Stereodivergent approaches to the synthesis of isoxazolidine analogues of alpha-amino acid nucleosides. Total synthesis of isoxazolidinyl deoxypolyoxin C and uracil polyoxin C

The synthesis of new nucleoside analogues is currently of high interest. We report here full details of a study leading to the synthesis of novel isox azolidinyl analogues of a-amino acid nucleosides. Three different synthetic approaches starting from L-serine have been evaluated for the construction of the isoxazolidine ring. These approaches consisted of Michael addition of N-benzylhydroxylamine to alpha,beta-unsaturated esters, nucleophilic add ition of silyl ketene acetals to nitrones and 1,3-dipolar cycloaddition of nitrones with vinyl acetate. Both Michael addition and nucleophilic additio n of enolates could be carried out with stereocontrol at the newly formed s tereogenic carbon. The stereocontrol observed in these reactions arises fro m the protecting group arrangement in the L-serine-derived substrates. Thus , whereas compounds having a diprotected nitrogen led to syn adducts, compo unds having a monoprotected nitrogen gave rise to anti adducts. On the othe r hand, substrates having either a diprotected or monoprotected nitrogen at om led to anti adducts through the cycloaddition route. So, by choosing the appropriate route, isoxazolidinyl analogues having either syn or anti conf iguration with respect to the glycine unit can be prepared in enantiomerica lly pure form. The stereoselective synthesis of isoxazolidinyl analogues of deoxypolyoxin C and uracil polyoxin C in both D and L enantiomeric forms u sing these techniques has been achieved in good yields.