Palladium-Catalyzed Asymmetric Allylic C–H Functionalization: Mechanism, Stereo- and Regioselectivities, and Synthetic Applications

Conspectus Asymmetric functionalization of inert C–H bonds is undoubtedly a synthetically significant yet challenging bond-forming process, allowing for the preparation of densely functionalized molecules from abundantly available feedstocks. In the past decade, our group and others have found that trivalent phosphorus ligands are capable of facilitating Pd-catalyzed allylic C–H functionalization of α-alkenes upon using p -quinone as an oxidant. In these reactions, a 16-electron Pd(0) complex bearing a monodentate phosphorus ligand, a p -quinone, and an α-alkene has been identified as a key intermediate. Through a concerted proton and two-electron transfer process, electrophilic π-allylpalladium is subsequently generated and can be leveraged to forge versatile chemical bonds with a wide range of nucleophiles. This Account focuses on describing the origin, evolution, and synthetic applications of Pd-catalyzed asymmetric allylic C–H functionalization reactions, with an emphasis on the fundamental mechanism of the concerted proton and two-electron transfer process in allylic C–H activation. Enabled by the cooperative catalysis of the palladium complex of triarylphosphine, a primary amine, and a chiral phosphoric acid, an enantioselective α-allylation of aldehydes with α-alkenes is established. The combination of chiral phosphoric acid and a palladium complex of a chiral phosphoramidite ligand allows the allylic C–H alkylation of α-alkenes with pyrazol-5-ones to give excellent enantioselectivities, wherein the chiral ligand and chiral phosphoric acid synergistically control the stereoselectivity. Notably, the palladium–phosphoramidite complexes are also efficient catalysts for allylic C–H alkylation, with a wide scope of nucleophiles. In the case of 1,4-dienes, the geometry and coordination pattern of the nucleophile are able to vary the transition states of bond-forming events and thereby determine the Z / E -, regio-, and stereoselectivities. These enantioselective allylic C–H functionalization reactions are tolerant of a wide range of nucleophiles and α-alkenes, providing a large library of optically active building blocks. Based on enantioselective intramolecular allylic C–H oxidation, the formal synthesis of (+)-diversonol is accomplished, and enantioselective intramolecular allylic C–H amination can enable concise access to letermovir. In particular, the asymmetric allylic C–H alkylation of 1,4-dienes with azlactones offers highly enantioenriched α,α-disubstituted α-amino acid derivatives that are capable of serving as key building blocks for the enantioselective synthesis of lepadiformine alkaloids. In addition, a tachykinin receptor antagonist and (−)-tanikolide are also synthesized with chiral molecules generated from the corresponding allylic C–H alkylation reactions.