Anomeric Triflates vs Dioxanium ions: Different Product-Forming Intermediates from 1-Thiophenyl-2-O-Benzyl-3-O-Benzoyl-4,6-O-Benzylidene-Mannose and Glucose

Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and the stereochemical outcome of their glycosylation reactions. It can be exceedingly hard to adequately account for the observed differences and our current understanding of the nature of different reactive intermediates and the reaction pathways in which these are involved often only allows for speculative explanations. Here we used the detection and characterization of fleeting reactive intermediates in combination with systematic glycosylation reactions to understand the disparate behavior of “benchmark” glycosylation systems involving benzylidene glucosyl and mannosyl donors. While these systems have been studied extensively, no satisfactory explanations are available for the differences observed between the 3-O-benzyl/benzoyl mannose and glucose donor systems. We report the use of in-depth computational studies to map the potential energy surfaces of the different reaction pathways available for these donors and through these we have discovered the underlying reasons for the disparate behavior of the seemingly very similar systems. Evidence has been provided for the intermediacy of benzylidene mannosyl 1,3-dioxanium ions while the formation of the analogous 1,3-glucosyl dioxanium ions is thwarted by a prohibitively strong flagpole interaction of the C-2-O-benzyl group with the C-5-proton in moving towards the transition state in which the glucose ring adopts a B2,5-conformation. This study provides a long-awaited explanation for the intermediacy of 1,3-dioxanium ions in the mannosyl system and an answer as to why these do not form from analogous glucosyl donors.