Synthesis of analogs of dicadalenol, an anti-inflammatory cadinanoid disesquiterpene

Dicadalenol is a disesquiterpenoid with notable anti-inflammatory activity. It was previously isolated from the plant Heterotheca inuloides but has never been re-isolated or synthesized. Herein, we report a semi-synthetic approach starting from two cadinane metabolites produced by the plant. Retrosynthetic analysis identified suitable fragments containing functional groups that could be used for the formation of the pentacyclic compound. The synthesis proceeded via an oxa-Michael addition, condensation, and dehydration sequence between a semi-synthetic sesquiterpene enal and natural 7-hydroxy-cadalene to afford the corresponding methyl anhydro-dicadalenol. The results show that substituted monomeric sesquiterpenes have reduced reactivity and that the dimerization reaction is retarded compared to model reactions performed with unsubstituted perillaldehyde and 2-naphthol. These results suggested a biogenetic pathway for the formation of dicadalenol.