Peptidic Scaffolds Enable Rapid and Multivariate Secondary Sphere Evolution for an Abiotic Metallocatalyst

Metalloenzymes have benefited from the iterative process of evolution to achieve the precise arrangements ofsecondary sphere non-covalent interactions that enhance metal-centered catalysis. Iterative synthesis of scaffolds that displaycomplex secondary sphere elements in abiotic systems can behighly challenging and time-intensive. To overcome this syntheticbottleneck, we developed a highly modular and rapid syntheticstrategy, leveraging the efficiency of solid-phase peptide synthesisand conformational control afforded by non-canonical residues toconstruct a ligand platform displaying up to four unique residues ofvarying electronics and sterics in the secondary coordinationsphere. As a proof-of-concept that peptidic secondary sphere cancooperate with the metal complex, we applied this scaffold to a well-known, modestly active C-H oxidizing Fe catalyst to evolvespecific non-covalent interactions that is more than double its catalytic activity. Solution-state NMR structures of several catalystvariants suggest that higher activity is correlated with a hydrophobic pocket above the Fe center that may enhance the formation of acatalyst-substrate complex. Above all, we show that peptides are a convenient, highly modular, and structurally defined ligandplatform for creating secondary coordination spheres that comprise multiple, diverse functional groups