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These Lanthionine FINALE FACULTÉ DES SCIENCES – DÉPARTEMENT DE CHIMIE CENTRE DE RECHERCHES DU CYCLOTRON SYNTHESIS AND BIOLOGICAL STUDIES OF LANTHIONINE DERIVATIVES Promoteur: Professeur André LUXEN Dissertation présentée par Thibaut DENOËL pour l’obtention du grade de Docteur en Sciences Année académique 2013 - 2014 Membres du Jury : Promoteur : Professeur André Luxen (Université de Liège) Président : Professeur Albert Demonceau (Université de Liège) Autres membres : Docteur Didier Blanot (Université Paris-Sud) Docteur David Thonon (Uteron Pharma) Professeur Bernard Joris (Université de Liège) Docteur Christian Lemaire (Université de Liège) Remerciements Les travaux présentés dans cette thèse ont été réalisés sous la direction du Professeur André Luxen dans les laboratoires du Centre de Recherches du Cyclotron de l’Université de Liège. Je voudrais tout d’abord remercier le Professeur André Luxen pour son accueil au sein du Cyclotron, sa grande patience et son exigence. Il a aussi inspiré nombre de manipulations et m’a guidé dans mes recherches. En outre, il a mis à ma disposition tout le matériel et la quantité de produits chimiques nécessaires à la réalisation de ce travail. Je tiens également à remercier Messieurs les membres du Jury pour m’avoir fait l’honneur d’accepter d’examiner ce travail, en l’occurrence le Docteur Didier Blanot (Université Paris-Sud), le Docteur David Thonon (Uteron Pharma), le Professeur Bernard Joris, le Docteur Christian Lemaire et le Professeur Albert Demonceau dans le rôle de Président. Je remercie aussi les Docteurs Didier Blanot et Mireille Hervé pour la réalisation des essais in vitro avec l’enzyme Mpl et l’aide dans les publications. Je remercie grandement le Docteur Astrid Zervosen pour la réalisation des manipulations biochimiques, ses conseils, sa disponibilité et la correction lors de la rédaction. Tous mes remerciements vont aussi au Docteur Christian Lemaire pour la relecture fastidieuse des manuscrits et les moments partagés. Enfin, je suis très reconnaissant au Professeur Albert Demonceau pour les nombreuses discussions et conseils judicieux prodigués tout au long de mon cursus. Je remercie également Thomas Gerards pour les centrifugations, le Docteur Gabriel Mazzucchelli et ses collègues du GIGA MSL pour les mesures HRMS, Christian Damblon et les membres du CREMAN pour la RMN, Guillermo Zaragozza pour la diffraction des rayons X, Eric Zigler pour la relecture de l’anglais de l’article Tetrahedron et Vedran Hasimbegovic pour l’aide apportée à la correction de l’anglais des publications. Je n’oublie pas mes collègues et amis : Alain, André B., Annick, Audrey, Brigitte, Caro, Cécile, Corentin, David G., David T., Eve, Fabrice, Fred Me., Fred Mi., Geoffroy, Jean, Jérôme, Jessica, Julien, Justine, Lionel, Louis, Ludo, Marlies, Mathias, Mathurin, Muhammad, Nathalie, Nico, Steve, Sylvestre, Vincent et tous les membres du Cyclotron. Enfin, pour leur soutien et leurs encouragements durant toutes ces années, je tiens à exprimer ma reconnaissance aux membres de ma famille, maman, papa, Clément, Louis, Mélanie, Philippe, Roseline. List of abbreviations [] specific rotation Abu 2-aminobutyric acid A2pm diaminopimelic acid Ac acetyl Acm acetamidomethyl ADDP 1,1 ′-(azodicarbonyl)dipiperidine AD-mix α reagent for asymmetric dihydroxylation (Sharpless) AG50-X8 strongly acidic cation exchange resin Ala alanine Alloc allyloxycarbonyl allo -Thr allo -threonine ATP adenosine triphosphate β-Me-Lan β-methyl-lanthionine BDP benzotriazol-1-yl diethyl phosphate Bn benzyl Boc tert -butoxycarbonyl (Boc) 2O di-tert -butyl dicarbonate Burgess reagent methyl N-(triethylammoniumsulfonyl)carbamate br broad C18 column reversed phase column with octadecyl carbon chain bonded silica CAN ceric ammonium nitrate Cbz benzyloxycarbonyl CC column chromatography Chiralcel OD-H chiral stationary phase for liquid chromatography Chirasil-Val chiral stationary phase for gas chromatography COSY correlation spectroscopy Cys cysteine dansyl 5-(dimethylamino)naphthalene-1-sulfonyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene d doublet DCC 1,3-dicyclohexylcarbodiimide DCE dichloroethane de diastereomeric excess DEAD diethylazodicarboxylate Dha dehydroalanine Dhb dehydrobutyrine DiPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMEDA N,N’-dimethylethylenediamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DNs dinitrobenzenesulfonyl EA elemental analysis E. coli W7 Escherichia coli strain auxotrophic for A2pm and for Lys EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess eq equivalents ES+ positive ion electrospray ionisation ES- negative ion electrospray ionisation ESI electrospray ionization Fmoc 9-fluorenylmethoxycarbonyl FT-ICR-MS Fourier transform ion cyclotron resonance mass spectrometry GlcNAc N-acetylglucosamine Glu glutamic acid HMBC heteronuclear multiple bond correlation spectroscopy HOBt 1-hydroxybenzotriazole HSQC heteronuclear single quantum correlation spectroscopy HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HP-20 polyaromatic adsorbent resin for hydrophobic compounds HPLC high performance liquid chromatography HRMS high resolution mass spectrometry i-Pr isopropyl ivDde 2-isovaleryldimedone J coupling constant KO t-Bu potassium tert -butoxide Lan lanthionine Lipid I undecaprenyl diphosphate-MurNAc-pentapeptide Lipid II undecaprenyl diphosphate-(MurNAc-pentapeptide)-GlcNAc lit. literature reference LPS lipopolysaccharides Lys lysine m multiplet MeLan β-methyllanthionine mesylate methanesulfonate mp melting point Mpl murein peptide ligase MPLC medium pressure liquid chromatography MppA murein peptide permease A MS mass spectrometry Ms methanesulfonyl MurNAc N-acetylmuramic acid NBD 7-nitro-2,1,3-benzoxadiazol-4-yl NMM N-methylmorpholine NMP N-methylpyrrolidone NMR nuclear magnetic resonance nor -Lan norlanthionine OPA/NAC o-phthaldehyde/ N-Ac-(R)-cysteine Opp oligopeptide permease OSu oxysuccinimide PBP penicillin-binding protein PDA photodiode array Pd/C palladium on carbon PG peptidoglycan PMB para -methoxybenzyl pNB para -nitrobenzyl pNZ para -nitrobenzyloxycarbonyl PTC phase transfer catalys(is/t) PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate q quartet Rf retention factor RP18 column C18 column rt room temperature s singlet SDS sodium dodecyl sulfate Ser serine SIL G/UV254 standard silica TLC plates with UV indicator SN2 bimolecular nucleophilic substitution SPPS solid phase peptide synthesis t triplet TBAB tetra-n-butylammonium bromide TBAF tetra-n-butylammonium fluoride TBAHS tetra-n-butylammonium hydrogensulfate t-Bu tert -butyl Tce 2,2,2-trichloroethyl Teoc β-(trimethylsilyl)ethoxycarbonyl TES triethylsilane TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol TFFH fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate THF tetrahydrofuran TIS triisopropylsilane TLC thin layer chromatography TMS trimethylsilyl TMSE trimethylsilylethyl tosyl p-toluene sulfonyl Tr trityl tR retention time Tris trishydroxymethylaminomethane Triton B benzyltrimethylammonium hydroxide Trityl triphenylmethyl Troc 2,2,2-trichloroethoxycarbonyl UDP uridine diphosphate UMP uridine monophosphate UV ultraviolet Weinreb amide N,O-dimethylhydroxyamide Z Cbz Contents Chapter 1 Introduction 1.1 General introduction .............................................................................................. 3 1.2 Peptidoglycan biosynthesis in Escherichia coli .................................................... 4 1.3 meso -Diaminopimelic acid replacement .............................................................. 6 1.4 Inhibitors of peptidoglycan biosynthesis .............................................................. 7 1.5 Labeling biomolecules ........................................................................................ 11 1.6 Objective.............................................................................................................. 13 Chapter 2 Bibliography 2.1 Background ......................................................................................................... 19 2.2 Chemical synthesis of unprotected lanthionines .............................................. 22 2.3 Chemical synthesis of protected lanthionines .................................................. 30 2.4 Applications ......................................................................................................... 56 Chapter 3 Stereoselective synthesis of lanthionine derivatives in aqueous solution and their incorporation into the peptidogly can of Escherichia coli 3.1 Introduction ......................................................................................................... 71 3.2 Results and discussion ...................................................................................... 73 3.3 Conclusion ........................................................................................................... 84 3.4 Experimental section .......................................................................................... 84 3.5 Biological experiments ....................................................................................... 91 Ch apter 4 Synthesis of protected α -alkyl lanthionine derivatives 4.1 Introduction ......................................................................................................... 99 4.2 Results and discussion .................................................................................... 100 4.3 Conclusion ........................................................................................................
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