An Efficient Route to β-d-Isoxazolidinyl Nucleosides via Diastereoselective Michael Addition of Hydroxylamine to Unsaturated Esters

Abstract

Enantioselective syntheses of β-d-isoxazolidinyl pyrimidine and purine nucleosides are described. Michael addition of N-methylhydroxylamine to α,β-unsaturated esters was investigated. Both E- and Z-esters 10 E and 10 Z produced the same intermediates which were cyclized to isoxazolidin-5-ones 8 with high diastereoselectivity. The major isoxazolidin-5-one 8a was reduced and acetylated to acetate 11 for the preparation of nucleosides. The coupling reaction of acetate 11 with silylated thymine, uracil, and N⁴-benzoylcytosine using TMSOTf as a Lewis acid yielded the corresponding nucleoside derivatives. The related purine analogue was produced by the BF₃·Et₂O-catalyzed condensation of acetate 11 with silylated 6-chloropurine. The predominant formation of the cis isomers for both pyrimidine and purine analogues was unexpected and the reaction mechanism was investigated. The nucleoside intermediates were converted to the corresponding 1,2-diols, which were latter oxidized and reduced to the desired monoalcohol products such as 14, 16, 19, and 24.