Solid-phase synthesis of 7-substituted 3H-imidazo[2,1-i]purines

Abstract

A method for solid-supported synthesis of N,N-disubstituted (3H-imidazo[2,1-i]purin-7-yl)methyl amines has been developed. The key features of this library synthesis are: (i) immobilization of commercially available N⁶-benzoyl-5′-O-(4,4′-dimethoxytrityl)-2′-deoxyadenosine 3′-(2-cyanoethyl N,N-diisopropylphosphoramidite) by phosphitylation to a hydroxyl-functionalized support, (ii) quantitative conversion of the deprotected adenine base to 3H-imidazo[2,1-i]purine-7-carbaldehyde with bromomalonaldehyde in DMF in the presence of formic acid and 2,6-lutidine, (iii) reductive amination of the formyl group followed by N-alkylation or N-acylation, and (iv) release from the support by acidolytic cleavage of the N-glycosidic bond. Steps (ii) and (iii) have been optimized in some detail by using (adenin-9-yl)acetic acid anchored to a Phe–Wang resin as a model compound.