Total Synthesis and Biological Assessment of Mandelalide A
Total Synthesis and Biological Assessment of Mandelalide A
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DOI：
10.1002/chem.201504230
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发表时间：
2016-01-22
影响因子：
4.3
通讯作者：
Altmann, Karl-Heinz
中科院分区：
文献类型：
--
作者：
Bruetsch, Tobias Michael;Bucher, Pascal;Altmann, Karl-Heinz
基于Shiina型大环内酯化的大环闭合反应和Sonogashira交叉偶联反应，合成了海洋大环内酯扁桃醛A（1）。酸结构单元的制备中的关键步骤是对映选择性的，催化添加的保护乙炔巴豆醛和建设的四氢吡喃单元，这是嵌入在大环通过酸催化的普林斯反应。醇片段的合成特征在于通过缩醛裂解/环氧化物开环级联反应和很少使用的伯烷基碘的自由基炔基化形成三取代的四氢呋喃环。有趣的是，作为该结构单元合成的一部分，末端双键的二羟基化得到了α-和β-AD-混合试剂的相同主要产物，尽管具有中等或低的选择性。人工合成的扁桃内酯A（1）在体外对A549、HT 460和H1299人肺癌细胞有较强的增殖抑制作用，但对SK-N-SH神经母细胞瘤细胞无抑制作用。然而，在任何情况下，我们没有观察到完全的细胞杀死，即使在最高的化合物浓度测试（5 μ m）。
A new convergent total synthesis of the marine macrolide mandelalideA (1) has been developed that is based on macrocyclic ring closure by a Shiina-type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross-coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid-catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tet-rahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the alpha- and beta-AD-mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A (1) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK-N-SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 mu m).