Enecarbamates as platforms for the synthesis of diverse polycyclic scaffolds

The efficient and continued exploration of novel chemical space is vital for the discovery of new drugs, with the construction of sp3-rich scaffolds being of particular interest. This thesis describes the elaboration of a common intermediate, via a toolkit of techniques, to access structurally diverse, novel, and highly three-dimensional polycyclic scaffolds, based on pharmaceutically valuable N-heterocyclic cores. Chapter one discusses the importance of properties and structure at several stages in the drug discovery process, including those for leads and fragments. Common motifs are highlighted and associated modern synthetic approaches discussed. Chapter two describes the delivery of a library of enecarbamate and hemiaminal ether-based building blocks through a unified approach. A toolkit of α- and β-functionalisation methods are applied for their elaboration. Chapter three describes the development and use of the β-functionalisation toolkit for enecarbamates, through the photocatalysed construction of spirocyclic systems. Herein, five exemplary spirocyclic structures are accessed based on two scaffolds. Chapter four evaluates the versatility of the photoredox toolkit via its application in the synthesis of ten bicyclic amides and five bicyclic anilines, from enecarbamates, through a modular approach. The resulting structural distortion regarding N lone pair and π-system overlap is assessed, via their physical properties, including measured nonaqueous pKaH. The subsequent impact on reactivity and bioactivity is evaluated. Chapter five discusses the use of enecarbamates in annulative technologies for the preparation of a series of fused motifs including two bicyclic lactams, seven oxetanes and nine cyclic aminals. A fully diastereoselective, photochemical synthesis of oxetanes is described and cyclic aminals have been highlighted as structures bearing a potential novel warhead. Chapters six and seven present the thesis conclusion and all associated experimental details, including full characterisation of synthesised compounds.