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.

项目总结/摘要 迫切需要新的方法来快速制备具有成为新的分子的潜力的复杂分子 毒品在难以利用的复杂核心结构的可及性和 核心结构的可用性还没有成为众多专利的主题。这一差距将是 通过确定新的合成方法来解决，这些方法实现了使有效获得有用的 核心和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。这个应用程序的目的是探索能力 铑给体-给体卡宾的研究，以从事各种各样的有用的新应用。核心假设 在卡宾上附加两个“供体”基团为有机化学的反应性开辟了新的途径。 这一假设得到了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，和B）一种新的温和的催化方法， 用于环加成反应的反应性二烯的形成！小分子构成了绝大多数治疗方法 在发达国家和发展中国家的急性和慢性疾病。本申请中的研究 将为拯救生命奠定基础，并通过专注于下一代药物发现， 三个研究领域。首先，我们将探索新的C-H插入反应，使复合物的合成 碳和杂环结构，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的能力，用于治疗创伤后应激障碍，抑郁症和其他疾病。 神经系统疾病第二，我们将探索铑给体-给体卡宾分支的新反应 形成C-H插入到新的反应中，从而获得新的化学型。最后，我们将首次建立一个 QSSR模型，可用于设计、合成和开发定制设计的新型催化剂 以增强给体-给体卡宾的反应性。所提出的方法是创新的，因为它基于 一个新的方法平台，使以前无法达到的化学反应。本研究是 重要的是，它将改变合成化学家接近目标的方式，同时开放 为发现医学和其他领域的有用分子开辟了新的前景。最终，这些发现 从我们的研究中出现的将代表分子结构组装的垂直步骤， 转化为新的药物，以应对我们社会最紧迫的健康挑战。