Stereoselective 1,1′-glycosylation via reactivity tuning with protecting groups

Abstract

Chemical 1,1′-glycosylation for the synthesis of non-reducing disaccharides is complicated by the need to simultaneously control the stereochemistry at two anomeric centers. While considerable progress has been made in the synthesis of α,α-disaccharides, the assembly of 1,1′-β,β- and 1,1′-β,α-linked non-reducing sugars has received comparatively less attention. Many naturally occurring non-reducing disaccharides and their biologically active mimetics feature asymmetrically located functional groups at different positions on the two pyranose rings, highlighting the demand for reliable stereoselective methods to synthesize fully orthogonally protected 1,1′-conjugated sugars suitable for targeted functionalisation to create important biomolecules. By exploiting specific electronic and torsional effects imposed by protecting groups on both glycosyl donor and lactol acceptor molecules, we achieved highly stereoselective β,β- and β,α-1,1′-glycosylation and successfully synthesised a library of fully orthogonally protected β,β- and β,α-linked diglucosamines. Our approach is based on the premise that acceptor reactivity can greatly influence the stereochemical outcome of the glycosylation reaction. We show that the tailored choice of orthogonal protecting groups can alter the anomeric preferences in lactol acceptors, stabilising specific anomeric conformations, and that protecting group-driven modulation of lactol nucleophilicity is a useful tool to achieve stereoselective 1,1′-glycosidic bond formation. Structure–activity relationships have been established for a number of fully orthogonally protected glycosyl donor–lactol acceptor pairs, with a focus on optimizing lactol acceptor nucleophilicity to facilitate stereoselective 1,1′-β,β- and 1,1′-β,α-glycosylation on the acceptor side and enhance neighboring group-driven stereoselectivity on the donor side.