9‐deazapurine nucleosides. The synthesis of certain N‐5‐2′‐deoxy‐β‐D‐erythropentofuranosyl and N‐5‐β‐D‐arabinofuranosylpyrrolo[3,2‐d]pyrimidines

Abstract

A number of 2,4‐disubstituted pyrrolo[3,2‐d]pyrimidine N‐5 nucleosides were prepared by the direct glycosylation of the sodium salt of 2,4‐dichloro‐5H‐pyrrolo[3,2‐d]pyrimidine (3) using 1‐chloro‐2‐deoxy‐3,5‐di‐O‐(p‐toluoyl)‐α‐D ‐erythropentofuranose (1) and 1‐chloro‐2,3,5‐tri‐O‐benzyl‐α‐D‐arabinofuranose (11). The resulting N‐5 glycosides, 2,4‐dichloro‐5‐(2‐deoxy‐3,5‐di‐O‐(p‐toluoyl) ‐β‐D‐erythropentofuranosyl)‐5H‐pyrrolo‐[3,2‐d]pyrimidine (4) and 2,4‐dichloro‐5‐(2,3,5‐tri‐O‐benzyl‐β‐D‐arabinofuranosyl‐5H ‐pyrrolo [3,2‐d)pyrimidine (12), served as versatile key intermediates from which the N‐7 glycosyl analogs of the naturally occurring purine nucleosides adenosine, inosine and guanosine were synthesized. Thus, treatment of 4 with methanolic ammonia followed by dehalogenation provided the adenosine analog, 4‐amino‐5‐(2‐deoxyerythropentofuranosyl) ‐5H‐pyrrolo[3,2‐d]pyrimidine (6). Reaction of 4 with sodium hydroxide followed by dehalogenation afforded the inosine analog, 5‐(2‐deoxy‐β‐D‐erythropentofuranosyl) ‐5H‐pyrrolo[3,2‐d]pyrimidin‐4(3H)‐one (9). Treatment of 4 with sodium hydroxide followed by methanolic ammonia gave the guanosine analog, 2‐amino‐5‐(2‐deoxy‐β‐D‐erythropentofuranosyl) ‐5H‐pyrrolo[3,2‐d]pyrimidin‐4(3H)‐one (10). The preparation of the same analogs in the β‐D‐arabinonucleoside series was achieved by the same general procedures as those employed for the corresponding 2′‐deoxy‐β‐D‐ribonucleoside analogs except that, in all but one case, debenzylation of the sugar protecting groups was accomplished with cyclohexene‐palladium hydroxide on carbon, providing 4‐amino‐5‐β‐D‐arabinofuranosyl‐5H‐pyrrolo [3,2‐d]pyrimidin‐4(3H)‐one (18). Structural characterization of the 2′‐deoxyribonucleoside analogs was based on uv and proton nmr while that of the arabinonucleosides was confirmed by single‐crystal X‐ray analysis of 15a. The stereospecific attachment of the 2‐deoxy‐β‐D‐ribofuranosyl and β‐D‐arabinofuranosyl moieties appears to be due to a Walden inversion at the C1 carbon by the anionic heterocyclic nitrogen (SN2 mechanism).

Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

“…35–39 Preparation of the sodium salt, followed by heating with phenylphosphonic dichloride (PhPOCl 2 ) at 170–175 °C gave 1 . 35–39 Next, we decided to introduce a halogen at C7 that would help us evaluate halogen other than chlorine and bromine, thereby expanding the repertoire of halogens on the fused pyrimidine scaffold. Iodine besides being a larger halogen is also easier to displace.…”

“…26,27,39,41,43 However, the potential of halogenated pyrrolo[3,2- d ]pyrimidines themselves as a therapeutically relevant scaffold has not previously been evaluated. Prompted by our earlier findings with the thieno[3,2- d ]pyrimidines, 28 2,4-dichloropyrrolo[3,2- d ]pyrimidines 1 and 2 were evaluated for their antiproliferative properties against a number of cancer cell lines (Table 1 and Fig.…”

Antiproliferative activities of halogenated thieno[3,2-d]pyrimidines

“…This was accomplished by preparation of the sodium salt of pyrrolo[3,2- d ]pyrimidin-2,4-dione 18 30,34–36 by stirring with 1 N NaOH at 40 °C followed by heating with phenylphosphonic dichloride (PhPOCl 2 ) at 170–175 °C for 5 h. The hot reaction mixture was poured on ice and upon purification by column chromatography 19 was obtained in 55–60% yield. 37 …”

Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics

“…Ring cyclization is accomplished by reduction of the nitro moiety to an amino group, with subsequent nucleophilic attack at C8 by the amino lone pair with loss of dimethylamine. The reduction of the nitro group is accomplished by stirring 3 in acetic acid and zinc dust overnight at 80 °C, followed by filtration, formation of the N5 sodium salt via NaOH dissolution, then re-acidification and collection of solid 4 [23,54].…”