A New Class of Nucleoside Analogues. Synthesis of N. -Pyrimidinyl-and N9-Purinyl-4′-hydrqxy-3-(Hydsoxymethyl)butanes1 # 2

Abstract

Interest in non-glycosidic derivatives of the nucleo-bases uracil, theymine, cytosine, adenine and guanine stems from their status as nucleoside analogues. It is noteworty in this connection that the anti-biotics aristeromycin³ and eritadenine⁴ consist of an adenine moiety linked, via N₉ -, to a cyclopentyl or a butiric acid derivative, respectively, in place of the conventional nucleoside sugars. A non-glycoaidic 5-fluorouracil derivative⁵ has been recently reported to be clinically effective in the treatment of Gastrointestinal cancer. In this communication the ficile synthesis of 4-hydroxy-3-(hydroxymethyl)butyl derivatives of the nucleobases (1) is described. These nucleoside analogues are characterized by the special feature that they incorporate two hydroxyl functions in a relationship corresponding to the 3′-and 5′-hydroxy groups of the 2-deodyribose Doiety. Phosphorylationj of the hydroxyl groups or their linkage via phosphodiester of the hydroxyl groups or their linkage via phosphodiester bridges should give nucleotide analogues or novel nucleic acid models. The latter molecular systems constitute a new class of potential anti-mitotic or anti-viral agents. One principle synthetic approach to compounds of general structure 1 was visualized via the intermediacy of 2-(hydroxymethyl) - 4-aminobutanol (2, ReH) which, acting as a common precursor, could be elaborated to the desired pyrimidine or purine derivative, via its amine function. The synthesis of amine 2 was achieved according to the reaction sequence described in Scheme I. Diethyl malonate was coupled with 2,2-dimethoxybromoethane, in presence of sodium ethoxide (EthoH, 170°, autoclave). The resulting diester (3) was reduced with LialH₄ to the corresponding diol (4), which was benzylated (NaH, C₆H₅CH₂Cl) to 5. When 5 was refluxed with NH₂OH.HCl in methanol for 30 min., a mixture of oximes 6a,b (syn- and anti-) and nitrile 7 was isolated. The latter mixture could be directly reduced with LiAlH₄ to amine 2,⁶ in high yield.