8,2 -Cyclonucleosides

Another deviation from the normal displacement reaction of primary tosylates occurs in nucleoside derivatives (39, 81) where cyclonucleosides and anhydronucleosides are formed by participation of a nitrogen atom (as in purine nucleosides) and oxygen atom (as in pyrimidine nucleosides ), respectively. Iodonucleosides can result from these reactions only if these cyclic compounds are prone to attack by iodide ion. Several new examples of unexpected reactions during the solvolysis of sulfonate esters in sugar derivatives have been recorded in the past few years (2, 4,5,7,15,44,62,63,94). 

In a similar way, 5-O-acetylthymidine was converted into the 3-deoxy-3-iodo derivative 72 in 55% yield. In this case, the replacement of the hydroxyl group by iodine was presumed to have taken place by retention of the configuration at C-3. The first intermediate in the reaction was proposed to be the phosphonate (70) which rapidly collapses to an O-3-cyclonucleoside (71) and the latter is subsequently attacked by iodide ion to give the product 72. It was also observed (106) that treatment of nucleosides containing a cis vicinal diol grouping such as 5-0-acetyluridine with triphenylphosphite methiodide failed to provide iodinated products but gave phosphonate derivatives instead. 

Reaction of the silyl derivative of quinoline with 2-acetoxyethyl acetoxy-methyl ether in dichloroethane with stannic chloride gave a cyclonucleoside. Removal of both the acetyl and ethyl ester groups in NaOH afforded the fully deprotected nucleoside 788. Acylation of 788 could be carried out with different esters in the presence of amino Ps lipase [91SC1477 92JCR(S)216]. The 4-quinolones showed no significant antiviral activity (91SC1477). 

The 5, 8-cyclonucleosides are now recognized as significant oxidative lesions that are chemically stable and form in mammalian DNA in vivo. In pig liver DNA, the levels of (5 5)-5, 8-cyclo-dA ( 0.7 lesions/10 DNA bases) were approximately four-to seven-fold lower than the levels of 8-oxo-dG, but were approximately three-fold higher than levels of 8-oxo-dA. Elevated levels of (5 S)-5, 8-cyclo-dA have also been observed in the breast connective tissue stroma of women between 33 and 46 years of age, which correlates with the known sharp increase in breast cancer incidence for women of this age group. 

The Cadet laboratory has prepared phosphoramidites of stereoisomers for 5, 8-cyclo-dA and 5, 8-cyclo-dG for incorporation into oligonucleotides. Primer extension assays using the mammalian replicative enzyme pol 8 demonstrated that 5, 8-cyclonucleosides block DNA replication in vitro and thus would be highly... 

Several examples of the synthesis of cyclonucleoside derivatives by radical ring-closure reactions are also available <1996T9496, 1999J(P1)1257, 2000T8689, 2002CBC534, 2005EJ04640>. 

Rearrangement to 3-glucoside (HgBr2). d Dehalogenation and reaction forming cyclonucleoside. 

M. Ikebara and H. Miki, Studies of nucleosides and nucleotides. LXXXH Cyclonucleosides. (39). Synthesis and Properties of 2 -halogeno-2 -deoxyadenosines, Chem. Pharm Butt. 26 2449 (1978). 

One of the first OH-induced purine damage detected was in the 5, 8-cyclonucleotides. This lesion was later also observed in DNA (Chap. 12.5). In the following, the non-trivial case, the reactions of organic radicals with pyrimidines and purines will be discussed, and a special section will devoted to 5, 8-cyclonucleosides and nucleotides whose mechanism of formation has been found to be very complex. 

The cyclonucleoside shown above has been synthesized and some of its properties such as piperidine stability were studied (Muller et al. 2002). 

It is usually assumed that an H-abstraction at C(5 ) by OH (see, however, below) leads to the C(5 ) radical which adds to C(8) [e.g., reaction (221) for details of this reaction see below, where experiments that lead to the specific generation of this radical are discussed]. In a disproportionation reaction with other radicals, the cyclonucleoside (cyclonucleotide) is formed [reaction (221)]. In competition, the C(5 ) radical maybe oxidized giving rise to the 5 -aldehyde [reaction (220)]. 

Halogenated purines. 8BrdAdo has been used to study some of the steps in the cyclization reaction that yields the purine cyclonucleosides/tides (Flyunt et al. 2000 Chatgilialoglu et al. 2003). Upon the reaction of eaq, the very reactive vinylic radical at C(8) is formed [reaction (238) k= 1.6 x 10 dm3 mol-1 s 1] which undergoes rapid H-abstraction from the hydroxymethyl group at C(5 ) [reaction (239)]. In neither of these reactions are radicals formed which strongly absorb in the accessible UV/Vis range. Upon addition of the C(5 ) radical to C(8) [reaction (239) k = 1.6 x 105 s-1], an aminyl radical is formed whose UV/Vis spectrum is... 

The formation of purine 5, 8-cyclonucleosides and -cyclonucleotides and pyrimidine 5, 6-cyclco-nucleosides are a typical product of an oxidation at C(5 ). Because it involves an addition of an alkyl radical to the base moiety, this reaction has already been discussed in Section 5.3.1. The dAdo C(5 ) radical was generated specifically by reacting 8BrdAdo with eaq. The ensuing reactions are discussed in Section 7.2. 

The formation of the cyclonucleosides shown below (for their synthesis see Ro-mieu et al. 1999b) shows that the addition of the C(5 ) radical can also add to the C(5)-C(6) Thy double bond [the corresponding Cyd case has been discussed... 

Unequivocal chemical proof of the glycosyl configuration of nucleosides in the ribose and deoxyribose series arose from studies of the anhydronu-cleosides ( cyclonucleosides ). Levene and Tipson129 had demonstrated that 2,3-0-isopropylideneuridine may be sulfonylated to the 5-0-tosyl... 

Although the term cyclonucleoside has been employed (see Ref. 144) for naming this class of compounds, the term anhydronucleoside, which is more in keeping with carbohydrate nomenclature, will be used in this Chapter. 

Cyclonucleosides. A typical protected cyt lopurine nucleoside (2) can be obtained by oxidation of a protected purine nucleoside (1 with LTA in refluxing benzene. 

A novel type of cyclonucleoside (4) is obtained from a similar oxidation of a protected pyrimidine nucleoside (3). 

---