Two strategies are reported for the diastereoselective synthesis of isoxazolidinyl nucleosides, as potential antiviral agents - a one-step approach based on 1,3-dipolar cycloaddition of sugar-derived nitrones with vinyl nucleobases derived from uracil and adenine, as well as a two-step methodology based on the Vorbruggen nucleosidation of the 5-acetoxyisoxazolidines. The 1,3-dipolar cycloadditions of sugar-derived nitrones with vinyl acetate proceed with very good diastereoselectivity to give the diastereoisomeric isoxazolidines. Condensation of the major diastereomerically pure acetoxyisoxazolidines with silylated uracil, thymine, cytosine, N-acetylguanine and purines occurs with moderate to excellent stereoselectivity with the formation of the expected isoxazolidinyl nucleosides. The stereoselectivity of the addition of the silylated nucleobase is dependent on the structure of the substituent at C-3 originating from the starting chiral nitrone and on the attacking nucleobase.

The condensation of the acetoxyisoxazolidines with silylated uracil, thymine, cytosine, N-acetylcytosine, and guanine proceeded in good yields and with moderate to good stereoselectivity to give isoxazolidinyl β- and α-nucleosides. The stereoselectivity of the addition is dependent on the structure of the substituent at C-3 originating from the starting chiral nitrone. The Vorbrüggen nucleosidation of isoxazolidine 8 at 70°C afforded β-anomers as the exclusive nucleosides together with the isoxazoline 11. It was found that the nucleosidation proceeded also in methylene chloride at room temperature.

The synthesis of isoxazolidinyl nucleosides based on the Vorbruggen nucleosidation of 5-acetoxyisoxazolidines 5 and 9 is reported. The 1,3-dipolar cycloaddition of D-erythro-nitrone 4 with vinyl acetate proceeded with respectable anti-facial (84:16) and endo-facial (72:28) diastereoselectivity to give the diastereomeric isoxazolidines 5-7. The reaction of D-threo-nitrone 8 with vinyl acetate is more selective and proceeds with excellent anti-facial preference producing only two diastereomers 9 and 10, although four diastereomers are possible. The condensation of the acetoxyisoxazolidines 5 and 9 with silylated uracil, thymine, N-acetylcytosine, N-2-acetylguanine, and purines proceeded with moderate to excellent stereoselectivity with formation of the expected isoxazolidinyl beta- and alpha-nucleosides. The stereoselectivity of the addition of sitylated nucleobase is depended on the structure of the substituent at C3 originating from the starting chiral nitrone and on the attacking nucleobase.

1,3-Dipolar cycloadditions of TBDPS substituted 6,7-dihydro-5-hydroxy-3-methoxy-7methylenepyrrolo[1,2-c] pyrimidin-1(5H)-one with methoxycarbonyl-and cyanonitrile oxide proceed with complete regioselectivity, the approach of the dipole taking place predominantly from the less sterically hindered side of the dipolarophile. The isoxazolinyl spironucleoside, bearing a primary hydroxymethyl group in C-3 position of the isoxazolinyl ring, was prepared in two steps from the major isoxazoline. The deprotection of cyanosubstituted spiroisoxazoline furnished the alpha,beta-unsaturated oxime.

Novel 7-methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones 11a-c were synthesized from commercially available orotic acid (6). 1,3-Dipolar cycloadditions of mesitonitrile oxide to the exocyclic double bond of the dipolarophiles 11 proceed with complete regioselectivity and lead to the spiroisoxazolinyl nucleosides 13 and 14 in good yields. Attack of the dipole from the less sterically hindered side of the dipolarophile affords C-5/C-7 trans isoxazolines as major isomers predominantly. The protection of the free hydroxyl group by the bulky substituent (TBDPS) leads to formation C-5/C-7 trans isomer 14c exclusively.