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The immobilization of cellulose 3,5-dimethylphenyl carbamate and amylose 3,5-dimethylphenyl carbamate on silica gel carrier was achieved by using photochemical and thermal processes. Both approaches provide an easy access to materials which were applied as chiral stationary phases (CSPs) for the chromatographic resolution of racemic molecules. The influence of parameters such as irradiation time and solvent on immobilization effectiveness was investigated. For the thermal processes, azo-bis-isobutyrontrile and di-tert-butyl peroxide were evaluated as radical initiators. The influence of parameters such as amount of radical initiator, solvent, temperature, and further handling operations on the immobilization rate was examined. The chiral recognition ability and the overall performance of the prepared immobilized phases were evaluated by injection of a series of racemic compounds onto packed HPLC columns. As there is almost no limitation of organic solvent types that can be used as mobile phases with the immobilized CSPs, they can be applied under chromatographic conditions which are prohibited with the corresponding non-bonded CSPs. This extended applicability considerably broadens the options for improving enantioselectivity and resolving chiral compounds which are not or only poorly soluble in the conventional mobile phases.

A photochemical method for immobilizing polysaccharide derivatives on silica gel has been developed and applied to 4-methylbenzoyl cellulose (PMBC). The photochemically immobilized materials have been used as chiral stationary phases (CSPs) for the chromatographic separation of the stereoisomers of chiral molecules. Through to the immobilization which makes the chromatographic material insoluble in almost all organic solvents, there no restriction regarding the kind of solvent used in the mobile phase. This feature permits to considerably extend the possibilities to improve the selectivity of the separations and or the solubility of the solute in the mobile phase. The influence of various parameters such as immobilization process, cross-linker type and amount on the chromatographic properties and chiral recognition ability of the resulting CSPs has been investigated using a set of chiral molecules. The impact of the amount of coated polysaccharide material on chiral recognition ability was also examined.

Cationic hetero[6]helicenes 1+, 2+ and 3+ have been recently disclosed. Herein we report on their enantiomeric separation using high-performance liquid chromatography. Separation of the antipodes can be achieved in preparative scale on neutral adducts with Chiralcel OD-I or Chiralpak ID CSP. Selectivity factors of 1.90, 1.67, and 1.96 were obtained for 1-H, 2-H, and 3-H, respectively. Separation can also be performed on the carbenium ions on regular Chiralpak IA CSP using water-containing eluents, thus allowing for enantiomeric purity determinations in aqueous environments. Resolution of neutral and cationic helicenes is also achieved on more recently developed LARIHC columns. The versatility of the cyclofructan phases allows for baseline separations for both cases and their loading capabilities are demonstrated. Finally, the configurational stability of 1+, 2+, and 3+ was measured. For each replacement of an oxygen atom by an amino group, the racemization barrier increases significantly (ΔG‡ = 29.8, 36.3 and >37 kcal mol(-1) for 1+, 2+, and 3+ respectively).

Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2.

From the beginning of the 1980s, the life science industry increasingly recognized the importance of chirality in biological interaction processes, but the methods for preparing optically pure drugs were still limited. Most of the syntheses of chiral compounds were performed starting from optically active building blocks (chiral pool), mainly from natural sources, or by resolution of the enantiomers via formation of diastereomers. In this context, there was a growing interest for enantioselective processes, such as synthetic methodologies and separation techniques for accessing optically pure substances in an effective manner. Among the separation approaches, enantioselective chromatography looked very promising and a project aiming to explore this option was started in the Central Research Laboratories of former Ciba-Geigy. This article reviews the story of this development which culminated in the discovery of highly efficient polysaccharide-based chiral stationary phases which have now become the gold standard in the world of enantioselective chromatography. It shows also how the technique of enantioselective chromatography has evolved from an analytical tool to a practical preparative technology, up to production scale.

The author describes the emergence and development of enantioselective chromatography as a powerful tool for the separation of stereoisomers, on analytical, preparative, and production scale. He summarizes his early contribution to the advance and propagation of this particular technology at the interface between chemistry, separation sciences, and physics, going back to his growing interest in chirality which was stimulated by a postdoctoral stay at the University of Geneva.

3,5-Disubstituted piperidines are versatile building blocks that find broad application in medicinal chemistry programs. Here we describe how all four diastereoisomers of a 5-aryl-substituted nipec...

A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.

The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3(sp) cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

A process to immobilize para-methylbenzoyl cellulose (PMBC) on silica gel has been developed and applied to prepare chiral stationary phases (CSPs) for enantioselective chromatography. The immobilization was achieved by simple irradiation of the polysaccharide derivative with ultraviolet light after coating on a silica gel support. The influence of parameters such as irradiation time and solvent on immobilization effectiveness were investigated. The performance of the prepared immobilized phases were evaluated by injection of a series of racemic compounds onto the packed columns and determination of their chiral recognition ability. By contrast to the classical coated phase, the immobilized CSP can be used under various chromatographic conditions without limitation of organic solvent types as the mobile phase. This extended applicability permits to improve selectivity and to resolve chiral compounds which are not or only poorly soluble in the mobile phases which are compatible with the non-immobilized PMBC stationary phase.

Analysis and production of enantiomerically pure compounds is a major topic of interest when active pharmaceutical ingredients are concerned. Enantioselective chromatography has become a favourite both at the analytical and preparative scales. High-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) are dominating the scene and are often seen as complementary techniques. Nowadays, for economic and ecologic reasons, SFC may be preferred over normal-phase HPLC (NPLC) as it allows significant reductions in solvent consumption. However, the transfer of NPLC methods to SFC is not always straightforward. In this study, we compare the retention of achiral molecules and separation of enantiomers under supercritical fluid (carbon dioxide with ethanol or isopropanol) and liquid normal-phase (heptane with ethanol or isopropanol) elution modes with polysaccharide stationary phases in order to explore the differences between the retention and enantioseparation properties between the two modes. Chemometric methods (namely quantitative structure-retention relationships and discriminant analysis) are employed to compare the results obtained on a large set of analytes (171 achiral probes and 97 racemates) and gain some understanding on the retention and separation mechanisms. The results indicate that, contrary to popular belief, carbon dioxide - solvent SFC mobile phases are often weaker eluents than liquid mobile phases. It appears that SFC and NPLC elution modes provide different retention mechanisms. While some enantioseparations are unaffected, facilitating the transfer between the two elution modes, other enantioseparations may be drastically different due to different types and strength of interactions contributing to enantioselectivity.

The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating hERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.

In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.

The acylglucuronide (3) of mycophenolic acid (1) was enzymatically synthesised on a preparative scale (450 mg substrate) under optimised reaction conditions with 51% conversion. By screening 9 liver homogenates from 8 vertebrate species, it was shown that only with liver homogenate from horse as the catalyst were the acyl- (3) and the O-glucuronide (2) were formed in a ca. 1 : 1 ratio. With homogenates from other sources, the O-glucuronide (2) was produced in high excess. By optimising the concentration of the co-substrate UDP-glucuronic acid and the reaction temperature, the conversion to the acylglucuronide (3) was increased from initially 34 to 55% and the ratio of acyl- (3) to O-glucuronide (2) from 1.5 : 1 to 3.9 : 1. The reaction was also performed continuously in an enzyme membrane reactor, however, with lower conversion yield and therefore, higher specific UDP-glucuronic acid consumption.

In the last few years, there has been a resurgence of supercritical fluid chromatography (SFC), which has been stimulated by the introduction of a new generation of instruments and columns from the main providers of chromatographic instrumentation, that are strongly committed to advancing the technology. The known limitations of SFC, such as weak UV sensitivity, limited reliability and poor quantitative performance have been mostly tackled with these advanced instruments. In addition, due to the obvious benefits of SFC in terms of kinetic performance and its complementarity to LC, advanced packed-column SFC represents today an additional strategy in the toolbox of the analytical scientist, which may be particularly interesting in pharmaceutical analysis. In the present review, the instrumentation and experimental conditions (i.e. stationary phase chemistry and dimensions, mobile phase nature, pressure and temperature) to perform "advanced SFC" are discussed. The applicability of SFC in pharmaceutical analysis, including the determination of drugs in formulations and biofluids is critically discussed.

The enantiomers of two different derivatives of tert-leucine were separated by continuous chromatography on chiral stationary phases applying the simulated moving bed technique. About 1 kg of racemic N-carbobenzoxy-tert-leucine was resolved on the cellulose-based phase Chiralcel OD using a mixture of heptane/ethanol and 0.1% of trifluoroacetic acid modifier as the mobile phase, while 520 g of the N-Boc-tert-leucine-benzylester was resolved on the amylose-based phase Chiralpak AD with a mixture of heptane/2-propanol as the mobile phase. In both instances the corresponding enantiomers were obtained in high yield and high optical purity.

A new synthesis of ( R , S )-PPG (4-phosphonophenylglycine) and the separation of the protected enantiomers leading after deprotection to (+)- and (−)-PPG are described. Pharmacological characterization at the group III metabotropic glutamate receptors hmGluR4a and hmGluR7b revealed (+)-PPG as the active enantiomer.

Reacting ethoxycarbonyl triphenyl phosphorane with activated alkylhalides in chloroform gave the ylides 4 -12. They react smoothly and in general without racemisation with oc-amino aldehydes resulting in the dipeptide mimetics 15 - 25. Exceptions are the highly labile aldehydes pyridinoalaninal and serinal. Enantiospecificity is proven via enantioselective chromatography.

The advantages that can be gained from derivatization of various racemic aliphatic and aromatic alcohols prior to enantiomeric chromatographic separation have been systematically investigated for a series of benzoate derivatives. Three cellulose-based CSPs available in the pure polymeric form—tribenzoyl cellulose (TBC), meta-methylbenzoyl cellulose (MMBC), and para-methylbenzoyl cellulose (PMBC)—were selected and several benzoate derivatives varying in the nature and the position of the substituent on the benzoyl group were prepared and analysed. TBC clearly gives the broadest application range, and among the different benzoate esters the best selectivity was generally obtained with either the 4-methoxybenzoate or the 4-methylbenzoate derivatives. Based on these results, some empirical rules could be formulated for optimizing the enantiomeric separation of racemic alcohols, which make up one of the most important classes of chemical substances used as drugs and biocides, or as building blocks for their synthesis. An application of this approach to the preparative separation of the enantiomers of a drug intermediate is also shown. Chirality 10:492–498, 1998. © 1998 Wiley-Liss, Inc.

Several γ-cyclodextrin sulfobutyl ether (γ-CD-SBE) derivatives, differing in the degree of substitution (DS), were synthesized and characterized by matrix-assisted laser desorption/ionization time-on-flight MS. They were evaluated as chiral selectors for the separation of enantiomers by capillary electrophoresis. The results demonstrate that the number of sulfobutyl groups attached to the cyclodextrin moiety significantly influences the enantioseparation towards the racemic analytes. For the examined racemic solutes, a good resolution was generally obtained when using γ-CD-SBE with an average DS ranging between 5 and 7, except for secobarbital which is only resolved when the average DS is higher than 7. For this compound the migration order of the enantiomers with γ-CD-SBE (DS 7.6) was opposite to that one observed with unmodified γ-cyclodextrin in the presence of sodium dodecyl sulfate micelles. For 1-(9-anthryl)-2,2,2-trifluoroethanol the resolution increases as DS is increasing. These different results clearly demonstrate that it is crucial to use well-characterized CD derivatives.

Although most preparative chiral separations have been performed in the conventional batch-mode process, interest in simulated moving-bed (SMB) chromatography is growing, because it permits large amounts of mobile phase to be saved and productivity increased, thus reducing production costs. Based on the examples of three different drugs, the usefulness of this technique for the separation of enantiomers on a preparative scale has been demonstrated. Compared to the batch elution chromatography, a reduction of the mobile phase consumption of respectively 81% and 84% has been achieved for the separation of the enantiomers of the antiasthmatic agent formoterol and of the antitussive agent guaifenesin. Furthermore, a higher throughput could be reached under SMB conditions. The influence of feed rate and extract on the separation has also been investigated. The results show that these two factors considerably affect purity and productivity, and constitute important parameters for finely adjusting the chromatographic conditions depending on the requirements. For all racemates, both enantiomers could be obtained with a purity ranging between 99 and 99.9%.

A stereospecific HPLC method for the quantitation of CGP 49309 in samples of its corresponding enantiomer valsartan has been developed and validated. The enantiomeric separation was achieved on a 5 micron silica-bonded, alpha 1-acid glycoprotein column (Chiral AGP) with a phosphate buffer, pH 7, containing 2% (v/v) 2-propanol as a mobile phase. The linearity was established in the range 0.1-4% (r0.999). The limit of quantitation was 0.1% and the limit of detection was 0.04%. The accuracy of the method was found to be 96.7% (average). For the precision (repeatability), a relative standard deviation value of 2.4% was found. Similarly, a stereoselective HPLC method was also developed and validated for the quantitation of the enantiomer of the starting material used for the synthesis of valsartan, namely (R)-valinebenzyl ester tosylate. Baseline resolution of the enantiomers of valinebenzyl ester tosylate could be achieved on the chiral crown ether column Crownpak CR (Daicel) at 50 degrees C using water-methanol-trifluoroacetic acid (850:150:1, v/v) as a mobile phase. The linearity was established in the range 0.5-5% (r0.999). The accuracy of the method was found to be 100.5% (average). For the precision (repeatability), a relative standard deviation value of 3.4% was found. Both methods were found to be suitable for the analysis of the respective analytes.

γ-Cyclodextrin sulfobutyl ether (γ-CD-SBE) was synthesized and evaluated as a chiral selector for capillary electrophoresis. As expected, the new derivative combined the good enantioselectivity of γ-cyclodextrin with the advantages of a negatively charged chiral selector, which have previously been reported also for the β-cyclodextrin analogon. However, it became evident that the attachment of the sulfobutyl ether groups to the periphery of the γ-cyclodextrin torus can markedly alter the enantioselectivity towards some racemic analytes. Thus, there was no general trend towards better separations with the use of γ-CD-SBE rather than unmodified γ-cyclodextrin or vice versa. Some racemates could only be resolved with one or the other system. For two racemates, even the elution order of the enantiomers with γ-CD-SBE was opposite to that one expected from the experiments using unmodified γ-cyclodextrin.

Dextrin 10 sulfopropyl ether (DSPE) was prepared and characterized by matrix-assisted laser-desorption ionization-mass spectrometry (MALDI-MS) using a recently developed matrix. The anionic compound was used as a novel chiral buffer additive for enantiomer separation by capillary electrophoresis, thereby changing into the elektrokinetic chromatography (EKC) mode. DSPE was systematically evaluated as a chiral selector and was compared to the respective nonderivatized maltodextrin. DSPE showed an increased separation power for cationic racemic solutes. Although not quite as versatile and powerful as cyclodextrins, the inexpensive dextrin 10 and its derivative DSPE showed remarkable enantioselectivity in some cases.

A series of chiral stationary phases (CSPs) were prepared from meta-methylbenzoyl cellulose (MMBC) by deposition on silica using different methods (evaporation or precipitation) and various solvating agents. The chromatographic properties of these CSPs were evaluated using a set of racemic compounds. Both the methods of deposition and the solvating agent have a profound influence on the optical resolving power of the MMBC CSPs. Surprisingly, variations were observed not only in the enantioselectivities, but also in the enantiomeric elution order of some of the substances. The precipitation method of deposition is preferable to coating by evaporation. The highest enantioselectivities were obtained with the phases prepared by precipitation of MMBC, either from pure methylene chloride (MC-P), or from methylene chloride solution in the presence of phenol (MC-PHN). These two CSPs show complementary properties in terms of resolution for most compounds investigated and in some cases exhibit opposite optical discrimination patterns. This phenomenon points to the importance of the supramolecular structure of the chiral polymer MMBC on its chiral recognition capability.

A sensitive and rapid high-performance capillary electrophoresis (HPCE) method combined with laser-induced fluorescence (LIF) detection is described, which is suitable for the analysis of racemic formoterol and formoterol enantiomers after derivatization with fluorescein isothiocyanate (FITC). The limit of detection is 1 pg/ml in the case of FITC-derivatized racemic formoterol in the absence of chiral selector. Upon injection of 5 nl, it corresponds to an amount of not more than 120 molecules. The chiral recognition occurs in the presence of heptakis(2,3,6-tri-O-methyl-β-cyclodextrin) as a chiral selector in the buffer electrolyte and yields a detection limit of 10·10 −12 g/ml for each enantiomer.

Chiral stationary phases (CSPs) prepared by mixing together two different cellulose derivatives, before or after being coated on macroporous silica gel, were developed in order to determine the mutual influence of two different polymers on global chiral recognition capacity. The chromatographic properties of these CSPs were evaluated using a wide range of racemic test solutes. The mixing method does not significantly affect the enantioselectivities. The composite CSPs obtained by cocoating of two different cellulose derivatives on silica generally exhibit chiral recognition capacities intermediate between those of the two individual phases, and thus broadening the application range of a single column. These results indicate that the simultaneous coating of two different cellulose derivatives does not significantly alter the optical resolution power of each chiral material and are discussed in relationship with the supramolecular structure of the polymeric stationary phases. © 1995 Wiley-Liss, Inc.

In the context of the investigation of the consequences of chirality on physical and biological phenomena, the demand for new general methods for preparing optically pure compounds in growing rapidly. In this respect, preparative chromatographic resolution on chiral stationary phases has been recognized as a powerful tool and its usefulness is demonstrated in this review with applications covering different fields and different kinds of molecular chirality. The applications are arranged in tables according to their use such as for drugs, pesticides, chiral agents and auxiliaries, or to their stereogenic unit.

The higher diffusivity and lower viscosity of supercritical and near-critical fluids can make packed-column supercritical fluid chromatography or subcritical fluid chromatography (SubFC) faster with improved resolution over normal-phase HPLC for chiral separations. However, superior fluid characteristics do not guarantee enhanced resolution or shorter analysis time. In the case of phenylalaninol, a 1 H NMR spectrum indicates interaction of the solute with carbon dioxide. Such interaction may explain the poorer resolution achieved by SubFC than by HPLC. For a secondary amine, its 1 H NMR spectra showed no shift while poorer resolution was again observed for SubFC when compared to HPLC. Thus, the NMR data by itself do not conclusively indicate either reaction between basic solutes and carbon dioxide or the likelihood of chiral resolution. The effects of column outlet pressure, organic modifier composition, pump flow-rate and column temperature for hydroxyzine were studied. Of the physical parameters studied, modifier composition has the greatest impact on retention. Increasing retention generally increases resolution. Changing temperature generally has less impact on retention but produces the greatest selectivity changes.

The synthesis of the title compound 1 has been accomplished in 20 chemical steps starting from D-ribonolactone. X-ray crystallography shows the bicyclic skeleton of 1 to adopt a boat-like (“2′-exo”) conformation and preliminary hybridization data indicate that the substitution of 1 for natural thymidine in DNA/RNA heteroduplexes may increase their thermodynamic stability.

The 8-amino-5,6,7,8-tetrahydronaphth-2-oic acid (1), 8-(aminomethyl)-5,6,7,8-tetrahydronaphth-2-oic acid (2), and 8-(aminomethyl)naphth-2-oic acid (3) were synthesized in their protected forms as turn-inducing dipeptide mimics.Two of them (2 and 3) were incorporated into a novel type of cyclic, peptide-based structures (see 21 and 34-36) designed as templates for the synthesis of TASP molecules.

The application of cellulose-based stationary phases for chiral separations has been extended to open tubular column chromatography. Efficient columns were obtained by coating the capillaries with mixtures of chiral cellulose materials and conventional achiral stationary phases for gas chromatography. In this study, various siloxane and polyethylene glycol polymers were used as achiral components and mixed with different substituted benzoylcellulose derivatives as chiral components. Systematic investigations were carried out to determine the optimal ratio for the components of the stationary phase. Depending on the chromatographic mode—gas chromatography (GC) or supercritical fluid chromatography (SFC)—the stationary phases were found to behave differently. The applicability of the technique was demonstrated by the resolution of various racemic compounds. © 1993 Wiley-Liss, Inc.

The resolution of racemic δ-phenyl-δ-valerolactone by chromatography on cellulose triacetate CTA I results in one of the best separations of optical antipodes observed so far on this chiral stationary phase. The thermodynamics of the stereoselective interaction of the enantiomers of δ-phenly-δ-valerolactone have been studied by chromatography at different temperatures and by direct microcalorimetric investigations of the complexation with CTA I. This analysis suggests that the separation process is mainly controlled thermodynamically and that kinetic effects, if any, play a minor role. Microcalorimetric titration experiments indicate that specific (optimum) complexation sites on CTA I for the stronger retained enantiomer of δ-phenly-δ-valerolactone are rapidly saturated, whereas the first eluted enantiomer seems to interact much less selectively with defined interaction sites on the chiral polymer matrix. © 1993 Wiley-Liss, Inc.

The potential of the chromatographic separation of enantiomers on a preparative scale as a tool for the isolation of optically pure compounds is gaining increasing recognition. This review surveys the different chiral stationary phases (CSPs) used for preparative chromatography, emphasizing the advantages and drawbacks of each. The strategy to be followed for preparative separations is discussed and tables summarizing separations reported in the literature give an overview of practical applications. Cellulose triacetate has been used most frequently, probably because of its broad application range and its low production costs in comparison with more recently introduced CSPs. Nevertheless, the high efficiency of some of the novel CSPs is likely to contribute to the further development and expansion of the method.

In the context of the investigation of the consequences of chirality on physical and biological phenomena, the demand for new general methods for preparing optically pure compounds in growing rapidly. In this respect, preparative chromatographic resolution on chiral stationary phases has been recognized as a powerful tool and its usefulness is demonstrated in this review with applications covering different fields and different kinds of molecular chirality. The applications are arranged in tables according to their use such as for drugs, pesticides, chiral agents and auxiliaries, or to their stereogenic unit.

A novel [1,2]-Stevens rearrangement of quaternary ammonium salts (I) leads readily to ethano-bridged Troeger bases (II) as a single diastereomer.

Reacting ethoxycarbonyl triphenyl phosphorane with activated alkylhalides in chloroform gave the ylides 4 -12. They react smoothly and in general without racemisation with oc-amino aldehydes resulting in the dipeptide mimetics 15 - 25. Exceptions are the highly labile aldehydes pyridinoalaninal and serinal. Enantiospecificity is proven via enantioselective chromatography.

An enantioselective liquid chromatographic assay for the simultaneous determination of the S-(+) and R-(-) enantiomers of the monohydroxylated metabolite of oxcarbazepine in human plasma is described. The metabolite is the active principle. The method is based on the extraction of plasma with diethyl ether-dichloromethane (2:1, v/v), separation of the organic phase, evaporation of the solvent and dissolution of the residue in the mobile phase. The two enantiomers were resolved on a Chiralcel OD (250 mm x 4.6 mm I.D.) high-performance liquid chromatographic column. The separation was achieved by isocratic elution with n-hexane-2-propanol (77:23, v/v). The flow-rate of the mobile phase was 1.0 ml/min and the two enantiomers were detected by ultraviolet absorbance at 210 nm. The analytical method is suitable for the quantitative and simultaneous determination of the two enantiomers in plasma at concentrations down to 0.4 mumol/l after administration of oxcarbazepine.

The potential of the chromatographic separation of enantiomers on a preparative scale as a tool for the isolation of optically pure compounds is gaining increasing recognition. This review surveys the different chiral stationary phases (CSPs) used for preparative chromatography, emphasizing the advantages and drawbacks of each. The strategy to be followed for preparative separations is discussed and tables summarizing separations reported in the literature give an overview of practical applications. Cellulose triacetate has been used most frequently, probably because of its broad application range and its low production costs in comparison with more recently introduced CSPs. Nevertheless, the high efficiency of some of the novel CSPs is likely to contribute to the further development and expansion of the method.

S-[1-(2,3-Diaminophenoxy)]-3′-(N-t-butylamino)propan-2′-ol is important as a precursor in the radiosynthesis of a 11C-labelled radioligand (S-[carbonyl-11C]CGf 12177) for the study of β-receptors in living man. The asymmetric synthesis of this precursor has been simplified based on the reaction of readily available 2-amino-3-nitrophenol and the chiral auxiliary, S-glycidyl-3-nitrobenzenesulphonate, followed by treatment of the resultant S-epoxide with t-butylamine and reduction with hydrogen in the presence of palladium on carbon. Chiral HPLC methods have been successfully developed to monitor the enantiomeric purity of the chiral auxiliary and of all intermediates in the asymmetric synthesis. All intermediates and products have been studied by CD. It has been demonstrated by chiral HPLC that S-CGP 12177 can be prepared in > 98.4% e.e. from the synthesised S-precursor. R-CGP 12177 (e.e.>96.2%) was prepared analogously.

The preparation of cellulose-based chiral stationary phases (CSPs) in the pure polymer from (i.e., without an achiral support such as silica gel), according to a process already reported for benzoyl cellulose, was extended to substituted benzoylcellulose derivatives. The chiral recognition abilities of benzoylcellulose and o-, m- and p-methylbenzoylcellulose were compared. The four CSPs are shown to exhibit different selectivites and in numerous instances an inversion of the elution order was observed on the different methylbenzoylcellulose CSPs, indicating that the CSPs undergo different interactions with the same racemic solute. The broad variety of racemic structures that can be resolved on the four CSPs indicate the great application potential of the new cellulose-based sorbents. This should be the case especially for preparative separations, as the materials are not deposited on an achiral supporting matrix and thus have a higher loading capacity than coated CSPs.

Low-energy crystal packings of cellulose triacetate (CTA) have been computed, based on a "two-dimers" unit cell as suggested for CTA I. In addition to the different packing arrangements, parallel versus antiparallel, the effect of changes in the main-chain conformation on the crystal packing was investigated. Minor alterations of the main-chain torsional angles were sometimes found to induce significant changes of unit-cell parameters, although yielding structures with comparable energies. Since small changes of the main-chain conformation do not involve large energy barriers, it is therefore assumed that, in crystalline CTA, local transitions between unit cells with slightly different parameters are possible. Even highly ordered CTA samples might thus consist of a distribution of marginally differing crystalline domains. The resulting imperfections at the interfaces of slightly different unit cells, conceivable on the basis of the computed structures, might explain the problems encountered in the experimental elucidation of the crystal structures in both CTA morphologies, CTA I and CTA 11.