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Genetically Tunable Enzymatic C‒H Amidation for Lactam Synthesis

Cho, Inha and Jia, Zhi-Jun and Arnold, Frances H. (2019) Genetically Tunable Enzymatic C‒H Amidation for Lactam Synthesis. . (Unpublished)

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A major challenge in carbon‒hydrogen (C‒H) bond functionalization is to have the catalyst control precisely where a reaction takes place. Here we report engineered cytochrome P450 enzymes that perform unprecedented enantioselective C‒H amidation reactions and control the site selectivity to divergently construct β-, γ- and δ-lactams, completely overruling the inherent reactivities of the C‒H bonds. The enzymes, expressed in Escherichia coli cells, accomplish this abiological carbon‒nitrogen (C‒N) bond formation via reactive iron-bound carbonyl nitrenes generated from nature-inspired acyl-protected hydroxamate precursors. This transformation is exceptionally efficient (up to 1,020,000 total turnovers) and selective (up to 25:1 regioselectivity and 96% enantiomeric excess), and can be performed easily on preparative scale.

Item Type:Report or Paper (Discussion Paper)
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URLURL TypeDescription Paper
Cho, Inha0000-0002-7564-5378
Jia, Zhi-Jun0000-0002-5143-4875
Arnold, Frances H.0000-0002-4027-364X
Additional Information:Preprint submitted on 12.02.2019, 21:02 and posted on 13.02.2019, 09:02. Declaration of Conflict of Interest: Caltech has filed a provisional patent application (CIT-8187-P). We thank K. Chen, S. Brinkmann-Chen, D. C. Miller and D. K. Romney for comments on the manuscript; X. Huang for helpful discussions; K. Chen for the parent variant E10FA; The Caltech Center for Catalysis and Chemical Synthesis and the Caltech Mass Spectrometry Laboratory for analytical support. Funding: Supported by NSF Division of Molecular and Cellular Biosciences grant MCB-1513007; Joseph J. Jacobs Institute for Molecular Engineering for Medicine (I.C.); and Deutsche Forschungsgemeinschaft (JI 289/1-1 to Z.-J.J.). Author contributions: I.C. and Z.-J.J. designed the research and performed the experiments with guidance from F.H.A.. I.C., Z.-J.J. and F.H.A. wrote the manuscript. Competing interests: Caltech has filed a provisional patent application (CIT-8187-P); and Data and materials availability: All data are available in the main text or the supplementary materials.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funding AgencyGrant Number
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)JI 289/1-1
Record Number:CaltechAUTHORS:20190312-131401661
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93736
Deposited By: Tony Diaz
Deposited On:12 Mar 2019 21:08
Last Modified:14 Oct 2019 17:51

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