Browsing by Author "Shi, Yian, committee member"
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Item Open Access Catalytically generated acyl triazoliums as versatile acylating reagents and progress toward the total synthesis of okilactomycin(Colorado State University. Libraries, 2013) Wheeler, Philip Andrew Merris, author; Rovis, Tomislav, advisor; Shi, Yian, committee member; Ferreira, Eric, committee member; Shores, Matthew, committee member; Fisk, John D., committee memberThe first chapter of this dissertation describes the development of reactions involving the NHC-catalyzed acylation of carbon and nitrogen nucleophiles. The overall goal of this work was to expand the scope of the NHC-redox reaction manifold and improve its applicability to the synthesis of products that would be useful to the organic chemistry community. An efficient and simple procedure for the preparation of amides from amine hydrochloride salts and α,β-unsaturated aldehydes was developed. This procedure was then applied to the asymmetric synthesis of α-fluoroamides which are valuable building blocks for the preparation of fluorinated compounds that are highly sought after in pharmaceutical, material, and agrichemical applications. The second chapter describes efforts toward the total synthesis of the complex polyketide natural product okilactomycin, enabled by the rhodium-catalyzed desymmetrization of 3,5-dimethylglutaric anhydride developed previously by our group. Progress includes construction of the entire carbon skeleton in two fragments, poised to be unified and elaborated to the natural product by closely precedented steps. This progress demonstrates the potential of the catalytic, enantioselective desymmetrization of anhydrides to build complexity in rapid fashion.Item Open Access Design and synthesis of biologically active Largazole derivatives, including development of improved syntheses of Largazole analogs(Colorado State University. Libraries, 2018) Dunne, Christine E., author; Williams, Robert M., advisor; Shi, Yian, committee member; Prieto, Amy, committee member; Thamm, Douglas, committee memberNatural product histone deacetylase inhibitor, Largazole, has been developed into a streamlined synthetic pathway for the development of a complex library of analogs. The library developed within the Williams laboratory encompasses an array of derivatives, including but not limited to: thiazole modification and macrocycle substitutions. The cap group of Largazole, portion of the molecule extending outside of the enzyme binding pocket, was successfully modified to install new chemical handles for biologic and dual therapeutic conjugation. Biological conjugates of Largazole, as well as its derivatives, aid in increasing selectivity and potency of the compound. Largazole has been conjugated to both biotin and folic acid for further studies. Additionally, a streamlined synthesis towards Wnt inhibitor 3289-5066 and a developed path for conjugation have been explored. Modified procedures were developed to aid in scale up and improvement of synthetic pathways. Scale up is crucial for development of sufficient material for biological testing and further development of conjugative therapeutics. One main impediment in the synthesis of Largazole peptide isostere is towards the southern fragment, specifically the Grubbs olefin metathesis. Multiple routes were explored to combat this low yielding step. Further exploration of these synthetic routes are underway.Item Open Access Development of asymmetric N-heterocyclic carbene-catalyzed reactions(Colorado State University. Libraries, 2017) Flanigan, Darrin Miles, author; Rovis, Tomislav, advisor; Chen, Eugene, committee member; Shi, Yian, committee member; Chatterjee, Delphi, committee memberN-Heterocyclic carbenes (NHCs) are ubiquitous organocatalysts in a variety of asymmetric transformations. The benzoin and Stetter reactions, which couple aldehydes to other aldehydes or Michael acceptors, respectively are the most commonly reported reactivity manifold employing NHC catalysts. However, other umpolung reactivity pathways exist, for example, when α,β-unsaturated aldehydes are reacted with NHCs, the Breslow intermediate can react through the double bond of the aldehyde to functionalize at the beta position of the carbonyl. A process that has come to be known has homoenolate reactivity. A range of reactivity manifolds were investigated, including the asymmetric intermolecular Stetter reaction and an enantioselective NHC-catalyzed nucleophilic dearomatization of pyridiniums. In the dearomatization chemistry, a homoenolate equivalent is first generated from an enal and an NHC, which then adds to the pyridinium to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine product. The asymmetric intermolecular Stetter reaction was also investigated in an attempt to broaden the scope of the reaction to include less activated Michael acceptors, specifically, α,β-unsaturated ketones. The coupling of heteroaryl aldehydes to enones could be achieved with appreciable levels of enantioselectivity (up to 80% ee), but reactivity remains a major challenge with this methodology.Item Open Access Elucidation of the biogenesis of the paraherquamides, malbrancheamides, citrinalins, and brevianamides(Colorado State University. Libraries, 2019) Klas, Kimberly R., author; Williams, Robert M., advisor; Shi, Yian, committee member; Chen, Eugene, committee member; Crick, Dean, committee memberVarious fungi of the genera Aspergillus, Penicillium and Malbranchea produce prenylated indole alkaloids that possess a bicyclo[2.2.2]diazaoctane ring system and a variety of biological activities such as insecticidal, cytotoxic, anthelmintic, and antibacterial properties. After the discovery of distinct enantiomers of the natural alkaloids Stephacidin A, Notoamide B and their corresponding diastereomers, from Aspergillus protuberus MF297-2, Aspergillus amoenus NRRL 35660 and Aspergillus taichungensis, the structurally diverse metabolites became of particular biosynthetic interest. The bicyclo[2.2.2]diazaoctane core of the divergent natural metabolites may be enzymatically derived via a putative intramolecular hetero-Diels-Alder cycloaddition. We completed the total synthesis of ZwtP and MeZwtP, unveiling the role of a newly discovered Diels-Alderase. We are also undergoing further synthetic efforts to access other novel natural products, as well as further understand additional unprecedented transformations in nature.Item Open Access Mechanistically-guided advancement of photoinduced organocatalyzed atom transfer radical polymerization(Colorado State University. Libraries, 2020) Buss, Bonnie Leigh, author; Miyake, Garret, advisor; Bailey, Travis, committee member; Shi, Yian, committee member; Herrera-Alonso, Margarita, committee memberPhotoinduced organocatalyzed atom transfer radical polymerization (O-ATRP) is a promising polymerization methodology which leverages radical reactivity to afford macromolecular products with a high degree of control over polymer molecular weights and molecular weight distributions, paired with the added benefit of spatial and temporal control over polymerization. This process, a metal-free approach, relies on photoexcitation of an organic photoredox catalyst which stringently mediates the radical activation and deactivation steps of an oxidative quenching catalytic cycle. To successfully operate this cycle, and thus control the polymerization, the rate of deactivation must be faster than both the rates of radical activation and monomer propagation. Central to the initial development of O-ATRP has been the design and study of strongly reducing organic photocatalysts, particularly in the context of methacrylate monomer polymerizations. However, as a burgeoning methodology, the full scope of O-ATRP has not yet been established. In this dissertation, efforts in addressing three key challenges in O-ATRP, including reaction scalability, complex architecture synthesis, and polymerization of challenging monomers, through manipulation of features of the oxidative quenching mechanistic cycle is presented. To address these challenges diverse approaches were employed, including adaptation to continuous-flow reactors, implementation of multifunctional initiating systems, and rational design of a new family of organic photocatalysts, ultimately facilitating progression of O-ATRP to a scalable and efficient approach in the well-defined synthesis of industrially-relevant materials.Item Open Access Rhodium(III)-catalyzed amide-directed C-H activation and [4+2] cycloaddition for modular assembly of nitrogen heterocycles(Colorado State University. Libraries, 2017) Semakul, Natthawat, author; Rovis, Tomislav, advisor; Kennan, Alan, committee member; Shi, Yian, committee member; McCullagh, Martin, committee member; Kipper, Matt, committee memberThis dissertation describes the ligand and reaction developments by amide-directed rhodium(III)-catalyzed C(sp2)-H bond activation followed by amidoannulation with alkenes to form nitrogen-containing heterocycles. Chapter 1 details the ligand development for stereoselective synthesis of [4.1.0] dihydroisoquinolones through benzamidation of cyclopropenes mediated by Rh(III) catalysis. Quantum chemical calculations revealed the important role of heptamethylindenyl (Ind*) ligand and O-substituted ester of benzhydroxamate for achieving high diastereoselectivity in cyclopropene insertion. Efforts toward stereoselective synthesis of [4.1.0] dihydroisoquinolones have been also studied by streptavidin-based artificial metalloenzyme. Chapter 2 presents the stereoselective synthesis of [4.2.0] dihydroisoquinolones via the benzamidation of cyclobutenes. The transformation proved to have a broad substrate scope and functional group tolerance that generates the cyclobutane-fused azacycles with excellent diastereoselectivity. The artificial metalloenzymes can render this reaction asymmetric furnishing the dihydroisoquinolone products in moderate enantioselectivity. Chapter 3 communicates Rh(III)-catalyzed C-H activation and [4+2] annulation reaction of N-pivaloyloxy acrylamides with alkenes for an efficient synthesis of α,β-unsaturated-δ-lactams. This process offers a platform for the rapid assembly of a diverse set of delta-lactams from simple and abundant precursors. These lactams could serve as useful building blocks to access substituted piperidines.Item Open Access Rhodium-catalyzed cycloadditions between alkenyl isocyanates and alkynes: study of scope, mechanism and applications toward total synthesis(Colorado State University. Libraries, 2010) Friedman, Rebecca Ann Keller, author; Rovis, Tomislav, 1968-, advisor; Kennan, Alan J., committee member; Prieto, Amy L. (Amy Lucia), committee member; Shi, Yian, committee member; McNeil, Michael R., committee memberRhodium-catalyzed cycloadditions between alkenyl isocyanates and unsymmetrical, internal alkynes has been studied. A wide variety of alkynes have proven successful components in the [2+2+2] cycloaddition. Excellent yields and enantioselectivities have been achieved in the resulting indolizidinone products. Furthermore, a single regioisomer is obtained for the vast majority of alkynes subjected to reaction conditions. A logical explanation for the highly regioselective insertion for internal, unsymmetrical alkynes was provided. Small variations in the electronics and/or steric bulk of the alkyne substitution were sufficient to predictably control the insertion of the alkyne into the initial rhodacycle. Mechanistic insight into the rhodium-catalyzed [4+2+2] cycloaddition between dienyl isocyanates and alkynes has been achieved. A series of competition and slow addition experiments, alongside analysis of enantioselectivity and product formation, provided evidence for a proposed mechanism of the [4+2+2] cycloaddition. It was determined that the diene preferentially coordinates to the rhodium, in the presence of a terminal alkyne, to provide eight-membered bicyclic azocene products. Steps towards the total synthesis of natural product Secu'amamine A have been made. The bicyclic core of the molecule has been successfully synthesized utilizing rhodium-catalyzed [2+2+2] methodology developed within the Rovis group. Additionally, a successful, diastereoselective 1,4-reduction of the resulting vinylogous amide product and subsequent deprotection of an enyne side-chain provided an intermediate that is hypothetically two steps (an alpha-oxidation and 2+2+1 cycloaddition) away from Secu'amamine A.Item Open Access Spin multiplets: theory and application(Colorado State University. Libraries, 2018) Nite, Jacob M., author; Rappé, Anthony K., advisor; Shores, Matthew, committee member; Shi, Yian, committee member; Lee, Siu Au, committee memberTransition metal complexes have seen an increased use as photocatalysts for organic reactions in recent literature, mostly involving the Ru(II)(bpy)3 family of catalysts. Due to the rarity of ruthenium in the Earth's crust, alternative catalysts using Earth abundant materials are desirable. Recent literature has shown that chromium based catalysts show great promise as a replacement for ruthenium for some reactions. The mechanisms of these first-row transition metal complexes are significantly more complex than those of the second and third row. The excited state complexities of first-row transition metal complexes are challenges for both experimental and theoretical research. The complexities of the excited states require theoretical methods beyond the standard single reference methods commonly used in the literature. Through the use of recent multi-reference post Hartree Fock (HF) methods as well as a new multi-reference density functional theory (DFT), insights into the character of chromium-based photocatalysts were examined. A new multi-determinant DFT method named few-determinant density functional theory (FD-DFT) was described. FD-DFT incorporates multiple DFT determinants using a finite difference approach to calculate the exchanges between multiple determinants for open shell multiplets. The method is implemented in a generalized bond valence (GVB) wave function, and can be converged through an SCF procedure. The system was benchmarked using oxygen atom and diatomic oxygen as well as atomic systems with more open shell orbitals. The benchmarking shows stability across many different functional choices, and gives good excitation energies with and without SCF convergence. The Cr(III)(AcAc)3 system has been long studied for its unique excited state properties that defy the standard cascade model for excited state relaxation. The tris(1,3-propanedionato)chromium(iii) (Cr(III)(PDO)3) complex was studied as an analog to the Cr(III)(AcAc)3 system to understand the excited state pathway between the initial excited 4T2g state and the long lived 2Eg state. Using the FD-DFT method as well as the multi-reference spectroscopy oriented configuration interaction (SORCI) method, the initial excited state energies were studied compared to previous perturbation theory (PT) approaches. Both SORCI and FD-DFT calculate reasonable 2Eg excitation energies, an improvement over earlier results. The SORCI method was also used to map the potential energy curve between the initial 4T2g excited state and its fully relaxed distorted structure. The pathway agrees with previous experimental and theoretical studies showing that a transitionless path exists between the quartet and doublet states, but spin-orbit coupling calculations suggest that a direct path between the 4T2g and 2Eg is possible rather than needing a internal conversion step to the lowest 2Eg state. Chromium-based photocatalysts have been recently studied in the literature as having a competitive mechanism between the reaction substrate and O2 whereby the O2 quenches the excited catalyst. Using the combined Cr(III)(PDO)3 • O2 system, the likely states by which this quenching event occurs were studied with FD-DFT as well as recent multi-reference PT approaches. Comparing the excited state calculated using the multi-reference based methods to standards DFT calculations shows the inability of single-determinant methods to correctly produce the proper excited state character even when obtaining somewhat reasonable energies. The excited state responsible for the quenching of the excited complex is identified using spin density plots of the CASSCF calculations. The search for suitable first-row transition metals requires a search across possible ligands and metal centers. Using the success of chromium-based catalysts, isoelectronic vanadium catalysts were studied to identify any potential differences between the complexes as well as identify the utility of vanadium-based catalysts. Using a variety of methods, including TDDFT-based absorption spectra, vibrational component plots of the excited state distortions, and SORCI potential energy curves (PEC), the differences between the chromium and vanadium catalysts were examined. It was found that vanadium catalysts absorptions are shifted significantly from chromium complexes and the vanadium excited states disperse the unpaired electron over the complex instead of localizing it on the metal center. The distortions in the chromium-based catalysts have a greater amount of asymmetric vibrational character compared to vanadium, which shows mostly symmetric behavior. Lastly, the SORCI PECs show that, unlike chromium, the doublet curves do not intersect the quartet curves, making a transition to a long lived doublet state a significantly slower process. The results highlight significant differences between the complexes even with ligand structure is controlled.Item Open Access Synthesis and exploration of biologically important, hydrophobic, redox-active molecules: investigation of partial saturation of mycobacterial electron transport lipids(Colorado State University. Libraries, 2019) Koehn, Jordan T., author; Crans, Debbie C., advisor; Reynolds, Melissa M., committee member; Shi, Yian, committee member; Crick, Dean C., committee memberThere are many types of molecules that are biologically important because they either carry out crucial functions or exhibit exploitable biological activity. Some of the most interesting and challenging molecules to work with are those that are redox-active and hydrophobic or water insoluble. Herein, the synthesis and investigation of two classes of hydrophobic redox-active molecules are explored. Chapter one provides background on menaquinone (MK) and vanadium chemistry and primes the reader for the subsequent chapters. Chapter two describes the synthesis and characterization of truncated MK derivatives with varying isoprenyl side chain length and degrees of saturation. Chapter three explores the conformational flexibility of the isoprenyl side chain of MK and shows that a truncated MK analog, MK-2, can adopt folded conformations in hydrophobic environments and within a model membrane system. Chapter four isolates the conformational and chemical effect of saturation of the isoprenyl side chain on MK and shows that saturation minimally affects folded conformations of truncated MK derivatives but remarkably, a 20 mV redox potential difference was observed between unsaturated MK-1 and the saturated analog MK-1(H2). Then in chapter five, hydrophobicity and steric bulk are explored as properties to enhance membrane affinity and anti-cancer properties of Schiff base vanadium(V) catecholate complexes, where the hydrophobic [VO(Hshed)(ditertbutylcatechol)] complex was found to have enhanced hydrolytic stability and potent activity against a bone cancer cell line. Together, the findings of the studies presented herein help to further understand how the conformation and the degree of saturation in the isoprenyl side chain of MK affects the recognition, reactivity, and function of MK within the electron transport system of pathogenic bacteria. These studies are important because they begin to explain and provide a working model behind the chemical rationale as to why partially saturated MK-9 is observed in pathogenic M. tuberculosis. Furthermore, the studies with the hydrophobic vanadium(V) catecholate metallo-complexes underpin a drug design concept exploiting hydrolytic stability imparted by hydrophobicity and steric bulk of a non-innocent ligand.Item Open Access Synthetic studies on (-) lemonomycin: construction of the tetracyclic core(Colorado State University. Libraries, 2013) Jiménez-Somarribas, Alberto, author; Williams, Robert M., advisor; Wood, John L., committee member; Shi, Yian, committee member; Ladanyi, Branka M., committee member; Crick, Dean C., committee memberDocumented herein are efforts towards the asymmetric total synthesis of (-)-lemonomycin, a member of the tetrahydroisoquinoline antitumor antibiotics family of natural products. We describe a concise route for the assembly of the tetracyclic core of this molecule, which involves a Pictet-Spengler reaction for the construction of the tetrahydroisoquinoline fragment and an azomethine ylide [3+2] dipolar cycloaddition for the construction of the diazabicyclo[3.2.1]octane ring system. The above-described synthetic efforts, while not totally successful, provide the basis for the future completion of the total synthesis of this natural product and other related compounds.Item Open Access Total synthesis of hapalindoles J and U, formal synthesis of haplaindole O, synthesis of the proposed biosynthetic precursor to hapalindole K and work towards the ambiguine family of alkaloids(Colorado State University. Libraries, 2011) Rafferty, Ryan J., author; Williams, Robert M., advisor; Shi, Yian, committee member; Crans, Debbie C., committee member; Prieto, Amy L., committee member; Thamm, Douglas H., committee memberHerein I discussed the total synthesis of hapalindoles J and U, the formal synthesis of hapalindole O, the proposed biosynthetic precursor to hapalindole K and efforts towards other hapalindole and ambiguine families of alkaloids. The hapalindoles and ambiguines both possess a highly functionalized 6:6:6:5, which I accessed over six synthetic steps via a developed silyl strategy with an overall 54% yield. Hapalindole J was synthesized in an overall 11% yield over eleven synthetic steps and hapalindole U in an overall 25% yield over thirteen synthetic steps from commercially available materials utilizing the silyl strategy developed. A formal synthesis of hapalindole O, intercepting Natsume's total synthesis, was accomplished as well via the developed silyl strategy. In addition, the synthesis of the proposed biosynthetic precursor to hapalindole K was accessed. Currently, this newly developed silyl strategy is being employed in accessing some of the more functionalized hapalindoles (such as K) as well as the complex ambiguine core.