A 16-Step Synthesis of the Isoryanodane Diterpene (+)-Perseanol

(+)-Perseanol is an isoryanodane diterpene with potent antifeedant and insecticidal properties isolated from the tropical shrub Persea indica.(1) It is structurally related to (+)-ryanodine, a high affinity ligand and modulator of ryanodine receptors (RyRs)—ligand-gated ion channels critical for intracellular Ca(2+) signaling in vertebrates and invertebrates.(2) Whereas ryanodine modulates RyR-dependent Ca(2+) release across many organisms, including mammals, preliminary data indicate that ryanodane and isoryanodane congeners that lack the pyrrole-2-carboxylate ester, such as perseanol, may have selective activity in insects.(3) Here we report the first chemical synthesis of (+)-perseanol, which proceeds in 16 steps from commercially available (R)-pulegone. The synthesis features a two-step annulation process that rapidly assembles the tetracyclic core from readily accessible cyclopentyl building blocks. This work demonstrates how convergent fragment coupling, when combined with strategic oxidation tactics, can enable the concise synthesis of complex and highly oxidized diterpene natural products.