Boronic acids are key reagents in a host of chemical applications. In particular, they have been utilised in a range of metal-catalysed coupling reactions, involving the facile formation of carbon-carbon or carbon-heteroatom bonds under mild conditions that often boasts high yields and selectivity, thus becoming a vital tool in the design of complex molecules. Alongside the increased application of boronic acids, there has been a substantial increase in their commercial availability and now a wide range of elaborate boronic acids exist. However, many of these motifs are prone to undesired and troublesome side reactions, namely protodeboronation. Although many efforts have been made towards mitigating decomposition during coupling, the general mechanistic understanding of in situ protodeboronation is remarkably limited and outdated. pH-rate profiles for the protodeboronation of many heterocyclic, vinyl and cyclopropyl boronic acids (1:1 H2O/dioxane, pH 1-13, 70 °C) have been constructed using NMR spectroscopy. A general model was constructed to allow the simulation of pH-rate profiles and allow facile extrapolation of equilibrium and rate constants. With computational support, a range of novel protodeboronation mechanisms have been elucidated. Concentration-dependent processes (self-/auto-catalytic protodeboronation and disproportionation of boronic acid into borinic acid and boranes) are present when both boronic acid and boronate are present in high concentrations. Non-basic heterocyclic, vinyl and cyclopropyl boronic acids display common acid- and base-catalysed protodeboronation mechanisms, however basic heterocyclic boronic acids exhibit additional pathways. The formation and subsequent fragmentation of zwitterion water adducts (particularly for 2-pyridyl, 5-thiazolyl and 5- pyrazolyl boronic acids) leads to surprisingly rapid protodeboronation at neutral pH values, which can be attenuated (2-pyridyl) or accelerated (5-thiazolyl/5-pyrazolyl) with various Lewis acid additives. Protodeboronation of a series of polyfluorophenyl boronic acids under alkaline conditions revealed an immense range of reactivity, spanning several orders of magnitude (phenyl boronic acid, t½ ≈ months; pentafluorophenyl boronic acid, t½ ≈ milliseconds). Ortho-fluorine substituents were found to heavily influence the reactivity of such substrates. Detailed KIE and computational studies indicate the presence of a unique mechanism involving rate-limiting fragmentation of aryl boronate to form an aryl anion intermediate. Strong correlations with LFER and computational parameters indicate this mechanism is predominant with extremely electron deficient or ortho-fluoro substituted substrates, and can be used as a predictive model for the reactivity of aryl and polyfluorophenyl boronic acids.

The research presented herein is concerned with the exploration of rhodium-catalysed addition reactions with organoboranes encompassing the 1,4-addition enolate protonation to benzyl acrylate esters, and the synthesis of chiral organoboranes for use in the synthesis of natural products Hermitamides A and B. Chapter 1 introduces the area of rhodium-catalysed conjugate addition as a tool for asymmetric synthesis. An extensive discussion of this methodology is included and recent advances in the area will be highlighted. In addition to this some recently published alternatives to organoboranes are outlined and their use in rhodium-catalysed chemistry documented. Chapter 2 discusses the tandem process of rhodium-catalysed conjugate addition enolate protonation, a recently observed asymmetric development. By using a novel route to benzyl acrylic esters the synthesis of α,α′-dibenzyl esters is achieved in excellent yields and selectivity. This study highlights the fact that when dealing with 1,1-disubstituted activated alkenes it is more difficult to produce enantioselective results as the chirality is determined in the protonation step and not during insertion. Some insights into the mechanism are proposed based on the outcomes observed. Chapter 3 describes the total synthesis of Lyngbic Acid and related structures Hermitamides A and B. Synthesis of these natural products are achieved by synthesis of an enantiopure organoborane species and its subsequent coupling via rhodium catalysis. Some interesting insights into the addition of alkenyl organoborane species to unsubstituted 1,1-activated alkenes are detailed. Chapter 4 describes the synthesis and characterisation for the compounds discussed in the previous chapters.

<p> Synthesis of new biocompatible siloxane surfactants, where hydrophobic siloxanes are modified by biocompatible hydrophilic functional groups (e.g., triethoxysilane (TES), polyethylene glycol (PEO), and carboxylic acid) is a research area of increasing interest. In this research project we have developed a new class of these biocompatible surfactants, based on siloxanes, as the hydrophobic part, and boronic acids as the hydrophilic part. The reasons for choosing boronic acidlboronates as a modifying agents include: their pH sensitivity, biocompatibility, possible interactions with sugars, and because of a broader general utility in synthesis. The promise of these properties combined with the hydrophobicity, flexibility and many other important features of siloxanes encouraged us to initiate these syntheses. </p> <p> We have explored different synthetic strategies to prepare siloxane boronic acid surfactants, including Grignard reactions and metal-catalyzed hydroboration reactions. Nevertheless, the main approach that was investigated is metal-catalyzed hydrosilylation reactions of vinylphenylboronic acid. Two different approaches were developed to prepare the target compounds: (1) metal-catalyzed hydrosilylation using non-protected vinylphenylboronic acid and (2) metal-catalyzed hydrosilylation using protected vinylphenylboronic acid that can be removed under gentle conditions. The protected compounds underwent hydrosilylation smoothly, but led after separation using column chromatography to the unprotected compounds in moderate yield. The conversion of the hydrosilylation of unprotected boronic acids was quite good, but the compounds underwent decomposition during chromatography. Thus, the two approaches are complementary, depending on whether pure molecules are required for further synthetic elaboration, or a mixture of materials is suitable for practical application as surfactants. </p> <p> The amphiphilic nature of these siloxane boronic acid surfactants was studied and the compounds were found to be surface active. The limited solubility of our compounds in H20 prevented us from studying their surface tension properties. However, their solubility in chloroform enabled us to study their interfacial properties. </p> / Thesis / Master of Science (MSc)

The research presented herein is concerned with the chemical modification of polysulfone towards the synthesis of a hollow fibre boronic acid fixed carrier membrane system for saccharide separation. Chapter 1 firstly introduces the area of boronic acids as chemosensors, in particular for detecting saccharides. Secondly, membrane separation techniques are discussed focussing on hollow fibre membranes and their synthesis. Chapter 2 discusses the potential of boronic acid fixed carrier hollow fibre membranes for saccharide separation. Three general routes are highlighted to achieve the desired boronic acid appended polymers: electrophilic aromatic substitution, lithiation and functional monomer polymerisation. Chapter 3 describes the various attempts at achieving the target polymer via electrophilic aromatic substitution methodology. Chapter 4 describes the various attempts at achieving the target polymer via lithiation methodology. Chapter 5 investigates the ability to create functional monomers with which functional polymers can be polymerised from. Chapter 6 describes the synthesis and characterisation of the compounds discussed in chapters 3, 4 and 5.

La modification d’oligonucléotides est un domaine attrayant de la chimie organique. De nombreuses études se sont intéressées à la génération de liens internucléosidiques artificiels à visée thérapeutique, diagnostic ou encore pour des applications en chimie prébiotique. Ce manuscript de thèse rapporte la synthèse et l’étude de biocompatibilité d’acides nucléiques modifiés à leurs extrémités 5’ par un acide boronique. Les comportement des oligomères boroniques a été évalué en présence de différentes classes d’enzymes telles que les ligases, les polymérases ou encore les phosphodiestérases. Les résultats de biocompatibilité obtenus en présence de ces enzymes nous ont permis d’utiliser ces acides nucléiques modifiés comme de réels outils de diagnostic pour réaliser de la détection de point de mutation ou encore de la détection de péroxynitrite in-cellulo. / The modification of oligonucleotides is an attractive field of organic chemistry. Many studies have focused on the generation of artificial internucleoside linkages for therapeutic, diagnostic or for applications in prebiotic chemistry. This thesis manuscript reports the synthesis and study of nucleic acids biocompatibility modified at their 5 'ends by a boronic acid function. The behavior of boronic oligomers was assessed in the presence of different classes of enzymes, such as ligases, polymerases or phosphodiesterases. The biocompatibility results obtained in the presence of these enzymes allowed us to use these modified nucleic acids as real diagnostic tools to achieve mutation point detection or detection of peroxynitrite in-cellulo.

Trichloroethylene, a simple and very inexpensive material, has been identified as a tri- and tetrafunctionalizable building block. A combination of selective palladium-catalyzed cross-coupling reactions with standard lithiation and electrophilic quenching yields a wide variety of unsaturated linear or cyclic compounds in excellent yields in few synthetic steps. Dichlorovinyl ethers, obtained from a nucleophilic displacement reaction with trichloroethylene, are the basic starting materials. Two sets of conditions have been developed to achieve the reaction of either electron-rich or –deficient phenols with trichloroethylene to give the resultant dichlorovinyl ethers in high yields. Site selective palladium-catalyzed cross-coupling for the specific functionalization of a single C-Cl bond was developed, and could install alkyl, alkenyl, alkynyl and (hetero)aryl moieties. The resulting electrophiles could be reacted with a second organometallic nucleophile forming trisubstituted, electron-rich alkenes, dienes, trienes or enynes in only two or three steps. Alternatively, the product from the first cross-coupling reaction could be isolated, deprotonated and quenched with an electrophile, then cross-coupled with a second organometallic nucleophile to give tetrasubstituted, electron-rich alkenes and dienes. In the course of studying the site selective cross-coupling, it was found that prolonged exposure of the C1-functionalized materials to palladium promoted an intramolecular C-H activation, forming 2-substituted benzofurans. This reaction proved to be very general, and a wide variety of benzofurans were synthesized, containing both electron-withdrawing and electron-donating group groups in the donor arenes, as well as alkyl, alkenyl, alkynyl and aryl functionalities at the 2-position. This method was also extended to the synthesis of 2-substituted indoles from anilines, trichloroethylene and boronic acids.

Trichloroethylene, a simple and very inexpensive material, has been identified as a tri- and tetrafunctionalizable building block. A combination of selective palladium-catalyzed cross-coupling reactions with standard lithiation and electrophilic quenching yields a wide variety of unsaturated linear or cyclic compounds in excellent yields in few synthetic steps. Dichlorovinyl ethers, obtained from a nucleophilic displacement reaction with trichloroethylene, are the basic starting materials. Two sets of conditions have been developed to achieve the reaction of either electron-rich or –deficient phenols with trichloroethylene to give the resultant dichlorovinyl ethers in high yields. Site selective palladium-catalyzed cross-coupling for the specific functionalization of a single C-Cl bond was developed, and could install alkyl, alkenyl, alkynyl and (hetero)aryl moieties. The resulting electrophiles could be reacted with a second organometallic nucleophile forming trisubstituted, electron-rich alkenes, dienes, trienes or enynes in only two or three steps. Alternatively, the product from the first cross-coupling reaction could be isolated, deprotonated and quenched with an electrophile, then cross-coupled with a second organometallic nucleophile to give tetrasubstituted, electron-rich alkenes and dienes. In the course of studying the site selective cross-coupling, it was found that prolonged exposure of the C1-functionalized materials to palladium promoted an intramolecular C-H activation, forming 2-substituted benzofurans. This reaction proved to be very general, and a wide variety of benzofurans were synthesized, containing both electron-withdrawing and electron-donating group groups in the donor arenes, as well as alkyl, alkenyl, alkynyl and aryl functionalities at the 2-position. This method was also extended to the synthesis of 2-substituted indoles from anilines, trichloroethylene and boronic acids.

Molecular recognition at biomembranes is one of the more poorly understood aspects of fundamental research in physical organic chemistry. Our aim was to improve our understanding of the molecular recognition of polysaccharides at biomembranes, in particular developing synthetic lipids that will recognise and report on the presence of glycosaminoglycans (GAG polysaccharides), like heparin and hyaluronic acid. Elevated levels of hyaluronic acid have been implicated in bladder carcinoma and osteoarthritis, and the use of heparin for medical applications is well documented. We synthesised a boronic acid capped lipid that also bore a fluorinated fluorescent reporter group, which could report on multivalent recognition events at bilayer membranes by fluorescent quenching and changes in the lateral distribution of the reporter groups. These preliminary studies showed these boronic acid capped fluorinated lipids gave a fluorescent signal upon interaction with simple mono- and poly- saccharides, albeit with unexpectedly weak binding to these saccharides. To understand and quantify the weaker binding of saccharides to membrane bound boronic acids a series of novel fluorescent and chromogenic lipids were synthesised that bore the reporter group close to the boronic acid. These studies revealed several underlying factors that had important roles in the recognition of oligosaccharides by boronic acid capped lipids. For the first time the effect of the bilayer on saccharide/boronic acid recognition was quantified, with the membrane weakening the interaction 33-fold. We were able to propose a model for the interaction of saccharides for membrane bound boronic acids that explained many of these unexpected observations.We also devised a parallel approach using GAGs to open or close synthetic membrane channels. Using a GAG to switch on the release of an ion or dye would generate a fluorescent signal that amplifies the original recognition event and improves sensitivity for GAGs. Proof-of-principle studies using palladium ions to open dye-transporting channels were successful and these studies were followed by the synthesis of boronic acid-capped cholates. Incorporation of boronic acid-capped cholates into membranes caused changes in the rate of release of alkali metal ions, which caused an enclosed fluorescent dye to give a signal, in the presence or absence of saccharides. These compounds successfully gave a response to the simple saccharide D-fructose but gave no response to other saccharides tested, including various hyaluronic acids. Although we were not able to develop a selective sensor for GAGs, we have developed a model for saccharide/boronic acid interactions that is a valuable addition to the physical organic chemistry of membranes.

The reaction of base-free Chan-Lam coupling was successfully used for functionalization of surface of mesoporous silica gel. Various aromatic, aliphatic, and heterocyclic compounds were immobilized by a copper-catalyzed reaction of corresponding boronic acids with surface amino groups at mild conditions. Obtained functionalized materials were mesoporous although their surface area decreased after immobilization. The reactivity of some surface functional groups was tested in their characteristic reactions.

In the everlasting battle against cancer the development of drugs targeting new therapeutic pathways is of crucial importance. In the attempt to develop new anticancer agents we have synthesized a library of anthraquinone compounds that show selectivity against leukemia. Mechanistic evaluation of the lead compound reveal that this class of compounds achieve their effects through inhibition of MDM2-MDM4 heterodimer and upregulation of the tumor suppressor p53. Computer aided rational design resulted in the development of a number of compounds with activities in the nanomolar range against various cancer cells. Analysis of the physicochemical properties of selected compounds allowed for their evaluation as potential drug candidates. The successful development of non-toxic formulations permits for the further in vivo investigation of the compounds. Click reactions have found wide spread applications in sensing, materials chemistry, bioconjugation, and biolabeling. A number of very useful click reactions have been discovered, which allow for various applications. In bioconjugation applications, the ability to conduct a secondary conjugation will be very useful in, e.g., protein pull down and binding site identification. Along this line, we describe a neighboring group-assisted facile condensation between an aldehyde and a vicinal aminothiol moiety, leading to the formation of benzothiazoles. The conversion is completed within 5 minutes at low micromolar concentrations at ambient temperature. The facile reaction was attributed to the presence of a neighboring boronic acid, which functions as an intramolecular Lewis Acid in catalyzing the reaction. The boronic acid group is compatible with most functional groups in biomolecules and yet can also be used for further functionalization via a large number of well-known coupling reactions.