Browsing by Subject "Organic Chemistry"

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    Library Synthesis Of Piperidinone Sulfonamides, Transition Metal-Free C-H Trifluoromethylation Of Cyclic Enaminones, And Elucidating The Binding Site Of Epothilones On Beta-Tubulin With Epothilone Photoaffinity Probes
    (2014-07) Ranade, Adwait
    Chapter 1 focuses on synthesizing a library of piperidinone sulfonamides. The piperidinones serve as valuables intermediates for the synthesis of nitrogen-containing bioactive molecules, various alkaloids, and drug candidates. Amongst the myriads of highly derivatized N-heterocyclic compounds, molecules possessing the piperidinone sulfonamide moiety in their structures show interesting biological activities. A library of 18 piperidinone sulfonamides was prepared under a Pilot Scale Library grant and submitted to NIH for testing in various biological assays. Two compounds from the library were identified as active hits. One of the compounds showed prion protein 5' UTR inhibition while the other showed inhibition of human platelet-activating factor acetylhydrolase 1b, catalytic subunit 2. Chapter 2 focuses on direct C-H trifluoromethylation of cyclic enaminones. Cyclic enaminones are of interest in natural product synthesis and are regarded as valuable synthons due to unique structural and chemical properties. They serve as versatile precursors for synthesizing piperidine-containing alkaloids and drug molecules. In this project, transition metal free, direct C-H trifluoromethylation of cyclic enaminones was developed with trimethyl(trifluoromethyl)silane (TMSCF3). This method proceeds under mild conditions at room temperature and possibly involves a radical mechanism. The C-H functionalization was successful with both electron-rich and electron-deficient cyclic enaminones. This methodology circumvents substrate prefunctionalization and transition metal catalysis, and allows a convenient and direct access to a variety of medicinally significant 3-trifluoromethylpiperidine derivatives. This chemistry also presents a rare example of a direct trifluoromethylation of an internal olefinic C-H bond. Chapter 3 focuses on efforts toward elucidating the binding site of epothilones on ß-tubulin. Epothilones are potent cytotoxic tubulin-binding polyketide-derived macrolides. Even though the binding sites for epothilones and paclitaxel on ß-tubulin overlap, epothilones show efficacy against paclitaxel-resistant cancer cell lines. This implies a significantly different binding mode for epothilones. To date, two epothilone binding models have been proposed based on NMR and electron-crystallography data. In order to differentiate the proposed binding modes, four epothilone A photoaffinity analogues were designed. Three of those analogues were successfully synthesized and showed excellent cytotoxicity as well as the required tubulin assembly. It was hypothesized that the protein region labeled by these photoprobes is dependent on the epothilone conformation at the binding site. For one of the analogues, the probe-labeled peptide fragment `TARGSQQY' (residues 274 to 281) in the ß-tubulin isoform TBB3 was identified by MS analysis. Our experimental results corroborated the consensus of both the models that Thr 274 and Arg 276 are necessary for binding of epothilones to ß-tubulin. However, based on the photoaffinity labeling studies results and molecular modeling studies, an orientation of the epothilone in the binding site is proposed that is significantly different from those previously proposed.
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    Macrocyclization Through Ene-Yne Cross-Coupling/Alkyne Reduction Tandem Reaction And Its Application In Natural Product Synthesis
    (2015-09) Li, Wei
    Chapter 1 — Macrocyclization Through Copper-Catalyzed Castro–Stephens Coupling/Alkyne Reduction Tandem Reaction Macrocycles, incorporating conjugated polyene subunits within the ring, are structural features found in a number of natural products that exhibit diverse and potent biological activities. Existing methods for the construction of such structures are limited and in many cases inefficient. We discovered an unprecedented copper-mediated reductive ene–yne macrocyclization reaction during our pursuit of the total synthesis of oximidine II. The reaction selectively generates an endocyclic Z-double bond through an intramolecular coupling of a vinyl iodide and a terminal alkyne fragment followed by in situ alkyne reduction. We developed this transformation as a general method for the preparation of polyunsaturated macrocycles. The reaction conditions were optimized and the scope of the reaction was extensively explored. It was found that the alkyne reduction step is driven by the release of the ring strain. Thus, the reaction is particularly efficient for suitably strained 11- to 13-membered E,Z-1,3-diene macrocycles. A complementary stepwise procedure was employed for the synthesis of larger rings. Finally, a plausible reaction mechanism was proposed based on experimental findings. HASH(0x7f87dd8493f8) Chapter 2 — Formal Total Synthesis of Lactimidomycin Lactimidomycin is a macrocyclic natural product that possesses potent in vitro and in vivo anti-tumor activities. We accomplished a facile, 9-step synthesis of an advanced intermediate for the total synthesis of lactimidomycin. The crucial 12-membered polyene lactone core structure was constructed employing our newly developed Castro–Stephens coupling/alkyne reduction tandem reaction. The stereocenters were established via asymmetric a vinylogous aldol reaction and a Marshall’s propargylation reaction. Chapter 3 — Synthesis and Biological Evaluation of Oximidine II Analogues Oximidine II belongs to a family of benzolactone enamide natural products that exert their cytotoxic effects through inhibition of V-ATPases. Unlike other members of this family, the structure-activity relationship (SAR) of oximidines has not been extensively investigated. Guided by computational analysis and previous studies in our group, we designed and synthesized two oximidine II analogues with simplified scaffold. The simplified benzolactone core was accessed through a ring-closing metathesis (RCM) reaction and the enamide side chain was installed via a copper-mediated C–N coupling reaction. The analogues were evaluated for their biological activity. The results revealed that these molecules were weakly cytotoxic to a number of cancer cell lines.
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    Organic Reaction Selectivity via Metal-Catalysis: Discovery, Development, and Mechanistic Analysis of Nitrile, Ester, Arene, Azide, and Alkene Transformations
    (2019-03) Frost, Grant
    The focus of my doctoral dissertation is the discovery, development, and mechanistic analysis of metal-catalyzed organic reactions. My work highlights organometallic catalysis as a strategy to achieve each of the three main types of organic reaction selectivity: stereo-, regio-, and chemoselectivity. I accomplished this through the study of three distinct reactions: stereoselective Pd-catalyzed alkene cyanoamidation, regioselective Ir-catalyzed arene acylation, and chemoselective Pd-catalyzed azide to alkene diazo group transfer (DGT). The selectivity outcomes are explored both in terms of synthetic scope as well as mechanistic understanding. The execution of each project involved varying degrees of collaboration. Emphasis and detail are granted to my specific contributions to each project. PART I Historical Development of Metal-Catalyzed C–C Bond Coupling I provide a brief overview of the evolution of metal-catalyzed C–C bond coupling reaction design. Although not comprehensive of the entire field, the goal of this part is to acquaint the reader with the general concepts underpinning the chemistry involved with my projects. Thus, the primary iterations of organometallic catalytic systems that influenced my research are covered. PART II Mechanistic Model for Enantioselective Intramolecular Alkene Cyanoamidation via Palladium-Catalyzed C–CN Bond Activation I present our mechanistic investigation of Pd-catalyzed C−CN bond activation for intramolecular enantioselective alkene cyanoamidation. Experiments designed to probe key features of the mechanism included: Lewis acid/Lewis base additive effects, initial rates kinetics, natural abundance 13C KIE measurements, 13C label crossover experiments, and a linear solvation energy relationship (LSER) with enantioselectivity. We discovered multiple factors influencing enantioinduction, which provided evidence for the conformation of the chiral ligand during the enantio-determining step. Our analysis is expected to aide future application of asymmetric cyanoamidation in total synthesis. My specific contribution to this project was performing most of the reactions for both screening additive effects and 13C label crossover experiments. In addition, I performed all of the LSER experiments and data analysis. PART III Integrating Metal-Catalyzed C–H and C–O Functionalization to Achieve Sterically-Controlled Regioselectivity in Arene Acylation I detail the development and mechanistic analysis of sterics-controlled regioselective Ir-catalyzed arene acylation. This research marked a significant advancement in synthesis as well as organometallic catalytic mechanistic design. Regarding synthesis, the sterics-controlled regioselectivity we achieved contrasts with the electronics-controlled regioselectivity of acylation via electrophilic aromatic substitution (Friedel-Crafts) as well as acylation via directed metal-catalyzed C–H activation. Regarding the mechanism, we integrated two bond activations of common organic functional groups, a C–H and C–O bond, into a C–C bond coupling reaction. We utilized the C–O bond as an endogenous Ir oxidant and the O atom itself as an endogenous base to achieve the C–H activation. We explored this reaction through substrate screens of both the ester and arene components, kinetics studies, KIE studies, and computations. My specific contribution to this project included the synthesis of the salicylate ester substrate library, the execution of most of the acylations of these substrates, and data acquisition/analysis involved. In addition, I developed a model to explain our KIE experimental results. PART IV Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene I disclose our development of Pd-catalyzed intramolecular azide to alkene diazo group transfer (DGT), which grants chemoselectivity over competing aziridination. Our results indicate a mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloaddition. The structural design of the standard azide substrates permitted the synthesis of medicinally relevant N-heterocyclic structural cores. We achieved the chemoselective catalytic synthesis of 2-quinazolinones, as well as the non-catalytic synthesis of 1,3-benzodiazepinones via a unique aziridine ring expansion. This was an individual project with contribution from an undergraduate supervisee.