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Asymmetric Alkylation of Ketones Catalyzed by Engineered TrpB

Watkins-Dulaney, Ella J. and Dunham, Noah P. and Straathof, Sabine and Turi, Soma and Arnold, Frances H. and Buller, Andrew R. (2021) Asymmetric Alkylation of Ketones Catalyzed by Engineered TrpB. Angewandte Chemie International Edition, 60 (39). pp. 21412-21417. ISSN 1433-7851. PMCID PMC8440449. doi:10.1002/anie.202106938. https://resolver.caltech.edu/CaltechAUTHORS:20210729-171601468

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Abstract

The β-subunit of tryptophan synthase (TrpB) catalyzes a PLP-mediated β-substitution reaction between indole and serine to form L-Trp. A succession of TrpB protein engineering campaigns to expand the enzyme's nucleophile substrate range has enabled the biocatalytic production of diverse non-canonical amino acids (ncAAs). Here, we show that ketone-derived enolates can serve as nucleophiles in the TrpB reaction to achieve the asymmetric alkylation of ketones, an outstanding challenge in synthetic chemistry. We engineered TrpB by directed evolution to catalyze the asymmetric alkylation of propiophenone and 2-fluoroacetophenone with a high degree of selectivity. In reactions with propiophenone, preference for the opposite product diastereomer emerges over the course of evolution, demonstrating that full control over the stereochemistry at the new chiral center can be achieved. The addition of this new reaction to the TrpB platform is a crucial first step toward the development of efficient methods to synthesize non-canonical prolines and other chirally dense nitrogen heterocycles.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/anie.202106938DOIArticle
ORCID:
AuthorORCID
Watkins-Dulaney, Ella J.0000-0002-0585-1598
Dunham, Noah P.0000-0001-8006-9566
Arnold, Frances H.0000-0002-4027-364X
Buller, Andrew R.0000-0002-9635-4844
Additional Information:© 2021 Wiley-VCH GmbH. Issue Online: 14 September 2021; Version of Record online: 18 August 2021; Accepted manuscript online: 15 July 2021; Manuscript received: 27 May 2021. We thank Nathaniel Goldberg for assistance with NMR interpretation and Dr. Nicholas Porter, Dr. David Miller, and Dr. Benjamin Levin for insightful discussions. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers R01GM125887 (to F.H.A.) and DP2-GM137417 (to A.R.B.) and the Rothenberg Innovation Initiative at Caltech. N.P.D. was supported by Ruth L. Kirschstein NIH Postdoctoral Fellowship (F32GM131620). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHR01GM125887
NIHDP2-GM137417
Rothenberg Innovation Initiative (RI2)UNSPECIFIED
NIH Postdoctoral FellowshipF32GM131620
Subject Keywords:asymmetric catalysis; biocatalysis; directed evolution; ketones; nitrogen heterocycles
Issue or Number:39
PubMed Central ID:PMC8440449
DOI:10.1002/anie.202106938
Record Number:CaltechAUTHORS:20210729-171601468
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210729-171601468
Official Citation:Asymmetric Alkylation of Ketones Catalyzed by Engineered TrpB. E. J. Watkins-Dulaney, N. P. Dunham, S. Straathof, S. Turi, F. H. Arnold, A. R. Buller, Angew. Chem. Int. Ed. 2021, 60, 21412; DOI: 10.1002/anie.202106938
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110068
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Aug 2021 18:52
Last Modified:17 Sep 2021 19:11

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