A New Route toward 4-Substituted Pyrazino[2,1-b]quinazoline-3,6-dione Systems. Total Synthesis of Glyantrypine Pilar Cledera, Carmen Avendan ˜ o,* and J. Carlos Mene ´ndez* Departamento de Quı ´mica Orga ´ nica y Farmace ´ utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain Received October 18, 1999 Treatment of sodium N-(o-azidobenzoyl)aminoacylglycinates 8 with acetic anhydride afforded 1-acetyl-4-(o-azidobenzoyl)-2,5-piperazinediones 7, with complete retention of the stereochemistry. The intramolecular aza Wittig reactions of compounds 7 in the presence of tributylphosphine followed by deacetylation gave 1,2-unsubstituted pyrazino[2,1-b]quinazoline-3,6-diones 1. This route was adapted to the synthesis of both enantiomers of the alkaloid glyantrypine. Introduction The pyrazino[2,1-b]quinazoline-3,6-dione system can be considered as a costrained peptidomimetic and is present in several families of natural products such as the fiscalins, 1 the fumiquinazolines, 2 glyantrypine, 3 and N- acetylardeemin. 4 Other natural products, like the asper- licins, 5 vasicinone, 6 and the luotonins, 7 among many others, contain related heteroareno[2,1-b]quinazoline substructures. Some of these compounds exhibit very interesting biological properties. For instance, N-acety- lardeemin is one of the most potent known inhibitors of multidrug resistance to antitumor compounds (MDR), which can be considered as the most important single factor that prevents the success of antitumor chemo- therapy in many cancer patients. 8 Because the anti-MDR activity of N-acetylardeemin can be ascribed to its pyrazino[2,1-b]quinazoline fragment, 9 we became inter- ested in developing new synthetic entries to this ring system. We were particularly interested in the prepara- tion of 1,2-unsubstituted derivatives 1 because of their potential role as starting materials for the synthesis of more complex derivatives with additional rings fused to the 1-2 bond and also to study their anti-MDR proper- ties. The currently known syntheses of pyrazino[2,1-b]- quinazoline-3,6-dione derivatives can be grouped as follows: (a) Transformation of 4-substituted 2,5-pipera- zinediones into the corresponding iminoethers 10 or thio- iminoethers, 11 followed by cyclocondensation with an- thranilic acid or methyl anthranilate. (b) Acylation of 4-substituted 2,5-piperazinediones with o-azidobenzoyl chloride, followed by Staudinger reaction with a phos- phine to yield the corresponding λ 5 -phosphazene and * Phone: 34-91-394 18 21/40. Fax: 34-91-394 18 22. E-mail: josecm@eucmax.sim.ucm.es. (1) (a) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum, A. M.; Cooper, R. J. Antibiotics 1993, 46, 545. (b) Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843. (2) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu, T. Tetrahedron Lett. 1992, 33, 1621. (b) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda, Y.; Numata A. J. Chem. Soc., Perkin Trans. 1 1995, 2345. (3) Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N. J. Chem. Soc., Perkin Trans. 1 1992, 1495. (4) (a) Karwowski, J. P.; Jackson, M.; Rasmussen, R. R.; Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.; McAlpine, J. B. J. Antibiot. 1993, 46, 374. (b) Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.; Whittern, D. N.; Hill, P.; McAlpine, J. B. J. Antibiot. 1993, 46, 380. (5) Liesch, J. M.; Hensens, O. D.; Springer, J. P.; Chang, R. S. L.; Lotti, V. J. J. Antibiot. 1985, 58, 1638. (6) (a) Isolation and structure: Mehta, D. R.; Naravane, J. S.; Desai, R. M. J. Org. Chem. 1963, 28, 445. (b) Absolute configuration: Joshi, B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.; Pelletier, S. W. Tetrahedron: Asymmetry 1996, 7, 25. (7) (a) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Heterocycles 1997, 46, 541. (b) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Heterocycles 1999, 51, 1883. (8) (a) Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells; Roninson, I. B., Ed.; Plenum Press: New York, 1991. (b) Kane, S. E. Adv. Drug Res. 1996, 28, 181. (9) Me ´ndez-Vidal, C.; Rodrı ´guez de Quesada, A. Cancer Lett. 1998, 132, 45. (10) (a) Rajappa, S.; Advani, B. G. Tetrahedron 1973, 29, 1299. (b) Rajappa, S.; Advani, B. G. J. Chem. Soc., Perkin Trans. 1 1974, 2122. (11) Bock, M. G.; DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C. F.; Springer, J. P.; Freidinger, R. M. J. Org. Chem. 1987, 52, 1644. 1743 J. Org. Chem. 2000, 65, 1743-1749 10.1021/jo991626e CCC: $19.00 © 2000 American Chemical Society Published on Web 02/24/2000 Downloaded by SPAIN CONSORTIA on July 28, 2009 Published on February 24, 2000 on http://pubs.acs.org | doi: 10.1021/jo991626e