The use of liquid chromatography and subcritical fluid chromatography for chiral separations using macrocyclic chiral stationary phases: Insights into mechanisms of retention and chiral discrimination

摘要

Enantiomeric separations are an essential component of pharmaceutical drug development, not only at the analytical scale, but also to separate usable quantities for further analysis. The field of asymmetric synthesis is also heavily dependent on chromatographic methods to separate and quantitate the results of asymmetric transformations as well as characterize new ligands and catalysts. This dissertation focuses on the use of macrocyclic chiral stationary phases for use in high performance liquid chromatography as well as subcritical fluid chromatography to separate individual enantiomers of molecules of importance to the scientific community. Optimized separation conditions are provided for many of these important analytes which will expedite the evaluation of their usefulness in a variety of applications. Particular emphasis is put on elucidating the mechanism of interaction between analyte and stationary phase. In chapters two and three, principle component analysis is applied to the chromatographic data to gain better understanding of the factors contributing to retention and enantioselectivity. Optimized separation conditions are also provided newly synthesized isochromene and Troger base derivatives using cyclodextrin and cyclofructan based chiral stationary phases. The fourth chapter provides separation conditions for a variety of newly synthesized biary atropisomers which have the potential to serve as useful ligands in asymmetric transformations as well as possessing antibiotic/antimicrobial properties. Preparative scale separation conditions are also provided allowing for these important analytes to be evaluated in their enantiomerically pure form. Insight into the mechanism of analyte retention is provided indicating that dipolarity/polarizability is the primary retentive interaction between substituted biaryls and derivatized cyclofructans. Chapter five provided a valuable comparison of commonly used chromatographic conditions for the separation of primary amines using cyclofructan based chiral stationary phases. The results indicate that a combination of acidic and basic additives is necessary to obtain optimal separations. The advantages of individual chromatographic modes are also provided. Normal phase separations provided the greatest selectivities at the cost of longer analysis times while modified carbon dioxide mobile phases provided excellent peak profiles and short analysis times. Preparative scale separations are also provided using modified carbon dioxide mobile phases allowing for enantiopure compounds to be prepared in an environmentally friendly manner without the use of petroleum based solvents.