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

摘要

The isolation of individual enantiomers of drugs is an important subject ofinterest in the pharmaceutical and medical fields, because stereochemistry can have asignificant effect on the biological activity of the drug. Therefore, it is important todevelop enantiomeric separation methods for the determination of the optical purity ofdrugs, since the undesired enantiomer is regarded as one of the impurities.The available single isomer anionic cyclodextrins (CD) can resolve theenantiomers of only a few weakly acidic analytes. To rectify this problem, the chloridesalts 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 cationiccyclodextrin family, have been synthesized. The purity of process intermediates andfinal products was determined by HPLC-ELSD and indirect UV-detection capillaryelectrophoresis. Structural identity was verified by 1D and 2D NMR and massBoth cationic CD derivatives have been used for the separation of theenantiomers of strong acid, weak acid, weak base, ampholytic, and neutral analytes bycapillary electrophoresis. Because the charge state of these cationic chiral resolvingagents is independent of the pH of the buffer, separation could be performed in both lowand high pH buffers without compromising the charge density of the resolving agent.Contrary to expectation, the multiply charged HMBCD showed poor complexation withthe newly synthesized strong electrolyte test analytes. The weak binding between theanalytes and HMBCD resulted in separation of enantiomers of only three strongelectrolyte analytes. Strong complexation was observed between PEMEDA-BCD andthe anionic and nonionic analytes in both low and high pH buffers, though complexationwas stronger in the high pH buffer. Due to strong complexation between the anions andPEMEDA-BCD, only low concentrations of the resolving agent were required to effectgood enantiomer resolutions.spectrometry.