Perseanol is an isoryanodane diterpene with potent antifeedant and insecticidal properties isolated from the tropical shrub Persea indica. 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. 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. 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. Main Text: The ryanodane and isoryanodane natural products are structurally related families of oxidized diterpenes with antifeedant and insecticidal activities against insects of the Hemiptera and Lepidoptera orders. Ryanodine (1, Figure 1a), isolated from Ryania speciosa Vahl, was the first of these natural products to be characterized, and powdered R. speciosa wood was marketed as a botanical insecticide with peak annual production reaching 200 metric tons. 1 The insecticidal properties of 1 result from its modulation of Ca 2+ release by the ligand-gated calcium ion channel now known as the ryanodine receptor (RyR). 2 In the early 2000s, renewed interest in the insect RyR as a biological target for pest control agents resulted in the discovery and development of the phthalic acid diamide and anthranilic diamide insecticides-which bind at an allosteric site in the transmembrane domain of the insect RyR 3-4-with sales of these products exceeding 1 billion USD. 5 In addition, the discovery of 1 led to the purification and characterization of mammalian RyRs, and 1 continues to be used as a probe to assess the functional state of these important mediators of Ca 2+ signaling. Decades after the discovery of 1, Fraga and coworkers isolated the natural product (+)-perseanol (3, Figure 1b) and related congeners from the shrub Persea indica found in the Canarian Archipelago. Perseanol (3) features an isomeric carbon framework to 1 but bears a similar oxidation pattern and likely results from a shared biosynthetic pathway. 6 A key difference between the structures of 3 and 1, in addition to their carbon skeletons, is that 3 lacks the pyrrole-2-carboxylate ester at C3, a functional group that is required for high affinity binding of 1 to mammalian isoforms of the RyR. 2 Indeed, in preliminary assays, 3, 4, and related metabolites 7-15 were found to exhibit potent antifeedant activity for lepidopteran pests with minimal toxicity toward mammalian...

With hundreds of unique members isolated to date, guaianolide lactones represent a particularly prolific class of terpene natural products. Given their extensive documented therapeutic properties and fascinating chemical structures, these metabolites have captivated the synthetic chemistry community for many decades. As a result of divergent biosynthetic pathways, which produce a wide array of stereochemical and oxidative permutations, a unifying synthetic pathway to this broad family of natural products is challenging. Herein we document the evolution of a chiral-pool-based synthetic program aimed at accessing an assortment of guaianolides, particularly those from the plant family Apiaceae as well as Asteraceae, members of which possess distinct chemical substructures and necessitate deviating synthetic platforms. An initial route employing the linear monoterpene linalool generated a lower oxidation state guaianolide but was not compatible with the majority of family members. A double-allylation disconnection using a carvone-derived fragment was then developed to access first an Asteraceae-type guaianolide and then various Apiaceae congeners. Finally, using these findings in conjunction with a tandem polyoxygenation cascade, we developed a pathway to highly oxygenated nortrilobolide. A variety of interesting observations in metal-mediated aldehyde allylation and alkene polyoxygenation are reported and discussed.

Scheme 2. Total Synthesis of (−)-Longikaurin E (3) and (−)-Trichorabdal A (2) Accounts of Chemical Research pubs.acs.org/accounts Article

An enantioselective Diels–Alder (DA) reaction of α-acyloxy enones has been developed to synthesize chiral oxidized cyclohexenes. Yttrium­(III) triflate, in conjunction with a chiral pyridinebisimidazoline (PyBim) ligand, was found to catalyze the asymmetric [4 + 2] cycloaddition with a variety of dienes and α-acyloxy enone dienophiles. Using this method, terpinene-4-ol, a key intermediate in the synthesis of commercial herbicide cinmethylin, can be prepared in four steps from isoprene. A combination of kinetic data and NMR studies support a mechanism involving reversible binding of a dienophile to a yttrium catalyst followed by cycloaddition with a diene as the rate-determining step.