Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides
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.
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.Attached Files
Accepted Version - nihms-1741559.pdf
Supplemental Material - anie202110873-sup-0001-misc_information.pdf
Supplemental Material - anie202110873-sup-0001-si.xlsx
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Additional details
- PMCID
- PMC8578410
- Eprint ID
- 111321
- DOI
- 10.1002/anie.202110873
- Resolver ID
- CaltechAUTHORS:20211008-224620449
- R01GM125887
- NIH
- American Chemical Society GCI Pharmaceutical Roundtable
- Binghamton University
- CHE-180061
- NSF
- CHE-210031
- NSF
- ACI-1548562
- NSF
- Created
-
2021-10-12Created from EPrint's datestamp field
- Updated
-
2023-07-07Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering