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Site-selective enzymatic C‒H amidation for synthesis of diverse lactams

Cho, Inha and Jia, Zhi-Jun and Arnold, Frances H. (2019) Site-selective enzymatic C‒H amidation for synthesis of diverse lactams. Science, 364 (6440). pp. 575-578. ISSN 0036-8075. https://resolver.caltech.edu/CaltechAUTHORS:20190509-153734557

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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. In this study, 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 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 97%, please refer to compound 2v enantiomeric excess), and can be performed easily on preparative scale.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aaw9068DOIArticle
https://science.sciencemag.org/content/364/6440/575PublisherArticle
https://science.sciencemag.org/content/364/6440/575/suppl/DC1PublisherSupplementary Materials
ORCID:
AuthorORCID
Cho, Inha0000-0002-7564-5378
Jia, Zhi-Jun0000-0002-5143-4875
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2019 American Association for the Advancement of Science. This is an article distributed under the terms of the Science Journals Default License. Received 4 February 2019; accepted 28 March 2019. 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; and the Caltech Center for Catalysis and Chemical Synthesis and the Caltech Mass Spectrometry Laboratory for analytical support. Funding: This work was supported by NSF Division of Molecular and Cellular Biosciences grant MCB-1513007; the Joseph J. Jacobs Institute for Molecular Engineering for Medicine (I.C.); and the 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: I.C. and Z.-J.J. are inventors on patent application CIT-8187-P submitted by the California Institute of Technology that covers the intramolecular and intermolecular enzymatic C–H amidation. Data and materials availability: All data are available in the main text or the supplementary materials. Plasmids encoding the enzymes reported in this study are available for research purposes from F.H.A. under a material transfer agreement with the California Institute of Technology.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
Joseph J. Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)JI 289/1-1
Issue or Number:6440
Record Number:CaltechAUTHORS:20190509-153734557
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190509-153734557
Official Citation:Site-selective enzymatic C‒H amidation for synthesis of diverse lactams. BY INHA CHO, ZHI-JUN JIA, FRANCES H. ARNOLD. SCIENCE 10 MAY 2019 : 575-578; doi: 10.1126/science.aaw9068
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:95385
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 May 2019 22:48
Last Modified:14 Oct 2019 17:50

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