Uridine derivative

The protected nucleoside-3-phosphoramidite monomer units such as 671 are used in the solid-phase oligonucleotide synthesis. In the 60mer synthesis, 104 allylic protective groups are removed in almost 100% overall yield by the single Pd-catalyze reaction with formic acid and BuNH2[432], N,(9-protection of uridine derivatives was carried out under pha.se-transfer conditions[433]. 

These were originally prepared by Khorana as selective protective groups for the 5 -OH of nucleosides and nucleotides. They were designed to be more acid-labile than the trityl group because depurination is often a problem in the acid-catalyzed removal of the trityl group. Introduction of p-methoxy groups increases the rate of hydrolysis by about one order of magnitude for each p-methoxy substituent. For 5 -protected uridine derivatives in 80% AcOH, 20°, the time for hydrolysis was... 

Bu4N F , THF, "2 min. The TBDS group is less reactive toward tri-ethylammonium fluoride than is the TIPDS group. It is stable to 2 M HCl, aq. dioxane, oyemight. Treatment with 0.2 MNaOH, aq. dioxane leads to cleavage of only the Si—O bond at the 5 -position of the uridine derivative. The TBDS derivative is 25 times more stable than the TIPDS derivative to basic hydrolysis. 

For 5 -protected uridine derivatives in 80% AcOH, 20°, the times for hydrolysis were as follows... 

A convenient synthesis of uridine 2, 3 -cyclic phosphite 15 (as a 3 4 mixture of diasteroisomers because of the chirality at phosphorus) was based on the reaction of the suitably protected uridine derivative 14 with ethyl dichlorophosphite carried out in the presence of triethylamine and anhydrous ethanol (Scheme 6) [21]. After adding ethanol into the reaction medium, an efficient chromatographic separation of the crude reaction product was achieved on silica gel with diethyl ether giving analytically pure phosphite 15 in 75% yield. It is interesting to note that without adding ethanol, 15 is very unstable. 

Example 27 Sekine and associates have used bis-0-(2-cyano-l,l-dimethy-lethyl)-iV,Ar-diethylphosphoroamidite in their studies on steric and electronic control of 2 -3 phosphoryl migration in 2 -phosphorylated uridine derivatives [57]. 

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. 

It was previously thought that 5-FU inhibits the enzyme by classical competitive inhibition. However, it was found that 5-FU is a transition-state substrate, and it forms a covalent complex with tetrahydrofolate and the enzyme in the same way that the natural substrate does. The reaction, however, will not go to completion, since the fluoro-uridine derived from the antimetabolite remains attached to the enzyme, and the latter becomes irreversibly deactivated. Recovery can occur only through the synthesis of new enzyme. Fluorouracil is used in the treatment of breast cancer and has found limited use in some intestinal carcinomas. Unfortunately, this drug has the side effects usually associated with antimetabolites. Its prodrug, fluorocytosine (8.35, which is also an antifungal agent) is better tolerated. 

Another process, depicted in Scheme 5, is frequently employed for synthesis of the uridine derivative 30 it comprises the reaction of... 

A similar effect occurs in the reaction of some pyrimidine nucleoside derivatives with hydroxylamine. Studies of the mechanism of this reaction with uridine derivatives340 shows that the initial point for nucleophilic attack is at C-6, and the resultant 5,6-dihydro-6-(hydroxy-amino)uridine derivative (86) is an intermediate in the conversion of the uridine derivative into the ribosylurea derivative 87 and 2-isoxazolin-5-one (88), as shown in Scheme 8. 

The analogous conversion of the uridine derivative 107d has been observed in extracts of tobacco leaves136 and Chlorella cells,137 although the enzyme has not yet been purified. The enzymic reactions described here are frequently used for preparation of the 6-deoxy-hexosyl-4-ulose esters of nucleoside pyrophosphates that are inacces-... 

A similar reaction with uridine derivatives was demonstrated with plant extracts,136,137,290 although it has been studied to a lesser degree. 

Some glycosyl transferases show an unusual double substrate specificity that is, they strongly favor as substrates a pair of unrelated sugar nucleotides, such as adenosine and uridine derivatives.505... 

A significantly different strategy is used in the preparation of the corresponding uridine derivative that retains a double bond in the sugar-like moiety. One of the... 

F-Teda BF4 (6) reacts with uridine derivatives to give 5-fluorouridines 19 in good yield.91... 

The reaction has been applied to the synthesis of C-2, C-3 branched-chain uridine derivatives of either lyxo 67a or ribo configuration 67b. Interestingly, only one diastereo-isomer 68a is formed when the olefin chain is located on the (3-face of the furanose ring lyxo configuration), whereas a mixture of the two possible diastereoisomers 68b is obtained when the olefin is located on the a-face ribo configuration) [91] (see Scheme 26). 

A 1,6-silyl migration from O to O was observed in the reactions of 3, 5 -cyclic dis-iloxanyl 0-uridine derivatives 331 with triflic anhydride which give quantitatively the 2 ,y-cyclic disiloxanyl 0-uridine derivatives 332 (equation 203)469,470. 

Robins and coworkers have explored methods for the introduction of fluorine on saturated carbon atoms in various uridine derivatives by use of phenylsulfanes, and they found that, in general, better results are obtained when a/ -methoxyphenyl group is used instead of thiophenyl58,59 (Scheme 14). 

Shuto and Matsuda also utilised a Sml2-mediated aldol reaction triggered by the reductive removal of an arylselenide group to construct l a-branched uridine derivatives.156... 

Selected crystal structures of thymidine and its derivatives. The hydrogenbonding patterns of thymidine and its derivatives are comparable to those of the uridine derivatives, but relatively simple and they have a uniformity which is rare. In three of the four structures, infinite chains involving a- and rr-cooperativity occur through the adjacent donor and acceptor groups of the thymine ring. 

Figure 6.19 shows an example of the application of this technique to select a catalytic site an RNA sequence that catalyzes Diels-Alder reactions. A library containing random sequences of RNA was first prepared using a uridine derivative with a pyridyl moiety instead of the usual uridine. Each oligo-RNA chain in the library was connected to a diene part via a flexible poly(ethylene glycol) (PEG) chain. 

Another method of seemingly general applicability to carbohydrates was used by Coat et al. to conjugate uridine to proteins. The isopropyli-dine derivative was allowed to react withp-nitrobenzoyl chloride to yield the 5 ester. Removal of the isopropylidine protecting group and hydrogenation of the nitro group made it possible to link the uridine derivative to the protein by a diazotization reaction. 

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