Chiral Reagent Research Articles

Analyzing Citramalic Acid Enantiomers in Apples and Commercial Fruit Juice by Liquid Chromatography-Tandem Mass Spectrometry with Pre-Column Derivatization.

Optically active citramalic acid (CMA) is naturally present as an acidic taste component in fruits, such as apples. The absolute configuration of CMA in such fruits was investigated by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) following pre-column derivatization with a chiral reagent, benzyl 5-(2-aminoethyl)-3-methyl-4-oxoimidazolidine-1-carboxylate. The developed LC-MS/MS method successfully separated the enantiomers of CMA using an octadecylsilica column with a resolution and separation factor of 2.19 and 1.09, respectively. Consequently, the R-form of CMA was detected in the peel and fruit of three kinds of apple at concentrations in the 1.24-37.8 and 0.138-1.033 mg/wet 100 g ranges, respectively. In addition, R- CMA was present in commercial apple juice, whereas no quantity was detected in commercial blueberry, perilla, or Japanese apricot juice.

Azepine-Embedded Seco-Hexabenzocoronene-Based Helix Nanographenes: Access to Modification of the Core by N–H Functionalization

Contorted polycyclic aromatic hydrocarbons (PAHs) or nanographenes (NGs) have received increasing attention and are mostly prepared by "bottom-up" strategies. Apparently, systematically tuning the properties of NGs for application is important but challenging. Here, a new type of helix, azepine-embedded NGs, were designed and synthesized by the introduction of NH into the hexa-peri-hexabenzocoronene (HBC) core. We demonstrate that this nitrogen-doped NG can be functionalized via N-H derivatization. Through modifications to the NH site with a chiral auxiliary reagent, optical resolution of the chiral NG was achieved. Meanwhile, it was found that by introducing various aryl groups with electron-donating or electron-withdrawing substituents, the emission intensity and the fluorescence mechanism can be modulated. Compared to the original NH-containing NG, the modified derivative exhibited improved fluorescence efficiency and tunable emission wavelength. A functionalized structure of benzoic acid with considerably improved fluorescence efficiency, hydrophilicity, and membrane permeability to stain the live cells was proved.

Efficient Preparation of Chloroquine Enantiomers via Crystallization Resolution and Palladium-Catalysed Coupling

Abstract: Chloroquine (CQ) was found to exhibit antiviral activity against novel coronaviruses, which makes the preparation of CQ enantiomers particularly important. In this work, we developed an efficient method for the preparation of CQ enantiomers by crystallization resolution and palladium-catalyzed coupling. The obtained chiral CQ had been fully assigned by 1H-1H COSY, 1H-13C HSQC, and 1H-13C HMBC spectra. Moreover, the enantiomeric excess value of CQ was rapidly detected by binaphthol phosphate as a chiral NMR shift reagent.

Kinetic Investigations on the Chiral Induction by Amino Acids in Porphyrin J-Aggregates.

The self-assembling kinetics of the 5,10,15,20-tetrakis(4-sulfonato-phenyl)porphyrin (TPPS4) into nano-tubular J-aggregates under strong acidic condition and in the presence of amino acids as templating chiral reagents have been investigated through UV/Vis spectroscopy. The ability of the chiral species to transfer its chiral information to the final J-aggregate has been measured through circular dichroism (CD) spectroscopy and compared to the spontaneous symmetry breaking process usually observed in these nano-aggregates. Under the experimental conditions here selected, including mixing protocol, we have observed a large difference in the observed aggregation rates for the various amino acids, those with a positively charged side group being the most effective. On the contrary, these species are less efficient in transferring their chirality, exhibiting a quite low or modest enhancement in the observed dissymmetry g-factors. On the other side, hydrophobic and some hydrophilic amino acids are revealed to be very active in inducing chirality with a discrete increase of intensity of the detected CD bands with respect to the spontaneous symmetry breaking.

One Step Selective Counterion Dependent Formation of Conjugated Chiral N-Sulfinylimines from Aldehydes.

We report a detailed study on the synthesis and aldehyde vinylogation applications of chiral N-sulfinyl imine phosphonate reagents. Two complementary scalable reagent routes, from trialkyl phosphites and methyl phosphonates, respectively, are presented. This reagent class enables significant streamlining in synthesis of conjugated Ellman imines from aldehydes, which can now be accomplished in a single step compared to a more classic 4-step redox-based approach. Aldehyde vinylogation optimizations have revealed significant counterion effects and unexpected competing reaction challenges that needed to be addressed to achieve high yields.

Chiral gem-difluoroalkyl reagents: gem-difluoroalkyl propargylic borons and gem-difluoroalkyl α-allenols.

Chiral fluorinated reagents provide new opportunities for the discovery of drugs and functional materials because the introduction of a fluorinated group significantly alters a molecule's physicochemical properties. Chiral gem-difluoroalkyl fragments (R-CF2-C*) are key motifs in many drugs. However, the scarcity of synthetic methods and types of chiral gem-difluoroalkyl reagents limits the applications of these compounds. Herein, we report two types of chiral gem-difluoroalkyl reagents chiral gem-difluoroalkyl propargylic borons and gem-difluoroalkyl α-allenols and their synthesis by means of methods involving rhodium-catalyzed enantioselective B-H bond insertion reactions of carbenes and Lewis acid-promoted allenylation reactions. The mild, operationally simple method features a broad substrate scope and good functional group tolerance. These two types of reagents contain easily transformable boron and alkynyl or allenyl moieties and thus might facilitate rapid modular construction of chiral molecules containing chiral gem-difluoroalkyl fragments and might provide new opportunities for the discovery of chiral gem-difluoroalkyl drugs and other functional molecules.

Separation of amyloid β fragment peptides with racemised and isomerised aspartic acid residues using an original chiral resolution labeling reagent.

We developed a system to separate and identify racemised and isomerised aspartic acid (Asp) residues in amyloid β (Aβ) by labeling with an original chiral resolution labeling reagent, 1-fluoro-2,4-dinitrophenyl-5-D-leucine-N,N-dimethylethylenediamine-amide (D-FDLDA). The racemised and isomerised Asp residues labeled with D-FDLDA in Aβ fragments generated by digesting with trypsin and endoproteinase Glu-C were separated and identified by liquid chromatography-mass spectrometry (LC-MS) under simple gradient conditions. Furthermore, the labeled Aβ fragments did not aggregate and remained stable at least for 1 week at 4 °C.

Synthesis of Quinoline-Based New Chiral Derivatizing Reagents and its use in the Derivatization and Enantioseparation of Few Structurally Similar β-Blockers using Liquid Chromatography and Structural Optimization using DFT

In this work, quinoline based new chiral derivatizing reagent was synthesized by introducing chiral amino acid (L-proline) in the molecule. Synthesized chiral derivatizing reagent was characterized by spectroscopic techniques (1H NMR, FT-IR, HRMS and CHNS analysis) and used in the synthesis of diastereomer of chosen β-blockers. The RP-HPLC system was used to separate synthesized diastereomers (indirect approach of enantioseparation). Acetonitrile and buffer solution was used as mobile phase for analysis. The effect of varying concentrations and pH of mobile phase was optimized for the separation of diastereomers. The density functional theory calculations were also carried out to develop the lowest energy-minimize optimized diastereomer structures and to design separation mechanisms and elution orders. The retention factor (k), selectivity factor (α), resolution factor (RS), the limit of detection (0.192 ng mL–1) and the limit of quantification (0.576 ng mL–1) were calculated in the context of the method’s validation in accordance with ICH guidelines.

Stereoselective RNA reaction with chiral 2'-OH acylating agents.

The reactivity of RNA 2'-OH groups with acylating agents has recently been investigated for high-yield conjugation of RNA strands. To date, only achiral molecules have been studied for this reaction, despite the complex chiral structure of RNA. Here we prepare a set of chiral acylimidazoles and study their stereoselectivity in RNA reactions. Reactions performed with unfolded and folded RNAs reveal that positional selectivity and reactivity vary widely with local RNA macro-chirality. We further document remarkable effects of chirality on reagent reactivity, identifying an asymmetric reagent with 1000-fold greater reactivity than prior achiral reagents. In addition, we identify a chiral compound with higher RNA structural selectivity than any previously reported RNA-mapping species. Further, azide-containing homologs of a chiral dimethylalanine reagent were synthesized and applied to local RNA labeling, displaying 92% yield and 16 : 1 diastereoselectivity. The results establish that reagent stereochemistry and chiral RNA structure are critical elements of small molecule-RNA reactions, and demonstrate new chemical strategies for selective RNA modification and probing.

A paper-based chemical tongue based on the charge transfer complex of ninhydrin with an array of metal-doped carbon dots discriminates natural amino acids and several of their enantiomers.

Simultaneous detection of multiple amino acids (AAs) instead of individual AAs is inherently worthwhile for improving diagnostic accuracy in clinical applications. Here, a facile and reliable colorimetric microfluidic paper-based analytical device (μPAD) using carbon dots doped with transition metals (Cr3+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, and Zn2+) has been provided to detect and discriminate 20 natural amino acids. To make the colourless metal-doped carbon dots suitable for colorimetric assays, they were mixed with ninhydrin to form a charge transfer complex. This optical tongue system, which was constructed by dropping mixtures of ninhydrin with a series of metal-doped carbon dots on a paper substrate in an array format, represented obvious but different colorimetric signatures for every examined amino acid. Since bovine serum albumin was used as a chiral selector reagent for synthesizing the CDs, the sensor device represented excellent selectivity to identify enantiomeric species of AAs. This is the first optical array device that can simultaneously discriminate AAs and several of their enantiomers. We employed various statistical and chemometric methods to analyze the digital data library collected by Image J software, including principal component analysis (PCA), linear discriminant analysis (LDA), and hierarchical cluster analysis (HCA). Twenty AAs could be well distinguished at various concentrations (10.00, 5.00, 2.50, and 1.25 mM). The colorimetric patterns were highly repeatable and were characteristic of individual AAs. Besides qualitative analysis, the designed μPAD-based optical tongue represented quantitative analysis ability, e.g., for lysine in the concentration ranges of 0.005-20.0 mM with a detection limit of 1.0 × 10-6 M and for arginine in the concentration range of 0.12-20.00 mM with a detection limit of 80.0 × 10-6 M. In addition, the binary, ternary, and quaternary mixtures of AAs could also be well recognized with this sensor.

Aggregation-Induced Catalysis: Asymmetric Catalysis with Chiral Aggregates.

So far, there have been 4 methods to control chirality including the use of chiral auxiliaries, reagents, solvents, and catalysts documented in literature and textbooks. Among them, asymmetric catalysts are normally divided into homogeneous and heterogeneous catalysis. In this report, we present a new type of asymmetric control-asymmetric catalysis via chiral aggregates that would not belong to the above categories. This new strategy is represented by catalytic asymmetric dihydroxylation reaction of olefins in which chiral ligands are aggregated by taking advantage of typical aggregation-induced emission systems containing tetrahydrofuran and H2O cosolvents. It was proven that the chiral induction can be enhanced from er of 78:22 to 97:3 simply by changing the ratios of these 2 cosolvents. The formation of chiral aggregates of asymmetric dihydroxylation ligands, (DHQD)2PHAL and (DHQ)2PHAL, has been proven by aggregation-induced emission and a new analytical tool-aggregation-induced polarization established by our laboratory. In the meanwhile, chiral aggregates were found to be formed either by adding NaCl into tetrahydrofuran/H2O systems or by increasing concentrations of chiral ligands. The present strategy also showed promising reverse control of enantioselectivity in the Diels-Alder reaction. This work is anticipated to be extended broadly to general catalysis, especially to asymmetric catalysis in the future.

Chemical resolution of spiroindanones and synthesis of chiroptical polymers with circularly polarized luminescence.

Herein, the synthesis and chemical resolution of 1,1'-spirobisindane-3,3'-dione have been accomplished utilizing inexpensive and readily available benzaldehyde and acetone as starting materials, and (1R,2R)- or (1S,2S)-1,2-diphenylethane-1,2-diol as a recyclable chiral resolution reagent. The further transformation of R- and S-1,1'-spirobisindane-3,3'-dione into chiral monomers and polymers has been achieved by the reasonable design of the synthetic route and the optimization of the polymerization conditions. The resulting chiroptical polymers exhibit blue emission with thermally activated delayed fluorescence (TADF), excellent optical activities with circular dichroism intensities per molar absorption coefficient (gabs) of up to 6.4 × 10-3, and intense circularly polarized luminescence (CPL) with luminescence dissymmetry factor (glum) values of up to 2.4 × 10-3.

Development and evaluation of a novel fluorescent chiral derivatization reagent DBD-S-M-Pro: first observation of four chiral amino acids in human hair.

This study reports a novel fluorescent chiral derivatization reagent, 4-(N,N-dmethylaminosulfonyl)-2,1,3-benzoxadiazole-(2-succinimidoxy)-trans-2-methyl-L-proline (DBD-S-M-Pro), with a benzoxadiazole structure containing an N-hydroxysuccinimide activation group. DBD-S-M-Pro targets chiral amino-functional compounds under alkaline conditions without a condensation agent. Gradient elution was performed on a BEH C18 (100 × 2.1 mm, 1.7 μm) column with a mobile phase of 0.05% formic acid (FA) in 10 mM ammonium acetate (CH3COONH4) and 0.1% FA in acetonitrile or methanol. The efficiency of the chiral resolution was evaluated under excitation and emission wavelengths of 450 nm and 560 nm, respectively. The 19 chiral amino acids were separated in the range of 1.45-14.84. The resolutions of almost all DL-amino acids exceeded 1.5; the exceptions were serine (Ser) and lysine (Lys), with resolutions of 1.45 and 1.46, respectively. In addition, a new approach was devised for the simultaneous analysis of four chiral amino acids (DL-Glu, DL-Ala, DL-Val, and DL-Phe) in human hair. These amino acids were analyzed in the range of 12.5-400 pmol, with R2 ≥ 0.9990, limits of detection (S/N = 3) of 4-10 pmol, and intraday and interday precisions of 0.57-6.23%. The average spikes in the hair recoveries were 89.76-111.54%, and the matrix effects were 92.47-102.40%. Next, the contents of free chiral amino acids in the hair samples of 10 healthy volunteers (five males and five females) were analyzed with this method, and the differences were compared. The developed DBD-S-M-Pro provides a novel strategy for the sensitive determination of free chiral amino acids in living organisms.

Simultaneous separation and identification of all structural isomers and enantiomers of aminobutyric acid using a highly sensitive chiral resolution labeling reagent.

Aminobutyric acid has structural isomers (α-, β-, and γ-aminobutyric acids) and enantiomers (D/L-forms) with various unique functions. Therefore, a quantitative method for determining the content of each aminobutyric acid must be developed. In general, quantitative simultaneous analysis of multiple compounds is conducted via high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). However, simultaneous separation and highly sensitive detection of all aminobutyric acids are complicated, so highly sensitive analytical methods for the separation and identification of each compound have not yet been established. We previously developed highly sensitive chiral resolution labeling reagents. Herein, we propose a highly sensitive analytical method for the simultaneous separation and identification of all aminobutyric acids via LC-MS and labeling with our original highly sensitive chiral resolution labeling reagent, 1-fluoro-2,4-dinitrophenyl-5-L-valine-N,N-dimethylethylenediamine amide (L-FDVDA). The labeling reagent was completely bound to all aminobutyric acids through incubation overnight (>15 h) at 50 °C. Additionally, the labeled aminobutyric acids could be stored for at least 1 week at 4 °C. Furthermore, we demonstrated simultaneous separation and identification of aminobutyric acids in biological samples and foods through LC-MS using a C18 column after labeling with L-FDVDA. Our method is expected to be adopted for the analysis of the contents of all aminobutyric acids in biological and clinical samples as well as various foods.

Asymmetric synthesis of the sex pheromone of the apple leafminer, Lyonetia prunifoliella.

Lyonetia prunifoliella is a significant pest in orchards and damages apple. The sex pheromones of this pest were prepared via a new and concise method. The central to our method were Evans' chiral auxiliaries, the addition of chiral Grignard reagent to aldehyde and Wittig coupling.

Development of a diphenyl sulfide structure derivatization reagent for amino acid enantiomers analysis: Application of dynamic monitoring in human urine after drinking wine

We developed a novel chiral mass spectrometry derivatization reagent (S)-(3-(4-carboxythiazolidin-3-yl)-3-oxopropyl) diphenylsulfonium (CTOD) with a positively charged sulfur-containing structure for high-sensitivity detection of the chiral resolution of amino acid enantiomers. CTOD reacted with DL-amino acids at 60oC for 60 min to generate the corresponding diastereomers, fifteen chiral amino acid-derived products were separated. Resolution (Rs) values were of the range 1.54-4.36, except Asn 1.07, achieving good separation. A highly sensitive and selective UHPLC-MS/MS method for the simultaneous determination and chiral separation of five chiral amino acids (Pro, Ala, Glu, Asp, and Phe) based on CTOD derivatization was established and applied to the detection of chiral amino acids in different wines. The diastereomeric resolution of the five amino acids was 1.71–5.42, and an excellent linear relationship was obtained in the range of 0.25–500 pmol (R2 ≥0.9993). The detection limit was 0.05–0.25 pmol. The intra- and inter-day precisions were 0.51–5.76% and 0.78–5.18%, respectively, and the average recovery was 90.03–99.99%. In addition, the metabolic concentration of chiral amino acids was monitored after drinking red wine and white wine, and the fitting curve of metabolic concentration was drawn.

C1-symmetric aza-crown ethers as chiral shift agents for amines and amino acid derivatives

Reported herein is our recent research progress in the development of macrocyclic chiral recognition studies. Highly enantiopure C1-symmetric aza-crown ethers, which were prepared previously by our lab from catalytic enantioselective symmetry-breaking C (sp3)-H bond transformation of readily available and inexpensive aza-crown ethers, were useful 1H NMR chiral shift reagents to resolve racemic amines and amino acid derivatives, providing an easy and rapid NMR assay of enantiomeric purity of chiral compounds, especially chromophore-devoid ones that are not detected and quantified by colorimetric method.

Facile and Environment-friendly Fluorinations using Ionic Liquids.

Significant advancement in the preparation of fascinating fluoroorganics is highly desirable in view of their limited natural occurrence and ever-increasing applications in medicinal and material sciences. Ionic liquids act as the most promising green media for a variety of nucleophilic and electrophilic fluorinations in terms of chemoselectivity, reaction yields, reusability, operational simplicity and scalability. The use of these designer solvents in stimulating the electrified synthesis of fluorinated compounds is also appreciable due to their tuneable electrochemical characteristics. Recent innovations in fluorination techniques depict the substantial role of ionic liquids in fluorotransformations such as the use of tagged ionic liquids in nucleophilic fluorinations, ionic liquid assisted biological fluorination, enantioselective fluorinations using chiral electrophilic reagents along with ionic liquid media, use of task-specific ionic liquids with mediators in electrochemical fluorinations and ionic liquid promoted electrifying synthesis of medicinally important fluorinated heteroaromatics and radiopharmaceuticals.

Nonlinear helical dichroism in chiral and achiral molecules

Chiral interactions are prevalent in nature, driving a variety of biochemical processes. Discerning the two non-superimposable mirror images of a chiral molecule, known as enantiomers, requires interaction with a chiral reagent with known handedness. Circularly polarized light beams are often used as a chiral reagent. Here we demonstrate efficient chiral sensitivity with linearly polarized helical light beams carrying an orbital angular momentum of ±lħ, in which the handedness is defined by the twisted wavefront structure tracing a left- or right-handed corkscrew pattern as it propagates in space. By probing the nonlinear optical response, we show that helicity-dependent nonlinear absorption occurs even in achiral molecules and can be controlled. We model this effect by considering induced multipole moments in light–matter interactions. Design and control of light–matter interactions with helical light may open new opportunities in chiroptical spectroscopy, light-driven molecular machines, optical switching and in situ ultrafast probing of chiral systems and magnetic materials.

Enantioselective [3 + 2] cycloadditions of terminal allenoates with β-sulfonyl-α,β-unsaturated ketones

A highly efficient and mild method for [3 ​+ ​2] cycloaddition of β-sulfonyl-α,β-unsaturated ketones with terminal allenoates was well-explored and developed. The reactions were successfully performed by applying multifunctional chiral phosphine P6 which was screened from eight chiral phosphorus reagents to finally result in a variety of enantioenriched sulfone-substituted cyclopentenes with two chiral centers (up to 81% yield with 94% ee). Moreover, 2.5 ​mol% catalytic equivalents were proved to be feasible when this reaction was performed on a 10 ​mmol scale.