Modern Synthetic Methods in Carbohydrate Chemistry

Daniel B. Werz is Professor at the Technical University of Braunschweig, Germany. Having obtained his diploma (2000) as well as his Ph.D. (2003) from University of Heidelberg he spent over two years of postdoctoral research with Peter H. Seeberger at ETH Zurich, Switzerland, before starting his independent career at the University of Göttingen, Germany. In spring 2013 he took up his present position as an associate professor in Braunschweig. Prof. Werz has authored and co-authored over 100 scientific publications and has received several scientific fellowships and awards, including the Ruprecht Karls Award of the University of Heidelberg (2004), a Feodor Lynen Fellowship of the Alexander von Humboldt Foundation (2004), the Klaus Grohe Award of the German Chemical Society (2006), the Emmy Noether Fellowship of the German Research Foundation (2007), the GlycoThera Award (2010) and the highly prestigious Dozentenstipendium of the Chemical Industry Fund (2011). Sébastien Vidal is Chargé de Recherche at Centre National de la Recherche Scientifique (CNRS) and is responsible of a small research team at ICBMS (Université Claude Bernard Lyon 1, France). In 2000, he has obtained his PhD in organic chemistry from Université Montpellier II (France) working on mannose 6-phosphate analogues. He then continued as a postdoctoral fellow in the group of J. Fraser Stoddart at University of California, Los Angeles for three years to design synthetic methodologies for the preparation of glycodendrimers. After another postdoctoral position at the National Renewable Energy Laboratory (NREL, Golden, Colorado, USA) under the guidance of Joseph J. Bozell, he then moved back to France and was appointed as a CNRS fellow in 2004. Dr. Vidal has co-authored over 60 scientific publications devoted to organic and carbohydrate chemistry.

• Foreword xvPreface xviiList of Contributors xix1 De Novo Approaches to Monosaccharides and Complex Glycans 1Michael F. Cuccarese, Jiazhen J. Li, and George A. O’Doherty1.1 Introduction 11.2 De Novo Synthesis of Monosaccharides 41.3 Iterative Pd-Catalyzed Glycosylation and Bidirectional Postglycosylation 51.3.1 Bidirectional Iterative Pd-Catalyzed Glycosylation and Postglycosylation 61.3.2 Synthesis of Monosaccharide Aminosugar Library 71.4 Synthesis of Monosaccharide Azasugar 91.5 Oligosaccharide Synthesis for Medicinal Chemistry 101.5.1 Tri- and Tetrasaccharide Library Syntheses of Natural Product 121.5.2 Anthrax Tetrasaccharide Synthesis 171.6 Conclusion and Outlook 211.7 Experimental Section 22List of Abbreviations 24Acknowledgments 25References 252 Synthetic Methodologies toward Aldoheptoses and Their Applications to the Synthesis of Biochemical Probes and LPS Fragments 29Abdellatif Tikad and Stéphane P. Vincent2.1 Introduction 292.2 Methods to Construct the Heptose Skeleton 292.2.1 Olefination of Dialdoses Followed by Dihydroxylation 312.2.1.1 Olefination at C-5 Position of Pentodialdoses 312.2.1.2 Olefination at C-1 Position of Hexoses 332.2.1.3 Olefination at C-6 Position of Hexodialdoses 332.2.2 Homologation by Nucleophilic Additions 352.2.2.1 Elongation at C-6 of Hexoses 352.2.2.2 Elongation at C-1 Position of Aldose 412.2.3 Heptose de novo synthesis 442.3 Synthesis of Heptosylated Oligosaccharides 462.3.1 Synthesis of the Core Tetrasaccharide of Neisseria meningitides Lipopolysaccharide 462.3.2 Synthesis of a Branched Heptose- and Kdo-Containing Common Tetrasaccharide Core Structure of Haemophilus influenza Lipopolysaccharides 472.3.3 Synthesis of the Core Tetrasaccharide of Neisseria gonorrhoeae Lipopolysaccharide 482.3.4 The Crich’s Stereoselective β-Glycosylation Applied to the Synthesis of the Repeating Unit of the Lipopolysaccharide from Plesimonas shigelloides 492.3.5 De Novo Approach Applied to the Synthesis of a Bisheptosylated Tetrasaccharide 512.4 Synthesis of Heptosides as Biochemical Probes 522.4.1 Bacterial Heptose Biosynthetic Pathways 532.4.2 Artificial D-Heptosides as Inhibitors of HldE and GmhA 542.4.3 Inhibition Studies of Heptosyltransferase WaaC 562.5 Conclusions 572.6 Experimental Part 582.6.1 Typical Synthesis of a D-glycero-Heptoside by Dihydroxylation of a C6–C7 Alkene 582.6.1.1 Phenyl 1-deoxy-2,3,4-tri-O-benzyl-1-thio-D-glycero-α-D-mannoheptopyranoside (167) 582.6.2 Typical Synthesis of a L-glycero-Heptoside by Addition of Grignard Reagent Followed by a Tamao–Fleming Oxidation 582.6.2.1 Methyl 2,3,4-tri-O-benzyl-7-(phenyldimethyl)silane-7-deoxy-L-glyceroα-D-manno-heptopyranoside (170) 592.6.2.2 Methyl 2,3,4-tri-O-benzyl-L-glycero-α-D-manno-heptopyranoside (171) 60List of Abbreviations 60Acknowledgments 61References 613 Protecting-Group-Free Glycoconjugate Synthesis: Hydrazide and Oxyamine Derivatives in N-Glycoside Formation 67Yoshiyuki A. Kwase, Melissa Cochran, and Mark Nitz3.1 Introduction 673.2 Glycosyl Hydrazides (1-(Glycosyl)-2-acylhydrazines) 683.2.1 Formation, Tautomeric Preference, and Stability of Glycosyl Hydrazides 683.2.2 Analytical Applications 703.2.3 Hydrazides in Synthesis 733.2.4 Biologically Active Glycoconjugates 753.2.5 Lectin-Labeling Strategies Using Glycosyl Hydrazides 773.2.6 Summary of Glycosyl Hydrazides 793.3 O-Alkyl-N-Glycosyl Oxyamines 793.3.1 Formation, Configuration, and Stability of O-Alkyl-N-Glycosyloxyamines 793.3.2 Uses of O-Alkyl-N-Glycosyl Oxyamines 803.4 N,O-Alkyl-N-Glycosyl Oxyamines 803.4.1 Uses of N-Alkyl-N-Glycosyloxyamines 833.4.2 Glycobiology 833.4.3 Medicinal Chemistry 863.4.4 Carbohydrate Synthesis Using N-Alkyloxyamines 873.4.5 Summary of N-Alkyl-N-Glycosyl Oxyamines 893.5 Concluding Remarks and Unanswered Questions 903.6 Procedures 913.6.1 Formation of the p-Toluenehydrazide Glycosides 913.6.2 Formation of Azido-Glycosides 913.6.3 Formation of Glycosyl Phosphate 923.6.4 Formation of N,O-Dialkyloxylamine Glycoside 92List of Abbreviations 93Acknowledgment 93References 944 Recent Developments in the Construction of cis-Glycosidic Linkages 97AlphertE.Christina,GijsbertA.vanderMarel,andJeroenD.C.Codée4.1 Introduction 974.2 Cis-Glycosylation 974.3 Conclusion 120Acknowledgments 120List of Abbreviations 120References 1215 Stereocontrol of 1,2-cis-Glycosylation by Remote O-Acyl Protecting Groups 125Bozhena S. Komarova, Nadezhda E. Ustyuzhanina, Yury E. Tsvetkov, and Nikolay E. Nifantiev5.1 Introduction 1255.2 Stereodirecting Influence of Acyl Groups at Axial and Equatorial O-3: Opposite Stereoselectivity Proves Anchimeric Assistance 1255.3 Acyl Groups at O-4 in the galacto Series: Practical Synthesis of α-Glycosides: Complete Stereoselectivity 1355.4 Lack of Stereocontrolling Effect of Acyl Groups at Equatorial O-4 in 4 C 1 Conformation 1435.5 Effect of Substituents at O-6 1455.6 Interplay of Stabilized Bicyclic Carbocation and Two H Conformations of Oxocarbenium Ions 1505.7 Conclusion 1545.8 Key Experimental Procedures 1555.8.1 Example of Stereocontrolled α-Fucosylation: Synthesis of Allyl 3-O-acetyl-4-O-benzoyl-2-O-benzyl-α-L-fucopyranosyl-(1 → 3)-4-O-benzoyl-2-O-benzyl-α-L-fucopyranoside(85)1555.8.2 Example of Stereocontrolled α-Glucosylation: Synthesis of Methyl 2,3,4-tri-O-benzoyl-α-L-rhamnopyranosyl-(1 → 3)-[3,6-di-O-acetyl-2,4-di-O-benzyl-α-D-glucopyranosyl-(1 → 6)]-2-O-benzoyl-4-O-benzyl-β-Dglucopyranosyl)-(1→ 3)-[6-O-benzoyl-2,3,4-tri-O-benzyl-α-Dglucopyranosyl-(1 → 4)]-2-zido-6-O-benzyl-2-deoxy-α-Dgalactopyranoside (119) 155List of Abbreviations 156References 1566 Synthesis of Aminoglycosides 161Yifat Berkov-Zrihen and Micha Fridman6.1 Introduction 1616.2 Amine-Protecting Group Strategies 1636.2.1 Chemoselective Amine Group Manipulations 1636.3 Controlled Degradation of Aminoglycosides 1656.4 Chemoselective Alcohol-Protecting Group Manipulations 1676.5 Strategies for Glycosylation of Aminoglycoside Scaffolds 1716.6 Synthesis of Amphiphilic Aminoglycosides 1736.7 Chemoenzymatic Strategies for the Preparation of Aminoglycoside Analogs 1766.8 Novel Synthetic Strategies to Overcome Resistance to Aminoglycosides 1796.9 Conclusions and Future Perspectives 1816.10 Selected Synthetic Procedures 182Acknowledgments 186List of Abbreviations 186References 1877 Synthesis of Natural and Nonnatural Heparin Fragments: Optimizations and Applications toward Modulation of FGF2-Mediated FGFR Signaling 191Pierre-Alexandre Driguez7.1 Introduction 1917.2 Total Synthesis of Standard HPN Fragments 1937.3 Total Synthesis of Modified HPN Fragments: Some Synthetic Clues 1997.3.1 Modifications on the Aglycon Moiety 1997.3.2 Modifications at Position 2 of Glucosamines 2017.3.3 Modifications of the O-Sulfonatation Pattern 2037.4 Alternative Synthetic Methods: Means to Build Libraries 2087.4.1 Synthesis of Tetrasaccharide Mixtures Followed by Purification 2107.4.2 Modular Synthesis of HPN/HS Oligosaccharides 2107.5 Biological Evaluation 2127.6 Conclusion and Outlook 2147.7 Experimental Section (General Procedures) 2147.7.1 General Conditions for Coupling Reactions 2147.7.2 General Conditions for Delevulinoylations 2157.7.3 General Conditions for Olefin Cross Metathesis Reactions 2157.7.4 General Conditions for Transesterifications 2157.7.5 General Conditions for Desilylations 2157.7.6 General Conditions for O-Sulfonatations 2157.7.7 General Conditions for Saponifications 2167.7.8 General Conditions for the Catalytic Reductions 2167.7.9 General Conditions for N-Sulfations 2167.7.10 General Conditions for N-Acylations 216Acknowledgments 217List of Abbreviations 217References 2188 Light Fluorous-Tag-Assisted Synthesis of Oligosaccharides 221Rajarshi Roychoudhury and Nicola L. B. Pohl8.1 Introduction 2218.2 Fluorous-Protecting Groups and Tags Amenable to Fluorous Solid-Phase Extraction in Carbohydrate Synthesis 2228.2.1 Mono- and Diol Protecting Groups 2228.2.2 Amine Protection 2248.2.3 Phosphate Protection 2248.3 Light Fluorous-Protecting Groups with Potential Use in Oligosaccharide Synthesis 2268.3.1 Alcohol Protection 2268.3.2 Carboxylic Acid Protection 2288.3.3 Amine Protection 2288.4 ‘‘Cap-Tag’’ Strategies or Temporary Fluorous-Protecting Group Additions 2298.5 Double-Tagging Carbohydrates with Fluorous-Protecting Groups 2318.6 Other Advantages to Fluorous-Assisted Oligosaccharide Synthesis 2328.6.1 Automated Oligosaccharide Synthesis Using Fluorous Tags 2328.6.2 Fluorous-Based Carbohydrate Microarrays 2348.7 Conclusions and Outlook 2348.8 Experimental Section 2358.8.1 Synthesis of 6-(Benzyl 2-bromo-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10- heptadecafluorodecyl phosphate)-1,2,3,4-di-O-isopropylidene-α-Dgalactopyranose 2358.8.2 Synthesis of 3-(Perfluorooctyl)propanyloxybutenyl-3,4,6-tri-O-acetyl-2- deoxy-2-(p-nitrobenzyloxycarbonylamino)-β-D-glucopyranoside 2368.8.3 Synthesis of 3-(Perfluorooctyl)propanyloxybutenyl-4-O-benzyl-3,6-di-O- (2-O-acetyl-3,4,6-O-tribenzyl-α-D-mannopyranoside)-2-O-pivaloyl-α-Dmannopyranoside 236Acknowledgments 237List of Abbreviations 237References 2379 Advances in Cyclodextrin Chemistry 241Samuel Guieu and Matthieu Sollogoub9.1 Introduction 2419.1.1 Nomenclature of Modified Cyclodextrins 2439.2 General Reactivity, Per- and Monofunctionalization 2449.2.1 General Reactivity of Cyclodextrins 2449.2.2 Perfunctionalization of Each Position 2459.2.3 Monofunctionalization 2479.2.3.1 Use of Reagent in Default 2479.2.3.2 Use of Supramolecular Inclusion Complex 2489.2.4 Random Multifunctionalization and Multidifferentiation 2499.3 Capping Reagents for Direct Modification 2509.3.1 Difunctionalization: Capping the Cyclodextrin 2509.3.1.1 Single Cap 2509.3.1.2 Double Capping 2539.3.2 Unsymmetrical Caps 2549.3.3 Modification of Capped Cyclodextrins 2569.3.3.1 Addition of Another Functionality 2569.3.3.2 Opening the Caps 2569.4 Bulky Reagents for Direct Modifications 2599.4.1 Trityl and Derivatives 2609.4.2 Triphenylphosphine 2619.4.3 Selective Transfer 2629.5 Selective Deprotections 2639.5.1 Diisobutylaluminum Hydride (DIBAL-H) as Deprotecting Agent 2639.5.1.1 General Mechanism 2639.5.1.2 Application to Cyclodextrins 2659.5.2 Second Deprotection 2699.5.2.1 Monoazide Cyclodextrins 2699.5.2.2 Deoxy and Bridged Cyclodextrins 2699.5.3 Third Deprotection 2769.6 Conclusion and Perspectives 2789.7 Experimental Procedures 2799.7.1 Tetrafunctionalization of the Primary Rim of α-Cyclodextrin Using Supertrityl 2799.7.2 Double Deprotection of Perbenzylated α-orβ-Cyclodextrins Using Dibal-h 279List of Abbreviations 280References 28010 Design and Synthesis of GM1 Glycomimetics as Cholera Toxin Ligands 285José J. Reina and Anna Bernardi10.1 Introduction 28510.2 Cholera Toxin and Its Specific Membrane Receptor, the GM 1Ganglioside 28710.2.1 Interaction of Cholera Toxin and GM1-os 28810.3 Rational Design of GM1-os Mimics as Cholera Toxin Inhibitors and Synthesis of First-Generation Ligands 28910.3.1 Second-Generation Mimics of GM1 Ganglioside: Replacement of the Sialic Acid Moiety 29310.4 Third Generation of GM1 Ganglioside Mimics: Toward Nonhydrolyzable Cholera Toxin Antagonists 29810.5 Conclusions 30410.6 Experimental Section 30510.6.1 Multigram-Scale Synthesis of (1S, 2S)-Cyclohex-4-ene-1,2-dicarboxylic acid 7 30510.6.1.1 Synthesis of (1S, 2R)-Cyclohex-4-ene-1,2-carboxylic acid monomethylester 9 30510.6.1.2 cis–trans Equilibration of the Monomethylester: Synthesis of 10 30510.6.1.3 Synthesis of (1S,2S)-Cyclohex-4-ene-1,2-dicarboxylic acid 7 30610.6.2 Synthesis of α-andβ-2,3,4,6-tetra-O-Acetyl-1-C-(2-oxo-ethyl)-Dgalactopyranose 49 and 50 30710.6.2.1 Synthesis of 2,3,4,6-tetra-O-Acetyl-1-C-allyl-α-D-galactopyranose 48 30710.6.2.2 Synthesis of 2,3,4,6-tetra-O-Acetyl-1-C-(2-oxo-ethyl)-α-D-galactopyranose 49 30710.6.2.3 Synthesis of 2,3,4,6-tetra-O-Acetyl-1-C-(2-oxo-ethyl)-β-D-galactopyranose 50 307Acknowledgments 308List of Abbreviations 308References 30911 Novel Approaches to Complex Glycosphingolipids 313Hiromune Ando, Rita Pal, Hideharu Ishida, and Makoto Kiso11.1 Introduction 31311.2 Syntheses of Complex Glycans of Gangliosides 31411.2.1 Glycan Moiety of Ganglioside Hp-s6 (Hp-s6 Glycan) 31511.2.2 Glycan Moiety of Ganglioside HPG-7 (HPG-7 Glycan) 31511.2.3 Glycan Moiety of Ganglioside AG-2 (AG-2 Glycan) 31611.2.4 Glycan Moiety of Ganglioside GP1c (GP1c Glycan) 31911.3 Total Syntheses of Complex Gangliosides 31911.3.1 Synthesis of Ceramide Moiety 31911.3.2 Glucosyl Ceramide Cassette Approach 31911.3.3 Total Synthesis of Ganglioside GQ1b 32311.3.4 Total Synthesis of Ganglioside GalNAc-GD1a 32311.3.5 Total Synthesis of Ganglioside LLG- 3 32611.3.5.1 Chemical Synthesis 32611.3.5.2 Chemo-Enzymatic Synthesis 32911.4 Conclusion and Outlook 32911.5 Experimental Section 32911.5.1 Synthesis of N-Troc Sialyl Donor 2 32911.5.2 Synthesis of N-Troc Sialyl Galactoside 45 330List of Abbreviations 331References 33212 Chemical Synthesis of GPI Anchors and GPI-Anchored Molecules 335Ivan Vilotijevic, Sebastian Götze, Peter H. Seeberger, and Daniel Varón Silva12.1 Introduction 33512.2 Challenges in the Synthesis of GPIs 33712.3 Tools for Synthesis of GPIs 33912.3.1 Synthesis of Building Blocks 34012.3.2 Glycosylation Strategy 34112.3.3 Phosphorylation Strategies 34212.3.4 Strategic Synthesis Planning 34312.4 Synthesis of GPIs with Linear Glycan Core 34612.4.1 Synthesis of the GPI from Plasmodium falciparum Using n-Pentenyl Orthoesters 34612.4.2 Synthesis of the GPI from Saccharomyces cerevisiae Using Trichloroacetimidates 34912.4.3 Synthesis of Unsaturated GPIs from Trypanosoma cruzi 35112.5 Synthesis of GPIs with Branched Glycan Core 35312.5.1 Synthesis of the Trypanosoma brucei VSG GPI Using Glycosyl Halides 35312.5.2 Synthesis of T. brucei VSG GPI from Chalcogenide Glycosides of Finely Tuned Reactivity 35612.5.3 A General Synthetic Strategy for the Synthesis of Branched GPIs 35712.6 GPI Derivatives for Biological Research 36112.7 Synthesis of GPI-Anchored Peptides and Proteins 36312.7.1 Synthesis of the GPI-Anchored Skeleton Structure of Sperm CD52 via Direct Amide Coupling 36412.7.2 Semisynthesis of GPI-Anchored Cellular Prion Protein via Native Chemical Ligation 36412.8 Conclusions and Outlook 366Acknowledgments 368List of Abbreviations 368References 370Index 373