Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 139, Issue 15, Pages 5293-5296Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.7b00768
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Funding
- U.S. NIH [GM098628]
- NSF [CHE-1609550]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1609550] Funding Source: National Science Foundation
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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 diastereoand enantioselectivity (97-99.9% de and ee). Furthermore, mirror-image forms of these products could be obtained using myoglobin variants featuring stereo divergent 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.
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