N-glycoside synthesis through combined copper- and photoredox-catalysed N-glycosylation of N-nucleophiles

State-of-the-art glycosylation methods primarily rely on ionic reactions of heteroatomic nucleophiles with electrophilic glycosyl oxocarbenium intermediates. Although such ionic glycosylation strategies can effectively form O-glycosides, their use in N-glycoside synthesis is often plagued by the subdued reactivity of N-nucleophiles under the acidic reaction conditions required for glycosyl donor activation. Exploration of the reactivity of glycosyl radical intermediates has begun to offer new glycosylation pathways. However, despite recent 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. Here we report the development of a glycosyl radical-mediated N-glycosylation reaction using readily accessible glycosyl sulfone donors and N-nucleophiles under mild copper-catalysed, photoredox-promoted conditions. The method is efficient, selective, redox neutral and broadly applicable, enabling ready 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 ionic N-glycosylation. Radical-mediated synthesis of N-glycosides is underdeveloped. Here a glycosyl radical-mediated N-glycosylation reaction using combined copper and photoredox catalysis is reported. This protocol exhibits high chemoselectivity and water tolerance, overcoming challenges associated with cationic glycosylation reactions.