Synthèse de glycosides bivalents biologiquement actifs

Les pathogènes se lient souvent à la cellule ou au tissu hôte via des interactions glycoconjugé-protéine faibles, mais acquérant une haute sélectivité par leur caractère multivalent. Les lectines bactériennes, comme la FimH de Escherichia coli, se lient de façon sélective au saccharide correspondant et jouent un rôle clé dans l'adhésion des pathogènes. Afin d'étudier les interactions entre les glycoconjugés et une protéine possédant un ou plusieurs domaines de reconnaissance du saccharide (CRDs), une variété de mannosides dimériques ont été synthétisés avec comme objectif de disposer de ligands pouvant surpasser l'affinité de la protéine avec son ligand naturel par multivalence. Les glycosides bivalents rigides permettent de réticuler les protéines solubles possédant plusieurs CRDs et de former des réseaux insolubles. Une grande variété de réactions a été utilisée dans la littérature pour synthétiser de telles molécules comme les couplages organométalliques de Sonogashira et de Glaser. Ces précédents couplages permettent d'obtenir des glycosides dimériques symétriques ou asymétriques à partir d'espaceurs alcynes et aryles. Cependant, ces réactions ne permettent pas d'accéder à un espaceur de type biaryle. La présence d'une aglycone aromatique permet d'accéder à des interactions secondaires favorables dans le site actif. C'est pourquoi une nouvelle méthodologie de couplage aryle-aryle de type Ullmann catalysé au palladium a été développée. Cette méthode peut générer avec efficacité une variété de glycosides dimériques originaux (10 exemples avec des rendements jusqu'à 96%). La capacité réticulante de trois mannosides bivalents envers la concanavalin A a été évaluée par turbidimétrie et par diffusion dynamique de la lumière. Dans un deuxième volet, ont été synthétisés des lactosides bivalents assemblés par couplage de Sonogashira et possédant des espaceurs de type éthylène glycol de longueur variable.\ud ______________________________________________________________________________ \ud MOTS-CLÉS DE L’AUTEUR : Multivalence, Lectines, Ligands bivalents, Réticulation, Calatyle au palladium, Ullmann, Sonogashira

Tandem Organocatalytic α-Chlorination−Aldol Reactions: A Powerful Tool for Carbohydrate and Iminosugars Synthesis

Carbohydrates play a vital role in regulating biological events that range from cell recognition to pathogen/host adhesion. Not surprisingly, inhibitors of carbohydrate binding and cleaving processes, such as iminosugars, have been identified as leads in various therapeutic areas and several glycomimetic drugs have been approved for use in humans. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration within modern high-throughput screening technologies. Progress in glycomimetic research is often closely tied to advances in the de novo synthesis of unnatural carbohydrates, with much success being realized through the use of organocatalytic reactions. Our continued interest in the use of α-chloroaldehydes as building blocks for natural product synthesis led us to probe their organocatalytic aldol reactions with 2,2-dimethyl-1,3-dioxan-5-one. These efforts resulted in the discovery of a one-pot α-chlorination—aldol reaction that involves the dynamic kinetic resolution of an in situ generated α-chloroaldehyde. This process provides direct access to novel, enantiomerically-enriched building blocks (β-ketochlorohydrins) that are well-suited for the synthesis of carbohydrates and C-glycoconjugates. In this thesis, a unique synthetic strategy to convert a wide range of acetaldehyde derivatives into imino-C-nucleoside analogues in two or three straightforward transformations is described. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this a promising process for diversity-oriented synthesis and should enable drug discovery efforts. Finally, the synthesis of configurationally divergent iminocyclitols is presented. This study led to the identification of potent, selective and brain penetrant OGA inhibitors as lead candidates for the treatment of Alzheimer’s disease

Synthesis of DNA‐encoded disulfide‐ and thioether‐cyclized peptides

DNA-encoded chemical library technologies enable the screening of large combinatorial libraries of chemically and structurally diverse molecules, including short cyclic peptides. A challenge in the combinatorial synthesis of cyclic peptides is the final step, the cyclization of linear peptides that typically suffers from incomplete reactions and large variability between substrates. Several efficient peptide cyclization strategies rely on the modification of thiol groups, such as the formation of disulfide or thioether bonds between cysteines. In this work, we established a strategy and reaction conditions for the efficient chemical synthesis of cyclic peptide-DNA conjugates based on linking the side chains of cysteines. We tested two different thiol-protecting groups and found that tert-butylthio (S-tBu) works best for incorporating a pair of cysteines, and we show that the DNA-linked peptides can be efficiently cyclized through disulfide and thioether bond formation. In combination with established procedures for DNA encoding, the strategy for incorporation of cysteines may be readily applied for the generation and screening of disulfide- and thioether-cyclized peptide libraries

A Tandem Organocatalytic α‑Chlorination–Aldol Reaction That Proceeds with Dynamic Kinetic Resolution: A Powerful Tool for Carbohydrate Synthesis

A tandem, proline-catalyzed α-chlorination/aldol reaction is described that involves a dynamic kinetic resolution of α-chloroaldehyde intermediates. The resulting <i>syn-</i>chlorohydrins are produced with good to excellent diastereoselectivity in high enantiopurity and provide new opportunities for the synthesis of carbohydrates

Palladium-Catalyzed Ullmann-Type Reductive Homocoupling of Iodoaryl Glycosides

A catalytic synthesis of novel biaryl-linked divalent glycosides was achieved using an electroreductive palladium-catalyzed iodoaryl–iodoaryl coupling reaction. This new method was optimized for the synthesis of divalent biaryl-linked mannopyranosides that was subsequently generalized toward several carbohydrate substrates with yields up to 96%