A Unified Strategy for the Regiospecific Assembly of Homoallyl-Substituted Butenolides and γ-Hydroxybutenolides: First Synthesis of Luffariellolide

Abstract

The first synthesis of the antiinflammatory marine ­natural product luffariellolide has been achieved by a convergent pathway involving sp³-sp³ cross-coupling and silyloxyfuran oxyfunctionalisation as key steps. An illustration of the inherent ­flexibility of this strategy is provided by a simple synthesis of α,β-acariolide and its γ-hydroxylated derivative from a common silyl­oxyfuran precursor.

cross-coupling - Grignard reagents - lactones - oxyfunctionalisation - 2-silyloxyfurans

References and Notes

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15

Data for 8: TLC, R _f = 0.42 (100% hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 6.85 (s, 1 H), 5.22 (s, 1 H), 4.38 (s, 2 H), 1.23 (m, 3 H) 1.09 (d, J = 7.1 Hz, 18 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.5, 129.6, 123.5, 84.2, 38.1, 17.4, 12.0.

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17

Experimental Procedure: Magnesium turnings (212 mg, 8.70 mmol) were activated by washing successively with aq 10% HCl, H₂O, acetone and Et₂O, and dried in a vacuum desiccator. The turnings were then flame-heated under an atmosphere of dry nitrogen, allowed to cool, and 1,2-dibromoethane (75 µL, 0.87 mmol) and anhyd THF (4 mL) were added. The mixture was heated to reflux, stirred for 15 min, and the THF was cannulated out and replaced with anhyd THF (3 mL). The resulting suspension was cooled to 0 °C and silyloxyfuran 8 (835 mg, 2.89 mmol), which was purified on a short column (SiO₂) before use, was added. Stirring was continued at 0 °C for 1 h, at which time no more starting material was detected by TLC. Anhyd THF (2 mL) was added, and the mixture was divided into two equal parts and placed into two separate dry vials at 0 °C. In each vial was then added prenyl chloride (9; 80 µL, 0.70 mmol) at 0 °C, followed immediately by a solution of Li₂CuCl₄ (0.1 M, 350 µL, 0.035 mmol) in THF. Each reaction mixture was stirred for 20 min at 0 °C and then poured (in parallel fashion) into H₂O (50 mL) and Et₂O (50 mL), and a solution of aq sat. NH₄Cl was added until the two layers separated. The product was extracted with Et₂O (3 × 50 mL), washed with brine (25 mL), dried (MgSO₄), and concentrated in vacuo to afford silyloxyfuran 10 as a yellowish oil that was carried forward without further purification. TLC, R _f = 0.81 (EtOAc-hexanes, 1:9). ¹H NMR (300 MHz, CDCl₃): δ = 6.57 (s, 1 H), 5.12 (t, J = 7.0 Hz, 1 H), 5.02 (s, 1 H), 2.31 (m, 2 H), 2.18 (t, J = 7.3 Hz, 2 H), 1.66 (s, 3 H), 1.57 (s, 3 H), 1.24 (m, 3 H), 1.07 (d, J = 7.0 Hz, 18 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.5, 131.6, 127.5, 126.5, 123.9, 85.1, 28.1, 25.8, 25.5, 17.4, 15.1, 12.0.
Preparation of α,β-Acariolide (11): To a solution of 10 (112 mg) in acetone (10 mL) and H₂O (5 drops) was added Amberlyst-15 (25 mg) and the mixture was stirred at r.t. for 45 min. The resin was filtered, washed with acetone (15 mL), and the solvent was evaporated in vacuo. The resulting oil was purified by flash chromatography (EtOAc-hexanes, 15:85, then 2:8) to afford 11 as a colourless oil (98 mg, 84%); TLC: R _f = 0.24 (EtOAc-hexanes, 2:8), whose NMR data matched those reported in ref. 13.
Preparation of γ-Hydroxybutenolide 12: To a solution of 10 (112 mg) in anhyd CH₂Cl₂ (10 mL) at -78 °C was added an acetone solution of DMDO (ca. 0.1 M, 0.4 mL). The mixture was stirred at -78 °C for 1 h and concentrated in vacuo at -78 °C. The crude oil was dissolved in acetone (10 mL) and H₂O (5 drops) was added followed by Amberlyst-15 (25 mg). The mixture was stirred at r.t. for 1.5 h, the resin was filtered off, washed with acetone (15 mL), and the solvent was evaporated in vacuo. The resulting oil was purified by flash chromatography (EtOAc-hexanes, 2:8, then 25:75) to afford 12 as a colourless oil (88 mg, 75%); TLC: R _f = 0.32 (EtOAc-hexanes, 3:7), whose NMR data matched those reported in ref. 14.

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23

Data for 16: TLC, R _f = 0.77 (100% hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 6.58 (s, 1 H), 4.94-5.21 (m, 3 H), 1.89-2.37 (m, 14 H), 1.53-1.65 (m, 11 H), 1.42 (m, 2 H), 1.17-1.31 (m, 3 H), 1.09 (d, J = 7.1 Hz, 18 H), 1.06 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.5, 137.1, 135.9, 135.3, 127.6, 126.8, 126.5, 123.8, 123.5, 85.1, 40.2, 39.7, 39.6, 34.9, 32.6, 29.6, 28.5, 28.0, 27.8, 26.5, 25.9, 19.7, 19.4, 17.4, 15.9, 12.1, 10.5.