Development of an Asymmetric Synthesis of Glionitrin A and B

In this thesis, studies in the chemical synthesis of the dithiodiketopiperazine natural products (—)-glionitrin A and B are described.In Chapter 2, a synthesis of the indoline-fused 2,5-diketopiperazine core of glionitrin A and B using a C-H activation approach is described. The tricyclic core was prepared in only six steps and in a good overall yield (41%). In addition, the synthetic approach was successfully applied to prepare two derivative structures. Exploratory work in elaborating these compounds to the corresponding epi-dithiodiketopiperazines by two different methods is discussed. The firstmethod involved reacting diketopiperazine enolates with electrophilic sulfur to directly install the disulfide bridge. This method was unproductive and gave aromatisation of the indoline ring instead. In the second method, permanganatereagents were used to decorate diketopiperazine substrates with hydroxyl groups by C-H oxidation. This was accomplished with several substrates and the the resulting hemi-aminal products were obtained. Subsequent acid promoted thio-aminal formation at the C10a position was unsuccessful due to indole formation.In Chapter 3, the first total syntheses of glionitrin A and B are discussed. The concise approach provided access to glionitrin A and B in only eight and nine steps, respectively, and in 15% overall yield. The absolute stereochemistry ofglionitrin A and B was revised from S,S to R,R. An asymmetric organocatalytic sulfenylation of a triketopiperazine substrate was developed for the purpose of preparing these natural products.In Chapter 4, the scope of the sulfenylation reaction is studied. Six different triketopiperazine substrates that are structurally related to epi-dithiodiketopiperazine natural products were selected for this purpose. The syntheses and evaluation of these six substrates in the sulfenylation reaction is discussed