New Methods and Strategies for the Concise Synthesis of Complex Indole Alkaloids

复杂吲哚生物碱的简洁合成新方法和新策略

• 批准号: 10345351
• 负责人: VIRESH H. RAWAL
• 金额: $ 30.68万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345351
• 关键词: Academia; Address; Alkaloids; Biological Testing; Catalysis; Cations; Chemistry; Claisen rearrangement; Communities; Complex; Cycloheptanes; Development; Development Plans; Drug Industry; Family; Funding; Goals; Government; Indole Alkaloids; Indoles; Investigation; Methodology; Methods; Natural Products; Organic Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Postdoctoral Fellow; Preparation; Problem Solving; Process; Reaction; Research; Route; Skeleton; Structure; Training; Work; base; bioactive natural products; career; chemical synthesis; cycloaddition; design; drug development; graduate student; indoline; innovation; interest; member; novel; programs; screening; skills training; tool; undergraduate student

PROJECT SUMMARY, ABSTRACT The objective of this program is to develop broadly effective chemistry for the stereocontrolled chemical synthesis of complex structures of use to chemists and medicinal chemists. The research plan is divided into two Specific Aims, each opening access to distinct classes of natural products. Aim 1 describes the development of an unexplored, dearomative-Claisen rearrangement, which allows functionalization of the C2 position of indoles, thereby enabling the stereocontrolled, asymmetric synthesis of 2,2-disubstituted indoline derivatives. This new Claisen rearrangement transform will be incorporated into the design of efficient strategies to indoline-containing natural products. Aim 2 presents the development of two [4+3]-cycloaddition based routes for the synthesis of indole-fused cycloheptanes and the application of this chemistry to the synthesis of the intricate and bioactive ambiguine natural products. The research plan is supported throughout with compelling preliminary results, and the synthesis applications are designed to make maximal use of the methodology, while addressing unmet synthetic challenges posed by the complex targets. The new chemistry is expected to be broadly useful to organic and pharmaceutical chemists involved in drug development, chemical synthesis, and natural product research. The final products of the total synthesis efforts and many advanced intermediates will be submitted to a screening facility for biological testing. The proposed projects will provide excellent training to graduate students and postdoctoral associates in chemical synthesis and problem solving, preparing them for successful careers in the pharmaceutical industry and academia.

项目概要、摘要 该计划的目标是为立体控制化学品开发广泛有效的化学 化学家和药物化学家使用的复杂结构的合成。研究计划分为 两个具体目标，每个目标都开放获取不同类别的天然产品。目标 1 描述了 开发了一种未经探索的脱芳香-克莱森重排，使 C2 功能化 吲哚的位置，从而实现 2,2-二取代吲哚啉的立体控制、不对称合成 衍生物。这种新的克莱森重排变换将被纳入高效的设计中 含二氢吲哚天然产物的策略。目标 2 介绍了两种 [4+3]-环加成反应的发展 吲哚稠合环庚烷的合成路线及其在化学中的应用 复杂且具有生物活性的模糊天然产物的合成。研究计划得到全程支持 具有令人信服的初步结果，合成应用程序旨在最大限度地利用 方法，同时解决复杂目标带来的未满足的综合挑战。新化学 预计对参与药物开发的有机化学家和药物化学家广泛有用， 化学合成、天然产物研究。全合成努力的最终产品和许多 高级中间体将提交给筛选机构进行生物测试。拟议项目 将为化学合成和化学合成领域的研究生和博士后提供优秀的培训 解决问题，为他们在制药行业和学术界的成功职业生涯做好准备。