Enyne Metathesis Approach towards the Cyclopentane Motif of Jatrophane Diterpenes

Abstract

A short and efficient synthesis of the cyclopentane moiety of the jatrophane diterpene Pl-3 has been developed. The route features an enyne metathesis reaction, and a stereoselective palladium-catalyzed reductive epoxide opening as key steps.

Key words

metathesis - palladium - natural products - stereoselective synthesis - terpenoids

• References and Notes

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• 33 Preparation of 21: NaH (60% dispersion in mineral oil, 0.224 g, 5.60 mmol, 2.2 equiv) was added to HMPA (1.66 mL, 9.57 mmol, 3.75 equiv) in one portion. After 5 min, a solution of 19 (0.500 g, 2.55 mmol, 1 equiv) in THF (1.66 mL) was added. After consumption of the starting material as indicated by TLC analysis (60 min) the reaction was quenched via addition of a sat. aqueous solution of NH₄Cl. The solution was acidified to pH 2 by addition of HCl (1 M) and stirred for approximately 20 min. The aqueous solution was extracted with CH₂Cl₂ (3 × 20 mL) and dried over MgSO₄. Silica was added and the solvent was reduced in vacuo. The crude product was purified by flash column chromatography (dry loading; pentane–Et₂O, 10:1). The solvent was carefully reduced under reduced pressure (700 mbar, 35 °C) to yield 21 (260 mg, 82%) as a colorless liquid. Note: The product is highly volatile; thus, yields vary between 40% and 82%. ¹H NMR (400 MHz, CDCl₃): δ = 6.45 (dd, J = 17.73, 11.00 Hz, 1 H), 5.82 (dd, J = 2.63, 2.63 Hz, 1 H), 5.41–5.46 (m, 1 H), 5.14 (dd, J = 10.89, 0.84 Hz, 1 H), 4.52 (br s, 1 H), 2.71–2.78 (m, 1 H), 2.14–2.23 (m, 1 H), 1.87–1.94 (m, 1 H), 1.51 (br s, 1 H), 1.10 (d, J = 7.16 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.58 (C), 133.11 (CH), 131.87 (CH), 115.01 (CH₂), 83.20 (CH), 42.56 (CH), 38.60 (CH₂), 19.67 (Me). HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₂NaO: 147.0786; found: 147.0788 ±5 ppm. [α] _d ²⁰ −70° (c = 0.2250, CHCl₃). IR (ATR): 3316, 2954, 2924, 2868, 1641, 1454, 1374, 1260, 1021, 988, 905, 813 cm^–1.
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• 45 Preparation of 23a: The reaction was carried out in Schlenk flasks using degassed solvents. A Schlenk flask containing Pd₂(dba)₃·CHCl₃ (4.4 mg, 2.5 mol%) and (R,R)-DACH ([138517-61-0], 8.7 mg, 7.5 mol%) was purged with argon five times before CH₂Cl₂ (0.6 mL) was added. After 5 min a mixture of Et₃N (117 μL, 0.844 mmol, 5.0 equiv) and formic acid (32 μL, 0.844 mmol, 5.0 equiv) in CH₂Cl₂ (0.6 mL) was added and stirring was continued for additional 5 min before epoxide 22 (50 mg, 0.169 mmol, 1.0 equiv) was added neat followed by CH₂Cl₂ (0.1 mL). The reaction was stirred until TLC analysis showed total consumption of the starting material (3 h). A sat. aqueous solution of NH₄Cl was added and the mixture was extracted with CH₂Cl₂ (3 × 20 mL), the organic extracts were dried over MgSO₄, filtered and reduced in vacuo. The crude product was purified by flash column chromatography (hexane–EtOAc, 40:1) delivering the desired product 23a (43 mg, 86%) as a colorless oil as sole isolable product. ¹H NMR (400 MHz, CDCl₃): δ = 6.20–6.26 (m, 1 H), 5.22–5.24 (m, 1 H), 5.20 (d, J = 0.78 Hz, 1 H), 4.07–4.11 (m, 1 H), 3.98 (br d, J = 3.90 Hz, 1 H), 3.25 (d, J = 11.16 Hz, 1 H), 2.36–2.40 (m, 1 H), 2.32–2.36 (m, 1 H), 2.25 (ddd, J = 14.42, 8.99, 0.95 Hz, 1 H), 1.51 (ddd, J = 14.37, 5.37, 5.37 Hz, 1 H), 1.05–1.13 (m, 21 H), 0.97 (d, J = 7.32 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.16 (CH), 117.43 (CH₂), 85.48 (CH), 78.18 (CH), 52.81 (CH), 43.47 (CH₂), 41.40 (CH), 20.87 (Me), 18.21 (Me), 18.16 (Me), 12.37 (CH). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₃₄NaO₂Si: 321.2226; found: 321.2223 ±5 ppm. [α] _d ²⁰ −5° (c = 1.0900, CHCl₃). IR (ATR): 3531, 2943, 2866, 2359, 2342, 1636, 1463, 1419, 1383, 1119, 1060, 1014, 997, 912, 881, 847, 823, 729, 678 cm^–1.