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

CIP-AS (-)-2, a chiral amino acid structurally related to glutamic acid, be haves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddit ion 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)-alpha -ethox ycarbonylnitrone 12. The mixture of stereoisomeric 3-ethoxycarbonyl-N-(4-me thoxybenzyl)iso prolines 13 was then converted into the corresponding 3-eth oxycarbonyl-Delta (2)-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. (C) 2001 Elsevier Science Ltd. All rights reserved.