Structure–activity relationships of IKM-159: Diverted synthesis and biological evaluation of a series of C5-oxy analogs

Menthyl esterification allows chiral resolution for synthesis of artificial glutamate analogs

“…Synthetic route for the racemate of heterotricyclic MC-27 (rac-4) has been established in 2015 as shown in Scheme 1 [5][6][7]. Starting from oxanorbornene rac-6 [6,8], the heterotricyclic framework was constructed over five-steps sequence including domino metathesis reaction as a key step to give rac-7.…”

“…(esterification with CH2N2, PMB removal, and ester hydrolysis) had been proven to be promising for preparation of subgram quantities of rac-MC-27 (rac-4), which was found to cause weak inhibition of voluntary movement of mice upon intracerebroventricular injection [5]. 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].…”

“…Finally, hydrolytic removal of menthyl, methyl, and TFA groups were attempted toward both enantiomers of TKM-38 (3/3*, Scheme 6). Preliminary study with 21* (2S) showed the low reactivity under acidic conditions (6 M aq HCl, MeOH, 65 °C) [5,21], which resulted in quantitative recovery of the substrate 21* (2S). We then examined alkaline hydrolysis (KOH, MeOH, H2O, 40 °C) [22,23]…”

“…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].…”

“…Previously employed alkaline hydrolysis (1 M aq LiOH, MeOH or THF, rt45 °C)[4], however, gave only a monocarboxylic acid product with the menthyl ester remained unaffected (structure not shown). Fortunately, complete deprotection of two esters was possible cleanly under acidic conditions (6 M aq HCl, 1,4-dioxane, 75 °C, 4 days) to furnish (2R)-MC-27 (4) in 48% yield (Scheme 3), which was chromatographically and spectroscopically identical to the racemate[5].On the other hand, N-PMB amide 9* (2S) (tR 7.0 min inFigure 2) was also deprotected by CAN (Scheme 4), and the configurational analysis of the product 10* was attempted separately. An important NOESY correlation observed for 10* is shown also in Scheme 4.…”