Abstract

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.

Highlights

  • Ring-size manipulation has emerged as a powerful strategy to convert readily available cyclic structures into ringexpanded or ring-contracted compounds that are more difficult to synthesize using conventional means

  • Enantiopure quaternary ammonium salts can undergo [1,2]Stevens rearrangements with N-to-C chirality transfer;15 escape of the radical pair from the solvent cage is often competitive with radical recombination,16 and erosion of enantiopurity is often observed in these reactions

  • The joint selectivity challenges presented by the one-carbon ring expansion of aziridines into azetidines require a potential catalyst to select the [1,2]-Stevens rearrangement in preference to cheletropic extrusion of ethylene and to exert enantiocontrol over a potential diradical intermediate

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Summary

Introduction

Ring-size manipulation has emerged as a powerful strategy to convert readily available cyclic structures into ringexpanded or ring-contracted compounds that are more difficult to synthesize using conventional means.1 In particular, “cut and sew” strategies relying on transition-metal catalyzed oxidative addition to form C-C bonds have emerged as powerful tools for insertion of carbon monoxide or twocarbon fragments such as olefins and alkynes into existing rings to effect one- or two-carbon ring expansions, respectively.2 For nitrogen-containing heterocycles, one possible strategy is to induce a [1,2]-Stevens rearrangement to enact a one-carbon ring expansion.3 Pioneering work by Hata, West, and Couty has demonstrated the power of this approach for 4- to 5-membered ring expansions, wherein treatment of an azetidine with a diazo compound in the presence of a copper catalyst provides facile access to the corresponding pyrrolidine.4 Conceptually, carbene transfer followed by an intramolecular [1,2]-Stevens rearrangement complements “cut and sew” reactions for non-carbonylative, one-carbon homologation of nitrogen-containing compounds. Application of a ring-expansion strategy for the asymmetric, one-carbon homologation of aziridines via carbene insertion would be a powerful new entry for the synthesis of chiral azetidines.

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