Enantioselective Synthesis of Functionalised Vinyl Sulfones

Peptidyl vinyl sulfones are a class of irreversible protease inhibitors due to their covalent bonding to a cysteine residue in the enzyme active site and have proven anti-trypanosomal activity. The traditional linear synthesis route is limited to commercially available single enantiomer precursors. Therefore, only the (S)-configuration vinyl sulfone can be formed and the range of substituents available is also limited. Presented herein is a new synthetic route to the vinyl-sulfone-based protease inhibitors. This new strategy features an enantioselective a-amination Horner-Wadsworth-Emmons reaction and the obtained enantioenriched N,N’-di-protected trans-[phenyl(sulfonyl)]vinyl hydrazine intermediates were successfully converted into both diastereomers of dipeptidyl vinyl sulfones. Chapter 1 introduces the chemistry and biology of vinyl sulfones. It briefly covers the background of cysteine proteases and specific bioactivity of cysteine proteases in parasites and viruses. Chapter 2 describes the attempts to synthesise peptide-based vinyl sulfones through an aminooxylation Horner-Wadsworth-Emmons reaction and the problematic reductions of the intermediate ¿-azido vinyl sulfones. Chapter 3 describes the development of an a-amination Horner-Wadsworth-Emmons featured synthetic route. The conversion of these ¿-hydrazino vinyl sulfones to the desired ¿-amino substituted compounds was achieved through a Boc-deprotection, Zn reduction, N-functionalisation sequence. This process enabled synthesis of the aimed dipeptide-based vinyl sulfones inhibitors, including the well-studied cysteine proteases inhibitor K11777 and its diastereomer. The deprotected enantioenriched vinyl sulfone hydrazinium salts in this sequence were also converted into the corresponding N-heterocycle vinyl sulfones. Chapter 4 includes the experimental details for Chapters 2 and 3 and an Appendix contains selected spectroscopic details.