Stereoselective Synthesis of Complex Fluorinated Motifs from Unactivated Alkynes

In this project, we will establish ambitious new strategies for the stereoselective synthesis of highly functionalised fluorinated motifs from unactivated and readily available alkynes. The selective incorporation of fluorine into complex organic molecules has been an essential factor in the growth of many fields and applications, ranging from crystal engineering, materials, polymers, agriculture, and medicinal chemistry. For example, the incorporation of fluorine into pharmaceuticals can enhance their activity, rationalising why 34% of commercial pharmaceuticals contain at least one fluorine atom. The progression of many fields of research is directly linked to the ability of synthetic chemists to construct complex molecules, and the selective addition of fluorine at very precise positions is an important part of this. Despite general progress in the synthesis of fluorinated moieties, there are still significant challenges in preparing them in regio-, diastereo- and enantio-selective ways. Preparing fluorinated motifs with exquisite control of this selectivity is essential for tuning the activity and function of the molecule. For example, fluorination is used by medicinal chemists to modulate the pKa of basic groups to improve the interaction with enzymatic active sites. Hence there remains an urgent requirement to invent new strategies for selective synthesis of fluorinated motifs, especially fluorinated alkyl motifs, which are especially under-developed. The aim of this research project is to fluoro-functionalise alkynes, which are one of the most versatile functional groups, to generate complex fluoroalkenes and alkyl fluorides with exquisite regio-, diastereo- and enantioselectivity. We will employ designer reagents to mediate this suite of transformations, and exploit state-of-the-art, machine learning (“digital chemistry”) algorithms to aid their optimisation. Specific objectives include: The generation of conditions to activate alkynes Stereoselective synthesis of monofluoroalkenes Synthesis of gem-difluorides Enantioselective alkyne fluorofunctionalisation Our novel and timely approach will provide far-reaching applications towards highly-substituted organofluorine motifs, and robust stereo-selective alkyne multi-functionalisation methods. These methods and techniques will aid synthetic chemists to readily design and implement function into molecules, and pave the way for scientific advancements and technological breakthroughs. This fundamental research, which underpins many fields of research and development, will provide broad ranging benefits. These include to, a) the chemical industry by providing pharmaceutical and agrochemical companies with innovative ways to make new products and training a highly skilled PDRA for the work force, as well as to, b) academia by supporting and growing the excellent international reputation of synthesis in the UK, and to, c) society by contributing to the growth of a technology-first economy and to the development of new medicines and products that will improve the quality of life for all.