Development and application of carbon-carbon bond forming methodologies
Bishop, Joshua Aaron
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The construction of novel small molecules is an invaluable tool to the fields of chemical biology and drug discovery. Information gained from introducing unique chemical moieties to biological systems allows for a better understanding of the governing dynamics of cellular mechanisms leading to new treatments for disease. The only way to explore uncharted biological space is by discovering and producing new chemical structures. The work described herein discusses the development and application of novel chemical methodologies to arrive at unique small molecules. An organocatalytic, asymmetric addition of carbon nucleophiles to prochiral aldimines was developed. This transformation capitalizes on the inherent properties of boron to promote a ligand exchange with chiral diols generating a chiral nucleophile in situ. Mechanistic studies were carried out to gamer a better understanding of this transformation. Propargyl, vinyl and aryl substituted amides are generated in high chemical yield and as single enantiomers. The transformation yields synthetically useful chiral building blocks as shown through the formal synthesis of the known pharmaceutical Xyzal©. Reaction discovery implementing a series of propargyl arnides lead to the development of unique Ag catalyzed 5-exo and 6-endo cyclizations to produce novel oxazolines and oxazines respectively. A novel, asymmetric formal [3+2] cycloaddition utilizing substituted isocyanoacetates as stabilized dipoles was invented. The transformation yields chemically unique nitrogen containing heterocycles with two stereogenic centers. The stereochemical outcome of the process is controlled through the choice of ligand to arrive at either the anti or syn dihydro-pynolidine product. The transformation represents the first reported application of a Ag/Trost ligand complex for a chemical process. As such, mechanistic investigations were canied out to illuminate the catalytic cycle. The synthesis and application of the first small molecule inhibitor of transcription factor LSF is discussed. The isoquinolinone scaffolds were modified from a medicinal chemistry standpoint to optimize the pharmacophore. Synthetic pathways, structure activity relationships and solubility characteristics of the isoquinolinones were addressed. A pharmacokinetic analysis was done to dete!Tlline a metabolic pathway and rate of metabolism of the lead compound in vitro. These unique small molecules are shown to have uM activity in vivo against human hepatocellular carcinoma cell lines with no signs of toxicity and uM activity in vitro against both 3T3 and HeLa cell lines.
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