Aspidosperma alkaloids have a pentacyclic skeleton (ABCDE) imbedded in an indoline structure. These molecules are known to have significant biological activities, and the class includes the antitumor agents vincristine and vinblastine. Deethylaspidospermidine is the parent structure for Aspidosperma alkaloids and as such has been the primary target for most of the attempts towards Aspidosperma alkaloid synthesis. Many synthetic approaches have been tried, including the intramolecular cascade transannular cyclization approach, the palladium[0]-catalyzed Ullmann cross coupling approach, and the oxidative Hosomi–Sakurai approach. In addition, significant efforts have been devoted to synthesize deethylaspidospermidine. The reported methods for the synthesis of these compounds have been limited. Therefore, we have decided to seek a shorter and more efficient route to the pyrido[3,2-c]carbazole, a key structural feature in Aspidosperma alkaloids such as melotenenine A, deethylaspidospermidine, ibophylidine and aspidospermidine, itself (Figure 1). In this vein, we previously reported a new synthetic strategy for the total synthesis of the alkaloid 20-deethyl-4-demethyldasycarpidone featuring an intramolecular cylization mediated by 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ), and an intramolecular aldol reaction. We now report an extension of this approach that leads to the total synthesis of deethylaspidospermidine (7). Our approach to the synthesis of 7 is outlined in Scheme 1 and targets hexahydropyrido[3,2-c]carbazole (3). It was hoped that the reduction of the nitrile group would lead to the generation of the skeleton of 3 in line with previously described work. To achieve this aim progenitor compound 1 was prepared from tetrahydrocarbazole through a benzylation reaction, followed by DDQ oxidation. Compound 1 was alkylated with 3-bromopropionitrile and reductively cyclized. The imine (3) was then converted to the alcohol (4) in accordance with previously described methods. We chose a one-pot treatment of imine 3 with ethylene oxide in the presence of montmorillonite K10 for opening of the epoxide ring, which led to an of overall yield of 81% for two steps. Deprotection of 4 in THF resulted in 5 with a yield of 86%. Compound 5 was mesylated in 76% yield. In the final step, treatment of 6 with LiAlH4 was utilized to complete the synthesis of deethylaspidospermidine.

中文翻译：

---

去乙基亚氨基亚精胺的简明全合成

Aspidosperma 生物碱具有嵌入二氢吲哚结构中的五环骨架 (ABCDE)。已知这些分子具有显着的生物活性，该类别包括抗肿瘤剂长春新碱和长春碱。Deethylaspidospermidine 是 Aspidosperma 生物碱的母体结构，因此一直是大多数 Aspidosperma 生物碱合成尝试的主要目标。已经尝试了许多合成方法，包括分子内级联跨环环化方法、钯[0]催化的 Ullmann 交叉偶联方法和氧化 Hosomi-Sakurai 方法。此外，大量的努力已经致力于合成 deethylaspidospermidine。报道的这些化合物的合成方法受到限制。所以，我们决定寻找一种更短、更有效的途径来获得吡啶并 [3,2-c] 咔唑，这是 Aspidosperma 生物碱的一个关键结构特征，如 melotenine A、deethylaspidospermidine、ibophylidine 和 aspidospermidine，本身（图 1）。在这方面，我们之前报道了一种全合成生物碱 20-deethyl-4-demethyldasycarpidone 的新合成策略，其特征是由 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ) 介导的分子内环化，和分子内醛醇反应。我们现在报告了这种方法的扩展，导致 deethylaspidospermidine 的全合成 (7)。方案 1 中概述了我们合成 7 的方法，目标是六氢吡啶并 [3,2-c] 咔唑 (3)。希望腈基的还原将导致生成与先前描述的工作一致的 3 骨架。为实现这一目标，从四氢咔唑通过苄基化反应制备前体化合物 1，然后进行 DDQ 氧化。化合物 1 用 3-溴丙腈烷基化并还原环化。然后根据先前描述的方法将亚胺(3)转化为醇(4)。我们选择在蒙脱石 K10 存在下用环氧乙烷一锅处理亚胺 3 以打开环氧化物环，这导致两步的总产率为 81%。4 在 THF 中脱保护得到 5，产率为 86%。化合物 5 以 76% 的产率被甲磺酰化。在最后一步中，使用 LiAlH4 处理 6 以完成去乙基蜘蛛精胺的合成。