An Empirical Understanding of the Glycosylation Reaction

Abstract

Reliable glycosylation reactions that allow for the stereo- and regioselective installation of glycosidic linkages are paramount to the chemical synthesis of glycan chains. The stereoselectivity of glycosylations is exceedingly difficult to control due to the reaction's high degree of sensitivity and its shifting, simultaneous mechanistic pathways that are controlled by variables of unknown degree of influence, dominance, or interdependency. An automated platform was devised to quickly, reproducibly, and systematically screen glycosylations and thereby address this fundamental problem. Thirteen variables were investigated in as isolated a manner as possible, to identify and quantify inherent preferences of electrophilic glycosylating agents (glycosyl donors) and nucleophiles (glycosyl acceptors). Ways to enhance, suppress, or even override these preferences using judicious environmental conditions were discovered. Glycosylations involving two specific partners can be tuned to produce either 11:1 selectivity of one stereoisomer or 9:1 of the other by merely changing the reaction conditions.

Acceptor reactivity in glycosylation reactions

“…75 By tweaking the reaction temperature and solvent, nearly complete aor b-stereoselectivity could be obtained. 76 A variety of different donors provided a similar reactivity-stereoselectivity trend.…”

Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity

“…Stereocontrolled glycosylation was the main challenge in carbohydrate chemistry owning to the lack of a clear mechanism and too many control variables . We herein first demonstrated that stereoselectivity can be predicted using reactivity of donors (RRVs) on different acceptors in a NIS/TfOH system.…”

“…Ye, Huang, and Yoshida have developed a preactivation strategy that allows iterative one‐pot glycosylation . However, similar to all other glycosylation reactions, the poorly controlled stereoselectivity remains a long‐standing problem . The promotor systems are generally a combination of a stoichiometric amount of an iodonium agent and a catalytic amount of TfOH.…”

“…These findings suggest that stereoselectivity is more closely related to inductive effects on donors and the reactivity of acceptors . For example, mannosides are commonly believed to produce α‐major (1.2‐ trans ) glycosides.…”

Phenanthroline‐Catalyzed Stereoretentive Glycosylations

“…Next, we investigated the ability of 4 to overturn the inherent bias of d ‐galactose, whose axial C4 benzyl group has been reported to favor β‐product formation . Under our catalytic system, galactosyl bromides served as effective electrophiles to deliver 16 – 18 (Table ) with high α‐selectivities.…”