Synthesis of isogranulatimide analogues possessing a pyrrole moiety instead of an imidazole heterocycle

Article abstract of DOI:10.1016/S0040-4039(03)00837-2

An efficient four step synthesis from commercial indoles of isogranulatimide analogues is reported. In the new compounds, the imidazole moiety is replaced by a pyrrole unit, the indole part is substituted or not in 5-position and the nitrogen of the imide moiety bears or not a methyl substituent.

Full text of DOI:10.1016/S0040-4039(03)00837-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3927–3930
Synthesis of isogranulatimide analogues possessing a pyrrole
moiety instead of an imidazole heterocycle
Bernadette Hugon,a Bruno Pfeiffer,b Pierre Renardb and Michelle Prudhommea,*
aUniversite´ Blaise Pascal, Synthe`se et Etude de Syste`mes a` Inte´reˆt Biologique, UMR 6504 du CNRS, 63177 Aubie`re, France
bLes Laboratoires SERVIER, 1 rue Carle He´bert, 92415 Courbevoie, France
Received 25 February 2003; accepted 27 March 2003
Abstract—An efficient four step synthesis from commercial indoles of isogranulatimide analogues is reported. In the new
compounds, the imidazole moiety is replaced by a pyrrole unit, the indole part is substituted or not in 5-position and the nitrogen
of the imide moiety bears or not a methyl substituent. © 2003 Elsevier Science Ltd. All rights reserved.
Granulatimide and isogranulatimide are natural com-
pounds isolated from the ascidian Didemnum granula-
tum (Fig. 1).1,2 Their biological activity is linked to their
capacity to inhibit the G2 checkpoint, which represents
a promising target for the development of new
chemotherapeutic anticancer agents. DNA damage acti-
vates signal transduction pathways called checkpoints,
which delay cell cycle progression and allow more time
to repair DNA. Most of the cancer cells have mutations
in genes involved in the G1 checkpoint such as the p53
Figure 1.
Keywords: G2 checkpoint inhibitors; isogranulatimide; pyrrolo[3,4-c]carbazole.
* Corresponding author. Tel.: +33-4-7340-7124; fax: +33-4-7340-7717; e-mail: mprud@chimtp.univ-bpclermont.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00837-2

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B. Hugon et al. / Tetrahedron Letters 44 (2003) 3927–3930
gene. If the G2 checkpoint is selectively disrupted, the
cancer cells with the impaired G1 checkpoint will
become more sensitive to a DNA-damaging treatment
compared with normal cells because normal cells retain
an intact G1 checkpoint.3–8 Accordingly, the biological
properties of granulatimide and isogranulatimide have
triggered theoretical studies and synthetic efforts.
Detailed computational studies were performed for
granulatimide and isogranulatimide and structurally
related didemnimides in order to initiate a quantitative
structure–activity relationship study.9 Various synthetic
pathways have been investigated to prepare granula-
timides and analogues and isogranulatimides A–C (Fig.
1).1,10,11 Since, in contrast with granulatimide and iso-
granulatimide, staurosporine aglycone is completely
inactive toward G2 checkpoint, it was deduced that the
imidazole moiety could play a central role in their G2
checkpoint activity.11
ence of stannous chloride gave the Michae¨l adduct in a
good yield (Scheme 1).
Various commercial 5-substituted indoles (5-chloro, 5-
bromo, 5-nitro, 5-benzyloxy) and two maleimides
(maleimide and N-methylmaleimide) were also used
(Table 1). In the case of the electron withdrawing nitro
group, coupling of the 5-nitroindole with pyrrole did
not occur. To obtain 5-hydroxy analogues, hydrogenoly-
sis of 5-O-benzyl compounds 12 and 13 using 10%
Pd/C in EtOAc/MeOH led to 18 and 19 in 100% and
89% yields, respectively. Several conditions were tried
for the cyclization of the Michae¨l adducts 10 and 11
with various catalysts11,15,16 (Pd/C, Pd black,
Pd(OAc)2), several solvents (diphenyloxide, chlorobenz-
ene, nitrobenzene, acetic acid) and different work-up.
They are reported in Table 2. The best yields were
obtained using Pd black and nitrobenzene and elimina-
tion of the solvent by filtration over silicagel. These
optimal conditions were applied for the cyclizations of
compounds 12–19, the yields are reported in Table
3.17–20 When R1=OH degradation products were
observed, the low yields could be due to the presence of
a phenol function sensitive to oxidation.
Here we present the synthesis of a new family of
isogranulatimide analogues in which the imidazole moi-
ety is replaced by a pyrrole heterocycle. The first step
consists in a selective bromination in 3-position of the
indole.12 Reaction of 3-bromoindole with pyrrole at
room temperature in dichloromethane in the presence
of trifluoroacetic acid led to the corresponding
indolylpyrrole as described by Bocchi and Palla.13
Cycloadditions between 2%,2%-bisindole and maleimides
failed to give the formal [4+2] cycloadduct, only the
fully aromatized product and the Michae¨l adduct were
isolated in low yields.14 Cycloaddition assays in acetic
acid only led to the degradation of indolylpyrrole.
Reaction of indolylpyrrole with maleimide in the pres-
In summary, in only four steps from commercial
indoles, we have synthesized in good yields isogranula-
timide analogues in which the imidazole part is replaced
by a pyrrole moiety. This way was only possible with
5-substituted indoles bearing an electron donor group.
The biological activities of the new isogranulatimide
analogues are being evaluated.
Scheme 1.

B. Hugon et al. / Tetrahedron Letters 44 (2003) 3927–3930
3929
Table 1. Yields obtained in the different steps from unsubstituted indole and 5-substituted indoles, and with maleimide and
N-methylmaleimide for the synthesis of the Michae¨l adducts (mp in °C)
Indole
Bromation
Coupling with pyrrole
Michae¨l adduct
NH
NCH3
Product Mp (°C) Yield
Product Mp (°C) Yield
Product Mp (°C) Yield
Product Mp (°C) Yield
(%)
(%)
(%)
(%)
5-H
1
2
3
4
5
65
83
6
216–218 83
10
67–69
90
11
142
89–94
92–102 79
81 96
89
5-NO2
5-OBn
5-Cl
191–194 91
89–92
84
92
65
61
7
8
9
178–182 69
223–227 72
12
14
16
103–107 68
138–144 56
163
13
15
17
82
5-Br
94
245
67
46
Table 2. Experimental conditions and yields for the cyclization of the Michae¨l adducts 10 and 11
Starting product Solvent
Catalyst
Temperature
Time of
Method for solvent elimination
Yield of
(°C)
reaction (h)
cyclization (%)
11
Ph2O
Ph2O
Pd/C 10%
Pd/C 10%
180
48
Distillation under reduced pressure
(5 mm Hg)
Filtration over silicagel
Evaporation under reduced pressure Degradation
Filtration over silicagel
Filtration over silicagel
30
16
10
11
10
11
10
180
132
200
200
118
48
48
8
7
3
Chlorobenzene Pd/C 10%
Nitrobenzene
Nitrobenzene
AcOH
Pd black
Pd black
Pd(OAc)2
72
89
Evaporation under reduced pressure Degradation
Table 3. Yields obtained in the cyclization of compounds 10–19 (mp in °C)
Substituent
Compounds
Yield (%)
Mp (°C)
Compounds
Yield (%)
Mp (°C)
H
OBn
Cl
Br
OH
10“20
12“22
14“24
16“26
18“28
89
35
52
42
16
218–220
275
298–304
\300
11“21
13“23
15“25
17“27
19“29
89
75
81
92
17
226–228
120
249
\300
192
\275
References
10. Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase,
M.; Kotani, E. Chem. Pharm. Bull. 2002, 50, 872–876.
11. Piers, E.; Britton, R.; Andersen, R. J. J. Org. Chem.
2000, 65, 530–535.
12. Bocchi, V.; Palla, G. Synthesis 1982, 1096–1097.
13. Bocchi, V.; Palla, G. Tetrahedron 1984, 40, 3251–3256.
14. Barry, J. F.; Wallace, T. W.; Walshe, N. D. A. Tetra-
hedron 1995, 51, 12797–12806.
1. 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.
2. 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.; Anderson, R. J. Cancer Res. 1998,
58, 5701–5706.
15. Pindur, U.; Kim, Y.-S.; Schollmeyer, D. J. Heterocyclic
Chem. 1994, 31, 377–386.
3. Smits, V. A. J.; Medema, R. H. Biochim. Biophys. Acta
16. Bergman, J.; Janosik, T.; Yudina, L.; Desarbre, E.; Lid-
gren, G.; Venemalm, L. Tetrahedron 2000, 56, 1911–1916.
17. Spectral data of 10: IR (KBr) wCꢀO 1700, 1780 cm−1, wNH
2001, 1519, 1–12.
4. Luo, Y.; Rockow-Magnone, S. K.; Kroeger, P. E.; Frost,
L.; Chen, Z.; Han, E. K.-H.; Ng, S.-C.; Simmer, R. L.;
Giranda, V. L. Neoplasia 2001, 3, 411–419.
5. Shapiro, I. G.; Harper, J. W. J. J. Clin. Invest. 1999, 104,
1645–1653.
6. Che`ne, P. Curr. Med. Chem. Anti-Cancer Agents 2001, 1,
151–161.
7. Sampath, D.; Plunkett, W. Curr. Opin. Oncol. 2001, 13,
484–490.
3100–3500 cm−1
.
HRMS (FAB+) (M+) calcd for
C16H13N3O2: 279.1007; found: 279.1004. 1H NMR (400
MHz, DMSO-d6): l 2.80 (1H, dd, J1=18.0 Hz, J2=5.0
Hz), 3.32 (1H, dd, J1=18.0 Hz, J2=10.0 Hz), 4.56 (1H,
dd, J1=9.5 Hz, J2=5.0 Hz), 6.25 (1H, br s), 6.47 (1H, br
s), 7.03 (2H, m), 7.14 (1H, d, J=7.5 Hz), 7.22 (1H, d,
J=8.0 Hz), 7.42 (1H, d, J=8.0 Hz), 11.12 (2H, s, NH),
11.50 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6): l
37.2 (CH2), 39.0 (CH), 106.0, 122.9, 126.2, 130.6, 135.9
(C quat. arom.), 108.7, 108.9, 111.4, 117.5, 119.2, 119.7,
121.3 (C tert. arom.), 178.2, 180.3 (CꢀO).
8. Molinari, M. Cell. Prolif. 2000, 33, 261–274.
9. Camargo, A. J.; Oliveira, J. H. H. L.; Trsic, M.; Berlinck,
R. G. S. J. Mol. Struct. 2001, 559, 67–77.

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B. Hugon et al. / Tetrahedron Letters 44 (2003) 3927–3930
18. Spectral data of 20: IR (KBr) wCꢀO 1710, 1750 cm−1, wNH
Hz), 8.25 (1H, s), 8.55 (1H, d, J=8.0 Hz), 11.09 (1H, s,
NH), 12.63 (1H, s, NH). 13C NMR (100 MHz, DMSO-
d6): l 99.7, 113.2, 116.8, 120.8, 122.2, 122.4, 124.8 (C tert.
arom.), 103.7, 117.0, 121.1, 121.6, 124.5, 133.6, 138.8 (C
quat. arom.), 166.4, 169.2 (CꢀO).
2900–3300 cm−1
.
HRMS (FAB+) (M+) calcd for
C16H9N3O2: 275.0694; found: 275.0698. 1H NMR (400
MHz, DMSO-d6): l 7.11 (1H, s), 7.12 (1H, s), 7.30 (1H,
t, J=7.5 Hz), 7.43 (1H, t, J=7.5 Hz), 7.62 (1H, d, J=8.0