Thesis advisor: Marc M. Snapper / Thesis advisor: James J. Morken / This dissertation will present three main projects focusing on the catalytic enantioselective synthesis and stereospecific functionalization of tertiary alkylboronates. In the first project, acyl chlorides were incorporated as a new class of electrophile in conjunctive cross-coupling, from which, a variety of tertiary β-boryl amides were successfully synthesized with high enantioselectivity. The utility of the tertiary alkylboronates products was also demonstrated through several orthogonal functionalizations of the boronic ester group and amide groups. The project culminated in the enantioselective total synthesis of natural product (+)-adalinine that leveraged this newly developed methodology. In the second project, a conjunctive cross-coupling enabled ring closure was developed to synthesize tertiary alkylboronates residing on carbocyclic and heterocyclic scaffolds. A Phosphinooxazoline (Phox) ligand was identified as a non-expensive ligand that catalyzed the conjunctive cyclization reaction with high enantioselectivity. A Series of synthetically challenging enantimerically enriched spirocyclic and aryl bicyclic tertiary alkylboronates were efficiently generated using this method, and several cyclopentyl boronic esters with two continuous stereogenic centers were synthesized with high diastereoselectivity. In the third project, a Rh-catalyzed diboration reaction was successfully employed to diborate monosubstituted cyclobutenes with excellent enantioselectivity. The less sterically hindered secondary boronic ester units in the diboron products can be regioselectively functionalized using the newly developed tert-butyllithium activation-transmetallation strategy. As a result, a variety of stereochemically defined β-substituted cyclobutyl tertiary boronic esters were synthesized with high efficiency. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Microgrid (MG) concept has been emerged to enable integration of renewable energy sources and storage devices using power electronic converters. An MG can be grid connected to exchange power with the main grid, isolated that is completely separated from the grid, or islanded that is temporarily separated from the grid. The P and Q-V drooping approach is commonly used to control and achieve power sharing among the generators.\\ This study presents an approach for systematically modeling a class of microgrid (MG) systems. The derived model 1) accommodates grid-connected and islanded operation of the MG simultaneously, and 2) allows modeling of converter-based as well as directly-interfaced resources. The originally nonlinear model is then converted to a linear model whose eigenvalues determine local stability of the MG. \\The model is used to analyze the impacts of adding cross-coupling droop terms (P-V and Q) on an MG's performance. Various performance aspects such as stability, stability robustness, transmission power loss, voltage profile, and power sharing are considered. The conclusions are as follows. (1) Addition of a small portion of cross-coupling will reduce the losses without compromising other aspects in a grid-connected MG. Larger cross-coupling terms will compromise the system stability. (2) Large cross-coupling terms can be added to reduce the power loss and to improve the system stability in an isolated MG. Simulation and experimental results are presented to verify the derivations.

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<p>The development of parallel syntheses that allow for rapid access to compound libraries is widely sought after in drug development and in the study of biological systems. These compound collections can be screened for biological activity and thereby provide useful structure-activity relationships (SAR) to help better understand the biological systems under investigation. This present thesis uses a small molecule library/SAR approach to probe a variety of biological problems such as: inhibiting the proliferation of breast cancer stem cells; inhibiting glutamine fructose-6-phosphate amidotransferase (GFAT, a key enzyme involved in Type II diabetes); and inhibiting aminoglycoside phosphotransferases (APHs, enzymes prevalent in antibiotic resistance). Specifically, synthetic protocols for the parallel preparation of libraries of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-(1H,6H)-diones, 1-alkyl-3-aryl-<em>1</em>H-pyrazolo[3,4-d]pyrimidin-4-amines, 6-amino-1-alkyl-3-aryl-1<em>H</em>-pyrazolo[3,4-<em>d</em>]pyrimidin-4(5<em>H</em>)-ones, substituted 3-(4-chlorophenyl)-1-(-1<em>H</em>-1,2,3-triazol-4-yl)-1<em>H</em>-pyrazolo[3,4-<em>d</em>]pyrimidin-4-amines and substituted isoquinolines are described. In all cases, a robust synthetic approach was developed allowing for the generation of a library of heterocycles based on hit compounds from high throughput screening. The SARs gained from the assaying of the libraries generated are shown to help in the furthering of the biological understanding of each system.</p> / Doctor of Philosophy (PhD)

The essential questions of the dissertation research described here address concepts in homogeneous catalysis and organometallic chemistry, with a focus on method development for catalytic reaction applications in organic synthesis. The unifying theme throughout the research is the development of rational design principles for cooperative catalysis through both mechanistic and empirical study. Cooperative catalysis – in which multiple catalysts enable increased activity or selectivity versus a single catalyst system – can involve some combination of a transition metal, Lewis acid, and Brønsted acid. Chapter 1 reviews the literature regarding the cooperativity of transition metal and Lewis acid catalysis, and discusses four main areas in organic synthesis and the facilitation of these trnasformations by Lewis acids: (a) C-C bond and C-H activation, (b) hydrogenolysis of carboxylic acid derivates and ethers, (c) Au catalyzed alkyne activation and cyclization reactions, and related reactions, and (d) Pd catalyzed C-C and C-N bond forming reactions. These different topics are selected based on the mechanistic insight provided into the nature of transition metal-Lewis acid cooperativity. Chapter 2 describes the observation of Lewis acid acceleration of a Pd catalyzed C-N bond coupling. The synthetic methodology is elaborated using metal triflates as cocatalysts, and Lewis acid acceleration is observed for a variety of different N-nucleophiles. Qualitative mechanistic study implicates the role of halide anions in inhibiting this catalytic reaction, and it is proposed that metal triflates are competent to accelerate catalysis by binding halide anions, and therefore attenuating halide inhibition. This hypothesis is supported by initial rate measurements and 31P NMR experiments. Rationalizing trends observed in the reactivity of Lewis acids in the cooperative reactions described in Chapters 1 and 2 is challenging. Therefore, our goal was to provide further insight into the behavior or Lewis acids in complex reaction settings. Inspired by 31P NMR experiments from Chapter 2, a next generation NMR probe to observe anion exchange reactions of metal triflate Lewis acids is developed. Metal-ligand titrations are performed for a variety of metal triflates with complexes of the type (POCOP)Pd(X) (X = Cl, Br, I, OAc) to observe a variety of different X anion affinities for metal triflates. The determined parameters are discussed within the context of Lewis acid catalyzed reactions, along with other Lewis acidity parameters, such as hydrolysis constants and effective charge density. The data suggest that the chloride and iodide anion affinities of a Lewis acid represent a continuum of π-acidity (high anion affinity) and propensity to dissociate into cationic Mz+ species (low anion affinity). The anion affinities do not correlate with the tendency of a metal salt to release Brønsted acids or their respective effective charge densities. Based on the insight into Lewis acidity from Chapters 1 and 3, the parallel between Brønsted and Lewis acids is realized, and the role of both Brønsted and Lewis acids in mediating organic reactions is often related. In Chapter 4, further questions into the cooperativity of π-acids and Brønsted acids is explored. It is demonstrated that selectivity of alkene isomerization can be controlled through a cooperative system. A series of Mo(0) complexes are prepared and explored in their ability to mediate the conversion of terminal alkenes to internal alkenes, and the reaction is found to be promoted by Brønsted acid (TsOH) cocatalyst. Rational design principles are developed to maximize selectivity for (Z)-2-alkenes in this catalyst system. It is proposed that TsOH acts to generate a catalytic MoH species which mediates catalysis, and the role of phosphine ligands is critical in inhibiting the formation of less selective isomerization catalysts. Chapter 5 and 6 entail further method development for catalytic reactions based on the mechanistic wisdom described in previous chapters. High throughput experimentation is employed to rapidly assess conceptual aspects of Pd catalysis, such as ligand and additive effects, and facilitate catalyst discovery and optimization. Based on the substrate scope performed in Chapter 2, it was realized there is a knowledge gap in the ability to synthesize tertiary sulfonamides, both in terms of conventional methods, or modern Pd-catalyzed methods. A significant advance in organic reaction methodology is described: a new Pd catalyst featuring the AdBippyPhos ligand is discovered to be apt for the coupling of secondary sulfonamides with heteroaryl halides to yield tertiary N-heteroarylhalides. Using high throughput experimentation, 24 diverse heterocycles are screened with 12 sulfonamide variants to prepare &gt;100 new products on microscale. Computational modelling reveals the unique steric parameters of the AdBippyPhos ligand, and a mechanistic rationale for its success in catalysis is provided. Lastly, Chapter 6 describes the use of a LiOTf additive to control the selectivity of Pd-catalyzed C-C bond forming reactions. In the presence of LiOTf, a Mizoroki-Heck type reaction, the alkenylation of an aryl halide with a vinyl ether, proceeds with regioselectivity. In the absence of LiOTf, a solvent (CH3CN) activation pathway proceeds to give benzyl nitrile products. High throughput microscale reactions discovered that the Pd/xantphos catalyst is uniquely selective to provide branched styrenes when using the Cs2CO3/CH3CN base/solvent combination. However, reaction performance differed on large scale reactions, where LiOTf was necessary to observe the Mizoroki-Heck reaction pathway. Mechanistic study, in the form of kinetic experiments and 31P NMR experiments, focused on the role of LiOTf in affecting chemoselectivity. It is proposed that xantphos oxidation is responsible for mediating the Mizoroki-Heck reaction pathway, whereas in the absence of xantphos oxidation, CH3CN α-arylation ensues. Due to the insoluble nature of the catalyst materials, xantphos oxidation is ordinarily slow under anaerobic conditions due to mass transfer limitation. LiOTf generates a soluble [(xantphos)Pd(NCCH3)2][OTf]2 and potentially mediates the formation of xantphos-monoxide catalyst which is competent for alkenylation. / Chemistry

Les lymphomes à grandes cellules anaplasiques ou ALCL (Anaplastic Large-Cell Lymphoma) sont des cancers appartenant à la famille des lymphomes de type non-Hodgkin. La majorité des ALCL est issue d'une translocation t(2;5)(p23;q35) donnant lieu à la formation d'une protéine de fusion appelée NPM-ALK. A ce jour, peu d'inhibiteurs présentent de bonnes activités contre cette protéine chimérique. L'obésité représente un problème socio-médical d'envergure, à la fois pour ses effets directs et indirects ; le surpoids étant un facteur primaire dans de nombreuses maladies, tout particulièrement les diabètes, les accidents cardiovasculaires, le cancer, etc. A contrario, une restriction calorique (RC) est associée à des bénéfices importants en terme de santé. A l'issue de plusieurs criblages, un inhibiteur au motif 2-acylaminothiazole a montré une activité anticancéreuse sur ALK mais également la faculté de mimer la restriction calorique chez C. Elegans. Par conséquent, les travaux de recherche réalisés lors de cette thèse ont concerné la synthèse d'inhibiteurs comportant le squelette 2-acylaminothiazole. Les chromatographies d'affinité effectuées sur deux de nos inhibiteurs ont permis l'identification de cibles principales potentielles dans le cadre de la restriction calorique et des cibles secondaires possibles pour NPM-ALK. Ensuite, la présence d'un atome de brome sur le cycle aromatique a mené à la formation de liaisons C(sp2)-C(sp2), C(sp2)-C(sp) et C(sp2)- N, en utilisant les couplages catalysés par le palladium. Les différentes méthodes de modulation chimique ont conduit à mettre en place une librairie de 134 molécules. Certains d'entres eux et plus précisément ceux possédant un atome de silicium ont démontré une très bonne activité contre ALK et son mutant L1196M. Enfin, des résultats préliminaires ont également été obtenus sur le sujet de la restriction calorique avec quatre composés montrant une réduction du taux de lipides chez C. Elegans / Anaplastic Large-Cell Lymphoma (ALCL) is a type of cancer belonging to the non-Hodgkin family. The majority of ALCL arises from a translocation t(2;5) (p23;35) which leads to the formation of a fusion protein called NPM-ALK. Nowadays, few molecules are known to inhibit the activity of this chimeric protein. Obesity is a major socio-medical problem, for both direct and indirect effects, overweight is a primary factor in many diseases, especially diabetes, cardiovascular events, cancer, etc... In contrast, caloric restriction (CR) is associated with significant benefits in terms of health. After several screenings, one inhibitor based on a 2-acylaminothiazol scaffold showed anticancer activity on the protein ALK but also the ability to mimic caloric restriction in C. Elegans. The aim of this PhD was to develop the synthesis of new inhibitors including the 2-acylaminothiazol scaffold. The affinity chromatography performed on two of our inhibitors was used to identify potential major cellular targets in the process of caloric restriction and secondary cellular targets for NPM-ALK. Then, the presence of a bromo group on the aromatic ring allowed the formation of C(sp2)-C(sp2), C(sp2)- C(sp) and C(sp2)-N bonds, using palladium-catalyzed couplings. The different chemical methodologies afforded the synthesis of a library of 134 molecules. Some of them especially with a silicon atom demonstrated very good inhibitory activity and high selectivity against NPM-ALK and L1196M-NPM-ALK. Finally, preliminary results were also obtained on the subject of calorie restriction with four compounds showing a reduction of lipids in C. Elegans

Les molécules aromatiques se retrouvent dans de nombreux produits de la chimie fine ou de spécialité. Aujourd'hui toutes sont obtenues par voie pétrochimique ; il est donc nécessaire de trouver des ressources alternatives renouvelables. Dans le cadre de cette thèse, nous nous sommes intéressés à des méthodologies applicables en chimie fine et mettant en oeuvre la transformation de molécules aromatiques issues de la biomasse soit pour obtenir des synthons équivalents à ceux de la filière pétrochimique, soit pour synthétiser des composés de chimie fine sans recourir à des fonctionnalisation intermédiaires. Ainsi, une nouvelle voie d'obtention de styrènes fonctionnels à partir d'acides cinnamiques par décarboxylation cuprocatalysée dans le PEG a été mise au point. Cette stratégie a été étendue à la préparation de composés aromatiques et hétéroaromatiques à partir des acides correspondants, et aux amines à partir d'aminoacides biosourcés. Un second axe a concerné le développement d'un système catalytique [Pd/Cu] homogène, et en partie hétérogène, pour la synthèse de biaryles par couplage décarboxylant de deux acides benzoïques. Appliqué aux acides 2-Nitrobenzoïque et 2,6- diméthoxybenzoïque, le système permet l'obtention du biaryle visé avec un rendement de 70%. Des études supplémentaires sont nécessaires pour lever les verrous technologiques limitant l'utilisation en termes de substrats. Le dernier axe traite de la synthèse de stilbènes par couplage d'un acide cinnamique et d'un halogénure d'aryle. L'étude a permis la mise au point d'une palladocatalyse très efficace qui permet d'obtenir la molécule cible avec un rendement allant jusqu'à 78%. La méthodologie a été transposée en catalyse hétérogène par l'utilisation de PdO/SiO2 et Pd/C ; le PdO/SiO2 s'est avéré stable sur au moins 4 cycles. Comme pour la synthèse de biaryles, le système nécessite d'autres développements pour étendre son champ d'action aux dérivés d'acides cinnamiques peu réactifs / Aromatic molecules are present in a large field of products in fine chemistry. Nowadays, all are obtained by petrochemical way ; Thus, it’s necessary to find alternative renewable resources. As part of this thesis, we are interested in the fine chemical methodologies and implementing the transformation of aromatic molecules from biomass either to obtain building blocks equivalent to those from the petrochemical industry, or to synthesize fine chemicals compounds without the necessity of intermediate functionalization. Thus, a new way to obtain functionalized styrenes from cinnamic acids by decarboxylation copper catalyzed into PEG was developed. This strategy has been extended to the preparation of aromatic and heteroaromatic compounds from the corresponding acids and amines from biosourced amino acids. A second axis concerned the development of a homogeneous catalytic system [Pd/Cu], and partly heterogeneous, for the synthesis of biaryls by decarboxylating coupling of two benzoic acids. Applied to 2-Nitrobenzoic acid and 2,6 dimethoxy acid, the system allows the production of biaryl covered with a yield of 70%. Further studies turn out to be necessary to remove technological barriers in terms of limited substrates. The last axis deals with the synthesis of carbons by coupling a cinnamic acid and an aryl halide. The study development allowed a very efficient palladocatalyse that achieves the target molecule with a yield up to 78%. The methodology has been implemented in heterogeneous catalysis using PdO/SiO2 and Pd/C; PdO / SiO2 was stable for at least 4 turnover. As for the synthesis of biaryls, the system requires further development to expand its scope to derivatives cinnamic acids less reactive

This thesis describes the development of robust methodology to access cyclic alkenylsiloxanes, and their subsequent application in Hiyama-Denmark cross couplings. An early chapter shows the identification of Lindlar reduction conditions capable of generating cyclic alkenylsiloxanes from alkynylsiloxanes in high yields. The use of such species in Hiyama-Denmark cross coupling is then examined, with particular emphasis on the development of fluoride-free conditions, previously unreported for this class of organosilane. A ring-size dependent orthogonality is revealed, where 5-membered cyclic alkenylsiloxanes cross couple under basic conditions, while 6-membered analogues are inert. The origins of this effect are investigated experimentally and theoretically, leading to the proposal of detailed mechanisms for coupling. In the final chapter, the methodology that has been developed is applied to total synthesis. The great potential of the orthogonality uncovered is demonstrated with the highly convergent construction of anti-inflammatory natural product resolvin D3 by sequential, one-pot, orthogonal cross couplings.

The diploma thesis presents the preparation of ,-bisterpyridinylfluorenes (unimers) containing fluorene unit in the central block either directly attached to terpyridine (tpy) end groups or via 1,4-phenylene or thiophene-2,5-diyl linker. Synthesized unimers were subsequently used for the preparation of metallo-supramolecular polymers with Zn2+ and Fe2+ ions. The prepared unimers were characterized by NMR, IR and HR-MS, their optical properties were investigated using absorption and emission spectroscopy and cyclic voltammetry. Molecular weight distribution for the prepared Fe-polymers was determined by GPC. The number-average degree of polymerization equal to 7 for an equimolar ratio between unimer and Fe2+ in a diluted solution was determined for polymers composed of unimer with thiophene-2,5- diyl linker. By using the viscometric measurements the ongoing constitutional dynamics in solutions of metallo-supramolecular polymers was proven. The overstoichiometric amount of metal ions in solution resulted in equilibrium shortening of the polymer chains together with end-capping of terminal tpy ligands by Mt2+ ions. Unimer with thiophene-2,5-diyl linker exhibited unique properties involving significantly red-shifted absorption and emission maxima, as well as the different behavior during assembling...

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