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Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme

Loskot, Steven A. and Romney, David K. and Arnold, Frances H. and Stoltz, Brian M. (2017) Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme. Journal of the American Chemical Society, 139 (30). pp. 10196-10199. ISSN 0002-7863. PMCID PMC5679227. https://resolver.caltech.edu/CaltechAUTHORS:20170720-100846797

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Abstract

An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A is described. Strategically, the synthesis relies on a late-stage C–H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C–H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/jacs.7b05196DOIArticle
http://pubs.acs.org/doi/abs/10.1021/jacs.7b05196PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/jacs.7b05196PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679227PubMed CentralArticle
ORCID:
AuthorORCID
Romney, David K.0000-0003-0498-7597
Arnold, Frances H.0000-0002-4027-364X
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2017 American Chemical Society. Received: May 19, 2017; Published: July 19, 2017. This work was supported by the NSF under the CCI Center for Selective C–H Functionalization (CHE-1205646). D.K.R. was supported by a Ruth Kirschstein NIH Postdoctoral Fellowship (F32GM117635). Additional financial support was provided by Caltech and Novartis. We thank Dr. Scott Virgil (CIT) and the Caltech 3CS for access to analytical equipment. The authors gratefully acknowledge Larry Henling and Dr. Michael Takase (CIT) for X-ray crystallographic structural determination, Dr. Mona Shahgholi and Naseem Torian (CIT) for mass spectrometry assistance, and Dr. David VanderVelde (CIT) for NMR experimental assistance and helpful discussions. The authors also acknowledge Dr. Sabine Brinkmann-Chen and Dr. Stephan Hammer (CIT) for helpful discussions regarding the enzymatic oxidation system.
Funders:
Funding AgencyGrant Number
NSFCHE-1205646
NIH Postdoctoral FellowshipF32GM117635
CaltechUNSPECIFIED
NovartisUNSPECIFIED
Issue or Number:30
PubMed Central ID:PMC5679227
Record Number:CaltechAUTHORS:20170720-100846797
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170720-100846797
Official Citation:Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme Steven A. Loskot, David K. Romney, Frances H. Arnold, and Brian M. Stoltz Journal of the American Chemical Society 2017 139 (30), 10196-10199 DOI: 10.1021/jacs.7b05196
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:79248
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:20 Jul 2017 18:15
Last Modified:03 Oct 2019 18:17

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