Heme-enzymatic biocatalysis for C−C or C−N bond formation

The C−C or C−N bond formation is critical in the synthesis of pharmaceuticals and other value-added products; however, traditional metal-catalysed synthesis has brought about environmental and resource issues. A plethora of engineered heme-dependent enzymes, such as cytochrome P450, have exhibited enormous potential in biocatalysis for C−C or C−N bond formation. With the development of computational and spectroscopic methods, the mechanisms underlying heme-catalysed C−C or C−N bond formation have been extensively investigated. In the presence of carbene or nitrene precursor, an active iron porphyrin carbene (IPC) or iron porphyrin nitrene (IPN) is formed, which subsequently reacts with a second substrate to form new C−C or C−N bonds. Apart from the widely studied IPC/IPN-facilitated catalytic pathway, halide-initiated radical cyclization pathway and Cpd-I-catalysed diradical pathway have also been proposed. These mechanistic insights have enabled rational engineering and de novo design of heme enzymes. This review summarises recent mechanistic advances in heme enzymatic C−C or C−N bond formation and presents successful applications of mechanism-based enzyme design. It would shed light on the development of tailored biocatalysts for the synthesis of complex but valuable industrial products.