The synthesis of 4-alkylsulphonyl-5-amino- and 5-amino-4-phosphono-imidazole nucleosides as potential inhibitors of purine biosynthesis

Abstract

Conversion of 4(5)-methylthio-5(4)-nitroimidazole (11) into its silyl derivative and subsequent condensation with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (9) in the presence of trimethylsilyl trifluoromethanesulphonate for a short reaction time gave 4-methylthio-5-nitro-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)imidazole (15) with high regioselectivity; use of longer reaction times gave predominantly the 5-methylthio-4-nitro-isomer (14). 5-Amino-4-methylsulphonyl-1-β-D-ribofuranosyl)imidazole (7) was obtained from (15) in three steps.

Similar chemistry was used to prepare 5-amino-4-[(carboxamido)methyl]sulphonyl-1 -β-D-ribofuranosylimidazole (8), 5-[(diethylphosphono)methyl]thio-4-nitro-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)imidazole (26), and 4-{[2,3-bis(methoxycarbonyl)propyl]thio}-5-nitro-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)imidazole (29).

Desulphurization of 3′,5′-di-O-t-butyldimethylsilyl-β-D-arabinofurano[1′,2′ : 4,5]oxazolidine-2- thione (33) and subsequent interaction with diethyl α-amino-cyanomethyl phosphonate (32) gave, after desilylation, 5-amino-4-diethylphosphono-1-(β-D-arabinofuranosyl)imidazole (36).