An efficient modification of ellipticine synthesis and preparation of 13-hydroxyellipticine

Article abstract of DOI:10.1016/j.tetlet.2007.07.160

A simple modification of a previously published ellipticine synthesis is reported, which decreases the reaction time and increases the yield and purity of the product. Benzylic oxidations of 1,4-dimethylcarbazole and ellipticine derivatives were studied and 13-hydroxyellipticine was prepared.

Full text of DOI:10.1016/j.tetlet.2007.07.160

Tetrahedron Letters 48 (2007) 6893–6895
An efficient modification of ellipticine synthesis
and preparation of 13-hydroxyellipticine
a,b,
b,z
b
c
*
´
´ ´
Barbora Rygerova and Marie Stiborova
Martin Dracˇınsky´,
Jan Sejbal,
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republick, 16610 Praha 6, Czech Republic
bDepartment of Organic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
cDepartment of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
Received 2 July 2007; revised 17 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—A simple modification of a previously published ellipticine synthesis is reported, which decreases the reaction time and
increases the yield and purity of the product. Benzylic oxidations of 1,4-dimethylcarbazole and ellipticine derivatives were studied
and 13-hydroxyellipticine was prepared.
Ó 2007 Elsevier Ltd. All rights reserved.
Ellipticine
(5,11-dimethyl-6H-pyrido[4,3-b]carbazole,
sis starts from indole requiring five reaction steps to
afford para-toluenesulfonamide 1a, which cyclizes in
boiling dioxane containing HCl to give ellipticine 2a in
70% yield.14 The major problem in all the syntheses of
ellipticine is the low solubility of the alkaloid in polar
as well as non-polar solvents, which makes chromato-
graphic purification inconvenient. Two syntheses of
13-hydroxyellipticine have been published,15,16 in both
cases the synthesis was rather complicated and the over-
all yields were low. Several unsuccessful synthetic ap-
proaches to ellipticines with a substituent at C-13 have
also been reported.17
2a), an alkaloid isolated from Apocyanaceae plants
and several of its derivatives exhibits promising results
in the treatment of osteolytic breast cancer metastases,
kidney sarcoma, brain tumors and myeloblastic leuke-
mia.1 The main reason for the interest in ellipticine
and its derivatives for clinical purposes is their high effi-
ciency against several types of cancer, limited toxic side
effects and complete lack of hematological toxicity.2 The
antineoplastic property of ellipticine was considered to
be based mainly on DNA intercalation and/or inhibi-
tion of topoisomerase II.3–7 Recently, it was demon-
strated that ellipticine covalently binds to DNA
in vitro and in vivo after being enzymatically activated
with cytochrome P450 or peroxidases.1,8–11 Deoxygua-
nosine was identified as the target base to which the
two ellipticine metabolites, 13-hydroxyellipticine and
12-hydroxyellipticine are bound,9 forming two major
ellipticine-derived DNA adducts.9–11 It was suggested
that 13-hydroxyellipticine might, depending on the
environment, decompose spontaneously to the reactive
carbenium ion ellipticine-13-ylium, which reacts with
one of the nucleophilic centers in the deoxyguanosine
residue in DNA (i.e., the exocyclic –NH2 group of
guanine).8,9,12
We found that a simple modification of the previously
published synthesis14 of ellipticine increases the yield
and purity of the product dramatically. When para-tol-
uenesulfonamide 1a was replaced with benzenesulfona-
mide 1b, the cyclization reaction to ellipticine (2a) was
much faster (100% conversion in 20 min compared to
6 h with para-toluenesulfonamide 1a) and the yield
was better (97%); ellipticine crystallizes directly from
the reaction mixture and no further purification was
necessary. 9-Methoxyellipticine (2b) was also prepared
from the appropriate benzenesulfonamide 1d and the
reaction rate and yield were also better than in the case
of para-toluenesulfonamide 1c (Scheme 1). The mecha-
nism of the reaction probably involves ring closure
and then solvolysis of sulfonamide. The para-toluenesul-
fonamide with a closed 1,2-dihydropyridine ring was
also isolated from the reaction of compound 1a.14 Elec-
tronic effects of the substituent at the para position of
the sulfonamides probably influence the stability of sul-
Many synthetic pathways for the preparation of ellipti-
cine have been proposed.13 The most convenient synthe-
*
Corresponding author. Tel.: +420 220183139; fax: +420
220183123; e-mail: dracinsky@uochb.cas.cz
z Deceased.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.160

6894
M. Dracˇı´nsky´ et al. / Tetrahedron Letters 48 (2007) 6893–6895
2´
3´
O
O
12
11
11
4
S
R2
1
2
12
R1
1´
4´
10
R1
N
5
N
6
14
dioxane
HCl
4b
4a
3
3
OEt
8
5
2
15
7
4
OEt
1
7
8a
N
H
9a
N
8
13
10
H
R1
2a -H (97%)
2b -OCH3 (94%)
R1
1a -H
1b -H
R2
-CH3
-H
1c -OCH3 -CH3
1d -OCH3 -H
Scheme 1.
fonamides against solvolysis dramatically. Electron
donating groups such as methyl make sulfonamide more
stable and consequently, solvolysis is slower.
and the reaction time was prolonged, tribromo deriva-
tive 4 was the only product of the reaction.
Dinitroderivative 6 was prepared by oxidation of 1,4-
dimethylcarbazole and was then oxidized with K2S2O8.
The reaction gave a mixture, which was not separated,
We wanted to explore the possibility of the preparation
of 13-hydroxyellipticine by oxidation of the benzylic
methyl groups. 1,4-Dimethylcarbazole (3) was used as
a model compound for studying the benzylic oxidation
with various oxidation agents. When K2S2O8–Cu(OAc)2
in acetic acid18 was used, the reaction mixture poly-
1
but according to the H NMR spectrum, the benzylic
methyls had been oxidized. The signals for the CH3
groups at 2.4 and 2.8 ppm were missing and new signals
at 5.4 and 5.8 ppm were apparent indicating the pres-
ence of acetoxy groups at the benzylic positions. A sig-
nal at 2 ppm was due to the acetate methyl group. The
dinitro derivative was reduced with SnCl2 and the result-
ing 3,6-diamino-1,4-dimethylcarbazole (7) oxidized with
K2S2O8, however, the reaction mixture polymerized
(Scheme 2).
merized. Polymerization also occurred when the
19
´
Etard reaction was applied to 1,4-dimethylcarbazole
(3). Oxidation with CrO3 led to a complex mixture,
which showed no evidence of oxidation products in
1
the H NMR. The reaction of 3 with bromine did not
lead to oxidation of benzylic positions, however
aromatic substitution took place and 3,6,8-tribromo-
1,4-dimethylcarbazole (4) was the reaction product.
The tribromo derivative was further oxidized with
K2S2O8 to yield 4-acetoxymethyl-3,6,8-tribromo-1-
methylcarbazole (5) as the major product. Hence, in this
case benzylic oxidation took place and the resulting hy-
droxy derivative was acetylated with acetic acid present
as the solvent. N-Bromoacetamide in the presence of
dibenzoylperoxide was used as another oxidation
reagent, but as in the case of bromine, no benzylic
oxidation took place. The result of this reaction was a
mixture of three products (probably monobromo deriv-
atives); when an excess of N-bromoacetamide was added
It is clear from the experiments described above that 1,4-
dimethylcarbazole is very sensitive to oxidizing agents.
The benzylic oxidation conditions led to aromatic sub-
stitution or to polymerization (probably by a radical
mechanism). When electron accepting substituents
(which in addition block the positions of possible aro-
matic substitution) were introduced into the molecule,
benzylic oxidation can take place preferably at the
methyl group at position 1. This is probably due to
the greater steric hindrance of the methyl group at posi-
tion 4 and also the higher stability of the intermediate
benzyl radical.
Br
Br
Br
Br
(i)
(ii)
N
H
N
N
H
Br
Br
OAc
H
3
4
100%
5
40%
(iii)
NH2
H2N
NO2
O2N
(iv)
N
N
H
H
7
62%
6
89%
Scheme 2. Reagents and conditions: (i) Br2, CHCl3 20 min, rt; (ii) K2S2O8, CuSO4, AcONa, AcOH, 2 h, reflux, 30 min, 100 °C; (iii) HNO3, AcOH;
(iv) SnCl2, HCl, 1 h, 100 °C.

M. Dracˇı´nsky´ et al. / Tetrahedron Letters 48 (2007) 6893–6895
6895
N
O2N
N
(ii)
(i)
2a
N
H
N
H
CH2OH
8
73%
9
27%
Scheme 3. Reagents and conditions: (i) HNO3, AcOH, 0 °C, 45 min; (ii) (1) K2S2O8, CuSO4, AcONa, AcOH, 2 h, reflux; (2) SnCl2, HCl, 1 h, 100 °C;
(3) NaNO2, 10 min, 5 °C; (4) EtOH.
5. Monnot, M.; Mauffret, O.; Simon, V.; Lescot, E.; Psaume,
B.; Saucier, J. M.; Charra, M.; Belehradek, J., Jr.;
Fermandjian, S. J. Biol. Chem. 1991, 25, 1820.
The information obtained from these experiments was
utilized to prepare 13-hydroxyellipticine. Firstly, 9-
nitroellipticine (8) was prepared by nitration of ellipti-
cine. Next, nitro compound 8 was oxidized with
K2S2O8 and the nitro group of the product was reduced
without isolation with SnCl2. The resulting amino deriv-
ative was diazotized and reduced with ethanol to give
13-hydroxyellipticine (9). The overall yield of this reac-
tion sequence was 27% after purification by preparative
HPLC (Scheme 3). Ellipticine could not be oxidized di-
rectly at the benzylic position as it, as well as 1,4-dimeth-
ylcarbazole (3), are very sensitive to oxidation and
polymerization or electrophilic substitution often
occurs.
´
´
6. Fosse, P.; Rene, B.; Charra, M.; Paoletti, C.; Saucier, J.
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Supplementary data
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Supplementary data (experimental procedures and char-
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doi:10.1016/j.tetlet.2007.07.160.
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