8
02
Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
sulfate, filtered and concentrated in vacuo. The residue was 1.93–1.85 (m, 1H), 1.48–1.33 (m, 2H), 0.60 (t, J=7.6Hz, 3H).
13
purified with flash column chromatography on silica gel
C-NMR (CDCl ) δ: 167.8, 160.5, 152.2, 151.4, 132.2, 130.0,
3
(
2–5% methanol in dichloromethane) to give 9.08g (21.9mmol, 126.8, 126.1, 123.0, 102.5, 93.8, 75.0, 68.3, 55.2, 54.2, 52.3,
2
2
quant.) of 5 as a white foam. [α] : −3.8° (c=1.55, CHCl ). 52.0, 51.8, 44.2, 43.6, 34.1, 30.1, 8.1. HR-MS (FAB): Calcd for
IR (neat): 3548, 2960, 1738, 1616, 1503, 1456, 1245, 1168, C H N O (M ) 380.2100. Found 380.2104.
D
3
+
2
3
28
2
3
1
−1
1
1
6
(
085, 1041, 822, 752cm . H-NMR (CDCl ) δ: 9.37 (br, 1H),
(3aS,3a S,5aR,10bR)-Methyl
3a-Ethyl-8-hydroxy-6-
.87 (d, J=8.2Hz, 1H), 6.28 (dd, J=8.2, 2.3Hz, 1H), 6.07 methyl-3a,3a ,5a,6,11,12-hexahydro-1H-indolizino[8,1-cd]-
d, J=2.3Hz, 1H), 5.87 (dd, J=10.3, 4.8Hz, 1H), 5.73 (d, carbazole-5-carboxylate (9) To a stirred solution of 8
J=10.3Hz, 1H), 4.08 (d, J=6.6Hz, 1H), 3.84 (s, 3H), 3.78 (s, (77mg, 0.20mmol) in 2.0mL of dichloromethane was added
H), 3.72 (s, 1H), 3.47–3.38 (m, 2H), 2.85 (d, J=15.8Hz, 1H), 2.0mL (2.0mmol) of boron tribromide (1.0M solution in
3
1
3
2
2
1
.73 (s, 3H), 2.66 (s, 1H), 2.60–2.50 (m, 2H), 2.29–2.19 (m, dichloromethane) at −78°C and the resulting mixture was
H), 1.45 (dq, J=14.9, 7.3Hz, 1H), 1.01 (dq, J=14.9, 7.3Hz, stirred for 30min. The reaction mixture was warm up to 0°C
13
H), 0.67 (t, J=7.3Hz, 3H). C-NMR (CDCl ) δ: 173.3, 161.0, and stirred. After 3h, the reaction mixture was added 2mL of
3
153.6, 130.6, 125.0, 123.7, 122.7, 104.2, 95.7, 82.9, 80.7, 73.8, methanol, then partitioned between saturated aqueous sodium
6
7.8, 55.3, 52.8, 52.3, 51.2, 51.0, 44.4, 42.6, 38.6, 32.4, 7.7. bicarbonate and ethyl acetate, and the aqueous layer was
+
HR-MS (FAB): Calcd for C H N O (M ) 414.2155. Found extracted with ethyl acetate 3 times. The combined organic
2
3
30
2
5
4
14.2138.
extracts were washed with brine. The organic layer was dried
1
(3aR,3a R,3bR,6aS,6bR,11bR)-Methyl 3a-Ethyl-9-meth- over anhydrous sodium sulfate, filtered and concentrated in
1
oxy-7-methyl-5-thioxo-3a,3a ,3b,6a,6b,7,12,13-octahydro- vacuo to give a crude product. In the same manner, 123mg
H-[1,3]dioxolo[4,5-a]indolizino[8,1-cd]carbazole-6a-car- (0.323mmol) of 8 in 3.2mL of dichloromethane was reacted
boxylate (6) To a stirred solution of 5 (1.54g, 3.71mmol) in with 3.2mL (3.2mmol) of boron tribromide (1.0M solution of
7mL of acetonitrile was added 2.72g (13.7mmol) of thiocar- dichloromethane) to give another crude product. These crude
1
3
bonyldiimidazole (90% purity) and the resulting mixture was products were purified with flash column chromatography
stirred for 2h at 80°C. The reaction mixture was partitioned on silica gel (50–80% ethyl acetate in hexane) to give 181mg
2
4
between saturated aqueous sodium bicarbonate and ethyl (0.494mmol, 95%) of 9 as a slightly yellow foam. [α] : −98°
D
acetate and the aqueous layer was extracted with ethyl acetate (c=1.14, CHCl ). IR (neat): 2962, 2360, 1710, 1614, 1500, 1383,
3
−1
1
3
times. The combined organic extracts were washed with 1250, 1219, 1083, 1002, 824, 751cm . H-NMR (CDCl ) δ:
3
brine. The organic layer was dried over anhydrous sodium 7.23 (s, 1H), 6.91 (d, J=7.8Hz, 1H), 6.14 (dd, J=7.8, 2.3Hz,
sulfate, filtered and concentrated in vacuo. The residue was 1H), 5.89 (d, J=2.3Hz, 1H), 5.86 (ddd, J=9.8, 4.8, 1.4Hz,
purified with flash column chromatography on silica gel 1H), 5.71 (d, J=9.8Hz, 1H), 4.22 (s, 1H), 3.74 (s, 3H), 3.47
(
8
10–100% ethyl acetate in hexane) to give 1.46g (3.20mmol, (dd, J=14.7, 4.8Hz, 1H), 3.18 (t, J=8.0Hz, 1H), 2.78 (d,
2
2
6%) of 6 as a slightly yellow foam. [α] : +49° (c=0.93, J=14.7Hz, 1H), 2.69 (s, 3H), 2.43–2.37 (m, 1H), 2.37 (s, 1H),
D
CHCl ). IR (neat): 2958, 1746, 1617, 1501, 1456, 1355, 1306, 2.29 (dd, J=12.8, 6.4Hz, 1H), 1.95–1.86 (m, 1H), 1.47–1.33 (m,
1
δ: 6.99 (d, J=8.2Hz, 1H), 6.40 (dd, J=8.2, 2.3Hz, 1H), 6.12 152.3, 151.3, 132.3, 129.5, 126.9, 126.1, 123.2, 104.4, 94.9, 74.9,
3
−1
1
13
265, 1221, 1087, 1041, 977, 831, 753cm . H-NMR (CDCl ) 2H), 0.60 (t, J=7.3Hz, 3H). C-NMR (CDCl ) δ: 167.8, 156.6,
3
3
(d, J=2.3Hz, 1H), 5.98 (ddd, J=9.8, 4.1, 1.8Hz, 1H), 5.32 (dt, 68.3, 54.2, 52.3, 52.1, 51.8, 44.2, 43.6, 34.1, 30.1, 8.1. HR-MS
+
J=9.8, 2.3Hz, 1H), 3.95 (s, 3H), 3.85 (s, 1H), 3.77 (s, 3H), 3.53 (FAB): Calcd for C H N O (M ) 366.1943. Found 366.1932.
2
2
26
2
3
1
(
1
7
3
ddd, J=16.7, 4.1, 2.3Hz, 1H), 3.32 (s, 1H), 2.71 (dt, J=16.7,
.8Hz, 1H), 2.64 (s, 3H), 2.40–2.30 (m, 5H), 1.80 (dq, J=14.7, ((methylsulfonyl)oxy)-3a,3a ,5a,6,11,12-hexahydro-1H-
.4Hz, 1H), 1.17 (dq, J=14.7, 7.4Hz, 1H), 0.28 (t, J=7.4Hz, indolizino[8,1-cd]carbazole-5-carboxylate (10) To a stirred
(3aS,3a S,5aR,10bR)-Methyl
3a-Ethyl-6-methyl-8-
1
13
H). C-NMR (CDCl ) δ: 190.2, 169.6, 160.7, 152.9, 129.8, solution of 9 (563mg, 1.54mmol) and 0.43mL (3.1mmol)
3
128.8, 127.3, 123.5, 105.9, 97.1, 87.7, 84.8, 76.2, 70.6, 55.4, of triethylamine in 15.4mL of dichloromethane was added
5
4.4, 53.7, 53.0, 51.5, 43.7, 42.2, 39.2, 27.9, 7.8. HR-MS (FAB): 0.18mL (2.3mmol) of methanesulfonyl chloride. After 5min,
+
Calcd for C H N O S (M ) 456.1719. Found 456.1728.
the reaction mixture was partitioned between dichlorometh-
3a-Ethyl-8-methoxy-6- ane and saturated sodium bicarbonate. The aqueous layer
2
4
28
2
5
1
(
3aS,3a S,5aR,10bR)-Methyl
1
methyl-3a,3a ,5a,6,11,12-hexahydro-1H-indolizino[8,1-cd]- was extracted with dichloromethane twice. The combined or-
carbazole-5-carboxylate (8) To a stirred solution of 6 ganic extracts were washed with brine, dried over anhydrous
(
4.77g, 10.4mmol) in 104mL of o-dichlorobenzene was added sodium sulfate, filtered and concentrated in vacuo. The residue
.12g (41.8mmol) of 1,3-dimethyl-2-phenyl-1,3,2-diazaphos- was purified by flash column chromatography on silica gel
pholidine (7) and the resulting mixture was heated at 160°C (3% methanol in dichloromethane) to give 685mg (1.54mmol,
8
1
8
for 2.5h. The reaction mixture was purified with flash col- quant.) of 10 as a slightly yellow foam. [α] : −112° (c=0.58,
D
umn chromatography on silica gel (100% hexane; 10–100% CHCl ). IR (neat): 2961, 1710, 1611, 1496, 1438, 1367, 1255,
3
−1 1
ethyl acetate in hexane) to give 3.61g (9.49mmol, 91%) of 1185, 1140, 1084, 961, 908, 816, 753cm . H-NMR (CDCl ) δ:
as a white foam. [α] : −105° (c=1.86, CHCl ). IR (neat): 7.26 (s, 1H), 7.07 (d, J=8.0Hz, 1H), 6.56 (dd, J=8.0, 2.1Hz,
958, 1711, 1618, 1498, 1436, 1253, 1147, 1085, 1001, 819, 767, 1H), 6.26 (d, J=2.1Hz, 1H), 5.87 (ddd, J=9.9, 5.1, 1.4Hz,
38cm . H-NMR (CDCl ) δ: 7.24 (s, 1H), 6.99 (d, J=8.0Hz, 1H), 5.69 (d, J=9.9Hz, 1H), 4.31 (s, 1H), 3.78 (s, 3H), 3.47
H), 6.24 (dd, J=8.0, 2.3Hz, 1H), 5.97 (d, J=2.3Hz, 1H), 5.86 (dd, J=16.2, 4.3Hz, 1H), 3.20 (t, J=8.0Hz, 1H), 3.13 (s, 3H),
ddd, J=9.8, 4.8, 1.4Hz, 1H), 5.70 (d, J=9.8Hz, 1H), 4.22 (s, 2.79 (d, J=16.2Hz, 1H), 2.73 (s, 3H), 2.45–2.42 (m, 1H), 2.37
3
2
5
8
2
6
1
(
1
D
3
−1 1
3
H), 3.78 (s, 3H), 3.77 (s, 3H), 3.46 (dd, J=16.0, 4.8Hz, 1H), (s, 1H), 2.32 (dd, J=12.8, 6.4Hz, 1H), 1.95–1.87 (m, 1H),
13
3
2
.18 (t, J=8.0Hz, 1H), 2.78 (d, J=16.0Hz, 1H), 2.72 (s, 3H), 1.45–1.29 (m, 2H), 0.60 (t, J=7.6Hz, 3H). C-NMR (CDCl3)
.43–2.39 (m, 1H), 2.37 (s, 1H), 2.30 (dd, J=12.8, 6.4Hz, 1H), δ: 167.6, 152.2, 151.6, 150.1, 136.5, 132.0, 126.3, 126.1, 123.4,