Synthesis of (±)-africanol

Article

Synthesis of (±)-Africanol

Francisco de A. Marquesa^*, José T. B. Ferreirab^† and Edward Piers^c

^aDepartamento de Química, Centro Politécnico, Universidade Federal do Paraná, 81.531-990, Curitiba-PR, Brazil

^bDepartamento de Química, Universidade Federal de São Carlos, São Carlos-SP, Brazil

^cDepartment of Chemistry, University of British Columbia, 2036 Main Mall,

University Campus, Vancouver - British Columbia V6t 1Z1, Canada

Os compostos 1a e 1b, diastereoisômeros do africanol, foram obtidos como produtos exclusivos através de uma metodologia que empregou como etapa chave a reação de ciclização intramolecular, mediada por ⁿBuLi, do iodeto vinílico 5. Utilizando processo de ciclização semelhante com o composto 19, obteve-se o álcool terciário 20 como único produto. O africanol pode ser obtido, juntamente com seus diastereoisômeros 1a e 1b, ao se efetuar a reação de ciclização intramolecular da cetona 21, em presença de iodeto de samário.

Two diastereomers of africanol, compounds 1a and 1b, were obtained exclusively through a methodology which employed, as the key step, the ⁿBuLi mediated intramolecular cyclization of the vinyl iodide 5. A similar cyclization of 19 provided exclusively the tertiary allylic alcohol 20. Africanol could be prepared, along with its diastereomers 1a and 1b, when ketone 21 was submitted to the cyclization reaction promoted by samarium iodide.

Keywords: samarium iodide, cyclization, africanol, synthesis

Introduction

Africanol 1, a tricyclic sesquiterpene alcohol, was isolated in 1974 from the soft coral Lemnalia africana collected around the island of Leti, province of Maluku, Indonesia¹. The structure of africanol, including its absolute configuration, was established by X-ray crystallography². Substance 1 is a member of the africanane group of sesquiterpenoids, which includes several other compounds such as isoafricanol 2, leptographiol 3 and isoleptographiol 4, all of which were isolated in 1986 from a sapwood staining ascomycete fungus, Leptographium lundbergii Lag. et Melin³.

There are four syntheses of africanol described in the literature^4-7 of which the one described by Fan and White⁷, is the shortest and most elegant. This route also provided the diastereomer isoafricanol 2. Our initial approach to the synthesis of africanol consisted of the construction of a five membered ring on the bicyclo[5.1.0]octanone precursor 6, employing methodology based on the intramolecular cyclization of a vinylic anion onto a carbonyl moiety⁸ as the key step, as shown in the retrosynthetic analysis in Scheme 1.

Experimental Section

General

Reagents and solvents were purified and dried using standard methods. Reactions involving organometallic reagents were carried out under argon in oven-dried glassware. Reactions were monitored by thin-layer chromatography (TLC; E. Merck, Type 5554 plates) and gas chromatography (GC) with a Hewlett-Packard model 5880 A GC (flame ionization detector (FID, 25 m x 0.21 mm fused silica column coated with cross-linked SE-54) or 5890 GC (FID, 25 m x 0.20 mm capillary column cross-linked with 5% phenyl methyl silicone). Conventional and flash column chromatography were carried out with 70-230 and 230-400 mesh silica gel (E. Merck), respectively. Radial chromatography purifications were performed using a Chromatotron^â model 7924 with plates of 1, 2 or 4 mm (silica gel 60, PF 254 with calcium sulphate, E. Merck 7749). Distillation temperatures, which refer to bulb-to-bulb (Kugelrohr) distillations, are uncorrected. IR spectra were recorded on a Perkin-Elmer 1710 spectrometer with internal calibration. ¹H NMR were recorded on CDCl₃ solutions using Bruker AC-200 or WH-400 spectrometers. Chemical shifts (d) are given in ppm and coupling constants (J) in Hz. Deuterated solvents were used as lock and reference signal (¹H NMR reference signal relative to the proton resonance resulting from incomplete deuteration of the CDCl₃: d 7.25). ¹³C NMR spectra were determined as solutions either in CDCl₃ or in C₆D₆ with the spectrometers described above. The chemical shifts (d) are reported in ppm relative to the center peak of CDCl₃ (d 77.0) or C₆D₆ (d 128.0). Low and high resolution mass spectra were obtained on Kratos/AEI 50 or MS 902 mass spectrometers. Combustion analyses were obtained with a Carlo Erba 1106 C, H, N analyzer.

3,6-Dimethyl-2-cyclohexenone (9)

To a solution of diisopropylamine (18.14 g, 179.3 mmol) in THF (450 cm³) at –78 ^oC was added ⁿBuLi in hexanes (108 cm³, 171 mmol). After stirring for 30 min at 0 ^oC the solution was recooled to –78 ^oC followed by dropwise addition of 3-methyl-2-cyclohexenone (17.9 g, 163 mmol) in THF (100 cm³). After 1 h at –78 ^oC iodomethane (69.4 g, 489 mmol) was added and the resulting mixture was stirred 1h at –78 ^oC and 3 h between –20 and –15 ^oC. Ether (600 cm³) was added and the solution of the crude product was washed with water (2 x 100 cm³) and saturated NaCl (2 x 70 cm³), and dried over anhydrous MgSO₄. The solvent and excess iodomethane were removed by rotary evaporation and the product was distilled at reduced pressure (17 mmHg, 85-90 ^oC) to give 3,6-dimethyl-2-cyclohexenone (17.21 g, 85%); IR n_max/cm^-1 2931, 1672, 1210, 1119 (film); ¹H NMR (CDCl₃, 400 MHz,) d 1.05 (d, J = 8 Hz, 3H), 1.56-1.68 (m, 1H), 1.87 (s, 3H), 1.92-2.03 (m, 1H), 2.13-2.36 (m, 3H), 5.76 (s, 1H); ¹³C NMR (CDCl₃, 50.3 MHz,) d 15.01, 24.12, 30.53, 30.64, 40.37, 126.05, 161.53, 202.05.

2,5,5-Trimethylcyclohexanone (10)

To a flask containing copper (I) cyanide (5.64 g, 63.0 mmol) and THF (250 cm³) at –78 ^oC was added MeLi in ether (43.0 cm³, 60.4 mmol). After stirring 20 min at –10°C the solution was recooled to –78 ^oC and a second portion of MeLi (43.0 cm³, 60.4 mmol) was added. After 30 min, chlorotrimethylsilane (13.69 g, 126.0 mmol) was added followed by addition of a solution of compound 9 (6.000 g, 48.32 mmol) and HMPA (22.58 g, 126.0 mmol) in THF (50 cm³). The mixture was stirred 2 h at –78 ^oC and 3 h at room temp, then quenched with saturated aqueous NH₄Cl/NH₄OH (100 cm³, pH 8). After 10 h at room temp the phases were separated and the aqueous layer was extracted with Et₂O (2 x 30 cm³). The combined organic extracts were washed with water (2 x 30 cm³) and concentrated under reduced pressure to 100 cm³. The product was then stirred with 1 mol.L^-1 HCl (10 cm³) for 2 h at room temp. Ether (100 cm³) was added, the phases were separated, and the organic layer was washed with saturated NaHCO₃ (3 x 30 cm³) and water (1 x 30 cm³), and dried over MgSO₄. The filtrate was concentrated and purified by distillation at reduced pressure (10 mmHg, 60-65 ^oC) affording ketone 10 (5.61 g, 83%); compound 10 (Found: C, 77.13; H, 11.60. Calc. for C₉H₁₆O: C, 77.09; H, 11.50%); IR n_max/cm^-1 2961, 1714, 1458, 1369, 1216, 1174 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.82 (s, 3H), 0.98 (d, J = 7 Hz, 3H), 1.00 (s, 3H), 1.39-1.56 (m, 2H), 1.58-1.68 (m, 1H), 1.88-1.99 (m, 1H), 2.08 (d, J = 13.6 Hz, 1H), 2.17 (d, J = 13.6 Hz, 1H), 2.20-2.33 (m, 1H); ¹³C NMR (CDCl₃, 50.3 MHz) d 14.40, 25.42, 31.61, 31.70, 36.87, 38.14, 44.20, 54.70, 213.20; MS m/z (relative intensity) 140 (M⁺, 18), 96 (17), 95 (11), 83 (100), 82 (18), 69 (17).

cis-1-Trimethylsilyloxy-3,3-6-trimethylbicyclo [4.1.0]heptane (11)

To a solution of ketone 10 (2.10 g, 15.0 mmol) and hexamethyldisilazane (3.356 g, 18.73 mmol) in pentane (250 cm³) at –25 ^oC was added iodotrimethylsilane (3.448 g, 17.23 mmol). After stirring 15 min at –25 ^oC and 4 h at room temp the mixture was filtered through celite eluting with petroleum ether, the organic phase was washed with saturated NaHCO₃ (3 x 30 cm³), dried over MgSO₄ and concentrated under reduced pressure. The product was purified by distillation (1.2 mmHg, 34-36 ^oC) to give a mixture of thermodynamic and kinetic silyl enol ethers, 19:1 ratio determined by GC (3.02 g, 95%); thermodynamic silyl enol ether (Found: C, 68.20; H, 11.50. Calc. for C₁₂H₂₄SiO: C, 67.92; H, 11.32%); IR n_max/cm^-1 2954, 2910, 1690, 1322, 1252, 1230, 1199, 1160 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.18 (s, 9H), 0.90 (s, 6H), 1.24 (t, J = 6.4 Hz, 2H), 1.67 (brs, 3H), 1.87-1.96 (m , 4H); ¹³C NMR (C₆D₆, 50.3 MHz,) d 0.90, 16.31, 28.10, 28.25, 30.78, 30.92, 35.98, 44.58, 109.56, 142.46; MS m/z (relative intensity) 212 (M⁺, 78), 197 (100), 183 (21), 144 (19), 141 (65), 75 (68), 73 (100).

The above mixture (3.000 g, 14.15 mmol) was dissolved in benzene (30 cm³) and a solution of diethylzinc in hexanes (28 cm³, 28 mmol) was added at 40 ^oC followed by the dropwise addition of CH₂I₂ (11.37 g, 42.45 mmol). After the addition was complete, a slow flow of O₂ was introduced into the headspace above the reaction mixture for 1 h. The resulting solid was removed by filtration over celite using hexane as eluent and the product was transferred to a separatory funnel containing ether (100 cm³). The mixture was washed with saturated aqueous NH₄Cl/NH₄OH (2 x 30 cm³, pH 8) and water (1 x 30 cm³), and dried over Na₂SO₄. The filtrate was concentrated under reduced pressure and purified by flash chromatography (petroleum ether/ether 92:8 v/v) to give compound 11 (2.72 g, 85%); compound 11 (Found: C, 68.78; H, 11.70. Calc. for C₁₃H₂₆SiO: C, 69.03; H, 11.50%); IR n_max/cm^-1 3062, 2935, 2861, 1460, 1218, 1161, 1136, 1112 (film); ¹H NMR (CDCl₃, 400 MHz,) d 0.23 (s, 9H), 0.29 (d, J = 4.6 Hz, 1H), 0.52 (d, J = 4.6 Hz, 1H), 0.77-0.93 (m, 1H), 0.88 (s, 3H), 1.00 (s, 3H), 1.06-1.15 (m, 1H), 1.36 (s, 3H), 1.60-1.76 (m, 3H), 1.89 (d, J = 14 Hz, 1H); ¹³C NMR (C₆D₆, 50.3 MHz,) d 1.57, 20.59, 21.43, 23.74, 25.55, 28.39, 29.51, 31.68, 33.97, 49.82, 59.55; MS m/z (relative intensity) 226 (M⁺, 12), 211 (64), 197 (15), 169 (16), 121 (20), 96 (30), 75 (39), 73 (100).

3,6,6-Trimethyl-2-cycloheptenone (7)

To a flask containing anhydrous FeCl₃ (5.815 g, 35.85 mmol) in DMF (24 cm³) at 0 ^oC under argon was added a solution of compound 11 (2.700 g, 11.95 mmol) in DMF (24 cm³). After 4 h at room temp the reaction mixture was poured into a beaker with 1 mol.L^-1 HCl (30 cm³) and ice. The mixture was transferred to a separatory funnel with ether (100 cm³), the phases were separated and the aqueous phase was extracted with ether (2 x 30 cm³). The combined organic extracts were washed with water (3 x 30 cm³) and saturated NaCl (2 x 30 cm³), and dried over MgSO₄. The filtrate was concentrated under reduced pressure and the crude product was taken up in methanol (60 cm³), CH₃COONa.6H₂O (4.878 g, 35.85 mmol) was added and the solution refluxed for 4 h. The mixture then was diluted in ether (120 cm³), washed with saturated NaHCO₃ and dried over MgSO₄. After removing the solvent under reduced pressure the crude product was purified by flash chromatography using CH₂Cl₂ as solvent affording cycloheptenone 7 (1.54 g, 85%); IR n_max/cm^-1 2957, 1662, 1466, 1312, 1238, 1195 (film); ¹H NMR (CDCl₃, 400 MHz,) d 0.91 (s, 6H), 1.47-1.52 (m, 2H), 1.85 (s, 3H), 2.20-2.28 (m, 2H), 2.32 (s, 2H), 5.75 (brs, 1H); ¹³C NMR (CDCl₃, 50.3 MHz) d 27.35, 29.36, 31.77, 32.03, 41.41, 56.24, 129.68, 161.27, 201.58; MS m/z (relative intensity) 152 (M⁺, 18), 137 (18), 109 (29), 95 (100), 82 (35), 68 (21), 67 (34); HRMS ( M⁺) Found: 152.1191. Calc. for C₁₀H₁₆O: 152.1196.

7,10,10-Trimethyl-1,4-dioxaspiro[4.6]7-undecene (12)

A solution of ketone 7 (1.40 g, 9.21 mmol), ethylene glycol (3.430 g, 55.26 mmol) and p-toluenesulfonic acid monohydrate (210 mg, 1.1 mmol) in benzene (15 cm³) was refluxed in a flask connected to a Dean Stark trap for 15 h. The mixture was diluted with ether (50 cm³), washed with saturated NaHCO₃ (2 x 20 cm³) and water (1 x 20 cm³), and dried over MgSO₄. The filtrate was concentrated in vacuo and purified by flash chromatography on basic alumina (petroleum ether/ether 20:1 v/v) to give ketal 12 (1.53 g, 85%); IR n_max/cm^-1 2952, 1675, 1454, 1365, 1228, 1104, 1073, 1044 (film); ¹H NMR (CDCl₃, 400 MHz,) d 0.92 (s, 6H), 1.68(s, 2H), 1.74 (s, 3H), 1.93 (d, J = 7.5 Hz, 2H), 2.35 (s, 2H), 3.90 (s, 4H), 5.46-5.51 (m, 1H); ¹³C NMR (CDCl₃, 50.3 MHz,) d 26.34, 29.90, 33.23, 39.71, 41.56, 52.98, 64.16, 108.28, 124.08, 134.47; MS m/z (relative intensity) 196 (M⁺, 4), 127 (100), 113 (44), 95 (21), 83 (13), 81 (19), 69 (10), 67 (17), 41 (27); HRMS (M⁺) Found: 196.1465. Calc for C₁₂H₂₀O₂: 196.1464.

cis-1,9,9-Trimethyltricyclo[4.5.1]4,7-dioxaspirododecane (13)

Compound 13 was prepared according to the cyclopropanation procedure reported for the preparation of 11, starting from 12 (1.400 g, 7.14 mmol), benzene (40 cm³), diethylzinc in hexanes (32.13 mmol) and diiodomethane (10.53 g, 39.31 mmol). The crude product was purified by flash chromatography on basic alumina (petroleum ether/ether 20:1 v/v) to give tricyclic 13 (1.33 g, 89%); IR n_max/cm^-1 3057, 2951, 1470, 1364, 1328, 1231, 1176, 1105, 1044, 1020 (film); ¹H NMR (CDCl_3, 400 MHz) d 0.08 (t, J = 4.8 Hz, 1H), 0.45 (dd, J = 8.8, 4.8 Hz, 1H), 0.62-0.72 (m, 1H), 0.91 (s, 3H), 0.93-1.02 (m, 1H), 1.07 (s, 3H), 1.13 (s, 3H), 1.43 (d, J = 8 Hz, 1H), 1.46 (d, J = 8 Hz, 1H), 1.73 (d, J = 14.4 Hz, 1H), 1.83 (dd, J = 15.2, 6.4 Hz, 1H), 2.02 (d, J = 15.2 Hz, 1H), 3.78-4.00 (m, 4H); ¹³C NMR (CDCl₃, 50.3 MHz) d 15.28, 20.69, 23.97, 25.53, 27.19, 32.30, 32.91, 43.33, 50.69, 63.10, 64.37, 112.00; MS m/z (relative intensity) 210 (M⁺, 1), 153 (26), 139 (37), 128 (28), 127 (100), 113 (55), 87 (26), 86 (51), 67 (22), 55 (36), 41 (48); HRMS (M⁺) Found: 210.1611. Calc. for C₁₃H₂₂O₂: 210.1615.

cis-1,5,5-Trimethylbicyclo[5.1.0]3-octanone (6)

A solution of ketal 13 (1.20 g, 5.71 mmol) and p-toluenesulphonic acid monohydrate (164 mg, 0.860 mmol) in acetone (7 cm³) was stirred at room temp for 2 h. The crude product was diluted with ether (50 cm³), washed with saturated NaHCO₃ (2 x 15 cm³) and water (1 x 15 cm³) and dried over MgSO₄. The filtrate was concentrated under reduced pressure to give ketone 6 (0.92 g, 97%); IR n_max/cm^-1 3057, 2957, 1700, 1464, 1192, 1101, 1060, 1023 (film); ¹H NMR (CDCl₃, 400 MHz,) d 0.25 (t, J = 4 Hz, 1H), 0.60-0.81 (m, 2H), 0.95 (s, 3H), 1.02 (brs, 4H), 1.08 (s, 3H), 2.00 (dd, J = 15, 5 Hz, 1H), 2.12 (d, J = 12 Hz, 1H), 2.15 (d, J = 15 Hz, 1H), 2.46 (d, J = 15 Hz, 1H), 2.52 (d, J = 12 Hz, 1H); ¹³C NMR (CDCl₃, 50.3 MHz,) d 14.79, 20.71, 23.72, 24.73, 26.83, 31.04, 34.55, 43.18, 49.01, 57.59, 210.18; MS m/z (relative intensity) 166 (M⁺, 19), 123 (41), 110 (57), 109 (51), 95 (39), 82 (73), 67 (98), 41 (100); HRMS (M⁺) Found: 166.1374. Calc. for C₁₁H₁₈O: 166.1366.

N-N-Dimethylhydrazone derived from ketone 6

A solution of ketone 6 (332 mg, 2.00 mmol) and N,N-dimethylhydrazine (480 mg, 7.99 mmol) in benzene (10 cm³) was heated at reflux for 10 h under argon with azeotropic removal of water (Dean-Stark trap). The excess of dimethylhydrazine was distilled off with the solvent and the product was purified by distillation (0.4 mmHg, 65-69 ^oC) affording hydrazone 15 (392 mg, 94.2 %); IR n_max/cm^-1 3059, 2953, 1624, 1467, 1366, 1196, 1021 (film); MS m/z (relative intensity) 208 (M⁺, 14), 193 (8), 164 (13), 152 (12), 151 (100), 83 (7), 51 (11); HRMS (M⁺) Found: 208.1931. Calc for C₁₃H₂₄N₂: 208.1939.

2[2-Trimethyltin-1-butene]1,5,5-trimethylbicyclo[5.1.0]3-octanone (17)

To a solution of diisopropylamine (114 mg, 1.13 mmol) in THF (1.5 cm³) at –78 ^oC was added ⁿBuLi in hexanes (0.83 cm³, 1.1 mmol). After stirring 10 min at 0 ^oC a solution of hydrazone 15 (195 mg, 0.937 mmol) in THF (1 cm³) was added. After 2 h at 0 ^oC iodide 14 (795 mg, 2.31 mmol) in THF (2 cm³) was added and the resulting mixture was stirred 15 h at room temp. Ether (50 cm³) was added and the organic layer was washed with water (2 x 10 cm³). The solvent was removed under reduced pressure and the crude product was taken up in methanol (15 cm³) and added to a round bottom flask containing phosphate buffer solution pH 7.2 (3 cm³) and sodium periodate (796 mg, 3.72 mmol) in water (5 cm³) at room temp. After stirring 48 h the reaction mixture was filtered, diluted with water (20 cm³), extracted with CH₂Cl₂ (3 x 20 cm³) and dried over MgSO₄. The filtrate was concentrated under vacuum and the crude product was purified by radial chromatography on silica gel (petroleum ether/dichloromethane 10:4 v/v) affording compound 17 (112 mg, 31%) and 23 mg of ketone 6. 17: IR n_max/cm^-1 3060, 2956, 1704, 1468, 1386, 1367, 915, 769 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.00 (s, 9H), 0.16 (t, J = 6 Hz, 1H), 0.43-0.52 (m, 1H), 0.58 (dd, J = 8, 4 Hz, 1H), 0.72 (s, 3H), 0.82 (s, 3H), 0.85 (s, 3H), 1.19 (dd, J = 16, 12 Hz, 1H), 1.37-1.45 (m, 1H), 1.69-1.80 (m, 1H), 1.84 (ddd, J = 14.8, 6.0, 1.6 Hz, 1H), 1.96-2.13 (m, 5H), 4.98 (d, J = 2.8 Hz, 1H), 5.46 (dd, J = 2.8, 1.6, 1H); ¹³C NMR (CDCl₃, 100.6 MHz,) d - 9.40, 16.98, 19.35, 21.96, 23.59, 25.07, 27.05, 32.41, 35.12, 38.86, 42.74, 53.78, 60.47, 124.87, 155.60, 209.34; MS m/z (relative intensity) 385 (0.3), 383 (0.5), 382 (0.4), 381 (0.7), 369 (95) 367 (72), 365 (40), 165 (100), 164 (30), 107 (48), 55 (20); M.S. (CI-NH₃) 383 (74), 385 (100), 389 (15).

2[2-Iodo-1-butene]1,5,5-trimethylbicyclo [5.1.0]3-octanone (5)

Iodine (73.2 mg, 0.288 mmol) in CH₂Cl₂ (6 cm³) was added dropwise to a solution of ketone 17 (54 mg, 0.14 mmol) in CH₂Cl₂ (2 cm³) at 0 ^oC under argon until the color of the resulting mixture was slightly pink. Ether (20 cm³) was added and the organic layer was washed with 0.1 M solution of sodium thiosulphate (1 x 4 cm³) and water (5 cm³), and dried over MgSO₄. The filtrate was concentrated under reduced pressure and the crude product was passed through a short pad of silica using CH₂Cl₂ as eluent to afford iodide 5 (48 mg, 97%); IR n_max/cm^-1 3058, 2956, 2926, 1703, 1617, 1467, 1455, 1386, 892 (film); ¹H NMR (CDCl₃, 400 MHz,) d 0.36 (t, J = 4.4 Hz, 1H), 0.65-0.73 (m, 1H), 0.78 (dd, J = 8.8, 4.4 Hz, 1H), 0.91 (s, 3H), 0.99 (s, 3H), 1.02 (s, 3H), 1.37 (dd, J = 14.8, 10.8 Hz, 1H), 1.73-1.83 (m, 1H), 1.93-2.08 (m, 2H), 2.15 (d, J = 5.6 Hz, 1H), 2.17 (d, J = 8.4 Hz, 1H), 2.27 (dd, J = 12, 1.8 Hz, 1H), 2.30-2.44 (m, 2H), 5.72 (brs, 1H), 6.02 (dd, J = 2.6, 1.4 Hz, 1H); ¹³C NMR (CDCl₃, 50.3 MHz,) d 16.97, 19.34, 22.07, 23.62, 25.19, 26.74, 32.40, 35.17, 42.70, 42.96, 52.86, 60.41, 112.17, 125.8, 209; HRMS (M⁺) Found: 346.0813. Calc. for C₁₅H₂₃IO: 346.0804.

Tricyclic alcohol 18

To a solution of vinyl iodide 5 (48 mg, 0.14 mmol) in THF (2 cm³) at –78 ^oC was added ⁿBuLi in hexanes (0.42 mmol, 0.32 cm³). After stirring 30 min, ether was added (20 cm³) and the product was washed with saturated NaHCO₃ (1 x 5 cm³), water (1 x 5 cm³) and dried over MgSO₄. The filtrate was concentrated under reduced pressure and the crude product was passed through a short pad of silica gel using CH₂Cl₂ as eluent giving the tricyclic alcohol 18 (29 mg , 95%); IR n_max/cm^-1 3055, 2950, 1650, 1183, 1101, 1062, 894 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.18 (t, J = 4.0 Hz, 1H), 0.52 (dd, J = 8.4, 4.0 Hz, 1H), 0.73-0.84 (m, 1H), 0.91 (s, 3H), 1.10-1.30 (m, 2H), 1.12 (s, 1H), 1.16 (s, 3H), 1.32 (s, 3H), 1.41 (dd, J = 12.8, 6.0 Hz, 1H), 1.69-1.78 (m, 1H), 1.86-2.00 (m, 3H), 2.18-2.30 (m, 1H), 2.55 (ddd, J = 16.4, 7.6, 0.8 Hz, 1H), 4.91 (dd, J = 2.48, 1.6 Hz, 1H), 5.02-5.07 (m , 1H); ¹³C NMR (CDCl₃, 50.3 MHz) d 17.87, 22.10, 23.44, 25.24, 25.43, 25.58, 31.27, 34.31, 35.15, 44.10, 54.13, 54.37, 81.75, 106.00, 161.78; MS m/z (relative intensity) 220 (M⁺, 0.7), 202 (12), 159 (20), 145 (29), 131 (31), 105 (30), 95 (23), 93 (25), 91 (41), 55 (20); HRMS (M⁺) Found: 220.1837. Calc. for C₁₅H₂₄O: 220.1832.

Africanol diastereomers 1a and 1b

A mixture containing alcohol 18 (27 mg, 0.12 mmol) in ethyl acetate (7 cm³) and PtO₂ (20 mg) was kept under hydrogen pressure (50 psi) for 24 h. After filtering through a short pad of celite using petroleum ether as solvent the crude product was purified by radial chromatography on silica gel (petroleum ether/dichoromethane 5:1 v/v) giving 13.1mg of compound 1a and 10.9 mg of its epimer 1b. 1a: IR n_max/cm^-1 3605, 2923, 1725, 1465, 1374, 1108, 1041 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.13 (t, J = 4.8 Hz, 1H), 0.46 (dd, J = 8.9, 4.8 Hz, 1H), 0.69-0.80 (m, 1H), 0.82 (d, J = 6.9 Hz, 3H), 0.87 (s, 3H), 0.99-1.10 (m, 2H), 1.12 (s, 3H), 1.22-1.30 (m, 1H), 1.24 (s, 3H), 1.33-1.42 (m, 2H), 1.52 (dd, J = 14.3, 2.15 Hz, 1H), 1.61-1.70 (m, 1H), 1.72-1.93 (m, 3H), 2.00-2.10 (m, 1H); ¹³C NMR (C₆D₆, 50.3 MHz) d 18.28, 18.36, 22.67, 24.03, 25.78, 25.83, 25.91, 32.87, 34.17, 35.64, 44.49, 49.99, 51.27, 52.39, 85.49; MS m/z (relative intensity) 222 (M⁺, 11), 207 (16), 204 (43), 189 (45), 165 (43), 162 (79), 147 (54), 133 (51), 109 (100), 107 (65), 105 (53), 93 (60), 83 (84), 81 (69), 69 (87), 67 (58), 57 (46); HRMS (M⁺) Found: 222.1981. Calc. for C₁₅H₂₆O: 222.1979. 1b: IR n_max/cm^-1 3602, 3054, 2922, 1461, 1374, 1115, 1041, 911 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.11 (t, J = 3.9 Hz, 1H), 0.43 (dd, J = 8.8, 3.9 Hz, 1H), 0.67-0.77 (m, 1H), 0.83 (s, 3H), 0.84 (d, J = 6.6 Hz, 3H), 0.92 (brs, 1H), 1.03-1.14 (m, 2H), 1.09 (s, 3H), 1.23 (s, 3H), 1.27-1.42 (m, 1H), 1.43-1.56 (m, 2H), 1.56-1.76 (m, 3H), 1.84-1.95 (m, 2H); ¹³C NMR (C₆D₆, 50.3 MHz,) d 12.83, 18.31, 22.92, 23.71, 23.81, 25.45, 30.53, 34.12, 35.30, 44.08, 46.51, 52.33, 54.72, 84.22; MS m/z (relative intensity) 222 (M⁺, 9), 204 (30), 189 (35), 165 (37), 123 (35), 109 (85), 107 (41), 98 (62), 83 (100), 81 (72), 69 (88), 67 (49), 55 (87); HRMS (M⁺) Found: 222.1978. Calc. for C₁₅H₂₆O: 222.1972.

2[(Z)-2-Iodo-2-butene]1,5,5-trimethylbicyclo [5.1.0]3-octanone (19)

To a solution of diisopropylamine (97 mg, 0.96 mmol) in THF (2 cm³) at 0 ^oC was added ⁿBuLi in hexanes (0.63 cm³, 0.82 mmol). After 10 min a solution of hydrazone 15 (100 mg, 0.480 mmol) in THF (1 cm³) was added and the mixture was stirred 2 h at 0 ^oC followed by addition, at –78 ^oC of (Z)-1-bromo-3-iodo-1-butene (378 mg, 1.44 mmol) in THF (2 cm³). The resulting mixture was stirred 1 h at –78 ^oC and 2 h at 0 ^oC. The product was diluted with ether (20 cm³) and washed with water (5 cm³), saturated NaCl (5 cm³) and the solvent was removed under reduced pressure. The crude product was taken up in methanol (10 cm³) and added to a round bottom flask containing phosphate buffer solution (2 cm³,pH 7.2) and sodium periodate (410 mg, 1.92 mmol) in water (4 cm³) at room temp. After stirring 48 h the mixture was filtered, diluted with water (15 cm³), extracted with CH₂Cl₂ (3 x 20 cm³) and dried over MgSO₄. The product obtained was purified by radial chromatography on silica gel (petroleum ether/ether 5:1 v/v) giving compound 19 (91 mg, 55%); IR n_max/cm^-1 3057, 2956, 1703, 1467, 1367, 1214, 1181, 1089, 810 (film); ¹H NMR (CDCl₃, 400 MHz) d 0.35 (t, J = 4.5 Hz, 1H), 0.61-0.71 (m, 1H), 0.75 (dd, J = 8.75, 4.5 Hz, 1H), 0.87 (s, 3H), 0.96 (s, 3H), 0.98 (s, 3H), 1.34 (dd, J = 15.0, 10.5 Hz, 1H), 1.99 (ddd, J = 15.0, 6.5, 1.65 Hz, 1H), 2.12-2.32 (m, 4H), 2.44 (s, 3H), 2.44-2.53 (m, 1H), 5.37-5.44 (m, 1H); ¹³C NMR (CDCl₃, 50.3 MHz) d 17.12, 19.51, 22.23, 23.78, 25.33, 32.46, 33.64, 34.41, 35.25, 42.62, 54.15, 60.29, 102.19, 133.09, 209; MS m/z (relative intensity) 346 (M⁺, 0.4), 234 (39), 219 (81), 149 (64), 109 (47), 107 (100), 91 (68), 67 (48), 55 (70), 41 (77), 39 (50); HRMS (M⁺) Found: 346.07864. Calc. for C₁₅H₂₃OI: 346.07857.

Tricyclic alcohol 20

Tertiary alcohol 20 was prepared as described above for 18 from vinylic iodide 19 (35 mg, 0.10 mmol) and ⁿBuLi in hexanes (0.23 cm³, 0.3 mmol). The crude product was passed through a small pad of silica using CH₂Cl₂ as eluent affording the tricyclic alcohol 20 (21 mg, 95%); IR n_max/cm^-1 3609, 3055, 2923, 1451, 1377, 1273, 1160, 1013 (film); ¹H NMR (C₆D₆, 400 MHz,) d 0.13 (t, J = 4.2 Hz, 1H), 0.47-0.53 (m, 2H), 0.77-1.09 (m, 3H), 0.88 (s, 3H), 1.21 (s, 3H), 1.42 (s, 3H), 1.50-1.58 (m, 4H), 1.78 (dd, J = 13.75, 2.3 Hz, 1H), 1.87-1.93 (ddd, J = 13.75, 6.5, 2.3 Hz, 1H), 1.93-2.20 (m, 1H), 2.30-2.41 (m, 1H), 5.28-5.33 (m, 1H); ¹³C NMR (CDCl₃, 50.3 MHz,) d 12.00, 18.18, 22.17, 23.10, 25.36, 26.20, 30.18, 30.66, 34.49, 35.34, 44.41, 52.26, 86.35, 126.96, 146.25; MS m/z (relative intensity) 220 (M⁺, 4), 202 (85), 187 (79), 177 (39), 160 (30), 159 (65), 145 (100), 119 (51), 105 (53), 91 (65), 55 (62), 41 (97); HRMS (M⁺) Found: 220.1818. Calc. for C₁₅H₂₄O: 220.1810.

2[1-Butene]1,5,5-trimethylbicyclo[5.1.0]3-octanone (21)

To a solution of diisopropylamine (97 mg, 0.96 mmol) in THF (2 cm³) at 0 ^oC was added ⁿBuLi in hexanes (0.63 cm³, 0.82 mmol). After 10 min a solution of hydrazone 15 (100 mg, 0.480 mmol) in THF (cm³) was added and the mixture was stirred for 2 h at 0 ^o C followed by addition of 4-iodo-1-butene (175 mg, 0.961 mmol) in THF (cm³). The mixture was stirred 17 h at room temp. The product was diluted with ether (30 cm³) and washed with water (5 cm³) and saturated NaCl (5 cm³) and the solvent was removed under reduced pressure. The crude product was transferred to a round bottom flask containing acetic acid/THF/ water/NaOAc (15:2:2:1 w/w) and stirred for 36 h at room temp. Ether (50 cm³) was added and the organic layer was washed with water (3 x 5 cm³) and saturated NaHCO₃ (2 x 5 cm³), dried over MgSO₄ and the solvent was removed under reduced pressure. The product obtained was purified by radial chromatography on silica gel (petroleum ether/CH₂Cl₂ 5:2 v/v) affording compound 21 (52 mg, 50%); IR n_max/cm^-1 3060, 2956, 1704, 1641, 1455; ¹H NMR (CDCl₃, 400 MHz,) d 0.28 (t, J = 4.3 Hz, 1H), 0.56-0.66 (m, 1H), 0.71 (dd, J = 8.7, 4.3 Hz, 1H), 0.85 (s, 3H), 0.95 (s, 3H), 0.97 (s, 3H), 1.32 (dd, J = 14, 10 Hz, 1H), 1.51-1.63 (m, 1H), 1.80-1.91 (m, 1H), 1.92-2.03 (m, 3H), 2.07-2.24 (m, 3H), 4.87-5.00 (m, 2H), 5.67-5.80 (m, 1H); ¹³C NMR (CDCl₃, 50.3 MHz) d 17.00, 19.29, 21.89, 23.63, 25.16, 26.36, 31.91, 32.41, 35.16, 42.74, 53.98, 60.40, 114.80, 138.59, 209.61; MS m/z (relative intensity) 220 (M⁺, 6), 205 (11), 179 (22), 164 (32), 161 (34), 123 (30), 112 (51), 109 (100), 108 (44), 95 (91), 81 (67), 67 (56), 55 (67); HRMS (M⁺) Found 220.1828. Calc. for C₁₅H₂₄O: 220.1829.

Africanol (1)

To a solution of SmI₂ (0.121g, 0.300 mmol) and HMPA (430 mg, 2.40 mmol) in THF (2 cm³) at room temp was added a solution of ketone 21 (22 mg, 0.10 mmol) and t-butyl alcohol (22 mg, 0.30 mmol) in THF (2 cm³). The mixture was stirred 4 h at 20 ^oC and another portion of SmI₂ (0.2 mmol) in THF (1.3 cm³) was added and stirred for 24 h. The reaction was quenched with saturated NaHCO₃ (3 cm³), the phases were separated and the aqueous layer was extracted with Et₂O (3 x 5 cm³). The combined organic extracts were washed with water (2 x 3 cm³) and saturated NaCl (1 x 3 cm³) and dried over MgSO₄. The filtrate was concentrated under reduced pressure and the product was purified by radial chromatography on silica gel (petroleum ether/dichloromethane 5:1 v/v) to give africanol 1 (5.1 mg), compound 1a (5.12 mg) and compound 1b (3.1 mg). 1: IR n_max/cm^-1 3483, 3078, 2965, 1461, 1387, 1267, 1109, 1087, 1024, 993 (CCl₄ solution); ¹H NMR (CDCl₃, 400 MHz) d 0.15 (t, J = 4.3 Hz, 1H), 0.47 (dd, J = 8.4, 4.0 Hz, 1H), 0.64-0.80 (m, 1H), 0.88 (d, J = 7.3 Hz, 3H), 0.95 (s, 3H), 1.01 (s, 3H), 1.10 (s, 3H), 1.24-2.11 (m, 11H); ¹³C NMR (CDCl₃, 50.3 MHz,) d 15.34, 18.25, 21.55, 22.97, 23.61, 26.02, 31.47, 31.75, 32.04, 34.32, 40.33, 45.16, 50.13, 55.94, 87.35; HRMS (M⁺ - H₂O) Found: 204.1863. Calc. for C₁₅H₂₄: 204.1878.

Results and Discussion

The cycloheptenone intermediate 7 was prepared as shown in Scheme 2, employing ring expansion of the silyloxybicyclo[4.1.0]heptane 11 as the key step.

Thus, alkylation of 3-methylcyclohex-2-en-1-one 8 with methyl iodide, at low temperature, afforded compound 9 in good yield. Conjugate addition of the higher order dilithium dimethylcyanocuprate to the a,b-unsaturated ketone 9 was carried out in the presence of the additives HMPA/TMSCl^9-11. A ratio ranging from 15:1 to 19:1 of the thermodynamic versus kinetic enol silyl ethers was achieved when ketone 10 was treated with trimethylsilyl iodide and hexamethyldisilazane in pentane¹² at –25ºC. Cyclo-propanation of the resultant silyl enol ether mixture with diethylzinc and diiodomethane, in the presence of oxigen, gave 11 in high yield^13,14. The ring expansion was then successfully carried out by treatment of compound 11 with FeCl₃ in pyridine/DMF¹⁵.

With the key precursor 7 in hand, a straightforward sequence of steps was employed to convert cycloheptenone 7 into bicyclic ketone 6 (see Scheme 3).

When ketone 7 was treated with ethylene glycol in the presence of PTSA in benzene, the ketal 12 was obtained as the only product. The migration of the double bond was confirmed by the ¹H NMR spectrum of 12, which showed a multiplet for the vinylic hydrogen. Ketal 12 was subjected to the cyclopropanation conditions as before (diethylzinc and diiodomethane in the presence of oxygen^13,14). Removal of the ketal protecting group of 13 by transketalization with PTSA in acetone generated bicyclic ketone 6.

Several reaction conditions were tried in unsuccessful attempts to alkylate ketone 6 directly with iodide 14, using LDA as base in THF/HMPA and varying the temperature of the reaction mixture from -78 ^oC to room temperature. This problem was surmounted by converting ketone 6 into its N,N-dimethylhydrazone derivative¹⁶, (see Scheme 4) and sequential treatment of the derivative 15 with LDA in THF and the alkyl iodide 14, yielding the desired alkylated product 16. After oxidative cleavage of the hydrazone with sodium periodate in phosphate buffer solution¹⁷, ketone 17 was obtained in 31% yield for the two steps. Vinyl iodide 5 was easily generated from vinylstannane 17 by treatment with a solution of iodine in methylene chloride⁸.

The alkylation of hydrazone 15 occurred regio-selectively and with high stereoselectivity (> 30:1 ratio as determined by GC) giving, as the major diastereomer, the product derived from alkylation of the ring on the same side as the adjacent methyl group. The synthesis of the tricyclic carbon skeleton was completed by treatment of the vinyl iodide with ⁿBuLi to effect lithium-halogen exchange, with the resulting anion undergoing an intramolecular cyclization to 18. The relative configuration of the tricyclic alcohol 18 was assigned after hydrogenation of the exo-methylene function, which gave compounds 1a and 1b, diastereomers of africanol. Pure samples of 1a and 1b could be obtained by chromatography of the mixture on silica gel. Compounds 1a and 1b exhibited ¹H NMR spectra data identical with those of the same two substances previously prepared by Tai and coworkers⁶.

In an analogous sequence of reactions, hydrazone 15 was alkylated with (Z)-1-bromo-3-iodo-2-butene, followed by cyclization to give compound 20 (see Scheme 5). The only product obtained displayed the trans ring junction. The product 20 exhibited a H¹ NMR spectrum identical with that of the same compound prepared by Paquette and Ham⁵.

The results outlined above revealed that the ⁿBuLi mediated cyclizations of the keto iodides 5 (Scheme 4) and 19 (Scheme 5) were higly stereoselective and produced only the corresponding trans fused alcohols 18 and 20, respectively. Thus, in each case, the intermediate alkenyl-lithium function (formed by lithium iodine exchange) attacks the carbonyl carbon from the side opposite to the cyclopropyl (angular) methyl group. It is evident from molecular modelling that, in each of the modes of cyclization that could lead to the cis-fused epimers of 18 and 20, the transition states for cyclization would experience significant steric hindrance (1,3-diaxial type interaction) between the alkenyl-lithium moiety and the angular methyl group. On the other hand, the transition states leading to 18 and 20 appear to be relatively free of steric compression.

In view of the results described above, it was decided to prepare compound 21 and treat it with samarium iodide in the presence of HMPA. It was expected that the samarium iodide would generate the ketyl radical which would be complexed with HMPA¹⁸, prior to attack on the terminal double bond.

Having made 21 by alkylation of the anion of 15 with 4-iodo-1-butene, the cyclization was attempted. The reaction produced a mixture of the compounds 1a and 1b, along with africanol, in a ratio of 1:0.6:1, respectively. The formation of isoafricanol was not observed.

Conclusion

The methodology presented herein was very effective up to the preparation of bicyclic ketone 6. The regioselective and highly stereoselective alkylation of hydrazone 15 allowed the preparation of the key compounds 5, 19 and 21 in reasonable yields. However, cyclization of intermediates 5 and 19 by treatment with ⁿBuLi gave products with trans instead of the desired cis ring junctions. This problem was overcome by using a samarium iodide cyclization of olefin 21, in which the radical intermediate yielded a mixture of products from both cis and trans ring closure.

Acknowledgments

F.A.M. thanks the Brazilian Council for the Development of Science and Technology (CNPq) for financial support. We also thank Prof. A. Tai; Himeji Institute of Technology-Hyogo-Japan, for kindly providing ¹H NMR spectra of compounds 1a and 1b and Prof. Jocelyn G. Millar, University of California-Riverside, for assistance in revising the manuscript.

Received: June 09, 2000

Published on web: September 15, 2000

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Publication Dates

• Publication in this collection
  15 Jan 2001
• Date of issue
  Oct 2000

History

• Received
  09 June 2000
• Accepted
  15 Sept 2000