Nucleic Acid Related Compounds. 107. Efficient Nitration of Uracil Base and Nucleoside Derivatives(1).

The 5′-phosphate ester of 5-nitro-2′-deoxyuridine (7c) is a potent mechanism-based inhibitor of thymidylate synthase.2 Compound 7c3 and 1-(â-D-arabinofuranosyl)5-nitrouracil4 have antiviral activity, and certain O-nitro esters of pyrimidine5 and purine6 nucleosides also have biological activity. The 5′-O-nitro esters of pyrimidine nucleosides function as good substrates for 5′-modification via SN2 displacement of nitrate and other transformations.7,8 Recently, we used 6′-O-nitro esters of 2′substituted homonucleosides to generate 6′-oxyl radicals, which abstract H3′ by 1,5-hydrogen transfer to initiate radical cascade reactions analogous to processes postulated to occur at the active site of ribonucleotide reductases.9 Reactions of N-nitro derivatives of uridine (N3) and inosine (N1) with NH3 have been utilized to obtain [15N]-nucleosides.10 The first synthesis of 5-nitrouridine employed nitration of 2′,3′,5′-tri-O-(3,5-dinitrobenzoyl)uridine with fuming nitric/sulfuric acid.11 Treatment of uracil with nitronium tetrafluoroborate in sulfolane gave 5-nitrouracil in high yield, but uridine and 2′-deoxyuridine (and protected derivatives) failed to give their 5-nitro derivatives.12 Analogous nitration (NO2BF4) of the 5′-phosphates of uridine and 2′-deoxyuridine (chromatographic separation from nitrate esters) and enzymatic dephosphorylation (alkaline phosphatase) gave 5-nitrouridine and 2′-deoxy5-nitrouridine (∼25%).12 Coupling of trimethylsilylated 5-nitrouracil with protected 2-deoxy-erythro-pentofuranosyl chlorides furnished the corresponding 2′-deoxy-5nitrouridines in good yields,13 but separation of anomers was required.13b Treatment of a 1,6-disubstituted uracil with nitric acid/acetic acid gave the 5-nitro derivative in 17% yield.14 Nitrations of uridine f 5′-O-nitrouridine (44%) and 2′deoxyuridine f 2′-deoxy-5′-O-nitrouridine (20%) were effected with fuming nitric acid,7a and O-nitro esters were obtained with other 2′-deoxynucleosides.7c,8 However, the strongly acidic conditions resulted in removal of protecting groups such as isopropylidene7b and silyl6b and gave variable product mixtures.7 Acetyl nitrate (in situ generation with nitric acid and acetic anhydride) at low temperatures gave higher yields of the O-nitro esters,5,6b,7b,9 but glycosyl cleavage occurred upon attempted nitration of homoadenosine.9b We now report efficient nitrations of uracil base and nucleoside derivatives.