Document Type

Theses, Ph.D

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1.4 CHEMICAL SCIENCES

Publication Details

Successfully submitted for the award of Doctor of Philosophy (Ph.D) to the Technological University Dublin 2007.

Abstract

The processes of separation and detection of chiral compounds are extremely important in the pharmaceutical industry. This study aims to investigate a safe and variable methods for the separation of the two enantiomers of the drug DOPA (Dihydroxyphenylalanine). L-DOPA is the most effective drug at present used to combat Parkinson’s disease while D-DOPA is inactive, thus for drug efficacy only the single biologically active enantiomer should be present in the formulation. In this work, cyclodextrins (CDS) were utilised fro their ability to act as a host for guest species, acting in the role as both a first and second sphere ligand. CDs are a class of naturally occurring receptor molecules with chiral hydrophobic cavities, which render them efficient hosts for a wide variety of guest molecules. The ability of these supermolecules to differentiate between enantiomers has been exploited in this context for the development of an efficient enantioseparation technique. Three diaminoalkane derivatives of B-CD were synthesised from the tosylate intermediate and used to coordinate with copper (II) resulting in the formation of binary complexes. Further coordination (through the metal ion) of these complexes to amino acids allowed the formation of ternary complexes and the possibility of inclusions of the amino acid within the cavity of the CD. The intended purpose for these materials is their use as chiral selectors for the separation of enantiomers of amino acids. The CD derivatives were analysed using vibration spectroscopes (both IR and Raman), electronic spectroscopes (UV-Vis, fluorescence and circular dichroism) and nuclear magnetic resonance spectroscopies (1H-NMR, 13C-NMR and HSQC). The amino acids examined in this study were D/L phenylalanine, D/L tyrosine and D/L DOPA. The former two were analysed as they are structurally similar to and are also the biological precursors for the in vivo production of DOPA. The results obtained from the electronic absorption spectra suggested the formation of CuCDAm binary complexes and that the derivatives CDEn and CDPn act as bidentate ligands while CDBn acts as a monodentate ligand due to the presence of the longer alkane chain. This study also showed that in the ternary complexes with the amino nitrogen atom and the hydroxyl oxygen atom of the drug. Circular dichroism allowed us to show that systematically increasing the chain length of the diaminoalkane moiety reduces the chiral selectivity of the metallo-complexes. On the basis of the results it was suggested that CuCDEn is the better enantioselective material for DOPA and it acts in a multi-site recognition manner, utilising the inclusion properties of the CD cavity in conjuction with the coordination properties of the metal ion. It was hypothesised that due to the differing degrees of inclusion within the CD cavity of the different enantiomers, the complexes formed were diasteroisomers and would differ as such in their chemico-physico properties. Capillary electrophoresis was employed as the technique of choice fro the development of a separation technique exploiting this characteristic. The findings determined that enantioseparation was possible using LECE and an optimum separation resolution of tyrosine was obtained. Based on the studies carried out, it was determined that CuCDEn was the preferred enantioselector for the enantiomers of tyrosine, as solubility problems were encountered with the other binary complexes CuCDPn and CuCDBn. The study with tyrosine allowed the predetermination of the experimental parameters to be used for the separation of the enantiomers of DOPA.

DOI

https://doi.org/10.21427/D77885

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