Catalytic Hydrofluorination for the Assembly of Chiral Fluorinated Building Blocks

用于组装手性氟化砌块的催化氢氟化反应

• 批准号: EP/X013081/1
• 负责人: Craig Paterson Johnston
• 金额: $ 52.91万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX013081%2F1
• 关键词: Catalytic; Hydrofluorination; Assembly; Chiral; Fluorinated

The linking of molecules to produce desirable products, such as pharmaceuticals and agrochemicals, has undoubtedly been revolutionised by the advent of catalysis. The importance of this field is highlighted by the award of three Nobel Prizes in Chemistry for the development of olefin metathesis processes (2005), transition-metal catalysed cross-coupling (2010), and asymmetric organocatalysis (2021). These reactions benefit from the addition of a small quantity of a tailored catalyst, which can enhance the rate of product formation and impart high levels of selectivity. The latter is fundamentally important, as controlling the spatial arrangement of atoms in a drug is key for potency and reducing side-effects, due to the three-dimensional structural characteristics of biological targets. Moreover, a fluorine atom can bestow several desirable properties on a molecule, which has led to its incorporation into a significant number of agrochemicals, pharmaceuticals, and various functional materials. A convenient method to install fluorine in an organic molecule involves the addition of hydrogen and fluorine atoms to opposite carbon atoms in a carbon-carbon double bond. This hydrofluorination process is a fundamental transformation in organic chemistry that has been studied extensively since its inception. Typical methods to achieve this involve the use of toxic hydrogen fluoride and despite significant advances that have improved the compatibility of this acidic reagent none have enabled control over the spatial arrangement of the fluorine atom giving only racemic mixtures of products. This project seeks to overcome this challenge and provide a general method to perform hydrofluorination reactions using a convenient fluoride source that is relatively non-hazardous and cost-effective with high control over the fluorine atom's spatial arrangement in three dimensions. Moreover, this will be a sustainable catalytic process that avoids toxic and endangered transition metals. The resulting non-racemic fluorine-containing products will be suitable as building blocks to construct new bioactive molecules with clear applications in drug discovery and agrochemistry.

毫无疑问，催化作用的出现彻底改变了分子间的连接，从而生产出理想的产品，如药品和农用化学品。这一领域的重要性被三项诺贝尔化学奖所强调，这三项诺贝尔化学奖是由于烯烃复分解过程（2005年）、过渡金属催化交叉偶联（2010年）和不对称有机催化（2021年）的发展。这些反应受益于添加少量的定制催化剂，它可以提高产物形成的速度，并赋予高水平的选择性。后者至关重要，因为由于生物靶标的三维结构特征，控制药物中原子的空间排列是药效和减少副作用的关键。此外，一个氟原子可以赋予一个分子一些理想的特性，这使得它被纳入大量的农用化学品、药品和各种功能材料中。在有机分子中安装氟的一种简便方法是将氢和氟原子加到碳-碳双键中相反的碳原子上。这种氢氟化过程是有机化学的一个基本转变，自其开始以来一直得到广泛研究。实现这一目标的典型方法涉及使用有毒的氟化氢，尽管取得了重大进展，改善了这种酸性试剂的相容性，但没有一种方法能够控制氟原子的空间排列，只产生消旋混合物。本项目旨在克服这一挑战，并提供一种使用相对无害和具有成本效益的方便氟化物源进行氢氟化反应的一般方法，这种方法可以高度控制氟原子在三维中的空间排列。此外，这将是一个可持续的催化过程，避免有毒和濒危的过渡金属。由此产生的非外消旋含氟产品将适合作为构建新的生物活性分子的基石，在药物发现和农业化学中具有明确的应用。