• 10.1248/cpb.47.966
  • CHEMICAL & PHARMACEUTICAL BULLETIN
  • Volume 47
  • January 1999
  • pp 966-970

Synthesis of 2'-fluorinated nucleosides

Details


The article presents a facile and practical method to prepare fluorinated nucleosides, which are known for antitumor and antiviral activity, through introducing fluorine at the up-side of the 2’-carbon of nucleosides.

Particularly, I used this synthetic route to obtain 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (FdaraA) with some modifications.

Introducing a fluorine at the 2’ (S)(ara) site of the nucleosides is very difficult. One key problem is the selectively protection of 3’- and 5’-hydroxyl group with appropriate protecting group (a group that is stable to the fluorine source during the fluorination step) and leaving the 2’-hydroxyl group intact. Traditionally, using trityl group to prepare 3’, 5’-di-O-protected nucleosides gave poor yield due to the similar reactivity of 2’- and 3’-hydroxyl group and the preferential N7-tritylation of purine. In this regard, this paper provided an efficient and low-cost methodology to prepare 3’,5’-di-O protected adenosine (compound 5a, scheme 1). I followed the reaction conditions and procedures reported in this article to obtain the 3’-O-protected derivative (compound 4a, scheme 1), and the actual yield is consistent with the reported yield. Furthermore, the purification procedure of 4a and 5a via crystallization in MeOH is simple and easy with high regioselectivity.     

Protection of 5’-hydroxyl group with dimethoxy-trityl (DMTr) instead of the trityl group (Tr) reported in the article also showed the equal performance with similar yield (70% for DMTr vs 71% for 5a). Such replacement avoided the subsequently unnecessary work to prepare FdaraA phosphoramidite via de-protecting the trityl group and re-protecting the 5’-hydroxyl group, which can be incorporated into oligonucleotides directly.

The fluorination step gave similar yield as the yield of compound 6 (scheme 1) but with relatively low yield of deprotection step (53% with DMTr vs 73% for compound 7). This is due to the much lability of DMTr protection group compared to the Trityl group.



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