Monatshefte flit Chemie 127, 979-988 (1996) blonatshe~ ff~, Chem~ Chemical Monthly © Springer-Verlag 1996 Printed in Austria Synthesis of 3'-Deoxy-3'-fluoro and -3'-amino Nucleosides from 2-Methylthiopyrimidin- 4(1H)-ones M. A. Zahran 1, A. E.-S. Abdel-Megied 1, A. A.-H. Abdel-Rahman 1, M. A. Sofan 1, C. Nielsen 2, and E. B. Pedersen ~'* 1 Department of Chemistry, Odense University, DK-5230 Odense M, Denmark 2 Retrovirus Laboratory, Department of Virology, Statens Seruminstitut, DK-2300 Copenhagen, Denmark Summary. Methyl 2,3-dideoxy-3-ftuoro-5-O-(4-phenylbenzoyl)-fl-D-erythro-pentofuranoside (3) as well as 1,5-di-O-acetyl-2,3-dideoxy-3-phthalimodo-~-D-erythro-pentofuranose (12) were condensed with silylated 2-methylthiopyridin-4(1H)-ones2a, b in the presence of trimethylsilyl triflate as a catalyst to produce the corresponding nucleosides 5, 6,13. In these reactions, an endocyclic cleavage of COin 3 took place; therefore, acyclic nucleosides 4a, b were also formed. All 3'-fluoro nucleosides were deprotected with NH3/MeOH; the Y-phthalimido nucleosides were deprotected with methylamine in ethanol. The latter method resulted in a concomitant substitution reaction in the pyrimidine moiety with replacement of the methylthio group. The 2-methylthio analogue of Y-deoxy-Y-fluorothylmidine showed moderate activity against HIV-1. Keywords. Nucleosides, convergent synthesis of; Nucleosides, 2',Y-dideoxy-Y-fluoro; Nucleosides, 2',3'-dideoxy-3'-amino; 2-Methylthiopyridin-4(1H)-one nucleosides; Human immunodeficiency virus; Herpes simplex virus. Synthese yon 3'-Deoxy-3'-fluoro- und -Y-amino-nucleosiden aus 2-Methylthiopyrimidin-4(1H)-onen Zusammenfassung. Methyl-2,3-didesoxy-3-fluoro-5-O-(4-phenylbenzoyl)-fl-D-erythro-pentofuranosid (3) und 1,5-di-O-Acetyl-2,3-didesoxy-3-phthalimido-f-D-erythro-pentofuranose (12) wurden in Gegen- wart von Trimethylsilyltriflat als Katalysator mit den silylierten 2-Methylthiopyridin-4(1H)-onen 2a, b zu den entsprechenden Nucleosiden 5-6 und 13 kondensiert. Bei diesen Reaktionen tritt als Nebenreaktion eine Offnung der endocyclischen C-O- Bindung auf, sodal3 auch die acyclischen Nucleoside 4a, b gebildet werden. Die Y-Fluoronucleoside wurden mit NH3/MeOH entschtitzt, die 3'-Phthalimidonucleoside mit Methylamin in Ethanol. Letztere Reaktion resultierte in eine gleich- zeitigen Substitution der Pyrimidineinheit unter Austausch der Methylthiogruppe. Das 2-Methyl- thioanalogon zu Y-Desoxy-Y-fluorthymidin zeigt m/il3ige Aktivit~it gegen HIV-1. Introduction The onset of AIDS has presented many challenges to the medical and pharmaceuti- cal professions. The most difficult one of these may prove to be the development of