Chiral Pockets Research Articles

Cobalt-Catalyzed Domino Transformations via Enantioselective C-H Activation/Nucleophilic [3 + 2] Annulation toward Chiral Bridged Bicycles.

Selective synthesis of chiral bridged (hetero)bicyclic scaffolds via asymmetric C-H activation constitutes substantial challenges due to the multiple reactivities of strained bicyclic structures. Herein, we develop the domino transformations through an unprecedented cobalt-catalyzed enantioselective C-H activation/nucleophilic [3 + 2] annulation with symmetrical bicyclic alkenes. The methods offer straightforward access to a wide range of chiral molecules bearing [2.2.1]-bridged bicyclic cores with four and five consecutive stereocenters in a single step. Two elaborate salicyloxazoline (Salox) ligands were synthesized based on the rational design and mechanistic understanding. The well-defined chiral pockets generated from asymmetric coordination around the trivalent cobalt catalyst direct the orientation of bicyclic alkenes, leading to excellent enantioselectivity.

Computer-aided accurate calculation of interacted volumes for 3D isosurface point clouds of molecular electrostatic potential

The quality of chiral environment (i.e. catalytic pocket) is directly related to the performance of chiral catalysts. The existing methods need super computing power and time, i.e., it is difficult to quickly judge the interaction between chiral catalysts and substrates for accurately evaluating the effects of chiral catalytic pockets. In this paper, for the 3D isosurface point clouds of molecular electrostatic potential, by using computer simulations, we propose a robust method to detect interacted points, and then accurately have the corresponding interacted volumes. First, by using the existing marching cubes algorithm, we construct the 3D models with triangular surface for isosurface point clouds of molecular electrostatic potentials. Second, by using our improved hierarchical bounding boxes algorithm, we significantly filter out most redundant non-collision points. Third, by using the normal vectors of the remaining points and related triangles, we robustly determine the interacted points to construct interacted sets. And finally, by combining the classical slicing with our multi-contour segmenting, we accurately calculate the interacted volumes. Over three groups of the point clouds of the chemical molecules, experimental results show that our method effectively removes the non-interacted points at average rates of 71.65%, 77.76%, and 71.82%, and calculates the interacted volumes with the average relative errors of 1.7%, 1.6%, and 1.9%, respectively.

Enantioselective Catalysis with Pyrrolidinyl Gold(I) Complexes: DFT and NEST Analysis of the Chiral Binding Pocket.

A new generation of chiral gold(I) catalysts based on variations of complexes with JohnPhos-type ligands with a remote C2-symmetric 2,5-diarylpyrrolidine have been synthesized with different substitutions at the top and bottom aryl rings: from replacing the phosphine by a N-heterocyclic carbene (NHC) to increasing the steric hindrance with bis- or tris-biphenylphosphine scaffolds, or by directly attaching the C2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine. The new chiral gold(I) catalysts have been tested in the intramolecular [4+2] cycloaddition of arylalkynes with alkenes and in the atroposelective synthesis of 2-arylindoles. Interestingly, simpler catalysts with the C2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine led to the formation of opposite enantiomers. The chiral binding pockets of the new catalysts have been analyzed by DFT calculations. As revealed by non-covalent interaction plots, attractive non-covalent interactions between substrates and catalysts direct specific enantioselective folding. Furthermore, we have introduced the open-source tool NEST, specifically designed to account for steric effects in cylindrical-shaped complexes, which allows predicting experimental enantioselectivities in our systems.

Rethinking catalyst design by using data science

In this issue of Chem, Sigman, Toste, and co-workers use data science tools to target the development of a novel family of chiral phosphoric acid scaffolds. These conformationally flexible catalysts were designed to induce enantioselectivity through predictable non-covalent interactions, offering an attractive alternative to state-of-the-art chiral catalyst scaffolds that rely on rigid chiral pockets. In this issue of Chem, Sigman, Toste, and co-workers use data science tools to target the development of a novel family of chiral phosphoric acid scaffolds. These conformationally flexible catalysts were designed to induce enantioselectivity through predictable non-covalent interactions, offering an attractive alternative to state-of-the-art chiral catalyst scaffolds that rely on rigid chiral pockets. Data science enables the development of a new class of chiral phosphoric acid catalystsLiles et al.ChemMarch 24, 2023In BriefAlthough catalyst design represents a fundamental challenge in asymmetric catalysis, data science can streamline the process of optimization by enabling the discovery of key catalyst structure-activity relationships. By carefully designing a training set and subsequent reactivity profiling, we herein demonstrate the successful application of data science tools for the design of a new class of adaptable phosphoric acids. These catalysts exhibit a single example of point chirality and can induce high levels of selectivity in a transfer hydrogenation reaction. Full-Text PDF

Renewable Resources for Enantiodiscrimination: Chiral Solvating Agents for NMR Spectroscopy from Isomannide and Isosorbide.

A new family of chiral selectors was synthesized in a single synthetic step with yields up to 84% starting from isomannide and isosorbide. Mono- or disubstituted carbamate derivatives were obtained by reacting the isohexides with electron-donating arylisocyanate (3,5-dimethylphenyl- or 3,5-dimethoxyphenyl-) and electron-withdrawing arylisocyanate (3,5-bis(trifluoromethyl)phenyl-) groups to test opposite electronic effects on enantiodifferentiation. Deeper chiral pockets and derivatives with more acidic protons were obtained by derivatization with 1-naphthylisocyanate and p-toluenesulfonylisocyanate, respectively. All compounds were tested as chiral solvating agents (CSAs) in 1H NMR experiments with rac-N-3,5-dinitrobenzoylphenylglycine methyl ester in order to determine the influence of different structural features on the enantiodiscrimination capabilities. Some selected compounds were tested with other racemic analytes, still leading to enantiodiscrimination. The enantiodiscrimination conditions were then optimized for the best CSA/analyte couple. Finally, a 2D- and 1D-NMR study was performed employing the best performing CSA with the two enantiomers of the selected analyte, aiming to determine the enantiodiscrimination mechanism, the stoichiometry of interaction, and the complexation constant.

Triazine- and Binaphthol-Based Chiral Macrocycles and Cages: Synthesis, Structure, and Solid-State Assembly.

A series of triazine- and binaphthol-based homochiral and heterochiral macrocycles and cages were easily synthesized. Either fragment coupling or a one-pot approach afforded the desired products in 52-91% yields on a multigram scale as enantiopure forms. As disclosed by the crystal structures, these macrocycles and cages possess intriguing chiral cavities and assembly properties. In particular, (S,S,S)-Cage features a D3-symmetric double-faced propeller-like structure with three chiral pockets at the side. It forms a highly ordered hexagonal column-like assembly and multiple distinct helical channels in its crystal.

Molecular fingerprint and machine learning to accelerate design of high‐performance homochiral metal–organic frameworks

AbstractComputational screening was employed to calculate the enantioseparation capabilities of 45 functionalized homochiral metal–organic frameworks (FHMOFs), and machine learning (ML) and molecular fingerprint (MF) techniques were used to find new FHMOFs with high performance. With increasing temperature, the enantioselectivities for (R,S)‐1,3‐dimethyl‐1,2‐propadiene are improved. The “glove effect” in the chiral pockets was proposed to explain the correlations between the steric effect of functional groups and performance of FHMOFs. Moreover, the neighborhood component analysis and RDKit/MACCS MFs show the highest predictive effect on enantioselectivities among the four ML classification algorithms with nine MFs that were tested. Based on the importance of MF, 85 new FHMOFs were designed, and a newly designed FHMOF, NO2‐NHOH‐FHMOF, with high similarity to the optimal MFs achieved improved chiral separation performance, with enantioselectivities of 85%. The design principles and new chiral pockets obtained by ML and MFs could facilitate the development of new materials for chiral separation.

Stretchable chiral pockets for palladium-catalyzed highly chemo- and enantioselective allenylation

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. We describe here the development of diphenylphosphinoalkanoic acid based chiral bisphosphine ligands, which are successfully applied to the palladium-catalyzed asymmetric allenylation of racemic pyrazol-5-ones. The reaction affords C-allenylation products, optically active pyrazol-5-ones bearing an allene unit, in high chemo- and enantioselectivity, with DACH-ZYC-Phos-C1 as the best ligand. The synthetic potential of the C-allenylation products is demonstrated. Furthermore, the enantioselectivity observed with DACH-ZYC-Phos-C1 is rationalized by density functional theory studies.

C2-Symmetric Hindered “Sandwich” ChiralN-Heterocyclic Carbene Precursors and Their Transition Metal Complexes: Expedient Syntheses, Structural Authentication, and Catalytic Properties

We present here a new family of C2-symmetric “sandwich” NHC ligands abbreviated as SITLAr and BzITLAr and their complexes. The chiral fragments incorporate bulky yet flexible cyclohexyl groups with α-stereocenters joined to nitrogens individually, which set up chiral pockets around pivotal carbene carbons (less than 2.5 A). Full characterization revealed unique structures with roughly parallel aryl moieties above and below imidazoline and benzimidazole planes in the Z-shaped arrangement. Extra hydrogen bonding interactions and steric stress between the square-planar frameworks and aryl groups led to the exceptional confinement and reversed the configurations in the iridium complexes. In accordance with Tolman’s electronic parameters and topographic steric maps of well-established metalated complexes, these new ligands possess strong electron-donating properties and exceptionally steric demands. Additionally, the preliminary results employing the BzITLAr ligands allowed appropriate activities and provided ...

Chirality at two-dimensional surfaces: A perspective from small molecule alcohol assembly on Au(111).

The delicate balance between hydrogen bonding and van der Waals interactions determines the stability, structure, and chirality of many molecular and supramolecular aggregates weakly adsorbed on solid surfaces. Yet the inherent complexity of these systems makes their experimental study at the molecular level very challenging. In this quest, small alcohols adsorbed on metal surfaces have become a useful model system to gain fundamental insight into the interplay of such molecule-surface and molecule-molecule interactions. Here, through a combination of scanning tunneling microscopy and density functional theory, we compare and contrast the adsorption and self-assembly of a range of small alcohols from methanol to butanol on Au(111). We find that longer chained alcohols prefer to form zigzag chains held together by extended hydrogen bonded networks between adjacent molecules. When alcohols bind to a metal surface datively via one of the two lone electron pairs of the oxygen atom, they become chiral. Therefore, the chain structures are formed by a hydrogen-bonded network between adjacent molecules with alternating adsorbed chirality. These chain structures accommodate longer alkyl tails through larger unit cells, while the position of the hydroxyl group within the alcohol molecule can produce denser unit cells that maximize intermolecular interactions. Interestingly, when intrinsic chirality is introduced into the molecule as in the case of 2-butanol, the assembly changes completely and square packing structures with chiral pockets are observed. This is rationalized by the fact that the intrinsic chirality of the molecule directs the chirality of the adsorbed hydroxyl group meaning that heterochiral chain structures cannot form. Overall this study provides a general framework for understanding the effect of simple alcohol molecular adstructures on hydrogen bonded aggregates and paves the way for rationalizing 2D chiral supramolecular assembly.

Microscopic chiral pockets in a tris(chelated) iridium(iii) complex as sites for dynamic enantioselective quenching

A microscopic pocket surrounded by bulky ligands in Ir(iii) acted as a site discriminating the chirality of an approaching molecule.

Investigation of chiral recognition by molecular micelles with molecular dynamics simulations

ABSTRACTMolecular dynamics simulations were used to characterize the binding of the chiral drugs chlorthalidone and lorazepam to the molecular micelle poly-(sodium undecyl-(L)-leucine-valine). The project’s goal was to characterize the nature of chiral recognition in capillary electrophoresis separations that use molecular micelles as the chiral selector. The shapes and charge distributions of the chiral molecules investigated, their orientations within the molecular micelle chiral binding pockets, and the formation of stereoselective intermolecular hydrogen bonds with the molecular micelle were all found to play key roles in determining where and how lorazepam and chlorthalidone enantiomers interacted with the molecular micelle.

Chiral NH-Controlled Supramolecular Metallacycles.

Chiral NH functionalities-based discrimination is a key feature of Nature's chemical armory, yet selective binding of biologically active molecules in synthetic systems with high enantioselectivity poses significant challenges. Here we report the assembly of three chiral fluorescent Zn6L6 metallacycles from pyridyl-functionalized Zn(salalen) or Zn(salen) complexes. Each of these metallacycles has a nanoscale hydrophobic cavity decorated with six, three, or zero chiral NH functionalities and packs into a three-dimensional supramolecular porous framework. The binding affinity and enantioselectivity of the metallacycles toward α-hydroxycarboxylic acids, amino acids, small molecule pharamaceuticals (l-dopa, d-penicillamine), and chiral amines increase with the number of chiral NH moieties in the cyclic structure. From single-crystal X-ray diffraction, molecular simulations, and quantum chemical calculations, the chiral recognition and discrimination are attributed to the specific binding of enantiomers in the chiral pockets of the metallacycles. The parent metallacycles are fluorescent with the intensity of emission being linearly related to the enantiomeric composition of the chiral biorelevant guests, which allow them to be utilized in chiral sensing. The fact that manipulation of chiral NH functionalities in metallacycles can control the enantiorecognition of biomolecular complexes would facilitate the design of more effective supramolecular assemblies for enantioselective processes.

Chirality Switching in the Crystallization of 1‐(4‐Chlorophenyl)ethylamine with Binaphthoic Acid by Ketimine Formation

Axially chiral binaphthoic acid (BNA) was studied as a resolving agent for a stereoselective crystallization of 1‐(4‐chlorophenyl)ethylamine (CPEA). The diastereomeric pair of (R)‐BNA/(S)‐CPEA crystallizes in methylene chloride, on the other hand, the pair of (S)‐BNA/(S)‐CPEA crystallizes in acetone. The switch of the solubility of the diastereomeric pair is due to the imine formation with acetone. The very low solubility of the BNA/imine pair appears to be responsible for the fast and complete imine formation. The crystal structure of the BNA part in both crystals of the diastereomers maintains a same feature. Asymmetric chiral channels and pockets composed by intermolecular packing of BNA molecules appear in the crystal structures, and the robustness of them seem to contribute to the recognition of the chirality of CPEA with high selectivity.

Chiral Weyl Pockets and Fermi Surface Topology of the Weyl Semimetal TaAs.

Tantalum arsenide is a member of the noncentrosymmetric monopnictides, which are putative Weyl semimetals. In these materials, three-dimensional chiral massless quasiparticles, the so-called Weyl fermions, are predicted to induce novel quantum mechanical phenomena, such as the chiral anomaly and topological surface states. However, their chirality is only well defined if the Fermi level is close enough to the Weyl points that separate Fermi surface pockets of opposite chirality exist. In this Letter, we present the bulk Fermi surface topology of high quality single crystals of TaAs, as determined by angle-dependent Shubnikov-de Haas and de Haas-van Alphen measurements combined with abinitio band-structure calculations. Quantum oscillations originating from three different types of Fermi surface pockets were found in magnetization, magnetic torque, and magnetoresistance measurements performed in magnetic fields up to 14T and temperatures down to 1.8K. Of these Fermi pockets, two are pairs of topologically nontrivial electron pockets around the Weyl points and one is a trivial hole pocket. Unlike the other members of the noncentrosymmetric monopnictides, TaAs is the first Weyl semimetal candidate with the Fermi energy sufficiently close to both types of Weyl points to generate chiral quasiparticles at the Fermi surface.

N,N′-Dimethylene-2,2′-biimidazole—A Mimic of Carboxylate for the Formation of Complexes with Copper(I) And the Anion Directed Formation of a Solvent Pocket

The reaction of N,N′-dimethylene-2,2′-biimidazole (L) with various copper salts gives eight complexes that were characterized structurally in the solid state. This showed that the ligand can effectively bridge two copper atoms in close proximity similarly to the well-known bridging carboxylate motif. In reaction with copper(II), this gives a dimer (acetate, 1) or quadruple helicate (perchlorate, 2). Extention to copper(I) with a coordinating counterion gives a one-dimensional polymer (iodide, 3), while reaction with noncoordinating counterion gives M2L3 triple helicate motifs. These helicates were found to form chiral solvate-containing pockets surrounding benzene when combined with a three-fold symmetric anion (BF4–, ClO4– and NO3–, 4, 5, and 6, respectively) or an achiral complex with only acetonitrile (ClO4–, 7). While the pocket could accommodate fluorobenzene (BF4–, 8), more highly substituted benzenes do not allow its formation.

Complex chiral colloids and surfaces via high-index off-cut silicon.

Silicon wafers are commonly etched in potassium hydroxide solutions to form highly symmetric surface structures. These arise when slow-etching {111} atomic planes are exposed on standard low-index surfaces. However, the ability of nonstandard high-index wafers to provide more complex structures by tilting the {111} planes has not been fully appreciated. We demonstrate the power of this approach by creating chiral surface structures and nanoparticles of a specific handedness from gold. When the nanoparticles are dispersed in liquids, gold colloids exhibiting record molar circular dichroism (>5 × 10(9) M(-1) cm(-1)) at red wavelengths are obtained. The nanoparticles also present chiral pockets for binding.

ChemInform Abstract: Design of Phosphorus Ligands with Deep Chiral Pockets: Practical Synthesis of Chiral β‐Arylamines by Asymmetric Hydrogenation.

AbstractThe newly developed bisphosphorus ligand shows high efficiency in the title reaction and several enamides are hydrogenated with excellent enantioselectivities.

Design of Phosphorus Ligands with Deep Chiral Pockets: Practical Synthesis of Chiral β‐Arylamines by Asymmetric Hydrogenation

The newly developed bisphosphorus ligand shows high efficiency in the title reaction and several enamides are hydrogenated with excellent enantioselectivities.

Design of Phosphorus Ligands with Deep Chiral Pockets: Practical Synthesis of Chiral β‐Arylamines by Asymmetric Hydrogenation

WingPhos, ein C2-symmetrischer Bisphosphorligand mit einer tiefen und definierten chiralen Tasche, wurde in der Rhodium-katalysierten asymmetrischen Hydrierung von (E)-β-Aryl-N-acetylenamiden, cyclischen β-Arylenamiden und heterocyclischen β-Arylenamiden eingesetzt. Chirale β-Arylisopropylamine, 2-Aminotetraline und 3-Aminochromane können mit ausgezeichneten ee-Werten synthetisiert werden (nbd=3,5-Norbornadien; TON=Umsatzzahl).