Catalytic Hydrofluorination for the Assembly of Chiral Fluorinated Building Blocks

随着催化技术的出现，将分子连接起来以生产理想的产品，如药品和农用化学品，无疑带来了革命性的变化。三项诺贝尔化学奖突出了这一领域的重要性，分别是开发烯烃歧化工艺(2005年)、过渡金属催化的交叉偶联反应(2010年)和不对称有机催化(2021)。这些反应得益于添加少量量身定做的催化剂，这可以提高产物形成速度并提供高水平的选择性。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有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几种理想的性质，这使得它被用于大量的农用化学品、药物和各种功能材料。一种在有机分子中安装氟的简便方法是在碳-碳双键中将氢和氟原子加到相反的碳原子上。这种氢氟化过程是有机化学中的一次根本性转变，自其诞生以来就得到了广泛的研究。实现这一点的典型方法包括使用有毒的氟化氢，尽管取得了重大进展，改善了这种酸性试剂的兼容性，但没有一种方法能够控制氟原子的空间排列，只产生外消旋的产物混合物。该项目旨在克服这一挑战，并提供一种使用方便的氟化源进行氢氟化反应的通用方法，该氟化源相对无害和成本效益高，可以高度控制氟原子在三维空间的排列。此外，这将是一个可持续的催化过程，避免有毒和危险的过渡金属。由此得到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基础，在药物开发和农用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.