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

David C Miller,Luca A Marchetti,Frances H Arnold,Ravi G Lal

doi:10.1021/jacs.2c00251

David C Miller, Luca A Marchetti + Show 2 more

Open Access

https://doi.org/10.1021/jacs.2c00251

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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

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.

Results

Conclusion