Strategies for Base Metal-Catalyzed Asymmetric Hydrogenation and Hydroboration Using N- and P-Donor Ligands

Abstract

Transition metal catalysis enables a variety of chemical transformations that facilitate the production of essential pharmaceuticals and commodity chemicals. Though precious metals such as rhodium and palladium are traditionally used for catalysis, Earth-abundant base metals such as iron, nickel, and cobalt are less costly, more sustainable, and easier to handle. Therefore, the development of base metal platforms for asymmetric hydrogenation and hydroboration of alkenes, two transformations typically catalyzed by precious metals, is highly desirable. Previous work by the Chirik group has led to the development of a cobalt-bis(phosphine) system for the synthesis of Levetiracetam, a drug used to treat epilepsy, by asymmetric hydrogenation. In this thesis, high-throughput experimentation was used to evaluate the performance of this cobalt-bis(phosphine) system with the addition of a zinc activator. Multiple functionalized substrates were successfully hydrogenated with high yield and enantioselectivity. The success of this cobalt-bis(phosphine) platform and the relatively high costs of chiral phosphine ligands motivated the development of a novel base metal-catalyzed asymmetric hydrogenation system using inexpensive, highly modular, and air-stable a-diimine ligands. Twenty-seven diimine ligands were synthesized, and diimine ligand library plates were subsequently prepared to facilitate high-throughput experimentation. Initial screens with iron, nickel, and cobalt precursors revealed limited, scattered hydrogenation activity. Diimine ligands were also evaluated with base metal precursors for the asymmetric Markovnikov-selective hydroboration of styrene. High regioselectivity was observed with a number of ligands; moderate yields and enantioselectivities are targets for future optimization.