Total Synthesis of Zoanthenol
Total Synthesis of Zoanthenol
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DOI：
10.1002/anie.200904537
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Miyashita, Masaaki
中科院分区：
文献类型：
--
作者：
Takahashi, Yu;Yoshimutra, Fumihiko;Miyashita, Masaaki
zoanthamine生物碱是由Zoanthus sp.产生的一类海洋代谢物，不仅具有一系列新颖的立体化学结构，而且具有独特的生物学和药理特性。例如，由Uemura等人从殖群虫Zoanthus sp.中分离出的norzoanthamine(1)，可以抑制去卵巢小鼠的体重下降，并增强骨骼，而没有不良的副作用[1]，因此是抗骨质疏松药物的有希望的候选物。此外，由Rao、Faulkner及其同事分离出的zoanthamine(2)对肉豆蔻酸磷诱导的炎症表现出强有力的抑制活性，同时具有强大的镇痛作用norzoanthamine和zoanthamine具有显著的生物学特性，再加上它们新颖的分子结构，使得这类生物碱作为合成靶点极具吸引力作为我们正在进行的zoanthamine生物碱合成研究的一部分，我们已经首次实现了1 [4a， c]和2的全合成。[4c]这些合成包括通过连续的三组分偶联反应立体选择性合成关键的三烯前体，一个关键的分子内diols - alder反应，以及随后的双（氨基）缩醛化作为关键的合成步骤。[4a]最近，Kobayashi和同事报道了1的第二次全合成，其中涉及一个优雅的分子内Diels-Alder反应，以构建AB环体系为关键步骤。在成功地化学合成了去甲氰胺和甲氰胺之后，我们重点合成了甲氰胺醇(3)，[6]是甲氰胺类生物碱的一员，它具有独特的芳香环。与去甲氰胺衍生物一样，已发现甲氰胺醇对人类血小板聚集具有有效的抗血小板活性尽管许多研究小组采用各种不同的策略进行了合成研究，但3的总合成尚未成功完成。[8-10]在此，我们报道了首次在合成1，[4a， c]的过程中使用合成中间体11合成了zoanthanol 3，并开发了一条从市售的norzoanthamine hydrochloride（1·HCl）到3的高效合成路线。
The zoanthamine alkaloids, a family of marine metabolites produced by the zoanthid Zoanthus sp., not only have a novel array of structures with stereochemical complexity, but also exhibit distinctive biological and pharmacological properties. For example, norzoanthamine (1), isolated from the colonial zoanthid Zoanthus sp. by Uemura et al., can suppress the loss of the weight of, and strengthen, bones in ovariectomized mice without problematic side effects [1] and thus is a promising candidate for an anti-osteoporotic drug. Furthermore, zoanthamine (2), isolated by Rao, Faulkner and co-workers, exhibits potent inhibitory activity toward phorbol myristateinduced inflammation, along with powerful analgesic effects.[2] The remarkable biological properties of norzoanthamine and zoanthamine, combined with their novel molecular architectures, make this family of alkaloids extremely attractive as synthetic targets.[3] As part of our ongoing synthetic studies of the zoanthamine alkaloids, we have achieved the first total syntheses of 1 [4a, c] and 2.[4c] These syntheses involved a stereoselective synthesis of the crucial triene precursor using sequential three-component coupling reactions, a key intramolecular Diels–Alder reaction, and subsequent bis-(amino) acetalization as the key synthetic steps.[4a] Recently, Kobayashi and co-workers reported the second total synthesis of 1, which involved an elegant intramolecular Diels–Alder reaction for the construction of the AB ring system as the key step.[5]Having achieved the efficient chemical syntheses of norzoanthamine and zoanthamine, we focused on the synthesis of zoanthenol (3),[6] a member of the zoanthamine alkaloids which is unique as it has an aromatic ring. As with the norzoanthamine derivatives, zoanthenol has been found to exhibit potent anti-platelet activity for human platelet aggregation.[7] In spite of synthetic studies by a number of research groups, employing a variety of distinct strategies, the total synthesis of 3 has yet to be successfully completed.[8–10] Herein, we report the first total synthesis of zoanthenol 3, using a synthetic intermediate 11 in our synthesis of 1,[4a, c] and the development of an efficient synthetic route from the commercially available norzoanthamine hydrochloride (1· HCl) to 3.