La grande variété de propriétés biologiques associées au noyau purine en fait une structure privilégiée pour la conception et la synthèse de nouvelles molécules à visée thérapeutique. Cette spécificité est étroitement liée à la grande diversité de substituants pouvant être introduits sur les différentes positions du noyau purine et en particulier sur C2, C6, C8 et N9. Par conséquent, le développement de méthodes de fonctionnalisation rapides de cette famille de composés est d'un grand intérêt synthétique. Nous nous sommes focalisés sur la formation de liaisons C-C et C-N sur les positions 6 et 8 du noyau purine pour pouvoir présenter de nouveaux outils de synthèse permettant d'introduire une plus grande diversité fonctionnelle. D'une part, nous avons étudié la fonctionnalisation directe de liaisons C-H de purines, sujet encore peu exploré. En effet, de nos jours, le traditionnel couplage croisé (Negishi, Suzuki-Miyaura), utilisé pour la création de liaisons C-C, se voit de plus en plus concurrencé par ces réactions puisqu'elles ne nécessitent pas la préparation d'un partenaire organométallique. Ce sont des réactions dites à économie d'atomes. En nous basant sur l'expérience du laboratoire dans le domaine de la fonctionnalisation directe de liaisons C-H, nous avons envisagé l'alcénylation et l'alcynylation directes en position 8 de la purine, les motifs alcényle et alcynyle étant présents dans certaines purines d'intérêt biologique. D'autre part, nous nous sommes intéressés à deux méthodes de couplage croisé pallado-catalysé permettant la formation de liaisons C-N et C-C : le couplage de Buchwald - Hartwig entre une 8-iodopurine et des amides ou des amines aromatiques, et le couplage de Liebeskind - Srogl entre une 6-thioétherpurine et divers acides boroniques.

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

The purpose of this thesis is to set in perspective, as far as is possible, the eschatology of the Early Church. The work required for it has been undertaken in the conviction that this is a significant area of investigation. It is impossible to gain an adequate picture of Early Church life and theology, if any one facet of thought, which was important to the people of the time, is left out of consideration. It is also felt that the writers and thinkers of the early centuries stood so much closer in their thought forms to those writers who set down the words of the Scriptures, and especially of the New Testament, that what they thought is a probable indication as to how the Scriptural writers themselves thought. It also seems to be true that the Church of Jesus Christ today has little to say concerning eschatology, and when it does speak, does so with an uncertain voice. The recovery of an understanding with regard to the assumptions of hope of the Early Fathers must put Christians today in a better position to make their own assessment in the field of eschatology. The study undertaken for this thesis has presented a constant challenge to the faith and understanding of the writer. It was originally intended to take the study through to the Council of Nicaea in 325 A.D. The volume of work made this impossible, but it is believed that the conclusions reached about the development of thought up to c.250 A.D. indicates. the trend of thought up to that watershed in the Ancient Church.

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Chapter 1 is a brief review on some of the recents developments in palladium-catalysed C-H functionalisation chemistry. The synthesis and functionalisation of heterocycles using these methodologies was particularly emphasised. Chapter 2 presents our efforts to identify a new catalytic system to promote the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds for the formation of benzofurans. Dihydrobenzofurans were obtained efficiently under mild conditions in the presence of Pd(OAc)₂, X-Phos and K₂CO₃ in DMA at 80 °C and a subsequent one-pot isomerisation under acidic conditions afforded the desired benzofurans. A new strategy has also provided access to more complex benzofurans by functionalisation of the exocyclic alkene isomer in both a chiral and achiral manner. In Chapter 3, mechanistic studies were performed on the benzofuran formation reaction. The analysis of substituent effects on the aromatic ring is in accordance with an electrophilic aromatic substitution mechanism (SEAr); however, the existence of both intra and intermolecular kinetic isotope effects suggest a SE3 type pathway rather than a pure SEAr. In Chapter 4, the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds was further extended to the synthesis of six-membered heterocycles by direct arylation of alkenyl bromide derivatives in the presence of Pd(OAc)₂, dppf and K₂CO₃ in DMA at 120 °C. The synthetic utility of this methodology was exemplified by the synthesis of substituted isoquinolines in six steps. Moreover, we have applied our methodology to the direct arylation of sulfonamides, leading to an interesting synthesis of widely used sultams. Both these new routes are currently being investigated and should provide access to a variety of differently substituted cyclic sulfonamides and isoquinolines. Finally, Chapter 5 presents a new strategy for the synthesis of benzo[b]furan was briefly investigated. It consists in consecutive Tsuji-Trost and C-H functionalisation reactions. This methodology requires simpler and more versatile substrates, allowing access to various heteroaromatics in a single step. We successfully proved the viability of this reaction through the synthesis of a range of benzofurans in modest yields. To our knowledge, this is the first example of a single palladium catalyst performing these different reactions in tandem in a simple procedure.

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The ever increasing demand for more efficient and environmentally benign routes for synthesizing target compounds, has led to the use of organometallic catalysts. This demand has created the need to understand the mechanistic details that are at work in these organometallic catalytic cycles. Along with this, there is a demand for new organometallic catalysts that are tailored for specific transformations. This presents a myriad of challenges for organometallic chemists. Unfortunately, it is often difficult to gain an understanding of the reaction mechanisms at work when the intermediates are too short lived to be observed in the condensed phase. It is also very time consuming to synthesize, purify, and characterize organometallic catalysts following standard condensed phase methods. Therefore, it would be beneficial to probe organometallic reactions in a way that the inherent reactivity of the organometallic complex can be uncovered and where purity is not a prerequisite. Using an ion-trap mass spectrometer that has been modified to allow introduction of neutral reagents to the buffer gas, organometallic ion-molecule reactions can be probed in an environment free from solvation effects. This enables the study of the inherent reactivity of the complexes and also provides insight into reaction mechanisms by allowing reactive intermediates to be probed. In addition, organometallic complexes probed in this manner do not need to be pure due to ability of the ion trap to function as a mass filter. This results in a quick and efficient method. This dissertation presents results found during the investigation of the reactions and mechanistic details of gold, silver, and iridium complexes using a modified ion-trap mass spectrometer.

C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC50 of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC50 = 0.17 μM) and 4-Cl HIPP (CtBP IC50 = 0.18 μM). These compounds also showed inhibition in HCT-116 colon cancer cells with GI50 values ~ 1-4 mM. The compounds showed no off-target toxicity against a closely related protein. This is a starting point for the development of CtBP inhibitors as anti-cancer therapeutics. The second part of this dissertation focuses on C–H activation chemistry. C–H activation is the most atom-economical method of introducing complexity into a molecule, even at late stages of drug/product development. We have used solid-supported palladium nanoparticle catalyst (Pd-MWCNT) to investigate the scope of C–H activation reactions it can catalyse. Pd-MWCNT was found to efficiently catalyse N-chelation directed C-H activation reactions – halogenations, oxygenations and arylations. The turn-over numbers for these reactions were significantly higher than that of the reported homogenous catalyst. The added advantages of reuse/recyclability of catalyst, low contamination of metal in the final product make this catalyst very attractive on an industrial scale. This work serves as a foundation for the further development of Pd-MWCNT catalyst in late-stage synthesis of drugs and/or diversification of products.

ABSTRACT “WHEN THE WIND BLOWS COLD”: THE SPIRITUALITY OF SUFFERING AND DEPRESSION IN THE LIFE AND MINISTRY OF CHARLES SPURGEON William Brian Albert, Ph.D. The Southern Baptist Theological Seminary, 2015 Chair: Dr. Donald S. Whitney This dissertation examines the spirituality of suffering and depression in the life and ministry of Charles Spurgeon. Chapter one frames the dissertation by presenting general facts concerning Spurgeon’s depression and the relationship that his depression has to his spirituality. Chapter 2 emphasizes particular facts and features of Spurgeon’s life and ministry that demonstrate his depression. This section places Spurgeon within the historical context of the nineteenth century, and especially within significant movements and events that established the setting for his depression. Chapter 3 features specific aspects of Spurgeon’s personality that influenced his depression and further document that he was in fact a depressed man. This section highlights certain dangers based on Spurgeon’s proclivity toward despondency. Chapter 4 highlights specific causes in Spurgeon’s depression. Specific focus is on physical, mental, circumstantial, ministerial, and other elements that contributed to his depression. A section on Spurgeon’s theological tension within this depression is also discussed. Chapter 5 discusses Spurgeon’s theology as it relates to his suffering and depression. For Spurgeon, a Trinitarian and Calvinistic doctrine was paramount in dealing with depression. These teachings would frame his understanding of man and human conduct both in life of the believer and unbeliever. The chapter also demonstrates Spurgeon’s understanding of church history within the context of a suffering faith. Chapter 6 examines the cures for Spurgeon’s physical and mental depression. Spurgeon had no aversion to medicine and doctors in assisting his physical maladies and depression. Diet, rest, exercise, the weather and the sea were all factors that aided in temporary recovery of Spurgeon when depressed. Chapter 7 explores the range of spiritual disciplines that Spurgeon practiced himself and which he encouraged other Christians to perform to maintain a vital experience of communion with God during times of depression. Spurgeon believed that means such as meditation of Scripture, prayer, service and the sacraments were essential practices for maintaining genuine Christian piety. Chapter 8 summarizes answers given to the research question and related questions. This section also provides concluding reflections and recommended further research on this topic.