9-Step synthesis of (-)-larikaempferic acid methyl ester enabled by skeletal rearrangement

Chem Commun (Camb). 2024 Jul 9;60(56):7164-7167. doi: 10.1039/d4cc01462f.

Abstract

We report here a concise synthesis of the anti-tumor-promoting (-)-larikaempferic acid methyl ester, a novel and rearranged abietane-type diterpene natural product containing a unique tetracyclic skeleton with a trans-hydrindane, an oxabicyclo[3.2.1]octane, and six stereogenic centers. Our synthesis starts with the cheap and abundant abietic acid and features an oxidative C-C bond cleavage followed by a transannular aldol reaction to skeletally rearrange the 6-6-6 tricyclic carbon skeleton of abietic acid to the desired 6-5-7 tricyclic carbon skeleton and an intramolecular oxa-Michael addition to form the oxa bridge. This skeletal rearrangement strategy enabled us to synthesize (-)-larikaempferic acid methyl ester in 9 steps.