A Unified Total Synthesis of Eudesmane-Type Sesquiterpenoid Dimers Chlorahupetenes A, B and E.

Chlorahupetenes A (1) and B (2) are eudesmane-type sesquiterpenoid dimers that contain unprecedented, rearranged carbon skeletons that were isolated as enantiomeric pairs by Liu and coworkers in 2022. Herein, we disclose the first total synthesis of chlorahupetenes A (1) and B (2) in 8 steps from commercial materials. Our synthesis employs a novel Diels–Alder strategy to rapidly access the decalin-core of the sesquiterpenoid atractylenolide I (3) and, to the best of our knowledge, represents the shortest total synthesis to date. The endgame of the synthesis features a novel proposed biomimetic, base-promoted cascade of chlorahupetene E (8) to afford chlorahupetenes A (1) and B (2) in a ratio that closely mirrors their isolation ratio. This successful rearrangement supports our hypothesis that chlorahupetene E (8) is a direct biosynthetic precursor of chlorahupetenes A (1) and B (2) and serves to correct an error in a previous biosynthetic proposal.