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.

项目摘要，摘要 该程序的目的是为立体控制化学制定广泛有效的化学反应 与化学家和药物学家的复杂结构合成。研究计划分为 两个具体的目标，每个开放式访问不同类别的天然产品。 AIM 1描述了 开发未探索的，可爱的冠状动物重排，该重排允许C2功能化 吲哚的位置，从而实现了2,2二取代的吲哚碱的立体控制，不对称的合成 衍生物。这种新的Claisen重排转换将纳入高效的设计 含吲哚天然产品的策略。 AIM 2提出了两个[4+3] -Cycloadition的开发 基于合成吲哚融合的环形烷的途径以及该化学的应用 复杂和生物活性歧义天然产物的合成。整个研究计划得到支持 以引人注目的初步结果，合成应用旨在最大程度地使用 方法学，同时解决复杂靶标提出的未满足的综合挑战。新化学 预计将对参与药物开发的有机和药物化学家广泛有用， 化学合成和天然产品研究。总合成工作的最终产品和许多 高级中间体将提交给筛查设施进行生物测试。拟议的项目 将为研究生和化学综合的博士后同事提供出色的培训 解决问题，为制药行业和学术界成功职业做好准备。