Chemical Approach to Explicate the Molecular Mechanism for Apoptosis

Bongkrekic酸是由椰毒假单胞菌产生的一种有毒抗菌剂，被发现与抑制细胞凋亡有关。目前，它已成为研究细胞凋亡的重要生物学工具之一。由于从发酵中几乎没有可利用的，所以强烈需要通过化学合成来补充。因此，我们探索了一条高效、对映体选择性的合成路线。我们选择了一种收敛策略，在这种策略中，分子被一分为二，左手部分和右手部分，最后两者可以耦合。本研究获得了以下三个方面的结果。左旋-2-丁烯-1，4-二醇的合成：顺-2-丁烯-1，4-二醇通过Evans的非对映选择性烷基化反应生成烯基硼酸酯，再通过Suzuki-Miyaura偶联反应连接到烯基碘上。将具有三级立体合成中心的三烯醇转化为CORE…更多的响应酮，这是bongkrekic酸的左手段。右旋链段的合成：将D-甘露醇衍生的(S)-甘油醛转化为丁烯内酯，再用DIBAH还原，再与Wittig叶立德缩合，得到具有立体中心的二烯醇。通过环氧化物与炔丙基阴离子的反应引入C-3单元，然后在改进的Lindlar型催化剂上三键加氢得到(Z，Z，Z)梯尼醇，它被转化为右链的三烯基溴。两个链段的偶联和合成bongkrekic酸的途径：两个链段的偶联是通过左手的磺酰阴离子与右手的溴化物的标准烷基化来实现的。这样得到的产物具有所需的bongkrekic酸的主链。苯磺酸基团的还原脱除和C1和C22的氧化生成了庚烯双酯，它是Bongkrekic酸的关键中间体。较少

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