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Enzymatic Primary Amination of Benzylic and Allylic C(sp³)–H Bonds

Jia, Zhi-Jun and Gao, Shilong and Arnold, Frances H. (2020) Enzymatic Primary Amination of Benzylic and Allylic C(sp³)–H Bonds. Journal of the American Chemical Society, 142 (23). pp. 10279-10283. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20200526-140743903

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Abstract

Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes are reported for their synthesis, methods that directly install a free amine group into C(sp³)–H bonds remain unprecedented. Here, we report a set of new-to-nature enzymes that catalyze the direct primary amination of C(sp³)–H bonds with excellent chemo-, regio-, and enantioselectivity, using a readily available hydroxylamine derivative as the nitrogen source. Directed evolution of genetically encoded cytochrome P411 enzymes (P450s whose Cys axial ligand to the heme iron has been replaced with Ser) generated variants that selectively functionalize benzylic and allylic C–H bonds, affording a broad scope of enantioenriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96% ee), and can be performed on preparative scale.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.0c03428DOIArticle
ORCID:
AuthorORCID
Jia, Zhi-Jun0000-0002-5143-4875
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2020 American Chemical Society. Received: March 28, 2020; Published: May 25, 2020. This work is supported by the National Science Foundation (NSF) Division of Molecular and Cellular Biosciences (grant MCB-1513007) and the Joseph J. Jacobs Institute for Molecular Engineering for Medicine. Z.-J.J. acknowledges support from Deutsche Forschungsgemeinschaft (JI 289/1-1). We thank S. Brinkmann-Chen, D. C. Miller, N. P. Dunham, S. Athavale, X. Huang, Y. Yang, and K. Chen for helpful discussions and comments on the manuscript; S. Athavale for reproduction of key experiments; and The Caltech Center for Catalysis and Chemical Synthesis for analytical support. The authors declare the following competing financial interest(s): Authors Zhi-Jun Jia and Shilong Gao have submitted a provisional patent application based on this manuscript.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)JI 289/1-1
Issue or Number:23
Record Number:CaltechAUTHORS:20200526-140743903
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200526-140743903
Official Citation:Enzymatic Primary Amination of Benzylic and Allylic C(sp3)–H Bonds. Zhi-Jun Jia, Shilong Gao, and Frances H. Arnold. Journal of the American Chemical Society 2020 142 (23), 10279-10283; DOI: 10.1021/jacs.0c03428
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103466
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:26 May 2020 21:17
Last Modified:11 Jun 2020 21:45

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