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.

Synthesis and α-glucosidase inhibitory activity of cinnnamamides

“…Furthermore, hydroxy benzotriazole (HOBt) can be used to synthesize amides, but concerns about its explosive properties have been raised [24]. However, 2-methyl-6-nitrobenzoic anhydride (MNBA) demonstrated great promise in the synthesis of large-ring lactones [25], artificial glutamate analogs [26], and carboxylic esters [27]. Further, the combination of MNBA, 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine N-oxide (DMAPO) was also effective for the synthesis of amides and peptides [28,29].…”