N-Methyl-D-Aspartate (NMDA) receptors are neuronal ionotropic channels that play an important role in memory and learning processes. Their exacerbated activation leads to neuron death by necrosis or apoptosis in a phenomenon called excitotoxicity. Compounds like memantine or amantadine act as antagonists of these receptors and are currently used for the treatment of Alzheimer's or Parkinson's diseases. We herein present the development of a series of new NMDA receptor antagonists using enantiopure tryptophanol and racemic δ-oxo-esters as synthetic precursors in only one synthetic step and good yields. The most active hit exhibited an IC50 of 63.4 µM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than the positive control used, amantadine (IC50 = 92 µM). The versatility of our synthetic approach together with the well-defined absolute stereoutcome of the tryptophanol-derived oxazolopiperidones is currently being explored to produce valuable structure activity relationships for the development of new potent NMDAR antagonists.