Chemical Approach to Explicate the Molecular Mechanism for Apoptosis

化学方法阐明细胞凋亡的分子机制

• 批准号: 12470481
• 负责人: SHISHIDO Kozo
• 金额: $ 9.15万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470481/
• 关键词: apoptosis; bongkrekic acid; total synthesis; enantioselective synthesis; Suzuki-coupling; 全合成研究; 不斉アルキル化; ミトコンドリア; 高井法

Bongkrekic acid, which is a toxic antibiobic produced by the bacterium Pseudomonas cocovenenans, was found responsible for inhibition of apoptosis. Now, it is one of the significant biological tools in the research area of apoptosis. Since it is little available from fermentation, the supplementation by the chemical synthesis has strongly been required. Therefore we have examined the exploitation of an efficient and enantipselective syntheti route for bongkrekic acid. We chose a convergent strategy, in which the molecule is bisected two segments, the left-hand segment and fight-hand segment, and finally both can be coupled. The following three results were obtained from this research.1. Synthesis of the left-hand segment: Cis-2-buten-1, 4-diol was converted by Evans' diastereoselective alkylation protocol into the alkenylboronic ester, which was joined with the alkenyliodide utilizing Suzuki-Miyaura coupling. The trienol with a tertiary stereogenic center was transformed into the corre … More sponding sulfone, which is the left-hand segment of bongkrekic acid.2. Synthesis of the right-hand segment: (S)-Glyceraldehyde, derived from D-mannitol, was converted into the butenolide which was reduced with DIBAH followed by condensed with Wittig ylide to give the dienol with a stereogenic center. Introduction of C-3 unit via reaction of the epoxide with propargyl anion followed by hydrogenation of the triple bond with the modified Lindlar catalyst provided the (Z, Z, Z) tirenol, which was transformed into the trienyl bromide of the right-hand segment.3. Coupling of the both segments and approach to bongkrekic acid: Coupling of the both segments was realized employing standard alkylation of the left-hand sufonyl anion with the right-hand bromide. The product thus obtained possesses the required backbone of bongkrekic acid. Sequential reductive removal of the benzenesulfon group and oxidation of C1 and C22 produced the heptaene diester, which is the key intermediate for bongkrekic acid. Less

发现由椰毒假单胞菌产生的有毒抗生素Bongkrekic acid负责抑制细胞凋亡。目前，它已成为研究细胞凋亡的重要生物学工具之一。由于它很少从发酵中获得，因此强烈需要通过化学合成来补充。因此，我们探索了一条有效的、对映选择性的合成邦克酸的路线。我们选择了一种收敛策略，将分子分为两段，左手段和右手段，最后两者可以耦合。本研究取得了以下三个结果：1.左链段的合成：通过Evans的非对映选择性烷基化方案将顺式-2-丁烯-1，4-二醇转化为烯基硼酸酯，利用Suzuki-Miyaura偶联将其与烯基碘连接。具有三级立体异构中心的三烯醇被转化为相应的三烯醇， ...更多信息 苯砜，它是邦克雷克酸的左手部分。右链段的合成：由D-甘露醇衍生的（S）-甘油醛转化为丁烯二醇，丁烯二醇用DIBAH还原，然后与Wittig叶立德缩合，得到具有立体异构中心的二烯醇。通过环氧化物与炔丙基阴离子反应引入C-3单元，然后用改性的Lindlar催化剂氢化三键得到（Z，Z，Z）替烯醇，其转化为右链段的三烯基溴.两个片段的偶联和获得邦克雷克酸的方法：使用左侧磺酰基阴离子与右侧溴化物的标准烷基化实现两个片段的偶联。由此获得的产物具有所需的米松酸骨架。依次还原除去苯磺酸基和氧化C1和C22产生庚烯二酯，其是米酵酸的关键中间体。少

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