Project summary: Asymmetric Catalytic Fluorination with Metal Alkali Fluoride

氟元素以其独特的特性和性质在药物设计中得到了广泛的探索和开发。这些性质包括对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可达性的限制，特别是在以立体碳上的氟为特征的含氟化合物的制备中。手性在化学和药物开发中的重要性导致了用于对映选择性氟化的新型催化技术的发展。虽然亲电氟化在这一领域的研究中占主导地位，有许多来源可以商业使用，但利用廉价的亲核来源，如金属碱，不对称合成形成C-F键的进展较慢。金属碱式氟化物具有安全、易操作、价格低廉等优点，是一种理想的氟化试剂，但由于其在有机溶剂中的溶解性差，对氟离子的反应活性缺乏控制，限制了其在化学合成中的应用。氢键相转移催化(HBPTC)是Gouverneur小组在2018年引入的一个新概念，目的是解决这些问题。手性催化剂通过氢键与难溶金属氟化物络合，为实现对映体选择性氟化提供了一种策略。金属碱氟化物一旦被输送到络合物中的溶液中，就可以形成后续的离子对到所需的电泳液中，这允许选择性地形成C-F键，并最终将HBD催化剂释放回溶液中。尿基催化剂已经成功地用来氟化亲电体，如环磺正离子和氮离子，这在文献中可以找到很好的对映选择性控制。但是，为了使HBPTC催化摆脱特定亲电体系的限制，需要设计新的氢键给体催化来获得所需的氟化分子，目前在药物发现和开发中的应用很难准备。该项目属于EPSCR物理科学、合成有机化学研究领域。该项目应提供更多选择性和可持续的选择，以便使用催化剂对与药物有关的分子进行对映选择性氟化，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.