Synthesis of accromelic acids and their derivatives

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A minute amount of acromelic acid A and B was isolated from a poisonous mushroom and their structures were deduced mainly from spectroscopic data and confirmed by the synthesis. The syntheses were designed to clear the stereochemistry and then kainic acid was chosen as the starting material because its absolute configuration was known. In order to convert isopropenyl group into pyridone, a new pyridine synthesis through 1,5-dicarbonyl compound using Pummerer rearrangement and a new effective condifions in the rearrangement of pyridine Noxide into pyridone were developed. The completion of the synthesis revealed the absolute configurations of three chiral senters of acromelic acid were the same as those kainic acid. These synthesis made bisassay possible and their most potent reuroexcitatory properties were disclosed. The more effective synthesis of the acids and their derivatives were thus attempted to look for their antagonists and agonists. i) Construction of three chiral centers on pyrrolidine ring employing control by the chirality of serine were under inverstigation. ii) To check which partial structure contributes to exhibition of strong neuroexcitation, several derivatives were synthesized and the relative strength or potentiation of excitatory responses to glutamate induced by them was examined. It was consequently revealed that a group possessing high density of -electron was necessary at the position 4 of pyrrolidin ring for enhancement of the bioactivity. iii) The syntheses of derivatives of acromelic acid carring phenol instead of pyridone was attempted and model experiments for conversion of isopropenyl group of kainic acid into phenol are now going on. For the stereoselective construction of pyrrolidine ring, trans annular radical ring chosure of 9-menbered lactone leading to bicyclo[9.3.0]nonane syntem and hetero- Diels-Alder reaction are also examined but any definite result is not obtained so for.