Synthesis of Isoxazolidine-Fused Eight-Membered Heterocycles via an Intramolecular Nitrone–Alkene Cycloaddition

Abstract

An intramolecular nitrone–alkene cycloaddition yielded novel tricyclic eight-membered ring with a cis-fused isoxazolidine in good to excellent yields under mild reaction conditions.

Key words

1,3-dipolar cycloaddition - diastereoselectivity - fused-ring systems - eight-membered ring - isoxazolidine

• References and Notes

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• 14 Typical Experimental Procedure for the Synthesis of 4Compound 1a (225 mg, 0.50 mmol) in CH₂Cl₂ (20 mL) was treated with DIPEA (0.697 mL, 4.0 mmol) and DMSO (0.709 mL, 10.0 mmol). The reaction mixture was cooled to 0–2 °C, and SO₃–pyridine (320 mg, 2.0 mmol) was added in two portions. The resulting solution was stirred for 2 h at 0–2 °C. The reaction mixture was then diluted with CH₂Cl₂ (20 mL), washed with 0.2 M aq KHSO₄ (20 mL), H₂O (20 mL), and brine (20 mL). Then it was dried over MgSO₄, filtered, and diluted with CH₂Cl₂ to give a solution of crude aldehyde 2a in CH₂Cl₂ (50 mL). To the above solution was added NaOAc (49 mg, 0.60 mmol) and N-methylhydroxylamine hydrochloride (49 mg, 0.60 mmol). The mixture was stirred for 2 h at 25 °C, then washed with sat. aq Na₂CO₃ (25 mL), dried over MgSO₄, and concentrated in vacuo. Purification by flash chromatography (PE–EtOAc, 5:1 to 1:2 v/v) afforded the desired product 4a (193 mg, 81% yield); mp 153–154 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.34 (s, 1 H), 7.44–7.42 (m, 2 H), 7.40–7.30 (m, 5 H), 7.00–6.96 (m, 2 H), 5.51 (d, 1 H, J = 13.5 Hz), 4.41 (t, 2 H, J = 7.5 Hz), 3.98 (t, 1 H, J = 8.4 Hz), 3.85 (s, 3 H), 3.51 (dd, 1 H, J = 15.6, 9.3 Hz), 3.46 (ddd, 1 H, J = 9.3, 8.4, 6.3 Hz), 3.21–3.16 (m, 4 H), 2.18 (br, 1 H), 2.11 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 169.6, 160.9, 158.2, 155.8, 137.4, 137.2, 128.92, 128.87, 128.2, 118.0, 116.1, 115.0, 70.4, 66.5, 55.4, 54.7, 49.4, 49.3, 42.9, 34.8. ESI-MS: m/z = 478.2 [M + H⁺].
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