Synthesis of nonproteinogenic amino acids via reactions of enone and ynone functional groups

Songsri, Sineenard (2024) Synthesis of nonproteinogenic amino acids via reactions of enone and ynone functional groups. PhD thesis, University of Glasgow.

Abstract

The main aim of this PhD was to develop novel syntheses of functional amino acids using synthetic chemistry involving ynone or enone side-chains. The first project focused on utilising amino acid-derived ynones to synthesise pyrimidine derivatives, that would have application as fluorescence probes for chemical biology. The approach involved starting with readily available chiral pool a-amino acids. These were transformed into Weinreb amide intermediates and subsequent reaction with the anion of an alkyne allowed for the synthesis of the ynone. Lewis acid catalysed heterocyclisation of the ynone with a range of amidines resulted in the efficient synthesis of pyrimidine-derived amino acids. By altering the alkyne side chain, a variety of pyrimidine analogues were prepared. These compounds were readily deprotected in a one-step process under acidic conditions to yield the parent amino acids. Analysis of the photophysical properties of these amino acids showed that electron-deficient pyrimidines with electron-rich or highly conjugated side-chains gave fluorophores with red-shifted emission and the highest quantum yields.

The next project investigated the synthesis of biphenyl amino acids using a short and efficient synthetic route from a readily available tyrosine derivative. The approach involved one-pot nonaflate formation, followed by a Suzuki-Miyaura cross-coupling reaction to create the biphenyl side-chain. Using the nonaflate as an excellent leaving group and the Buchwald XPhos Pd G2 pre-catalyst for the cross-coupling step, rapid access to a variety of biphenyl amino acids was achieved. The optical properties of these amino acids were also investigated and showed the 2-naphthyl derivative as the brightest with a molar attenuation coefficient of ~31,000 cm–1 M–1 and a quantum yield of 0.18.

The final project describes the development of a new synthetic approach for the preparation of the biologically important meso-DAP and L,L-DAP amino acids using enones as key intermediates. An enone intermediate was prepared by the Horner-Wadsworth-Emmons (HWE) reaction of a phosphonate ester-derived amino acid with benzaldehyde. The enone was subjected to a diastereoselective reduction using L-selectride or the (S)-CBS-Me reagent to access either diastereomer. The resulting allylic alcohols were then used to install the amino group via an Overman rearrangement. Hydrogenation, oxidation of the phenyl ring and esterification of the resulting carboxylic acid led to the synthesis of protected DAP amino acids.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from the Royal Thai Government and Maejo Phrae University.
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Sutherland, Professor Andrew and Boyer, Dr. Alistair
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84250
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Apr 2024 12:49
• Last Modified: 23 Apr 2024 12:51
• Thesis DOI: 10.5525/gla.thesis.84250
• URI: https://theses.gla.ac.uk/id/eprint/84250

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