Enantioselective Synthesis of Heterocycles via Palladium Catalyzed Alkene Difunctionalization Reactions.

Abstract

Enantiopure nitrogen and oxygen containing heterocycles are prominently displayed in a variety of important pharmaceuticals and biologically active products. As such accessing these scaffolds in an enantioselective and efficient manner is an interesting challenge. We envisioned that novel asymmetric carboamination and carboetherification reactions would be powerful methods to synthesize these enantiopure heterocycles, as you can generate a library of enantiopure compounds in a facile manner with this approach. While these enantioselective carboamination and carboetherification reactions are robust methods of accessing enantiopure heterocycles, at the onset of the work detailed in this thesis all of the efforts in this area were related to the formation of 5-membered rings bearing a single nitrogen heteroatom. As such, this thesis entails the development of new enantioselective carboamination and carboetherification reactions meant to address the above limitations. Chapter 2 details the development of an enantioselective carboamination reaction to access enantiopure imidazolidin-2-ones in up to 97:3 er. This work also shows how reaction conditions, namely the choice of aryl halide, use of water additive and substrate electronics, affect the final enantioselectivity observed in the products. Chapter 3 details the development of a general procedure to access tetrahydroquinolines, tetrahydroisoquinolines and tetrahydroquinoxalines all in > 95:5 er. Furthermore, these reactions in chapter 3 are rare transformations of this type that allow for the synthesis of quaternary centers in high enantioselectivity. Chapter 4 details the xiii development of a novel carboetherification reaction, and how using a modular TADDOL ligand scaffold allowed us to rationally design a ligand that afforded our desired products in >95:5 er. Lastly, Chapter 5 entails the initial results looking into the synthesis of enantiopure benzofused oxygen heterocycles.