Efficient synthesis of isogranulatimide C, an analogue of the marine G2 checkpoint inhibitor alkaloid isogranulatimide

Article abstract of DOI:10.1016/j.tetlet.2011.09.109

A three-step procedure to isogranulatimide C starting with the thermal condensation of 3-chloroindole with imidazole and proceeding in 41% yield is described.

Full text of DOI:10.1016/j.tetlet.2011.09.109

Tetrahedron Letters 52 (2011) 6560–6561
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Efficient synthesis of isogranulatimide C, an analogue of the marine G2
checkpoint inhibitor alkaloid isogranulatimide
⇑
Evelyne Delfourne
Laboratoire de Synthèse et Physicochimie de Molécules d’Intérêt Biologique, UMR CNRS 5068, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cédex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2011
Revised 22 September 2011
Accepted 23 September 2011
Available online 1 October 2011
A three-step procedure to isogranulatimide C starting with the thermal condensation of 3-chloroindole
with imidazole and proceeding in 41% yield is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Marine alkaloid
Isogranulatimide
Granulatimide
G2 checkpoint inhibitor
Cells respond to DNA damage by activating checkpoint path-
ways that cause an arrest in the cell cycle progression to allow time
for DNA repair. In more than 50% of human tumor, the G1 check-
point is lacking due to mutation of the p53 gene. In this context, a
combination of DNA damaging agents with a G2 checkpoint inhib-
itor should selectively drive cancer cells to a lethal mitosis.1–3
Among the G2-checkpoint inhibitors identified to date, granu-
latimide 1 and isogranulatimide 2 are natural alkaloids isolated
from the brazilian ascidian Didemnum granulatum (IC50, 2 and
Our synthetic strategy to isogranulatimide C is outlined in
Scheme 2. It was inspired from methods previously used by us
and the Prudhomme’s group8 to prepare pyrazolic and pyrrolic
analogues of the marine alkaloids, respectively.
The first step consisted of the thermal condensation of 3-chlor-
oindole with excess imidazole under solvent- and metal-free con-
ditions, according to the coupling methodology recently reported
by Poirier et al.9 The so-obtained 2-(imidazol-1-yl)indole
3
l
M, respectively (Fig. 1).4
As part of Andersen and Roberge groups’ investigations leading
to the structural elucidation, a first route to these marine metabo-
lites based on the condensation of an imidazo-glyoxylate with
indole-3-acetamide was developed. As a final step of this synthesis,
the photolysis of didemnimide A 3 led both granulatimide and iso-
granulatimide. This reaction scheme was adapted later on to pre-
pare the analogue isogranulatimide C 4 from imidazole. In this
case, the last cyclization step was a thermal reaction, the synthesis
proceeding in 18% overall yield (Scheme 1).5
Although isogranulatimide and isogranulatimide C have shown
equal potency against checkpoint inhibition, isogranulatimide C
seems the most selective inhibitor toward different kinases.6
In the course of our research program which aims at defining
new G2 checkpoint inhibitors,7 we report herein a different effi-
cient route to isogranulatimide C.
Figure 1.
⇑
Tel.: +33 561556293; fax: +33 561556011.
E-mail address: delfourn@chimie.ups-tlse.fr
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.109

E. Delfourne / Tetrahedron Letters 52 (2011) 6560–6561
6561
6 (84% yield) was subsequently reacted with TBDMS-protected
dibromomaleimide 7 under Megger’s conditions10 to afford the
unprotected-maleimide/monobromide 811 in 60% yield (this key
step was performed on a 1 g scale). Photocyclisation of this last
compound furnished exclusively compound 4 in 82% yield. The
overall yield of this synthesis was 41% from imidazole which con-
stitutes a serious improvement of the method described by Britton
and co-workers5 and should allow access to a library of substi-
tuted-isogranulatimide C derivatives.
References and notes
1. Vermeulen, K.; Van Bockstaele, D. R.; Berneman, Z. N. Cell Prolif. 2003, 36, 131–
149.
2. Cuddihy, A. R.; O’Connell, M. J. Cytology 2003, 222, 99–140.
3. McGowan, C. H. Mutat. Res. 2003, 532, 75–84.
Scheme 1.
4. 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.
5. Piers, E.; Britton, R.; Andersen, R. J. J. Org. Chem. 2000, 65, 530–535.
6. 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, 1221–1227.
7. (a) Deslandes, S.; Chassaing, S.; Delfourne, E. Mar. Drugs 2009, 7, 754–786; (b)
Deslandes, S.; Chassaing, S.; Delfourne, E. Tetrahedron Lett. 2010, 51, 5640–
5642.
8. Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M. Tetrahedron Lett. 2003, 44,
3927–3930.
9. Poirier, M.; Goudreau, S.; Poulin, J.; Savoie, J.; Beaulieu, P. L. Org. Lett. 2010, 12,
2334–2337.
10. Bregman, H.; Williams, D. S.; Meggers, E. Synthesis 2005, 9, 1521–1527.
11. Monobromide 8: HRMS (DCI-CH4) HRMS calcd for C15H10N4O2Br 356.9987,
found 356.9995. 1H NMR (300 MHz, DMSO-d6) 7.11 (s, 1H); 7.16 (dd, 1H,
J = 7.3 Hz); 7.26 (dd, 1H, J = 7.3 Hz); 7.47 (d, 1H, J = 8.1 Hz); 7.54 (d, 1H, 7.8 Hz),
7.59 (s, 1H); 8.09 (s, 1H). 13C NMR (75 MHz, DMSO-d6) 94.4, 112.4, 120.4,
121.3, 121.5, 123.5, 124.3, 125.7, 130.0, 132.7, 134.0, 137.6, 137.8, 167.3, 169.5.
Scheme 2.