Violet light and a common household chemical—periodate, found in some disinfectants—can insert oxygen atoms into drug molecules, a reaction that has historically required explosive gases or toxic metals. Many promising drug candidates fail because their molecular structures are too flat and lack the three-dimensional, oxygen-rich features found in natural products. Current methods to add oxygen are dangerous, expensive, or incompatible with delicate drug-like molecules. This project tackles that bottleneck by generating a highly reactive intermediate called oxene—a single oxygen atom—through a simple, metal-free process. The researchers have already used this approach to convert simple starting materials into oxygenated fragments and to edit complex molecules. If successful, the PhotoOxyEdit platform could give chemists a safe, practical tool for late-stage oxygen insertion. This would allow pharmaceutical and agrochemical companies to salvage failed clinical candidates, create more three-dimensional drug libraries, and access entirely new classes of oxygen-containing molecules. The same method might also be extended to insert sulfur atoms, broadening its impact on fine-chemical synthesis. The work is fundamental synthetic chemistry, but it directly addresses a practical bottleneck in drug discovery pipelines.
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Small molecule drugs continue to play a central role in the progress of medicine, accessing target space and opening up new modes of action that are inaccessible to other drug modalities. However, over the last decade, it has been widely recognised that compound libraries and lead compounds have become increasingly populated with flat and heteroatom-rich functional groups that are far removed from those present in natural products and biomolecules, instead, tending to mirror advances in contemporary synthetic chemistry. While these have undoubtedly led to the development of countless pharmaceutical products, many argue that these gaps in molecular architecture have limited biological coverage. As such, efforts are currently underway to include more three-dimensionality, bioavailability, and metabolite-likeness in emerging candidates. Nowhere is this paucity more acutely demonstrated than in the prevalence of oxygen-based functional groups such as alcohols and carbonyls in small-molecule therapeutics. Therefore, the development of new late-stage oxygen-atom insertion methodologies that are simple, general, and robustly applicable to the synthetic demands required in drug discovery pipelines is crucial. To meet this challenge, this proposal will introduce a novel strategy for the metal-free insertion of oxygen atoms into unsaturated carbon frameworks, termed PhotoOxyEdit. This approach seeks to leverage a widely underutilised reactive intermediate – monoatomic oxygen (oxene) – to generate valuable biradical intermediates. We propose that these seldom-encountered species can act as linchpins for the synthesis of complex oxygen-containing molecular architectures. Such intermediates have historically proven challenging to access due to the lack of practical methods for oxene generation. To overcome this, we have designed a new platform that employs violet light and the ubiquitous two-electron oxidant periodate. Through a process of targeted photoactivation, we can unlock a previously elusive pathway to selectively generate oxene under mild conditions. This approach will not only convert abundant unsaturated carbon feedstocks into value-added oxygenated fragments but also permit late-stage oxygen-atom insertion and editing within complex molecules and the potential repurposing of failed clinical candidates. Preliminary work in the group has established the successful implementation of our periodate photoactivation platform resulting in the oxene-mediated epoxidation of olefins. In addition, we have demonstrated the successful oxidative cleavage of olefins to carbonyl compounds; current methods rely heavily on the use of explosive gases and toxic transition metals. Capitalizing on these results, we propose to expand our photo-mediated oxygen editing approach towards the preparation of novel oxy-heterocyclic molecules via unprecedented oxygen-based cycloadditions, strain-release oxy-annulation, and oxidative skeletal modification. We further seek to explore the activation of strained C–C bonds to generate previously elusive oxygenated aryl bioisosteres. We finally propose to use our experience in photogenerated reactive intermediates to expand the toolkit of low-valent atom insertion chemistry to other chalcogens, including sulfur. This program is set to provide a new blueprint for the synthesis of oxygenated molecules using a novel and operationally straightforward platform centred on the targeted photoactivation of periodate. By allowing facile access to underutilised biradical intermediates, we will develop a range of new C–O and C–S bond-forming reactions from readily available feedstocks. Our research will contribute towards the UK pharmaceutical, agrochemical, and fine-chemical sectors by overcoming bottlenecks in organic synthesis and repurposing existing function-orientated molecules.
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