Isolating Conformers to Assess Dynamics of Peptidic Catalysts Using Computationally Designed Macrocyclic Peptides
Elizabeth A. Stone, Parisa Hosseinzadeh, Timothy W. Craven, Michael J. Robertson, Yaodong Han, Sheng‐Ying Hsieh, Anthony J. Metrano, David Baker, Scott J. Miller
Abstract
Studying the relationship between catalyst conformational dynamics and selectivity in an asymmetric reaction is a challenge. In this study, cyclic peptides were computationally designed to stabilize different ground state conformations of a highly effective, flexible tetrapeptide catalyst for the atroposelective bromination of N-aryl quinazolinones. Through a combination of computational and experimental techniques, we have determined that dynamic movement of the lead catalyst plays a crucial role in achieving high enantioselectivity in the reaction of study. This approach may also serve as a valuable method for investigating the mechanism of other peptide-catalyzed transformations.