SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS

This doctoral thesis explores strategies for the synthesis of structurally advanced glycomimetics. The first project focuses on the design of selective antagonists of C-type lectins, specifically targeting L-SIGN over DC-SIGN, two closely related receptors involved in viral recognition and SARS-CoV-2 infection. Inspired by the selective ligand Man84, a library of C2-triazole-modified mannosides bearing guanidine isosteres was synthesized. Structure–activity relationship studies combined with SPR assays identified several potent and selective L-SIGN ligands, including Man96, Man97, and Man102, displaying low micromolar affinity. X-ray crystallography of the L-SIGN/Man96 complex revealed the key interactions determining affinity and selectivity, highlighting the important role of residues E370, F325, and N385 in L-SIGN CRD. The second project develops a nickel-photoredox methodology for the synthesis of α-C-arylglycosides via deoxygenative arylation of unprotected anomeric hydroxyl groups. By replacing expensive iridium photocatalysts with sustainable organic dyes such as 5CzBN, an efficient and economical catalytic system was established. The protocol proved compatible with various monosaccharides and (hetero)aryl bromides, affording α-selective C-arylglycosides under mild conditions. Mechanistic investigations, including fluorescence quenching experiments, supported a radical pathway initiated by reductive quenching of a sugar–NHC adduct. The third project investigates racemic crystallization as a novel strategy for structural studies of glycans. Through automated glycan assembly, both D- and L-enantiomers of a galactosylated xyloglucan hexasaccharide were synthesized. Preliminary results suggest that racemic crystallization may overcome longstanding challenges in glycan structural analysis. Overall, this work expands the chemical space of glycomimetics, introduces sustainable synthetic methodologies for C-arylglycosides, and pioneers structural approaches for complex oligosaccharides, contributing to the advancement of medicinal and structural glycoscience.