The Design and Synthesis of Novel Chiral Z-Nitrones with Applications Towards the Syntheses of Enantiomerically Pure 4-Hydroxy Amino Acids

A number of 4-hydroxy amino acids have been synthesized via 1,3-dipolar cycloadditions of novel Z-nitrones and substituted olefins. Three achiral nitrones were synthesized in pursuit of a conformationally stable yet reactive Z-nitrone. The carboisopropoxynitrone was determined to be the best synthon in cycloadditions that favored a Z-nitrone oriented transition state. Solvent studies were performed for cycloaddition reactions and it was determined that polar solvents lead to "Z-derived" isoxazolidines whereas non-polar solvents primarily afford "E-derived" isoxazolidines. The incorporation of MgBr₂·OEt,₂ to the reaction further enhanced the selectivity of the cycloaddition reaction in favor of "Z-derived" intermediates.

Chiral carboisopropoxynitrone derivatives were also realized and used in reactions with chiral olefins to afford optically active 4-hydroxy amino acids after several steps. (2R,4R) 4-hydroxyl-4-methylglutamic acid and (2R,4R) Monatin were both synthesized in high purity from corresponding olefins and the chiral carboisopropoxynitrone. Furthermore, the (2S,4S) enantiomers of both amino acids could be synthesized via enantiomers of the chiral nitrone and olefins.