Stereodivergent Approach to Enantiopure Hydroxyindolizidines Through 1,3-Dipolar Cycloaddition of 3-Hydroxypyrroline N-oxide Derivatives

The (3S)-3-alkoxypyrroline N-oxides 7 and 27 were easily prepared from l-malic acid and used as starting materials for enantiospecific syntheses of stereodifferentiated polyhydroxyindolizidines. Selection of the appropriate modality (interor intramolecular) for 1,3-dipolar cycloaddition of the cyclic nitrone with 5-hydroxypentenoic acid derivatives gave access to either [1,8a]-trans- or -cis-hydroxyindolizidines 31 and 24, respectively, through elaboration of the primary cycloadducts. Moreover, the choice of the esterification conditions (Ph3P/DEAD or DIC/DMAP) used in linking the nitrone and the dipolarophile moieties in the intramolecular approach determined the absolute configuration of the final product, allowing the selective synthesis of both enantiomers, (−)-24 and (+)-24. This strategy required protection of the nitrone functionality to avoid racemization of the unprotected hydroxy nitrone during the introduction of the dipolarophile moiety. Protection/deprotection were achieved by cycloaddition/retro-cycloaddition reactions. The different propensity of some pyrrolo[1,2-b]isoxazolidines to undergo retro-cycloaddition with regeneration of the nitrone functionality was investigated both experimentally and by semiempirical and ab initio calculations on model compounds. The relative calculated activation energies were qualitatively in good agreement with the experimental observations. Fumaronitrile was found to be a convenient protecting reagent for the nitrone moiety and could be removed by retro-cycloaddition at lower temperatures than styrene and ethyl acrylate.