Design and Synthesis of a 3-D Fragment Library

This thesis describes the design and synthesis of a library of novel 3-D fragments for use in
drug discovery. Chapter 1 explains the process of fragment based drug discovery in detail,
as well as why the synthesis of novel 3-D fragments is needed and the previous work carried
out in the group to design and select 33 initial 3-D fragments. These fragments were
designed to fit industry-recommended guidelines on physicochemical properties and their 3-
D shape was analysed using principal moments of inertia (PMI) plots to demonstrate that
they occupied under-explored areas of 3-D space. Chapter 2 describes synthetic efforts
towards four of these fragments.
Chapter 3 details a new approach that was devised in order to synthesise 3-D fragments that
contained greater functional group variation. This route focussed on the triflation, Suzuki-
Miyaura cross-coupling, hydrogenation and derivatisation of β-ketoesters to give 3-D
fragments. Using this route, 24 novel 3-D fragments were synthesised.
Finally, Chapter 4 contains an analysis of both the physicochemical properties and the 3-D
shapes of the 1st and 2nd generation 3-D fragments. These properties are compared to both
industry-recommended guidelines and commercially available fragment libraries.