UC San Diego

Inspired by atropisomerism and examples of differential biology displayed by enantiomeric compounds, I set out to develop a late stage regioselective functionalization of known kinase inhibitors that exhibit atropisomerism. The regioselective functionalization of these target atropisomeric scaffolds is pivotal in order to increase their barrier to rotation, rendering them isolable enantiomers. Chapter 1 explores the chemical methods developed in order to achieve this transformation. The mild late stage regioselective chlorination, and more broadly, halogenation of several diverse aromatics along with the target atropisomeric kinase inhibitor was achieved by employing phosphine sulfide Lewis base catalysts. Encouraged by this mild catalytic approach to functionalizing electron rich aromatics and heterocycles, I was intrigued to see if similar conditions could be extended to aromatic sulfenylation. Chapter 2 explores aromatic sulfenylation and the development of several bifunctional Lewis base-Bronsted acid catalysts to affect a mild sulfenylation of electron rich aza-heterocycles. The sulfenylation reagents employed in this project were diverse and the notable azido group was incorporated into one of the reagents. This advancement was applied to bioactives and peptides. When functionalizing di-substituted and tetra-substituted peptides our sulfenylation conditions were shown to be amenable in the presence of other electron rich side chains included amino acids, histidine and tyrosine. Though this methodology is selective, the limitation of this methodology is the scope of the reaction, limited to electron rich aza-heterocycles. This limitation was overcome by employing more electron rich selenoether Lewis base catalysts along with catalytic acid described in chapter 3. The findings in chapter 3 provide an improvement to mild sulfenylation methodologies by increasing the scope of reaction along with uncovering key mechanistic findings. The SCF3 group was applied to 3 FDA-approved drugs and shown to have significant increases in reactivity when catalytic selenoether Lewis base, along with catalytic acid are present. A comparison of electron rich and electron poor sulfenylation reagents corroborate the kinetic findings in this project.