Highly Diastereo- and Enantioselective Synthesis of Trifluoromethyl-Substituted Cyclopropanes via Myoglobin-Catalyzed Transfer of Trifluoromethylcarbene

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 (CF 3 CHN 2 ) as the carbene donor. These transformations were realized using a two-compartment setup in which ex situ generated gaseous CF 3 CHN 2 is 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.