A One-Pot Synthesis of 1-α- And 1-β-D-Arabinofuranosyl-2-Nitroimidazoles: Synthons to the Markers of Tumor Hypoxia

Abstract

1-alpha- and 1-beta-D-Arabinofuranosyl-2-nitroimidazole (alpha-AZA and beta-AZ A) are synthons for a number of potential markers of tissue hypoxia. A one pot synthesis in which 2-nitroimidazole is coupled with a mixture of alpha- and beta-1-O-acetyl-2,3,5-tri-O-benzoyl-D-arabinofuranose in the presence of stannic chloride, followed by deprotection using ammonia/methanol, is described Previously reported conditions for coupling 2-nitroimidazole to 1-alpha-bromoarabinofuranose protected by base-hydrolyzable groups afforded alpha-AZA almost exclusively.

Preparation of Nucleosides Derived from 2-Nitroimidazole and d-Arabinose, d-Ribose, and d-Galactose by the Vorbrüggen Method and Their Conversion to Potential Precursors for Tracers To Image Hypoxia

“…At last, commercially available β- d -galactopyranose pentaacetate was converted to the 2-nitroimidazole nucleoside β- 22 in high yield (92%) in CH 3 CN under very mild conditions, when the reaction mixture was stirred for 1 h at 0 °C and 1 h at rt (Scheme ). For comparison, the coupling of acetobromo-α- d -galactose with 2-nitroimidazole catalyzed by 2.5 equiv of Hg(CN) 2 for 23 h at 40 °C in a large volume of CH 3 CN yielded 88% of the desired β-nucleoside …”

“…The 2-nitroimidazole nucleosides underlying tracers 4 , 5 , and 6 are formed by a Königs–Knorr reaction of 2-nitroimidazole or in some cases its trimethylsilylated species in acetonitrile at 50–60 °C with a benzoyl- or an acetyl-protected d -1-bromofuranose or d -1-bromopyranose derivatives of d -arabinose or d -galactose, respectively. Normally, excess Hg(CN) 2 (2.2 equiv), sometimes in combination with SnCl 4 , was used as a catalyst. − This method was used by Schneider et al to prepare a number of 2-nitroimidazole nucleosides, two of which were converted to radioiodinated tracers. When we started this project to prepare known and new precursors for tracers to image hypoxia, we decided to search for an alternative to the Königs–Knorr procedure not involving metal salts, especially toxic Hg(CN) 2 .…”