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

新型脱芳香吲哚成环反应、贝克曼断裂及其在合成中的应用

• 批准号: 10501186
• 负责人: JIMMY WU
• 金额: $ 39.58万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501186
• 关键词: 1,3-Butadiene; Active Sites; Address; Alkaloids; Antineoplastic Agents; Binding; Biological; Cancer cell line; Cations; Chemicals; Clinical; Complex; Development; Elements; Goals; Heterocyclic Compounds; Hydrogen Bonding; Indoles; Intercept; Ketones; Lysine; Medicine; Methods; Microtubules; Modification; Molecular; Molecular Structure; Monoterpenes; Natural Products; Nature; Organic Chemistry; Pattern; Process; Property; Reaction; Reporting; Research; Resistance; Route; Sodium Chloride; Strategic vision; Structure; System; Technology; Therapeutic; Variant; Vinblastine; analog; anthropogenesis; base; carboxylate; chemical reaction; chemical synthesis; design; dosage; indoline; innovation; interest; invention; member; novel; refractory cancer; side effect

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.

该提案的总体目标是开发基于以下成环反应的新化学技术： 氧烯丙基阳离子，然后将所得产物片段化，以提供新的分子实体， 生物医学的兴趣。这一贡献是重要的，因为它将推动跨学科的发现， 为具有重要生物学性质的结构独特的二氢吲哚生物碱提供了合成方法。 这个项目是创新的，因为我们将制定一个统一的战略愿景，使我们的目标 分子以及属于几种重要的单萜二氢吲哚生物碱类的化合物。 因此，我们将追求以下三个具体目标。目标#1：完成全合成 番木鳖色胺和卡布克林，目标#2：开发结构信息长春碱的有效途径 目标#3：发明新的（3+2）环化和贝克曼片段化 反应.番木鳖色胺是在自然界或人类起源中发现的唯一分子， 所述密集官能化的五环系统包括其核。它被发现有抗原生动物 迄今为止还没有报道番木鳖色胺的全合成。Cabucraline是一种Akuammiline 一种生物碱，与以前合成的所有其他C2构型的生物碱不同 立体中心，这是以前从未有过的。它的综合将需要一部小说的发展 与杂环氧基烯丙基阳离子的区域选择性（3+2）成环反应。拟定的长春碱类似物 由于前所未有的C7羧酸盐和C3−C5的结构修饰而独特。自然 长春碱是一种抗癌药物，被列入世界卫生组织基本药物清单，但其临床用途是 伴随着不希望的副作用。此外，长春碱耐药癌细胞系正在成为 越来越成问题。由于其预测的更大功效，我们假设这些变体可能需要 维斯长春碱维斯，治疗剂量更小，从而导致不良副作用的发生率更低， 方面的影响.类似物的结构差异也可能解决与长春碱耐药性相关的问题。所有 在前两个具体目标中提出的合成方法中，有一个是以新的脱芳（3+2）吲哚为特征的 我们的研究小组发现了环化和碎裂。在第三个目标中，我们寻求发展 通过应用显着拓宽我们脱芳香（3+2）环化技术范围的策略 产生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 导致形成致密官能化的四氢咔唑产物的串联方法， 独特和立体定向的取代模式。