Stereocontrolled 1,3‐Nitrogen Migration Catalyzed by Artificial Metalloenzymes Bearing Stereogenic Metal Centers

Abstract Octahedral complexes with linear tetradentate ligands are effective catalysts for various chemical transformations, with the cis ‐α geometry typically being the active form. These complexes possess stereogenic metal centers, adopting either Λ‐ or Δ‐configurations. We hypothesized that embedding these complexes within the chiral environment of protein scaffolds could yield artificial metalloenzymes (ArMs) with both an enantioenriched metal center and a chiral catalytic pocket. This combination could potentially act synergistically, enhancing catalytic reactivity and selectivity, thereby producing more powerful and tunable catalysts compared to the complexes alone. In this study, we designed two cofactors featuring octahedral Fe complexes: cofactor 1 , which, due to its rigid chiral backbone, exclusively forms the Δ‐configuration, and cofactor 2 , which forms a racemic mixture. Using biotin‐streptavidin technology, we developed ArMs based on these cofactors and evaluated them in a 1,3‐nitrogen migration reaction to produce chiral α‐amino acids. Both ArMs exhibited protein mutant‐dependent reactivity and selectivity, with cofactor 1 demonstrating notable synergistic or conflicting effects between the protein scaffold and the metal‐centered configuration. This work highlights the potential of developing ArMs with stereogenic metal centers for highly selective catalysis.