title: Highly Diastereo- and Enantioselective Synthesis of Trifluoromethyl-Substituted Cyclopropanes via Myoglobin-Catalyzed Transfer of Trifluoromethylcarbene.
abstract: We report an efficient strategy for the asymmetric synthesis of trifluoromethyl-substituted cyclopropanes by means of myoglobin-catalyzed olefin cyclopropanation reactions in the presence of 2-diazo-1,1,1-trifluoroethane (CF3CHN2) as the carbene donor. These transformations were realized using a two-compartment setup in which ex situ generated gaseous CF3CHN2is processed by engineered myoglobin catalysts expressed in bacterial cells. This approach was successfully applied to afford a variety of trans-1-trifluoromethyl-2-arylcyclopropanes in high yields (61-99%) and excellent diastereo- and enantioselectivity (97-99.9% de and ee). Furthermore, mirror-image forms of these products could be obtained using myoglobin variants featuring stereodivergent selectivity. These reactions provide a convenient and effective biocatalytic route to the stereoselective synthesis of key fluorinated building blocks of high value for medicinal chemistry and drug discovery. This work expands the range of carbene-mediated transformations accessible via metalloprotein catalysts and introduces a potentially general strategy for exploiting gaseous and/or hard-to-handle carbene donor reagents in biocatalytic carbene transfer reactions.
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14620, United States.
authors.forename: Antonio
authors.identifier: 0000-0003-3960-9457
authors.initials: A
authors.lastname: Tinoco
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14620, United States.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Steck
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14620, United States.
authors.forename: Vikas
authors.initials: V
authors.lastname: Tyagi
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14620, United States.
authors.forename: Rudi
authors.identifier: 0000-0003-4636-9578
authors.initials: R
authors.lastname: Fasan
mesh_terms: D002384:Catalysis; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D009211:Myoglobin / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D003521:Cyclopropanes; D006845:Hydrocarbons, Fluorinated; D009211:Myoglobin; C030011:carbene; D008697:Methane