Page 5 of 7
The Journal of Organic Chemistry
1
quenched with saturated aqueous NH
ture was extracted with CH Cl (2 x 5 mL). The combined organic
layers were washed with water (5 mL) and brine (5 mL), and dried
over anhydrous MgSO . Filtration and evaporation in vacuo furnished
the crude product, which was purified by column chromatography
silica gel, 5% MeOH in CH Cl ) to provide 11 (5.7 mg, 16%) as a
brown oil: IR (film, cm ) n 2937, 2866, 1601, 1554, 1496, 1444,
4
Cl (5 mL), and the whole mix-
1196; H NMR (400 MHz, CDCl
3
) d 3.62 (td, J = 10.8, 4.0 Hz, 1H),
1
2
3
4
5
6
7
8
9
2
2
3.32–3.24 (m, 2H), 2.86 (td, J = 12.0, 4.0 Hz, 1H), 2.80 (td, J = 12.0,
4.0 Hz, 1H), 2.68 (dtd, J = 14.8, 11.2, 2.0 Hz, 1H), 2.41–2.34 (m,
3H), 2.01–1.94 (m, 3H), 1.85 (m, 1H), 1.61 (tt, J = 12.0, 9.4 Hz, 1H),
1.17 (m, 1H); 13C{
107.8, 53.4, 46.3, 37.0, 33.4, 29.9, 26.7, 24.0, 22.8; HRMS (EI) m/z
calcd for C11
6a-Ethyl-1,2,4,5,6,6a,7,8-octahydro-9H-pyrrolo[3,2,1-ij]quinolin-
9-one (9).8a,j
solution of LiHMDS (0.88 mL, 0.83 in
THF/hexane, 0.73 mmol) was added to a solution of 8 (120 mg, 0.67
mmol) in THF (6.7 mL) at −78 °C. After stirring at −78 °C for 1 h,
ethyl iodide (0.27 mL, 3.35 mmol) was added to the mixture and the
whole was allowed to warm to room temperature over 1.5 h. The
4
1
3
H} NMR (100 MHz, CDCl ) d 190.8, 169.5,
(
2
2
−1
+
H15NO (M ) 177.1154, found 177.1147.
1
1352, 1298, 1244, 1173, 946, 908; H NMR (400 MHz, CDCl
.78 (m, 1H), 5.25 (dd, J = 10.4, 2.4 Hz, 1H), 5.21 (dd, J = 17.2, 2.4
Hz, 1H), 3.80 (d, J = 5.0 Hz, 2H), 3.58–3.43 (m, 2H), 2.78–2.72 (m,
3
) d
5
A
M
2
1
H), 2.43–2.35 (m, 2H), 2.20 (m, 1H), 2.05 (dt, J = 13.6, 3.2 Hz, 1H),
.95 (tt, J = 13.6, 5.0 Hz, 1H), 1.69–1.49 (m, 2H), 1.05 (t, J = 7.6 Hz,
3H); 13C{ H} NMR (100 MHz, CDCl
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
) d 190.5, 171.7, 132.4, 117.7,
1
08.4, 51.0, 48.7, 33.3, 31.3, 25.0, 23.8, 23.2, 12.4; HRMS (FAB) m/z
reaction mixture was quenched with saturated aqueous NH
and the whole mixture was extracted with CH Cl (2 x 5 mL). The
combined organic layers were washed with water (5 mL) and brine (5
mL), and dried over anhydrous MgSO . Filtration and evaporation in
vacuo furnished the crude product, which was purified by column
chromatography (silica gel, 5% MeOH in CH Cl ) to provide 9 (123
mg, 88%) as a pale yellow solid: mp 63–64 °C; IR (KBr, cm ) n
4
Cl (5 mL),
+
calcd for C13
H
20NO (M+H) 206.1545, found 206.1541.
2
2
Intramolecular/intermolecular alkylation sequence (route B). 1-
3-Hydroxy)propyl-2,3,6,7-tetrahydro-1H-indol-4(5H)-one (5b). 3-
(
4
Amino-1-propanol (4b) (535 mg, 7.12 mmol) was added to a solution
of spirocyclopropane 3a (492 mg, 3.56 mmol) in THF (7 mL). After
stirring at 50 °C for 2.5 h, the reaction mixture was concentrated in
vacuo, and the residue was purified by column chromatography (silica
2
2
−1
1
2940, 2860, 1551, 1522, 1463, 1439, 1355, 1302, 1267, 1192;
H
gel, 11% MeOH in CH
yellow solid: mp 80–81 °C; IR (KBr, cm ) n 3398, 2939, 2869, 1585,
2
Cl
2
) to provide 5b (630 mg, 91%) as a pale
NMR (400 MHz, CDCl ) d 3.60 (ddd, J = 11.2, 10.4, 3.6 Hz, 1H),
3
–1
3.30 (dd, J = 11.2, 5.2 Hz, 1H), 3.17 (q, J = 10.4 Hz, 1H), 2.85–2.74
(m, 2H), 2.62 (dt, J = 14.8, 11.2 Hz, 1H), 2.44 (ddd, J = 17.6, 13.2,
2.8 Hz, 1H), 2.27 (ddd, J = 17.6, 5.2, 2.4 Hz, 1H), 1.99 (dd, J = 4.4,
2.0 Hz, 1H), 1.96 (dd, J = 5.2, 2.0 Hz, 1H), 1.90 (dt, J = 13.4, 3.2 Hz,
1H), 1.79 (m, 1H), 1.71–1.63 (m, 2H), 1.55 (tdd, J = 13.4, 5.2, 1.2 Hz,
1
1
3
535, 1511, 1439, 1290, 1190; H NMR (400 MHz, CDCl ) d 3.96 (s,
1H), 3.65 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 9.6 Hz, 2H), 3.37 (t, J = 6.4
Hz, 2H), 2.75 (t, J = 9.6, 2H), 2.39 (t, J = 6.2 Hz, 2H), 2.27 (t, J = 6.2
Hz, 2H), 1.97 (quint, J = 6.4 Hz, 2H), 1.80 (quint, J = 6.2 Hz, 2H);
13
1
13
1
C{ H} NMR (100 MHz, CDCl
3
) d 190.5, 169.6, 108.6, 58.7, 51.4,
1H), 1.13 (td, J = 13.2, 3.6 Hz, 1H), 0.89 (t, J = 7.6 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) d 190.1, 174.8, 107.7, 53.9, 47.2, 35.0, 33.6,
32.5, 28.7, 25.2, 24.1, 18.7, 7.8; HRMS (FAB) m/z calcd for
4
3.1, 35.4, 30.4, 23.8, 22.5, 22.1; HRMS (FAB) m/z calcd for
3
+
C
11
H
18NO
2
(M+H) 196.1338, found 196.1337.
-(3-Iodo)propyl-2,3,6,7-tetrahydro-1H-indol-4(5H)-one (5c). Ac-
cording to the typical procedure for halogenation of alcohols, iodide
c was prepared from 5b (100 mg, 0.51 mmol), NIS (201 mg, 0.77
+
1
C
13
H
20NO (M+H) 206.1545, found 206.1542.
Synthesis of (±)-aspidospermidine (1a). rac-(6aR,9aR,9bS)-6a-
Ethyldecahydro-4H-pyrrolo[3,2,1-ij]quinolin-9-one (2).6 10% Pd/C
(82 mg, 200 wt% of 9) was added to a solution of 9 (41 mg, 0.2
mmol) in AcOH (4 mL). The reaction mixture was vigorously stirred
under H2 atmosphere at 50 °C for 12 h. The mixture was filtered
–8
5
mmol), and triphenylphosphine (173 mg, 0.77 mmol) at 0 °C for 0.5 h.
The crude product was purified by column chromatography (silica gel,
5% MeOH in CH
(
2
Cl
film, cm ) n 2936, 2862, 1594, 1556, 1506, 1187; H NMR (400
MHz, CDCl ) d 3.51 (t, J = 9.6 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 3.19
t, J = 6.6 Hz, 2H), 2.78 (t, J = 9.6 Hz, 2H), 2.40 (t, J = 6.2 Hz, 2H),
2
) to provide 5c (150 mg, 96%) as a brown oil: IR
−1
1
through a pad of Celite and the filter cake was rinsed with CH
mL). The filtrate was concentrated in vacuo, and saturated aqueous
NaHCO (20 mL) was added to the residue. The whole mixture was
extracted with CH Cl (2 × 10 mL), and the combined organic layer
was washed with brine (10 mL) and dried over anhydrous MgSO
The filtrate was concentrated in vacuo, and the residue was purified
by column chromatography (silica gel, 1% MeOH in CHCl ) to pro-
vide 2 (14 mg, 34%) as a colorless oil: IR (film, cm ) n 2929, 1711,
2 2
Cl (20
3
(
3
13
1
2
.32 (t, J = 6.2 Hz, 2H), 2.10–1.99 (m, 4H); C{ H} NMR (100
) d 191.2, 168.4, 109.7, 51.5, 46.6, 35.7, 31.0, 24.1, 22.9,
2
2
MHz, CDCl
22.2, 2.3; HRMS (EI) m/z calcd for C11
05.0284.
-(3-Bromo)propyl-2,3,6,7-tetrahydro-1H-indol-4(5H)-one
3
4
.
+
H
16INO (M ) 305.0277, found
3
3
−1
1
(5d).
1
According to the typical procedure for halogenation of alcohols, bro-
mide 5d was prepared from 5b (1.05 g, 5.35 mmol), NBS (1.43 g,
8.03 mmol), and triphenylphosphine (2.11 g, 8.03 mmol) at 0 °C for
3
1457; H NMR (400 MHz, CDCl ) d 3.03–2.99 (m, 2H), 2.67 (ddd, J
= 9.0, 4.8, 1.6 Hz, 1H), 2.45–2.17 (m, 3H), 1.97–1.60 (m, 7H), 1.51–
1.47 (m, 2H), 1.37–1.28 (m, 2H), 1.10 (td, J = 13.4, 4.8 Hz, 1H), 0.94
0
(
.5 h. The crude product was purified by column chromatography
silica gel, 5% MeOH in CH Cl ) to provide 5d (1.27 g, 93%) as a
yellowish brown oil: IR (film, cm ) n 2941, 2868, 1581, 1542, 1508,
438, 1190; H NMR (400 MHz, CDCl
.44 (t, J = 6.4 Hz, 2H), 3.38 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 9.6 Hz,
(t, J = 7.6 Hz, 3H); 13C{
1
H} NMR (100 MHz, CDCl ) d 211.5, 73.6,
3
2
2
53.2, 52.9, 48.2, 36.8, 34.8, 32.9, 30.1, 29.7, 26.1, 21.3, 7.1; HRMS
−1
+
(EI) m/z calcd for C13H21NO (M ) 207.1623, found 207.1616.
1
6b
1
3
3
) d 3.52 (t, J = 9.6 Hz, 2H),
(±)-Aspidospermidine (1a). According to the procedure of Aubé
et al., we demonstrated conversion of 2 into aspidospermidine (1a).
Phenylhydrazine (3.8 mg, 0.035 mmol) was added to a solution of 2
(6.0 mg, 0.029 mmol) in benzene (0.83 mL). After stirring at reflux
for 3 h, the reaction mixture was concentrated in vacuo, and the resi-
due was dissolved in AcOH (0.83 mL). After stirring at reflux for 3.5
h, the reaction mixture was concentrated in vacuo, and the residue
2H), 2.39 (t, J = 6.4 Hz, 2H), 2.30 (t, J = 6.4 Hz, 2H), 2.11 (quint, J =
.4 Hz, 2H), 2.01 (quint, J = 6.4 Hz, 2H); 13C{ H} NMR (100 MHz,
CDCl ) d 191.2, 168.4, 109.6, 51.4, 44.4, 35.7, 30.3, 30.0, 24.0, 22.6,
2.2; HRMS (FAB) m/z calcd for C11
found 258.0496.
,2,4,5,6,6a,7,8-Octahydro-9H-pyrrolo[3,2,1-ij]quinolin-9-one (8).
1
6
3
+
2
H17BrNO (M+H) 258.0494,
1
4
was dissolved in THF (0.83 mL). LiAlH (11 mg, 0.29 mmol) was
A solution of LiHMDS (11.9 mL, 0.83 M in THF/hexane, 9.87 mmol)
was added to a solution of 5d (1.27 g, 4.93 mmol) and TBAI (182 mg,
added to a solution of the crude product at 0 °C, and the reaction mix-
ture was stirred at reflux for 11 h. After cooling to 0 °C, the reaction
mixture was quenched by addition of one drop of aqueous 10%
NaOH. The mixture was filtered through a pad of Celite and the filter
0
.49 mmol) in THF (49 mL) at −78 °C. After stirring at −78 °C for 1
h, the reaction mixture was allowed to warm to room temperature
over 1.5 h. The reaction mixture was quenched with saturated aque-
2 2
cake was rinsed with CH Cl (10 mL). The filtrate was concentrated
ous NH
CH Cl (2 x 10 mL). The combined organic layers were washed with
water (10 mL) and brine (10 mL), and dried over anhydrous MgSO
4
Cl (10 mL), and the whole mixture was extracted with
in vacuo, and the residue was purified by column chromatography
2
2
(silica gel, 11% MeOH in EtOAc) to provide 1a (2.6 mg, 32%) as a
1
4
.
colorless oil: H NMR (400 MHz, CDCl
3
) d 7.07 (d, J = 8.0 Hz, 1H),
Filtration and evaporation in vacuo furnished the crude product,
which was purified by column chromatography (silica gel, 5% MeOH
7.02 (t, J = 7.2 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 8.0 Hz,
1H), 3.52 (m, 1H), 3.12–3.06 (m, 2H), 2.35–2.20 (m, 3H), 1.98–1.91
(m, 2H), 1.79–1.66 (m, 3H), 1.53–1.34 (m, 4H), 1.13 (m, 1H), 1.07
in CH
2 2
Cl ) to provide 8 (753 mg, 86%) as a pale yellow solid: mp 62–
−1
63 °C; IR (KBr, cm ) n 2936, 2860, 1550, 1524, 1436, 1361, 1294,
5
ACS Paragon Plus Environment