Construction of the "left domain" of haplophytine.
Construction of the "left domain" of haplophytine.
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DOI：
10.1002/anie.200701947
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发表时间：
2007-06
影响因子：
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通讯作者：
K. Nicolaou;K. Nicolaou;K. Nicolaou;U. Majumder;Stéphane P. Roche;D. Chen
中科院分区：
文献类型：
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作者：
K. Nicolaou;K. Nicolaou;K. Nicolaou;U. Majumder;Stéphane P. Roche;D. Chen
单植酸碱(1，图1)是一种具有杀虫特性的结构上耐人寻味的合成令人望而生畏的异二聚体生物碱。最初是由Snyder和他的同事[1a-d]于1952年从墨西哥植物单叶单胞菌中分离出来的，由于对Cava，[1e，h]Yates，[1f，h]和Zacharias基团的开创性研究，单藻基团的结构终于在1973年被揭示。单藻基团由一个中心吲哚部分组成，上面有两个四环杂环连接，右边的一个融合在吲哚系统上，而左边的一个通过空间要求很高的碳-碳键(C9‘-C15)连接到吲哚的芳香核上。单藻蛋白分子的两个重叠结构域被指定为截断的单藻蛋白(2，“左结构域”，图1)和顶藻蛋白(3，“右结构域”，图1)。虽然已经报道了四种天然存在的天冬氨酸的全合成(3)，[2]从1999年科里·S的精彩合成开始，[2a]单叶植物的“左”结构域与吲哚部分的连接具有挑战性，至今仍是一个棘手的合成问题。[3]我们现在报告化合物2的结构(图1)，它是单叶植物碱(1)的截短版本，包含天然产物的整个“左翼”骨架，包括它的六个环和它的C9‘-C15键。在生物合成考虑和降解研究的基础上，[1H]我们设想吲哚衍生物4和5(图1)将成为构建所需单叶植物骨架的潜在关键构件。一种可能的方案是，它们的偶联能够提供它们之间所需的但具有挑战性的碳-碳键(C15-C9‘，单藻编号)，即用适当的试剂激活其中一种以进行亲核攻击，并允许另一种充当传入的亲核剂。为了验证这一假设，我们着手合成4和5。
Haplophytine (1, Figure 1) is an architecturally intriguing and synthetically daunting heterodimeric alkaloid endowed with insecticidal properties. Originally isolated in 1952 by Snyder and co-workers [1a–d] from the Mexican plant Haplophyton cimicidum, the structure of haplophytine was finally revealed in 1973 as a result of the pioneering studies of the groups of Cava,[1e, h] Yates,[1f, h] and Zacharias.[1f, g] The haplophytine molecule consists of a central indole moiety onto which two tetracyclic heterocycles are attached, the one on the “right” fused onto the indole system, and the one on the “left” bridged through a sterically demanding carbon–carbon bond (C9’–C15) to the aromatic nucleus of the indole. The two overlapping domains of the haplophytine molecule are designated as truncated haplophytine (2,“left domain”, Figure 1) and aspidophytine (3,“right domain”, Figure 1). While four total syntheses have already been reported for the naturally occurring aspidophytine (3),[2] beginning with Corey s brilliant synthesis in 1999,[2a] the “left” domain of haplophytine with its challenging connectivity to the indole moiety remains to this day as a thorny synthetic problem.[3] We now report the construction of compound 2 (Figure 1), a truncated version of haplophytine (1) housing the entire “left wing” skeleton of the natural product, including six of its rings and its C9’–C15 bond.On the basis of biosynthetic considerations and degradation studies,[1h] we envisioned indole derivatives 4 and 5 (Figure 1) to be potential key building blocks for constructing the required haplophytine skeleton. A possible scenario for their coupling to afford the desired but challenging carbon–carbon bond between them (C15–C9’, haplophytine numbering) would be to activate one of them with a suitable reagent towards nucleophilic attack and allow the other to act as an incoming nucleophile. To test this hypothesis, we set out to synthesize 4 and 5.