This study was aimed at investigating the suitability of 2-alkyl/alkenylbenzo-1,3,2-diazaborolane compounds as potential nucleophilic coupling partners in the Suzuki-Miyaura cross-coupling reaction. A range of aryl bromides and iodides bearing electron-donating as well as electron-withdrawing substituents were reacted with 2-alkyl/alkenylbenzo-1,3,2-diazaborolane compounds under the influence of Pd(OAc)2/PCy3 combination. The cross coupling reaction afforded the desired products in yields ranging from 35% to 89% in less than 20 minutes. The catalytic system was found to be versatile and general tolerating a variety of functional groups including OMe, NO2, OH, COOMe and COMe2, thus demonstrating the suitability of 2-alkyl/alkenylbenzo-1,3,2-diazaborolane as coupling partners in the Suzuki-Miyaura cross-coupling methodology. The results from this study have been accepted for publication, full reference: (Sithebe, S., Hadebe, S. W., Robinson, R. S. Tetrahedron, 2011, 67, 4277.) Encouraged by the successful application of 2-alkyl/alkenylbenzo-1,3,2-diazaborolanes as coupling partners in the Suzuki-Miyaura (SM) cross-coupling reaction, we then extended our studies to investigate the synthesis and subsequent application of 2-arylbenzo-1,3,2-diazaborole analogues as potential coupling partners under the Suzuki-Miyaura cross-coupling reactions. The cyclocondensation of arylboronic acids with the corresponding 1,2-phenylenediamine afforded 2-arylbenzo-1,3,2-diazaboroles in yields ranging from 43% to 93%. The cross-coupling reaction of 2-arylbenzo-1,3,2-diazaboroles with the range of aryl bromides afforded the desired biaryl products in moderate to excellent yields ranging from 62% to 96%. Substrates bearing electron-withdrawing substituents were shown to be more reactive under these reaction conditions affording biphenyls in excellent isolated yields ranging from 83% to 96%. While our yields are comparable with the yields reported in literature, our reactions take only 10 minutes (!) compared to many hours of reflux as reported in the literature. This project was also aimed at investigating the spectroscopic characteristics of 2-arylbenzo-1,3,2-diazaborole compounds by acquiring and studying their absorption and emission spectra. The data obtained revealed the lack of significant v solvatochromism for all the compounds in the ground state which is indicative of the presence of low dipole moments. These values were confirmed computationally which showed low calculated dipole in a range 0.1379-2.2773 D. In the excited state, all chromophores are influenced by the polarity of the solvent used pointing to the presence of solvatochromism. The introduction of a donor group such as thioether (MeS) and the introduction of bromine atom, on the π-system, have proven beneficial for the emission maxima of the species investigated. The extension of π-conjugation length at the 2-position of these species and the methylation at the backbone of 1,3,2-benzodiazaborolyl group leads to bathochromic shifts of the emission maxima, which in turn lead to large Stokes shifts of up to 11000 cm-1. Alternatively, the formal insertion of the phenyl spacer between the naphthyl ring and the 1,3,2-benzodiazaborolyl group does not have any influence on the photophysical properties of these compounds. The HOMOs solvatochromism for all the compounds in the ground state which is indicative of the presence of low dipole moments. These values were confirmed computationally which showed low calculated dipole in a range 0.1379-2.2773 D. In the excited state, all chromophores are influenced by the polarity of the solvent used pointing to the presence of solvatochromism. The introduction of a donor group such as thioether (MeS) and the introduction of bromine atom, on the π-system, have proven beneficial for the emission maxima of the species investigated. The extension of π-conjugation length at the 2-position of these species and the methylation at the backbone of 1,3,2-benzodiazaborolyl group leads to bathochromic shifts of the emission maxima, which in turn lead to large Stokes shifts of up to 11000 cm-1. Alternatively, the formal insertion of the phenyl spacer between the naphthyl ring and the 1,3,2-benzodiazaborolyl group does not have any influence on the photophysical properties of these compounds. The HOMOs of all the chromophore are purely represented by the 1,3,2-benzodiazaborolyl group except for anthracenyl-functionalised benzo-1,3,2-diazaborolane compounds in which the HOMO are located on the π-system with no contribution of the vacant 2pz-orbital of the boron atom. The large Stokes shifts and significant solvatochromism displayed by these compounds are suggestive of the potential application in organic light emitting diodes (OLED) as emitters. The results from this study have been drafted for publication in Dalton Transition. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2013.

A methodology for the catalytic asymmetric hydroboration of vinylarenes with pinacolborane has been developed. Use of pinacolborane in hydroboration, especially catalytic asymmetric hydroboration grants direct access to chiral boronate esters, without the cryogenic temperatures required for catalytic hydroboration with catecholborane and the subsequent transesterification with excess pinacol. These chiral boronate esters were then subjected to a homologation/oxidation sequence previously refined in our labs to prepare Naproxen™ in 66% yield and 88% enantiopurity from its corresponding vinyl arene precursor. A survey of metal catalysts, solvents and ligands revealed remarkable changes in regioselectivity with changes in metal. Rhodium catalysts in combination with pinacolborane were able to provide regioselectivity for the secondary branched isomer equivalent to those obtained with catecholborane. Iridium catalysts showed a near perfect regioselectivity for the primary linear isomer. With respect to the choice of chiral ligand, complete reversal in the enantiomer obtained was observed with the choice of hydroborating reagent from catecholborane to pinacolborane. In order to understand the regioselectivity observed under iridium catalysis, deuterium labeling studies were undertaken. A synthesis of the deuterated hydroboration reagent pinacolborane was first completed. From the results of these studies, in combination with published thermodynamic data, a mechanism for the iridium catalyzed hydroboration of alkenes was proposed. / Thesis (Ph.D, Chemistry) -- Queen's University, 2007-08-29 09:30:38.571

No description available.

No description available.

Organoboron compounds are commonly used precursors for a variety of reactions in organic synthesis as is exemplified by the Suzuki-Miyaura cross-coupling, which is ubiquitous in industry and academia. Additionally, the Chan-Evans-Lam cross-coupling, lithiation-homologation, allylboration, and many other reactions rely on boron to achieve otherwise difficult chemical transformations. Thus, developing novel methods towards the regio- and/or stereoselective installation of boron into organic molecules remain important for designing new drugs. Boron reagents are also useful in chemical transformations that do not ultimately install a boron moiety on the organic molecule. We have developed several methods that achieve the trans-selective borylation or semireduction of internal alkynes, a process dominated by transition metals and often results in incomplete (E)-stereoselectivity. This dissertation describes three novel uses of a diboron reagent or pinacolborane that reduce propiolic acid derivates selectively to (E)-alkenes and one method that installs pinacolatoboron yielding exclusively (E)-β-borylacrylamides. We investigated the trans-selective hydroboration of primary and secondary propiolamides as reports in the literature accomplish trans-hydroboration via transition metal catalysis, which are limited in substrate scope. We discovered that addition of n-butyllithium to propiolamide and pinacolborane exclusively yields (E)-β-borylacrylamides in good to excellent yield. During the reaction, deprotonation of the amide with a strong base generates an alkoxide that coordinates to pinacolborane and forms a boronate complex. Upon warming to room temperature, a hydride transfer is directed to the α-carbon generating a β-carbanion that subsequently captures boron. Workup protonates the amide, furnishing the (E)-β-borylacrylamide product. As a follow-up from the trans-hydroboration of propiolamides described above, we developed a complementary semireduction of primary and secondary propiolamides. In this reaction, addition of catalytic amounts of potassium tert-butoxide to propiolamides generates an alkoxide that coordinates to pinacolborane and rapidly produces (E)-cinnamamides in 35 – 96% yield and >99:1 E:Z stereoselectivity. This reaction effectively reduces an internal alkyne to afford a product with trans geometry. A deuterium labeling study provided mechanistic insight for the transformation suggesting that the β-proton in the products is derived from the amide nitrogen of the propiolamide. Further, we demonstrated the utility of this reaction by augmenting the total synthesis of FK866, a potent nicotinamide mononucleotide adenyltransferase (NMNAT) inhibitor, and isolated the cinnamamide product in good yield with >99:1 E:Z stereoselectivity. Using a similar strategy, we investigated the ability of bis(pinacolato)diboron and base to mediate the α-borylation of propiolic acids. We observed the formation of a semireduced product, i.e., cinnamic acid. In the presence of a crown ether and cesium carbonate, propiolic acid is deprotonated and activates bis(pinacolato)diboron. Subsequent α-borylation and β-carbon protonation affords a highly unstable α-boronic acid derivative that undergoes rapid protodeborylation yielding predominantly (E)-cinnamic acids. The dual role of the carboxylate in activating the diboron reagent and directing α-borylation was unprecedented and is the first transition metal-free method to reduce propiolic acids to (E)-cinnamic acids. In contrast with boron activation from in situ generated alkoxide, an alternative approach is using phosphine catalysts—a major interest in the development of transition metal-free methodology. As such, we investigated the ability of phosphines to mediate the borylation of primary and secondary propiolamides. Surprisingly, we observed an efficient semireduction of primary and secondary propiolamides to their respective (E)-cinnamamides in the presence of catalytic n-tributylphosphine and stoichiometric pinacolborane. We surveyed the scope and reactivity of substrates bearing N-substitutions, electron-rich or deficient aryls, and aliphatics using optimized reaction conditions and produced a library of (E)-cinnamamides in 31 – 98% yield with >99:1 E:Z stereoselectivity. Deuterium labeling studies suggest that hydrogens on the α- and β-carbon come from pinacolborane and the amide hydrogen, respectively. We also trapped and characterized a key intermediate using tris(pentafluorophenyl)borane that supports a mechanism wherein the phosphine catalyst activates the propiolamide by conjugate addition. / Doctor of Philosophy / Boron reagents are ubiquitous in chemical reactions utilized in industry and academia. There are many transformations involving the conversion of a boron group into a different functional group. Thus, designing new chemical reactions that install boron onto organic molecules is critical to increasing access to novel drugs, polymers, and other consumables. Modern boron chemistry strives towards transition metal-free chemical reactions to reduce the use of costly, low abundance transition metals, such as palladium and platinum, that are also implicated in environment and human toxicity. This dissertation discusses four novel reactions that rely on the unique reactivity of boron. Three of these methods involve the semireduction of alkynes to alkenes, i.e., a carbon-carbon triple or double bond, respectively. The other method involves the addition of boron and hydrogen to an alkyne producing an unprecedented molecule with potential for subsequent chemical modification or conversion to a drug. Each of the reactions reported in this dissertation were optimized without transition metals and the products are potentially useful in organic synthesis or in the design of pharmaceuticals or in other industries.

Organoboron derivatives represent an important class of compounds due to the versatility of the carbon-boron bond in a variety of chemical reactions. Boron-containing compounds have garnered increasing attention as synthetic intermediates and medicinal agents. Therefore, the introduction of carbon-boron bonds to organic molecules continues to be an important field of study. This dissertation describes novel methodology for the regio- and stereo-selective introduction of carbon-boron bonds to generate β-borylacrylonitrile and 1-boryl-1,3-enyne products. Propiolonitriles are intriguing research targets due to the electron-withdrawing nature of the cyano group on the adjacent alkyne. In this dissertation, we developed a phosphine-catalyzed regio- and stereo-selective hydroboration of propiolonitriles to generate novel β-borylacrylonitriles in up to 89% yield and 97:3 (E)-selectivity. These products were converted to the corresponding postassium 1,2-vinylcyanotrifluoroborate salts and demonstrated applications in oxidation and Suzuki-Miyaura cross-coupling reactions. Interestingly, 31P and 13C NMR studies suggest that this hydroboration reaction proceeds in a 1,2-phosphine addition pathway instead of a canonical 1,4-conjugate addition pathway. We also developed a transition metal-free cis hydroboration of 1,3-diyne substrates. In the presence of catalytic amounts of tri-n-butylphosphie and the unsymmetric diboron reagent pinBBdan, 1-boryl-1,3-enyne products were generated in up to 63% and >99:1 (Z)-selectivity. These 1,8-diaminonaphthalene products can be converted to the corresponding pinacolboranes or trifluoroborate salts. They also demonstrated applications in protodeboronation and Suzuki-Miyaura cross-coupling reactions. We propose that this hydroboration occurs via a nucleophilic boron addition mechanism. / Doctor of Philosophy / Incorporating boron into organic molecules provides access to a variety of otherwise difficult chemical reactions. Therefore, our laboratory seeks to develop new methods for synthesizing organoboron compounds. A major goal of our work is to develop transition metal-free reactions due to the expense and environmental impact of transition-metal mediated methodology. This dissertation reports two new methods for installing boron to organic molecules without the use of transition metals. The reported reactions utilize mild conditions to selectively generate functionalized products, and applications of these products are demonstrated. Chapter 1 describes a hydroboration reaction of propiolonitrile derivatives to afford (E)-β-borylacrylonitrile products. Notably, this reaction proceeds via a unique mechanism, contrasting that of similar reported reactions. Chapter 2 reports a transition metal-free hydroboration of 1,3-diynes to afford (Z)-1-boryl-1,3-enyne products. These products are structurally similar to relevant molecules in medicinal, polymer, and synthetic chemistry.

Organoboron compounds are ubiquitous in organic chemistry. Fundamental transformations utilizing organoboron compounds are a necessary addition to any organic chemist's synthetic toolbox. In addition to their extensive use as synthetic intermediates, organoboron compounds are being increasingly studied for their material and medicinal properties. Excitingly, significant advances have been made over the years towards the synthesis of a wide variety of organoboron substrates. In the case of vinylboronic acids, synthesis primarily occurs through cis addition of boron reagents across triple bonds. However, methods affording trans addition products are scarce. Furthermore, many current methods rely on the use of expensive and toxic transition-metal catalysts. Herein, we describe the development of trans addition of boron reagents across polarized triple bonds to afford novel vinylboronic acids. Emphasis is placed on the transition metal-free nature of the reactions as well as the regio- and stereoselectivity observed in the products. In addition, the synthetic utility of the resulting trans addition products is demonstrated in the synthesis of biologically relevant molecules. We first describe the Brønsted base-mediated trans silaboration of propiolamides in which two functional groups with orthogonal reactivity are simultaneously installed. We then go on to describe an organocatalyzed trans hydroboration of propiolate esters as well as a complementary Brønsted base-mediated trans hydroboration reaction of propiolamides. To conclude this portion, we demonstrate how the products from the previous methods can be used to synthesize difluoroborylacrylamides which possess unique and versatile reactivity. Herein we disclose the first small-molecule inhibitors of the sphingosine-1-phosphate (S1P) transporter spinster homolog 2 (SPNS2). While little is known in regard to the structure and function of SPNS2, previous studies have demonstrated the vital role SPNS2 plays in S1P mediated processes and have identified SPNS2 as a potential clinical target. For example, SPNS2 is critical to S1P-mediated lymphocyte egress from primary lymphoid tissues. Thus, small molecule inhibition of SPNS2 represents a novel therapeutic strategy for the treatment of autoimmune disorders such as multiple sclerosis. In this study, we report the discovery of small molecule inhibitors that display low micromolar activity using a novel yeast-based SPNS2 assay. Inhibitor structure-activity-relationship studies led to the discovery of the imidazole-based amine inhibitor 7.54. Furthermore, administration of 7.54 to mice recapitulates the lymphopenic phenotype observed in previous SPNS2 knockout studies. / Doctor of Philosophy / Boron-containing compounds are important in organic chemistry and are involved in the synthesis of a variety of materials and medicines used in everyday life. As such, the ability to efficiently and sustainably prepare boron-containing compounds has far reaching consequences. Access to an important class of boron-containing compounds known as vinylboronic acids has previously been established; however, product selectivity is often limited to what is referred to as cis addition products. Furthermore, access to the corresponding trans addition products is often limited to processes involving expensive transition metal catalysts that produce environmentally toxic waste. Herein, novel transition metal-free trans addition processes are described for preparing vinylboronic acids. In addition, the application of the resulting products is demonstrated through the synthesis of biologically relevant compounds. Sphingosine-1-phosphate (S1P) is an important signaling lipid that is involved in a variety of physiological processes. Improper balance in the amount of S1P in the body is associated with a variety of disease states such as autoimmunity and cancer. Two drugs that inhibit S1P-mediated processes have been approved by the FDA, fingolimod (Gilenya®) and siponimod (Mayzent®). However, there are drawbacks to targeting the S1P receptor directly, including dose-limiting side effects that are associated with these drugs. Consequently, recent efforts have focused on developing new ways to control the effects of S1P. Herein, we describe the discovery and development of the first reported inhibitors of the S1P transporter, spinster homolog 2 (SPNS2). A library of compounds was synthesized and tested for SPNS2 inhibition. The resulting structure-activity-relationship studies led to the discovery of the imidazole-based propanamine derivative 7.54. Furthermore, we demonstrate the potential of SPNS2 inhibition to control the effects of S1P in mice. These studies provide a foundation for future SPNS2-based drug discovery that will hopefully lead to the development of improved therapies for the treatment of autoimmune disease and cancer.

The mechanism of catalytic hydroboration was studied through the use of iridium and rhodium model complexes. Oxidative addition of the B-H bond in (1,2-phenylenedioxy) borane (catecholborane) to (Me₃P)₃Ir(Cl)(H) (BO₂C₆H₄ (<B>II</B>) produces <i>mer</i>-(Me₃P}₃Ir(Cl)(H)(B0₂C₆H₄) (<B>II</B>), which was characterized by ¹H NMR spectroscopy and single crystal X-ray diffraction. Compound <B>II</B> reacted with alkynes to form vinyliridium complexes and will catalyze the hydroboration of alkynes with (1,2- phenylenedioxy)borane. The reaction of <B>II</B> with acetylenes was inhibited by the presence of free Lewis bases indicating that the reaction proceeds by a dissociative mechanism. Exchange of the chloride ligand in <B>II</B> occurred with other Lewis bases, indicating that chloride dissociation was responsible for opening up the vacant coordination site on the complex and thus providing for acetylene coordination. When the chloride ligand on <B>II</B> was replaced with other Lewis bases, the reactivity towards trimethylsiliylacetylene was qualitatively determined to be inversely proportional to the strength of the new ligand. The above experiments indicated that the mechanism of catalytic hydroboration of acetylenes with catecholborane involves: oxidative addition of the B-H bond to the iridium center, followed by chloride dissociation and acetylene coordination, migratory-insertion into the Ir-H bond to form the metallo-vinyl complex, and finally reductive elimination to produce trans-alkylvinylborole esters. The stable metallo-vinyl complex, <b>IX</b>, produced in the reaction of <b>II</b> with dimethyl acetylene dicarboxylate produced twO isomers in solution, one of which showed fluxional behavior. Single crystal X-ray diffraction elucidated a single solid state structure, but the structures of the isomers in solution and the fluxional properties observed have not yet been explained. The rhodium complex was synthesized by oxidative addition of the B-H bond in (1,2- phenylenedioxy) borane to (Me₃P)₃RhCl producing <i>mer</i>-(Me₃Rh(CI)(H)(BO₂C₆H-₄) (<b>XXIV</b>), which was characterized by ¹H NMR spectroscopy. This complex reacted with acetylenes, but more slowly than the iridium complex, <b>II</b>. The resulting vinyl products were also different than those produced in the iridium case. Phosphine dissociation in <b>XXIV</b> was observed, indicating the possibility of a different mechanism than proposed for the iridium complex. / Ph. D.

Les ressources carbonées fossiles (pétrole, charbon, gaz) couvrent 85 % des besoins énergétiques mondiaux et servent de matières premières pour 95 % des consommables chimiques organiques (plastiques, engrais, pesticides…). L’amenuisement des ressources pétrolières et l’accumulation du CO2 résultant de leur utilisation posent donc un problème écologique, énergétique et de disponibilité en matières premières pour l’industrie chimique. Dans ce contexte, il convient de proposer de nouvelles voies de synthèse de consommables chimiques, de manière à construire une industrie durable basée sur l’utilisation de ressources carbonées renouvelables. Contourner la pétrochimie et valoriser au maximum son déchet carboné, le CO2, pour construire des édifices moléculaires sans vocation énergétique (polymères, engrais, textiles synthétiques…) représente donc un enjeu scientifique de premier plan. Dans cet optique, de nouveaux procédés de synthèse de molécules azotées ont été mis au point à partir de CO2 comme source de carbone, d’amines comme source d’azote et de réducteurs doux de type hydrosilanes et hydroboranes comme source d’hydrogène. Ces procédés sont accélérés par l’utilisation de catalyseurs sans métaux et permettent de produire des formamides, des formamidines, des aminals et des méthylamines, qui constituent des molécules de bases de l’industrie chimique. / The fossil carbon resources (oil, coal, gas) cover 85% of world energy portfolio and serve as raw materials for 95% of organic chemicals consumables (plastics, fertilizers, pesticides...). The decrease of oil resources and the accumulation of CO2 arising from their use thus pose environmental, energetic and availability of raw materials problems for the chemical industry. In this context, it is appropriate to propose new methods of chemical synthesis to build a sustainable industry based on the use of renewable carbon resources. Bypassing petrochemicals and valorize its carbon waste, CO2, to build molecular structures without energy purposes (polymers, fertilizers, synthetic textiles ...) represents a leading scientific challenge. From this perspective, new nitrogen molecules synthetic processes have been developed from CO2 as a carbon source, amines as nitrogen source and mild reductant such as hydrosilanes and hydroboranes as a hydrogen source. These processes are accelerated by the use of metal-free catalysts and enable the production of formamides, formamidines, aminals and methylamines, which are basic molecules of the chemical industry.

Thesis advisor: James P. Morken / (+)-Discodermolide is a marine natural product and is one of the most potent microtubule stabilizers in human cell lines. Because of its unique linear structure and important properties, a number of total syntheses of (+)-discodermolide and its derivatives have been reported. Herein, an efficient, highly convergent, and stereocontrolled total synthesis is presented (Chapter 2). The synthesis relied on the development of three catalytic and stereoselective processes: platinum-catalyzed asymmetric diene diboration, nickel-catalyzed diastereoselective hydroboration of chiral dienes (Chapter 1), and nickel-catalyzed borylative diene-aldehyde coupling (see Chapter 4). Combination of these reactions allows preparation of the target in a short sequence. Moreover, the development of rhodium-catalyzed asymmetric hydroformylation (Chapter 3) makes this approach the first Roche ester free (+)-discodermolide synthesis. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.