Yang Yang1, Inha Cho1, Xiaotian Qi2, Peng Liu3, Frances H Arnold4. 1. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA. 2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA. 3. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA. pengliu@pitt.edu. 4. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA. frances@cheme.caltech.edu.
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.
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 n class="Chemical">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.
Authors: Thomas W Thorpe; James R Marshall; Vanessa Harawa; Rebecca E Ruscoe; Anibal Cuetos; James D Finnigan; Antonio Angelastro; Rachel S Heath; Fabio Parmeggiani; Simon J Charnock; Roger M Howard; Rajesh Kumar; David S B Daniels; Gideon Grogan; Nicholas J Turner Journal: Nature Date: 2022-04-06 Impact factor: 49.962
Authors: Soumitra V Athavale; Shilong Gao; Zhen Liu; Sharath Chandra Mallojjala; Jennifer S Hirschi; Frances H Arnold Journal: Angew Chem Int Ed Engl Date: 2021-10-13 Impact factor: 15.336
Authors: Zhen Liu; Zi-Yang Qin; Ledong Zhu; Soumitra V Athavale; Arkajyoti Sengupta; Zhi-Jun Jia; Marc Garcia-Borràs; K N Houk; Frances H Arnold Journal: J Am Chem Soc Date: 2021-12-23 Impact factor: 15.419
Authors: Kohki M Nakafuku; Zuxiao Zhang; Ethan A Wappes; Leah M Stateman; Andrew D Chen; David A Nagib Journal: Nat Chem Date: 2020-06-22 Impact factor: 24.427