New methods for the stereoselective synthesis of fluorescent amino acids, natural products and biomolecules

Bell, Jonathan D. (2019) New methods for the stereoselective synthesis of fluorescent amino acids, natural products and biomolecules. PhD thesis, University of Glasgow.

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Abstract

The stereoselective synthesis of fluorescent amino acids, biomolecules and natural products was achieved using a chiral pool strategy with α-amino acids. The use of L-aspartic acid gave access to a small library of enone derived amino acids via a Horner-Wadsworth-Emmons (HWE) reaction. Transformation of the enones via a number of steps gave a series of pyrazoloquinazoline derived amino acids. Due to the rigid structure of these amino acids, high quantum yields were observed. The lead compound from this series, a dimethylamino substituted pyrazoloquinazoline also displayed high excitation and emission wavelengths. It was found that this compound could be excited either by a one or a two-photon process. This amino acid was also incorporated into a short cell-penetrating pentapeptide in high yield, with no loss of fluorescence.

A second series of fluorescent amino acids bearing benzotriazole side-chains was synthesised from L-asparagine in five steps. The conjugation of these was extended using a Suzuki-Miyaura reaction that led to a highly fluorescent 4-methoxyphenyl substituted analogue. This new chromophore was also rigidified using a copper-catalysed C-H insertion reaction, which yielded a new carbazole derived amino acid.

The HWE reaction used in the first project was investigated as a new approach for bioconjugation. The aspartic acid derived phosphonate ester was coupled with alanine, and this model dipeptide was subjected to successful HWE reactions with various aldehydes, showing this as a possible new method for incorporating chromophores within peptides and proteins.

Finally, L-aspartic acid was also used as a starting material to synthesis a small library of enones, using a HWE reaction. These were found to be excellent substrates for an acid-mediated 6-endo-trig¬¬ cyclisation for the stereoselective synthesis of a series of 2,6-dialkyl-4-oxopiperidines. This transformation was then used as the key step for the synthesis of the alkaloids, (+)-myrtine and (−)-solenopsin A.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Sutherland, Dr. Andrew
Date of Award: 2019
Depositing User: Mr Jonathan Bell
Unique ID: glathesis:2019-76773
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 07 Feb 2020 09:28
Last Modified: 05 Mar 2020 22:38
Thesis DOI: 10.5525/gla.thesis.76773
URI: http://theses.gla.ac.uk/id/eprint/76773
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