D-Glucuronate and d-Glucuronate Glycal Acceptors for the Scalable Synthesis of d-GlcN-α-1,4-d-GlcA Disaccharides and Modular Assembly of Heparan Sulfate.

Abstract

Reported herein is a scalable chemical synthesis of disaccharide building blocks for heparan sulfate (HS) oligosaccharide assembly. The use of d-glucuronate-based acceptors for dehydrative glycosylation with d-glucosamine partners is explored, enabling diastereoselective synthesis of appropriately protected HS disaccharide building blocks (d-GlcN-α-1,4-d-GlcA) on a multigram scale. Isolation and characterization of key donor (1,2 glycal)- and acceptor (ortho-ester, anhydro)-derived side products ensure methodology improvements to reduce their formation; protecting the d-glucuronate acceptor at the anomeric position with a para-methoxyphenyl unit proves optimal. We also introduce glycal uronate acceptors, showing them to be comparative in reactivity to their pyranuronate counterparts. Taken together, this gram-scale access offers the capability to explore the iterative assembly of defined HS sequences containing the d-GlcN-α-1,4-d-GlcA repeat, highlighted by completing this for two tetrasaccharide syntheses.