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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.

The synthesis of fused nitrogen heterocycles has been investigated. Chapter 1 describes the synthesis of quinolones through a copper catalyzed amide coupling to ortho acetyl aryl halide followed by an aldol condensation that produces the quinolone in modest to good yields. The reaction works well with lactam partners and leads to tricyclic ring systems. Chapter 2 describes the synthesis of 8 membered enamide rings through a [3,3] sigmatropic rearrangement ring expansion of N-vinyl β-lactams. The N-vinyl β-lactams also undergo a 6π electrocyclization following the [3,3] sigmatropic rearrangement to furnish amino cyclobutanes. Previously reported amino cyclobutanes have been made using [2+2] photocycloaddition and resulted in a mixtures of diastereoisomers. Our method produces the amino cyclobutanes in good to high yields and with excellent levels of diastereoselectivity. Chapter 3 describes the synthesis and applications of reduced hydantoins from aziridine aldehydes and isocyanates. The resulting heterocycles contain an aziridine ring fused to a 5 membered urea. We also demonstrate that the reduced portion of the hydantoin, namely the hydroxyl group, can undergo further displacement with β-ketoesters similar to iminium ion chemistry.

The synthesis of fused nitrogen heterocycles has been investigated. Chapter 1 describes the synthesis of quinolones through a copper catalyzed amide coupling to ortho acetyl aryl halide followed by an aldol condensation that produces the quinolone in modest to good yields. The reaction works well with lactam partners and leads to tricyclic ring systems. Chapter 2 describes the synthesis of 8 membered enamide rings through a [3,3] sigmatropic rearrangement ring expansion of N-vinyl β-lactams. The N-vinyl β-lactams also undergo a 6π electrocyclization following the [3,3] sigmatropic rearrangement to furnish amino cyclobutanes. Previously reported amino cyclobutanes have been made using [2+2] photocycloaddition and resulted in a mixtures of diastereoisomers. Our method produces the amino cyclobutanes in good to high yields and with excellent levels of diastereoselectivity. Chapter 3 describes the synthesis and applications of reduced hydantoins from aziridine aldehydes and isocyanates. The resulting heterocycles contain an aziridine ring fused to a 5 membered urea. We also demonstrate that the reduced portion of the hydantoin, namely the hydroxyl group, can undergo further displacement with β-ketoesters similar to iminium ion chemistry.

Méthodologie d'addition-cyclisation de guanidines et amidines sur les quinones pour la synthèse de 2-aminobenzimidazole. Application de cette stratégie à la synthèse de benzo-bis-2-aminoimmidazole, un motif important de la benzosceptrine.Valorisation de produits synthétisés par évaluation biologique : l'inhibition de kinase, la cytotoxicité sur les lignées cellulaires cancéreuses du sang. / Methodology of addition-cyclization of guanidines and amidines on quinones for the synthesis of 2-amino-benzimidazole. Applying this strategy to the synthesis of benzo-bis-2-aminoimmidazole, an analogue of benzosceptrine.Reclamation of products synthesized by biological evaluation: inhibition of kinase, cytotoxicity on cancer cell lines of blood.

The thesis describes synthesis and reactions of allene azides tethered to various functional groups and the application of the discovered cascade transformations towards the synthesis of radianspene J model system. Chapter 1 covers reactions of simple allene azides containing alkyl and cycloalkyl substituents. Thermal rearrangements of these substrates delivered isocyanides and azadienes via the proposed azatrimethylenemethane (ATMM) intermediates. On the other hand, vinylidenecyclopropanes (VDCPs) gave dramatically different products, as described in Chapter 2. A phenyl-substituted VDCP was transformed into an unstable polycyclic compound by a divinylcyclopropane rearrangement. Chapter 3 discusses allene azides tethered to furan, N-substituted pyrroles, and E- and Z-dienes. Depending on the structure of the starting material, products of formal (3+4)- or (2+3)-cycloaddition were formed. Finally, an application of the discovered cyclisation cascade towards total synthesis is described in Chapter 4. A model system of radianspene J was assembled using a key transannular cycloaddition of a macrocyclic allene.

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