Solid-Supported Heterocumulenes: Preparation and Crystal Structure of Azaaplysinopsins Jean M. Chezal, 1a Gre ´gory Delmas, 1a Sylvie Mavel, 1b Hamed Elakmaoui, 1c Jacques Me ´tin, 1a Anna Diez, 1d Yves Blache, 1c Alain Gueiffier, 1b Mario Rubiralta, 1d Jean C. Teulade, 1a and Olivier Chavignon* ,1a De ´ partement d’Analyse Structurale et de Pharmacologie, Faculte ´ de Pharmacie, 28, Pl. H. Dunant, BP 38, 63001 Clermont-Fd Cedex 1, France, Laboratoire de Chimie The ´ rapeutique, Faculte ´ de Pharmacie, 34 Avenue Monge, 37200 Tours, France, Laboratoire de Chimie Organique, Faculte ´ de Pharmacie 15, Avenue Ch. Flahault, 34060 Montpellier, France, and Laboratori de Quı ´mica Orga ` nica, Facultat de Farma ` cia, Universitat de Barcelona, 08028-Barcelona, Spain Received November 20, 1996 X Annulation of carbodiimides 6a,b, on alumina solid support, selectively gives (Z)-hydantoins 8a,b determined on the basis of X-ray analysis while thermal cyclization affords, after purification, 8a,b with imidazolones 10a,b. In the imidazopyrimidine series, thermal reaction of heterocumulenes 6d yields, via a Dimroth rearrangement, the dipyridoimidazolic compound 11. In all cases, mechanisms for the observed cyclizations have been proposed. Introduction Aplysinopsin (1) (Figure 1), isolated from the sponge Aplysinopsis reticulata (Dictyoceartida), 2 has been shown to be active as a specific cytotoxin of cancer cells 3 and to affect neurotransmission. 4 The classical approach to the synthesis of C-5 unsaturated hydantoins such as 2 is based on the coupling of an aromatic aldehyde and an appropriately substituted hydantoin. However, poor yields, purification difficulties, and the formation of mixtures of E and Z isomers are generally encountered. 5 Such inconveniences have been circumvented by the development of a tandem Staudinger/aza-Wittig reaction followed by electrocyclic ring closure. 6 Such methodology allows the formation of nitrogenated heterocycles from heterocumulenes which in turn are easily available from iminophosphoranes. Using this route, an elegant syn- thesis of several aplysinopsin-type alkaloids has been accomplished by Molina and co-workers. 7 In the course of our studies on the reactivity of nitrogen bridgehead azaindolizines, and in view of the pharma- cological 8 and theoretical 9 interest of azaindole struc- tures, we embarked on the development of a model system of imidazo[1,2-a](di)azines which may increase greatly the pharmacological profile. 10 We reported re- cently a highly effective method for the synthesis of azacarboline and -aplysinopsin mimic structures from heterocumulenes. 11 We describe now the synthesis of hydantoins 8, potential selective competitive NMDA antagonists, 12 via stereospecific ring-opening/ring-closure of an azalactone obtained from an alumina-supported heterocumulene. Results and Discussion The 3-formyl derivative 3a 9 was condensed with ethyl azidoacetate in the presence of sodium ethoxide at -30 °C to give azidovinyl 4a (ν azido 2050 cm -1 ) in 78% yield. Measurement of the long-range 13 C- 1 H coupling constant between the olefinic proton and the carbonyl carbon in the coupled 13 C NMR spectra proved to be diagnostic of a(Z) arrangement. 13 The preparation of iminophospho- rane 5a was accomplished by Staudinger’s reaction of 4a with triphenylphosphine in dichloromethane at room temperature in 81% yield (Scheme 1). Spectral and analytical data were consistent with the identity of compound 5a and the (Z) configuration assignment ( 3 J H-C,CO ) 3.5 Hz). An aza-Wittig type reaction of iminophosphorane 5a with aliphatic or aromatic isocyanates in dry toluene at * Author to whom correspondence should be addressed. Fax: (33) 04 73 27 77 27. E-mail: olivier.chavignon@u-clermont1.fr X Abstract published in Advance ACS Abstracts, March 15, 1997. (1) (a) Clermont-Ferrand. (b) Tours. (c) Montpellier. (d) Barcelona. (2) Kazlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J. Tetrahedron. Lett. 1977, 61. (3) Hollenbeak, K.; Schmitz, F. J. Lloydia 1977, 40, 479. (4) Backer, J. T.; Wells, R. J. In Natural Products as Medicinal Agents, Beal, J. L., Reinhard, E., Eds.; Hippokrates Verlag: Stuttgart, 1981; pp 299-303. (5) (a) Ware, E. Chem. Rev. 1950, 46, 403. (b) Bateman, J. H. Kirk- Othmer Encyclopedia of Chemical Technology; Wiley-Interscience: New York, 1978; Vol. 12, p 692. (c) Djura, P.; Faulkner, D. J. J. Org. Chem. 1980, 45, 735. (d) Guella, G.; Mancini, I.; Zibrowins, H.; Pietra, F. Helv. Chim. Acta 1988, 71, 773. (e) Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv. Chim. Acta 1989, 72, 1444. (6) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197. (7) Molina, P.; Almendros, P.; Fresneda, P. M. Tetrahedron 1994, 50, 2241. (8) Arbilla, S.; Allen, J.; Wick, A.; Langes, S. Eur. J. Pharmacol. 1986, 130, 257. (9) (a) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1975, 40, 2916. (b) Teulade, J. C.; Gueiffier, A.; Viols, H.; Chapat, J. P.; Grassy, G.; Perly, B.; Dauphin, G. J. Chem. Soc., Perkin Trans. 1 1989, 1895. (c) Chavignon, O.; Teulade, J. C.; Madesclaire, M.; Gueiffier, A.; Blache, Y.; Viols, H.; Chapat, J. P. J. Heterocycl. Chem. 1992, 29, 691. (d) Diez, A.; Mavel, S.; Teulade, J. C.; Chavignon, O.; Sinibaldi, M. E.; Troin, Y.; Rubiralta, M. Heterocycles 1993, 36, 2451. (10) (a) Chermann, J. C.; Gruest, J.; Montagnier, L.; Wendling, F.; Tambourin, P.; Perrin, M.; Pochon, F.; Ducrocq, C.; Rivalle, C.; Bisagni, E. C. R. Seances Acad. Sci., Ser. D 1977, 285, 945. (b) Marsais, F.; Pineau, P.; Nivolliers, F.; Mallet, M.; Godard, A.; Quequiner, G. J. Org. Chem. 1992, 57, 565. (11) Chavignon, O.; Teulade, J. C.; Roche, D.; Madesclaire, M.; Blache, Y.; Gueiffier, A.; Chabard, J. L.; Dauphin, G. J. Org. Chem. 1994, 59, 6413. (12) (a) Hamilton, S. G.; Huang, Z.; Yang, X. J.; Patch, R. J.; Narayanan, B. A.; Ferkany, J. W. J. Org. Chem. 1993, 58, 7263. (b) Cordi, A.; Sun, E. US Patent 5, 252, 563. (13) Vo ¨geli, U.; Von Philipsborn, W.; Nagarajan, K.; Nair, M. D. Helv. Chim. Acta 1978, 61, 607. Figure 1. 4085 J. Org. Chem. 1997, 62, 4085-4087 S0022-3263(96)02174-3 CCC: $14.00 © 1997 American Chemical Society