Electrostatic Interactions in Asymmetric Organocatalysis.

ConspectusElectrostatic interactions are ubiquitous in catalytic systems and can be decisive in determining the reactivity and stereoselectivity. However, difficulties quantifying the role of electrostatic interactions in transition state (TS) structures have long stymied our ability to fully harness the power of these interactions. Fortunately, advances in affordable computing power, together with new quantum chemistry methods, have increasingly enabled a detailed atomic-level view. Empowered by this more nuanced perspective, synthetic practitioners are now adopting these techniques with growing enthusiasm.In this Account, we narrate our recent results rooted in state-of-the-art quantum chemical computations, describing pivotal roles for electrostatic interactions in the organization of TS structures to direct the reactivity and selectivity in the realm of asymmetric organocatalysis. To provide readers with a fundamental foundation in electrostatics, we first introduce a few guiding principles, beginning with a brief discussion of how electrostatic interactions can be harnessed to tune the strength of noncovalent interactions. We then describe computational approaches to capture these effects followed by examples in which electrostatic effects impact structure and reactivity. We then cover some of our recent computational investigations in three specific branches of asymmetric organocatalysis, beginning with chiral phosphoric acid (CPA) catalysis. We disclose how CPA-catalyzed asymmetric ring openings of meso-epoxides are driven by stabilization of a transient partial positive charge in the SN2-like TS by the chiral electrostatic environment of the catalyst. We also report on substrate-dependent electrostatic effects from our study of CPA-catalyzed intramolecular oxetane desymmetrizations. For nonchelating oxetane substrates, electrostatic interactions with the catalyst confer stereoselectivity, whereas oxetanes with chelating groups adopt a different binding mode that leads to electrostatic effects that erode selectivity. In another example, computations revealed a pivotal role of CH···O and NH···O hydrogen bonding in the CPA-catalyzed asymmetric synthesis of 2,3-dihydroquinazolinones. These interactions control selectivity during the enantiodetermining intramolecular amine addition step, and their strength is modulated by electrostatic effects, allowing us to rationalize the effect of introducing o-substituents. Next, we describe our efforts to understand selectivity in a series of NHC-catalyzed kinetic resolutions, where we discovered that the electrostatic stabilization of key proton(s) is the common driver of selectivity. Finally, we discuss our breakthrough in understanding asymmetric silylium ion-catalyzed Diels-Alder cycloaddition of cinnamate esters to cyclopentadienes. The endo:exo of these transformations is guided by electrostatic interactions that selectively stabilize the endo-transition state.We conclude with a brief overview of the outstanding challenges and potential roles of computational chemistry in enabling the exploitation of electrostatic interactions in asymmetric organocatalysis.

Mechanism and Enantioselectivity in QUINOX-Catalyzed Asymmetric Allylations of Aromatic Aldehydes: Solvent and Substituent Effects.

Computational investigations were conducted on the QUINOX-catalyzed asymmetric allylation of aromatic aldehydes with allyltrichlorosilanes. Our calculations provide evidence that the catalytic allylation can follow distinct mechanisms, depending on the solvent employed. In toluene and CH2Cl2, the QUINOX-catalyzed allylation predominantly follows an associative pathway, while in CH3CN, a dissociative pathway becomes more favorable. Noncovalent interactions, such as π-stacking effects for the associative mechanism and CH/π interactions for the dissociative mechanism, play a pivotal role in enantiostereodifferentiation in the asymmetric QUINOX-catalyzed reactions of benzaldehyde. Furthermore, the study unveils how different aldehyde substituents exert differing influences on the catalytic allylation reaction. Specifically, the QUINOX-catalyzed allylation of 4-(trifloromethyl)benzaldehyde displays a strong preference for the associative pathway, yielding excellent results in both yield and enantioselectivity. Conversely, 4-methoxybenzaldehyde tends to favor a dissociative mechanism with reduced yields and enantioselectivity. The mechanistic basis for these remarkable substituent effects on the catalytic allylation reaction was also elucidated. In summary, this research enhances our understanding of the QUINOX-catalyzed asymmetric allylation, shedding light on the role of solvents and substituents in the reaction mechanism and enantioselectivity.

Unusual Enantiodivergence in Chiral Brønsted Acid-Catalyzed Asymmetric Allylation with ß-Alkenyl Allylic Boronates.

We report herein a rare example of enantiodivergent aldehyde addition with ß-alkenyl allylic boronates via chiral Brønsted acid catalysis. 2,6-Di-9-anthracenyl-substituted chiral phosphoric acid-catalyzed asymmetric allylation using ß-vinyl substituted allylic boronate gave alcohols with R absolute configuration. The sense of asymmetric induction of the catalyst in these reactions is opposite to those in prior reports. Moreover, in the presence of the same acid catalyst, the reactions with ß-2-propenyl substituted allylic boronate generated homoallylic alcohol products with S absolute configuration. Unusual substrate-catalyst C-H⋅⋅⋅π interactions in the favoured reaction transition state were identified as the origins of observed enantiodivergence through DFT computational studies.

SEQCROW: A ChimeraX bundle to facilitate quantum chemical applications to complex molecular systems.

We describe a bundle for UCSF ChimeraX called SEQCROW that provides advanced structure editing capabilities and quantum chemistry utilities designed for complex organic and organometallic compounds. SEQCROW includes graphical presets and bond editing tools that facilitate the generation of publication-quality molecular structure figures while also allowing users to build molecular structures quickly and efficiently by mapping new ligands onto existing organometallic complexes as well as adding rings and substituents. Other capabilities include the ability to visualize vibrational modes and simulated IR spectra, to compute and visualize molecular descriptors including percent buried volume, ligand cone angles, and Sterimol parameters, to process thermochemical corrections from quantum mechanical computations, to generate input files for ORCA, Psi4, and Gaussian, and to run and manage computational jobs.

Importance of model size in quantum mechanical studies of DNA intercalation.

The convergence of DFT-computed interaction energies with increasing binding site model size was assessed. The data show that while accurate intercalator interaction energies can be derived from binding site models featuring only the flanking nucleotides for uncharged intercalators that bind parallel to the DNA base pairs, errors remain significant even when including distant nucleotides for intercalators that are charged, exhibit groove-binding tails that engage in noncovalent interactions with distant nucleotides, or that bind perpendicular to the DNA base pairs. Consequently, binding site models that include at least three adjacent nucleotides are required to consistently predict converged binding energies. The computationally inexpensive HF-3c method is shown to provide reliable interaction energies and can be routinely applied to such large models.

Predicting the Strength of Stacking Interactions between Heterocycles and Aromatic Amino Acid Side Chains.

Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. On the basis of rigorous ab initio data, we developed simple predictive models of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. These models provide reliable predictions of the stacking ability of a given heterocycle based on readily computed heterocycle descriptors, eliminating the need for quantum chemical computations of stacked dimers. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual means for understanding stacking interactions in protein binding sites and tuning their strength in the context of drug design.

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

Fluxional chiral DMAP-catalyzed kinetic resolutions of axially chiral biaryls were examined using density functional theory. Computational analyses lead to a revised understanding of this reaction in which the interplay of numerous non-covalent interactions control the conformation and flexibility of the active catalyst, the preferred mechanism, and the stereoselectivity. Notably, while the DMAP catalyst itself is confirmed to be highly fluxional, electrostatically driven π⋅⋅⋅π+ interactions render the active, acylated form of the catalyst highly rigid, explaining its pronounced stereoselectivity.

Tuning Stacking Interactions between Asp-Arg Salt Bridges and Heterocyclic Drug Fragments.

Stacking interactions can play an integral role in the strength and selectivity of protein-drug binding and are of particular interest given the ubiquity and variety of heterocyclic fragments in drugs. In addition to traditional stacking interactions between aromatic rings, stacking interactions involving heterocyclic drug fragments and protein salt bridges have also been observed. These "salt-bridge stacking interactions" can be quite strong but are not well understood. We studied stacked dimers of the acetate···guanidinium ion pair with a diverse set of 63 heterocycles using robust ab initio methods. The computed interaction energies span more than 10 kcal mol-1, indicating the sensitivity of these salt-bridge stacking interactions to heterocycle features. Trends in both the strength and preferred geometry of these interactions can be understood through analyses of the electrostatic potentials and electric fields above the heterocycles. We have developed new heterocycle descriptors that quantify these effects and used them to create robust predictors of the strength of salt-bridge stacking interactions both in the gas phase and a protein-like dielectric environment. These predictive tools, combined with a set of qualitative guidelines, should facilitate the choice of heterocycles that maximize salt-bridge stacking interactions in drug binding sites.

Converting SMILES to Stacking Interaction Energies.

Predicting the strength of stacking interactions involving heterocycles is vital for several fields, including structure-based drug design. While quantum chemical computations can provide accurate stacking interaction energies, these come at a steep computational cost. To address this challenge, we recently developed quantitative predictive models of stacking interactions between druglike heterocycles and the aromatic amino acids Phe, Tyr, and Trp (DOI: 10.1021/jacs.9b00936 ). These models depend on heterocycle descriptors derived from electrostatic potentials (ESPs) computed using density functional theory and provide accurate stacking interactions without the need for expensive computations on stacked dimers. Herein, we show that these ESP-based descriptors can be reliably evaluated directly from the atom connectivity of the heterocycle, providing a means of predicting both the descriptors and the potential for a given heterocycle to engage in stacking interactions without resorting to any quantum chemical computations. This enables the rapid conversion of simple molecular representations (e.g., SMILES) directly into accurate stacking interaction energies using a freely available online tool, thereby providing a way to rank the stacking abilities of large sets of heterocycles.

Chiral phosphoric acid catalysis: from numbers to insights.

Chiral phosphoric acids (CPAs) have emerged as powerful organocatalysts for asymmetric reactions, and applications of computational quantum chemistry have revealed important insights into the activity and selectivity of these catalysts. In this tutorial review, we provide an overview of computational tools at the disposal of computational organic chemists and demonstrate their application to a wide array of CPA catalysed reactions. Predictive models of the stereochemical outcome of these reactions are discussed along with specific examples of representative reactions and an outlook on remaining challenges in this area.

Lone-Pair-Induced Topicity Observed in Macrobicyclic Tetra-thia Lactams and Cryptands: Synthesis, Spectral Identification, and Computational Assessment.

The synthesis of a rigid macrobicyclic N,S lactam L1 and a topologically favored in/in N,S cryptand L2 are reported with X-ray structure analysis, dynamic correlation NMR spectroscopy, and computational analysis. Lactam L1 exhibits two distinct rotameric conformations (plus their enantiomeric counterparts) at 25 °C, as confirmed via NMR spectroscopy and computational analysis. Coalescence of the resonances of L1 was observed at 115 °C, allowing for complete nuclei to frequency correlation. Combining computational investigations with experimental data, topological equilibria and relative energies/strain relating to the perturbation of the pore were determined. Due to the increased conformational strain of the N2S2 template, the nitrogen lone pairs in L2 elicit a unique transannular interaction, resulting in a thermodynamically favored in/in nephroidal racemate. The combination of preferred topology, steric relief, and electronic localization of L2 induces a chiral environment imparted through the amine with a computed inversion barrier of 10.3 kcal mol-1.

Anion-π Interactions in Computer-Aided Drug Design: Modeling the Inhibition of Malate Synthase by Phenyl-Diketo Acids.

Human infection by Mycobacterium tuberculosis (Mtb) continues to be a global epidemic. Computer-aided drug design (CADD) methods are used to accelerate traditional drug discovery efforts. One noncovalent interaction that is being increasingly identified in biological systems but is neglected in CADD is the anion-π interaction. The study reported herein supports the conclusion that anion-π interactions play a central role in directing the binding of phenyl-diketo acid (PDKA) inhibitors to malate synthase (GlcB), an enzyme required for Mycobacterium tuberculosis virulence. Using density functional theory methods (M06-2X/6-31+G(d)), a GlcB active site template was developed for a predictive model through a comparative analysis of PDKA-bound GlcB crystal structures. The active site model includes the PDKA molecule and the protein determinants of the electrostatic, hydrogen-bonding, and anion-π interactions involved in binding. The predictive model accurately determines the Asp 633-PDKA structural position upon binding and precisely predicts the relative binding enthalpies of a series of 2-ortho halide-PDKAs to GlcB. A screening model was also developed to efficiently assess the propensity of each PDKA analog to participate in an anion-π interaction; this method is in good agreement with both the predictive model and the experimental binding enthalpies for the 2-ortho halide-PDKAs. With the screening and predictive models in hand, we have developed an efficient method for computationally screening and evaluating the binding enthalpy of variously substituted PDKA molecules. This study serves to illustrate the contribution of this overlooked interaction to binding affinity and demonstrates the importance of integrating anion-π interactions into structure-based CADD.

Importance of Electrostatic Effects in the Stereoselectivity of NHC-Catalyzed Kinetic Resolutions.

Three N-heterocyclic carbene (NHC) catalyzed kinetic resolutions (KR) and one dynamic kinetic resolution (DKR) were examined using modern density functional theory methods to identify the origin of catalytic activity and selectivity and the role of cocatalysts in these reactions. The results reveal electrostatic interactions as the common driver of selectivity. Furthermore, in the case of a recently described KR of BINOL-derivatives, a computational examination of the full catalytic cycle reveals that a benzoic acid byproduct changes the turnover limiting transition step, obviating the need for an added cocatalyst. Together, these data provide key insights into the activity and selectivity of NHC-catalyzed kinetic resolutions, and underscore the importance of electrostatic interactions as a driver of selectivity.

Noncovalent Interactions in Organocatalysis and the Prospect of Computational Catalyst Design.

Noncovalent interactions are ubiquitous in organic systems, and can play decisive roles in the outcome of asymmetric organocatalytic reactions. Their prevalence, combined with the often subtle line separating favorable dispersion interactions from unfavorable steric interactions, often complicates the identification of the particular noncovalent interactions responsible for stereoselectivity. Ultimately, the stereoselectivity of most organocatalytic reactions hinges on the balance of both favorable and unfavorable noncovalent interactions in the stereocontrolling transition state (TS). In this Account, we provide an overview of our attempts to understand the role of noncovalent interactions in organocatalyzed reactions and to develop new computational tools for organocatalyst design. Following a brief discussion of noncovalent interactions involving aromatic rings and the associated challenges capturing these effects computationally, we summarize two examples of chiral phosphoric acid catalyzed reactions in which noncovalent interactions play pivotal, although somewhat unexpected, roles. In the first, List's catalytic asymmetric Fischer indole reaction, we show that both π-stacking and CH/π interactions of the substrate with the 3,3'-aryl groups of the catalyst impact the stability of the stereocontrolling TS. However, these noncovalent interactions oppose each other, with π-stacking interactions stabilizing the TS leading to one enantiomer and CH/π interactions preferentially stabilizing the competing TS. Ultimately, the CH/π interactions dominate and, when combined with hydrogen bonding interactions, lead to preferential formation of the observed product. In the second example, a series of phosphoric acid catalyzed asymmetric ring openings of meso-epoxides, we show that noncovalent interactions of the substrates with the 3,3'-aryl groups of the catalyst play only an indirect role in stereoselectivity. Instead, the stereoselectivity of these reactions are driven by the electrostatic stabilization of a fleeting partial positive charge in the SN2-like transition state by the chiral electrostatic environment of the phosphoric acid catalyst. Next, we describe our studies of bipyridine N-oxide and N,N'-dioxide catalyzed alkylation reactions. Based on several examples, we demonstrate that there are many potential arrangements of ligands around a hexacoordinate silicon in the stereocontrolling TS, and one must consider all of these in order to identify the lowest-lying TS structures. We also present a model in which electrostatic interactions between a formyl CH group and a chlorine in these TSs underlie the enantioselectivity of these reactions. Finally, we discuss our efforts to develop computational tools for the screening of potential organocatalyst designs, starting in the context of bipyridine N,N'-dioxide catalyzed alkylation reactions. Our new computational tool kit (AARON) has been used to design highly effective catalysts for the asymmetric propargylation of benzaldehyde, and is currently being used to screen catalysts for other reactions. We conclude with our views on the potential roles of computational chemistry in the future of organocatalyst design.

Stacked homodimers of substituted contorted hexabenzocoronenes and their complexes with C60 fullerene.

Stacking interactions involving substituted contorted hexabenzocoronene (c-HBC) with C60 were studied at the B97-D3M(BJ)/TZVPP//B97-D/TZV(2d,2p) level of theory. First, we showed that substituent effects in benzeneC60 complexes are uncorrelated with those in the benzene sandwich dimer, underscoring the importance of local, direct interactions in substituent effects in stacking interactions. Second, we showed that c-HBC preferentially forms stacked homodimers over complexes with C60; however, if the bowl depth of c-HBC is increased beyond 1.25 Å, the c-HBCC60 complex becomes preferred over the c-HBC homodimer. Ultimately, we showed that the perfluorination of c-HBC leads to sufficient curvature to allow the c-HBCC60 heterodimers to form preferentially over c-HBC homodimers, suggesting the possibility of the development of c-HBC derivatives that assemble into alternating stacks with C60.

Conformational behavior and stacking interactions of contorted polycyclic aromatics.

We present a systematic computational analysis of the conformations and stacking interactions of a set of 18 saddle-shaped, contorted polycyclic aromatic compounds at the B97-D3M(BJ)/TZV(2d,2p)//B97-D/TZV(2d,2p) level of theory. These doubly-concave systems offer a means of tuning the strength of stacking interactions through variations in molecular curvature, and understanding the intermolecular non-covalent interactions exhibited by these systems will aid the design of contorted polycyclic systems with precisely defined packing in the solid state. Computations reveal wide variations in both the nature of the low-lying conformations and the stacking affinities of these systems. In particular, the introduction of both thiophene rings around the periphery of these systems and the incorporation of B and N atoms into the coronene core can greatly enhance their tendency to form strongly stacked dimers. Overall, these data provide a reminder that curvature does not always lead to stronger stacking interactions.

Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium-Catalyzed Asymmetric Hydrogenation.

A computational toolkit (AARON: An automated reaction optimizer for new catalysts) is described that automates the density functional theory (DFT) based screening of chiral ligands for transition-metal-catalyzed reactions with well-defined reaction mechanisms but multiple stereocontrolling transition states. This is demonstrated for the Rh-catalyzed asymmetric hydrogenation of (E)-ß-aryl-N-acetyl enamides, for which a new C2 -symmetric phosphorus ligand is designed.

Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones.

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzed by a chiral BINOL-derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.

Low Band Gap Coplanar Conjugated Molecules Featuring Dynamic Intramolecular Lewis Acid-Base Coordination.

Ladder-type conjugated molecules with a low band gap and low LUMO level were synthesized through an N-directed borylation reaction of pyrazine-derived donor-acceptor-donor precursors. The intramolecular boron-nitrogen coordination bonds played a key role in rendering the rigid and coplanar conformation of these molecules and their corresponding electronic structures. Experimental investigation and theoretical simulation revealed the dynamic nature of such coordination, which allowed for active manipulation of the optical properties of these molecules by using competing Lewis basic solvents.

Stacking Interactions between 9-Methyladenine and Heterocycles Commonly Found in Pharmaceuticals.

Complexes of 9-methyladenine with 46 heterocycles commonly found in drugs were located using dispersion-corrected density functional theory, providing a representative set of 408 unique stacked dimers. The predicted binding enthalpies for each heterocycle span a broad range, highlighting the strong dependence of heterocycle stacking interactions on the relative orientation of the interacting rings. Overall, the presence of NH and carbonyl groups lead to the strongest stacking interactions with 9-methyadenine, and the strength of π-stacking interactions is sensitive to the distribution of heteroatoms within the ring as well as the specific tautomer considered. Although molecular dipole moments provide a sound predictor of the strengths and orientations of the 28 monocyclic heterocycles considered, dipole moments for the larger fused heterocycles show very little correlation with the predicted binding enthalpies.