Expedient Assembly of Bioactive Maleic Anhydrides Using Click Diels–Alder Chemistry

Abstract

A versatile pathway to substituted maleic anhydrides is illustrated by the synthesis of the nanomolar FTase inhibitor chaetomellic anhydride A, a germination promoter, and a novel bis-­anhydride cross-linking reagent for cell or tissue fixation. Starting from commercial or easily prepared alkynes, these targets were assembled in two steps by click–unclick oxazole–alkyne cycloaddition–cycloreversion and furan oxyfunctionalization.

Key words

alkynes - click chemistry - furans - natural products - ­oxazoles - total synthesis

• References and Notes

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• 21 Data for New Compounds: Heptadec-2-yne (9) FTIR (NaCl, film): 2924, 2854, 1466, 1378, 722 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.87 (t, J = 7.1 Hz, 3 H), 1.24 (s, 20 H), 1.30–1.38 (m, 2 H), 1.41–1.49 (m, 2 H), 1.75 (t, J = 2.6 Hz, 3 H), 2.07–2.12 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 3.5, 14.2, 18.9, 22.9, 29.1, 29.3, 29.4, 29.6, 29.76, 29.84, 29.86, 29.87, 29.89 (2 C), 32.1, 75.3, 79.5. APPI-HRMS: m/z calcd for C₁₇H₃₂ [M*]⁺: 236.2504; found: 236.2484. 3-Methyl-4-tetradecylfuran (10) FTIR (NaCl, film): 2925, 2854, 1768, 1466, 1143, 1049, 878, 781, 722 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.22–1.40 (m, 22 H), 1.48–1.58 (m, 2 H), 1.95 (d, J = 1.1 Hz, 3 H), 2.33 (t, J = 7.9 Hz, 2 H), 7.13 (s, 1 H), 7.14 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 8.3, 14.3, 22.9, 23.7, 29.50, 29.53, 29.63, 29.65, 29.79, 29.83, 29.84, 29.85 (2 C), 29.87, 32.1, 120.2, 125.8, 139.1, 139.4. ESI-HRMS: m/z calcd for C₁₉H₃₅O [M + H]⁺: 279.2688; found: 279.2683. 2-(4-Hexylfuran-3-yl)ethanol (12) FTIR (ATR, ZnSe, neat): 3342, 2958, 2930, 2858, 1464, 1049, 790 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 7.1 Hz, 3 H), 1.27–1.39 (m, 6 H), 1.49–1.58 (m, 3 H), 2.34 (t, J = 8.3 Hz, 2 H), 2.64 (t, J = 6.6 Hz, 2 H), 3.77 (t, J = 6.6 Hz, 2 H), 7.17 (s, 1 H), 7.25 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 22.8, 23.7, 27.1, 29.3, 29.6, 31.8, 62.1, 121.0, 125.4, 139.6, 140.1. ESI-HRMS: m/z calcd for C₁₂H₂₁O₂ [M + H]⁺: 197.1542; found: 197.1528. 1,5-Bis(4-methylfuran-3-yl)pentane (14) FTIR (NaCl, film): 2929, 2857, 1455, 1141, 1047, 876, 783, 597 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.42–1.51 (m, 2 H), 1.54–1.66 (m, 4 H), 1.99 (d, J = 1.2 Hz, 6 H), 2.38 (t, J = 7.9 Hz, 4 H), 7.15–7.17 (m, 2 H), 7.17–7.19 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 8.2, 23.5, 29.27, 29.34, 120.1, 125.6, 139.1, 139.5. ESI-HRMS: m/z calcd for C₁₅H₂₁O₂ [M + H]⁺: 233.1542; found: 233.1526. 3-[5-(4-Methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)pentyl]-4-methylfuran-2,5-dione (5) FTIR (NaCl, film): 2930, 2863, 1761, 1276, 1119, 922, 890, 732 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.36–1.46 (m, 2 H), 1.58–1.67 (m, 4 H), 2.08 (s, 6 H), 2.46 (t, J = 7.6 Hz, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 9.7, 24.3, 27.2, 29.3, 141.0, 144.2, 166.0, 166.2. ESI-HRMS: m/z calcd for C₁₅H₁₇O₆ [M + H]⁺: 293.1025; found: 293.1026. Although 5 is described in a patent,¹¹ characterization data have not been reported.
• 22 Oxidation of 3-Methyl-4-tetradecylfuran (10) to Chaetomellic Anhydride A (1a) – Typical Procedure Cr₂O₃ (1.34 g) was weighed in a 5 mL volumetric flask and dissolved in a minimum of nanopure water. Sulfuric acid (aq 98%, 1.15 mL) was cautiously added, and the final volume (5 mL) was adjusted with nanopure water to form the Jones reagent with a concentration of 2.68 M based on CrO₃. Furan 10 (47.7 mg, 0.17 mmol, 1.0 equiv) was dissolved in acetone (4.3 mL) in a conical flask (25 mL) and cooled to 0 °C, at which point the Jones reagent (0.32 mL, 0.86 mmol of Cr₂O₃, 5.05 equiv) was slowly added dropwise under strong agitation. The reaction was stirred at that temperature for 30 min. The temperature was then slowly raised to r.t. After 4 h, the reaction was cooled to 0 °C and quenched with i-PrOH (0.3 mL). The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried over MgSO₄, filtered, and concentrated to yield a yellow oil. Subjection of this oil to flash chromatography on silica gel (gradient of 0–15% hexanes–EtOAc) delivered chaetomellic anhydride A (1a) as a colorless oil (40.3 mg, 76%) that turned into a white waxy solid when stored in the freezer. FTIR (NaCl, film): 2925, 2854, 1768, 1276, 922 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.20–1.35 (m, 22 H), 1.52–1.61 (m, 2 H), 2.07 (s, 3 H), 2.45 (t, J = 7.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 9.7, 14.3, 22.9, 24.6, 27.8, 29.4, 29.5, 29.6 (2 C), 29.72, 29.76, 29.80 (2 C), 29.83, 32.1, 140.6, 144.9, 166.0, 166.4. ESI-HRMS: m/z calcd for C₁₉H₃₃O₃ [M + H]⁺: 309.2430; found: 309.2405.
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