Design and Synthesis of Three-Dimensional Pyrrolidine Fragments

The research described in this thesis concerns the design and synthesis of three- dimensional pyrrolidine fragments for use in fragment-based drug discovery. Chapter 1 provides an overview of fragment-based drug discovery and highlights the importance of three-dimensionality in drugs and fragments.

In Chapter 2, a principal moments of inertia (PMI) analysis of the three-dimensional shape of pyrrolidine fragments in described. The PMI plot that was used to select pyrrolidine fragments with methyl and methyl ester groups and four different nitrogen substituents (NH, NMe, NMs, NAc) is shown below.

In Chapter 3, the synthetic efforts towards some of the three-dimensional pyrrolidine fragments are described. The synthesis of A1·HCl, A2·HCl, A3-4 and A40 was successful, but problems were found in the synthesis of H16 and G16.