Enantiomers cyclodextrins

Yashima, E., Yamada, M., Yamamoto, C., Nakashima, M., and Okamoto, Y. (1997) Chromatographic enantioseparation and chiral discrimination in NMR by trisphenylcarbamate derivatives of cellulose, amylose, oligosaccharides, and cyclodextrins, Enantiomer 2, 225-240. 

Table 17 Chromatographic data and molecular interaction energy values of p-cyclodextrin enantiomer complexes, a. represents the selectivity. Numbers 21R-29S were calculated as a complex with TFA. Reproduced by permission of Taylor Francis, ref. 19.

The recognition mechanism is based on the formation of a cyclodextrin-enantiomer inclusion complex, which is stabilized partially by hydrophobic and ion pairing interactions. The increasing polarity of the solvent system was shown to stabilize this complex. The influence of CS concentration in the stationary phase on enantioselectivity has also been studied. The increase of the CS/racemate molar ratio from 10- to 160-fold resulted in an improvement of enantioselectivity and resolution. 

Appllca.tlons. The first widely appHcable Ic separation of enantiomeric metallocene compounds was demonstrated on P-CD bonded-phase columns. Thirteen enantiomeric derivatives of ferrocene, mthenocene, and osmocene were resolved (7). Retention data for several of these compounds are listed in Table 2, and Figure 2a shows the Ic separation of three metallocene enantiomeric pairs. P-Cyclodextrin bonded phases were used to resolve several racemic and diastereomeric 2,2-binaphthyldiyl crown ethers (9). These compounds do not contain a chiral carbon but stiU exist as enantiomers because of the staggered position of adjacent naphthyl rings, and a high degree of chiral recognition was attained for most of these compounds (9). 

Catechin and epicatechin are two flavanols of the catechin family. They are enantiomers. The capillary zone electrophoresis (CE) methods with UV-detection were developed for quantitative determination of this flavanols in green tea extracts. For this purpose following conditions were varied mnning buffers, pH and concentration of chiral additive (P-cyclodextrin was chosen as a chiral selector). Borate buffers improve selectivity of separation because borate can make complexes with ortho-dihydroxy groups on the flavanoid nucleus. 

The curves relate log(k ) against 1/T for two pairs of enantiomers on a chiral BBP column containing 1,6-dipentyl-buteryl cyclodextrin that was 20 m long, 250 pm... 

Acidimetric, spectrophotometric and HPLC assays were developed for determination of 2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidine-l,3-diones 135 (98M133). Its solubility properties were also characterized. Resolution of the enantiomers of 4-phenyl-2- 4-[4-(2-pyrimidinyl)piperazi-nyl]butyl perhydropyrido[l,2-c]pyrimidine-l,3-dione was achieved on hep-takis(2-N, V-dimethylcarbamoyl)- 6-cyclodextrines (01 JC(A)249). 

A stereoselective determination of enantiomers of 5, its A -oxide and N-desmethyl metabolites in human urine was developed by capillary electrophoresis using laser-induced fluorescence detection and sulfonated /1-cyclodextrin in the running buffer (01JC(B)169). 

Figure 10.2 MDGC-MS differentiation between the enantiomers of theaspiranes in an aglycone fraction from puiple passion fruit DB5 pre-column (25 m X 0.25 mm i.d., 0.25 p.m film thickness canier gas He, 0.66 ml/min oven temperature, 60-300 °C at 10 °C/min with a final hold of 25 min) permethylated /3-cyclodextrin column (25 m X 0.25 mm i.d., 0.25 p.m film thickness canier gas He, 1.96 ml/min 80 °C isothermal for 20 min and then programmed to 220 °C at 2 °C/min). Reprinted from Journal of High Resolution Chromatography, 16, G. Full et al., MDGC- MS a powerful tool for enantioselective flavor analysis , pp. 642-644, 1993, with permission from Wiley-VCH.

Recently, two examples of the separation of enantiomers using CCC have been published (Fig. 1-2). The complete enantiomeric separation of commercial d,l-kynurenine (2) with bovine serum albumin (BSA) as a chiral selector in an aqueous-aqueous polymer phase system was achieved within 3.5 h [128]. Moreover, the chiral resolution of 100 mg of an estrogen receptor partial agonist (7-DMO, 3) was performed using a sulfated (3-cyclodextrin [129, 130], while previous attempts with unsubstituted cyclodextrin were not successful [124]. The same authors described the partial resolution of a glucose-6-phosphatase inhibitor (4) with a Whelk-0 derivative as chiral selector (5) [129]. 

Recently, the separation of some milligram quantities of terbutaline by classical gel electrophoresis has been reported [194]. A sulfated cyclodextrin impregnated on the agarose gel was used as a chiral selector and the complete resolution was achieved in 5 h. Analogously, small amounts of enantiomers can be isolated using thin-layer... 

A. M. Stalcup, Cyclodextrin bonded chiral stationary phases in enantiomer separations in A practical approach to chiral separations by liquid chromatogra.phy, G. Subramanian, VCH, Weinheim (1994) Chapter 5. 

Addition of a chiral carrier can improve the enantioselective transport through the membrane by preferentially forming a complex with one enantiomer. Typically, chiral selectors such as cyclodextrins (e.g. (4)) and crown ethers (e.g. (5) [21]) are applied. Due to the apolar character of the inner surface and the hydrophilic external surface of cyclodextrins, these molecules are able to transport apolar compounds through an aqueous phase to an organic phase, whereas the opposite mechanism is valid for crown ethers. 

Comparisons of LC and SFC have also been performed on naphthylethylcar-bamoylated-(3-cyclodextrin CSPs. These multimodal CSPs can be used in conjunction with normal phase, reversed phase, and polar organic eluents. Discrete sets of chiral compounds tend to be resolved in each of the three mobile phase modes in LC. As demonstrated by Williams et al., separations obtained in each of the different mobile phase modes in LC could be replicated with a simple CO,-methanol eluent in SFC [54]. Separation of tropicamide enantiomers on a Cyclobond I SN CSP with a modified CO, eluent is illustrated in Fig. 12-4. An aqueous-organic mobile phase was required for enantioresolution of the same compound on the Cyclobond I SN CSP in LC. In this case, SFC offered a means of simplifying method development for the derivatized cyclodextrin CSPs. Higher resolution was also achieved in SFC. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

The Diels-Alder reaction of nonyl acrylate with cyclopentadiene was used to investigate the effect of homochiral surfactant 114 (Figure 4.5) on the enantioselectivity of the reaction [77]. Performing the reaction at room temperature in aqueous medium at pH 3 and in the presence of lithium chloride, a 2.2 1 mixture of endo/exo adducts was obtained with 75% yield. Only 15% of ee was observed, which compares well with the results quoted for Diels-Alder reactions in cyclodextrins [65d]. Only the endo addition was enantioselective and the R enantiomer was prevalent. This is the first reported aqueous chiral micellar catalysis of a Diels-Alder reaction. 

Cyclodextrins, toroidal molecules composed of 6, 7 and 8 D-gJucose units, are now commercially available at reasonable cost. They form inclusion compounds with a variety of molecules and often differentially include sulfoxide enantiomers . This property has been used to partially resolve some benzyl alkyl, phenyl alkyl and p-tolyl alkyl sulfoxides. The enantiomeric purities after one inclusion process ranged from 1.1% for t-butyl p-tolyl sulfoxide to 14.5% for benzyl t-butyl sulfoxide. Repeating the process on methyl p-tolyl sulfoxide (10) increased its enantiomeric purity from 8.1 % to 11.4% four recrystallizations raised the value to 71.5%. The use of cyclodextrins in asymmetric oxidations is discussed in Section II.C.l and in the resolution of sulfinate esters in Section II.B.l. 

There is a wide variety of commercially available chiral stationary phases and mobile phase additives.32 34 Preparative scale separations have been performed on the gram scale.32 Many stationary phases are based on chiral polymers such as cellulose or methacrylate, proteins such as human serum albumin or acid glycoprotein, Pirkle-type phases (often based on amino acids), or cyclodextrins. A typical application of a Pirkle phase column was the use of a N-(3,5-dinitrobenzyl)-a-amino phosphonate to synthesize several functionalized chiral stationary phases to separate enantiomers of... 

Makino, Y., Suzuki, A., Ogawa, T., and Shirota, O., Direct determination of methamphetamine enantiomers in urine by liquid chromatography with a strong cation-exchange precolumn and phenyl-p-cyclodextrin-bonded semimicrocolumn, ]. Chromatogr. B, 729, 97, 1999. 

Capillary electrophoresis employing chiral selectors has been shown to be a useful analytical method to separate enantiomers. Conventionally, instrumental chiral separations have been achieved by gas chromatography and by high performance liquid chromatography.127 In recent years, there has been considerable activity in the separation and characterization of racemic pharmaceuticals by high performance capillary electrophoresis, with particular interest paid to using this technique in modem pharmaceutical analytical laboratories.128 130 The most frequently used chiral selectors in CE are cyclodextrins, crown ethers, chiral surfactants, bile acids, and protein-filled... 

Gas chromatography (GC) has also been used for preparative purposes, but is restricted to relatively volatile racemates such as anesthetics, pheromones or monoterpenes and, therefore, very few applications are reported. Nevertheless, in the cases to which GC may be applied, it could be considered as an economical alternative to HPLC. Most of the resolutions of enantiomers were performed on cyclodextrin-derived CSPs [109, 144-153], and only on very few occasions were other chiral selectors used [153]. 

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