Palladium-Catalyzed Enantioselective β-C(sp3)-H Activation Reactions of Aliphatic Acids: A Retrosynthetic Surrogate for Enolate Alkylation and Conjugate Addition

CONSPECTUS: Enolate alkylation and conjugate addition into an alpha,beta-unsaturated system have served as long-standing strategic disconnections for the installation of alpha-or beta-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 beta-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 Xray 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 beta-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 beta-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 beta-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 beta-methyl and now methylene C(sp(3))-H activation reactions. These advancements also enabled the use of economical oxidants, such as peroxides and molecular oxygen, to facilitate catalyst turnover. In the future, continued progress in designing more efficient bifunctional chiral ligands is likely to provide a myriad of enantioselective beta-C-H activation reactions of readily available native substrates.

Automated summary

CONSPECTUS: The development of asymmetric beta-C-H activation reactions for organic synthesis has been described in this Account. By studying reaction mechanisms and stereochemical properties, both strongly coordinating and weakly coordinating directing groups were designed to achieve beta-C-H activation of aliphatic acids and carboxylic acids, respectively. The development of five classes of chiral ligands enabled enantioselective beta-C-H activation reactions of readily available substrates.