bluuebunny/crossref_metadata_2025 huggingface dataset:
HPLC resolution of atropoisomeric compounds on a csp derived from (1R;2R)‐diaminocyclohexane: Thermodynamic data from variable temperature chromatography
Authors: Galli B. , Gasparrini F. , Misiti D. , Pierini M. , Villani C. , Bronzetti M.
Published: January 2005

The preparation and a preliminary chromatographic evaluation of a novel polymeric chiral stationary phase (CSP) derived from (1R;2R)‐diaminocyclohexane (DACH) are presented. A radical copolymerization process has been employed to generate a silica‐based chiral sorbent, showing considerable high chemical and thermal stability and stereoselectivity toward racemic compounds capable of H‐bonding (3‐hydroxy‐benzodiazepin‐2‐ones, chlorthalidone, atropoisomeric sulfur compounds, etc.); in the present paper we present the investigation on the resolution of racemic dihydroxy biarylic atropoisomers; the effects of eluent composition and of temperature on the separation ability of the CSP have been studied in order to elucidate the recognition mechanism operating in these chiral separations. © 1992 Wiley‐Liss, Inc.
Chromatographic optical resolution on trans‐1,2‐diaminocyclohexane derivatives: Theory and applications
Authors: Gasparrini F. , Misiti D. , Villani C.
Published: January 2005

An overall view on some new chiral stationary phases based on (trans)‐1,2‐diaminocyclohexane is illustrated. The selected chiral moiety, derivatized with different aroyl groups, has been linked to a silica matrix in order to give chiral stationary phases (CSPs) enabling them to be used efficiently in the normal and reverse phase, both for analytical and preparative purposes. In addition new polymeric CSPs have been prepared by using the same selector, suitably modified, as monomer. The new chiral stationary phases have been characterised by physicochemical methods and used for the resolution of various racemic compounds classes such as α‐aryloxyacetic acids, alcohols, sulfoxides, selenoxides, phosphinates, tertiaryphosphine oxides, benzodiazepines etc. without prederivatization or as amines, amino acids, amino alcohols, nonsteroidal antiinflammatory agents in a derivatized form. The separated solutes structural variety suggests that multiple interaction sites are involved in the recognition process: some thermodynamic data relative to the CSPs—selectands interactions are also illustrated. © 1992 Wiley‐Liss, Inc.
Use of cellulose‐based stationary phases for chiral separation in open tubular column chromatography
Authors: Juvancz Z. , Grolimund K. , Francotte E.
Published: January 2005

Application of cellulose‐based chiral stationary phases was extended to open tubular columns. These chiral materials were mixed with achiral matrix stationary phases. Compromises were found among the polarity and the ratio of achiral matrix polymers against the content of the chiral cellulose derivative in order to optimize the resolution of the investigated racemates. In GC, the high efficiency feature of open tubular columns allows fast analysis, however, compounds which express strong H‐bond interaction with cellulose derivatives elute with a bad peak shape. The application of these stationary phases for open tubular SFC was more successful, because the solvation power of the mobile phase can compensate the strong interaction between the solute and the cellulose derivative. Immobilization of the stationary phases were achieved for SFC purposes. © 1992 Wiley‐Liss, Inc.
Stereoselective features of (R)‐ and (S)‐atenolol: Clinical pharmacological, pharmacokinetic, and radioligand binding studies
Authors: Stoschitzky Kurt , Egginger Gabriele , Zernig Gerald , Klein Werner , Lindner Wolfgang
Published: January 2005

In a randomized, double‐blind, cross‐over study in 12 healthy volunteers, the effects of single oral doses of 100 mg rac‐atenolol were compared during exercise to those of equal amounts of the optically pure enantiomers, i.e., 50 mg (R)‐ and 50 mg (S)‐atenolol. The mean rate pressure product decreased with rac‐atenolol (−37%; P < 0.01) and half‐dosed (S)‐atenolol (−35%; P < 0.01) to the same extent, whereas (R)‐atenolol caused no effect. Radioligand binding studies in beta‐adrenergic receptors of the guinea pig heart yielded a eudismic ratio of 46 for (S)‐ to (R)‐atenolol. The mean AUCs, maximal plasma concentrations, and plasma half‐lives of the enantiomers were similar regardless of whether they were administered as optically pure enantiomers or as racemic mixture. On the other hand, the AUC of (R)‐atenolol was 1.08‐fold greater (P < 0.01) than that of the (S)‐enantiomer. The reason for this finding remains unclear. We conclude that only (S)‐atenolol, but not (R)‐atenolol, contributes to the beta‐blocking effect of currently used rac‐atenolol since the same effect can be elicited with the (S)‐enantiomer alone. © 1993 Wiley‐Liss, Inc.
Stereoselective hydrolysis of triglycerides by animal and microbial lipases
Authors: Rogalska Ewa , Cudrey Claire , Ferrato Francine , Verger Robert
Published: January 2005

In the present paper, a study on the stereoselectivity of 25 lipases of animal and microbial origin towards homogeneous prochiral triglycerides is presented. All the lipases tested catalyse the hydrolysis of the chemically alike but sterically nonequivalent ester groups in trioctanoin and triolein with different degrees of stereobias, depending on the fatty acyl chain length of the substrate (Rogalska et al., J. Biol. Chem. 256:20271–20276, 1990). Hydrolysis of the sn‐2 ester group is catalysed by very few lipases and only Candida antarctica A shows a clear preference for this position. Most of the lipases investigated (12 with trioctanoin and 16 with triolein) showed a preference for the sn‐1 position. Using trioctanoin as substrate we observed a total stereoselectivity for position sn‐1 with Pseudomonas sp. and Pseudomonas aeruginosa and for position sn‐3 with Candida antarctica B. This was not the case with triolein as substrate. Among the 23 lipases studied here and the other two lipases described previously (Rogalska et al., J. Biol. Chem. 256:20271–20276, 1990), 17 show a higher stereoselectivity with trioctanoin than with triolein. With guinea pig pancreatic lipase and with three mold lipases (Geotrichum candidum M, Geotrichum candidum A, and Candida antarctica B), the preference switches from sn‐3 to sn‐1 when the acyl chain length increases from eight to 18 carbon atoms. The main conclusion to emerge from the present study is that the specific stereopreference of each lipase for a given substrate under given lipolytic conditions can be said to be its fingerprint. © 1993 Wiley‐Liss, Inc.
Stereoselective analysis of ketorolac in human plasma by high‐performance liquid chromatography
Authors: Hayball Peter J. , Tamblyn Julie G. , Holden Yvonne , Wrobel Jan
Published: January 2005

A high‐performance liquid chromatographic (HPLC) analytical method is described for the quantification of the (R)‐ and (S)‐enantiomers of ketorolac when present together in human plasma. The method involves derivatization with thionyl chloride/(S)‐1‐phenylethylamine and subsequent reversed‐phase chromatography of the diastereomeric (S)‐1‐phenylethylamides of (R)‐ and (S)‐ketorolac. The method is suitable for the analysis of large numbers of plasma samples and has been applied in this report to a pharmacokinetic study of ketorolac enantiomers upon intramuscular administration of racemic drug to a human subject. The limit of quantification for each enantiomer of ketorolac is 50 ng/ml (signal‐to‐noise ratio > 10). © 1993 Wiley‐Liss, Inc.
Asymmetric transformation of a racemic α‐(phthalimidooxy)arylacetic ester by a combination of preferential crystallization and simultaneous racemization
Authors: Murakami Kimihiro , Ohashi Masayuki , Matsunaga Atsuo , Yamamoto Ichiro , Nohira Hiroyuki
Published: January 2005

An asymmetric transformation of racemic t‐butyl 2‐(3,4‐O‐carbonyldioxy‐phenyl)‐2‐(phthalimidooxy)acetate [(RS)‐2b] into one of its optically active forms was carried out by a combination of preferential crystallization of a desired enantiomer and the simultaneous racemization of the antipode. (R)‐2b was easily racemized in diethylketone in the presence of a small amount of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). Under the conditions for racemization, the asymmetric transformation was achieved successfully to give (S)‐2b with 84% optical purity in 80% yield. A potent antipseudomonal cephalosporin M‐14659 (1) was prepared from the pure (S)‐2b which was obtained by the recrystallization of the crude (S)‐2b. © 1993 Wiley‐Liss, Inc.
Theoretical study of enantiodifferentiation in solid state cyclodextrins
Authors: Lipkowitz Kenny B. , Green Karen M. , Yang Jia‐An , Pearl Greg , Peterson Michael A.
Published: January 2005

A molecular mechanics investigation of R‐ vs. S‐phenylethanol, R‐ vs. S‐mandelic acid, R‐ vs. S‐flurbiprofen, and R‐ vs. S‐fenoprofen in their cyclodextrin crystal environments was undertaken. It was found that the dominant force responsible for guesthost complexation is the short‐range London force; the enantiodiscriminating forces tend to be very small and are generally, but not always, dominated by long‐range electrostatic contributions. Derivatized cyclodextrins are generally more enantiodiscriminating than native cyclodextrins, perhaps due to exterior rather than interior guest‐host binding. © 1993 Wiley‐Liss, Inc.
Racemization and hydrolysis of tropic acid alkaloids in the presence of cyclodextrins
Authors: Blaschke Gottfried , Lamparter Erich , Schlüter Jürgen
Published: January 2005

Because of the constantly increasing demand for optically pure drugs it is of great importance to elucidate factors affecting stereochemistry, in order to provide a stable formulation with a high chiral quality of the desired isomer. Therefore, the effects of cyclodextrins (CyDs) and their alkylated and hydroxyalkylated derivatives on racemization and hydrolysis of (−)‐(S)‐hyoscyamine and (−)‐(S)‐scopolamine were examined kinetically and spectroscopically (NMR). Direct methods, based on a chiral and achiral chromatographic phase system, were used to determine their degradation products and enantiomer composition during stability tests. All different CyDs, except α‐CyD, retarded racemization and hydrolysis. The inclusion of the drug substances in CyDs inhibits the attack of hydroxyl ions and/or water molecules and thus retards the racemization and hydrolysis. The racemization of the tropic acid alkaloids is dependent on the pH and temperature. NMR studies were used to evidence the formation of a soluble 1:1 complex in aqueous solution. © 1993 Wiley‐Liss, Inc.
Direct separation of cone‐shaped tri‐O‐alkylated chiral calix[4]arenes by enantioselective HPLC
Authors: Caccamese Salvatore , Pappalardo Sebastiano
Published: January 2005

The direct HPLC separation of eight inherently chiral atropisomeric calix[4]arenes has been achieved using Chiralcel OD phase. A rationale is given for the variation of the enantioselectivity as a function of the O‐alkyl or O‐aryl groups. In closely related structures hydrogen bond formation between the free hydroxyl of the analyte and the chiral phase plays an important role in the chiral recognition process. © 1993 Wiley‐Liss, Inc.
Chiral resolution of some antimalarial agents by sub‐ and supercritical fluid chromatography on an (S)‐naphthylurea stationary phase
Authors: Peytavin Gilles , Gimenez Françlois , Genissel Brigitte , Gillotin Catherine , Baillet Arlette , Wainer Irving W. , Farinotti Robert
Published: January 2005

The behavior of mefloquine, halofantrine, enpiroline, quinine, quinidine, chloroquine and primaquine is studied by subcritical fluid chromatography on a (S)‐naphthylurea column (250 mm × 4.6 mm ID) with a subcritical mobile phase composed of carbon dioxide, methanol and triethylamine (flow rate of 3 ml/min). Except for primaquine and chloroquine, each enantiomer was separated at a temperature between 40 and 60°C, and at a pressure below 15 MPa. A 98/2, v/v CO2/methanol 0.1% triethylamine mixture allowed the separation of halofantrine enantiomers while the enantiomers of the more polar metabolite (N‐desbutylhalofantrine) were separated with a 80–20 v/v mixture as used for mefloquine, enpiroline, quinine and quinidine. The influence of temperature, pressure and of the nature of the mobile phase is discussed. © 1993 Wiley‐Liss, Inc.
Determination of the enantiomeric purity of 5,6‐ and 6,7‐dihydroxy‐2‐aminotetralins by chiral HPLC
Authors: Castelnovo Pierfrancesco
Published: January 2005

5,6‐ and 6,7‐Dihydroxy‐2‐aminotetralin (ADTN), racemic dopamine receptor agonists, were resolved into their enantiomers by a new chiral HPLC assay. The separation was performed on a Crownpack CR column, which contains an 18‐crown‐6‐type chiral crown ether as a chiral selector. The chiral recognition is based on the compiexation of the protonated primary amino group and the oxygen atoms inside the cavity of the crown ether. The amino group is attached to the chiral centre and therefore these compounds could be resolved. Mobile phase was perchloric acid pH 2.0 and the detection was UV at 200 nm. Resolution factors were 3.1 for 5,6‐ADTN and 1.1 for 6,7‐ADTN resulting in very low limits of quantitation (<0.1%) of the enantiomer present as impurity. Data on the validation of the assay and on the stability of the column are also reported. © 1993 Wiley‐Liss, Inc.
Direct resolution of enantiomers of basic imidazol‐2‐yl‐substituted alcohols by gas chromatography on chirasil‐val
Authors: Briody John M. , Keenan David , Nicholson Graeme J. , Koppenhoefer Bernhard
Published: January 2005

The direct resolution of enantiomers of a series of imidazol‐2‐yl‐substituted alcohols has been achieved by gas chromatography on a well‐deactivated fused‐silica capillary column, coated with L‐Chirasil‐Val as the chiral stationary phase. The separation of these basic compounds is accomplished without exaggerated peak tailing. Compared to simpler alcohols the resolution factors (α) observed are extraordinarily large. While the imidazolyl substituent may contribute to the mechanism of the chiral discrimination, the crucial interaction is assumed to be through the hydroxy group, based on the observation that the resolution factors for the corresponding O‐acetyl derivatives are markedly reduced. © 1993 Wiley‐Liss, Inc.
High‐Performance liquid chromatography (HPLC) chiral separations of guaifenesin, methocarbamol, and racemorphan
Authors: Demian Iulia
Published: January 2005

HPLC chiral separations on silica gel coated with derivatized cellulose stationary phases are described. Most examples make use of the Chiralcel OD column from Daicel, Inc. With a judiciously chosen mobile phase, baseline separations of the enantiomers can be achieved. If those separations are used as a base for enantiomeric purity determination, detectable limits of 0.1% of the minor enantiomer are routinely accessible. Examples are given concerning separations of guaifenesin, methocarbamol, and racemorphan. © 1993 Wiley‐Liss, Inc.
Helical stereochemistry and chiral apple halves. 2. La coupe du roi via double helical complexation using oligo(bipyridine) strands and Cu(I)/Ag(I)
Authors: Glaser Robert
Published: January 2005

Oligo(bipyridine) strands and Cu(I)/Ag(I) form duplexes having a 21‐screw coincidental with a C2‐axis. A segment containing a complete turn of the duplex can be considered to be a coupe du roi ensemble of two homochiral strands. Moreover, for D2d symmetry monocationic Cu(I) complexes of bipyridine trimers and pentamers, addition of the requisite Cu(I) cations is a true chemical example of la coupe du roi. In this reaction, an achiral monocationic complex is converted into a multiple‐cationic duplex of two homochiral and homotopic 21‐helical halves. The chirality of the resulting duplex is a function of the particular set of bipyridine enantiotopic faces which are used for binding the additional cations. © 1993 Wiley‐Liss, Inc.
Feasibility of chiral discrimination using X‐ray anomalous scattering
Authors: Grochowski Jacek , Serda Pawel
Published: January 2005

The paper discusses several feasibility prediction criteria with particular emphasis on light atom molecules. For several examples of refined absolute structures, feasibility predictions are calculated and compared with a posteriori calculated values of the Bijvoet ratio. An extension of the Pathasarathy table of the expected value of the Bijvoet ratio is given for parameter ranges corresponding to light anomalous scatters. Practical conclusions are drawn for absolute structure determination of compounds containing oxygen or nitrogen as anomalous scatterers. © 1993 Wiley‐Liss, Inc.
Stereoselectivity in β‐cyclodextrin complexation of 1,4‐dihydropyridine derivatives
Authors: Ferčej‐Temeljotov Darja , Kmet Matevž , Kocjan Darko , Kotnik Sonja , Resman Aleksander , Urleb Uroš , Verhnjak Katarina , Zver Igor , Žmitek Janko
Published: January 2005

Structure–interaction relationships, stereoselectivity, and solubility enhancement in inclusion compexation of β‐cyclodextrins (CDs) with some racemic and enantiomerically pure 1,4‐dihydropyridine derivatives (DHPs) were investigated. 1:1 and 1:2 (mole ratio) complexes were prepared and characterized by X‐ray powder diffraction, differential scanning calorimetry (DSC), MS‐FAB spectrometry,1H‐NMR spectroscopy, water and phase solubility. The solubility studies have revealed different complexation equilibria for optically pure DHP enantiomers, and corresponding racemic mixtures in water solutions. By means of1H‐NMR chemical shift measurements, the inclusion of aromatic fragments of racemic and enantiomerically pure DHP molecules within the cavities of different CDs was elucidated. Considerable stereoselectivity in complexation interactions was observed. The results indicate the potential use of cyclodextrins as chiral selectors for enantiomeric resolution of 1,4‐DHP calcium antagonists. © 1993 Wiley‐Liss, Inc.
Development of the enzyme‐catalysed Baeyer–Villiger reaction as a useful technique in organic synthesis
Authors: Roberts Stanley M. , Willetts Andrew J.
Published: January 2005

The current practices of using monooxygenase enzymes to perform regio‐ and stereoselective oxidation reactions in organic syntheses are reviewed. The isolation of a monooxygenase from Pseudomonas putida NCIMB 10007 and its use in the conversion of bicyclo[3.2.0]hept‐2‐en‐6‐one into two isomeric optically active lactones is described. The monooxygenase utilises NADH as cofactor and NADH‐recycling is accomplished using formate and formate dehydrogenase. As alternative methodology, it is shown that a secondary alcohol can be converted into a chiral lactone using a dehydrogenase and a monooxygenase working in tandem with in situ cofactor recycling. © 1993 Wiley‐Liss, Inc.
Chirality of azelastine and flezelastine: Investigation of their enantiomers
Authors: Fleischhauer Ilona , Kutscher Bernhard , Engel Jürgen , Achterrath‐Tuckermann Ute , Borbe Harald O. , Schmidt Jürgen , Szelenyi Istvan , Camuglia Giancarlo
Published: January 2005

The racemic phthalazinone derivatives azelastine and flezelastine were resolved via formation of diastereomeric salts and fractional crystallization thereof. The optical purity of the enantiomers was checked by HPLC. Pharmacological investigations in vitro and in vivo related to antiallergic/antiasthmatic activity revealed some stereospecific differences. However, chiral discrimination could not be observed with regard to overall activity of azelastine and flezelastine. © 1993 Wiley‐Liss, Inc.
Pharmacokinetics of the enantiomers of verapamil in the dog
Authors: Bai Stephen A. , Lankford Susan M. , Johnson Lynetta M.
Published: January 2005

The intravenous (0.5 mg/kg) and oral (5 mg/kg) dose kinetics of verapamil were studied in 6 dogs during steady‐state oral verapamil dosing (5 mg/kg every 8 h for 3 days). Racemic verapamil and norverapamil, a metabolite of verapamil, were quantitated in plasma by HPLC‐fluorescence detection. The verapamil peaks eluting off the column were collected and rechromatographed on an Ultron‐OVM column, which resolved the two verapamil enantiomers. After intravenous administration, the systemic clearance and apparent volume of distribution of (−)‐(S)‐verapamil were nearly twice that of the (+)‐(R)‐isomer. There was no difference in the elimination half‐lives between the two isomers. After oral administration, the oral clearance of (−)‐(S)‐verapamil was 20 times that of the (+)‐(R)‐isomer. The apparent bioavailability of (+)‐(R)‐verapamil was over 14 times that of (−)‐(S)‐verapamil. The plasma protein binding of the (+)‐(R)‐isomer was slightly higher by 5% than (−)‐(S)‐verapamil; however, this effect was not enough to account for the difference between the apparent volume of distribution of the enantiomers, indicating that the tissue binding of (−)‐(S)‐verapamil was greater than that of the (+)‐(R)‐isomer. This data on the disposition of the enantiomers of verapamil in the dog is similar to that reported for man and demonstrates that the dog may be an appropriate animal model for man in future studies on the disposition of the enantiomers of verapamil. © 1993 Wiley‐Liss, Inc.
Enantiomeric resolution of sulfoxides on a DACH‐DNB chiral stationary phase: A quantitative structure–enantioselective retention relationship (QSERR) study
Authors: Altomare Cosimo , Carotti Angelo , Cellamare Saverio , Fanelli Francesca , Gasparrini Francesco , Villani Claudio , Carrupt Pierre‐Alain , Testa Bernard
Published: January 2005

The interaction mechanism of a variety of racemic alkyl aryl sulfoxides with a π‐acid HPLC stationary phase containing N,N′‐(3,5‐dinitrobenzoyl)‐trans‐1,2‐diaminocyclohexane chiral selector was investigated by means of quantum‐chemical calculations (MNDO), partial least squares (PLS) analysis, and 3D comparative molecular field analysis (CoMFA). Quantitative structure–enantioselective retention relationships (QSERR), were derived which have yielded significant insights into physicochemical properties primarily responsible for chiral recognition. The increase in retention (k′) is favored especially by the analyte π‐basic character, accounted for by the sum of the electrophilic superdelocalizabilities of all aromatic carbon atoms (SPhHOMO), and to minor extent by the H‐bond basicity of the sulfoxide oxygen and the hydrophilicity of solutes. In contrast, the separation factor (α) varied mainly with the steric properties of the substituents and with polar and electrostatic properties of the sulfoxide group. A 3D‐QSERR analysis using CoMFA methodology has provided a more complete description of factors responsible for chiral recognition and has proven to be a useful tool to examine differences in noncovalent fields (both the electrostatic and the steric) mostly associated with variations of enantioselectivity. © 1993 Wiley‐Liss, Inc.
Comparison between cellulose and amylose tris(3,5‐dimethylphenylcarbamate) chiral stationary phases for enantiomeric separation of 17 amidotetralins
Authors: Witte Dirk T. , Bruggeman Frank J. , Franke Jan Piet , Copinga Swier , Jansen Johanna M. , De Zeeuw Rokus A.
Published: January 2005

Direct enantiomeric separations of 17 chiral amidotetralins by means of high performance liquid chromatography were performed on stationary phases composed of tris(3,5‐dimethylphenylcarbamate) derivatives of cellulose and amylose, coated on silica gel. The enantiomers of 15 out of 17 amidotetralins were resolved with a resolution of more than 1.5 by at least one of the chiral stationary phases. The stationary phases showed complementary results with regard to the separation of the amidotetralins, that is, pairs that did not separate on the cellulose‐type column were well separated on the amylose‐type column, and vice versa. There was no significant correlation between the chromatographic properties of the chiral stationary phases. © 1993 Wiley‐Liss, Inc.
Enantiomeric conformers of the opioid agonist ketobemidone HCl in the crystal state
Authors: Froimowitz Mark , Cody Vivian
Published: January 2005

A crystal of the potent opioid agonist ketobemidone [1‐methyl‐4‐(3‐hydroxyphenyl)‐4‐propionylpiperidine] HCl was analyzed by X‐ray crystallography. The crystal was monoclinic, space group P21/n with four molecules in the unit cell. In agreement with MM2 calculations (J. Med. Chem. 25:1127–1133, 1982), the crystal contains mirror image conformers in which the phenyl ring is equatorial to the piperidine ring. The conformers are enantiomers since they are not superimposable. One conformer is predicted to be responsible for the typical morphine‐like activity of the compound since it closely matches the preferred conformer of the morphine‐like (+)‐phenylmorphan whereas the other conformer resembles the preferred conformers of (+)‐β‐prodine and (−)‐phenylmorphan which have atypical opioid properties and/or structure–activity relationships. The importance of considering the conformational enantiomers of a nonchiral receptor ligand in centrosymmetric crystal structures is emphasized. © 1993 Wiley‐Liss, Inc.
Resolution of enantiomers by HPLC on tris(4‐alkoxyphenylcarbamate)s of cellulose and amylose
Authors: Okamoto Yoshio , Ohashi Toshiaki , Kaida Yuriko , Yashima Eiji
Published: January 2005

Ten phenylcarbamate derivatives of cellulose and amylose having alkoxy groups such as ethoxy, isopropoxy, and isobutoxy at 4‐position, and methyl groups at 3‐ and 5‐positions and methoxy group at 4‐position were synthesized and their chiral recognition abilities as stationary phases for high‐performance liquid chromatography were investigated and compared to those with tris(4‐methoxyphenylcarbamate)s of cellulose and amylose. In 4‐alkoxy derivatives of cellulose, chiral recognition ability increased as the bulkiness of 4‐alkoxy groups increased. 4‐Isopropoxy and 4‐isobutoxy derivatives showed high chiral recognition. On the other hand, chiral discrimination of amylose 4‐alkoxy derivatives scarcely depended on the bulkiness of the alkoxy group, and 4‐methoxy and 4‐isopropoxy derivatives showed high chiral recognition. 3,5‐Dimethyl‐4‐methoxyphenylcarbamates of cellulose and amylose possessed higher chiral recognition ability than the corresponding 4‐methoxy derivatives. © 1993 Wiley‐Liss, Inc.
Enantiomeric LC separation of calcium antagonists on protein‐based chiral stationary phases
Authors: De Lorenzi Ersilia , Fell Anthony F. , Holmes Alan L. , Caccialanza Gabriele , Massolini Gabriella , Gandini Carlo , Kitsos Mikes , Ponci Carolina
Published: January 2005

Three chiral calcium antagonist drugs, bepridil and two dihydropyridine derivatives (nicardipine and REC 15/2375), have been successfully separated within short retention times using either the α1‐acid glycoprotein chiral stationary phase (Chiral AGP) or the ovomucoid column (Ultron ES‐OVM). Aqueous buffer at defined pH is modified by the addition of an organic component (propan‐2‐ol, acetonitrile, ethanol) in order to modulate the retention properties of each system. The influence of pH and percentage of organic modifier on retention, selectivity, resolution, and column performance are discussed for bepridil analyzed on Chiral AGP and for the two dihydropyridines (nicardipine and REC 15/2375) analyzed on Ultron ES‐OVM stationary phases. © 1993 Wiley‐Liss, Inc.
Comparison of the potencies of (+)‐ and (−)‐2‐ethylhexanoic acid in causing peroxisome proliferation and related biological effects in mouse liver
Authors: Sundberg Carola , Wachtmeister Carl‐Axel , Lundgren Bo , DePierre Joseph W.
Published: January 2005

Male C57BL/6 mice were exposed to 1% (w/w) (+)‐ or (−)‐2‐ethylhexanoic acid or an equimolar mixture of these enantiomers in their diet for 4 or 10 days. A significant increase in liver weight and a 2‐ to 3‐fold increase in the protein content of the mitochondrial fraction were seen in all cases. Peroxisomal palmitoyl‐CoA oxidation was increased 2‐ to 3.5‐fold after 4 days of treatment and 4‐ to 5‐fold after 10 days, while the corresponding increases in peroxisomal lauroyl‐CoA oxidase activity were 2‐ to 3‐fold and 9‐ to 12‐fold, respectively. Peroxisomal catalase activity was unchanged, whereas the microsomal and cytosolic activities were increased 2‐ to 3‐fold and 6‐ to 16‐fold, respectively. These treatments also induced microsomal ω‐hydroxylation of lauric acid 7‐fold and soluble epoxide hydrolase activity in the mitochondrial and cytosolic fractions, as well as microsomal epoxide hydrolase activity about 50–100%. The only significant differences observed between the effects of (+)‐2‐ethylhexanoic acid and its (−)‐enantiomer were on peroxisomal palmitoyl‐CoA oxidation and lauroyl‐CoA oxidase activity after 4 days of treatment. In both these cases the (+)‐enantiomer resulted in increases which were 50–75% greater than those seen with the (−)‐form. © 1994 Wiley‐Liss, Inc.
(Z)‐1,1‐dichloro‐2‐(4‐benzyloxyphenyl)‐2,3‐bis(4‐methoxyphenyl)cyclopropane: The synthesis and enantiomeric separation of an antitumor agent
Authors: Meyer Karen L. , Magarian Robert A.
Published: January 2005

(Z)‐1,1‐Dichloro‐2‐(4‐benzyloxyphenyl)‐2,3‐bis(4‐methoxyphenyl)cyclopropane (5), a potential antitumor agent designed to treat breast cancer, was prepared in three steps. A stereospecific palladium‐catalyzed cross coupling reaction which provided the intermediate (Z)‐triaryl alkene 4 was a crucial step in the synthesis. Makosza phase transfer reaction on 4 gave the enantiomeric (Z)‐dichlorocyclopropane derivatives 5 which were resolved by semipreparative HPLC on a chiral stationary phase consisting of amylose tris‐3,5‐dimethylphenyl carbamate coated on silica gel. © 1994 Wiley‐Liss, Inc.
Species variability in the stereoselective N‐oxidation of pargyline
Authors: Hadley Mark R. , Švajdlenka Emil , Damani Lyaquatali A. , Oldham Harriet G. , Tribe Jeanette , Camilleri Patrick , Hutt Andrew J.
Published: January 2005

The monoamine oxidase inhibitor pargyline (N‐benzyl‐N‐methyl‐2‐propynylamine) is known to undergo extensive in vitro microsomal N‐oxidation, thought to be mediated predominantly by the flavin‐containing monooxygenase (FMO) enzyme system. Formation of the pargyline N‐oxide (PNO) metabolite creates a chiral nitrogen centre and thus asymmetric oxidation is possible. This study describes a reverse‐phase high‐performance liquid chromatographic (HPLC) method for the quantitation of PNO and a chiral‐phase HPLC method for the determination of the enantiomeric ratio of PNO. In vitro microsomal N‐oxidation of pargyline was found to be highly steroselective in a number of species, with the (+)‐enantiomer being formed preferentially. This metabolic transformation was stereospecific when purified porcine hepatic FMO was used as the enzyme source. © 1994 Wiley‐Liss, Inc.
Chiral assay methods for lifibrol and metabolites in plasma and the observation of unidirectional chiral inversion following administration of the enantiomers to dogs
Authors: Walters Rodney R. , Hsu Chang‐Yuan L.
Published: January 2005

Lifibrol, a new drug for the treatment of hypercholesterolemia, contains a stereogenic center bearing a secondary alcohol group. A normal‐phase achiral–chiral HPLC separation of the enantiomers of lifibrol and two of its metabolites was developed and validated for quantitation in dog plasma. A silica and a Chiralcel OD‐H column were operated in series and all six enantiomeric components and internal standard were directly separated. An initial solid‐phase extraction (phenyl) clean‐up step and a column‐switching step to eliminate late‐eluting compounds were also utilized. The solid‐phase extraction step was automated using a robotic system. Assay development, validation, and application of the method to a bioavailability study of the racemate and enantiomers of lifibrol in dogs are described. The lower limit of quantitation was 0.0125 μg/ml for each enantiomer of lifibrol using 200 μl of dog plasma with UV detection (255 nm). In dog plasma following oral or intravenous administration of the racemate, the (R)/(S) ratio of the enantiomers of lifibrol was greater than one and increased with time. Following administration of the individual enantiomers, chiral inversion of the (S)‐enantiomer but not the (R)‐enantiomer was observed. © 1994 Wiley‐Liss, Inc.
Input rate‐dependent stereoselective pharmacokinetics: Effect of pulsatile oral input
Authors: Mehvar Reza
Published: January 2005

Computer simulation was used to test the effects of pulsatile oral input on the stereoselectivity in the area under the blood concentration–time curves (AUCs) of the enantiomers of racemic drugs. The effects of input rate determinants, namely, dose, dosage interval, and formulation on the stereoselectivity were investigated under both steady‐state and nonsteady‐state conditions. Simulations were carried out for drugs undergoing Michaelis–Menten hepatic metabolism with different enantiomeric maximum velocity (Vmax) or constant (Km) values. With pulsatile input, the enantiomeric AUC ratios of both types of drugs were dependent on all the determinants of input rate. However, in most cases, the direction of input rate‐dependent changes in the enantiomeric AUC ratios for drugs with different enantiomeric Vmax was opposite of that for drugs with different enantiomeric Km. The direction and magnitude of changes in the enantiomeric AUC ratios were also dependent on the selected dose, dosage interval, and formulation. Further, different conclusions could be reached based on the nonsteady‐state and steady‐state data. Additional simulations were then performed to test the effects of input rate‐dependent stereoselective pharmacokinetics on the bioequivalence of chiral drugs with nonlinear metabolism. These simulations suggested that bioequivalence studies based on the racemic drug measurement may result in erroneous conclusions for the individual enantiomers. The results of this study may be used as a tool for the design of experiments to test the input rate dependence of stereoselective pharmacokinetics and bioequivalence of racemic drugs in animals and humans. © 1994 Wiley‐Liss, Inc.
(R,R)‐N,N′‐Dimethylcyclohexyl‐1,2‐diazaseleno‐phospholidine as a chiral derivatizing agent for the evaluation of chiral alcohols
Authors: House Karen L. , O'Connor Megan J. , Silks Louis A. , Dunlap R. Bruce , Odom Jerome D.
Published: January 2005

Previously, a diazaphospholidine has been synthesized and evaluated as a chiral derivatizing reagent for the determination of the optical purity of chiral alcohols via 31P NMR spectroscopy (Alexakis et al., J. Org. Chem. 57:1224–1237, 1992). Our laboratory is interested in the advantageous and practical applications of 77Se NMR spectroscopic studies in many facets of chemistry and biochemistry. To this end we have used this diazaphospholidine as a starting point and have investigated chiral alcohols coupled to an optically pure diazaselenophospholidine. The diastereomers formed were then evaluated by 77Se NMR spectroscopy, and these results were compared to the 31P NMR results published by Alexakis and co‐workers. It was found that addition of the Se atom produced diastereomers that were air stable and, in many cases, the individual diastereomers could be distinguished by 77Se NMR spectroscopy. Preliminary results indicate that the 77Se nucleus is somewhat more sensitive to remotely disposed chiral centers than is the 31P nucleus. Furthermore, because of their stability, these compounds do not readily decompose and can, therefore, be studied by a variety of chromatographic and spectroscopic techniques. © 1994 Wiley‐Liss, Inc.
π‐Facial hydrogen bonding in the chiral resolving agent 2,2,2‐trifluoro‐1‐(9‐anthryl)‐ethanol and its racemic modification
Authors: Webb Michael L. , Rzepa Henry S.
Published: January 2005

2,2,2‐Trifluoro‐(9‐anthryl)‐ethanol (TFAE) has been extensively used, in its pure enantiomeric forms, as a chiral solvating agent in nuclear magnetic resonance spectroscopy (NMR). It has also played an important role in the development of chiral stationary phases in liquid chromatography (LC). X‐ray crystallography of the enantiomeric and racemic crystals shows, in both cases, the formation of an intermolecular hydrogen bond between the OH and the π‐face of one of the rings of the anthracene aromatic system.1 Few examples of such hydrogen bonding have been published previously, and those that have are not as clear cut as in this case. An explanation for the hydrogen bonding is sought using molecular modelling via the PM3 analytically derived molecular electrostatic potentials. Using NMR and dynamic lineshape analysis, the barrier to rotation about the aryl‐carbon bond is estimated, indicating the CCF3 bond to be perpendicular to the anthracene axis in nonpolar solution. This conformation is identical to the conformation in the crystal. Evidence is also presented to support the formation of intermolecular π‐facial hydrogen bonding in TFAE solutions. It is thought that such hydrogen bonding may be implicated in chiral recognition using this compound. © 1994 Wiley‐Liss, Inc.
Effects of alkyl substituents on chiral separation of N‐arylthiazolin‐2‐(thi)‐one atropisomers on tris (p‐methylbenzoyl)cellulose beads and cellulose triacetate: Lipophilicity aspects
Authors: Roussel Christian , Popescu Cristina
Published: January 2005

The determination of lipophilicity of the title compounds allowed treatment of the data for chiral separation (capacity factors) on CTA and CTPB according to these parameters. A linear correlation between In k′(+) and log k′w was found on both CTA and CTPB, as far as the substituents are situated in the plane of the aryl ring or the heterocycle. This correlation with a nonchiral descriptor allows treatment of capacity factors for (−)‐enantiomers as deviations from the lipophilicity line or derived parallels. It results in a clear description of the molecular area affecting enantioselectivity. Application to larger alkyl derivatives shows that the effect of the substituent should be treated on a basis of attractive effect in the case of CTA and on the basis of attractive and repulsive effects for CTPB. © 1994 Wiley‐Liss, Inc.
Use of a new pirkle‐type chiral stationary phase in analytical and preparative subcritical fluid chromatography of pharmaceutical compounds
Authors: Blum Andrew M. , Lynam Kenneth G. , Nicolas Edgar C.
Published: January 2005

Good results have been obtained with use of the new bonded chiral stationary phase Whelk‐O 1 in analytical and preparative subcritical fluid chromatography. A wide variety of enantiomeric pairs of compounds with different functional groups that are of pharmaceutical and biological interest have been resolved. This Pirkle‐concept CSP appears to be more rugged than cellulosic phases (e.g., Chiralcel) with regards to solvents and pressure. In comparing the usefulness of the column for SFC versus HPLC chiral analysis, we have observed a clear superiority of SFC in terms of higher speed and efficiency of analysis, and faster method development. This is consistent with our experience with Chiralcel CSPs. With the Whelk‐O 1 we have shown that the effects of temperature and modifier on SFC separations are similar to what has been reported for most other CSPs. We also observed a unique selectivity advantage of SFC for verapamil. We had good success with using a 1‐in. diameter column packed with Whelk‐O 1 to perform preparative SFC separations of a number of enantiomeric mixtures. The advantages of preparative SFC over preparative HPLC will be discussed. The feasibility of preparative SFC is dependent on how well we meet the practical challenges such as sample introduction issues, special hardware requirements due to the high pressure, and fraction collection issues. © 1994 Wiley‐Liss, Inc.
New technique in optical resolutions
Authors: Ács Mária , Mravik András , Fogassy Elemér , Böcskei Zsolt
Published: January 2005

The present paper illustrates the development of an advanced technique in optical resolution. Both of the amphetamine enantiomers can be obtained by a two‐step distillation in nearly quantitative yield without any loss of the resolving agent. It is proved that the second‐order interactions (H‐bond) are sufficient for separation of enantiomers by distillation. © 1994 Wiley‐Liss, Inc.
Distribution of the enantiomers of hydroxychloroquine and its metabolites in ocular tissues of the rabbit after oral administration of racemic‐hydroxychloroquine
Authors: Wainer Irving W. , Chen John C. , Parenteau Heli , Abdullah Sami , Ducharme Julie , Fieger Hiltrude , Iredale Joanna
Published: January 2005

The disposition of the enantiomers of hydroxychloroquine (HCQ) and its major metabolites in ocular tissues of rabbits has been studied. Both albino, New Zealand White (NZW), and pigmented animals were administered daily oral doses of rac‐HCQ, (S)‐HCQ or (R)‐HCQ (20 mg/kg) over 1, 6, or 8 day periods or for 8 days followed by a 7‐day washout period. At the end of the study periods, plasma and whole blood samples were collected and the rabbits were sacrificed. The eyes were collected, the aqueous humor removed with a syringe, and the eyes separated into the cornea, lens, vitreous body, iris, choroid‐retina, sclera, and conjunctiva. The concentrations of (R)‐HCQ, (S)‐HCQ, and their respective metabolites were determined using a validated enantioselective liquid chromatographic assay. The data from these studies indicate that HCQ accumulated in both pigmented and nonpigmented ocular tissues. In the pigmented tissues, HCQ and its metabolites were bound to melanin and the binding was not enantiospecific. In the nonpigmented tissues and in the iris and retina‐choroid of the NZW rabbits, the accumulation appeared to be the result of a reversible and enantioselective binding of HCQ and its metabolites to an unidentified biopolymer present in these ocular tissues. © 1994 Wiley‐liss, Inc.
Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate
Authors: Tett Susan E. , McLachlan Andrew J. , Cutler David J. , Day Richard O.
Published: January 2005

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac‐hydroxychloroquine, and one of 43 patients who had received rac‐hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (−)‐(R)‐hydroxychloroquine were higher than those of the (+)‐(S)‐antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)‐(S)‐enantiomer. From the observational, cross‐sectional study design used, it was not possible to differentiate concentration–effect relationships of the two enantiomers. The 11‐fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease. © 1994 Wiley‐Liss, Inc.
Disposition and absorption of hydroxychloroquine enantiomers following a single dose of the racemate
Authors: McLachlan Andrew J. , Tett Susan E. , Cutler David J. , Day Richard O.
Published: January 2005

The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (−)‐(R)‐hydroxychloroquine exceed those of (+)‐(S)‐hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (−)‐(R)‐hydroxychloroquine were higher than (+)‐(S) ‐hydroxychloroquine after oral dosing (121 ± 56 and 99 ± 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half‐life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (−)‐(R)‐ and (+)‐(S)‐hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution. © 1994 Wiley‐Liss, Inc.
Stereoisomeric flavour compounds LXVIII. 2‐, 3‐, and 4‐Alkyl‐branched acids, part 2: Chirospecific analysis and sensory evaluation
Authors: Karl Volker , Gutser Jutta , Dietrich Armin , Maas Birgit , Mosandl Armin
Published: January 2005

Enantioselective GC analysis of 4‐ethyloctanoic and 4‐methylheptanoic acid, using heptakis(2,3‐di‐O‐methyl‐6‐O‐tert‐butyldimethylsilyl)‐β‐cyclodextrin as the chiral stationary phase, is described and the sensory properties of several 4‐alkyl‐branched acids, using gas chromatography‐olfactometry (GC‐O) equipment and octakis(2,3‐di‐O‐methyl‐6‐tert‐butyldimethylsilyl)‐γ‐cyclodextrin as the stationary phase, are evaluated. The chirospecific analysis of various 2‐, 3‐, and 4‐alkyl‐branched acids from commercially available Roman chamomile (Chamaemelum nobile (L.) Allioni), Parmesan cheese, and subcutaneous mutton adipose tissue, using either GC‐GC (MDGC) or GC‐MS analytical methods, is described. © 1994 Wiley‐Liss, Inc.
Separation of the optical isomers of a new 1,4‐dihydropyridine calcium channel blocker (LF 2.0254) by liquid and supercritical fluid chromatography
Authors: Siret Laurent , Macaudiere Pierre , Bargmann‐Leyder Nathalie , Tambute André , Caude Marcel , Gougeon Émile
Published: January 2005

The four optical isomers of a new calcium channel blocker LF 2.0254 (developed by Laboratoires Fournier) are resolved by chromatography using chiral stationary phases. Two methods are proposed: the first one involving two chiral stationary phases [(S)‐N‐(2‐naphthyl)alanine, a Pirkle type CSP and Chiralcel OJ, a cellulose derived CSP] in the liquid chromatographic mode, the second one involving a single CSP (Chiralcel OJ) in the supercritical fluid chromatographic mode. © 1994 Wiley‐Liss, Inc.
Pronase in amino acid technology: Optical resolution of nonproteinogenic α‐amino acids
Authors: Pugniere Martine , Domergue Nicole , Castro Bertrand , Inserm Aldo Previero
Published: January 2005

We describe a practical method to produce pure enantiomers of non‐proteinogenic α‐amino acids by pronase‐catalyzed hydrolysis of their methyl esters. Each of the two pure enantiomers was obtained in high yield, while the reaction conditions were optimized with a view to large scale production. Part of this work was devoted to conceiving an analytical procedure especially designed to monitor the steric course of enzymatic reactions. © 1994 Wiley‐Liss, Inc.
A preliminary pharmacokinetic study of the enantiomers of the terfenadine acid metabolite in humans
Authors: Surapaneni Sekhar , Khalil Shoukry K. W.
Published: January 2005

A stereoselective and sensitive achiral/chiral method for the determination of terfenadine acid metabolite in human plasma was developed. The metabolite was separated and quantitated using an achiral chromatographic procedure with a cyano column. The mobile phase was 1 mM sodium acetate buffer (pH 4.0) and acetonitrile (25:75% v/v) at a flow rate of 2 ml/min, at ambient temperature. The stereospecific resolution was accomplished using a chiral‐AGP column and a mobile phase consisting of sodium acetate (0.01 M): methanol (98.7:1.3% v/v), and 20 mM di‐n‐butylamine at a flow rate of 1.2 ml/min. The column temperature was maintained at 32°C. The eluent was monitored at 230 nm (excitation) and 300 nm (emission) with a cut‐off filter at 270 nm. This assay was used for a pharmacokinetic study in five subjects after administration of a single dose of 60 mg of terfenadine. The t½ values of the two enantiomers were similar, but the AUC values of the (+)‐enantiomer were 2.05–2.35 times higher than those of (−)‐enantiomer. © 1994 Wiley‐Liss, Inc.