Total Synthesis and Biological Evaluation of (+)-Neopeltolide and Its Analogues
Total Synthesis and Biological Evaluation of (+)-Neopeltolide and Its Analogues
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DOI：
10.1002/chem.200901675
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发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Sasaki, Makoto
中科院分区：
文献类型：
--
作者：
Fuwa, Haruhiko;Saito, Asami;Sasaki, Makoto
利用新开发的Suzuki-Miyaura偶联/闭环复分解策略，实现了（+）-新潘托内酯（一种新型海洋大环内酯天然产物，具有对几种癌细胞系的高效抗增殖活性以及有效的抗真菌活性）的最初提出的（1）和正确的（2）结构的立体控制全合成。由碘化物34原位产生的硼酸烷基酯44通过Suzuki-Miyaura偶联与烯醇磷酸8偶联。衍生的二烯45的闭环复分解，然后立体选择性氢化，以高的总收率从34得到作为单一立体异构体的四氢吡喃47。我们的收敛策略使我们能够以快速有效的方式构建2的14元大环内酯核心结构。对合成中间体和设计的合成类似物进行全合成和生物学评价，以建立2的结构-活性关系，发现了结构简单但有效的细胞毒性类似物9-去甲基新戊内酯（54）。
The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent anti-proliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki-Miyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).