In this manuscript, the application of different nanocatalysts derived from metal oxides impregnated on the surface of the magnetite in different reaction of general interest in Organic Chemistry is described. In the First Chapter, a cobalt derived catalyst was used to study the hydroacylation reaction of azodicarboxylates with aldehydes. In the Second Chapter, a catalyst derived from copper was used to perform different reactions, including homocoupling of terminal alkynes and the subsequent hydration reaction to obtain the corresponding 2,5-disubstituted benzofurans, the reaction of alcohols and amines (or nitroarenes) to obtain the corresponding aromatic imines, the cross-dehydrogenative coupling reaction of N-substituted tetrahydroisoquinolines using deep eutectic solvents and air as final oxidant. Finally, the formation of benzofurans from aldehydes and alkynes through a tandem coupling-allenylation-cyclization process has been performed. In the Third Chapter, a bimetallic catalyst derived from nickel and copper was used to study the multicomponent reaction between benzyl bromides, sodium azide and alkynes to obtain the corresponding triazoles. In the Fourth Chapter, a catalyst derived from palladium was used in the direct arylation of heterocycles using iodonium salts. Also the synthesis of 4-aryl coumarins through the Heck arylation reaction and subsequent cyclization using the same catalyst is described. In the last Chapter, the use of different eutectic mixtures were studied as alternative media to perform in a single vessel the cyclation reaction of N-hydroxy imidoyl chlorides and alkynes, without any type of catalyst under oxidizing conditions.

Thesis advisor: Shih-Yuan Liu / This dissertation describes progress in the field of polycyclic boron- nitrogen-containing systems, especially for potential application in organic-based optoelectronic devices and hydrogen storage materials. The replacement of a BN unit for a CC unit organic compounds (BN/CC isosterism) can have a profound effect on the electronic structure and even function of a given molecular topology without changing its physical structure very much. Direct comparison between a BN-containing molecule and its direct all-carbon analogue is crucial to establishing the origin of these differences. The synthesis and optoelectronic characterization of boron- nitrogen-containing analogues of naphthalene, anthracene, and tetracene are disclosed. Also examined herein is the aromatic Claisen rearrangement applied to an azaboryl allyl ether. Finally, the chemistry of saturated BN heterocycles, including an iridium-catalyzed transfer dehydrogenation method for synthesizing BN-fused azaborines. Also disclosed is the actual application of these cyclic amine-boranes in supplying hydrogen for a proton exchange membrane (PEM) fuel cell. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Chemistry is on the verge of a new era where the attention of chemists has shifted from covalent bonds to noncovalent interactions and their use as a predictable way to guide reactions pathways and product formation. Nature synthesizes elegant molecules under mild conditions and the designed syntheses have been demonstrated to be largely dependent on recognition, self-assembly and templating effects between molecular building blocks. Although covalent synthesis in fluidic medium via supramolecular control has been achieved with limited success, organic solid state has been of particular interest since it avoids solvent effects, and is able to provide unique materials with remarkable stereoselectivity under environment-friendly conditions. Although reactions in solids have resulted in a number of remarkable discoveries in chemistry and materials science, solid-state synthesis is generally not considered as a mainstream synthetic medium and solid-state reactions are seldom appreciated as an efficient way to access molecular targets. Owing to the limited number of solid-state reactions and the uncontrollable nature of crystal packing, solid state has not been utilized readily as a primary synthetic medium. In this context, reactions conducted in multicomponent molecular assemblies or co-crystals have been attracting much attraction in recent years as a general way of controlling the reactivity of molecules in solid state. A molecular component in the multicomponent molecular solid, acting as a linear template, has been shown to preorganize molecules in a modular way via intermolecular interactions and engineer their physical and/or chemical properties. The [2+2]photodimerization of olefins is a successful demonstration how templated solid state synthesis can efficiently synthesize complex targets that are synthetically challenging via conventional routes. In this dissertation, the generality and synthetic applicability of the templated synthetic approach in solid state will be described. How supramolecular interactions in molecular co-crystals precisely guide covalent bond formation in order to construct complex molecular targets will be demonstrated. Finally, co-crystallization will be shown as a general way to control optical properties in crystals.

Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Total Synthesis of Sesquiterpenes Seychellene, Trachyopsanes and Bisepoxysecocalamenenes” describes the studies directed towards the total synthesis of the sesquiterpenes mentioned in the title. For convenience, the results are presented in three chapters; viz (1) First Enantiospecific Total Synthesis of Seychellene; (2) Enantiospecific First Total Synthesis of Trachyopsanes; and (3) Total Synthesis of Bisepoxysecocalamenenes. In each chapter of the thesis, the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. The tricyclic sesquiterpene (−)-seychellene, containing an interesting tricyclo[5.3.1.03,8]undecane carbon framework, was isolated in 1967 by the research group of Hirose from the leaves of Pogostemon cablin Benth. An enantiospecific total synthesis of seychellene has been described in the first chapter of the thesis. To begin with, (R)-carvone has been transformed into 10-(1-methylethylidene)-3,8-dimethyl-tricyclo[5.3.1.03,8]undecan-2-one employing a tandem intermolecular Michael addition followed by intramolecular Michael addition reaction and intramolecular alkylation reactions. Degradation of the isopropylidene group followed by methylenation transformed 10-(1-methylethylidene)-3,8-dimethyltricyclo[5.3.1.03,8]-undecan-2-one into norseychellene. This methodology has been extended to the first enantioselective total synthesis of (+)-seychellene and (−)-seychellene via (S)-3-methylcarvone and (R)-3-methylcarvone, respectively. The marine sesquiterpene 2-isocyanotrachyopsane was isolated in 1996 by Fusetani and co-workers from the nudibranch Phyllidia varicosa. 2Isocyanotrachyopsane shows potent antifouling activity. During a search for DNA damaging agents, in 1997, Patil and co-workers reported the bioassay guided isolation of two new sesquiterpenes 2-formylaminotrachyopsane and N-phenethyl-N'-2-trachyopsanylurea from a sponge collected in Palau, Axinyssa aplysinoides Dendy 1922. In the second chapter of the thesis enantioselective first total synthesis of 2formylaminotrachyopsane and 2-isocyanotrachyopsane, establishing the absolute configuration of the natural products, has been described. To begin with, (R)-carvone has been transformed into a neopupukeandione employing a tandem double Michael reaction and intramolecular rhodium carbenoid CH insertion reactions. Neopupukea-nan-4-ol was transformed into 2-formylaminotrachyopsane by an acid catalyzed biomimetic rearrangement followed by Ritter reaction. Dehydration of formamide group in 2-formylaminotrachyopsane led to 2-isocyanotrachyopsane. In 1998, the research group of Weyerstahl reported the isolation of two new sesquiterpenes 1,10;7,10-bisepoxy-1,10-seco-calamenene and 6,7;7,10-bisepoxy-6,7-seco-calamenene from the essential oil Hedychium gardnerianum Roscoe. Presence of an interesting benzofused dioxabicyclo[3.2.1]octane framework coupled with the fact that the structures of the natural products were assigned on the basis of the spectral data of a mixture of two compounds prompted us to investigate the total synthesis to confirm their structures. The third chapter of the thesis describes the first total synthesis of these two compounds using an intramolecular ketalisation reaction. p-Cresol was converted into 2-(methoxymethoxy)-5-methylisobutyrophenone, which was further transformed in three steps into 1,10;7,10-bisepoxy-1,10-seco-calame-nene. Catalytic hydrogenation of 1,10;7,10-bisepoxy-1,10-seco-calamenene led to litseachromolaevane A, a new sesquiterpene isolated from an anti-HIV fraction of the leaves and twigs of Litsea verticillata Hance by Fong and co-workers in 2003. For the synthesis of 6,7;7,10-bisepoxy-6,7-seco-calamenene, m-cresol was converted into the 6-(methoxymethoxy)-6-[2-(methoxymethoxy)-4-methylphenyl]-2-methylheptan-3-one, which was transformed into 6,7;7,10-bisepoxy-6,7-seco-calamenene by an intramolecular ketalisation reaction.

The synthesis of glycoconjugates is of interest in biological and medicinal research. There are numerous approaches to the synthesis of glycosides involving protecting group free methods. This thesis outlines what has been achieved in the field and two novel approaches for O-glycosidation. The first approach involves the use of a toluenesulfonohydrazide glycoside with a purification handle designed for simple glycoside purifications. The butyl 3-O-octyl-D-glucopryanoside was successfully synthesized but did not have the desired property of yielding simple-to-purify glycosides as products. The second approach uses a thiouronium glycosyl donor; a variety of glycosidations using this donor were investigated. The glucosyl thiouronium salt donor was shown to undergo glycosidation effectively with simple alcohols.

The synthesis of glycoconjugates is of interest in biological and medicinal research. There are numerous approaches to the synthesis of glycosides involving protecting group free methods. This thesis outlines what has been achieved in the field and two novel approaches for O-glycosidation. The first approach involves the use of a toluenesulfonohydrazide glycoside with a purification handle designed for simple glycoside purifications. The butyl 3-O-octyl-D-glucopryanoside was successfully synthesized but did not have the desired property of yielding simple-to-purify glycosides as products. The second approach uses a thiouronium glycosyl donor; a variety of glycosidations using this donor were investigated. The glucosyl thiouronium salt donor was shown to undergo glycosidation effectively with simple alcohols.

S’han sintetitzat quatre alquil i aril (9 anthry1) carbinol (metil, fenil isopropil, terc-butil, i) que van revelar la rotació restringida al voltant de l'enllaç C9-C11. La seva energia lliure d'activació per a la rotació s'ha determinat, sent 11.0, 14.0, 21.7, i 9.8 kcal / mol, respectivament. Es descriuen l’aplicació mètodes de mesura del NOE i del temps de relaxació per a la determinació de l'energia d'activació per a la rotació de bons. El bon acord amb els valors obtinguts amb el mètode de la temperatura de coalescència confirma que l'enfocament basat NOE és una bona alternativa per a la determinació de les elevades barreres de rotació. Els càlculs de Mecànica Molecular (MM2) donen valors propers als experimentals. S’han preparat els carbamats homoquirals del 9-anthryl-terc-butylcarbinol i s’ha estudiat el seu equilibri conformacional. La configuració absoluta es va determinar mitjançant la comparació de les dades de RMN amb càlculs de MM. Els enantiòmers de l'alcohol es van obtenir després de la separació cromatogràfica dels derivats de carbamat i la seva hidròlisi. Els alcohols homoquirals van ser preparats per columna de cromatografia quiral directa. S’han detectat i o separat a temperatura ambient els confòrmers cisoid i transoid del 9,10 dipivaloylantracè i del 9,10-bis(1-imino-2,2-dimetilpropil)antracè. La transformació entre dues atropisómers va ser estudiada per RMN i modelat pels mètodes de MM. La difracció de raigs X es va realitzar per als derivats imino. El 9-antril-terc-butilcarbinol es va provar com a agent de solvatació quiral (CSA) en presència de formes racèmica de p-toluenesulfinate de mentil, 9-(1-amino-2,2- dimetilpropil)-9,19-dihydroantracè, àcid R-methoxyfenylacetic i 1-phenyl-1,2- ethanediol. Es formaren els complexes diastereòmers entre el reactiu quiral i cada enantiòmer d'aquests últims compostos. Un dels enantiòmers de 9-antril-tertbutylcarbinol va ser estudiat mitjançant NOE intermolecular i càlculs de dinàmica molecular. Es trobaren les principals diferencies termodinàmiques i estructurals. / Se han preparado Cuatro alquil- y aril- (9-antril)carbinols (metil, isopropil, tert-butil, y fenil) y mostraron la rotación restringida del enlace de C9-Cll. Su energía libre de activación para la rotación ha sido determinada, siendo 11.0, 14.0, 21.7, y 9.8 kcal/mol, respectivamente. Hemos determinado la energía de activación para la rotación de enlace C9-C11 por la aplicación de medidas de NOE y de tiempo de relajación. El buen acuerdo con los valores obtenidos con el método de temperatura coalescencia confirma que el método basado en el NOE es una buena alternativa para la determinación de barreras de rotatorión altas. La Mecánica Molecular (MM2) da valores cercanos a los experimentales. Se ha preparado el carbamato homochiral de 9-antril-tert-butilcarbinol y se ha estudiado su equilibrio conformacional. La configuración absoluta fue determinada por la comparación de los datos NMR con cálculos de MM. Los enantiomers del alcohol fueron obtenidos después de la separación cromatográfica de los carbamatos y tres su hidrólisis. Los mismos alcoholes se obtuvieron a través de una columna HPLC quiral Se han detectado o separado, a temperatura ambiente, los confórmeros cisoide y transoide del 9,10 dipivaloylantraceno y del 9,10-bis(1-imino-2,2- dimetilpropil)antraceno. La transformación entre los dos atropoisómeros se estudió por RMN i se modeló por métodes de MM. La difracción de rayos X se realitzó con los derivados imino. Se ha probado el 9-anthryl-tert-butylcarbinol como agente solvatación chiral (CSA) en presencia de las formas de racemicas de p-toluenesulfinato de mentilo, 9-(1-amino-2,2- dimetilpropil) - 9,19-dihydroanthracene, ácido de R-methoxyphenylacetic y 1-phenyl- 1,2-ethanediol. Se formaron los complejos diastereoisómericos el reactivo quiral y cada enantiomer de estos últimos compuestos. Uno de los enantiomers de 9-anthryltertbutylcarbinol fue estudiado por medio de NOE intermolecular y cálculos de dinámica moleculares. Las diferencias termodinámicas y estructurales principales fueron encontradas. / Four alkyl- and aryl-(9-anthry1)carbinols (methyl, isopropyl, tert-butyl, and phenyl) were synthesized and revealed restricted rotation about the C9-Cll bond. Their free energy of activation for rotation has been determined, being 11.0, 14.0, 21.7, and 9.8 kcal/mol, respectively. The application of NOE enhancement and relaxation time measurements for the determination of the activation energy for bond rotation is described. The good agreement with the values obtained with the coalescence temperature method bears out that the NOE based approach is a good alternative for the determination of high rotational barriers. Molecular Mechanics (MM2) calculations give values close to the experimental ones. The homochiral carbamates of 9-anthryl-tert-butylcarbinol were prepared and their conformational equilibrium was studied. The absolute configuration was determined by comparison of the NMR data with MM calculations. The enantiomers of the alcohol were obtained after chromatographic separation of carbamate derivatives and their hydrolysis. The same homochiral alcohols were prepared by direct chiral column chromatography Cisoid and transoid conformations of 9,10-dipivaloylanthracene and 9,10-bis(1-imino- 2,2-dimethylpropyl) anthracene were separated and detected for the former and isolated for the latter at room temperature. The transformation between two atropisomers was studied by NMR and modeled by MM methods. X-ray diffraction was performed for the imino derivatives. The 9-anthryl-tert-butylcarbinol was tested as a chiral solvating agent (CSA) in the presence of racemic forms of mentil-p-toluenesulfinate, 9-(1-amino-2,2- dimethylpropyl)-9,19-dihydroanthracene, R-methoxyphenylacetic acid and 1-phenyl- 1,2-ethanediol. Diastereomeric complexes were found to form between each enantiomer of these last two compounds. One of the enantiomers of 9-anthryltert-butylcarbinol was studied by means of intermolecular NOE and molecular dynamics calculations. Major thermodynamic and structural differences were found.

3,3'-Neotrehalosadiamine (NTD) is a diaminosugar that possesses a rare alpha,beta-1,1'-linked glycosidic bond and has been reported to possess antimicrobial activity against Staphylococcus aureus. The ntdABC operon contains three structural genes that are necessary for the production of NTD in certain mutants of Bacillus subtilis. The gene predicted to be the first in the NTD biosynthetic pathway, ntdC, was subcloned into pET-28b as the hexa-histidine tagged fusion. The gene product was expressed, purified to homogeneity, and found to be an NAD+-dependent glucose 6-phosphate 3-dehydrogenase, likely operating according to a ternary complex mechanism and possessing a catalytic dyad composed by D176 and H180. The advent of this knowledge suggests that additional genes are required for the biosynthesis of NTD aside from the three encoded by the ntdABC operon.

Diphtheria Toxin-like ADP-Ribosyltransferases The Human ADP-ribosyl transferases (ARTDs) are a group of poorly studied enzymes which are believed to be involved in e.g. DNA repair, protein degradation, transcription regulation and cell death. Medicinal chemistry programmes aimed at developing selective inhibitors of these ARTDs were initiated. A suitable starting compound for one of these enzymes, ARTD3, was found by screening a library of NAD-mimics using a thermal shift assay. A virtual screening protocol was instead developed in order to find novel inhibitors of ARTD7, 8, and 10. The hit compounds were then further developed into selective inhibitors of the corresponding ARTDs by systematically varying different structural features using a combination of synthetic organic chemistry, computational chemistry and structural biology. Compounds were initially characterized using differential scanning fluorimetry which was later replaced with an enzymatic assay to obtain IC50 values. Biotinylated analogs were also synthesized in an attempt to develop an AlphaScreen assay. A selective ARTD3 inhibitor was ultimately identified and found to delay DNA repair in cells after γ-irradiation. These compounds are potentially valuable tools for elucidating the biological role of the poorly characterized ARTD-family of proteins. Total Synthesis of Resveratrol Based Natural Products The polyphenolic natural product (-)-hopeaphenol was found to inhibit the type III secretion system present in certain gram-negative bacteria. (-)-Hopeaphenol is a tetramer of resveratrol and in order to investigate whether the entire structure was essential for inhibition two resveratrol dimers, ε-viniferin and ampelopsin B, were synthesized using a flexible and divergent synthetic route. Highlights of the synthetic strategy include the use of cyclopropylmethyl protecting groups, allowing an acid mediated three-step-one-pot deprotection-epimerization-cyclization of an advanced intermediate to form ampelopsin B. All previously reported syntheses of these two natural products include a dimerization of resveratrol which severly limits the possibilities to synthesize structural analogs. This new strategy enables the synthesis of a wide variety of analogs to ε-viniferin and ampelopsin B. / Populärvetenskaplig sammanfattning Små molekyler för att identifiera proteiners funktion Vår arvsmassa innehåller cirka 24000 gener som i sin tur innehåller information för hur de tusentals proteiner vi är uppbyggda av ska framställas. Många läkemedel fungerar genom att en molekyl interagerar med ett av dessa proteiner och hämmar dess funktion för att på så sätt framkalla en önskad effekt. Vi vet dock inte vilken funktion många av våra proteiner fyller vilket ofta gör utvecklingen av nya läkemedel svår eller omöjlig. Den första delen av denna avhandling beskriver en grupp proteiner kallade ARTDs och hur små molekyler kan framställas och systematiskt förbättras för att till slut helt kunna slå ut vissa av dessa ARTDs. Genom att sedan studera vilka effekter detta medför kan man ta reda på vilken funktion proteinet fyller. På längre sikt skulle denna kunskap sedan kunna användas för att utveckla nya läkemedel genom att till exempel slå ut de proteiner som orsakar en sjukdom. Totalsyntes av naturprodukter Naturprodukter defineras inom kemin som naturligt förekommande molekyler som produceras av levande organismer. De kan hittas i allt från mikroorganismer och växter till djur och kan vara en del av deras ämnesomsättning, en restprodukt eller ha någon annan funktion, känd eller okänd. Människor, och i vissa fall även andra djur, har sedan urminnes tider ovetandes använt dessa molekyler för en mängd olika syften, som gifter, färgämnen eller läkemedel. Penicillin är en av de mest kända, men mer än hälften av de nya läkemedel som godkänts de senaste trettio åren bygger på naturprodukter eller har inspirerats av dessa. De fortsätter således att vara viktiga för utvecklingen av nya läkemedel trots att vi idag har möjligheten att utveckla sådana från grunden. Att framställa naturprodukter på konstgjord väg kallas totalsyntes och är ofta en mycket svår och tidskrävande process. Vanligtvis rör det sig om mycket stora och komplexa molekyler och det finns sällan ett uppenbart sätt att genomföra totalsyntesen. För att bättre klara av detta måste nya metoder utvecklas. Den andra delen av denna avhandling beskriver nya metoder för att framställa komplexa molekyler kallade polyfenoler. Målet var att dessa metoder skulle vara så pass flexibla att de även kan användas för att framställa nya polyfenoler som aldrig tidigare existerat men som har förbättrade egenskaper.

A series of small molecules was synthesized to probe three protein targets in order to elucidate the key small molecule-protein interactions required for potency. Triclosan is an antibacterial compound that has surfaced as a potential environmental hazard and is hypothesized to cause perturbations in the thyroid hormone response of frogs. Using a C-fin assay and a GH3 cell line, our work suggests that triclosan itself may not in fact be the cause of the observed endocrine disruptions. Instead, methyl triclosan (a result of biological methylation during waste water treatment) was shown to disrupt the thyroid hormone response in tadpoles. Secondly, a set of probes was designed based on a cyclopentane scaffold derived from the known neuraminidase inhibitor peramivir. Kinetic assays using both a recombinant neuraminidase protein and an inactivated sample of influenza virus showed that the guanidine group contributes a 10 fold increase in potency while the α-hydroxyl group was observed to have little to no effect. This result suggests that future neuraminidase drug design based on a cyclopentane scaffold may forgo the use of both the guanidinium group and the hydroxyl group to potentially increase the oral availability of these drugs while sacrificing little in the way of potency. Finally, a series of truncated analogues related to the western half of the natural product didemnaketal A was synthesized. These compounds will be used as probes to better understand the mechanism of didemnaketal-mediated protease inhibition. It is hypothesized that a more rigid structure (due to molecular gearing enforced by the presence of additional methyl groups, relative to previously examined analogues) will increase the potency of these molecules toward HIV-1 protease and may lead to new information for designing next-generation dissociative inhibitors. Work was also begun toward the total synthesis of the natural product itself. / Graduate