Chiral separation of the four stereoisomers of a novel antianginal agent using a dual cyclodextrin system in capillary electrophoresis

Reported here is an analytical method enabling the stereochemical resolution of a new antianginal compound possessing two stereogenic centers, leading to four stereoisomers. Only one of these isomers is currently under development as a novel antianginal agent and consequently, the other three isomers are considered as unwanted chiral impurities. Therefore, an enantioselective method is required in order to check its enantiomeric purity. This paper presents a method exploiting the high efficiency of capillary electrophoresis and the complexing properties of cyclodextrins to achieve the separation of the four stereoisomers of this weakly basic compound (pKa = 7.4). For this purpose, the combination of a neutral cyclodextrin, hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), and an anionic cyclodextrin, carboxymethyl-beta-cyclodextrin (CM-beta-CD), was added to the separation buffer running in an uncoated silica capillary. After selection of the suitable cyclodextrin system, satisfactorily separation conditions were as follows: 30 mM phosphate buffer (pH 6.4) containing 10 mM of HP-gamma-CD and 10 mM of CM-beta-CD, running voltage +30 kV. The resulting run time and resolutions were respectively about 17 min and between 1.95 and 2.84. Linearity curves (0.993 < r2 < 0.998) are also shown.     

Simultaneous assay of four stereoisomers of diltiazem hydrochloride. Application to in vitro chiral inversion studies

Summary The simultaneous stereospecific assay of four stereoisomers of diltiazem hydrochloride in bulk drug and aqueous solution was developed using HPLC on a Chiralcel OF column. The four isomers were quantitated with good precision by the internal standard method. The chiral inversion of (+)-cis-diltiazem hydrochloride in vitro, stability of its (2S, 3S) configuration in the solid and aqueous states was examined by HPLC. Chiral inversion of (+)-cis-diltiazem hydrochloride was not observed in the solid state, and its (2S, 3S) configuration was stable to heat, humidity and light. Chiral inversion of (+)-cis-diltiazem hydrochloride (2S, 3S) was observed in aqueous solution under UV, but not in aqueous solution stored at 80°C for 5h nor under visible light for 10 h. The (+)-cis-diltiazem hydrochloride (2S, 3S) epimerized to (+)-trans-diltiazem hydrochloride (2R, 3S) with a half-life of 5h in aqueous solution under UV but the reverse chiral inversion of (+)-trans-diltiazem hydrochloride (2R, 3S) to (+)-cis-diltiazem hydrochloride (2S, 3S) was not observed.     

First synthesis of enantio-uracil dinucleotide, comparison of physicochemical properties of their enantiomers, and separation by chiral column chromatography

Enantio-uracil dinucleotide 5, which consists of two l-uridylic acids and one pyrophosphate, was synthesized for the first time in our laboratory. Benzolyated l-uridine was prepared by a stereoselective glycosylation of silylated uracil with l-1-O-acetyl-2,3,5-tri-O-benzoylribose (l-ABR 7). After deprotection, l-uridine 9 was converted to P¹,P⁴-di(l-uridine 5′-) tetraphosphate tetrasodium salt (l-UP₄U 5) by treatment of l-UMP morpholidate 10c with triethylammonium pyrophosphate (TEA-PPi 11b). Spectral data of synthesized l-UP₄U 5 are given in the references. All spectral data were identical with those of UP₄U 3 except the specific rotation, which showed a positive value compared to UP₄U 3 having a negative value. Furthermore, the separation by chiral column chromatography was investigated.     

Organophosphines in PtP2Si2 derivatives – structural aspects

Abstract

In this review, the structural data of monomeric platinum(II) complexes with inner coordination spheres of Pt(η²-P₂L)(SiL)₂, Pt(η²-P₂L)(η²-Si₂L) and Pt(η²-P,SiL)₂ are classified and analyzed. These complexes crystallize in three crystal systems: monoclinic (8 examples), triclinic (4 examples) and orthorhombic (4 examples). Distorted square-planar environments about the Pt(II) atoms are built up by combination of homobi-P,P with two monodentate Si donor ligands; homobi-PP with homo-Si,Si donor ligands, or heterobi-P,Si donor ligands. The chelating ligands create metallacycles with the following angles: 65.0° (SiOSi) < 83.1° (SiC₂Si) < 85.2° (PC₂P) < 88.8° (SiSi₂Si)). The mean Pt-P and Pt-Si bond distances in Pt(η²-P₂L)·(SiL)₂ complexes are 2.319 and 2.365?Å; in Pt(η²-P₂L)(η²-Si₂L) the values are 2.316 and 2.360?Å. The complex [Pt{η²-Me₂P(C₂B₁₀H₁₀)SiMe₂}₂] exists in two isomeric forms, a monoclinic cis- and a triclinic trans-isomer. The structural data are compared and discussed with the complexes of inner coordination spheres: Pt(η²-P₂L)(XL)₂ (X?=?O, N, CN, BL, Cl, SL, SeL, Br, or I) and Pt(η²-P₂L)(η²-X₂L) (X?=?OL, NL, SL or SeL).     

Investigation in the Area of Furan Acetal Compounds. 13. Synthesis and Structure of 1,3-Dioxacyclanes Based on Furfural and Glycerol

The optimum conditions were found for the condensation of glycerol with furfural. It was shown that the reaction of glycerol with furfural gives a mixture of the cis and trans isomers of five- and six-membered furan 1,3-dioxacyclanes. The cis- and trans-5-hydroxy-2-furyl-1,3-dioxanes were isolated by column chromatography, and their stereochemical structure was established by IR and NMR spectroscopy.     

Steric and Electronic Effects on the Configurational Stability of Residual Chiral Phosphorus‐Centered Three‐Bladed Propellers: Tris‐aryl Phosphane Oxides

A series of tris‐aryl phosphane oxides existing as residual enantiomers or diastereoisomers with substituents on the aryl rings differing in size and electronic properties were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation and reduction potentials together with those of the corresponding “blade bromides” (i.e., the naphthalene derivatives displaying the same substitution pattern of the tris‐naphthyl phosphane oxide blades, with a bromo substituent where the phosphorus atom is located) determined by CV. The residual stereoisomeric phosphane oxides were isolated in a stereochemically pure state and were found to be highly configurationally stable at room temperature (stereoisomerization barriers of about 27 kcal mol^?1). The chiroptical properties of the residual stereoisomers and the assignments of absolute configuration are discussed. The configurational stability of residual tris‐aryl phosphane oxides was found to be scarcely influenced by the electronic properties of the substituents present on the aromatic rings constituting the blades, while steric effects play the most relevant role. Detailed theoretical calculations are in agreement with the experimental results and also contribute to a rational interpretation of the stereodynamics of these systems.     

Synthesis of Stereoisomers of Cryptofolione 6'-Mono- and 4', 6'-Di-O-benzyl Ethers

Synthesis of stereoisomers of 6′‐mono‐ and 4′,6′‐di‐O‐benzyl cryptofolione is described through a key intermediate 6 , which was prepared by coupling of iodobenzene 8 with chiral propargyl alcohol 9 under Cosford protocol conditions. Monobenzyl ether 4 is obtained via epoxide 6 opening with vinyl Grignard, followed by cross‐metathesis reaction with a vinyl lactone 11 . Whereas, dibenzyl ether 5 is prepared by epoxide 6 opening with chiral propargyl alcohol 7 followed by simple transformations and finally cis‐Wittig olefination.     

Different responses of E:Z‐isomers of pesticides in liquid chromatography–electrospray ionization–mass spectrometry

The mass spectrometric behavior of four pairs of stereoisomers was investigated by liquid chromatography–electrospray ionization–mass spectrometry (LC–ESI–MS). The E‐ and Z‐isomers of the pesticides chlorfenvinphos, dimethomorph, mevinphos and phosphamidon—each with one double bond—were chosen for this study. The MS response of the individual isomers was investigated by infusing the isomers individually into the MS or after the separation of isomer mixtures via high‐performance liquid chromatography(HPLC). In the case of dimethomorph, the same MS response was found for the two isomers. In contrast to that, the individual isomers of chlorfenvinphos, mevinphos and phosphamidon showed different MS response both in the single ion monitoring (SIM) mode in single quadrupole MS and multiple reaction monitoring (MRM) mode in tandem MS. The MS response of the isomers partly depends on (1) the declustering potential of the precursor ion in the SIM mode, (2) the selected transition and (3) the collision energy in the MRM mode. Consequently, quantification by summation of the peak areas of the isomers is inaccurate due to over‐ or underestimating of one of the stereoisomers. Accurate quantitative results can only be achieved when the compound‐specific MS parameters are separately determined for each isomer. This can be done by using pure isomers or by the determination of the MS parameters after HPLC separation and the measurement of the actual isomer ratio with an independent technique. Copyright © 2010 John Wiley & Sons, Ltd.     

Encapsulation-Controlled Photoisomerization of a Styryl Derivative: Stereoselective Formation of the Anti Z-Isomer in the Cucurbit[7]uril Cavity

The photochemical isomerization of a styrylpyridinium dye ( SP ) bearing an unsymmetrically attached benzo-15-crown-5 ether has been studied in aqueous solution in the absence and presence of cucurbit[7]uril (CB[7]). The detailed analysis of the UV/Vis and NMR spectra showes that the isomeric composition of the photostationary mixtures of SP can be modulated by the host-guest complexation with CB[7]. It was found that steric hindrance caused by encapsulation of SP in the host cavity induces the exclusive formation of the anti conformer of Z- SP in contrast with the mixture of both anti and syn conformers obtained during photoisomerization of the dye without CB[7]. Remarkably, the displacement of anti Z- SP from CB[7] does not lead to the transformation of the anti Z-isomer into the syn Z-isomer pointing out the conformational memory of the system. The results provide an interesting example of the supramolecular stereorecognition by the achiral CB[7] host.     

Total Synthesis of Amphidinolide E and Amphidinolide E Stereoisomers

Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and vinylstannane 6. The C19 stereocenters of the C19 epimeric allylsilanes 7 and 8 were introduced via crotylboration reactions early in the synthesis. [3+2] Annulation reactions of aldehyde 5 with allylsilanes 7 and 8 were employed to set the core tetrahydrofuran units of 1-4. Finally, the C2 stereocenter was installed by esterification using acid 9, without incident, or with acid 10, in which case an unexpected and completely stereoselective inversion of C2 occurs.