Enantioselective C-H Functionalisation of Heterocycles: Catalytic Routes to Essential Scaffolds for Medicines and Screening Compounds
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
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.
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.
