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Bile acids are naturally made from cholesterol and then derivatized through biotransformation by gut bacteria in most vertebrates including humans. Iso bile acids designates the C3-β hydroxy subfamily of bile acid derivatives, with emerging biological discoveries but low commercial accessibility. Previous synthesis of iso bile acid targeted only a few substrates and some are limited by poor stereoselectivity of the methods. This thesis herein reports a concise three-step synthesis of iso bile acids generalizable to four common bile acid substrates with consistent yields above 85%. A base-catalyzed Mitsunobu reaction using TFA as the pronucleophile was employed to achieve the key C3 inversion, affording a synthetically useful intermediate that could be converted into the corresponding iso bile ester or undergo selective acylation at the sterically hindered C7 and C12 hydroxyl positions with above 90% yield. Rigorously dry condition was proven optimal for the Mitsunobu reaction, with azeotrope using benzene sufficient to remove extraneous water trapped in the reactant under high humidity in the atmosphere. The later chapter uncovers the extent and targeting step in the mechanism of water sensitivity in the Mitsunobu reaction. We observed that 0.25 equiv of water diminished the yield by 33%, and 1 equiv of water is sufficient to terminate the reaction with no conversion. Depending on the order the addition of pronucleophile, the first two stable intermediates betaine and H-betaine or phosphorane all exhibit high water sensitivity and rapid decomposition to O=PPh3 with presence of water, whilst the last oxyphosphonium intermediate only expresses a medium reactivity with water in the beginning of the reaction.

Oxazolidinones are known as a new class of antibacterial agents. In our group, the 4,5-disubstituted oxazolidinones have been previously identified to exhibit high affinity for the T box antiterminator transcription system. Among those compounds, ANB-22 and ANB-40 emerged to be the lead compounds showing good RNA-binding activity with high affinity and specificity. In medicinal chemistry, conformationally constraining molecules is a useful approach to optimize the biological activities of drug candidates. This dissertation is devoted to the design and synthesis of the fused tricyclic piperazine analogues and tricyclic triazole analogues of ANB-22 and ANB-40. By employing the aziridine-ring-opening and the Mitsunobu reaction, a series of fused bicyclic and tricyclic oxazolidinone-piperazine derivatives have been prepared. Using similar synthetic strategy and subsequent structural modification, the fused tricyclic piperazine analogues of ANB-22/40 have been successfully obtained as well.The application of the intramolecular azide-alkyne cycloaddition leads to the tricyclic fused oxazolidinone-piperazine-triazole compounds. After appropriate structural modification, the triazole analogues of ANB-22/40 have been prepared. By hydrolyzing the oxazolidinone ring of these tricyclic compounds, a series of amino alcohol derivatives with a piperazine-triazole framework have been generated. In addition, the use of copper catalyst allows the occurrence of the intermolecular cycloaddition to afford four macrocyclic dimers.

I. Maintaining high standards of science training is important for pharmacy graduates to practice knowledgeably, responsibly, and confidently. Instrumentation and resource constraints are maximal in the pharmaceutical analysis laboratory due to the nature of the experiments that need to be conducted and the need to provide as much individualized learning experience as possible. Therefore, the 1st year PharmD students perform the laboratory exercises in subgroups, rotating each week in three tri-weekly cycles. Although this arrangement optimizes space, instrument and resources utilization, it creates inevitable educational gaps related to each subgroup's experiment. More specifically, there are gaps with the lectures' progress and the necessary pre-laboratorial instruction for each experiment. Therefore, online instructional tutorials and technique-demos as well as accompanying online quizzes were prepared and delivered through a secure course-website. Each student had to view the tutorials and pass the quizzes before coming to the laboratory. In addition, virtual laboratories were designed as an additional aid for some experiments. As shown by student surveys, these changes were well-received and improved many aspects of this class. II. Most cancer mortality results after it has metastasized from its primary growth site and spread to remote sites. Metastasis is a complex succession of events that the cancer cell manages to accomplish as the disease progresses. One necessary step is the breakdown of the physical barriers, such as endothelial basal membrane and extra-cellular matrix. In order to achieve this, cancer cells express heparanase, a beta-endoglucuronidase that breaks down the glycan part of heparan sulfate, which is a basic constituent of these physical barriers. Amino-sugars have been shown to inhibit this type of carbohydrate-processing enzymes by virtue of their transition state mimicry. Since the substrate of heparanase carries acidic moieties, its inhibitors also carry acidic groups. Few efficient synthetic routes are available for the synthesis of sugar amino-acids. The feasibility of the use of an unprecedented intramolecular SN2’Mitsunobu reaction and alpha-aminomethyl radical cyclizations is explored for the synthesis of alpha- and beta- sugar amino-acids respectively.

The alkoxytriphenylphosphonium ion intermediate of the Mitsunobu reaction for the esterification and inversion of configuration of an alcohol can be generated using the Hendrickson reagent, triphenylphosphonium anhydride trifluoromethanesulfonate, 27. While 27 was used in place of the Mitsunobu reagents (triphenylphosphine and a dialkyl azodicarboxylate) for the esterification of primary alcohols, the reaction failed with secondary alcohols such as (-)-menthol giving predominately elimination rather than the desired SN2 displacement. The difference between the two reactions was shown to be related to the more 'ionic' conditions generated when the Hendrickson reagent 27 was employed. An extreme sensitivity of the Mitsunobu reaction to the presence of salts was discussed and may indicate a mechanism involving ion pair clustering. Five-, six- and seven-membered cyclic analogues of the Hendrickson reagent 90-92 were prepared. A kinetic comparison of the cyclic analogues 90-92 revealed that a considerable increase in the rate of esterification could be achieved when the five-membered ring analogue 90 was used in a non-polar solvent such as toluene. Selected acyclic analogues of the Hendrickson reagent 27 possessing tributyl 118, tricyclohexyl 130 and diphenyl-2-pyridyl 137 functionalities were synthesised. However when 118, 130 and 137 were used for the attempted esterification of (-)-menthol, elimination was the major reaction pathway. Diphenyl-2-pyridylphosphonium anhydride triflate 137 was found to be a useful reagent for the synthesis of acyclic dialkyl ethers from primary alcohols. A polymeric version of the five-membered ring analogue 56, prepared by reaction of the polymer-supported 1,2-bis(diphenylphosphinyl)ethane 57 with triflic anhydride, was used for the preparation of simple esters and amides. A new dehydrating agent, polymer-supported triphenylphosphine ditriflate 157, was readily prepared from the oxidised form of commercially available polymer-supported triphenylphosphine and triflic anhydride. A wide range of dehydration-type reactions, such as ester, amide, anhydride, peptide, ether and nitrile formation, were performed in high yield using polymer-supported triphenylphosphine ditriflate 157. The reagent 157 was easily recovered and re-used several times without loss of efficiency. The use of 4-dimethylaminopyridine allowed the esterification of secondary alcohols with 157 to proceed without elimination and gave esters in high yield but with retention of configuration. Both reagents 56 and 157 provide an alternative to the Mitsunobu reaction, where the use of azodicarboxylates and chromatography to remove the phosphine oxide by-product can be avoided. However, the Mitsunobu reaction retains its supremacy for the inversion of configuration of a secondary alcohol. Preliminary investigations on the phosphityation of alcohols via the Hendrickson reagent 27, 1,3-benzodioxole formation using the Mitsunobu reaction and azodicarboxylate alternatives in the Mitsunobu reaction are described.