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Engineering cytochrome P450s for enantioselective cyclopropenation of internal alkynes

Chen, Kai and Arnold, Frances H. (2020) Engineering cytochrome P450s for enantioselective cyclopropenation of internal alkynes. Journal of the American Chemical Society, 142 (15). pp. 6891-6895. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20200330-105819372

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Abstract

We report a biocatalytic platform of engineered cytochrome P450 enzymes to carry out efficient cyclopropene synthesis via carbene transfer to internal alkynes. Directed evolution of a serine-ligated P450 variant, P411-C10, yielded a lineage of engineered P411 enzymes that together accommodate a variety of internal aromatic alkynes as substrates for cyclopropenation with unprecedented efficiencies and stereoselectivities (up to 5760 TTN, and all with >99.9% ee). Using an internal aliphatic alkyne bearing a propargylic ether group, different P411 variants can selectively catalyze cyclopropene formation, carbene insertion into a propargylic C–H bond or [3 + 2]-cycloaddition. This tunable reaction selectivity further highlights the benefit of using genetically encoded catalysts to address chemoselectivity challenges.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.0c01313DOIArticle
ORCID:
AuthorORCID
Chen, Kai0000-0002-3325-3536
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2020 American Chemical Society. Received: February 3, 2020; Published: March 29, 2020. This work was supported by NSF Division of Molecular and Cellular Biosciences grant MCB-1513007, US Army Research Office Institute for Collaborative Biotechnologies cooperative agreement W911NF-19-2-0026, and US Army Research Office Institute for Collaborative Biotechnologies contract W911NF-19-D-0001. K.C. thanks the Resnick Sustainability Institute at Caltech for fellowship support. We thank R. K. Zhang, N. P. Dunham, D. J. Wackelin, Y. Yang, and M. Garcia-Borràs for helpful discussions and comments. The authors declare no competing financial interest.
Group:Resnick Sustainability Institute
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
Army Research Office (ARO)W911NF-19-2-0026
Army Research Office (ARO)W911NF-19-D-0001
Resnick Sustainability InstituteUNSPECIFIED
Issue or Number:15
Record Number:CaltechAUTHORS:20200330-105819372
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200330-105819372
Official Citation:Engineering Cytochrome P450s for Enantioselective Cyclopropenation of Internal Alkynes. Kai Chen and Frances H. Arnold. Journal of the American Chemical Society 2020 142 (15), 6891-6895; DOI: 10.1021/jacs.0c01313
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102170
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Mar 2020 18:07
Last Modified:16 Apr 2020 17:32

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