The conjugate acid of pyridine had been found to catalyze decarboxylation of alpha-mandelylthiamin (MTh). It was proposed this occurs by association between the substrate and pyridinium ion in a pi-stacked complex prior to cleavage of the C-C bond. Despite the evidence for selective acid catalyzed decarboxylation of MTh with pyridine and its derivatives, the nature of proton transfer occuring after the C-C bond breaks and before the final products form had not been investigated. General base catalyzed deprotonation of hydroxybenzylthiamin (HBnTh) has been applied as a model for the reverse reaction of acid-catalyzed decarboxylation. Kinetic analysis of this process suggests the acceleration by a preassociated pyridinium ion and the product-determining step in the decarboxylation of MTh are facilitated by independent sequential proton transfers.

Our group has developed a strategy for the synthesis of benzofused carbocycles and heterocycles through tandem palladium-catalyzed reactions of gem-dibromoolefins. In these syntheses, one bromide undergoes a Pd-catalyzed cyclization reaction, and the other participates in an orthogonal inter- or intramolecular Pd-catalyzed reaction to functionalize or annulate that ring, respectively. Chapter 1 describes the pairing of an intramolecular C–N bond forming reaction (the Buchwald-Hartwig coupling) with an intramolecular direct arylation for the synthesis of fused indole derivatives. A range of previously unknown heterocycles were synthesized through this method. Chapter 2 describes the synthesis of benzothiophenes through the combination of a Pd-catalyzed C–S coupling with an orthogonal Suzuki, Heck, or Sonogashira reaction. This represents the first example of the incorporation of Pd-catalyzed C–S coupling into a tandem reaction. In Chapter 3, a tandem intramolecular Heck / intermolecular Suzuki reaction is described for the synthesis of methyleneindenes. Studies on this reaction have provided advanced understanding of the mechanism, including how variation of the ligand controls the regioselectivity of the reaction.

The realization that oligosaccharides play a central role in many biological processes has led to increasing interest in the preparation of synthetic targets for use in medical or biochemical research and drug discovery. The preparation of oligosaccharides from simple carbohydrate derivatives requires efficient methods for the construction of O-glycosidic bonds. Much effort has been made towards the development of selective methods for the preparation of oligosaccharide targets. The most common method to overcome the challenge of regioselectivity is the use of protecting group manipulations to suppress glycosylation at undesired positions. This is highly inefficient in terms of atom and step economy. Organoboron catalysis is a recent strategy that imparts regioselective activation of the equatorial hydroxy group of cis-vicinal diols towards functionalization. Following the initial findings that diarylborinic acid catalyzes the regioselective acylation of carbohydrate derivatives, an analogous method for regioselective glycosylation under Koenigs-Knorr conditions has been developed.

The realization that oligosaccharides play a central role in many biological processes has led to increasing interest in the preparation of synthetic targets for use in medical or biochemical research and drug discovery. The preparation of oligosaccharides from simple carbohydrate derivatives requires efficient methods for the construction of O-glycosidic bonds. Much effort has been made towards the development of selective methods for the preparation of oligosaccharide targets. The most common method to overcome the challenge of regioselectivity is the use of protecting group manipulations to suppress glycosylation at undesired positions. This is highly inefficient in terms of atom and step economy. Organoboron catalysis is a recent strategy that imparts regioselective activation of the equatorial hydroxy group of cis-vicinal diols towards functionalization. Following the initial findings that diarylborinic acid catalyzes the regioselective acylation of carbohydrate derivatives, an analogous method for regioselective glycosylation under Koenigs-Knorr conditions has been developed.

Unprotected N-H aziridine aldehydes are surprisingly stable compounds which can undergo reactions in the absence of protecting groups. In total, three different transformations were explored during my Master’s thesis. The conversions include the dissociation of the aziridine aldehydes, which exist as dimers, and their subsequent re-dimerization in various solvents. The development of mixed aziridine aldehyde adducts and their attempted modifications will also be discussed. Finally, the discovery of N-H aziridine compounds containing a 1,3-dicarbonyl functionality will be discussed, as will their attempted transformations.

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.

The addition of an aldehyde C−H bond across a ketone functionality, formally a hydroacylation, has emerged as an atom-economical approach to the synthesis of esters. While this is an efficient strategy for producing biologically-relevant materials, the field of transition metal-catalyzed ketone hydroacylation is currently limited to intramolecular systems. The development of a new rhodium catalyst will be presented, and its application to intermolecular ketone hydroacylation will be discussed. Ester products were synthesized from unfunctionalized, aliphatic aldehydes and chelating ketones in excellent yields under relatively mild reaction conditions. Efforts towards an asymmetric intermolecular ketone hydroacylation will be described, including the application of known chiral catalysts and the development of novel chiral phosphine ligands for asymmetric catalysis. Ester products were obtained in as high as 78% enantiomeric excess.

Methods are being developed to produce “designer proteins” from unnatural amino acids that are added into specific locations by the ribosome using an altered mRNA. To date, over seventy unnatural amino acids have been incorporated at specific sites in proteins by in vitro biosynthetic methods using chemically acylated-tRNAs and in vivo protein mutagenesis based on orthogonal tRNA/aminoacyl-tRNA synthetase pairs. Lanthanum-mediated aminoacylation of cis-diols provides a general and selective method for the one-step preparation of aminoacyl-tRNA. The nature of this biomimetic process was studied for the reaction of ribonucleosides and nucleotides with N-t-Boc-protected aminoacyl ethyl phosphates. Successful aminoacylation was also achieved with unprotected aminoacyl ethyl phosphates. This method was extended for the aminoacylation of tRNA and analyzed by reversed-phased HPLC and MALDI-MS. These results will provide an insight to the ultimate goal of lanthanum-mediated direct acylation of tRNA and its applications in in vitro site-specific incorporation of unnatural amino acids.

Unprotected N-H aziridine aldehydes are surprisingly stable compounds which can undergo reactions in the absence of protecting groups. In total, three different transformations were explored during my Master’s thesis. The conversions include the dissociation of the aziridine aldehydes, which exist as dimers, and their subsequent re-dimerization in various solvents. The development of mixed aziridine aldehyde adducts and their attempted modifications will also be discussed. Finally, the discovery of N-H aziridine compounds containing a 1,3-dicarbonyl functionality will be discussed, as will their attempted transformations.

Methods are being developed to produce “designer proteins” from unnatural amino acids that are added into specific locations by the ribosome using an altered mRNA. To date, over seventy unnatural amino acids have been incorporated at specific sites in proteins by in vitro biosynthetic methods using chemically acylated-tRNAs and in vivo protein mutagenesis based on orthogonal tRNA/aminoacyl-tRNA synthetase pairs. Lanthanum-mediated aminoacylation of cis-diols provides a general and selective method for the one-step preparation of aminoacyl-tRNA. The nature of this biomimetic process was studied for the reaction of ribonucleosides and nucleotides with N-t-Boc-protected aminoacyl ethyl phosphates. Successful aminoacylation was also achieved with unprotected aminoacyl ethyl phosphates. This method was extended for the aminoacylation of tRNA and analyzed by reversed-phased HPLC and MALDI-MS. These results will provide an insight to the ultimate goal of lanthanum-mediated direct acylation of tRNA and its applications in in vitro site-specific incorporation of unnatural amino acids.