A 'top down' approach to the synthesis of complex, diverse lead-like scaffolds

Lead-oriented synthesis (LOS) is a concept that seeks to underscore the usefulness of developing new methodologies suitable for making a diverse library of highly three-dimensional small organic molecules with controlled molecular properties that qualify them to most likely serve as lead compounds or be in the 'lead-like' space. The 'top down' approach to LOS seeks to gain rapid access to complex polycyclic assemblies which can then be deconstructed or modified through ring addition, cleavage and expansion to generate multiple, diverse lead-like scaffolds. This strategy hopes to solve the problem of high attrition rates in drug discovery. 14 diverse sp3-rich scaffolds have been synthesized through this means from relatively cheap and simple materials using a novel oxidative dearomatisation reaction as the complexity-generating step. The scaffolds have been decorated along different vectors with exemplar medicinal chemistry capping groups to generate 52 final compounds, with their molecular properties assessed by LLAMA (Lead-likeness and Molecular Analysis) prior to the decoration, and shall be tested for biological activity against a wide range of targets. Chapter 1 discusses the the general overview to small molecule drug discovery. Some of the issues touched are the high attrition rates of drug discovery, factors linked to such attrition rates and the importance of synthetic chemistry in the drug discovery process. Chapter 2 discusses the key scaffold synthesis and the application of the ‘top down’ approach to generate complex and diverse molecular scaffolds. Chapter 3 discusses the functionalisation of the diverse scaffolds along different vectors to generate final compounds for biological screening, as well as the LLAMA analysis of such compounds