3.2. General synthetic procedures
4-(tert-Butyldimethylsilanyloxy)-3-methoxybenzaldehyde (2): Vanillin (1, 1 g, 6.57 mmol) was dissolved under N2 in dry CH2Cl2 (20 mL) and treated sequentially with 2,6-lutidine (1.14 mL, 9.86 mmol) and TBSOTf (1.66 mL, 7.23 mmol).The reaction mixture was then stirred for 1 h at 0ºC. After this time the reaction mixture was poured onto a saturated aq. NH4Cl solution and extracted with CH2Cl2. Column chromatography on silica gel (hexanes-EtOAc 4:1) afforded the desired silylated derivative 2 in 99% yield. 1H-NMR: δ 0.00 (s, 6H), 0.85 (s, 9H), 3.62 (s, 3H), 6.61 (dd, 2H, J = 9.3 Hz, J = 8 Hz), 6.70 (s, 1H), 9.80 (s, 1H); 13C-NMR: δ 18.30 (C), 25.50 (CH3), 46.80 (CH3), 73.60 (CH), 110.20 (CH), 118.10 (CH), 120.20 (CH), 137.30 (C), 143.60 (C), 150.30 (C), 189.00 (CH).
1-[4-(tert-Butyldimethylsilanyloxy)-3-methoxyphenyl]-but-3-en-1-ol (3): The aldehyde 2 (0.18 mmol) was dissolved in dry ether (50 mL) a 0ºC, allylmagnesium bromide (0.18 mmol, 1M solution in THF) was added and then the mixture was stirred for 4 h under N2. The reaction mixture was then quenched through addition of a saturated aq. solution of NH4Cl and extracted with Et2O. The combined organic phases were washed with a saturated aq. solution of NaCl, and dried with Na2SO4. After filtration and evaporation of the solvent under vacuum the residue was column chromatography on silica gel (hexanes-EtOAc 8:2 and then 3:2) to afford the homoallylic alcohol in 70% yield. 1H-NMR: δ 0.00 (s, 6H), 0.85 (s, 9H), 2.29 (t, 2H, J = 6.8 Hz), 3.62 (s, 3H), 4.43 (t, 1H, J = 6.5 Hz), 4.90-4.96 (m, 1H), 5.57-5.63 (m, 2H), 6.61 (dd, 2H, J = 9.3 Hz, J = 8 Hz), 6.70 (s, 1H); 13C-NMR: δ 18.32, 25.52 (CH3), 43.84 (CH2), 46.86 (CH3), 73.65 (CH), 110.20 (CH), 117.70 (CH2), 118.11 (CH), 120.22 (CH), 134.83 (CH), 137.34 (C), 150.38 (C), 143.66 (C).
Acrylic acid 1-[4-(tert-butyldimethylsilanyloxy)-3-methoxyphenyl]-but-3-enyl ester (4): Alcohol 3 (0.75 mmol) was dissolved under N2 in dry CH2Cl2 (11 mL), cooled to 0°C, and treated sequentially with DIPEA (3.74 mmol) and acryloyl chloride (32.26 mmol). The reaction mixture was stirred for 2 h at 0°C and then work-up (extraction with CH2Cl2). Column chromatography on silica gel (hexanes-EtOAc 4:2) afforded ester 4 in 97% yield. 1H-NMR: δ 0.14 (s, 6H), 0.99 (s, 9H), 2.50-2.70 (m, 2H), 3.80 (s, 3H), 5.01-5.11 (m, 3H), 5.79- 5.85 (m, 2H), 6.10-6.20 (m, 1H), 6.41 (dd, 1H, J = 1.0 Hz, J = 17.3 Hz), 6.70-6.80 (m, 2H), 6.80 (s br, 1H); 13C-NMR: δ 18.30 (C), 26.49 (CH3), 40.39 (CH2), 55.48 (CH3), 75.19 (CH), 110.71(CH), 117.99 (CH), 119.00 (CH2), 120.50 (CH), 128.60 (CH), 130.80 (CH2), 133.30 (CH), 134.50 (C), 144.70 (C), 150.70 (C), 165.34 (C).
6-[4-(tert-Butyldimethylsilanyloxy)-3-methoxyphenyl]-5,6-dihydropyran-2-one (5): Compound 4 (0.86 mmol) was dissolved under N2 in dry, degassed CH2Cl2 (35 mL) and treated with ruthenium catalyst PhCH=RuCl2(PCy3)2 (10% mmol). The mixture was heated at reflux until consumption of the starting material (ca. 3 h, TLC monitoring!). Solvent removal in vacuum and column chromatography on silica gel (hexanes-EtOAc, 9:1) furnished lactone 5 in 60% yield. 1H-NMR: δ 0.00 (s, 6H), 0.84 (s br, 9H), 2.37-2.57 (m, 2H), 3.67 (s, 3H), 5.22 (dd, 1H, J=4.3Hz, J=7.4Hz), 5.96 (d, 1H, J=9.8Hz), 6.63-6.70 (m, 2H), 6.78- 6.83 (m, 2H); 13C-NMR: δ 18.18, 25.29(CH3), 31.60(CH2), 55.45(CH3), 79.32(CH), 109.94(CH), 118.60(CH), 120.64(CH), 121.48(CH), 131.85 (C), 144.89(CH), 145.31 (C), 151.13 (C), 164.44 (C).
6-(4-Hydroxy-3-methoxyphenyl)-5,6-dihydropyran-2-one (6): The silylated lactone 5 (0.1 g, 0.3 mmol) was dissolved in THF (10 mL), treated with TBAF (5 mg, 0.0007 mmol) and the mixture stirred for 9 h at 25ºC. The reaction was then quenched by addition of a solution of NH4Cl, and after work-up (CH2Cl2), the organic phase was washed with a saturated NaCl solution, dried with Na2SO4, and evaporated under vacuum. The residue was subjected to column chromatography on silica gel (hexanes-EtOAc 1:1 and 3:2) furnishing lactone 6 as an amorphous solid in 89.3 % yield. Mp: 109-111 ºC; IR (KBr) νmax (cm-1): 3392 (OH), 1709 (C = O), 1136 (C(= O)-O), 1033 (O – C = C, O-CH3); 1H-NMR: δ 2.51- 2.69 (m, 2H), 3.91 (s, 3H), 5.38 (dd, 1H, J=4.5Hz, J=11.5Hz), 5.72 (s br, 1H), 6.13 (dd, 1H, J=2.2Hz, J=9.8Hz), 6.85- 6.90 (m, 2H), 6.90 -7.00 (m, 2H); 13C-NMR: δ 32.02(CH2), 56.16(CH3), 79.62(CH), 109.03(CH), 114.50(CH), 119.50(CH), 121.93(CH), 130.88, 145.21(CH), 146.69, 147.48; HR EIMS, m/z 221.1902 (M+H).
Dimer of 6-(4-hydroxy-3-methoxyphenyl)-5,6-dihydropyran-2-one (7): Lactone 6 was dissolved in acetonitrile (10 mL), Et3N (1.5 eq, 2.3 mL) was added and the reaction mixture stirred for 15 min. Then 1,3-dibromopropane (0.5 eq, 0.02 mL) was added, and the resulting mixture was heated at reflux for 8 h. After this time an aq. solution of HCl was added and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel (hexanes-EtOAc 9:1) to furnish dimeric compound 7 in 69 % yield. Mp: 81-83ºC; I.R (KBr) νmax (cm−1): 1708 (C = O), 1171 (C(= O)-O), 1128 (O – C = C, O-CH3); 1H-NMR: δ 2.21- 2.26 (m, 2H), 2.32-2.41 (m, 2H), 3.89 (s, 3H), 4.15-4.32 (m, 4H), 5.28-5.44 (m, 2H), 5.65-5.97 (m, 2H), 6.78-7.01(m, 8H); 13C-NMR: δ 29.69 (CH2), 56.061 (CH3), 61.89 (CH2), 109.82 (CH), 123.659 (CH), 133.220, 145.97 (CH); HR EIMS, (M+H): 481.2
Dilactone 6,6'-octane-1,8-diylbis(5,6-dihydro-2H-pyran-2-one) (15): Amorphous solid. Mp: 81-84 ºC; IR (KBr) νmax (cm-1): 1698 (C = O), 1262 (C(= O)-O), 1028 (O – C = C); 1H-NMR: δ 1.25-1.37 (m, 14H), 1.56-1.67 (m, 4H), 2.30-2.35 (m, 4H), 4.37-4.46 (m, 2H), 6.02 (d, J = 9.8 Hz, 2H2), 6.87 (m, 2H3); 13C-NMR: δ (CH2), 29.90-30.10 (6CH2), 35.50 (CH2), 78.20 (CH), 122.10 (CH), 145.80 (CH), 165.20; HR EIMS: (M+H): 307.1911 (C18H27O4), calc. 307.1909.
6-Dodecyl-4-methoxytetrahydro-pyran-2-one (16): The lactone 8 (200 mg, 0.962 mmol) was dissolved in MeOH (30 mL), and treated with Et3N (0.962 mmol). The mixture was heated at reflux until the starting material was consumed (ca. 4 h, TLC monitoring); after this time, the mixture is neutralized with a solution of sodium bicarbonate, extracted with ethyl acetate, and the organic phase dried with Na2SO4, concentrated and purified by column chromatography (silica gel, hexane: ethyl acetate 1:1 ) to give an amorphous solid. Mp: 54-56 ºC; IR (KBr) νmax (cm-1): 1724 (C = O), 1245 (C(= O)-O), 1081 (O – C = C, O-CH3); 1H-NMR: δ 0.88 (t, 3H, J=6.6Hz), 1.25-1.38 (m, 26 H), 1.60-1.70 (m, 2H), 2.03-2.17 (m, 2H), 2.67-2.69 (m, 2H), 3.33 (s, 3H), 3.70-3.80 (m, 1H), 4.49-4.58 (m, 1H); 13C-NMR: δ 14.11 (CH3), 22.68 - 29.69 (10CH2), 31.92 (CH2), 33.17 (CH2), 35.52 (CH2), 56.09 (CH3), 71.47(CH), 75.91 (CH); HR EIMS, (M+H): 341.3044 C21H41O3 calc.341.3056.