Boronic Acid-Catalysed Dehydrative Synthesis

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.