PAPER
Total Synthesis of 1-Methoxycanthin-6-one
31
1
3
added to the solution and then stirred for 15 min at –78 °C. To this
solution, b-carboline-1-carbaldehyde (7a, 49.1 mg, 0.250 mmol) in
THF (2 mL) was added and then stirred for 20 min at –78 °C. The
C NMR (CDCl ): d = 116.1, 117.0, 122.5, 124.0, 125.4, 128.9,
3
130.3, 130.7, 131.7, 135.5, 138.9, 139.2, 145.0, 159.0.
+
MS: m/z = 220 [M , 100].
whole reaction mixture was poured into aq sat. NH Cl (15 mL) un-
4
Anal. Calcd for C H N O: C, 76.35; H, 3.66; N, 12.72. Found: C,
7
der ice cooling, extracted with EtOAc, washed with brine, dried
14
8
2
6.54; H, 3.78; N, 12.83.
over anhyd MgSO and evaporated in vacuo. The crude solid was
4
purified by SiO column chromatography using hexane–EtOAc to
give the title compound 13a as colorless crystals (43.7 mg, 61%).
2
1
-Methoxycanthin-6-one (2b) (Direct Method from 7b)
To a stirred mixture of HMDS (340 mL, 1.6 mmol) in THF (1 mL),
n-BuLi (1.59 M in hexane, 760 mL, 1.2 mmol) was added at –78 °C
under an Ar atmosphere. The mixture was warmed to r.t. within 30
min with stirring and then recooled to –78 °C. EtOAc (90 mL, 0.92
mmol) in THF (1 mL) was added to the solution and then stirred for
15 min at –78 °C. To this solution, 4-methoxy-b-carboline-1-car-
baldehyde (7b, 44.5 mg, 0.20 mmol) in THF (2 mL) was added and
then stirred for 15 min at –78 °C. To the reaction mixture, EtOH (3
mL) was added and then stirred for 30 min at r.t. The whole reaction
Recrystallization from EtOAc–hexane gave colorless prisms; mp
1
21–123 °C.
–
1
IR (KBr): 3387, 1720 cm .
1
H NMR (acetone-d ): d = 1.20 (t, J = 7 Hz, 3 H, OCH CH ), 2.89
6
2
3
(
dd, J = 15, 9 Hz, 1 H, CH CO), 3.11 (dd, J = 15, 4 Hz, 1 H,
2
CH CO), 4.13 (q, J = 7 Hz, 2 H, OCH CH ), 5.65 (dd, J = 9, 4 Hz,
2
2
3
1
H, CHOH), 7.25 (br t, J = 8 Hz, 1 H, C -H or C -H), 7.54 (br t,
6 7
J = 8 Hz, 1 H, C -H or C -H), 7.72 (br d, J = 8 Hz, 1 H, C -H or C -
6
7
5
8
H), 7.99 (d, J = 5 Hz, 1 H, C -H or C -H), 8.21 (br d, J = 8 Hz, 1 H
mixture was poured into aq sat. NH Cl (15 mL), extracted with
3
4
4
C -H or C -H), 8.28 (d, J = 5 Hz, 1 H, C -H or C -H), 10.61 (br s, 1
EtOAc, washed with brine, dried over anhyd MgSO and evaporat-
5
8
3
4
4
H, NH).
ed in vacuo. The crude solid was purified by silica gel column chro-
1
3
matography using hexane–EtOAc to give the title compound 2b as
C NMR (acetone-d ): d = 14.5, 42.3, 60.6, 71.5, 112.7, 114.2,
6
colorless crystals (43.1 mg, 88%). Recrystallization from CHCl –
3
1
20.0, 121.6, 121.9, 128.6, 129.8, 133.8, 137.7, 141.4, 146.2, 171.5.
4
hexane gave colorless needles; mp 258–259 °C (lit. mp 250–250.5
+
MS: m/z = 284 [M , 20], 197 (100).
°
C).
Anal. Calcd for C H N O : C, 67.59; H, 5.67; N, 9.85. Found: C,
IR (KBr): 1671 cm–1.
1
6
16
2
3
6
7.46; H, 5.70; N, 9.77.
1
H NMR (CDCl ): d = 4.27 (s, 3 H, OCH ), 6.86 (d, J = 10 Hz, 1 H,
3
3
C -H or C -H), 7.53 (br t, J = 8 Hz, 1 H, C -H or C -H), 7.68 (br t,
4
5
9
10
Canthin-6-one (2a) from Aldol Product 13a by EtONa
J = 8 Hz, 1 H, C -H or C -H), 7.98 (d, J = 10 Hz, 1 H, C -H or C -
9
10
4
5
To a stirred solution of compound 13a (50.2 mg, 0.18 mmol) in an-
hyd EtOH (3 mL), freshly prepared EtONa solution (580 mL) [Na
H), 8.24 (br d, J = 8 Hz, 1 H, C -H or C -H), 8.51 (s, 1 H, C -H),
8
11
2
8
.70 (br d, J = 8 Hz, 1 H, C -H, or C -H).
8 11
(430 mg) in EtOH (50 mL) (0.21 mmol as a EtONa)] was added at
1
3
0
1
°C under an Ar atmosphere. The reaction mixture was stirred for
C NMR (CDCl ): d = 56.8, 116.8, 117.1, 123.5, 124.3, 125.5,
3
0 min. The mixture was poured into cold aq sat. NH Cl, evaporated
129.4, 130.1, 130.5, 132.9, 138.2, 138.8, 151.9, 160.0.
4
in vacuo to remove EtOH. The residual aqueous layer was extracted
+
MS: m/z = 250 [M , 100].
with CHCl . The organic layer was washed with brine, dried over
3
Anal. Calcd for C H N O : C, 71.99; H, 4.03; N, 11.19. Found: C,
MgSO and evaporated to dryness in vacuo. The residue was sub-
15 10
2
2
4
7
1.88; H, 4.07; N, 11.08.
jected to column chromatography using EtOAc–benzene to give the
title compound 2a as colorless crystals (35.8 mg, 92%). This com-
pound was identical to the standard sample synthesized from 7a by
the direct method described below.
Acknowledgment
We are grateful to Professor T. Nikaido and Dr. K. Koike of Toho
University for the gift of a sample of natural product 2b.
Canthin-6-one (2a) (Direct Method from 7a)
To a stirred mixture of HMDS (420 mL, 2.0 mmol) in THF (2 mL),
n-BuLi (1.59 M in hexane, 940 mL, 1.5 mmol) was added at –78 °C
under an Ar atmosphere. The mixture was warmed to r.t. within 30 References
min with stirring and then recooled to –78 °C. EtOAc (112 mL, 1.2
(
1) This paper is ‘Synthetic Studies on Indoles and Related
mmol) in THF (2 mL) was added to the solution and then stirred for
Compounds. Part 53’. For Part 52, see: ‘The Vilsmeier–
Haack Reaction on Methyl Homologues of N-Benzyl-
tetrahydrocarbazole’: Murakami, Y.; Ishii, A.; Ozawa, H.;
Okahira, H.; Hosokawa, K.; Tashiro, T.; Muto, J.; Suzuki,
H.; Tani, M.; Yokoyama, Y. Heterocycles 2003, 61, 225.
2) Current address: Faculty of Pharmaceutical Sciences, Chiba
Institute of Science, 3 Shiomi-cho, Choshi, Chiba 288-0025,
Japan.
1
9
1
5 min at –78 °C. To this solution, b-carboline-1-carbaldehyde (7a,
5.6 mg, 0.49 mmol) in THF (4 mL) was added and then stirred for
0 min at –78 °C. To the reaction mixture, EtOH (6 mL) was added
and then stirred for 30 min at r.t. The whole reaction mixture was
poured into aq sat. NH Cl (30 mL), extracted with EtOAc, washed
with brine, dried over anhydrous MgSO and evaporated in vacuo.
The crude solid was purified by silica gel column chromatography
using hexane–EtOAc to give the title compound 2a as colorless
crystals (88.8 mg, 83%). Recrystallization from EtOAc–hexane
4
(
(
4
3) (a) Johns, S. R.; Lamberton, J. A.; Sioumis, A. A. Aust. J.
Chem. 1970, 23, 629. (b) Kitagawa, I.; Mahmud, T.;
Simanjuntak, P.; Hori, K.; Uji, T.; Shibuya, H. Chem.
Pharm. Bull. 1994, 42, 1416. (c) Ouyang, Y.; Mitsunaga,
K.; Koike, K.; Ohmoto, T. Phytochemistry 1995, 39, 911.
5
gave pale orange needles; 158–159 °C (lit. mp 154–156 °C).
–
1
IR (KBr): 1671 cm .
1
H NMR (CDCl ): d = 6.98 (d, J = 10 Hz, 1 H, C -H or C -H), 7.52
br t, J = 8 Hz, 1 H, C -H or C -H), 7.70 (br t, J = 8 Hz, 1 H, C -H
3
4
5
8
a
(
(d) Further references are cited in ref.
9
10
9
or C -H), 7.94 (d, J = 5 Hz, 1 H, C -H or C -H), 8.02 (d, J = 10 Hz,
1
(4) Ohmoto, T.; Tanaka, R.; Nikaido, T. Chem. Pharm. Bull.
1976, 24, 1532.
1
0
1
2
H, C -H or C -H), 8.09 (br d, J = 8 Hz, 1 H, C -H or C -H), 8.66
4 5 8 11
(
br d, J = 8 Hz, 1 H, C -H or C -H), 8.81 (d, J = 5 Hz, 1 H, C -H or
(5) Ohomoto, T.; Koike, K. Canthin-6-one Alkaloids, In The
Alkaloids, Vol. 36; Brossi, A., Ed.; Academic Press: San
Diego, 1989.
8
11
1
C -H).
2
Synthesis 2005, No. 1, 28–32 © Thieme Stuttgart · New York