Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 30, Pages 10148-10152Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201903455
Keywords
benzofuran cyclopropanation; biocatalysis; carbene transfer; dihydrobenzofurans; myoglobin
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Funding
- U.S. National Institute of Health [GM098628]
- National Science Foundation [CHE-1300912]
- NSF Graduate Fellowship Program
- U.S. National Science Foundation [CHE-0946653, CHE-1725028]
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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.
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