New Applications of Electrochemistry in Organic and Peptide Chemistry

Peptide therapeutics are an attractive alternative to both small molecule drugs and biologics, as their size and complexity enables them to hit unique targets like Protein-Protein Interactions (PPIs) effectively. However, the current development of peptide therapeutics is hindered by inherent weaknesses within this class of molecule e.g., poor bioavailability, cell permeability, and solubility. The incorporation of unnatural amino acids into peptides has been used to modify their physicochemical properties and improve their ‘drug-likeness’. Synthetic electrochemistry is a versatile tool that is rapidly emerging as a ‘green’ alternative to more traditional synthetic techniques due to its atom efficiency and selectivity. The application of electrochemistry to modify amino acids is the primary research aim of this thesis. Electrochemical methods have been explored in the selective fluorination of a range of amino acids, and the compatibility of synthetic electrochemical procedures with various amino- protecting groups has been evaluated. Successful fluorination of a Boc-protected amino acid derivative was achieved in a yield of 34%. Chlorination has also been explored, resulting in the development of an electrochemical chlorination method that uses dichloromethane (DCM) as a chlorinating reagent under mild conditions. Successful chlorination of a range of electron rich molecules including the amino acid tryptophan (in a 55% yield) was achieved. Electrochemical modification of amino acid substrates using transition metal catalysts was also investigated. Nickel catalysis was used to facilitate coupling of alkyl bromides with aryl bromides, generating novel arylated amino acids in varying yields. Pd-catalysed electrochemical oxidation was also explored, resulting in successful acetoxylation of a valine derived substrate with a methoxyiminoacetic acid (MIA) directing group in a 35% yield. Electrochemical oxidative coupling of tyrosine was investigated, and a dityrosine derivative was successfully synthesized with a 20% yield. In addition, the coupling conditions were successfully applied to a tyrosine-containing dipeptide. A Shono-type oxidation reaction of proline derivatives mediated by Selectfluor was also developed giving ready access to 5 oxoproline derivatives. In summary, investigation into the electrochemical modification of several amino acid substrates was undertaken, resulting in synthesis of several unnatural amino acids. New insights into electrosynthetic transformations across a broad range of reaction classes were gained.