Background: A chiral HPLC technique was developed to determine sitagliptin phosphate enantiomers in rat plasma in compliance with US FDA regulations. Methods & results: The technique used a Phenomenex column with a mobile phase consisting of a 60:35:5 (v/v/v) blend of pH4, 10-mM ammonium acetate buffer, methanol and 0.1% formic acid in Millipore water. The precision for both (R) and (S) sitagliptin phosphate varied between 0.246 and 1.246%, while the accuracy was 99.6-100.1%. A glucose uptake assay was used to assess enantiomers in 3T3-L1 cell lines through flow cytometry. Conclusion: Investigation of the pharmacokinetic impacts of sitagliptin phosphate racemic enantiomers in rat plasma revealed notable contrasts in R and S enantiomers in female albino Wistar rats, suggesting enantioselectivity for sitagliptin phosphate.

The development of the merger of a Ni(II) catalyst with an appropriate photocatalyst under visible-light irradiation provides a new strategy for realizing direct functionalization of C(sp3 )-H bonds. Mechanistically, whether the reduction of Ni catalyst to form a Ni(0) species is necessary in the dual catalysis still remains under debate. Herein, DFT calculations were carried out to gain a mechanistic insight into the enantioselective acylation of α-amino C(sp3 )-H bonds to furnish α-amino ketones via photoredox and Ni dual catalysis. A feasible mechanistic pathway for the Ni catalysis via the Ni(I)-Ni(III)-Ni(II)-Ni(III)-Ni(I) cycle is suggested with the sequential elementary steps of oxidative addition, single electron reduction, radical addition, and reductive elimination in leading to the final product, whereas a nickel catalytic cycle, Ni(I)-Ni(0)-Ni(II)-Ni(III)-Ni(I), might not be feasible for the photoredox and Ni dual-catalyzed acylation of α-amino C(sp3 )-H bonds. The origin of the stereoselectivity for this reaction is also discussed, which could be attributed to the minimization of the steric hindrance between the alkyl moiety of radical part and phenyl group of the chiral ligand.

Hexaconazole (Hex) has been widely used in agricultural products, and its residues may pose a potential risk to human health. However, the metabolic behavior of Hex enantiomers in mammal organisms is still unknown, which is important for evaluating the differences in their toxicity. In this study, the distribution of S-(+)- and R-(-)-Hex in mice was detected by an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS), and the mechanism differences in the toxicokinetic behavior were analyzed by molecular docking. Good linearities, accuracies, and precisions were achieved for S-(+)- and R-(-)-Hex, with recoveries of 88.7~104.2% and RSDs less than 9.45% in nine tissues of mice. This established method was then used to detect the toxicokinetic of Hex enantiomers in mice after oral administration within 96 h. The results showed that the half-lives of S-(+)- and R-(-)-Hex were 3.07 and 3.71 h in plasma. Hex was mainly accumulated in the liver, followed by the kidneys, brain, lungs, spleen, and heart. The enantiomeric fraction (EF) values of Hex enantiomers in most of the samples were below 1, indicating that S-(+)-Hex decreased faster than its antipode. The molecular docking showed that the binding of S-(+)-Hex with P450arom was much more stable than R-(-)-Hex, which verified the fact that S-(+)-Hex was prefer to decrease in most of the tissues. The results of this study could be helpful for further evaluating the potential toxic risk of Hex enantiomers and for the development and usage of its pure monomer.

Herein the reaction mechanism and the origin of stereoselectivity of asymmetric hydrogenation of oximes to hydroxylamines catalyzed by the cyclometalated iridium (III) complexes with chiral substituted single cyclopentadienyl ligands (Ir catalysts A1 and B1) under acidic condition were unveiled using DFT calculations. The catalytic cycle for this reaction consists of the dihydrogen activation step and the hydride transfer step. The calculated results indicate that the hydride transfer step is the chirality-determining step and the involvement of methanesulfonate anion (MsO-) in this reaction is of importance in the asymmetric hydrogenation of oximes catalyzed by A1 and B1. The calculated energy barriers for the hydride transfer steps without an MsO- anion are higher than those with an MsO- anion. The differences in Gibbs free energies between TSA5-1fR/TSA5-1fS and TSB5-1fR/TSB5-1fS are 13.8/13.2 (ΔΔG‡ = 0.6 kcal/mol) and 7.5/5.6 (ΔΔG‡ = 1.9 kcal/mol) kcal/mol for the hydride transfer step of substrate protonated oximes with E configuration (E-2a-H+) with MsO- anion to chiral hydroxylamines product R-3a/S-3a catalyzed by A1 and B1, respectively. According to the Curtin-Hammet principle, the major products are hydroxylamines S-3a for the reaction catalyzed by A1 and B1, which agrees well with the experimental results. This is due to the non-covalent interactions among the protonated substrate, MsO- anion and catalytic species. The hydrogen bond could not only stabilize the catalytic species, but also change the preference of stereoselectivity of this reaction.

Development of stereoisomeric neonicotinoid pesticides with lower toxicity is key to preventing global population declines of honeybees, whereas little is known about the in situ metabolic regulation of honeybees in response to stereoisomeric pesticides. Herein, we demonstrate an integrated mass spectrometry imaging (MSI) and untargeted metabolomics method to disclose disturbed metabolic expression levels and spatial differentiation in honeybees (Apis cerana) associated with stereoisomeric dinotefuran. This method affords a metabolic network mapping capability regarding a wide range of metabolites involved in multiple metabolic pathways in honeybees. Metabolomics results indicate more metabolic pathways of honeybees can be significantly affected by S-(+)-dinotefuran than R-(-)-dinotefuran, such as tricarboxylic acid (TCA) cycle, glyoxylate and dicarboxylate metabolism, and various amino acid metabolisms. MSI results demonstrate the cross-regulation and spatial differentiation of crucial metabolites involved in the TCA cycle, purine, glycolysis, and amino acid metabolisms within honeybees. Taken together, the integrated MSI and metabolomics results indicated the higher toxicity of S-(+)-dinotefuran arises from metabolic pathway disturbance and its inhibitory role in the energy metabolism, resulting in significantly reduced degradation rates of detoxification mechanisms. From the view of spatial metabolomics, our findings provide novel perspectives for the development and applications of pure chiral agrochemicals.

Ene-reductases from the Old Yellow Enzyme (OYE) superfamily are a well-known and efficient biocatalytic alternative for the asymmetric reduction of C=C bonds. Considering the broad variety of substituents that can be tolerated, and the excellent stereoselectivities achieved, it is apparent why these enzymes are so appealing for preparative and industrial applications. Different classes of C=C bonds activated by at least one electron-withdrawing group have been shown to be accepted by these versatile biocatalysts in the last decades, affording a vast range of chiral intermediates employed in the synthesis of pharmaceuticals, agrochemicals, flavours, fragrances and fine chemicals. In order to access both enantiomers of reduced products, stereodivergent pairs of OYEs are desirable, but their natural occurrence is limited. The detailed knowledge of the stereochemical course of the reaction can uncover alternative strategies to orient the selectivity via mutagenesis, evolution, and substrate engineering. An overview of the ongoing studies on OYE-mediated bioreductions will be provided, with particular focus on stereochemical investigations by deuterium labelling.

In a combined experimental and computational study, the isomerization activity of the dinuclear palladium(I) complex [PdI (μ-Br)(Pt Bu3 )]2 towards allyl arenes, esters, amides, ethers, and alcohols has been investigated. The calculated energy profiles for catalyst activation for two alternative dinuclear and mononuclear catalytic cycles, and for catalyst deactivation are in good agreement with the experimental results. Comparison of experimentally observed E/Z ratios at incomplete conversion with calculated kinetic selectivities revealed that a substantial amount of product must form via the dinuclear pathway, in which the isomerization is promoted cooperatively by two palladium centers. The dissociation barrier towards mononuclear Pd species is relatively high, and once the catalyst enters the energetically more favorable mononuclear pathway, only a low barrier has to be overcome towards irreversible deactivation.

This work presents the study of a series of electrocyclic reactions with the main aim of obtaining new insights into the reaction process along IRCs. The energy variation of the different reaction paths as well as the different transition states have been calculated. These trends are according to the experimental data. The natural bond orbitals have been obtained and the second order perturbational theory analysis has been carried out to determine the main charge transfers due to delocalization. Bond reactivity indexes have been used to describe the reactivity mechanism in a local way. These reactivity indexes are also based on NBOs and this has made it possible to connect the results of the indexes with the previous analysis. To determine quantitatively the bond structure, we used the quantum theory of atoms in molecules and we have hereby completed the information obtained from the NBO analysis. Finally, we used the Hirshfeld population analysis as an approximation to understand how the load density changes in the different reaction pathways, and we have connected these variations with the information obtained from the bond structure. The results has found that the reaction path with the lowest energy barrier Transition State Inward Conrotatory (TSIC) or Transition State Outward Conrotatory (TSOC) is determined by two magnitudes: the charge donations by delocalisation of the substituents (which we obtained from the Second Order Perturbational Theory Analysis of the NBOs) and in the case that these donations were very similar, the non-covalent interactions dominated (which we studied by means of the interaction energies of the Hirshfeld charges). Additionality, the most important factor influencing the lower energy reaction path was the interaction of lone pairs of the substituents with the σ∗(C-C) bond that is broken at the opening of the cycle. The alignment of these lone pairs with the C-C bond favours charge donation between them and, as can be seen in the discussion, this alignment varies depending on whether the structure is TSIC and TSOC.

Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine.
Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites.
A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output.
S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner.
Dutch Cochrane Center 5359.

The chiral pesticide famoxadone is mainly applied to control fungal diseases on fruiting vegetables. The fungicidal activity, ecotoxicological effects, and degradation behavior of famoxadone enantiomers are less well known. In this study, a systemic assessment of the stereoselectivity of famoxadone was performed in cucurbits and soil. Famoxadone enantiomers presented distinct inhibitory activities among different fungal species. The bioactivities of R-(-)-famoxadone were 2.7-178 times higher than S-(+)-famoxadone toward five phytopathogens. Based on the obtained LC50 values, famoxadone was super toxic to Eisenia foetida (E. foetida). Moreover, the acute toxicity of R-(-)-famoxadone presented 167 times greater to E. foetida than that of S-(+)-famoxadone, indicating that R-(-)-famoxadone showed higher bioactivity toward target organisms and non-target organisms than S-(+)-famoxadone. In addition, a simple high-performance liquid chromatography (HPLC) method was established to determine the stereoselective degradation of famoxadone in two species of cucurbits (cucumber and chieh-qua) and in field soil. The half-life values of famoxadone degradation were from 5.4 to 14.1 days, indicating that famoxadone was easily degraded. Additionally, no stereoselective degradation was found in cucurbits and soil. The results may provide promising implications for comprehensive environmental and ecological risk assessments of famoxadone.