Cobalt(III)-Catalyzed Enantioselective C-H Functionalization: Ligand Innovation and Reaction Development.

ConspectusIn contrast to precious transition metals, such as palladium and rhodium, the development of novel chiral ligands for enantioselective C-H functionalizations catalyzed by earth-abundant, cost-effective, and environmentally friendly 3d metals poses substantial challenges, primarily due to the variable oxidation states, intricate coordination patterns, and limited mechanistic insights. In this Account, we summarize our research endeavors in the development of three novel types of Co(III) catalysis: pseudotetrahedral achiral Cp*Co(III)/chiral carbonyl acid (CCA) catalysis, in situ-generated chiral octahedral cobalt(III) via cobalt/salicyloxazoline (Salox) catalysis, and Co(II)/chiral phosphoric acid (CPA) cooperative catalysis, achieved through strategic chiral ligand design. Our initial objective was to achieve enantioselective C-H functionalization catalyzed by achiral Cp*Co(III) catalysts with external chiral ligands, aiming to circumvent the laborious preparation of chiral Cp^xCo(III) complexes. To this end, we developed several CCA ligands, incorporating non-covalent interactions (NCIs) as a crucial design element. Next, to address the limitations associated with the lengthy synthesis of Cp-ligated Co(III) complexes and the difficulties of modification, we explored the concept of the in situ generation of Co(III) catalysis using commercially available cobalt(II) salts with tailor-made chiral ligands. This exploration led to the development of two innovative catalytic systems, namely, Co(II)/Salox catalysis and Co(II)/CCA sequential catalysis. The Co(II)/Salox catalysis emerged as a versatile strategy, demonstrating excellent enantioselectivities across a range of asymmetric C-H functionalization reactions to construct various chiral molecules with central, axial, planar, and inherent chirality. The facile synthesis in a single step, along with ease of modification, further enhances the versatility and applicability of this approach. Moreover, we successfully applied cobalt/Salox catalysis in electro- and photochemical-catalyzed enantioselective C-H functionalization, using electrons or oxygen as traceless oxidant, thereby eliminating the need for stoichiometric chemical oxidants. Through mechanistic studies and reaction developments, we elucidated the detailed ligand structure-enantioselectivity relationships in cobalt/Salox catalysis, which are expected to inform future research endeavors. Finally, the Co(II)/CPA cooperative catalysis enabled the synthesis of chiral spiro-γ-lactams through sequential C-H olefination/asymmetric [4 + 1] spirocyclization. Mechanistically, the establishment of stereochemistry occurs during the cyclization step, where the CPA ligand serves as both a neutral ligand and a chiral Brønsted acid, with stereoinduction independent of the C-H cleavage step. We anticipate that the insights and advancements detailed in this Account will inspire further innovations in ligand development and drive progress in the exploration of 3d metal-catalyzed asymmetric C-H functionalization reactions.