Palladium-Catalyzed Enantioselective β-C(sp

Enolate alkylation and conjugate addition into an α,β-unsaturated system have served as long-standing strategic disconnections for the installation of α- or β-substituents on carbonyl-containing compounds. At the onset of our efforts to develop C-H activation reactions for organic synthesis, we set our eye toward developing asymmetric β-C-H activation reactions of aliphatic acids with the perspective that this bond-forming event could serve as a more flexible retrosynthetic surrogate for both canonical carbonyl-related asymmetric transformations.In this Account, we describe our early efforts using strongly coordinating chiral oxazolines to probe reaction mechanism and the stereochemical nature of the C-H cleavage transition state. The characterization of key reactive intermediates through X-ray crystallography and computational studies suggested a transition state with C-H and Pd-OAc bonds being approximately coplanar for optimum interaction. We then moved forward to develop more practical, weakly coordinating monodentate amide directing groups, a necessary advance toward achieving the β-C-H activation of weakly coordinating native carboxylic acids. Throughout this journey, gradual deconvolution between a substrate's directing effect and its intimate interplay with ligand properties has culminated in the design of new ligand classes that ultimately allowed the competency of native carboxylic acids in β-C-H activation. These efforts established the importance of ligand acceleration in Pd-catalyzed C-H activation, where the substrate's weak coordination is responsible for positioning the catalyst for C-H cleavage, while the direct participation from the bifunctional ligand is responsible for enthalpically stabilizing the C-H cleavage transition state.Building upon these principles, we developed five classes of chiral ligands (MPAA, MPAQ, MPAO, MPAThio, MPAAM) to enable enantioselective β-C-H activation reactions, including carbon-carbon and carbon-heteroatom bond formation. The accumulated data from our developed enantioselective C-H activation reactions indicate that ligands possessing point chirality are most effective for imparting stereoinduction in the C-H activation step, the application of which enabled the desymmetrization and subsequent C-H functionalization of enantiotopic carbon and protons across a range of weakly coordinating arylamides and, more recently, free carboxylic acids. Progress in ligand design, in conjunction with the enabling nature of alkali metal countercations, led to the realization of a suite of β-methyl and now methylene C(sp