Enantioselective and site-selective C-H activation reactions with Bifunctional ligands - Project Summary Highly selective and diverse C(sp3)–H and C(sp2)–H functionalizations could greatly facilitate and impact the development and synthesis of therapeutics for human health and probes for chemical biology in three key aspects: the discovery of expedient new synthetic disconnections, the application of novel catalytic asymmetric methods for chiral synthesis, and molecular editing for late-stage diversification. The impact of our C–H activation reactions thus far is demonstrated by syntheses from over 20 laboratories and numerous successful drug discovery programs in pharma, ranging from Nav 1.8 (Vertex), KRAS12D (Eli Lilly), PD-1 (BMS), to WRN Helicase (Vividion). Realizing our ultimate vision of C–H functionalization requires addressing two key challenges: regio-/stereo-selectivity (activating the targeted C–H bonds with high precision) and functionalization diversity (installing diverse C–C, C–O, C–X, and C–N bonds). We first aim to develop next-generation ligands capable of the enantio- and site-selective C(sp3)–H activation of aliphatic carboxylic acid substrates. Through extensive bifunctional ligand development, we have achieved the challenging Pd-catalyzed C(sp3)–H activation reactivity of aliphatic carboxylic acids. Moving forward, we seek to develop enantioselective C(sp3)–H activation reactions at the β-, γ-, and δ-methylene C–H bonds relative to the carboxylic acid, with concomitant high site-selectivity. We will also use our newly developed ligand to broaden functionalization scope to olefination, alkylations, and valuable C–O/N/X bond formations with sustainable oxidants (molecular oxygen, peroxides). We also will develop enantio- and site-selective ring forming C–H functionalizations in which multiple C–H bonds are transformed in a single step to provide a new formal cycloaddition strategy for rapid carbocycle construction. Second, we aim to achieve enantioselective C(sp3)–H activation reactions of other weakly coordinating aliphatic substrates, specifically alcohols, ketones, and neutral amides. We have recently developed several strategies to improve Pd recruitment, including the use of non-covalent interactions to enhance catalyst-substrate affinity, ligand tuning of Pd binding affinity, and the formation of transient assemblies with the substrate (TDG strategy). We propose the enantioselective C(sp3)–H activation reactions of these substrates using next-generation chiral ligands and the complementary chiral tridentate TDG strategy. Finally, we propose the development of new and general template strategies for remote site-selective C(sp2)–H activation reactions of extended hetero(arenes), with an emphasis on ligand-enabled C–O/N bond formations with sustainable oxidants.
