Rhodium and Cobalt Transition Metal Catalysis for Heteroarene Dearomatization and Natural Product Synthesis

Abstract

Nitrogen heterocycles are ubiquitous in pharmaceuticals, agrochemicals, and natural products and occur often as partially or fully saturated non-aromatic six-membered rings. Much work has gone into the development of methodologies for the synthesis of non-aromatic nitrogen heterocycles. However, substrate limitations, and/or the need for reagents and starting materials that require multistep syntheses have left room for improvement in the synthesis of non-aromatic nitrogen heterocycles. The transition metal mediated asymmetric dearomatization of activated heteroarenium salts yields dihydroheteroarene compounds that can act as building blocks to access either functionalized pyridines through oxidation, or tetrahydropyridines and piperidines through functionalization or reduction. Further the use of transition metal catalysis would allow for the development of substrate independent regio- and enantioselective dearomatization methods. To date no one solution has been reported that allows for the control of both enantioselectivity and regioselectivity in the dearomatization of pyridiniums to yield chiral dihydropyridines.

This thesis focused on the development of regioselective and enantioselective pyridinium dearomatization methodologies. Chapter 2 focuses on the first reported rhodium catalyzed C2-selective dearomatization of pyridinium salts derived from nicotinic acid esters to generate chiral dihydropyridines. Chapter 3 extends this same approach to the synthesis of dinitrogen heterocycles in the form of quinoxalines. Chapter 4 reports the use of the developed rhodium-based asymmetric dearomatization methodologies to access chiral, natural products nuphar indolizidine and deoxylasubine II. Finally, Chapter 5 reports preliminary data on the first reported asymmetric dearomatization of quinolinium salts utilizing a cost-effective and less toxic, earth abundant metal, cobalt, and several novel binaphthalene Schiff-base-type ligands.