Dynamic metal coordination controls chemoselectivity in a radical halogenase

The activation of inert C(sp³)–H bonds by nonheme Fe enzymes provides a powerful biocatalytic platform for the chemical synthesis of molecules with increased sp³ complexity. In this context, Fe^II/α-ketoglutarate-dependent radical halogenases are uniquely capable of carrying out transfer of a diverse array of bound anions following C–H activation. Here, we provide experimental evidence that bifurcation of radical rebound after H-atom abstraction can be driven both by the ability of a dynamic metal coordination sphere to reorganize and by a second-sphere hydrogen-bonding network where only two residues are sufficient. In addition, we present crystallographic data supporting the existence of an early peroxyhemiketal intermediate in the O₂ activation pathway of Fe^II/α-ketoglutarate-dependent enzymes. These data provide a paradigm for understanding the evolution of catalytic plasticity in these enzymes and yields insight into the design principles by which to expand their reaction scope. (Figure presented.)