Milligram scale enantioresolution of promethazine and its main metabolites, determination of their absolute configuration and assessment of enantioselective effects on human SY-SY5Y cells.

The misuse of pharmaceuticals has significantly increased in recent decades, becoming a major public health concern. The risks associated with medication misuse are particularly high in cases of overdose, especially when the active substances are chiral, as enantioselectivity plays an important role in toxicity. Promethazine (PMZ) is a chiral antihistamine marketed as a racemate and it is misused in "Purple Drank", a recreational drug beverage, that combines codeine and/or PMZ, with soda or alcohol leading to serious health consequences and fatalities in consumers around the world, particularly among teenagers. Information regarding the enantioselectivity in the toxicity of (R,S)-PMZ and its main metabolites, namely promethazine sulfoxide (PMZSO) and desmonomethyl promethazine (DMPMZ), is unknown. This work reported, for the first time, the enantioseparation, in milligram scale, of (R,S)-PMZ, (R,S)-DMPMZ, (R,S)- PMZSO and the determination of their absolute configurations by electronic circular dichroism (ECD). The enantioseparation of all the six enantiomers was accomplished in a homemade semi-preparative column with amylose tris-3,5-dimethylphenylcarbamate (AD) coated with aminopropyl Nucleosil silica. The enantiomeric purity was evaluated using the analytical Lux® 3 µm i-Amylose-3 column, yielding enantiomeric purity values ranging between 94.4% and 99.7%. The elution order of all the enantiomers was accomplished combining the ECD results with an optical rotation detector. The elution order of the enantiomers was influenced only by the chiral selector, rather than the mobile phase. The cytotoxicity of the racemates and the isolated enantiomers towards differentiated SH-SY5Y cells was evaluated. (R,S)-DMPMZ exhibited a significantly higher cytotoxicity than (R,S)-PMZ, suggesting the metabolic bioactivation of (R,S)-PMZ. Conversely, no significant cytotoxicity was found for (R,S)-PMZSO, underscoring a metabolic detoxification pathway. Remarkably, enantioselectivity was observed for the cytotoxicity of PMZ; (R)-PMZ was significantly more cytotoxic than (S)-PMZ. The results underscore the importance to isolate the enantiomers in their enantiomerically form and their correct identification for toxicity enantioselectivity studies, which are vital to understand the drug's behaviour and safety, especially in case of overdoses.

Bioequivalence risk assessment of oral formulations containing racemic ibuprofen through a chiral physiologically based pharmacokinetic model of ibuprofen enantiomers.

The characterization of the time course of ibuprofen enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence studies. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents the most efficient methodology to virtually assess bioequivalence outcomes. In this work, we aim to develop and verify a PBPK model for ibuprofen enantiomers administered as a racemic mixture with different immediate release dosage forms to anticipate bioequivalence outcomes based on different particle size distributions. A PBPK model incorporating stereoselectivity and non-linearity in plasma protein binding and metabolism as well as R-to-S unidirectional inversion has been developed in Simcyp®. A dataset composed of 11 Phase I clinical trials with 54 scenarios (27 per enantiomer) and 14,452 observations (7129 for R-ibuprofen and 7323 for S-ibuprofen) was used. Prediction errors for AUC0-t and Cmax for both enantiomers fell within the 0.8-1.25 range in 50/54 (93 %) and 42/54 (78 %) of scenarios, respectively. Outstanding model performance, with 10/10 (100 %) of Cmax and 9/10 (90 %) of AUC0-t within the 0.9-1.1 range, was demonstrated for oral suspensions, which strongly supported its use for bioequivalence risk assessment. The deterministic bioequivalence risk assessment has revealed R-ibuprofen as the most sensitive analyte to detect differences in particle size distribution for oral suspensions containing 400 mg of racemic ibuprofen, suggesting that achiral bioanalytical methods would increase type II error and declare non-bioequivalence for formulations that are bioequivalent for the eutomer.

Enantioselective fate and risk assessment of chiral fungicide pydiflumetofen in rice-fish and wheat farming systems.

Fungicides have been widely used for reducing the losses caused by plant diseases. Rice and wheat are the most basic food crops, and the potential risks after applying fungicides are worthy of attention. Especially rice-fish farming system is an ecological symbiosis system that is beneficial to both environmental and ecological protection. However, the application of pesticides will stress the ecosystem, and the pesticide residues in rice and fish would be transmitted along the food chain, which is harmful to human health. Here, the enantioselective behaviors of chiral pydiflumetofen in rice-fish and wheat farming systems were clarified. In the rice-fish farming system, pydiflumetofen enantiomers were preferentially attached to the plants, entering the paddy water and settling into the paddy soil, and then accumulating and dissipating in the fish. With the growth of rice, it was transported to rice fruits. The wheat farming system was similar. Enantioselective dissipation occurred in carp (Cyprinus carpio), brown rice and wheat soil, and S-(+)-pydiflumetofen was preferentially dissipated. In other words, R-(-)-pydiflumetofen showed higher concentrations, especially in carp, which meant R-(-)-pydiflumetofen was more easily accumulated in the environment, and posed a greater potential risk to the farming system. The pydiflumetofen residues in brown rice and wheat were lower than MRLs from the EFSA (0.02 mg/kg) and eCFR (0.3 mg/kg), respectively. What deserves attention is that the MRL of pydiflumetofen in fish is not clear. Meanwhile, pydiflumetofen in paddy soil and wheat soil had a persistent residual effect, and the risks could not be ignored. Combined with the previous research, developing S-(+)-pydiflumetofen products will help to reduce the dosage and reduce the risks to environment and people. This study evaluated the environmental fate and risk of chiral pydiflumetofen from the perspective of farming system, and would provide data support for its rational use and risk assessment.

Stereoselective study on chiral fungicide metconazole in four kinds of fruits: Absolute configuration, SFC-MS/MS enantioseparation, degradation and risk assessment.

Metconazole is a novel chiral fungicide with two chiral carbon atoms, but the research on its stereoselective behavior is limited. Therefore, the stereoselective behaviors of metconazole in four fruits, including grape, peach, pear and jujube, were summarized in this study. After determining the absolute configuration of metconazole stereoisomers, a chiral separation method through supercritical fluid chromatography/tandem triple quadrupole mass spectrometry was first developed, which combined an improved QuEChERS method obtained the recoveries of 71.6-113 % with RSD ≤ 19.8 %. The LOD and LOQ were 4.30-95.9 and 10.5-143.2 ng/kg, respectively. Different stereoselective and diastereoselective behaviors were observed in four fruits. Dietary risk assessments of rac-metconazole were performed in populations with different ages and genders. Both acute (RQa, 0.0124-0.140 %) and chronic (HQ, 0.0234-0.0794 %) intake risks were acceptable. The results of this study would contribute to more complete risk assessments of metconazole and provide data for chiral studies.

Chiral analysis and semi-preparative separation of metconazole stereoisomers by supercritical fluid chromatography and cytotoxicity assessment in vitro.

Metconazole is one of the widely-used chiral triazole fungicides in controlling wheat leaf rust, powdery mildew, Fusarium head blight with high efficacy, and so forth. In the current work, the effects of chiral stationary phases, alcoholic modifiers, and column temperature on the chiral separation of metconazole were discussed in detail. Amylose tris(3,5-dimethylphenylcarbamate)-coated chiral stationary phase exhibited much stronger chiral recognition ability toward metconazole stereoisomers in the CO2 /ethanol mixture as compared to the others. Then, a two-step semi-preparative separation of metconazole was performed through supercritical fluid chromatography and high-performance liquid chromatography, and the enantiomeric excess values of four stereoisomers were achieved over 98%. Moreover, the enantioselective cytotoxicity of cis-metconazole against HepG2 cells has been investigated, and the order of the cell proliferation toxicity against HepG2 cells was (1R, 5S)-metconazole > (1S, 5R)-metconazole > the mixture. Briefly, this study would provide valuable information in the preparative separation of optically pure metconazole products through chromatographic techniques and their environmental risk assessment.

Relevance of the calculation of the diffusion coefficient in a capillary electrophoresis experiment.

This paper analyzes the role of the diffusion coefficient in the movement of analytes that can reversibly react with a selector given a product in the presence of drift. The problem mimics the movement of enantiomers in a capillary electrophoresis experiment. As is well known, the signal in the capillary must be sharp enough to make a good determination of the effective mobility of the analytes being analyzed. The essence of the technique is based on fast interconversion rates. Therefore, the effective diffusion coefficient must be negligible during the experiment. In the present work, an exact expression for both the apparent mobility and the diffusion coefficient is obtained. This is done by writing the rate equations governing the process and solving them using the generating function technique. The effective mobility coincides with the Wren and Rowe equation, whereas the diffusion coefficient allows us to determine the values of the parameters to be taken into account so that this quantity is minimal or close to zero. On the other hand, the numerical solution of the kinetic equations and Monte Carlo simulations allow us to follow the signal in the capillary and to determine its space-time evolution.

Stereoselective, Diastereoselective Dissipation and Risk Assessment of Chiral Metconazole in Soybean, Peanut, Cabbage, Celery, Tomato, and Soil.

The stereoselective behaviors and dietary risks of metconazole (MZE) in soil and five vegetables were investigated. The results showed that there was species-specific stereoselective and diastereoselective dissipation, and the half-lives ranged from 0.69 to 8.17 days. cis-(+)-1S,5R-MZE was preferentially dissipated in soybean pods, cabbages, celeries, and tomatoes, which was contrary to soybean plants and soil. trans-(+)-1R,5R-MZE was preferentially dissipated in peanut plants, peanut shells, celeries, and tomatoes, while trans-(-)-1S,5S-MZE was preferentially dissipated in soybean plants. cis-MZE was preferentially dissipated in the test vegetables and soil, except celery. The stereoisomeric excess changes were higher than 10%, indicating that the stereoselectivity and diastereoselectivity should be considered in the risk assessment of MZE in soybean plants, pods, and peanut plants. The acute and chronic dietary intake risks of rac-MZE for different groups of people were acceptable. The preferentially dissipated and high activity cis-(+)-1S,5R-MZE with lower toxicity might be suitable for application as monocase.

Comprehensive Stereoselectivity Assessment of Toxicokinetics, Tissue Distribution, Cytotoxicity, and Environmental Fate of Chiral Pesticide Propiconazole.

Propiconazole (PRO) has been widely used in the treatment of fungal infection in fruits, vegetables, cereals, and seeds. In this study, a newly established chiral liquid chromatography tandem mass spectrometry method was applied to the systemic stereoselectivity evaluation of PRO enantiomers, including toxicokinetics, tissue distributions, cytotoxicity, accumulation, and degradation. Our results showed that both trans (+)-2S,4S-PRO and cis (-)-2S,4R-PRO had lower Cmax and AUC0-∞ and higher CLz/F values in plasma and lower accumulation concentrations in the liver, heart, and brain. In cytotoxic assays, cis (-)-2S,4R-PRO exhibited the lowest cytotoxicity in PC12 neuronal, N9 microglia, SH-SY5Y neuroblastoma, and MRC5 lung fibroblast cell lines. Moreover, the Eisenia fetida incubation experiment revealed that the accumulations of both trans (+)-2S,4S-PRO and cis (-)-2S,4R-PRO were higher than those of their antipodes in E. fetida. In summary, our findings first suggested that the application of cis (-)-2S,4R-PRO for agriculture would hugely reduce the environmental risk.

Enantioselective Transformations in the Synthesis of Therapeutic Agents.

The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008-2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.

Comprehensive Assessment of Enantioselective Bioactivity, Toxicity, and Dissipation in Soil of the Chiral Herbicide Flurtamone.

Flurtamone is a typical chiral pesticide with a pair of enantiomers. In this study, the enantioselective biological effects of flurtamone enantiomers were systematically investigated. The bioactivities of R-flurtamone were 6.3-35.6 and 1.7-9.9 times higher than S- and Rac-flurtamone, respectively. The contribution of the R-enantiomer to herbicidal activity was 86.3-97.3%. The carotenoid content in the R-flurtamone treatment group was 1.31-2.14 times lower than that in the S-flurtamone treatment group. Molecular docking found that flurtamone can form aromatic H-bonds with phenylalanine (PHE) 233 of phytoene desaturase (PDS), while R-flurtamone can form π-π stacking with PHE 202 and PHE 311. The binding energies of R- and S-flurtamone were -10.239 and -7.555 kcal/mol, respectively. Furthermore, the acute toxicity levels to Selenastrum capricornutum of R- and Rac-flurtamone were both highly toxic, and S-flurtamone has moderate toxicity. S-Flurtamone dissipated preferentially. Therefore, the development of R-flurtamone can decrease environmental risks and protect human health.

Economic Separations of Organic Acidic or Basic Enantiomeric Mixtures-A Protocol Suggestion.

In this review, we aim to present new concepts for the revisited separation of enantiomers from racemic compounds and a protocol worth to be followed in designing the preparation of pure enantiomers. We have taken into account not only the influence of the properties (eutectic composition) and characteristics of the reactants (racemic compound, resolving agent), but also the behavior of the resulting diastereomers and the different conditions (e.g., crystallization time, solvents used, solvate-forming compounds, achiral additives, etc.). The examples discussed are resolutions developed by our research team, through which we will try to illustrate the impact of all these considerations, presenting the methodological investigations interpreting recent discoveries and observations. Some special solid-state analytical and structural investigations assisting us in the elucidation and invention design of the resolution processes of some active pharmaceutical ingredients, such as Tetramisole, tofisopam, and Amlodipine, are also shown.

Economical Access to Diverse Enantiopure Tetrahydropyridines and Piperidines Enabled by Catalytic Borrowing Hydrogen.

We disclose herein a catalytic borrowing hydrogen method that enables an unprecedented, economical one-pot access to enantiopure tetrahydropyridines with minimal reagent use or waste formation. This method couples a few classes of readily available substrates with commercially available 1,3-amino alcohols, and delivers the valuable tetrahydropyridines of different substitution patterns free of N-protection. Such transformations are highly challenging to achieve, as multiple redox steps need to be realized in a cascade and numerous side reactions including a facile aromatization have to be overcome. Highly diastereoselective functionalizations of tetrahydropyridines also result in a general access to enantiopure di- and tri-substituted piperidines, which ranks the topmost frequent N-heterocycle in commercial drugs.

A Cheminformatics Study Regarding the Human Health Risks Assessment of the Stereoisomers of Difenoconazole.

Difenoconazole is a chemical entity containing two chiral centers and having four stereoisomers: (2R,4R)-, (2R,4S)-, (2S,4R)- and (2S,4S)-difenoconazole, the marketed product containing a mixture of these isomers. Residues of difenoconazole have been identified in many agricultural products and drinking water. A computational approach has been used to evaluate the toxicological effects of the difenoconazole stereoisomers on humans. It integrates predictions of absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles, prediction of metabolism sites, and assessment of the interactions of the difenoconazole stereoisomers with human cytochromes, nuclear receptors and plasma proteins by molecular docking. Several toxicological effects have been identified for all the difenoconazole stereoisomers: high plasma protein binding, inhibition of cytochromes, possible hepatotoxicity, neurotoxicity, mutagenicity, skin sensitization potential, moderate potential to produce endocrine disrupting effects. There were small differences in the predicted probabilities of producing various biological effects between the distinct stereoisomers of difenoconazole. Furthermore, there were significant differences between the interacting energies of the difenoconazole stereoisomers with plasma proteins and human cytochromes, the spectra of the hydrogen bonds and aromatic donor-acceptor interactions being quite distinct. Some distinguishing results have been obtained for the (2S,4S)-difenoconazole: it registered the highest value for clearance, exposed reasonable probabilities to produce cardiotoxicity and carcinogenicity and negatively affected numerous nuclear receptors.

Evaluation of Chiral Fungicide Penflufen in Legume Vegetables: Enantioseparation and Its Mechanism, Enantioselective Behaviors, and Risk Assessment.

Illustrating the enantioselective behaviors of the novel chiral fungicide penflufen was extremely important for ecological safety and human health. For penflufen enantiomers, an excellent separation method including a short analysis time (4 min), a high sensitivity (2 ng/g), and lesser consumption of an organic solvent was first established through supercritical fluid chromatography-tandem mass spectrometry. The enantioseparation mechanism was explained by computational chemistry, and the stronger binding ability of S-(+)-penflufen with cellulose tris-(3-chloro-4-methylphenylcarbamate) (the chiral stationary phase OZ-3 column) contributed to the posterior elution. In legume vegetables, penflufen dissipation was the fastest in Pisum sativum Linn plants (half-life, 1 day) and the slowest in Glycine max plants (half-lives, 11.3-12.9 days). After 30, 50, and 40 days, the rac-penflufen residues were lower than the maximum residue level value in the Electronic Code of Federal Regulations (10 ng/g) in G. max, P. sativum Linn, and Vigna unguiculata, respectively. Abundant S-(+)-penflufen was found in these plants with stereoisomeric excess (se) changes being >10% in the initial stage, so the risk assessment might be driven by S-(+)-penflufen. However, the se changes were <10% in V. unguiculata plants, and the risk assessment might be calculated based on rac-penflufen. Moreover, penflufen enantiomers could be transferred from legume vegetables to soils, and the concentrations increased with time. The high persistence and medium mobility of penflufen in soils might lead to potential groundwater contamination, which was noteworthy. These results could contribute to a more accurate risk assessment of penflufen in legume vegetables.

Enantioselective bioaccumulation, oxidative stress, and thyroid disruption assessment of cis-metconazole enantiomers in zebrafish (Danio rerio).

Chiral triazole pesticides may cause enantioselectively adverse effects to non-target organisms. In this work, we employed zebrafish as an aquatic organism model to explore stereoselective acute toxicity, bioaccumulation, oxidative stress, and thyroid disruption of cis-metconazole enantiomers. The median lethal concentration values of (1S, 5R)-metconazole, (1R, 5S)-metconazole, and the mixture of them against zebrafish were 4.01, 2.61 and 3.17 mg⋅L-1, respectively. (1R, 5S)-Metconazole was preferentially bioaccumulated in zebrafish than (1S, 5R)-metconazole, and the bioconcentration factor of (1R, 5S)-metconazole was 1.28-fold larger than that of (1S, 5R)-metconazole. Then, the activity order of catalase, superoxide dismutase, and glutathione-S transferase enzymes in zebrafish was expressed as (1S, 5R)-metconazole > the mixture > (1R, 5S)-metconazole, while the order of malondialdehyde content in zebrafish was (1R, 5S)-metconazole > the mixture > (1S, 5R)-metconazole. Moreover, cis-metconazole exhibited enantioselective regulation effects on the levels of triiodothyronine and thyroxine in zebrafish, and (1R, 5S)-metconazole possessed stronger thyroid disruption ability to zebrafish than the others. By virtue of molecular docking methodology, the binding affair and docking energy results supported that interactions between (1R, 5S)-metconazole and thyroid hormone receptors were much stronger than those between (1S, 5R)-metconazole and same receptors. This study of enantioselective evaluation of cis-metconazole in zebrafish can provide favorable information for risk assessments of chiral pesticides toward environment and health of aquatic organisms.

Systemic assessment of the chiral insecticide pyriproxyfen in a citrus nectar source system: Stereoselective degradation, biological effect and exposure risk.

BACKGROUND: Balancing the safety and efficiency of chiral pesticides can help protect pollinators. We evaluated the stereoselective behavior, bioactivity, toxicity and exposure risk of the chiral insecticide pyriproxyfen in a citrus nectar system. RESULTS: Density functional theory (DFT) and ultra-performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS) were applied for absolute configuration appraisal and chiral analysis validation, respectively. The recoveries ranged from 72.3% to 100.5% with an relative standard deviation (RSD) ranging from 1.2% to 9.7%. In a field trial, we determined insecticide half-lives in citrus leaves and flowers, which were 7.0 and 8.6 days for R-(+)-pyriproxyfen, and 11.7 and 14.7 days for S-(-)-pyriproxyfen, respectively. We found that the bioactivity of R-(+)-pyriproxyfen was 3.39 and 2.37 times higher than S-(-)-pyriproxyfen against Unaspis yanonensis and Diaphorina citri nymphs, respectively. S-(-)-pyriproxyfen had 3.8 times higher acute toxicity than R-(+)-pyriproxyfen on Apis mellifera L., and its exposure risk was moderate based on the hazard quotient. CONCLUSION: The phenomenon of stereoselective degradation and biological effect demonstrated that the high-risk stereoisomer of S-(-)-pyriproxyfen degraded more slowly than R-(+)-pyriproxyfen, but R-(+)-pyriproxyfen with better efficiency for target. Therefore, an increased duration of R-(+)-pyriproxyfen activity on citrus was beneficial for efficacy. Our results could guide the scientific application and evaluation of chiral pesticides on nectar plants. © 2022 Society of Chemical Industry.

Risk Assessment of the Chiral Fungicide Triticonazole: Enantioselective Effects, Toxicity, and Fate.

The enantioselective toxicity of triticonazole (TRZ) to non-target organisms, the effect on wheat growth and quality, and the environmental fate of TRZ were investigated systematically in this study. The acute toxicity of S-TRZ to non-target aquatic and terrestrial organisms was greater than that of rac-TRZ and R-TRZ. The S-enantiomer significantly inhibited the growth and lodging resistance of wheat. S- and R-TRZ not only reduced the grain yield but also inhibited the activities of ADP-glucose pyrophosphorylase (AGPase) and starch synthase. The results of homology modeling and molecular docking further showed that the inhibition of AGPase activity by the two enantiomers hindered the accumulation of starch. By contrast, the racemate promoted the growth and development of wheat and improved grain quality. And the half-lives of the racemate in stems, grains, leaves, and soils were shorter than those of the enantiomers. The results of risk quotient (RQ) values showed that the application of TRZ enantiomers during wheat planting would bring a higher potential dietary risk to Chinese consumers. In comprehensive consideration of these results, the application of the racemate may be safer and more reasonable at the flowering stage of wheat.

Evaluation of chiral triticonazole in three kinds of fruits: enantioseparation, degradation, and dietary risk assessment.

The enantioselective behaviors of chiral pesticides would affect the accuracy of risk assessment. This study evaluated the enantioselectivity of chiral triticonazole (a widely used fungicide) in three kinds of fruits. Firstly, the enantioseparation of triticonazole enantiomers was carried out within 1.2 min utilizing CHIRALPAK OJ-3 column with a mixture of CO2 and methanol (93:7, v/v) using SFC-MS/MS. Secondly, field trials were conducted to clarify the enantioselective degradation and residue of S-( +)-triticonazole and R-(-)-triticonazole in fruits. The initial concentrations of rac-triticonazole were 25.1-93.1 ng/g, and enantioselective degradation was observed in pear, peach, and jujube after 2 h, 10 days, and 3 days, respectively. The degradation of S-( +)-triticonazole was fastest in pear (T1/2, 2.01 days), while the T1/2 of R-(-)-triticonazole was 5.02 days. The residue concentrations of rac-triticonazole were less than the MRL set by EU (10 ng/g) on the 3rd and 21st day in pear and peach, respectively, which were lower than 10 ng/g in jujube on the 30th day (no MRL). Finally, we found that the dietary intake risks of rac-triticonazole in fruits were low for 2-7 age, 20-50 age/female, and 20-50 age/male. The current study could provide complimentary references for the rational usage, MRL formulation, and risk assessment of chiral triticonazole.

Direct and Catalytic C-Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside.

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.

Analytical developments of p-hydroxy prenylamine reference material for dope control research: Characterization and purity assessment.

Prenylamine was initially used for the treatment of angina pectoris and later on withdrawn from the market in 1988 due to cardiac arrhythmias concern. The major phase I metabolite of prenylamine is p-hydroxy prenylamine that has a chiral center in the structure. Even though p-hydroxy prenylamine was synthesized earlier, it lacked complete analytical developments for chiral high-performance liquid chromatography (HPLC) separation. However, p-hydroxy prenylamine reference material is not commercially available. The innovation of this manuscript is the development and validation of a chiral HPLC separation method and more extensive characterization of the reference material than previously reported method. Therefore, it was hypothesized to develop and validate normal phase HPLC method for p-hydroxy prenylamine reference material. p-Hydroxy prenylamine was synthesized in two batches and characterized successfully using 13 C NMR, 1 H NMR, high-resolution mass spectrometry (HRMS), Fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). A normal phase chiral HPLC method was developed to analyze the p-hydroxy prenylamine purity. Separation of the p-hydroxy prenylamine enantiomers were achieved using ultra-high-performance liquid chromatography (UHPLC) on a ChiralCel ODH column at wavelength of 220 nm. The developed method was validated in terms of its linearity, accuracy, precision, and robustness for purification, purity assessment, and stability studies. Proton and carbon peaks were confirmed by nuclear magnetic resonance (NMR) analysis. Functional groups were confirmed by FT-IR. Loss on drying was 0.3% and 0.6% for Batches 1 and 2, respectively. The purity of the developed reference material for Batches 1 and 2 was found to be 99.59% and 100%, respectively. Therefore, the synthesized batches of p-hydroxy prenylamine can be used in dope testing as reference material.