A Catalytic Asymmetric Cross-Coupling Approach to the Synthesis of Cyclobutanes

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This project aims to expand on previous work by the Fletcher group which described a novel strategy for the formation of chiral cyclobutanes by an asymmetric Rh-catalysed Suzuki-Miyaura reaction between a cyclobutene and an arylboronic acid. Initially we seek to extend the strategy to 2-azetine substrates, enabling the formation of chiral azetidines. Further work may include the extension of the reaction strategy to ring-opening of spirocyclic acetals connected to cyclobutenes; and Rh-catalysed tandem reactions with bifunctional boronic acids. Azetidine motifs are found in marketed drugs, natural products and desirable synthetic intermediates, so the synthesis of chiral azetidines is relevant to both academic and industrial chemistry. However, the synthesis and functionalisation of azetidines are underexplored problems and few catalytic routes to chiral azetidines are known. This project aims to develop a convenient, enantioselective approach to azetidine synthesis, which may find applications in drug development and production as well as providing a useful tool for chemical synthesis.Fragment-based drug discovery is an established and effective approach for the discovery of small-molecule drug candidates, and usually involves screening of large libraries of molecules made by combinatorial chemistry methods. These methods traditionally rely on well-established sp2-sp2 coupling methods, so the compounds screened tend to be flat and sp2-rich. Due to the lack of simple, general and functional group tolerant methods for their formation, there has not been extensive screening of sp3-rich small molecules with complex, 3-dimensional structures although such molecules are known to have advantages as drug candidates. The methodology developed in this project would allow efficient access to a range of complex, chiral, sp3-rich small molecules based on azetidine scaffolds, enabling the synthesis of interesting candidates for fragment-based screening. The methodology may also be of use to pharmaceutical production due to its ability to form difficult motifs and increase structural complexity highly enantioselectively. This project falls within the ESPRC catalysis and synthetic organic chemistry research areas, under the physical sciences and healthcare technologies research themes. It is jointly funded by ESPRC and GSK through a UCASE studentship.