2,3-Dihydrofuran (4.2g, 60mmol) in water (15ml) was stirred at room temperature whilst conc. hydrochloric acid (1.2ml) was added dropwise. The mixture was stirred until homogeneous and then neutralised with 2 M aqueous sodium hydroxide. To this mixture potassium carbonate (15g, 110mmol) and triethyl phosphonoacetate (11ml, 55mmol) were added and the reaction mixture stirred for 3h. The product was then extracted with ethyl acetate (3x50ml) and the organics washed with brine before being dried and concentrated. Ethyl 6-hydroxyhex-2(E)-enoate (11) was obtained as a colourless liquid after distillation (5.2g, 60%), b.p. 80degC at 0.3mmHg. (Lit. b.p. 86-90degC at 15mmHg)[1].
Proton nmr (300 MHz, CDCl3) delta 6.96 (1H, dt, J = 15.7, 7.0 Hz, CH=CHCO2Et), 5.80 (1H, d, J = 15.7 Hz, CHCO2Et), 4.17 (2H, q, J = 7.4 Hz, CO2CH2), 3.87 (2H, t, J = 7.4 Hz, CH2OH), 2.25 (2H, m, CHCH2), 1.80 (2H, m, -CH2-), 1.26 (3H, t, J = 7.4 Hz, CH3); Vmax (neat) 2980, 2940, 2880, 1715, 1645 cm-1; m/z (CI, NH3) 176 (M+NH4)+, 159 (M+H)+,157, 140, 104, 87, 70. Found %C 60.42; %H 9.07. Calculated %C 60.74, %H 8.92.
Preparation of 5-tButyldimethylsilyloxy-pent-1-ene (14)
5-Hydroxy-pent-1-ene (5.0g, 58mmol) was added to a stirred solution of tbutyldimethylsilyl chloride (10.6g, 70mmol) and imidazole (8.1g, 139mmol) in the presence of a catalytic amount of 4-dimethyl-aminopyridine (10mg) in dry N,N-dimethylformamide (50ml) under argon. When the reaction had gone to completion by tlc, diethyl ether (200ml) was added, and the mixture washed with water (3x100ml). The ethereal solution was dried and the solvent removed under reduced pressure. The crude product was purified by filtration through a silica pad (cyclohexane) to give the silyl ether (14) as a colourless liquid (11.7g, ~100%).
Proton nmr (300MHz, CDCl3) delta 5.84 (1H, m, CH=CH2), 4.96 (2H, m, CH=CH2), 3.60 (2H, t, J = 6.4 Hz, CH2OSi), 2.08 (2H, dt, J = 11.4, 7.4 Hz, CH2CH), 1.58 (2H, m, -CH2-), 0.87 (9H, s, C(CH3)3), 0.03 (6H, s, Si(CH3)2); Vmax (neat) 2920, 2880, 2840, 1820, 1635, 1465, 1455, 1435, 1380, 1360, 1245, 1090 cm-1; m/z (CI, NH3) 218 (M+NH4)+, 201 (M+H)+, 69. Found (M+NH4)+ 218.1947. C11H28ONSi requires 218.1940.
Preparation of Ethyl 6-tbutyldimethylsilyloxy-hex-2(E)-enoate (12)
Method A
Ethyl 6-hydroxy-hex-2(E)-enoate (11) (1.3g, 8.3mmol) was added to a stirred solution of tbutyldimethylsilyl chloride (1.5g, 10.0mmol) and imidazole (1.2g, 19.9mmol) in the presence of a catalytic amount of 4-dimethyl-aminopyridine (10mg) in dry N,N-dimethylformamide (10ml) under argon. When the reaction had gone to completion by tlc, diethyl ether (100ml) was added, and the mixture washed with water (3x50ml). The ethereal solution was dried and the solvent removed under reduced pressure. Distillation of the crude product gave the silyl ether (12) as a colourless liquid (1.02g, 45%), b.p 79degC at 0.015mmHg.
Proton nmr (300 MHz, CDCl3) delta 7.08 (1H, dt, J = 15.7, 7.0 Hz, CH=CHCO2Et), 5.78 (1H, d, J = 15.7 Hz, CHCO2Et), 4.16 (2H, q, J = 7.4 Hz, COCH2), 3.61 (2H, t, J = 7.4 Hz, CH2OSi), 2.30-2.19 (2H, dt, J = 7.0, 7.5 Hz, CHCH2), 1.75-1.59 (2H, m, -CH2-), 1.26 (3H, t, J = 7.4 Hz, CH3), 0.84 (9H, s, C(CH3)3), 0.03 (6H, s, Si(CH3)2); Vmax (neat) 2960, 2880, 1720, 1660, 1470, 1445 cm-1; m/z (CI, NH3) 290 (M+NH4)+, 273 (M+H)+, 246, 206, 176, 150, 92, 91. Found %C 61.49; %H 10.52. Calculated %C 61.72; %H 10.36.
Method B
5-tButyldimethylsilyloxy-pent-1-ene (13) (5.0g, 25mmol) was placed in dry dichloromethane (50ml) and ozone bubbled through the solution at -78degC until tlc analysis showed the reaction to be complete. Nitrogen was then bubbled through the solution to remove excess ozone and the solution warmed to room temperature and stirred with triphenylphosphine (7g, 27mmol) for 1h. Ethyl (triphenylphosphoranylidene)acetate (8.8g, 25mmol) was added portionwise with stirring to the aldehyde in solution. After 3h the solvent was removed in vacuo and diethyl ether (50ml) was added. The resultant white precipitate was removed by filtration and the organics concentrated. Purification of the crude product by distillation afforded ethyl 6-tbutyldimethylsilyloxy-hex-2(E)-enoate (12) as a colourless liquid (2.8g, 41% overall from the starting alkene), identical with previously prepared material.
Preparation of 6-tButyldimethylsilyloxy-hex-2(E)-en-ol
DIBAL (111.6ml of a 1.0M solution in toluene, 111.6mmol) was added dropwise to a solution of ethyl 6-tbutyldimethylsilyloxy-hex-2(E)-enoate (12) (14g, 51mmol) in dry toluene (110ml) at -78degC under argon. After 30min the reaction mixture was allowed to warm up to -10degC and stirred for a further 1h. The reaction was then quenched with excess saturated potassium sodium tartrate solution (Rochelle's salt), diluted with chloroform (50ml) and filtered through Celite. The organic layer was then washed with Rochelle's salt (3x20ml) and brine before being dried and concentrated. Distillation gave 6-tbutyl-dimethylsilyloxy-hex-2(E)-en-ol as a colourless liquid(11.8g, ~ 100%), b.p. 75-76degC at 0.3mmHg.
Proton nmr (300 MHz, CDCl3) delta 5.63 (2H, m, CH=CH), 4.06 (2H, d, J = 4.6 Hz, CH2OH), 3.60 (2H, t, J = 6.4 Hz, CH2OSi), 2.07 (2H, dt, J = 8.8, 5.0 Hz, CH2CH), 1.61 (2H, m, -CH2-), 1.23 (1H, s, OH), 0.89 (9H, s, C(CH3)3), 0.02 (6H, S, Si(CH3)2); Vmax (neat) 2950, 2880, 2860, 1495, 1460 cm-1; m/z (CI, NH3) 248 (M+NH4)+, 231 (M+H)+, 213, 212, 175, 134, 88. Found %C 62.19; %H 11.48. Calculated %C 62.55; %H 11.37.
Preparation of 1-Bromo-6-tbutyldimethylsilyloxy-hex-2(E)-ene (15)
A solution of bromine (0.84g, 5.28mmol) in dry dichloromethane (5ml) was added to a 0.1M solution of DIPHOS (1.05g, 2.64mmol) in dry dichloromethane (20ml), at -10degC under argon. After stirring at this temperature for 20min., the complex was cooled to -78degC and dry pyridine (0.88ml, 11.0mmol) added. Then a solution of 6-tbutyldimethylsilyloxy-hex-2(E)-en-ol (0.50g, 2.2mmol) in dry dichloromethane (1ml) was added to the complex and the reaction mixture allowed to warm to 0degC. Tlc analysis indicated the complete consumption of starting material after 1h. at this temperature. The reaction mixture was then diluted with a pentane / diethyl ether mixture (giving a total solvent ratio of pentane / ether / dichloromethane 4:2:1, v/v/v) to precipitate the phosphorus by-products as a white solid which was removed by filtration. After removal of the solvent the crude product was purified by filtration through a silica pad to afford 1-bromo-6-tbutyldimethylsilyloxy-hex-2(E)-ene (15) as a clear liquid (0.54g, 84%).
Proton nmr (300 MHz, CDCl3) delta 5.73-5.62 (2H, m, CH=CH), 4.05 (2H, d, J = 6.8 Hz, CH2Br), 3.58 (2H, t, J = 6.3 Hz, CH2OSi), 2.12 (2H, m, CH2CH), 1.60 (2H, m, -CH2-), 0.89 (9H, s, C(CH3)3), 0.04 (6H, s, Si(CH3)2); Vmax (neat) 2950, 2870, 1470, 1395, 1365, 1265 cm-1.
Preparation of Diethyl 2-(6-tbutyldimethylsilyloxy-hex-2(E)-enyl) propanedioate
To a stirred suspension of sodium hydride (50mg of a 60% dispersion in oil, washed twice with dry petroleum ether, ~1.25mmol) in anhydrous tetrahydrofuran (10ml) was added diethylmalonate (200mg, 1.25mmol) at 0degC under argon. The mixture was warmed to room temperature and a solution of 1-bromo-6-tbutyldimethylsilyloxy-hex-2(E)-ene (15) (337mg, 1.15mmol) in dry tetrahydrofuran (1ml) was slowly added. After stirring for 6h, saturated ammonium chloride solution (10ml) was added followed by ethyl acetate (40ml). The organic layer was washed with brine (20ml) and dried. Purification by distillation afforded diethyl 2-(6-tbutyldimethylsilyloxy-hex-2(E)-enyl) propanedioate as a colourless liquid (330mg, 77%), b.p. 142degC at 0.53mmHg.
Proton nmr (300MHz, CDCl3) delta 5.49 (1H, dt, J = 13.5, 6.8 Hz, CH=C), 5.35 (1H, dt, J = 13.5, 6.8 Hz, CH=C), 4.16 (4H, q, J = 7.3 Hz, 2xCH2CO2), 3.55 (2H, t, J = 6.5 Hz, CH2OSi), 3.33 (1H, t, J = 7.5 Hz, CH(CO2Et)2), 2.54 (2H, t, J = 7.5 Hz, CHCH2CH), 1.99 (2H, dt, J =7.3, 6.8 Hz, CH2CH), 1.52 (2H, m, -CH2-), 1.23 (6H, t, J = 7.3 Hz, 2xCH2CH3), 0.85 (9H, s, C(CH3)3), 0.01 (6H, s, Si(CH3)2); Vmax (neat) 2920, 2840, 1730 cm-1; m/z (CI, NH3) 390 (M+NH4)+, 373 (M+H)+, 301, 276, 259, 190, 178, 149, 108, 94, 78. Found (M+NH4)+ 390.2672. C19H40O5NSi requires 390.2675.
Preparation of 2-(6-tButyldimethylsilyloxy-hex-2(E)-enyl) propanedioic acid
To a stirred solution of diethyl 2-(6-tbutyldimethylsilyloxy-hex-2(E)-enyl) propanedioate (1g, 2.7mmol) in ethanol (7ml) was added an aqueous solution of 10M potassium hydroxide (0.54ml). When the reaction had gone to completion by tlc the ethanol was removed under reduced pressure. The residue was then cooled to -10degC, acidified with 1 M hydrochloric acid to pH 1 and extracted with ethyl acetate (5x20ml). After washing with brine, the organics were dried and concentrated to give the diacid as a clear liquid (0.73g, ~100%).
Proton nmr (300 MHz, CDCl3) delta 7.83 (2H, br.s, 2xCO2H), 5.54 (1H, dt, J = 13.5, 7.0 Hz, C=CH), 5.38 (1H, dt, J = 13.5, 7.0 Hz, CH=C), 3.58 (2H, t, J = 6.6 Hz, CH2OSi), 3.44 (1H, t, J = 7.0 Hz, CH(CO2H)2), 2.59 (2H, t, J = 7.0 Hz, CHCH2CH), 1.99 (2H, dt, J = 7.0, 6.8 Hz, CH2CH2CH), 1.54 (2H, m, -CH2-), 0.87 (9H, s, C(CH3)3), 0.04 (6H, s, Si(CH3)2); Vmax (neat) 3495 br, 2930, 2855, 1717 br, 1695, 1472, 1464, 1440, 1410 cm-1; m/z (CI, NH3) 290 [(M+NH4)+ -CO2], 273 [(M+H)+ -CO2], 214, 200, 176, 158, 141, 32, 91, 58.
Preparation of 8-tButyldimethylsilyloxy-oct-4(E)-enoic acid (16)
2-(6-tButyldimethylsilyloxy-hex-2(E)-enyl) propanedioic acid (2.15g, 6.8mmol) was heated at reflux in toluene (100ml) for 4h. The solvent was then evaporated and the crude product purified by chromatography on silica gel, to yield 8-tbutyldimethylsilyloxy-oct-4(E)-enoic acid (16) as a clear liquid (0.5g, 21%).
Proton nmr (300MHz, CDCl3) delta 5.45 (2H, m, CH=CH), 3.57 (2H, t, J = 6.6 Hz, CH2OSi), 2.38 (2H, t, J = 6.6 Hz, CH2CO2H), 2.30 (2H, dt, J = 6.8, 6.6 Hz, CH2CH2CO2H), 2.01 (2H, dt, J = 6.8, 6.6 Hz, CH2CH), 1.53 (2H, m, -CH2-), 0.87 (9H, s, C(CH3)3), 0.02 (6H, s, Si(CH3)2); Vmax (neat) 3300 br, 2930, 2857, 1713, 1472, 1444, 1361 cm-1; m/z (CI, NH3) 290 (M+NH4)+, 273 (M+H)+, 214, 200, 176, 158, 141, 132, 91, 58. Found (M+H)+ 273.1885. C14H29O3Si requires 273.1886.