Optical chirality sensing ensembles : mechanistic studies and applications in synthetic methodology development

Jo, Hyun Hwa
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In the pharmaceutical industry, the development of molecular or chemical sensors for an analyte of interest and the determination of the enantiomeric purity of chiral molecules is essential. Chirality sensors were developed for analytes, such as alcohols, carboxylic acids, ketones, etc., which are valuable building blocks for the synthesis of complex pharmaceuticals. As such, the development of protocols for enantiomeric excess (ee) analysis of alcohols is of significant interest. Furthermore, high-throughput ee screening (HTS) has become crucial due to advances in the methods of combinatorial chemistry and parallel synthesis. Chapter 1 presents the overview of optical detection methods for ee analysis, as they are more suitable for HTS, compared to chromatographic techniques. The alcohols are important functional groups that are widely found in natural products such as terpenes, steroids and saccharides. Accordingly, the development of protocols involving multi-component dynamic assembly for ee analysis of alcohols has been extensively explored. Chapter 2 presents the ee screening method utilizing a reversible tetradentate ligand-based assembly that incorporates the chiral alcohols. The inclusion of alcohols into the ligand structure induces a twist which results in large Cotton effects in the circular dichroism spectra; indicative of the handedness of the alcohol. The objective of the work has been applying this chiral alcohol sensing assay for a true HTS in combination with the parallel synthesis of chiral homo-allylic alcohol. Chapter 3 reports on past studies performed to further gain kinetics and the mechanistic insight toward the multi-component assembly reaction. By elucidating the mechanism of the assembly reaction, we can further optimize the experimental conditions of the reaction in the development of a new assembly. Finally, Chapter 4 presents an effort toward the advancement of a novel sensor for α-chiral ketones. Chiral ketones produced by α-arylation of α,α-difluorocarbonyl compounds has been of interest in medicinal chemistry. This is not only contributed by carbonyl functionality, but by the importance of aromatic compounds containing a fluorine atom or a trifluoromethyl group on an aromatic ring. Improving the original chiral ketone assay to achieve HTS will substantially aid developments in synthetic methodology.