Divergent Total Syntheses of 7,20-Epoxy, 3,20-Epoxy, and 6,7-seco-ent-Kaurane Diterpenoids

The genus Isodon is a well-known traditional medicinal herb that serves as a rich source of cytotoxic ent-kaurane diterpenoids, which bear the same tetracyclic core of ent-kaurane with different oxygenation, bond-cleavage, and rearrangement patterns. The 7,20-epoxy-ent-kaurane diterpenoids are the most studied subclasses, which show promising anticancer activities. Moreover, they also have the potential for transforming to other subclasses of ent-kaurane diterpenoids. Herein, the details of this study on developing a highly diastereoselective synthetic strategy for the 7,20-epoxy-ent-kaurane diterpenoid (5 natural products) and its conversion to the 3,20-epoxy (2 natural products) and 6,7-seco derivatives (2 natural products) are reported. The synthetic strategy features a thermal Diels–Alder cycloaddition for the construction of the AB ring system, an intramolecular Mukaiyama Michael/carbocyclization cascade reaction for establishing the CD ring system, a site-stereoselective oxidation/reduction strategy for completion of the total syntheses of several representative 7,20-epoxy-ent-kaurane diterpenoids, and the divergent syntheses of Isodon diterpenoids in the 3,20-epoxy and 6,7-seco subclasses via bioinspired strategies.