Chapter 1 briefly covers the development and utility of allylboron reagents in organic synthesis. Transition models proposed for addition to carbonyl groups and imines are discussed and selected examples of the utility of these reagents to the synthesis of complex molecule covered. In chapter 2 the allylation and crotylation of ketones using allyl- and crotyltrifluoroborates and montmorillonite K-10 are described. The method is scalable and utilizes a reliable catalyst with high functional group tolerance. A conventional work-up is not required for further purification, since the boric acid by-product of the reagent remains trapped in the cavity of the K-10. The method is quite robust and provides an operationally straightforward procedure for the allylation of a range of ketones using the air and moisture stable potassium allyltrifluoroborate. In Chapter 3, the first indium-mediated highly chemo- and diastereoselective allylation of α,β- epoxyketones using allyltrifluoroborate was developed. It was shown in the case of simple ketone substrates, the loading of indium can be reduced to catalytic quantities without a diminishment in yield. The stereochemical nature of the epoxy homoallylic alcohols was ii unequivocally established through Payne rearrangement. Mechanistic studies indicate that the reaction proceeds through an allylindium species; although the nature of the indium species was not fully elucidated. Finally, in chapter 4 regioselective allylation and diastereoselective crotylation of various indoles are discussed using BF3·Et2O as a promoter. It was shown that the electronic effects of the substituents on the indole ring had little effect on the outcome of the reaction. However, steric factors were more influential on the yields and reactivity of the substrates. Stereospecific addition of the E- and Z-crotyltrifluoroborates could also be achieved under the reaction conditions, providing the corresponding anti and syn products, respectively.

Chapter 1 briefly covers the development and utility of allylboron reagents in organic synthesis. Transition models proposed for addition to carbonyl groups and imines are discussed and selected examples of the utility of these reagents to the synthesis of complex molecule covered. In chapter 2 the allylation and crotylation of ketones using allyl- and crotyltrifluoroborates and montmorillonite K-10 are described. The method is scalable and utilizes a reliable catalyst with high functional group tolerance. A conventional work-up is not required for further purification, since the boric acid by-product of the reagent remains trapped in the cavity of the K-10. The method is quite robust and provides an operationally straightforward procedure for the allylation of a range of ketones using the air and moisture stable potassium allyltrifluoroborate. In Chapter 3, the first indium-mediated highly chemo- and diastereoselective allylation of α,β- epoxyketones using allyltrifluoroborate was developed. It was shown in the case of simple ketone substrates, the loading of indium can be reduced to catalytic quantities without a diminishment in yield. The stereochemical nature of the epoxy homoallylic alcohols was ii unequivocally established through Payne rearrangement. Mechanistic studies indicate that the reaction proceeds through an allylindium species; although the nature of the indium species was not fully elucidated. Finally, in chapter 4 regioselective allylation and diastereoselective crotylation of various indoles are discussed using BF3·Et2O as a promoter. It was shown that the electronic effects of the substituents on the indole ring had little effect on the outcome of the reaction. However, steric factors were more influential on the yields and reactivity of the substrates. Stereospecific addition of the E- and Z-crotyltrifluoroborates could also be achieved under the reaction conditions, providing the corresponding anti and syn products, respectively.

Verdazyl radicals are a unique class of stable radicals that have found uses as reporter molecules in biological systems, substrates for molecular-based magnets and mediators in living radical polymerizations. Over the past few years, our laboratory has pioneered the use of verdazyl radicals as substrates in 1,3-dipolar cycloaddition reactions to provide unique small molecule five-membered ring systems containing structural features commonly found in therapeutic agents. As an extension to this work we became interested in seeing whether this chemistry could be applied to the synthesis of macrocyclic scaffolds, in particular cyclophanes. Cyclophanes have been attractive synthetic targets for organic chemists because of their unique structural properties, conformational behaviours and molecular recognition capabilities. Presented in this thesis is the successful demonstration of the extension of the verdazyl chemistry to novel [n]-paracyclophanes. The structural features and conformational biases of these molecules as evidenced by 1H-NMR and X-ray crystallography are highlighted along with molecular recognition studies.

Due to the scarcity of energy resources that we are facing today, there is an increasing need for new methodology developments that are green and sustainable while minimizing unnecessary substrate pre-functionalization, by-product formation and waste generation. In this context, asymmetric rhodium-catalyzed hydroacylation is an atom-economical method for the preparation of chiral ketone derivatives from aldehyde and olefin precursors. This transformation is also applicable to keto-aldehyde precursors en route to chiral lactones. This dissertation describes the development of three specific methodologies, namely: 1) the synthesis of enantioenriched cyclopropyl ketones by enantio- and diastereoselective intermolecular rhodium-catalyzed hydroacylation of cyclopropenes, 2) the synthesis of enantioenriched phthalides by enantioselective rhodium-catalyzed intramolecular hydroacylation of ketones, and 3) the synthesis of tertiary branched allylic amines by silver-catalyzed ring-opening hydroamination of cyclopropenes.

Organic synthesis allows access complex materials in the context of fine chemicals, pharmaceuticals, and natural products, but many contemporary methods are wasteful – the focus is on the target rather than the process. Stoichiometric reagents, protecting groups, and multi-step processes are often involved to synthesize moieties such as chiral lactones and lactams, which are prevalent in biologically-relevant molecules like antibiotics (for example, the macrolides, typified by erythromycin) and cyclic peptides (such as cyclosporin and gramicidin). We have developed a rhodium-catalyzed lactonization of prochiral keto-aldehydes to access chiral lactones in a mild and atom-economical fashion, and a synthesis of cyclic peptides from achiral dehydropeptides using asymmetric rhodium-catalyzed hydrogenation to set the chirality in the peptide. In this fashion, we avoid using expensive and wasteful activating agents, protecting groups, and a host of other drawbacks endemic in lactonizations and peptide synthesis. This dissertation details: 1) the development of asymmetric rhodium-catalyzed hydroacylation, elucidation of the mechanism of this transformation through experimental and theoretical analyses, and the synthesis of chiral benzoxazecinones using this method, and 2) the synthesis of prochiral linear dehydropeptides, efficient cyclization of these molecules, and asymmetric reduction of multiple enamides in a highly enantio- and diastereoselective manner to access cyclic peptides.

As the need for developing environmentally friendly chemistry continues to become more apparent, catalytic asymmetric hydrogenation has risen to the forefront as a reliable and eco-friendly method for enantioselective synthesis. We herein describe our progress toward the synthesis of valuable structural motifs via hydrogenation: chiral 1,2-diamines, 1,3-diamines and substituted cyclohexanes. We propose a strategy whereby protected 1,2-diimine and 1,3-diimine surrogates can be hydrogenated selectively and deprotected to furnish the desired chiral amines. Using this strategy, it was demonstrated that imidazolone precursors could be hydrogenated with >20:1 diastereoselectivity to give latent 1,2-diamines, albeit with no enantiomeric excess. We further propose that substituted benzene rings linked to an oxazolidinone chiral-auxiliary can be diastereoselectively hydrogenated using a heterogeneous metal catalyst. Following hydrogenation, the chiral cyclohexanes could be obtained in up to quantitative yield and 99% diastereomeric excess.

The synthesis of glycoconjugates has facilitated a wide variety of techniques for the detailed study of carbohydrates and their interactions in biological systems. However, when only small amounts of the isolated oligosaccharide are available, multistep synthetic approaches are not possible. This thesis explores new synthetic methods for the preparation of glycoconjugates without protecting group manipulations. A new glycosidation method was developed which introduces N-glycopyranosylsulfonohydrazides as glycosyl donors for the protecting group-free synthesis of O-glycosides, glycosyl azides and oxazolines. The glycosyl donors were synthesized in a single chemical step by condensing p-toluenesulfonylhydrazide with the corresponding mono- and disaccharides. The N-glycopyranosylsulfonohydrazides were activated with NBS and subsequently glycosylated with the desired alcohol or transformed to the oxazoline or glycosyl azide. Recent advances in chemoselective ligation methods for the functionalization of unprotected carbohydrates have provided new routes towards complex glycoconjugates. Despite the wide use of those chemoselective methods, the properties of these linkages have not been thoroughly investigated. Characterization of a series of glycoconjugates formed by chemoselective ligation of xylose, glucose and N-acetylglucosamine with either an acyl hydrazide, a p-toluenesulfonylhydrazide or an N-methylhydroxylamine were carried out to gain further insight into the optimal conditions for the formation and the stability of these useful conjugates. Their apparent association constants (9-74 M-1) at pD 4.5, as well as rate constants for hydrolysis were determined at pH 4.0, 5.0 and 6.0. The half-lives of the conjugates varied between 1 h and 300 days. All the compounds were increasingly stable as the pH approached neutrality. Finally, selective chemical modification of a glycosaminoglycan chondroitin sulfate was attempted at the non-reducing end by utilizing the Δ4-uronic acid functional group formed upon cleavage of the glycosaminoglycan with a bacterial lyase enzyme. The captodative double bond of the unique Δ4-uronic acid functionality was unreactive towards Michael addition, even if the carboxylate was methylated. Trials towards radical addition using thiyl radicals were unsuccessful, although a synthesized model phenyl Δ4-uronic acid monosaccharide was successfully functionalized under the same conditions.

Due to the scarcity of energy resources that we are facing today, there is an increasing need for new methodology developments that are green and sustainable while minimizing unnecessary substrate pre-functionalization, by-product formation and waste generation. In this context, asymmetric rhodium-catalyzed hydroacylation is an atom-economical method for the preparation of chiral ketone derivatives from aldehyde and olefin precursors. This transformation is also applicable to keto-aldehyde precursors en route to chiral lactones. This dissertation describes the development of three specific methodologies, namely: 1) the synthesis of enantioenriched cyclopropyl ketones by enantio- and diastereoselective intermolecular rhodium-catalyzed hydroacylation of cyclopropenes, 2) the synthesis of enantioenriched phthalides by enantioselective rhodium-catalyzed intramolecular hydroacylation of ketones, and 3) the synthesis of tertiary branched allylic amines by silver-catalyzed ring-opening hydroamination of cyclopropenes.

Cyclodextrins (CDs) are macrocycles composed of several glucose units bound through α-1,4 glycosidic linkages. They can be chemically modified to display functional groups on their primary or secondary rim. CDs display these groups in defined geometries ideally suited to bind biomacromolecules. Moreover, CDs have a hydrophobic cavity that allows them to form stable host-guest complexes with lipophilic molecules. This combination of functionality and guest binding ability makes CDs important scaffolds for the design of functional supramolecular systems. This thesis explored the interaction of heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-β-cyclodextrin (1) with many hydrophobic guest molecules. The binding constants of CD host-guest interactions were measured using ITC and fluorometry-based approaches. These studies revealed 1 to form the highest affinity 1:1 cyclodextrin-guest complexes reported to date. This thesis then explored the use of CD inclusion complexes as biomacromolecular sensors. CD 1 and its derivatives were used to develop self-assembling sensors. First, a library of polycationic CDs with differing charge distribution was synthesized. The sensing motif was synthesized by covalently linking a quinolinium fluorophore to lithocholic acid (LCA). The CD-based binding motifs and the LCA-based sensing motif self-assemble through host-guest interactions (i.e. 1 binding to LCA displays a Ka = 5.52 × 107 M-1). These inclusion complexes were then used as an array of self-assembling sensors capable of differentiating between pure and contaminated samples of heparin (anticoagulant). To capitalize on the promise of CD 1 a new technique was explored to functionalize a single amine of 1. The technique relies on an S to N acyl transfer from a guest molecule to a CD host resulting in the mono-acylation of the host. The importance of the linker between the guest and the reactive acylating agent was fully explored. Furthermore, two CD probes are synthesized and are shown to display differential fluorescent responses with a small series of proteins.

Organic synthesis allows access complex materials in the context of fine chemicals, pharmaceuticals, and natural products, but many contemporary methods are wasteful – the focus is on the target rather than the process. Stoichiometric reagents, protecting groups, and multi-step processes are often involved to synthesize moieties such as chiral lactones and lactams, which are prevalent in biologically-relevant molecules like antibiotics (for example, the macrolides, typified by erythromycin) and cyclic peptides (such as cyclosporin and gramicidin). We have developed a rhodium-catalyzed lactonization of prochiral keto-aldehydes to access chiral lactones in a mild and atom-economical fashion, and a synthesis of cyclic peptides from achiral dehydropeptides using asymmetric rhodium-catalyzed hydrogenation to set the chirality in the peptide. In this fashion, we avoid using expensive and wasteful activating agents, protecting groups, and a host of other drawbacks endemic in lactonizations and peptide synthesis. This dissertation details: 1) the development of asymmetric rhodium-catalyzed hydroacylation, elucidation of the mechanism of this transformation through experimental and theoretical analyses, and the synthesis of chiral benzoxazecinones using this method, and 2) the synthesis of prochiral linear dehydropeptides, efficient cyclization of these molecules, and asymmetric reduction of multiple enamides in a highly enantio- and diastereoselective manner to access cyclic peptides.