Enantiospecific total synthesis of the sesterterpenoid astellatol

Astellatol is a synthetically highly challenging sesterterpenoid that possesses a congested pentacyclic ring system, which contains 10 stereocenters, a unique bicyclo[4.1.1]octane motif, a cyclobutane moiety that possesses two quaternary centers, an exo-methylene group, and a sterically encumbered isopropyl trans-hydrindane motif. Herein, we describe the full account of our synthesis of astellatol, including two generations of synthetic design and corresponding experimental attempts. The key transformations of our synthetic strategy include a facile construction of 5/7-bicyclic motif, an intramolecular Pauson–Khand reaction that quickly constructed the hydrindane scaffold, a SmI-induced reductive radical 1,6-addition that successfully forged the cyclobutane ring, and a key strategic late-stage reduction of a fully substituted olefin that produced the critical trans-hydrindane moiety of astellatol.