Increasing attention has recently been directed toward 1,2,3-triazole-containing compounds. With their unique properties and excellent stability, 1,4-disubstituted triazoles are readily accessible via the copper catalyzed azide alkyne cycloaddition (CuAAC). As compounds containing fused triazoles become common in pharmaceutical targets and biologically active substances, new strategies to synthesize this class of molecules are highly desirable. An efficient and highly modular approach toward the synthesis of three different heterocyclic motifs containing fused 1,2,3-triazoles is reported. The synthesis involved a Pd-catalyzed annulation of 5-iodo-1,2,3-triazoles, which were prepared by a Cu(I)-catalyzed cycloaddition of iodoalkynes and azides. This work demonstrates the versatility of iodotriazoles in Heck reactions and in direct arylations.

The development of a novel palladium-catalyzed domino reaction with indole-based gem-dibromoolefin substrates is described. The reaction allowed access to a new class of polycyclic nitrogen heterocycles: N-fused benzo[c]carbazoles. A key feature of this domino reaction was the participation of both bromides in C–H functionalization processes, a hitherto unprecedented reactivity. Various substituents and substitution patterns were tolerated in this reaction, allowing for a highly modular approach to these challenging synthetic targets. Mechanistic studies were performed to gain further insight into the reactivity of these systems and elucidate the sequence of reaction steps. The results indicate that isomerization of reaction intermediates likely played a key role in promoting a successful reaction.

There has been increasing interest in the syntheses of carbohydrates due to their profound role in various biological processes and thus their potential in drug development. Various methods have been developed for the preparation of these oligosaccharides from simpler carbohydrate derivatives both chemically and enzymatically but they must be carefully applied to obtain the desired linkages. The main method that has been used to control the regioselectivity of glycosylations is protecting group chemistry. Unfortunately this requires additional steps lengthening the synthesis sequence. Extensive literature has shown the ability for carbohydrate recognition via organoboron methods through selective binding and their ability to undergo regioselective glycosylation through sugar-derived boronate esters. Exploiting these factors and in extension of previous work done in our laboratory on borinic acid- and boronic acid-catalyzed regioselective glycosylations of carbohydrate derivatives, we proposed a target oriented synthesis of a pentassacharide moiety found in four saponins isolated from Spergularia ramosa.

We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to the enantioselective synthesis of nitrogen-substituted polycyclic heterocycles. By using a cationic Rh(I) triflate catalyst in the presence of the chiral Josiphos ligand PPF-PtBu2, the ring opening reactions on dihydrooxaquinoline and dihydrooxaisoquinoline using different nucleophiles afford access to multiple dihydroquinolines and dihydroisoquinolones in high yield and high enantioselectivity (up to 99% total yield and >99%ee). A variety of nucleophiles were shown to be compatible with the catalytic system. The electronic effects in the new ring opening reactions were investigated using a variety of nucleophiles. It was found that reactivity and enantioselectivity of the ring opening products depends on the electronic effects as well as the position of the substituents on the substrates. Good yields and high ee of regioisomeric products are obtained using electron donating substituents, whereas electron withdrawing substituents decelerate the reactions.

Carbohydrates play major roles in many biological processes. Therefore, the synthesis of oligosaccharides is of considerable interest for biological, medicinal, and pharmacological studies. Many approaches have been developed for the synthesis of oligosaccharides, in which the main focus is often the formation of the glycosidic bonds. Traditional approaches use protecting group strategies that can be time consuming and can result in poor overall yield. This thesis describes the protecting group-free synthesis of a series of glycosyl donors of a range of mono- and disaccharides. These donors can be used to synthesize unprotected glycosyl chlorides, observed in situ. Reaction of the glycosyl chlorides with a variety of nucleophiles afforded the expected displacement products, giving access to a range of O-, N-, and S-linked glycosides, without resorting to the use of protecting groups.

The synthesis of glycoconjugates is of interest in biological and medicinal research. There are numerous approaches to the synthesis of glycosides involving protecting group free methods. This thesis outlines what has been achieved in the field and two novel approaches for O-glycosidation. The first approach involves the use of a toluenesulfonohydrazide glycoside with a purification handle designed for simple glycoside purifications. The butyl 3-O-octyl-D-glucopryanoside was successfully synthesized but did not have the desired property of yielding simple-to-purify glycosides as products. The second approach uses a thiouronium glycosyl donor; a variety of glycosidations using this donor were investigated. The glucosyl thiouronium salt donor was shown to undergo glycosidation effectively with simple alcohols.

Due to inherent rigidity of oligoproline peptides, forcing the C- and N-terminus in proximity for cyclization can be of significant challenge. To address this issue, a cyclization condition involing the help of amphoteric aziridine aldehydes has been developed. This one step cyclization protocol generally proceeds in high yields and goes to completion in relatively short period of time. Despite their cyclic nature, the resulting molecules display spectroscopic characteristics of polyproline II helices. These macrocycles should facilitate systematic studies of various conformational states of polyproline-containing protein regions.

Increasing attention has recently been directed toward 1,2,3-triazole-containing compounds. With their unique properties and excellent stability, 1,4-disubstituted triazoles are readily accessible via the copper catalyzed azide alkyne cycloaddition (CuAAC). As compounds containing fused triazoles become common in pharmaceutical targets and biologically active substances, new strategies to synthesize this class of molecules are highly desirable. An efficient and highly modular approach toward the synthesis of three different heterocyclic motifs containing fused 1,2,3-triazoles is reported. The synthesis involved a Pd-catalyzed annulation of 5-iodo-1,2,3-triazoles, which were prepared by a Cu(I)-catalyzed cycloaddition of iodoalkynes and azides. This work demonstrates the versatility of iodotriazoles in Heck reactions and in direct arylations.

The development of a novel palladium-catalyzed domino reaction with indole-based gem-dibromoolefin substrates is described. The reaction allowed access to a new class of polycyclic nitrogen heterocycles: N-fused benzo[c]carbazoles. A key feature of this domino reaction was the participation of both bromides in C–H functionalization processes, a hitherto unprecedented reactivity. Various substituents and substitution patterns were tolerated in this reaction, allowing for a highly modular approach to these challenging synthetic targets. Mechanistic studies were performed to gain further insight into the reactivity of these systems and elucidate the sequence of reaction steps. The results indicate that isomerization of reaction intermediates likely played a key role in promoting a successful reaction.

There has been increasing interest in the syntheses of carbohydrates due to their profound role in various biological processes and thus their potential in drug development. Various methods have been developed for the preparation of these oligosaccharides from simpler carbohydrate derivatives both chemically and enzymatically but they must be carefully applied to obtain the desired linkages. The main method that has been used to control the regioselectivity of glycosylations is protecting group chemistry. Unfortunately this requires additional steps lengthening the synthesis sequence. Extensive literature has shown the ability for carbohydrate recognition via organoboron methods through selective binding and their ability to undergo regioselective glycosylation through sugar-derived boronate esters. Exploiting these factors and in extension of previous work done in our laboratory on borinic acid- and boronic acid-catalyzed regioselective glycosylations of carbohydrate derivatives, we proposed a target oriented synthesis of a pentassacharide moiety found in four saponins isolated from Spergularia ramosa.