The Laulimalide Family: Total Synthesis and Biological Evaluation of Neolaulimalide, Isolaulimalide, Laulimalide and a Nonnatural Analogue
The Laulimalide Family: Total Synthesis and Biological Evaluation of Neolaulimalide, Isolaulimalide, Laulimalide and a Nonnatural Analogue
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DOI：
10.1002/chem.200802605
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发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Mulzer, Johann
中科院分区：
文献类型：
--
作者：
Gollner, Andreas;Altmann, Karl-Heinz;Mulzer, Johann
我们在本文中详细描述了抗肿瘤药物新劳利马来酸和异劳利马来酸的首次全合成以及劳利马来酸的高效路线。使用Kulinkovich反应，然后环丙基-烯丙基重排来安装外亚甲基。C-2-C-16醛片段与C-17-C-28砜片段通过高度（E）选择性Julia-Lythgoe-Kocienski烯化反应偶联，以提供所有三种合成的关键中间体。应用山口大环内酯化的各种条件来封闭各个大环。最后，一个精心设计的残局，以解决酰基迁移的情况下，neolaulimalide。所有化合物都针对几种细胞系进行了测试。自从其最初分离以来，可以首次证实新劳利马胺的细胞毒性，并且可以显示其与劳利马胺一样有效地诱导微管蛋白聚合。
We herein describe in full detail the first total synthesis of the antitumor agents neolaulimalide and isolaulimalide as well as a highly efficient route to laulimalide. A Kulinkovich reaction followed by a cyclopropyl-allyl rearrangement is used to install the exo-methylene group. The C-2-C-16 aldehyde fragment is coupled with the C-17-C-28 sulfone fragments by a highly (E)selective Julia-Lythgoe-Kocienski olefination to deliver the key intermediates of all three syntheses. Various conditions for the Yamaguchi macrolactonization are applied to close the individual macrocycles. Finally a carefully elaborated endgame was developed to solve the problem of acyl migration in the case of neolaulimalide. All compounds were tested against several cell lines. ne cytotoxicity of neolaulimalide could be confirmed for the first time since its original isolation and it could be shown that it induces tubulin polymerization as efficiently as laulimalide.