3'-SUBSTITUTED-7-DEAZAGUANINE 2',3'-DIDEOXYNUCLEOSIDES AND 2',3'-UNSATURATED 7-DEAZAGUANINE 2',3'-DIDEOXYNUCLEOSIDES - SYNTHESES AND INHIBITION OF HIV-1 REVERSE-TRANSCRIPTASE

Abstract

The syntheses of 2',3'-dideoxy-2',3'-didehydro-beta-D-ribofuranoside 1 and 2',3'-dideoxy-3'-fluoro-beta-D-ribofuranoside 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, silylation of 2-amino-4-chloro-7-(2-deoxy-beta-D-erythropentofuranosyl)-7-H-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 nucleophilic 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.