Molecular design to develop a novel tool for the elucidation of the function of glutamates

手性亚磺酰基马来酰亚胺是一种典型的亚磺基乙烯类亲二烯化合物，它与各种二烯类化合物以高度非对映选择性的方式反应生成相应的环加合物。本研究项目的目的是开发一种新的工具来阐明谷氨酸在人脑中的功能和分子理解。为此，我们研究了具有双环[2.2.1]庚烷体系的谷氨酸和磷酸谷氨酸衍生物的手性合成，得到了以下结果：1)具有双环[2.2.1]庚烷体系的谷氨酸和磷酸谷氨酸衍生物的手性合成：亚磺酰亚胺与环戊二烯的不对称Diels-Alder反应生成了单一的非对映异构环加合物。环加合物的还原和N-酰亚胺的氰化反应为谷氨酸的合成提供了关键中间体。经过几次转化过程，得到目标谷氨酸衍生物，即二甲基铵盐…其生物活性测定表明其具有NMDA拮抗活性。这些谷氨酸可能是进一步分子设计的良好先导化合物。磷亲核试剂的酰亚胺加成反应生成相应的磷酸酯。2)亚磺酸乙烯类化合物在超高压下的不对称Diels-Alder环加成反应：为了扩大上述Diels-Alder反应的范围，系统地研究了不同亚磺酸基乙烯与低活性双烯的反应。结果表明，在超高压条件下，低活性的双烯与亚磺基乙烯反应生成相应的高度非对映选择性环加合物。结果表明，该反应的立体过程与在常压下建立的过程相同。因此，超高压方法对于具有双环[2.2.1]-庚烷-正辛烷体系的谷氨酸受体拮抗剂(或激动剂)的分子设计是非常有用的。较少

Chiral sulfinylmaleimides, a typical sulfinylethene-type dienophiles, react with various dienes to give the corresponding cycloadducts in highly diastereoselective manner. The aim of this research project is to develop a new tool to clarify the fucntion and the molecular understanding of glutamates in the human brain. For that purpose the chiral synthesis of glutamate and phosphoglutamate derivatives having the bicyclo [2.2.1] heptane ring system have been investigated and the following results were obtained.1) The chiral synthesis of glutamate and phosphoglutamate derivatives having the bicyclo [2.2.1] heptane ring system : Asymmetric Diels-Alder reaction of the sulfinylmaleimides with cyclopentadiene afforded the single diastereomeric cycloadduct. The reduction of the cycloadduct followed by the N-acyliminium cyanation afforded the key intermediate for the glutamate synthesis. After several conversion process, the objective glutamate derivatives were obtained as dimethylammonium salt … More , whose bioassay show the NMDA antagonistic activity. These glutamate could be good lead compounds for further molecular design. The acyliminium addition of phosphorus nucleophiles afforded the corresponding phosphorus esters. The hydrolytic cleavage of the phosphorus esters was very difficult to give the objective phosphoglutamate derivatives.2) Asymmetric Diels-Alder Cycloaddition of the Sulfinylethenes under Ultrahigh Pressure : In order to extend the scope of the above Diels-Alder reaction, the reaction of various sulfinylethenes with low-reactive dienes have been systematically studied. It was turned out that under the ultrahigh pressure conidition the low reactive dienes react with sulfinylethenes to give the corresponding cycloadducts highly diastereoselectively. The steric course of the reaction turned out to be the same as that was established under atmospheric pressure. So, the ultrahigh pressure methodology is quite useful for the molecular design of the glutamate receptor antagonists (or agonists) having the bicyclo [2.2.1] -heptane and-octane system. Less