New methods for the stereoselective synthesis of fluorescent amino acids, natural products and biomolecules
Year: 2019
Type: dissertation
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.
Author: Bell, Jonathan D.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3012903208