The Synthesis of Bioactive Polycyclic Natural Products

生物活性多环天然产物的合成

• 批准号: 9886091
• 负责人: BRIAN M STOLTZ
• 金额: $ 34.88万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-02 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886091
• 关键词: Acylation; Alkaloids; Alkylation; Anti-Cholinergics; Applications Grants; Architecture; Area; Biological; Biology; Breathing; California; Carbon; Catalysis; Chemicals; Chemistry; Complement; Complex; Copper; Development; Discipline; Elements; Government; Human; Indole Alkaloids; Industrialization; Inorganic Chemistry; Institutes; Investigation; Iridium; Laboratories; Medicine; Methodology; Methods; Molecular; Molecular Biology; Monoterpenes; Multi-Drug Resistance; Natural Products; Nickel; Organic Chemistry; Organic Synthesis; Organometallic Chemistry; Palladium; Pharmaceutical Chemistry; Preparation; Process; Production; Public Health; Reaction; Research; Rest; Route; Science; Series; Structure; Synthesis Chemistry; System; Techniques; Technology; Testing; Work; arm; c new; chemical synthesis; cytotoxic; enolate; invention; new technology; novel; novel strategies; physical property; programs; research and development; tool

Project Summary/Abstract: The objective of this research program is to discover and develop new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the investigation and optimization of technologies that enable the synthesis of core structural and stereochemical subunits prevalent in many bioactive, polycyclic natural products. The processes that we develop will find utility in the synthesis of a variety of structures for which there are currently no efficient synthetic roadmaps. Importantly, the methods presented in this application will be useful outside of the contexts described herein and will arm practitioners of synthetic chemistry (in academic, government, and industrial laboratories) with a new set of important tools to access enantioenriched and functionally diverse chemical building blocks for synthesis. The research proposed in this grant application is focused on a) the development of new palladium- and iridium-catalyzed stereoselective alkylation reactions that produce densely substituted, acyclic building blocks for synthesis, b) the development of novel nickel- and copper-catalysis for asymmetric alkylation and acylation processes, c) the development of these novel methods specifically for the preparation of all-carbon quaternary stereocenters and arrays of quaternary centers, and d) the implementation of these new tactics in the syntheses of highly complex, bioactive bis-indole alkaloids. Specifically, we outline approaches to leucophyllidine, strempeliopidine, and norpleiomutine. These molecules are not only important from a biological standpoint, they also serve as a testing ground for our new technologies. As a consequence of this approach, we will have access to a) novel, medicinally relevant structures, b) a general platform for their synthesis, and c) new synthetic methodology that will impact a host of diverse applications.

项目摘要/摘要： 这项研究计划的目标是发现和发展新的反应 合成复杂生物活性分子的方法学。我们的建议 研究的重点将是调查和优化能够使 合成许多生物活性物质中普遍存在的核心结构和立体化学亚基， 多环天然产物。我们开发的流程将在 合成各种结构，目前还没有有效的合成方法 路线图。重要的是，本应用程序中提供的方法在外部也很有用 并将武装合成化学从业者(在 学术、政府和工业实验室)具有一套新的重要工具 获取用于合成的富含对映体和不同功能的化学构件。 在这项赠款申请中提出的研究重点是a)发展 Pd和Ir催化的新型立体选择性烷基化反应 用于合成的密集取代的、非环的构筑基团，b)新的 镍和铜催化的不对称烷基化和酰化过程，c) 开发这些专门用于制备全碳的新方法 第四级立体中心和第四级中心阵列，以及d)实施 这些新策略在合成高度复杂、生物活性的双吲哚生物碱中的应用。 具体地说，我们概述了亚亮氨酸、链培利匹定和 去甲普利奥马汀。这些分子不仅从生物学角度来说很重要， 它们也是我们新技术的试验场。其结果就是 方法，我们将有机会获得a)新颖的、与医学相关的结构，b)一般 它们的合成平台，以及c)新的合成方法，将影响一系列 多样化的应用。