How electronic and steric effects in acceptor alcohols shape SN1- and SN2-type glycosylation reactions

Hoogers, D.; Vrande, K.N.A.van de; Meij, D. van der; Remmerswaal, W.A.; Tugny, C.; Marel, G.A. van der; Codée, J.D.C.

doi:doi:10.1039/d5sc07201h

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 SN1-SN2 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 SN1-SN2 continuum. Our findings reveal that alpha-glycosides can originate from SN1 and SN2 pathways, while the beta-products are always generated through an SN2-like mechanism....Show moreThe 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 SN1-SN2 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 SN1-SN2 continuum. Our findings reveal that alpha-glycosides can originate from SN1 and SN2 pathways, while the beta-products are always generated through an SN2-like mechanism. Sterically hindered and electron poor acceptors favor the SN1-like pathway, and the stereoselectivity of the reaction can be controlled, in part, by adjusting the concentration of the acceptor.Show less

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How electronic and steric effects in acceptor alcohols shape SN1- and SN2-type glycosylation reactions