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

doi:10.1021/jacs.7b00768

Paper

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

Published Apr 10, 2017 · Antonio Tinoco, Viktoria Steck, V. Tyagi

Journal of the American Chemical Society

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125

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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 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.

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Study Snapshot

Myoglobin-catalyzed olefin cyclopropanation reactions enable the efficient synthesis of trifluoromethyl-substituted cyclopropanes with high yields and excellent diastereo- and enantioselectivity, valuable for medicinal

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

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Sperm whale myoglobin variant Mb(L29S,H64V,V68F) efficiently catalyzes the Doyle-Kirmse reaction, enabling the synthesis of valuable C-C bonds and propargylic sulfides.

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Artificial metalloenzymes with iridium in place of iron show similar kinetics and stability to natural enzymes, enabling the merging of chemical and biocatalysis for highly active, productive, and selective reactions.

Citations

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Biocatalytic Generation of Trifluoromethyl Radicals by Nonheme Iron Enzymes for Enantioselective Alkene Difunctionalization.

Nonheme iron enzymes can generate trifluoromethyl radicals and direct them for enantioselective alkene trifluoromethyl azidation, expanding the catalytic repertoire for radical transformations and creating a new enzymatic space for organofluorine synthesis.

Stereoselective Synthesis of Silyl Enol Ethers with Acylsilanes and α,β-Unsaturated Ketones.

This study presents a siloxycarbene-mediated stereoselective synthesis of silyl enol ethers using visible-light-induced intermolecular reactions between acylsilanes and,-unsaturated ketones, offering atomic economics, exclusive stereo

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Myoglobin-based carbene transferases designed using computer-aided protein engineering broaden the substrate scope for heme protein-catalyzed reactions, offering new perspectives in the synthesis of bioactive molecules.

Development of novel transition metal-catalyzed synthetic approaches for the synthesis of a dihydrobenzofuran nucleus: a review

Novel transition metal-catalyzed synthetic approaches have been developed for the efficient synthesis of dihydrobenzofuran nuclei, with potential pharmaceutical applications.