One-pot Synthesis of Perhydrofuro[2,3-b]pyran Derivatives

Abstract

TiCl₄ mediated addition of 3,4-dihydro-2H-pyran to (2-trimethylsilyl)ethyl pyruvate results in a one-pot addition-cyclisation sequence to deliver a functionalised perhydrofuro[2,3-b]pyran derivative in good yield.

Key words

acetals - lactones - ene reactions - Lewis acid - titanium

References

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12

Preparation of pyruvate 8: Sodium hydrogen sulfate on silica (0.1 g/mmol of hydroxyl prepared according to the procedure of Breton [16] ) was added to a stirred solution of pyruvic acid (4.3 mL, 62.0 mmol) and 2-(trimethyl-silyl)ethanol (8.0 mL, 56.0 mmol) in DCM (100 mL). The reaction mixture was heated at reflux overnight. The mixture was then cooled to room temperature, filtered and the solvent removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with saturated sodium bicarbonate (100 mL) and saturated brine (50 mL). The organic layer was dried (Na₂SO₄), filtered and the solvent removed in vacuo. Purification by flash chromatography (20% EtOAc-petroleum ether) followed by distillation under reduced pressure gave TMSE-pyruvate 8, (6.54 g, 62% yield) as a colourless liquid. R_f 0.56 (20% EtOAc-petroleum ether); bp 100 °C at 2 mmHg; (liquid film)/cm^-1 2995, 2899, 1732, 1298, 1251, 1138, 861, 839; δ_H (300 MHz, CDCl₃) 4.28 (2 H, m), 2.40 (3 H, s), 1.04 (2 H, m), 0.0 (9 H, s); δ_C (75 MHz, CDCl₃) 192.6, 161.4, 65.4, 27.1, 17.7, -1.2; m/z (CI +) 206.1 (94%, M + NH₄)⁺, (EI+) 145.0 (M
- MeC=O)⁺, 101.1 (Me₃SiCH₂CH₂)⁺, 73 (Me₃Si)⁺; Found 206.1211 (M + NH₄)⁺, C₈H₂₀NO₃Si requires 206.1212.

13

All novel compounds were fully characterised.

14

Preparation of 13: Titanium(IV) chloride (0.22 mL, 2.0 mmol) was added to a stirred solution of 3,4-dihydro-2H-pyran (0.27 mL, 3.0 mmol) and TMSE-pyruvate 8 (0.30 g, 1.5 mmol) in DCM (10 mL) at -78 °C. The reaction mixture was stirred for 1 h at -78 °C, then at room temperature for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution (30 mL) and EtOAc was added (30 mL). The layers were separated and the aqueous phase washed with additional EtOAc (3 × 25 mL). The combined organic fractions were washed with saturated brine (1 × 100 mL) and dried (Na₂SO₄). The solution was filtered and the solvent removed in vacuo. Purification by flash chromato-graphy (40% EtOAc-petroleum ether) gave lactone 13 (0.19 g, 81% yield) as a pale yellow oil. R_f 0.3 (40% EtOAc-petroleum ether); (liquid film)/cm^-1 2995, 2928, 2858, 1770, 1703, 1446, 1348, 1234, 1037, 1011; δ_H (300 MHz, CDCl₃) 5.45 (1 H, s), 4.08-3.97 (1 H, m), 3.75-3.61 (1 H, m), 2.84-2.72 (1 H, m), 2.24 (1 H, ddd, J = 11.1 Hz, 6.7 Hz, 4.0 Hz), 1.88-1.70 (2 H, m), 1.76 (3 H, s); δ_C (75 MHz; CDCl₃) 170.6, 155.3, 120.4, 97.3, 63.6, 24.8, 22.5, 6.5; m/z (CI +) 171.9 (100%, M + NH₄)⁺, 154.9 (6, M)⁺; Found (M + NH₄)⁺ 172.0974, C₈H₁₄NO₃ requires 172.0974.

15

Preparation of 14: Potassium permanganate (0.12 g, 0.77 mmol) was added to a stirred solution of unsaturated lactone 13 (0.12 g, 0.77 mmol) and benzo-18-crown-6 (0.36 g, 1.16 mmol) in CH₂Cl₂ (10 mL) and the reaction mixture was stirred at room temperature for 3 days. The mixture was poured into water (10 mL) and the layers separated. The aqueous layer was washed with CH₂Cl₂ (3 × 10 mL) and the combined organic layers were dried (Na₂SO₄), filtered and the solvent was removed in vacuo. Purification by flash chromatography (50% EtOAc-petroleum ether) gave diol 14 (86 mg, 60% yield) as a light brown oil. R_f 0.15 (40% EtOAc-petrol); (liquid film)/cm^-1 3425, 2956, 1776, 1174, 1125, 1026, 936, 915; δ_H (300 MHz; CDCl₃) 5.62 (1 H, s), 3.82-3.74 (1 H, m), 3.73-3.63 (1 H, app dt), 3.00 (1 H, br. s), 2.81 (1 H, br. s), 2.01-1.79 (2 H, m), 1.61-1.45 (2 H, m), 1.38 (3 H, s); δ_C (75 MHz; CDCl₃) 173.8, 103.6, 79.0, 72.6, 62.6, 27.6, 20.5, 16.8; m/z (CI +) 206.0 (100%, M + NH₄)⁺, 188.9 (5, M)⁺, 172.0 (8, M - OH)⁺, 126.0 (3, M - CO₃H)⁺, 110.9 (4, C₆H₇O₂); Found (M + NH₄)⁺ 206.1027, C₈H₁₆NO₅ requires 206.1028.