Total Syntheses of â-Carboline Alkaloids
J . Org. Chem., Vol. 66, No. 26, 2001 8797
for C16
H, 6.18; N, 9.33.
-[3-(Met h oxym et h yloxy)p r op -1-yn -1-yl]in d ole-2-ca r -
ba ld eh yd e (16a ). A mixture of 3-iodoindole 12a (250 mg, 0.92
mmol), [(methoxymethyloxy)propynyl] tributyltin 15 (535 mg,
H
18
N
2
O
4
: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.74;
was purified by column chromatography (silica gel, 20 g) using
EtOAc-hexane (2:3) as an eluent to give the oily pyridone 17a
-
1 1
3
3
(24 mg, 67%). IR (neat) ν: 1640, 2950 cm ; H NMR (CDCl )
δ: 3.46 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.92 (s, 1H), 7.31 (m,
1H), 7.46-7.61 (m, 1H), 7.94 (d, J ) 8 Hz, 1H), 8.27 (s, 1H),
+
1
(
4
.38 mmol), Et
32 mg, 0.046 mmol) in DMF (15 mL) was heated at 80 °C for
0 min. After being cooled to ambient temperature, 30%
4
NCl (152 mg, 0.92 mmol), and PdCl
2
(PPh
3
)
2
8.91 (br s, 1H); MS m/z: 258 (M ). HRMS (EI) calcd for C16
H
19
-
4
NO 258.1004, found 258.1021.
3-(Met h oxym et h yloxy)m et h yl-N-m et h oxym et h yl-9H -
p yr id o[3,4-b]in d ol-1(2H)-on e (17b). The same procedure as
above was carried out using 8b (3.3 g, 10.93 mmol) to give the
pyridone 17b (90%). mp 214-216 °C (hexane); IR (KBr) ν:
aqueous KF solution (10 mL) was added to the reaction
mixture and then stirred at room temperature for 30 min,
which was filtered through the Celite pad. The filtrate was
extracted with EtOAc. The EtOAc layer was washed with
-1 1
1640, 2950 cm ; H NMR (CDCl ) δ: 3.36 (s, 3H), 3.47 (s, 3H),
3
brine, dried over Na
2
SO
4
, and concentrated. The residue was
4.16 (s, 2H), 4.76 (s, 2H), 6.25 (s, 2H), 6.86 (s, 1H), 7.31 (td, J
) 1, 8 Hz, 1H), 7.53 (td, J ) 1, 8 Hz, 1H), 7.65 (dd, J ) 1, 8
purified by column chromatography (silica gel, 10 g) using
EtOAc-hexane (1:9) as an eluent to give the oily 3-propy-
Hz, 1H), 7.94 (d, J ) 8 Hz, 1H), 9.82 (br s, 1H); MS m/z: 302
-
1
+
nylindole 16a (108 mg, 48%). IR (neat) ν: 1650, 3300 cm
;
(M ). Anal. Calcd for C16
H
18
N
2
O
4
: C, 63.56; H, 6.00; N, 9.27.
1
H NMR (CDCl
3
) δ 3.46 (s, 3H), 4.59 (s, 2H), 4.84 (s, 2H), 7.23
m, 1H), 7.40-7.43 (m, 2H), 7.84 (d, J ) 8 Hz, 1H), 8.88 (br s,
H), 10.06 (s, 1H); MS m/z: 243 (M ). HRMS (EI) calcd for
243.0895, found 243.0909.
-[3-(Me t h oxym e t h yloxy)p r op -1-yn -1-yl]-N -(m e t h -
Found: C, 63.59; H, 6.11; N, 9.15.
3-(Meth oxym eth yloxy)m eth yl-1-tr iflu or om eth an esu lfo-
n yloxy-9H-p yr id o[3,4-b]in d ole (18a ). Tf O (20 µL, 0.12
mmol) was added to a stirred solution of the pyridone 17a (20
mg, 0.078 mmol) and pyridine (19 µL, 0.23 mmol) in CH Cl
(
1
+
2
16 4
C H19NO
3
2
2
oxym eth yl)in d ole-2-ca r ba ld eh yd e (16b). The same proce-
dure as above was carried out using 12b (2 g, 6.35 mmol) to
give the 3-propynylindole 16b (97%). mp 70-70.5 °C (hexane);
(5 mL) under cooling with ice. After stirring at room temper-
ature for 10 min, the solution was treated with water, and
the mixture was extracted with CH . The CH
2
Cl
2
2 2
Cl layer was
-
1 1
IR (KBr) ν: 1655 cm ; H NMR (CDCl
3
) δ 3.29 (s, 3H), 3.45
washed with brine, dried over Na SO , and concentrated. The
2
4
(
8
1
s, 3H), 4.59 (s, 2H), 4.38 (s, 2H), 5.89 (s, 2H), 7.30 (dd, J ) 1,
residue was purified by column chromatography (silica gel, 10
Hz, 1H), 7.48 (td, J ) 1, 8 Hz, 1H), 7.57 (dd, J ) 1, 8 Hz,
g) using EtOAc-hexane (1:4) as an eluent to give the oily
1
H), 7.48 (dd, J ) 1, 8 Hz, 1H), 10.21 (s, 1H); MS m/z: 287
triflate 18a (28 mg, 93%). H NMR (CDCl
3
) δ 3.45 (s, 3H), 4.83
+
(M ). Anal. Calcd for C16
H
17NO
4
: C, 66.89; H, 5.96; N, 4.88.
(s, 2H), 4.85 (s, 2H), 7.35 (td, J ) 1, 7 Hz, 1H), 7.60 (m, 1H),
Found: C, 67.03; H, 6.12; N, 4.83.
-[3-(Met h oxym et h yloxy)p r op -1-yn -1-yl]in d ole-2-ca r -
ba ld eh yd e Oxim e (11a ). A suspention of 2-formylindole 16a
100 mg, 0.41 mmol), NH OH‚HCl (57 mg, 0.82 mmol), and
AcONa (67 mg, 0.82 mmol) in EtOH (5 mL) was heated at 80
C for 30 min. After being cooled to ambient temperature, the
mixture was extracted with EtOAc. The EtOAc layer was
washed with brine, dried over Na SO , and concentrated. The
7.62 (dd, J ) 1, 7 Hz, 1H), 8.12 (d, J ) 7 Hz, 1H), 8.13 (s, 1H),
+
3
8.65 (br s, 1H); MS m/z: 390 (M ). HRMS (EI) calcd for C16
H
19
-
4
NO 390.0497, found 390.0502.
(
2
3-(Meth oxym eth yloxy)m eth yl-N-m eth oxym eth yl-1-tr i-
flu or om eth a n esu lfon yloxy-9H-p yr id o[3,4-b]in d ole (18b).
The same procedure as above was carried out using 17b (1 g,
°
3.31 mmol) to give the triflate 18b (99%). mp 50-52 °C (Et
2
O);
-
1 1
2
4
IR (KBr) ν: 1620 cm ; H NMR (CDCl
3
) δ 3.28 (s, 3H), 3.45
residue was purified by column chromatography (silica gel, 10
(s, 3H), 4.57 (s, 2H), 4.83 (s, 2H), 5.87 (s, 2H), 7.22 (td, J ) 1,
8 Hz, 1H), 7.34 (td, J ) 1, 7 Hz, 1H), 7.48 (d, J ) 8 Hz, 1H),
g) using EtOAc-hexane (1:4) as an eluent to give the oily
-1
1
+
oxime 11a (45 mg, 42%). IR (neat) ν: 1650, 3300 cm ; H NMR
7.73 (dd, J ) 1, 7 Hz, 1H), 8.54 (s, 1H); MS m/z: 434 (M ).
(
7
8
CDCl
3
) δ 3.45 (s, 3H), 4.56 (s, 2H), 4.48 (s, 2H), 7.30 (m, 1H),
17 3 2 6
Anal. Calcd for C17H F N O S: C, 47.00; H, 3.94; N, 6.45.
.72 (m, 1H), 7.77 (d, J ) 8 Hz, 1H), 7.82 (s, 1H), 8.37 (s, 1H),
.68 (br s, 1H); MS m/z: 258 (M ). HRMS (EI) calcd for C16
Found: C, 47.18; H, 4.10; N, 6.37.
1-E t h en yl-3-(m et h oxym et h yloxy)m et h yl-9H -p yr id o-
[3,4-b]in d ole (19a ). A mixture of the triflate 18a (25 mg, 0.064
+
H
19
-
NO
3
4
258.1004, found 258.1015.
-[3-(Me t h o x y m e t h y lo x y )p r o p -1-y n -1y l]-N -(m e t h -
mmol), vinyltributyltin (31 mg, 0.096 mmol), Et
0.064 mmol), and PdCl (PPh (2 mg, 0.0032 mmol) in dried
4
NCl (11 mg,
oxym eth yl)in d ole-2-ca r ba ld eh yd e Oxim e (11b). The same
procedure as above was carried out using 16b (6 g, 20.88 mmol)
to give the oxime 11b (93%). mp 79-80.5 °C (hexane); IR (KBr)
2
3 2
)
DMF (3 mL) was heated at 80 °C for 40 min. After being cooled
to ambient temperature, 30% aqueous KF solution (5 mL) was
added to the reaction mixture and then stirred at room
temperature for 30 min, which was filtered through the Celite
pad. The filtrate was extracted with EtOAc. The EtOAc layer
-
1
1
ν: 3400 cm ; H NMR (CDCl
4
1
3
) δ 3.27 (s, 3H), 3.45 (s, 3H),
.57 (s, 2H), 4.84 (s, 2H), 5.84 (s, 2H), 7.21 (td, J ) 1, 8 Hz,
H), 7.33 (td, J ) 1, 8 Hz, 1H), 7.45 (d, J ) 8 Hz, 1H), 7.71
(
3
dd, J ) 1, 8 Hz, 1H), 8.06 (br s, 1H), 8.55 (s, 1H); MS m/z:
2 4
was washed with brine, dried over Na SO , and concentrated.
The residue was purified by column chromatography (silica
+
02 (M ). Anal. Calcd for C16
.27. Found: C, 63.46; H, 6.07; N, 9.38.
-(Me t h o x y m e t h y lo x y )m e t h y l-9H -p y r id o [3,4-b ]in -
d ole N-Oxid e (8a ) fr om 11a . A solution of the oxime 11a
45 mg, 0.17 mmol) in o-dichlorobenzene (3 mL) was heated
H
18
N
2
O
4
: C, 63.56; H, 6.00; N,
9
gel, 10 g) using EtOAc-hexane (1:9) as an eluent to give the
1
3
oily 1-vinyl-â-carboline 19a (12 mg, 87%). H NMR (CDCl
3
) δ
3.49 (s, 3H), 4.86 (s, 2H), 4.90 (s, 2H), 5.73 (dd, J ) 2, 11 Hz,
1H), 6.36 (dd, J ) 2, 17 Hz, 1H), 7.20 (dd, J ) 11, 17 Hz, 1H),
7.30 (m, 1H), 7.55 (m, 2H), 8.01 (s, 1H), 8.13 (d, J ) 8 Hz,
(
at 180 °C for 20 min. After being cooled to ambient temper-
ature, the reaction mixture was concentrated under reduced
pressure. The residue was purified by column chromatography
+
1H), 8.36 (br s, 1H); MS m/z: 268 (M ). HRMS (EI) calcd for
C
16
H
19NO
4
268.1212, found 268.1198.
(
3
silica gel, 10 g) using MeOH-CHCl (1:9) as an eluent to give
1-E t h e n y l-3-(m e t h o x y m e t h y lo x y )m e t h y l-N -m e t h -
oxym eth yl-9H-p yr id o[3,4-b]in d ole (19b). The same proce-
dure as above was carried out using 18b (2.3 g, 5.30 mmol) to
give the 1-vinyl-â-carboline 19b (72%). mp 84-86 °C (hexane);
3
H NMR (CDCl ) δ 3.40 (s, 3H), 3.49 (s, 3H), 4.87 (s, 2H), 4.93
the â-carboline N-oxide 8a (20 mg, 45%). The physical and
spectral data of 8a from 11a were identical with those of 8a
obtained from 9a .
1
3
-(Met h oxym et h yloxy)m et h yl-N-m et h oxym et h yl-9H -
p yr id o[3,4-b]in d ole N-Oxid e (8b) fr om 11b. The same
procedure as above was carried out using 11b (805 mg, 2.67
mmol) to give the â-carboline N-oxide 8b (95%). The physical
and spectral data of 8b from 11b were identical with those of
(s, 2H), 5.64 (dd, J ) 2, 11 Hz, 1H), 5.76 (s, 1H), 6.45 (dd, J )
2, 18 Hz, 1H), 7.31 (m, 1H), 7.59 (m, 1H), 7.65 (dd, J ) 11, 18
Hz, 1H), 8.03 (s, 1H), 8.12 (d, J ) 8 Hz, 1H); MS m/z: 312
+
(M ). Anal. Calcd for C18
20 2 3
H N O : C, 69.21; H, 6.45; N, 8.97.
8
b obtained from 9b.
-(Met h oxym et h yloxy)-9H -p yr id o[3,4-b]in d ol-1(2H )-
Found: C, 69.45; H, 6.48; N, 8.69.
3
1-Eth en yl-3-h ydr oxym eth yl-9H-pyr ido[3,4-b]in dole (7a).
Trifluoromethanesulfonic acid (1 mL, 11.52 mmol) was added
to an ice-cooled mixture of N-MOM-â-carboline 19b (1.2 g, 3.84
mmol), MeOH (1.56 mL, 38.40 mmol), and trimethyl ortho-
formate (4.2 mL, 38.40 mmol) in nitromethane (20 mL). The
on e (17a ). A solution of â-carboline N-oxide 8a (36 mg, 0.14
mmol) in acetic anhydride (10 mL) was heated at 100 °C for 3
h. After being cooled to ambient temperature, the reaction
mixture was concentrated under reduced pressure. The residue