New Catalytic Reductive Functionalization Reactions of Carbonyl Derivatives

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Despite the suite of new reductive transformations of tertiary amides achievable with Vaska's complex that have been established over the past 7 years, the analogous application of Vaska-type complexes to other less Lewis basic functional groups such as secondary amides, esters, and carbamates has remained essentially unexplored. However, new computational mechanistic insight (vide infra) into enhanced reducing capability of Vaska-type complexes, combined with a simple and modular route to their synthesis, has uncovered a wealth of untapped potential in the reductive functionalization of other common carbonyl derivatives. This PhD project aims to explore these new applications and to and exploit them in late stage functionalisation of drug-like molecules and synthesis of complex natural products. Investigation into the scope, functional group tolerance, and selectivity of these reactions will be carried out in full. Development of this methodology may lead to trivial chemical modification allowing access to complex chemical motifs of pharmaceutical relevance, and wide potential industrial application. Within this project a range of catalysts will be explored allowing for fine tuning of reactivity, as well as modulation of regioselectivity of the reductive functionalisation. This project falls within the EPSRC "manufacturing the future" research area. The development of new methodology is imperative to the future of the chemical industry and help medicinal chemists to access new tools to late-stage functionalise drugs to study structure activity relationships (SAR). Expanding the chemical toolbox available to synthetic chemists can enable access to previously inaccessible motifs and simplify existing chemical transformations. Traditionally time consuming, resource demanding reactions can be carried out in a single step from readily available starting materials, allowing for the construction of target molecules and lowering the environmental impact of multi-step reactions. Applications of this methodology aims to extend to the generation of valuable bio-isosteres, functional groups which mimic those found in nature allowing the tuning tuning DMPK and ADME properties such as binding strength, solubility, stability, permeability and other optimisable parameters. This project aligns its self with the EPSRC strategic priority of transforming heath and healthcare due to the wide potential industrial applications of this project as outlined above.