3.2. Preparation of PBT derivatives
3.2.1. Synthesis and spectroscopic data of 4-acetoxy-α-(3,4-dimethoxyphenyl)-3-methoxycinnamic acid (2a) and 3,4-dimethoxy-α-(3,4-dimethoxyphenyl)cinnamic acid (2b)
A mixture of 4-hydroxy-3-methoxybenzaldehyde (1a, 0.15 g, 1 mmol), 3,4-dimethoxyphenylacetic acid (0.19 g, 1 mmol), acetic anhydride (2 mL) and triethylamine (0.3 mL) was heated to reflux at 140 °C for 7 h using a CaCl2 tube. Then the mixture was cooled to room temperature, diluted with water (10 mL) and refluxed at 120 °C for 30 min. The cooled mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with saturated brine (150 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo and the residue recrystallized from methanol to afford 2a (0.32 g, 86%) as pale-yellow crystals. m.p. 166-168 °C; 1H-NMR (300 MHz, CDCl3) δ: 2.28 (s, 3H, CH3CO), 3.47 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.67 (d, 1H, J = 1.5 Hz, Ar-H), 6.79 (d, 1H, J = 1.5 Hz, Ar-H), 6.83 (dd, 1H, J = 8.2, 1.5 Hz, Ar-H), 6.84 (dd, 1H, J = 8.1, 1.5 Hz, Ar-H), 6.91 (d, 1H, J = 8.1 Hz, Ar-H), 6.92 (d, 1H, J = 8.2 Hz, Ar-H), 7.87 (s, 1H, C=CH); IR (KBr) cm-1 ν: 3421, 3062, 2964, 2839, 1764, 1674, 1619, 1516; EIMS m/z: 372 [M]+ (C20H20O7), 330 (100%) [M-acyl]+. Compound 2b (0.31 g, 90%) was synthesized as a deep yellow solid from 3,4-dimethoxy-benzaldehyde (1b, 0.17 g, 1 mmol) and 3,4-dimethoxyphenylacetic acid (0.19 g, 1 mmol) in the same synthetic route as that for 2a. m.p. 217-219 °C; 1H-NMR (300 MHz, CDCl3) δ: 3.47 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.55 (d, 1H, J = 1.8 Hz, Ar-H), 6.70 (d, 1H, J = 1.8 Hz, Ar-H), 6.72 (d, 1H, J = 8.5 Hz, Ar-H), 6.84 (dd, 1H, J = 8.2, 1.8 Hz, Ar-H), 6.85 (dd, 1H, J = 8.5, 1.8 Hz, Ar-H), 6.92 (d, 1H, J = 8.2 Hz, Ar-H), 7.86 (s, 1H, C=CH); IR (KBr) cm-1 ν: 3448, 3043, 2938, 2835, 1668, 1593, 1510; ESI MS m/z: [M-H]- 343 (C19H20O6).
3.2.2. Synthesis and spectroscopic data of methyl N-[4-acetoxy-α-(3,4-dimethoxyphenyl)-3-methoxy)-cinnamyl]pyrrolidine-2-carboxylate (3a) and methyl N-[3,4-dimethoxy-α-(3,4-dimethoxyphenyl)-cinnamyl]pyrrolidine-2-carboxylate (3b)
To a stirred solution of 2a (0.74 g, 2 mmol) and DMF (0.1 mL) in anhydrous THF (10 mL), oxalyl chloride (2 mL, 22.4 mmol) in anhydrous THF (2 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. Excess oxalyl chloride was removed under reduced pressure. The yellow residue was dissolved in anhydrous CH2Cl2 (20 mL), to which was added dropwise a solution of l-proline methyl ester hydrochloride (0.35 g, 2.1 mmol) and pyridine (1 mL, 12.4 mmol) in anhydrous CH2Cl2 (4 mL) with stirring. The mixture was stirred overnight at room temperature. Then 1 N HCl (15 mL) was added to the reaction system with vigorous stirring to quench the reaction. The organic layer was seperated and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with saturated brine (90 mL) and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo, the residue was purified by column chromatography on silica gel (hexane/EtOAc, 1:1.25 v/v) to afford 3a (0.92 g, 95%) as a colorless solid; m.p. 53-55 °C; 1H-NMR (300 MHz, CDCl3) δ: 1.81-1.94 (m, 3H overlapped, 1.5×CH2), 2.23 (m, 1H, 0.5×CH2), 2.26 (s, 3H, CH3CO), 3.30 (m, 2H, CH2N), 3.53 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.55 (m, 1H, CHN), 6.76-6.92 (m, 7H overlapped, 7×Ar-H); IR (KBr) cm-1 ν: 3041, 2954, 2836, 1764, 1745, 1633, 1600, 1513; EIMS m/z: 483 [M]+ (C26H29NO8), 441 [M-acyl]+, 424 [M-COOMe]+, 327 [M-CO-C6H10NO2]+, 285 (100%) [M-CO-C6H10NO2 -acyl]+. Compound 3b (1.27 g, 96%) was synthesized as a light yellow solid from 2b (1 g, 2.9 mmol) and l-proline methyl ester hydrochloride (0.49 g, 3.0 mmol) by the same synthetic route as that for 3a; m.p. 44-46 °C; 1H-NMR (300 MHz, CDCl3) δ: 1.81-1.98 (m, 3H overlapped, 1.5×CH2), 2.24 (m, 1H, 0.5×CH2), 3.34 (m, 2H, CH2N), 3.57 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.56 (m, 1H, CHN), 6.70-6.95 (m, 7H overlapped, 7×Ar-H); IR (KBr) cm-1 ν: 3047, 2953, 2836, 1743, 1632, 1600, 1514; EIMS m/z: 455 [M]+ (C25H29NO7), 327 [M-C6H10NO2]+, 299 (100%) [M-CO-C6H10NO2]+.
3.2.3. Synthesis and spectroscopic data of methyl N-(3-acetoxy-2,6,7-trimethoxyphenanthr-9-ylcarbonyl)pyrrolidine-2-carboxylate (4a) and methyl N-(2,3,6,7-tetramethoxyphenanthr-9-ylcarbonyl)-pyrrolidine-2-carboxylate (4b)
To a solution of 3a (0.48 g, 1 mmol) in anhydrous CH2Cl2 (15 mL) was added anhydrous FeCl3 (0.68 g, 4.3 mmol), and the mixture was stirred at room temperature for 2 h under nitrogen. Then 1 N HCl (1 mL) diluted with saturated brine (10 mL) was added to the stirred reaction system. The organic layer was seperated and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with saturated brine (80 mL) and dried over anhydrous Na2SO4. After filtration and evaporation, the residue was purified by column chromatography on silica gel (hexane/EtOAc, 1:1.5 v/v) to afford 4a (0.41 g, 85%) as an off-white solid; m.p. 229-231 °C; 1H-NMR (600 MHz, CDCl3) δ: 1.88 (m, 1H, 0.5×CH2), 1.95 (m, 1H, 0.5×CH2), 2.09 (m, 1H, 0.5×CH2), 2.37 (m, 1H, 0.5×CH2), 2.43 (s, 3H, CH3CO), 3.22 (m, 1H, 0.5×CH2N), 3.36 (m, 1H, 0.5×CH2N), 3.84 (s, 3H, CH3O), 3.97 (s, 3H, CH3O), 4.00 (s, 3H, CH3O), 4.01 (s, 3H, CH3O), 4.84 (dd, 1H, J = 8.4, 4.8 Hz, CHN), 7.29 (s, 1H, Ar-H), 7.59 (s, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 8.14 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3083, 2953, 2836, 1763, 1743, 1631, 1508; ESI MS m/z: [M+H]+ 482 (C26H27NO8). Compound 4b (1.33 g, 84%) was synthesized as a light yellow solid from 3b (1.6 g, 3.5 mmol) and anhydrous FeCl3 (2.27 g, 14 mmol) by a similar synthetic route as that of 4a; m.p. 200-202 °C; 1H-NMR (300 MHz, CDCl3) δ: 1.77-1.98 (m, 2H overlapped, CH2), 2.06 (m, 1H, 0.5×CH2), 2.32 (m, 1H, 0.5×CH2), 3.22 (m, 1H, 0.5×CH2N), 3.36 (m, 1H, 0.5×CH2N), 3.81 (s, 3H, CH3O), 3.98 (s, 3H, CH3O), 4.06 (s, 3H, CH3O), 4.09 (s, 6H, 2×CH3O), 4.81 (m, 1H, CHN), 7.14 (s, 1H, Ar-H), 7.52(s, 1H, Ar-H), 7.64 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.74 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3077, 2952, 2836, 1741, 1628, 1509; EIMS m/z: 453 [M]+ (C25H27NO7), 325 (100%) [M-C6H10NO2]+.
3.2.4. Synthesis and spectroscopic data of N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-l-prolinol (5a) and N-(2,3,6,7-tetramethoxyphenanthr-9-ylmethyl)-l-prolinol (5b)
To a stirred, ice-salt bath cooled solution of 4a (3.1 g, 6.4 mmol) in anhydrous THF (100 mL) was added LiAlH4 (1.3 g, 39 mmol) in one portion. After being stirred for 30 min kept at 0 °C, the mixture was heated to reflux at 100 °C for 2 h using a CaCl2 tube. To the cooled mixture were added ice and saturated NaHCO3 solution (100 mL). After stirring for 10 min, the THF layer was separated and the aqueous layer was extracted with THF (2 × 50 mL). The combined organic extracts were washed with saturated brine (200 mL) and dried over anhydrous Na2SO4. After filtration and evaporation, the residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1 v/v) to afford 5a (2.3 g, 90%) as an off-white solid. m.p. 178-180 °C; 1H-NMR (600 MHz, CDCl3) δ: 1.70 (m, 1H, 0.5×CH2), 1.74 (m, 1H, 0.5×CH2), 1.87 (m, 1H, 0.5×CH2), 2.02 (m, 1H, 0.5×CH2), 2.46 (m, 1H, 0.5×CH2N), 2.95 (m, 1H, 0.5×CH2N), 2.97 (m, 1H, CHN), 3.52 (d, 1H, J = 10.8 Hz, 0.5×CH2O), 3.74 (d, 1H, J = 12.6 Hz, 0.5×ArCH2N), 3.79 (d, 1H, J = 10.8 Hz, 0.5×CH2O), 4.03 (s, 3H, CH3O), 4.08 (s, 6H, 2×CH3O), 4.47 (d, 1H, J = 12.6 Hz, 0.5×ArCH2N), 7.18 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3388, 3050, 2953, 2839, 1617, 1513; ESI MS m/z: 398 [M+H]+ (C23H27NO5). Compound 5b (0.84 g, 93%) was synthesized as a white solid from 4b (1 g, 2.2 mmol) and LiAlH4 (0.7 g, 21 mmol) by the same synthetic route as that described for 5a; m.p. 217-218 oC; 1H-NMR (300 MHz, CDCl3) δ: 1.57-1.67 (m, 2H overlapped, CH2), 1.79 (m, 1H, 0.5×CH2), 1.91 (m, 1H, 0.5×CH2), 2.38 (m, 1H, 0.5×CH2N), 2.80 (m, 1H, 0.5×CH2N), 2.87 (m, 1H, CHN), 3.42 (dd, 1H, J = 10.5, 2.4 Hz, 0.5×CH2O), 3.65 (d, 1H, J = 12.6 Hz, 0.5×ArCH2N), 3.68 (dd, 1H, J = 10.5, 3.6 Hz, 0.5×CH2O), 3.96 (s, 3H, CH3O), 4.00 (s, 3H, CH3O), 4.02 (s, 3H, CH3O), 4.04 (s, 3H, CH3O), 4.39 (d, 1H, J = 12.6 Hz, 0.5×ArCH2N), 7.12 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.74 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3423, 3050, 2958, 2836, 1617, 1510; ESI MS m/z: 412 [M+H]+ (C24H29NO5).
3.2.5. Synthesis and spectroscopic data of N-[4-acetoxy-α-(3,4-dimethoxyphenyl)-3-methoxy-cinnamyl]-l-valine methyl ester (6)
Compound 6 (1.90 g, 91%) was synthesized as a colorless solid from 2a (1.6 g, 4.3 mmol) and l-valine methyl ester hydrochloride (0.75 g, 4.5 mmol) by a similar synthetic route as that for 3a; m.p. 46-48 °C; 1H-NMR (300 MHz, CDCl3) δ: 0.76 (d, 3H, J = 6.9 Hz, CH3), 0.91 (d, 3H, J = 6.8 Hz, CH3), 2.13 (m, 1H, CH), 2.27 (s, 3H, CH3CO), 3.48 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.65 (brdd, 1H, J = 8.7, 4.9, CHN), 6.10 (d, 1H, J = 8.7 Hz, NH), 6.62 (d, 1H, J = 1.7 Hz, Ar-H), 6.75 (dd, 1H, J = 8.1, 1.7 Hz, Ar-H), 6.81 (d, 1H, J = 1.7 Hz, Ar-H), 6.85 (d, 1H, J = 8.2 Hz, Ar-H), 6.88 (dd, 1H, J = 8.2, 1.7 Hz, Ar-H), 6.98 (d, 1H, J = 8.1 Hz, Ar-H), 7.77 (s, 1H, C=CH); IR (KBr) cm-1 ν: 3420, 3050, 2961, 2836, 1767, 1740, 1670, 1616, 1513; EIMS m/z: 485 [M]+ (C26H31NO8), 443 (100%) [M-acyl]+, 328[M-CO-C6H12NO2]+, 285[M-acyl-CO-C6H12NO2]+.
3.2.6. Synthesis and spectroscopic data of N-(3-acetoxy-2,6,7-trimethoxyphenanthr-9-ylcarbonyl)-l-valine methyl ester (7)
Compound 7 (335 mg, 86%) was synthesized as an off-white solid from 6 (390 mg, 0.80 mmol) and anhydrous FeCl3 (0.53 g, 3.24 mmol) using the same synthetic route as that for 4a; m.p. 205-206 °C; 1H-NMR (300 MHz, CDCl3) δ: 1.02 (d, 3H, J = 6.9 Hz, CH3), 1.12 (d, 3H, J = 6.8 Hz, CH3), 2.36 (m, 1H, CH), 2.43 (s, 3H, CH3CO), 3.83 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.09 (s, 3H, OCH3), 4.93 (brdd, 1H, J = 8.8 Hz, 4.9Hz, CHN), 6.64 (d, 1H, J = 8.8 Hz, NH), 7.29 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.76 (s,1H, Ar-H), 7.79 (s, 1H, Ar-H), 8.11(s, 1H, Ar-H); IR (KBr) cm-1 ν: 3288, 3050, 2961, 2834, 1760, 1742, 1635, 1598, 1508; ESI MS m/z: 482[M-H]- (C26H28NO8).
3.2.7. Synthesis and spectroscopic data of N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylcarbonyl)-l-valinol (8)
A 100 mL dry three-necked flask was charged with a stirred suspension of LiAlH4 (61 mg, 1.6 mmol) in anhydrous THF (15 mL) kept at −10~0 °C for 10 min. Compound 7 (150 mg, 0.31 mmol) dissolved in anhydrous THF (15 mL) was added dropwise to the suspension with stirring at −10~0 °C. After the addition was complete, stirring was continued for 10 min, then the warmed reaction system was refluxed at 100 °C for 2 h using a CaCl2 tube. To the cooled mixture were added ice and saturated NaHCO3 solution (30 mL). After being stirred for 10 min, the THF layer was separated and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with saturated brine (90 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 30:1 v/v) to afford 8 (106 mg, 83%) as a white solid; m.p.182-183 °C; 1H-NMR (300 MHz, DMSO) δ: 0.94 (d, 3H, J = 6.8 Hz, CH3), 0.99 (d, 3H, J = 6.8 Hz, CH3), 1.98 (m, 1H, CH), 3.56 (m, 2H, CH2O), 3.81 (s, 3H, OCH3), 3.92(s, 3H, OCH3), 3.96(m, 1H, CHN), 3.98(s, 3H, OCH3), 7.43 (s, 1H, Ar-H), 7.69 (s, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.98 (s, 1H, Ar-H), 8.12(d, 1H, J = 9.15 Hz, NH); IR (KBr) cm-1 ν: 3296, 3050, 2957, 2835, 1620, 1593, 1508; ESI MS m/z: 412 [M-H]- C23H26NO6 .
3.2.8. Synthesis and spectroscopic data of N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-l-valinol (9)
Compound 8 (41 mg, 0.1 mmol) dissolved in anhydrous THF (5 mL) was added dropwise to a stirred solution of NaBH4 (20 mg, 0.5 mmol) in anhydrous THF (20 mL) kept at −5~0 °C. Then I2 (59 mg, 0.23 mmol) dissolved in anhydrous THF (7 mL) was added dropwise to the stirred reaction system at −5~0 °C over 2 h. After the addition was complete, the mixture was warmed to room temperature and heated to reflux at 100 °C for 4 h. Then to the cooled mixture, 1 N HCl (8 mL) was added dropwise with stirring to quench the excess hydride. After the gas evolution ceased, saturated NaHCO3 solution (8 mL) was added dropwise to neutralize the excess HCl. The THF layer was separated and dried over anhydrous Na2SO4. After filtration, a solution of BF3·Et2O (2 mL) in THF (5 mL) was added dropwise to the filtrate, then saturated NaHCO3 solution (10 mL) was added to dissociate the target amine. The THF layer was separated, and the aqueous layer was extracted with THF (2 × 30 mL). The combined extracts were washed with saturated brine (100 mL) and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo, the residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 15:1 v/v) to afford 9 (31 mg, 78%) as an off-white solid; m.p. 224-225 °C; 1H-NMR (300 MHz, DMSO) δ: 0.91 (d, 3H, J = 6.7 Hz, CH3), 0.96 (d, 3H, J = 6.7 Hz, CH3), 2.15 (m, 1H, CH), 2.98 (m, 1H, CHN), 3.60 (m, 1H, 0.5×OCH2), 3.73 (m, 1H, 0.5×OCH2), 3.92 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.45 (m, 2H, ArCH2N), 7.33 (s, 1H, Ar-H), 7.59 (s, 1H, Ar-H), 7.68 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.97(s, 1H, Ar-H); IR (KBr) cm-1 ν: 3423, 3050, 2927, 2836, 1618, 1508; ESI MS m/z: [M+H]+ 400 (C23H29NO5).
3.2.9. Synthesis and spectroscopic data of [N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-pyrrolidin-2-yl]methyl acetate (10) and [N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)pyrro-lidin-2-yl]methyl hydrogen sulfate (11)
To a dry 50 mL three-necked flask charged with 5a (1 g, 2.52 mmol) was added glacial acetic acid (5 mL) at −15 °C. The mixture was stirred for 5 min. Then frozen concentrated sulfuric acid (10 mL) was added dropwise to the stirred system at −15 °C. After the addition was complete, stirring was continued for 20 min. Then the solution was warmed to room temperature and gently heated to 35 °C. Thirty min later, the reaction mixture was cooled to room temperature, poured into water (100 mL) and adjusted to pH 10 with 1N KOH solution. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined extracts were washed with saturated brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 15:1 v/v) to afford 10 and 11. Compound 10 (0.3 g, 27%), a white solid; m.p. 136-137 °C; 1H-NMR (600 MHz, CDCl3) δ: 1.66 (m, 3H overlapped, 1.5×CH2), 2.01 (m, 1H, 0.5×CH2), 2.06 (s, 3H, CH3CO), 2.35 (m, 1H, 0.5×CH2N), 2.84 (m, 1H, 0.5×CH2N), 2.96 (m, 1H, CHN), 3.68 (d, 1H, J = 13.2 Hz, 0.5×ArCH2N), 4.03 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 4.09 (s, 3H, OCH3), 4.13 (m, 1H, 0.5×CH2O), 4.29 (m, 1H, 0.5×CH2O), 4.61 (d, 1H, J = 13.2 Hz, 0.5×ArCH2N), 7.18 (s, 1H, Ar-H), 7.49 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.96 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3430, 3050, 2953, 2834, 1736, 1618, 1509; ESI MS m/z: 438 [M-H]-, 440 [M+H]+ (C25H29NO6). Compound 11 (0.2 g, 17%), a white solid; m.p. 216-218 °C; 1H-NMR (600 MHz, DMSO) δ: 1.78 (m, 1H, 0.5×CH2), 1.80 (m, 1H, 0.5×CH2), 2.02 (m, 1H, 0.5×CH2), 2.23 (m, 1H, 0.5×CH2), 3.10 (m, 1H, 0.5×CH2N), 3.35 (m, 1H, 0.5×CH2N), 3.94 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.14 (m, 2H, CH2O), 4.34 (d, 1H, J = 13.2 Hz, 0.5×ArCH2N), 4.57 (m, 1H, CHN), 5.33 (d, 1H, J = 13.2 Hz, 0.5×ArCH2N), 7.35 (s, 1H, Ar-H), 7.56 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 8.01 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3423, 3050, 2924, 2850, 1624, 1514; ESI MS m/z: 476 [M-H]-, 478 [M+H]+ (C23H27NO8S).
3.2.10. Synthesis and spectroscopic data of N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (12)
A 250 mL dry three-necked flask fitted with a dropping funnel and a condenser was charged with 5a (2 g, 5.04 mmol) and anhydrous CH2Cl2 (70 mL). The condenser was fitted with a trap to remove the vapors of hydrogen chloride and sulfur dioxide. Freshly distilled SOCl2 (5 mL) in anhydrous CH2Cl2 (30 mL) was added dropwise to the stirred system at 0 °C. After the addition was complete, the mixture was warmed to room temperature and heated to reflux at 45 °C for 1.5 h, after which the reaction system was cooled to room temperature and adjusted to pH 10 with saturated Na2CO3 solution (100 mL) at 0 °C. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL), the combined extracts were washed with saturated brine (200 mL) and dried over anhydrous Na2SO4. After filteration and evaporation in vacuo, the residue was purified by column chromatography on silica gel (PE/EtOAc, 3:1 v/v) to afford 12 (1.78 g, 85%) as an off-white solid; m.p. 184-185 °C; 1H-NMR (300 MHz, CDCl3) δ: 1.67 (m, 2H overlapped, CH2), 1.82 (m, 1H, 0.5×CH2), 2.12 (m, 1H, 0.5×CH2), 2.26 (m, 1H, 0.5×CH2N), 2.41 (m, 1H, 0.5×CH2Cl), 2.72 (m, 1H, 0.5×CH2N), 3.08 (m, 1H, 0.5×CH2Cl), 3.83 (d, 1H, J = 13.2 Hz, 0.5×ArCH2N), 3.97 (d, 1H, J = 13.2 Hz, 0.5×ArCH2N), 3.98 (m, 1H, CHN), 4.03 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 7.17 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.96 (s, 1H, Ar-H); IR (KBr) cm-1 ν: 3442, 3050, 2947, 2832, 1619, 1508; ESI MS m/z: 416 [M+H]+ (C23H26ClNO4).