Catalytic Asymmetric Total Synthesis of (+)‐Chamaecydin and (+)‐Isochamaecydin and their Stereoisomers

A modular approach was developed for the first catalytic asymmetric total syntheses of naturally occurring C30 terpene quinone methides and their non‐natural stereoisomers, which feature the presence of an unprecedented spiro[4.4]nonane‐containing 6‐6‐6‐5‐5‐3 hexacyclic skeleton. Resting on a chiral phosphinamide‐catalyzed enantioselective reduction of 2,2‐disubstituted cyclohexane‐1,3‐dione, a concise route for the synthesis of enantioenriched 6‐6 bicyclic fragment was developed. The 6‐6 ring fragment and the five‐membered ring fragment were unified via a metal‐halogen exchange/intermolecular addition reaction. Subsequently, the central 6‐5 bicyclic ring system was constructed through a Michael/aldol cascade. The successful establishment of these strategic transformations allowed for an efficient and rapid construction of spiroannulated 6‐6‐6‐5‐5 pentacarbocyclic core via a convergent manner. Finally, the total syntheses of naturally occurring (+)‐chamaecydin and (+)‐isochamaecydin and their corresponding 1’,5’‐stereoisomers have been achieved divergently by appropriately orchestrating the reaction sequence including isopropyl incorporation, oxidation state adjustment, and carbonyl group‐directed regio‐ and stereoselective cyclopropanation at a late stage.