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A Biocatalytic Platform for Synthesis of Chiral α-Trifluoromethylated Organoborons

Huang, Xiongyi and Garcia-Borràs, Marc and Miao, Kun and Kan, S. B. Jennifer and Zutshi, Arjun and Houk, K. N. and Arnold, Frances H. (2019) A Biocatalytic Platform for Synthesis of Chiral α-Trifluoromethylated Organoborons. ACS Central Science, 5 (2). pp. 270-276. ISSN 2374-7943. PMCID PMC6396380. https://resolver.caltech.edu/CaltechAUTHORS:20181023-102546587

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Abstract

There are few biocatalytic transformations that produce fluorine-containing molecules prevalent in modern pharmaceuticals. To expand the scope of biocatalysis for organofluorine synthesis, we have developed an enzymatic platform for highly enantioselective carbene B–H bond insertion to yield versatile α-trifluoromethylated (α-CF_3) organoborons, an important class of organofluorine molecules that contain stereogenic centers bearing both CF_3 and boron groups. In contrast to current “carbene transferase” enzymes that use a limited set of simple diazo compounds as carbene precursors, this system based on Rhodothermus marinus cytochrome c (Rma cyt c) can accept a broad range of trifluorodiazo alkanes and deliver versatile chiral α-CF_3 organoborons with total turnovers up to 2870 and enantiomeric ratios up to 98.5:1.5. Computational modeling reveals that this broad diazo scope is enabled by an active-site environment that directs the alkyl substituent on the heme CF_3-carbene intermediate toward the solvent-exposed face, thereby allowing the protein to accommodate diazo compounds with diverse structural features.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscentsci.8b00679DOIArticle
https://pubs.acs.org/doi/suppl/10.1021/acscentsci.8b00679PublisherSupporting Information
https://chemrxiv.org/articles/A_Biocatalytic_Platform_for_Synthesis_of_Chiral_-Trifluoromethylated_Organoborons/7130852OrganizationDiscussion Paper
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396380PubMed CentralArticle
ORCID:
AuthorORCID
Huang, Xiongyi0000-0001-7156-8881
Garcia-Borràs, Marc0000-0001-9458-1114
Miao, Kun0000-0001-6567-3650
Kan, S. B. Jennifer0000-0001-6371-8042
Houk, K. N.0000-0002-8387-5261
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2019 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: September 25, 2018; Published: February 1, 2019. We thank Kai Chen, Zhijun Jia, and Russell Lewis for helpful discussions. This work was supported by National Institutes of Health, National Institute for General Medical Sciences, GM-124480 (to K.N.H.); Jacobs Institute for Molecular Engineering for Medicine at Caltech (F.H.A.); National Science Foundation Division of Molecular and Cellular Biosciences Grant MCB-1513007 (F.H.A.). X.H. is supported by an NIH pathway to independence award (Grant K99GM129419). M.G.-B. thanks the Ramón Areces Foundation for a postdoctoral fellowship. Computational resources were provided by the University of California, Los Angeles Institute for Digital Research and Education and the Extreme Science and Engineering Discovery Environment, which is supported by National Science Foundation Grant OCI-1053575. Author Contributions: X.H. and M.G.-B. contributed equally to this work. The authors declare no competing financial interest.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funders:
Funding AgencyGrant Number
NIHGM-124480
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
NSFMCB-1513007
NIHK99GM129419
Ramón Areces FoundationUNSPECIFIED
NSFOCI-1053575
Subject Keywords:Directed evolution; MD Simulations; chiral α-trifluoromethylated organoborons; organofluorine compounds
Issue or Number:2
PubMed Central ID:PMC6396380
Record Number:CaltechAUTHORS:20181023-102546587
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20181023-102546587
Official Citation:A Biocatalytic Platform for Synthesis of Chiral α-Trifluoromethylated Organoborons. Xiongyi Huang, Marc Garcia-Borràs, Kun Miao, S. B. Jennifer Kan, Arjun Zutshi, K. N. Houk, and Frances H. Arnold. ACS Central Science 2019 5 (2), 270-276. DOI: 10.1021/acscentsci.8b00679
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90359
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Oct 2018 19:48
Last Modified:03 Oct 2019 20:24

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