Biocatalytic strategy for highly diastereo- and enantioselective synthesis of 2,3-dihydrobenzofuran based tricyclic scaffolds

Abstract

2,3-Dihydrobenzofurans are key pharmacophores in many synthetic and naturally occurring bioactive molecules. A biocatalytic strategy is reported here for the highly diastereo- and enantioselective construction of stereochemically dense 2,3-dihydrobenzofurans in excellent 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 iron-catalyzed 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 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 the mechanistic insights accrued here should prove useful for further development of metalloprotein catalysts for abiotic carbene transfer reactions.

Graphical Abstract:

Forging rings with iron: A novel biocatalytic strategy for the highly stereoselective cyclopropanation of benzofurans is reported. This approach enables the efficient construction of enantiopure 2,3-dihydrobenzofuran-based tricyclic scaffolds useful for the synthesis of pharmaceuticals and bioactive natural products. Computational and structure-activity studies provide insights into the mechanism of this reaction and the protein-mediated control of its stereochemical outcome.