Nitration of pyrimidine bases and nucleotides by nitronium tetrafluoroborate. Synthesis of 5-nitro-2'-deoxyuridine

Abstract

The reagent nitronium tetrafluoroborate in sulfolane was investigated as a nitrating agent for pyrimidine bases, nucleosides, and nucleotides. Reaction of uracil (l), 1-methyluracil (3), or 1,3-dimethyluracil (5) with N02BF4 in sulfolane led to 80-90% yields of the corresponding 5-nitro derivatives, 5-nitrouracil (2), 1-methyl-5-nitrouracil (4), and 1,3-dimethyl-5-nitrouracil (6). Uridine (7) and 2'-deoxyuridine (8) failed to give significant yields of 5-nitro nucleosides, but rather suffered extensive glycoside bond rupture under the conditions employed. However, 2'-deoxyuridine 5'-monophosphate (12) was readily nitrated to give two products that accounted for 70% of the starting material, namely, 5-nitro-2'-deoxyuridine 5'-monophosphate (13) and its 3'-O-nitrate (14). These nucleotides 13 and 14 were dephosphorylated by Escherichia coli alkaline phosphatase t o the corresponding nucleosides, 5-nitro-2'-deoxyuridine (15) and 3'-0,5-dinitro-2'-deoxyuridine (16). In addition, uridine 5'-monophosphate (10) was converted by nitronium tetrafluoroborate/sulfolane to 5-nitrouridine 5'-monophosphate (1 l), which was also prepared by the action of POCl&riethyl phosphate on 5-nitrouridine (9).Pyrimidine nucleosides and nucleotides, substituted a t the 5 position by various functional groups, are of interest for a t least two reasons: first, C-5 substituted nucleosides may possess antiviral and/or antitumor properties;lA second, when incorporated into nucleic acids, the structural modification may provide valuable information for the study of, for instance, t h e physicochemical properties5 and interferon-inducing abilitys of polynucleotides. The nitro group, because of its potent electron-withdrawing properties, would seem a modification of special interest in view of the well-documented antiviral and/or antitumor activities of two deoxyribonucleosides, namely, 5-fluoro-and 5-trifluoromethyl-2'-deoxyuridine.5 5-Nitrouridine was first synthesized by Wempen et al.' who used nitric acid t o nitrate 2',3',5'-tri-0-(3,5-dinitrobenzoyl)-uridine; later, the nucleoside was prepared by the Hg(CN)2 nitromethane condensation procedure.8 Prystas and Sormg found t h a t an analogous nitration approach to a similarly protected 2'-deoxyuridine afforded only glycoside bond cleavage. They did, however, obtain a 1% yield of an anomeric mixture of t h e di-0-toluyl derivative of 5-nitro-2'-deoxyuridine when 5-nitrouracilylmercury was reacted with the protected 2'-deoxy-~-ribofuranosyl chloride. An enzymatic synthesis of 5-nitro-2'-deoxyuridine was reported by Kluepfel e t a1.,I0 but this method cannot be regarded as unambiguous since only UV spectra and elemental analysis were provided to support t h e structure of the product. Additionally, this approach is inconvenient, since large amounts of crude trans-N-deoxyribos ylase from Lactobacillus cultures must be employed. In view of the report by Kluepfel e t al.10 t h a t this enzymatically prepared 5-nitro-2'-deoxyuridine possessed potent antiviral properties, we considered it imperative t ...

Synthesis and Reaction of Pyrimidine Nucleosides

“…Arabinofuranosyl-5-fluorouracil (116), when treated with 0.1 N sodium hydroxide at 60°C for 30 min., gave the ring-opened 0 6 , 2'-cyclo nucleoside (117). This product (117) was recyclized by further alkaline treatment to afford I-p-D-arabinofuranosyl-2-oxo-4-imidazoline-4-carboxylic acid (118). A similar ring contraction to afford an imidazoline derivative has been observed using l-p-D-arabinofuranosyl-5bromouracil as the starting material.…”

Interaction of tRNA (uracil-5-)-methyltransferase with NO2Ura-tRNA

“…5-Nitro-uridine triphosphate (NO 2 UTP) was prepared by a slight modification of the method of Huang and Torrence (10). Briefly, the trisodium salt of UTP (Yamasa, Choshi, Japan; 550 mg, 1 mmol) was mixed with a solution of nitronium tetrafluoroborate (Aldrich, 0.5 M, 10 ml) in sulfolane.…”

Nucleic Acid Related Compounds. 107. Efficient Nitration of Uracil Base and Nucleoside Derivatives1

“…The first synthesis of 5-nitrouridine employed nitration of 2‘,3‘,5‘-tri -O- (3,5-dinitrobenzoyl)uridine with fuming nitric/sulfuric acid . 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 .…”

“…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 . Coupling of trimethylsilylated 5-nitrouracil with protected 2-deoxy- erythro- pentofuranosyl chlorides furnished the corresponding 2‘-deoxy-5-nitrouridines in good yields, but separation of anomers was required 13b.…”