Novel Synthesis and Functionalisation of Indoles: Application to The First Synthesis of The Natural Product Echinosulfone A Methyl Carbamate

This thesis describes the development of novel methods for the synthesis and functionalisation of indoles. These compounds are of importance since they are prevalent in a wide range of naturally occurring compounds, pharmaceuticals and several important synthetic molecules.
The first part of this thesis describes the development of an effective synthetic approach to introduce the azetidine ring into indoles through a direct C-S bond forming reaction that provides a simple access to the azetidine analogues of the analgesic 3-indole thiopiperidine using azetidine sulfinate and thiosulfate salts, the former appearing to show significantly broader scope. Further functionalisation of the products can be exploited for the synthesis of multi-functionalised indole based sulfides, sulfoxides and sulfones. In addition, this chemistry was successfully extended to include other heterocycles of interest such as pyrroles and imidazo[1,2]pyridines using a variety of aliphatic and aromatic organothiosulfate salts. The mechanism of the direct C-H bond sulfenylation was subsequently investigated. Despite the fact that both sulfinate and thiosulfate salts have been proposed to act as reactive electrophiles via the formation of a sulfenyl iodide, the obvious differences in reactivities found in their reaction with indoles has led us to propose the intermediacy of sulfoxonium iodides from the sulfinate salts during this electrophilic aromatic substitution. Moreover, the coupling of azetidine thiosulfate to less nucleophilic aromatic systems such benzene and thiophene via the corresponding Grignard reagents is included in last section of this chapter.

The second part of this thesis involves the development of a convenient synthetic strategy for the first total synthesis of the natural product echinosulfone A. In this context, the synthesis and use of indole Bunte salts as a valuable key intermediates was investigated. Pleasingly, the synthesis of methyl protected echinosulfone A was successfully achieved. The route is short and completely regioselective.

The third part of this thesis describes an investigation into the synthesis and stabilities of 3-borylated indoles. Specifically, 3-indole pinacol boronic esters were found to undergo facile protodeborylation in the presence of palladium catalysts and base, whereas the corresponding boronamides were more stable. Suginome’s reagent provides an alternative species to access 3-indole boronamides as these compounds are less susceptible to protodeborylation. The first synthesis of 3-indole boronamides (indole-Bdan) from their corresponding 3-iodoindoles under Pd-catalyst is presented in this chapter along with the investigation of relative stability of indole-Bdan and indole-BPin compounds towards the borylative cyclisation conditions. It was found that indoles-Bdan are more stable than their corresponding indole boronic ester counterparts. Furthermore, the successful borylative cyclisation of 2-alkynylanilides to their corresponding indole boronamides using Suginome’s reagent is described, followed by the attempts of their further elaboration.