Nucleosides unprotected

Selective reaction at the ci.s-2,3-diol grouping of unprotected D-ribonucleosides has occasionally been observed. Treatment of D-ribonucleosides with tris(tetramethylammonium) trimetaphosphate in M sodium hydroxide for 4 days at room temperature led to a mixture of nucleoside 2 - and 3 -phosphates in yields of >70% no 5 -phosphate was detected.213 Reaction of ethyl (trichloromethyl)phos-phonate with nucleosides in N,N-dimethylformamide containing triethylamine, followed by basic hydrolysis of the reaction product, yielded 2 (3 )-phosphates in variable yields.214 The participation of the cis-diol grouping in the reaction was suggested by the failure of thymidine or 2, 3 -0-isopropylideneuridine to undergo reaction. 

Despite the fact that secondary hydroxyl groups of nucleosides also react with 23 (see later), selective iodination of only the primary hydroxyl group in some unprotected, pyrimidine nucleosides can also be achieved.82 Thus, brief treatment of thymidine with 1.1 mol-equivalents of 23 in N,N-dimethylformamide gave crystalline 5 -deoxy-5 -iodothymidine in 63% yield. It was even possible to effect some selective iodination of the 5 -hydroxyl group of 2,2 -anhydrouri-dine without excessive cleavage of the (quite labile) anhydro linkage. 

The stereospecificity of the reduction of these hexosulose nucleosides, trans to the aglycon, parallels previous observations62-64 with several hexopyranosulose derivatives. Attempted, similar reduction of the unprotected 2 -ketonucleoside 36a gave 7-(6-deoxy-/ -L-talopyranosyl)-theophylline (87) in 60% yield. This lesser stereospecificity may be ex-... 

In the 1,3,2-dioxaphosphole method a bis(2-butene-2,3-diyl) pyrophosphate is used as the condensing agent. It allows two successive esterifications of one phosphate group to be performed without additional activation. First a 5 -O-protected nucleoside is added in methylene chloride in the second reaction an unprotected nucleoside can be used, since only the 3 OH group is able to attack the cyclic enediol 3 -nucleosidyl phosphotriester. Protected dinucleoside triesters are obtained in 80% yield. Removals of protective groups, methoxytrityl by means of trifluoroacetic acid in methylene chloride and 1-methylacetonyl by aqueous triethyl-amine, also give about 80% yield (F. Ramirez, 1975, 1977). 

Anhydronucleosides 125 (X = Y = 0) and 126 (Scheme 25) are generally prepared by cyclocondensation of 3-0-protected and unprotected nucleosides 124, with the reaction pathway being dependent on the C(3 )-substitution. 

Otherwise, compound 30, and differently 0-substituted analogues, can be made efficiently from O-protected 2-deoxy nucleosides. Heating thymidine diether 29 in refluxing 1,1,1,3,3,3-hexamethyldisalazene in the presence of ammonium sulfate under an inert atmosphere gives 30 in 47% overall yield from the nucleoside. A notable feature of this approach is that thymidine itself can be converted directly to the unprotected parent of diether 30 with 80% efficiency.26... 

The unprotected 5-hydroxy group is then reacted with a 3-phosphoramidite derivative of the next nucleoside in the presence of tetrazole, which acts as a weak acid catalyst. (These phosphoramidite derivatives are now commercially available.) The diisopropylamino group is displaced by the 5-hydroxy group, and the phosphorus-oxygen bond is formed. 

The synthesis of the target ON conjugate 5 -XTCTCACTACCTCTT (X = 2.72, Fig. 2.20) was performed using the SP phosphoramidite protocol with PNT (N-pent-4-enoyl)-protected phosphoramidites 2.69 and 2.70, the unprotected phosphoramidite 2.71, and the conjugated phosphoramidite 2.72 (147). Their structure and synthesis (76) from natural nucleosides is reported in Fig. 2.20. The protection of the base was... 

However, under similar reaction conditions the N-benzoyl-cytidine derivative furnished a mixture of N-benzoyl-3 -0-DMTr-deoxycytidine and the corresponding N-unprotected nucleoside. However, this limitation was avoided using the corresponding levuUnic derivative because the protecting group was easily removed using hydrazine (Scheme 10.8). 

Purine nucleotides are probably best made by phosphorylation of the corresponding nucleosides. In recent years phosphoryl chloride has proved most convenient for this purpose and may be used with an unprotected nucleoside to give yields of about 50% (B-78MI40903, p. 827). Yields of purine nucleotides up to 60% may also be obtained using a phosphotransferase and a suitable phosphate donor with the unprotected nucleoside. Typical preparations of this type using an enzyme from wheat shoots and p-nitrophenyl phosphate as a phosphate donor have been described (B-78MI40903, p. 955). 

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