6194
Scheme 3. Construction of nucleobase rings from AAls and ABes. Reagents: (i) ADCP; (ii) DCNP; (iii) Raney±Ni; (iv)
CH(OEt)3/HCl; (v) NH3/MeOH; (vi) H2/Pd-C; (vii) MMPI; (viii) NH4OH or HCl/EtOH
The thymine ring of the iso-ddN analogues 5, 6 and 8±10 was constructed upon reacting the
appropriate AAls 17, 20 and 27 or the ABes 18 and 28 (Scheme 3) with the freshly prepared acyl
isocyanate MeOCHC(Me)C(O)NCO (MMPI)9 in the presence of Et3N in anhydrous CH2Cl2,
initially at 0ꢀC and then rt for 30 min, followed by treatment with a catalytic quantity of conc.
HCl in re¯uxing EtOH for 2 h and ®nally catalytic hydrogenolysis, where appropriate. The ®nal
products were obtained in 45±76% yields. Best results were obtained when ABes were used in the
reaction with MMPI. Biological tests, to determine the eect of the nucleobase, the relative
stereochemistry of the nucleobase and the hydroxyethyl side-chain, the absolute stereochemistry
and the size of the pseudosugar ring on the potential anti-HIV activity of the iso-ddN analogues
4±10, are currently in progress.
Acknowledgements
The General Secretariat for Research and Technology of the Greek Ministry for Development
is gratefully acknowledged for the ®nancial support of this research project.
References
1. Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745±1768; De Clercq, E. AIDS Res. Human Retrovirus. 1992, 8,
119±134; De Clercq, E. J. Med. Chem. 1995, 38, 2491±2517; De Clercq, E. Clin. Microbiol. Rev. 1997, 10, 674±693.
2. Phadtare, S.; Zemlicka, J. J. Am. Chem. Soc. 1989, 111, 5925±5931; Coe, D. M.; Roberts, S. M.; Storer, R.
J. Chem. Soc., Perkin Trans. 1 1992, 2695±2704
3. Franchetti, P.; Cappellacci, L.; Grifantini, M.; Messini, L.; Sheikka, G. A.; Loi, A. G.; Tramontano, E.; De
Montis, A.; Spiga, M. G.; La Colla, P. J. Med. Chem. 1994, 37, 3534±3541, and references cited therein.
4. Papaioannou, D.; Stavropoulos, G.; Sivas, M.; Barlos, K.; Francis, G. W.; Aksnes, D. W.; Maartmann-Moe, K.
Acta Chem. Scand. 1991, 45, 99±104.
5. Barlos, K.; Mamos, P.; Papaioannou, D.; Patrianakou, S. J. Chem. Soc., Chem. Commun. 1987, 1583±1584.
6. The structures of intermediates and ®nal products referred to in this work were determined by a combination of
spectroscopic techniques and microanalysis. In particular, the structures of lactam 26 and of the chloropurines 30
and 31 were unambiguously determined by single crystal X-ray analysis: Balayiannis, G.; Argiris, I.; Papaioannou,
D.; Kavounis, C. Acta Cryst. 1999, C55, 1005±1008; Nastopoulos, V.; Gourgioti, O.; Balayiannis, G.; Karigiannis,
G.; Papaioannou, D.; Kavounis, C. Acta Cryst. 1997, C55, 1971±1973. The yields of the reactions performed in
the context of this project were not optimized.
7. Borges, J.; Fernandes, F.; Garcia, X.; Hergueta, A.; Lopez, C.; Andrei, G.; Snoeck, R.; Witrouw, M.; Balzarini, J.;
De Clercq, E. Nucleosides Nucleotides 1998, 1237±1253, and references cited therein.
8. Coe, D. M.; Myers, P. L.; Parry, D. M.; Roberts, S. M.; Storer, R. Chem. Commun. 1990, 151±153.
9. Ezzitouni, A.; Marquez, V. E. J. Chem. Soc., Perkin Trans. 1 1997, 1073±1078, and references cited therein.