Structure Determination, Synthesis and Biological Activity of Neuroactive Compounds

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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.