Synthesis of certain fluorescent tricyclic nucleosides derived from pyrazolo[3,4-d]pyrimidine nucleosides

Abstract

The synthesis of certain tricyclic nucleosides with a dihydroimidazole, imidazole, triazole, or tetrazole, or tetrazole ring fused to the pyrazolo[3,4-d]pyrimidine ring system in an angular position (C-4 and N-5) has been accomplished. The 4-aziridinyl derivative (2) was prepared by a nucleophilic displacement of the chlorine atom of 4-chloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (1) with ethylenimine. The nucleoside (2) was then treated with sodium iodide to furnish 7-(β-D-ribofuranosyl)-2,3-dihydroimidazo[1,2-c]pyrazolo[4,3-e]pyrimidine (3). The reaction of (1) with lithium azide gave 7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[4,3-e]-tetrazolo[1,5-c]pyrimidine (5) and cyclization of 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine with chloroacetaldehyde provided the tricyclic nucleoside 7-(β-D-ribofuranosyl)imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine (7). 2,4-Dinitrophenoxamine was treated with 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6) to give an intermediate (8) which on cyclization with diethoxymethyl acetate gave 7-(2,3-O-methoxymethylene-β-D-ribofuranosyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (9). Acid-catalysed deblocking of (9) provided the desired tricyclic nucleoside (10). The reaction of trimethyl orthoformate with 4-hydrazino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine under different experimental conditions resulted in the formation of a mixture of diastereoisomers due to the 2′,3′-O-methoxymethylene group. Treatment of (10) with alkali gave a ring-opened intermediate which on treatment with sodium nitrite and acetic acid cyclized to give an aza-derivative (16) of (10).