Design, Synthesis and Functionalisation of 3-D Building Blocks for Fragment-Based Drug Discovery & Studies Towards the Synthesis of Quinine

This thesis presents a novel approach for the three-dimensional elaboration of fragments and a new strategy for the total synthesis of quinine. The fragment elaboration approach introduces new bifunctional 3-D building blocks, specifically designed to overcome synthetic bottlenecks in fragment elaboration within the context of fragment-based drug discovery. It emphasizes functionalization methodology to address these challenges.
Chapter 1 provides an introduction to saturated nitrogen heterocycles, highlighting their utility and prevalence in medicinal and natural product chemistry. Chapter 2 introduces fragment-based drug discovery and the concept of fragment elaboration, showcasing prior group efforts in designing and synthesizing cyclopropyl-containing bifunctional 3-D building blocks for fragment elaboration. It also details the development of robust methodology for using cyclopropyl-containing 3-D building blocks A-E in fragment elaboration through Suzuki-Miyaura cross-coupling and N-functionalization. Chapter 3 focuses on the design, synthesis, and development of cross-coupling methodology for a new generation of cyclobutyl-containing 3-D building blocks exemplified by F.
Chapter 4 explores a novel synthesis of quinine, starting from piperidine G. It investigates the synthesis of quinine via an unprecedented lithiation-trapping approach, followed by Suzuki-Miyaura cross-coupling and a late-stage N1-C2 bond formation to assemble the quinuclidine motif.