Diversity Oriented Synthesis of Chiral Saturated Heterocycles: A New Approach to a Screening Collection of Fragment and Lead-like Compounds

To underpin the exploration and modulation of biology for drug discovery, there is considerable demand to expand the traditional confines of accessible chemical- and IP-space. This is particularly relevant to probe challenging targets where hit compounds have been difficult to find. An important approach has been to examine less planar, more sp3 rich, topologically diverse and chiral systems that present substituents along defined vectors. With this aim, we are interested in generating new synthetic approaches towards novel screening collections based around substituted heterocyclic derivatives, with defined relative and absolute stereochemistry, and bearing different types of functionality that can make valuable binding contacts, or be used to further elaborate a scaffold.

The aims of this studentship are to develop a DOS process to prepare chiral saturated heterocycles with diverse substitution by combining a matrix of readily available building blocks through catalytic X-H insertion and cyclisation. This strategy will provide a highly modular approach to heterocycle synthesis, and generate a library of enantioenriched 4, 5, 6 and 7 membered heterocycles. Enantioenriched building blocks as well as novel enantioselective cyclisations will be examined. Within each heterocyclic series, subsets of compounds will be selected for synthesis based on physicochemical properties and shape parameters. In addition, heterocycles substituted with boron groups will be prepared as building-block reagents for cross-coupling. The heterocyclic products will be suitable for screening directly, and will carry functionality for further elaboration.