Copper/photoredox catalysis enables desulfonylative radical N-glycosylation

Abstract

The state-of-the-art for glycosylation primarily relies on the classical polar reactions of heteroatomic nucleophiles with electrophilic glycosyl oxocarbenium intermediates. While such an ionic glycosylation strategy has worked well to deliver O-glycosides, its utilization in N-glycoside synthesis is often plagued by the subdued reactivity of N-nucleophiles under the acidic reaction conditions required for activating glycosyl donors. Exploring the reactivity of glycosyl radical intermediates could open up new glycosylation pathways. However, despite the recent significant progress in radical-mediated synthesis of C-glycosides, harnessing the reactivity of glycosyl radicals for the generation of canonical O- or N-glycosides remains elusive. Herein, we report the first examples of glycosyl radical-mediated N-glycosylation reaction using readily accessible glycosyl sulfone donors and N-nucleophiles under mild copper-catalyzed photoredox-promoted conditions. The method is efficient, selective, redox-neutral, and broadly applicable, enabling facile access to a variety of complex N-glycosides and nucleosides in a streamlined fashion. Importantly, the present system tolerates the presence of water and offers unique chemoselectivity, allowing selective reaction of NH sites over hydroxyl groups that would otherwise pose challenges in conventional cationic N-glycosylation.