Ethers, Esters and Acetals of Nucleosides

3 - And 5 -C -alkyl derivatives of 2 -deoxy-5-fluorouridine, and some 5 -0-aminoacyl derivatives, have been described, as have 3 - or 5 -0-arylmethyl derivatives of FdU which also have an aminoacyloxymethyl group at N-3 (e.g. 235).  

Selective enzymic acylation and deacylation of nucleosides have been reviewed. Cordycepin (3 -deoxyadenosine) has been linked to various lipophilic vitamins and to diacylglycerols via dicarboxylic acid spacers at 0-2 and 0-5, and similar conjugates have been made to the cordycepin trimer core, with linkages at either the 5 - or the 2 -end. 3 -(9-Aminoacyl-2 -deoxynucleosides have been made using Fmoc aminoacid fluorides as acylating agents.  

The diacetylated derivative 236 of (P-D-glucopyranosyl)thymine has been prepared as an intermediate for incorporation of this nucleoside into oligonucleotides by 4 -6 -links.  

Dicarboxylic acid 5 -monoesters of thymidine and of 5-(2-thienyl)-2 -deoxy-uridine have been prepared as triphosphate mimics. The ester of d4T with citric acid has also been made with the same objective, and more lipophilic bioisosteres 237 and the AZT equivalent have been reported, these being designed to mimic the conformation of the nucleoside triphosphate when complexed to a metal ion. Neither of these last two classes were effective, since all the activity against HIV could be shown to be due to hydrolysis to the parent nucleoside. 

A tripyridyl unit has been linked to a known ketose nucleoside via a spacer arm to give 238 this, and similar structures with the tripyridyl group linked to C-5 of the uracil, were incorporated into oligonucleotides, and the Cu(II) complexes were functional mimics of ribozymes.  

The 3-bromopropyl-substituted nucleoside phosphoramidite 244 has been prepared, with a view to its incorporation into oligonucleotides which would permit post-synthetic functionalization of the sugar moiety on the solid support by reaction with appropriate nucleophiles.  

2 Esters. - A Pseudomonas hpase deposited on ceramic particles or on diatomite can acetylate 2 -deoxynucleosides regioselectively at 0-3 by acetyl 

The ester 246 has been prepared as a potential bioreductively-activated prodrug of 5-fluoro-2 -deoxyuridine (FUDR). It was resistant to human serum esterases due to the steric hindrance of the a-methyl groups, but chemical reduction led to rapid release of FUDR by intramolecular aminolysis.  

When the ester 247 was treated with lauroyl peroxide in the presence of 15 equivalents of styrene, the polymer 248 was obtained. This was soluble in many common organic solvents but which could be precipitated with methanol, making the technique potentially useful for parallel synthesis. 5 -0-Methacryloyl-uridine and -adenosine have been polymerized onto a silica support, using Cu(I) mediated radical polymerization, under conditions favouring products of narrow polydispersity.  

Analogues 249 (X = H, OH) of UDP-GlcNAc have been prepared as potential inhibitors of chitin synthetases. The synthetic route involved a C-allyl derivative of GlcNAc, which was elaborated by ozonolysis, Wittig reaction and coupling with the nucleoside, followed by hydrogenation or hydroxylation as appropriate. The corresponding amides were also prepared from 5 -amino-5 -deoxyuridine. Lipophilic amino acid methyl esters and methylamides have been coupled to 0-5 of AZT by carbamate links. The products showed anti-HIV activity, but this was not due to carbamate hydrolysis or to direct inhibition of reverse transcriptase, and the mechanism of action may be one not previously observed with nucleoside antivirals.  

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The 6-, and 6,6 -trityl ethers of a- and j3-cellobiose have been produced by standard methods, and boron trifluoride etherate in methanol has been used as a detritylation procedure for primary ethers. A range of common ether, ester, and acetal groups were stable to the reagent. Removal of trityl ethers in the nucleoside series has been effected using trifluoroacetic acid, sometimes diluted with butanol. ... 

Protective group for nucleosides. Stepwise synthesis of oligonucleotides utilizing 2-cyanoethyl phosphate (1, 172-173) requires protection of the 3 -hydroxyl group which can be cleaved under essentially neutral conditions, since a methoxy-trityl ether is sensitive to acid and a /3-cyanoethyl phosphoric ester is sensitive to alkali. The /3-benzoylpropionyl group meets these requirements, since it is quantitatively cleaved by dilute solutions of hydrazine hydrate in pyridine-acetic acid. The esters are prepared by condensation with DCC (dicyclohexylcarbodiimide). Definitive paper R. L. Letsinger and P. S. Miller, Am. Soc., 91, 3356 (1969)... 

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