Origins of Temperature‐Dependent Anomeric Selectivity in Glycosylations with an L–Idose Thioglycoside

L–Idose thioglycosides are useful glycosyl donors for the construction of glycosaminoglycan oligosaccharides. When activated with NIS and catalytic TMSOTf in the presence of methanol, the stereoselectivity of O‐glycosylation displays an intriguing dependence on the reaction temperature, with an increased preference for formation of the α‐glycoside at higher temperatures. Using a combination of vt‐NMR spectroscopy and DFT calculations, we show how a simple mechanistic model, based on competing reactions of the iodinated thioglycoside, can explain the main features of the temperature dependence. In this model, the increased selectivity at high temperature is attributed to differences among the entropy and energy terms of the competing reaction pathways. Neighbouring‐group participation (giving an intermediate acyloxonium ion) plays an increasingly dominant role as temperature is raised. The general features of this kinetic regime may also apply more broadly to other glycosylations that likewise favour α‐glycoside formation at high temperature. Computational modelling reveals the key mechanistic details explaining why glycosylations involving L‐idose thioglycoside donors, and potentially also a wide range of other donors, become increasingly α‐selective as the temperature is raised.