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In the scope of our BACE1 inhibitor project we used an originally designed microtiter plate-based screening to discover 4 triazole-linked reduced amide isosteres that showed modest (single digit micromolar) BACE1 inhibition. Our ligands were designed based on a very potent (single digit nanomolar) isopththalamide ligand from Merck. We supplanted one of the amide linkages in order to incorporate our triazole and saw a 1000-fold decrease in potency. We then enlisted Molsoft, L.L.C. to compare our ligand to Merck's in silico to account for this discrepancy. They found that the triazole linkage gives rise to a significantly different docking pose in the active site of the BACE1 enzyme, therefore diminishing its potency relative to the Merck ligand. The ability to control the regio- and stereochemical outcome of organic reactions is an ongoing interest and challenge to synthetic chemists. The pre-association of reacting partners through hydrogen bonding (H-bonding) can often to yield products with extremely high stereoselectivity. We were able to show that anilines, due to their enhanced acidity relative to amines, can serve as substrate directing moieties in the opening of cyclohexene oxides. We observed that by judicious choice of conditions we could control the regiochemical outcome of the reaction. These studies demonstrate that an intramolecular anilino-NH hydrogen bond donor can direct Fürst-Plattner epoxide opening. A unified mechanism for this phenomenon has been proposed in this work which consists of a novel mechanistic route we call "NH-directed Fürst-Plattner." We further studied the opening of cyclohexene oxides by incorporating amide and amide derivative substituents in both the allylic and homoallylic position relative to the epoxide moiety. Our attempts to control regioselectivity in the allylic systems were unsuccessful; however when the directing substituent was in the homoallylic position, we could demonstrate some degree of regioselectivity. An additional project that the author worked on for approximately one year during his graduate student tenure is not described within this work. In February of 2009 AstraZeneca, Mayo Clinic, and Virginia Tech Intellectual Properties Inc. concomitantly announced that AstraZeneca licensed a portfolio of preclinical Triple Reuptake Inhibitor (TRI) compounds for depression. The lead compound, PRC200, was discovered by a collaborative effort between the Carlier and Richelson (Mayo Clinic Jacksonville) research groups in 1998. The author was tasked to develop backup candidates of PRC200 in order to improve the pharmacokinetics of the lead compound. Due to confidentiality agreements, this work is not reported herein. / Ph. D.

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes. Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use. The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed. The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.

Human African trypanosomiasis (sleeping sickness) is a devastating disease which is endemic in parts of sub-Saharan Africa. It is caused by the protozoan parasite T. brucei, which are transmitted by the bite of infected tsetse flies. Although the disease is fatal if left untreated, there is a lack of safe, effective and affordable drugs available; therefore new drugs are urgently needed. The aim of the work presented in this thesis is to develop novel trypanocidal compounds. It is divided into two parts to reflect the two distinct strategies employed to achieve this aim. The first part focuses on the inhibition of glycophosphoinositol (GPI) anchor synthesis by inhibiting the Zn2+-dependent enzyme, GlcNAc-PI de-N-acetylase. Trypanosomes have a variable surface glycoprotein (VSG) coat, which allows them to evade the human immune system. The GPI anchor attaches the VSG to the cell membrane; therefore inhibiting GPI synthesis should expose the parasite to the immune system. Initially, large substrate analogues were synthesized. These showed weak inhibition of the enzyme. Zinc-binding fragments were screened, and small molecule inhibitors based on salicylhydroxamic acid were then synthesized. These compounds showed modest inhibition, but the excellent ligand efficiency of salicylhydroxamic acid indicates this may be a promising starting point for further inhibitors. The second part details the P2 strategy. The P2 transporter is a nucleoside transporter unique to T. brucei, which concentrates adenosine. The transporter also binds and selectively concentrates compounds that contain benzamidine and diaminotriazine P2 motifs, which can enhance the potency and selectivity of these compounds. The sleeping sickness drugs melarsoprol and pentamidine contain P2 motifs. Compounds comprising a P2 targeting motif, a linker and a trypanocidal moiety were synthesized. Initially, a diaminotriazine P2 motif was attached to a trypanocidal tetrahydroquinoline (THQ) protein farnesyl transferase (PFT) inhibitor, with limited success. The P2 strategy was also applied to a non-selective, trypanocidal, quinol moiety. The quinol moiety was attached to diaminotriazine and benzamidine P2 motifs, and an increase in selectivity for T. brucei over MRC5 cells was observed.

Les carbapénèmes occupent actuellement une place centrale dans la lutte contre les bactéries résistantes aux antibiotiques classiques de type pénicilline. Notre thèse a pour objectif de développer une synthèse de leurs intermédiaires dans l'optique d'une application à l'échelle industrielle. Nous avons exploité, comme stratégie de fermeture de l'hétérocycle, la formation du lien C-3/C-4 par attaque nucléophile intramoléculaire sur un époxyde. Celui-ci est obtenu à partir de la L thréonine qui fournit deux stéréocentres et permet d'induire le troisième carbone asymétrique. Nous avons utilisé le groupe benzhydryle comme groupe protecteur, nouveau dans cette chimie, pour remplacer le groupe para-anisyle habituel qui pose des problèmes industriels. Ce nouveau groupe change fortement la réactivité de l'époxyamide impliquant une optimisation délicate des conditions et un choix judicieux des substituants. De plus, une nouvelle méthode de déprotection par bromation photochimique a été mise au point, complètement compatible avec la fragilité du cycle beta-lactame. Enfin, pour générer le groupe partant en C-4, nous avons utilisé une oxydation de Baeyer-Villiger. La régiosélectivité de cette étape dépend fortement des substituants et apparaît contradictoire avec les exigences de la fermeture de cycle. L'étude de l'influence des substituants sur ces deux étapes nous a permis de sélectionner le substituant optimal. Dans la seconde partie de cette thèse, nous nous intéressons à l'introduction du 4e centre asymétrique caractéristique des carbapénèmes. Nous avons étudié la possibilité de l'effectuer avec des dérivés de l'acide de Meldrum pour substituer la position C-4 de l'intermédiaire-clef, suivi d'une décarboxylation asymétrique. Nous clôturons ce travail par une évaluation économique de notre synthèse d'un précurseur équivalent à l'acétoxyazétidinone. /Carbapenems occupy a central role in the fight against bacteria that are resistant to classical antibiotics such as penicillins. Our thesis has the aim to develop a synthesis of their principal intermediates with the objective to apply it at the industrial scale. We have explored, as strategy of the heterocycle closing, the formation of the C-3/C-4 bond by a nucleophilic attack on an epoxide. This one was obtained from L-threonine which brings two stereocenters and allows the induction for the creation of the third asymmetric carbon. We used the benzhydryl group as protecting group, new in this chemistry, to replace the usual para-anisyl group which causes industrial problems. This new group strongly affects the reactivity of the epoxyamide imposing a fine optimization of the conditions and an adequat choice of substituents. Furthermore, a new deprotection method by photochemical bromination was developed, entirely compatible with the fragility of the beta-lactam ring. Finally, to create the leaving group in C-4, we used a Baeyer-Villiger oxidation. Regiochemistry of this step strongly depends on substituents and appears contradictory with the requirements of the ring closing. The study of the influence of the substituents on these two steps permits us to choose the optimal substituent. In a second part of the work, we were interested in the introduction of the fourth asymmetric center of carbapenems. We studied the feasibility to perform it with Meldrum's acid derivatives by substituting the C-4 position of the key-intermediate, followed by an asymmetric decarboxylation. We ended this work by an economic evaluation of the synthesis of our precursor similar to acetoxyazetidinone.