Glycochemical Synthesis E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Veröffentlichungsjahr: 2016

Beschreibung

This book is a comprehensive and concise review on principles, strategies, and crucial advances in glycochemistry. It focuses on synthesis and practical applications and emphasizes state-of-the-art approaches to the assembly and design of sugars.

•    Provides detailed discussion on specific topics like oligosaccharide assembly and design of sugars, techniques in glycoconjugate preparation, multivalency, and carbohydrate-based drug design
•    Uses notable examples, like solution-based one-pot methods and automated methods for sugar assembly, to illustrate important concepts and advances in a rapidly emerging field
•    Discusses practical applications of carbohydrates, like medicine, therapeutics, drug and vaccine development

Leseprobe

Table of Contents

COVER

TITLE PAGE

CONTRIBUTORS

FOREWORD

PREFACE

1 GLYCOCHEMISTRY

1.1 INTRODUCTION

1.2 NOMENCLATURE, STRUCTURES, AND PROPERTIES OF SUGARS

1.3 HISTORICAL OVERVIEW OF CARBOHYDRATE RESEARCH

1.4 ONWARD TO THE TWENTY‐FIRST CENTURY

1.5 CONCLUSION AND OUTLOOK

REFERENCES

2 PROTECTING GROUP STRATEGIES IN CARBOHYDRATE SYNTHESIS

2.1 INTRODUCTION

2.2 GENERAL CONSIDERATIONS FOR PROTECTING GROUP SELECTION

2.3 COMMON PROTECTING GROUPS IN CARBOHYDRATE SYNTHESIS

2.4 REGIOSELECTIVE PROTECTION OF MONOSACCHARIDES

2.5 ONE‐POT PROTECTION METHODS

2.6 CONCLUSION

REFERENCES

3 GENERAL ASPECTS IN O‐GLYCOSIDIC BOND FORMATION

3.1 INTRODUCTION

3.2 SOME BASIC CONCEPTS

3.3 METHODS FOR GLYCOSIDIC BOND FORMATION

3.4 GLYCOSYLATION STRATEGIES

3.5 CONCLUSION

REFERENCES

4 CONTROLLING ANOMERIC SELECTIVITY, REACTIVITY, AND REGIOSELECTIVITY IN GLYCOSYLATIONS USING PROTECTING GROUPS

4.1 INTRODUCTION

4.2 PROTECTING GROUP AND CONTROL OF ANOMERIC SELECTIVITY OF GLYCOSYLATIONS

4.3 USE OF PROTECTING GROUPS FOR CHEMOSELECTIVE GLYCOSYLATIONS

4.4 PROTECTING GROUPS IN REGIOSELECTIVE GLYCOSYLATIONS

4.5 CONCLUSION

REFERENCES

5 STEREOCONTROLLED SYNTHESIS OF SIALOSIDES

5.1 INTRODUCTION

5.2 CONFORMATIONAL ANALYSIS OF SIALYL OXOCARBENIUM IONS

5.3 ADDITIVES IN SIALYLATIONS

5.4 LEAVING GROUPS IN SIALYLATIONS

5.5 INFLUENCE OF THE N5 PROTECTING GROUP ON REACTIVITY AND SELECTIVITY

5.6 4‐

O

,5‐

N

‐OXAZOLIDINONE GROUP AND ITS STEREODIRECTING INFLUENCE ON SIALYLATIONS

5.7 4,5‐

O

‐CARBONATE PROTECTING GROUP IN α‐SELECTIVE KDN DONORS

5.8 OTHER CYCLIC AND BICYCLIC PROTECTING SYSTEMS FOR SIALYL DONORS

5.9 MECHANISTIC ASPECTS OF SIALYLATION WITH CYCLICALLY PROTECTED SIALYL DONORS

5.10 INFLUENCE OF HYDROXY PROTECTING GROUPS ON SIALYL DONOR REACTIVITY AND SELECTIVITY

5.11 STEREOSELECTIVE C‐SIALOSIDE FORMATION

5.12 STEREOSELECTIVE S‐SIALOSIDE FORMATION

5.13 CONCLUSION

REFERENCES

6 STRATEGIES FOR ONE‐POT SYNTHESIS OF OLIGOSACCHARIDES

6.1 INTRODUCTION

6.2 ONE‐POT GLYCOSYLATION FROM THE NONREDUCING END TO THE REDUCING END

6.3 REGIOSELECTIVE ONE‐POT GLYCOSYLATION: CONSTRUCTION OF OLIGOSACCHARIDES FROM THE REDUCING END TO THE NONREDUCING END

6.4 HYBRID ONE‐POT GLYCOSYLATION

6.5 CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

7 AUTOMATED OLIGOSACCHARIDE SYNTHESIS

7.1 INTRODUCTION

7.2 CHALLENGES AND LIMITATIONS IN SOLUTION‐PHASE OLIGOSACCHARIDE SYNTHESIS

7.3 SOLID‐PHASE OLIGOSACCHARIDE SYNTHESIS

7.4 AUTOMATED OLIGOSACCHARIDE SYNTHESIS

7.5 MICROFLUIDIC TECHNIQUES FOR OLIGOSACCHARIDE SYNTHESIS

7.6 CONCLUSION AND OUTLOOK

ACKNOWLEDGMENTS

REFERENCES

8 SUGAR SYNTHESIS BY MICROFLUIDIC TECHNIQUES

8.1 INTRODUCTION

8.2 MICROFLUIDIC GLYCOSYLATION

8.3 CONCLUSION

REFERENCES

9 CHEMOENZYMATIC SYNTHESIS OF CARBOHYDRATES

9.1 INTRODUCTION

9.2 OLIGOSACCHARIDES AND POLYSACCHARIDES PRODUCED BY GTases

9.3 CHEMOENZYMATIC SYNTHESIS OF HS

9.4 CONCLUSION

REFERENCES

10 SYNTHESIS OF GLYCOSAMINOGLYCANS

10.1 INTRODUCTION

10.2 GENERAL STRATEGIES

10.3 SYNTHESIS OF DERIVATIVES OF L‐IDOSE AND IdoA

10.4 SYNTHESIS VIA STEPWISE SOLUTION‐PHASE ASSEMBLY AND COMPOUND DIVERSIFICATION

10.5 SYNTHESIS VIA SOLUTION‐PHASE ONE‐POT ASSEMBLY

10.6 POLYMER‐SUPPORTED SYNTHESIS AND AUTOMATION

10.7 GAG MIMETICS

10.8 CONCLUSION

REFERENCES

11 CHEMICAL GLYCOPROTEIN SYNTHESIS

11.1 INTRODUCTION

11.2 OLIGOSACCHARIDE STRUCTURES

11.3 BIOSYNTHESIS OF GLYCOPROTEINS

11.4 CHEMICAL PROTEIN SYNTHESIS

11.5 SYNTHESIS OF GLYCOPEPTIDES

11.6 SYNTHESIS OF GLYCOPEPTIDE‐THIOESTERS

11.7 CHEMICAL SYNTHESIS OF GLYCOPROTEINS

11.8 CONCLUSION

REFERENCES

12 SYNTHESIS OF GLYCOSPHINGOLIPIDS

12.1 INTRODUCTION

12.2 CLASSIFICATION AND NOMENCLATURE OF GSLs

12.3 BIOLOGICAL SIGNIFICANCE OF GSLs

12.4 SYNTHESIS OF GSLs

12.5 CONCLUSION

REFERENCES

13 SYNTHESIS OF GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORS

13.1 INTRODUCTION

13.2 SYNTHESIS OF THE

TRYP

.

BRUCEI

GPI ANCHOR

13.3 SYNTHESIS OF THE YEAST GPI ANCHOR

13.4 SYNTHESIS OF THE RAT BRAIN THY‐1 GPI ANCHOR

13.5 SYNTHESIS OF

PLASMODIUM FALCIPARUM

GPI ANCHOR

13.6 SYNTHESIS OF

TRYPANOSOMA CRUZI

GPI ANCHOR

13.7 SYNTHESIS OF A HUMAN SPERM CD52 ANTIGEN GPI ANCHOR

13.8 SYNTHESIS OF A HUMAN LYMPHOCYTE CD52 ANTIGEN GPI ANCHOR

13.9 SYNTHESIS OF THE BRANCHED GPI ANCHOR OF

TOXOPLASMA GONDII

13.10 CONCLUSION

ACKNOWLEDGMENT

REFERENCES

14 SYNTHESIS OF BACTERIAL CELL ENVELOPE COMPONENTS

14.1 INTRODUCTION

14.2 PEPTIDOGLYCAN AND RELATED GLYCOCONJUGATES

14.3 LPS AND RELATED GLYCOCONJUGATES

14.4 LIPOTEICHOIC ACID

14.5 MYCOLYL ARABINOGALACTAN, LAM, AND RELATED GLYCOCONJUGATES

14.6 OLIGOSACCHARIDES OF BACTERIAL GLYCOPROTEIN AND RELATED GLYCOCONJUGATES

14.7 CONCLUSION

REFERENCES

15 DISCOVERIES AND APPLICATIONS OF GLYCAN ARRAYS

15.1 INTRODUCTION

15.2 DISCOVERIES OF GLYCAN ARRAYS

15.3 APPLICATIONS OF GLYCAN ARRAY

15.4 CONCLUSION

REFERENCES

16 SYNTHESIS AND APPLICATIONS OF GLYCONANOPARTICLES, GLYCODENDRIMERS, AND GLYCOCLUSTERS IN BIOLOGICAL SYSTEMS

16.1 INTRODUCTION

16.2 SIGNIFICANCE OF MULTIVALENT BINDING INTERACTIONS IN BIOLOGICAL SYSTEMS

16.3 GLYCONANOPARTICLES, GLYCODENDRIMERS, AND GLYCOCLUSTERS: GENERAL OVERVIEW

16.4 PLANT LECTINS

16.5 AB

5

TOXINS

16.6 BACTERIAL ADHESION LECTINS

16.7 INFLUENZA VIRUS

16.8 DETECTION OF BACTERIA

16.9 GLYCO‐MNPs AS NANOPROBES FOR LABELING CELLS AND MAGNETIC RESONANCE IMAGING AGENTS

16.10 CYCLOPEPTIDE‐BASED GLYCOCLUSTERS AS VACCINE ADJUVANTS

16.11 CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

17 DESIGN AND SYNTHESIS OF CARBOHYDRATES AND CARBOHYDRATE MIMETICS AS ANTI‐INFLUENZA AGENTS

17.1 INTRODUCTION

17.2 INFLUENZA VIRUSES

17.3 DEVELOPMENT OF ANTI‐INFLUENZA THERAPEUTICS

17.4 SIALIC ACID: THE VIRAL CELL‐SURFACE RECEPTOR LIGAND

17.5 HEMAGGLUTININ

17.6 SIALIDASE

17.7 INFLUENZA VIRUS SIALIDASE AS A DRUG DISCOVERY TARGET

17.8 STRUCTURAL DIFFERENCES RECENTLY IDENTIFIED IN INFLUENZA A VIRUS SIALIDASE SUBTYPES

17.9 NEW INFLUENZA VIRUS SIALIDASE INHIBITORS TARGETING THE 150‐CAVITY

REFERENCES

18 DESIGN AND SYNTHESIS OF LIGANDS AND ANTAGONISTS OF SIGLECS AS IMMUNE RESPONSE MODIFIERS

18.1 INTRODUCTION

18.2 LECTINS

18.3 SIGLECS

18.4 SIGLECS AND INNATE IMMUNITY

18.5 DESIGN AND SYNTHESIS OF HIGH‐AFFINITY LIGANDS FOR SIGLECS

18.6 CONCLUSION AND FUTURE DIRECTIONS

REFERENCES

19 SUGAR–PROTEIN HYBRIDS FOR BIOMEDICAL APPLICATIONS

19.1 INTRODUCTION

19.2 CHALLENGES IN THE DEVELOPMENT OF GLYCOPROTEIN‐BASED THERAPEUTICS

19.3 WHY UNNATURAL?

19.4 RETROSYNTHETIC ANALYSIS

19.5 LINKAGES

19.6 GLYCOPROTEIN‐BASED THERAPEUTICS

19.7 CONCLUSION

REFERENCES

INDEX

END USER LICENSE AGREEMENT

List of Tables

Chapter 02

Table 2.1 Benzylidene Acetal Opening Conditions

Chapter 04

Table 4.1 C2 Chiral Auxiliaries in Stereoselective Glycosylation

Table 4.2 Use of Strongly Electron‐Withdrawing Groups to Ensure β‐Mannosylation through α‐Triflate Formation

Table 4.3 Regioselective Glycosylation of 4,6‐

O

‐Benzylidene‐Protected Glucopyranoside Acceptors

Table 4.4 Regioselective Glycosylations on

trans

‐Diols

Table 4.5 Effect of O2 Protecting Groups on Regioselective Glycosylation

Table 4.6 Donor‐Dependent Regioselective Glycosylations

Table 4.7 Regioselective Glycosylations of Glucosamine Acceptors Having Different N‐Protecting Groups

Chapter 08

Table 8.1 Microfluidic Sialylation Using

N

‐Phthaloyl‐ and Azido‐Protected Donors

Table 8.2 Optimization of the α‐Selective Sialylation Involving the N‐Acetylated Donor 15

Table 8.3 N‐Glycosylation of Asparagine under the Integrated Microfluidic and Batch Conditions

Chapter 09

Table 9.1 Summary of HS/Heparin Oligosaccharides Prepared by the Chemoenzymatic Approach

Chapter 10

Table 10.1 Structures of GAGs

Chapter 12

Table 12.1 GSL Sugar Root Names, Abbreviations, and Structures

Chapter 17

Table 17.1 Inhibition of Influenza A Virus Sialidases With C3 C‐Alkylated Derivatives 30 and 31 [137]

Chapter 18

Table 18.1 Established and Putative Contributions of Siglecs to Immune Regulation

Table 18.2 Comparison of Inhibitory Potential of Synthetic Sialosides [36, 40]

List of Illustrations

Chapter 01

Figure 1.1 Common carbohydrate oxidation levels.

Figure 1.2 Fischer projection of glyceraldehyde and its manipulation.

Figure 1.3 The family tree of

D

‐aldoses with the trivial and abbreviated names.

Figure 1.4 The family tree of

D

‐ketoses with the trivial and derived names.

Figure 1.5 The (a) linear Fischer projection of

D

‐glucose and the (b) cyclic Fischer, (c) Haworth, (d) simplified Haworth, and (e) Mills projections of α‐

D

‐glucopyranose.

Figure 1.6 Reeves projections for α‐

D

‐pentoses and α‐

D

‐hexoses.

Figure 1.7 Pyranose ring nomenclature and conformations.

Figure 1.8 Furanose ring nomenclature and conformations.

Figure 1.9 Nomenclatures and structures of selected disaccharides.

Figure 1.10 The anomeric effect. (a) The

n

–σ* interaction stabilizes the α anomer. (b) The β anomer experiences unfavorable dipole–dipole interaction that is reduced in the α anomer. (c) Greater electrostatic repulsion between the lone‐pair electrons of the endocyclic oxygen and the electronegative anomeric substituent in the β anomer.

Figure 1.11 Mutarotation of

D

‐glucose in water at pH 7.

Scheme 1.1 The formose reaction.

Scheme 1.2 Convergence of glucose and mannose to the same osazone.

Scheme 1.3 Early examples of chemical glycosylations. (a) The first reported chemical glycosylation. (b) A Koenigs–Knorr reaction. Ac, acetyl.

Figure 1.12 The first identified branched‐chain sugar, hamamelose.

Scheme 1.4 Enantioselective synthesis of

L

‐glucose via the LACDAC reaction. hfc, 3‐(heptafluoropropylhydroxymethylene)‐

D

‐camphorato; TBS,

tert

‐butyldimethylsilyl.

Scheme 1.5 LACDAC reaction in the total synthesis of Neu5Ac. Bz, benzoyl; TMS, trimethylsilyl.

Scheme 1.6 General scheme for a reagent‐controlled approach to the total synthesis of all eight

L

‐hexoses.

Scheme 1.7 General glycosylation pathway.

Scheme 1.8 Regioselective one‐pot protection of carbohydrates by Hung et al.

Figure 1.13 The immunological adjuvant QS‐21A.

Figure 1.14 Structures of the aminoglycoside antibiotics kanamycin and neamine.

Figure 1.15 Structures of immunological glycolipids and gangliosides.

Chapter 02

Scheme 2.1 A retrosynthetic analysis of the model trisaccharide

1

.

Scheme 2.2 Bn and substituted Bn ether formations. DMF, dimethylformamide.

Scheme 2.3 Cleavage conditions of Bn and substituted Bn ethers.

Scheme 2.4 Allyl and substituted allyl ether formations.

Scheme 2.5 Cleavage conditions of allyl and substituted allyl ethers.

Scheme 2.6 Typical methods for silyl ether formation and cleavage.

Scheme 2.7 Commonly used methods of ester formation.

Scheme 2.8 Commonly used conditions to cleave esters into alcohols.

Scheme 2.9 Selective cleavage of the anomeric acetate.

Scheme 2.10 Common types and methods of amine protection.

Scheme 2.11 Cleavage of amine protecting groups.

Scheme 2.12 Protection of diols with acetals or ketals.

Figure 2.1 The hydroxy groups of glucosides, galactosides, and mannosides.

Scheme 2.13 Selective protection of the primary hydroxyl using bulky groups.

Scheme 2.14 Acetylation of the 6‐

O

‐protected glucoside

18

and galactoside

22

.

Scheme 2.15 Regioselective tin‐activated etherification.

Scheme 2.16 Preparation of the orthogonally protected galactoside

36

. NIS,

N

‐iodosuccinimide; Tol, 4‐tolyl.

Scheme 2.17 Regioselective tin‐mediated protection of glucoside

37

, galactoside

38

, and mannoside

39

. DIPEA, diisopropylethylamine; Ts, tosyl.

Scheme 2.18 Regioselective isopropylidenation among the three secondary hydroxyls. PTSA,

p

‐toluenesulfonic acid.

Scheme 2.19 Notable formations of acetals and ketals on pyranosides.

Scheme 2.20 Monoacylations of benzylidene‐protected glucosides.

Scheme 2.21 Regioselective benzylation of the diol

68

.

Scheme 2.22 Tin‐mediated benzylation or benzoylation of diols

59

and

64

.

Scheme 2.23 TMSOTf‐ or Cu(OTf)

2

‐catalyzed Et

3

SiH‐reductive 3‐O‐benzylation of 4,6‐

O

‐benzylidenated glucopyranosides.

Scheme 2.24 Dependence of the regioselective acylation of 4,6‐

O

‐benzylidene‐

D

‐galactopyranosides with (a) solvent and (b) anomeric configuration.

Scheme 2.25 Differentiation of the 2,6‐diol in galactopyranosides.

Scheme 2.26 Differentiation of 4,6‐diol in galactopyranosides.

Scheme 2.27 Differentiation of the 2,3‐diol in mannopyranosides.

Scheme 2.28 Reductive opening of the 2,3‐

O

‐benzylidene ring of mannosides.

Scheme 2.29 Regioselective protection of the 2,6‐diol in mannopyranosides.

Scheme 2.30 Orthogonal protection of the thioglucoside

107

via acetal and ketal ring openings.

Scheme 2.31 One‐pot tritylation–silylation–acylation of (a) methyl α‐glycosides and (b) β‐thioglycosides.

Scheme 2.32 One‐pot orthoesterification–benzylation–orthoester rearrangement methodology for the protection of the

L

‐rhamnopyranoside

120

.

Scheme 2.33 TMSOTf‐catalyzed regioselective one‐pot protection of glucopyranosides.

Scheme 2.34 Regioselective one‐pot protection of the anomerically nonfixed

D

‐glucosamine derivative

130

.

Scheme 2.35 TMSOTf‐catalyzed regioselective one‐pot protection of mannopyranoside

137

.

Chapter 03

Scheme 3.1 The glycosidic bond formation.

Scheme 3.2 Stereoselective glycosylation by using chiral auxiliaries.

Scheme 3.3 Synthesis of β‐mannosides via remote participation. Bn, benzyl; Pic, picolinyl.

Scheme 3.4 Synthesis of 1,2‐

cis

‐glycosides using halide additives.

Scheme 3.5 Stereoselective glycosylation via solvent participation.

Figure 3.1 Typical glycosyl donors and their corresponding promoters or activating reagents. DTBMP, 2,6‐di‐

tert

‐butyl‐4‐methylpyridine; TMS, trimethylsilyl; Tf, triflyl.

Scheme 3.6 Synthesis of glycosyl bromides. Ac, acetyl.

Scheme 3.7 Koenigs–Knorr glycosylation promoted by insoluble silver salts.

Scheme 3.8 Synthesis of the 1,2‐

cis

‐linked disaccharide

10

using a glycosyl fluoride.

Scheme 3.9 Synthesis of the α‐glycolipid

14

using a glycosyl iodide. DIPEA, diisopropylethylamine; PMB,

p

‐methoxybenzyl.

Scheme 3.10 Preparation of glycosyl trichloroacetimidates.

Scheme 3.11 Applications of trichloroacetimidates in glycosidic bond formation. Troc, 2,2,2‐trichloroethoxycarbonyl.

Scheme 3.12 Preparation of thioglycosides.

Scheme 3.13 Activation of thioglycosides with DMTST.

Scheme 3.14 One‐pot assembly of a trisaccharide using thioglycosides as donors. Bz, benzoyl; Tol, 4‐tolyl.

Scheme 3.15 Synthesis of disaccharide

33

using glycosyl sulfoxide. Piv, pivaloyl.

Scheme 3.16 Synthesis of disaccharide

36

using a thioimidate glycosyl donor.

Scheme 3.17 Synthesis of

n

‐pentenyl glycosides.

Scheme 3.18 Mechanism of glycosylation involving

n

‐pentenyl glycosides.

Scheme 3.19 Glycosylation using

n

‐pentenyl glycoside. ClAc, chloroacetyl.

Scheme 3.20 Mechanism of glycosylation using CB glycosides.

Scheme 3.21 Synthesis of disaccharide

47

using the CB glycoside

45

.

Scheme 3.22 Mechanism of the Au(

I

)‐catalyzed glycosylation with glycosyl

ortho

alkynylbenzoates.

Scheme 3.23 Orthogonal activation of isomeric glycosyl phosphates.

Scheme 3.24 Dehydrative glycosylation promoted by Tf

2

O/Ph

2

SO.

Scheme 3.25 Synthesis of a 2‐deoxyglycoside using the glycal approach. AIBN, azobisisobutyronitrile.

Scheme 3.26 Approaches utilized for the synthesis of 2‐amino‐2‐deoxyglycosides from glycals.

Scheme 3.27 Stereoselective control of glycosylation by using glycosyl epoxide. TBAF, tetrabutylammonium fluoride.

Scheme 3.28 Programmable one‐pot synthesis of Globo‐H. ClBn,

o

‐chlorobenzyl; NBz,

p

‐nitrobenzoyl; RRV, relative reactivity value.

Scheme 3.29 Solid‐phase synthesis of a pentasaccharide with glycals.

Scheme 3.30 Enzymatic synthesis of the blood group B antigen tetrasaccharide. UDP, uridine diphosphate.

Scheme 3.31 Chemoenzymatic synthesis of high‐mannose type RNase B.

Chapter 04

Figure 4.1 Type of glycosides based on the orientations of substituents at C1 and C2.

Scheme 4.1 Neighboring group participation of a 2‐

O

‐acyl functionality to provide 1,2‐

trans

‐glycosides.

Scheme 4.2 Nucleophilic traps to explore neighboring group participation from nonvicinal positions. Bn, benzyl; Tf, triflyl.

Scheme 4.3 Use of the picolyl ether for the stereoselective synthesis of 1,2‐

trans

‐glycosides.

Scheme 4.4 1,2‐Migration of an anomeric participating group to afford α‐ or β‐deoxyglycosides.

Scheme 4.5 1,2‐Migration in the stereoselective synthesis of 1,2‐

trans

(amino)‐glycosides and 2‐deoxyglycosides as reported by (a) Danishefsky, (b) Yu, and (c) Lowary. Ac, acetyl; All, allyl; Bn, benzyl; Bz, benzoyl; DTBMP, 2,6‐di‐

tert

‐butyl‐4‐methylpyridine; TBDPS,

tert

‐butyldiphenylsilyl; THF, tetrahydrofuran; TIPS, triisopropylsilyl; Tol, 4‐tolyl.

Scheme 4.6 Chiral auxiliaries designed to form

cis

‐ or

trans

‐decalin oxonium intermediates to afford 1,2‐

trans

‐ or 1,2‐

cis

‐glycosides, respectively. Nu, nucleophile; TMS, trimethylsilyl.

Scheme 4.7 Generation of sulfonium ions using electrophilic aromatic substitution of oxathiane glycosyl donors. PTSA,

p

‐toluenesulfonic acid.

Scheme 4.8 IAD (a) by the use of anomeric linkers, (b) by the use of rigid spacers at nonreacting centers, and (c) by tethering from C2 to form 1,2‐

cis

‐glycosides.

Scheme 4.9 IAD by acetal tethering to afford 1,2‐

cis

‐glycosides.

Scheme 4.10 Trapping of an intermediate oxocarbenium ion using a 3‐

O

‐TMS ether in the synthesis of β‐

L

‐rhamnosides. Naph, 2‐naphthyl.

Scheme 4.11 Dual anomeric control using IAD in the synthesis of α,α‐trehalose. PCB,

p

‐chlorobenzyl; PIB,

p

‐iodobenzyl.

Scheme 4.12 Use of the 4,6‐

O

‐benzylidene acetal in mannosyl donors to favor the α‐triflate intermediate. TTBP, 2,4,6‐tri‐

tert

‐butylpyrimidine.

Figure 4.2 The nature of the disarming ability of 4,6‐

O

‐acetals.

Scheme 4.13 Application of the 1‐cyano‐2‐(2‐iodophenyl)‐ethylidene acetal for the synthesis of a β(1→3)‐

D

‐rhamnotetraose. CSA, 10‐camphorsulfonic acid.

Scheme 4.14 β selectivity in the glycosylation of mannuronate esters.

Scheme 4.15 Securing of the

E

3

conformer using the 3,5‐

O

‐DTBS protecting group to ensure 1,2‐

cis

‐glycosylation.

Scheme 4.16 Use of the DTBS group in α‐galactosylation.

Scheme 4.17 Anomerization of 2,3‐

N

,

O

‐oxazolidinone‐protected glycosides.

Figure 4.3 Correlation of the calculated TS energies from inner strain caused by the two fused rings and the experimental results.

Scheme 4.18 Selective glycosylation using the armed–disarmed glycosylation strategy. Cbz, benzyloxycarbonyl.

Scheme 4.19 Competition experiment showing the super‐arming effect of a participating group at C2 in

trans

orientation with respect to the leaving group. Box, benzoxazolyl; DMTST, dimethyl(methylthio)sulfonium triflate.

Scheme 4.20 Super‐arming by steric effect. (a) Influence of conformation on the reactivity of glycosides. (b) Conformational change induced by bulky silyl ethers.

Figure 4.4 Examples of (a) glycosyl acceptors and (b) glycosyl donors used in trityl ether‐assisted regioselective glycosylation. Tr, trityl.

Scheme 4.21 Trityl ether‐assisted regioselective glycosylation.

Figure 4.5 Martín‐Lomas’ rationale for the preferred reaction site of diols. (a) 1,2‐

cis

‐Diequatorial diols with Bn or Bz protecting groups. (b) 1,2‐

cis

‐Axial‐equatorial diols in

D

‐mannosides. (c) 1,2‐

trans

‐Diaxial diols in

L

‐iduronic acid and

D

‐altrose.

Chapter 05

Figure 5.1 Commonly occurring sialic acids.

Scheme 5.1 The anomeric equilibrium in Neu5Ac. Ac, acetyl.

Scheme 5.2 Stereoelectronic considerations for the reaction of interconverting conformers of a sialyl oxocarbenium ion.

Figure 5.2 Nitrile and sulfoxide adducts.

Scheme 5.3 Effect of

N

,

N

‐diacetylation of a thioglycoside donor on sialylation. Bz, benzoyl; TMS, trimethylsilyl; Ts, toluenesulfonyl.

Scheme 5.4 Beneficial effect of the imide function on acceptor reactivity. Bn, benzyl.

Scheme 5.5 Selectivity in the reactions of an

N

,

N

‐diacetylsialyl chloride.

Scheme 5.6 Sialylation with an

N

‐acetyl‐

N

‐Boc‐protected donor. TFA, trifluoroacetyl.

Scheme 5.7 Use of a phthalimide‐protected sialyl donor. All, allyl; Phth, phthaloyl.

Figure 5.3 Computationally optimized structures of oxocarbenium ions

25

and

26

.

Scheme 5.8 Use of an

N

‐TFA‐protected donor.

Scheme 5.9 Use of an

N

‐Troc‐protected donor in a one‐pot trisaccharide synthesis. AgOTf, silver(I) triflate; Cbz, benzyloxycarbonyl.

Figure 5.4 RRVs of various sialyl donors relative to 4‐tolyl peracetyl‐α‐

D

‐thiomannopyranoside.

Scheme 5.10 Use of an azide‐protected sialyl donor.

Scheme 5.11 Examples of sialylations with a 4‐

O

,5‐

N

‐oxazolidinone‐protected sialyl thioglycoside. AcCl, chloroacetyl.

Scheme 5.12 Convergent synthesis of the GP1c ganglioside epitope assisted by the 4‐

O

,5‐

N

‐oxazolidinone group.

Scheme 5.13 Sialylation with an

N

‐acetyl‐4‐

O

,5‐

N

‐oxazolidinone‐protected donor and subsequent removal of the oxazolidinone group.

Scheme 5.14 Synthesis of an α‐Neu5Gc‐based disaccharide.

Scheme 5.15 One‐pot synthesis and subsequent deprotection of an Neu5Gc‐based trisaccharide.

Scheme 5.16 Use of an

N

‐acetyl‐4‐

O

,5‐

N

‐oxazolidinone‐protected sialyl phosphate in a one‐pot trisaccharide synthesis.

Scheme 5.17 Use of a 4,5‐

O

‐carbonate‐protected KDN donor.

Figure 5.5 Oxazinone‐protected sialoside donors. TBS,

tert

‐butyldimethylsilyl.

Scheme 5.18 Use of a tricyclic sialyl donor and the influence of the acceptor protecting system on stereoselectivity. PMP,

p

‐methoxyphenyl.

Figure 5.6 Threshold cone voltages for the fragmentation of sialyl phosphates.

Scheme 5.19 Nucleophilic C‐sialylation. THF, tetrahydrofuran.

Scheme 5.20 Use of the Ireland–Claisen rearrangement in C‐sialylation. BOM, benzyloxymethyl; LiHMDS, lithium bis(trimethylsilyl)amide; TMS, trimethylsilyl.

Scheme 5.21 Electrophilic C‐sialidation with an

N

‐acetyloxazolidinone‐protected sialyl donor.

Scheme 5.22 Stereoselective S‐sialoside formation by reaction of a β‐sialyl chloride with a thiolate. DMF,

N

,

N

‐dimethylformamide.

Scheme 5.23 Oligothiosialoside synthesis by iterative alkylation of a sialic acid‐based anomeric thiolate. DIPEA, diisopropylethylamine.

Scheme 5.24 Sialylation of a thiol under Lewis acid‐mediated conditions by an

N

‐acetyl oxazolidinone‐protected sialyl phosphate.

Chapter 06

Scheme 6.1 General scheme for reactivity‐based one‐pot glycosylation.

Scheme 6.2 Ley’s one‐pot synthesis of trisaccharide

11

. Bn, benzyl.

Scheme 6.3 Yu’s synthesis of tricolorin A. DDQ, 2,3‐dichloro‐5,6‐dicyano‐1‐4,‐benzoquinone.

Scheme 6.4 Kondo’s one‐pot synthesis of the Lewis X derivative

21

.

Scheme 6.5 Wong’s programmable one‐pot synthesis of Lewis Y carbohydrate hapten. Ac, acetyl; Lev, levulinyl; Tol, 4‐tolyl; Troc, trichloroethoxycarbonyl.

Figure 6.1 Building blocks employed by Huang in examining relative reactivities. Phth, phthaloyl; TBDPS,

tert

‐butyldiphenylsilyl.

Scheme 6.6 One‐pot synthesis of trisaccharide

33

using the super‐armed building block

30

. TBS,

tert

‐butyldimethylsilyl.

Scheme 6.7 Yb(OTf)

3

‐mediated one‐pot synthesis of trisaccharide

37

. Tf, triflyl.

Scheme 6.8 Sulikowski’s one‐pot synthesis of trisaccharide

41

. PMP,

p

‐methoxyphenyl; TES, triethylsilyl; TMSOTf, trimethylsilyl triflate.

Scheme 6.9 Huang’s (a) postsynthetic aglycone modifications and (b) one‐pot synthesis of tetrasaccharide

51

.

Scheme 6.10 Synthesis of tetrasaccharide

58

.

Scheme 6.11 Kobayashi’s one‐pot synthesis of trisaccharide

63

through chemoselective activation of glycosyl

N

‐trichloroacetylcarbamate.

Scheme 6.12 Oscarson’s one‐pot synthesis of trisaccharide

66

.

Scheme 6.13 Baasov’s one‐pot synthesis of tetrasaccharide

71

.

Scheme 6.14 One‐pot glycosylation based on chemoselective activation of different types of glycosyl donors.

Scheme 6.15 Takahashi’s one‐pot synthesis of hexasaccharide

80

. MBn,

p

‐methylbenzyl; MBz,

p

‐methylbenzoyl.

Scheme 6.16 Stereoselective one‐pot synthesis of trisaccharide

86

.

Scheme 6.17 Wu’s one‐pot synthesis of tetrasaccharide

90

.

Scheme 6.18 Wong’s one‐pot synthesis of the SSEA‐4 hexasaccharide

94

.

Scheme 6.19 One‐pot synthesis of trisaccharide

97

.

Scheme 6.20 Ito’s stereoselective one‐pot synthesis of trisaccharide

101

. ClAc, chloroacetyl; DTBMP, di‐

tert

‐butylmethylpyridine.

Scheme 6.21 Demchenko’s one‐pot synthesis of tetrasaccharide

106

.

Scheme 6.22 One‐pot synthesis of trisaccharide

111

. Piv, pivaloyl.

Scheme 6.23 Preactivation‐based one‐pot synthesis of the hyaluronic acid trisaccharide

115

. TTBP, 2,4,6‐tri‐

tert

‐butylpyrimidine.

Scheme 6.24 Huang and Ye’s preactivation‐based one‐pot synthesis of oligosaccharides.

Scheme 6.25 Huang’s one‐pot assembly of the Globo H construct

127

.

Scheme 6.26 Coupling efficiency of donors bearing electron‐withdrawing protecting groups compared with those containing electron‐donating protecting groups under the preactivation strategy.

Scheme 6.27 Fluorous‐assisted one‐pot synthesis of tetrasaccharide

138

.

Scheme 6.28 Mong’s stereoselective one‐pot synthesis using DMF as the novel additive to facilitate the 1,2‐

cis

‐glycoside formation. (a) The glycosyl imidates formed with DMF. (b) The one‐pot synthesis of trisaccharide

142

.

Scheme 6.29 Ning’s one‐pot synthesis of trisaccharide

147

.

Scheme 6.30 HClO

4

–silica‐promoted one‐pot synthesis of trisaccharide

152

.

Scheme 6.31 One‐pot synthesis of a timosaponin AIII analogue.

Scheme 6.32 One‐pot synthesis of a globotetraose analogue.

Scheme 6.33 Hung’s one‐pot synthesis of tetrasaccharide

168

. Cbz, benzyloxycarbonyl.

Scheme 6.34 One‐pot synthesis of protected ciclamycin trisaccharide

172

.

Scheme 6.35 One‐pot synthesis of tetrasaccharide

176

. FBn, 4‐fluorobenzyl.

Scheme 6.36 Mong’s one‐pot synthesis of trisaccharide

180

through combination of selective activation and armed–disarmed approach.

Scheme 6.37 Takahashi’s one‐pot synthesis of the glycosyl amino acid

187

by combining selective activation and regioselective glycosylation.

Scheme 6.38 Bidirectional one‐pot synthesis of hexasaccharide

193

.

Scheme 6.39 Huang’s one‐pot synthesis of the Lewis X trisaccharide

196

.

Chapter 07

Scheme 7.1 Solution‐phase oligosaccharide synthesis strategy.

Figure 7.1 Synthetic strategies for oligosaccharide assembly on solid support. (a) Donor‐bound strategy. (b) Acceptor‐bound strategy. (c) Bidirectional strategy.

Scheme 7.2 The first solid‐supported oligosaccharide synthesis. Bn, benzyl.

Figure 7.2 Three platforms for automated solid‐phase oligosaccharide synthesis. (a) Pressure‐driven system. (b) Syringe pump‐driven system. (c) HPLC pump‐driven system.

Figure 7.3 Oligosaccharides synthesized by automation using octenediol or butenediol linkers and the major milestones achieved. Piv, pivaloyl; TCA, trichloroacetyl.

Figure 7.4 Automated synthesis utilizing the bifunctional linker gives access to ready‐to‐use oligosaccharide constructs that are useful for various biomedical applications.

Scheme 7.3 Optimization of glycosylation reactions in a microreactor. (a) Mannosylation optimization by varying temperature and incubation time. (b) Mannosylation optimization by solvent effect. (c) Sialylation optimization by donor and activator concentration.

Chapter 08

Figure 8.1 Continuous flow synthesis using microreactor and affinity separation system. Ac, acetyl; Bn, benzyl; TfO, triflate; Troc, trichloroethoxycarbonyl.

Scheme 8.1 Solid‐phase synthesis of an N‐glycan. Cbz, benzyloxycarbonyl, DDQ, 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Fmoc, 9‐fluorenylmethoxycarbonyl.

Figure 8.2 Microfluidic glycosylation to form the sialoside

16

.

Scheme 8.2 α‐Sialylation with the 6‐hydroxyl of glucosamine and the 3‐hydroxyl of galactose acceptors.

Figure 8.3 α‐Selective glycosylation of KDO with a disaccharide acceptor using the microfluidic method. Alloc, allyloxycarbonyl; Cbz, benzyloxycarbonyl, PMB,

p

‐methoxybenzyl.

Figure 8.4 α‐Selective glycosylation of monosaccharide acceptors with KDO using the microfluidic method.

Figure 8.5 Stereoselective β‐mannosylation.

Chapter 09

Figure 9.1 Nucleotide sugaR substrates for GTases. CMP, cytidine monophosphate; GDP, guanidine diphosphate; UDP, uridine diphosphate.

Scheme 9.1 Biosynthesis of HS. (a) Elongation reactions to prepare the precursor polysaccharide backbone using both EXT1 and EXT2 enzymes. (b) Polysaccharide modifications.

Scheme 9.2 Chemoenzymatic synthesis of ULMW heparin

27

.

Scheme 9.3 Substrate specificity of C

5

‐epi. (a) C5‐epi recognition site resulting to irrevesible epimerization. (b) C5‐epi recognition site resulting to revesible epimerization. (c) Site not acted upon by C5‐epi.

Scheme 9.4 Enzymatic synthesis of PAPS starting from Na

2

SO

4

and ATP. Pi, phosphate; PPi, pyrophosphate.

Chapter 10

Figure 10.1 Some monosaccharide building blocks used in the assembly of (a) HA, (b) CS, and (c) heparin/HS showing the array of protecting groups. All, allyl; Bn, benzyl; Bz, benzoyl; Fmoc, 9‐fluorenylmethoxycarbonyl; Lev, levulinyl; NAP, 2‐naphthylmethyl; PBB,

p

‐bromobenzyl; Phth, phthaloyl; PMB,

p

‐methoxybenzyl; PMP,

p

‐methoxyphenyl; TBDPS,

tert

‐butyldiphenylsilyl; TBS,

tert

‐butyldimethylsilyl; TCA, trichloroacetyl; TDS, dimethylthexylsilyl; Tol, 4‐tolyl.

Scheme 10.1 Preparation of a disaccharide building block for heparin and HS assembly that includes oxidation to form the uronic acid residue. DMAP,

N

,

N

‐dimethyl‐4‐aminopyridine; NIS,

N

‐iodosuccinimide; Pyr, pyridine; Tf, triflyl; TMS, trimethylsilyl.

Scheme 10.2 Preparations of IdoA and

L

‐idose derivatives. Ms, mesyl.

Scheme 10.3 Preparation of oligosaccharides based on heparin and HS in a [2 + 

n

] manner. DMF,

N

,

N

‐dimethylformamide.

Scheme 10.4 Preparation of a dodecasaccharide based on heparin and HS in a [4 + 4 + 4] manner. Cbz, benzyloxycarbonyl; DDQ, 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone.

Scheme 10.5 Hung’s preparation of various disaccharide building blocks with compound

52

as the common precursor. PTSA,

p

‐toluenesulfonic acid.

Scheme 10.6 The heparin/HS‐based octasaccharides prepared by Hung and coworkers.

Scheme 10.7 Preparation of various disaccharide derivatives from a common precursor by Jacquinet and coworkers. DBU, 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DCC,

N

,

N'

‐dicyclohexylcarbodiimide.

Scheme 10.8 Divergent preparation of various CS oligomers by Jacquinet and coworkers. AIBN, azobisisobutyronitrile.

Scheme 10.9 Various heparin and HS oligomers prepared by the laboratories of (a) Hung, (b) Boons, and (c) Tyler by postassembly divergent transformation.

Scheme 10.10 Synthesis of HA oligomers involving one‐pot assembly to the trisaccharide level.

Scheme 10.11 Anomeric reactivity‐based one‐pot assembly and preparation of a pentasaccharide based on heparin and HS.

Scheme 10.12 Preparation of hexasaccharides based on heparin and HS via preactivation. TTBP, 2,4,6‐tri‐

tert

‐butylpyrimidine.

Scheme 10.13 Polymer‐supported assembly and release of an octasaccharide with a heparin/HS backbone. DIC,

N

,

N

′‐diisopropylcarbodiimide; Piv, pivaloyl.

Scheme 10.14 Automated solid‐phase assembly and synthesis of HA oligomers.

Scheme 10.15 Automated solid‐phase synthesis of CS‐based hexasaccharides.

Scheme 10.16 Synthesis of CS glycomimetic polymers through ROMP.

Chapter 11

Figure 11.1 O‐Linked oligosaccharide structures. Ac, acetyl.

Figure 11.2 N‐Linked oligosaccharide structures.

Figure 11.3 Biosynthesis of glycoproteins.

Scheme 11.1 Native chemical ligation and a concept using amino acid having thiol at the β position. Acm, acetamidomethyl; PG, protecting group; VA‐044, 2,2′‐ azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride.

Scheme 11.2 Synthetic strategies of glycopeptides. (a) Convergent coupling, (b) solid‐phase glycopeptide synthesis, and (c) enzymatic coupling. Asp, aspartic acid.

Scheme 11.3 Synthesis of glycopeptide‐

α

thioesters by (a) using safety‐catch linker and (b) thioesterification of activated C‐terminal carboxylic acids. Boc,

tert

‐butoxycarbonyl.

Scheme 11.4 Convergent concept demonstrated by the Lansbury group. Bn, benzyl; cHex, cyclohexyl; DIPEA, diisopropylethylamine; DMSO, dimethyl sulfoxide; DNP, 2,4‐dinitrophenyl; HBTU, 2‐(1

H

‐benzotriazol‐1‐y1)‐1,1,3,3‐tetramethyluronium hexafluorophosphate; HOBt, 1‐hydroxybenzotriazole; Ts, tosyl.

Scheme 11.5 Efficient concept for convergent method using the pseudoproline scaffold reported by (a) Unverzagt et al. and (b) Danishefsky et al. BMP, butyl‐3‐mercaptopropionate; DIC, diisopropylcarbodiimide; DMF,

N

,

N

‐dimethylformamide; Gly, glycine; HATU,

O

‐(7‐azabenzotriazol‐1‐yl)‐

N

,

N

,

N

′,

N

′‐tetramethyluronium hexafluorophosphate; HOAt, 1‐hydroxy‐7‐azabenzotriazole.

Scheme 11.6 Glycopeptide

α

thioesterification via O‐to‐S acyl shift. MESNa, sodium 2‐mercaptoethanesulfonate.

Scheme 11.7 Glycopeptide‐

α

thioesters by Boc‐SPPS conditions. DEPBT, 3‐(diethoxyphosphoryloxy)‐1,2,3‐benzotriazin‐4(3

H

)‐one.

Scheme 11.8 Synthesis of antibacterial glycoprotein diptericin.

Scheme 11.9 Synthesis of lymphotactin.

Scheme 11.10 Synthesis of the Im7 domain of E colicin immunity protein. Glu, glutamic acid; His, histidine; Met, methionine.

Scheme 11.11 Synthesis of the 23 kDa MUC‐2. Gln, glutamine.

Scheme 11.12 Semisynthesis of O‐linked GlyCAM derivatives. (a) Preparation of a glycoform containing O‐linked GalNAc residues only in the N‐terminal segment. (b) Other assembled glycoforms with GalNAc residues at various positions. Arg, arginine; Ile, isoleucine.

Scheme 11.13 Chemical synthesis of the glycosylated MCP‐3.

Scheme 11.14 Semisynthesis of the glycosylated RNase.

Scheme 11.15 Synthesis of antifreeze glycoproteins.

Scheme 11.16 Synthesis of an IL‐8 analogue having high mannose‐type oligosaccharide.

Scheme 11.17 Synthesis of IFN‐β‐1a.

Scheme 11.18 Synthesis of saposin C.

Scheme 11.19 Semisynthesis of EPO analogues.

Scheme 11.20 Chemical synthesis of EPO having a complex‐type sialyloligosaccharide.

Scheme 11.21 Synthesis of EPO bearing three N‐linked chitobioses and an O‐linked tetrasaccharide.

Chapter 12

Figure 12.1 GSL structures. (a) Sphingoid bases. (b) Examples of GSLs and their classification based on the basic structural features in parentheses. Ac, acetyl.

Figure 12.2 Important cancer‐related GSLs.

Scheme 12.1 Ogawa’s synthesis of Gb

3

Cer. DAST,

N

,

N

‐diethylaminosulfur trifluoride; Tf, triflyl.

Scheme 12.2 Nicolaou’s synthesis of Gb

3

Cer. DMAP, 4‐dimethylaminopyridine; NBS,

N

‐bromosuccinimide; TBAF, tetrabutylammonium fluoride.

Scheme 12.3 Hashimoto’s synthesis of Gb

3

Cer. TMS, trimethylsilyl.

Scheme 12.4 One‐pot synthesis of Gb

3

and iGb

3

. Tol, 4‐tolyl.

Scheme 12.5 Mong’s synthesis of Gb

3

and iGb

3

. NIS,

N

‐iodosuccinimide.

Scheme 12.6 Synthesis of iGb

3

Cer by Zhou et al.

Scheme 12.7 Wang’s synthesis of iGb

3

Cer. DBU, 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; EDC, 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide.

Scheme 12.8 Danishefsky’s first‐generation total synthesis of Globo‐H ceramide. DMDO, dimethyldioxirane; TIPS, triisopropylsilyl.

Scheme 12.9 Danishefsky’s second‐generation synthesis of Globo‐H. DMF,

N

,

N

‐dimethylformamide; DTBP, 2,6‐di‐

tert

‐butylpyridine; IDCP, iodonium di‐

sym

‐collidine perchlorate; LHMDS, lithium bis(trimethylsilyl)amide.

Scheme 12.10 Schmidt’s synthesis of Globo‐H. All, allyl.

Scheme 12.11 Boons’ synthesis of Globo‐H.

Scheme 12.12 Wong’s synthesis of Globo‐H. ClBn,

o

‐chlorobenzyl; NBz,

p

‐nitrobenzoyl; PMP,

p

‐methoxyphenyl; RRV, relative reactivity value.

Scheme 12.13 Seeberger’s automated synthesis of Gb

3

and Globo‐H. TCA, trichloroacetyl.

Scheme 12.14 Hasegawa’s total synthesis of sLe

x

hexasaccharide ceramide.

Scheme 12.15 Wong’s one‐pot assembly of sLe

x

hexasaccharide. Phth, phthaloyl.

Scheme 12.16 Seeberger’s synthesis of the key sialo disaccharide. BAIB, [bis(acetoxy)iodo]benzene.

Scheme 12.17 Synthesis of a‐series ganglioside glycans. TASF, tris(dimethylamino)sulfonium difluorotrimethylsilicate.

Scheme 12.18 Kiso’s total synthesis of GQ1b.

Figure 12.3 LcGg hybrid GSLs synthesized by Kiso and coworkers.

Scheme 12.19 Takahashi’s synthesis of GP1c. CSA, camphorsulfonic acid.

Scheme 12.20 Total synthesis of starfish ganglioside LLG‐3. CAN, ceric ammonium nitrate, DTBMP, 2,6‐di‐tert‐butyl‐4‐methylpyridine, HOBt, 1‐hydroxybenzotriazole.

Scheme 12.21 Synthesis of the glycan moiety of HPG‐7. Boc,

tert

‐butoxycarbonyl.

Chapter 13

Figure 13.1 GPI core structure and modification sites.

Scheme 13.1 Synthesis of the pseudopentasaccharide intermediate

9

. CAN, ceric ammonium nitrate; PMB,

p

‐methoxybenzyl; Pyr, pyridine; TBAF, tetrabutylammonium fluoride; Tf, triflyl.

Scheme 13.2 Completion of Ogawa’s synthesis of the target GPI

17

. Cbz, benzyloxycarbonyl; THF, tetrahydrofuran; TMS, trimethylsilyl.

Scheme 13.3 Synthesis of the pentasaccharide donor

26

.

Scheme 13.4 Completion of Ley’s synthesis of the

Trypanosoma brucei

GPI anchor. All, allyl; TBAI, tetrabutylammonium iodide.

Scheme 13.5 Synthesis of tetramannosyl donor

38

. DBU, 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; TBDPS,

tert

‐butyldiphenylsilyl.

Scheme 13.6 Completion of Schmidt’s synthesis of the yeast GPI anchor. CSA, camphorsulfonic acid.

Scheme 13.7 Fraser‐Reid’s synthesis of building blocks for the convergent assembly of the rat brain Thy‐1 GPI anchor. DMAP, 4‐dimethylaminopyridine; PPTS, pyridinium

p

‐toluenesulfonate.

Scheme 13.8 Completion of Fraser‐Reid’s synthesis of the rat brain Thy‐1 GPI anchor. TES, triethylsilyl.

Scheme 13.9 Synthesis of the pentasaccharide donor

68

.

Scheme 13.10 Completion of Schmidt’s synthesis of rat brain Thy‐1 GPI with differentiated phosphoethanolamine moieties.

Scheme 13.11 Synthesis of pseudopentasaccharide

84

. Tr, trityl.

Scheme 13.12 Completion of Fraser‐Reid’s synthesis of the

Plasmodium falciparum

GPI anchor.

Scheme 13.13 Synthesis of the key tetramannosyl donor

93

and pseudodisaccharide acceptor

96

for the assembly of the

Plasmodium falciparum

GPI anchor.

Scheme 13.14 Completion of Seeberger’s synthesis of the

Plasmodium falciparum

GPI anchor.

Scheme 13.15 Synthesis of tetramannose donor

107

.

Scheme 13.16 Synthesis of pseudodisaccharide acceptor

111

.

Scheme 13.17 Completion of Vishwakarma’s synthesis of the

Trypanosoma cruzi

GPI anchor.

Scheme 13.18 Synthesis of the pseudohexasaccharide core

122

.

Scheme 13.19 Completion of Nikolaev’s synthesis of two

Trypanosoma cruzi

GPI anchors.

Scheme 13.20 Synthesis of the tetramannose donor

135

and the pseudodisaccharide acceptor

139

.

Scheme 13.21 Completion of Guo’s synthesis of the CD52 antigen GPI anchor

141

.

Scheme 13.22 Synthesis of the tetramannose donor

146

and the pseudodisaccharide acceptor

151

. COD, 1,5‐cyclooctadiene.

Scheme 13.23 Completion of Guo’s synthesis of the human lymphocyte CD52 antigen GPI anchor. Fmoc, 9‐fluorenylmethoxycarbonyl.

Scheme 13.24 Functionalization of GPIs using click chemistry.

Scheme 13.25 Synthesis of the pentasaccharide donor

165

. DDQ, 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Lev, levulinyl; TIPS, triisopropylsilyl.

Scheme 13.26 Completion of Seeberger’s synthesis of a

Toxoplasma gondii

GPI anchor.

Chapter 14

Figure 14.1 Cell envelope structures of (a) Gram‐negative bacteria, (b) Gram‐positive bacteria, and (c) mycobacteria.

Figure 14.2 Peptidoglycan biosynthesis. Ac, acetyl; Gly, glycine.

Scheme 14.1 Synthesis of lipids I and II by VanNieuwenhze et al. Bn, benzyl; CDI, 1,1′‐carbonyldiimidazole; DBU, 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DIPEA, diisopropylethylamine; EDC, 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide; NHS,

N

‐hydroxysuccinimide; Pyr, pyridine; TFA, trifluoroacetyl; Troc, 2,2,2‐trichloroethoxycarbonyl.

Scheme 14.2 Synthesis of lipid IV by Wong, Cheng, and coworkers. ClAc, chloroacetyl; NIS,

N

‐iodosuccinimide; Phth, phthaloyl; PyBOP, benzotriazol‐1‐yl‐oxytripyrrolidinophosphonium hexafluorophosphate; RRV, relative reactivity value; TBAF, tetrabutylammonium fluoride; TBS,

tert

‐butyldimethylsilyl; Tf, triflyl; TMS, trimethylsilyl; Tol, 4‐tolyl.

Scheme 14.3 Synthesis of mycobacterial lipid II. TMSE, 2‐(trimethylsilyl)ethyl.

Scheme 14.4 Synthesis of a lipid IV analogue by Khane and coworkers. ADMB, 4‐allyl‐1,2‐dimethoxybenzene; DTBMP, 2,6‐di‐

tert

‐butyl‐4‐methylpyridine; HATU,

O

‐(7‐azabenzotriazole‐1‐yl)‐

N

,

N

,

N

′,

N

′‐tetramethyluronium hexafluorophosphate; mCPBA,

m

‐chloroperoxybenzoic acid; TCP, tetrachlorophthaloyl; Teoc, 2‐trimethylsilylethoxycarbonyl.

Scheme 14.5 Synthesis of a peptidoglycan fragment by Mobashery and coworkers. Cbz, benzyloxycarbonyl; DMM, dimethylmaleoyl.

Scheme 14.6 Synthesis of muramyl pentapeptide

48

with DAP residue by Boons et al. All, allyl; Boc,

tert

‐butoxycarbonyl; HOBt, 1‐hydroxybenzotriazole.

Scheme 14.7 Synthesis of peptidoglycan fragments by Fukase and coworkers. COD, 1,5‐cyclooctadiene.

Figure 14.3 Structure of LPS with the core structure from

Escherichia coli

and the

Salmonella

species. Gal, galactose; Glc, glucose; Hep,

L

‐

glycero

‐

D

‐

manno

‐heptose; O‐PS, O‐antigen polysaccharide.

Scheme 14.8 Synthesis of the Re‐type lipid A from

Escherichia coli

. DCC,

N

,

N

′‐dicyclohexylcarbodiimide; DMAP, 4‐dimethylaminopyridine; LHMDS, lithium bis(trimethylsilyl)amide; TES, triethylsilyl.

Scheme 14.9 Synthesis of lipid A from

Helicobacter pylori

. Alloc, allyloxycarbonyl; CbzOBt, 1‐(benzyloxycarbonyl)benzotriazole; CPME, cyclopentylmethyl ethel; CSA, camphorsulfonic acid; DMDO, dimethyldioxirane; MNBA, 2‐methyl‐6‐nitrobenzoic anhydride; PMB,

p

‐methoxybenzyl.

Scheme 14.10 Synthesis of an oligo‐KDO structure by using a KDO glycal.

Scheme 14.11 Synthesis of the LPS inner‐core structure of

Francisella tularensis

by Boons et al. DDQ, 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; DEIPS, diethylisopropylsilyl; NAP, 2‐naphthylmethyl.

Scheme 14.12 Synthesis of core structure of LPS from

Neisseria meningitidis

. Bz, benzoyl; NBS,

N

‐bromosuccinimide; PBB,

p

‐bromobenzyl.

Figure 14.4 Outer‐core polysaccharides and CPS as synthetic targets. Man, mannose; PMP,

p

‐methoxyphenyl; Rha, rhamnose.

Scheme 14.13 Synthesis of the SCWP fragment from

Bacillus anthracis

by Boons and coworkers. Fmoc, 9‐fluorenylmethoxycarbonyl; TDS, dimethylthexylsilyl.

Scheme 14.14 Synthesis of PS A1 repeating tetrasaccharide unit from

Bacteroides fragilis

by Seeberger and coworkers. DMTST, dimethyl(methylthio)sulfonium triflate; TTBP, 2,4,6‐tri‐

tert

‐butylpyrimidine.

Figure 14.5 Structure of type I–IV lipoteichoic acid. GalNAc,

N

‐acetylgalactosamine.

Scheme 14.15 Synthesis of a type IV lipoteichoic acid by Schmidt et al. TBDPS,

tert

‐butyldiphenylsilyl.

Figure 14.6 Structure of mycobacterial mycolyl arabinogalactan–peptidoglycan complex. Ara, arabinose; MurNGc,

N

‐glycolylmuramic acid.

Figure 14.7 Structures of the docosasaccharide arabinan prepared by the laboratories of Lowary and Ito.

Scheme 14.16 Synthesis of the docosasaccharide arabinan

124

by Lowary and coworkers. CAN, ceric ammonium nitrate.

Scheme 14.17 Synthesis of the docosasaccharide arabinan

125

by Ito and coworkers.

Scheme 14.18 Synthesis of mycolyl arabinan

151

. Ts, tosyl.

Figure 14.8 Structure of mycobacterial LAM.

Scheme 14.19 Lipomannan synthesis by Fraser‐Reid and coworkers. Tr, trityl.

Scheme 14.20 Synthesis of a 28‐mer LAM core by Fraser‐Reid and coworkers.

Scheme 14.21 Synthesis of the O‐linked oligosaccharide of BclA by Seeberger and coworkers. AIBN, azobisisobutyronitrile; TCA, trichloroacetyl.

Scheme 14.22 Synthesis of N‐linked oligosaccharide and lipid‐linked oligosaccharide from

Campylobacter jejuni

by Ito and coworkers. DAST,

N

,

N

‐diethylaminosulfur trifluoride.

Chapter 15

Figure 15.1 Noncovalent immobilization methods to construct a glycan array.

Figure 15.2 Covalent immobilization methods.

Chapter 16

Figure 16.1 Multivalent binding of a bacterium to the clustered carbohydrate ligand carrying matching terminal carbohydrate residue(s) found in the host cell surface. The multivalent interaction prevents the attachment of the bacterium to the host cell surface. The functional role of the linker is the optimal presentation of the glycan into the binding site of the receptor, but it may also be involved in additional hydrophobic contacts.

Scheme 16.1 Structures of multivalent architectures and their general synthetic strategies. (a) Convergent approach. (b) Divergent approach.

Figure 16.2 Molecular structures of different glycodendrimers. (a) A carbohydrate‐coated dendrimer with 24 pendant monosaccharide residues. (b) A carbohydrate‐centered dendrimer with a β‐cyclodextrin (βCD) core and 14 copies of a glycosyl thiol residue. (c) A β‐

D

‐glucosamine‐based glycodendrimer comprising 16 monosaccharide residues arranged around a tetravalent polyphenylene core.

Figure 16.3 Glycodendrimer‐mediated protein aggregation in solution. (a) Structures of the Man‐coated PAMAM dendrimers with G values referring to various dendrimer generations. (b) Transformation of uncomplexed Con A to the cross‐linked state in the presence of a glycodendrimer.

Figure 16.4 (a) Glycodendrimer‐coated gold nanoparticles used for protein detection based on the SET process. (b) A representative heteroglycocluster on a βCD core used to investigate comparative binding on lectin–carbohydrate interactions.

Figure 16.5 A schematic representation of (a) SPR competitive and (b) direct binding assays of Con A–Man recognition. (c) The structure of clicked [G3]‐Man glycodendrimer used for studying the glycoside cluster effect.

Figure 16.6 Scanometric strategy for the in situ detection of Man groups on living cells.

Figure 16.7 Structure of the βCD‐scaffolded heteroglycocluster used to study the heterocluster effect.

Figure 16.8 Gb

3

coated on (a) a carbohydrate core and (b) a gold nanoparticle used to study the binding interactions with Shiga‐like toxin.

Figure 16.9 Selected mannosylated glycocluster based on (a) a carbohydrate and (b) an

L

‐lysine core used as a potential antagonist against

Escherichia coli

FimH.

Figure 16.10 High‐affinity glycocluster ligands for PA‐IL. (a) Gold glycoclusters. (b) Calix[6]arene‐based hexavalent glycoclusters. (c) Fullerene‐based dodecavalent galactosylated glycoclusters synthesized using azide–alkyne click chemistry.

Figure 16.11 (a) The heterobifunctional glycodendrimer bearing both Gal and Fuc residues for simultaneous binding to PA‐IL and PA‐IIL, respectively. (b) A tetravalent C‐fucoside neoglycopeptide and (c) FD2 are the best ligand candidates for PA‐IIL as selected from a library of glycopeptidomimetics. His, histidine; Ile, isoleucine; Leu, leucine; Lys, lysine; Pro, proline.

Figure 16.12 Schematic representation of the glyco‐MNP‐based pathogen detection.

Figure 16.13 Well‐defined multifunctional fluorescent Gal‐MNP was used to specifically target HepG2 cells.

Figure 16.14 Template‐assembled cyclopeptide vaccine candidates containing (a) the Tn antigen and (b) the D1 arm of the Man

9

GlcNAc

2

antigen. Ala, alanine; Asp, aspartic acid; Phe, phenylalanine; Thr, threonine; Trp, tryptophan; Tyr, tyrosine; Val, valine.

Figure 16.15 RAFT‐antigen constructs by Danishefsky et al. (a) HIV vaccine construct with three Man

9

GlcNAc

2

structures for gp120 recognition. (b) RAFT scaffold‐based STn antigen construct.

Chapter 17

Figure 17.1 Representation of influenza A virus.

Figure 17.2 Life cycle of influenza virus and sites targeted by drugs for viral inhibition.

Figure 17.3 Anti‐influenza compounds that act as (a) M2 ion channel inhibitors and (b) RNA polymerase inhibitors.

Figure 17.4 Representation of the three major sialic acid subfamilies.

Figure 17.5 X‐ray structures of influenza A virus HA with sialyllactose bound (PDB 1hgg) [51]. (a) Trimer of HA showing Neu5Ac (as spheres) bound in the binding site. (b) Monomer of HA showing the receptor‐binding site in complex with Neu5Ac (as spheres) on the top.

Figure 17.6 X‐ray structures of influenza virus sialidases. (a) Structure of influenza B virus sialidase tetramer (PDB 1a4g) viewed from the top [62]. (b) Structure of influenza A virus sialidase N9 monomer (PDB 1mwe) with α‐Neu5Ac (shown as spheres) bound in the active site [63].

Figure 17.7 Some important direct interactions between conserved amino acid residues of the active site of influenza A virus sialidase and α‐Neu5Ac. Ala, alanine; Arg, arginine; Asn, asparagine; Asp, aspartic acid; Glu, glutamic acid; His, histidine; Ile, isoleucine; Typ, tryptophan; Tyr, tyrosine.

Scheme 17.1 Proposed enzymatic mechanism for the cleavage of an α‐sialoside by the influenza virus sialidase.

Figure 17.8 Developed sialidase inhibitors following structural modifications of compound

11

.

Figure 17.9 Key interactions of zanamivir (

13

) with the active site of influenza A virus sialidase (Figure generated from crystal structure data (PDB 1nmc) using LIGPLOT [92, 93]). To the right is

13

shown in the same orientation.

Figure 17.10 Analogues of zanamivir with improved bioavailability: (a) phosphonate analogues, (b) C7‐functionalized derivatives, and (c) hydrophobic side‐chain analogues.

Figure 17.11 Oseltamivir and its analogues.

Figure 17.12 Interaction of oseltamivir carboxylate (

20

) with the influenza virus sialidase active site.

Figure 17.13 Sialidase inhibitors with five‐membered rings.

Figure 17.14 Sialidase inhibitors with core aromatic rings.

Figure 17.15 Comparison of the active site and 150‐loop regions of

apo

group 1 and group 2 sialidases. (a) Superposition of the sialidases of group 1 (N1, N4, N8) showing an “open” conformation of the 150‐loop. (b) Superposition of the sialidases N1 and N9 showing “open” (N1) and “closed” (N9) conformations of the 150‐loop. Val, valine.

Figure 17.16 Comparison of group 1 and group 2 sialidase active sites. (a) Oseltamivir carboxylate binds into the open catalytic site of group 1 sialidase N1. (b) Binding between oseltamivir carboxylate and group 2 sialidase N9 with the closed 150‐loop.

Figure 17.17 Sialidase inhibitors designed to target the 150‐cavity.

Figure 17.18 Compound

11

positioned in N1 active site. 150‐loop open (electrostatic surface), closed (magenta surface), dotted lines indicate approximate area of the 150‐cavity.

Figure 17.19 Influenza A virus sialidase N8 complex with 3‐(

p

‐tolylallyl) derivative

31

. (a) Superimposition of N8–inhibitor complexes of

31

(PDB 3O9k) and

11

(PDB 2htr). (b) N8–

31

complex with an open 150‐loop. (c) N8–

11

complex with a closed 150‐loop.

Chapter 18

Figure 18.1 Representative diagram of the members of siglec family and the main sialic acid preference of the human counterpart, with the exception of Siglec‐E. Fuc,

L

‐fucose; Gal,

D

‐galactose; GalNAc,

N

‐acetyl‐

D

‐galactosamine; GlcNAc,

N

‐acetyl‐

D

‐glucosamine; Neu5Ac,

N

‐acetylneuraminic acid; Neu5Gc,

N

‐glycolylneuraminic acid.

Figure 18.2 Interactions of the α(2→3)‐linked sialyllactose in the binding site of sialoadhesin [37]. Leu, leucine; Ser, serine.

Figure 18.3 High‐binding ligands for Siglec‐9 (

1

) and Siglec‐10 (

2

). Ac, acetyl.

Figure 18.4 Modified sialosides used in determining high‐affinity ligands for sialoadhesin. (a) Sialosides modified at 2‐ and 5‐positions. (b) Methyl sialosides modified at C9. (c) A high‐affinity ligand for sialoadhesin.

Figure 18.5 Some C9‐modified sialosides and their comparative potencies.

Figure 18.6 Structure of the heterobifunctional ligand that drive the assembly of IgM–CD22 complexes.

Figure 18.7 C9‐ and C2‐modified sialosides as CD22 antagonists and their comparative potencies.

Figure 18.8 CD22 antagonists modified at various positions of sialic acid.

Chapter 19

Scheme 19.1 Glycoprotein retrosynthetic analysis. Three strategies utilize four major disconnection pathways: (a) amino acid/peptide glycosylation, (b) linear assembly of glycoamino acids/glycopeptides, (c) convergent protein glycosylation, and (d) glycoprotein remodeling.

Figure 19.1 Examples of unnatural linkages used to prepare glycoproteins.

Scheme 19.2 Examples of Cys alkylation to prepare glycoconjugates.

Scheme 19.3 Formation of thioethers by nonnucleophilic methods.

Scheme 19.4 Different strategies to form amine linkages.

Scheme 19.5 Conjugation of carbohydrates by amidine formation with Lys side chains.

Scheme 19.6 Modification of the Lys side chain to form urea or thiourea linkages.

Figure 19.2 Examples of unnatural amino acid residues that can be biologically introduced and used to prepare triazole‐linked proteins.

Scheme 19.7 Amber codon suppression strategy for unnatural azido amino acid incorporation in proteins.

Scheme 19.8 Site‐specific modification of aldehydes. Ac, acetyl.

Scheme 19.9 Endo‐A‐catalyzed glycosylation of glycoproteins bearing unnatural linkages.

Figure 19.3 Traditionally proposed mechanism for immune response of (a) polysaccharide‐based vaccines and (b) polysaccharide–protein conjugate‐based vaccines.

Figure 19.4 Inhibition strategy in which the synthetic glycodendrinanoparticle competes with Ebola virus for binding to DC‐SIGN‐displaying cells.

Scheme 19.10 The LEAPT strategy. (a) Synthetic scheme used to prepare LEAPT glycoconjugates for enzyme‐mediated drug release. (b) Schematic representation of LEAPT.

Scheme 19.11 Double‐differential modification of a protein by triazole and disulfide conjugations allowed the creation of a synthetic glycoprotein reporter.

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GLYCOCHEMICAL SYNTHESIS

Strategies and Applications

Edited by

SHANG-CHENG HUNGMEDEL MANUEL L. ZULUETA

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750‐8400, fax (978) 750‐4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748‐6011, fax (201) 748‐6008, or online at http://www.wiley.com/go/permissions.

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Library of Congress Cataloguing‐in‐Publication Data:

Names: Hung, Shang‐Cheng, editor. | Zulueta, Medel Manuel L., editor.Title: Glycochemical synthesis : strategies and applications / edited by Shang‐Cheng Hung, Medel Manuel L. Zulueta.Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2016] | Includes bibliographical references and index.Identifiers: LCCN 2016023028 | ISBN 9781118299845 (cloth)Subjects: | MESH: Glycoconjugates–chemical synthesis | Glycosylation | Glycomics | Drug DiscoveryClassification: LCC QP702.G577 | NLM QU 75 | DDC 572/.567–dc23LC record available at https://lccn.loc.gov/2016023028

CONTRIBUTORS

Hajjaj H. M. Abdu‐Allah, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt

Avijit Kumar Adak, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan

Thomas Jan Boltje, Cluster for Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands

Geert‐Jan Boons, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA

Kasemsiri Chandarajoti, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Thailand

Shih‐Huang Chang, Genomics Research Center, Academia Sinica, Taipei, Taiwan

David Crich, Department of Chemistry, Wayne State University, Detroit, MI, USA

Benjamin G. Davis, Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK

Yukari Fujimoto, Graduate School of Science and Technology, Keio University, Kanagawa, Japan

Koichi Fukase, Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Jacquelyn Gervay‐Hague, Department of Chemistry, University of California, Davis, Davis, CA, USA

Zhongwu Guo, Department of Chemistry, Wayne State University, Detroit, MI, USA

Yu‐Peng Hu, Genomics Research Center, Academia Sinica, Taipei, Taiwan

Xuefei Huang, Department of Chemistry, Michigan State University, East Lansing, MI, USA

Shang‐Cheng Hung, Genomics Research Center, Academia Sinica, Taipei, Taiwan

Mattan Hurevich, Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

Hideharu Ishida, Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Japan

Akihiro Ishiwata, Synthetic Cellular Chemistry Laboratory, RIKEN, Saitama, Japan

Yukishige Ito, Synthetic Cellular Chemistry Laboratory, RIKEN, Saitama, Japan

Charles Johnson, Department of Chemistry, Wayne State University, Detroit, MI, USA

Yasuhiro Kajihara, Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Jeyakumar Kandasamy, Department of Chemistry, Indian Institute of Technology (BHU)–Varanasi, Varanasi, India

Makoto Kiso, Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Japan

Suvarn S. Kulkarni, Department of Chemistry, Indian Institute of Technology–Bombay, Mumbai, India

Chun‐Cheng Lin, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan

Shu‐Yi Lin, Genomics Research Center, Academia Sinica, Taipei, Taiwan

Jian Liu, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Lin Liu, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA

Weigang Lu, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China and Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA

Yoshiyuki Manabe, Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Masumi Murakami, Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Chandrasekhar Navuluri, Department of Chemistry, Wayne State University, Detroit, MI, USA

Mauro Pascolutti, Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

Macarena Sánchez‐Navarro, Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain and Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK

Matthew Schombs, Department of Chemistry, University of California, Davis, Davis, CA, USA

Peter H. Seeberger, Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

Atsushi Shimoyama, Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Katsunori Tanaka, Biofunctional Synthetic Chemistry Laboratory, RIKEN, Saitama, Japan

Carlo Unverzagt, Bioorganische Chemie, Universität Bayreuth, Bayreuth, Germany

Mark von Itzstein, Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

Cheng‐Chung Wang, Institute of Chemistry, Academia Sinica, Academia Road, Nangang, Taipei, Taiwan

Chung‐Yi Wu, Genomics Research Center, Academia Sinica, Taipei, Taiwan

Bo Yang, Department of Chemistry, Michigan State University, East Lansing, MI, USA

Xin‐Shan Ye, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China

Keisuke Yoshida, Department of Chemistry, Michigan State University, East Lansing, MI, USA

Ching‐Ching Yu, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan

Medel Manuel L. Zulueta, Genomics Research Center, Academia Sinica, Taipei, Taiwan

FOREWORD

The importance of carbohydrates in biological systems and, particularly, in cell–cell interaction has been witnessed by a great explosion of new knowledge that received attention and recognition. Carbohydrates found in nature are generally constituents of glycosides, oligosaccharides, and polysaccharides or of quite complex glycoconjugates. The sugar units are attached to one another or to aglycones commonly through O‐ or N‐glycosidic linkages. As most of these compounds are not readily accessible by isolation from natural sources, tremendous efforts have been undertaken to develop efficient procedures for their chemical synthesis, whereby the main focus was and still is on the generation of glycosidic linkages. Hence, a compilation of recent developments and future directions of this field is of great significance.

Chemical glycosylation usually involves the coupling of a fully protected glycosyl donor with a leaving group at the anomeric center and a suitably protected glycosyl acceptor generally containing only one free hydroxy group. Hence, protecting group strategies are essential in the design and success of glycosidic bond formation. Additionally, the selection of the leaving group and its activation in the glycosylation step through promoters are equally essential aspects. As different leaving group types have been profiled, a general discussion of their power and eventual weaknesses is needed. Together with solvent effects, these factors are generally decisive for efficient intermolecular glycosylation reactions.