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<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>

Ruthenium polypyridyl complexes have long been studied due to their unique photophysical characteristics and their synthetic accessibility. We report here the use of new ruthenium polypyridyl’s in photodynamic chemotherapeutic and solar fuel applications. Nearly half of all chemotherapeutics administered today are derived from platinum-based drugs (platins) which lack specificity and can cause sever side-effects. Photodynamic chemotherapeutics (PDT) circumvent these issues utilizing light activation at the site of cancerous cells to generate a cytotoxic Ru(II) center and eventually trigger cellular apoptosis. The new PDT pro-drugs presented push their metal-to-ligand charge transfer (MLCT) light absorption out into the near-IR which is able to penetrate skin at greater depths than traditional PDT drugs. New Ru(II) hydrogen fuel evolution catalyst for use in dye-sensitized photoelectrosynthesis cells (DSPECs) based off of the extensively explored octahedral tridentate-bidentate coordination motif is also investigated. In particular, pendant bases are oriented toward the active site of the catalyst to increase catalytic rates and lower overpotentials. Preliminary density functional theory calculations show that strategic placement of the pendant amine on the bidentate ligand allows for productive interactions between the base and the active site of the catalyst to evolve hydrogen.

<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>

Over the past decades, numerous studies have shown that curcumin has potent biological activities. As a potential chemopreventing agent, curcumin was demonstrated to exert anti-cancer effects in both in vitro and in vivo studies. However, low bioavailability of curcumin limited human clinical trials and its application to be formulated as therapeutics. In this thesis, we will summarize the anti-cancer effects of curcumin in animal studies and clinical trials. In addition, an SAR study will be introduced to elucidate the mechanism of curcumin degradation at physiological pH. We synthesized various curcumin analogues and compared their stability in phosphate buffer using HPLC and colorimetry assay. The results not only demonstrated that the -OH group and the methoxy group play a critical role in stability of curcumin in physiological environment, but also support the proposed mechanism of phenolic radical formation by which curcumin degrades to its major product bicyclopentadione.

<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>