Biocatalytic Synthesis of Isoxazolines Enabled by Cryptic Nitrile Oxide Formation by a Vanadium‐Dependent Chloroperoxidase

Abstract

ABSTRACT 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.