Catalytic Selective Cyclizations of Aminocyclopropanes: Formal Synthesis of Aspidospermidine and Total Synthesis of Goniomitine
Catalytic Selective Cyclizations of Aminocyclopropanes: Formal Synthesis of Aspidospermidine and Total Synthesis of Goniomitine
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DOI：
10.1002/anie.201001853
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Waser, Jerome
中科院分区：
文献类型：
--
作者：
De Simone, Filippo;Gertsch, Juerg;Waser, Jerome
多杂环结构存在于大多数具有重要生物活性的天然和合成分子中。[1]因此，发现新的有效的环化反应对于获得天然产物和探索具有潜在增强的生物活性的广泛的复杂支架是重要的。[2]我们最近报道了乙烯基环丙基酮的第一个催化的正式均Nazarov环化反应，用于合成环己烯酮（方案1a）。[3]与二乙烯基酮的纳扎罗夫环化反应得到环戊烯酮不同，[4]同纳扎罗夫环化反应的例子很少，需要化学计量的强刘易斯酸或高温。[5]在我们的工作中开发的温和催化条件使我们能够将我们的方法应用于几种前所未有的杂环结构，但反应的范围受到富电子芳香基团的存在的限制，以稳定形成的碳阳离子中间体A。杂原子还应该能够稳定所形成的碳阳离子，如通过供体-受体环丙烷的丰富化学所证明的。[6]氨基环丙烷尤其可导致许多生物学相关生物碱的稠合氨基环己烷核心（在方案1中R1= N）。酰基吲哚取代的氨基环丙烷1的环化将构成Aspidosperma生物碱的一般条目，如aspidospermidine（2;方案1b）。在环化中获得的四环核心不仅存在于Aspidosperma家族中，而且存在于更复杂的天然产物如长春碱和长春新碱中，它们是癌症治疗的一线药物。[7]尽管在过去，具有合成挑战性的结构和潜在的医学应用的结合导致了大量成功的aspidospermidine的全合成[8]，但仍然需要开发更通用和灵活的合成方法来获得新的类似物。本文报道了第一个氨基环丙烷的同型Nazarov环合反应及其在aspidospermidine（2）的全合成中的应用。此外，我们证明了反应条件的简单修改如何导致goniomitine（3）的支架，goniomitine是一种从树Gonioma malagasy中分离的吲哚生物碱，[9]从氨基环丙烷1开始。与Aspidosperma支架相比，goniomitine环系统在天然产物中是独特的，迄今为止仅报道了两种全合成。[9b基于我们的环化策略，完成了高诺米汀（3）的有效全合成，并且我们在此首次研究了其生物活性，揭示了对几种癌细胞系（包括长春碱和紫杉醇抗性P-糖蛋白）的显著细胞毒性（Pgp，MDR-1）我们的研究开始于检查简单模型系统4的环化，该系统4含有衍生自过表达细胞的氨基环丙烷。未取代的四氢吡啶环和N-甲基吲哚（方案2）。[10]我们开发的用于催化均-Nazarov环化的标准条件是非常成功的，并且反应以90%的产率发生，对于顺式稠合产物5具有高的非对映选择性。[11]这一结果表明氨基甲酸酯也是环化反应的优良活化基团。受到这一有希望的结果的鼓舞，我们随后合成了Aspidosperma生物碱核心所需的乙基取代的环丙烷12（方案3）。羧酸10的合成是使用稍微改性的合成方法完成的。
Polyheterocyclic structures are present in most natural and synthetic molecules with important biological activity.[1] Therefore, the discovery of new efficient cyclization reactions is important to access natural products and to explore a broad range of complex scaffolds with potentially enhanced bioactivity.[2] We have recently reported the first catalytic formal homo-Nazarov cyclization of vinyl cyclopropyl ketones for the synthesis of cyclohexenones (Scheme 1 a).[3] In contrast to the well-established Nazarov cyclization of divinyl ketones to give cyclopentenones,[4] examples of homo-Nazarov cyclizations are rare and require stoichiometric amounts of strong Lewis acids or high temperatures.[5] The mild catalytic conditions developed in our work allowed us to apply our method to several unprecedented heterocyclic structures, but the scope of the reaction was limited by the required presence of an electron-rich aromatic group to stabilize the formed carbocationic intermediate A. A heteroatom should also be able to stabilize the formed carbocation, as demonstrated by the rich chemistry of donor–acceptor cyclopropanes.[6] Aminocyclopropanes in particular may lead to the fused aminocyclohexane core of numerous biologically relevant alkaloids (R1= N in Scheme 1). Cyclization of an acyl indole substituted aminocyclopropane 1 would constitute a general entry into the Aspidosperma alkaloids, such as aspidospermidine (2; Scheme1b). The tetracyclic core obtained in the cyclization is present not only in the Aspidosperma family, but also in more complex natural products such as vinblastine and vincristine, which are frontline drugs in cancer therapy.[7] Although the combination of synthetically challenging structures and potential medical applications has resulted in a large number of successful total syntheses of aspidospermidine in the past,[8] the development of more general and flexible synthetic approaches is still required to access new analogues. Herein, we report the first example of the formal homo-Nazarov cyclization of aminocyclopropanes and its application in the formal total synthesis of aspidospermidine (2). Additionally, we demonstrate how a simple modification in reaction conditions leads to the scaffold of goniomitine (3), an indole alkaloid isolated from the tree Gonioma malagasy,[9] starting from aminocyclopropane 1. In contrast to the Aspidosperma scaffold, the goniomitine ring system is unique in natural products, and only two total syntheses have been reported so far.[9b, c] Based on our cyclization strategy, an efficient total synthesis of goniomitine (3) was accomplished and we present herein the first study of its bioactivity, revealing significant cytotoxicity against several cancer cell lines, including vinblastine and taxol-resistant P-glycoprotein (Pgp, MDR-1) overexpressing cells.We began our research by examining the cyclization of the simple model system 4 containing the aminocyclopropane derived from the unsubstituted tetrahydropyridine ring and a N-methylindole (Scheme 2).[10] Our standard conditions developed for the catalytic homo-Nazarov cyclization were highly successful and the reaction occurred in 90% yield with high diastereoselectivity for the cis-fused product 5.[11] This result demonstrated that carbamates were also excellent activating groups for the cyclization reaction. Encouraged by this promising result, we then synthesized the ethyl-substituted cyclopropane 12 required for the core of the Aspidosperma alkaloids (Scheme3). The synthesis of carboxylic acid 10 was accomplished using a slightly modified