A universal O-glycosylation platform enabled by pyridinium catalysis using gas-releasing oxazolidinone-based carbamates donors

TL;DR

A new O-glycosylation method using pyridinium catalysis and carbamates enables efficient carbohydrate synthesis for research and drug development.

Contribution

A novel O-glycosylation platform using pyridinium catalysis and oxazolidinone-based carbamates is introduced for scalable carbohydrate synthesis.

Findings

The method uses bench-stable oxazolidinone-based glycosyl carbamates as efficient donors.

Pyridinium catalysts activate carbamates via CO₂ release to form oxocarbenium ions.

The platform enables orthogonal and iterative glycosylations for oligosaccharide synthesis.

Abstract

Chemical glycosylation facilitates the scalable synthesis of structurally well-defined carbohydrates for functional studies and therapeutic development, with progress being driven by donors and strategies. Herein, we present an efficient and versatile O-glycosylation method utilizing newly designed, bench-stable and readily accessible oxazolidinone-based glycosyl carbamates as donors. This reaction is catalyzed by 2-pentafluorophenyl pyridinium salts under mild conditions and demonstrates elegant performance compared to conventional promoters. This robust protocol facilitates orthogonal, iterative and latent-active glycosylations for streamlined synthesis of oligosaccharides. Mechanistic studies, including NMR, deuteration and kinetic isotope effect experiments, establish that the pyridinium catalyst initiates glycosylation by first binding glycosyl acceptors. It then activates carbamate donors via CO₂ release to generate the oxocarbenium ion, which is identified as the rate-determining step of the glycosylation process.

Chemical synthesis of carbohydrates provides an efficient, scalable approach, facilitating therapeutic development and mechanistic studies. Herein, the authors report an O-glycosylation method utilizing bench-stable and readily accessible oxazolidinone-based glycosyl carbamates as donors.

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