Modular Chemoenzymatic Synthesis of Ten Fusicoccane Diterpenoids

Fusicoccane diterpenoids display intriguing biological activities, including the ability to act as molecular glue modulators of 14-3-3 protein–protein interaction. However, their innate structural complexity and diverse oxygenation patterns present enormous synthetic challenges. Here, a modular chemoenzymatic approach to this natural product family that combines de novo skeletal construction and late-stage hybrid C–H oxidations is presented. A convergent fragment coupling strategy allowed rapid access to a key tricyclic intermediate, which was subjected to chemical and enzymatic C–H oxidations to modularly prepare five oxidized family members. Complementarily, a biomimetic skeletal remodeling was conceived to render five rearranged fusicoccanes with unusual bridgehead double bonds synthetically accessible for the first time.