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首页> 外文期刊>Chemistry: A European journal >Total Synthesis, Stereochemical Revision, and Biological Reassessment of MandelalideA: Chemical Mimicry of Intrafamily Relationships
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Total Synthesis, Stereochemical Revision, and Biological Reassessment of MandelalideA: Chemical Mimicry of Intrafamily Relationships

机译：曼德拉利德A的总合成，立体化学修饰和生物学评估：家族内关系的化学模拟

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MandelalideA and three congeners had recently been isolated as the supposedly highly cytotoxic principles of an ascidian collected off the South African coastline. Since these compounds are hardly available from the natural source, a concise synthesis route was developed, targeting structure 1 as the purported representation of mandelalideA. The sequence involves an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening as entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal acetylene metathesis into natural product total synthesis, which is remarkable in that this class of substrates had been beyond the reach of alkyne metathesis for decades. Synthetic 1, however, proved not to be identical with the natural product. In an attempt to clarify this issue, NMR spectra were simulated for 20 conceivable diastereomers by using DFT followed by DP4 analysis; however, this did not provide a reliable assignment either. The puzzle was ultimately solved by the preparation of three diastereomers, of which compound 6 proved identical with mandelalideA in all analytical and spectroscopic regards. As the entire northern sector about the tetrahydrofuran ring in 6 shows the opposite configuration of what had originally been assigned, it is highly likely that the stereostructures of the sister compounds mandelalidesB-D must be corrected analogously; we propose that these natural products are accurately represented by structures 68-70. In an attempt to prove this reassignment, an entry into mandelalidesC and D was sought by subjecting an advanced intermediate of the synthesis of 6 to a largely unprecedented intramolecular Morita-Baylis-Hillman reaction, which furnished the -lactone derivative 74 as a mixture of diastereomers. Whereas (24R)-74 was amenable to a hydroxyl-directed dihydroxylation by using OsO4/TMEDA as the reagent, the sister compound (24S)-74 did not follow a directed path but simply obeyed Kishi's rule; only this unexpected escape precluded the preparation of mandelalidesC and D by this route. A combined spectroscopic and computational (DFT) study showed that the reasons for this strikingly different behavior of the two diastereomers of 74 are rooted in their conformational peculiarities. This aspect apart, our results show that the OsO4/TMEDA complex reacts preferentially with electron deficient double bonds even if other alkenes are present that are more electron rich and less encumbered. Finally, in a brief biological survey authentic mandelalideA (6) was found to exhibit appreciable cytotoxicity only against one out of three tested human cancer cell lines and all synthetic congeners were hardly active. No significant fungicidal properties were observed.
机译：MandelalideA和三个同源物最近被分离出来，因为据推测是南非海岸线附近收集的海鞘的高度细胞毒性原理。由于这些化合物几乎不能从天然来源获得，因此开发了一种简明的合成路线，以结构1作为声称的曼荼罗A的代表。该序列涉及铱催化的双向Krische烯丙基化反应和钴催化的羰基化环氧化物开口作为制备主要结构单元的入口。最后阶段的特征是首先将末端乙炔复分解应用于天然产物的全合成中，这一点引人注目，因为这类底物数十年来一直不在炔复分解的范围内。然而，合成物1与天然产物并不完全相同。为了澄清这个问题，通过使用DFT然后进行DP4分析，模拟了20种可能的非对映异构体的NMR光谱。但是，这也没有提供可靠的分配。最终，通过制备三种非对映异构体解决了这一难题，其中所有化合物6在所有分析和光谱方面均被证明与扁桃苷A相同。由于6中四氢呋喃环的整个北部区域显示出与最初指定的构型相反的构型，因此很有可能必须类似地校正姊妹化合物曼荼罗酯B-D的立体结构;我们建议这些天然产物由结构68-70准确表示。为了证明这种重新分配，试图通过使6的合成的高级中间体经历基本上空前的分子内Morita-Baylis-Hillman反应，从而使-内酯衍生物74成为非对映异构体的混合物，从而进入曼荼罗C和D。 。通过使用OsO4 / TMEDA作为试剂，可将（24R）-74进行羟基定向的二羟基化反应，而姊妹化合物（24S）-74则没有遵循直接的路线，只是遵循了Kishi的规则。只有这种意外的逃逸才阻止了通过该路线制备曼荼罗利德C和D。光谱和计算（DFT）的组合研究表明，这两种74的非对映异构体具有如此显着不同的行为的原因是由于它们的构象特殊性。从这个方面来看，我们的结果表明，即使存在其他富含电子且受累较少的烯烃，OsO4 / TMEDA络合物也会优先与缺电子双键反应。最后，在简短的生物学调查中，发现真实的mandelalideA（6）仅对三种测试的人类癌细胞系中的一种表现出明显的细胞毒性，并且所有合成同源物几乎没有活性。没有观察到明显的杀真菌特性。

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