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

Kenji Morokuma; Shuntaro Tsukamoto; Kyosuke Mori; Kei Miyako; Ryuichi Sakai; Raku Irie; Masato Oikawa

doi:10.3762/bjoc.17.48

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

Beilstein J Org Chem. 2021 Feb 24:17:540-550. doi: 10.3762/bjoc.17.48. eCollection 2021.

Authors

Kenji Morokuma^#¹, Shuntaro Tsukamoto^#¹, Kyosuke Mori¹, Kei Miyako², Ryuichi Sakai², Raku Irie¹, Masato Oikawa¹

Affiliations

¹ Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan.
² Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan.

^# Contributed equally.

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.

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

Grants and funding

This work was supported by the grant for Academic Research Promotion (No. SG2803) of Yokohama City University, Japan. The JSPS grant in aid for scientific research 15H0454608 to R. S. is also gratefully acknowledged.