Cu/Ru Relay Catalysis Enables Functionalization of Allenic Alcohols with Stereodivergence and Skeleton Diversity

The stereodivergent synthesis of structurally complex molecules bearing multiple stereochemical elements represents a pivotal challenge in modern synthetic chemistry, particularly for bioactive compounds, where stereochemical nuances dictate pharmacological profiles. While stereodivergent dual catalysis has advanced full access to stereoisomers with stereogenic centers, the integration of stereodefined alkenes into chiral molecules with both stereochemical and skeletal diversification remains elusive. In this study, we report stereo- and skeleton-divergent access to chiral fluorinated <i>N</i>-heterocycles with comprehensive stereocontrol of [(<i>R</i>,<i>R</i>), (<i>S</i>,<i>S</i>), (<i>S</i>,<i>R</i>), (<i>R</i>,<i>S</i>)] and [(<i>Z</i>,<i>R</i>), (<i>Z</i>,<i>S</i>), (<i>E</i>,<i>R</i>), (<i>E</i>,<i>S</i>)] enabled by a bimetallic Cu/Ru relay catalytic system, featuring redox-neutral efficiency and atom/step economy. The success is achieved through orthogonally merging an asymmetric borrowing-hydrogen reaction with the asymmetric Michael addition between allenic alcohols and α-fluoro azaaryl acetamides/acetates by simply tuning the chiral ligands in the copper and ruthenium catalysts associated with temporal and basicity regulation. Control experiments and kinetic studies provide insights into the underlying mechanisms, revealing that the kinetic resolution of racemic allenic alcohol is involved in this relay-catalyzed cascade dehydrogenation/Michael addition/hydrogenation sequence and Michael addition is the rate-limiting step.