Halogen-bond-assisted radical activation of glycosyl donors enables mild and stereoconvergent 1,2-cis-glycosylation

Abstract

The chemistry of carbohydrates has a history of over 100 years, but simple, stereoselective and efficient glycosylation methods remain highly needed to facilitate the studies of sugars in various disciplines. Here we report a strategy for 1,2-cis-glycosylation without using metals, strong (Lewis) acids, elaborate catalysts or labile substrates. Our method operates by a unique mechanism: it activates glycosyl donors through a radical cascade rather than the conventional acid-promoted, ionic process. As elucidated by computational and experimental studies, the allyl glycosyl sulfones (as donors) form halogen bond complexes with perfluoroalkyl iodides, which—merely by visible light irradiation—fragment via radical intermediates to give the electrophilic glycosyl iodides. In situ trapping by various nucleophiles affords, in a stereoconvergent manner, the challenging 1,2-cis-glycosides. This metal- and acid-free reaction shows remarkable tolerance to functional groups. The high stereoselectivity holds for a broad array of donors. This study suggests that the simple C2-alkoxy group can serve as an effective directing group for building 1,2-cis-glycosidic bonds. Most chemical glycosylation methods operate by acid-promoted, ionic activation of donors. Now, by exploiting the formation of a halogen-bond complex, the activation of glycosyl donors was achieved via a visible light-promoted radical cascade process, resulting in a general, simple and mild way to build challenging 1,2-cis-glycosidic bonds.