Diastereoselective Synthesis of Chiral [4.4]- and [4.5]-Spiroketals from Furan Derivatives: Study on the Asymmetric Synthesis of Tonghaosu Analogs

Abstract

Diastereoselective syntheses of [4.4]- and [4.5]-spiro­ketal featured tonghaosu analogs were explored. An excellent dia­stereoselectivity was achieved for [4.5]-spiroketals due to anomeric, steric, and perhaps π-π interactions; [4.4]-spiroketal could be obtained in good diastereoselectivity by tuning substituted pattern of the tetrahydrofuran ring.

spiroketal - diastereoselectivity - Tonghaosu analogs

References

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Typical Procedure of Acid Catalyzed Sipoketalization for Synthesis of Compound 11a: A mixture of 9a (1.16 g, 5 mmol), (1R, 2R)-(-)-pseudoephedrine (0.83 g, 5 mmol), MeOH (20 mL) and Et₃N (10 mL) was refluxed under nitrogen for 24 h. Removal of the solvents under reduced pressure gave a yellow oily crude product amide. Without further purification the oil was solved in anhyd CH₂Cl₂ (20 mL) and to the obtained solution was added CSA (20 mg). The reaction mixture was stirred at r.t. until the disappearance of all the starting material (ca. 24 h) and then quenched with sat. aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were washed with brine and dried over Na₂SO₄. Removal of solvent gave the crude spiroketal, which was purified by flash chromatography to yield compound 11a (1.58 g, 91%): mp 162-163 °C, [α]_D ²⁰ +345.2 (c 1.0, CHCl₃). IR (KBr): 3101, 1674, 1658, 1490, 1450, 1243, 1009, 925, 746, 693 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.47-7.13 (10 H, m), 6.50 (1 H, d, J = 5.5 Hz), 6.19 (1 H, d, J = 5.5 Hz), 5.50 (1 H, s), 4.81 (1 H, d, J = 5.8 Hz), 4.17 (1 H, m), 3.15 (3 H, s), 1.37 (3 H, d, J = 6.7 Hz). MS: m/z (%) = 347 (17.0) [M⁺], 256 (2.1), 173 (12.5), 172 (79.0), 128 (10.0), 118 (100.0), 117 (34.6), 116 (10.7), 115 (12.8). HRMS: m/z calcd for C₂₂H₂₁O₃N: 347.1516. Found: 347.1509.

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Typical Procedure of Acid Catalyzed Sipoketalization for Synthesis of Compound 20 and 21: To a solution of 19 (1.2 g, 3.48 mmol) in 15 mL of CH₂Cl₂ was added catalytic amount of CSA (40 mg). The reaction mixture was stirred at r.t. for 24 h, and the separated aqueous phase was extracted with CH₂Cl₂, and the combined organic layers were washed with brine and dried over Na₂SO₄ After removal of the solvent, the residue was chromatographed to afford 20 (828 mg, 72.7%) and 21 (230 mg, 20.2%). Compound 20: mp 142-143 °C. IR (film): 3180, 2974, 1656, 1492, 1352, 1237, 1097, 1014, 747, 690 cm^-1. ¹H NMR (300 MHz, CDCl₃):
δ = 7.60 (2 H, d, J = 7.4 Hz), 7.27 (2 H, m), 7.15 (1 H, m), 6.51 (1 H, d, J = 5.7 Hz), 6.07 (1 H, dd, J = 0.9 Hz, 5.7 Hz), 5.52 (1 H, s), 4.19 (1 H, ddd, J = 3.3 Hz, 6.9 Hz, 11.1 Hz), 3.63-3.37 (3 H, m), 3.28 (1 H, dd, J = 3.3 Hz, 12.3 Hz), 1.85 (1 H, m), 1.22 (3 H, t, J = 7.5 Hz), 0.99 (6 H, t, J = 5.7 Hz). MS: m/z (%) = 313 (31.8) [M⁺], 173 (27.5), 172 (100.0), 144 (19.8), 128 (16.0) Anal. Calcd for C₁₉H₂₃NO₃: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.99; H, 7.62; N, 4.31.
Compound 21: syrup. IR (film): 3086, 2964, 2935, 1669, 1597, 1491, 1352, 1238, 825, 690 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.58 (2 H, d, J = 7.5 Hz), 7.26 (2 H, m), 7.16 (1 H, m), 6.47 (1 H, d, J = 5.7 Hz), 6.22 (1 H, d, J = 5.7 Hz), 5.50 (1 H, s), 3.85 (2 H, m), 3.52 (2 H, dq, J = 1.8 Hz, 7.2 Hz), 3.34 (1 H, dd, J = 1.8 Hz, 10.8 Hz), 1.94 (1 H, m), 1.21 (3 H, t, J = 7.2 Hz), 1.02 (3 H, d, J = 7.2 Hz), 0.96 (3 H, d, J = 7.2 Hz). MS: m/z (%) = 313 (38.3) [M⁺], 173 (26.0), 172 (100.0), 144 (22.1), 128 (12.9), 116 (17.0), 115 (22.1). Anal. Calcd for C₁₉H₂₃NO₃: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.69; H, 7.46; N, 4.41.