Organofluorine compounds have had an important influence on the advances in the healthcare and agricultural industries. Selective substitution with fluorine can produce a significant impact on the pharmacokinetic properties of bioactive compounds; generally this is through stereoelectronic effects that the fluorine atom can confer. As such, there is a continuous interest in the development of novel organofluorine compounds and the incorporation of fluorine into bioactive compounds and natural products. The all-cis-1,2,4,5-tetrafluorocyclohexane motifs were the first examples of facially polarised cyclohexane rings which possess a dipolar nature arising from two 1,3-diaxial C-F bonds. The fluorine face, which possesses a negative electrostatic profile, along with the positively polarized methylene hydrogens on the opposite face give a unique facial polarity to this motif. These highly polarized fluorinated ring systems present as novel building blocks for use in drug development and agricultural programs; hence the aim of this study was the development of functionalised derivatives of these all-cis tetrafluoro-cyclohexanes. Transformations of previously reported phenyl all-cis-2, 3, 5, 6-tetrafluoro-cyclohexane were explored in a variety of directions and new pathways towards partially fluorinated cyclohexanes were investigated. The range of all-cis-tetrafluorocyclohexane motifs produced, with functional groups attached directly to the fluorinated cyclohexane ring, varied from methyl substituted all-cis-tetrafluorocyclohexane alcohols, aldehydes, nitriles and amines to all-cis-tetrafluorocyclohexane amino acid, pentafluoro carboxylic acid and alcohol derivatives. These novel derivatives were then used in liquid-phase peptide synthesis, incorporated into peptidomimetic systems through Ugi multi-component reactions and utilised in the formation of bis-systems, in order to demonstrate their reactivity and to gain an insight into their possible intramolecular conformational preferences and supramolecular arrangements.