Development and application of methods for the synthesis of lead-like scaffolds

This thesis describes the development of novel methodology for the synthesis of diverse heterocycles with physicochemical properties desirable in early stage drug development. The methodology developed in this thesis aims to allow the systematic variation of molecular scaffold from readily available building blocks by using strategies utilising the chemoselective pairing of ambiphilic/ bifunctional building blocks.
Chapter 1 evaluates the requirement for lead-like compounds in early stages of drug development as well as summarising methods for the generation of diverse libraries of compounds. Chapter 2 describes the approaches taken towards the development of a modular approach to ketopiperazines, piperazines and related ring systems through the pairing of either amino acid or cyclic sulfamidate building blocks with amino alcohol derived building blocks. Key to this methodology was a ‘hydroxy-activation’ approach to induce cyclisation to generate heterocyclic scaffolds. Chapter 3 describes the synthesis of tetrahydropyrazine and related heterocycles through the pairing of cyclic sulfamidate and propargyl amine derived building blocks. Key to this approach was the transition metal‒mediated cyclisation of unsaturated acyclic substrates to give unsaturated heterocycles. Furthermore, unsaturated heterocycles were used as substrates for further complexity‒generating reactions to give saturated heterocycles. The potential ability of the methods described in both Chapter 2 and Chapter 3 to deliver lead-like heterocycles was illustrated by the in silico generation of virtual libraries of compounds from readily available materials and assessed according to calculated physicochemical properties.