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

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.

Kinetic Analysis of a Cysteine-Derived Thiyl-Catalyzed Asymmetric Vinylcyclopropane Cycloaddition Reflects Numerous Attractive Noncovalent Interactions

“…These calculated structures provide atomistic pictures that support the plausibility of I R and I S as intermediates. A comprehensive computational assessment of various contingencies for these flexible systems, for example combining molecular dynamics simulations with DFT-level refinement, − could well reveal more insight. Nevertheless, the structures of I R and I S ground each as reasonable catalyst–substrate complexes of differing energy along the complex reaction coordinate surface.…”

Conformational enantiodiscrimination for asymmetric construction of atropisomers

“…However, in asymmetric catalysis, it is well-known that structural rigidity of non-enzymatic chiral catalysts, such as the 2,2′-bis(diphenylphosphino)−1,1′-binaphthyl (BINAP)-metal complexes 3 , 4 and BINOL-based phosphoric acids 5 , 6 shown in Fig. 1c , is usually essential in achieving high levels of asymmetric inductions 7 – 9 and less attention has been paid to the molecular flexibility and conformational dynamics of the chiral catalysts 10 – 15 . Due to the great difficulty in isolating the conformers, it is very challenging to reveal the relationship between the conformations of chiral catalysts and the enantiodiscrimination.…”

A Combined DFT, Energy Decomposition, and Data Analysis Approach to Investigate the Relationship Between Noncovalent Interactions and Selectivity in a Flexible DABCOnium/Chiral Anion Catalyst System

“…An Eyring analysis demonstrated that the solvent-dependent enantioselectivity of the conformationally flexible catalyst was a result of switching between an enthalpically and entropically controlled mechanism. Within the realm of organocatalysis, some of the most prolifically studied flexible systems have been small-molecule peptide catalysts. , Recent work by the Miller and Baker groups demonstrated that, in a peptide-catalyzed, atroposelective bromination, , a more flexible peptide enhanced enantioselectivity, as compared to a less flexible analogue (Scheme C) . This outcome resulted from the catalyst’s ability to more easily access selective and reactive catalyst conformations in transition states.…”

“…8,9 Recent work by the Miller and Baker groups demonstrated that, in a peptide-catalyzed, atroposelective bromination, 10,11 a more flexible peptide enhanced enantioselectivity, as compared to a less flexible analogue (Scheme 1C). 12 This outcome resulted from the catalyst's ability to more easily access selective and reactive catalyst conformations in transition states. Despite these advances, understanding the origins of selectivity in conformationally flexible catalyst systems remains an ongoing challenge.…”