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 of secondary sphere non-covalent
interactions that enhance metal-centered catalysis. Iterative synthesis
of scaffolds that display complex secondary sphere elements in abiotic
systems can be highly challenging and time-intensive. To overcome
this synthetic bottleneck, we developed a highly modular and rapid
synthetic strategy, leveraging the efficiency of solid-phase peptide
synthesis and conformational control afforded by non-canonical residues
to construct a ligand platform displaying up to four unique residues
of varying electronics and sterics in the secondary coordination sphere.
As a proof-of-concept that peptidic secondary sphere can cooperate
with the metal complex, we applied this scaffold to a well-known,
modestly active C–H oxidizing Fe catalyst to evolve specific
non-covalent interactions that is more than double its catalytic activity.
Solution-state NMR structures of several catalyst variants suggest
that higher activity is correlated with a hydrophobic pocket above
the Fe center that may enhance the formation of a catalyst–substrate
complex. Above all, we show that peptides are a convenient, highly
modular, and structurally defined ligand platform for creating secondary
coordination spheres that comprise multiple, diverse functional groups.