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Synthesis of cationic single-isomer cyclodextrins for the chiral separation of amino acids and anionic pharmaceuticals

Nature Protocols volume 2, pages 31953200 (2007) | Download Citation

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Abstract

We describe a protocol for the synthesis of mono-6A-(1-butyl-3-imidazolium)-6A-deoxy-β-cyclodextrin chloride (BIMCD), a cationic, water-soluble cyclodextrin used in the chiral separation of amino acids and anionic pharmaceuticals by capillary electrophoresis. Starting from commercially available chemicals, BIMCD is synthesized in five steps. The first step involves a nucleophilic substitution between p-toluenesulfonyl chloride and imidazole to afford 1-(p-toluenesulfonyl)imidazole (A). In the second step, a nucleophilic substitution between β-cyclodextrin and A affords mono-6A-(p-toluenesulfonyl)-6A-deoxy-β-cyclodextrin (B). In the third step, a nucleophilic substitution between 1-bromobutane and imidazole affords 1-butylimidazole (C). In the fourth step, a nucleophilic addition between A and C affords BIMCD tosylate. In the final step, anion exchange using an ion-exchange resin yields BIMCD as a highly water-soluble solid. Each step takes up to 2 d, including the time required for product purification. The overall protocol requires approximately 6 d.

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References

  1. 1.

    Chiral Separations by Chromatography (ACS, New York, USA, 2000).

  2. 2.

    , , & Immobilized polysaccharide derivatives: chiral packing materials for efficient HPLC resolution. Chem. Rec. 7, 91–103 (2007).

  3. 3.

    , & Putting chirality to work: the strategy of chiral switches. Nat. Rev. Drug Discov. 1, 753–768 (2002).

  4. 4.

    Chiral separation. Anal. Chem. 78, 3947–3956 (2006).

  5. 5.

    , , & Recent innovations in the use of charged cyclodextrins in capillary electrophoresis for chiral separations in pharmaceutical analysis. Electrophoresis 21, 3220–3239 (2000).

  6. 6.

    & Evaluation of two amine-functionalized cyclodextrins as chiral selectors in CE: comparisons to vancomycin. Microchem. J. 57, 199–217 (1997).

  7. 7.

    & Enantioseparations in capillary electromigration techniques: recent developments and future trends. J. Chromatogr. A 906, 309–363 (2001).

  8. 8.

    & A family of single-isomer, sulfated γ-cyclodextrin chiral resolving agents for capillary electrophoresis: octa(6-o-sulfo)-γ-cyclodextrin. Electrophoresis 24, 130–138 (2003).

  9. 9.

    & Heptakis(2-o-methyl-3,6-di-o-sulfo)-β-cyclodextrin: a single-isomer, 14-sulfated–β-cyclodextrin for use as a chiral resolving agent in capillary electrophoresis. Electrophoresis 22, 3152–3162 (2001).

  10. 10.

    , , , , & Influence of (hydroxy)alkylamino substituents on enantioseparation ability of single-isomer amino-β-cyclodextrin derivatives in chiral capillary electrophoresis. Electrophoresis 25, 2675–2686 (2004).

  11. 11.

    & Chiral separation of anionic and neutral compounds using a hepta-substituted cationic β-cyclodextrin as a chiral selector in capillary electrophoresis. Electrophoresis 23, 1314–1319 (2002).

  12. 12.

    , & Chiral separation of pyrethroic acids with single isomer permethyl monoamino β-cyclodextrin selector. Electrophoresis 22, 3232–3241 (2001).

  13. 13.

    , , , & Heptakis(6-amino-6-deoxy)-β-cyclodextrin as a chiral selector for the separation of anionic analyte enantiomers by capillary electrophoresis. Electrophoresis 25, 2795–2802 (2004).

  14. 14.

    , , , & Synthesis and applications of single-isomer 6-mono(alkylimidazolium)-β-cyclodextrins as chiral selectors in chiral capillary electrophoresis. Electrophoresis 26, 3839–3848 (2005).

  15. 15.

    , , & Facile synthesis and enantioseparation performance of positively charged single-isomers of α- and γ-cyclodextrin. Tetrahedron Asymmetry 18, 1548–1553 (2007).

  16. 16.

    , , , & Synthesis and application of mono-6-ammonium-6-deoxy-β-cyclodextrin chloride as chiral selector for capillary electrophoresis. J. Chromatogr. A 1094, 187–191 (2005).

  17. 17.

    , , & Enantioseparation of acidic enantiomers in capillary electrophoresis using a novel single-isomer positively charged β-cyclodextrin: mono-6A-N-pentylammonium-6A-deoxy-β-cyclodextrin chloride. J. Chromatogr. A 1091, 152–157 (2005).

  18. 18.

    , , & Effect of alkylimidazolium substituents on enantioseparation ability of single-isomer alkylimidazolium-β-cyclodextrin derivatives in capillary electrophoresis. Anal. Chim. Acta 585, 227–233 (2007).

  19. 19.

    , & Chiral separation of dansyl amino acids in capillary electrophoresis using mono-(3-methyl-imidazolium)-β-cyclodextrin chloride as selector. J. Sep. Sci. 30, 1343–1349 (2007).

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Acknowledgements

We are grateful to the National University of Singapore and the Institute of Chemical and Engineering Sciences, Singapore, for their financial support.

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Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.

    • Weihua Tang
  2. Division of Chemical and Biomolecular Engineering, College of Engineering, Nanyang Technological University, Singapore 627833, Singapore.

    • Siu-Choon Ng

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Correspondence to Weihua Tang or Siu-Choon Ng.

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DOI

https://doi.org/10.1038/nprot.2007.479

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