Stereocontrolled synthesis of 5 alpha- and 5 beta-substituted kainic acids

A general and efficient method for the stereoselective synthesis of racemic 5 beta- and 5 alpha-substituted kainic acids 3 and 4 has been developed st arting from the bicyclic pyroglutamate derivative 6, readily available on a large scale. Compound 6 proved to be a versatile synthon from which straig htforward functionalizations at both C-5 beta and C-5 alpha were accomplish ed in a stereoselective manner without compromising the stereogenic integri ty of the potentially labile C-2 center. The key steps involved the stereos elective nucleophilic addition of organocopper reagents to the N-acyliminiu m ion I, and the stereoselective hydrogenation of the cyclic imine 9 derive d from 6. Transformations of the bicyclic intermediates 7 and 8 into the fi nal substituted kainic acids 3 and 4 were accomplished via stepwise sequenc es that avoid the facile and undesirable intramolecular Claisen and epimeri zation reactions. Compounds 3 and 4 have shown no significant binding affin ity for the kainate receptors, which reflects the sensitivity of the recogn ition site to steric and conformational factors.