New applications of organocatalysis, in particular the use of the bicyclic amidine DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and then iodide as nucleophilic catalysts for Friedel-Crafts reactions, have been investigated. Firstly, the use of amidines and guanidines as nucleophilic catalysts is reviewed. Amidines and guanidines are traditionally thought of as strong, non-nucleophilic bases. However, there is increasing evidence to suggest that amidines and guanidines are actually strong nucleophiles and can act as catalysts in a number of reactions. The development of the first organocatalytic Friedel-Crafts acylation reaction is then described. It was found that DBN catalyses the regioselective C2-acylation of pyrroles and C3-acylation of indoles using acyl chlorides. The protocol was shown to work for a wide range of aromatic and alkyl acyl chlorides, as well as for a number of protected pyrroles and substituted indoles. The synthetic utility of the methodology was demonstrated with the synthesis of the non-steroidal anti-inflammatory drug Tolmetin. Detailed mechanistic studies have confirmed that DBN acts as a nucleophilic catalyst in the reaction, forming an N-acyl DBN intermediate with the acyl chloride. The structure of the intermediate has been confirmed by X-ray crystallographic analysis of an N-acyl DBN species as its tetraphenylborate salt. As the N-acyl DBN tetraphenylborate salt was found to be bench stable, the use of such salts as alternatives to acyl chlorides was investigated. A number of crystalline and air stable N-acyl DBN tetraphenylborate salts were synthesised and were shown to act as acylating agents towards a wide range of nucleophiles, including primary and secondary amines, sulfonamides, and alcohols. The DBN hydrotetraphenylborate side-product could be conveniently removed from the reaction mixtures by filtration, allowing pure acylated products to be isolated without the need for column chromatography. Finally, whilst investigating the Friedel-Crafts acylation of pyrroles, it was found that lithium iodide was a highly active catalyst for the process. Preliminary mechanistic studies suggest that the iodide acts as a nucleophilic catalyst towards acyl chlorides to form an acyl iodide intermediate in the reaction

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

This thesis describes the development and application of a new class of bifunctional organocatalysts, incorporating the novel triaryliminophosphorane organosuperbases, for asymmetric synthesis. This thesis seeks to address some of the limitations of organocatalysis, namely long reaction times, high catalyst loadings and poor atom economy was sought. Chapter 2 outlines the design and synthesis of the bifunctional iminophosphorane (BIMP) catalysts such as <b>1</b> which were synthesised on gram scale. Chapter 3 describes the application of the BIMP catalysts to the first general organocatalytic enantioselective ketimine nitro-Mannich reaction. Twenty ketimines <b>2</b> were investigated and the &beta;-nitroamine products <b>3</b> were formed in up to 97&percnt; yield and 95&percnt; ee. The reaction was demonstrated on a 10 gram preparative scale with 1 mol&percnt; catalyst. Chapter 4 describes the first organocatalytic enantioselective sulfa-Michael addition of alkyl and benzylic thiols <b>5</b> to simple &alpha;-substituted &alpha;,&beta;-unsaturated esters <b>6</b>. The reaction required the development of BIMP catalysts such as <b>4</b> that incorporated an amide thiourea H-bond donor group. 31 examples were investigated with quantitative yields and up to 96&percnt; ee obtained in the formation of &beta;-mercaptoesters <b>7</b>. Catalyst loadings as low as 0.05 mol&percnt; were achieved on a 100 mmol scale. Chapter 5 describes some structure and stability properties of the BIMP catalysts. The work disclosed in chapter 6 demonstrates the rate enhancements of the BIMP catalysts relative to tertiary amine bifunctional organocatalysts in the key steps of Dixon's total syntheses of nakadomarin A. Rate enhancements of up to 1300 times were observed in related reactions such as the Michael addition of &beta;-amido ester <b>8</b> to nitrostyrene 7. Chapter 7 describes a miscellany of reactions catalysed by the BIMP catalysts to demonstrate the efficacy of the new catalysts. The organocatalytic enantioselective addition of nitromethane to &beta;-substituted &alpha;,&beta;-unsaturated esters <b>10</b> such as methyl crotonate is disclosed with quantitative yields and enantiomeric excesses up to 73&percnt; achieved.

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

N-Hetereocyclic carbenes (NHC) have been intensively investigated since Ukai et al had reported the first NHC-catalyzed coupling of two equivalents of benzaldehyde, to form what is known as the benzoin product. A plethora of reports have since been published on NHC-catalyzed reactions, such as the cross-benzoin, Stetter, redox reactions, and many others. An attractive feature of NHCs is their ability to effect the umpolung (inversion of reactivity) of aldehydes. The efforts in the introduction of β,γ-unsaturated-α-ketoesters as acceptors for the Stetter reaction have led to the first highly enantioselective intermolecular Stetter reaction with β-aryl substituted Stetter acceptors (up to >99% ee). The synthetic applications of the Stetter adducts generated from the α-ketoester acceptors were demonstrated to give access to a diverse number of useful building blocks. Furthermore, the α-ketoester substrates were found to also be applicable for the cross-benzoin reaction. Through the development of a new electron-deficient, morpholine-based triazolium-derived carbene, a highly chemo- and enantioselective cross-benzoin reaction was achieved using aliphatic aldehydes and α-ketoesters. This methodology constitutes as the first highly enantioselective intermolecular cross-benzoin reaction with aliphatic aldehydes (up to 93% ee). In addition, a highly divergent synthesis of Stetter adducts and cross-benzoin products could be achieved in excellent regioselectivity. Interested in utilizing NHCs as organocatalysts for the development of new reactions, tetrahydrofuran and prolinal derivatives were found to undergo efficient ring-expansions. This methodology gives access to highly functionalized lactones and lactams, which could serve as synthetically useful building blocks for the synthesis of natural products and biologically active compounds.

Stereoselective hydroaminations of unactivated alkenes are rare as this represents a very challenging synthetic transformation. The most efficient examples occur in biased intramolecular systems and highly enantioselective intermolecular examples are rare, which is consistent with the forcing conditions required to catalyze the reactions. This limited reactivity also accounts for the lack of highly diastereoselective hydroamination variants. Recently our group has shown that intermolecular Cope-Type hydroamination of unactivated alkenes can be achieved using simple aldehydes as catalysts. The aldehyde promotes pre-association of the two reaction partners, inducing temporary intramolecularity resulting in a remarkably facile hydroamination event. This thesis will present the development of two reactions: intermolecular enantioselective Cope-type hydroamination and intermolecular diastereoselective Cope-type hydroamination of allylic amines.

Stereoselective hydroaminations of unactivated alkenes are rare as this represents a very challenging synthetic transformation. The most efficient examples occur in biased intramolecular systems and highly enantioselective intermolecular examples are rare, which is consistent with the forcing conditions required to catalyze the reactions. This limited reactivity also accounts for the lack of highly diastereoselective hydroamination variants. Recently our group has shown that intermolecular Cope-Type hydroamination of unactivated alkenes can be achieved using simple aldehydes as catalysts. The aldehyde promotes pre-association of the two reaction partners, inducing temporary intramolecularity resulting in a remarkably facile hydroamination event. This thesis will present the development of two reactions: intermolecular enantioselective Cope-type hydroamination and intermolecular diastereoselective Cope-type hydroamination of allylic amines.

The conceptually simple process of linking carbohydrate units by glycosylation has proven to be one of the most difficult synthetic processes to control from a stereochemical perspective. In particular it is the stereocontrolled synthesis of 1,2-cis glycosyl linkages (e.g. α-glucosides, β-mannosides) which poses the most difficult challenge. The research presented in this thesis describes new ways in which stereocontrol in glycosylation reactions can be achieved. New methods of neighbouring group participation have been explored, utilising novel protecting groups at the 2-postion of a series of glycosyl donors. In particular the use of glucosyl donors bearing a 2-O-(2-(2,4,6- trimethoxyphenyl)thio)ethyl protecting group at the 2-hydroxyl, have shown exceptional α-selectivity especially when a completely armed donor was used. Work within this thesis also describes the use of chiral Brønsted acid catalysts in stereoselective glycosylation reactions. However the yields and stereoselectivity obtained were not very encouraging.