Browsing by Subject "Organic synthesis"
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Item Cu-catalyzed three-component carboamination of 2-arylacrylates(2021-08) Popov, Andrei; Hull, KamiThere is an increasing demand for modern methods to construct one of the most ubiquitous bonds in biologically active molecules: a carbon-nitrogen bond. Transition metal catalysis represents a powerful tool to create new chemical bonds with great efficiency and selectivity. Thus, the development of novel catalytic techniques, based on transitions metals, for quick and effective assembly of nitrogen-containing organic molecules can be an advancement in synthetic routes to many drug molecules, agrochemicals, functional materials and many others. 1,2-carboamination of alkenes is the approach that unlocks the access to rapid assembly of complex organic nitrogen-containing frameworks from readily available feedstocks. In particular, the carboamination of acrylates can provide a synthetic access to various aminoacid derivatives. The present thesis is devoted to the development of the Cu-catalyzed carboamination of 2-arylacrylates. A wide substrate scope with good functional group tolerance is demonstrated. The mechanistic aspects of the reaction are discussed.Item From small molecules to macromolecules : design, synthesis, and evaluation of functional organic materials(2018-05) McCarty, Zachary Ryan; Willson, C. G. (C. Grant), 1939-; Baiz, Carlos R; Brodbelt, Jennifer S; Lynd, Nathaniel; Makarov, Dmitrii EThe incorporation of electronic device technology into our everyday lives has become an unavoidable reality in today’s connected world. Getting to this point has taken countless ingenious measures by scientists and engineers dedicated to increasing the speed and efficiency of the microelectronic devices that power many of the tools we rely on every day. For more than 50 years, the microelectronics industry has successfully manufactured generations of devices by shrinking the transistors on their chips. This shrinkage was made possible by improvements in photolithography. However, the physical limits to the resolution of lithography has now been reached leading leaving the microelectronic industry to employ costly and inefficient double patterning processes, which are expensive and unsustainable to extend the resolution of photolithography in high-volume manufacturing. Many question whether the ever cheaper and faster demand can continue. This dilemma has inspired the exploration at alternative patterning processes, one of which is the directed self-assembly (DSA) of block-copolymers (BCPs). Through careful and judicious design, the self-assembly of BCPs allows access to sub-5 nm features which are inaccessible by all current photolithographic technologies. While there has been extensive work done on the DSA of BCPs to produce aligned, lamellae in thin films, there is still a need for improvement in this field. Forming BCP films with a thickness on the order of their domain size and transferring the patterns formed by self-assembled BCPs into useful substances by reactive ion etching (RIE) is one area that requires more thorough investigation. Several strategies have been devised to impart some degree of etch-selectivity to one of the domains of a BCPs. One such strategy, which will be the focus of the work presented in this dissertation is the selective formation of a metal-oxide etch mask in one of the polymer domains of a BCPs. The development of a suitable BCP candidate will be presented as well as the results of several studies on vapor-phase infiltration processes. The challenges and discoveries made will be presented throughout this work.Item Synthesis and evaluation of novel anti-trypanosomal compounds, diversity-oriented synthesis of spirocyclic [beta]-phenethylamines, and the total synthesis of exotines A and B(2019-07-16) Lepovitz, Lance Thomas; Martin, Stephen F.; Anslyn, Eric V; Liu, Hung-Wen; Krische, Michael J; Keatinge-Clay, AdrianFirst, collections of conformationally flexible 𝛿-lactam and piperidine analogs were designed and synthesized following the discovery of a rigid indoloquinolizidine scaffold whose derivatives inhibit the growth of Trypanosoma brucei¸ the protozoan parasite that causes human African trypanosomiasis, via the inhibition of methionyl-tRNA synthetase (TbMetRS). Many of 𝛿-lactam and piperidine analogs were found to be superior T. brucei growth inhibitors relative to the initial indoloquinolizidine compounds; however, it was also found that these flexible compound sets displayed greatly diminished activity against TbMetRS. Then, a diversity-oriented synthesis (DOS) of spirocyclic β-phenethylamines was realized via the development of an intramolecular aza-Hosomi-Sakurai reaction. Facile elaboration of these aza-spirocyclic scaffolds was demonstrated through a variety of means, and several derivatives were identified as potent Sigma-1 receptor (σ1R) ligands in a biochemical screen. Finally, a one-step biomimetic total synthesis of the cyclohepta[b]indole-coumarin natural products exotines A and B was achieved via the development of an acid-catalyzed three-component cyclization reaction between indole, prenal, and trans-dehydoosthol. Some mechanistic aspects of this process are investigated, and evidence is obtained which supports the mechanism of a [4 + 2] cycloaddition followed by a 1,2-migration, in accordance with the original biosynthetic proposal of Jiang.Item Synthetic approaches to investigate the chemical mechanism in the biosynthesis of natural products(2012-08) Choi, Sei Hyun; Liu, Hung-wen, 1952-The study of the biosynthetic logic of natural products has established itself to be one of the more exciting areas of research and have become an important part of modern drug discovery and development efforts. Therefore, understanding the pathway and the chemical mechanism of the biosynthesis of natural products is important in that knowledge on these processes can be applied for combinatorial biosynthesis to generate new natural product derivatives with enhanced biological activities. In addition to the practical value, a lot of unprecedented chemical mechanisms can be found in the enzymes involved therein, which will significantly advance our understanding of enzyme catalysis. The works described in this dissertation focus on elucidating the chemical mechanism of a number of enzymes involved in natural product biosynthesis by utilizing the versatility of synthetic chemistry to prepare enzyme substrates and mechanistic probes. First, SpnF and SpnL responsible for constructing the tetracyclic architecture of spinosyn A have been investigated. In vitro assay revealed the importance of the highly conjugated system for the [4+2]cycloaddition catalyzed by SpnF. Biochemical studies strongly suggest that SpnL employs the Rauhut-Currier mechanism for the second cyclization step in the biosynthesis of spinosyn A. It was also demonstrated that SpnL requires SAM for its activity. Second, a radical SAM enzyme DesII involved in the desosamine pathway has been investigated. It has been demonstrated that DesII can catalyze the dehydrogenation of TDP-D-quinovose as well as the deamination of the natural substrate, which makes DesII unique among radical SAM enzymes. In vitro assays revealed that DesII requires stoichiometric amount of SAM, which. EPR study firmly established the intermediacy of a C-3 radical in the DesII-catalyzed dehydrogenation of TDP-D-quinovose. Finally, the chemical mechanism of AXS responsible for the biosynthesis of UDP-apiose has been investigated. In vitro activity assay using UDP-2F-glucuronic acid showed that the analog is a competitive inhibitor of AXS. A coupled assay strategy was also developed to investigate the chemical mechanism of AXS in the reverse direction. In addition, the stereospecificity of two separate hydride transfer steps of AXS reaction has been firmly established.Item Thermodynamic analysis of protein-ligand interactions of linear tripeptide HCV NS3 protease inhibitors and progress toward the total synthesis of (±)-arboridinine(2017-08-09) Wypych, Rachel Marie; Martin, Stephen F.; Anslyn, Eric V; Keatinge-Clay, Adrian; Sessler, Jonathan L; Webb, Lauren JInteractions between proteins and small molecules dictate an overwhelmingly large number of biological processes, yet our knowledge of the effects of ligand structural changes on the thermodynamics of these interactions is fundamentally lacking. In an effort to expand our understanding of protein-ligand thermodynamics, the binding profiles of a series of linear tripeptide HCV NS3 protease inhibitors were analyzed by ITC. Substituents on the P2 proline residue were examined individually, and important trends were elucidated. The addition of a phenyl group to the 2-position of the heteroaryl subunit of the P2 residue resulted in more favorable binding entropy, which is possibly due to the desolvation of nonpolar surface area. Quinolines without a 2-phenyl substituent were found to bind in an alternate conformation with thermodynamic profiles that were dominated by favorable binding enthalpies rather than entropies. This could possibly be due to a favorable hydrogen bonding interaction between the quinoline nitrogen and Asp81 of the catalytic triad. A series of analogs were prepared to examine the effect of incrementally increasing steric bulk at the P3 side chain of HCV NS3 inhibitors in order to preorganize the ligand into the extended conformation. As steric bulk was increased, the binding affinities improved in turn, notably due to increasingly favorable binding enthalpies along with small gains in entropy. This could possibly attributed to a combination of factors including the entropic benefit derived from preorganization and an enthalpy-driven hydrophobic effect. Several concise synthetic routes were designed toward the total synthesis of the pentacyclic indole alkaloid (±)-arboridinine. A novel Diels-Alder cycloaddition of an indole-3-glyoxamide with a diene to form a key tricyclic intermediate was attempted, but no reaction was observed under a variety of conditions. A second-generation attempt featured attempts at a challenging cascade reaction involving a conjugate addition of an indole-3-glyoxamide into an enone and subsequent attack of an enolate into the intermediate 3,3-disubstituted indolenine. The conjugate addition was successful, providing the first example of indole-3-glyoxamides as substrates for conjugate additions into enones. The resulting indolenine was found to be unreactive under acidic conditions and underwent a retro-Michael reaction to return the indole-3-glyoxamide under basic conditions.