Dongyuan Qiu, Zihan Zhao, Leyi Liu, Zhen Xie, Hou‐Wen Lin, Li Huang, Fan Yang, Yu Sun
Pepluanol A ( 1 ) and pepluacetal ( 2 ) belong to a structurally unique class of pepluanol-type Euphorbia diterpenoids, exhibiting immunosuppressive activity via targeting K v 1.3 channels. Herein, we report a divergent synthetic strategy that enables efficient and concise total syntheses of both 1 and 2 from a common advanced intermediate. The synthesis of pepluanol A ( 1 ) features an intramolecular Diels–Alder reaction to accomplish the [4 + 2] type cycloaddition for framework construction, whereas the synthesis of pepluacetal ( 2 ) is centered on a photoinduced intramolecular [2 + 2] cycloaddition as the key step. Both routes proceed with high stereoselectivity and synthetic efficiency. Further biological evaluation revealed that these diterpenoid natural products and derivatives possess antipulmonary fibrosis activity.