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Chemo-enzymatic fluorination of unactivated organic compounds

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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Authors and Affiliations

Authors

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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