Synthesis of Carba-Cyclophellitols: a New Class of Carbohydrate Mimetics

Abstract

Cyclophellitol and cyclophellitol aziridine are potent and irreversible inhibitors of retaining β-glucosidases. They preferentially adopt a 4H3 half-chair conformation, thereby mimicking the substrate-transition-state conformation characteristic of retaining β-glucosidases. As a consequence, both compounds bind tightly to the enzyme active site, and attack of the catalytic nucleophile onto the epoxide/aziridine results in enzyme deactivation. Replacement of the epoxide oxygen in cyclophellitol by a (substituted) carbon yielded carba-cyclophellitols, a conceptually new class of inhibitors of retaining β-glucosidases, as we demonstrated in a recent communication. In this paper, in-depth synthetic studies of this class of compounds are described, and the preparation of a comprehensive set of structurally and configurationally new carba-cyclophellitols is presented.