Total synthesis of (±)-axinellamines A and B
Total synthesis of (±)-axinellamines A and B
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DOI：
10.1002/anie.200801138
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Baran, Phil S.
中科院分区：
文献类型：
--
作者：
O'Malley, Daniel P.;Yamaguchi, Junichiro;Baran, Phil S.
Quinn 及其同事于 1999 年分离出 axinellamines（1, 2，图 1），是迄今为止分离出的最复杂的海洋天然产物之一。 [1]这些分子的复杂结构包括具有八个连续立体中心的四环双胍核心。 1和2中存在的两个胍单元的高极性性质使处理此类分子的实际方面进一步复杂化。事实上，与马萨丁胺和帕劳胺（参见前面的结构通讯中的图 1）一起，[2] 这些分子代表了化学合成的复杂性前沿。尽管许多团体做出了广泛的努力，但迄今为止这个难题的解决方案仍然难以捉摸。[3, 4] 在此，我们首次提出了axinellamines A (1)和B (2)的全合成。之前的通讯报告了1, 9-双脱氧-pre-axinellamine的合成(3)，[2]这是实证检验“前axinellamine”生物发生假说（路径A，图1）复杂形成的关键的第一步。二聚吡咯-咪唑生物碱（PIA）。[3]在该工作过程中，我们发现中间体中的螺环胍单元（例如 4）（图 1）很容易取代 C-5（axinellamine 编号）处的离去基团形成 5，从而建立在 axinellamine 中发现的 N-4ÀC-5 键。尽管化合物 5 的形成是 1, 9-二脱氧-前axinellamine (3) 合成过程中必须克服的障碍，但人们认识到，这种闭环的便利性提供了通过 6 选择性靶向 axinellamine 家族的机会（路径 B，图 1）；通过通过亚胺 7 等中间体建立 N-4ÀC-5 连接，可以避免马萨丁、帕劳胺或苯乙烯胍型闭环的干扰。在连接吡咯侧链并在 C-1 处氧化之前，先对 axinellamines 的四环核心进行加工，这被证明是一种成功的策略，如方案 1 所示。
The axinellamines (1, 2, Figure 1), isolated by Quinn and coworkers in 1999, are among the most complex marine natural products isolated to date.[1] The intricate architecture of these molecules includes a tetracyclic bisguanidine core with eight contiguous stereocenters. The highly polar nature of the two guanidine units present in 1 and 2 further complicate the practical aspects of dealing with such molecules. Indeed, together with the massadines and palau amines (see Figure 1 in the preceeding communication for structures),[2] these molecules represent a complexity frontier for chemical synthesis. Despite extensive efforts by many groups, a solution to this puzzle has thus far remained elusive.[3, 4] Herein, we present the first total synthesis of axinellamines A (1) and B (2).The preceding communication reported the synthesis of 1, 9-dideoxy-pre-axinellamine (3),[2] a pivotal first step towards empirically testing the “pre-axinellamine”-biogenetic hypothesis (Path A, Figure 1) for the formation of complex dimeric pyrrole-imidazole alkaloids (PIA).[3] During the course of that work, it was found that the spirocyclic guanidine unit in intermediates such as 4 (Figure 1) would readily displace leaving groups at C-5 (axinellamine numbering) to form 5, thereby establishing the N-4ÀC-5 bond found in the axinellamines. Although the formation of compound 5 represented a hurdle that had to be overcome during the synthesis of 1, 9-dideoxy-pre-axinellamine (3), it was recognized that the facility of this ring closure provided an opportunity to target the axinellamine family selectively via 6 (Path B,, Figure 1); by forging the N-4ÀC-5 connection by way of an intermediate such as imine 7, interference by massadine, palau amine, or styloguanidine type ring closures could be avoided. Elaboration of the tetracyclic core of the axinellamines prior to attachment of the pyrrole side chains and oxidation at C-1 proved to be a successful strategy, as demonstrated in Scheme 1.