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.
Highlights
The ionotropic glutamate receptor mediates the majority of the excitatory neurotransmission in the mammalian central nervous system (CNS) and plays an important role in higher brain functions, such as learning and memory [1]
On the basis of the racemate synthesis shown in Scheme 1, in the present study, we envisioned that both enantiomers of MC-27 could independently be synthesized from the racemic carboxylic acid intermediate-7 [6]
For such a chiral resolution, we recently discovered that ʟ-(−)-menthol (8) is of use as a chiral auxiliary in the enantiospecific synthesis of the other analogs 2 and 5 [4], and the strategy was found to be effective here (Scheme 2)
Summary
The ionotropic glutamate receptor (iGluR) mediates the majority of the excitatory neurotransmission in the mammalian central nervous system (CNS) and plays an important role in higher brain functions, such as learning and memory [1]. The synthesis reported is based on the menthol-mediated chiral resolution, which was developed de novo thereafter for the enantiospecific synthesis of the seven-membered-ring analogs TKM-107 (2 and the antipode 2*, see Figure 1) and IKM-154 (5 and the antipode 5*) [4].
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