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 <i>O</i>-, <i>S</i>-, and <i>N</i>-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 <i>o</i>-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.