Taming N-Fused Saturated Bicycles for Discovery Chemistry and Scale-Up

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Despite being common in bioactive alkaloids and having broad commercial availability of parent compounds, saturated N-fused bicycles are rarely exploited in drug discovery. This could be attributed to their low commercial availability as well as high cost and high synthetic effort required to access functionalised derivatives. They currently require long multi-step reactions to prepare making them not readily available. This project aims to use existing knowledge of amine alpha-C-H bond functionalisation to access saturated N-fused bicycles in a simplified and automated manner. This will allow medicinal chemists access to a space of structures with potentially untapped potential. Once this has been achieved, these structures will be used to demonstrate new late-stage C-H functionalisation processes. It is crucial that new methodologies are applicable on a discovery (mg) and large (kg) scale. The first aim of the project will look at automating the synthesis of saturated N-fused bicycles via catalytic ring fusion. This will involve combining automated 'catalytic ring fusion' methodology for secondary amines with recently developed, fully automated annulation chemistry with primary amines. The second aim will move on to the automated synthesis of a-(hetero)arylated, saturated N-fused bicycles. A recently invented, scalable synthesis of a-(hetero)aryl N-heterocycles from aromatic aldehyde feedstocks using novel y-amino sulfoxides as reagents will be expanded to the automated synthesis of a-(hetero)arylated pyrrolizidines, using novel y-amino sulfoxide as the key reagent. The chemistry will be automated in 96-plates using ChemSpeed platform at the University of Bristol.Thirdly, this project will aim to develop late-stage C-H functionalisation at several different positions on the N-fused bicycle structure, the stereoselectivity is controlled by the bicyclic system. In summary, this project aims to deliver new C-H functionalisation reactions applicable to both discovery and scale-up, novel N-fused bicyclic scaffolds for use in drug discovery, new methodology for metal-free synthesis of a-(hetero)aryl N-heterocycles, new late-stage C-H functionalisations for tertiary amines and a new bioisostere concept for 1,2-disubstituted aromatics.