Radical Ring-Opening Reaction of Non-Activated Oximes Catalyzed by Aldoxime Dehydratases

The iminyl radical is a distinctive N-centered radical which serves as a versatile synthon in preparation of nitrogen-containing compounds. In principle, iminyl radicals can be directly generated by single electron reduction of oximes through elimination of OH group. However, due to the low reactivity of the oxime N─OH bonds, direct conversion of the oximes does not proceed efficiently, thereby enforcing chemical activation of the oxime OH group which results in the formation of stoichiometric by-products. To overcome this problem, we are developing a new biocatalytic system using aldoxime dehydratases. Through a series of enzyme screenings, we identified an aldoxime dehydratase from N. simplex (NsOxd) which is capable of catalyzing iminyl radical-mediated ring-opening reactions. Notably, NsOxd efficiently converts the "non-activated" 2-phenylcyclobutanone oxime within 10 min under ambient conditions and quantitatively produces the corresponding γ-sulfinylated nitrile in >95% yield. This enzyme activity is even faster than that of previously-reported chemo-catalysts. Furthermore, evaluation of the scope of potential substrates indicates that NsOxd has a versatile N─O bond cleaving activity which efficiently generates iminyl radicals from various "non-activated" oximes. These findings highlight the utility of aldoxime dehydratases for managing the reactivity of "non-activated" oximes and for achieving challenging iminyl radical-mediated catalytic reactions.