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 first
method 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, permanganate
reagents 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 of
glionitrin 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

Throughout history, humans have turned to nature for medicinally beneficial
substances. This is still common practise today, and new natural products with
potent biological activities are discovered on a regular basis from plants and microorganisms. Nature often produces these compounds in minute quantities. Studies aimed at developing such compounds as new anti-biotics and anti-tumour agents often require larger quantities than those available from nature. One way to solve the supply problem is by chemical synthesis. In this thesis, development of a chemical synthesis of the rare natural products glionitrin A and B is described.

Developing a chemical synthesis of a natural product is similar to climbing a
mountain. After selecting a particular mountain, the mountaineer makes a plan to
reach the top. The number of possible paths to reach the summit are vast and it is up to the mountaineer to find a desirable one. Armed with a plan to reach the peak, the mountaineer starts the ascent. Somewhere along the journey, unforeseen obstacles might be encountered that block the way. Faced with this scenario, it is up to the mountaineering pathfinder to either revise the current plan or invent a way to overcome the obstacle. The destined peak patiently awaits, and the persevering adventurer might succeed in the journey.

Similarly, having set eyes on a natural product to target for chemical synthesis,
such as glionitrin A and B, the chemist begins by devising a plan for the chemical
synthesis. There are many possible ways to reach glionitrin A and B in the
laboratory. The goal of the chemist is to do so in the most efficient way, and more often than not, this is also the shortest way. In practise, a series of consecutive chemical reactions are performed on a molecule. Each chemical reaction adds or removes a specific feature from the molecule until the desired target(s), in this case glionitrin A and B, are reached. The chemical pathfinder often encounters unforeseen obstacles too that prevent completing the planned synthesis. The chemist must then revise the synthetic plan or invent new chemical methods to overcome these obstacles.

The targets of this thesis, glionitrin A and B, originate from an unusual place:
An abandoned South-Korean coal mine. Studies showed that glionitrin A is a novel antibiotic compound that also has anti-tumour properties. Its sibling, glionitrin B, does not have such properties, but is known to suppress the spreading of certain cancer cells. The purpose of developing a chemical synthesis of glionitrin A and B is to provide sufficient material for further studies into their promising medicinally benevolent properties.