Carbohydrates

Momcilo Miljkovic

Carbohydrates

Synthesis, Mechanisms,and Stereoelectronic Effects

123

Momcilo MiljkovicDepartment of Biochemistry &

Molecular BiologyPennsylvania State UniversityMilton S. Hershey Medical Center500 University DriveHershey PA 17033H171USAmxm60@psu.edu

ISBN 978-0-387-92264-5 e-ISBN 978-0-387-92265-2DOI 10.1007/978-0-387-92265-2Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2009933276

© Springer Science+Business Media, LLC 2010All rights reserved. This work may not be translated or copied in whole or in part without the writtenpermission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York,NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use inconnection with any form of information storage and retrieval, electronic adaptation, computer software,or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they arenot identified as such, is not to be taken as an expression of opinion as to whether or not they are subjectto proprietary rights.

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Dedicated to the memory of Professors MilivojeS. Lozanic and Djordje Stefanovic University ofBelgrade, Serbia

Foreword

The development of organic chemistry over the last 40 years has been absolutelyphenomenal, particularly the deepened understanding of chemical reactivity, molec-ular construction, and tools for analysis and purification. Without doubt, carbohy-drate chemistry has played a major role in this historic advance and in the future willhave crucial ramifications in most areas of biomedical research into the functioningof Nature at the molecular level.

This book covers all basic carbohydrate chemistry, including most importantsynthetic methods and reaction mechanisms and notably takes into account the prin-ciple of stereoelectronic effect which has played a key role in understanding the con-formation and chemical reactivity of this important class of natural product. Evennomenclature has been properly covered and it is fair to say that all the key refer-ences of carbohydrates have been cited. Such a book could only have been writtenby an expert who has spent his entire research career in this area.

This book of Momcilo Miljkovic will be of interest not only to specialists inthe field, but also to synthetic chemists in general. This book also contains most ofthe material needed for a graduate course in carbohydrate chemistry. Furthermore,it should be particularly valuable for investigators working in various aspects ofbioorganic chemistry including the discovery of new medicines.

Quebec, Canada Pierre Deslongchamps, FRS, FRSC

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Preface

Carbohydrates are one of the three most important components of living cells (theother two being amino acids and lipids). In order to understand their biochemicalbehavior one must understand steric and electronic factors that control their reactiv-ity and chemistry. Two properties of carbohydrates that are most important for theirchemical behavior are their shape (conformation) and stereoelectronic interactionsthat are unique and characteristic for each carbohydrate structure.

So chapters on anomeric effect, a very important electronic effect first discov-ered in studies of carbohydrates and later found to be of general importance in manyother organic molecules, glycosidic bond hydrolysis, isomerization of free carbohy-drates in aqueous solution, relative reactivity of hydroxyl groups in a carbohydratemolecule, nucleophilic displacement with or without change of the configuration atthe reacting carbon atom, addition of nucleophiles to glycopyranosiduloses, etc., areall to a various extent related to stereoelectronic effects that exist in carbohydratestructures.

Cyclic acetals and ketals and anhydrosugars are both very important intermedi-ates in synthetic carbohydrate chemistry, first being used for protection of hydroxylgroups that are not supposed to take part in further chemical transformation ofthe intermediate and second being used as synthetic intermediates in carbohydratechemistry because they can serve as starting materials for the synthesis of many dif-ferent carbohydrate derivatives, for example, the amino sugars, the branched chainsugars, oligosaccharides. The amino sugars, being important components of manybiomolecules such as glycosaminoglycans, heparin, chondroitin as well as manynatural products, such as sugar-based antibiotics, macrolide antibiotics, are dis-cussed in a separate chapter.

The last three chapters of the book deal with topics not usually found in car-bohydrate chemistry texts like this one, although according to the author’s opinionthey are very important and they are unjustly neglected. These are carbohydrate-based antibiotics, synthesis of polychiral natural products from carbohydrates, andchemistry of higher-carbon carbohydrates.

Much attention has been paid to the mechanisms of various carbohydrate reac-tions as well as to the role of stereoelectronic effects that they play in the reac-tivity of carbohydrates and the stereochemical outcome of various carbohydratereactions.

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x Preface

In the end, I wish to express my deep gratitude to Professor Pierre Des-longchamps for taking time to read the entire book and provide me with invaluablecomments and critique. I would also like to thank my wife, Irina Miljkovic, for herpatience and understanding throughout my scientific life.

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Representation of Monosaccharides . . . . . . . . . . . . . . . . . . 2

Acyclic Form of Monosaccharides . . . . . . . . . . . . . . . . . 2Cyclic Forms of Monosaccharides . . . . . . . . . . . . . . . . . . 4

The Nomenclature of Carbohydrates . . . . . . . . . . . . . . . . . . 9Trivial Names . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Stem and Systematic Names . . . . . . . . . . . . . . . . . . . . . 9Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Choice of Parent Monosaccharides . . . . . . . . . . . . . . . . . 10Choice Between Alternative Names for Substituted Derivatives . . 11Configurational Symbols and Prefixes . . . . . . . . . . . . . . . . 11Ketoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Deoxy-monosaccharides . . . . . . . . . . . . . . . . . . . . . . . 14Amino-monosaccharides . . . . . . . . . . . . . . . . . . . . . . . 15O-Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Acyclic Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Anomers and the Anomeric Configurational Symbols(“α” or “β”). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Glycosyl Radicals and Glycosylamines . . . . . . . . . . . . . . . 20Aldonic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Uronic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Aldaric Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Cyclic Acetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Intramolecular Anhydrides . . . . . . . . . . . . . . . . . . . . . 24

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2 Conformational Analysis of Monosaccharides . . . . . . . . . . . 27Conformational Analysis of Acyclic Hydrocarbons . . . . . . . . . . 28Conformational Analysis of Acyclic (Aldehydo) Formsof Monosaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . 31

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Conformational Analysis of Cyclic (Lactol, Hemiacetal)Forms of Monosaccharides . . . . . . . . . . . . . . . . . . . . . . . 33

Furanoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Pyranoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Calculation of Conformational Energies of Pyranoses . . . . . . . . . 41References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

3 Anomeric Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Endo-anomeric Effect . . . . . . . . . . . . . . . . . . . . . . . . 57The Quantum-Mechanical Explanation . . . . . . . . . . . . . . . 63Exo-anomeric Effect . . . . . . . . . . . . . . . . . . . . . . . . . 67Generalized Anomeric Effect . . . . . . . . . . . . . . . . . . . . 69Reverse Anomeric Effect . . . . . . . . . . . . . . . . . . . . . . 72Anomeric Effect in Systems O–C–N . . . . . . . . . . . . . . . . 84

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

4 Isomerization of Sugars . . . . . . . . . . . . . . . . . . . . . . . . 95Mutarotation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Anomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Lobry de Bruyn–Alberda van Ekenstein Transformation . . . . . . . 108References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

5 Relative Reactivity of Hydroxyl Groups in Monosaccharides . . . 113Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113Selective Acylation (Esterification) . . . . . . . . . . . . . . . . . . 114

Selective p-Toluenesulfonylation (Tosylation)and Methanesulfonylation (Mesylation) . . . . . . . . . . . . . . . 116Selective Benzoylation . . . . . . . . . . . . . . . . . . . . . . . . 120Selective Acetylation . . . . . . . . . . . . . . . . . . . . . . . . 127Other Acylating Reagents . . . . . . . . . . . . . . . . . . . . . . 129Acyl Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Selective Alkylation and/or Arylation of Glycopyranosides . . . . . . 136Tritylation of Monosaccharides (Triphenylmethyl Ethers) . . . . . 136Selective Benzylation of Monosaccharides . . . . . . . . . . . . . 137Selective Alkylation of Metal Complexes of Monosaccharides . . . 138

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

6 Cyclic Acetals and Ketals . . . . . . . . . . . . . . . . . . . . . . . 143Acetalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

Benzylidenation . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Ethylidenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Ketalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Isopropylidenation (Acetonation) . . . . . . . . . . . . . . . . . . 150

Transacetalation and Transketalation . . . . . . . . . . . . . . . . . . 152The Isomerization of Cyclic Acetals and Ketals . . . . . . . . . . . . 154

The Migration of Acetal or Ketal Group . . . . . . . . . . . . . . 155Removal of Acetal and Ketal Groups . . . . . . . . . . . . . . . . . 157

Contents xiii

Benzylidene Group . . . . . . . . . . . . . . . . . . . . . . . . . 157Isopropylidene Group . . . . . . . . . . . . . . . . . . . . . . . . 163

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

7 Nucleophilic Displacement and the Neighboring GroupParticipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169Nucleophilic Displacement . . . . . . . . . . . . . . . . . . . . . . . 169Nucleophilic Displacements with Neighboring Group Participation . 179References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

8 Anhydrosugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1911,6-Anhydrosugars (Glycosanes) . . . . . . . . . . . . . . . . . . . . 1911,4-Anhydrosugars . . . . . . . . . . . . . . . . . . . . . . . . . . . 1981,2-Anhydrosugars (Brigl’s Anhydrides) . . . . . . . . . . . . . . . . 200Anhydrosugars Not Involving the Anomeric Carbon . . . . . . . . . 203

Epoxides or Oxiranes . . . . . . . . . . . . . . . . . . . . . . . . 203Rearrangements of Anhydrosugars . . . . . . . . . . . . . . . . . . . 211

Epoxide Migration . . . . . . . . . . . . . . . . . . . . . . . . . . 211Other Isomerizations of Epoxides . . . . . . . . . . . . . . . . . . 212

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

9 Amino Sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Ammonolysis of Oxiranes . . . . . . . . . . . . . . . . . . . . . . . 221Nucleophilic Displacement of Sulfonates (or Halides)with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . 226Glycosylamines and N-Glycosides . . . . . . . . . . . . . . . . . . . 231Acid-Catalyzed Hydrolysis of Purine and Pyrimidine Nucleosides . . 237References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

10 Oxidation of Monosaccharides . . . . . . . . . . . . . . . . . . . . 245Selective Oxidations of Monosaccharides . . . . . . . . . . . . . . . 245

Catalytic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . 245Bromine Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . 247

Nonselective Oxidation of Secondary Hydroxyl Groups . . . . . . . 248Ruthenium Tetroxide (RuO4) Oxidation . . . . . . . . . . . . . . . 249Dimethyl Sulfoxide Oxidation . . . . . . . . . . . . . . . . . . . . 254

DMSO–DCC Method (Pfitzner–Moffatt Oxidation) . . . . . . . . . . 255DMSO–Acetic Anhydride Method . . . . . . . . . . . . . . . . . . . 258DMSO–Phosphorus Pentoxide . . . . . . . . . . . . . . . . . . . . . 263DMSO–Sulfurtrioxide Pyridine (“Parikh–Doering” Oxidation) . . . . 264Chromium Trioxide Oxidation . . . . . . . . . . . . . . . . . . . . . 266Chromium Trioxide–Pyridine Oxidation . . . . . . . . . . . . . . . . 266Chromium Trioxide–Acetic Acid . . . . . . . . . . . . . . . . . . . 270Pyridinium Chlorochromate . . . . . . . . . . . . . . . . . . . . . . 270Nicotine Dichromate . . . . . . . . . . . . . . . . . . . . . . . . . . 272Pyridinium Dichromate–Acetic Anhydride . . . . . . . . . . . . . . 272

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Oxidation of Carbohydrates with the Cleavageof Carbohydrate Chain . . . . . . . . . . . . . . . . . . . . . . . . . 273

Periodate Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . 273Lead Tetraacetate Oxidation . . . . . . . . . . . . . . . . . . . . . 277Pentavalent Organobismuth Reagents . . . . . . . . . . . . . . . . 283

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

11 Addition of Nucleophiles to Glycopyranosiduloses . . . . . . . . . 291The Addition of a Hydride Ion (Reduction) . . . . . . . . . . . . . . 291The Addition of Carbon Nucleophiles: Synthesis of BranchedChain Sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

The Addition of Organometals . . . . . . . . . . . . . . . . . . . 298Addition of Diazomethane . . . . . . . . . . . . . . . . . . . . . . 306

Synthesis of Branched Chain Sugars with FunctionalizedBranched Chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

2-Lithio-1,3-Dithiane as the Nucleophile . . . . . . . . . . . . . . 309Vinyl Carbanion as the Nucleophile . . . . . . . . . . . . . . . . . 312Methoxyvinyl Lithium and 1,1-Dimethoxy-2-Lithio-2-Propene . . 312Reformatsky Reaction . . . . . . . . . . . . . . . . . . . . . . . . 314Opening of Oxiranes with Nucleophiles . . . . . . . . . . . . . . . 316

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

12 Chemistry of the Glycosidic Bond . . . . . . . . . . . . . . . . . . 323Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323Glycoside Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 324

Fischer Glycosidation . . . . . . . . . . . . . . . . . . . . . . . . 325Königs – Knorr Synthesis . . . . . . . . . . . . . . . . . . . . . . 330Synthesis of Acylated Glycosyl Chlorides and Bromides . . . . . . 335Glycosyl Fluorides in Glycosylation . . . . . . . . . . . . . . . . 336Synthesis of Glycosyl Fluorides . . . . . . . . . . . . . . . . . . . 338Orthoester Method of Glycosidation . . . . . . . . . . . . . . . . 340Trichloroacetimidate Method of Glycosidation . . . . . . . . . . . 349Glycoside Synthesis via Remote Activation . . . . . . . . . . . . . 353n-Pentenyl Glycosides as Glycosyl Donors . . . . . . . . . . . . . 354Glycals as Glycosyl Donors . . . . . . . . . . . . . . . . . . . . . 357Thioglycosides as Glycoside Donors . . . . . . . . . . . . . . . . 364Synthesis of Thioglycosides . . . . . . . . . . . . . . . . . . . . . 368Glycosyl Sulfoxides as Glycosyl Donors . . . . . . . . . . . . . . 368Solid-Phase Synthesis of Oligosaccharides . . . . . . . . . . . . . 369Automated Oligosaccharide Synthesis . . . . . . . . . . . . . . . 374

Cleavage of Glycosidic Bonds . . . . . . . . . . . . . . . . . . . . . 374Acid-Catalyzed Hydrolysis of Glycosides . . . . . . . . . . . . . . 374The Acid-Catalyzed Hydrolysis of Glycopyranosides . . . . . . . 377Acid-Catalyzed Hydrolysis of Glycofuranosides . . . . . . . . . . 385Some Recent Developments Regarding the Mechanismof Glycoside Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . 389

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Acetolysis of Glycosides . . . . . . . . . . . . . . . . . . . . . . . 396References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

13 Synthesis of Polychiral Natural Products from Carbohydrates . . 423Macrolide Antibiotics: Erythronolides A and B . . . . . . . . . . . . 423Thromboxane B2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438Swainsonine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441Biotin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443Pseudomonic Acid C . . . . . . . . . . . . . . . . . . . . . . . . . . 445Aplasmomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462

14 Carbohydrate-Based Antibiotics . . . . . . . . . . . . . . . . . . . 469Aminoglycoside Antibiotics . . . . . . . . . . . . . . . . . . . . . . 469

Kanamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470Amikacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472Gentamicins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473Tobramycin (Nebramycin) . . . . . . . . . . . . . . . . . . . . . . 474Neomycin B (Actilin, Enterfram, Framecetin, Soframycin) . . . . . 476Paromomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476Butirosins A and B . . . . . . . . . . . . . . . . . . . . . . . . . . 477Streptomycin A . . . . . . . . . . . . . . . . . . . . . . . . . . . 477Orthosomycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477Destomycin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479Flambamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481Everninomicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

15 Higher-Carbon Monosaccharides . . . . . . . . . . . . . . . . . . 487Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487Synthesis of Higher-Carbon Sugars . . . . . . . . . . . . . . . . . . 490

Wittig Olefination . . . . . . . . . . . . . . . . . . . . . . . . . . 490Aldol Condensation . . . . . . . . . . . . . . . . . . . . . . . . . 498The Butenolide Approach . . . . . . . . . . . . . . . . . . . . . . 503Total Synthesis of Higher-Carbon Monosaccharides . . . . . . . . 503

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539