Enantiodivergent Functionalization of Aryl Alkenes into Diverse Biarylalkanoic Acids by Integrating Biocatalytic Cascades with Chemocatalysis

Chemo-enzymatic reactions have received great attention for asymmetric synthesis, but most reported systems use only one- or two-step enzymatic reactions for relatively simple functionalization and are based on a chemo-enzyme sequence, which is limited by the substrate scope of enzymes. Herein, we report a "multienzyme cascade─chemocatalysis" concept via an enzyme-chemo sequence for complex asymmetric functionalization of simple substrates by integrating multistep biocascades to introduce functionality and enantioselectivity, with robust chemocatalysis to diversify the product scope. The concept was successfully demonstrated through the enantiodivergent synthesis of 12 structurally diverse (S)- and (R)-2-biarylpropanoic acids (94–97% ee; up to >99% conversion) from easily available aryl alkenes by engineering epoxidation–isomerization–oxidation biocascades containing enantio-complementary enzymes and combining with Pd-catalyzed cross-coupling. The enzyme-chemical strategy was extended to the high-yielding synthesis of NSAID drugs (S)-flurbiprofen, (S)-ketoprofen, and felbinac. This concept enables streamlined synthetic routes that are inaccessible by each type of catalyst alone or a chemo-enzyme sequence.