Controlled Catalytic Functionalization of Alkenes and Alkynes

Project Summary/Abstract Fundamentally, a major bottleneck in the drug discovery process across all medical indications is the difficulty of synthesizing topologically complex small molecules for initial biological evaluation and ultimately for large-scale production. This, in turn, points back to limitations in the synthetic toolkit, specifically the paucity of reactions that can be deployed to rapidly and efficiently synthesize families of structurally intricate compounds from simple starting materials. In line with the goals of NIHGMS, our research laboratory seeks to address this problem by developing novel transformations to expedite organic synthesis. Central to our approach is the use of transition metal catalysts that enable otherwise impossible modes of bond construction and that facilitate sustainable synthesis consistent with goals of green chemistry. Since our laboratory’s inception, we have been motivated by the goal of achieving “universal functionalization” of carbon–carbon π-bonds, namely the introduction of any two functional groups desired by an end-user with complete control of regio-, stereo-, and chemoselectivity. In this way, we endeavor to unlock alkenes, alkynes, and related functional groups as general progenitors for all functional group combinations needed in synthesis. Our efforts to date have resulted in the discovery of numerous historically challenging transformations; the invention of new catalysts, reagents, and ligands that have been subsequently commercialized; and the development of novel strategies for reaction development that have been widely adopted within the field. In the current proposal we seek to continue this positive momentum. The described projects build on our established platform for reaction development, wherein gaps in synthetic methodology for π-bond functionalization are targeted, catalyst design principles and mechanistic insights are extracted, and practical utility and scope are iteratively improved. In the next five years, we will generate chemical knowledge that that advances the field of π-bond functionalization and transcends it. First, we will refine and leverage an auxiliary-directed approach to unlock novel reactivity modes with earth-abundant first-row metal catalysts. Second, we will develop strategies that obviate auxiliary installation and removal by relying on interactions with native functional groups. Third, through innovations in ligand design, we will invent non-directed methods that integrate α-olefins and other unsaturated feedstocks.