Methodological and mechanistic studies of chiral auxiliary assisted stereoselective glycosylations and the development of glycoconjugate vaccines for α-dystroglycan
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Oxathiane ethers have been developed as stable, versatile and easily accessible precursors for sulfonium ion mediated 1,2-cis-stereoselective glycosylations. The preparation of glycosyl 1,2-oxathiane ethers starts from the regioselective intramolecular cyclization and stereoselective reduction of 1-thio-β-D-glucopyranosyl acetophenone in a one-pot fashion. Due to the stability of oxathiane ether under acidic, basic and reductive conditions, orthogonally protected donors can be prepared efficiently. Subsequent sulfoxidation, triflation and nucleophilic aromatic substitution by trimethoxylbenzene generate β-sulfonium ions. The SN2 displacement of β-sulfonium ion by various O- nucleophiles resulted excellent to exclusive 1,2-cis-stereoselectivity. The utility of this methodology was further tested for the stereoselective assembly of a branched α-glucan derived from P. Boydii with immune activation properties. The mechanism of β-sulfonium ion mediated glycosylations was systemically surveyed by modulating the nucleophilicity of neighboring participating moieties on chiral auxiliaries or by reversing the chirality of auxiliaries. Results suggested strong dependence of stereoselectivity on the participation and the chirality of the auxiliary. Further computational studies found that there is a shift from SN2-like to SN1-like reaction pathway by reversing the chirality of auxiliaries from (S) to (R). This observation solved the previous puzzle for the inferior trans-stereoselectivity after reversing the chirality of auxiliaries. The stereoselective glycosylation was further pursued for the synthesis of a α- dystroglycan tetrasaccharide SiaAα(2-3)Galβ(1-4)GlcNAcβ(1-2)Manα-threonine and its truncated library with implication in the pathology of muscular dystrophy. The resulted glycosylated amino acids were either incorporated into fully synthetic tripartite vaccines or conjugated to various carrier proteins for eliciting the immune response in mice. Abundant antibodies against synthetic carbohydrate epitopes have been detected. Further characterization and production of monoclonal antibodies are currently ongoing.