Fusicoccane diterpenoids display intriguing biological activities, including the ability to act as modulators of 14-3-3 protein–protein interactions. However, their innate structural complexity and diverse oxygenation patterns present enormous synthetic challenges. Here we develop a modular chemoenzymatic approach that combines de novo skeletal construction and late-stage hybrid C–H oxidations to achieve the synthesis of ten complex fusicoccanes in 8–13 steps each. 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. We also conceived a complementary biomimetic skeletal remodelling strategy to synthetically access five rearranged fusicoccanes with unusual bridgehead double bonds. This work may facilitate future investigation into the biological activities of the fusicoccanes and also inspire the implementation of similar hybrid strategies to provide family-level synthetic solutions to other natural product scaffolds.

Fusicoccane 二萜类化合物表现出有趣的生物活性，包括作为 14-3-3 蛋白质-蛋白质相互作用调节剂的能力。然而，它们固有的结构复杂性和多样化的氧化模式带来了巨大的合成挑战。在这里，我们开发了一种模块化化学酶方法，该方法结合了从头骨架构建和后期混合 C-H 氧化，以实现 10 种复杂的 fusicoccanes 的合成，每个步骤需要 8-13 个步骤。聚合片段偶联策略允许快速获得关键的三环中间体，该中间体经过化学和酶促 C-H 氧化，以模块化制备五个氧化家族成员。我们还构想了一种互补的仿生骨骼重塑策略，以综合获得五种具有不寻常桥头双键的重新排列的 fusicoccanes。这项工作可能有助于未来对褐藻类生物活性的研究，并启发类似混合策略的实施，为其他天然产物支架提供家族级合成解决方案。