Boronic Acid-Catalysed Dehydrative Synthesis
Lead Research Organisation:
University of Bath
Department Name: Chemistry
Abstract
Progress in the development of pharmaceuticals and agrochemicals, chemical biology, and materials science is underpinned by our ability to create molecules selectively. For example, all pharmaceuticals contain organic molecules and, consequently, organic synthesis is central to all future developments. However, recent analysis has shown that medicinal chemistry currently explores only a fraction of chemically accessible space and is reliant on a limited number of synthetic reactions. Therefore, synthetic chemistry is often a bottleneck in the development of new medicines. Furthermore, traditional organic synthesis must adapt to ensure future sustainability in the face of the changing availability of both precious elemental resources and chemical feedstocks. Catalysis represents the single most effective way of simultaneously advancing organic synthesis and addressing the challenges in sustainability.
This proposal will develop a range of clean and efficient catalytic methods for the functionalisation of simple, readily available starting materials containing hydroxyl (OH) groups using boron-based catalysts. The new reactions will be initiated by the catalytic removal of an hydroxy group to form a reactive intermediate and release water as the only by-product. Such reactivity is significantly more efficient and environmentally friendly than traditional methods, which require additional transformations of the hydroxy group and generate large amounts of organic waste by-products.
The project will focus on the development of new catalytic dehydrative reactions for the preparation of valuable small molecule motifs that are widely found in modern pharmaceuticals. For example, 85% of all biologically active entities are reported to contain at least one heterocycle, yet less than 2% of all possible ring systems have been made. We will use catalytic dehydration to explore new reactivity for the preparation of heterocyclic targets for which no general synthetic method exists to enhance accessible drug-like chemical space. We will also apply these methods to the preparation of other common heterocycles currently found in drug compounds to provide more sustainable catalytic alternatives to current synthetic methods. Another aim is to develop new catalytic reactions for the direct activation of N-OH bonds to promote rearrangement into protected amines, again releasing water as the by-product. As over 80% of drug candidates contain amine functionality, the new reactions developed will provide more sustainable and effect methods of accessing these important motifs.
The development of the new synthetic methods will be supported by work to prepare and gain fundamental understanding of new bifunctional boron-based catalysts. We will explore readily available boron systems as Bronsted acid catalysts in combination with a tethered Lewis base. The bifunctional acid/base system will allow for stabilisation of reaction intermediates that may enhance overall reactivity and/or selectivity. Mechanistic studies will be used to elucidate the structure and dynamic behaviour of the catalysts in solution, with the knowledge gained used to aid further catalyst development and support the optimisation of the new synthetic methods.
Overall, the new catalytic technology developed, alongside increased fundamental understanding of the processes will provide both industry and academia with an enhanced toolbox for the sustainable synthesis of valuable organic molecules.
This proposal will develop a range of clean and efficient catalytic methods for the functionalisation of simple, readily available starting materials containing hydroxyl (OH) groups using boron-based catalysts. The new reactions will be initiated by the catalytic removal of an hydroxy group to form a reactive intermediate and release water as the only by-product. Such reactivity is significantly more efficient and environmentally friendly than traditional methods, which require additional transformations of the hydroxy group and generate large amounts of organic waste by-products.
The project will focus on the development of new catalytic dehydrative reactions for the preparation of valuable small molecule motifs that are widely found in modern pharmaceuticals. For example, 85% of all biologically active entities are reported to contain at least one heterocycle, yet less than 2% of all possible ring systems have been made. We will use catalytic dehydration to explore new reactivity for the preparation of heterocyclic targets for which no general synthetic method exists to enhance accessible drug-like chemical space. We will also apply these methods to the preparation of other common heterocycles currently found in drug compounds to provide more sustainable catalytic alternatives to current synthetic methods. Another aim is to develop new catalytic reactions for the direct activation of N-OH bonds to promote rearrangement into protected amines, again releasing water as the by-product. As over 80% of drug candidates contain amine functionality, the new reactions developed will provide more sustainable and effect methods of accessing these important motifs.
The development of the new synthetic methods will be supported by work to prepare and gain fundamental understanding of new bifunctional boron-based catalysts. We will explore readily available boron systems as Bronsted acid catalysts in combination with a tethered Lewis base. The bifunctional acid/base system will allow for stabilisation of reaction intermediates that may enhance overall reactivity and/or selectivity. Mechanistic studies will be used to elucidate the structure and dynamic behaviour of the catalysts in solution, with the knowledge gained used to aid further catalyst development and support the optimisation of the new synthetic methods.
Overall, the new catalytic technology developed, alongside increased fundamental understanding of the processes will provide both industry and academia with an enhanced toolbox for the sustainable synthesis of valuable organic molecules.
Organisations
Publications
Babcock EG
(2022)
Brønsted acid-catalysed desilylative heterocyclisation to form substituted furans.
in Organic & biomolecular chemistry
Boyce G
(2022)
Arylboronic Acid-Catalyzed Racemization of Secondary and Tertiary Alcohols
in The Journal of Organic Chemistry
| Description | Progress has been made towards one of the key objectives of developing new, mild catalytic reactions that can be use to prepare structural motifs found in pharmaceuticals. The processes we have developed use readily available catalysts under easily accessible reaction conditions, making the protocols widely accessible to other researchers. We also have promising preliminary results applying the new catalytic systems to the synthesis of challenging motifs that cannot be easily accessed in any other way. This is important, as it potentially opens up new chemical space that can be explored for applications, for example in the pharmaceutical or agrochemical industries, and possibly materials science. |
| Exploitation Route | We have published two open-access articles on this research to date, with more expected in the near future. Initial benefits will likely be seen in the academic community, as our methods can be used to conveniently prepare important chemical structures that have many uses. The longer-term impact could potentially be seen if any of the molecules that we can prepare with our new method have interesting properties (e.g. biological activity, material properties). |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |