Synthesis of Diverse Natural Products and Complex Heterocycles with Donor/Donor Carbenoids

用供体/供体类胡萝卜素合成多种天然产物和复杂杂环

• 批准号: 10091475
• 负责人: Jared Thomas Shaw
• 金额: $ 35.42万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091475
• 关键词: Acute Disease; Address; Alkanes; Antibiotics; Architecture; Area; Biological Phenomena; Biology; Carbon; Chemicals; Chemistry; Chronic Disease; Complex; Dangerousness; Data; Development; Electrons; Exhibits; Future; Generations; Goals; Health; Hydrazones; Hydrogen; In Situ; Journals; Lead; Legal patent; Life; Literature; Medicine; Metabolic; Metals; Methodology; Methods; Mission; Natural Products; Nitrogen; Organic Chemistry; Organic Synthesis; Oxygen; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Process; Public Health; Reaction; Research; Rhodium; Science; Societies; Structure; Sulfur; System; Technology; Testing; Tetrahydroisoquinolines; Time; Translating; United States National Institutes of Health; Work; base; carbene; catalyst; chemical reaction; cycloaddition; diazo compound; disability; drug discovery; experimental study; functional group; high throughput screening; indoline; innovation; interest; molecular assembly/self assembly; next generation; novel; novel therapeutics; pharmacophore; small molecule

Project Summary/Abstract An urgent need exists for new methods to rapidly prepare complex organic molecules with the potential to become new drugs. There is a widening gap in both the accessibility of complex core structures that are difficult to exploit and in the availability of core structures that are not already the subject of numerous patents. This gap will be addressed by identifying new synthetic methods that achieve the dual goals of enabling efficient access to useful cores while also exploring previously inaccessible "chemical space." The long-term goal is to understand the reactivity of unstabilized carbenes and their immediate precursors. The objective of this application is to explore rhodium-catalyzed C–H insertion reactions of carbenes that are generated without the isolation of diazo compounds while also exploring new tandem cycloaddition/rearrangement processes. The central hypothesis is that appending two "donor" groups to a carbene precursor will open up new avenues of reactivity for organic chemistry. This hypothesis is supported by preliminary results regarding a) the unique ability of donor/donor carbenes to engage in highly enantioselective C–H insertion reactions and b) a remarkable cycloaddition/ rearrangement sequence that produces drug-like heterocyclic core structures absent from the patent literature! Small molecules comprise the vast majority of treatments for both acute and chronic diseases in both the developed and developing world. Research in this application will lay the groundwork to save lives and enable the next generation of pharmaceutical discovery by advancing three Specific Aims. 1) Synthesis of oxygen and sulfur heterocycles by catalytic C–H insertion. This aim will explore asymmetric carbene reactions under conditions that avoid isolation of dangerous intermediates, exhibit unprecedented functional group tolerance, and lead to core structures common to both drug discovery leads and natural products that modulate biological phenomena. 2) Assembly of densely-substituted indolines, indanes and tetrahydro-isoquinolines (THIQs) by catalytic C–H insertion. The insertion technology will become a platform for discovery in the assembly of nitrogen- and carbon-based polycyclic systems representing useful starting points for drug discovery. 3) Rapid construction of complex heterocycles from new one-pot dipolar cycloaddition-[1,5] shift sequence. Our one-pot system for the generation and immediate reaction of diazo intermediates will be used to construct complex spiro-heterocycles in a single step, yielding unexplored molecules for pharmaceutical and biomedical applications. The proposed approach is innovative because it is based on a new methodological platform that accesses previously inaccessible chemical reactivity. This research is significant because it will change the way synthetic chemists approach targets while at the same time opening up new vistas for discovery of useful molecules for medicine and other fields. Ultimately, the discoveries emerging from our research will represent a vertical step in the assembly of molecular architectures that will translate into new medicines to address our society's most pressing health challenges.

项目摘要/摘要 迫切需要新的方法来快速制备复杂的有机分子，从而有可能 成为新的毒品。在复杂的核心结构的可达性方面，两者之间的差距越来越大 难以开发，以及尚未成为众多专利主题的核心结构的可用性。 这一差距将通过确定新的合成方法来解决，这些方法实现了使 在探索以前无法进入的“化学空间”的同时，高效地获取有用的核心。长期的 目的是了解不稳定的卡宾及其直接前体的反应性。的目标是 这一应用是为了探索在没有Rh的情况下产生的卡宾的Rh催化的C-H插入反应 分离重氮化合物，同时探索新的串联环加成/重排过程。 中心假设是，在卡宾前体上加上两个“供体”基团将开辟新的途径。 有机化学的反应性。这一假说得到了关于a)唯一的 供体/供体卡宾参与高对映选择性C-H插入反应的能力和b)a 显著的环加成/重排序列，不产生类药物杂环核心结构 来自专利文献！小分子药物是治疗急性和慢性疾病的主要药物。 发达国家和发展中国家的疾病。对这一应用程序的研究将为 通过推进三个具体目标来拯救生命和实现下一代药物发现。1) 催化C-H插入法合成氧和硫杂环。这一目标将探索不对称 在避免分离危险中间体的条件下，卡宾反应表现出前所未有的 官能团耐受性，并导致药物发现线索和天然线索共同的核心结构 调节生物现象的产品。2)稠密取代吲哚、吲哚和 催化C-H插入法合成四氢异喹啉(THIQ)。插入技术将成为一个平台 在氮基和碳基多环体系的组装中发现代表有用的起始 药物发现的积分。3)从新的一锅偶极快速构建复杂杂环 环加成-[1，5]移位序列。我们的一锅法重氮生成和即时反应系统 中间体将被用来在一步内构建复杂的螺杂环，产生未被探索的产物 用于制药和生物医学应用的分子。建议的方法是创新的，因为它是 基于一种新的方法学平台，该平台可以访问以前无法获得的化学反应。这 研究意义重大，因为它将改变合成化学家接近靶标的方式，同时 时间为发现医学和其他领域的有用分子开辟了新的前景。归根结底， 我们研究中出现的发现将代表着分子组装的垂直一步 将转化为新药的架构，以应对我们社会最紧迫的健康挑战。