Expedited synthesis of substituted dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6- tetraones structurally related to granulatimide

Article abstract of DOI:10.1055/s-2006-926308

Dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones can be considered as granulatimide analogues. In view of structure-activity relationship studies in these series, a parallel liquid-phase microwave-assisted synthesis was developed to generate a small library of compounds bearing various substituents at positions 8, 9, 10, or 11 on the aromatic framework. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926308

PAPER
711
Expedited Synthesis of Substituted Dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-
tetraones Structurally Related to Granulatimide
E
xpedited Synthe
s
é
is of
D
ipyrr
l
olo[3, 4
è
-
a
:3,4-
c
]ca
n
r
bazole-1,3,4
e
,6-tetraone
s
Hénon,a Fabrice Anizon,a Nathalie Kucharczyk,b Armelle Loynel,b Patrick Casara,b Bruno Pfeiffer,b
Michelle Prudhomme*a
a
Laboratoire SEESIB, Université Blaise Pascal, UMR 6504 du CNRS, 63177 Aubière, France
Institut de Recherches SERVIER, Division Recherche Cancérologie, 125 Chemin de ronde, 78290 Croissy sur Seine, France
b
Fax +33(4)73407717; E-mail: Michelle.PRUDHOMME@univ-bpclermont.fr
Received 14 July 2005; revised 2 September 2005
DNA damaging agents with G2 checkpoint inhibitors
should force cancer cells selectively into a premature and
lethal mitosis.5–7 In connection with this, phase I and II
clinical trials are reported with UCN-01, a G2 checkpoint
Abstract: Dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones can
be considered as granulatimide analogues. In view of structure–ac-
tivity relationship studies in these series, a parallel liquid-phase mi-
crowave-assisted synthesis was developed to generate a small
library of compounds bearing various substituents at positions 8, 9, inhibitor (Figure 1), in combination with topotecan in
10, or 11 on the aromatic framework.
ovarian cancers and in combination with cisplatin or car-
boplatin in patients with advanced refractory solid tu-
mors.8–10 To improve the biological activities of
granulatimide and isogranulatimide, structure–activity re-
lationship studies have been carried out.11–18 In particular,
analogues have been synthesized in which the imidazole
moiety has been replaced by a pyrrole or in which the in-
dole unit has been replaced by a 7-azaindole. In another
family of granulatimide analogues, the imidazole hetero-
cycle has been replaced by a maleimide moiety
(Figure 1).16–18
Key words: parallel synthesis, granulatimide, antitumor agents,
dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone
Granulatimide and isogranulatimide (Figure 1), natural
compounds isolated from the ascidian Didemnum granu-
latum, have triggered considerable interest since the dis-
covery in 1998 of their inhibitory properties toward the
G2 checkpoint of the cell cycle.1–4 The G2 checkpoint rep-
resents a promising target for the development of antican-
cer drugs. Indeed, because of the inefficiency of the G1
checkpoint in more than 60% of cancer cells, combining
In this paper, we report a more efficient synthetic method
to prepare new bis-imide analogues substituted at posi-
H
N
H
H
N
N
HO
O
O
O
O
O
NH
N
N
N
N
N
N
N
H
O
H
Me
MeO
granulatimide
UCN-01
isogranulatimide
NHMe
NR1
NR1
O
O
O
O
R3
O
O
NR2
N
H
NH
NR2
N
O
O
R
R
R
R
R
R
1 = R2 = R3 = H
R1 = R2 = H, R3 = OH
1 = CH3, R2 = R3 = H
1 = R3 = H , R2 = Me
1 = R2 = Me, R3 = H
1 = R2 = Me, R3 = OBn
1 = R2 = H, R3 = OBn
R
R
R
R
R
1 = R2 = H, R3 = Br
1 = R2 = H, R3 = Cl
1 = R2 = H, R3 = F
R1 = Me, R2 = H
R
R
R
1 = CH2OH, R2 = H
1 = R2 = H
1 = Me, R2 = –(CH2)2-NEt2, HCl, R3 = H
1 = -(CH2)2-NEt2, HCl, R2 = Me, R3 = H
1 = H, R2 = β-glucosyl
Figure 1 Chemical structures of granulatimide, isogranulatimide, UCN-01, and bis-imide analogues previously synthesized.
SYNTHESIS 2006, No. 4, pp 0711–0715
x
x
.
x
x
.2
0
0
6
Advanced online publication: 19.01.2006
DOI: 10.1055/s-2006-926308; Art ID: Z13705SS
© Georg Thieme Verlag Stuttgart · New York

712
H. Hénon et al.
PAPER
H
H
N
H
N
O
O
O
O
N
O
O
a)
DDQ, dioxane
b)
R
MeCOOH
R
R
1b–20b
N
H
N
H
N
H
H
1a–20a
N
c) Diels–Alder
O
O
H
H
N
N
O
O
O
O
d) oxidation
R
11
10
O
O
R
9
NH
NH
N
H
N
H
8
O
O
1d–20d
1c–20c
Scheme 1 Synthetic scheme for bis-imide analogues.
tions 8, 9, 10, or 11 of the indole heterocycle (Tables 1 . The oxidation step (step b) was carried out in parallel on
The general synthetic scheme for the bis-imide analogues a Büchi Syncore reactor using 0.2 M DDQ in dioxane at
(1d–20d) required four steps from the corresponding sub- room temperature for one hour. The reaction mixtures
stituted indoles (Scheme 1). Compared with the previous- were then centrifuged in Whatman filtration tubes. It was
ly described procedures, the efficiency of the syntheses necessary to perform the centrifugation rapidly when the
was greatly improved by using a parallel solution-phase required products were formed to avoid a further addition
method for step b and microwave irradiation for two reaction of DDQ-2H to the maleimides followed by re-ox-
steps: the Michael addition (step a) and the Diels–Alder idation leading to compounds A (Figure 2).
cycloaddition (step c), and in some cases for the last oxi-
H
dation step (step d).
N
O
O
The typical method for the synthesis of the bis-imide
granulatimide analogues was carried out as follows. For
the first step (step a), commercially available substituted
indoles and maleimide (three equivalents) in glacial acetic
acid were heated in sealed tubes at 190 °C in a CEM Ex-
plorer microwave oven (200 W, no cooling). With several
compounds, additional amounts of maleimide were re-
quired for complete disappearance of the indoles to be ob-
served (HPLC). The mixtures were then poured into water
and purified by solid phase extraction (SPE) on Waters
Oasis HLB cartridges.19 The yields for step a varied from
37–99%. The reactivity is dependant on the nature of the
substituent and on its position on the indole moiety
(Table 1). Several substitutions on the indoles are not
compatible with the AcOH/microwave method. For ex-
ample, nitro substituents induced only degradation/poly-
merization, cyano substituents were transformed into the
corresponding primary amides, CF3 substituents were hy-
drolyzed to COOH groups, and unprotected anilines were
rapidly acetylated.
Cl
Cl
O
OH
R
N
NC
CN
H
A
Figure 2
After centrifugation, the solid (DDQ-2H) was washed
with dioxane and the filtrates were lyophilized. For the
Diels–Alder reaction (step c), a mixture of the crude com-
pounds obtained in step b, and maleimide (three equiva-
lents) in dioxane were heated in sealed tubes in a
microwave oven (200 W, CEM) at 170 °C for one hour.
After concentration, water was added, and the mixtures
were filtered in Whatman tubes. The precipitates were
dissolved in dioxane and freeze-dried. It was observed
from LC/MS analysis that the final bis-imide products
were in some cases obtained directly after step c
(Table 1). The Diels–Alder adducts were then oxidized
(step d) using DDQ (2.1 equivalents) or in the presence of
TFA in dioxane for various reaction times and at various
temperatures. Alternatively, these mixtures can be heated
via microwave irradiation in sealed tubes at 170 °C (200
W, no cooling). After evaporation, water was added to the
residues, the mixtures were filtered, and the solid residues
were washed with water then with ethyl actetate to give
the bis-imides 1d–20d. The yields for step d varied from
Hydroxymethyl and formyl groups in positions 5 or 6 in-
duced polymerization. For the synthesis of compound 1d,
the hydroxyl group had to be protected first with a benzyl
group. As expected, the Michael reaction proceeded
smoothly with the benzyl ether. The benzyl group was
then removed at this stage of the synthesis by catalytic hy-
drogenation.
Synthesis 2006, No. 4, 711–715 © Thieme Stuttgart · New York

PAPER
Expedited Synthesis of Dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones
713
Table 1 New Bis-imides 1d–20d
Compd C-8
C-9
C-10
C-11
Step a
Step b
Step c
Step d
1a–20a
1b–20b
1c–20c
1d–20d
Heating
time (h)
Yield
Yield
(%)b
Heating Yieldc Conditionsd
time (h)
Yield (%) Puritye
(%)
89a
75
99
69
84
68
78
66
49
50
92
67
89
37
43
45
66
73
81
84
1
2
H
OH
H
H
1a
2
nd
nd
26
65
nd
nd
nd
nd
10
nd
nd
nd
nd
nd
nd
7
1
1
1
1
5
2
1
2
1
1
2
1
1
2
5
1
2
1
4
1
nd
nd
63
70
21
nd
52
nd
19
82
nd
51
80
nd
nd
nd
nd
88
19df
nd
reflux, 60 h
MW, 1 h
33
56
28
38
65
24
23
27
15
51
nd
>99
97
>99
nd
97
nd
98
86
nd
96
nd
nd
91
99
92
85
nd
99
99
OMe
H
H
H
H
3
OMe
H
H
2
45 °C, 3 d
80 °C, 55 h
reflux, 60 h
MW, 2 h
4
H
H
OMe
H
H
1
5
H
H
OMe
H
1.5
3
6
F
H
H
7
H
F
H
H
3.3
3
reflux, 60 h
MW, 1 h
8
H
F
F
H
9
Cl
H
H
H
H
20
4
45 °C, 3 d
reflux, 60 h
10
11
12
13
14
15
16
17
18
19
20
Cl
H
H
H
Br
H
H
3
MW, 30 min 27
CH3
H
H
H
H
1
reflux, 3 d
r.t., 24 h
27
31
42
23
38
15
31
5
CH3
H
H
1
H
COOH
H
H
4
MW, 1 h
H
H
COOH
H
H
5
40 °C, 24 h
MW, 1 h
H
H
COOH
H
5
H
COOMe
H
3
nd
nd
16
65
MW, 1 h
H
H
H
COOMe H
COOMe
7
reflux, 60 h
MW, 30 min
80 °C, 55 h
H
H
8
H
-OCH2O-
H
1
59
a Step a performed with benzyl protecting group.
b The yield was not determined (nd) when the required product formed as a mixture with DDQ-H2 and/or with the starting
material.
c For step c, the yield was not determined when the required product formed as a mixture with the final product, generally
obtained after step d.
d DDQ used as the oxidant except for compound 12, where TFA (13 equiv) and dioxane were employed.
e Determined by HPLC (210 nm).
f Major product.
IR spectra were recorded on a Perkin-Elmer 881, Perkin-Elmer Par-
agon 500 or Bruker Vector 22 spectrometer. NMR spectra were per-
formed on a Bruker AVANCE 400 or Bruker AVANCE 200 DPX.
Low resolution mass spectra (ESI+ and APCI+) and HRMS were
determined on a MS Hewlett Packard engine or Q-TOF 2 Micro-
mass. Due to the insolubility of some compounds, their 13C NMR
spectra could not be recorded.
5–65% (Table 1). The melting points of 1d–20d were
found to be >300 °C. Due to the insolubility of some com-
pounds, their 13C NMR spectra could not be recorded.
In conclusion, we have synthesized a series of granulatim-
ide and isogranulatimide bis-imides analogues 1d–20d
bearing various substituents on positions 8, 9, 10, and 11
of the aromatic framework. The method differs from the
procedure previously described by the use of parallel syn-
thesis for step b. Moreover, the microwave-assisted reac-
tions allowed a reduction in the reaction times from at
least two days to about one hour. The biological activities
of these compounds are currently under investigation.
9-Hydroxy-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (1d)
IR (KBr): 1604 (C=C), 1650–1840 (C=O), 3100–3650 (=NH) cm–1.
1H NMR (400 MHz, DMSO-d6–D2O): d = 6.91 (1 H, dd,
J = 8.5, 2.0 Hz), 7.13 (1 H, d, J = 2.0 Hz), 8.77 (1 H, d, J = 8.5 Hz).
Synthesis 2006, No. 4, 711–715 © Thieme Stuttgart · New York

714
H. Hénon et al.
PAPER
HRMS (ESI+): m/z calcd for C16H7N3NaO5 [M + Na]+: 344.0283;
HRMS (ESI+): m/z calcd for C16H6F2N3O4 [M + H]+: 342.0326;
found: 344.0288.
found: 342.0353.
8-Methoxy-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (2d)
8-Chloro-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (9d)
IR (ATR): 1706, 1768 (C=O), 3180, 3276, 3459 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.40 (1 H, br), 7.70 (1 H, d),
9.00 (1 H, d), 11.50 (3 H, br, NH).
1H NMR (400 MHz, DMSO-d6): d = 4.00 (3 H, s, CH3), 7.22 (1 H,
d, J = 7.5 Hz), 7.32 (1 H, t, J = 7.5 Hz), 8.55 (1 H, d, J = 7.5 Hz),
11.45 (1 H, s, NH), 11.50 (1 H, s, NH), 12.18 (1 H, s, NH).
MS (ESI): m/z = 340 [M + H]+.
9-Chloro-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (10d)
MS (EI): m/z = 335 [M]+.
IR (KBr): 1604 (C=C), 1723, 1761 (C=O), 3110–3390 (NH) cm–1.
9-Methoxy-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (3d)
1H NMR (400 MHz, DMSO-d6): d = 7.45 (1 H, d, J = 8.5 Hz), 7.70
(1 H, s), 8.89 (1 H, d, J = 8.5 Hz), 11.61 (1 H, s, NH), 11.63 (1 H,
s, NH), 12.77 (1 H, s, NH).
13C NMR (100 MHz, DMSO-d6): d = 112.3, 121.9, 126.8 (Ar-CH),
118.2, 118.3, 120.0, 123.4, 126.0, 131.5, 134.3, 137.0, 144.5 (Ar-
C), 166.2 (2 C), 168.4, 169.0 (C=O).
1H NMR (400 MHz, DMSO-d6): d = 3.90 (3 H, s, CH3), 7.00 (1 H,
dd, J = 8.5, 1.5 Hz), 7.20 (1 H, d, J = 1.5 Hz), 8.80 (1 H, d, J = 8.5
Hz), 11.60 (2 H, br, NH).
MS (EI): m/z = 335 [M]+.
10-Methoxy-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (4d)
HRMS (ESI+): m/z calcd for C16H6ClN3NaO4 [M + Na]+: 361.9945;
found: 361.9964.
IR (ATR): 1709, 1775 (C=O), 3174, 3367 (NH) cm–1.
1H NMR (200 MHz, DMSO-d6): d = 3.90 (3 H, s, CH3), 7.28 (1 H,
dd), 7.61 (1 H, d), 8.48 (1 H, d), 11.5 (2 H, 2 s, NH), 12.5 (1 H, s,
NH).
9-Bromo-1,3,4,6-tetrahydro-1,3,4,6-tetraoxo-7H-dipyrrolo[3,4-
a:3,4-c]carbazole (11d)
IR (KBr): 1600 (C=C), 1720, 1760 (C=O), 3100–3380 (NH) cm–1.
HRMS (ESI+): m/z calcd for C17H9N3NaO5 [M + Na]+: 358.0440;
found: 358.0474.
1H NMR (400 MHz, DMSO-d6): d = 7.62 (1 H, dd, J = 8.5, 1.5 Hz),
7.91 (1 H, d, J = 1.5 Hz), 8.88 (1 H, d, J = 8.5 Hz), 11.63 (1 H, s,
NH), 11.65 (1 H, s, NH), 12.83 (1 H, s, NH).
11-Methoxy-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (5d)
13C NMR (100 MHz, DMSO-d6): d = 115.4, 124.6, 127.0 (Ar-CH),
118.4, 118.5, 120.1, 122.9, 123.5, 126.2, 131.7, 136.9, 144.8 (Ar-
C), 166.2, 166.3, 168.4, 169.1 (C=O).
HRMS (ESI+): m/z calcd for C16H6BrN3NaO4 [M + Na]+: 405.9439;
found: 405.9424.
IR (KBr): 1717, 1771 (C=O), 3344, 3100–3400 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.04 (3 H, s, CH3), 6.91 (1 H,
d, J = 8.0 Hz), 7.37 (1 H, d, J = 8.0 Hz), 7.64 (1 H, t, J = 8.0 Hz),
11.31 (1 H, s, NH), 11.51 (1 H, s, NH), 12.73 (1 H, s, NH).
13C NMR (100 MHz, DMSO-d6): d = 55.2 (CH3), 102.8, 104.8,
131.6 (Ar-CH), 110.0, 117.3, 121.1, 121.8, 124.9, 130.7, 137.0,
146.0, 156.5 (Ar-C), 165.8, 166.2, 166.6, 168.6 (C=O).
8-Methyl-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (12d)
IR (KBr): 1715, 1770 (C=O), 3254, 3307 (NH) cm–1.
HRMS (ESI+): m/z calcd for C17H9N3NaO5 [M + Na]+: 358.0440;
found: 358.0439.
1H NMR (400 MHz, DMSO-d6): d = 2.75 (3 H, s, CH3), 7.38 (1 H,
pseudo t, J = 7.5 Hz), 7.52 (1 H, d, J = 7.0 Hz), 8.95 (1 H, d, J = 8.0
Hz), 11.58 (1 H, s, NH), 11.60 (1 H, s, NH), 12.36 (1 H, s, NH).
8-Fluoro-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (6d)
13C NMR (100 MHz, DMSO-d6): d = 17.5 (CH3), 121.7, 123.0,
130.9 (Ar-CH), 118.1, 119.5, 119.8, 122.5, 125.0, 125.8, 131.3;
137.1, 143.1 (Ar-C), 166.2 (2 C), 168.2, 169.1 (C=O).
HRMS (ESI+): m/z calcd for C17H9N3NaO4 [M + Na]+: 342.0491;
found: 342.0501.
IR (ATR): 1702, 1784 (C=O), 3100–3350 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.40 (1 H, m), 7.55 (1 H, dd),
8.90 (1 H, d), 11.60 (2 H, 2 s, NH), 13.15 (1 H, s, NH).
HRMS (ESI+): m/z calcd for C16H7FN3O4 [M + H]+: 324.0421;
found: 324.0452.
9-Methyl-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (13d)
9-Fluoro-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-a:3,4-
c]carbazole-1,3,4,6-tetraone (7d)
IR (KBr): 1720, 1765 (C=O), 3100–3400 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.56 (3 H, s, CH3), 7.26 (1 H,
d, J = 8.5 Hz), 7.54 (1 H, s), 8.82 (1 H, d, J = 8.0 Hz), 11.53 (1 H,
s, NH), 11.54 (1 H, s, NH), 12.62 (1 H, br, NH).
HRMS (ESI+): m/z calcd for C17H9N3NaO4 [M + Na]+: 342.0491;
found: 342.0494.
IR (KBr): 1700, 1735, 1780 (C=O), 3100–3600 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.31 (1 H, pseudo dt,
J = 9.5, 2.0 Hz), 7.46 (1 H, dd, J = 9.5, 2.0 Hz), 8.98 (1 H, dd,
J = 9.0, 5.5 Hz), 11.60 (1 H, s, NH), 11.62 (1 H, s, NH), 12.82 (1 H,
s, NH).
HRMS (ESI+): m/z calcd for C16H7FN3O4 [M + H]+: 324.0421;
found: 324.0424.
1,3,4,6-Tetrahydro-1,3,4,6-tetraone-2H,5H,7H-dipyrrolo[3,4-
a:3,4-c]carbazole-9-carboxylic Acid (14d)
1H NMR (400 MHz, DMSO-d6): d = 7.95 (1 H, d, J = 8.5 Hz), 8.30
(1 H, s), 8.95 (1 H, dd, J = 8.5, 1.0 Hz), 11.50 (3 H, br s), 12.80 (1
H, br).
9,10-Difluoro-1,3,4,6-tetrahydro-2H,5H,7H-dipyrrolo[3,4-
a:3,4-c]carbazole-1,3,4,6-tetraone (8d)
IR (ATR): 1714, 1759 (C=O), 3100–3380 (NH) cm–1.
HRMS (ESI+): m/z calcd for C17H7N3NaO6 [M + Na]+: 372.0233;
found: 372.0247.
1H NMR (400 MHz, DMSO-d6): d = 7.55 (1 H, t), 8.69 (1 H, t),
11.60 (2 H, 2 s, NH), 12.75 (1 H, s, NH).
Synthesis 2006, No. 4, 711–715 © Thieme Stuttgart · New York

PAPER
Expedited Synthesis of Dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones
715
1,3,4,6-Tetrahydro-1,3,4,6-tetraone-2H,5H,7H-dipyrrolo[3,4-
a:3,4-c]carbazole-10-carboxylic Acid (15d)
References
IR (ATR): 1710, 1770 (C=O), 3100–3500 (NH) cm–1.
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International Patent WO99/47522, 1999; Chem. Abstr. 1999,
131, 243451.
(4) Jiang, X.; Zhao, B.; Britton, R.; Lim, L. Y.; Leong, D.;
Sanghera, J. S.; Zhou, B. B.; Piers, E.; Andersen, R. J.;
Roberge, M. Mol. Cancer Ther. 2004, 3, 1221.
(5) Kawabe, T. Mol. Cancer Ther. 2004, 3, 513.
(6) Prudhomme, M. Curr. Med. Chem: Anti-Cancer Agents
2004, 4, 435.
(7) Zhou, B. B.; Bartek, J. Nat. Rev. Cancer 2004, 4, 216.
(8) Dancey, J.; Sausville, E. A. Nat. Rev. Drug Discovery 2003,
2, 296.
1H NMR (400 MHz, DMSO-d6): d = 7.80 (1 H, d, J = 8.5 Hz), 8.25
(1 H, dd, J = 8.5, 1.0 Hz), 9.15 (1 H, s), 11.6 and 13.0 (4 H, br).
HRMS (ESI+): m/z calcd for C17H7N3NaO6 [M + Na]+: 372.0233;
found: 372.0246.
1,3,4,6-Tetrahydro-1,3,4,6-tetraone-2H,5H,7H-dipyrrolo[3,4-
a:3,4-c]carbazole-11-carboxylic Acid (16d)
1H NMR (400 MHz, DMSO-d6): d = 7.65 (1 H, d, J = 8.0 Hz), 7.70
(1 H, t, J = 8.0 Hz), 7.95 (1 H, d, J = 8.0 Hz), 11.4 (1 H, s), 11.6 (1
H, s), 13.0 (1 H, br s).
HRMS (ESI+): m/z calcd for C17H7N3NaO6 [M + Na]+: 372.0233;
found: 372.0237.
9-Methoxycarbonyl-1,3,4,6-tetrahydro-2H,5H,7H-dipyrro-
lo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (17d)
IR (ATR): 1708, 1760 (C=O), 3100–3680 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.98 (3 H, s), 8.00 (1 H, d,
J = 8.5 Hz), 8.35 (1 H, s), 9.05 (1 H, d, J = 8.5 Hz), 11.65 (2 H, 2 s,
NH), 13.0 (1 H, s, NH).
HRMS (ESI+): m/z calcd for C18H9N3NaO6 [M + Na]+: 386.0389;
found: 386.0418.
(9) Senderowicz, A. M. Cancer Biol. Ther. 2003, 2, S84.
(10) Sausville, E. A.; Elsayed, Y.; Monga, M.; Kim, G. Annu.
Rev. Pharmacol. Toxicol. 2003, 43, 199.
(11) Piers, E.; Britton, R.; Andersen, R. J. J. Org. Chem. 2000,
65, 530.
(12) Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase, M.;
Kotani, E. Chem. Pharm. Bull. 2002, 50, 872.
(13) Terpin, A.; Winklhofer, C.; Schumann, S.; Steglich, W.
Tetrahedron 1998, 54, 1745.
(14) Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M.
Tetrahedron Lett. 2003, 44, 3927.
(15) Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M.
Tetrahedron Lett. 2003, 44, 4607.
(16) Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M.
10-Methoxycarbonyl-1,3,4,6-tetrahydro-2H,5H,7H-dipyrro-
lo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (18d)
IR (KBr): 1715, 1774 (C=O), 3100–3400 (NH) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.97 (3 H, s, CH3), 7.88 (1 H,
d, J = 9.0 Hz), 8.31 (1 H, dd, J = 8.5, 1.5 Hz), 9.72 (1 H, d, J = 1.5
Hz), 11.68 (1 H, s, NH), 11.72 (1 H, s, NH), 13.15 (1 H, s, NH).
HRMS (ESI+): m/z calcd for C18H9N3NaO6 [M + Na]+: 386.0389;
found: 386.0396.
Tetrahedron Lett. 2003, 44 3935.
(17) Ator, M. A.; Bihovsky, R.; Chatterjee, S.; Dunn, D.;
Hudkins, R. L. International Patent WO01/85686 A2, 2001;
Chem. Abstr. 2001, 135, 371989.
11-Methoxycarbonyl-1,3,4,6-tetrahydro-2H,5H,7H-dipyrro-
lo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (19d)
1H NMR (400 MHz, DMSO-d6): d = 3.80 (3 H, s), 7.65 (1 H, d,
J = 8.0 Hz), 7.75 (1 H, t, J = 8.0 Hz), 8.00 (1 H, d, J = 8.0 Hz).
(18) Hénon, H.; Messaoudi, S.; Hugon, B.; Anizon, F.; Pfeiffer,
B.; Prudhomme, M. Tetrahedron 2005, 61, 5599.
(19) For SPE purifications, Waters Oasis HLB extraction
cartridges (6 g) were used with the following eluents: H2O,
then H2O–MeCN (80:20), and then MeCN. For some
compounds a gradient performed with Jones Flash master II
was necessary. After evaporation, Et2O was added to the
solid residues, the compounds were filtered and dried.
HRMS (ESI+): m/z calcd for C18H9N3O6 [M]+: 363.0491; found:
363.0482.
9,10-Methylenedioxy-1,3,4,6-tetrahydro-2H,5H,7H-dipyrro-
lo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (20d)
IR (ATR): 1627 (C=C), 1706, 1753 (C=O), 3248 (NH) cm–1.
1H NMR (200 MHz, DMSO-d6): d = 6.20 (2 H, s), 7.05 (1 H, s), 8.18
(1 H, s), 11.4 (2 H, s, NH), 12.4 (1 H, s, NH).
MS (EI+): m/z = 349 [M]+.
Synthesis 2006, No. 4, 711–715 © Thieme Stuttgart · New York