Synthesis of granulatimide bis-imide analogues

Article abstract of DOI:10.1016/j.tet.2005.03.101

The synthesis of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to granulatimide is reported. These compounds can be considered as granulatimide analogues in which a maleimide heterocycle replaces the imidazole moiety. The synthes

Full text of DOI:10.1016/j.tet.2005.03.101

Tetrahedron 61 (2005) 5599–5614
Synthesis of granulatimide bis-imide analogues
a
Helene Henon, Samir Messaoudi, Bernadette Hugon, Fabrice Anizon, Bruno Pfeiffer
a
a
a
b
´ `
´
and Michelle Prudhommea,
*
a
´ `
Laboratoire SEESIB, Universite Blaise Pascal, UMR 6504 du CNRS, 63177 Aubiere, France
´
Institut de Recherches SERVIER, Division Recherche Cancerologie, 125 Chemin de ronde, 78290 Croissy sur Seine, France
b
Received 13 October 2004; revised 13 January 2005; accepted 22 March 2005
Abstract—The synthesis of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to granulatimide is reported. These
compounds can be considered as granulatimide analogues in which a maleimide heterocycle replaces the imidazole moiety. The synthesis of
pyridino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraones is also reported. In these compounds, a 7-azaindole unit replaces the indole
moiety present in the granulatimide and isogranulatimide structures.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Many antitumor compounds from natural sources contain a
carbazole maleimide or maleamide framework. Rebecca-
mycin is a topoisomerase I inhibitor1 whereas staurosporine
is a non specific kinase inhibitor interacting with the ATP
binding site of the enzymes.2 UCN-01, structurally related
to staurosporine, also inhibits various kinases. Moreover,
like granulatimide and isogranulatimide, natural compounds
isolated from an ascidian, UCN-01 inhibits the cell cycle
checkpoint in the G2 phase which is activated in response to
DNA damage (Fig. 1).3–6 This cell cycle checkpoint is
mainly regulated by the two kinases Chk1 and Chk2.
Compounds structurally related to granulatimide, iso-
granulatimide isomers and analogues bearing modified
heterocycles, have been recently synthesized.7–11
To get an insight into the possible interactions of
granulatimide and isogranulatimide with the ATP binding
site of the target kinases, a detailed computational study was
performed.12 The electronic density in specific regions of
the molecules appears to play a pivotal role toward activity.
Both granulatimide and isogranulatimide are almost planar.
The molecular planarity creates a broad negative electro-
Figure 1. Chemical structures of rebeccamycin, staurosporine, UCN-01,
granulatimide and isogranulatimide.
whereas the positive potential resulting from a low electron
static potential on the two sides which are lypophilic sites
density in the central core increases their hydrophilicity.
In a previous brief communication, we reported the
synthesis of the first granulatimide analogues bearing a
Keywords: Granulatimide; Pyridino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-
1,3,4,6-tetraone; Dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone; 7-
maleimide instead of an imidazole heterocycle.13 In this
paper, the synthesis of new analogues in this series 7a–7l is
described (Fig. 2).
Azaindole.
*
Corresponding author. Tel.: C33 4 73 40 71 24; fax: C33 4 73 40 77 17;
e-mail: Michelle.PRUDHOMME@univ-bpclermont.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.101

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H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
5600
Figure 2. Granulatimide bis-imide analogues and related compounds.
Azaindoles, biosters of indole, are found in many natural
and synthetic compounds of biological interest.14–16 The
replacement of a carbon atom by a nitrogen atom could
increase the affinity for the binding site on the target
enzyme(s) and also modify the electronic distribution of
the aromatic framework and the lipophilicity of the
molecule. In this paper, the synthesis of new bis-imide
analogues in which a 7-azaindole replaces the indole unit is
also reported 13a–c (Fig. 2). To mimic the sugar part
present in UCN-01 and ATP, compound 20 in which a
b-glucopyranosyl moiety is attached to the azaindole was
also synthesized.
Scheme 1. Synthesis of compounds 7a–7l.

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H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
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Scheme 2. Synthesis of 7m–7o.
2. Results and discussion
been isolated. According to the work-up (filtration or
chromatography on silicagel), the Diels–Alder cycloadduct
5a or its isomer 6a were isolated. The non-aromatic
intermediates were further oxidized in the presence of
either TFA or DDQ to yield 7a–7l. Compound 4h was
obtained from 4b by opening of the imide heterocycle in a
basic medium followed by acidic treatment.
In our previous communication, we described the synthetic
pathways to access to compound 7a and its analogues 7b,
7d, 7e, 7j and 7o.13 The key step consists in a Diels–Alder
reaction between 3-indolylmaleimides and maleimides or
maleic anhydride.17 The 3-indolylmaleimides or maleic
anhydrides 4a–g were obtained either by oxidation with
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) of the corre-
sponding 3-(indol-3-yl)-succinimides or succinic anhy-
drides 2a–g resulting from acid induced addition of
indoles to maleimides18 (Scheme 1). In some cases, together
with compound 2a–g, small amounts of compounds 3 have
To synthesize the analogue 7m bearing a hydroxy
substituent (Scheme 2), hydrogenolysis of 2c led to
succinimide 8. The same sequence of reactions as described
in Scheme 1 from compounds 2a–g yielded 7m. To obtain
more soluble compounds, a N,N-diethylaminoethyl
Scheme 3. Synthesis of 13c.

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5602
substituent was introduced on one of the imide nitrogens via
the corresponding anhydrides according to a method
previously developed in indolocarbazole series
(Scheme 2).1
In the aza series, the method used for the synthesis of
compounds 12a and 12b (Scheme 3) was a little bit different
from that previously described for the synthesis of the non
aza analogues. The advantage of the Michael addition used
for the non aza compounds was to avoid the steps of
hydrogenolysis/hydrogenation then oxidation (compare
Schemes 1 and 3). Unfortunately, in aza series, the reaction
between 7-azaindole and maleimide in refluxing acetic acid
afforded compound 10 (Scheme 4). The structure of
compound 10 was assigned from NMR 1H–1H COSY
correlations, HMBC and HSQC experiments (Scheme 4).
Consequently, the strategy described on Scheme 3 was
chosen. Moreover, the presence of an electron-withdrawing
Scheme 4. (a) Reaction of 7-azaindole with maleimide. (b) Long range
1H–13C coupling (chemical shifts in ppm).
Scheme 5. Synthesis of compound 20.

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5603
group such as Br is necessary to increase the reactivity of the
Mitsunobu reaction used for the coupling of the sugar part
(Scheme 5).19,20
the indole moiety and a diethylaminoethyl chain was
attached to the imide nitrogen of the upper heterocycle. In
the aza series, in contrast to what observed in non aza series,
the Michael addition between 7-azaindole and maleimide
did not work. A different sequence of reactions has to be
performed from dibromomaleimide. An analogue in which a
glucose moiety is attached to the 7-azaindole unit was
prepared. According to the presence or the absence of a
sugar part, the methods carried out for the oxidation of the
Diels–Alder adducts were different. The classical methods
usually used for the deprotection of the benzyl groups did
not afford the required compounds and the debenzylation
procedures were modified. The biological evaluation of
these new compounds is now under investigation
Compounds A and B were prepared as previously
described.16 Hydrogenolysis with Pd/C in methanol led to
11a and 11b in 90 and 68% yields, respectively, from A and
B. Oxidation of 11a and 11b with DDQ gave 12a and 12b in
94 and 100% yields, respectively. Diels–Alder reactions
were carried out in refluxing p-xylene leading to a mixture
of isomers which were further oxidized with DDQ to give
13a and 13b in 83 and 77% yields, respectively. For the
removal of the benzyloxymethyl protective group of
compound 13b, the classical method by hydrogenolysis
then aminolysis could not be performed due to, firstly the
insolubility of 13b which could not be separated from the
catalyst and secondly to the sensitivity of the maleimide
units to basic media which often led to the opening of the
maleimide heterocycles. The BOM group was eliminated in
two steps: reaction with trifluoroacetic acid21,22 which led to
the N-hydroxymethyl-tetraone followed by refluxing in
xylene23 to give the required compound 13c. A glucose
moiety was attached to the azaindolic nitrogen. The
carbohydrate could reinforce the hydrogen bond net in the
target enzyme(s) (Scheme 5). A Mitsunobu reaction was
carried out with compounds A and B and 2,3,4,6-tetra-O-
benzyl-D-glucopyranose leading to 14a and 14b as the
major products of the reactions in 46 and 64% yields,
respectively. Hydrogenolysis/hydrogenation was performed
4. Experimental
4.1. General
IR spectra were recorded on a Perkin–Elmer 881 spec-
trometer (n in cmK1). NMR spectra were performed on a
Bruker AVANCE 400 and AVANCE 500 (chemical shifts d
in ppm, the following abbreviations are used: singlet (s),
broad singlet (br s), doublet (d), doubled doublet (dd), triplet
(t), pseudo triplet (pt), multiplet (m), tertiary carbons (C
tert), quaternary carbons (C quat). The signals were
1
assigned from H–1H COSY and 13C–1H correlation. Low
resolution mass spectra (ESIC, CI) were determined on a
Hewlett Packard MS engine. HRMS (FABC) were
determined at CESAMO (Talence, France) on a high
resolution Fisons Autospec-Q spectrometer. Chromato-
graphic purifications were performed by flash silicagel
Geduran SI 60 (Merck) 0.040–0.063 mm column
chromatography.
24
using 10% Pd/C in EtOAc and NaHCO3 affording 15a
and 15b in 48 and 46% yields, respectively, as a mixture
of two diastereoisomers. Oxidation with DDQ gave 16a
and 16b in 61 and 64% yields, respectively. Diels–Alder
reaction with maleimide in refluxing toluene afforded 17a
and 17b in 41 and 85% yields, respectively, as a mixture of
isomers. Oxidation with DDQ only gave degradation
products whereas using MnO2 in chloroform25 18a and
18b were isolated in 61 and 86% yields, respectively. For
debenzylation, several methods were tried. Reaction with
boron tribromide26 or trimethylsilyliodide27 led to a mixture
of partially debenzylated compounds which could not be
easily recovered from an aqueous phase during the work-up.
Classical hydrogenolysis using Pd/C or Pd(OH)2/C as
catalysts reduced the pyridine moiety. A method for the
removal of the protective groups carried out from 18b using
trifluoroacetic acid led to 19b in 73% yield. Surprisingly, in
these conditions, 20 was not directly obtained from 18b.
After isolation 19b could be converted to 20 with TFA in
43% yield. A second method for debenzylation using
dimethyldioxirane28,29 led to 19a and 19b in 59 and 76%
yields from 18a and 18b, respectively.
4.1.1. 3-(Indol-3-yl)-succinimide (2a). A mixture of indole
(2.34 g, 20 mmol) and maleimide (1.96 g, 20 mmol) in
acetic acid (18 mL) was refluxed for 36 h. After evapor-
ation, the residue was purified by flash chromatography
(eluent: EtOAc/cyclohexane from 1:1 to 4:1) to give 2a
(3.33 g, 15.6 mmol, 74% yield) as a pale yellow solid.
Mp 196–197 8C. IR (KBr): nC]O 1696 cmK1, nNH 3292–
3370 cmK1
.
1H NMR (400 MHz, DMSO-d6): 2.78 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 3.18 (1H, dd, J1Z18.0 Hz, J2Z9.5 Hz), 4.33
(1H, dd, J1Z9.5 Hz, J2Z5.5 Hz), 7.00 (1H, t, JZ7.0 Hz),
7.10 (1H, t, JZ7.0 Hz), 7.33 (1H, d, JZ2.5 Hz), 7.38 (1H,
d, JZ8.0 Hz), 7.42 (1H, d, JZ8.0 Hz), 11.07 (1H, s, NH),
11.34 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 37.5 (CH2), 39.1 (CH),
111.8, 118.5, 118.9, 121.5, 123.5 (C tert arom), 110.0,
126.0, 136.6 (C quat arom), 178.2, 180.1 (C]O).
3. Conclusion
In conclusion, this work reports the synthesis of
dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones and pyri-
dino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraones,
bearing or not a methyl group on the nitrogen of the upper
maleimide heterocycle. These compounds are structurally
related to granulatimide.
4.1.2. 1-Methyl-3-(indol-3-yl)-pyrrolidine-2,5-dione (2b)
and 2-methyl-1,3-dihydro-2H,4H,9H-indolo[3,2-a]pyr-
rolo[3,4-c]carbazole-1,3-dione (3b). A mixture of indole
(2.34 g, 20 mmol) and N-methylmaleimide (2.22 g,
20 mmol) in acetic acid (18 mL) was refluxed for 48 h.
After evaporation, the residue was purified by flash
In the first series, various substituents were introduced on

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chromatography (eluent: EtOAc/cyclohexane from 3:7 to
7:3) to give 3b (66 mg, 0.195 mmol, 1% yield) as an orange
solid and 2b (2.50 g, 11 mmol, 55% yield) as a pale yellow
solid.
HRMS (FABC) [MCH]C calcd. for C20H19N2O3
335.1396, found 335.1397.
1H NMR (400 MHz, DMSO-d6): 2.79 (1H, dd, J1Z18.0 Hz,
J2Z5.0 Hz), 2.96 (3H, s, CH3), 3.26 (1H, dd, J1Z18.0 Hz,
J2Z9.5 Hz), 4.35 (1H, dd, J1Z9.5 Hz, J2Z5.0 Hz), 5.11
(2H, s, CH2), 6.88 (1H, dd, J1Z9.0 Hz, J2Z2.5 Hz), 7.00
(1H, d, JZ2.0 Hz), 7.30–7.38 (3H, m), 7.43 (2H, t, JZ
7.5 Hz), 7.49 (2H, d, JZ7.0 Hz), 10.95 (1H, s, NH).
Compound 2b: Mp 172–174 8C. IR (KBr): nC]O 1670,
.
1680 cmK1, nNH 3340 cmK1
1H NMR (400 MHz, DMSO-d6): 2.83 (1H, dd, J1Z18.0 Hz,
J2Z5.0 Hz), 2.96 (3H, s, CH3), 3.27 (1H, dd, J1Z18.0 Hz,
J2Z9.5 Hz), 4.40 (1H, dd, J1Z9.5 Hz, J2Z5.0 Hz), 7.03
(1H, dt, J1Z7.5 Hz, J2Z1.0 Hz), 7.13 (1H, dt, J1Z8.0 Hz,
J2Z1.0 Hz), 7.37 (1H, d, JZ2.5 Hz), 7.41 (1H, d, JZ
8.0 Hz), 7.43 (1H, d, JZ7.5 Hz), 11.12 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 24.5 (CH3), 36.0 (CH2),
37.5 (CH), 69.8 (CH2), 102.0, 111.9, 112.3, 124.0, 127.6
(3C), 128.3 (2C) (C tert arom), 110.4, 126.3, 131.7, 137.7,
152.2 (C quat arom), 176.6, 178.4 (C]O).
13C NMR (100 MHz, DMSO-d6): 24.5 (CH3), 36.1 (CH2),
37.6 (CH), 110.7, 125.9, 136.4 (C quat arom), 111.7, 118.4,
118.8, 121.3, 123.4 (C tert arom), 176.6, 178.4 (C]O).
Compound 3d: Mp 286 8C. IR (KBr): nC]O 1680,
.
1790 cmK1, nNH 3300–3400 cmK1
1H NMR (400 MHz, DMSO-d6): 3.18 (3H, s, CH3), 5.26
(2H, s, CH2), 5.32 (2H, s, CH2), 7.28 (1H, dd, J1Z9.0 Hz,
J2Z2.5 Hz), 7.30 (1H, dd, J1Z9.0 Hz, J2Z2.5 Hz), 7.39–
7.51 (6H, m), 7.62 (4H, t, JZ7.0 Hz), 7.68 (1H, d, JZ
9.0 Hz), 7.70 (1H, d, JZ9.0 Hz), 8.42 (1H, d, JZ2.0 Hz),
8.65 (1H, d, JZ2.5 Hz), 12.01 (1H, s, NH), 12.14 (1H, s,
NH).
1
Compound 3b: H NMR (400 MHz, DMSO-d6): 3.21 (3H,
s, CH3), 7.40 (1H, t, JZ7.0 Hz), 7.45 (1H, t, JZ8.0 Hz),
7.55 (1H, d, JZ5.5 Hz), 7.59 (1H, d, JZ6.5 Hz), 7.77 (1H,
d, JZ8.0 Hz), 7.80 (1H, d, JZ8.0 Hz), 8.80 (1H, d, JZ
8.0 Hz), 8.98 (1H, d, JZ8.0 Hz), 12.22 (1H, s, NH), 12.35
(1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 23.6 (CH3), 69.9, 70.5
(CH2), 106.3, 110.5, 111.7, 120.6, 121.8, 123.8, 132.9,
135.8, 136.0, 137.3, 137.4, 138.7, 153.0, 153.3 (C quat
arom), 106.0, 107.8, 112.0, 112.7, 115.6, 115.8, 127.6 (2C),
127.8 (2C), 128.1 (2C), 128.4 (4C) (C tert arom), 168.9,
169.7 (C]O).
4.1.3. 3-(5-Benzyloxy-indol-3-yl)-pyrrolidine-2,5-dione
(2c). Identical method as described for the preparation of
2b gave from 5-benzyloxyindole (1.79 g, 8.0 mmol) and
maleimide (776 mg, 8.0 mmol) compound 2c (1.01 g,
3.16 mmol, 39% yield) as a pale yellow solid.
Mp 175 8C. IR (KBr) nC]O 1690, 1780 cmK1, nNH 3210,
4.1.5. 3-(5-Bromo-indol-3-yl)-pyrrolidine-2,5-dione (2e).
Identical method as described for the preparation of 2b gave
from 5-bromo-indole (1.0 g, 5.10 mmol) and maleimide
(495 mg, 5.10 mmol) compound 2c (647 mg, 2.21 mmol,
43% yield) as a pale yellow solid.
3420 cmK1
.
HRMS (FABC) [M]C calcd. for C19H16N2O3 320.1161,
found 320.1168.
1H NMR (400 MHz, DMSO-d6): 2.76 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 3.21 (1H, dd, J1Z18.0 Hz, J2Z9.5 Hz), 4.33
(1H, dd, J1Z9.5 Hz, J2Z5.5 Hz), 5.10 (2H, s), 6.88 (1H,
dd, J1Z9.0 Hz, J2Z2.5 Hz), 7.06 (1H, d, JZ2.5 Hz), 7.31
(1H, d, JZ9.0 Hz), 7.31 (1H, d, JZ2.5 Hz), 7.36 (1H, m),
7.43 (2H, m), 7.51 (2H, m), 10.92 (1H, d, JZ2.0 Hz, NH),
11.32 (1H, s, NH).
Mp 208–215 8C. IR (KBr) nC]O 1700, 1775 cmK1, nNH
3420 cmK1
.
HRMS (FABC) [MCH]C calcd. for C12H10N2O2Br
292.9926 found 292.9915.
1H NMR (400 MHz, DMSO-d6): 2.84 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 3.20 (1H, dd, J1Z18.0 Hz, J2Z9.5 Hz), 4.40
(1H, dd, J1Z9.5 Hz, J2Z5.5 Hz), 7.25 (1H, dd, J1Z8.5 Hz,
J2Z2.0 Hz), 7.38 (1H, d, JZ8.5 Hz), 7.45 (1H, d, JZ
2.5 Hz), 7.68 (1H, d, JZ2.0 Hz), 11.30 (1H, s, NH), 11.35
(1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 37.3, 69.9 (CH2), 38.9
(CH), 102.2, 111.8, 112.3, 123.9, 127.6, 127.7 (2C), 128.3
(2C) (C tert arom), 110.6, 126.4, 131.7, 137.6, 152.1 (C quat
arom), 178.0, 179.8 (C]O).
13C NMR (100 MHz, DMSO-d6): 34.0 (CH2), 35.6 (CH),
113.7, 120.9, 123.8, 124.8 (C tert arom), 110.8, 111.3,
128.1, 135.1 (C quat arom), 177.9, 179.7 (C]O).
4.1.4. 1-Methyl-3-(5-benzyloxy-indol-3-yl)-pyrrolidine-
2,5-dione (2d) and 2-methyl-7,12-dibenzyloxy-4H,9H-
indolo[3,2-a]pyrrolo[3,4-c]-carbazole-1,3-dione (3d).
Identical procedure as described for the synthesis of 2b
and 3b gave from 5-benzyloxy-indole (1.79 g, 8 mmol) and
N-methylmaleimide (0.89 g, 8 mmol) compound 3d (68 mg,
0.123 mmol, 2% yield), and 2d (1.10 g, 3.29 mmol, 41%
yield) as a light brown solid.
4.1.6. 3-(5-Chloro-indol-3-yl)-pyrrolidine-2,5-dione (2f).
Identical method as described for the preparation of 2b gave
from 5-chloro-indole (1,0 g, 6.6 mmol) and maleimide
(640 mg, 6.6 mmol) compound 2f (412 mg, 1.66 mmol,
25% yield) as an amorphous orange solid.
Compound 2d: Mp 49–53 8C. IR (KBr): nC]O 1690,
.
1700 cmK1, nNH 3300–3500 cmK1
IR (KBr) nC]O 1700, 1780 cmK1, nNH 3200–3500 cmK1
.

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HRMS (FABC) [M]C calcd. for C12H9N2O2Cl 248.0353,
found 248.0354.
136.7, 139.0 (C quat), 112.6, 114.0, 120.4, 121.4, 123.0,
131.0 (C tert), 171.6, 171.9 (C]O).
1H NMR (400 MHz, DMSO-d6): 2.84 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 3.21 (1H, dd, J1Z18.0 Hz, J2Z9.5 Hz), 4.40
(1H, dd, J1Z9.5 Hz, J2Z5.5 Hz), 7.14 (1H, dd, J1Z8.5 Hz,
J2Z2.0 Hz), 7.43 (1H, d, JZ8.5 Hz), 7.46 (1H, d, JZ
2.5 Hz), 7.53 (1H, d, JZ2.0 Hz), 11.29 (1H, s, NH), 11.34
(1H, s, NH).
4.1.9. 3-(5-Benzyloxy-indol-3-yl)-2,5-dihydro-1H-pyr-
role-2,5-dione (4c). A solution of DDQ (339 mg,
1.49 mmol) in dioxane (15 mL) was slowly added to a
solution of 2c (456 mg, 1.42 mmol) in dioxane (15 mL).
The mixture was stirred at room temperature for 12 h. After
filtration, the filtrate was evaporated under reduced
pressure. The residue was purified by flash chromatography
(eluent cyclohexane/EtOAc 7:3) to give 4c (409 mg,
1.28 mmol, 90% yield) as an orange solid.
13C NMR (100 MHz, DMSO-d6): 37.0 (CH2), 38.6 (CH),
113.2, 117.9, 121.3, 125.0 (C tert arom), 110.8, 123.4,
127.3, 134.9 (C quat arom), 177.9, 179.7 (C]O).
Mp 211 8C. IR (KBr) nC]C 1600 cmK1, nC]O 1705,
1755 cmK1, nNH 3150–3450 cmK1
.
4.1.7. 3-(5-Fluoro-indol-3-yl)-pyrrolidine-2,5-dione (2g).
Identical method as described for the preparation of 2b gave
from 5-fluoro-indole (1.0 g, 7.40 mmol) and maleimide
(718 mg, 7.40 mmol) compound 2g (679 mg, 2.92 mmol,
40% yield) as an orange solid.
HRMS (FABC) [MCH]C calcd. for C19H15N2O3
319.1083, found 319.1089.
1H NMR (400 MHz, DMSO-d6): 5.25 (2H, s), 6.86 (1H, s),
6.99 (1H, dd, J1Z9.0 Hz, J2Z2.5 Hz), 7.36 (1H, m), 7.44
(2H, m), 7.46 (1H, d, JZ9.0 Hz), 7.50 (1H, d, JZ2.5 Hz),
7.54 (2H, m), 8.35 (1H, s), 10.77 (1H, br s, NH), 11.93 (1H,
br s, NH).
Mp 190–195 8C. IR (KBr) nC]O 1690, 1775 cmK1, nNH
3360 cmK1
.
HRMS (FABC) [M]C calcd. for C12H9N2O2F 232.0648,
found 232.0644.
13C NMR (100 MHz, DMSO-d6): 69.9 (CH2), 103.9, 113.3,
113.5, 114.7, 127.6, 127.7 (2C), 128.4 (2C), 131.2 (C tert),
105.3, 126.2, 131.6, 137.6, 139.4, 154.2 (C quat), 173.3,
173.5 (C]O).
1H NMR (400 MHz, DMSO-d6): 2.83 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 3.21 (1H, dd, J1Z18.0 Hz, J2Z9.5 Hz), 4.37
(1H, dd, J1Z9.5 Hz, J2Z5.5 Hz), 6.99 (1H, dt, J1Z9.0 Hz,
J2Z2.5 Hz), 7.24 (1H, dd, J1Z10 Hz, J2Z2.5 Hz), 7.40
(1H, dd, J1Z9.0 Hz, J2Z4.5 Hz), 7.45 (1H, d, JZ2.5 Hz),
11.18 (1H, s, NH), 11.33 (1H, s, NH).
4.1.10. 2,5-Dihydro-1-methyl-3-(5-benzyloxy-indol-3-yl)-
pyrrole-2,5-dione (4d). Identical method as described for
the preparation of 4b gave from 2d (668 mg, 2 mmol)
compound 4d (442 mg, 1.33 mmol, 67% yield).
13C NMR (100 MHz, DMSO-d6): 37.1 (CH2), 38.7 (CH),
103.3 (d, JC,FZ23 Hz), 109.5 (d, JC,FZ26 Hz), 112.6 (d,
JC,FZ9.5 Hz), 125.2 (C tert arom), 111.2 (d, JC,FZ4.5 Hz),
126.4 (d, JC,FZ10 Hz), 133.1, 156.7 (d, JC,FZ232 Hz) (C
quat arom), 177.9, 179.7 (C]O).
Mp 176–182 8C. IR (KBr): nC]O 1690, 1700 cmK1, nNH
3300–3440 cmK1
.
HRMS (FABC) [MCH]C calcd. for C20H17N2O3
333.1239, found 333.1238.
4.1.8. 2,5-Dihydro-1-methyl-3-(indol-3-yl)-pyrrole-2,5-
dione (4b). A solution of DDQ (456 mg, 2 mmol) in
dioxane (20 mL) was slowly added to a solution of 2b
(454 mg, 2 mmol) in dioxane (20 mL). The mixture was
stirred at room temperature for 12 h. After filtration and
removal of the solvent, the residue was dissolved in
isopropanol (23 mL). After cooling for 12 h at 0 8C, the
precipitate was filtered off, and the solid was washed with
isopropanol before purification by flash chromatography
(eluent: EtOAc/cyclohexane 3:7) to give 4b (112 mg,
0.496 mmol, 25% yield). The filtrate was concentrated and
purified by flash chromatography (eluent: EtOAc/cyclo-
hexane 3:7) to give 4b (197 mg, 0.872 mmol, 44% yield),
total yield: 69%.
1H NMR (400 MHz, DMSO-d6): 2.98 (3H, s, CH3), 5.28
(2H, s, CH2), 6.98 (1H, s), 7.00 (1H, dd, J1Z9.0 Hz, J2Z
2.0 Hz), 7.36 (1H, t, JZ7.5 Hz), 7.41 (1H, d, JZ7.5 Hz),
7.45 (2H, t, JZ8.5 Hz), 7.53 (1H, d, JZ2.0 Hz), 7.56 (2H,
d, JZ7.5 Hz), 8.39 (1H, d, JZ3.0 Hz), 11.96 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 23.4 (CH3), 69.9 (CH2),
103.9, 113.4, 113.6 (2C), 127.6 (2C), 127.7, 128.3 (2C),
131.3 (C tert), 105.4, 126.1, 131.6, 137.6, 138.9, 154.3 (C
quat), 171.7, 172.1 (C]O).
4.1.11. 3-(5-Bromo-indol-3-yl)-2,5-dihydro-1H-pyrrole-
2,5-dione (4e). Identical method as described for the
preparation of 4c gave from 2e (499 mg, 1.70 mmol)
compound 4e (476 mg, 1.64 mmol, 96% yield) as an orange
solid.
Mp 188 8C. IR (KBr) nC]C 1610 cmK1, nC]O 1680,
1690 cmK1, nNH 3220 cmK1
.
1H NMR (400 MHz, DMSO-d6): 2.95 (3H, s, CH3), 6.92
(1H, s), 7.24 (1H, t, JZ7.5 Hz), 7.30 (1H, dt, J1Z7.5 Hz,
J2Z1.0 Hz), 7.56 (1H, d, JZ8.0 Hz), 8.01 (1H, d, JZ
8.0 Hz), 8.44 (1H, d, JZ3.0 Hz), 12.10 (1H, s, NH).
Mp 268 8C. IR (KBr) nC]C 1595 cmK1, nC]O 1705,
1750 cmK1, nNH 3200, 3340 cmK1
.
HRMS (FABC) [MCH]C calcd. for C12H8N2O2Br
290.9769, found 290.9766.
13C NMR (100 MHz, DMSO-d6): 23.4 (CH3), 105.5, 125.4,

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1H NMR (400 MHz, DMSO-d6): 6.95 (1H, d, JZ1.0 Hz),
7.41 (1H, dd, J1Z8.5 Hz, J2Z2.0 Hz), 7.52 (1H, d, JZ
8.5 Hz), 8.19 (1H, d, JZ2.0 Hz), 8.41 (1H, d, JZ2.5 Hz),
10.82 (1H, s, NH), 12.19 (1H, s, NH).
1H NMR (400 MHz, DMSO-d6): 7.30 (1H, t, JZ7.3 Hz),
7.32 (1H, s), 7.35 (1H, t, JZ7.2 Hz), 7.60 (1H, d, JZ
7.7 Hz), 8.08 (1H, d, JZ7.7 Hz), 8.46 (1H, d, JZ2.9 Hz),
12.38 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 114.4, 116.5, 122.5,
125.6, 131.9 (C tert), 104.9, 114.2, 127.2, 135.4, 138.7 (C
quat), 173.0, 173.2 (C]O).
13C NMR (100 MHz, DMSO-d6): 105.0, 125.2, 136.9, 141.3
(C quat), 112.9, 113.9, 120.5, 122.1, 123.6, 133.0 (C tert),
166.1, 166.6 (C]O).
4.1.12. 3-(5-Chloro-indol-3-yl)-2,5-dihydro-1H-pyrrole-
2,5-dione (4f). Identical method as described for the
preparation of 4c gave from 2f (394 mg, 1.58 mmol)
compound 4f (219 mg, 0.89 mmol, 56% yield) as an orange
solid.
4.1.15. 1,3,4,6-Tetrahydro-2-methyl-5H,7H-dipyrrolo-
[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (7b). A mixture
of 4b (226 mg, 1 mmol) and maleimide (106 mg,
1.10 mmol) in p-xylene (17 mL) was refluxed for 48 h.
After cooling, the yellow precipitate was filtered off, washed
with xylene and dried. The residue was purified by flash
chromatography (eluent: EtOAc/cyclohexane from 1:1 to
100% EtOAc, then EtOAc/methanol 98:2) to give an orange
solid. A mixture of this solid in dioxane (40 mL) and
trifluoroacetic acid (636 mL) was refluxed for 48 h. After
evaporation, EtOAc was added to the residue, and the
mixture was successively washed with saturated aqueous
NaHCO3 and brine. The solid at the interface was filtered off
to give 7b (48 mg, 0.150 mmol, 15% yield) as an orange
solid.
Mp 254–264 8C. IR (KBr) nC]C 1605 cmK1, nC]O 1710,
1750 cmK1, nNH 3100–3350 cmK1
.
HRMS (FABC) [MCH]C calcd. for C12H8N2O2Cl
247.0274, found 247.0278.
1H NMR (400 MHz, DMSO-d6): 6.95 (1H, d, JZ1.0 Hz),
7.29 (1H, dd, J1Z8.5 Hz, J2Z2.0 Hz), 7.57 (1H, d, JZ
8.5 Hz), 8.06 (1H, d, JZ2.0 Hz), 8.43 (1H, d, JZ3.0 Hz),
10.82 (1H, s, NH), 12.18 (1H, s, NH).
MpO300 8C. IR (KBr): nC]O 1710, 1720, 1760, 1780 cmK1
nNH 3260, 3395 cmK1
,
13C NMR (100 MHz, DMSO-d6): 114.0, 116.4, 119.6,
123.0, 132.1 (C tert), 105.1, 126.2, 126.6, 135.1, 138.7 (C
quat), 173.0, 173.3 (C]O).
.
HRMS (FABC) [MCH]C calcd. for C17H10N3O4
320.0671, found 320.0666.
4.1.13. 3-(5-Fluoro-indol-3-yl)-2,5-dihydro-1H-pyrrole-
2,5-dione (4g). Identical method as described for the
preparation of 4c gave from 2g (569 mg, 2.45 mmol)
compound 4g (464.5 mg, 2.02 mmol, 82% yield) as an
orange solid.
1H NMR (400 MHz, DMSO-d6): 3.16 (3H, s, CH3), 7.45
(1H, t, JZ6.5 Hz), 7.70 (1H, t, JZ6.0 Hz), 7.78 (1H, d, JZ
7.5 Hz), 9.00 (1H, br s), 11.59 (1H, s, NH), 12.76 (1H, s,
NH).
Mp 255–265 8C. IR (KBr) nC]C 1605 cmK1, nC]O 1720,
13C NMR (100 MHz, DMSO-d6): 24.0 (CH3), 117.5, 118.5,
119.3, 124.3, 125.5, 130.6, 136.8, 144.1 (C quat arom),
112.9, 121.6, 125.4, 130.1 (C tert arom), 165.1, 166.3,
167.9, 168.5 (C]O).
1750 cmK1, nNH 3150–3350 cmK1
.
HRMS (FABC) [MCH]C calcd. for C12H8N2O2F
231.0570, found 231.0567.
1H NMR (400 MHz, DMSO-d6): 6.91 (1H, d, JZ0.5 Hz),
7.14 (1H, dt, J1Z9.0 Hz, J2Z2.5 Hz), 7.56 (1H, dd, J1Z
9.0 Hz, J2Z4.5 Hz), 7.83 (1H, dd, J1Z10 Hz, J2Z2.5 Hz),
8.44 (1H, d, JZ2.5 Hz), 10.81 (1H, s, NH), 12.13 (1H, s,
NH).
4.1.16. 1,3,4,6-Tetrahydro-5-methyl-2H,7H-dipyrrolo-
[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (7c). A mixture
of 4a (193 mg, 0.91 mmol) and N-methylmaleimide
(121 mg, 1.09 mmol) in p-xylene (19 mL) was refluxed
for 12 h. After cooling, the mixture was filtered off and the
orange solid was washed with xylene and dried. This solid
(223 mg) was dissolved in dioxane (12 mL). DDQ (344 mg,
1.52 mmol) was added and the mixture was refluxed for 3
days. After cooling, water and EtOAc were added. The solid
at the interface was filtered off and washed with water then
EtOAc to give compound 7c (187 mg, 0.586 mmol, 64%
yield) as an orange solid.
13C NMR (100 MHz, DMSO-d6): 105.7 (d, JC,FZ25 Hz),
111.0 (d, JC,FZ26 Hz), 113.6 (d, JC,FZ10 Hz), 115.8, 132.4
(C tert), 105.5, 125.9 (d, JC,FZ11 Hz), 133.2, 139.0, 158.3
(d, JC,FZ234 Hz) (C quat), 173.1, 173.3 (C]O).
4.1.14. 2,5-Dihydro-3-(indol-3-yl)-furane-2,5-dione (4h).
A mixture of 4b (200 mg, 0.884 mmol) and NaOH (500 mg)
in water (100 mL) was refluxed for 2 h. After cooling,
concentrated HCl was added dropwise until formation of a
yellow precipitate. The precipitate was filtered off, washed
with water to give 4h (125 mg, 0.59 mmol, 66% yield) as a
yellow solid.
MpO300 8C. IR (KBr) nC]O 1695, 1725, 1765, 1775 cmK1
nNHZ3220, 3330 cmK1
,
.
HRMS (FABC) [MCH]C calcd. for C17H10N3O4
320.0671, found 320.0677.
Mp 210–214 8C. IR (KBr) nC]O 1740, 1800 cmK1, nNH
1H NMR (400 MHz, DMSO-d6): 3.16 (3H, s, NCH3), 7.48
(1H, t, JZ7.5 Hz), 7.73 (1H, dt, J1Z7.5 Hz, J2Z1.0 Hz),
3320 cmK1
.

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5607
7.82 (1H, d, JZ8.0 Hz), 9.04 (1H, d, JZ8.0 Hz), 11.65 (1H,
s, NH), 12.83 (1H, s, NH).
Compound 7e: MpO300 8C. IR (KBr) nC]O 1700, 1720,
1775 cmK1, nNH 3480 cmK1
.
HRMS (FABC) [MCH]C calcd. for C25H18N3O5
440.1246, found 440.1246.
4.1.17. 1,3,4,6-Tetrahydro-2,5-dimethyl-7H-dipyrrolo-
[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (7d). A mixture
of 4b (226 mg, 1 mmol) and N-methylmaleimide (122 mg,
1.10 mmol) in xylene (17 mL) was refluxed for 24 h. After
cooling, the precipitate was filtered off, washed with xylene
and dried. The solid residue was purified by flash
chromatography (eluent: EtOAc/cyclohexane from 1:1 to
100% EtOAc then EtOAc/methanol 98:2) to give an orange
solid (156 mg). A mixture of this solid (156 mg,
0.465 mmol) in dioxane (25 mL) and trifluoroacetic acid
(480 mL) was refluxed for 84 h. After evaporation, EtOAc
was added to the residue. Identical work-up as for 7b gave
7d (91 mg, 0,271 mmol, 27% yield) as an orange solid.
1H NMR (400 MHz, DMSO-d6): 3.08 (3H, s, CH3), 3.10
(3H, s, CH3), 5.16 (2H, s, CH2), 7.33 (1H, d, JZ8.5 Hz),
7.43 (1H, d, JZ7.0 Hz), 7.47 (2H, t, JZ7.0 Hz), 7.55 (1H,
d, JZ9.0 Hz), 7.63 (2H, d, JZ7.5 Hz), 8.35 (1H, s), 12.40
(1H, br s, NH).
4.1.19. 10-Benzyloxy-1,3,4,6-tetrahydro-7H-dipyrrolo-
[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (7f). Identical
method as described for the preparation of 7c gave from
4c (190 mg, 0.597 mmol) and maleimide (64 mg,
0.66 mmol) compound 7f (172.5 mg, 0.419 mmol, 70%
yield) as a red solid.
Mp 300 8C. IR (KBr): nC]O 1695–1720 cmK1, nNH
3410 cmK1
.
MpO300 8C. IR (KBr) nC]O 1725, 1755, 1780 cmK1, nNH
HRMS (FABC) [MCH]C calcd. for C18H12N3O4
334.0828, found 334.0825.
3150–3500 cmK1
.
HRMS (FABC) [MCH]C calcd. for C23H14N3O5
412.0933, found 412.0933.
1H NMR (400 MHz, DMSO-d6): 3.12 (3H, s, CH3), 3.13
(3H, s, CH3), 7.41 (1H, t, JZ7.5 Hz), 7.68 (1H, t, JZ
7.0 Hz), 7.73 (1H, d, JZ8.0 Hz), 8.88 (1H, d, JZ8.0 Hz),
12.67 (1H, s, NH).
1H NMR (400 MHz, DMSO-d6): 5.24 (2H, s), 7.38 (1H, m),
7.42 (1H, dd, J1Z9.0 Hz, J2Z2.5 Hz), 7.46 (2H, m), 7.60
(2H, m), 7.67 (1H, d, JZ9.0 Hz), 8.60 (1H, d, JZ2.5 Hz),
11.54 (1H, br s, NH), 11.56 (1H, br s, NH), 12.58 (1H, br s,
NH).
13C NMR (100 MHz, DMSO-d6): 24.0 (2CH3), 116.5,
118.4, 119.3, 124.4, 124.6, 131.2, 136.6, 144.2 (C quat
arom), 112.9, 121.7, 125.4, 130.2 (C tert arom), 165.0,
166.8, 167.2, 167.8 (C]O).
13C NMR (125 MHz, DMSO-d6): 69.9 (CH2), 108.6, 113.6,
120.0, 127.8, 127.9 (2C), 128.4 (2C) (C tert arom), 117.9,
119.0, 119.8, 124.1, 125.5, 131.5, 136.9, 137.0, 139.0, 153.5
(C quat arom), 166.4, 166.5, 168.6, 169.3 (C]O).
4.1.18. 2,5-Dimethyl-10-benzyloxy-1,3,3a,3b,4,6,6a,6b-
octahydro-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-
tetraone (5 RZOBn, XZYZNCH3) and 1,3,4,6-tetra-
hydro-2,5-dimethyl-10-benzyloxy-7H-dipyrrolo[3,4-
a:3,4-c]carbazole-1,3,4,6-tetraone (7e). A mixture of 4d
(216 mg, 0.650 mmol) and N-methylmaleimide (80 mg,
0.715 mmol) in p-xylene (17 mL) was refluxed for 48 h.
After cooling, the yellow precipitate was filtered off, washed
with p-xylene and dried. The solid was washed with CH2Cl2
to give 7e (20 mg, 0.046 mmol, 7% yield) as a yellow solid.
The filtrate was evaporated and the residue purified by flash
chromatography (eluent: EtOAc/cyclohexane from 3:2 to
100% EtOAc then EtOAc/methanol 95:5) to give 5 (RZ
OBn, XZYZNCH3) (59 mg, 0.133 mmol, 21% yield) as an
orange solid.
4.1.20. 10-Bromo-1,3,4,6-tetrahydro-7H-dipyrrolo[3,4-
a:3,4-c]carbazole-1,3,4,6-tetraone (7g). Identical method
as described for the preparation of 7c gave from 4e (150 mg,
0.515 mmol) and maleimide (55 mg, 0.567 mmol) com-
pound 7g (125 mg, 0.325 mmol, 63% yield) as an orange
solid.
MpO300 8C. IR (KBr) nC]C 1600 cmK1, nC]O 1710, 1720,
1760 cmK1, nNH 3150–3350 cmK1
.
HRMS (FABC) [MCH]C calcd. for C16H7N3O4Br
383.9620, found 383.9619.
Compound 5 (RZOBn, XZYZNCH3): Mp 173–174 8C.
IR (KBr): nC]O 1700, 1710, 1760, 1770 cmK1, nNH
3400 cmK1. Mass (EI) [MCH]C: 444.
1H NMR (400 MHz, DMSO-d6): 7.75 (1H, d, JZ8.5 Hz),
7.86 (1H, d, JZ8.5 Hz), 9.15 (1H, s), 11.64 (1H, s, NH),
11.69 (1H, s, NH), 12.93 (1H, s, NH).
1H NMR (400 MHz, DMSO-d6): 2.56 (3H, s, CH3), 3.00
(3H, s, CH3), 3.64 (4H, s, CH), 5.00 (2H, s, CH2), 6.92 (1H,
d, JZ9.0 Hz), 7.13 (1H, dd, J1Z9.0 Hz, J2Z2.5 Hz), 7.36
(1H, t, JZ7.0 Hz), 7.42 (2H, t, JZ7.0 Hz), 7.48 (2H, d, JZ
7.0 Hz), 7.53 (1H, d, JZ2.5 Hz), 8.01 (1H, s, NH).
4.1.21. 10-Chloro-1,3,4,6-tetrahydro-7H-dipyrrolo[3,4-
a:3,4-c]carbazole-1,3,4,6-tetraone (7h). Identical method
as described for the preparation of 7c gave from 4f (158 mg,
0.64 mmol) and maleimide (62 mg, 0.64 mmol) compound
7h (104 mg, 0.306 mmol, 48% yield) as an orange solid.
13C NMR (100 MHz, DMSO-d6): 24.5 (2C) (NCH3), 41.2
(2C), 45.7 (2C), 69.8 (CH2), 108.8, 117.7, 137.0, 146.8,
150.4, 153.4 (C quat), 109.0, 111.6, 125.2, 127.9 (3C), 128.3
(2C) (C tert arom), 164.0, 172.1, 172.6, 173.9 (C]O).
MpO300 8C. IR (KBr) nC]C 1600 cmK1, nC]O 1710, 1720,
1760 cmK1, nNH 3120–3380 cmK1
.

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5608
HRMS (FABC) [MCH]C calcd. for C16H7N3O4Cl
340.0125, found 340.0121.
1H NMR (400 MHz, DMSO-d6): 3.20 (3H, s, NCH3), 7.51
(1H, ddd, J1Z8.0 Hz, J2Z6.0 Hz, J3Z2.0 Hz), 7.78 (2H,
m), 8.99 (1H, d, JZ8.0 Hz), 13.22 (1H, s, NH).
1H NMR (400 MHz, DMSO-d6): 7.75 (1H, dd, J1Z9.0 Hz,
J2Z2.0 Hz), 7.81 (1H, d, JZ9.0 Hz), 9.01 (1H, d, JZ
2.0 Hz), 11.64 (1H, s, NH), 11.69 (1H, s, NH), 12.94 (1H, s,
NH).
13C NMR (125 MHz, DMSO-d6): 23.9 (CH3), 113.0, 121.2,
124.8, 129.1 (C tert arom), 112.6, 117.8, 119.3, 120.2,
128.5, 130.4, 142.6, 143.0 (C quat arom), 166.0, 167.0,
167.1, 167.6 (C]O).
4.1.22. 10-Fluoro-1,3,4,6-tetrahydro-7H-dipyrrolo[3,4-
a:3,4-c]carbazole-1,3,4,6-tetraone (7i). Identical method
as described for the preparation of 7c gave from 4g (347 mg,
1.51 mmol) and maleimide (146 mg, 1.51 mmol) compound
7i (464 mg containing 11.4% dioxane (w/w) measured from
1H NMR spectrum, 1.27 mmol, 84% yield) as an orange
solid.
4.1.25. 1,3,4,6-Tetrahydro-2H,7H-furo[3,4-a]pyrrolo-
[3,4-c]carbazole-1,3,4,6-tetraone (7l). Identical method
as described for the preparation of 7c gave from 4a
(200 mg, 0.942 mmol) and maleic anhydride (111 mg,
1.13 mmol) compound 7l (235 mg, 0.767 mmol, 81%
yield) as an orange solid.
MpO300 8C. IR (KBr) nC]C 1610 cmK1, nC]O 1700–
MpO300 8C. IR (KBr) nC]O 1710, 1780 cmK1, nNH 3100–
1850 cmK1, nNH 3240, 3380 cmK1
.
3350 cmK1
.
HRMS (FABC) [MCH]C calcd. for C16H7N2O5 307.0355,
found 307.0357.
HRMS (FABC) [MCH]C calcd. for C16H7N3O4F
324.0421, found 324.0424.
1H NMR (400 MHz, DMSO-d6): 7.55 (1H, t, JZ7.5 Hz),
7.79 (1H, t, JZ7.5 Hz), 7.85 (1H, d, JZ8.0 Hz), 9.06 (1H,
d, JZ8.0 Hz), 11.86 (1H, br s, NH), 13.28 (1H, br s, NH).
1H NMR (400 MHz, DMSO-d6): 7.57 (1H, dt, J1Z9.0 Hz,
J2Z2.5 Hz), 7.75 (1H, dd, J1Z9.0 Hz, J2Z4.5 Hz), 8.63
(1H, dd, J1Z9.5 Hz, J2Z2.5 Hz), 10.61 (2H, br s, 2 NH),
12.77 (1H, br s, NH).
4.1.26. 2,5-Dihydro-3-(5-hydroxy-indol-3-yl)-1H-pyr-
role-2,5-dione (9). A mixture of compound 2c (450 mg,
1.40 mmol), methanol (90 mL) and Pd/C 10% (135 mg) was
hydrogenated (1 bar) for 3 h. After filtration over celite, the
filtrate was evaporated to give compound 8 as a grey oil. A
solution of DDQ (318 mg, 1.40 mmol) in dioxane (15 mL)
was slowly added to a solution of 8 (323 mg, 1.40 mmol) in
dioxane (15 mL). The mixture was stirred at room
temperature overnight then filtered off. After removal of
the solvent, the residue was purified by flash chromato-
graphy (eluent cyclohexane/EtOAc 1:1) to give 9 (166 mg,
0.73 mmol, 52% yield) as an orange solid.
13C NMR (125 MHz, DMSO-d6): 110.2 (d, JC,FZ25 Hz),
114.2 (d, JC,FZ9 Hz), 118.0 (d, JC,FZ26 Hz) (C tert arom),
118.4, 119.4, 119.6 (d, JC,FZ11 Hz), 123.5 (d, JC,F
Z
4.5 Hz), 126.2, 131.9 137.3, 140.5, 157.2 (d, JC,FZ236 Hz)
(C quat arom), 166.2, 166.3, 168.4, 169.2 (C]O).
4.1.23. 2-Methyl-1,3,4,6-tetrahydro-7H-furo[3,4-c]pyr-
rolo[3,4-a]carbazole-1,3,4,6-tetraone (7j). Identical
method as described for the preparation of 7c gave from
4h (213 mg, 0.997 mmol) and N-methylmaleimide (122 mg,
1.26 mmol) compound 7j (40 mg, 0.125 mmol, 13% yield)
as an orange solid.
Compound 8: IR (film) nC]O 1700 cmK1, nNH,OH 3000–
3700 cmK1
.
Mp 294 8C (decomposition). IR (KBr) nC]O 1775,
.
1840 cmK1, nNH 3370 cmK1
1H NMR (400 MHz, DMSO-d6): 2.75 (1H, dd, J1Z18 Hz,
J2Z5.0 Hz), 3.18 (1H, dd, J1Z18 Hz, J2Z9.5 Hz), 4.26
(1H, dd, J1Z9.5 Hz, J2Z5.0 Hz), 6.65 (1H, dd, J1Z8.5 Hz,
J2Z2.0 Hz), 6.75 (1H, d, JZ2.0 Hz), 7.20 (1H, d, JZ
8.5 Hz), 7.24 (1H, d, JZ2.5 Hz), 8.74 (1H, s, OH), 10.74
(1H, s, NH), 11.34 (1H, s, NH).
HRMS (FABC) [MCH]C calcd. for C17H9N2O5 321.0511,
found 321.0494.
1H NMR (400 MHz, DMSO-d6): 3.20 (3H, s, NCH3), 7.58
(1H, t, JZ8.0 Hz), 7.82 (1H, t, JZ8.0 Hz), 7.90 (1H, d, JZ
8.0 Hz), 8.91 (1H, d, JZ8.0 Hz), 13.20 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 37.2 (CH2), 39.1 (CH),
102.3, 111.7, 112.1, 123.9 (C tert arom), 109.9, 126.4,
131.0, 150.4 (C quat arom), 178.1, 180.0 (C]O).
4.1.24. 1,3,4,6-Tetrahydro-2-methyl-7H-furo[3,4-a]pyr-
rolo[3,4-c]carbazole-1,3,4,6-tetraone (7k). Identical pro-
cedure as described for the preparation of 7c gave from 4b
(315 mg, 1.39 mmol) and maleic anhydride (164 mg,
1.67 mmol) compound 7k (235 mg, 0.734 mmol, 53%
yield) as a yellow solid.
Compound 9: Mp 292–298 8C. IR (KBr) nC]C 1610 cmK1
nC]O 1690, 1760 cmK1, nNH,OH 3260, 3370, 3430 cmK1
,
.
HRMS (FABC) [MCH]C calcd. for C12H9N2O3 229.0613,
found 229.0609.
MpO300 8C. IR (KBr) nC]O 1705, 1760, 1835 cmK1, nNH
3370 cmK1
.
1H NMR (400 MHz, DMSO-d6): 6.47 (1H, s), 6.80 (1H, dd,
J1Z8.5 Hz, J2Z2.0 Hz), 7.20 (1H, d, JZ2.0 Hz), 7.36 (1H,
d, JZ8.5 Hz), 8.29 (1H, d, JZ3.0 Hz), 9.09 (1H, s, OH),
10.74 (1H, s, NH), 11.85 (1H, s, NH).
HRMS (FABC) [MCH]C calcd. for C17H9N2O5 321.0511,
found 321.0513.

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H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
5609
13C NMR (100 MHz, DMSO-d6): 104.7, 112.7, 113.1,
113.5, 131.1 (C tert), 104.6, 126.7, 130.7, 139.9, 152.8 (C
quat), 173.1, 173.3 (C]O).
2-methyl-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-
tetraone hydrochloride (7n). To a solution of 7k (30 mg,
0.094 mmol) in THF (5.5 mL) was added dropwise N,N-
diethylethylenediamine (20 mL, 0.142 mmol). The light-
protected mixture was stirred at 65 8C for 4 days. After
cooling, the solvent was removed. Acetic anhydride (1 mL)
and NaOAc (75 mg, 0.91 mmol) were added to the residue.
The mixture was stirred at 90 8C for 4 h. After cooling, 1 N
HCl (40 mL) then EtOAc were added. After extraction,
EtOAc and saturated aqueous NaHCO3 were added to the
aqueous phase. After extraction with EtOAc, the organic
phase was dried over MgSO4, and the solvent was removed
under reduced pressure without heating. The free amine
(33 mg) was obtained as a yellow solid. To a solution of the
free amine in methanol (1 mL) at 0 8C was added dropwise
1 N HCl (172 mL). The mixture was stirred for 30 min. The
solvent was removed to give 7n (31 mg, 0.068 mmol, 72%
yield) as a yellow-orange solid.
4.1.27. 1,3,4,6-Tetrahydro-10-hydroxy-7H-dipyrrolo-
[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone (7m). Identical
method as described for the preparation of 7c gave from 9
(79.5 mg, 0.348 mmol) and maleimide (33.8 mg,
0.348 mmol) compound 7m (38.5 mg, 0.120 mmol, 34%
yield) as a brown solid.
MpO300 8C. IR (KBr) nC]O 1715, 1770 cmK1, nNH,OH
3100–3650 cmK1
.
HRMS (FABC) [MCH]C calcd. for C16H8N3O5 322.0464,
found 322.0460.
1H NMR (400 MHz, DMSO-d6): 7.21 (1H, dd, J1Z2.5 Hz,
J2Z9.0 Hz), 7.63 (1H, d, JZ9.0 Hz), 8.45 (1H, d, JZ
2.5 Hz), 9.52 (1H, br s, OH), 11.49 (1H, s, NH), 11.52 (1H,
s, NH), 12.51 (1H, s, NH).
Mp 278–280 8C. IR (KBr) nC]O 1710, 1770 cmK1, nNH
3200, 3600 cmK1
.
HRMS (FABC) [MCH]C calcd. for C23H23N4O4 calcd.
for 419.1719, found 419.1720.
13C NMR (100 MHz, DMSO-d6): 109.7, 113.4, 120.0 (C
tert arom), 117.7, 118.7, 120.2, 124.2, 125.4, 131.6, 137.1,
138.1, 152.5 (C quat arom), 166.5, 166.6, 168.8, 169.4
(C]O).
1H NMR (400 MHz, DMSO-d6): 1.29 (6H, t, JZ7.0 Hz),
3.19 (3H, s, NCH3), 3.31 (4H, m), 3.46 (2H, m), 4.08 (2H, t,
JZ6.5 Hz), 7.48 (1H, t, JZ7.5 Hz), 7.74 (1H, t, JZ7.5 Hz),
7.81 (1H, d, JZ8.0 Hz), 9.00 (1H, d, JZ8,0 Hz), 10.04 (1H,
br s), 12.87 (1H, s).
4.1.28. 2-(2-N,N-Diethylaminoethyl)-1,3,5,6-tetrahydro-
5-methyl-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-
tetraone hydrochloride (7o). To a solution of 7j (28.3 mg,
0.088 mmol) in THF (5.2 mL) was added dropwise N-N-
diethylethylenediamine (19 mL, 0.132 mmol). The light-
protected mixture was stirred at 65 8C for 4 days. After
cooling, 1 N HCl (40 mL) was added. The mixture was
washed with EtOAc and the aqueous phase was adjusted to
pH 8 by addition of saturated aqueous NaHCO3 then
extracted with EtOAc. The organic phase was dried over
MgSO4 and the solvent was removed under reduce pressure
at 20 8C to give the free amine (29 mg) as a yellow solid. To
a solution of the amine at 0 8C in methanol (400 mL) was
added dropwise 1 N HCl (190 mL). The mixture was stirred
for 30 min. The solvent was removed to give hydrochloride
7o (32.3 mg, 0.071 mmol, 81% yield) as a yellow solid.
13C NMR (100 MHz, DMSO-d6): 8.2 (2C), 24.0 (CH3),
32.5, 46.1 (2C), 47.9 (CH2), 112.9, 121.8, 125.4, 130.3 (CH
arom), 116.3, 118.3, 119.1, 124.3 (2C), 130.0, 136.5, 144.2
(C quat arom), 164.7, 164.9, 166.8, 167.5 (C]O).
4.1.30. 1-(2,5-Dioxopyrrolidin-3-yl)-pyrrolo[2,3-b]pyri-
dine 10. A solution of 7-azaindole (1 g, 8.47 mmol) and
maleimide (904 mg, 9.32 mmol) in acetic acid (10 mL) was
refluxed for 60 h. Acetic acid was evaporated and EtOAc
was added. The solution was washed with saturated aqueous
NaHCO3 then dried over Na2SO4. The solvent was removed
and the residue was purified by flash chromatography
(eluent EtOAc/cyclohexane from 1:2 to 7:3) to give a solid
which was washed with EtOAc then with Et2O to give 10
(184 mg, 0.86 mmol, 10% yield) as a white solid.
Mp 184 8C (decomposition). IR (KBr) nC]O 1710, 1720,
.
1765, 1775 cmK1, nNH 3300–3600 cmK1
HRMS (FABC) [MCH]C calcd. for C23H23N4O4
419.1719, found 419.1713.
MpO200 8C (sublimation). IR (KBr) nC]O 1720,
1780 cmK1
.
1H NMR (400 MHz, DMSO-d6): 1.27 (6H, t, JZ7.0 Hz),
3.18 (3H, s, NCH3), 3.35 (4H, m), 3.50 (2H, m), 4.09 (2H, t,
JZ6.5 Hz), 7.51 (1H, t, JZ8.0 Hz), 7.75 (1H, t, JZ8.0 Hz),
7.84 (1H, d, JZ8.5 Hz), 9.04 (1H, d, JZ8.5 Hz), 9.43 (1H,
br s), 12.95 (1H, s, NH).
HRMS (FABC) [MCH]C calcd for C11H10N3O2
216.0773, found 216.0770.
1H NMR (400 MHz, DMSO-d6): 3.14 (1H, dd, J1Z17.5 Hz,
J2Z6.0 Hz), 3.26 (1H, dd, J1Z17.5 Hz, J2Z9.5 Hz), 5.86
(1H, dd, J1Z9.5 Hz, J2Z6.0 Hz), 6.57 (1H, d, JZ3.5 Hz),
7.16 (1H, dd, J1Z8.0 Hz, J2Z4.5 Hz), 7.71 (1H, d, JZ
3.5 Hz), 8.04 (1H, d, JZ8.0 Hz), 8.26 (1H, d, JZ4.5 Hz),
11.69 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 8.2 (2C) (CH3), 24.0
(NCH3), 32.6, 46.1 (2C), 47.9 (CH2), 113.0, 121.8, 125.4,
130.4 (C tert arom), 116.7, 118.2, 119.2, 124.5, 124.7,
130.1, 136.6, 144.3 (C quat arom), 164.8, 165.0, 167.1,
167.6 (C]O).
13C NMR (100 MHz, DMSO-d6): 36.4 (CH2), 54.6, 100.1,
116.2, 129.0, 129.1, 142.5 (CH), 120.5, 146.8 (C quat
arom), 175.8, 176.3 (C]O).
4.1.29. 5-(2-N,N-Diethylaminoethyl)-1,3,4,6-tetrahydro-

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5610
4.1.31. 1-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyr-
rolidine-2,5-dione 11a. A mixture of A (199 mg,
0.65 mmol) and 10% Pd/C (20 mg) in methanol (40 mL)
was hydrogenated (1 bar) for 3.5 h. The mixture was filtered
over Celite, the filtrate was evaporated and the residue was
purified by flash chromatography (eluent from EtOAc 100%
to EtOAc/MeOH 9:1) to give 11a (135 mg, 0.59 mmol, 90%
yield) as a white solid.
HRMS (FABC) [MCH]C calcd for C12H10N3O2
228.0773, found 228.0774.
1H NMR (400 MHz, DMSO-d6): 2.98 (3H, s, NCH3), 7.08
(1H, s), 7.29 (1H, dd, J1Z8.0 Hz, J2Z4.5 Hz), 8.40 (1H,
dd, J1Z4.5 Hz, J2Z1.5 Hz), 8.47 (1H, d, JZ2.5 Hz), 8.52
(1H, dd, J1Z8.0 Hz, J2Z1.5 Hz), 12.59 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 23.4 (CH3), 115.9, 117.4,
128.9, 130.9, 144.3 (C tert), 104.3, 117.7, 138.3, 149.1 (C
quat), 171.3, 171.8 (C]O).
Mp 199–202 8C. IR (KBr) nC]O 1690, 1770 cmK1, nNH
3250–3500 cmK1
.
HRMS (FABC) [MCH]C calcd for C12H12N3O2
230.0930, found 230.0925.
4.1.34. 1-Benzyloxymethyl-2,5-dihydro-3-(1H-pyrrolo-
[2,3-b]pyridin-3-yl)-pyrrole-2,5-dione 12b. DDQ
(234 mg, 1.03 mmol) was added slowly to a solution of
11b (329 mg, 0.98 mmol) in dioxane (20 mL). The mixture
was stirred at room temperature overnight. The solvent was
removed and the residue was purified by flash chromato-
graphy (eluent cyclohexane/EtOAc 1:1 then THF/cyclo-
hexane 1:1) to give 12b (327 mg, 0.98 mmol, 100% yield)
as a yellow solid.
1H NMR (400 MHz, DMSO-d6): 2.92 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 2.95 (3H, s, NCH3), 3.25 (1H, dd, J1Z
18.0 Hz, J2Z9.5 Hz), 4.42 (1H, dd, J1Z9.5 Hz, J2Z
5.5 Hz), 7.10 (1H, dd, J1Z8.0 Hz, J2Z4.5 Hz), 7.53 (1H,
d, JZ2.5 Hz), 7.92 (1H, dd, J1Z8.0 Hz, J2Z1.0 Hz), 8.26
(1H, dd, J1Z4.5 Hz, J2Z1.5 Hz), 11.64 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 24.6 (CH3), 37.5 (CH2),
35.6 (CH), 115.2, 123.8, 127.0, 142.9 (C tert arom), 109.5,
118.4, 148.6 (C quat arom), 176.5, 178.1 (C]O).
Mp 186 8C. IR (KBr): nC]C 1585, 1600 cmK1, nC]O 1705,
1760 cmK1. Mass (ESIC) [MCH]C 334, [MCNa]C 356.
1H NMR (400 MHz, DMSO-d6): 4.60 (2H, s, CH2), 5.02
(2H, s, CH2), 7.16 (1H, s), 7.31 (1H, dd, J1Z8.0 Hz, J2Z
4.5 Hz), 7.31 (1H, m), 7.37 (4H, m), 8.41 (1H, dd, J1Z
4.5 Hz, J2Z1.5 Hz), 8.51 (1H, d, JZ3.0 Hz), 8.54 (1H, dd,
J1Z8.0 Hz, J2Z1.0 Hz), 12.66 (1H, br s, NH).
4.1.32. 1-Benzyloxymethyl-3-(1H-pyrrolo[2,3-b]pyridin-
3-yl)-pyrrolidin-2,5-dione 11b. A mixture of B (607 mg,
1.47 mmol), NaHCO3 (618 mg, 7.36 mmol) and 10% Pd/C
(607 mg) in EtOAc (57 mL) was hydrogenated (1 bar) for
24 h. The mixture was filtered over Celite, the filtrate was
evaporated and the residue was purified by flash chroma-
tography (eluent cyclohexane/EtOAc 3:7) to give 11b
(334 mg, 1.00 mmol, 68% yield) as a white solid.
13C NMR (100 MHz, DMSO-d6): 66.4, 70.3 (CH2), 116.0,
117.5, 127.4 (2C), 127.5, 128.2 (2C), 129.0, 131.4, 144.4 (C
tert), 104.1, 117.7, 137.7, 138.5, 149.1 (C quat), 171.0,
171.2 (C]O).
Mp 136–138 8C. IR (KBr) nC]O 1707, 1776 cmK1, nNH
3143 cmK1
.
4.1.35. 2-Methyl-1,3,4,6-tetrahydro-5H,7H-pyridino[2,3-
b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraone 13a. A
mixture of 12a (55 mg, 0.242 mmol) and maleimide
(26 mg, 0.267 mmol) in p-xylene (5 mL) was refluxed for
20 h. After cooling, then filtration, the solid was washed
with p-xylene. A mixture of the solid (70.8 mg) and DDQ
(116 mg, 0.509 mmol) in dioxane (5 mL) was refluxed for 3
days. After removal of the solvent, water was added. After
filtration, the residue was washed with water then with
EtOAc affording 13a (64.7 mg, 0.202 mmol, 83% yield) as
a yellow-orange solid.
Mass (ESIC) [MCH]C 336. 1H NMR (400 MHz, DMSO-
d6): 3.00 (1H, dd, J1Z18.0 Hz, J2Z5.5 Hz), 3.30 (1H, dd,
J1Z18.0 Hz, J2Z9.5 Hz), 4.47 (1H, dd, J1Z9.5 Hz, J2Z
5.5 Hz), 4.60 (2H, s, CH2), 4.99 (2H, s, CH2), 7.07 (1H, dd,
J1Z8.0 Hz, J2Z4.5 Hz), 7.30–7.42 (5H, m), 7.54 (1H, d,
JZ2.5 Hz), 7.93 (1H, dd, J1Z8.0 Hz, J2Z1.0 Hz), 8.26
(1H, dd, J1Z4.5 Hz, J2Z1.5 Hz), 11.66 (1H, br s, NH).
13C NMR (100 MHz, CDCl3): 35.9, 68.0, 72.4 (CH2), 38.2
(CH), 116.0, 123.1, 127.6 (2C), 127.8, 127.9, 128.5 (2C),
143.1 (C tert arom), 109.4, 118.8, 137.5, 149.0 (C quat
arom), 175.8, 177.4 (C]O).
MpO300 8C. IR (KBr) nC]C 1600 cmK1, nC]O 1710, 1730,
1770, 1780 cmK1, nNH 3200 cmK1
.
Mass (FABC) [MCH]C 321.
4.1.33. 2,5-Dihydro-1-methyl-3-(1H-pyrrolo[2,3-b]pyri-
din-3-yl)-pyrrole-2,5-dione 12a. A solution of DDQ
(138 mg, 0.61 mmol) in dioxane (10 mL) was added
dropwise to a solution of 11a (133 mg, 0.581 mmol) in
dioxane (5 mL). After stirring for 15 h at room temperature,
the solvent was removed and CH2Cl2 was added to the
residue. After filtration, the solid was washed with CH2Cl2
then with methanol to give 12a (124 mg, 0.546 mmol, 94%
yield) as a white solid.
1H NMR (400 MHz, DMSO-d6): 3.19 (3H, s, NCH3), 7.56
(1H, dd, J1Z8.0 Hz, J2Z4.5 Hz), 8.77 (1H, dd, J1Z4.5 Hz,
J2Z1.5 Hz), 9.29 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz), 11.67
(1H, s, NH), 13.39 (1H, s, NH).
Due to its insolubility, the 13C NMR spectrum could not be
recorded.
MpO250 8C. IR (KBr) nC]O 1700, 1760 cmK1, nNH 3300–
4.1.36. 2-Benzyloxymethyl-5H,7H-pyridino[2,3-b]dipyr-
rolo[3,4-e:3,4-g]indole-1,3,4,6-tetraone 13b. A mixture of
3600 cmK1
.

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H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
5611
12b (329 mg, 0.99 mmol) and maleimide (101 mg,
1.04 mmol) in p-xylene (17 mL) was refluxed for 24 h.
After cooling, then filtration, the solid was washed with
p-xylene. A mixture of the solid (361 mg) and DDQ
(417 mg, 1.84 mmol) in dioxane (15 mL) was refluxed for
40 h. After filtration, the residue was washed with water
then with EtOAc affording 13b (325 mg, 0.76 mmol, 77%
yield) as a pale-yellow solid.
purified by flash chromatography (eluent cyclohexane/
EtOAc from 8:2 to 7:3) to give 14a (65 mg, 0.078 mmol,
46% yield) as the major product of the reaction and as a
yellow oil.
IR (NaCl film) nC]O 1710, 1760 cmK1
.
HRMS (FABC) [MCH]C calcd for C46H43N3O7Br
828.2284, found 828,2283.
MpO300 8C. IR (KBr) nC]O 1715, 1780 cmK1, nNH
3200 cmK1
.
1H NMR (400 MHz, CDCl3): 3.21 (3H, s, NCH3), 3.74–3.87
(3H, m), 3.74 (1H, t, JZ9.5 Hz), 3.97–4.05 (2H, m), 4.51
(1H, d, JZ11.0 Hz), 4.53 (1H, d, JZ12.0 Hz), 4.63 (1H, d,
JZ12.0 Hz), 4.70 (1H, d, JZ10.5 Hz), 4.92 (1H, d, JZ
10.5 Hz), 4.98 (3H, s), 6.17 (1H, d, JZ7.5 Hz, H1’), 6.60
(2H, d, JZ7.0 Hz), 6.99 (2H, t, JZ7.5 Hz), 7.06 (1H, t, JZ
7.5 Hz), 7.22–7.40 (15H, m), 8.27 (1H, s), 8.47 (1H, d, JZ
5.0 Hz), 8.49 (1H, d, JZ8.0 Hz).
HRMS (FABC) [MCH]C calcd for C23H14N4O5
427.1042, found 427.1042.
1H NMR (400 MHz, DMSO-d6): 4.69 (2H, s, CH2), 5.22
(2H, s, CH2), 7.28 (1H, m), 7.32–7.42 (4H, m), 7.54 (1H, dd,
J1Z8.0 Hz, J2Z4.5 Hz), 8.74 (1H, dd, J1Z4.5 Hz, J2Z
1.5 Hz), 9.21 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz), 11.70 (1H,
s, NH), 13.39 (1H, s, NH).
13
RMN C (100 MHz, CDCl3): 24.9 (N–CH3), 68.5 (C6 ),
0
0
73.5, 74.9, 75.2, 75.8 (CH2), 77.5, 78.0, 81.7, 82.2, 85.7 (C1 ,
Due to its insolubility, the 13C NMR spectrum could not be
recorded.
C2 , C3 , C4 , C5 ), 118.0, 127.6–128.5, 130.0, 132.0, 144.4,
152.6 (C tert arom), 104.7, 116.2, 118.2, 136.4, 136.9, 137.9,
138.0, 138.3, 148.0 (C quat arom), 166.4, 169.0 (C]O).
0
0
0
0
4.1.37. 1,3,4,6-Tetrahydro-2H,5H,7H-pyridino[2,3-b]-
dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraone 13c. A sol-
ution of compound 13b (100 mg, 0.234 mmol) in TFA
(14 mL) was refluxed for 3 days. After removal of the
solvent, water was added. After fitration the solid residue
was washed with EtOAc then dried under vacuum. A
mixture of the solid residue in p-xylene (3 mL) was refluxed
for 7 days. After cooling then filtration, the solid was
washed with p-xylene, water, EtOAc, and finally with THF
to give 13c (45 mg, 0.147 mmol, 63% yield) as a green-
yellow solid.
4.1.39. 3-Bromo-1-benzyloxymethyl-2,5-dihydro-4-[1-
(2,3,4,6-tetra-O-benzyl-b-D-glucopyranos-1-yl)-pyrrolo-
[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione 14b. To a solution
of B (774 mg, 1.88 mmol) in THF (5 mL) were added
2,3,4,6-tetra-O-benzyl-D-glucopyranose (3.04 g, 5.62 mmol)
and triphenylphosphine (1.74 g, 5.62 mmol). The mixture
was cooled to K78 8C then DIAD (1.12 mL, 5.62 mmol)
was added dropwise. The mixture was allowed to reach
room temperature then was stirred at room temperature
for 15 h. Water was added. After extraction with EtOAc,
the organic phase was dried over MgSO4. The solvent
was removed and the residue was purified by flash
chromatography (eluent cyclohexane/EtOAc 8:2 then
CH2Cl2/EtOAc 95:5) to give 14b (1.12 mg, 1.20 mmol,
64% yield) as the major product of the reaction and as a
yellow oil.
MpO300 8C. IR (KBr) nC]C 1590 cmK1, nC]O 1718,
1780 cmK1, nNH 3000–3300 cmK1
.
HRMS (FABC) [MCH]C calcd for C15H6N4O4 307.0467,
found 307.0477.
1H NMR (400 MHz, DMSO-d6): 7.53 (1H, dd, J1Z8.0 Hz,
J2Z4.5 Hz), 8.74 (1H, dd, J1Z4.5 Hz, J2Z1.5 Hz), 9.24
(1H, dd, J1Z8.0 Hz, J2Z1.5 Hz), 11.63 (1H, br s, NH),
11.68 (1H, br s, NH), 13.32 (1H, br s, NH).
IR (NaCl film) nC]O 1720–1780 cmK1
.
Mass (ESIC) [MCNa]C 956, 958, [MCK]C 972, 974.
1H NMR (400 MHz, CDCl3): 3.66 (1H, m), 3.72 (2H, d,
JZ9.0 Hz), 3.83 (1H, m), 3.89–3.93 (3H, m), 4.42 (1H,
d, JZ11.0 Hz), 4.43 (1H, d, JZ12.0 Hz), 4.52 (1H, d, JZ
12.0 Hz), 4.59 (1H, d, JZ11.0 Hz), 4.60 (2H, s), 4.82 (1H,
d, JZ11.0 Hz), 4.87 (2H, s), 5.09 (2H, s), 6.09 (1H, br s,
13C NMR (100 MHz, DMSO-d6): 117.9, 134.0, 150.5 (C
tert arom), 112.4, 118.8, 120.3, 122.1, 126.8, 132.4, 136.2,
155.4 (C quat arom), 166.2, 166.3, 167.9, 169.1 (C]O).
0
H1 ), 6.49 (2H, d, JZ7.0 Hz), 6.86–6.97 (3H, m), 7.10–7.25
(21H, m), 8.14 (1H, s), 8.36–8.42 (2H, m).
4.1.38. 3-Bromo-2,5-dihydro-1-methyl-4-[1-(2,3,4,6-
tetra-O-benzyl-b-D-glucopyranos-1-yl)-pyrrolo[2,3-b]-
pyridin-3-yl]-pyrrole-2,5-dione 14a. To a solution of A
(50 mg, 0.172 mmol) in THF (4 mL) were added 2,3,4,6-
tetra-O-benzyl-D-glucopyranose (264 mg, 0.488 mmol)
and triphenylphosphine (128 mg, 0.488 mmol). The mixture
was cooled to K78 8C then diisopropyl azodicarboxylate
(DIAD, 97 mL, 0.488 mmol) was added dropwise. The
mixture was allowed to reach room temperature then was
stirred at room temperature for 15 h. Water was added. After
extraction with EtOAc, the organic phase was dried over
MgSO4. The solvent was removed and the residue was
13C NMR (100 MHz, CDCl3): 67.6, 68.6, 72.0, 73.6, 74.9,
0
75.3, 75.8 (CH2), 77.6, 78.1, 81.5, 82.2, 85.8 (C1 , C2 , C3 ,
0
0
0
0
C4 , C5 ), 118.1, 127.7–128.5, 130.5, 132.4, 132.5, 144.1 (C
tert arom), 118.6, 125.3, 136.9, 137.4, 138.0 (2C), 138.4 (C
quat arom), 165.5, 168.0 (C]O).
4.1.40. 1-Methyl-3-[1-(2,3,4,6-tetra-O-benzyl-b-D-gluco-
pyranos-1-yl)-pyrrolo[2,3-b]pyridin-3-yl]-pyrrolidine-
2,5-dione 15a. To a suspension of 14a (65 mg, 0.078 mmol)

´
H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
5612
in EtOAc (10 mL) were added NaHCO3 (66 mg,
0.93 mmol) and 10% Pd/C (65 mg). The mixture was
hydrogenated (1 bar) at room temperature for 24 h. After
filtration over Celite, the filtrate was evaporated and the
residue was purified by flash chromatography (eluent
cyclohexane/EtOAc from 8:2 to 7:3) to give 15a (28 mg,
0.037 mmol, 48% yield) as a colourless oil and as a mixture
of two diastereoisomers (diastereoisomeric ratio: 1:1
13C NMR (100 MHz, CDCl3): 35.2, 35.8 (CH2), 37.9, 38.1
(CH), 68.0, 68.1, 68.6, 72.4, 73.5, 74.4, 74.6, 75.2, 75.6,
0
75.7 (CH2), 77.6, 81.5, 81.7, 85.6, 85.7 (C1 , C2 , C3 , C4 ,
0
0
0
0
C5 ), 110.3, 110.4, 119.2, 137.2, 137.5, 137.9, 138.0, 138.5
(C quat arom), 116.8, 122.4, 127.4, 127.5, 127.7, 127.8,
127.9, 128.0, 128.1, 128.4, 128.5, 129.7, 144.0 (C tert
arom), 175.4, 175.5, 176.6, 176.7 (C]O).
1
4.1.42. 2,5-Dihydro-1-methyl-3-[1-(2,3,4,6-tetra-O-ben-
zyl-b-D-glucopyranos-1-yl)-pyrrolo[2,3-b]pyridin-3-yl]-
pyrrole-2,5-dione 16a. To a solution of 15a (420 mg,
0.56 mmol) in dioxane (20 mL) was slowly added a solution
of DDQ (227 mg, 0.98 mmol) in dioxane (20 mL). The
mixture was stirred for 48 h at room temperature. The
solvent was removed and the residue was purified by flash
chromatography (eluent cyclohexane/EtOAc 8:2) to give
16a (270 mg, 0.360 mmol, 61% yield) as a yellow oil.
calculated from H NMR spectrum on signals at 3.04 and
3.05 ppm).
IR (NaCl film) nC]O 1700–1750 cmK1
.
HRMS (FABC) [MCH]C calcd for C46H46N3O7
752.3335, found 752.3333.
1H NMR (400 MHz, CDCl3): 2.80 (1H, dd, J1Z18.0 Hz,
J2Z5.0 Hz), 2.83 (1H, dd, J1Z18.0 Hz, J2Z5.0 Hz),
3.04 (3H, s, NCH3), 3.05 (3H, s, NCH3), 3.18 (1H, dd,
J1Z18.0 Hz, J2Z9.0 Hz), 3.21 (1H, dd, J1Z18.0 Hz, J2Z
9.0 Hz), 3.65–3.94 (14H, m), 4.21 (2H, m), 4.34 (2H, d,
JZ11.0 Hz), 4.45 (2H, d, JZ12.0 Hz), 4.54 (2H, d, JZ
12.0 Hz), 4.60 (2H, d, JZ11.0 Hz), 4.84 (2H, d, JZ
IR (NaCl film) nC]O 1710, 1770 cmK1
.
1H NMR (400 MHz, CDCl3): 3.04 (3H, s, NCH3), 3.63–3.75
(3H, m), 3.79 (1H, t, JZ9.5 Hz), 3.87–3.98 (2H, m), 3.91
(1H, d, JZ11.0 Hz), 4.41 (1H, d, JZ10.5 Hz), 4.44 (1H, d,
JZ12.0 Hz), 4.52 (1H, d, JZ12.0 Hz), 4.59 (1H, d, JZ
10.5 Hz), 4.83 (1H, d, JZ11.0 Hz), 4.87 (2H, s), 6.02 (1H,
0
11.0 Hz), 4.87–4.91 (4H, m), 6.03 (1H, br s, H1 ), 6.55 (4H,
d, JZ7.0 Hz), 6.98 (4H, t, JZ7.5 Hz), 7.00–7.18 (8H, m),
7.20–7.33 (28H, m), 7.82 (1H, d, JZ8.0 Hz), 7.85 (1H, d,
JZ8.0 Hz), 8.35 (2H, d, JZ5.0 Hz).
0
d, JZ8.0 Hz, H1 ), 6.49 (2H, d, JZ7.5 Hz), 6.55 (1H, s),
6.87 (2H, t, JZ7.5 Hz), 6.96 (1H, t, JZ7.5 Hz), 7.12–7.30
(16H, m), 7.99 (1H, dd, J1Z8.0 Hz, J2Z1.0 Hz), 8.38 (1H,
dd, J1Z5.0 Hz, J2Z1.0 Hz), 8.44 (1H, s).
13C NMR (100 MHz, CDCl3): 25.0 (NCH3), 35.4, 35.9
0
(CH2), 38.0, 38.1 (CH), 68.6 (C6 ), 73.5, 74.4, 74.5, 75.1,
13C NMR (100 MHz, CDCl3): 23.8 (NCH3), 68.6, 73.5,
0
0
75.6, 75.7 (CH2), 77.7, 81.5, 81.7, 82.0, 85.7, 85.8 (C1 , C2 ,
0
74.9, 75.3, 75.7 (C1 , C2 , C3 , C4 , C5 ), 77.7, 78.0, 81.6,
0
0
0
0
0
0
0
C3 , C4 , C5 ), 116.8, 122.2, 127.4–128.4, 144.0 (C tert
arom), 110.7, 110.8, 119.2, 119.3, 137.2, 138.0, 138.5,
148.3 (C quat arom), 175.3, 175.8, 175.9, 176.5 (C]O).
0
82.1, 85.8 (CH2 of OBn, C6 ), 105.7, 119.0, 136.9, 137.9,
138.0, 138.4, 138.6, 148.5 (C quat arom), 116.8, 118.3,
127.5–128.6, 144.7 (C tert arom), 171.2, 171.8 (C]O).
4.1.41. 1-Benzyloxymethyl-3-[1-(2,3,4,6-tetra-O-benzyl-
b-D-glucopyranos-1-yl)-pyrrolo[2,3-b]pyridin-3-yl]-pyr-
rolidine-2,5-dione 15b. To a suspension of 14b (117 mg,
0.125 mmol) in EtOAc (10 mL) were added NaHCO3
(53 mg, 0.625 mmol) and 10% Pd/C (117 mg). The mixture
was hydrogenated (1 bar) at room temperature for 24 h.
After filtration over Celite, the filtrate was evaporated and
the residue was purified by flash chromatography (eluent
cyclohexane/EtOAc 8:2) to give 15b (50 mg, 0.058 mmol,
46% yield) as a colourless oil and as a mixture of two
diastereoisomers (diastereoisomeric ratio: 1:1 calculated
4.1.43. 1-Benzyloxymethyl-2,5-dihydro-3-[1-(2,3,4,6-
tetra-O-benzyl-b-D-glucopyranos-1-yl)-pyrrolo[2,3-b]-
pyridin-3-yl]-pyrrole-2,5-dione 16b. To a solution of 15b
(420 mg, 0.490 mmol) in dioxane (20 mL) was slowly
added a solution of DDQ (227 mg, 0.98 mmol) in dioxane
(20 mL). The mixture was stirred for 48 h at room
temperature. The solvent was removed and the residue
was purified by flash chromatography (eluent cyclohexane/
EtOAc 8:2) to give 16b (270 mg, 0.315 mmol, 64% yield)
as a yellow oil.
1
IR (NaCl film) nC]O 1710, 1770 cmK1
.
from H NMR spectrum on signals at 7.77 and 7.81 ppm).
IR (NaCl film) nC]O 1715–1780 cmK1. Mass (ESIC) [MC
Na]C 880, [MCK]C 896.
Mass (ESIC) [MCNa]C 878, [MCK]C 894.
1H NMR (400 MHz, CDCl3): 3.76–3.95 (4H, m), 3.98–4.08
(2H, m), 4.04 (1H, d, JZ11.0 Hz), 4.53 (1H, d, JZ
11.0 Hz), 4.56 (1H, d, JZ11.0 Hz), 4.64 (1H, d, JZ
12.0 Hz), 4.71 (1H, d, JZ10.0 Hz), 4.72 (2H, s), 4.95 (1H,
d, JZ11.0 Hz), 5.00 (2H, s), 5.17 (2H, s), 6.15 (1H, d, JZ
1H NMR (400 MHz, CDCl3): 2.71 (1H, dd, J1Z18.0 Hz,
J2Z5.5 Hz), 2.73 (1H, dd, J1Z18.0 Hz, J2Z5.5 Hz), 3.04
(1H, dd, J1Z18.0 Hz, J2Z9.0 Hz), 3.07 (1H, dd, J1Z
18.0 Hz, J2Z9.0 Hz), 3.64–3.89 (12H, m), 4.00–4.10 (2H,
m), 4.31 (2H, d, JZ11.0 Hz), 4.42 (2H, d, JZ12.0 Hz), 4.51
(2H, d, JZ12.0 Hz), 4.57 (2H, d, JZ11.0 Hz), 4.60 (2H, s),
4.83 (2H, d, JZ11.0 Hz), 4.86 (2H, dd, J1Z5.0 Hz, J2Z
3.5 Hz), 5.03 (2H, d, JZ3.5 Hz), 6.00 (2H, br s), 6.50 (4H,
d, JZ7.5 Hz), 6.90–6.95 (4H, m), 6.98–7.10 (4H, m), 7.12–
7.15 (4H, m), 7.18–7.31 (36H, m), 7.76 (1H, d, JZ8.0 Hz),
7.81 (1H, d, JZ8.0 Hz), 8.32 (2H, d, JZ4.5 Hz).
0
7.0 Hz, H1 ), 6.60 (2H, d, JZ7.5 Hz), 6.69 (1H, s), 6.97 (2H,
t, JZ7.5 Hz), 7.06 (1H, t, JZ7.5 Hz), 7.23–7.46 (21H, m),
8.08 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz), 8.49 (1H, dd, J1Z
5.0 Hz, J2Z1.0 Hz), 8.55 (1H, s).
13C NMR (100 MHz, CDCl3): 66.7, 68.6, 71.5, 73.5, 74.8,
0
75.3, 75.7 (CH2), 77.7, 78.0, 81.5, 82.0, 85.8 (C1 , C2 , C3 ,
0
0

´
H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
5613
0
0
C4 , C5 ), 116.9, 118.4, 126.5–128.6, 130.5, 144.8 (C tert
arom), 105.4, 118.9, 136.9, 137.5, 137.9 (2C), 128.4, 138.6,
148.5 (C quat arom), 170.8, 171.2 (C]O).
Masse (ESIC) [MCH]C 949.
1
0
H NMR (400 MHz, CDCl3): 3.84 (1H, d, JZ11.0 Hz, H6 ),
0
3.92 (1H, dd, J1Z12.0 Hz, J2Z5.0 Hz, H6 ), 3.95 (1H, d,
0
0
JZ12.0 Hz), 4.01–4.05 (2H, m, H3 CH4 ), 4.17 (1H, m,
4.1.44. 2-Methyl-7-(2,3,4,6-tetra-O-benzyl-b-D-glucopyr-
anos-1-yl)-1,3,4,6-tetrahydro-5H-pyridino[2,3-b]dipyr-
rolo[3,4-e:3,4-g]indole-1,3,4,6-tetraone 18a. A mixture of
16a (605 mg, 0.790 mmol) and maleimide (384 mg,
3.95 mmol) in toluene (12 mL) was refluxed for 14 h. The
solvent was removed and the residue was purified by flash
chromatography (eluent cyclohexane/EtOAc from 8:2 to
7:3) to give the mixture of isomers 17a (277 mg,
0.327 mmol, 41% yield) as a pale yellow solid. To a
solution of 17a (277 mg, 0.327 mmol) in CHCl3 (13 mL)
was added MnO2 (491 mg, 5.65 mmol). The mixture was
refluxed for 24 h. The solvent was removed and the residue
was purified by flash chromatography (eluent cyclohexane/
EtOAc 7:3) to give 18a (168 mg, 0.199 mmol, 61% yield) as
a pale yellow solid.
0
H5 ), 4.51 (1H, d, JZ12.0 Hz), 4.59 (1H, d, JZ12.0 Hz),
4.71 (2H, d, JZ12.0 Hz), 4.75 (2H, s), 4.97 (1H, d, JZ
11.0 Hz), 4.99 (1H, d, JZ11.0 Hz), 5.02 (1H, d, JZ
0
11.0 Hz), 5.34 (2H, s), 5.50 (1H, m, H2 ), 6.38 (2H, d,
JZ7.5 Hz), 6.60–6.75 (2H, m), 6.83 (1H, t, JZ7.5 Hz),
7.15–7.50 (22H, m), 8.65 (1H, dd, J1Z5.0 Hz, J2Z1.5 Hz),
8.82 (1H, s, NH), 9.37 (1H, dd, J1Z8.0 Hz, J2Z1.5 Hz).
13C NMR (100 MHz, CDCl3): 67.4, 68.9, 72.1, 73.2, 74.4,
0
75.2, 75.9 (CH2), 77.2, 78.1, 78.2, 86.4, 87.0 (C1 , C2 , C3 ,
0
0
0
0
C4 , C5 ), 119.2, 126.9, 127.1, 127.4–128.5, 135.3, 150.5 (C
tert arom), 114.5, 119.0, 119.8, 124.2, 130.9, 137.3, 137.8,
138.0, 138.1, 138.5, 140.5, 154.1 (C quat arom), 163.5,
164.0, 166.2, 166.9 (C]O).
4.1.46. 2-Methyl-7-(b-D-glucopyranos-1-yl)-1,3,4,6-tetra-
hydro-5H-pyridino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-
1,3,4,6-tetraone 19a. To a solution of 18a (168 mg,
0.199 mmol) in CH2Cl2 (6 mL) was added during 48 h a
solution of dimethyldioxirane (0.8 1.0 M, 56 mL). After
evaporation, EtOAc was added. After filtration, the solid
residue was washed with EtOAc, then with CH2Cl2 and
finally with acetone to give 19a (57 mg, 0.118 mmol, 59%
yield) as a yellow solid.
Mp 68–70 8C.
IR (KBr) nC]O 1710, 1720, 1735, 1780 cmK1, nNH
3280 cmK1
.
Mass (ESIC) [MCNa]C 865.
1H NMR (400 MHz, CDCl3): 3.17 (3H, s), 3.72–3.80 (2H,
m), 3.81 (1H, d, JZ9.5 Hz), 3.85 (1H, d, JZ8.0 Hz), 3.93
(1H, t, JZ9.0 Hz), 4.12 (1H, m), 4.43 (1H, d, JZ12.0 Hz),
4.47 (1H, d, JZ12.0 Hz), 4.60 (2H, d, JZ12.0 Hz), 4.85–
4.95 (3H, m), 5.43 (1H, t, JZ9.0 Hz), 6.26 (2H, d, JZ
7.5 Hz), 6.60 (2H, t, JZ7.5 Hz), 6.71 (1H, t, JZ7.5 Hz),
7.00–7.30 (16H, m), 7.34 (1H, d, JZ9.0 Hz), 8.54 (1H, dd,
J1Z5.0 Hz, J2Z1.5 Hz), 9.20 (1H, dd, J1Z8.0 Hz, J2Z
1.5 Hz), 9.34 (1H, s,NH).
MpO300 8C. IR (KBr) nC]O 1700, 1710, 1720, 1770 cmK1
nNH, OH 3000–3660 cmK1
,
.
HRMS (FABC) [MCNa]C calcd for C22H18N4O9Na
505.0971, found 505.0981.
1H NMR (400 MHz, DMSO-d6): 3.19 (3H, s, NCH3), 3.30–
3.39 (2H, m), 3.51 (1H, m), 3.66–3.82 (2H, m), 4.56 (1H, pt,
JZ5.5 Hz), 5.01 (1H, d, JZ5.5 Hz, OH), 5.08–5.17 (2H, m,
2OH), 5.19 (1H, d, JZ4.0 Hz, OH), 7.27 (1H, d, JZ9.0 Hz,
H1’), 7.64 (1H, m), 8.82 (1H, d, JZ3.5 Hz), 9.48 (1H, d, JZ
7.5 Hz), 11.93 (1H, s).
13C NMR (100 MHz, CDCl3): 24.5 (CH3), 69.1, 73.1, 74.4,
0
75.0, 75.2, 75.9 (CH2), 59.1, 69.3, 76.8, 78.1, 78.5 (C1 , C2 ,
0
0
0
0
C3 , C4 , C5 ), 86.3, 87.0, 119.0, 126.9–129.5, 135.2, 150.4
(C tert arom), 114.5, 118.3, 119.8, 123.7, 131.0, 137.0,
137.6, 137.8, 138.0, 138.4, 140.2, 154.1 (C quat arom),
163.4, 164.1, 166.4, 167.1 (C]O).
13C NMR (100 MHz, DMSO-d6): 24.2 (CH3), 61.2 (C6’),
0
0
0
0
0
68.8, 70.3, 78.1, 79.4, 87.2 (C1 , C2 , C3 , C4 , C5 ), 118.8,
134.1, 150.1 (C tert arom), 113.9, 120.3, 122.3 (2C), 128.5,
131.8, 140.1, 153.7 (C quat arom), 164.4, 165.2, 167.4,
167.8 (C]O).
4.1.45. 2-Benzyloxymethyl-7-(2,3,4,6-tetra-O-benzyl-b-
D-glucopyranos-1-yl)-1,3,4,6-tetrahydro-5H-pyridino-
[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraone 18b.
A mixture of 16b (100 mg, 0.117 mmol) and maleimide
(56.6 mg, 0.584 mmol) in toluene (2 mL) was refluxed for
14 h. The solvent was removed and the residue was purified
by flash chromatography (eluent cyclohexane/EtOAc from
8:2 to 7:3) to give the mixture of isomers 17b (95 mg,
0.100 mmol, 85% yield) as a pale yellow solid. To a solution
of 17b (192 mg, 0.202 mmol) in CHCl3 (9 mL) was added
MnO2 (352 mg, 4.06 mmol). The mixture was refluxed for
24 h. The solvent was removed and the residue was purified
by flash chromatography (eluent cyclohexane:EtOAc 7:3) to
give 18b (166 mg, 0.174 mmol, 86% yield) as a pale yellow
solid.
4.1.47. 2-Hydroxymethyl-7-(b-D-glucopyranos-1-yl)-
1,3,4,6-tetrahydro-5H-pyridino[2,3-b]dipyrrolo[3,4-e:
3,4-g]indole-1,3,4,6-tetraone 19b. To a solution of 18b
(20 mg, 0.021 mmol) in CH2Cl2 (1.5 mL) was added during
72 h a solution of dimethyldioxirane (0.8–1.0 M, 13 mL).
After evaporation, EtOAc was added. After filtration, the
solid residue was washed with EtOAc, then with CH2Cl2
and finally with acetone to give 19b (8 mg, 0.016 mmol,
76% yield) as a yellow solid.
MpO250 8C (decomposition).
Mp 59–61 8C. IR (KBr) nC]O 1725, 1770, 1790 cmK1, nNH
HRMS (FABC) [MCNa]C calcd for C22H18N4O10Na
521.0921, found 521.0938.
3200–3300 cmK1
.

´
H. Henon et al. / Tetrahedron 61 (2005) 5599–5614
5614
IR (KBr) nC]O 1710, 1720, 1760, 1780 cmK1, nNH,
4. Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.;
Moreira da Rocha, R.; Andersen, R. J. J. Org. Chem. 1998, 63,
9850–9856.
OH
2900–3600 cmK1
.
1H NMR (400 MHz, DMSO-d6): 3.34–3.45 (2H, m), 3.52
(1H, m), 3.71 (1H, m), 3.77 (1H, m), 4.55 (1H, t, JZ5.5 Hz,
5. Roberge, M.; Berlinck, R. G. S.; Xu, L.; Anderson, H. J.; Lim,
L. Y.; Curman, D.; Stringer, C. M.; Friend, S. H.; Davies, P.;
Vincent, I.; Haggarty, S. J.; Kelly, M. T.; Britton, R.; Piers, E.;
Andersen, R. J. Cancer Res. 1998, 58, 5701–5706.
6. Jiang, X.; Zhao, B.; Britton, R.; Lim, L. Y.; Leong, D.;
Sanghera, J. S.; Zhou, B.-B.S.; Piers, E.; Andersen, R. J.;
Roberge, M. Mol. Cancer Ther. 2004, 3, 1221–1227.
7. Piers, E.; Britton, R.; Andersen J. Org. Chem. 2000, 65,
530–535.
0
OH), 5.01 (1H, d, JZ5.5 Hz, H2 ), 5.10–5.16 (4H, m,
CH2OH C2OH), 5.18 (1H, d, JZ4.0 Hz, OH), 6.55 (1H, t,
JZ7.5 Hz), 7.29 (1H, d, JZ8.5 Hz, H1’), 7.65 (1H, dd, J1Z
7.0 Hz, J2Z5.0 Hz), 8.83 (1H, d, JZ3.0 Hz), 9.50 (1H, d,
JZ8.0 Hz), 11.94 (1H, s).
13C NMR (100 MHz, DMSO-d6): 60.6, 61.2 (C6’, CH2OH),
0
0
0
0
0
68.8, 70.3, 78.1, 79.5, 87.2 (C1 , C2 , C3 , C4 , C5 ), 118.8,
134.1, 150.2 (C tert arom), 113.9, 119.5, 120.0, 122.6,
129.0, 131.3, 140.2, 153.7 (C quat arom), 163.7, 165.1,
166.9, 167.7 (C]O).
8. Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase, M.;
Kotani, E. Chem. Pharm. Bull. 2002, 50, 872–876.
9. Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase, M.;
Kotani, E. Chem. Pharm. Bull. 2003, 51, 209–214.
10. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M. Tetrahedron
Lett. 2003, 44, 3927–3930.
4.1.48. 7-(b-D-Glucopyranos-1-yl)-1,3,4,6-tetrahydro-
5H-pyridino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-
tetraone 20. A solution of 19b (32 mg, 0.064 mmol) in TFA
(2.5 mL) was refluxed for 3 days. After evaporation, the
residue was purified by flash chromatography (eluent
EtOAc 100%) to give a solid to which was added EtOAc.
The precipitate was filtered off washed with EtOAc, then
with CH2Cl2 and finally with Et2O to give 20 (13 mg,
0.028 mmol, 43% yield) as a yellow solid.
11. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M. Tetrahedron
Lett. 2003, 44, 4607–4611.
12. Camargo, A. J.; Oliveira, J. H. H. L.; Trsic, M.; Berlinck,
R. S. G. J. Mol. Struct. 2001, 559, 67–77.
13. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M. Tetrahedron
Lett. 2003, 44, 3935–3937.
´
14. Desarbre, E.; Coudret, S.; Meheust, C.; Merour, J. Y.
Tetrahedron 1997, 53, 3637–3648.
´
´
´
15. Marminon, C.; Pierre, A.; Pfeiffer, B.; Perez, V.; Leonce, S.;
Joubert, A.; Bailly, C.; Renard, P.; Hickman, J.; Prudhomme,
M. J. Med. Chem. 2003, 46, 609–622.
MpO260 8C (decomposition). IR (KBr) nC]O 1720, 1740,
1755, 1780 cmK1, nNH, OH 3100–3600 cmK1
.
HRMS (FABC) [MCNa]C calcd for C21H16N4O9Na
491.0815, found 491.0818.
´
´
´
16. Marminon, C.; Pierre, A.; Pfeiffer, B.; Perez, V.; Leonce, S.;
Renard, P.; Prudhomme, M. Bioorg. Med. Chem. 2003, 11,
679–687.
1H NMR (400 MHz, DMSO-d6): 3.32–3.48 (2H, m), 3.51
17. Bergman, J.; Janosik, T.; Koch, E.; Pelcman, B. J. Chem. Soc.,
Perkin Trans. 1 2000, 2615–2621.
0
(1H, m), 3.67–3.80 (2H, m), 4.55 (1H, t, JZ6.0 Hz, OH6 ),
0
4.99 (1H, d, JZ5.5 Hz), 5.13 (1H, m, H2 ), 5.12 (1H, d, JZ
18. Bergman, J.; Desarbre, E.; Koch, E. Tetrahedron 1999, 55,
2363–2370.
4.5 Hz, OH), 5.18 (1H, d, JZ4.5 Hz, OH), 7.28 (1H, d, JZ
0
9.0 Hz, H1 ), 7.62 (1H, dd, J1Z8.0 Hz, J2Z5.0 Hz), 8.81
19. Zembower, D. E.; Zhang, H.; Lineswala, J. P.; Kuffel, M. J.;
Aytes, S. A.; Ames, M. M. Bioorg. Med. Chem. 1999, 9,
145–150.
(1H, dd, J1Z4.5 Hz, J2Z1.5 Hz), 9.47 (1H, dd, J1Z8.0 Hz,
J2Z1.5 Hz), 11.79 (1H, s, NH), 11.80 (1H, s, NH).
20. Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Ito, S.;
Morishima, H. Tetrahedron 1997, 53, 5937–5950.
21. DeFrees, S. A.; Reddy, K. S.; Cassady, J. M. Syn. Commun.
1988, 18, 213–220.
13
0
C NMR (100 MHz, DMSO-d6): 61.2 (C6 ), 68.8, 70.3,
0
0
0
0
0
78.1, 79.4, 87.2 (C1 , C2 , C3 , C4 , C5 ), 118.7, 134.3, 150.0
(C tert arom), 113.9, 119.2, 121.3, 122.4, 128.7, 132.7,
140.1, 153.7 (C quat arom), 165.3, 165.7, 167.9, 168.7
(C]O).
22. Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249–282.
23. Battersby, A. R.; Westwood, S. W. J. Chem. Soc., Perkin
Trans. 1 1987, 1679–1687.
24. Gottstein, W. J.; Haynes, U. J.; McGregor, D. N. J. Med.
Chem. 1985, 28, 518–522.
References and notes
25. Terpin, A.; Winklhofer, C.; Schumann, S.; Steiglich, W.
Tetrahedron 1998, 54, 1745–1752.
1. Rodrigues Pereira, E.; Belin, L.; Sancelme, M.; Prudhomme,
`
M.; Ollier, M.; Rapp, M.; Severe, D.; Riou, J.-F.; Fabbro, D.;
26. Messaoudi, S.; Anizon, F.; Pfeiffer, B.; Golsteyn, R.;
Prudhomme, M. Tetrahedron Lett. 2004, 45, 4643–4647.
27. Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761–3765.
28. Marples, B. A.; Muxworthy, J. P.; Baggaley, K. H. Synlett
1992, 646.
Meyer, T. J. Med. Chem. 1996, 39, 4471–4477.
2. Prudhomme, M. Curr. Pharm. Des. 1997, 3, 265–290.
3. Zhao, B.; Bower, M. J.; McDevitt, P. J.; Zhao, H.; Davis, S. T.;
Johanson, K. O.; Green, S. M.; Concha, N. O.; Zhou, B.-B.S.
J. Biol. Chem. 2002, 277, 46609–46615.
¨
29. Csuk, R.; Dorr, P. Tetrahedron 1994, 50, 9983–9988.