Project summary: Asymmetric Catalytic Fluorination with Metal Alkali Fluoride

氟元素由于其独特的性质和性质，在药物设计中得到了广泛的探索和利用。这些性质包括其对pKa、构象、亲脂性和代谢途径的影响。氟在药物中的应用在很大程度上受到其合成方法的限制，特别是在制备以立体碳上的氟为特征的氟化化合物时。手性在化学和药物发现中的重要性导致了对映选择性手性催化新技术的发展。虽然亲电性亲核试剂在这一领域的研究中占据主导地位，但利用廉价的亲核性来源（如金属碱）形成C-F键的不对称合成进展较慢。碱金属氟化物是一种安全、易操作、价格低廉的理想试剂，但由于缺乏对氟离子反应性的控制以及在有机溶剂中溶解性差，限制了其在化学合成中的应用。氢键相转移催化（HBPTC）是Gouverneur集团在2018年推出的一个新概念，旨在解决这些问题。手性催化剂通过氢键与不溶性金属氟化物的络合提供了介导对映选择性异构化的策略。金属碱金属氟化物一旦被输送到络合物中的溶液中，就可以与所需的亲电体形成后续离子对，这允许选择性C-F键形成并最终将HBD催化剂释放回溶液中。脲基催化剂已经成功地用于氟化亲电试剂如表锍和氮杂铱离子，具有良好的对映选择性控制，这可以在文献中找到。需要设计新的氢键供体催化剂来获得氟化分子，所述氟化分子是需要的并且目前难以制备用于药物发现的应用，发展本项目属于EPSCR物理科学、合成有机化学研究领域的福尔斯。该项目将为使用催化剂对药物相关分子的对映选择性取代提供更具选择性和可持续性的选择，该催化剂也可适用于许多其他底物和亲核试剂。

The element fluorine has been extensively explored and exploited in pharmaceutical drug design due to its unique characteristics and properties. Such properties range from its influence on pKa, conformation, lipophilicity and metabolic pathways. Fluorine's incorporation into pharmaceuticals has been largely limited by its synthetic accessibly, especially in the preparation of fluorinated compounds which feature fluorine on a stereogenic carbon. The importance of chirality in chemistry and drug discovery has led to the development of novel catalytic techniques for enantioselective fluorination. Whilst electrophilic fluorination has dominated this field of research with many sources commercially available, asymmetric synthesis forming C-F bonds utilising inexpensive nucleophilic sources, such as metal alkalis, has progressed slower. Metal alkali fluorides are ideal fluorination reagents as they are safe, easy to handle and inexpensive, however their use in chemical synthesis has been limited due to the lack of control in fluoride ions reactivity and their poor solubility in organic solvents. Hydrogen bonding phase transfer catalysis (HBPTC) is a novel concept which the Gouverneur group introduced in 2018 to combat these problems. Complexation of a chiral catalyst to the insoluble metal fluoride through hydrogen bonding provides a strategy to mediate enantioselective fluorination. The metal alkali fluoride, once transported into the solution in the complex, can form a subsequent ion pair to the desired electrophile which allows for selective C-F bond formation and ultimately releases the HBD catalyst back into solution. Urea based catalysts have been used to successfully fluorinate electrophiles such as episulfonium and aziridium ions with good enantioselective control, which can be found in the literature.However, to advance HBPTC catalysis out of the limitations of specific electrophile systems, the design of new hydrogen bond donor catalysis is required to access fluorinated molecules which are needed and currently difficult to prepare for applications in drug discovery and development. This project falls within the EPSCR physical science, synthetic organic chemistry research area. This project should provide more selective and sustainable options for enantioselective fluorination of pharmaceutically relevant molecules using catalysts which could also be applicable to many other substrates and nucleophiles.