Cyclic imine sugars: towards the synthesis of transition-state mimics as potential glycosyltransferase inhibitors

Abstract

This thesis describes the development of methodology for the synthesis of cyclic imine-sugars, and their use in the synthesis of aza-sugars as potential sugar-processing enzyme inhibitors. Our goals include the synthesis of cyclic imines of L-rhamnose, D-glucose, and L-idose stereochemistry, and the introduction of functionality via nucleophilic addition reactions. Work on the synthesis of cyclic imines commenced with the use of the simple model systems piperidme and 2-methylpiperidine. N-Chlorination of these systems was performed and the products converted into their cyclic imine derivatives through elimination of HCl. Nucleophilic addition reactions to these systems were attempted, but the low stability and reactivity of the imines led to the isolation of only one adduct. The synthesis of novel cyclic pyrrolidine imine-sugars of L-rhamnose stereochemistry was performed by a Staudinger aza-Wittig reaction. The aza-Wittig reaction of a known L-rhamnose derived azido-sugar gave a novel cyclic L-rhamnopyrrolidine aldimine A novel synthesis of this azido-sugar was also devised. Successful nucleophilic additions to the cyclic L-rhamnopyrrolidine aldimine were performed with a range of Grignard reagents giving novel protected aza-sugars in good yields and with excellent diastereoselectivities. A novel cyclic L-rhamnopyrrolidme ketimine was also synthesised via a Staudinger aza-Wittig from a novel azido-sugar, although time constraints prevented screening this system with nucleophiles. The synthesis of novel cyclic piperidine imine-sugars of D-glucose, and L-idose stereochemistry was performed, both via N-chlorination/elimination of the protected parent aza-sugars, and via the Staudinger aza-Wittig reaction of novel azido-sugars. The elimination of HCl from six-membered iV-chloro aza-sugars of D-glucose and L- idose stereochemistry was investigated, and methodology developed in the case of D- glucose system for the regioselective elimination of HCl to give either the aldimme or the ketimine derivative. Comparison of elimination reactions of the N-chloro aza- sugars of D-glucose, and L-idose stereochemistry allowed rationalisation of the observed regiocontrol. Screening of the cyclic imines of D-glucose and L-idose stereochemistry with nucleophiles, followed by deprotection of the adducts, allowed the synthesis of novelaza-sugars via late-stage introduction of functionality. Low yields were obtained for these additions, but diastereocontrol was generally good, and could be rationalised by accepted stereoelectronic and steric approach control factors. The formation of cyclic piperidine imines of L-idose, and D-glucose stereochemistry was also performed via the Staudinger aza-Wittig reaction. These systems were found to be identical to those synthesised by the N-chlorination/elimination protocol. We also performed the first synthesis of the enantiomer of the natural product (+)- adenophorine thereby allowing assignment of the absolute configuration of the natural product (+)-adenophorine. The key synthetic step in this synthesis was stereoselective reduction of a novel intermediate cyclic piperidine ketimine-sugar of L-idose stereochemistry.