Synthesis of 2'- and 3'-Spiro-isoxazolidine Derivatives of Thymidine & Their Conversions to 2',3'-dideoxy-2',3'-didehydro-3'-C-substituted nucleosides by Radical Promoted Fragmentation.

Article abstract of DOI:10.1016/S0040-4020(01)80209-X

We herein report the synthesis of a new class of 2'- and 3'-spiro-nucleosides (3 - 19, 38 - 55) by the 1,3-dipolar cycloaddition reaction of 2'- or 3'-methylnitrone (2, 3 or 37) with ethyl vinyl ether and acrylonitrile.It has been also shown that the free-radical promoted deoxygenation of 3'-hydroxy group vicinal to the 2'-spiro function in the free-radical precursor 15, 17 or 19 gives a mixture of 2',3'-dideoxy-2',3'-didehydro-2'-C-substituted thymidines (20, 21, 24, 26, 28 or 32) and/or 2',3'-dideoxy-2'-spiro-derivatives (30).Similarly, the deoxygenation of 2'-hydroxy group vicinal to the 3'-spiro function in the free-radical precursor 49, 52 or 55 gives a mixture of 2',3'-dideoxy-2',3'-didehydro-3'-C-substituted nucleosides (59, 60 or 62) and/or 2',3'-dideoxy-3'-spiro-nucleosides (56 and 57).The results described herein constitute the first report of the synthesis of spiro-(1,2-isoxazolidine) derivatives of nucleosides and their use in the unique free-radical cleavage reactions to give 2',3'-dideoxy-2',3'-didehydro-C-branched nucleosides.