Diastereoselective preparation of (R)- and (S)-2-methoxy-2-phenylpent-3-ynoic acids and their use as reliable chiral derivatizing agents

Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both enantiomers of 2-methoxy-2-phenylpent-3-ynoic acids (MPPAs). The latter were condensed with several chiral secondary alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The (1)H NMR spectra of the corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties, whose observed ΔδL(1) and ΔδL(2) values were in the ranges of 0.1-0.4 and 0.02-0.12 ppm, respectively.     

Asymmetric hydrolytic kinetic resolution with recyclable macrocyclic Co(III)-salen complexes: a practical strategy in the preparation of (R)-mexiletine and (S)-propranolol

A chiral cobalt(III) complex (1e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47% with respect to the epoxides, 53% with respect to the diols) and high enantioselectivity (ee>99% for the epoxides, up to 96% for the diols) were achieved in 2.5-16 h. The Co(III) macrocyclic salen complex (1e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol.     

利用“网包法”制备高效液相色谱大环抗生素类手性固定相

万古霉素和替考拉宁都属于糖肽类的大环抗生素，具有立体的环状结构和多个手性中心，是两种常见的手性识别材料，广泛应用于对映体的色谱手性分离分析。该文以万古霉素和替考拉宁为手性选择剂，哌嗪为单体，4，4'-二苯基甲烷二异氰酸酯（MDI）、1，6-己二异氰酸酯（HDI）和2，4-甲苯二异氰酸酯（TDI）为交联剂，通过界面聚合反应形成网状层包裹硅胶载体的方法制得6种高效液相色谱手性固定相，用于分离外消旋化合物，并与MDI直接交联万古霉素和替考拉宁在硅胶表面所得固定相进行了比较。结果表明，利用"网包法"和直接交联法制备的手性柱与商品万古霉素和替考拉宁柱之间具有互补性，均对不同的外消旋体有不同程度的拆分。     

PtCl3(C2H4)]-[AmH]+ complexes containing chiral secondary amines: use as chiral derivatizing agents for the enantiodiscrimination of unsaturated compounds by 195Pt NMR spectroscopy and NMR stereochemical investigation.

Ionic complexes [PtCl3(C2H4)]-[AmH]+, containing chiral secondary amines, constitute a versatile class of chiral derivatizing agents (CDAs) for the enantiomeric purity determination of chiral unsaturated compounds via 195Pt NMR spectroscopy. The NMR conformational analysis allows us to search for the stereochemical basis of their enhanced versatility.     

High-performance liquid chromatographic enantioseparation of 2-aminomono- and dihydroxycyclopentanecarboxylic and 2-aminodihydroxycyclohexanecarboxylic acids on macrocyclic glycopeptide-based phases

The direct separation of the enantiomers of four 2-aminomono- or dihydroxycyclopentanecarboxylic acids and four 2-aminodihydroxycyclohexanecarboxylic acids was performed on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Astec Chirobiotic T and T2), teicoplanin aglycone (Chirobiotic TAG) or ristocetin A (Chirobiotic R) as chiral selectors. The effects of the nature of organic modifiers, the pH, the mobile phase composition and the structures of the analytes on the separation were investigated. Chirobiotic TAG, and in some cases Chirobiotic T, proved to be the most useful of these columns. The elution sequence was determined in most cases.     

Self-assembly of achiral and chiral macrocyclic ligands: synthesis,protonation constants,conformation and asymmetric catalysis

New 30-membered achiral and chiral polyaza macrocyclic ligands, L1 and L2 were synthesized directly from [3 + 3] condensation of phthalic dicarboxaldehyde with cis- and (1R,2R)-diaminocyclohexane, respectively. The trimeric macrocyclic structures were confirmed by electrospray ionization mass spectrometry (ESI-MS), 1H NMR, 13C NMR spectroscopy and elemental analysis. Potentiometry was used to determine the protonation constants of the ligands. UV-vis spectrophotometric titration was employed to investigate the coordination and conformational properties of the chiral ligand (L2). Direct enantioselective aldol reaction has been successfully performed using 4-nitrobenzaldehyde and acetone in the presence of the chiral macrocycle and its zinc(II) complexes as catalysts.     

Synthesis of a chiral macrocyclic dibenzodicyclohexanotetraamide-containing stationary phase for liquid chromatography

Allyloxy-substituted macrocyclic dibenzodicyclohexanotetraamide 2 was prepared by the following sequence. MonoBoc-protected chiral 1,2-cyclohexanediamine ( 3 ) was treated with isophthaloyl chloride followed by removal of the Boc group to form bisisophthalamide 5. Compound 5 was then treated with allyloxyphthaloyl chloride to form the macrocyclic tetraamide 2 in a 56% yield. Chiral selector 2 was converted to its ethoxydimethylsilane derivative and heated in a suspension of silica gel and toluene to form the chiral macrocycle-containing silica gel phase 1. This phase separated the enantiomers of (±)-α-methylbenzylamine and (±)-DL-α-aminobutyric acid methyl ester in a liquid chromatograph.     

Artificial glycosyl phosphorylases

alpha- and beta-Cyclodextrin 6(A),6(D)-diacids (1 and 2), beta-cyclodextrin-6-monoacid (14), beta-cyclodextrin 6(A),6(D)-di-O-sulfate (16) and beta-cyclodextrin-6-heptasulfate (19) were synthesised. Acids 1, 2 and 14 were made from perbenzylated alpha- or beta-cyclodextrin, by diisobutylaluminum hydride (DIBAL)-promoted debenzylation, oxidation and deprotection. Addition of molecular sieves was found to improve the debenzylation reaction. Sulfates 16 and 19 were made by sulfation of the appropriately partially protected derivatives and deprotection. Catalysis of 4-nitrophenyl glycoside cleavage by these cyclodextrin derivatives was studied. Compounds 1, 2 and 16 were found to catalyse the reaction, with the catalysis following Michaelis-Menten kinetics and depending first order on the phosphate concentration. In a phosphate buffer (0.5 M, 59 degrees C, pH 8.0), K(M) varied from 2-10 mM and the k(cat)/k(uncat) ratio from 80-1000 depending on the stereochemistry of the substrate and the catalyst, with 2 being the best catalyst and with the sulfated 16 also displaying catalytic ability. The monoacid 14 and the heptasulfate 19 were not catalytic.     

High efficiency,narrow particle size distribution,sub-2 μm based macrocyclic glycopeptide chiral stationary phases in HPLC and SFC

State of the art chiral chromatography still employs 3–5 μm bonded or immobilized chiral selectors in 10–25 cm columns. With the availability of 1.9 μm narrow particle size distribution (NPSD) silica, it is now possible to make ever shorter, high efficiency columns practical for sub-minute chiral separations. Three macrocyclic glycopeptides (teicoplanin, teicoplanin aglycone, and vancomycin) were bonded onto 1.9 μm NPSD particles. Such packed columns had ∼80% lower backpressure as compared to polydisperse (PD) 1.7 μm silica materials when using the same mobile phase. The decreased backpressure allowed for diminution of frictional heating and allowed for the use of the 1.9 μm NPSD particle based columns at high flow rates. The 1.9 μm NPSD particle based columns showed up to 190,000 plates m⁻¹ for chiral molecules and 210,000 plates m⁻¹ for achiral probes. Representative enantiomeric separations are shown for wide classes of compounds, including different types of amino acids, β-blockers, and pharmaceutically important heterocyclic compounds such as oxazolidinones. Applications in three liquid chromatography modes, namely, reversed phase, polar organic mode and normal phase chiral separations were shown with resolution values ranging from 1.5 to 5.7. Additionally, the same columns were used with supercritical fluid chromatography (SFC) for ultrafast separations.     

Separation of chiral sulfoxides by liquid chromatography using macrocyclic glycopeptide chiral stationary phases

A set of 42 chiral compounds containing stereogenic sulfur was prepared. There were 31 chiral sulfoxide compounds, three tosylated sulfilimines and eight sulfinate esters. The separations were done using five different macrocyclic glycopeptide chiral stationary phases (CSPs), namely ristocetin A, teicoplanin, teicoplanin aglycone (TAG), vancomycin and vancomycin aglycone (VAG) and seven eluents, three normal-phase mobile phases, two reversed phases and two polar organic mobile phases. Altogether the macrocyclic glycopeptide CSPs were able to separate the whole set of the 34 sulfoxide enantiomers and tosylated derivatives. Five of the eight sulfinate esters were also separated. The teicoplanin and TAG CSPs were the most effective CSPs able to resolve 35 and 33 of the 42 compounds. The three other CSPs each were able to resolve more than 27 compounds. The normal-phase mode was the most effective followed by the reversed-phase mode with methanol-water mobile phases. Few of these compounds could be separated in the polar organic mode with 100% methanol mobile phases. Acetonitrile was also not a good solvent for the resolution of enantiomers of sulfur-containing compounds, neither in the reversed-phase nor in the polar organic mode. The structure of the chiral molecules was compared to the enantioselectivity factors obtained with the teicoplanin and TAG CSP. It is shown that the polarity, volume and shape of the sulfoxide substituents influence the solute enantioselectivity factor. Changing the oxidation state of the sulfur atom from sulfoxides to sulfinate esters is detrimental to the compound's enantioselectivity. The enantiomeric retention order on the teicoplanin and TAG CSPs was very consistent: the (S)-(+)-sulfoxide enantiomer was always the less retained enantiomer. In contrast, the (R)-(-)-enantiomer was less retained by the ristocetin A, vancomycin and vancomycin aglycone columns, showing the complementarity of these CSPs. The macrocyclic glycopeptide CSPs provided broad selectivity and effective separations of chiral sulfoxides.     

Asymmetric Hydrolytic Kinetic Resolution with Recyclable Macrocyclic CoIII–Salen Complexes: A Practical Strategy in the Preparation of (R)‐Mexiletine and (S)‐Propranolol

A chiral cobalt(III) complex ( 1 e ) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R‐(?)‐1,2‐diaminocyclohexane with trigol bis‐aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1 e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47 % with respect to the epoxides, 53 % with respect to the diols) and high enantioselectivity (ee>99 % for the epoxides, up to 96 % for the diols) were achieved in 2.5–16 h. The Co^III macrocyclic salen complex ( 1 e ) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)‐mexiletine and (S)‐propranolol.     

Comparative study of three teicoplanin-based chiral stationary phases using the linear free energy relationship model

Teicoplanin (T) is a macrocyclic glycopeptide that is highly effective as a chiral selector for enantiomeric separations. In this study, we used three teicoplanin-based chiral stationary phases (CSPs) - native teicoplanin, teicoplanin aglycon (TAG) and recently synthesized methylated teicoplanin aglycon (MTAG). In order to examine the importance of various interaction types in the chiral recognition mechanism the three related CSPs were evaluated and compared using a linear free energy relationship (LFER). The capacity factors of 19 widely different solutes, with known solvation parameters, were determined on each of the columns under the same mobile phase conditions used for the chiral separations. The regression coefficients obtained revealed the magnitude of the contribution of individual interaction types to the retention on the compared columns under those specific experimental conditions. Statistically derived standardized regression coefficients were used to evaluate the contribution of individual molecular interactions within one stationary phase. It has been concluded that intermolecular interactions of the hydrophobic type significantly contribute to retention on all the CSPs studied here. Other retention increasing factors are n- and pi-electron interactions and dipole-dipole or dipole-induced dipole ones, while hydrogen donating or accepting interactions are more predominant with the mobile phase than with the stationary phases. However, these types of interactions are not equally significant for all the CSPs studied.     

A comparison of the direct and indirect LC methods for separating enantiomers of unusual glycine and alanine amino acid analogues

Summary Reversed-phase high-performance liquid chromatographic methods were developed for the separation of the enantiomers of five glycine and twelve alanine analogues. The enantioselective separation involved two methods. The direct separations were performed on chiral stationary phases containing a macrocyclic glycopeptide antibiotic: teicoplanin (Chirobiotic T column), ristocetin A (Chirobiotic R column) or chiral crown ether (Crownpak CR(+) column). The indirect methods involved pre-column derivatization with the chiral derivatizing agents 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate andN-α-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (Marfey's reagent). The different methods were compared in systematic chromatographic examinations. The effects of organic modifier content, mobile phase composition, pH and flow rate on the separation were investigated. Presented at Balaton Symposium '01 on High-Performance Separation Methods, Siófok, Hungary, September 2–4, 2001     

冠醚修饰型手性固定液的合成及其气相色谱性能的研究

合成了两种含冠醚功能基的手性固定液：（１Ｓ,２Ｓ）－１－对硝基苯基－２－（４＇－西佛碱基苯并１５－冠－５）－丙烷－１,３－烯丙氧基聚硅氧烷和３－甲基－２－（４＇－甲酰胺－苯并１５－冠－５）－丁酸乙酯。用它们涂制的石英毛细管柱呈强极性,色谱性能良好。并探讨了固定液的结构对分离能力的影响。     

Evaluation of generic chiral liquid chromatography screens for pharmaceutical analysis

Two different automated generic liquid chromatography screens for the separation of chiral compounds of pharmaceutical interest have been evaluated. The test set comprised 53 chemically diverse chiral compounds involving 55 enantiomeric pairs from the pharmaceutical industry (i.e. starting materials, synthetic intermediates and drug substances). The first screen utilised four polysaccharide-based columns with five mobile phases and showed enantioselectivity for 87% of the test compounds. The second screen employed three macrocyclic glycopeptide columns with two mobile phases and showed enantioselectivity for 65% of the test compounds. Merging of the two screening procedures resulted in an enantioselectivity for 96% of the chiral compounds. It is anticipated that the systematic use of the automated chiral HPLC screens described in this report will substantially reduce the necessary time for method development of pharmaceutically related chiral analytical methods.     

Comparison of the chiral resolution of econazole, miconazole, and sulconazole by HPLC using normal-phase amylose CSPs

Resolution of the enantiomers of (+/-)-econazole, (+/-)-miconazole, and (+/-)-sulconazole has been achieved on different normal-phase chiral amylose columns, Chi-ralpak AD, AS, and AR. The mobile phase used was hexane-2-propanol-diethylamine, 400:99:1 (v/v). The flow rates of the mobile phase used were 0.50 and 1.00 mL min(-1). The alpha values for the resolved enantiomers of econazole, miconazole, and sulconazole on the chiral phases were in the range 1.63 to 1.04; the Rs values varied from 5.68 to 0.32.     

5-Amino-4-aryl-2,2-dimethyl-1,3-dioxans: application as chiral NMR shift reagents and derivatizing agents for acidic compounds

The use of (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxan (ADPD) and (4R,5R)-5-amino-(4′-biphenyl)-2,2-dimethyl-1,3-dioxan (ABDD) as chiral solvating agents (CSA) for the ee determination of compounds bearing an acidic proton by means of ¹H NMR spectroscopy is demonstrated. In addition, based on the well known rigid conformation of these amines, ADPD and ABDD are suitable as chiral derivatizing agents (CDAs) in order to determine absolute configurations.     

New Chiral Macrocyclic Compounds from D-Mannitol

We have recently reported the synthesis of new chiral macrocyclic polyhydroxyethers by reduction of cyclodextrins 1. These compounds display appreciable conformational freedom in solution as it occurs with the ionophores. Our chiral macrocycles may be considered as built by units of alditol (1 → 4) alditols. Such units, conveniently substituted, prepared by us by reduction of disaccharide derivatives2, are possible synthons for the synthesis of other macrocyclic polyhydroxyethers in which the nature and number of alditol (1 → n) alditol components can be varied at will. We are interested in the preparation and the structural studies of these type of receptors since the synthesis of new chiral macrocycles is a topic of interest and the building of chiral cavities may be of importance in the study of host-guest interactions. We now report on the preparation, from D-mannitol, a readily available starting material with C₂symmetry, and tetraethylene glycol, of the chiral macrocycles 1, 2, and 3, as model compounds in exploring the synthesis of more complex macrocyclic polyhydroxyethers derived from alditol (1 → n) alditol. Other macrocyclic compounds from D mannitol have been previously synthesised.     

Determination of the enantiomeric purity of albuterol on sorbents modified by macrocyclic antibiotics

The separation of albuterol enantiomers on sorbents with macrocyclic glycopeptide antibiotics immobilized on the silica surface was investigated. Commercial columns—Nautilus-E (BioKhimMak, Russia) with eremomycin as a chiral selector and ChirobioticTAG (Astec, United States) with teicoplanin aglycone as a chiral selector—were used for enantioseparation. Levalbuterol is the (R)-enantiomer of albuterol. We managed to separate albuterol enantiomers on both columns in a polar organic mode, but selectivity was higher on the ChirobioticTAG column (R _s = 1.7). The maximum resolution of enantiomer peaks (1.7) was observed in methanol–acetonitrile–triethylamine–acetic acid (90: 10: 0.05: 0.05) as the mobile phase. The detection limit of the compound calculated by a signal–background ratio of 3: 1 was 0.00002 mg/mL, which corresponds to 0.1% of (S)-enantiomer with respect to the total amount. The results made it possible to determine the enantiomeric purity of the active pharmaceutical substances of levalbuterol.     

Synthesis and characterisation of macrocyclic diamino chiral crown ethers

A benign and efficient synthesis of chiral macrocyclic 'aza-crown' ethers of varying ring size is reported. The synthesis involves a Schiff base condensation of ether linked dialdehydes of varying chain length and (1R,2R)-(-)-1,2-diaminocyclohexane under mild conditions to yield the macrocycles, which are subsequently reduced to yield the diamino analogues.