Chirality最新文献

(S)-Lifitegrast (LFT) is the novel integrin antagonist, approved by the Food and drug administration, to treat signs and symptoms of dry eye disease. Synthesis of racemic LFT, preparative and analytical enantiomer separation, and chiral interconversion studies are lacking in the literature. Hence, in our study, synthesis of LFT racemate, chiral preparative purification procedure of enantiomer, and comprehensive analytical advancements are focused on rapid enantioselective separation and pH-dependent chiral interconversion studies. The synthesis of LFT racemate employed 2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid hydrochloride and 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbonyl chloride as starting materials. (R)-LFT was isolated from the racemate by preparative chiral HPLC and characterized using Q-TOF, FT-IR, NMR spectroscopy, and chiral HPLC. The purity of (R)-LFT was determined to have an enantiomeric excess of 99.12%. A precise, accurate, rapid HPLC-DAD enantioselective analytical method has been developed on Chiralpak IC [tris(3,5-dichloro phenyl carbamate) immobilized on cellulose] using water and methanol as mobile phase. The chiral interconversion study reveals 0.22% and 0.21% of interconversion of (S)-LFT into (R)-LFT at 80°C in pH 7.4 and 9.5 buffers, respectively, on the 24th day. An alternative route to enantioselective synthesis of LFT enantiomers by chromatographic separation is proposed. The validated enantioselective HPLC method will help to test the regular quality control samples.

Chiral pesticides have the special chiral structures, so enantioselective biological effects are usually observed in living organisms. Current study used paclobutrazol as a case study and explored the enantioselective degradation and oxidative stress effect on wheat. The results demonstrated that the degradation of R-paclobutrazol was faster than S-paclobutrazol significantly and improved the content of MDA and O₂⁻ in wheat plants, which proved that the R-paclobutrazol induced oxidative damage in wheat, showing selective biological effects, and S-paclobutrazol was friendly to wheat. This study provided a theoretical basis for the selective activity of chiral pesticides and the development of chiral pesticide monomers.

Composite enantioselective voltammetry sensors provide a well-known solution for the analysis and discrimination of enantiomerical drugs by voltammetry. The design of such sensor presumes the use of chiral substances to impart chirality to the electrode surface. We present the results of applying a theoretical approach based on simulating the adsorption of analyte enantiomers for preparing high enantioselectivity of pioneering enantioselective sensors using homochiral zeolites as chiral modifiers.

We investigated the ability of some homochiral zeolites like CZP, ITV, OSO, STW, MFI, and SOF to act as solid chiral modifiers. Using tryptophan and tyrosine as model objects, we found that the maximum difference between the adsorption energies (ΔE_ads) of enantiomers on zeolites occurs if enantiomers are placed into the pores of zeolites. The SOF zeolite demonstrates the best enantioselectivity to both amino acids. Moreover, we compared the theoretical results with the experimental enantioselectivity value for tryptophan on a sensor designed as a paste electrode with MFI as the chiral modifier. We found that the calculated value ΔE_ads(R-S) = −11.0 kJ/mol for MFI, though it is not the best value in the zeolite set considered, it is still enough for the sensor with MFI as the chiral modifier to demonstrate a higher than usual enantioselectivity (i_p1/i_p2 = 1.58) in an experiment with R- and S- tryptophan as the analyte.

To quantify chiral shape, a tensor describing the particle shape has been proposed. This tensor, named the shape tensor (S-tensor), is an analog of the hydrodynamic tensor that relates the rotational and translational motions of particles in a liquid. The determinant of the S-tensor, named chirality measure density (CMD), was calculated for chiral tetrahedrons and octahedrons. It was found that CMD is opposite in sign when the mirror images are chiral to each other and vanishes when they are achiral. Therefore, the CMD is a good measure to distinguish the mirror images. The interaction between chiral particles was discussed in terms of the CMD.

To investigate the thermodynamic and molecular self-assembly mechanism of trans-1,2-cyclohexane dicarboxylic acid containing two carboxylic acid groups in the chiral resolution process, (S)-phenylethylamine was used as the chiral resolving agent. Two stoichiometric salts were formed when the raw materials were fed at different molar ratios: cyclohexane dicarboxylate monophenylethylamine salt and cyclohexane dicarboxylate diphenylethylamine salt. When the molar ratio of the (S)-phenylethylamine to trans-1,2-cyclohexane dicarboxylic acid was less than 3:1, trans-(1S,2S)-cyclohexane dicarboxylic acid was obtained with 97 e.e% purity. But when the molar ratio exceeded 3:1, the product was the racemic trans-(1,2)-cyclohexane dicarboxylic acid. In addition, single crystal structures of more soluble mono-salt, less soluble mono-salt, and less soluble di-salt were obtained. The weak intermolecular interactions and the way of the molecules packing in the crystals were analyzed. The hydrogen bond was stronger in the less soluble salt than that in the more soluble salt. And a “lock-and-key” structure in the hydrophobic layers makes it more tightly packed through the van der Waals interaction, which is responsible for the stability of less soluble salts.

The R,S-enantiomer impurity and diastereomer impurities (S,S-isomer and R,R-isomer) of the solifenacin (S,R-enantiomer) were effectively separated and quantified simultaneously utilizing normal-phase high-performance liquid chromatography with a chiral stationary phase consisting of amylose tris (3,5-dimethylphenylcarbamate) coated on silica-gel (Chiralpak, AD-H). The enantiomeric and stereo-selective separation was achieved within a run time of 35 minutes using a mobile phase of ‘n-hexane, ethanol, and diethylamine’ in an isocratic elution mode with a detection wavelength of 220 nm. The validation attributes assessed were accuracy (which showed excellent recoveries between 97.5% and 100.4%) and linearity (which was proven in the range of 0.081–1.275 μg.mL⁻¹, with a linear regression of 0.999). The stress testing experiments proved that the developed methodology by the HPLC technique has stability-indicating characteristics, as all closely eluting peak pairs were separated well with a resolution of 2.3 and without any interference. The proposed methodology was highly efficient in separating and simultaneously determining the chiral impurities (enantiomers and diastereomers) of the solifenacin in the release and stability sample analyses of drug substances and tablets in pharmaceutical formulations.

A series of chiral ligands were synthesized using chloramphenicol base as starting materials. These ligands were applied to the asymmetric catalytic reactions of terminal alkynes with aldehydes to obtain a propargyl alcohol product in high yield (80–94%) with excellent enantioselectivities (82–96%).

First antibiotic in the oxazolidinone class, linezolid fights gram-positive multiresistant bacteria by inhibiting protein synthesis through its interaction with the 50S subunit of the functional bacterial ribosome. For its antimicrobial action, it is necessary that its chiral carbon located in the oxazolidinone ring is in the S-conformation. Computational calculation at time-dependent density functional theory methodology, ultraviolet–visible (UV–Vis), and electronic circular dichroism spectra was obtained for noncomplexed and complexed forms of linezolid to verify the possible chirality of nitrogen atom in the acetamide group of the molecule. The molecular system has two chiral centers. So, there are now four possible configurations: RR, RS, SR, and SS. For a better understanding of the system, the electronic spectra at the PBE0/6-311++G(3df,2p) level of theory were obtained. The complexed form was obtained from the crystallographic data of the ribosome, containing the S-linezolid molecular system. The computational results obtained for the electronic properties are in good agreement with the experimental crystallographic data and available theoretical results.

Chiral N-substituted secondary 1,2-aminoalcohols have been developed for the enantioseparation of ortho-halomandelic acids (o-X-MAs) via diastereomeric salt formation. Two structural isomers, N-methyl-2-amino-1,2-diphenylethanol and N-benzyl-2-amino-2-phenylethanol, showed high separation abilities for o-X-MAs (X = Cl, Br, I). The chiral recognition mechanism was elucidated by crystallographic analysis of the less-soluble salts. The substituents on the nitrogen atom of the resolving agents and the inclusion of the crystallization solvent stabilized the salt and enhanced their separation ability.

The β-adrenergic receptor blocking agents are an important class of drug molecules. The present study reports a new chemo and chemo-enzymatic synthetic process for (RS)-, (R)-, and (S)-bunolol, one of the potent β-adrenergic receptor blocker. In chemo-enzymatic process, CAL L4777 lipase was employed for enantioselective kinetic resolution to synthesize the enantiopure (R)-alcohol and (S)-ester from the corresponding racemic alcohol. Thereafter, the corresponding (R)-alcohol and deacylated (S)-ester were treated with tert-butylamine to produce (S)- and (R)-bunolol, respectively. In chemical approach, epichlorohydrin (RS-, R-, and S-) was used as a starting material via respective (RS)-, (S)-, and (R)-glycidyl ether as intermediates for synthesis of enantiomeric (RS)-, (R)-, and (S)-bunolol. In comparison between two approaches, it was found that the chemo-enzymatic process was more effective and resulted in enantiomeric excess of 98% with 35% yield.