Stereodivergent Approaches to the Synthesis of Isoxazolidine Analogues of α-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 isoxazolidinyl analogues of α-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 α,β-unsaturated esters, nucleophilic addition of silyl ketene acetals to nitrones and 1,3-dipolar cycloaddition of nitrones with vinyl acetate. Both Michael addition and nucleophilic addition of enolates could be carried out with stereocontrol at the newly formed stereogenic carbon. The stereocontrol observed in these reactions arises from the protecting group arrangement in the l-serine-derived substrates. Thus, whereas compounds having a diprotected nitrogen led to syn adducts, compounds having a monoprotected nitrogen gave rise to anti adducts. On the other hand, substrates having either a diprotected or monoprotected nitrogen atom led to anti adducts through the cycloaddition route. So, by choosing the appropriate route, isoxazolidinyl analogues having either syn or anti configuration with respect to the glycine unit can be prepared in enantiomerically pure form. The stereoselective synthesis of isoxazolidinyl analogues of deoxypolyoxin C and uracil polyoxin C in both d and l enantiomeric forms using these techniques has been achieved in good yields.