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DOI: 10.1055/s-2005-863742
Enantioselective Total Synthesis of Marine Natural Products Untenone A and Plakevulin A
Publication History
Publication Date:
09 March 2005 (online)
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Abstract
An enantioselective total synthesis of untenone A and plakevulin A has been achieved. Construction of a cyclopentene derivative, the key intermediate in this synthesis, was carried out by using a ruthenium-catalyzed ring-closing metathesis reaction of a divinyl compound, prepared from octadecanal in several steps including the Sharpless asymmetric epoxidation to generate a chiral quaternary carbon center.
Key words
natural product - total synthesis - DNA polymerase inhibitor - Sharpless asymmetric epoxidation - ring-closing metathesis
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References
Preparation and Spectroscopic Data of Compound 18.
To a stirred solution of aldehyde 17 (844 mg, 2.13 mmol) in THF (11.0 mL) was added a solution of vinylmagnesium bromide in THF (2.98 mL, 2.98 mmol) at -20 °C under argon, and the mixture was allowed to stir for 1 h. After quenching by addition of sat. aq NH4Cl, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 40:1) to give 18 (737 mg, 82%) as a colorless oil. 1H NMR (CDCl3): δ = 0.14 and 0.17 (each 3 H, each s), 0.87 (3 H, t, J = 6.7 Hz), 1.19-1.33 (28 H, br m), 1.60-1.79 (4 H, m), 3.93 and 4.13 (each 0.5 H, each s), 4.32-4.48 (1 H, m), 5.01-5.30 (4 H, m), 5.73-6.00 (2 H, m). 13C NMR (CDCl3): δ = 2.47, 2.48, 14.0, 22.6, 24.0, 24.5, 29.3, 29.5, 29.5, 29.6, 30.0, 30.1, 31.9, 40.0, 42.2, 44.2, 45.5, 69.4, 69.7, 79.1, 80.8, 113.4, 113.5, 113.8, 114.0, 140.8, 141.0, 141.9, 143.6. IR (thin film): 3510, 2925, 2855, 1676, 1644, 1468, 1413, 1252, 1144, 1048, 922, 842, 755 cm-1. HRMS: m/z calcd for C26H52O2Si: 424.3736; found: 424.3755. Anal. Calcd for C26H52O2Si: C, 73.52; H, 12.34. Found: C, 73.50; H, 12.27.
Preparation and Spectroscopic Data of Compound 19.
To a stirred solution of compound 18 (100 mg, 0.24 mmol) in CH2Cl2 (23.5 mL) was added Grubbs’ 2nd generation ruthenium catalyst (2.00 mg, 2.36 µmol) at r.t., and the mixture was allowed to stir for 45 min. After removal of the solvent, the residue was purified by silica gel column chromatography (n-hexane-EtOAc, 7:1) to give 19 (92.9 mg, 99%) as a white solid; mp 31.5-33 °C. 1H NMR (CDCl3): δ = 0.06 and 0.12 (each 4.5 H, each t, J = 3.3 Hz), 0.87 (3 H, t, J = 6.7 Hz), 1.19-1.65 (30 H, br m), 1.72-1.73 and 1.78 (each 0.5 H, each m), 2.32 (0.5 H, dd, J = 7.09, 14.2 Hz), 2.45 (0.5 H, dd, J = 7.0, 13.6 Hz), 4.61 (0.5 H, m), 4.96 (0.5 H, m), 5.83-5.91 (2 H, m). 13C NMR (CDCl3): δ = 2.1, 2.4, 14.1, 22.7, 24.3, 24.4, 29.3, 29.7, 30.0, 30.0, 31.9, 42.4, 43.4, 48.8, 49.6, 75.3, 76.1, 86.1, 87.3, 134.1,135.1, 140.3, 140.3. IR (thin film): 3320, 2920, 2855, 1468, 1360, 1250, 1105, 1050, 960, 880, 840, 755 cm-1. HRMS: m/z calcd for C24H48O2Si: 396.3424; found: 396.3410. Anal. Calcd for C24H48O2Si: C, 72.66; H, 12.20. Found: C, 72.76; H, 12.03.
Preparation of Compound 20.
A mixed suspension of compound 19 (386 mg, 0.97 mmol) and MnO2 (3.86 g, 44.4 mmol) in CH2Cl2 was stirred for 11.5 h at r.t. After filtration of the mixture through a Celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 40:1) to give 20 (379 mg, 99%) as a white solid; mp 32.5-34.0 °C. [α]D
25 -14.9 (c 1.00, CHCl3). 1H NMR (CDCl3): δ = 0.10 (9 H, s), 0.87 (3 H, t, J = 6.6 Hz), 1.18-1.35 (28 H, br m), 1.58-1.74 (2 H, m), 2.48 (2 H, s), 6.09 (1 H, d, J = 5.6 Hz), 7.43 (1 H, d, J = 5.8 Hz). 13C NMR (CDCl3): δ = 2.14, 14.1, 22.7, 24.3, 29.4, 29.5, 29.5, 29.7, 29.8, 31.9, 41.9, 49.6, 81.3, 132.8, 166.8, 206.9. IR (thin film): 2924, 2854, 1726, 1464, 1252, 1200, 1078, 840 cm-1. HRMS: m/z calcd for C24H46O2Si: 394.3267; found: 394.3253. Anal. Calcd for C24H46O2Si: C, 73.03; H, 11.75. Found: C, 72.90; H, 11.86.
Preparation and Spectroscopic Data of (-)-Untenone A (1).
To a mixed solution of compound 21 (195 mg, 0.43 mmol) in MeOH-THF (5:1, 6 mL) were added Dowex 50W-X8 (1.95 g) and MS 4 Å (975 mg) at r.t. and the resulting mixture was allowed to stir for 5 h. After filtration through a Celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 6:1) to give (-)-unte-none A (1, 102 mg, 62%) as a white solid; mp 63-65 °C. [α]D
26 -79.7 (c 1.00, CHCl3). 1H NMR (CDCl3): δ = 0.88 (3 H, t, J = 6.5 Hz), 1.22-1.33 (28 H, m), 1.64-1.88 (2 H, m), 3.47 (1 H, s), 3.61 (1 H, s), 3.80 (3 H, s), 6.11 (1 H, d, J = 5.6 Hz), 7.52 (1 H, d, J = 5.6 Hz). 13C NMR (CDCl3): δ = 14.1, 22.7, 23.8, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 40.3, 52.9, 60.8, 79.9, 132.3, 167.0, 169.0, 199.9. IR (thin film): 3480, 2918, 2850, 1742, 1736, 1708, 1468, 1436, 1320, 1218, 1156, 770 cm-1. HRMS: m/z calcd for C23H40O4: 380.2926; found: 380.2924. Anal. Calcd for C23H40O4: C, 72.59; H, 10.59. Found: C, 72.60; H, 10.74.
Preparation and Spectroscopic Data of Compound 22.
To a mixed solution of (-)-untenone A(1) (30.0 mg, 0.08 mmol) and ZnBr2 (17.8 mg, 0.08 mmol) in THF (1.0 mL) was added 0.97 M DIBALH in hexane (0.21 mL, 0.20 mmol) at -50 °C under argon, and the resulting mixture was allowed to stir for 2 h. After quenching by addition of sat. NH4Cl aq, the mixture was filtrated through a Celite pad, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 4:1) to give compound 22 (15.1 mg, 50%) as colorless needles; mp 70-71 °C. [α]D
22 -54.6 (c 0.90, CHCl3). 1H NMR (CDCl3): δ = 0.88 (3 H, t, J = 6.6 Hz), 1.22-1.33 (28 H, br m), 1.60-1.78 (2 H, m), 2.99 (1 H, d, J = 6.1 Hz), 3.04 (1 H, d, J = 8.2 Hz), 3.50 (1 H, s), 3.80 (3 H, s), 4.82 (2 H, ddd, J = 2.4, 5.8, 8.2 Hz), 6.04 (1 H, d, J = 5.8 Hz), 6.09 (1 H, dd, J = 2.4, 5.8 Hz). 13C NMR (CDCl3): δ = 14.1, 22.7, 24.4, 29.3, 29.5, 29.6, 29.6, 29.7, 29.9, 31.9, 39.3, 52.0, 55.0, 75.8, 83.9, 134.7, 140.0, 172.9. IR (thin film): 3527, 3462, 2916, 2848, 1720, 1464, 1396, 1366, 1240, 1176, 1096, 1049, 1030, 970, 924, 800, 781 cm-1. HRMS: m/z calcd for C23H42O4: 382.3083; found: 382.3085. Anal. Calcd for C23H42O4: C, 72.21; H, 11.07. Found: C, 72.70; H, 11.20.
Preparation and Spectroscopic Data of p
-Bromo-benzoate of 22 and (+)-Plakevulin A (2).
To a solution of compound 22 (37.0 mg, 0.10 mmol) in THF (2.0 mL) were added PPh3 (107 mg, 0.41 mmol), 40% DEAD in toluene solution (0.16 mL, 0.42 mmol) and p-bromobenzoic acid (70.1 mg, 0.35 mmol) at r.t. under argon, and the resulting mixture was allowed to stir for 6 h. After quenching by addition of sat. NaHCO3 aq, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 5:1) to give p-bromobenzoate (39.4 mg, 72%) as a white solid; mp 59-62 °C. [α]D
20 +89.9 (c 0.60, CHCl3). 1H NMR (CDCl3): δ = 0.88 (3 H, t, J = 6.6 Hz), 1.16-1.46 (28 H, br m), 1.82-1.88 (2 H, m), 2.32 (1 H, s), 3.11 (1 H, d, J = 4.3 Hz), 3.79 (3 H, s), 5.99-6.06 (2 H, m), 6.27 (1 H, m), 7.58 (2 H, dd, J = 1.8, 6.8 Hz), 7.87 (2 H, dd, J = 1.8, 6.8 Hz). 13C NMR (CDCl3): δ = 14.1, 22.7, 24.2, 29.3, 29.6, 29.6, 29.7, 29.9, 31.9, 40.8, 52.3, 57.9, 81.2, 85.4, 128.3, 128.7, 131.2, 131.3, 131.7, 140.2, 165.4, 171.7. IR (thin film): 3486, 2924, 2852, 1724, 1590, 1268, 1172, 1114, 1100, 1012, 758 cm-1. HRMS: m/z [M + 1] calcd for C30H46O5Br: 565.2528; found: 565.2534. Anal. Calcd for C30H45O5Br: C, 63.71; H, 8.02. Found: C, 63.81; H, 8.03.
To a mixed solution of the p-bromobenzoate of 22 (45.0 mg, 0.08 mmol) in MeOH-THF (1:1, 1.0 mL) was added K2CO3 at r.t., and the mixture was allowed to stir for 1.5 h. After quenching by addition of sat. NH4Cl aq, the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 2:1) to give (+)-pla-kevulin A (2, 28.0 mg, 92%) as colorless needles; mp 74-75 °C. [α]D
22 +24.1 (c 0.60, CHCl3). 1H NMR (CDCl3): δ = 0.88 (3 H, t, J = 6.7 Hz), 1.19-1.38 (28 H, br m), 1.75-1.86 (2 H, m), 2.02 (1 H, d, J = 14.7 Hz), 2.45 (1 H, s), 2.83 (1 H, d, J = 5.3 Hz), 3.79 (3 H, s), 5.30-5.38 (1 H, m), 5.84 (1 H, dd, J = 1.6, 5.7 Hz), 5.94 (1 H, dd, J = 1.8, 5.7 Hz). 13C NMR (CDCl3): δ = 14.1, 22.7, 24.5, 29.4, 29.6, 29.7, 29.9, 31.9, 40.6, 52.1, 60.5, 78.2, 84.9, 135.7, 137.0, 172.6. IR (thin film): 3430, 2916, 2848, 1728, 1464, 1436, 1380, 1366, 1265, 1198, 1085, 994, 862, 786, 722 cm-1. HRMS: m/z [M + 1] calcd for C23H43O4: 383.3161; found: 383.3138. Anal. Calcd for C23H42O4: C, 72.21; H, 11.07. Found: C, 71.96; H, 10.95.
The melting point of optically active 2 has not been reported in the literature.