1,3-Dimethyl-2'-deoxypseudoUridine

Synthesis of 1,3-dimethyl-2^'-deoxypseudoUridine from 1,3-dimethylpseudoUridine

Compound 1,3-dimethyl-2^'-deoxypseudoUridine is a C-nucleoside isomer of 1,3-dimethyl-2^'-deoxyuridine. The 1,3-dimethyl-2^'-deoxypseudoUridine can be synthesized from 1,3-dimethylpseudoUridine which can be obtained directly by treatment of pseudoUridine with dimethylformamide dimethyl acetal. C-nucleosides have attracted the attention of researchers since their discovery. Replacement of nucleobase nitrogen by carbon results in C-nucleosides which contain more stable C-C bond connected between ribose and base compared the C-N bond. C-nucleosides and their analogues present promising application for drug design. In recent years, C-nucleosides have shown great potential of the development of more effective and safer drugs.

A general method for producing 2^'-deoxy C-nucleosides was developed. There were several 2^'-deoxy C-nucleosides synthesized, including 1-methyl-2'-deoxypseudoUridine, 2^'-deoxypseudoUridine and 2^'-deoxypseudoisocytidine besides the 1,3-dimethyl-2^'-deoxypseudoUridine. Take the example of the 1,3-dimethyl-2'-deoxypseudoUridine synthesis, the 3^',5^'-hydroxyl groups of C-nucleoside 1,3-dimethylpseudoUridine first were protected by treatment with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPSCl) in pyridine to give the corresponding protected nucleoside in which only the 2'-hydroxyl group is available for modification. Following by the treatment with 1,1^'-thiocarbonyldiimidazole (TCDI) in dimethylformamide to quantitatively convert into the 2'-O-thiocarbonyimidazole derivatives. Notably, under this condition, protected 1,3-dimethylpseudoUridine is treated with TCDI without the formation of by-products such as dinucleosidyl thiocarbonates. Removal of the silyl protecting group of 3^',5^'-hydroxyls with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran caused the formation of the 2^',3^'-cyclic thiocarbonate. Thus, the step of deprotection has to be performed after reduction. Upon treatment of the 2^'-O-thiocarbonyimidazole C-nucleoside with n-Bu3SnH, the TIPS protected 1,3-dimethyl-2'-deoxypseudoUridine was generated in good yields as the only isolable products. Due to the methylations of N1 and N3, the synthesis of 1,3-dimethyl-2^'-deoxypseudoUridine do not need the procedures of protection and deprotection for amine. Finally, silyl protection (TIPS) of the C3^' and C5^' was removed by treatment with n-Bu4NF to afford the target product 1,3-dimethyl-2^'-deoxypseudoUridine.

In conclusion, it has shown in literature that the C-nucleosides of biological interest were synthesized in good overall yields. The procedure for the synthesis of 2^'-deoxy C-nucleosides described should have wide applicability in the C-nucleoside area.