Biocatalytic Synthesis of Isoxazolines Enabled by Cryptic Nitrile Oxide Formation by a Vanadium-Dependent...

Isoxazolines are an important class of heterocycles with a broad range of biological activities. One of the most prevalent synthetic strategies to access isoxazolines is through the oxidative [3+2] cycloaddition between nitrile oxides and alkenes initiated by halogenation of a starting aldoxime, but current methods rely on toxic oxidants that produce significant quantities of waste and are largely bioincompatible. We have recently discovered that the vanadium-dependent haloperoxidase (VHPO) class of enzymes are efficient catalysts for the in situ generation of nitrile oxides. Herein, we have developed a chemoenzymatic protocol for the conversion of aldehydes to nitrile oxides that features a sequential condensation of hydroxylamine with a starting aldehyde, followed by oxidative [3+2] cycloaddition with alkenes enabled by VHPO-catalyzed halogenation of aldoximes on a broad range of structurally diverse substrates in high yield and excellent chemoselectivity. The protocol is conducted on a gram scale, demonstrated using whole cells and cell lysate, and extended to isoxazole synthesis. Finally, this process is coupled to lipase-mediated conversion of amines to oximes to generate isoxazolines.