Titanium-catalyzed hydroamination and iminoamination reactions are valuable methods for one-pot syntheses of a variety of nitrogen-containing heterocycles. These synthetic methodologies have significantly shortened the steps to access complex heterocycles. Great potential for heterocycles synthesized by titanium catalysis in drug discovery was demonstrated by the two applications in NRF2 pathway inhibition (chapter 2) and proteasome inhibition (chapter 3). Studies on quantifying ligand effects in titanium catalysis have made great contributions to the improvement of reaction rate, selectivity, and catalyst stability. Computational estimation of ligand donor parameter (LDP) is presented using calculated bonding parameters (chapter 4). Finally, models of the ligand properties as a function of reaction rate are developed to predict catalyst performance and guide future catalyst design. A possible new mechanism with unsubstituted indolyl ligands is investigated. Collectively, these studies demonstrate the importance of titanium catalysis in drug discovery and a deeper understanding of ligand effects.
Read
