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Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer |
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| Authors: | Lucas Schaus Dr Anuvab Das Dr Anders M Knight Dr Gonzalo Jimenez-Osés Prof Dr K N Houk Dr Marc Garcia-Borràs Prof Dr Frances H Arnold Prof Dr Xiongyi Huang |
| Institution: | 1. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd., Pasadena, CA 91125 USA
These authors contributed equally to this work. Contribution: Data curation (lead), Formal analysis (equal), Investigation (lead), Methodology (lead), Validation (equal), Writing - original draft (equal);2. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd., Pasadena, CA 91125 USA;3. Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160 Derio, Spain;4. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095 USA;5. Institut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, C/M. Aurèlia Capmany, 69, 17003 Girona, Spain;6. Department of Chemistry, Johns-Hopkins University, Baltimore, MD 21218 USA |
| Abstract: | 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. |
| Keywords: | Biocatalysis Carbenes Cyclopropanes Organofluorines Protoglobins |