Bioinspired Glycosylpyridinium Donors for Mild and Stereoselective Glycosylation.

Despite substantial progress in glycosyl donor design, the development of mild and stereoselective glycosylation methods remains a central challenge in carbohydrate chemistry. Inspired by the native enzymatic ADP-ribosylation process, in which NAD+ serves as the glycosyl donor and nicotinamide acts as the leaving group, we developed a pyridinium-based glycosyl donor that chemically mimics this biological transformation. The donor enables the α-selective formation of O-, S-, and N-glycosides under mild activation conditions. Mechanistic studies indicate that the product configuration is independent of that of the donor and is instead governed by thermodynamic control, favoring formation of the α-configured product. Modification of the protecting groups on the donor allows selective access to β-configured products. This pyridinium donor is fully orthogonal to conventional donors, such as glycosyl thioglycosides and o-alkynylbenzoates, enabling iterative assembly of complex oligosaccharides. This bioinspired platform provides a versatile and complementary approach for the stereoselective construction of both α-and β-glycosidic linkages.