Facile Orthoester Formation in a Model Compound of the Taxol Oxetane: Are Biologically Active Epoxy Esters, Orthoesters, and Oxetanyl Esters Latent Electrophiles?

A steroidal oxetanyl ester was synthesized in eight steps as a biomimetic model of taxol oxetane. The model compound was surprisingly reactive under acidic conditions, rearranging in the absence of H₂O to a [2.2.1]-bicyclic orthoester. Both the oxetanyl ester and the orthoester readily hydrolyze to produce the same triol monoacetate. On the basis of the oxetanyl ester/orthoester rearrangement, a novel biochemical function is suggested for the epoxy esters and oxetanyl esters found in taxoids whereby dioxonium ions, generated from these functional groups, react with cellular proteins to form mixed orthoesters or ethers. A similar process could be involved in the mechanism of action of natural orthoesters such as resiniferatoxin.