Synthesis of fragments of Salmonella Typhi capsular polysaccharide and their zwitterionic analogues

Salmonella enterica serovar Typhi (often called S. Typhi) is a motile Gram-negative bacterium, whose capsular polysaccharide (often referred to as Vi antigen) is an anionic polymer composed of α-(1-4)-linked N-acetyl-galactosaminuronic acid repeating units predominantly O-acetylated at position 3. The degree of acetylation was found to be crucial for the immunogenicity. We investigated two different synthetic routes for the oligomers assembly: a late stage post-glycosylation oxidation approach and a pre-glycosylation oxidation strategy, the latter employing suitably protected uronates donor and acceptor. Glycosylation reactions were carried out using N-phenyltrifluoroacetimidates as glycosyl donors, and experimental conditions were carefully screened in order to ensure the stereoselective formation of the desired α product. The azido group at C-2 can be converted into either an acetamido function (natural Vi) or a free amino group (zwitterionic derivatives). Finally, a pentenyl linker was installed at C-1 of the reducing end in order to facilitate the subsequent conjugation to protein carrier and/or multivalent scaffolds.