This thesis describes Further studies on the utilisation of the diterpenoid natural product , 12-hydrxypodocarpa-8,11,13-trim 19-oic acid* (podocarpic acid) (1) . In particular it describes transformations of the C-ring to give suitable intermediates for the synthesis of optically active steroids and terpenoids. An investigation has been carried out on the Birch reduction of 12-methoxypodocarpa-8,11,13-trien-19-ol (8), and conditions for the optimum formation of the ketonic products (10) and (12) are suggested. The enones (25) and (26) have been synthesised from 12-hydroxypodocarpa-8,11,13-trien-19-oic acid (1) by sequences involving reduction of the aromatic ring followed by ring C transformations. Methyl 12-hydroxypodocarpa-8,11,13-trien-19-oate (3) has been converted in ca. 60% yield to the dextrorotatory C 13 methyl ether which has then been reduced in good yield to the enone (163). Potential routes for conversion of the enones (25), (26), and (163)into steroidal analogues are described. Initial steps in the transformation of the C 13 methyl ether(62) into an intermediate (176) suitable for the synthesis of (+)-a-onocerin (80) have been investigated. A preliminary study on the synthesis of the C 14 phenol (190) or its methyl ether (191) is also reported. * The numbering system used throughout this thesis is that proposed by J.W. Rowe (personal communication to Professor R. C. Cambie) in "The Common and Systematic Nomenclature of Cyclic Diterpenes", 3rd Revision, Oct. 1966, to be submitted to the IUPAC Commission on Organic Nomenclature (see page 144)

<div>Carbenes are reactive organic intermediates comprised of a neutral, divalent carbon atom. The reactivity of carbenes is often orthogonal to polar functional groups (nucleophiles and electrophiles), making them valuable intermediates for organic synthesis. For example, carbenes can engage in cheletropic reactions with olefins to form cyclopropane rings or undergo insertions into weak element-hydrogen bonds. The most established strategy for accessing carbene intermediates is through a redox-neutral decomposition of diazoalkanes to form a transient M=CR₂ species. Over the course of nearly a half-century of development, many instrumental synthetic methods have emerged that operate on this basis. Despite the combined utility of these methods, the scope of catalytic carbene transfer reactions remains largely constrained by the inherent instability of the starting materials. Diazoalkanes often require electron-withdrawing groups to provide stability through resonance effects.</div><div>Contrary to redox-neutral methods, reductive carbene transfer reactions utilize non-stabilized 1,1-dihaloalkanes as carbene precursors. The Simmons-Smith cyclopropanation reaction represents the most documented example of this class, and remains today as the most practical method for parent methylene (:CH₂) transfer. Nevertheless, reductive carbene transfer processes have proven to be remarkably resistant to catalysis. Our group is interested in developing first-row transition metal catalysts which can initiate an oxidative addition into 1,1-dihaloalkanes, followed by a two-electron reduction with an outer-sphere reductant to provide access to a M=CR₂ intermediate for carbene transfer.</div><div>The application of this mechanistic hypothesis toward reductive methylene transfer using CH₂Cl₂ as the carbene source and a Ni catalyst is outlined in chapter one. The discovery of an unexpected cyclooligomerization of methylene carbenes is discussed. Mechanistic studies are presented, which are consistent with a pathway in which carbenes are iteratively inserted into an expanding metallacycle. In chapter two, the corresponding activation of 1,1-dichloroalkenes for vinylidene transfer in [5+1]-cycloadditions with vinylcyclopropanes is outlined. Finally, in the third and final chapter, organic reactions catalyzed by complexes which feature metal-metal bonds are reviewed.</div>

<p>  </p> <p>Aromatic C-N bond formation is critical for synthetic chemistry in pharmaceutical, agrochemical, and natural product synthesis. Due to the prevalence of this bond class, many synthetic routes have been developed over time to meet the demand. The most recent and robust C-N bond formation reaction is the palladium catalyzed Buchwald-Hartwig amination. Considering the importance of the Buchwald-Hartwig amination, a high-throughput experimentation (HTE) campaign was devised to create a library in which chemists can refer to optimal reaction conditions and ligand/catalyst choice based on the nature of their substrates to be coupled. This study showed trends for the appropriate choice of ligand and catalyst, along with what bases, temperatures, stoichiometries, and solvents are appropriate for the selected substrate combination at hand. </p>

<p>The hamigeran diterpenoid is a family of natural products with diverse structures and biological activities. Most of the syntheses focus on hamigerans with [6–6–5] tricyclic core, but synthetic efforts toward the more challenging [6–7–5] tricyclic hamigerans are very limited. Herein, our studies in synthesizing the [6–7–5] tricyclic hamigerans are disclosed.  Through a benzyne-β-ketoester annulative ring expansion and a Nazarov reaction, an approach toward the [6–7–5] tricyclic carbon skeleton of the hamigeran natural products was developed. A Ni-catalyzed conjugate methyl addition or a Corey–Chaykovsky reaction installed the all-carbon quaternary center, and a Suzuki cross coupling followed by reduction introduced the isopropyl group. However, the reduction of challenging tetra-substituted double bond or the regio-selective cyclopropane opening was not successful despite multiple conditions were tried. A revised synthetic strategy was proposed and resulted in a convergent total synthesis of (±)-hamigeran M, enabled by five C–H functionalization reactions and proceeding in 11 steps in 3.9% overall yield. The C–H functionalizations include a hydroxy-directed C–H borylation, one C–H metalation-1,2-addition, one C–H metalation-Negishi coupling, a late-stage oxazole-directed C–H borylation-oxidation, and one electrophilic bromination. Further elaboration of the intermediates obtained here has delivered an advanced polysubstrituted precursor towards multiple other hamigerans.</p>

<p>A significant number of resources are allocated to maintaining the resiliency of pharmaceutical supply chain as failure to do so thoroughly can result in drug shortages of essential medicines. Recently, the effects of COVID-19 exacerbated flaws in the current system causing the pharmaceutical industry and government organizations and to reassess relief strategies that could also strengthen the supply chain. Flow chemistry has become an attractive and prominent platform enabling continuous manufacturing (CM) technologies to synthesize active pharmaceutical ingredients (API) quickly according to demand. Compared to traditional batch chemistry, flow chemistry has demonstrated to be more robust in terms of throughput, scalability, and hazard reduction while maintaining a high degree of control and product quality. This work demonstrates these capabilities in reaction optimization and discovery with the overarching goal of domesticating CM to make essential medicines more affordable. A two-step process for the synthesis in diazepam was developed using a Chemtrix Labtrix S1 and Start microfluidic systems where purities as high as 98% were achieved. The system was successfully scaled up to a larger system that was able to produce 96% pure diazepam at a 91% yield. </p>

<p> The study of proteasome is a rapidly evolving field with multifaceted implications in neuroscience, aging, and cancer. Recent developments structural biology of the proteasome machinery has catapulted the drug discovery and targeted protein degradation. The success of proteasome inhibitors like Bortezomib and Ixazomib has also led to new interests in developing more precise inhibitors for the various proteasome isoforms. Proteasome activation is a relatively new field, and much has to be done in the field. The 20S CP is an emerging target in chemical biology and drug discovery for its implications in maintaining protein homeostasis and immune regulation. The central theme of the thesis is to study the proteasome in cellular contexts to develop new chemical biology tools to study the proteasome and its modulation by small molecules and probes in cellular contexts to ameliorate protein accumulation-mediated neurodegeneration </p>

<p>Natural products, along with natural product derivatives, are known to be at the root of the development of many pharmaceuticals, oftentimes showing unique bioactivity against interesting targets. Specifically, natural products containing furans show activity against a variety of diseases including fungal infections, and cancers. It is hypothesized that unknown natural products containing furans could show more potent or other biological activities. However, it is challenging to discover and isolate these small molecules from cell supernatant. The work described herein showcases the development of a molecular probe that can covalently attach to furan moieties via a [4 + 2] Diels-Alder cycloaddition, making them easily identifiable on liquid chromatography mass spectroscopy (LC-MS). The molecular probe, which undergoes this reaction with a variety of furans, was designed with both a UV-tag and a mass tag to enable easy identification. The probe has been tested with a variety of purified furans, including natural products, methylenomycin furan (MMF) hormones, and MMF derivatives. Moreover, work has begun to test the molecular probe in cell supernatants. </p>

<p>An original palladium-catalyzed ring opening carbonylative lactonization of synthetic available hydroxycyclopropanols was reported to efficiently synthesize tetrahydrofuran (THF) and tetrahydropyran (THP)-fused bicyclic γ-lactones, two unique scaffolds often found in quite a few natural products. This new developed reaction features mild reaction conditions, good functional group tolerability, and the scale-up abilities. The synthetic application was demonstrated in a short total synthesis of (±)-Paeonilide. The THF-fused bicyclic γ-lactone products can be readily diversified into some medicinally important structures, which further broadens the application of this new carbonylation approach.</p> <p>The first total synthesis of Phleghenrine A was reported. This synthesis features an unprecedented inverse electron-demand Diels-Alder reaction and Tiffeneau-Demjanov ring expansion to rapidly construct bicyclo[3,2,2]-nonane core structure of Phleghenrine alkaloids. Two Diels-Alder adducts were synthesized, which were the synthetic precursors for divergent synthesis of Phleghenrine A and B, respectively.</p>

<p>  </p> <p>Quinolines are benzopyridine complexes present in many modern antimalarial, anticancer, anti-inflammatory, antimicrobial, and other useful pharmaceuticals and natural products.1,2 Quinolines form the scaffold for many potent anticancer drugs; this is because quinolines can undergo both nucleophilic and electrophilic substitution reactions, can be ingested and inhaled by humans without any harm, and possess a great deal of biological importance.3 My research has focused on synthesizing 3H-pyrazolo[4,3-f]quinoline analogs. The 3H-pyrazolo[4,3-f]quinoline scaffold was modified using various amine groups to obtain amide analogs as well as see how a change in the scaffold affects the anticancer activity of the synthesized complexes by screening them against kinases such as FLT3, CDK2, CDK4, and CDK9 to see if they are effective inhibitors. The synthesized complexes were then characterized using proton, carbon NMR and FTIR spectroscopy.</p>

<p> Over 40 years since the emergence of the AIDS epidemic and still no cure exists for AIDS or its causative HIV-1 infection. Protease inhibitors are an integral part of the most effective treatment regimen for HIV-1 infected patients known as combination antiretroviral therapy (cART), which is extremely effective at decreasing viral loads to nearly undetectable levels. One of the most alarming issues with current treatments is the emergence of multi-drug resistant strains. Even darunavir, which has shown exceptional activity against drug resistant strains, has experienced this issue. Herein we designed a novel series of heterocyclic based P2 ligand HIV-1 protease inhibitors based on kinase inhibitors such as imatinib and dasatinib. These inhibitors were designed to promote hydrogen bonding with the peptide backbone atoms of HIV-1 protease. Compounds were synthesized, biologically evaluated, and underwent X-ray structural studies. Inhibitors displayed activity as low as sub-nanomolar potency and low nanomolar antiviral activity. Important ligand-binding site interactions were determined through two X-ray crystal structures.</p> <p>Emergence of SARS-CoV-2 at the end of 2019 resulted in a global pandemic that has affected millions. Researchers all over the world turned their attention to developing drug therapies aimed at preventing and treating the viral infection. One such target became the main viral protease, or 3-chymotrypsin like protease (3CLpro). 3CLpro is an essential viral enzyme responsible for polypeptide cleavage during the viral replication cycle to produce 16 nonstructural proteins (nsps). Thus, it has been a highly researched area for effective SARS-CoV-2 drug therapies. Therefore, we designed, synthesized, and biologically evaluated a series of competitive reversible SARS-CoV-2 3CLpro inhibitors. </p>