A new synthetic route to indoloquinones: Formal synthesis of ellipticine

Article abstract of DOI:10.1055/s-2005-864826

The anionic [4+2] cycloaddition of furoindolones with arynes and quinol ethers is introduced as an efficient strategy for the synthesis of indoloquinones. The utility of the strategy is exemplified by a very short synthesis of elipticine.

Full text of DOI:10.1055/s-2005-864826

994
LETTER
A New Synthetic Route to Indoloquinones: Formal Synthesis of Ellipticine
Formal Synthesis
o
i
f
E
llip
p
ticine akranjan Mal,* Bidyut K. Senapati, Pallab Pahari
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Fax +91(3222)255303; E-mail: dmal@chem.iitkgp.ernet.in
Received 6 December 2004
O
Abstract: The anionic [4+2] cycloaddition of furoindolones with
arynes and quinol ethers is introduced as an efficient strategy for the
synthesis of indoloquinones. The utility of the strategy is exempli-
fied by a very short synthesis of elipticine.
Me
O
O
N
N
N
N
H
N
H
N
H
O
O
Me
Key words: indoles, quinones, anionic cycloaddition
3
1
2
Figure 1
Ellipticine (1), a representative member of pyrido[4,3-
b]carbazole alkaloids, was isolated in 1959 from the stems
of Ochrosia elliptica Labill.1 In 1967, this alkaloid and its
derivatives were reported to possess promising anti-
tumour activities.2 Since then, a large number of investi-
gations of the structure–activity have been made
concomitantly with the development of efficient synthetic
routes to ellipticines and structurally allied derivatives.3
Several ellipticine analogs are in phase II clinical trials,
though the parent ellipticine is too toxic to be useful.
However, elliptium, an ellipticine analog is used for treat-
ment of thyroid, breast and kidney cancer.4 Calothrixins
(e.g., calothrixins A, 2), a newer class of alkaloids with an
indolo[3,2-j]phenanthridine ring system were isolated
from the cyanobacteria Calothrix in 1999.5 They exhibit
potent activity against both malaria parasites and human
cancer cell lines at nanomolar scales. The striking struc-
tural resemblance between ellipticines and calothrixins
provoked us to develop a common strategy for their syn-
thesis. More interestingly, both calothrixin A (2) and el-
lipticine quinone (3, Figure 1) have very similar EC50
values to HeLa cell lines.6 Several indolonaphthoqui-
nones also have shown promising antileukemic activity,
but pharmacological studies are inhibited by the lack of
easy accessibility.7 Above all, simple indoloquinones are
useful synthetic intermediates for the total synthesis of
alkaloids.8 Herein, we report our preliminary finding that
the anionic [4+2] cycloaddition of furoindolones with
arynes, quinol ethers and quinone monoketals provides a
straightforward route for the preparation of indoloqui-
nones. We also report that ellipticine (1) can be synthe-
sized in only three steps from the known furoindolone 4,
which, in turn, is obtainable in two steps from commer-
cially available inexpensive starting materials.
mation of the heterocyclic ring as the last crucial step.10
Our continued interest in the application of anionic [4+2]
cycloaddition11 of isobenzofuranones led us to undertake
a study on anionic reactivity of furoindolones (e.g. 5).
Moreover, anionic [4+2] cycloaddition has never been in-
vestigated in the context of heterocyclic quinone com-
pounds.12 Accordingly, we devised Scheme 1 for the
direct entry to indoloquinones.
X
O
O
i) base
O
E
ii) oxidation
E
N
N
P
O
P
P = protecting group, E = electron withdrawing group, X = SO2Ph
Scheme 1 Proposed methodology for the synthesis of indoloqui-
nones.
Our study began with the preparation of precursor furo-
indolone 4,13 following the literature procedure. Fischer
indolization of 3-(2-phenylhydrazono)dihydrofuran-
2(3H)-one in the presence of HCl afforded 4 in 40% yield.
This was then derivatized to N-ethoxycaronyl derivative 5
(92%, Figure 2) by treatment with ethyl chloroformate in
the presence of triethylamine. N-Phenylsulfonyl deriva-
tive 6 was similarly prepared in 68% yield from com-
pound 4, using benzenesulfonyl chloride, K2CO3 and a
catalytic amount of triethylbenzylammonium chloride.
Furoindolone 5 was further functionalized at C-1 with a
phenylsulfonyl group (Scheme 2) in line with the work
previously reported by Hauser et al.12b on benzoisofura-
nones for the synthesis of quinonoids.
The established synthetic avenues to indoloquinones
commonly entail Friedel–Crafts acylation or carbolithia-
tion as one of the key steps.9 Alternative methods rely
upon use of 2-phenylamino-1,4-napthoquinones and for-
1
O
O
O
3
O
O
O
N
N
N
SO2Ph
4
COOEt
H
SYNLETT 2005, No. 6, pp 0994–0996
0
6.
0
4.
2
0
0
5
6
4
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864826; Art ID: D36104ST
© Georg Thieme Verlag Stuttgart · New York
Figure 2

LETTER
Formal Synthesis of Ellipticine
995
PhO2S
Me
Br
N
HO
MeO
CH3
O
O
O
a
b
5
O
O
N
N
H
N
H
O
OH
O
OH
COOEt
O
COOEt
7
8
10
9
11
MeO
Scheme 2 Reagents and conditions: a) NBS, benzoyl peroxide,
CCl4, reflux, 70%; b) PhSO2Na, DMF, 85%.
O
O
MeO
OMe
CH3
CH3
Bromination of compound 5 with N-bromosuccinimide in
the presence of benzoyl peroxide proceeded smoothly to
give 1-bromo derivative 7 in 70% yield. Further transfor-
mation of the compound 7 to 8 was conveniently per-
formed by direct displacement of bromine with
benzenesulfinate ion.
N
H
N
R
OH
O
O
O
12
13a: R = H, 13b: R = CO2Et
14
Figure 3
reacted only with 2 equivalents of LDA at room tempera-
ture, deprotection took place, giving furoindolone 4. The
structure of quinone 14 was established by spectroscopic
With all four potentially important1,4-dipolar synthons,
i.e. 5, 6, 7 and 8 in hand, we chose to initiate the cycload-
dition study with compound 8, in view of the remarkable
successes with 3-phenylsulfonylphthalide in the total syn-
thesis of aromatic polyketide natural products. When
compound 8 was treated with lithium diisopropylamide
(3.0 equiv), followed by 2-cyclohexenone at –78 °C and
the resulting mixture processed in the usual manner, the
expected quinol 9 was not obtained. Nor were the starting
materials recovered, meaning that both the substrates had
been destroyed. We reasoned this failure to be due to ex-
tensive base-catalyzed self-condensation of 2-cyclohex-
enone.11a Consequently, we chose to work with quinol
ether 10, which does not undergo decomposition in the
presence of LDA even at room temperature.
The reaction of 1014 with compound 8 was performed in
the manner described above and the expected product 11
was isolated in 70% yield. It is interesting to note that no
separate step was required to remove the ethoxycarbonyl
group. Stirring the reaction mixture at room temperature
cleaved the protecting group. Likewise, the reaction be-
tween 12 and 8 gave compound 13a in 72% yield. When
the reaction mixture was worked up at 0 °C, the N-pro-
tected quinone 13b (74%) was isolated as the only prod-
uct. Following this success, we directed the study to
examining the reactivity of 8 to arynes and to our surprise,
the reaction between compound 8 and bromobenzene un-
der the benzyne-generating conditions15 reported by
Sammes et al. did not yield any condensed product, i.e. 14
(Figure 3). Thus, we experimented with other indole-1,4-
dipolar synthons, namely 5 and 6.
1
means as well as by comparison with literature H NMR
and 13C NMR data.6 Finally, the synthesis of ellipticine
quinone 3 was taken up (Scheme 3). Annulation of furoin-
dolone 5 with 3-pyridyne16 prepared in situ from 3-bro-
mopyridine under the conditions described above yielded
a yellow-orange TLC homogeneous product after chro-
1
matographic purification. Examination of its H NMR
spectrum revealed it to be a mixture of two compounds,
which could not be separated by chromatography. De-
tailed comparison of the NMR data3e,6 with those reported
for ellipticine quinone (3) and isoellipticine quinone 15
(45% combined yield) confirmed their formation. Al-
though there are no significant differences in the patterns
of their NMR data, the singlets at d = 9.20 and 9.22 ppm
were indicative of 2:1 formation of the two isomers, ellip-
ticine quinone (3) being the major product. Since both el-
lipticine quinone (3) and isoellipticine quinone (15) have
been previously transformed to ellipticine (1) and isoellip-
ticine,17 respectively, this study constitutes the formal
syntheses of these alkaloids.
In conclusion, the anionic [4+2] cycloaddition of furo-
indolones has been, for the first time, introduced as a tool
for synthesizing various indoloquinones. Extension of this
methodology to the synthesis of calothrixins and carba-
zole alkaloids is in progress.
Li
O
The reaction of 6 with bromobenzene in the presence of
LDA provided the quinone 14 in only 10% yield. The cor-
responding N-SO2Ph product was not obtained. It is pos-
sible that the phenylsulfonyl group was cleaved under the
reaction conditions or during work-up. Further experi-
mentation showed that synthon 5 is better suited for an-
ionic [4+2] cycloaddition with arynes. Thus, the reaction
between 5 and benzyne, generated from bromobenzene
gave quinone 14 in 64% yield and the corresponding N-
CO2Et product was not obtained. When compound 5 was
O
O
N
Br
LDA
COOEt
N
+
3
N
N
N
H
O
15
Scheme 3
Synlett 2005, No. 6, 994–996 © Thieme Stuttgart · New York

996
D. Mal et al.
LETTER
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General Procedure for the Annulation: In a flame-dried flask
flushed with nitrogen, LDA (3 mmol) was prepared by adding di-
isopropylamine (3.6 mmol) to a solution of n-BuLi (3 mmol, 1.6 M
in hexane) in THF (20 mL) at –78 °C under nitrogen atmosphere.
After the solution was stirred for 10 min at –78 °C, the appropriate
furoindolone (3 mmol) in THF (10 mL) was added dropwise over
15 min. Stirring of the reaction mixture was continued at –78 °C for
15 min and then allowed to warm to –40 °C. A solution of appropri-
ate Michael acceptor (3 mmol) in THF (10 mL) was added dropwise
over 15 min at –40 °C (bromobenzene and 3-bromopyridine were
dried over CaH2 and distilled). The reaction mixture was further
stirred and allowed to warm slowly to r.t. over 3 h. The dark reddish
brown solution was then quenched with sat. NH4Cl solution, THF
evaporated under reduced pressure and the residue extracted with
EtOAc (3 × 100 mL). The combined extracts were washed with
brine, dried over Na2SO4 and concentrated to provide crude prod-
uct, which was purified by column chromatography on silica gel
using mixtures of EtOAc and petroleum ether as eluents.
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Selected Physical Data
Compound 5: mp 121–123 °C. H NMR (200 MHz, CDCl3): d =
1
8.39 (d, 1 H, J = 8.6 Hz), 7.52–7.65 (m, 2 H), 7.38 (t, 1 H, J = 7.6
Hz), 5.34 (s, 2 H), 4.56 (q, 2 H, J = 5.80 Hz), 1.53 (t, 3 H, J = 5.8
Hz). 13C NMR (50 MHz, CDCl3): d = 160.43, 149.97, 143.26,
142.60, 128.79, 127.87, 124.06, 121.43, 120.67, 116.87, 65.12,
63.96, 14.05. FT-IR (KBr): 1777, 1742, 1043.
Compound 8: mp 220–222 °C. 1H NMR (CDCl3): d = 8.36 (d, 1 H,
J = 8.6 Hz), 8.05 (d, 1 H, J = 7.6 Hz), 7.86 (dd, 2 H, J = 1.4, 8.6 Hz),
7.45–7.80 (m, 5 H), 6.25 (s, 1 H), 4.51 (q, 2 H, J = 7.0 Hz), 1.51 (t,
3 H, J = 7.0 Hz). 13C NMR (CDCl3): d = 156.99, 149.52, 142.93,
136.65, 135.11, 134.30, 129.90, 129.71, 129.54, 129.35, 125.22,
122.75, 121.30, 116.82, 87.51, 64.51, 14.08.
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1
Compound 11: mp 308–310 °C. H NMR (CDCl3 + 2 drops of
DMSO-d6): d = 12.65 (s, 1 H), 12.23 (br s, 1 H), 8.05 (d, 1 H, J = 7.8
Hz), 7.31 (d, 1 H, J = 7.8 Hz), 7.00–7.20 (m, 3 H), 6.81 (d, 1 H,
J = 8.6 Hz), 2.48 (s, 3 H). 13C NMR (d6-DMSO): d = 182.66,
182.36, 160.79, 141.79, 138.51, 135.25, 133.19, 129.99, 127.05,
123.92, 123.63, 123.21, 122.31, 118.15, 115.71, 113.54, 22.24.
FT-IR (KBr): 1630, 1629.
Compound 13b: mp 153–155 °C. 1H NMR (CDCl3): d = 12.93 (s, 1
H), 8.55 (d, 1 H, J = 6.8 Hz), 7.97 (d, 1 H, J = 8.4 Hz), 7.35–7.62
(m, 2 H), 7.21 (s, 1 H), 4.60 (q, 2 H, J = 7.2 Hz), 4.03 (s, 3 H), 2.38
(s, 3 H), 1.50 (t, 3 H, J = 7.2 Hz). 13C NMR (CDCl3): d = 181.11,
180.74, 156.26, 154.0, 150.49, 139.36, 137.90, 134.67, 129.34,
125.95, 125.41, 124.43, 124.30, 123.54, 116.47, 115.24, 113.89,
65.02, 56.73, 16.62, 13.91.
Acknowledgment
This work was financially supported by CSIR and DST, New Delhi.
PP and BS gratefully acknowledge the receipt of their Senior
Research Fellowships of CSIR, New Delhi.
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Synlett 2005, No. 6, 994–996 © Thieme Stuttgart · New York