2134 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Holl et al.
5.5 Hz, 1H, 2-H), 5.13 (d, J ) 14.1 Hz, 1H, NCH2Ar), 5.20-5.29
(m, 2H, NCH2CHdCH2), 5.75 (ddt, J ) 17.2/10.2/6.3 Hz, 1H,
NCH2CHdCH2), 6.74 (d, J ) 8.6 Hz, 2H, 3′-H4-methoxybenzyl, 5′-
V ) 10 mL, Rf ) 0.07) to give 17a as a yellow oil, yield 46 mg
1
(46%). [R]2D0 ) -82.9 (c ) 0.73; CH2Cl2). H NMR (CDCl3): δ
[ppm] ) 1.76-1.95 (m, 2H, 4-H), 2.35 (ddd, J ) 14.8/6.5/2.8 Hz,
1H, 3-H), 2.69 (dd, J ) 10.6/1.6 Hz, 1H, 7-H), 2.80-2.90 (m, 2H,
3-H (1H), 9-H (1H)), 2.96-3.03 (m, 2H, 7-H (1H), 9-H (1H)),
3.04-3.08 (m, 1H, 5-H), 3.15-3.26 (m, 2H, NCH2CHdCH2), 3.55
(s, 2H, NCH2Ar), 3.78 (s, 3H, ArOCH3), 3.85 (d br, J ) 2.8 Hz,
1H, 1-H), 5.10 (d, J ) 10.2 Hz, 1H, NCH2CHdCH2), 5.18 (d, J )
16.6 Hz, 1H, NCH2CHdCH2), 5.91 (ddt, J ) 16.6/10.2/6.5 Hz,
1H, NCH2CHdCH2), 6.31 (s, 1H, CdCHPh), 6.77 (d, J ) 8.3 Hz,
2H, 3′-H4-methoxybenzyl, 5′-H4-methoxybenzyl), 6.94 (d, J ) 7.4 Hz, 2H,
2′-Hbenzylidene, 6′-Hbenzylidene), 7.09-7.21 (m, 5H, 2′-H4-methoxybenzyl, 6′-
H4-methoxybenzyl), 6.90 (d, J ) 7.8 Hz, 2H, 2′-Hphenoxy, 6′-Hphenoxy),
6.96-7.03 (m, 3H, 4′-Hphenoxy, 2′-H4-methoxybenzyl, 6′-H4-methoxybenzyl),
7.31 (t, J ) 7.8 Hz, 2H, 3′-Hphenoxy, 5′-Hphenoxy).
(-)-(1R,2S,5S)-6-Allyl-8-(4-methoxybenzyl)-2-phenoxy-6,8-
diazabicyclo[3.2.2]nonane (15a). Under N2 atmosphere, LiAlH4
(56 mg, 1.48 mmol) was added to an ice-cooled solution of 14a
(120 mg, 0.30 mmol) in THF (30 mL). The mixture was stirred at
0 °C for 10 min and then heated to reflux for 16 h. Then water was
added under ice-cooling until H2 formation was finished. The
mixture was stirred at 0 °C for 10 min and then heated to reflux
for 30 min. After cooling down, the mixture was filtered, the solvent
was removed in vacuo, and the residue was purified by flash column
chromatography (Ø ) 2 cm, h ) 15 cm, CH2Cl2/methanol ) 50/1,
V ) 10 mL, Rf ) 0.11) to give 15a as a yellow oil, yield 30 mg
H4-methoxybenzyl, 4′-Hbenzylidene, 3′-Hbenzylidene, 5′-Hbenzylidene).
(+)-(1S,4S)-11-Allyl-2-(4-methoxybenzyl)-1,2,5,10-tetrahydro-
4,1-iminomethanoazepino[3,4-b]indole-3,12(4H)-dione (18a). A
solution of 5a (130 mg, 0.40 mmol) and phenylhydrazine (107 mg,
0.99 mmol) in HCl(g)-saturated ethanol (50 mL) was heated to
reflux under N2 for 16 h. Then the solvent was evaporated and the
residue was purified by flash column chromatography (Ø ) 2 cm,
h ) 15 cm, cyclohexane/ethyl acetate ) 2/1, 10 mL, Rf ) 0.13) to
give 18a as a colorless solid, mp 253 °C, yield 67 mg (42%). [R]D20
1
(27%). [R]2D0 ) -56.3 (c ) 2.9; CH2Cl2). H NMR (CDCl3): δ
[ppm] ) 1.64-1.76 (m, 1H, CH2CH2), 1.81-1.89 (m, 1H,
CH2CH2), 1.92-2.01 (m, 1H, CH2CH2), 2.28-2.41 (m, 1H,
CH2CH2), 2.72-2.77 (m, 1H, piperazine-H), 2.79-2.85 (m, 2H,
piperazine-H), 2.87-2.95 (m, 2H, piperazine-H), 3.05-3.08 (m,
1H, piperazine-H), 3.14-3.26 (m, 2H, NCH2CHdCH2), 3.59-3.67
(s, 2H, NCH2Ar), 3.79 (s, 3H, ArOCH3), 4.65 (dd, J ) 10.2/4.7
Hz, 1H, 2-H), 5.13 (d, J ) 10.2 Hz, 1H, NCH2CHdCH2), 5.20 (d,
J ) 17.2 Hz, 1H, NCH2CHdCH2), 5.89 (ddt, J ) 17.2/10.2/6.3
Hz, 1H, NCH2CHdCH2), 6.72 (d, J ) 7.8 Hz, 2H, 2′-Hphenoxy, 6′-
1
) +232 (c ) 0.21; CH2Cl2). H NMR (CDCl3): δ [ppm] ) 3.23
(dd, J ) 17.2/3.9 Hz, 1H, 5-H), 3.32 (dd, J ) 17.2/2.3 Hz, 1H,
5-H), 3.70 (s, 3H, ArOCH3), 3.94-4.01 (m, 1H, NCH2CHdCH2),
4.18-4.25 (m, 1H, NCH2CHdCH2), 4.40 (d, J ) 14.9 Hz, 1H,
NCH2Ar), 4.47 (dd, J ) 3.9/2.3 Hz, 1H, 4-H), 4.56 (s, 1H, 1-H),
4.71 (d, J ) 14.9 Hz, 1H, NCH2Ar), 5.25-5.31 (m, 2H,
H
phenoxy), 6.81 (d, J ) 8.6 Hz, 2H, 3′-H4-methoxybenzyl, 5′-H4-methoxybenzyl),
NCH2CHdCH2), 5.81 (ddt,
NCH2CHdCH2), 6.68 (d, J ) 8.6 Hz, 2H, 3′-H4-methoxybenzyl, 5′-
J ) 17.2/10.2/6.3 Hz, 1H,
6.85 (t, J ) 7.8 Hz, 1H, 4′-Hphenoxy), 7.19 (t, J ) 7.8 Hz, 2H, 3′-
H
phenoxy, 5′-Hphenoxy), 7.29 (d, J ) 8.6 Hz, 2H, 2′-H4-methoxybenzyl, 6′-
H4-methoxybenzyl), 7.01 (d, J ) 8.6 Hz, 2H, 2′-H4-methoxybenzyl, 6′-
H4-Methoxybenzyl), 7.06-7.12 (m, 1H, Hindole), 7.14-7.17 (m, 2H,
Hindole), 7.42 (d, J ) 7.8 Hz, 1H, Hindole), 7.81 (s br, 1H, NH).
(+)-(1S,4S)-11-Allyl-7-methoxy-2-(4-methoxybenzyl)-1,2,5,10-
H4-methoxybenzyl).
(+)-(1S,5S,Z)-6-Allyl-2-benzylidene-8-(4-methoxybenzyl)-6,8-
diazabicyclo[3.2.2]nonane-7,9-dione (16a). Under N2 atmosphere,
benzyltriphenylphosphonium bromide (317 mg, 0.73 mmol) was
suspended in THF (50 mL) and the mixture was cooled to -10
°C. Then potassium tert-butoxide (103 mg, 0.91 mmol) was added
in portions. Subsequently, a solution of 5a (200 mg, 0.61 mmol)
in THF (20 mL) was added dropwise and the mixture was stirred
at room temperature for 16 h. Then water was added and the mixture
was extracted with CH2Cl2 (3×). The combined organic layers were
dried (Na2SO4), filtered, and the solvent was removed in vacuo.
The residue was purified by flash column chromatography (Ø ) 3
cm, h ) 15 cm, cyclohexane/ethyl acetate ) 2/1, 20 mL, Rf )
0.18) to give 16a as a colorless solid, mp 156 °C, yield 219 mg
(89%). C25H26N2O3 (402.5). [R]2D0 ) +267 (c ) 0.29; CH2Cl2). 1H
NMR (CDCl3): δ [ppm] ) 1.79-1.89 (m, 1H, 4-H), 2.15-2.23
(m, 1H, 4-H), 2.34-2.50 (m, 2H, 3-H), 3.75 (s, 3H, ArOCH3), 3.85
(dd, J ) 14.9/6.3 Hz, 1H, NCH2CHdCH2), 3.99 (dd, J ) 5.5/2.3
Hz, 1H, 5-H), 4.21 (dd, J ) 14.9/6.3 Hz, 1H, NCH2CHdCH2),
4.27 (d, J ) 14.1 Hz, 1H, NCH2Ar), 4.33 (d, J ) 14.1 Hz, 1H,
NCH2Ar), 4.82 (s, 1H, 1-H), 5.22-5.28 (m, 2H, NCH2CHdCH2),
5.78 (ddt, J ) 16.4/10.2/6.3 Hz, 1H, NCH2CHdCH2), 6.48 (s, 1H,
CdCHPh), 6.61 (d, J ) 8.6 Hz, 2H, 3′-H4-methoxybenzyl, 5′-
tetrahydro-4,1-iminomethanoazepino[3,4-b]indole-3,12(4H)-di-
one (19a). A solution of 5a (141 mg, 0.43 mmol) and p-methox-
yphenylhydrazine hydrochloride (187 mg, 1.07 mmol) in HCl(g)-
saturated ethanol (70 mL) was heated to reflux under N2 for 16 h.
Then the solvent was evaporated and the residue was purified by
flash column chromatography (Ø ) 3 cm, h ) 15 cm, cyclohexane/
ethyl acetate ) 2/1, 20 mL, Rf ) 0.10) to give 19a as a colorless
solid, mp 263 °C, yield 90 mg (49%). [R]2D0 ) +214 (c ) 0.29;
CH2Cl2). 1H NMR (CDCl3): δ [ppm] ) 3.18 (dd, J ) 17.2/3.9 Hz,
1H, 5-H), 3.27 (dd, J ) 17.2/3.1 Hz, 1H, 5-H), 3.71 (s, 3H,
ArOCH3), 3.83 (s, 3H, ArOCH3), 3.97 (dd, J ) 15.7/6.3 Hz, 1H,
NCH2CHdCH2), 4.20 (dd, J ) 15.7/6.3 Hz, 1H, NCH2CHdCH2),
4.40 (d, J ) 14.9 Hz, 1H, NCH2Ar), 4.46 (dd, J ) 3.9/3.1 Hz, 1H,
4-H), 4.50 (s, 1H, 1-H), 4.72 (d, J ) 14.9 Hz, 1H, NCH2Ar),
5.25-5.31 (m, 2H, NCH2CHdCH2), 5.80 (ddt, J ) 17.2/10.2/6.3
Hz, 1H, NCH2CHdCH2), 6.68 (d, J ) 8.6 Hz, 2H, 3′-H4-methoxybenzyl
,
5′-H4-methoxybenzyl), 6.80-6.84 (m, 2H, 6-H, 8-H), 7.00 (d, J ) 8.6
Hz, 2H, 2′-H4-methoxybenzyl, 6′-H4-methoxybenzyl), 7.04 (d, J ) 9.4 Hz,
1H, 9-H), 7.57 (s br, 1H, NH).
(+)-(1R,4S)-11-Allyl-2-(4-methoxybenzyl)-1,2,3,4,5,10-hexahy-
dro-4,1-iminomethanoazepino[3,4-b]indole (20a). Under N2 at-
mosphere, LiAlH4 (52 mg, 1.37 mmol) was added to an ice-cooled
solution of 18a (110 mg, 0.27 mmol) in THF (30 mL). The mixture
was stirred at 0 °C for 10 min and then heated to reflux for 16 h.
Then water was added under ice-cooling until H2 formation was
finished. The mixture was stirred at 0 °C for 10 min and then heated
to reflux for 30 min. After cooling down, the mixture was filtered,
the solvent was removed in vacuo, and the residue was purified by
flash column chromatography (Ø ) 2 cm, h ) 15 cm, CH2Cl2/
methanol ) 50/1, V ) 10 mL, Rf ) 0.02) to give 20a as a pale-
yellow solid, mp 161 °C, yield 42 mg (41%). [R]2D0 ) +97.4 (c )
H
4-methoxybenzyl), 6.77 (d, J ) 8.6 Hz, 2H, 2′-H4-methoxybenzyl, 6′
-H4-methoxybenzyl), 7.31 (t, J ) 7.0 Hz, 1H, 4′-Hbenzylidene), 7.38 (t, J )
7.0 Hz, 2H, 3′-Hbenzylidene, 5′-Hbenzylidene), 7.50 (d, J ) 7.0 Hz, 2H,
2′-Hbenzylidene, 6′-Hbenzyidene). NOE: irradiation at 4.82 ppm (1-H): δ
[ppm] ) 4.27 (NCH2Ar), 4.33 (NCH2Ar), 6.77 (2′-H4-methoxybenzyl
6′-H4-methoxybenzyl), 7.50 (2′-Hbenzylidene, 6′-Hbenzyidene); irradiation at 6.48
,
ppm (CdCHPh): δ [ppm] ) 2.34-2.50 (3-H), 7.50 (2′-Hbenzylidene
,
6′-Hbenzyidene).
(-)-(1S,5S,Z)-6-Allyl-2-benzylidene-8-(4-methoxybenzyl)-6,8-
diazabicyclo[3.2.2]nonane (17a). Under N2 atmosphere, LiAlH4
(51 mg, 1.33 mmol) was added to an ice-cooled solution of 16a
(107 mg, 0.27 mmol) in THF (30 mL). The mixture was stirred at
0 °C for 10 min and then heated to reflux for 16 h. Then water was
added under ice-cooling until H2 formation was finished. The
mixture was stirred at 0 °C for 10 min and then heated to reflux
for 30 min. After cooling down, the mixture was filtered, the solvent
was removed in vacuo, and the residue was purified by flash column
chromatography (Ø ) 2 cm, h ) 15 cm, CH2Cl2/methanol ) 50/1,
1
0.15; CH2Cl2). H NMR (CDCl3): δ [ppm] ) 2.40-2.46 (m, 1H,
3-H), 2.72-2.82 (m, 2H, 5-H (1H), 12-H (1H)), 3.24-3.42 (m,
4H, NCH2CHdCH2 (2H), 5-H (1H), NCH2Ar (1H)), 3.55-3.60
(m, 4H, 4-H, 3-H (1H), 12-H (1H), NCH2Ar (1H)), 3.67-3.71 (m,
1H, 1-H), 3.82 (s, 3H, ArOCH3), 5.11-5.16 (m, 1H,
NCH2CHdCH2), 5.19-5.26 (m, 1H, NCH2CHdCH2), 5.94-6.06
(m, 1H, NCH2CHdCH2), 6.88 (d, J ) 8.6 Hz, 2H, 3′-H4-methoxybenzyl
,