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

Abstract

(−)‐Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9]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.

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“…A further structure, adenophorone 9 from Eupatorium adenophorum , was confirmed by X-ray analysis. 8 It is proposed that the unusual caged structure of adenophorone 9 is formed from a cadinane sesquiterpenoid precursor involving an intramolecular Michael addition reaction. The first nitrogen-bearing phomactin diterpenoid, phomactinine 10 , has been identified as a metabolite of Biatriospora sp.…”