Programmable late-stage C−H bond functionalization enabled by integration of enzymes with chemocatalysis

New chemo- and biocatalytic methodology is important for the future sustainable synthesis of essential molecules. Transition metal catalysis enables the late-stage C−H functionalization of some complex molecular scaffolds, providing rapid routes to valuable products, although this is largely dependent on the availability of electronically or sterically predisposed C−H bonds for selective metalation, leaving certain regioselectivities inaccessible. Unlike metal chemocatalysis, enzymes can catalyse C−H bond functionalization, discriminating between near-identical, non-activated C−H bonds, delivering products with exquisite regioselectivity. However, enzymes typically provide access to fewer functionalities than more divergent chemocatalysis. Here we report programmable, regioselective C−H bond functionalization methodologies for the installation of versatile nitrile, amide and carboxylic acid moieties through integration of halogenase enzymes with palladium-catalysed cyanation and subsequent incorporation of nitrile hydratase or nitrilase enzymes. Using two- or three-component chemobiocatalytic systems, the regioselective synthesis of complex target molecules, including pharmaceuticals, can be achieved in a one-pot process operable on a gram scale.