The combination of thioglycoside and NIS/TfOH promoter system is one of the most commonly used glycosylation reactions to construct challenging glycosidic bond in chemical carbohydrate synthesis. However, over the past three decades, the mechanism remains unclear with glycosyl triflate commonly believed as intermediate. Even if glycosyl triflate exhibits high reactivity, stereocontrolled glycosylation is still a long-standing challenge because the behaviors and effects of the byproducts present in the reaction system were unknown. In this paper, for the first time, we confirm that glycosyl iodide is the real intermediate dominating glycosylation with its role in this glycosylation system being clarified. The relative quantities of glycosyl triflate to iodide greatly influence stereoselectivity.
Intermediate transformation is governed by numerous factors, including donor reactivity, temperature, activation time, TfOH, and promotors (NXS). Based on our findings, stereoselectivity is now predictable on various thioglycosides, as indicated by their relative reactivity values (RRVs). We also disclosed new guidelines to achieve intermediate-controlled stereoselective glycosylation reactions.