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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742649
• 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，氟化分子是高度可取的药物发现和发育靶标。在医学成像领域，由于其长期寿命长，18F是正电子发射断层扫描（PET）成像的广泛使用的放射性同位素。尽管> 50％的领先的大片药物中含有氟原子，但对过去三十年中引入的氟 - 药物的分析表明，目前市场上几乎没有手性有机荧光药物。这种低的表示可以归因于手性分子的结构复杂性的增加，并结合有限的工业友好方法来综合这些靶标。许多开发的不对称氟化方法依赖于亲电荧光试剂，这些试剂呈现出几种规模的缺点，例如高成本，低原子经济，强大的氧化能力和功能较差的群体耐受性。拟议的研究计划旨在开发新的有机反应，以利用易于访问的含氟的构件的合成潜力，这些块具有成本效益，更安全且具有选择性的反应性。我们的总体目标是设计可以将简单的起始材料转化为有机氟氨酸化合物的结构和化学多样性文库进行生物测试的方法。我的小组将探索两种主要的化合物，酰基氟化物和二氟乙酸酯衍生物的化学性质，因为它们的制备不需要亲电氟氟源，并且它们在催化不对称转化中的应用仍然不足。我已经确定了三个关键领域，具有未满足的综合挑战：1）酰基氟化物的复杂性建筑，原子 - 经济插入反应的发展； 2）在适合不对称催化的条件下，受控的过渡金属二氟化合物的受控产生； 3）开发的方法将开发方法的有效翻译为PET成像应用的18F-二醇标记。在合成有机和有机金属化学中利用工具，我的小组将开发新型的催化剂，这些催化剂可以促进这些构件的激活，以朝着多种碳碳和碳纤维 - 异位摩正键形成反应。我们的主要重点是使用镍和硼催化剂，这是由于这些元素的自然丰度与常用的贵金属（PD，PT，RH）相比。中心假设是，有理配体，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，在我的实验室中开发的合成方法将在药物发现，医学成像和疾病诊断中找到直接应用，从而为跨学科合作创造了机会。