Acyclic nucleoside analogues: methods for the preparation of 2′,3′-secoguanosine, 5′-deoxy-2′,3′-secoguanosine, and(R,S)-9-[1-(2-hydroxyethoxy)-2-hydroxyethyl]guanine

Abstract

A high yielding, one-pot method for the preparation of 2′,3′-secoguanosines 5 and 6 by treatment of 5′-deoxyguanosine (4) and guanosine (2), respectively, with sodium periodate and then sodium borohydride is described. The final products 5 and 6 were purified from contaminating salts by passage of the reaction mixture over a column of activated charcoal. An additional acyclic derivative 14 was prepared in racemic form by an approach involving a novel condensation reaction. Alkylation of N2,9-diacetylguanine (8) with 2,3-dichlorotetrahydrofuran (7) resulted in selective N-9 alkylation to give adduct 9a. Compound 9a was deacylated with ammonium hydroxide to give 10, which was monomethoxytritylated to 11. Elimination of hydrogen chloride from 11 using potassium tert-butoxide afforded 12, which was reacted with OsO4–NaIO4 followed by treatment with NaBH4 to give 13, which was then deprotected with acid to 14. Compounds 5, 6, 14, and 16 were tested in vitro against herpes simplex virus types 1 and 2 and were found to be inactive.