Diastereoselective synthesis of (2S,4R)-4-Methylglutamic acid (sym 2081): A high affinity and selective ligand at the kainate subtype of glutamate receptors

(2S,4R)-4-Methylglutamic acid, a high affinity (IC50 = 35 nM) and selective ligand for the kainate (KA) receptor subtype, has been synthesized in multi-gram quantities starting from (S)-1-t-butoxycarbonyl-5-t-butyldiphenylsiloxymethylpyrrolidine-2-2-one. The diastereoselective methylation step provides the required trans product in 47% isolated yield.