72 立体配座を制御したグルタミン酸類縁体の合成(ポスター発表の部)

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L-Glutamate (Glu) has been attracted much attention because of its excitatory neurotransmittier action and its neurotoxic action in the mammalian central nervous system. Glu receptors have been classified into two major types, metabotropic Glu receptors (mGluRs) and ionotropic Glu receptors. In the course of our studies concerning the syntheses and the pharmacology of 2-(2-carboxycyclopropyl)glycines (CCG-I〜IV), conformationally constrained Glu analogues, we proposed that the conformational requirements of Glu for activating mGluRs would be an extended conformer while that for ionotropic receptors would be a folded conformer. To examine, further, conformational requirements of Glu receptors as well as to develop new Glu agonists, we synthesized 6 diastereomers of 2-(2-carboxy-3-methoxymethylcyclopropyl)glycines (MCGs), 3 diastereomers of 2-(2-carboxy-4-methylenecyclopentyl)glycines (CPGs), 3 analogues of 4-substituted glutamic acids, and 2-(2,3-dicarboxycyclopropyl)glycine (DCG). The syntheses of MCGs were characterized by (1) intramolecular cyclopropanation of the diazoacetamides with (E)- or (Z)-allyl ether and (2) inversion of cis-substituted α-cyclopropyl acyl anion to the trans ester (Figure 3). Palladium catalyzed [3+2] cycloaddition of the (E)- or (Z)-α,β-unsaturated trifluoroethyl ester with trimethylenemetane (TMM) equivalent furnished the desired cycloadducts which were converted to the 2'R isomers, CPG-II and IV, respectively (Figure 6). The 2'S isomer, CPG-I, was prepared by the stereoselective 1,4-addition of TMM species to the (Z)-ester. Amino carbonylation of the propargylglycine derivative prepared from L-aspartic acid gave 4-methylene Glu derivative which was used for thesyntheses of 4-substituted glutamic acids (Figure 7). The synthesis of DCG was carried out starting from the trans ester, a common synthetic intermediate of MCGs (Figure 8). Cis-MCG-I and IV, which freeze the rotation of α-amino acid moiety of CCGs, showed similar activities to their parent CCGs, respectively, suggesting the conformation of α-amino acid moiety of Glu for activating mGluRs and NMDA receptors as shown in Figure 4. Trans-MCG-IV and CPG-IV were classified as kainate (KA) receptor agonists. Their conformational relationship suggests that the folded form of Glu is also responsible for activating KA receptors (Figure 5). Moreover, DCG was found to be a potent and selective mGluR agonist.
天然有機化合物討論会の論文
1993-09-10

72 立体配座を制御したグルタミン酸類縁体の合成(ポスター発表の部)

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