Transition metal-catalyzed carbene transfer reactions are powerful transformations for the construction of new carbon-carbon and carbon-heteroatom bonds, but current chemocatalytic methods often require rare and non-sustainable metals and/or lack of selectivity. Our group has previously established that engineered myoglobins are promising catalysts for catalyzing carbene transfer reactions with high degrees of catalytic activity and stereoselectivity. Building upon this progress, we developed and report here the first examples of biocatalytic strategies for the carbene-mediated functionalization of indoles and benzofurans. These hetererocycles are prevalent motifs in drug molecules and bioactive natural products. Using engineered myoglobin as catalysts, we developed an efficient biocatalytic approach for the chemoselective C-H functionalization of unprotected indoles and for the stereoselective cyclopropanation of benzofurans with excellent degrees of diastereo- and enantiocontrol (&gt;99% <i>de</i> and <i>ee</i>). The mechanism of these transformations was investigated experimentally and computationally, revealing the interplay of substrate- and catalyst-dependent factors in controlling the divergent reactivity of the biocatalyst (C-H functionalization vs. cyclopropanation) toward the structurally related heterocycles. Lastly, these biocatalytic methodologies could be applied to implement concise chemoenzymatic routes for the synthesis of two drug molecules.

Selective functionalization of heterocycles via myoglobin-catalyzed carbene transfer chemistry

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.