Development of methods for the lead-oriented synthesis of molecular scaffolds

There is an unmet and continuing need for diverse compounds with appropriate physicochemical properties for screening collections. This thesis focusses on the preparation of diverse scaffolds which may provide access to lead-like compounds after decoration. The approach was underpinned by robust connective reactions and cyclisations. Computational tools were used in the design and subsequent analysis of the compounds obtained. Chapter 1 discusses the pharmaceutical sector and the challenges associated with creating and maintaining diverse screening colections. Molecular properties are key to the solving the problems with that industry. The concept of Lead-Oriented Synthesis (LOS) is introduced to help address these challenges. Chapter 2 details the significant challenges which were encountered when attempting to use the Petasis reaction for LOS. Ultimately however, it was not possible to retool this reaction for the synthesis a library of diverse lead-like compounds. Chapter 3 details the use of a computation protocol to direct the selection of a new connective reaction to support lead-oriented synthesis. The tools were used to compare five alternative connective reactions. On the basis of this analysis, the nitro-Mannich reaction was prioritised for experimental investigation. Chapter 4 describes the preparation of small functionalised nitro adducts and the exploitation of a small toolkit of robust methodologies to access seven scaffolds. A virtual library of 2413 compounds was enumerated from the scaffold, of which 46% were found to be lead-like. It was concluded that the nitro-Mannich reaction can support lead-oriented synthesis