Enantioselective fluorination of bioactive amines and succinic acids for selected bioassays

Abstract

Since its isolation by Henri Moissan in 1886, fluorine has garnered a growing interest within many fields of chemistry. This attention is a result of the unique properties of fluorine, explained by it being the most electronegative element in the Periodic Table. Chapter I introduces the principal characteristics of fluoro-compounds. A description of the different synthetic processes that have been developed to afford fluoro-organic molecules is then detailed. Finally, a brief history of fluoro-containing drugs is reviewed, including the impact of fluorine regarding essential parameters that are necessary in their design, such as lipophilicity, acidity, and hydrogen bonding. Chapter II gives an overview of the three different methodologies of enantioselective α fluorination of aldehydes that were developed in 2005. This is followed by development of a new approach to the determination of enantiomeric ratios (er) of fluoro-amines using ¹⁹F{¹H}-NMR. Finally, the optimisation of α-fluorination of aldehydes toward the synthesis of the fluoro-bioactives will be explored in this chapter. Chapter III focuses on GABA, the principal neurotransmitter inhibitor of the central nervous system, detailing its mode of action and its importance in treating many diseases,alongside its existing analogues. This chapter includes a shorter enantioselective synthesis of 3-F-GABA developing from previous synthesis. Chapter IV explores calcium-sensing receptors (CaSR), their existing modulators and previous enantioselective synthesis of F-cinacalcet. An optimised α-fluorination of aldehydes is explored towards a 2 step 1 pot synthesis of F-cinacalcet ((ꟳS,R)-269, (ꟳR,R)-269) and other fluoro allosteric modulators ((ꟳS,R)-280, (ꟳR,R)-280, (ꟳS,R)-281, (ꟳR,R)-281, (ꟳS,R)-286, (ꟳR,R)-286). The potency of these new F-cinacalcet analogues is assessed in a CaSR bioassay giving an insight into the active molecular conformation. Chapter V gives a general introduction to the importance of isocitrate lyase (ICL) as a drug target for tuberculosis (TB). The design and synthesis of 4 fluoro-succinic acids (S)-315, (R)-315, 316 and 317 as potential ICL inhibitors is achieved. Finally, a ICL bioassay with (S)-315, (R)-315, and 316 is utilised to assess their mode of action.