1.Development and application of chiral crown ethers as selectors for chiral separation in high-performance liquid chromatography and nuclear magnetic resonance spectroscopy.
Paik MJ1, Kang JS, Huang BS, Carey JR, Lee W. J Chromatogr A. 2013 Jan 25;1274:1-5. doi: 10.1016/j.chroma.2012.11.086. Epub 2012 Dec 10.
Chiral crown ethers have been widely used in the resolution of various chiral compounds containing a primary amino group. Covalently bonded chiral stationary phases derived from (18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA) were developed in our groups and utilized for the resolution for several types of analytes. By use of NMR spectroscopy, chiral discrimination studies were performed for α-amino acids and their esters using 18-C-6-TA. Here, advances in the development and application of chiral stationary phases and chiral solvating agents using 18-C-6-TA for enantiomer resolution are described in relationship to recent chiral recognition mechanism studies.
2.Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid.
Lee GR1, Hyun MH2. Molecules. 2014 Dec 19;19(12):21386-97. doi: 10.3390/molecules191221386.
Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (RS) of 1.55 when a mobile phase consisting of methanol-acetonitrile-trifluoroacetic acid-triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition.
3.Utilization of (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent for diamines and β-amino acids.
Rodriguez YC1, Duarte TM1, Szakonyi Z2, Forró E2, Fülöp F2, Wenzel TJ1. Chirality. 2015 Oct;27(10):708-15. doi: 10.1002/chir.22491. Epub 2015 Aug 18.
The compound (18-crown-6)-2,3,11,12-tetracarboxylic acid was evaluated as a chiral nuclear magnetic resonance (NMR) solvating agent for a series of diamines and bicyclic β-amino acids. The amine must be protonated for strong association with the crown ether. An advantage of (18-crown-6)-2,3,11,12-tetracarboxylic acid over many other crown ethers is that it undergoes a neutralization reaction with neutral amines to form the protonated species needed for binding. Twelve primary diamines in neutral and protonated forms were evaluated. Diamines with aryl and aliphatic groups were examined. Some are atropisomers with equivalent amine groups. Others have two nonequivalent amine groups. Association equilibria for these systems are complex, given the potential formation of 2:1, 1:1, and 1:2 crown-amine complexes and given the various charged species in solution for mixtures of the crown ether with the neutral amine. The crown ether produced enantiomeric differentiation in the (1) H NMR spectrum of one or more resonances for every diamine substrate.
4.Enantioseparations of primary amino compounds by high-performance liquid chromatography using chiral crown ether-based chiral stationary phase.
Hyun MH1. Methods Mol Biol. 2013;970:165-76. doi: 10.1007/978-1-62703-263-6_9.
Liquid chromatographic resolution of racemic compounds containing a primary amino group has been known to be most successful when chiral crown ether-based chiral stationary phases (CSPs) are used. Among various crown ether-based CSPs, the stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel has been successfully applied in the resolution of various racemic compounds containing primary amino groups. In this chapter, the preparation of the CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel and examples for the application to the enantioseparation of racemic compounds including α-amino acids, cyclic amines, amino alcohols, and chiral drugs are described.