Highly stereoselective synthesis of allylic β-lactams via enzymatic C(sp3)–H amidation

Abstract

β-Lactams are versatile synthons for organic synthesis as well as valuable pharmacophores for drug development. Here, we describe a biocatalytic strategy for the enantioselective synthesis of allylic β-lactams via a hemoprotein-catalyzed intramolecular C(sp³)–H amidation reaction with dioxazolone substrates. Leveraging a stepwise radical mechanism and overriding the typical reactivity of metallonitrenes, this system provides access to a variety of β-lactam products with consistently high enantioselectivity (≥99% ee) by favoring the amination of an allylic C(sp³)-H bond over the more facile functionalization of the adjacent olefin group. This works expands the range of stereoselective strategies for C–N bond formation via C(sp³)–H functionalization and demonstrates the value of new-to-nature biocatalysis to promote chemical transformations not currently accessible through chemocatalysis.