Kinetic Studies to Enable a Scalable Direct Glycosylation of a GalNAc Donor

A direct glycosylation was developed to enable the supply of a key intermediate in the synthesis of a targeting N-acetylgalactosamine (GalNAc) ligand. Kinetic experiments were performed to elucidate possible mechanistic differences between transformations catalyzed by two potential metal triflate catalysts, revealing a change in the rate-limiting step upon alteration of the metal center. Selection of a bismuth triflate catalyst led to a more efficient and robust process, which halved the number of unit operations, reduced solvent waste by 70%, and increased the isolated yield by 60% compared to traditional indirect glycosylation conditions.