1,2-trans and regioselective glycosylation of multihydroxy sugars via a simple yet synergistic combination of BF3·Et2O in THF†

Abstract

Carbohydrates play pivotal roles in numerous biological processes. The precise synthesis of structurally defined and pure carbohydrates is of paramount importance in pathological research and drug development. However, achieving stereo- and regioselective glycosylation during carbohydrate synthesis is often a tedious process that exhibits low atom economy. Herein, we present a surprisingly simple yet synergistic combination of BF₃·Et₂O in THF as a green solution to shorten the synthetic procedures, utilizing readily accessible imidate donor mixtures, regardless of their anomeric configuration. Glycosylation selectively occurs on the more nucleophilic hydroxyl group, giving 1,2-trans glycosides across a broad substrate scope in a highly stereo- and regioselective manner. This strategy is easy to apply and scale up, as demonstrated by an atom-economical synthetic route to achieve an oligosaccharide framework related to the Enterococcus faecalis antigen. Variable-temperature (VT) NMR studies revealed the formation of BF₃·ROH complexes, suggesting their roles as the true promoters and acceptors during glycosylation. Density functional theory (DFT) calculations suggested that 1,2-trans selectivity arises from the energy discrepancy between putative transition states involving [BF₃OR]⁻ and the oxocarbenium–solvent complex.