Collect. Czech. Chem. Commun. 2005, 70, 85-102

A Regioselective Synthesis of Alkyl 2-(Guanin-9-yl)acetates as PNA Building Blocks from 7-(4-Nitrobenzyl)guanine Derivatives

Györgyi Ferenca, Péter Forgób, Zoltán Kelea and Lajos Kovácsa,*

a Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
b Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary


Guanine derivatives substituted at N7 with 4-R-benzyl groups (R = H, MeO, NO2) have been evaluated in the regioselective N9-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 N7 followed by N-glycoside hydrolysis (10), N9-alkylation (13) and deprotection with sodium dithionite to afford the peptide nucleic acid building block tert-butyl [N2-(pent-4-enoyl)guanin-9-yl]- acetate (15) in 36% overall yield. This avoids N7 regioisomer formation, solubility problems and any chromatographic purification. A remarkable influence of the O- and/or N2-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.

Keywords: Guanine; Regioselective alkylation; Guanosine; Nucleoside analogues; Nucleosides; Purines; Peptide nucleic acids.

References: 62 live references.