Bioinspired Total Synthesis and Bioactivity Evaluation of a Novel Sesquiterpene (–)-Adenophorone

Key words

neuroprotectant - MBH–Tsuji–Trost cyclization - bioinspired Michael addition - Reformatsky reaction

Significance

Neurodegenerative diseases (NDs), such as Alzheimer’s disease and Parkinson’s disease, have gained public attention. Excessive formation of reactive oxygen species can result in oxidative stress, a common cause of NDs. In light of studies finding new natural neuroprotective agents, the authors isolated (–)-adenophorone, a sesquiterpene with an unprecedented tricyclo[4.3.1.05,9]decane skeleton, from Eupatorium adenopharum. The structure of (–)-adenophorone is established with X-ray and spectroscopic analysis. A concise total synthesis is accomplished in nine steps, starting with commercially available (–)-carvone.

Comment

The nine-step synthesis features a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation with Crabtree’s catalyst. The subsequent MBH–Tsuji–Trost cyclization yields (+)-euptox A, which undergoes a Robinson annulation to give (–)-adenophorone with a high yield. The bioinspired Michael addition further validates the hypothesis that (–)-adenophorone could be biosynthetically generated from cadinene sesquiterpene (+)-euptox A. (–)-Adenophorone also shows potent neuroprotective activity in H₂O₂-treated SH-SY5Y and PC12 cells. The efficient synthetic strategy is expected to provide access to other structurally similar sesquiterpenes in the future.

Publication History

Article published online:
16 August 2023