Synthesis of sugar-modified analogs of bredinin (mizoribine), a clinically useful immunosuppressant, by a novel photochemical imidazole ring-cleavage reaction as the key step

Abstract

The imidazole nucleoside bredinin (mizoribine) is a clinically useful immunosuppressant. Derivatization of bredinin by the usual nucleoside chemistry is often troublesome due to the unusual zwitterionic structure of the base moiety. We achieve the synthesis of 5′-modified analogs of bredinin via a novel photochemical imidazole ring-cleavage reaction as the key step. When a solution of 2′,3′-O-isopropylidenebredinin 5 in 0.1 M AcOH is irradiated with a high-pressure mercury lamp, an imidazole ring-cleavage reaction occurs to give the 2-aminomalonamide riboside derivative 16 in 71% yield. Appropriate modifications of the 5′-position of 16 and subsequent condensation with (EtO)₃CH to reconstruct the imidazole base moiety follow. Using this imidazole ring-cleavage–reconstruction strategy, some biologically important 5′-modified bredinin analogs, i.e., the 5′-phosphate 2, the 5′-deoxy derivative 3, and the 5′-O-aminopropylcarbamate 4 are efficiently synthesized.