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A chemical investigation on Sporormiella sp. led to the isolation and structural elucidation of tripodalsporormielones A–C (1–3), a new class of polyketide possessing unprecedented cage-like skeletons with polyvdent bridged and fused ring systems. These polyketides with cage-like skeletons were characterized as a high non-protonated carbon-containing system, which resulted in few HMBC correlations observed and made the accurate structures hard to be obtained by NMR. Especially, some signals of non-protonated sp2 carbons are weak and even unobservable in compound 1. In order to establish the structure of 1, the calculated NMR with DP4 evaluation was applied to determine the structure from the plausible structure candidates obtained from the detailed NMR analysis. Based on NMR experiments and calculated NMR, the structures of isolated compounds were established and confirmed by X-ray technology. Through chiral isolation, the optically pure enantiomers of 1 and 3 were obtained, and their absolute configurations were determined based on ECD quantum chemical calculation. Based on the isolated compounds and our previous work, 1–3 would be derived from 3-methylorcinaldehyde, and their plausible biosynthetic mechanism was proposed. Furthermore, 1 exhibited obvious short-term memory improvement activity on an Alzheimer's disease fly model., Graphical abstract Tripodalsporormielones A–C (1–3), a new class of C–C coupled orsellinic acid derivative dimer possessing unprecedented cage-like skeletons with polyvdent bridged and fused ring systems from Sporormiella sp.Image 1

A direct enantio-, diastereo-, and chemo-selective high-performance liquid chromatographic method was developed for determining the content, enantiomeric purity, and related substances of the chiral antidepressant drug sertraline HCl in a single chromatographic run. The separation was achieved on a chiral stationary phase based on amylose tris(3-chloro-5-methylphenylcarbamate) under reversed-phase conditions. The method was optimized by evaluating the influence of the temperature and mobile phase composition on the retention and selectivity. The application of the single-run approach allowed to baseline resolve all investigated species in less than 15 min, without using buffers or tandem-coupled columns. The chromatographic method was validated according to the guidelines of the Official Medicines Control Laboratory and applied to control the content of sertraline HCl and related chiral substances in a generic antidepressant formulation., Graphical abstract Image 1, Highlights • Sertraline displays two stereogenic centers but only the (1S,4S) form is clinically useful. • A direct method was developed for evaluating assay and impurities in a single HPLC run. • The single-run RP method allowed resolving all species within 15 min, without using buffers. • Amylose tris(3-chloro-5-methylphenylcarbamate)-based CSP was used as a chiral support. • The method is selective, precise and accurate and it meets the requirements of the EP guidelines.

In Korea and China, ilaprazole is a widely used proton pump inhibitor in the treatment of gastric ulcers. In this study, a specific and sensitive LC-MS/MS method has been developed and validated for the quantification of ilaprazole enantiomers in the rat plasma, using R-lansoprazole as the internal standard. The enantioseparation was achieved on a CHIRALPAK AS-RH column (4.6 mm × 150 mm, i.d. 5 μm), with a mobile phase composed of 10 mM ammonium acetate aqueous solution and acetonitrile (60:40, V/V), at a flow-rate of 0.5 mL/min. The method was validated over the concentration range of 0.5–300 ng/mL for both, R- and S -ilaprazole. The lower limit of quantification was 0.5 ng/mL for both enantiomers. The relative standard deviation (RSD) of intra- and inter-day precision of R-ilaprazole and S-ilaprazole was less than 10.9%, and the relative error accuracy (RE) ranged from −0.5%–2.0%. Finally, the method was successfully evaluated in rats in a stereoselective pharmacokinetic study of the ilaprazole racemate., Graphical abstract Image 1, Highlights • The enantioseparation of ilaprazole enantiomers was achieved on Chiralpak AS-RH column. • The LC-MS/MS was specific and sensitive. • The PK profiles of ilaprazole enantiomers showed significant difference.

The illegal production of amphetamine and its derivatives has rapidly increased in the last years to provide the increasing demand all over the world. Since amphetamine is chiral, its enantiomers have different pharmacological activities. The present work aims to study the enantiomeric profile of amphetamine in several batches of tablets seized from the illegal market. The R and S antipodes were first converted to diastereomers by reaction with trifluoroacetyl-l-prolyl chloride (L-TPC) as chiral reagent. The obtained diastereomers were then full separated by gas chromatography with a resolution factor RS of 1.69, then characterized by mass spectrometry. Both S and R-amphetamine showed similar contents in all investigated samples, with a slight excess of the more active S eutomer. The calculated enantiomeric excess (ee%) values are all positive in the range 0.60–9.72%. The total concentration of amphetamine was from 36.44 to 96.22 mg/g in all tablets. The seized materials showed also the presence of some other ingredients used as additives in manufacturing the tablets such as caffeine, phenazocine, diphenhydramine, dibutyl phthalate and 9-octadecenamide. These findings confirmed that the synthesis of amphetamine used in these tablets was performed using inexpensive and achiral starting substances.

An overview of molecular modelling approaches, related to chiral separations on polysaccharide-based and macrocyclic antibiotic chiral selectors, is presented. Both atomistic calculations and empirical fitting procedures are discussed. Atomistic calculations, such as docking and molecular dynamics can be used to model the interactions between enantiomers and the chiral stationary phase. This may help obtaining information about the chiral recognition mechanism. Conversely, in empirical fitting procedures, mathematical models for relevant separation parameters are fitted to experimental observations. The latter use theoretical molecular descriptors, calculated from the molecular structure, which are combined into a model to predict a given response, for example, retention. Such relationships, when used in chiral separations, are often called quantitative structure enantioselective retention relationships (QSERR) and an increased interest in them can be observed in the literature. Different regression models are discussed, such as multiple linear regression and partial least squares.

Locust plagues are still worldwide problems. Selecting active enantiomers from current chiral insecticides is necessary for controlling locusts and mitigating the pesticide pollution in agricultural lands. Herein, two enantiomers of isocarbophos (ICP) were separated and the enantioselectivity in insecticidal activity against the pest Locusta migratoria manilensis (L. migratoria) and mechanisms were investigated. The significant difference of LD50 between (+)-ICP (0.609 mg/kg bw) and (−)-ICP (79.412 mg/kg bw) demonstrated that (+)-ICP was a more effective enantiomer. The enantioselectivity in insecticidal activity of ICP enantiomers could be attributed to the selective affinity to acetylcholinesterase (AChE). Results of in vivo and in vitro assays suggested that AChE was more sensitive to (+)-ICP. In addition, molecular docking showed that the -CDOKER energies of (+)-ICP and (−)-ICP were 25.6652 and 24.4169, respectively, which suggested a stronger affinity between (+)-ICP and AChE. Significant selectivity also occurred in detoxifying enzymes activities (carboxylesterases (CarEs) and glutathione S-transferases (GSTs)) and related gene expressions. Suppression of detoxifying enzymes activities with (+)-ICP treatment suggested that (−)-ICP may induce the detoxifying enzyme-mediated ICP resistance. A more comprehensive understanding of the enantioselectivity of ICP is necessary for improving regulation and risk assessment of ICP.

In this study, a heart-cutting two-dimensional liquid chromatography (2D-LC) method for the determination of intracellular 2-hydroxyglutarate (2-HG) enantiomers is proposed. D-2-HG is an oncometabolite produced by tumors harboring isocitrate dehydrogenase (IDH) mutations. Hence, achieving accurate quantification of the 2-HG enantiomers in cancer cells is important. In this study, a fluorescence derivatization reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), was used. We found that 2-HG was successfully derivatized with NBD-PZ after lactonization. The enantiomers of 2-HG derivatized with NBD-PZ were quantified using the heart-cutting 2D-LC method. NBD-PZ-2-HG was stable for 1 week and was separated from endogenous compounds using an octadecyl silica column before enantiomeric separation on a chiral column. The developed heat-cutting 2D-LC method was validated and successfully applied to cell samples. The amount of D-2-HG and L-2-HG in U937 cells were 9.8 and 8.3 pmol/5.0 × 105 cells, respectively. Furthermore, high amounts of D-2-HG were measured in U937 cells expressing mutant IDH proteins as expected. This method can therefore be applied to further elucidate the role of 2-HG in cancer cells, particularly those harboring isocitrate dehydrogenase mutations.

Various substances classified by the World Anti-Doping Agency (WADA) as prohibited in sports feature one or more chiral centers. Amongst those, few analytes exist that are so-called threshold substances, for which also enantiomerically pure drugs are available. The commonly employed non-chiral analysis of these compounds does not allow for differentiating between the use of a racemic mixture of e.g. salbutamol and formoterol from their enantiomerically pure analogs. In order to support identifying the exclusive use of the pharmacologically active compound, a multi-analyte chiral chromatography-based analytical approach was developed. The test method considering the β2-agonists fenoterol, formoterol, and salbutamol, the stimulant methamphetamine, the anabolic agent clenbuterol, and the β-blockers metoprolol, pindolol, and propranolol was based on liquid chromatography with a chiral column comprising a stationary phase based on the macrocyclic glycopeptide antibiotic teicoplanin as chiral selector. The liquid chromatograph was interfaced via electrospray ionization to a high resolution/high accuracy mass spectrometer, and urine samples were prepared for analysis following a protocol including enzymatic hydrolysis and subsequent liquid-liquid extraction. For proof-of-concept, authentic urine samples containing the target compounds were analyzed and their enantiomeric composition was assessed. The approach proved suitable for the chiral separation of a total of eight selected enantiomeric doping agents, allowing to determine their ratio at urinary concentrations relevant for sports drug testing purposes, i.e. between 0.01 and 2 ng/mL. Enantioselective assays provide the tool to overcome the limitations of non-chiral approaches in routine doping analysis and can offer support in studies where questions of pharmacokinetics and stereoselectivity are to be addressed for result management and decision-making processes.

New amphetamine derivatives, a substance class belonging to the New Psychoactive Substances (NPS), have fundamentally changed the global drug market during the last years. Also known as “legal highs” they are sold under various names like "bath salts", "air fresheners" and so forth. Structures of well-known illicit drugs such as amphetamine, methamphetamine and 3,4-methylenedioxyamphetamine are slightly modified to circumvent law and samples are traded worldwide via various internet shops. Many of these new derivatives possess a chiral centre and the pharmacological differences of the two enantiomers are not yet investigated for many of them. This makes the continuous development of analytical methods for their chiral separation crucial. The aim of this study was to develop a simple, isocratic HPLC-UV method for enantioseparation and to test this method on a set of 26 amphetamine derivatives, including latest products on the drug market. A Daicel Chiralpak® CBH 150×3.0 mm column (5 µm particle size) served as chiral stationary phase. The influence of the organic modifier and type, molarity and pH of the buffer on separation results was investigated. UV detection was performed at 210 and 254 nm. As final mobile phase, a mixture of 5 mM sodium dihydrogen phosphate buffer (pH = 6.9) / methanol (85 : 15 v/v) was chosen. Under these conditions, all 26 tested amphetamines were separated successfully into their enantiomers. Thus, the results showed that all analytes were traded as racemic mixtures.

Highlights • Evidence short sonication time induces primary nucleation. • More primary nucleation events at 98 kHz compared to 200 kHz. • Primary nucleation requires more intense cavitational collapse bubbles. • 98 kHz and 200 kHz induced the same secondary nucleation rate., Ultrasound is known to promote crystal nucleation, but despite significant research there remains uncertainty about how the mechanisms are affected. Despite the proposal of various primary nucleation theories, most studies provide no way to quantify or observe the extent to which primary nucleation is taking place, leaving open the possibility that sonocrystallisation is occurring by a secondary nucleation-driven mechanism. By utilising the widely reported enantiomeric properties of sodium chlorate, the extent to which ultrasound can induce primary nucleation can clearly be observed. It was demonstrated during seeded cooling crystallisation that when stirring the seed similarity was 99.3% on average, indicating secondary nucleation had almost exclusively taken place. The application of ultrasound however, decreased the seed similarity to 85.8% and 92.4% when applying 98 kHz and 200 kHz ultrasound respectively, clearly showing that primary nucleation had been induced and indicating the frequency dependency of the induced primary nucleation. This frequency dependency suggests a link between crystal nucleation and high intensity cavitation collisions and collapses, and the potential existence of a collapse/collision intensity threshold required to induce primary nucleation. In addition, secondary nucleation rate was investigated using anti-solvent crystallisation and was observed to increase with the application of ultrasound, though it appeared frequency independent (between 98 kHz & 200 kHz), suggesting that higher energy cavitational events are less important in inducing secondary nucleation or that a lower cavitation intensity threshold exists compared to primary nucleation.

Chiral separation of short peptides is of great interest, due to different pharmacological, pharmacokinetic, and/or toxicological activities often possessed by different stereoisomers of chiral drugs. Crown ether chiral stationary phases have been successfully used for separating enantiomers of various racemic compounds containing primary amino groups. Even though chiral recognition mechanism for crown-ethers CSPs is generally understood, on a molecular level, the exact chiral recognition mechanisms for the resolution are still unclear. Furthermore, short peptide analytes often contain multiple amino moieties capable of binding to the crown ether selector. A research of relationship between peptide chemical structure and chiral chromatographic interactions was performed, by comparing the retention profiles of µ-opioid receptor agonist tetrapeptide Tyr-Arg-Phe-Lys-NH2 and its structural analogues on two commercially available S- and R-(3,3’-diphenyl-1,1′-binaphthyl)-20-crown-6) stationary phases [CROWNPAK CR-I (+) and (-)], in order to clarify, which of the potential interaction sites are responsible for retention and chiral recognition in Tyr-Arg-Phe-Lys-NH2 tetrapeptide.

Chirality is a relevant topic in pharmaceutical, food and agrochemical fields because enantiomers, in spite of their similar physical-chemical properties, can exhibit different dynamics, kinetics and effects. Their enantiomeric determination implies a significant analytical challenge because of their identical physical-chemical properties, except light rotation. This review provides a state-of-the-art overview of analytical methods reported from 2010 to the date for the determination of chiral pollutants, including pharmaceuticals, pesticides, musk fragrances, perfluorinated compounds (PFCs), brominated flame retardants (BFRs) and polychlorinated biphenyls (PCBs), in environmental samples and biota. Recent reviews in this topic, mainly focused on pharmaceuticals and pesticides, have been also included. Special attention has been focused on analytical techniques most commonly applied for such determination. Finally, future trends and mainly challenges to be overcome are stated. unta de Andalucía (Consejería de Economía y Conocimiento project I+D+i FEDER Andalucía US-1254283

Acetochlor is one of the most widely used chiral herbicides in the world, and it is usually produced and used as racemic form (Rac). The potential effects of acetochlor in human body are mainly induced by its residue in agriculture food. The direct target exposed is the liver in human body. However, the potential toxic and mechanism threat to human liver cells caused by chiral acetochlor has been rarely reported. The purpose of this study is to explore the potential mechanism of the toxicity caused by chiral acetochlor in HepG2 cells. The results revealed that acetochlor and its enantiomers could inhibit cell activity and cause DNA damage in HepG2 cells. The toxicity of Rac was higher than that of the two enantiomers, mainly derived from S configuration. The mechanism is through inducing decreased membrane potential (△Ψ), up-regulated Bax/BcL-2 expression, caused a cascade reaction, activated casepase-3 and casepase-9 and cleaved PARP, which maybe lead to cell death through apoptotic-signaling pathway in the end. These results illuminate that the genotoxic and cytotoxic risks of chiral acetochlor are major coming from S configuration. It provides a theoretical basis for the production of single pesticide to reduce the effects of human health.

Carvedilol is a chiral drug with potent antihypertensive and antianginal activities. Although it is clinically used as a racemic mixture, its enantiomers show different pharmacokinetic and pharmacodynamic profiles. Here, the direct chiral separation of racemic drug by high performance liquid chromatography using two immobilized-type amylose-based chiral stationary phases is presented. Some chromatographic parameters, such as retention and selectivity, were determined under multimodal eluent conditions and different temperatures. A temperature-dependent inversion of the elution order of enantiomers was observed in the operative temperature range of chiral chromatographic support. Finally, an effective direct enantioselective method was successfully applied to the separation of the enantiomers of carvedilol on a semipreparative scale. Keywords: Chiralpak® IG-3, Enantioselective HPLC, Carvedilol, Column temperature, Isoenantioselective temperature, Semipreparative enantioseparation

Graphical abstract, Chiral polymers have aroused great attention in among chiral supramolecular materials based on their features. Herein, for the first time, the synthesis of chiral polymeric composites (CMNPs/1,4-Zbtb & 1,3-Zbtb) have been reported with entrapment through three strategies: ultrasonic irradiation, solvothermal, and mechanical stirring. According to the obtained results, it is found that ultrasound-assisted synthesis can be considered as an inexpensive and efficient method than the others, from the point of view of energy and time consuming. In this strategy, encapsulation of chiral magnetic nanoparticles (CMNPs) by using tetrazole-based polymers (Zbtbs) happens, in-situly. These chiral sphere-like inorganic–organic polymers can be considered as core and shell composites with catalytic activity due to their acidic (semi unsaturated Zn: open metal sites) and basic (abundant basic nitrogens) centers. In these structures, the unprecedented chirality induction can happen from the core to shell by non-covalent interaction, easily. They could catalyze symmetric oxidation and asymmetric henry condensation to give chiral β-nitroalkanol. Circular dichroism and chiral gas chromatography were used to characterize the produced enantiomers. These chiral polymeric materials can be considered as unique acid-base bifunctional catalysts with efficient properties such as high stability, enantiomeric excess, enantioselectivity to the main product, and protecting from CMNPs leaching.

The inducement of physical, chemical, structural and biological properties to entice of pharmaceutical property was analyzed by Vibrational spectroscopic, biological and theoretical tools. The structural arrangement for describing structure activity was investigated by injecting ligand groups in internal coordinate system by molecular tools (FT adopted IR, Raman, and NMR). Bond length and bond angle strain was pronounced much due to the chemical equivalent forces extension due to the injection of substitutional groups on base compound and thus non-Centro symmetry was processed. The molecular charge depletion profile was thoroughly studied to persuade protonic and electronic delocalization setup for arranging the drug potential. The chemi-equivalent potential exchange was monitored among different parts of the molecule for obtaining drug mechanism. The biological profile was keenly observed to look at the biological ambiance of the present molecule to fabricate advanced drug. The Lipinski five rule parameters; MV = 137.18, LogP = 0.27, HBD = 2, HBA = 2 and TPSA = 46.2 A2 showed the enhancement of additive drug quality. The exchange of oscillating chemical energy in the core and allied carbons of the base skeleton was keenly noted to find the prearranged chemical environment for successful drug mechanism. The non bonded transitions between Lewis acid and base of bonded molecular system were observed to determine the restoring potential to customize drug potential. The drug assistance for enantiomer characteristics of chirality sequence was displayed to expose the toxicity effect of the molecule. The active molecular bondings on different sites of molecule were measured by estimating polarizability and associated biological inhibition was validated., 2-Amino-1-phenyl-1-propanol, FT-IR, FT-Raman, NMR, Structure activity, Biological profile, Biological ambiance, Chemical property, Enantiomer

Supercritical fluid chromatography (SFC), combined with mass spectrometry (MS), was employed for the determination of five chiral fungicides, from two different chemical families (acylalanine and triazol) in wine and vineyard soils. The effect of different SFC parameters (stationary phase, chiral selector, mobile phase modifier and additive) in the resolution between enantiomers and in the efficiency of compounds ionization at the electrospray source (ESI) was thorougly described. Under final working conditions, chiral separations of selected fungicides were achieved using two different SFC-MS methods, with an analysis time of 10 min and resolution factors from 1.05 to 2.45 between enantiomers. In combination with solid-phase extraction and pressurized liquid extraction, they permitted the enantiomeric determination of target compounds in wine and vineyard soils with limits of quantification in the low ppb range (between 0.5 and 2.5 ng mL−1, and from 1.3 to 6.5 ng g−1, for wine and soil, respectively), and overall recoveries above 80%, calculated using solvent-based standards. For azolic fungicides (tebuconazole, myclobutanil and penconazole) soil dissipation and transfer from vines to wines were non-enantioselective processes. Data obtained for acylalanine compounds confirmed the application of metalaxyl (MET) to vines as racemate and as the R-enantiomer. The enantiomeric fractions (MET-S/(MET-S+MET-R)) of this fungicide in vineyard soils varied from 0.01 to 0.96; moreover, laboratory degradation experiments showed that the relative dissipation rates of MET enantiomers varied depending on the type of soil L.P.M acknowledges a FPU grant to the Spanish Ministry of Science. This study was supported by Xunta de Galicia and Spanish Government through grants GRC-ED431C 2017/36, PGC2018-094613-B-I00, both co-funded by the EU FEDER program SI

This chapter reports on the status of chiral recognition with gas chromatography (enantioselective-GC, Es-GC). The chapter consists of two main parts. The first one illustrates properties and performance of chiral selectors nowadays available for everyday enantiomer separation (α-amino acid derivatives, chelate chiral selectors, and derivatized cyclodextrin) and concisely describes the other recently introduced chiral selectors of a different chemical nature but not yet available for routine enantiomer recognition. The second part deals with possible approach(es) to chiral GC analysis of real-world samples and determination of peculiar parameters (enantiomeric excess or ratio). It includes enantiomer automatic identification by Es-GC or Es-GC-MS, fast-GC, multidimensional GC, and mass spectrometry in chiral recognition, micropreparative Es-GC, and routine methods with total analysis systems. All subjects are illustrated with examples on both standard and real-world samples.

A putative Solanum lycopersicum epoxide hydrolase, SlEH2, was discovered based on computer-aided analysis. Then, its encoding gene (sleh2) was expressed in E. coli BL21(DE3). The substrate spectrum assay exhibited that E. coli/sleh2, an E. coli transformant expressing SlEH2, possessed the activity of 74.8 U/g wet cell and enantiomeric ratio (E) of 145 towards racemic (rac-) para-chlorostyrene oxide (4a). The scale-up kinetic resolution of 400 mM rac-4a was conducted using 200 mg/mL wet cells of E. coli/sleh2 in the presence of 1% (v/v) Tween-20, retaining (R)-4a with 98.4% ees and 47.1% yields while affording (R)-4b with 92.0% eep and 49.5% yieldp.

Enantiomers are molecules found in two variants being non-superimposable mirror images of each other. Chemical synthesis typically produces a 50:50 % mixture of both enantiomers. The separation of such a mixture is crucial for many applications, because enantiomer and counter-enantiomer often have completely different effects on biological organisms or the human body. However, the separation is a challenging task, as the physical properties of both enantiomers are identical. The presented work consists of two parts, which are based on model optimization. The first part of this paper describes the process of fitting the model to experimental data described in ( Gansch et al., 2020 ). The focus of the second part is on optimization considering two conflicting objectives: total harvested product mass and purity of the product. A sensitivity analysis presented in ( Gansch et al., 2020 ) is used as a basis for the selection of optimization variables. Some parameters have a significant impact, and their optimization allows to control not only the key characteristics as productivity and purity, but also the mean crystal size. The genetic algorithm CMAES ( Hansen, 2006 ) and parallel computing techniques are applied for optimization.

The Pictet-Spengler reaction continues to be widely employed in the synthesis of bioactive natural products, as well as synthetic compounds containing the THβC and THIQ moieties. The asymmetric version of this reaction has been central to the enantiospecific total synthesis of >150 sarpagine/macroline/ajmaline alkaloids. The diastereospecific Pictet-Spengler reaction under thermodynamic control is crucial to the large-scale synthesis of the important tetracyclic bicyclo[3.3.1] core in >98% ee towards many indole alkaloids from this superfamily. Extensive exploration of the Pictet-Spengler reaction for the emerging class of C-19 methyl-substituted sarpagine/macroline/ajmaline alkaloids has resulted in the ambidextrous version, which has enabled access to both the natural and unnatural enantiomers of alkaloids starting with either D- or L-tryptophan, at will. Some noteworthy recent applications of the large scale Pictet-Spengler reaction in the total synthesis of sarpagine-related alkaloids and the development of the ambidextrous Pictet-Spengler reaction are described in this chapter.

This work aims to take full advantage of ionic liquids’ (ILs) “designer solvent” nature in order to expand the applicability of solid-liquid biphasic systems (SLBS) as alternative chiral resolution techniques. To this purpose, twelve chiral ILs, bearing chirality on the cation or the anion, were used as chiral selectors in SLBS to selectively precipitate mandelic acid enantiomers. The precipitation studies were performed using aqueous solutions of the chiral ILs or their chiral precursors, where the impact of the chemical structure and chirality was investigated. The most efficient chiral ILs were employed to evaluate the influence of different operational conditions on the formed precipitate, namely resolution time, resolution speed, temperature, initial concentration of chiral IL, initial concentration of racemic mandelic acid and water content. When compared to their precursors, chiral ILs showed an enhanced ability to induce enantioselective precipitation. The composition of the precipitate formed, and the molecular-level mechanisms leading to enantioselective precipitation, were also uncovered. Due to cooperative interactions between the chiral IL and the target mandelic acid enantiomer, the [N4444][D-Phe]-based SLBS proposed allowed to obtain maximum enantiomeric excess of 51% in a single-step, without any further additives.

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans.

Summary Chromatographic-based approaches are most widely used for the analysis of enantiomers. Unambiguous results are achieved through the visualization of each enantiomer, while the separation process is often time consuming. By endowing 19F probes with suitable dynamic recognition properties, we develop here a detection scheme that produces chromatogram-like output in the analysis of enantiomeric mixtures without separation. A wide range of chiral compounds, including alcohols, ethers, amides, carbamates, oxazolidinones, sulfoxides, and sulfoximines, are successfully resolved, and the simultaneous enantiodifferentiation of different classes of chiral compounds is achieved. The method is also amenable for the determination of the enantiopurity of crude reaction products and the assignment of absolute configurations. The potential utility in high-throughput screening is demonstrated by the analysis of 24 nonracemic samples in 30 min with an NMR spectrometer equipped with an autosampler.

The present work aimed to discuss the enantiomeric occurrence of chiral pharmaceuticals including 5 parent compounds (PCs) metoprolol, propranolol, atenolol, venlafaxine and fluoxetine as well as 6 of their transformation products (TPs) in surface water in Beijing. Among which, 9 out of 11 were detected during the two sampling campaigns with N-O-Didesmethylvenlafaxine (NODDV) and α-hydroxymetoprolol confirmed in the catchment for the first time. Metoprolol acid (MTPA) was the most abundant up to 1508 ng L−1, followed by metoprolol and O-desmethylvenlafaxine (ODV). Most compounds showed 100% detection frequency or nearly, while norfluoxetine (the main metabolite of fluoxetine) and 4-hydroxypropranololone (one TP of propranolol) were not detected. Metoprolol (MTP) and venlafaxine (VFX) did not vary significantly between two sampling periods with mean concentrations of 280.7 and 22.9 ng L−1, respectively. Enantiomeric enrichment was observed for venlafaxine, metoprolol and NODDV, where R-venlafaxine was preferentially biotransformed than the S-form through O-desmethylation. Risk assessment indicated that fluoxetine and atenolol could pose harmful effects to aquatic organisms. This work provides enantiospecific profiles of pharmaceutically active compounds (PhACs), and extended the concept of applying the ratio of TPs vs. parent compound plus their enantiomeric traits for quantitative assessment of in situ biodegradation. Due to the considerable contribution by TPs (64% in present study) as well as the unexpected impacts from enantiomeric existence, the stereoselectivity of chiral pollutants during environmental process should be taken into account in future study. To the best of the authors’ knowledge, it is the first comprehensive evaluation of chiral pharmaceuticals and transformation products at enantiomeric level in aquatic environment in China, which would facilitate better understanding of their environmental fate. Keywords: Pharmaceutical, Transformation product, Enantiomer, Surface water, Risk assessment

Determination of enantiomeric ratios in food and beverages is a research area of great interest because enantiomers can exhibit different biological activities. Chiral analysis can provide valuable information about food safety, bioactivity, quality and traceability. In this work, the potential of separation techniques such as liquid chromatography, gas chromatography, supercritical fluid chromatography and capillary electrophoresis for chiral analysis of food is reviewed. The analysis of enantiomers based on other chiral methodologies such as countercurrent chromatography, sensors, biosensors and direct mass spectrometry (MS) analysis is also included. The present review article provides an updated perspective on the importance of chiral analysis in food matrices and beverages covering the period from February 2017 to July 2019, following the previous work published in this journal on the same topic (G. D'Orazio et al., TrAC-Trends in Analytical Chemistry 96 (2017) 151–171)., G.A.-R. and M.B. would like to acknowledge the Ministry of Economy and Competitiveness for their “Juan de la Cierva-Formación” postdoctoral grants FJCI-2015-25504 and FJCI-2016-30902, respectively. Authors thank to the project AGL2017-89417-R (Ministerio de Ciencia y Universidades) for the support.

Official method in Ph. Eur. for evaluation of timolol enantiomeric purity is normal-phase high performance liquid chromatography (NP-HPLC) method. Compared to other HPLC modes, NP is depicted as quite expensive with high consumption of organic solvents which leads to chronic exposure of analysts to toxic and carcinogenic effects. In order to overcome above-mentioned drawbacks, the aim of this study was to develop new method with better eco-friendly features. This was enabled by using protein type Chiral Stationary Phase (CSP) in reversed-phase mode that required up to 10 % (v/v) of organic solvent. Therefore, an enantioselective HPLC method was developed and validated for quantification of (S)-timolol and its chiral impurity, (R)-isomer. Optimized separation conditions on ovomucoid column were set using Analytical Quality by Design (AQbD) approach in method development. Optimization step was performed following the Box-Behnken experimental plan and the influence of three critical method parameters (CMPs) towards enantioseparation of the above-mentioned peak pair was examined. CMPs included variation of acetonitrile content in the mobile phase (5–10 %, v/v), pH value of the aqueous phase (6.0–7.0) and ammonium chloride concentration in the aqueous part of the mobile phase (10−30 mmol L−1). The most relevant critical method attributes (CMAs) in this case were the separation criterion between studied critical pair and retention factor of the second eluting peak, (S)-timolol. Qualitative Design Space (DS) was defined by Monte Carlo simulations providing adequate assurance of method’s qualitative robustness (π = 95 %). The selected working point situated in the middle of the DS was characterized by following combination of CMPs: acetonitrile content in the mobile phase 7 % (v/v), pH value of the aqueous phase 6.8 and concentration of ammonium chloride in aqueous phase 14 mmol L–1. In the next step, the quantitative robustness was tested by Plackett-Burman experimental design. The validation studies confirmed adequacy of the proposed method for its intended purpose. Finally, Analytical Eco-Scale metric tool was applied to confirm that developed method represents excellent green analytical method compared to the official one.

About 60% commonly used drugs have one or more chiral centers, and many herbal active ingredients contain several chiral centers. Due to the difference of binding force and molecular recognition site, drug enantiomer binds on different receptors, leading to different pharmacological effects or toxic-side reactions. Stereoselectivity in drug pharmacokinetics and ADME properties can not only influence the drug pharmacological activities, toxicity, and bioavailability, but also cause different kinds of drug-drug interactions. Assessment of stereoselectivity in pharmacology, toxicology, and drug metabolism is of great significance for pharmaceutical research and development and reasonable therapy in clinic. This review introduces several typical examples of drug stereoselective metabolism and chiral inversion during the metabolic processes and presents various methods available for chiral bioanalytical assays of individual enantiomers and/or their metabolites.

A case of a false-positive levorphanol on an LC–QTOF urine drug screen due to the presence of dextromethorphan is described. Levorphanol is a stereoisomer of dextrorphan, the main metabolite of dextromethorphan. Dextromethorphan does not produce the same analgesic and sedative effects as opioids, which exhibit nervous system and respiratory depression. LC–MS assays are not able to distinguish between stereoisomers, and thus dextrorphan in the sample will be recognized as levorphanol. Only enantiomeric chiral LC–MS/MS analysis can help differentiate the two compounds. The primary caregiver was notified that with dextromethorphan present, the detected levorphanol was most likely the metabolite dextrorphan.

Epoxy PUFAs are endogenous cytochrome P450 (P450) metabolites of dietary PUFAs. Although these metabolites exert numerous biological effects, attempts to study their complex biology have been hampered by difficulty in obtaining the epoxides as pure regioisomers and enantiomers. To remedy this, we synthesized 19,20- and 16,17-epoxydocosapentaenoic acids (EDPs) (the two most abundant EDPs in vivo) by epoxidation of DHA with WT and the mutant (F87V) P450 enzyme BM3 from Bacillus megaterium. WT epoxidation yielded a 4:1 mixture of 19,20:16,17-EDP exclusively as (S,R) enantiomers. Epoxidation with the mutant (F87V) yielded a 1.6:1 mixture of 19,20:16,17-EDP; the 19,20-EDP fraction was ∼9:1 (S,R):(R,S), but the 16,17-EDP was exclusively the (S,R) enantiomer. To access the (R,S) enantiomers of these EDPs, we used a short (four-step) chemical inversion sequence, which utilizes 2-(phenylthio)ethanol as the epoxide-opening nucleophile, followed by mesylation of the resulting alcohol, oxidation of the thioether moiety, and base-catalyzed elimination. This short synthesis cleanly converts the (S,R)-epoxide to the (R,S)-epoxide without loss of enantiopurity. This method, also applicable to eicosapentaenoic acid and arachidonic acid, provides a simple, cost-effective procedure for accessing larger amounts of these metabolites.

A series of phenanthrene-fused N2O-type boron-dipyrrin complexes (BODIPYs) with various substituents were synthesized. The synthesized BODIPYs show light absorption and emission in the red to near-infrared region due to their extended π-system. Furthermore, the first optical resolution of the N2O-type BODIPY was achieved using the phenyl-substituted complex. The separated enantiomers are stable to racemization at room temperature, and exhibited a Cotton effect in the deep-red region.

Five new sulfur-enriched alkaloids isatithioetherins A–E (1–5), and two pairs of scalemic enantiomers (+)- and (−)-isatithiopyrin B (6a and 6b) and isoepigoitrin and isogoitrin (7a and 7b), along with the known scalemic enantiomers epigoitrin and goitrin (8a and 8b), were isolated and characterized from an aqueous extract of the Isatis indigotica roots. Their structures were determined by extensive spectroscopic data analysis, including 2D NMR and theoretical calculations of electronic circular dichroism (ECD) spectra based on the quantum-mechanical time-dependent density functional theory (TDDFT). Compounds 1–5 represent a novel group of sulfur-enriched alkaloids, biogenetically originating from stereoselective assemblies of epigoitrin-derived units. Isolation and structure characterization of 6a and 6b support the postulated biosynthetic pathways for the diastereomers 9a and 9bvia a rare thio-Diels–Alder reaction. Compounds 2 and 4 showed antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2, IC50 0.60 and 1.92 μmol/L) and the herpes simplex virus 1 (HSV-1, IC50 3.70 and 2.87 μmol/L), and 2 also inhibited Coxsackie virus B3 (IC50 0.71 μmol/L)., Graphical abstract Five new sulfur-enriched alkaloids (1–5) and two pairs of scalemic enantiomers (+)- and (−)-isatithiopyrin B (6a and 6b), and isoepigoitrin (7a) and isogoitrin (7b) were characterized from an aqueous extract of the Isatis indigotica roots. Compounds 1–5 represent a novel group of sulfur-enriched alkaloids biogenetically originated from epiprogoitrin. Compounds 2 and 4 showed antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2, IC50 0.60 and 1.92 μmol/L) and the herpes simplex virus 1 (HSV-1, IC50 3.70 and 2.87 μmol/L). Compound 2 also inhibited Coxsackie virus B3 (IC50 0.71 μmol/L).fx1