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‐glucosyl 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 dichlorophenylborane (PhBCl₂) and triethylsilane (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.