Carbohydrate ChemistryChemical and Biological Approaches

Volume 40

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A Specialist Periodical Report

Carbohydrate ChemistryChemical and Biological

Approaches

Volume 40

EditorsAmelia Pilar Rauter, Universidade de Lisboa, PortugalThisbe K. Lindhorst, Christiana Albertina University of Kiel,Germany

Yves Queneau, Universite de Lyon, France

AuthorsIsabelle Andre, Universite de Toulouse, FranceJean-Marie Aubry, Universite Lille Nord de France, FranceJacques Auge, University of Cergy-Pontoise, FranceCaroline Ballet, Ecole Nationale Superieure de Chimie de Rennes,France

Chantal Barberot, Universite de Reims Champagne-Ardenne,France

Jean-Marie Beau, Universite Paris-Sud, Orsay, and CNRS, Gif-sur-Yvette,France

Thierry Benvegnu, Ecole Nationale Superieure de Chimie de Rennes,France

Davide Bini, Universita degli Studi di Milano-Bicocca, ItalyYves Bleriot, Universite de Poitiers, FranceJulie Bouckaert, Universite Lille Nord de France, FranceYann Bourdreux, Universite Paris-Sud, Orsay, FranceFrancois-Didier Boyer, CNRS, Gif-sur-Yvette, and INRA, Versailles,France

Alexandre Cavezza, LOreal Research & Innovation, Aulnay-sous-Bois,France

Yves Chapleur, Universite de Lorraine, Nancy, FranceLaura Cipolla, Universita degli Studi di Milano-Bicocca, ItalyClaire Coifer, Universite de Reims Champagne-Ardenne, FranceFlorent Colomb, Universite Lille Nord de France, FranceXavier Coqueret, Universite de Reims Champagne Ardenne, FranceStephen Cowling, University of York, UKMaria Dalko-Csiba, LOreal Research & Innovation, Aulnay-sous-bois,France

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Richard Daniellou, Universite dOrleans, FranceSamuel J. Danishefsky, Sloan-Kettering Institute for Cancer Researchand Columbia University, New York, USA

David Daude, Universite de Toulouse, FranceEdward Davis, University of York, UKPhilippe Delannoy, Universite Lille Nord de France, FranceGilles Doisneau, Universite Paris-Sud, Orsay, FranceSandrine Donadio-Andrei, SiamedXpress, Gardanne, FranceNassima El Ma, SiamedXpress, Gardanne, FranceAlberto Fernandez-Tejada, Sloan-Kettering Institute for CancerResearch, New York, USA

Vincent Ferrie`res, Ecole Nationale Superieure de Chimie de Rennes,France

Luca Gabrielli, Universita degli Studi di Milano-Bicocca, ItalyCharles Gauthier, Universite de Poitiers, FranceMarkus Glafg, Johannes Gutenberg-Universitat Mainz, GermanyPeter Goekjian, Universite de Lyon, FranceJohn Goodby, University of York, UKAlexandra Gouasmat, Universite Paris-Sud, Orsay, FranceEric Grand, Universite de Picardie Jules Verne, Amiens, FranceJaros"aw M. Granda, Institute of Organic Chemistry, Polish Academy ofSciences, Warsaw, Poland

Sophie Groux-Degroote, Universite Lille Nord de France, FranceCeline Guillermain, Universite de Reims Champagne Ardenne, FranceLaure Guillotin, Universite dOrleans, CNRS, FranceDominique Harakat, Universite de Reims Champagne Ardenne, FranceSebastian Hartmann, Johannes Gutenberg-Universitat Mainz,Germany

Arnaud Haudrechy, Universite de Reims Champagne-Ardenne, FranceEric Henon, Universite de Reims Champagne-Ardenne, FranceS"awomir Jarosz, Institute of Organic Chemistry, Polish Academy ofSciences, Warsaw, Poland

Janusz Jurczak, Institute of Organic Chemistry, Polish Academy ofSciences, Warsaw, Poland

Jose Kovensky, Universite de Picardie Jules Verne, Amiens, FranceMicha" Kowalski, Institute of Organic Chemistry, Polish Academy ofSciences, Warsaw, Poland

Horst Kunz, Johannes Gutenberg-Universitat Mainz, GermanyLaure LHaridon, Ecole Normale Superieure, Paris, FrancePierre Late, Universite dOrleans, CNRS, FranceLaurent Legentil, Ecole Nationale Superieure de Chimie de Rennes,France

Aurelie Lemetais, Universite Paris-Sud, Orsay, FranceLoc Lemie`gre, Ecole Nationale Superieure de Chimie de Rennes, FranceNade`ge Lubin-Germain, University of Cergy-Pontoise, FranceJun Luo, Tongji School of Pharmacy, Huazhong University of Scienceand technology, Wuhan, P. R. China

Carine Maalaki, Universite de Namur, BelgiumJean-Maurice Mallet, Ecole Normale Superieure, Paris, France

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Alberto Marra, Ecole Nationale Superieure de Chimie de Montpellier,France

Olivier Massinon, Universite de Namur, BelgiumAurelie Mathieu, CNRS, Gif-sur-Yvette, FranceYong Miao, Universite Lille Nord de France, FranceJean-Claude Michalski, Universite Lille Nord de France, FranceValerie Molinier, Universite Lille Nord de France, FrancePierre Monsan, Universite de Toulouse, FranceAndre Mortreux, Universite Lille Nord de France, FranceMagali Nicollo, SiamedXpress, Gardanne, FranceFrancesco Nicotra, Universita degli Studi di Milano-Bicocca, ItalyStephanie Norsikian, CNRS, Gif-sur-Yvette, FranceCaroline Nugier-Chauvin, Ecole Nationale Superieure de Chimie deRennes, France

Jean-Marc Nuzillard, Universite de Reims Champagne-Ardenne, FranceBjorn Palitzsch, Johannes Gutenberg-Universitat Mainz, GermanyNadia Pellegrini-Mose, Universite de Lorraine, Nancy, FranceMichel Philippe, LOreal Research & Innovation, Aulnay-sous-Bois,France

Patrick Pichaud, LOreal Research & Innovation, Aulnay-sous-Bois,France

Loc Pichavant, Universite de Reims Champagne Ardenne, FranceDaniel Plusquellec, Ecole Nationale Superieure de Chimie de Rennes,France

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

Yvan Portier, Ecole Nationale Superieure de Chimie de Rennes, FranceGwladys Pourceau, Universite de Picardie Jules Verne, Amiens, FranceMagali Remaud-Simeon, Universite de Toulouse, FranceMyle`ne Richard, Universite de Lorraine, Nancy, FranceCatherine Robbe-Masselot, Universite Lille Nord de France, FranceMaria C. Rodrguez, Center for Biomolecular Chemistry, Havana, CubaCatherine Ronin, SiamedXpress, Gardanne, FranceLaura Russo, Universita degli Studi di Milano-Bicocca, ItalyRam Sagar, Universite de Poitiers, FranceMathieu Sauthier, Universite Lille Nord de France, FranceMarie-Christine Scherrmann, Universite Paris-Sud, Orsay, FranceAntonella Sgambato, Universita degli Studi di Milano-Bicocca, ItalyJean-Francois Soule, CNRS, Gif-sur-Yvette, FranceArnaud Stevenin, CNRS, Gif-sur-Yvette, FranceIsabelle Suisse, Universite Lille Nord de France, FranceSylvestre Toumieux, Universite de Picardie Jules Verne, Amiens, FranceSylvain Tranchimand, Ecole Nationale Superieure de Chimie de Rennes,France

Simon Trouille, LOreal Research & Innovation, Aulnay-sous-Bois, FranceDominique Urban, Universite Paris-Sud, Orsay, FranceYury Valdes Balbin, Center for Biomolecular Chemistry, Havana, CubaBoris Vauzeilles, Universite Paris-Sud, Orsay, and CNRS, Gif-sur-Yvette,France

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Vicente Verez Bencomo, Center for Biomolecular Chemistry, Havana,Cuba

Stephane P. Vincent, Universite de Namur, BelgiumAnne Wadouachi, Universite de Picardie Jules Verne, Amiens, FranceQian Wan, Tongji School of Pharmacy, Huazhong University of Scienceand technology, Wuhan, P. R. China

Amandine Xolin, CNRS, Gif-sur-Yvette, FranceRui Xu, Universite de Lyon, FrancePhilippe Zinck, Universite Lille Nord de France, France

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If you buy this title on standing order, you will be given FREE accessto the chapters online. Please contact sales@rsc.org with proof ofpurchase to arrange access to be set up.

Thank you.

ISBN: 978-1-84973-965-8ISSN: 0306-0713DOI: 10.1039/9781849739986

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

& The Royal Society of Chemistry 2014

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PrefaceDOI: 10.1039/9781849739986-FP009

Volume 40 of the Specialist Periodical Reports entitled CarbohydrateChemistry Chemical and Biological Approaches is dedicated to thememory of Prof. Andre Lubineau. This chemist, well known amongstorganic, carbohydrate, and green chemists for his work, left behind himnot only his innovative work applied in industry and recognized for itsexcellence and uniqueness, but also many, many friends among hiscolleagues and students. His former Ph.D. student, Dr. Yves Queneau,had the initiative to dedicate this volume to his memory and is verywelcome as guest editor.The first book chapter describes the industrial development of

Lubineaus C-glycosylation reaction to access a product for skin anti-ageing marketed by LOreals, a leading company in cosmetics. Theprinciples of green chemistry concerning water-promoted reactions suchas cycloaddition, N-glycosylation and C-glycosyl compound formation,implemented by Andre Lubineau, are well documented in Chapter 2.The use of carbohydrates in sustainable chemistry is highlighted inChapter 3, exemplifying Andre Lubineaus contributions in this field withvarious applications, namely carbohydrates as surfactants. In Chapter 4,synthesis and properties of sugar-based hydrotropes are revised. Thesecompounds exhibit amphiphilicity and can be regarded as weaksurfactants, being considered promising alternatives to the currentlyused hydrotropes from petroleum origin. Chapter 5 shows how greencatalysis can be used in carbohydrate etherification.A diversity of synthetic strategies are described in Chapters 610,

focusing particularly on anomeric functionalization, either using exo-glycals or glycosylation catalysed with iron salts or by gold, supplementedby electrochemical or enzymatic (thio)glycosylation.Recent protocols for the synthesis of anionic oligosaccharides, that

exhibit interesting biological activities in cell proliferation, angiogenesisand cancer, host-pathogen interactions, Alzheimers disease and plantprotection are presented in Chapter 11. Synthesis of macrocycles fromsucrose with interesting complexing properties, of carbohydrate-baseddendrimers, and of polymers via radical free polymerization startingfrom allyl or vinyl pentosides, or by organo-catalysed polymerization ofpolyester-functionalized carbohydrates, is covered by Chapters 1215.This volume illustrates the importance of glycochemistry for the pro-

duction of biomolecular entities that are innovative regarding structureand usefulness. Covering from simple sugars to polymeric structures andto glyco-conjugated biomolecules, this volume also demonstrates theimportance of glyco-structures and technology for innovation inmolecular glycobiology and health. Glycolipid liquid crystals are revisedin Chapter 16 giving a particular attention to their self-assemblingproperties, while Chapter 17 shows how glycolipid-containing nano-systems can be applied for novel nanotherapeutic strategies based on

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drug/gene delivery systems or on adjuvants for vaccine applications. Alsoa new approach to describe furanose ring conformational dynamics isrevealed, based on inherent ring motions rather than arbitrarilyrestrictive descriptors, which is better able to describe unsymmetricalconformations that are lost by pseudo-rotational analysis (Chapter 18).In Chapter 19, glycofuranosyl-containing conjugates are reviewed asmolecular tools for understanding enzyme activity as well as relatedbiochemical pathways. Chapters 20 and 21 include conformationallyrestricted glycosides as inhibitors of sugar-processing enzymes and re-ceptors, as well as anion receptors having their binding pocket modifiedwith monosaccharides. It was shown how incorporation of a sugar intothe backbone of a host molecule aects structural and binding propertiesof anion receptors.Therapeutic glycoprotein hormone gonadotropins and anti-cancer

multivalent constructs are documented in Chapters 22 and 23, respect-ively, while the field of carbohydrate-based vaccines is covered in the nextthree chapters, focusing on anti-cancer vaccines (Chapters 24 and 25),and antibacterial and antifungal vaccines (Chapter 26).Chapters on the role of mucins and mucin glycosylation in bacterial

adhesion (Chapter 27), and on bioengineering of glucansucrases(Chapter 28) complete the collection of topics assembled in this volume.The described achievements in glycochemistry and glycobiology

demonstrate the importance of the glycosciences for innovation in healthand in the corresponding societal challenges facing us. More than that,they show the charisma of Andre Lubineau as a scientist, and as acolleague and a friend. Those who had the privilege of working orcollaborating with him confirmed, through their contributions in thisvolume, their devotion to his memory.As editors of the Specialist Periodical Reports: Carbohydrate

Chemistry Chemical and Biological Approaches, we are very honored todedicate this book to the memory of Andre Lubineau.

Amelia P. Rauter, Thisbe K. Lindhorstand Yves Queneau

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Andre Lubineau: a life dedicated tocarbohydrate chemistryYves Queneau,a,b,c Jacques Auge,d Gerard Descotesb andDavid Bonnaffee

DOI: 10.1039/9781849739986-FP011

The aim of this volume 40 of Carbohydrate Chemistry, Chemical andBiological Approaches is to illustrate how wide is the scope of carbohydratechemistry, from synthetic methodology to chemical biology, and toacknowledge Professor Lubineaus contributions to the field.

Andre Lubineau was born on June 12, 1943 in Paris. He wassoon interested by chemistry and entered the well-known EcoleNationale Superieure de Chimie de Paris. After his diploma in 1966, hewas appointed as an assistant teacher in the university of Paris-Sud,Orsay where he concomitantly pursued doctoral studies in the fieldof nucleosides, under the guidance of Professor Serge David, a greatfigure of carbohydrate chemistry who has passed away last year(19212013). After having graduated as Docteur e`s Sciences in 1973,

aINSA Lyon, ICBMS, Bat J. Verne, 69621 Villeurbanne Cedex, France.E-mail: yves.queneau@insa-lyon.fr

bInstitut de Chimie et de Biochimie Moleculaires et Supramoleculaires,UMR 5246;CNRS, Universite de Lyon; Universite Lyon 1; INSA-Lyon; CPE-Lyon; Bat. Curien,43 Bd du 11 Novembre 1918, F 69622 Villeurbanne, France.E-mail: descotes@dbmail.com

cDepartment of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UKdUniversity of Cergy-Pontoise, 5 mail Gay-Lussac, Neuville-sur-Oise, 95031Cergy-Pontoise, France. E-mail: jacques.auge@u-cergy.fr

eInstitut de Chimie Moleculaire et des Materiaux dOrsay, UMR 8182, LabExLERMIT, Bat. 420, Universite Paris-Sud, 91405 Orsay Cedex, France.E-mail: david.bonnae@u-psud.fr

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Andre Lubineau together with Serge David then embraced a new field inthe laboratory, i.e. the exploration of hetero Diels-Alder reaction as a newtool to build dihydropyrans. Successfully applied to the formation ofdisaccharides starting from a monosaccharide dienyl ether, this strategywas a breakthrough in asymmetric cycloadditions in which the chiralinduction was brought by a chiral diene. They developed this method tobuild the D-galacto unit of the antigenic blood groups, such as the Atrisaccharide, on the gram scale. This was the beginning of a long storyconcerning the synthesis of oligosaccharides of biological interest,in close collaboration with Professor Ten Feizi, at Harrow Hospital,England.In 1979, interested in widening his knowledge in new methodologies

and total synthesis, Andre Lubineaus joined for one year the group ofProfessor Barry M. Trost in Madison, Wisconsin. After returning to Orsayand being appointed as Assistant Professor then Full Professor, he star-ted his research on the use of water as solvent for cycloadditions. Hesucceeded rapidly in this field and was able to propose a new paradigm,i.e. all reactions with a negative activation volume should be prone to beaccelerated in water. Confirmed in the case of other reactions such asaldolisation, Michael and Baylis-Hillman reactions, the acceleration wasdemonstrated to originate mainly from an entropic eect. Though greenmethodologies were at that time not as fashionable as they are today, healso showed strong interest for carbohydrate-based synthons andchemicals.In the mid 1980s, Andre Lubineau and his team joined a mixed

academic-industrial consortium which evolved from an initialcollaboration between the University of Lyon and the sugar companyBeghin-Say under the auspices of the CNRS. This consortium gatheredcarbohydrate chemists located in the universities of Bordeaux, Clermont-Ferrand, Grenoble, Lille, Lyon, Orsay and Poitiers, as well as industrialresearchers specialised in chemical and biotechnological sugar processes.It was also at this time that, in a friendly and stimulating thematiccommunity including groups such as those of L. Hough and F. W.Lichtenthaler, the meetings Carbohydrates as organic Raw Materialson innovative processes (ultrasound, microwaves, electrochemistry,enzymes. . .) and industrial applications (detergents, emulsifiers, polymers,food additives. . .) took place in Darmstadt, Lyon, Wageningen and Vienna.The presence of Andre Lubineau with his exceptional experience and hiscontagious positive spirit was precious to these meetings and to thecollaborative work achieved within the French consortium. Andres per-manent joviality and friendly availability impressed all colleagues duringthis 10-year collaboration. We associate all former members of this group,notably their founders and friends of Andres: Alain Bouchu, JacquesDefaye, Alain Deeux, Bernard Fournet, Jacques Gelas, Claude Lamy, JulioMentech, Andre Mortreux, Serge Perez and Bernard Thiriet.From this time, while also deeply involved in projects related to

biological applications, Andre Lubineau never stopped being interestedin the industrial side of glycochemistry. Actually, for both types ofprojects, he followed the same strategy, always looking for solutions to

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problems, not for problems to solutions, always asking: is this new, isthis useful?The chemoenzymatic approaches Serge David and Andre Lubineau de-

veloped with Claudine Auge and Christine Le Narvor are perfectillustrations of the way he conceived challenges in organic synthesis, es-pecially for the total syntheses of bioactive oligosaccharides: use chem-istry when it is the most ecient route and enzymes when they do the jobbetter. If no clear option was obvious, both methods were explored con-vinced that the answers would be precious to future generation of gly-cochemists. This even led to a contest in the lab for determining the mostecient access to sialic acid, either by extraction from edible swallowsnests, (enjoyed by Andre who was a gourmet), or by aldolisation of N-acetyl-D-mannosamine using sialylaldolase. At that time, extracting sucientamounts of glycosyltransferases for the synthesis of an oligosaccharide onthe multi-milligram chemist scale was a tedious and time consumingwork. Together with the late Andre Verbert, Andre Lubineau met thechallenge and promoted an interdisciplinary consortium on RecombinantGlycosylTransferases (the GTREC) and within few years, recombinant a-2,6- and a-2,3-sialyltransferases and a-1,3/4-fucosyltransferase were avail-able in Orsay, giving the group a decisive advantage in the synthesis ofLewis type antigens at the origin of seminal discoveries in the field toge-ther with Ten Feizi. In the selectin domain, thanks to his chemists eyewhich considered a sulphate group mimicking the carboxylate moiety ofsialic acid, he foresaw that the sulphated versions of the Lewis antigensidentified by glycobiologists were not artefacts and demonstrated, throughunambiguous total synthesis, that 30-sulfo-Lewis was the most potent lig-and of E-Selectin known at that time.From sulphated Lewis antigens to glycosaminoglycans (GAG), the path

may seem straightforward. However, addressing the challenge of GAGsmolecular diversity was like finding a needle in a haystack, and for AndreLubineau, the answer should arise from modern developments in or-ganic synthesis. At that time, combinatorial synthesis was rising andAndre was among the first ones to think about applying this strategy fordesigning complex oligosaccharides. Twenty years later, this paradigmhas been well established although much work remains to be done: thisoers good reasons to follow Andre Lubineaus determination to inventnew chemistries able to oer solutions to the exciting challenges faced bycarbohydrate chemists.In addition to his scientific legacy, Andre Lubineau will be remem-

bered as a charismatic pedagogue and a demanding and rewardingmentor by his students. Always pushing them to widen their scientificculture while continuingly digging deeper into their field to reach thebest possible level once they fly with their own wings, encouraging themto take risks as he always did throughout his life.

Acknowledgements

We are extremely grateful to the Specialist Periodic Reports Board and tothe Editors of the series Carbohydrate Chemistry, Professor Amelia P. Rauter

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and Thisbe K. Lindhorst, for their kind invitation to elaborate thisbook dedicated to the memory of Professor Lubineau. We thank allthe authors who have contributed to this volume, and we also associatein this tribute all other Andres former friends, colleagues and studentswho could not join on this occasion.

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CONTENTS

Cover

Tetrahydropyran-enclosed ball-and-stick depiction of a glucosemolecule, and (in the background)part of an a-glycosyl-(1-4)-D-glucoseoligosaccharide and a glycosidase, allrepresentative of the topics coveredin Carbohydrate Chemistry Chemicaland Biological Approaches.Cover prepared by R. G. dos Santos.

Preface ix

Amelia P. Rauter, Thisbe K. Lindhorst and Yves Queneau

Andre Lubineau: a life dedicated to carbohydrate chemistry xi

Yves Queneau, Jacques Auge, Gerard Descotes and David BonnaeAcknowledgements xiii

C-glycosylation invented by Pr Lubineaus team: a key-reaction forinnovation in cosmetics

1

Michel Philippe, Alexandre Cavezza, Patrick Pichaud, Simon Trouilleand Maria Dalko-Csiba

1 Introduction 12 Eco-design of new biomimetic carbohydrates:

fundamental interest of Lubineaus C-glycosylationreaction

2

3 Synthesis of new eco-designed C-glycosylderivatives

3

4 Biological activities of synthesized C-glycosyl derivatives:major interest of a C-b-xylosyl compound

7

5 From a biomimetic approach to an industrialdevelopment of a new eco-friendly active ingredient incosmetics

7

Acknowledgements 8References 9

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Lubineaus green synthons 11

Jacques Auge and Nade`ge Lubin-Germain1 Introduction 112 Hetero Diels Alder reactions as a new tool to build

dihydropyrans12

3 Glycosylamines 174 The Lubineau reaction: a new access to C-glycosyl

derivatives22

5 Conclusion 26References 26

How the polarity of carbohydrates can be used in chemistry 31

Rui Xu and Yves Queneau1 Introduction 312 Water solubility assistance for reactions in aqueous

media32

3 Carbohydrate-water mixtures as solvents for organicreactions

37

4 Polarity as a targeted property in functional biobasedmolecules

41

5 Conclusion 47Acknowledgements 47References 47

Sugar-based hydrotropes: preparation, properties andapplications

51

Valerie Molinier and Jean-Marie Aubry1 Hydrotropes 512 Sugar-based hydrotropes 543 Physico-chemical properties of sugar-based hydrotropes 604 Conclusion 69References 69

From conventional to greener catalytic approaches forcarbohydrates etherification

73

Mathieu Sauthier, Andre Mortreux and Isabelle Suisse1 Introduction 732 Stoichiometric use of alkyl halides The Williamson

reaction74

3 Salt free catalyzed alkylation reactions 774 Conclusion 93Acknowledgements 94References 94

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Exo-glycals as useful tools for anomeric functionalization ofsugars

99

Nadia Pellegrini-Mose, Myle`ne Richard and Yves Chapleur1 Introduction 992 Functionalization of exo-glycal double bond 1003 Addition reactions on the exo-glycal double bond 1054 Conclusions 113Abbreviations 113Acknowledgement 114References 114

Recent results in synthetic glycochemistry with iron salts atOrsay-Gif

118

Jean-Marie Beau, Yann Bourdreux, Franois-Didier Boyer, StephanieNorsikian, Dominique Urban, Gilles Doisneau, Boris Vauzeilles,Alexandra Gouasmat, Aurelie Lemetais, Aurelie Mathieu,Jean-Franois Soule, Arnaud Stevenin and Amandine Xolin

1 Introduction 1182 Brief historical background including Andre Lubineaus

contribution119

3 Iron(III) chloride hexahydrate-promoted cascadecyclization to bioactive dihydropyrans

121

4 Tandem catalysis with iron(III) chloride hexahydrate 1275 Direct synthesis of b-D-N-acetyl glucosamine motifs using

catalytic iron(III) triflate131

Conclusion 136References 136

Recent advances in gold-catalyzed glycosylation 140

Jun Luo and Qian Wan1 Introduction 1402 Gold(III)-catalyzed glycosylation 1403 Gold(I)-catalyzed glycosylation 1484 Gold-catalyzed glycosylation in natural product

synthesis157

5 Conclusions 157Acknowledgments 158References 158

Electrochemical glycosylation 160

Alberto Marra and Marie-Christine Scherrmann1 Introduction 1602 Electrooxidative glycosylation 160

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3 Electroreductive glycosylation 1744 Conclusion 175References 175

Enzymatic thioglycosylation: current knowledge and challenges 178

Laure Guillotin, Pierre Lafite and Richard Daniellou1 S-glycosyltransferases 1782 Glycoside Hydrolases to thioglycoligases:

A mechanism-based evolution of natural enzymes182

3 Conclusions & perspectives 191References 192

Anionic oligosaccharides: synthesis and applications 195

Eric Grand, Jose Kovensky, Gwladys Pourceau, Sylvestre Toumieuxand Anne Wadouachi

1 Introduction 1952 Synthesis 1963 Polysaccharide depolymerisation 2214 Applications 2235 Concluding remarks 228Abbreviations 229References 230

Sucrose as chiral platform in the synthesis of macrocyclicreceptors

236

S!awomir Jarosz, Mykhaylo A. Potopnyk and Micha! Kowalski1 Introduction 2362 Synthesis of sucrose based precursors by selective

modification at primary positions238

3 Synthesis and properties of sucrose basedmacrocycles

243

4 Complexation studies 2525 Conclusion 253Acknowledgments 254References 254

Carbohydrate-based dendrimers 257

Laure LHaridon and Jean-Maurice Mallet1 Introduction 2572 Assembling full carbohydrate dendrimer by glycosylation 2583 Assembling full carbohydrate dendrimer by amide

coupling261

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4 Click type approaches for assembling fullcarbohydrate dendrimer

263

5 Conclusion 267References 267

Reactivity of allyl and vinyl pentosides in photo-initiated donor-acceptor copolymerization

270

Loc Pichavant, Dominique Harakat, Celine Guillermain andXavier Coqueret

1 Introduction 2702 State-of-art for carbohydrate-based monomers 2713 Homopolymerization and copolymerization of

vinyl and allyl ethers275

4 Donor-acceptor copolymerization of allyl and vinylpentosides

278

5 Conclusion 2936 Perspectives 294Acknowledgements 294References 294

Polyester functionalized carbohydrates via organocatalyzed ring-opening polymerization

298

Yong Miao, Andre Mortreux and Philippe Zinck1 Introduction 2982 Polyesters functionalized mono-, di- and

tri-saccharides via organocatalyzed ring-openingpolymerization

300

3 Polyesters functionalized cyclodextrins (CD) viaorganocatalyzed ring-opening polymerization

302

4 Polyesters functionalized polysaccharides viaorganocatalyzed ring-opening polymerization

305

5 Conclusion 308References 309

Liquid crystal glycolipids 312

John Goodby, Stephen Cowling, Edward Davis and Yves Queneau1 Introduction 3122 Lamellar phases 3163 Hexagonal (columnar) phases 3254 Cubic phases micellar and bicontinuous 3325 Complex systems 3336 Conclusion 337Acknowledgements 338References 338

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Glycolipid-based nanosystems for the delivery of drugs,genes and vaccine adjuvant applications

341

Thierry Benvegnu, Loc Lemie`gre, Caroline Ballet, Yvan Portier andDaniel Plusquellec

1 Introduction 3412 Glycolipid-based drug delivery nanosystems 3443 Glycolipid-based gene delivery nanosystems 3594 Glycolipid-based adjuvants for vaccine

nanosystems367

5 Conclusion 372Abbreviations 373References 374

Ring dihedral Principal Component Analysis of furanoseconformation

378

Claire Coier, Chantal Barberot, Jean-Marc Nuzillard, PeterGoekjian, Eric Henon and Arnaud Haudrechy

1 Introduction 3782 The Altona model: scope and limitations 3803 Results for static quantum mechanics investigations

of C-xylosyl compounds382

4 Results for classical and quantum molecular dynamicsinvestigations for b-D-xylosyl derivatives

385

5 Dihedral PCA on the five endocyclic angles of thedihydroxylated b-D-xylosyl derivatives: an orientation tableto fully explore the conformational landscape

388

6 Conclusions and perspectives 394Computational details 395Acknowledgements 397References 398

How recent knowledge on furano-specific enzymes hasrenewed interest for the synthesis of glycofuranosyl-containingconjugates

401

Vincent Ferrie`res, Caroline Nugier-Chauvin, Laurent Legentil andSylvain Tranchimand

1 Introduction 4012 Furanosyl conjugates and mutases 4023 Furanosyl conjugates and transferases and

polymerases405

4 Glycofuranoside hydrolases as green biocatalysts for thesynthesis of furanosides

411

5 Conclusion 413References 413

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Conformationally restricted glycoside derivatives asmechanistic probes and/or inhibitors of sugar processing enzymesand receptors

418

Carine Maaliki, Charles Gauthier, Olivier Massinon, Ram Sagar,Stephane P. Vincent and Yves Bleriot

1 Introduction 4182 Conformationally restricted sugar analogues targeting

glycosidases419

3 Constrained glycosides as conformational probes fornon-hydrolytic biochemical processes

429

4 Conclusions 437References 438

Sugar decorated receptors for chiral anions 445

Jaros!aw M. Granda and Janusz Jurczak1 Introduction 4452 Monosaccharides in anion binding 4483 Sugar decorated anion receptors in chiral recognition 4534 Conclusion 458Acknowledgements 459References 459

Carbohydrate-targeted optimization of therapeutic gonadotropins 461

Sandrine Donadio-Andrei, Nassima El Ma, Magali Nicollo andCatherine Ronin

1 Introduction 4612 Physiology of gonadotropins 4613 Structure of gonadotropins 4634 Therapeutic use of gonadotropins 4685 Bioactivity of gonadotropins 4716 Engineering recombinant gonadotropins 4747 Conclusions 483References 484

Multivalent glycidic constructs toward anti-cancer therapeutics 491

Francesco Nicotra, Luca Gabrielli, Davide Bini, Laura Russo,Antonella Sgambato and Laura Cipolla

1 Carbohydrate-based anticancer therapeutics: generalconsiderations

491

2 Multivalent glycidic constructs 4933 Glyco-nanotools for cancer therapy 4974 Conclusion 502References 503

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Tumour-associated glycopeptide antigens and their modificationin anticancer vaccines

506

Sebastian Hartmann, Bjorn Palitzsch, Markus Glag and Horst Kunz1 Introduction 5062 Synthesis of glycosyl amino acid building blocks 5073 Solid-phase syntheses of tumour-associated mucin

glycopeptide antigens512

4 Fully synthetic two- and three-component glycopeptidevaccines

517

5 Vaccines obtained by conjugation of glycopeptideantigens to carrier proteins

522

6 Conclusion 529References 530

Development of cancer vaccines from fully synthetic mucin-basedglycopeptide antigens. A vision on mucins from the bioorganicchemistry perspective

533

Alberto Fernandez-Tejada and Samuel J. Danishefsky1 Introduction 5332 Synthetic strategies for the preparation of mucin-related

glycopeptide vaccines535

3 Synthesis and evaluation of antigen clusters as mucinmimics for glycopeptide-based cancer vaccines

540

4 Conclusion 560References 560

Antibacterial and antifungal vaccines based on syntheticoligosaccharides

564

Yury Valdes Balbin, Maria C. Rodrguez and Vicente Verez Bencomo1 Introduction 5642 Bacterial meningitis and pneumonia 5653 Diarrheal disease 5784 Hospital-acquired infections 5815 Fungal disease 5856 Mycobacterium tuberculosis 5867 Borrelia burgdorferi 5888 Concluding remarks 588References 588

Epithelial mucins and bacterial adhesion 596

Florent Colomb, Catherine Robbe-Masselot, Sophie Groux-Degroote,Julie Bouckaert, Philippe Delannoy and Jean-Claude Michalski

1 Introduction 596

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2 Structure of epithelial mucin O-glycans 5963 Biosynthesis of epithelial mucin O-glycan chains 5994 Tissue and physio-pathological specific glycosylation

repertoire of mucins608

5 Role of mucin glycans in bacterial adhesion 6096 Conclusion 615Abbreviations 616Acknowledgement 616References 616

Successes in engineering glucansucrases to enhanceglycodiversification

624

David Daude, Isabelle Andre, Pierre Monsan andMagali Remaud-Simeon

1 Introduction 6252 Random approach for glucansucrase overproduction or

engineering631

3 Structure-based engineering of glucansucrases 6354 Screening methods applied to detect novel or improved

glucansucrases639

5 Prospects 640References 641

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C-glycosylation invented by Pr Lubineausteam: a key-reaction for innovation incosmeticsMichel Philippe,* Alexandre Cavezza, Patrick Pichaud,Simon Trouille and Maria Dalko-CsibaDOI: 10.1039/9781849739986-00001

The aim of this chapter is to provide a brief description of why and how the ResearchGroup of LOreal, a leading company in cosmetics, has developed on an industrial scalethe C-glycosylation reaction invented by Pr. Lubineaus team. This first example of in-dustrial development in the world comes from the compliance of this technology with theprinciples of green chemistry and the access to original structures of high interest for skinanti-ageing. From various C-6 and C-5 saccharides, original C-glycosyl derivatives weresynthesized for evaluating their potential role as activators of the biosynthesis of glyco-sylaminoglycans, polysaccharides that are essential to maintain the mechanical propertiesof skin. A b-C-xylosyl derivative combined the highest activity in vitro with confirmationin vivo. This eco-designed compound was developed using the calculation of green in-dicators and further marketed under the name of Pro-Xylanet.

1 Introduction

Carbohydrates are of fundamental importance to human skin. For in-stance, proteoglycans (PGs) and glycosaminoglycans (GAGs) are pivotal indermal matrix structure that embeds and sustains collagen fibers net-work.1 A decrease in the content of GAGs has been linked to changes inthe mechanical properties of human skin with ageing and aged skincontains less GAGs than young skin.2 GAGs also play a basic role instructural arrangement of water supply at a molecular level, in celladhesion and in signalling through their ability to interact with cells,growth factors and cytokines at both dermal and epidermal levels. Themajor way to maintain dermal matrix structure during ageing or torestore its functions following alteration is to stimulate GAGs synthesis.As a consequence, the discovery of a new class of molecules active on thestimulation of GAGs biosynthesis was a key-objective in the field of anti-ageing formulae. In most GAGs found in human skin, xylose is anessential carbohydrate unit. It is involved in their biosynthesis and intheir linking to a protein core via a b-O-glycoside bond between xyloseand the hydroxyl group of a specific serine amino acid of protein core toform PGs (Fig. 1 and Fig. 2).Here, we report a brief description of the work of LOreals Research

group in the eco-design of a new class of activators of GAGs biosynthesisbased on xylose and close carbohydrate units.3

LOreal Research & Innovation, 1, Avenue Eugene Schueller, 93600 Aulnay-sous-Bois,France. E-mail: mphilippe@rd.loreal.com

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c The Royal Society of Chemistry 2014

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2 Eco-design of new biomimetic carbohydrates:fundamental interest of Lubineaus C-glycosylationreaction

For several years, the LOreal Research group has been implementingaction plans for sustainable innovation, and has been reporting pro-gresses of these actions annually.4 Among these actions, the commitmentto green chemistry plays an essential role with respect of the greenchemistry principles5 based on the following fundamental pillars:

Use of renewable raw materials from plants. Development of eco-friendly processes. Launching of new ingredients with very low environmental impact.In order to respect and deepen our commitment of eco-design, we have

also set up green indicators:

Atom economy6 evaluation. E-Factor7 for the evaluation of amount of waste generated by the

processes. Rate of renewable carbon. Environmental risk assessment according to European guidelines.8

To ensure ecient energy, the use of processes which show too highenergy demand was avoided such as:

Temperature o15 1C or W150 1C DurationW10 h

Fig. 1 Example of structure of PG.

OOHO

OH

NH

O

OO

Fig. 2 Bond between xylose and serine in PG.

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In compliance with this strong commitment, the known interest ofC-glycosyl derivatives as carbohydrates biomimetics9 and the discovery ofa new process of C-glycosylation invented by Pr. Lubineau and his team10

(Scheme 1) were instrumental in such strategy.The new process, contrarily to other processes known to synthesize

C-glycosyl compounds,11 is in perfect agreement with green chemistryprinciples, notably avoiding the use of protecting groups and toxic re-agents and solvents. It proceeds10 via a Knoevenagels reaction betweenactivated methylene and a naked aldose followed by a Michael-typeintramolecular addition and a retro-Claisen aldol condensation leadingto the b-C-glycosyl anomer (Scheme 2). The yield of the pure anomer breinforced our interest in this reaction in complete agreement with thebiomimetic approach.

3 Synthesis of new eco-designed C-glycosyl derivatives

In order to study the potential of this reaction in our research for GAGsbiosynthesis activators, various C-glycosyl derivatives were synthesizedfrom dierent carbohydrate units and b-diketones as described inScheme 3.Table 1 shows that the nature of the sugar has an impact on the re-

action yield with, for instance, a limited interest for arabinose as com-pared to xylose, illustrating the importance of the stereochemistry.Moreover, the choice of activated methylenes is also restrictive since onlythe b-diketone with a simple methyl residue (2,4-pentanedione) givesquantitative yields.In our hands, malonates, malonamide, malononitrile, Meldrums acid,

hexafluoroacetylaceton, 1,3-indanedione, ethyl cyanoacetate also failed tolead to C-glycosyl products. However, collaborating with Pr. Lubineausteam,12 we succeeded in replacing the 2,4-pentanedione by diketonesbearing long alkyl chains as described in Scheme 4, but without quan-titative yields.End-products with a C8 chain (total chain with n= 5) in particular are

obtained with 75% yields from D-glucose and 65% from D-maltose. Asdepicted in Scheme 4, the diketonic reagent should necessarily besymmetric to avoid the concomitant synthesis of a mixture of C-glycosylketones of various chain lengths, inevitable with asymmetrical diketones.Moreover, the synthesis of the C-maltosyl products clearly points out thatthese disaccharides also show reactive in the Lubineaus reaction.

OR3

HO

R1

OHR2

HOO

R3HO

R1

R2

HO

O

CH3

NaHCO3H2O

90CH3C

O O

CH3+

glucose: R1 = H, R2 = OH, R3 = H

mannose: R1 = OH, R2 = H, R3 = H

cellobiose: R1 = H, R2 = OH, R3 = -D-glucose

Scheme 1 The Lubineau reaction.

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OHO

HO OHOH

HOOH

HOHO

OH

HO

O

CH3

H3C

O

O

H3C

+

NaHCO3H2O

90C

OH

O CH3Na+ ONa

HOHO

OH

HO

O

CH3

O CH3H2O

OHO

HO

OH

HO

O

CH3

O CH3Na+ OHO

HO

OH

HO

O

CH3

OH-

- CH3COONa

H

Scheme 2

4|Carbohyd

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,40,1

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:

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/

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1

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In order to increase the yield of the respective C-glycosyl compounds,the conditions (nature of the base, time, temperature, solvent) of thereaction were modified. Xylose was chosen as a model carbohydrate(Scheme 5), due to its potential interest in the activation of GAGs bio-synthesis, as seen before.

n

O OH

OHR R

O O

n

O R

OOH

ONaR

O

+

1-13n = 0,1

+

Scheme 3

Table 1 Influence of the sugar and/or the diketone on the yield of the C-glycosylproducts.

C-glyc. Starting sugar R Yield %

1 D-glucose Me 100a

2 D-xylose Me 87a

3 D-lactose Me 79a

4 D-galactose Me 98a

5 D-fucose Me 92a

6 D-arabinose Me 40a

7 3-deoxy-D-arabinose Me 59a

8 D-glucose Ph 58a

9 L-fucose Ph 12a

10 D-xylose Ph 6a

11 D-glucose 4-OBn-Ph 37b

12 D-glucose 4-OMe-Ph 52c

13 D-glucose 4-OH-Ph 34c

Solvent: awater; bdioxane/H2O;cEtOH/H2O.

OR

HO OHOH

HOO

RHO

OH

HO

O

(CH2)nCH3

NaHCO3H2O

90 C

(CH2)nCH3

O

O

(CH2)nCH3

+

glucose: R = H

maltose: R = -D-glucose

n = 0 to 8

Scheme 4 Amphiphilic C-glycosyl compounds.

O OO OH

OH

OH OH

O

OH

OH OH

O

+

2 D-Xylose

Scheme 5

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The nature of the base also has a very significant eect on the yield andon the reaction time as shown in Table 2. We confirmed on the modelreaction using the 2,4-pentanedione that NaOH is the ablest base toquantitatively yield the b-C-xylosyl product with a decreasing reactiontime at a lower temperature (50 1C).To allow further structure-activity relationships studies, we chose to

enhance the structural diversity of this new class of C-glycosyl derivativesby subjecting the keto C-glycosyl compound to further transformations.For this objective, the reduced products 1420 (mixture of diastereo-isomers obtained, see list in Table 3) were synthesized after treatmentwith aqueous sodium borohydride for the first batch at a laboratoryscale.13

In order to respect the principles of green chemistry and avoid complexprocedure to remove borate salts, a catalytic hydrogenation was de-veloped. Accordingly, Ru/C was used as catalyst as described in Scheme 6on a model reaction based on the reduction of the keto C-xylose14 thenconfirming that the reduced C-xylosyl compound 18 is a 50/50 diaste-reoisomer mixture.

Table 2 Eect of the base on the model reaction depicted in Scheme 6.

Entry Base Yield Time Temp.

A NaHCO3 87% 18h 90 1CB NaHCO3 Mixture 1h 90 1CC LiOH 56% 18h 90 1CD NaOH 88% 18h 90 1CE NaOH 90% 1h 90 1CF NaOH 97% 45min 50 1C

Table 3 Reduction products of the keto C-glycosyl derivatives by reaction with NaBH4.

Compound Starting sugar R Yield %

14 D-glucose Me 8815 D-fucose Me 6516 D-arabinose Me 9017 D-lactose Me 6518 D-xylose Me 9819 L-fucose Me 8620 D-glucose 4-OMe-Ph 100

CH3O

OCH3

O OH

HO OHOH

HO OHOH

O

O CH3

HO OHOH

O

HO CH3

+H2O

D-xylose

Lubineau

reaction

Ru/C

18

Scheme 6

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4 Biological activities of synthesized C-glycosylderivatives: major interest of a C-b-xylosyl compound

The interest of synthesized C-glycosyl derivatives as potential activatorsof the biosynthesis of GAGs was evaluated using human fibroblastcultures and assessed by the incorporation of the D-[6-H3]-glucosaminewithin the GAG fraction.15 The main results, reported in Table 4, highlightthe better activity of compound 18.This evaluation confirms the interest of xylose unit in the biosynthesis

of GAGs.16 It also confirms that the C-xylosyl structure and the reductionof the exocyclic ketone are essential to obtain the best results. Moreover,further studies gave evidence that the b anomer was crucial to maintainactivity, as compared to the a anomer.

5 From a biomimetic approach to an industrialdevelopment of a new eco-friendly active ingredient incosmetics

These results show the interest of our approach based upon biomimicryand green chemistry to select a new active ingredient of high perform-ance in skin anti-ageing strategy. Compound 18 selected as the best ac-tivator of the biosynthesis of GAGs in vitro, was further confirmed alsovery active in vivo in a clinical trial when topically applied. Introduced incosmetic skin care products,17 it has been marketed under the tradename Pro-Xylanet.

Table 4 Activity of C-glycosyl derivatives on the D-(6-H3)-glucosamine incorporation inthe GAG fraction by human fibroblasts (P evaluates the reproducibility of the results).

Compound [C] % P

None 100 Transforming Growth Factor-b(TGF-b) (positive control)

10 ng/mL 348 o0.01

Xylose 0.5 mM 52 o0.010.1 mM 85 W0.050.02 mM 106 W0.05

Lyxose 2.0 mM 86 W0.050.4 mM 102 W0.050.08 mM 90 W0.05

Compound 2 10.0 mM 161 o0.012.0 mM 141 o0.010.4 mM 110 W0.05

Compound 4 10.0 mM 99 W0.053.0 mM 119 W0.051.0 mM 136 o0.01

Compound 18 3.0 mM 218 o0.011.0 mM 169 o0.010.3 mM 139 W0.05

Compound 10 1.0 mM 95 W0.050.3 mM 102 W0.050.1 mM 120 W0.05

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This active ingredient respects the green chemistry principlesincluding:

Sustainable origin of D-xylose from beech trees originating fromrenewable forest certified by Forest Stewardship Council. A two-step process in water using Lubineaus C-glycosylation and a

catalytic hydrogenation (Scheme 6). This new process avoids activationsteps used in previously described syntheses.18

Low environmental impact of Pro-Xylanet since not ecotoxic.The calculation of green indicators based on Pro-Xylanet validated thisrespect of green chemistry principles (see Fig. 3). For example, we tookinto account the amount of water used in the reaction for the calculationof the E-Factor.This compound is the first example of green chemical described in

cosmetics, LOreal being the first company to develop a C-glycosyl de-rivative originating from Lubineaus reaction at an industrial scale.In summary, the successful launch of a new ingredient of high per-

formance counter-acting skin ageing stresses the high interest of theLubineaus reaction for green innovation and new green building blocks.For such, illustrative examples are given in the literature.19

Acknowledgements

We dedicate this chapter to the memory of Professor Lubineau. We thankPr. Lubineaus team for their essential contribution to the elaboration ofthe C-glycosylation reaction in water. Special thanks to all LOreal par-ticipants, being from Research or Industry for their valuable contribution.

Fig. 3 Pro-Xylanet: green chemistry ingredient.

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References

1 (a) Y. Nomura, Connective Tissue Research, 2006, 47, 249; and (b) J. M.Trowbridge and R. L. Gallo, Glycobiology, 2002, 12, 117R.

2 B. Vuillermoz, Y. Wegrowski, J. L. Contet-Audonneau, L. Danoux, G. Paulyand F. X. Maquart, Mol. Cell. Biochem., 2005, 277, 63.

3 (a) A. Cavezza, C. Boulle, A. Gueguiniat, P. Pichaud, S. Trouille, L. Ricardand M. Dalko-Csiba, Bioorg. Med. Chem. Lett., 2009, 19, 845; (b) M. Philippe,B. Didillon and L. Gilbert, Green Chem., 2012, 14, 952; (c) WO Pat., 2002/051828, 2002; (d) Eur. Pat., 1589010, 2005; and (e) WO Pat., 2002/051803,2002.

4 http://www.loreal.com/Article.aspx?topcode=CorpTopic_Comt_DevDur_Innovation_CAPI

5 (a) P. T. Anastas and J. C. Warner, Green Chemistry, Theory and Pratice, OxfordUniversity Press, New York, 1998, 3; and (b) P. T. Anastas and J. B.Zimmerman, Environ. Sci. Technol., 2003, 37, 94A.

6 B. M. Trost, Science, 1991, 254, 1471.7 R. A. Sheldon, Chem. Ind., London, 1992, 903.8 ECHA Guidance on information requirements and chemical safety assess-

ment Chapter R.11: PBT Assessment May 2008. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_r11_en.pdf?vers= 20_08_08.

9 (a) D. Specker and V. Wittmann, Top. Curr. Chem., 2007, 267, 65; and (b) P.Compain and O. R. Martin, Bioorg. Med. Chem., 2001, 9, 3077.

10 F. Rodrigues, Y. Canac and A. Lubineau, Chem. Commun., 2000,2049.

11 D. E. Levy, The Organic Chemistry of Sugars, CRC Press LLC, 2006, 269.12 (a) Y. Hersant, R. Abou-Jneid, Y. Canac, A. Lubineau, M. Philippe, D. Semeria,

X. Radisson and M-C. Scherrmann, Carbohydr. Res., 2004, 339, 741; and(b) M. Philippe, D. Semeria, WO Pat., 2002/051803, 2002.

13 General procedure: the C-glycosyl compound (1equiv) was allowed to reactwith NaBH4 (1.2 equiv) in ethanol. After 12h, the reaction mixture wasquenched with aqueous HCl (1N), and the aqueous phase was extracted withbutanol. The organic phase was dried and concentrated in vacuo, to aordthe compound. The structure of the C-glycosyl compounds was confirmed byNMR and mass spectroscopy.

14 A. A. Wismeijer, A. P. G. Kieboom and H. Van Bekkum, React. Kinet. Catal.Lett., 1985, 29, 311.

15 General experiment procedures : Normal human dermal fibroblast (NHDF)monolayers were cultured in control medium with or without TGF-b (10ng/ml)or compounds X-Y for 72 hours at 37 1C in humid atmosphere of 95% air and5% CO2 and labeled with 35S- sulfur during the final 24 hours. The GAGfraction was isolated from both the medium and the fibroblast layer (solubleand insoluble GAGs) and purified by anion exchange chromatography. 35S-radioactivity incorporated into the GAGs was then measured. Experimentaltested doses were selected as maximal non toxic doses.

16 (a) C. Gotting, J. Kuhn, R. Zahn, T. Brinkmann and K. Kleesiek, J. Mol. Biol.,2000, 304, 517; and (b) A. Lindblom, G. Bengtsson-Olivecrona and L. A.Fransson, The Biochemical Journal, 1991, 279, 821.

17 (a) G. Cassin, J.-T. Simonnet, L. Thiebaut, WO Patent 7,020,536, 2007; (b) S.Jitsukawa and K. Hara, Fragrance Journal, 2006, 34, 35; and (c) M. Dalko, L.Breton, WO Patent 2,051, 828, 2002.

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18 (a) J. Prandi, C. Audin and J.-M. Beau, Tetrahedron Lett., 1991, 32, 769; (b) USPat., 4454123, 1984; P. Allevi, M. Anastasia, P. Cinreda, A. Fiecchi and A.Scala, J. Chem. Soc., Chem. Commun., 1987, 101; and (c) C. Leteux and A.Veyrie`res, J. Chem. Soc.Perkin Trans, 1994, 1, 2647.

19 P. M. Foley, A. Phimphachanh, E. S. Beach, J. B. Zimmerman and P. T.Anastas, Green Chem., 2011, 13, 321.

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Lubineaus green synthonsJacques Auge* and Nade`ge Lubin-GermainDOI: 10.1039/9781849739986-00011

Some seminal contributions of Professor Lubineau in the field of water-promotedreactions and glycochemistry are reviewed. Notably, three types of synthons, namelya-hydroxy-g-lactones, glycosylamines and C-glycosyl compounds, can be regarded asnew tools in the hands of chemists or biochemists involved in green chemistry,bioconjugate chemistry, glycochemistry or glycobiology, as evidenced by theirapplications in many dierent fields.

1 Introduction

Organic synthesis using carbohydrates was the main thread of ProfessorLubineau works. His researches went from mechanistic and syntheticadvances in organic and glycochemistry up to interaction studies inglycobiology. His contribution in cycloaddition reactions used as a newway to produce mono- and oligosaccharides led him to initiate the firstasymmetric inductions by a grafted sugar.1 After noting an analogybetween glucose and water structures, he highlighted the uniquephysicochemical properties of water and pioneered organic reactions inwater.2 Among the salient features in that field, we must cite theconvenient preparation in water of three green synthons, namelya-hydroxy-g-lactones, glycosylamines and C-glycosyl derivatives (Fig. 1).The greenness of these synthons, at least for two of them, was not

noticed by Lubineau when he has developed their synthesis, since greenchemistry was not yet the concept defined as the utilisation of a set ofprinciples that reduces and eliminates the use of hazardous substancesin the design, manufacture and application of chemical products.Today, modern chemical synthesis should be based upon the twelvegreen chemistry principles.3 The use of renewable materials such ascarbohydrates, which constitute 75% of the vegetal biomass is one of thetwelve principles. The atom economy is another salient feature since thisconcept highlights the importance of the incorporation of all the atoms;for a total synthesis it means that protection and deprotection ofcarbohydrates should be avoided; if not, the global atom economydramatically decreases. This situation is worse when considering theglobal reaction mass eciency and the global material economy.4 Thesemetrics are proportional to the atom economy; the coecient ofproportionality depends on the yields, the excesses of reactants, the useof auxiliaries, such as solvents which participate greatly to the waste. As amatter of fact, the prevention of waste is the principle number 1 of greenchemistry. The importance of such prevention was emphasized as soonas 1992 by Sheldon through the promotion of the E-factor defined as the

University of Cergy-Pontoise, 5 mail Gay-Lussac, Neuville-sur-Oise, 95031Cergy-Pontoise, France. E-mail: jacques.auge@u-cergy.fr

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ratio between the mass of the total waste and the mass of the finalproduct. Indeed the global material economy (GME), named by analogywith the global atom economy, and defined as the ratio between the massof the final product and the mass of the inputs is correlated to theE-factor by the following relationship: GME=1/(E 1).This chapter shows that the pioneering work of Lubineau in

glycochemistry has also embraced green chemistry whereas this field wasstill in its infancy. The common point between the three Lubineau greensynthons which were largely used and cited in the literature, is theirstraightforward accessibility avoiding a lot of tedious steps and thuspreventing side-products and waste.

2 Hetero Diels Alder reactions as a new tool to builddihydropyrans

2.1 From an innovative strategy of oligosaccharide synthesis to agreen conceptThe hetero Diels-Alder reaction (HDAR) using carbonyl compounds hasbeen extensively studied by David and Lubineau in the aim to obtainfunctionalized dihydropyrans and the subsequent carbohydrates. Due tothe relative low reactivity of carbonyl compounds in this reaction, it isnecessary to activate the carbonyl group or to work under thermalconditions. Using a buta-1,3-dienyl ether grafted to a sugar, a 97/3facial selectivity with respect to diene was obtained in the cycloadditionwith (-)-menthylglyoxylate (Scheme 1). Unfortunately, no endoselectivity(endo/exo = 52/48) was observed. However, after acidic treatment andpurification, pure dihydropyran with a-D configuration was obtained in43% yield, allowing an ecient synthesis of the epitope of the bloodgroup antigen A.5

In 1980, Breslow showed that water as solvent enhanced both the rateand the endo selectivity in the Diels-Alder reaction.6 Such a seminaldiscovery prompted Lubineau to investigate HDAR but also numerousother reactions in water. By grafting a sugar to a diene at the anomericposition,7 Lubineau solved two problems. First, the reactants were nowentirely soluble in water since this was considered as a prerequisite atthat time. Actually Grieco devised a water-soluble diene synthesis using acarboxylate group as the hydrophilic part.8 Second the carbohydrate partcould be easily removed by enzymatic hydrolysis.A major contribution of Lubineau in water-promoted organic reactions

was the pioneering work concerning the acceleration of aldolisation

OO

OH

Glyoxylic acid

-hydroxy--lactone

ONH2

Free sugar

HO

one step one step one step

O

O

HO

glycosylamine C-glycosyl compounds

Free sugar

Fig. 1

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reactions (Scheme 2) as a result of their negative volume of activation.9

Stereoselectivity was reversed in water aording syn adducts as the majorisomers. This main feature was attributed to the fact that syn transitionstate occupies a smaller volume than the anti one.In order to prove the origin of the reactivity in water for reactions with

negative volume of activation, Lubineau measured the thermodynamicactivation parameters of a Diels-Alder reaction (Scheme 3) as a model of areaction with high negative volume of activation (DV6= 30 cm3 mol1).The whole acceleration comes from a favorable change of entropy, showingclearly the implication of the hydrophobic eect.10 In the cycloadditionbetween cyclopentadiene and methyl vinyl ketone, the acceleration inwater is mainly caused by destabilisation of the initial state relative to theorganic solvent.11 The slight stabilisation of the transition state whichwas observed results from enforced hydrophobic interactions, the termenforced being used by Engberts to distinguish the hydrophobicbonding of the reactants during the activation process from hydrophobicinteractions not dictated by the activation process.12

Following these mechanistic studies, Lubineau was clearly convincedthat it was not necessary to work with compounds having a goodsolubility in aqueous phase. As the soluble reactants molecules disappearto give the product, new molecules go again through the solution.

OSiMe3

+ PhCHO

O OH

Ph+

O OH

Ph

syn anti

Scheme 2

OO

OOPh

OBnOAll

O

MO2C

re face

Osugar

MO2C

facial selectivity: 97/3

60 C

M = (-)-menthyl

16 h

99%

Scheme 1

+

O

COMeendo

COMe

exo

+

G

activation parameters (kJ.mol1) at 25 C

8089.8

3838

4251.8

watermethanol

HS

Scheme 3

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In order to minimize unfavourable hydrophobic interactions, the organicmolecules enter into clathrates of the network of water molecules. Thisphenomenon induces a driving force leading to a higher reactivity of theorganic molecules so that clathrates can be considered as nanoreactors.With the necessity to develop a greener chemistry, organic reactions in

or on water are now well studied and used for a number of industrialapplications.13

There is a paradox with hetero Diels Alder reactions. In water thecarbonyl group of the dienophile is mostly under the hydrate form,making the cycloaddition dicult, owing to the relatively low concen-tration of the reactive form of the carbonyl group. However dierentcarbonyl compounds were tested with success by Lubineau, such aspyruvic acid, pyruvaldehyde and glyoxal (Scheme 4).14

Using butyl glyoxylate as the dienophile a new strategy to prepare3-deoxy-D-manno-2-octulosonic acid (KDO), 2-deoxy-KDO and thioglyco-side of KDO has even been proposed, starting from a diene derived fromD-glyceraldehyde.15

The HDAR was also studied on reactive dienes such as cyclopenta-diene. In spite of the propensity of cyclopentadiene to dimerise, itsreactivity with carbonyl compounds was observed in water. The capacityof water to accelerate the hetero cycloaddition was sucient compared tothe rate of the dimerisation in these conditions. As mentioned recently byChisholm,16 the cycloaddition of cyclopentadiene with aldehydes areuncommon, but can be observed in water.

2.2 a-Hydroxy-c-lactones: synthesis in water and applications2.2.1 Glyoxylic acid as dienophile. Glyoxylic acid as dienophile was

first investigated by Lubineau in 1991. In the presence of cyclopentadieneand glyoxylic acid at 40 1C, a mixture of two a-hydroxy-g-lactones wereobtained (Scheme 5).17 In fact, in a first step, the cycloadducts were formedand they rearranged in situ to give the lactones in a 73/27 ratio. The two-steps transformation could be observed by TLC since adducts and lactonesgave coloured spots on the TLC plate. The major lactone arising froman endo transition state could be isolated in a pure form by crystallisationin ether, the minor lactone remaining in the mother liquor. The structureof the lactones was ascertained by 2D-NMR experiments.

The same transformation was observed starting from cyclohexadieneand glyoxylic acid. Transient 2-oxabicyclooctene carbocyclic acids arisingfrom HDAR rearranged in situ to give the corresponding lactones. Incontrast the HDAR with cyclohexadiene and butyl glyoxylate gavecycloadducts, which could be isolated. The rearrangement of the endoand exo acids required high temperature.18

O

H

O

R

R = H or Me

+O

O

R

cis/trans = 1/1

H2O

Scheme 4

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The concept of water as solvent, the synthesis and the spectroscopicanalysis were then proposed to students by submitting the experiment tothe Journal of Chemical Education in 1998.19

As postulated by Lubineau, the adducts resulting from a [4 2]cycloaddition were able to rearrange leading to the lactones (Scheme 5).However the HDAR is often competitive with the ene reaction and insome cases, it has been reported that the adducts could result from sucha reaction.20 Prins reaction could also be considered in this process sincelactones could be obtained from alkenes21 but it seems improbable inwater as depicted in Scheme 5.

The duality between the dienophilic and the enophilic character of theglyoxylic acid is well known and could be partially managed by the use ofwater soluble Lewis acids.19,22 In this field, significant contributions haveto be underlined. Dierent Lewis acids (CuSO4, Cu(NO3)2, Yb(OTf)3,Nd(OTf)3) were able to control the mechanism and to catalyze the HDARwith cyclopentadiene and with other less reactive dienes.14,23 Finally, therole of the pH should be mentioned. The best results have been obtainedunder strongly acidic conditions for the synthesis of the lactones, at pH0.9 of the commercial aqueous solution of glyoxylic acid. With alkenessensitive in acidic conditions, it was however necessary to use a highervalue of pH.24

2.2.2 Optically pure a-hydroxy-c-lactones. The a-hydroxy-g-lactonesobtained by Lubineau were racemic mixtures; many groups have workedin the aim to develop an asymmetric version of the synthesis or to de-velop ecient methods for their resolution. Most of the time, the syn-theses used the enzymatic resolution described by Roberts in 1994.25

Thus a-hydroxy-g-lactones could be resolved by an enantioselectiveacetylation using Candida cylindracea lipase or Pseudomonas Fluorescenslipase. In a large scale (W2 kg), the enzymatic hydrolysis of the racemicbutyrate ester was preferred because the reaction is faster and leads to apurer compound with a best yield (Scheme 6).

It can be noted that another enzymatic resolution has been describedon the diol 1 (Scheme 7) resulting from the reduction of the lactone.26

O

COOH

OO

HDAR

Ene-reaction

O

COOH

Prins reacton

H

O

COOH

H OH

COOH

H2OOH

COOH

OH

O

O O H

H+

OH

O

O H

H+

H

H

OH

endo

Scheme 5

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Concerning the asymmetric approach, Jorgensen has published aseries of articles dealing with the use of copper(II) bisoxazoline asasymmetric catalyst of the HDAR27 and the ene-reaction28 with glyoxylateesters. In the presence of cyclopentadiene, ethyl glyoxylate led with a highendoselectivity to a single cycloadduct with an ee of 60% (72% yield). Therearrangement was induced by the alkaline hydrolysis of the compoundand the (-)-a-hydroxy-g-lactone was finally obtained with an ee of 99.5%after recrystallisation. This method appeared superior to the enzymaticresolution because of the complete endoselectivity.

Finally, the a-hydroxy-g-lactones could be obtained optically pure, byesterification with acetyllactyl chloride and the resulting acetyllactylderivatives were separated.29 Recently, a kinetic resolution of the a-hydroxy-g-lactones has been described by Shiina,30 using an asymmetricacyl-transfert catalyst ((R)-BTM) in the presence of an acetylating agent.

OH

H

O

racemic racemic

lipase (Amano PS)OH

OH

H

O

OCOC3H7

OH

H

O

OH

phosphate buffer

ee > 99%

Scheme 6

OO

OH

OO

OHR

R

HOO

OH

Pd

Hon43

avenaciolide

Aggarwal44

polyoxin C

OOH

OH Roberts32b : (+)-BrefeldinA

DIBAL-H

OHOH

Olivo41 ()- homoCarbovir

LiAlH4 OHOH

OH

OH

OH

Rhee36

(1S, 2R)-guanineanalogues

Fourrey39

carba DNA

1

2

34

Roberts36Mevinic acid

O

O

OH

HO

O

ON

N

N

N

NH2

ClOMeO

O

O

HOOH

O

HO

N

N

N

N

NH2

HN

HO

Carba nucleosides

Rhee37

()carbaguanine

N

N

N

NNH2

HO HO Toyota38

(+/)-epinor-BCA

N

N

N

NHHO

O

NH2

Roberts35

()-carbovir

OTMD

PN O CN

HO

OH

N N

NO

t-Bu

Grieco40

(+ /)-sesbanimide A

NH

O O

OH

O

O

HOHOOC

HO

N

OH

NHH2N

O

OO

O

O

R

Scheme 7

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Moreover, the importance of the lactones as key building blocks justifythe research of new asymmetric synthesis. For example, we can notice theapproach of Helmchen.31 He has showed that the lactones could beobtained using an asymmetric palladium-catalyzed allylic substitutionwith acetoxymalonate.

2.2.3 a-Hydroxy-c-lactones as building blocks. a-Hydroxy-g-lactonesconstitute very attractive multipurpose synthons that have been used asstarting materials for several syntheses of natural products. Dierentstrategies have been used for these syntheses involving either the re-duction of the lactone moiety or the modification of the cyclopentenepart (Scheme 7).

Roberts was greatly involved in the use of optically pure a-hydroxy-g-lactones as building blocks in the synthesis of natural products. Forexample, he obtained the brefeldin A by a partial reduction of the lactoneinto the diol 2.32 After an extensive study of the reactivity of thebutyrolactones,33 he has undertaken the complete reduction of thelactones leading to the triol 3, then to the diol 4 after oxidative cleavageand reduction. The diol constitutes the point of divergence for thesynthesis of a part of the mevinic acid34 and for the synthesis of carba-nucleosides, such as carbovir.35 Leading this strategy, others groups havedescribed the synthesis of dierent carbanucleosides (carbaribavirin,36

carbaguanine,37 epinor-BCA).38 Fourrey has extended this methodology tothe synthesis of carbocyclic DNA.39 Moreover, starting from the inter-mediate triol 3, Grieco has described an access to the ( ) sesbanimide Aand B.40 Olivo has described in the same time the synthesis of homocarbonucleosides from the diol 1, following a dierent strategy.41 Anotherreactivity related to the carbonyl function of the lactones has beenpublished and allowed to obtain tricyclic oxygen heterocycles in thepresence of SmI2 after the opening of the lactone.

42

The opening of the cyclopentene moiety involved the ozonolysis of thedouble bond and this has been used by Hon for the synthesis of alkenylbutyrolactones.43 This cyclopentene cycle could also be used for thepalladium-catalyzed nucleophilic substitution of the C-4 of the fusedlactones. By this strategy, Aggarwal described an access to carbocyclicuracil polyoxin C and the nikkomycins analogues.44

3 Glycosylamines

3.1 Green access to glycosylaminesLubineau et al. has proposed an improved synthesis of glycosylaminesobtained directly from the reducing sugars.45 This method allowed toavoid the use of protected sugars, their activation, the formation ofglycosyl azides and their reduction under palladium catalysis. Anotherclassical synthesis of N-acylglycosylamines went through the previousformation of glycosylthiocyanates prepared by reaction of silver orammonium thiocyanate with glycosyl halides, which was tedious,hazardous, reactant-consuming and waste-producing. Even the novelroutes to glycosylamines using an acid-catalysed rearrangement of

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glycosyl trichloroacetimidates46 or the use of Burgess reagent47 suerfrom multiple protection/deprotection steps.It means that the straightforward synthesis of glycosylamines brings

about a maximal atom economy and a minimal production of waste,which are pre-requisite for green chemistry. This strategy was basedon the methodology introduced by Kochetkov for the synthesis ofaminoacids and applied to various mono- and disaccharides.48 TheKochetkov protocol required a large quantity of ammonium hydrogencarbonate which was a major drawback since the elimination of the saltturned out to be problematic. In the Lubineau protocol 0.2 M ammoniumhydrogen carbonate (and not a saturated solution) and 0.2 M reducingsugar was added to an aqueous 16 M ammonia. After 36 h at 42 1C, thereaction mixture was evaporated to the third of the initial volumeand then freeze-dried yielding quantitatively the correspondingglycosylamine (Scheme 8).Due to the recent and huge interest to use renewable feedstocks, such

a reaction was revisited for a more rapid reaction under microwaves.49

Since the new conditions required DMSO as the solvent, Richel et al.concluded that the microwave route does not compete with the greenerprotocol developed by Lubineau.50

A new and interesting protocol was recently introduced by Likhosherstovusing ammonium carbamate instead of ammonium hydrogenocarbonateas the reactant.51 The method was successfully applied by Imperiali forthe amination of chitobiose carried out with ammonium carbamate(4 equiv) in methanol for 24 h at 37 1C (Scheme 9).52

Glycosylamines could easily undergo hydrolysis in water solution atroom temperature overnight or in water solution with addition of a fewdrops of 1 M acetic acid.53 They were prone to Amadori rearrangement,i.e. the conversion of N-glycosyl aldoses into the corresponding N-glycosylketoses. Under aqueous ammonia conditions, carbohydrates gave at least

O

OHHO

HO

OH

OHO

OHHO

HO

OH

NH2

NH3

H2O NH3

t > 50CO

OHHO

HO

OH

HN O

OH

HOOH

OH

NH4+ HCO3

- H2O

O

OHHO

HO

OH

HN

O

O- NH4+

Scheme 8

O

NHAcHO

O

OH

OHNH3

O

NHAc

HOHO

OHNH4CO2NH2

CO2O

NHAcHO

O

OH

NH2

O

NHAcHOHO

OH

chitobiose

Scheme 9

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15 components, owing to epimerisations, rearrangements, degradationsand condensations.54 These features prompted Lubineau group to studycarefully the synthesis and physicochemical properties of glycosylamines,in order to optimize the experimental conditions leading to themaximum yield in the shortest time and the smallest amount of reagents.The formation of glycosylamines was monitored by analysing the

anomeric region of the 13C NMR spectrum of the medium. The anomericcarbon of glucose gave two signals at 96.05 (b) and 92.23 (a) ppm,whereas D-glucosylamine could be identified by its C-1 resonance at85.19 ppm (b). The anomeric carbon of D-glucosylcarbamate anddi-D-glucosylamine at 83.21 (b) and 88.17 (b) ppm, respectively, could bedetected in some cases. The formation of di-D-glucosylamine could beobviated by performing the reaction at moderate temperature (o50 1C)when using D-glucose at a concentration o0.5 M. The formation ofD-glucosylcarbamate was a consequence of the presence of ammoniumhydrogen carbonate. When performing the reaction at 42 1C with 0.2 MD-glucose, the amount of D-glucosylcarbamate progressively increasedfrom 17 to 100% when the ammonium hydrogen carbonate increasedfrom 1 to 7 M. The equilibrium between D-glucosylamine andD-glucosylcarbamate was rapid at 42 1C and could be totally shifted byevaporation, lyophilisation or dilution (Scheme 8).Using the same methodology, a kinetic study of the synthesis of

glucopyranuronosylamine was performed in order to get the optimalconditions for acylation in aqueous conditions.55

A library of 50 glycosylamines has been prepared directly from the cor-responding unprotected mono- and oligosaccharides.56 These unprotectedglycosylamines are used as intermediates in the synthesis of a number ofglycoconjugates such as surfactants, glycopeptides or glycopolymers.

3.2 Reactivity and applications of glycosylaminesSince glycosylamines are highly reactive it is important to find the bestconditions to trap them immediately after their formation. In order to getstable glycosylamides, glycosylamines are opposed to electrophiles, suchas acyl chlorides, anhydrides or other activated acids.It is worth to note that classical methods of condensation of protected

glycosylamines with aminoacids use coupling reagents, such asN,N0-dicyclohexylcarbodiimide (DCC) or 2-ethoxy-N-(ethoxycarbonyl)-1,2-dihydroquinoline (EEDQ).As a model to test the nucleophilicity of glycosylamines, pre-

formed D-glucosylamine was opposed to acetic anhydride at 0 1C toaord N-acetyl-b-D-glucosylamine, which was further acetylated (Ac2O,CH3COONa, 100 1C) to yield the crystalline peracetylated D-glucosylamine(78% from glucose, reaction scaled up to 100 g of D-glucose). Thiscompound turned out to be an excellent booster for detergency.57

Independently of reactivity towards activated acids, esters, carbamatesthat we develop through the following examples, the pre-formedglycosylamines can add to Michael adducts.58 On the other hand,glycosylamine derived from N-acetylglucosamine, can be acylated byenzymatic b-aspartylation.59

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3.2.1 Glycosurfactants. Alkylpolyglucosides (APG) are biodegradabledetergents, industrially produced from renewable feedstocks. Theopportunity to trap lipophilic acyl chlorides or anhydrides by pre-formedglycosylamines to create new amphiphilic compounds was investigatedby Lubineau (Scheme 10).

Two methods were published.45 The best one required an excess ofglycosylamine, which is cheaper than the acyl chloride. More interestingin terms of green chemistry, this method allowed to avoid a chromato-graphic step for the isolation of N-acylglycosylamine, which could berecovered in the aqueous phase after the extraction of theproduct. The reaction occurred at 0 1C in a mixture of ethanol and water.The purification of the glycosylamides was carried out after extractionand crystallisation from ethanol. The yield in N-octanoyl-, N-decanoyl-,N-lauryl- and N-myristoyl-b-D-glucopyranosylamine was approximativelyequal to 40%. Amphiphilic properties of N-acylglycosylamine surfactantswere determined for comparison with those of APG. The critical micelleconcentration (CMC) of N-octanoyl-b-D-glucosylamine, N-octanoyl-b-D-maltosylamine and N-decanoyl-b-D-maltosylamine were found to be equalto 40, 51 and 4.1 mM respectively, whereas the same authors using thesame method (colorimetry with Coomassie Brilliant blue G) have found avalue of 17 mM for the CMC of octyl-b-D-glucoside.

3.2.2 Glycoaminoacids. Carbohydrates can be coupled to