Synthesis of unnatural fluorescent α-amino acids

Gourlay, Ben (2025) Synthesis of unnatural fluorescent α-amino acids. PhD thesis, University of Glasgow.

Abstract

Unnatural α-amino acids are important probes that can be incorporated into proteins and peptides for biological study using fluorescence spectroscopy. The objective of this MSc research programme was to investigate the synthesis of novel fluorescent unnatural amino acid using transition metal catalysis to implement the key steps.

The aim of the first project was to construct a phenoxathiin α-amino acid and to extend its conjugation by halogenation and subsequent Suzuki-Miyaura reactions. Initially, the phenoxathiin α-amino acid core was prepared using a dual catalytic thioarylation reaction using iron triflimide as a Lewis acid and diphenyl selenide as a Lewis base, followed by a copper mediated cyclisation. Various approaches using succinimide and saccharin reagents were investigated for halogenation but due to either poor conversions or difficult separations, an effective halogenation was not possible. However, the reaction with N-iodosaccharin did give access to a novel phenoxathiinsulfoxide α-amino acid which displayed fluorescent properties with an emission maximum at 372 nm.

The aim of the second project was to develop a synthesis of a nitro-substituted dibenzofuran α-amino acid. The strategy involved the synthesis of a biaryl analogue of tyrosine, followed by a metal-catalysed C–H activation and cyclisation reaction. Initially, the cyclisation precursor was prepared in three steps. This involved aminogroup protection, ortho-bromination and then Suzuki-Miyaura cross-coupling reaction with 4-nitrophenyl boronic acid. The first attempted cyclisation used a palladium catalyst and a per-ester as the oxidant was successful but gave the product in only 6% yield. Other methods were investigated in an effort to improve the efficiency of this transformation. Using a simpler method involving a copper(II)-mediated single electron transfer cyclisation was more efficient and gave the desired nitro-substituted dibenzofuran α-amino acid in 16% yield.

• Item Type: Thesis (PhD)
• Qualification Level: Masters
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Sutherland, Professor Andrew
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-84909
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 18 Feb 2025 10:56
• Last Modified: 20 Feb 2025 09:57
• Thesis DOI: 10.5525/gla.thesis.84909
• URI: https://theses.gla.ac.uk/id/eprint/84909