3′-Substituted and 2′,3′-Unsaturated 7-Deazaguanine 2′,3′-Dideoxynucleosides: Syntheses and Inhibition of HIV-1 Reverse Transcriptase

The syntheses of 2′,3′‐dideoxy‐2′,3′‐didehydro‐β‐D‐ribofuranoside 1 and 2′,3′‐dideoxy‐3′‐fluoro‐β‐D‐ribo‐furanoside 5 of 7‐deazaguanine as well as 7‐deaza‐2′‐deoxyxyloguanosine (3) are described. The corresponding 2,4‐diamino compounds 2 and 4 were also prepared. Thus, silytation of 2‐amino‐4‐chloro‐7‐(2‐deoxy‐β‐D‐erythro‐pentofuranosyl)‐7H‐pyrrolo[2,3‐d]pyrimidine (6) afforded 7, which gave the oxo‐nucleoside 13 after oxidation with CrO3. NaBH4 reduction yielded 14 which, upon deprotection (Bu4NF) and nucieophific displacement, afforded 3 and 4. On the other hand, the N2‐formyl derivative of 7 was mesylated (→ 10), treated with Bu4NF, and deprotected with NH3 yielding the 2′,3′‐dideoxy‐2′,3′‐didehydro‐nucleoside 12, Nucleophilic displacement reactions on 12 yielded 1 and 2. The fluoro‐nucleoside 5 was obtained from 14 after methoxytritylation of the NH2 group (→ 16), fluorination with DAST (→ 17), and treatment with 2M NaOH. The 5′‐triphosphates of 5 and other pyrrolo[2,3‐d]pyrimidine 2′,3′‐dideoxy‐3′‐fluoro‐nucleosides were found to be highly active inhibitors of HIV‐1. reverse transcriptase, similar to those of 1 and 2.