A regioselective synthesis of alkyl 2-(guanin-9-yl)acetates as PNA building blocks from 7-(4-nitrobenzyl)guanine derivatives

Guanine derivatives substituted at N-7 with 4-R-benzyl groups (R = H, MeO, NO2) have been evaluated in the regioselective N-9-alkylation of guanine. Given the capricious removal of (substituted) benzyl groups from guanine derivatives and pent-4-enoylation of guaninium hydrochloride, an improved alternative approach has been elaborated consisting in the pent-4-enoylation and per-O-acetylation of guanosine (8), 4-nitrobenzylation at N-7 followed by N-glycoside hydrolysis (10), N-9-alkylation (13) and deprotection with sodium dithionite to afford the peptide nucleic acid building block tert-butyl [N-2-(pent-4-enoyl)guanin-9-yl]-acetate (15) in 36% overall yield. This avoids N-7 regioisomer formation, solubility problems and any chromatographic purification. A remarkable influence of the O- and/or N-2-acyl groups on the stability of N-glycosidic bond and reactivity of 2-amino group was observed. The structure of a pyrimidine by-product 12 arising from the imidazole ring-opening of guaninium salt 4d in alkaline medium has been elucidated by 2D NMR.