One‐Pot Two‐Step Chemoenzymatic Cascade for the Synthesis of a Bis‐benzofuran Derivative

Abstract

Chemoenzymatic cascades enable reactions with the high productivity of chemocatalysts and high selectivity of enzymes. Nevertheless, the combination of these different fields of catalysis is prone to mutual deactivation of metal- and biocatalysts. In this study, a one-pot sequential two-step catalytic cascade reaction was successfully implemented for the synthesis of a methylene-bridged bis(2-substituted benzofuran). In the first step, a palladium-free Sonogashira reaction is used for the synthesis of a benzofuran derivative. In the subsequent step, the formed 2-substituted benzofuran is hydroxylated by the monooxygenase P450 BM3 variant (A74S-F87V-L188Q) and undergoes further elimination reactions. The study proofs that combination of Cu scorpionate catalyzed Sonogashira cross-coupling and P450 mediated oxidation is possible and results in up to 84 % yield of the final product. The oxidation reaction is boosted by capturing inhibiting reaction components.