Nouvelles technologies pour fonctionnaliser sélectivement de sucres: APPLICATION À LA SYNTHÈSE DE MOLÉCULES BIOLOGIQUEMENT ACTIVES

Selective Functionalization of Sugar by Using news technologies: APPLICATION TO THE SYNTHESIS OF BIOLOGICALLY ACTIVE GLYCOSIDES

• Auteur / Autrice : Linhua Shen
• Direction : Samir Messaoudi
• Type : Projet de thèse
• Discipline(s) : Chimie médicinale
• Date : Inscription en doctorat le 30/09/2020
• Etablissement(s) : université Paris-Saclay
• Ecole(s) doctorale(s) : École doctorale Innovation thérapeutique : du fondamental à l'appliqué
• Partenaire(s) de recherche : Laboratoire : Biomolécules : conception, isolement, synthèse
• Partenaire(s) de recherche : référent : Université Paris-Saclay. Faculté de pharmacie (Orsay, Essonne ; 2020-....)

Mots clés

Mots clés libres

Fonctionnaliser

Sucres

Biologiquement

Functionalization

Sugar

Biologically

Résumé

Le développement de nouvelles stratégies efficaces et stéréosélectives de fonctionnalisation de sucres reste un défi majeur de la communauté des glycochimistes. Dans ce contexte, le but principal de ce projet consiste à développer de nouvelles approches de fonctionnalisation innovantes de sucres basées sur leur utilisation d'approches nouvelles telles que la photoredox, l'électrochimie ou les processus de couplages croisés. Ces méthodes permettront de fonctionnaliser une liaison glycosidique avec un parfait contrôle de la stéréosélectivité indépendamment des groupements protecteurs. De plus, des études mécanistiques seront envisagées si nécessaire, afin de mieux comprendre les paramètres fondamentaux qui gouvernent la réactivité mais aussi la stéréosélectivité de la réaction. Ces méthodes seront appliquées à la synthèse d'hétérosides et de glycoconjugués, outils précieux pour étudier les interactions qui contrôlent les processus biologiques complexes du monde du vivant.

The field of glycobiology has exploded in the last few decades, identifying glycoconjugates to serve critical roles in a wide range of biological processes. Most carbohydrates found in nature or used in therapeutics exist as glycoconjugates in which the sugars are attached to aglycones through N-, S- or O-glycosidic bonds. These units are important or essential for biological activity. The rapid expansion of knowledge surrounding the function of carbohydrates has led to increasing attention from biological, medicinal, and pharmacological study. To meet their demands, investigators require access to significant quantities of well-defined bioactive glycoconjugates. This necessity has prompted resurgence in the interest of synthesis, with a predominant focus on new approaches to the glycosidic bond. The chemical synthesis of glycoconjugates usually involves the transformation of a sugar into a fully protected glycosyl donor with a leaving group at its anomeric center (eg. acetate, halides, trichloroacetimidates, thiols). Glycosylation of a suitably aglycone, which react as nucleophile, then follows. (In other words, the “glycosyl donor” transfers the glycosyl moiety (generally as an electrophile) to the “aglycon” (generally the nucleophile)). Hence, the leaving group of the glycosyl donor and the protecting groups are the most fundamental parameters with respect to the yield and anomeric selectivity of glycosidation reactions. These additional steps however, decrease the yield and selectivity, are costly in time, resources and produce waste. Our project deals with the use of news technologies such as photoredox chemistry, electrochemistry as well as metal-catalyzed cross couplings to imagine and explore new ways to build C-glycosides. The chemistry in this proposal involves the development of a series of processes concerning C-glycosidic bonds forming reaction under various processes. These processes will involve photoredox dual cross coupling, electrochemistry and C-H activation . All these process will be performed aunder mil reaction conditions (room temperature). In this context, we recently reported some of ours results in this field. (see references) The use of these catalytic methods is conducive to achieving “greener” chemistry, where air and moisture tolerance, performance at room temperature, and enhanced synthetic efficiency through reduction of unnecessary waste is attained. Additionally, the ligand–transition metal complex system could provide stereocontrol during the glycosylation, rather than the nature of protecting groups on the substrate. This approach is, to our knowledge, unique and has never been explored in the world. Based on the successful outcome of this project, an unlimited number of organic transformations will be possible in the future, and the development of such new sustainable methodologies will make a tremendous impact into routine organic synthesis of glycoconjugates and into selective late-stage modification of pharmaceuticals. This conceptually novel approach would provide chemists in both the academic and industrial worlds with new disconnection strategies that give access to molecules with original structures and properties in a simple, efficient, and ecological manner. References of selected results: Messaoudi et al. Org. Lett. 2019, 21, 5132-5137 Messaoudi et al. Chem. Sci., 2018, 9, 8753-8759 Messaoudi et al. ACS Catal. 2018, 8, 7781-7786 Messaoudi et al. Chem. Eur. J 2018, 24, 1795-1800 Messaoudi et al. Org. Lett. 2018, 20, 4067 Messaoudi et al. Org. Lett. 2017, 19, 5038–5041 Messaoudi et al. Chem. Eur. J, 2016, 22, 15006-15010 (VIP)