Making a drug molecule often requires chemists to selectively break and remake a single carbon-hydrogen bond on a ring-shaped heterocycle—a common scaffold in medicines—while also ensuring the product has the correct 3D mirror-image form. Current methods to do this are inefficient, requiring multiple synthetic steps and generating waste. The pharmaceutical industry has called for cleaner, faster ways to build these complex molecules. This research develops catalytic methods that directly convert a simple, unactivated C–H bond on a heterocycle into a more valuable carbon–carbon bond, with precise control over the molecule’s 3D shape. The team will also use a “transient directing group” strategy, which temporarily guides the reaction using existing chemical handles, cutting out extra synthetic steps. If successful, the work will give medicinal chemists a straightforward, intuitive tool to rapidly build screening compound libraries and modify known drug scaffolds. This could accelerate early-stage drug discovery by reducing the time and waste needed to produce candidate molecules. The project is fundamental synthetic chemistry—it does not test a specific drug—but similar catalytic methods have previously enabled entire classes of pharmaceuticals, from cancer treatments to antivirals.
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The ability to prepare new molecules is crucial to address major societal challenges, including the development of pharmaceutical drugs. The pharmaceutical industry has repeatedly called for improved streamlined synthetic methods and new bond forming processes to aid discovery and development of drug molecules. To minimise environmental impact, chemistry must increasingly be performed catalytically, where a small amount of catalyst transforms a large amount of starting materials to products. A leading catalytic technology for complex molecule synthesis is known as 'C-H functionalisation'. This selectivity converts carbon-hydrogen (C-H) bonds into much more valuable linkages such as carbon-carbon bonds, to build a desired molecule. Furthermore, to ensure appropriate interactions with biological systems, synthetic methods must control the 3D shape of molecules. Heterocycles are carbon-based ring structures that contain at least one heteroatom in the ring (i.e. an oxygen, nitrogen or sulfur atom). They are crucial components in medicines. This research will develop methods for the 'C-H functionalisation' of heterocycles. Furthermore, this will be 'enantioselective' i.e. will control the precise 3D location of the reaction to produce only one of the two mirror image forms. High value heterocyclic products useful in the discovery of new drugs will be prepared directly from simple, readily available precursors. The developed methods will aid in divergent synthesis of the collections of compounds required in drug discovery and will present an intuitive synthetic disconnection option for medicinal chemists to accelerate drug discovery and development. Specifically, this research will: - Develop methods for exquisite control of 3D shape by selective functionalisation of a precise unactivated C-H bond on heterocycles and study the mechanism by which this can occur. - Develop more streamlined methods to achieve enantioselective C-H functionalisation on heterocycles, by using existing, common and useful functionality to form a 'transient' directing group. This will further reduce the required synthetic operations to generate the valuable heterocyclic products. - Prepare screening collections of compounds, as well as develop the synthesis of analogues of known drug compounds in a divergent manner. - Develop compounds as reactive mirror-image pairs, using the developed methodology, that will be useful in screening efforts in drug discovery and in developing our understanding of biological systems. Overall, this research will develop new synthetic and catalytic methods for the generation of enantioenriched heterocycles that can be widely applicable in fields of chemical synthesis and medicinal chemistry to accelerate the development of new therapeutics.
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