3-Ketonucleosides

Stereoselective synthesis of 3 -substituted 2 -deoxy C-nucleoside pyrazolo[l,5- ][l,3,5]triazines and their 5 -phos-phate nucleotides starting from related 3 -ketonucleosides have been accomplished <2006TL5099>. Regioselective ring closure to derivatives of the same ring system - reminiscent of those discussed in Section 11.17.5.3.5 - has been described <2006TL5441>. 

Ketonucleosides constitute a class of nucleosides containing in the sugar moiety a keto group that results from the oxidation of an asymmetric carbon atom. This article considers all so-called ketonucleosides deriving from aldosyl derivatives, and excludes those in which the keto group of the sugar moiety is involved in the nucleosidic bond (for example, nucleosides of psicose1), which have occasionally been termed ketonucleosides. 

Biological results published during the past ten years concerning the in vitro10 13 and in vivo14 15 activity of ketonucleosides themselves have... 

A brief review on keto derivatives of aldohexosyl nucleosides appeared16 in 1975, and a plenary lecture entitled Recent Developments in the Chemistry of Ketonucleosides has been given.17... 

This Subsection deals with the preparation of 2 - and 4 -ketohexosyl-purines and -pyrimidines, which have proved to be versatile synthetic intermediates. A 5 -keto derivative of a hexofuranose nucleoside is also described. The synthesis of epoxy-, halogeno-, unsaturated, epimino-, and thio-ketonucleosides will be developed in subsequent Subsections and Sections. 

The Me2SO-oxalyl chloride method34 was successfully used13 to obtain2-(6-deoxy-2,3-0-isopropylidene-a-L-h/xo-hexopyranosyl-4-ulose)-8-nitro-t>-triazolo[l,5-fl]pyridine (49a) in 62% yield from the partially protected L-rhamnose nucleoside 48a. Treatment of 49a with formic acid gave the free ketonucleoside 50a. Hydrogenation over 10% Pd-C afforded the amino derivative 49b. 

The synthesis of the first reported51,52 unsaturated ketonucleoside, 61a, was accomplished by acetylation of the known 7-(6-deoxy-/ -L-h/xo-... 

Among the unsaturated ketonucleosides may be classified the disaccharide derivative 74, which is an analog of the biologically active compound 68c. The key intermediate for the synthesis of this unsaturated ketodisaccharide nucleoside was the partially protected, disaccharide nucleoside 73, which was prepared by two separate routes,56 Treatment of 73 with the Me2SO-acetic anhydride reagent for two days at room temperature afforded 7-[2,3-di-0-benzoyl-4-0-(3-0-benzoyl-2,6-di-deoxy - / - d - glycero - hex - 2 - enopyranosyl - 4 - ulose) - 6 - deoxy - / - d -glycopyranosyl]theophylline (74), isolated crystalline.56... 

The role of the reaction medium for the successful synthesis and study of the reactions of ketonucleosides has also been emphasized by Hersco-vici and Antonakis, who reported40,41 catalytic solutions to this problem. Thus, the use of inorganic catalysts proved to be of great efficiency for the oxidation of fragile molecules, especially in the nucleoside field. 

Unsaturated ketonucleosides have been shown to be remarkably stable under acidic conditions. 7-(3-0-Acetyl-4,6-dideoxy-/ -L-g/t/cm>-hex-3-enopyranosyl-2-ulose)theophylline (61a) proved to be stable in 0.1 M hydrochloric acid, as no glycosylic cleavage had occurred51 after 20 h. Similarly, no decomposition was observed when 7-(3,6-di-0-ace-tyl-2-deoxy-/ -D-gh/cero-hex-2-enopyranosyl-4-ulose)theophylline (66) was treated with 0.1 M sulfuric acid during 48 h at room temperature, and attempted, ionic hydrogenation with triethylsilane - trifluoroacetic acid failed.31... 

The use of ketonucleosides as synthetic intermediates is based on their stability, particularly in alkaline media. Unlike ketopentosylpyrimi-dines, which are rapidly decomposed, ketohexose nucleosides appear to be convenient intermediates for syntheses of branched-chain, deoxy, and rare sugar nucleosides. 

Other pyrimidine keto-nucleosides, such as 47a and 47b, could be treated with acetic anhydride-pyridine without glycosylic cleavage.33 The stability of 47a and 47b in this medium permitted elaboration of a new, mild, regioselective synthesis of enol acetates, The reaction of 4 -ketonucleosides of uracil with acetals of N,N-dimethylformamide led,33 after addition of acetic anhydride, to the corresponding enol acetate-nucleosides 77a and 77b. 

Study of the stability of these ketonucleoside derivatives in alkaline media has shown that they can readily revert to the starting ketone. 

Some examples of the behavior of unsaturated ketonucleosides under alkaline conditions have also been reported. The enol acetate 61a is more stable than the parent ketonucleoside 36a. In 0.1 M methanolic sodium hydroxide, free theophylline was detected only after 4 h, by which time, loss of the acetyl group was complete a reaction time of more than 18 h was needed for complete cleavage of the glycosylic bond.51 In alcoholic solution, the unsaturated 4 -ketonucleoside 66 was very sensitive to nucleophilic attack, and decomposed rapidly, with elimination of the nitrogenous base.31 Thus, treatment with sodium borohydride at — 70° led to complete decomposition within 10 min but, when sodium borohydride was added to a solution of 66 in 1,2-dichloroethane containing acetic acid, fast reduction occurred, and no degradation was observed.31... 

The 5 -0-trityl 3 -ketothymidine 33b exhibited an i.r. absorption at 1778 cm-1, attributed to the keto group introduced.44 Also, theophylline 4 -ketonucleoside derivative 41a had26,27 an i.r. spectrum similar to that of the parent 40a, except for a carbonyl band at 1755 cm-1. Thymine 4 -ketonucleoside derivative 45 exhibited a carbonyl band at 1725 cm-1, assigned to the C=0 and -C(=0)-C=C- groups of the base.30 The... 

In the case of 2 -ketonucleosides, this shifting of the H-l resonance is further enhanced by the purine or pyrimidine ring. 

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