Most pharmaceuticals are flat, two-dimensional molecules, but drug targets inside the body are three-dimensional—and a new chemical method aims to bridge that gap in a single step. The problem is that many promising drug candidates are complex, three-dimensional heterocycles, which are difficult and expensive to make using current methods. Chemists typically start with flat aromatic compounds, then need multiple steps to build the desired shape. This project develops a catalytic process that transforms flat aromatics directly into complex 3D molecules in one step, using very low loadings of a metal catalyst. This reduces waste, energy use, and cost. If successful, the approach could give pharmaceutical companies rapid access to molecules that are currently unobtainable, accelerating drug discovery and reducing the environmental footprint of synthetic chemistry. The project includes an industrial partner, AstraZeneca, ensuring the outputs are relevant to real-world drug development. While the work is fundamental in nature—understanding and optimising a catalytic dearomatisation reaction—it has clear, near-term applications in the manufacture of new medicines.
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This project seeks to solve the challenge of making complex '3 dimensional' molecules (here heterocycles) that are of interest and of use to the pharmaceutical industry. The proposed solution is to transform flat '2-dimensional' aromatic compounds into stereochemically and functionally diverse target molecules in just one step. The route that will be developed to transform readily available aromatic compounds into complex heterocycles uses catalysis to promote a dearomatisation (essentially here a reduction) reaction. This approach will revolutionise the way that such complex targets are made and give rapid access to molecules that were hitherto unobtainable. Here, the utilisation of very low loadings of a metal catalyst to allow an otherwise impossible or extremely difficult transformation is in itself a valuable and worthwhile goal that reduces the environmental impact of synthetic chemistry and is clearly of great interest to both academia and industry. We have plans to optimise the processes that are developed further so that they can use smaller amounts of easily available metal catalysts. This project will study all aspects of the catalytic dearomatisation reaction and in so doing will understand and exploit it fully. A team of academic collaborators and an industrial project partner (AstraZeneca) has been assembled and this will ensure that the work can expand to follow all worthwhile directions and also retain a focus on producing industrially relevant outputs. For example, we have the possibility to collaborate with specialist academic chemists as well as having access to the enormously diverse set of expertise found in the chemical industry.
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