Racemic Research Articles

Reaction, Recognition, Relay: Anhydride Hydrolysis Reported by Conformationally Responsive Fluorinated Foldamers in Micelles

AbstractNatural membrane receptors are proteins that can report on changes in the concentration of external chemical messengers. Messenger binding to a receptor produces conformational changes that are relayed through the membrane into the cell; this information allows cells to adapt to changes in their environment. Artificial membrane receptors (R)‐1 and (S)‐1 are helical α‐aminoisobutyric acid (Aib) foldamers that replicate key parts of this information relay. Solution‐phase 19F NMR spectroscopy of zinc(II)‐capped receptor 1, either in organic solvent or in membrane‐mimetic micelles, showed messenger binding produced an enrichment of either left‐ or right‐handed screw‐sense; the chirality of the bound messenger was relayed to the other receptor terminus. Furthermore, in situ production of a chemical messenger in the external aqueous environment could be detected in real‐time by a racemic mixture of receptor 1 in micelles. The hydrolysis of insoluble anhydrides produced carboxylate in the aqueous phase, which bound to the receptors and gave a distinct 19F NMR output from inside the hydrophobic region of the micelles.

Optimization of Liquid Crystalline Mixtures Enantioseparation on Polysaccharide-Based Chiral Stationary Phases by Reversed-Phase Chiral Liquid Chromatography.

Enantioseparation of nineteen liquid crystalline racemic mixtures obtained based on (R,S)-2-octanol was studied in reversed-phase mode on an amylose tris(3-chloro-5-methylphenylcarbamate) (ReproSil Chiral-MIG) and a cellulose tris(3,5-dichlorophenylcarbamate) (ReproSil Chiral-MIC). These polysaccharide-based chiral stationary phase (CSP) columns for High-Performance Liquid Chromatography (HPLC) were highly effective in recognizing isomers of minor structural differences. The mobile phase (MP), which consists of acetonitrile (ACN)/water (H2O) at different volume ratios, was used. The mobile phases were pumped at a flow rate of 0.3, 0.5, or 1 mL·min-1 with a column temperature of 25 °C, using a UV detector at 254 nm. The order of the elution was also determined. The chromatographic parameters, such as resolution (Rs), selectivity (α), and the number of theoretical plates, i.e., column efficiency (N), were determined. The polysaccharide-based CSP columns have unique advantages in separation technology, and this study has shown the potential usefulness of the CSP columns in separating liquid crystalline racemic mixtures belonging to the same homologous series.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

Magterpenes A-C: Three Meroterpenoids with an Unprecedented 6/6/6/6/6 Polycyclic Skeleton Extracted from Magnolia officinalis Rehd. et Wils.

Magterpenes A-C (1-3), three unprecedented meroterpenoids featuring a unique 6/6/6/6/6 polycyclic skeleton, were isolated from the ethanol extract of Magnolia officinalis Rehd. et Wils. The compounds were obtained as racemic mixtures that were completely resolved through chiral columns. Their structures were elucidated by extensive analyses of one-dimensional (1D) and 2D nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, chemical calculations of 1H/13C NMR, and electronic circular dichroism calculations. The compounds were constructed via two Diels-Alder reactions in the proposed biosynthetic pathway. All isolates were evaluated for their nephroprotective and hepatoprotective activities. The results demonstrated that (+)-1 and (-)-1 possessed promising nephroprotective activities in a dose-dependent manner, while (-)-2 and (+)-3 exhibited moderate hepatoprotective activities.

Trace-Amount Detection of Chiral Molecules Based on Plasmonic Racemic Arrays Fabricated via Direct Laser Writing.

Superchiral fields, supported by chiral plasmonic structures, have shown outstanding performance for chiral molecule sensing via enhanced chiral light-matter interaction. However, this sensing capability cannot fully reveal the chiral origin of the molecules as the chiroptic response of the molecules is intertwined with the chiroptic response of the chiral plasmonic nanostructures, which can potentially be excluded by using a plasmonic racemic mixture. Such a plasmonic racemic mixture is not easily attainable, as it normally requires complex fabrication and expensive instrumentation, whose structural fineness is limited by the fabrication precision. Here, we demonstrate trace-amount chiral molecule detection with plasmonic racemic arrays fabricated by direct laser writing with vector beams, which is facile, cost-effective, and highly controllable. The racemic arrays present no inherent circular differential scattering but a large local superchiral field, which reflects the intrinsic chiral features of the chiral molecules. They are further applied to discriminate enantiomers of phenylalanine with a limit of detection (LOD) of 10.0 ± 2.8 μM, which is an order of magnitude smaller than the LOD of conventional circular dichroism spectroscopy. The strong local superchiral field provided by the plasmonic racemic arrays enlightens the design of a superior sensing platform, which holds promising applications for biomedical detection and enantioselective drug development.

Solid-state green synthesis of two (1:1) organic intermolecular compounds; their physico-chemical, thermal, single crystal growth, and atomic packing studies

The solid-state solvent free reaction method has been adopted for the one-pot synthesis of novel organic materials with utmost 100 % yield. To identify the composition forming the intermolecular compound (IMC), the solid-liquid equilibria of entire compositions have been studied by establishing the phase diagram of n, n-dimethylaminobenzaldehyde (DMAB) with anthranilamide (AN) and 2-chloro-4-nitro benzoic acid (CNBA). The structural changes and novelty of the IMCs to that of parents are studied using FTIR, NMR and X-ray diffraction. The studies of optical properties of intermolecular compounds using UV–vis absorption and fluorescence spectroscopy infer the significant fluorescence emission. The single crystals of both intermolecular compounds, ANDMAB and DMABCNBA, are grown from solution using slow evaporation technique. The single crystal X-ray diffraction studies reveal that IMC of AN and DMAB is a racemic mixture whereas IMC of DMAB and CNBA is a co-crystal, and both the crystals have crystallized in triclinic P1‾ space group. The thermal stability and thermal behaviors are also studied using the experimental heat of fusion values obtained from differential scanning calorimetry (DSC).

Acetoacetate and d- and l-β-hydroxybutyrate have distinct effects on basal and insulin-stimulated glucose uptake in L6 skeletal muscle cells.

Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Previous studies suggest that there is a negative relationship between increased muscle ketolysis and muscle glucose metabolism in mice with obesity and/or type 2 diabetes. Therefore, we investigated the connection between increased ketone body exposure and muscle glucose metabolism by measuring the effect of a 3-h exposure to ketone bodies on glucose uptake in differentiated L6 myotubes. We showed that exposure to acetoacetate at a typical concentration (0.2 mM) resulted in increased basal glucose uptake in L6 myotubes, which was dependent on increased membrane glucose transporter type 4 (GLUT4) translocation. Basal and insulin-stimulated glucose uptake was also increased with a concentration of acetoacetate reflective of diabetic ketoacidosis or a ketogenic diet (1 mM). We found that β-hydroxybutyrate had a variable effect on basal glucose uptake: a racemic mixture of the two β-hydroxybutyrate enantiomers (d and l) appeared to decrease basal glucose uptake, while 3 mM d-β-hydroxybutyrate alone increased basal glucose uptake. However, the effects of the ketone bodies individually were not observed when acetoacetate was present in combination with β-hydroxybutyrate. These results provide insight that will help elucidate the effect of ketone bodies in the context of specific metabolic diseases and nutritional states (e.g., type 2 diabetes and ketogenic diets).NEW & NOTEWORTHY A limited number of studies investigate the effect of ketone bodies at concentrations reflective of both typical fasting and ketoacidosis. We tested a mix of physiologically relevant concentrations of ketone bodies, which allowed us to highlight the differential effects of d- and l-β-hydroxybutyrate and acetoacetate on skeletal muscle cell glucose uptake. Our findings will assist in better understanding the mechanisms that contribute to muscle insulin resistance and provide guidance on recommendations regarding ketogenic diets.

CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children

Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7–15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.

Five undescribed meroterpenoids from Ganoderma lucidum and their inhibitory activities against renal fibrosis

Five undescribed meroterpenoids, baosglucidnes A − E (1–5), were isolated from the fruiting bodies of Ganoderma lucidum. Among them, baosglucidne B (2) as a racemic mixture was obtained. Chiral HPLC was employed to separate a pair of enantiomers (+)-2 and (−)-2. The structures and stereochemical features of these substances were characterized by utilizing spectroscopic data and ECD calculations. Finally, the results of anti-renal fibrosis activity evaluation showed that baosglucidne E (5) could inhibit the expression of collagen I in TGF-β1-induced rat kidney proximal tubular cells at 20 μM.

Enantiomeric profile of amphetamines in seized drug samples and in blood of impaired drivers in Iceland: The rise of (R)-methamphetamine?

Amphetamine (AMP) and methamphetamine (METH) use is increasing globally. Illegal AMP is generally a racemic mixture, whereas AMP-containing attention-deficit hyperactivity disorder drugs prescribed in Iceland consist of S-AMP. AMP is also a main metabolite of interest after METH intake. Distinguishing between legal and illegal AMP intake is vital in forensic toxicology. A chiral UPLC-MS-MS method was used to determine the enantiomeric profile of AMP and METH in circulation in Iceland by analysing blood samples from drivers suspected of driving under the influence of drugs (DUID) and seized drug samples from 2021 and 2022. All seized AMP samples (n = 48) were racemic, whereas all but one seized METH sample (n = 26) were enantiopure. Surprisingly, a large portion of the enantiopure METH samples was R-METH. DUID blood samples positive for AMP (n = 564) had a median blood concentration of 180 ng/mL (range 20-2770 ng/mL) and a median enantiomeric fraction (EFR) of 0.54 (range 0-0.73), whereas samples positive for METH (n = 236) had a median blood concentration of 185 ng/mL (range 20-2300 ng/mL) and a median EFR of 0.23 (range 0-1). The findings of this study show a significantly lower blood concentration in drivers with only S-AMP detected compared with when the R-isomer is also detected. No significant difference in blood concentration was detected between the sample groups containing S-METH, R-METH or both enantiomers. The occurrence of R-METH in both seized drug samples and DUID cases indicates a change in drug supply and a need for better scientific knowledge on R-METH abuse.

Chromatographic methods and approaches for bioequivalence study, drug screening and enantioseparation of indapamide

AbstractIndapamide (Indp) and certain other diuretics have been abused in sports, therefore, having sensitive methods for its detection and assay in biological fluids (whole blood, plasma, serum, and urine) is of significant importance. The racemic mixture of Indp is being used as an active pharmaceutical ingredient among other commonly prescribed diuretics. The regulatory authorities and pharmaceutical industries demand analytical methods for successful enantioseparation of such molecules. The paper presents a critical overview of the scientific issues of the application of contemporary techniques involving various chromatographic approaches (with liquid or supercritical fluid as mobile phases) and capillary electrophoresis and method development, for drug screening, assay, bioequivalence studies and enantioseparation of indapamide with their results. It also covers the historical developments that led to significant breakthroughs in research and concise evaluations of research in the area.Different types of chromatographic methods (HPLC, CEC, SFC etc) discussed herein provide an insight and a choice to select a method to (i) screen Indp for drug abuse, (ii) separate, isolate and quantify the enantiomers of Indp and (iii) investigate their pharmacokinetics as markedly different species and not as a total drug. The article evaluates the field's status with a broad base and practical oriented approach so that the underlying principles are easily understood to help chemists and non-specialists gain useful insights into the field outside their specialization and provide experts with summaries of key developments. To the best of authors' knowledge there has been no attempt to review such methods for analysis of Indp and this is the first report of its kind.

Synthesis of chiral Cu(II) complexes from pro-chiral Schiff base ligand and investigation of their catalytic activity in the asymmetric synthesis of 1,2,3-triazoles

A pro-chiral Schiff base ligand (HL) was synthesized by the reaction of 2-amino-2-ethyl-1,3-propanediol and pyridine-2-carbaldehyde in methanol. The reaction of HL with CuCl2·2H2O and CuBr2 in methanol gave neutral mononuclear Cu(II) complexes with general formula of [Cu(HL)Cl2] (1) and [Cu(HL)Br2] (2), respectively. By slow evaporation of the methanolic solutions of 1 and 2, their enantiomers were isolated in crystalline format. The formation of pure chiral crystals in the racemic mixture was amply authenticated by single crystal X-ray analysis, which indicated that S-[Cu(HL)Cl2], R-[Cu(HL)Cl2], and S-[Cu(HL)Br2] are crystallized in chiral P212121 space group of orthorhombic system. Preferential crystallization was used to isolate the R and S enantiomers as single crystals and the isolated compounds were also studied by CD analysis. Structural studies indicated that the origin of the chirality in these compounds is related to the coordination mode of the employed pro-chiral ligand (HL) because one of its carbon atoms has been converted to a chiral center in the synthesized complexes. Subsequently, these complexes were used in click synthesis of a β-hydroxy-1,2,3-triazole and the results of catalytic studies indicated that 1 and 2 can act as enantioselective catalysts for the asymmetric synthesis of β-hydroxy-1,2,3-triazole product under mild condition. This study illustrates the significant capacity of the use of pro-chiral ligands in preparing chiral catalysts based on complexes which can also be considered as an effective approach to cheap chiral catalysts from achiral reagents.

CHIRAL SWITCHING CONTROL OF PHARMACEUTICAL SUBSTANCES

Objective: The aim of this study was to demonstrate that chiral switching should be recognized as a widespread phenomenon that extends beyond the production of pure enantiomeric drugs. Methods: To investigate the optical activity of substances from various chemical classes, enantiomers of chiral compounds (Sigma-Aldrich, USA) were chosen: valine and its racemic form (D-valine, L-valine, and racemic valine with optical purity ≥ 99%), L-ascorbic acid (content ≥ 99%), carbohydrates (D-glucose, D-galactose, L-galactose, contents ≥ 99.5%). Solutions were prepared using deuterium-depleted water (DDW–"light" water, D/H=4 ppm), natural deionized high-ohmic water (BD, D/H=140 ppm), and heavy water (99.9% D2O; Sigma-Aldrich). Optical activity was measured using the Atago POL-1/2 polarimeter. Results: One of the components in the racemic medication mixture can act as an inert agent, exhibit toxicity, or undergo undesirable biotransformation mechanisms, resulting in the formation of products with unknown properties. It has been established that a change in the deuterium/protium (D/H) ratio in water leads to a change in the equilibrium and kinetic characteristics of optically active compounds across various chemical classes, such as amino acids, carboxylic acids, and carbohydrates. An inequality was observed in the absolute values of the optical rotation of the L-and D-isomers of valine and galactose, depending on the D/H isotope ratio. The impact of chiral water clusters on optical rotation accounts for the sudden shift in the specific rotation of dilute solutions (less than 0.5%) of L-ascorbic acid in water, based on the D/H ratio. The influence of the isotopic composition of water was confirmed by studying the temperature-dependent mutarotation kinetics of D-glucose and L-and D-galactose in Arrhenius coordinates. The mutarotation process in natural high-resistivity water is characterized by an activation energy (Ea) of 40.8±1.4 kJ mol-1, while in deuterium-depleted water, Ea = 63.6±3.5 kJ mol-1. This results in a kinetic isotope effect for deuterium (KIED) of 1.6. Conclusion: Methodological approaches have been developed to control chiral switching based on the isotopic composition of water in vivo and in vitro. The study of changes in the optical activity of hierarchical structures in the human body, the influence of solvent properties on the mechanisms of optical rotation, as well as the use of KIED values, can be utilized to monitor various chiral transitions in vitro and living organisms.

Evaluating the Role of Nicotine Stereoisomer on Nicotine Pouch Abuse Liability: A Randomized Crossover Trial.

Many oral nicotine pouch (ONP) brands use synthetic nicotine, which typically contains a racemic (50:50) mixture of nicotine's two stereoisomers: S-nicotine and R-nicotine. Because tobacco-derived nicotine contains more than 99% S-nicotine, the effects of R-nicotine in humans are not well known. We compared systemic nicotine exposure and product appeal of ONPs containing more than 99% S-nicotine versus racemic nicotine. N = 18 adult smokers (Mage = 45 years, 66.7% male, 77.8% White) enrolled in a three-visit single-blind, randomized crossover study. During each visit, participants used one wintergreen-flavored, 3mg nicotine ONP for 30min following at least12h nicotine abstinence. Study ONP #1 contained more than 99% S-nicotine and the other two study ONPs contained racemic nicotine (collapsed for analyses). Plasma nicotine assessments and measures of withdrawal relief occurred at t = 0, 5, 15, 30, 60, and 90min; measures of product appeal were assessed following ONP use. Using the ONP with more than 99% S-nicotine resulted in greater plasma nicotine concentration from 15 to 90min (p < .0001) and greater maximum plasma nicotine concentration than the ONPs with racemic nicotine (M = 9.9ng/mL [SD = 2.5] vs. M = 5.7ng/mL [SD = 2.8], respectively; p < .0001). Product liking and withdrawal relief were similar across ONPs, although participants reported more "bad effects" when using the ONP with more than 99% S-nicotine. Participants reported few subjective differences in ONPs according to nicotine stereoisomer, but plasma nicotine concentration was greater for ONPs using more than 99% S-nicotine. ONPs with more than 99% S-nicotine (vs. racemic nicotine) might be better substitutes for cigarettes, but research into other ONP characteristics (eg flavors, freebasenicotine) is needed to inform regulation. Little is known about the effects of racemic (vs. S-) nicotine in humans. In a sample of adults who smoke cigarettes, we identified that oral nicotine pouches containing racemic nicotine exposed participants to less nicotine than oral nicotine pouches containing only S-nicotine, but both types of oral nicotine pouches held similar, moderate appeal. Additional research evaluating the roles that flavorings, total nicotine concentration, and freebase nicotine play in the abuse liability of oral nicotine pouches would inform comprehensive product regulations to support public health.

Enantiomer-specific analysis of amphetamine in urine, oral fluid and blood.

Illegal amphetamine is usually composed of a racemic mixture of the two enantiomers (S)- and (R)-amphetamine. However, when amphetamine is used in medical treatment, the more potent (S)-amphetamine enantiomer is used. Enantiomer-specific analysis of (S)- and (R)-amphetamine is therefore used to separate legal medical use from illegal recreational use. The aim of the present study was to describe our experience with enantiomer-specific analysis of amphetamine in urine and oral fluid, as well as blood, and examine whether the distribution of the two enantiomers seems to be the same in different matrices. We investigated 1,722 urine samples and 1,977 oral fluid samples from prison inmates, and 652 blood samples from suspected drugged drivers, where prescription of amphetamine was reported. Analyses were performed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS). The enantiomer separation was achieved by using a chiral column, and results from the method validation are reported. Samples containing <60% (S)-amphetamine were interpreted as representing illegal use of amphetamine. The distribution of the two enantiomers was compared between different matrices. In urine and oral fluid, the mean amount of (S)-amphetamine was 45.2 and 43.7%, respectively, while in blood, the mean amount of (S)-amphetamine was 45.8%. There was no statistically significant difference in the amount of (S)-amphetamine between urine and oral fluid samples and between urine and blood samples, but the difference was significant in blood compared to oral fluid samples (P < 0.001). Comparison of urine and oral fluid between similar populations indicated that enantiomers of amphetamine can be interpreted in the same way, although marginally higher amounts of (R)-amphetamine may occur in oral fluid. Oral fluid, having several advantages, especially during collection, could be a preferred matrix in testing for illegal amphetamine intake in users of medical amphetamine.

Chiral Induction in a Self-Assembled Pd4 Coordination Cage with Chiral Guests.

The dynamic interplay of coordination bonds within metal-organic cages offers a unique avenue for structural evolution in response to external stimuli, presenting a promising strategy for the construction of chiral assemblies. This adaptability is crucial for the selective synthesis of homochiral assemblies and advancement of asymmetric catalysis. In this study, we report the self-assembly of an achiral square-planar Pd(II) acceptor with a C2-symmetric tetrapyridyl donor resulted in the formation of a racemic mixture of the chiral octahedral cage Pd4L2. The existence of this racemic mixture was confirmed using circular dichroism spectroscopy as well as single crystal X-ray diffraction analysis. We encoded chiral information into the asymmetric cavity of the cage by encapsulating chiral aromatic guests through efficient π-π stacking and hydrophobic interactions in aqueous media. The inclusion of a chiral guest induces a preference for one enantiomeric conformation of the cage over the other, effectively shifting the equilibrium towards a single, enantiopure host-guest complex. While the concept of chiral guest recognition by a chiral host is well-established, this work constitutes a remarkable example of guest-mediated chirality transfer leading to the formation of a single enantiopure coordination complex from achiral building blocks.

The stereoselective pharmacokinetics of the desmethyl-phencynonate hydrochloride in beagle dogs.

The aim of this study was to investigate the chiral inversion and the stereoselective pharmacokinetic profiles of desmethyl-phencynonate hydrochloride after administration of the single isomer and its racemate to beagle dogs. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was established for determination of the stereoisomers on chiral columns in beagle dog plasma, which met all the requirements. The chiral inversion in dogs of the desmethyl-phencynonate hydrochloride were studied after administration of the single isomer or the racemic modification. The stereoselective pharmacokinetic profiles of the desmethyl-phencynonate hydrochloride were studied by assays for simultaneous isomers after administration of the racemic modification. The results showed that the absorption of the R-configuration dosed as the single isomer was higher than it dosed as the racemic modification. The AUC(0-t), AUC(0-∞), and Cmax of the S-configuration were much higher than those of R-configuration after oral administration of the racemic desmethyl-phencynonate hydrochloride. The chiral inversion of desmethyl-phencynonate isomers could not occur in dogs after administration of the R-configuration.

Enantioselective three-dimensional high-performance liquid chromatographic determination of amino acids in the Hayabusa2 returned samples from the asteroid Ryugu

The chirality of amino acids in extraterrestrial materials may provide an insight into the origin of the essential l-enantiopure amino acids in the terrestrial biosphere. In 2020, the Hayabusa2 mission succeeded in bringing back surface materials from the C-type asteroid (162173) Ryugu to the Earth. Amino acids were one of the targeted organic molecules to be studied in the Ryugu samples. To analyze the various structural isomers of amino acids, which were expected to be present, from the limited amount of the returned samples, the development of a highly-sensitive and selective analytical method was necessary. In the present study, a three-dimensional high-performance liquid chromatography (3D-HPLC) system has been developed for the enantioselective determination of five proteinogenic and three non-proteinogenic amino acids in the Ryugu samples, in which amino acids in the sample were separated by reversed-phase, anion-exchange and enantioselective columns after the fluorescence derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiozole. The applicability of the analytical system to the extraterrestrial samples was evaluated by analyzing several types of carbonaceous meteorites before applying the system to the Ryugu samples. In the analysis of the Ryugu samples, all of the target amino acids were successfully determined quantitatively. Non-proteinogenic amino acids including 2-amino-n-butyric acid, isovaline and norvaline, rarely present in the terrestrial environment, were found as almost racemic mixtures with 47.1 to 55.2%l.

Radical Stereochemistry: Accounting for Diastereomers in Kinetic Mechanism Development.

Recent work in combustion and atmospheric chemistry has revealed cases in which diastereomers must be distinguished to accurately model a reacting flow. This paper presents an open-source framework for introducing such stereoisomer resolution into a kinetic mechanism. We detail our definitions and algorithms for labeling and enumerating the stereoisomers of a molecule and then generalize our system to describe the transition state (TS) of a reaction. This allows for the stereospecific enumeration of reactants and products while accounting for "fleeting" stereochemistry that is unique to the TS. We also present the AutoMech Chemical Identifier (AMChI), an InChI-like string identifier that accounts for stereocenters omitted by InChI. This identifier is extended to describe the TSs of reactions, providing a universal lookup key for specific reaction channels. The final piece of our methodology is an analytic formula to remove redundancy from a stereoresolved mechanism when its enantiomers exist as a racemic mixture, making it as compact as possible while fully accounting for the differences between diastereomers. In applying our methodology to two subsets of the NUIGMech1.1 mechanism, we find that our approach reduces the extra species added for large-fuel oxidation from 2231 (133%, full expansion) to 694 (41%, nonredundant expansion). We also find that for pyrolysis more than a quarter of the species in the expanded mechanism cannot be properly described by an InChI string, requiring an AMChI string to communicate their identity. Finally, we find that roughly one-quarter of the large-fuel oxidation reactions and one-third of the pyrolysis reactions include fleeting TS stereochemistry, which may have relevant effects on their kinetics.

Chemoenzymatic Asymmetric Synthesis of Chiral Triazole Fungicide (R)-Tebuconazole in High Optical Purity Mediated by an Epoxide Hydrolase from Rhodotorula paludigensis.

Tebuconazole is a chiral triazole fungicide used globally in agriculture as a racemic mixture, but its enantiomers exhibit significant enantioselective dissimilarities in bioactivity and environmental behaviors. The steric hindrance caused by the tert-butyl group makes it a great challenge to synthesize tebuconazole enantiomers. Here, we designed a simple chemoenzymatic approach for the asymmetric synthesis of (R)-tebuconazole, which includes the biocatalytic resolution of racemic epoxy-precursor (2-tert-butyl-2-[2-(4-chlorophenyl)ethyl] oxirane, rac-1a) by Escherichia coli/Rpeh whole cells expressed epoxide hydrolase from Rhodotorula paludigensis (RpEH), followed by a one-step chemocatalytic synthesis of (R)-tebuconazole. It was observed that (S)-1a was preferentially hydrolyzed by E. coli/Rpeh, whereas (R)-1a was retained with a specific activity of 103.8 U/g wet cells and a moderate enantiomeric ratio (E value) of 13.4, which was remarkably improved to 43.8 after optimizing the reaction conditions. Additionally, a gram-scale resolution of 200 mM rac-1a was performed using 150 mg/mL E. coli/Rpeh wet cells, resulting in the retention of (R)-1a in a 97.0% ees, a 42.5% yields, and a 40.5 g/L/d space-time yield. Subsequently, the synthesis of highly optical purity (R)-tebuconazole (>99% ee) was easily achieved through the chemocatalytic ring-opening of the epoxy-precursor (R)-1a with 1,2,4-triazole. To elucidate insight into the enantioselectivity, molecular docking simulations revealed that the unique L-shaped substrate-binding pocket of RpEH plays a crucial role in the enantioselective recognition of bulky 2,2-disubstituted oxirane 1a.