Integrated catalysis opens new arylation pathways via regiodivergent enzymatic C–H activation

Despite major recent advances in C–H activation, discrimination between two similar, unactivated C–H positions is beyond the scope of current chemocatalytic methods. Here we demonstrate that integration of regioselective halogenase enzymes with Pd-catalysed cross-coupling chemistry, in one-pot reactions, successfully addresses this problem for the indole heterocycle. The resultant ‘chemobio-transformation’ delivers a range of functionally diverse arylated products that are impossible to access using separate enzymatic or chemocatalytic C–H activation, under mild, aqueous conditions. This use of different biocatalysts to select different C–H positions contrasts with the prevailing substrate-control approach to the area, and presents opportunities for new pathways in C–H activation chemistry. The issues of enzyme and transition metal compatibility are overcome through membrane compartmentalization, with the optimized process requiring no intermediate work-up or purification steps. Biocatalysis and metal catalysis often provide complimentary reactivities and selectivities. Here, the authors exploit the regioselectivity of an enzymatic C–H activation followed by palladium catalysed carbon-carbon bond formation in one pot, with membrane compartmentalization used to isolate the two chemistries.