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Chemo-enzymatic fluorination of unactivated organic compounds

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Abstract

Fluorination has gained an increasingly important role in drug discovery and development. Here we describe a versatile strategy that combines cytochrome P450–catalyzed oxygenation with deoxofluorination to achieve mono- and polyfluorination of nonreactive sites in a variety of organic scaffolds. This procedure was applied for the rapid identification of fluorinated drug derivatives with enhanced membrane permeability.

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Figure 1: Cytochrome P450-based approach for selective fluorination of organic molecules.
Figure 2: Chemo-enzymatic fluorination of organic molecules.
Figure 3: Chemo-enzymatic methoxy-to-fluorine transformation.

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Acknowledgements

We are grateful to M. Shahgholi for assistance with the LC-MS and HRMS analyses. This work was supported by US National Institutes of Health grant GM068664 and US Department of Agriculture grant 2006-35505-16660 to F.H.A. and by the Jacobs Institute (Caltech). A.R. acknowledges the Deutsche Forschungsgemeinschaft for financial support.

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  1. Rudi Fasan

    Present address: Present address: Department of Chemistry, University of Rochester, Hutchison Hall, RC Box 270216, Rochester, New York 14627, USA.,

Authors and Affiliations

  1. Department of Chemistry and Chemical Engineering, California Institute of Technology 210-41, 1200 East California Boulevard, Pasadena, 91125, California, USA

    Andrea Rentmeister, Frances H Arnold & Rudi Fasan

Authors
  1. Andrea Rentmeister
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  2. Frances H Arnold
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  3. Rudi Fasan
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Contributions

R.F. and F.H.A. conceived the project; R.F. and A.R. performed the experiments; all authors discussed the results; R.F. wrote the paper with help and edits from F.H.A. and A.R.

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Correspondence to Rudi Fasan.

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Competing interests

R.F. and F.H.A. filed an international patent application (WO/2008/016709) entitled “Methods and systems for selective fluorination of organic molecules.” Some of the P450 enzymes described in this work are available commercially from Codexis, Inc. F.H.A. is a minor shareholder of Codexis and serves on the Codexis Science Advisory Board.

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Supplementary Figures 1–7, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 1238 kb)

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Rentmeister, A., Arnold, F. & Fasan, R. Chemo-enzymatic fluorination of unactivated organic compounds. Nat Chem Biol 5, 26–28 (2009). https://doi.org/10.1038/nchembio.128

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  • DOI: https://doi.org/10.1038/nchembio.128

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