An Efficient Enantiospecific Synthesis of Neuroactive Glutamate Analogs

Menthyl esterification allows chiral resolution for synthesis of artificial glutamate analogs

“…Construction of such medium-sized ring is generally highly challenging [14,15], and this was also the case with rac- 13 N-Boc derivatization of rac-16 (87% yield), followed by alkaline methanolysis (74% yield) [16] and Pinnick oxidation (43% yield) [17][18][19], delivered carboxylic acid rac-19. The stereochemical analyses carried out here and in our previous study [4] have become possible owing to the conformational rigidity of four contiguous single bonds between the heterotricycle and the menthyl ring. The correctness of the analysis has been proven by single-crystal X-ray analysis of MC-27 precursor 10 (2R, Figure 4).…”

“…On the basis of the racemate synthesis shown in Scheme 1, in the present study, we envisioned that the both enantiomers of MC-27 would be independently synthesized from racemic carboxylic acid intermediate rac-7 [6]. For such chiral resolution, we recently discovered that L-(-)-menthol (8) is of use as a chiral auxiliary in the enantiospecific synthesis of other analogs 2 and 5 (see Figure 1) [4], and the strategy was found to be also effective here (Scheme 2). Thus, esterification mediated by 2-methyl-6-nitrobenzoic anhydride (MNBA, Shiina esterification) [9], followed by chromatographic separation of the diastereomers generated, successfully provided 9* ((2S)-isomer, tR 7.0 min) and 9 ((2R)-isomer, tR 11.5 min) in 45.3% and 44.4% yields, respectively ( Figure 2).…”

“…Previously, we have synthetically developed (2R)-IKM-159 (1) as an artificial glutamate analog that is antagonistic selectively to AMPA-type iGluR ( Figure 1) [2,3]. From a series of these studies (see 1, 2, and 5 in Figure 1) [3,4], we found that 1) the (2R)-enantiomer is responsible for the neuroactivity, and 2) the activity is controlled by the structure of In 2015, we reported synthesis and evaluation of six-membered oxacyclic analog rac-4 (MC-27) in the racemic form, which was shown to be weakly hypoactive in vivo [5].…”

“…For synthesis of enantiomerically pure artificial glutamate analogs, we previously developed enantiospecific synthesis using chiral amine as a starting material, and applied to the synthesis of both enantiomers of IKM-159 (1 and the antipode) in 2013 [3]. The synthesis reported herein is based on the menthol-mediated chiral resolution which has been de novo developed thereafter for enantiospecific synthesis of sevenmembered ring analogs TKM-107 (2 and the antipode, see Figure 1) and IKM-154 (5 and the antipode) [4]. Structural analysis of the diastereomeric menthyl esters obtained after chiral resolution had been conducted based on a combination of NOESY data and conformational calculation in that study [4].…”

“…The synthesis reported herein is based on the menthol-mediated chiral resolution which has been de novo developed thereafter for enantiospecific synthesis of sevenmembered ring analogs TKM-107 (2 and the antipode, see Figure 1) and IKM-154 (5 and the antipode) [4]. Structural analysis of the diastereomeric menthyl esters obtained after chiral resolution had been conducted based on a combination of NOESY data and conformational calculation in that study [4]. In this study, the configurational analysis of the menthyl ester is reasonably justified by X-ray crystallographic analysis, as follows.…”