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

Yang, Yang and Cho, Inha and Qi, Xiaotian and Liu, Peng and Arnold, Frances H. (2019) An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp³)–H bonds. Nature Chemistry, 11 (11). pp. 987-993. ISSN 1755-4330. PMCID PMC6998391. doi:10.1038/s41557-019-0343-5. https://resolver.caltech.edu/CaltechAUTHORS:20191014-083130371

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41557-019-0343-5DOIArticle
https://rdcu.be/bUfPJPublisherFree ReadCube access
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6998391/PubMed CentralArticle
ORCID:
AuthorORCID
Yang, Yang0000-0002-4956-2034
Cho, Inha0000-0002-7564-5378
Qi, Xiaotian0000-0001-5420-5958
Liu, Peng0000-0002-8188-632X
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2019 Springer Nature Limited. Received 12 April 2019; Accepted 15 August 2019; Published 14 October 2019. Data availability: All data necessary to support the paper’s conclusions are available in the main text and the Supplementary Information. Solid-state structures of 2a, 4a, 5a and 5f are available free of charge from the Cambridge Crystallographic Data Centre under reference nos CCDC 1905551, 1905553, 1905552 and 1905554. Plasmids encoding the enzymes reported in this study are available for research purposes from F.H.A. under a material transfer agreement with the California Institute of Technology. This work was supported by the NSF (grant nos MCB-1513007 for F.H.A. and CHE-1654122 for P.L.). Y.Y. thanks the National Institutes of Health for a postdoctoral fellowship (grant no. 1F32GM133126-01). Calculations were performed at the Center for Research Computing at the University of Pittsburgh. We thank R. K. Zhang, K. Chen, D. C. Miller, D. K. Romney (Caltech) and Y. Wang (University of Pittsburgh) for helpful discussions and comments on the manuscript, L. Henling for X-ray diffraction analysis and S. Virgil for assistance with chiral supercritical fluid chromatography analysis. Author Contributions: Y.Y. designed the overall research with F.H.A. providing guidance. Y.Y. and I.C. designed and performed the initial screening of haem proteins and directed evolution experiments. Y.Y. designed and performed the substrate scope study and mechanistic study. X.Q. carried out the computational studies with P.L. providing guidance. Y.Y. and F.H.A. wrote the manuscript with the input of all other authors. Competing interests: A provisional patent application (inventors Y.Y. and I.C.) has been filed through the California Institute of Technology. The provisional patent covers the development and application of engineered cytochromes P450 for the synthesis of chiral diamine derivatives by C–H amination.
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
NSFCHE-1654122
NIH Postdoctoral Fellowship1F32GM133126-01
Subject Keywords:Asymmetric catalysis; Biocatalysis; Synthetic chemistry methodology
Issue or Number:11
PubMed Central ID:PMC6998391
DOI:10.1038/s41557-019-0343-5
Record Number:CaltechAUTHORS:20191014-083130371
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191014-083130371
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99246
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Oct 2019 16:18
Last Modified:15 Feb 2022 22:59

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