Systematic studies toward the synthesis of <scp>d</scp>-galactosamine-containing coumarin glycosides

An <i>O</i>-glycosylation method for accessing coumarin glycosides is presented. We report the reaction of 6,8-difluoro-7-hydroxy-4-methylcoumarin and 4-methylumbelliferone with a variety of glycosyl imidate donors using BF₃·Et₂O as activator to access a series of coumarin glycosides in 64%-76% isolated yields. Several reaction parameters are evaluated including promotors, temperature and reagent equivalents. Following initial methodology development using simple D-glucose donors, D-galactosamino mono- and disaccharides are explored as substrates, showcasing applicability towards late-stage transformation of biologically relevant chondroitin sulfate glycosides. Glycosylation diastereoselectivity trends were also considered, proposing that the identity of the D-galactosamino <i>N</i>-protecting group and the coumarin acceptor contribute to observed anomeric product ratios. This methodology provides a convenient access to D-galactosamino-coumarin glycoconjugates and provides a benchmark for the development of related systems for biological evaluation.