Abstract
C–H bonds are ubiquitous structural units of organic molecules. Although these bonds are generally considered to be chemically inert, the recent emergence of methods for C–H functionalization promises to transform the way synthetic chemistry is performed. The intermolecular amination of C–H bonds represents a particularly desirable and challenging transformation for which no efficient, highly selective, and renewable catalysts exist. Here we report the directed evolution of an iron-containing enzymatic catalyst—based on a cytochrome P450 monooxygenase—for the highly enantioselective intermolecular amination of benzylic C–H bonds. The biocatalyst is capable of up to 1,300 turnovers, exhibits excellent enantioselectivities, and provides access to valuable benzylic amines. Iron complexes are generally poor catalysts for C–H amination: in this catalyst, the enzyme's protein framework confers activity on an otherwise unreactive iron-haem cofactor.
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Acknowledgements
Our research is supported by the National Science Foundation, Division of Molecular and Cellular Biosciences (grant MCB-1513007) and by funds from the American Recovery and Reinvestment Act (ARRA) through the National Institutes of Health Shared Instrumentation Grant Program (S10RR027203). C.K.P. thanks the Resnick Sustainability Institute for a postdoctoral fellowship. R.K.Z. was supported by a National Science Foundation Graduate Research Fellowship (NSF GRFP; DGE-1144469), is a trainee in the Caltech Biotechnology Leadership Program, and has received financial support from the Donna and Benjamin M. Rosen Bioengineering Center. A.R.B. is funded by a Ruth Kirschstein NIH Postdoctoral Fellowship F32G110851. We thank S. Virgil, J. Kaiser, and R. D. Lewis for experimental assistance, and O. F. Brandenberg, S. C. Hammer, and S. B. J. Kan for helpful discussion and comments on the manuscript.
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C.K.P. and R.K.Z. designed, carried out, and analysed all amination experiments, with F.H.A. providing guidance. C.K.P., R.K.Z. and S.B.-C. obtained protein crystals. R.K.Z. and A.R.B. solved the crystal structure. C.K.P. and F.H.A. wrote the manuscript with input from all of the authors.
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Prier, C., Zhang, R., Buller, A. et al. Enantioselective, intermolecular benzylic C–H amination catalysed by an engineered iron-haem enzyme. Nature Chem 9, 629–634 (2017). https://doi.org/10.1038/nchem.2783
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DOI: https://doi.org/10.1038/nchem.2783