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Anti-Markovnikov alkene oxidation by metal-oxo–mediated enzyme catalysis

Hammer, Stephan C. and Kubik, Grzegorz and Watkins, Ella and Huang, Shan and Minges, Hannah and Arnold, Frances H. (2017) Anti-Markovnikov alkene oxidation by metal-oxo–mediated enzyme catalysis. Science, 358 (6360). pp. 215-218. ISSN 0036-8075. http://resolver.caltech.edu/CaltechAUTHORS:20171012-132542523

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Abstract

Catalytic anti-Markovnikov oxidation of alkene feedstocks could simplify synthetic routes to many important molecules and solve a long-standing challenge in chemistry. Here we report the engineering of a cytochrome P450 enzyme by directed evolution to catalyze metal-oxo–mediated anti-Markovnikov oxidation of styrenes with high efficiency. The enzyme uses dioxygen as the terminal oxidant and achieves selectivity for anti-Markovnikov oxidation over the kinetically favored alkene epoxidation by trapping high-energy intermediates and catalyzing an oxo transfer, including an enantioselective 1,2-hydride migration. The anti-Markovnikov oxygenase can be combined with other catalysts in synthetic metabolic pathways to access a variety of challenging anti-Markovnikov functionalization reactions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aao1482DOIArticle
http://science.sciencemag.org/content/358/6360/215PublisherArticle
http://www.sciencemag.org/content/358/6360/215/suppl/DC1PublisherSupplementary Materials
ORCID:
AuthorORCID
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2017 American Association for the Advancement of Science. Received 19 June 2017; accepted 5 September 2017. We thank A. Buller, S. Brinkmann-Chen, K. Chen, P. Hanley (Dow Chemical Company), X. Huang, K. Mayer, C. Prier, D. Romney, and R. Zhang for fruitful discussions. This work was supported by the Deutsche Forschungsgemeinschaft (fellowships HA7668/1 to S.C.H. and KU3523/1 to G.K.) and by the Dow Chemical Company and the Resnick Sustainability Institute through the Dow/Resnick CI2 innovation program. All data necessary to support the conclusions are available in the supplementary materials. The work presented in this manuscript is part of a provisional patent filed with S.C.H. as inventor. 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. S.C.H. designed the overall research project, with F.H.A. providing guidance. S.C.H., E.W., and H.M. designed and conducted directed evolution experiments. S.C.H., G.K., and S.H. designed and conducted the substrate scope studies. S.C.H., G.K., E.W., and F.H.A wrote the manuscript. The authors declare no competing financial interests.
Group:Resnick Sustainability Institute
Funders:
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)HA7668/1
Deutsche Forschungsgemeinschaft (DFG)KU3523/1
Dow Chemical CompanyUNSPECIFIED
Resnick Sustainability InstituteUNSPECIFIED
Record Number:CaltechAUTHORS:20171012-132542523
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20171012-132542523
Official Citation:Anti-Markovnikov alkene oxidation by metal-oxo–mediated enzyme catalysis BY STEPHAN C. HAMMER, GRZEGORZ KUBIK, ELLA WATKINS, SHAN HUANG, HANNAH MINGES, FRANCES H. ARNOLD SCIENCE13 OCT 2017 : 215-218
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:82315
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Oct 2017 22:06
Last Modified:12 Oct 2017 22:06

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