BIS(PHOSPHINE) COBALT CATALYSIS: MECHANISM, METHOD DEVELOPMENT, AND APPLICATIONS IN PHARMACEUTICAL SYNTHESIS

Abstract

Bis(phosphine)-ligated transition metal complexes are amongst the most powerful catalysts for organic synthesis, as has been routinely demonstrated for more than half a century. In particular, precious metal complexes of rhodium, ruthenium, and iridium bearing chiral bis(phosphine) ligands have been extensively studied in the context of asymmetric synthesis, wherein much is known about their reactivity, scope, and mechanism of action. In contrast, before the last decade, little exploration had been done on the potential utility of chiral bis(phosphine) complexes of first-row transition metals, such as iron, cobalt, and nickel. In this dissertation, the expansion of mechanistic understanding, scope, and precatalysts design within the context of bis(phosphine) cobalt catalysis is described. Extensive studies, combining experimental and computational techniques, elucidated the mechanism of the asymmetric hydrogenation of prochiral enamides by neutral, bis(phosphine) cobalt complexes. A surprisingly rhodium-like Co(0)-Co(II) unsaturated pathway was determined, shifting paradigms in the nature of paramagnetic, first-row transition metal catalysis. Efforts have also been made to expand the scope of bis(phosphine) cobalt-catalyzed asymmetric hydrogenation, particularly to those substrates relevant to pharmaceutical synthesis. In a collaboration with Biohaven pharmaceuticals, both neutral and cationic bis(phosphine) cobalt complexes were applied to the asymmetric hydrogenation of a precursor to zavegepant, a recently FDA-approved medication for the treatment of migraine headaches, in up to a 20-gram scale. Method development work in collaboration with Merck has also been performed on the asymmetric hydrogenation of unprotected allylic amines. High-throughput experimentation helped reveal that the combination of cobalt triflate salt and bis(phosphine) provided efficient and highly enantioselective catalysisfor allylic amine hydrogenation through a surprising neutral Co(II) to cationic Co(I) in-situ activation event in the presence of zinc or amine base. Initial forays have also been made into the insertion of unactivated arenes into chiral bis(phosphine) cobalt complexes, as well as fluorine- directed asymmetric hydrogenation. The effect of carbonyl ligands on the reactivity of bis(phosphine) cobalt complexes has also been explored. Switchable mechanistic behavior was observed from bis(phosphine) cobalt bis(carbonyl) hydride complexes in their hydrogenation reaction with alkenes, demonstrating outer-sphere, radical hydrogen atom transfer reactivity under thermal conditions and inner-sphere, coordination-insertion reactivity under visible light irradiation.