Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

• Main Authors: Kenji Morokuma, Shuntaro Tsukamoto, Kyosuke Mori, Kei Miyako, Ryuichi Sakai, Raku Irie, Masato Oikawa
• Format: Article
• Language: English
• Published: Beilstein-Institut 2021-02-01
• Series: Beilstein Journal of Organic Chemistry
• Subjects: chiral resolution; configurational analysis; glutamate; metathesis; neuroactivity
• Online Access: https://doi.org/10.3762/bjoc.17.48

Herein, we report the enantiospecific synthesis of two artificial glutamate analogs designed based on IKM-159, an antagonist selective to the AMPA-type ionotropic glutamate receptor. The synthesis features the chiral resolution of the carboxylic acid intermediate by the esterification with ʟ-menthol, followed by a configurational analysis by NMR, conformational calculation, and X-ray crystallography. A mice in vivo assay showed that (2R)-MC-27, with a six-membered oxacycle, is neuroactive, whereas the (2S)-counterpart is inactive. It was also found that TKM-38, with an eight-membered azacycle, is neuronally inactive, showing that the activity is controlled by the ring C.