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

ABSTRACT: 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.

SUBMITTER: Morokuma K

PROVIDER: S-EPMC7934734 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Morokuma Kenji K Tsukamoto Shuntaro S Mori Kyosuke K Miyako Kei K Sakai Ryuichi R Irie Raku R Oikawa Masato M

Beilstein journal of organic chemistry 20210224

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 ...[more]

PMID: 33727977

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