Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits S_N2 Glycosylations

Abstract

Here we demonstrate that highly β-selective glycosylation reactions can be achieved when the electronics of a sulfonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not relied upon to control selectivity. Instead, β-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an S_N2-like mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calculations.