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Atropisomerism as inspiration towards the development of new chemical methodologies
Maddox, Sean Michael
Gustafson, Jeffrey L.
Crowell, JohnGrotjahn, DouglasMoore, BradleyTheodorakis, Emmanuel
Atropisomerism represents a form of chirality that is often swept under the rug in medicinal chemistry and drug development. Nonetheless, our lab has demonstrated that atropisomerism can in fact be exploited to increase the target selectivity of kinase inhibitors, with subsequent perspectives and reports leveraging our findings as a “call to arms” to invoke atropisomerism as a design element in drug discovery efforts. As atroposelective methodology remains a relatively underdeveloped niche in chemistry, we focused our efforts to develop new chemical methodology to move the field of atropisomer synthesis forward. Rigidifying the atropisomeric axis of known kinase inhibitor scaffolds remained a challenging task until we developed a Lewis base catalyzed chlorination of arenes and heterocycles, which is discussed in Chapter 2. We then extended this mode of catalysis towards a regiodivergent chlorination of phenols presented in Chapter 3. The ability to control the site of electrophilic aromatic chlorination by choice of catalyst has been utilized in the synthesis of several natural products and drug-like molecules. Lastly, Chapter 4 discloses a proof of concept towards a first-in-class enantioselective synthesis of diverse atropisomeric scaffolds with the potential for unparalleled access to several different functional groups proximal to the atropisomeric axis. We expect these developed methodologies to make an impact beyond our own research program, hopefully with implications in drug discovery efforts.
Doctor of Philosophy (Ph.D.) University of California, San Diego and San Diego State University, 2018
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