Part I of this dissertation includes the chronological synthetic background of mandelalide A as well as the synthesis of the C1-C14 glycosylated southern subunit of mandelalide. A key aspect of the synthesis includes a novel silver-catalyzed cyclization (AgCC) of a propargylic benzoate to construct the substituted cis-pyran ring system present...
Sunscreen products are used worldwide to protect the skin from ultraviolet radiation. However, some of the ingredients used in sunscreen products are fatal to coral reefs especially in areas where tourism is a large part of the economy. In this study, we explored a synthetic route to produce 4-deoxygadusol, which...
The first part of this manuscript is about the total synthesis of the aspidosperma alkaloids leuconoxine, melodinine E and mersicarpine. Our synthetic strategy used a radical translocation-conjugate addition cascade to construct the core of the natural product. Specifically, a vinyl radical was generated from the homolysis of the C–I bond...
Substituted phenols are important substructures for pharmaceuticals, agrochemicals, natural products and biological probe molecules. The properties of phenolic molecules are substantially influenced by the substitution patterns of the phenolic ring. The chemical synthesis of phenols with various substitution patterns is an enduring challenge and multiple strategies have emerged. However, some...
In the past decades, femtosecond stimulated Raman spectroscopy (FSRS) has been gaining tremendous popularity in fundamental sciences stemming from chemistry to biology. It is capable of capturing both equilibrium and non-equilibrium structural information across a broad range of timescales with simultaneously high temporal and spectral resolutions. Femtosecond transient absorption spectroscopy...
Exploring bioactive natural products has contributed largely to clinically approved drugs we have been using over the last 100 years. Especially among the anti-infective drugs, around 70% of currently used antibiotics were discovered or derived from microbial secondary metabolites, among them compounds like vancomycin, chloramphenicol, and erythromycin. Facing the unavoidable...
Fungi have long been used for discovery of new chemical scaffolds. In the clinical setting, the fungal natural products penicillin, statins, and cyclosporine have revolutionized medicine to treat diseases and infections. In the environment, fungal natural products have been used as herbicides, fungicides, and insecticides to protect crops, livestock, and...
Dearomatization reactions exist broadly in biosynthesis and chemical synthesis. The highly functionalized atoms of arenes can be masked by it aromaticity, and upon dearomatization, those reactive atoms can be readily applied to bond formation and further manipulation. The total synthesis of (–)-cephalotaxine and (–)- homoharringtonine is described via an oxidative...
Mandelalide A has attracted considerable interest from the synthetic community due to its intriguing structure and important cytotoxic activity. Madeirolide A, a structurally related macrolide, shows promising antifungal activity but no appreciable anticancer activity. This dissertation describes synthetic studies toward mandelalide A, madeirolide A and their hybrid structures.
Part I...
The furanyl diterpenoid family of natural products has drawn the attention of both synthetic organic chemists and pharmacologists due to their complex structural architectures and diverse biological activity. Among them, wortmannin has been most extensively studied for biological activities. All these furanyl diterpenoids consist of a highly strained naptha[1,8-bc]furan core,...
This dissertation investigates the structure and topological properties of cyclicallypresented groups. First, a family of groups called groups of type Z is considered. Withfew exceptions, the finiteness, asphericity, fixed point, and 3-manifold spine problemsare solved. Most groups of type Z have a central element of infinite order fixed by theshift....
Lycopodium alkaloids have shown widespread and noteworthy biological activity, consisting of over 250 known natural products. Moreover, their structural complexity and diversity have attracted considerable attention from numerous laboratories including our own. Recently, we have developed a unified approach that would provides access to numerous, previously unprepared C₁₀-functionalized lycopodium alkaloids....
Carbon Nanotubes are a unique family of nanostructures that have shown remarkable promise for mechanical, electrical, and optical applications. Fundamentally similar to the earlier discovered Buckminsterfullerene (C₆₀), carbon nanotubes are hollow cylinders formed from a single sheet of carbon atoms. The research presented in this dissertation investigates several carbon nanotube...
The structural architecture present in marine toxin azaspiracid - 20 stereocenters, 9 rings, 3 separated spirocenters - has attracted considerable synthetic attention. Our efforts toward the synthesis of azaspiracid have led to the completion of both C₁-C₂₆ northern and C₂₇-C₄₀ southern halves. Herein, the
synthesis of southern FGHI ring system...
Three approaches toward the core of halichlorine and pinnaic acid are described. The first approach entails a racemic transannular nitrone-olefin [3+2] cycloaddition from nitrone 238. Construction of the nitrone 238 began with aldehyde 241. Another key feature in this route involved a ring-closing metathesis for the formation of a 14-membered...
This dissertation is separated into two parts according to the two major distinct research projects. In Part I, the full account of synthetic studies toward C10-functionalized lycopodium alkaloids is described. In Part II, the detailed discussion on the exploration of the Pummerer cyclization methodology and its application to the total...
Aminal radical intermediates were generated by the method of radical translocation and reacted in C-C bond forming reactions with electronically deficient alkenes (Schiedler et al. Org. Lett. 2012, 14, 6092). Aminal radical intermediates can participate in inter- and intra-molecular reactions using both Bu3SnH and (TMS)₃SiH as hydride donors. Carbon–carbon bonds...
Organic compounds which contain one or more nitrogen atoms are especially important as they are disproportionately represented among biologically active molecules. As a result, significant effort has been focused on the development of methods for the synthesis of nitrogenous molecules. We identified the aminal as an under-explored functional group. Despite...
More than 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated over last three decades. From this family, amphidinolides C and F stand among the most complex and densely functionalized affiliates. Recently, we have accomplished the first total synthesis of amphidinolide F. The all-carbon framework...
Pharmaceuticals, molecular catalysts, and secondary metabolites often contain nitrogen. The problems faced synthesizing compounds which contain nitrogen was because of the Lewis base reactivity of nitrogen lone pairs, and the acidic protons of some nitrogenous functional groups. We developed two methods for the synthesis of nitrogeous compounds. Additionally, we successfully...
This thesis is separated into three distinct projects. First, synthetic studies towards the furanosteroid viridin shown in part I. Second, synthetic studies towards the diperene obtusanal shown in part II. Third, the analysis, characterization, and synthesis of coronene derivatives towards their application in organic batteries shown in part III. Significant...
Natural products from both terrestrial and marine sources represent a significant source of novel drug leads, and have previously been developed into clinically-approved agents for the treatment of various human diseases. This work represents the biological characterization of the mechanistic basis for activity of several natural product structures in models...
Complex organic transformations, such as the addition of pyrrole to ketene using planar chiral organocatalyst (*PPY), the four-component anhydride- Manniach reactions, and the site-selective desymmetrization of meso-1,2-diol, are remarkable synthetic reactions that provide high yield and high selectivity. However, the exact mechanism and origins of stereocontrol for theses synthetic organic...
This thesis describes the development of a new enantioselective synthetic method employing chiral cis-2,5-diaminobicyclo[2.2.2]octane-based organometallic catalysts. The significance of this new method to organic synthesis is illustrated with preparation of enantioenriched products that are transformed to important pharmaceutical agents. Chapter 1 provides a brief historical overview of asymmetric catalysis, especially...
The continued propagation of antibiotic resistance requires the development of new therapeutics. The lipopeptide antibiotic enduracidin has demonstrated high activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus. In addition to a lack of cross-resistance with existing antibiotic classes, enduracidin has no known transferrable resistance mechanism. The development of enduracidin as...
Azaspiracid-1, a novel marine toxin that contains 9 rings and 20 stereogenic centers, has drawn considerable attention from synthetic groups worldwide due to its structural complexity, which includes a unique trioxabisspiroketal fused to a tetrahydrofuran ring (ABCD rings), a piperidine-tetrahydrofuran spiroaminal system fused to a 2,9-dioxabicyclo[3.3.1]nonane system (FGHI rings), a...
Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient...
Studies toward the total synthesis of (+)-providencin (1), a highly oxygenated cembranoid dipterpene with a unique bicyclo[12.2.0]hexadecane skeleton and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediates 320 and 332 which contain all of the carbon atoms of 1. In a first generation approach...
Ion-selective polymeric optical sensors – ion optodes – are a promising alternative to ion-selective electrodes and fluorescent dyes for analytical and biological applications, e.g. extra- and intracellular measurements. They are non-toxic, highly selective robust probes for ionic fluxes monitoring.
A large-scale fabrication of ion optodes using a solvent displacement method...
A Diels-Alder approach to biaryls (DAB) has been applied towards the synthesis
of highly substituted, programmable biaryl templates. Tri- and tetra-ortho-substituted
biaryls can be produced in just three to four steps from commercially available materials
utilizing the Diels-Alder [4+2] cycloaddition. The methods described herein will
illustrate the ability of mono...
An expedient approach to the synthesis of a wide range of highly programmable biaryl templates has been accomplished. Utilizing the Diels-Alder [4+2] cycloaddition, a wide range of tri- and tetra-ortho-substituted biaryls have been synthesized in only three to four steps from commercially available materials. We have successfully synthesized entire classes...
Studies towards the total synthesis of (−)-kendomycin (1), a bacterial metabolite with
a unique molecular architecture and pronounced biological activity, are described. These
studies resulted in the synthesis of advanced intermediate 208, containing all of the
carbon atoms of 1.
A Dötz annulation between alkyne 122 and novel chromium carbenoid...
The total synthesis of a highly potent cytotoxic marine natural product, phorboxazole A, is described. Both a palladium(II)-mediated and a palladium(II)-catalyzed intramolecular alkoxycarbonylation were used as key steps for the preparation of the two cis-2,6-disubstituted tetrahydropyran rings (C22-C26 and C11-C15) of phorboxazole A.
The synthesis used a convergent approach involving...
Part 1: A Diels-Alder Approach to the Synthesis of Novel Analogues of the Natural
Product Siamenol
Due to the prevalence of biaryl motifs in natural product synthesis, the Carter
research group has been exploring the utility of a Diels-Alder approach to biaryl
synthesis. The Diels-Alder approach involves a [4+2] cycloaddition...
F1FO-ATP synthase targeting antimicrobials apoptolidin 1 (A1), (+)-erythromefloquine,
and oligomycin were tested in vitro for synergistic minimum inhibitory
concentrations against Staphylococcus aureus. Synergy was strictly defined as inhibition
by at most 25% the MIC of each participating drug. Ampicillin, with an MIC of 0.8
ug/mL, served as a negative control....
In this report, three studies are presented that aid in the development of drug discovery and their synthesis. In each, the importance of the marriage between computations and experiments is highlighted. Continued efforts in this vein are essential for future efforts towards improving human health.
The first case study investigated...
This dissertation describes the racemic and enantioselective synthesis cavicularin. Cavicularin is a macrocyclic bisbibenzyls family member natural product. It has been an attractive synthetic target due to its intriguing structure: the macrocyclic core imparts sufficient strain on the system to force one benzene rings to adopt a boat-shaped conformation, out...
Molecular chirality plays a critical role in chemistry, biology, and medicine. To study and better understand conformational chirality, it is necessary to obtain structurally interesting molecules that exhibit this form of chirality. Our lab utilizes total synthesis and methodological development to obtain conformationally chiral natural products of interest. We believe...
In this thesis, I present studies in the field of terahertz [THz] spectroscopy. It covers both the generation and detection of ultra-fast broadband THz pulses, as well as the transmission properties of vertically grown multi-walled carbon nanotube forests [MWCNTs]. We have found that these vertically grown MWCNTs respond strongly to...
Two improvements to the established procedures for synthesis and response detection of ion-selective optical sensors (optodes) were introduced.
The first improvement addresses the drawback of organic dye (optode-localized chromoionophore) photobleaching. This positively impacts fluorescence response and allows for (1) direct measurement of hydrogen ion activity upon binding with the dye,...
Effective methods for the enantiopure formation of substituted piperidine rings are significantly important due to their presence in alkaloid products. A valuable method to form these ring systems would be via an intramolecular heteroatom Michael addition from the corresponding enone or enal. Described herein is a methodolgy that has been...
Studies towards the total synthesis of (+)-Phomactin A (1), D (6), and G (9), fungal metabolites with unique molecular architecture and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediates 354 and 356, which contain all of the carbon atoms of 1, 6 and 9....
Since the discovery of molecular chirality in 1848, this notion has had a substantial impact on medicine, biology, and chemistry. Extensive effort has been directed towards the construction of chiral molecules that contain sp³ hybridized stereogenic centers. In contrast, less effort has been dedicated to molecules that are chiral by...
Aromatic heterocycles are core structural motifs in natural products, pharmaceuticals and biological polymers. Indoles, in particular, represent a significant subclass of aromatic heterocycles, both in terms of sheer numbers, but also in biological and pharmaceutical relevance. As such, new methodologies for the synthesis of indoles represent an important and continually...
Oligotrophic bacteria are adapted to low nutrient concentrations. As most of the ocean is oligotrophic (low in nutrients), oligotrophic bacteria thrive in the ocean and make up the majority of planktonic cells. Because of this, oligotrophs are crucial to oceanic nutrient cycles. However, marine oligotrophic bacteria are dwarfed by their...
Let H be a cyclically-presented group on n generators with a single defining relator. Attempts have been made to classify such groups by their order, their status as a 3-manifold group, and the asphericity status of their presentations. For groups with a defining relator of length 3 these classifications are...
Small molecule drugs have been instrumental in our fight against diseases, beginning when some of the earliest ancient cultures used plant remedies to treat illnesses. More recently, the skill of isolating and characterizing the active ingredients within bioactive plants and microbial extracts has led to the isolation and design of...
Mensacarcin is a stereogenic complex polyketide with potent anti-tumor activity produced by a soil-dwelling Streptomyces bottropensis. The US National Cancer Institute (NCI) 60 human tumor cell line anticancer drug screen (NCI-60) reveals mensacarcin’s cytostatic properties in almost all tested cell lines and distinct cytotoxic properties specifically in eight melanoma cell...
Fungi have long been a prolific source of clinically approved drugs. The antibiotic penicillin, the cholesterol lowering statins, and the immunosuppressant cyclosporine have changed the treatment of human diseases in the last century. Recently, genome analysis of filamentous fungi has revealed that the biosynthetic potential for natural product expression is...
The first part of this manuscript is about the total synthesis of the Arundo donax bis(indole) natural products. The A. donax alkaloids were prepared using the first example of an ynindole Diels–Alder reaction. Each were then separated, isolated, and determined to have stable enantiomeric conformations at room temperature (Chen, J.;...