Direct construction of aryl amide N-glycosides from glycosyl oxamic acids via photoredox palladium-catalyzed aminocarbonylations

Abstract

Despite the flourishing synthesis of O-glycosides, progress in N-glycoside synthesis has been impeded by significant challenges due to the weak nucleophilicity of amides. Here, we unveil an interesting photoredox palladium (Pd)-catalyzed aminocarbonylation of glycosyl oxamic acids with (hetero)aryl bromides to synthesize aryl N-amide glycosides. This method employs a merging single- and two-electron strategy for the first time, leveraging glycosyl oxamic acids as traceless carbamoyl radical precursors. By bypassing the elusive anomeric control of C–N glycosidic bond formation between sugars and aglycones, our approach offers a promising alternative for the synthesis of aryl amide N-glycosides. The versatility and applicability of this innovative strategy are demonstrated through a comprehensive examination of 65 examples, encompassing diverse (hetero)aryl electrophiles, saccharides, oligosaccharides, oligopeptides, and complex drug molecules. Mechanistic insights, gleaned from experimental and computational studies, elucidate a successive SET pathway and the generation of carbamoyl radicals in this synergistic catalytic process.