Synthesis of 1,2-Disubstituted Carbocyclic Analogs of Pyrimidine and Purine Nucleosides

Abstract

Pyrimidine- and purine-based members of a new class of carbocyclic analogs of nucleosides with 1,2-disubstituted carbocycles were synthesized. For the synthesis of the thymidine analog 3, construction of the base on the amino group of (2-aminocyclopentyl)methanol was more efficient than condensation of the base with a diol. The former strategy was accordingly used to prepare other members of the pyrimidine series, namely uracil and thymine derivatives with a methylene between the base and the carbocycle. The uracil derivatives with and without this methylene were halogenated with Cl, Br and I at uracil position 5. The carbocyclic analogs of purine nucleosides with 2-amino-6-chloro purine and 8-azapurine as bases were also efficiently synthesized by construction of the heterocyclic framework on the primary amino group of the appropriate amino alcohol. The chlorine in position 6 of the base was then replaced in good yields by an amino or hydroxyl group, both of which are present at this position in natural nucleosides.

Key words

amino alcohols - cyclization - heterocycles - Mitsunobu reaction - nucleosides

References

• 1 Nucleoside Analogs in Cancer Therapy   Cheson BD. Keating MJ. Plunkett W. Marcel Dekker; New York: 1997. 
• 2 De Clercq E. Clin. Microb. Rev.  1997,  10:  674 
• 3 Marquez VE. Adv. Antiviral Drug Des.  1996,  2:  89 
• 4 Balzarini J. De Clercq E. Nucleoside and Non Nuclease Reverse Transcriptase Inhibitors Active Against HIV, In Textbook of AIDS Medicine   Merigan TC. Bartlett JG. Bolognesi D. Williams and Wilkings; Baltimore: 1999.  p.815-847  
• 5 Ezzitouni A. Marquez VE. J. Chem. Soc., Perkin Trans 1  1997,  1073 
• 6 Guan H.-P. Ksebati MB. Cheng YCh. Drach JC. Kern ER. Zemlicka J. J. Org. Chem.  2000,  65:  1280 
• 7 Dueholm KL. Pedersen EB. Synthesis  1992,  1 
• 8 Wilson LJ. Hager MW. El-Kattan YA. Liotta DC. Synthesis  1995,  1465 
• 9 Mitsunobu O. Synthesis  1981,  1 
• 10 Girard F. Lee MG. Agrofolio LA. J. Heterocycl. Chem.  1998,  35:  911 
• 11 Shaw G. Warrener RN. J. Chem. Soc.  1958,  157 
• 12 Shealy YF. O"Dell GA. J. Heterocycl. Chem.  1976,  13:  1041 
• 13 Teijeira M. Nucleósidos Carbocíclicos 1,2-Disubstituidos, Doctoral Thesis   University of Santiago de Compostela; Spain: 1996. 
• 14 Theil F. Ballschuh S. Tetrahedron: Asymmetry  1996,  7:  3565 
• 15 In a better yield than that reported by Nativ E. Rona P. Isr. J. Chem.  1972,  40:  55 
• 16 Qui Y.-L. Hempel A. Camerman N. Camerman A. Geiser F. Ptak RG. Breitenbach JM. Kira T. Li L. Gullen E. Cheng Y.-C. Kern ER. Drach JC. Zemlicka J. J. Med. Chem.  1998,  41:  5257 
• 17 Estrada E. Uriarte E. Montero A. Teijeira M. Santana L. De Clercq E. J. Med. Chem.  2000,  43:  1975 
• 18 Vince R. Hua M. J. Med. Chem.  1990,  33:  17 
• 19 Santana L. Teijeira M. Uriarte E. J. Heterocycl. Chem.  1999,  36:  293 
• 20 Hronowski LJJ. Szarek WA. Can. J. Chem.  1985,  63:  2787 
• 21 Santana L. Teijeira M. Uriarte E. Terán C. Casellato U. Graziani R. Nucleosides Nucleotides  1996,  15:  1179 
• 22 Herdewijn E. De Clercq E. Balzarini J. Vanderhaeghe H. J. Med. Chem.  1985,  28:  550 
• 23 Awano H. Shuto S. Baba M. Kira T. Shigeta S. Matsuda A. Bioorg. Med. Chem. Lett.  1994,  4:  367