Refined Protocols for the Preparation of 3-Alkoxy-2,5-dihydrofurans, Allylic Oxidation to β-Alkoxybutenolides and Short Synthesis of (±)-Annularin H

Abstract

The 5-endo cyclization of α-allenyl alcohols derived from carbonyl compounds and lithiated alkoxyallenes was reinvestigated by comparing the known reagents KOt-Bu, AgNO₃ or AgBF₄ with the reagent system AuCl/pyridine. A variety of 3-alkoxy-2,5-dihydrofurans 4 was efficiently prepared, in some cases with high diastereoselectivity. These product compounds were ­subjected to manganese(III)-catalyzed allylic oxidation which led to β-alkoxybutenolides with moderate to good yield. Combination of these newly tuned methods allowed for a concise and short syn­thesis of (±)-annularin H.

Key words

allenes - gold catalysis - dihydrofurans - allylic oxidation - butenolides

References and Notes

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• 16 Typical Procedure for the Au(I)-Catalyzed Cyclization: Preparation of Compound 4g Methoxyallene (0.35 mL, 294 mg, 4.19 mmol) was dissolved in Et₂O (5 mL) at -40 °C. n-BuLi (1.40 mL, 2.5 M in hexane, 3.50 mmol) was added, the mixture was stirred for 20 min and then cooled to -78 °C. A solution of ketone 1g (180 mg, 1.15 mmol) in Et₂O (2 mL) was slowly added and the mixture was stirred at -78 °C for 2.5 h. Then, H₂O (10 mL) was added and the mixture was warmed to r.t. The layers were separated and the aqueous layer was extracted with Et₂O (3×). The combined organic layers were dried (MgSO₄), filtered, and evaporated. Drying at 0.1 mbar provided the allenyl alcohol as a yellow oil (285 mg, quant.). The crude product (max. 1.15 mmol) was dissolved in CH₂Cl₂ (17 mL). Pyridine (15 µL, 15 mg, 190 µmol) and AuCl (13 mg, 56 µmol) were added with rapid stirring. After 1 h, TLC showed complete conversion. The mixture was concentrated in vacuo and directly chromatographed (silica gel, EtOAc-hexane = 1:3) to provide 222 mg (85% over 2 steps) of 4g as a colorless solid. Analytical data for 4g: mp 72-74 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.59-1.67, 1.86-1.91 (2 m, 2 × 4 H, 4 × CH₂), 3.61 (s, 3 H, OCH₃), 3.92 (m_c, 4 H, 2 × CH₂), 4.50 (t, J = 1.7 Hz, 1 H, 4-H), 4.52 (d, J = 1.7 Hz, 2 H, 5-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 30.7, 31.8 (2 t, 4 × CH₂), 57.4 (q, OCH₃), 64.1, 64.2 (2 t, 2 × CH₂), 70.2 (t, C-5), 82.5 (s, C-2), 88.2 (d, C-4), 108.3 [s, C(OR)₂], 161.4 (s, C-3) ppm. IR (KBr): ν = 2960-2850 cm^-1 (=CH, CH). ESI-TOF: 249.1095 [M + Na]⁺, 227.1277 [M + H]⁺. Anal. Calcd for C₁₂H₁₈O₄ (226.3): C, 63.70; H, 8.02. Found: C, 63.47; H, 8.11
• 17 Typical Procedure for the Allylic Oxidation: Preparation of (±)-Annularin H (17) Dihydrofuran 16 (520 mg, 2.03 mmol) was dissolved in MeCN (22 mL). Then, Cs₂CO₃ (335 mg, 1.03 mmol) and powdered 4 Å MS (1.02 g) were added. After cooling to 0 °C, TBHP (1.90 mL, 5.5 M solution in nonane, 10.5 mmol) and Mn(OAc)₃·2H₂O (27 mg, 101 µmol) were added and the flask was equipped with a balloon of O₂. The mixture was vigorously stirred at 0 °C for 72 h, then poured into an aqueous solution of FeSO₄·7H₂O (ca. 2.5 g in 30 mL H₂O), rinsing with EtOAc (10 mL). After 10 min of stirring, the mixture was filtered through Celite^® with the aid of EtOAc (50 mL). The filtrate layers were separated and the aqueous layer was extracted with EtOAc (5×). The combined organic layers were dried (MgSO₄), filtered, and evaporated to dryness. The residue was dissolved in acetone-H₂O (8 mL/0.50 mL) and HCl (0.20 mL, 37% aq) was added. After 22 h of stirring at r.t., the mixture was poured into pH 7 phosphate buffer solution (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO₄), filtered, concentrated, and chromatographed (silica gel, 100% EtOAc, R _f = 0.6) to provide 192 mg (51% over 2 steps) of 17 as a yellowish oil that solidified to a light yellow solid in the refrigerator. Analytical data for 17: mp 55-57 °C (lit.¹⁵ oil). ¹H NMR (500 MHz, CDCl₃): δ = 1.02 (t, J = 7.3 Hz, 3 H, CH₃), 2.46 (q, J = 7.3 Hz, 2 H, CH₂), 2.67 (dd, J = 8.5, 16.9 Hz, 1 H, 1′-H), 2.85 (dd, J = 3.6, 16.9 Hz, 1 H, 1′-H), 3.86 (s, 3 H, OCH₃), 5.05 (d, J = 1.0 Hz, 1 H, 3-H), 5.21 (ddd, J = 1.0, 3.6, 8.5 Hz, 1 H, 5-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 7.29 (q, CH₃), 36.7 (t, CH₂), 43.7 (t, C-1′), 59.5 (q, OCH₃), 74.4 (d, C-5), 88.7 (d, C-3), 171.8 (s, C-2), 181.8 (s, C-4), 206.1 (s, C-2′) ppm. Anal. Calcd for C₉H₁₂O₄ (184.2): C, 58.69; H, 6.57. Found: C, 58.25; H, 6.56. The analytical data are in agreement with those given in ref. 15

9

It was proposed that the KOt-Bu-promoted cyclizations proceed via a SET mechanism, see ref. 2c.