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An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes

Liu, Zhen and Qin, Zi-Yang and Zhu, Ledong and Athavale, Soumitra V. and Sengupta, Arkajyoti and Jia, Zhi-Jun and Garcia-Borràs, Marc and Houk, K. N. and Arnold, Frances H. (2022) An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes. Journal of the American Chemical Society, 144 (1). pp. 80-85. ISSN 0002-7863. PMCID PMC8765727. doi:10.1021/jacs.1c11340. https://resolver.caltech.edu/CaltechAUTHORS:20220119-572949000

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Abstract

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp3)–H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene precursor. Cytochrome P450 variant PA-G8 catalyzing this transformation was identified after eight rounds of directed evolution. A variety of 1-aryl-2-alkyl alkynes are accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process is efficient and selective (up to 2610 total turnover number (TTN) and 96% ee) and can be performed on preparative scale.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c11340DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8765727/PubMed CentralArticle
ORCID:
AuthorORCID
Liu, Zhen0000-0002-1119-0693
Athavale, Soumitra V.0000-0001-5620-6997
Sengupta, Arkajyoti0000-0002-9917-2472
Jia, Zhi-Jun0000-0002-5143-4875
Garcia-Borràs, Marc0000-0001-9458-1114
Houk, K. N.0000-0002-8387-5261
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2021 American Chemical Society. Received 26 October 2021. Published online 23 December 2021. Published in issue 12 January 2022. This work is supported by the NSF Division of Molecular and Cellular Biosciences (grant 2016137 to F.H.A.), the National Institute of General Medical Sciences of the NIH (grant R01GM138740 to F.H.A. and R01GM124480 to K.N.H.), and the US Department of Energy, Office of Basic Energy Sciences (grant DE-SC0021141 to F.H.A.). M.G.-B acknowledges support from the Spanish Ministerio de Ciencia e Innovación (project PID2019-111300GA-I00) and the Generalitat de Catalunya AGAUR (Beatriu de Pinós H2020 MSCA-Cofund 2018-BP-00204 project). We thank David C. Miller, Anuvab Das, Kai Chen, Shilong Gao, Runze Mao, and Sabine Brinkmann-Chen for helpful discussions and comments on the manuscript. We thank Dr. Scott C. Virgil for his assistance with chiral-phase HPLC experiments. We further thank Mona Shahgholi for HRMS analysis. Author Contributions. Z.L. and Z.Y.Q. contributed equally. This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe on privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof. The views and opinions of the authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NSFMCB-2016137
NIHR01GM138740
NIHR01GM124480
Department of Energy (DOE)DE-SC0021141
Ministerio de Ciencia e Innovación (MCINN)PID2019-111300GA-I00
Generalitat de Catalunya2018-BP-00204
Subject Keywords:Hydrocarbons, Peptides and proteins, Amines, Organic reactions, Propargyls
Issue or Number:1
PubMed Central ID:PMC8765727
DOI:10.1021/jacs.1c11340
Record Number:CaltechAUTHORS:20220119-572949000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220119-572949000
Official Citation:An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes Zhen Liu, Zi-Yang Qin, Ledong Zhu, Soumitra V. Athavale, Arkajyoti Sengupta, Zhi-Jun Jia, Marc Garcia-Borràs, K. N. Houk, and Frances H. Arnold Journal of the American Chemical Society 2022 144 (1), 80-85 DOI: 10.1021/jacs.1c11340
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112996
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:19 Jan 2022 23:04
Last Modified:21 Jan 2022 19:40

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