Paper
Biocatalytic Strategy for Highly Diastereo- and Enantioselective Synthesis of 2,3-Dihydrobenzofuran-Based Tricyclic Scaffolds.
Published Jun 24, 2019 · David A Vargas, R. Khade, Yong Zhang
Angewandte Chemie
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Abstract
2,3-Dihydrobenzofurans are key pharmacophores in many natural and synthetic bioactive molecules. A biocatalytic strategy is reported here for the highly diastereo- and enantioselective construction of stereochemically rich 2,3-dihydrobenzofurans in high enantiopurity (>99.9% de and ee), high yields, and on a preparative scale via benzofuran cyclopropanation with engineered myoglobins. Computational and structure-reactivity studies provide insights into the mechanism of this reaction, enabling the elaboration of a stereochemical model that can rationalize the high stereoselectivity of the biocatalyst. This information was leveraged to implement a highly stereoselective route to a drug molecule and a tricyclic scaffold featuring five stereogenic centers via a single-enzyme transformation. This work expands the biocatalytic toolbox for asymmetric C-C bond transformations and should prove useful for further development of metalloprotein catalysts for abiotic carbene transfer reactions.
This biocatalytic strategy allows for the highly diastereo- and enantioselective synthesis of 2,3-dihydrobenzofurans, potentially benefiting metalloprotein catalysts for abiotic carbene transfer reactions.
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