Catalytic Asymmetric 1,6-Diene Cyclization via Designed Carbocationic 5- and 6- exo Pathways

Abstract Catalytic asymmetric electrophilic alkene functionalization provides a powerful strategy for the construction of complex chiral molecules. Despite significant progress in this field, the asymmetric functionalization of alkenes promoted by an electrophilic carbon species via an exo-cyclization mode remains a formidable challenge. Herein, we report a solution to this challenge: alkenes can undergo designed 5-exo- and 6-exo-carbocationic cyclizations to generate optically pure, complex chiral compounds with high enantio- and diastereoselectivities. In this approach, for 1,6-dienes bearing bulky sulfonamide or quaternary carbon linkers, one double bond of the substrate interacts with an external electrophile, such as a trifluoromethylthio, arylthio, alkylthio, or chlorine species, generating an electrophilic carbon species that promotes the transformation of 1,6-dienes under chiral indane-based chalcogenide catalysis. Notably, the reaction can be terminated by intramolecular nucleophiles via cis-addition or can be captured by various intermolecular nucleophiles. A diverse array of optically pure polycyclic and monocyclic compounds can be obtained, including 5-5-6 tricyclic N-heterocycles and pentasubstituted chiral cyclohexanes. The same strategy can also be efficiently applied to 6-endo cyclizations, leading to the formation of 6-6-6 tricyclic and monocyclic N-heterocycles. The resulting products can be readily converted to various other valuable compounds, further demonstrating the utility of this methodology. Density functional theory (DFT) calculations were performed to rationalize the observed selectivities, revealing that the preferential transition-state conformations lower the activation barriers for the desired cyclization pathways. This work offers a versatile platform for the synthesis of enantioenriched chiral scaffolds prevalent in bioactive molecules and pharmaceuticals, significantly expanding the scope of polyene cyclization chemistry.