New eras of catalysis: Towards the development of pseudotransition metal organocatalysts for metal-free cross-coupling transformations - Transition-metal catalyzed cross-coupling transformations are indispensable to pharmaceutical development and medicinal chemistry, allowing access to innumerable bond connections in extremely complex molecular settings. Despite its power, continued reliance on transition-metal catalysis poses many challenges. For example, a most pressing challenge in pharmaceutical synthesis is the extreme cost associated with the noble metals that form these precious, high-powered catalysts (e.g., Ru, Rh, Pd, Pt, and Ir). Furthermore, transition- metals are treated with strict regulation due to their elemental toxicity, imparting significant cost in the upstream synthetic stages of delivering a drug to the marketplace. Finally, continued reliance on transition-metal catalysis is unsustainable, threatened by the rapid depletion of raw materials at known global deposits and consistent supply-chain disruptions. Thus, the development of alternative strategies for mild and general bond formation is necessary for continued productivity in pharmaceutical and medicinal chemistry. Organocatalysis is an attractive surrogate to traditional transition-metal catalysis, leveraging readily accessible, inexpensive, and practical small molecules as catalysts. The identification of an organocatalyst with the ability to mimic the behavior of a transition-metal catalyst forms an ideal approach; a priori, such a strategy would be “plug and play,” invoking only a change in catalyst identity while preserving the nature of cross-coupling partners traditionally utilized in cross-coupling chemistry. If successful, this approach would address each of the challenges previously enumerated. The goal of this proposal is to design, synthesize, and develop a series of “pseudometal” organocatalysts to facilitate a vast array of catalytic cross-coupling transformations. These catalysts are termed pseudometal to reflect their ability to mimic the classical bond-breaking and bond-forming behavior of transition-metal catalysts. Specifically, this research plan details the development of ortho-dithioquinones as pseudometal organocatalysts, guided by principles of rational design, structure-activity-relationships, computational modeling, and hypothesis- driven experimentation. Our preliminary computational results direct us to ortho-dithioquinones due to the neutral Gibbs free energies predicted for oxidative insertion of these scaffolds into several s-bond types. In this research, rigorous mechanistic and characterization studies will profile the key principles inherent to organocatalyst speciation and the associated elementary steps, featuring stoichiometric studies, linear free-energy relationship analyses, and catalytic intermediate characterization. Guided by a rich mechanistic understanding, we will examine the synthetic capabilities of these organocatalysts through a series of cross-coupling transformations, including examples of C–N, C–O, C–SF5, and N–CF3 bond formation. Overall, this research will establish a new paradigm for sustainable, accessible cross-coupling chemistry, and will significantly contribute to medical research, pharmaceutical development, and fundamental knowledge in organic synthesis.
