A "top down" approach to diverse small molecule scaffolds

Historically, chemists' exploration of chemical space has been uneven and unsystematic. Most diversity-oriented approaches to expand the range of available molecular scaffolds have exploited a the "build-couple-pair" approach in which building blocks are linked and then cyclised to yield scaffolds. This iCASE project (with AstraZeneca) will develop a complementary "top down" approach in which complex, yet synthetically accessible, intermediates are simplified/developed to yield alternative molecular scaffolds. Specifically, cycloaddition chemistry will be developed and exploited in the synthesis of complex intermediates, which will then be transformed into alternative scaffolds by ring cleavage, annulation and ring expansion. The synthetic approach will be highly efficient, and will enable the synthesis of many diverse molecular scaffolds. The biological relevance of the novel scaffolds will be investigated in order to establish the value of the approach in driving bioactive small molecular discovery. The project focuses on the development of a new chemical approach to drive ligand discovery, and aligns with the EPSRC's chemical biology research area.