Novel Dearomative Indole Annulation Reactions, Beckmann Fragmentations, and Their Applications to Synthesis

这项提议的总体目标是开发基于环状反应的新化学技术。 氧烯丙基阳离子随后裂解生成的产物以提供新的分子实体 对生物医学感兴趣。这一贡献意义重大，因为它将通过以下方式推动跨学科发现 提供具有重要生物学特性的结构独特的吲哚生物碱的合成方法。 这个项目是创新的，因为我们将制定一个统一的战略愿景，以实现我们的目标 分子，以及属于几个重要类别的单萜吲哚生物碱的化合物。 因此，我们将追求以下三个具体目标。目标1：完成全合成 士的诺色胺和卡布卡林，目标2：开发一种有效的途径来获得结构信息的长春花碱 具有新的C7羧酸盐的变体，目标#3：发明新的(3+2)环状和Beckmann碎裂 反应。士的诺色胺是自然界中发现的或人类起源的唯一一种具有 包括其核心的稠密功能化的五环环系。它被发现具有抗原虫作用。 到目前为止，还没有报道士的诺色胺的活性和全合成。卡布卡林是一种阿夸米林 不同于以前在C2构型下合成的所有其他成员的生物碱 立体中心，这是以前从未制造过的。它的合成将需要开发一部小说 与杂环氧烯丙基阳离子的区域选择性(3+2)环化反应。建议的长春花碱类似物 是独一无二的，因为C3−C5上前所未有的C7羧酸盐和结构修饰。天然 长春花碱是世界卫生组织基本药物清单上的一种抗癌药物，但其临床用途是 伴随着不良的副作用。此外，对长春花碱耐药的癌细胞株正在成为 问题越来越多。由于其预测的更大疗效，我们假设这些变种可能需要 与长春花碱相比，治疗剂量较小，从而导致不良反应的发生率较低。 效果。类似物的结构差异也可能解决与长春花碱耐药相关的问题。全 在前两个特定目标的建议合成中，将以新型脱芳烃(3+2)吲哚为特色 我们的研究小组发现了环状结构和碎裂结构。在第三个目标中，我们寻求发展 显著扩大我们的(3+2)除芳烃环化技术范围的策略 生成关键活性氧烯丙基阳离子中间体的创新方法。简而言之，我们将发明新的 串联过程，导致形成具有浓密官能化的四氢咔唑产物 独特的、固定定义的替换模式。

The overall goal of this proposal is to develop new chemical technologies based on ring-forming reactions of oxyallyl cations followed by fragmentation of the resultant products to deliver novel molecular entities that are of biomedical interest. This contribution is significant because it will fuel cross-disciplinary discoveries by providing synthetic approaches to structurally unique indolines alkaloids with important biological properties. This project is innovative because we will develop a unified strategic vision for making both our target molecules and also compounds belonging to several important classes of monoterpene indoline alkaloids. Thus, we will pursue the following three specific aims. Aim #1: Complete the total synthesis of strychnochromine and cabucraline, Aim #2: Develop an efficient route to structurally-informed vinblastine variants with a novel C7 carboxylate, and Aim #3: Invent new (3+2) annulation and Beckmann fragmentation reactions. Strychnochromine is the only molecule found in nature or of anthropogenic origin that possesses the densely-functionalized pentacyclic ring system comprising its core. It was found to have anti-protozoal activity and no total synthesis of strychnochromine has been reported to date. Cabucraline is an akuammiline alkaloid that is distinct from all the other members previously synthesized at the configuration of the C2 stereocenter, and it has never been made before. Its synthesis will require the development of a novel regioselective (3+2) annulation reaction with a heterocyclic oxyallyl cation. The proposed vinblastine analogue is unique by virtue of the unprecedented C7 carboxylate and structural modifications at C3−C5. Natural vinblastine is an anti-cancer drug that is on the WHO list of essential medicines, but its clinical use is accompanied by undesirable side-effects. In addition, vinblastine-resistant cancer cell lines are becoming increasingly problematic. Due to its predicted greater efficacy, we hypothesize that these variants may require smaller therapeutic dosages vis-à-vis vinblastine, thereby resulting in lower occurrences of adverse side- effects. Structural differences of the analogues may also address issues related to vinblastine resistance. All of the proposed syntheses in the first two specific aims will feature the novel dearomative (3+2) indole annulation followed by fragmentation discovered by our research group. In the third aim, we seek to develop strategies that significantly broaden the scope of our dearomative (3+2) annulation technology by applying innovative methods for generating key reactive oxyallyl cation intermediates. In short, we will invent new tandem processes that result in the formation of densely-functionalized tetrahydrocarbazoles products with unique and stereodefined substitution patterns.