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
(CF3CHN2) as the carbene donor. These transformations
were realized using a two-compartment setup in which ex situ generated gaseous CF3CHN2 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.