Catalytic Stereochemical Relay for the Enantioselective Synthesis of Acyclic Quaternary Stereocenters

The catalytic enantioselective construction of acyclic quaternary stereocenters remains a central challenge in modern organic synthesis, with far-reaching implications for the design and synthesis of complex natural products and functional molecules. In particular, γ-quaternary stereocenters are exceptionally difficult to access catalytically, as few methods enable precise stereochemical control at positions distal to an activating group. Although [3,3]-sigmatropic rearrangements provide a powerful means to reorganize molecular frameworks with high stereochemical fidelity, their strategic integration with asymmetric catalysis remains underdeveloped. Herein, we report a unified catalytic strategy that merges iridium-catalyzed enantioselective allylic alkylation of α,β-unsaturated malononitriles with a stereospecific Cope rearrangement to deliver γ-quaternary nitrile derivatives with exceptional regio- and enantiocontrol (up to 96% ee). Density functional theory calculations demonstrate that the reaction proceeds via reversible α-allylation followed by a low-barrier, stereospecific Cope rearrangement, thereby establishing a stereochemical relay mechanism for remote stereocenter construction. This platform enables modular, scalable access to α-, β-, and γ-quaternary stereocenters from a common intermediate without erosion of enantiomeric enrichment, establishing a unified strategy for the stereocontrolled construction of densely functionalized acyclic frameworks.