Athavale, Soumitra V. and Gao, Shilong and Liu, Zhen and Mallojjala, Sharath Chandra and Hirschi, Jennifer S. and Arnold, Frances H. (2021) Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides. Angewandte Chemie International Edition, 60 (47). pp. 24864-24869. ISSN 1433-7851. PMCID PMC8578410. doi:10.1002/anie.202110873. https://resolver.caltech.edu/CaltechAUTHORS:20211008-224620449
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Abstract
Directed evolution of heme proteins has opened access to new-to-nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron-nitrenoid intermediates present a powerful strategy to forge C−N bonds with high site- and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C−H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic compounds can be converted to chiral amides with excellent enantioselectivity (up to >99 % ee) and high yields (up to 87 %). Kinetic and computational analysis of the enzymatic reaction reveals rate-determining nitrenoid formation followed by stepwise hydrogen atom transfer-mediated C−H functionalization.
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Additional Information: | © 2021 Wiley-VCH GmbH. Issue Online: 08 November 2021; Version of Record online: 13 October 2021; Accepted manuscript online: 17 September 2021; Manuscript revised: 16 September 2021; Manuscript received: 12 August 2021. This research was supported in part by the NIH National Institute of General Medical Sciences (R01GM125887), the ACS GCI Pharmaceutical Roundtable Research Grant (F.H.A., S.V.A.), and Binghamton University startup funds (J.S.H.). J.S.H. and M.S.C. acknowledge support from the XSEDE Science Gateways Program (CHE180061 and CHE210031), which is supported by NSF grant number ACI-1548562. We thank S. Brinkmann-Chen for helpful discussion and comments. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The authors declare no conflict of interest. | ||||||||||||||
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Subject Keywords: | asymmetric C−H functionalization; biocatalysis; nitrene transfer; P411 enzymes | ||||||||||||||
Issue or Number: | 47 | ||||||||||||||
PubMed Central ID: | PMC8578410 | ||||||||||||||
DOI: | 10.1002/anie.202110873 | ||||||||||||||
Record Number: | CaltechAUTHORS:20211008-224620449 | ||||||||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20211008-224620449 | ||||||||||||||
Official Citation: | Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides. S. V. Athavale, S. Gao, Z. Liu, S. C. Mallojjala, J. S. Hirschi, F. H. Arnold, Angew. Chem. Int. Ed. 2021, 60, 24864; DOI: 10.1002/anie.202110873 | ||||||||||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||
ID Code: | 111321 | ||||||||||||||
Collection: | CaltechAUTHORS | ||||||||||||||
Deposited By: | George Porter | ||||||||||||||
Deposited On: | 12 Oct 2021 15:00 | ||||||||||||||
Last Modified: | 11 Jan 2022 00:38 |
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