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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.

Cyclophellitol and cyclophellitol-aziridine are potent, mechanism-based and irreversible retaining β-glucosidase inhibitors. We have become interested in these configurational β-glucoside analogues as they proved to be a highly suitable starting point for the development of activity-based glycosidase probes. In this review, we provide an overview of the cyclophellitol-aziridine synthesis reported in the literature. Two conceptually different strategies for the introduction of the aziridine moiety have been used, one starting from the inverted epoxide and one with intramolecular iodocyclisation from a homo-allylic alcohol as the key step. These are discussed in this microreview, and their application in the synthesis of configurational and functional cyclophellitol-aziridine isomers is presented as well.

Cyclitol epoxides and aziridines are potent and selective irreversible inhibitors of retaining glycosidases. We have previously reported on our studies on the use of activity-based probes derived from cyclophellitol and from its aziridine analogue for activity-based profiling of retaining -glucosidases in vitro, in situ, and in some examples also in vivo. In this work we disclose full details of the synthesis, purification, and analysis of a comprehensive panel of cyclophellitol analogues, all featuring the -glucose configuration and designed as tools for selective inhibition and/or imaging of human acid glucosylceramidase (epoxides) or as broad-spectrum probes for retaining -glucosidases (aziridines).

Cyclophellitol and cyclophellitol aziridine are potent and irreversible mechanism-based inhibitors of retaining β-glucosidases. Alterations in the configuration of these compounds can lead to irreversible inhibition of different classes of retaining glycosidases. We have recently reported on the design of a set of α-galactopyranose-configured cyclophellitol and cyclophellitol aziridine derivatives that inhibit human retaining α-galactosidases. Moreover, we have shown

Cyclitol epoxides and aziridines are potent and selective irreversible inhibitors of retaining glycosidases. We have previously reported on our studies on the use of activity-based probes derived from cyclophellitol and from its aziridine analogue for activity-based profiling of retaining -glucosidases in vitro, in situ, and in some examples also in vivo. In this work we disclose full details of the synthesis, purification, and analysis of a comprehensive panel of cyclophellitol analogues, all featuring the -glucose configuration and designed as tools for selective inhibition and/or imaging of human acid glucosylceramidase (epoxides) or as broad-spectrum probes for retaining -glucosidases (aziridines).