UC San Diego

Atropisomerism refers to a form of conformational chirality that arises when there is a hindered rotation about a single bond. Atropisomers have major effects on the biological activity of small molecules as they can bind to the given target in a small subset of accessible conformations. Off-target binding can cause side effects in patients and failure in the clinic. Therefore, interconversion rates and barriers to rotation of biologically active atropisomers are critical factors to consider during drug development. As the role of atropisomerism expands in the drug discovery, there is a growing need for reliable methods for obtaining atropisomerically pure pharmaceutical compounds. Conventional chiral resolution strategies for separating atropisomers can be laborious, expensive, and difficult to scale. This demonstrates the need for the development of atroposelective methodologies towards pharmaceutically relevant scaffolds. Our lab has developed a rhodium catalyzed atropisomer selective ring expansion of 3-aryl indoles to 4-aryl quinolines, as discussed in Chapter 2. We also explored atroposelective cyclodehydration chemistry towards pyrazolopyrimidines using chiral ammonium salt catalysts, detailed in Chapter 3. We collaborated with the Magolan group from McMaster University to develop a chiral phosphoric acid catalyzed atroposelective Fischer indole synthesis using vinyl sulfides, discussed in Chapter 4. Finally, we are also collaborating with Zage group at Moores Cancer Center to evaluate atroposelective RET kinase inhibitor developed by our group in neuroblastoma tumors. We believe our research can be utilized to obtain a diverse range of atroposelective, pharmaceutically relevant heterocycles and can be beneficial to inform and advance ongoing medicinal chemistry endeavors.