Catalytic Enantioselective C(sp 3 )–C(sp 3 ) Cross-Coupling of Tertiary Nitriles with Allyl Halides to Quaternary Stereocenters

Quaternary stereocenters are prevalent in natural products and bioactive molecules, where they influence the molecular structure, conformation, and function by enhancing the fraction of sp³ character. The enantioselective construction of such structures via cross-coupling remains a long-standing challenge, owing to the steric demands of forging C(sp³)-C(sp³) bonds and the limited accessibility of suitable tertiary carbon coupling partners. Here, we report a palladium-catalyzed asymmetric decyanative allylation (AD_CNA) platform of C(sp³)-C(sp³) cross-coupling that transforms stable and readily available tertiary nitriles into enantioenriched acyclic and cyclic compounds bearing quaternary centers. This process proceeds via the selective addition of in situ-formed allyl zinc reagent to the cyano group, followed by retro-Thorpe-type C-CN bond cleavage and asymmetric allylation, guided by newly developed chiral ligands. The method exhibits a broad substrate scope across three classes of tertiary nitriles─malononitriles, α-cyano indolinones, and α-cyano lactones─offering high yields and excellent enantioselectivities under mild conditions. This research establishes a conceptually distinct retrosynthetic paradigm, from prochiral or racemic quaternary carbons to enantioenriched quaternary centers, enabled by chemoselective C-C bond cleavage and stereoselective C-C bond formation. The synthetic utility of this strategy is demonstrated by the downstream synthesis of a monoamine reuptake inhibitor and a CNGA2 channel blocker as well as synthetic intermediates of natural products physovenine and physostigmine.