Synthesis of MOS
MOS (SM_7)
A solution of 5 (50.0 mg, 0.104 mmol) in Tetrahydrofuran (THF) (5.6 mL) was hydrogenated over 10% Pd/C (55% water, 22.2 mg) at room temperature (RT) for 20 h. The catalyst was removed by celite filtration and the filtrate was concentrated in vacuo to give MOS (SM_7) (33.6 mg, quant) as a colorless solid.
1 H NMR (400 MHz, CDCl3) δ: 6.84 (1 H, d, J = 7.8 Hz), 6.68 (1 H, dd, J = 1.7, 7.8 Hz), 6.61 (1 H, d, J = 1.7 Hz), 6.34 (2 H, s), 5.49 (1 H, brs), 5.39 (1 H, brs), 3.84 (6 H, s), 3.84 (3 H, s), 2.81 (4 H, s). 13 C NMR (100 MHz, CDCl3) δ: 146.8, 146.2, 143.7, 133.6, 132.8, 132.8, 121.0, 114.1, 111.2, 105.1, 56.2, 55.8, 38.4, 37.9. IR (KBr cm− 1): 3537, 3010, 2939, 1614, 1515, 1463, 1428, 1325, 1220, 1149, 1114, 1034, 927, 770, 662, 566, 557, 541, 518, 512, 500, 486, 457, 532, 426, 420, 412, 407. EI-MS m/z (%): 274 (M+, 32), 138 (11), 137 (100). HRMS (EI): Calcd for C17H29O5, 304.1311; Found: m/z 304.1307.
4-(benzyloxy)-3-methoxybenzaldehyde (1)
A solution vanilline (10.0 g, 65.7 mmol) in CH3CN (54 mL) was added NaHCO3 (6.29 g, 74.9 mmol, 1.14 equiv.) and KI (1.09 g, 6.57 mmol, 0.1 equiv.), and the obtained solution was heated to 60 °C. After benzyl chloride (8.00 mL, 69.5 mmol, 1.06 equiv.) was added to this solution, refluxed for 5 h. After cooling to RT, the reaction mixture was evaporated under vacuum. The residue was diluted with HCl solution (2.1 mL, 1 mol/L) and extracted with EtOAc (50 mL×3), washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified over SiO2 column (n-Hex. : EtOAc = 7 : 3) to give 1 (8.33 g, 52%) as a colorless solid.
1 H NMR (300 MHz, CDCl3) δ: 9.84 (1 H, s), 7.30–7.45 (7 H, m), 6.99 (1 H, d, J = 8.2 Hz), 5.25 (2 H, s), 3.95 (3 H, s).
(4-(benzyloxy)-3-methoxyphenyl)methanol (2)
A solution of 1 (3.00 g, 12.4 mmol) in methanol (30 mL), tetrahydrofuran [(THF) 30 mL], and H2O (3 mL) was added NaBH4 (515 mg, 13.6 mmol, 1.1 equiv.) at 0 °C, and the reaction mixture was stirred for 1 h. The reaction was diluted with Et2O (30 mL) and quenched with HCl solution (11 mL, 1 mol/L). The obtained solution was evaporated under vacuum. The residue was diluted with H2O (10 mL) and extracted with EtOAc (60 mL×3), washed with brine, dried over anhydrous Na2SO4, and concentrated to give 2 (2.99 g, 100%) as a colorless solid.
1 H NMR (400 MHz, CDCl3) δ: 7.43 (2 H, d, J = 7.1 Hz), 7.36 (2 H, t, J = 7.1 Hz), 7.30 (1 H, t, J = 7.1 Hz), 6.95 (1 H, d, J = 1.6 Hz), 6.86 (1 H, d, J = 8.4 Hz), 6.82 (1 H, dd, J = 1.6, 8.4 Hz), 5.16 (2 H, s), 4.61 (2 H, s), 3.91 (3 H, s).
diethyl (4-(benzyloxy)-3-methoxybenzyl)phosphonate (3)
A solution of NBS (7.65 g, 43.0 mmol, 3.5 equiv.) in CH2Cl2 (44 mL) was added dimethylsulfide (3.77 mL, 51.6 mmol, 4.2 equiv.) at 0 °C over 7 min. The reaction mixture was stirred at this temperature for 10 min. A solution of 2 (3.00 g, 12.3 mmol) in CH2Cl2 (44 mL) was cooled at − 18 °C and was added above solution. The reaction mixture was stirred at − 18 °C for 3 h. The reaction mixture was warmed to 0 °C and diluted with H2O and extracted with CH2Cl2 (80 mL×3), washed with saturated NaHCO3 solution and H2O, dried over anhydrous Na2SO4, and concentrated. The crude product was dissolved in triethyl phosphite (2.79 mL, 16.1 mmol, 1.24 equiv.). The reaction mixture was stirred at 140 °C for 4 h. After cooling to RT, the reaction mixture was evaporated under vacuum. The residue was purified over SiO2 column (n-Hex. : EtOAc = 1 : 9) to give 3 (2.01 g, 45%) as a yellow oil.
1 H NMR (400 MHz, CDCl3) δ: 7.29–7.44 (5 H, m), 6.89 (1 H, s), 6.82 (1 H, d, J = 8.0 Hz), 6.75 (1 H, d, J = 8.0 Hz), 5.13 (2 H, s), 3.93–4.11 (4 H, m), 3.89 (3 H, s), 3.04 (2 H, d, J = 21.2 Hz), 1.20 (6 H, t, J = 7.1 Hz).
4-(benzyloxy)-3,5-dimethoxybenzaldehyde (4)
A solution syringaldehyde (10.0 g, 54.9 mmol) in CH3OH (33 mL) was added K2CO3 (9.1 g, 65.9 mmol, 1.2 equiv.) and benzyl bromide (7.82 mL, 65.9 mmol, 1.2 equiv.), and the obtained solution was refluxed for 20 h. After cooling to RT, the reaction mixture was filtered, and the obtained filtrate was evaporated under vacuum. The residue was diluted with H2O and extracted with CHCl3 (50 mL×3), washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified over SiO2 column (n-Hex. : EtOAc = 7 : 3) to give 4 (9.40 g, 63%) as a yellow oil.
1 H NMR (400 MHz, CDCl3) δ: 9.86 (1 H, s), 7.47 (2 H, dd, J = 1.6, 7.3 Hz), 7.28–7.38 (3 H, m), 7.11 (2 H, s), 5.13 (2 H, s), 3.90 (6 H, s).
(E)-2-(benzyloxy)-5-(4-(benzyloxy)-3-methoxystyryl)-1,3-dimethoxybenzene (5)
A solution of 3 (400 mg, 1.10 mmol, 1.2 equiv.) in THF (5.5 mL) was stirred at − 78 °C and added t-BuOK solution in THF (1.46 mL, 1.46 mmol, 1.6 equiv., 1.0 M) over 30 min. The reaction mixture was stirred for 20 min. at the same temperature, and was added 4 (249 mg, 0.915 mmol) in THF (1.0 mL) over 20 min. and the mixture was stirred for 1 h at − 78 °C and for 10 min. at 0 °C. Then, the reaction mixture was stirred for 2 h at RT. The reaction mixture was cooled to 0 °C and diluted with saturated NH4Cl solution and extracted with EtOAc (60 mL×3), washed with saturated NH4Cl solution and H2O, dried over anhydrous Na2SO4, and concentrated. The crude product was purified over SiO2 column (CH2Cl2) to give 5 (231 mg, 52%) as a colorless solid.
1 H NMR (400 MHz, CDCl3) δ: 7.49 (2 H, d, J = 6.8 Hz), 7.44 (2 H, d, J = 7.3 Hz), 7.27–7.39 (6 H, m), 7.07 (1 H, d, J = 2.0 Hz), 6.97 (1 H, dd, J = 2.0, 8.3 Hz), 6.94 (1 H, d, J = 16.1 Hz), 6.88 (1 H, d, J = 16.1 Hz), 6.86 (1 H, d, J = 8.3 Hz), 6.70 (2 H, s), 5.17 (2 H, s), 5.02 (2 H, s), 3.95 (3 H, s), 3.87 (6 H, s). 13 C NMR (100 MHz, CDCl3) δ: 153.6, 149.8, 148.0, 137.8, 137.0, 136.6, 133.3, 130.8, 128.5, 128.5, 128.1, 127.8, 127.8, 127.2, 127.0, 119.6, 114.0, 109.3, 103.4, 75.1, 71.0, 56.1, 56.0. IR (KBr cm− 1): 3547, 3019, 2399, 1507, 1331, 1214, 1030, 928, 753, 668, 501, 476, 454, 441, 435, 429, 407, 401. EI-MS m/z (%): 482 (M+, 13), 392 (28), 391 (100), 91 (62). HRMS (EI): Calcd for C31H30O5, 482.2093; Found: m/z 482.2092.