A single molecule of pyridone, when hit with the right wavelength of light, snaps into a strained, cage-like shape called a Dewar-heterocycle—and this research aims to catch that shape before it springs back. Most drugs are built from flat, ring-shaped aromatic compounds, which lack the three-dimensional complexity needed to fit precisely into biological targets. Current methods to add bulk to these rings either destroy the ring entirely or fail to attach new chemical groups. This project solves that by using light to temporarily warp simple starting materials into reactive, three-dimensional structures, then using a metal catalyst to lock a new chemical group onto them in a single step. The key advance is a newly discovered way to generate the reactive Dewar form cleanly, without the side reactions that have historically made this approach impractical. If successful, the method will give medicinal chemists a reliable tool to create rigid, spatially defined molecular scaffolds—bioisosteres—that can replace flat rings in drug candidates. This could improve how tightly a drug binds its target and reduce the energy cost of the molecule adopting the right shape, potentially leading to more effective pharmaceuticals with fewer side effects.
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Within contemporary chemical science the drive towards sustainable innovation is paramount, particularly as finite natural resources continue to diminish. With an annual production exceeding 100 million tons, aromatic compounds represent a fundamental feedstock across various sectors, including pharmaceuticals, agrochemicals, and materials science. These compounds typically form flat, C(sp2)-rich molecules, which, while versatile, often lack the three-dimensional complexity needed for modern applications. One powerful approach to enhance the utility of these aromatic compounds involves dearomatisation, typically through hydrogenation, to give saturated analogues. However, this method fails to introduce new groups which constrains its value in synthesising complex molecules important for drug discovery and materials innovation. Our research develops an innovative dearomative functionalisation approach that efficiently converts simple aromatic compounds such as pyridone and pyridine into functionalised, bicyclic Dewar-heterocycles. Given that on average 6 new ring systems enter drug-space each year and 28% of new drugs contain a new ring system, this research represents an important capability for long-term innovation. Our aims centre on leveraging the photochemically induced [4p]-electrocyclisation of simple heterocycles like pyridone and pyridine to generate Dewar-heterocycles. This reversible process gives a racemic mixture, which will enable the selective capture and functionalisation of one enantiomer over the other. Using an enantiopure metal catalyst, the alkene fragment within these photogenerated Dewar-heterocycles will be targeted for selective hydrofunctionalisation. We will harness stereomutation of Dewar-heterocycle enantiomers to implement a dynamic kinetic resolution that facilitates the enantioconvergent synthesis of topologically unique 3D structures in a single synthetic operation. The question must be asked: Why has the development of a comprehensive catalogue of synthetic methods for functionalised Dewar-heterocycles remained elusive? Synthesis of Dewar-heterocycles necessitates light irradiation, often triggering concomitant side-reactions which render reactions inefficient and purifications challenging. In particular, photogeneration of Dewar-pyridone has historically been both inefficient and unselective. However, we have recently developed a solution to overcome these drawbacks. Specifically, we have discovered a new approach that allows for efficient photogeneration, and reversion, of Dewar-pyridone with exceptional fidelity. This advance provides the basis necessary for capture and stereoselective functionalisation, enabling the synthesis of unique, high complexity bicyclic structures with well-defined spatial configurations. Our research will specifically target the enantioconvergent metal-catalysed hydroarylation of Dewar-heterocycles, selectively giving functionalised, rigid bicyclic structures with well-defined substituent orientations. This rigidity offers substantial benefits in medicinal chemistry by reducing entropic penalties associated with conformational reorganisation at biological targets and by increasing the concentration of bioactive conformers. This synthetic concept will enable selective and efficient access to a diverse array of new bioisosteres, key for enhancing molecular efficacy in pharmaceutical and agrochemical applications. The use of a wide variety of commercially available aryl-boronic acid reaction partners expands the ability to generate a broad diversity of compounds, facilitating strategic design of core structures. Consequently, our generic platforms are geared to promote the development of compounds with optimised target interactions and potentially improved pharmacokinetic properties.
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