Chemical synthesis of a hyaluronic acid decasaccharide.

The chemical synthesis of a hyaluronic acid decasaccharide using the preactivation-based chemoselective glycosylation strategy is described. Assembly of large oligosaccharides is generally challenging due to the increased difficulties in both glycosylation and deprotection. Indeed, the same building blocks previously employed for hyaluronic acid hexasaccharide syntheses failed to yield the desired decasaccharide. After extensive experimentation, the decasaccharide backbone was successfully constructed with an overall yield of 37% from disaccharide building blocks. The trichloroacetyl group was used as the nitrogen protective group for the glucosamine units, and the addition of TMSOTf was found to be crucial to suppress the formation of trichloromethyl oxazoline side product and enable high glycosylation yield. For deprotections, the combination of a mild basic condition and the monitoring methodology using (1)H NMR allowed the removal of all base-labile protective groups, which facilitated the generation of the fully deprotected HA decasaccharide.