Enantioselective Total Syntheses of Grayanane Diterpenoids and (+)-Kalmanol: Evolution of the Bridgehead Carbocation-Based Cyclization and Late-Stage Functional Group Manipulation Strategies.

Grayanane diterpenoids contain over 300 highly oxidized and structurally complex members, many of which possess important biological activities. Full details are provided for the development of the concise, enantioselective and divergent total syntheses of grayanane diterpenoids and (+)-kalmanol. The unique 7-endo-trig cyclization based on a bridgehead carbocation was designed and implemented to construct the 5/7/6/5 tetracyclic skeleton, demonstrating the practical value of the bridgehead carbocation-based cyclization strategy. Extensive studies of late-stage functional group manipulation were performed to forge the C1 stereogenic center, during which a photoexcited intramolecular hydrogen atom transfer reaction was discovered and the mechanism was further studied through density functional theory (DFT) calculations. The biomimetic 1,2-rearrangement from the grayanoid skeleton provided a 5/8/5/5 tetracyclic framework and resulted in the first total synthesis of (+)-kalmanol.

Enantioselective Total Syntheses of Grayanane Diterpenoids: (-)-Grayanotoxin III, (+)-Principinol E, and (-)-Rhodomollein XX.

Enantioselective total syntheses of (-)-grayanotoxin III, (+)-principinol E, and (-)-rhodomollein XX were accomplished based on a convergent strategy. The left- and right-wing fragments were assembled via the diastereoselective Mukaiyama aldol reaction catalyzed by a chiral hydrogen bond donor. The unique 7-endo-trig cyclization based on a bridgehead carbocation forged the 5/7/6/5 tetracyclic skeleton that underwent redox manipulations and 1,2-migration to access different grayanane diterpenoids.