No description available.

No description available.

No description available.

Phosphoryl transfer reactions are vital to life. In response to the slow intrinsic rates of phosphoryl transfer, Nature has evolved a series of enzymes designed to accelerate these reactions and allow them to occur at biologically relevant rates. These metallo-enzymes are largely characterized by bi- or tri-nuclear active sites with effective dielectric constants that more closely resemble those of organic solvents than water. This project was designed to better understand the mechanisms by which metalloenzymes cleave phosphodiesters with poor leaving groups. The stability of the phosphodiester is central to the storage of genetic information in DNA and RNA. The cleavage of a series of more reactive RNA models, 2-hydroxylpropyl aryl phosphates 1a-g, catalyzed by a dinuclear Zn(II)2 complex of 53 in methanol was explored. A solution of 53:Zn(II)2:(-OCH3) was observed to accelerate the decomposition of 1a-g with rates that were 10^11-10^12-fold greater than the methoxidepromoted reaction at ss pH 9.47, approaching rate accelerations achieved by natural enzymes. The remarkable activity of 53:Zn(II)2:(-OCH3) and 36:Zn(II)2:(-OCH3) towards the cleavage of 1a-g probed the study of the decomposition of diribonucleotides(3'->€™ 5')UpU and (3'->€™ 5'€™)ApC in methanol. The 53:Zn(II)2:(-OCH3)- and 36:Zn(II)2:(-OCH3)-catalyzed decomposition of UpU achieved k2 values of 1.21 ± 0.17 and (7.04 ± 0.99) x 10^-2 M^-1s^-1. The reactivity of ApC in the presence of these systems was unimpressive, however Zn(II) ions in ethanol resulted in the isomerization of 3'->€™ 5'€™)ApC to (2'->™ 5'€™)ApC providing support for the existence of a pentacoordinate phosphorane intermediate. The pentacoordinate phosphorane was further explored through the reaction of 36:Zn(II)2:(-OCH3) with the cyclic phosphate 58 and 2-hydroxylpropyl methyl phosphate (59). In the presence of 36:Zn(II)2:(-OCH3) the rate of isomerization of 59/59a (kobs = (4.7 ± 0.5) x 10^-3 s^-1) exceeded that of expulsion of the methoxy group (kobs = 1.62 x 10^-3 s^-1), thus confirming the existence of a pentacoordinate phosphorane intermediate (60)and providing support for a two-step phosphodiester cleavage reaction. The catalytic efficiency of 36:Zn(II)2:(-OCH3) towards the cleavage of stable phosphodiesters probed its application towards the decomposition of dimethyl phosphate (2) in methanol-d4. The exchange of OCH3 for OCD3 occurred with kcatmax = (2.27 ± 0.03) x 10^-6 s^-1. / Thesis (Master, Chemistry) -- Queen's University, 2008-09-12 13:09:42.427

Presented herein is the development, optimization and mechanistic investigation of an Cu catalytic system for the oxidation of sp 3 C-H bond of simple arenes to form C-N bond in a direct manner. Due to the prevalence of nitrogen containing molecules among biologically active synthetic and natural compounds, synthetic chemists have always been motivated to develop new efficient ways to directly transform ubiquitous carbonhydrogen (C-H) bonds into carbon- nitrogen (C-N) bonds. Recent advances in transition metal catalyzed C-H amination has demonstrated that it is not only possible but also practical to functionalize C-H bonds that are often considered inert in one step, circumventing more classical, sequential functional group interconversion approaches. Existing catalytic systems that promote the transition metal-catalyzed, amination of sp 3 C-H bonds displayed certain limitations, especially the lack of built-in versatility and stability in their amination reagents. To overcome these drawbacks of these existing catalytic system, our group developed a new Cu amination protocol that deployed versatile hydroxylamine-based with general structure RSO 2 NH-OAc as amination reagents. Although the reactivity of the catalytic system ranges from moderate to good, the catalytic system provided promising results using simple arene substrates. Further detailed mechanistic studies revealed that the reaction undergoes an unprecedented two subsequent cycles divided by a major intermediate PhCH 2 (NTsOAc). The proposed mechanism is consistent with radical clock experiments, observed reaction profiles, the need for excess of substrate, and the documented role of the ligand in the catalytic system. The exciting proposed mechanism led to a new type of copper catalyzed amination reaction using N- fluorobenzenesulfonimide (NFSI) as oxidant, which overcomes the need to use an excess of substrate. A wide range of unactivated amines HNR 1 R 2 , including sulfonamide and benzamide, can be used as amine sources, which enables the installation of different nitrogen groups on benzylic sp 3 C-H bond of a variety of substrates in moderate to excellent yield. Moreover, mechanistic experiments and critical analysis of related reactivity in the literature provide insight into the catalytic cycle, resulting in a proposal that details the role of both oxidant and amine source in the new system.

Free radical cyclization methodology has been used extensively in synthesis for manipulation of complex molecules such as alkaloids, terpenes, carbohydrates, peptides and nucleic acids. The methodology has emerged as a result of work by physical organic chemists who determined rate constants for the most common radical reactions used in organic synthesis. A novel route to cyclic imines based on 5-exo radical cyclization was explored. The radical precursors were imines prepared from allylamine and readily available a-phenylselenenyl ketones. The synthesis of conformationally constrained bicyclic nucleosides is also reported using 5-exo and 6-exo cyclizations of hexenyl and heptenyl radicals in thymidine nucleosides. The nucleosides were incorporated in a 15mer antisense oligonucleotide via solid-phase oligonucleotide synthesis. The AONs with the modifications were tested for target affinity and stability and compared with the well known LNA modified AONs. The thesis discusses the unique qualities of these novel molecules and presents them as potential candidates for antisense therapeutic agents. Keeping up with the theme of intramolecular carbon-carbon bond formation, microwave induced carbodechalcogenation of chalcogenoanhydrides was explored. Poor generality in these reactions made us turn to transition metal catalysis for Sonogashira cross-coupling reactions using alkyl aryl and diaryl tellurides as coupling partners.

The development of a palladium-catalyzed intramolecular carboesterification of unactivated olefins is described. Olefin difunctionalization is a powerful tool for adding complexity to a molecule, and this formal [3+2] cycloaddition generates highly functionalized fused ring systems. Initially discovered by Dr. Yang Li in our group, it was found that when propiolic acids with a pendant terminal olefin were treated with 1 mol % Pd(MeCN)2Cl2, 3 equivalents of copper (II) chloride, and 3 equivalents of lithium chloride in acetonitrile at 50 °C, cyclization occurred in up to 90% yield. The optimization of this reaction and the extension to propiolamides and propargyl alcohols is described in this thesis. A mechanism involving a novel palladium-carboxylate species is proposed. Preliminary investigations into the synthesis of chiral sulfoxide pincer ligands are also described. The nucleophilic aromatic substitution of 1,3-dibromobenzene and 2,6-dichloropyridine with various thiols, followed by oxidation of the sulfides to sulfoxides is investigated as a route to the desired proligands.

The development of a palladium-catalyzed intramolecular carboesterification of unactivated olefins is described. Olefin difunctionalization is a powerful tool for adding complexity to a molecule, and this formal [3+2] cycloaddition generates highly functionalized fused ring systems. Initially discovered by Dr. Yang Li in our group, it was found that when propiolic acids with a pendant terminal olefin were treated with 1 mol % Pd(MeCN)2Cl2, 3 equivalents of copper (II) chloride, and 3 equivalents of lithium chloride in acetonitrile at 50 °C, cyclization occurred in up to 90% yield. The optimization of this reaction and the extension to propiolamides and propargyl alcohols is described in this thesis. A mechanism involving a novel palladium-carboxylate species is proposed. Preliminary investigations into the synthesis of chiral sulfoxide pincer ligands are also described. The nucleophilic aromatic substitution of 1,3-dibromobenzene and 2,6-dichloropyridine with various thiols, followed by oxidation of the sulfides to sulfoxides is investigated as a route to the desired proligands.

This thesis documents the development of novel synthetic methodologies for the incorporation of sulfur dioxide into organic molecules employing the amine-sulfur dioxide complex DABSO (vide infra). These developed processes serve to access a range of sulfonyl-containing (-SO₂-) compounds including sulfones and sulfonamides, via sulfinic acid precursors. <b>Chapter 1</b> provides an overview of the synthesis and applications of sulfonyl-containing compounds and the organic chemistry of sulfur dioxide. A comprehensive introduction to the developed uses of sulfur dioxide surrogates in organic chemistry is given. The synthetic utility of metal sulfinates towards accessing sulfonyl-containing compounds is also discussed. <b>Chapter 2</b> details the development of a one-pot sulfone synthesis via metal sulfinates generated from organometallic reagents and DABSO. Alkyl, alkenyl and (hetero)aryl sulfinates prepared from organolithium and Grignard reagents can be efficiently coupled with a range of electrophiles to access a range of products including diaryl, aryl-heteroaryl and &beta;-hydroxy sulfones. <b>Chapter 3</b> describes an array-compatible, one-pot sulfonamide synthesis employing metal sulfinates and N-chloroamines as in situ-generated intermediates. This employs DABSO and sodium hypochlorite (bleach) as simple reagents and organolithium, organozinc and Grignard reagents along with amines as readily-accessible building blocks. The robust nature of this methodology and its potential application in discovery chemistry is demonstrated with a 65-compound array synthesis. <b>Chapter 4</b> documents the development of a palladium-catalysed sulfination reaction of boronic acids to access a range of sulfonyl-containing compounds. This involved the establishment of a one-pot/one step synthesis of sulfones leading to the discovery of a redox-neutral, ligand-free sulfination procedure using DABSO and palladium(II) catalysis. Sulfinic acid derivatives can be generated and subsequently trapped in situ with a variety of electrophiles to furnish sulfones and sulfonamides. <b>Chapter 5</b> summarises the research and the potential future work. <b>Chapter 6</b> provides experimental details and data.

The first part of this thesis presents a novel approach for synthesising enantioenriched cyclic allylsilanes via asymmetric ring-closing metathesis (ARCM). The second part of this thesis focuses on the reactivity of allylsilanes in electrophilic trifluoromethylation under transition metal and photoredox catalysis. <strong>Chapter 1</strong> provides a general introduction to existing methods for preparing compounds containing Si-stereogenic centres. The motivation for using ARCM to form Si-stereogenic centres is discussed. To set the stage for this work, the development of olefin metathesis as a tool in organic synthesis is briefly summarised. <strong>Chapter 2</strong> describes the synthesis of various prochiral silicon-containing trienes and their reactivity in Ru-, Mo- and W-catalysed ring-closing metathesis. . Following extensive screening of chiral catalysts, few catalysts were identified that enabled selective ARCM to access Si-stereogenic products in up to 98% ee. A systematic investigation of the relationship between the structure of the starting material (i.e., hydrocarbon chain length, steric and electronic properties of the silicon substituents) and the resulting efficacy in ARCM was undertaken, the results from these experiments are discussed. Importantly, this study represents the first example in which ARCM has been successfully used to desymmetrise prochiral substrates to form a new chiral Si centre (Scheme 1). <strong>Chapter 3</strong> provides a general introduction to the field of trifluoromethylation, with a special focus on recent applications of transition metal catalysts in Csp²–CF₃ and Csp³–CF₃ bond formation. A myriad of effective nucleophilic, electrophilic and radical trifluromethylating reagents have been developed during the past several years; the properties of these reagents and their compatibility with various modes of catalysis are summarised to provide a context for the second part of this thesis research. <strong>Chapter 4</strong> presents two novel methods for effecting trifluoromethylation of allylsilanes . First, it was discovered that the combination of an electrophilic trifluoromethlyating reagent and a copper catalyst effectively mediated trifluoromethylation of allylsilanes. The silicon substituent was crucial for improving the nucleophilicity of the substrate and dictating the regioselectivity of the Csp³–CF₃ bond-forming step. With this method, alkyl or aryl substitution at the &beta;-position of the allylsilane was critical for reactivity. Second, in a complementary study, it was found that copper could be replaced by a ruthenium photocatalyst and visible light. This latter method allowed for trifluoromethylation of substrates that were ineffective with copper catalysis. Mechanistic studies of both reaction systems were undertaken, and plausible reaction pathways for both reactions are proposed. <strong>Chapter 5</strong> gives full experimental procedures and characterisation data for all compounds.