Stereodefined synthesis of O3′-labeled uracil nucleosides. 3′-[17O]-2′-azido-2′-deoxyuridine 5′-diphosphate as a probe for the mechanism of inactivation of ribonucleotide reductases

Article abstract of DOI:10.1021/jo010899i

Thermolysis of a 2′-[¹⁶O]-O-benzoyl-[¹⁷O]-5′-O-(tert- butyldimethylsilyl)-O²,3′-cyclouridine derivative gave the more stable 3′-[¹⁷O]-O-benzoyl-[¹⁶O]-5′-O-(tert- butyldimethylsilyl)-O²,2′-cyclouridine isomer, which was converted into 3′-[¹⁷O]-2′-azido-2′-deoxyuridine by deprotection and nucleophilic ring opening at C2′ with lithium azide. The 5′-diphosphate was prepared by nucleophilic displacement of the 5′-O-tosyl group with tris(tetrabutylammonium) hydrogen pyrophosphate. Model reactions gave ¹⁶O and ¹⁸O isotopomers, and base-promoted hydrolysis of an O²,2′-cyclonucleoside gave stereodefined access to 3′-[¹⁸O]-1-(β-D-arabinofuranosyl)uracil. Inactivation of ribonucleoside diphosphate reductase with 2′-azido-2′-deoxynucleotides results in appearance of EPR signals for a nitrogen-centered radical derived from azide, and 3′-[¹⁷O]-2′-azido-2′-deoxyuridine 5′-diphosphate provides an isotopomer to perturb EPR spectra in a predictable manner.