Syntheses of pyrrolo2,3-d]pyrimidine 2′,3′- dideoxyribonucleosides related to 2′,3′-dideoxyadenosine and 2′,3′-dideoxyguanosine and inhibitory activity of 5′-triphosphates on HIV-1 reverse transcriptase

Article abstract of DOI:10.1002/hlca.19910740312

The synthesis of 4-chloropyrrolo[2,3-d]pyrimidine a nd 2-amino-4- chloropyrrolo[2,3-d]pyrimidine α-D- and β-D-2′,3′- dideoxyribonucleosides 6a, b and 7a, b is described (Scheme 1). Glycosylation of the pyrrolo[2,3-d]-pyrimidinyl anions of 1a, b with in situ prepared 2,3-dideoxy-α /β-D-glycero-pentofuranosyl chloride (2) was regioselective but afforded anomeric mixtures of the 2′,3′- dideoxyribonucleosides 3a/4a and 3b/4b, respectively. The glycosylation products were deprotected and subjected to nucleophilic displacement yielding various pyrrolo[2,3-d]pyrimidine 2′,3′-deoxyribonucleosides related to 2′,3′-dideoxyadenosine and 2′,3′-dideoxyguanosine. One-pot phosphorylation gave the corresponding triphosphates. Some of them are strong inhibitors of HIV- 1 reverse trauscriptase, similar to corresponding purine 2′,3′-dideoxynucleotides, but exhibit a better selectivity index in comparison to DNA polymerases. According to that, the N(7) of the purine moiety is not an essential binding position of ddATP or ddGTP at the active centre of HIV-1 reverse transcriptase.