An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp³)–H bonds

Abstract

The ability to selectively functionalize ubiquitous C–H bonds streamlines the construction of complex molecular architectures from easily available precursors. Here we report enzyme catalysts derived from a cytochrome P450 that use a nitrene transfer mechanism for the enantioselective amination of primary, secondary and tertiary C(sp³)–H bonds. These fully genetically encoded enzymes are produced and function in bacteria, where they can be optimized by directed evolution for a broad spectrum of enantioselective C(sp³)–H amination reactions. These catalysts can aminate a variety of benzylic, allylic and aliphatic C–H bonds in excellent enantioselectivity with access to either antipode of product. Enantioselective amination of primary C(sp³)–H bonds in substrates that bear geminal dimethyl substituents furnished chiral amines that feature a quaternary stereocentre. Moreover, these enzymes enabled the enantioconvergent transformation of racemic substrates that possess a tertiary C(sp³)–H bond to afford products that bear a tetrasubstituted stereocentre, a process that has eluded small-molecule catalysts. Further engineering allowed for the enantioselective construction of methyl–ethyl stereocentres, which is notoriously challenging in asymmetric catalysis.

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