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，氟化分子由于其改进的效力、选择性和药代动力学特征而成为药物发现和开发的高度期望的靶标。在医学成像领域，18F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，因为其半衰期长。虽然超过50%的主要畅销药物含有氟原子，但对过去三十年引入的氟药物的分析表明，目前市场上几乎没有手性有机氟药物。这种低代表性可归因于手性分子的结构复杂性增加，以及有限的工业友好方法来合成这些靶标。许多已开发的不对称氟化方法依赖于亲电氟化试剂，其在规模上存在几个缺点，例如高成本、低原子经济性、强氧化能力和差官能团耐受性。拟议的研究计划旨在开发新的有机反应，利用容易获得的含氟结构单元的合成潜力，这些结构单元具有成本效益，更安全，反应性选择性强。我们的首要目标是设计方法，可以将简单的起始材料转化为结构和化学上不同的有机氟化合物库，用于生物测试。我的小组将探索两个主要类别的化合物，酰氟和二氟乙酸衍生物的化学，因为它们的制备不需要亲电氟源，它们在催化不对称转化中的应用仍然不发达。我已经确定了三个关键领域与未满足的合成挑战：1）复杂的建设，原子经济的插入反应的酰基氟的发展; 2）过渡金属二氟卡宾的条件下，服从不对称催化的控制生成;和3）开发的方法有效的翻译为PET成像应用的18 F-放射性标记。利用合成有机和有机金属化学的工具，我的团队将开发新型催化剂，可以促进这些构建块的活化，使其成为各种碳-碳和碳-杂原子键形成反应。我们主要关注镍和硼催化剂的使用，因为与常用的贵金属（Pd，Pt，Rh）相比，这些元素的天然丰度更高。其核心假设是，合理的配体，催化剂和试剂的设计将导致可靠的预测反应途径和发现新的反应活性。总的来说，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。