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Synlett 2002(5): 0743-0746
DOI: 10.1055/s-2002-25353
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of (+) and (-)-Furocaulerpin

Laurent Commeiras, Maurice Santelli, Jean-Luc Parrain*
Laboratoire de Synthèse Organique associé au CNRS (UMR 6009), Faculté des Sciences de Saint Jérôme, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
e-Mail: jl.parrain@lso.u-3mrs.fr;
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Publication History

Received 5 February 2002
Publication Date:
07 February 2007 (online)

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Abstract

The first total synthesis of (+)- and (-)-furocaulerpin was accomplished. The key steps in the sequence are 1) the control of the chiral center by enzymatic resolution, 2) the control of the configuration of the central double bond, 3) the construction of the dienyne moiety via a Stille cross-coupling.

Key words

furocaulerpin - Stille cross-coupling - dienyne function

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Capillary GC monitored the progress of the reaction. In parallel, enantiomeric excess(ee) was determined by the ratio of the peak areas obtained by GC separation using a chiral phase (WCOT Fused Silica 25m × 0.25mm Coating CP CHIRASIL-DEX CB DF = 0.25). The enantiomers of both alcohol and the acetate were separable.

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(+)-1-(3-Furyl)pent-3-yn-1-yl acetate [(+)-7]: To a solution of (±)-6 (1.00 g, 6.7 mmol) in hexane (100 mL) was added vinyl acetate (1.84 mL, 20 mmol) and Ps. fluorescens lipase (0.5 g). The mixture was stirred magnetically in a hermetically stoppered one-neck flask at room temperature. The reaction was monitored by capillary GC on chiral column. After 26 h and 40% of conversion rate, the reaction was stopped by filtration. Removal of the solvent, followed by silica gel column chromatography (petroleum ether-Et2O, 7:3), yielded 620 mg (57%) of nonreactive alcohol
(-)-6 (ee = 65%, determined by chiral GC) and 457 mg (37%) of acetate (+)-7 ([α] +41.4, c = 1.0 in CHCl3, ee 92%). 1H NMR (300 MHz, CDCl3) 1.74 (t, J = 2.6 Hz, 3 H), 2.06 (s, 3 H), 2.57-2.74 (m, 2 H), 5.83 (t, J = 6.6 Hz, 1 H), 6.42 (dd, J = 1.7, 0.8 Hz, 1 H), 7.36 (br t, J = 1.7 Hz, 1 H), 7.47 (m, 1 H); 13C NMR (75 MHz, CDCl3) 3.49, 21.16, 25.47, 67.06, 74.16, 78.14, 109.00, 124.04, 140.53, 143.13, 170.18; MS (70 eV): 192 (M, 0.2), 150(12), 139(17), 132(10), 97(39), 43(100), 39(15).
(-)-1-(3-Furyl)pent-3-yn-1-ol [(-)-6]: The remaining alcohol (-)-6 (ee = 65%) was resubjected to the same conditions using the recovered active enzyme. The progress of the reaction was monitored by chiral GC. After 100 h, GC analysis showed that one enantiomer was completely consumed. The reaction was stopped by filtration. Removal of the solvent followed by silica gel column chromatography yielded 400 mg [40% overall yield from (±)-6] of alcohol
(-)-6 ([α] -32.8, c = 1 in CHCl3, ee>99%). 1H NMR (300 MHz, CDCl3) 1.79 (t, J = 2.6 Hz, 3 H), 2.24 (d, J = 4.5 Hz, 1 H), 2.48-2.65 (m, 2 H), 4.75 (m, 1 H), 6.41 (dd, J = 1.7, 0.8 Hz, 1 H), 7.37 (br t, J = 1.7 Hz, 1 H), 7.42 (m, 1 H); 13C NMR (75 MHz, CDCl3) 3.50, 28.69, 65.66, 74.97, 78.80, 108.59, 124.68, 139.23, 143.19; MS (70 eV): 150 (M, 2), 121(10), 97(100), 95(11), 69(61), 53(14), 51(18), 41(95), 39(53).

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(-)-1-(3-Furyl)-[( E )-4-tributylstannyl]pent-3-en-1-ol[(-)-8]: CuCN (0.238 g, 2.7 mmol) was suspended in freshly distilled THF (8 mL), cooled at -78 °C and treated with BuLi in hexane (2.5 M, 2.13 mL, 5.3 mmol). The mixture was allowed to warm slightly to yield a colorless, homogenous solution which was recooled to -78 °C where Bu3SnH (1.41 mL, 5.3 mmol) was added dropwise via syringe. Stirring was continued and, over ca. 10 min, the solution yellowed and H2 gas was liberated. MeOH (3 mL, 0.073 mol) was then added, and the mixture was allowed to warm up to -40 °C and (-)-1-(3-furyl)pent-3-yn-1-ol (0.1 g, 0.66 mmol) was added at -78 °C. The reaction was allowed to warm up to -10 °C and was stirred overnight. The mixture was quenched with a saturated aqueous NH4Cl solution, filtered and aqueous layer was extracted with Et2O (3 × 15 mL). The organic layers were washed with a saturated aqueous NaCl solution, dried over MgSO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether-Et2O, 7:3) to yield 24 mg of (-)-6 and 125 mg (43%) of (-)-8 ([α] -11.7, c = 1 in CHCl3). 1H NMR (200 MHz, CDCl3) 0.81-0.90 (m, 15 H), 1.19-1.58 (m, 12 H), 1.84 (br s, 3 J Sn-H = 45 Hz, 3 H), 1.86 (br s, 1 H), 2.46-2.72 (m, 2 H), 4.69 (m, 1 H), 5.52 (br t, J = 6.8 Hz,
3 J Sn-H = 69 Hz, 1 H), 6.40 (br t, J = 1.4 Hz, 1 H), 7.35 (s, 1 H), 7.36 (s, 1 H); 13C NMR (50 MHz, CDCl3) 9.24 (1 J Sn-C = 330 Hz, 3 C), 13.75 (3 C), 19.50, 27.43 (3 J Sn-C = 55 Hz, 3 C), 29.23 (2 J Sn-C = 20 Hz, 3 C), 36.83, 66.75, 108.69, 128.79, 135.22, 139.08, 143.03, 143.25; MS (70 eV): 385 (M-57, 85), 367(14), 303(10), 251(100), 235(10), 195(18), 177(40), 135(43), 121(27), 105(28), 97(28), 69(22), 55(14), 43(12), 41(53), 39(25).

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(-)-Furocaulerpin 1: In a dry 10-mL Schlenk tube, vinyl iodide (-)-10 (60 mg, 0.187 mmol) in DMF (2 mL) was added PdCl2(MeCN)2 (2.5 mg, 0.009 mmol). The solution was degassed and 1-trimethylstannyl-4-methylpent-3-en-1-yne 3 (68 mg, 0.3 mmol) was added and the reaction mixture immediately turned black. The reaction was followed by GC. After complete conversion water (1 mL) was added. The aqueous layer was extracted with Et2O (3 × 5 mL). The organic layers were washed with water (2 × 5 mL), dried over MgSO4 and concentrated under vacuum. Chromatography (petroleum ether -Et2O, 9:1) yielded 46 mg (90%) of (-)-1 ([α] -14.6, c = 1 in CHCl3). 1H NMR (500 MHz, CDCl3) 1.79 (s, 6 H), 1.87 (s, 3 H), 2.03 (s, 3 H), 2.57 (ddd, J = 14.7, 7.3, 6.8 Hz, 1 H), 2.68 (ddd, J = 14.7, 7.3, 6.8 Hz, 1 H), 5.33 (s, 1 H), 5.69 (br t, J = 7.3 Hz, 1 H), 5.77 (t, J = 6.8 Hz, 1 H), 6.38 (br s, 1 H), 7.36 (m, 1 H), 7.40 (br s,
1 H); 13C NMR (50 MHz, CDCl3) 17.80, 21.02, 21.25, 24.86, 33.95, 67.75, 85.20, 94.15, 105.28, 108.93, 121.36, 124.44, 130.20, 140.45, 143.29, 148.20, 170.32; MS (70 eV): 272 (M, 0.3), 212(21), 133(21), 105(15), 97(46), 91(20), 77(16), 43(100), 41(22), 39(16).