Isopropylidene uridine

The reaction has been extended (106) to the nucleoside field and provides a means for the direct iodination of suitably protected nucleosides. Thus treatment of 2,3-O-isopropylidene uridine (68) with tri-phenylphosphite methiodide in N,2V-dimethylformamide at room temperature afforded the corresponding crystalline 5-deoxy-5-iodo analog 69 in 77% yield. 

Selective replacement of primary hydroxyl groups in carbohydrates by iodine atoms has been achieved by using the Rydon reagent, namely, methyltriphenoxyphosphonium iodide.368 Treatment of methyl 3,4-O-isopropylidene-jS-D-galactopyranoside with the phosphonium salt in benzene for 48 hours at room temperature yielded 60% of the 6-deoxy-6-iodo derivative,369 and reaction of thymidine, uridine, and 2,2 -anhydrouridine in N,N-dimethylformamide afforded 5 -deoxy-5 -iodo derivatives in yields of 63, 65, and 31%, respectively.370... 

A solution of 5 -0-acetyl-2 3 -0-isopropylidene-3-nitrouridine [44, prepared from 5 -0-acetyl-2 3 -0-isopropylideneuridine and nitronium triflu-oroacetate (91JOC7038)] in acetonitrile gave, when treated with an acetonitrile-water solution of N-ammonium choride, potassium hydroxide, and triethylamine for 5 days, 5 -(9-acetyl-2 3 -(9-isopropylideneuridine (45) in 73% yield. It contained the label at position 3. Deprotection of the O-acetyl and O-isopropylidene groups by methanol/hydrochloric acid gave [3- N]uridine (46) (Scheme III.26). 

Monomolar benzylation of methyl 2,3-di-0-benzyl-a-D-galactopyranoside in DMF gave 2,3,6-tri-O-benzyl derivative in 73% yield [52], The primary 6-benzyl ether also forms the major part of the monobenzyl fraction obtained from methyl a-D-galactopyranoside or from its p-anomer [53]. Interestingly, position 6 becomes less reactive than position 2 if 3,4-0-isopropylidene acetals is used to protect the other two secondary hydroxyl groups. The ratio of 2- and 6-benzyl ethers was found to be 11 1 in the a-anomer and 2.5 1 in the p-anomer [53] (see also, Ref. [54]). Uridine [55], cyti-dine [56], and 4-(methylthio)uridine [56] also prefer OH-2 over the primary position when benzylated in dimethyl sulfoxide (for other benzylations in this solvent, see Refs. [35, 57]). 

Silver nitrate displayed a pronounced effect on the selectivity of silylation [380, 392, 440, 441], The treatment of uridine (63) with 2.2 molar equiv. of each fm-butylchloro-dimethylsilane and silver nitrate in oxolane led to the exclusive formation of 5 -0-silyl derivative 64 in 95% isolated yield [380], Under analogous conditions, 1,2-0-isopropylidene-ct-D-glucofuranose was selectivity silylated at 0-6, and 1,2-0-isopro-pylidene-oc-D-xylofuranose at 0-5, with 94-96% yield [442]. Combination of silver nitrate with pyridine resulted in disilylation of nucleosides at 0-5 and 0-2 with excellent selectivity. Interestingly, the selectivity for secondary hydroxyl groups is reversed with a combination of silver nitrate and l,4-diazabicyclo[2.2.2]octane as a base. Such a disilylation led to 3, 5 -6 -0-(/ert-butyldimethylsilyl) derivatives in as high yields as 94%. Other soluble silver salts, e.g., silver perchlorate, behaved similarly [380],... 

The studies of Levene and LaForge60 on the nitration of uridine have since been re-investigated. It had been reported, several decades ago, that treatment of uridine with nitric acid produced a Nitro-Uridin-Carbon-saure which was stated to be a dimer containing an anhydro typeof linkage (positions unspecified) between two nucleoside residues.60 According to an abstract,269 this compound has now been identified as the monomeric 5-ni-tro-l-(/8-D-ribosyluronic acid)uracil (CXXII) this was converted to the isopropyl ester and the 2,3-O-isopropylidene acetal thereof. Nitration of the pyrimidine moiety of uridine without oxidation of the 4-(hydroxy-... 

Triethylammonium-Salz XII/2, 906 (2 ,3 -0-Isopropyliden-uridin-5 - -benzylester-(4-brom-benzylamid) XII/2, 435 2, 3 -0-Isopropyliden-uridin-5 - -benzylester-ehlorid XII/2, 906... 

Furthermore Levene and Tipson discovered that uridine will condense with acetone in the presence of sulfuric acid and anhydrous copper sulfate to give a mono-isopropylidene-uridine. On treatment with tosyl chloride it gave a tosyl-isopropylidene-uridine which reacted readily with sodium iodide in acetone to give a crystalline monoiodo-isopropyli-dene-uridine, showing that the tosyl group is at position (5) of the sugar chain. Hence the isopropylidene derivative is 2,3-isopropylidene-uridine with a furanose ring structure, and uridine is D-ribofuranosyl-uracil. 

In order to prepare this compound, with the phosphoryl group definitely situated at position (5) of the ribose chain, it was first necessary to obtain a uridine derivative in which the hydroxyl group at position (5) is free and the other two are substituted by groups capable of subsequent hydrolysis, after phosphorylation, without splitting off the phosphoryl group. Such a substance was found in 2,3-isopropylidene-uridine, the structure of which has been previously discussed. 

This was phosphorylated with phosphorus oxychloride in pyridine, and the resulting 5-phospho-isopropylidene-uridine hydrolyzed to give 5-phospho-uridine, a substance whose phosphoryl group is hydrolyzed off at a lower rate than that of any other knowm ribose nucleotide. Hence uridylic acid is not 5-phospho-uridine. 

Removal of the isopropylidene (acetonide) group. Hampton et al. found that for a given concentration of acid (0.01 N), the conversion of isopropylideneuridine (1) into uridine (2) proceeds ten times more rapidly in ethyleneglycol solution than in water. Methanol and ethanol were significantly less effective. 

As pyrimidine nucleosides are rather stable under acidic conditions, they may be phosphorylated with a mixture of 85% phosphoric acid and phosphorus pentaoxide ( polyphosphoric acid )- The 2, 3 -0-isopropylidene acetals of uridine and of cytidine were treated with polyphosphoric acid for two hours at 60°. After acid hydrolysis, the 5 -phosphates of these nucleosides were obtained in good yield. 2, 3 -0-Benzylidenecytidine was phosphorylated similarly to cytidine 5 -phosphate. The polyphosphoric acid method was also used to convert the 2, 3 -0-isopropylidene acetals of 5-bromouridine, 3-methyluridine, and A -methyl- and A -dimethyl-cytidine into their respective nucleoside 5 -phosphates. 

---