Cavity Catalysis of an Enantioselective Reaction under Vibrational Strong Coupling.

Strong light-matter interaction is emerging as an exciting tool for controlling chemical reactions. Here, we demonstrate an L-proline-catalyzed direct asymmetric Aldol reaction under vibrational strong coupling. Both the reactants (4-nitrobenzaldehyde and acetone) carbonyl bands are coupled to an infrared photon and react in the presence of L-proline. The reaction mixture is eluted from the cavity, and the conversion yields and enantiomeric excess are quantified using NMR and chiral HPLC. The conversion yields increase by up to 90 % in ON-resonance conditions. Interestingly, a large increase in the conversion yield does not affect the enantiomeric excess. Further control experiments were carried out by varying the temperature, and we propose that the rate-limiting step may not be the deciding factor in enantioselectivity. Whereas the formation of the enamine intermediate is modified by cavity coupling experiments. For this class of enantioselective reactions, strong coupling does not change the enantiomeric excess, possibly due to the large energy difference in chiral transition states. Strong coupling can boost the formation of enamine intermediate, thereby favouring the product yield. This gives more hope to test polaritonic chemistry based on enantioselective reactions in which the branching ratios can be controlled.

Chiral recognition and discrimination studies of tyrosine enantiomers on (-)-18-crown-6-tetracarboxylic acid as a chiral selector by nuclear magnetic resonance spectroscopy and docking simulations.

Considering the substantial significance of chiral biomolecules, such as amino acids, in our daily routines, we performed chiral recognition and discrimination of tyrosine (Tyr) enantiomers on (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid [(-)-18-C-6-TA] as crown-ether type chiral selector (CS) by nuclear magnetic resonance (NMR) spectroscopy and docking simulations. In this study, successful discrimination of the enantiomers of Tyr was achieved, as evidenced by the proton chemical shift differences (ΔΔδ) of Tyr enantiomers observed in the 1 H NMR spectra with (-)-18-C-6-TA CS. We compared the results of these two techniques with the findings obtained from high performance liquid chromatography (HPLC) investigations. In both NMR and HPLC experimental and docking simulation studies, a stronger interaction between the L-Tyr enantiomer with (-)-18-C-6-TA CS than the D-Tyr was consistently observed. Also, the binding energy differences (ΔΔEL-D ) found in simulation data that correspond to enantioselectivity aligned well with the NMR experimental result.

Chirality Discrimination at Binary Organic|Water Interfaces Monitored by Interfacial Tension Measurements with Preliminary Comparison with Molecular Dynamics Simulations.

Chirality discrimination at a binary toluene (organic)/water(aqueous) interface between R- or S-Tol-BINAP (2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl) molecules and the water-soluble serine chiral specie is examined for the first time, using a combination of interfacial tension measurements and molecular dynamic simulations. Experimental interfacial measurements exhibit a clear chirality-controlled difference when a homochiral versus a heterochiral enantiomeric pairs are introduced at the interfaces. The related molecular dynamics simulations support the experimental results and provide further molecular insight of intermolecular interactions at the interfaces. The results indicate that interfacial tension measurements can capture the preferential interactions which exist between different pairs of enantiomers at the binary interfaces, opening up a new way for probing chirality discrimination at liquid-liquid interfaces.

19 F-Labeled Probes for Recognition-Enabled Chromatographic 19 F NMR.

The NMR technique is among the most powerful analytical methods for molecular structural elucidation, process monitoring, and mechanistic investigations; however, the direct analysis of complex real-world samples is often hampered by crowded NMR spectra that are difficult to interpret. The combination of fluorine chemistry and supramolecular interactions leads to a unique detection method named recognition-enabled chromatographic (REC) 19 F NMR, where interactions between analytes and 19 F-labeled probes are transduced into chromatogram-like 19 F NMR signals of discrete chemical shifts. In this account, we summarize our endeavor to develop novel 19 F-labeled probes tailored for separation-free multicomponent analysis. The strategies to achieve chiral discrimination, sensitivity enhancement, and automated analyte identification will be covered. The account will also provide a detailed discussion of the underlying principles for the design of molecular probes for REC 19 F NMR where appropriate.

NMR chiral recognition of lipoic acid by cinchonidine CSA: A stereocenter beyond the organic function.

Alpha-lipoic acid is a natural product that possesses distinct pharmacological properties. Lipoic acid is a short-chain fatty acid containing an asymmetric carbon at five bonds of distance to the organic function. Herein, we developed a nuclear magnetic resonance protocol to access the chiral recognition of lipoic acid in a simple and rapid procedure employing cinchonidine as a cheap chiral solvation agent in deuterated chloroform. To optimize this method, a statistical design of the experimental model was performed to produce a clear understanding of the optimal concentration, temperature, and molar ratio parameters. Based on the obtained spectra, the cinchonidine H8 -H9 scalar coupling indicated a conformational preference in the chiral discrimination procedure. Density functional theory calculations established a proximity between the asymmetric center of lipoic acid and the aromatic moiety of cinchonidine, clarifying possible conformations in this ion-pair interaction. The described protocol demonstrates how far is far enough to chiral discrimination using a chiral solvation agent, expanding the method to compounds that contain a remote stereocenter.

Side Group of Hydrophobic Amino Acids Controls Chiral Discrimination among Chiral Counterions and Metal-Organic Cages.

The self-assembly of chiral Pd12L24 metal-organic cages (MOCs) based on hydrophobic amino acids, including alanine (Ala), valine (Val), and leucine (Leu), into single-layered hollow spherical blackberry-type structures is triggered by nitrates through counterion-mediated attraction. In addition to nitrates, anionic N-(tert-butoxycarbonyl) (Boc)-protected Ala, Val, and Leu were used as chiral counterions during the self-assembly of d-MOCs. Previously, we showed that l-Ala suppresses the self-assembly process of d-Pd12Ala24 but has no effect on l-Pd12Ala24, i.e., chiral discrimination. Here, we indicate when the amino acid used as the chiral counterion has a bulkier side group than the amino acid in the MOC structure, no chiral discrimination exists; otherwise, chiral discrimination exists. For example, Ala can induce chiral discrimination in all chiral MOCs, whereas Leu can induce chiral discrimination only in Pd12Leu24. Moreover, chiral anionic d- and l-alanine-based surfactants have no chiral discrimination, indicating that bulkier chiral counterions with more hydropohobic side groups can erase chiral discrimination.

Synthesis of Chiral Au Nanocrystals with Precise Homochiral Facets for Enantioselective Surface Chemistry.

Metal surfaces with intrinsic chirality play an irreplaceable role in many significant enantioselective chemical processes such as enantioselective catalysis, sensing, and separation. Nonetheless, current methods for the precise preparation of such chiral surfaces suffer with issues of unscalable production and low surface areas. Herein, we report the synthesis of chiral Au nanoparticles with precisely determined homochiral facets. Though a scalable wet chemical method, {125̅8}R and {85̅12}S high-Miller-index facets are obtained with the l- and d-chiral Au nanocrystals, respectively. The growth process of these homochiral facets is investigated, and a new nanocrystal growth pathway is revealed. More importantly, the remarkable enantioselective recognition properties of these homochiral surfaces are demonstrated and enable an efficient electrochemical method for chiral discrimination of l-/d-tryptophan. These results provide a foundation of fundamental studies of heterogeneous enantioselective processes and may pave way for the development of nanocatalysts for enantioselective chemistry.

(2-Hydroxy-3-Methoxybenzylidene)thiazolo[3,2-a]pyrimidines: Synthesis, Self-Assembly in the Crystalline Phase and Cytotoxic Activity.

A series of new 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with different aryl substituents at the 5 position are synthesized and characterized by 1H/ 13C NMR and IR-spectroscopy and mass-spectrometry, as well as single crystal X-ray diffraction (SCXRD). It was demonstrated that the type of hydrogen bonding can play a key role in the chiral discrimination of these compounds in the crystalline phase. The hydrogen bond of the O-H...N type leads to 1D supramolecular heterochiral chains or conglomerate crystallization in the case of the formation of homochiral chains. The hydrogen bond of O-H...O type gave racemic dimers, which are packed into 2D supramolecular layers with a parallel or angular dimers arrangement. Halogen bonding of the N...Br or O...Br type brings a new motif into supramolecular self-assembly in the crystalline phase: the formation of 1D supramolecular homochiral chains instead 2D supramolecular layers. The study of cytotoxicity against various tumor cells in vitro was carried out. It was found that 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with 3-nitrophenyl substituent at C5 carbon atom demonstrated a high efficiency against M-HeLa (cervical adenocarcinoma) and low cytotoxicity against normal liver cells.

Selenocystine and Photo-Irradiation Directed Growth of Helically Grooved Gold Nanoarrows.

The fabrication of discrete nanostructures with both plasmonic circular dichroism (PCD) and chiral features is still a challenge. Here, gold nanoarrows (GNAs) with both chiroptical responses and chiral morphologies are achieved by using L-selenocystine (L-SeCys2 ) as a chiral inducer. While L-SeCys2 generates GNAs with a weak PCD signal, the irradiated L-SeCys2 (irr-L-SeCys2 ) leads to GNAs with featured helical grooves (HeliGNAs) accompanying with a strong PCD signal. It is revealed that when L-SeCys2 is photo-irradiated, the emergence of selenyl radicals plays an important role in the formation of HeliGNAs and enhancement of the chiroptical signal. In comparison with L-SeCys2 and the other kinds of sulfur-containing amino acids, the formation mechanism of helical grooves on the surface of GNAs is proposed. Both HeliGNAs and GNAs are used to discriminate amino acids by utilizing surface enhanced Raman scattering (SERS) effect. In the presence of either GNAs or HeliGNAs as the substrate, Fmoc-L-Phe shows more significant SERS than Fmoc-D-Phe. This study may advance the design of discrete plasmonic nanomaterials with both chiral morphology and potential applications in discrimination of chiral molecules.

Preparation of fluorescein-modified polymer dots and their application in chiral discrimination of lysine enantiomers.

Fluorescein-functionalized fluorescent polymer dots (F-PDs) were prepared by a facile one-pot method by magnetic stirring under mild conditions based on carboxymethylcellulose (CMC) and fluorescein as the precursors. The obtained F-PDs exhibited a nanoscale size of 3.2 ± 1.1 nm, excellent water solubility, and bright yellow fluorescence emission with a fluorescence quantum yield of 12.0%. The fluorescent probe displays rapid and sensitive chiral discrimination for lysine focused on different complexation abilities between lysine enantiomers and Cu2+. The concentration of L-lysine in the range 4 to 14 mM (R2 = 0.997) was measured by the fluorescence intensity ratio (I513/I429); the exitation wavelength was set to λex = 365 nm. The detection limit was 0.28 mM (3σ/slope). Importantly, this sensor accurately predicted the enantiomeric excess (ee) of lysine enantiomers at the designed concentration (lysine: 20 mM; Cu2+: 10 mM) ranges. The proposed sensor was successfully applied to determine L-lys (recovery: 95.8-101%; RSD: 0.465-3.34%) and ee values (recovery: 98.5-102%; RSD: 2.61-3.21%) in human urine samples using the standard addition method.

Nuclear magnetic resonance chiral discrimination of fipronil and malathion agrochemicals: A case study.

The aim of the present study was to optimize a protocol for nuclear magnetic resonance (NMR) chiral discrimination to be used to determine the enantiomers ratio of agrochemicals. For this goal, the commercial agrochemicals fipronil and malathion were employed as active targets due the distinct physicochemical properties. We used the cyclodextrins to evaluate the chiral discrimination in aqueous media and chiral solvent agents to check in organic media. The fipronil chiral discrimination was accessed by ß-CD in aqueous solution, although this procedure was ineffective for malathion due the low solubility. In organic media, the NMR chiral discrimination was successful for both agrochemicals and sensitive to dilution process. The NMR experiments explore very sensitive nuclei, for instance 1 H, 19 F, and 31 P, in a simple, practical and low residue experimental protocol.

Hydrolysis and Enantiodiscrimination of (R)- and (S)-Oxazepam Hemisuccinate by Methylated ß-Cyclodextrins: An NMR Investigation.

Partially and exhaustively methylated ß-cyclodextrins [(2-methyl)-ß-CD (MCD), heptakis-(2,6-di-O-methyl)-ß-CD (DIMEB), and heptakis-(2,3,6-tri-O-methyl)-ß-CD (TRIMEB)] have been compared in the hydrolysis and enantiodiscrimination of benzodiazepine derivative (R)- or (S)-oxazepam hemisuccinate (OXEMIS), using nuclear magnetic resonance (NMR) spectroscopy as an investigation tool. After 6 h, MCD induced an 11% hydrolysis of OXEMIS, remarkably lower in comparison with underivatized ß-CD (48%), whereas no hydrolysis was detected in the presence of DIMEB or TRIMEB after 24 h. DIMEB showed greater ability to differentiate OXEMIS enantiomers in comparison to TRIMEB, by contrast MCD did not produce any splitting of racemic OXEMIS resonances. Both enantiomers of OXEMIS underwent deep inclusion of their phenyl pendant into cyclodextrins cavities from their wider rims, but tighter complexes were formed by DIMEB with respect to TRIMEB.

Isoleucine Residues Determine Chiral Discrimination of Odorant-Binding Protein.

Enzymes, receptors, and carrier proteins discriminate between enantiomers of natural and synthetic chemicals. Whereas the structural details of this phenomenon have been investigated in enzymes and receptors, much less is known for carrier proteins of hydrophobic ligands, particularly concerning the contribution of asymmetric centers in the side chains of amino acids to chirally selective binding. Working with a pig odorant-binding protein, we have found that the replacement of either one or both isoleucine residues in the binding pocket by leucines abolishes discrimination of menthol and carvone enantiomers. The results indicate that isoleucines are crucial for chiral discrimination of hydrophobic ligands, and that asymmetry in the side chain may be as important as the overall asymmetry of the protein. The results provide suggestions and guidelines for improving chiral selectivity of binding proteins and enzymes, with consequent applications in the production of enantiomerically pure drugs.

Chiral discrimination in a mutated IDH enzymatic reaction in cancer: a computational perspective.

Chiral discrimination in biological systems, such as L-amino acids in proteins and d-sugars in nucleic acids, has been proposed to depend on various mechanisms, and chiral discrimination by mutated enzymes mediating cancer cell signaling is important in current research. We have explored how mutated isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate which in turn is converted to d-2-hydroxyglutatrate (d-2HG) as a preferred product instead of l-2-hydroxyglutatrate (l-2HG) according to quantum chemical calculations. Using transition state structure modeling, we delineate the preferred product formation of d-2HG over l-2HG in an IDH active site model. The mechanisms for the formation of d-2HG over l-2HG are assessed by identifying transition state structures and activation energy barriers in gas and solution phases. The calculated reaction energy profile for the formation of d-2HG and l-2HG metabolites shows a 29 times higher value for l-2HG as compared to d-2HG. Results for second-order Møller-Plesset perturbation theory (MP2) do not alter the observed trend based on Density Functional Theory (DFT). The observed trends in reaction energy profile explain why the formation of D-2HG is preferred over l-2HG and reveal why mutation leads to the formation of d-2HG instead of l-2HG. For a better understanding of the observed difference in the activation barrier for the formation of the two alternative products, we performed natural bond orbital analysis, non-covalent interactions analysis and energy decomposition analysis. Our findings based on computational calculations clearly indicate a role for chiral discrimination in mutated enzymatic pathways in cancer biology.

BODIPY- and Porphyrin-Based Sensors for Recognition of Amino Acids and Their Derivatives.

Molecular recognition is a specific non-covalent and frequently reversible interaction between two or more systems based on synthetically predefined character of the receptor. This phenomenon has been extensively studied over past few decades, being of particular interest to researchers due to its widespread occurrence in biological systems. In fact, a straightforward inspiration by biological systems present in living matter and based on, e.g., hydrogen bonding is easily noticeable in construction of molecular probes. A separate aspect also incorporated into the molecular recognition relies on the direct interaction between host and guest with a covalent bonding. To date, various artificial systems exhibiting molecular recognition and based on both types of interactions have been reported. Owing to their rich optoelectronic properties, chromophores constitute a broad and powerful class of receptors for a diverse range of substrates. This review focuses on BODIPY and porphyrin chromophores as probes for molecular recognition and chiral discrimination of amino acids and their derivatives.

A Chiral-Label-Free SERS Strategy for the Synchronous Chiral Discrimination and Identification of Small Aromatic Molecules.

A versatile and robust chiral discrimination strategy for small aromatic compounds is of significant importance in multidisciplinary fields. However, most current methods lack either the sufficient sensitivity for recognizing the chirality of the target molecules or their molecular specificity information. We have developed a versatile and chiral-label-free surface-enhanced Raman scattering (SERS)-based chiral discrimination sensing system for small aromatic molecules, where the molecular structural specificity and enantioselectivity can be given synchronously in a single SERS spectrum. More than 10 types of chiral aromatic molecules were successfully identified by using this system. This work has enormous potential for recognizing chiral products effectively in sophisticated systems, especially in the fields of chiral synthesis and chiral catalysis.

Synthesis and Stereostructure-Activity Relationship of Novel Pyrethroids Possessing two Asymmetric Centers on a Cyclopropane Ring.

2-Methylcyclopropane pyrethroid insecticides bearing chiral cyanohydrin esters or chiral ethers and two asymmetric centers on the cyclopropane ring, were synthesized. These compounds were designed using a "reverse connection approach" between the isopropyl group in Fenvalerate, and between two dimethyl groups in an Etofenprox analogue (the methyl, ethyl form), respectively. These syntheses were achieved by accessible ring opening reactions of commercially available (±)-, (R)-, and (S)-propylene oxides using 4-chlorobenzyl cyanide anion as the crucial step, giving good overall yield of the product with >98% ee. The insecticidal activity against the common mosquito (Culex pipiens pallens) was assessed for pairs of achiral diastereomeric (1R*,2S*)-, (1R*,2R*)-cyanohydrin esters, and (1R*,2S*)-, (1R*,2R*)-ethers; only the (1R*,2R*)-ether was significantly effective. For the enantiomeric (1S,2S)-ether and (1R,2R)-ether, the activity was clearly centered on the (1R,2R)-ether. The present stereostructure‒activity relationship revealed that (i) cyanohydrin esters derived from fenvalerate were unexpectedly inactive, whereas ethers derived from etofenprox were active, and (ii) apparent chiral discrimination between the (1S,2S)-ether and the (1R,2R)-ether was observed. During the present synthetic study, we performed alternative convergent syntheses of Etofenprox and novel 4-EtO-type (1S,2S)- and (1R,2R)-pyrethroids from the corresponding parent 4-Cl-type pyrethroids, by utilizing a recently-developed hydroxylation cross-coupling reaction.

The influence of relativistic effects on nuclear magnetic resonance spin-spin coupling constant polarizabilities of H2 O2 , H2 S2 , H2 Se2 , and H2 Te2.

Relativistic and nonrelativistic calculations have been performed on hydrogen peroxide, dihydrogen disulfide, dihydrogen diselenide, and dihydrogen ditelluride, H2 X2 (X = O, S, Se, Te), to investigate the consequences of relativistic effects on their structures as well as their nuclear magnetic resonance (NMR) spin-spin coupling constants and spin-spin coupling constant polarizabilites. The study has been performed using both one-component nonrelativistic and four-component relativistic calculations at the density functional theory (DFT) level with the B3LYP exchange-correlation functional. The calculation of nuclear spin-spin coupling constant polarizabilities has been performed by evaluating the components of the third order tensor, nuclear spin-spin coupling polarizability, using quadratic response theory. From this, the pseudoscalar associated with this tensor has also been calculated. The results show that relativistic corrections become very important for H2 Se2 and H2 Te2 and hint that a new chiral discrimination technique via NMR spectroscopy might be possible for molecules containing elements like Se or Te. © 2018 Wiley Periodicals, Inc.

Improved Resolution of 4-Chloromandelic Acid and the Effect of Chlorine Interactions Using (R)-(+)-Benzyl-1-Phenylethylamine as a Resolving Agent.

In order to avoid the disadvantage of commonly used resolving agent 1-phenylethylamine (hereafter: PEA), which is soluble in water, (R)-(+)-benzyl-1-phenylethylamine ((R)-(+)-BPA) was used to resolve 4-chloromandelic acid (4-ClMA) in this study. The optimal resolution conditions were determined: absolute ethanol as a solvent, the molar ratio of 4-ClMA to (R)-(+)-BPA as 1:1, the filtration temperature as 15 °C, and the amount of solvent as 1.6 mL/1 mmol 4-ClMA. Thermophysical properties, such as melting point, heat of fusion, and solubility, exhibited significant differences between the less and more soluble salts. The single crystals for the pair of diastereomeric salts were cultivated and their crystal structures were examined thoroughly. In addition to commonly observed interactions like hydrogen bonding and CH/π interactions. The chlorine…chlorine interaction was observed in the less soluble salt presenting as Cl…Cl between adjacent hydrogen network columns, while the Cl/π interaction was observed in the more soluble salt. It was found that halogen interactions played an important role in chiral recognition of 4-ClMA by (R)-(+)-BPA.

Chiral discrimination in NMR spectroscopy.

Nuclear magnetic resonance is the most important form of molecular spectroscopy in chemistry and biochemistry but it is normally blind to chirality. It was predicted in 2004 that precessing nuclear spins in chiral molecules in a liquid in a strong magnetic field induce a rotating electric polarization that is of opposite sign for enantiomers. This polarization arises from the distortion of the electronic structure by the nuclear magnetic moment in the presence of the strong magnetic field and is equivalent to the linear effect of an electric field on the nuclear shielding tensor. The polarization is strongly enhanced in dipolar molecules through the partial orientation of the permanent dipole through the antisymmetric part of the nuclear magnetic shielding tensor. Alternatively, an applied electric field will induce a chirally sensitive magnetization perpendicular to the field and to the nuclear spin. Progress towards the experimental realization of chiral discrimination by NMR is assessed.