A facile synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazoles via oxidative photocyclization of bisindolylmaleimides

Article abstract of DOI:10.1055/s-2003-37645

A simple and inexpensive oxidative photocyclization of the bisindolylmaleimides in the presence of a catalytic amount of iodine leading to indolo[2,3-a]pyrrolo[3,4-c]carbazoles in 84-90% yields is described.

Full text of DOI:10.1055/s-2003-37645

PAPER
497
A Facile Synthesis of Indolo[2,3-a]pyrrolo[3,4-c]carbazoles via Oxidative
Photocyclization of Bisindolylmaleimides
A
G
F
acile Synthesis
.
of
I
ndolo[2,
M
3-
a
]pyrrolo[3,4-
c
]carb
a
a
zoles hesh Reddy, Shyh-Yeon Chen, Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300, Republic of China
Fax +886(3)5711082; E-mail: bjuang@mx.nthu.edu.tw
Received 31 October 2002; revised 18 December 2002
approach involving oxidative cyclization of bisindolylma-
leimide 6 is the most attractive because it is short and the
starting materials are readily available. Various oxidizing
Abstract: A simple and inexpensive oxidative photocyclization of
the bisindolylmaleimides in the presence of a catalytic amount of
iodine leading to indolo[2,3-a]pyrrolo[3,4-c]carbazoles in 84–90%
yields is described.
11g–i
agents, such as DDQ (with or without p-TsOH),
1
1j
11f
Pd(OAc) ,
PdCl2, Pd(O CCF )
and PIFA/
2
2
3 2
Key words: photooxidation, indole alkaloid, heterocycle, stauro-
sporine, aglycon
1
1c
BF ⋅OEt2 have been previously employed in this oxida-
3
tive cyclization. However, most of these reagents have
their own limitations, for example a) with DDQ/p-TsOH
used as an oxidant, it is difficult to remove DDQ by-prod-
ucts, b) reactions with Pd are stoichiometric, expensive,
and further, removal of Pd from indolocarbazoles is diffi-
cult (due to poor solubility), c) the yields are low with
PIFA/BF ⋅OEt . An alternate method is an oxidative pho-
The indolocarbazole alkaloids are structurally rare, but bi-
ologically very interesting class of natural products. The
1
most well known members of this family are rebeccamy-
2
3
4
cin 1 , staurosporine 2, and K252a 3 owing to their wide
3
2
range of pharmacological activities such as antimicrobi-
5
6
3a
tocyclization. Earlier, a couple of photocyclizations of in-
dolocarbazole lactams were reported12 to provide the
staurosporine aglycon moiety in 37% and 65% yields, re-
al, hypotensive, cell cytotoxic, inhibition of protein ki-
3
a
7
nase C and platelet aggregation. Their unique structures
coupled with their wide range of biological activities have
recently attracted intensive synthetic studies on these
9c
spectively. Danishefsky and co-workers have disclosed
the photocyclization of indole glycoside derivative using
Hanvonia medium pressure Hg lamp 450 W with Vycor
filter in the presence of a catalytic amount of iodine while
air was bubbled into the benzene solution for 8 hours. The
8
–10
11
molecules
and their aglycon.
The indolocarbazole, the common aglycon moiety of
these compounds, is known to retain much of the activity
of the parent molecule. Several methods have been report-
ed for the synthesis of aglycons 4 and 5. Among them, the
corresponding indolocarbazole glycoside was obtained in
11e
7
3% yield. Recently Slater and co-workers have ac-
H
H
H
N
O
N
O
O
N
O
N
N
N
N
N
N
H
O
O
Cl
Cl
OH
Me
H
O
Me
H
MeO
MeO
2
C
OH
NH
OH
HO
Me
OMe
3
2
1
H
H
N
O
N
O
O
N
N
N
N
H
H
H
H
4
5
Figure 1
Synthesis 2003, No. 4, Print: 18 03 2003.
Art Id.1437-210X,E;2003,0,04,0497,0500,ftx,en;F08902SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
©

4
98
G. M. Reddy et al.
PAPER
Scheme 1
complished a similar photocyclization in isopropanol us- hours to afford the lactam 5 in 68% yield. Most of the re-
ing excess of iodine in an inert atmosphere to provide the ported methods that converted 4 to 5 have conducted in a
product in 72% yield.
three-step procedure involving the initial protection of im-
ide nitrogen and subsequent Clemmensen reduction and
As part of our ongoing research program towards the total
deprotection.1
0c,11i,15
Although there exist two reports
16
1
3
synthesis of staurosporine and K252a, herein we report
an improved and practical procedure for the synthesis of
indolo[2,3-a]pyrrolo[3,4-c]carbazole ring system (4).
describing a one-step conversion of 4 to 5 by Clemmensen
reduction, the lactam is obtained in a relatively better
yield in the present case.
Table 1 Oxidative Photocyclization of Indolylmaleimides 6a–e
H
H
N
O
N
O
R1
O
Entry
R
Time (h) Product
Yield (%)
1
2
3
4
5
H
H
H
H
H
Cl
12
6
4a
4b
4c
4d
4e
85
90
90
84
87
Zn/Hg, THF,
M HCl
6
F
N
N
68%
N
N
H
H
H
H
Br
OCH3
H
3
4a
5
24
6
Scheme 2
In conclusion, a simple and practical procedure was de-
A series of bisindolylmaleimides 6a–e were readily ob- veloped for the synthesis of pharmacologically important
tained by the reaction of appropriately substituted indolyl- rebeccamycin, staurosporine, and K252a aglycons and
magnesium bromide with 3,4-dichloromaleimides.14 their analogues by the photooxidation of bisindolylmale-
Oxidative cyclization of 6a–e using an ordinary 400 W imides using an ordinary Hg lamp. The method is opera-
mercury lamp in the presence of a catalytic amount of io- tionally simple, obviating the need for oxygen bubbling
dine in THF–CH CN (1:1) at room temperature furnished and expensive equipment.
3
the desired indolo[2,3-a]pyrrolo[3,4-c]carbazoles 4a–e in
8
4–90% yields (Scheme 1, Table 1). It is noteworthy that,
even without protection of imide N–H or indolo N–H, the
reaction still gives good yields. The presence of an elec-
Oxidative Photocyclization of 6; Typical Procedure
Indolylmaleimide (6a, 0.150 g, 0.45 mmol) was dissolved in THF–
tron-withdrawing group in the substrate 6 enhances the re- CH CN (1:1, 100 mL) and catalytic amount of I (0.010 g) was add-
3
2
activity (entries 2, 3, and 5) while the reaction was slow ed. The reaction mixture was irradiated at r.t. using two 400 W mer-
cury lamps (Eye lighting Co., LTD, Taiwan, Model-H 400, high
pressure, 560 nm) for 12 h. The solvent was removed in vacuo, the
when an electron donating substituent was present in 6
(
entry 4). This high-yielding photocyclization process can
residue was dissolved in THF (3 mL) and reprecipitated with hex-
ane. The solid was filtered, dried at 150 °C under vacuum and was
be successfully scaled up to multigram level. In addition,
the chemical yield of the reaction is independent on the
substrate concentration over a range of 0.004–0.015 M.
11e
characterized as 4a (0.127 g, 85%). On a 5.0 g scale at 0.015 M
concentration, the reaction was completed in 96 h under similar re-
However, at concentration higher than 0.015 M the reac- action conditions and the desired product was obtained in 86%
tion could not reach completion owing to the precipitation yield; mp > 350 °C.
of the product, which blocked light for the photocycliza- IR (KBr): 3354, 3216, 1722, 1681 cm .
–
1
tion. The reduction of symmetric imide 4a to the stauro-
sporinone 5 was achieved by slightly modifying the
1
H NMR (400 MHz, DMSO-d ): δ = 11.71 (s, 2 H, indole NH),
0.96 (s, 1 H, imide NH), 8.97 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0
6
1
Clemmenson reduction method. Thus, zinc amalgam pre- Hz, 2 H), 7.53 (t, J = 7.2 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 2 H).
pared from zinc powder was washed with dilute hydro-
chloric acid and used in the reduction of 4a in a mixture
of 6 N HCl and THF under refluxing conditions for 1.5
13
C NMR (100 MHz, DMSO-d ) δ = 171.3, 140.3, 129.0, 126.7,
6
1
24.3, 121.6, 120.2, 119.9, 115.5, 112.0.
HRMS (EI): m/z calcd for C H N O , 325.0850; found, 325.0854.
2
0
11
3
2
Synthesis 2003, No. 4, 497–500 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Synthesis of Indolo[2,3-a]pyrrolo[3,4-c]carbazoles
499
–
1
1
2,13-Dihydro-3,9-difluoro-5H-indolo[2,3-a]pyrrolo[3,4-c]car-
IR (KBr): 3435, 3304, 1647 cm .
1
7
bazole-5,7-(6H)-dione (4b)
Mp > 350 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 11.48 (s, 1 H, NH), 11.31 (s, 1
6
H, NH), 9.20 (d, J = 8.0 Hz, 1 H), 8.47 (s, 1 H, lactam NH), 8.02 (d,
J = 7.5 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H,), 7.70 (d, J = 7.5 Hz, 1
H), 7.47 (dd, J = 7.5, 8.0 Hz, 1 H), 7.43 (dd, J = 7.5, 7.5 Hz, 1 H),
–
1
IR (KBr) 3364, 3199, 1746, 1699 cm .
1
H NMR (500 MHz, DMSO-d ): δ = 11.80 (s, 2 H, indole NH),
6
7
.28 (dd, J = 7.0, 7.5 Hz, 1 H), 7.21 (dd, J = 7.0, 8.0 Hz, 1 H), 4.95
1
1.04 (s, 1 H, imide NH), 8.62 (dd, J = 2.5, 10.0 Hz, 2 H), 7.81 (dd,
(s, 2 H, lactam CH2).
J = 4.5, 9.0 Hz, 2 H), 7.40 (ddd, J = 2.5, 9.0, 9.0 Hz, 2 H).
13C NMR (125 MHz, DMSO-d
): δ = 172.5, 139.2, 139.1, 132.9,
27.9, 125.4, 125.2, 125.0, 122.8, 122.6, 121.1, 119.9, 119.0, 118.9,
1
3
6
C NMR (125 MHz, DMSO-d ): δ = 171.2, 157.8, 155.9, 136.7,
6
1
1
1
1
30.0, 121.8, 121.7, 120.0, 115.2, 115.1, 114.8, 114.6, 113.4, 113.3,
09.1, 108.9.
15.6, 114.2, 111.9, 111.4, 45.3.
+
+
HRMS (FAB ): m/z calcd for C20
H
13
N
3
O, 311.1059; found,
HRMS (FAB ): m/z calcd for C H F N O , 361.0663; found,
3
2
0
9
2
3
2
3
11.1021.
61.0667.
1
2,13-Dihydro-3,9-dibromo-5H-indolo[2,3-a]pyrrolo[3,4-c]car-
Acknowledgment
1
1e
bazole-5,7-(6H)-dione (4c)
Mp > 350 °C.
We thank the National Science Council, Republic of China for the
financial support.
–
1
IR (KBr) 3364, 3199, 1738, 1699 cm .
1
H NMR (400 MHz, DMSO-d ): δ = 11.59 (s, 2 H, indole NH),
6
1
7
0.93 (s, 1 H, imide NH), 8.86 (s, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), References
.53 (d, J = 8.8 Hz, 2 H).
(
1) Gribble, G. W.; Berthel, S. J. Studies in Natural Products
Chemistry 1993, 12, 365.
2) Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.;
Tomita, K. J. Antibiotics 1987, 40, 668.
1
3
C NMR (100 MHz, DMSO-d ): δ = 170.9, 138.7, 129.0, 126.1,
23.0, 120.0, 114.3, 113.8, 112.2.
6
1
(
+
HRMS (FAB ): m/z calcd for C H Br N O , 480.9001; found,
2
0
9
2
3
2
4
80.8990.
(3) (a) Tamaoki, T.; Nomoto, H.; Takahishi, I.; Kato, Y.;
Morimoto, M.; Tomita, F. Biochem. Biophys. Res. Commun.
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1
2,13-Dihydro-3,9-dimethoxy-5H-indolo[2,3-a]pyrrolo[3,4-c]-
1
1e
carbazole-5,7-(6H)-dione (4d)
Mp > 350 °C.
(
4) Kase, H.; Iwahashi, K.; Matsuda, Y. J. Antibiotics 1986, 39,
059.
–
1
IR (KBr): 3333, 3245, 1746, 1713 cm .
1
1
H NMR (400 MHz, DMSO-d ): δ = 11.52 (s, 2 H, indole NH),
0.92 (s, 1 H, imide NH), 8.54 (s, 2 H), 7.69 (d, J = 8.8 Hz, 2 H),
.17 (d, J = 8.8 Hz, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H).
6
(5) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.;
Tsuchiya, H.; Takakashi, Y.; Masuma, R. J. Antibiotics
1977, 30, 275.
1
7
1
3
(6) (a) Omura, S.; Iwai, Y.; Hirano, A. Japan Kokai 7873501,
C NMR (100 MHz, DMSO-d ): δ = 171.4, 153.8, 135.0, 129.6,
22.1, 119.6, 116.0, 115.3, 112.7, 106.6, 55.5.
6
1
978; Chem. Abstr. 1978, 89, 178086h. (b) Omura, S.; Iwai,
Y.; Hirano, A. Ger. Offen. 2745326, 1978; Chem. Abstr.
978, 89, 58348y.
1
+
HRMS (FAB ): m/z calcd for C H N O , 385.1063; found,
2
2
15
3
4
1
3
85.1056.
(
(
7) Oka, S.; Kodama, M.; Takada, H.; Tomizuka, N.; Suzuki,
H.; Agric, G. Biol. Chem. 1986, 50, 2723.
1
2,13-Dihydro-2,10-dichloro-5H-indolo[2,3-a]pyrrolo[3,4-
8) For recent work on rebeccamycin and its analogues see:
c]carbazole-5,7-(6H)-dione (4e)
Mp > 350 °C.
(
a) Akao, A.; Hiraga, S.; Iida, T.; Kamatani, A.; Kawasaki,
M.; Mase, T.; Nemoto, T.; Satake, N.; Weissman, S. A.;
Tschaen, D. M.; Rossen, K.; Petrillo, D.; Reamer, R. A.;
Volante, R. P. Tetrahedron 2001, 57, 8917. (b)Chisholm, J.
D.; Van Vranken, D. L. J. Org. Chem. 2000, 65, 7541.
9) For the reports on synthesis of staurosporine see: (a) Wood,
J. L.; Stoltz, B. M.; Goodman, S. N.; Onwueme, K. J. Am.
Chem. Soc. 1997, 119, 9652. (b) Wood, J. L.; Stoltz, B. M.;
Goodman, S. N. J. Am. Chem. Soc. 1996, 118, 10656.
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Chou, T. C.; Ballas, L. J. Am. Chem. Soc. 1996, 118, 2825.
–
1
IR (KBr) 3390, 3221, 1738, 1698 cm .
1
H NMR (400 MHz, DMSO-d ): δ = 11.61 (s, 2 H, indole NH),
0.93 (s, 1 H, imide NH), 8.75 (d, J = 8.4 Hz, 2 H), 7.76 (s, 2 H),
.25 (d, J = 8.4 Hz, 2 H).
6
1
7
(
1
3
C NMR (125 MHz, DMSO-d ): δ = 171.0, 140.8, 131.3, 129.2,
25.4, 120.5, 120.3, 120.0, 115.0, 111.9.
6
1
+
HRMS (FAB ): m/z calcd for C H Cl N O , 393.0272; found,
2
0
9
2
3
2
3
93.0269.
(
d) Link, J. T.; Raghaven, S.; Danishefsky, S. J. J. Am.
Chem. Soc. 1995, 117, 552.
10) For recent work on K252a and its analogues see:
a) Tamaki, K.; Huntsman, E. W. D.; Petsch, D. J.; Wood, J.
Preparation of Staurosporinone 5
(
To a solution of indolocarbazole (4a, 0.100 g, 0.3 mmol) in THF (20
mL) was added zinc amalgam (2 g) and the reaction mixture was
heated under reflux. As the refluxing commenced, 6 N HCl (2.5
mL) was added dropwise over a period of 30 min. After the addi-
tion, heating was continued for an additional 1 h and then diluted
with EtOAc (25 mL). The inorganic solid was filtered off and the
filtrate was washed with brine (20 mL), dried (Na SO ) and concen-
trated in vacuo. The residue was subjected to flash chromatography
eluting with EtOAc–hexanes (3:1) to furnish 5 in 68% yield
0.065 g,); mp > 350 °C.
(
L. Tetrahedron Lett. 2002, 43, 379. (b) Tamaki, K.;
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2
4
(
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1
8
(
1
(
Synthesis 2003, No. 4, 497–500 ISSN 0039-7881 © Thieme Stuttgart · New York

5
00
G. M. Reddy et al.
PAPER
(
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(
(
1
Synthesis 2003, No. 4, 497–500 ISSN 0039-7881 © Thieme Stuttgart · New York