Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.0(5,9)]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2O2-treated SH-SY5Y and PC12 cells.

Automated summary

(-)-Adenophorone, a compound with a unique tricyclo[4.3.1.0(5,9)]decane skeleton, was isolated from Eupatorium adenopharum Spreng. Its structure was determined using spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. The synthesis of its precursor, (+)-euptox A, was achieved in 8 steps from commercially available (-)-carvone, demonstrating excellent diastereoselectivity. Bioinspired synthesis of (-)-adenophorone was achieved from a plausible biogenetic precursor via transannular Michael addition. Furthermore, compound (-)-adenophorone exhibited potent neuroprotective activity in H2O2-treated SH-SY5Y and PC12 cells.