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

Abstract

(+)-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.

Figure 1.. The ryanodane and isoryanodane diterpenes.

(a) Chemical structure, carbon numbering, and ring system letter assignment for the ryanodane diterpenes. (b) Chemical structure, carbon numbering, and ring system letter assignment for the isoryanodane diterpenes. (c) Retrosynthetic analysis of the isoryanodane diterpene (+)-perseanol.

Figure 2.. Fragment preparation for the synthesis of (+)-perseanol.

Reagents and conditions as follows for C-ring fragment preparation: (1) Br₂, NaHCO₃, Et₂O, –10 °C then NaOMe, MeOH, 55 °C, 78%. (2) KHMDS, THF then O₂ (1 atm), P(OMe)₃, −78 °C, 67%. (3) m-CPBA, NaHCO₃, CH₂Cl₂, 0 °C, 92%. (4) Et₂Al(TMP), PhMe, 0 °C, 68%. (5) benzaldehyde dimethyl acetal (PhCH(OMe)₂), (±)-10-camphorsulfonic acid (CSA), 1,2-dichloroethane (DCE), 23 °C then DIBAL, 0 °C, 87%. (6) Cu(MeCN)₄OTf, 4,4′-dimethoxy-2,3′-bipyridine (^MeObpy), 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), 1-methylimidazole (NMI), air, MeCN, 23 °C, 98%. Reagents and conditions as follows for A-ring fragment preparation: (1) 2-iodopropane (20), lithium diisopropylamide (LDA), diethylzinc (Et₂Zn), hexamethylphosphoramide (HMPA), THF, −78 °C to 23 °C, 70%. (2) I₂, CAN, MeCN, 0 °C to 23 °C, 73%. (3) 1.0 M NaOH (aq), 1,4-dioxane/MeOH (1:1), 23 °C. (4) oxalyl bromide ((COBr)₂), DMF, CH₂Cl₂, 0 °C to 23 °C, 68%, 2 steps. (5) 25 (0.4 equiv), BH₃•NEt₂Ph (0.7 equiv), CH₂Cl₂, 23 °C, 44% (–)-27, 91% ee. (6) 28 (2.0 equiv), CSA, CH₂Cl₂, 23 °C, 81%.

Figure 3.. 16-step synthesis of (+)-perseanol.

Reagents and conditions as follows: (7) 29 (1.25 equiv), n-butyllithium (1.25 equiv), THF, −78 °C to −50 °C, 75%. (8) Pd(PPh₃)₄ (50 mol %), N-formylsaccharin (1.2 equiv), KF, Et₃N, 1,4-dioxane, 100 °C, 57%. (9) DDQ, CH₂Cl₂/pH 7 buffer (5:1), 0 °C, 80%. (10) DMDO (3.0 equiv), Na₂SO₄, acetone, 23 °C. (11) MeMgCl (2.0 equiv), CeCl₃•2LiCl (2.0 equiv), THF, 0 °C, 55%, 2 steps. (12) TFA, CH₂Cl₂, 0 °C, 90%. (13) SeO₂, 1,4-dioxane, 100 °C, 78%. (14) VO(On-Pr)₃, tert-butyl hydroperoxide (TBHP), PhMe, 60 °C, 68%. (15) 44 (4.5 equiv), PhH/THF (1:1), 10 °C, 25% (43% BRSM). (16) Pd(OH)₂/C, H₂ (1 atm), MeOH, 90%.