N-Methyl-D-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C-F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepared by synthesis in enantiomerically pure forms and it was found that (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C-F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C-N(+) bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilisation, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the molecular conformation of β-fluorinated amino acids and thus probing the active conformations of bioactive compounds at receptors.
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