An Efficient Synthesis Of Acyclic N⁷- and N⁹-Adenine Nucleosides Via Alkylation With Secondary Carbon Electrophiles to Introduce Versatile Functional Groups At the C-1 Position of Acyclic Moiety

The introduction of versatile functional groups, allyl and ester, at the C-1 position of the acyclic chain in acyclic adenine nucleosides was achieved for the first time directly by alkylation of adenine and N⁶-protected adenine. Thus, the C-1′-substituted N⁹-adenine acyclic nucleoside, adenine-9-yl-pent-4-enoic acid ethyl ester (11), was prepared by direct alkylation of adenine with 2-bromopent-4-enoic acid ethyl ester (6), while the corresponding N⁷-regioisomer, 2-[6, (dimethylaminomethyleneamino)-purin-7-yl]-pent-4-enoic acid ethyl ester (10), was obtained in one step by the coupling of N,N-dimethyl-N′- (9H-purin-6-yl)-formamidine (9) with 2-bromopent-4-enoic acid ethyl ester (6). The functional groups, ester and allyl, were converted to the desired hydroxymethyl and hydroxyethyl groups, and subsequently to phosphonomethyl derivatives and corresponding pyrophosphorylphosphonates.

Keywords:

• N⁷- and N⁹-Adenine nucleosides
• N-Alkylation of adenine

The authors thank Drs. Charlie Bugg and Claude Bennett for their encouragement throughout this work. The authors appreciate the assistance of Raman Krishnan at BioCryst Pharmaceuticals, Inc., for crystallizing compound 10 for X-ray crystallography, and Scott T. Griffin and Robin D. Rogers at the University of Alabama in Tuscaloosa for getting the crystal structure of compound 10. We also thank Ken Belmore for helpful discussions with NMR spectral data.