Mild, aqueous α-arylation of ketones : towards new diversification tools for halogenated metabolites and drug molecules

The authors thank the European Research Council (FP7/2007-2013/ERC grant agreement no 614779 to RJMG) and (FP7 2009-2014/ERC agreement no 227817 to SPN) for generous funding.The palladium-catalyzed aqueous α-arylation of ketones was developed and tested for a large variety of reaction partners. These mild conditions enabled the coupling of aryl/ alkyl-ketones with N-protected halotryptophans, heterocyclic haloarenes, and challenging base-sensitive compounds. The synthetic potential of this new methodology for the diversification of complex bioactive molecules was exemplified by derivatising prochlorperazine. The methodology is mild, aqueous and flexible, representing a means of functionalizing a wide range of halo-aromatics and therefore has the potential to be extended to complex molecule diversification.PostprintPeer reviewe

New organometallic methods for the creation of C-S bond in complex systems

Résumé: Le travail rapporté dans cette thèse concerne le développement de nouvelles réactions organométalliques pour la création de liaisons C-S dans des systèmes complexes.Dans Le premier chapitre, nous rapportons une méthode originale de bioconjugation de peptides et protéines dans l'eau à température ambiante. La méthode a été appliquée avec succès à la bioconjugation de l'anticorp Trastuzumab.Le deuxième chapitre est consacré à l'étude de la réactivité des alpha ou béta thiosucres dans le couplage de Buchwald-Hartwig-Mitiga avec différent partenaires électrophiles.Dans un premier sous chapitre, nous rapportons une réaction inattendue de couplage de thiosucres avec le précatalyseur G3-Xanthphos pour conduire à de 2-aminobiphenyl glycosides bifonctionnels. La reaction a lieu à température ambiante et dans l'eau et produit des atropidiastéréomères stables.Dans une seconde partie de ce travail, nous décrivons une méthode originale d'accès à benzothiapinones et benzoxathiapinones glycosylées.Cette méthode fait intervenir un couplage de thiosucres avec des aryls iodés ayant un ester en ortho, suivi d'une lactonisation (ou lactimisation) pour conduire aux produits cyclisés.L'avant dernière partie de ce travail, concerne la synthèse de polysaccharides via une réaction de couplage de 2-iodo glycals avec des thiosucres de configuration définie.Ce travail se termine par l'application de couplage de thiosucres à la synthèse de Carbènes N-Hétérocycliques thioglycosylés (NHCs) hydrosolubles.Abstract: The work reported in this thesis concerns the development of new organometallic reactions for the creation of C-S bonds in complex systems.In the first chapter, we report an original method of bioconjugation of peptides and proteins in water at room temperature. The method has been successfully applied to the bioconjugation of the antibody Trastuzumab.The second chapter is devoted to the study of the reactivity of alpha or beta-thiosugars in the Buchwald-Hartwig-Mitiga coupling with different electrophilic partners.In a first sub-chapter, we report an unexpected reaction of thiosugar coupling with the G3-Xanthphos precatalyst to yield bifunctional 2-aminobiphenyl glycosides. The reaction takes place at room temperature and in water and produces stable atropidiastereomers.In a second part of this work, we describe an original method of access to glycosylated benzothiapinones (and benzoxathiapinones).This method involves thiosugar coupling with iodinated aryls having an ortho ester, followed by lactonization (or lactimization) to yield cyclized products.The last part of this work concerns the synthesis of polysaccharides via a coupling reaction of 2-iodo glycals with thiosugars of defined configuration.This work ends with the application of thiosugar coupling to the synthesis of water-soluble thioglycosylated N-Heterocyclic Carbenes (NHCs)

Synthesis of (1 → 2)-S-Linked Saccharides and S‑Linked Glycoconjugates via a Palladium-G3-XantPhos Precatalyst Catalysis

Buchwald–Hartwig–Migita cross-coupling of 1-thiosugars with 2-iodoglycals has been accomplished under mild and operationally simple reaction conditions through the use of Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, di-, and polythiosugar derivatives to synthesize efficiently a series of (1 → 2)-S-linked thiosaccharides and S-linked glycoconjugates, which are difficult to synthesize by classical methods

Azoliums and Ag(I)‐N‐Heterocyclic Carbene Thioglycosides: Synthesis, Reactivity and Bioactivity

International audienceA versatile protocol for the synthesis of azolium thioglycosides is reported. This protocol is based on a PdG3-catalyzed Migita cross-coupling between p-di-iodo azoliums and protected or unprotected β-1-thioglucose partners. Moreover, a solvent-free mechanochemistry approach was developed as a unique access to the corresponding Ag(I)-N-heterocyclic carbene thioglycosides. Finally, chemical reactivity and antiproliferative bioactivity were examined with azoliums and Ag(I)-NHC thioglycosides. This study demonstrates a promising potential of these newly synthesized carbohydrate-based N-heterocyclic derivatives

Palladium-Mediated Labeling of Nucleic Acids

International audienc