Optimizing the Local Chemical Environment on a Bifunctional Helical Peptide Scaffold Enables Enhanced Enantioselectivity and Cooperative Catalysis.

ABSTRACT

We describe a proof-of-concept study in which peptide-bound enamine and thiourea catalysts are used to facilitate the conjugate addition of cyclohexanone to nitroolefins. Our bifunctional peptide scaffold is modified to optimize the local environment around both catalysts to enhance both reactivity and enantioselectivity, affording selectivities of ≤95% ee. Circular dichroism, nuclear magnetic resonance nuclear Overhauser effect studies, and molecular dynamics simulations verify the helical structure of our catalyst in solution and the importance of the secondary structure in catalysis.