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Synlett 2011(17): 2541-2544  
DOI: 10.1055/s-0030-1260329
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of the Hypoxic Signaling Inhibitor Furospongolide

John Boukouvalas*, Vincent Albert
Département de Chimie, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue de la Médecine, Quebec City, QC, G1V 0A6, Canada
Fax: +1(418)6567916; e-Mail: john.boukouvalas@chm.ulaval.ca;
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Publication History

Received 3 August 2011
Publication Date:
27 September 2011 (online)

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Abstract

The first synthesis of the marine HIF-1 inhibitor furospongolide has been achieved in eight linear steps from geranyl acetate. Key steps include Schlosser sp³-sp³ cross-coupling and Sonogashira alkynylation of β-bromobutenolide.

Key words

alkynes - butenolides - cross-coupling - furanoterpenoids - neotorreyol

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A 0.3 M solution of Grignard reagent 4a in THF was prepared as follows: Magnesium powder (1.04 g, 42.65 mmol) was flame heated, allowed to cool to r.t., and activated by successively adding a crystal of iodine and a solution of 1,2-dibromoethane (0.1 mL) in THF (7 mL) under argon. The mixture was refluxed for 25 min (until bubbling of acetylene gas ceased), and then cooled to 0 ˚C. A solution of 3-chloromethylfuran¹5a (497 mg, 4.27 mmol) in THF (3 mL) was then added at once. Vigorous stirring was continued for 4 h at -3 to 0 ˚C (salt-water bath). The mixture was decanted over 15 min without stirring. The resulting THF solution of 4a (0.3 M) could be kept for 1-3 h at -3 to 0 ˚C without any signs of decomposition.

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Synthesis of Neotorreyol (8)
To a stirred solution of acetate 5a (434 mg, 1.33 mmol) in THF (3 mL) was added Li2CuCl4 in THF (0.1 M, 1.33 mL, 0.133 mmol). After cooling to 0 ˚C, a freshly prepared solution of Grignard reagent 4a in THF¹6 (0.3 M, 8.5 mL, 2.55 mmol) was added over 10 min at 0 ˚C. After 10 min the reaction mixture was allowed to warm to r.t. and stirring continued for 18 h before quenching with brine (3 mL). The mixture was poured to EtOAc (15 mL), the organic layer was separated, washed with brine (2 × 10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (2% EtOAc in hexanes) to give 361 mg of a mixture consisting of cross-coupled product 10 and 1,2-di-3-furylethane. Due to difficulties in separating the Wurtz homocoupling product at this stage, crude 10 was used as is for the subsequent reaction; it was dissolved in THF (3 mL) and aq HCl (1 M, 1.25 mL) was added with stirring at r.t. After 16 h, the mixture was poured into EtOAc (15 mL), the organic layer was separated, washed with brine (1 × 10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel (8% EtOAc in hexanes) to give neotorreyol (8) as a colorless oil (227 mg, 73% over 2 steps); R f = 0.35 (20% EtOAc-hexanes). IR (NaCl, film): 3341, 2920, 2855, 1501, 1446, 1383, 1164, 1065, 1025, 874, 778 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.34 (s, 1 H), 7.21 (s, 1 H), 6.28 (s, 1 H), 5.37 (t, J = 5.8 Hz, 1 H), 5.17 (t, J = 5.8 Hz, 1 H), 3.99 (s, 2 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.25 (q, J = 7.4 Hz, 2 H), 2.13 (q, J = 7.4 Hz, 2 H), 2.03 (t, J = 7.4 Hz, 2 H), 1.67 (s, 3 H), 1.60 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 142.8, 139.1, 135.6, 135.0, 126.2, 125.2, 124.3, 111.3, 69.2, 39.5, 28.6, 26.3, 25.2, 16.3, 13.9. ESI-HRMS: m/z calcd for C15H22O2: 234.1627; found: 234.1620.

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Data for Acetylene 11
Colorless oil; R f = 0.20 (hexanes). IR (NaCl, film): 3302, 2921, 2855, 1501, 1444, 1384, 1164, 1065, 1025, 874, 779, 634 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.34 (s, 1 H), 7.21 (s, 1 H), 6.28 (s, 1 H), 5.39 (t, J = 5.8 Hz, 1 H), 5.17 (t, J = 5.8 Hz, 1 H), 2.88 (s, 2 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.25 (q, J = 7.4 Hz, 2 H), 2.13 (q, J = 7.4 Hz, 2 H), 2.09 (s, 1 H), 2.03 (t, J = 7.4 Hz, 2 H), 1.69 (s, 3 H), 1.59 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 142.8, 139.1, 135.7, 129.6, 126.3, 125.2, 124.2, 111.3, 82.4, 70.3, 39.6, 28.8, 28.7, 26.8, 25.2, 16.3, 16.2. ESI-HRMS: m/z calcd for C17H22O: 242.1673; found: 242.1671.

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Synthesis of Butenolide 12
A vial charged with PdCl2(PPh3)2 (18.0 mg, 0.024 mmol), CuI (3.5 mg, 0.018 mmol), and 7a (50.0 mg, 0.291 mmol) was placed on a vacuum pump for 30 min and then purged with argon. Degassed 1,4-dioxane (0.5 mL) was added, and the mixture was stirred for 30 min at r.t. To this mixture was added (using a cannula) a solution of Hünig’s base (64 mg, 0.485 mmol) and alkyne 11 (58.8 mg, 0.243 mmol) in 1,4-dioxane (0.8 mL, purged with Ar). The mixture was stirred for 18 h at r.t. and then quenched with brine (2 mL). EtOAc (5 mL) was added and the aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and the residue was subjected to flash chromatog-raphy on silica gel (15% Et2O in pentane) to give butenolide 12 as a yellow oil (51.6 mg, 66%); R f = 0.23 (10% EtOAc-hexanes). IR (NaCl, film): 2920, 2856, 2225, 1779, 1750, 1611, 1446, 1301, 1145, 1043, 1025, 881, 874, 855, 780 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.34 (s, 1 H), 7.20 (s, 1 H), 6.27 (s, 1 H), 6.12 (s, 1 H), 5.35 (t, J = 5.8 Hz, 1 H), 5.17 (t, J = 5.8 Hz, 1 H), 4.78 (s, 1 H), 3.13 (s, 2 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.25 (q, J = 7.4 Hz, 2 H), 2.13 (q, J = 7.4 Hz, 2 H), 2.02 (t, J = 7.4 Hz, 2 H), 1.70 (s, 3 H), 1.60 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 173.8, 148.2, 142.8, 139.1, 135.5, 128.4, 127.5, 125.1, 124.4, 121.9, 111.3, 105.8, 73.4, 73.3, 39.4, 30.2, 28.6, 26.8, 25.2, 16.4, 16.3. ESI-HRMS: m/z calcd for C21H24O3: 324.1742; found: 324.1725.

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Synthesis of Furospongolide (1)
To a solution of butenolide 12 (48.7 mg, 0.1501 mmol) in EtOAc-MeOH (3:2, 1 mL) was added 5% Pd(0) on BaSO4 (127.8 mg). The reaction mixture was stirred for 5.25 h under a balloon of hydrogen at r.t., filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% Et2O in pentane) to furnish furo-spongolide (1, 29.4 mg, 60%). Some of the remaining fractions containing 12 and partially hydrogenated product were combined, concentrated under reduced pressure, and the residue was dissolved in EtOAc-MeOH (3:2, 1 mL) and rehydrogenated using 30.2 mg of 5% Pd(0) on BaSO4 for 30 min at r.t. The solution was filtered through Celite and silica gel and concentrated to afford an additional 14.5 mg (29%) of pure 1, thereby making the total yield 89%; colorless oil, R f = 0.23 (30% Et2O-pentane). IR (NaCl, film): 2929, 2857, 1781, 1749, 1638, 1501, 1446, 1384, 1168, 1130, 1064, 1025, 886, 874, 854, 780 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.34 (s, 1 H), 7.21 (s, 1 H), 6.28 (s, 1 H), 5.84 (s, 1 H), 5.16 (t, J = 6.8 Hz, 1 H), 5.11 (t, J = 6.8 Hz, 1 H), 4.73 (s, 1 H), 2.45 (t, J = 7.5 Hz, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 2.26 (q, J = 7.5 Hz, 2 H), 2.11-1.98 (m, J = 7.5 Hz, 6 H), 1.69 (quin, J = 7.5 Hz, 2 H), 1.60 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 174.4, 170.7, 142.8, 139.0, 135.8, 133.6, 125.9, 125.1, 124.1, 115.6, 111.3, 73.3, 39.8, 39.1, 28.6, 28.1, 26.7, 25.5, 25.3, 16.3, 16.0. ESI-HRMS: m/z calcd for C21H28O3: 328.2050; found: 328.2038.