Catalytic Hydrofluorination for the Assembly of Chiral Fluorinated Building Blocks

毫无疑问，催化作用的出现使分子间的连接产生了革命性的变化，从而产生了理想的产品，如药品和农用化学品。这一领域的重要性突出体现在三项诺贝尔化学奖的颁发，即烯烃复分解过程（2005年），过渡金属催化的交叉偶联（2010年）和不对称有机催化（2021年）。这些反应得益于添加少量定制催化剂，这可以提高产物形成速率并赋予高水平的选择性。后者是非常重要的，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，氟原子可以赋予分子几种期望的性质，这导致其被掺入大量农用化学品、药物和各种功能材料中。在有机分子中安装氟的一种方便方法涉及将氢和氟原子添加到碳-碳双键中的相对碳原子上。这种氢化过程是有机化学中的一种基本转变，自其诞生以来就被广泛研究。实现这一点的典型方法涉及使用有毒的氟化氢，并且尽管已经改进了这种酸性试剂的相容性的显著进步，但是没有一种能够控制氟原子的空间排列，仅得到产物的外消旋混合物。该项目旨在克服这一挑战，并提供一种使用方便的氟化物源进行加氢反应的通用方法，该方法相对无害且具有成本效益，并高度控制氟原子在三维空间中的空间排列。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。所得的非外消旋含氟产物将适合作为构建新的生物活性分子的结构单元，在药物发现和农业化学中具有明确的应用。

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.