New Building Blocks for the Catalytic Synthesis of Organofluorine Compounds

有机氟化合物催化合成的新结构单元

• 批准号: RGPIN-2021-03630
• 负责人: Le, Christine
• 金额: $ 2.11万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747966
• 关键词: New; Building; Blocks; Catalytic; Synthesis

Fluorinated molecules are highly desirable targets for drug discovery and development owing to their improved potency, selectivity, and pharmacokinetic profiles when compared to non-fluorinated analogues. In the medical imaging field, 18F is a widely used radioisotope for positron emission tomography (PET) imaging due to its long half-life. Although >50% of the leading blockbuster drugs contain a fluorine atom, an analysis of fluoro-pharmaceuticals introduced in the last three decades reveals that there are few chiral organofluorine drugs currently on the market. This low representation can be attributed to the increased structural complexity of chiral molecules, combined with limited industrially friendly methods to synthesize these targets. Many of the developed asymmetric fluorination methods rely on electrophilic fluorinating reagents, which present several disadvantages on scale, such as high costs, low atom-economy, powerful oxidizing capabilities, and poor functional group tolerance. The proposed research program seeks to develop new organic reactions that harness the synthetic potential of readily accessible fluorine-containing building blocks, which are cost-effective, safer, and selective in their reactivity. Our overarching goal is to design methodologies that can transform simple starting materials into structurally and chemically diverse libraries of organofluorine compounds for biological testing. My group will explore the chemistry of two main classes of compounds, acyl fluorides and difluoroacetate derivatives, as their preparation does not require electrophilic fluorine sources and their application in catalytic asymmetric transformations remains underdeveloped. I have identified three critical areas with unmet synthetic challenges: 1) the development of complexity-building, atom-economical insertion reactions of acyl fluorides; 2) the controlled generation of transition metal difluorocarbenes under conditions amenable to asymmetric catalysis; and 3) the efficient translation of developed methodologies to 18F-radiolabeling for PET imaging applications. Leveraging tools in synthetic organic and organometallic chemistry, my group will develop novel catalysts that can facilitate the activation of these building blocks towards diverse carbon-carbon and carbon-heteroatom bond-forming reactions. Our primary focus will be on the use of nickel and boron catalysts, due to the higher natural abundance of these elements in comparison to commonly used precious metals (Pd, Pt, Rh). The central hypothesis is that rational ligand, catalyst, and reagent design will lead to the reliable prediction of reaction pathway and the discovery of new reactivity. Overall, the synthetic methodologies developed in my lab will find direct applications in drug discovery, medical imaging, and disease diagnosis, creating opportunities for interdisciplinary collaborations.

与非氟化类似物相比，氟化分子具有更高的效力、选择性和药代动力学特征，因此成为药物发现和开发非常理想的靶标。在医学成像领域，18F由于其半衰期长，是一种广泛用于正电子发射断层扫描（PET）成像的放射性同位素。尽管超过 50% 的主要重磅药物含有氟原子，但对过去三十年推出的氟药物的分析表明，目前市场上的手性有机氟药物很少。这种低代表性可归因于手性分子结构复杂性的增加，以及合成这些靶标的工业友好方法有限。许多已开发的不对称氟化方法依赖于亲电子氟化试剂，其在规模上存在一些缺点，例如成本高、原子经济性低、氧化能力强和官能团耐受性差。拟议的研究计划旨在开发新的有机反应，利用易于获得的含氟结构单元的合成潜力，这些反应具有成本效益、更安全且具有选择性。我们的首要目标是设计方法，将简单的起始材料转化为结构和化学多样化的有机氟化合物库，用于生物测试。我的小组将探索两类主要化合物的化学：酰基氟化物和二氟乙酸酯衍生物，因为它们的制备不需要亲电子氟源，并且它们在催化不对称转化中的应用仍未开发。我已经确定了三个尚未解决的合成挑战的关键领域：1）开发复杂性、原子经济的酰基氟化物插入反应； 2)在不对称催化条件下控制过渡金属二氟碳烯的生成； 3) 将已开发的方法有效转化为用于 PET 成像应用的 18F 放射性标记。利用合成有机和有机金属化学的工具，我的小组将开发新型催化剂，可以促进这些构件的活化，以实现各种碳-碳和碳-杂原子成键反应。我们的主要重点是镍和硼催化剂的使用，因为与常用的贵金属（Pd、Pt、Rh）相比，这些元素的自然丰度更高。中心假设是合理的配体、催化剂和试剂设计将导致反应途径的可靠预测和新反应性的发现。总体而言，我实验室开发的合成方法将直接应用于药物发现、医学成像和疾病诊断，为跨学科合作创造机会。