A 16-step synthesis of the isoryanodane diterpene (+)-perseanol

(+)-Perseanol is an isoryanodane diterpene that is isolated from the tropical shrub Persea indica¹ and has potent antifeedant and insecticidal properties. It is structurally related to (+)-ryanodine, which is a high-affinity ligand for and modulator of ryanodine receptors-ligand-gated ion channels that are critical for intracellular Ca²⁺ signalling in most multicellular organisms². Ryanodine itself modulates ryanodine-receptor-dependent Ca²⁺ release in many organisms, including mammals; however, preliminary data indicate that ryanodane and isoryanodane congeners that lack the pyrrole-2-carboxylate ester-such as perseanol-may have selective activity in insects³. Here we report a chemical synthesis of (+)-perseanol, which proceeds in 16 steps from commercially available (R)-pulegone. The synthesis involves 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.