Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination

Abstract

It is widely accepted that structural rigidity is required to achieve high levels of asymmetric induction in catalytic, enantioselective reactions. This fundamental design principle often does not apply to highly selective catalytic peptides that often exhibit conformational heterogeneity. As a result, these complex systems are particularly challenging to study both experimentally and computationally. Herein, we utilize molecular dynamics simulations to investigate the role of conformational mobility on the reactivity and selectivity exhibited by a catalytic, β-turn-biased peptide in an atroposelective bromination reaction. By means of cluster analysis, multiple distinct conformers of the peptide and a catalyst-substrate complex were identified in the simulations, all of which were corroborated by experimental NMR measurements. The simulations also revealed that a shift in the conformational equilibrium of the peptidic catalyst occurs upon addition of substrate, and the degree of change varies among different substrates. On the basis of these data, we propose a correlation between the composition of the peptide conformational ensemble and its catalytic properties. Moreover, these findings highlight the importance of conformational dynamics in catalytic, asymmetric reactions mediated by oligopeptides, unveiled through high-level, state-of-the-art computational modeling.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…Second, it exhibits high degrees of selectivity despite the use of a highly‐fluxional chiral catalyst. This is contrary to the conventional view that highly selective catalysts should be fairly rigid, raising fundamental questions regarding the interplay of catalyst flexibility and selectivity . Finally, Sibi et al .…”

“…This is contrary to the conventional view that highly selective catalystss hould be fairly rigid, raising fundamentalq uestions regarding the interplay of catalyst flexibility and selectivity. [36,37] Finally, Sibi et al [28] observed that biaryl alcohols with electronrich substituents at the b'-position exhibit much higher selectivitiest han those with electron-poor ones. Although this was explained in terms of ap ossible non-covalent interaction betweenthese substituents and the N-acyl group, the established precedento fp···p + interactions in similara cylation reactions [32][33]35] raises the possibility that these substituent effects are due to the modulation of p···p + interactions in the stereochemistry-controllingtransition state (TS).…”

Conformational Dynamics in Asymmetric Catalysis: Is Catalyst Flexibility a Design Element?

“…Computational approaches, particularly multivariate linear regression tools and molecular dynamics simulations have been used to further study the atroposelective bromination of quinazolinones. 53…”

“…6a ,6c, 7a One strategy to potentially address this challenge and gain insight into key structural features that influence selectivity is to develop structure-function relationships through the application of modern physical organic tools to relate the reaction output(s) to computed structural parameters. 53a ,55…”

“…Miller, Sigman, and coworkers applied this type of analysis to gain insight into which conformation is more responsible for the observed selectivity and to gain insight into key catalyst features to inform future catalyst development. 53a Because the most significant variations in selectivity were observed when altering the i+ 2 residue, an initial truncation design was employed to reduce the conformational space and focus on changes at the i+2 residue (Figure 2c). Both major turn types (I′ and II′) were computed (M06–2X/def2-TZVP) and parameters, including IR stretching frequencies, natural bond orbital (NBO) charges, 56 Sterimol parameters, 57 and dihedral angles, were extracted.…”