Nucleoside aldehydes

An important question with regard to the scope of this method for complex carbohydrate synthesis was whether an unstabilized carbohydrate phosphorane might be compatible with a suitably blocked nucleoside aldehyde. Condensation of the ylide derived from XXI with uridine derivative XXIII proceeded under the usual conditions to give a 25% yield of XXIV, from which the N-benzoyl group could be readily removed with methanolic ammonia. The yield from this condensation reaction was not optimized, but its success clearly demonstrated the feasibility of such a transformation, if design considerations dictate the use of a nucleoside directly. 

Abramov nucleophilic addition of various phosphorus acid esters to nucleoside aldehyde derivatives yielded the phosphonate-based iso-polar, non-iso-steric 5 -nucleotide analogues (28) containing a geminal hydroxy phosphonate moiety on the 5 -carbon of the pentofuranose ring. The enantiomerically pure D- and l- 2, 3, 5 -trideoxy-4 -[(ethoxyphosphoryl) difluoromethyl] thymidine analogues(29) have been synthesized from (i 5)-( )-2-methyl-5-(4-methyl-phenyl-sulfinyl)pent-2-ene and ethyl 2-(diethoxyphosphoryl)-2,2-difluoro-acetate in 45% overall yield over seven steps. ... 

Kutterer, K.M.K., and Just, G.. Cyano/diallylamine additions to glycoside and nucleoside aldehydes and its application to the synthesis of polyoxin L and uracil polyoxin C, Heterocycles, 51. 1409, 1999. 

Two sulfone-based nucleoside diphosphate isosters (71a,b) has been synthesised and reported by Gervay-Hague to be inhibitors of Neisseria meningitidis CMP-sialic acid synthetase, which is a key enzyme in the biosynthesis of capsular polysaccharides required for bacterial infection. The synthetic methodology includes a condensation reaction of the nucleoside aldehydes with bisphosphonate Horner-Wadsworth-Emmons reagents (Scheme 4). The deprotection sequence was crucial for the appropriate completion of the synthetic targets. 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

In contrast to other 2,5-anhydroaldoses (which exhibit mutarota-tion, possibly due to the formation of hemiacetals28), 2,5-anhydro-D-glucose does not show any mutarotation.27 The importance of this compound as a potentially useful precursor to C-nucleosides warrants a reinvestigation of the deamination reaction, and the definitive proof of the structure of the compound. The readily accessible 2,5-anhydro-D-mannose (11) does not possess the cis-disposed side-chains at C-2 and C-5 that would be required of a synthetic precursor to the naturally occurring C-nucleosides, with the exception of a-pyrazomycin (8). The possibility of an inversion of the orientation of the aldehyde group in 11 by equilibration under basic conditions could be considered. 

The aldehyde 38 was obtained from 35, by way of 36 and 37, by the carbodiimide—dimethyl sulfoxide oxidation procedure52 in the presence of 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide hydrochloride (EDAC)53 and dichloroacetic acid. It was isolated in the form of its crystalline 1,3-diphenylimidazolidine derivative (39) by trapping the freshly prepared aldehyde 38 with N,N -diphen-ylethylenediamine. (This reagent was developed by Wanzlick and Lochel54 for the selective derivatization of aldehydes, and has been exploited for the isolation of nucleoside 5 -aldehydes55 and other aldehydo derivatives of carbohydrates by Moffatt and coworkers.52(b))... 

Lactol 128 has been converted into a variety of racemic C-nucleosides. The unstable aldehyde 130 was prepared from 128 by way of oxazolidine 129. Lactone 131 was also derived from 128 and used as starting material in the synthesis of racemic C-nucleosides. Adducts 77 + 77 were transformed into epoxide 132. Opening of the epoxide, followed by ozonolysis and reduction allowed one to... 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

As mentioned above for RuO (1.2.7.10) and [RuO ]" (1.3.4.6) there are reports of Ru-catalysed oxidations for which the nature of the active catalyst or catalyst precursor is unclear but is probably predominantly [RuO ]. Electronic and Raman spectroscopy have been used to establish the nature of the catalytic species, but incorrectly fran.y-[Ru(0H)2(0)3] " rather than [RuO ] " was the formula ascribed to the ruthenate solute [212, 222]. Examples in which [RuO ] is the catalytic species include oxidations of nucleosides by RuCl3/K3(S20g)/aq. M KOH (Fig. 2.11) [547], and of primary alcohols oxidised to aldehydes RuClj or Ru03/Na(C10)/aq. base [551]. 

Sulfur compounds with divalent sulfur functionalities are much more prone to dioxirane oxidation on account of their higher nucleophilicity compared to the above-presented oxygen-type nucleophiles. Examples of this type of dioxirane oxidation abound in the literature. Such a case is the oxidation of thiols, which may be quite complex and afford a complex mixture of oxidation products, e.g. sulfinic acids, sulfonic acids, disulfides, thiosulfonates and aldehydes , and is, therefore, hardly useful in synthesis. Nevertheless, the oxidation of some 9i/-purine-6-thiols in the presence of an amine nucleophile produces n >( -nucleoside analogs in useful yields (equation 19). This reaction also displays the general chemoselectivity trend that divalent sulfur functionalities are more reactive than trivalent sp -hybridized nitrogen compounds P. 

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