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Synlett 2014; 25(15): 2139-2142
DOI: 10.1055/s-0034-1378559
letter
© Georg Thieme Verlag Stuttgart · New York

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

John Boukouvalas*
Département de Chimie, Pavillon Alexandre-Vachon, 1045 Avenue de la Médecine, , Université Laval, Quebec City, Quebec, G1V 0A6, Canada   Fax: +1(418)6567916   Email: john.boukouvalas@chm.ulaval.ca
,
Charles Thibault
Département de Chimie, Pavillon Alexandre-Vachon, 1045 Avenue de la Médecine, , Université Laval, Quebec City, Quebec, G1V 0A6, Canada   Fax: +1(418)6567916   Email: john.boukouvalas@chm.ulaval.ca
,
Richard P. Loach
Département de Chimie, Pavillon Alexandre-Vachon, 1045 Avenue de la Médecine, , Université Laval, Quebec City, Quebec, G1V 0A6, Canada   Fax: +1(418)6567916   Email: john.boukouvalas@chm.ulaval.ca
› Author Affiliations
Further Information

Publication History

Received: 19 May 2014

Accepted after revision: 02 July 2014

Publication Date:
11 August 2014 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information
 

  • 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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