Synthesis and properties of selectively fluorinated aliphatic motifs in the context of medicinal chemistry

This thesis examines the effect of selective fluorination of aliphatic motifs, and how this can be applied in a medicinal chemistry context. Chapter 1 provides a brief introduction to organofluorine chemistry, exploring how the C-F bond is able to impart unique properties into molecules. This includes a focus on fluorine’s role within medicinal chemistry, as well as highlighting potential environmental consequences of fluorine’s use, whether that be through mining or PFAS - per/polyfluoroalkyl substances. Chapter 2 explores utilising the all-cis-multifluorinated cyclohexanes in a series of naphthalene diimide based G-quadruplex ligands. This explores both the synthesis of these molecules, as well as some understanding of their effect on LogP, stabilisation of G-quadruplex and double stranded DNA. Finally, an examination of their use as potential antitrypanosomal agents. Chapter 3 expands on the existing chemistry surrounding the β,β’,β”-trifluoro-tert-butyl (TFTB) motif. This highlights a new and efficient route for the synthesis of the trifluoroneopentyl alcohol building block, in addition to the synthesis of novel selectively fluorinated amino acids and heterocyclic compounds. Some insight is provided into the defluorocyclisation reaction, with examples of lactones and a proline derivative formed in this manner. Properties associated with selective incorporation of fluorine, such as LogP, pKₐ and electron withdrawing effects are also explored, and highlight the importance and magnitude of the effect fluorine incorporation can have on small molecules. Finally, synthesis of drug analogues of Vertex Pharmaceuticals’ Elexacaftor and Tezacaftor are reported, as well as the effect of incorporation of the TFTB group on LogP. Chapter 4 provides all experimental for the projects, including methods and analytical data of compounds reported.