Development of synthetic approaches towards molecules with potential SERM activity

Download files
Access & Terms of Use
open access
Copyright: Da Silva, Paulo Alexandre Reis
Altmetric
Abstract
The primary aim of this project was to develop organometallic methodologies for the conversion of aryl benzyl ketones into aryl- and/or aroyl- substituted stilbenes related to Selective Estrogen Receptor Modulators (SERMs): Tamoxifen and Raloxifene, respectively. Consideration was given to target molecules that were acyclic, cyclic or heterocyclic. A secondary aim of the project was to develop methodologies that would allow combinatorial methods to be applied to the synthesis of these compounds, allowing quick access to a diverse range of SERM-candidate libraries of compounds. Primary methodologies that were examined included: Grignard, organocerium, and palladium-catalysed Negishi, Stille and Suzuki cross-coupling reactions. In addition, the rearrangement reaction of epoxides and nucleophilic ring opening of epoxides were explored as secondary means of new C-C bond construction. It was found the Grignard chemistry demanded the application of heat and suffered greatly from competing deprotonation reactions of the ketones due to the basicity of the organomagnesium reagents. The corresponding, less basic, organocerium reagents also gave low yields (0-11%). While these methodologies demonstrated some advantages, such as the direct addition of the nucleophilic components to the carbonyl groups of model ketones, they demonstrated some limitations, which were poor yields and restriction to using only carbonyl containing starting materials. Palladium-catalysed Negishi cross-coupling methodology was reliable in C-C bond formation but gave only moderate yields of isolated products. Stille reagents gave crosscoupled products readily and in high yields with sterically unhindered reactants, such as the enol triflate of â- tetralone. However, they did not readily cross-couple with the corresponding á-enol triflate and á-vinyl bromide reactants. This became an insurmountable barrier to their widespread use in SERM synthesis but did provide a sequence with selectivity. The Suzuki methodology was discovered to be superior to other methods of cross-coupling and the most reliable in furnishing both á- and â-coupled products in high yields. The yield of the palladium-catalysed Suzuki cross-coupling reaction at the á-position was found to follow the following order of reactivity: I &gt Br &gt OTf, in keeping with literature precedent, while the stability of the palladium-catalyst, and the choices of base and solvent affected the outcome of the reaction. The Suzuki reaction was also employed in a three-component carbonylative reaction to furnish unsymmetrical ketones, in model reactions towards Raloxifene-like structures, but the products were obtained in low to moderate yields. Initial investigations into the synthesis of closer model compounds through two-fold Suzuki cross-coupling reactions were limited by access to suitable precursors and this indicated a direction for future research.
Persistent link to this record
Link to Publisher Version
Link to Open Access Version
Additional Link
Author(s)
Da Silva, Paulo Alexandre Reis
Supervisor(s)
Creator(s)
Editor(s)
Translator(s)
Curator(s)
Designer(s)
Arranger(s)
Composer(s)
Recordist(s)
Conference Proceedings Editor(s)
Other Contributor(s)
Corporate/Industry Contributor(s)
Publication Year
2005
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
Files
download whole.pdf 1.51 MB Adobe Portable Document Format
Related dataset(s)