Synthetic Studies on the Zwitterionic Disaccharide Repeating Unit from the Shigella Sonnei Polysaccharides and Its Oligomerization

Shigellosis is a diarrheal disease caused by a family of bacteria named Shigella. Phase III trials have demonstrated the protective capacity of a Shigella sonnei detoxified lipopolysaccharide-conjugate against S. sonnei infection in young adults and children older than 3 years of age.[1] As a possible alternative towards a highly immunogenic S. sonnei vaccine, we have engaged in the use conjugates made of synthetic oligosaccharides covalently attached to a carrier protein. 

The S. sonnei polysaccharides feature a zwitterionic disaccharide repeat encompassing two rare monosaccharides, a 2-acetamido-2-deoxy-L-altruronic acid (residue A) and a 2-acetamido-4-amino-2,4,6-trideoxy-D-galactopyranose (AAT, residue B), 1,2-trans linked to one another. This communication will report our investigations on the synthesis of oligosaccharides that have the {-D-FucpNAc4N-(1→}0,1[4)--L-AltpNAcA-(1→3)--D-FucpNAc4N-(1→]1,2,3…{4)--L-AltpNAcA}0,1 core sequence (B0,1(AB)1,2,3…A0,1) (Figure 1).[2]

Focus is on the identification of a suitable orthogonally protected AB disaccharide compatible with chain elongation at both ends, release in its free form, and subsequent site-selective conjugation onto a carrier or solid support. The synthesis of such a disaccharide intermediate, obtained by the post-glycosylation oxidation strategy, will be presented with emphasis on the selected A and B precursors, and their preparation from L-glucose and D-glucosamine, respectively. Besides, proper protecting group manipulation ensuing that a robust [A+B] glycosylation is achieved and the feasibility of the overall strategy will be exemplified for the (AB)3 hexasaccharide.