The research in this thesis describes an asymmetric pericyclic cascade approach to the synthesis of a range of enantioenriched oxindoles using enantiopure oxazolidine derived nitrones and disubstituted ketenes. Chapter 1 aims to place this work in the context of the literature, describing other commonly employed or state-of-the-art asymmetric approaches to oxindoles and related compounds. Examples of where these approaches have been used successfully in the total synthesis of related indole alkaloids are also presented. The conception of this project within the group is also described alongside initial attempts to develop the first enantioselective variant of the same reaction using nitrone chiral auxiliaries. Chapter 2 details the optimisation of this asymmetric oxindole forming reaction by structural variation of the nitrone component, culminating in the preparation of an N-TIPBS nitrone based on an oxazolidine framework, which proved to be optimal for this process. Also detailed are attempts to gain insight towards the mechanism of this transformation and to understand the mode of chirality transfer. Chapter 3 details the use of the N-TIPBS nitrone scaffold as a transmitter of chiral information in the synthesis of 3-alkyl-3-aryloxindoles and spirocyclic oxindoles. Chapter 4 delineates the mechanism of this transformation as a pericyclic cascade process. The key stereo-determining features are discussed including the conformational preferences of such chiral oxazolidine derived nitrones and the influence of the N-protecting group on the stereochemical outcome. Synthetic endeavours to provide evidence as to the validity of this computational mechanistic rationale are also presented. Chapter 5 describes regioselectivity studies, and tolerance of both the racemic and asymmetric reactions to varying substitution on the nitrone N-aryl ring. Initial studies were undertaken using achiral nitrones before the interplay between regio- and stereoselectivity was explored, initially with enantiopure N-Boc Garner's aldehyde derived nitrones, and further with N-TIPBS nitrones. Chapter 6 initially describes attempts to transform this chiral auxiliary methodology into a catalytic asymmetric protocol, by investigating in situ ketene formation via various strategies including activation of carboxylic acids. Also described are investigations into related nitrone-ketenimine cycloadditions, and related [3+2] nitrone cycloadditions. Chapter 7 describes the application of this methodology toward the synthesis of compounds with biological relevance. The concise asymmetric synthesis of a Roche anti-cancer agent is outlined, as is the extension of this methodology to the synthesis of indole alkaloid-like species. Finally, the attempted application of this methodology toward the asymmetric synthesis of (+)-gliocladin C is outlined.

A novel application of the Pauson-Khand reaction was applied to the synthesis of a series of bridged azatricyclic piperazines. This method represents the first application of the Pauson-Khand reaction to synthesize azabridged scaffolds. The ubiquity of bridged azabicyclic ring systems in biologically active natural product skeletons has provided the synthetic chemist with a wealth of opportunity for development over the last century. To this day, the development of new methodologies to tackle these structurally challenging systems remains at the forefront of synthetic chemistry. During our efforts to achieve a total synthesis of the stemofoline alkaloids, we have thus far developed a novel and scalable synthetic strategy to access the fully functionalized caged azatricyclic core of these challenging alkaloids. The overall synthetic strategy we have implemented began with the commercially available and affordable 2-deoxy-D-ribose as a chiral starting material. Furthermore, we have developed a novel 1,3-dipole cascade cycloaddition, which was successfully employed as the key step in the construction of the bridged azatricyclic core of the stemofoline alkaloids. / text