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

Abstract

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...

Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

“…The Reisman laboratory previously synthesized the related isolate (+)‐ryanodol, and later developed a distinct approach to (+)‐perseanol ( 180 ) [98] . Retrosynthetically, they envisioned that the cyclohexane ring of (+)‐perseanol ( 180 ) could be constructed from the aldehyde 181 and the dihaloalkene 182 (Scheme 32).…”

“…[97] TheR eisman laboratory previously synthesized the related isolate (+ +)-ryanodol, and later developed ad istinct approach to (+ +)-perseanol (180). [98] Retrosynthetically,t hey envisioned that the cyclohexane ring of (+ +)-perseanol (180) could be constructed from the aldehyde 181 and the dihaloalkene 182 (Scheme 32). Addition of an organometal reagent derived from 182 to the aldehyde in 181 would forge the C11 stereocenter.T he remaining vinyl halide was anticipated to provide ah andle for an intramolecular carbopalladation-carbonylationcascade to set the C5 quaternary center.…”

Fragmentverknüpfungen in der Totalsynthese – Bildung von C‐C‐Bindungen über intermediäre Carbanionen oder freie Radikale

“…Reisman et al. hatten den verwandten Naturstoff (+)‐Ryanodol bereits synthetisiert und entwickelten später einen anderen Zugang zu (+)‐Perseanol ( 180 ) [98] . Ihr retrosynthetischer Ansatz sah vor, den Cyclohexanring von (+)‐Perseanol ( 180 ) aus dem Aldehyd 181 und dem Dihalogenalken 182 aufzubauen (Schema 32).…”

“…[97] Reisman et al hatten den verwandten Naturstoff (+ +)-Ryanodol bereits synthetisiert und entwickelten später einen anderen Zugang zu (+ +)-Perseanol (180). [98] Die Synthese des Alkenylaldehyds 181 begann mit einer Eintopfreaktion, in der (R)-(+ +)-Pulegon (85)d urch Bromierung und nachfolgende Favorskii-Umlagerung (Brom, NaOMe) und anschließende diastereoselektive Hydroxylierung des resultierenden Esters (Kalium-bis(trimethylsilyl)amid, O 2 )z um a-Hydroxyester 183 (52 %, 9:1dr) umgesetzt wurde (Schema 33). Die substratgesteuerte Epoxidierung (mCPBA) von 183,g efolgt von einer durch Lewis-Säure vermittelten Isomerisierung des Epoxids, [99] ergab das Diol 184 (63 %).…”

“…Erhitzen einer Lçsung von 189 mit Tetrakis(triphenylphosphan)palladium, N-Formylsaccharin (190; [104] als CO-Quelle) und Kaliumfluorid in 1,4-Dioxan bewirkte die gewünschte Carbopalladierungs-/Carbonylierungskaskade und ergab 191 in 57 %A usbeute.D rei weitere Schema 32. Retrosynthese von (+ +)-Perseanol (180)d urch Han et al [98] PMB = p-Methoxybenzyl.…”