A new total synthesis of an indolo[3,2-j]phenanthridine alkaloid calothrixin B

Article abstract of DOI:10.1016/j.tetlet.2005.06.042

A new total synthesis of calothrixin B is described. The key step is an allene-mediated electrocyclic reaction involving the indole 2,3-bond for the construction of a suitable 4-oxygenated 2,3,4-trisubstituted carbazole ring system.

Full text of DOI:10.1016/j.tetlet.2005.06.042

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5263–5264
A new total synthesis of an indolo[3,2-j]phenanthridine
alkaloid calothrixin B
Shigeo Tohyama, Tominari Choshi, Kohji Matsumoto, Akira Yamabuki,
Kouichiro Ikegata, Junko Nobuhiro and Satoshi Hibino*
Graduate School of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences,
Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
Received 23 May 2005; revised 10 June 2005; accepted 13 June 2005
Abstract—A new total synthesis of calothrixin B is described. The key step is an allene-mediated electrocyclic reaction involving the
indole 2,3-bond for the construction of a suitable 4-oxygenated 2,3,4-trisubstituted carbazole ring system.
Ó 2005 Elsevier Ltd. All rights reserved.
The novel pentacyclic metabolites, calothrixins A (1)
and B (2) having an indolo[3,2-j]phenanthridine nucleus
were isolated from Calothrix cyanobacteria in 1999 (Fig.
1).1 They display potent inhibitory effects on the in vitro
growth of both the human malarial parasite and human
cancer cells1 and inhibition of a bacterial RNA polymer-
ase.2 Synthetic efforts of these interesting targets have
been reported by three groups of Kelly et al.,3 Chai
and co-workers4 and Guingant and co-workers.5
phenylsulfonylindole (3)7 as a starting material (Scheme
1).
The Wittig reaction of 3 with 2-nitrobenzyltriphenyl-
phosphorane gave the trans-2-(2-styryl)indole 4 (96%).8
Treatment of 4 with a,a-dichloromethyl methyl ether
9
in the presence of AlCl3 at À78 °C afforded the 3-
formylindole 5 (96%). The Grignard reaction of 5 with
ethynyl magnesium bromide yielded the propargyl alco-
hol 6 (92%), which was protected with chloromethyl
methyl ether in the presence of i-Pr2NEt to produce
the methoxymethyl ether 7 (93%). The propargyl ether
7 was subjected to an allene-mediated electrocyclic reac-
tion6 in the presence of t-BuOK in t-BuOH and THF at
90 °C to yield the desired 4-oxygenated 2,3,4-trisubsti-
tuted carbazole 8 (29%). Subsequent oxidation of 8 with
DDQ in the presence of lithium perchlorate in CH2Cl2
and H2O gave the 3-formyl-4-hydroxycarbazole 9 with
elimination of methoxymethyl group (70%). Reduction
of the nitro group of 9 with 10% Pd–C and H2, followed
by the intramolecular condensation afforded the penta-
cyclic indolo[3,2-j]phenanthridine 10, which was oxi-
dized to quinone with CAN (cerric ammonium nitrate)
to provide calothrixin B (2) (67% yield from 9).10 The
physical and spectroscopic data of synthetic sample 2
were identical with those of natural calothrixin B (2).1
We herein, describe a new total synthesis of calothrixin
B (2) through a construction of a 4-oxygenated 2,3,4-tri-
substituted carbazole ring, derived from a disconnection
at the C-5 and C-6 bond, based on an allene-mediated
electrocyclic reaction of 6p-electron system involving
the indole 2,3-bond.6 For the synthesis of 4-oxygenated
2,3,4-trisubstituted carbazole 8, we chose 2-formyl-N-
O
O
O
8
O
6
N
N5
12
4
N
H
N
H
11
O
1
1
2
Figure 1.
Thus, a synthetic route to calothrixin B (2) was newly
completed with a 10.7% overall yield by the construction
of an appropriate 4-oxygenated 2,3,4-trisubstituted car-
bazole ring 8 based on our methodology,6 followed by
the connection between C-5 and C-6 to the pentacyclic
Keywords: Indolo[3,2-j]phenanthridine; Calothrixin B; Synthesis;
Quinone.
*
Corresponding author. Tel.: +81 84 936 2111; fax: +81 84 936
2024; e-mail: hibino@fupharm.fukuyama-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.042

5264
S. Tohyama et al. / Tetrahedron Letters 46 (2005) 5263–5264
CHO
O2N
i
ii
N
SO2
N
SO2
CHO
N
SO2
Ph
Ph
Ph
O2N
iv
3
4
5
OMOM
OH
iii
N
SO2
N
SO2
Ph
O2N
OH
Ph
O2N
6
7
OMOM
CHO
Me
vi
v
N
H
N
H
O2N
O
O2N
OH
8
9
viii
vii
N
N
N
H
N
H
O
2
10
Scheme 1. Reagents and conditions: (i) 2-nitrobenzyl triphenylphosphonium bromide, n-BuLi, THF, 0 °C, 3 h (96%); (ii) Cl2CHOMe, AlCl3,
CH2Cl2, À78 °C, 1 h (96%); (iii) ethynylmagnesium bromide, THF, 0.5 h (92%); (iv) MOMCl, i-Pr2NEt, CH2Cl2, 50 °C, 12 h (93%); (v) t-BuOK, t-
BuOH, THF, 0.5 h (29%); (vi) (1) DDQ, LiClO4, CH2Cl2, H2O, rt, 40 h, (2) 6 N HCl, ethylene glycol, THF, 60 °C, 3 h (70%); (vii) 10% Pd–C, H2,
EtOH, rt, 5 h; (viii) CAN, MeCN, H2O, 0 °C, 1 h (67% from 9).
5. Sissouma, D.; Collet, S. C.; Guingant, A. Y. Synlett 2004,
2612–2614.
indolo[3,2-j]phenanthridine ring 10. Although our route
to 2 had the lower overall yield in the comparison with
those of the earlier three groups,3–5 it would be charac-
terized that our synthetic strategy facilitates a construc-
tion of a chemical library, in particular E-ring of
calothrixins A (1) and B (2) for biological evaluations.
6. (a) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.;
Sugino, E.; Hibino, S. Tetrahedron Lett. 1996, 15, 2593–
2596; (b) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama,
C.; Sugino, E.; Hibino, S. J. Org. Chem. 1997, 62, 2535–
2543; (c) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino,
E.; Hibino, S. Chem. Pharm. Bull. 1998, 46, 1948–1949; (d)
Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.;
Hibino, S. Tetrahedron 2000, 56, 5807–5811; (e) Hagiwara,
H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S.
Chem. Pharm. Bull. 2001, 49, 881–886; (f) Hirayama, M.;
Choshi, T.; Kumemura, T.; Tohyama, S.; Nobuhiro, J.;
Hibino, S. Heterocycles 2004, 63, 1765–1770.
Acknowledgements
This work was supported in part by Grants-in Aid for
Scientific Research (C) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
7. Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982, 47,
757–761.
References and notes
8. All new compounds have been characterized by physical
and spectroscopic analyses.
1. Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de
Chazal, N. M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G.
D. Tetrahedron 1999, 55, 13513–13520.
2. (a) Doan, N. T.; Stewart, P. R.; Smith, G. D. FEMS
Microbiol. Lett. 2001, 196, 135–139; (b) Doan, N. T.;
Rickards, R. W.; Rothschild, J. M.; Smith, G. D. J. Appl.
Phycol. 2000, 12, 409–416.
3. Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org.
Lett. 2000, 2, 3735–3737.
4. (a) Bernardo, P. H.; Chai, C. L. L.; Elix, J. A. Tetrahedron
Lett. 2002, 43, 2939–2940; (b) Barnardo, P. H.; Chai, C. L.
L. J. Org. Chem. 2003, 68, 8906–8909.
9. This Friedel–Crafts type reaction was carried out by a
modification of the MurakamiÕs procedure: Tani, M.;
Aoki, T.; Ito, S.; Matsumoto, S.; Hideshima, M.; Fuku-
shima, K.; Nozawa, R.; Maeda, T.; Tashiro, M.; Yokoy-
ama, Y.; Murakami, Y. Chem. Pharm. Bull. 1990, 38,
3261–3267.
10. Calothrixin B: mp >300 °C. 1H-NMR (DMSO-d6,
300 MHz): d 7.39 (1H, t, J = 7.7 Hz), 7.47 (1H, t, J =
7.7 Hz), 7.63 (1H, d, J = 7.7 Hz), 7.89 (1H, t, J = 7.7 Hz),
7.96 (1H, t, J = 7.7 Hz), 8.17 (1H, d, J = 7.7 Hz), 8.19 (1H,
d, J = 7.7 Hz), 9.58 (1H, d, J = 7.7 Hz), 9.63 (1H, s), 13.18
(1H, br s).