How electronic and steric effects in acceptor alcohols shape S_N1- and S_N2-type glycosylation reactions

The stereochemistry of glycosidic bonds dictates the glycan structure and function. Therefore, their selective introduction is crucial in the synthesis of oligosaccharides. This study systematically maps the influence of electronic and steric properties of alcohol acceptors on the glycosylation mechanism of the 4,6-O-benzylidene glucosyl donor, which has been shown to engage in glycosylation reactions spanning the whole breadth of the S_N1-S_N2 reaction continuum. Using kinetic isotope effects (KIEs), competition experiments and the determination of stereoselectivity as a function of acceptor concentration, we have quantified the influence of electronic and steric effects in the acceptor on the stereochemical outcome of the glycosylation reaction. In this way, we were able to pinpoint the mechanism on the S_N1-S_N2 continuum. Our findings reveal that α-glycosides can originate from S_N1 and S_N2 pathways, while the β-products are always generated through an S_N2-like mechanism. Sterically hindered and electron poor acceptors favor the S_N1-like pathway, and the stereoselectivity of the reaction can be controlled, in part, by adjusting the concentration of the acceptor.