Click Chemistry in Glycoscience E-Book

Zbigniew J. Witczak

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

Seitenzahl: 497

Veröffentlichungsjahr: 2013

Beschreibung

Lays the foundation for new methods and applications of carbohydrate click chemistry Introduced by K. Barry Sharpless of The Scripps Research Institute in 2001, click chemistry mimics nature, giving researchers the tools needed to generate new substances quickly and reliably by joining small units together. With contributions from more than thirty pioneering researchers in the field, this text explores the many promising applications of click chemistry in glycoscience. Readers will learn both the basic concepts of carbohydrate click chemistry as well as its many biomedical applications, including synthetic antigens, analogs of cell-surface receptors, immobilized enzymes, targeted drug delivery systems, and multivalent cancer vaccines. Click Chemistry in Glycoscience examines a broad range of methodologies and strategies that have emerged from this rapidly evolving field. Each chapter describes new approaches, ideas, consequences, and applications resulting from the introduction of click processes. Divided into four sections, the book covers: * Click chemistry strategies and decoupling * Thio-click chemistry of carbohydrates * Carbohydrate click chemistry for novel synthetic targets * Carbohydrate click chemistry in biomedical sciences Thoroughly researched, the book reflects the most recent findings published in the literature. Diagrams and figures throughout the book enable readers to more easily grasp complex concepts and reaction processes. At the end of each chapter, references lead to the primary literature for further investigation of individual topics. The application of click chemistry to carbohydrates has tremendous implications for research. With this book as their guide, researchers have a solid foundation from which they can develop new methods and applications of carbohydrate click chemistry, including new carbohydrate-based therapeutics.

Leseprobe

Contents

Cover Page

Title Page

Copyright

Foreword

Preface

Contributors

List of Abbreviations

PART I: CLICK CHEMISTRY STRATEGIES AND DECOUPLING

Chapter 1: Paradigm and Advantage of Carbohydrate Click Chemistry Strategy for Future Decoupling

1.1 INTRODUCTION

1.2 COUPLING USING HUISGEN DIPOLAR CYCLOADDITION

1.3 COUPLING USING THIOL-ENE COUPLING CLICK CHEMISTRY

1.4 PROCESSES WHERE BOTH CuAAC AND TEC CLICK CHEMISTRIES ARE USED

1.5 DECOUPLING

1.6 CONCLUSION

REFERENCES

PART II: THIO-CLICK CHEMISTRY OF CARBOHYDRATES

Chapter 2: Thio-Click Chemistry in Glycoscience: Overview and Perspectives

2.1 INTRODUCTION

2.2 THIO-BASED CLICK REACTIONS

2.3 S-THIODISACCHARIDE SYNTHESIS

2.4 SYNTHESIS OF GLYCOSYL THIOLS

2.5 SYNTHESIS OF S-LINKED GLYCOSPHINGOLIPIDS

2.6 CONCLUSION AND PERSPECTIVES

REFERENCES

Chapter 3: Free-Radical Thiol-Ene and Thiol-Yne Couplings as Click Processes for Glycoconjugation

3.1 INTRODUCTION

3.2 S-LINKED OLIGOSACCHARIDES

3.3 CALIX[4]ARENE-BASED GLYCOCLUSTERS

3.4 SILSESQUIOXANE-BASED GLYCOCLUSTERS

3.5 GLYCODENDRIMERS

3.6 AMINO ACID, PEPTIDE, AND PROTEIN GLYCOCONJUGATES

3.7 CONCLUSION

REFERENCES

PART III: CARBOHYDRATE CLICK CHEMISTRY FOR NOVEL SYNTHETIC TARGETS

Chapter 4: The Development and Application of Clickable Lipid Analogs for Elucidating and Harnessing Lipid Functions

4.1 INTRODUCTION TO THE ADVANTAGES OF APPLYING CLICK CHEMISTRY FOR STUDYING LIPIDS

4.2 APPLICATION OF CLICK CHEMISTRY FOR THE FUNCTIONALIZATION OF MEMBRANE SURFACES

4.3 CLICK CHEMISTRY AND THE GENERATION OF FUNCTIONALIZED LIPID ANALOGS

4.4 DIRECT IN SITU LABELING AND IMAGING OF SYNTHETICALLY TAGGED LIPID ANALOGS

4.5 ACTIVITY-BASED CHARACTERIZATION OF LIPID-BINDING AND LIPID-MODIFYING PROTEINS

4.6 PROBING COVALENT PROTEIN LIPIDATION

4.7 CONCLUSION

REFERENCES

Chapter 5: Clicking Sugars onto Sugars: Oligosaccharide Analogs and Glycoclusters on Carbohydrate Scaffolds

5.1 INTRODUCTION

5.2 TRIAZOLE-LINKED OLIGOSACCHARIDE ANALOGS

5.3 CLICKED CYCLODEXTRINS

5.4 TRIAZOLE-LINKED MACROCYCLES

5.5 MULTIVALENT GLYCOCLUSTERS ON CARBOHYDRATE SCAFFOLDS

5.6 CONCLUSION

REFERENCES

Chapter 6: Click Multivalent Glycomaterials: Glycoclusters, Glycodendrimers, Glycopolymers, Hybrid Glycomaterials, and Glycosurfaces

6.1 INTRODUCTION

6.2 CLICK GLYCOCLUSTERS

6.3 CLICK GLYCODENDRIMERS

6.4 CLICK GLYCOPOLYMERS

6.5 CLICK HYBRID GLYCOMATERIALS

6.6 CLICK GLYCOSURFACES AND GLYCOARRAYS

6.7 CLICK MULTIVALENT GLYCOMIMETICS

REFERENCES

Chapter 7: Toward Imaging Glycotools by Click Coupling

7.1 INTRODUCTION

7.2 NUCLEAR IMAGING AND RADIOTRACERS

7.3 TRIAZOLE-CONTAINING RADIOTRACERS

7.4 OTHER METHODS

7.5 CONCLUSION AND OUTLOOK

REFERENCES

Chapter 8: Bioorthogonal Reactions for Labeling Glycoconjugates

8.1 INTRODUCTION

8.2 KETONE-BASED BIOORTHOGONAL LABELING OF GLYCOCONJUGATES

8.3 AZIDO- AND ALKYNE-BASED STRATEGIES FOR BIOORTHOGONAL LABELING OF GLYCOCONJUGATES

8.4 STAUDINGER LIGATION

8.5 CuI-CATALYZED AZIDE–ALKYNE CYCLOADDITIONS (CuAAC)

8.6 STRAIN PROMOTED AZIDE–ALKYNE CYCLOADDITIONS (SPAAC)

8.7 STRAIN-PROMOTED CYCLOADDITIONS WITH NITRONES, NITRILE OXIDES, AND DIAZOCARBONYL DERIVATIVES

8.8 METABOLIC LABELING WITH PHOTOACTIVATABLE CROSSLINKING SUGARS

8.9 METABOLIC LABELING WITH THIOL-CONTAINING SUGARS

8.10 CONCLUDING REMARKS

REFERENCES

Chapter 9: “Sweet” Sucrose Macrocycles via a “Click Chemistry” Route

9.1 INTRODUCTION

9.2 CONCLUSION

ACKNOWLEDGMENT

REFERENCES

PART IV: CARBOHYDRATE CLICK CHEMISTRY IN BIOMEDICAL SCIENCES

Chapter 10: Neoglycoprotein Synthesis Using the Copper-Catalyzed Azide–Alkyne Click Reaction and Native Chemical Ligation

10.1 INTRODUCTION

10.2 STRATEGIES FOR THE SYNTHESIS OF NEOGLYCOPEPTIDES AS GLYCOPEPTIDE MIMETICS

10.3 SYNTHESIS OF NEOGLYCOPEPTIDE MIMICS OF FISH ANTIFREEZE GLYCOPEPTIDES

10.4 SYNTHESIS OF NEOGLYCOPEPTIDE MIMICS OF THE MUCINS

10.5 APPLICATION OF NCL TO THE SYNTHESIS OF NEOGLYCOPEPTIDES

10.6 LARGE COMPLEX NEOGLYCOPROTEINS

10.7 CONCLUSION

REFERENCES

Chapter 11: Biomedical Applications of “Click”-Modified Cyclodextrins

11.1 INTRODUCTION

11.2 CHEMICAL MODIFICATION OF CYCLODEXTRINS

11.3 BIOMEDICAL APPLICATIONS

11.4 SUMMARY

ACKNOWLEDGMENT

REFERENCES

Chapter 12: Triazolyl Glycoconjugates in Medicinal Chemistry

12.1 INTRODUCTION

12.2 Cu(I)-CATALYZED ALKYNE–AZIDE CYCLOADDITION (CuAAC) REACTION

12.3 MECHANISM OF Cu-CATALYZED CLICK REACTION

12.4 TRIAZOLE RING AS BIOISOSTERES OF AMIDE

12.5 TRIAZOLYL GLYCOCONJUGATES IN MEDICINAL CHEMISTRY

12.6 CONCLUSION AND FUTURE PERSPECTIVE

ACKNOWLEDGMENT

REFERENCES

Chapter 13: Click Chemistry Applied to Carbohydrate-Based Drug Discovery

13.1 INTRODUCTION

13.2 CLICK CHEMISTRY AND CARBOHYDRATE-BASED LIGANDS FOR LECTINS (GALECTINS AND SELECTINS)

13.3 CLICK CHEMISTRY AND GLYCOCONJUGATE ANTITUMOR VACCINES

13.4 CLICK CHEMISTRY AND CARBOHYDRATE-BASED ENZYME INHIBITORS

REFERENCES

Index

Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data

Click chemistry in glycoscience : new developments and strategies / edited by Zbigniew J. Witczak, Roman Bielski. p. ; cm. Includes bibliographical references and index. ISBN 978-1-118-27533-7 (cloth) I. Witczak, Zbigniew J., 1947- II. Bielski, Roman, 1946- [DNLM: 1. Glycoconjugates-chemistry. 2. Click Chemistry-methods. 3. Glycoconjugates-physiology. QU 75] 572′.567-dc23

2012040254

ISBN: 9781118275337

FOREWORD

This book, compiled by Zbigniew Witczak and Roman Bielski, brings together contributions from authors around the world in addressing the impact of a single chemical reaction that permits the covalent connection of two complex precursor molecules under mild conditions. The reaction has found wide application in the fields of carbohydrate chemistry and glycobiology for building complex glycoconjugate target structures of interest in many biomedical areas.

The particular reaction is the (3 + 2) 1,3-dipolar cycloaddition of an alkyne to an azide at room temperature under copper(I) catalysis to generate a 1,2,3-triazole. Since its initial discovery by Huisgen in 1963, there have been numerous publications where it has been employed for a multitude of purposes, including applications in the carbohydrate field that date back to the 1970s.

However, it was not until the beginning of the present millennium that an “explosion” of research on the scope of this reaction began after Sharpless, and independently, Meldal, employed this procedure for the rapid synthesis, through heteroatom links, of many useful new compounds, peptide conjugates, and combinatorial libraries. At that point in time, the awkward formal name of Huisgen's excellent reaction was whimsically dubbed “click” chemistry, presumably because the simplicity of the reaction could be likened to the ends of a bracelet being “clicked” together.

The same concept of covalently connecting two complex molecules under very mild conditions has more recently led to valuable new procedures that also meet the “click” reaction criteria. These include the photoinduced reaction between a thiol and either an alkene or an alkyne, and the coupling between a thiol and a Michael enone acceptor.

The 13 chapters in the Witczak–Bielski book bring together a wide range of applications of these ligation strategies directed toward carbohydrate-based targets, including various types of glycoconjugates, such as neoglycoproteins, glycoclusters, glycodendrimers, and cyclodextrin conjugates. The reaction offers potential in diverse biomedical areas, including synthetic antigens, analogs of cell-surface receptors, immobilized enzymes, targeted drug delivery systems, multivalent cancer vaccines, and many others.

Beyond the original Huisgen reaction, there now have evolved several variants, some involving modifications of the original alkyne and azide reactants, along with such adaptations as novel catalysts for effecting the reaction under the mildest conditions, and performing the ligation reaction in vivo. Many of these extensions are detailed in different chapters in the book, together with the thiol–alkene, thiol–alkyne, and thiol–enone conjugation reactions that also merit the “click” designation.

This book derives from presentations made in a 2011 symposium at a meeting of the American Chemical Society. Not all relevant literatures on the alkyne–azide cycloaddition are documented. With new work being published almost daily, the coverage, even in the carbohydrate field alone, can never be complete. Nevertheless, the compilers of this volume have made a valuable contribution by bringing together the collective efforts of more than 30 researchers working on the applications of “click” chemistry to numerous targets in the carbohydrate and glycoconjugate area. The book provides a valuable resource for both the specialist researcher and the general reader.

Derek HortonProfessor of Chemistry EmeritusOhio State University

PREFACE

Synthesis of compounds designed to fulfill special requirements or exhibit specific properties has belonged and will belong to the most important targets of organic chemistry. This area of synthesis, particularly when applied to synthesis of constructs containing carbohydrates, has experienced a dramatic acceleration in recent years. One factor explaining the observed acceleration has been a better understanding of the function and structure of glycoproteins and other naturally occurring sugar derivatives. Another factor, perhaps even more significant, is the introduction of the concept of click chemistry by Finn, Kolb, and Sharpless, which dramatically facilitated the formation of various constructs. Chemistry of carbohydrates containing molecules has benefited tremendously from the introduction of this concept. The presented book attempts to offer an insight into the new developments created by marrying click and carbohydrate chemistries.

Carbohydrates represent a unique family of polyfunctional compounds that can be chemically or enzymatically manipulated in a multitude of ways. They have been extensively used as starting materials in enantioselective synthesis of many complex natural products with a plurality of chirality centers. Synthetic organic chemistry that utilizes these carbohydrate building blocks continues to spawn revolutionary discoveries in medicinal chemistry, pharmacology, molecular biology, glycobiology, and medicine simply by providing not only the raw material but also the mechanistic insight of modem molecular sciences.

Click chemistry was introduced over 10 years ago. Its founders offered the following description:

A click reaction must be modular, wide in scope, high yielding, create only inoffensive by-products (that can be removed without chromatography), are stereospecific, simple to perform, and that require benign or easily removed solvent.

Since then, Sharpless' concept of click chemistry was quickly transplanted to carbohydrate chemistry and the number of publications in the field has been steadily growing.

This book originates from the symposium “Click Chemistry Approaches in Carbohydrate Chemistry,” which we organized during the 242nd Meeting of the American Chemical Society in Anaheim in Spring 2011. It attracted several prominent speakers, had a relatively large attendance, and was met with a lot of interest. Some of the chapters in this book are based on the presentations delivered at the symposium. Other contributions are also from leading experts in the field of carbohydrate chemistry. Some of the chapters are reviews of the recent literature; some describe recent experiments performed at the authors' laboratories. We believe that all the articles are of very high standard and offer a novel perspective on the discussed subjects.

The medical and biomedical applications of synthetic organic chemistry were probably more affected than any other area of research (perhaps with the exception of polymer chemistry) by the development of click chemistry. Thus, it is not surprising that almost all of the chapters in the book are to some extent concerned with such applications. It confronts the editors with a dilemma that is impossible to address satisfactorily – how to divide the book into consistent segments. By no means are we satisfied with our choice but some kind of division had to be introduced. Thus, the reader should not be surprised finding biomedical applications described in segments carrying a title suggesting that the emphasis was put on an entirely different topic.

Each chapter in the book covers issues related to click chemistry and glycoconjugation, and discusses synthetic methodologies and potential applications of the synthesized constructs. In the last few years, it has been documented that the addition of thiols to unsaturated compounds is a legitimate click process. Thus, we made sure that this type of click reactions is represented in the book together with the most popular click reaction, that is, 1,3-dipolar addition of azides to alkynes.

The topics covered in the book are grouped into four categories:

1. Click chemistry strategies

2. Thio-click chemistry of carbohydrates

3. Click chemistry related to life science and glycobiology

4. Click chemistry related to medicinal chemistry

The introductory chapter written by both editors of the volume discusses the important aspects of carbohydrate click chemistry methodologies and proposes a novel strategy applicable to synthesizing certain glycoconjugates.

Chapter 2 authored by Witczak deals with thio-click strategies employed to the synthesis of thiodisaccharides and other sulfur-bridged oligosaccharide scaffolds. Interestingly, the most efficient methodologies compiled in this review were developed before the official birth of thio-click chemistry.

Chapter 3 authored by Dondoni and Marra describes intriguing results of the experiments employing various thio-click glycoconjugation processes.

The development and application of clickable lipid analogs for elucidating and harnessing lipid function were thoroughly explored by Best in Chapter 4. The chapter discusses most types of natural molecules, including nucleic acids, proteins, various lipids, and many substituted glycerols and, of course, carbohydrates.

In Chapter 5, Uhrig and Kovensky review the important topic of syntheses of oligosaccharide analogs and glycoclusters on carbohydrate scaffolds.

Mellet and coworkers offer in Chapter 6 a different perspective on the closely related subject of click multivalent glycomaterials, including glycosurfaces, glycodendrimers, and glycopolymers.

Chapter 7 by Chapleur and coworkers addresses clickable formation of carbohydrates labeled with radiotracers for molecular imaging.

Chapter 8 by Friscourt and Boons is a very broad review of bio-orthogonal reactions for labeling glycoconjugates. The review discusses the processes belonging to click chemistry as well as other important coupling reactions, such as Staudinger ligation and labeling with photoactivatable sugars.

Potopnyk and Jarosz explore in Chapter 9 quite a new topic of click functionalization of sucrose in the synthesis of interesting sucrose-based macrocycles.

Brimble and coworkers contribute in Chapter 10 with a discussion of novel syntheses of neoglycoproteins via copper-assisted azide–alkyne click reaction and native chemical ligation.

Chapter 11 by Wang and coworkers describes the formation and new fascinating biomedical applications of “click-modified” cyclodextrins.

In Chapter 12, Tripathi, Tiwari, and coworkers explore the important applications of triazolyl glycoconjugates in medicinal chemistry. The review highlights the synthesis of prototypes of drug molecules with high chemotherapeutic potential.

Finally, Chapter 13 by Campo and Carvalho provides a general overview of the potential applications of click reactions in the synthesis of highly valuable, bioactive, carbohydrate-based ligands for lectins, antitumor vaccines, and various enzyme inhibitors.

With the increasing complexity of modern sciences in the twenty-first century, a need to educate industrial leaders, public, and governmental funding agencies about the intellectual and technical potential and economic importance of specific areas of life sciences has become more and more crucial. One such area is the part of glycoscience emerging as a result of a marriage between the concepts of click and carbohydrate chemistries. We hope that this book will fill this need, at least to some extent.

In conclusion, we believe the presented collection of articles offers an insight into the present stage of click-based glycosciences and will help steer future discoveries to fulfill the enormous potential in the area of click carbohydrate chemistry.

Acknowledgment

We wish to thank all the authors for excellent contributions to this volume. We also wish to thank the peer reviewers of the chapters for their expertise and helpful efforts to improve the quality of the manuscripts. We dedicate this book to our wives Wanda and Barbara.

Zbigniew J. Witczak, Ph.D Department of Pharmaceutical Sciences Nesbitt School of Pharmacy Wilkes University, PA, USA

Roman Bielski Value Recovery, Inc., NJ Department of Pharmaceutical Sciences Wilkes University, PA, USA

CONTRIBUTORS

Michael D. Best, Department of Chemistry, University of Tennessee, TN USA

Roman Bielski, Value Recovery, Inc., Bridgeport, NJ, USA; Department of Pharmaceutical Sciences, Wilkes University, PA, USA

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

Margaret A. Brimble, School of Chemical Sciences, University of Auckland, Auckland, New Zealand; School of Biological Sciences, University of Auckland, Auckland, New Zealand

Vanessa Leiria Campo, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, São Paulo, Brazil

Ivone Carvalho, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, São Paulo, Brazil

Yves Chapleur, Laboratoire Structure et Réactivité des Systèmes Moléculaires Complexes, Université de Nancy, Groupe SUCRES, Vandoeuvre les Nancy, France

Françoise Chrétien, Laboratoire Structure et Réactivité des Systèmes Moléculaires Complexes, Université de Nancy, Groupe SUCRES, Vandoeuvre les Nancy, France

Alessandro Dondoni, Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Ferrara, Italy

Pratibha Dwivedi, Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi, India

Clive W. Evans, School of Biological Sciences, University of Auckland, Auckland, New Zealand

José Manuel García Fernández, Instituto de Investigaciones Químicas, CSIC – Universidad de Sevilla, Sevilla, Spain

Frédéric Friscourt, Complex Carbohydrate Research Center, University of Georgia, GA

Sławomir Jarosz, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland

Zhenshan Jia, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE, USA

Stephen B.H. Kent, Department of Chemistry, Institute for Biophysical Dynamics, Center for Integrative Science, University of Chicago, IL, USA

José Kovensky, Laboratoire des Glucides-CNRS FRE 3517, Université de Picardie Jules Verne, Amiens, France

Divya Kushwaha, Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi, India

Sandrine Lamandé-Langle, Laboratoire Structure et Réactivité des Systèmes Moléculaires Complexes, Université de Nancy, Groupe SUCRES, Vandoeuvre les Nancy, France

Dong Jun Lee, School of Chemical Sciences, University of Auckland, Auckland, New Zealand; Department of Chemistry, Institute for Biophysical Dynamics, Center for Integrative Science, University of Chicago, IL, USA

Kalyaneswar Mandal, Department of Chemistry, Institute for Biophysical Dynamics, Center for Integrative Science, University of Chicago, IL, USA

Alberto Marra, Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Ferrara, Italy

Carmen Ortiz Mellet, Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, Spain

Alejandro Méndez-Ardoy, Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, Spain

Mykhaylo A. Potopnyk, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland

Anindra Sharma, Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India

Rakesh K. Singh, Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, NE, USA

Vinod Kumar Tiwari, Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi, India

Rama Pati Tripathi, Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India

Maria Laura Uhrig, CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina

Christine Vala, Laboratoire Structure et Réactivité des Systèmes Moléculaires Complexes, Université de Nancy, Groupe SUCRES, Vandoeuvre les Nancy, France

Dong Wang, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE, USA

Zbigniew J. Witczak, Department of Pharmaceutical Sciences, Nesbitt School of Pharmacy, Wilkes University, Wilkes-Barre, PA, USA

Joanna M. Wojnar, School of Chemical Sciences, University of Auckland, Auckland, New Zealand

LIST OF ABBREVIATIONS

[18F]FC[18F]fluorocholine[18F]FLT3′-deoxy-3′-[18F]fluorothymidineα-MSHα-melanocyte-stimulating hormoneAcacetylADIBOazodibenzocyclooctyneAFMatom force microscopyAIBNazobisisobutyronitrileAIDSacquired immune deficiency syndromeAllallylAMEsaminoglycoside-modifying enzymesANLAspergillus niger lipaseATR-FTIRattenuated total reflectance-Fourier transform infrared spectroscopyATRPatom transfer radical polymerizationBLGbovine liver galactosidaseBnbenzylBoct-butyloxycarbonylBrBzbromobenzylBSAbovine serum albuminBTMSSbis(trimethylsilyl)sulfideBTTEStris(triazolylmethyl)amineCADcoupling and decouplingCAL BCandida antarctica B lipaseCbzbenzyloxycarbonylCCCTPcobalt catalyzed chain transfer polymerizationCCTPcatalytic chain transfer polymerizationCDcyclodextrinCMPcytidine monophosphateCNBrcyanogen bromideCNTscarbon nanotubesConAconcanavalin ACSA10-camphorsulfonicCTcomputerized tomographyCuAACcopper-catalyzed azide−alkyne cycloadditionDABCO1,4-diazobicyclo[2,2,2]octaneDAGdiacylglycerolDBU1,8-diazabicyclo[5.4.0]undec-7-eneDCMdichloromethaneDCR1,3-dipolar cycloadditionDDQdichlorodicyanoquinoneDEGMAdi(ethylene glycol) methyl ether methacrylateDFdiclofenacDFTdensity functional theoryDIADdiisopropyl azidodicarboxylateDIPEAN,N-diisopropylethylamineDLSdynamic light scatteringDMAcN,N-dimethylacetamideDMAPN,N-dimethylaminopyridineDMFN,N-dimethylformamideDMPA2,2-dimethoxy-2-phenylacetophenoneDMPPdimethylphenylphosphineDMSOdimethyl sulfoxideDMTr4,4′-dimethoxytritylDNAdeoxyribonucleic acidDNJdeoxynojirimycinECGEscherichia coli galactosidaseEDCethylene dichlorideELISAenzyme-linked immunosorbent assayELLAenzyme-linked lectin assayEMCN-(ɛ-maleimidocaproyl)ERendoplasmic reticulumEtethylFDG2-deoxy-2-fluoro-D-glucoseFRETFörster resonance energy transferGalNAzN-azidoacetylgalactosamineGDP-fucoseguanosine diphosphate β-L-fucoseGlcNAzN-azidoacetylglucosamineGM3monosialo ganglioside 3HAhyaluronanHEMA2-hydroxyethyl methacrylateHNE4-hydroxynonenalHPGshyperbranched polyglycerolsHPLChigh-performance liquid chromatographyK222Kryptofix® 2.2.2 (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane)KLHkeyhole limpet hemocyaninLASlipase AS Amano (from Aspergillus niger)LCSTlower critical solution temperatureLDI-MSlaser desorption ionization mass spectrometryLPClysophosphatidylcholineMBLmannose-binding lectinm-CPBAm-chloroperoxybenzoic acidMemethylMEMmethoxyethoxymethylMFmefenamic acidMHCminimal hemolytic concentration indexMICminimal inhibitory concentrationMOMmethoxymethylMRImagnetic resonance imagingMRSAmethicillin-resistant Staphylococcus aureusMUNANA2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acidNaAscsodium ascorbateNAPnaphthylmethylNBD7-nitrobenz-2-oxa-1,3-diazol-4-ylNCLnative chemical ligationNeu5AcN-acetylneuraminic acidNISN-iodo succinimideNMRnuclear magnetic resonanceNP(S)-naproxenNTneurotensinNTRneurotensin receptorOEGoligoethylene glycolPAphosphatidic acidPABTC2-propanoic acid butyltrithiocarbonatePBSphosphate buffered salinePCphosphatidylcholinePCphotocleavablePDTphotodynamic therapyPEphosphatidylethanolaminePEGpolyethylene glycolPETpositron emission tomographyPGphosphatidylglycerolPhphenylPIPnphosphatidylinositol polyphosphatesPivpivaloylPKCprotein kinase CPLEporcine liver esterasePMAMpolyamidoaminePMB4-methoxybenzylPMPp-methoxyphenylPNApeanut agglutininPocpropargyloxycarbonylPPIpoly(propylene imine)PPTSpyridinium toluene-4-sulfonatePrpropylPSphosphatidylserinep-TSAp-toluenesulfonic acidPypyridineQCMquartz crystal microbalanceRAFTreversible addition–fragmentation chain transferRGDarginine-glycine-aspartic acid peptidic sequenceRGDarginylglycylaspartic acidRGDCH-Arg-Gly-Asp-Cys-OHRNAribonucleic acidROPring opening polymerizationRuAACRu-catalyzed azide alkyne cycloadditionSAGsweet almond glucosidaseSAMself-assembled monolayerSARstructure-activity relationshipSATES-acetylthioethylSBSsequencing by synthesissec-Butsec-butanolSiRNAsmall interfering ribonucleic acidSLBsupported lipid bilayerSMsphingomyelinSPECTsingle-photon emission computerized tomographySPPSsolid phase peptide synthesisSPRsurface plasmon resonanceSSTsomatostatinTAMRAtetramethylrhodamineTBAFtetrabutylammonium fluorideTBAHStetrabutylammonium hydrogen sulfateTBDMSt-butyldimethylsilylTBDPSt-butyldiphenylsilylTBTAtris-(triazolyl)benzylamineTCEPtris(2-carboxyethyl)phosphineTcTSTrypanosoma cruzi trans-sialidaseTEAtriethylamineTEABtetraethylammonium bromideTECthiol-ene couplingTEGtetraethylene glycolTFAtrifluoroacetic acidTfOHtrifluoromethanesulfonic acidTHFtetrahydrofuranTLLThermomyces lanuginosa lipaseTMEAthiol Michael enone additionTMStrimethylsilylTMSOTftrimethylsilyl trifluoromethanesulfonateToltolylTsp-toluenesulfonylTTMAtriethyl-2,2′,2′′-(4,4′,4′′-nitrilotris(methylene)tris(1H-1,2,3-triazole-4,1-diyl))-triacetateTYCthiol-yne couplingTyctyrocidineUVultravioletVREvancomycin resistant enterococci

PART I

CLICK CHEMISTRY STRATEGIES AND DECOUPLING

1

PARADIGM AND ADVANTAGE OF CARBOHYDRATE CLICK CHEMISTRY STRATEGY FOR FUTURE DECOUPLING

Roman Bielski and Zbigniew J. Witczak

1.1 INTRODUCTION

When discussing click chemistry, the exceptionally successful methodology of connecting molecules, it seems natural to look at ways of disconnecting them. Thus, while preparing a symposium on applications of the click chemistry in carbohydrates, we began thinking about effective methods of disconnecting molecular units from each other. It turns out that the number of options is rather limited. We reasoned that the need for such reactions must be rather rare. However, it is easy to list several situations that require decoupling after certain experiments or procedures had been completed. Recently, we discussed circumstances calling for a design of coupling of the molecular units that takes into account a future necessity for the decoupling of these units [1]. The review lists almost a dozen such situations. Examples include releasing of the radio part from the radiotherapeutic or the chemo part from the chemotherapeutic after the treatment had been completed; decoupling of molecular units to enable or facilitate analytical procedures; decoupling various constructs from the surface either to produce a specific structure on the surface or to release a product from the surface after its special properties had been taken advantage of; and cleavage of the synthesis's product from the solid support.

For a variety of reasons, coupling is performed much more often than decoupling. The language gives strong support to this notion. While there are at least five words describing various types of coupling processes leading to the increase in the molecular weight (bioconjugation, derivatization, labeling, ligation, tagging), there are only two words describing decoupling processes (cleavage, scission). There are, additionally, at least three words whose negation is a proper word (coupling, protection, connection).

Let us consider possible protocols of coupling molecular units when it is known that the decoupling will be necessary later on. Let the molecules of interest potentially include large biomolecules. One obvious option is to couple molecular units by taking advantage of the click chemistry reactions, and later, utilize processes that are the reverse of the click reactions. Unfortunately, most click processes are not reversible or the retro reactions require conditions that cannot be applied to most (bio)macromolecular structures. Recently, Bielawski and coworkers [2] published an interesting paper showing that in the presence of ultrasound the popular click products, cyclic triazoles, can be transformed back to an azide and an alkyne. However, at this point, it seems unlikely that the ultrasound-generated reverse Huisgen cycloaddition process can find a broad application.

Since click reactions are usually not reversible, one has to develop other strategies. At least, two potentially successful strategies can be devised:

One strategy asks for the use of reversible reactions (not belonging to click chemistry) such as formation of esters, amides, benzyl ethers during the coupling process and hydrolysis or debenzylation during the decoupling process (Scheme 1.1a). While such an option is often useful and effective, it is worth noting that hydrolysis of a specific ester or amide group from a construct containing protein(s) with many peptide bonds or polysaccharide with many acetal and/or ester groups may be problematic. The same applies to debenzylation, which may not be sufficiently regio- or chemoselective for various constructs.An alternative strategy asks for the introduction of a unit that is coupled (preferably via the click chemistry forming XZ and WB connections) to two (or more) molecular units and contains an easy cleavable functionality (AB) somewhere in the middle (Scheme 1.1b). We call such a unit a “sacrificial unit” containing a “sacrificial functionality.” We coined the term for such chemistry—coupling and decoupling chemistry (CAD) [1]. The advantage of this option is that the sacrificial functionality (AB) can be tailor-made for specific molecular units; that is, it can be a functionality that is not found in the molecular units and thus can be safely decoupled when needed.

SCHEME 1.1 Possible approaches to the issue of future decoupling of connected molecular units: (a) use of reversible reactions; (b) use of sacrificial units.

A construct 5 containing a sacrificial functionality can be synthesized on a step-by-step basis that comprises the introduction of appropriate linkers and other necessary components of sacrificial units. However, taking advantage of the pre-synthesized sacrificial units 4 equipped with all the required linkers, as shown in Scheme 1.1b, seems to be a better approach.

First, let us discuss the requirements of the reactive groups Z and W which are to connect the sacrificial unit to (macro)molecules of interest. Of course, the choice of Z and W depends very strongly on the type of available X and Y groups and on reactivity of the various other functional groups present in molecular units 1 and 2. It must be emphasized that the click chemistry should be used to connect the molecular units whenever possible. Besides all the virtues of the click chemistry reactions, the products of these reactions are, as a rule, very stable and we may be sure that unexpected and undesired disconnections will not happen.

While experts disagree on the exact scope of the click chemistry and what reactions truly belong to the click chemistry domain [3], it is probably worth at least listing the chemical reactions considered to belong there. Carvalho, Field, and coworkers recently reviewed applications of Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click chemistry” in carbohydrate drug and neoglycopolymer synthesis [4]. In the review, they list four categories of “click reactions” (Scheme 1.2).

SCHEME 1.2 Click reactions according to Carvalho, Field, et al. [4].

The Huisgen addition of azides to terminal alkynes (1A) is, by far, the most popular click reaction. The second most often employed click reactions is the addition of thiols to double (and triple) bonds. Depending on the substituents of the double bond, the reaction mechanism can be free radical or nucleo or electrophilic. Only a few of other reactions listed by Carvalho and Field [4] fulfill the conditions that open a door to a “distinguished” club of click processes. There are two more reviews of click-related carbohydrate chemistry. One of them discusses the impact of click chemistry on the carbohydrate-based drug development and glycobiology [5]. The other one, recently published by Lucas and coworkers [6], describes novel developments of click chemistry in polysaccharides. The authors are mainly focused on the catalyzed version of Huisgen 1,3-dipolar cycloaddition between terminal alkynes and azides.

Interestingly, the list of click reactions utilized in polymer chemistry [7] (Scheme 1.3) is slightly different from the one outlined in Reference 4.

SCHEME 1.3 Click reactions in polymer chemistry according to Becer, Schubert, et al. [7].

Luckily, there are more than one click processes. It is important because taking advantage of a single click process (to form XZ and WY connections—see Fig. 1.1b) is rather problematic. Assume that a square is a functionality forming the click reaction product with the “open square.” Figure 1.4 shows clearly that both functionalities involved in a click process should not be attached to a sacrificial unit. In such a case, the molecule of a sacrificial unit will react with another molecule of a sacrificial unit to form a polymer (Scheme 1.4a). Even if the same functionalities are attached to the sacrificial units, certain amounts of undesired symmetrical products will be formed (Scheme 1.4b).

SCHEME 1.4 The use of the same click process on both sides of the sacrificial unit: (a) different functionalities attached to the sacrificial unit; (b) same functionalities on both sides of the sacrificial unit.

Employing two different click reactions solves the problem (Scheme 1.5).

SCHEME 1.5 Use of two different click reactions.

What chemical functionalities can act as sacrificial functionalities? The answer depends mainly on the structure of molecular units that are to be coupled. If one (or more) of the molecular units to be connected is a (poly)saccharide, such functionalities as acetals and esters should be rather avoided since polysaccharides usually have an abundance of such groups.

Let us take a look at a few applicable examples of click chemistry reactions. It has been already more than 10 years since the concept was introduced [8]. Since then, thousands of papers employing click reactions have been published. Thus, there is a plethora of data describing the connection of large and small, natural and non-natural molecules equipped with a variety of functional groups. For many click reactions, their scope is well known and it is relatively easy to choose the one that will be effective at the given circumstance. The following carbohydrate examples are meant to serve as an illustration only.

1.2 COUPLING USING HUISGEN DIPOLAR CYCLOADDITION

Let us begin with [3 + 1] dipolar cycloaddition of azides to acetylenes. These reactions are usually very easy to perform, particularly since the use of copper-containing catalysts was introduced [9,10]. Since copper salts are not always applicable, Bertozzi et al. [11] and Boons et al. [12] developed methodologies employing no copper catalyst, but offering most of the advantages of CuAAC reactions. Both methodologies use a substituted cyclooctyne.

As we already mentioned, the Cu(I)-catalyzed [3 + 1] dipolar cycloaddition of azides to acetylenes (CuAAC) is, by far, the most popular click process. A few years ago, Marmuse, Nepogodiev, and Field [13] synthesized starch fragments analogs. The results of 1,3-dipolar cycloaddition of dipropargylated maltosides and azidoglucosides are shown in Figure 1.1. All reactions were carried out using (Ph3P)3·CuBr as a catalyst in the presence of DIPEA as a base for a relatively long reaction time (12 hours) at room temperature. The yields of cycloaddition reactions varied between 65% and 27%, decreasing with increasing length of the azidooligosaccharide chain.

FIGURE 1.1 Example of rapid assembly of starch fragment analogs using CuAAC “click chemistry.”

Huerta-Angeles et al. [14] also synthesized truly large molecules by taking advantage of the Cu(I)-assisted AAC. Actually, they used the formation of the cyclic triazole as the cross-linking reaction to form hyaluronan (HA)-based hydrogels with well-defined 3D-molecular architecture for potential application in tissue engineering. Figure 1.2 shows the relevant chemistry.

FIGURE 1.2 Use of CuAAC reaction as cross-linking to form HA-based hydrogels.

Maillard and coworkers [15] synthesized a series of porphyrins each containing three glycosyl units using microwave activation. The products were designed as photodynamic therapy (PDT) agents. They are linked by a triazole group to chromophore in the aim to target tumor cells overexpressing lectin-type membrane receptors. Figure 1.3 shows the synthesis of the constructs. Importantly, zinc(II) cations in porphyrins are sufficiently stable under Cu-assisted azide acetylene cycloaddition click reaction conditions to avoid replacement by a copper(II) ions. The products turned out to be less active than analogs containing no triazole rings. The yields were very reasonable.

FIGURE 1.3 Porphyrin-based constructs synthesized by Maillard et al.

Chapleur and coworkers [16] synthesized more than a dozen neoglycopeptides via a direct functionalization of cysteine. The employed monosaccharides include acetylated and unprotected glucose, mannose, galactose, and 6-deoxy-6-fluoroglucose. Interestingly, the reaction of the fluoro compound equipped with the azido group and the tetrapeptide, Arg-Gly-Asp-Cys (RGDC) substituted with the propargyl group gave the highest yield. The synthetic strategy is shown in Figure 1.4.

FIGURE 1.4 Chapleur et al.'s synthetic strategy for neoglycopeptides construction.

1.3 COUPLING USING THIOL-ENE COUPLING CLICK CHEMISTRY

In recent years, another reaction, thiol-ene coupling (TEC), joined the exclusive club of click chemistry processes [17,18,19]. It is worth noting that the TEC reaction has been known for more than 100 years [20]. The addition of thiols to simple alkenes (and alkynes) is almost always free radical and can be initiated either thermally or photolytically.

Fiore, Marra, and Dondoni [21] took advantage of photoinduced coupling of anomeric sugar thiols with sugar alkenes to synthesize 1,6-linked S-disaccharides in good to excellent yields (76–92%) and high diastereoselectivities (up to 99%). Figure 1.5 shows a typical example of the synthesized disaccharide.

FIGURE 1.5 Example of Dondoni et al.'s [21] photoinduced TEC as a click ligation tool for thiodisaccharide synthesis.

Stenzel and coworkers [22] synthesized a block copolymer containing di(ethylene glycol) methyl ether methacrylate (DEGMA) and 2-hydroxyethyl methacrylate (HEMA) by reversible addition-fragmentation chain transfer (RAFT) polymerization, which was subsequently modified with glucothiose. Glucothiose was introduced via UV-promoted TEC process. The resulting glycosylated block copolymer led to the formation of thermoresponsive micelles, a potential candidate for targeted drug delivery. Figure 1.6 illustrates the methodology.

FIGURE 1.6 Stenzel et al.'s [22] synthetic strategies for the preparation of glucose functionalized (co)polymers.

Most Michael additions of thiols to double bonds conjugated to carbonyl and similar groups are reversible. Nevertheless, some of the Michael additions of thiols have been shown to offer stable and easy-to-isolate products. For example, Chandrasekaran et al. [23] synthesized several thioglycosides and other thiosugar analogs using benzyltriethylammonium tetrathiomolybdate [(BnNEt3)2MoS4] or ammonium tetrathiomolybdate as a sulfur-transfer reagent. The reagent reacts with sugar halides to give sugar disulfides, which then undergo reductive cleavage in situ to provide the corresponding thiolates, followed by Michael addition to give the corresponding thioglycosides or other monosaccharides containing sulfur. Alternatively, the authors also made sugar enones to react with disulfides to form thiosugars, often with excellent diastereoselectivity (but sometimes the ratio of diastereoisomers was 1:1). The process is simple, offers good to excellent yields, and is performed in one pot. While the authors did not consider the process to belong to click chemistry, it definitely shows most features of the click chemistry. Figures 1.7 and 1.8 illustrate the methodology.

FIGURE 1.7 Thio-glucoside forming tandem sulfur transfer/reduction/Michael addition assisted by tetrathiomolybdate [23].

FIGURE 1.8 Synthesis of 3-deoxy-3-thiosugar derivatives via Michael addition according to Reference 23.

Witczak et al. [24] synthesized an interesting thiodisaccharide presented in Figure 1.9. The synthesis takes advantage of a click chemistry reaction, the (Michael) addition of a thiol to the enone system.

FIGURE 1.9 Witczak et al.'s [24] synthesis of thiodisaccharide using Michael addition of monosaccharide with a thiol functionality.

1.4 PROCESSES WHERE BOTH CuAAC AND TEC CLICK CHEMISTRIES ARE USED

Perrier et al. [25] synthesized highly branched and hyperbranched glycopolymers via RAFT polymerization and click chemistry which includes Cu(I)-catalyzed Huisgen 1,3-cycloaddition of azides and alkynes (CuAAC), thiol-ene addition, and thiol-yne addition. The authors explain that in some circumstances, the drawback of the RAFT approach is the poor availability and compatibility of specific functional monomers. They circumvent the problem by introducing functionalities via post-polymerization modification employing click chemistry. The TEC reactions were performed in the presence of HCl using glucothione sodium salt as the carbohydrate component and 2,2-dimethoxy-2-phenylacetophenone (DMPA) as a photoinitiator, under UV at room temperature. 2-azidoethyl-β-D-galactopyranoside served as a carbohydrate component of CuAAC reactions. Figure 1.10 shows the relevant products.

FIGURE 1.10 Synthetic strategy for the preparation of highly branched glycopolymers devised by Perrier et al. [25].

Haddleton and coworkers [26] also synthesized polymers capable of forming click products deriving from both CuAAC and thiol-ene reactions. They took advantage of the catalytic chain transfer polymerization (CCTP) to form alkyne-functional macromonomers which were subsequently functionalized with sugar azides (CuAAC) and thiols. Interestingly, the addition of thiol was a Michael-type reaction and benzyl mercaptan in the presence of dimethylphenylphosphine (DMPP) was employed as a thiol. Figure 1.11 shows this convenient synthesis of end-functionalized glycopolymers and the utilized carbohydrate azides.

FIGURE 1.11 Haddleton and coworkers' [26] synthetic approach to end-functionalized glycopolymers and structures of utilized carbohydrate azides.

Marra, Dondoni, et al. [27] also use both CuAAC and TEC chemistries when synthesizing calix[4]arene-based S-glycoclusters. They describe the dual clustering at the upper and lower rim of a calix[4]arene with two different sugars (galactose and glucose) via sequential copper(I)-catalyzed azide–alkyne cycloaddition and photoinduced TEC. Figure 1.12 illustrates the approach.

FIGURE 1.12 Structure of one of the dual clusters at the upper and lower rim of a calix [4] arene with two different sugars (galactose and glucose) synthesized by Dondoni et al. [27].

1.5 DECOUPLING

It should be very strongly emphasized that the number of literature examples of decoupling large molecules is very limited. At this point, we must rely on examples of decoupling in which small molecules were split to smaller fragments. We hope that soon there will be many examples of decoupling reactions applied to large molecules consisting of two or, at least, one macromolecule. It will help researchers to understand the scope and limitations of various reactions and will minimize guessing (or extrapolating) whether a specific coupling or decoupling reaction is applicable in a specific situation.

The following examples show some of the decoupling which includes carbohydrates sacrificial functionalities that can be found in the literature.

1.5.1 Enzymatic Cleavage

Let us start with decoupling processes that are triggered by enzymes. It is well known that enzymes are highly sensitive to the structure of reactants. Thus, one has to be exceptionally cautious when trying to expand the use of specific enzymes to other categories of compounds. It applies particularly to reactions performed on small molecules. It may not translate well to much larger (macro) molecules even when the specific part of the molecule is the same. We can only hope that with time our understanding of specific enzymatic processes will improve and there will be the abundance of literature data enabling successful application of enzymatic decoupling to specific situations. The following examples derive from small molecule chemistry, but hopefully will find application in decoupling processes as well.

Iglesias and coworkers [28] studied alcoholysis of methyl 2,3,5-tri-O-acetyl-α-D-ribofuranoside and methyl 2,3,5-tri-O-acetyl-β-D-ribofuranoside using the Candida antarctica lipase B (CAL B). The reaction of the α-anomer lead to the isolation of the monodeacetylated product. The reaction of the β-anomer lead to a variety of partially deacetylated products but eventually provided the fully deacetylated product in a quantitative yield (Fig. 1.13).

FIGURE 1.13 Highly regioselective and exhaustive deacetylation using lipases described by Iglesias and coworkers [28].

Italian and Spanish researchers [29] performed selective hydrolysis of peracetylated β-monosaccharides using immobilized lipases from different sources [Thermomyces lanuginosa (TLL), Aspergillus niger (ANL), and Candida antarctica B (CAL B)]. Figure 1.14 shows some of the results. The shown yields represent isolated yields. The results illustrate a crucial role played by the procedure applied to the immobilization of enzymes. The paper is an example of a larger series of papers devoted to studying regioselectivity of various enzymatic hydrolyses [30] and references quoted therein. The acquired knowledge was employed to a very elegant synthesis of linear oligosaccharides by a simple monoprotective, chemoenzymatic approach.

FIGURE 1.14 Specific and regioselective hydrolysis of different 1,2,3,4,6-penta-O-acetyl-D-glycopyranoses using immobilized lipases [29].

Baba and Yoshioka [31] prepared 1-β-O-acyl glucuronides of three nonsteroidal, anti-inflammatory drugs, diclofenac (DF), mefenamic acid (MF), and (S)-naproxen (NP) (their structures are shown in Fig. 1.15). Next, after some screening, they employed selected commercial enzymes—lipase AS Amano LAS: (from ANL), and porcine liver esterase (PLE). LAS hydrolyses the O-acetyl groups with high chemoselectivity to provide the methyl ester equipped with three OH groups and PLE hydrolyses the methyl ester groups with high chemoselectivity to provide glucuronic acid containing three acetyl groups. Any combination of two esters leads to high yields (90% or more) of glucuronic acids with unchanged substituent at the aglycone position (Fig. 1.15).

FIGURE 1.15 Chemo-enzymatic synthesis of 1-β-O-acyl glucuronides described by Baba and Yoshioka [31].

1.5.2 Photocleavage

Maki and Ishida [32] designed and synthesized photocleavable molecules for laser desorption ionization-mass spectrometry (LDI-MS). The authors envisaged that a photocleavable molecule, which affords an MS-detectable ion upon irradiation without matrix assistance, would simplify the ionization mechanism and be a reliable and selective labeling device for LDI-MS. As expected, the connection takes advantage of the click chemistry. The final step of the synthetic procedure is shown in Figure 1.16. The cleavage takes place under the laser pulse at 337 nm.

FIGURE 1.16 Maki and Ishida's [32] synthesis of compounds containing carbohydrate and photocleavable parts.

Ju and coworkers [33] designed and synthesized a 3′-modified photocleavable fluorescent nucleotide, 3′-O-allyl-dUTP-PC-Bodipy-FL-510 (PC-Bodipy, photocleavable 4,4-difluoro-4-bora-3α,4α-diaza-s-indacene), as a reversible terminator for DNA sequencing by synthesis (SBS). Figure 1.17 shows the design and synthesis of the product.

FIGURE 1.17 Ju and coworkers' [33] design and synthesis of a 3′-O-allyl photocleavable fluorescent nucleotide as a reversible terminator for DNA sequencing by synthesis.

1.5.3 Chemical Cleavage

Manabe, Ueki, and Ito [34] developed a very convenient method of deprotecting propargyl ethers using the samarium–amine–water system. The method requires little time (usually 15 minutes), reactions take place at room temperature, offer good yields, and chemoselectivity (Fig. 1.18). The method was applied to the solid state synthesis of oligosaccharides (Fig. 1.19).

FIGURE 1.18 Examples of selective deprotection of propargyl ethers using samarium–amine–water system [34].

FIGURE 1.19 Polymer-supported disaccharide synthesis according to Manabe, Ueki, and Ito [34].

At this point, it is impossible to say if the same decoupling can be applied to a propargyl group in which one of the hydrogen atoms (in either of the two possible positions) was replaced with a large (macromolecular) substituent.

Chen and coworkers [35] developed a novel method of selective deacylation using dioxomolybdenum dichloride as a catalyst. The conditions are mild and the yields are very high. Figure 1.20 shows more spectacular examples of removal of acyl group in the presence of other protecting functionalities.

FIGURE 1.20 Effective deacetylation developed by Chen et al.

Padrón, Bermejo, and collaborators [36] used as simple reagent as p-toluenesulfonic acid (or 10-camphorsulfonic; CSA) to selectively cleave acetates in the presence of benzoates and p-bromobenzoates. The reactions are performed in DCM/methanol at 40°C and yields are high. The examples shown in Table 1.1 illustrate the methodology.

Table 1.1 Selective Deacetylation Described by Padrón, Bermejo et al.

Kroutil and collaborators [37] developed conditions enabling chemoselective cleavage of benzylamines in the presence of such functionalities as azide, O-benzyl, and N-tosyl using diisopropyl azidodicarboxylate (DIAD). Figure 1.21 shows some examples of this high-yielding methodology.

FIGURE 1.21 Selective N-debenzylation of benzylamines by DIAD according to Kroutil et al. [37].

Spencer et al. [38] compared the rate of hydrogenation of benzyl ethers containing different substituents in the aromatic ring. The differences are significant. For example, the reaction of the compound with the benzyl group containing trifluoromethyl group in the para position is about five times slower than the reaction of a compound with unsubstituted benzyl group. Introduction of t-butyl group into the para position of the benzyl ether increases the rate of hydrogenation about 25 times. The researchers found that the naphthylmethyl (NAP) group is exceptionally selective. Figure 1.22 shows the carbohydrate examples.

FIGURE 1.22 Selective removal of the NAP group in the presence of benzyl ethers according to Spencer et al. [38].

It is worth adding that the NAP group can be introduced either using NAP bromide [38,39] or by forming the cyclic naphthyl acetal followed by hydrogenation [40]. Interestingly, the NAP group can be cleaved also at room temperature using entirely different conditions than Spencer and coworkers. Matta et al. [39] developed a method based on DDQ. Figure 1.23 shows the conditions and yields. Recently, Boons et al. [41] took advantage of this approach when synthesizing an unusual phosphoglycopeptide derived from α-dystroglycan. Yields were equally high.

FIGURE 1.23 Selective removal of NAP groups in the presence of benzyl ethers using DDQ according to Matta et al. [39].

Kovensky and coworkers [42] demonstrated quantitative yields of the allyl group removal from the anomeric position of allyl galactopyranosiduronic acid derivatives. The authors employ a two-step procedure consisting of DABCO and (Ph3P)3RhCl followed by mercuric-assisted cleavage. Their work is an excellent example of difficulties one often encounters when employing a specific reactant to a novel structure. It turned out that standard literature procedures lead to mixtures consisting of the starting material, the desired product, and a significant amount of the allyl group oxidation product. Most alternatives did not offer any improvement. Eventually, the researchers developed a very successful method as shown in Figure 1.24.

FIGURE 1.24 Barbier et al.'s [42] two-step method to remove the allyl group from allyl galactopyranosiduronic acid derivatives using DABCO and (Ph3P)3RhCl followed by mercuric-assisted cleavage.

Recently, Finnish and Hungarian scientists [43] have shown the effectiveness of utilizing flow chemistry to deprotection of benzyl/benzylidene protected carbohydrates. While the required conditions (that were not optimized) include a relatively high pressure of hydrogen (40 bar) and elevated temperature (80°C), the method offers excellent yields and does not affect such protecting groups as acetates and silyl ethers. Figure 1.25 shows the results. The presented yields are isolated yields.

FIGURE 1.25 Application of flow chemistry to deprotection of benzyl-/benzylidene-protected carbohydrates [43].

Das and collaborators [44] developed a method enabling an effective and mild removal of a trityl group in the presence of various protecting groups. The method employs silica-supported sodium hydrogen sulfate. Figure 1.26 shows the results.

FIGURE 1.26 Chemoselective deprotection of trityl ethers using silica-supported sodium hydrogen sulfate developed by Das et al. [44].

Sharma et al. [45] describe a novel, zirconium chloride-based methodology enabling a highly selective deprotection of t-butyldimethylsilyl (TBS) ethers in the presence of t-butyldiphenylsilyl (TPS) ethers. Figure 1.27 shows the only carbohydrate example from the paper. Other examples are equally impressive. While the difference between the TPS and TBS ethers seems to be very minute, one can accomplish a spectacular selectivity in deprotection of these species. However, without appropriate experiments, it is impossible to say whether similar selectivity is achievable when, for example, one of the hydrogen atoms in a t-butyl group is replaced with a large macromolecular unit.

FIGURE 1.27 Sharma et al.'s deprotection of t-butyldimethylsilyl ethers in the presence of t-butyldiphenylsilyl ethers.

Another accomplishment in deprotection of silyl ethers has been developed by Chen, Le, Lin, and coworkers [46] who deprotect primary silyl ethers in the presence of the secondary ones and other protecting groups such as benzyl ethers. The methodology requires that the silyl ethers are treated with a catalytic amount of CBr4 in methanol under photochemical reaction conditions. Selected results are shown in Figure 1.28.

FIGURE 1.28 Chen, Lee, Lin, and coworkers' selective deprotection of secondary silyl ethers.

Pale and coworkers [47] developed a new type of a protecting group-bis (4-methoxy-phenyl) methyl group. The relevant ethers are formed (in acetonitrile) and deprotected (in ethanol) in the presence of Cu(II) bromide. The yields are high. Figure 1.29 shows the carbohydrate deprotection (decoupling) example. It is worth noting that the size of the protecting group suggests that it may be equally effective when large substituent is attached to one of the methoxyphenyl groups.

FIGURE 1.29 Deprotection of a new protecting group-bis (4-methoxyphenyl) methyl group developed by Pale and coworkers [47].

Sridhar and Chandrasekaran [48] developed a novel protecting group for amines and alcohols, propargyloxycarbonyl (Poc) group. It can be easily removed under neutral conditions using tetrathiomolybdate MoS42− in acetonitrile at room temperature. Such groups as benzylidene acetals, benzyl ethers, acetyl and levulinoyl esters, and allyl and benzyl carbonates are left untouched. Importantly, the new protective group (Poc) is compatible with acidic, basic, and also glycosylation conditions. While all the examples relate to the gluco configuration, there are no reasons to believe that other configurations would not give similar results. Figure 1.30 shows a few examples of Poc deprotection.

FIGURE 1.30 High-yielding removal of propargyloxycarbonyl (Poc) group developed by Sridhar and Chandrasekaran [48].

1.6 CONCLUSION

We hope that the present review convincingly shows click chemistry to be an exceptionally useful methodology not only applicable to coupling larger molecular units but also when such coupling must be later somehow reversed. The proposed strategy of using sacrificial units is simple and should become the approach of choice when the units must be later decoupled. The review shows that there are several excellent click reactions and some of them such as azide alkyne addition or thiol addition to unsaturated systems have been applied very successfully to the synthesis of various large molecules including macromolecular units containing carbohydrates. Nevertheless, the field of decoupling is much less often visited, and thus, there is an acute need for novel methods of decoupling. In addition, we hope that future availability of a variety of sacrificial units will encourage chemists to take advantage of them. It will enable much better assessment of what the limitations of specific decoupling methods are. The area of research that should strongly benefit from such knowledge is the sequencing of complex, natural polysaccharides.

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PART II

THIO-CLICK CHEMISTRY OF CARBOHYDRATES

2

THIO-CLICK CHEMISTRY IN GLYCOSCIENCE: OVERVIEW AND PERSPECTIVES

Zbigniew J. Witczak

2.1 INTRODUCTION

The new concept by Sharpless, Finn, and Kolb for conducting organic reactions capable of producing wide libraries of fully functionalized synthetic molecules has been classified as click chemistry. The traditional azide--alkyne click chemistry approaches with multiple types of clickable functional groups were the leading examples of the early strategy.

Recently, thiol-ene chemistry became a well-accepted part of the click reaction toolbox and is rapidly developing in many strategic areas of thio-conjugation. In carbohydrate chemistry the most important substrates are glycosyl thiols. Few years ago, they became available in both anomeric forms, which created new opportunities for the expansion of the existing techniques for thio-conjugation to form products deriving from both stereo isomers.

2.2 THIO-BASED CLICK REACTIONS

The addition of a thiol to the double bond is known as the thiol-ene reaction. The scope of the thiol-ene approach is quite impressive with respect to the endless applicability of reactive thiols and almost all molecules with a double bond (ene) moiety. The reactions take place under various experimental conditions, such as, base or acid catalysis and radical induction (thermal or photochemical). Most of these approaches are applicable to polymer chemistry [1,2].

In carbohydrate chemistry, a reactive sugar thiol can be added to a double bond of unsaturated sugar quite easily, always with the formation of thio-adduct in high yields.

Since several review articles have dealt with many aspects of thio-functionalization [3,4] via click reaction in polymer chemistry and there is no extensive compilation in synthetic carbohydrate chemistry, the aim of this chapter is to review only synthetic methods involving genuine thio-click approaches either via thiol-ene coupling (TEC) or thiol Michael addition enone (TMAE) to the conjugated systems of carbohydrate enones.

The application of TEC and thiol-yne coupling (TYC) approaches to glycoconjugation in carbohydrate chemistry was recently reviewed by Dondoni and Marra [5,6]. Other pertinent articles by Davis [7] deal exclusively with the design and formation of disulfide linkers and its incorporation into specific biological systems.

In carbohydrate chemistry, functional group manipulations are highly dependent on the availability of the position for all thio-click reactions and are designated to form either internal or external thio-linking functional group. The external thio-functionalized group or linker could be further manipulated to build macromolecular assemblies with specific moieties containing blocked or exposed thiol groups suitable for additional chemical ligation or glycoconjugation. These structural thio-conjugation strategies via click chemistry are the most promising among elaborate new developments in the multidisciplinary chemistry/biology methodologies. The thio-click chemical reactions toolbox is depicted in Scheme 2.1.

SCHEME 2.1 Thio-click chemical reaction toolbox.

2.3 S-THIODISACCHARIDE SYNTHESIS

S-thiodisaccharides are simple functionalized sugars bearing sulfur bridge in one of the strategically important positions, C-1, C-4 (head–tail) or C-1, C-6 (head–tail). Other less strategically important structural connections via sulfur bridge include C-1, C-1 (head–head) and C-1, C-2 or C-1, C-3 and are summarized in Scheme 2.2.

SCHEME 2.2 Strategical connections of thiodisaccharides.

Several methods for the synthesis of S-thiodisaccharides have been published. Most of them involve SN2-type substitution of thiolate anions on glycosyl halides, or 1-thio-donors on acceptors bearing a good leaving group. None of these approaches are considered thio-click reactions.

The alternative formation of thio-bridge via TMEA addition to the conjugate system can clearly fit the definition of thio-click approach, despite their development before the official birth of click chemistry. Our group was the first to develop this attractive strategy [8–13] of the synthesis of S-thiodisaccharides, followed by others [14–17]. These strategies were compiled and reviewed [18–21]. Many other strategies for the synthesis of thiodisaccharides were published [22–24].

Chandrasekaran and coworkers [23] developed a new methodology for the S-bridge formation of many thioglycosides by employing benzyltriethylammonium tetrathiomolybdate. The proposed mechanism postulates the tetrathiomolybdate reaction with sugar halides to proceed with the formation of sugar disulfides, which then undergo reductive cleavage in situ