New Applications of Electrochemistry in
Organic and Peptide Chemistry

Abstract

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.