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Enantiodivergent α-Amino C–H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s

Zhang, Juner and Huang, Xiongyi and Zhang, Ruijie K. and Arnold, Frances H. (2019) Enantiodivergent α-Amino C–H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s. Journal of the American Chemical Society, 141 (25). pp. 9798-9802. ISSN 0002-7863. PMCID PMC6666315. https://resolver.caltech.edu/CaltechAUTHORS:20190607-130827085

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Abstract

The introduction of fluoroalkyl groups into organic compounds can significantly alter pharmacological characteristics. One enabling but underexplored approach for the installation of fluoroalkyl groups is selective C(sp^3)–H functionalization due to the ubiquity of C–H bonds in organic molecules. We have engineered heme enzymes that can insert fluoroalkyl carbene intermediates into α-amino C(sp3)–H bonds and enable enantiodivergent synthesis of fluoroalkyl-containing molecules. Using directed evolution, we engineered cytochrome P450 enzymes to catalyze this abiological reaction under mild conditions with total turnovers (TTN) up to 4070 and enantiomeric excess (ee) up to 99%. The iron-heme catalyst is fully genetically encoded and configurable by directed evolution so that just a few mutations to the enzyme completely inverted product enantioselectivity. These catalysts provide a powerful method for synthesis of chiral organofluorine molecules that is currently not possible with small-molecule catalysts.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.9b04344DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6666315/PubMed CentralArticle
ORCID:
AuthorORCID
Zhang, Juner0000-0001-8181-1187
Huang, Xiongyi0000-0001-7156-8881
Zhang, Ruijie K.0000-0002-7251-5527
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2019 American Chemical Society. Received: April 22, 2019; Published: June 7, 2019. This work was supported by the National Science Foundation (NSF), Division of Molecular and Cellular Biosciences (grant MCB-1513007). X.H. is supported by an NIH pathway to independence award (Grant K99GM129419). R.K.Z. acknowledges support from the NSF Graduate Research Fellowship (grant DGE-1144469) and the Donna and Benjamin M. Rosen Bioengineering Center. We thank S. Brinkmann-Chen, K. Chen, Z. Jia, S. B. J. Kan, A. M. Knight, L. J. Schaus, D. J. Wackelin, E. J. Watkins, and Y. Yang for helpful discussion and comments. We also thank N. Torian, M. Shahoholi and the Caltech Mass Spectrometry Laboratory, and L. M. Henling and the Caltech X-ray Crystallography Facility for analytical support. Author Contributions: J.Z. and X.H. contributed equally. The authors declare no competing financial interest.
Group:Rosen Bioengineering Center
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
NIHK99GM129419
NSF Graduate Research FellowshipDGE-1144469
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
Issue or Number:25
PubMed Central ID:PMC6666315
Record Number:CaltechAUTHORS:20190607-130827085
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190607-130827085
Official Citation:Enantiodivergent α-Amino C–H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s Juner Zhang, Xiongyi Huang, Ruijie K. Zhang, and Frances H. Arnold. Journal of the American Chemical Society 2019 141 (25), 9798-9802. DOI: 10.1021/jacs.9b04344
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96204
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Jun 2019 21:27
Last Modified:03 Apr 2020 23:43

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