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Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides

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. 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/anie.202110873DOIArticle
ORCID:
AuthorORCID
Athavale, Soumitra V.0000-0001-5620-6997
Gao, Shilong0000-0003-2808-6283
Liu, Zhen0000-0002-6313-823X
Hirschi, Jennifer S.0000-0002-3470-0561
Arnold, Frances H.0000-0002-4027-364X
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.
Funders:
Funding AgencyGrant Number
NIHR01GM125887
American Chemical Society GCI Pharmaceutical RoundtableUNSPECIFIED
Binghamton UniversityUNSPECIFIED
NSFCHE-180061
NSFCHE-210031
NSFACI-1548562
Subject Keywords:asymmetric C−H functionalization; biocatalysis; nitrene transfer; P411 enzymes
Issue or Number:47
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 Nov 2021 17:42

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