The Development and Application of Chirotechnology Using Chiral Crown Ethers for Enantiomer Separation

광학분리를 위한 키랄 크라운 에테르를 이용한 키랄공학의 개발과 응용

  • 백만정 (순천대학교 약학대학 약학과) ;
  • 윤원남 (조선대학교 약학대학 약학과) ;
  • 이원재 (조선대학교 약학대학 약학과)
  • Received : 2012.07.30
  • Accepted : 2012.08.20
  • Published : 2012.08.31


Chiral crown ethers are synthetic macrocyclic polyethers that bind protonated chiral primary amines with high selectivity and affinity. They have been widely used to separate or distinguish the enantiomers of chiral compounds containing a primary amino moiety by high-performance liquid chromatography, capillary electrophoresis, and NMR spectroscopy. In this paper, two important chiral crown ethers including chiral binaphthyl unit and (18-crown-6)-2,3,11,12-tetracarboxylic acid as chiral selectors are focused. And several chiral resolution techniques and their applications in chirotechnology using these chiral crown ethers with related chiral recognition mechanism studies are reviewed. Especially, it was shown that the commercially available HPLC columns based on (18-crown-6)-2,3,11,12-tetracarboxylic acid have been developed and successfully applied for the resolution of various primary amino compounds including amino acids.



  1. Pedersen, C. J. (1967) Cyclic polyethers and their complexes with metal salts. J. Am. Chem. Soc. 89: 2495-2496.
  2. Cram, D. J. (1988) The design of molecular hosts, guests, and their complexes. Angew. Chem. Int. Engl. 27: 1009-1020.
  3. Zhang, X.-X., J. S. Bradshaw, and R. M. Izatt (1997) Enantiomeric recognition of amine compounds by chiral macrocyclic receptors. Chem. Rev. 97: 3313-3362.
  4. Vogtle, F. and E. Weber (1985) Host Guest Complex Chemistry-Macrocycles, pp. 1-41. Springer-Verlag, Berlin.
  5. Shinbo, T., T. Yamaguchi, K. Nishimura, and M. Sugiura (1987) Chromatographic separation of racemic amino acids by use of chiral crown ether-coated reversed-phase packings. J. Chromatogr. A. 405: 145-153.
  6. Application guide for chiral HPLC selection, 3rd Ed., (2002) Daicel Chemical Industries, Ltd.
  7. Lee, W. and C. Y. Hong (2000) Direct liquid chromatographic enantiomer separation of new fluoroquinolones including gemifloxacin. J. Chromatogr. A. 879: 113-120.
  8. Shinbo, T., T. Yamaguchi, H. Yanagishita, D. Kitamoto, K. Sakaki, and M. Sugiura (1992) Improved crown ether-based chiral stationary phase. J. Chromatogr. A. 625: 101-108.
  9. Hyun, M. H., S. C. Han, B. H. Lipshutz, Y.-J. Shin, and C. J. Welch (2001) New chiral crown ether stationary phase for the liquid chromatographic resolution of $\alpha$-amino acid enantiomers. J. Chromatogr. A. 910: 359-365.
  10. Hyun, M. H. (2006) Preparation and application of HPLC chiral stationary phases based on (+)-(18-crown-6)-2,3,11,12- tetracarboxylic acid. J. Sep. Sci. 29: 750-761.
  11. Hyun, M. H. (2005) Development and application of crown ether-based HPLC chiral stationary phases. Bull. Kor. Chem. Soc. 26: 1153-1631.
  12. Kuhn, R., F. Erni, T. Bereuter, and J. Hausler (1992) Chiral recognition and enantiomeric resolution based on host-guest complexation with crown ethers in capillary zone electrophoresis. Anal. Chem. 64: 2815-2820.
  13. Kuhn, R., J. Wagner, Y. Walbroehl, and T. Bereuter (1994) Potential and limitations of an optically active crown ether for chiral separation in capillary zone electrophoresis. Electrophoresis. 15: 828-834.
  14. Behr, J.-M., J.-M. Girodeau, R. C. Heyward, J.-M. Lehn, and J.-P. Sauvage (1980) Molecular receptors. functionalized and chiral macrocyclic polyethers derived from tartaric acid. Helv. Chim. Acta. 63: 2096-2111.
  15. Lee W., S. La, Y. Choi, and K.-R. Kim (2003) Chiral discrimination of aromatic amino acids by capillary electrophoresis in (+)- and (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid selector modes. Bull. Kor. Chem. Soc. 24: 1232-1234.
  16. Park H.-J., Y. Choi, W. Lee, and K.-R. Kim (2004) Enantioseparation of aromatic amino acids and amino acid esters by capillary electrophoresis with crown ether and prediction of enantiomer migration orders by a three-dimensional quantitative structureproperty relationship/comparative field analysis model. Electrophoresis 25: 2755-2760.
  17. Paik, M.-J. and W. Lee, Unpublished results.
  18. Hyun, M. H., J. S. Jin, and W. Lee (1998) A new HPLC chiral stationary phase for the direct resolution of racemic quinolone antibacterials containing a primary amino group. Bull. Kor. Chem. Soc. 19: 819-821.
  19. Hyun, M. H., J. S. Jin, and W. Lee (1998) Liquid chromatographic resolution of racemic amino acids and their derivatives on a new chiral stationary phase based on crown ether. J. Chromatogr. A. 822: 155-161.
  20. Hyun, M. H., J. S. Jin, and W. Lee (1999) Liquid chromatographic resolution of racemic amines and amino alcohols on a chiral stationary phase derived from crown ether. J. Chromatogr. A. 837: 75-82.
  21. Hyun, M. H., S. C. Han, J. S. Jin, and W. Lee (2000) Separation of the stereoisomers of racemic fluoroquinolone antibacterial agents on a crown-ether-based chiral HPLC stationary phase. Chromatographia 52: 473-476.
  22. Hyun, M. H., S. C. Han, Y. J. Cho, J. S. Jin, and W. Lee (2002) Liquid chromatographic resolution of gemifloxacin mesylate on a chiral stationary phase. Biomed. Chromatogr. 16: 356-360.
  23. Lee, W., C.-S. Baek, and K. Lee (2002) Chromatographic enantiomer separation of diphenylalanine on chiral stationary phases derived from chiral crown ethers. Bull. Kor. Chem. Soc. 23: 1677-1679.
  24. Lee, W., J. Y. Jin, and C.-S. Baek (2005) Comparison of enantiomer separation on two chiral stationary phases derived from (+)-18-crown-6-2,3,11,12-tetracarboxylic acid of the same chiral selector. Microchem. J. 80: 213-217.
  25. Jin, J. Y., W. Lee, and M. H. Hyun (2006) Development of the antipode of the covalently-bonded crown ether type chiral stationary phase for the advantage of the reversal of elution order. J. Liq. Chrom. & Rel. Tech. 29: 841-848.
  26. Machida, Y., H. Nishi, K. Nakamura, H. Nakai, and T. Sato (1998) Enantiomer separation of amino compounds by a novel chiral stationary phase derived from crown ether. J. Chromatogr. A. 805: 85-92.
  27. Machida, Y., H. Nishi, and K. Nakamura (1998) Nuclear magnetic resonance studies for the chiral recognition of the novel chiral stationary phase derived from 18-crown-6 tetracarboxylic acid. J. Chromatogr. A. 810: 33-41.
  28. Hyun, M. H., Y. J. Cho, J. A. Kim, and J. S. Jin (2003) Preparation and application of a new modified liquid chromatographic chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. J. Chromatogr. A. 984: 163-171.
  29. Hyun, M. H., H. J. Koo, J. S. Jin, and W. Lee (2000) Liquid chromatographic resolution of racemic compounds containing a primary amino group on a dynamic chiral stationary phase derived from chiral crown ether. J. Liquid Chrom. & Rel. Tech. 23: 2669-2682.
  30. Jin, J. Y. and W. Lee (2007) Liquid chromatographic enantiomer resolution of N-hydrazide derivatives of 2-aryloxypropionic acids on a crown ether derived chiral stationary phase. Chirality. 19: 120-123.
  31. Bang, E., J.-W. Jung, W. Lee, D. W. Lee, and W. Lee (2001) Chiral recognition of (18-crown-6)-tetracarboxylic acid as a chiral selector determined by NMR spectrocropy. J. C. S. Perkin Trans. 2: 1685-1692.
  32. Lee, W., E. Bang, and W. Lee (2003) Chiral resolution of diphenylalanine by high-performance liquid chromatography on a crown-ether-based chiral stationary phase and by NMR spectroscopy. Chromatographia. 57: 457-461.
  33. Lee, W., E. Bang, C.-S. Baek, and W. Lee (2004) Chiral discrimination studies of (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid by high-performance liquid chromatography and NMR spectroscopy. Magn. Reson. Chem. 42: 389-395.
  34. Lee, T., W. Lee, M. H. Hyun, and J. H. Park (2010) Enantioseparation of native ${\alpha}$-amino acids on an 18-crown-6-tetracarboxylic acidbonded silica by capillary electrochromatography. J. Chromatogr. A. 1217: 1425-1428.
  35. Jeon, S. H., M. H. Kim, H.-K. Han, and W. Lee (2010) Direct enantiomer separation of thyroxine in pharmaceuticals using crown ether type chiral stationary phase. Arch. Pharm. Res. 33: 1419-1423.
  36. Jeon, S. H. and W. Lee (2010) Monitoring of the optical purity for levothyroxine sodium in pharmaceuticals using crown ether derived chiral columns. KSBB J. 25: 449-452.
  37. Jin, J. Y., C.-S. Baek, and W. Lee (2007) Development of a validated HPLC method for the simultaneous determination of D- and L-thyroxine in human plasma. Bull. Kor. Chem. Soc. 28: 1070-1072.
  38. Lee, W. (2009) The application of chiral HPLC columns for enantiomer separation of chiral drugs. Yakhak Hoeji. 53: 60-68.
  39. Kim, K. J., I. Choi, K. Seo, H.-K. Han, and W. Lee (2011) Regulatory requirements on the safety and efficacy evaluation for the development of stereoisomeric drugs. Yakhak Hoeji. 55: 426-431.