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

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.