Artificial Metalloenzyme-Catalyzed Enantioselective Amidation via Nitrene Insertion in Unactivated C(sp ³)-H Bonds

Enantioselective C-H amidation offers attractivemeans toassemble C-N bonds to synthesize high-added value, nitrogen-containingmolecules. In recent decades, complementary enzymatic and homogeneous-catalyticstrategies for C-H amidation have been reported. Herein, wereport on an artificial metalloenzyme (ArM) resulting from anchoringa biotinylated Ir-complex within streptavidin (Sav). The resultingArM catalyzes the enantioselective amidation of unactivated C(sp (3))-H bonds. Chemogenetic optimizationof the Ir cofactor and Sav led to significant improvement in boththe activity and enantioselectivity. Up to >700 TON and 92% eeforthe amidation of unactivated C(sp (3))-Hbonds was achieved. The single crystal X-ray analysis of the artificialnitrene insertase (ANIase) combined with quantum mechanics-molecularmechanics (QM-MM) calculations sheds light on critical second coordinationsphere contacts leading to improved catalytic performance.