Project summary: Asymmetric Catalytic Fluorination with Metal Alkali Fluoride

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.