New Metal-mediated Cyclisation Methods for the Generation of Heteroatom Functionalised Polycyclic Systems

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This collaborative project will explore a combination of cobalt-mediated Pauson-Khand methodology and new applications for chiral magnesium amide-mediated asymmetric deprotonation of prochiral ketones. Access to enantiomerically-enriched novel bicyclic substrates possessing enol phosphate motifs will allow transformation into chiral, sp3-rich heterobicyclic frameworks through an iterative cross-coupling-oxidation-heterocycle formation sequence, enabling the rapid construction of a broad range of novel heterobicyclic scaffolds. Such polar, three-dimensional structures have attracted considerable pharmaceutical interest in recent years, due to their favourable physical properties and occupation of underexplored regions of chemical space.The joint proposal contains the combined aims and deliverables from both GSK and the University of Strathclyde regarding the areas of asymmetric deprotonation and target synthesis. The proposed work combines the expertise of both partners to fully explore the organic cyclisation techniques, the asymmetric methodology, and the bicyclic substrate classes amenable to these new processes, to deliver a wide range of functionalised chemical scaffolds that will be of particular interest to the pharmaceutical industry, as well as to the wider preparative chemistry community. As part of the overall programme of work, computationally-driven methods will inform reagent design, direct reaction scope, and investigate reaction mechanism. The main EPSRC research areas addressed are Catalysis, Chemical Reaction Dynamics and Mechanism, and Synthetic Organic Chemistry.