Vibrio vulnificus is a human pathogen that can cause fatal septicemia and necrotizing infections with a high lethal rate exceeding 50%. V. vulnificus MO6-24 and BO62316 are two predominant virulent strains associated with approximately one-third of the clinical infections. The capsular polysaccharides (CPSs) of V. vulnificus consist of several structurally unique sugars and are excellent targets for developing effective glycoconjugate vaccines. This article describes the first total synthesis of the challenging tetrasaccharide repeating units of V. vulnificus MO6-24 and BO62316 CPSs. A key feature of this synthesis was the assembly of the tetrasaccharide skeleton using a 3,4-branched trisaccharide as the glycosyl donor. A modified TEMPO/BAIB oxidation protocol was developed to directly convert α- d -GalN into α- d -GalAN in not only disaccharides but also tri- and tetrasaccharides. The synthetic haptens were covalently coupled with CRM 197 carrier protein via a bifunctional linker. Preliminary immunological studies of the resultant glycoconjugates in mice revealed their high efficacy to induce robust T-cell-dependent immune responses, and the IgG antibodies elicited by each glycoconjugate showed weak cross-reactivity with the other synthetic tetrasaccharide.

Comprehensive Summary Here we report a systematic investigation on the stereodirecting effects of a 4‐O‐ortho‐cyanobenzyl ether (oBCN) group with a glucopyranosyl donor. Experimental studies revealed that the glycosylation reactions using this donor generally show dual‐stereoselectivities depending on the acceptor nucleophilicity, that is, glycosylation of weak nucleophile acceptors generally affords α‐glycosides specifically while glycosylation of strong nucleophile acceptors affords β‐glycosides preferentially. DFT computations suggested that strong nucleophiles preferentially attack the predominant covalent α‐glycosyl triflate intermediate in an SN2‐like manner, while weak nucleophiles preferentially attack the less stable and more reactive β‐glycosyl triflate with H‐bond mediated direction. The first and facile synthesis of a hexasaccharide repeating unit of serotype IV group B Streptococcus capsular polysaccharide demonstrated the versatile utility of glucosyl building blocks with an oBCN functionality in carbohydrate chemistry.

No abstract