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.

Asymmetric Catalysis Mediated by Synthetic Peptides, Version 2.0: Expansion of Scope and Mechanisms.

Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759-5812). The overarching goal of this new Review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C-C bond formation, in which peptides have been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.

Catalytic Hydroetherification of Unactivated Alkenes Enabled by Proton-Coupled Electron Transfer.

We report a catalytic, light-driven method for the intramolecular hydroetherification of unactivated alkenols to furnish cyclic ether products. These reactions occur under visible-light irradiation in the presence of an IrIII -based photoredox catalyst, a Brønsted base catalyst, and a hydrogen-atom transfer (HAT) co-catalyst. Reactive alkoxy radicals are proposed as key intermediates, generated by direct homolytic activation of alcohol O-H bonds through a proton-coupled electron-transfer mechanism. This method exhibits a broad substrate scope and high functional-group tolerance, and it accommodates a diverse range of alkene substitution patterns. Results demonstrating the extension of this catalytic system to carboetherification reactions are also presented.

Troponoid Atropisomerism: Studies on the Configurational Stability of Tropone-Amide Chiral Axes.

Configurationally stable, atropisomeric motifs are an important structural element in a number of molecules, including chiral ligands, catalysts, and molecular devices. Thus, understanding features that stabilize chiral axes is of fundamental interest throughout the chemical sciences. The following details the high rotational barriers about the Ar-C(O) bond of tropone amides, which significantly exceed those of analogous benzamides. These studies are supported by both experimental and computational rotational barrier measurements. We also report the resolution of an axially chiral α-hydroxytropolone amide into its individual atropisomers, and demonstrate its configurational stability at physiological pH and temperatures over 24 h.

Peptide-Based Catalysts Reach the Outer Sphere through Remote Desymmetrization and Atroposelectivity.

Nature's catalytic machinery has provided endless inspiration for chemists. While the enzymatic ideal has yet to be fully realized, the field has made tremendous strides toward synthetic, small-molecule catalysts for a wide array of transformations, often drawing upon biological concepts in their design. One strategy that has been particularly influenced by enzymology is peptide catalysis, wherein oligopeptides are implemented as chiral catalysts in synthetically relevant reactions. The fundamental goal has been to mimic enzymatic active sites by taking advantage of secondary structures that allow for multifunctional activation of substrates within a framework of significantly reduced molecular complexity. Our group has now been studying peptide-based catalysis for over two decades. At the outset, there were many reasons to be concerned that general contributions might not be possible. Precedents existed, including the Juliá-Colonna epoxidations mediated by helical oligopeptides, among others. However, we sought to explore whether peptide catalysts could find broad applications in organic synthesis despite what was expected to be their principal liability: conformational flexibility. Over time, we have been able to identify peptidic catalysts for a variety of site- and enantioselective transformations ranging from hydroxyl group and arene functionalizations to redox and C-C bond forming reactions. The peptides often exhibited excellent catalytic activities, in many cases enabling never-before-seen patterns of selectivity. Recent studies even suggest that, in certain situations, the conformational flexibility of these catalysts may be advantageous for asymmetric induction. In the course of our studies, opportunities to employ peptide-based catalysis to solve long-standing and stereochemically intriguing problems in asymmetric synthesis presented themselves. For example, we have found that peptides provide exceptional enantiotopic group differentiation in catalytic desymmetrization reactions. Early results with symmetrical polyol substrates, such as myo-inositols and glycerols, eventually spurred the development of remote desymmetrizations of diarylmethanes, in which the enantiotopic groups are separated from the prochiral center by ∼6 Å and from one another by nearly 1 nm. Various hydroxyl group functionalizations and electrophilic brominations, as well as C-C, C-O, and C-N cross-coupling reactions using peptidic ligands on copper(I) have now been developed within this reaction archetype. Additionally, the preponderance of axially chiral, atropisomeric compounds as ligands, organocatalysts, and pharmacophores encouraged us to employ peptides as atroposelective catalysts. We have developed peptide-catalyzed brominations of pharmaceutically relevant biaryl, non-biaryl, and hetero-biaryl atropisomers that take advantage of dynamic kinetic resolution schemes. These projects have vastly expanded the reach of our original hypotheses and raised new questions about peptide-based catalysts and the extent to which they might mimic enzymes. Herein, we recount the development and optimization of these stereochemically complex reactions, with a particular focus on structural and mechanistic aspects of the peptide-based catalysts that make them well-suited for their respective functions. The ability of these peptides to address important yet fundamentally challenging issues in asymmetric catalysis, combined with their modularity and ease-of-synthesis, make them primed for future use in organic synthesis.

Parameterization and Analysis of Peptide-Based Catalysts for the Atroposelective Bromination of 3-Arylquinazolin-4(3H)-ones.

We report the development of a method to parameterize and predict the performance of structurally flexible ß-turn-containing peptide catalysts, using the atroposelective bromination of 3-arylquinazolin-4(3H)-ones as a case study. The multivariate correlations obtained for tetrapeptides of two ß-turn types, type I' pre-helical and type II' ß-hairpin, indicate that although one conformer may be associated with a more dominant contribution to the observed enantioselectivity, it is possible that multiple conformers contribute to a complex transition state ensemble.

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

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, ß-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.

Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst.

Diarylmethylamido bis(phenols) have been subjected to peptide-catalyzed, enantioselective bromination reactions. Desymmetrization of compounds in this class has been achieved such that enantioenriched products may be isolated with up to 97:3 er. Mechanistically, the observed enantioselectivity was shown to be primarily a function of differential functionalization of enantiotopic arenes, although additional studies unveiled a contribution from secondary kinetic resolution of the product (to afford the symmetrical dibromide) under the reaction conditions. Variants of the tetrapeptide catalyst were also evaluated and revealed a striking observation-enantiodivergent catalysis is observed upon changing the achiral amino acid residue in the catalyst (at the i+2 position) from an aminocyclopropane carboxamide residue (97:3 er) to an aminoisobutyramide residue (33:67 er) under a common set of conditions. An expanded set of catalysts was also evaluated, enabling structure/selectivity correlations to be considered in a mechanistic light.

Diversity of Secondary Structure in Catalytic Peptides with ß-Turn-Biased Sequences.

X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical ß-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H-1H-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.

Enantioselective synthesis of 3-arylquinazolin-4(3H)-ones via peptide-catalyzed atroposelective bromination.

We report the development of a tertiary amine-containing ß-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.

Spontaneous transfer of chirality in an atropisomerically enriched two-axis system.

One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

Peptide-catalyzed conversion of racemic oxazol-5(4H)-ones into enantiomerically enriched α-amino acid derivatives.

We report the development and optimization of a tetrapeptide that catalyzes the methanolytic dynamic kinetic resolution of oxazol-5(4H)-ones (azlactones) with high levels of enantioinduction. Oxazolones possessing benzylic-type substituents were found to perform better than others, providing methyl ester products in 88:12 to 98:2 er. The mechanism of this peptide-catalyzed process was investigated through truncation studies and competition experiments. High-field NOESY analysis was performed to elucidate the solution-phase structure of the peptide, and we present a plausible model for catalysis.