Convenient Preparation of 5-Alkylidene-2,5-dihydropyrrol-2-ones by Ring-Transformations of γ-Alkylidenebutenolides: Formal Synthesis of Pukeleimide A

Abstract

The reaction of γ-alkylidenebutenolides, readily available by cyclization of 1,3-bis-silyl enol ethers with oxalyl chloride, with amines in glacial acetic acid allows a convenient synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones. This method was applied to a formal total synthesis of the natural product pukeleimide A.

Key words

butenolides - cyclization - natural products - pyrrolones - ring-transformation

References

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18

Typical Procedure (Synthesis of 5c). A solution of 4b (292 mg, 1.0 mmol) and ammonium acetate (385 mg, 5.0 mmol) in glacial acetic acid (5 mL) was refluxed for 20 h. The mixture was cooled to 20 °C and EtOAc was added. The organic layer was neutralized by repeated washing with a sat. aq solution of NaHCO₃. The aqueous layer was extracted with EtOAc (3 ×) and the combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo to give 5c as a colorless solid (280 mg, 96%) without the need of further purification; mp 103 °C, R _f = 0.25 (hexane-EtOAc = 4:1). ¹H NMR (300 MHz, CDCl₃): δ = 3.75 (s, 3 H, OCH₃), 3.89 (s, 3 H, OCH₃), 5.30 (s, 2 H, CH₂Ph), 5.44 (s, 1 H, CH), 7.37 (m, 5 H, Ph), 8.48 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 51.63, 59.36 (OCH₃), 74.17 (CH₂Ph), 92.60 (CH), 127.35 (C), 128.56, 128.57, 128.73 (CH, Ph), 136.02, 144.36, 144.50 (C), 166.25, 167.35 (C=O). MS (EI, 70 eV): m/z (%) = 289 (6) [M]⁺, 261 (3), 170 (3), 109 (5), 91 (100). The exact molecular mass for C₁₅H₁₅NO₅: m/z = 289.0950 ± 2 ppm was confirmed by HRMS (EI, 70 eV). IR (KBr): 3401 (br, w), 3332 (s), 3263 (w), 3257 (w), 3036 (w), 3003 (w), 2953 (m), 2928 (w), 2859 (w), 1733 (s), 1702 (s), 1674 (s), 1451 (s), 1414 (w) cm^-1. Anal. Calcd for C₁₅H₁₅NO₅ (289.28): C, 62.28; H, 5.23; N, 4.84. Found: C, 62.74; H, 5.71; N, 4.38. All new compounds gave satisfactory spectroscopic and correct analytical and/or high resolution mass data.