The synthesis of oligosaccharides remains a challenging task. In our studies, we applied glycosyl iodides to the synthesis of oligosaccharides. The mechanism of formation of glycosyl iodides from anomeric acetates of glucose, galactose and mannose, and 1,2 and 1,6 anhydro sugars were investigated by NMR. Glycosyl iodides were then applied in glycosidation studies and specifically in the synthesis of a precursor to the trisaccharide of Lewis x, a blood group antigen.

Twenty-two compounds of the type R¹C₆H₄CH₂(CO)NHCHR²(CO)OCHR³COOH, where R¹ = H or OH, R² = H or Me, and R³ = H, Me, Et, i-Pr, Ph, or CH₂COOH, have been synthesized for testing as β-lactamase inhibitors. All of the intermediates and products were characterized by NMR, and mass spectra were run on some of the final products.

Ceramide serves as a precursor to sphingomyelins and glycosphingolipids, and as an important intermediate in the de novo biosynthesis. Ceramide will act as second messenger in cell systems to induce programmed cell death (apoptosis). Ceramide is composed of a sphingosine backbone and fatty acid linked in an amide bond, and its structural variations have been modified and synthesized by many research group. The diene ceramide, unusual analogues of ceramide with a conjugated diene may have higher reactivity than other novel ceramide in mitochondria by facilitated oxidation at C3. One of the most important synthetic methodologies for diene ceramide was organozirconocene hydrochloride (Schwartz reagents) used for forming long chain dienyl sphingosine backbone. The organozirconocene complexes are also known for the transmetalation with other metal complexes for further nucleophilic additions. In this thesis, the synthesis of diene ceramide with chiral aldehyde for sphingosine head group and organozirconocene complexes will be described.

Studies pertaining to the dirhodium(II) carboxamidate catalyzed hetero-Diels-Alder reaction between 1-methoxy-2-methyl-3-(trimethylsilyloxy)-1,3-butadiene and various aldehydes have been carried out. It has been demonstrated that the overall yield, enantioselectivity, and rate of reaction for the hetero-Diels-Alder process are influenced by the substitution pattern of the diene. Collected data has allowed for the evaluation of the structural and electronic properties of the catalysts and for comparisons to be made between several dienes of interest. The complete synthesis of Rh₂(4R-dFIBAZ)₄, a dirhodium(II) carboxamidate catalyst that has shown increased reactivity for diazo decomposition and enhanced selectivity for ylide formation, has been previously reported by our group. Presented herein are the attempts taken to improve the existing synthesis through optimization and scale-up.

This thesis describes the development of palladium catalyzed, multicomponent synthetic routes to imidazoline carboxylates. Chapter 2 describes the design of an active catalyst for the multicomponent assembly of imidazoline carboxylates from two imines, acid chlorides and carbon monoxide. By modifying reaction conditions, two different imines can be selectively incorporated into the imidazoline core. This provides a method to assemble imidazolines in one pot, with independent control of five separate substituents. This approach has been used to assemble a diverse range of imidazoline carboxylates. In Chapter 3, a new, palladium catalyzed route to generate imidazoline carboxylates is described, via a five component coupling of two imines, two carbon monoxides and aryl-iodide. This process proceeds via a similar mechanism to that reported in Chapter 2, but replaces sensitive acid chlorides with an phenyl-iodide. Finally, Appendix A briefly describes methods to decarboxylate these products to imidazolinium and imidazolium salts. / Cette thèse décrit le développement d'itinéraires synthétiques pour former des carboxylates d'imidazoline, catalysés par le palladium. Le chapitre 2 décrit la conception d'un catalyseur actif pour la synthèse de carboxylates d'imidazoline à partir de deux imines, de chlorures acides et d'oxyde de carbone. En modifiant les conditions réactionnelles, deux imines différentes peuvent être sélectivement incorporées au noyau d'imidazoline. Cette méthode permet d'assembler des imidazolines en un seul pot, avec la possibilité de varier les différents substituants. Cette approche a été employée pour la synthèse d'une large gamme une gamme de carboxylates d'imidazoline. En chapitre 3, une nouvelle synthèse catalysée par le palladium pour produire des carboxylates d'imidazoline est décrite, via le couplage de cinq composants, à savoir deux imines, deux oxydes de carbone et un iodure d'aryle. Ce processus procède par l'intermédiaire d'un mécanisme semblable à celui rapporté au chapitre 2, où le chlorure d'acide est remplacé par un iodure d'aryle. En conclusion, l'annexe A décrit brièvement différents méthodes pour décarboxyler ces produits en sels d'imidazolinium et d'imidazolium.

This thesis describes the development of four synthetic routes towards the syntheses of N, N' ethylene-bridged dipeptides and their application towards the synthesis of such 2-oxopiperazine derivatives on solid support. / The first route proceeds by the generation of an N-allyl substituted amino ester, its coupling to a second amino acid and subsequent oxidative cleavage of the carbon-carbon double bond to provide the cyclized product. The second route proceeds by the generation of 4-nitrobenzenesulfonamide dipeptides and their alkylation by 1,2-dibromoethane. The third route proceeds by a Mitsunobu reaction between sulfonamide dipeptides and bromoethanol followed by treatment with DBU to generate the desired 2-oxopiperazine derivative. The fourth route again uses the sulfonamide dipeptide esters as intermediates. This time an allyl group is installed and this is then converted to the diol that is subsequently oxidatively cleaved by action of sodium periodate. Alternatively, the allyl group is converted to the epoxide that is treated with periodic acid to effectively carry out the same transformation. / The synthesis of these ethylene-bridged dipeptides was also carried out on solid support in an effort to create a combinatorial library of such constrained peptidomimetics. The partial success of the above-mentioned approaches on solid support is described. / Finally, the synthesis of two new analogs of Thyrotropin Releasing Hormone (TRH) incorporating the 2-oxopiperazine ring is described.

A general synthesis for bridged bicyclic disulfide compounds was refined and expanded from (3.2.1) to (4.2.1) and (2.2.1) systems. Various derivatives were synthesized through modification of the hydroxyl functionality in these molecules. The oxidation of all bridged bicyclic disulfide compounds to their corresponding bridged bicyclic thiosulfinate esters (a previously unknown class of compounds) was performed. Three crystal structures were obtained and selected bond lengths, bond angles and torsion angles were compared with the calculated values obtained using MMX molecular mechanics via the PCMODEL program. / The m-CPBA oxidation of the above bridged bicyclic thiosulfinate esters was followed at low temperature using $ sp1$H and $ sp{13}$C NMR spectroscopy. $ alpha$-Disulfoxides were detected as the first intermediates in this oxidation process and were seen at temperatures and concentrations greater than any previously reported. Strong evidence was also found to suggest the intermediacy of O,S-sulfenyl sulfinates. A clear mechanistic proposal for the rearrangement of bridged bicyclic $ alpha$-disulfoxides to their corresponding thiosulfonate esters was presented based on experimental results. / Attempts towards the synthesis of the bridged bicyclic disulfide analogue of ergosterol peroxide using diatomic sulfur methodologies were reported. These attempts were not successful. / The generation of the pseudo-diatomic species, R-P = S (thioxophosphanes), using a methodology previously developed in our laboratory was examined. The thioxophosphanes (R = C$ sb6$H$ sb5$, C$ sb2$H$ sb5$ and p-Cl-C$ sb6$H$ sb4$) were trapped with 1,3-dienes to give cyclic and bridged bicyclic thiophosphoranes.

The scope of the indium-mediated allylations in aqueous media has been successfully expanded and an improved understanding of the synthetic utility of the reaction has been developed. The range of useful functionalities that can be efficiently produced by the methodology has been increased and the concise construction of naturally occurring and/or biologically significant substrates has been undertaken. / We have demonstrated how N-acylimidazoles could be allylated under controlled temperature conditions, in aqueous media furnishing predominantly 4-alkyl-1,6-heptadien-4-ols. The intermediate alpha-alkyl-beta,gamma-unsaturated ketones were present in significant amounts only when the bulk of the acyl or alpha substituents were such that it interfered with a subsequent allylation. An investigation into the efficient production of the homo allylic ketone, independent of bulk was also performed. Success in this light was effected with the introduction of infrequently used, N-acylpyrazoles in a unique Wienreb-amide type role. These substrates also proved useful for the generation of beta-keto esters in a direct manner via a indium-mediated Reformatsky-type reaction in THF. / A successful extension of the methodology into the realms of intramolecular carbocylizations proved to be high yielding and exclusive in terms of gamma-regio and cis-diastereoselectivity. The high utility of the reaction was shown with the synthesis of oxygen heterocyles fused with alpha-methylene-gamma-butyrolactones, substrates, which were revealed to be cytotoxic against several cancer cell lines. An easy incorporation of chiral auxiliaries to the cyclization reactions was also introduced, and a path to possibly produce these important compounds in an enantioselective manner, revealed. / Indium-mediated allylations in aqueous media also proved useful as a tool for the general construction of paraconic acids, which are naturally occurring, densely functionalized and biologically active 5-membered lactones. A facile route free of labor-intensive tasks was designed and utilized in the production of naturally occurring methylenolactocin and protolichesterinic acid. A further extension to include the synthesis of a related bis -fused lactone, canadensolide, encountered serious problems. Here it was discovered that the reaction of an enolizable allylic indium species with water occurred more quickly than the intended reaction of this species with an aldehyde in an intramolecular cyclization. This, coupled with other results observed throughout our research, revealed that though very useful, the indium-mediated allylation is negatively affected by the presence of gamma-carboxylate groups. While the C-In bond appears to have a low propensity to react with the aqueous media and react quantitatively with appropriate electrophiles, the presence of a gamma-carboxylate group offers the possibility of enol formation leading to the generation of an O-In species that is rapidly protonated. We were therefore able to successfully use the methodology in this circumstance, only for the production of a deoxy analog while canadensolide remained illusive.

A new method for the synthesis of the [4,3,1] carbocyclic core of the squalene synthase and farnesyl transferase inhibitor CP-225,917 is developed. The key step relies on the [6+4] cycloaddition between a tropone and a cyclopentadiene. This reaction proceeds with excellent regio- and stereoselectivity and allows rapid and convergent access to the polycyclic core of the molecule. / In the course of this work, it was discovered that the cycloaddition process is significantly accelerated in presence of the catalytic amount of ZnCl2. This is the first example of Lewis acid catalyzed [6+4] tropone cycloaddition. / Introduction of other functional groups towards the synthesis of CP-225,917 skeleton is described. The key to the success of this strategy is a position selective Baeyer-Villiger oxidation on the tricyclic cycloadduct. This reveals functionality which can be used to elaborate the C9 side-chain and incorporate the bridgehead olefin.* / *Please refer to dissertation for diagrams.

The regio- and diastereoselectivity in the coupling of $ gamma$-substituted allylic bromides with aldehydes mediated by indium in water were examined and found to be dependent on the steric effect of the substituents on both the allylic bromides and the aldehydes. / Despite the efficiency with which indium mediates carbon-carbon bond formation between allyl halides and aldehydes in an aqueous environment, it is not without short-comings. Nitro-functionalised aldehydes were found to be susceptible to the reductive conditions of this aqueous indium Barbier-Type reaction. In this connection, bismuth was found to chemoselectively mediate the coupling of allyl halides with aldehydes in water in the presence of tetrabutylammonium halides. / The indium Barbier reaction in an aqueous medium was extended to include propargylic bromides. The coupling of aldehydes with propargylic bromides gave regioselectively either the homopropargyl alcohol or the $ alpha$-allenic alcohol depending on the $ gamma$-substituent of the propargylic bromides. / The regio- and stereochemical course of the indium-promoted coupling of $ gamma$-substituted allylic halides with aldoses (water soluble carbohydrates) has been investigated. The stereoselective generation of two new contiguous stereogenic centres has been applied to the synthesis of novel 2-substituted carbohydrates. The stereoselectivity of the reaction was explained on the basis of chelation of the allyl indium species with the $ alpha$-hydroxycarbonyl function. This gives syn selectivity for the $ rm C gamma$-$ rm C beta$ diol function in the product. The relative stereochemistry of the $ rm C beta$-$ rm C alpha$ linkage in the product is governed by the preferred geometry of the allyl indium species.