.133 De-N-acetylated modifications of the tetrasaccharide have been obtained by chemical procedures and a di-deacyl derivative showed enhanced binding to E- and P- selectins. * 34

a-L-Col-( 1 +2)-P-D-Gal-( 1 + 3)-[a-~-Col-( 1 +4)]-p-~-GlcNAc (Col = 3,6- dideoxy-a-L-xylo-hexopyranose), which was required for studies of SalmoneZZa lipopolysaccharides, 35 and P-D-G~cNHR-( 1 + 4)-p-~-GlcNAc-( 1 + 4)-[2-0- Me-P-L-Fuc-( 1 +6)]-~-GlcNAc (R = long alkenoyl chain), which is the nodula- tion factor Rf-111, 136 have been reported.

Chemical procedures were also used to obtain the blood group Sd" antigen a-NeuNAc-(2+ 3)-[p-~-GalNAc-( 1 +4)]-p-~-Gal-( I + 4)-p-~-GlcNAc and analogues with P-D-Gal and P-D-G~cNAc replacing the P-D-GalNAc unit

(=$ CH20H ~ f f i l c - ( l + 4 ~ - f f i b CH20H

Bn xa HO

OH OH Na02C a-L-Fuc 10 11


3.4 Analogues of Tetrasaccharides - An analogue (10) of acarbose which contains a carba-sugar is noted above (Ref. 115).

A plethora of Sia LeX mimics have been described, such is the interest in their potential biological activity. These will be reported in rough order of their variation from Sia LeX itself. A tetrasaccharide having the desialated Lex trisaccharide glycosidically bonded to 0-6 of D-Man and with a sulfate group at 0 - 3 of the D-Gal moiety has been described,138 as has an analogue of Sia LeX having a 1,2,3,5-tetrahydroxy-5-(hydroxymethyl)cyclohexane in place of the terminal GlcNAc

An analogue having ~-L-Fuc and P-D-Gal appropriately linked to trans- cyclohexane- 1 ,Z-diol and with a cyclic non-carbohydrate substituent at 0-3 of the D-Gal unit to mimic the NeuNAc was made,'@ and the same laboratory made a derivative of this compound with the two sugars held rigid by a lactone bridge and found it to be recognized by E-selectin, but less well than is Sia LeX.14' A further mimic had the Fuc and Gal linked to trans-cyclohexane- 1,2-diol, the latter sugar carrying a malonic acid group at the end of an ether tether bonded to O-2.'42 Other mimics have the NeuNAc and Fuc units glycosidically linked together by way of alkyl or ether bridges or via trans-cyclohexane- 1,2-di01,'~~ and others have two sialic acid units bonded by way of alkyl spacer chains to catechol or cyclohexane

A range of analogues have been reported which have only one sugar constituent of the Sia LeX tetrasaccharide: a-L-Fucose 0-bonded to D-Ser-L- Glu and L-Ser-D-Glu were potent blockers of E-selectidsia LeX binding; 14' the same sugar glycosidically linked to one hydroxyl group of cyclohexane- 1,2-diol also carrying a malonic acid tethered to the other hydroxyl group gave products which were equivalent to Sia LeX in inhibiting selectin-mediated cell a d h e ~ i 0 n . I ~ ~ Compound 11 was made as a mimic with the aromatic spacer in place of the D-Gal moiety.'47

1,2-dio1.144

4 Pentasaccharides

4.1 Linear Homopentasaccharides - The homologous series of a-( 1-2)- linked glucoses up to the pentaose have been synthesized and bonded by way of a spacer group to human serum albumin to give neoglycoproteins with up to 28 oligosaccharides per albumin molecule.'48 p-Nitrophenyl a-D-maltopen- taoside has been made by enzymic p r~cedures . ' ~~

4.2 Linear Heteropentasaccharides - The structure of Acantha ganglioside has been shown to be P-D-Gav-( 1 - 3)-a-~-Galp-( 1 -+ 3)-a-NeuNAc-(2-+4)-P-~- Gab-( 1 - 4)-P-~-Glc-O-Cer rather than that proposed formerly which had both galactopyranosyl moieties (1 -+4)-linked.150 The synthesis of ganglioside GT3, a-Neu-(:! -+ 8)-a-Neu-(2 - 8)-a-Neu-(2 + 3)-P-~-Gal-( 1 - 4)-p-~-Glc-O- Cer, has been reported' l 6 and P-D-Gal-( 1 + 4)-[a-~-Glc-( 1 -4)I3-~-Glc has been made by enzymic methods.'49


OS03Na OMe OS03Na OS03Na OS03Na S@Na 12

The synthetic partially sulfated pentamer 12, which is an analogue of the antithrombin binding sequence of heparin with glucose units replacing glucosamine and the unsulfated hydroxyl groups methylated, has a better pharma- cological profile than has the natural c~mpound. '~ ' In the same research area the analogue 13, with a methylene inter-sugar link, which was made by an intramolecular radical trapping process, has been shown to have similar biological activity to the corresponding 0-linked compound. 52

4.3 Branched Homopentasaccharides - In work focussing on novel protecting group srategies several D-mannose-based oligomers were made including a-D- Man-( 1 + 6)-a-~-Man-( 1 + 6)-[a-~-Man-( 1 + 6)-a-~-Man-( 1 -+2)]-~-Man. 153

4.4 Branched Heteropentasaccharides - P-D-GaWAc-( 1 + 3)-[P-D-( 3H)GlcNAc- (1 +6)]-a-~-Gal-( 1 + 4)-p-~-Gal-( 1 --+ 4)-Glc is a novel hybrid pentasaccharide of the lacto-globo type made by use of a transferase to introduce the labelled GlcNAc moiety. 54 The pentamer a-NeuNAc-(2-, 3)-P-~-Gal-( 1 -, 4)-[a-~-Fuc- (1 + ~)]-P-D-G~CNAC-( 1 -+6) -~ -Man was made by chemical methods and is Sia LeX-( 1 -+6)-~-Man. * 38

Danishefsky's and Ogawa's groups have reported quite different syntheses of the high-mannose pentamer a-D-Man-( 1 -6)-[a-~-Man-( 1 -+ 3)]-P-~-Man- (1 3 4)-p-~-GlcNAc-( 1 4)-~-GlcNAc for incorporation by N-linking into glycopeptides. 559156 A further GlcNAc-terminating compound to have been made is p-D-Gal-( 1 + 4)-P-~-GlclVAc-( 1 + 3)-[p-~-GlcNAc-( 1 -+6)]-P-~-Gal- (1 -+ 4)-~-GlcNAc, the branching group having been introduced by enzymic means. 57

Modelling studies using MM3(92) and CICADA protocols have been used in conformational analyses of a-L-Rha-( 1 + 4)-a-~-Gau-( I -+2)-[P-~-Gal- (1 +4)]-a-~-Rha-( 1 + 4)-~-GalA which is related to the plant rhamnogalac- turonan I.158


5 Hexasaccharides

As has become customary in these volumes, an abbreviated method is now used for representing higher saccharides. Sugars will be numbered as follows, and linkages will be indicated in the usual way:

1 D - G ~ c ~ 2 D-Manp 3 D-Calp 4 D-GIc~NAc 5 ~-GalpNAc 6 NeupNAc 7 L-Rhap 8 L-FUCP 9 D-XYlP

10 D - G ~ c ~ N H ~ 11 ~-GlcpA 12 D - Q ~ (6-deoxy-wglucopyranose) 13 L-Clycero-mmanno- 14 L-Araf 15 Kdn

heptose

5.1 Linear Hexasaccharides. - Amongst the products of enzymic hydrolysis of birch kraft pulp xylan the following were characterized:

4-0-Me- 0 0 0 0 0 0 ~ 11 1-4 P4 1+4 p4 1-4 p4 1+4 p4 1-4 84 the cor-

responding compound with a 4,5-double bond in the uronic acid moiety and the pentaose analogues having one fewer xylose unit.*59

Treatment of the p-( 1 + 3)-linked laminaribiosyl P-fluoride with a bacterial (1 + 3), (1 -+4)-glucan 4-hydrolase gave oligomeric products with alternate (1 +3), (1 +4)-linkages, the major product being the hexamer.lm

A striking example of the application of synthetic methods to medical problems is the synthesis of hexamer 14 which, after coupling with a peptide, was used to raise anti-human cancer antibodies in mice.

14

Boons's selective glycosylation methods have been used very impressively in the preparation of the hetero mannose-terminating compound 15,42 and the a-(l+4) linked D-mannohexaose having methyl groups at 0-3 of all units

except that at the non-reducing terminus, which is a fragment of a mycobacterial polysaccharide, has been synthesized. 162

Hexasaccharides terminating in amino-sugars to have been prepared synthetically are 16, which is representative of heparin cofactor 11,163 and oligomers up to the hexamer based on a-( 1 +2)-linked 4-acylamino-4,6-dideoxy-~- mannose (acyl = 2,4-dihydroxybutanoyl) which represent fragments of the 0- antigen of Vibria cholerae have been described. 64


5.2 Branched Hexasaccharides - Compounds of this set terminating in D-G~c are 17165 and 18166 which are, respectively, a component of group B type 111 streptococcus polysaccharide and a sulfated Sia Lex-based compound which was made in attempts to find the structure of L-selectin.

1 1

1 6

1 3

l? 6 6

S03Na S03Na t t

18

Synthesis of 19 was effected with 65% efficiency by lactosyl trichloroacetimidate coupling to 0 -2 of the branching mannosyl unit of the protected tetrasaccharide in the form of the a-methyl glycoside. Surprisingly, no hexamer was produced from the corresponding P-glycoside. 167

19

6 Heptasaccharides

6.1 Linear Heptasaccharides - By careful acid hydrolysis of peracetylated P-cyclodextrin maltoheptaose acetylated at all positions except 0-1 and 0-4 of


the reducing and non-reducing terminal glucoses, respectively, has been produced, 16* and a-tocopheryl p-maltoheptaoside as well as the hexaoside, tetraoside and trioside have been prepared by chemical methods from the oligosaccharide peracetates. 169 In related work, a chitoheptaoside [a heptamer of p-( 1 -+ 4)-linked GlcNAc] with tetradecanoyl and tetradecyloxy at N-2 and 0-1 of the reducing moiety was produced by successive additions of chitobiose units. 70

6.2 Branched Heptasaccharides - Solid-phase methodology has been used to make the heptasaccharide phytoalexin elictor comprising the p-( 1 + 6)-linked glucopentaose with p-( 1 + 3)-branching glucose moieties on units 2 and 4. 171 An analogue was made of this compound with the ( I +6)-glycosidic linkages replaced by amide bonds involving glycosylamino and uronic acid functions. 172

In the area of ganglioside chemistry Hasegawa and colleagues have reported the syntheses of the highly sialated GTla (20)173 and GTlaa (21).174

@ 1

1 J

2

1 4

@ 2+6 @ 1 +4 @ 1-4 @ -0-peptide

3 3

t t 2 2

21

Mannose-containing heptamers to have been synthesized are the phospho- glycan portion 22 of a Leishmania lipophosphoglycan (trichloroacetimidate and H-phosphonate meth~dology), '~~ and 23 which was made for the solid phase synthesis of glycopeptides. 176


0

@ 1+4 @ -1-0-P-0-6- @ 1+4 @ II

I 3

OH t

@ 1 - + 3 @ 1 - + 3 6

22

@ 1+2 @ 1+6 @ 1+4 @ 144@

3

t 1

23

7 Octasaccharides

For studies associated with a mycobacterial 3-O-methyl-~-mannose-based polysaccharide an octamer of a-( 1 + 4)-linked 2,6-di-O-benzyl-3-O-methyl-~- mannose was made by coupling of two t e t r a m e r ~ . ' ~ ~ Compound 24, with the S-1-carboxyethyl group in place of sialic acid, has been made to mimic the repeating unit of type 111, group B Streptococcus capsular polysaccharide. 178

@ 1 4 4 @ 1 4 3 @ 1+4 @ 1-6 @ 1+3@

3 6 4

t t C02H t CHsCHC02H I 1

HsCCH -+ 3@

24

Dimers of the 'tetrasaccharide' of calicheamicin, which has four appreciably modified monosaccharides linked in very uncommon ways, have been made and studies of the DNA binding properties of oligomers of this type have been reviewed by Nicolaou and colleagues. 179

8 Nonasaccharides

The synthesis of the highly branched mannose nonamer 25, which is like portions of the high-mannose N-linked glycoproteins, was achieved in five


steps by judicious tuning of the glycosyl donors used and employment of controlled selectivity in hydroxyl group protection, and represents the ‘state of the art’ in oligosaccharide work. 180

1

1

1

1 6

25

In related work which used a modular approach nonamer 26 was made as the glycosyl azide for incorporation into N-asparagine-linked glycoproteins. 18’

Important work in the glycolipid area has yielded 27, which is a sialated dimer of the LeX antigen, and a closely related nonamer with a-( 1 -+2)-linked fucose in place of the sialic acid, both compounds being tumour-associated antigens. lg2 Two groups have synthesized the latter compound. 1 8 2 9 1 8 3

1

1 6

1

1 6

@ 1+4 @ 1+4 @-N3

3

t 1

6

t 1


1

1 3

1

1 3

@ 2 4 3 @ 1-4 @ 1+3 @ 1+4 @ 1-3 @ 1+4 @ -0-Cer

27

9 Higher Oligosaccharides

The decamer 28 has been prepared as a mimic of a similar decamer with glucosamine instead of the D-glucose unit, and shown to release lipase activity in rat tissue.184 The decamer 29, a biantennary N-glycan, has been made by enzymic galactosylation of an octamer, lg5 and Unverzagt has also reported the undecamer analogue without the fucose unit, but carrying NeuNAc-(2-+ 6)- linked to both galactose unitslg6 and also the dodecamer with the fucose again present.lg5 An isomer of the latter having the NeuNAc-( 1 +3)-linked was also reported.lg5 In this work the final steps were all enzymically controlled.

@1+4 @1+2 @ 1 1

1 6

1 6

@ 1+4 @ 1+4 @ -NHAcyl 29

3

t 1

Solid-phase methods were used to make the set of oligomers 30 with n = 2-5 as heparan sulfate-like compounds,187 and the dodecasaccharide 31, a component of a Vibrio cholerae polysaccharide, was produced by use of trichloroacetimidate coupling. ' 88

On a maltopentaose 'primer' bound to silica D-glucal additions occurred under the influence of glycogen phosphosylase to give a set of a-( 1 -+ 4)-linked


ox ox OS03-

30 X = Me, Y = SO,- X = SO3-, Y = Me

2-deoxy-~-glucose oligomers bonded to malt~tetraose. '~~ Oligomers containing up to 20 p-( 1 + 4) linked D-glucose units have been made by chemical methods starting from 3-U-benzyl-2,6-di-U-pivaloylglucose. lgo

10 Cyclodextrins

Interest in these compounds continues to increase rapidly. As usual, this report concentrates almost exclusively on the chemistry of the cyclodextrins and their derivatives and disregards work related to their associating properties, the complexes they form and their effects as reaction catalysts.

10.1 General Matters, and Synthesis of Cyclodextrins - A review has appeared on the production, characteristics and applications of the cyclodextrins, l g l

another on their chemical modifi~ation, '~~ and a third on the use of derivatives as artificial enzymes, in molecular recognition and in organic synthesis. lg3

A new type of cyclodextrin having alternating a-(l+4)-linked D- and L-

rhamnose or D- and L-mannose and built from disaccharide repeating units has been made by TrC104-catalysed condensation. They have S,-symmetry and are not optically active. Compounds containing 6, 8, 10, 12 and 14 sugar units were r e p ~ r t e d . ' ~ ~ ? ' ~ ~

Syntheses of the a-D-ah-analogues of a-, P- and y-cyclodextrins were made by way of the corresponding manno-ep~xides,'~~ and the same workers have reported three regioisomeric P-cyclodextrins each containing two altrose units, these having been made by way of disulfonates and hence diepoxides.197 Cyclic heptamers of a-L-rhamnose, and related compounds, have been made by acid-catalysed cycloglycosylation,198 and cyclodextrins with 10, 1 1 and 13 199

and 14- 1 7200 glucose units have been isolated by chromatographic methods from commercial cyclodextrin powder made by the use of cyclodextrin glucanotransferase.

0 OH I I I

32 31 R = C-CHCHSH20H


10.2 Branched Cyclodextrins - A symposium report on methods for making branched a-cyclodextrins has appeared. The enzymic attachment of maltose to the cyclic compound by use of pullulanase, and the subsequent cleavage of the intra-maltose bond with glucoamylase were particularly noted.201 The same approach also gave rise to 6A,6N-di-O-a-~-gl~~~~yl~ycl~dextrins.202 Branched a-( 1 -+ 6)-linked cycloisomaltooligosaccharides, having an a-glucosyl on an a-maltosyl unit bonded to 0-4 of a glucose unit were also made by enzymic procedures,203 and a different type of branched compound was made by condensing 6-monoamino-~-cyclodextrin with oligosaccharide aldonolact ones .204

In the area of hetero-branched compounds one P-D-mannose unit has been linked enzymically to 0-6 of a-, P- and y-cyclode~trins,~~~ and the six positional isomers of 6A,2N-di-O-a-~-galactopyranosyl-a-cyc~odextrin (N = A-F) were obtained by HPLC separtion of a mixture produced from the cyclodextrin treated with a-galactosidase in the presence of melibiose.206

10.3 Cyclodextrin Ethers - Several peralkylated (short chain alkyl groups) P-cyclodextrins have been made by a two-step procedure,207 but the heptakis- 2,6-di-O-methyl ether is the product of methylation in DMSO/NaOH.208 Permethylation of mixed 6,6-di-O-Tbdms derivatives of P-cyclodextrin allowed access to the 6A,6B-, 6A,6C- and 6A,6D-dihydroxypermethyl ethers. Interestingly, the ditosylate derived from the A,B-diol has the aromatic ring of one of the ester groups within the molecule's cavity.209'

2-0-Allyl- P-cyclodextrin, treated with Hg(OAc)Z/TFA and the product demercurated with NaBH4, gave the 2A,3A-0-(propane-l ,2-diyl) product, and epoxidation of the same ally1 compoound, followed by TFA treatment, led to the related 3-hydroxypropane- 1,2-diyl derivative.210 The hexakis- and heptakis-2,3-dimethyl ethers of a- and P-cyclodextrin were used as a source of the corresponding 6-carboxymethyl compounds.21

Mixtures of 4-sulfobutyl ethers of P-cyclodextrin were partially fractionated to give products for use as solubilizing and stabilizing compounds for drug delivery.212 In the course of the work the 2-, 3- and 6-mono-substituted compounds were isolated and ~haracterized.~~ Compounds with complex alkaryl ether substituents to have been reported are 0-cyclodextrin having violagen (32)214 and the porphyrin derivative (33)215 linked as indicated to one of the 0-2 positions of the dextrin.

In work aimed at making a photochemical microreactor, P-cyclodextrin carrying n-butyl groups at all 0-2,3 positions and a naphthalenesulfonic acid ester linked at all 0-6 positions, was made and studied.216 m-Di(bromo- methy1)benzene has been used to join two P-cyclodextrin molecules by way of an 0-2,O-2' diether linkage to give face-to-face dimeric products.217

10.4 Cyclodextrin Esters - The secondary ester groups of a-, P- and y-cyclodextrin per-pivaloates are much more labile than the primary groups and can be removed selectively with hydrazine to give the per-6-pivaloates in high yield.21 The anti-inflammatory (4-bipheny1)acetic acid has been ester-linked to


0-6 of a-, P- and y-cyclodextrin and thus the latter was used to deliver the acid to the colon where the carbohydrate is metabolized microbiologically.219 y-Cyclodextrin has been reported with (R)-2-( 1 -naphthyl)propanoyl groups on sugars A and E,220 and the product of coupling the cyanine dye 34 and P-cyclodextrin via 0-6 is a photostable, fluorescent reagent.221

The 6A6B-, 6A6C-, 6A6D- and 6A6E-bis-(2-naphthylsulfoyl)-y-cyclodextrins have been made as fluorescent sensors,222 and P-cyclodextrin 6-diphenyl phosphate and monoethyl phosphate are enantioselective for amino

Ph 33 34

10.5 Amino Derivatives - Per-6-amino-6-deoxy-a-, P- and y-cyclodextrins have been made from the corresponding bromo-derivatives via the azides, as well as the per-6-amino-6-deoxy-2,3-di-O-methyl- and per-N,N-(dimethy1amino)ethyl- amino compounds. They were tested as peptidomimetics for the peptide binding site of antithrombin Mono-2-amino-2-deoxy-~-cyclodextrin was made from the perbenzoylated derivative by selective debenzoylation at 0-2 of one of the units, oxidation to the ketone and oxime formation. This amine and the 6-amino-isomer were then p ~ l y s u l f a t e d . ~ ~ ~ 6-Amino compounds having additional amino groups at other centres have been produced by displacement of the leaving group of 6-O-tosyl-~-cyclodextrin with diamines such as 1,2-diamin0ethane.~~~ A related report described similar compounds derived from the 6-bromo-6-deoxy-derivatives of a-, P- and y-cy~lodextrin.~~~

Several derivatives having complex amino-substituents have been reported. Chemical coupling of mono-6-amino-6-deoxy-~-cyclodextrin with a suitably protected and activated GlcNAc-asparagine derivative led to a starting material for specific enzymic glycosylation of the GlcNAc moiety. Subsequent glycosylations led to several oligosaccharides bound to the dextrin, the most complex being the branched high-mannose N-linked nonasaccharide of glycoproteins.228 Compounds having acyclic, variable length tethers to dansyl groups [N-(5-diethylaminonaphthalenesulfonamido)] have been made for study of the inclusion of the chromophore into the cavity.229 Coupling of bis-[2-aminoethylamino]-bis-2-deoxy-~-cyclodextrin with N-2-(carboxyethyl)- thymine gave a product with two thymine-containing 6-substituents. Under light these thymine rings underwent 2+2 revisible d i m e r i ~ a t i o n . ~ ~ ~

Attachment of the phenyl porphyrin sulfonate 35 by reductive amination to 6-monoformyl P-cyclodextrin gave a water-soluble product which, by NMR


evidence, exists in solution as a dimer with a phenylsulfonate group of one molecule bound within the cavity of another.231 A further communication has appeared (see Vol. 30, p. 82) on the product of reaction of 6A6C-(or 6A6D-) di- 0-tosyl-P-cyclodextrin with o-phenylenediamine and the condensation of the diary1 product with p-cresol-2,6-dialdehyde which gave a bonded symmetrical bis-benzimidazolylphenyl system having the aromatic methyl group within the The following N-substituted derivatives have also been described: 0-cyclodextrin with a 6-deoxy-6-N-triazole dicarboxylic or 6-deoxy-6-N-(2-methylamino) pyridinium group234, and P-cyclodextrin having N-imidazole groups N-bonded at two or three C-3 positions, these compounds having been made from the di- or tri-2,3-anhydro-~-aZZo-derivatives.~~~

Several 6-mono-acylamino-6-monodeoxy derivatives of P-cyclodextrin have been reported: the (4-biphenyl)acetyl, 2-hydroxy-5-nitrobenzoyl and 2-(2’-hydro~y-4’-nitrophenyl)benzoyl,~~~ and compounds having the following complex N-acyl substituents on N-6: P-D-G~~NHCO(CH~),CO,~~~ (n = 1-4, 7), peptide-CO(CH2)2C0238 and N-dansyl-D and ~ - 1 e u c y l . ~ ~ ~ Sulfonamide derivatives, made with the N-dansyl group (5-dimethylaminonaphthalene- 1 - sulfonyl), and related compounds with ether spacer groups between the dextrin and the amino function have been made.240

10.6 Thio- and Halogeno-Derivatives - 6-Deoxy-6-iodo- P-cyclodextrin coupled with a cobalt porphyrin cobalamin disulfide gave a 6-thio-linked artificial enzyme which discriminates substrates and mimics mutase activity using coenzyme B- l Z.241 Heptakis-6-thio-P-cyclodextrin has yielded a peptide-linked derivative made in studies of enzyme inhibition.238

The previously known per-6-chloro-6-deoxy-a-, 0- and y-cyclodextrins and the previously unknown bromo-analogues have been made in high yields by Vilsmeyer-Haack-like halogenations (using halomethylenemorpholium halides).242

10.7 Other Features of Cyclodextrins - Although the characteristics of cyclodextrins as complexing agents are not dealt with in this Report, other features of interest were noted as follows: vibrational Raman optical activity (ROA) studies of cylodextrins allowed the measurement of conformational flexibility


as a function of methylation, solvent interaction and complex formation.243 Cyclo-a-D-rhamno-( 1 -+ 4)-decaose forms nanotubes in the crystalline form.244 Hexakis-(2,3-di-O-benzoyl)-and-(2,3,6-tri-O-benzoyl)-a-cyclodextrins are

enantiomerically selective for chiral amines, aminoalcohols, carboxylic acids and amino-acids bearing a 3,5-dinitrophenyl Laser flash photolysis of 01-, P- and y-cyclodextrins as complexes with ketones gives cyclodextrin free radicals.246

Both the hydrolysis and cyclizing formation of cyclodextrins have been subjected to thermodynamic examination. Equilibrium constants for the closure of long linear maltodextrins to give cyclodextrins and shortened linear compounds were determined.247 a-Cyclodextrin together with trehalose, treated with cyclomaltodextrin glucanotransferase then P-amylase, gave a-D-maltotriosyl a-D-maltotrioside and four similar shorter-chain non-reducing olig~saccharides.~~~

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A.M.P. Borrajo, B.I. Gorin, S.M. Dostaler, R.J. Riopelle and G.R.J. Thatcher, Bioorg. Med. Chem. Lett., 1997,7, 185. N. Sakairi, H. Kuzuhara, T. Okamoto and M. Yajima, Bioorg. Med. Chenz., 1996,4,2187 (Chem. Abstr., 1997,126,225 489). B.L. May, S.D. Kean, C.J. Easton and S.F. Lincoln, J. Chem. Soc., Perkin Trans. I , 1997, 3 157. D. Vizitiu, C.S. Walkinshaw, B.I. Gorin and G.R.J. Thatcher, J. Org. Chem., 1997,62,8760. K. Matsuda, T. I n m , K. Haneda, M. Mizuno, T. Yamanoi, K. Hattori, K. Yamamoto and H. Kumagai, Bioorg. Med. Chem. Lett., 1997,7,2353. R. Corradini, A. Dossena, G. Galaverna, R. Marchelli, A. Panagia and G. Sartor, J. Org. Chem., 1997,62,6283. T. Nozaki, M. Maeda, Y. Maeda and H. Kitano, J. Chem. Soc., Perkin Trans. 2, 1997,1217. T. Carofiglio, R. Fornasier, G. Gennari, V. Lucchini, L. Simonato and V. Tonel- lato, Tetrahedron Lett., 1997,38, 7919. D.-Q. Yuan, K. Koga, K. Fujita and M. Yamaguchi, Tetrahedron Lett., 1997,38, 7593. C. Roehri-Stoeckel, 0. Dangles and R. Brouillard, Tetrahedron Lett., 1997, 38, 1551. R.P. Bonomo, V. Cucinotta, F. D’Alessandro, G. Impellizzeri, G. Maccarrone, E. Rizzarelli, G. Vecchio, L. Carima, R. Corradini, G. Sartor and R. Marchelli, Chirality, 1997,9, 341 (Chem. Abstr., 1997,127,262 929). W.-H. Chen, D.-Q. Yuan and R. Fujita, Tetrahedron Lett., 1997,38,4599. A. Matsushita, T. Kuwabara, A. Nakamura, H. Ikeda and R. Ueno, J. Chem. SOC., Perkin Trans. I , 1997, 1705. R. Kassab, C. Felix, H. Parrot-Lopez and R. Bonaly, Tetrahedron Lett., 1997,38, 7555. N. Schaschke, H.-J. Musiol, I. Assfalg-Machleidt, W. Machleidt and L. Moroder, Biorg. Med. Chern. Lett., 1997,7,2507. H. Ikeda, M. Nakamura, N. Ise, F. Toda and A. Ueno, J. Org. Chem., 1997,62, 141 1 . H.F.M. Nelissen, F. Venema, R.M. Uittenbogaard, M.C. Feiters and R.J.M. Nolte, J. Chem. Soc., Perkin Trans. 2, 1997,2045. M. Rezac and R. Breslow, Tetrahedron Lett., 1997,38, 5763. K. Chmurski and J. Defaye, Tetrahedron Lett., 1997,38,7365. A.F. Bell, L. Hecht and L.D. Barron, Chem. Eur. J., 1997,3,1292. G. Gattuso, S. Menzer, S.A. Nepogodiev, J.F. Stoddart and D.J. Williams, Angew Chem., Int. Ed Engl., 1997,36, 1451. G. Uccello-Barretta, A. Cuzzola, F. Balzano, R. Menicagli, A. Iuliano and P. Salvaderi, J. Org. Chem., 1997,62, 827. M.N. Lehmann and M.G. Bakker, J. Chem. Soc., Perkin Trans. 2 , 1997,2131. Y .B. Tewari, R.N. Goldberg and M. Sato, Carbohydr. Res., 1997,301, 1 1 . M. Kurimoto, A. Tabuchi, T. Mandai, T. Shibuya, H Chaen, S. Fukuda, T. Sugimoto and Y. Tsujisaka, Biosci Biotechnol. Biochem., 1997, 61, 1146 (Chem. Abstr., 1997,127,205 775).

5 Ethers and Anhydro-Sugars

1 Ethers

1.1 Methyl Ethers. - 6-Deoxy-2-0-methyl-~-~-glucopyranosyl residues have been identified in toxicariosides B and C isolated from the latex of Antiaris toxicaria’ while toxicarioside A contains a 2-0-methyl-~-~-fucopyranoside residue.2 Pentacyclic triterpenoid glycosyl esters isolated from aerial parts of Rubus pileatus contain esterified 6-0-methyl- and 3-0-methyl-P-~-glucopyranosyl m~iet ies .~ A hydroxyquinoline 0-glycoside of 2,4-di-O-methyl-P-~- xylopyranose has been isolated from the marine cyanobacterium Lyngbya majuscZa4 and malyngamide J, isolated from the same cyanobacterium, also has a 2,4-di-~-methyl-xylopyranosyl re~idue.~

Partial methylation and then acylation has afforded all the positional isomers of 0-methylated and benzoylated (or acetylated) 1,5-anhydro-~- xylito16 and the corresponding eight positional isomers of 1,5-anhydro-~- rhamni tol.

1.2 Other Alkyl and Aryl Ethers - Junipetridoside A 1, isolated from Juniperus phoenica leaves, has an unusual phenylglycolyl substituent as both a glycoside and 0-2 ether.* A review on the protection of hydroxy groups as allyl ethers has included numerous carbohydrate example^.^ The use of PdC12 under Wacker reaction conditions to effect de-0-allylation of a variety of sugar allyl glycosides and allyl ethers has been examined. Mixtures of the desired products and ‘Wacker ketones’ (such as 3 from 2) were formed in unpredictable ratios. lo

YH20H AcO

AcO +-p OAc OAc

2 3

The use of phenylboronate ester derivatives with the boron complexed with a nitrogen base to selectively activate hydroxy groups in a manner analogous to organotin activation has been described. Thus the phenylboronate 4 was


92

5: Ethers and Anhydro-Sugars 93

converted into the 3-butyl ether 5 in 80% yield (Scheme I), whereas in the absence of Et3N alkylation occurs, as expected, at the free OH group.

Ph-B-0 OBu 4 5

Reagent: i, Bu"1, Ag20, EkN, benzene Scheme 1

0-Benzylations under acidic conditions using benzyl trichloroacetimidate can be performed with dioxane as solvent and perbenzylated aldonolactones were prepared in this way.12 Freshly fused ZnClz with Ac20/HOAc has been used to selectively debenzylate some hexopyranose glycosides at 0-6. The 6-0- acetates were the products formed. l 3

Convenient syntheses of 2,3,4,6-tetra-O-allylated and benzylated D-glUC0- pyranose and -D-galactopyranose have been developed by hydrolysis of per- 0- alkylated sucrose and oxidative cleavage of ethyl 2,3,4,6-tetra-O-benzyl-l-thio- D-galactopyranoside with N-bromosuccinimide in the presence of water, respectively. l4

The use of 0-p-chlorobenzyl ethers as protecting groups on the three hydroxyls of a fucopyranoside moiety has been reported to stabilize the glycosidic bond to acid hydrolysis relative to the parent 0-benzyl-protected glycoside.15

The Hanessian reagents (NBS, CaC03, CC14) applied to benzylidene acetals have been investigated in the presence of substituted benzyl ethers. Electron withdrawing substituents on the aromatic rings of the benzyl groups improved the selectivity of the acetal reactions by reducing the competing radical reactions of the benzyl ether groups.'6

Quantitative detritylation of carbohydrate trityl ethers has been achieved by use of FeC13.6H2O in CH2C12.17

Improved conditions for separation of the R,S diastereomers of muramic acid 6 and isomuramic acid 7 has allowed a more convenient procedure for their synthesis. l8

Some 0-cyanomethyl ether derivatives of N-acetyllactosamine have been prepared and the nitrile groups were converted into carboxylic acid, amide, amidine and amino groups.I9

2-Hydroxypropyl ethers of methyl a-D-glucopyranoside have been synthesized as standards for analysis of modified starch.20

A number of carbohydrate per-ally1 ethers have been functionalized into micelle-like anti-HIV polyanionic compounds by radical thiol addition to the olefin moieties (Scheme 2).21

The guanidine-functionalized carbohydrate ethers 8 and 9 have been synthesized as potential anti-angiogenesis agents.z2


R

--O--CH2--CH=CH2 - i -O-CH2-CH,-CH2-SA(CH2),,C~Me

R

Reagents: i, HSA(CH2)&0~Me, AIBN, hv; R = H or C02Me; n = 0 or 1 Scheme 2

Me0 Qy

X 8 X = a-OMe, W H 2 C 0 2 H or H

Y = a or &OCH2C02H, OMe n = 2 o r 3

NH II

9

Carbohydrate alkoxides have been used to open 5,6-cyclic sulfate derivatives of protected manno- and gluco-furanoses. For example, treatment of cyclic sulfate 10 with alkoxide 11 afforded 12, and the alkoxide of 12 was further treated with 10 to give 13.23

10

HO

11 ’ 12 13

Chiral aza-crown ethers such as 14, derived from D-glucose, have been prepared as catalysts for enantioselective Michael additions.24

1.3 Silyl Ethers - Tri- and tetra-alkoxysilanes have been prepared with different alkoxy substituents by condensing MeSiCl3 or Sick in pyridine with alcohols. Examples include 15-17.25


(R0)aSiMe 15

W 14

B U n O i

14

R'O, R20-,SiMe

16 ~ 3 0

OR' &OR2

O OR^ OR^

17 Bno

, R3 = All R ' - R 2 - GoMe BnO

R3 = R4 = Bn OBn

R ' , R ~ =

2 Intramolecular Ethers (Anhydro-Sugars)

2.1 Oxiranes. - The synthesis of 1,2-anhydro-gluco-pyranose and -furanose benzyl ethers has been reviewed. They were prepared by an intramolecular S N ~ reaction of C-2 alkoxides with C-1 chlorides, or C-1 alkoxides with C-2 tosylates.26 1,2-Anhydro-3,5-di- 0-benzyl-a-~-and-~-ribofuranose have been prepared separately by the same procedure and opening of the anhydro-sugars by alcohols and 0-silylated uracil has been in~est igated.~~*~* The glycosidation of phenols with 1 ,Z-anhydro-3,4,6-tri- 0-methyl-a-~-ghcopyranose is mentioned in Chapter 3.

2.2 Other Anhydrides. - The synthesis of 1,3-anhydro-glucopyranose benzyl ethers has been reviewed,26 and the preparation of 1,3-anhydro-2,6-dideoxy-4- 0-methyl-a-D-ghcopyranose as a thromboxane A2 model has been described. 29

The formation of 3,6-anhydro-~-glucofuranosides by acid catalysed alcoho- lysis of 6-0-tosyl glucose derivatives has been reported. 30

The halohydrins 18 (X=Br, I) derived from the corresponding glycal undergo ring contraction to give the 2,Sanhydro aldose 19 (Scheme 3). When R = Me or Bn the same conditions afford predominantly methyl P-glucopyranosides via a 1,2-epo~ide.~*


- i RopcHo RO OH OR

18 R-TWms 19 R=Tbdms Reagent: i, Cs2C03, MeOH

Scheme 3

The syntheses of 2,5-anhydro-~-mannitol derivatives with a nucleoside base attached at the 4- or 6- position as well as 3,5-anhydro-nucleosides are covered in Chapter 20.

The low calorie sweetner di-D-fructofuranose 1,2':2,3'-dianhydride 20 has been isolated from the supercritical C02 extracts of Lycoris radiata. This is the first time it has been isolated from natural

OH 20

References

LOH

1

2

9 10 1 1 12

13 14

15 16

17

C.A. Carter, E.A. Gray, T.L. Schneider, C.M. Lovett, Jr., L. Scott, A.C. Messer and D.P. Richardson, Tetrahedron, 1997,53, 16959. C.A. Carter, R.W. Forney, E.A. Gray, A.M. Gehring, T.L. Schneider, D.B. Young, C.M. Lovett, Jr., L. Scott, A.C. Messer and D.P. Richardson, Tetrahe- dron, 1997,53, 13557. B.-G. Wang, X.-M. Shen, L. Yang and Z.-J. Jia, Phytochernistry, 1997,46, 559. J. Orjala and W.H. Gerwick, Phytochernistry, 1997,45, 1087. M. Wu, K.E. Milligan and W.H. Gerwick, Tetrahedron, 1997,53, 15983. L.E. Elvebak 11, V. Knowles and G.R. Gray, Carbohydr. Res., 1997,299,143. L.E. Elvebak 11, P. Wittmeyer and G.R. Gray, Carbohydr. Res., 1997,299, 151. G. Comte, J. Vercauteren, A.J. Chulia, D.P. Allais and C. Delage, Phytochem- istry, 1997,45, 1679. F. Guibti, Tetrahedron, 1997,53, 13509. H.B. Mereyala and S. Reddy Lingannagaru, Tetrahedron, 1997,53, 1750 1. K. Oshima, E.-i. Kitazono and Y. Aoyama, Tetrahedron Lett., 1997,38, 5001. H. Stampe Jensen, G. Limberg and C. Pedersen, Carbohydr. Rex, 1997, 302, 109. G. Yang, X. Ding and F. Kong, Tetrahedron Lett., 1997,38,6725. L. Kaesbeck and H. Kessler, Liebigs Ann.lRecl., 1997, 169 (Chern. Abstr., 1997, 126, 118 113). N.L. Pohl and L.L. Kiessling, Tetrahedron Lett., 1997,38,6985. L.J. Liotta, K.L. Dombi, S.A. Kelley, S. Targontsidis and A.M. Morin, Tetrahedron Lett., 1997,38,7833. X . Ding, W. Wang and F. Kong, Carbohydr. Res., 1997,303,445.


18

19 20 21

22 23

24 25 26 27 28 29 30

31

32

V. Ragoussis, L. Leondiadis, E. Livaniou and G.P. Evangelatos, Carbohydr. Res., 1997,297,289. C . Malet and 0. Hindsgaul, Carbohydr. Res., 1997,303,5 1. L. Gan, X. Ansui and P.A. Seib, J. Carbohydr. Chem., 1997,16, 155. A, Leydet, C. Jeantet-Segonds, C. Bouchitte, C. Moullet, B. Boyer, J.P. Rogue, M. Witvrouw, J. Este, R. Snoeck, G. Andrei and E. De Clercq, J. Med. Chem., 1997,40,350. K.C. Nicolaou, J.I. Trujillo and K. Chibale, Tetrahedron, 1997,53, 8751. T. Gourlain, A. Wadonachi, R. Uzan and D. Beaupkre, J. Carbohydr. Chem., 1997,16,1089. P. Bako, T. Kiss and L. Toke, Tetrahedron Lett., 1997,38, 7259. R.P. Clausen and M. Bols, J. Org. Chem., 1997,62,4457. F. Kong, Youji Huaxue, 1997,17,38 (Chem. Abstr., 1997,126, 186 258). J. Ning and F. Kong, Carbohydr. Rex, 1997,300, 355. J . Ning and F. Kong, J. Carbohydr. Chem., 1997,16,311. A. Fernandez Cirelli, H. Mohn and J. Thiem, Carbohydr. Res., 1997,303,417. E.A. Djurendic, M. Popsavin, S. Velimirovic, N. Vukojevic, B. Peric, V. Popsavin and D. Miljkovic, J. Serb. Chem. SOC., 1997, 62, 551 (Chem. Abst., 1997, 127, 1766 12). J.S. Kozlowski, C.H. Marzabadi, N.P. Rath and C.D. Spilling, Carbohydr. Res., 1997,300,30 1. H. Li, H. Hagiwara, W. Zhu, C. Yokoyama and N. Harada, Carbohydr. Res., 1997,299,30 I .

6 Acetals

1 Methylidene, Isopropylidene and Benzylidene Acetals

A new, high-yielding method for the synthesis of methylidene acetals from sugar diols employs DMSO as the source of methylene and POC13 or SOC12 as catalyst.' Preparation of a methylidene acetal by reduction of a thionocarbonate with Ph3SnH/AIBN (1 -, 2) changed a base-sensitive protecting group to an acid-sensitive one.2

x

O A X t-0

1 X,X= =s 2 X - H

3 4

Acetonation of ~-mannurono-6,3-lactone, the main product in the acid hydrolysis of alginic acid from kelp, gave the all-cis-furanoid derivative 3, which on reduction with LiBH4 furnished the new isopropylidene acetal4 of or-~-mannofuranose.~ Treatment of the methyl pyranoside of WD-KDN methyl ester with excess of 2,2-dimethoxypropene in the presence of an acid catalyst gave the 5,7:8,9-di-O-acetal 5, accompanied by smaller quantities of the 8,9-mono-a~etal,~ whereas the p-anomer afforded the 5,8:7.9-di- O-isopropylidene derivative 6 under the same condition^.^

OH 5 R1 = C02Me, R2 = OMe, R3, R4 = R5, R6 = 7 R = H

8 R = C(Me)20Me


98

6: Acetals 99

Improved procedures for the preparation of 2,3:5,6:3’,4’-tri- O-isopropylide- nelactose dimethylacetal derivatives 7 and 8 have been reportedn6

2 Other Acetals

Tantalum pentachloride absorbed on silica gel has been used as acid catalyst for the 3-0-tetrahydropyranylation of diacetoneglu~ose.~

PFmctose -- (YF CH2OH

BzO OBz

iu-vii, iii I i-iii I

HOH2C Me 9 %0 10

Reagents: i, H+; ii, BnOCH2C(0)Me, (MeO)&H, H+; iii, H2, PUC; iv, BnOCH2C(O)Me, H2S04, EtOAc; v, KOH, EtOH; vi, Me2C(OMe)2, H+; vii, H2NSQClr Et3N

Scheme 1

The mono- and di-(hydroxymethy1)ethylidene acetal derivatives 9 and 10, respectively, of D-fructopyranose 1 -sulfamate have been synthesized, as shown in Scheme 1. When making the latter compound it was necessary to introduce the sulfamate group as the last step, since no 2,3-O-acetalation took place when 0 -1 was substituted.* Long-chain acetals 11 and 12 of sucrose have been prepared as new surfactants. Compounds 11 were obtained by treatment of sucrose 1’,2,3,3’,4’,6’-hexaacetate with the appropriate aldehyde in pyridine in the presence of TsOH, followed by deacetylation, whereas compounds 12 were available from the free sugar by classical transacetalation with 2,2-dimethoxy- alkane^.^ Classical transacetalation has also been employed in the synthesis of 4,6:4,6-di-O-acetals 13 of a,a-trehalose.’O

The syntheses of two iodinated acetals of D-glucose, compounds 14 and 15, are outlined in Scheme 2.” Ethyl orthoacetate was used as promoter in the acid-catalysed condensation of the anticancer agent podophyllotoxin glucoside with the appropriate aldehydes to furnish the spin-labelled 4,6-acetal derivatives 16.’*

Full details on the preparation (by use of 1,1,2,2-tetramethoxycyclohexane in the presence of an acid catalyst), structure, derivatization and NMR analysis


R2 R<q 0

OH &D-Frum

11 R' = H, R2 = (CH2),,Me

12 R' = Me, R2 = (CH2),,Me n- 5 8 , 10, 12, 14, 16

n= 4,7, 10, 12

,Ol

1°1 PH

OH

13 R=(CH2)&le n==30rlO

CH20H

r c H 2 < o g o F OH - i-vi HO cot OAc

vii, vi i OAC

14 OH

l*(+*H

OH 15

Reagents: i, @CHO, PhSOsH, (Ph0)3P; ii, 0 2 ; iii, NaBH4; iv, Tf20, Py; v, Nar, acetone;

vi, MeO-, MeOH; vii,I O C H B r 2 . Py Scheme 2

OH 16

OMe O M e 17

of cyclohexane- 1,2-diacetal-protected sugars have been published (see Vol. 28, Chapter 6, refs. 22, 23).*3 Diacetal 17 has been obtained by direct reaction of methyl a-D-mannopyranoside with buta-2,3-dione in the presence of methyl orthoformate and camphorsulfonic acid in methanol, i.e., there was no need to first convert the diketone to its tetramethoxydiacetal. l4 The use of butane-2,3- diacetal-protected intermediates in the synthesis of rare natural deoxysugars is covered in Chapter 12.

Glycosylidene acetals of sugars have been made, as exemplified in Scheme

6: Acetals 101

3.15 The 4,6-OH groups of D-glucal have been efficiently protected by treatment with di-tert-butylsilyl ditriflate in DMF to give the 4,6-di-O-(tert- buty1)silanediyl derivative 18.16

OBn

Reagents: i, ($0, MeOTms, TmsOTf BnO

OBn Scheme 3

3 Reactions of Acetals

Selective hydrolysis of isopropylidene acetals has been achieved by use of ozone in aqueous MeOH. As usual, acetals involving primary positions were hydrolysed selectively (e.g., 19+20, 80%). l7 One-pot oxidation of dioxolane acetals with FeC13/NaI04 in aqueous THF proceeded selectively to give aldehydes in high yield (e.g., 19-+21, 72%).18

18 I

21

The reductive cleavage of dioxolane-type diphenylmethylene and fluoryli- dene acetals with LAH/A1C13 (see Vol. 27, Chapter 6, Ref. 17 and Vol. 25, Chapter 5, ref. 2, respectively) has been studied in some detail; fully protected methyl a-L,-rhamnosides 22 furnished, as expected, mixtures of hydroxyethers 23 and 24, with predominance of the equatorial 3-ethers 24; when 4-OH was unprotected, however, the axial 2-ether 25 was formed exclusively, which is thought to be due to complexation of the free 4-hydroxyl group with aluminium. l9 Application of the same reagents to 2-methoxybenzylidene derivatives 26 with unprotected 3-OH gave the expected mixture of hydroxyethers; when 3-OH was protected as the methyl, benzyl, or ally1 ether; however, little or no acetal cleavage was observed, and reaction took place at the amido group instead, affording products 28-30, arising from a postulated


isocyanate intermediate 27.20 Oxidative opening of benzylidene acetals with 2,2-bispyridinium chlorochromate/MCPBA is referred to in Chapter 7.

Cyclohexane diacetal protection has been used for tuning the reactivity in glycosylations. In glycosyl donor 31, for example, 2-OH is deactivated by the syn-axial methoxyl group, thus avoiding homocoupling.21

I

X 26 X = NHCbz, R = H 27 X I: N=C=O, R = Me, All, Bn 28 x NHMe, R = Me, All, Bn 29 = NHCHo* = Bn

22 R',R2 =xFl, R3 = Me, Et, Bu, Bn, All efc..

23 R' = CHPh2, R2 = H, R3 = Me, Et, Bu, Bn, All etc.. 24 R' = H, R2 = CHPh2, R3 = Me, Et, Bu, Bn, All etc.. 25 R' = CHPh2, R2 = R3 = H

References

M. Guiso, C. Procaccio, M.R. Fizzano and F. Piccioni, Tetrahedron Lett., 1997, 38,4291. F. De Angelis, M. Marzi, P. Minetti, D. Misiti and S. Muck, J. Org. Chem., 1997, 62,4 159. M.P. Watterson, A. Martin, T.M. Kriille, J.C. Estevez and G.W.J. Fleet, Tetrahedron: Asymm., 1997,8,4111. T. Kai, X.-L. Sun, H. Takayanagi and K. Furuhata, J. Carbohydr. Chem., 1997, 16, 533. T, Kai, X.-L. Sun, H. Takayanagi and K. Furuhata, J. Carbohydr. Chem., 1997, 16, 521. P.L. Barili, G. Catelani, F. D' Andrea, F. De Rensis and P. Falcini, Carbohydr. Res., 1997,298,75. S . Chandrasekhar, M. Takhi, Y. Ravindra Reddy, S. Mohapatra, C. Rama Rao and K. Venkatram Reddy, Tetrahedron, 1997,53, 14997. S.O. Nortey, W.-N. Wu and B.E. Maryanoff, Carbohydr. Res., 1997,304,29.

6: Acetals 103

9 10 11 12 13

14

15 16 17

18 19

20

21

E. Fanton, C. Fayet and J. Gelas, Carbohydr. Res., 1997,298,85. J. Besson, C. Fayet and J. Gelas, Carbohydr. Res., 1997,303, 159. M.-D. Desruet, C. Morin and L. Ogier, Carbohydr. Res., 1997,301,225. K-.k. Lu, Y.-g. Wang and Y .-z. Chen, Synth. Commun., 1997,27, 1963. P. Grice, S.V. Ley, J. Pietruszka, H.W.M. Priepke and S.L. Warriner, J. Chem. SOC., Perkin Trans. I , 1997,351. A. Hense, S.V. Ley, H.M.I. Osborn, D.R. Owen, J.-P. Poisson, S.L. Warriner and K.E. Wesson, J. Chem. Soc., Perkin Trans. I , 1997,2023. H. Ohtake, T. Iimori and S. Ikegami, Tetrahedron Lett., 1997,38,3413. J.O. Hoberg, Carbohydr. Res., 1997,300,365. B.V. Rao, B.V.N.B.S. Sarma, S.V. Ravindranadh, M.K. Gurjar and M.S. Chorghade, Carbohydr. Lett., 1997,2,377. S . Chandrasekhar, R. Kache and Y.R. Reddy, Carbohydr. Lett., 1997,2,217. J. Hajko, A. Borbas, G. Szabovik, M. Kajtor-Peredy and A. Liptak, J. Carbo- hydr, Chem., 1997,16, 1123. H.P. Wessel, I. Plessis, S. Cassel and W. Arnold, J. Carbohydr. Chem., 1997, 16, 789. M.-K. Cheung, W.L. Douglas, B. Hinzen, S.V. Ley and X . Pannecourt, Synlett, 1997,257.

7 Esters

1 Carboxylic Esters

1.1 Synthesis - The relative reactivities of the carbohydrate hydroxyl groups have been reviewed with particular attention to the selective acylation of pentoses.' The high selectivity for D-ribose in the acylation of equimolar mixtures of all four D-aldopentoses under chemical or enzymic conditions is covered in Chapter 2.

I. 1. 1 Chemical Acylation and Deacylation - Highly efficient crotonoylation ha! been achieved with the acyl chloride in dichloromethane in the presence of 3A molecular sieves instead of the traditional pyridine or triethylamine.2 The efficiency of iodine as a Lewis acid to promote per-0-acylation, regioselective acylation and selective acetolysis of primary benzyl ether groups in carbohydrates has been e~plored.~ All mono-, di-, and tri-pivaloates of methyl P-D- xylopyranoside have been obtained by use of varied amounts of pivaloyl chloride in ~yridine.~

i

OR OR R = Tri-Obenzyl-galloyl

iii L 1 R = H iC 2 R = Tri-Obenzyl-galloyl 3 R = Galloyl

Reagents: i, Tri-Obenzylgallic acid, DCC, DMAP; ii, hv; iii, H2, Pd/C Scheme 1

1,2-cis-Configured peracetylated hexopyranoses (e. g., the P-peracetates of D-mannose, L-rhamnose, D-lyxose) have been prepared from unprotected sugars via 1,2-cis-stannylene a~eta l s .~ Anomerically pure 1,2,3,4,6-penta-O- galloyl-P-D-glucose 3 was synthesized by way of the tetraester 2, using the photolabile 2-nitrobenzyl P-D-glucoside 1 as starting material (Scheme 1).6 Various p- 1 -0-acyl derivatives of ally1 glucuronate, such as compounds 5, have been obtained in good yields from the free sugar, e.g. 4, under M it sun0 bu conditions.


1 04

7: Esters 105

The 3-O-(thiocarbonylimidazole) derivative 6 was prepared in 89% yield simply by grinding together diacetone glucose and thiocarbonyldiimidazole.* Benzyl L-rhamnopyranoside was selectively 3-O-acylated via tin-containing intermediate^.^ 3’-Aminoacylated 3’-deoxynucleosides are referred to in Chapter 20.

4 R’ = a,&OH 5 R’ = B-OCOR2

6 7 R = stearyl, palmityl etc.

DCCIDMAP-Promoted condensations were applied to the preparation of 1 - O-fatty acid esters 7 of 2,5,6-tri-O-benzyl-~-mannitol’~ and glutamate 8 of methyl 2,3-O-isopropylidene-P-~-riboside. * Regioselective primary acylation with methyl orthoacetate and chlorides of rare earths on silica furnished primary esters of methyl pentofuranosides and methyl hexopyranosides selectively and in near 90% yields.12

Oxidative cleavage of benzylidene acetals with 2,2-dipyridinium chlorochro- matelMCPBA gave mainly 4-hydroxy benzoates (e.g., 9+ 10, 70?4).13 Guani- dine/guanidinium nitrate removed O-acetates without affecting other base- sensitive protecting groups such as, for example, the 2,2,2-trichloroethoxy- carbonyl group in compound 11. l4 Decarboxylation of the 6”-O-malonyl ester groups in isoflavone glucosides to give 6’- O-acetates occurred efficiently on heating in DMF at 60°C, which may explain the increase in the latter components which occurs in soyabeans on t0a~t ing. l~

Rl&C) A c d F y E t

OMe

OMe NHCOCH2CCI3 r, 11

If 9 R’,R2= CHPh

10 R’ = Bz, R2 = H

8

A stereocontrolled synthesis of a-2’-deoxyribonucleosides, which is outlined in Scheme 2, involved selective hydrolysis of the 3-O-benzoate of arabinofur- anose derivative 12 with hydrazine in pyridine, and then relied on the 2-O-


benzoate group acting as directing group before being removed by photoinduced electron transfer. l6 A further example of photosensitized selective deoxygenation of a secondary benzoate is given in Chapter 12.

BzO __t

1 I OAc OAc

12 R' = Me, R2 = Bz '' ii

R' = R2 iit Ac Reagents: i, H2NNH2, Py; ii, AqO, HOAc, H2S04; iii, VorbrUggen glycosylation;

iv, 3,6dimethyl-9-ethylcarbazole, Mg(CIO&, P$OH,h

Scheme 2

In a study on the influence of the interaction between water and sucrose hydroxyl groups on the selectivity of esterification, sucrose was exposed to octanoyl chloride in aqueous base over a range of concentrations, which resulted in various degrees of substitution. Sucrose 6- 0-long-chain-fatty acid esters were obtained in yields of 50-70% via the 4,6-O-dibutylstannylene acetal, which was formed preferentially. * Benzoylation of lactose derivative 13 with benzoyl cyanide under a variety of conditions gave lactosides with 1,2, or 3 free hydroxyl groups, e.g., tetrabenzoate 14 and dibenzoate 15.19 Acetyl chloride in DMF in the presence of collidine at -70°C caused selective acetylation of the primary hydroxyl groups of a tetrasaccharide.20

During the exploration of the reactivity of 1 -deoxy-heteroaryl-substituted ketoses 16, ester-linked disaccharide analogues 17 have been produced.21 Diester-linked disaccharides, similar to that shown in Vol. 30, Chapter 7, structure 20, have been synthesized in the course of intramolecular glycosylation s t ~ d i e s ? ~ , ~ ~ and as surf act ant^.^^ Positional isomers of glycolipid A-60 are referred to in Chapter 10.

N Ar = -( 1 , erc.

7 Born

OH OR' OBn 16 R - H

Tds = thexyldimethylsilyl +c=o 13 R' R2 = H 14 R' = R2 = BZ 15 R' = H, R ~ = BZ

OBn

1.1.2 Enzymic Acylation and Deacylation - Reviews on ester synthesis by enzymic transesterificati~n~~ and on the use of lipases in acylation/deacylation reactions of carbohydrates26 have been published.

7: Esters 107

Mono-acrylates, -methacrylates and -crotonates were formed when sugars were exposed to activated esters of the respective carboxylic acids in the presence of an alkaline protease in anhydrous ~ y r i d i n e . ~ ~ Various lipases have been tested for substrate-selectivity when added to a mixture of methyl WD- galactopyranoside, p-D-glucopyranoside, P-D-mannopyranoside and octanoic acid in acetonitrile; the enzyme from Pseudomonas cepacia displayed high acylating specificity for the first-named sugar.28

Methyl 6-0-tosyl-a-~-glucopyranoside (18) was acetylated at 0-2 by P. cepacia lipase and vinyl acetate, whereas its P-anomer 19 reacted preferentially at 0-3. The corresponding D-galactose and D-mannose derivatives behaved similarly.2g Use of the same enzyme gave mixtures of the 2- and 3-0-acetates of phenyl 6-0-trityl-~-glucopyranoside (20), the ratio depending on the solvent,30 but the 3-0-acetate was the sole product obtained from diol21 with P. fluorescens lipase .

OH 18 R' =Ts, R2= H, R3=a-OMe 19 R1 =Ts, R2=H, R3=p-OMe 20 R1 = Tr, R2 = H, R3 = p P h

22 R = H, a-OMe, 23 R' =a,&OH, R2 = (CH2)&02CH=CH2

R2 = CH(NHCbZ)Ph

p-OMe, p-OBn, etc. 24 R' = &O(CH&Me,

21 R',R2 = 'CHPh, R3 = &SEt #

Good primary selectivity has been observed in the lipase-mediated acyl transfer from vinyl acetate to methyl 2,3-di-O-acetyl-~-glycopyranosides~~ and to 3,4-0-isopropy~idene-~-ga~actose derivatives 22.33 Primary esters were also the main-products in the lipase-catalysed acylations of free sugars, especially D-glucose, with long-chain fatty acids in acetone or d i ~ x a n e , ~ ~ of a-glucono- 1,5-lactone with fatty acid esters in t - b ~ t a n o l , ~ ~ of alkyl glucosides with long- chain fatty acids at 75"C/0.01 bar36 or in microemulsions,37 and of 1,2-0- isopropylidene-a-D-glucofuranose with fatty acid esters.38 In the last three of these reports no added solvents were used.

The 6-vinyl adipate 23 was synthesized by exposure of D-glucose to divinyl adipate in the presence of an alkaline Streptomyces protease in DMF; this protease was chosen from 34 enzymes examined for their efficiency in the preparation of vinyl derivatives of sugar e s t e r ~ . ~ ~ 9 ~ Use of cross-linked crystals of subtilisin, a versatile new catalyst with improved stability, gave the 6-(amino acid) ester 24 of octyl P-D-glucoside in 65% yield.41

The desymmetrization of D-galactitol has been achieved biocatalytically via its 1,6-di- 0-acetyl-2,3:4,5-di-O-isopropylidene derivative 25, as shown in Scheme 3?2 Out of 28 enzymes tested, 9 displayed good activity and selectivity for deacetylation at 0 - 2 of peracetylated derivatives of D-galacturonic acid in DMF.43 Results obtained in a kinetic study on the pig liver esterase-catalysed hydrolysis of both anomers of methyl D-xyloside derivatives 26 have been


OAc Reagents: i, Pseudomonas fluorescens lipase; ii, Lipase PS

Scheme 3

interpreted in terms of the active site model proposed by Jones (J. Org. Chem., 1994, 59, 2729)? Lipase-promoted acetylatioddeacetylation reactions of conduritols are covered in Chapter 18.

Regioselective transesterifications between various disaccharides and an active ester of terephthalic acid have been undertaken, using Optimase M-440 in pyridine; in the case of sucrose, the 1'-mono- and 1',6-di-terephthalate, 27 and 28, respectively, were the main-prod~cts.~~ 6'-O-Monoesters of sucrose have been prepared via selectively acetal-protected intermediates (e.g., 29-30) by use of lipases in organic solvents or under solvent-free conditions.*

OAc 28

1.2 Natural Products - The octanol-water partition coefficients of various hydrolysable gallotannins and ellagitannins have been determined; special attention was paid to the increased water solubility of tannins in hydrophobic association with the water-soluble, natural glycosides contained in crude medicinal herb e~tracts.4~

The synthesis of 1,2,3,4,6-penta-O-galloy~-~-~-glucose is referred to in Section 1.1.1 above. The enantiomerically pure ellagitannins ~ t r i c t in in ,~~ praecoxin B and pterocarinin C49 have been synthesized by diastereoselective esterification of appropriately protected 2-nitrophenyl P-D-glucosides with racemic hexabenzyloxydiphenic acid as the key-step.

7: Esters 109

Carotenoid glucoside 6-0-mycolic acid esters were discovered for the first time in a red actinomycetes fungus.50 The presence of 6-O-tigloyl-~-glu- cosy1 moieties has been found responsible for the anti-sweet properties of certain oleanane-type triterpenoid glycosides (see Vol. 28, Chapter 4, ref. 51).51

31

The resins of the Mexican plant Ipomoea tricolor are a complex mixture of glycolipids formed from tri- and tetra-saccharide cores and hydroxy-fatty acids; minor, dimeric constituents containing (1 1 S)-hydroxyhexadecanoate moieties linking two tri-saccharide cores as well as two glycosyl residues within one trisaccharide unit have now been ~haracterized.~~ Compound 31 and related esterified dimannosylglycerol derivatives have been found in Arthro- bacter a t r o c y a n e u ~ . ~ ~

2 Phosphates and Related Esters

Uridine diphospho-a-D-gluco-dialdose 32 has been synthesized (see Chapter 13) to examine its intermediacy in the UDP-glucose dehydrogenase-promoted oxidation of UDP-glucose (33) to UDP-glucuronic acid (34).54 The L-

fucose 1-phosphate analogues 35 were intermediates in the synthesis of carbon-backbone-elongated GDP-L-fucose derivatives (see Chapter 2 for ~hain-elongation),~~ and 1 -phosphate 36 was an intermediate in the synthesis of dTDP-6-deoxy-~-ribo-3-hexulose (see Chapter 15). 56 The glycogen phosphorylase-catalysed addition of inorganic phosphate to glucal with formation of 2-deoxy-a-~-arabino-hexopyranosyl phosphate is referred to in Chapter 12.

OH OBz 32 R = CHO 33 R = CH20H 34 R=C&H

35 36


A new synthesis of D-galactopyranose- 1,2,6-trisphosphate as an analogue of D-myo-inositol 1,4,5-trisphosphate has been reported.57 The synthesis of further D-myo-inositol 1,4,5-trisphosphate analogues and of several D-myO- inositol pentakisphosphates are referred to in Chapter 18. The 0-2-, 0-3-, 0-4-, 0-6-and O-7-monophosphates of L-glycero-D-manno-heptose have been prepared from suitably protected precursors by standard methods (see Chapter 2 for a synthesis of ~-glycero-~-manno-heptose).~~ The tris- phosphinate 38, obtained by phosphitylation of trio1 37, has been converted into tris(benzylpropanoy1)phosphonate 39 under Arbuzov condi- t i o n ~ . ~ ~

CH20Tr

HO &OM. I

37 R = H 40 R = H 38 fi = P(OBn), 0 I

39 R = P(OBn)CH2CH2C02Bn II II 41 R = POCH2CH2NHC 0 II

0 0 0 II

II 0

42 R = POCH2CH2NH2

Ethanolamine phosphate moieties have been introduced by first preparing N-phenacetyl-protected intermediates by use of the phosphoramidite method, followed by cleavage of the protecting group with immobilized penicillin G acylase (e.g., 40-~41+42).~~ Two further papers on the preparation and reactions of 6-deoxy-6-chloro- 1,2- 0-alkylidene-a-D-glucofuranose 3,5-cyclo- phosphorochloridate have appeared (see Vol. 30, Chapter 7, ref. 62),61*62 and the synthesis of bicyclophosphito-phosphonates, such as 44, from ketofuranose 43 has been described (Scheme 4).63

i n v

4 3 ' 44 I

Reagents: i, (P+0)2P(0)OTrns; ii, MeOH; iii, aq. HOAc; iv, P(NEt2)3 Scheme 4

Preparative primary phosphorylation with yeast hexokinase (EC 2.4.1.1) has been carried out on a wide range of furanose and pyranose derivatives; the

7: Esters 111

enzyme was very tolerant of structural changes at C-2 and C-3, but less tolerant and intolerant, respectively of changes at C-1 and C-4.@ D-Glucose 6- (sodium-secondary alky1)phosphates 45 are a new family of amphiphilic tubule-forming anionic glycophospholipids.65

SePh

HNO-P-OCH

46 OH 8'Ph

45 R = (CH&Me, (CH2)2(CF&CF3, etc.

In a synthesis of C-disaccharides by radical coupling, the donor and acceptor were first connected through a phosphoramidite tether as, for example, in compound Lactosyl phosphate- and thiophosphate-diesters of Ara-C and Ara-A have been prepared employing H-phosphonate and phosphoramidite methodology, re~pectively.~~ Novel phosphorylated galactolipids are mentioned in ref. 69 below.

Treatment of cyclodextrin with inorganic metaphosphate at pH 4 gave mixtures of 2-, 3-, and 6-monophosphates, which were separated by anion exchange chromatography .

3 Sulfates and Related Esters

Novel sulfated galactolipids 47 have been prepared with introduction of the sulfate groups via stannylene-intermediates; the 3,4-bisphosphorylated analogues have also been made.69 Synthetic approaches towards chondroitin sulfate oligomers have resulted in the systematic synthesis of sulfated disaccharides 48-50.70 During on-going efforts in the area of selectin ligands and blockers, a series of mono-and di-sulfated D-galactose derivatives, e.g., sulfatide analogue 51,71 were prepared by conventional sulfation of protected precursors directly or via tin-intermediate~.~l-~~ Sulfate groups were similarly introduced at 0 -3 andor 0-6 of the D-galactosyl residues and of the adjacent D-glucosyl- or 2-acetamido-2-deoxy D-glUCOSY1 residues, respectively, of 2-(tetradecy1)hexadecyl P - l a ~ t o s i d e ~ ~ . ~ ~ and of sialyl Lewis X tri- and hexa-saccharide ~ e r a m i d e s . ~ ~ ~ ~ ~ A trisaccharide glycoside sulfate, structurally related to these synthetic products, is the first sulfatide found in a starfish. 79

The trifluoroethyl group has been used as a protecting group for sulfates that is stable under Zemplen conditions; conditions for its introduction and removal are indicated in Scheme 5.80 The opening of carbohydrate cyclic sulfates by carbohydrate alkoxides is referred to in Chapter 3.


3-Sulfo-po-Galp, , (CH2),Me

3Sulfo-fi-~-Galp' 'R 47 R = H or (CH2)J4e

C

X = 13 or 15

OH 51

iii. iv

OH

Reagents: i, SO3, Py; ii, CF3CHN2; iii, TFA, EtOH; iv, BubK, ButOH Scheme 5

4 Sulfonate Esters

The mechanisms of the reactions undergone by certain triflates on treatment with t-BuOK (strong base) or pyridine (weak base) have been further elucidated by use of deuterated derivatives (see Vol. 30, Chapter 7, ref. 8 2). ' ' 3 82

4-0-Triflated derivatives 52 of D-fucose have been synthesized from the corresponding 6-deoxy-~-glucose derivatives by conventional triflation following inversion at 0-4 by oxidation/red~ction.'~ h i d e 56, required for the preparation of-D-glucose- and D-galactose-related triazole derivatives (see Chapter lo), was obtained from D-glucuronolactone by double inversion via triflate 53, trifluoroacetate 54, and triflate 55.84 The monomesylates 57 and

qH20TWms

T f O g y R "-b OTbdms 0

CH2R' I

R20 &)OH

i>Bn OTbdms OH 52 R = Me, Bn, etc. 53 R' = TfO, R2 = H

54 R' = H, R2 = OC(O)CF3 57 R' or R2 or R3 = Ms, others = H 58 R2 or R3 = H, others = Ms

55 R' = H, R2 = OTf 50 R'=N3, R 2 = H

7: Esters 113

dimesylates 58, available by standard procedures, are hydrophilic analogues of the brain-tumour therapeutic 1,4-dime~yloxybutane.~~ The 6-O-dansyl derivative of 2-acetamido-2-deoxy-~-glucose has been prepared by conventional sulfonation for biological incorporation into chitin.86

Removal of tosyl groups by sodium naphthalenide in THF is referred to in Chapter 20, and the preparation of sucrose analogues via the 2-O-triflate is covered in Chapter 3.

5 Other Esters

O-Benzyloxycarbonyl-protected derivatives of D-mannose (an alternative to benzyl ether protection) have been obtained in good yields by use of CbzCl and stochiometric quantities of DMAP.87,88 Reduction of a thionocarbonate with Ph3SnH/AIBN ( 5 9 4 0 ) changed a base-sensitive protecting group to an acid-sensitive Glycosyl P-carbamates, such as 61 , formed on treatment of peracetylated free sugars with an aliphatic isocyanate in the presence of DABCO, are new glycosyl donors, as well as surfactants capable of solubilizing proteins.g0 Bis(carbamoy1 ester) derivatives 63 of 1,2- O-isopropylidene- a-D-xylose and the thio-analogues 64 have been prepared as antifungals; the carbamoyl and thiocarbamoyl groups were introduced by reaction of 62 with either N, N-diethylcarbamoyl chloride or N-ethylisocyanate, or with the corresponding sulfur-containing reagents, respectively. The analogous dithiocarba- mate derivatives are referred to in Chapter 1 1 .91 The per-(4-chloro- or -bromo- pheny1)carbamates of malto-penta-, -hexa- and -heptaose have been used as chiral recognizing HPLC stationary phases.92

x

59 x,x = =s 60 X = H

k y . O ) N H P h CH20Ac

AcO

OAc 61

ROCH2

ki>o 62 R = H O h 63 R=C(O)NXEt 64 R=C(S)NXEt

X = H or Et

The action of fuming HN03/Ac2 on the 3”’,4”’-O-acetonide of the cardiac agent gitoxin (65) produced a mixture of mono-, di-, and tri-nitrate esters with


nitrate groups in one or both of the internal 2,6-dideoxy-P-~-ribo-hexopyra- nosy1 residues and/or in the a g l y ~ o n . ~ ~ Orthoesterification under kinetically controlled conditions [CH2=C(OMe)~/TsOH/DMF] gave the 4,6-derivative of sucrose and the 4,6'-derivative of maltose; under similar conditions, a,a-trehalose formed the 4,6:4',6'-di-orthoester in 47% yield (see Vol. 29, Chapter 7, refs. 94, 95).94 An unusual side-reaction in the TmsOTf-promoted orthoester + glycoside rearrangement, which produced a disaccharide, has been reported.95 evMe - i qpHYJe

0 p OBu

I Ph

HO

Reagent: i, BunI, Ag20, Et3N, benzene Scheme 6

Cyclic sugar phenylboronates regioselectively activate hydroxyl groups, in parallel to stannylene acetals, provided the boron atom is N-coordinated. An example is given in Scheme 6. In the absence of triethylamine the unprotected hydroxyl group undergoes reaction.96

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71

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7: Esters 117

72

73 74

75

76

77

78

79

80 81 82 83 84

85

86 87

88

89

90

91 92

93

94 95 96

D.D. Manning, L.E. Strong, X. Hu, P.J. Beck and L.L. Kiessling, Tetrahedron, 1997,53,11937. T.Yoshida, Carbohydr. Res., 1997,304,249. T. Ikami, H. Hamajima, T. Usui, T. Mitani, H. Ishida, M. Kiso and A. Hase- gawa, J. Carbohydr. Chem., 1997,16,859. A. Marinier, A. Martel, J. Banville, C. Bachand, R. Remillard, P. Lapointe, B. Tunnel, M. Menard, W.E. Harte, Jr., J.J.K. Wright, G. Todderud, K.M. Tramposch J. Baiorath, D. Hollenbaugh and A. Aruffo, J. Med Chem., 1997,40, 3234. W.J. Sanders, D.D. Manning, K.M. Koeller and L.L. Kiessling, Tetrahedron, 1997,53, 1639 1. S. Komba, H. Ishida, M. Kiso and A. Hasegawa, Bioorg. Med Chem., 1996, 4, 1833 (Chem. Abstr., 1996,126,186 283). K. Yoshino, H. Ohmoto, N. Kondo, H. Tsujihita, Y. Hiramatsu, Y. Inoue, H. Kondo, H. Ishida, M. Kiso and A. Hasegawa, J. Med. Chem., 1997,40,455. S . Kawatake, M. Inagaki, R. Isobe, T. Miyamoto and R. Higuchi, Liebigs Ann. Chem., 1997,1797. A.D. Proud, J.C. Prodger and S.L. Flitsch, Tetrahedron Lett., 1997,38,7243. A. El Nemr and T. Tsuchiya, Carbohydr. Res., 1997,301,77. A. El Nemr and T. Tsuchiya, Carbohydr. Res., 1997,303,267. J.C. McAuliffe and R.V. Stick, Aust. J. Chem., 1997,50, 197. T.M. Kriille, C. de la Fuente, L. Pickering. R.T. Aplin, K.E. Tsitsanou, S.E. Zographos, N.G. Oikonomakos, R.J. Nash, R.C. Griffith and G.W.J. Fleet, Tetrahedron: Asymm., 1997,8,3807. T. Halmos, M. Santarromana, K. Antonakis and D. Scherman, Carbohydr. Res., 1997,299,15. L. Carrano, P. Tavecchia, F. Sponga and F. Spreafico, J. Antibiot., 1997,50, 177. A. Morere, C. Menut, C. Vidil, P. Skaanderup, J. Thorsen, J.-P. Roque and J.-L. Montero, Carbohydr. Res., 1997,300, 175. A. Morere, F. Mouffouk, C. Chavis and J.-L. Montero, Tetrahedron Lett., 1997, 38, 7519. F. De Angelis, M. Marzi, P. Minetti, D. Misiti and S. Muck, J. Org. Chem., 1997, 62, 4159. C. Prata, N. Mora, J.-M. Lacombe, J.C. Maurizis and B. Pucci, Tetrahedron Lett., 1997,38, 8859. C . Len, D. Postel, G. Ronco and P. Villa, J. Carbohydr. Chem., 1997,16, 1029. E. Yashima, P. Sahavattanapong, C. Yamamoto and Y. Okamoto, Bull. Chem. SOC. Jpn., 1997,70, 1977. A. Nagatsu, Y. Nakamura, K. Takemoto, K. Shibatomi, S. Nagai, T. Ueda, J. Sakakibara, H. Hidaka, M. Fujita, Y. Hotta, K. Takeya, M. Asano, T. Ha- shimoto and Y. Asakawa, Chem. Pharm. Bull., 1997,45,599. M. Bouchra and J. Gelas, Carbohydr. Res., 1998,305, 17. T.K. Lindhorst, J. Carbohydr. Chem., 1997,16,237. K. Oshima, E.4. Kitazono and Y. Aoyama, Tetrahedron Lett., 1997,38, 500.

8 Halogeno-sugars

1 Fluoro-sugars

O-Acetylated glycosyl bromides when treated with trifluoromethylzinc bromide afforded the corresponding glycosyl fluorides and the same reagent with TiF4 also converts anomerically unprotected derivatives to the glycosyl fluorides.’ O-Acetylated or -bemyfated glycals have been treated with an electrophilic fluorine source (‘Selectfluor’ 7) in the presence of water to give 2-deoxy-2-fluoro-sugars. The fluorine was incorporated at C-2 from the opposite face of the ring to that of the C-3 substituent. Thus, for example, 1 gave 2 and 3 afforded 4. Related conditions but with dimethyl sulfide replacing the water could be utilized to prepare the glycosyl fluoride 6 from 5 (Scheme 1).2

AcO AcO

OAc 1

OAc 2 3

F 4

F

OBn OBn F 5 6 7

Scheme 1 Reagents: i, 7, DMF/H20; ii, 7, MezS, DMF “Selectof luor”

2’-Deoxy-2’-fluorocellobiose has been prepared by standard methods as a mechanism-based inhibitor of ‘retaining’ glyco~idases,~ and homologous series of ampiphilic alkyl2-deoxy-2-fluoro- 1 -thio-a-D-gluco- and -mannopyranosides have been made using standard method^.^ 4-Deoxy-4-fluoro-~-arabinose has been synthesized starting from 2-deoxy-2-fluoro-~-glyceraldehyde, by way of a Wittig reaction and a Sharpless dihydr~xylation.~

The fluorocyclitol derivatives 8 and 10, obtained from halobenzene-derived microbial oxidation products, undergo oxidative cleavage by ozonolysis, the


118

8: Halogeno-sugars 119

products being convertible to 9 and 11 respectively (Scheme 2).6 Analogues of the terpenoid glycoside glycyrrhizin have been prepared which incorporated the 3’-, 4-, 6 - , 3- and 4-monodeoxyfluoro derivatives of 2-0-P-~-glucopyranosyl-P-D-glucopyranoside as well as the 3- and 4-monodeoxyfluoro derivatives of 2-~-~-~-g~ucopyranuronosy~-~-D-g~ucopyranos~de,~ and a synthesis of methyl 3-deoxy-3-fluoro-~-~-allopyranoside has been described.*

HOCH2

OH

8

Br Ffi OH

iv, v __c

F 9

I-F

10 11 Reagents: i, 03, Me2S; ii, FeCI3, AQO; iii, NaOMe; iv, 0 3 ; v, NaBH4

Scheme 2

4-P-Glycosylation of a 6-deoxy-6-fluoroglucose derivative has given access to 6-deoxy-6-fluorocellobiose, whereas 6’-deoxy-6’-fluorocellobiose has been prepared from benzyl P-cellobi~side.~ Steroidal a-cellobiosides have been modified to the 6,6-dideoxy-6,6-difluoro analogues as potential cholesterol absorption inhibitors. lo

The keto-sugar derivatives 12 and 14 have been converted into the difluoro- alkenes 13 and 15 respectively (Scheme 3). Further processing of 15 gave rise to the mono-, di- or tri-fluoro compounds 16-18.’*~’~

A Reformatsky reaction of ethyl bromodifluoracetate applied to 2,3-0- isopropylidene-L-glyceraldehyde, and further processing of the product followed by lactonization, has afforded the 2,2-difluorolactone 19 which was converted into some pyrimidine L-nucleosides. Similarly, an aldol-like reaction of tert-butyl difluorothioacetate on 2,3-O-isopropylidene-~-glyceraldehyde has led, after further processing, to the 2,2-difluoro-~-lactone

Full details have been published on the preparation of anomeric difluoromethylene phosphonates by phosphonyl radical addition to carbohydrate 1 - difluoromethylene compounds (cf: Vol. 30, p. 119).15 A synthesis has been reported of 6-deoxy-6,6-difluoro-a-~-glucopyranosyl fluoride as a potential inhibitor of sucrase phosphorylase. l6

A synthesis of the enantiomerically pure 3-C-arylsulfonyl-4-fluoromethyl-5- phosphonate 21 from non-carbohydrate materials has been effected. The syntheses of some 4‘-C-fluoromethyl nucleosides as well as some 3’-deoxy- 3’-difluoromethylene nucleosides are covered in Chapter 20.

20.14


TbdmsO TbdmsO

0 OMe - F 2 C G O M e

12 13 OBz OBz

0 CF2 CF3 14 15 18

iii,/ \

CH2F CHF2 16 17

Reagents: i, CF2Br2, (Me2N)SP; ii, CF2Br2, HMPT; iii, Red-Al; iv, H2, Pd/C; v, Bu4NF; vi, DAST Scheme 3

0

19 20 21

2 Chloro-, Bromo- and Iodo-sugars

A new mild procedure for the conversion of aldopyranose peracetates into acetylated glycopyranosyl halides uses BiX&I'msX in CH2C12 (X = C1, Br or 1).l8 A significant improvement has been claimed in the synthesis of the well known synthetic intermediate 2-deoxy-3,5-di-O-toluoyl-a-~-erythro-pentofuranosyl ~hloride. '~ Iodine bromide has been used to convert acetylated thioglycosides into the corresponding glycosyl bromides.20

Treatment of aldopyranose peracetates with TmsI at low temperatures affords the p-glycosyl iodides which readily isomerize to the a-anomers when allowed to warm to RT. With a non-participating group at C-2 the glycosyl acetate is displaced with inversion at - 100 "C, followed by equilibration to the a-iodide at higher temperatures.21 2,3,4,6-Tetra-O-benzyl-a-~-glucopyranosyl iodide prepared in this way has been treated with various nucleophiles (eg, azide, carboxylate ions) to give predominantly P-products.22 Another group has utilized an alternative synthesis of the unstable 2,3,4,6-tetra-O-benzyl-

8: Halogeno-sugars 121

P-D-glucopyranosyl iodide, and when treated with alcohols this P-iodide produced mainly a-glyc~sides.~~

The influence of substituents at C-6 and C-4 on the stereoselectivity in the addition of PhSCl and PhSeCl to D-glucal derivatives has been in~estigated,~~ and the product ratios formed on addition of electrophilic halogen reagents (Br2, NBS, ICl, Bu4NBr3, NBS-Et3N.3HF) to tri-0-benzyl-D-glucal in aprotic and protic solvents have been determined by NMR spectro~copy.~~

The synthesis and crystal structure of 6,6’-dichloro-6,6-dideoxy- 2,3,4,3’,4-penta-O-benzylsucrose has been reported.26

The reaction of cyclic phosphite 22 with Clz or N-chloroamines has given 23.27

Treatment of carbohydrate epoxide derivatives with Ti(OP&/Sm12 has afforded the corresponding iodohydrins by trans-diaxial opening of the oxirane rings,28 and reaction of epoxide 24 with LiBr, HOAc, NaOAc in CH2C12 has generated the expected bromohydrin 25 as the major product.29 A study of the regioselectivity in the ring opening reactions of some aziridines with halide nucleophiles is mentioned in Chapter 9.

22 ‘ 23 ‘ TbdmsOl T W m s O l

A synthesis of I-radiolabelled 4-deoxy-4-iodo-~-g~ucose from D-glucose has been reported.30

References

R. Mietchen, C. Hager and M. Hein, Synthesis, 1997, 159. M.D. Burkart, Z. Zhang, S.-C. Hung and C.-H. Wong, J. Am. Chem. SOC., 1997, 119, 11743. J.D. McCarter, W. Yeung, J. Chow, D. Dolphin and S.G. Withers, J. Am. Chem. SOC., 1997, 119, 5792. R. Miethchen, H. Kowalek, A. Niemann, S. Diele and C. Schick, Liebigs Ann. Chem., 1997,279. F.A. Davis, P.V.N. Kasu, G. Sundarababu and H. Q., J. Org. Chem., 1997, 62, 7546.


6 7

8

9 10

11 12 13

14 15

16 17

18

19 20 21 22 23 24 25

26

27

28

29 30

F. Yan, B.V. Nguyen, C. York and T. Hudlicky, Tetrahedron, 1997,53,11541. N. Morishima and Y. Mori, Bioorg. Med. Chem., 1996, 4, 1799 (Chem. Abstr., 1997,126,171 785). C.B. Myers, M.M. Ramanjulu, H.L. Correll and J.P. Glusker, Struct. Chem., 1997,8,65 (Chem. Abstr., 1997, 126, 186 259). W.M. Best, R.V. Stick and D.M.G. Tilbrook, Aust. J. Chem., 1997,50, 13. M.P. DeNinno, P.A. McCarthy, K.C. Duplantier, C. Eller, J.B. Etienne, M.P. Zawistoski, F. W. Bangerter, C.E. Chandler, L.A. Morehouse, E.D. Sugarman, R. W. Wilkins, H.A. Woody and L.M. Zaccaro, J. Med. Chem., 1997,40,2547. S . Hiroaka, T. Yamazaki and T. Kitazume, Chem. Commun., 1997, 149. S. Hiraoka, T. Yamazaki and T. Kitazume, Synlett, 1997,669. L.P. Kotra, Y. Xiang, M.G. Newton, R.F. Schinazi, Y.-C. Cheng and C.K. Chu, J. Med. Chem., 1997,40,3635. J.A. Weigel, J. Org. Chem., 1997,62, 6108. T.F. Herpin, W.B. Motherwell, B.P. Roberts, S. Roland and J.-M. Weibel, Tetrahedron, 1997,53, 15085. L.A. Noecker and J.R. Edwards, Tetrahedron Lett., 1997,38,5779. A. Amone, P. Bravo, M. Frigerio, F. Viani, G. Salani and C. Zappala, J. Chem. Res. (S), 1997,458. J.-L. Montero, J.-Y. Winum, A. Leydet, M. Kamal, A.A. Pavia and J.-P. Rogue, Carbohydr. Res., 1997,2W, 175. V. Rolland, M. Kotera and J. Lhomme, Synth. Commun., 1997,27,3505. K.P.R. Kartha and R.A. Field, Tetrahedron Lett., 1997,38,8233. J. Gervay, T.N. Nguyen and M.J. Hadd, Carbohydr. Res., 1997,300, 119. J. Gervay and M.J. Hadd, J. Org. Chem., 1997,62,6961. U. Schmid and H. Waldmann, Liebigs Ann. Chem., 1997,2573. W.R. Roush, D.P. Sebesta and C. Bennett, Tetrahedron, 1997,53,8825. G. Bellucci, C. Chiappe, F. D'Andrea and G.L. Moro, Tetrahedron, 1997, 53, 3417. Z. Ciunik and S. Jarosz, Pol. J. Chem., '1997, 71, 207 (Chem. Abstr., 1997, 126, 225 467). M.P. Koroteev, S.B. Khrebtova, A.R. Bekker, N.M. Pugashova, V.K. Bel'skii, A.Yu. Zotov and E.E. Nifant'ev, Zh. Obshch. Khim., 1996, 66, 1615 (Chem. Abstr., 1997,126, 171 774). N. Khan, Y. Al-Abed, H.J. Kohlbau, F. Latif-Ansavi, W. Kowolik and W. Voelter, Z, Naturforsch., B: Chem. Sci., 1996, 51, 1781 (Chem. Abstr., 1997, 126, 144449). A.T. Cirelli, 0. Moradei and J. Thiem, Liebigs Ann. Chem., 1997, 1983. M. Abbadi, J.-P. Mathieu and C. Morin, J. Labelled Compd. Radiopharm., 1997, 39,487 (Chem. Abstr., 1997, 127, 81 679).

9 Amino-sugars

1 Natural Products

Acacic acid lactone 3-0-[2-acetamido-6-0-(a-~-arabinopyranosyl)-2-deoxy- P-D-glucopyranoside], a triterpenoid glycoside that is a rare example of a plant natural product containing an amino-sugar, has been isolated from Acacia auriculiformis.' The branched-chain amino sugars moieties 1 and 2 of undefined absolute stereochemistry are present in callipeltosides C, a 14-membered ring macrolide isolated from a CaZZipeZta sp. marine sponge,2 and nocardicyclins A and B, anthracycline antibiotics isolated from Nocardia pseudobrasiliensis, re~pectively.~

oHcHNFT RO q y the NMe2

1 2 R = H o r A c

2 syntheses

Syntheses covered in this section are grouped according to the method used for introducing the amino-functionality.

2.1 By Chain Extension - Dipolar cycloaddition of 2-trimethylsilyloxyfuran and the nitrone 3, derived from D-glyceraldehyde, gave a mixture containing all four possible cis-fused isomers 4, which could be separated and converted into the 5-amino-2,5-dideoxy-6,7-O-isopropylidene-~-aZ?ro-heptonolactam (5) and its Dido-, D-galrcro- and D-gluco-isomers (Scheme l).4 6-Deoxynojiri- mycin (8), isolated as its bisulfite adduct, was prepared by a Lewis acid- catalysed addition of methyl Grignard reagent to the nitrone 6, which led to a separable 7:l mixture of D-glUC0-7 and its L-ido-isomer (Scheme 2). Addition of methyl Grignard reagent to the C-3 epimer of 6 was also investigated.


123


3 4

Reagents: i, &OTrns, TmsOTf; ii, H2, Pd(OH)& Scheme 1

Bn I

OHN\Qo

O L

5

- ii-iv Q OH

HO

OH 6 1 7 8

Scheme 2 Reagents: i,MeMgCI, TfOTms; ii, Zn/Cu, HOAc, H20; iii, HC02NH4, Pd/C; iv, H30+

2.2 By Epoxide Ring Opening - The 2-amino-2-deoxy-~-altruronic acid derivative 11 was synthesized from the ditosylate 9 by way of a ~-allo-2,3- epoxide which was ring opened with azide ion to give 10. This was followed by oxidation at C-6 using the TEMPO method (Scheme 3). This sugar acid and

P y O F y - NV% ___t 5steps HO@Y)/OMe

0' 3 3

N3 OTs NHAc

9 10 11 Reagents: i, NaOMe; ii, NaN3. NH4CI; iii, BnBr, NaH

Scheme 3

2,4-diamino-2,4,6-trideoxy-~-galactose (the synthesis of which is covered in Section 4) are the constituent sugar residues of the O-specific lipopolysaccharide of the bacterium Shigella sonnei.6 In studies directed towards the synthesis of a stereo-isomer of acarbose as a potential P-glucosidase inhibitor, reaction of the 1,6:3,4-dianhydride 12 with cyclohexylamine or the amino- cyclitol derivative from which the substituent 12a is derived gave the 4-amino- sugar derivatives 13, which could be converted into aziridine or cyclic carbamate derivatives, 14 and 15, respectively, and thence into the methyl P-glycoside 16 (Scheme 4).778 Synthesis of the C-6 branched-chain aminohep- tose derivative 17, by way of a reaction of a spiro-epoxide with azide, is covered'in detail in Chapter 14.9

9: Arnino-sugars 125

OH

iii

OH 16 OH

12 13 14 15 BnOCH2

Reagents: i, RNH2 where R = cyclohexyl or @'-; ii, Im2CO; iii, EtOCOCl or COCl2 BnO

OBn 12a

Scheme 4

yH20Bn

AcHN-f Me

17 '

2.3 By Nucleophilic Displacement - Full details (cf. Vol. 29, p. 111, ref. 15) have been published of the synthesis of an L-daunosamine derivative and its 6-hydroxy-analogue from 1,2: 5,6-di- O-isopropylidene-a-D-glucofuranose, starting with sulfonate displacement by azide with inversion at C-3.l0 The 2,3- aziridino-D-lyxonolactone 5-phosphonate 19 has been synthesized by reaction of the D-ribfuranoside 2,3-cyclic sulfate 18 with azide with inversion at C-3 (Scheme S)." Its D-lyxo-isomer was obtained in the same way starting from D-

ribose. l2 Thiols opened aziridine 19 nucleophilically at C-2, while alcohols gave 2-amino-2-deoxy-~-ribonolactone 5-phosphonates following participation by the phosphonate in ring opening at C-3. The amino-sugar components of the E-ring of calicheamicin and esperamycin A1 have been synthesized as the methyl a- or P-glycosides 23 and 24 from 2-deoxy-~-erythro-pentofuranosides 20, the key step being the opening of the 3,4-cyclic sulfate 21 at both C-3 and C-4 with azide to give a mixture of azido-sulfates which are converted into

0 0 I1 II

(Et0)2PCH2 CH2P(OEt)2 &:z SO2 iv-vi_ #p: 6steps- Po N3 NC02Bn

18 19 Reagents: i, 12, MeOH; ii, SOC12, EtsN; iii, RuC13, NaI04; iv, NaN3; v, H3O+; vi, TsCI, py

Scheme 5


the single aziridine 22 on reaction with lithium aluminium hydride (Scheme 6).13

OR OMe 20 R = H 22 23 R = Et 21 R,R=S02 24 R = Pr i, ii C

Reagents: i, SOC12, Et3N; ii, NaI04, RuC13; iii, LiN3; iv, LiAIH4; v, K2CO3, AQO; vi, MeOH, H+ Scheme 6

Solution phase methods were used to prepare hybrid structures such as 25 incorporating alternating amino acid (D- or L-) and sugar moieties, with the key building block being 26, which was available from a known galactose derivative by azide displacement of a 4-triflate group with inversion. Some showed anti-cancer activity. l4 Methyl 4-acetamido-4-deoxy-2,3,6-tri-O-methyl- a-D-galacto- and gluco-pyranoside (as well as the corresponding 4- O-acetyl derivatives) were prepared for studies on the impact of substituents on the rate of acetolysis at the glycosidic centre. The amino-functions were again introduced by sulfonate displacements reactions with azide. Attempted displacement of secondary triflates with amines, as an alternative approach to the compounds exemplified in Scheme 4 above, led to low or no yield of the desired products, elimination being the main competing pathway. Surprisingly,

OBn 25 26

OBn , 27 28

RN@oBn

OBn 29 R = Me, Bn, But 30

9: Amino-sugars 1 27

when potassium carbonate was introduced into the reaction mixture, carbamates such as 27 were obtained in addition to the elimination products. l6

Intramolecular sulfonate displacement reactions were utilized for the preparation of a variety of lactams such as the D-do-derivative 28 from an N- benzyl-D-gulonamide 4-mesylate derivative, the products being converted to lactim ethers and amidine ana10gues.l~ 4,6-Fused azetidines such as 29 were the major products on reaction of the corresponding D-glucopyranoside 4,6- ditosylate with primary amines in ethanol at 120 "C, whereas the 4,6-diamino- 4,6-dideoxy-~-taloside 30 was obtained on reaction of the corresponding D-

mannopyranoside 4,6-ditosylate with tert-butylamine. l8 The 1,4-epimino-derivative 32, obtained from the P-D-glucosylamine 4-mesylate 31 , was converted either into the 4-amino-4-deoxy-~-galactopyranose derivative 33 on hydrolysis, or the five-membered ring derivative 34 on acetolysis (Scheme 7). In the same way, a D-xylosylamine 4-mesylate gave an 4-amino-4-deoxy-~-arabinose derivatives. l9

iii

OAc OBz OBz OBr 33

CH20Bt 31 32

R =am2Et 34

C02Et

Reagents: i, NaOMe, HMPT; ii, CF3C02H, H20; iii, AeO, TmsOTf

Scheme 7

5-Amino-5-deoxy-~-ribo-, -arabino- and -xylonolactams were synthesized from unprotected D-pentonolactones in three steps and high yield as shown for the synthesis of D-ribo-isomer 35 (Scheme 8).20 Methyl 6-amino-2,3-di-0- benzyl-6-deoxy-a-~-gluco- and galacto-pyranosides (and the N-benzyl derivative of the former) were made through ring opening reactions of the corresponding 4,6-cyclic sulfates with azide or benzylamine as analogues of the amino-alcohol components of neomycin B. Their ability to bind to RNA was studied by NMR methods with phosphodiester and nucleoside base compounds as models.21 Various sugar-amino acid conjugates 36 were prepared by reaction of the corresponding 6-chloride or 6-tosylate with azide, succinimide

N3CH2 HOCH2 ko i,ii 4cx p0 HO OH HO OH

- - HO

35 Reagents: i, SOBr2, DMF; ii, LiN3, DMF; iii, HP, Pd/C

Scheme 8


or cyanide ions before further elaboration; several were then deprotected.22 The modest a-glucosidase inhibitor 37 (see Chapter 18) was N-alkylated with a 2-azidoethyl a-D-glucopyranoside 6-triflate derivative to give, after deprotection, the 2-deoxy-isomaltose analogue 38 of acarbose, but it was not an a-glucosidase inhibitor. 23

CH2X I

Me0 Q M e

The 2,5:3,4-dianhydro-talitol 6-tosylate 40 (R = Ts), prepared from the tritosylate 39 (R = Ts), reacted preferentially at C-6 with uracil and thymidine to give 41, but underwent eliminationhearrangement to 42 on reaction with adenine (Scheme 9). The epoxide ring of 40 (R = Bz) could be opened at C-4 to give 2,5-anhydro-4-deoxy-4-(nucleobase)-~-mannitols.~~

39 R=TsOrBz 40 R=TsorBz 41 B = uracil, thymine 42 B = adenine

Scheme 9

Reagents: i, HCI, MeOH; ii, K2C03, MeOH; iii, BH, KzC03, 18crown-6

2.4 By Amadori Reaction - 4,6-0-Benzylidene- 1 -deoxy- 1 -(2-hydroxyethylamino)-D-fructose was synthesized by reaction of 4,6-O-benzylidene-~-glucose with ethanolamine to form a P-glucopyranosylamine which underwent Amadori rearrangement in the presence of oxalic acid. It was converted into 4,6-unprotected 0-methyloxime and chromogenic hydrazone derivatives as standards in GLC and HPLC analyses. 1 -Deoxy- 1 -(2-hydroxyethylamino)-~- fructose could then be detected in a solution of glucose and a phosphatidyl- ethanolamine kept at physiological pH and temperature for 4 weeks, after phospholipase D treatment and deri~atization.~~

2.5 From Azido-sugars - Amphiphilic derivatives such as 6-deoxy-6-(n- octanoylamin0)-D-glucose and its methyl a-glycoside have been prepared by Staudinger reaction (Ph3P, n-C7H 15COCl) of the corresponding 6-azido-sugar

9: Amino-sugars 129

peracetates, followed by deacetylation.26 A new method of converting azides to tert-butoxycarbonyl-protected amines, applied to 6-azido-6-deoxy- 1,2:3,4- di-0-isopropylidene-D-galactopyranose, involved reaction with Et3SiH over Pd(OH)2/C in the presence of ( B u ' O ~ C ) ~ ~ . ~ ~ The synthesis of a 1,7-diamino- 1,2,6,7-tetradeoxy-2,6-iminoheptitol from a 6-azido-glucoside is covered in Chapter 18.

2.6 From Unsaturated Sugars - A new direct, stereoselective route to 2- trifluoroacetamido-sugars by addition to pyranoid or furanoid glycals involves reaction with the complex nitrido [N,N'-( 1,1,2,2-tetramethyl)ethylenebi~(sali- cylideneaminato)]manganese(V) and trifluoroacetic anhydride, followed by silica gel. It was applied to a wide range of ether and acetal protected glycals. The substituents at C-2 of the main products were truns to those at C-3; thus the galactosamine derivative 43 was obtained in a 15:l mixture with its C-2 epimer.28 Azido-selenation of a glycal features in the synthesis of C-linked amino-sugars (detailed in Chapter 3).29

NHCOCF~ 43

The 2-amino-2-deoxy-~-allopyranoside 45 was synthesized from a hex-3- enopyranoside by allylic rearrangement of the trichloroacetimidate 44, the resulting 3,4-double bond being cis-dihydroxylated by a new procedure using a ruthenium oxidant which works well at low temperatures (Scheme lO)?O A similar allylic rearrangement of an ally1 cyanate (from a hex-4-enopyranoside) to an isocyanate (Vol. 28, p.124; Vol. 30, p. 127) featured in syntheses of the 4- amino-4,6-dideoxy-~-mannose (perosamine) and vicenisamine derivatives 46 and 47.31

44 45

Ar = --@k

Scheme 10 Reagents: i, A; ii, NaI04, RuCl

The L-acosamine derivative 48 was synthesized in 12 steps from ethyl 2,3- dideoxy-a-~-erythro-hex-2-enopyranoside utilizing the previously detailed conjugate addition of N-benzylhydroxylamine to an a$-unsaturated lactone (Vol.


MeHN

OH NHAc 46 47 48

HO

MeHN QOMe

OMe

C02Me

49 50 51

30, p. 15 1, ref. 50) and subsequent intramolecular sulfonate displacement to invert at C-5.32 Reaction of 3,6-anhydo-2-deoxy-~-ara6ino-hexofuranose with 1,2-diaminobenzene gave the tricylcic 3-amino-sugar derivative 49, the reaction being presumed to proceed by P-elimination of the anhydro-bridged substituent followed by Michael-type addition of the diamine at C-3 and then glycosylamine formation. 33

2.7 From Aldosuloses - The 4-methylamino-sugar 50 was obtained in 95% yield by electrochemical reductive amination (MeNH2, CF3S03H, MeCN in cathode cell; LiCl, MeCN in anode cell) of the corresponding 4-keto compound. This approach was also applied to a 4-oxo-derivative of avermectin B1.34 For the synthesis of the sialic acid analogue 51, the free 4-OH in the 5,8:7,9-di-O-isopropylidene derivative of the methyl ester, methyl glycoside of KDN (a 3-deoxy-nonulosonic acid) was replaced with inversion by an NH2- group by an oxidation-oximation-reduction sequence.35

2.8 From Aminoacids - D-Fucosamine and its N-methyl derivative 54 (R = Me) were synthesized by addition of the L-threonine-derived aldehyde 52 to the lithium salt of the glycine and L-valine-derived dihydropyrazine 53 (Scheme 1 1). 36 The 4-amino-4,6-dideoxy-~-gulopyranoside 57 was synthesized

I

I

OH

v + EtorJ - --

Me OEt

54 52 53

Me Scheme 11

9: Amino-sugars 131

from L-threonine in nine steps, 30% yield, via the known intermediate 55 (Scheme 12). The D-epi-tolyposamine derivative 58 was similarly obtained by reduction of the trans-isomer of intermediate 56.37

HO OH 57

Reagents: i, Bu'2AIH; ii, MCQCCH~P(O)(OCH~CF~)~, K2CO3, 18crown-6; iii, HOAc; iv, Os04, NMNO; v, MeOH, H+

Scheme 12

Me

58

2.9 From Chiral Non-carbohydrates - Methyl a-L-daunosaminide 61 was synthesized by coupling an (5')-lactaldehyde derivative with 59, lactonization of the resulting adduct to 60, and introduction of the 3-amino-group by a Curtius reaction (Scheme 13). The C-5 epimer, methyl a-D-ristosamine, was obtained in the same way, starting from the corresponding (R)-lactaldehyde derivativea3* 6-Deoxygenation, then epoxidation, of the enantiomerically pure dihydropyran 62, available from a hetero-Diels-Alder reaction employing a chiral auxiliary, gave the D-ribo-epoxide 63 and its D-Zyxo-isomer in a 1:2 ratio, the former giving mainly the 3,4,6-trideoxy-3-dimethylamino-~-xyZo-hexoside 64 on reaction with dimethylamine (Scheme 14).39

dQMe CQH 59 60

?Tbdms

NH2 61

Reagents: i, LiHMDS; ii, Me*CHO; iii, H+; iv, LiOH, H2Q; v, EbN, Ph3P(O)N3, BubH; vi, Bu~NF; vii, Bu'2AIH; viii, MeOH, HCI

Scheme 13


CH20H

- i i i i boMe 3 2

- OMe

0 OH 62 03 64

Reagents: i, TsCI, Py; ii, LiAIH4; iii, MCPBA; iv, MeNH, H20 Scheme 14

2.10 From Achiral Non-carbohydrates - The 3-amino-3,6-dideoxy-~-taloside 67 was synthesized from ethyl sorbate 65 (Scheme 15), the chirality in aldehyde 66 arising from a Sharpless asymmetric cis-dihydroxylation reaction, and the amino-function being introduced by formation of a nitrone and subsequent dipolar cycloaddition with vinylene carbonate. Compound 67 was attached to a macrocycle to afford the antifungal agent fluvirucin B.40 Sharpless asymmetric dihydroxylation was also used to introduce chirality (a) in the synthesis of the L-daunosamine derivative 70, diol 69 being obtained from an alkene derived from acetylene 68 (Scheme 16),41 and (b) in the synthesis of the branched-chain amino-sugar glycoside 73, for the preparation of alkyne 71 from an alkenyne precursor. The subsequent conversion of 71 to the pyranoid glycal 72 was effected by tungsten- or molybdenum-mediated cyclizations (Scheme 17).42 Full details (cJ Vol. 29, p.135, Scheme 22) of the syntheses of 6- deoxy-allo-nojirimycin (racemic and D-forms), 6-deoxy-talo-nojirimycin (racemic), and 2-acetamido-2,6-dideoxy-~~-allose using hetero-Diels-Alder chemistry have been published.43

C02Et /

NH2.HCI "

65 66 67 Reagents: i, MeSaNH2, AD-mix-a; ii, Me&(OMe)2, HOTS; iii, Bu$AIH; iv, 03;

v, P ~ ~ N H O H ; vi,oAo ; vii, HCI; viii, H2, Pd(OH)2; ix, HCI, MeOH

0 Y9

u Scheme 15

Me 68

HO

Me 69

Scheme 16

AcO QoMe

NHAc

70

9: Amino-sugars

H I

133

CH20H 71

i or ii ___)

NBn

0 72

- 0 i i i h N B n QOp'

0 73

Reagents: i, W(C0)5*THF, then Et3N; ii, (Et3N)Mo(CO),, Et3N iii, Pr'OH, Ph3P.HBr

Scheme 17

3 Properties and Reactions

3.1 Interconversions - Two groups have reported detailed studies on the synthesis of sialic acids from 2-acetamido-2-deoxy-~-glucose (GlcNAc), and these are covered in detail in Chapter 16. In both cases, GlcNAc was epimerized to ManNAc (either with base resin or Ca2+), N-deacetylated in strong acid, and re-N-acylated to the N-tert-butoxycarbonyl or N-glycolyl derivative, before chain extension using a sialic acid a l d ~ l a s e . ~ * ~ ~ Another group has reported similarly on the preparation of a variety of sialic acid derivatives, N-acylated with amino-acids, aromatic acids or biotin, by acylation of 2-amino-2-deoxy-~-mannose and condensation of the products with pyruvic acid using sialic acid aldolase.46

The carboxylate and phosphonate derivatives 74, made from lincomycin by hydrazinolysis, peracetylation, glycosidation [HOCH2C02Me or HOCH2PO(OBn)2, NIS, TfOH] and deprotection, were Clostridium sialidase inhibitors with Ki values in the mM range.47 The extent of regiocon- trol in the ring opening reactions of the racemic aziridines 75 and 76 with nucleophiles (Cl, OMe, N3, NEt2, SPh) under various conditions (alone, metal-assisted or acid catalysis) has been determined. Good stereoselectivity was attained with some combinations, attack occurring predominantly at C-2 or C-3 in each case.48 Oxidation of the alcohol 77, derived from Grignard reaction of a D-arabinopyranosylambe derivative, resulted pri- marily in the formation of lactam 78 following oxidative cleavage of the chain at C-6/C-7 and lactam formation (Scheme 18). Oxidation of related alcohols such as 79, derived from D-gluco- or DGmanno-pyranosylamhe

JOH

AcHN

74 R = C02Na or PO(ONa)2 75 76 R' = H or Me, R2 P Ts or -Me


derivatives, however, stopped at the keto-ester stage to give hemiaminals such as 80 (Scheme 19).49

+OH OBn

7CH20Bn 77 78

Scheme 18 Reagent: i, PCC, CH2C12

H2C-

CO2Bn B n H N d I

OBn

OH OBn

CH20Bn 79 80

Reagent: i, PCC, CH2C12 Scheme 19

3.2 N-Acyl and N-Carbamoyl Derivatives - Recent advances in the use of N- protecting groups, such as N-tetrachlorophthaloyl, N-4,5-dichlorophthaloyl, N-dithiasuccinoyl, N-pent-4-enoyl and N,N-diacetyl, and their advantages/ disadvantages in the synthesis of amino-sugar-containing oligosaccharides have been reviewed,50 while in another report the same authors have focused on the utility of the N-tetrachlorophthaloyl (TCP)

2-Deoxy-2-[ 3-( 1 -pyrenyl)propanamido]-glucose has been prepared as a fluorescent amphiphilic derivative of glucosamine, and its fluorescence properties were reported briefly.52 Compound 81, which adopts the hydrogen-bonded structure shown (as determined by IR and variable temperature NMR studies), was obtained following condensation of 3-amino- 1,6-anhydr0-2,4-di- O-benzyl- P-D-glucopyranose with the pyridine-2,6-dicarboxylic acid in the presence of DCC.53

0 OBn

81 82

One 'approach to the synthesis of N-glycolyl-neuraminic acid derivatives is covered in Section 3.1, but in an alternative approach, resulting in the derivative 82 used subsequently as a glycosyl donor, sialic acid was converted into its peracetylated anomeric methyl thioglycosides, O,N-deacetylated (MeS03H, MeOH), N-acylated [with N-(benzyloxacetoxy)succinimide] and 0- a~ety la ted .~~ Chitosan oligosaccharides (DP 3 and 4) and P-GlcNH2-( 1 + 4)- GlcNHAc were obtained by N-deacetylation of the corresponding chito-

9: Amino-sugars 135

oligosaccharide using the purified chitin deacetylase from Colletotrichum lindernu~hianurn.~~ A mild, one-pot method to convert an acetamido-group to a carbamate is exemplified in Scheme 2O?

NHCQBU'

NHAc Reagents: i , (BuaC)20, DMAP, THF; i i , NH2NH2 or LiOH, MeOH

Scheme 20

Reduction then attempted acylation of the 2-azido-sugar disaccharide P-glycoside 83 gave the cyclic amide 84 (Scheme 21). In contrast, the corresponding a-anomer was smoothly converted to the 2-acetamido-derivative and then into a biotinylated T-antigen by conjugation via the acid group in its aglycon to biotinaminocaproyl hydrazide and deprotection. 57 Circular dichroism and FTIR studies on peptides carrying an N-terminal 1 -deoxy-D- fructos-l-yl moiety, i.e. Amadori compounds (see Vol. 30, p. 125 for their synthesis), have been reported.58

- NHFmoc

i, ii

HN

N3 0 83 84

Reagents: i, NaBH4, NiCI2; ii, AQO Scheme 21

Attempted reductive cleavage of the 4,6-0-(2-methoxybenzyIidene) acetal in 85 led instead to mixtures of compounds 87 and 88 as well as the dimer 89, which can be explained as arising from a 2-isocyanate intermediate 86 (Scheme 22).59 Ureido-sugar derivatives such as 90 have been synthesized by reaction of peptides with the corresponding N-(4-nitrophenyloxycarbonylated) amino- sugar derivative, and characterized by solution and solid-state NMR techniques.60

3.3 N-Sulfonates and N-Sulfates - N-Arylsulfonyl-groups (e.g. PhS02) can be reductively cleaved from amino-sugars using samarium( 11) iodide, the method being compatible with p-methoxybenzyl acetals and N-acetyl but not O-acetyl groups.61 Full details (cf. Vol. 30, p.160, ref. 11) have been published on the use of a 2-N,3-O-cyclic sulfated derivative of allosamine for the introduction of thio, azido and acetoxy nucleophiles at C-3 with inversiona6*


0 1

Ar<Q 0 OBn -L[{d% N=C=O ]-$4L{4-- NH NHMe I

NHC02Bn CHO 86 87 88

Ar -4- OMe I iq7dh 85 R = Me, Bn or ally1

Reagent: i, LiAiH4, AIC13 89

Scheme 22

91 0 Y C02Et

90 Me

3.4 Imide, Isothiocyanate and Thiocarbonyl Derivatives - Unsymmetrical sugar carbodiimides such as 91 were obtained by aza-Wittig coupling between a glycosyl phosphimine and a sugar isothiocyanate, or between a glycosyl isothiocyanate and a sugar phosphimine (made in situ by reaction of Ph3P with an azido-sugar derivative). These could be further converted to urea or thiourea linked d i r n e r ~ . ~ ~ ? 64 N-Thioacetyl derivatives of amino-sugars and glycosylamines react with Hg(0Ac)z or AgOBz to give the corresponding N,N-diacetyl- or N-acetyl-N-benzoyl derivatives, respecti~ely.~~ The a-D-gluco-thiocarbonyl- azasugar 93 was obtained by DCC-induced condensation of the amine 92 with CS2, acid hydrolysis then treatment with a base resin (Scheme 23). Its ~- ido - isomer was prepared in the same way from the C-5 epimeric arnine?

CH20H I H2NNo

O k

i -

92 Reagents: i, CS2, DCC; ii, CF&@H, H20; iii, Resin (OH-)

Scheme 23

ii, iii

HO 8 OH

93

9: Amino-sugars 137

3.5 N-Alkyl Derivatives - N,N-Dialkylation of 2- and 6-amino- and 2,6- diamino-glucosides was achieved by N-benzylation, through borohydride reduction of an imine formed by condensation with benzaldehyde, then N- ethylation. This was surprisingly effected by treatment with excess of NaBH4 in acetic acid solution.67

3.6 Lipid A Analogues - A variety of Lipid A analogues based upon acylated 2-amino-2-deoxy-~-glucosides of N-acyl-L-homoserine, -L-serine or -L-threonine derivatives, as exemplified by compounds 94 and 95, have been prepared and their mitogenic activities studied in a mouse 69 Related glycopeptides such as 96, combining a Lipid A analogue with the Tn or sialyl-Tn antigen [a-D-GalNAc or a-~-NeuSAc-(2+6)-a-~-GalNAc, respectively], were made as potential cancer vaccines.70 Full details (cJ: Vol. 30, p. 205, ref. 27) on the synthesis and anti-inflammatory properties of Lipid A analogues, based on 3-amino-2,6-anhydro-3-deoxyheptonic acid and its 7-deoxy-7-fluoro-analogue as the core, have been published.71

CH20H

3.7 Other References to Amino-sugars - A mechanistic study on the oxidative degradation of 2-amino-2-deoxy-~-ghcose and -D-galactose to D-arabinonic and D-lyxonic acids, respectively, by Chloramine T and N-chlorotoluenesul- fonamide in alkaline solution has been reported.72 The 6-0-dansyl derivative of 2-acetamido-2-deoxy-~-glucose is covered in Chapter 7 , while the use of a 5- amino-5-deoxy-~-xyloside as a chiral auxiliary is covered in Chapter 20.

4 Diamino-sugars

The synthesis of 2,4-diamino-2,4,6-trideoxy-~-galactoside 97, a constituent sugar of the 0-specific lipopolysaccharide of Shigella sonnei, from a 2-deoxy-2- phthalimido-D-glucoside 4,6-ditosylate involved selective formation and reduc-


CH20Ac 97 98 X = O o r S

tion of a 6-iodide, then a i d e displacement at C-4 with inversion.6 The 5- acetamido-4-azido-derivatives 98, with either an 0- or an S-atom in the ring, were obtained from the corresponding 4-acetoxy-derivatives of the same configuration on reaction with NaN3 and catalytic Pd(PPh3)4, the reactions proceeding via mPd complexes.73 Synthesis of the D-purpurosamine donor 102 from acrolein dimer involved reduction and acetylation to the racemic 3,4- dideoxyglycal 99, iodo-amidation to racemic 100, rearrangement via a 1,2- aziridine intermediate to introduce the 2-amino function, and enantioselective lipase-catalysed hydrolysis of the &acetate to provide the g-D-glycoside 101 (Scheme 24). A 6-azido-group was then introduced by sulfonate displacement, and acetolysis then gave 102, which was used to glycosylate a cyclitolamine to give 103 under Lewis acid catalysis.74

- ii, iii OR

2

(*)-loo kHCOCF3 101 R=&OMe, X=OH 102 R=u,&OAC, X=N3

1 0 3 R 3 : f > , X = N 3 a-0 OMe

0 Reagents: i, I(symcollidine)pC104, CF3CONH2, MeCN; ii, EtsN, MeOH; iii, lipase, H20

Scheme 24

Rhenium complexes of 2’,3’-diamino-2’,3’-dideoxy-uracil are covered in Chapter 17, while syntheses of 1 -N-substituted 3-acetamido-l,3,5-trideoxy- 1 3 - imino-D-xylitols (by reduction of a 3,5-diacylamino-3,5-dideoxy-~-xylose) and of 1 -amino- 1,2,5-trideoxy-2,5-imino-~-mannitol (by reduction of a 5-azido- 1,5-dideoxy- 1 -N,N-dibenzyIamino-D-fructose) are covered in Chapter 18.

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9: Amino-sugars 139

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64

65


T. Kai, X.-L. Sun, H. Takayanagi and K. Furuhata, J. Carbohydr. Chem., 1997, 16, 521. V. Ojed, M. Ruiz and J.M. Quintela, Synlett, 1997, 83. A.M.P. Koskinen and L.A. Otsomaa, Tetrahedron, 1997,53,6473. M.P. Sibi, J. Lu and J. Edwards, J. Org. Chem., 1997,62,5864. T. Bauer, Tetrahedron, 1997,53,4763. Z. Xu, C.W. Johannes, A.F. Houri, D.S. La, D.A. Cogan, G.E. Hofilena and A.H. Hoveyda, J. Am. Chem. Soc., 1997,119,10302. P.A. Wade, S.G. D’Ambrosio, J.A. Rao, S. Shah-Patel, D.T. Cole, J.K. Murray and P.J. Carroll, J. Org. Chem., 1997,62, 3671. F.E. McDonald and H.Y.H. Zhu, Tetrahedron, 1997,53, 11061. A. Defoin, H. Sarazin and J. Streith, Tetrahedron, 1997,53, 13769. W.-Y. Wu, B. Jin, D.C.M. Kong and M. von Itzstein, Carbohydr. Res., 1997, 300, 171. A. Kuboki, H. Okazaki, T. Sugai and H. Ohta, Tetrahedron, 1997,53,2387. C.-C. Lin, C.-H. Lin and C.-H. Wong, Tetrahedron Lett., 1997,38,2649. A.M. Maione, E. Giordani, M. Costa and A. Spirito, Arch. Pharm. (Weinheim, Ger.), 1997,330, 17 (Chem. Abstr., 1997,126,277 674). P . Crotti, V. Di Bussolo, L. Favero and M. Pineschi, Tetrahedron, 1997,53, 1417. L. Cipolla, F. Nicotra and C. Pangrazio, Gazz. Chem. Ital., 1996,126, 663 (Chem. Abstr., 1997,126, 8 446). J. Debenham, R. Rodebaugh and B. Fraser-Reid, Liebigs Ann. Chem., 1997,791. J.S. Debenham, S.D. Debenham and B. Fraser-Reid, Bioorg. Med Chem., 1996, 4, 1909 (Chem. Abstr., 1997,126, 171 805). M.C. Carre, T.R.E. Sousa, F. Baros, M.L. Viriot and J.C. Andre, J. Fluoresc., 1997,7, 83s (Chem. Abstr., 1997, 127,95 499). M. Lopez de la Paz, G. Ellis, S. Penades and C. Vicent, Tetrahedron Lett., 1997, 38, 1659. T. Sugato, Y. Kan, Y. Nagaregawa, T. Miyamoto and R. Higuchi, J. Carbohydr. Chem., 1997,16,917. K. Tokuyasu, H. Ono, M. Ohnishi-Kameyama, K. Hayashi and Y. Mori, Carbohydr. Res., 1997,303, 353. M.J. Burk and J.G. Allen, J. Org. Chem., 1997,62, 7054. S . Bay, 0. Berthier-Vergnes, V. Biberovic and D. Cantacuzene, Carbohydr. Res., 1997,303,25. S . Horvat, A. Jakas, E. Vass, J. Samu and M. Hollosi, J. Chem. Soc., Perkin Trans. 2, 1997, 1523. H.P. Wessel, I. Plessis, S. Cassol and W. Arnold, J. Carbohydr. Chem., 1997, 16, 789. A. Temeriusz, B. Piekarska-Bartoszewicz and I. Wawer, Carbohydr. Res., 1997, 304,335. D.C. Hill, L.A. Flugge and P.A. Petillo, J. Org. Chem., 1997,62,4864. B. Aguilera, A. Fernandez-Mayoralas and C. Jaramillo, Tetrahedron, 1997, 53, 5863. J.M. Garcia Fernandez, C. Ortiz Mellet, V.M. Diaz Perez, J. Fuentes, J. Kovacs and I. Pint&, Tetrahedron Lett., 1997,38,4161. J.M. Garcia Fernandez, C. Ortiz Mellet, V.M. Diaz Ptrez, J. Fuentes, J. Kovacs and I. Pinter, Carbohydr. Res., 1997,304,261. M. Avalos, R. Babiano, P. Cintas, C.J. Duran, F.J. Higes, J.L. JimCnez, I. Lopez and J.C. Palacios, Tetrahedron, 1997,53, 14463.

9: Amino-sugars 141

66

67

68 69

70

71

72

73 74

J.L. Jimenez-Blanco, V.M. Diaz Pkrez, C. Ortiz Mellet, J. Fuentes, J.M. Garcia Fernindez, J.C. Diaz Arribas and F.J. Canada, Chem. Commun., 1997,1969. J . Cai, B.E. Davison, C.R. Ganellin, S. Thaisrivongs and K.S. Wibley, Carbo- hydr. Res., 1997,300, 109. K. Miyajima and K. Achiwa, Chem. Pharm. Bull., 199’7,45, 312. K. Miyajima, N. Gomi, K. Ikeda and K. Achiwa, Chem. Pharm. Bull., 1997,45, 1089. K. Miyajima, T. Nekado, K. Ikeda and K. Achiwa, Chem. Pharm. Bull., 1997, 45, 1544. M. Shiozaki, S. Kurakata, T. Tatsuta, H. Maeda and M. Nishijima, Tetrahedron, 1997,53, 1604 1. M.P. Raghavendra, D.S. Mahadevappa, K.M.L. Rai and K.S. Rangappa, J. Carbohydr. Chem., 1997,16, 343. G.B. Kok and M. von Itzstein, Curbohydr. Res., 1997,302,237. S . Erbeck and H. Prinzbach, Tetrahedron Lett., 1997,38,2653.

10 Miscellaneous Nitrogen-containing Derivatives

1 Glycosylamines and Related Glycosyl-N-bonded Compounds

1.1 Glycosylamines - The 3,6-anhydro-2-deoxy-hexosylamine derivative 1 was obtained by direct condensation of the corresponding free sugar with 2- aminopyridine in methanol. Analogous reaction with 1,2-diaminobenzene led to a cyclized rearrangement product (see Chapter 9, Section 2.6).' The kinetics and mechanism for the acid-catalysed mutarotation of N-(4-chlorophenyl)- P-D-glucopyranosylamine in methanolic benzoate buffer solution have been reported.* Tijpanazole F1 (2) has been synthesized by direct condensation of D-xylose with a precursor with a tetrahydro-C-ring followed by dehydrogena- tion (with DDQ); no glycosylation occurred on the indole nitrogen atom.3

Lewis acid-catalysed glycosylation was used in the synthesis of three ergot alkaloid N-(2-deoxy-~-erythro-pentofuranosyl)-der~vat~ves.~ The new anticancer agents NB-506 (3), which has topoisomerase inhibitory properties from its indolocarbazole moiety and enhanced aqueous solubility due to its sugar moiety, has been synthesized by reaction of benzyl protected aglycon and glycosyl chloride moieties in the presence of KOH in MeCN.5 A range of related unsymmetric indolocarbazole N-glycosides were synthesized by application of the Mitsunobu reaction to benzylated sugar derivatives with a free 1 -hydroxy group.6 N-P-D-G~uco- and galacto-pyranosylated condensed pyridine-2( 1 H)-thiones were synthesized using a glycosyl bromide and KOH, or by reaction of a silylated base derivative with a glycosyl a ~ e t a t e . ~ The aglycon moieties in various 2-glycosylamino-4,5-di(methoxycarbonyl)pyridines have been modified to yield 5-glycosylaminopyrrolo[3,4-d]pyridin- 1,3(2H)- diones and 7-glycosylaminopyrido[ 3,4-dJpyridazin- 1,4(2H,3H)-diones.*

The synthesis of 1 -C-difluoromethyl- 1,4-dideoxy- 1,4-iminopentitols from pentofuranosylamine derivatives is covered in Chapter 18.

1.2 Glycosylamides including N-Glycopeptides - N-Retinoyl p-D-glucopyranosyl- and glucuronosyl-amines were prepared by acylation of the corresponding glycosylamines with a retinoid acyl chloride and tested as antitumour agent^.^ (2S)-2-Hydroxy-3-phenyl-N-(~-~-glucopyranosyl)propanoamide was prepared, by DCC coupling of the corresponding acid and glycosylamine moieties, as a simple mimic of the C-7-C-10 fragment of the antitumour sponge metabolites, the mycalamides. lo Glycosyl azides have been converted


142

10: Miscellaneous Nitrogen-containing Derivatives 143

into glycosylamides, e.g. N-heptanoyl-P-D-glucopyranosylamine, potential non-ionic surfactants, using the Staudinger reaction (Ph3P and an acyl chloride in CH2C12, then H20). A range of N-chloroacetyl-glycosylamines were synthesized by reaction of the corresponding glycosylamines with chloroacetic anhydride in DMF. l2 Galactosylated-cyclodextrins were created by amide linking the amino-groups of mono- or hepta-(6-aminodeoxy)-~-cyclodextrin with the carboxylic acid moiety of N-(a)-carboxyalkanoy1)-P-D-galactopyrano- sylamine (made by reaction of tetra- 0-acetyl-P-D-galactopyranosyl isothiocyanate with a 3, 4, 5 , 6 or 8-carbon chain o-methoxycarbonylalkanoic acid and Et,N, and deprotection). Their abilities to bind to a galactose-specific lectin were determined.I3 ‘Bolaamphiphiles’ such a 4 have been synthesized by treating 0-acetylated glycosylamines with bis-acid chlorides; their singlk crystal X-ray structures were determined.I4-l6 The elaboration of the sugar chains of an oligosaccharide ~-(6-aminohexanoyl)glycosylamine is covered in Chapter 4.

N-Nonanoyl-, lauroyl-, and stearoyl-di-a-D-mannofuranosylamines (e.g. 5) were prepared as non-ionic surfactants by conversion of 2,3:5,6-di-O-isopropylidene-a-D-mannofuranosylamine into the 0-protected di-P-D-manno- furano-sylamine by heating in methanol under reflux. This was then condensed with the corresponding acid chloride, and the protecting groups were removed by acid-catalysed ethanolysis. l7 N-Acetyl-di-P-D-gluco- and P-L-rhamno- pyranosylamine were obtained by peracetylation then 0-deacetylation of the corresponding per- 0-acetyl-di- 0-D-glycosylamines. * *

‘Peptidodisaccharides’ such as 6 were synthesized by reduction of glycosyl azides and coupling the resulting glycosylamines with uronic acid deriva- t i v e ~ . ’ ~ The syntheses of positional isomers such as 7 of the Lipid A moiety GLA-60, a 2-N-,3-0-diacyl-2-amino-2-deoxy-~-glucose 4-phosphate, have been reported.20

The catalytic reaction mechanism of aspartylglucosaminidase, which converts N4-(2-acetam~do-2-deoxy-~-~-glucopyranosy~)asparag~ne into aspartic acid and the corresponding glycosylamine, has been studied by ab initio quantum mechanical and molecular dynamics calculations.21 Chemical and enzymatic methods were employed for the synthesis of glycosylpeptides containing this N4-(2-acetam~do-2-deoxy-~-~-glucopyranosyl)asparag~ne core and of C-glycosyl analogues (see Chapter 4), the products being evaluated as inhibitors of the above enzyme.22 A one-pot two-step synthesis of glutamic acid glycoconjugates, exemplified in Scheme 1 for lactose, involved direct condensation of an unprotected oligosaccharide with the amino acid derivative 8 in DMF with imidazole at 50°C to give the P-glycosylamine 9, which could be stabilized by intramolecular acylation on addition of a carboxylic acid group activator, leading to the pyroglutamate derivative The solid-phase synthesis of the carbohydrate-modified enkephalins 13 with 5 or 6 amino acid peptide moieties, one of which proved to be a potent a-selective 6-opiod receptor agonist, involved preparing the glucuronosyl azide 11 from D-gh- curonic acid (i, Ac20, 12; ii, TmsN3, SnC14), coupling this to a o-chlorotrityl- resin to give 12, reducing the azido-group, then using conventional solid-phase


NHCHO I

3

CH20H

H02C 8 R = H 9 R = f3-D-laCtOSyl

Scheme 1

0 10 R = f3-0-lactosyl

peptide coupling methods (Scheme 2).24 A review on the enzymatic synthesis of peptide conjugates has included a section on gly~opeptides.~~

1.3 N-Glycosyl-carbamate, -isothiocyanates, 4hioureas and Related Corn- pounds - 2,3,5,6-Tetra- 0-benzoyl- P-D-galactofuranosyl isothiocyanate has been prepared from the corresponding pentabenzoate via the glycosyl chloride or bromide. It reacts with alcohols to give thiourethanes, e.g. 14, with amines


OAc OH 11 X-OH

13 X = OH, NH2 or HO @- OH

Scheme 2

or amino acid esters to give thioureas e.g. 15. It was used in this way to resolve racemic 1 -amino-2-propanol by chromatographic separation of the derived thiourea derivative^.^^^^^ Per-0-acetyl-N-thioacetyl-P-giycosylamines are converted into the corresponding N,N-diacetyl-derivatives on reaction with mer- cury(I1) or silver(1) acetate. An N-propyl-N-thioacetyl analogue was similarly converted into an N-acetyl-N-propyl derivative.28 Syntheses of 5-substituted 2-pentosylamino- 1,3,4-0xadiazoles such as 16 have been r e p ~ r t e d . ~ ~ . ~ ~

N-N

16 OH OH

The 1 -epi-hydantocidin and thiohydantocidin analogues 18 and 19, respectively, were synthesized from the 1 -bromo-P-D-galactopyranosyl cyanide 17 (Scheme 3). Addition of cyanate and cyclization occurred with retention of configuration at the anomeric centre, while addition of thiocyanate and cyclization occurred with inversion.31 The D-gluco-analogue 22 was synthesized from the 2-azido-heptonolactone 20 or its C-2 epimer, by way of the bicyclic derivative 21 formed from an 2-imine intermediate (Scheme 4), and shown to be a potent inhibitor of glycogen phosphorylase (Ki 3 P M ) . ~ ~ An alternative route starting with the 2-azido-heptonolactone 23, and relying upon oxidative cyclization of 24 led to a mixture of anomers 25, in a 2:l ratio favouring the inactive a-anomer (Scheme 5).33

2 Azido-sugars

The combination of 2,4,4,6-tetrabromo-2,5-cyclohexadienone, Ph3P and Zn(N3),.2Py in acetonitrile-toluene is effective for converting primary and


i, iv, iii

CH20H

NH

OAc OH OH 0 17 18 19

Reagents: i, Ti&, H20, HOAc; ii, AgOCN, MeN02; iii, NaOMe, MeOH; iv, KSCN

Scheme 3

HOH2C H

0- nil B n O h 0 0-- & OH

NH HO

HO N3 HO NHC02Me OH 0 20 21 22

Scheme 4 Reagents: i, Ha, Pd then Et3N, CIC02Me; ii, AcOH, H20 iii, NBS, AcONa

Po 0 H

VNFO

i-iii - iv & NH

OH HO

OH OH 0

CH~OH

Scheme 5

23 24 25 Reagents: i, H2, W/C; ii, KOCN, AcOH; iii, AcOH, H20; iv, Br2, AcONa

secondary alcohols into azides. In this way, 2,3,4,6-tetra-0-benzyl-~-glucose was quantitatively converted into the p-glucosyl azide, and the unsaturated sugar 26 gave the azide 27 with inversion in 72% yield.34 The ability of the Ph3P-CBr4-NaN3 reagent system to effect azidation of primary alcohol groups in mono-, di- and oligo-saccharides (cyclodextrins) has been investigated. For optimal yields, the reactive species [(Ph3P-CBr3)+ N3-] must be preformed using a large excess of NaN3. The reaction was found to be sensitive to substrate structure. Uridine gave 92% of the 5’-azide, whereas M-benzoyl- guanosine gave no product. The primary hydroxy group on glucose was more reactive than those on fructofuranose, so that 6-azido-6-deoxysucrose could be obtained directly in 45% yield.35

Reaction of per-0-benzyl-sucrose with TmsN3 - BF,.OEt, gave the anomeric tetra-0-benzyl-D-fructofuranosyl azides along with 2,3,4,6-tetra-O-benzyl- ~ - g l u c o s e . ~ ~ Similar reaction of the unsaturated ulosonic acid derivatives such

10: Miscellaneous Nitrogen-con ta ining Derivatives 147

as 28 gave mixtures of C-3 epimeric azides such as 29.37 The proportions of isomeric 2-deoxy-2-iodo-glycosyl azides formed on reaction of tr i-0-benzyb glucal with ICl-NaN3 were determined by NMR spectro~copy.~~

X 26 X=OH. Y = H 28 X = OAC, Y = H 30 27 X=H, Y=N3 29 X,Y = N3, H

The a-azido-aldehyde 30 was obtained from the corresponding 5-keto- derivative by reaction with dichloromethyllithium followed by azide ion, the reaction proceeding by way of a spiro-epoxide intermediate.39 3-Azido-2,3- dideoxy-D-threo-pentose derivative 32 (Scheme 6) was synthesized from the tosylate 31, derived in several steps from 2,3-O-cyclohexylidene-~-glyceralde- h~de.~O 5-Azido-5-deoxy-~-gulurono-6,3-lactone was obtained from D-mannurono-6,3-lactone by reaction of the 1,2-O-isopropylidene-5-triflyl derivative with NaN3.41

OTs 31 32

Reagents: i, 0 3 then Ph3P; ii, NaN3, DMF Scheme 6

Reaction of the 1-azido-1-cyano-galactoside 33 with Ph3P gave the phospha- zide 35 (which crystallized from the reaction mixture in ether) rather than the expected phosphinimine (Scheme 7). In toluene, 35 gave mainly the ring- opened elimination products 36 and 37. In contrast the corresponding carbox- arnide 34 gave the expected phosphinimine as a mixture of relatively unreactive a n o m e r ~ . ~ ~

R’ CH20Ac

Ac0QN3 OAc 1 X - N kNrN*“” ___t ii R 2 p z P h 3

I.1. CH20Ac OAc

33 X-CN 35 36 R’ = H, R2 = CN 34 X=CONH2 37 R’ = OAC, R2 = H

Reagents: i, Ph3P, Et20; ii, PhMe Scheme 7


3 Nitro-sugars

@Protected 2-amino-2-deoxy-sugar derivatives have been converted into the corresponding 2-nitro-sugars, e.g. 38, on treatment with m-chloroperbenzoic acid, and some reactions of these nitro-sugar products were studied.43 The potential rubranitrose precursor 39 was synthesized from the known C-4 epimeric branched-chain 3-aminosugar, by treatment with dimethydioxirane (3-NH2--+3-N02) and inversion at C-4 by triflate displacement with CsOAc in the presence of a crown ether. An alternative approach to effect epimerization of the 3-nitrosugar intermediate at C-4 with NaOMe in MeOH led to a mixture from which 40 could be isolated in a 42% yield, along with 22% of its C-4 epimer, both of which have undergone epimerization at C-3.44 Methyl 5- O-benzoyl-2,3-dideoxy-3-nitro-a- and P-D-erythro-pentofuranosides were synthesized in several steps from 5-0-benzoyl-3-deoxy- 1,2-O-isopropylidene-3- nitro-~ribofuranose.~~

h e No2 38 39 40

4 Carbodiimides

The 1,3-dicellobiosylcarbodiimide 42 was obtained by reaction of hepta-acetyl- P-cellobiosyl azide 41 with Ph3P and CO2 (Scheme 8), and converted into the urea or guanidine derivatives 43 and 44, re~pectively.~~ Unsymmetrical carbodiimides such as 45 were obtained by condensation either of a 6-deoxy-6- isothiocyanato-sugar derivative with a phosphinimine derived from a glycosyl azide, or of a glycosyl isothiocyanate with a phosphinimine derived from a 6- azido-6-deoxy-sugar derivative. These could be converted to the corresponding urea and thiourea derivative^.^'.^*

iii

0

R-N3 - i R-N=L'- ii RHNJLHR

41 42 43 44 X = 0, CH2 or NMe where R = &cellobiosyl-Ac7

Reagents: i, Ph3P, CQ; ii, AcOH, H20; iii, HNnX, NH&I U

Scheme 8


OAc

5 Oximes, Hydroxylamines, Nitriles, Imines and Amidines

Oximes 46 were converted exclusively or largely into the corresponding glucuronide derivatives 47 on deoximation and reduction (Scheme 9). Reaction of 46 with sodium azide in ethanol heated under reflux gave the 3-azido sugar derivatives 48, smaller amounts of their C-3 epimers and, in the case of R = Et, the product 49 proposed to have arisen by Curtius rearrangement of an intermediate hexosiduronoyl a ~ i d e . ~ ~ Syntheses of the 4- and 5-oximino- derivatives of sialic acid from KDN have been described.50

H % +

N- OH OAc H - O H N-OH NHCO~BU' 47 48

46 R = E t o r A C02Me

Reagents: i, MeCHO, HCI; ii, NaBH4; iii, A g o , Py; iv, NaN3, EtOH Scheme 9

49

N-Benzyl-N-glycosyl-hydroxylamines such as 50 were prepared by reaction of the corresponding free sugar derivatives with BnNHOH and ZnC12.51-52 Addition of BnNHOH to the unsaturated lactone 51 gave the isoxazolidinone 52, which was further cyclized to 53 (Scheme 10) by a rearrangement that is proposed to involve intramolecular displacement of a triflate group from C-6, p-elimination then intramolecular addition to the resulting a, P-unsaturated lactone. 53


,CH2 ii BnN t o

- 0- OBn - ‘ 0 0

BnO OH BnO 53

CH20H 52

Scheme 10

51 .

Reagents: i, BnNHOH; ii, Tf20, lutidine

A review on the synthesis of optically active isoxazolidines by dipolar cycloaddition of nitrones to alkenes, and the use of the products in organic synthesis, covered a number of carbohydrate examples involving sugar nitrones or unsaturated sugars as reactant^.^^ The regioselectivity observed in addition reactions between nitrones and unsaturated sugars, e.g. Scheme 1 1, was shown to be consistent with predictions from frontier molecular orbital calculations. Additions involving two nitrones and seven unsaturated sugars were examined.55 Eight examples of the addition to alkenes of sugar keto- nitrones such as 55, obtained by reaction of the corresponding keto-sugar derivative (e.g. 54) with MeNHOH, which gave isoxazolidines such as 56 (obtained in 62% yield along with 11% of its C-4 epimer) (Scheme 12), have been reported and included an intramolecular example in which the alkene component was in an 0-ally1 protecting The synthesis of a 1,4- dideoxy-2-C-(~-glucos-2-yl)- 1,4-imino-~-threitol from the cycloadduct obtained from tri- 0-acetyl-D-glucal and a pyrroline N-oxide is detailed in Chapter 18.

0 I

Reagent: i, PhCH=N, Me Scheme 11

56 Et’

54 55 Reagents: i, MeNHOH, Py; ii, EtOCH=CHZ

Scheme 12


The nitrile 58 was obtained from cleavage of the C-1-C-2 bond of the 2-azido-2-deoxy-~-glucose derivative 57 (Scheme 1 3). Two similar examples were also reported.57

The oxyamidine glycosidase inhibitors 59 and 60 were synthesized from the corresponding O-acetylated lactams by conversion to the thiolactams (with Lawesson's reagent), reaction with (0-substituted)-hydroxylamine and deacetylation. Compound 60 had a Ki of 0.15 pM against jack bean a-rnannosida~e.~~

@ OH - A c O T OAc

AcO 02CH

57 58 N3 CH20Ac

Reagent: i, PhI(OAc)p, 12 Scheme 13

(-+/ox

HO

Y 59 X = CHzSMe, Y = OH, Z = H 60 X = Y = H . Z-OH

6 Hydrazones and Related Compounds

1 -Glycosyl-2-acetylhydrazines have been prepared by condensation of N-acetylhydrazine with aldoses (1 5 examples) and characterized by 'H-NMR spectrosc~py.~~ Acetylation of the phenylhydrazone of D-mannose (til), D-gahCtOSe, D-arabinose or L-rhamnose gave acetylated 1 -phenylazo-ald- 1 - enitols (e.g. 62) which on reduction afforded the corresponding 2-deoxyaldose phenylhydrazones (e.g. 63) (Scheme 14). Deacetylation and hydrolysis then provided the 2-deoxyaldose (e. g. 2-deoxy-~-arabino-hexose The peracetylated derivatives of N-p-D-gluco- (65), N-0-D-galacto-, and N-0-L-arabinopyranosyl-aminoguanidine have been prepared (cf. Vol. 29, p. 146) and cyclized by deacetylation to the corresponding 3-amino-N-glycosyl-5-methyl- lH-l,2,4-triazoles (e.g. 66) (Scheme 15).61 A one pot synthesis of heterocyclic compounds such as 67 involved condensation of free sugar such as D-glucose with a pyrazinehydrazone such as 68 and subsequent treatment of the resulting hydrazone with bromine in methanoL6* 1,3,4-Thiadiazole derivatives such as

NYNHPh r//

i

OH

OH

CHO

CH20H CH~OAC CH20Ac CH20H 61 62 63 64

Scheme 14 Reagents: i, AcpO, Py; ii, NaBH4, pH 8; iii, NaOMe, MeOH; iv, Resin(H+), H20


i " ' L N dNHAC N\ J.( AC-N, NHAc -

P-D-GIcP(Ac)~ IN Me P-D-Glcp

65 66 Reagent: i, NaOMe, MeOH

Scheme 15

Hof: NHNH2

OH CI CHpOH

67 68

69 (cf. Vol. 29, p. 160) have been obtained by condensation of aldoses with S-methyl- or benzyl-hydrazonecarbodithioates followed by oxidative cyclization (Brz, AcOH).~' Similar chemistry applied to a 6-aldehydo-sugar derivative provided 70?

y=(SBn

,YS OH

OH

OH

CH20H 69

7 Other Heterocycles

The hexosaminidase inhibitor 72, with a Ki of 160 pM against the enzyme from jack bean, was synthesized from D-glucosamine via the known 2-isothiocyanato-derivative 71 (Scheme 16).65 Benzylation of the known cyclic thiourea 73 gave the cyclic or acyclic imidazole derivatives 74 or 75 in the presence or absence of base, respectively (Scheme 17).66 An improved synthesis of the unsaturated epoxide 77 from the D-glucosamine derivative 76 is shown in Scheme 18.67

CH20Ac CH20H

rlcs 71 72 NMe2

Reagents: i, Me2NH, H20; ii, Et3SiOTf; iii, NaOMe, MeOH Scheme 16

10: Miscellaneous Nit r ogen-con ta in ing Derivatives 153

SBn i l

A r N 4

___t

!$/Ar' SBn H T OH OH

74 CH20H 75

Ar = a x , - X = CI or Br

Reagents: i, BnCI, NaHC03, EtOH; ii, BnCI, EtOH Scheme 17

p h < o G O H

NHBz 76

i, ii ~ s 0 4 iii-iv ___c

/ FPh Reagents: i, NaBH4; ii, MsCI, EtsN, Py; iii, NBS, AIBN, CaCO,; iv, NaI, Na2S203, CaC03;

v, K2CO3, MeOH Scheme 18

The fused imidazoles 79 and 80 and the triazole 81 were synthesized from the known thionolactam 78 as shown in Scheme 19, compound 79 being a good inhibitor of two P-glucosidases.68 The D-gluco-fused triazole carboxylic acid 84 was synthesized from D-gluconolactone, the key step being the intramolecular cyclization of the unsaturated azide 83 produced by Wittig chain extension of the 5-azido-hexose 82, followed by oxidation then deprotection of the initial cyclization product (Scheme 20). The D-galacto-analogue was similarly prepared from D-galactonolactone. Neither showed significant glycosidase inhibitory proper tie^.^^ In the synthesis of the racemic 3-fluoro-analogue 85 of 1 -azafagomine (Scheme 2 I), deprotection with hydrazine surprisingly resulted in partial displacement of the fluorine to give hydrazino-derivative 86. Compound 85 was a weaker glycosidase inhibitor than 1 -azafagomine, im- plicating the 3-OH group in binding to the enzyme.70

iv, ii, i i i

\ CH20H

OH

HO

OBn X OH

80 X=H, Y=OH 78 79 X=OH, Y = H 81

Reagents: i, H2NCH2CH(OMe)2, Hg(OAc)2; ii, TsOH, PhMe, H20; iii, H2, Pd(OH)2, AcOH; iv, H2NNCH0, H~(OAC)~

Scheme 19


N3+4-0H - OR

82 R-Tbdms OR J b H

83 84

Reagents: i, Ph3P=CHC02Me; ii, Br2; iii, CF&QH, H20; iv, NaOH, H20 then Resin(H+)

Scheme 20

0

(+)a X = F (&)a6 X = NHNH2

Reagents: i, HF, Py; ii, AqO; iii, NaOMe; iv, NH2NH2

Scheme 21

Periodate oxidation of the P-D-glUCOpyranOSyl units of octyl P-D-G~c~ or octyl P-lactosaminide, followed by reductive amination of the resulting dialdehydes with amines or amino acids, provided a range of morpholine-like derivatives such as 87.71 Syntheses of nucleobase-substituted anhydroalditols are covered in Chapters 9 and 18. Reactions of P-lactams obtained by cycloadditions of trichloroacetyl isocyanate to glycals are covered in Chapter 24.

CH20H I

A 87 R = Bn, OH, CH20H, CH2CH2NH2 or RN = Asp, Phe, Tyr

References

1 2

3 4

5

J.A. Serrano, M. Jimenez and E. Rorniin, J. Curbohydr. Chem., 1997, 16, 1051. K. Smiataczowa, K. Maj and R. Korewa, Pol. J. Chem., 1997, 71, 831 (Chem. Abstr., 1997, 127, 95 491). E.J. Gilbert, J.W. Ziller and D.L. Van Vranken, Tetrahedron, 1997,53, 16553. V. Kren, P. Olsovsky, V. Havlicek, P. Sedrnera, M. Witvrouw and E. De Clercq, Tetrahedron, 1997,53,4503. M. Ohkubo, H. Kawamoto, T. Ohno, M. Nakano and H. Morishirna, Tetra- hedron, 1997,53,585.


6

7 8

9

10

11 12

13

14 15 16 17

18

19 20

21 22

23

24

25 26

27 28

29

30

31 32

33

34

M. Ohkubo, T. Nishimura, H. Jona, T. Honma, S. Ito and H. Morishima, Tetrahedron, 1997,57, 5937. A. M. Attia, G. H. Elgemeie and L.A. Shadhada, Tetrahedron, 1997,53, r7441. J. Cobo, A. Sanchez, M. Nogueras and E. De Clercq, Tetrahedron, 1997, 53, 8225. V. Balakrishnan, N.E. Gilbert, R. W. Brueggemeier and R. W. Curley, Jr., Bioorg. Med. Chem. Lett., 1997,7, 3033. A.D. Abell, J.W. Blunt, G.J. Foulds and M.H.G. Munro, J. Chem. SOC., Perkin Trans. I , 1997, 1647. V. Maunier, P. Boullanger and D. Lafont, J. Carbohydr. Chem., 1997,16, 23 1. L.M. Likhosherstov, O.S. Novikova, V.N. Shibaev and N.K. Kochetkov, Izv. Akad. Nauk. Ser. Khim. 1996, 1848 (Chem. Abstr., 1997,126,8 434). R. Kassab, C. Fklix, H. Parrot-Lopez and R. Bonaly, Tetrahedron Lett., 1997,38, 7555. T. Shimizu and M. Masuda, J. Am. Chem. Soc., 1997,119,2812. T. Shimizu, M. Masuda and M. Shibakami, Chem. Lett., 1997,267. M. Masuda and T. Shimizu, Carbohydr. Res., 1997,302, 139. D.F. Ewing, J.W. Goodby, S. Guenais, P. Letellier, G. Mackenzie, I. Piastrelli and D. Plusquellec, J. Chem. Soc., Perkin Trans. I , 1997,3459. K. Linek, J. Alfoldi, T. Stach and V. Patopristy, Chem. Pap., 1996, 50, 359 (Chem. Abstr., 1997,126,251 325). S . Sabesan, Tetrahedron Lett., 1997,38,3127. M. Shiozaki, M. Arai, W.M. Macindoe, T. Mochizuki, T. Wakabayashi, S.4. Kurakata, T. Tatsuta, H. Maeda and M. Nishijima, Bull. Chem. SOC. Jpn., 1997, 70, 1149. M. Perakyla and P.A. Kollamn, J. Am. Chem. SOC., 1997,119, 1189. L.-X. Wane, M. Tang, T. Suzuki, K. Kitajima, Y. Inoue, S. Inoue, J.-Q. Fan and Y.C. Lee, J. Am. Chem. SOC., 1997,119, 11137. C. Quetard, N. Normand-Sdiqui, R. Mayer, G. Strecker, A X . Roche and M. Monsigny, Carbohydr. Lett., 1997,2,415. B. Drouillat, B. Kellam, G. Dekany, M.S. Starr and I. Toth, Bioorg. Med. Chem. Lett., 1997,7,2247. T. Keppes and H. Waldmann, Liebigs Ann. Chem. 1997,803. C. Marino, 0. Varela and R.M. de Lederkremer, Carbohydr. Res., 1997, 304, 257. C. Marino 0. Varella and R.M. de Lederkremer, Tetrahedron, 1997,53, 16009. M, Avalos, R. Babiano, P. Cintas, C.J. D u r h , F.J. Higes, J.L. JimCnez, I. Lopez and J.C. Palacios, Tetrahedron, 1997,53, 14463. M. Wojtowicz, E. Kopczynska, A. Jonczyk and E. Nastarowicz, Acta Pol. Pharm., 1996,53,457 (Chem. Abstr., 1997,126,238 609). M. Wojtowicz, Acta Pol. Pharm., 1996, 53, 467 (Chem. Abstr., 1997, 126, 251 344) E. Osz, E. Sos, L. Somsak, L. Szilagyi and Z. Dinya, Tetrahedron, 1997,57, 58 13. T.M. Kriille, C. de la Fuente, K.A. Watson, M. Gregoriou, L.N. Johnson, K.E. Tsitsanou, S.E. Zographos, N.G. Oikonomakos and G. W.J. Fleet, Synlett, 1997, 211. C. de la Fuente, T.M. Kriille, K.A. Watson, M. Gregoriou, L.N. Johnson, K.E. Tsitsanou, S.E. Zographos, N.G. Oikonomakos and G.W.J. Fleet, Synlett, 1997, 485. A. Saito, K. Saito, A. Tanaka and T. Oritani, Tetrahedron Lett., 1997,38, 3955.


35

36 37 38

39

40 41

42

43 44

45

46 47

48

49 50

51 52

53

54 55

56

57

58

59 60 61 62 63

64 65 66

J.L. Jimenez Blanco, J.M. Garcia Fernandez, A. Gadelle and J. Defaye, Carbohydr. Res., 1997,303, 367. L. Kisbeck and H. Kessler, Liebigs Ann. Chem., 1997, 169. G.B. Kok and M. von Itzstein, Synthesis, 1997, 769. G. Bellucci, C. Chiappe, F. D’Andrea and G.L. Moro, Tetrahedron, 1997, 53, 3417. S. Deloisy, T.T. Thang, A. Olesker and G. Lukacs, Bull. SOC. Chim. Fr., 1997, 133, 581 (Chem. Abstr., 1997,126,8442). A. Chattopadhyay, Tetrahedron: Asymm., 1997,8,2727. M.P. Watterson, A. Martin, T.M. Kriille, J.C. Estevez and G.W.J. Fleet, Tetrahedron: Asymm., 1997,8,4111. J. KovLcs, I. Pint&, M. Kajthr-Peredy and L. Somshk, Tetrahedron, 1997, 53, 15041. J.M. Vega-Perez, J.I. Candela and F. Iglesias-Guerra, J. Org. Chem., 1997,62,6608. H. Ye, L. Noecker, W.J. Boyko, R.M. Giuliano, G.P.A. Yap and A.L. Rheingold, J. Curbohydr. Chem., 1997, 16, 373. D.-Q. Shi, L.-H. Zhou, Y. Gao and G.-Y. Dai, Guodeng Xuexiao Huuxue Xuebuo, 1996,17, 1586 (Chem. Abstr., 1997,126, 104 314). P. Mtszaros, J. Kovacs and I. Pinttr, Carbohydr. Lett., 1997,2,355. J.M. Garcia Fernandez, C. Ortiz Mellet, V.M. Diaz Ptrez, J. Fuentes, J. KovLcs and I. Pinter, Tetrahedron Lett., 1997,38,4161. J.M. Garcia Fernandez, C. Ortiz Mellet, V.M. Diaz Perez, J. Fuentes, J. Kovhcs and I. Pinter, Carbohydr. Res., 1997,304,261. Z . Smiatacz, I. Chrzczanowicz and H. Myszka, Curbohydr. Res., 1997,298,341. T. Kai, X.-L. Sun, H. Takayanagi and K. Furuhuta, J. Curbohydr. Chem., 1997, 16, 521. F.L. Merchan, P. Merino and T. Tejero, Glycoconj. J., 1997,14,497. P. Merino, S. Franco, F.L. Merchan and T. Tejero, Synth. Commun., 1997, 27, 3529. D. Socha, J. Rabiczko, D. Koneru, Z. Urbanczyk-Lipkowska and M. Chmie- lewski, Curbohydr. Lett., 1997,2, 349. M. Frederickson, Tetrahedron, 1997,53,403. S. Baskaran, C. Baskaran, P.J. Nadkarni, G.K. Trivedi and J. Chandrasekhar, Tetrahedron, 1997,53,7057. S. Torrente, B. Noya, M.D. Paredes and R. Alonso, J. Org. Chem., 1997, 62, 67 10. R. HernLndez, E.I. Leon, P Moreno and E. Suarez, J. Org. Chem., 1997, 62, 8974. R. Hoos, A. Vasella, K. Rupitz and S.G. Withers, Carbohydr. Res., 1997, 298, 291. B. Bendiak, Curbohydr. Res., 1997,304,85. C. Jorgensen and C. Pedersen, Curbohydr. Res., 1997,299,307. Z. Gyorgydeak, W. Holzer and J. Thiem, Curbohydr. Res., 1997,302,229. J. Svete, L. Golic and B. Stanovnik, J. Heterocycl. Chem., 1997,34, 11 15. M.A.E. Shaban, M.F. Iskander and S.M. El-Badry, fharmuzie, 1997, 52, 350 (Chem. Abstr., 1997,127,50 929). M.A. Martins Alho and N.B. D’Accorso, J. Hetercycl. Chem., 1997,34, 1415. S , Knapp, B.A. Kirk, D. Vocadlo and S.G. Withers, Synlett, 1997,435. J. Fuentes, J.L. Molina, A. Caballero and M. Angeles Pradera, J. Carbohydr. Chem., 1997,16,93.


67 68 69

T. Murakami and T. Shimizu, Synth. Commun., 1997,27,4255. T. Granier, N. Panday and A. Vasella, Helv. Chim. Acta, 1997,80,979. T.M. Kriille, C. de la Fuente, L. Pickering, R.T. Aplin, K.E. Tsitsanou, S.E. Zographos, N.G. Oikonomakos, R.J. Nash, R.C. Griffith and G.W.J. Fleet, Tetrahedron: Asymm., 1997,8, 3807. I. Thomsen, B.V. Ernholt and M. Bols, Tetrahedron, 1997,53,9357. M. Du and 0. Hindsgaul, Synlett, 1997,395.

70 71

11 Thio-, Seleno- and Telluro-sugars

A review on recent developments in the chemistry of thiocarbonyl carbohydrate derivatives has been published.

The synthesis of a,m-dithioalditols is referred to in Chapter 18.

OR OAc 1 R=Ac, X-Br, Y=OAc 3 2 R=H, X=OMe, Y=Br

2 HO QMe

OH 4

Sugar bromides have been converted to sugar disulfides (e.g., 1-+3,2+4) by treatment with benzyltriethylammonium tetrathiomolybdate in acetonitrile.2 In connection with the development of new glycosyltransferase inhibitors, C-glycosidic sulfones, e.g. 6, have been obtained by radical addition of thioacetic acid to exocyclic methylene derivatives, e.g. 5, followed by de-S- acetylation, S-methylation and ~xidation.~

CH20Bn CH~OR’ CHpOH

BnO Q; R’O 0; HO @- OBn OR’ OH

5 X,Y = CH;! R’ = Ac, Bz, pMeBz 9 !? 7 X=H, Y=Br

II 0

6 X =CH2SMe, y H 8 X = SeR2 orTeR2 R2 = Me, Ph, Bn

New 1 -seleno-and 1 -telluro-P-D-ghcopyranosides 8 have been prepared by reaction of 1 -bromides 7 with sodium alkyl selenolates and tellurolates, respectively. The reagents were obtained in situ by sodium borohydride- reduction of the appropriate dialkyl- or diaryl-chal~ogenides.~ A facile transformation of benzylated methyl glycosides to the corresponding phenyl 1 -thioglycosides has been achieved by use of trimethylsilyl bromide and thiophenol


158

I I : Thio-, Seleno- and Telluro-sugars 159

in the presence of zinca5 A number of 2-chloroethyl 1 -thio-P-D-hexopyranosides, such as compound 9, have been synthesized from the corresponding 2,3,4,6-tetra-O-acetyl-l -thio-p-D-hexopyranoses by alkylation of the thiol group with BrCH2CH2Cl and subsequent deacetylation.6

CH20Ac CH20H

F F 10 X = H, Y = Br 11 12 ‘c, X-STr, Y = H

Reagents: i, Bu4NSTr; ii, PhHgOAc, Ac20, Py, H& iii, MeONa, MeOH Scheme 1

The thioglucosidase inhibitor 12 has been prepared from tri-O-acetyl-2- deoxy-2-fluoro- 1 -thio-P-D-glucopyranose (1 l), following the general procedure for the synthesis of glucosinolates (see Vol. 27, Chapter 11, ref. 20). The required l-thiosugar 11 was obtained in low yield, as shown in Scheme 1, after failure of bromide 10 to react with t h i ~ u r e a . ~ A 14C-labelled glucosinolate analogue has been prepared by the standard route for such compounds.8

Glycosylation of triethylammonium phosphoro-thioates, -selenoates and -dithioates with glycosyl halides gave new glycosyl donors, such as compounds 13.9 A study on the diastereoselective synthesis and hydrolysis of p-D- galactopyranosyl sulfoxides is referred to in Chapter 3.

OAc SPh NH 13 X = S , Y = O o r X = Y = S o r X = S e , Y = O 14

In an approach to the stereoselective synthesis of 2-deoxy-~-glycosides via 2- thio-sugar intermediates the influence of the substituents at C-6 and C-4 on the steric course of the addition of PhSCl and PhSeCl to D-glucal derivatives has been examined; it was found that electron-withdrawing groups at the 4- and 6-positions strongly favoured the formation of gluco-configured addition products. l o Amongst a group of closely related 2-thioglucosyl donors, the trichloro-acetimidate 14 with a bulky substituent at 0 -3 was the most effective and selective for the synthesis of 2-deoxy-P-~-glucosides. The preparation of 2’-deoxy-2’-phenylselenyl nucleosides from furanoid glycals is referred to in Chapter 20. The cycloaddition product 15 of 2,4-dioxopentane-3-thione and tri-O-benzyl-D-ghcal was converted to oxothiirane 16, which served as glycosyl donor in the stereoselective preparation of 2-deoxy-P-~-glycosides 17 (Scheme 2).’2


Reagents:

i

i,

17

15 X,Y = 0 16 X,Y = H, OAC

.iiC

IAH; ii, Ac20, Py; iii, ROH, MeOTf; iv, Raney Ni "i-

Scheme 2

Full details on the radical-induced 0,s-rearrangement of 3,4- and 5,6- cyclothionocarbonates have been published (see Vol. 21, Chapter 11, refs. 16, 17) in a paper which also includes the rearrangement of trans-disposed 2,3- thionocarbonates to cis-disposed 2- and/or 3-thiosugar derivatives, for example 18+ 19 + 20. l 3 A full report on the use of the cyclic sulfamidate 21 of allosamine for the introduction of sulfur nucleophiles at C-3 with inversion of configuration has appeared (see Vol. 30, Chapter 11, ref. 1 l).14 The synthesis of D-glucose derivatives with thiocarbamoyl and dithiocarbamoyl groups at 0-3 and/or 0-6 is covered in Chapter 7.

S 18

0 NH 'S' o//\\o

21

ph%T 7f0 0

F ' h x 0 b e

19 20

22 23

A de novo synthesis of 1 -deoxy-4-thio-~-ribofuranose (23) from methyl 2,5-dihydrothiophene-2-carboxylate has been developed. Key steps were the enzymic resolution of the acetylated reduction product 22 of the starting material and the subsequent cis-dihydroxylation without concomitant oxidation at sulfur. l5 2-Deoxy-~-ribose has been converted to the dimethyl ether 26 of 2-deoxy-4-thio-~-threo-pentofuranose in 5 steps via dibenzyl


dithioacetal derivative 24 and 1,4-dithiosugar derivative 25, as detailed in Scheme 3. The mechanism of the ring-closure step, which was low-yielding (31%), is briefly discussed.16

2-Deoxy-o-ribose - - OnSY SBn p; CH20Me 24

i __t

MeOH2C QR

OMe 25 R = S B n 26 R=OH

ii C Reagents: i, NaI, BaC03; ii, ( 02N

Scheme 3

Several analogues (compounds 28-30, 34-36) of the antithrombotic agent beciparcil(27) have been synthesized, using standard reactions. Di-O-acetyl-5- thio-D-xylal31 was the starting compound for making 4-cyanophenyl2-deoxy- 1,5-dithio-P-~-xylopyranoside (28)17 and the 2-azido-2-deoxy derivative 29, '* and the 4-azido-4-deoxy analogue 30 was obtained in a multi-step process from L-arabinose diethyl dithioacetal via 4-azido-5-benzoylthio-4-deoxy-~- xylose derivative 32.19 The thioglucose equivalent 34 of 27 was available from the known O-acetyl-protected 5-thio-P-~-glucopyranosyl trichloroacetimidate (33), and primary iodination of 34, followed by acetylation, reduction or elimination, respectively, and deacetylation furnished analogues 35 and 36.20 The X-ray analysis of the sulfoxide of beciparcil (27) is referred to in Chapter 23.

X qGcN Y

27 X=Y=OH 28 X = W , Y - H 29 X=OH, Y=N3 30 X=N3, Y =OH

AcO QYCCl3

NH

CHO co

31 32

34 R=CH20AC 35 R = M e 36 R5=CH2

33

1 62 Carbohydrate Chemistry

2-Benzamido-2-deoxy-4-thio-~-galactose 38 has been obtained from methyl 2-benzamido-2-deoxy-~-~-glucopyranoside derivative 37, as shown in Scheme 4. Following introduction of a sulfur substituent at C-4 via a triflate intermediate, Zemplen de-0-benzoylation and subsequent acid hydrolysis furnished the free sugar which was present in methanolic solution as an anomeric mixture of thiofuranoses 38.2

iii, iv

NHBz OH 37 38

Reagents: i, Tf20, Py; ii, KSAc; iii, MeONa, MeOH; iv, H+, H20 Scheme 4

The synthesis of 5-thio-~-fucopyranose (40) from dialdopentofuranose derivative 39 involved 1 -carbon chain-elongation by use of trimethylalumi- nium, followed by five conventional reaction steps, including introduction of the sulfur substituent at C-5 by displacement of a triflate with potassium thioacetate (Scheme 5).22 A similar standard substitution reaction was employed in the preparation of 3-azido-3-deoxy-S-thio-~-~-ribopyranose 42 from 5-0-tosylate 41 .23 1,5-Dithio-P-~-xylopyranose, as the tri-0-acetate 44, was obtained in a further standard synthesis involving treatment of bromide 43 with thiourea.24

CHO DOMe i-vi_ H O P O H

OTWms OH 39 40

Reagents: i, MeAI; ii, MsCI, Py; iii, KSAc; iv, LAH; v, AqO, AcOH, H2S04; vi, NaOMe, MeOH Scheme 5

OAc 43 X - H , Y=Br

N3 N3 OH

41 42 44 X-SH, Y - H

Cyclic sulfates of terminal 1,2-diols were opened with KSAc and KSeCN to give primary thio- and seleno-sugar 5-sulfates, respectively (e.g., 45-+46 or 47).25 In a synthesis of sulfoquinovose (49) from D-glucofuranose derivative 48, the sulfo group was introduced by displacement of the tosylate group at


C-6 with sodium sulfite. Oxidation with iodine, after acid hydrolysis, gave the diacid 50 quantitatively.26 Monitoring of the regioselective Mitsunobu thio- functionalization of pentofuranose derivatives by 31P NMR spectroscopy is covered in Chapter 2 1.

R 1 l R2bo O - b

45 R1 =o* R0* ’ O”/S‘O*

46 R’ = SAC, R2 = OS03Na 47 R’=SeCN, R2=OS03K

H O E

TsOCH2 1

0-

48

CH20Ac I

I

CH2SO3H 6Ac 50

-(=+ X,Y = H,Z

Z = H, OMe, F, CI, CCl3, NO2 51

CH2SOsH

HO @OH

OH \

49

-03s0 HO Q OH

52

The influence of the aglycon structure on the nucleophilicity of the sulfur atoms in aryl 5-thio-a- and P-D-ghcopyranoside derivatives has been examined by inspection of Hammett plots of the pseudo-first-order rate constants (kobs) for the oxidation of compounds 51 by MCPBA.27

A full report on the reactions of 3,4-O-protected 1,2:5,6-dianhydrohexitols with sodium sulfide, producing anhydrothioalditol derivatives with 5-, 6-, and 7-membered rings has been published (see Vol. 29, Chapter 11, ref. 21).28

Salacinol (52), a natural a-glucosidase inhibitor, is the active principle of a traditional Indian antidiabetic from Salacia r e t i ~ u l a t e . ~ ~

B n o v 2 T m s CH20Bn i-viii AcoQ CH20Ac HoQQ CH20H CH20H e

OAc - OAc --t--L--t 0 OH

O(CH&Tms

N3 NHAc NHAc NHAc 53 54

Reagents: i, H2, PdC; ii, Ac20, Py; iii, MepBBr, Pr$NEt, AcSH; iv, Swern; v, DIBAL; vi, PPh3, DEAD; vii, Na, NH3; viii, TFA, CH2C12

Scheme 6


The 2-acetamido-2-deoxy-5-thio-~-~-galactopyranos~de derivative 53, obtained as shown in Scheme 6, was deprotected and coupled to UDP to serve as donor in* the lactase-mediated synthesis of 5’-thio-disaccharide (54).30 In the synthesis of 4-thio-P-cellobioside derivative 55, the interglycosidic linkage was formed by reaction of tetra-0-acetyl- 1 -thio-P-D-glucopyranose with methyl 2,3,6-tri-0-benzyl-4-0-triflyl-P-~-galactopyranoside.~* The same 0-protected 1 -thio-sugar was used in the Michael addition to levoglucosenone to give, after reduction and acetolysis, the 3-deoxy-4-thio-~-cellobioside derivative 56.32 Procedures similar to that of ref. 31 have been employed in the synthesis of thio-linked analogues of Lewis x and sialyl Lewis x,33 and of the ganglioside GM3 e p i t ~ p e , ~ ~ and a series of sulfur-linked oligosaccharides have been prepared chemoenzymically, as inhibitors of 1,3- and 1,4-glu~anases.~~ Six easy reaction steps furnished the ganglioside GM 1 analogue containing a thioglycosidic bond to ceramide from the natural ganglio~ide.~~

r e CH20Bn I

OBn OH 55 56

CHflAc

R = Aco Qt OAc

References

1

2 3 4

5

6 7

8 9

10 11 12

F. Garcia, M. Jose and M.C. Ortiz, Sulfur Rep., 1996,19,61 (Chem. Abstr., 1997, 127,251 292). D. Bhar and S. Chandrasekaran, Carbohydr. Res., 1997,301,221. J. Gervay, T.M. Flaherty and D. Holmes, Tetrahedron, 1997,53,16355. R.V. Stick, D.M.G. Tilbrook and S.J. Williams, Aust. J. Chem., 1997, 50, 233. B. Prybysz, W. Szeia, G. Grynkiewicz and W. Priebe, Pol. J. Chem., 1996, 70, 1270 (Chem. Abstr., 1997,126,3 1 544). P.-J. Svanem, A.M. Bones and J.T. Rossiter, Phytochemistry, 1997,44, 1251. M. Cerny, T. Trnka and M. Budesinsky, Collect. Czech. Chem. Commun., 1996, 61,1489 (Chem. Abstr., 1997,126,118 130). S.Cottaz, P. Rollin and H. Driguez, Carbohydr. Res., 1997,298, 127. J. Borowiecka, Liebigs Ann. Chem., 1997,2147. W.R. Roush, D.P. Sebesta and C. Bennet, Tetrahedron, 1997,53,8825. W.R. Roush, D.P. Sebesta and R.A. James, Tetrahedron, 1997,53,8837. G. Capozzi, F. Mannocci, S . Menichhetti, C. Nativi and S. Paoletti, J. Chem. SOC., Chem. Commun., 1997,2291.


13

14

15 16 17 18 19 20 21

22 23 24 25

26 27

28

29

30

31 32

33 34 35

36

Y. Tsuda, S. Noguchi, K. Kanemitsu, Y. Sato, K. Kakimoto, Y. Iwakura and S. Hosoi, Chem. Phurm. Bull. 1997,45,971. B. Aguilera, A. Fernandez-Mayoralas and C. Jaramillo, Tetrahedron, 1997, 53, 5863. H.-J. Altenbach, D.J. Brauer and G.F. Merhof, Tetrahedron, 1997,53,6019. C. Birk, J. Voss and J. Wirsching, Curbohydr. Res., 1997,304,239. E. Bozo, S. Boros and J. Kuszmann, Curbohydr. Res., 1997,299,59. E. Bozo, S. Boros and J. Kuszmann, Curbohydr. Res., 1997,301,23. E. Bozo, S. Boros and J. Kuszmann, Curbohydr. Res., 1997,302, 149. E. Bozo, S. Boros and J. Kuszmann, Curbohydr. Res., 1997,304,271. J.G. Fernandez-Bolaiios, E. Zafra, S. Garcia, J. Fernandez-Bolaiios and J. Fuentes, Curbohydr. Res., 1997,305, 33. S . Takahashi and H. Kuzuhara, J. Chem. Soc., Perkin Trans. I , 1997,607. N.A. Al-Masoudi, Surfur Lett., 1995,19, 149 (Chem. Abstr., 1997,126, 118 118). V. Barberousse and L. Mignon, Synth. Commun., 1997,27,3789. F.-G. Calvo-Flores, P. Garcia-Mendoza, F. Hernandez-Mateo, J. Isac-Garcia and F. Santoyo-Gonzales, J. Org. Chem., 1997,62,394. A.B. Roy and M.J.E. Hewlins, Curbohydr. Res., 1997,302, 1 13. H. Yuasa, Y. Kamata and H. Hashimoto, Angew. Chem., Int. Ed Engl., 1997,36, 868. Y. Le Merrer, M. Fuzier, I. Dosbaa, M.-J. Foglietti and J.-C. Depezay, Tetrahedron, 1997,53, 1673 1. M. Yoshikawa, t. Murakami, H. Shimada, H. Matsuda, J. Yamahara, G. Tanabe and 0. Muraoka, Tetrahedron Lett., 1997,38,8367. 0. Tsurutu, G. Shinohara, H. Yuasa and H. Hashimoto, Bioorg. Med. Chem. Lett., 1997,7, 2523. V. Moreau, J.C. Norrild and H. Driguez, Curbohydr. Res., 1997,300,271. Z.J. Witczak, R. Chhabra, H. Chan and X.-Q. Xie, Curbohydr. Res., 1997, 301, 167. T. Eisele and R.R. Schmidt, Liebigs Ann. Chem., 1997, 1303. T. Eisele and R.R. Schmidt, Liebigs Ann. Chem., 1997,865. V. Moreau, J.-L. Viladot, E. Smain, A. Planas and H. Driguez, Bioorg. Med. Chem., 1996,4,1849. G. Schwarzmann, P. Hofmann and U. Piitz, Curbohydr. Res., 1997,304,43.

12 Deoxy-sugars

A review on deoxy-sugars and deoxy-sugar oligosaccharides included biological, biochemical and chemical aspects, such as synthesis and chemical as well as enzymic glycoside formation.

Acetylation of aldose phenylhydrazones gave acetylated 1 -phenylazoald- 1 - enitols (e.g., 1+2). On reduction with sodium borohydride these furnished 2- deoxyaldose phenylhydrazones and, after deacetylation and hydrolysis, 2- deoxyaldoses (e.g., 2 -+ 3 +4).2

CHO HYNNHPh CH2 I

1:: p: CH20H CH~OAC CH20Ac CH20H 1 2 3 4

BzOCH~

k= 5 6

Application of the Wacker reaction [Pd(II)-catalysed oxidation of terminal olefins to methyl ketones] to 1,2-dideoxy-hex- 1 -enitols with unsubstitued OH-5 gave 1 -deoxyketofuranoses (e.g., 5+6), the reduction of which to C-glycosides on exposure to Et3SiH is referred to in Chapter 3.3

The synthesis of C-3-modified 2-deoxy-~-ribose derivatives is covered in Chapter 2. L-Ribose, obtained from D-ribose via 1,2,3,4-tetra-O-acetyl-5-0- trityl-D-ribitol (see Chapter 2), has been converted to 2-deoxy-~-ribose (7) in six steps and 60% overall yield by use of Giese's method, as outlined in Scheme 1 .4

When 1-xanthates, such as glucose derivative 8, were heated in cyclohexane in the presence of lauroyl peroxide, clean conversion to 2-deoxy-sugars, in this case compound 9, took place indicating that, as in Giese's examples, radical migration from C-1 to C-2 had occurred and that the radical at C-2 was capable of abstracting hydrogen from a saturated hydrocarbon.


166

12: Deoxy-sugars 167

D-Ribose - - - Reagents: i, BusSnH, AIBN; ii, MeO-, MeOH

Scheme 1

Glycogen phosphorylase in the presence of Si02-bound maltopentaose as recyclable primer catalysed the addition of inorganic phosphate to glucal with formation of 2-deoxy-a-~-arabino-hexopyranosyl phosphate

CH20Ac CHO

S 10 11 I t

9 R = X = H , Y = A c 8 R = OAc, X = SCOCH~BU', Y = H

L-Fucopyranose has been synthesized from a-D-arabino-pentodialdo- 1,4- furanoside derivative 11 by reaction with methylmagnesium iodide, followed by depr~tection.~

The methyl pyranosides of some rare deoxy- and dideoxy-sugars have been obtained from either methyl a-D-manno- or methyl a-D-galactopyranoside via the selectively 1,2-diacetal-protected intermediates 12 and 13, respectively. Deoxygenations at the 6-positions were achieved by iodinatiodhydrogenation; for the subsequent removal of a secondary hydroxyl group the Barton- McCombie method was employed. An example is given in Scheme 2.*

Me

12 13

Me Me

iii-vi

Reagents: i, 12, PPh3, Irn; ii, H2, Pd/C; iii, BuLi, CS2; iv, MeI; v, Bu3SnH, AIBN; vi, aqu. TFA

Scheme 2


Further deoxygenation of sugars have been carried out by way of iodides ( 1 4 j 15,9 16+ 17'9, by photosensitized reductive removal of secondary benzoates (184 19l l) and by conventional (20+2112) or catalytic Barton-McCombie reduction (22-*2313) which uses Bu3SnH generated in situ using catalytic amounts of (Bu3Sn)zO and polymethylhydroxysiloxane as stoichiometric reductant. Routes to 6-deoxy-~-daunosamine from diacetoneglucose using reductive removal of bromine or thionocarbonate groups are covered in Chapter 9.

OAc

OAc 16 X I I, Y = CO2Bu' 17 X=CQBU', Y = H 19 X - H

18 X P O B Z 14 X = I 15 X = H

20 X = OCOPh II S

21 X - H

22 X=OCOPh II S

23 X = H

Enantiomerically pure 2-hydroxymethyl-2-methoxy-5,6-dihydro-2H-pyran (U), obtained in a hetero-Diels-Alder reaction with a chiral auxiliary, was first deoxygenated at the primary position via tosylate 25, then epoxidized to give a 2:l mixture of 26 and 27. Ring-opening with sodium hydroxide and sodium methoxide, respectively, gave only the arabino-product 28 from 26 and mainly the xylo-isomer 29 from 27 (Scheme 3).14

Attempts to prepare the precursor 30 of rubranitrose (31) from the known branched trideoxy-nitrosugar 32 by base-induced epimerization at C-4 via a retroaldol process failed, because epimerization occurred also at C-3, producing an isomeric mixture 34. Inversion of configuration at C-4 was later achieved by way of triflate 33. l5

The P,y-unsaturated a-ketoester 36, which was readily obtained by reaction of the per-0-acetyl-D-gluconic acid-derived Barton ester 35 with ethyl 2- trifluoroacetylacrylate (see D.H.R. Barton et al., Tetrahedron, 1996, 52, 271 7), has been converted by methoxymercuration to KDO derivative (37) and its gluco-isomer 38. l6 The preparation of 2-deoxy- and 2,3-dehydro-2-deoxy- KDN is covered in Chapter 16.

A new route to 6'-deoxy-P-~-glucopyranosyl disaccharides, such as 40, involved acid-catalysed opening of 1,6-epithio- and 1,6-episeleno-P-~-glucopyranose derivatives, such as 39, with NIS-triflic acid in the presence of a sugar

12: Deoxy-sugars I 69 6 - ii,iii +b OMe OMe OMe

- 0 iC 25 R = T s 26 27

24 R - H

J v 1 iv

Me Me

OH OH 28 29

Reagents: i, TsCI, Py; ii, LAH; iii, MCPBA; iv, NaOH, H20; v, NaOMe, MeOH

Scheme 3

No2 Me- No2 30 R'=OH, R 2 = H 34 31 R'=OMe, R 2 = H 32 R1 =H, R2rOH 33 R1=H, R2=OTf

ACO AcO AcO

OAc OAc OAc

OAc OAc

35 36 37 R1 =OMe, R 2 = H 38 R1 = H, R2 = OMe

CH20Ac CH20Ac CH20Ac

alcohol, followed by reduction of the disulfide- or diselenide-intermediates formed initially (Scheme 4). l 7

By use of trityl tetrakis(pentfluoropheny1)borate as catalyst, 3,4,6-tri-0- benzyl-2-deoxy-~-arabino-hexopyranose (41) has been glycosidated efficiently and with high a-stereoselectivity. An example is given in Scheme 5.'* The preparation of aryl C-2-deoxyglycosides is covered in Chapter 3, and studies on the stereoselective synthesis of 2-deoxy-P-glycosides by way of 2-thiosugar derivatives are referred to in Chapter 1 1 .

6-Deoxy-2-O-methyl- P-D-glucopyranosyl residues have been found in toxicariosides B and c , isolated from the latex of Antiaris toxicaria. l9 Toxicario-


OBz OBz OBz OAc X = S or Se

39 40

OAc Reagents: i, ROH, NIS, TfOH; ii, Bu3SnH, AIBN

Scheme 4

CH20Bn CH20Bn CH20Bn

&OH-

AcO OMe BnO BnO 41

OBz Reagent: i, TrB(CeF&, drierite, PhH, PhMe

Scheme 5

side A, a dart poison from the same latex, is referred to in Chapter 5 . A polyhydroxylated spirostanol saponin from the tubers of Brodiaea californica contained a 6-deoxy-P-~-gulopyranosyl residue, the first report of this sugar in a saponin.20

References

1

2 3

4 5 6 7 8

9

10 11 12 13 14

A. Kirschning, A.F.-W. Bechtold and J. Rohr, Top. Curr. Chem., 1997, 188, 1 (Chem. Abstr., 1997,127, 66 001). C. Jorgensen and C. Pedersen, Carbohydr. Res., 1997,299, 307. G.V.M. Scharma, A.S. Chandor, K. Krishnudu and P.R. Krishna, Tetrahedron Lett., 1997,38, 905 1. M.E. Jung and Y. Xu, Tetrahedron Lett., 1997,38,4199. B. Quicelet-Sire and S.Z. Zard, J. Am. Chem. SOC., 1996, 118,9190. B. Evers and J. Thiem, Bioorg. Med. Chem. Lett., 1997,5, 857. S . Takahashi and H. Kuzuhara, J. Chem. SOC., Perkin Trans. I , 1997,607. S.V. Ley, D.R. Owen and K.E. Wesson, J. Chem. Soc., Perkin Trans. I , 1997, 2805. J. Moravcova, J. Capkova, J. Stanek and I. Raich, J. Carbohydr. Chem., 1997, 16, 1061. J. Gervay and T.Q. Gregar, Tetrahedron Lett., 1997,38,5921. D.R. Prudhomme, 2. Wang and C.J. Rizzo, J. Org. Chem., 1997,62,825. H.P. Wessel and R. Minder, J. Carbohydr. Chem., 1997,16, 807. R.M. Lopez, D.S. Hays and G.C. Fu, J. Am. Chem. SOC., 1997,119,6949. T. Bauer, Tetrahedron, 1997,53,4763.

12: Deoxy-sugars 171

15

16 17

18 19

20

H. Ye, L Noecker, W.J. Bayko, R.M. Giuliano, G.P.A. Yap and A.L. Rheingold, J. Carbohydr. Chem., 1997,16, 373. Z. Pakulski and A. Zamojski, Tetrahedron, 1997,53,3723. R.V. Stick, D.M.G. Tilbrook and S.J. Williams, Tetrahedron Lett., 1997, 38, 274 1. K. Takeuchi, S, Higuchi and T. Mukayama, Chem. Lett., 1997,969. C.A. Carter, G.A. Gray, T.L. Schneider, C.M. Lovett, Jr., L. Scott, A.C. Messer and D.P. Richardson, Tetrahedron, 1997,53, 16959. Y . Mimaki, M. Kuroda, 0. Nakamura, Y. Sashida, T. Satou, K. Koike and T. Nikaido, Chem. &arm. Bull., 1997,45, 558.

13 Unsaturated Derivatives

.@* 1 General

A review covering the following reactions has appeared: the transition metal (mainly palladium)-catalysed Heck-type couplings of glycals with arenes to give 2,3-unsaturated aryl C-glycosides, Stille-type couplings of 1 -iodo- or 1 -tri- n-butylstannyl-glycals with aryl-zinc or -boron compounds to afford 1,2- unsaturated aryl C-glycosides and the additions of anions (e.g. malonate) to the n-ally1 complexes derived from 2,3-unsaturated pyranosides to produce 2,3-unsaturated C-glycosides. *

2 Pyranoid Derivatives

2.1 l,2-Unsaturated Cyclic Compounds and Related Derivatives - 4-C-Sub- stituted hex-2-enopyranosides underwent a reductive rearrangement reaction when treated with lithium aluminium hydride affording good yields of 3- deoxy-glycals (Scheme 1). Several other examples were described and the importance of the tertiary OH group was discussed.2

HO Reagent: i, LAH

Scheme 1

The reaction of 4,6- O-benzylidene-2,3-dideoxy-~-erythro-hexono- 1,s-lactone with strong base followed by quenching with diphenylphosphoryl chloride gave the cyclic ketene acetal phosphate 1. This latter compound readily underwent a Pd(0)-catalysed coupling with vinyltributylstannane to give the conjugated diene 2. A similar reaction sequence was also performed on 3,4,6- tri-O-benzyl-2-deoxy-~-arabino-hexono- 1,Slactone.

The glycal-carbene complexes 3 were produced by treating the corresponding 1 -1ithiated glycal derivative with metal (Cr, Mo, W) hexacarbonyl complexes followed by trimethyloxonium tetrafluoroborate. Compound 3


172

13: Unsaturated Derivatives 173

1

3 M = Cr, Mo, W; R = SiPr$ 4 R = SiPr'3

(M = Cr) underwent a benzannulation reaction with 3-hexyne affording a moderate yield of benzoglycal 4.4 (See Sections 2.2.2 and 4 for related work).

A significantly improved yield of 3,4-di- O-acetyl-~-fucal over previously reported methods has been obtained by treating per-acetylated L-fucopyranose with titanium tetrabromide followed by standard reductive elimination of the resulting glycosyl bromide with zinc.5 (See next Section also for the dimerization of this and other glycals).

A report that the formation of I -cyano-3,4,6-tri- O-acetyl-~-galactal proceeded by a free radical chain mechanism, when the corresponding peracetylated 1 -bromogalactopyranosyl cyanide was treated with zinc in the presence of a N-base, has appeared.6

The Pd(0)-promoted Heck-type cyclization of ethyl 4-0-(2-bromoprop-2- enyl)-6-0-Tbdms-2,3-dideoxy-a,~-~-erythro-hex-2-enopyranoside gave the branched-chain glycal 5. As well as ring closure, double bond migration occurred with ejection of the OEt group. In contrast, the corresponding D-thWO starting material gave an acyclic derivative (see Section 4) as a result of ejection at 0 - 5 instead of the aglycon. Other examples of these processes were also de~cribed.~ Standard 'one pot' methodology has been used to prepare tri- O-acetyl-~-[ 1,2,3,4,5,6-'3C6]glucal from ~-[U-*~C]glucose. The related, labelled D-[ 1 ,2,3,4,5,6-13C6]galactal derivative 6 was also prepared from the same starting material by a sequence of reactions in which the configuration at C-4 was inverted by use of a Mitsunobu process.*

The glycal derivative 7 was formed when alkyn-ol 8 was treated with a tungsten- or molybdenum-pentacarbonyl complex. (See also Vol. 30, p. 180, ref. 39 for related work).9

Full details of the mechanism of action of bacterial UDP-N-acetylglucosa-

CHzOTbdms I -

0 P 5

YH20Tbdps

o 7


mine-2-epimerase have been elucidated with the aid of kinetic isotope effect measurements. 2-Acetamidoglucal is an enzyme-bound intermediate in the process. (See preliminary report, Vol. 30, p. 174, ref. 13).1°

Alcohols and activated methylene compounds reacted with the branched glycal-carbonate derivative 9 in the presence of Pd(0) to yield 2-deoxy-2-C- methylene 0- and C-glycosides, respectively. For example, with p-cresol the aryl glycoside 10 was produced and with dimethyl malonate compound 11 was formed. Secondary hydroxyl groups in sugars also participated in the reaction. '

BnO Q BnO QR

CHzOC02Me CH2 9

10 R =*+Me - 11 R = CH(C02Me)2

15

Pyranoid (and also furanoid, see Section 3.1) glycals underwent a facile reaction with 'selectfluor' (12) in aqueous or alcoholic media to give 2-deoxy-2- fluoro-pyranoses or -pyranosides, respectively. For example, 3,4-di-O-acetyl-~- fucal on treatment with 12 in aqueous DMF gave 3,4-di-O-acetyl-2-deoxy-2- fluoro-L-fucopyranose, whereas the same glycal on treatment with 12 and anhydrous benzyl alcohol in acetonitrile afforded benzyl 3,4-di-U-acetyl-2- deoxy-2-fluoro- p- L-fucopyranoside,

It has previously been reported that addition of malonyl radicals [formed from dialkyl malonates using Mn(OAc)3 as oxidant] to hexopyranoid glycals in the presence of alcohols yielded 2-C-branched-chain-2-deoxypyranosides, but that an undesired Ferrier rearrangement suppressed the yields. Use of CAN as oxidant proved to be superior with no rearrangement observed (See Vol. 30, pt 189, ref. 19 and p. 177, ref. 26) Full details of this reaction have now been published and its scope extended to pyranoid pentoses. l 3

Pyranoid (and also furanoid, see Section 3.1) glycals underwent reaction with the manganese complex, nitrido[N,N'-( 1,1,2,2-tetramethyl)ethylenebis(sa- licylideneaminato)]manganese(V) and trifluoroacetic anhydride followed by treatment with silica gel or aqueous acid to afford 2-deoxy-2-trifluoroacetami- dopyranoses in high yield. Stereoselectivity was observed and resulted in the introduction of the N-function trans to the substituents at C-3.14

The C-glycoside 13, a potential thromboxane precursor, was conveniently


prepared by adding the (,??)-vinyl cuprate derived from 3-tert-butyldiphenyl- siloxy-oct- 1 -ene to 4,6-di-O-benzyl- 1,2-dideoxy-~-threo-hex- 1 -enopyranos-3- ulose. Studies have also shown that other anions (e.g. LiCX(SMe) where X = SMe or SiMe3) add in a similar 1,4-manner. In contrast, the 6-deoxy-5-epi- analogue of the enone, accepts anions giving rise to mixtures of 1,2- (to the C=O) and 1,4-prod~cts.'~

The synthesis of 2-deoxy-a-~-arabino-hexopyranosyl phosphate from D-glUCal and glycogen phosphorylase using a silica bound maltopentaose primer is covered in Chapter 12 and the synthesis of oligosaccharides composed of 2-deoxy- fl-~-glucose units from D-glucal and glycogen phosphorylase is mentioned in Chapter 3. The electrophilic addition of various halogen- containing reagents to tri-0-benzyl-D-glucal is noted in Chapter 8.

2.2 2,SUnsaturated Cyclic Compounds 2.2.1 Syntheses Involving Allylic Rearrangements of Glycals. - The racemic p-lactam compound 14 (one enantiomer depicted for clarity) has been resolved by iodine-promoted Ferrier reaction with 3,4-di-O-acetyl-~-rhamnal to give 15 (together with the corresponding separable diastereomer) followed by acid- catalysed hydrolysis.16

Tri-0-acetyh-glucal reacted with the chiral (a-crotylsilane 16 in the presence of boron trifluoride etherate to afford unsaturated derivative 17 with a d.e. > 30:l. Examples were also described using other silanes and also involving tri-O-acetyl-D-galactal.

~ H ~ O A C

Me

Me+COzMe

M&iP h AcO 0 16 17 18

Improved methods have been reported for preparing C-linked disaccharides by the Lewis-acid catalysed dimerization of tri- 0-acetyl-D-glucal, -D-galactal and 3,4-di-O-acetyl-~-fucal. For example tri-0-acetyl-D-glucal gave a 55% yield of the known 18. In addition, dihydroxylation of the double bond of 18 proceeded unexpectedly with high allo selectivity. (See Vol. 30, p. 176, ref. 21 for related work).5

2.2.2 Other Syntheses and Reactions. - Alkene metathesis reaction of D-threo- derivative 19 catalysed with Grubbs' reagent ( [ ( C ~ H ~ ~ ) ~ P ] ~ C ~ ~ R U = C H P ~ ) gave a 90% yield of 1,5-anhydro-4,6-di-O-benzoyl-2,3-dideoxy-~-threo-hex-2- enitol. *

The branched-chain a-~-erythro-hex-2-enopyranoside 20, conveniently pre-


pared by Claisen-Meerwein-Eschenmoser rearrangement of methyl 6-0- Tbdps-3,4-dideoxy-a-~-erythro-hex-3-enopyranoside with MeC(OMe)2NMe2 (see Vol. 24, p. 157, ref. 18), was selectively epoxidized to the G t - D - a b

derivative under Payne's conditions (perbenzimidic acid) as a useful intermediate in the preparation of thromboxane A2. The unexpected formation of this epoxide was explained through H-bond interaction of the C=NH group of the epoxidzing agent with the anomeric methoxy or 4-C-(N,N'-dimethylcar- boxamido)methyl substituent resulting in a favourable orientation for allo- epoxidation. The a-D-manno-epoxide expected under these conditions was not observed. In contrast the D-threo-derivative 21, prepared in a similar manner from methyl 6-0-Tbdps-3,4-dideoxy-a-~-t~re~-hex-3-enopyranoside, led via the presumed D-gulo-epoxide only to a low yield of D-galacto-lactone 22. l9

CH~OTWPS Bzof? CH20Bz R b CH20TWps FG R 3

- OMe - R2 OMe

OH 0 OMe R2

22 23 R' = CH(C02Et)2, R2 = H 24 R' = H, R2 = CH(C02Et)2

/ \ 19 20 R' = H, R2 = CH2C(0)NMe2

21 R' = CH2C(0)NMe2, R2 = H

25 26

It has been observed that reaction of sodio diethyl malonate with methyl 4- 0-benzoyl-2,3-dideoxy-~-~-gZycero-pent-2-enopyranoside or methyl 4-0- benzoyl-2,3-dideoxy-a-~-glycero-pent-2-enopyranoside in the presence of Pd(0) afford the substitution products 23 and 24, respectively, with overall retention of configuration. (See Section 2.3 for a different outcome when branching groups are present in the C-5 position).20 In a similar way Pd(0)- catalysed coupling of allylic carbonate 25 with 23: 5,6-di-O-isopropylidene-~- mannofuranose gave unsaturated disaccharide 26.21

The preparation of 4-amino-4,6-dideoxy-~-mannose (D-perosamine) and of vicenisamine (found in the antibiotic vicenistatin) involved in the key step allyl cyanate to allyl isocyanate rearrangements (the double migrating from a 3,4- to a 2,3-position). (See Vol. 30, p. 178, ref. 30 and Vol. 28, p. 178, ref. 32).22

The a, P-unsaturated glycosylidene complex 27 was prepared from 1 - C- lithio-3,4,6-tri-O-isopropylsilyl-~-gluca~ by treatment with a chromium pentacarbonyl complex containing triphenylphosphine ligands. Compound 27 underwent reaction with ethoxyethyne to give 28 in which the OEt group was easily displaced by ammonia. (See also Section 4 for the direct reaction of 27 with a m m ~ n i a ) . ~


OBn OBn TfO OBn 29 30 31 32

In previous reports it has been shown that certain carbohydrate triflates, depending on the configuration of the sugar, reacted with the strong bases methyl- or butyl-lithium to give unsaturated or ketonic products of which the latter reacted further. Although the formation of the unsaturated products appeared to have resulted from an overall p-elimination (E-2 elimination) process, deuterium labelling experiments indicated that a mechanism involving an initial a-hydrogen abstraction at the carbon bearing the OTf group took place first followed by a 1,2-H shift then loss of CF3S03Li. (See Vol. 30, p. 185, ref. 3 and p. 180, ref. 41). Full details and further examples addressing this mechanistically interesting reaction have now appeared. For example deutera tion studies have shown that met h y 1 2- U- benzyl-4,6- U- benzylidene- 3 - O-triflyl-a-D-glucopyranoside gave the products 29 and 30, by a mechanism involving an initial a-hydrogen abstraction. In contrast the ah-triflate 31 gave only 30, but involved a mixture of initial a- and coventional P-hydrogen loss processes.23 Further investigations by the same group have also demonstrated that when the milder base potassium tert-butoxide (KOBu') was used a similar pathway operated in the 3-O-triflyl-glucopyranoside series as seen with strong bases, affording the same products, as above, i.e. those arising by an initial a-hydrogen abstraction. With 3-O-triflyl-allopyranosides and KOBu', products formed by initial P-hydrogen loss predominated. The use of pyridine as base was also investigated but led only to 3-pyridinium derivatives. (See Section 3.2

Reactions at the carbonyl groups of 2,3-unsaturated enones, involving Horner-Wadsworth-Emmons olefination or addition of allyl- or aryl-lithiums resulting in unsaturated branch-chain sugars, is mentioned in Chapter 14. Also covered in Chapter 14 are the preparations of branched 3- C-derivatives from protected 2,3-dideoxy-3-U-triflyl-hex-2-enpyranoside derivatives and of tricyclic systems formed by cyclization of 4- 0-(2-propynyl)-2,3-unsaturated sugar derivatives. The preparation of cyclopentane-based compounds from 2,3-unsaturated-aldono- 1,4-1actones is noted in Chapter 18.

2.3 3,4-Unsaturated Cyclic Compounds - Reaction of sodio diethyl malonate with methyl 4-0-benzoyl-2,3,6-trideoxy-~-~-threo-hex-2-enopyranoside af-


forded a 1 5 mixture of the rearranged branched-chain sugar 32 and the product formed by nucleophilic displacement of the ester group with retention of configuration (see Section 2.2.2) as products. When the reaction was conducted on the substrate lacking the methoxy group, rearrangement became the major pathway.20

2.4 5,6-Unsaturated Cyclic Compounds - Full details have been reported on the simple preparation of the ketopyranoside glycal, methyl 5-deoxy-4-0- Tbdms- 1,3- 0-~sopropyl~dene-~-~-threo-hex-5-en-2-ulopyranos~de, used to make the synthetically useful vinylogous lactone 33. (See Vol. 28, p. 170, ref. 4 for preliminary details).25

3 Furanoid Derivatives

3.1 1,2-Unsaturated Cyclic Compounds - Two new methods for the synthesis of furanoid glycals have been reported. Various 0-protected (allyl, benzyl, benzoyl and pivaloyl) D - d O - , D-galacto-, ~-ribo- and D-xylo-pento- and hexofuranose 1,2 diols were treated with a mixture of triphenylphosphine, imidazole and iodine to give high yields of products. Alternatively, conversion of the 1,2-diols into their respective 1 ,Zthionocarbonates with thiophosgene followed by heating with 1,3-dimethy1-2-phenyl- 1,3,2-diazaphospholidine also gave good yields.26 Furanoid glycals, prepared by the first method, have been converted into 2-deoxy-2-iodo nucleoside derivatives (see Chapter 20).

Reaction of 1,4-anhydro-2-deoxy-3,5-di-O-benzyl-~-erythro-pnt- 1 -enit01 with ‘selectfluor’ (12) in aqueous media gave a high yield of 3,5-di-O-benzyl-2- deoxy-2-fluoro-~-arabino-pentofuranose. Furanoid glycals could be converted in a stereoselective way into 2-deoxy-2-trifluoroacetamido-derivatives by use of trifluoroacetic anhydride and a manganese complex followed by treatment with acid. (See Section 2.1 for the same reaction with pyranoid glycals). Overall, yields were higher with the more reactive furanoid glycals as compared with their pyranoid counterparts. l4

A large scale adaptation of a previously reported method (see Vol. 28, p. 170, ref. 1) for converting 0-protected-2-deoxy-thymidine derivatives into protected furanoid glycals by use of 1 , 1 , 1,3,3,3-hexarnethyldisilazane-ammonium sulfate has been described.27

3.2 2,3-, 3,4- and 5,6-Unsaturated Cyclic Compounds - In an attempt to react sodio acetophenone with the carbonyl group of 2,3,5-tri-O-benzyl-~-arabjno- pentono- 1,4-1actone, elimination product 34 unexpectedly formed (presumably through enolate formation followed by p-elimination). The formation of 2,5- di-O-benzyl-3-deoxy-~-glycero-pent-2-enono- 1,4-lactone was not observed. This unusual type of elimination has been observed before when 2,4,6-tri-0- benzyl-3 -deoxy-D-erythro- hex-2-enono- 1 , 5-lact one resulted after 2,3,4,6- tetra- 0-benzyl-D-glucono- 1 ,5-lactone was treated with sodio acetophenone. (See S.B. Rosenblum et al., J. Am. Chem. SOC., 1990, 112, 2746; Y. Tsuda et. al.,


Chem. Pharm Bull., 1980,28, 3223; and R.H. Hall et. al., J. Chern. SOC., Perkin Trans. I , 1977, 2236).2g

33 34 35 R’ = OTf, R2 = H 37 36 R’ = H, R2 = OTf

It has previously been reported that 3-O-triflyl-a-~-glucofuranose derivative 35 reacted with the strong bases methyl- or butyl-lithium affording the corresponding 3,4-elimination product 37. The formation of 37 appeared to have been formed by an overall p-elimination (E-2 elimination) process but it was shown by deuteration studies to involve an initial a-hydrogen abstraction at the carbon bearing the OTf group followed by a 1,2 hydride shift then loss of CF3S03Li. In contrast, reaction of the a-D-allose-derivative 36 with the same bases gave a 3-0XO product, again by initial abstraction of the a-hydrogen followed by loss of CF3S02Li. (See Vol. 30, p. 185, ref. 3 and p. 180, ref. 4). In an extension of these studies, and by the further use of deuterium labelled compounds, it has been shown that treatment of 35 or 36 with the milder base potassium tert-butoxide both gave 37 but by a process involving an initial P-hydrogen loss. The use of other bases such as pyridine or sodium methoxide with 35 gave a preponderance of 37 mainly by P-hydrogen abstraction, but reaction of 36 with pyridine gave only a 3-pyridinium de r i~a t ive .~~

A ‘one pot’ process for converting cyclic sulfates of furanoid 5,6-diols into 5,6-unsaturated sugars is illustrated in Scheme 2. Several other examples were described. 29

CH2SeCN

Scheme 2 Reagents: i, KSeCN; ii, NaBH4, MeOH

4 Acyclic Derivatives

The reaction of the a, P-unsaturated glycosylidene complex 27 with ammonia led to the amino carbene complex 38 in high yield.4


Ethyl 4- 0-(2-brornoprop-2-enyl)-6- O-Tbdms-2,3-dideoxy-a, P-~-threo-hex-2- enopyranoside underwent a Pd(0)-catalysed Heck-type coupling to afford compound 39. (See Section 2.1 for a different outcome with the erythro derivative).

OEt

CHzOTbdms 38 39 40

Treatment of 1,2:5,6-di-O-isopropylidene-3,4-di-O-mesyl-~-glucitol with lithium phenyl selenide (PhSeLi) formed in situ from a mixture of lithium triethylborohydride and diphenyl diselenide gave (a-alkene 40 in 77% yield The same reagent, however, failed to convert 1,2-0-isopropylidene-5,6-di-O- mesyl-3- ~-methy~-a-~-ghcofuranose into its 5,6-unsaturated d e r i ~ a t i v e . ~ ~

Full details of an earlier report (see Vol. 30, p. 180 and p. 182, ref. 36) on the use of tributyltin cuprate as a mild alternative to tributyltin lithium in the preparation of unsaturated derivatives such as that shown in Scheme 3 have been rep~rted.~’

BnoG OBn - ,AT 5 - ii Bnf BnO

OMe OBn /

\ Reagents: i, ‘Bu3SnCu’; ii, ZnC12 Scheme 3

The diastereoselective addition of azomethine imines to various acyclic 5,6- unsaturated aldehydes affording highly functionalized cyclopentanoids is mentioned in Chapter 18.

5 Miscellaneous Compounds

Addition of diethylzinc-diiodomethane to 4,6-O-di-tert-butylsilanediyl-~- glucal, followed by reaction with acetic anhydride-pyridine, gave the cyclopro- pane compound 41. Trimethylsilyl triflate-catalysed reaction of 41 with various silylated nucleophiles led to mixtures of oxepanes 42 and eliminated product

f3: Unsaturated Derivatives 181

43. (See Vol. 30, p. 189, ref. 21 and Vol. 29, p. 197, ref. 28 and p. 187, ref. 24 for similar In a related paper, oxepane 44 was obtained when the dibromocyclopropane derivative 45 was treated with potassium carbonate- met han o 1.

41 42 NUC = N3, CN, H, All, CH2C02Et 43 44

CH20Bn

BnO QL 45

Br Br

CH~OAC

AcO

AcO OAc 46

Reaction of 2,3,4,6-tetra- 0-acetyl- 1 -bromo-P-~-hexopyranosyl chlorides

The addition of the radical generated from thioacetic acid to 2,6-anhydro- 1- with tributylallyltin then DBU gave C-glycodienes 46 in moderate yields.34

deoxy-D-gluco-hept- 1 -enitol derivatives is covered in Chapter 1 1.

References

1 2 3

4

5 6 7 8 9

10 11 12

13

14

15 16

I. Frappa and D. Sinou, J. Carbohydr. Chem., 1997, 16,255. 0. Achmatowicz and B. Szechner, Tetrahedron Lett., 1997,38,470 1. K.C. Nicolaou, G.-Q. Shi, J.L. Gunzner, P. Gartner and Z. Yang, J. Am. Chem. SOC., 1997, 119, 5467. K.H. Dotz, R. EhIenz and D. Paetsch, Angew. Chem., Int. Ed. Engl., 1997, 36, 2376. A.H. Franz and P.H. Gross, Carbohydr. Lett., 1997,2, 371. L. Somsak, J. Carbohydr. Chem., 1997,16, 1075. J.F. Nguefack, V. Bolitt and D. Sinou, J. Org. Chem., 1997,62, 1341. R. Wu and L.A. Silks, Carbohydr. Lett., 1997,2, 363. F.E. McDonald and H.Y.H. Zhu, Tetrahedron, 1997,53,11061. P.M. Morgan, R.F. Sala and M.E. Tanner, J. Am. Chem. SOC., 1997,119, 10269. S. Bouoit, C. Goux and D. Sinou, Carbohydr. Lett., 1997,2,267. M.D. Burkart, Z. Zhang, S.-C. Hung and C.-H. Wong, J. Am. Chem. SOC., 1997, 119,11743. T. Linker, T. Sommermann and F. Kahlenberg, J. Am. Chem. SOC., 1997, 119, 9377. J. Du Bois, C.S. Tomooka, J. Hong and E.M. Carreira, J. Am. Chem. Soc., 1997, 119,3179. A. Kirschning and J. Harders, Tetrahedron, 1997,53,7867. B.K. Banik, M.S. Manhas and A.K. Bose, Tetrahedron Lett., 1997,38, 5077.


17 18 19 20 21

22

23 24 25 26

27 28 29

30 31 32 33 34

J.S. Panek and J.V. Schaus, Tetrahedron, 1997,53, 10971. M.T. Crimmins and A.L. Choy, J. Org. Chem. 1997,62,7548. A.T. Cirelli, 0. Moradei and J. Thiem, Liebigs Ann. Chem., 1997, 1983. M.-R. Brescia, Y.C. Shimshock and P. DeShong, J. Org. Chem., 1997,62, 1257. I. Frappa, B. Kryczka, P. Lhoste, S. Porwanski and D. Sinou, J. Carbohydr. Chem., 1997,16,891. Y. Ichikawa, M. Osada, 1.1. Ohtani and M. Isobe, J. Chem. Soc., Perkin Trans. I, 1997, 1449. A. El Nemr and T. Tsuchiya, Carbohydr. Res., 1997,301,77. A. El Nemr and T. Tsuchiya, Carbohydr. Res., 1997,303,267. K.J. Hale, S. Manaviazar and R. Tupprasoot, Tetrahedron, 1997,53, 16365. R.R. Diaz, C.R. Melgarejo, 1.1. Cubero and M.T.P. Lopez-Espinosa, Carbohydr. Res., 1997,300, 375. M.A. Cameron, S.B. Cush and R.P. Hammer, J. Org. Chem., 1997,62,9065. R. Csuk, M. Kuhn and D. Strohl, Tetrahedron, 1997,53, 131 1 . F.G. Calvo-Flores, P. Garcia-Mendoza, F. Hernandez-Mateo, J. Isac-Garcia and F. Santoyo-Gonzklez, J. Org. Chem., 1997,62,3944. D.L.J. Clive, P. W.M. Sgarbi and P.L. Wickens, J. Org. Chem., 1997,62,3751. S . Jarosz, Tetrahedron, 1997,53, 10765. J.O. Hoberg, J. Org. Chem., 1997,62,6615. C.V. Ramana, R. Murali and M. Nagarajan, J. Org. Chem., 1997,62,7694. J.-P. Praly, G.-R. Chen, J. Gola, G. Hetzer and C. Raphoz, Tetrahedron Lett., 1997,38,8185.

14 Branched-chain Sugars

R I

I 0

1 Compounds with aC-C-C Branch-point

1.1 Branch at C-1 or C-2 - 0-Pivaloyl-protected glycosyl diazirines reacted with cyclic enol ethers in a higher yield than did the corresponding 0-benzyl protected derivatives to give spiro products, as indicated in Scheme 1 .

CHaOPiv

PivO Ql A "0

OH OPiv n = 1,2 (R = H or Me) Reagents: i, 45°C or hv; i i , Bu~NOH

Scheme 1

The glycosyl hydroperoxides 1, prepared from the corresponding methyl glycosides by reaction with hydrogen peroxide-molybdenum(V1) oxide, underwent rearrangement in the presence of titanium(1V) isopropoxide to afford 2 and the pyranose C-1-OH forms of 1.2

OH

1 R' = H, R2 = OBn 2 R' = H, R2 = OBn Ph 3 or R' = OBn, R2 = H or R' = OBn, R2 = H

1.2 Branch at C-3 - Dimerization of methyl 4,6-0-benzylidene-3-deoxy-3-C- methylene-a-~-erythro-hex-2-ulopyranoside by an inverse demand hetero


183


Diels-Alder reaction gave product 3.3 A quantum AM1 study of this reaction was performed to account for the observed regio- and stereo-~electivity.~

Common starting materials for the synthesis of C-3 branched sugars are 3- ulose derivatives. Thus the branched-chain amino acid derivative 4 was produced by addition of a protected glycine enolate to the corresponding 3- ulose compound. Saponification of the methyl ester in 4, followed by intramolecular lactoniziition, afforded 5.5 Further reaction of 5 with glycine methyl ester in dichloromethane containing DMAP gave peptide derivative 6. This latter step was also performed with derivatives of alanine and phenylalanine.6

NBn2

4 R = O M e ’ 5 ‘ 6 R = NHCH2C02Me

Condensation of the anion derived from methyl 3,3-dimethyacrylate with 1,2:5,6-d~-0-isopropylidene-a-~-~ib~-hex-3-ulofuranose afforded a mixture of 7 (a-anion attack) and 8 (y-anion attack). Successive reaction of 8 with hydrogen peroxide, lithium aluminium hydride, aqueous mineral acid and sodium periodate afforded (R)-mevalonolactone. A fully deuterated (R)- mevalonolactone analogue was also prepared in the same way using (C2H&C=C2HC02Me and LiA12H4 as reagent^.^

Wittig reaction of 5-azido-6-O-Tbdps-5-deoxy- 1,2-O-isopropylidene-a-~- ribo-hexos-3-ulofuranose with (ethoxycarbonylmethy1ene)triphenylphosphorane, followed by removal of the silyl protecting group, led to the formation of 9 as a precursor of C-3 branched analogues of 3,6- anhydrodeoxynojirimycin. * * were all prepared by initial addition of allylmagnesium bromide to the corresponding 5-0-silyl-protected 3-ulose compounds, followed by de-silylation then acetylation or benzylation under standard conditions. Compound 12 was further transformed into the bicyclic derivative 13 by successive treatment with methanolic hydrochloric acid, borane, tosyl chloride-pyridine and potassium hydroxide. Compounds 10 - 12 were useful precursors for the synthesis of nucleoside analogues. The preparation of some 2’-deoxy-3‘-C- ethynyl-, 2’-deoxy-3’-C-difluoromethyl- and 2’,3’-dideoxy-3’-C-difluoromethylene-nucleosides are covered in Chapter 20.

The mono lithium salt derived from 2,6-dibromopyridine added smoothly to 1,2:5,6-di- O-isopropylidene-a-~-ribo-hex-3-ulofuranose affording 14, and from the same ulose, a wide range of C-3 branched compounds have been made through the intermediacy of the previously reported (Vol. 30, p. 186, ref.

The 3-C-allyl-2-deoxy compounds 10, 119 and 3-C-ally1 compound 12

14: Branched-chain Sugars 185

9

Me

0 7 8

CHpOBn

10 R’ =All, R2 = OAC 12 11 R’ = OAC, R2 = All

9) 3-deoxy-3- C-(dichloromethy1)- 1’2: 5,6-di-O-isopropylidene-a-~-allofuran- ose, whose chemistry proceeds via a spiro-chloro-epoxide intermediate. (See also ref. 27 for related work).13

The marine sponge Callipelta sp. yielded the bioactive 14-membered ring macrolides callipeltosides B and C containing 4,6-dideoxy-2-0-3-C-dimethyl- 4-formamido-P-talopyranosyl- and 4,6-dideoxy-2-0-3-C-dimethyl-P-mannopyranosyl-units, respectively. The absolute stereochemistries of the sugars were not determined. l4

15 Reagents: i, Rh2(OAc)4; ii, BF3.0Et2; iii, 0 3 , DMS; iv, ptsa, MeOH

Scheme 2

In the synthesis of compounds structurally related to staurosporine, an asymmetric approach to branched-chain sugar 15 has been adopted (Scheme 2). The rhodium-catalysed carbene insertion into the chiral decenol, followed by a [3,3] sigmatropic rearrangement and Lewis acid-catalysed 1’2-allyl migration all take place in ‘one pot’. Compound 15 was further transformed into the protein kinase C inhibitor (+)-K252a (16). The enantiomer of 15 was also


R

14

H I

& HO MeOv 0

I

OMe

prepared by an identical method but (S)-(+)-l-buten-3-01 was used as chiral starting material. The enantiomer of 16, (-)-K252a, was thereby obtained.15 Furanoid compound 16 was also transformed into the pyranoid derivative 17 by boron trifluoride etherate treatment of the easily prepared derivative 18 (2 steps from 16). Compound 17 acted as a precursor for the synthesis of (+)- staurosporine and a range of related analogues.16

1.3 Branch at C-4 - The chiral, non-carbohydrate derived compound 19 was transformed into 20 by reaction with ‘ruthenium tetroxide’ then acetic anhydride-pyridine, as an intermediate in the synthesis of branched-chain nucleoside analogues.

R’ R20Tbdms

OMe

yzr Sptol FH~(&LAAc SO2ptol CH20Bn

H

BnO

(Et0)2PH2C 0 I I FH2C (Et0)2PH2C 0 I I BnO Pe 19 20 21 R ’ , R ~ = o

22 R’=H, R2=OH

The relative configuration of the recently isolated antigenic lipooligo- saccharide LOS (111) from Mycobacterium gastri has been established by synthesis. The key step involved the samarium diiodide-promoted coupling of methyl 2-0-Tbdms-3,6-dideoxy-cr-~-erythro-hex-4-ulopyranoside with 2- deoxy-3-O-methyl-4,5,6,7-tetra-0-benzyl-~-galacto-heptonoyl chloride to give the ketone derivative 21. Protection of the tertiary OH as a Tms ether, then


reduction of the ketone with Red-A1 (which also resulted in loss of the Tms group) gave 22, which was methylated at the secondary alcohol, de-benzylated and de-silylated to give the product. l 8

Compound 23, containing an (A)- 1 -hydroxyethyl branching group was synthesized, as shown in Scheme 3, as a semi rigid lactone with structural similarities to bryostatins and debromophysiatoxin. l 9

C02Me

Me kro C13H27

23 Reagents: i, PCC; ii, LiHMDS, C13H27CHO; iii, MsCI, Et3N; iv, DBU; v, HCI; vi, NaI04

Scheme 3

Butyl-, benzyl- and 2,5-dimethyl-4-methylphenyl-lithium added with increased stereoselectivity to the carbonyl groups (1,2-addition) of ethyl 6 - 0 - Tbdms-2,3-dideoxy-a-~-glycero-hex-2-en-4-ulopyranoside and methyl 2,3,6- trideoxy-a-~-glycero-hex-2-en-4-ulopyranoside to give epimeric mixtures of 4- C-branched products. In contrast, 2,5-dimethoxybenzyllithium gave a mixture of 1,2- and 1,4-addition (Michael-like) products.20

1.4 Branch at C-5 - A new route to chiral tertiary alcohols involving the indium-promoted coupling of a ketone with an ally1 bromide is shown in Scheme 4. Selectivities ranged from 80:20 to 98:2 for the D:L isomers.21

i

HO

+

R = Tbdms, Tbdps, H; R1 = H, CO2Me

Scheme 4 Reagent: i, R'


The syntheses, involving Cannizzaro reactions, of a series of 5- C-hydroxymethyl-hexoses which are resistant to metabolism have been described. For example, treatment of 1,2:3,4-di-O-isopropylidene-a-~-g~Z~cto-hexodialdo- 13- pyranose with formaldehyde and aqueous sodium hydroxide solution gave 24. The aldehyde function in the starting material was introduced by standard chemical oxidation of the corresponding alcohol and the sequence was also applied to D-glucopyranose, D-mannopyranose and D-fructopyranose derivatives. Alternatively, by use of a purified D-galactose oxidase, unprotected galacto-sugar derivatives could be oxidized in aqueous solution and in high yield.22

R I

I 2 Compounds with a C-C-C Branch-point

N

2.1 Branch at C-3 or C-4 - 3-C-Allylic thiocyanates undergo a stereoselective [3,3] sigmatropic rearrangement on heating to give 3-deoxy-3(S)-isothiocyanato-3- C-vinyl derivatives from which the corresponding acetamido compounds are available as depicted in Scheme 5.23

\

HO NCS Reagents: i, MsCI, EBN; ii, KSCN, MeCN; iii, 70 "C, xylene; iv, MeCOSH, KOBd

Scheme 5

The keto-nitrone produced by reaction of N-methylhydroxylamine with 1,6- anhydro-2,3-O-isopropylidene-~-~-Zyxo-hex-4-ulopyranose underwent a 1,3- dipolar cycloaddition reaction with ethyl vinyl ether and gave 25 in 62% yield together with 11% of its C-4 epimer. Likewise, the nitrone derived from 1,6- anhydro-2-O-benzyl-4-O-v~nyl-~-~-ara~ino-hex-3-ulopyranose and N-methyl-


hydroxylamine reacted with ethyl vinyl ether to give 26. Several other similar examples were also described.24

Reaction of alkynol 27 with a tungsten or molybdenum pentacarbonyl complex gave a branched glycal derivative which, on treatment with isopro- panol and triphenylphosphine hydrobromide, gave glycoside 28.25 The synthesis of a rubranitrose precursor is mentioned in Chapter 10.

27 28

CH20Bn

N3+cH0

29 30 R = Tbdms or Bn

2.2 Branch at C-5 or C-6 - Treating 7-O-benzyl-l,2:3,4-di-O-isopropylidene- a-~-galacto-hept-6-ulopyranose with dichloromethyllithium, followed by sodium hydride (to form a spiro-chloro-epoxide), then with sodium azide, gave 29. Elaboration of the azido and aldehyde groups into an acetamido and methyl group, respectively, afforded a lincosamine analogue.26 In a similar way treating 3-O-benzyl- 1,2- O-isopropylidene-6- O-Tbdms-a-~-xyZo-hex-5-ulofuranose with dichloromethyllithium followed directly with sodium azide, gave exclusively the azido-aldehyde 30 (R = Tbdms). Use of the 6-O-benzyl analogue gave a 2: l mixture of 30 (R = Bn) and its C-5 e ~ i m e r . ~ ~ Other examples involving the addition of dichloromethyllithium to ketones which react through the intermediacy of spiro-chloro-epoxides can be found in ref. 13.

R I

3 Compounds with a C-CH-C Branch-point

3.1 Branch at C-2 - This section initially deals with compounds containing a single branch-point at C-2. Those compounds containing additional branch- points are treated at the end of this section.

In studies aimed towards the preparation of the C-10-C-15 portion of the immunosupressant FK 506, a 1:l mixture of compounds 31:32 was prepared by a-methylation of 6-0-Tbdps-2,3-dideoxy-4-O-methyl-~-erythro-hexono- 1,5-1actone with methyl iodide-LDA. Equilibration of this mixture with base (DBU or potassium t-butoxide) surprisingly led to an increase in the propor- tion of 32. NMR experiments on compound 32 indicated that the C-2 methyl group occupied an equatorial orientation with the C-4 and C-5 substituents axially orientated in a half-chair structure. An axial preference for the C-4 and C-5 substituents was also observed in the precursor to 31 and 32. A conformational analysis of these compounds by molecular mechanics and molecular


orbital calculations indicated gauche effects and electrostatic interactions as a cause for the preference of axial oriented conformers.28

0- OH

HO..

HO

31 R’ = H, R2 I Me 33 34 32 R’ = Me, R2 = H

Cycloaddition of N-oxide 33 to tri-0-acetyl-D-glucal gave an intermediate tricycle which, on treatment with sodium methoxide-methanol, TFA, then hydrogen-Pd/C, afforded 34.29

The fluorinated compounds 35 - 37 have all been prepared from methyl 4,6- 0-benzylidene-3-O-Tbdms-2-C-difluoromethylene-a-~-arabino-pyranoside, itself derived from the corresponding 2-ulose and dibromodifluoromethane. Thus the difluoromethylene intermediate was transformed into 35 by reaction with Red-Al, then hydrogenolysis, into 36 by hydrogenolysis and into 37 by reaction first with TBAF, then DAST to give methyl 4,6-0-benzylidene-2,3- dideoxy-2-C-trifluoromethyl-a-~-er~~hro-hex-2-enopyranoside, followed by hydr~genat ion.~~

35 R ’ = R 2 = H , R3=0TWms 38 36 R’ = H, R2 P F, R3 = OTbdrns 37 R’=R2=F, R 3 = H

39

.

40 41 42 43


The reaction of ketene dithioacetal 38 with iodotrifluoromethane in the presence of sodium formate and sulfur dioxide (conditions that generated a trifluoromethyl radical) produced 39 in 75% yield. Removal of the dithioacetal protecting group gave 2-deoxy-3,4:6,7-di-~-isopropylidene-2-C-trifluoromethyl-D-glycero-D-galacto-heptano-1,5-lactone which could be readily epimerized at c -2 to the D-glycero-D-talo-derivative by treatment with triethylamine. (See Vol. 28, p. 193, ref. 48 for a preliminary account of this ~ o r k ) . ~ '

Methyl 2,3-anhydro-5-0-benzyl (or trityl)-a-D-ribo-pentofuranoside and methyl 2,3-anhydro-5,6-0-cyclohexylidene-a-~-allofuranos~de reacted with 2- propynyl metallic reagents in the C-2 position giving the corresponding 2- deoxy-2-C-(2-propynyl)-a-~-arabirto-pentofuranos~des and 2-deoxy-2-C-(2- propyny1)-a-D-ah-hexofuranosides, respectively. When the P-glycosides were used the reaction was not as successful, but where it did occur the products were 3-deoxy-3- C-(2-propynyl)-substituted. (See also Section 3.2).32

Lewis-acid-catalysed dimerization of tri- 0-acetyl-D-glucal gave a 55% yield of 40. Tri-0-acetyl-D-galactal and 3,4-di- O-acetyl-~-fucal could be dimerized in the same way.33

The Pd(0)-catalysed reaction of sodio diethyl malonate with methyl 4-0- benzoyl-2,3,6-trideoxy-a-~-threo-hex-2-enopyranoside afforded a 1 :5 mixture of rearranged branched sugar 41 and the product formed by substitution of the 4-OBz group (see Section 3.4). This substitution with rearrangement became the major pathway in the absence of a substituent at C-1 .34

Full details have now appeared on the preparation of 2-deoxy-2-C-(diethyl ma1onate)-branched sugars by reaction of tri- 0-acetyl-D-glucal with diethyl malonate promoted by CAN. The work has now been extended to include tri- 0-acetyl-D-galactal and pentose-derived glycals. (See Vol. 30, p. 189, ref. 19 and p. 177, ref. 26 for preliminary details).35

Hydroxyl-directed cyclopropanation (CH212-Et2Zn) of 4,6-0-di-tert-butylsilanediyl-D-glucal gave, after 0-acetylation, cyclopropanoid derivative 42, a useful precursor in the preparation of oxepanes (see also Chapter 13).36 In a related way a similar cyclopropanation took place with tri-0-benzyl-D-glucal. However addition of dichlorocarbene to the same glycal, followed by treatment with lithium aluminium hydride, gave cyclopropanoid 43. The latter compound reacted with NBS-methanol to give a 1:4 mixture of methyl 2-C-(bromomethyl)- 2-deoxy-3,4,6-tri-0-benzyl-a-:-~-~-glucopyranos~des. The anhydro sugar 44 was produced when 1,5-anhydro-3,4-di-O-benzyl-2-deoxy- 1,2- C-methylene-D- glycero-D-guko-hexito1 was treated with NBS in a~etoni t r i le .~~ (See also Vol. 30, p. 189, ref. 21 and Vol. 29, p. 197, ref. 28 and p. 187, ref. 24 for related work).

Hydrogenation of the double bond in 45 over a chiral ruthenium catalyst, followed by cyclization with camphor sulfonic acid, gave

Iodo-glycoside 47 underwent a radical-mediated tandem cyclization when treated with boron trifluoride etherate and oxygen to give 48.39 Compound 49 underwent a similar reaction?' (See Vol. 29, p. 196, ref. 21 for similar work).

The synthesis of an indolizidine alkaloid skeleton fused onto a sugar template is illustrated in Scheme 6. Cyclization takes place in a 6-endo-trig


Qo ' c o w o H CH20Tbdps TMpZv BnO OMe

CH2Br OAc OAc 44 45 46

CH20Ac

AcO H

47 48 49

mode. (See also Vol. 27, p. 168, ref. 20 for similar work).41 When unsaturated lactone 50 was subjected to the same reaction conditions as shown in Scheme 6, bicyclic lactone 51 was formed.42 (See Section 4 also). The same researchers have also prepared the tricyclic derivative 52 by treating lactone-ester 53 with potassium te r t -b~toxide .~~

CH20SiPi3

MeO. \ MeO. H\ /

Reagents: i, hv, PhpCO, MeCN Scheme 6

CHaOTbdms

To CH20Tbdms

0 8 CH2OTbdms

H-. xyo CH20TWms w

'&NAC02Me

50 51 52 53

The reaction of allyl 6-0-Tbdms-2,3-dideoxy-4-U-(2-propynyl)-a-~-erythro-hex-2-enopyranoside with iodobenzene in the presence of Pd(O), triethylamine and tetrabutylammonium hydrogen sulfate in aqueous acetonitrile at 80 "C produced tricycle 54.44 (See Section 3.2 also). In a similar way treatment of allyl 6-0-Tbdms-2,3-dideoxy-4-~-(2-bromoprop-2-enyl)-a-~-ery~~ro-hex-2- enopyranoside under the same reaction conditions but substituting iodo-


benzene with triphenylphosphine resulted in compound 55. Many related examples were also described.45 Scheme 7 shows a similar Pd(0)-catalysed cascade process to produce tricyclic systems. In these cases the starting materials were all prepared from methyl 4,6-di-O-acetyl-2,3-dideoxy-a-~-ery- thru-hex-2-enopyranoside. Products were also reported from starting materials with a 4-amin0-4-deoxy-substituent.~~ The syntheses of some nucleoside derivatives containing a 2,3-cyclopropyl branch group are mentioned in Chapter 20.

p.0Tbdms CH20TWmS

O@ R

54 R=Ph 55 R = H

Reagents:

OH 56

Ph 57

( \ // ) \ E.@EE,

E = C02Et, E' = C02Me E = SOzPh, E' = C02Me

CI' 'CI

i, Pd(O), (2-MeCsH4)3P, AcOH, benzene; ii, Pd(O), CuC12, LiCI, AcOH, MeCN Scheme 7

3.2 Branch at C-3 - This section initially deals with compounds containing a single branch-point at C-3. Those compounds containing additional branch- points are treated at the end of this section.

Reaction of 2-propynylmagnesium bromide with methyl 2,3-anhydro-5,6-0- cyclohexylidene-P-D-aZZu-hexofuranoside gave an 89% yield of compound 56. Similar reactions using methyl 2,3-anhydro-5-O-benzyl (or trityl)-P-D-ribU- pentofuranoside with various 2-propynyl metallating agents did not proceed in such a specific manner. In contrast, the corresponding a-glycosides underwent reaction exclusively at the C-2 position.33

Treatment of ethyl 6- O-Tbdms-2,3-dideoxy-4- O-(2-propynyl)-a-~-erythra- hex-2-enopyranoside with iodobenzene in the presence of Pd(O), triethylamine and tetrabutylammonium hydrogen sulfate in aqueous acetonitrile at 80 "C


afforded cyclized product 57.44 In like fashion, Pd(0)-catalysed cyclization of ethyl 4-~-(2-bromoprop-2-enyl)-6-O-Tbdms-2,3-dideoxy-~-erythro-hex-2-enopyranosides afforded 58 as product as a consequence of cyclization with ejection of the OEt group. When the corresponding D-threo derivative was subjected to the same reaction, cyclization took place, but resulted in ejection of the 0 - 5 group to give an acyclic unsaturated compound (see Chapter 1 3).47

FH20Tbdms

0 !? 58

OBZ 62

dOH MOM0

A2 A2 OH kH20MOM 59 R'=OH, R 2 = H 61 60 R'-H, R2=OH

F \\ 0

63 64 65

The synthesis of 3-deoxy-3-C-monofluoromethyl-, difluoromethyl- and trifluoromethyl-D-ah-hexopyranoside derivatives from methyl 2-O-benzoyl-4,6- O- bezylidene- 3 -deox y- 3- C-difluoromet hylene- P-~-ribo- hexopyranoside, by use of similar chemistry to that described in ref. 30, have been reported."*

The racemic disaccharide mimics 59 and 60 have been synthesized and the former shown to be a moderate a-mannosidase inhibitor. The galactose units in these compounds were introduced through manipulation of the known anhydride 61 (see Vol. 29, p. 200, ref. 42).49

Olefination of 2-(trimethylsily1)ethyl 2,4,6-tri-O-benzyl-P-~-xylo-hex-3-~10- pyranoside with diethyl phosphonoacetate catalysed by sodium methoxide, followed by hydrogenation-hydrogenolysis and finally benzolylation, gave 62, which was further transformed into 3'-C-carboxymethyl-3'-deoxy-Lewis x analogue. 50

Reaction of the anion derived from methyl methylthiomethyl sulfoxide [MeS(O)CH$Me] with 2,3-anhydro-4-O-triflyl-pyranosides afforded 3,4-cyclo- propanated analogues. (See also Vol. 30, p. 194, ref. 38 for related work)?

Full details (see Vol. 25, p. 173, ref. 42 for a preliminary report) on the stereoselective Pd(0)-catalysed intramolecular cyclizations of 2,3-unsaturated sugars bearing C-, N- and O-linked alkenyl and alkynyl substituents have been published. For example, tricycle 63 was produced from phenyl 2,3-dideoxy-4- 0-(2-propynyl)-P-~-gZycero-pent-2-enopyranoside by Pd(0)-catalysed cycli-


zation with carbon monoxide insertion in the presence of acetic acid and triisopropyl ph~sphite?~

3.3 Branch at C-4 - Substitution with retention of configuration of the 4-0- benzoate groups of methyl 4-0-benzoyl-2,3-dideoxy-a-~-gZycero- or p-L- gZycero-pent-2-enopyranosides, on reaction with sodio diethyl malonate and catalytic Pd(O), afforded the corresponding 4-deoxy-4-C-(diethyl malonyl) derivatives. 34

The reaction of methyl 2,3-di-O-benzoyl-4-deoxy-4-iodo-a-~-xylopyranos~de with an excess of ally1 ethyl sulfone (CH2=CHCH2S02Et)-AIBN afforded a 1 : 1 mixture of methyl 4-C-allyl-2,3-di-0-benzoyl-4-deoxy-a-~-xylo- and p-L- arabino-pyranosides in a new radical allylation process.53 Cyclopropanation of methyl 2,3-di- O-acetyl-4-deoxy-~-~-erythro-hex-4-enopyranoside gave compound 64 together with its stereoisomer. Reaction of 64 with carbon tetrabromide-triphenylphosphine then tributyltin hydride-AIBN gave the 4-deoxy- 4-C-methyl derivative 65 used to prepare a C-7-C-16 segment of lasonolide A. 54

Further details on the synthesis (see Vol. 24, p. 157, ref. 18) and unexpected epoxidation products formed from some 4-deoxy-4-C-(N,N'-dimethylcarbox- amido)methyl-hex-2-enopyranosides are mentioned in Chapter 13.

R R R I II I

I 4 Compounds with a C-C-C, C-C-C or CZC-C Branch-point

R

Irradiation of compound 50 in acetone with light afforded low yields of spiro- bicyclic lactones (Scheme 8).42

CH20Tbdms

ho 50

Reagents: i, hv, Me&O

CH20Tbdms CH20TWms

H+ 0

CH20Tbdms CH20Tbdms

'0 Scheme 8


Alcohols and activated methylene compounds reacted with glycal-carbonate derivative 66 in the presence of Pd(0) to yield 2-deoxy-2-C-methylene 0- and C-glycosi'des, respectively. For example, with p-cresol the aryl glycoside 67 was produced and with dimethyl malonate compound 68 was formed. Secondary hydroxyl groups in sugars also participated in this rea~tion.'~

CH20Bn CH20Bn

BnO Q BnO QR

CH20C02Me CH2

66 67 R = O O M e - 68 R = CH(C02Me)2

70 R' = H, R2 = CHO 71 R'=CHO, R2=H

72

Full details have been published on the lithium bromide-initiated ring contraction of 2,3-anhydrohexopyranosides bearing a hydroxyl group at C-4 giving 3-C-formyl unsaturated furanosides. (See Vol. 24, p. 168, ref. 30 for a preliminary account). The present work has also been extended to include a range of appropriate starting materials such as C-glycosidic derivatives. For example, compound 69 on treatment with lithium bromide and tetramethyl- urea afforded product 70 in 81% yield, together with 71 and 72 in 18% and 1%,

R 73 R=CHO 74 R = C(O)CH=CH2

ph'@Me H SMe

78

$H20Tbdrns F;H20TWms qH20Tbdms

MsO OMe

Ph-

79

CF3 75

' B M e O/ -

R = Me or C02Et R

CF2 CF3 76 77

CHzOR

Meo2c+oMe H

OP(OMe)2 80 R = BZ 81 R =TbdpS


respectively. By use of the isomeric a-D-manno- starting material the same products were obtained but in 71%, 17% and 12% yield?

Methyl 4,6-O-benzylidene-2-deoxy-3-O-triflyl-a-~-erythro-hex-2-enopyranoside acted as a useful precursor for the syntheses of the corresponding 3-C- alkyl-2,3-dideoxy derivatives. Thus on Pd(0)-catalysed reaction with carbon monoxide and tributyltin hydride, compound 73 was produced and with carbon monoxide and vinyltributyltin, compound 74 was formed. Other similar coupling reactions were also described.57

Treatment of mesylate 75 with Me2CuLi-LiI in ether unexpectedly gave diene 76, whereas under the same reaction conditions, but with added boron trifluoride etherate or with the reagent Me2CuCNLi, branched-sugar 77 was produced. A related example was also described?*

Addition of pentane-2,4-dione or ethyl 2,4-dioxovalerate to 78 gave tricyclic compounds 79. Cyclic dicarbonyl compounds such as dimedone also reacted affording tetracyclic products, whilst 3-oxoglutarate gave a benzannulated product. (For related work see Vol. 29, p. 201, ref. 49 and 50).59

Homer-Wadsworth-Emmons olefination of methyl 3,6-di-O-benzoyl-2- deoxy- or 3-O-benzoyl-6-O-Tbdps-2-deoxy-a-~-gZ~cero-hex-2-en-4-ulopyrano- sides with dimethylphosphonoacetate, unexpectedly produced compounds 80 and 81, respectively.m

The preparation of 3-deoxy-3-C-methylene sugar derivatives as masked 3- keto-analogues is covered in Chapter 15. By their use, unwanted reactions that occur with ulose derivatives can be circumvented.

References

1 2

3 4 5

6

7

8 9

10

1 1 12 13

C. Waldraff, B. Bernet and A. Vasella, Helv. Chim. Acta, 1997,80, 1882. H.-J. Hasmann, E. Hoft, D. Mostowicz, A. Mishnev, 2. Urbanczyk-Lipowska and M. Chrnielewski, Tetrahedron, 1997,53, 185. J. Xie and S. Czernecki, J. Carbohydr. Chem., 1997,16, 1101. B.T. Fan, A. Barbu and J.-P. Doucet, J. Chem. Sac., Perkin Trans. 2 , 1997, 1937. S. Bouifraden, J.-P. Lavergne, J. Martinez, P.Viallefont and C. Riche, Tetrahe- dron: Asymm., 1997,8,949. S . Bouifraden, J.-P. Lavergne, J. Martinez and P.Viallefont, Synth. Comrnun., 1997,27,3909. M. Kishida, N. Yamauchi, K. Sawada, Y. Ohashi, T. Eguchi and K. Kakainuma, J. Chem. SOC., Perkin Trans. I , 1997,891. C.K. Lee, H. Jiang and A.M. Scofield, J. Carbohydr. Chem., 1997,16,49. P.N. Jsrgensen, U.S. Ssrensen, H.M. Pfundheller, C.E. Olsen and J. Wengel, J. Chem. SOC., Perkin Trans. I , 1997,3275. P. Nielsen, H.M. Pfundheller, C.E. Olsen and J. Wengel, J. Chem. Soc., Perkin Trans. I , 1997, 3423. P. Nielsen, H.M. Pfundheller and J. Wengel, Chem. Commun., 1997,825. M.A. Peterson and J.R. Mitchell, J. Org. Chem., 1997,62, 8237. K.4. Sato, K. Suzuki, M. Ueda, Y. Kajihara and H. Hori, Bull. Chem. SOC. Jpn., 1997,70,225.


14

15

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 45 46 47 48 49

A. Zampella, M.V. D’Auria, L. Minale and C. Debitus, Tetrahedron, 1997, 53, 3243. J.L. Wood, B.M. Stoltz, H.-J. Dietrich, D.A. Mum and D.T. Petsch, J. Am. Chem. SOC., 1997,119,9641. J.L. Wood, B.M. Stoltz, S.N. Goodman and K. Onwueme, J. Am. Chem. SOC., 1997,119,9652. A. Arnone, P. Bravo, M. Frigerio, F. Viani, G. Salani and C. Zappala, J. Chem. Res. ( S ) , 1997,458. J. LongepC, J. Prandi and J.-M. Beau, Angew. Chem., Int. Ed. Eng., 1997,36,72. J. Lee, S.H. Jeong, M.W. Chun, N.E. Lewin, P.M. Blumberg and V.E. Marquez, Carbohydr. Lett., 1997,2, 307. 0. Achmatowicz, B. Szechner and J.K. Maurin, Tetrahedron, 1997,53,6035. T.-P. Loh, D.S.-C. Ho, G.-L. Chua and K.-Y. Sim, Synlett, 1997,563. A.W. Mazur and G.D. Hiler, J. Org. Chem., 1997,62,4471. J. Gonda and M. Bednarikova, Tetrahedron Lett., 1997,38, 5569. S . Torrente, B. Noya, M.D. Paredes and R. Alonso, J. Org. Chem., 1997, 62, 67 10. F.E. McDonald and H.Y.H. Zhu, Tetrahedron, 1997,53, 11061. P. Sarda, A. Olesker and G. Lukacs, Tetrahedron, 1997,53, 5493. S . Deloisy, T.T. Thang, A. Olesker and G. Lukacs, Bull. SOC. Chim. Fr., 1996, 133, 581 (Chem. Abstr., 1997,126,8 442). Y. Morimoto and H. Shirahama, Tetrahedron, 1997,53,2013. F. Cardona, S. Valenza, A. Goti and A. Brandi, Tetrahedron Lett., 1997, 38, 8097. S. Hiraoka, T. Yamazaki and T. Kitazume, Synlett, 1997,669. G. Foulard, T. Brigaud and C. Portella, J. Org. Chem., 1997,62,9107. D. Kubota and 0. Mitsunobu, Chem. Lett., 1997,517. A.H. Franz and P.H. Gross, Carbohydr. Lett., 1997,2, 371. M.-R. Brescia, Y.C. Shimshock and P. DeShong, J. Org. Chem., 1997,62, 1257. T. Linker, T. Sommermann and F. Kahlenberg, J. Am. Chem. SOC., 1997, 119, 9377. J.O. Hoberg, J. Org. Chem., 1997,62, 6615. C.V. Rama, R. Murali and M. Nagarajan, J. Org. Chem., 1997,62,7694. H. Shimizu, Y. Shimada, A. Tomita and 0. Mitsunobu, Tetrahedron Lett., 1997, 38, 849. M. Breithor, U. Herden and H.M.R. Hoffmann, Tetrahedron, 1997,53,8401. H.M.R. Hoffmann, U. Herden, M. Breithor and 0. Rhode, Tetrahedron, 1997, 53,8383. E. Farrant and J. Mann, J. Chem. Soc., Perkin Trans. 1 , 1997, 1083. D. Brown, M.G.B. Drew and J. Mann, J. Chem. SOC., Perkin Trans. 1, 1997, 3651. E. Santiago de Alvarenga, C.J. Cardin and J. Mann, Tetrahedron, 1997,53, 1457. J.-F. Nguefack, V. Bolitt and D. Sinou, Carbohydr. Lett., 1997,2, 395. J.-F. Nguefack, V. Bolitt and D. Sinou, J. Org. Chem., 1997,62,6827. C.W. Holzapfel and L. Maracs, Tetrahedron Lett., 1997,38,8585. J.-F. Nguefack, V. Bolitt and D. Sinou, J. Org. Chem., 1997,62, 1341. T. Yamazaki, S. Hiraoka and T. Kitazume, Tetrahedron: Asymm., 1997,8, 1 157. K. Kraehenbuehl, S. Picasso and P. Vogel, Bioorg. Med. Chem. Lett., 1997, 7 , 893.


50

51

52

53

54

55 56 57 58 59

60

I. Ishida, H. Hosokawa, H. Kondo, M. Kiso and A. Hasegawa, Carbohydr. Res., 1997,303,131. N. Khan, H.J. Kohlbau and W. Voelter, 2. Naturforsch., B: Chem. Sci., 1996,51, 1517 (Chem. Abstr., 1997, 126,8 395). C.W. Holzapfel, G.J. Engelbrecht, L. Marais and F. Toerien, Tetrahedron, 1997, 53, 3957. F. Le Guyader, B. Quiclet-Sire, S. Seguin and S.Z. Zard, J. Am. Chem. Soc., 1997,119,7410. M.K. Gurjar, A. Chakrabarti, B.V. Rao and P. Kumar, Tetrahedron Lett., 1997, 38, 6885. S. Bouoit, C. Goux and D, Sinou, Carbohydr. Lett., 1997,2,267. F. Pontkn and G. Magnusson, J. Org. Chem., 1997,62,7972. Y . Al-Abed and W. Voelter, Tetrahedron Lett., 1997,38, 7303. S . Hiraoka, T. Yamazaki and T. Kitazume, Chem. Commun., 1997, 1497. K. Peseke, G. Thiele, M. Michalik and D.R. Powell, Liebigs Ann. Chem., 1997, 1019. O.M. Moradei, C.M. du Mortier and A.F. Cirelli, Tetrahedron, 1997,53,7397.

I5 Aldosuloses and Other Dicarbonyl Compounds

1 Aldosuloses

~-xy~o-Hexos-5-ulose has been synthesized from the known hex-4-enoside 1 (Scheme l).* Further work on the synthesis of putative biosynthetic intermediates of deoxy sugars has included more details on the synthesis of the thymidine diphospho-6-deoxy-cx-~-ribo-hexos-3-ulose 2.2 Ozonolysis of 3 generated the 2-deoxy analogue 4 of 2, but it was too unstable for isolation because of elimination of the diph~sphate.~

CH20Bn

OH

0

I ‘-OH

Reagents: i, NaH, BnBr; ii, MCPBA; iii, MeOH, TsOH; iv, H2, Pd/C; v, H30+ Scheme I

Me 0

OH 2 X=O, R=OH 3 X=CH2, R = H 4 X=O, R = H

. . 0 0

5 R = CH20Bn or H, X =A,,, A p t ,

6 R = CH20Bn or H, X = f i c ~

CHO

7 8 Reagent: i, FeC13, NaI04, THF, H20

Scheme 2


200

15: Aldosuloses and Other Dicarbonyl Compounds 201

2 Other Dicarbonyl Compounds

The 2,4-diuloses 5 were obtained by condensation of the corresponding aldonolactones with acetone and acetophenone using NaH in THF to generate the required carbanions. Parallel work with acetonitrile afforded the 4- ulosononitriles 6.4

The selective hydrolysis of dioxolane rings on sugars can be accompanied by in situ periodate cleavage of the released diols. For example, the dialdose 8 is formed in one pot from 7 (Scheme 2).5

h0ch2

OMe OMe OH 9 10 11

Irradiation of uronic acid derivatives in acetonitrile in the presence of phenyl iodonium diacetate and iodine affords products of oxidative decarboxylation, e.g. 10 from 9.6

Synthesis of the symmetric C-C bonded dicarbonyl analogue 11 of trehalose has been r e p ~ r t e d . ~

The use of a 3-keto-fructose derivative as catalyst for the asymmetric epoxidation of olefins is mentioned in Chapter 24.

References

1 P.L. Barili, G. Berti, G. Catelani, F. D’Andrea and F. De Rensis, Tetrahedron, 1997,53,8665. T. Miiller and R.R. Schmidt, Liebigs Ann. Chem., 1997, 1907. T. Miiller and R.R. Schmidt, Tetrahedron Lett., 1997,38,5473. R.Csuk, M. Kuhn and D. Strohl, Tetrahedron, 1997,53, 131 1. S. Chandrasekhar, R. Kache and Y.R. Reddy, Carbohydr. Lett., 1997,2,217. C.G. Francisco, C.C. Gonzalez and E. Suarez, Tetrahedron Lett., 1997,38,4141. T. Mochimki and M. Shiozaki, Chem. Lett., 1997,801.

16 Sugar Acids and Lactones

1 Aldonic and Aldaric Acids and Lactones

The preparation of selectively activated aldonolactones as chiral synthons has been reviewed. * Potassium D-idarate has been isolated from the nyctinastic plant Cassia mimosoides and was found to cause leaf closing during daytime.2

Treatment of unprotected D-ribono-, -arabinono- and -xylono- 1,4-1actones with SOC12 or SOBr2/DMF led to the corresponding 5-deoxy-5-halo derivatives in 70-95% yields. The same conditions applied to D-lyxono-1 ,4-lactone, however, afforded 2-chloro-2-deoxy-~-xylono- 1,4-lactone. Subsequent treatment of the 5-bromo-5-deoxy-lactones with lithium azide and then hydrogenolysis of the resulting 5-azido-5-deoxy compounds led to the corresponding 1 3 - lac tarn^.^

Tosylation (TsCl, Py) of ~-glucono-l $lactone followed by in situ acetylation gave 70% of 1, which on hydrogenation gave 2 (93%). More forcing hydrogenation conditions has afforded up to 20% of 3.5 D-Glucono- 1,Slactone has been selectively acylated at 0-6 using fatty acid esters with Candida antarctica lipase in Bu'OH. Treatment of the products in methanol with C16 or c18 amines precipitated the 6-0-alkanoyl-N-alkylgluconamides.6 Per-0-alkylated glycono- 1,5-lactones are the major products on reaction of the corresponding glycosides with trimethylsilyl azide and stannic chloride. The mechanism proposed involves formation of the glycosyl azide, loss of nitrogen and a hydride shift to give an imine that hydrolyses on ~ o r k - u p . ~ Aldonolac- tones have been successfully per-0-benzylated under acidic conditions by use of benzyl trichloroacetimidate in dioxane.8

n ,y"

TsO

OTs 1 2 X-OTS 4

3 X = H

CF3 5


202

16: Sugar A c i h and Lactones 203

OH

6 X-H, Y=CF3 7 X=CF3, Y - H

8 X-H, YPMe 9 X=Me, Y-OH

11 X=Me, Y = H 10 X-OH, Y = H

Radical trifluoromethylation (CF31, HC02Na, S02) of unsaturated dithioacetal 4 gave 5, which on hydrolysis gave lactone 6. Under basic conditions 6 could be epimerized to 7.9 Ozonolysis of fully protected sugar hydrazones and subsequent oxidation of the released aldehydes has provided a way of obtaining acyclic aldonic acids. lo Analogues 8-10 of the immunomodulator conagenin 11 have been synthesized from D-XylOSe or calcium D-xylonate using standard methods.'

Epoxides such as 12 have undergone intramolecular epoxide opening to form 2-deoxy-5-C, C-dialkyl-pentonolactones 13 (Scheme l).I2

R2 OTWps 12 13

R1,R2=Me, 7 Scheme 1

Reagents: i, ZnC12; ii, TFA

Photolysis of N-hydroxy-2-thiopyridone ester 14 in the presence of acrylamide led to adduct 15, apparently formed by addition of the C-2 radical 17 to the amide, which on desulfurization with nickel boride gave amide 16 (Scheme 2).13 Others have reported that attempts to prepare 14 were unsuc-

o*c,o-N , ST /

AcO

LOAc 14 15

Scheme 2


cessful and the product isolated was always that of decarboxylation i.e. the 0,s-acetal 18 (Scheme 3), presumably formed via the radical intermediate 17. In the presence of ethyl 2trifluoroacetoxyacrylate this radical was trapped to give a,P-unsaturated keto ester 19.14

AcO Ac%so AcO T O A c / 18

14 - C O A c

Acol;! 19

Scheme 3

A calix[4]resorcarene derivative containing eight primary amine residues has been treated with excess lactobiono-l,5-lactone to give a molecule with eight glyconamide residues.

The p-elimination reactions catalysed by D-galactonate dehydratase from E. coli and D-glucarate dehydratase from Pseudornonas putida have been studied mechanistically focussing on the importance of the pK,s of the protons a- to the carboxylic acid groups of the substrates.16 The participation of acetate ions in the oxidation of D-galactose by Cu(I1) in acetic acid has been studied, with the results confirming that CuOAc+ is the reactive species.17 The electrooxidation of D-glucose to calcium gluconate in the presence of NaBr and CaC03 has been optimized. The optimal conditions are those that promote NaOBr formation. I 8

The synthesis of both enantiomers of the chain-extended aldonolactone epi- muricatacin is covered in Chapter 24, and the 2-C-methylation of 2,3-dideoxy- aldonolactone derivatives is discussed in Chapter 14. The oxidation of glycosylamines by chloramine T to the corresponding aldonic acids is mentioned in Chapter 9.

2 Anhydroaldonic Acids and Lactones

Hydrogenation of Kdn derivatives 20 and 21 has allowed the synthesis of anhydroaldonic acid derivatives 22-24 (Scheme 4).19 The glycosyl iodide 25 in the presence of excess HI/HOAc is reductively cleaved to give exclusively 2ti20

16: Sugar Acids and Lactones 205

A ring contraction of 2-deoxy-2-iodoaldonolactone derivative 27 on reaction with K2CO3 or NaOMe/MeOH gave 28.21 Syntheses have been reported of analogues 29 of lipid A with anti-inflammatory potential.22

OAc 20 I ii

OAc 21

OAc OAc 22 23 24

Reagents: i, DBU, CH2Cl2; ii, H2, Pd/C, toluendpy; iii, H2, Pd/C; MeOWHOAc; iv, H2, Pd/C, MeOH Scheme 4

OAc

OAc OR 25 X = I, Y = C a B n 27 28 26 X - COpBn, Y = H R = TWms

3 Ulosonic Acids

The preparation and modification of sialic acids and sialyl glycosides has been reviewed,23 as has the platinum-catalysed oxidation of L-sorbose to 2-keto-~- gulonic acid.24 The diamino-tetradeoxy-L-glycero-D-talo-nonulosonic acid derivative 30 is released by mild acid hydrolysis of the Legionella pneumophilia seragroup lipopoly~accharide.~~

II

O R

29 R1 =uCllH23, R2 = hc,,H23 , X = OH or F

R=HOrOH


The bis-phosphate 31 has been synthesized as a putative intermediate in the biosynthesis of 3-deoxy-~-rnanno-2-octulosonate-8-phosphate by Kdo-8P synthase.26 It was a poor substrate, however, and the acyclic bis-phosphate 32 has been proposed as an inte~mediate.~~

Polyvalent dendrimers of sialic acid thioglycosides have been prepared with even-numbered valencies of between 4 and 12.28

31 32 33

The fluorinated ulosonic acid phosphate 33 has been prepared and shown to be an excellent substrate for dehydroquinate synthase, whereas its C-3 epimer was a relatively poor substrate for the enzyme.29

The novel spirocyclic derivative 34 was isolated from the cyanate-producing plant Solanum tuberosum, and it has been synthesized by reaction of cyanate with dehydroascorbic acid.30

A chemical synthesis has been described of CMP-NeuAc which utilizes phosphite diester coupling; analogues with variation in the NeuAc moiety were also produced.31

A non-enzymic synthesis of Kdo-%phosphate utilized an interesting approach (Scheme 5) that is similar to that proposed for the biosynthetic pathway. 32

A new method for the homologation of aldonolactones, analogous to a

34

. ,J2Me 6

Scheme 5

HO

OH

16: Sugar Acidr and Lactones 207

Reformatsky reaction, involves a magnesium-graphite mediated coupling of an a-halogenated ~ u l t a m . ~ ~

A synthesis of Kdo features the addition of ethyl diazoacetate to an aldehydo-D-mannose derivative followed by extensive synthetic manipulation to release the 3-deoxy-2-keto product .34 An indium-mediated allylation of D-erythrose in an aqueous solvent system has been used in the synthesis of 3-deoxy-~-arabino-2-heptulosonate.~~ The displacement of a primary iodide has been used to effect chain extension in a new synthesis of Kdo (Scheme 6).36

+ CO~BU'

NCAOCH2CH20Et

i - CO~BU'

F b O E t

ii-v - Aco@c@Me OAc

Reagents: i, NaH, DMF; ii, CF3C02H; iii, NH40H; iv, AqO, DMAP; v, CH2N2 Scheme 6

Further work on the radical reactions of N-hydroxy-2-thiopyridone esters (see Scheme 3 above) has resulted in the synthesis of 3-deoxy-~-arabino- 2-heptulosonic acid from D-ribonolactone (Scheme 7).37938

CH20H

1

Scheme 7

Process improvements for the large scale production of N-acetylneuraminic acid using Nacetylneuraminic acid aldolase have been described,39 and N- glycolylneuraminic acid has been prepared by the action of N-acetylneuraminic acid aldolase on N-glycolyl-D-mannosamine and pyruvic acid,40 while similar procedures were used to convert N-t-butoxycarbonyl-D-mannosamine to N-t- butoxycarbonylneuraminic acid.41 Others have adopted the same procedure


using N-acetylneuraminic acid aldolase applied to a number of N-acyl-D- mannosamines in which the acyl groups were more complex, including aromatic and long chain aliphatic sub~tituents.~~ 3C-Labelled pyruvate has been used in the same aldolase-catalysed reaction with N-acetyl-mmannosa- mine to give N-acetylneuraminic acid labelled at C-1 and C-2.43

A sialylphospholipid has been synthesized using standard sialyl glycosidation techniques,44 and participation of the sialic acid ester group in the stabilization of the anomeric oxocarbenium ion intermediate has been utilized in the selective formation of a-glycosides of sialic acid.45 The sialyl donor 35, when activated with phenyl sulfenyl triflate, affords only a-glycosides with a number of carbohydrate glycosyl accept01-s.~~ By use of different deliberately designed donors and acceptors either a- or P-8-0-sialylation of neuraminic acid could be achieved.47 The a- and P-methyl glycosides of 3-deoxy-~- lyxo-hept-2-ulosonic acid have been prepared ~epa ra t e ly .~~

An unusual furanoside product obtained from a Koenigs-Knorr glycosidation with a Kdn donor is covered in Chapter 3, as is the synthesis of C-glycosides from neuraminic acid glycosyl sulfones using samarium iodide.

Intramolecular sialic acid lactones have been treated with ethyl glycinate to give new amide-linked sialic acid-amino acid conjugate^.^^

Allylic displacements applied at C-4 to 2,3-unsaturated sialic acid derivatives have allowed the synthesis of predominantly 4-deoxy-4-epi-4-halogeno deriva- t i v e ~ . ~ ~ The 4-epimer of the well known 4-azido-4-deoxy-2,3-unsaturated sialic acid has been prepared using a Pd-catalysed allylic displacement .51

A c H N p C 0 2 M e OAc PhS SMe C02Me

OAc 35

OH 36

3 37 X=H, Y=OH 38 X = NHAc, Y = H

Isopropylidenation of Kdn derivative 36 gave the 5,8:7,9-di-O-isopropylidene derivative 37 which, after oxidation, oxime formation, reduction and acetylation gave the 4-N-acetyl-4-deoxy analogue 38.52 Alternative isopropylidenation conditions applied to 36 led to the 8,9-O-isopropylidene and/or the 5,7:8,9-di-O-isopropylidene derivatives. Oxidation of these, at C-7 and C-4 respectively, led to enone products after p-eliminati~ns.’~

The known trimethylsilyl triflate-catalysed reaction of acetonitrile with 2,3- unsaturated sialic acid 0-acetates to give the 4-N-acetyl-4-deoxy derivatives has been extended to other nitriles such as benzonitrile and CH30CH$N.54

Methyl 3-deoxy-a- and P-~-ribo, -xylo, and -lyxo-hept-2-ulosonic acids have been prepared from methyl (methyl 3-deoxy-a- and P-~-arabino-hept-2- u1opyranosid)onate by controlled triflate displacement with inversion at C-4 andlor C-5 using caesium acetate.55 2,5-Diketo-~-threo-hexonic acid 39, an intermediate in the microbial pro-


duction of ascorbic acid, has been isolated and hydrogenated to give mixtures of 40 and 41 .56

HOfH HOfH

H O T OH OH

OH OH OH 39 40 41

HO

Oxidative decarboxylation of ulosonic acid derivative 42 gave 86% of lactone 43 (Scheme 8).57

OMe OMe 42 43

Scheme 8 Reagents: i, PhI(OAc)p, 12, hv, MeCN

4 Uronic Acids

The colourless glucuronoside 44 has been synthesized as a colorimetric substrate for P-glucuronidase. It releases a strongly fluorescent phenol on hydrolysis and can detect as little as loA3 U/ml of enzymic activity in solution.58 The 4-nitrophenyl glucuronosides 45-47 have been prepared as potential colorimetric substrates for bovine p-glucuronidase, but none was better than 4-nitrophenyl P-D-glucopyranosiduronic acid.59 A synthesis of 7-hydroxycoumarin glucuronide has also been described.60

The glucuronic acid C-glycoside derivative 48 has been prepared as a trisubstrate analogue inhibiter for UDP glucuronosyltransferases.61 Glucuro- nide metabolites have been prepared of the anti-inflammatory drugs DUP69762 and ML-3000.63

The methyl glucuronate glycoside 49 has been synthesized as a prodrug of a phosphorodiamidic mustard. It is released by a carboxylic esterase followed by a P-glucuronidase.a

The TEMPO-catalysed sodium hypochlorite oxidation of a- and P-D-glUC0- pyranosyl phosphate and a-D-glucopyranosyl fluoride has afforded the corresponding glucuronosyl phosphates and fluoride.65 In a comparative study of the oxidation of methyl and n-octyl a-D-glucopyranoside with molecular oxygen over a graphite-supported platinum catalyst, it was found that the n- octyl glycoside reacts 10 times more slowly, but with increased selectivity to


CI

OH 44

.CI

OH OH 45 46 R=C02H

47 R =Hod CO2H

OH OH 48

give the glucuronoside,66 and a further study has looked at the effect of particle size of the platinum catalyst on the oxidation products formed?'

The addition of 2-fury1 anions to sugar nitrones has led to the synthesis of uronic acid derivatives (Scheme 9); a number of other examples were reported.68

Uronic acids are oxidized in alkaline media by Chloramine T or Chloramine

Bn

Scheme 9

16: Sugar Acids and Lactones 21 1

B to the corresponding glycaric acids. A study of the kinetics of these reactions has been reported.69

The addition of a propargyl anion to C-5 of a variety of 5-aldehydopentofuranose derivatives gave anti-addition products, generally with high diastereoselectivity. These could be ozonolysed to 6-deoxy-hepturonate deriva- t i v e ~ . ~ ~ A synthesis of 2-amino-2-deoxy-~-altruronic acid derivatives is covered in Chapter 9.

The conversion, over several steps, of D-glucuronic acid esters into L-iduronic acid derivatives has been rep~rted,~ ' and L-iduronic acids have been prepared by hydroboration and subsequent oxidation of hex-5- enopyran~sides.~~

Acid hydrolysis of alginic acid from kelp has given D-mannurono- 6,3-lactone in 33% yield based on the mannuronic acid content of alginic acid.73

Benzyl 2,3,4-tri-O-methyl-~-~-glucopyranosiduronic acid has been oxidatively decarboxylated with iodobenzene diacetate to give the corresponding 5-acetoxy -pentopyranoside. Other examples were given. 57

Some methyl ~-~-ary~carbony~-~,~,~-tr~-O-acety~-~-~-g~ucopyranuronates have been prepared from the corresponding glycosyl bromide under standard conditions .74

Novel amphiphilic bis-amides have been prepared with glucuronic or galacturonic acid moieties as polar head groups by the reaction of long chain diamines with n-octyl p-D-gluc- or galacturono-6,3-lactones.75 Amide bonds have also been formed between D-galaCtUrOniC acid derivatives and suitably protected amino acids.76 Some glucuronides with 1251 labels (in the aglycon) have been prepared.77 Treatment of D-glucuronic acid with benzaldehyde dimethyl acetal under acid conditions has given the fully protected furanosid- uronate 50.78

oYoMe 50 Ph

5 Ascorbic Acids

The novel phloroglucinol derivative 51 was isolated from Sargassum spinuli- gerum, a brown seaweed, after ace t~ la t ion .~~ The preparation of a series of 2-0-alkylascorbic acids as oxygen radical scavengers has been reviewed. 8o

Isopropylidenation of L-ascorbic acid followed by phosphorylation and deace- talation has afforded magnesium L-ascorbate 2-ph0sphate.~ The thermal

212 Carbo h y dr a te Chemistry

degradation of lascorbic acid at 300 "C, or 180 "C in propyleneglycol, has been investigated, and the products identified by GC-MS.82

The tocopheryl ascorbic acid 52 has been synthesized and shows promise as a prodrug form of vitamin E.83 Each of the 2-deoxy-2-halo-~-ascorbic acids 53 have been prepared from 2-deoxy-~-ascorbic acid.84 A kinetic study has been reported on the mechanism of oxidation of L-ascorbic acid by the molybdato- pentamine cobalt(II1) ion in aqueous solution.85

roH

5

6

7 8 9

10

I 1

12

13 14 15

16

0 OAC & \

OAc 51

References

bo Ho O 7

52

k o HO X

53 X = F, CI, Br or I

I. Lundt, Top. Curr. Chem., 1997,187,117 (Chem. Abstr., 1997,127, 17 867). M. Ueda, T. Ohnuki and S. Yamamura, Tetrahedron Lett., 1997,38,2497. V. Bouchez, I. Stasik, D. Beaupkre and R. Uzan, Curbohydr. Res., 1997,300, 139. V. Bouchez, I. Stasik, D. Beaupere and R. Uzan, Tetrahedron Lett., 1997, 38, 7733. N. Vukojevic, B. Peric, T. Dramicanin, M. Popsavin and D. Miljkovic, Carbo- hydr. Res., 1997,299,295. M. Woudenberg-van-Oosterom, F. Van Rantwijk and R.A. Sheldon, FettlLipid, 1996,98,390 (Chem. Abstr., 1997,126,89 681). M. Goebel, H.-G. Nothofer, G Ross and I. Ugi, Tetrahedron, 1997,53, 3123. H. Stampe Jensen, G. Limberg and C. Pedersen, Curbohydr. Res., 1997,302, 109. G. Foulard, T. Brigaud and C. Portella, J. Org. Chem., 1997,62,9107. R.P. Spencer, H.K.B. Yu, C.L. Cavallaro and J. Schwartz, J. Org. Chem., 1997, 62,4507. A. Kovacs-Kulyassa, P. Herczegh and F. Sztaricskai, Tetrahedron, 1997, 53, 13883. K. Nacro, M. Baltas, J.-M. Escudier and L. Gorrichon, Tetrahedron, 1997, 53, 659. D.H.R. Barton and W. Liu, Tetrahedron Lett., 1997,38,2431. Z. Pakulski and A. Zamojski, Tetrahedron, 1997,53, 3723. T. Fujimoto, C. Shimizu, 0. Hayashida and Y. Aoyama, J. Am. Chem. Soc., 1997,119,6676. D.R.J. Palmer, S.J. Wieczorek, B.K. Hubbard, G.T. Mrachko and J.A. Gerly, J. Am. Chem. Soc., 1997,119,9580.

16: Sugar Acids and Lactones 21 3

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

45 46 47

48

S. Signorella, L. Ciullo, R. Lafarga and L.F. Sala, New J. Chem., 1996, 20, 989 (Chem. Abstr., 1997, 126, 8 449). B.D. Popovic and A.V. Tripkovic, Hem. Ind., 1996, 50,405 (Chem. Abstr., 1997, 126,405). X.-L. Sun, T. Kai, H. Takayanagi and K. Furuhata, J. Carbohydr. Chem., 1997, 16, 541. J. Gervay and T.Q. Gregar, Tetrahedron Lett., 1997,38, 59. J.S. Kozlowski, C.H. Marzabadi, N.P. Rath and C.D. Spilling, Carbohydr. Res., 1997,300,301. M. Shiosaki, S. Kurakata, T. Tatsuta, H. Maeda and M. Nishijima, Tetrahedron, 1997,53, 1604 1, M. von Itzstein and R.J. Thomson, Top. Curr. Chem., 1997, 186, 119 (Chem. Abstr., 1997, 126,264 249). T. Mallat, C. Broennimann and A. Baiker, J. Mol. Catal. A: Chem., 117, 425 (Chem. Abstr., 1997,126,251 289). Y.A. Knirel, H. Moll, J.H. Helbig and U. Ziihringer, Carbohydr. Res., 1998, 304, 77. F.W. D’Souza, Y.Benenson and T. Baasov, Bioorg. Med. Chem. Lett . , 1997, 7, 2457. P.H. Liang, A. Kohen, T. Raasov and K.S. Anderson, Bioorg. Med. Chem. Lett., 1997,7,2463. D. Zanini and R. Roy, J. Am. Chem. SOC., 1997,119,2088. E.J. Parker, J.R. Coggins and C. Abell, J. Org. Chem., 1997,62, 8582. I. Koshiishi, H. Takayama, N. Aimi, K. Yamaguchi, H. Toyoda and T. Imanari, Chem. Pharm. Bull., 1997,45, 344. M.D. Chappell and R.L. Halcomb, Tetrahedron, 1997,53, 11 109. S. Du, D. Plat, V. Belakhov and T. Baasov, J. Org. Chem., 1997,62,794. R. Csuk, C. Schroder and C. Krieger, Tetrahedron, 1997,53, 12947. F.J. Lopez-Herrera and F. Sarabia-Garcia, Tetrahedron, 1997,53, 3325. R.H. Prenner and W. Schmid, Monatsh. Chem., 1996, 127, 1045 (Chem. Abstr., 1997,126,277 695). H. Tsukamoto and T. Takahashi, Tetrahedron Lett., 1997,38,6415. D.H.R. Barton and W. Liu, Tetrahedron Lett., 1997,38,367. D.H.R. Barton and W. Liu, Tetrahedron, 1997,53, 12067. M. Muhmoudian, D. Noble, C.S. Drake, R.F. Middleton, D.S. Montgomery, J.E. Piercey, D. Ramlakhan, M. Todd and M.J. Dawson, Enzyme Microb. Technol., 1997,20, 393 (Chem. Abstr., 1997, 126,293 546). A. Kuboki, H. Okazaki, T. Sugai and H. Ohta, Tetrahedron, 1997,53,2387. W.-Y. Wu, B. Jin, D.C.M. Kong and M. von Itzstein, Carbohydr. Res., 1997, 300,171. C.-C. Lin, C.-H. Lin and C.-H. Wong, Tetrahedron Lett., 1997,38,2649. J. Gervay, N.N. Mamuya and R.A. Barber, Tetrahedron Lett., 1997,38, 1865. M. Koketsu, T. Nitoda, H. Sugino, L.R. Juneja, M. Kim, T. Yamamoto, N. Aoe, T. Kajimoto and C.-H. Wong, J. Med. Chem., 1997,40,3332. T. Takahashi, H. Tsukamoto and H. Yamada, Tetrahedron Lett., 1997,38,8223. V. Martichonok and G.M. Whitesides, Carbohydr. Res., 1997,302, 123. J.C. Castro-Palomino, Y.E. Tsvetkov, R. Schneider and R.R. Schmidt, Tetrahe- dron Lett., 1997,38, 6837. J. Mlynarski and A. Banaszek, Carbohydr. Lett., 1997,2,409.

49 J. Gekay, P.S. Ramamoorthy and N.N. Mamuya, Tetrahedron, 1997,53, 11039.


50 51 52

53

54

55 56 57 58

59

60

61

62

63

64 65

66 67

68

69

70 71 72 73

74

75

76 77

78

79

G.B. Kok, A.K. Norton and M. von Itzstein, Synthesis, 1997, 1185. G.B. Kok and M. von Itzstein, Carbohydr. Res., 1997,302, 237. T. Kai, X.-L. Sun, H. Takayanagi and K. Furuhuta, J. Carbohydr. Chem., 1997, 16, 521. T. Kai, X.-L. Sun, H. Takayanagi and K. Furuhata, J. Carbohydr. Chem., 1997, 16, 533. X.-L. Sun, T. Kai, H. Takayanagi and K. Furuhata, Carbohydr. Res., 1997,298, 181. J. Mlynarski and A. Banaszek, Tetrahedron, 1997,53, 10643. Z. Hamersak, N. Pavlovic, V. Delic and V. Sunjic, Carbohydr. Res., 1997,302,245. C.G. Francisco, C.C. Gonzalez and E. Suarez, Tetrahedron Lett., 1997,38,414. 2. Diwu, Y. Lu, R.H. Upson, M. Zhou, D.H. Klaubert and R.P. Haugland, Tetrahedron, 1997,53,7 1 59. M. Azoulay, N. Ivastchenko, J.-C. Florent and C. Monneret, Bioorg. Med. Chem. Lett., 1997,7, 1307. R.T. Brown, F. Scheinmann and A.V. Stackulski, J. Chem. Res., Synop., 1997, 370 (Chem. Abstr., 1997,127,331 674). C.M. Timmers, M. Dekker, R.C. Buijsman, G.A. van der Marel, B. Ethell, G. Anderson, B. Burchell, G.J. Mulder and J.H. van Boom, Bioorg. Med, Chem. Lett., 1997,7, 1501. S . Nakamura, M. Kondo, K. Goto, M. Nakamura, Y. Tsuda and K. Shishido, Heterocycles, 1996,43, 2747 (Chem. Abstr., 1997, 126, 144 487). A. Kirschning, M. Ries, S. Domann, W. Martin, W. Albrecht, P. Arnold and S. Laufer, Bioorg. Med. Chem. Lett., 1997, 7, 903. A.K. Ghosh and D. Farquhar, Tetrahedron Lett., 1997,38,8795. A. Heeres, H.A. van Doren, K.F. Gotlieb and I.P. Bleeker, Carbohydr. Res., 1997,299,221. J.H. Vleeming, B.F.M. Kuster and G.B. Marin, Carbohydr. Res., 1997,303, 175. J.H. Vleeming, B.F.M. Kuster and G.B. Marin, Catal. Lett., 1997, 46, 187 (Chem. Abstr., 1997, 127, 190 932). A. Dondoni, F. Junquera, F.L. Merchan, P. Merino, M.C. Scherrmann and T. Tejero, J. Org. Chem., 1997,62, 5484. K.S. Rangappa, M.P. Raghavendra and D.S. Mahadevappa, J. Carbohydr. Chem., 1997,16,359. Z . Pakulski and A. Zamojski, Tetrahedron, 1997,53,2653. H.G. Bazin, R.J. Kerns and R.J. Linhardt, Tetrahedron Lett., 1997,38,923. L. Rochepeau-Jobron and J.C. Jacquinet, Carbohydr. Res., 1997,303,395. M.P. Watterson, A. Martin, T.M. Krulle, J.C. Estevez and G.W.J. Fleet, Tetrahedron: Asymm., 1997,8,4111. C. Sun, Y. Wang, H. Li, Y. Qi, 2. Chen and P. Xue, Shandong Daxue Xuebao, Ziran Kexueban, 1996,31, 327 (Chem. Abstr., 1997,126,47 435). J.-N. Bertho, A. Coue, D.F. Ewing, J.W. Goodby, P. Letellier, G. MacKenzie and D. Plusquellec, Carbohydr. Res., 1997,300, 34 1, C. Vogel, U. Jeschke, S. Kramer and A.-J. Ott, Liebigs. Ann. Chem., 1997,737. T. Unak, P. Unaic, B. Ongun and Y. Duman, Appl. Radiat. Isot., 1997, 48, 777 (Chem. Abstr., 1997,127,95 504). M. Polakova and D. Joniaic, Chem. Pap., 1997,51,230 (Chem. Absrr., 1997, 127, 248 334). M. Keusgen, M. Falk, J.A. Walter and K.-W. Glombitza, Phytochemistry, 1997, 46, 341.


80

81

82

83 84 85

K. Kato, M. Murakami and S. Terao, New Methods Drug Res., 1995, 4, 153 (Chem. Abstr., 1997,126,212 293). Y . Liu, M. Shi and H. Shen, Jingxi Huagong, 1997, 14, 19 (Chem. Abstr., 1997, 126, 317 553). G. Vernin, S. Chakib, S.M. Rogacheva, T.D. Obretenov and C. Parkanyi, Curbohydr. Res., 1997,305, 1. T. Rosenau and W.D. Habicher, Chem. Pharm. Bull., 1997,45, 1080. P. G e and R.L. Kirk, J. Org. Chem., 1997,62,3340. S.-C. Im, Transition Met. Chem., 1997,22, 135 (Chem. Abstr., 1997, 127, 17 894).

17 Inorganic Derivatives

1 Carbon-bonded Phosphorus Derivatives

A review of the synthesis of enantiomerically pure phosphonates has included some carbohydrate examples.' A phosphonate analogue 1 of a- L-rhamnose-l- phosphate has been prepared,2 as has the protected a-D-glucopyranosyl phosphonate 2, by standard method^.^ An indium-mediated addition to D- mannose has furnished vinyl phosphonate 3 from which the C-1 phosphonate 4 was prepared (Scheme 1). The same chemistry applied to N-acetylmannosa- mine afforded 5.4 These compounds were prepared as potential sialidase inhibitors.

HOCH2 I

H O ~ ~ ~ ~ ~ " " " ' BnO Qpzo

I OMe OH OH BnO OMe

1 2

0

P(OMe)2

H

o-mannose + +pcO -Ho$i i z x p H p m 2

0 HO

(OMe)2 Br

OH 4 X=OH 5 X=NHAc

3 Reagents: i, Indium, H20; ii, 0 3 ; iii, Me2S

Scheme 1

The thymidine 5'-phosphonate analogue 7 has been prepared by way of resolution of the non-carbohydrate precursor The Diels-Alder reactions of a vinyl phosphonate separately with furan, cyclopentadiene and E- 1 -acetoxy- 1,3-butadiene have been utilized as the initial steps in the preparations of racemic myo-inositol phosphonate analogues6


216

17: Inorganic Derivatives 217

The synthesis of some 2,3-azir~d~no-~-pentono-1,4-lactone-5-phosphonates is covered in Chapter 9 and the preparation of glycosyl difluorophosphonates is discussed in Chapter 8, while phosphonate analogues of nucleoside di- and tri-phosphates are detailed in Chapter 20.

Full details of the regioselective ring opening of 2,3-anhydro-sugar derivatives by LiPPhz have appeared (cf. Vol. 29, p. 219).7

The four stereoisomers of cyclic phosphonate 8 have been prepared8 and the phospholene-1-oxides 9 and 10 have been converted into 11, 12 and 1 3 - 1 5 ~ ~

pTolS 6

0

66n 8

0 OMe

OAc

OAc Me OAc Me AcO Me

9 10 11 12 R = OMe, OEt or Ph

0 OMe OAc

OAc

8 OAcAcO

OAc 13 14 15

2 Other Carbon-bonded Derivatives

The arsine oxide 16, a red algal constituent, has been synthesized from ribitol, lo and the organoiron-complexed derivative 17 was prepared as a racemate.


RO 0 18

R = sip+,

Y

% -Li

H d 'Et

Reagents: i, Cr(CO)6; ii, Me30BF4; iii, Cr(C0)5PPh3; iv, Et-Et; v, e O E t

Scheme 2

iii ( c o ) 5 M . q

0 - CHO i CH

R ' - ?OH-

R R R

R = 1::; or B n o l o B n OBn

OBn

OBn OBn

0 p M ( C 0 ) 5 x:ii M - C r o r W Ph

Ph

iik0 x Reagents: i,=.--MgBr; ii, M(C0)s.THF; iii, BuLi then PhCHO or M&=CH2 cr; iv, (C015M==(

Scheme 3

Organochromium carbohydrate compounds have been prepared from the lithiated glycal 18 (Scheme 2),12 and the same group have synthesized 2- oxacyclopentylidene complexes of chromium and tungsten from aldehydo- sugars and from sugar lactones (Scheme 3). 13*14

Various 0-( 3-trialkyl- or triaryl-stanny1)propyl sugar derivatives have been prepared by hydrostannylation of selected 0-ally1 mannose, glucose and lactose derivatives, and a number of trialkyl- or triaryl-stannylmethyl ether derivatives of D-xylose have been synthesized. l 6

Some C-tributylstannyl sugar derivatives are mentioned in Chapter 13 and a nucleoside carborane is discussed in Chapter 20.

17: Inorganic Derivatives 219

3 Oxygen-bonded Derivatives

The regioselective manipulation of hydroxyl groups using organotin ether intermediates has been reviewed, l 7 as have the interactions between transition metal ions and sugars. *

Some sugar alcohols have been treated with chlorophosphines to give phosphinic acid monoesters. l 9

New oxovanadium( IV) complexes of D-glucose, D-fructose, D-ribose and sucrose have been isolated crystalline as their sodium salts and characterized spectroscopicaIIy.20*2*

The equilibrium reactions between deprotonated 4-O-P-~-galactopyranosyl-D-gluconic acid and Co(II), Ni(II), Cu(II), Zn(II), CD(I1) and Hg(I1) ions have been studied by potentiometric and spectrophotometric methods. Compounds of the type M(X),.2H20.EtOH and CD(X)2.2H20.$EtOH have been isolated and characterized (M=Co, Ni, Cu, Zn and X=the disaccharide).22

Crystalline cobalt complexes with bis(N-~-glucopyranosyl-2-aminoethyl)(2- aminoethy1)amine have been prepared23 and sugar complexes of Co(I1) and Ni(I1) with, separately, D-glucose, D-fructose, D-galactose, D-xylose, D-ribose and maltose have been made and characterized by diffuse reflectance, CD, FTIR, EPR and cyclic v ~ l t a m m e t r y . ~ ~ ~ ~ ~ Some Ni(I1) complexes of glycosylamine derivatives of glucose, galactose, mannose and talose have been studied by MS (electrospray and CI). Specific cleavage of the sugar C-3- C-4 bond was identified .26

The glucose mannose epimerization reaction catalysed by Ni( 11) complexes has been studied using different Ni(I1)-coordinating l i g a n d ~ . ~ ~

D-Galactonic acid has been found to form four complexes with W(V1) in aqueous solution depending on the pH and concentration. Homologous species were also observed with Mo(V1) under similar conditions as well as four additional complexes.28 Nine complexes of L-mannonic acid with, separately, W(V1) and Mo(V1) in aqueous solution have been identified using multinuclear NMR spectro~copy.~~

The interactions of La(II1) with D-glucitol and ribitol in aqueous solution have been studied by NMR spectros~opy,~~ and manganese complexes with the adducts of tris(aminoethy1)amine and D-mannose or L-rhamnose have been identified.

The 1,2: 5,6-bis-O-[(4-~inylphenyl)boronate] of 3,4-O-cyclohexylidene-~- mannitol has been intramolecularly cyclized by radical initiation with AIBN to give 19.32

4 Nitrogen-bonded Derivatives

Oxorhenium(V) and oxotechnetium(V) complexes as inhibitors of ribonucleases have been reviewed33 and the new oxorhenium(V) complexes 20 and 21 have been prepared.34


19 20 R = H 21 R = Uracil-l-yl

References

1 2

3 4 5

6

7

8

9

10

11 12

13

14

15

16

17

D.F. Wiemer, Tetrahedron, 1997,53, 16609. L. Cipolla, B. La Ferla, F. Nicotra and L. Panza, Tetrahedron Lett., 1997, 38, 5567. G. -t. Zhang, Z.-w. Guo and Y.-z. Hui, Syntlz. Commun., 1997,27, 1907. T.-H. Chan, Y.-C. Xin and M. von Itzstein, J. Org. Chem., 1997,62, 3500. A. Arnone, P. Bravo, M. Frigerio, F. Viani, G. Salani and C. Zappala, J. Chem. Res. (9, 1997,458. C.K. McClure, K.B. Hansen, K.J. Herzog, J.S. Link and F.P. Arnold, Phos- phorus, SuIfur Silicon Relat. Elem., 1996, 109-110, 333 (Chem. Abstr., 1997, 126, 19 125). J.-C. Shi, T.-B. Wen, D.-X. Wu, G.-T. Lu, M.-C. Hong, Q.-T. Liu, B.-S. Kang, H.-Q. Wang and S.-J. Lu, Chin. J. Chem., 1996, 14,454 (Chem. Abstr., 1997, 126, 47 436). T.C. Harvey, C. Simiand, L. Weiler and S.G. Withers, J. Org. Chern., 1997, 62, 6722. M. Yamashita, A. Yabui, K. Suzuki, Y. Kato, M. Ushimura, A. Iida, H. Mizuno, K. Ikai, T. Oshikawa, L. Parkanyi and J. Clardy, J. Carbohydr. Chem., 1997,16,499. J.S. Edmonds, Y. Shibata, F. Yang and M. Morita, Tetrahedron Lett., 1997, 38, 58 19. P. J. Kleindl and W.A. Donaldson, J. Org. Chem., 1997,62,4176. K.-H. Dotz, R. Ehlenz and D. Paetsch, Angew. Chem., In?. Ed. Engl., 1997, 36, 2376. R. Ehlenz, 0. NeuS, M. Techenbrock and K.-H. Dotz, Tetrahedron, 1997, 53, 5143. K.-H. Dotz, W.-C. Haase, M. Klumpe and M. Nieger, Chem. Commun., 1997, 1217. S.J. Garden and J.L. Wardell, Main Group Met. Chem., 1997, 20, 711 (Chem. Abstr., 1997, 127, 346 575). L.A. Burnett, P.J. Cox and J.L. Wardell, J. Chem. Crystallogr., 1996, 26, 591 (Chem. Abstr., 1997, 126, 118 11 1). Y. Tsuda, Yuki Gosei Kagaku Kyokaishi, 1997,55, 907 (Chem. Abstr., 1997, 127, 319 148).

17: Inorganic Derivatives 22 1

18

19

20

21

22

23

24

25 26 27

28 29 30 31

32 33 34

R.P. Bandwar and C. Rao, Curr. Sci., 1997, 72, 788 (Chem. Abstr., 1997, 127, 95 456). D.I. Kolodiazhnyi and E.V. Grishkun, Phosphorus, Surfur Silicon Relat. Hem., 1996,115,115 (Chem. Abstr., 1997,126,47 433). S.B. Etcheverry, P.A.M. Williams and E.J. Baran, Carbohydr. Res., 1997, 302, 131. P.A.M. Williams, S.B. Etcheverry and E.J. Baran, J. Inorg. Biochem., 1997, 65, 133 (Chem. Abstr., 1997,126, 199 719). A.A. Frutos, G.M. Escondar, J.M.S. Peregrin, M.G. Sierra and L.F. Sala, Can. J. Chem., 1997,75,405. T. Tanase, T. Onaka, M. Nakagoshi, I. Kinoshita, K. Shibata, M. Doe, J. Fujii and S. Yano, Chem. Commun., 1997,2115. R.P. Bandwar, M.D. Sastry, R.M. Kadam and C.P. Rao, Carbohydr. Res., 1997, 297,333. R.P. Bandwar and C.P. Rao, Carbohydr. Res., 1997,297,341. G. Smith, S.F. Pedersen and J.A. Leary, J. Org. Chem., 1997,62,2152. H . Brunner and D. Opitz, J. Mol. Catal. A: Chem., 1997, 118,273 (Chem. Abstr., 1997,126,317 530). M.L. Ramos, M.M. Caldeira and V.M.S. Gil, Carbohydr. Res., 1997,297, 191. M.L. Ramos, M.M. Caldeira and V.M.S. Gil, Carbohydr. Res., 1997,299,209. Y. Israeli and C. Detellier, Carbohydr. Res., 1997,297,201. S. Yano, M. Doi, S. Tamakoshi, W. Mori, M. Mikuriya, A. Ichimura, I. Ki- noshita, Y. Yamamoto and T. Tanase, Chem. Commun., 1997,997. G. Wulff and B. Kuhneweg, J. Org. Chem., 1997,62,5785. P. Wentworth Jr., and K.D. Janda, Synlett, 1997, 537. D.P. Weiner, T. Wiemann, M.M. Wolfe, P. Wentworth and K.D. Janda, J. Am. Chem. Soc., 1997,119,4088.

18 Alditols and Cyclitols

1 Alditols and Derivatives

1.1 Alditols - A review on the application of D-(-)-quinic acid in natural product synthesis briefly mentions the synthesis of 2,4-di-O-benzoyl-3,5- dideoxy-D-erythro-hexitol and that of an epimeric mixture of 3-deoxy-4,5-di- 0-isopropylidene-6-0-(4-methoxybenzyl)-~-aZZo-l~-aZtro-heptitols as intermediates in the synthesis of (+)-negamycin and hepotoxin B3, respectively.'

Stereoselective (CpzZrCl)z-promoted pinacol-like coupling of isopropylidene-D-glyceraldehyde, followed by isopropylidenation, gave an 88: 12 mixture of 1,2:3,4:5,6-tri-O-isopropylidene-~-mannitol and 1,2:3,4:5,6-tri-O-isopropylidene-D-iditol.2

A short, multigram synthesis of 1,3,4,6-tetradeoxy-~-threo-hexitol has been achieved by treating 1,2: 5,6-di- O-isopropylidene-~-manni to1 successively with tosyl chloride-pyridine, aqueous mineral acid then more tosyl chloride-pyridine (to form 1,3,4,6-tetra-0-tosyl-~-mannitol) and finally with lithium aluminium hydride.

Symmetrical diols can be cleanly mono-benzylated with 1.1 equiv. of benzyl chloride in the presence of silver(1) oxide. For example, 1,3:4,6-di-O-benzylidene-D-mannitol gave a 92% yield of 2-0-benzyl- 1,3:4,6-di-O-benzylidene- D-mannitol and 1,6-di-0-benzyl-3,4-O-isopropylidene-~-mannitol gave the corresponding 1,2,6-triether in 93% yield.4

Several new, neutral amphiphiles of the type 1,2-di-O-alkyl-~-mannitols (alkyl = C12, C14, cl6 or C18) and derived from 1,2:3,4-di-O-kopropylidene-~- mannitol have been prepared. Aggregates formed between these compounds and a lipase functioned in organic solvent as an immobilized enzyme system for the enantioselective-acetylation or -hydrolysis of a-hydroxy esters or a-acetoxy esters, respectively.

D-Xylose has been converted by standard methods into mono-alkylxylitol derivatives as novel thermotropic liquid crystals. Thus 2-, 3-, 4- and 5-0-octyl- or -dodecyl-D-xylitols were prepared.6 Unprotected pentitols and hexitols have been converted into 1 3 - or 1,6-dibromo-peracetylated derivatives, respectively, by treatment with acetyl bromide followed by acetic anhydride-pyridine. Substitution of the dibromides with thioalkyl groups (butyl, octyl, dodecyl and hexadecyl) then de-acetylation gave the corresponding 1,5- or 1,6-alkyl- dithi~alditols.~


222

18: Alditols and Cyclitols 223

Addition of ethyl, allyl, vinyl or isopropenyl Grignard reagents to 4-0- protected (ethers, silyl ethers or esters)- 1,2:5,6-di-O-isopropylidene-~-arabino- 3-uloses was highly stereoselective in favour of the 3,4-~-ery?hro products. The stereochemistry of the additions were discussed and the Felkin-Anh and chelate transition state models were found not to be applicable in this series.8

A short synthesis of the red algal constituent 1 has been reported starting from 1,2:4,5-di- 0-isopropylideneribitol and involving treatment first with carbon tetrachloride-triphenylphosphine which caused acetal migration and led to l-chloro-l-deoxy-2,3:4,5-di-0-isopropylideneribitol. Substitution of the chloride with sodio dimethylarsine (Me2AsNa) then oxidation with hydrogen peroxide, acid-catalysed hydrolysis and sulfation gave ( + ) 1 (one enantiomer drawn for clarity). The absolute configuration of the natural 1 was not determined but is likely to be as drawn since the D-ribofuranosylarsine 2 is also found in the algae.9

Sharpless asymmetric dihydroxylation of alkene 3 under the usual conditions with hydroquinine 1,4-phthalazinediyl diether as chiral ligand [(DHQ)2PHAL, matched case] afforded D-galactitol derivative 4 as major product together with D-iditol derivative 5. The same reaction in the presence of hydroquinidine 3,6-pyridazinediyl diether as chiral ligand [(DHQD)zPYDZ, mismatched case] gave 5 as major product together with some 4. In a similar way, 1 -O-(4-methoxybenzoyl)-~-galacto- or D-do-hexito1 derivatives were prepared from 6.1°

0

0 II

CH2AsMe2

1:: CH20S03H

1

0 w OH OH

2 3 R = H

6 R = O ~ O M ~

4 R’ = H, R2= OH 7 5 R’ =OH, R2= H

8

Interaction of lithiated heterocycles with ribofuranose derivatives produced intermediate aldityl heterocycles, for example, 7, having mainly the R-config-


uration at the indicated carbon. These reacted further by Mitsunobu reaction to give mainly a-C-glycosides (C-nucleoside analogues) and full details of this work have now been reported. (See Vol. 28, p. 282, ref. 171 for preliminary report). Included also was the use of less basic metallated (Mg, Ce, Cd or Zn) heterocyles from which mainly S-configured aldityl heterocyclic intermediates were obtained, the R,S-ratio depending on the structure of the heterocycle. The S-products were further converted into P-C-glycosides. * Base hydrolysis of scorzoneroside A, a novel hepatoprotective triterpene glycoside isolated from a Chinese plant, generated ribitol glycoside 8. The structure and absolute configuration of 8 was confirmed by synthesis.12

The dipole moment of D-mannitol in aqueous solution has been determined by optical, dielectric and volumetric methods. l 3

1.2 Anhydro-alditols - Treatment of 1,4:3,6-dianhydrohexitol-iodide 9 with ally1 ethyl sulfone-AIBN in heptane or a mixture of heptane and chloroben- zene afforded an endo:exo mixture of C-allyl-derivatives 10, the former being favoured, in a new radical-based allylation reaction. l4 The reaction of 1,4:3,6- dianhydro-D-glucitol (isosorbide) with a mixture of trimethylsilyl chloride, sodium iodide and acetone gave the 3,6-anhydro- 1 -deoxy- 1 -iodo-D-gluco- compound 11. The same reaction performed on 1,4:3,6-dianhydro-~-mannitol gave the D-mannO-eqUiValent of 1 l?

Bzo H

CH2I

CH20Bn

BnO @ NHAC

9 R = - - - I 11 12 R-SnBus 10 R = *All 13 R - H

Compound 12, when treated with 1 equiv. of butyllithium at -78°C (deprotonates amide NH) then 1 equiv. of butyllithium at -65 "C (tin-lithium exchange, which does not occur at lower temperature) generated a dianion which trapped carbon dioxide at C-1 to give a P-C-glycosyl carboxylic acid as a peptide precursor for making derivatives with a reversed amide bond. (See Vol. 30, p. 47, ref. 310). A by-product from this reaction was 13. Now, NMR- deuteration experiments have established that the new proton at C-1 in 13 originated from the amide NH during treatment of 12 with base. Further, the amide NH could be selectively deprotonated with methyllithium-LiBr without any tin-lithium exchange and, when complete, treatment with BuLi generated a dianion in optimized yield. Hence maximum yields of P-C-glycosides could be made.16

1,4-Anhydro-2,3:5,6-di-O-isopropylidene-~-allitol has been prepared in 63% yield from the corresponding 1 -0-P-glycofuranosylphenylthionocarbonate by a catalytic Barton-McCombie deoxygenation reaction. The method used a new reagent combination of a catalytic amount of bis(tributy1tin)oxide-AIBN with


an excess of polymethylhydrosiloxane and n-butanol, conditions which generated catalytic amounts of tributyltin hydride in situ. l7

1,4-Anhydro-5-azido-5-deoxy-3-thio-~-erythro-pentitol' * and an N-pro tected 1,4-anhydro- 5-deoxy-5-met hylamino-3 - thi0-D- threo-pentit 01 have been prepared from 2-deoxy-~-ribose and coupled with carbapenams to produce novel antibacterial agents.

2,5:3,4-Dianhydro-1 -0-benzybribitol and -L-arabinitol have been prepared by standard means from 2,Sanhydro D-xylose diisobutyldithioacetal, itself prepared by conversion of D-xylose into its diisobutyldithioacetal derivative, followed by 5-O-tosylation with concomitant ring closure.20 The nucleophilic opening of (-t)-l,3:2,5-dianhydro-xylitol with 1,2-ethane- or 1,3- propane-diol under basic conditions afforded the corresponding 1 -O-(2-hyd- roxyethy1)- and 1 -O-(3-hydroxypropyl)-deri~atives.~~

Several papers reporting on the synthesis of anhydro-sugar-derived nucleosides have appeared. Thus 1,4-anhydro-erythritol has been converted in several steps into ( f )- 1,4-anhydro-2-azido-3-0-Tbdms-2-deoxy-erythritol and further elaborated into 14. The trans-isomer of 14 was also made, starting from 1,4: 2,3-dianhydro-eryt hritol .22 Treatment of 1,2-0-isopropylidene-3,5-di- 0- mesyl-or-D-xylofuranose with trifluoroacetic acid then potassium carbonate gave 23: 3,4-dianhydro-~-ribose dimethylacetal which was treated with azide to open the epoxide then further transformed through standard chemistry into the triazole isonucleoside 15 as well as into related pyrrolo[2,3-d]pyrimidine derivative^.^^ 1,4-Anhydro-~-ribitol has been converted in five straightforward steps into 16 in which the 5-OH group was bonded to a polymer support through a succinyl linker, as a universal solid support for oligonucleotide synthesis.24 2-Deoxy-~-ribose has been transformed in six steps into 17 for use in machine-assisted oligonucleotide synthesis.25

14

0 II

0

P=O I

OH

0 16

CH20Bn

BnO 0 Thy

19

0 I

Pr$N-P-O(CH2)2CN 17


Treatment of methyl 2-deoxy-a, P-D-erythro-pentofuranoside with N, 0- bis(Tms)trifluoroacetamide then triethylsilane gave the corresponding 1,4- anhydro sugar which was ultimately converted into the bis-abasic dinucleotide derivative 18 as an inhibitor of HIV-1 integrase.26 Several examples of a-analogues of 1,5-anhydrohexitol nucleosides have been reported. For example, treatment of 4,6-di-O-benzyl-3-deoxy-2-O-Thp-~-arabino-hexitol with tosyl chloride, sodium hydride-DMF then tosic acid gave 1 ,5-anhydro- 4,6-di-O-benzyl-3-deoxy-~-arabinitol. Further reaction of the latter derivative with N3-benzoylthymine-diethyl diazodicarboxylate-triphenylphosphine, then treatment with sodium hydroxide, gave thymine derivative 19. Several other purine and pyrimidine analogues were made in the same way and all deprotected. The cytidine equivalent of 19 showed moderate but selective antiviral activity. (See Vol. 30, p. 230, ref. 50 for related work on the synthesis of acyclic alditol nucleoside derivative^).^^

A facile synthesis of 1,2:5,6-dianhydro-alditols has been reported by treating various 3,4-0-acetal-protected-~-mannitol or -D-glucitol derivatives first with trimethyl orthoacetate-pyridinium tosylate then with acetyl bromide (to generate the 2,5-di-O-acetyl- 1,6-dibromo- 1,6-dideoxy derivatives) and finally with methanolic potassium carbonate. When 3,4-di-O-benzyl-protected derivatives in the mannitol series were used, the 1,s-anhydro compound 20 and bicyclo- [2.2.2]octane 21 were formed in addition to the expected products. 1,2:4,5- Dianhydro-6-O-benzyl-~-glucitol was also prepared from L-ascorbic acid.28

CH2Br

CH2OH

OBn

@ &CH2NHBn.HCI

BnO Me 20 21 22

3,6-Dideoxy-~-xyZo-hexono- 1,4-1actone on reaction with dimethylamine, borane then aqueous hydrochloric acid gave 1,3,6-trideoxy- 1 -dimethylamino- D-xyb-hexito1 hydrochloride. Treatment of this with anhydrous hydrofluoric acid-formic acid generated in the key step a 4,5-0-formoxonium ion intermediate which underwent intramolecular SN2 attack at C-5 by the 2-OH to form a 2,5-anhydro ring. Further treatment with basic ion exchange resin then methyl iodide afforded a facile route to (-)-do-muscarine. Compound 22 was also prepared as an analogue of the latter in a similar way and ent-22 was made from 3,6-dideoxy-~-xyZo-hexono- 1,4- la~tone.~~ In a related manner 1 -deoxy-1-trifluoroacetamido-hexitol derivatives on treatment with anhydrous hydrofluoric acid gave a reactive 2-trifluoromethyloxazolinium ion intermediate which underwent substitution by the 5-OH at C-2 with inversion of configuration to form a 2,5-anhydro ring. For example 1 -deoxy- 1 -trifluoroacetamido-D-glucitol gave 2,5-anhydro- 1 -deoxy- 1 -trifluoroacetamido-D-mannitol as major product together with small amounts of 1 -amino-3,6-anhydro- 1 - deoxy-D-glucitol and 1 -amino- 1 -deoxy-D-glucitol hydrofl~oride.~~


1.3 Amino- and Imino-alditols - Reviews on the chemical and chemoenzymatic syntheses of piperidine- and pyrrolidine-based sugar derivatives3 and on the chemoenzymatic syntheses of 5-, 6- or 7-membered ring imino- aldit01s~~ as glycosidase inhibitors have appeared. A review on the preparation of alditols using furan Diels-Alder chemistry has also been reported.33

1.3. 1 Acyclic Derivatives - Several non-ionic surfactant-like molecules have been prepared from 1 -deoxy- 1 -methylamino-D-glucitol. Thus treatment of the alditol with oleic acid and a Rhizomucor miehei lipase in h e ~ a n e ~ ~ or with oleic acid and a Candida antarctica lipase at 90 0C35 gave 1 -amino- 1 -deoxy-N- methyl-N-oleoyl-D-glucitol in 50% and 97%, respectively. Similarly, reaction of the same starting amino alditol with a commercially available mixture of fatty acid methyl esters [e.g. oleic (59%), linoleic (22%), linolenic (1 l%), palmitic (5%), etc.] and a Candida antarctica lipase in tert-butanol again gave a mixture of N-acylated derivatives as major products in a form suitable for direct use.36 In all cases, some 6-O-acylation took place.

The synthesis of the tacaman indole alkaloid 23 has been accomplished in several steps from the phthalimide derivative 24. The latter was made by treating 2,3 - O-isopropylidene-~-ribose with O- benzylhydroxylamine and reducing the intermediate oxime ether with lithium aluminium hydride to produce 1 -amino- 1 -deoxy-2,3-O-isopropylidene-~-ribitol which on treatment with N- e t hox ycarbon ylph t halimide- trie t hy lamine gave 24. 37

Reaction of 1 -( tert-butyloxycarbony1amino)- 1 -deoxy-2,3,4-tri-O-methyl-~- arabinitol with phthalic anhydride-pyridine followed by pentachlorophenol- dicyclohexylcarbodiimide then hydrochloric acid furnished 25. Attempts to polycondense 25 by heating in various solvents gave only minor amounts of desired oligomeric materials. The main product was the phthalimide 26.38

The (ribity1amino)uracils 27 have been synthesized as inhibitors of lumazine synthase. 39

The 1 -amino-l-deoxymannitol compound 28 has been prepared, the key steps being treatment of 2,3:5,6-di-O-isopropylidene-~-mannofuranose first with ethyl glycinate-sodium cyanoborohydride then diethylphosphonomethyl triflate to afford the corresponding 2,3:5,6-di-O-isopropylidene triethyl ester. The protonated form of 28 was found to be a potent inhibitor of 3-deoxy-~- manno-2-octulosonate-8-phophate (Kdo8P) synthase and believed to be effective by mimicking an intermediate oxycarbenium ion involved in the formation of K ~ O ~ P . ~

1.3.2 Cyclic Imino Compounds - Six new pyrrolidine alkaloids fitting within the generic structure 29 have been isolated from the branches of the plant Broussonetia kazinoki and have displayed potent glycosidase inhibitory activity. In particular, 29 (X = OH, Y = H, Z = OH, m = 8, n = 3, R = H) had IC50 values in the nanomolar region versus a P-glucosidase, P-galactosidase and P-mannosidase. The stereochemistry at the carbon where Z = OH remained undefined?I Isolated from the same plant also were the new compounds broussonetines C (29, X = OH, Y = H, Z = H, m = 8, n = 3) and D


M e O

CH20H

0

CH20H 24

0

QCI

CI CI

26 28

(29, X = OH, Y = H, 2 = H, m = 7, n = 4) which were also strong P-galactosidase and P-mannosidase inhibitors, but without effect on u- or P-glucosi- d a ~ e s . ~ ~ The 'homo DMDP' compound 30 has been isolated from the plant Hyacinthoides nun-scripta along with its 7-0-apiosyl deri~ative:~ and the new calystegine C2 (31) has been isolated, along with several pentahydroxy-nor- tropane alkaloids from Duboisia leichhardtii (solanaceae).4

R I

31 32 R = Boc or PO(OPh)2 33 R P Boc or PO(OPh)2

Treatment of carbamate or phosphoramidate derivatives of 5-amino-5-deoxy- 2,3-O-isopropylidene-~-ribofuranose with iodosylbenzene (PhIO) and iodine


generated anomeric O-alkoxyl radicals which underwent a P-fragmentation- oxidation process leading to the intermediate oxycarbenium ions 32 which were intercepted by the nitrogen group to give pyrrolidines 33. A similar reaction was observed starting with 6-tert-butyloxycarbonylamino-6-deoxy- 2,3,4-tri-O-methyl-~-glucopyranose and this gave a piperidine derivative."'

Displacement with inversion of the 5-O-triflyl group by the 2-amino group in 34 (prepared from D-glycero-D-gulo-heptono-y-lactone) upon treatment with sodium acetate-methanol gave 2,5-dideoxy-2,5-imino-~-glycero-~-galacto- heptitol. The product along with two related analogues inhibited UDP- galactose mutase and mycobacterium galactan bio~ynthesis.~~

Treating glycosyl enamine 35 with base resulted in displacement of the O-mesyl group by nitrogen. The resulting bicycle gave pyrrolidine 36 when treated with acetic anhydride-trimethylsilyl t ~ i f l a t e . ~ ~

n

OBz 34 35

36 37 Ar = 3-pyridyl or 38 substituted phenyl

39

A facile synthesis has been reported of 1 -amino- 1,2,5-trideoxy-2,5-hino-~- mannitol by Amadori rearrangement reaction of 5-azido-5-deoxy-~-glucofuranose with dibenzylamine to give 5-azido-1 -dibenzylamino- 1,Sdideoxy- P-D-fnictopyranose which was hydrogenated-hydr~genolysed.~~

The syntheses of a large range of 1,4-dideoxy- 1,4-imino-~-ribitol derivatives 37 as transition state analogue inhibitors of nucleoside hydrolases using a previously reported general method involving addition of lithiated aromatics to a cyclic imine (Vol. 30, p. 230, ref. 51 and Vol. 27, p. 21 1, ref. 68) have been reported.49

The use of 2,3: 5,6-di-O-isopropylidene- 1 -C-nitroso-p-~-mannofuranosyl chloride as a chiral dienophile for Diels-Alder reactions has been further demonstrated by its cycloaddition reaction with sorbaldehyde in the key step


and subsequent transformation into pyrrolidine 38 and its C-5 hydroxymethyl epimer as potential glycosidase inhibitor^.^^ The same nitroso-chloride has also been used to prepare 6-deoxy-~-nojirimycin, D-fuco-nojirimycin and 6-deoxy-~-guZo-nojirimycin and full details of this work are now described. (See Vol. 29, p. 236, ref. 86 for a preliminary acc~unt).~’

Furanosylamines reacted with (diethylphosphinoy1)-difluoromethyllithium followed by treatment with mesyl chloride-triethylamine to afford (difluoro- ethy1)phosphonate aza sugars such as 39. The deprotected form of this compound together with a series of differentialy configured derivatives were designed as transition state mimics for glycosyltransferases.52

The known methyl 2,3-dideoxy-5,6-~-isopropylidene-~-e~y~~ro-hexonate, derived from D-glucono- 1,5-1actone, on successive treatment with tosyl chloride-pyridine, sodium azide, DIBAL and hydrogen-PdC afforded 1,4- dideoxy- 1,4-imino-5,6- 0-isopropylidene-D-threo-hexitol which was further elaborated into @)-proline via manipulation of the side chain. ($)-Proline was also prepared by treating the same starting material successively with triphenylphosphine-carbon tetrabromide, lithium azide, DIBAL and hydrogen-Pd/C producing 1,4-dideoxy- 1,4-imin0-5,6- 0-isopropylidene-D-erythvo-hexitol, followed by degradation of the diol side chain.53 An analogue, 4-hydroxyprolinol, has also been synthesized from the uncommon keto sugar, 3-deoxy-~-g/ycero- pent~lose.’~

Treatment of 6-azido-5,6-dideoxy-5-fluoro-~-idofuranose with ‘sweetzyme T’, an immobilized glucose isomerase, gave 6-azido-5,6-dideoxy-5-fluoro-~- xylo-hex-2-ulose which on hydrogenation gave 2-fluoro-deoxynojirimycin. 1,2,5-Trideoxy- 1 -fluoro-2,5-imino-~-mannitol and 2,5-dideoxy-2,5-imino- 1-0- methybmannitol, for which the key step involved the use of the same glucose isomerase, were also prepared. The fluoro-derivatives were found to be poorer glycosidase inhibitors than the corresponding hydroxy 1,5,6,6‘-Tetradeoxy-6,6’-difluoro- 1,5-imino-~-glucitol has been achieved in a

straightforward manner starting from ~ - s o r b o s e . ~ ~ Full details on the synthesis of 7-carbonyl homologue derivatives of

deoxynojirimycin have been reported. (See Vol. 28, p. 227, ref. 53 for a preliminary account). 57

A five-step synthesis of D-nojirimycin and L-ido-nojirimycin from readily accessible 3- O-acetyl-5,6-dideoxy- 1,2- 0-isopropylidene-6-ni tro-ct-D-xylo- hex- Senofuranose has been achieved.58

The preparations of some C-glycoside derivatives of nojirimycin such as 40 have been described in which the key steps involved conversion of a protected 1 -methoxy nojirimycin derivative into a 1-deoxy- 1 -fluoride analogue by treatment first with phenylthiotrimethylsilane-trimethylsilyl triflate then N-bromosuccinimide-DAST. The resulting fluorides reacted with various trimethylsilyl C-nucleophophiles in the presence of Lewis acids. Compounds 40 were deprotected and all unsaturated groups hydr~genated?~

The 3-C-branched-3,fi-anhydro deoxynojirimycin compound 41 has been synthesized. The route involved treatment of 5-azido-6-O-Tbdps-5-deoxy- 1,2- O-isopropylidene-a-~-ribo-hex-3-ulofuranose with (ethoxycarbonylmethy1ene)-

18: Alditols and Cyclitols 23 1

CH20Ac

HO @ I

OAc EtO&H& OH 40 R = c N , ~ , [ = , 41

triphenylphosphorane then TBAF to produce a 3,6-anhydro-3-C-branched furanose. Subsequent removal of the acetonide and reductive amination furnished 41. An analogue of 41 containing a 3-C-hydroxyethyl group was also prepared.60

A new route to 6-deoxynojirimycin is illustrated in Scheme 1. The nitrone starting material was made by treating the corresponding 5-aldehyde derivative with N- benzylhydroxylamine.6 *

Bn Me

Me I

iii-v 1 Me

HO @OH

OH Reagents: i, MeMgCI, TrnseOTf; ii, Zn/Cu, AcOH; iii, HC02NH4, Pd/C; iv, SO2, H 2 0 v, HO-

Scheme 1

The syntheses of some N-alkylsilyl-, N-alkenyltrialkylsilyl- and N-benzyltri- methylsilyl-deoxynojirimycin derivatives have been described and their inhibitory activities against a range of intestinal glycosidases assessed. It was found that 42 was a potent inhibitor of intestinal sucrase but the (2)-isomer of 42 was only a weak inhibitor.62

1 -Deoxygalactonojirimycin has been prepared with high diastereoselectivity by double reductive amination of ~.-arabino-hexos-5-ulose with benzhydrylamine followed by hydrogenolysis. In contrast, double reductive amination of 2,6-di-U-benzyl-~-arabino-hexos-5-ulose with ammonia or methylamine followed by deprotection gave 1-deoxygalactonojirimycin and its N-methyl derivative together with 1 ,5-deoxy- 1,5-imino-~-altritol and its N-methyl deriva-

In a similar way a double reductive amination of 3-O-benzyl-6-deoxy-~- xylo-hexos-5-ulose with benzhydrylamine was the key step in the formation of 1,6-dideoxynojirimy~in.~

The synthesis of several 1,5-deoxy- 1,54minopentitols from 5-bromo-5-


deoxy- or 5-0-mesyl-pentonolactones has been reported. For example, treatment of 5-bromo-5-deoxy-~-arabino- 1,44actone with ammonia then 2,2- dimethoxlpropane-tosic acid, followed by sodium borohydride-trifluoroacetic acid, gave 43. The compounds were tested for inhibition of a glycosidase from human liver.65

Previous reports have demonstrated the utility of aldolases in the preparation of azido sugars which upon hydrogenation afford aza sugars, (See for example Vol. 30, p. 234, ref. 79 and Vol. 28, p. 231, ref. 67). Scheme 2 illustrates a way in which the latter hydrogenation step can be controlled, allowing the isolation of imine intermediates. The method was also applicable to the formation of 6- membered cyclic analogues. In general, it was found that the cyclic imines were more potent glycosidase inhibitors than their reduced forms.66

H0JCHO - i, ii N3 QH - iii, iv H2N

CHpOH CH~OCOBU

OH OH

H O H ~ C ~ C H ~ O C O B U

OH Reagents: i, Dihydroxyacetone phosphate, aldolase; ii, phosphatase; iii, CH2=CHOCOBu, Lipase;

Scheme 2 iv, H2/Pd/C, HCI; v, NaOH

A synthesis of 1,7-diamino- 1,2,6,7-tetradeoxy-2,6-irnino-~-glycero-L-gulo- heptitol has been described in which the key step involved intramolecular amination of aziridine 44 upon treatment with base to give 45 which was hydrogenated-hydrogenolysed to product.67

NHBn

CN

Q-TmS CH2OH H@ BnO-/l:l B n D

HO CH2NHBoc

OBn 42 43 44 45

BocN OH OH

R R

@ l C O 2 H

HO

OH OH OH 46 R=HorBn 47 R=HorBn 48


1,5-Dideoxy- 1,5-imino-~-fucitol has been prepared from intermediate methyl 2,3-di-O-Tbdms-a-~-arabino-pentodialdo- 1,4-furanoside in several conventional steps. 68

The 4-acetamido-3,5-dihydropiperidines 46 have been synthesized and found to inhibit bacterial sialidases. The synthesis involved substitution of 3- azido-3-deoxy- 1,2- 0-isopropylidene-5- U-triflyl-a-D-xylofuranose with glycine- or phenylalanine-methyl esters followed by protecting group manipulations to afford intermediates 47 which were hydrogenolysed then ~aponif ied.~~

The N-protected 6-deoxy-6-C-phenyl analogue 48 of isofagomine has been made as a precursor for an isofagomine-based peptide derivative by treating 1,6:2,3-dianhydr0-4-O-benzyl-P-~-mannopyranose with benzylmagnesium chloride, hydrochloric acid then benzylamine-sodium cyanoborohydride to give 1 -aminobenzyl-2- C,4- 0-dibenzyl- 1,2-dideoxy-~-glucitol which was oxidized with periodate, hydrogenolysed and treated with (Boc)20. (See Vol. 28, p. 229, ref. 58 for related

Full details have been reported on the synthesis of 1,4,5-trideoxy-l,5-imino- D-ribitol from L-arabinose. (See Vol. 30, p. 231, ref. 63 for a preliminary report). '

The synthesis of some L-iduronic acid-like 1 -N-imino-sugars from micro- organism-derived siastatin B is covered in Chapter 19 and the synthesis of 5- amino-~-deoxy-~-pentonolactones from unprotected D-pentonolactones is mentioned in Chapters 10 and 16.

The synthesis. of the C-linked D-aza-Manp-P-( I +6)-~-Glcp-OH analogue 49 in which the key step involved a Suzuki-like cross coupling of a cyclitol- derived vinyl bromide with a glucopyranose-derived alkyl borane, followed by conversion of the cyclitol moiety into a 1,5-deoxy-l ,S-imino-D-mannitol ring structure, has been described. The method is similar to a previously reported one (Vol. 28, p. 229, ref. 61) and was also applied to the synthesis of analogous D-aza-Manp-P-( 1 -+ 6)-~-Manp-OH, D-aza-Manp-P-( I -+ 4)-~-Talp-OH and D-aza-Manp-P-( 1 -+ l)-~-Glcp-OH products. The compounds were evaluated as glycosidase and HIV inhibitor^.^^

Compound 50 has been prepared by linking 1,2,6-trideoxy-2,6-imino-3,4-0- isopropylidene-D-galactitol (a deoxy-L-fuconojirimycin derivative) with 2-(2- bromo benzyl) 2,3,4,6- tet ra- 0-acetyl- P-D-galactopyranoside and depro tecting . An analogue of 50 was also prepared in which the aromatic linker group was replaced with a n-butyl one. The deoxyfuconojirimycin derivative above was prepared from a known 1 -C-methyl-2,3:5,6-di-U-isopropylidene-P-~- mannofuranose. 73

The aza- C-disaccharide 51 has been made by treating tri-@acetyl-D-glucal with nitrone 52 and the resultant cycloadduct successively with sodium methoxide-methanol, trifluoroacetic acid then hydr~gen-Pd/C.~~

Scheme 3 illustrates a route to an aza-C-linked disaccharide structure, starting from a known protected imino-octitol (Vol. 30, p. 233, ref. 75, compound 45).75

Several iminoalditols have been prepared from non-carbohydrate sources. Thus (+)-aza-C-disaccharide 53 together with an analogue have been made as


CHzOH

HO LQOH OH

49

i-iv ___c

OH 50

V __c

?-

OH OBut 51 52

Cl

I OBn

OH

Reagents: i, BnBr, NaH; ii, BnOCOCI; iii, AcOH, H20; iv, I04-; v, "no, LiN(Tms)z PhSe'

Scheme 3

moderate a-mannosidase inhibitors from a known bicyclic cycloadduct formed between furan and 1-cyano vinyl acetate.76 D-Tartaric acid has served as chiral starting material for the synthesis of 1,4-dideoxy- 1,4-imino-~-arabinitol~~ and of nectricine and epi-ne~tricine.~~ D-Serine was the starting material for the preparation of nucleoside analogue 54 which when incorporated into an oligonucleotide, followed by conversion of the 6-chloropurine ring into an adenine ring, bound to a base-excision DNA repair enzyme with a Kd < lpM.79 trans- 3-Hydroxyprolinol has been prepared as major product from L-serine and converted to the N-acyl derivative 55 for incorporation into oligonucleotides. Likewise the enantiomer of 55 was made from D-serine. cis-3-Hydroxyprolinol enantiomers were also formed as minor products.80

Addition of ally1 bromide to an N , 0-protected D-serinal derivative, mediated by tin(I1) chloride-sodium iodide, gave 56 as the major isomer. Successive treatment with triphenylsilyl chloride-pyridine, osmium tetroxide, TEMPO-

18: Alditols and Cyclitols

CH20H

235

CI I

I

OH 53

GHzoH OH

55 B = Thy, AdeBz

54

"CbZ CHzOTbdms

56

sodium hypochlorite then hydrogen-Pd/C produced 6-O-Tbdms- 1,3,5-trideoxy- 1,5-imin0-4-O-triphenylsilyl-~-ribo-hexitol which, after treatment with TBAF, afforded 1,3-dideoxynojirimycin, offering an alternative route to this system. (See for example Vol. 28, p. 227, ref. 54).81

Tin-mediated aldol reactions between L-tartrate-derived 4-0-benzyl-2,3-0- isopropylidene-L-threose and protected alanine and glycine amino acids was the key step in the synthesis of several aza-sugars. For example, l-deoxy-L- ah-nojirimycin was made involving a glycine derivative.82

Cycloaddition reaction between 2-trimethylsiloxyfuran and (9-lactaldehyde-derived nitrone 57 gave 58 together with the isomer inverted at the indicated carbons. Hydrogenolysis of 58 gave a lactam which was treated with borane to afford 6-O-benzyl-l,2,5,7-tetradeoxy-l,5-imino-~-altro-heptitol. Similar treatment of the isomer of 58 gave 2-O-benzyl-l,3,6,7-tetradeoxy-3,7- imino-~-gahcto-heptitol.~~

57 " 5 8 59 R = Ph, n-C8Hl7 or (CHz),OBn

Full details on the preparation of 1 -deoxy-D-mannojirimycin and 1 -deoxy-L- altrojirimycin from (2R,6R)- and (2S,6S)-6-hydroxy-2-methoxymethyl-N- tosyl- 1,2,3,6-tetrahyroxypyridin-3-one, respectively, both prepared from an a-furfurylamine, have been published. (See Vol. 30, p. 236, ref. 92).84 Aryl- and


alkyl substituted deoxynojirimycin analogues such as 59 have been prepared from benzene cis-diols (microbial oxidation p r o d u ~ t s ) . ~ ~ , ~ ~

2 Cyclitols and Derivatives

The synthesis of carba-sugars, inositols and carba-amino-sugars such as valiolamine from D-( - )-quinic acid has been reviewed. Reviewed also are intramolecular cycloaddition reactions of sugar-based C-centred radicals onto oxime ethers or hydrazones giving amino- and hydrazino-cyclitols, respectively . 87

2.1 Cyclopentane Derivatives - The involvement of free radicals in the C-C bond forming step in the synthesis of cyclopentane rings has received much attention. Thus the cyclitol moiety found in the natural product caryose (Vol. 30, p. 237, structure 74) has been prepared by treatment of 2,3,4-tri-O-benzyl- 6-deoxy-~-xylo-hexos-5-ulose with samarium diiodide to give 60. The synthesis of caryose itself was completed in five standard steps from 60. (See Vol. 30, p. 237, ref. 101 for the characterization of caryose).88 The cyclization of 1,5- iodo-oxime ether derivatives with samarium diiodide proceeds to give trans- products about the newly formed bonds. Thus for example 61 gave 62. In this case an O+N migration of a pivaloyl group and breakage of the N-0 bond of the oxime ether were observed. Several other examples were described.89 Many examples of the synthesis of 4-amino-l,2,3-cyclopentanetriol derivatives by reductive couplings of 1 ,5-halogeno-, keto- or aldehydo-oxime ethers have also been reported.90 Likewise, the carbocyclic nucleoside precursor 63 has been prepared by an improved procedure (see also Vol. 25, p. 21 1, ref. 82) using a similar kind of radical-based ring closure of an iodo-oxime ether followed by conventional cherni~try.~~ Treatment of unsaturated iodide 64, available in three steps from 5-deoxy-5-iodo-2,3-O-isopropylidene-~-~-r~bofuranose, with samarium diiodide gave cyclopentane 65, whereas with tributyltin hydride- AIBN, cyclopentane 66 was produced.92

CH20H

OBn Me RO 60 61 R = Piv 62 R = Piv

63 64 65 R=CH=CH2 66 R = (CH2)zOAc


Grob fragmentation of methyl 6-deoxy-6-iodo-2,3-0-isopropylidene-4-O- (substituted 2-propynyl)-a-~-mannopyrannoside derivatives, followed by treatment with samarium diiodide, gave the 5:6-bicyclic compounds 67. When the 2,3-di-O-methyl- or benzyl-D-glucopyrannoside equivalent starting materials were used, the 5:7-membered ring products 68 pred~mina ted .~~

Treatment of 2,3,4- tri- 0- benzyl-5,6,7,8- te tradeoxy-D-xy Zo-oct- 5( E), 7-dienose (see Vol. 28, p. 8, ref. 30 for its preparation) with tributyltin hydride-AIBN gave compound 69. Reduction of the aldehyde group in the starting material to an alcohol and conversion of this into a xanthate then treatment with tributyltin hydride gave the deoxy version of 69 at the indicated carbon. Some other similar examples

R

h

were descii bed.94

R' I

67 R = H, Me or Tbdms 68 R = Me or Bn, R1 = H or Me 69

Po CH28r

OAC Acoqn ~ H P O H

@ BnO

OBn - 70 71 72

Treatment of the bromo-lactone derivative 70 with tributyltin hydride- AIBN gave cyclopentane 71. The lactone function of 71 was hydrolysed and the carboxylic acid-containing substituent was reduced to a hydroxyethyl group. Other similar examples were also reported.95

Treatment of 2,3,4-tri-O-benzyl- 1,5,6-trideoxy- 1 -iodo-~-xyZo-hex-5-enitol with a Co(salicy1ideneiminato) complex in the presence of sodium hydroxide gave 72 as the major product together with its hydroxymethyl epimer. Many other examples with different sugar configurations were also d e ~ c r i b e d . ~ ~

The bicyclic cyclopentane derivative 73 was produced when 2,3,6,?-tetradeoxy-4-O-methyl-~-erythro-hept-2,6-dieno- 1,5-lactone was irradiated with light in i s o p r ~ p a n o l . ~ ~

The preparation of cyclopentane-based bicyclic and tricyclic systems, formed by intramolecular cycloaddition reaction, has been further exploited. For example, addition of the azomethine imine derived by treatment of ethyl N- benzylcarbazate ( BnNHNHC02E t) with triet hylamine to 2,3,4- tri- 0- benzyl-5,6-dideoxy-~-xyZo-hex-5-enose gave 74. Some similar examples were also described.98


Me OH Me

C02Et

BnO Q-Bn OBn

Bn I

73 74 75

Bn I

0-N

OBn 76 R = OH, OMe, OBn or OAll 77 70

The nitrones 75 underwent facile cyclization on heating to give new tricyclic systems. For example 75 (n = 1) gave 76.99

Bicyclic derivative 77 was prepared by intramolecular Diels-Alder reaction of (E),(E)-methy14,5,6-tri-0-benzy1-2,3,7,8,9,10-hexadeoxy-~-arabio-2,7,9-tri- decanoate catdysed by aluminium trichloride. loo 2,3,4-Tri-O-benzyl-xylodialdose has been converted into its 1,5-di-oxime

derivative and oxidized with N-chlorosuccinimide-pyridine to its bis-nitrile oxide which dimerized to give 78 plus its N-oxide isomer. Hydrogenolysis of the heterocyclic ring without loss of the 0-benzyl groups produced the corresponding cyclic bis-oxime derivative. lo1

Full details of a preliminary report (M.P. van Boggelen et al., Tetrahedron Lett., 1995, 36, 1899) on an efficient, short synthesis of a cyclopentene aldehyde has been published (Scheme 4). The method involved a novel methyl iodide-induced N-0 bond cleavage reaction in the key step. A quaternary ammonium iodide alcohol was also produced as shown which could be converted to the cyclopentene aldehyde by oxidation with concomitant elimination of triethylamine lo*

vi

CH20H

__t

Reagents: i, CH2=CHMgBr; ii, Na104; iii, MeNHOH, Py; iv, Ac20. Py; v, Mel, THF, reflux;

Scheme 4 vi, (COC1)2, DMSO


Treating compound 79, available from a protected D-gulonolactone, with periodic acid gave as intermediate, N,N-diethyl 5-deoxy-2,3-O-isopropylidene- ~-erythro-hex-4-uluronamide, which cyclized to cyclopentenone 80. lo3

The carbocyclic analogue of 5-phophoribosyl 1 -pyrophosphate has been synthesized by reaction of 81 first with methanol under light irradiation, then reduction with sodium triacetoxyborohydride to give 82 which was phosphorylated and deprotected. lo4

t:>< 79

CONEt2 I

0 0

Y Ph

FH20H

QH 0 0

Y bh a2

CH20Bn

'Q OBn

83

C02Me

CH20Bn p H 2 'p' CHpOH V T F N H C O P h N3b H

OBn OR OR OH OMe 84 85 R = Bn, R1 = COpMe

86 R=H, R'=NH2 87 R = Bn, R' = CH~NHAC

88

A chiral synthesis of the known cyclopentane epoxide 83 has been achieved from sodio cyclopentadiene, as an intermediate useful in the synthesis of carbocyclic nucleosides. lo5 The same epoxide was transformed into amine 84 and on into carbocyclic nucleoside derivatives based on adenine, guanine and cytidine in the same way as that described for the thymine analogue in Vol. 29, p. 285, ref. 167.1°6

The chiral ester derivative 85 has been prepared by an initial Diels-Alder reaction and converted into carbocyclic nucleoside precursors 86 and 87. lo7

( -)-( lR,4S)-2-Azabicyclo[2.2.1 Jhept-5-en-3-0ne was used as starting material for the synthesis of 881°8 and enantiomerically enriched norborn-5-en- 2-yl acetate was used as starting material in the preparation of 89, a precursor to carbocyclic analogues of the nucleoside antibiotics nikkomycins and polyoxins. lo9

l-Dimethylphenylsilylcyclopenta-2,4-diene was the starting material for the cyclopentane ring found in the carba-disaccharide 90. Compound 90 in which the cyclopentane ring had the enantiomeric stereochemistry was also prepared. lo

240 Carbohydrate Chern istry

2.2 Inositols and Other Cyclohexane Derivatives - A review on the stereospecific syntheses of all conduritol isomers derived from appropriate cyclohexa-l,3-dienes has appeared. l 1

Full details on the preparation of (-)-shikimic acid and related compounds involving a novel methyl iodide-induced N-0 bond cleavage reaction of isoxazolidine derivatives have been reported. (See M.P. van Boggelen et aZ., Tetrahedron Lett., 1995,36, 1899 for a preliminary account).*02

The addition of allyl magnesium bromide to 2,3-O-isopropylidene-~- ribofuranose gave a mixture of 1,2,3-trideoxy-5,6-0-isopropylidene-~-all-oct- 1 -enitol (major isomer) together with the corresponding D-altritol derivative. Treatment of this mixture with sodium periodate followed by N-methylhydroxylamine gave isoxazolidine 91 as the major isomer which was converted into the novel (-)-5-epi-shikimic acid, the key step being hydrogenolytic N - 0 bond cleavage in 91. In contrast allyl magnesium bromide added to protected D-ribono- 1,4-lactone, followed by reduction with DIBAL, to give exclusively 1,2,3-trideoxy-5,6-0-isopropylidene-~-a~tro-oct-l -enit01 from which ( -)-shikimic acid was obtained again via a hydrogenolytic N - 0 bond cleavage reaction of an isoxazolidine intermediate. l 2

(3R)-3-Fluoro-Dahp and its C-3 epimer have been made by enzymic methods and used as substrates for dehydroquinate (DHQ) synthase. The (3R)-epimer was found to be consumed rapidly to produce (6R)-6-fluorode- hydroquinate whereas the (3S)-epimer was only consumed slowly and gave mixtures of (6R/6S)-6-fluorodehydroquinates. The results were interpreted to reveal a subtle role for the enzyme in the natural process.113

0

"x" PH R OH

I

90 91 92 R = OPO3H2 or CH(C@H)2

(-)-Quinic acid has been used to prepare useful biologically active cyclo- hexitols. For example, unsaturated derivative 92 and related compounds were prepared and found to be very potent DHQ synthase inhibitors; more potent than their saturated equivalents. l4 Carbocyclic analogues of N-acetyl-2,3- didehydro-2-deoxy-neuraminic acids in which the trihydroxypropyl unit found in the natural compound was replaced by a range of small linear and branched alkyl groups have been made as very strong influenza neuraminidase inhibitors. l 5 Other carbocylclic analogues of sialic acid prepared from quinic acid as well as shikimic acid starting materials have also been reported.l16 An efficient way of making myo-inositols with free 1,3-hydroxyl groups via a chelation


assisted C - 0 bond cleavage of ortho ester derivatives has been described. For example treatment of 2,4,6-tri-O-methyl-myo-inositol 1,3,5-0rthoformate with two equivalents of methylmagnesium Grignard gave the ex0-3~5-O-ethylidene derivative 93 which on further treatment with excess phenylmagnesium Grignard reagent gave 5-O-benzhydryl-2,4,6-tri-O-methyl-myo-inositol. In a similar way treatment of the corresponding orthobenzoate-derived starting material with excess lithium aluminium hydride-aluminium chloride furnished 3-0-benzyl-2,4,6-tri-O-methyl-myo-ino~itol.~ l7 Treatment of 2,4-di-O-benzoyl- myo-inositol- 1,3,5-orthofomate with alkyl halides and silver(1) oxide unusually led to the 4,6-di-O-alkylated or 4-O-mono-alkylated myo-inositol-l,3,5- orthoformate derivatives. The products produced were very dependent on the nature of the reagents and solvent used.' l8

Full details (Vol. 29, p. 239, ref. 104 for preliminary account) on the syntheses of 3-deoxy-~-chiro-4-inosose and 6-deoxy-~-myo- I -inosose as precursors of 3-deoxy-~-chiro- and 6-deoxy-~-myo-inositols, respectively, have been reported. The cyclitol ring was made by a Ferrier carbocyclization reaction on a methyl D-galactopyranoside derivative. In addition the synthesis of 2-O-benzyl-3,6-dideoxy-3-fluoro-~-myo-inos~toI was also described. ' l9 A lH- and I3C-NMR investigation of myo-inositol hexaacetate is covered in Chapter 21.

Cyclohexene derivative 94 has been prepared from D-glucose by a Ferrier carbocyclic reaction and converted into its P-epoxide derivative or induced to undergo a thermal Claisen rearrangement with dimethylformamide dimethylacetal. D-Quinic was also converted into unsaturated cyclitol derivatives which also underwent similar epoxidation-rearrangement reactions. 120

Me--{@

Me0 BnO OR OH OR OH OMe

93 94 95 R = Bn or Tbdms 96 R = Bn or TWms

Treatment of 3,4,5-tri-O-benzyl- 1,2,7,8-tetradeoxy-~-gZuco-oct- 1,7-dienitol with TbdmsC1-imidazole followed by ozone and samarium diiodide afforded 3,4,5-tri-0-benzyl-6-O-Tbdms-~-chiro-inositol. The dienitol starting material was prepared in three straightforward steps from D-xy1ose.I2' Oxidation of 2 , s di- O-Tbdms- or 2,5-di-0-benzyl-3,4-O-isopropylidenemannitol followed by treatment with samarium diiodide yielded mixtures of neo-inositol derivatives 95 and do-inositol derivatives 96. The former isomers predominated with the 2,5-di-O-Tbdms-alditol starting material whereas the latter was the major isomer with the 2,5-di-O-benzyl-alditol. Compound 96 (R = Bn) was also converted into ( - )-conduritol E when treated under Corey-Winter conditions.122 A simple synthesis of a (-)-conduritol E derivative has been achieved by potassium hydroxide treatment of sulfone !V leading to expulsion of sulfur dioxide (Ramburg-Biicklund reaction) followed by deacetylation.123


(+)-D-Conduritol tetraacetate has been synthesized from 1,2:4,5-di-O-cyclohexylidene myo-inositol, the key step involving resolution of a dispiroketal intermediate. 124

Successive treatment of compound 79 first with aqueous acid, sodium periodate then base gave unsaturated derivative 98. lo3

2,3,4,5-Tetra-O-benzyl-~-rnannitol has been converted to its corresponding 1,6-di-oxime derivative and oxidized with N-chlorosuccinimide-pyridine to its bis-nitrile oxide which dimerized to give 99 plus its N-oxide isomer. Hydro- genolysis of the heterocyclic ring without loss of the 0-benzyl groups produced the corresponding cyclic bis-oxime derivative. lol

A short synthesis of (+)-pinit01 from benzene has been achieved in which the key step involved a catalytic photoinduced charge-transfer osmylation in the presence of sodium bromate. Treatment with acetone-acid then led to the key intermediate, 4-bromo-4-deoxy- 1,2: 5,6-di-O-isopropylidene-neo-inositol, together with two other cyclitol derivatives. (See W.B. Motherwell et al., Angew. Chem. Int. Ed. Eng., 1995,34,280 for preliminary

The most common routes to cyclitols derived from benzene are those that involve a microbial oxidation step to produce a cis-diol derivative. By use of this method 3-deoxy-3-fluoro-~-chiro-inositol, 5-deoxy-5-fluoro-myo- inositol,126 allo-in~sitol '~~ and conduritol D12* have all been prepared from bromobenzene. The formation of the last of these compounds is notable in that in the key step a syn-dihydroxylation of the initial cis-diol oxidation product was achieved using osmium tetroxide-trimethylamine N-oxide. Anti- dihydroxylation is more commonly observed in these systems. From benzene itself, ( f )-conduritol E,129 (-)-conduritol E, (-)-conduramine F4130 and partial 0-acetyl derivatives of (+)- and (-)-conduritol have been reported; asymmetry being introduced by lipase-mediated kinetic resolution. Full details on the preparation of mono-epoxy derivatives of various benzene cis-diols and their regioselective opening with 0, N, C and halogen centred nucleophiles have appeared. (See Vol. 28, p. 242, ref. 142, Vol. 27, p. 218, ref. 1 12 and 1 13 for

A route to ( +)-trans-cyclohexa-3,5-diene- 1,2-diol derivatives from ( k )- myo-inositol derivatives has been r e ~ 0 r t e d . I ~ ~

Oxidation of ( f )-3,4,5-tri-O-benzyl- 1,2-O-isopropylidene-myo-inositol gave the corresponding inosose. Reduction of this ketone with sodium borohydride gave an epi-inositol derivative, whereas treatment with methylmagnesium iodide gave a 4-C-methyl-epi-inositol (iso-laminitol) derivative. The same inosose, on treatment with diazomethane, gave a spiro-epoxide which reacted with lithium aluminium hydride to give a 4-C-methyl-myo-inositol (laminitol) compound.134

The bicyclic cyclohexane derivative 100 was produced when 6-0-acetyl- 2,3,7,8-tetradeoxy-4-methyl-~-ri~o-oct-2,7-d~eno-l,5-lactone was irradiated with light in i sop r~pano l .~~

In the area of carba-disaccharides a new inositol glycoside, a-D-Galp-( 1-2)- 2-0-~-chiro-inositol has been isolated from the jojoba plant Simmondsia chinensis together with known a-D-Galp-( 1 -+ 1)- 1 -O-L-myo-inositol (galac-


t i n ~ l ) . ' ~ ~ A route to galactinol has also been described by coupling an appropriate L-myo-inositol derivative with a protected galactosyl trichloroacetimidate donor. 136 The structure of 'galactosylononitol' has been revised to a-D-Galp-( 1 + 3)-4-O-methyl-3-O-~-rnyo-inositol.'~~ The synthesis of sialyl LeX mimics containing a cyclitol in place of a galactose or GlcNAc ring is mentioned in Chapter 4.

0 j9 Me OAc

X 0 0

HO Q0 CONEt2 OBn

97 98 99

6@n CH~NHAC

OBn

AcO

OAc

CH20H I

OH 100 I01 102

The carba-disaccharide 101 has been synthesized by coupling tetra-O-acetyl- a-D-glucopyranosyl bromide with the corresponding mono-hydroxy cyclitol derivative under Koenigs-Knorr conditions. The cyclitol portion was made from D-glucose by Ferrier carbocyclization reaction.I3* The cyclitol moiety in 102 (a 2-deoxyisomaltose analogue of acarbose) was made by a similar carbocyclic ring forming reaction applied to methyl 3,4-di-O-benzyl-2,6- dideoxy-~-threo-hex-5-enopyranoside. The D-glucose unit was attached by displacement of a 6-O-triflate by the cyclitol amino group. 139

The acarbose analogue 103 has also been made by coupling an amino cyclitol to a sugar epoxide.lN The carbamate compound 104 was surprisingly obtained in 25% yield when benzyl 2,3-di- O-benzyl-6-deoxy-4-O-triflyl-P-~- galactopyranoside was treated with amino cyclitol 105 and potassium carbonate-HMPA. A similar reaction took place between 105 and a trisaccharide t~iflate.'~' Improved procedures for the large scale synthesis of 105 have also been described.14z

The syntheses of some novel carba-disaccharide types of aminocyciitol antibiotic model compounds by glycosylating a suitably protected (azido) deoxy inosose with mono-saccharides derived of D-arabinose, D-ribose, D- glucosamine, L-ristosamine and L-acosamine have been described. * 43

The carbo-lactosaminide 106 and its (1 -+ 3)-linked equivalent have been prepared by nucleophilic opening of a cyclitol epoxide with a D-glucosamine-

244

Me

CH20Bn


CH20Bn 1

OH 103

BnO (kJ OBn

104

OBn BnO QH2

b n 105

based alcohol. Compound 106 was found to be a substrate for human milk fucosyltransferase. 144

1 -tert-Butyldimethylsilylcyclohexa-2,5-diene was the starting material for the cylclitol unit found in 107 and was produced in chiral form using Sharpless asymmetric dihydroxylation chemistry. lo The same dienylsilane, after asymmetric dihydroxylation, was also used to prepare carba-a-D-galactopyranose-, carba-P-L-altropyranose and related-derivatives. 145

Validamine (carba-a-D-glucopyranosylamine) has been transformed by standard chemistry into its ‘manno’ and ‘galacto’ equivalents. 146 The morpholino group in the known glucosylceramide synthase inhibitor, 1 -phenyl-2-decanoyl- amino-3-morpholino- 1 -propanol, has been replaced with valienamine and validamine. The products were no longer inhibitors of the synthase but were found to be potent inhibitors of a P-glucocerebrosidase. 147

A synthesis of (+)-cyclophellitol by a stereoselective Diels-Alder reaction has been described. 48

2.3 Inositol Phosphates and Derivatives - A review on the total syntheses of inositol phospholipids involved in signal transduction has been published. It includes the preparation of inositol 3,4,5-trisphosphate, 4,5- bisphosphate and 2,6-dimannopyranosylphosphate and the use of new benzoyl derivatives bearing oxyethyl substituents at the ortho-positions as protection for hydroxyl groups. The latter are selectively removable in the presence of OAc groups. 149

Studies on the elucidation of the catalytic mechanism of phosphatidylinositol-specific phospholipase C (PI-PLC) (converts phosphatidyl inositol into 1-inositol phosphate) and its comparison with that of ribonuclease A have been r e ~ 0 r t e d . l ~ ~ The synthesis of the [l3H]-1abelled form of the potent PI-PLC in hi bi tor 1 -octadec ylphospho t hiolyl-myo-inosi to1 has also been described to help elucidate its mechanism for inhibition. 151

In the field of phosphatidylinositols, full details on the synthesis of 2,6- di- 0-a -D-mannopyranosyl- 1 -0-( 1,2-di-O-heptadecanoylphosphatidyl)-~-myo- inositol by coupling of a mannosyl phosphite donor with a (+-)-myo-inositol diol acceptor, followed by separation of the diastereomers, have been reported. (See Vol. 30, p. 23, ref. 101 for a preliminary account).152

A route to 1 -0-( 1,2-di-0-heptadecanoylphosphatidyl)-~-myo-inositol 3,4,5- trisphosphate from D-glucose via a known 2,3,4,5,6-penta-0-(4-methoxybenzyl)-D-myo-inositol intermediate has been reported. 53 The syntheses of


HOQ OQ (CH2)7Me

107 NHAc OH 106

R'O OH X

R'O ~ - ~ ' y 1 ~ O R 2 OCOR2 NH2 o=P-o 0- %OR2

OH OCOR~ 108 R' = P(S)022-, X = Y = 0, R2 = Ci5H31

109 R' = H, X = 0, Y = S, R2 = C7H15

110 R' = Me, R2 = COC15H31, R3 = C15H31 or R' = P(S)Op2-, X = S, Y = 0, R2 = C15H31

or R' = H, X = 0, Y = S, R2 = C15H31

R' = H, R2 2 Me, R3 = Cl6HS R' = H, R2 = R3 = C18H37

2,5,6- t ri- 0- benzy 1- 1 - 0-(4-met hoxy benzyl)-~-myo-inositol and 2,6-di- 0-benzyl- 1-0-(4-methoxybenzyl)-~-myo-inositol from (+)-myo-inositol via resolution with (1 @-(+)-camphor dimethylacetal have been described. ls4 These compounds were converted into 1 -0-( 1,2-di-0-pentadecanoylphosphatidyl)-~- myo-inositol 3,4-bisphosphate and 3,4,5-trisphosphate, respectively. The enantiomers of the products were also prepared.155 Syntheses of 1-0-( 1,2-di-0- pentadecanoy1)-, ( 1,2-di-O-heptanoyl)-, and (1 -0-aminooctyl-2-0-octanoy1)- (designed to be cross-linkable) phosphatidyl-D-myo-inositol 3,4-bisphosphates have been prepared from 1,2:5,6-di-O-cyclohexylidene-~-myo-inositol' or 5,6-di- 0- benzyl-3,4-di- ~-(4-methoxybenzyl)-~-myo-inosi tol. * 57 It should be noted that the glycerol moieties in the last two references have been drawn in the papers in their wrong enantiomeric forms. 1 -0-( 1,2-Di-O-hexadecanoyl- phosphatidy1)-D-myo-inositol 3,4,5-trisphosphate has been synthesized from 3,4,5- tri- 0-allyl-6- 0-benzyl- 1,2- 0-cyclohexylidene-D-myo-inositol, 58 and 1 - 0- ( 1 - 0-heptadecanoyl-2- 0-arachidonoylphosphatidy1)-~-myo-inositol 3,4,5- trisphosphate together with three stereoisomers have also been synthesized from a differentially protected D-myo-inositol de r i~a t ive . '~~ A synthesis of ( f )- 1 -0-( 1,2-di-O-oleoylphophatidyl)-myo-inositol 4,5-bisphosphate which uses a novel 9-fluorenylmethyl phosphate protecting group strategy160 and a synthesis of phosphorothioate analogues 108 which utilized in the key step a cleavage of an 0-benzylphosphorothioate triester intermediate with trimethylamine-trimethylsilylchloride16' have been described. Full details have been reported on the synthesis of 1 -0-( 1,2-di-O-pentadecanoylphosphatidyl)-3- deoxy-D-myo-inositol from L-quebrachitol (see Vol. 29, p. 244, ref. 148 for


preliminary details) together with new material on the synthesis of the 2,3- dideoxy-D-myo-inositol equivalent, also from L-quebrachitol.'62

0,SPhosphorothioate analogues of phosphatidyl-inositol 109 have been prepared in which a chiral thiophosphoramidite, prepared from (2R)-glycidol, was utilized to introduce the glycerol moiety. 163

Compounds 110 and a related derivative have been made as substrate analogues of 6-~-(~-am~no-~-deoxy-a-~-g~ucopyranosy~)-~-myo-~nos~to~-( 1,2- di- 0-tetradecanoylphosphatidate), an early intermediate in the biosyntheis of glycosylphosphatidylinositol and tested with an a-( 1 + 4)-~-mannosyltrans- ferase from the protozoan parasite Trypanosoma brucei. 164 The related derivatives 6- 0-( ~-am~no-~-deoxy-a-~-g~ucopyranosy~)-~-myo-~nos~to~ 1 -phosphate and the corresponding 1,2-cyclic phosphate have also been prepared employing a D-camphor acetal-resolved inositol and a 2-azido-2-deoxy-glycosyl fluoride donor.

The preparation of ( )-myo-inositol 1 -p-nitrophenylphosphoryl-4,5- bisphosphate166 and an improved one of myo-inositol 1 -p-nitrophenylphos- hate'^^ as chromogenic substrates useful in the assaying of PI-PLC have been reported.

The synthesis of D-myo-inositol 1-phosphate in which the key step involved use of a chiral phosphorylating reagent to simultaneously monophosphorylate and resolve ( & )- 1,2:4,5-di-0-cyclohexylidene-myo-inositol has been des- cri bed. 16*

All six isomeric myo-inositol pentakisphosphates have been prepared from known regioselctively protected myo-inositol derivatives for metabolic studies in a cytosolic extract from calf thymus. 169 D-myo-Inositol 1,3,4,5-tetrakisphosphate and its enantiomer D-myo-inositol 1,3,5,6-tetrakisphosphate (equivalent to L-myo-inositol 1,3,4,5-tetrakisphosphate) have been prepared via resolution of (1 S)-( - )-camphanate esters derived from myo inositol 1,3,5- orthoformate. 170

( +)-myo-Inositol 1,2,4,5-tetrakisphosphate has been prepared from 3,6-di- O-benzoyl-l,2:4,5-di-O-isopropylidene-myo-inositol and tested for its ability to mobilize intracelular Ca2+. Individual enantiomers were also made by conventional processes. 71 myo-Inositol 1,2,3-trisphosphate has been prepared from myo-inositol by way of regioselective benzoylation * 72 and a proposed binding model of myo-inositol 1,4,5-trisphosphate kinase based upon the inhibitory effects of all thirty-eight regioisomers of inositol phosphates has been described. The compounds used in the study were prepared using the acyl migration method (see Vol. 30, p. 243, refs. 151-153).173 The syntheses of myo- inositol 1,2,3,5- and 2,4,5,6-tetrakisphosphates as novel myo-inositol 1,4,5- trisphosphate kinase inhibitors have been achieved from myo-inositol orthoformate intermediates. 174

D-myo-Inositol 1,2,6-trisphosphate (a-trinositol), obtainable from baker's yeast treatment of phytic acid, has been converted into 1,2-0-isopropylidene- D-myO-inOSitOl and 3,4,5-tri-O-benZyl-D-myo-inOSitOl as intermediates for the synthesis of optically active myo-inositol derivatives. 17'

D-~Jk-hlOSitOl 1,3,4,5,6-pentakisphosphory1-2-pyrophosphate and D-myo-


inositol 1,2,3,4,6-pentakisphosphory1-5-pyrophosphate have been reported as in t racellular mediators, * 76

Five potentially membrane-permeable phosphate ester derivatives of myo- inositol have been synthesized. For example the ( f )-myo-inositol 1,4,5-tris- phosphatehexakis(propionyloxymethy1) ester and the hexakis(butyry1oxy- methy1)ester were effective Ca2+ mobilizing agents. 177 Various phosphate ester derivatives of D-myo-inositol 1,2,6-trisphosphate have also been prepared as potential analgesics. 178

myo-Inositol 1,4,5-trisphosphate derivatives having 3-0-methyl, -ethyl, -propyl or -glycollyl substituents' 79 and myo-inositol hexakisphosphate o-nitrobenzyl esters which are photolabilelgO have been reported. The synthesis of D-galactopyranosyl- 1,2,6-trisphosphate as an analogue of D-myo-inositol 1,4,5-trisphosphate is mentioned in Chapter 7. Some phosphate derivatives of 6-O-(2-hydroxyethyl)cyclohexane- 1,2,4,6-tetraol have been prepared from cis/ trans-cyclohexane- I94-diol as mechanistic probes for the inositol mono- phosphatase reaction.lg'

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S. Ogawa, T. Mito, E. Taiji, M. Jimbo, K. Yamagishi and J.-i. Inokuchi, Bioorg. Med Chem. Lett., 1997,7, 1915. S.-K. Khim and A.G. Schultz, Chemtracts, 1997, 10, 541 (Chem. Abstr., 1997, 127, 136 013). Y. Watanabe, Yuki Gosei Kagabu Kyokaishi, 1997, 55, 705 (Chem. Abstr., 1997, 127, 176 603). R.J. Hondal, Z. Zhao, S.R. Riddle, A.V. Kravchuk, H. Liao, K.S. Bruzik and M.-D. Tsai, J. Am. Chem. SOC., 1997,119,9933. G. Angelini, A. Margonelli, P. Ragn, C. Sparapani, L. Cellai, M.A. Ianelli, M.C. Cesta and S. Lappa, J. Labelled Compd. Radiopharm., 1997, 39, 747 (Chem. Abstr., 1997,121, 262 943). Y. Watanabe, T. Yamamoto and T. Okazaki, Tetrahedron, 1997,53,903. T. Sawada, R. Shirai and S. Iwasaki, Chem. Pharm. Bull., 1997,45,1521. S.J.A. Grove, I.H. Gilbert, A.B. Holmes, G.F. Painter and M.L. Hill, Chem. Commun., 1997, 1633. S.J.A. Groves, A.B. Holmes, G.F. Painter, P.T. Hawkins and L.R. Stephens, Chem. Commun., 1997, 1635. K.K. Reddy, J. Rizo and J.R. Falck, Tetrahedron Lett., 1997,38,4729. K.K. Reddy, J. Ye, J.R. Falck and J.H. Capdevila, Bioorg. Med Chem. Lett., 1997,7, 21 15. S.G. Aneja, A. Parra, C. Stoenescu, W. Xia and R. Aneja, Tetrahedron Lett., 1997,38,803. P.R.J. Gaffney and C.B. Reese, Bioorg. Med. Chem. Lett., 1997,7, 3 171. Y. Watanabe, T. Nakamura and H. Mitsumoto, Tetrahedron Lett., 1997, 38, 7407. R.J. Kubiak and K.S. Bruzik, Bioorg. Med. Chem. Lett., 1997,7, 1231. A.P. Kozikowski, L. Qiao, W. Tuckmantel and G. Powis, Tetrahedron, 1997, 53, 14903. C. Mihai, J. Mataka, S. Riddle, M.-D. Tsai and K.S. Bruzik, Bioorg. Med. Chem. Lett., 1997,7, 1235. A. Crossman, J.S. Brimacombe and M.A.J. Ferguson, J. Chem. SOC., Perkin Trans. I , 1997,2769. P.J. Garegg, P. Konradsson, S. Oscarson and K. Ruda, Tetrahedron, 1997, 53, 17727. A.V. Rukavishnikov, M. Ryan, O.H. Griffith and J.F.W. Keana, Bioorg. Med Chem. Lett., 1997,7, 1239. A.V. Rukavishnikov, T.O. Zaikova, O.H. Griffith and J.F.W. Keana, Chem. Phys. Lipids, 1997,89, 153 (Chem. Abstr., 1997, 127, 331 658). I.D. Spiers, C.H. Schwalbe, A.J. Blake, K.R.H. Solomons and S. Freeman, Carbohydr. Res., 1997,302,43. M.T. Rudolf, T. Kaiser, A.H. Guse, G.W. Mayr and G. Schultz, Liebigs Ann. Chem., 1997, 1861. A.M. Riley, M.F. Mahon and B.V.L. Potter, Angew. Chem. Int. Ed. Engl., 1997, 36, 1472. S.J. Mills and B.V.L. Potter, J. Chem. SOC., Perkin Trans. I , 1997, 1279. S.-K. Chung and Y.T. Chang, Korean J. Med. Chem., 1996,6,253 (Chem. Abstr., 1997, 126, 144 470). G. Choi, Y.-T. Chang, S.-K. Chung and K.Y. Choi, Bioorg. Med Chem. Lett., 1997,7,2709. S.-K. Chung and Y.-T. Chang, Bioorg. Med Chem. Lett., 1997,7,2715.


175

176 177 178 179 180 18 1

C. Blum, N. Rehnberg, B. Spiess and G. Schlewer, Carbohydr. Res., 1997, 302, 163. K.M. Reddy, K.K. Reddy and J.R. Falck, Tetrahedron Lett., 1997,38,4951. W. Li, C. Schultz, J. Llopis and R.Y. Tsien, Tetrahedron, 1997,53, 12017. M. Malmberg and N. Rehnberg, J. Carbohydr. Chem., 1997,16, 109. C . Liu and B.V.L. Potter, J. Org. Chem., 1997,62,8335. J. Chen and G.D. Prestwich, Tetrahedron Lett., 1997,38,969. J. Schulz and D. Gani, J. Chem. Soc., Perkin Trans. I , 1997,657.

19 Antibiotics

1 Aminoglycosides and Aminocyclitols

Dibekacin has been converted into 5-deoxy-5-epi-5-fluorodibekacin (1); the related 2”-keto-compound and the 2”-ketone acylated at N’ with 4-amino-2- hydroxybutanoic acid were also reported. A 2”-keto-derivative of 5-deoxy-5- epi-5-fluorodibekacin (1) was also used as an intermediate in the preparation of the 2”-amino-2”-deoxy-analogue 2 and its 2”-epimer; various 2”-N-acylated derivatives of 2 were also synthesised.2 Amikacin is a semisynthetic antibiotic made from kanamycin by acylation at N1 of the 2-deoxystreptamine unit with 4-amino-2-hydroxybutanoic acid; it has been found that the major by-products in the synthesis of amikacin are the compounds with an additional acyl unit at the 3”-amino-group and the one with an extra acyl group at the 6-amino- p~s i t i on .~

There have been studies reported on the interaction of aminoglycoside antibiotics with RNA. A series of compounds have been made in which two aminoglycoside units are linked together, via their primary alcohol groups, by a 14-atom spacer containing four sulfur atoms. These were designed to interact with two similar structural motifs in RNA, and the dimers did indeed display enhanced activity as ribozyme inhibitors relative to their natural counterparts, with the highest inhibition of the hammerhead ribozyme being displayed by the tobramycin-spacer-neomycin B and neomycin-spacer-neomycin d i m e r ~ . ~ The same workers have also investigated electrostatic interactions in RNA- aminoglycoside binding. On the theory that more basic aminoglycosides should bind more tightly, a comparison was made of kanamycin, tobramycin, and various deoxy-analogues of tobramycin including dibekacin. It was found that dibekacin, 4”-deoxytobramycin and 2”-deoxytobramycin, which each lack one secondary alcohol function of tobramycin, were much better inhibitors of the hammerhead ribozyme than was tobramycin itself. It was also found that 6”-amino-6”-deoxytobramycin was a potent inhibitor. A novel assay has been developed based on surface plasmon resonance that allows the direct observation of interaction between neomycin B and related aminoglycosides with RNA strands, in order to better understand the specificity of these antibiotics for the Rev response element (RRE) of HIV-1 mRNA. The results indicated that neomycin B interacts with three different sites in RRE.6


254

19: Antibiotics 255

A novel bifunctional bacterial enzyme that confers resistance to aminoglycoside antibiotics through an ATP-dependent phosphorylation and an acetyl CoA-dependent acetylation has now been purified and characterized. An extensive NMR investigation of the acetylation and phosphorylation products from kanamycin A, and the product of both enzyme activities, led to the identification of the 6'-amino-group as the site of acetylation, and 0-2" as the phosphorylation site. Some kinetic parameters for both the acetylation and phosphorylation reactions were determined with a variety of aminoglycoside subst rates.

Further work has been reported on the mechanism of action of 2-deoxy- scyllo-inosose synthase, which is involved in the biosynthesis of 2-deoxystreptamine. A deuterium label at C-4 of glucose-6-phosphate (3) was retained at C-6 of the product (4), relative to l 8 0 at C-3, even though a redox process occurs at C-4 in order to facilitate the elimination of phosphate. The product was isolated as its oxime-Tms ether for identification.8

A synthesis has been reported of the 2-deoxyisomaltose analogue 9 related to acarbose (Scheme 1). The 6-bromo-2,6-dideoxy-compound 5 was made from the known 2,6-dibromo-2,6-dideoxy-~-mannono- 1,4-1actone by a three-

CH2Br

,,,, NHC02Me vii, viii

BnO"' BnO"' HO

OBn 5 6

H OBn H

xi

9 8 Reagents: i, BnOC(N=H)CCI3, TfOH; ii, NaH, DMF; iii, HgCI2; iv, MsCI, py, DMAP; .

v, BnOCHpLi, THF, -1 1 OOC; vi, C13CCONC0, then Al2O3; vii, Tf20, EtNPr'2; viii, MeOH; ix, NaOH, DMSO; x. 6-Qtriflyl-glucoside, EtNPrb; xi, Na, NH3

Scheme 1


step sequence involving a selective hydrogenolysis of a secondary bromide. In the conversion of 6 to 7, a cyanate was formed by dehydration, and this underwent a [3,3]-sigmatropic rearrangement to the allylically-rearranged isocyanate. One of the aims of this work was the production of compounds which could be used to create catalytic antibodies for glycoside hydrolysis. The intermediate 8 is of potential use in this respect, and the chemistry of Scheme 1 could also be applicable to the synthesis of valienamine, the 2-deoxy analogue of which was made by deprotection of 7.9

2 Macrolide Antibiotics

There have been further reports on 16-membered macrolide antibiotics bearing modified cladinose and mycarose units (see Vol. 30, p. 255). After protection of the macrocycle, alkylation was used to make analogues of leucomycin A7 with the L-mycarose unit 3,4-di-O-alkylated, and containing 4-0-alkyL~- cladinose (i.e. with the 3”-position 0-methylated). lo Midecamycin Al, which contains a 4-0-propanoyl L-mycarose residue, has been methylated at 0 - 3 ” to give the analogue with a 4-0-acyl-~-cladinose unit (lo), which was an enhanced antibacterial agent. Various 9-0-acyl derivatives were also prepared, and similar chemistry was carried out on josamycin. l 1

Formamycin, which contains a 24-carbon polyketide chain with a 16- membered macrolide ring, carries a 2,6-dideoxy-~-~-arabino-hexopyranose (2- deoxy-P-D-rhamnose) unit (1 1) at 0 - 2 I . *

A new derivative of amphotericin B with low toxicity, N-methyl-N-( 1 -deoxy- D-frUCtOS- 1-y1)-amphotericin B (with sugar unit 12), has been reported.

3 Anthracyclines and Other Glycosylated Polycyclic Antibiotics

A new anthracycline antibiotic IT-62-B, which converts the morphology of ras-transformed cells back to normal, has been assigned the structure 13 by spectroscopic means, and is a new member of the baumycin ~ 1 a s s . l ~ The compound 14, related to steffimycin but lacking a methoxy group at C-8, has been isolated; the 10-ketone, and the 2’-0-demethyl compound (i.e. with L-

rhamnose as sugar) were also identified. Genetic engineering techniques were also used to produce 2,8-demethoxy-steffimycins. Nocardicyclins A and B, new antibiotics from Nocardia pseudobrasiliensis, have been assigned the

19: Antibiotics 257

structures 15 and 16 respectively. The structure assigned to the aglycon is thus epimeric at C-9 with the steffamycin class, and the sugar in 15 is novel, termed brasiliose, but no evidence is presented for the absolute configuration.16 10-0- Rhodosaminyl-P-rhodomycinone (17, R = H) and obelmycin H (17, R = OH) have been isolated from a culture of obelmycin-producing Streptomyces violaceus after acid treatment. l 7

Me \ 0 "OH

OMeO OH -

M e q o q o

Me 'fi'i2OH 13

0

OH OMe

14

"OQ

0 OH OH 17

RO 0" NMe2 15 R = H 16 R = A c

The theory that doxorubicin and daunorubicin alkylate DNA by catalytic production of formaldehyde prompted an investigation of drug-formaldehyde reactions. It was found that interaction of the drugs with formalin at pH 6 gives 40-50% yields of the condensation products doxoform (18, X = OH) and daunoform (18, X = H) respectively, the structures of which were determined spectroscopically. These products are labile with respect to hydrolysis, and the oxazolidines 19 are intermediates in the hydrolysis (Scheme 2). Daunoform (18, X = H) reacted with the self-complementary deoxyoligonucleotide (GC)4 faster than did daunorubicin and formaldehyde at equivalent concentrations, and doxoform was effective against resistant tumour cells. **


The glucuronide 20, containing an unusual acetal linkage, was prepared from daunorubicin by a sequence involving reductive amination of the anthracycline. It was found that 20 was highly toxic to human A375 melanoma cells in the presence of E. coli 0-glucuronidase, and it was speculated that hydrolysis led to the species 21 which could act as an alkylating agent.19 Reductive amination of daunorubicin with nucleoside dialdehydes gave rise to morpholino-derivatives 22 (B = Ade, Gua, Ura, Cyt, Hypoxanthinyl, 6-aza- Ura),20 and an increase in the lipophilicity of daunorubicin, doxorubicin and carminomycin was achieved by trimethylsilylation of the 4’-hydroxy groups with N, 0- bis( t rime thylsilyl)trifluoroacetamide.2

Q0

__t HO

YH OEt

Na+ C02- ‘r HO Q0

OH 20

21

Base b - - O CH20H

22

Doxorubicin has been linked via spacers to the nitrogen atom of maleimide, the linking either being at the 3’-amino-group or through an N-acylhydrazone at the methyl ketone, with a view to subsequent conjugation to proteins.22

4 Nucleoside Antibiotics

Full details have been published of a synthesis of the IP3 receptor agonist adenophostin A (23) in which the nucleosidic link is introduced at a late stage (see Vol. 30, p. 258).23 The same group have also prepared a number of more flexible analogues of adenophostin A, including 24. For this, the condensation of a 3’- 0-phosphoryloxymethy1 nucleoside with a monohydroxyalditol derivative was a key synthetic step. Analogue 25 was made by imidate glycosyla- t i ~ n , ~ ~ and the diphosphates 26 (R = H, CH20H) have also been prepared; in these cases coupling of silylated p-benzoyladenine with 0-acetoxymethyl derivatives were employed.25 Additionally, the same team has described interesting compounds in which two and four units of the triphosphorylated disaccharide found in the adenophostins are connected as glycosides to a benzene core via four-atom spacers; these polyvalent compounds were prepared with the intention of allowing cooperative binding to the IP3 receptor, which has four binding sites for IP3.26

19: Antibiotics 259

The selectively-protected nucleoside 27 has been prepared by the interaction of silylated thymine and the 1,2-anhydrosugar, as also reported for the uridine analogue;27 glycosylation of 27 with a derivative of L-fucose was then used to make the analogue 28 of shimofuridin A (Vol. 28, p. 254; for other analogues see Vol. 30, p. 259).28

Ade Ade

23 25

26

BnO OH

27

BnO I

28

There has been a further report on the synthesis of the sugar unit of tunicamycin, which gives a full account of the synthesis of tunicamine derivative 29 by a Wittig reaction followed by a regio- and stereo-selective hydroboration (Vol. 28, p. 255). The coupling of 29 with a glycosyl bromide gives predominantly the a$-disaccharide 30, the stereochemical outcome

OH BzO

30

fYn O X 0

Reagents: i, BCI3; ii, AQO, AcOH, H2SO4; iii, RuC13, Nal04, CCldMeCN/H20, then CH2N2; iv, silylated 2-acetamidopurine, SnC14; v, H2, PdC; vi, Mtrifluoroacetyl acid anhydride; vii, LiOH

Scheme 3


being a function of the phthalimido- and benzoyloxyimino functions (Vol. 28, p. 125).29

A report from Czernecki's laboratory describes the synthesis, from a previously-described alkyne, of a compound 31 (Scheme 3) which is related to amipurimycin. Since the P-aminoacid used was the' racemic cis-material (the absolute stereochemistry of this part of amipurimycin is not definitely established) a diastereomer of 31 was also produced; the condensation to form the nucleoside was regio- and stereo-selective in the required sense. 30 Amipur- imycin itself has a chain-branch at C-3'; for some work from the same group which introduces this feature see Vol. 30, p. 186.

The intermediate 32 was prepared in racemic form by amination of a silyl enol ether derived from the oxabicyclic ketone, and used to make a derivative of thymine polyoxin C (33).3' A report from the laboratories of Dondoni and Merino gives a full account of their synthesis of polyoxin C (33) and polyoxin J (34) in which both a-aminoacid units are derived by diastereoselective addition of 2-furyllithium to an appropriate nitrone, the reagent acting as a C02H ~ y n t h o n . ~ ~ The carbocyclic analogue (36) of uracil polyoxin C has been made in racemic form, the Pd-catalysed cis-allylic substitution reaction of ( +)- 35 with uracil, and cis-dihydroxylation with Os04-NMNO being key s t e p ~ . ~ ~

OTips

TsHNla e7 RNHk-ly OH OH

NHTs OH OH OH OH 35 36 37 38 39

These key transformations in the synthesis of carbocyclic nucleosides were also applied to 37, readily available in chiral form by a resolution procedure, to give (-)-aristeromycin (38, B = Ade) and (-)-carbodhe (38, B = Cyt); in the latter case, the use of the Cs salt of N-benzoylcytosine was necessary to ensure a good yield.34 A new route has been described, using an asymmetric Diels- Alder reaction, to make the amine 39 which has previously been used to prepare ari~teromycin.~~ The (+)-enantiomer 41 of aristeromycin has been made as indicated in Scheme 4, the cyclopentenone 40 being accessible in three steps from D-ribose (Vol. 24, p. 302). A variation on this sequence led to the thymine analogue.36 A synthesis of ( + )-aristeromycin and its S-homo-derivative has been carried out from norborn-5-en-2-0ne.~~

19: Antibiotics 26 1

PRibose

oxo Me Me

40

i-iii __t

iv, v

oxo Me Me

w OH OH

41

Reagents: i, (B~bCH2)~cuLi; ii, DIBAL; iii, Tf20; iv, adenine, NaH; v, TFA, H20 Scheme 4

The glucose-derived alkene 42 was converted as indicated in Scheme 5 into the cyclopentane 43 using an intramolecular nitrone-alkene cycloaddition, after which standard transformations were used to make the analogue 44 of arister~mycin.~~ The methylated derivative 45 of 5’-noraristeromycin has been prepared in enantiopure form from a chiral allylic alcohol using organopalla- dium chemistry,39 and the (+)-enantiomer 46 of 7-deaza-5’-noraristeromycin was similarly prepared and shown to have anti-trypanosomal activity (for the enantiomer see Vol. 27, p. 235).40 Various 8-aza-7-deaza-5’-noraristeromycin derivatives such as 47 and its enantiomer, have also been prepared; the antitrypanosomal activity of these was not high, but compounds of the L-series performed better than their enanti~mers.~’

\ bo -* Civ HOlll 6 N H 2 ~ Hoe O--p b H

42 Me 43 44

Reagents: i, H2S04, MeCN-H20; ii, BnNHOH; iii, LAH; iv, Pd/C, cyclohexene Scheme 5

YH2

Meow OH OH

45

[> KT OH OH

OBz

- 46 X-CH 48 47 X = N

?

49

Trost’s group have applied their technique of Pd(@)-catalysed desymmetrization in the presence of a chiral catalyst to convert 48 into 49 of high e.e., which was subsequently transformed into neplanocin A.42 Another synthesis of the derivative 50 of neplanocin A, using the reductive cleavage of isopropylidene adenosine with excess DIBAL (Vol. 27, p. 270; see also Chapter 20) as the initial step, is indicated in Scheme 6; the desired p-‘anomer’ was the major product (4: 1) in the insertion reaction.43 An improved synthesis of the antiviral C-methylated neplanocin A analogue 51 of R-chirality (RMPNA) involved the diastereoselective transformation of the S-epimer using adenosine deaminase,4


0 Ade Ade

iii i T b d m s O H 2 C w H 2 - iv T b d m s O H 2 C a

0 0 MeXMe

50

O x 0 Me Me

Reagents: i, DIBAL; ii, TWmsCI, Im; iii, Dess-Martin reagent; iv, TmsC(Li)N2 Scheme 6

HO AddGua

Me OH OH CHpOH 51 52 53

and a number of related epimeric C-ethynyl, -ethenyl and -ethyl derivatives of neplanocin A were made by Grignard reactions with an aldehyde.45

The nor-analogues 52,& and the diastereoisomer 5347 of carbocyclic oxetanocin have been prepared as racemates.

Some analogues of the C-nucleoside antibiotic showdomycin are mentioned in Chapter 20.

5 Miscellaneous Antibiotics

Heliquinomycin, a new inhibitor of DNA helicase isolated from a Strepto- myces species, has been assigned the structure 54 by X-ray crystallography. Heliquinomycin contains the sugar L-cymarose, and the absolute configuration of the antibiotic was determined by hydrolysis and measurement of the optical rotation of the sugar? The absolute configurations of the pyralomycins (Vol. 30, p. 261) have now been determined as being based upon D-glucose, by X-ray crystallography of heavy-atom derivatives of pyralomycins l a and 2a.49

Oxidation of lincomycin with dimethyldioxirane gives two diastereomeric sulfoxides, which with Os04-NMN0 give the same sulfone. An unsaturated analogue of clindamycin has also been made by elimination between C-6 and c-7.50

The indolocarbazoles 55 (D-gluco- and D-gdacto-), related to rebeccamycin and AT 2433-A1 and -B1, were prepared by reaction of the heterocycle with glycosyl bromides, which also gave the a-anomers. The L-fucosyl analogues were also synthe~ised.~~ A similar glucosylation was also used during the synthesis of the related topoisomerase inhibitor and anticancer agent NB-506; conditions for obtaining good P-selectivity in the glucosylation were defined.52

Siastatin B (56) has been converted into a number of analogues epimeric at C-3 such as 57 and its 5-epimer. A 3,4-ene was involved as an intermediate in this chemistry, and compounds with a trifluoroacetyl group at N-6 were also described .53

A report from Ganguly’s laboratory has established unambiguously for the

19: Antibiotics 263

NHAc 56

OH NHAc 57

MeO

i OH 0 OH 0

54

C02Me

0 \NMe

OH 55

first time the stereochemistry of the everninomycin antibiotics at the C-16 orthoester (Scheme 7). Treatment with acid of compounds such as ziracin, with a hydroxy group at C-23 (part-structure 58, X = OH), led to a mixture of the C-16 epimer 59 (X=OH) and the 0-23, 0-24-orthoester 60, with more of 60 after longer reaction times. Treatment of everninomycin D (part-structure 58, X = H) gave the epimer 59 (X = H). Detailed NMR studies, including NOE work, allowed assignment of stere~chemistry.~~ Complete IH- and I3C-NMR assignments of the oligosaccharide antibiotic Sch 27899 have been reported.55

Me

Me Me H 0 ~ ~ ~ ~ ~ O - i 24

i - Me

OH 58 OH 59 Reagents: i, pnitrobenzoic acid, THF, reflux

Scheme 7

HO F”””::,

&D-GlCp( 1 +4)-&DGlcNAcp 61

Corynandecin is a new antifungal glycolipid of the papulacandin type, which contains the commonly-occurring P-D-Ga@-( 1 -+4)-p-~-Glcp-C-glycoside unit with a novel fatty acid esterified at 0-3’.56

A series of papers have described the synthesis of analogues of the phosphoglycolipid antibiotic moenomycin Al 2. A trisaccharide was prepared as its ally1 glycoside from peracetylcellobial and a galacturonamide derivative using Danishefsky’s sulfonamidoglycosylation ~ r o c e d u r e , ~ ~ and then con-


verted into the moenomycin analogue 61. This structure differs from the smallest antibiotically-active fragment of moenomycin A12 in having a glucose unit at the non-reducing terminus in place of an N-acetylglucosamine residue, but 61 was not active.58 The analogue 61, but with a galactopyranose unit replacing the glucose moiety, was also made, using an oxazoline derived from lactosamine as a glycosyl donor and an ally1 galactosiduronamide derivative as aceptor, but again the modification led to loss of antibiotic activity.59 Moenomycin A has been linked to various reporter groups (e.g. biotin and the dansyl group), the linkage being via the 2-amino-cyclopentanedione ring (ring A) of the antibiotice60

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50

51

M. Kriiger, U. Beyer, P. Schumacher, C. Unger, H. Zahn and F. Kratz, Chem. Pharm. Bull., 1997,45, 399. N.C.R. van Straten, G.A. van der Marel and J.H. van Boom, Tetrahedron, 1997, 53, 6509. N.C.R. van Straten, G.A. van der Marel and J.H. van Boom, Tetrahedron, 1997, 53, 6523. N.C.R. van Straten, N.M.A.J. Kriek, Z.A.C. Cziria, G.A. van der Marel and J.H. van Boom, Tetrahedron, 1997,53,6539. M. de Kort, A.R.P.M. Valentijn, G.A. van der Marel and J.H. van Boom, Tetrahedron Lett., 1997,38, 7629. J. Ning and F. Kong, Carbohydr. Res., 1997,300, 355. J. Ning and F. Kong, Bioorg. Med. Chem. Lett., 1997,7,2941. W. Karpiesiuk and A. Banaszek, Carbohydr. Res., 1997,299,245. S. Czernecki, S. Franco and J.-M. Valery, J. Org. Chem., 1997,62,4845. D.M. Gethin and N.S. Simpkins, Tetrahedron, 1997, 53, 14417. A. Dondoni, S. Franco, F. Junquera, F.L. Merchan, P. Merino and T. Tejero, J. Org. Chem., 1997,62, 5497. S.E. Ward, A.B. Holmes and R. McCague, Chem. Commun., 1997,2085. F. Burlina, A. Faure, J.-L. Fourrey and M. Thomas, Bioorg. Med. Chem. Lett., 1997,7,247. S.J. Boyer and J.W. Leahy, J. Org. Chem., 1997,62, 3976. P. Wang, L.A. Agrofoglio, M.G. Newton and C.K. Chu, Tetrahedron Lett., 1997, 38, 4207. M. Kapeller, H. Baumgartner and H. Griengl, Monatsh. Chem., 1997, 128, f91 (Chem. Abstr., 1997,127,8 1 724). A. Roy, R. Patra, B. Achari and S.B. Mandal, Synlett, 1997, 1237. K.L. Seley, S.W. Schneller and E. De Clercq, J. Org. Chem., 1997,62, 5645. K.L. Seley, S.W. Schneller, D. Rattendi and C.J. Bacchi, J. Med Chem., 1997, 40,622. K.L. Seley, S.W. Schneller, D. Rattendi, S. Lane and C.J. Bacchi, J. Med. Chem., 1997,40, 625. B.M. Trost, R. Madsen and S.D. Guile, Tetrahedron Lett., 1997,38, 1707. S. Niizuma, S. Shuto and A. Matsuda, Tetrahedron, 1997,53, 13621. S. Shuto, T. Obara, S. Yaginuma and A. Matsuda, Chem. Phurm. Bull., 1997,45,138. S . Shuto, T. Obara, Y. Saito, K. Yamashita, M. Tanaka, T. Sasaki, G. Andrei, R. Snoeck, J. Neyts, E. Padalko, J. Balzarini, E. De Clercq and A. Matsuda, Chem. Pharm. Bull., 1997,45,1163. J. Wu, S.W. Schneller, K.L. Seley, R. Snoeck, G. Andrei, J. Balzarini and E. De Clercq, J. Med. Chem., 1997,40, 1401. L. Mevellec and F. Huet, Tetrahedron, 1997,53, 5797. M. Chino, K. Nishikawa, T. Tsuchida, R. Sawa, H. Nakamura, K.T. Nakamura, Y. Muraoka, D. Ikeda, H. Naganawa, T. Sawa and T. Takeuchi, J. Antibiotics, 1997,50, 143. N. Kawamura, H. Nakamura, R. Sawa, Y. Takahashi, T. Sawa, H. Naganawa and T. Takeuchi, J. Antibiotics, 1997,50, 147. F. Sztaricskai, Z. Dinya, G. Batta, A. Mocsari, M. Hollosi, Z. Majer, R. Masuma and S. Omura, J. Antibiotics, 1997,50, 877. F. Anison, L. Belin, P. Moreau, M. Sancelme, A. Voldoire, M. Prudhomme, M. Ollier, D. Severe, J.-F. Riou, C. Bailly, D. Fabbro and T. Meyer, J. Med. Chem., 1997,40,3456.


52

53

54

55

56

57

58

59

60

M. Ohkubo, H. Kawamoto, T. Ohno, M. Nakano and H. Morishima, Tetra- hedron, 1997,53,585. Y . Nishimura, T. Satoh, H. Adachi, S. Kondo, T. Takeuchi, M. Azetaka, H. Fukuyasu and Y. Iizuka, J. Med. Chem., 1997,40,2626. A.K. Ganguly, J. L. McCormick, T.-M. Chan, A.K. Saksena and P.R. Das, Tetrahedron Lett., 1997,38, 7989. T.-M. Chan, R.M. Osterman, J.B. Morton and A.K. Ganguly, Magn. Reson. Chem., 1997,35, 529 (Chem. Abstr., 1997,127,262930). G. Gunawardena, R.R. Rasmussen, M. Scherr, D. Frost, K.D. Brandt, W. Choi, M. Jackson, J.P. Karwowski, G. Sunga, L.-H. Malmberg, P. West, R.H. Chen, S. Kadam, J.J. Clement and J.B. McAlpine, J. Antibiotics, 1997,50,884. 0. Ritzeler, L. Hennig, M. Findeisen, P. Welzel and D. Muller, Tetrahedron, 1997,53,1665; corrigenda, 5337. 0. Ritzeler, L. Hennig, M. Findeisen, P. Welzel, D. Muller, A. Marcus, G. Lemoine, M. Lampilas and J. van Heijenoort, Tetrahedron, 1997,53, 1675. G. Range, R. Krlhmer, P. Welzel, D. Muller, G.F. Herrmann, U. Kragl, C. Wandrey, A. Marcus, Y. Van Heijenoort and J. van Heijenoort, Tetrahedron, 1997,53,1695. U. Kempin, L. Hennig, D. Knoll, P. Welzel, D. Muller, A. Marcus, and J. van Heijenoort, Tetrahedron, 1997,53, 17669.

20 Nucleosides

1 General

Structure-activity relationships of novel nucleosides for the treatment of AIDS have been reviewed, and reviews have also appeared on seco-nucleosides2 and di-seco-nucle~sides.~ The synthesis and reactions of nucleosides and nucleotides under conditions relevant to early evolution have been incorporated into a review on prebiotic ~hemistry.~

A glycosylated zeatin has been identified as the compound in coconut milk responsible for over 20% of its potent cytokinin a~t ivi ty .~

2 Synthesis

Sodium triacetoxyborohydride in acetic acid reduces 2'- and 3'-ketonucleosides with high stereoselectivity, 5'-0-Tbdms-protected derivatives being reduced from the a-face, whereas 5'-unprotected compounds are reduced from the p- face. Use of N~BD(OAC)~ gave rise to stereoselectively deuteriated species, as in the cases illustrated in Scheme 1.6

HOCHPO Ade

OH OH 0 OTbdms D OH Reagents: i , NaBD(OAc)3, HOAc; ii, NH4F, MeOH

Scheme 1

Ribonucleosides uniformly-labelled with 13C in the sugar unit have been prepared from [ 'C16-di- 0-isopropylidene-D-glucofuranose by a sequence in which a ribofuranose derivative was made by configurational inversion at C-3, followed by periodate cleavage of C-6 and coupling to the nu~leobase.~ Di-0- isoyropylidene-D-glucofuranose has also been converted, again via the ~-allo- epimer, into the L-ribose derivative 1, C-5 of D-glucose becoming C-1 of 1. p-L- Ribonucleosides were then made, and incorporated into oligonucleotides.*

Conventional base-sugar coupling procedures have been used to make hydroxamic acids related to ~ r i d i n e , ~ 5-carboranyluracil nucleosides, lo 5- (alkyVarylthioethyl)thio-6-azauridines,1' and 6-methyl-5-aza-cytidine (2),

~~


267


which could also be prepared by reaction of tri-0-benzoyl-P-D-ribofuranosyl isocyanate with monoacetylguanidine and subsequent cyclization. l 2 A condensation promoted by ultrasound was used in an improved synthesis of the 1’- cyano-nucleoside 3.” The protected nucleosides 4 (R = Ph, Bn) were made by base-sugar condensation, but debenzoylation with methanolic ammonia led to the pyrazole nucleosides 5. l 4

Ribavirin has been prepared from inosine in good overall yield by acetolysis, condensation with the triazole and ammonolysis. Ribosylation of 3-mer- capto- 1,2,4-triazole with 1 - O-acetyl-2,3,5- tri- 0-benzo yl- P-D-ribofuranose gave three nucleosides, including the N4-regioisomer, l 6 whilst in similar work, condensation of isothiocyanate 6 with hydrazine, followed by cyclization with acyl derivatives, gave thio-substituted 1,3,4-triazole nucleosides of type 7. 179 l 8

The thiadiazole nucleoside 8, and its N3-regioisomer, were both obtained using a base-sugar condensation.

I BzO OBz I. tizu OBz P-o-Rib4 BzO OBz

The imidazo[4,5-djisothiazole nucleoside 9, and the 4-ribosylated analogue, have been prepared by coupling using the silylated base; 2‘-deoxy- and D- arabinofuranosyl nucleosides were made similarly. l9 N-P-D-Ribofuranosyl derivatives of ergot alkaloids have been reported,20 as have 2-substituted-4,6- dichloro- and -4,5-dichloro-benzimidazole nucleosides such as The analogues 11 (X = F, Br, I) of the anti-cytomegaloviral agent TCRB (1 1, X = Cl) have also been described.22 Some 4-thioalkyl-imidazo- and triazolo- [4,5-djpyridazine nucleosides such as 12 have been prepared as inhibitors of nucleoside transport into human erythrocytes, but were less active than known inhi bi tors.23 Some novel 1 - P-D-ri bofuranosyl-pyrido[ 2,3-dJpyrimidin-2,4- (1 H,3H)-diones have been described,24 and the pyrimido[4,5-djpyrimidine-2,4- dione 13 has been made by base-sugar condensation, as has the a-D-arabino- analogue.25 A paper describing a route to 3’,5’-di-O-benzylthyrnidine is mentioned in Chapter 19.

In the area of pyranosyl nucleosides, solid-state glycosylation has been reported. Peracetylated glycopyranosyl bromides were separately ground with

20: Nucleosides 269

AgOTf, silylated uracil or thymine was added, and after a further period of grinding in a ball mill, the acetylated p-D-glUC0-, p-D-ribo- or a-L-arabinopyranosyl nucleosides could be obtained in moderate yield.26

6-D-Ribf f3-D-Rib-f p-D-Rib4 p-D-Ribf 9 10 11 12

p- D-R ib f 14 15

Treatment of aldoses with hydrazine gave the hydrazones, mainly as the acyclic isomers: subsequent treatment with pentane-2,4-dione gave isomeric glycopyranosyl-3,5-dimethylpyrazoles (e.g. 14), together with the furanosyl nuc le~s ides .~~ Triazole nucleosides such as 15 have been made by the cyclization of peracetylated glycopyranosylaminoguanidines (Vol. 29, p. 146), which occurs on heating in ethanol, followed by deacetylation.28 Coupling procedures have been used to prepare 1 -~-~-glucopyranosyl-5-methyl-2-methylthio- and 2-morpholino-pyrimidin-4(3H)-one and related some 2-substituted-5-fluorouracil xylopyrano~ides,~~ some 3-glycopyranosyl-2,4-dioxy- pyrimidine^,^' 3-~-~-glucopyranosyl-6-methyl-2-methylth~o-pyrimidin-4-one,~~ some glycopyranosylated pyrazolo[5,4-e]- 1,2,4-tria~ines,~~ and various p- D- hexopyranosylated 7,8-di hydrobenzo[flquinoline-3( 2H)-thiones. 34

3 Anhydro- and Cyclo-nucleosides

Reaction of furanoid glycals with silylated pyrimidine bases and NIS gave products such as 16; subsequent base treatment of this compound gave the D-

Zyxo-epoxide 17.35 A similar intramolecular displacement of 2’-O-tosyl groups also gives rise to 2’,3’-anhydrolyxofuranosyl pyrimidine nuc leo~ides .~~ The 2’,3’-anhydride of 2-aminoadenosine has been made from the parent nucleoside, and was converted to the guanosine analogue by use of adenosine deaminase. 37

Spiro-uracil nucleosides have been prepared using hypoiodite-induced cyclizations. When 18 was photolysed in the presence of P ~ ( O A C ) ~ and iodine, the p-anomer 19 was the major isomer formed (p:cc, 7:1), whereas the 7-epimer gave the a-product almost exc l~s ive ly .~~ The compound lacking the methyl group gave similar amounts of both a n o m e r ~ , ~ ~ ? ~ ~ and these results could be rationalized on a model of the transition state. In the D-YibO-SerieS, similar


reactions on 2’,3’-O-isopropylidene derivative^^^ or on the tris(Tbdms) ether of 6-hydro~ymethyluridine~~ were p-selective.

Treatment of the alkyne 20 (Vol. 29, p. 281) with Bu3SnH/AIBN gave the cyclonucleoside 21 .40

When the 5’-thionucleoside derivative 22 was treated with NaOH in ethanol, followed by acid hydrolysis, S5’,6-methano-5’-thiouridine (23) was obtained, via an allylic substitution on the tautomer of 22. A route similar to that used to make the oxygen-containing analogue of 23 (Vol. 26, p. 227) was less successful for the sulfur compound.41

Some uses of anhydro- and cyclo-nucleosides in the synthesis of other types of nucleoside are mentioned later in this Chapter.

16 17 ” 18 19

hu nu W 1 I W I I

23

OH OTbdms OH OTbdms

20 21 22

4 Deoxynucleosides

2’-Deoxy-2’-phenylselenyl nucleosides such as 24 can be obtained by reaction of glycals with PhSeC1, AgOTf and a silylated base; these products can be converted to 2-deoxynucleosides (e. g. 25) by radical reduction using B u ~ S ~ H . ~ ~ A similar reduction of 2‘-deoxy-2’-iodocompounds of type 16 gave 2’-deoxy-P-~-threo-pentofuranosyl pyrimidine nuc le~s ides ,~~ and an approach to the same type of compound using intramolecular glycosidation is outlined in Scheme 2; this work also gave a route to the N3-linked cyclonucleoside 26.43

The synthesis of 5,6-dihydro-5-hydroxythymidine (27) is indicated in Scheme 3; the hydroxylated cyclonucleoside 28 could also be prepared by oxygenation of a previously-reported intermediate (Vol. ,29, pp. 270-27 l), and the chlorocompound 29 could be dehydrated prior to reductive dehalogenation to provide a route to 2’-deoxy-pyrimidine nucleosides.44 A new route to 2- deoxy-5-ethyluridine also involves a 2,2’-anhydronucleoside as an intermediate.45

20: Nucleosides 27 1

Memo 6ePh Memt) 24 25

iv/ \V

26 Reagents: i, NaH; ii, 6-allyloxy-2chloro-5-rnethylpyrirnidine; iii, Rh( PPh3)&I; iv, TmsOTf;

Scheme 2 v, HF, PY

&Me.

OH 28 29- Reagents: i, MeCONMe; ii, PivCI; iii, Ha, Pd/C or Bu3SnH; iv, NaOMe

Scheme 3

A route to 2’-deoxy-P-~-ribonucleosides reported last year (Vol. 30, ref. 50) has now been applied to the synthesis of the a-isomers by the use of an arabinofuranosyl precursor$6 whilst an alternative method for stereoselective synthesis of 2’-deoxy-a-ribonucleosides involves condensation of the 5 - 0 - diethylthiocarbamoyl compound 30 with a silylated pyrimidine in the presence of 20 mol% of SiC12(OTf)2, to give, for example, 31 as a 93:7 mixture with the p - a n ~ r n e r . ~ ~

2’-Deoxyuridine stereoselectively deuteriated at C-2 (33) can be prepared by reduction of the bromocompound 32 with (Tms)3SiD and triethylborane in perdeuteriated THF; if the deuterium was already present in the bromocompound, then the P-deuteriated product was obtained using non-deuteriated reagent^.^' Aldehyde 34, uniformly labelled with 13C, was made from [‘3c6]- D-glucose; reduction of 34 with [2-2H I]isobornyloxymagnesium bromide gave a stereoselectively-deuteriated alcohol which could be converted to the thymidine isotopomer 35, also with 13C in all sugar positions.49 Various 2’- deoxyribonucleosides deuteriated at C-5’ have also been made by reduction of 5’-0-acetyl-5’-phenylselenyl-compounds with Bu3SnD and Et3B.50

Base-sugar condensation methods have been used in a new stereoselective


route to 2’-deo~ycytidine,~’ to prepare hydrophilic carborane-containing uridine derivative^,^^ and various 5-(3-substituted-pheny1)-2-deoxy~ridines.~~ Condensation under phase-transfer conditions gives significant quantities of the N7-isomer 36, which was used in the preparation of oligodeoxynucleotides containing N7-linked guanine.54 A better route, by base-sugar condensation, has been reported to 7-dea~a-2’-deoxy-isoguanosine;~~ 7-deaza-2’-deoxy-7- methylguanosine analogues have been similarly made, and again incorporated into oligon~cleotides.~~ The pyrrolo[2,3-dJpyridazin-7-one 37 has been made by a procedure in which a pyrrole 2’-deoxy-nucleoside was prepared by condensation, and the second ring built on by reaction with hydrazine; the 2’,3’-dideoxy-~ompound was also made by subsequent deo~ygenat ion .~~ When the pyrazolo[3,4-dJpyrimidine 38 was prepared by anion glycosylation, a major by-product was an N2-nucleoside which had lost bromine, and an addition- elimination mechanism after glycosylation was proposed.58 Some N-(2’-deoxy- a- and -~-~-ribofuranosyl)-quinazoline-2,4-diones, variously substituted in the phenyl ring, have been de~cribed,’~ and synthetic routes have been developed to the isoxanthopterin nucleoside 39 and its 6-phenyl derivative, along with forms suitable for incorporation into oligodeoxynucleotides.60 2-Deoxyribo- nucleosides have also been made from lumazine, 6,7-diphenyllumazine, allox- azine, naphtho[2,3,g]lumazine, naphtho[ 1,2-g]lumazine and anthra[ 1,2- gllumazine, and incorporated into oligonucleotides.61

S S

OAC - 33

OBn OBn Ura 30 31 32

CHO

34 35 36 OH 37

41 SePh OTol 38 39 40

In the area of 2‘,3’-dideoxy-~ompounds, it has been found that when 2’,3’- dimesyliites of ribofuranosyl pyrimidines, protected at 0-5’, are treated with

20: Nucleosides 273

PhSeLi, the 2’,3’-didehydro-2’,3’-dideoxy-compounds are produced in high yield; this gives an alternative to the use of telluride anion to accomplish the same transformation (Vol. 30, ref. 78).62 A method noted above for the formation of 2’-deoxy~ompounds~~ can also be adapted to the synthesis of dideoxy- and didehydro-dideoxy-systems. Thus, treatment of the glycal 40, itself made by selenoxide elimination, with PhSeCl, AgOTf and a silylated base, gives compounds of type 41 (B = Thy, Ura, 6-chloropurine) with high 0- selectivity; reductive removal of the selenium then gives the dideoxy-compound, whilst selenoxide elimination produces the dideoxy-didehydro- system.63 A phenylselenyl group was also used to direct glycosidation in the formation of 42; oxidation and elimination then gave the potent antiviral agent P - L - F ~ ~ C (Vol. 30, ref. 84), whilst reductive deselenation gave P-L-FddC (Vol. 28, pp. 269-270).@ The L-enantiomers of P-L-ddA and P - L - ~ ~ A had better substrate activities towards deoxycytidine kinase than did the ~ - f o r m s . ~ ~ Condensation of 2-t-butyldimethylsilyloxyfuran with the enantiomers of isopropylidene glyceraldehyde, followed by further manipulations including side- chain degradation gave 43 (from the D-glyceraldehyde derivative) and its enantiomer, and these were used to make dideoxynucleosides in both enantiomeric series, but without control over the orientation (a@) of the base.66 A further report has appeared on the synthesis of d4T from ~ - x y l o s e , ~ ~ , and there have been descriptions of d4T68 and d4U69 by opening of 2,2’-anhydronucleosides with iodide ion.

The adenosine kinase inhibitor GP 3269 (44) has been made by base-sugar conden~ation,~~ and various 2‘,5’-dideoxy-purine nucleosides were made on a small scale by transglycosylation between 5’-dideoxythymidine and the purine base catalysed by purine nucleoside phosphorylase; pyrazolo[3,2-dJpyrimidine and 1 -deazapurine 2’,5’-dideoxynucleosides could also be made in this way.71 Thymidine has been converted into the extended system 45 for incorporation into homologated DNA.72

F fJ NH2 42 43 44

ODrntr I cH2-wy

OH 45

@i03 HOH2C

F -. . 46 47 48 49


5 Halogenonucleosides

9-(2-Deoxy-2-fluoro-~-L-arabinofuranosyl)purine nucleosides have been made by a coupling procedure; the adenosine and hypoxanthine analogues had significant anti-HBV activity without significant (2-Deoxy-2-fluoro- ~-~-arabinofuranosyl)-5-iodocytosine has also been prepared by base-sugar coupling,74 as has the 3’-deoxy-compound 46; during this work, the analogous tetrazole-fused derivative of ara-C was also made as a potential p r ~ d r u g . ~ ~ A series of 2’,2’-difluorocompounds of type 47, in the L-series, have been prepared from a difluoro-sugar (Chapter 8) and the appropriate base; the cytidine analogue is the enantiomer of gemcytabine, but these compounds did not show useful antiviral activity.76

When the anhydronucleosides 48 (R =p-toluoyl or Piv) were treated with DDQ, substantial amounts of the 2’-chlorocompounds 49 were formed, as well as the dehydrogenated cyclonucleoside, which was itself inert to the conditions. A mechanism was proposed involving attack by chloride ion derived from the reduced form of DDQ.77 The formation of 2’-deoxy-2’-iodo-compounds such as 16 was mentioned above.35

The racemic difluoronucleoside 51 has been made from an oxabicyclo[2.2.1]- heptene, via the intermediate 50.78

Methyl 2,3-dideoxy-3-fluoro-5-O-(4-phenylbenzoyl)-~-~-e~~~~~~-pentofuranoside whas been condensed with silylated 2-(methylthio)pyridine-4( 1 H)-one in the presence of TmsOTf to give the corresponding nuc le~s ides .~~ In an improved route to the fluorinated adenosine analogue 52, fluorine was inserted into 2’,5’-di-O-tosyladenosine using DAST, and the tosyl groups were then removed reductively using sodium naphthalenide. 8o

All four 5’-deoxy-5’-halo-derivatives of the anticytomegaloviral agent TCRB (11) (X = Cl) have been described.81 5’-Deoxy-5’-iodothymidine has been converted into a phosphoramidite for incorporation at the 5’-end of deoxyoligonucleotides. When such an oligonucleotide and another one bearing a phosphorothioate at the 3’-end were brought together on a complementary template, non-enzymic ligation could be demonstrated. 82

6 Nucleosides with Nitrogen-substituted Sugars

To prepare a fluorescent probe for incorporation into oligonucleotides, 2’- amino-2’-deoxyuridine has been converted into its 6-dimethylamino-2-naphthyl- amide. 83 1 -(N-Acetyl-2-amino-2-deoxy- ~-~-glucopyranosyl)-derivatives of uracil and 5-halo-uracils have been synthesized by silyl coupling procedure^.^^

Isocyanato-derivatives of nucleosides have been prepared using various synthetic procedures. Thus, for example, AZT was treated with PPh3 and the resultant phosphinimine allowed to react with CS2 to give 53, and 2’-deoxy-2’- isocyanatouridine was similarly prepared. An attempt to simultaneously reduce the azide to an amine and to deoxygenate C-3’ of uridine derivative 54 formed the cyclic compound 55 instead.85

20: Nucleosides 275

A review from Janda’s laboratory discusses the synthesis of complexes of type 56 (M = Re or Tc) as inhibitors of ribonucleases and for the generation of catalytic antibodies,86 and the same group has also reported on the use of 56 (M=Re, B = Ura) in eliciting antibodies able to catalyse the cleavage of uridine 3’-@-nitrophenylphosphate). An anhydroribitol derivative lacking the base unit was also effective, implying that the nucleobase is not essential, in contrast to earlier studies on RNase U2 (Vol. 30, p. 279), in which the presence of the base was important.87

A number of N6-cyclopentyl-3’-acylamino-3’-deoxy-xylofuranosyladenines have been prepared, providing a new class of non-xanthine adenosine A1 receptor antagonists.88 1 -( 3’-Amino-2’, 3’-dideoxy-P-~-erythro-pentofuranosyl)thieno[2,3-dJpyrimidine-2,4-( 1 H,3H)-dione has been d e ~ c r i b e d , ~ ~ and there has been a further report on the synthesis of AZT from thymidine (3 steps, 61% overall).g0

Oximes 57 (R = H, Me, Ac) have been described, along with the 2-isomers (R=Me or Ac). Oxidation of 57 (R=H), protected at 0 - 5 ’ , gave after deprotection a new route to 3’-deoxy-3’-nitrothymidine. Some of the oximes had significant antiviral activity.g1

Oximes at C-5’ of adenine nucleosides have also been prepared. As well as 58, various oxime ethers were made, as were the 2’- and 3’-deoxy- and D- arabino-analogues of 58. The compounds were investigated as antiviral and antitumour agents, and 58 was a potent inhibitor of SAH h y d r ~ l a s e . ~ ~

Amides have been prepared by reaction of 5’-amino-5’-deoxythymidine with activated esters of quinaldic acid and 4-(quinoline-2-carbonylamino)butyric acid, and interactions with DNA were studied.93

7 Thio- and Seleno-nucleosides

Nucleoside 2’-thionitrites 59 (B = Ura, Cyt) have been synthesized by reaction of the 2‘-thiocompounds with t-butyl nitrite, and the ability of these compounds to generate NO was studied.94 A paper dealing with some branched- chain 2’-phenylthio-nucleosides is mentioned in the next Section.


A series of novel 3’-alkylthio-2’,3’-dideoxynucleosides were made by Michael addition of alkylthiols to an a, P-unsaturated hexose aldehyde, followed by acetylation, nucleoside coupling and deprotection, forming the basis for a combinatorial synthesis of libraries of 3’-substituted 2’,3’-dideoxynucleosides.95

In the area of sulfur-in-ring analogues, a review has been given of the synthesis and antiviral activity of 4’-thio-2’-deoxyribonucleosides.96 There has been a fuller account of the synthesis of the 4’-thio-analogues of gemcytabine and 2‘-deoxy-2’-methylenecytosine (see Vol. 30, p. 281), and this work was extended to the preparation of the azide The same group have also used related intermediates to make various 5-substituted uracil 4-thionucleosides 61 (R = e.g. Et, Me, I, CH = CHBr), and the adenine, guanine and 2,6-diamino- purine analogues were also reported.98 A fuller account has been given of the preparation of compounds of type 62, their enantiomers and the or-anomers, from the condensation of 2-t-butyldimethylsilyloxythiophene and the enantiomers of isopropylidene glyceraldehyde (see Vol. 29, p. 279).66 A route has been developed for the synthesis of 3-azido-2,3-dideoxy--thio-cc/P-~-erythr-pentofuranose derivatives from D-xylose, which led to the synthesis of the 4-thio- analogue of AZT and related pyrimidine nuc le~s ides .~~ The doubly-branched 4’-thionucleoside analogue 63 (X = S) has been made by base-‘sugar’ coupling, although the condensation gave more of the a-anomer (or:p, 2.5:l); the ‘sugar’ unit was made from L-tartrate. loo

OH I “we OH OH

58 OH SNO

59 OH N3

60 0’ 61

CH20H OAc OAc 62 63 64 65 66

5’-Thiopentofuranosylpyrimidines such as 64 (R = Me, Et), together with sulfoxides and sulfones, and 2’,3’-saturated compounds, have been prepared from d4T. lo’

In previous work (see Vol. 28, pp. 275 and 280), the phenylselenyl pyrimidine nucleoside 65 was produced as essentially the only epimer through reaction of the 5’-aldehyde with PhSeCl and Et3N. It has now been found that 65 can be epimerized to 66 by photolysis in the presence of diphenyl diselenide to give an equilibrium mixture 6655 of about 2.5:l. Epimer 66 was incorporated into modified oligonucleotides, in which it can provide a source of radicals at C-4’ for chain scission. lo2 Some papers on the stereoselective formation of 2’-phenylselenyl nucleosides from glycals, followed by removal of the PhSe group, were mentioned above42* 63 (see also the next Section).

20: Nucleosides 277

8 Nucleosides with Branched-chain Sugars

There has been a full account of the synthesis of 2’-C-methyl ribonucleosides by addition of MeTiC13 to a 2-keto-sugar, followed by nucleoside formation (see Vol. 29, pp. 191 and 280), and the method has been extended, using organocerium reagents, to C-ally1 and C-ethynyl systems. *03 A multistep synthesis of 2’,3’-dideoxy-2’-(hydroxymethyl)nucleosides from isopropylidene- glycerol has been reported.lo4 A full account has also appeared of the synthesis of 2’-deoxyribonucleosides with a two-carbon branch at C-2’ (see Vol. 29, pp. 280-281; for the incorporation of such structures into a dinucleotide analogue, see Section 13). lo5 The branched-chain thionucleoside derivative 67 was produced stereoselectively by addition of LiSPh to the 2’-enoate; interestingly, addition of KSPh to the analogous t-butyl enoate gave predominantly the opposite epimer at C-2’, a result attributed to different chelation patterns in the two cases.lo6

In work based on earlier precedent (Vol. 23, pp. 218-219), reaction of the selenone 68 with the anion of benzyl (phenylthio)acetate, followed by reductive removal of the PhS group, gave the separable isomers of the cyclopropyl-fused system 69; for the use of these in making conformationally-restricted dinucleotide analogues, see Section 13. lo7

As regards compounds with the branch at C-3’, the selenoester 70 was made by a sequence involving oxidative cleavage of a 3’Gvinyl compound, which had been prepared through stereoselective addition of a vinylcerium species to a 3’-keto-nucleoside in which 0-5’ was protected as a Tbdms ether. Photolysis of 70 gave a 3’-radical of the type implicated in the mechanism of ribonucleotide reductase.lo8 There has been a fuller report (see Vol. 29, p. 281) on the synthesis of the 3’Gethynyl compounds 71, again through addition of an organocerium species to a 3’-one; here the reaction was highly 0-selective, since the substrate had the 5’-hydroxyl group unprotected. The 2’-deoxy analogues of 71 were made by Barton deoxygenation of the 3’,5’-0-Tipds derivatives.log

Wengel’s laboratory has reported the synthesis of the conformationally- restricted nucleoside 72, This was made from the intermediate 73, prepared from 1,2-~-isopropy~idene-a-~-xylofuranose, in a sequence involving stereoselective glycosidation of thymine, inversion of stereochemistry at C-2’ via an anhydronucleoside, and then formation of the extra ring after oxidative cleavage of the alkene. Inclusion of thirteen of these modified units into an almost completely modified oligonucleotide gave a duplex with complementary RNA that was considerably more stable than the unmodified RNA-DNA duplex.llO*lll The intermediate 73 was also used to form the trans-fused bicyclic nucleoside 74. The same group has also described the 3’-C-allyl-2’- deoxy-compound 75, as well as the or-anomer, the compounds with opposite stereochemistry at C-3’, and aminopropyl compounds prepared from the C- allylated nucleosides. l 2

Workers at Eli Lilly have developed two efficient routes to the promising antiviral agent 77. In one of these, the key step was hydroformylation [Rh(C0)2acac, Ph3P, CO (40 psi), H2] of the 2’-ene 76, itself easily accessible


from cytosine by literature l4 whilst in the other approach stereoselective borohydride reduction of the alkene 78, made from the ~ 4 ~ x 0 - epoxide, was a feature.I14 A report from Mann’s laboratory has described the application of their method of photochemical addition of methanol to butenolides (see Vol. 26, p. 242 and Vol. 28, p. 278) to the preparation of the enantiomer of 77 and some related compounds. I5

\ I 0 CH2C02Et I S/e02Ph

67 68

HOCH2 UrdAde HOW2 ,a vyy I

O H OH OH 71 72

C02Bn 3 e 69 70

73 ‘ 74

Access to compounds with an ‘up’ hydroxymethyl group, and related bicyclic systems, comes from the chemistry of Scheme 4. The cyclic lactol 79 was made by ring-contraction of a 3-O-triflyl hexopyranoside (Vol. 29, p. 199); the routes to both 80 and 81 were p-selective, but the sequence to 82 gave the a-product, due possibly to delivery of the electrophilic PhSe group to the p- face by association with the carbonyl oxygen atom. l6

The 3’-G‘-aminomethylthymidine derivative 83 (R = NH2), and also 3’-C- methylthymidine, have been made from the previously-known hydroxymethyl compound 83 (R =OH) (Vol. 38, p. 278), via an epoxide as interrnediate.’l7

A two-carbon branch has also been introduced in the p-orientation on uridine using an intramolecular Reformatsky-type reaction to give a bicyclic intermediate, as outlined in Scheme 5.Il8 3’-Deoxy-3’-difluoromethylenethymine has been made by a method pre-

viously applied to the uridine analogue (Vol. 30, ref. 145), and the difluoromethyl compound 84 was prepared by addition of the anion of difluoromethyl phenyl sulfone to the 3’-keto-group, followed by desulfonation using Sm12.l l9

New analogues of TSAO-T, either of L-Zyxo-configuration or 5’-deoxy-5’- modified, have been described, * 2o and 3’- C-isoxazoline, -isoxazolidine and -alkoxyimine derivatives have been prepared from 3’-deoxy-3’- C-formylthymi- dine, the heterocyclic cases being made using cycloaddi tions of nitrile oxides and nitrones respectively. 12’

20: Nucleosides 279

i. vi. vii

Reagents: i, PCC; ii, PhSH, BF3.Et20; iii, (Tms)2uracil, NBS; iv, LiAIH4; v, BnBr, NaH; vi, PhSeH, BF3; vii, BubOH, Ti(OPrj4; viii, PhSeCI, (Tms)2uracil, AgOTf

Scheme 4

DmtrOCH2 vq OH

83 Reagents: i, Sm12, THF

Scheme 5

The doubly-branched adenosine analogue 63 (X=O) has been made by coupling silylated 6-chloropurine to a sugar acetate derived from L-tartrate. loo

A number of reports have appeared concerning systems with a branch at C- 4 . The fused oxetan 86 has been prepared by base-induced cyclization of 85 followed by acidic deprotection; the cytidine analogue was also reported. 122

When 0-3’ was protected, then cyclization proceeded with 0-2’ as the nucleophile to give after deprotection the interesting bicyclic system 87, in which the furanose ring is fixed in a C-3’-endo-conformation. 123 A preparation has been described of 1 -(2-deoxy-4-C-hydroxymethyl-cc-~-threo-pentofurano- ~yl)uracil ,’~~ and chloro and sulfanyl derivatives of this have also been reported. 25 Thymidine-4’-C-carboxylic acid and derivatives have been prepared by oxidation of a 4’- C-hydroxymethyl-compound. 26 The 4’-C-fluoromethyl nucleosides 88 (X, Y = H, OH and X = Y = H) have been prepared from a known 4’-C‘-hydroxymethylribose der i~a t ive , ’~~ and the 4’-C-fluoromethyl- thymidine 5’-phosphonate 89 has been prepared from a non-carbohydrate source, 28

HOCH2 FjlY CF2t-i

a4

OH Y 88

OH OH 85

0 ( EtO)2P-CfoJy It

FH2C

89

H2C de 0 OH

90

HOCH2

@ OH

87

NHFmoc 91


9 Nucleosides of Unsaturated Sugars, Aldosuloses and Uronic Acids

As in previous volumes, 2’, 3’-didehydro-2’,3’-dideoxyfuranosyl nucleosides (d4 systems) are discussed in Section 4, together with their saturated analogues.

The mechanism of the time-dependent inactivation of S-adenosylhomocys- teine hydrolase by 5’-deoxy-5’-difluoromethylthioadenosine (preparation, Vol. 25, p. 254) has been studied, and evidence was adduced that the mechanism involves the generation of the enone 90 and the powerful acylating agent HFC = S. 129

A convenient route has been described to convert cytidine into the 2’-keto- nucleoside, acetylated at 0-3’, 0-5’ and N-4, in which formation of a 2,2’- anhydronucleoside was used to differentiate the hydroxyl groups. 130

Conjugates of adenosine- and 2-chloroadenosine-5’-carboxylic acids with tetra-aspartate and with the pentapeptides Pro-(Asp)4 and Sar-(Asp)4 have been made by solid-phase synthesis. The compounds can be viewed as highly- charged ATP analogues. l 3 The N-2’-amino-2’-deoxy-glucuronic acid nucleosides 91 (B=Thy, Cyt, Ade, Gua) have been made as building blocks for oligonucleotide amide-linked analogues (see Section 13); oxidation of the primary alcohol to the acid using NaOCl catalysed by TEMPO was the final step in the synthetic sequence. 132 N-P-D-Glucuronides of the cytokinins N6- benzyladenine and isopentenyladenine have been prepared by Koenigs-Knorr chemistry for use in selecting plant cells transformed with a P-glucuronidase gene. I 33

10 C-Nucleosides

A review has appeared on the synthesis of C-nucleosides of monocyclic heterocycles, 34 and the preparation of pseudouridine under prebiotic conditions has been discussed in a review The ionization constant of 9- deazainosine (pK, 6.0, for protonation at N3) has been determined for the first time, and a third ionisation constant (pK, 1.3, for protonation at N3) was identified for formycin. 136

‘Selenophenfurin’ (92) has been made by a method analogous to those used for the thiophene and furan compounds (Vol. 29, p. 283), and it was found to inhibit IMP dehydrogenase and to have antitumour activity.137

There have been further reports on pyridine C-nucleosides. The preparation of 93 (R = X = H) has been described in detail, as have routes to 93 (R = Me, X = H, and R = H, X = OMe); these were made as more basic analogues of cytidine, and the incorporation of these into DNA was studied.13* An improved route to the pyrimidinone 94 has been described,139 and the isomer 95 has also been made, using addition of a lithiated pyridine to 2,3,5-tri-O- benzylribonolactone, followed by stereoselective reduction with Et3SiH and BF3.Et20.IN A similar approach was used to make the imidazo[l,2-a]pyridine 96, where the site of ribosylation (C-3) was unexpected.

There has been an extended report on the synthesis of ribofuranosyl and 2’-


deoxyribofuranosyl heterocycles by reaction of protected (deoxy)ribose derivatives with metallated heterocycles, followed by Mitsunobu cyclization (see Vol. 28, p. 282). Use of less basic organometallics tended to give more of the p- product. 142

Palladium-catalysed cross-couplings have been used to make some new 2’- deoxypyrazine C-nucleosides such as 9, 143 and the 2’-deoxypyrazofurin analogues 98 (X = Br, C02Me). 3-~-~-Ribofuranosylpyrazole-4-carbox- amide has been made by cyclization of a previously-reported intermediate. 145

The L-enantiomer of 9-deazaadenosine has been prepared using methods similar to those employed for the D-form, and 4-amino-8-~-~-ribofuranosyl- pyrdzolo[ 1,5-a]-1,3,5-triazine was also synthesized from one of the intermediates in this work. 146

Dehydrative cyclization was used to make some 2-tetrosylbenzimidazoles such as 99,147 and some 2-(D-erythrosyl)furdns have been described, with additional nitrogen heterocycles attached to the furan via a carbon spacer. 1487149

2-(cc-~-Mannofuranosyl)maleimide, an analogue of showdomycin, has been reported,150 and two routes have been developed for the synthesis of the apiofuranosyl maleimide 100, a showdomycin analogue with a transposed hydroxymethyl group, both proceeding from 2,3-O-isopropylidene-~-apio-p- D-furanose, itself available from D-mannose in good yield (Liebigs Ann. Chem., 1995, 551).15’3 152

The homo-C-nucleoside 101, with a ‘split’ 8-azapurine system, has been prepared; the triazole was made by cycloaddition of Tms-acetylene and an azide, which was assembled by Wittig reaction-cyclization involving 2,3- 0- isopropylidene-5- O-trityl-~-ribofuranose. 53

NH2 spcoNHZ H W a ‘N &. c$q p-D-Ribf HO X p-D-Rib-f p-D-Rib1 p-D-Ribf

’ CI

92 93 94 95 96

1 1 Carbocyclic Nucleosides

The carbocyclic ribosylamine 102 has been used to prepare 103 (X = CH2 and X=O), which, when cyclized via a diphosphate unit will give carbocyclic


analogues of cADPR in which the labile "-ribose link has been stabilized by the presence of the methylene unit?" A new synthesis of the antiherpetic agent (+)-cyclaradine (104) has been reported, * 55 and ring-opening of an epoxide with various nucleobases in the presence of Et,Al has been used to make a number of racemic carbocyclic nucleosides of xylo-configuration. 156 The racemic compound 105 has been made from carbomethoxycyclopentanone. 57

OXO

101

HOCH2 we OH

102 103 104

1 05 106 107 108

The racemic nor-analogue 106 related to aristeromycin has been prepared using the cycloaddition of a-chloronitrosocyclohexane and cyclopentadiene to establish the 1,3-cis-stereochernistry of nitrogen and oxygen. 158 The ' L-type aristeromycin analogues 107, their enantiomers and a related alkene have been prepared as potential antitrypanosomal agents, 59 several racemic compounds of type 108 have been made by Pd(0)-catalysed reactions of the bases with cyclopentadiene monoepoxide, 160 and the chiral iso-nucleoside analogue 109 was prepared by alkylation of adenine; N4- and N9-alkylated products were also formed, and the N4-product could be selectively extracted from the mixture by an acid wash due to its higher basicity.161

The 5'-homo-systems 110 (B = Purine) have been prepared enantioselec- tively, again using Pd(0) chemistry to add the base,'62 and analogues have been made in which the carbocycle and base are separated by a two-carbon chain. 163

Some racemic bicyclic dideoxynucleoside analogues such as 11 1 have been prepared. A report from Marquez's laboratory has described an alternative route to the anti-HSV agent 113, in which a key step was the formation of the azidoselenide 112 from the enantiopure alkene (J. Chem. SOC., Perkin Trans. I , 1988, 549),165 and the same group have also given an extended account of the synthesis of the isomeric systems 114 (B = Thy, Cyt, Ade, Gua) (see Vol. 29, p. 285) from the same chiral alkene.166 Other workers have used very similar

20: Nucleosides 283

intermediates, made in the same way, to produce the methylene-substituted compounds 115 (B=Ade, Gua, Thy, SodoUra), and the Gua analogue showed particularly good activity against hepatitis B virus. 167 The chiral cyclopentanone 116 has been used to produce the fluoronucleosides 117, and also isomers with the fluorine 'down', and the two epimers where the fluorine is at C-2'. Introduction of fluorine was by electrophilic fluorination of the Tms enol ether of 116.168 The iridoid glycoside aucubin has been used as a chiral precursor for the doubly-branched carbanucleoside 118, 16' and 119 and related purines and 8-azapurines have been prepared in chiral form. 170

The cyclobutyl derivatives 120 have been synthesized. 171

HO Ici 109

OH 114

OH

HOH2C 118

kLY 110

OH 115

BnO SePh

TWpsO OH 111 112 113

T W P s 0 H 2 c y 3 0 HOCH2 Ade/Gua

__c - TbdpsOH2C OH

116 117

HOCH2 L O $

HOH2C Ade/Ura 9 OH

'r( '0'7\O'-NO2 0-

119 120 121

Some references to phosphates and phosphonates of carbocyclic nucleosides are mentioned in the next Section, some references to cyclopropyl nucleoside analogues are given in Section 15, and a number of papers on aristeromycin, neplanocin and their close analogues are covered in Chapter 19, along with carbocyclic analogues of oxetanocin.

12 Nucleoside Phosphates and Phosphonates

12.1 Nucleoside Mono-phosphates and -phosphonates and Their Analogues - A review on the synthesis of non-racemic phosphonates discusses a number of examples from the nucleoside field.172 Thymidine 5'-O-diphenylphosphate has been prepared by the reaction of thymidine and diphenyl phosphate in the presence of a polystyryl diphenylphosphine-iodine complex. The 3W-diphenylphosphate was formed if 0 - 5 ' was protected as the Dmtr ether.173 The 3'- phosphate 121 has been prepared labelled both with 15N and with l8O at, separately, either of the positions asterisked, for use in studies of isotope effects in the mechanism of ribonuclease


When the lyxo-epoxide 122 was treated with disodium hydrogen phosphate, the 3’-phosphate 123 (R = H) was formed as the major (5:l) product of epoxide opening, and use of UMP as nucleophile led to the formation of the dinucleotide (123) (R = uridyl-5’-yl). 175 A new route to the nucleoside boranophosphate 124 involves the reaction of 5’-0-Dmtr-thymidine with t-BuLi followed by tetramethylboranopyrophosphate (125), and then acidic deprotection. 176 The phosphorothioate 126 has been prepared by the reaction of the corresponding phosphite with propylene sulfide in the presence of ReOC13(PPh3)2 as cata- 1 y ~ t . I ~ ~ A study has been reported of the acid-base properties of adenosine-5’- 0-thiomonophosphate in aqueous solution; in the monoanion, the thiophosphate-protonated species dominates (3: 1) over the N1-protonated species, and calculations locate the proton in the former species mainly on 0 ~ y g e n . l ~ ~ Nucleoside 5’-phosphorodithioates have been prepared from 2-thio- 1,3,2- dithiaphospholanes (Vol. 28, pp. 288-289) as indicated in Scheme 6, and 3’- phosphorodithioates could be made in the same way. 179

122

Reagents: i , HOCH2CH2CN, DBU; ii, NH3, H20

Scheme 6

Carbocyclic analogues of the four 2’-deoxyribonucleoside S-monophosphates have been prepared by methods involving Mitsunobu reactions to link the base to a chiral cyclopentane unit.180

Adenine-activated nucleosides such as 127, and related species derived from adenine itself (N9-phosphorylated) and N3-methyladenine (N7-phosphorylated) have been prepared. These compounds underwent oligomerization catalysed by montmorillonite to give products in which 3’,5’-links predominated.18‘

A 3‘-phosphoramidite derived from 5-hydroxy-2’-deoxycytidine has been prepared, and used to incorporate the modified base into oligonucleotides. lg2

The 5’-phosphonate of 2’,3’-dideoxythymidine has been prepared, as has the regioisomer 128 in which the positions of the base and the phosphonate are reversed. 83

Flavin has been linked via short chains of methylene groups so as to form a phosphodiester with thymidine-5’-phosphate, and a phosphorothioate diester and an 0-methyl phosphotriester were also prepared. 84

20: Nucleosides 285

There have been a number of further reports (see Vol. 30, p. 294) from Meier and co-workers on a new type of lipophilic prodrug designed to deliver nucleoside 5'-monophosphates. These cyclosaligenyl (cycZoSa1) phosphotri- esters have been described for d4T (129, X=Cl, H, Me, N02),185 ddA,'86 FdU,'87 and AZT.'88 In each case the nucleoside monophosphate can be generated under physiological conditions by initial hydrolysis of the phenyl phosphate, which then leads to a more rapid cleavage of the benzylic phosphate. The derivatives of d4T185 and ddA186 were more active against HIV than were the parent nucleosides. A range of phosphoramidates related to AZT and to FLT (3'-fluoro-3'-deoxythymidine) have been reported, including ones which are phosphomonoesters (e.g. 130). The mechanism of enzymic hydrolysis was investigated, and it was found that initial hydrolysis of the C02Me group was not involved, unlike the situation for aromatic phosphodiesters. 89 Various long-chain alkyl phosphonoformate esters of AZT have been prepared,lgO and ara-C has been linked via a 5'-phosphate to ~-1,2- diacylgl ycerols. *

P-D-Lactose has been linked through a 3-hydroxypropyl glycoside to ara-C and ara-A via S-phosph~diesters, '~~ and in related work, the anti-hepatitis B agent IdU monophosphate has been linked to a trivalent lactose array recognised by a receptor on the liver; the structure 131 uses tris and 6- hydroxyhexanoic acid to link the units.'93

n -

128 127 OH OH

0

H N$F

130 OH 131

12.2 Cyclic Monophosphates and Related Phosphonates - The sequence of Scheme 7 has been used to prepare the 2',3'-cyclic phosphates of adenosine and cytosine. Deoxyribonucleosides gave the benzoin phosphodiesters, predominantly at 0-5'.194 Uridine 2',3'-cyclic phosphite has been prepared, and the diastereomers were analysed by 2D-NMR techniques to assign configuration.lg5

Membrane-permeant but bioactivatable triesters of 8-substituted cyclic AMP derivatives, such as 132, have been made by reaction of the cyclic diester with AcOCH2Br. lg6 The 5'-nor-aristeromycin derivative 133 (Vol. 27, p. 235)


has been converted into various racemic carbocyclic phosphonate analogues of CAMP such as 134 (X = NH2, OH).197

Reagents: i, cytosine or adenosine; ii, H20, r.t. Scheme 7

CI x

133 134

12.3 Nucleoside Triphosphates and Their Analogues - Nucleoside triphosphates have been prepared from the corresponding 5’-monophosphates by treatment with TFAA and tertiary amines, followed by N-methylimidazole and inorganic pyrophosphate. 19* 1 3 C 6 - ~ - G 1 ~ c ~ ~ e , 2H7-D-glucose, and 3C6,2H7-~-gl~~ose have been converted enzymically into multiply-labelled ribonucleoside triphosphates, which were incorporated into oligomers for NMR studies.199 4-C- Acylthymidines (Vol. 30, p. 285) have been converted into their 5’-triphosphates and incorporated into deoxyoligonucleotides which underwent chain- scission on photolysis.200 The 5’-thioribonucleoside 5’-triphosphates 135 have been prepared from the 5’-deoxy-5’-iodonucleosides, either by diplacement of iodide by monothiophosphate followed by formation of the triphosphate, or by direct substitution of iodide by monothiotriphosphate. The products were not substrates for E. coli DNA-dependent RNA polymerase, but were weak competitive inhibitors.201

A number of analogues of deoxynucleoside triphosphates have been made, in which the a$- P-0-P unit is replaced by P-NH-P; they were prepared by the reaction of the 5‘-imidodiphosphates with phosphoenolpyruvate in the presence of pyruvate kinase, and were inhibitors of HIV reverse transcriptase.202 The ATP analogue in which the P,y-oxygen is replaced by a difluoromethylene unit has been made, as has the related arsenic species 136, the products being competitive inhibitors of glycerol k i n a ~ e . ~ ~ ~

The 3’-triphosphate of 2’,5’-dideoxyadenosine is an inhibitor of adenyl cyclases. The species 137 has now been made and used, linked to Affi-Gel 10, for affinity chromatography. Similar derivatives of nucleoside 5’-triphosphates were also prepared.204

p-Hydroxyphenacyl esters at the y-phosphate of nucleoside triphosphates have been made as photolabile protecting gr0ups,2~~ and a good synthetic

20: Nucleosides 287

method has been (CH3pppG), in which

@@@S-CH2 AddUra

kY OH OH

135

described for P1 -met h yl-P3-( 5’-guanosyl) triphosphate GDP reacts with methyl phosphorimidazolate.206

0 0 II I1 I I OH OH

OH OH 136

CH20H

137

140 X = OH, Y = F

12.4 Nucleoside Mono- and Di-phosphosugars - An enzymic synthesis of CMP- NeuNAc has been reported, using CMP-NeuNAc ~ y n t h e t a s e . ~ ~ ~ Khorana’s original synthesis of nucleoside diphosphosugars from sugar 1 -phosphates and nucleoside 5’-monophosphomorpholidates has now been shown to proceed in higher yields and in shorter times if tetrazole is present; UDP-Gal, GDP-Fuc, and GDP-Man were prepared in high yields using this method.208 The phosphomorpholidate method was used to make the TDP-sugar derivative 138 (X = CH2). Ozonolysis gave the aldosulose derivative 138 (X = 0), a potential intermediate in the biosynthesis of rare sugars, but the product was too unstable to be isolated due to P-eli~nination.~~~ Various analogues of GDP- fucose have been prepared,210 as have the UDP-Gal analogues 139 and 140. These compounds were prepared as potential inhibitors of UDP-galactopyranose mutase, and were found to be fairly weak inhibitors of the reaction in the direction UDP-Galf-+UDP-Galp.21 * The analogue 139 has also been prepared in Wong’s laboratory by a chemoenzymatic sequence, and it was found to be an inhibitor of p-1,4-galactosyl transferase, providing support that the mechanism of this enzyme proceeds through a transition state with sp2 character at the anomeric centre.212

12.5 Di- and Tri-nucleotides and Their Analogues - 12.5. I 3’+5’-Linked systems - A new protecting group has been developed for use during phosphodiester synthesis. The triesters 141 (n = 4, 5 ) were made by phosphoramidite chemistry, and, on treatment with NH3, TpT was formed. The alkyl group is lost, after hydrolysis of the trifluoroacetyl group, by cyclization producing piperidine or pyrr~lidine.~


Selective 0-phosphonylation of 5'-O-Dmtr-2'-deoxy-adenosine7 -cytidine and -guanosine, without reaction on nitrogen, can be achieved using P-H reagents such as pyrophosphonate and diphenyl phosphonate. The method was further developed to make H-phosphonate internucleotidic links, followed by oxidation to phosphates using an N-sulfonyloxaziridine.2'4 A report from Reese's laboratory describes a new approach to the solution-phase synthesis of dinucleoside phosphates and phosphorothioates. The method involves H- phosphonate coupling, followed by formation of a P-S bond, as indicated in Scheme 8. The products of type 142 could be very cleanly deprotected without side reactions to give dinucleotides, whilst if a 2-cyanoethyl group was used instead of the p-chlorophenyl unit dinucleoside phosphorothioates could be obtained.

" O W y 0

I

NHCOCF3

14' 07

DmtrO-CHp

0 DmtrO-CH2

0 i, ii 9

0 1 42 I

Reagents: i, di(2chlorophenyl)phosphorochloridate, py; ii, Phth-S-pC&i&I, CH2C12, py, -40°C, then py, H20

Scheme 8

Stawinski and Kraszewski have reviewed recent work from their laboratories, including the preparation of dinucleoside H-phosphonates and H- phosphonothioates, work on 5'-methylenephosphonate analogues, and routes to P-F compounds from H-phosphonates and related compounds.216 A solution-phase synthesis of dithymidine phosphorodithioate uses a chemo- selective coupling reagent QNOP [6-nitrobenzotriazol- 1 -yl-oxy-tris- (pyrro1idino)phosphonium hexafluorophosphate], which activates the intermediate 143 selectively at oxygen for coupling with 3'-O-acetylthymidine; the use of the 4-chloro-2-nitrobenzyl protecting group on sulfur led to less of the competing attack at C-5' when it was removed using phenylthiolate anion, as compared with earlier work (Vol. 24, p. 243).217 The same team has also applied similar chemistry to the synthesis of dithymidine phosphorothioate.21 *

A report from Just's laboratory describes some improvements on their previous work (Vol. 30, pp. 290-291) in which a xylose-based chiral auxiliary was used to prepare dithymidine phosphorothioate with good diastereomeric excess; in the new work, the xylose derivative used has a base-labile protecting group at 0-2, so that the auxiliary can be removed using ammonia.219 The same group has also described the use of an indolic chiral auxiliary for

20: Nucleosides 289

DmtrO- CH2

Ply CI

143

ii-iv - Howy ?

O H Reagents: i, 3-O-Tbdps-thymidine; ii, Beaucage’s reagent; iii, NH3, H20; iv, TBAF

Scheme 9

producing dithymidine phosphorothioate in high diastereomeric excess, as outlined in Scheme 9, where again the removal of the auxiliary under basic conditions is advantageous.220 The phosphorothioate 144 has been prepared; the diastereomers were separated by reverse-phase HPLC, the absolute configurations being deduced from their behaviour towards snake-venom phospho- diesterase, and incorporated into oligonucleotides.221

There has been interest in protecting groups for internucleosidic phosphates, phosphorothioates and phosphorodithioates that are removable under physiological conditions. The glucuronic acid derivatives 145 (X = 0, S) have been prepared, and similar systems in which the glucuronic acid was attached by a thioester were also described.222 The same team has also reported on a series of six triesters of TpT and its mono- and di-thioanalogues, of which 146 and 147 proved best in releasing the phosphodiester and phosphorothioate respectively.223 Other workers have prepared the trinucleoside analogues 148 (X=O, S), in which the phosphorothioate could be unveiled by esterases. 224

Various dinucleoside phosphorofluoridates have been prepared using 3’- phosphoramidites with a P-F unit present,225 and a new method for forming the P-F bond involves the synthesis of dinucleosidyl phosphorofluoridates and phosphorofluoridothioates from phosphorothioates and phosphorodithioates respectively, when they are subjected to desulfurization with iodine in the presence of triethylamine tris(hydroflu0ride). Phosphoroselenoates and phos- phoroselenothioates undergo loss of Se under these conditions, again forming the P-F species.226

A P(II1) coupling reagent containing an indole unit has been used to prepare


X I II

dT-P-dT

X II

dT- P- dT

OH 144 145 1 4 6 X - 0 148

1 4 7 X = S

deoxyoligonucleotide methylphosphonates and methylthiopho~phonates,~~~ and there have been reports on diastereoselective syntheses of 2 ’ - d e o ~ y - ~ ~ * - ~ ~ ~ and 2’-O-methyl dinucleoside 3’,5’-methylpho~phonates.~~~~~~~

A new method for the synthesis of N3’--5’ phosphoramidate oligonucleotides is illustrated in Scheme 10. This procedure follows a 5’-3’ strategy, with phosphoramidite-amine exchange as a key step. Removal of the N-trityl group with dichloroacetic acid permits repetition of the cycle.23’ 7232 A similar phosphoramidite-amine exchange was used to prepare the phosphoramidate 149, from which the o-nitrobenzyl group could be removed on photolysis. An alternative route to the same type of link was also developed, involving dinucleosidyl H-phosphonate diesters as intermediates, and this was applied to the synthesis of isomers of 149 with the bases ~ t - o r i e n t e d . ~ ~ ~

NHTr Reagents: i, 1H-tetrazole; ii, 12, H20, py, THF

Scheme 10

Treatment of 2’-deoxynucleosides with phosphoryl chloride in DMF leads to cyclic dinucleoside dipyrophosphates 150 as major products.234


Some chemistry concerning protecting groups used in oligonucletide work is mentioned in Section 14 below.

12.5.2 5’ +5’-Linked systems - The methylene bis-phosphonate analogue of benzamide adenine dinucleotide (BAD) has been prepared,235 and a similar analogue 151 in which adenosine is replaced by 2’-deoxy-2’-fluoro-ara-A has also been described. The similar tiazofurin adenine dinucleotide (TAD) analogue was also prepared, and in this case the compound with CH2 replaced by CF2 was also made.236 These methylene bisphosphonates were prepared by activating a 2’,3’-0-isopropylidene nucleoside-5’-methylenebisphosphonate with DCC in pyridine, prior to the addition of a second 2’,3’-04sopropylidene nucleoside. The mechanism of such reactions has been investigated, and found to involve bicyclic tris-anhydride intermediate^.^^^

In the area of cyclic ADP-ribose (cADPR), a chemoenzymatic approach was used in Sih’s laboratory to prepare cATPR, which is more stable and of higher bioactivity, carrying a (6-aminohexy1)amino-substituent at C-8 of the adenosine. The compound is of application as an affinity probe for cADPR-binding proteins.238 Potter’s group have described the synthesis of 152, a carbocyclic inosine analogue of S ~ C O - C A D P R . ~ ~ ~

12.5.3 2’-+5’-Linked systems - The 2‘-5’-adenylate trimer has been prepared with a positively-charged (4-aminobuty1)amino group at C-8 of the 2’(3’)- terminal adenosine unit,240 with 2’,3’-dideoxy-3’-fluoro-derivatives of adenosine at the 2’-end,241 and with the triazole base of ribavirin and with N6- benzyladenine at all three locations in the The 3’-deoxy trimer (cordycepin trimer) has been made with a-hydroxyalkyl chains attached at 0-3 of the 2’(3’)-end (this unit being adenosine rather than cordycepin), and a cholesterol conjugate was also made, which showed appreciable anti-HIV

The cordycepin trimer has also been attached to fatty acids, and to folic acid, at either the 5’- or the 2’-end, the acids being linked to the core by a 6-aminohexanoyl spacer.244

13 Oligonucleotide Analogues with Phosphorus-free Linkages

Amide replacements continue to attract attention. De Mesmaeker’s group has described thioamides of type 153 (X = S), together with amides in which the furanose rings are linked by the three-atom chains -NHCOCH2-, -CH2CONH- and -CONHCH2-, and also by a five-atom link previously developed by others (Vol . 29, p. 293).245 A dithymidyl unit with the four-atom amide link (153) (X = 0) has been made with an intercalating anthraquinone unit attached to the nitrogen via a short chain, and incorporated into oligonucleotides.246 The same team have also made the dimer 154; inclusion in oligomers led to improved T,s with complementary RNA of up to 4.4”C per modification.247 Other workers have prepared the 2’-5’ four-atom amide replacement 155 through reaction of a fused butyrolactone with 5’-amino-S’-deoxythymidine. lo5


0Tbdms 149

? f ?

CH2-O-P-O-P-0 I

150 0- b

OH OH 152

DmtY X

H N w y OH

153

m C O N H 2

OH 151

DmtPy 0

H72y OH OMe

154

The conformationally-restricted amide 156, and its diastereomer at the cyclopropyl carbon, have been prepared from 69, and reaction of the unsaturated selenone 68 with 157 in the presence of t-BuOK gave the sulfonamide-linked dimer 158. lo7

A novel linkage which has now been reported is the sulfamide 159, prepared as indicated in Scheme 11. The 5’-furanose ring exists predominantly in an N- type conformation, which should be favourable for forming heterod~plexes.~~~

The group at Isis Pharmaceuticals have given an overview of their work on the MMI [methylene(methylimino)] linkage,249 and also described an improved route to this system (160) involving reductive amination between a C-3’- aldehyde and the N-methylhydr~xylamine.~~~ Formacetal-linked systems have now been made in cases where both bases are purines; the synthesis involves the reaction of the 3’-O-methylthiomethyl ether with the 5’-OH group in the presence of NIS and 2.5 equivalents of TfOH,251 and a similar procedure has been used to make formacetal-linked analogues in the ribo-series; the unit 161 was made for incorporation into oligonucleotides using solid-phase H-phosphonate methods.252 The novel isosteric disulfide 164 has been prepared from the building blocks 162 and 163, and the shorter 3-atom link 165 was made in a similar way.253

Altmann and colleagues have made the cis-alkene 166 by a Wittig reaction, and have also prepared the triazoles 167 and 168, in each case assembling the heterocycle by a cycloaddition-elimination reaction between an azide and a stabilized p h ~ s p h o r a n e . ~ ~ ~ The related imidazoles 169 and 170 were also prepared; the imidazole ring was made by reaction of an appropriate aldehyde

20: Nucleosides 293

OTbdms

Scheme 11

ow O m p s

180

CH2-S-S \ ' P NO2

1 62 I S

OTbdrns OH 163 164

with glyoxal and ammonia, and the N-nucleosidyl unit was introduced by alkylation of the imidaz~ le .*~~ All of these analogues were incorporated into oligomers by phosphoramidite methods. Matteucci's laboratory has prepared the hemiacetal 171 by oxidative cleavage of a 2'Gallyl group, and hence made the dinucleotide analogue 172, and its epimer at the acetal carbon. These were incorporated into oligonucleotides by H-phosphonate tech- n 0 1 o g y . ~ ~ ~

Workers at Roche have used solid-phase methods to incorporate building blocks of type 91 into glucopyranosyl nucleic amides (GNA, 173), capped by a lysine unit. A homopyrimidine 13-mer complementary to a homopurine sequence in the HIV gag gene was prepared, and also a decamer containing all four DNA bases. Complementarity studies with RNA and DNA were reported.2s7


s

sw OH

105

Dm‘a-Py

DmtrO .w OH

166

OH 1 69

DmrO-v

OH 170

OH 167

DmtrO-w

OH 168

DmtrO-

OdCHPoPh \

O-R HO O w 0

171

RY 0

p

0bY OH

172

14 Ethers, Esters and Acetals of Nucleosides

The problem of effecting alkylation at 0-2’ of guanosine without alkylating the purine has been solved in a new way which involves silylation of 3’,5’-O- Tipds-guanosine selectively at 0-6, followed by alkylation at 0-2’ using an alkyl halide and a strong, sterically-hindered organic base.258-259 Alterna- tively, 0-6 can be protected as its o-nitrophenyl ether.259 A different solution to the same problem emerged in work designed to make guanosines with pendant alkylthiol chains at 0-2’; it was found that alkylation of 2,6- diamino-9-( p-~-ribofuranosyl)purine with NaH and the appropriate alkyl bromide gave mostly (-50% yield) the 2’-O-alkyl derivatives 174 (n=2, 3), which could be deaminated with adenosine deaminase and then converted to the targets 175.260 2’-O-Allyl-fbD-arabinofuranosyl-uracil, -cytosine and -adenine have been made as potential inhibitors of ribonucleotide reductase, in the cases of the pyrimidines via the 2,2’-anhydron~cleoside,~~’ which was also involved in a route to 3’,S’-di-O-trityl-~-~-arabinofuranosyluracil from uridine.262 2,2‘-Anhydro-a-uridine was used to prepare 5’-O-dimethoxytrityl- a-uridine . 263

Tetra-n-butylammonium peroxydisulfate has been used for the removal of trityl groups from nucleoside derivatives without affecting the glycosidic bond.264

Silylation of a mixture of 5’-O-dimethoxytrityl-nucleoside-2’- and -3’-H- phosphonates gives selectively the 0-2’-silylated 3’-H-phosphonates 176.265 Lithium bromide and 18-crown-6 have been used to remove selectively the

20: Nucleosides 295

NHp

n

173 174 175 176

primary Tbdms group from 3’,5’-di-O-Tbdms-thymidine and -2’-deoxyuridine.266

In a dual-targetting approach to antitumour agents, the ester of retinoic acid at 0-2’ of ara-A has been prepared.267 In an extension of earlier work (Vol. 30, p. 299), the aminoacylated dinucleotide 177 has been made using an Fmoc aminoacid fluoride; the product 177 could be deprotected by removal of both the P-cyanoethyl and the Fmoc groups with oximate anion, which did not affect the ester, followed by detritylation.268 Anthranilic acid esters of adenosine at 0-2’- and 0-3’ have been used as mimics of the t-RNA terminus with an attached a m i n ~ a c i d , ~ ~ ~ and 3’(2’)-0-(p-azidobenzoyl)-adenosine-5’-triphosphate has been prepared as a photoaffinity label for the catalytic subunit of protein kinase C.270 Fluorescent thymidine 3’-urethanes have been made from the corresponding 3’-carbonylimidazolide and aminoalkyl derivatives of fluor- escein or ~ y r e n e . ~ ~ ’

Selective 5’-0-acetylation of nucleosides and 2’-deoxynucleosides has been accomplished in high yield by a modified version of Mitsunobu’s original procedure. In the new method, DEAD is added to a mixture of the (deoxy)- nucleoside and PPh3 in acetic acid and dioxane. This adaptation was not however successful for g ~ a n o s i n e . ~ ~ ~ N-Protected L-aminoacids have been coupled to 0-5’ of isopropylidene adenosine. The products after deprotection were tested as potential inhibitors against UDP-glucuronosyl t r a n ~ f e r a s e . ~ ~ ~ When the ester 178 of thymidine and 2’-carboxypsoralen was photolysed, followed by methanolysis of the products, the ‘furan-side’ furocoumarin- thymidine photoproduct 179 was obtained. This reaction has the potential to place such a photo-adduct selectively in mutational ‘hot spots’ in proto- oncogenes and tumour-suppressor genes.274 The citrate ester of d4T has been synthesized as a mimic for the triphosphate, and the amide from the corresponding 5’-amino-5’-deoxynucleoside was also described.275

There have been reports on new ester protecting groups for the 5’-hydroxyl group during oligonucleotide synthesis. The 2-(levulinyloxymethyl)-5-nitrobenzoyl group (180) has been used in solid-phase synthesis of ribonucleotides,


Dmtmv 0

0 in

OAc 178

OH 179

0

180 181 182

in conjunction with 2'-O-Thp ethers; it is removable by treatment with 0.5M hydrazine hydrate in acetic acid:pyridine, followed by imidazole in MeCN.276 The (2-cyano-1 -phenyl)ethoxycarbonyl (Cpeoc) group (181) has also been advocated as a base-labile unit for use in the phosphoramidite approach to oligoribonucleotides, using the 4-methoxytetrahydropyran-4-yl group at O-2'.277 The rates of photo-deprotection of 5'-O-(o-nitrobenzyloxycarbo- ny1)thymidine and a number of related derivatives, such as .o- nitrophenylethoxycarbonyl compounds, were found to vary quite widely. One of the most rapidly removed is the system as in 182.278

The photolabile (o-nitrobenzy1oxy)methyl (Npm) group was used in work on the synthesis of oligoribonucleosides to protect 0-2', and the protecting group was introduced with higher regioselectivity than previously by using modified conditions.8 Treatment of 3',5'-U-Tipds-uridine with DMSO and Ac2O gave the 2'-0-methylthiomethyl ether, which with NIS, MeOH and catalytic TfOH gave the methoxymethyl ether. Subsequently, 2'-O-Mom- uridine was incorporated into oligoribonucleotides.279 Some 2'-O-P-~-ribofuranosyl-nucleosides (disaccharide nucleosides), made by glycosylation of 3',5'- O-Tipds-nucleosides, have been reported.280

15 Miscellaneous Nucleoside Analogues

The chain-extended thymidine derivatives 183 and 184 have been prepared and incorporated into oligonucleotides via phosphamidites. A related compound with a two-carbon extension was also described.281 The bicyclic compound 185 has been made by intramolecular cycloaddition between a nitrone at C-5' and a 3'4-allyl ether, followed by N-0 bond cleavage. Related structures in which the annulated ring is carbocyclic were prepared from similar products of

20: Nucleosides 297

intramolecular cycloadditions (see Vol. 30, pp. 237 and 240), after attachment of the nucleobase.282

Some isonucleosides with a 7-deazapurine base, such as 186, have been prepared, along with some related 1,2,3-triazole~,~~~ and similar structures of (S, 5‘)-stereochemistry, such as 187, have also been described.284

In the area of 1,3-dioxolanes and related analogues, 188 has been prepared by base-‘sugar’ coupling, and related compounds including 1,3-0xathiolanes were also made by chemistry on compounds with a monocyclic a g l y c ~ n e . ~ ~ ~ A number of 2,3-dioxolanyl, 1,3-0xathiolanyl (both regiochemistries) and 1,3- dithiolanyl nucleoside analogues with an additional 2’-hydroxymethyl group (e.g. 189) have been reported,286 and other workers have also made two compounds of this type, and converted them into the cyclic phosphates 190.287 The same type of cyclic phosphates, which can be regarded as acyclonucleoside phosphates with a conformationally-restraining thiomethylene tether, were also independently prepared, including the guanosine analogue, in a third laboratory.288 The oxaselenolane nucleosides 191 (B = Cyt, 5-fluoro-Cyt) have been synthesized and shown to have good anti-HIV activities,289 and 3’-aza-4‘- thia-2’,3’-dideoxynucleosides such as 192 have been made by SnC14-catalysed coupling of bases to N-protected 1,3-thia~olidines.~~~ 2’-Thia-2’,3’-dideoxy- cytidine (193) has been prepared, as have the enantiomer and the a-anomers of both enantiomers, starting from 2,3-O-isopropylidene-~- and +glycerol; 193 had the best anti-HBV activity of the four isomers.291

Isoxazolidines 194 (R=H, C02H) have been made by cycloadditions of nitrones to 9-vinyladenine, in a manner similar to that described earlier (Tetrahedron Lett., 1996, 37, 1277) for N-vinylthymine. The cycloadduct 194, (R=C02H) could be resolved to give the (-)-enantiomer using pig liver e ~ t e r a s e . ~ ~ ~ In an asymmetric route to such systems, the isoxazolidinone 195 was prepared by diastereoselective addition of N-methylhydroxylamine to an a, P-unsaturated ester, and could be transformed into the nucleoside analogues 196 (B = Thy, Ura, Ade, Cyt).293


Some further chemistry of 1,5-anhydrohexitol nucleoside analogues has been reported, along with studies on their incorporation into oligonucleo- t i d e ~ : ~ ~ ahd a route has been developed for the preparation of the a-anomers lW.295 The 1,3-dioxane analogues 198, and the trans-isomers, have been prepared,296 and the hemiacetal 199, obtained from uridine by periodate cleavage followed by borohydride reduction in the presence of boric and acetic acids, was coupled to another nucleobase to give the product 200 (both epimer s). 297

There has been a fuller account, extended to other bases, of the asymmetric synthesis of cyclopropyl systems 201 (see Vol. 29, pp. 298-299),298 and the oxetanocin-like analogue 202 has been prepared.299

Interaction of adenosine derivatives with VOC13 has been used to make two types of vanadyl nucleotide, one of which was a bis-vanadyl equivalent of ADP, and one of which was a 2’,3‘-cyclic vanadyl chloride.3m

Some other references to anhydro- and -imino-alditols with attached nucleobases are given in Chapter 18.

16

191 192

MeN-0 MeN-0 195 196

CH20H I Ura

OH

199

Reactions

F 200

193

CH20H

Q OH

VH20H 201

197

194

HOCH2 Ura/Thy

(2 1 98

Ade

CH20H +H20H

202

An interesting study by Crich and Mo has shown that, when B=AdeBz, the radical 203 (X=H), formed by addition of PhS to the C-4’-ene, fragments to give 204 via the 3’,4‘-radical cation, but when X = OMe, the equivalent reaction does not occur, implying that the rate of fragmentation is much slower. This result has implications for the mode of action of antitumour agents of the bleomycin type that cleave DNA via a C-4’-radical, but which cleave RNA much more slowly.3o1 The same workers have also studied the dependence of

20: Nucleosides 299

the conversion of 203 (X = H) to 204 on the nature of the base, with the faster rates being found for bases best able to support a resonance structure of type 205.302

A report from R.K. Robins’s laboratory describes further model experiments designed to probe the mechanism of action of ribonucleoside diphosphate reductase, building on their earlier studies (Vol. 30, pp. 275 and 304). The radical 206 (Scheme 12) was generated by Bu3SnD reduction of the nitrate ester, and gave the C-3‘-radical 207 by 1,5-translocation. The enone 208 was formed in good overall yield, and contained about 30% deuterium, implying the sequence of events shown, with loss of tosylate as an anion. The earlier similar experiment with the 2’-chlorocompound (Vol. 30, p. 304) had given 208 with no deuterium, implying loss of chlorine as a radical.303 The mechanism by which 2’-azido-2’-deoxy-~-~-arabinofuranosyl adenosine triphosphate inhibits bacterial ribonucleside triphosphate reductase has been examind by the use of radiolabelled inhibitors and the observation of paramagnetic intermediate^.^^

@*- OH OTs

206

7H20H

207

qH20H

-Be 0 D-SnBu3 - u

qH20H

208 Scheme 12

There has been a further report on the formation of l’-C-acyl-2’-deoxy- uridines from 3’-deoxypsicofuranosyluracil, and the photolysis of these compounds to give a,P-2’-deoxyuridine via a radical at C-1’ (Vol. 30, p. 304).305

Hydrolysis of nucleoside monophosphates catalysed by Ce( IV) ions occurs under physiological conditions, and much more rapidly than for diesters. Thus d(pApA) undergoes selective hydrolysis of the terminal m o n o p h ~ s p h a t e . ~ ~ ~ In aqueous acid, various phosphodiesters at the 3‘-position of uridine isomerize to the 2’-esters and give rise to the 2’,3’-cyclic phosphate. In alkali, only the latter reaction occurs, and the reaction rate is very sensitive to the nature of the leaving group, whilst the acidic reaction is rather insensitive to the nature of the alkyl The hydrolysis and transesterification of the 2’- and 3’- dimethylphosphorothioates of 5’-O-methyluridine has been studied from pH 9 to strong acid. Two reactions were found to compete, namely the mutual interconversion of the 2’- and 3’-isomers, and phosphoester hydrolysis to the 2’,3’-cyclic thiophosphate and the 2’- and 3’-monomethyl thiophosphates. It


was suggested that all reactions proceed via a pentacoordinated thiophos- ph~rane.~O* The kinetics and mechanism of the hydrolysis of 209 (X = 0 or S) have been studied. Both species underwent specific 2’-dephosphorylation much faster than did thymidine 3’-phosphate and -phosphorothiate, with acid catalysis due to the presence of the neighbouring phosphodiester. The effect of divalent metal ions in inhibiting the process was also i n ~ e s t i g a t e d . ~ ~ The hydrolysis of the phenyl ester 210 has been studied over a wide pH range. At pH 2-7, the reaction is pH-independent, and from methanolysis experiments the main product appears to arise from cleavage of the C-5’-oxygen bond, whilst at higher pH values the P-O bonds rupture. At pH <4, glycosidic bond cleavage competes with P-0 cleavage.310 A study has been reported on the correlation between the nature of the nitrogen-based ligand and the catalytic effect of Co(II1) complexes on the hydrolysis of 3’,5’-cyclic AMP, the cyclen complex giving a 101O-fold acceleration as compared with the uncatalysed reaction.31 The hydrolysis of dinucleotides catalysed by Eu3+ and Co3+ has also been investigated, with rate enhancements >lo7 being observed.

The transpurination of acetylated guanosine and its N7-regioisomer with 1 - acetoxy-2-(acetoxymethyl)ethane has been studied, and a mechanism involving ions carrying the acetylated sugar and AcOCH2CH20CH2- groups on N7 and N9 was proposed.

Quantum mechanical methods have been used to study the transition state for uridine phosphorolysis. It was concluded that enzymic uridine phosphorolysis takes place by an acid-catalysed SN2 process.314 Oxidative cleavage of the glycosidic bond of AMP and dAMP can occur in a heme-catalysed reaction with cumene hydroperoxide.

0 0-P; I 0-

OH OH

CH2 -0 A N

k O Y CH2NRR’ CH2N RR’

209 210 21 1

Full details and further examples have been given of the reduction of 2’,3‘- 0-isopropylidene purine ribonucleosides with DIBAL to give 9-~-ribityl- purines (see Vol. 27, p. 270),316 and an interesting application of this reaction for the synthesis of neplanocin A from adenosine is mentioned in Chapter 19. A novel cyclization product derived from 5-aminocytidine and N-methylisatin (Vol. 30, p. 272) has been subjected to periodate cleavage and reductive amination to give compounds of type 211, which had antitumour Products from interaction of seco-nucleosides and daunomycin are mentioned in Chapter 19.

20: Nucleosides 301

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20: Nucleosides 309

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21 NMR Spectroscopy and Conformational Features

1 General Aspects

Reviews on the development of force fields for saccharides' and on optimized force field parameters for the application of AMBER to carbohydrates2 have been published.

A new, empirical molecular mechanics force field for alcohols and carbohydrates (PEF95SAC) which addresses, in particular, flexibility, the presence of hydrogen-bonding hydroxyl groups and the combination of energetic, structural and kinetic effects at the anomeric centre has been r e p ~ r t e d . ~ Papers on new force field parameters for application of the SPASIBA potential energy function to saccharides4 and on a force field model suitable for studying N- and O-sulfated sugars5 have appeared, and new software for a database of 13C- NMR spectra of sugars has been describedO6

Monte Carlo/stochastic dynamics simulations have been used in new conformational analyses of saccharide^.^ Theoretical and experimental evidence suggests that, contrary to widely held beliefs, internal motion and overall motion in carbohydrates, even those of moderate size, occur on similar time scales.* The free energy differences between three conformations of D-glucose and of D-galactose have been calculated from molecular mechanics simulations using two versions of the GROMOS force field. The study showed how comparison of the theoretical findings with NMR data resulted in improvements in the force field.9

A MM3 investigation of the tautomeric equilibrium of D-fructose included an evaluation of the hydrogen-bond strength for the various tautomeric forms. l o Seven tautomers of ~-~yxo-hexos-5-ulose in D20 have been observed by 'H- and 13C-NMR spectroscopy, with furanose 1 as the most abundant form. ' ' The 2-aminoethylimines and 3-aminopropylimines of several aldoses,' as well as the 1 -glycosyl-2-acetylhydrazines of all D-hexoses, all D-pentoses, 2- acetamido-2-deoxy-~-glucose, 2-acetamids-2-deoxy-~-galactose and L-

fucoseI3 have been subjected to similar analyses. In the hydrazine derivatives cisltrans-isomerism caused by the substantial double bond character of the NHC(0) bond was also examined, and the 'H-NMR spectroscopic data of the most abundant forms were reported.

The absolute configuration of monosaccharides can be determined from the

Carbohydrate Chemistry, Volume 3 1 The Royal Society of Chemistry, 2000

312

21: N M R Spectroscopy and Conformational Features 313

OH 1 2 R = Me, Ph, 2-pyridyl benzothiazol-2-yl 3

high-field H-NMR spectra of their per-O-(S)-2-methylbutyrates; the method has been applied to the constituent sugars of three complex g1~cans.l~ (9- a-Methoxyphenylacetic acid has been used as an NMR shift reagent to determine the absolute configuration of a number of D-galactose-derived sulfoxides 2. The conformations of some nitro-sugar derivatives have been determined by semi-empirical MO calculations. l6

2 Furanose Systems

A novel method for determining the absolute configuration of secondary alcohols, the so-called ‘fucofuranoside method’, is based on the characteristic chemical shifts in their ‘H- and 13C-NMR spectra induced by p-D- and P-L- fucofuranosylation, using L-fucose tetraacetate as glycosylating agent in the presence of T m ~ 0 T f . l ~ A best-fit conformational analysis between calculated and experimental coupling constants has been undertaken with both anomers of methyl 5-deoxy-~-xylofuranoside (3).’* Ab initio molecular calculations performed on glycosides 4 and 5 with specific 13C-labelling at each carbon atom, combined with NMR data on the free sugars 6 and 7, hold promise as a tool for determining furanose ring conformations applicable, for example, to DNA and RNA structures. l9 2-Deoxy-~-D-g~ycero-tetrofuranose (8) served as model in an investigation by ‘H-NMR spectroscopy and ab initio molecular orbital calculations on the effect exerted by protonation of the ring oxygen atoms on the conformations of furanosyl rings.20

I

OH I? OH 8 4 R’ = Me, R2 =OH

5 R’ = Me, R2 = H

7 R ’ = R ~ = H 6 R’ = H, R2 = OH

The medium-dependent anomeric effects in nucleosides21 and in C-nucleo- sides22 have been investigated in thermodynamic studies employing ‘H-NMR spectroscopy and PSEUDOROT conformational analyses, and similar techniques furnished the first experimental evidence that ~-~-2’,3’-dideoxynucleosides


have greater medium-dependent flexibilities than their ~x-counterparts.~~ These and related findings have been summarized in a report on the intramolecular stereoelectronic forces that drive the sugar conformations in nucleosides and C-nucle~sides.~~

The 1-, 2- and 3-bond ‘H-13C and l3C-I3C spin-coupling constants involving C-2’ of thymidine, 2’-deoxyadenosine and 2’-deoxycytidine, singly enriched in 13C at C-T, have been measured; these data may be useful for analysing the conformations of oligonucleotides in solution.25

OH

I 1 X = 0 or S, Y = H 12 X = O o r S , Y=Br

X = H, Me, CI, Br, I, CN, NO;, etc.

B =

OH 14

: Ade, Gua. Cyt, 15

Thy 16

r=fCONH2

OH OH R=CH20H, X = S , Y = R = CH20H or H X = S Se, Oor NH Y=NorCH

17 OH OH

N

Conformational studies by use of computational techniques and/or NMR spectroscopy have been reported for the following nucleosides: 5-ethyl- 2’-deoxyuridine 9 and 5-ethyl-2’-deoxycytidine 5-(2-furanyl)- and 5-(2- thienyl)-2’-deoxyuridine 11 and their brominated analogues 12;27 7-deaza- 2’-deoxy-adenosine derivatives 13 and similarly substituted g u a n ~ s i n e s ; ~ * ~ ~ ~ C-7 substituted 8-aza-7-deazapurines and 8-a~apurines;~~ 3’-deoxy-P-D-ribonucleosides 14;30 thiazofurin (15), an important inhibitor of inosine 5’-mOnO- phosphate dehydrogenase and thiazofurin analogues, such as compounds 16;31 S6-(4-nitrobenzyl)mercaptopurine riboside (17), a potent nucleoside transport inhibitor;32 and a series of uridine 2’,3’-dideoxy-2’- or 3’-flUOrO- nucleosides 18.33

21: NMR Spectroscopy and Conformational Features 315

3 Pyranose and Related Systems

Electrostatic stabilization of glycosyl oxocarbonium ions by axial 0-4, as indicated in structure 19, has been introduced as an important new stereoelectronic effect under the term 'through-space electrostatic stabilization'. The effect is greatest in the gulucto-series, where acetolysis rates decrease from ether 20 to ester 21 to amide 22.34

Hvra X Y

yH20Me

'QMe

OMe 18 X=H, Y=ForX=F, Y = H 19 20 R=OMe

21 R=OAC 22 R=NHAC

The chemical shifts and spin-spin coupling constants of methyl f3-D-xylopyranoside in solution and in the solid state have been ~a lcu la t ed .~~ The solid state 13C-NMR spectra of ureido sugar derivatives 2336 and 2437 have been recorded, as well as the high resolution 'H- and 13C-NMR spectra of compounds 24 in solution. A 'H-NMR study of 2-amino-2-deoxy-a- and fbD-glUCOSe, -galactose and -mannose as their ammonium ions in D20 was aimed at determining their acid dissociation constants.38

Computational techniques andlor NMR spectroscopy have been used in the conformational analyses of a set of alkyl a-D-glucopyranosides (with emphasis on the rotamer population around the C-5-C-6 bond,39 penta-0-acetyl-a-D- idopyranose,m methyl 6-0-[(R)- and (8- 1 -carboxyethyl]-a-D-galactopyrano- sides 25:* sialic acid, sialyl-l,4-lactone and sialyl- 1,7-la~tone:~ 1,2:4,5-di-U- isopropylidene-myo-inosito1,43 and in a detailed structural analysis of myo- inosit ol hexaacetate

Ab initio calculations on the pyranosyl oxocarbenium ion 26 support a transition state model for the solvolysis of CMP-NeuAc involving a nearly fully formed, nearly planar sialyl cation considerably stabilized by the carboxylate group in the same plane.45

YH20Ac

AcO qe HNCNR

II 0

C02Et /

23 R=CH CHMQ

24 R = CHCNH-CC02Et I II I x o Y X,Y = H, Me; H, Pr'; H, Bn etc.

OH 25

OH 26


The reaction of a- and p-D-glucosyl azides with PPh3 and COz furnishing 1,2-cyclic carbamates has been investigated by PM3 semi-empirical quantum chemistry computation^.^^

4 Disaccharide

Several molecular mechanics programs were compared for their efficiency in the molecular modelling of methyl a-lactoside; MM3 and CVFF gave satisfactory predictions of the solution NMR spectra, and a good fit with the expected X-ray crystal distances and angles was furnished by CVFF, whereas AM1, ESFF and CFF91 performed poorly.47 Application of the PEF95SAC force field (see ref. 3 above) to an analysis of p-lactose demonstrated the excellent extrapolative power of this modelling method and led to the proposal of a new linkage geometry region for P-lactose in both the solid state and in aqueous solution.4g

The complete assignment of the ‘H- and 13C-NMR spectra of permethylated sucrose has been reported.49 The solid state 13C-NMR spectra for hydrated and anhydrous aptrehalose, including data for a new anhydrous crystalline form, have been p ~ b l i s h e d , ~ ~ and NOES between chemically equivalent protons in a,a-trehalose-containing molecules have been measured by use of selective DANTE-Z-based 13C-NMR editing experiment^.^^

The following disaccharides have been examined by NMR spectroscopy and/or computational methods: N,N’-diacetyl-chit~biose,~~ compounds 27,53 28 and 29 (as hyaluronan models),54 deoxy- and deoxyfluoro analogues of compound 30 (a constituent of the 0-polysaccharide of ShigeZZa dy~enter iae) ,~~ disaccharide 31 (which was used as model compound in the conformational analysis of a bacterial peptid~glycan),~~ the disaccharide moiety of the new doxorubicin analogue 32,57 and the constituent disaccharides of trisaccharides 34 and 35, shown in Section 5 below.

27 P-D-GIc~NAc-(~+~)-P-D-G~I~-OM~ 30 a-L-Rhap-(l+2)-a-~-Manp-OMe 28 P-D-G IcpA-( 1 -+ ~)-P-D-G Icp NAc 29 P-~-GlcpNAc-(l+ 4)-p-~-GlcpA

31 P-~-GlcpNAc-(l-+ 4)-a-MurNAc

~ ~ a d r i a r n y c i n o n - 7 - y l

HO

NH* oH 32

The low-energy conformations of isomaltose and several of its monodeoxy analogues have been determined in a study of their interactions with the active site of gluc~amylase.~~


5 Oligosaccharides

Current modelling techniques for the conformational analysis of oligosaccharides have been reviewed. 59960961 Review articles have also appeared on the conformational analysis of asparagine-linked oligosaccharides by molecular dynamics simulations62 and on the NMR assignments of laminarapentaose peracetate and dodecyl laminarapentaoside pera~etate;~ and a paper dealing with the development of a quantum mechanically-derived all atom force field for pyranose oligosaccharides has been published.@

P-~-Gl~p-(l-+2)-p-~-Glcp-( 1 +3)-P-~-Glcp-OMe Glyp-(l-+3)[GIyp-(l+4)]-P-~-Rhq~-OMe 33 Gly = a-D-Man, P-D-GIc, a-L-Rha, P-L-Fuc

34 a-L-Rhap-(l +2)-a-~-Rhap-(l-+3)-a-~-Rhap-OMe

35

The following compounds have been examined by NMR andlor computational methods: 1 -kestose and n y ~ t o s e ; ~ ~ trisaccharides 33,65 34,66 35,67 and 36 (a heparin fragment analogue);68 tetrasaccharide 3769 the sialyl Lewis x tetrasa~charide,~~ a (2+ 8)-a-linked tetramer of sialic acid,71 the asialo-GM 1 gangl i~side,~~ the lipotetrasaccharide glycoside 38,73 and a series of inulin-type oligosaccharides. 74

A solid complex of c60 with y-cyclodextrin has been investigated by NMR- spectroscopy. 75

a-D-GalpNAc-(l+3)-p-~-Galp-(l + 4)[a-~-Fucp-(l+3)]-P-~-Glcp-OMe 37

38


6 NMR of Nuclei Other than 'H and 13C

19F-NMR spectroscopy has been used in the analysis of 2-deoxy-2-fluoronucleosides . 76

Phosphorylation sites in small to medium-sized oligosaccharides have been identified easily and reliably by a combination of 31P decoupling and TOCSY experiment^.^^ 31P-NMR spectroscopy has also been used in a study on cyclic ADP-ribose and 2'-phosphocyclic A D P - r i b ~ s e . ~ ~

Tris-( 1 -butyl)stannyl D-glUCOnate79 and a series of sugar-tin derivatives, such as compounds 39, with tin attached to vinylic, allylic or carbinol centres,g0 have been examined by *19Sn-NMR spectroscopy, and a multinuclear approach (lH, 13C, I7O, 95Mo and lg3W) has been employed to investigate the complexation of D-gluconic acid with tungsten(V1) and molybdenum(VI).*'

R

BnO QM*

References

I 2

3

4

5

6 7

8

9

10

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11

12

13 14

15

16

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19

20

21 22

23 24 25

26

27

28 29

30

31 32 33

34

35

36

37

38

39

D.E. Kiely, R.E. Harry-O'Kuru, P.E. Morris, Jr., D.W.' Morton and J.M. Riordan, J. Carbohydr. Chem., 1997,16, 1159. K.N. Zelenin, V.V. Alekseyev, I.V. Ukraintsev and I.V. Tselinski, Mendeleev Commun., 1997,111 (Chem. Abstr., 1997,127,95 498). B. Bendiak, Carbohydr. Res., 1997,304,85. W.S. York, S. Hantus, P. Albersheim and A.G. Darvill, Carbohydr. Res., 1997, 300, 199. P.H. Buist, B. Behrouzian, S. Cassel, C. Lorin, P. Rollin, A. Imberty and S. Perez, Tetrahedron: Asymm., 1997,8, 1959. T. Sakakibara, Yokohama-shiritsu Daigaku Ronso, Shizen Kagaku Keiretsu, 1996, 47,73 (Chem. Abstr., 1997, 127, 121 917). M. Kobayashi, Tetrahedron, 1997,53, 5973. J. Moravcovi, J. Capkova, J. Stanek and I. Raich, J. Carbohydr. Chem., 1997, 16, 1061. T.J. Church, I. Carmichael and A.S. Serianni, J. Am. Chem. Soc., 1997, 119, 8946. J. Kennedy, J. Wu, K. Drew, I. Carmichael and A.S. Serianni, J. Am. Chem. SOC., 1997, 119, 8933. I. Luyten, C. Thibaudeau and J. Chattopadhyaya, J. Org. Chem., 1997,62,8800. I. Luyten, C. Thibaudeau, A. Sandstrom and J. Chattopadhyaya, Tetrahedron, 1997,53,6433. C. Thibaudeau, A. Foldesi and J. Chattopadhyaya, Tetrahedron, 1997,53, 14043. C. Thibaudeau and J. Chattopadhyaya, Nucleosides Nucleotides, 1997,16, 523. T. Bandyopadhyay, J. Wu, W.A. Stripe, I. Carmichael and A.S. Serianni, J. Am. Chem. Soc., 1997,119, 1737. A.L. Stuart, S.V.P. Kumar, S.V. Gupta, W.M. Zoghaib, S. Napper, K.C. Brown, S. Mannala and L.T.J. Delbaere, Nucleosides Nucleotides, 1997, 16,2219. I. Creuven, F. Lebon, R. Busson, P. Herdewijn and F. Durant, Nucleosides Nucleotides, 1997, 16, 339. H. Rosemeyer and F. Seela, J. Chem. SOC., Perkin Trans. 2, 1997,2341. H. Rosemeyer, M. Zulauf, N. Ramzaeva, G. Becher, E. Feiling, K. Muhlegger, I. Miinster, A. Lohmann and F. Seela, Nucleosides Nucleotides, 1997,16,821. A. Kumar, S.B. Katti, H. Roserneyer and F. Seela, Nucleosides Nucleotides, 1997, 16, 507. G.M. Makara and G.M. Keseril, J. Med. Chem., 1997,40,4154. J.K. Buolamwini and J.J. Barchi, Jr., Nucleosides Nucleotides, 1997, 16,2101. J.J. Barchi, Jr., L A . Jeong, M.A. Siddiqui and V.E. Marquez, J. Biochem. Biophys. Methods, 1997,34, 11 (Chem. Abstr., 1997, 126,330 787). M. Miljkovic, D. Yeagly, P. Deslongchamps and Y.L. Dory, J. Org. Chem., 1997,62,7597. M. Hricovini, O.L. Malkina, F. Bizik, L. Nagy and V.G. Malkin, J. Phys. Chem., 1997,101,9756 (Chem. Abstr., 1997,127,359 OOO). R. Anulewicz, 1. Waver, P. Piekarska-Bartoszewicz and A. Temeriusz, J. Carbohydr. Chem., 1997,16,751. A. Temeriusz, P. Piekarska-Bartoszewicz and I. Wawer, Carbohydr. Res., 1997, 304,335. A. Blasko, C.A. Bunton, S. Bunel, C. Ibara and E. Moraga, Carbohydr. Res., 1997,298, 163. J.I. Padron and J.T. Vazquez, Chirality, 1997, 9, 626 (Chem. Abstr., 1997, 127, 307 561).

320

40 41 42

43

44

45 46

47

48 49

50

51

52

53

54

55

56

57

58 59

60

61 62

63

64 65 66

67

68


D.A. Horita, P.J. Hajduk and L.E. Lerner, Glycoconjugate J., 1997, 14,691. R. Stenutz and G. Widmalm, Glycoconjugate J., 1997,14,973. A.L. Parrill, N. Mamuya, D.P. Dolata and J. Gervay, Glycoconjugate J., 1997, 14, 523. S.-K. Chung and Y.-T. Chang, Korean J. Med. Chem., 1997,7, 15 (Chem. Abstr., 1997,127, 162 044). Y. Fukazawa, Kenkyu Hokoku-Kanagawaken Sangyo Gdjutsu Sogo Kenkyusho, 1996,2, 67 (Chem. Abstr., 1997, 127, 17 876). B.A. Horenstein, J. Am, Chem. Soc., 1997, 119, 1 101. P. Friant-Michel, A. Marsura, J. Kovacs, I. Pinter and J.L. Rivail, Theochem., 1997,395-396,61 (Chem. Abstr., 1997,127, 162 049). M. Martin-Pastor, J. F. Espinosa, J.L. Asensio and J. Jimenez-Barbero, Curbo- hydr. Res., 1997,298, 15. S.B. Engelsen and K. Rasmussen, J. Carbohydr. Chem., 1997, 16,773. J.W. Timmermans, P.M.P. Bogaert, D. de Wit and J.F.G. Vliegenthart, J. Carbohydr. Chem., 1997,16, 1145. A.M. Gil, P.S. Belton and V. Felix, Spectrochim. Acta, 1996, 52A, 1649 (Chem. Abstr., 1997, 126,47 443). A. Poveda, C. Vicent, S. Penadis and J. JimCnez-Barbero, Carbohydr. Res., 1997, 301, 5. J.F. Espinosa, J.L. Asensio, M. Bruix and J. Jimenez-Barbero, An. Quim., Int. Ed., 1996,92, 320 (Chem. Abstr., 1997,126, 75 153). G. Shim, S. Lee and Y. Kim, Bull. Korean Bull. SOC., 1997, 18,415 (Chem. Abstr., 1997,127, 50 891). M. Moulabbi, H. Broch, L. Robert and D. Vasilescu, Theochem., 1997, 395-396, 477 (Chem. Abstr., 1997,127,149 336). B. Coxon, N. Sari, L.A. Mulard, P. Kovac, V. Pozsgay and C.P.J. Glaudemans, J. Carbohydr. Chem., 1997, 16,927. H. Matter, L. Szilagyi, P. Forgo, 2. Marinic and B. Kalic, J. Am. Chem. SOC., 1997,119,2212. E. Monteagudo, A. Modami, F. Animati, P. Lombardi and F. Arcamone, Carbohydr. Res., 1997,300, 1 1. P.M. Continho, M.K. Dowd and P.J. Reilly, Carbohydr. Res., 1997,297, 309. R.J. Woods, Rev. Comput. Chem., 1996, 9, 129 (Chem. Abstr., 1997, 127, 176 602). C.-W. von der Lieth, T. Kozrir and W.E. Hull, Theochem., 1997, 395-396, 225 (Chem. Abstr., 1997, 127, 149 287). T. Kozar and C.-W. von der Lieth, Glycoconjugate J., 1997,14,925. P.K. Qasba, P.V. Balaji and V.S.R. Rao, Theochem., 1997, 395-3%, 225 (Chem. Abstr., 1997,127, 149 288). J. Sano, N. Ikushima, K. Takada and T. Shoji, DIC Tech. Rev., 1995, 1, 19 (Chem. Abstr., 1997, 126,75 124). H. Senderowitz and W.C. Still, J. Org. Chem., 1997,62,1427. C. Landersjo, R. Stenutz and G Widmlam, J. Am. Chem. SOC., 1997,119,8695. E.A. Khatuntseva, A.S. Shashkov and N.E. Nifant’ev, Magn. Res. Chem., 1997, 35,414 (Chem. Abstr., 1997, 127, 81 688). B.J. Hardy, S. Bystricky, P. Kovac and G. Widmalm, Biopolymers, 1997, 41, 83 (Chem. Abstr., 1997, 126, 144 455). S. Cros, M. Petitou, P. Sizun, S. Perez and A Imberty, Bioorg., Med. Chem., 1997,5, 1301 (Chem. Abstr., 1997,127,220 91 1).

21: NMR Spectroscopy and Conformational Features 32 1

69

70

71

72

73

74

75

76

77

78

79

80

81

A. Poveda, J.L. Asensio, M. Martin-Pastor and J. Jimenez-Barbero, Carbohydr. Res., 1997,300, 3. L. Poppe, G.S. Brown, J.S. Philo, P.V. Nikrad and B.H. Shah, J. Am. Chem. Soc., 1997, 119, 1727. R.M. Venable, F. Bizik, T.J. Henderson and W. Egan, Theochem., 1997,395-396, 375 (Chem. Abstr., 1997,127, 149 334). H.J. Park, G.-J. Jhon, J. Seong and Y.K. Kang, Biopolymers, 1997,42, 19 (Chem. Abstr., 1997, 127, 109 124). I. Robina, E. Lopez-Barba, J. Jimenez-Barbero, M. Martin-Pastor and J. Fuentes, Tetrahedron: Asymm., 1997,8, 1207. C. Cui, M. Yang, 2. Yao, B. Cai, 2. Luo, Y. Xu and Y. Chen, Zhonguo Yaowu Huaxue Zazhi, 1995,5,32 (Chem. Abstr., 1997,127,66 037). W.-Y. Tseng, Y.-H. Chen, 1.1. Khairullin, S. Cheng and L.-P. Hwang, Solid State Nucl. Magn. Reson., 1997,8,219 (Chem. Abstr., 1997, 127, 346 577). B. Reif, V. Wittmann, H. Schwalbe, C. Griesinger, K. Worner, K. Jahn- Hofmann and J.W. Engels, Helv. Chim. Acta, 1997,80, 1952. J. Schraml, A. De Bruyn, R. Contreras and P . Herdewijn, J. Carbohydr. Chem., 1997, 16, 165. K.D. Schnackerz, C.Q. Vu, D. Gani, R. Alvarez-Gonzalez and M.K. Jacobson, Bioorg. Med. Chem. Lett., 1997,7,581. A. Lycka, J. Holecek and D. Micak, Collect. Czech. Chem.Commun., 1997, 62, 1169 (Chem. Abstr., 1997,127,262 950). S . Jarosz, E. Kozlowska, J. Sitkowsi and L. Stefaniak, J. Carbohydr. Chem., 1997, 16,911. M.L. Ramos, M.M. Caldeira and V.M.S. Gil, Carbohydr. Res., 1997,304,97.

22 Other Physical Methods

1 IR Spectroscopy

Solid-phase reactions can be monitored on-bead, at high throughput rates, using diffusion reflectance infrared Fourier transform spectroscopy (DRIFTS). Specifically, the reduction of the azido group in the resin-supported 2-azo sugar 1 was monitored in this way.'

Vibrational Raman optical spectroscopy has been employed to study the conformational flexibility of a series of P-cyclodextrins. Parameters explored in this study were the effect of solvent (DMSO vs. water) and 2,6-di- or 2,3,6- trimethylation of the cyclodextrin. The effect of different guests was evaluated leading to the conclusion that tighter-bound guests lead to greater reduction of conformationat mobility.2

OH H 2

IR spectroscopy of crystalline meso-erythritol and Dpthreitol at 20 K and 300 K, as both OH and 02H systems, showed that all the H-bonds in the crystalline meso-erythritol are strong, while there are additional weak H-bonds in the crystals of ~ , ~ - t h r e i t o l . ~ The complete vibrational (IR and Raman) spectra of pentaerythritol have been ~bta ined .~

The influence of grinding and thermal treatment on anhydrous mono- and di-hydrated lactitol has been investigated using IR, and also by DSC and X- ray diffraction (powder) methods?

Surface-enhanced Raman scattering (SERS) spectra have been reported, with assignments, for several N-acetylneuraminic acid glycosides and derivatives.6

The C-O-S vibrational bands of the potassium salt of D-galactose 3-sulfate observed using FT-IR spectroscopy are dependent on the anomeric configuration and on hydration. The differences are proposed to be of potential use in


322

22: Other Physical Methods 323

determination of configuration of biologically significant galactose 3-sulfate units.

IR and Raman spectra of crystalline powders of (2’S)-[2’-2H]thymidine 2 were recorded and the data compared with the non-deuterated system.8 Raman spectra can be used to differentiate between 2’- and 3’-O-silylated N- benzyl-cytidine, -adenosine and -guanosine derivative^.^ The FT-IR and FT- Raman spectra of cytidine 3‘-monophosphate and its deuterated derivative have been reported.1° Far IR spectral characterization of mono- and disaccharides and some metal complexes have been described.” A separate IR study of metal ion interactions with galactose and xylose has been reported.I2

2 Mass Spectrometry

A number of mass spectrometric techniques (CI-MS, liquid SIMS with tandem MS) have been applied to characterization of furanose compounds containing 1,2-0-isopropylidene group^.'^ The rare loss of a neutral fragment (CH402) from a nucleoside derivative was observed using FAB- and electrospray MS.I4 Studies of acyclic 2’,3’-dideoxy nucleoside analogues bearing 8-azapurine bases, using EI MS, have indicated that a nitrogen in the 8-position strongly inhibits fragmentation. l5 A novel quantitative electrospray MS method has been developed for identifying (azasugar) glycosidase inhibitors. FAB- tandem MS has been employed in the investigation of sulfoquinovosyl diacylglycerol and mono- and di-galactosyl diacylglycerols. l7 FAB MS has also been used in the structural characterization of the glycosides 3 and 4, isolated from the stem-bark of Fagraea blumei. l8

’OH 3 R=H,OH

A series of peptide conjugated oligonucleotides (up to 8-mers in solution and 15-mers on solid support) have been characterized by MALDI-TOF, and capillary gel electrophoresis, l9 and a number of 2’,5’-dinucleotides (C-G, G-C and T-C) have been characterized using negative ion FAB MS.20

Collision-induced dissociation (CID) mass spectra of [M+Na]+ ions produced by FAB MS of glycosylsphingolipids gave fatty acid chain length


information on ceramide moieties,21 Delayed extraction MALDI-TOF MS has been applied to various lysoglycosphingolipids.22 Complexat ion of polysul- fated oligosaccharides with basic peptides or proteins facilitates analysis by electrospray negative ion MS.23 A MALDI- based technique using a time-lag focusing TOF spectrometer has been developed for analysis of monosulfated oligosaccharides. 24

Oligosaccharide alditols with a deuterium on C-1 can be used to obtain information about the masses and linkages of the various residues using high energy CID spectra.25 EI and tandem MS have been used in the analysis of metal-containing oligosaccharides, specifically a-D-Man-( 1 ++[a- D-Man-( 1 + 3)]-~-Man trisaccharide and this trisaccharide attached to chitobiose, with coordination to Cu2+, Mn2+, Zn2+ and Ca2+. The optimium conditions for observing [M+MetI2+, [M+MetCl]+ and [M+Met-H]+ were determined. 26

The liquid SIMS spectra of methyl glycosides of oligoxylans show intense cluster ions corresponding to protein-bound hetero-dimers when an aliphatic carboximide in glycerol is used as the liquid matrix.27 The fragmentation patterns of [M+H]+ ions of a series of (1 +6) linked trisaccharides with one or two deoxy or deoxyfluoro residues were observed using CID FAB MS, and showed an unusual rearrangement process.28 A new method for combining sequential exoglycosidase digestion with MALDI-TOF MS permits structural characterization of underivatized oligosaccharides in picamole amounts of material.29 The structural elucidation of 2-aminopyridine-derivatized sialyloli- gosaccharides by ESI MS has been described.30 Fragments from glycosidic and cross-ring cleavage were observed from MALDI-TOF MS of complex oligosaccharide^.^^ The linkage positions of a series of underivatized linkage- isomeric oligosaccharides have been detected using FAB MS. 32 Dissolution of malto-oligosaccharides with a-( 1 + 4) links in N,N-dimethylacetamide/lithium chloride produces multiple neutral alkali halide attachments which enable easier ES MS ~haracterization.~~ ES tandem MS coupled to reverse phase HPLC has been used for characterization of permethylated oligosa~charides.~~ The heptasaccharide, a-D-Ara-p-( 1 +6)-P-~-Glc-( 1 + 4)-[a-~-Ara-p-( 1 +6)-]-p- ~-Glc-( 1 +4)-[a-~-Ara-p-( 1 + 6)-]-P-~-Glc-( 1 +4)-glucitol, from tamarind seeds, was analysed using post-source decay fragmentation from MALDI- TOF MS. This identified eleven sodium-adduct fragment ions and a precursor ion. Almost all the fragment ions from species larger than trisaccharide fragments were detected; therefore such information enables structural determination of xyloglucan oligosaccharides.35

ES MS has aided the characterization of a series of amphipathic functionalized ether-linked di- and trisaccharides (units of alkyl derivatives of glucofuranose and either glucofuranose or diacetyl galactose). A novel eight-membered macrocyclic ether linked trisaccharide was also characterized using ES MS. Low energy CID MS/MS analysis of the [M+H]+ precursor ion proved to be a sensitive method of chara~terization.~~

MALDI-TOF MS has been employed in the characterization of cyclodextrins. Analysis of post-source decay fragment spectra showed this to be a


powerful technique for analysis of sugar-substituted cyclodextrin~.~~ Differen- tially ethylated P-cyclodextrins have been characterized by EI MS.38

3 X-ray and Neutron Diffraction Crystallography

Specific X-ray crystal structures have been reported as follows (solvent molecules of crystallization are frequently not reported).

3.1 Free Sugars and Simple Derivatives Thereof - 3-Acetamido-5- O-acetyl-3- deoxy- 1,2- O-isopropylidene-a-~-ribofuranose,~~ 3-deoxy- P-D-erythro-hexulose (3-deoxy-~-fructose),~ ~-erythro-hexos-2,3-diulose dihydrate (5)!l Crystal- lization of maltopentaose has been studied by X-ray analysis,42 and an ab initio calculation of the crystal structure of a- and P-D-glucose has been reported using the Car-Parrinello method.43

Ho-7

Ho 63- 5

,OH

6

3.2 Glycosides, Disaccharides and Derivatives Thereof - Monosaccharides: p - nitrophenyl tetra-O-acetyl-P-D-glucopyranoside,44 p-nitrophenyl a-D-manno- pyran0side,4~ methyl 3-deoxy-a-~-arabino-hexopyranoside>~ estronyl P-D-gh- copyranosidic uronic acid.47 The C-glycoside isopropyl [4,6-di-O-acety1-2,3- dideoxy-a-~-erythro-hex-2-enopyranosyl] rnethylmal~nate.~~ DNA helicase inhibitor heliquinomycin (6), isolated from Streptomyces sp. MJ929-SF2 (the component sugar is ~-cymarose).~~ Epoxide 750 and aldehyde gS1 (see Chapter 24 for chemistry). The structure of benzyl 2,6-di-O-( P-anthracenylsulfonyl) glucopyranoside bound in the thrombin active site.52

Q- CHO

7 8


7-Deoxy- lY2:5,6-di- 0-isopropyl~dene-~-gZycero-a-~-gaZacto-heptofuranose (9) and related bicyclic derivative The glucose-derived oxepin-fused system 11 (see Chapter 24 for ~ynthesis).~~

Disaccharides: 2,3,4,3’,4‘-penta-0-benzy1-6,6’-dich1oro-6,6’-dideoxy- sucrose,55 nitrile-containing glycoside 12,56 3,3’,4,4‘,6,6’-hexa-O-acetyl-2,1’- anhydro-2-O-a-~-g~ucosyl-~-g~ucose (13)y57 methyl (2-O-a-~-mannopyra- nosy1)- ~-D-glucopyranoside, 58 p-nitrophenyl 4- 0-( 3,4,6-tri- 0-acetyl-2-deoxy- 2-ph thalimido-P-~-glucopyranosyl)-2,3-di- 0-benzo yl-6- 0-pivalo yl- p-~-glucopyranoside (14),59 a,P-trehalose,60 and a,a-trehalose.6’

CN

&D-Xyl-p( 1 +6)-f3-D-GlC-pO

12

3.3 have

OAc qo 13

0

NPhth 14

HO - - - - HO OH

15n - 5 17 OH l 6 n = 4

1

Higher Oligosaccharides and C-Glycosides - Most reports in this area related to cyclic oligosaccharides (cyclodextrins) or related cyclic carbon-


linked systems. Stoddart and co-workers have reported X-ray structural analyses showing that 1562 and 1663 form nanotubes. The latter forms a C2 symmetric system with the internal nanotube diameter being 1 nm. The inclusion complex of heptakis-(2,6-di-O-methyl)-P-cyclodextrin with A c O H , ~ a cyclodextrin constituted of alternating L-rhamnose and D-mannose, and 6-deoxy-6- { 4-[2-(N- t-butoxycarbonyl)aminoethyl]imidazolyl~ cyclomaltohep- taose66 have been structurally characterized.

Comparison of X-ray data on havamine (a plant chitinase-1ysozyme)- chitotetraose and chitinase A-chitobiose with the published data for hevamine-allosamidin and chit obiase-chit o biose indicates that the enzymes are stereochemically retaining because of the involvement of C-2 NAc and also a protein carboxylate in the reaction. The X-ray analysis also shows how the substrate is bound in the active site and how a sugar ring is distorted. 67

The X-ray structures of cyclic tetrameric acetylene linked saccharide 17,68 C- disaccharides 1869 and 19,70 and of the bis-acetylenic C-disaccharide 20,71 and furan C-glycoside 2172 have been reported.

OAc Ql) phqo~cH*oMe HO H2 Me0

19

20 i m s 21

3.4 Anhydro-sugars - 1,4:3,6-Dianhydr0-2-O-p-tosyl-~-mannitol~~ and sugar-derived spiro-acetals 22-U.74

22 23 24


3.5 Halogen, Phosphorus, Sulfur, Selenium and Nitrogen-containing Com- pounds - D-Galactonic acid hydrazide and its hemih~drate ,~~ 2-(2-deoxy-u-~- erythro-pentopyranosy1)urazole (25),76 2-(2-deoxy-a-~-erythro-pentopyra- nosyl)-4-methylurazole (26),77 N-( P-~-lactopyranosyl)urea,~~ N-acetyl P-D-glu- copyran~sylamine?~ N-acetyl-2,3,4,6- tetra- O-acetyl-N-benzyl- P-D-glucopyranosylamine,80 and 5-deoxy-5-C-(5-ethoxycarbonyl- 1,2,3-tetrazol- 1 -yl)- 1,2-O- isoprop ylidene-a-D-xylofuranose. *

Oey-(O

27 OH HNXNMe

OH

2s 26

The glucosidase inhibitor 27,82 1 -amino-2,5-anhydro-l -deoxy-D-glucitol hydr~chloride,~~ N-benzyl 2,3: 5,6-di- O-isopropylidene-u-D-mannopyranosyl hydroxylamine 28,84 the aza-Diels Alder adduct 29,85 the amide linked disaccharide analogues 30 and 31,86787 and 32.88

29 ' N(0H)Bn 28

OH 30 n = l l 31 n = 12,13 or 14

OMe 33

OH &Me " 0 2

34

32 OH

AcO,

AcO @, HN K "Y C02Et

0 CHMe2 35

Sulfonamide 33,89 1 -(3,4-di- O-acetyl-2-deoxy-2-hydroxyimino-a-~-erythro- pentopyranosy1)pyrazole and ethyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-a-~-arabino-hexopyranoside,~~ 3-nitro-branched chain glycoside 34,91 the glucosamine-valine conjugate N-(methyl 3,4,6-tri-O-acetyl-P-~-glucopyranos-2-y1)- N'-carbamoyl-D-vahe ethyl ester (35).92

The macrocyclic lactam 36,93 sugar-fused oxazolidinone 37, aziridine 38 and


compound 39,94 tricylic 40,95 spirocyclic 41,96 Oppolzer sultam adduct 42,97 7- epi-7- C-methyl-castanospermine 43 and 1 - C-methyl-castanosperine 44.98 The C2-symmetric system 45,99 spirocyclic oxazolidinone 46, loo the 1,4-imino- arabinitol 47,1°1 pyralomycin la 48 and 2a 49.*02

0 36

OH

OAc

tie

AcO, otY OAc

Tips0

40

43 \ 42

pti 45

37

41

44

co2- HO

OH 46 47

CH20H 0 OH HOH2C wR @ R='WC'

Me0 OMe OH Me -.

49 OH

48

4,6-O-Ethylidene-2,3-di-O-methanesulfonyl-a-~-glucopyranosyl chloride,'03 methyl 3-deoxy-3-fluoro-~-~-allopyranoside,'~~ (6S)-8-C-chIoro-6,7,8-trideoxy- 1,2: 3,4-di- O-~sopropyl~dene-a-~-guZacto-octa-6,7-dienopyranose (50), lo'


diphenyl-(methyl 4,6'-O-benzylidene-2'-deoxy-a-~-altropyranosid-2-yl)-phosphine oxide, '06 methyl 4,6- O-benzylidene-3-deoxy-3-(diphenylphosphino)-a-~- altropyranoside, lo7 1,6-anhydr0-4-deoxy-4-(diphenylphosphine oxide)-D-glucopyranose, lo8 cyclic phosphonate 51,'09 chiral phosphine oxide 52.' lo

5 0 1 OH

51

Thioglycoside 53,' ' disulfide 54,' l 2 methyl 4,6-O-benzylidene-2,3-U,S-carbonyl-3-thio-P-~-allopyranoside (55) and methyl 4,6-O-benzylidene-2,3-O,S- carbonyl-3-thio-~-~-mannopyranoside 56, ' and the natural a-glucosidase inhibitor 57 isolated from the traditional antidiabetic medicinal plant SaZacia reticdata (no definitive evidence of absolute configuration). l4

OTWms

TWmsO""

OTWms 53 54

phjob SHO 0

55

56 57

3.6 Branched-chain Sugars - The unusual branched chain dichloromethyl sugar 58,115 spirocyclic cyclopropanes 59 and 6O,ll6 exocyclic alkene 61 and spiro-epoxide 62,' l 7 spirocycle 63,Il8 C-4 branched system and the interesting diary1 system 65.120

3.7 Inorganic Derivatives - [{ Co[D-GlcI2tren]) 202]X3.H2), where tren = bis- (N-glucosyl-2-aminoethyl)(2-aminoethyl)amine), showing cobalts bridged by peroxo ligands and each metal ligated by four nitrogens and the C-2 oxygens of a sugar, with the other D - G ~ anchored by only the N-glycosidic atorn.l2' Chromium carbene 66,'22 [(MnL2)2Mn(H20)][NO3]3 with L = ~arbohydra t e '~~ and triphenylstannane 67. 124

22: Other Physical Methods 33 1

5 8 1

PivO,

,,&&13 PivO

OMe 59

P iv0

60 TbdmsO

BnO &; .s+y

61 62 OH O 6 3

64 65

O-CHEt2

H,N'

TrO

67

Me%

-%o

RO 68 R = (-)camph

70 71 72 73

3.8 Alditols and Cyclitols and Derivatives Thereof - Potter's group prepared bis-camphanate and Freeman's group reported the structure of (+)- 1,2:4,5-di-O-cyclohexylidene-myo-inositol (69), in which some unusual H- bonding features are evident (3R,4R,SS)-4-Acetamido-5-arnino-3-( I -ethyl-


propoxy)- 1 -cyclohexene- 1 -carboxylic acid (70), 127 the ( -)-5-epi-shikimic acid precursor 71 (from D-ribose),128 72, 129 and conduritol precursor 73.130

3.9 Nucleosides and Their Analogues and Derivatives Thereof - 3‘-Deoxyade- nosine, 31 3’-deoxycytidine (shows C-3’-endo sugar ring puckering and anti- conformation about glycosidic bond), 32 cytidine 3’,5’-cyclic phosphate 74 (furanose ring has northern conformation - 3T2, C3’-endo - which is notably different from other 3’,5’-cyclic nucleoside phosphates reported),133 trans- adenosine 3’,5’-cyclic-N,N-dimethylphosphoramidate 75 (ribose ring is 3T4, and the phosphoramidate ring is a flattened chair with an equatorial, planar dimethylamino bicyclic [2.2.1] nucleoside analogue 76. 35 The 3‘,3’- difluoro L-nucleoside analogue 77,136 E- and Z- isomeric oxime ethers 78 and 79, 37 carbocyclic nucleoside 80, 38 and the dioxane nucleoside analogue 81, 39

5-(5-methylthien-2-y1)-2‘-deoxyuridine, 5-(5-thien-2-y1)-2’-deoxyuridine and 5- (S-bromothien-2-y1)-2’-deoxyuridine, 140 and the spirocyclic system 82. 3,4-Etheno-5-methoxymethyl-2’-deoxycytidine 83, 142 the interesting bis-thio-

phenyl substituted base analogue 84, 143 5-formylamino-l-( P-D-ribofuranosy1)- imidazole 85, 144 the 5-carboranyl-2’,3’-dideoxy-3’-thiauridine 86,145 3- carbamoyl-4-(N-phenylcarbamoyl)- I -( P-D-ribofuranosyl) pyrazole 87. 146 A number of C-nucleoside analogues have been reported: pseudouridine 88, 147

the selenium system 89,148 and 90,149 prepared as a cimetidine analogue. The I (note: ether replacing phosphate link). 50 2’4 P-~-ribofuranosyl) nucleoside 91

0 7 Cyt’ 0 1

-0 F OH 74 75 76 77

Ade

OJra N ‘OMe MeO-N PhC(0)Ol\co

78 79 80 81

3.10 Neutron Diffraction - Neutron scattering has been used to determine the H-bond structure in glassy and liquid glucose. 151

4 Polarimetry, Circular Dichroism, Calorimetry and Related Studies

The luminescent decay times of several y-irradiated saccharides (including glucose, mannose, lactose and maltose) have been studied using a photon


OH OH 82

OH 83

85 86 87

NHMe

OH OH OH OH 88 89 90 91

counting technique. 152 The absolute configuration of the acyclic side chain of heptopyranosides and heptofuranosides has been determined by exciton coupled CD (employing the strongly fluorescent 2-anthroate chromophore). 153

The enthalpies and heat capacities of aqueous solutions of a range of saccharides (ribose, mannose, galactose, glucose, fructose, or-D-lactose mono- hydrate and saccharose) have been recorded. 154 Solvent effect rotatory dispersion, CD and UV spectra of monosaccharide xanthates (e.g. 92) have been correlated with stereochemistry . 55

S

OAc 92

The conformational properties and gauche effect of the C-6 CH20H and CH20Me groups of sugars have been examined using ab initio methods (on unsubstituted methyl pyranoside models).'56 ESR has been used to study


photo- and sonic bromination of 2,3,5-tri-O-benzoyl-P-~-ribofuranosyl cyanide with NBS in non-aqueous solution. 157

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(Chem. Abstr., 1997, 127,331 677).

339

S. Bottka, J. Tomasz, W. B. T. Cruse, S. Zhang and 0. Kennard, Nucleosides Nucleotides, 1997, 16, 2 123. S. Obika, D. Nanbu, Y. Hari, K. Morie, Y. In, T. Ishida and T. Imanishi, Tetrahedron Lett., 1997,38, 8735. L. P. Kotra, Y. Xiang, M. G. Newton, R. F. Schinazi, Y.-C. Cheng and C. K. Chu, J. Med. Chem., 1997,40,3635. I. I. Fedorov, E. M. Kazmina, G. V. Gurskaya, M. V. Jasko, V. E. Zavodnic, J. Balzarini, E. De Clercq, A. Faraj, J.-P. Sommadossi, J.-L. Imbach and G. Gosselin, J. Med Chem., 1997,40,486. S . Shuto, T. Obara, Y. Saito, K. Yamashita, M. Tanaka, T. Sasaki, G. Andrei, R. Snoeck, J. Neyts, E. Padalko, J. Balzarini, E. De Clercq and A. Matsuda, Chem. Pharm. Bull., 1997,45, 11 63. D. C. Capaldi, A. Eleuteri, G. Chen and R. F. Shinazi, Nucleosides Nucleotides, 1997,16,403. I. Creuven, B. Norberg, A. Olivier, C. Evrard, G. Evrard, P. Wigerinck, P. Herdewijn and F. Durant, J. Chem. Crystallogr., 1996, 26,777 (Chem. Abstr., 1997,126,277 705). T. Gimisis, C. Castellari and C. Chatgilialoglu, Chem. Cornrnun., 1997,2089. G. F. Audette, W. M. Zoghaib, G. Tourigny and S. V. Gupta, Acta Crysallogr., Sect. C, 1997,53, 1099. J. Wouters, I. Creuven, B. Norberg, G. Evrard, F. Durant, A. van Aerschot and P. Herdewijn, Acta Crysallogr., Sect. C, 1997,53, 892. M. P. Groziak, 2.-W. Huan, H. Ding, Z. Meng, W. C. Stevens and P. D. Robinson, J. Med. Chem., 1997,40,3336. N. A. Goudgaon, Y. A. El-Kattan, X. Xia, J. McAtee, J. Soria, S.-J. Wey, D. C. Liotta and R. F. Schinazi, Nucleosides Nucleotides, 1997,16,2133. S. Kim, W. Won and Y. Kang, Nucleosides Nucleotides, 1997,16,2025. A. Hempel, B. G. Lane and N. Camerman, Acta Crystallogr., Sect. C, 1997, 53, 1707. P. Franchetti, L. Cappellacci, G. A. Sheikha, H. N. Jayaran, V. V. Gurudutt, T. Sint, B. P. Schneider, W. D. Jones, B. M. Goldstein, G. Perra, A. De Montis, A. G. Loi, P. La Colla and M. Grifantini, J. Med Chem., 1997,40, 1731. S . Harusawa, H. Moriyama, Y. Murai, T. Imazu, H. Ohishi, R. Yoneda, T. Kurihara, H. Hata and Y . Sakamoto, Chem. Pharm. Bull., 1997,45,53. S. N. Mikhailov, E. V. Efimtseva, G. V. Gurskaya, M. V. Tomitaheva and S. V. Meshkov, J. Carbohydr. Chem., 1997,16,75. R. H. Tromp, R. Parker and S. G. Ring, J. Chem. Phys., 1997,107,6038. C. Haldar, Indian J. Phys., 1997,71A, 299 (Chem. Abstr., 1997, 127,95 463). I. Akritopoulou-Zanza, K. Nakanishi, H. Stepowska, B. Grzeszczyk, A. Za- mojski and N. Berova, Chirality, 1997,9, 699 (Chem. Abstr., 1997,127, 346 563). V. K. Absrosimov and R. V. Chumakova, Zh. Fiz. Khim., 1996, 70, 1778 (Chem. Abstr., 1997, 126,47 428). K. Satsumabayashi, Y. Nishida and K. Tanemura, Nippon Shika Daigaku Kiyo, Ippan Kyoiku-kei, 1997,26,47 (Chem. Abstr., 1997, 126,277 694). I. Tvaroska and J. P. Carver, J. Chem. Phys. B, 1997,101,2992. G. Chen, T. Chen, K. Chen, Z. Lou and Y. Xie, Huaxue Shijie, 1997, 38, 249

23 Separatory and Analytical Methods

Contrary to an undertaking given in Volume 30, it has, regrettably, not proved possible to include in the current Volume 1996 material published in The Journal of Chromatography.

1 Chromatographic Methods

1 .l Gas-liquid Chromatography - Quantitative analyses of the following compounds present in biological samples have been carried out: glucitol as its trifluoroacetylated derivative with [U-13C] as internal standard,' ascorbate and dehydroascorbate by isotope dilution (with the [ 1 -13C]-labelled compound) as the Tbdms perethers,2 and the sugars present in apricots as their trimethylsilyl derivatives .3

A Tbdms ether of P-cyclodextrin, which is used as a GLC stationary phase, has been shown by MS methods to contain homologues with 7-10 ether group^.^

The members of eight of eleven pairs of enantiomers of trifluoroacetylated alditols and aldose diethyl dithioacetals wqre separable on permethylated a-, p- and y-cyclodextrins as capillary stationary p h a ~ e s , ~ and various ethers of p- and y-cyclodextrins were used to resolve the enantiomers of permethylated sugars and 1,5-anhydroalditol~.~ A successful alternative method involved the separation of the peracetylated or persilylated di-(+)-or di-( - )-I -phenylethyl dithioacetals of enantiomeric sugars and affords a means of obtaining absolute configurations.

1.2 Thin-layer Chromatography - Methods involving the use of high pressure have been reported for the separation and analysis of gentamicin components in urine and plasma,* ascorbigen and its 1'-methyl etherg and saturated and unsaturated oligogalacturonic acids. lo

1.3 High-pressure Liquid Chromatography - A further method for determining the absolute configuration of monosaccharides depends on separation of their acetylated aldononitriles on a Chiracel OD-H column. ' Several separations of sugar^,^^*^^ a ldi t~ls , '~- '~ and glucuronic acid14 have used anion exchange resins and pulsed amperometric detection. Other related methods

~ _ _ _ ~


340

23: Separatory and Analytical Methods 341

have also employed anionic resin-based separations, but the quantitative methods used involved pyranose oxidase followed by colorimetric determination of H202,16917 while a different approach has involved reductive amination and separation of 1 -deoxy- 1 -[(p-ethoxycarbonyl)phenylamino]alditols.

Simple sugar derivatives to have been analysed by HPLC are ascorbic acid and isoascorbic acid (on basic polymer-coated silica),lg unsulfated or partially sulfated unsaturated disaccharides (ion-pair, revex se phase)20 and unsaturated disaccharides (also from heparin and its sulfate; TSK gel-Amide 80 column).21

Analysis of methyl P-cyclodextrin in plasma and cell lysates was carried out by use of size-exclusion HPLC,22 and oligosaccharides (DP up to 27) have been detected in sea water by application of reverse phase HPLC with mass spectrometric detection and size determinati~n.~~

HPLC analyses have also been applied to the following carbohydrate- containing compounds: long chain alkyl glycosides (on porous graphitized carbon with evaporative light-scattering de te~t ion) ,~~ glucosinolates (reverse phase, MS),25 saponins from soya flour (reverse phase, MS),26 the glucuronide of 25-hydroxyvitamin D3 (UV detection)27 and the glucuronides of morphine and codeine (reverse phase, MS).28

The following medicinal chemistry applications have been reported: amipri- lose [3-0-(3’-aminopropyl)- ~,2-~-isopropylidene-~-glucofuranose] (an immu- nomodulatory compound, reverse phase, fl~orimetry),~~ the eight components of commercial kanamycin sulfate (two new components were observed for the first time; pulsed amperometric de te~t ion) ,~~ several aminoglycoside antibiotics including neomycin, netilmicin, sisomycin (fl~orimetry)~ and paromycin. 32

Glycolipid compounds to have been examined are octyl, dodecyl, hexadecyl and 3,6,9-trioxapentacosyl P-D-glucopyranosides (reverse phase, MS),33 and monophosphoryl lipid A immunostimulants from a SaZmoneZZa which are based on P-D-G~cNAc-( 1 -+6)-~-GlcNAc (where Ac = long chain acyloxy groups; reverse phase, ion-pair HPLC).34 Glycopeptide-based compounds to have been submitted to HPLC are galactosyl- and glucosylgalactosyl-lysine from collagen (reverse phase, f l~orimetry)~~ and the synthetic peptide hor- mones dalargin and desmopressin coupled to sugars by reductive amination or reaction with 2-chloroethyl- 1 -thiogalactoside (reverse phase).36

Nucleosides and related compounds to have been separated by HPLC methods are carbocyclic nucleoside antitumour agents in biological and 16 urinary ribonucleosides which were separated on a phenylboronic acid column then by reverse phase HPLC. The method was intended for the detection of modified nucleosides originating from degradation of RNA produced by patients with malignant turn our^.^^ Various reverse phase HPLC and detection methods have been applied in the examination of nucleotides (as well as nuc leo~ides) ,~~-~~ one giving good differentiation of mono-, di- and tri- phosphates41 and another allowing identification of adenine nucleotide metabolites of bisphosphonate drugs, for example ADP having the H203P-CC12- PH02-O-PH02- group bonded to 0-5’.42 Ion pair reverse phase HPLC and negative ion MS were employed in the separation and identification of cyclic nucleotides in biological samples.43


1.4 Column Chromatography - Affinity chromatography using a GalNAc- specific lectin immobilized on agarose beads resolved GalNAc, its a-l-phosphate and UDP-GalNAc, the last being the most strongly bound? In similar fashion lysozyme and a-lactalbumin, both of which have carbohydrate binding sites, bound on a column have been used in the isolation of the aminoglycoside antibiotic hygromycin B from biological samples.45

Atmospheric pressure anion exchange methods have been used in the separation of ribonucleotides derived from ribosomal RNA constituents!6

Relatively novel sub-critical fluid chromatography operating at 200 bar and 40-60 “C has been applied to the separation of aldoses, ketoses and alditols as well as various glycolipids. Silica and trimethylsilyl silica were the stationary phases; C02-methanol with water and triethylamine as additional components were the e l ~ a n t s . ~ ~

2 Electrophoresis

2.1 Capillary Electrophoresis - Capillary zone electrophoresis is the simplest form of capillary electrophoresis, but the two names are sometimes used interchangeably. They will now be dealt with together, but work specified as having been done under capillary zone conditions will be identified by use of ‘CZE’.

Methods have been developed for the use of CZE in measuring ionization constants of and aldoses have been examined as their 3-methyl-l- phenyl-5-pyrazolone derivative^:^ and (for those derived from glycoproteins) following reductive amination with 8-aminopyrene- 1,3,6-trisulfonate or, in the case of sialic acids, with 9-aminoa~ridine.~~ The isomeric disaccharides p-D- Gal-( 1 + 3)-~-GlcNAc and p-D-Gal-( 1 + 4)-p-~-GlcNAc and compounds derived by enzymic action on them in human carcinoma cells have been examined as their tetramethylrhodamine derivative^,^^ and oligosaccharides have been sequenced by exo-glycosidase step-wise degradation followed by capillary electrophoresis of 8-aminopyrene- 1,3,6-trisulfonate-labelled pro- d u c t ~ . ~ ~ Other dextran- and malto-oligosaccharides have been examined (CZE) following reductive amination with the charged and UV-absorbing 4-amino- benzoyl-L-glutamic acid. Detection was possible at the sub-picomole

Two reports have appeared on the simultaneous analysis of ascorbic acid and dehydroascorbic acid in foods and plant t i s s ~ e s , ~ ~ , ~ ~ and several sugar acids and ganglioside-derived sialo-oligosaccharides have been analysed as their 7-aminonaphthalene- 1,3-disulfonic acid derivative^.^^ Another report describes the examination of gangliosides themselves (CZE).57

Other relevant compounds to have been examined are inositol phosphates in fermentation broths and blood plasma (by on-line concentration by electro- dialysis, capillary electrophoresis, MS),58 and acarbose and its metabolites (as their 7-aminonaphthalene- 1,3-disulfonic acid derivatives) in human urine

Purine bases, ribonucleosides and ribonucleotides have been simultaneously ( ~ 2 ~ 1 . 5 9

23: Separatory and Analytical Methodr 343

determined by capillary electrophoresis with consistent potential amperometric detection with a copper electrode under alkaline conditions.60 Related studies have been carried out on all the common ribonucleotides,61 ATP in blood plasma and inositol phosphates in fermentation broth (CZE),62 twelve ribonucleotides (mono-, di- and tri-ph~sphates),~~ deoxyribonucleotides in the presence of P-cyclodextrina and twelve deoxyribonucleotides (mono, di- and triphosphates) in the presence of a soluble polymer (CZE).65

2.2 Other Electrophoretic Methods - Micellar electrokinetic chromatography (MEKC) has been used for analysing for common anti-AIDS drugs (AZT, ddA, ddC, ddI and d4T) and AZT gluc~ronide,~~ and for monitoring the phospholipase C cleavage of phosphatidylinositol into diacylglycerol and inositol 1,2-cyclic phosphate.66 For the separation of the relatively hydrophobic cardiac glycosides microemulsion electrokinetic chromatography (MEEKC) was superior to MEKC,67 and was also used with N,N-diphenyl- hydrazones of dicarbonyl sugar compounds e. g. D-xylosone, D-glucosone, D-

galactosone, and D-threo- he~-2,5-diulose.~* Capillary isotachophoresis was the method selected for the determination of

alditols in pharmaceutical preparation^^^ and aldonic acids produced on PdC12 oxidation of aldoses in alkaline solution. Unexpectedly at pH 9 only mannonic acid was produced from mannose or glucose.70

3 Other Analytical Methods

A subnanomol colorimetric method for determining sugars is based on dark violet derived with Fe(I1) 2,4,6-tri-2-pyridyl-s-triazine which is stoichiometri- cally destroyed by periodate ion. Excess ion can therefore be determined following the oxidation of the carbohydrate^.^^ 1,5-Anhydro-~-arabino-hex-2- ulose can be specifically assayed by treatment with alkaline dinitrosalicylic acid under defined condition^.^^ A spectrophotometric determination of ascorbic acid at M levels depends on its interference in the diazotization of 5,10,15,20-tetrakis(4-aminophenyl)porphine and was applied to analyses in soft drinks and pharmaceutical^.^^

A new electrode [TEMPO bound to a poly(pheny1ene oxide) film on glassy carbon] is suitable for the electrochemical determination of sugars by flow injection methods,74 and a further electrochemical method for post-HPLC separation of carbohydrates depends on periodate oxidation and determination of derived iodate.75 A novel simultaneous potentiometric determination of carboxylic acids and amperometric assay of sugars has been described.76

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24 Synthesis of Enantiomerically Pure Non-carbohydrate Compounds

1 Carbocyclic Compounds

Glucosylidene carbene reactions with enol ethers provides a route to cyclopro- pane spiro-fused glucose derivatives. Thus, compounds 1 react with cyclic enol ethers 2 to give, after deprotection, 3, whilst 1 react with acyclic enol ether 4 to afford a mixture of the possible regio- and diastereomeric outcomes (5-8).' Quinic acid has been converted into the fused cyclobutane Ci-lactone 9 in 15 steps and leads to an intermediate which has previously been converted into (+)-grandis01 (lo).*

n = 1 (R' =Me)

The cyclopentane 12 has been synthesized via 11 starting, ultimately, from D-glucose (Scheme l).3 Highly functionalized cyclopentanes have also been prepared by other carbohydrate-based procedures, as have C-nucleosides (see Chapter 20). Radical cyclization was employed in the synthesis of 15, starting from 13 and proceeding via final radical deiodination of 14 (Scheme 2), Analogous chemistry provided a route from 16 to 17. Both routes furnish the products in 4248% overall yields (Scheme 2).4

Samarium diiodide mediates the cyclization of carbohydrate-derived oxime ethers 18 and 20 to cyclopentanes 19 and 21, respecti~ely.~


347


702Et

13 Reagents: i, PhlO, 12; ii, Bu3SnH, AIBN.

. AcO.

TsO' -*OAc "7- 11 12 Reagents: i, H2S04, MeCN-H20; ii,PhCH2NHOH; iii, Pd-C,EtOH, C6Hl0; iv, AqO, Py.

Scheme 1

Scheme 2

BnO, Me0 PivO. ""Vi BnO"" BnO, ,,,, b , , , , $NHOMe p i V o ~ ~ p i v pivo'**'' P~VO,,,~,~,,,,,NHOM~

PivO 21 OPiv 08n BnO 20 OPiv 18 19

D-Ribonolactone was converted into hemiacetal lactone 22, which was further elaborated to cyclopentenone 23 (Scheme 3).6 Carbohydrate-derived starting material 24 has been elaborated into 15(RS)-5,6-dehydro-8-epi-prosta- glandin F2a (26) via intermediate 25 (Scheme 4).7

Reagents: i, CeHloO, FeCI3; ii, KOH, H20, A; iii, K104, H20; iv, 2M HCI; v, PPTS, CPIOH, . vi, MePO(OMe)2, BuLi.

Scheme 3

24: Synthesis of Enantiomerically Pure Non-carbohydrate Compounds 349

24 I 25

Reagents: i, ZnClp, EtSH; ii, EtsSiCI, Py; iii, HgO, HgC12, Me2C0, H20; iv, Ph3P=CHCHO V, Ph3P=CHC5H11.

Scheme 4

A number of syntheses of fused ring systems containing five- and/or six- membered carbocylic rings have been reported this year. The trieneoate 27 (see Vol. 28, p. 8, Chapter 2 for synthesis) undergoes an intramolecular Diels-Alder reaction catalysed by AlC13 to yield bicyclic product 28 and other examples of such cycloadditions were described.8 Trieneones 29 (from L-arabinose) and 30 (from L-ascorbic acid) undergo IMDA reactions to yield bicyclics 31 and 32, respectively, in 75 -79% yield. The isopropylidene groups provide conformational restriction to direct stereocontrol via chair-like and boat-like endo- transition states for 31 and 32, respe~tively.~

0

32

A tandem Wittig-Intramolecular Diels-Alder reaction provides a useful entry to highly oxygenated, carbohydrate-bearing decalin systems. Thus, reaction of 33 with 34 generated 35. Analogous chemistry using other carbohydrate-derived aldehydes gave 36 and 37 (isomeric mixture).IO

Intramolecular Diels-Alder chemistry (conversion of 38 to 39) was also the key step in a synthesis of the skeleton of the forskolin analogue 40 from 3,4,6- tri-O-acetyl-D-galactal (Scheme 5).11

Methyl a-D-xylopyranoside derivative 41 was converted into the acyclic chiral unit 42, which was treated with two equivalents of methyl acetoacetate to afford (via double Claisen chemistry) the chiral a-tetralone 43 (an intermediate related to benanomycinone, the aglycon of benanomycin A) (Scheme 6).12

Levoglucosan was converted to the tricyclic system 46 in a number of steps (Scheme 7), via derivative 44, the key reaction being the introduction of the five-membered ring (to give 45) by means of an intramolecular Horner- Wadsworth-Emmons type olefination. Compound 1AE is an advanced intermediate towards synthesis of ( -)-quadrone.13


CHO

C O H

33 34

(OAc

tx 36

H V -

OBn

II

37

/OTbdms

WMe YTbdms

OTbdms

0 - H

0 39

/ / /

3 8 0

Reagents: i, AllylTms, BF3; ii, MeOH, EtsN, H2O; iii, TbdmsCI; iv, MeCH2CQH, DCC; v, HMDS, BuLi, TWmsCI; vi, A; vii, KF, Mel, KHCa.

Scheme 5

41 42 43 Reagents: i, S0Cl2; ii, BusSnH, AIBN; iii, HCI, dioxane, H20, r.t.; iv, BnBr;

v, HCI, dioxane, H20,1OO0C; vi, PDC; vii, TsOH, MeOH; viii, PDC, CH2Cl2; ix, PDC, MeOH, DMF; x, Pd(OH)p, cyclohexene; xi, NaH, BuLi, THF, MeC(0)CH2CQMe

Scheme 6

24: Synthesis of Enantiornerically Pure Non-carbohydrate Compounds 351

rOTbdms

6 45 46

Reagents: i, MeOH, H+ resin; ii, TbdmsCI, Py; iii, NMNO, Os04; iv, lo4-; v, (MeO)zP(0)CHzLi; vi, Dess-Martin; vii, LiCI, i-PrZNEt.

Scheme 7

Palladium chemistry was instrumental in two other syntheses of tricyclic systems. Firstly, D - ~ ~ U C O S ~ derivative 47 was converted into the pancratistatin C-ring precursor 50, via rearrangement to 48 and elaboration to 49 which then underwent intramolecular Heck closure (to yield 50) (Scheme 8). l4

Palladium-catalysed conditions were employed to convert 51 to 52 [Pd2(dba)3.CHC13, tri-O-tolylphosphine in acetic acidbenzene]; or to 53 [PdC12(MeCN)*, CuC12, LiCl, in acetic acid/MeCN]. The second set of conditions also converted 54 to the N-containing system 55.15

/

0 47 48 L o 49

Reagents: i, HgOTf2, aq. Me2CO; ii, TbdmsOTf; iii, LAH; iv, MsCI, Et3N; v, Bu~NF; vi, DMSO, (COC1)z; vii, Pd(OAc)z, Ph3P, EtaN, AgN03.

Scheme 8

51 (a) X = C02Et, Y = CQMe (b) X = S02Ph, Y = C@Me

kBu02C0,

,OAc PAC

/ocozkBu


iwii /

-- B"oh\$" ---t H 0 8 " ' K

OMe 56 Reagents: i, rod-; ii, Ph3P=C(Me)C@Me; iii, K2CO3, MeOH; iv, TwpsCI, DMAP;

v, CCI3C(=NH)OBn, CF3S03H; vi, DIBAL; vii, Mn02.

Scheme 9

D-Glucose has been converted into (-)-fumagillol56 (Scheme 9). l 6

An interesting synthesis of the cyclooctenone 58 utilizes the (thermally induced) sigmatropic rearrangement (via lC4 chair) of 57 (derived from D-glucose) (Scheme

OBZ BzO OBz

57 58 OH

Reagents: i, TsCI, Py; ii, BzCI, Py; iii, DMSO, A; iv, NaI, Bu~NI, DBU; v, xylene, A.

Scheme 10

2 Lactones

Both enantiomers, 60 and 61, of epi-muricatacin have been prepared from furanose 59 (Scheme 11). l 8 Intramolecular Wittig reaction was the key

Reagents: i, CllH23PPh3Brr KOBu-t, Py; ii, DMSO, DCC, Py; iii, PPh3P=CHC02Me; iv, TsCI, Et3N; v, H2, Pd-C; vi, HCI, THF; vii, (C11H23)2CuLi.

Scheme 11


Brio+ o ~ B r E n O ~ O -0. / Bnoho a * 63 64 65

chemistry in a synthesis of the bicyclic C-glycosidic lactone 65. Treatment of 62 with Ph3P and less than an equivalent of DBU generates only 64, hydrogenation being employed to take this to 65. If more than an equivalent of DBU is used, epimerization occurs at C-2 and both 63 and 64 are produced.19

A synthesis of (R)-mevalonolactone 68 and its perdeuterated analogue (R)- [2H~]mevalonolactone [using (C2H3)2C=C2HC02Me and LiA12H4], has been reported based on diacetone-D-glucose as a template,2o only one of the carbons (the lactone carbonyl) of the final product coming from the sugar. The key C-C bond forming reaction involves addition of an allylic anion to the sugar C-3 carbonyl group to give 67 (30%) (and the alternative allylic anion addition product 66 in 51% yield) and a key step is the diastereoselective epoxidation of the C=C bond of 66 (Scheme 12).

66 67 Reagents: i, (Me)&=CHC&Me, LDA; ii, H202; iii, LAH; iv, H+; v, NaIO4.

Scheme 12

Me,,,, OH a* 68

The bicyclic lactone 71 was prepared in 13 steps from carbohydrate starting material 69. The first step involved epoxidation of the sugar aldehyde followed by ring close ring opening of the epoxide to re-establish the five-membered ring (5-exo-tet). A later key step involved the oxidative Pd-catalysed cyclization of 70 followed by lactol oxidation and debenzylation to give 71 (Scheme 13).21

69

t-OH

vi-x __c

@ y - xi-xiii

f OBn

Ph 70

4 OH

Ph 71

Reagents: i, trirnethylsulfoxoniurn iodide, KOBu-f, DMSO; ii, Swern; iii, PhMgBr; iv, PDC; v, NaBH4; vi. BnBr, NaH; vii, 60% AcOH; viii, MsCI, TEA; ix, Nal; x, 5% H2SO4, dioxane; xi, PdCI2, CuCI, 0 2 ; xii, PDC; xiii, H2, PdS04.

Scheme 13


3 Macrolides, Macrocyclic Lactams, Polyether Ionophores and Their Constituent Segments

This year has seen a variety of reports of syntheses of components of a range of well known bioactive marine systems. Full details of the synthesis of the C- 1 -C- 15 component of halichondrin B, a potent antitumour polyether macrolide, have been reported (preliminary communication see: Vol. 28, p. 361, ref. 58).22 A companion paper from the same group reported synthesis of two C-27-C-36 units from dimethyl tartrate.^^

Ciguatoxin, the algal red-tide toxin, again proves to be a continuing target for synthetic efforts, with full details of the synthesis of AB ring fragments having been published (preliminary communciation: Vol. 29, p. 379, ref. 59). Proof of the C-2 configuration (of both ciguatoxin and synthetic fragments) as S was obtained from exciton chirality method applied to the p-bromo- benzoate esters.24 Another Japanese group reported the synthesis of an ABC ring fragment (73) of ciguatoxin. The starting material was D-glucose, which was converted into 72 in 17 relatively routine steps and thence to the tricyclic 73.25

A synthesis of the BC ring system (76) of ciguatoxin has also been reported starting from methyl a-D-glucopyranoside, Key steps include the diastereoselective epoxidation with MCPBA yielding 74 and a final intramolecular 0- alkylation via tosylate displacement (Scheme 14).26

Reagents: i, DIBAL; ii, TsCI, DMAP; iii, MomCI, DIPEA; iv, D W ; v, NaH, 15crown-5 Scheme 14

Full details of the synthesis of the spiroacetal section of tautomycin (77) have been reported (preliminary report: Vol. 29, p. 369, ref. 33),27 with a second paper by the same group describing the total synthesis (only the spiroacetal section is carbohydrate-derived).28


77

Ireland and co-workers have completed a total synthesis of the immuno- suppressant FK-506,29 the synthesis of a carbohydrate-derived section (78) being described in an adjoining paper (Scheme 1 5).30

OH

78 Reagents: i, MeMgCI, CuBr.SM@; ii, EtSH, H+; iii, TWmsCI; iv, HgC12, CaC03, H20; v, NaBH4;

Scheme 15 vi, Tslm, NaH

Me

CHO

t-Bf 6Bn OBn

79 a0 81

a2

Forsyth's group have completed a total synthesis of okadaic acid from carbohydrate-based starting materials 79 and 80. Complex elaboration of 79 provided spiroketal 81 and 82 was derived from 80 in a multi-step procedure. Convergent coupling of these components (generating the trans-olefin isomer) and further manipulations led to the natural pr~duct .~ '

Carbohydrate epoxide 83 was the starting point for a synthesis of the C-1-C-10 fragment of carbonolide B, in the form of intermediate 84 (Scheme 16), which has already been converted into carbonolide A.32

The supramolecular host systems 86, macrocylic bis-lactams, have been prepared from carbohydrate-derived 85 (Scheme 1 7).33


azl OMe - w 0 a3

i - OH

ii ---t

m o a n ()Me

Reagents: i, CH2=C(Me)CH2MgCI; ii, BH3.SMe then H2&. Scheme 16

)”

C a M e

_.)

CaMe

05 86 n = 3,5 Reagents: i, mN02C6H4CH0, H2SO4; ii, HdPd-C; iii, (COC1)2, iv, HO(CH2CH2)”OH ( n = 2, 3).

Scheme 17

4 Other Oxygen Heterocycles

A series of 3,4- 0-diprotected hexitols 87 (mannitol or glucitol-derived) were converted into 1,2:5,6-bis-epoxides 88 in three steps (6145% yields), by reaction with PPTS and trimethyl orthoformate, then acetyl bromidekriethyl- amine and finally potassium carbonate in methanol. In the case of the mannitol-derived starting material, when the diols were protected as benzyl ethers (R = Bn) the furan 89 (10%) and bicyclic system 90 (24%) were also obtained. [The reaction involves the conversion of intermediate orthoacetals into bromohydrins from the action of AcBr, leading to ring closure to epoxides or alternative pathways for 89 and 903. When the alternatively bis-protected hexitol 91 (from L-ascorbic acid) was exposed to the same sequence, bis- epoxide 92 and furan 93 were obtained. Galactitol-derived 94 gave rise to bis- epoxide 95 (68%).34

Full details have been reported (preliminary report: Vol. 29, p. 376, ref. 52) of iododetherification reactions (with IDCP) of C-6-allylated pyranosides to

24: Synthesis of Enantiornerically

?H

Pure Non-carbohydrate Compounds 357

87 88

RO%o

92

A OBn OBu-t

96

89 90 91

BnO

f CHO ox H

97 OH 98 BnO

OH 99

afford 2,5-dialkyl-3-alkyloxy tetrahydrofurans, by which, for example, 96 is converted into !37.35

The tetrahydrofuran-based oligomer 99, bearing sulfated D-galactoside units (X=S03H), was obtained by olefin metathesis polymerization of 98. The attached starting bicyclic olefin was racemic. 36

The known C-ally1 glycoside lo0 (Nicolaou et al., J. Am. Chem. SOC. 1989, 111, 6682) has been elaborated into allixin (101), providing the first synthesis of this antitumour promoter found in garlic. It is noteworthy that ALL the carbohydrate chiral centres are lost (Scheme 18).37

loo 101 Reagents: i, NaH, Mel; ii, -04, Nal04; iii, PhsPCH2Et1, NaHMDS; iv, SO3.Py, Et3N; v, TMSBr.

Scheme 18


Novel analogues (105) of the antibiotic pseudomonic acid A (106), with the C-9-C-14 unit removed, have been prepared (Scheme 19). The key approach involves elaborating sugar 102 through Wittig reaction, intramolecular conjugate addition and acetal migration, followed by Mitsunobu azidation of 103 to give, after a i d e and ester reduction and selective N- protection, 104.

A further Wittig homologation completes the natural product functionality on the ‘right hand side’. The amino function then provides a common point for reaction with various actived acids, sulfonyl chlorides, isocyanates and aldehydes to afford a range of analogues. Analogue 105 (R=S02(CH2)$1) was the most active compound tested against isoleucyl tRNA synthetase (though about two orders of magnitude less active than the natural product 1061.38

3 iwi .&OH vicix

- __c

i-iii OH

x x 104

- 0 OH

1 02 103

1 05 106 Reagents: i, Ph,P=CHCQH; ii, NaOMe; iii, (MeO)pCM*, H+; iv, PhSP, DEAD, (Ph0)2P(O)N3;

v, LAH; vi, (Boc)zO; vii, TEMPO, NaOCI; viii, (Et0)2P(0)CHzC(O)O(CH2)aCQMe, LiN(Tms)2; ix, TFA.

Scheme 19

D-XylOse is the starting material (providing known 107) for a synthesis of ( -)-trans-kumausyne (110), by way of a stereoselective radical cyclization of 108 to 109 (Scheme 20).39

L-Arabinose-derived 111 provided 112 as the major epimer from ester enolate addition to piperonal, which was elaborated to 113. Subsequent oxidation, Tebbe reaction, osmylation and acetylation led to 114, which was then converted into bicycle 115, which then underwent bromination, Zn- promoted fragmentation and oxidative cleavage to afford 116, (+)- (1 S,2S,5R,6S)- 1 -hydroxysamin (Scheme 2 1).40

The furan 118 was prepared by reaction of 117 with iodine. A mechanism was proposed as shown and 118 was converted further into 119. The related starting material 120 was converted into 121 by treatment with potassium butoxide and then refluxing in benzene?’


CH(SEt)2 I

H V __t

1 07 108 109 110

Scheme 20

Reagents: i, HCCC02Et, NMM; ii, TsOH, MeOH then Phl(Tfa)*; iii, TsCI, py; iv, Bu4NI; v, BySnH, AIBN.

---c

OH

Ill

Ar Ar Ar

HO

mdps/ 114 mdps 115 116 Reagents: i, LDA, piperonal; ii, TbdmsOTf; iii, DIBAL, -78OC; iv, Et3SiH, BF3.Et20.

Scheme 21


A simplified core analogue (124) of zaragozic acid has been prepared starting from 122. Key steps include a diastereoselective vinylation of ketone 123 and subsequeht hydroboration (Scheme 22).42 An intermediate (127) towards another complex natural product, tetrodotoxin, has also been prepared from 1,6-anhydro-~-mannose (125). The key step involved a vinyl radical cyclization of 126 onto a oxime ether (Scheme 23).43

0 OBn

OBn OBn OH

1 22 1 23

OBn OBn OBn OBn 0

124 Reagents: i, NaH, BnBr; ii, 2M H2SO4, AcOH; iii, LiAIH4; iv, TWmsCI, ImH; v, Swern.

Scheme 22

Po ’0 OH - i-v Po 0 O H - vi -0 vii &/NHOMe

NOMe

OH TbdpsO dTWps TbdpsO

Reagents: i, TWpsCI, ImH; ii, H20, AcOH; iii, Bu2SnO; iv, Br2; v, MeONH2; vi, NaH, BrCH2C(Br)=CH2; vii, Bu3SnCI, AIBN, NaCNBH3.

125 126 127

Scheme 23

Asymmetric hydrogenation (chiral ruthenium catalyst) of 128 yielded 129, a precursor towards 130.44

TbdpsO A c o w O B n TbdpsO A C O w OBn

OMe OMe AcO

120 AcO

129

Me

TbdpsO

AcO 130

D-Glucose was converted into both 131 and 132, which were incorporated into analogues of mycalamide A (the natural product contains a 1,2- dihydroxypropyl instead of the C-5 hydroxymethyl group and a geminal

24: Synthesis of Enantiomerically Pure Non-carbohydrate Compounh 361

dimethyl group at C-4) (Scheme 24).45 The azido intermediate was obtained as a mixture of isomers and the derived amine was also a mixture of isomers (the natural product has this centre with R configuration).

TWpsO TWpsO

A m w o B n Bn

OMe OMe AcO

1 28 AcO

129

TWpsO

130 CC24A013

OPiv

OMe 131

AcO

1 32 Reagents: i, Ac20, Py; ii, TMSOTf, HCCCH2Tms; iii, MeOH, K2CO3; iv, PivCI; v, MeOH, 03;

vi, CSA, (CH20)"; vii, AqO, Py; viii, TMSN3, TMSOTf, ix, PdE, H2; x, Me&(OMe)2. Scheme 24

D-Glucose was also the starting material for a synthesis of chiral furo[3,2-c]- [2]benzoxacines 135, via 8-endo-trig radical cyclization of 134. Alkylation of diacetone-D-glucose provides 133, which was converted into 134 by selective deprotection and then elimination using imidazole (Scheme 25).46

Br Br

i,ii L

133 R = H, OMe 134

triphenylphosphine, iodine and

Reagents: i, AcOH; ii, PPh3, 12, ImH, A; iii, Bu3SnH, AIBN, h. Scheme 25

135

Carbohydrate-fused bicyclic crown ethers were also prepared from D-glucose, via the known derivative 136, treatment of which with potassium carbonate and tosylamine yielded 137. Further desulfonylation gave 138. Other analogues were similarly prepared and the products were examined as ch'iral phase-transfer catalysts (see Section 7).47


ph4kiAM* 0

139

137 R = TS 138R=H

6h

An iodoglycosylation of tri- O-acetyl-D-glucal gave 139, which was desilyl- ated then tandem radical cyclized to the tricyclic system

142 ' 14

Reagents: i, toluene, reflux; ii, H+, H20; iii, H+, MeOH; iv, PdC, H2.

Scheme 26

Syntheses of (+)- (142) and (-)-syringolide 1 and ( -)-A7- syringolide 1 have been achieved starting from D-xylose [( -)-enantiomer) or L-xylose, (+)- isomer] via xylulose-derived 141 (Scheme 26).49

5 N- and S-Heterocycles

Full details have been reported of the synthesis of the bicyclic aziridine 143, a component of the azinomycins, from D-glucosamine (preliminary report: Vol. 26).50 A number of syntheses of azetidine and azetidinone-containing compounds have been described. The carbohydrate-fused azetidine 144 (see: Carbohydr. Res., 1997, 299, 253) was converted into polyhydroxylated azetidine 145.51

The 1-oxa-cephems 146 and 147 have been prepared via [2+2] cycloadditions of chlorosulfonyl isocyanate to precursor D-arabinal and L-rhamnal derivatives, as the key step.52 Related work has been reported by the same group, with the conversion of glycal 148 to azetidinone 149, followed by elaboration


143 144 145

Amy.. / OAc

COpMe 146

0 149

147 148

150 151

to 150 (oxidation and Baeyer-Villiger rearrangement) or to 151 (Beckmann- type rearrangement). 53

The same group also described another [2+2] cycloaddition of chlorosul- fonylisocyanate to an enol ether - on this occasion exocyclic as a substituent of 152 - and obtained the azetidinones 153 and thence 154 in four further steps (Scheme 27).54

TbdmsO

i 0

: Me

1 52 153 154

Scheme 27 Reagents: i, ClS02NC0, Na2C03 then Red-AI

D-Glucose was the starting material in a synthesis of (-)-mesembranol (155), which involves Ferrier carbocyclization as a key step (Scheme 28)? The same group have reported full details (preliminary report: Vol. 29, p. 385) of the synthesis of (+)-lactacystin (157) also starting from D-glUCOSe and proceeding via the known branched sugar 156 (Scheme 29).56

L-Arabinose was converted into 2-C-methyl- 1,2,5-trideoxy- 1,5-imino-~- ribitol (159) in nine steps overall via stereospecific reduction of the known


Dglucose - - Ph q0b M o d - i, ii Mom0 - iii, iv oe OMe BzO OMe BzO

OMom OMom OMom

OMe OMe

P O M e

v-viii

- 0 -- OMom

&:H MeH 155

Reagents: i, NBS, BaCO3; ii, DBU; iii, Hg2*; iv, MsCI; v, 3,4dimethoxy-C~H3Li; vi, NaOMe; vii, ImC=S; viii, P(OMe)3.

Scheme 28

NHCOCC13

4-

1 57 Scheme 29 156

alkene 158. In addition, lactose was converted into methyl- 1,3,5-trideoxy-2-C- hydroxymethyl-l,5-imino-~-erythro-pentitol(161) via the known isosaccharinic acid derivative 160 (Scheme 30).57

CH~OTS

y!.!.oB"L iv-vi ~ 6:,oH Me.*+8

CH~OTS OH 158 159

H

&OH

vii. v, viii

160 O# 161

Scheme 30

H 08''' OH

Tso*o - Reagents: i, H2, PdC, NH3; ii, Na, NH3; iii, TsCI, Py; iv, BnNH2; v, H3O+; vi, H2, Pd/C, HCI;

vii, NHs(1); viii, BH3, Me2S.

The 6-deoxy-6-phenyl analogue (163) of isofagomine has been synthesized from dianhydro sugar 152, for inclusion in and isofagmine-based peptide (Scheme 3 1)? a-~-Isosaccharino- 1,4-lactone has been converted into the

24: Synthesis of Enantiomerically Pure Non-carbohydrate Compounth 365

spirocyclic piperidine 164 or into the bridged system 165 and piperidine 166 (Scheme 32).59

CH2NHBn

CH2Ph B0 - ~ i i i HfHZph OBn - iv-vi ,+NcO2But

OBn OH 1 62 OH 163

CH2OH Reagents: i, BnMgCI, NH3; ii, H30t, dioxane; iii, BnNH2, HOAc, NaBHSCN; iv, Na104;

v, H2, Pd/C, HCI; vi, (Bu'OCO)~~. Scheme 31

U

164 165 166 - iii, iv t

Reagents: i, Me2C0, Ht; ii, NaBH4; iii, TsCI, Py; iv, NH2Bz, A.

Scheme 32

Deoxynojirimycin and castanospermine analogues 167 and 168, respectively, have been prepared from 1 -amino- 1 -deoxy-D-glucitol. A preliminary communication has been reviewed previously (Vol. 28, p. 227, refs. 52 and 53). In this current paper, new work describes the cyclization of 169 (R = CH2C02Me) and elaboration to 168 (Scheme 33).60

R I OMe

OH

167 168 OTWms

169

0 ii

---t

R = Me, Ph, OH, NH2 X,Y = H, OH R = H X,Y = 0 R = CHZCO2Me 1

Reagents: i, BrCH2C02Me, K2CO3; ii, KOBu'; iii, 6M HCI; iv, NaBH4. Scheme 33

1 iii,iv 1

168

The a- 1 - C-substituted deoxymannonojirimycin 171 has been prepared from 170, whose synthesis is described in Chapter 18.61

A synthesis of four diastereomers of casuarine (pentahydroxy pyrrolizidines) (e.g. 172) involves reduction of acyclic azido dimesylates with sodium hydrogen telluride (Scheme 34).62

Two syntheses of pyrrolizidines have been reported both using intermolecular nitrone cycloadditions. Thus, 175 was prepared from 2,3-O-isopropylid-


OTbdms OH x~CfJH20Tbdms HOm - H

HO I

CH~OH 171

I - -- '>(o OTWms

I HO

172 Scheme 34

Reagents: i, Te, NaBH4; ii, CF3CQH.

he-P-D-ribofuranose, which was converted to nitrone 173 and underwent cycloaddition with ally1 Tbdms ether to give (after desilylation and mesylation) 174. Further elaboration led to the target (175) (Scheme 35). The oxime 176 was prepared analogously from carbohydrate material and elaborated into 177 (Scheme 36). Phenylselenyl activation of the olefin was in this case a key early step, the selenide being ultimately reduced concomitantly during the late-stage reductive cyclizat ion .63

2,3-CXsopropylidine-&D-ribofuranose

U ?Ms U

iiiiv )(" o,,,, T,,,,,~' N-O vi-viii H O , , , , r O H

Reagents: i, NaI04; ii, NH20H; iii, TbdmsOCH2CH=CH2; iv, TBAF; v, MsCI, Et3N; vi, H2, PdlC;

___c ___t HO~II' N+ CF3CG-

OH

175 CQEt

174

Scheme 35 vii, IAH; viii, TFA, H20.

OMS

HO

SePh 177

OH 176

Reagents: i, Ph3P=CH2; ii, Swem; iii, NH20H; iv, PhSeBr; v, TbdmsOCH2CH=CH2, A; vi, TBAF; vii, MsCI, Et3N; viii, H2, Raney Ni, EtOH; ix, TFA, H20.

Scheme 36


Ribose was the starting material for a synthesis of tacaman indole alkaloid model compound 180, via the derivative 178. The key step is the intramolecular radical conjugate addition of 179, affording 180 as the major isomer (Scheme 37).64

6 1 78

v-viii ___c

x, EtQC J-Yib 0

0 179

ix __t

0 180

Reagents: i, H2SO4, acetone; ii, BnONH2.HCl, Py; iii, LAH; iv, W 0 2 E t phthalimide, Et3N; v, NaI04;

Scheme 37 vi, Ph3P-CHCQEt; vii, NaBH4; viii, PhSH, BF3.0Et2, ix, Bu3SnH, AIBN.

Nagstatin, 181, a glycosidase inhibitor, has been prepared from 2,3,5-tri-0- benzyl-L-ribofuranose, the imidazole component being introduced by addition of 2-lithio-N-trityl imidazole to the starting sugar (Scheme 38).65

BnO OBn

BnO Y O H - rn

Li

rn

OH

BnO

HO

OBn

i-iii ___)

OBn

BnO --+.j/=J" HO

HO NHAc 181 ..

Reagents: i, BnSaCI, Py; ii, AqO, Py; iii, MeONa. Scheme 38

Intramolecular nitrone cycloaddition of 183 (from reaction of 182 with benzylhydroxylamine) afforded the tricyclic system 184. Similar chemistry was also reported for the C-3 epimeric system (D-~~40). When the same


chemistry was carried out using the nitrogen unprotected starting material, the azepinc 185 was formed instead.66 Seven-membered ring formation predominates with analogous ally1 ethers (Vol. 27, pp. 203-204 and Vol. 29, p. 230).

Sulfur-containing indolizidine and pyrrolizidine alkaloid analogues have been prepared starting from pentoses, using either a two-step or a one- step approach. The synthesis is illustrated by the examples in Scheme 39; the two-step approach yielded an equal mixture of diastereomers, whereas the one-step method afforded only the R-ring junction configuration isomer. 67

The D-gluco- and L-ido-N-thiocarbonylazasugars 188 and 187 (R = H) were prepared from carbohydrate starting material 186 (Scheme 40).68

\ I:I mixture ' Reagents: i, HS(CH2)2NH2, MeOH; ii, nBuLi, TsCI; iii, MeONa, HS(CH&NH3+CT

Scheme 39

HO-

H2N- OH

186 t

RO bR RO bR 188 1 87

Reagents: i, CS2, DCC; ii, 9:l TFA: H20; iii, co-evaporate with H20, then IR45 (OH-) resin, GPC. Scheme 40

The novel mannosidase inhibitor (3R)-3-(hydroxymethyl)swainsonine 193 and its (3S)-epimer have been prepared from D-ribose via 189 (Scheme 41). Key steps are Grignard addition and cyclohexylidene acetal protection to generate 190, orthoester Claisen rearrangement to 191, cis-dihydroxylation, lactonization, mesylation and a ide displacement yielding 192, a common intermediate to both 193 (shown) and its 3 - e ~ i m e r . ~ ~


\ c""" 0

N3::0 0 ">(

192 . 1 89 190 191 1 7 s t q s

HO& ,,o" p"

HO

Reagents: i, CH2=CHMgBr; ii, MgCO, H+; iii, MeC(OMe)3, EtC02H. Scheme 41

1 93

The terminal amino acid of nikkomycin B2 has been prepared from the L-gulose-derived oxime 194, via allylation of 195, generating isomers 196 and 197. Elaboration of isomer 1% (R2 = 4-methoxyphenyl) provided the target 199 (Scheme 42).70

194

196

-*o -0

197

Reagents: i, MeOCH(OH)CO#le; ii, R'C(R2)=CHCH20H, TiC14; iii, MO(CO)~; iv, HCI. scheme 42


The C2-symmetric cyclic ureas 203 (R = phenyl, other aryls), targeted as HIV- 1 protease inhibitors, has been prepared via a bidirectional synthetic approach from the L-mannonolactone-derived bis-epoxide 200. The epoxide rings are opened using aryl cuprate derived from 201, followed by Mitsunobu double azide substitution to yield 202 (Scheme 43).7' A very similar sort of approach has been employed in the synthesis of both cyclic sulfamides and ureas 206 and 207 via the bis-azide 205, which was also derived from 204 (Scheme 44).72 This latter method differs from the former in using either phenoxide or Grignard nucleophiles to ring open the starting epoxides.

200

202 203

201 Reagents: i, nBuLi, CuCN, THF; ii, PhsP, DEAD, (Ph0)2PON3.

Scheme 43

y3

CH2Ph N3

205 206 R =a OPh, (CH2)nPh [n = 1,2]

Reagents: i, PhO- or Grignard; ii, Ph3P, DEAD, (Ph0)2PON3. Scheme 44

Syntheses of two diastereomer s of 3 -me thoxy-2-oxa-6- t hia bicyclo[ 3.2.01 - heptan-4-ol from D-XylOSe and of two diastereomers of 3-methoxy-2-oxa-5- thiabicycl0[2.2.l]heptan-7-01 from methyl 5-acetylthio-2- O-mesyl-D-xylofuranoside have been reported.73

Glycal 208 was the starting material for a synthesis of sulfur-containing heterocycles 209, reaction of which with alcohols generating P-glycosides 210. Further reaction with methyl triflate in nitromethane yielded the new heterocycle 212, whilst treatment with Raney Ni yielded 2-deoxyglycosides 211 (Scheme 45). 74

A review on synthesis of both acyclic and heterocyclic natural products from cyclitols [36 refs.] has appeared,75 and a review of free radical cyclizations involving nitrogen includes examples of preparation of aminocyclitols and polycyclic systems.76

24: Synthesis of Enantiomerically Pure Non-carbohydrate Cornpounds 37 1

208

ii "&OR1 RO

/ 211

Reagents: i, R'OH, MeOTf, MeN02; ii, Raney Ni, wet THF; iii, MeOTf, MeNQ. Scheme 45

6 Acyclic Compounds

A convergent total synthesis of (-)-PA-48153C (218) has been reported starting from L-quebrachitol derivative 213, elaboration of which afforded intermediate 214, which was converted into 215 by periodate cleavage, reduction and diol protection. The terminal functionality was then modified by standard means to facilitate a CrC12-mediated homologation, which, after diol release and Mitsunobu-type conversion of the diol to epoxide, gave 216. L-Malic acid was the starting material for the other arm of the convergent synthesis, its completion proceeding via alkylation of the malic acid-derived dithiane 217 with 216. Four more steps completed the synthesis of 218 (Scheme 46).77

\ 213 21 4 215 OTbdms

viii. iv, ix-+ CQ == \

Reagents: i, NaOH, NaOMe; ii, MeAI; iii, RBzCI, DMAP, Py; iv, CSA, MeOH; v, Na104; vi, NaBH4; vii, CSA, acetone; viii, MeCH12, CrC12, THF; ix, Ph3P, DEAD; x, f-BuLi, HMPA then add 216; xi, NCS, AgNO3,2,4,6collidine, MeCN, H20; xii, NaBH(OAc)& xiii, TBAF; xiv, Mn02

21 6

21 7 21 8

Scheme 46

The vinyl ethers 220, derived respectively from D-glucal and D-galactal, have been converted via mesylates 221 into the phytosphingosines 2217*


OH OBn

Bno+oMe

R2 R' 220 R1 = H; R2 = OBn

R1 = OBn; R2 = H

H O T (CH2)lsMe

YH2 w

R 2 R

R' = H; R2 = OH

- -

222 R' = OH; R2 = H

OMe

TbdmsO. A

OAc OBn

221

3r

OTWms

OTbdms BnO

0

OMe

OTWms vii L

OTWms

viii __c

02N o,,

TbdmsO rrns ""OBn

OTbdms 227 228 229

Reagents: i, ArZnCI; ii, EbN, MsCI, then LAH; iii, EhSH, MgBr2; iv, CSA, PhCH(OMe)2; v, HgO, HgCh; vi, t-BuOK, MeN&; vii, Ag20, ultrasound; viii, DMAP, CH2C12.

Scheme 47

An approach to the narciclasine alkaloids, such as pancratastatin, starts from D-glucose derived 223, which underwent arylzinc addition and then mesylation and hydride substitution of the mesylate to give 224. A key step was the Henry reaction of 225 to give 226 as a single diastereomer, which after deprotection and silylation gave 227 (note that Henry reaction on a silylated analogue of 226 lacked stereocontrol). Ultrasound and silver(1) oxide oxidation generated the key acyclic intermediate quinonemethide 228 (hence coverage in this section - see Section 1, Scheme 8 for other pancratistatin work) which on treatment with base underwent cyclization with the anion derived from the methylene carbon a to nitro adding to the quinonemethide to give 229, which has all the stereochemistry of the pancratistatin cyclohexane, except at the aryl bonded centre (Scheme 47).79

24: Synthesis of Enantiornerically Pure Non-carbohydrate Cornpoundr 373

7 Carbohydrates as Chiral Auxiliaries, Reagents and Catalysts

This year has again seen considerable expansion in the application of carbohydrates as chiral auxiliaries, reagents and catalysts and some notable consequen- tial developmen ts.

7.1 drate derivatives as chiral auxiliaries has appeared.80

Carbohydrate-derived Reagents and Auxiliaries - A review on carbohy-

230 R=Me 231 R = B n

232

pivo\ 233

This year two examples of chiral allylations with carbohydrate systems have been reported. The first involves a Lewis acid catalysed allylation of aldehydes using carbohydrate allylsilyl ethers 230 or 231. The best examples involved boron trifluoride as catalyst and heptanal as substrates, but enantioselectivity was modest even in this case, affording products of only 25% and 33% e.e. respectively (S enantiomers predominating).8 The second report features the application of ally1 titanium complex 233 (derived from @glucosyloxy- butadiene 232) to diustereoselective allylations of the (chiral) aldehyde myrtenal and gave exclusively diastereomeric product 234. The use of the a-anomer of 233 led to complementary diastereoselectivity, with 235 predominating. 82

An example of a traditional separation of enantiomers by forming separable covalent carbohydrate-linked diastereomeric mixtures involves iodoetherifica- tion of 236 with racemic azetidinone, followed by elimination, yielding the azetidinone glycoside 237 as a mixture of separable (trans) diastereomers. Glycoside cleavage then led to resolved optically active azetidinones 238 and 239.83

OAc Ph

OAC 236 237 238 239 240

374 Curb0 hydrate Chemistry

La,Ce, Pr, Nd Eu Gd DY Ho Er Yb

Although not an example of a sugar acting as an auxiliary in the traditional sense, a resolution of the chiral pyrrolidine 240 was achieved by co-crystallization with di-O-isopropylidene-~-xylo-hex-2-ulosonic acid (diacetone-2- ke to-L-gulonic acid).84

This year has again seen a range of effective examples of cycloaddition reactions involving one component bearing a sugar auxiliary. The natural lignan U-dimethyl-sugiresinol (244) was prepared via the hetero Diels-Alder reaction of carbohydrate enone 241 and styrene 242 using Eu(fod)3 catalysis, which gave intermediate cycloadduct 243. This was elaborated to the natural product in a further five steps.85

247 -5 18 26 55 61 69 66

OMe I

Q

241 242

OMe

244 "Q OMe

Stoodley's group have again reported further examples of applications of their use of glucose-derived auxiliaries. A further example of cycloaddition chemistry was provided by an investigation of the effect of lanthanide catalysts on the diastereomeric outcome of cycloadditions of sugar-derived aryl aldehyde 245, with diene 246. This work demonstrated a dependence of diastereomeric outcome on the ionic radius of the lanthanide involved. High selectivity (>90% d.e.) for 248 was seen using Ln(fod)3 where Ln = La, Ce, Pr or Nd. The selectivity in favour of 248 decreased with increasing ionic radius, switching to a 55:45 selectivity in favour of diastereomer 247 at Dy (Table 1).86

QCH0 P O T M m s

OR OMe 245 246

R 5 Aco

OAC

w m s OR 0 %OTMms OR 0

- 248 >95 82 74 45 39 31 34 -

Table 1


OAc

%-+ Me 69

86 OEt 67

3 14

Table 2

The same group have reported the diastereoselective epoxidation of a range of enones 249 with dimethyldioxirane, all giving predominantly isomer 250 (over 251) with diastereomeric ratios of 67:33 to 91:9 (Table 2) The dithiane derivatized building block 252 (released from the auxiliary) was also prepared from 250 (R' = R2 = Me); use of dithiane directly led to 82% e.e. product, whereas an indirect route through the mixed acetals 253 (a 9:l mixture) leads to isolated 252 with 98% e.e.87

Kunz and co-workers have reported further applications of hetero cycloadditions of glycosylimines. Glycosylamine 254 was converted to the heterocycle 255 with diastereomeric ratios of at least >20:1 and up to 38:1, through formation of a range of imines and cycloaddition with 1 -methoxy-3-trimethylsiloxybuta- 1,3-diene under zinc chloride catalysis (Scheme 48). These heterocycles were then elaborated in a number of ways. Hydride reduction and acid catalysed auxiliary release gives 256, while hydride reduction followed by desulfurization then auxiliary release gives 257. Diastereoselective conjugate addition of 255 was also employed, giving 258, which could be further modified by desulfurization to 259. The disubstituted piperidine 258 (R = Pr", R' = EEO(CH&) was further elaborated to the bicycle 260 and thence to 261 .88

PivO OPiv Piv& ~~ 0

i,ii NH2 - pivo

PivO !& R

PivO PivO

254 255 R = n-Pr, 3-Py, CPr, 4-CN-Ph Reagents: i, RCHO; ii, 1 -methoxy-3-trimethylsiloxybuta-l,3diene, ZnCI2.

Scheme 48

Cycloaddition of the nitroso-bearing sugar 262 with the diene 263 provides entry to the bicyclic oxazine 264 after release of the auxiliary. This was then elaborated via 265 into the target radiosumin (266).89

One example of a higher cycloaddition has been reported. The carbohydrate-bearing diene 267 underwent a [6 + 41 cycloaddition reaction with


HbJ 7 HN? ':Po *:p 9 R R R R R 256 257 258 259 260 x = o

261 X=H2

R = mPr, 3-pyridyl; R1 = Me, EEO(CH&-, [ O h \ 0

tropone, providing the first example of such a reaction under aqueous conditions. The reaction proceeded under quite mild conditions (50 "C), affording (after and 269.90

acylation) a mixture of the expected exo-diastereomers 268

r O H #/ OH OH OH OH

267 268 269

Two examples of the use of sugar-derived chiral oxazolidinones (see the earlier report, Vol. 29, Chapter 24) for controlling asymmetric reactions have been described. The D-xylose derived system 271 was acylated to give 271 the lithium enolate of which (generated using LHMDS) reacted with various aldehydes leading to 'non-Evans' syn-aldol products, 272.91 The same type of acylated systems 271 (R' = R2 = Me) also underwent diastereoselective acylations and halogenation at the active methine centre, yielding compounds of types 273 and 274.92

The sugar-fused oxazolidinone 275 has been used to control alkylatiod chlorination reactions of a, P-unsaturated systems. Thus, it reacts with ethyl aluminium dichloride and then N-chlorosuccinimide to afford adducts 276, oxidative auxiliary cleavage then providing the chiral a-chloro acids as a 4:l


R3

270 271 272 R1,R2 = Me or H, Ph R3 = H, Me, Et, Ph

R4 = Me, Et, Ph, t-Bu R3 = Me, Et, CPr, Ph

mixture of (2R:3R) and (22235') enantiomers 277 (Scheme 49).93 Benzyl 3,6- anhydro-a-D-glucofuranoside (278) has been used as an auxiliary to control a hydride reduction, as a methodology for synthesis of optically active lactones. Thus, 278 was acylated to give 279, which underwent. diastereoselective reduction with zinc borohydride. Hydrolytic removal of the auxiliary then led to concomitant cyclization to the lactones 280, with e.e. of 82-91Y0.9~

OPiv Go - &N"*. pivobo C02H

0 Et 275 Et 276 277

Reagents: i, Et2AICI; ii, NCS; iii, LiOH, H24. Scheme 49

L-Selectride and lithium aluminium hydride reductions of ketone 281 give >98% diastereosele~tivity.~~ Reaction of 282 (S configuration at sulfur) with methylmagnesium Grignard led to the chiral sulfoxide 283 (R configuration at sulfur). In this sense the carbohydrate is not functioning truly as an auxiliary as it it is not affecting the outcome of generation of new chirality, but is simply a chiral template for an achiral reagent subst i t~t ion.~~

278 279 280 R1 = Ph, Me


Ph

\ / p+

281 Pr' 282 283

The aryl glycoside 284 (from reaction of the naphthoxide with the precursor a-gluco-epoxide; see Chapter 3) was acylated to give enonate 285. Addition of a cuprate to this led to conjugate adduct 286 with the S-configuration at the new chiral centre with >95% selectivity (Scheme 50).97

285 286 Reagents: i, MeCH-CHCOCI; ii, EtMgBr, CuBr, Me2S.

Scheme 50

A tandem reaction of 287 with aromatic aldehyde 288 followed by dimethyl- sulfoxonium methylide [CH2SO(CH3)2] generated adduct 289, by way of nitrone formation between 287 and 288 (concomitant carbohydrate ring closure to activate the N-nucleophile), ylide addition and then phenoxide promoted expulsion of dimethylsulfoxide to yield 289 (Scheme 5 1; major isomer shown). Hydroxylamine 289 was then elaborated post-release of the auxiliary into urea-based 5-lipooxygenase inhibitors 290.98

287 288

An interesting application of a carbohydrate benzylidene auxiliary has been reported. The benzylidene acetal 291 thus formed an aryl chromium complex (292) when treated with chromium hexacarbonyl under standard conditions. Lithiation of this complex then proceeded with high diastereoselectivity and alkylation (with a wide range of electrophiles) and cleavage


i 287+ 288 - -

Reagents: i, CH2SO(Me)2. - oq

Scheme 51

of the acetal yielded the chiral complex 283 with >98% e.e. (Scheme 52).99

E = Tms. Me, BusSn, PhpCOH, SPh, PPh2, ally1 Reagents: i, Cr(C0)e; ii, BuLi; iii, E+; iv, H2SO4, H20.

Scheme 52

An unusual use of a 5-amino-5-deoxy-~-xyloside auxiliary to control the construction of a P-chiral dinucleotide is illustrated in Scheme 53. The auxiliary-bearing derivative 294 thus controls the outcome of the synthesis of 295 from this intermediate.lW Similar work has been reported previously by these workers (Vol. 30, Chapter 20, ref. 202).

TbdmsO \ Thy

P+H

i. ii - % Me

O K N H P h 0

0 I

I OMe

TbdmsO

0 I s- P:

0' '0

OTbdms OKNHPh

294 0 Reagents: i, PC13, Et3N; ii, 5'-QTbdms thymidine, Et3N.

Scheme 53

295

A review has appeared on the preparation of monodeuterated glycerol, chiral deuterated glycines, chiral amino acids and (2R,3S)-3-alkylmalic acids using diacetone-D-glucose as a chiral template.

7.2 Carbohydratederived Catalysts - A review on the applications of phase transfer catalysts in carbohydrate chemistry has appeared, covering anomeric


transformations, glycosylations (see Chapter 3) and the use of sugar derivatives as phase transfer catalysts. lo*

The carbohydrate aza-crown 2% (see Section 4 for synthesis) has been employed as a phase transfer catalyst for asymmetric conjugate addition of nitroalkyl anions. The a-anion of nitroisopropane (generated using sodium tert-butoxide), reacts with chalcone 2 9 in toluene with 7 mol% of catalyst, to give the chiral adduct 298 with 90% e.e, with the S-configuation at the new centre. Other conjugate systems were evaluated but this is the most selective example.47

A study of the electronic tuning in sugar-derived bis-phosphinite ligands (299 and 300) used as catalysts for asymmetric hydrogenations of dehydro- amino acids established that electron-releasing substitutents in the aryl phosphorus substituents leads to higher e.e.s. By use of the information gained enantiomeric purity in excess of 99% was obtained for the reaction shown in Scheme 54. It is notable that ligands 299 led to S amino acids, while the ligand 300 led to R-amino acids (both sugars having the configuration).^^^

- 300

Ph-NHAc - phyH NHAc

C02Me CQMe

(Ligand = 299,300)

Scheme 54 Reagents: i, H2, Rh(ligand)+X-

A significant development reported in full this year is the use of a sugar- derived ketone as a catalyst ligand to effect dioxirane-based asymmetric alkene epoxidation. Although a number of groups have proposed andor evaluated various C2- or pseudo-C2 symmetric ketones (including carbohydrate-based compounds) for this process, this provides the first practically successful example which proceeds with high selectivity. Thus, fructose-derived ketone 301 is an effective agent for the epoxidation of a number of alkenes, using Oxone@ (KHS05) as primary oxidizing agent (Scheme 55) (see also a


preliminary report: J. Am. Chem. SOC, 1997, 62, 2326). As had been proposed by other workers, E-alkenes (or trisubstituted) would be the favoured substrate types from transition state models, to provide a complement to Jacobsen- Katsuki type technology. Styrene was epoxidized to (R,R)-styrene epoxide using 30 mol% catalyst in 75% yield and 97% e.e. (Scheme 55). An evaluation of the pH-dependence and optimization of the catalytic system was re- p ~ r t e d . ' ~ ~ ~ ~ ~

Reagents: i, Oxone, 301. ' 301 Scheme 55

These authors subsequently reported further details and more examples, including some which widened the range of substitution patterns (Scheme 56). They also made the enantiomer of 301 (from L-sorbose) and showed that this gives the same degree of (opposite sense) enantioselectivity as 3O1.lo6

1 2 3 4

5 6

7

8 9

10 11 12

Reagents: i, Oxone, 301.

References

Scheme 56

C. Waldraff, C. Bernet and A. Vasella, Helv. Chim. Acta, 1997,80, 1882. K. Matsuo, M. Morita and K. Kawashima, Chem. Pharm. Bull., 1997,45,1734. A. Roy, R. Patra, B. Achari and S.B. Mandal, Synlett, 1997, 1237. P. de Armas, F. Garcia-Tellado, J.J. Marrero-Tellado and J. Robles, Tetrahedron Lett,, 1997,38, 808 1. J.J.C. Grove and C.W. Holzapfel, Tetrahedron Lett., 1997,38,7429. C L. Marien, E.L. Esmans, F. Lemiere and R.A. Domisse, Synth. Commun., 1997,27,205. A. Guy, T. Durand, J.-P. Vidal and J.-C. Rossi, Tetrahedron Lett., 1997, 38, 1543. S. Jarosz, E. Kozlowska and A. Jerewski, Tetrahedron, 1997,53, 10775. T. Wong, P.D. Wilson, S. Woo and A.G. Fallis, Tetrahedron Lett., 1997, 38, 7045. S. Jarosz, J. Chem. SOC., Perkin Trans. I , 1997. I. Hanna and P. Wlodyka, J. Org. Chem., 1997,62,6985. T. Nishizuka, S. Hirosawa, M. Tsushima, S. Kondo and D. Ikeda, Chem. Lett., 1997,543.

382 Carbo hydra te Chemistry

13 14 15 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

45

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57 58 59 60

61 62

63 64 65 66 67 68

69 70

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72

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75 76 77

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78

79 80 81 82 83 84 85 86

87

88 89 90

91 92 93 94 95 96 97 98

99 100 101

102

103

104 105 106

E. Bettelli, P. Chinzau, P. D’Andrea, P. Passacantille, G. Piancatelli and A. Topai, Korean J. Med. Chem., 1996,6,339 (Chem. Abstr., 1997,126, 157 730). S.R. Angle and T. Wada, Tetrahedron Lett., 1997,38, 7955. P.G. Hultin, M.A. Earle and M. Sudharshan, Tetrahedron, 1997,53, 14823. T.K..M. Shing and L.-H. Li, J. Org. Chem., 1997,62, 1230. D. Felix, J. Szymoniak and C. Moise, Tetrahedron, 1997,53, 16097, B.K. Bank, M.S. Manhas and A.K. Bose, Tetrahedron Lett., 1997,38, 5077. G.P. Roth, M. Emmanuel and L. Tong, Tetrahedron: Asymm., 1997,8, 185. E. Brown, G. Dujardin and M. Maudet, Tetrahedron, 1997,53,9679. R.P.C. Cousins, W.C. Ding, R.G. Pritchard and R.J. Stoodley, Chem. Commun., 1997,2171. G.S. Bhatia, R.F. Lowe, R.G. Pritchard and R.J. Stoodley, Chem. Commun., 1997, 1981. M. Weymann, W. Pfrengle, D. Schollmeyer and H. Kunz, Synthesis, 1997. H. Noguchi, T. Aoyama and T. Shioiri, Tetrahedron Lett., 1997,38,2883. A. Lubineau, G. Bouchain and Y. Queneau, J. Chem. Soc., Perkin Trans, I , 1997, 2863. A. Lutzen and P. Koll, Tetrahedron: Asymm., 1997,8, 1193. A. Lutzen and P. Koll, Tetrahedron: Asymm., 1997,8,29. K. Ruck-Braun, A. Stamm, S. Engel and H. Kunz, J. Org. Chem., 1997,62,967. V. Nair, J. Prabhakaran and T.G. George, Tetrahedron, 1997,53, 1506. K.-Y. KO and J.-Y. Park, Tetrahedron Lett., 1997,38,407. N. Mase, Y. Watanabe, Y. Ueno and T. Toru, J. Org. Chem., 1997,62,7794. C. Chiappe, G. Lo Moro and P. Munforte, Tetrahedron: Asymm., 1997,8,23 1 1, I. Lantos, J. Flisak, L. Liu, R. Matsuoka, W. Mendelson, D. Stevenson, K. Tubman, L. Tucker, W.-Y. Zhang, J. Adams, M. Sosenson, R. Garigipati, K. Erhardt and S. Ross, J. Org. Chem., 1997,62,5385. J.W. Han, S.U. Son and Y.K. Chung, J. Org. Chem., 1997,62,8264. E. Marsault and G. Just, Tetrahedron, 1997,53, 16945. T. Eguchi and K. Kakinuma, Yuki Gosei Kakagu Kyokaishi, 1997,55,814 (Chem. Abstr., 1997,127,262 9 14). R. Roy, Handbook Phase Tranfer Catal., 1997, 244 (Chem. Abstr., 1997, 127, 95457). T.V. Rajanbabu, T.A. Ayers, G.A. Halliday, K.K. You and J.C. Calabrese, J. Org. Chem., 1997,62,6012. Z.-X. Wang and Y. Shi, J. Org. Chem., 1997,62,8622. Z.-X. Wang, Y. Tu, M. Frohn and Y. Shi, J. Org. Chem., 1997,62,2328. Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang and Y. Shi, J. Am. Chem. SOC., 1997, 119, 11224.

Author Index

In this index the number in parenthesis is the Chapter number of the citation and this is followed by h e reference number or numbers of the relevant citations within t h t Chapter.

Abad, J.-L. (20) 265 Abbadi, M. (8) 30 Abbasi, M.M. (20) 32 Abboud, K.A. (22) 39,44,59 Abdel-Megied, A.E.S. (20) 79 Abdel-Rahman, A.A.-H. (20) 29,

Abdmkhmanov, I.B. (20) 36,67,

Abe, H. (4) 56 Abell, A.D. (10) 10 Abell, C. (16)29;(18) 113 Abraham, T.W. (20) 189

Abramski, W. (24) 53 Abrosimov, V.K. (22) 154 Abushanab, E. (20) 44,77 Achari, B. (18) 99; (19) 38; (24) 3 Achiha, T. (4) 89

Achmatowicz, 0. (13) 2; (14) 20;

Adachi, H. (19) 53 A h , E. (23) 30 Adam, J. (24) 98 - Adelson; M.E. '(20) 244 Adhika~i, S. (4) 128 Adinolfi, M. (18) 88 Adiwidjaja, G. (24) 73 Adluri, S. (4) 161 Agianian, B, (22) 45 Agoston, K. (3) 75; (4) 54 Agrawal, H. (20) 24 Agrawal, S. (20) 224 Agrofoglio, L.A. (19) 36; (20) 7,

Aguilera, B. (9) 62; (1 1) 14 Ahn, S.K. (24) 16 Ahn, Y.M. (3) 68 Aimi, N. (16) 30; (22) 100 Ait, H. (20) 99 Ajisaka, K. (3) 179, 185, 190; (4)

58,62

79

68

Abraham, W.-R (7) 53

Achiwa, K. (3) 96, 108; (9) 68-70

(22) 89, 119

101

Ajito, K. (4) 37; (19) 10,l l Akaike, T. (3) 200 Akazawa, N. (18) 41 Akita, H. (18) 5

Al-Abed, Y. (3) 2; (8) 28; (14) 57 Alais, J. (3) 27 Alatgov, D.K. (3) 104; (20) 273 Albersheim, P. (21) 14 Albrecht, W. (16) 63 Alekseyev, V.V. (21) 12 Alemany, L. (18) 104 Alfoldi, J. (10) 18 Allais, D.P. ( 5 ) 8 Allen, J.G. (9) 56

Aktitopo~lo~-zanZa, I. (22) 153

Al-MaSoudi, N.A. (1 1) 23; (20) 16,84

Alonso, I. (3) 252 Alonso, R (10) 56; (14) 24; (24)

Alper, P.B. (9) 21 Altenbach, H.-J. (1 1) 15

43

Al-Timari, U.A. (20) 16 Altmann, K.-H. (20) 254,255 Alvarez-Gonzalez, R (21) 78 Amato, J.A. (9) 34 Ami, E. (24) 26 Amouroux, R. (18) 15

Andersch, P. (7) 25 Andersen, S.M. (18) 55 Anderson, G. (16) 61 Anderson, K.S. (16) 27 Ando, H. (4) 116, 173 Ando, K. (24) 56 Andre, C. (22) 75 Andre, J.C. (9) 52 Andrei, G. (5 ) 21; (19) 45,46;

(22) 138 Aneja, R (18) 158 Aneja, S.G. (18) 158 Angelaud, R. (3) 309; (18) 110,

An, Y .-Z. (20) 28 1

145

Angela Pradera, M. (9) 19; (10) 66; (1 8) 47

Angelini, G. (18) 151 Angle, S.R (24) 79 Angyal, S.J. (2) 41 Animati, F. (21) 57 Anison, F. (19) 51 Anker, D. (4) 50 Ansari, F.L. (3) 2 Ansui, X. (5 ) 20 Antonakis, K. (7) 85 Anufriev, V.P. (3) 161 Anulewicz, R. (21) 36; (22) 92 Anwar, M. (20) 32 Am, N. (3) 95; (16) 44 Aoi, K. (3) 89 Aonuma, M. (3) 217 Aoyagi, M. (4) 204 Aoyama, T. (24) 89 Aoyama, Y. ( 5 ) 11; (7) 96; (16)

Apffel, A. (23) 41 Aplin, R.T. (7) 84; (10) 69 Apostolakis, N.E. (18) 98 Appleman, J.R (20) 70 Aqvist, J. (24) 72 Araake, M. (19) 11 Arai, M. (10) 20 A d , S. (23) 12 Araki, T. (9) 27 Arburton, J.B. (20) 177 Armone, F. (21) 57 Ariente, C. (3) 73 Arihara, S. (7) 51 Arima, S. (3) 117,220 Arimoto, €3. (24) 37 Arisawa, M. (18) 44 Armishaw, O.A. (22) 103 Armstrong, RW. (4) 105 Amau, N. (20) 160 h o l d , F.P. (17) 6 h o l d , L.J., Jr. (20) 229 h o l d , P. (16) 63

15

385

3 86

Amold, W. (6) 20; (9) 59 Amone, A. (8) 17; (14) 17; (17) 5;

Arsequell, G. (4) 36 Artymiuk, P.J. 11) 5 Aruffo, A. (3) 97; (7) 75 Aqa, P. (3) 268 Asaad, A.N. (3) 154 Asahara, T. (3) 96 Asai, A. (3) 292 Asakawa, Y. (7) 93 Asano, M. (7) 93 Asano, N. (3) 136; (18) 43,44,

Asano, S. (24) 37 Asanuma, H. (20) 306 Asensio, J.L. (21) 47,52,69 Ashida, N. (20) 98 Ashley, G.W. (20) 304 Ashry, E.S.H. (20) 2,3 Ashton, P.R (3) 81,84,86, 99;

(4) 195; (22) 63 Assag-Machleidt, I. (4) 238 Astre, C. (23) 22 Atkins, M.B. (20) 229 Attia, A.M. (10) 7; (20) 34 Audette, G.F. (22) 142 Audraq G. (3) 132 Aug6, C. (4) 81 Auriola, S. (23) 42 Avalos, M. (9) 65; (10) 28 Aytrs, F.A. (24) 103 A m , B. (3) 320; (24) 19 Azegami, K. (7) 50 Azctalta, M. (19) 53 h l a y , M. (3) 5% (16) 59 Azucc~~a,.E. (19) 7 Azuma, I. (3) 5

(20) 128

146

Baasov, T. (3) 219; (16) 26,27, 32; (18) 40

Babady-Bila, (1'8) 57; (24) 60 W h o , R (9) 65; (10) 28 Bacchi, C.J. (19) 40,41; (20) 159 Bachard, C. (3) 97; (7) 75; (18)

105; (20) 167 Bacheler, L.T. (24) 71 Bacher, A. (1 8) 39 Back, N.I. (4) 84 Badaksi, F. (9) 13 Bae, H. (24) 16

BEmteli, R (4) 147 Bagp, K. (3) 29 Ba4 M. (7) 52 Baiker, A. (16) 24 Bailly, C. (19) 51

B& N.4. (3) 161

Bairamova, N.E. (3) 22 Baisch, G. (4) 73, 133; (20) 210 Bajoratb, J. (3) 97; (7) 75 Baker, R (22) 14 Bakina, E. (19) 19 Bakker, M.G. (4) 246 Bakb, N. (24) 47 Bakd, P. (5) 24 Balaji, P.V. (21) 62 Balakrishnan, v. (10) 9 Balci, M. (18) 111,129 Ball, RG. (22) 93 Balogh, J. (3) 191 Baltas, M. (16) 12 Baltina, L.A. (3) 62,63,119,120 Balzano, F. (4) 245 Balzarini, J. (19) 20,45,46; (20)

261,267; (22) 137,138 Banaszek, A. (3) 58; (4) 85; (16)

48,55; (19) 29 Bando, M. (3) 132; (18) 77; (22)

101 Bandwar, RP. (17) 18,24,25 Bandyopadhyay, T. (21) 25 Bangerter, F.W. (3) 121; (8) 10 Bank, B.K. (13) 16; (24) 83 Bank, R A . (23) 35 Banner, D. (22) 52 Banoub, J. (22) 36 Banville, J. (3) 97; (7) 75 Banwcll, M.G. (18) 132; (22) 129 Bar, N.C. (18) 99, (20) 282 Baraldi, P.G. (20) 261 Baran, E.J. (17) 20,21 Barber, RA. (16) 43 Barberousse, V. (1 1) 24 Barby A. (14) 4 Barbuch, R (20) 161 Barchi, J.J., Jr. (21) 32,33 Barco, A. (18) 1 Barden, M.C. (18) 2 Barfoed, M. (7) 37 Mi, P.L. (6) 6; (7) 33; (15) 1;

Bark, W.K.C. (4) 90 Barnard, M.J. (7) 46 Barnes, C.L. (20) 119 Barane, G. (18) 88 Baros, F. (9) 52 Barrcsi, F. (4) 26 Bamtt, K.E. (20) 196 Barroa, L.D. (4) 242; (22) 2 Barth, T. (23) 36 W e # , M.G. (20) 75 Bartolozzi, F. (23) 3 Barton, D.H.R (16) 13,37,38 Bhrzu, T. (4) 151

91,92,120,170,185-188,

(18) 63

Cmbohy&ate Chemistry Baskaran, c. (10) 55 BaslwaQ s. (10) 55 Basset-Carpentier, K. (4) 81 Bassi, D. (23) 3 Bassily, R.W. (3) 154 Batley, M. (20) 27 Batta, G. (3) 75; (4) 54; (18) 120,

143; (19) 50 Battistini, L. (20) 66 Baudat, A. (3) 311; (18) 75 h e r , T. (9) 39; (12) 14 -er, H. (19) 37; (20) 156 Bauw, G. (23) 54 Bay, S. (3) 189; (9) 57 Bayko, W.J. (12) 15 Bazin, H.G. (16) 71 Bazzanini, R. (20) 261,267 Beau, J.-M. (3) 260,281,296;

(14) 18; (22) 69 Beaucage, S.L. (20) 213 Beaup&, D. (3) 231; (5) 23; (9)

20; (16) 3,4; (18) 138; (24) 67

Bccher, G. (21) 29

Beck, P.J. (7) 72; (24) 36 Becktr, G. (20) 58 Becucci, T. (18) 54 Beddoes, RL. (18) 128; (22) 130 Bedddcova, M. (14) 23 Bedairski, M. (3) 259 Beekmaq B. (23) 35 Beever, RJ. (23) 51 Begcy, T. (20) 157,266 Behr, J.-B. (18) 52 Bthnnan, E.J. (20) 234 Bthrouzian, B. (21) 15 Beigelman, L. (20) 139,140 Beijer, B. (20) 258,259 Bekker, A.R (7) 61; (8) 27 Bebkhov, V. (3) 219; (16) 32

Bell, A.A. (24) 62 Bell, A.F. (4) 242; (22) 2 Bellini, B. (3) 76 Bellucci, G. (3) 32; (8) 25; (10) 38 Bel'skii, V.K. (7) 61-63; (8) 27 Belton, P.S. (21) 50; (22) 61 Belzccki, C. (24) 52 BeMiller, J.N. (3) 265 Be- M. (1 8) 7 Bencomo, V.V. (3) 48 Bendas, G. (4) 113 Bend& E. (22) 66 Bcndiak, B. (10) 59; (21) 13 Benenson, Y. (16) 26 Benet. L.Z. (23) 29 B e n d , S. (18) 1

Bechthold, A.F.-W. (4) 27; (12) 1

Belin, L. (19) 51

Author I& Bedce, P. (18) 120 Bennett, C. (3) 64; (8) 24; (11) 10 Bennett, S.M. (18) 92 Bennis, K. (24) 59 Benvegnu, T. (3) 4 Benvides, J.M. (22) 8 Bergemann, C. (2) 25; (4) 94; (7)

Berger, M. (7) 25 Berkessel, A. (2) 27; (22) 120 Berlin, Y.A. (20) 271 Be&, M. (1 8) 90 B e d , A. (21) 7 Bernardinelli, G. (22) 118 Bernat, A. (4) 151, 184 Bemet, B. (2) 34; (14) 1; (22) 112,

Bernet, C. (24) 1 Bernlind, C. (4) 123 Berova, N. (22) 153 Bertazza, G. (23) 3 Berthier-Vergnes, 0. (3) 189; (9)

Bertho, J.-N. (16) 75 Berti, G. (15) 1; (18) 63 Bertozzi, C. (3) 259; (4) 43 Besra, G.S. (18) 46 Besson, J. (6) 10 Best, W.M. (3) 282; (8) 9 Bettelli, E. (24) 78 Beyer, U. (19) 22 Bhachech, N. (18) 18 Bhar, D. (11) 2 Bhat, B. (20) 249 Bhatia, G.S. (22) 50; (24) 87 Bha#achajya, A. (24) 66 Bhogte, C.P. (23) 8 Bian, J. (22) 11 Bianco, A. (7) 12; (20) 169 Biberovic, V. (9) 57 Bickle, T.A. (20) 200 Biellmann, J.-F. (20) 40, 109 Biessen, E.A.L. (3) 100 Bilodeau, M.T. (4) 12 Birk, C. (1 1) 16 Birk, R. (3) 253 Bisacchi, G.S. (18) 105; (20) 167 Bischofberger, N. (18) 115; (20)

Bisdena, E. (20) 279 Bitha, P. (18) 18.19 Bizik, F. (21) 35.71 Blackburn, G.M. (20) 154 Blackwell, L.F. (22) 47 Blake, P. (7) 38 Blake, A.J. (18) 168; (22) 126 Blanco, J.M. (20) 170 Blaschke, G. (23) 59

55

116

57

251,272; (22) 127

Blaser, A. (20) 138 Blasko, A. (21) 38 Blaton, N.M. (20) 88, 153 Bleeker, I.P. (16) 65 Blhriot, Y. (2) 13, 14; (22) 53 Blixt, 0. (4) 97 Blommes, M.J.J. (4) 140 Blond, A. (3) 140 Blum, C. (18) 175 Blumberg, P.M. (14) 19 Blumenstein, M. (24) 35 Blunt, J.W. (10) 10 Bobb, R A . (7) 13 Bock, K. (3) 107, 110; (4) 59,99,

Boeycns, J.C.A. (22) 48 Bogachev, V.S. (20) 198 Bogaert, P.M.P. (21) 49 Boggs, J.M. (22) 7 Bogusiak, J. (3) 23 Bogusz, M.J. (23) 28 Bofitt, V. (13) 7; (14) 44,45,47 Bollmsuk, M. (20) 216,226 Bols, M. (5) 25; (9) 23; (10) 70;

(18) 70,71, 139; (19) 9; (24) 57,58

100

B o d y , R. (4) 237; (10) 13 Bond, T.J. (3) 144 Bones, A.M. (1 1) 6 Bonham, N.M. (24) 72 Bonini, C. (7) 42 B o d e , D. (3) 27 Bonomo, R.P. (4) 234 BOOM, G.-J. (3)44,99, 159, 170,

251; (4) 42, 106,109, 165; (20) 21 1

B o r k , A. (6) 19 Borcbardt, RT. (20) 92 Boresov, Y.G. (20) 271 Borges, C. (22) 13 Bornancini, ERN. (4) 212 Bornscheuer, U. (7) 34 Boros, S. (11) 17-20 Borowiecka, J. (1 1) 9 Borowski, E. (19) 13 Borrachero-Moya, P. (3) 3 13 Bonajo, A.M.P. (4) 224 Boryski, J. (20) 313 Boscarato, A. (3) 294 Bosco, M. (4) 82 Bose, A.K. (13) 16; (24) 83 Bosslet, K. (3) 54 Bottka, S. (22) 134 Bouchain, G. (24) 90 Bouchemal-Chibani, N. (21) 8 Bouchez, V. (9) 20; (16) 3,4 Bouchittk, c. (5) 21 Bouchou, A. (3) 6; (7) 17

3 87

Bouchra, M. (7) 94 BouWen, S. (14) $6; (22) 96 Boullanger, P. (3) 79,113,195;

(4) 39; (9) 26; (10) 11 Bouoit, S. (13) 11; (14) 55 Bourhis, P. (4) 163 Bouzide, A. (18) 4; (24) 72 Bovin, N.V. (3) 22, 187; (22) 6 Bowen, B.R (18) 73 Bowers, s. (4) 109 Boyd, S.E. (3) 84,86 Boyer, B. (5) 21 Boyer, S.J. (18) 107; (19).35 Boyka, W.J. (10) 44; (22) 91

Braccini, I. (21) 8 Brade, H. (4) 69 Bradshaw, J.S. (4) 209 Brammer, L.E. (18) 127 BranWd, B.P. (20) 203; (24) 14 Brandi, A. (14) 29; (18) 74 Brandt, K.D. (19) 56 Brauer, D. J. (1 1) 15 Braun, S. (3) 253 Bravdo, B. (3) 253 Bravo, P. (8) 17; (14) 17; (17) 5;

Breithor, M. (14) 39,40; (24) 48 Brennan, P.J. (18) 46 Brereton, I. (18) 137 Btescia, M.-R (13) 20; (14) 34 Breslow, R (4) 241 Bresolle, F. (23) 22 Bretting, H. (23) 6 Brigaud, T. (14) 31; (16) 9 Brimacombe, J.S. (4) 175; (18)

Brimble, M.A. (22) 74 Brimmer, S.P. (22) 26 Brinza, I.M. (18) 87; (24) 76

Broadhurst, M. (4) 158 Broch, H. (21) 54 Brochette, S. (3) 6

Brouillard, R (4) 233 Brown, C.L. (3) 84,86 Brown, D. (14) 42 Brown, E. (24) 85 Brovh, G.S. (21) 70 Brown, J. (22) 3 1 Brown, J.M. (4) 75 Brown, K.C. (21) 26 Brown, P.R (23) 63 Brown, RT. (3) 128; (16) 60 Bruckner, s. (3) 155 Brueggemeier, RW. (10) 9 Brufani, M. (7) 12

Bod, E. (11) 17-20

(20) 128

164

Britz-McKibbh, P. (23) 64

Broennimann, c. (1 6) 24

388

Bruix, M. (21) 52 BruU, L.P. (22) 28 Bruni, P. (22) 12 Brunner, H. (2) 42; (17) 27 Bruno, I.J. (1) 5 Brunow, G. (3) 21 Brusentov, N.A. (19) 20 Brudk, K.S. (18) 150,161, 163 Buchstaller, H.P. (20) 104 BudeSi l j , M. (4) 21 1; (1 1) 7;

Bueno Martinez, M. (18) 38 Buettner, U. (2) 46 Buijsman, RC. (16) 61 Buist, P.H. (21) 15 Bulten-Ponce, V. (3) 140 Bundsschuh, R.M. (9) 25 Bunel, S. (21) 38 Bunton, C.A. (21) 38 Buolamwini, J.K. (21) 32 Burchell, B. (16) 61 Burger, A. (20) 40, 109 Burk, M.J. (3) 287; (9) 56 Burk, N.A.D. (4) 216 Burlart, M.D. (3) 67; (8) 2; (13)

Burkhart, F. (3) 286 Biirli, R. (3) 304,305; (22) 68,71 Burlina, F. (1 9) 34 Burnett, L.A. (17) 16; (22) 124 Bum, M.R (18) 104 Burrell, A.K. (22) 47 Burton, A. (20) 21 1 Buscher, B.A.P. (23) 58,62 Buschmann, J. (18) 8 Bush, K. (18) 18, 19 Bussolari, J.C. (20) 23 Bussolo, V.D. (1 8) 20 Busson, R. (20) 153; (21) 27 Butler, LS. (22) 9 Bystricky, S. (21) 67 Bystrom, C.E. (20) 203

(20) 124

12

Caamano, 0. (20) 170 Caballero, A. (10) 66

Cadet, J. (20) 182 Cafhrena, E.R (2) 38 Cagnolini, C. (3) 320; (24) 19 Cai, B. (21) 74 Cai, J. (9) 67

Cabmm-Escribano, F. (3) 3 13

Ck, M.-S. (3) 8, 12, 131, 171; (4)

Cai, T.-W. (7) 67; (20) 192 2, 118, 167; (20) 33

C a b , A.J. (18) 43 Cairns, P. (22) 42 Calabrese, J.C. (24) 103

Caldeira, M.M. (17) 28,29; (21)

Calvo-Asin, J.A. (3) 243 81

CalVO-FlORS, F.G. (3) 243; (11)

C m M.-J. (20) 120 25; (13) 29

Camerman, N. (22) 147 Cameron, M.A. (13) 27 Campbell, N.F. (23) 45 Campbell, RE. (7) 54 Campio, M. (20) 290 Campos, M. (22) 10 Canada, F.J. (9) 66 Canali, G. (23) 15 Candela, J.I. (10) 43 Cano, F. (3) 252 Cantacuzine, D. (3) 189; (9) 57 Cantrill, S.J. (4) 195; (22) 63

Capaldi, D.C. (20) 296; (22) 139 Capdevila, J.H. (18) 157 Caperelli, C.A. (20) 180 Capkovi, J. (7) 44; (12) 9; (21) 18 Capozzi, G. (1 1) 12; (1 8) 54; (24)

Cappellacci, L. (20) 137; (22) 148 Caputo, R (20) 173 Carcanague, D.R (24) 38 Cardin, C.J. (14) 43 Cardona, F. (14) 29; (18) 74

cao, L. (7) 34

74

Carey, c. (2) 1 carima, L. (4) 234 Carmichael, E. (20) 64 Carmichael, I. (21) 19,20,25 Carofiglio, T. (4) 23 1 Carpenter, A.J. (24) 50 CarpLntero, M. (18) 122 Can, S.F. (20) 235 Carrano, L. (7) 86 Carre, M.C. (9) 52 Carreira, E.M. (9) 28; (13) 14 h l l , H.L. (22) 104 Carroll, P.J. (9) 41 Carsten, M.A. (4) 67 Carter, C.A. (5) 1,2; (12) 19 Carvalho, F. (3) 195 Carver, J.P. (22) 156 Casella, I.G. (23) 13 h i + , G. (20) 66 Casnati, A. (3) 77 Cassady, J.M. (20) 147 Cassel, S. (6) 20; (9) 59; (21) 15 Castellari, C. (9) 5; (18) 61; (20)

Castellino, A.J. (20) 70 Castillon, S. (20) 42,63, 116 Castro, M.J.L. (7) 24 Castro-Palomino, J.C. (3) 216; (4)

39; (22) 141

CarbohHate Chemistry 125; (16) 47

Cataldi, T.RI. (23) 13 Catelani, G. (3) 32; (6) 6; (7) 33;

(15) 1; (18) 63 Catoire, L. (21) 8 Cavalcanti, S. (20) 75 Cavallaro, C.L. (16) 10 Cech, D. (20) 85 Cejka, J. (20) 149; (22) 72 Cellai, L. (18) 151 Centonze, D. (23) 13 Ctrceau, C. (3) 140 Ced, V. (18) 123 Cemy, M. (1 1) 7 Cesaro, A. (3) 155 Cesta, M.C. (18) 151 Cesutti, P. (4) 82 Ceulemans, G. (18) 80 Chaen, H. (4) 248

Chakel, J.A. (23) 41 Chakib, S. (16) 82 Chakrabad, A. (14) 54 Chakraborty, T.K. (18) 67 Chan, H. (1 1) 32

Chan, T.H. (17) 4

Chan, T.Y. (22) 1 Chandler, C.E. (3) 121; (8) 10 Chandor, A.S. (3) 3 12; (12) 3

Chandrasekhar, J. (1 0) 55 Chandrasekhar, S.' (6) 7, 18; (15)

chaix, c. (20) 222

Chan, M.-Y. (20) 105

Chan, T.-M. (19) 54,55

chandrasekaran, s. (1 1) 2

5 Chanet-Ray, J. (9) 18; (24) 5 1 Chang, C.-H. (24) 71 Chang, H.N. (7) 45 Chang, Y.B. (20) 195

174; (21) 43 C h g , Y.-T. (7) 57; (18) 172-

Chao, Q. (20) 164,287 Chao, S.T. (18) 105; (20) 167 Chapleur, Y. (3) 71,308; (18) 103 Chappell, M.D. (4) 77; (16) 31 Charlwood, J. (2) 13, 14; (22) 53 Charpin, P. (22) 64 C~~ITOII, M. (20) 285 Chatgilaloglu, C. (20) 39; (22)

Chattejee, M. (18) 28; (24) 34 Chattopadhyay, A. (2) 4; (10) 40 Chatbpadhyay, P. (22) 54; (24)

Chattopadhyaya, J. (20) 136; (21)

Chaudhuri, N.C. (3) 322 Chavis, C. (7) 88

14 1

46

2 1-24

Author Index Chen, A. (3) 115 Chen, D. (3) 321 Chen, D.D.Y. (23) 64 Chen, F. (20) 90 Chen, G. (22) 139,157 Chen, G.-R (3) 275; (13) 34; (20)

Chen, H. (3) 34 Chen, H.-M. (3) 12, 171 Chen, H.-Y. (23) 60 Chen, J. (3) 315; (18) 180 Chen, J.J. (20) 143 Chen, K. (22) 157 Chen, K.-X. (20) 314 Chen, M. (3) 61 Chen, M.S. (18) 115; (22) 127 Chen, Q. (20) 296 Chep, R. (22) 1 Chen, RH. (19) 56 Chen, R.-T. (4) 223 Chen, R.-X. (19) 14 Chen, S.-H. (20) 64 Chen, T. (22) 157 Chen, W.-H. (4) 235 Chen, X. (20) 194 Chen, X.-T. (4) 101 Chen, Y. (20) 56; (21) 74 Chen, Y.-H. (21) 75 Chen, Y . 4 . (20) 17,18, 195 Chen, Y.-z. (3) 133; (6) 12 Chen, Z. (4) 209; (16) 74; (20) 30

Chenault, H.K. (7) 64; (18) 26 Chihevert, R (2) 11; (7) 11 Cheng, C. (20) 299 Cheng, S. (21) 75 Cheng, Y.-C. (8) 13; (20) 73,76,

Cheon, H . 4 . (24) 39 Cheung, M.-K. (4) 153; (6) 21 Chevalier, Y. (9) 26 Chhabra, R (3) 295; (1 1) 32 Chiapge, C. (3) 30-32; (7) 2; (8)

25; (10) 38; (24) 97 Chiappini, P.L. (3) 198 Chiara, J.L. (18) 90 Chiaroni, A. (3) 296; (22) 69,% Chiba, K. (4) 168 Chibale, K. (5) 22 Chida, N. (24) 55,56,75,77 Chierici, S. (3) 79, 113 Chiffoleau-Gimud, V. (3) 192 Childress, c. (19) 3 Chino, M. (19) 48; (22) 49 Chinzau, P. (24) 78 Chirlian, L.E. (2) 1 Chima, V.Ya. (3) 18 Chittenden, G.J.F. (18) 53

13

Chen, 2.-L. (23) 76

289,291; (22) 136

Chmielewski, M. (9) 32; (10) 53;

Chmurski, K. (4) 242 Cho, S. (3) 55 Cho, S.Y. (3) 293

Choi, G. (18) 173 Choi, K.Y. (18) 173 Choi, 0.-K. (23) 55 Choi, S.-Y. (3) 235 Choi, W. (19) 56 Choi, W.J. (24) 16 Chojnaclci, J. (3) 295 Chong, Y.H. (24) 39 Chopra, D. (2) 44 Chorghade, M.S. (6) 17

Chou, S. (9) 18; (24) 5 1 Choudhury, A.K. (3) 2 18 Chow, J. (3) 212; (8) 3 Choy, A.L. (13) 18 C W e n , F. (3) 71; (18) 103 Chrzczanowicz, I. (10) 49 Chu, C.K. (8) 13; (19) 36; (20) 73,

75,76,146,289,298; (22) 136

(14) 2; (22) 117; (24) 52-54

Cho, Y . 4 . (24) 39

Chou, C.-L. (23) 7 1

Chu, S.-H. (20) 291 Chua, G.-L. (14) 21 Chulia, A.J. (5) 8 Chumakova, RV. (22) 154 Chun, M.W. (14) 19; (20) 286,

298

174; (21) 43 Chung, Y.K. (24) 99 Chupeau, Y. (3) 78 Church, T.J. (21) 19 Cieslak, J. (20) 216 Cintas, P. (9) 65; (10) 28 Cipolla, L. (3) 276,283,291; (9)

Cirelli, A.F. (5) 29; (7) 24; (14) 60 Cirelli, A.T. (8) 29; (13) 19 Cirillo, P.F. (4) 155 Ciullo, L. (16) 17 Ciunik, 2. (4) 85; (8) 26; (22) 55,

Claeys, M. (22) 13 Clardy, J. (17) 9; (22) 110 Classen, B. (24) 72 Classon, B. (20) 168 Clausen, R.P. (5) 25 Clauss, R (18) 37; (24) 64 Clegg,' W. (3) 250; (22) 11 1 Cleland, W.W. (20) 174 Clement, J.J. (19) 56 Cleophax, J. (3) 7; (18) 119 Clive, D.L.J. (2) 22; (13) 30; (20)

Chug, S.-K. (7) 57; (18) 172-

49; (17) 2

90

389 62

Coates, J.A.V. (20) 288 Cobo, J. (10) 8 Coe, D.M. (4) 109 Cogan, D.A. (9) 40 Coggins, J.R (16) 29; (18) 113 Cogliandro, E. (23) 15 Cole, D.T. (9) 41 Cole, R.B. (22) 33 Coleman, R.S. (24) 50

Colloton, P.A. (22) 76 Colonno, R (18) 105; (20) 167 Colquhoun, I.J. (3) 139 Compernolle, F. (18) 57; (24) 60 Compston, C.A. (23) 5 1 Comte, G. (5) 8 Conley, S.R (3) 176; (4) 47 Continho, P.M. (21) 58 Contreras, R (21) 77 Cook, A.F. (20) 71 Cooperwood, J.S. (20) 146 Cordova, A. (7) 28 Cordova, B. (24) 71 Corey, E.J. (18) 10 Cornelius, L. (24) 71 Cornwell, P. (20) 278 Corradini, R. (4) 229,234; (23) 15 Correll, H.L. (8) 8 Cob, J. (20) 160 Cosstick, R (20) 105,253 Costa, M. (9) 47 Costantino, V. (3) 146 Costello, C.E. (4) 154 Cow S. (11) 8 Cotte-Pattat, N. (4) 50 Cou6, A. (16) 75 Coulet, P.R (3) 79 Cousins, R.P.C. (22) 5 1; (24) 86 Cox, B. (3) 320; (24) 19 Cox, P.J. (17) 16; (22) 103, 124 Coxon, B. (21) 55 Craig, D. (3) 272 Cramer, C. J. (2) 2 Crasto, C.F. (2) 29 Crawley, S. (4) 17 Crdpon, P. (4) 151 Creuven, I. (21) 27; (22) 140, 143 Crich, D. (3) 178; (20) 301,302 Crimmins, M.T. (13) 18 Cristaferi, G. (23) 3 cristescu, c. (20) 11 Cntchley, G. (22) 3 1 Crombez-Robert, C. (18) 7 Crone, G.M. (22) 40 Crook, S. (2) 13; (22) 53 Cros, S. (4) 158; (21) 68 Crossman, A. (1 8) 164

Collingwood, S.P. (20) 105

3 90

Crotti, P. (9) 13,48; (18) 20 Cruse, W.B.T. (22) 134 Csanadi, J. (18) 21 Csuk, R (3) 278,316; (13) 28;

(15) 4; (16) 33; (22) 97 Cubero, 1.1. (13) 26 Cucunotta, V. (4) 234 Cuendet, M. (22) 18 Cui, C. (21) 74 Cui, Y. (4) 208 Curley, R.W., Jr. (10) 9 Cunan, T.T. (20) 161 currid, P. (20) 9 Cush, S.B. (13) 27 Cushman, M. (18) 39 Cuzzola, A. (4) 245 Cvak, L. (3) 129 Cvetovich, RJ . (9) 34 Cwik, M. (23) 32 Czech, J. (3) 54 Czemecki, S. (14) 3; (19) 30 Cziria, Z.A.C. (19) 25 Czobor, F. (20) 11

Dabrowski, J. (3) 210 D'ACCOTSO, N.B. (10) 64 Dahl, 0. (20) 217,218 Dahlhoff, W.V. (2) 25; (4) 94; (7)

Dahlman, 0. (4) 159 Dai, G.-Y. (10) 45 Dais R (4) 207 Dais Y. (22) 24 Daily, W.J. (20) 229 d'AIarcao, M. (18) 121 D'Alessandro, F. (4) 234 Daley, L. (9) 10 Dalle, J. (23) 30 D'Ambrosio, S.G. (9) 41 D'hdrea, F. (3) 32; (6) 6; (7) 33;

55

(8) 25; (10) 38; (15) 1; (18) 63; (24) 78

Dangles, 0. (4) 233 Danielson, U.H. (24) 72 Danishefsky, S.J. (4) 12,60,72,

Danzin, C. (18) 62 DaRe, J. (20) 70 Daris, J.P. (18) 105; (20) 167 Darvill, A.G. (21) 14 Das, P.R (19) 54 Das,T. (18) 118 Dasser, M. (2) 11 Dauban, P. (9) 11,12 Daubresse, N. (3) 78 DAuria, M.V. (9) 2; (14) 14 Dauvergne, J. (20) 40

101, 155,161,183

Davey, M.W. (23) 54 David, S. (1) 13 Davis, F.A. (8) 5 Davison, B.E. (9) 67 Davydova, V.A. (3) 63 Dawson, M.J. (16) 39 Dax, K. (3) 175 Dealler, S. (18) 43 De Angelis, F. (6) 2; (7) 89 de Armas, P. (24) 4 Debart, F. (20) 233 Debenham, J.S. (3) 287; (4) 136;

(9) 50,51 Debenham, S.D. (3) 287; (9) 5 1 De Bie, E. (23) 30 Debitus, C. (3) 140; (9) 2; (14) 14 De Bruyn, A. (20) 88, 153; (21)

Debusschere, L. (23) 67 De Clercq, E. ( 5 ) 21; (10) 4,8;

77

(18) 27; (19) 20,39,45,46;

188,261,267,295; (22) 137, 138

(20) 20,91,92, 120, 170, 185-

D ~ o u ~ , J.-L. (20) 94, 184 Defaye, J. (4) 242; (10) 35 Defoin, A. (9) 43; (18) 50,51 Degiorgis, F. (9) 4; (18) 83 de Hoffmann, E. (22) 34 Dekany, G. (4) 130, 143; (10) 24 De Keukeliere, D. (20) 88, 153 Dekker, M. (16) 61 de Kort, M. (3) 172; (19) 26 de la Fuente, C. (7) 84; (10) 32,

33,69 Delage, C. (5) 8 Delbaere, L.T.J. (21) 26 de Lederkremer, RM. (10) 26,27 Delia, TJ. (20) 25 Delic, V. (16) 56 Della Rocca, A. (3) 45 Deloisy, S. (10) 39; (14) 27 Demailly, G. (2) 24; (3) 318,319;

Demchenko, A.V. (3) 163,170;

De Mesmaeker, A. (20) 245-247 Demesmay, C. (23) 67 De Montis, A. (20) 137; (22) 148 Den& L. (1 8) 79 DeNinno, M.P. (3) 121, 165; (8)

Denisov, V.M. (7) 27 Denkova, P.S. (3) 104; (20) 273 Depew, W.T. (3) 82,93; (20) 193 Depezay, J.-C. (1 1) 28 De Raadt, A. (18) 31 De Ranao. C. (22) 64

(18) 7

(4) 165

10

Carboh@ate Chemistry De Rensis, F. (6) 6; (15) 1; (18)

De Risi, C. (18) 1 DeRoose, F. (4) 17 1 Dcrvan, P.B. (18) 108 Desai, V.N. (9) 5 ; (18) 61,64 Desaubry, L. (20) 204 Deschenaux, R. (22) 66 Descotes, G. (3) 6; (7) 17 Desgagnb, J. (7) 11 DeSbong, P. (13) 20; (14) 34 Deshpande, P.P. (4) 183 DeSimone, G. (22) 66 Desimoni, E. (23) 13 Wid, J. (18) 96 Desjardin, M. (7) 11; (18) 127 Deslongchamps, P. (21) 34 De Smedt, I. (23) 30 Desruet, M.-D. (6) 11 Destabel, C. (18) 90 Detellier, C. (17) 30 Devarajan, P.V. (23) 8 de Vroom, E. (7) 60 de Wit, D. (21) 49 Deyl, Z. (23) 68 Dhavale, D.D. (9) 5 ; (18) 61.64 Dihez, M.J. (22) 80 Diaz, G. (22) 10 Diaz, M. (20) 163 Diaz, RR (13) 26 Diaz, Y. (20) 42.63 Diaz Arribas, J.C. (9) 66 Diaz Perez, V.M. (9) 63,64,66;

DiBlasio, B. (22) 66 Di Bussolo, V. (9) 48 Dickinson. RP. (3) 44 Diele, S. (3) 248; (8) 4 Dietrich, H.-J. (14) 15 Dijkstra, B.W. (22) 67 Dimichele, L. (9) 34 Dimock, S. (20) 249 Ding, H. (22) 144 Ding, P.Y. (4) 118 Ding, W.C. (22) 51; (24) 86 Ding, X, ( 5 ) 13,17 Ding,Y. (20) 17, 18, 195 Dinya, 2. (10) 31; (19) 50 Dio4 S. (3) 268 Di StefBno, C. (23) 38 Diwu, 2. (16) 58 Dixon, R. (20) 70 Djurendic, E.A. (2) 8; (5 ) 30; (18)

Dodd, R.H. (9) 11, 12 Dodge, J.A. (3) 55 Doe, M. (17) 23; (22) 121

63

(10) 47.48; (24) 68

21

- . . ~ Dk, K.H. (13) 4; (17) 12-14;

Author Index

Doi, M. (17) 31 Doi, Y. (3) 42 Doisneau, G. (3) 296; (22) 69 Dolata, D.P. (21) 42 Dolphin, D. (3) 212; (8) 3 Dome, T. (3) 273 Domann, S. (16) 63 Dombi, K.L. (5) 16 Dominguez-Aciego, RM. (20)

Domisse, RA. (24) 6 Domon, B. (22) 34 Donaldson, W.A. (17) 11 Dondoni, A. (2) 20; (3) 77,180,

181,294,302; (16) 68; (19) 32

(22) 122

150

Dong, I. (3) 19 Dongowski, G. (23) 10 Donohoe, T.J. (18) 128; (22) 130 Dordick, J.S. (7) 45 Dory, Y.L. (21) 34 Dosbaa, I. (1 1) 28; (1 8) 50 Doss, G.A. (22) 93 Dossena, A. (4) 229 Dostaler, S.M. (4) 224 Doubek, D.L. (3) 144 Doucet, J.-P. (14) 4 Douglas, M. (20) 258,259 Douglas, N.L. (4) 153 Douglas, W.L. (6) 21 Doutheau, A. (4) 50 Dovichi, N.J. (23) 5 1 Dowd, M.K. (21) 10,58 Doyle, T.W. (20) 64 Drach, J.C. (20) 19,21,22,57,

Drake, C.S. (16) 39 Dramicanin, T. (16) 5 Dreef-Tromp, C.M. (4) 187 Dreisbusch, C.M. (9) 25 Drescher, M. (20) 152 Dreux, M. (23) 47 Drew, K. (21) 20 Drew, M.G.B. (14) 42 Driessen, S. (23) 28 Driguez, H. (4) 28,44, 160; (1 1)

Driguez, P.A. (4) 152; (22) 70 Drouillard, S. (4) 44 Drouillat, B. (3) 10; (10) 24 D'Souza, F.W. (16) 26 Du, J. (20) 146,289, 298 Du, M. (4) 103; (10) 71 Du, S. (16) 32; (18) 40 Dua, G. (3) 29 Dubber, M. (3) 74 Dubois, E.P. (3) 162; (4) 148; (22)

81, 141

8,31,35

57 Du Bois, J. (9) 28; (13) 14 Dubreuil, D. (18) 119

Duchaussoy, P. (4) 151, 163, 184 Duchene, D. (22) 38 Duhamet, J. (2) 10 Dujardin, G. (3) 266; (24) 85 Dulina, R (3) 115 Dullweber, U. (2) 33 Duman, Y. (16) 77 du Mortier, C.M. (14) 60 Dunlap, S.E. (20) 114 Dupeyroux, H. (3) 308 Duplantier, K.C. (3) 121; (8) 10 Duque, C. (3) 92 Dunin, C.J. (9) 65; (10) 28 Durand, R (2) 10 Durand, T. (24) 7 Durant, F. (21) 27; (22) 140, 143 Durier, V. (21) 4 Duthaler, RO. (3) 246 Dutta, A.S. (3) 102 Duus, J.O. (3) 107 Duynstee, H.I. (7) 60 Dworkin, J.P. (20) 135

DUMP, J.-B. (18) 62

Earle, M.A. (4) 76; (24) 80 Easton, C.J. (4) 226 Ebner, M. (3) 175; (18) 31,55 Eckhardt, E. (3) 199; (4) 55 Eckhardt, M. (4) 60 Eckstein, F. (20) 201 Edmonds, J.S. (17) 10; (18) 9 Edwards, J. (8) 16; (9) 38 Edwards, P.J. (18) 124 Efimtseva, E.V. (3) 223; (20) 280;

(22) 150 Egan, W. (21) 71 Eguchi, S. (22) 99 Eguchi, T. (14) 7; (24) 20, 101 Egusa, K. (4) 5 Ehlenz, R. (13) 4; (17) 12,13 Ehrhard, A. (1 8) 62 Eichler, E. (4) 129 Eisele, T. (4) 107; (1 1) 33,34 Eisenhardt, S. (20) 225 Eijiyar, S. (18) 15 Ekelof, K. (4) 9 Ekhart, C.W. (18) 31,55 Ektova, L.V. (20) 93 El-Ashry, E.S.H. (20) 31 El-Badry, S.M. (10) 63 El Barbary, A.A. (20) 89 Elbein, A.D. (3) 184; (18) 72; (24)

El-Brollosy, R (20) 89 62

391

El-Eter, K.A.A. (20) 147 Eleuteri, A. (20) 296; (22) 139 ElfBkir, C. (23) 24 Elgemeie, G.H. (10) 7; (20) 34

El Kilany, Y. (20) 2,3

Eller, C. (3) 121; (8) 10 Ellervic, U. (7) 14 Elling, L. (3) 152; (4) 24 Ellis, G. (9) 53 Elmouchir, M. (3) 296; (22) 69 El Nemr, A. (7) 81,82; (13) 23,

Elofson, M. (3) 215 El Rassi, 2. (23) 56

Elvebak, L.E., I1 (5) 6,7 Emmanuel, M. (24) 84 Endo, M. (4) 123 Endo, T. (3) 229; (4) 199,200 Eneyskaya, E.V. (3) 49 Engberts, J.B.F.N. (3) 247 Engel, S. (24) 93 Engelbrecht, G.J. (14) 52; (22) 48 Engels, J.W. (20) 225,228; (21)

Engelsen, S.B. (21) 3,48 Erbeck, S. (9) 74 E r h d t , K. (24) 98 Erikson-Viitanen, S. (24) 71 Eriksson, L. (22) 58 Eriksson, S. (20) 65 Erion, M.D. (20) 70,144 Eritja, R. (20) 258,259 Erkens, M. (23) 28 Ermolenko, M.S. (24) 13 Emholt, B.V. (10) 70 Emst, B. (3) 246; (4) 96,140,147 Escher, S. (3) 27 Escondar, G.M. (1 7) 22 Escudier, J.-M. (16) 12 Esmans, E.L. (23) 43; (24) 6 Esnault, J. (3) 297; (7) 66; (9) 29 Espinosa, J.F. (21) 47,52 Essigmann, J.M. (20) 274 Este, J. (5) 21 Estevez, J.C. (6) 3; (10) 41; (16)

Estmda, M.D. (22) 80 Estramareix, B. (1) 13 Esumi, Y. (4) 170 Etcheveny, S.B. (17) 20,21 Ethell, B. (16) 61 Etienne, J.B. (3) 121; (8) 10 Evangelatos, G.P. (5) 18 Evans, C.A. (20) 285 Evdokimov, A.G. (22) 46

El-Kattan, Y.A. (20) 10; (22) 145

El-Laghdach, A. (20) 42,63

24

El-Sokkary, R.I. (3) 154

76

73

3 92 Everitt, S.R.L. (3) 81 Evers, B. (4) 189; (12) 6 Evina, C.M. (18) 52 Evrard, C. (22) 140,143 Ewing, D.F. (3) 28; (10) 17; (16)

Exposito-Lopez, J.M. (3) 243 Ezzitouni, A. (18) 106; (20) 165,

75

166

Fabbro, D. (1 9) 5 1 Fabricius, J. (21) 3

Fairhurst, R A . (20) 105 Falcini, P. (6) 6 Falck, J.R (18) 156, 157, 176 Falk, M. (16) 79 Fa&, N. (3) 233 Fallis, A.G. (18) 87; (24) 9,76 Fan, B.T. (14) 4

Fang, X.M. (23) 48 Fang, Y.Z. (23) 48 Fanton, E. (6) 9 Fmj , A. (20) 91; (22) 137 Farda, A.M. (22) 15 Fa~ines, M. (7) 38 Farkas, E. (3) 48; (9) 6 Farquhar, D. (3) 53; (16) 64; (19)

Farrant, E. (14) 41; (22) 95 Fathi, R (20) 71 Fathy, N.M. (20) 34 Fatima, A. (3) 2 Fattorusso, E. (3) 146 Faul, M.M. (20) 114 Faure, A. (19) 34 Faury, P. (20) 290 Favero, L. (9) 13,48; (18) 20 Favretto, D. (22) 15 Fayet, C. (6) 9, 10 Fearon, K.L. (20) 23 1,232 Fedorov, 1.1. (20) 91; (22) 137 Feiling, E. (21) 29 Feiters, M.C. (4) 240 Felix, C. (4) 237; (10) 13 Felix, D. (24) 82 Felix, V. (21) 50; (22) 61 Feng, R. (3) 13 1 Fenical, W. (3) 138 Fenick, D.J. (19) 18 Ferguson, M.A.J. (4) 175; (18)

Fernandez, F. (20) 170 Femhdez-Bolaiios, J. (1 1) 21 Fehdez-Bolaiios, J.G. (1 1) 2 1 Fernandez Cirelli, A. (5) 29; (7)

Fahmi, N.-E. (20) 99

Fan, J.-Q. (3) 264; (10) 22

19

164

24; (14) 60 Fernandez-Mayoralas, A. (3) 36,

252; (7) 26; (9) 62; (1 1) 14; (18) 122

Ferreira, MA. (22) 13 Fem, M. (3) 320; (24) 19 Femer, D. (22) 38 Femer, R.J. (1) 15 Femeres, V. (3) 11 Fems, J.P. (20) 181 Ferro, D.R. (21) 5 Ferro, S. (4) 82 Ferro, V. (3) 107,282 Ferroni, R. (20) 267 Festanov, A.V. (22) 6 Fettes, K.J. (20) 248 Field, R.A. (3) 188; (4) 75; (7) 3;

Finch, P. (3) 197 Findeisen, M. (19) 57,58 Finner, J. (3) 83 Fischer, A. (7) 34 Fischer, S. (23) 41 Fisher, J. (20) 105 F h o , M.R (6) 1 Flaherty, T.M. (3) 227; (1 1) 3 Fleet, G.W.J. (2) 13, 14; (6) 3;

(8) 20

(10) 32,33,41,69; (16) 73; (18) 43,46; (22) 53; (24) 62

Flekhter, O.B. (3) 62,63, 119, 120 Flisak, J. (24) 98 Flitsch, S.L. (4) 64; (7) 80 Florent, J . 4 . (3) 54,57; (16) 59 Flugge, L.A. (9) 61

Fogelqvist, E. (23) 23 Foglietti, M.-J. (1 1) 28; (18) 50 Foldesi, A. (21) 23 Fomitchcva, M.V. (3) 223; (20)

Fontecave, M. (20) 94, 184 Foote, R.S. (20) 278 Ford, H., Jr. (23) 37 Forgo, P. (21) 56 Fornasier, R (4) 231 Forney, RW. (5) 2 Forsyth, C. J. (24) 3 1 Fortt, S.M. (20) 239 Fortunato, S.R (4) 125 Foulard, G. (14) 31; (16) 9 Foulds, G.J. (10) 10

Fox, K.F. (23) 14 Foxall, C. (4) 90 Foy, M.F. (20) 232 Franchetti, P. (20) 137; (22) 148 Francisco, C.G. (15) 6; (16) 57;

FOC~S-FOC~S, C. (3) 252

280

FOUIXY, J.-L. (19) 34

(18) 45

Carbohydrare Chemistry Franck, RW. (3) 65 Francl, M.M. (2) 1 Fmco, S. (10) 52; (19) 30,32;

Franach, C. (3) 78 Frank, S.A. (20) 114 Franz, A.H. (13) 5; (14) 33 Frappa, I. (2) 23; (3) 183,262;

(13) 1,21 Fraser-Reid, B. (3) 205; (4) 13,

48, 87, 136; (9) 50.51 Frkhou, C. (2) 24; (3) 318,3 19;

Frederickson, M. (10) 54 Frediani, J.E. (20) 232 Freeman, S. (18) 168; (22) 126 Freire, R (1 8) 45 French, A.D. (2) 2; (21) 10 Friant-Michel, P. (21) 46 Fner, C. (20) 184 Friestad, G.K. (24) 14 Frigerio, M. (8) 17; (14) 17; (17)

5; (20) 128 Frische, K. (24) 33 Fnth, J. (23) 42 Fritsch, V. (20) 246,247 Fritz, J.E. (20) 113, 114 Frohn, M. (24) 105,106 Frolik, C.A. (3) 55 Frolow. F. (22) 46 Frost, D. (19) 56 Frost, J.W. (18) 114 Frutos, A.A. (17) 22 Fnrzinski, A. (22) 89 Fu, G.C. (12) 13; (18) 17 Fu, H. (20) 190

Fu, R (4) 207 Fuchs, B. (24) 33 Fuchss, T. (1 8) 59 Fuentes, J. (4) 119; (9) 19,63,64,

66; (10) 47,48,66; (11) 21; (18) 47; (21) 73; (24) 68

(22) a4

(18) 7

Fu, H.-X. (22) 108

Fuglsang, C.C. (7) 36

Fujii, J. (17) 23; (22) 121 Fujikura, T. (7) 29 Fujimoto, H. (3) 179, 186, 190,

193; (4) 58,62 Fujimoto, T. (16) 15 Fujita, K. (4) 196, 197,205,232;

(24) 45 Fujita, M. (7) 93 Fujita, R (4) 235 Fujita, S. (3) 46, 196,239 Fujitaki, J.M. (20) 70 Fujiwara, K. (24) 25 Fukase, K. (3) 204; (4) 5

Fuhrhop, J.-H. (22) 75

Author Index Fukase, R. (4) 123 Fukazawa, Y. (21) 44 Fukuda, E.K. (23) 25 Fukuda, S. (4) 248 Fukui, H. (24) 45 Fukuyasu, H. (19) 53 Fume, K. (3) 203 Furman, B. (24) 54 Fumeaux, RH. (18) 49; (22) 98 Furuhata, K. (3) 239; (6) 4,5; (9)

Furusawa, M. (23) 16 Fuselli, N. (18) 22 Fuzier, M. (1 1) 28 Fuzzati, N. (23) 26

35; (10) 50; (16) 19,52-54

Gabriel, J. (23) 68 Gadelle, A. (10) 35 Gadikota, RR. (3) 103; (24) 21 Giirtner, P. (3) 270; (13) 3 Gaetani, E. (20) 66 Gafkey, B.L. (20) 265 Gaf3%ey, P.RJ. (18) 159 Gainsford, G.J. (22) 98

Galavema, G. (4) 229 Galbis, J.A. (18) 38 Galdecka, E. (22) 89 Galdecki, 2. (22) 89 Galdiero, S. (22) 66 Galema, S.A. (3) 247 Gallagher, T. (3) 260 Gallego, P. (18) 90 Mi-Stampino, L. (4) 100 Gallos, J.K. (18) 98, 101 Galtuso,.G. (4) 195 Gambert, U. (3) 48,106 Gan, L. (5) 20 Ganellin, C.R (9) 67 Gange, D.M. (2) 1 Ganguly, A.K. (19) 54,55 Gani, D. (18) 181; (21) 78 Gao, Y. (10) 45 Garai, S. (9) 1 Garbex, S. (24) 71 Garcia, B.A. (3) 26 Garcia, C.D. (20) 229 Garcia, F. (1 1) 1 Garcia, RG. (20) 259 Garcia, S. (11) 21 Garcia Conesa, M.T. (3) 139 Garcia FernBndez, J.M. (9) 63,64,

66; (10) 35,47,48; (24) 68 Garcia-Lopez, J.J. (3) 243 Garcia-Mendoza, P. (1 1) 25; (13)

Garcia-Tellado, F. (24) 4

Galateo, c. (4) 93

29

Garden, S.J. (17) 15

Garegg, P.J. (3) 112; (4) 8,9, 127; (7) 20; (18) 165

Garigipati, R (24) 98 Gasparutto, D. (20) 182 Gataullin, RR (20) 36,67,68 Gathrso, G. (4) 194,244; (22) 62,

Gautham, N. (22) 131,132 Gavira, J.M. (22) 10 Ge, M. (1) 10; (4) 45 Ge, P. (16) 84; (20) 317 Gebhardt, R (3) 129 Gehring, A.M. (5) 2 Gelas, J. (6) 9, 10; (7) 94; (9) 18;

(24) 5 1,59 Geldart, S.E. (23) 63 Gelhausen, M. (3) 113 Gelin, M. (3) 4, 11 Gelo-Pujic, M. (3) 40,43 Genet, J.-P. (3) 266 Gennari, G. (4) 231 George, K.S. (20) 158 George, T.G. (24) 94 Geremia, R.A. (4) 44 Gerken, M. (3) 54 Gerly, J.A. (16) 16 Gero, S.D. (18) 119 Gemm, F. (2) 46 Gervay, J. (3) 227,228; (8) 21,

22; (11) 3; (12) 10; (16) 20, 43,49; (21) 42

Genvick, W.H. (5) 4,5 W i n , D.M. (19) 31 Geurtsen, R. (3) 159 Gewehr, M. (3) 166 Geyer, A. (4) 113 Geysen, H.M. (4) 48,87 Ghiselba, 0. (20) 207 Ghosh, A.K. (3) 53; (16) 64 Ghosh, S. (22) 54; (24) 46 Gi, H.-J. (20) 293 Gibbons, W.A. (22) 66 Gibson, R.R (3) 44 Giegrich, H. (20) 278 Giese, B. (20) 102,108,200 Gigg, J. (18) 134 Gigg, R. (18) 134 Gil, A.M. (21) 50; (22) 61 Gil, V.M.S. (17) 28,29; (21) 81 Gilbert, E.J. (10) 3 Gilbert, LH. (1 8) 154; (20) 275 Gilbert, N.E. (10) 9 Gildersleeve, J. (1) 10; (4) 45 Gilmour, S.G. (4) 16,46 Gimisis, T. (20) 39; (22) 141 Gin, D.Y. (3) 26

Gareau, Y. (7) 7

63,65

393

Giordani, E. (9) 47 Girard, F. (20) 101 Giuliano, R.M. (10) 44; (12) 15;

Giulieri, F. (7) 65 Givens, R.S. (20) 205 Glahov, I.R. (3) 298 Glahova, P.I. (3) 298 Glasebrook, A.L. (3) 55 Glaudemans, C.P.J. (21) 55 Gleason, J.L. (24) 29 Gleet, G.W.J. (7) 84 G~CMOII, D. (22) 1 Glennon, T.M. (21) 2 Glick, G.D. (20) 260 Glombitza, K.-W. (16) 79 Glucker, J.P. (22) 104 Glusker, J.P. (8) 8 G d , P. (18) 6 Godskesen, M. (18) 65 Goebel, M. (16) 7 Goethals, G. (3) 230; (18) 6; (20)

Goggin, K.D. (3) 122 Gola, J. (3) 275; (13) 34 Goldberg, R.N. (4) 247 Goldstein, B.M. (20) 137,235,

236; (22) 148 Golender, L. (24) 33 Golic, L. (10) 62 Golovinsky, E.V. (3) 104; (20)

Golubev, A.M. (3) 49 Mrnez, A.M. (18) 97 Gomez, G. (20) 170 Gomez-Guillen, M. (3) 3 13 Gomez-Lopez, M. (3) 8 1 Gomi, N. (9) 69 Gonada, R (22) 56 Gonda, J. (14) 23 Gong, F.Y. (23) 48 Gong, K.W. (3) 269 Godlez , C.C. (15) 6; (16) 57;

Gonzalez, G.I. (3) 127 Goodby, J.W. (3) 28; (10) 17; (16)

Goodman, B.K. (20) 305 Goodman, S.N. (14) 16 Goodnow, R.A. (20) 132,257 Gorey-Feret, L.J. (24) 71 Gorin, B.I. (4) 224,227 Gomchon, L. (16) 12 Gosselin, G. (3) 244; (20) 65,91;

Gotanda, K. (3) 279 Goti, A. (14) 29; (18) 74 Gotlieb, K.F. (16) 65

(22) 91

99

273

(18) 45

75; (18) 6

(22) 137

394 Goto, K. (16) 62 Goto, M. (23) 75 Goudgaon, N.A. (20) 10; (22) 145 Goueth, P.Y. (3) 230; (22) 36 Gould, J.H.M. (20) 115 Gourlain, T. (3) 23 1; (5 ) 23 Gourvenec, F. (4) 15 1 Goux, C. (13) 11; (14) 55 Gozzi, C. (18) 20 Graber, L. (4) 161 Gradnig, G. (1 8) 55 Griife, U. (9) 3; (19) 16 Graille, J. (7) 38 Grancharov, K. (20) 273 Grand, E. (3) 307 Grandel, R. (18) 82 Grandjean, C. (4) 50 Granier, T. (10) 68; (22) 82 Grapsas, I. (19) 7 Gravett, D.M. (4) 216 Gray, C.J. (3) 102 Gray, E.A. ( 5 ) 1,2 Gray, G.A. (12) 19 Gray, G.R (3) 68; ( 5 ) 6,7 Greenberg, M.M. (20) 305 Greenberg, W.A. (18) 108 Greenwald, M. (24) 33 Gregar,T.Q. (12) 10; (16) 20 Gregoriou, M. (10) 32,33 Grenier, J. (7) 65 Grewal,RK.(18)46 Grice, P. (4) 180; (6) 13 Gridley, J.J. (7) 31 Griengl, H. (18) 109; (19) 37; (20)

Griesinger, C. (21) 76 GrifBntini, M. (20) 137; (22) 148 Griffith, O.H. (18) 166,167 Griffths, R.C. (3) 136; (7) 84;

(10) 69; (18) 43,46 Griffiths, S.L. (3) 205 Grigera, J.R (2) 38 Grigo, G. (3) 32 Grindley, T.B. (1) 6; (7) 23 Grishkun, E.V. (17) 19 Gronowitz, S. (20) 53 Grootenhuis, P.D.J. (4) 172 Gross, P.H. (13) 5; (14) 33 Grosse, P.V. (23) 22 Grothus, M. (3) 152 Grotli, M. (20) 258,259 Grovb, J.J.C. (18) 89,93; (24) 5 Groves, S.J.A. (18) 154,155 Groziak, M.P. (22) 144 Gruetmacher, H.-F. (22) 27 Gryko, D. (1 8) 8 1 Grynluewicz, G. (1 1) 5 Grzesczyk, B. (7) 58; (22) 153

156

Grzybowska, J. (19) 13

Guaragna, A. (20) 173 Gubernator, K. (22) 52 Gudmundsson, K.S. (20) 81,141 Guegen, G. (20) 59 Guenais, S. (10) 17 Guerrini, M. (3) 283,291 Guether, R. (4) 22 1 Guibi?, F. ( 5 ) 9 GUM-Jampel, E. (3) 40,43 Guibourdenche, C. (22) 19 Guile, S.D. (19) 42 Guillerm, D. (20) 129 Guillerm, G. (18) 52; (20) 129 Guillet, J.E. (4) 216 Guillod, F. (7) 65 Guiso, M. (6) 1 Gumienak, J. (19) 13 Gunawardena, G. (19) 3,56 Gundlach, C.W. (20) 260 Gunzi, H. (24) 65 Gunner, J.L. (3) 270; (13) 3 Guo, 2. (3) 118; (20) 303

GUW M.-X. (20) 241-244

GUO, 2.-W. (4) 122, 156, 176; (17) 3

Gupta, S.V. (21) 26; (22) 142 Gurjar, M.K. (3) 284; (4) 128; (6)

17; (14) 54 Gurrala, S.R. (3) 103 Gurskaya, G.V. (3) 223; (20) 91,

Gurudutt, V.V. (20) 137; (22) 148 Guse, A.H. (18) 169 Gutteridge, C.E. (4) 60 Guttman, A. (23) 50,52 Guy, A. (24) 7 Guyot, B. (7) 38 Guyot, M. (3) 140 Guman-Perez, A. (1 8) 10 Gyorgydeak, 2. (10) 61; (20) 28 Gypser, A. (24) 18

280; (22) 137, 150

Haase, W.-C. (17) 14 Haatja, S. (3) 83 Habata, Y. (4) 209 Haberhauer, G. (20) 104 Habicher, W.D. (16) 83 Hachiya, S. (24) 22 Hacking, A.J. (7) 31 Hadd, M.J. (8) 21,22 Haddad, N. (18) 132; (22) 129 Hiillgren, C. (2) 25; (4) 94; (7) 55 Hagen, S.R (23) 34 Hager, C. (8) 1 Hager, M.H. (20) 43 Hagwam, H. ( 5 ) 32; (7) 8

Carbohydrate Chemistry Hahn, B. (20) 26 Hahn, F. (22) 75 Hajduk, P.J. (21) 40 Hajkb, J. (6) 19 Hakala, J. (19) 15 Hakamata, W. (7) 29 Halada, P. (3) 129 Halcomb, R.L. (4) 77; (16) 3 1 Haldar, C. (22) 152 Hale, K.J. (13) 25 Haley, J. (18) 6 Hall, A. (24) 63 Hallberg, A. (24) 72 Halliday, GA. (24) 103 Halmos, T. (7) 85 Hamada, F. (4) 192,222 Hamajima, H. (7) 74 Hamann, H.-J. (22) 117 Hamayasu, K. (4) 205 Hamazaki, K. (4) 192 Hamblcy, T.W. (22) 74 Hamersak, Z. (16) 56 Hammer, RP. (13) 27 Hammerschmidt, F. (20) 151, 152

Han, J.W. (24) 99 Han, S.Y. (4) 214 Hanaoka, M. (3) 158 Hanaya, T. (3) 135 Hancock, W.S. (23) 41 Haneda, K. (4) 228 Hanessian, S. (4) 139 Hankamiiki, T. (20) 3 10 Hanna, I. (24) 11 Hanna, N.B. (20) 12 Hansen, A. (18) 71; (24) 57 Hansen, H.C. (3) 83 k e n , K.B. (17) 6 Hanssen, T. (24) 72 Hansske, F. (20) 37 Hantus, S. (21) 14 Haque, W. (4) 30 Hara, A. (22) 22 Hara, K. (4) 205,206 Hara, 0. (19) 11 Harada, K. (3) 135 Harada, N. (5) 32; (24) 24 Hafano, Y. (22) 21 Harata, K. (4) 210 Harayama, S. (3) 21 1 Harden, J. (13) IS Hardy, B.J. (21) 67 Hari, Y. (20) 123; (22) 135 Harigaya, Y, (3) 1 17,220,22 1 Harle, J. (3) 282 Hamouch, B. (18) 6 Hamfeldt, A.-B. (20) 53 Harris, R (4) 75

Han, B.-H. (4) 223

Author Index Harry-o’kuru, RE. (20) 103; (21)

Harte, W.E., Jr. (3) 97; (7) 75 Hartenstein, H. (3) 137 Hartley, 0. (22) 98 Hartman, N.R (23) 37 Harusawa, S. (3) 323; (22) 149 Harvey, D.J. (18) 43; (22) 29,31 Harvey, T.C. (17) 8; (22) 109 Hasan, A. (20) 278 Hasegawa, A. (3) 80,208; (4) 34,

92, 116,124,166, 173,174; (7) 69,71,74,77,78; (14) 50

11

Hashimoto, A. (23) 40 Hashimoto, H. (3) 21 1,229; (4)

19, 191,205; (11) 27,30 Hashimoto, M. (3) 204 Hashimoto, S.4. (3) 169; (4) 56 Hashimoto, T. (7) 93 Hashimoto, Y. (20) 5; (23) 11

Hassan, A.E.A. (20) 106 Hassan, A.K. (22) 103 Hassanein, M. (20) 32

Hata, H. (3) 323; (22) 149 Hatano, K. (22) 56 Hatse, S. (20) 267 Hatton, K. (4) 204,228 Hakn-Buhler, N.T. (3) 115 Haughd, R.P. (16) 58 &tala, A. (19) 15 Haverkamp, J. (22) 28 Havlas, Z. (20) 124 Havlicek, V. (10) 4; (20) 20; (22)

Hawkins, P.T. (18) 155 Hay, D.A. (20) 161 Hayakawa, Y. (3) 194 Hayashi, H. (20) 83 Hayashi, K. (9) 55 Hayashi, M. (3) 91; (4) 144 Hayashi, T. (20) 212 Hayashida, 0. (16) 15 Hays, D.S. (12) 13; (18) 17 HaZen, G. (9) 34 He, G.-X. (20) 25 1,272 He, L. (20) 117 He, W. (3) 257 Heath, S.L. (3) 250; (22) 11 1 Heathcock, C.H. (4) 121 Hecht, L. (4) 242; (22) 2 Heeres, A. (16) 65 Heerma, W. (22) 25,28 Hegedus, L. (23) 37 Heidelberg, T. (9) 22 Hein, M. (8) 1 Heinen, A.W. (2) 43

Has- H.-J. (14) 2

Hasse, W.C. (22) 122

41

Heinrich, J. (23) 6 Helbig, J.H. (16) 25 Helin, J. (4) 154 Helm, RF. (3) 21 Helmboldt, A. (4) 152; (22) 70 Hembre, E.J. (24) 69 Hempel, A. (22) 147 Henderson, E.E. (20) 241-244 Henderson, T.J. (21) 7 1 Hendrix, C. (20) 294 Hendrix, M. (3) 148; (9) 21; (19)

Hengge, A.C. (20) 174 Hennig, L. (19) 57,58,60 Heme, A. (6) 14 Her, G.-R (23) 57 Herald, D.L. (3) 144 Heras-Lopez, A. (3) 267

6

Hhul t , J.-P. (4) 151, 152, 163; (22) 70

Herbert, J.-M. (4) 151, 152, 163, 184; (22) 70

Herbretau, B. (23) 47 Herczegh, P. (16) 11 Herden, U. (14) 39,40; (24) 48 Herdewijn, P. (18) 27,80; (20) 88,

153,294,295; (21) 27,77; (22) 140, 143

Hermann, J. (7) 25 Hernindez, R. (2) 7; (10) 57 HernBndez-Mateo, F. (3) 243; (1 1)

25; (13) 29 Hernanz, A. (22) 10 Herpin, T.F. (3) 314; (8) 15 Herrmaun, G.F. (19) 59 Hewe du Penhoat, C. (21) 8 Hery, C. (3) 167 Herzog, K.J. (17) 6 Hettich, R. (20) 3 12 Hetzer, G. (3) 275; (13) 34 Hewlins, M.J.E. (1 1) 26 Heyraud, A. (4) 44 Hibbert, D.B. (23) 76 Hidaka, H. (7) 93 Higes, F.J. (9) 65; (10) 28 Higuchi, R. (4) 71, 150; (7) 79;

Higuchi, S. (3) 206; (12) 18 Hildbrand, S. (20) 138 Hileman, E.R (22) 23 Hiler, G.D. (14) 22 Hill, D.C. (9) 61 Hill, M.L. (18) 154 Hillenbrand, R (20) 269 Hillman, J.M.L. (20) 197 Hindsgaul, 0. (2) 25; (3) 14, 174;

(4) 26,66,94, 103; (5) 19; (7) 55; (10) 71; (22) 24; (23) 51

(9) 54; (22) 21

395 Hinkley, J.M. (20) 143 Hinou, H. (4) 170 Hinzen, B. (4) 153; (6) 21 Hiplert, K. (22) 52 Hirama, M. (24) 24 Hiramatsu, Y. (4) 145; (7) 78 Hirano, K. (3) 173; (18) 12 Hirano, T. (4) 52 Himka, S. (8) 11, 12; (14) 30,48 Hirata, R (23) 21 Hirayama, F. (4) 219 Hiroka, S. (14) 58 Hirosawa, S. (24) 12 Hirota, K. (20) 3 16 Hirsch, J. (22) 25,27 Hirschbein, B.L. (20) 231,232

Hishayama, S. (24) 24 Hjerpe, A. (23) 20 Ho, D.S .4 . (14) 21 Ho, N. (20) 224 Hoberg, J.O. (6) 16; (13) 32; (14)

Hodosi, G. (3) 177; (7) 5 H6ft, E. (14) 2; (22) 117 H6rndler. C. (20) 243 HGrsch, B. (4) 134 Hoflhann, H.M.R (14) 39,40;

Hoffinann, M. (3) 286; (18) 16 Hofham, P. (4) 158, 184; (11)

Hofilena, G.E. (9) 40 Hofmger, A. (4) 69 Hofmann, B. (9) 12 Hofte, A.J.P. (23) 58 Holecek, J. (21) 79 Holkes, K.M. (4) 117 Hollenbaugh, D. (3) 97; (7) 75 Holler, E.R (24) 71 Holl6si, M. (9) 58; (19) 50 Holmes, A.B. (18) 154, 155; (19)

Holmes, D.S. (3) 159; (1 1) 3

Holzapfel, C.W. (14) 46,52; (18) 89,93; (22) 48; (24) 5, 15

Holzer, W. (10) 61; (20) 28 Holzner, A. (20) 104 Homans, S.W. (4) 75 Honda, F. (20) 214 Honda, K. (23) 73 Honda, S. (23) 49 Honda, T. (3) 169; (4) 56 Hondal, R.J. (18) 150 Hong, F. (3) 168 Hong, J. (9) 28; (13) 14 Hong, M . 4 . (17) 7

Hisaeda, Y. (3) 101

36

(24) 48

36

33

Holy, A. (20) 124-126

3 96

Honma, T. (10) 6 Hoogmartens, J. (23) 30 Hooper, J.N.A. (3) 144 Hoornaert, G. (18) 57; (24) 60 Hoos, R. (1 0) 5 8 Hopkins, S.A. (20) 229 Horan, N. (1) 10 Horenstein, B.A. (18) 69; (21) 45;

Hori, H. (14) 13 Horikawa, S. (3) 116 Horita, D.A. (21) 40 Horita, K. (24) 22,23 Hornberger, K.R. (7) 64 Home, D.A. (2) 40 Homemaq A.M. (18) 95 Hornyak, M. (1 8) 143 Horon, N. (4) 45 Horton, D. (22) 81,105 Horvat, S. (9) 58 Horvatb, S.E. (20) 241,242,244 Hosain, N. (20) 295 Hoshi, J. (22) 8 Hoshino, H. (3) 96 Hoshino, M. (22) 5 Hosoi, S. (11) 13; (22) 113 Hosokawa, H. (4) 92; (14) 50 Hosokawa, S. (3) 15 Hosomi, 0. (23) 44 Hossain, N. (18) 27 Hostetler, K.Y. (20) 190 HosteUmann, K. (22) 18 Hotta, Y. (7) 93 Hou, Y. (22) 77 Houri, A.F. (9) 40 Hoveyda, A.H. (9) 40 Hovinen, J. (1 8) 25

Hricovini, M. (21) 35 Hricoviniova, Z. (2) 12 Hsiao, K.-F. (7) 32 Hsieh, Y.-L. (22) 78 Hu, B. (4) 193 Hu, M. (22) 78 Hu, S. (4) 155 Hu, X. (7) 72; (24) 36

Huang, B . 4 . (4) 138

(22) 39,44,59

Hrebabecky, H. (20) 124-126

H w Z.-W. (22) 144

Huang, H.-Q. (3) 8 H~ang, M.-Y. (19) 14

Huang, X.-Y. (22) 108 Huang, Q. (20) 265

Huang, Z.T. (3) 20,315 Hubbard, B.K. (16) 16 Hubbard, L.E. (23) 45 Hubert, B.J. (20) 125 Hudlicky, T. (8) 6; (18) 126,127,

132; (22) 129

Has, C. (4) 142 Huet, F. (19) 47 Hiittelen, J. (7) 22 Huff, B.E. (20) 114 Hui, Y. (3) 118 Hui, Y.W. (3) 115 Hui, Y.-2. (4) 122; (7) 10; (17) 3 Hull, W.E. (21) 60 Hult, K. (7) 28,37 Hultkn, J. (24) 72 Hulthe, G. (23) 23 Hultin, P.G. (4) 76; (24) 80 Humez, S. (3) 319 Hummel, G. (4) 182 Hung, S.-C. (3) 67,269,274; (8)

2; (13) 12 Hunter, R (1 8) 37; (24) 64 Hurihara, T. (3) 323 Hurttlen, J. (3) 157 Hutchinson, E.J. (20) 154 Huynh, H.K. (4) 139

Hymavathi, L. (3) 301 Hyodo, I. (4) 198

H-g, L.-P. (21) 75

Iacussi, M. (22) 12 Iadonisi, A. (18) 88 Ianaro, A. (3) 146 Ianelli, M.A. (18) 151 Ianoil, A.I. (22) 6 Ibara, C. (21) 38 Ibrahim, E.E. (20) 3 1 Ibrahim, E.I. (20) 147 Ichida, T. (20) 123 Ichikawa, M. (9) 14 Ichikawa, Y. (3) 263; (4) 20; (9)

14,3 1; (13) 22; (24) 27,28 Ichimura, A. (17) 31; (22) 123 Ichimura, S. (23) 17 Ida, Y. (3) 217; (4) 6 Igarashi, M. (19) 12 Igarashi, S. (23) 73 Igarashi, Y. (3) 263; (7) 71 Iglesias-Guerra, F. (10) 43 ha, M. (4) 150 Iida, A. (17) 9; (22) 110 Iida, T. (4) 217 Iijima, H. (4) 33 Iimori, T. (3) 164; (6) 15 Iizuka, Y. (19) 53 Ijichi, K. (20) 98 IJzerman, A.P. (20) 88 Ikai, K. (17) 9 Ikami, T. (3) 80,208; (7) 69,74 Ikan, A. (3) 253 Ikeda, D. (19) 48; (22) 49; (24) 12 Ikeda, H. (4) 236,239

Carbohy&ate Chemistry Ikeda, K. (3) 96, 108; (9) 69,70;

(18) 146 Ikeda, M. (3) 60 Ikeda, S. (20) 52 Ikeda, T. (3) 123; (23) 75 Ikeda, Y. (18) 135 Ikegami, S. (3) 141, 164, 169; (4)

56; (6) 15 Ikegami, Y. (4) 197; (23) 39 Ikikura, M. (20) 3 15 Ikushima, N. (2 1) 63 Im, J. (20) 26 Im, S,-C. (16) 85 Imada, T. (2) 47 Imagawa, H. (4) 198 Imamari, T. (22) 100 Imamoto, T. (20) 176 Imamura, K. (4) 40 Imanari, T. (16) 30; (23) 21 Imanishi, T. (20) 122, 123; (22)

Imata, H. (4) 204 Imazu, T. (3) 323; (22) 149 Imbach, J.-L. (3) 244; (20) 65,91,

222,223; (22) 137 Imberty, A. (21) 15,68 Impellizzeri, G. (4) 234 Imrich, J. (3) 302 In, Y. (20) 123; (22) 135 Inaba, T. (23) 1 Inadzuki, M. (3) 142,173; (18) 12 hagalu, M. (4) 150; (7) 79; (22)

Inazu, T. (4) 228 Ingate, s. (20) 120 Inoaimo, S. (18) 105; (20) 167 Inn=, J.E. (18) 124 Inokuchi, J.4. (18) 147 Inoue, S. (3) 264 Inoue, Y. (3) 264; (4) 166; (7) 78;

(10) 22 Inouye, S. (19) 11 Ippolito, R.M. (4) 30 Ireland, RE. (24) 29,30 Isaac, M.B. (2) 29 Isac-Garcfa, J. (3) 243; (1 1) 25;

(13) 29 Ise, N. (4) 239 Isham, K.R (20) 278 Ishida, H (2) 45; (3) 80,208,234;

(4) 116, 124, 166, 173, 174; (7) 69,71,74,77,78

135

21

Ishida, H.-K. (4) 173 Ishida, I. (4) 92; (14) 50 Ishida, M. (3) 288 Ishida, T. (22) 135 Ishido, Y. (20) 48,50,276; (22) 8 Ishidsu, J. (7) 50

Author Index Ishikawa, S. (20) 118 Ishikawa, T. (3) 3 17; (20) 47 Ishimaru, Y. (4) 215,217 Ishizuka, Y. (22) 37 Iskander, M.F. (10) 63 Ismagilova, A.F. (3) 63 Ismail, A.E.A.A. (20) 183 Isobe, M. (9) 3 1; (13) 22; (24) 27,

Isobe, R. (4) 150; (7) 79; (22) 21 Isogai, Y. (22) 24 Isomura, M. (3) 179; (4) 58,62 Israeli, Y. (17) 30 Issa, F.B. (20) 16,84 Isumi, M. (9) 14 Ito, H. (4) 173,174; (24) 42 Ito, S. (10) 6 Ito, Y. (3) 52, 190,213; (4) 4, 80,

124 Itoh, T. (3) 158,194; (4) 66 Iuiano, A. (4) 245 Ivanova, N.P. (7) 27 Ivanova, T.P. (20) 93 Ivastchenko, N. (3) 57; (16) 59 Iversen, T. (7) 28 Ives, D.H. (20) 52 Iwakura, Y. (1 1) 13; (22) 113 Iwasaki, S. (18) 153; (20) 5; (23)

Iwasaki, Y. (3) 220 Iwata, N. (3) 80; (7) 69 Iyer, R.P. (20) 224 Izquierdo, I. (2) 26; (20) 35 Izumi, M. (3) 21 1 Izumi, T. (7) 15

28

11

Jackson, M. (19) 56 Jackson, RF.W. (3) 250; (22) 11 1 Jacobs, G.A. (18) 105; (20) 167 Jacobs, K. (24) 71 Jacobson, M.K. (21) 78 Jacobus, N.V. (18) 18 Jacques, F. (3) 308 Jacquinet, J.-C. (20) 7 Jadhav, P.K. (24) 71

Jain, RK. (4) 138 Jakas, A. (9) 58 James, RA. (3) 13; (11) 11 Janda, K.D. (17) 33,34; (20) 86,

Janke, W. (4) 140 Jankowska, J. (20) 216 Jansson, P.-E. (23) 5,7 Jaramillo, C. (9) 62; (1 1) 14; (18)

Jarosz, S. (2) 17; (3) 149,151; (8)

Jahn-H~fmann, K. (21) 76

87

122

26; (13) 31; (18) 94, 100; (21) 80; (22) 55; (24) 8, 10

Jarowicki, K. (1) 7 Jasko, M.V. (20) 91; (22) 137 JastorfF, D. (20) 196 Jatzke, H. (24) 33 Jaurand, G. (4) 151 Jayamma, Y. (18) 28; (24) 34 Jayapfatash, S. (18) 67 Jayaram, H.N. (20) 137; (22) 148 Jayamman, N. (1) 19; (3) 81,84,

85; (18) 13 Jeanneret, V. (3) 3 10 Jeantet-Segonds, C. (5) 21 Jefferies, I. (18) 73 Jegorov, A. (3) 129; (22) 41 Jennings, H.J. (4) 129, 178 Jensen, P.R (3) 138 Jensen, T. (4) 100 Jeong, L.S. (20) 286; (21) 33 Jeong, S. (3) 235; (14) 19 Jeneton, 0. (3) 281 Jeschke, U. (16) 76 Jezewski, A. (18) 100; (24) 8

Ji, R.-Y. (20) 3 14 Jia, 2.-J. (5) 3 Jiang, H. (14) 8; (18) 60 Jiang, H.-L. (20) 3 14 Jiang, S. (18) 102, 112; (22) 128 Jiang, T. (3) 3 Jiang, Y. (20) 194; (24) 27,28 Jiang, 2.-D. (3) 138 Jiang, 2.-H. (7) 47 Jie, M. (20) 263 Jimbo, M. (18) 147 Jimhez, J.L. (9) 65; (10) 28 Jimhez, M. (9) 33; (10) 1 Jimhez-Barbem, J. (3) 252; (4)

119; (21) 47,5 1,52,69,73 Jimhez-Blanco, J.L. (9) 66; (10)

35; (24) 68 Jin, B. (9) 44; (16) 41 Jin, H. (18) 22 Jin, W. (3) 56 Jin, 2. (3) 56, 176; (4) 47 Jindoh, C. (4) 204 Jindrich, J. (4) 2 10 Jing, D.S. (4) 43 Jiralerspong, S. (1 8) 104 Jiskra, J. (23) 36 Jo, J.-S. (23) 55 Joersbo, M. (20) 133 Johannes, C.W. (9) 40 Johansson, N.G. (20) 53 Johdo, 0. (19) 17 Johns, B.A. (3) 184,306; (18) 72,

Jhon, G.-J. (21) 72

85,86; (24) 61

397

Johnson, C.R (3) 184,306; (18) 72,85,86; (24) 61

Johnson, L.N. (10) 32,33 Johnson, RA. (20) 204 Johnston, A. (22) 74 Joly, G. (18) 57; (24) 60

Jomori, T. (3) 80; (7) 69 Jona, H. (10) 6 Jonczyk, A. (10) 29 Jones, M.G. (3) 136 Jones, P.R. (3) 320; (24) 19 Jones, R.A. (20) 265 Jones, W.D. (20) 137; (22) 148 Joniaic, D. (16) 78 Jorgensen, C. (10) 60; (12) 2 Jergensen, P.N. (14) 9; (20) 112 J~rgensen, T.J.D. (18) 24 Jose, M. (1 1) 1 Joshi, S. (4) 48

Joulia, J.M. (23) 22 Joyce, G.F. (19) 6

Jullien, L. (21) 8 Jun, J.W. (4) 5 1 Juneja, L.R (3) 95; (16) 44

Joly, J.-P. (3) 308

JOU~UUO, C. (20) 245-247

Ju, D.-D. (23) 57

J u g , J.-K. (3) 293 J ~ n g , K.-H. (3) 24 Jung, M.E. (12) 4 Jung, P.M.J. (18) 125; (20) 40,

Junquera, F. (16) 68; (19) 32 Juodvirsis, A. (3) 242 Jurczak, J. (18) 8 1 Jurczak, M. (9) 32 Just, G. (20) 107,219,220,227;

(24) 100 Juteau, H. (7) 7

109

Kabir, A.K.M.S. (7) 9 Kache, R (6) 18; (15) 5 Kachurin, A.M. (3) 49 Kadam, RM. (17) 24 Kadam, S. (19) 56 Kadokawa, J.4. (4) 168 Kadokura, M. (20) 206 Kiisbeck, K. (2) 9; (5) 14 Kiisbeck, L. (3) 238,249; (10) 36 K a f d T. (20) 183 Kagan, M.Z. (22) 23 Kahlenberg, F. (13) 13; (14) 35 Kai, T. (3) 239; (6) 4,5; (9) 35;

Kainosho, M. (20) 49,50 Kaiser, T. (18) 169 Kaji, E. (3) 117,220,221

(10) 50; (16) 19,52-54

398 Kajiham, Y. (3) 229; (4) 19; (14)

Kiijimoto, N. (20) 297 Kajimoto, T. (2) 19; (3) 95, 123,

217; (4) 6; (16) 44 Kajimoto, Y. (23) 1 Kajtk-Peredy, M. (6) 19; (10) 42 Kakainuma, K. (14) 7 Kakarla, R. (3) 115 Kakimoto, K. (1 1) 13; (22) 113 Kakinuma, K. (19) 8; (24) 20, 101 Kakinuma, T. (20) 276 Kaldor, S.W. (20) 113, 114 Kalic, B. (21) 56 Kalinichenko, E.N. (20) 240 Kalman, T.I. (20) 317 KaIuza, 2. (24) 54 Kamada, T. (23) 1 Kamaike, K. (20) 276 Kamal, M. (8) 18 u Y . (11)27 Kameda, Y. (18) 146 Kamei, M. (23) 18 Kamerling, J.P. (4) 53,61,63,67,

117, 137 Kameyama, A. (4) 52 Kameyama, M.O. (4) 203 Kamezawa, Y. (23) 27 Kan, Y. (4) 71, 198; (7) 51; (9) 54 Kanai, M. (3) 90 Kaneko, C. (20) 78,155 Kaneko, H. (3) 60 Kaneko, J. (7) 29 Kaneko, M. (2) 19 Kanellopoulos, P.N. (22) 45 Kanemitsu, K. (11) 13; (22) 113 Kanemitsu, T. (3) 109

Kang, Y. (20) 14; (21) 72; (22)

Kanie, 0. (2) 19 Kano, K. (23) 75 Kano, T. (3) 292 Kanyok, T. (23) 32 Kapeller, H. (1 8) 109; (1 9) 37;

Kappe, C.O. (18) 33 Karamanos, N.K. (23) 20 Karamitrou, V.I. (18) 101 Karasy M. (4) 168 Karldn, A. (24) 72 klsson, H. (23) 4 Karokawa, K. (4) 145 Karpiesiuk, W. (19) 29 Kartha, K P . R (3) 188; (7) 3; (8)

M e , P. (22) 131, 132 Karwowski, J.P. (19) 56

13

Kang, B . 4 . (17) 7; (22) 107

146

(20) 156

20

Kassab, R (4) 237; (10) 13 Kassou, M. (20) 116 Kasu, P.V.N. (8) 5 Katagiri, N. (20) 155 Kataoka, S. (7) I5 Katay, G. (23) 9 Kato, A. (3) 136; (18) 43,44 Kato, H. (20) 38 Kato, K. (3) 41; (16) 80; (18) 5;

Kato, M, (7) 8 Kato, Y. (4) 220; (17) 9; (22) 110 Katopodis, A. (4) 73,133 Katti, S.B. (21) 30; (22) 20, 131,

Kavrakovshi, 2. (23) 70

Kawachi, E. (20) 5; (23) 11 Kawahara, S. (20) 214 Kawakami, T. (23) 73 Kawaminami, M. (20) 299 Kawamori, R (23) 1 Kawamoto, H. (3) 135; (10) 5;

Kawamura, M. (4) 114 Kawamura, N. (3) 91; (4) 144;

Kawasaki, N. (23) 71 Kawase, M. (3) 217 Kawase, Y. (3) 217 Kawashima, E. (20) 48,50; (22) 8 Kawashima, K. (18) 146; (24) 2 Kawatake, S. (7) 79 Kawauchi, T. (19) 14 Kazanina, G.A. (7) 27 Kazmaier, U. (18) 82 Kazmina, E.M. (20) 91; (22) 137 Kean, S.D. (4) 226 Keana, J.F.W. (18) 166, 167 Keely, S. (20) 196 Keen, N.T. (24) 49 Kehrt, K. (7) 44 Kehler, J. (20) 217,218 Keiburg, C. (3) 87 Keim, S.H. (4) 79 Kellam, B. (10) 24 Kelley, J.A. (23) 37 Kelley, S.A. (5) 16 Kelly, S. (3) 28; (18) 6 Kelve, M. (20) 240 Kemp, N.M. (1) 5 Kempin, U. (19) 60 Kennard, 0. (22) 134 Kennedy, J. (21) 20 Kenyon, G.L. (20) 202 Keppes, T. (4) 22; (10) 25 K e d k g j d , J. (3) 72,75; (4) 54,

(20) 100

132

Kawabatq s. (22) 37

(19) 52

(19) 49; (22) 102

117

Carbohydrate Chemistv Kerns, RJ. (16) 71 Kers, A. (20) 2 16 Ken, I. (20) 216 Keseru, G.M. (21) 31 Kessler, H. (2) 9; (3) 238,249,

Kett, W.C. (20) 27 Keusgen, M. (16) 79 Kever, E.E. (7) 27

Khaldi, M. (18) 103 Khan, N. (8) 28; (14) 5 1 Khanbabaee, K. (7) 6,48,49 Khane, D. (1) 9 Kbatuntseva, E.A. (3) 210; (21)

Khiar, N. (3) 252; (18) 90

Khlebnikova, T.B. (3) 94 Khodair, A.I. (20) 31 Khorosheva, E.V. (20) 93 Khrebtova, S.B. (7) 61,62; (8) 27 Kiba,N. (23) 16 Kido, M. (3) 132; (18) 77; (22)

Kieburg, C. (3) 74 Kiely, D.E. (21) 11 Kiessling, L.L. (3) 90; (4) 91,95;

(5) 15; (7) 72,76; (24) 36 Kihlberg, J. (3) 215 Kikuchi, J.4. (3) 101 Kikuchi,N. (19) 10, 11 Kikuchi, Y. (20) 100 Kilonda, A. (18) 57; (24) 60 Kim, B.W. (3) 156; (4) 51 Kim, C.U. (18) 115; (22) 127 Kim, D. (24) 16 Kim, D.H. (3) 156; (4) 51 Kim, H.S. (24) 16 Kim, I.J. (4) 161 Kim, J. (20) 26 Kim, J.M. (3) 88,98 Kim, J.N. (20) 121 Kim, K. (23) 14 Kim, K.B. (20) 234 Kim, M. (3) 95; (16) 44 Kim, M.S. (22) 17 Kim, S. (3) 15, 161; (20) 14; (22)

Kim, Y. (21) 53 Kim, Y.H. (20) 264; (22) 17 Kim, Y.J. (18) 77,78; (22) 101 Kim, Y.S. (23) 66 Kimoto, H. (22) 99 Kinney, M. (2) 33 Kinoshita, I. (17) 23, 3 1; (22) 121,

Kinoshita, Y. (24) 40

286; (5) 14; (10) 36; (18) 16

Khainlllin, 1.1. (21) 75

66

Khim, S.-K. (18) 148

101

146

123

Author Index Kirk, B.A. (10) 65 Kirk, 0. (7) 36 Kirk, RL. (16) 84 Kirschning, A. (4) 27; (12) 1; (13)

15; (16) 63 Kishi, Y. (3) 277 Kishida, M. (14) 7; (24) 20 Kishimoto, H. (24) 26 Kishimoto, Y. (23) 1 Kiso, M. (3) 80,208; (4) 92,116,

124, 166, 173, 174; (7) 69,71, 74,77,78; (14) 50

Kiss, T. (5) 24; (24) 47 Kita, Y. (3) 33,279 Kitade, Y. (20) 3 16 Kitagawa, I. (4) 84 Kitagawa, M. (7) 39,40 Kitagawa, S. (18) 41,42 Kitagawa, Y. (4) 18 Kitahara, K. (23) 12 Kitahara, S. (4) 206 Kitahara, T. (18) 77,78; (22) 101 Kitahata, S. (4) 205 Kitajima, K. (3) 264; (10) 22 Kitano, H. (4) 230 Kitano, K. (20) 97, 127 Kitao, S. (4) 203 Kitazono, E.4. (5) 11; (7) 96 Kitazume, T. (8) 11, 12; (14) 30,

Kittaka, A. (20) 38 Kittelmann, M. (20) 207 Kiyoi, T. (4) 89, 145 Kiyosada, T. (3) 201 Kizu, H. (3) 136; (18) 43,44 Kjell, D.P. (20) 51, 130 Klabe, R.M. (24) 71 Klaubert, D.H. (16) 58 Kleban, M. (2) 20 Klecan, 0. (20) 149; (22) 72 Klein, RS. (20) 41 Kleindl, P.J. (17) 11 Klevinghaus, P. (21) 9 Klufers, P. (22) 73 Kluge, M. (3) 134, 137 Klumpe, M. (17) 14; (22) 122 Knapp, S. (10) 65 Kniezo, L. (3) 302 Knight, D.J. (20) 288 Knirel, Y.A. (16) 25 Knispel, T. (20) 186 Knoll, D. (19) 60 Knowles, V. (5) 6

Kobayashi, H. (20) 5; (23) 11 Kobayashi, K. (3) 200; (4) 18,203 Kobayashi, M. (21) 17 Kobayashi, S. (2) 30; (3) 182,

48,58

KO, K.-Y. (24) 95

201; (4) 199-202; (24) 42 Kobayashi, Y. (19) 1 Kobertz, W.R (20) 274 Koch, T.H. (19) 18 Kochetkov, N.K. (3) 163; (10) 12 Kocienski, P. (1) 7 Kocy, 0. (18) 105; (20) 167 Koll, P. (24) 91,92 Koeller, K.M. (4) 91; (7) 76 Koenig, W.A. (23) 6 Kofoed, I. (20) 72 Koftis, T.V. (1 8) 101 Koga, K. (4) 232 Koga, T. (4) 196,197 Kogan, N. (3) 115 Koganty, R.R. (4) 98, 102 Kogure, T. (23) 44 Kohen, A. (16) 27 Kohlbau, H.J. (8) 28; (14) 5 1 Koike, H. (3) 91 Koike, K. (4) 52; (12) 20 Koivuniemi, A. (23) 42 Koizumi, K. (4) 205,206 Kok, G.B. (9) 73; (10) 37; (16)

Koketsu, M. (3) 95; (16) 44 Kokofuda, H. (20) 155 Kokubo, K. (3) 256; (23) 18 Kokusenya, Y. (23) 40 Kolb, H.C. (4) 96, 140, 141 Kolb, V.M. (22) 76,77 Kolbinger, F. (4) 73 Kollamn, P.A. (10) 21 Kolodiazhnyi, D.I. (17) 19 Kolossvary, I. (2) 35 Komatsu, C. (24) 32 Komatsu, H. (4) 37 Komatsu, M. (22) 8 Komatsu, N. (3) 273 Komba, S. (7) 77 Komiyama, M. (20) 306,311 Kon, N. (20) 244 Konda, Y. (3) 220 Kondo, H. (3) 123; (4) 89,92,

Kondo, M. (16) 62 Kondo, N. (4) 166; (7) 78 Kondo, S. (18) 135; (19) 53; (24)

Kondo, Y. (3) 117,221; (4) 205;

Koneru, D. (10) 53 Kong, D.C.M. (9) 44; (16) 41 Kong, F. (3) 224,225; (4) 112; (5)

Konishi, Y. (4) 110 Kononov, L.O. (3) 213 Konradsson. P. (3) 112; (18) 165

50,51

145, 166; (7) 78; (14) 50

12

(7) 1

13, 17.26-28; (19) 27,28

399 Koo, Y.S. (23) 66 Kool, E.T. (3) 322; (20) 82 Koole, L.H. (20) 3 €0 Koos, M. (18) 58 Kopczynska, E. (10) 29 Korba, B.E. (20) 285 Korewa, R (10) 2 Kornienko, A. (18) 121 Korolev, A.M. (19) 21 Koroteev, M.P. (7) 61-63; (8) 27 Koshiishi, I. (16) 30; (22) 100 Koshino, H. (24) 45 Koshy, K.M. (22) 7 Koskinen, A.M.P. (9) 37 Kosma, P. (4) 69 Kosonen, M. (20) 307 Kostina, V.G. (20) 69 Kotera, M. (8) 19 KO- L.P. (8) 13; (20) 75,76;

(22) 136 Kotsuki, H. (9) 27 Koumbis, A.E. (18) 98, 101 Kouwijzer, M.L.C.E. (4) 172; (21)

KovBC, P. (3) 16, 177; (4) 164, 9

188; (7) 5; (21) 55,67; (22) 28

Kovacik, V. (22) 25,27,28 Kovacs, I. (22) 118

48; (21) 46 KOV~CS, J. (9) 63, 64; (10) 42,46-

Kovacs, L. (1) 2

Kovensky, J. (7) 24 Kowalek, H. (3) 248; (8) 4 Kowolik, W. (8) 28 Kodr, T. (2 1) 60,6 1 Kozikowski, A.P. (18) 162 Kozlowska, E. (18) 100; (21) 80;

Kozlowski, J.S. (5) 31; (16) 21 Kraehenbuehl, K. (14) 49; (1 8) 76 Kriihmcr, R. (19) 59 Kriimer, L. (2) 6 Krafft, M.P. (7) 65 Kragl, U. (19) 59; (20) 207 Krajewska, D. (20) 179 Krajewski, D. (3) 92 Kramer, S. (7) 43; (16) 76 Kraszewski, A. (20) 216 Kratochvil, B. (20) 149; (22) 72 Kratz, F. (19) 22 Kraus, G.A. (20) 157 US, J.-L. (20) 290 Kraus, T. (4) 21 1 Krause, M. (4) 142 Kravchuk, A.V. (18) 150 Krawiecka B. 171 59

Kov~cs -KuI~~ss~ , A. (16) 11

(24) 8

400 Kren, V. (3) 129; (1 0) 4; (20) 20 Krepinsky, J.J. (4) 3 Kretzschmar, G. (4) 104, 134,

Krieger, C. (3) 278; (16) 33; (22)

Kriek, N.M.A.J. (2) 18; (4) 68;

Krihova, A. (3) 265 Krishandu, K. (3) 312 Krishna, P.R (3) 301,312; (12) 3 Krishnamurthy, N. (22) 4 Krishnan, R.K. (24) 21 Krishnudu, K. (1 2) 3 Krwhta, J.M. (22) 78 Kroon, J. (21) 9 Kroon, P.A. (3) 139 Kriiger, M. (19) 22 Kriille, T.M. (6) 3; (7) 84; (10) 32,

33,41,69; (16) 73 Kruppa, J. (20) 196 Kryczka, B. (3) 183; (13) 21 Kryukova, E.Y. (22) 6 Kubiak, R.J. (18) 161 Kubisch, J. (3) 129 Kuboki, A. (9) 30,45; (16) 40 Kubota, D. (14) 32 Kubota, K. (4) 204 Kubota, S. (4) 149 Kuboto, M. (23) 1 Kudo, F. (19) 8 Kuenzel, J.K.von F.D. (20) 88 Kuester, B. (22) 29 Kugelbrey, K. (18) 39 Kuhn, M. (3) 316; (13) 28; (15) 4 Kuhneweg, B. (17) 32

Kulak, T.I. (20) 24 1,242 Kumagai, H. (4) 228 Kumar, A. (20) 95; (21) 30; (22)

20,131,132 Kumar, P. (14) 54 Kumar, R (20) 95 Kumar, S.V.P. (21) 26 Kumazawa, T. (3) 288 Kunieda, T. (3) 41 Kunnari, T. (19) 15 Kunz, H. (3) 166,214; (22) 85;

(24) 88,93 Kuono, I. (7) 47 Kurahashi, H. (22) 22 Kurahashi, T. (3) 240 Kurakata, S. (9) 71; (10) 20; (16)

Kurata, H. (20) 100 Kurihara, K. (19) 10,ll Kurihara, T. (22) 149 Kurimoto, M. (4) 248

142, 146

97

(19) 25

Kula, M.-R (3) 152

22

Kuroda, M. (12) 20 Kuroda, N. (4) 52 Kurokawa, K. (4) 89 Kurokawa, T. (4) 203 Kurono, S. (4) 120; (7) 70 Kurosaki, M. (2) 3 1 Kuroyanagi, N. (20) 145 Kurth, M. (22) 78 Kurusu, N. (3) 35 Kur'yanov, V.O. (3) 18 Kusaka, N. (24) 70 Kusano, G. (18) 41,42 Kuster, B.F.M. (16) 66,67 Kusmoto, S. (3) 203,204; (4) 5,

123 Kus~nann, J, (11) 17-20 Kuthan, J. (20) 148, 149; (22) 72 Kuwabara, T. (4) 236 Kuwahara, R (19) 2 Kumik, G. (4) 134 Kuzuhara, H. (4) 170,225; (1 1)

22; (12) 7; (18) 68 Kvarnstriim, I. (24) 72 Kvasyuk, E.I. (20) 241,242 Kwon, Y.-U. (7) 57 Kyogoku, Y. (20) 50

La, D.S. (9) 40 Labelle, M. (7) 7 Lachatre, G. (23) 67 La Colla, P. (20) 137; (22) 148 Lacombe, J.-M. (7) 90 Lacoste, L. (7) 1 1

R (16) 17 La Ferla, B. (17) 2 Lafont, D. (3) 113, 195; (9) 26;

Lafosse, M. (23) 24,47 Lahmann, M. (3) 130; (4) 169

Laiie, R.A. (4) 38

Lam, G.N. (24) 71 Lambert, J.F. (3) 122 Lampilas, M. (19) 58 Lancelot, G. (20) 7 Ladais, Y. (3) 309; (1 8) 110,145 Landersjii, C. (21) 65 Lane, A.L. (2) 13; (22) 53 Lane, B.G. (22) 147 Lane, S. (19) 41; (20) 159 Lang, S.A. (18) 18,19 Lantos, I. (24) 98 Lapieme, C. (3) 78 Lapointe, J. (7) 11 Lapointe, P. (3) 97; (7) 75; (18)

105; (20) 167

(10) 11

Lai, C.-C. (23) 57

Lallo~, M.-N. (18) 62

Carbohydrate Chemistry Lappa, S. (18) 151 Lano4 D.P. (4) 121 Larsson, K. (7) 37 Laslo, K. (18) 66; (22) 16 Laszlo, P. (18) 143 Latif-Ansavi, F. (8) 28 Laufer, S. (16) 63 Laumen, K. (7) 25 Laurent, A. (20) 233 Laver, W.G. (18) 115; (22) 127 Lavergne, J.-P. (14) 5,6; (22) 96 Lavoie, M. (2) 11 Lawrence, A.J. (20) 105 Lawrence, C.C. (20) 304 Lay, L. (3) 276,285; (4) 88; (7)

Lazhko, I.E. (19) 21 Ley X.C. (23) 5 1 Leahy, J.W. (18) 107; (19) 35 Leary, J.A. (17) 26; (22) 26 Lebon, F. (21) 27 Lebreton, J. (20) 247 Lederer, M.O. (9) 25 Lederman, I. (4) 15 1 Lcc, C.K. (14) 8; (18) 60; (20)

Lee, D.H. (20) 264 Lee, E. (24) 39 Lee, G.H. (18) 117 Lee, J. (14) 19; (20) 286 Lee, M.G. (20) 298 Lee, M.L. (4) 209 Lee, RE. (18) 46 Lee, S. (3) 235; (21) 53 Lee, V.J. (18) 18 Lee, W. (20) 270; (22) 127 Lee, Y.C. (3) 264; (10) 22; (23)

Lee, Y.H. (3) 161 Leebach, J. (4) 45 Leenwenburgh, M.A. (3) 303 Lees, E. (18) 43 Leggio, A. (20) 292 Legler, G. (1 8) 55 Le Guyader, F. (14) 53; (18) 14 Lehbauer, J. (20) 60 Le Hir de Fallois, L. (20) 94 Lehmann, M.N. (4) 246 Lehmann, T.E. (2) 27; (18) 108;

(22) 120 Lehmann, T.J. (20) 225 Lei, C. (3) 3 15 Lemercinier, X. (7) 68 Le Merrer, Y. (1 1) 28 Lemesle-Lamache, V. (22) 38 Lemiere, F. (24) 6 Lemoine, G. (19) 58 Len, C. (7) 91

19

121

71

Author I d x Lenz, R (20) 108 kn, E.I. (2) 7; (10) 57

LBonce, S. (20) 101 Leondiadis, L. (5) 18 Lerner, L.E. (21) 40 Lesiak, K. (20) 235-237 Leskovac, V. (23) 46 Lesur, B. (18) 62 Letcllier, P. (3) 28; (10) 17; (16)

75; (18) 6, 138 Le Tourneau, M.E. (20) 114 Leumann, C.J. (20) 138 Levine, B.R. (22) 8 1 Lew, W. (18) 115 Lewandowska, E. (20) 80 Lewin, N.E. (14) 19 Ley, S.V. (4) 153, 180; (6) 13, 14,

21; (12) 8; (18) 124 Leydet, A. (5) 21; (8) 18 Lhomme, J. (8) 19 Lhoste, P. (3) 183; (13) 21 Li, A. (4) 112 Li, B. (4) 223 Li, H. (3) 61, 168; (4) 66,76; (5)

Li, J. (3) 321; (20) 64 Li, K. (3) 21 Li, L. (22) 24 Li, L.-H. (24) 81 Li, R (20) 202 Li, S . 4 . (3) 171 Li, S.F.Y. (23) 61 Li, T. (3) 15 Li, W. (18) 177 Li, X. (20) 64 Li, Y. (20) 90 Li, Y.-M. (4) 223; (20) 194 Li, Y.-T. (4) 124 Li, Z. (4) 193; (18) 18 Li, Z.-J. (3) 8,20, 13 1; (4) 2 Liaigre, J. (18) 119 Liang, C. (20) 146 Liang, P.H. (16) 27 Liang, R. (1) 10; (4) 45 Liao, H. (18) 150 Liao, W. (4) 112, 162,177 Liberles, D.A. (18) 108 Lichtenthaler, F.W. (3) 66, 150 Lichtenwalter, K. (23) 41 Lidaks, M.Y. (20) 240 Liebe, B. (3) 214 Liebich, H. (23) 38 Lihvre, C. (2) 24; (3) 318,319 Likacs, G. (3) 7 Likhosherstov, L.M. (10) 12 Limberg, G. (5) 12; (16) 8; (18)

Leonard, P. (20) 54

32; (16) 74; (20) 30

49

Limtner, S. (20) 269 Limousin, C. (3) 7 Lin, C.C. (3) 269,274; (9) 46;

Lin, C.-H. (9) 46; (16) 42 Lin, G.T. (23) 29 Lin, H. (23) 60

Lin, K.K.C. (4) 72

Lincoln, S.F. (4) 226 Lindberg, B. (4) 210 Lindhorst, T.K. (2) 25; (3) 74,87;

(4) 94; (7) 55,95 Lindner, B. (3) 202 Lindqvist, L. (23) 5,7 Linek, K. (10) 18 Lingannaganr, S.R (3) 232 Linhardt, R.J. (3) 298; (7) 18; (16)

Link, J.S. (17) 6 Linker, T. (13) 13; (14) 35 Liotta, D.C. (20) 10,43; (22) 145 Liotta, L.J. (5) 16 Liptilt, A. (3) 48; (6) 19; (9) 6 Liquori, A. (20) 292 Liu, C. (18) 179 Liu, D. (3) 115 Liu, H. (18) 115; (22) 127 Liu, L. (24) 29,30,98 Liu, M. (3) 1 18 Liu, Q. (22) 105 Liu, Q.-T. (17) 7; (22) 107 Liu, W. (16) 13,37,38 Liu, W.-C. (3) 204 Liu, Y. (4) 223; (16) 81 Livaniou, E. (5) 18 Livingston, P.O. (4) 161 Ljevakovic, D. (7) 4 Llopis, J. (18) 177 Lloyd, K.O. (4) 161 Lobell, M. (7) 25 Lochmann, T. (20) 254 Locke, RD. (4) 138 Loebach, J. (1) 10 Liinnberg, H. (20) 307,308,3 10 Likerich, K. (7) 6,48,49 Loewenschuss, A. (22) 3 Lofti, H. (23) 67 Logue, K.A. (24) 71 Loh, T.9. (14) 21 Lo- A. (21) 29 Lohray, B.B. (18) 28; (24) 34 Lohse, A. (18) 70; (24) 58 Lois A.G. (20) 137; (22) 148 Lombardi, P. (2 1) 57 Lombardo, M. (9) 4; (18) 83 Lo Moro, G. (3) 30,31; (7) 2; (24)

(16) 42

Lin, J . 4 . (20) 73,289

Li Y.4. (18) 18,19

71; (22) 23

40 1

97 Longw, J. (14) 18 Ibpes-Espinosa, M.T.P. (1 3) 26 Lhpez, I. (9) 65; (10) 28 Upez, J.C. (18) 97 Lopez, R.M. (12) 13; (18) 17

Ibpez-Castro, A. (22) 80 Ibpez de la Paz, M. (9) 53 Ldpez-Herrem, F.J. (3) 267; (16)

34; (20) 150 Lorey, M. (20) 185,187 Lorin, C. (21) 15 Lormeau, J.C. (4) 151, 152; (22)

Lotter, H (3) 162; (22) 57 Lou, 2. (20) 13; (22) 157 Loukine, N. (4) 216 Loupy, A. (3) 7,40,43 Lovett, C.M., Jr. (5) 1,2; (12) 19 Lowe, RF. (22) 50; (24) 87 Lu, D. (4) 112, 162,177 Lu, G.-T. (17) 7 Lu, J. (9) 38; (23) 32 Lu, K.-k. (3) 133; (6) 12 Lu, P.-P. (4) 66 Lu, S.-F. (4) 122 Lu, S.-J. (17) 7; (22) 108

IbpeZ-Barba, E. (4) 119; (21) 73

70

Lu, Y. (16) 58 Lubineau, A. (3) 10, 27,307; (4)

81; (24) 90 Lucchini, V. (4) 23 1 Luck, RD. (22) 105 Luck, R.L. (22) 81 Lfitzen, A. (24) 91,92 Lugar, C.W. (3) 55 Luger, P. (1 8) 8; (22) 75

Lukacs, G. (9) 9; (10) 39; (14) 26,

Luna, E.A. (4) 212,213 Lundt, I. (16) 1; (18) 55,65,95 Luo, z. (21) 74 Luyten, I. (20) 136; (21) 21,22 Luzzio, F.A. (7) 13 Lycka, A. (21) 79

Luh, T.-Y. (18) 117

27; (22) 115

Ma, L.T. (9) 24 Ma, T. (20) 73, 146 Maaheimo, H. (4) 157 McAlpine, J.B. (19) 56 McAtee, J. (20) 10; (22) 145 McAuliffe, J.C. (3) 174; (4) 115;

(7) 83; (9) 7, 8, 16; (18) 140- 142; (22) 94

McCague, R (19) 33 Maccarrone, G. (4) 234

402 Mccarter, J.D. (3) 212; (8) 3 Mccarthy, K.E. (3) 165 Mccarthy, P.A. (3) 121; (8) 10 Macchia, F. (9) 13 McClure, C.K. (17) 6 McComas, W.W. (20) 257 McCormick, J.L. (19) 54 McCullough, K.J. (18) 112; (22)

McCurdy, S.N. (20) 23 1,232 McDonald, F.E. (9) 42; (13) 9;

Macedo, E.A. (2) 37 McGarvey, G.J. (1) 14; (18) 32 Mach, M. (2) 17; (3) 151; (18) 94 Machetto, F. (4) 163 Machida, H. (20) 98 Machida, R (23) 17 Machleidt, W. (4) 238 Macindoe, W.M. (7) 17; (10) 20 McIntee, E.J. (20) 189 Mackay, M.F. (22) 129 Mackenzie, G. (3) 28; (10) 17;

(16) 75; (18) 6 Mackie, W. (4) 65, 158 MacManus, D.A. (7) 30,46 McNaught, A.D. (1) 1 McNeil, M. (18) 46 MacWilliams, M.P. (20) 200 Madhusanadan, K.P. (22) 20 Madine P u s h , M. (18) 143 Madrid-Diaz, R. (3) 313 Madsen, R (3) 205; (18) 65; (19)

Maeba, I. (20) 145 Maeda, H. (9) 71; (10) 20; (16)

22; (23) 74 Maeda, M. (4) 230; (20) 297 Maeda, Y. (4) 230 Magaud, D. (4) 50 Magnani, J.L. (3) 246; (4) 140 Magausson, G. (3) 83, 191,233;

(4) 83; (7) 14; (14) 56 Magyar, E. (18) 120 Mahadevappa, D.S. (9) 72; (16)

Mahato, S.B. (9) 1 Mahon, M.F. (18) 170; (22) 125 Maier, R-D. (23) 28 Maillard, P. (3) 167 Maione, A.M. (9) 47 Maiuolo, L. (20) 292 Maj, K. (10) 2 hhjer, 2. (19) 50 Majumdar, A. (20) 235,236 Majumdar, S. (24) 66 Makaiyama, T. (3) 206 Maka~a, G.M. (21) 31

128

(14) 25

42

69

Makatsubo, F. (4) 190 Malay, M.F. (18) 132 Malakhova, 1.1. (7) 27

Mali, RS. (9) 5; (18) 61 Malik, A. (3) 2 Makin, V.G. (21) 35 Makina, O.L. (21) 35 Malko, D. (20) 182 Mallat, T. (16) 24

Malet, c. (5) 19

Mallet, J.-M. (3) 1,297; (4) 152, 163; (7) 66, (9) 29; (22) 70

Mahberg, L.-H. (19) 56 Mahberg, M. (18) 178 Malysheva, N.N. (3) 163 M d , Y. (4) 52 Mamuya, N.N. (16) 43.49; (21)

Manat, R (3) 110 Manaviazar, S. (13) 25 Mandai, T. (4) 248 Mandal, S.B. (18) 99; (19) 38;

Mandel, S. (3) 150 Mandes, R.F. (7) 64; (1 8) 26 Manfred& S. (20) 261,267 Mangoni, A. (3) 146 Mangoni, L. (1 8) 88 Manhas, M.S. (13) 16; (24) 83 Manku, S. (4) 76 Manley-Harris, M. (1) 20 Mann, J. (14) 41-43; (20) 115;

Manna, R (18) 88 Mannala, S. (21) 26 Manning, D.D. (4) 91; (7) 72,76;

Mannocci, F. (1 1) 12; (24) 74 Mansour, T.S. (18) 22; (20) 285,

Mantechxi, S. (18) 97 Mhtsiilii, P. (19) 15 Manzer, S. (4) 195 Mao, J. (4) 208

Maracs, L. (14) 46 Marais, L. (14) 52; (24) 15 Maras. A. (18) 129 Marchelli, R. (4) 229,234 Marchetti, P. (18) 1 Marcdontelles, J. (3) 73; (18)

90,91; (24) 41 Marcus, A. (19) 58-60 Marcus, Y. (22) 3 Marcussen, J. (23) 72 Marek, D. (24) 67 Margolin, A.L. (7) 41 Margolis, S.A. (23) 19

42

(20) 282; (24) 3

(22) 95

(24) 36

288

Mm, J.-M. (3) 12, 171

Carbohya?ate Chemistry Margonelli, A. (18) 15 1 M e n , C.L. (24) 6 Marin, G.B. (16) 66,67 Marinic, 2. (21) 56 Marinier, A. (3) 97; (7) 75 Marino, C. (10) 26,27 Marquez, V.E. (14) 19; (18) 106;

Marra, A. (2) 20; (3) 77,180,18 1 Marrero-Tellado, J.J. (24) 4 Marron, T.G. (3) 269 Marron-Brignon, L. (3) 79 Marsault, E. (20) 219; (24) 100 Marschner, C. (20) 156 Marsura, A. (21) 46 Martel, A. (3) 97; (7) 75; (18)

Martichonok, V. (4) 70; (16) 46 Martin, A. (6) 3; (10) 41; (16) 73 Martin, G. (24) 41 Martin, 0.R (22) 40 Martin, P. (3) 230; (18) 6 Martin, R. (4) 132; (18) 66; (22)

Martin, W. (16) 63 Martinez, J. (14) 5,6 MartineZ-Grau, A. (1 8) 90 Martinkova, M. (3) 302

Martin-Pastor, M. (4) 119; (21)

Martins Alho, M.A. (10) 64 Marvin, W.B. (20) 229 Manr, A. (20) 200 Maryanoff, B.E. (6) 8 Manabadi, C.H. (5) 31; (16) 21 Marzi, M. (6) 2 Masaguer, C.F. (2) 13, 14; (22) 53 Mase, N. (24) 96 Masojidkova, M. (20) 124 Mason, J.M. (22) 98 Massi, A. (3) 180, 18 1 Massoui, M. (18) 15 Mastrorilli, E. (7) 33 Masuda, H. (20) 176

(20) 165, 166; (21) 33

105; (20) 167

16

M a t t i n - L o ~ , M. (3) 252

47.69.73

Ma~uda, M. (10) 14-16; (22) 86- 88

Masuda, S. (3) 256 Masuda, T. (4) 2 17; (23) 12 Massuma, R. (19) 50 Mataka, J. (18) 163 Matheu, MI. (20) 63

Mathieux, N. (4) 59.99 Matin, M.M. (7) 9 Matsuba, S. (3) 288 Matsuda, A. (19) 43-45; (20) 97,

Mathie~, J.-P. (8) 30

98,106,118; (22) 138

Author Index Matsuda, H. (3) 116,142, 173;

Matsuda, K. (4) 228 Matsude, H. (18) 12 Matsugi, M. (3) 279 Matsuhashi, Y. (20) 155 Matsui, K. (3) 136; (18) 44, 146 Matsui, T. (3) 33 Matsukura, H. (18) 5 Matsumi, N. (3) 240 Matsumoto, H. (19) 14 Matsumoto, K. (3) 153 Matsumoto, M. (24) 42 Matsumoto, T. (3) 290 Matsumoto, Y. (20) 3 11 Matsumura, M. (24) 32 Matsumura, S. (3) 47,289,292 Matsunaga, K. (3) 145 Matsunaga, N. (18) 144 Matsuo, G. (3) 289 Matsuo, I. (4) 58,62 Matsuo, K. (24) 2 Matsuoka, K. (4) 170 Matsuoka, R (24) 98 Matsushita, A. (4) 236 Matsushita, Y. (3) 33 Matta, K.L. (3) 38; (4) 138 Matter, H. (21) 56 Matteucci, M.D. (20) 256 Matulic-Adamic, J. (20) 139, 140 Matulova, M. (2) 12 Maudet, M. (24) 85 Maugard, T. (18) 34-36 Maunier, V. (9) 26; (10) 11 Maurin, J.K. (14) 20; (22) 119 Maurizis, J.C. (7) 90 M q , G. (20) 65 Mavandadi, F. (18) 39 May, B.L. (4) 226 Mayer, R. (10) 23 Mayer, T.G. (3) 11 1; (18) 136 Mayr, G.W. (18) 169 Maidas, D. (3) 2%; (22) 69 Mazenko, RS. (23) 45 Mazur, A.W. (14) 22 Mazzei, R.A. (20) 169 Mazzini, C. (18) 53 Meade, E.A. (20) 57 Mechaly, A. (3) 2 19 Mechref, Y. (23) 56 Med~ges, A. (9) 6

Meerpoel, L. (3) 3 10 Megati, S. (20) 41 Meguro, H. (20) 127; (24) 26 Mehta, S. (3) 107; (4) 11 Meier, C. (20) 185-188 Meijer, E.W. (3) 86

(11) 29; (22) 114

Medina, M.-B. (23) 45

Meinjohanns, E. (4) 100 Meisenbach, M. (4) 49 Mekki, B. (1 8) 1 12; (22) 128 Melander, C. (2) 40 Melchioni, C. (7) 12 Meldal, M. (3) 107, 110,285; (4)

59, 99, loo Meldrum, K.P. (24) 63 Melgmjo, C.R (13) 26 Mel'nik, S.Ya. (20) 93 Meltsner, B.R. (20) 25 Menard, M. (3) 97; (7) 75 Mendel, D.B. (18) 115; (22) 127 Mendelson, W. (24) 98 Men& 2. (22) 144 Menicagli, R. (4) 245 Menichetti, S. (1 1) 12; (18) 54;

(24) 74 Menut, C. (7) 87 Menzer, S. (4) 244; (22) 62,63 MerchBn, F.L. (10) 51,52; (16)

Merchant, Z. (18) 105; (20) 167 Mereyala, H.B. (3) 103,232; (5)

Merhof, G.F. (1 1) 15 Merino, P. (10) 51,52; (16) 68;

(19) 32; (22) 84 Men, K.M., Jr. (21) 2 Meshkov, S.V. (3) 223; (20) 280;

(22) 150 Messer, A.C. (5) 1,2; (12) 19 M&&os, P. (10) 46 Metz, T.W. (3) 66 Meunier, S.J. (3) 245 Mkvellec, L. (19) 47 Meyer, H. (7) 53 Meyer, T. (1 9) 5 1 Meyers, C.L. (22) 77 Meyers, C.Y. (22) 76 M i d , D. (21) 79 Michalk M. (14) 59 Michalski, J. (7) 59 Michaud, T. (9) 18; (24) 51 Michel, J. (20) 59 Michelet, V. (3) 266 Micklefield, J. (20) 248 Middleton, P.J. (20) 117,281 Middleton, RF. (16) 39 Midland, S.L. (24) 49 Miethchen, R (3) 207,248; (8) 1,

Miglierini, G. (3) 76 Mignet, N. (20) 222,223 Mignon, L. (1 1) 24 Mihai, C. (18) 163 Mikami, Y. (9) 3; (19) 16

68; (19) 32; (22) 84

10; (18) 133; (24) 21

4

M i k h a i l ~ p ~ l ~ , I.A. (20) 240-242

403

Mikhailov, S.N. (3) 223; (20) 280; (22) 150

Miklovic, T. (18) 120 MikSik, I. (23) 68 Mikuriya, M. (17) 31; (22) 123 Miljkovic, D. (2) 8; (5) 30; (16) 5;

Miljkovic, M. (9) 15; (21) 34 Milligan, K.E. (5) 5 Mills, S.J. (18) 171 Milton, M.J. (4) 75 M i d i , Y. (12) 20 Min, J.M. (9) 24; (20) 300 Min, 2. (22) 60 Mhakawa, N. (20) 11 8 Minale, L. (9) 2; (14) 14 Minami, K. (4) 219 Minab, S. (4) 222 Mincsovics, E. (23) 9 Minder, R. (12) 12 Minehan, T.G. (3) 277 Minetti, P. (6) 2; (7) 89 Mischnick, P. (23) 6 Mishncr, A. (22) 1 17 Mishncv, A. (14) 2 Misiti, D. (6) 2; (7) 89 Misiura, K. (20) 221 Misra, A.K. (4) 11 1, 126 Mita, N. (24) 70 Mitamura, K. (3) 236; (23) 27 Mitani, T. (7) 74 Mitchell, H.J. (3) 176; (4) 47 Mitchell, J.R (14) 12 Mito, T. (18) 147 Mitsui, T. (20) 83 Mitsuishi, Y. (22) 35 Mitsumoto, H. (18) 160 Mitsunobu, 0. (14) 32,38; (24)

Mitzel, T.M. (2) 29 Miu, J.-M. (7) 67; (20) 192 Miura, S. (20) 97, 127; (24) 65 Miura, T. (3) 217

Miyahara, M. (20) 48 Miyajima, K. (3) 108; (9) 68-70 Miyama, S. (20) 306 Miyamoto, D. (3) 80; (7) 69 Miyamoto, T. (4) 71, 150; (7) 79;

Miyasaka, T. (20) 38 Miyauchi, H. (3) 91 Miyauchi, M. (4) 144 Miyazaki, K. (3) 25 Miyazaki, T. (4) 62 Mizuno, H. (17) 9; (22) 110 Mizuno, M. (4) 228 Mizutani, A. (7) 51

(18) 21

32,44

Mi% Y. (22) 60

(9) 54

404 Mizutani, T. (3) 240 Mlynarski, J. (3) 58; (16) 48,55

Moates, G.K. (22) 42 Mobashery, S. (19) 7 Mochizuki, T. (2) 32; (3) 300;

(10) 20; (15) 7 MocsBui, A. (19) 50 M O M , A. (21) 57 Moellet, C. (5) 21 Mohapatra, S. (6) 7 Mohn, H. (5) 29 Moise, C. (24) 82 Moitessier, N. (3) 71 Molina, J.L. (10) 66 Molina Pinilla, I. (18) 38 Moll, M. (16) 25 Molotov, S. (24) 54 Molteni, C. (22) 43 Momenteau, M. (3) 167 Monguchi, Y. (20) 3 16 Mtinkkonen, J. (23) 42 Monneret, C. (3) 54,57; (9) 10;

Monnicr, N. (3) 6

Monsigny, M. (10) 23 Montchamp, J.-L. (18) 114 Monteagudo, E. (21) 57 Montero, J.-L. (7) 87,88; (8) 18 Montgomery, D.S. (16) 39 Monti, D. (3) 198 Moon, H.R. (20) 286 Moore, P.R (18) 128; (22) 130 Mootoo, D.R. (24) 35 Mora, N. (7) 90 Moracova, J. (7) 44; (12) 9; (21)

Moradei, 0. (8) 29; (13) 19; (14)

Moraga, E. (21) 38 Moran, A.P. (3) 202 Moreau, C. (2) 10 Moreau, P. (19) 51 Moreau, S. (20) 59 Moreau, V. (4) 160; (9) 17; (1 1)

Morehouse, L.A. (3) 121; (8) 10 Moreno, P. (2) 7; (10) 57 Moreno-Maiias, M. (20) 160 Morens, R.M. (3) 79 Modre, A. (7) 87,88 Morgan, P.M. (13) 10 Mori, K. (3) 125, 126,132; (23)

Mori, S. (3) 204 Mori, T. (3) 46,50, 196 Mori, W. (17) 3 1; (22) 123

Mo, X . 4 . (20) 301,302

(16) 59

MOW, P. (18) 34-36

18

60

31,35

39

Mori, Y. (8) 7; (9) 55 Morie, K. (22) 135 Moriguchi, M. (3) 292 Morimoto, T. (3) 80; (7) 69 Morimoto, Y. (14) 28 Morin, A.M. (5) 16 Morin, C. (6) 11; (8) 30

Mono, K. (20) 122, 123 Morisaki, N. (20) 5; (23) 11 Morishima, H. (10) 5,6; (19) 52 Morishima, N. (8) 7

Morita, M. (17) 10; (18) 9; (24) 2 Monk, T. (23) 2 Moriyama, H. (3) 323; (4) 145;

(22) 149 Moro, G.L. (8) 25; (10) 38 Moroder, L. (4) 238 Morohoshi, K. (20) 276 Morris, P.E., Jr. (2 1) I1 Moms, V.J. (22) 42 Mortell, K.H. (3) 90 Morton, D.W. (21) 1 1 Morton, J.B. (19) 55 Morvan, F. (20) 223 Moseley, R.T. (22) 93 Mostowicz, D. (14) 2; (22) 117 Mota, A. (2) 26; (20) 35 Motherwell, W.B. (3) 314; (8) 15;

Mouffouk, F. (7) 88 Moulabbi, M. (21) 54 Mourier, N. (20) 290 Mountsen, S. (4) 100 Mrachko, G.T. (16) 16 Muck, S. (6) 2; (7) 89 Miihlegger, K. (21) 29 Mdler, D. (19) 57-60 Miiller, L. (23) 4 Miiller, T. (7) 56; (15) 2,3; (20)

Miinch, U. (20) 277 Miinster, I. (21) 29 Muhmoudian, M. (16) 39 Mukai, C. (3) 158 Mukaiyama, T. (3) 22,25,35,

Mukayama, T. (12) 18 Mukherjee, M. (22) 54; (24) 46 Mulard, L.A. (21) 55 Mulder, G.J. (16) 61 Muller, K. (22) 52 Mulzer, J. (18) 8 Mun, H. (3) 235 Munfotte, P. (3) 30,31; (7) 2: (24)

Morin, M.-P. (7) 1 I

Mo~~s-VWU, F. (3) 269

(18) 125

209

237,317; (20) 47

97

CarbohHaie Chemistry Murahashi, N. (3) 60 Murai, A. (24) 25 Murai, Y. (3) 323; (22) 149 Murakami, M. (16) 80 Murakami, T. (3) 116, 142,240;

(10) 67; (11) 29; (22) 114 Murakami, Y. (3) 101 Murali, R. (13) 33; (14) 37 Mumka, M. (20) 45 Muraoka, 0. (1 1) 29; (22) 114 Mumoka, Y. (19) 48; (22) 49 Mumse, H. (3) 41 Murase, K. (7) 71 Mumta, K. (3) 279 Murata, M. (24) 24 Murata, T. (3) 194; (4) 23,66;

Murikami, T. (3) 173; (18) 12 Murphee, S.S. (18) 33 Murphy, PJ. (3) 320; (24) 19 Murray, B.W. (20) 212 Murray, J.K. (9) 4 1 Muscate, A. (20) 202 Musiol, H.-J. (4) 238 Mussini, P.R (3) 299 Mustafin, A.G. (20) 36,67,68 Muto, N.F. (20) 243 Muzard, M. (20) 129 Myers, C.B. (8) 8; (22) 104 Mycrs, K.R. (23) 34 Myszka, H. (10) 49

(23) 18

Nabiev, I.R. (22) 6 Nacro, K. (16) 12 Nadkami, P.J. (10) 55 Nagahara, K. (20) 297 Nagai, S. (7) 93 Nagai, T. (4) 199,200; (22) 99 Naganam, A. (24) 28 Naganawa, H. (19) 12,48,49;

(22) 49,102 Nagarajan, A. (20) 25 Nagarajan, M. (13) 33; (14) 37 Nagaregawa, Y. (4) 71; (9) 54 Nagasawa, M. (24) 23 Nagase, H. (4) 199,200 Nagashima, T. (23) 21 Nagata, R. (20) 5; (23) 11 Nagata, T. (4) 203 Nagatsu, A. (7) 93 Nagiel, D.A. (24) 71 Nagpal, M.L. (23) 14 Nagy, L. (21) 35 Nagy, 2. (3) 72 Nair, V. (20) 164,287; (24) 94 Naitou, T. (24) 22 Nakagawa, T. (24) 45 Munro, M.H.G. (10) 10 - - . .

Author Index Nakagishi, M. (22) 121 Nakagoshi, M. (17) 23 Nakaham, Y. (3) 132; (4) 33,80,

156, 176 Nakai, H. (4) 114; (23) 40 Nakai, Y. (4) 5,89 Nakamum, A. (4) 236 Nakamura, H. (19) 12,48,49;

(22) 49, 102 Nakamura, K.T. (19) 48; (20) 38;

(22) 49 Nakamura, M. (4) 239; (16) 62 Nakamum, N. (4) 149 Nakamura, 0. (12) 20 Nakamura, S. (4) 56; (16) 62; (18)

Nakamura, T. (18) 160; (23) 40 Nakamura, Y. (7) 93 Nakanishi, H. (22) 35,37 Nakanishi, K. (22) 153 Nakano, H. (4) 205; (20) 83 Nakano, M. (10) 5; (19) 52 Nakasubo, F. (4) 25 Nakata, T. (24) 45 Nakatani, I. (3) 236 Namazi, H. (7) 23 Nanbu, D. (20) 122, 123; (22) 135 Napoli, A. (20) 292 Napper, S. (21) 26 Nash, RJ. (3) 136; (7) 84; (10)

69; (18) 43,46; (24) 62 Nashed, M.A. (3) 154 Nasr, A.Z. (20) 134 Nastarowicz, E. (1 0) 29 Nasu,A. (7) 15 Nasu, K. (4) 196 Nativi, C. (11) 12; (18) 54; (24)

Natunen, J. (4) 154 Navarre, N. (4) 106 Navarro, R (22) 10 Navaza, A. (22) 64 Naven, T.I.P. (22) 29,3 1 Nawoschik, K.J. (20) 71 Nawrot, B. (20) 269 Naydenova, Z. (20) 273 Naz, N. (3) 2 Nazarov, A.A. (7) 62 Negato, E. (20) 176 Nekado, T. (3) 108; (9) 70 Nelissen, H.F.M. (4) 240 Nelson, J.S. (20) 23 1,232 Nepogodiev, S.A. (1) 19; (3) 86;

41

74

(4) 194, 195,244; (22) 62,63, 65

Neschadimenko, V. (20) 80 Neszmdlyi, A. (3) 162; (22) 57 Neubert, R. (23) 33

Neumann, K.W. (4) 120; (7) 70 NeuR, 0. (17) 13 Neustroev, K.N. (3) 49 Newton, M.G. (8) 13; (19) 36;

(20) 73,75,76,289; (22) 136 Neyts, J. (19) 45; (22) 138 Nguefack, J.F. (13) 7; (14) 44,45,

Nguyen, B.V. (8) 6; (18) 126 Nguyen, C. (3) 227 Nguyen, M.Q. (20) 232 Nguyen, T.N. (8) 21 Nicolaou, K.C. (3) 15, 176,270;

(4) 47, 171, 179; (5) 22; (13) 3

47

Nicoletti, I. (23) 15 Nicolosi, G. (18) 130, 131 Nicotra, F. (3) 258,261,276,283,

Niddam, V. (20) 290 Nieger, M. (17) 14; (22) 122 Nielsen, C. (20) 79, 183 Nielsen, P. (14) 10, 11; (20) 110,

Niemann, A. (3) 248; (8) 4 Niepel, T. (7) 53 Nieto, M.I. (20) 170 Nieto, 0. (3) 252 Niewiarowski, W. (20) 230 Nifant'ev, E.E. (7) 61-63; (8) 27 Nibt'ev, N.E. (3) 210; (21) 66 Niizuma, S. (19) 43 Nikaido, T. (4) 52; (12) 20 Nikolaev, A.V. (4) 175 Nikrad, P.V. (21) 70 Nillroth, V. (24) 72 Nilsson, K.G.I. (3) 37; (4) 15,57 Ning, J. (3) 224,225; (5) 27,28;

Ninomiya, K. (3) 142, 173; (18)

Nishi, N. (4 218 Nishida, Y.\4) 18; (22) 155 Nishijima, M. (9) 71; (10) 20; (16)

Nishikawa, K. (19) 48; (22) 49 Nishimura, N. (20) 145 Nishimura, S . 4 (4) 78 Nishimura, T. (4) 190; (10) 6 Nishimura, Y. (19) 53; (23) 12 Nishio, T. (7) 29 Nishiyama, S. (20) 100 Nishiyama, Y. (20) 145 Nishizuka, T. (24) 12 Nitoda, T. (3) 95; (16) 44 Niu, C. (20) 64 Niu, D. (20) 293

285,291; (9) 49; (17) 2

111

(19) 27,28

12

22

405

Noe, C.R (20) 104 Noecker, L.A. (8) 16; (10) 44;

(12) 15; (22) 91 Noel, T,R (22) 42 Nogami, Y. (4) 196,197 Noguchi, H. (24) 89 Noguchi, S. (11) 13; (22) 113 Nogueras, M. (10) 8 Nolte, R.J.M. (4) 240 Nomura, K. (4) 2 18 Nonaka, Y. (20) 38 Norberg, B. (22) 140,143 Norberg, T. (4) 10,97 Norbreck, D.W. (20) 1 Normand-Sidiqui, N. (10) 23 Nomld, J.C. (1 1) 3 1; (18) 29,30;

(22) 83 Noms, P. (22) 81 Nortey, S.O. (6) 8 Norton, AX. (16) 50 Noshizawa, M. (4) 198 Nothofer, H . 4 . (16) 7 Novikova, O.S. (10) 12 Novitny, M.V. (23) 53 Nowakowska, M. (4) 216 Nower, P. (20) 107 Nowick, J.S. (4) 7 Noya, B. (10) 56; (14) 24; (24) 43 Nozaki, T. (4) 230 Nugent, T.C. (18) 132; (22) 129 Nyilas, A. (20) 191

Obara, T. (19) 44,45; (22) 138 Obata, A. (7) 15 Obika, S. (20) 122,123; (22) 135 Obretenov, T.D. (16) 82 Oehme, M. (23) 4 (Ihrlein, R (4) 73, 133 Ogawa, K. (4) 149; (18) 135 Ogawa, S. (18) 144, 147; (24) 55,

Ogawa, T. (3) 52,213; (4) 33,80,

Ogawa, Y. (4) 188 Ogier, L. (6) 11 Ogihara, Y. (3) 109 Ogilvie, K.K. (22) 9 Ogoshi, H. (3) 240 Oguma, T. (4) 203 Oguri, H. (24) 24 Oh, J. (3) 271 Ohashi, K. (4) 84 Ohashi, Y. (14) 7; (24) 20 Ohishi, H. (3) 323; (22) 149 Ohishi, T. (9) 27 Ohizumi, Y. (3) 145

56,75,77

120, 156, 176; (7) 70

Noble, D. (16) 39 Ohkubo, M. (10) 5,6; (19) 52

406

Ohler, E. (20) 15 1 Ohmori, H. (23) 74 Ohmoto, H. (4) 145, 166; (7) 78 Ohnishi-Kameyama, M. (9) 55 Ohno, T. (10) 5; (1 9) 52 Ohnuki, T. (3) 143; (16) 2 Ohrlein, R (3) 246; (20) 210 Ohmi, H. (20) 127; (24) 26 Ohshima, E. (3) 101 Ohshima, T. (3) 15 Ohta, E. (3) 141 Ohta, H. (9) 30,45; (16) 40 Ohta, K. (4) 196,197; (24) 32 Ohta, S. (3) 141 Ohtake, H. (3) 164; (6) 15 Ohtake, Y. (3) 236 Ohtani, 1.1. (9) 31; (13) 22 Ohtsubo, S. (7) 8 Oilrawa, M. (3) 203,204 Oikonomakos, N.G. (7) 84; (10)

32,33,69 Oishi, T. (24) 24 Oivanen, M. (20) 308,310 Ojea, V. (9) 36 Oka, K. (4) 52 Oka, M. (3) 279 Oka, T. (24) 25 Okada, M. (3) 89 0- Y. (4) 206 Okahata, Y. (3) 46,50,196 Okahira, A. (22) 5 Okamoto, M. (22) 30 Okamoto, T. (4) 225 Okamoto, Y. (7) 92; (20) 297 Okano, T. (22) 99 Okawa, E. (23) 17 Okazaki, H. (9) 30,45; (16) 40 Okazaki, T. (18) 152 Okazaki, Y. (3) 292; (4) 206 Okkels, F.T. (20) 133 Okonogi, T. (19) 11 Okruszek, A. (20) 179 Oh, T. (7) 29 O h o , D. (9) 19; (18) 47 Olbncb, F. (24) 73 Old, L.J. (4) 125 Oleinkov, V.A. (22) 6 Olesiak, M. (20) 179 Olcsker, A. (9) 9; (10) 39; (14) 26,

27; (22) 115 Oliver, J.S. (20) 268 Olivier, A. (22) 140 Olivo, H.F. (20) 162 Ollier, M. (19) 51 Olmstead, M.M. (22) 78 Olscn, C.E. (14) 9, 10; (20) 11 1,

112; (23) 72 olsovsky, P. (10) 4

Olsson, L. (4) 9, 127; (7) 20 Olsufyeva, E.N. (1 9) 20 Omoto, S. (19) 11 Omura, S. (19) 50 Onaka, T. (17) 23; (22) 121 O'Neil, I.A. (20) 105 Ongun, B. (16) 77 Onishi, Y. (7) 29 Ono, A. (20) 49 Ono, A.M. (20) 49 Ono, H. (9) 55 Onodera, J. (3) 288 Onwueme, K. (14) 16 Opitz, D. (2) 42; (17) 27 Ora, M. (20) 308 Oritani, T. (10) 34 Ojala, J. (5) 4 Onini, F. (3) 76 Ortiz Mellet, C. (9) 63,64,66;

(10) 47,48; (11) 1; (24) 68 OrNio, R.M. (20) 163 Osa, T. (4) 220,222 Osada, M. (9) 3 1; (13) 22 Osada, N. (7) 29 Osborn, H.M.I. (4) 180; (6) 14;

(7) 31 Osborne, J.J. (3) 55 Oscarson, S. (3) 112; (4) 9, 123,

127,135; (7) 20; (18) 165 Oshhwa, T. (17) 9; (22) 110 0s- K. (5) 11; (7) 96; (20) 50 Oshitari, T. (3) 182 Osterman, RM. (19) 55 Ostrander, G.K. (23) 56 bsz, E. (10) 31 Otani, T. (19) 14 Otim, 0. (23) 65 Otsomaa, L.A. (9) 37

55; (16) 76 Otter, B.A. (20) 41 Oucbi, H. (3) 292 Ovchinnikova, T.V. (3) 187 Owen, D.R (6) 14; (12) 8 Oya, T. (4) 201,202 Oyamada, H. (2) 30 O'Yang, Q. (4) 122 Oyelere, A.K. (20) 268

Ott, A.-J. (2) 25; (4) 94; (7) 43,

Pacakova, V. (23) 36 Pace, R (23) 26 Padalko, E. (19) 45; (20) 170; (22)

Padron, J.I. (21) 39 Padwa, A. (18) 33 Paetsch, D. (13) 4; (17) 12 Pai,N. (20) 190

138

CarbohHate Chemistry Painter, G.F. (18) 154, 155 Pakhomova, S. (22) 41 Pakulski, 2. (2) 15; (12) 16; (16)

Palacias, J.C. (9) 65; (10) 28 Palaima, A. (3) 242 Palcic, M.M. (2) 25; (4) 17.66,

14,70

76,94; (7) 55; (18) 144; (23) 51

Palmer, D.RJ. (16) 16 Palumbo, G. (20) 173

Pan, J. (4) 139 Pan, S. (3) 168 Pan, Y.T. (3) 184; (18) 72; (24) 62 Fanagia, A. (4) 229 Panaiin, E.F. (7) 27 Panday, N. (10) 68; (22) 82 Pandit, C.R (3) 34 Panek., J.S. (13) 17

Pankiewicz, K.W. (20) 235-237 P d a , M. (18) 133 Pannccouckc, X. (4) 153 Pannecourt, X. (6) 21 Pannell, L. (4) 148 Panza, L. (3) 198,258,285; (17) 2 Panzica, RP. (20) 23 Paoletti, S. (4) 74,82,93; (1 1) 12;

Papoo, G. (23) 26 Paquette, L.A. (2) 29,33 Paredes, M.D. (10) 56; (14) 24 Parel, S.P. (20) 138

Park, H. (20) 286 Park, HG. (3) 235; (7) 45 Park, H.J. (21) 72 Park, J.D. (3) 161 Park, J.H. (3) 293

Park, J.W. (4) 214

Park, K.K. (4) 214 Park, M.K. (3) 293 Park, T.K. (4) 161

PdrkBnyi, C. (16) 82 Parkanyi, L. (17) 9; (22) 110 Parker, E.J. (16) 29; (18) 113 Parker, R (2) 39; (22) 42, 15 1

Parr. LB. (18) 69; (22) 39 Pam, A. (18) 158

Pan, B . 4 . (20) 291

Pangrazio, c. (9) 49

(24) 74

Park, C.-H. (20) 205

Park, J . 4 . (20) 270

Park, J.-Y. (24) 95

Park, Y.-H. (4) 214

Parmar, V.S. (20) 95

Parra-Rapado, L. (3) 309; (18) 110

Parrill, A.L. (2 1) 42 Paninello, M. (22) 43

Author Index

Pany, RJ. (18) 104 ParthaSarathy, R (22) 133 Passacantile, G. (24) 78 Pastor, J. (4) 171,' 179 Pastuch, G. (3) 241 Patch, R.J. (3) 34 Patel, B.K. (20) 201 Pati,A. (18) 130,131 Paton, RM. (2) 21 Patopristy, V. (10) 18 Patra, A. (24) 66 Patra, R (19) 38; (20) 282; (24) 3 Patravale, V.B. (23) 8 Paul, C.C. (2) 22 Paulsen, H. (3) 110; (4) 1,59,99 Pavey, J.B.J. (20) 105 Pavia, A.A. (8) 18 Pavlovic, N. (16) 56 Payet, J.-M. (20) 99 Pazynina, G.V. (3) 187 Pearson, W.H. (24) 69 Peci, L.M. (3) 70 Pedatella, S. (4) 139; (20) 173 Pedersen, C. (5) 12; (10) 60; (12)

2; (16) 8; (18) 29,30 Pedersen, E.B. (20) 72,79,89,

183 Pedersen, E.V. (20) 262 Pedersen, F.D. (7) 36 Pedersen, S.F. (17) 26 Pederson, C. (22) 83 Pedone, C. (22) 66 Peerlings, H.W.I. (3) 86 Peeters, K. (18) 57; (24) 60 Peeters, O.M. (20) 88,153 Pehk, T. (20) 13 1 Peinsipp, R. (3) 175 Pelicano, H. (20) 65 Pelizzoni, F. (3) 76 Pelyvh, I.F. (18) 120, 143 Penad&, S. (9) 53; (21) 51 Penno, M.B. (9) 14 Penny, M. (3) 144 Peoc'h, D. (20) 107,249 Pedkyli, M. (10) 21 Pereda-Miranda, R (7) 52 Peregrin, J.M.S. (17) 22 Peres, A.M. (2) 37 Perez, S. (4) 158; (21) 8, 15,68 P6rez-Garrido, S. (22) 80 Pen, F. (18) 123 Peric, B. (5) 30; (16) 5; (20) 151 Perigaud, C. (3) 244 Perra, G. (20) 137; (22) 148 Perrakis, A. (22) 45,67 Peny, B. (22) 38 Perry, M.C. (20) 177

P ~ o t - L o p e ~ H. (4) 237; (10) 13 Peseke, K. (14) 59 Peterbauer, T. (18) 137 Peterek, M. (24) 18 Peterlongo, F. (23) 26 Peters, J.A. (2) 43 Petersen, P.J. (18) 18,19 Peterson, M.A. (14) 12 Petillo, P.A. (9) 61 Petit; A. (3) 7 Petitou, M. (4) 151,152, 163,

184; (2 1) 68; (22) 70 Petkov, D.D. (20) 175

Petrier, C. (3) 6 Petrovic, v. (7) 4 Petrus, L. (2) 12; (3) 265 Petrushevska-Tozi, L. (23) 70 Petrusova, M. (2) 12; (3) 265 Petsch, D.T. (14) 15 Pettigrew, D.W. (20) 203 Pettit, G.R (3) 144 Pettit, RK. (3) 144 Pfeffervorn, J. (3) 15 Pfleidercr, W. (3) 135; (20) 60,

Pflum, D.A. (14) 15 P h g l e , W. (24) 88 Phndheller, H.M. (14) 9-1 1; (20)

110-1 12 Phillips, D.L. (3) 55 Philo, J.S. (21) 70 Phung, N. (18) 52 Piancatelli, G. (24) 78 Piastrelli, I. (10) 17 Piatelli, M.P. (18) 130, 131 Picasso, S. (14) 49; (18) 76 Piccioni, F. (6) 1 Pickering, L. (7) 84; (10) 69; (24)

62 Piekarska-Bartoszewict, B. (9)

60; (21) 36,37; (22) 92 Piercey, J.E. (16) 39 Pierra, C. (20) 65 Pietruszka, J. (4) 180; (6) 13 Pietschmann, C. (18) 8 Pikrylova, V. (3) 129 Pikul, S. (3) 114 Pina, M. (7) 38 Pineschi, M. (9) 13,48; (18) 20 Pino-Godez, M.S. (3) 267; (20)

Pinquet, F. (23) 22 Pint&, I. (9) 63,64; (10) 42,46-

48; (21) 46 Pinto, B.M. (4) 11 Piotrowiak, P. (22) 33 Piotrowski, H. (22) 73 Pipelier, M. (24) 13

Petre, D. (18) 34-36

61,241-244,277,278

150

407

Pirrung, M.C. (20) 229 Piskala, A. (20) 12,20 Pitha, J. (4) 210 Pitsch, S. (20) 8 Planas, A. (4) 160; (1 1) 35 Plat, D. (1 6) 32 Plaza, M.T. (2) 26; (20) 35 Pleixats, R (20) 160 Plessis, I. (6) 20; (9) 59 Plocek, J. (23) 53 Plusquellec, D. (3) 4, 11; (10) 17;

Pod& G. (22) 15 Podkopacva, T.L. (20) 240 Pohl, N.L. (4) 95; (5) 15 Poisson, J.-P. (6) 14 Polakova, M. (16) 78 PoIaSek, M. (23) 69 Poli, G. (4) 14 Pollet, B. (3) 78 Pollicino, S. (18) 123 Pollini, G.P. (18) 1 Pan@ F. (14) 56 Poole, J.L. (3) 26 Popovic, B.D. (16) 18 Popovid, D.A. (23) 46 Poppe, L. (21) 70 Popsavin, M. (2) 8; (5) 30; (16) 5 Popsavin, V. (2) 8; (5) 30 Portella, C. (14) 31; (16) 9 Porwanski, S. (3) 183; (13) 21 PospiliilovB, M. (23) 69

Potter, B.V.L. (1 8) 170,17 1,179; (20) 239; (22) 125

Potterat, 0. (22) 18 Povatov, L.S. (19) 21 Poveda, A. (21) 51,69 Powell, D.R. (14) 59 Powis, G. (18) 162 Pozsgay, V. (3) 162; (4) 148; (9)

6; (21) 55; (22) 57 Prabahar, K.J. (20) 18 1 Prabhakam, J. (24) 94 P d e r a , M.A. (9) 19; (10) 66;

(16) 75

Postel, D. (7) 91

(18) 47

77 Pragnacharyula, P.V.P. (20) 44,

Prakash, L. (20) 24 PAY, J.-P. (3) 275; (13) 34 Prandi, J. (14) 18; (18) 96 Prasad, A.K. (20) 95 Prata, c. (7) 90 Prenner, RH. (2) 28; (16) 35 Preobrazhenskaya, M.N. (19) 20,

Prestwich, G.D. (18) 180 Priebe, W. (1 1) 5

21

408 Priepke, H.W.M. (4) 180; (6) 13 Priestley, E.S. (9) 21; (19) 6

Princivalle, F. (3) 155 Prinzbach, H. (9) 74 Pritchard, R.G. (22) 50,s 1; (24)

86,87 Privat, E. (3) 4 Priya, K. (22) 79 Probert, M.A. (4) 75 Procaccio, C. (6) 1 ProchBzka, J. (23) 69 Procopio, A. (20) 292 Prodger, J.C. (7) 80 Proud, AD. (7) 80 Prudhomme, D . R (12) 11 Prudhomme, M. (19) 5 1 Pruess, D.L. (20) 257 P d a n o v , V. (20) 148 Prybysz, B. (1 1) 5 Pucci, B. (7) 90 Puccioni, L. (18) 63 Pucher, R (20) 156 Piischl, A. (20) 217,218 Piitz, U. (11) 36 Pugashova, N.M. (7) 61,62; (8)

Pyzowski, J. (20) 230

PnkrylOVB, v. (20) 20

27

Qasba, P.K. (21) 62 Qi, H. (8) 5 Qi, Y. (16) 74 Qiao, L. (18) 162 Qiu, D. (4) 98 Quan, X. (3) 14 Queneau, Y. (3) 6; (7) 17; (24) 90 Q u h d , C. (10) 23 Qui, D. (4) 102 Qui. Y. (20) 30 Quicelet-Sire, B. (12) 5; (14) 53;

(18) 14 Quin, F. (3) 3 Quintela, J.M. (9) 36

Rabiczko, J. (10) 53 Rabiller, C. (3) 192 Rabina, J. (4) 154, 157 Racioppi, R. (7) 42 Rademann, J. (3) 209 Ragazp, M. (21) 5 Raghavendra, M.P. (9) 72; (16) 69 Ragn, P. (18) 151 Ragoussis, V. (5) 18 Ragupathi, G. (4) 161 Rahmani, s. (2) 44

Raich, I. (12) 9; (21) 18 Raimondi, L. (21) 7 Raina, S. (18) 3 Raith, K. (23) 33 Rajanbabu, T.V. (24) 103 Rajewski, RA. (4) 212,213 Ralainairina, R. (18) 138 Rama, C.V. (14) 37 Ramamoorthy, P.S. (3) 228; (16)

Ramana, C.V. (13) 33 Ramanjulu, M.M. (8) 8; (22) 104 Rama Rao, C. (6) 7 Ramirez, J. (3) 321 Ramlakhan, D. (16) 39 Ramos, M.L. (1 7) 28,29; (2 1) 8 1 Ramzaeva, N. (21) 29 Ran- S. (20) 158 Rangappa, K.S. (9) 72; (16) 69 Range, G. (19) 59 Rao, B.V. (6) 17; (14) 54 Rao, C.P. (17) 18,24,25 Rao, J.A. (9) 41 Rao, V.S.R (21) 62 Raphoz, C. (3) 275; (13) 34 Rasmussen, K. (21) 1,3,48 Rasmussen, P.B. (20) 72 Rasmussen, R.R (19) 56 Rassu, G. (20) 66 Rastall, RA. (4) 16,46 Ratcliffe, R.W. (22) 93 Rath,N.P. (5) 31; (16) 21 Rattendi, D. (19) 40,41; (20) 159 Raul, G. (3) 48 Ravindranadh, S.V. (6) 17 Rayner, B. (20) 222,223,233 Reddington, M.V. (4) 221 Reddy, G.V. (4) 139 Reddy, K.K. (18) 156,157,176 Reddy, K.M. (18) 176 Reddy, R (3) 284 Reddy, Y.R (6) 7,18; (15) 5 Reddy Lingannagam, S. (5) 10 Redman, I. (7) 38 Redmond, J.W. (20) 27 Rees, N.H. (3) 250; (22) 11 1 Reese, C.B. (18) 159; (20) 215 Regeling, H. (18) 53 Rehnberg, N. (7) 59; (18) 175,

Reichel, F. (3) 99 Reid, C. (24) 71 Reif, B. (21) 76 Reilly, P.J. (21) 10,58 Reiner, M, (3) 226 Reinhardt, S. (4) 88, 113, 125; (7)

49; (22) 4

178

19 Rai, K.M.L. (9) 72 Reinhold, B.B. (4) 154

Carbohydrate Chemistry Remaud-Simeon, M. (18) 34-36 Remillard, R (3) 97; (7) 75 Remington, S.J. (20) 203 Remmel, R.P. (20) 189 Ren, R.X.F. (3) 322 Rcnkoncn, 0. (4) 154, 157 Rentsch, D. (3) 207 Rethfeld, I. (23) 59 Revers, L. (4) 64 kzac, M. (4) 241 Rheingold, A.L. (10) 44; (12) 15;

(22) 91 Rhie, S.Y. (20) 121

Mode, 0. (14) 40; (24) 48 Ribles, R. (2) 26 Richards, G.N. (1) 20 Richards, R.M.E. (23) 3 1 Richards, S.L. (18) 132; (22) 129 Richardson, D.P. (5) 1,2; (12) 19 Riche, C. (3) 296; (14) 5; (22) 69,

Richman, D.D. (20) 190

Richter, A. (18) 137 Riddle, S .R (18) 150, 163 Ries, M. (16) 63 Riess, J.G. (7) 65 Riley, A.M. (18) 170; (22) 125 Riley, T.A. (20) 229 Rinco, G. (22) 36 Ring, S.G. (2) 39; (22) 42, 151 Riopelle, RJ. (4) 224 Riordan, J.M. (21) 11

Ristov, T. (23) 70 fitter, A. (3) 157; (7) 22 Ritter, G. (4) 125 Ritzau, M. (9) 3; (19) 16 Ritzeler, 0. (19) 57, 58 Riva, s. (3) 198 Rivail, J.L. (21) 46 Rivalier, P. (2) 10 Rim, J. (18) 156 Rizzarelli, E. (4) 234; (22) 66 fizzo, C.J. (7) 16; (12) 11; (20)

Roas, M.D. (3) 146 Robert, L. (21) 54

Roberts, B.P. (3) 3 14; (8) 15 Robeits, S.M. (1) 11; (20) 197 Robina, I. (4) 119; (21) 73 Robins, M.J. (20) 6,37,80, 92,

303,304 Robinson, P.D. (22) 76,77, 144 Robles, J. (24) 4 Robles, R. (20) 35

Rho, M . 4 . (3) 145

96

Richou, A.-R. (20) 132

R~ou, J.-F. (19) 5 1

46

Robe~t-Baud~~y, J. (4) 50

Author Index Rocca, J.L. (23) 67 Roche, A.4. (10) 23 Rochepeau-Jobron, J.C. (16) 72 Rodebaugh, R. (4) 48,87,136; (9)

Rodriguez, C. (20) 35 Rodriguez, E.C. (4) 43 Rodriguez, N. (3) 252 Rodriguez, RM. (3) 176; (4) 47 Rodriguez-Femandez, M. (1 8) 90,

Roehri-Stoeckel, C. (4) 233 RaSler, A, (20) 61 Roets, E. (23) 30 Rogacheva, S.M. (16) 82 Roger, P. (9) 10 Rogers, M.J. (23) 42 Rogue, J.P. (5) 21; (8) 18 Rob, J. (4) 27; (12) 1 Roland, S. (3) 314; (8) 15 Rolando, C. (3) 78 Rolland, V. (8) 19 Rollin, P. (1 1) 8; (21) 15 Romagnoli, P. (7) 12 Roman, E. (9) 33; (10) 1 Romieu, A. (20) 182 Ronco, G. (3) 230; (7) 91; (18) 6;

Rondinini, S. (3) 299 Rong, F . 4 . (20) 52 Roper, T.D. (24) 29,30 Roque, J.-P. (7) 87 Rosemeyer, H. (20) 240,294; (2 1)

Rosen, R.T. (23) 25 Rosenau, T. (16) 83 Rosenblum, M. (19) 19 Rosenbohm, C. (18) 24 Rosenski, J. (20) 88,295 Rosowsky, A. (20) 190 Ross, G. (16) 7 Ross, S. (24) 98 Rossi, J . 4 . (24) 7 Rossiter, J.T. (1 1) 6 Roszak, A.W. (22) 40 Rotella, D.P. (18) 116 Roth, G.P. (24) 84 Rothe, U. (4) 113 Roush, W.R. (3) 13,64; (8) 24;

(11) 10,ll Roussev, C.D. (20) 175 Roux, B. (3) 113 Roy, A. (11) 26; (18) 99; (19) 38;

(24) 3 Roy, N. (3) 218; (4) 111, 126 Roy, R (1) 8; (3) 88,98,245; (4)

32,35,90; (16) 28; (24) 102 Rozenberg, M. (22) 3

50

91

(20) 99

28-30

409 Rozenski, J. (I 8) 27,80 Romers, E. (20) 252,279 Rubinstem, G. (3) 297; (7) 66; (9)

Salvador, L.A. (3) 2 15 Samain, E. (4) 44 Samano, V. (20) 6

29 Ruda, K. (3) 112; (18) 165 Rudolf, M.T. (18) 169

b i z , M. (9) 36 Rukavishnikov, A.V. (1 8) 166,

Rupitz, K. (10) 58 Russ, P. (20) 165 Russell, M.P. (22) 8 Rum, G. (3) 198,285 Ryan, M. (18) 166 Rydcr, T.R (20) 260 Rydlund, A. (4) 159 Rydzewski, R.M. (20) 144 Ryu, E.K. (20) 121

RuNk-Braq K. (24) 93

167

Saanna, M. (20) 240 Sabes, S.F. (24) 3 1 Sabesan, S. (10) 19 Sachleben, RA. (20) 278 Saegwa, K. (23) 16 Sago, S. (3) 208 Saha, N.N. (1 8) 64 Saha, U.K. (3) 105 Sahavattanapong, P. (7) 92 Saito, A. (10) 34 Saito, K. (3) 236; (10) 34 Saito, T. (4) 145 Saito, Y. (19) 45; (22) 138 Sajiki, H. (20) 316 Sakagami, M. (3) 60; (4) 84 Sakairi, N. (4) 218,225 Sakakibara, J. (7) 93 Sakakibara, T. (4) 62; (21) 16 Sakamoto, H. (3) 169; (4) 56 Sakamdo, M. (24) 70 Sakamoto, Y. (3) 323; (22) 149 Sakata, S. (20) 97,98

Saksenas, A.K. (19) 54 Sakurai, Y. (24) 23 Sakya, S.M. (18) 18,19 Sala, L.F. (16) 17; (17) 22 Sala, R.F. (13) 10 Salamonczyk, G. (7) 59 Salani, G. (8) 17; (14) 17; (17) 5;

(20) 128 Sallam, M.A.E. (20) 32,147 Salo, H. (18) 25 Salsini, L. (1 8) 54 Saluza, C. (18) 15 Salvaderi, P. (4) 245 Salvador. A. (23) 47

s a k i y m H. (22) 21

Sambamurthy, T. (1 8) 3 Sambri, L. (18) 53 Samcs, D. (4) 101 Samu, J. (9) 58 Samuelsson, B. (20) 168; (24) 72 Sancelme, M. (19) 5 1 Sanchez, A. (10) 8 Sanders, M.P. (4) 67 Sanders, W.J. (4) 91; (7) 76 Sandstriim, A. (21) 22 Sanfilippo, C. (18) 130, 131 Sanghvi, Y.S. (20) 107,249,250 Sano, A. (3) 279 Sam, J. (21) 63 Sam, K. (23) 39 Sansone, F. (3) 77 Santana, L. (20) 171 Sanmmana, M. (7) 85 Santiago de Alvarcnga, E. (14) 43 SantoycSodlez, F. (3) 243;

Sambia&h, F. (3) 267; (16)

Saravanan, P. (18) 3 Sarazin, H. (9) 43; (18) 51 Sarda, P. (9) 9; (14) 26; (22) 115 Sari, N. (21) 59 Sarker, S. (20) 6 Sarma, B.V.N.B.S. (6) I7 Sarma, M.S.P. (20) 41 Samcy, D.B. (7) 46 Sartor, G. (4) 229,234 Sasaki, A. (3) 60 Sasaki, T. (3) 190; (19) 14,45;

(20) 97; (22) 138 Sashida, Y. (4) 52; (12) 20 Sasinkova, V. (18) 58 Sastry, M.D. (17) 24 Satake, Y. (3) 198 Sato, K.4. (3) 51; (14) 13 Saw, M. (4) 168,247 Sato, 0. (24) 24 Sato, S. (3) 288 Sato, T. (23) 40 Sato, Y. (11) 13; (20) 214; (22)

Satoh, H. (20) 97,98 Satoh, T. (19) 53 Satou, T. (12) 20 Satsumabayashi, K. (22) 155 Sauvd, G. (1 8) 4 Savel'ev, A.N. (3) 49 Saviano, M. (22) 66 Sawa, R (19) 48,49; (22) 49, 102

(11) 25; (13) 29

34

113

- . < Sawa, T. (19) 48,49; (22) 49, 102

410

Sawada, K. (14) 7; (24) 20 Sawada, M. (4) 114 Sawada, T. (18) 153 Schaade, M. (3) 278 Schiirer, O.D. (18) 79 Schapira, RM. (23) 19

Scharma, G.V.M. (3) 312; (12) 3 Schaschke, N. (4) 238 Schaus, J.V. (13) 17 Schemer, G. (3) 160 Scheinmann, F. (3) 128; (16) 60 Schell, P. (20) 228 Schenkman, S. (4) 75 Schennan, D. (7) 85 Scherr, M. (19) 56 Schenmann, M . 4 . (3) 77,307;

Scheuer-Larsen, C. (1 8) 24 Schick, C. (3) 248; (8) 4 Schinazi, RF. (8) 13; (20) 10,76,

189,289,293,296; (22) 136, 139,145

Scharfl H.-D. (24) 18

(16) 68

Schlewer, G. (18) 175 Schleyer, A. (3) 110; (4) 59 Schlienger, N. (3) 244 Schmid, H.R (23) 38 Schmid, R.D. (7) 34 Schmid, U. (3) 17; (8) 23 Schmid, W. (16) 35 Schmidt, F. (3) 54 Schmidt, R.R (3) 9,24, 105, 11 1,

160,209,216,226; (4) 31,88, 107, 113, 125, 182; (7) 19,21, 56; (1 1) 33,34; (15) 2,3; (16) 47; (18) 59, 136; (20) 209

Schmidt, W. (2) 28 Schmitt, L. (20) 180 Schnackerz, K.D. (21) 78 Schneider, B.P. (3) 134; (20) 137;

Schneider, H.-J. (20) 312 Schneider, M.P. (7) 25 Schneider, R (3) 216; (16) 47 Schneider, T.L. (5) 1,2; (12) 19 Sheller, S.W. (19) 39-41,46;

Schollmeyer, D. (24) 88 Schollmeyer, W.D. (22) 85 Schomer, W.W. (2) 29 Schraml, J. (20) 153; (21) 77 Schramm, V.L. (1 8) 49 S h i e r , P. (3) 92 S c W e r , C. (16) 33; (22) 97 Schiile, G. (4) 41 Schultz, A.G. (18) 148 Schultz, C. (18) 177; (20) 196 Schultz, G. (18) 169

(22) 148

(20) 159

Schultz, P.G. (3) 235 Schulz, C. (7) 48 Schulz, J. (18) 181 Schulze, 0. (24) 73 Schumacher, P. (19) 22 Schuth, S. (4) 146 Schwalbe, C.H. (18) 168; (22) 126 Schwalbe, H. (21) 76 Schwartz, D.A. (20) 229 Sch- J. (3) 280; (16) 10; (18)

Schwarzenbach, F. (3) 246 Schwarzma~, G. (1 1) 36 Schwede, F. (20) 196 Schwittcr, U. (20) 102,200 Scofield, A.M. (14) 8; (18) 60 Scolastico, C. (4) 14 Scott, A.I. (1) 16 Scott# L. (5) 1,2; (12) 19 Screicher, H. (18) 59 Scume, M.A. (20) 229 Sears, P. (4) 132 Sebesta, D.P. (3) 13,64; (8) 24;

Secen, H. (18) 129 Sedmera, P. (3) 129; (10) 4; (20)

20; (22) 41 Secbach, D. (22) 19 Seeberger, P.H. (4) 60, 155 Seela, F. (20) 54-56,58,240,294;

Seemayer, R. (7) 25 Seepersaud, M. (24) 35 Seffers, P. (4) 210 Segal, I. (20) 262 Seguin, S. (14) 53; (18) 14 Seib, P.A. (5) 20 Seidman, M. (20) 235,236 Seifert, J. (4) 185 Seifert, W.E. (20) 117 Seitz, 0. (4) 131 Seitz, S.P. (24) 71 Sekanina, K. (1) 10; (4) 45 Sekine, M. (20) 206,214,309 Sekine, T. (22) 8 Sekljic, H. (4) 69 Seley, K.L. (19) 3941,46; (20)

Selkti, M. (22) 64 Sello, G. (3) 299 Senderowitz, H. (2) 36; (2 1) 64 Sentyureva, S.L. (20) 241,242 Seong, J. (21) 72 Seppo, A. (4) 154 Serafinowski, P.J. (20) 119 Seri, K. (2) 45; (3) 234 Seriami, A.S. (21) 19,20,25 S e m o , J.A. (9) 33; (10) 1

2

(11) 10,ll

(2 1) 28-30

159

Carbohyckate Chemistry Sevke, D. (19) 5 1 Severin, T, (2) 46 Sgarbi, P.W.M. (13) 30; (20) 62

Shaban, M.A.E. (10) 63; (20) 134 Shadhada, L.A. (10) 7 Shah, B.H. (21) 70 Shahgholi, M. (23) 14 Shah-Patel, S. (9) 41 Shahnay, A.S. (2) 5; (20) 69 Shanmuganathan, K. (20) 75 Sharma, G.V.M. (3) 301 Shashidhar, M.S. (18) 118 Shashkov, A.S. (3) 210; (21) 66 Sheikha, G.A. (20) 137; (22) 148 Sheldon, R A . (7) 35; (16) 6 Sheldrick, B. (22) 45 Shen, H. (16) 81 Shen, X.-M. (5) 3 Shen, Y.-F. (4) 209 Sherman, A.A. (3) 210 Shevik, V. (4) 50 Shi, D . 4 . (10) 45 Shi, G.4. (3) 270; (13) 3 Shi, J.X. (17) 7; (22) 106, 107 Shi, M. (16) 81

Shiba, Y. (23) 1 Shibaev, V.N. (10) 12 Shibahara, S. (19) 11 Shibakami, M. (10) 15; (22) 88 Shibano, M. (18) 41,42 Shibasaki, M. (3) 182 Shibata, K. (17) 23; (22) 121 Shibata, Y. (17) 10; (18) 9 Shibatani, S. (7) 40 Shibatomi, K. (7) 93 Shibuya, M. (4) 84; (7) 71 Shibuya, T. (4) 248 Shigihara, A. (4) 200 Shikishima, M. (20) 315 Shim, G. (21) 53 Shimada, H. (3) 116; (4) 196, 197;

Shunada, K. (3) 236; (23) 27 Shimada, Y. (14) 38; (24) 32 Shimbayashi, S. (20) 3 15 Shimida, Y. (24) 44 Shimizu, C. (16) 15 Shimizu, G.K.H. (3) 268 Shimizu, H. (14) 38; (24) 44 Shimizu, M. (18) 11; (20) 142 Shimizu, T. (10) 14-16,67; (22)

Shimo, T. (20) 299 Shimoda, H. (3) 116 Shimshock, Y.C. (13) 20; (11) 34 Shimum, T. (24) 32

sha, Y. (20) 33

Shi, Y. (24) 104-106

(1 1) 29; (22) I14

86-88

Author Index Shin, D.H. (20) 286 Shin, S. (20) 270 Shin, Y.G. (3) 293 Shindo, K. (4) 110 Shing, T.K.M. (1) 18; (24) 81

Shinohara, G. (1 1) 30 Shioiri, T. (24) 89 Shiozaki, M. (2) 32; (3) 300; (9)

71; (10) 20; (15) 7; (16) 22 Shioawa, T. (3) 263 Shipway, A.N. (4) 195; (22) 63 Shirahama, H. (14) 28 Shirai, R (18) 153 Shishido, K. (16) 62 Shnipor, I.P. (2) 5 Shoda, S.4. (3) 201 Shoham, V. (3) 219 Shohda, K. (20) 309 Shoji, T. (21) 63 Shoseyov, 0. (3) 253 Shudo, K. (20) 5; (23) 11 Shuto, S. (19) 43-45; (20) 106,

118; (22) 138 Sibi, M.P. (9) 38 Sible, E.M. (22) 26 Siciliano, C. (20) 292 Sicker, D. (3) 134, 137 Siddiqui, M A . (21) 33 Siegeb M.M. (22) 23 Sierra, M.G. (17) 22 Sifferlen, 7%. (18) 50 Sigel, H. (20) 178 Sigel, R.K.O. (20) 178 Signorella, S. (16) 17 Sih, C.J. (20) 238 Silks, L.A. (13) 8 Silverton, J.V. (22) 81,105

Simaaek, V. (3) 129 Simaoni, L.A. (3) 22 Simiand, C. (17) 8; (22) 109 Simmonds, R.J. (3) 29 Simonato, L. (4) 231 Simoni, D. (20) 261,267 Simonov, M.F. (20) 175 Simpkins, N.S. (19) 31 Sims, J.J. (24) 49 S h y , P. (3) 1,297; (4) 152, 163;

Shdkhedkar, M.D. (9) 5; (18) 61 Sindona, G. (20) 292 Singh, A. (20) 24,95 Singh, A.K. (2) 44 Singh, G. (18) 102,112; (22) 128 Singh, V.K. (18) 3 Singhal, R (23) 65

shinkai, s. (2) 47

Sim, K.-Y. (14) 21

(7) 66; (9) 29; (22) 70

(13) 1,7, 11,21; (14) 44,45, 47,s

Sin$ T. (20) 137; (22) 148 Sisti, N. (20) 43 Sitkowsi, J. (21) 80 Siudak, G. (18) 66; (22) 16 Sizun, P. (21) 68 Skaanderup, P. (7) 87 Skagerlind, P. (7) 37 Skelton, B.W. (9) 7; (22) 94 Skrydstrup, T. (3) 281,2%; (22)

Slattery, B.J. (20) 130 Sliedregt, L.A.J.M. (3) 100 Slusarchyk, W.A. (18) 105; (20)

Smain, E. (11) 35 Smales, C.M. (22) 47 Smiatacz, Z. (10) 49 Smiatacmwa, K. (1 0) 2 Smith, B.C. (22) 1 Smith, B.M. (4) 179 Smith, G. (17) 26 Smith, J.M. (20) 103 Smith, M.D. (1 8) 46 Smith, N.K. (4) 16,46 Snoeck, R (5) 21; (19) 45,46;

Snyder, D.S. (23) 34 Socha, D. (9) 32; (10) 53 Sochacki, M. (20) 221,235 Sodamo, G. (3) 45 Sofan, M.A. (20) 79 Sofia, M.J. (3) 115; (22) 1 Soholov, K.V. (22) 6 Solomons, K.RH. (18) 168; (22)

Soloway, A.H. (20) 52 Somekawa, K. (20) 299 Somers, P.J. (3) 102 Sommadossi, J.-P. (20) 91; (22)

Sommermann, T. (13) 13; (14) 35 So& L. (10) 3442; (13) 6 Son, S.U. (24) 99 Song, B. (20) 178 Song, J. (20) 263 Song, Q. (20) 215 Song, S.K. (3) 156; (4) 51 Sonnentag, M. (4) 146 Serensen, U.S. (14) 9; (20) 112 Soria, J. (20) 10; (22) 145 Soriente, A. (3) 45 S b , E. (10) 31 Sosenson, M. (24) 98 Soth, M.J. (4) 7 SetOAe. I. (18) 30: (22) 83

69

167

(22) 138

126

137

Sinou, D. (2) 23; (3) 183,262; Sousa, T.RE.-(9) 32 ~

41 1 Sowa, G.A. (20) 174 Sowinski, P. (19) 13 Spackman, D.G. (7) 3 1 Spada, M.R (20) 41 Spangenberg, P. (3) 192 Spampani, C. (18) 151 Spencer, R.P. (3) 280; (16) 10 Spiers, I.D. (18) 168; (22) 126 Spies, B. (18) 175 Spilling, C.D. (5) 31; (16) 21 Spirikhin, L.V. (20) 36,67,68 Spirito, A. (9) 47 Sponga, F. (7) 86 Spreafico, F. (7) 86 Sprinzl, M. (20) 269 SproaG B. (20) 258,259 Smnivasan, H. (22) 79 Sreif, M. (4) 73 Srikrishnan, T. (22) 133 Srinivasachar, K. (20) 213 srinivasan, s. (22) 79 Sriram, D. (22) 79 Srivastava, O.P. (4) 90 Stach, T. (10) 18 Stachulski, A.V. (3) 128; (16) 60 Stamm, A. (24) 93 Stamp Jensen, H. (5) 12; (16) 8 Stanek, J. (7) 44; (12) 9; (21) 18 Staniulyte, 2. (3) 242 Stanovnik, B. (10) 62 Starr, M.S. (10) 24 Stash, A.I. (7) 62 Stasdc, I. (9) 20; (16) 3,4 Staszak, M.A. (20) 114 S k u 4 T. (3) 170,251 Stawinski, J. (20) 216,226 Stead, D.A. (23) 3 1 Stec, W.J. (20) 179,221,230 Steckhan, E. (2) 6 Stefhiak, L. (21) 80 Stella, V.J. (4) 212,213

Stenhagen, G. (23) 23 Stcnutz, R (21) 41,65; (22) 58 Stephens, L.R. (18) 155 Stepowska, H. (2) 16; (22) 153 Stevens, RC. (18) 115; (22) 127 Stevens, W.C. (22) 144 Stevenson, D. (24) 98 Stewart, G.C. (23) 14 Stick, R.V. (3) 69,70,254,255,

282; (4) 115; (7) 83; (8) 9; (9) 7,8, 16;(11)4;(12) 17;(18)

Stargelc, K.-P. (20) 278

140-142; (22) 94 Still, W.C. (2) 36; (21) 64 Stoddart, J.F. (1) 19; (3) 81,84-

86; (4) 194,195,244; (18) 13; (22) 62,63,65

412

Stoeckler, J.D. (20) 23 Stoeaescu, C. (18) 158 Stoisavljevic, V. (20) 117 Stoltz, B.M. (14) 15,16 Stoodley, RJ. (22) 50,Sl; (24)

86,87 Strassel, J.-M. (4) 151 Straub, R (3) 54 Strecker, G. (1 0) 23 Streicher, H. (3) 226; (7) 21 Streiger, A.M. (22) 33 Streith, J. (9) 43; (18) 50,51 Sthpe, W.A. (21) 25 Striihl, D. (3) 316 (13) 28; (15) 4 Strhberg, R (20) 252,279,307 Strobeyer, T.W. (18) 18 Strong, L.E. (7) 72 Stuart, A.L. (21) 26 Stubbe, J. (20) 304 Stiitz, A.E. (3) 175; (18) 31,48,

Stulik, K. (23) 36 Sdrez , E. (2) 7; (10) 57; (15) 6;

(16) 57; (18) 45 Suda, Y. (3) 204; (4) 123 Sudharshan, M. (24) 80 Suemura, M. (3) 279 Sugai, T. (9) 30.45; (16) 40 Sugamoto, K. (3) 33 Sugarman, E.D. (3) 121; (8) 10 Sugata, T. (4) 71 Sugato, T. (9) 54 Sugihara, K. (24) 55 Sugimoto, T. (4) 248 Sugino, H. (3) 95; (16) 44 Sugiyama, E. (22) 22 Suh, M.J. (23) 66 Suh, Y . 4 . (3) 293

Subara, Y. (9) 14 Sultanova, V.S. (20) 36 Sumaoka, J. (20) 3 11 Sun, C. (16) 74; (20) 30 Sun, S. (3) 178

SuaQrababu, G. (8) 5 Sundeer4 J.E. (18) 105; (20) 167 Sunga, G. (19) 56 Sunjic, V. (16) 56 Surzhykov, S. (20) 289 Sussich, R (3) 155 Sutbcyaz, Y. (18) 129 Sutherland, J.D. (2) 3; (20) 4 Suthcrlin, D.P. (4) 105 Suyundukova, M.V. (20) 68 Suzuki, H. (3) 273; (19) 11; (24)

55

Suhadohdt, RJ. (20) 241-244

Sun, X.-L. (3) 239; (6) 4; (9) 35; (10) 50; (16) 19,52-54

70

Suzuki, I. (4) 192,220 Suzuki, K. (3) 190,290; (14) 13;

(17) 9; (22) 110 Suzuki, N. (23) 71 Suzuki, R (19) 8

Suzuki, T. (3) 264, (10) 22; (23)

Suzuki, Y. (3) 42,80; (7) 69 Svanem, P.-J. (1 1) 6 Svcte, J. (10) 62 Swaminathan, S. (18) 115; (22)

Swayze, E.E. (20) 19,249,250 Switzer, A.G. (3) 114 S&, T. (20) 216 Szabovik, G. (6) 19 Szarek, M.A. (1 8) 56 Szarek, W.A. (3) 82,93; (18) 56;

(20) 193; (22) 40 Szechner, B. (13) 2; (14) 20; (22)

Szegedi, C. (18) 120

Szeja, W. (3) 23,241 Sddgyi, L. (10) 3 1; (2 1) 56 Szokan, G. (23) 9 Sztaricskai, F. (16) 11; (18) 120,

143; (19) 50 Szunnai, 2. (3) 72,75; (4) 54 Szymonlak, J. (24) 82

suzuki, s. (18) 44

17

127

89,119

szeia, w. (11) 5

Taatjes, D.J. (19) 18 Tabei, K. (22) 23 Tabuchi, A. (4) 248 T h o , K.4. (3) 198 Taga, A. (23) 49 Taga, T. (22) 60 Tagaya, H. (4) 168 Tagmose, T.M. (9) 23; (18) 71,

139; (19) 9; (24) 57 Tago, Y. (20) 5 Tai, C.Y. (18) 115; (22) 127 Taiji, E. (18) 147 Tait, RJ. (4) 213 Tajima, S. (23) 17 Takada, K. (21) 63 Takada, M. (4) 149 Takagari, K. (4) 123 Takahashi, H. (20) 276 Takahashi, K.4. (22) 30 Takahashi, S. (4) 170; (1 1) 22;

(12) 7; (18) 68 Takahashi, T. (2) 3 1; (3) 59,273;

(4) 40; (16) 36,45 Takahashi, Y. (19) 49; (22) 102 Takaha@ S. (3) 220

CarbohHate Chemistry Takai, N. (23) 12 Takai, Y. (3) 51; (4) 114 Takaichi, S. (7) 50 Takanashi, S. (3) 125, 126 T h o , K. (3) 182; (24) 42 Takayama, H. (16) 30; (22) 100 Takayama, S. (18) 66; (22) 16 Thyanagi, H. (3) 239; (6) 4,5;

(9) 35; (10) 50; (16) 19,52- 54; (20) 297

Takebayashi, M. (20) 155 Takechi, M. (3) 222 Takeda, K. (3) 117,220,221 T a k a T. (3) 109; (22) 56 Takemoto, K. (7) 93 Takenaka, K. (20) 45 Takaka, J. (24) 56 Taketomi, T. (22) 22 Takeuchi, K. (3) 206,237; (12) 18 Takeuchi, M. (2) 47; (18) 146 Takeuchi, T. (19) 12, 17,48,49,

Talceya, A. (23) 44 Takeya, K. (7) 93 Takhi, M. (6) 7 Takimoto, Y. (22) 30 Takumi, K. (22) 99 Talekar, R.R (18) 23; (20) 283,

Tally, F.P. (18) 18 Tam, S. (20) 132,257 Tamakoshi, S. (17) 31; (22) 123 Tamura, J. (4) 120; (7) 70 Tamura, 0. (24) 70 Tamura, Y. (7) 50 Tanabe, G. (1 1) 29; (22) 114 Tanabe, T. (23) 17 Tanahashi, E. (4) 124; (7) 71 Tanaka, A. (10) 34 Tanaka, H (3) 80; (7) 69; (20) 38 Tanaka, M. (3) 91; (4) 144; (19)

Tanaka, T. (7) 47; (20) 3 15 Tanaka, Y. (3) 222; (4) 150; (9) 3;

Tanase, T. (17) 23,31; (22) 121,

Tandon, M. (20) 266 Tanemura, K. (22) 155 Tang, M. (3) 264; (10) 22 Tanimoto, T. (4) 205 Tanner, M.E. (7) 54; (13) 10 Tarclli, E. (7) 68 Targontsidis, S. (5) 16 Tashiro, A. (4) 66 Tatsuta, K. (24) 65 Tatsuta, T. (9) 71; (10) 20; (16) 22 Tavecchia, P. (7) 86

53; (22) 49, 102

284

45; (22) 138

(19) 16

123

Author I d x Taverna, M. (22) 38 Tawada, E. (3) 200 Taylor, B.F. (20) 154 Tber, B. (20) 99 Techenbrock, M. (1 7) 13 Ted&& U. (4) 135 Teida, T. (3) 117 Teijeira, M. (20) 171; (22) 15 Tejero, T. (10) 51,52; (16) 68;

(19) 32; (22) 84 TeKoppeIe, J.M. (23) 35 Temeriusz, A. (9) 60; (21) 36,37;

(22) 92 Tenni, R (23) 35 Teran, C. (20) 171 Terao, J. (3) 41 Terao, S. (16) 80 Ter-Grigoryan, A.G. (3) 187 Terjung, A. (3) 24 Terunuma, D. (4) 170 Teruya, K. (4) 150 Terwisscha van Scheltinga, A.C.

Testa, RT. (18) 18, 19 Tewari, Y.B. (4) 247 Tews, I. (22) 67 Thaisrivongs, S. (9) 67 Thang, T.T. (10) 39; (14) 27 Thatcher, G.RJ. (4) 224,227 Therond, P.R (24) 63 Thevernet, S, (7) 17 Thibaudeau, C. (20) 136; (21) 21-

Thibault, P. (22) 36 Thiele, G. (14) 59 Thiem, J. (2) 25; (3) 48, 106,130;

(4) 94, 169, 189; (5) 29; (7) 55; (8) 29; (9) 22; (10) 61; (12) 6; (13) 19; (20) 28; (24) 17

(22) 67

24

Thoma, G. (3) 246 Thomas, G.J., Jr. (22) 8 Thomas, M. (19) 34 ThOma~Qate~, J. (22) 28 Thomassigny, C. (24) 59 Thompson, C. (1) 10; (4) 45 Thompson, D.O. (4) 212,213 Thompson, J.D. (23) 34 Thomsen, I. (10) 70 Thomson, R.J. (16) 23 Thorsen, J. (7) 87 Wtha, M.V. (22) 79 Thher, R (4) 49; (24) 54 Ticha, M. (23) 36 Tierncy, J.P. (3) 272 Ti=, L.F. (4) 79 Tikkanen, J.M. (4) 63 Tilbmk, D.M.G. (3) 70,254,

255,282; (8) 9; (1 I) 4; (12) 17

Timmermans, J.W. (21) 49 Timmers, C.M. (2) 18; (3) 303;

(4) 68,86, 172; (16) 61 Thpa, J.D. (22) 33 Tjaden, U.R (23) 58,62 TkachenJco, O.V. (20) 241,242 Tobc, K. (4) 203; (7) 15 Tobe, T. (24) 77 Toda, F. (4) 239; (20) 26 Todd, M. (16) 39 Todderud, G. (3) 97; (7) 75 Todorova, N. (19) 20 Toepfer, A. (4) 104,142,146 Toerien, F. (14) 52 Togashi, K. (23) 49 Togo, H. (3) 257; (18) 11; (20)

Togo, Y. (23) 11 Toida, T. (3) 220,221; (23) 21 Toisdra, M. (3) 21 T&e, L. (5) 24; (24) 47 Tokiwa, Y. (7) 39,40 Tokura, S. (4) 218 Tokutake, S. (7) 15 Tdruyapu, K. (9) 55 Tolbert, T.J. (20) 199 Tolstikov, A.G. (3) 94 Tolstikov, G.A. (3) 62,63,94,

Tolstikova, O.V. (3) 94 Tomasic, J. (7) 4 Tomasz, J. (22) 134 Tomita, A. (14) 38; (24) 44 Tomita, M. (3) 182 Tomitaheva, M.V. (22) 150 Tomiya, N. (3) 80; (7) 69 Tommic, S. (7) 4 Tomooka, C.S. (9) 28; (13) 14 Tonegawa, M. (23) 12 Tonellato, V. (4) 23 1 Tong, L. (24) 84 Tono-oh, S. (3) 5 Toone, E.J. (3) 287 Topai, A. (24) 78 Toporek, S.S. (22) 44,59 Toppet, S. (24) 60 Tor, Y. (19) 4,s Torimura, M. (23) 75 Torrente, S. (10) 56; (14) 24 Toni, G. (3) 291 Tom, T. (24) 96 Toshima, K. (3) 47,289,292 Tosi, G. (22) 12 Toth, I. (4) 130,143; (10) 24 T&h, Z.G. (18) 120,143 Touripy, 0. (22) 142

142

119, 120; (20) 36,67,68

413 Townsend, L.B. (20) 19,2422,

57,81,14i, 143 Toyama, K. (20) 50 Toy* A. (20) 78 Toyoda, H. (16) 30; (22) 100; (23)

Toyoshima, H. (18) 11; (20) 142 Trabaud, C. (20) 290 Tmposch, K.M. (3) 97; (7) 75 Traulos, S.D. (22) 48 TrincOne, A. (3) 43,45 Tripkovic, A.V. (16) 18 Tripp, M. (19) 3 TriStram, F. (21) 4 Trivedi, P.J. (10) 55 Tmka,T.(I1)7 Trombini, C. (9) 4,5; (18) 61,83 Tromp, RH. (2) 39; (22) I5 1 Tronchet, J.M.J. (22) 118 Trost, B.M. (19) 42 Truhlar, D.G. (2) 2 Trujillo, J.L. (5) 22 Tnuntel, M. (4) 108 Tsai, 1.H (23) 71

Tschakert, J. (3) 2 Tscbopp, T. (22) 52 Tse, H.L.E. (20) 288 Tsegenidis, T. (23) 20 Tselinski, LV. (21) 12

Tsien, RY. (18) 177 Tsipori, H. (1 8) 40 Tsitsanou, K.E. (7) 84; (10) 32,

Tsuboi, K. (24) 28 Tsuboi, M. (22) 8 Tsuchida, T. (19) 48; (22) 49 Tsuchiya, T. (7) 81,82; (13) 23,

24; (19) 1,2 Tsuchiya, Y. (24) 45 Tsuda, Y. (11) 13; (16) 62; (17)

17; (22) 113 Tsuge, H. (3) 42; (22) 99 Tsuji, M. (20) 3 15 Tsuji, T. (20) 45 Tsujihita, H. (4) 145, 166; (7) 78 TsujisaCa, Y. (4) 248

Tsukida, T. (4) 89, 145 Tswoka, H. (20) 309 Tsuruta, 0. (3) 211; (11) 30 Tsushima, M. (24) 12 Ts\ltsumi, N. (24) 56 Tsutsumiuchi, K. (3) 89 Tsuzdci, W. (4) 201,202 Tsvetkov, Y.E. (3) 216; (16) 47

21

Tsai, M.-D. (18) 150, 163

Tmg, W.-Y. (21) 75

33,69

.T-o~o, H. (2) 31; (3) 59; (16) 36.45

4 14

Tu, Y. (24) 105,106 Tubman, K. (24) 98 Tucker, L. (24) 98 Tfickmantel, W. (18) 162 Tuikkanen, J. (19) 15 Tupprasoot, R. (13) 25 Turek, D. (4) 135 Tunnel, B. (3) 97; (7) 75 Turner, J.J. (4) 172 Turner, P. (22) 74 Tuzikov, A.B. (3) 22; (22) 6 Tvaroska, I. (22) 156 Tyihak, E. (23) 9 Tyler, P.C. (18) 49; (22) 98 Tzamakakis, G.N. (23) 20

Uccello-Barretta, G. (4) 245 Uchida, K. (3) 42 Uchida, S. (20) 48 Uchimara, T. (20) 176 Uchimira, M. (22) 110 Uchiro, H. (3) 22,25,35,237,

3 17; (20) 47 Uchiyama, T. (4) 114 Uda, M. (3) 273 Ueda, H. (4) 199,200 Ueda, M. (3) 143; (14) 13; (16) 2 Ueda, T. (7) 93; (23) 75 Uekama, K. (4) 219 Uemura, D. (24) 37 Uemura, K.4. (22) 22 Uenishi, J. (24) 22 Ueno, A. (4) 222,239 Ueno, R (4) 236 Ueno, Y. (24) 96 Uesawa, Y. (23) 39 Uesugi, T. (23) 39 Ugarkar, B.G. (20) 70 Ugi, I. (16) 7 Uhlendorf, J. (22) 73 Uittenbogaard, RM. (4) 240 Ukraintsev, I.V. (21) 12 Welder, K.W. (23) 52 Ulrichova, J. (3) 129 Umezawa, I. (18) 5 Umino, A. (4) 170 Unaic, P. (16) 77 Unak, T. (16) 77 Ungaro, R (3) 77 Unger, C. (19) 22 Uno, C. (3) 222 Uno, T. (20) 3 15 Unvenagt, C. (4) 134, 181,185,

186 uozumi, Y. (1) 10; (4) 45 Upson, RH. (16) 58 Urashima, C. (20) 206

Urbanczyk-Lipkowska, Z. (10) 53; (14) 2; (22) 117; (24) 52, 53

Urbaneh R.A. (24) 3 1 Urbani, R (3) 155 Urbanski, R (24) 52 Uri, A. (20) 131 Uriarte, E. (20) 171 Usenko, L.S. (20) 69 Ushiki, Y. (3) 289 Ushimura, M. (17) 9 Ushiyama, M. (20) 78 Usui, T. (3) 80,194,200; (4) 23,

66,149; (7) 69,74 Uzan, R. (3) 23 1; (5) 23; (9) 20;

(16) 3 , 4 ; (18) 138 UZ-W, F. (3) 2

Vaino, A.R (3) 82,93; (20) 193 Valdor, J.-F. (4) 65 Valencia, G. (4) 36 Valentijn, A.R.P.M. (3) 100,172;

Valentin-Hansen, P. (20) 72 Valenza, S. (14) 29; (18) 74 Valery, J.-M. (19) 30 Valtrova, S. (20) 148 Valverde, S. (18) 97 Van Aerschot, A. (18) 80; (20) 88,

294; (22) 143 van Bekkum, H. (2) 43 van Bcrkel, T.J.C. (3) 100 van Boeckel, C.A.A. (4) 187 van Boggelen, M.P. (18) 102 van Boom, J.H. (2) 18; (3) 100,

(19) 26

172,303; (4) 68,86, 172; (7)

Van Calenbergh, S. (20) 88,153 VanClOV& z. (7) 44 van Delft, F.L. (3) 15, 176; (4) 47 van den Heuvel, H. (22) 13 Vandenplas, C. (20) 129 van der Greet J. (23) 58,62 van der Marel, G.A. (2) 18; (3)

60; (16) 61; (19) 23-26

100, 172,303; (4) 68,86, 172; (7) 60; (16) 61; (19) 23-26

Vanderveen, K. (20) 236 van der Velde, D.G. (4) 213 vim Dommelen, B.F.G.A. (18)

Van Dongen, W. (23) 43 van Doren, H. (3) 247; (16) 65 van Dorst, J.A.L.M. (4) 53,61,

van Eijck, B.P. (21) 9 van Heijenoort, J. (19) 58-60 van Heijenoort, Y. (19) 59

102

63,117

Carboh9ate Chemisty van Heusden, C.J. (4) 63 Vanky, P. (23) 20 Van Montagu, M. (23) 54 van Oijen, A.H. (4) 106 Van Onckelen, H.A. (23) 43 Van Rantwijk, F. (7) 35; (16) 6 van Seeventer, P.B. (4) 67,117,

van Straten, N.C.R. (2) 18; (4) 68;

van Vtclen, P. (4) 187 Van Vranken, D.L. (10) 3 Varela, 0. (10) 26,27 Varga, Z. (18) 143 Vargas-Berenguez, A. (3) 243 Vada, J. (20) 3 10 Varvoglis, A. (1) 17 Vasella, A. (2) 34; (3) 124,304,

305; (10) 58,68; (14) 1; (22) 68,71,82,112, 116; (24) 1

137

(7) 60; (19) 23-25

V a s i c - W , D. (20) 207 Vasilcscu, D. (21) 54 Vasil'eva, E.V. (3) 62,63, 119 Vass, E. (9) 58 Vass, G. (18) 119 Vaz, R.J. (20) 161 Vazquez, J.T. (21) 39 Vecchio, G. (4) 234; (22) 66 Vcgad, H. (3) 102

Velimirovic, S. (2) 8; (5) 30; (18)

Velty, R. (3) 4 Venable, R.M. (21) 71 Venema, F. (4) 240 Vcnkatram Reddy, K. (6) 7 Vercauteren, J. (5) 8; (20) 59 Verdine, G.L. (18) 79 Vergotcn, G. (2 1) 4 Verhcggen, I. (20) 294 Verheijen, J.C. (4) 86 Vernin, G. (16) 82 Verre-Sebrik, C. (18) 119 Vertuani, S. (20) 267 Vetere, A. (4) 74,82,93 Viallefont, P. (14) 5,6 Viani, F. (8) 17; (14) 17; (17) 5;

(20) 128 Vicent, C. (9) 53; (21) 5 1 Vidal, J.-P. (24) 7 Vidil, C. (7) 87 Vieirade Almeida, M. (18) 119 Viggiani, L. (7) 42 Viladot, J.L. (4) 160; (I 1) 35 Villa, P. (3) 230; (7) 91; (18) 6;

(20) 99; (22) 36 Villain, F. (22) 64 Viharoya, M. (20) 160

V ~ g a - P t h ~ , J.M. (10) 43

21

Aurhr Index Viriot, M.L. (9) 52 Viseux, N. (22) 34 Vismara, E. (3) 283,291,299 Vizitiu, D. (4) 227 Vlahov, I.R. (7) 18; (22) 23 Vlahova, P.I. (7) 18 Vleeming, J.H. (16) 66,67 Vliegenthart, J.F.G. (4) 53,61,63,

Vocadlo, D. (10) 65 Voelter, W. (3) 2; (4) 49; (8) 28;

(14) 51,57; (24) 54 Vogel, C. (2) 25; (4) 94; (7) 43,

55; (16) 76 V0gel.P. (3) 310,311; (14)49;

(18) 75,76 Vogtherr, M. (20) 269 Volc, J. (22) 41 Voldoire, A. (19) 5 1 von der Lieth, C.-W. (21) 60,61 von Itzstein, M. (9) 44,73; (10)

von Matt, P. (20) 254,255 Voskamp, A.F. (4) 53 Voss, J. (1 1) 16; (24) 73 Vottero, P. (3) 195 Vourloums, D. (3) 15 Vriarte, E. (22) 15 Vu, C.Q. (21) 78 Vukojevic, N. ( 5 ) 30; (16) 5 Vulfson, E.N. (7) 30,46

67, 117, 137; (21) 49

37; (16) 23,41,50,51; (17) 4

Wachtmeister, J. (20) 168 Wackernagel, F. (20) 102 Wada, A. (3) 203 Wada, C.K. (18) 108 Wada, M. (3) 273 Wada, T. (20) 206,214,309; (24)

Wada, Y. (4) 145; (20) 176 Wade, P.A. (9) 41 Wadomchi, A. (3) 23 1; (5) 23;

Waever, R (20) 275 Wagler, T. (3) 1 15 Wagner, C.R (20) 189 Wakabayashi, T. (2) 30; (10) 20 Waldinger, C. (7) 25 Waldmann, H. (3) 17; (4) 22; (8)

23; (1 0) 25 W a l M , C. (2) 34; (14) 1; (22)

116; (24) 1 Walford, C. (3) 250; (22) 11 1 Walinski, S.W. (3) 122 Walker, J.A., II(20) 143 Walker, R.T. (20) 96 Walkinshaw, C.S. (4) 227

79

(24) 67

Wallberg, A. (3) 233 Walsh, E.J. (3) 202 Walter, J.A. (16) 79 Walt04 R (4) 62 Wandrey, C. (19) 59; (20) 207 Wag, A.-B. (3) 13 1 Wang, A.-L. (22) 108 Wang, B.G. (5) 3 Wan& E. (20) 74 Wang, G. (20) 117,281 Wang, H. (19) 4,5; (22) 107

Wang, J. (20) 43,256

Wang, K. (20) 300

Wmg, H.-Q. (17) 7; (22) 106, 108

Wang, J.-C. (20) 220,227

Wag, K.-T. (7) 32 Wan& L.-x. (3) 264; (10) 22

Wang, P.P. (20) 75 Wan& R (20) 212

Wang, P. (19) 36 Wang, P.G. (3) 321

Wang, S.-N. (3) 245 Wang, T. (23) 61 Wang, W. (5 ) 17; (18) 22 Wang, X. (19) 21; (20) 33, 157 Wag, Y. (4) 49; (16) 74; (18)

117; (20) 30 Wag, Y.-F. (7) 41 W w , Y.-g. (3) 133; (6) 12 Wang, 2. (2) 22; (7) 16; (12) 11;

W w , Z.-X. (24) 104-106 Ward, C.M. (4) 172 Ward, J.A. (20) 113,114 Ward, J.L. (20) 133 Ward, P. (4) 143 Ward, S.E. (19) 33 Wardell, J.L. (17) 15, 16; (22)

103,124 Warren, H. (9) 17 Warriner, S.L. (4) 180; (6) 13, 14 Wasner, M. (20) 244 Watanabe, K.A. (20) 235-237 Watanabe, M. (20) 97,98 Watanabe, N. (4) 201,202 Watanabe, T. (18) 135 Watambe, Y. (4) 179; (18) 149,

152, 160; (24) 96 Waterai, T. (23) 1 Waters, J.M. (22) 47 Watkin, D.J. (2) 13; (22) 53 Watson, A.A. (3) 136; (18) 43;

Watson, K.A. (10) 32.33 Watson, M. (1 8) 6 Watt, G.M. (4) 64,175 Watterson, M.P. (6) 3; (10) 41;

(20) 46

(24) 62

(16) 73

415 Wawer, I. (9) 60; (21) 37; (21) 36;

Webbedey, M.C. (4) 64 Wcber, M. (3) 124 Wei, C. (20) 55 Weibei, J.-M. (3) 314; (8) 15 Weigel, J.A. (8) 14 Weigelt, D. (3) 233 Weiler, L. (17) 8; (22) 109 Weimer, D.F. (20) 172 Weiner, D.P. (17) 34; (20) 87 Weinstein, D.S. (4) 179 Weinstock, L. (9) 34 Weiss, W.J. (18) 18, 19 Weitz-Schmidt, G. (3) 269 Wellmar, U. (20) 53 Welzel, P. (19) 57-60 Wen, T.-B. (17) 7 Wendebom, S. (20) 245-247 Wengel, J. (14) 9-11; (18) 24; (20)

110-1 12 Wentworth, P., Jr. (17) 33,34;

(20) 86,87 Werdelin, 0. (4) 100 We&& A. (20) 148, 149; (22) 72 Wedell, A. (22) 72 Werner, J.A. (20) 114 Werschkun, B. (24) 17 Wessel, H.P. (4) 29, 108; (6) 20;

(9) 59; (12) 12; (22) 52 Wesson, K.E. (6) 14; (12) 8 West, P. (19) 3,56 Westerduin, P. (4) 187 Wey, S.J. (20) 10; (22) 145 Weymann, M. (24) 88 Weymann, P. (22) 85 Weymouth-Wilson, A.C. (1) 12 Wheeler, S. (7) 68 White, A.H. (9) 7; (22) 94 Whitesides, G.M. (4) 70; (16) 46 Whitfield, D.M. (4) 129 Whitfield, J.N. (2) 3; (20) 4 Whittal, RM. (22) 24 Wibley, K.S. (9) 67 Wickens, P.L. (13) 30; (20) 62 Widmalm, G. (21) 41,65,67; (22)

Wieczorek, S.J. (16) 16 Wiemann, T. (17) 34; (20) 87 Wiemer, D.F. (17) 1 Wiesner, J.B. (20) 70 Wigchert, S.C.M. (2) 18; (4) 68 Wigerinclc, P. (22) 140 Wightman, RH. (18) 23, 112;

(20) 9,283,284; (22) 128; (24) 63

(22) 92

58

Wik, A. (20) 213 Wiutening, R.R (22) 93

416 Wilkins, RW. (3) 121; (8) 10 Willems, H.A.M. (4) 187 Willett, P. (1) 5 Williams, A.S. (18) 125 Williams, D.J. (4) 195,244; (22)

Williams, G. (3) 29 Williams, J.M. (3) 39; (9) 17 Williams, M.A. (18) 115; (22) 127 Williams, M.D. (3) 144 William, P.A.M. (17) 20,21 Williams, S.J. (3) 254,255; (11)

Williamson, C. (3) 272 Williamson, G. (3) 139 Williamson, J.R (20) 199 Wilson, I.B.H. (4) 64 Wilson, K.S. (22) 67 Wilson, P.D. (24) 9 Wilstermann, M. (3) 191; (4) 83 Wimmer, N. (4) 69 Win, W.W. (3) 65 Winans, K.A. (4) 43 Winamo, H. (3) 204 Winchester, B.G. (2) 13, 14; (18)

65; (22) 53,98 Windmiiller, R (4) 88; (7) 19 Wingsle, G. (23) 2

Winslade, M.L. (3) 70 Winum, J.-Y. (8) 18 Wirsching, J. (11) 16 Wise, D.S. (20) 143 Wissinger, N. (4) 17 1 Witch, E.M. (20) 253 Witczak, Z.J. (3) 295; (1 1) 32 Withers, S.G. (3) 212; (8) 3; (10)

58,65; (17) 8; (18) 48,55;

62,63

4; (12) 17

WiMtrOSki, L.L. (20) 114

(22) 109 Witte, K. (4) 132 Witters, E. (23) 43 Wittmann, V. (20) 208; (21) 76 Wittmeyer, P. (5) 7 Wihmuw, M. (5) 21; (10) 4; (20)

Wixforth, A. (23) 38 Wlodyka, P. (24) 11 Wnuk, S.F. (20) 6,37,80,92,303 Wiimer, K. (21) 76 Wojtowicz, M. (10) 29,30 Wolf, R. (23) 33

Wolfe, M.M. (17) 34; (20) 87 Wolfe, M.S. (20) 103 Won, W. (20) 14; (22) 146 Wong, C.-H. (1) 14; (2) 19; (3)

20

Wolf, RM. (20) 245-247

67,95,123,148,269,274; (4) 21, 131, 132; (8) 2; (9) 21,46;

(13) 12; (16) 42,44; (18) 32, 66; (19) 6; (20) 208,212; (22) 16

Wong, T. (24) 9 Woo, S. (24) 9 Woad, J.L. (14) 15, 16 Woods, R.J. (21) 59 Woody, H.A. (3) 121; (8) 10 Wormald, M.R (1 8) 43 Wotrbg, L.L. (20) 19,57,81 Woudeoberg-van Oesterom, M.

(7) 35; (16) 6 Wouessidjewe, D. (22) 38 Wouters, J. (22) 143 Womiak, L.A. (20) 230

Wright, J.J.K. (3) 97; (7) 75 Wright, K. (4) 130, 143 Wrodnigg, T.M. (18) 48,55

Wu, H.W. (9) 24 Wu, J. (18) 66; (19) 46; (21) 20,

25; (22) 11, 16 Wu, M. (5) 5 Wu, Q. (3) 245; (20) 90 Wu, R (13) 8 WU, S.-H. (7) 32 Wu, S.T. (23) 29 wu, w. (20) 74

Wu, X. (18) 56

WuE, G. (17) 32 Wunschel, D.S. (23) 14 Wyatt, P. (20) 21 1

wray, v. (7) 53

WU, D.-X. (17) 7

WU, W.-N. (6) 8 WU, W.-Y. (9) 44; (16) 41

wu, z. (19) 19

Xia, J. (7) 10 Xia, W. (18) 158 Xia, X. (20) 10,43; (22) 145 Xian, J. (23) 65 Xiang, J. (4) 193 Xiang, Y. (8) 13; (20) 76,293;

(22) 136 Xie, J. (14) 3 Xie, X.-Y. (1 1) 32 Xie, Y. (22) 157 Xie, Y.-Y. (20) 13 Xin, Y.4. (17) 4 Xu, D. (22) 11

Xu, G. (4) 193; (22) 11 Xu, J. (3) 15 Xu, Y. (12) 4; (20) 82; (21) 74

XU, D.-K. (23) 60

XU, Y.-M. (18) 84 xu, z. (9) 40; (20) 75 Xu, Z.H. (22) 9

Carbohpkate Chernistty Xue, D.P. (20) 300 Xue, P. (16) 74

Yabui, A. (17) 9; (22) 110 Yabuuchi, M. (23) 17 Yadov, A.K. (20) 24

Yajima, K. (22) 5 Yajima, M. (4) 225 Yakovlevsky, K. (7) 41 Yam, L. (4) 45 Yamada, H. (2) 3 I; (3) 59,60; (4)

40, 198; (16) 45 Yamada, K. (4) 78; (20) 97 Yamagachi, T. (23) 18 Yamagalu, T. (22) 35,37 Yamagishi, K. (18) 147 Yamguchi, H. (3) 290 Yamaguchi, K. (16) 30; (20) 176;

Yamaguchi, M. (4) 232 Yamaham, J. (3) 116; (1 1) 29;

Yamaimmi, Z. (20) 297 Yamatnoto, A. (3) 89 Yamamoto, C. (7) 92 Yamamoto, H. (3) 135 Yamamoto, K. (4) 201,202,228 Yamamoto, T. (3) 95; (16) 44;

Yamamoto, Y. (7) 50; (17) 31;

Yamamura, S. (3) 143; (16) 2;

Yamana, K. (20) 83 Yamanoi, T. (4) 228 Yamasaki, Y. (23) 1 Yamashita, J. (23) 12 Yamashita, K. (19) 45; (22) 138 Yamashita, M. (17) 9; (22) 110 Yamauchi, N. (14) 7; (19) 8; (24)

Yamauchi, R. (3) 41 Yamauchi, S. (24) 40 Yamauchi, Y. (23) 74 Yamazaki, H. (3) 47 Yamazaki, T. (8) 11, 12; (14) 30,

Yan, F. (8) 6

Yan, W. (18) 46 Yanago, S. (3) 256 Yang, F. (7) 11; (17) 10; (18) 9 Yang, F.L. (7) 32 Yang, G. (5) 13

Yang, M. (21) 74

Yaginuma, s. (19) 44

(22) 100

(22) 114

(18) 152

(22) 123

(20) 100

20

48,58; (24) 22

Yan, L. (1) 10

Yang, L. (5) 3; (22) 11

Author Index Yang, S.G. (20) 264 Yang, x.4. (20) 221 Yang, Y. (18) 18, 19; (20) 263;

Yang, Z. (3) 19,270; (13) 3 Yang, Z.J. (9) 24 Yannopoulos, C.G. (20) 107 Yano, S. (17) 23,31; (22) 121,

(22) 11

123 Yao, 2. (21) 74 Yap, G.P.A. (10) 44; (12) 15; (22)

Yartseva, I.V. (20) 93 Yashima, E. (7) 92 Yashiro, M. (20) 3 11 Yasuda, K. (3) 145 Yasukochi, T. (4) 123 Yasumoto, T. (24) 24 Yasuno, S. (23) 18 Yavorskaya, N.P. (20) 93 Yaziwa, K. (9) 3; (19) 16 Ye, H. (10) 44; (12) 15; (22) 91 Ye, J. (18) 157 Ye, J.N. (23) 48 Yeagley, D. (9) 15; (21) 34 Yeh, S.-M. (18) 117 Yeung, W. (3) 212; (8) 3 Ylihonko, K. (19) 15

Yokoyama, C. (5) 32 Yokoyama, M. (3) 257; (18) 11;

Yoneda, R (3) 323; (22) 149 Yonemitsu, 0. (24) 22,23 Yonezawa, K. (20) 3 11 Yoo, D.J. (20) 305 Yoo, J.S. (22) 17

Yoon, E.Y. (22) 32

Yoon, J.H. (3) 197 York, C. (8) 6; (18) 126 York, W.S. (21) 14 Yoshida, J.-i. (3) 256 Yoshida, K. (19) 14 Yoshida, M. (4) 89, 145 Yoshida, T, (7) 73 Yoshikawa, K. (7) 5 1 Yoshikawa, M. (3) 116,142, 173;

91

Yoda, s. (2) 47

(20) 142

YOO, S.-K. (24) 39

YOOXI, H.-J. (3) 235

(4) 84; (1 1) 29; (18) 12; (22) 114

Yoshikawa, Y. (3) 153 Yoshimoto, A. (19) 17 Yoshimura, Y. (20) 97,98 Yoshinaga, M. (24) 77 Yoshino, K. (4) 166; (7) 78 Yoshino, T. (21) 6 Yoshioka, T. (19) 17

Yoshita, Y. (3) 217 Yoshitomo, A. (3) 5 1 Yoshizaki, H. (3) 203 Yoshizawa, T. (3) 182; (24) 42 You, K.K. (24) 103 Young, A.A. (2) 2 1 Young, D.B. (5) 2 Young, M.G. (18) 105; (20) 167 Youseti-Salakdeh, E. (20) 307 Youssef, RH. (3) 154 Yu, B. (3) 118, 168; (4) 122 Yu, D. (20) 224 Yu, H. (20) 90 Yu, H.K.B. (16) 10 Yu, J. (3) 235; (20) 162 Yu, L. (3) 321 Yu, S. (23) 72

Yuan, D . 4 . (4) 232,235 Yuasa, H. (1 1) 27,30 Yun, J.W. (3) 156 Yuri, M. (4) 144

Yuan, C.-S. (20) 92

Zablotskaya, A. (20) 262 Zaccarello, G. (24) 72 Zaccaro, L.M. (3) 121; (8) 10 Ziihringer, U. (16) 25 Zafia, E. (11) 21 Zahler, R. (18) 105; (20) 167 Zahn, H. (19) 22 Zahram, M.A. (20) 79 Zailova, T.O. (18) 167 Zain, R. (20) 216 Zajicek, J. (20) 12 Zamojska, A. (3) 147 Zamojski, A. (2) 15, 16; (7) 58;

Zampella, A. (9) 2; (14) 14 Zanardi, F. (20) 66 Zanferrari, D. (21) 7 Zanini, D. (4) 90; (16) 28 Zanirato, V. (18) 1 Zappala, C. (8) 17; (14) 17; (17)

5; (20) 128 Zard, S.Z. (12) 5; (14) 53; (18) 14 Zarudii, F.S. (3) 63 zatorski, A. (20) 235 zbvada, J. (4) 21 1 Zavoda, M. (20) 71 Zavodnic, V.E. (20) 91; (22) 137 Zawistoski, M.P. (3) 121; (8) 10 Zehl, A. (20) 85 Zelenin, K.N. (21) 12 Zemlyakov, A.E. (3) 18 Zeng, F. (20) 265 Zervosen, A. (3) 152 Zhai, K. (3) 168

(12) 16; (16) 14,70; (22) 153

417 Zhang, B. (7) 41 Zhang, D. (20) 263

Zhang, G. (17) 3 Zhang, H. (4) 49; (7) 47 Zhang, J. (4) 164; (20) 17, 18,30

Z h & F.-J. (20) 238

Zhang, J.-R. (24) 106 zhang, K.-Q. (3) 171

zhang, L.-H. (7) 67; (9) 24; (20)

Zhang N.-J. (20) 194

Zhang, L. (18) 115; (22) 127

192,300

Zhang, S. (4) 161; (22) 134 Zhang, S.Q. (3) 131 Zhang, W. (3) 315 zhang, W.-Y. (24) 98 Zhang, X. (19) 3; (20) 194 Zhang, Y. (23) 5 1

Zhang, Z. (3) 67; (8) 2; (13) 12;

Zhao, K. (3) 61; (20) 293

zhang, Y.-Y. (20) 18

(20) 265

Zhao, S.-R (20) 314 Zhao, Y.-F. (20) 194 zhao, Z. (18) 150 Zheng, C.-M. (24) 49 Zhong, Y.-L. (1) 18

Zhou, M. (16) 58 Zhou, Q. (22) 11

Zhou, T. (20) 15 Zhou, W.Q. (20) 107

Zhou, Z. (18) 92 Zhu, H.Y.H. (9) 42; (13) 9; (14)

Zhu, J. (3) 19, 127 Zhu, T. (4) 42 Zhu, W. (5) 32 Zhu, X.X. (4) 11 8,167 Zhukova, N.A. (7) 63 Ziegler, T. (3) 157, 199; (4) 41,

55; (7) 22 Zieniawa, T. (19) 13 Ziller, J.W. (10) 3 Zoghaib, W.M. (21) 26; (22) 142 Zographos, S.E. (7) 84; (10) 32,

Zoric, S. (22) 27 Zotov, A.Yu. (7) 61; (8) 27 Zou, R (20) 21,22,37 Zou, W. (4) 178 Zrybko, C.L. (23) 25 Zulauf, M. (20) 58; (21) 29 Zuumond, H.M. (3) 294 Zwanenburg, B. (1 8)

Zhw, L.-H. (10) 45

Zhou, R-L. (4) 167

Z ~ O U , W.-S. (18) 84

25

33,69

[r j ferrier; regine blattner; royal society of c(bookza.org)

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