Chapter 1 introduces the concept of cell death, the role of caspases and attempts by synthetic organic medicinal chemists to develop compounds which target caspases selectively and the challenges they face. The rationale behind the targets and inhibitor designs are discussed along with homologation strategies. This includes iterative processes as well as C-C bond forming reactions. The initial aims of this work, namely, to replace diazomethane as a homologation strategy, are set out.

Chapter 2 describes the use of sulfoxonium ylides in the production of amino acid derived α-halomethylketones, key intermediaries in caspase inhibitor synthesis. This includes the initial proof-of-concept work, analysis of stereochemistry and application to the production of three known caspase inhibitors. The use of further substituted sulfoxonium salts to introduce stereocentres adjacent to the enzyme’s prime sites is discussed with applications.

Chapter 3 continues along these themes, looking at the production of mono- and dichloromethyl ketone derivatives of N-protected amino acids. The former directly via a Claisen-type reaction with chloroacetic acid and the latter using dichloromethyllithium which can be further transformed into the monochlorinated species. Analysis of the stereochemical outcome of these reactions and comparison with the ylide chemistry is explored.

Chapters 4-6 look at the utility of producing mono- and dichloromethylketones via the routes outlined in chapter 3. Specifically, chapter 4 focuses on the production of peptide chains containing 1,2,3-triazoles which act as non-hydrolysable peptide bond mimetics, along with the applications thereof. Chapter 5, however, looks in-depth at HIV inhibitor compounds and their synthesis from a common epoxide intermediate and chapter 6 outlines the synthesis of two of these compounds, darunavir and amprenavir.