Synthesis of 2,6-Dialkyl(aryl)purine Nucleosides by Exploiting the Reactivity of Nebularine N1-Oxide towards Grignard Reagents

The synthesis of 2,6-dialkyl(aryl)purine nucleosides by application of a double addition of Grignard reagents to N1-oxide purine nucleosides is described. The synthetic protocol exploits the reactivity of both the C6-N1-O- and C2-N1-O- moieties of the purine base. The overall process consists of initial Grignard reagent addition to the C6 of nebularine N1-oxide followed by aromatization to give a C6-substituted nucleoside. Regeneration of the N1-oxide is then followed by a second Grignard addition at C2 causing the opening of the pyrimidine ring. Cyclization of the transiently opened pyrimidine is then driven by aromatization of the system to afford the final purine system.