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

Abstract

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.

Revisiting 310-helices: biological relevance, mimetics and applications

“…Girvin et al [213] reported a catalytic covalent template-directed aldol macrocyclization of a linear dialdehyde (Figure 13B). The catalytic template is a hybrid α-/β-peptide foldamer with an αββ backbone pattern containing constrained 5-membered residues.…”

“…The catalytic template is a hybrid α-/β-peptide foldamer with an αββ backbone pattern containing constrained 5-membered residues. As featured in the previous section entitled "Stabilization of 3 10 -helices in peptides", this type of peptide foldamers can adopt 3 10 -helix-like conformations, critical for the formation of an enamine and an iminium adduct with the substrate displaying the right geometrical constrains to favor the macrocyclization reaction over potential linear polymerization pathways [213].…”