Photooxidation of Oxazoles - A New Method for Late-Stage Peptide Modification

Abstract

Peptide therapeutics are becoming increasingly prevalent on the global market. Consequently, methods that allow the total chemical synthesis and late-stage modification of peptides are in high demand. This thesis, comprised of five chapters, describes the development of a new method for selective late-stage peptide modification through the photooxidation of oxazoles.

Chapter One highlights the allure of peptides as therapeutics and identifies the current limitations of peptides that can be addressed through chemical synthesis. Modern strategies for the late-stage modification of peptides are discussed with a focus on methods that utilise Fmoc solid-phase peptide synthesis (SPPS).

Chapter Two introduces singlet oxygen as a reagent for the late-stage modification of peptides and the established photooxidation properties of oxazoles are discussed. The photooxidation-mediated rearrangement of oxazoles to reactive triamide species, which serve as valuable acyl donors, is emphasised as this sequence underpins much of the chemistry presented in this thesis. Amino acid derived model 2,4,5-trisubstituted oxazoles were synthesised and optimal photooxidation conditions were developed and found to be compatible with standard Fmoc-SPPS. Critically, unwanted reactivity with some oxidatively sensitive amino acid side-chains could be mitigated through careful optimisation of the reaction conditions. Exploration of potential nucleophile scope was accomplished via nucleophilic substitution of triamides generated from the photooxidation of model oxazoles.

Chapter Three outlines the development of a new method to access diverse cross-benzoin products; key reagents in the synthesis of amino acid-derived, substituted oxazoles. Our approach exploited an underutilised disconnection to synthesise a wide array of substituted cross-benzoin and a-siloxy ketone products via acyl substitution of a-siloxy Weinreb amides. The method was shown to retain stereochemistry at the a-siloxy position, installed through a chiral pool approach, as well as demonstrate the utility of benzoins and a-siloxy ketones through a range of synthetic transformations.

Chapter Four examines the design and synthesis of a SPPS resin linker for the C-terminal modification of peptides. The linker incorporates a 2,4,5-trisubstituted oxazole moiety synthesised using the cross-benzoin methodology developed in Chapter Three. Selective C-terminal peptide modification was achieved through photooxidation of an oxazole-linker containing peptide whereby an amine nucleophile was found to be compatible with the method.

Chapter Five discusses the extension of our late-stage oxazole photooxidation method to the selective modification of carboxylic acid side-chain residues. We discovered that selective modification of oxazoles as carboxylic acid side-chain surrogates could be carried out in the presence of unprotected carboxylic acids including the peptide C-terminus as well as glutamic and aspartic acid residues. The mild nature of the photooxidation reaction proved compatible with other SPPS protecting group strategies and can therefore be utilised as an additional orthogonal pathway in the synthesis of functionalised peptides. Show more