Synthesis of Quaternary Stereocentres via Hydrogen Borrowing Catalysis

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


Hydrogen borrowing catalysis is a powerful method for the formation of C-C bonds employing reversible oxidation state changes. We have shown that pentamethylphenyl (Ph*) ketones can be alkylated with alcohols in the presence of a transition metal catalyst to give both alpha- and beta- branched products. The process works by the abstraction of hydrogen from the alcohol to generate the corresponding carbonyl compound and a metal-hydride species. The reactive carbonyl compound can then undergo an aldol condensation with the Ph* ketone to give the corresponding enone, which is subsequently reduced by the metal-hydride species to give alkylated product and close the catalytic cycle. Therefore, hydrogen borrowing methodology combines three processes (oxidation, condensation and reduction) into one pot and consequently illustrates the synthetic utility of alcohols. In all hydrogen borrowing reactions to date, the termination of the catalytic cycle results in the delivery of a hydrogen atom to both the alpha- and beta- positions, precluding the synthesis of quaternary centres at these positions. Such quaternary-substituted products are of great synthetic interest due to their high prevalence in biologically relevant molecules, such as drug molecules and natural products.
The aim of this project is therefore to investigate strategies to synthesise quaternary centres using hydrogen borrowing catalysis. We will investigate a variety of strategies (including displacement and rearrangement) to make both alpha- and beta- quaternary centres within the hydrogen borrowing manifold and produce the first examples of such motifs via hydrogen borrowing catalysis. In order to achieve this ambitious goal, we will both utilise and expand upon the methodology developed by the group. We will also investigate the cleavage of the Ph* protecting group in the quaternary products and aim to develop mild cleavage conditions to allow the synthesis of a range of different alpha-quaternary functionality. As an extension of the chemical synthesis methodology, we will investigate further reactions of the product alpha-quaternary carbonyl compounds, by exploiting their properties to gain access to other functionality previously inaccessible via hydrogen borrowing catalysis. This approach may allow the development of a highly convergent synthesis of key motifs which are present within drug molecules. This project is expected to provide a high impact programme of research and falls within the EPSRC Physical Sciences research area.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/T517811/1 30/09/2020 29/09/2025
2417436 Studentship EP/T517811/1 30/09/2020 29/09/2024 Jessica Crompton