Anti-Markovnikov alkene oxidation by metal-oxo–mediated enzyme catalysis
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.
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.Attached Files
Supplemental Material - aao1482_Hammer_SM.pdf
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Additional details
- Eprint ID
- 82315
- DOI
- 10.1126/science.aao1482
- Resolver ID
- CaltechAUTHORS:20171012-132542523
- HA7668/1
- Deutsche Forschungsgemeinschaft (DFG)
- KU3523/1
- Deutsche Forschungsgemeinschaft (DFG)
- Dow Chemical Company
- Resnick Sustainability Institute
- Created
-
2017-10-12Created from EPrint's datestamp field
- Updated
-
2021-11-15Created from EPrint's last_modified field
- Caltech groups
- Resnick Sustainability Institute