Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity ofengineeredcarbene transferaseenzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only exertsunparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement but also overrides the inherent reactivity of aziridiniumylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactiveaziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed usingother catalyst classes.

Automated summary

The study reports the enantioselective one-carbon ring expansion of aziridines to form azetidines through engineered carbene transferase enzymes. A variant of cytochrome P450BM3, P411-AzetS, showed unparalleled stereocontrol (99:1 er) in the [1,2]-Stevens rearrangement and could override the inherent reactivity of aziridinium ylides to perform this rearrangement. By controlling the reactive aziridinium ylide intermediates, these evolvable biocatalysts enable a transformation not achievable by other catalyst classes.