Synthesis of new, single-isomer quaternary ammonium derivatives of beta-cyclodextrin for electrophoretic enantiomer separations

The isolation of individual enantiomers of drugs is an important subject of interest in the pharmaceutical and medical fields, because stereochemistry can have a significant effect on the biological activity of the drug. Therefore, it is important to develop enantiomeric separation methods for the determination of the optical purity of drugs, since the undesired enantiomer is regarded as one of the impurities. The available single isomer anionic cyclodextrins (CD) can resolve the enantiomers of only a few weakly acidic analytes. To rectify this problem, the chloride salts of heptakis(6-deoxy-6-morpholinio)-cyclomaltoheptaose (HMBCD), and mono(6- deoxy-6-N,N,N r,N r,N r-pentamethylethylenediammonio)-cyclomaltoheptaose (PEMEDA-BCD), the first members of the permanently charged, single-isomer cationic cyclodextrin family, have been synthesized. The purity of process intermediates and final products was determined by HPLC-ELSD and indirect UV-detection capillary electrophoresis. Structural identity was verified by 1D and 2D NMR and massBoth cationic CD derivatives have been used for the separation of the enantiomers of strong acid, weak acid, weak base, ampholytic, and neutral analytes by capillary electrophoresis. Because the charge state of these cationic chiral resolving agents is independent of the pH of the buffer, separation could be performed in both low and high pH buffers without compromising the charge density of the resolving agent. Contrary to expectation, the multiply charged HMBCD showed poor complexation with the newly synthesized strong electrolyte test analytes. The weak binding between the analytes and HMBCD resulted in separation of enantiomers of only three strong electrolyte analytes. Strong complexation was observed between PEMEDA-BCD and the anionic and nonionic analytes in both low and high pH buffers, though complexation was stronger in the high pH buffer. Due to strong complexation between the anions and PEMEDA-BCD, only low concentrations of the resolving agent were required to effect good enantiomer resolutions. spectrometry