Structure Determination, Synthesis and Biological Activity of Neuroactive Compounds

1.苯丙酸：作者从有毒蘑菇中分离得到的非蛋白质氨基酸。它对神经元上的谷氨酸受体是一种特殊的兴奋性化合物，为了研究谷氨酸受体，需要使用这种酸作为试剂，所以我们开发了几种合成这种酸的方法。这次对合成方法进行了进一步的开发。(1)用新开发的方法合成了一种类似物。关键步骤包括丙二酸酯基与4-羟基苯基-3-脱氢脯氨酸的反应。经10步反应制得苯基海人藻氨酸，总收率12%。(2)红藻氨酸的去极化活性依赖于C-4侧链中不饱和体系的存在。为了研究这一侧链的构象，我们合成了一种双环海人藻类化合物，其醋酸残基与异丙烯基甲基相连。在该化合物中，不饱和体系和吡咯烷环平面几乎在同一平面上。它们的活度显著降低表明，不饱和体系的平面必须与吡咯烷平面成直角才能表现出较强的活性。(3)为了研究吡咯烷环在红藻氨酸活性中的作用，我们合成了通过消除C-5碳而得到的开环红藻氨酸。它们活性的显著降低意味着吡咯烷环对海人藻类构象进行了适当的排列。(4)建立了由核磁共振化学位移推算海人藻类化合物构型的规则。揭示了该反应的反应机理，该反应是已开发的海人藻素合成方法中的关键反应。绞股蓝是我们从有毒蘑菇中分离得到的一种神经毒素，是一种手性HMGA酯类化合物。为了从非手性HMGA合成手性HMGA酯，提出了一种以HMGA为新试剂的手性β-内酯的合成方法。

1. Acromelic acid : Non-protein amino acid isolated from a poisonous mushroom by the author. It is an extraordinary excitatory compound to the glutamate receptor of a neuron.To study the glutamate trceptor, use of this acid as a reagent is desired and so we developed several methods to synthesize this acid. This time further development of the synthetic method was performed. (1) An analog was synthesized by a newly developed method. The key step contains the reaction of malonic ester radical and 4-phenyl-3-dehydroproline which was furnished from 4-hydroxplorine. A phenyl kainoid was obtained through 10 steps with 12% overall yield. (2) Depolarizing activity of kainoid depends on the existence of unsaturated system in C-4 side chain. In order to study the conformation of this side chain, we synthesized a bicyclic kainoid whose acetic acid residue linked to the methyl of isopropenyl group. In this compound the unsaturated system and the pyrrolidine ring plane are almost in the same plane. Notable decrease in their activity shows that the plane of the unsaturated system must be at right angle to pyrrolidine plane to exhibit strong activity. (3) To study a role of pyrrolidine ring in the kainoid activity, we synthesized acyclic kainoids which are derived by elimination of the C-5 carbon. Notable decrease in their activity means that an adequate arrangement of the kainoid conformation are made by pyrrolidine ring. (4) A rule deducing the configuration of kainoid by NMR-chemical shifts was developed. The mechanism of the reaction which was the key reaction in the previously developed synthetic method of kainoid was revealed.2. Gymnopilin, a nerve toxin isolated from poisonous mushroom by us, is a chiral HMGA ester. In order to synthesize a chiral HMGA ester from the achiral HMGA, a new synthetic method of a chiral beta-lactone of HMGA as a new reagent was developed.