Myrtoidine and malagashanine, highly complex indole alkaloids, are effective adjuvant in developing cures for plasmodium malaria and also potent multi-drug resistant agents. Despite nearly 30 years of progress, myrtoidine and related a family of other Malagasy alkaloids still present formidable challenges for synthetic chemists. A diastereoselective [2+2+2] tandem cyclization reaction with alkyl substituted methylene malonate was developed, enabling the highly efficient collective total synthesis of four Malagasy alkaloids within 10–13 steps from commercial available tryptamines. The synthetic strategy includes rapid and highly stereoselective assembly of the tetracyclic indoline core containing 5–7 contiguous stereogenic carbon centers, which is rarely seen in indole alkaloids. Among the four natural products, (±)-myrtoidine, (±)-11-demethoxymyrtoidine and (±)-12-hydroxymalagashanine were synthesized for the first time, and the work on (±)-malagashanine represented the shortest synthetic route so far. This work should enable further explorations of chemical and biological spaces based on myrtoidine, malagashanine, and related natural products.

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中文翻译：

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烷基取代亚甲基丙二酸酯催化[2+2+2]串联环化实现四种马达加斯加生物碱的简明全合成

Myrtoidine 和 malagashanine 是高度复杂的吲哚生物碱，是开发疟原虫治疗药物的有效佐剂，也是有效的多药耐药剂。尽管取得了近 30 年的进步，但桃金娘苷和相关的其他马达加斯加生物碱家族仍然给合成化学家带来了巨大的挑战。开发了与烷基取代的亚甲基丙二酸酯的非对映选择性 [2+2+2] 串联环化反应，能够在 10-13 步内从市售的色胺中高效地集体全合成四种马达加斯加生物碱。合成策略包括快速和高度立体选择性组装含有 5-7 个连续立体碳中心的四环二氢吲哚核心，这在吲哚生物碱中很少见。在四种天然产物中，(±)-myrtoidine，首次合成了(±)-11-demethoxymyrtoidine和(±)-12-hydroxymalagashanine，(±)-malagashanine的工作代表了迄今为止最短的合成路线。这项工作应该能够进一步探索基于 myrtoidine、malagashanine 和相关天然产物的化学和生物空间。

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