A New Straightforward Synthesis of 2 ’ , 3 ’-Didehydro-2 ’ , 3 ’-dideoxy-2 ’-( 2 ”-( trimethylsilyl ) ethylthio ) thymidine , Key Intermediate for the Synthesis of 2 ’-Substituted Thionucleosides

We describe herein a straightforward and efficient preparation of 2',3'-dideoxy-2'-(2''- (trimethylsilyl)ethylthio)thymidine, which allows the preparation of diverse potentially antiviral and/or anticancer nucleosides (disulfides, thiols, sulfides, thiocyanates).

Here, we report on a new straightforward efficient preparation of this nucleoside.
The saturated TMSE intermediate ( 5) was prepared through the reaction of 2,2'-anhydrothymidine (4) with 2-(trimethylsilyl)ethanethiol (prepared from trimethylvinylsilane) at 120 °C in DMF (88% yield).2,2'-Anhydrothymidine (4) can be prepared in 63% yield through (i) reaction of 5-methyluridine (3) with diphenyl carbonate in the presence of sodium hydrogen carbonate in DMF at reflux (1 h), (ii) precipitation from the reaction mixture in diethyl ether (1.8 L for 10 g of starting 5-methyluridine) to remove phenol, (iii) filtration and then (iv) crystallization in methanol.The main drawbacks of this synthesis result from the large volume of diethyl ether necessary for phenol removal and from the possible presence of moisture, (4) being very hygroscopic.Thus, we developed another method of preparation of (4) using dimethyl carbonate as reagent.According to the low boiling point of dimethyl carbonate, the reaction temperature was decreased (130 °C) and the reaction time increased (2 h) in comparison to the reaction performed with diphenyl carbonate.Compound (4) was obtained in 78% yield after precipitation in a small volume of diethyl ether, filtration and crystallization from methanol.
Then, from (5), we developed a straightforward synthesis of the unsatured thionucleoside (9) which was prepared in three steps (Scheme 2, 48% overall yield): (i) mesylation of the 3' and 5'-hydroxyl functions, (ii) elimination in the presence of sodium benzoate in DMF at 90 ºC (iii) removal of the introduced 5'-benzoyl group under basic conditions (KOH/MeOH).
The presence of two mesyl groups in ( 6) could be a source of side reactions decreasing the yield.Since compound (8) has a benzoate group at C-5', we rationalized that this compound could also be prepared from a 3',5'-dibenzoate derivative by selective elimination of the 3'-benzoate group.Thus, the saturated TMSE dibenzoyl intermediate (7) was prepared from ( 5) by reaction with benzoic anhydride at 60 ºC for 1 h (Scheme 2, 72% yield).Then, the obtained 2',3'-unsaturated nucleoside carrying a benzoyl group at the 5'-position (8) was obtained in 62% yield by reaction of ( 7) with potassium carbonate.Finally, (8) was treated with potassium hydroxide at room temperature in MeOH to lead in good yield (86%) to corresponding the 2', 3'-unsaturated nucleoside (9).Following this synthetic route compound (9) was obtained in 38% overall yield.
Both synthetic routes allowed the preparation of unsaturated thionucleoside (9) in a very straightforward manner.The main difference between the two methods was the high yield obtained in the preparation of dimesylate (6), which could be easily isolated by direct precipitation from the reaction mixture and filtration while the dibenzoate (7) needed purification by column chromatography.Side products were detected by TLC and could be due elimination in the presence of pyridine.This led to a higher overall yield (48%) from the former route, compared to the 38% obtained via the second one.Although the synthetic routes depicted in this work had overall yields lower than the previously described method, 29 they are one step shorter and can be easily scaled up, besides making use of cheaper and more stable reagents (methanesulfonyl chloride and benzoyl anhydride) as compared to the more expensive and less stable dimethoxytrityl chloride.Moreover, the new methods of synthesis of nucleoside ( 9) described here led rapidly to the unsaturated nucleoside (8) carrying a 5'-benzoyl protective group useful for further modifications of the sugar.

Conclusions
In summary, we have developed two new, simple and efficient methodologies for the synthesis of unsatured thionucleoside ( 9), a key-intermediate in the preparation of potentially antiviral or antiproliferative thionucleosides.