Synthesis of β-azomycin nucleosides: 1-(β-d-2-iodo-2-deoxyarabinofuranosyl)-2-nitroimidazole (β-2-IAZA), a novel marker of tissue hypoxia

This study describes a non-conventional approach to the synthesis of 1-β-d-[2-deoxy-2-iodoarabinofuranosyl]-2-nitroimidazole (β-2-IAZA), a positional and configurational isomer of 1-α-d-[5-deoxy-5-iodoarabinofuranosyl]-2-nitroimidazole (IAZA). [123I]IAZA, a radiopharmaceutical used clinically to image regional tissue hypoxia in a number of pathologies, is synthesized by coupling the appropriately protected 1-α-halo arabinofuranoside, with azomycin, with retention of configuration. To circumvent participation of the C-2′ protecting group, which prevents β-anomer formation during coupling, the riboside 1-β-d-(ribofuranosyl)-2-nitroimidazole (AZR) was elaborated to 1-β-d-(3,5-tetraisopropyldisylyloxy-2-O-trifluoromethanesulfonylribofuranosyl)-2-nitroimidazole. Nucleophilic displacement of the 2-O-trifluoromethanesulfonyl leaving group by iodide results in inversion of configuration at the ribosyl C-2-position, thereby affording silylated arabinofuranosyl-2′-IAZA, which was desilylated under neutral conditions to afford β-2-IAZA.