ࡱ> `b_9 R?Nbjbj:4 lnnn8\;6**@@@@@@:<<<<<<$q  v`@@@@@`@@@@@:@:::@ \+>rn\:: 0;: x : Supporting Information Concise Enantiospecific Synthesis of a Coccimellied Alkaloid, (-)-Adakinine Organic Letters Toshio Honda* Mika Kimura Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan General Experimental Procedures. IR spectra were recorded as thin films. 1H NMR and 13C NMR spectra were obtained for a solution in CDCl3, and chemical shifts are reported on the d-scale from TMS as an internal standard. 13C multiplicities were determined with the aid of an APT sequence, separating methylene and quaternary carbons = up, from methyl and methine carbons = down. Ethyl (S)-(-)-2-pyrrolidinethione-5-carboxylate 3: A stirred solution of ethyl (S)-(-)-2-pyrrolidinone- 5-carboxylate 2 (5 g, 31.8 mmol) and phosphorus pentasulfide (4.3 g, 19.1 mmol) in THF (400 mL) was heated at reflux for 23 h. After being cooled to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was treated with saturated aqueous NaHCO3. The resulting whole mixture was extracted with CHCl3 and the extract was dried (Na2SO4). Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel. Elution with hexane / Et2O (1 / 1, v/v) gave thioamide 3 (4.78 g, 87%) as a pale yellowish oil. IR 3300, 3180, 1740, 1510 cm-1; 1H NMR d 1.31 (3H, t, J = 7.1 Hz), 2.29 - 2.64 (2H, m), 2.86  3.08 (2H, m), 4.26 (2H, q, J = 7.1 Hz), 4.52 (1H, dd, J = 6.3 and 8.7 Hz), 8.14 (1H, br s). 5(S)-Ethoxycarbonyl-2-(2-oxopropylthio)-1,2-dehydropyrrolidine 4: To a stirred solution of thioamide 3 (2 g, 11.6 mmol) in CH2Cl2 (20 mL) was added bromoacetone (1 mL, 11.9 mmol) at ambient temperature, and the mixture was stirred for further 3 h under evaporation of the solvent in vacuo. The mixture was partitioned between CH2Cl2 (20 mL) and saturated KHCO3 solution (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with hexane / Et2O (1 / 3, v/v) as eluent to afford thio-ether 4 (2.46 g, 93%) as a yellowish oil. [a]D +49.9 (c 1.1, CHCl3); IR 1740, 1590 cm-1; 1H NMR d 1.29 (3H, t, J = 7.1 Hz), 2.15  2.40 (2H, m), 2.31 (3H, s), 2.54  2.87 (2H, m), 3.93 (1H, d, J = 16.2 Hz), 4.01 (1H, d, J = 16.2 Hz), 4.19 (2H, q, J = 7.1 Hz), 4.65 (1H, distorted t, J = 7.3 Hz); 13C NMR d up: 27.8, 38.2, 41.2, 60.9, 172.4, 174.5, 202.7; down: 14.1, 28.8, 73.2; HRMS (EI) Calcd for C10H15NO3S (M +) 229.0772. Found 229.0784. Ethyl (S)-(Z)-5-(acetonylidene)pyrrolidine-2-carboxylate 5: To a stirred solution of thio-ether 4 (2.2 g, 9.61 mmol) and Ph3P (10 g, 38.4 mmol) in benzene (80 mL) was added N-methylpiperidine (4.7 mL, 38.4 mmol) at ambient temperature under argon, and the mixture was heated at reflux for 24 h. After evaporation of the solvent, the residue was partitioned between CH2Cl2 (50 mL) and 2N H3PO4 (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with hexane / Et2O (1 / 1, v/v) as eluent to afford enaminone 5 (1.29 g, 68%) as a yellowish oil. [a]D  182.4 (c 1.1, CHCl3); IR 3300, 1740, 1630, 1560 cm-1; 1H NMR d 1.29 (3H, t, J = 7.1 Hz), 2.05 (3H, s), 2.09  2.37 (2H, m), 2.55  2.79 (2H, m), 4.23 (2H, q, J = 7.1 Hz), 4.41 (1H, dd, J = 5.1 and 8.4 Hz), 5.16 (1H, s), 9.89 (1H, br s); 13C NMR d up: 25.5, 31.1, 61.5, 165.6, 171.5, 195.9; down: 14.1, 28.6, 60.9, 90.9; HRMS (EI) Calcd for C10H15NO3 (M+) 197.1052. Found 197.1068. Ethyl (S)-(E)-1-tert-butoxycarbonyl-5-(acetonylidene)pyrrolidine-2-carboxylate 6: To a stirred solution of DMAP (1.7 g, 13.5 mmol), Boc2O (8.0 mL, 27.0 mmol), and Et3N (1.9 mL, 13.5 mmol) in CH2Cl2 (70 mL) was added a solution of enaminone 5 (2.66 g, 13.5 mmol) in CH2Cl2 (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for further 15 h. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel with hexane / Et2O (1 / 1, v/v) as eluent to afford N-Boc derivative 6 (3.88 g, 97%) as colorless needles. M.p. 63-65.5C; [a]D +29.4 (c 1.1, CHCl3); IR 1745, 1735, 1670, 1590 cm-1; 1H NMR d 1.28 (3H, t, J = 7.1 Hz), 1.49 (9H, s), 1.95 - 2.28 (1H, m), 2.17 (3H, s), 2.94  3.08 (1H, m), 3.01 (1H, dddd, J = 1.2, 9.2, 9.2, and 18.5 Hz), 3.42 (1H, dddd, J = 1.5, 3.5, 9.1, and 18.5 Hz), 4.18 (2H, q, J = 7.1 Hz), 4.58 (1H, dd, J = 3.3 and 9.4 Hz), 7.27 (1H, s); 13C NMR d up: 25.5, 30.7, 61.4, 83.0, 151.0, 156.3, 171.6, 198.5; down: 14.2, 28.0(3), 32.0, 62.0, 104.7; HRMS (EI) Calcd for C15H23NO5 (M+) 297.1576. Found 297.1568. Anal. Calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.39; H, 7.75; N, 4.64. Ethyl (S)-1-tert-butoxycarbonyl-5-(2-oxopropyl)-5-pentylpyrrolidine-2-carboxylate 7: To a stirred solution of copper(I) bromide dimethyl sulfide complex (620 mg, 3.0 mmol) in THF (10 mL) at -78C was added a solution of 2.0 M pentylmagnesium bromide in Et2O (2.0mL, 4.0 mmol) under argon, and the resulting mixture was stirred for 1 h. To this mixture was added boron trifluoride etherate (0.4 mL, 3.0 mmol) at the same temperature. After stirring for 5 min, a solution of the enaminone 6 (300 mg, 1.0 mmol) in THF (4mL) was added to the above mixture and the whole was stirred for further 16 h at the same temperature. The mixture was treated with a mixture of 20% NH4Cl solution - 25% ammonium hydroxide solution (50 mL, 1:1, v/v) and extracted with a mixture of Et2O EtOAc. The extract was washed with brine, dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with hexane / Et2O (20 / 1, v/v) as eluent to give the adduct 7 (330 mg, 87%) as a yellowish oil, as a ca. 1:1 mixture of the rotation isomer of carbamates. [a]D -20.5 (c 1.1, CHCl3); IR 1750, 1700 cm-1; 1H NMR d 0.86 (1.5H, t, J = 6.4 Hz), 0.88 (1.5H, t, J = 6.4 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.22 2.20 (15H, m), 1.41 (9H, s), 2.64 3.51 (2H, m), 4.11 4.37 (3H, m). HRMS (EI) Calcd for C20H35NO5 (M+) 369.2515. Found 369.2498. Anal. Calcd for C20H35NO5: C, 65.01; H, 9.55; N, 3.79. Found: C, 65.28; H, 9.68; N, 3.63. Ethyl (S)-1-tert-butoxycarbonyl-5-(2-hydroxypropyl)-5-pentylpyrrolidine-2-carboxylate 8: To a stirred solution of ketone 7 (0.5 g, 13.6 mmol) in EtOH (10 mL) was added portionwise NaBH4 (50 mg, 13.6 mmol) at 0C, and the mixture was stirred at the same temperature for further 8 h. After evaporation of the solvent, the residue was partitioned between CH2Cl2 (50 mL) and saturated NH4Cl solution (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with hexane / EtOAc (8 / 1, v/v) as eluent to give an inseparable diastereoisomeric mixture of alcohol 8 (0.5 g, 100%) as a colorless oil. [a]D  23.6 (c 0.7, CHCl3); IR 3490, 1750, 1730, 1705, 1685 cm-1; 1H NMR d 0.85  0.89 (3H, m), 1.40 (9H, s), 1.18  2.71 (21H, m), 4.15  4.43 (4H, m). HRMS (EI) Calcd for C20H37NO5 (M+) 371.2671. Found 371.2654. Ethyl (S)-5-(2 -hydroxypropyl)-5-pentylpyrrolidine-2-carboxylate 9: To a stirred solution of N-Boc compound 8 (670 mg, 1.8 mmol) in CH2Cl2 (8.4 mL) was added TFA (2.4 mL, 29.6 mmol) at room temperature and the resulting mixture was stirred for 2 h at the same temperature. After evaporation of the solvent, the residue was basified with 5% NH4OH solution and extracted with CH2Cl2. The extract was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with hexane / EtOAc (3 / 2, v/v) as eluent to give an inseparable diastereoisomeric mixture of alcohol 9 (430 mg, 94%) as a colorless oil. [a]D  7.1 (c 1.0, CHCl3); IR 3420, 1740 cm-1; 1H NMR d 0.89 (3H, t, J = 6.9 Hz), 1.14 (1.5H, br d, J = 6.3Hz), 1.15 (1.5H, br d, J = 6.3Hz), 1.23  2.27 (18H, m), 3.76  4.23 (5H, m); 13C NMR d up: 22.5, 22.6, 24.0, 24.8, 29.4, 29.5, 32.2, 32.3, 32.8, 38.2, 39.0, 43.4, 44.9, 45.1, 60.8, 60.9, 64.6, 65.5, 173.7, 174.4; down: 14.0(2), 14.1(2), 24.0, 24.3, 58.6, 60.0, 64.5(2). HRMS (EI) Calcd for C15H29NO3 (M+) 271.2147. Found 271.2163. Ethyl (S)-5-(2-tert-butyldimethylsiloxypropyl)-5-pentylpyrrolidine-2-carboxylate 10: To a stirred solution of alcohol 9 (110 mg, 0.41 mmol), DMAP (50 mg, 0.41 mmol), and triethylamine (0.1 mL, 1.4 mmol) in CH2Cl2 (3 mL) was added a solution of TBDMSCl (100 mg, 0.61 mmol) in CH2Cl2 (2 mL) at ambient temperature under argon and the resulting solution was stirred for 48 h. The mixture was treated with saturated NH4Cl solution and extracted with CH2Cl2. The extract was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with hexane / EtOAc (10 / 1, v/v) as eluent to give an inseparable diastereoisomeric mixture of silyl ether 10 (140 mg, 91%) as a colorless oil. [a]D  8.9 (c 1.1, CHCl3); IR 3380, 1735 cm-1; 1H NMR d 0.06  0.10 (6H, m), 0.86  0.95 (12H, m), 1.15  2.22 (20H, m), 2.50 (1H, br s), 3.70  3.84 (1H, m), 3.96  4.09 (1H, m), 4.16 (1H, q, J = 7.1 Hz), 4.18 ((1H, q, J = 7.1 Hz); 13C NMR d up: 17.9, 22.6, 24.2, 24.4, 24.7, 29.6, 30.2, 30.4, 32.6, 36.7, 36.9, 37.1, 39.3, 39.7, 47.4, 48.3, 48.5, 60.6, 60.7, 64.0, 64.4, 64.7, 175.4; down: -4.5, -3.8, 14.1, 14.2, 25.5, 25.6, 59.3, 59.9, 66.3, 66.4. HRMS (EI) Calcd for C21H43NO3Si (M+) 385.3012. Found 385.3020. 6-(2-tert-Butyldimethylsiloxypropyl)-6-pentyl-2-piperidone 11: To a stirred suspension of samarium metal (1.15 g, 7.6 mmol) in THF (2 mL) was added a solution of 1,2-diiodoethane (2.13 g, 7.6 mmol) in THF (11.7 mL) under argon at ambient temperature, and the solution was diluted with THF (18 mL), and then stirred for further 30 min. After adding HMPA (5.6 mL, 32.2 mmol), the resulting solution was stirred for 10 min at the same temperature. This solution was added slowly to a stirred solution of ester 11 (0.59 g, 1.5 mmol) in THF (5.8 mL) at 0C, and then a solution of pivalic acid (0.4 g, 3.8 mmol) in THF (2 mL) was also added to the mixture under argon. The mixture was allowed to warm to room temperature gradually, and stirred for 4 h at the same temperature. The mixture was treated with saturated NaHCO3 solution (2 mL), Celite (10 g), and CHCl3 MeOH (50 mL, 8 / 1, v/v). Insoluble materials were filtered off, and the filtrate was treated with NaCl (5 g) and 20% NH4OH solution (20 mL). The organic layer was separated, washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue, which was taken up with benzene and heated at 60C, and then purified by column chromatography on silica gel with hexane / EtOAc (5 / 2, v/v) as eluent to afford a diastreoisomeric mixture of piperidone derivative 11 (0.97 g, 70%) as a colorless oil. [a]D  0.6 (c 1.5, CHCl3); IR 3200, 1665 cm-1; 1H NMR d 0.08 (3H, br s), 0.13 (1.5H, s), 0.14 (1.5H, s), 0.81  0.93 (3H, m), 0.88 (4.5H, s), 0.94 (4.5H, s), 1.17 (3H, d, J = 5.9 Hz), 1.26 1.34 (6H, m), 1.43 1.81 (8H, m), 2.17 2.35 (2H, m), 3.96 4.00 (0.5H, m), 4.09 4.14 (0.5H, m); HRMS (EI) calcd for C19H39NO2Si (M+) 341.2750. Found 341.2771. 6-(2-Hydroxypropyl)-6-pentyl-2-piperidone 12: To a stirred solution of silyl ether 11 (68 mg, 0.20 mmol) in THF (2 mL) was added conc. HCl (2 drops) at ambient temperature, and the mixture was stirred for 1.5 h at the same temperature. The mixture was treated with saturated NaHCO3 solution and extracted with CHCl3. The extract was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with CHCl3 / MeOH (25 / 1, v/v) as eluent to give an diastereoisomeric mixture of alcohol 12 (44 mg, 97%) as a colorless oil. [a]D  6.9 (c 1.6, CHCl3); IR 3310, 1645 cm-1; 1H NMR d 0.87 (1.5H, br t, J = 7.1 Hz), 0.88 (1.5H, br t, J = 7.1 Hz), 1.21 (3H, d, J = 6.1 Hz), 1.20  1.80 (14H, m), 2.18  2.35 (2H, m), 3.75 (0.5H, br s), 3.92  4.02 (0.5H, m), 4.06  4.17 (0.5H, m), 5.14 (0.5H, s), 6.96 (0.5H, s), 7.83 (0.5H, s); 13C NMR d up: 16.7, 17.0, 22.5(2), 23.2, 24.0, 30.5, 30.7, 31.4, 31.7, 32.09, 32.13, 37.5, 41.6, 46.8, 47.4, 56.7, 57.1, 171.7. 172.9; down: 13.9(2), 25.2, 25.3, 64.0, 64.5; HRMS (EI) calcd for C13H25NO2 (M+) 227.1885. Found 227.1882. (-)-Adalinine 1: To a stirred solution of alcohol 12 (0.06 g, 0.25 mmol) and NMO (0.04 g, 0.37 mmol) in CH2Cl2 (2.2 mL) in the presence of molecular sieves 4A (0.06 g) was added TPAP (0.02 g, 0.49 mmol) at room tempetature under argon. After stirring for 20 min, the insoluble material was filtered off through a pad of Celite, and the filtrate was treated with saturated Na2SO3 solution, and extracted with CH2Cl2. The extract was dried (Na2SO4) and concentrated to leave a residue, which was purified by column chromatography on silica gel with CHCl3 / EtOAc (1 / 1, v/v) as eluent to give (-)-adalinine 1 (59 mg, 100%) as a colorless oil. [a]D  30.4 (c 0.8, CH2Cl2); IR 3380, 3200, 1709, 1659 cm-1; 1H NMR d 0.88 (3H, t, J = 6.9 Hz), 1.11  1.33 (6H, m), 1.52  1.91 (6H, m), 2.15 (3H, s), 2.22  2.38 (2H, m), 2.64 (1H, d, J = 17.6 Hz), 2.73 (1H, d, J = 17.6 Hz), 6.77 (1H, br s); 13C NMR d up: 17.1, 22.4, 23.7, 31.1, 31.6, 31.8, 39.2, 51.2, 56.1, 171.5. 207.2; down: 13.8, 31.3; HRMS (EI) calcd for C13H23NO2 (M+) 225.1729. Found 225.1738. .  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