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Thesis advisor: Amir Hoveyda / Chapter 1: E- and Z-, Di- and Trisubstituted Alkenyl Nitriles through Catalytic Cross MetathesisWe have described the development of several catalytic cross-metathesis strategies, which can deliver a considerable range of Z- or E-disubstituted alkenyl nitriles and their corresponding trisubstituted variants. Through careful examination of the steric and electronic attributes of the starting materials, a Mo-based monoaryloxide pyrrolide or chloride complex may be the optimal choice depending on the reaction type. In the event, equimolar amounts of the two substrates are necessary to maximize reaction efficiency; a pyridine ligand is more desirable than a phosphine ligand, as a stabilizing ligand for a Mo-based complex, for improving reaction stereoselectivity. We also highlighted the utility of this approach with the synthesis of several biologically active compounds, such as LR5182 (Cocaine abuse treatment), alliarinoside (anti-feedant), perhydrohistrionicotoxin (natural product), CC-5079 (anti-cancer) and indatraline (anti-depressant). Chapter 2: Traceless Protection for More Broadly Applicable Olefin Metathesis We have devised an operationally simple in-situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic olefin metathesis. Pretreatment of an olefin containing a protic group with commercially available HB(pin) or HB(trip)2 is sufficient for generating the desired product efficiently through the catalytic cross-metathesis reaction. A wide range of stereochemically defined Z- and E-alkenyl halides and boronates as well as Z-trifluoromethyl-substituted alkenes with a hydroxy or carboxylic acid group were prepared. We also discovered that a small amount of HB(pin) may be used for the removal of residual water and impurities, significantly enhancing the efficiency of a multigram-scale olefin metathesis transformation. Chapter 3: E- and Z-Macrocyclic Trisubstituted Alkenes for Natural Product Synthesis and Skeletal Editing We have introduced a reliable catalytic strategy for the synthesis of a variety of macrocyclic trisubstituted olefins in either stereoisomeric form. This was achieved by overcoming the unexpected difficulties through careful mechanistic studies, including addressing complications arising from pre-metathesis alkene isomerization. Macrocyclic ring-closing metathesis can be performed with a commercially available Mo-based complex and an easily accessible linear diene precursor. Accordingly, we can synthesize a skeletally diverse array of otherwise difficult-to-access macrocyclic alkenes, a critical set of compounds in drug discovery, in either isomeric form. The utility of the method is highlighted in two instances. The first is the near complete reversal of substrate-controlled selectivity in the generation of the macrolactam intermediate, in the total synthesis of the anti-fungal agent Fluvirucin B1. The second is an exceptionally stereoselective late-stage formation of a 24-membered macrocyclic E-trisubstituted alkene, enabling the completion of the total synthesis of a cytotoxic natural product dolabelide C, which is seven times more efficient than that reported previously. Chapter 4: Stereodefined Alkenes with a Fluoro-Chloro Terminus as a Uniquely Enabling Compound Class We have offered a practical solution for the synthesis of trisubstituted alkenyl fluorides by unveiling a widely applicable strategy for stereodivergent synthesis of olefins bearing a fluoro and chloro terminus. The core transformation is unprecedented: cross-metathesis between two trisubstituted olefins, one of which is a commercially available but scarcely utilized trihalo alkene. Alkenes bearing a fluoro,chloro-terminus are versatile substrates for the generation of otherwise difficult-to-access trisubstituted alkenyl fluorides, through stereospecific catalytic cross-coupling reactions. We also highlighted the utility of the method throguh synthesis of, among others, a fluoro-nematic liquid crystal component, peptide analogs bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluoro-rumenic ester (anti-cancer). / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The scope of this research entailed the synthesis of novel polyorganosiloxanes with pendent phosphine, phosphine oxide, nitrile and carboxylic acid moieties. Such polysiloxanes were prepared with controlled concentrations of both the polar moieties and hydrido or vinyl pendent crosslinkable sites to afford precursor materials for well-defined networks. The intention was to generate stable microcomposite dispersions with very high concentrations of polar thermally conductive fillers. Lightly crosslinked elastomeric networks with controlled amounts of polar moieties were prepared via a hydrosilation curing mechanism. High concentrations of thermally conductive micro-fillers were dispersed throughout the resins and the microcomposites were investigated as thermally conductive adhesives. Random polysiloxane copolymers containing controlled number average molecular weights (Mns) and compositions with systematically varied concentrations of hydridomethylsiloxy- or vinylmethylsiloxy- units were prepared via ring-opening equilibrations of cyclosiloxane tetramers. These precursors were functionalized with precise concentrations of polar pendent moieties via hydrosilation (nitrile) or free radical addition reactions (phosphine and carboxylic acids). Valuable additions to the family of polysiloxanes were prepared by oxidizing the phosphine moieties to form phosphine oxide containing polysiloxanes. Defined concentrations of residual hydrido- or vinyl- reactive sites were crosslinked via hydrosilation to yield elastomeric adhesives. Specific interactions between the nitrile and phosphine oxide substituted polysiloxanes and the acidic proton of chloroform were shown using 1H NMR. The magnitude of the shift for the deshielded chloroform proton increased with the degree of hydrogen bonding, and was larger for the phosphine oxide species. The polar polysiloxane resins were filled with high concentrations of thermally conductive fillers including silica-coated AlN, Al spheres, BN and Ag flake, then hydrosilated to form microcomposite networks. Microcomposite adhesive strengths, thermal properties (glass transition temperature (Tg) and high temperature stability), and thermal conductivities were studied. An unfilled polysiloxane network containing only 15 mole percent phosphine oxide exhibited a dramatic improvement (46 N/m) in adhesive strength to Al adherends relative to a control polydimethylsiloxane network (2.5 N/m). Importantly, stable polysiloxane micro-dispersions were obtained with up to 67 volume percent (86 weight percent) silica-coated AlN. TEM data confirmed the dispersion homogeneity and XPS demonstrated that the particle surfaces were well-coated with the functionalized polysiloxanes. A microcomposite comprised of 67 volume percent silica-coated AlN and a polysiloxane containing only 9 molar percent nitrile groups had a thermal conductivity of 1.42 W/mK. The glass transition temperatures of the microcomposites were controlled by the amounts of polar functional moieties on the resins and the network crosslink densities. All of the microcomposites exhibited Tgs lower than -44°C and the materials remained stable in dynamic TGA measurements to approximately 400°C in both air and nitrogen. / Ph. D.

Dans un monde où la fin du pétrole est prévisible, l’utilisation de ressources renouvelables, issues de la biomasse, pour la production de bio-carburants et de matières premières pour l’industrie chimique est un domaine de recherche intense. La transformation de dérivés d’acides gras a pu être réalisée par des réactions de métathèse croisée, catalysées au ruthénium. La synthèse de nitriles dits «courts» comme additifs pour le kérosène ainsi que de monomères pour l’industrie des polymères a été développée. La purification des ressources renouvelables a été étudiée. Un traitement thermique, simple à mettre en œuvre, a montré son efficacité pour la réalisation de réactions de métathèse toujours plus efficientes. Enfin, pour des réactions de catalyse toujours plus efficaces, la synthèse de nouveaux complexes de ruthénium à ligand indénylidène chélatant de seconde génération a été entreprise. / In the context of depletion of crude oil, the production of bio-fuels and raw materials from renewable resources for the chemical industry is a topic of tremendous research. The transformation of fatty acid derivatives was developed by using olefin metathesis, using ruthenium catalysts. Short nitriles as kerosene additives and monomers for the polymer industry were synthesized. Purification of the renewable feedstock was studied. A simple thermal treatment was found to promote an increased efficiency for cross-metathesis reactions with fatty acid derivatives. Finally, the synthesis of new second generation ruthenium complexes with a chelating indenylidene ligand was investigated for the development of active and robust catalysts for olefin metathesis reactions.

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Die vorliegende Arbeit befasst sich mit der Synthese, dem Reaktionsverhalten, den Festkörperstukturen und den elektronischen Eigenschaften von neuartigen Übergansmetall-komplexen der Gruppen 4, 8 und 10 des Peridoensystems der Elemente. Die Arbeit befasst sich unter anderem mit der Darstellung von Alkyloxy- und Aryloxy-substituierten Titanocenverbindungen des Typs [Ti](Cl)(OR) {[Ti] = (C5H5SiMe3)2Ti; R = organischer Rest). Mittels cyclovoltammetrischer Experimente und anhand von Festkörpestrukturen wird der elektronische Einfluss der organischen Reste auf das Metallzentrum untersucht. Weiterhin befasst sich die Arbeit mit der Synthese von in para-Position substituierten NCN-Pincerverbindungen. Durch die Wahl des Substituenten in para-Postition sowie des Übergangsmetalls der Gruppe 10 des Periodensystems der Elemente ist es möglich, verschiedenartig gerichtete polymere Strukturen zu bilden. Ein weiterer Schwerpunkt der vorliegenden Arbeit liegt in der Synthese und Untersuchung der elektronischen Eigenschaften von NCN-Pincer-substituierten Ferrocenen. Der Einfluss der NCN-Pincer auf die Elektronendichte des Ferrocens wird bestimmt sowie die Eignung derartiger Systeme als elektrochemische Sensoren zur molekularen Erkennung von Schwefeldioxid wird untersucht.

Philosophiae Doctor - PhD / In bacteria, nitrile hydratases and enzymes of nitrilase and signature amidase superfamilies hydrolyse nitriles and amides to their corresponding carboxylic acids releasing ammonia. Bacteria expressing these enzymes are typically isolated where a sole nitrogen and/or carbon source is used to support their growth. The majority of characterised enzymes of industrial potential have been identified for their stabilities at elevated temperatures. To date, no reports of such enzymes have been isolated from cold adapted bacteria.In this study, an extensive screening program of cold-active microbial isolates for enzymes of this group led to the selection and detailed characterisation of an aliphatic amidase from Nesterenkonia.Nesterenkonia AN1, a new psychrotrophic isolate of the genus, was isolated from soil samples collected from the Miers Valley, Antarctica. AN1 showed significant 16S rRNA sequence identity to known members of the genera, but this is the only strain that had optimal growth at approximately 21oC. AN1, similar to known members, is an obligately alkaliphilic (pH 9-10) and halotolerant (Na+ 0- 15% (w/v)) strain.The genome of Nesterenkonia AN1, sequenced in-house, revealed two ORFs encoding putative nitrilases, referred to as Nit1 and Nit2. Based on analysis of their deduced protein sequences, both belonged to the nitrilase superfamily. Both sequences showed conserved catalytic residues (EKEC), glycine residues and contained the characteristic áââá monomer fold. Homology modelling using known structures suggested that both genes could encode N-carbamoyl D-amino acid amidohydrolases, although neither showed conserved residues implicated in the hydrolysis of carbamoyls.Nit1 and Nit2 were expressed in Escherichia coli BL21 (DE3) pLysS as Cterminal and N-terminal hexahistidine tagged fusion proteins, and purified using Ni-chelation chromatography. Nit1 showed no activity towards nitrile, amide and carbamoyl substrates. This protein, unlike members of the multimeric enzymes of the nitrilase superfamily, was a monomer ~30 kDa protein. It is possible that the C-terminal hexahistidine tag might have prevented Nit1 from forming multimeric proteins.Nit2 showed substrate specificity similar to known aliphatic amidases with a preference for small amides. Nit2 had maximal activity at 30oC and between pH 6.5 and 7.5, properties compatible with its cold-adapted alkaliphilic origins. In addition, the enzyme was irreversibly inactivated at temperatures above 30oC and had a half-life of approximately 7 mins at 60oC. The crystal structure of Nit2 was solved to 1.66 Å. It revealed a ~45.5 kDa dimer, composed of two tightly bound ~30 kDa monomers. These monomers associated along the A surface forming a áââá-áââá sandwich architecture that is conserved in known structures of the nitrilase superfamily.Nit2 is distinct from known aliphatic amidases in both its structure and enzymic activity: the enzyme did not possess an extended C-terminal region; is active in dimeric form; has high affinity for 3C amides rather than 2C amides; and has a low overall catalytic rate. The short C-terminal region of Nit2 may have contributed to the low stability of the enzyme at elevated temperatures. A dendrogram composed of protein sequences of members of the nitrilase superfamily and Nit2 further supported evidence that this aliphatic amidase falls within a distinct group of enzymes.This is the first report of the enzymic characterisation and structural analysis of an aliphatic amidase from a psychrotolerant, alkaliphilic and halotolerant extremophile.

The strain Rhodococcus erythropolis A4 is a source of enzymes nitrilhydratase and amidase, that catalyse conversion of nitriles and amides. These enzymes are used in industrial biotransformation and bioremediation. Since it was difficult to carry out genetic manipulations aimed at increasing the production of these enzymes in the strain A4, the corresponding genes (ami and nha1 + nha2) of a related strain R. erythropolis CCM2595, in which both plasmid and chromosome manipulations can be routinely performed, were identified and analyzed in this diploma theses. The ami and nha1 + nha2 genes from the strain R. erythropolis CCM2595 were isolated and sequenced together with the flanking regions (5.5 kb in total). The organization of these genes and the expected regulatory genes was described in the strain CCM2595 and mechanisms of regulation of expression of these genes were studied. For the analysis of transcription of amidase and nitrilhydratase genes from both strains of R. erythropolis, the promoter-probe vector pEPR1 replicating in Escherichia coli and R. erythropolis was used. Transcriptional fusion of Pami promoters of the strains A4 and CCM2595 and the reporter gfp gene were constructed. The activity of the Pami promoter was measured by means of fluorescence of gfp gene product (green fluorescent...

Stereochemistry is important aspect of chemistry that customarily includes the study of the relative spatial arrangement of atoms within molecules (static stereochemistry), and the study of the stereochemical requirements and outcomes of chemical reactions (dynamic stereochemistry). These two branches complement each other in modern stereochemistry. Chiral organometallics feature prominently in organic synthesis as reactive intermediates. The possibility of exploring their stereochemistry in synthesis is associated with the configurational stability of the metal-bearing stereogenic center. We were interested in the configurational stability of lithiated and magnesiated nitriles. We developed a new series of lithio-cyclopropylnitriles bearing chelating groups for intramolecular coordination, as a possible strategy to impart configurational stability. Although this strategy has not yet been successful, using density functional theory (DFT) method, we addressed the effect of chelating groups on racemization via the "conducted tour" mechanism. We then explored metal-bromine exchange on enantiopure bromonitrile as alternative route to metalated nitriles. In this way, we demonstrated that magnesiated 2,2-diphenyl cyclopropylnitrile is configurationally stable on the macroscopic timescale. No other metallated nitrile has ever demonstrated configurational stability on this timescale. In contrast, bromine-lithium exchange of 1-bromo-2,2-diphenyl-cyclopropylnitrile demonstrated fast racemization under the same conditions. Another major project focused on conformational control of acyclic molecules. Using X-ray crystallography and NMR spectroscopy, we found that the 2,6-disubstituted aryl group eclipses its geminal hydrogen, and induces an antiperiplanar relationship of the geminal and vicinal hydrogens. Interestingly, anti-nitrile aldols or syn-ketone aldols bearing 2,6-disubstituted aryl groups demonstrate unanticipated remote effects on acyclic conformation: the 2,6-disubstituted aryl group prefers to be in a gauche position to the largest vicinal group. The minimization of allylic 1,3-strain and syn-pentane-like interaction works together in establishing this conformational preference. / Ph. D.

La toxoplasmose est une anthropozoonose ubiquitaire causée par Toxoplasma gondii. Malgré de nombreuses recherches, l'arsenal thérapeutique reste très restreint. L'objectif des travaux présentés dans ce mémoire est la synthèse de carbazolequinones et l'évaluation de leur efficacité sur T. gondii. Les carbazolequinones naturelles comme les calothrixines ont des propriétés antiparasitaires et cytotoxiques. La synthèse de para- et ortho-quinones de type benzo-, isoxazolo- et triazolo-carbazolequinones a été réalisée par application des réactions de cycloaddition [4+2] ou 1,3-dipolaires régiosélectives. La stratégie de synthèse à partir de dipolarophiles monobromés permet en effet, d'accéder sélectivement au régioisomère souhaité. Les attributions de structure des régiosiomères ont été confirmées par RMN 1H NOE et par une étude des corrélations 1H -13C HMBC. Concernant l'évaluation biologique in vitro, les composés inhibent la croissance de T. gondii comme la sulfadiazine et la pyriméthamine, avec une cytotoxicité sur les cellules myélomonocytiques THP1. Aucun des composés synthétisés n'inhibent la PNP, enzyme clé de la voie de sauvetage des purines, seule voie d'accès pour le parasite aux bases puriques. L'inhibition de la croissance de T. gondii par nos composés n'est pas liée directement liée à l'inhibition de la PNP.