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

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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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Figure 1: Synthesis of intermediate compounds B and C.
Figure 2: Synthesis of BIMCD.
Figure 3: Enantiomeric separation of a mixture containing four Dns-amino acids with 10 mM BIMCD.

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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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Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, 117543, Singapore, 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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  1. Weihua Tang
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  2. Siu-Choon Ng
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Correspondence to Weihua Tang or Siu-Choon Ng.

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Tang, W., Ng, SC. Synthesis of cationic single-isomer cyclodextrins for the chiral separation of amino acids and anionic pharmaceuticals. Nat Protoc 2, 3195–3200 (2007). https://doi.org/10.1038/nprot.2007.479

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