Adaptable Synthesis of Chondroitin Sulfate Disaccharide Subtypes Preprogrammed for Regiospecific O‐Sulfation

Wootton, Hannah S.; Berry, Sian S.; Ferguson, Elaine L.; Mahon, Clare S.; Miller, Gavin J

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.

Citation

Wootton, H. S., Berry, S. S., Ferguson, E. L., Mahon, C. S., & Miller, G. J. (2024). Adaptable Synthesis of Chondroitin Sulfate Disaccharide Subtypes Preprogrammed for Regiospecific O‐Sulfation. European Journal of Organic Chemistry, 27(40), Article e202400587. https://doi.org/10.1002/ejoc.202400587

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2024
• Online Publication Date: Jul 29, 2024
• Publication Date: Oct 21, 2024
• Deposit Date: Oct 14, 2024
• Publicly Available Date: Oct 15, 2024
• Journal: European Journal of Organic Chemistry
• Print ISSN: 1434-193X
• Electronic ISSN: 1099-0690
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 40
• Article Number: e202400587
• DOI: https://doi.org/10.1002/ejoc.202400587
• Public URL: https://durham-repository.worktribe.com/output/2957046