Partially Protected N-Acetylglycosamine Donors Enable Direct β-O-Glycosylation: Applications and Mechanistic Insights.

The efficient synthesis of complex molecules with precise control over site-, stereo-, and chemoselectivity─while minimizing reliance on protecting-group manipulations─remains a long-standing goal in synthetic chemistry. 2-Acetamido-2-deoxy-d-hexoses (GlcNAc and GalNAc) are ubiquitous components of biologically important glycans and glycoconjugates; however, direct and rapid methods to access their glycosides remain limited. Conventional strategies often require harsh conditions to open the stable oxazoline intermediate or involve extensive protecting-group transformations on the acetamido group. Here, we report an Au(I)-catalyzed, direct and mild β-O-glycosylation of GlcNAc and GalNAc enabled by 2-acetamido-2-deoxy-6-O-tert-butyldiphenylsilyl-d-glycosyl 8-alkynyl-1-naphthoate donors, avoiding harsh oxazoline activation and extensive protecting-group use. Mechanistic studies reveal a distinct oxazoline ring-opening pathway: an intramolecular hydrogen bond between the 2-acetamido group and the C-3 hydroxyl promotes ring cleavage, enabling glycosylation of a broad range of alcohols and carboxylic acids. This nonenzymatic transformation parallels the substrate-assisted mechanism of O-GlcNAcase and offers a practical route to 2-acetamido glycosides under synthetically accessible conditions.