Stereoreversed C-O Activation Unlocks All-Carbon Tetrasubstituted Z-Alkene Synthesis

Stereochemically defined all-carbon tetrasubstituted alkenes are key structural motifs in various bioactive compounds and organic materials. Owing to the congested nature of the carbon-carbon double bond, controlling regio- and stereochemistry still remains a crucial challenge in modern synthetic chemistry. As such, we herein disclose a practical cobalt-catalyzed stereoselective Negishi cross-coupling between readily available alkenyl acetates and organozinc pivalates through a novel stereoreversed C-O bond-cleavage strategy. Detailed experimental and computational studies strongly suggest that the mechanism for stereoreversed C-O-bond activation involves a cobalt(0/II) redox process, whereas the chelation-assisted dihedral rotation event is crucial to the origin of stereochemical inversion. Moreover, the simple cobalt catalysis also allows broad tetrasubstituted alkenyl acetates, either diastereomeric mixtures or Z-isomers, to undergo stereoconvergent and stereoretentive transformations, thus unlocking a new platform for modular and straightforward access to the longstanding challenge of the stereocontrolled synthesis of all-carbon tetrasubstituted Z-alkenes. Notably, the concise synthesis of drug molecules with high yield and stereocontrol should highlight the potential applications of this technology to the drug-discovery setting in medicinal chemistry.