Thesis
The synthesis of single enantiomer thiolactomycin analogues utilising deracemisation by crystallisation
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2025
- Thesis identifier
- T17196
- Person Identifier (Local)
- 201758499
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Single enantiomers play a crucial role in the pharmaceutical industry. A preferred enantiomer can be obtained through enzymatic kinetic resolution, preferential crystallisation, diastereomeric crystallisation (also called classical resolution), or chromatographic resolution. The use of safe single enantiomers instead of potentially problematic racemic enantiomers has dramatically increased in drug development and design. The objective of this study was to develop a method for converting racemic mixtures into active enantiomers following syntheses of racemates with a thiolactone scaffold. Our deracemisation by crystallisation approach would then provide a basis for the future development of chiral thiolactomycin analogues (TLM) as potential antibiotics. In the first part of the project, we explored the use of existing crystal structures in an existing database towards the understanding and facilitation in obtaining the conglomerate crystal form necessary for our intended approach. Structural data from compounds with a thiolactone, or related structure, were sourced and processed with Mercury software. The corresponding Hirshfeld surface analysis of these structures disappointingly did not lead to the key structural insights required to guide the subsequent synthesis of racemic TLM analogues. A synthetic campaign to generate a large library of racemic analogues led to only to the successful generation of three molecules. 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one, 3hydroxy-4-methyl-2H-thiophen-5-one, and 3-benzyl,5-methyl-4-hydroxy-5H-thiophen-2one. The identification of the crystal form was performed using single-crystal X-ray diffraction, Xray powder diffraction, and differential scanning calorimetry. These data confirmed the presence of racemic crystal-forming systems and not the conglomerate form required for the subsequent crystallisation and deracemisation experiments. The final section of the project was concerned with developing a proof-of-concept ibuprofen model for implementation in subsequent crystallisation by racemisation experiments in cases where racemates possessed a conglomerate crystal lattice. Conversation of racemic and enantiopure forms of ibuprofen were converted to their diastereoisomers and studied by NMR spectroscopy and polarimetry analytical methods. The data obtained indicated that this method was valid for the important determination of the % enantiomeric excess, required as part of the overall process to resolve racemates by decracemisation by crystallisation.
- Advisor / supervisor
- Coxon, Geoff
- Resource Type
- DOI
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PDF of thesis T17196 | 2025-03-04 | Public | Download |