Design and Synthesis of 3-D Fragments to Explore New Areas of Pharmaceutical Space

The thesis is focused on the design and synthesis of 3-D fragments to explore new areas of pharmaceutical space. Chapter 1 provides an overview of fragment-based drug discovery including, fragment design, screening and synthesis. The diastereoselective synthesis of nine pyrrolidine and piperidine fragments A-I is described in Chapter 2. These fragments were identified as suitable 3-D fragments based on a 3-D shape analysis using principal moments of inertia. The key step in the synthesis of the 2,3-disubstituted pyrrolidines was the stereoselective reduction of the dihydropyrrole to afford the cis-diastereoisomer, with the trans¬-isomers accessed via epimerisation. The piperidines were synthesised via hydrogenation of the pyridine to give the cis-diastereoisomer as the major product, with the trans again access via epimerisation of the methyl ester. Chapter 3 covers of methodology for the synthesis of all 20 regio- and diastereosiomers of piperidines J. The syntheses were completed using three main types of methodology: pyridine hydrogenation, epimerisation and lithiation-trapping of N-Boc piperidines.

In Chapter 4, a different approach to 3-D fragment design and synthesis was developed. Here, the focus was on the identification of synthetic methodology that would allow the incorporation of different scaffolds and a range of aromatic/heteroaromatic groups. Ester enolate α-arylation and α-alkylation were the two approaches used to design fragments K and L which had their shapes analysed, with the most 3-D fragments selected and synthesised.

Finally, the entire York 3-D fragment library was compared against a set of commercial fragment libraries to evaluate their usefulness in drug discovery, with the analysis fully summarised in chapter 5.