An improved synthesis of enantiomerically pure CIP-AS,a potent and selective AMPA-kainate receptor agonist

CIP-AS (−)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to N-BOC-3,4-didehydro-(S)-proline methyl ester (−)-6. Herein, we report an alternative strategy based on the cycloaddition of the same dipolarophile to N-(4-methoxybenzyl)-α-ethoxycarbonylnitrone 12. The mixture of stereoisomeric 3-ethoxycarbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines 13 was then converted into the corresponding 3-ethoxycarbonyl-Δ²-isoxazolinyl prolines by DDQ mediated oxidation. The new strategy yielded the precursor of CIP-AS in satisfactory overall yield and represents an improvement upon the existing procedure in terms of yield and efficiency.