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

Abstract

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.

Fig. 1. (a) Mechanistic pathways to account for the selectivity in glycosylation reactions of the 4,6-O-benzylidene glucosyl donor, 1. (b) Kinetic isotope effects (KIEs) for ⁱPrOH were recorded by Crich and coworkers on a similar, 2,3-di-O-methyl protected, glucosyl sulfoxide donor. Acceptor competition experiments and KIE measurements for TFE were performed by Asensio and colleagues. Numbers in brackets are relative formation rates for the O-glycosides in the competition experiments. (c) An overview of experiments performed in recent times to probe the mechanistic picture and the experiments that we present in this work.

Fig. 2. (a) Competition experiments performed with the 4,6-O-benzylidene glucoside donor, 1, and the sets of electronically and sterically varying acceptors. (b) Relative formation rates, shown with respect to α-O-ethyl glucoside. The apparent RRV values, shown in the center of each square, were calculated by adding up both α and β species. (c) An example of a quantitative 2D HSQC experiment for the competition between EtOH and MFE, allowing for the accurate determination of relative conversions towards the four different products.

Fig. 3. (a) Mechanistic pathways to account for the selectivity in glycosylation reactions of benzylidene glucoside donor 1. (b) Stereoselectivity data for glycosylation reactions using acceptors from both sets of model O-nucleophiles with different acceptor concentrations fitted to a reciprocal equation, (c) and a linear fit through the points plotted against reciprocal initial acceptor concentration. (d) A comparison between the S_N1 vs. S_N2 preference for the formation of the alpha product as computed from the concentration experiments and the computed values for the kinetic isotope effects (KIEs) for these reactions. Reported errors for the KIEs are at 1σ. *Concentration dependence cannot be determined for anomerically selective glycosylation reactions, as the determination of an accurate α : β ratio is not possible. **Reaction yielded inseparable anomers, so accurate integration, and therefore the calculation of a KIE, was not possible.