Synthetic Studies on Protein Phosphatase Inhibitor Dysidiolide

蛋白磷酸酶抑制剂地西二内酯的合成研究

• 批准号: 09672165
• 负责人: YAMADA Yasuji
• 金额: $ 1.79万
• 依托单位: Tokyo University of Pharmacy and Life Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672165/
• 关键词: dysidiolide; synthesis; Diels-Alder reaction; protein phosphatase cdc25A; protein phosphatase inhibitor; sponge; lipase; プロテインホスファターゼ阻害; cdc25A

Dysidiolide, a novel sesterterpenoid isolated from the Caribbean sponge Dysidia eiheria de Laubenfels, exhibits inhibition of the protein phosphatase cdc25A.Dysidiolide possesses a unique carbon skeleton with structural features that find no precedent in nature. Thus, its unique structure and biological activity prompted me to undertake the synthetic studies of dysidiolide. I have achieved following three heading in this study.1. Exploitation of Synthetic Method for Decalin Part of Dysidiolide using Intramolecura Diels-Alder ReactionI developed synthetic method for decalin part of dysidiolide using model compound. This synthesis involves preparation of alpha, beta-unsaturated lactone by intramolecura Diels-Alder reaction, stereoselective methylation by Me_2CuLi at C-6 position and stereoselective alkylation at C-7 position.2. Formal Synthesis of (*)-DysidiolideDecalin part of dysidiolide was synthesized according to above method. Deoxyganation of the C-12 and C-24 positions and extension of side chain completed the formal synthesis of (*)-dysidiolide.3. Synthesis of Optically Active Cyclohexene Derivative Using LipaseOptically active cyclohexene derivative was synthesized by optical resolution using Lipase AK.This compound is useful for the synthesis of optically active dysidiolide as a starting material.The synthesis of optically active dysidiolide is now in progress.

Dysidiolide是从加勒比海海绵中分离得到的一种新的二萜类化合物，对蛋白磷酸酶cdc 25 A具有抑制作用。Dysidiolide具有独特的碳骨架，其结构特征在自然界中没有先例。因此，其独特的结构和生物活性促使我进行了dysidiopathy的综合研究。在本研究中，我取得了以下三个方面的成果。分子内Diels-Alder反应合成双氢萘的方法的探索我以模型化合物为原料，研究了双氢萘的合成方法。该合成方法包括分子内Diels-Alder反应、Me_2CuLi在C-6位的立体选择性甲基化和C-7位的立体选择性烷基化反应，得到α，β-不饱和内酯.（*）-二氢吲哚的形式合成按上述方法合成了二氢吲哚的十氢萘部分。C-12和C-24位的脱氧和侧链的延伸完成了（*）-dysidiolide的正式合成.使用脂肪酶AK通过光学拆分合成光学活性的环己烯衍生物。该化合物可用作合成光学活性的二氢吲哚的起始原料。光学活性的二氢吲哚的合成目前正在进行中。

项目成果

Hiroaki Miyaoka, Yasuhiro Kajiwara, Miho Hara, Akira Suma and Yasuji Yamada: "Kinetic Resolution of Primary Alcohol attached Quaternary Carbon by Lipase-Catalyzed Acetylation" (in preparation).

Hiroaki Miyaoka、Yasuhiro Kajiwara、Miho Hara、Akira Suma 和 Yasuji Yamada：“通过脂肪酶催化乙酰化动力学拆分伯醇连接的季碳”（准备中）。

Hiroaki Miyaoka, Yasuhiro Kajiwara and Yasuji Yamada: "Total Synthesis of *-Dysidiolide" (in preparation).

Hiroaki Miyaoka、Yasuhiro Kajiwara 和 Yasuji Yamada：“*-Dysidiolide 的全合成”（准备中）。