Chiral resolution case studies

The triester and triphenylcarbamate derivatives of amylose were prepared as in the case of cellulose, but the triester derivatives of amylose are not useful for chiral resolution. Therefore, the triester derivatives of amylose have not been studied extensively. The chemical structures of the triphenylcarbamate derivatives are shown in Fig. 3. Similarly, the chiral resolution power of amylose derivatives was studied by introducing electron-donating and electron-withdrawing groups on the phenyl ring of the amylose derivatives [21-24],... 

Temperature is also an important parameter for controlling the resolution of enantiomers in HPLC. The enthalpy and entropy control of chiral resolution on antibiotic CSPs is similar to the case of polysaccharide-based CSPs (Chapter 2). Armstrong et al. [1] have studied the effect of temperature on the resolution behavior of proglumide, 5-methyl-5-phenylhydantoin and A-carbamyl-D-pheny-lalanine on the vancomycin column. The experiments were carried out from 0°C to 45°C. These results are given in Table 6 for three chiral compounds. It has been observed that the values of k, a, and Rs for the three studied molecules have decreased with the increase in temperature, indicating the enhancement of chiral resolution at low temperature. In another work, the same workers [22] have also studied the effect of temperature on the resolution of certain amino acid derivatives on the teicoplanin chiral stationary phase. They further observed poor resolution at ambient temperature, whereas the resolution increased at low... 

As in the case of other CSPs, the chiral resolution is effected by the structure of the solute. The chiral resolution of amino acids may be considered as the best example for this study. The work of Fukushima et al. [20] (i.e., the chiral resolution of amino acids) indicated the different behavior of the chiral resolution on (i8 )-/V-3,5-dinitrobcnzoyl-l -naphthylglycine CSP. Altomare etal. [142] studied the chiral resolution of a series of 3-phenyl-4-(l-adamantyl)-5-A-phcnyl-A2-1,2,4-oxadiazolines on A,Af,-(3,5-dinitrobenzoyl)-l(7 ),2( )-diaminocyclohcxanc CSP. The effect of the influence of aromatic ring substituents on enantioselectivity was studied by traditional linear free-energy-related equations and comparative molecular field analysis methods. The authors reported that an increase in retention was favored by the re-basicity and the hydrophilicity of the solutes. In... 

As in case of other CSPs, the chiral resolution is also effected on protein phases by the structures of the racemic compounds. Allenmark and co-workers [23] resolved several sulfoxides on the BSA-based CSP. These sulfoxides contain different structures with various groups such as methyl, methoxy, and acetate. We analyzed the results of this study and, generally, it was found that the separation factor decreased by introducing larger groups in the sulfoxides. This behavior may be the result of a steric effect the author did not consider in the discussion... 

As in the case of other CSPs, the chiral resolution on these CSPs is also affected by a change in the structures of the racemic compounds. The different selectiv-ities of amino acids on these CSPs may be considerd as the best example. The effect of structures of the racemates on the chiral resolution may be understood from the work carried out by Shieh et al. [71]. The authors studied the chiral resolution of amino acids as their Schiff s bases. These racemates differ slightly in their structure and the substituent, such as alkyl groups, hence showed different values of enantioselectivities. The values of retention and separation factors decreased by introducing bulky groups in the racemates. Aboul-Enein and Ali [70] observed the lower values of retention factors of miconazole in comparison to econazole and sulconazole. The authors explained this sort of behavior on the basis of the steric effect exerted by the extra chlorine atom in miconazole molecule. 

Tan H, Cui S, Gahm K, Luu V, Walker SD. Rational screening approach for classical chiral resolution under thermodynamic equilibrium a case study of diphenyl-substituted Af-methyl-piperazine. Org. Process Res. Dev. 2011 15 53-63. 

Further studies on L-Phe-An MIP plates with the enantiomers of various compounds, such as anilide, dansyl, methyl and ethyl esters, and amide derivatives of amino acids, showed that polymer interacts more weakly with enantiomers of these compounds and, in the case of dansyl derivatives, no chiral resolution was observed, probably due to the dansyl group that blocks the ammine group of phenylalanine. 

A comprehensive study on the temperature effect was done in 2004 for 71 chiral compounds on four glycopeptide CSPs TE, TAG, ristocetin A, and vancomycin phases, using the three RP, POM, and NP elution systems [95]. The separations were studied in the 5 5°C temperature range. Peak efficiencies always increased with temperature, but in only 17% of the separations studied, a small increase of the resolution was observed. In the rest of the cases, the resolution decreased or even vanished when temperature increased. All van t Hoff plots were linear, showing that... 

Avery recent study [128] deals with the comparison of two commercially available vancomycin-based CSPs with different surface coverage of the chiral selector in the enantioseparation of P-blockers and profens, by RP and POM separation modes. Higher retention and better resolution were obtained on the CSP with higher coverage of vancomycin in both the separation modes. However, in the case of pro fens, higher retention was not always accompanied by an improvement of the enantioselectivity in the RP mode. An accurate study of the influence of the mobile phase composition was also performed in both the separation modes. 

In a different approach, fluorescence-based DNA microarrays are utilized (88). In a model study, chiral amino acids were used. Mixtures of a racemic amino acid are first subjected to acylation at the amino function with formation of A-Boc protected derivatives. The samples are then covalently attached to amine-functionalized glass slides in a spatially arrayed manner (Fig. 10). In a second step, the uncoupled surface amino functions are acylated exhaustively. The third step involves complete deprotection to afford the free amino function of the amino acid. Finally, in a fourth step, two pseudo-Qn nX. om.Qx c fluorescent probes are attached to the free amino groups on the surface of the array. An appreciable degree of kinetic resolution in the process of amide coupling is a requirement for the success of the ee assay (Horeau s principle). In the present case, the ee values are accessible by measuring the ratio of the relevant fluorescent intensities. About 8000 ee determinations are possible per day, precision amounting to +10% of the actual value ((S(S). Although it was not explicitly demonstrated that this ee assay can be used to evaluate enzymes (e.g., proteases), this should in fact be possible. So far this approach has not been extended to other types of substrates. 

Extraction of 25 different binary mixtures of racemic acids (2-(4-isobutylphenyl)-propionic acid (1), and cis- and trans-chrysanthemic (2)), and various chiral bases with supercritical carbon dioxide permitted the conclusion that molecular chiral differentiation in a supercritical fluid is more efficient than in conventional solvents. In the majority of cases, however, complete separation could not be achieved. In five cases, remarkable partial resolutions were realized (30-75% ee) and resolution was possible on a preparative scale. The pair ds-chrysanthemic acid and (S)-(-i-)-2-(benzylamino)-1-butanol (3) was studied in detail. Pressure, temperature, and time, as well as the molar ratio of base and acid, had a marked influence on the quantity and quality of the products. Increasing pressure or decreasing temperature resulted in higher ee values. (-)-cw-Chrysanthemic acid in 99% ee was obtained from the raffinate in a single extraction step. Multiple extractions produced the (-i-)-cA-acid in 90% ee (see fig. 6.3) (Simandi et al., 1997). 

From other approaches to optically active [2.2]metacyclophanes the following are noteworthy as just mentioned for 64 (medium pressure) liquid chromatography on microcrystalline triacetylcellulose (cf. Ref. 82 ) in ethanol or ether (practicable also at lower temperatures) is a very efficient and successful method for the optical resolution of many axial and planar chiral (aromatic) compounds 83). In many cases baseline-separations can be achieved and thereby both enantiomers obtained with known enantiomeric purity and in amounts sufficient for further investigations, especially for studying their chiroptical properties (see also 3.2 and 3.3). The disub-stituted [2.2]metacyclophanes 57 and 59 (which had been previously correlated to many other derivatives) 78- 79) were first resolved by this method83). 

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