Engineered and Artificial Metalloenzymes for Selective C-H Functionalization.

The direct functionalization of C-H bonds constitutes a powerful strategy to construct and diversify organic molecules. However, controlling the chemo- and site-selectivity of this transformation in particularly complex molecular settings represents a significant challenge. Metalloenzymes are ideal platforms for achieving catalyst-controlled selective C-H bond functionalization as their reactivities can be tuned by protein engineering and/or redesign of their cofactor environment. In this review, we highlight recent progress in the development of engineered and artificial metalloenzymes for C-H functionalization, with a focus on biocatalytic strategies for selective C-H oxyfunctionalization and halogenation as well as C-H amination and C-H carbene insertion via abiological nitrene and carbene transfer chemistries. Engineered heme- and non-heme iron dependent enzymes have emerged as promising scaffolds for executing these transformations with high chemo-, regio- and stereocontrol as well as tunable selectivity. These emerging systems and methodologies have expanded the toolbox of sustainable strategies for organic synthesis and created new opportunities for the generation of chiral building blocks, the late-stage C-H functionalization of complex molecules, and the total synthesis of natural products.