A facile synthesis of bispyrroloquinone and bispyrroloiminoquinone ring system of marine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2009.04.021

Bispyrroloquinone and bispyrroloiminoquinone are two important polycyclic ring systems present in biologically active marine alkaloids such as Zyzzyanones, tsitsikammamines, and wakayin. A facile synthesis of these two ring systems starting from a 6-benzy

Full text of DOI:10.1016/j.tetlet.2009.04.021

Tetrahedron Letters 50 (2009) 3074–3076
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A facile synthesis of bispyrroloquinone and bispyrroloiminoquinone
ring system of marine alkaloids
*
Srinivasan Murugesan, Dwayaja H. Nadkarni, Sadanandan E. Velu
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 December 2008
Revised 4 April 2009
Accepted 7 April 2009
Available online 11 April 2009
Bispyrroloquinone and bispyrroloiminoquinone are two important polycyclic ring systems present in
biologically active marine alkaloids such as Zyzzyanones, tsitsikammamines, and wakayin. A facile syn-
thesis of these two ring systems starting from a 6-benzylamino indole-4,7-quinone or 6-benzylamino
pyrroloiminoquinone is described here. This chemistry involves the construction of a pyrrole ring in a sin-
gle step by treatment of the starting reagents with ethyl acetoacetate or phenylbutane-1,3-dione in the
presence of ceric ammonium nitrate in MeOH/CH2Cl2 solvent.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
unique fused ring skeletons carrying interesting biological proper-
ties have made them targets for several synthetic and biological
Due to their potential for drug discovery, marine natural prod-
ucts have attracted the attention of scientists from various disci-
plines. Pharmacological value of the marine alkaloids is
illustrated by the fact that about a dozen of marine alkaloids are
currently undergoing various phases of human clinical trials for
treatment of different cancers.1–3 A large number of bioactive mar-
ine alkaloids with novel structures have been isolated from marine
sponges.4,5 Sponges produce a plethora of chemical compounds
with widely varying carbon skeletons. Most bioactive compounds
from sponges have exhibited a variety of activities such as anti-
inflammatory, antitumor, immunosuppressive, neurosuppressive,
antiviral, antimalarial, and antibiotic activities. While a number
of these alkaloids have been isolated in quantities sufficient to
ascertain their biological profile, many with unique structures
are available only in minute quantities, precluding their thorough
biological evaluations. Laboratory synthesis of these alkaloids
and their analogs is the only practical way to access these materials
in larger quantities.
studies. There has been a rapid growth of interest in the synthesis
and biological evaluation of this class of compounds and their ana-
logs. Several reviews have been published on the chemistry and
bioactivity of this class of compounds.6,29–31
Of these alkaloids, wakayin and tsitsikammamines possess a
unique tetracyclic bispyrroloiminoquinone ring system (Fig. 1).
Wakayin was isolated by Ireland etal in 1991 from an ascidian of
Clavelina species.18 It has exhibited cytotoxic properties and inhibi-
tion of topoisomerase I. Several aza analogs of these alkaloids re-
HO
HO
H
OHC
CH3
CH3
N
N
O
O
O
O
N
H
N
R1
N
H
N
R1
Marine sponges of the genera Latrunculia, Batzella, Prianos, and
Zyzzya are a rich source of alkaloids bearing a pyrrolo[4,3,2-
de]quinoline skeleton.6,7 This series of alkaloids comprise about
60 metabolites including discorhabdins,8 epinardins,9 batzel-
lines,10 isobatzellines,10 makaluvamines,11–16 veiutamine,17 waka-
yin,18 and tsitsikammamines.19,20 Pyrrolo[4,3,2-de]quinoline
alkaloids have shown a variety of biological activities such as inhi-
bition of topoisomerases I11 and II,14 cytotoxicity against different
tumor cell lines,21,14 antifungal11 and antimicrobial activities.22
Pyrrolo[4,3,2-de]quinoline alkaloids have recently received
increasing attention as a source of new anticancer drugs.23–28 Their
1a, Zyzzyanone A, R = CH3
1b, Zyzzyanone B, R = H
1c, Zyzzyanone A, R = CH3
1d, Zyzzyanone B, R = H
HO
H
N
HN
HN
N
N
N
N
H
H
H
R
O
O
2a, Tsitsikammamine A, R = H
2b, Tsitsikammamine B, R = CH3
3, Wakayin
* Corresponding author. Tel.: +1 205 975 2478; fax: +1 205 934 2543.
E-mail address: svelu@uab.edu (S.E. Velu).
Figure 1. Zyzzyanones, tsitsikammamines, and wakayin.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.021

S. Murugesan et al. / Tetrahedron Letters 50 (2009) 3074–3076
3075
ported recently have shown inhibition of both topoisomerases I
O
O
O
O
R
and II. Tsitsikammamines A and B were isolated from four new
species of South African latrunculid sponges namely, Tsitsikamma
pedunculata, Tsitsikamma favus, Latrunculia bellae, and Strong-
ylodesma algoaensis.19,20 They do exhibit cytotoxic properties, but
do not inhibit either topoisomerase I or II. A related class of tricy-
clic bispyrroloquinone alkaloids called Zyzzyanones A–D (Fig. 1)
has been isolated recently from the Australian marine sponge Zyz-
zya fuliginosa.32,33
CH3COCH2COR
7a, R = OEt
H3C
7b, R = Ph
Bn
N
Ts
N
N
Ts
N
H
CAN
Bn
MeOH / CH2Cl2
O
6
8a, R = OEt
8b, R = Ph
NaOEt
EtOH
Because of their potent biological activities and unique struc-
tural features several attempts were made toward the synthesis
of these alkaloids and the unique ring system present in these alka-
loids.34,35 While there is a very recent report of total synthesis of
tsitsikammamine A,36 there are several other reports available on
the synthesis and biological evaluation of the analogs of these
alkaloids.37,26,27,38
As a part of our work on the synthesis and biological evaluation
of analogs of marine natural products,39,40 we were interested in
studying the anticancer activity of analogs of zyzzyanones, tsitsi-
kammamines, and wakayin. We report herein a facile synthesis
of bispyrroloquinone ring system present in zyzzyanones and bis-
pyrroloiminoquinone ring system present in wakayin and tsitsi-
kammamines (Fig. 2).
Synthesis of bispyrroloquinone ring system (4) is outlined in
Scheme 1. The synthesis was started with the previously reported
N-tosyl-6-(benzylamino)-1H-indole-4,7-dione (6).41 Treatment of
compound 6 with ethyl acetoacetate (7a) in the presence of ceric
ammonium nitrate (CAN) in MeOH/CH2Cl2 resulted in the forma-
tion of bispyrroloquinone derivative 8a in 58% yield. The reaction
was also carried out with 1-phenylbutane-1,3-dione (7b) under
the same reaction conditions to afford bispyrroloquinone deriva-
tive 8b in 67% yield. This cyclization reaction proceeds via an oxi-
dative free radical mechanism as reported previously in the cases
of aminoquinones such as 2-amino-1,4-benzoquinones42 and 2-
amino-1,4-naphoquinones.43,44 Tosyl groups present in com-
pounds 8a and 8b were removed by treatment with NaOEt in
anhydrous EtOH to form the detosylated compounds 9a and 9b
in 71% and 86%, respectively. Debenzylation of compounds 9a
and 9b using Pd black in the presence of HCOONH4 in anhydrous
EtOH afforded the debenzylated compounds 10a and 10b in 75%
and 74% yields, respectively.
O
O
O
O
R
R
Pd black
H3C
H3C
HCOONH4
EtOH
N
N
H
N
N
H
H
Bn
O
O
10a, R = OEt
9a, R = OEt
10b, R = Ph
9b, R = Ph
Scheme 1. Synthesis of bispyrroloquinone ring system.
O
N
N
EtO
H3C
CH3COCH2COOEt
(7a)
Bn
CAN
MeOH
N
N
N
N
H
R
Bn
R
O
O
11a, R = Ts
11b, R = H
12a, R = Ts
12b, R = H
Scheme 2. Synthesis of bispyrroloiminoquinone ring system.
9b are shown in Figure 3. The three-proton singlet at 2.18 ppm is
assigned to the methyl group at C-6 position. The two-proton sin-
glet at 5.77 ppm is assigned to CH2 group at N-7 position, which
has a NOESY correlation with the singlet at 2.18 ppm. This assign-
ment clearly shows that the more stable regioisomer A is formed as
opposed to less stable regioisomer B. This is presumably due to the
steric interaction between the benzyl group at N-7 and the phenyl
ring at C-6 position in B regioisomer.
Similarly, the products 12a and 12b shown in Scheme 2 were
found to exist as a single regioisomer in each case, as evident from
one set of signals found in the NMR spectra. The structure of tetra-
cyclic quinone 12b was also confirmed by 2D NOESY spectroscopic
studies (Fig. 4). The three-proton singlet at 2.55 ppm is assigned to
the methyl group on the newly formed pyrrole ring. The two-pro-
We employed the same synthetic methodology for the synthe-
sis of bispyrroloiminoquinone ring system (5) present in wakayin
and tsitsikammamines as outlined in Scheme 2.
Treatment of previously reported N-tosylpyrroloiminoquinone
derivative, 11a40 with ethyl acetoacetate (7a) in the presence of
CAN in MeOH resulted in the formation of bispyrroloiminoquinone
derivative 12a in 38% yield. Similarly, cyclization reaction of previ-
ously reported detosylated compound 11b40 with ethyl acetoace-
tate (7a) in the presence of CAN in MeOH proceeded smoothly
and resulted in the formation of bispyrroloiminoquinone deriva-
tive 12b in 41% yield.
The intermediates and final products shown in Scheme 1 were
found to exist as a single regioisomer in each case, as evident from
one set of signals found in the NMR spectra. The structures of tri-
cyclic quinones 9a and 9b were further confirmed by two-dimen-
sional NOESY experiments. The 2D NOESY experimental data for
O
O
5
O
O
H3C
O
3
4
8
6
2
2.18, s
H3C
1
7
N
N
H
N
N
H
O
5.77, s
NOESY
More stable regioisomer A
Less stable regioisomer B
Figure 3. Two-dimensional NOESY correlation in 9b.
O
N
O
N
O
H3C
Ph
2.55, s
N
N
H
N
H
N
H
N
H
N
H
NOESY
O
O
O
4
5
5.94, s
Figure 2. Bispyrroloquinone and bispyrroloiminoquinone ring systems.
Figure 4. Two-dimensional NOESY correlation in 12b.

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S. Murugesan et al. / Tetrahedron Letters 50 (2009) 3074–3076
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This project was supported by Grant No. 1UL1RR025777 from
the NIH National Center for Research Resources. The authors also
wish to acknowledge the financial support from the Breast Spore
Pilot Grant and a Collaborative Programmatic Development Grant
from the University of Alabama at Birmingham (UAB) Comprehen-
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(AHA0865323E) from American Heart Association Greater South-
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Supplementary data
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Supplementary data associated with this paper can be found, in
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