Graduation Semester and Year
Spring 2026
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Daniel W. Armstrong
Abstract
Novel calcium channel blockers (CCBs) with dihydropyridine (DHP) or tetrahydro-4H-chromene moieties are often chiral, so effective enantiomer separation methods are needed for continued drug development. The purpose of this dissertation is to outline a comprehensive method development model for the chiral separations of DHPs and tetrahydro-4H-chromene derivatives. The scope of this dissertation is to address analytical challenges during initial synthesis, chiral separations, and data analysis during post-processing for this class of chiral compounds. The first section focuses on the method development strategies for separations of DHPs in the sub/supercritical fluid (SFC) and normal phase modes with the 2-hydroxypropyl-β-cyclodextrin stationary phase. Cyclodextrin-based stationary phases have become a cornerstone of chiral stationary phases in the reversed-phase mode, with a selection mechanism that relies on inclusion complexation with the analyte and the hydrophobic interior. However, it was demonstrated that chiral selectivity of DHP derivatives can be achieved in SFC with high separation efficiency. Retention and enantiomeric selection mechanisms were determined to depend on external adsorption rather than internal complexation. SFC separations are advantageous because the primary eluent is environmentally green and offers high throughput separations due to higher flow rates.
The second portion of this dissertation expands the scope of separations to include additional chiral column chemistries for a more complete chiral screening comparison. In addition to the cyclodextrin-based stationary phase, chiral separation methods of the CCB candidates were developed and compared with derivatized macrocyclic glycopeptide-based and π-interaction-based stationary phases in the reversed-phase, normal phase, and SFC modes. For the majority of the DHP library, SFC separations that relied on π-interaction were the most effective. These studies establish general chiral screening methods directly applicable to the development of future CCBs.
A detailed investigation into synthesis reveals that one-pot multicomponent reactions for tetrahydro-4H-chromene derivatives consistently generates isomeric product pairs that standard characterization techniques cannot adequately distinguish. Chromatographic separations are supplemented by heteronuclear 2D-NMR and mechanistic analysis to characterize and explain the isomeric products.
Finally, generalized peak models are introduced for chiral separations that more accurately characterize asymmetric chiral peaks than conventional Gaussian or exponentially modified Gaussian (EMG) methods. The chromatographic peaks commonly achieved by these chiral analytes suffer from non-ideal peak behavior resulting in asymmetry. This peak asymmetry is shown to cause significant error in the van Deemter analysis when efficiency is measured by conventional methods. However, sophisticated peak models such as the generalized Haarhoff-Van der Linde (GHVL) or twice generalized normal (TGN) allow for accurate and precise evaluations of kinetics and van Deemter curves.
Keywords
Separations, Chiral, chromatography, supercritical fluid, cyclodextrin, isomerization
Disciplines
Analytical Chemistry | Organic Chemistry
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Burk, Ryan J., "Comprehensive Analytical Investigation of Tetrahydro-4H-chromene and dihydropyridine derivatives" (2026). Chemistry & Biochemistry Dissertations. 6.
https://mavmatrix.uta.edu/chemistry_dissertations2/6