Proximity-Induced Reactivity and Product Selectivity with a Rationally Designed Bifunctional Peptide Catalyst

Abstract

Cooperative catalytic systems are making significant advances in modern organic synthesis due to the potential to combine multiple catalytic cycles or enable enzyme-like proximity effects. We report the rational design of a bifunctional helical peptide catalyst that displays an imidazolidinone catalyst in close proximity to a thiourea binding site and enables proximity-enhanced reactivity and selectivity. The helical structure of the peptide and the binding of both reactants are shown to be essential for enhanced reactivity in Diels–Alder and indole alkylation reactions, and up to 28 000 catalyst turnovers are achieved. A variety of Lewis basic functional groups facilitate binding and proximity-enhanced reactivity, and product selectivity is observed that cannot be achieved in the absence of the peptide template.

CAN: A new program to streamline preparation of molecular coordinate files for molecular dynamics simulations

“…To test our CAN program, we first built several non‐native residues and created mol2 files using Avogadro. These non‐native residues include commonly used amino acids like aminoisobutyric acid (Aib) and very unique residues such as thiourea and enamine catalytic groups that we previously used in the development of peptide‐based catalysts 28 . We also included a stapled polypeptide containing a non‐native squaric acid staple (WW‐domain) previously developed by our group (see Supporting Information for detailed structures) 29 .…”

Foldamer Catalysis

“…Price, Michaelis et al have developed helical α-peptides that serve as bifunctional catalysts of enantioselective Diels−Alder and indole alkylation reactions. 41 These catalysts can be considered "foldamers" because they feature non-proteinogenic residues not only to provide catalytic functionality (an imidazolidinone and a thiourea, projecting from side chains) but also to promote a helical conformation (Aib residues). The Diels−Alder reaction between 2-butenal and a carbamate- functionalized diene occurred with high yield and enantioselectivity with a peptide catalyst (5) (Figure 7A).…”

DNA-Scaffolded Synergistic Catalysis

“…Examples include synergistic combinations of transition metal catalysts, photocatalysts, organocatalysts, radical catalysts, and Lewis acid catalysts. − In scaffolded synergistic catalysis, the proximity afforded by precise positioning of the cocatalysts accelerates the reaction compared to unscaffolded reactions, in which the large mean distance between the cocatalysts limits synergistic interactions, often necessitating high loadings . Successful demonstrations of scaffolded synergistic catalysis have utilized peptoids, peptides, , foldamers, soluble proteins, , metal–organic frameworks, , covalent–organic frameworks, and polymers . However, it remains challenging to fine-tune the spacing of each cocatalyst.…”