Studies in the Synthesis of Complex Organic Molecules with Donor-Donor Carbenes

供体-供体卡宾合成复杂有机分子的研究

• 批准号: 10622253
• 负责人: Jared Thomas Shaw
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622253
• 关键词: Acute Disease; Address; Alkaloids; Architecture; Area; Chemicals; Chemistry; Chronic Disease; Complex; Custom; Development; Goals; Health; Legal patent; Life; Medicine; Mental Depression; Metals; Methodology; Methods; Mission; Modeling; Natural Products; Neuronal Plasticity; Organic Chemistry; Pharmacologic Substance; Post-Traumatic Stress Disorders; Process; Public Health; Reaction; Research; Rhodium; Societies; Structure; Time; Translating; United States National Institutes of Health; carbene; catalyst; cycloaddition; design; diene; disability; drug discovery; experimental study; innovation; molecular assembly/self assembly; nervous system disorder; next generation; novel; novel therapeutics; programs; small molecule

Project Summary/Abstract An urgent need exists for new methods to rapidly prepare complex 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 and exploring previously inaccessible "chemical space." The long-term goal of our research program is to understand the reactivity of unstabilized metal carbenes. The objective of this application is to explore the ability of rhodium donor-donor carbenes to engage in a wide variety of useful new applications. The central hypothesis is that appending two "donor" groups to a carbene opens 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 new mild and catalytic process for the formation of reactive dienes for cycloaddition reactions! 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 focusing on three areas of research. First, we will explore new C–H insertion reactions the enable the synthesis of complex carba- and heterocyclic structures, culminating in an efficient synthesis of polycyclic alkaloid natural products that will be studies for the ability to induce neuroplasticity for the treatment of PTSD, depression and other neurological disorders. Second, we will explore new reactions of rhodium donor-donor carbenes that branch out form C–H insertion into new reactions that access new chemotypes. Finally, we will, for the first time, build a QSSR model that will enable the design, synthesis and exploration of new catalysts that are custom-designed to enhance the reactivity of donor-donor carbenes. The proposed approach is innovative because it is based on a new methodological platform that enables 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.

项目概要/摘要 迫切需要新方法来快速制备具有新潜力的复杂分子 药物。难以利用的复杂核心结构的可访问性和可访问性方面的差距正在扩大 核心结构的可用性尚未成为众多专利的主题。这个差距将是 通过确定新的合成方法来解决这一问题，这些方法可以实现有效获取有用物质的双重目标 核心并探索以前无法进入的“化学空间”。我们研究计划的长期目标是 了解不稳定金属卡宾的反应性。该应用程序的目的是探索能力 铑供体-供体卡宾用于各种有用的新应用。中心假设 是在卡宾上附加两个“供体”基团为有机化学反应开辟了新的途径。 该假设得到以下初步结果的支持：a) 供体/供体卡宾的独特能力 参与高度对映选择性的 C–H 插入反应，b) 一种新的温和催化过程 形成用于环加成反应的活性二烯！小分子构成绝大多数治疗方法 适用于发达国家和发展中国家的急性和慢性疾病。本应用研究 将通过专注于拯救生命并实现下一代药物发现奠定基础 三个研究领域。首先，我们将探索新的 C–H 插入反应，以合成复杂的 碳环和杂环结构，最终有效合成多环生物碱天然产物 这将是研究诱导神经可塑性以治疗创伤后应激障碍、抑郁症和其他疾病的能力 神经系统疾病。其次，我们将探索铑供体-供体卡宾的新反应。 形成 C-H 插入到获得新化学型的新反应中。最后，我们将首次构建一个 QSSR 模型将支持定制设计的新型催化剂的设计、合成和探索 增强供体-供体卡宾的反应性。所提出的方法是创新的，因为它基于 一个新的方法平台，可以实现以前无法实现的化学反应。这项研究是 意义重大，因为它将改变合成化学家接近目标的方式，同时打开 为发现医学和其他领域有用的分子开辟新的前景。最终，发现 我们的研究中出现的结果将代表分子结构组装的一个垂直步骤，这将 转化为新药物来解决我们社会最紧迫的健康挑战。