7326
I. Beria, M. Nesi / Tetrahedron Letters 43 (2002) 7323–7327
and 2-imidazolidinones. In addition to this type of
reactivity, it is also reported that secondary amines,
when reacted with N-(2-nitrobenzenesulfonyl)-2-imida-
zolidinone, open the imidazolidinone ring and give
ureas.29
2. (a) Baraldi, P. G.; Beria, I.; Cacciari, B.; Cozzi, P.;
Franzetti, C.; Mongelli, N.; Romagnoli, R.; Spalluto, G.
Bioorg. Med. Chem. Lett. 1996, 6, 1241–1246; (b) Baraldi,
P. G.; Beria, I.; Cacciari, B.; Coplongo, L.; Cozzi, P.;
Mongelli, N.; Romagnoli, R.; Spalluto, G. Bioorg. Med.
Chem. Lett. 1996, 6, 1247–1252; (c) Cozzi, P.; Beria, I.;
Biasoli, G.; Caldarelli, M.; Capolongo, L.; Geroni, C.;
Mongelli, N. Bioorg. Med. Chem. Lett. 1997, 7, 2979–
2984; (d) Cozzi, P.; Beria, I.; Biasoli, G.; Caldarelli, M.;
Capolongo, L.; D’Alessio, R.; Geroni, C.; Mazzini, S.;
Ragg, E.; Rossi, C.; Mongelli, N. Bioorg. Med. Chem.
Lett. 1997, 7, 2985–2990; (e) Cozzi, P.; Beria, I.; Cal-
darelli, M.; Capolongo, L.; Geroni, C.; Mongelli, N.
Bioorg. Med. Chem. Lett. 2000, 10, 1269–1272; (f) Cozzi,
P.; Beria, I.; Caldarelli, M.; Geroni, C.; Mongelli, N.;
Pennella, G. Bioorg. Med. Chem. Lett. 2000, 10, 1273–
1276; (g) Baraldi, P. G.; Romagnoli, R.; Beria, I.; Cozzi,
P.; Geroni, C.; Mongelli, N.; Bianchi, N.; Mischiati, C.;
Gambari, R. J. Med. Chem. 2000, 43, 2675–2684.
3. Geroni, C.; Pennella, G.; Capolongo, C.; Moneta, D.;
Rossi, R.; Farao, M.; Marchini, S; Cozzi, P. Proc. AACR
Annual Meeting, San Francisco 2000, 41 Abstr. 2708, 425.
4. Ciomei, M.; Pastori, W.; Cozzi, P.; Geroni, C. Proc.
AACR Annual Meeting, Philadelphia 1999, 40, Abstr.
1490, 224.
Therefore, we were positively surprised to find out that
imidazolidinone derivative 9, upon treatment of with
1N NaOH in DMF, afforded amine 10.30 As far as our
knowledge is concerned this type of ring opening of
1-acyl-2-imidazolidinones has not been reported so far.
The synthesis was then completed by standard method-
ology. Guanidinylation of amine 10 with N,N%-di-Boc-
N%%-trifyl-guanidine,31 removal of the Boc groups and
final coupling with 4-[(2-bromoacryloyl)amino]-1-
methyl-1H-pyrrole-2-carbonyl
chloride
afforded
brostallicin 3.
In summary, we have described two syntheses of
brostallicin, starting from distamycin A. Method A is
based on the selective hydrolysis of 6 that leads to the
formation of the N-Boc protected carboxylic acid 7.
This is a key intermediate for the preparation of several
distamycin-like derivatives and up to now has only
been prepared by total synthesis. Furthermore, the
rather non-selective di-tert-butoxycarbonylation of 4
can also be achieved using PS-DMAP that allows a
more simple reaction work-up by filtration of the resin
and evaporation of the volatile components.
5. Geroni, C.; Marchini, S.; Cozzi, P.; Galliera, E.; Ragg,
E.; Colombo, T.; Battaglia, R.; Howard, M.; D’Incalci,
M.; Broggini, M. Cancer Res. 2002, 62, 2332–2336.
6. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem.
1983, 48, 2424–2426.
7. (a) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed.
Engl. 1985, 24, 510–511; (b) Grehn, L.; Gunnarsson, K.;
Ragnarsson, U. Acta Chem. Scand., Ser. B 1986, 40,
745–750.
8. (a) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta
Chem. Scand., Ser. B 1987, 41, 18–23; (b) Kano, S.;
Yokomatsu, T.; Shibuya, S. J. Org. Chem. 1989, 54,
513–515.
9. Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J.
C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38,
4535–4538. For some recent applications see also: (a)
Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.; Lin-
nane, P.; Tavares, F.; Lynch, V. Tetrahedron 1999, 55,
6435–6452; (b) Oscarsson, K.; Classon, B.; Kvarnstro¨m,
I.; Hallberg, A.; Samuelsson, B. Can. J. Chem. 2000, 78,
829–837; (c) Evans, D. A.; Katz, J. L.; Peterson, G. S.;
Hintermann, T. J. Am. Chem. Soc. 2001, 123, 12411–
12413.
Method B is based on the Curtius rearrangement of
carboxylic acid 8a to give the acyl imidazolidinone 9.
Although intramolecular isocyanate trapping by car-
boxamide functions has already been reported in the
literature, we have shown its useful application in the
degradation of an oligopeptidic natural product. Fur-
thermore, the unusual ring opening by aqueous bases of
the imidazolidinone led to the identical product obtain-
able in a typical Curtius reaction and therefore the
inconvenience of the isocyanate trapping by a carbox-
amide function was eventually overcome.
Both approaches have been carried out on small scale
and most of the single steps have not been optimized.
However, the overall yields with method A and method
B, 10% and 18%, respectively, are comparable with that
reported for the step-by-step total synthesis approach2c.
10. Treatment of intermediate 5 in dichloromethane at 0–
25°C with i-C5H12ONO afforded a complex mixture of
1
Acknowledgements
products. Both H NMR and MS spectra determinations
were consistent with extensive nitrosation of the pyrrolic
rings.
We thank Paolo Cozzi and Nicola Mongelli (Pharma-
cia, Department of Chemistry) for helpful discussions.
11. Caldarelli, M.; Biasoli, G.; Cozzi, P.; Mongelli, N. Tetra-
hedron Lett. 1998, 39, 3551–3554.
12. Dimethylaminopyridine, polymer-bound, dry ꢀ2.5 mmol
g−1, available from Sigma-Aldrich Cat. No. 35,988–2.
13. Basel, Y.; Hassner, A. Synthesis 2001, 4, 550–552.
14. The reaction seems to start selectively in favor of interme-
diate 6 but when forced to completion non-selective paths
take over.
References
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15. For recent advances in the field of polymer-supported
reagents see (a) Ley, S. V.; Baxendale, I. R.; Bream, R.