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

Abstract

We will report on the synthesis of oligomers of Salmonella enterica serovar Typhi (often called S. Typhi) CPS, and their zwitterionic analogues. S. Typhi is a motile Gram-negative bacterium, whose CPS (often referred to as Vi antigen) is an anionic polymer composed by \u3b1-(1-4)-linked N-acetyl galactosaminuronic acid repeating units predominantly O-acetylated at position 3. We developed a strategy based on versatile intermediates enabling chain elongation either by iterative single monomer attachment or by faster and more flexible approaches using disaccharide donors. All these intermediates were obtained from commercially available D-galactosamine hydrochloride. The non participating azide group was used to mask C-2 amino functionality, which can be converted into the animo group (ZPS) or into the acetamido function (natural Vi) and allows the formation of 1,2-cis glycosidic linkages. Glycosylation reactions were carried out using N-phenyltrifluoroacetimidates as glycosyl donors, yielding stereoselectively the desired \u3b1 product. C-6 oxidation was done with TEMPO/NaClO2. By orthogonally protecting position 3 we were able to obtain both fully 3-O-acetylated and fully 3-O-deactetylated oligomers. Finally, a suitable l inker was installed at C-1 of the reducing end in order to facilitate a subsequent conjugation to protein carrier and/or multivalents caffolds. The immunological properties of the synthetic oligomers will be also investigated in order to correlate the structural features (in particular 3-O-acetylation) with their biological behaviour