Abstract
Recently, kainoids, such as kainic acid, have received significant attention due to their potent binding affinity for ionotropic glutamate receptors (iGluRs). iGluRs are involved in important neurophysiological processes, such as memory and learning. Although many synthetic investigations of kainoids have been reported to date, efficient synthetic methods are still strongly required. During the pioneering investigations on acromelic acid A, isolated by the Shirahama group, it was discovered that a synthetic derivative, methoxyphenyl kainic acid, possessed more potent activity than the natural compound. Inspired by this interesting structure-activity relationship, we launched an investigation into the development of efficient synthetic methods for achieving MFPA and phenylkainic acid. In our synthetic strategy, we envisioned that the three consecutive chiral centers were constructed based on the stereochemistry of the C4 position. We employed our asymmetric intermolecular C-H insertion reaction assisted by the chiral auxiliary using diazo ester and cyclohexadiene to afford the desired diene ester in high yield with good diastereoselectivity. After the conversion into the lactone by successive ozonolysis of cyclohexadiene, nitrogen was installed with Ns amide to give the corresponding hemiaminal. The reduction of the aminal and deprotection of the acetal induced the cyclization to construct a pyrrolidine ring with the correct stereochemistry. Introduction of two cyano groups were performed by diastereoselective Strecker-type reaction and Mitsunobu reaction. Finally, hydrolysis of the two cyano groups gave the synthetic kainoids. Furthermore, several investigations using the synthesized kainoids have elucidated that these compounds selectively bind to iGluRs and are equally effective for mice in vivo.
