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Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer

Schaus, Lucas and Das, Anuvab and Knight, Anders M. and Jimenez-Osés, Gonzalo and Houk, K. N. and Garcia-Borràs, Marc and Arnold, Frances H. and Huang, Xiongyi (2023) Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer. Angewandte Chemie International Edition, 62 (4). Art. No. e202208936. ISSN 1433-7851. PMCID PMC9894577. doi:10.1002/anie.202208936.

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Trifluoromethyl-substituted cyclopropanes (CF₃-CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans-CF₃-CPAs, stereoselective production of corresponding cis-diastereomers remains a formidable challenge. We report a biocatalyst for diastereo- and enantio-selective synthesis of cis-CF₃-CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low-to-excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron-carbenoid and substrates to adopt a pro-cis near-attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF₃-CPAs for drug discovery.

Item Type:Article
Related URLs:
URLURL TypeDescription
Schaus, Lucas0000-0002-6094-7402
Das, Anuvab0000-0002-9344-4414
Knight, Anders M.0000-0001-9665-8197
Jimenez-Osés, Gonzalo0000-0003-0105-4337
Houk, K. N.0000-0002-8387-5261
Garcia-Borràs, Marc0000-0001-9458-1114
Arnold, Frances H.0000-0002-4027-364X
Huang, Xiongyi0000-0001-7156-8881
Additional Information:The authors thank Dr. Sabine Brinkmann-Chen for critical reading of the manuscript. This research is supported by the NSF Division of Molecular and Cellular Biosciences (2016137); the Spanish Ministry of Science and Innovation MICINN (grant PID2019-111300GA-I00 and RYC2020-028628-I fellowship to M.G.B; and grant RTI2018-099592-B-C22 to G.J.-O.); the National Institute for General Medical Sciences (grant R00GM129419 to X.H.). L.S. is grateful to the Fonds National de la Recherche Luxembourg (FNR) for an AFR individual PhD grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NSF. A.M.K. acknowledges support from the NSF Graduate Research Fellowship (Grant No. DGE-1745301).
Funding AgencyGrant Number
Ministerio de Ciencia e Innovación (MICINN)PID2019-111300GA-I00
Ramón y Cajal ProgrammeRYC2020-028628-I
Ministerio de Ciencia e Innovación (MICINN)RTI2018-099592-B-C22
Fonds de la Recherche Scientifique (FNRS)UNSPECIFIED
NSF Graduate Research FellowshipDGE-1745301
Issue or Number:4
PubMed Central ID:PMC9894577
Record Number:CaltechAUTHORS:20230123-451841300.46
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:118906
Deposited By: Research Services Depository
Deposited On:24 Feb 2023 17:43
Last Modified:24 Feb 2023 17:43

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