We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new, abiologcal activity of engineered 'carbene transferase' enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only overrides the inherent reactivity of aziridinium ylides to undergo cheletropic extrusion of ethylene, it also exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, a notoriously challenging reaction class for asymmetric catalysis. These unprecedented selectivities enable an entirely new strategy for the synthesis of chiral azetidine products from readily available synthetic precursors. The utility of this reaction is highlighted by the synthesis of an enantiopure azetidine on gram scale. The exquisite selectivity of the enzyme enables new-to-nature ring-expansion chemistry that overcomes a longstanding synthetic problem.

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity of engineered ‘carbene transferase’ enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, but also overrides the inherent reactivity of aziridinium ylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactive aziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed using other catalyst classes.

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new, abiologcal activity of engineered ‘carbene transferase’ enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only overrides the inherent reactivity of aziridinium ylides to undergo cheletropic extrusion of ethylene, it also exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, a notoriously challenging reaction class for asymmetric catalysis. These unprecedented selectivities enable an entirely new strategy for the synthesis of chiral azetidine products from readily available synthetic precursors. The utility of this reaction is highlighted by the synthesis of an enantiopure azetidine on gram scale. The exquisite selectivity of the enzyme enables new-to-nature ring-expansion chemistry that overcomes a longstanding synthetic problem

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity of engineered ‘carbene transferase’ enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, but also overrides the inherent reactivity of aziridinium ylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactive aziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed using other catalyst classes.

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new, abiologcal activity of engineered 'carbene transferase' enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only overrides the inherent reactivity of aziridinium ylides to undergo cheletropic extrusion of ethylene, it also exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, a notoriously challenging reaction class for asymmetric catalysis. These unprecedented selectivities enable an entirely new strategy for the synthesis of chiral azetidine products from readily available synthetic precursors. The utility of this reaction is highlighted by the synthesis of an enantiopure azetidine on gram scale. The exquisite selectivity of the enzyme enables new-to-nature ring-expansion chemistry that overcomes a longstanding synthetic problem. Figure 1: Classification of enzyme-mediated carbene transfer reactions for various bond disconnections.