The work in this project has focuses the development and exemplification of new catalysts and new green methodologies for effective enantioselective halogenation (chlorination, bromination and fluorination), constituting a new platforms for the discovery and cost-effective green manufacture of pharmaceutical compounds.
This work covered during the lifetime of the project has involved the following:
WP1. The design and synthesis of 2 ammonium salts and 4 bifunctional designer enantiopure compounds to be screened halogenation catalysts was performed. The syntheses of the target catalysts were met with some hurdles, however were each successfully prepared, including with additional support via the development of a novel microwave synthesis method which was published in an OA journal.
WP2. The development of synthetic procedures for enantiospecific halogenation was performed. Several advanced methods for the preparation of fluorinated targets has been developed with high yields, fast reaction times, and broad substrate tolerance. A method for the selective preparation of acetoxylated compounds was also discovered, further expanded the utility of the GreenX4Drug synthesis platform.
WP3. Halogenation methods from WP2 were used to syntheses of a range of halogenated compounds. Stereocontrol of the desulfurative halogenation was challenging due to competing reaction pathways favouring products with loss of chiral information. We performed an NMR-based study to further understand the interactions of our novel catalysts with findings published in an OA journal. The best methods developed in WP2 were used to target multiple halogenated pharmaceutical intermediates successfully.
WP4. The batch halogenation methods developed to prepare halogenated compounds were adapted to continuous flow protocols to target key halogenated intermediates towards pharmaceuticals. The behaviour of the halogenation chemistry was investigated using continuous flow systems, which involved careful evaluation of the system parameters to ensure high yields and reliability of the continuous flow methods. The desulfurative bromination of alpha-beta unsaturated compounds was investigated where factors such as flow rate, bromination reagent, solvent and residence time were evaluated. Using analytical methods included gas chromatography, high-performance liquid chromatography, and nuclear magnetic resonance, the continuous flow method for desulfurative bromination was successfully developed and exemplified against a range of substrates with broad functionalities bearing close relationship to pharmaceutical compounds. The methods developed were scaled to multi-gram quantities and findings were published in an OA journal. Plans for exploitation of the methods did not lead to publication of a patent before the end of the project, however the methods are still under development and the consortium plans to patent those methods as early as 2024.
