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

S5.3 Oligosaccharide synthesis II
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:20 to 15:25

Debashis Dhara1, Hélène B.  Pfister1,2, Julie  Paoletti1, Marion Bouchet1, Laurence A.  Mulard1

1Chimie des Biomolécules, Institut Pasteur, UMR3523, CNRS, 28 rue du Dr Roux, 75724 Paris Cedex 15, France, 2Université Sorbonne Paris Cité, Paris, , France

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.

Figure 1: Schematic representation of the synthetic challenges. 

  1. Passwell, J. H.; Ashkenazi, S.; Miron, D.; Ramon, R.; Farzam, N.; Lerner-Geva, I.; Levi, Y.; MHA and the israel Shigella study group.; Chu, C., Shiloach, J.; Robbins, J. B.; Schneerson R.; Safety and immunogenicity of Shigella sonnei-CRM9 and Shigella flexneri type 2a-rEPAsucc conjugate vaccines in one- to four-year-old children. Pediatr. Infect. Dis. J. 2003, 22, 701-706. 
  2.  Pfister, H. B.; and Mulard, L. A.; Synthesis of the zwitterionic repeating unit of the o-antigen from Shigella sonnei and chain elongation at both ends. Org. Lett. 2014, 16, 4892-4895.