Adaptable synthesis of chondroitin sulfate disaccharide subtypes preprogrammed for regiospecific O-sulfation

Abstract

A divergent synthetic route to chondroitin sulfate (CS) disaccharide precursors, including rarer subtypes such as CS-D, has been developed. From common intermediates, a series of thioglycoside D-glucose donors and 4,6-O-benzylidene protected D-galactosamine acceptors are utilised in a robust glycosylation reaction, achieving β-selectivity and consistent yields (60-75%) on scales >2.0 g. A post-glycosylation oxidation to D-glucuronic acid and orthogonal protecting groups delivers access to CS-A, CS-C, CS-D, CS-E and CS-O precursor subtypes. Of further note is a 4-O-benzyl regioselective reductive ring opening of a 4,6-O- benzylidene protected disaccharide using PhBCl2 and Et3SiH to access a CS-D precursor, in 73% yield over two steps. Finally, synthesis of a 6-O-sulfated CS-C disaccharide containing a conjugable anomeric allyl tether is completed. These materials will provide a benchmark to further synthesise and study chondroitin sulfates.