Total Syntheses of All the Amathaspiramides
Total Syntheses of All the Amathaspiramides
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DOI：
10.1002/anie.201109221
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Fukuyama, Tohru
中科院分区：
文献类型：
--
作者：
Chiyoda, Koji;Shimokawa, Jun;Fukuyama, Tohru
为了追求具有多种可获得同系物的高度功能化天然产物的可规模合成，我们认为由于它们在统一的核心骨架内的不同亚结构，合成amathaspiramidesA（1）-F（6）在概念上具有挑战性（图1）。Prinsep及其同事于1999年从新西兰收集的海洋苔藓虫Amathia wilsoni中分离出这些天然产物。[1]这些化合物的结构基序的特征在于致密官能化的二氮杂螺[3.3]壬烷框架，其在C-8处配备有令人感兴趣的稳定的N-酰基半缩醛胺，在C-9处连接到二溴甲氧基苯基的苄基中心，以及通过四取代的连接的可变吡咯烷部分。C-5处的螺环中心。在这些化合物中，氨乙酰螺酰胺A和E表现出抗脊髓灰质炎病毒1型的抗病毒活性、对BSC-1细胞的细胞毒性和对枯草芽孢杆菌的抗微生物活性。[1]此外，最近的报告已经证明结构相似的化合物是有前途的b-转角模拟物。[2]尽管有这些有价值的方面，天然样品的有限可用性阻碍了对这些分子及其类似物的进一步研究。在这六种化合物中，Trauner [3]和Ohfune小组仅报道了8 S成员amathaspiramideF的全合成。[4]在我们的合成研究的开始，我们设想建立一种可扩展的和通用的合成路线，以获得所有的氨基乙酰螺酰胺，其吡咯烷部分的范围包括环亚胺（5）、仲胺（3，6）和叔胺（1）到未取代的（4）和N-甲基半乳糖胺（2）。因此，需要系统的访问，以建立在C-8和可变的氧化态的螺吡咯烷单元从一个共同的中间体开始的配置。
In pursuit of the scalable synthesis of highly functionalized natural products with a diverse spectrum of accessible congeners, we considered it conceptually challenging to synthesize amathaspiramidesA (1)–F (6) owing to their diverse substructures within a uniform core skeleton (Figure1). Prinsep and co-workers isolated these natural products in 1999 from a New Zealand collection of the marine bryozoan Amathia wilsoni.[1] The structural motif of these compounds is characterized by the densely functionalized diazaspiro [3.3] nonane framework equipped with an intriguingly stable N-acyl hemiaminal at C-8, a benzylic center at C-9 linked to a dibromomethoxyphenyl group, and a variable pyrrolidine moiety connected through the tetrasubstituted spiro center at C-5. Among these compounds, amathaspiramides A and E exhibit antiviral activity against poliovirus type 1, cytotoxicity to BSC-1 cells, and antimicrobial activity toward Bacillus subtilis.[1] Furthermore, a recent report has proved structurally similar compounds to be promising b-turn mimetics.[2] Despite these valuable aspects, the limited availability of natural samples has hampered further investigations on these molecules and their analogues. Of these six compounds, total synthesis has been reported for only amathaspiramideF, an 8S member, by the Trauner [3] and Ohfune groups.[4] At the outset of our synthetic study, we envisioned establishing a scalable and versatile synthetic route to all amathaspiramides whose pyrrolidine moieties range over the cyclic imine (5), and secondary (3, 6) and tertiary amines (1) to unsubstituted (4) and N-methyl glactam (2). Therefore, a systematic access is required for establishing the configuration at C-8 and the variable oxidation states of the spiro pyrrolidine units starting from a common intermediate.