Helvetica Chimica Acta Vol. 86 (2003)
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(m, 2 H); 7.48 7.35 ( m, 1 H); 5.92 5.75 (m, 1 H); 5.35 5.10 (m, 2 H); 3.94 3.72 (m, 2 H); 3.71 3.51
(m, 2 H); 3.07 (br., 1 H); 2.80 2.68 (m, 2 H); 2.67 2.58( m, 2 H). 13C-NMR (CDCl3): 164.3, 143.5 (2s);
132.6, 132.1, 128.2, 128.1 (4d); 126.6 (s); 123.7 (d); 120.0 (t); 118.1, 70.2 (2s); 57.0, 44.5, 43.9, 16.4 (4t). CI-MS:
274 (100, [M NH4] ), 257 (21, [M 1] ).
3,4-Dihydro-4-hydroxy-1-oxo-4-(2-oxoethyl)isoquinoline-2(1H)-propanenitrile (5). A soln. of 6 (0.530 g,
2.07 mmol) in MeOH (30 ml) was cooled to À 788, and then an excess of ozone was passed through the mixture
( ! deep blue soln. when saturated with ozone). After the mixture was purged with N2 for 20 min at À 788, it
was treated with Me2S (2 ml). The cold bath was removed, and the mixture was allowed to warm to r.t. and
stirred for 2 h. Evaporation provided crude 5, which was purified by CC (CH2Cl2/MeOH 30 :1): 5 (0.43 g, 80%).
Colorless oil. IR (film): 3382s, 2928w, 2251w, 1717s, 1650s, 1603m, 1578m, 1487m, 1424m, 1324m, 1297m, 1237w,
1162w, 1130w, 1094w, 1030m, 953w, 768w, 704w. 1H-NMR (CDCl3): 9.77 (t, 1 H); 7.99 7.91 (m, 1 H); 7.64 7.50
(m, 2 H); 7.44 7.36 (m, 1 H); 4.80 (br., 1 H); 3.89 3.75 (m, 2 H); 3.72 3.59 (m, 2 H); 2.90 (d, 2 H); 2.78 2.65
(m, 2 H). 13C-NMR (CDCl3): 201.5 (d); 164.2, 143.1 (2s); 132.9, 128.3, 128.2 (3d); 126.3, 123.6, 118.3, 69.9 (4s);
56.9, 51.1, 44.1, 16.3 (4t). CI-MS: 276 (100, [M NH4] ), 259 (10, [M 1] ), 248(15), 232 (44), 215 (11).
Methyl (bS)-b-{{2-[2-(2-Cyanoethyl)-1,2,3,4-tetrahydro-4-hydroxy-1-oxoisoquinolin-4-yl]ethyl}amino}ben-
zenepropanoate (11). To a soln. of 4 (0.316 g, 1.76 mmol) in dry MeOH (15 ml) was added 5n HCl/MeOH
(0.71 ml, 3.53 mmol), followed by 5 (0.455 g, 1.76 mmol) and NaBH3CN (0.138g, 2.20 mmol). The mixture was
stirred at r.t. for 12 h. The residue obtained after evaporation was purified by CC (CH2Cl2/MeOH 30 :1): 11
(0.564 g, 75%). Colorless oil. IR (film): 3291s, 2952m, 2855m, 2250w, 1732s, 1651s, 1603m, 1578w, 1477m, 1435m,
1366w, 1317m, 1293m, 1195w, 1164m, 1130w, 1082w, 1029w, 919w, 8 45w, 766m, 702m. 1H-NMR (CDCl3): 8.01
7.98( m, 1 H); 7.66 7.55 (m, 1 H); 7.49 6.98( m, 7 H); 4.12 3.98( m, 1 H); 3.95 3.10 (m, 8H); 2.92 2.45
(m, 6 H); 2.04 1.78( m, 2 H). 13C-NMR (CDCl3): 171.8, 164.5, 145.2, 144.8, 140.8, 140.7 (6s); 132.4, 131.9, 128.7,
128.0, 127.8, 127.7, 127.4, 127.3, 127.2, 127.0 (10d); 126.1 (s); 124.3, 124.1 (2d); 118.2, 118.0, 72.0, 71.8 (4s); 59.7,
59.6 (2d); 58.8, 56.9 (2t); 51.8( q); 44.3, 44.2, 43.1, 42.8, 41.5, 41.1, 37.5, 37.1, 16.5, 16.4 (10t). CI-MS: 422 (100,
[M 1] ), 404 (15), 306 (35), 260 (12), 232 (26), 206 (28), 180 (11).
Methyl (bS)-b-{{2-[2-(3-Aminopropyl)-1,2,3,4-tetrahydro-4-hydroxy-1-oxoisoquinolin-4-yl]ethyl}amino}-
benzenepropanoate (12). To a soln. of 11 (0.535 g, 1.27 mmol) in EtOH was added 32% aq. HCl soln. (0.32 g,
2.81 mmol) and PtO2 (0.100 g). The hydrogenation was carried out at r.t./50 psi H2 for 6 h. Then the mixture was
¾
filtered through a pad of Celite . The filtrate was evaporated and the residue purified by CC (CH2Cl2/MeOH/
25% aq. NH4OH soln. 90 :10 :1): 12 (0.471 g, 87%). Colorless oil. IR (CHCl3): 3300m, 3000m, 2940m, 2880m,
1730s, 1640s, 1600m, 1580m, 1490m, 1475m, 1440m, 1300m, 1260w, 1160w, 1120s, 1010w, 700m. 1H-NMR
(CDCl3): 7.99 7.88 (m, 1 H); 7.62 7.47 (m, 1 H); 7.44 6.96 (m, 7 H); 4.09 3.94 (m, 1 H); 3.72, 3.67 (2s, 3 H);
3.65 3.36 (m, 4 H); 3.30 2.94 (m, 3 H); 3.24, 2.98(2 d, 1 H); 2.88 2.40 (m, 6 H); 1.95 1.46 (m, 4 H).
13C-NMR (CDCl3): 171.9, 171.8, 164,1, 164.0, 144.8, 144.0, 140.8, 140.7 (8s); 131.8, 131.4, 128.7, 128.7, 127.9, 127.8,
127.3, 127.2, 127.1, 127.0 (10d); 126.9 (s); 123.9, 123.7 (2d); 71.9, 71.7 (2s); 59.8, 59.7 (2d); 56.8, 55.3 (2t); 51.7 (q);
44.2, 44.1, 43.0, 42.7, 41.6, 41.2, 38.8, 37.4, 37.1, 30.8 (10t). CI-MS: 426 (100, [M 1] ), 408(15), 292 (10), 278
(30), 264 (90), 246 (75).
()-(9S,13R)- and ()-(9S,13S)-13-Hydroxyisocyclocelabenzine ((9S,13R)- and (9S,13S)-
3,4,5,6,8,9,10,11,12,13-Decahydro-13-hydroxy-9-phenyl-2,13-methano-2H-2,6,10-benzotriazacyclopentadecine-
1,7-dione, resp.; 3a and 3b, resp.). A soln. of 12 (0.330 g, 0.776 mmol) and LiOH ¥ H2O (35.8mg, 0.853 mmol) in
THF/MeOH/H2O 3 :1 :1 (10 ml) was stirred at r.t. for 4 h, and the solvent was evaporated. The residue was
dissolved in EtOH (10 ml) and the soln. evaporated; this process was repeated twice. After further drying under
h.v., the residue was dissolved in dry DMF (50 ml) and added to a soln. of (EtO)2POCN (0.190 g, 1.16 mmol)
and Et3N (2 ml) in DMF (100 ml) at r.t. within 5 h. The mixture was stirred at r.t. for another 24 h and
evaporated. The residue was dissolved in sat. aq. NaHCO3 soln. and extracted with CH2Cl2. The combined org.
phase was evaporated and the residue purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 90 :10 :1): 3a/3b
(185 mg, 60%), 1:1 by NMR. IR (CHCl3): 3306s, 3064w, 2926m, 2853m, 1728w, 1638s, 1603w, 1550w, 1492w,
1449w, 1430w, 1309m, 1236w, 1160w, 1113m, 1038w, 8 77w, 765m, 702m. ESI-MS: 416 ([M Na] ).
The two epimers were separated by repeated FC (CH2Cl2/MeOH/25% aq. NH4OH soln. 94 :6 :0.6):
optically pure, natural 13-hydroxyisocyclocelabenzine (3a; 80 mg) and 3b (85 mg).
Data of 3a: Colorless solid. M.p. 136 1388. [a]D 108( c 0.93, CHCl3). 1H-NMR (CDCl3): 8.03 (d, J
7.7, 1 H ): 7.88 ( t, 1 H); 7.58( d, J 7.1, 1 H); 7.50 (t, J 7.5, 1 H); 7.34 (t, J 7.6, 1 H); 7.12 7.03 (m, 3 H); 6.73
6.66 (m, 2 H); 4.05 3.91 (m, 3 H); 3.90 3.78( m, 2 H); 3.60 (d, J 12.3, 1 H); 2.98 2.82 ( m, 1 H); 2.71 (t, J
11.2, 1 H); 2.48 2.35 ( m, 1 H); 2.34 2.23 (m, 2 H); 2.17 (t, J 12.4, 1 H); 1.85 1.55 (m, 3 H). 13C-NMR
(CDCl3): 172.4, 164.9, 145.9, 142.9 (4q); 132.5, 128.4, 127.8, 126.9, 125.9, 123.6 (7d); 70.3 (q); 61.5 (d); 53.7, 45.5,
43.6, 42.9, 40.9, 38.2, 24.1 (7t).