Carbon-carbon bond formation is the foundation to synthesizing complex molecules and has gathered the attention of many synthetic chemists. One must keep in mind that these reactions are dependent on materials for a specific agenda when tackling a structural framework, which may require additional steps to create, and at times, are difficult to prepare. As significant as C-C bond formation reactions are, these minor setbacks may draw caution when synthesizing a complicated molecule whose structural framework cannot be easily accessed by the unity of two fragments. On the other hand, the less familiar C-C bond cleavage reactions have, over time, demonstrated the potential to generate unique structural building blocks that can be used to overcome certain obstacles that other synthetic methods cannot provide. Here, we will be focusing on concerted anionic five-center fragmentation reactions using vinylogous acyl triflates. The generated alkynogenic fragments will then be used in different applications. We will begin by looking at chemoselective “click” reactions. The strained-promoted alkyne is synthesized by a tandem intramolecular nucleophilic addition / fragmentation. The expanded ring will contain a strained cycloalkyne which will later be tethered to a terminal alkyne. The diyne will be used to provide an example of a “dual-click” coupling via SPAAC or CuAAC in either sequential order. Next, we will expand the tandem fragmentation / olefination methodology developed in this work to include dienynes. The dienyne provides the structural backbone needed to produce neopentylene indanes. This methodology is used to design new ibuprofen derivatives that demonstrate rigidity and increase hydrophobicity to modulate the molecular pharmacology of ibuprofen. / A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2017. / August 24, 2017. / Includes bibliographical references. / Piotr Fajer, University Representative; Jack Saltiel, Committee Member; Lei Zhu, Committee Member.

by Chan Shau-lung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1980. / Bibliography: leaves 54-56.

Increasing legislative and economic pressure to find more sustainable methods of organic waste management has fuelled innovation in biological treatment technology. By-products of paper manufacturing industries provide a large source of organic waste, which is known to have a high environmental impact. This waste paper sludge has been shown to be amenable to biological treatment. Recent research has confirmed that windrow-composting and vermicomposting techniques have potential to treat these wastes and share many economic and environmental benefits. Many authors have suggested that sludge specific composting methods need to be developed and this research aims to provide fundamental data in this respect. The treatment of specific waste paper sludges was investigated through small and larges calee xperimentsw ith the aim of optimising thesep rocessesw ith minimal intervention. Identical samples of a selected waste paper sludge feedstock were used in large scale investigations into the application of each composting technique, and the performance of each process and resulting products was evaluated. Windrow composting and vermicomposting were found to stabilise and enhance waste paper sludge in very different ways, producing unique products. In terms of processing, windrow composting resulted in more rapid rates of stabilisation and although the performance of the vermicomposting process was less effective in these respects, it afforded additional benefits as a treatment of waste paper sludge. Both processes were found to stabilise and enhance waste paper sludge but the selection of one system or the other will depend largely on the objectives of the project and the criteria required of the finished product.

The first synthesis and full characterization of a new functionality, called the diaziridinium ion, is reported. The original synthetic intent behind its design was to explore its potential use as a non-metal based N-transfer reagent. During this study, we have uncovered a practical rearrangement to access 2,3-benzodiazepines reliably and efficiently. Efforts to achieve N-transfer from these species are described and are ongoing. We have identified the tropylium ion as a highly efficient organic-based amine oxidant and have demonstrated its practical use in a one-pot protocol for alpha-aminonitrile synthesis. We also report an application of this new oxidant towards an aza-Cope rearrangement. Finally, we report a multicatalytic method that uses bismuth(III) triflate to catalyze a nucleophilic addition to an aldehyde followed by hydroalkoxylation to generate highly functionalized tetrahydrofuran rings, a motif that is often encountered in natural product architectures.

This thesis describes progress toward to the total synthesis of the natural product platensimycin, the development of proficient carbon nucleofuges for the Tsuji-Trost allylation, and the use of chiral cyclopropenones and formamides for the kinetic resolution of alcohols by chlorodehydration. The first chapter describes efforts in the total synthesis of platensimycin. The synthesis attempted to use a thermal rearrangement, through a biradical intermediate, and then radical induced [3+2] cycloaddition between a vinyl cyclopropane and pendant olefin to create the core of platensimycin. A revised strategy was employed using a palladium(0) catalyzed Heck cascade and palladium(II) catalyzed alkoxypalladation. The second chapter describes the development of a carbon-based nucleofuge. A substituted cyclopentadienyl anion served as a competent leaving group in the Tsuji-Trost allylation. Various substrates were examined including carbon and nitrogen nucleophiles. The reaction mechanism with nitrogen nucleophiles is studied. The third chapter describes the synthesis of chiral cyclopropenones and their use in the kinetic resolution of alcohols by chlorodehydration. Chiral formamides are also studied for their use in chlorodehydration. Transition states for enantiodifferentiation are proposed.

This thesis describes the development of novel synthetic methods in the areas of methylene transfer cyclopropanation and reaction design with aromatic cations. The first chapter presents a new cyclopropanation method involving intramolecular methylene transfer from an epoxide to an olefin. The lanthanum(III) triflate-catalyzed process proceeds with high stereoselectivity and a range of examples are presented to illustrate the reaction scope. An asymmetric cyclopropane synthesis combining enantioselective epoxidation and the methylene transfer protocol is also presented. The second chapter describes the application of aromatic cation activation for nucleophilic acyl substitution. The strategy is used to rapidly convert carboxylic acids to their corresponding acid chlorides with dichlorocyclopropene reagents. The effect of cyclopropene substituents and amine base additives on the rate of conversion is examined. A mild amidation protocol employing acid chloride formation is described and applied to acid-sensitive substrates and preparative peptide couplings. The final chapter discloses the development of aromatic cation photoredox catalysts. Investigations into the relationship between cyclopropenium substitution and ultraviolet/visible light absorption are presented. Cyclopropenium ions are shown to be effective photocatalysts for a variety of photoredox transformation.

This thesis describes in detail our journey toward Maoecrystal V, a potential anti-cancer diterpenoid. Maoecrsytal V was isolated in 2004 from a Chinese herbal medicine. It has a highly congested structure, in which there are three continuous quaternary carbon center embedded within a rigid pentacyclic scaffold. The first chapter of this thesis covers the isolation, bioactivity, and synthetic efforts from other groups. The second chapter discusses our first generation strategy toward Maoecrystal V. During our early studies, we successfully found the conditions for the key intramolecular Diels-Alder reaction. We also identified that the facial selectivity of this Diels-Alder reaction is a big challenge for our synthesis plan. The third chapter describes our solution to the core structure of Maoecrystal V. The exploration resulted in the discovery of a novel exo-glycal epoxide rearrangement. The last chapter describes the total synthesis of Maoecrystal V. The difficulties we met and our solution is discussed.

The myrmicarin family of oligomeric natural products comprises one of the most ornate collections of polycyclic alkaloids known. The structural characterization of their unique scaffolds was accomplished through elegant spectroscopic studies. Furthermore, the synthesis of these alkaloids has attracted the attention of the synthetic community, with several syntheses of the monomeric myrmicarins completed. Significant effort has been put forth toward the synthesis of the higher order structures, though no successful approach has been reported to date. These isolation and characterization studies as well as synthetic approaches toward the family are reviewed. Chapter 2. The Evolution of Efficient, Enantioselective Total Syntheses of Monomeric Myrmicarin Alkaloids. In order to provide a family-level solution to the myrmicarin alkaloids, we adopted a strategy-level approach to their synthesis. Utilizing concepts from retrosynthetic analysis and diversity oriented synthesis, an enantioselective and highly streamlined synthesis of the monomeric myrmicarin alkaloids as well as potential dimerization precursors was established from a common intermediate with late stage diversification. Chapter 3. Dimerization Studies toward the Synthesis of Myrmicarin 430A. An alternative strategy for the synthesis of myrmicarin 430A is presented using a dienamine precursor. This approach allows for the stereoselective synthesis of the all trans stereotriad of the central cyclopentane moiety of myrmicarin 430A. Mechanistic aspects concerning the final bond closure are presented in light of quantum chemical calculations. Chapter 4. An Introduction to the Securinega Alkaloids and NHC Catalysis The Securinega alkaloids comprise a large family of tetracyclic alkaloids, many of which contain a conjugated butenolide moiety. While many distinct synthetic approaches have appeared for the synthesis of members of this family, only a relatively small number of approaches are applied to the synthesis of the butenolide portion of these natural products. The various synthetic endeavors to accessing this structural motif are presented. NHC catalysis is a growing field of research for its ability to promote unusual chemical transformations. As this field of research is of relevance to our latter studies, a brief overview of modern NHC catalysis is presented. Chapter 5. Development of an NHC-Catalyzed Cascade Reaction to Access the Core Architecture of the Securinega Alkaloids. In targeting the family of <italic>Securinega</italic> alkaloids, a retrosynthesis was devised that proposes a novel intramolecular cyclization approach of an ynal and ketone to deliver the bridging butenolide moiety of these natural products. The development of this reaction and its application toward the synthesis of various <italic>Securinega</italic> alkaloids is presented.

Chapter 1. Introduction Natural product total synthesis has long fulfilled many roles in synthetic organic chemistry, one of the foremost being inspiration of the development of novel methods and strategies to access particular structures. The halogenated natural products represent one class of secondary metabolites that can serve to inspire new chemical methods. Although nature's enzymatic machinery is capable of installing halogen atoms onto organic frameworks efficiently, synthetic chemists often lack these same tools. In particular, the development of halonium-induced polyene cyclization, asymmetric halogenation, and medium-ring haloether formation would facilitate access to hundreds of halogenated natural products, but these reactions have traditionally proven challenging. Chapter 2. The Discovery of BDSB and Initial Investigations into Halonium-Induced Polyene Cyclizations Currently available electrophilic bromination reagents are often not suitable initiators for halonium-induced polyene cyclizations, likely due to competing inter- and intramolecular processes. As such, we explored bromosulfonium salts for this purpose and in doing so developed a novel bromonium reagent (BDSB, bromodiethylsulfonium bromopentachloroantimonate). This easily synthesized and handled reagent proved capable of cyclizing an array of polyene precursors rapidly, in good yield, and with high diastereocontrol. The chlorinated analogue (CDSC) proved somewhat successful for initiating the analogous chloronium-induced polyene cyclizations. Chapter 3. The Total Syntheses of 4-Isocymobarbatol, Peyssonol A, and Peyssonoic Acid A, and Evaluation of Peyssonol A Analogues for Anti-HIV Activity Our novel reagent, BDSB, was applied to the successful total syntheses of three brominated natural products (4-isocymobarbatol, peyssonol A, and peyssonoic acid A). These syntheses were predicated upon bromonium-induced polyene cyclizations of substrates of increasing complexity. The total synthesis of peyssonol A uncovered a structural mischaracterization, one that would require the synthesis of four diastereomeric final products to rectify. Given that the anti-HIV properties of peyssonol A have been documented, we undertook an exploration of the structure-activity relationship of peyssonol A utilizing the many synthetic precursors and analogues at our disposal. These studies indicated that both the aromatic and aliphatic portions of peyssonol A contributed to its observed bioactivity. Chapter 4. Enantioselective Halogenation Chiral variants of BDSB, CDSC, and IDSI (the iodinated analogue) were synthesized from chiral sulfides and applied to halonium-induced polyene cyclizations and other asymmetric halogenation reactions. While no enantioselectivity was observed for cyclization reactions, moderate e.e. values (up to 63%) were observed for both asymmetric dichlorination and asymmetric iodohydroxylation of alkenes. Additionally, we developed an effective two-step surrogate for asymmetric halonium-induced polyene cyclizations that proved capable of affording the desired cyclic products in good yield and with moderate enantiomeric excess (up to 81%). Chapter 5. Bromonium-Induced Ring Expansion for Accessing 8-Membered Bromoethers and Application of this Reaction to the Formal Total Synthesis of (E)- and (Z)-Pinnatifidenyne A fortuitous rearrangement led to the development of a novel method for bromonium-induced ring expansion, one that transforms tetrahydrofurans into brominated oxocanes (8-membered ring ethers). This BDSB-mediated process is high yielding and both regio- and diastereoselective, making it ideal for application to the synthesis of lauroxocanes: a large family of natural products built around an 8-membered ring bromoether core. This synthetic utility was demonstrated during the application of this strategy to the formal total synthesis of (E)- and (Z)-pinnatifidenyne; the completed route represents the most expedient total synthesis (of more than two dozen) of any lauroxocane natural product.

This dissertation presents new approaches towards the asymmetric allylation of the imino and formyl functionalities by using strained silanes as Lewis acids. Here in the Laboratory of Professor James L. Leighton, chiral homoallylic alcohols and amines are considered privileged products given their important role as building blocks in natural product synthesis. The new approaches reported herein are focused on expanding the scope of imine allylation reactions and gaining full synthetic utility of the corresponding homoallylic amine products by means of economic and user-friendly protocols. In addition, the discovery of a novel catalytic and mild approach to the asymmetric allylation of aldehydes will be the focus of discussion at the end of this works. Chapter 1 will give a brief introduction about general concepts in asymmetric allylation of aldehydes and imines as well as in applications of strained silane Lewis acids in these reactions. Chapter 2 will discuss the development of a novel asymmetric allylation method for N-heteroaryl hydrazones and the N-heteroaryl cleavage from the product to unmask the corresponding free amines. Chapter 3 will carry on these studies into different imine activating groups in search for a more general and user-friendly approach towards both allylation and cleavage protocols. Finally, Chapter 3 will discuss the development of a new methodology in which chiral bismuth (III) complexes can catalyze the asymmetric allylation of aldehydes with achiral strained allylsilanes.