Biocatalytic Strategy for Highly Diastereo- and Enantioselective Synthesis of 2,3-Dihydrobenzofuran-Based Tricyclic Scaffolds

David A. Vargas, Rahul L. Khade, Yong Zhang, Rudi Fasan

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish
Pages (from-to)10148-10152
Number of pages5
JournalAngewandte Chemie - International Edition
Volume58
Issue number30
DOIs
StatePublished - 22 Jul 2019

Keywords

  • benzofuran cyclopropanation
  • biocatalysis
  • carbene transfer
  • dihydrobenzofurans
  • myoglobin

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