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Direct arylation of thiazolesTurner, Gemma L. January 2009 (has links)
An introduction to the thiazole ring system is presented together with a detailed, but non-exhaustive review of the rapidly emerging area of palladium-mediated directed arylation. The direct arylation of thiazole is also discussed together with our attempts to improve the established methods. A high-yielding, mild protocol has been developed for the functionalisation of the most electron-rich carbon-hydrogen bonds in a number of heterocyclic ring systems, this represents the first example of a C-H activation reaction being accomplished in aqueous media and allows access to a diverse range of functionalised aryl heterocycles. In addition, work towards functionalisation of the thiazole C4 position is described. A number of different approaches are discussed and our endeavors are recorded.
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Studies of multiheme proteins from the disimilatory metal reducing bacteria Shewanella oneidensis MR-1 and Geobacter sulfurreducensAtkinson, Sally January 2009 (has links)
Genomic analysis of the dissimilatory metal-reducing bacteria Shewanella oneidensis MR-1 and Geobacter sulfurreducens PCA has shown that both are capable of expressing an unprecedented number of multiheme cytochromes. The isolation and characterisation of two of the multiheme cytochromes from these bacteria is the subject of this thesis. Octaheme tetrathionate reductase (OTR) from Shewanella oneidensis has been previously shown to catalyse the reduction of tetrathionate to thiosulfate (Rothery, 2003). Despite having an amino-acid sequence suggesting the presence of eight standard CXXCH hemeattachment motifs, the crystal structure of OTR has shown the enzyme to contain seven normally-coordinated bis-histidine-ligated hemes, with one unusual lysine-coordinated heme at the active site. Analysis of the structure of this enzyme has shown its heme architecture to have a significant similarity to those of hydroxylamine oxidoreductase and the pentaheme cytochrome c nitrite reductases. An improved protocol for the purification of OTR has been developed, and work has been carried out in order to identify further possible substrates for the enzyme. Results show that OTR is capable of reducing nitrite, hydroxylamine, nitrous oxide and nitric oxide, suggesting that OTR may have a role as a nitrogen cycle enzyme. In particular, the reactions of OTR with hydroxylamine and nitrite have been shown to be more efficient than that with tetrathionate (kcat / KM = 5.3 x 105 M -1 s -1 and 3.9 x 105 M -1 s -1 respectively). The product of the reactions of nitrite and hydroxylamine with OTR has been directly detected in solution and shown to be the ammonium ion. This activity is consistent with a nitrogen cycle enzyme, with the conversion of nitrite to ammonium representing a “short cut” in the cycle, as performed by the cytochrome c nitrite reductases. In addition to this, site-directed mutagenesis has been used to investigate the catalytic properties of key active site residues, including the unusual heme-ligating lysine. The complete genome sequence of Geobacter sulfurreducens PCA was determined in 2003 and genomic analysis predicted the presence of a putative octaheme protein, GSU0357. This protein was predicted to contain an unusual CXXCK heme-binding amino acid motif and showed a high sequence similarity to the pentaheme cytochrome c nitrite reductase from Desulfovibrio desulfuricans ATCC 27774. The purification of GSU0357 has been non-trivial and a range of approaches have been used. The ability of GSU0357 to act as a nitrite reductase has been confirmed.
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Active template strategies for the assembly of mechanically interlocked moleculesRonaldson, Vicki E. January 2009 (has links)
Chemical templates have allowed the synthesis of increasingly complex mechanically interlocked molecular architectures. Transition metals are useful templating agents. Their coordination requirements result in the well-defined, threedimensional orientation of reactive fragments. Judicious choice of ligand and metal leads to a mechanically interlocked product upon covalent bond formation between the fragments. In such ‘passive’ templates a stoichiometric quantity of metal, with respect to the reacting components, is required. The metal atom acts as ‘glue’ until covalent, and consequent mechanical, bond formation has occurred. Recently in the Leigh group a fundamentally novel approach to interlocked architectures has been discovered and takes its cue from transition metal catalysis: in addition to inducing the necessary degree of preorganization in the system, the metal also mediates the covalent bond formation. This thesis describes further investigation of the original active template reaction—a ‘click’ reaction—and the subsequent extension of the strategy to new reactions and architectures. The effect of varying the macrocyclic ligand on the original Cu(I)-catalyzed 1,3- dipolar cycloaddition between alkynes and azides was investigated. Notably, the interlocked nature of the products provided new mechanistic insights into the nature of this widely used reaction. Following this, a Ni(II) active template was developed for the homocoupling of terminal alkynes. An unusual Ni/Cu system for this reaction was discovered and the resulting [2]rotaxanes were produced in excellent yield. The utility of the active template strategy was further demonstrated by the synthesis of a [3]rotaxane from a bifurcated macrocycle with a pyridyl bridging unit. Cu(I) catalyzed the formation of a triazole thread through each cavity, showing that multiple mechanical bonds can be formed from a single active template binding site. Lastly, the potential of carbene transfer reactions in the active template approach was investigated. A stoppered diazoester compound was synthesized and used in studies towards X-H insertion and cycloaddition reactions in the presence of a range of macrocyclic ligands.
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Development of catalytic stereoselective reductive aldol reactionsJoensuu, Pekka Matias January 2008 (has links)
The chemistry of enolates can be considered one of the cornerstone areas in organic chemistry. Regioselective generation of an enolate in the presence of several enolisable sites can often prove to be a difficult task. Discoveries in recent years have led to new areas of enolate formation in the presence of other carbonyl groups. These include reductive aldol chemistry where direct reductive aldol coupling of an alpha,beta - unsaturated carbonyl group in presence of a carbonyl electrophile enables often perfectly regioselective reactions to occur. This tandem conjugate reductionelectrophilic trapping process enables the reaction to be performed in a “one-pot” manner. The first examples of asymmetric copper-catalysed reductive aldol reactions have been developed for the formation of a range of beta-hydroxylactone products. A combination of Cu(OAc)2.H2O with different bisphosphine ligands catalyses these intramolecular reductive aldol reactions. TMDS (1,1,3,3-tetramethylhydrosiloxane) is used as a stoichiometric hydride source. The reaction proceeds with high relative stereocontrol (>19:1 dr), while absolute stereocontrol remains modest (up to 83% ee). The yields range from moderate to good. A continuous search for improved reaction conditions led to the discovery that cobalt-catalysed reductive aldol reactions have an advantage over the coppercatalysed reaction in the cases where 4-hydroxypiperidin-2-one products are formed. When Co(acac)2·H2O is used together with Et2Zn as the stoichiometric reductant, an increased substrate scope is observed while the diastereoselectivity of the reaction remains high. Yields are also remarkably higher compared to the results obtained with the copper catalyst. These reaction conditions are also used to perform intermolecular reductive aldol reactions between a range of alpha,beta-unsaturated amides and ketones. The reactions proceed readily with high diastereoselectivities (up to >19:1 syn:anti) and good yields. Asymmetric variants have been studied by the use of a chiral oxazolidine auxiliary. Although good selectivities have been obtained, this method currently suffers from the fact that the chiral auxiliary is difficult to cleave. Ni(acac)2 was also found to perform the intramolecular reductive aldol reaction. Et2Zn was again used as the stoichiometric reductant. The nickel-catalysed reaction increased the reaction scope still further. This time both beta-hydroxylactone and 4-hydroxypiperidin-2-one products were readily formed. The former proceeded with increased yields compared to those obtained with the copper catalyst, and, the latter with comparable results to those obtained with the cobalt catalyst.
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Palladium cross-couplings of oxazolesFlegeau, Emmanuel Ferrer January 2008 (has links)
A review covering the literature until April 2008 concerning organometallic reactions to funcionalise oxazoles is described. A protocol for the functionalisation of the oxazole 2- and 4-positions using the Suzuki coupling reaction is described. 2- Aryl-4-trifloyloxazoles undergo rapid, microwave-assisted coupling with a range of aryl and heteroaryl boronic acids in good to excellent yields. The methodology is similarly effective using 4-aryl-2-chlorooxazoles as the coupling partner and has been extended to the synthesis of a novel class of homo- and heterodimeric 4,4- linked dioxazoles. In addition, a regioselective Suzuki-Miyaura cross-coupling of 2,4-dihalooxazoles followed by a Stille coupling has been successfully developed. The procedure affords convergent syntheses of trisoxazoles in high yield and in a minimum number of steps. Furthermore, C-2 direct arylation of oxazoles is discussed. This methodology is extended to the synthesis of C2-C4’ linked bis and tris oxazoles of the type found in the Ulapualide A family of natural products.
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Synthesis of apramycin and paromomycin derivatives as potential next generation aminoglycoside antibiotics and chemistry of isothiocyanato sialyl donorsMandhapati, Appi Reddy 03 September 2016 (has links)
<p> AGAs are clinically important antibacterials for human therapy and have long been used as highly potent antibiotics for treating several bacterial infections. The fidelity of protein synthesis is affected by AGAs in the course of binding to specific sites of the bacterial rRNA. The clinical use of AGAs and their applications as therapeutics is restricted by toxicity (irreversible ototoxicity and reversible nephrotoxicity) and by the resistance of pathogens. The objective of this research was the development of proficient AGAs that are less toxic (i.e., more selective) and that evade resistance. The first three chapters of this thesis are aimed towards developing new aminoglycoside antibiotics with the emphasis on their chemical synthesis, and the biological evaluation of newly synthesized analogues, as well as the exploration of structure-activity relationships to understand the mechanism of their antimicrobial activity. In particular, studies have focused on the modification of the aminoglycosides apramycin and paromomycin so as to develop the next generation of potent AGAs. </p><p> Chapter two reveals the importance of the 6' and <i>N</i>7' positions of the apramycin by investigation of the antibacterial activity and antiribosomal activity of the ten apramycin derivatives which were synthesized by modifying these locations. The effect of such modifications on antiribosomal activity is discussed in terms of their influence on drug binding to specific residues in the decoding A site. This information is useful in the development of a structure activity relationship for the antibacterial activity of the apramycin class of aminoglycosides and will also assist in the future design and development of more active and less toxic aminoglycoside antibiotics. </p><p> Chapter three describes the structure-based design of an improved paromomycin derivative which carries an apramycin-like bicyclic ring I and a conformationally restricted hydroxyl or amine functionality. The influence of the bicyclic paromomycin 6'-hydroxy or amine groups on the binding pattern between AGA and bacterial RNA was investigated by using cell free translational assays. It was found that the bicyclic paromomycin derivative 155 with the equatorial 6’-hydroxy group has a better activity profile than parent paromomycin. </p><p> In chapter four, an efficient sialyl donor was developed for the challenging α-sialylation by means of a highly electron withdrawing isothiocyanato group incorporated at C-5 position sialic acid. The isothiocyanato sialyl donor 218 proved to be an excellent α-directing group in sialylation for a wide range of acceptors, and provided high yields. Further, the sialylation of corresponding sialyl phosphate donor 231 was also demonstrated to give excellent selectivity, but yields are lower due to competing elimination. In addition, the rich chemistry of isothiocyanate functionality is explored to introduce a variety of novel functionalities at the 5-position of the sialosides including deamination, an alkyl chain, various amides, and guanidine derivatives.</p>
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Visible light mediated photocatalysis of N-N bond based compoundsIyer, Akila 28 December 2016 (has links)
<p> The well-established principles of organic photochemistry, offer chemists the fundamental understanding and tools for studying light induced chemical transformations. Employing visible light for photocatalysis, one can design and develop benign routes for the synthesis of new organic materials. In our present investigation, we have developed novel <i>N-N</i> bond based compounds for visible light mediated phototransformations. We have presented synthesis for targeting achiral/chiral <i>N-N</i> bond based compounds and their study for various light driven applications. To name a few applications, these compounds have shown to react smoothly under visible light, metal-free conditions for classical photoreactions, chloromethylation, asymmetric photocyclization and photopolymerization. A diverse range of compounds has shown to react smoothly to afford products in high yields. </p><p> The scope of this methodology has been evaluated for both intermolecular and intramolecular reactions. Our work benefits from the ability of these compounds to undergo desired phototransformation in both solution and in crystalline media. We have provided photochemical and photophysical details that corroborates our experimental findings and highlights the role of excited state reactivity of the novel N-N bond based compounds. This thesis will be an effort to make chemists familiarize with potential of these compounds in light induced reactions. </p>
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Synthesis and Optimization of Non-Phenolic Inhibitors of Macrophage Migration Inhibitory FactorTrivedi-Parmar, Vinay 27 March 2019 (has links)
<p> Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and an upstream regulator of inflammation and cell proliferation. Interestingly, MIF is also an enzyme that functions as a keto-enol tautomerase, though this function is believed to be vestigial in humans. Implicated in the pathogenesis of multiple infectious and autoimmune diseases, including rheumatoid arthritis and cancer, MIF has emerged as an attractive drug target, with the tautomerase active site serving as a convenient binding pocket for small molecule inhibitors. Most MIF inhibitors include a phenol ring, which forms an essential hydrogen bond with an asparagine residue at the back of the binding pocket. While phenol is not an uncommon moiety in approved dugs, it is particularly susceptible to rapid phase 11 metabolic processes and excretion from biological systems, resulting in low oral bioavailability and short half-life. Therefore, potent non-phenolic MIF inhibitors are desirable. Two series of MIF inhibitors lacking the commonly employed phenol group were pursued and are described in this thesis.</p><p> The first was a series of benzoxazolone inhibitors. Attempts at lead optimization were stymied by sensitivity of tautomerase assay results to protein source and incubation conditions, inconsistencies between molecular modeling studies and experimental activity data, and the inability to obtain a crystal structure of the protein–inhibitor complex. A binding mode could not be resolved for the scaffold, preventing a rational, structure-based approach to drug development. Nevertheless, a methodical medicinal chemistry strategy was employed to elaborate the structure-activity relationships (SAR) of the series and discover potent inhbitors. A circa 5 µM inhibitor was obtained, but when further attempts to optimize the series proved ineffective, attention was turned to a new scaffold.</p><p> The second series of MIF inhibitors pursued involved bioisosteric replacement of phenol with a pyrazole, which is capable of forming dual hydrogen bonds with the asparagine residue at the back of the binding pocket. From a 113-µM virtual screening hit, a structure-based, computer-aided lead optimization strategy was employed. X-ray crystal structures of MIF-inhibitor complexes and molecular modeling results guided effective selection and placement of substituents on the scaffold. Methodical derivitization and expansion of the scaffold to include auxiliary aryl functionality near the rim of the binding pocket and recognition of the benefit of pyrazole fluorination were essential breakthroughs in optimizing this series, resulting in inhibitors with potencies around 60-70 nm. From a metabolic perspective, bioisosteric replacement of a salt bridge-forming carboxylate group on the scaffold with a pharmacologically favorable sulfonamide was found to be well tolerated. Additionally, modification of the solvent-exposed region of the scaffold with solubilizing groups was shown to improve aqueous solubility without affecting activity. The pyrazoles are the only the second series of MIF inhibitors to be optimized from an initial screening hit to give inhibitors with nanomolar potency. With their high potencies and expected favorable metabolism, compounds in this series have the potential to be developed into true MIF-directed therapeutics.</p><p>
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Iridium-Catalyzed Asymmetric Allylic Substitution Reactions with Unstabilized Enolates and Prochiral EnolatesJiang, Xingyu 11 April 2019 (has links)
<p>The following dissertation discuss the development of iridium-catalyzed asymmetric allylic substitution reactions with unstabilized enolates and prochiral enolates. These reactions include the enantioselective allylic substitutions with silyl ketene acetals, diastereo- and enantioselective allylic substitutions with ?-alkoxy ketones, and stereodivergent allylic substitutions with aryl acetic acid esters, azaaryl acetamides and azaaryl acetates.
Chapter 1 provides a brief overview of transition-metal-catalyzed asymmetric allylic substitutions with enolates. This overview focused on the mechanism of allylations of enolates catalyzed by palladium complexes and iridium complexes. Additionally, methodologies for asymmetric allylations of unstabilized enolates are discussed in detail. Furthermore, this overview highlights the challenges and the strategies for the control of diastereoselectivity for the allylic substitutions with prochiral enolates.
Chapter 2 describes the development of iridium-catalyzed enantioselective allylic substitution reactions with silyl ketene acetals, the silicon enolates of esters, under relatively neutral conditions. The ester products contain a quaternary carbon atom at the nucleophile moiety and a chiral tertiary carbon atom at the electrophile moiety.
Chapter 3 describes the study on diastereoselective and enantioselective allylic substitution reactions with acyclic ?-alkoxy ketones. A metallacyclic iridium complex catalyzes the allylation of unstabilized copper(I) enolates generated in situ from acyclic ?-alkoxy ketones to form products with contiguous stereogenic centers.
Chapter 4 describes the development of stereodivergent allylic substitutions with aryl acetic acid esters catalyzed synergistically by a metallacyclic iridium complex and a Lewis base co-catalyst. Through permutations of the enantiomers of the two chiral catalysts, all four stereoisomers of the products bearing two adjacent stereocenters are accessible with high diastereoselectivity and enantioselectivity. A stereochemical model is provided to understand the origin of high stereoselec-tivity.
Chapter 5 describes a combination of catalysts that enable stereodivergent allylic substitution reactions with azaaryl acetamides and acetates. This combination of catalysts comprises a chiral metallacyclic iridium complex and a chiral bisphosphine-ligated copper(I) complex, which individually control the configuration of the electrophilic and nucleophilic carbon atoms, respectively.
Chapter 6 extends from the work discussed in Chapter 5 and demonstrates iridium and copper complexes synergistically catalyze stereodivergent allylations to construct vicinal fully substituted and tertiary stereogenic centers in acyclic structures. In particular, fluorine-containing fully substituted stereocenters are readily constructed from fluorinated acetates.
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Allenes, Alkenes & Alkynes| My Piece of the pi ...in Water at Room Temperature...Lippincott, Daniel John 07 March 2019 (has links)
<p> I. An environmentally responsible, mild method for the synthesis of functionalized 1,3-butadienes is presented. It utilizes allenic esters of varying substitution patterns, as well as a wide range of boron-based nucleophiles under palladium catalysis, generating sp–sp<sup>2</sup>, sp<sup>2</sup>–sp<sup> 2</sup>, and sp<sup>2</sup>–sp<sup>3</sup> bonds. Functional group tolerance measured via robustness screening, along with room temperature and aqueous reaction conditions highlight the methodology’s breadth and potential utility in synthesis. </p><p> II. A mild method for the synthesis of highly functionalized [3]–[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patterns, along with a wide range of boron and alkenyl nucleophiles that couple under palladium catalysis leading to sp-, sp<sup> 2</sup>-, and sp<sup>3</sup>-substituted arrays. Regioselective transformations of the newly formed unsymmetrical dendralene derivatives are demonstrated. The use of micellar catalysis, where water is the global reaction medium, and room temperature reaction conditions, highlights the green nature of this technology. </p><p> III. A copper-catalyzed oxidative cleavage of electron-rich olefins into their corresponding carbonyl derivatives is described as an alternative to ozonolysis. The scope includes various precursors to aryl ketone derivatives, as well as oxidations of enol ethers bearing atypical alkyl and dialkyl substitution, the first of their kind among such metal catalyzed alkene cleavage reactions. The use of an inexpensive copper salt, room temperature conditions, an aerobic atmosphere, and water as the global reaction medium highlight the green features of this new method. Associated mechanistic investigations are also presented. </p><p>
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