Synthesis of accromelic acids and their derivatives

丙烯二酸及其衍生物的合成

• 批准号: 61470029
• 负责人: SHIRAHAMA Haruhisa
• 金额: $ 2.05万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1986
• 资助国家: 日本
• 起止时间: 1986 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-61470029/
• 关键词: acromelic acid; neurotransmittance; potentiation of glutamate response; a new method of pyridine synthesis; アクロメリン酸(A)の合成の合成; アクロメリン酸(B)の合成; ピリジン環の新合成法; α-ピリドンの新合成法

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.

从一种有毒蘑菇中分离得到了微量的丙烯酸A和B，其结构主要由光谱数据推断，并经合成证实。设计了明确立体化学的合成方法，然后选择红藻氨酸作为起始原料，因为它的绝对构型是已知的。为了将异丙烯基转化为吡啶酮，提出了一种由1，5-二羰基化合物经Pummerer重排反应合成吡啶的新方法，并提出了一种新的有效条件。合成结果表明，三个手性中心的绝对构型与红藻氨酸的完全相同。这些合成使双分析成为可能，并揭示了它们最有效的神经兴奋特性。因此，试图更有效地合成这些酸及其衍生物，以寻找它们的拮抗剂和激动剂。i）研究了利用丝氨酸的手性控制在吡咯烷环上构建三个手性中心。ii）为了检查哪个部分结构有助于显示强神经兴奋，合成了几种衍生物，并检查了它们诱导的对谷氨酸的兴奋性反应的相对强度或增强。结果表明，在吡咯烷环的4位上引入高电子密度的基团是提高其生物活性的必要条件。iii）尝试了以苯酚代替吡啶酮合成丙烯酸衍生物，并进行了红藻氨酸异丙烯基转化为苯酚的模型实验，对于吡咯烷环的立体选择性构建，9-元内酯的反式环自由基选环，得到双环[9.3.0]壬烷和杂- Diels-对桤木反应也进行了研究，但没有得到明确的结果。

项目成果

K,Konno, H,Shirahama: "Neuroexcitatory substances from a poisonous mushroom, Acromelic acids, Principles of Clitocybe acromelalga" Kagaku to Seibutu. 25. 480-484 (1987)

K、Konno、H、Shirahama：“有毒蘑菇中的神经兴奋物质、Acromelic 酸、Clitocybe acromelalga 的原理” Kagaku 到 Seibutu。

紺野勝弘, 白浜晴久: 化学と生物. 25. 480-484 (1987)

Katsuhiro Konno，Haruhisa Shirahama：化学与生物学。25. 480-484 (1987)

K,Konno, K,Hashimoto, H,Shirahma, T,Matsumoto: "Improved Procedures for Preparation of 2-Pyridones and 2-Hydroxymethylpyridines from Pyridine N-Oxides" Heterocycles. 24. 2169-2172 (1986)

K，Konno，K，Hashimoto，H，Shirahma，T，Matsumoto：“从吡啶 N-氧化物制备 2-吡啶酮和 2-羟甲基吡啶的改进程序”杂环。

紺野勝弘, 橋本貴美子, 白浜晴久, 松本毅: Heterocycles. 24. 2169-2172 (1986)

Katsuhiro Konno、Kimiko Hashimoto、Haruhisa Shirahama、Takeshi Matsumoto：杂环。24。2169-2172 (1986)

K,Hashimoto, K,Konno, H,Shirahama, T,Matsumoto: "Synthesis of Acromelic Acid B, a Toxic Principle of Clitocybe acromelalga" Chemistry Letters. 1399-1400 (1986)

K、Hashimoto、K、Konno、H、Shirahama、T、Matsumoto：“Acromelic Acid B 的合成，Clitocybe acromelalga 的毒性原理”化学快报。