Uridine, tosylation

Tipson devoted most of his years in Levene s laboratory accomplishing seminal work on the components of nucleic acids. To determine the ring forms of the ribose component of the ribonucleosides he applied Haworth s methylation technique and established the furanoid structure for the sugar in adenosine, guanosine, uridine, and thymidine. He showed that formation of a monotrityl ether is not a reliable proof for the presence of a primary alcohol group in a nucleoside, whereas a tosyl ester that is readily displaced by iodide affords clear evidence that the ester is at the 5-position of the pentofuranose. Acetonation of ribonucleosides was shown to give the 2, 3 -C -isopropyl-idene derivatives, which were to become extensively used in nucleoside and nucleotide chemistry, and were utilized by Tipson in the first chemical preparation of a ribonucleotide, inosinic acid. 

In the following year, Levene and Tipson107 discovered that chlorination of a monosaccharide derivative can also occur on tosylation of uridine in pyridine during 18 hours at room temperature, 3 -(5-chloro-5-... 

Of incidental interest is the observation that an w-chlorine atom may be replaced by iodine under Oldham and Rutherford s conditions, without affecting secondary sulfonyloxy groups. Thus, Levene and Tipson107 found that 5-chloro-5-deoxy-2,3-di-0-tosyl-uridine affords the corresponding 5-deoxy-5-iodo derivative plus sodium chloride on the other hand, methyl 4-chloro-4-deoxy-2,3,6-tri-0-tosyl-a-D- glucoside gives117 the 4-chloro-4,6-dideoxy-6-iodo derivative. These observations, taken... 

Likewise, reaction of 2, 3, 5 -tri-0-acetyluridine with tosyl chloride/ K2CO3 in methylisobutyl ketone for 4 hr at 80°C affords the corresponding 4-tosyloxy derivative in practically quantitative yield. Subsequent treatment with methanol/concentrated aqueous ammonia affords 91% cytidine and 8.1% uridine (86EUP204264). 

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. 

To date, the sugar ring structure of only one desoxyribosyl nucleoside (namely, thymidine) is known. In 1935, Levene and Tipson - found that thymidine condenses with trityl chloride in the presence of dry pyridine to give a crystalline monotrityl-thymidine. From their previous proof of the structure of monotrityl-uridine as the 5-trityl ether, it seemed probable that the thymidine ether is 5-trityl-thymidine. This was confirmed by tosylation, to give tosyl-trityl-thymidine, followed by treatment with sodium iodide in acetone under standard conditions. 

Treatment of bromomethyl acetate with the sodium salt of a dialkyl phosphite, followed by deacetylation with methoxide affords the corresponding dialkyl hydroxymethanephosphonate. If this is tosylated with tosyl chloride, and the product treated with nucleosides [protected at the 3 -(and 2 -, if present) hydroxy groups] and sodium hydride in DMF, the monoalkyl ester of a 5 -0-phosphonyl-methyl nucleoside (60) is obtained after deblocking the sugar, and subsequent dealkylation with TMS-iodide affords (61). Like alkyl esters of 5 -mononucleotides, (60) is resistant to acid and alkaline hydrolysis, while (61) is stable in acidic and alkaline media, and is also resistant to hydrolysis by alkaline phosphomono-esterase and snake venom 5 -nucleotidase. Treatment of (61) with DCC and morpholine, and subsequently with orthophosphate or pyrophosphate, affords (62) and (63), respectively. Alkaline phosphomonoesterase from E. co/i hydrolyses the pyrophosphate links in (62) and (63) to give (61) and orthophosphate. The UTP and CTP analogues (63 B = U or C) are inhibitors of uridine kinase from... 

An interesting new procedure was employed in the synthesis of L-adenosine, L-guanosine, L-cytidine, L-uridine, L-5-methyluridine, and L-6-azauridine, involving the reaction of 2-0-tosyl-5-0-trityl-L-arabinose (I) with a suspension of the sodium salt of the appropriate base in DMF, to give 32-92% yields of the 5 trityl derivatives of the corresponding L-p-ribofuranosides (111). The reaction presumably proceeds through an epoxide intermediate (II) resulting from the action of the base on 1. ... 

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