Radical Strategy towards N-glycosides: Current Advances and Future Prospects.

Abstract

N-glycosides exhibit diverse biological and pharmacological activities, making their efficient synthesis crucial for both biological research and drug development. Traditional acid-promoted N-glycosylation methods, which rely on the formation of oxocarbenium intermediates, often face significant challenges. These methods are water-sensitive and typically require neighboring group participation to achieve high selectivity. Furthermore, they depend on acid activation, rendering them incompatible with alkyl amine. Additionally, low-nucleophilicity amides often need to be converted into their TMS-derivatives to enhance reactivity, limiting the direct use of such substrates. In contrast, radical-based strategies have emerged as a promising alternative, addressing many of these limitations and leading to notable advances in N-glycosylation. This review explores the unique properties of N-glycosides, the inherent challenges of traditional N-glycosylation techniques, and the transformative advantages offered by radical-based approaches. Specifically, it highlights recent advancements in radical-mediated N-glycosylation, including photoredox radical strategies, radical/ionic hybrid approaches, and metallophotoredox catalysis, accompanied by a detailed discussion of the underlying mechanisms. Finally, the ongoing challenges and potential future directions of N-glycoside synthesis using radical strategies are presented.