Cho, Inha and Jia, Zhi-Jun and Arnold, Frances H. (2019) Genetically Tunable Enzymatic C‒H Amidation for Lactam Synthesis. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20190312-131401661
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Abstract
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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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 | ||||||||
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Record Number: | CaltechAUTHORS:20190312-131401661 | ||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20190312-131401661 | ||||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||
ID Code: | 93736 | ||||||||
Collection: | CaltechAUTHORS | ||||||||
Deposited By: | Tony Diaz | ||||||||
Deposited On: | 12 Mar 2019 21:08 | ||||||||
Last Modified: | 14 Oct 2019 17:51 |
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