IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.

The Ugi reaction is a useful four-component coupling reaction for α-(acylamino)amide. However, selective transformation of the two amides is generally difficult. Here, we report 1-hydroxy-2-methyl-2-propyl isocyanide (HMPI) as a new member of a 'convertible isocyanide' class used to solve the problem. HMPI is odorless and shows good reactivity in the Ugi reaction to give N-(1hydroxy-2-methyl-2-propyl) amides, which are smoothly converted into esters upon Zn(OTf) 2 -mediated solvolysis. Overall, structurally diverse α-amino acid esters are readily accessible in two steps by using HMPI.

1-Hydroxy-2-methyl-2-propyl Isocyanide (HMPI) as a New Convertible Isocyanide for the Ugi Four-Component-CouplingReaction. -The successful use of isocyanide (IV) in Ugi four-component reactions is shown. The mild chemoselective cleavage of the resulting N-(1-hydroxy-2-methyl-2-propyl) amides is achieved by alcoholysis mediated by Zn(OTf)2 and diethyl carbonate. -(OIKAWA*, M.; SUGAMATA, Y.; CHIBA, M.; FUKUSHIMA, K.; ISHIKAWA, Y.; Synlett 24 (2013) 15, 2014-2018, http://dx.