Spirotetronate polyketides are naturally occurring natural products that are highlighted by their complex structures and intruiging biological activities. Chapter 1 emphasizes the importance of this class of natural products from their synthetic endeavors to their molecular targets as cancer therapeutics. Chapter 2 discusses the synthesis of the decalin moiety for the class of spirotetronate polyketides. The synthesis is highlighted by an intramolecular Diels-Alder reaction (IMDA) that proceeds through an energetically unfavored endo-axial transition state. Chapter 3 examines synthetic efforts toward the total synthesis of maklamicin and the difficulties in the synthesis of spirotetronates polyketides in the laboratory. Chapter 4 elaborates upon a general synthetic strategy towards the synthesis of this class of natural products addressing the main struggles faced towards the total synthesis of maklamicin. This strategy also opens a general strategy to potentially synthesize spirotetronate polyketides with varying sizes of the macrocyclic motif.

The understanding of a dye’s electronic nature is fundamentally important as well as vital to the rational design of subsequent dyes. The elucidation of the conjugation path in a naphthalene dye, substituted by a donor and acceptor on the long axis, is reported. This was accomplished via a combination of theoretical and empirical methods aimed at measuring the results of perturbing the electronic pi-structure. The replacement of methine units in naphthalene with nitrogen through the synthesis of analogues resulted in characteristic changes to the optical and electrochemical properties. These observations are consistent with the donor and acceptor being conjugated to specific positions in naphthalene. The results add to fundamental knowledge about the electronic nature of push-pull naphthalene, while directly providing a map of sites on naphthalene that may be synthetically targeted and altered to obtain bespoke dyes with desired photophysical or electrochemical properties.

Decalin-containing natural products along with tetramic acid moieties present characteristic functionalities for antibiotic and antifungal activity. Thus, the total synthesis of a natural product in this class was determined to be of importance in a world where antibiotic resistance is an ever-growing issue. This creates the need to consistently develop novel antibiotics that can effectively attack various targets that are essential to the microorganism’s survival. Exploring the total synthesis of Conipyridoin analogs, which are decalin and tetramic acid-containing natural products, was carried out in this paper in 12 efficient steps. Major transformations in this synthesis include the creation of the decalin moiety through a Lewis acid-mediated intramolecular Diels Alder reaction along with a Lacey-Dieckmann condensation with an amino acid to build the tetramic acid core. This biomimetic synthesis allows for similar analogs of Conipyridoin to be synthesized with ease.

Small molecule fluorescent probes provide a non-invasive way to obtain accurate microviscosity measurements for biological analyses, especially when bulk measurements are not feasible. A family of push-pull fluorescent dyes, inspired by the benzothiazole motif of Thioflavin T, are reported, along with preliminary data on their use for visualizing long-range bacterial signaling and binding affinities for amyloids. By altering the ?-wire through increased conjugation and heteroatom substitution, a red-shifted ThT analogue was successfully synthesized. Synthetic analogues of previously reported fluorescent probes were also synthesized. Increasing the ?-wire from phenyl to naphthyl induced a bathochromic shift. It was also observed that switching from an ester to an amide altered photophysical properties in both sets of analogues. There was a slight hypsochromic shift due to the amide, likely attributed to the slight decrease in electron-withdrawing character of the acceptor group. Moreover, the emission intensity of the FRET donor decreased in the amide ratiometric system as compared to that of its ester counterpart, potentially indicating an enhancement of energy transfer between the donor and acceptor pair. These studies point towards ways to optimize the chemical structures of various fluorescent probes for specific applications.

Nearly 20 years ago, mitochondria were mistakenly considered only as the home production of energy molecule, adenosine triphosphate. However, a large growing research body has uncovered numerous vital roles of the mitochondria in various biological processes, such as aging, signaling, immunity, calcium homeostasis, and diseases including diabetes, cancer, and Parkinson’s disease.Mitochondrial dysfunction could result from mutation of its genetic component. It’s quite tricky to relate mitochondrial dysfunction with certain pathogenic phenotype. Thus, metabolomic study was conducted to reveal causal metabolites, and classify their association with various symptoms. The untargeted metabolomic study was performed in favor of the detection of bioactive lipid in the plasma of approximately two thousand patients with genetic mitochondrial diseases. Bioactive lipids are major chemical class in the body, containing inflammatory meditated lipids. Our studies on this topic led to the discovery of new hydroxyl fatty acid family that has been associated with mitochondrial diseases. Mitochondria, on the other hand, have involved in cancer, and they are considered a great potential therapeutic target for the initiation of death pathway, and hence, it leads to the apoptosis of cancerous cells. Caged Garcinia xanthones (CGXs), which are natural products, have been identified as potent antitumor agents targeting the mitochondria. On this topic, we synthesized forbesione, a member of the CGX family, and various synthetic analogs in order to potentially produce more potent analogs compared to the parent compound.

Natural products have long been looked to as sources for novel therapeutics. Perhaps the most notable example of a therapeutic natural product is the venerated Penicillin, which for decades was the gold standard for the treatment of bacterial infection. As bacterial infection has proliferated, Scientists have had to develop novel antimicrobial compounds, rather than isolating them from natural sources as they had done initially. An efficacious strategy for developing new drugs is through the diverted total synthesis of natural products, wherein analogs of natural products are synthesized to increase their potency while still maintaining the original biological profile imbued by their structural archetype. Taking inspiration from this strategy, we identified four natural products of related biological activity and conserved structural features. We resolved to substitute the shared structural motifs through total synthetic chemistry to generate new compounds in the hopes of developing a novel platform for antibiotic discovery. The first chapter of this thesis covers the synthetic studies toward this end. Our strategy demonstrates the ability to target different intramolecular Diels-Alder reaction pathways to selectively direct toward endo-axial or endo¬-equatorial decalins. It then covers our successful manipulation of this key intermediate to remove all protecting groups and chiral auxiliaries while avoiding undesirable side reactions. We then demonstrate our ability to install the requisite E-Z diene and tricarbonyl motifs to show the feasibility of our strategy to make the final natural product analogs.The second part of this thesis details a study into the fundamental reactivity modes of aminoboranes. Over the course of my studies on macrocyclic polyketides I experienced firsthand the intrinsic inefficiencies of synthetic chemistry. The compounding loss of material through each transformation can make the preparation of large quantities of final product challenging, even for longest-linear-sequences of twenty steps. The easiest way to avoid material loss is to shorten synthetic sequences by avoiding unnecessary steps and manipulations. Difunctionalization reactions, where two functional groups are installed in one synthetic transformation are a powerful way to shorten synthetic sequences. We identified aminoboranes as useful reagents for difunctionalization reactions because they are amphiphilic, giving us multiple activation modes from which to work; furthermore, amination and borylation reactions are of immense interest to the synthetic community and there is a dearth of difunctionalization reactions that use aminoboranes. We set out by examining the nature of coordination between aminoboranes and neutral Lewis bases in solution, using NMR spectroscopy to quantify coordination and chemical shift. We then determined the redox potential of aminoboranes using cyclic voltammetry. From these data we screened a library of commercially available photocatalysts and identified two that were competently quenched by aminoboranes. Finally, we derived Stern-Volmer quenching constants for these photocatalysts and our library of aminoboranes. Using these data we attempted to develop a difunctionalization reaction employing photoactivated aminoborane species, however these pursuits were unfruitful. Ultimately, we were able to discover and develop a ground-state carbene-insertion reaction of aminoboranes.

According to the World Health Organization, almost 10 million people worldwide died of cancer in 2020, a number that is expected to rise to over 16 million annually by 2040. As a result, there is a pressing need for drugs that effectively eliminate cancer in new and innovative ways. This dissertation addresses this challenge by first discussing an improved method for the extraction and purification of gambogic acid (GBA), a highly cytotoxic compound that is part of a family of synthetic and natural products collectively known as caged Garcinia xanthones (CGXs) . We next identify novel CGXs with improved cytotoxicity in several breast cancer cell lines. Lastly, we identified novel drug leads for proteins that have not been previously identified as amenable to pharmaceutical modulation. Specifically, we developed an in vitro model that identified new CGXs that can bind to the surface of the mitochondrial NEET protein MiNT and modulate the release of its Fe-S clusters. We identified an improved method for the expression and purification of MiNT, and by utilizing various spectroscopic methods, we measured binding constants of CGXs to MiNT and determined that they have a stabilizing effect on its Fe-S clusters as seen in spectroscopic measurements of their decay. In addition, we identified structural changes of MiNT that occur due to binding of xanthone ligands and their contribution to the stability of MiNT Fe-S clusters. Taken together, our results demonstrate that CGXs are highly cytotoxic in numerous cancer cell lines, and that one of their protein targets, the Fe-S protein MiNT, is a novel promising target for anticancer pharmaceutical development, specifically with CGXs.