The synthesis of novel olfactory receptor agonists and explorations in the selective fluorination of the tert-butyl group for bioactives discovery

Abstract

In Chapter 1, an introduction to fluorine chemistry is given. The physical properties of fluorine are discussed, and examples of how the introduction of fluorine into a molecule can influence the structure and properties of a molecule are provided. Strategies for the incorporation of fluorine within a molecule are also discussed.

In Chapter 2, the structure and properties of (R)-muscone are discussed. The mechanism of olfaction is outlined, and the debate between the conformation and vibrational theories of olfaction is discussed. The development of a series of derivatives of (R)-muscone is explored, in particular trifluoromethyl, chloro and sulfoxide derivatives. Their effectiveness as olfactory molecules is compared to that of (R)-muscone to determine how altering the structure of (R)-muscone effects interactions with known olfactory receptors.

In Chapter 3, the structure and properties of synthetic musk compounds previously developed as alternatives to (R)-muscone is developed. The development of a new series of bis-acetylene compounds as prospective musk odorants is outlined. Their effectiveness as odorants is measured and targets are developed to determine the optimal shape and configuration of this class of molecule for interacting with olfactory receptors.

In Chapter 4, the effect of fluorine on the lipophilicity of compounds is outlined, and the tert-butyl group is discussed, particularly its uses in medicinal chemistry. The development of a new motif, the aryl trifluoro tert-butyl group is outlined, followed by an investigation into the structure, reactivity and properties of the group, to measure the effect of the fluorination of the tert-butyl group.

In Chapter 5, the chiral methyl group is introduced, and its use in biosynthetic studies is discussed. The development of a chiral tert-butyl group is outlined, and attempts to develop ¹H and ¹³C NMR assays of the group are discussed.

Date of Award	13 Jun 2024
Original language	English
Awarding Institution	University of St Andrews
Supervisor	David O'Hagan (Supervisor)