Insights into boric acid-mediated chemoselective transformation of D-glucosamine

Boric acid (B(OH)₃) can significantly improve the chemoselectivity of the transformation of D-glucosamine to 2,5-deoxyfructosazine (2,5-DOF), but the origin of the chemoselective formation of 2,5-DOF over fructosazine (FZ) has long remained unknown. In this work, we systematically investigated the possible mechanisms of boric acid-mediated transformation of D-glucosamine using density functional theory (DFT). The fundamental reaction pathway includes four stages: ring-opening, C-N bond formation, dehydration, and selective generation of 2,5-DOF over FZ. This study shows that boric acid plays a key role in both the dehydration stage and the selective formation stage of 2,5-DOF. Notably, the dehydration stage has been theoretically studied for the first time and identified as the rate-determining step, and the pathway promoted by two molecules of boric acid, 2B(OH)₃, is more energetically favorable than the widely proposed pathway involving the coordination of only one boric acid. Using the projection of orbital coefficient vector (POCV) method, we further analyzed the atomic activity vector and Fukui function vector values at the possible reaction sites in the presence and absence of boric acid to explore the role of boric acid and predict the chemoselectivity. This work clarifies the specific roles of boric acid and advances the application of theoretical calculations to this kind of organocatalytic reaction with high chemoselectivity.