Department of Chemistry, Biomolecular Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK.
Chemistry. 2012 Jul 9;18(28):8813-9. doi: 10.1002/chem.201200071. Epub 2012 Jun 12.
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.
N-甲基-D-天冬氨酸（NMDA）是离子型谷氨酸受体 NMDA 受体亚型的典型激动剂。（S）-NMDA 的 3-位立体选择性地引入 C-F 键会生成（2S,3S）-或（2S,3R）-3F-NMDA 的非对映异构体。通过纯对映异构体的合成制备了各个非对映异构体，发现（2S,3S）-3F-NMDA 是一种与 NMDA 本身具有相当效力的激动剂，而（2S,3R）-非对映异构体则几乎没有效力。这些立体异构体效力的差异归因于 C-F 键（2S,3S）-3F-NMDA 优先采用 gauche 构象与结合构象中的 C-N(+)键，而（2S,3R）-3F-NMDA 迫使这些键呈反式，失去静电稳定化，以达到所需的结合构象。这些观察结果说明了立体选择性氟化在影响β-氟化氨基酸的分子构象方面的实用性，从而可以探测受体中生物活性化合物的活性构象。
