Total Synthesis and Structure Activity Relationship of Cynaropicrin

Cynaropicrin (1) is a sesquiterpene lactone natural product isolated from artichokes (Cynara scolymus). 1 has attractive biological activity including anti-trypanosomal activity, inhibition of NF-kappa B activation, antihepatitis C activity, etc. Herein, we report the first total synthesis of cynaropicrin 1. The structure activity relationship study is also described. The synthesis involved stereoselective Favorskii rearrangement and indium-promoted diastereoselective Barbier reaction. At first, 8 was obtained from commercially available (S)-alpha-pinene 9 in three steps. Diol 7 was then obtained in two steps from 8. Protection of primary and secondary hydroxyl groups of 7 gave Favorskii rearrangement precursors 10, 11, and 12. The investigation of Favorskii rearrangement with NaOMe in MeOH was then performed to afford 13. 5-Membered ring 13 was subjected to 8-steps reactions including a [2,3]-sigmatropic rearrangement for the construction of the exo-olefin to give an aldehyde 5. Next, the Barbier reaction between the obtained 5 and the prepared bromolactone 4 was examined. In this reaction, using indium in THF and H2O gave moderate yield with good stereoselectivity. To construct the main skeleton of 3, 4-step reactions including intramolecular ene reaction for compound 19 were conducted to afford 3. Prepared side chain 2 was then introduced into the hydroxyl group of 3 via a Mitsunobu-Mukaiyama reaction. Removal of PMB groups gave cynaropicrin 1. Spectroscopic data of synthesized 1 showed good agreement with natural 1. The first total synthesis of 1 was thus achieved in 2.6% overall yield over 23-steps from 9. Structure activity relationship studies on Trypanosoma brusei and NF-kappa B were also carried out. It was turned out that natural product 1 holds the most potent biological activity.