Direct Resolution Of Enantiomers Research Articles

Direct resolution of enantiomers by impregnated TLC

Direct resolution of enantiomers by impregnated TLC

Enantiomeric Resolution of a Germacrene-D Derivative by Chiral High-performance Liquid Chromatography

Direct enantiomeric resolution of the germacrene-D derivative, (5E,7S*,9S*)-9-hydroxy-7-isopropyl-4,10-bis(methyIene)-5-cyclodecen-1-one, was carried out by HPLC with a chiral stationary phase. This method showed that germacrene-D contained in ylang ylang oil was 98% e.e., whereas germacrene-D extracted from Solidago altissima L. was almost racemic.

Direct enantiomeric resolution of monoterpene hydrocarbons via reversed-phase high-performance liquid chromatography with an α-cyclodextrin bonded stationary phase

Chiral recognition in liquid chromatography (LC) generally requires relatively strong interactions between the analyte and the chiral stationary phase, often in combination with steric interactions. Hence most LC enantiomeric separations favor compounds that have hydrogen bonding groups, aromatic rings, strong dipoles, possibilities for π-π or charge transfer interactions, etc. Compounds with little or no functionality are usually difficult to resolve by LC methods. Conversely gas chromatography (GC) has been very useful in resolving compounds with limited functionality, including hydrocarbons. In this sense GC has been very complementary to LC methodologies. In this work the enantiomeric separation of hydrocarbons by reversed-phase LC is described. It appears that chiral recognition results largely from “shape-selectivity” ( i.e., the tight fit of a hydrophobic moiety into a hydrophobic cavity) with few other substantial contributing interactions. Small amounts of methyl tert.-butyl ether greatly enhanced the separation efficiency. All commercial samples contain significant quantities of enantiomeric impurities.

Direct enantiomeric resolution of ibuprofen and flurbiprofen by packed column SFC

AbstractPacked column SFC is used to resolve the enantiomers of two nonsteroidal antiinflammatories. A Chiralpak AD column is used with a binary mobile phase of carbon dioxide/methanol to achieve resolution. The effects of composition, pressure, temperature, and flow on ibuprofen enantiomer separation are examined. In this instance, temperature affords the greatest change in resolution followed by pressure and composition. Baseline resolution of ibuprofen is achieved in less than 7 min and fluibiprofen is baseline resolved in less than 4 min. © 1994 Wiley‐Liss, Inc.

Direct Enantiomeric Resolution of Pyriproxyfen (Sumilarv®) on a Cellulouse-Ðased Chiral Stationary Phase

The enantiomeric separation of pyriproxyfen(Sumilarv ®), a new insect growth regulator, was investigated on several commercially available chiral stationary phases consisting of cellulose esters coated on sillica. The resolution has been only achieved by using a cellulose tris (4-methylbenzoate)-coated sillica gel. The enantiomeric elution order changed according to the steric bulk of the alcohols. The possible mechanisms of the reveral of elution order are discussed

Proposed primary reference methods for the determination of some commercially important chiral aryloxypropionate herbicides in both free acid and ester forms

The direct enantiomeric high-performance liquid chromatographic resolution of the free acid form of the herbicide 2-(4-chloro-2-methylphenoxy)propanoic acid (CMPP) was demonstrated using a second-generation α 1-acid glycoprotein (Chiral-AGP) chiral stationary phase (CSP). Analysis times were short, separations and retention times were reproducible during intermittent use and the baseline resolution of the enantiomers of the herbicide 2-(2,4-dichlorophenoxy)propanoic acid (2,4-DP) could also be achieved. This system was found to be far superior to the earlier separation using EnantioPac α 1-AGP CSP. Commercially important 2-butoxyethyl and 2-ethylhexyl esters and also model methyl and ethyl esters of racemic CMPP were resolved using an ionically bonded d-phenylglycine (Pirkle type 1-A) CSP. The same esters were chromatographed using a covalent d-phenylglycine CSP but the separations observed were inferior. These CSPs were capable of recognizing chirality at the phenoxypropionic moiety but no recognition of chirality associated with the 2-ethylhexyl ester was observed. The reproducibility and reliability of these methods of chiral analysis makes them suitable for both reference purposes and also for the routine determination of the newly introduced, optically active phenoxypropionate herbicides.

Direct separation of albendazole sulfoxide enantiomers by liquid chromatography on a chiral column deriving from (S)-N-(3,5-dinitrobenzoyl) tyrosine: application to enantiomeric assays on plasma samples.

The direct enantiomeric resolution of albendazole sulfoxide (SOABZ), an anthelmintic drug belonging to the benzimidazole class, is reported on a chiral stationary phase (CSP) synthesized by covalent binding of (S)-N-(3,5-dinitrobenzoyl)tyrosine-O-(2-propen-1-yl) methyl ester on a gamma-mercaptopropyl-silanized silica gel. A comparison with the resolution achieved on commercially available Pirkle-type CSPs obtained from N-(3,5-dinitrobenzoyl) derivatives of (R)-phenyglycine or (S)-phenylalanine is described. Some structurally related chiral sulfoxides including oxfendazole (SOFBZ) are also studied. Optimization of the mobile phase nature and composition is investigated showing that a hexane-dioxane-ethanol ternary mixture affords an almost baseline resolution (Rs = 1.25); however, in this case, albendazole sulfone (SO2ABZ) is eluted between the two sulfoxide enantiomers; accordingly, a hexane-ethanol mobile phase would be preferred for biological samples containing both metabolites. The influence of temperature on the resolution is depicted with a hexane-ethanol mobile phase. Finally, application to the enantiomeric assays of SOABZ in plasmatic extracts of rat, sheep, bovin, and man after oral administration of albendazole (sulfoxidized to SOABZ and SO2ABZ) is reported. Some distortions in the enantiomeric ratios are evidenced depending on the species.

Direct enantiomeric resolution of disopyramide and its metabolite using chiral high-performance liquid chromatography : Application to stereoselective metabolism and pharmacokinetics of racemic disopyramide in man

A method for the simultaneous determination of disopyramide and mono-N-desisopropyldisopyramide enantiomers extracted from human plasma and urine is presented. Separation and quantitation were carried out using two columns coupled in series, and UV detection at 254 nm. First, the racemates of the two compounds were separated using a reversed-phase column, and then the enantiomers were separated using a stereoselective column packed with human α 1-acid glycoprotein. The mobile phase was 8 m M phosphate buffer, pH 6.20-2-propanol (92:8, v/v). The coefficients of variation (%) for the plasma daily determination were 6.7% for R(−)- and S(+)-disopyramide at drug levels of 1.5 μ/ml, and 8.5% and 7.7% for R(−)- and S(+)-mono-N-desisopropyldisopyramide, respectively, at drug levels of 0.375 μ/ml. The method has allowed the study of stereoselective metabolism and pharmacokinetics of disopyramide after oral administration as a racemate.

Optimization of the direct chiral separation of potential cytotoxic α-methylene-γ-butyrolactones and α-methylene-γ-butyrolactams by liquid chromatography

The direct enantiomeric resolution of a series of racemic α-methylene-γ-butyrolactones and α-methylene-γ-butyrolactams was carried out on various commercially available chiral stationary phases (CSPs). Particular interest was paid to compounds which exhibit physiological activity as cytotoxic agents. On a Pirkle-type column packed with ( R)-N-(3,5-dinitrobenzoyl)phenylglycine (DNBPG) covalently bonded to γ-aminopropylsilanized silica gel, only α-methylene-γ-lactams containing two aromatic groups were resolved; a chiral recognition mechanism is proposed. (+)-Poly-(triphenylmethyl methacrylate) (PTrMA) coated on silica gel [Chiralpak OT(+)] with methanol as eluent afforded fairly good selectivities (up to 1.8) especially for α-methylene γ-lactones. Temperature had a great influence on the resolution. Cellulose tribenzoate and triphenylcarbamate (Chiralcel OB and OC, respectively) coated on macroporous silica gel displayed selectivities from 1.1 to 1.3, but, because of the very poor efficiency of these CSPs, no baseline resolution was achieved. Investigations on two protein CSPs are reported, α 1-acid glycoprotein ( α 1-AGP) and bovine serum albumin (BSA) immobilized on microparticulate silica gel (Enantiopac and Resolvosil-BSA, respectively). The separations were performed using an aqueous sodium phosphate buffer as eluent and 2-propanol as organic modifier to regulate retention and selectivity. Both CSPs exhibited a good chiral recognition ability, especially towards cytotoxic solutes with resolution factors between 1 and 2.

Chiral high-performance liquid chromatographic studies of 2-(4-chloro-2-methylphenoxy)propanoic acid

The direct enantiomeric resolution of the racemic herbicide 2-(4-chloro-2-methylphenoxy)propanoic acid (CMPP) was demonstrated on an Enantiopac (α 1-acid glycoprotein) chiral high-performance liquid chromatographic (HPLC) column. The HPLC separation of various amide derivatives of CMPP on a chiral “Ionic Pirkle” column comprising of N-(3,5-dinitrobenzoyl) ( R)-(−)phenylglycine as chiral ligand, was also accomplished. These amides and racemic ibuprofen, however could not be separated on the Enantiopac system. The performance, stability and cost of the two systems were compared. Using optically pure CMPP enantiomers the elution order was determined and shown to reverse between the two systems. It was also shown that negligible racemisation occurred during derivatization.

ChemInform Abstract: Direct Resolution of Enantiomers by Liquid Chromatography with the Novel Chiral Stationary Phase Derived from (R,R)‐Tartramide.

AbstractAus dem Bis‐acet‐oxysuccinimid (I) erhält man mit (II) über (IIIa) und (IIIb) das unsymmetrische Diamid (IIIc), das an Kieselgel (IV) bzw. dem modifizierten Kieselgel (V) kondensiert wird.

Stereoselective metabolism of chrysene by rat liver microsomes. Direct separation of diol enantiomers by chiral stationary phase h.p.l.c.

The direct enantiomeric resolution of non-K region trans-1,2-dihydrodiol, 1,2,3,4-tetrahydro-trans-1,2-diol, trans-3,4-dihydrodiol and 1,2,3,4-tetrahydro-trans-3,4-diol, K region trans- and cis-5,6-dihydrodiols and their monomethyl ethers of chrysene was studied by chiral stationary phase high-performance liquid chromatography (CSP-h.p.l.c.). The chiral stationary phase columns were packed with gamma-aminopropylsilanized silica to which either (R)-N-(3,5-dinitrobenzoyl)-phenylglycine or (S)-N-(3,5-dinitrobenzoyl)leucine was bonded either ionically or covalently. Enantiomers of all dihydrodiol derivatives were resolved by one or more, but not all, of the chiral stationary phases utilized. Enantiomeric resolutions were substantially improved when the non-K region dihydrodiols were converted to tetrahydrodiols. The absolute configurations of the K region trans- and cis-5,6-dihydrodiols were established by the exciton chirality circular dichroism method. The (R,R):(S,S) enantiomer ratios, determined by CSP-h.p.l.c., of the 1,2-, 3,4- and 5,6-trans-dihydrodiols formed in the metabolism of chrysene by liver microsomes from untreated male rats of the Sprague--Dawley strain were found to be 51:49, 99:1 and 86:14, respectively; from phenobarbital-treated rats, 41:59, 99:1 and 87:13, respectively; from 3-methylcholanthrene-treated rats, 96:4, 99:1 and 92:8, respectively. The absolute configurations of chrysene 5,6-epoxide enantiomers, resolved by CSP-h.p.l.c., were elucidated by the determination of the structures and absolute configurations of their methoxylation products. Both enantiomers of chrysene 5,6-epoxide were hydrated by microsomal epoxide hydrolase to chrysene trans-5,6-dihydrodiol enriched (67-92%) in the 5R,6R enantiomer. Chrysene 5R,6S-epoxide was hydrated to trans-5,6-dihydrodiol at a rate approximately 6-fold faster than chrysene 5S,6R-epoxide.

Direct resolution of enantiomers by liquid chromatography with the novel chiral stationary phase derived from (R,R)-tartramide

The synthesis of the novel chiral stationary phase (CSP) derived from (R,R)-tartramide and direct resolution of a series of β-hydroxycarboxylic acid derivatives on this CSP are described.

Direct enantiomeric resolution of some 7,12-dimethylbenz[a]anthracene derivatives by high-performance liquid chromatography with ionically and covalently bonded chiral stationary phases.

The direct resolution of the enantiomers of trans-3,4-dihydrodiol, trans-5,6-dihydrodiol, cis-5,6-dihydrodiol, trans-8,9-dihydrodiol, and 8,9,10,11-tetrahydro-trans-8,9-diol of 7,12-dimethylbenz(a)anthracene was evaluated by high-performance liquid chromatography using commercially available columns packed with (R)-N-(3,5-dinitrobenzoyl)phenylglycine and (S)-N-(3,5-dinitrobenzoyl)leucine either ionically or covalently bonded to ..gamma..-aminopropylsilanized silica. The enantiomers of all diol derivatives were resolved by one or more, but not all, of the chiral stationary phases tested. Resolution of enantiomers was confirmed by ultraviolet-visible absorption, mass, and circular dichroism spectral analyses.

Direct enantiomeric resolution of mephenytoin and its N-demethylated metabolite in plasma and blood using chiral capillary gas chromatography

A gas chromatographic method was developed for the determination of the R- and S-enantiomers of the anticonvulsant, mephenytoin, and its N-demethylated metabolite, 5-phenyl-5-ethylhydantoin (PEH), in plasma and blood. Direct enantiomeric separation of mephenytoin and its internal standard was obtained using a chiral capillary column (Chirasil-Val®) followed by nitrogen specific detection. However, resolution of the enantiomers of PEH and its internal standard required propylation at the 3-position of the hydantoin ring prior to analysis. Similar linear and reproducible standard curves were obtained from both plasma and blood over the concentration range 50 ng/ml to 5 μg/ml, and above 100 ng/ml the reproducibility was less than 8% (coefficient of variation). Pronounced stereoselective differences in the plasma concentration—time curves for both mephenytoin and PEH were observed in a normal subject who received a single oral dose of 300 mg racemic mephenytoin. The peak plasma level of S-mephenytoin was only one-fifth that of the R-enantiomer and its elimination half-life was less than 3 h compared to over 70 h for R-mephenytoin. Similarly, S-PEH levels were barely detectable whereas concentrations of R-metabolite steadily increased over 4–6 days before slowly declining.

A unique reversal of elution order during direct enantiomeric resolution of amide derivatives of 1‐phenyl‐2‐aminopropane by high performance liquid chromatography on chiral stationary phases

AbstractEnantiomeric amide derivatives of (S)‐ and (R)‐1‐phenyl‐2‐aminopropane (dextro‐ and levoamphetamine, respectively) were resolved by high performance liquid chromatography on commercially available ionically and covalently bonded chiral stationary phases ((R)‐N‐(3,5‐dinitrobenzoyl)phenylglycine). Ten enantiomeric amide pairs were synthesized and chromatographed on the columns by using a mobile phase of hexane‐isopropanol (97 : 3), a flow rate of 2 ml/min, and a column temperature of 20°C. The (R)‐isomer of all 10 amides eluted first on the covalent column as did the (R)‐isomer of nine derivatives on the ionic column. however, the 3,5‐dinitrobenzoyl amide of (S)‐ amphetamine eluted before the (R)‐isomer on the ionic column. This reversal in enantiomeric elution order reveals the complexity of the interactions occurring on these columns and emphasizes the hazards of relying on observed elution order as an a priori indication of absolute configuration.

Application of high-performance liquid chromatographic chiral stationary phases to pharmaceutical analysis structural and conformational effects in the direct enantiomeric resolution of α-methylarylacetic acid antiinflammatory agents

A series of four α-methylarylacetic acids of pharmaceutical interest were directly resolved as enantiomeric amide derivatives on a high-performance liquid chromatographic chiral stationary phase consisting of covalently bound ( R)-N-(3,5-dinitrobenzoyl)phenylglycine. Enantiomers of ibuprofen, naproxen fenoprofen and benoxaprofen all exhibited optimum separation (α = 1.12, 1.23, 1.12 and 1.10, respectively) as 1-naphthalenemethylamides. Derivatives of ibuprofen were studied in detail; measurable separations were observed for secondary and tertiary amides of diverse structural types, but not for the primary amide or for ester derivatives. The results, which are consistent with an interaction model involving stacking of amide dipoles, with or without supplementary π—π and hydrogen-bonding effects, appear to be strongly dependent on conformational requirements of both the solute and the chiral stationary phase.

Direct enantiomeric resolution of cyclic alcohol derivatives of polycyclic aromatic hydrocarbons by chiral stationary phase high-performance liquid chromatography

The enantiomers of some cyclic alcohol derivatives of phenanthrene, benz-[ a]anthracene, benzo[ a]pyrene, cholanthrene, and 3-methylcholanthrene were resolved by high-performance liquid chromatography using a commercially available preparative column packed with an ( R)-N-(3,5-dinitrobenzoyl)phenylglycine ionically bonded to γ-aminopropylsilanized silica. Resolution of enantiomers was confirmed by ultraviolet—visible absorption, mass and circular dichroism spectral analyses. This method has been applied to the determination of optical purity of 1-hydroxycholanthrene and 1-hydroxy-3-methylcholanthrene formed in the metabolism of cholanthrene and 3-methylcholanthrene, respectively, by rat liver microsomes.

Application of high-performance liquid chromatographic chiral stationary phases to pharmaceutical analysis : Direct enantiomeric resolution of amide derivatives of 1-phenyl-2-aminopropane

A series of amide derivatives of the enantiomers of 1-phenyl-2-aminopropane (amphetamine) were resolved by high-performance liquid chromatography on a chiral stationary phase (CSP), ( R)-N-(3,5-dinitrobenzoyl)phenylglycine, which is commercially available in ionically and covalently bonded columns. The separation factor ranged from 1.01 to 1.09 and was consistently larger when the compounds were chromatographed on the covalent column. Chromatographic parameters correlate in detail with a solute-CSP interaction model requiring up to four binding sites and a fifth repulsive interaction which is steric in origin and which provides the key chiral discriminant.

Direct resolution of enantiomers by liquid affinity chromatography on albumin-agarose under isocratic conditions

Direct resolution of enantiomers by liquid affinity chromatography on albumin-agarose under isocratic conditions