Approaches to spiropiperidine scaffolds : targeting G-protein coupled receptors

Abstract

Spiropiperidines have been labelled as “privileged structures” in regard to their ability to provide ligands for G-protein coupled receptors (GPCRs).  These GPCRs are a superfamily of cell regulators implicated in the control of a vast number of disorders that range from arthritis and atherosclerosis to anxiety and depression.

The work in this thesis describes the synthesis of a novel spiro [1-benzofuran-2,4’-piperidine]-3-one scaffold, aimed at providing efficient access to lead compounds within the GPCR family.  Derivatisation of the spiropiperidine core has been achieved both in single chemoselective reactions, and later in the composition of multi-step telescope reaction matrices.  In the latter case, the compounds synthesised exhibit physical characteristics consistent with guidelines for sound drug-like properties.

Synthesis of an analogous indoline-spiropiperidine was also accomplished.  Taking advantage of sulfur’s ability to undergo neighbouring group participation led to the optimisation of a 5-endo-tet cyclisation to afford another privileged spiropiperidine core with the potential to serve as a novel scaffold to target GPCRs.

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