Periodic Reporting for period 1 - SEAROX (Sulfur Enabled Annulations for Modular, Efficient and General Routes into Oxazoles)
Reporting period: 2019-08-07 to 2021-08-06
Heterocycles, such as oxazoles, are critically important constituent motifs in several areas including bioactive compounds (e.g. drug discovery) and materials. However their preparation, especially with varied groups surrounding them, is very challenging and resource intensive. Methods that can be applied to different types of system are limited. Nucleophilic nitrenoids have emerged as highly effective reactants for the preparation of the nitrogen-based heterocycles that are ubiquitous across biologically active species and vital to the pharmaceutical and agrochemical industries. The nucleophilic nitrenoid approach however has been dependent on strongly donor-activated alkynes. As the donor group translates into the products it limits the application of these methods. Being able to combine the nucleophilic nitrenoid approach with more varied or useful alkynes would significantly increase the applicability of the methods, and hence enable faster, more flexible and more effective routes into important heterocyclic structures. SEAROX aimed to build upon a recent discovery in the host group and pioneer the use of sulfur-based directing groups to establish optimal gold-catalyzed annulations and address the problems of donor substitution.
The research aim of SEAROX was to generate a truly general, rapid, modular entry into densely functionalised oxazoles. SEAROX will deliver an efficient and readily diversifiable method to access important motifs with broad utility in academic and industrial R+D. By reducing the chemical and energy demand of complex molecule preparation, the European
science base and economy benefits from enhanced sustainability.
The research aim of SEAROX was to generate a truly general, rapid, modular entry into densely functionalised oxazoles. SEAROX will deliver an efficient and readily diversifiable method to access important motifs with broad utility in academic and industrial R+D. By reducing the chemical and energy demand of complex molecule preparation, the European
science base and economy benefits from enhanced sustainability.
SEAROX aimed at exploring the synthetic utility of alkynyl thioethers in a gold catalysed reaction to make oxazoles. The unique reactivity and selectivity observed with alkynyl thioethers and to generate a range of thioether oxazoles under Au-catalysis was disclosed by our group (ACIE, 2017, 56, 13310). This approach offered significant opportunity to realise a modular, convergent and flexible entry into desirable heterocycles that are commonly found in applications spanning drug discovery and materials science. SEAROX aimed to study and explore this chemistry in order to ascertain the potential applicability of the new approach.
SEAROX has involved a detailed exploration of the synthetic chemistry potential of the oxazole-forming annulation reaction looking into the factors that affect the reactivity, and the changes that can be incorporated as a result into the products. This involved extensive optimization studies, structure-reactivity and structure-scope studies as well as mechanistic investigation. This has led to a more sustainable set of reaction conditions that reduce the resource impact of this strategy and enhance its applicability. This study has been supplemented by the development of a second set of conditions allowing the formation of different products from the same starting materials, delivering great flexibility and modularity to the alkynyl thioether approach.
The enhanced conditions have been used to prepare a range of heterocyclic compounds, testing the scope of the process and providing insight by a structure-reactivity relationship study. A mechanistic investigation into the new transformation has been carried out to provide fundamental insights into the broader field of chemistry. Processes have then been developed to exploit the utility of the products, transforming the initial annulation compound into different and more complex products. These outcomes enable the rapid formation of desirable motifs that can enable discovery programmes. The synthesized compounds have been submitted for screening tests to identify the potential bioactivity of these compounds in common assay formats.
Substantial time was lost due to university closure during the COVID crisis. To make the best use of this enforced ‘work from home’ time a major review article on aspects of wider chemistry pertaining to the SEAROX approach has been planned and worked on.
the best use of this enforced ‘work from home’ time a major review article on aspects of wider chemistry pertaining to the SEAROX approach has been planned and worked on.
Dissemination of the results: The project fellow collaborated with a post-graduate student from the host group and published a paper as a co-author in ACS catalysis (ACS Catal. 2021,11, 6357), and this has been disseminated more widely using social media channels. We expect that at least 1 additional paper will come out in near future on the results from SEAROX in addition to a major review article. Other interesting avenues initiated in SEAROX are udner active investigation and will be reported in due course on completion of those studies.
Conclusions: The MC Fellowship has offered the necessary support and funding for the development of thioether oxazole chemistry using alkynyl thioethers and nitrenoid under Au-catalysis. This study has delivered effective new synthetic methodology for the efficient preparation of important s-substituted heterocycles. The use and development of environmentally more benign methodology and reagents has been achieved, and this area is crucial to society for more sustainable preparation of complex molecules from limited natural resources. In addition SEAROX has identified key aspects of reactivity that will inform and focus future study in the alkynyl thioether chemistry more widely. SEAROX has also delivered a range of novel chemical entities that are being tested for their biological activity
SEAROX has involved a detailed exploration of the synthetic chemistry potential of the oxazole-forming annulation reaction looking into the factors that affect the reactivity, and the changes that can be incorporated as a result into the products. This involved extensive optimization studies, structure-reactivity and structure-scope studies as well as mechanistic investigation. This has led to a more sustainable set of reaction conditions that reduce the resource impact of this strategy and enhance its applicability. This study has been supplemented by the development of a second set of conditions allowing the formation of different products from the same starting materials, delivering great flexibility and modularity to the alkynyl thioether approach.
The enhanced conditions have been used to prepare a range of heterocyclic compounds, testing the scope of the process and providing insight by a structure-reactivity relationship study. A mechanistic investigation into the new transformation has been carried out to provide fundamental insights into the broader field of chemistry. Processes have then been developed to exploit the utility of the products, transforming the initial annulation compound into different and more complex products. These outcomes enable the rapid formation of desirable motifs that can enable discovery programmes. The synthesized compounds have been submitted for screening tests to identify the potential bioactivity of these compounds in common assay formats.
Substantial time was lost due to university closure during the COVID crisis. To make the best use of this enforced ‘work from home’ time a major review article on aspects of wider chemistry pertaining to the SEAROX approach has been planned and worked on.
the best use of this enforced ‘work from home’ time a major review article on aspects of wider chemistry pertaining to the SEAROX approach has been planned and worked on.
Dissemination of the results: The project fellow collaborated with a post-graduate student from the host group and published a paper as a co-author in ACS catalysis (ACS Catal. 2021,11, 6357), and this has been disseminated more widely using social media channels. We expect that at least 1 additional paper will come out in near future on the results from SEAROX in addition to a major review article. Other interesting avenues initiated in SEAROX are udner active investigation and will be reported in due course on completion of those studies.
Conclusions: The MC Fellowship has offered the necessary support and funding for the development of thioether oxazole chemistry using alkynyl thioethers and nitrenoid under Au-catalysis. This study has delivered effective new synthetic methodology for the efficient preparation of important s-substituted heterocycles. The use and development of environmentally more benign methodology and reagents has been achieved, and this area is crucial to society for more sustainable preparation of complex molecules from limited natural resources. In addition SEAROX has identified key aspects of reactivity that will inform and focus future study in the alkynyl thioether chemistry more widely. SEAROX has also delivered a range of novel chemical entities that are being tested for their biological activity
SEAROX has delivered several novel transformations that advance our understanding of alkynyl thioether chemistry and provide the ability to access important types of structures in a modular and flexible manner. This process efficiency advances the ability to undertake sustainable chemical synthesis. as needed in order to be able to make the types of molecules needed for societal benefit (such as new pharmaceuticals) to minimize the environmental impact and best use limited natural resources. The study has shed light onto the control factors operating in this type of catalytic chemistry and will form the fundamental basis for new advances in the fields of gold-catalysis and alkynyl thioether chemistry.