Total synthesis of the Bacteroides fragilis zwitterionic polysaccharide A1 repeating unit

Nearly all bacteria capsular polysaccharides are T-cell-independent antigens that do not promote immunoglobulin class switching from IgM to IgG nor memory responses. In contrast, zwitterionic polysaccharides activate T-cell-dependent immune responses by major histocompatability complex class II presentation, a mechanism previously believed to be reserved for peptidic antigens. The best studied zwitterionic polysaccharide, polysaccharide A1 (PS A1) is found on the capsule of the commensal bacteria Bacteroides fragilis . Its potent immunomodulatory properties have been linked to postoperative intra-abdominal abscess formation. Here, we report the synthesis of the PS A1 tetrasaccharide repeating unit (2) as a tool to investigate the biological role of this polysaccharide. A modular synthetic strategy originating from the reducing end of the PS A1 repeating unit was unsuccessful and illustrated the limitations of glycosylation reactions between highly armed glycosylating agents and poor nucleophiles. Thus, a [3 + 1] glycosylation relying on trisaccharide 5 and pyruvalated galactose 6 was used to complete the first total synthesis of the PS A1 repeating unit (2).