Isolating Conformers to Assess Dynamics of Peptidic Catalysts Using Computationally Designed Macrocyclic Peptides

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.

研究不对称反应中催化剂构象动态与选择性之间的关联，是一项颇具挑战性的课题。本研究通过计算设计环肽，用以稳定一款用于N-芳基喹唑啉酮阻转选择性溴化反应的高效柔性四肽催化剂的不同基态构象。通过计算与实验技术相结合的手段，我们证实：该先导催化剂的动态运动，对本研究反应实现高对映选择性起到关键作用。该策略亦可作为研究其他肽催化转化反应机制的有效手段。