Menthyl esterification allows chiral resolution for synthesis of artificial glutamate analogs

Herein we report enantiospecific synthesis of two artificial glutamate analogs designed based on IKM–159, an antagonist selective to AMPA-type ionotropic glutamate receptor. The synthesis features chiral resolution of the carboxylic acid intermediate by esterification with L–menthol, followed by configurational analysis by NMR, conformational calculation, and X–ray crystallography. Mice in vivo assay showed that (2R)–MC–27 with six-membered oxacycle is neuroactive, whereas the (2S)–counterpart is inactive. It was also found that the TKM–38 with eight-membered azacycle is neuronally inactive to suggest the possibility that the analog with a smaller five-membered azacycle may act as a potent agent.

Keywords: chiral resolution; configurational analysis; glutamate; metathesis; neuroactivity

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Morokuma, K.; Tsukamoto, S.; Miyako, K.; Sakai, R.; Irie, R.; Oikawa, M. Beilstein Arch. 2020, 202045. doi:10.3762/bxiv.2020.45.v1