β-Thioglycosylation from Unactivated Carbohydrates

Abstract

Thioglycosides are prominent glycosides in biology and drug discovery because of their unique physicochemical and biological properties. The stereoselective construction of thioglycosides from unactivated carbohydrates has been historically challenging. Herein, we unearthed an S N 2 strategy with anomeric non-prefunctionalized glycosyl donors to achieve β-stereoconvergent thioglycosylation, featuring in situ activation–acceptor integration via designed reagents. The thioglycosylating reagent featured an iminium motif of a six-electron/four-center system, not only activating the anomeric hydroxyl groups but also facilitating reversible convergence from β to α anomer, which enabled the stereospecific S N 2 coupling from the β-face via the intimate ion pair of the imine cation and sulfide anion. The adjustable assembly of sp 3 -, sp 2 -, and sp-type sulfur acceptors was comprehensively achieved with a 130-membered library of β-thioglycosides for overwhelming functional group compatibility and β-selectivity. Click linkages have been successfully realized for alkenyl/alkynyl thioglycosides with diversely functional molecules via site-selective methionine bioconjugation and azide–alkyne cycloaddition.

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