Alkali Metal Chemistry-Structures, Mechanisms, and Applications

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Summary and Abstract Organoalkali metal-based reagents are used in both academic and industrial laboratories to carry out syntheses of medicinally important compounds. The underlying aggregates and central importance of solvation cause these reagents to be as structurally and mechanistically confounding as any subdiscipline in organometallic chemistry. Through a combination of structural and mechanistic studies we address key issues pertaining to reactivity and selectivity. The program is fully integrated starting from a synthetic goal, observation, or question, proceeding through structural, mechanistic, and computational studies, and finishing with synthetically useful insights and methods. Treating solvation as a molecular rather than bulk phenomenon is central to all of our studies. We will emphasize the role of non-covalent auxiliaries and focus on two subsets of alkali metal chemistry that have proven virtually impenetrable to careful scrutiny: lithium enolates and sodium amides. Both arenas require a combined effort involving (1) the elucidation of profoundly lacking basic structural and mechanistic principles, and (2) pushing a mechanism-driven approach to develop new strategies for controlling reactivity and selectivity. In the enolate program, we emphasize the role of mixed aggregates with chiral lithium alkoxides as vehicles to control relative and absolute stereochemistry. In the organosodium chemistry, we will continue studying the principles of structure and mechanism to develop completely absent principles of reactivity and selectivity. Among a multitude of differences of sodium- versus lithium-based reagents discovered so far, it is the capacity to catalyze organosodium reactions with triamines that stands out. We will focus on catalytically active chiral triamines to induce stereocontrol via kinetic resolutions by sodium amides and catalyzed asymmetric functionalizations of the resulting sodiated intermediates. The Holy Grail for us is finding universal additives—amino alkoxides for lithium enolates and chiral triamines for the organosodium reactions.