This thesis is based on research in Cu-catalyzed electrophilic trifluoromethylation and exploiting Cu/Cu2O nanowires with novel catalytic reactivity for developing of catalytic and greener synthetic methods. A large number of biological active pharmaceuticals and agrochemicals contain fluorine substituents (-F) or trifluoromethyl groups (-CF3) because these moieties often result in profound changes of their physical, chemical, and biological properties, such as metabolic stability and lipophilicity. For this reason, the introduction of fluorine or trifluoromethyl groups into organic molecules has attracted intensive attention. Among them, transition metal-catalyzed trifluoromethylation reactions has proved to be an efficient and reliable strategy to construct carbon-fluorine (C-F) and carbontrifluoromethyl (C-CF3) bond. We have developed a catalytic process for the first time for trifluoromethylation of terminal alkynes with Togni’s reagent, affording trifluoromethylated acetylenes in good to excellent yields. The reaction is conducted at room temperature and exhibits tolerance to a range of functional groups. Derived from this discovery, the extension of work of copper catalyzed electrophilic trifluoromethylation were investigated which include the electrophilic trifluoromethylation of arylsulfinate salts and electrophilic trifluoromethylation of organotrifluoroborates. Because of growing environmental concern, the development of greener synthetic methods has drawn much attention. Nano-sized catalysts are environment-friendly and an attractive green alternative to the conventional homogeneous catalysts. The nano-sized catalysts can be easily separated from the reaction mixture due to their insolubility and thus they can be used recycled. Notably, because of the high reactivities of nano-sized metal catalysts, the use of ligands can be avoided and the catalysts loadings can be reduced greatly. Moreover, the nano-sized catalysts can increase the exposed surface area of the active component, thereby enhancing the contact between reactants and catalyst dramatically. Based on the above-mentioned concepts and with the aim of achieving one “green and sustainable” approach, C-S bond formation and click reactions catalyzed by Cu/Cu2O nanowires were investigated. It was found that the recyclable core-shell structured Cu/Cu2O nanowires could be applied as a highly reactive catalysts for the cross-coupling reaction between aryl iodides and the cycloaddition of terminal alkynes and azides under ligand-free conditions. Furthermore, these results were the first report for the crosscoupling reaction and click reaction catalyzed by one-dimensional (1D) copper nanowires.

Copper is an inexpensive, earth-abundant, non-toxic metal that is found to have widespread applications in catalysis. Ullmann and Ullmann-type reactions and Glaser-Hay oxidative coupling of terminal alkynes are some of the well-established copper catalyzed coupling reactions used for the construction of important organic molecules, including pharmaceuticals, commodity chemicals and polymers. Those reactions have been mainly performed homogeneously, where the removal of residual copper from the reaction mixture is a challenge. Therefore, many researchers tried supporting copper precatalysts in order to help recover, and thus reduce final product contamination. Some studies showed that copper leached significantly from the support, with others showing that leached copper has a role in the catalysis. Nevertheless, many studies reported that the used supported catalysts were recyclable and claimed catalyst's heterogeneity. In most cases, the nature of the truly active copper species is still not clear. The objectives of this thesis were (1) to assess the heterogeneity/homogeneity of active copper species in popular catalytic C-N coupling reactions with already studied catalysts, mainly a copper exchanged zeolite and copper oxide nanoparticles, and (2) to use the collected information in designing a truly heterogeneous (stable and recyclable) catalyst. Initially, and because of its shape selectivity characteristics, copper-exchanged NaY zeolite, Cu(II)Y, was chosen to study the heterogeneity of copper catalyzed amination of aryl iodide with imidazole. The collected results from conducted shape selectivity tests indicated that Cu(II)Y might be heterogeneous catalyst, but because of the used base, that is crucial for this C-N coupling reaction, the crystallinity of the zeolite structure was diminished. Therefore, it was important to support copper on a framework that is stable under the basic conditions required for this type of reaction if a heterogeneous, recyclable catalyst were to be achieved. For this purpose, cerium oxide was chosen, and copper oxide supported on cerium oxide, CuO-CeO₂, was investigated as a potential heterogeneous catalyst for C-N coupling reaction. This investigation included the role of each reaction reagent in facilitating copper leaching into solution. It was found that copper leached from the support and it was demonstrated through hot filtration tests that the leached copper species was the main active catalyst. Leaching was caused by the solvent (DMSO) as well as the used reactants and the base. Similar conclusions were drawn when this CuO-CeO₂ catalyst was used for the direct synthesis of imines from amines under aerobic conditions. Although this CuO-CeO₂ catalyst has the advantages of being more recoverable and active than unsupported CuO nanoparticles at similar copper loadings, it is not fully recyclable, as the copper catalysis occurs in solution. These findings meant that designing a truly heterogeneous catalyst for this reaction is a challenging task. Understanding the effect of each individual factor of this complicated system might help in achieving the second goal - designing a truly heterogeneous catalyst. Therefore, further studies were carried out to understand the effect of reaction conditions, including temperature, base, support, and solvent, on copper leaching. Homocoupling of terminal alkynes was chosen as a model reaction for this study, and CuO was supported on TiO₂ (10CuO-TiO₂) and on γ-Al₂O₃ (10CuO-Al₂O₃). It was found that copper interaction with the support affects the extent of leaching as well as the nature and activity of leached species. High temperature also facilitates copper leaching especially when a ligating amine, like piperidine, is present in the system.

The synthesis of natural products has always been, and still is, of great interest for various reasons. Firstly, the molecular diversity of natural products pushes organic chemists to develop and apply new strategies and methods in organic synthesis. Secondly, the practice of natural product synthesis remains one of the best way to confirm the structure of a natural product. Meanwhile, it also provides a way for examining the true robustness of novel synthetic methods, which has to be highly selective and efficient to be applied in total synthesis. Thirdly, developing a total synthesis of a natural product, which is in most cases isolated with low yields and after intensive purifications, will in general allow to produce sufficient quantities for the study of its biological properties. Finally, chemists also have the opportunity to synthesize a series of analogs of a natural product by slight modifications of the synthetic route, these analogues enabling the study of structure/activity relationships and potentially possessing better pharmacological and physicochemical properties compared to the original natural product. In that context, this thesis work has focused on the total synthesis of two natural macrocyclic alkaloids by using copper catalysis in the key steps. In the case of synthesis of (-)-melanthioidine, a member of the dimeric macrocyclic diaryl ether tetrahydroisoquinoline alkaloid, copper catalysis was utilized in the key cyclodimerization step to form a diaryl ether bond bridged 20-membered ring constituted by two phenethyltetrahydroisoquinoline subunites. In this synthesis the configuration of the phenethyltetrahydroisoquinoline was controlled by a Bischler-Napieralski cyclization / Noyori asymmetric hydrogenation sequence starting from the corresponding amide, which could be readily prepared by a multi-step sequence from commercially available compounds. With the success we met in the synthesis of (-)-melanthioidine, we next turned our attention to the synthesis of paliurine F, which is a member of cyclopeptide alkaloids. In this synthesis, the copper-mediated cross coupling was implemented to install not only C(sp2)-O bond but also more challengingly to form C(sp2)-N bond to construct the 13-member ring of paliurine F in the regio-, chemo- and diastereo-selective manner, which eventually enabled us to develop a highly convergent approach to paliurine F.Finally, we also put our effort to the development of an efficient copper-mediated domino double Ullmann coupling-double Claisen rearrangement process starting from readily availble ene-diols and vinyl iodides. In this synthesis, the double Ullmann coupling product in situ underwent a single Claisen rearrangement followed by a microwave-assisted Claisen rearrangement to provide a highly functionalized 1,6-dicarbonyl compounds. In addition, our process was also shown to be successful for the functionalization of glycals. In conclusion, our work further highlight the efficiency of copper-mediated transformation in the synthesis of natural products and provide new strategies for the formation of symmetrial or, even more interestingly, non-symmetrical macrocyclic molecules. Moreover, combining copper-mediated reactions with pericyclic process such as Claisen rearrangement was also shown to be an efficient way for the development of novel synthetic methods. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Thesis advisor: Amir H. Hoveyda / Chapter 1. Ligand-Controlled Site-Selective NHC–Cu-Catalyzed Protoboration of Monosubstituted Allenes. Site-selective proto–boryl additions to monosubstituted allenes promoted by NHC–Cu complexes are disclosed. Synthetically useful 1,1-disubstituted and Z-trisubstituted alkenylboron compounds are afforded in high efficiency (71%–92% yield) and site selectivity (88% to >98%) through proper choice of NHC ligands. Mechanistic study with the assistance of DFT calculations indicates that protonation of 2-boron-substituted allylcopper complex occurs through six-membered cyclic transition state. The utility of this protocol is demonstrated through application to fragment synthesis of an antibiotic macrolide natural product elansolid A. Chapter 2. Cu-Catalyzed Chemoselective Copper–Boron Additions to Monosubstituted Allenes Followed by Allyl Additions to Carbonyl Compounds. The first examples of catalytic generation of 2-boron-substituted allylcopper species and their in situ use for C–C bond formation are described. The reactions are performed in the presence of bisphosphine– or NHC–Cu complexes at 22 oC. High-value alcohol-containing alkenylboron compounds are provided in high efficiency (68–92% yield after oxidation) and stereoselectivity (88:12 to >98:2 dr). The reactions proceed with exclusive γ-addition mode through a cyclic six-membered transition state. Enantioselectivity can be achieved with chiral bisphosphine ligands in up to 97:3 enantiomeric ratio. Chapter 3. Chemo-, Site- and Enantioselective Copper–Boron Additions to 1,3-Enynes Followed by Site- and Diastereoselective Additions of the Resulting Allenylcopper Complexes to Aldehydes. Catalytic enantioselective multicomponent reactions involving 1,3-enynes, aldehydes and B2(pin)2 are described. The resulting products contain a primary C–B(pin) bond, as well as alkyne- and hydroxyl-substituted tertiary stereogenic centers. A critical feature is high enantioselectivity of the initial Cu–B addition to an alkyne-substituted terminal alkene. The key mechanistic issues are investigated by DFT calculations. Reactions are promoted in the presence of the Cu complex of an enantiomerically pure C1-symmetric bisphosphine and are complete in 8 h at ambient temperature. Products are generated in 66–94% yield (after oxidation or catalytic cross-coupling), 90:10 to >98:2 diastereomeric ratio, and 85:15–99:1 enantiomeric ratio. Aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes and enynes are suitable substrates. Utility is demonstrated through catalytic alkylation and arylation of the organoboron compounds as well as applications to synthesis of fragments of tylonolide and mycinolide IV. Chapter 4. Multifunctional Alkenylboron Compounds through Single-Catalyst-Controlled Multicomponent Reactions and Their Applications in Scalable Natural Product Synthesis. A facile multicomponent catalytic process that begins with a chemo-, site- and diastereoselective copper–boron addition to a monosubstituted allene followed by addition of the resulting boron-substituted organocopper intermediate to an allylic phosphate, generating products that contain a stereogenic center, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group in up to 89% yield with >98% branch selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly column chromatography purification. The utility of the method is demonstrated through enantioselective synthesis of gram quantities of two natural products, rottnestol and herboxidiene/GEX1A. Chapter 5. Cu-Catalyzed Enantioselective Allyl and Propargyl 1,6-Conjugate Additions through 3,3’-Reductive Elimination. Catalytic enantioselective 1,6-conjugate additions of allyl-type nucleophiles promoted by NHC–Cu complexes are reported. Propargyl and 2-boron allyl 1,6-conjugate products are formed in high efficiency, diastereo- and enantioselectivity. The unique mechanistic feature is that the transformations proceed through Cu-catalyzed 3,3’-reductive elimination, that is unprecedented for copper catalysis. Further mechanistic study and application to complex molecule synthesis will be conducted. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The unifying theme of this thesis is the exploitation of the reactivity of aryliodonium salts as electrophile transfer reagents. In the first part of the thesis, diaryliodonium salts are employed as arylation reagents for the enantioselective copper-catalysed arylative semipinacol rearrangement (SPR) of various tertiary allylic alcohols. This cascade reaction is a rare example of asymmetrically activating SPR using carbon electrophiles. Different substrate classes - including dihydropyran, indene and dihydronaphthalene moieties - are converted to enantioenriched beta-aryl spirocyclic ketones in excellent yields and enantioselectivities, and often as a single diastereomer. These are in turn useful functional handles for transformations into other moieties, including further rearrangements via Baeyer-Villiger oxidation. In the second part of this thesis, a two-step process for the macrocyclisation of native peptides via a non-natural linkage is developed. This study exploits previous work conducted in the group on the use of aryliodonium salts as methionine-selective diazoacetate transfer reagents. The functionalised methionine is in turn used for an intramolecular rhodium-catalysed insertion into tryptophan. Eventual translation onto solid-phase enables facile access into various macrocyclic peptides.

Direct, gas phase propylene epoxidation reactions are carried out on model slabs representing Ru-Cu(111) bimetallic and Cu(111) metallic catalyst surfaces with periodic Density Functional Theory (DFT) calculations. Ru-Cu(111) surface is modelled as a Cu(111) monolayer totally covering the surface of Ru(0001) surface underneath. The catalytic activity is evaluated following the generally accepted oxametallacycle mechanism. It is shown that the Ru-Cu(111) surface has a lower energy barrier (0.48 eV) for the stripping of the allylic hydrogen of propylene and a higher energy barrier (0.92 eV) towards propylene oxametallacycle (OMMP) formation compared to 0.75 eV barrier for OMMP formation and 0.83 eV barrier for allylic hydrogen stripping on Cu(111), and thus ineffective for propylene oxide production based on the investigated models and mechanism. In order to analyze the observed inability of the Ru-Cu(111) surface to selectively catalyze propylene oxide formation, a Lewis acid probe, SO2, was adsorbed on the oxygenated Cu(111) and Ru-Cu(111) surfaces and the binding energies, a measure of the basicity of the chemisorbed oxygen on the surfaces, on two systems are compared. As a conclusion, the reason behind this ineffectiveness of the Ru-Cu(111) surface for selectively catalyzing propylene epoxidation is related to the higher basicity of the atomic oxygen adsorbed on Ru-Cu(111) compared to the oxygen on Cu(111). The results are consistent both with recent publications about propylene epoxidation and previous studies performed about the structure of Ru-Cu catalysts.

The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more than a century, further studies of boronic acids were sparsely published. Suzuki and Miyaura jumpstarted the field in 1979 with an innovative carbon-carbon bond forming reaction employing an organoboronic acid and a carbon halide under palladium catalysis. Indeed, the Nobel Prize in Chemistry was awarded to Professor Akira Suzuki, along with Professors Richard Heck and Ei-ichi Negishi, in 2010 for their important contributions in palladium-catalyzed cross-coupling chemistry. Over the last 30 years, reports on organoboron compounds have increased exponentially. This dissertation describes the author's contributions to the development of preparative methods for organoboronic acid derivatives using transition metal-catalyzed reactions of diboron reagents. A unique "mixed" diboron reagent was developed (PDIPA diboron) that contains sp2- and sp3-hybridized boron atoms, unambiguously confirmed by X-ray crystallography. PDIPA diboron is sufficiently activated internally through a dative-bonding amine to selectively transfer the sp2-hybridized boron regioselectively, in the presence of copper, to electron deficient alkenes including α,β-unsaturated ketones, esters, amides, aldehydes, and nitriles to provide the corresponding boratohomoenolates. A unique β,β-diboration of an α,β-acetylenic ketone was also discovered. The scope of PDIPA diboron reactions was then expanded to a set of substrates with a more complex structural backbone. Allenoates are α,β,γ-unsaturated esters with orthogonal pi systems, which pose several possible difficulties with the regioselectivity of addition, not to mention known isomerizations catalyzed by copper. However, we successfully installed the boron moiety regioselectively on the β-carbon of a variety of allenoates, providing a vinyl boronic ester, and also observed exclusive formation of the (Z)-isomer from racemic starting materials. The resulting vinyl boronic ester was then shown to be an excellent Suzuki-Miyaura cross-coupling partner, affording a diastereopure, trisubstituted alkene in quantitative yield. Commercially available bis(pinacolato)diboron has shown remarkable stability towards hydrolysis and autoxidation. Using this reagent, we developed a copper- and amine-catalyzed boration protocol performed entirely in water and open to air. Using only 1 mol% copper, extraordinary activity was observed. UV-Vis, 11B NMR, and solvent kinetic isotope experiments were employed to gain insight into the mechanism, which showed the possibility of autocatalysis. Attempts to control stereoselectivity were not successful, although these results were rationalized by a dynamic catalyst structure. / Ph. D.

An environmentally friendly, operationally simple copper-amine catalyst system is disclosed. Using this catalyst system, electron deficient alkenes and alkynes with diverse functional groups are borylated and silylated in high yields and with short reaction times. In the case of electron deficient alkynes the identity of the electron withdrawing group controlled diastereoselectivity. Esters and amides exclusively form E-product, while aldehydes and ketones favor Z-product. Mechanistic insights into the catalytic cycle as well as origin of diastereoselectivity are discussed. / Master of Science

In the last century, no less than five nobel prizes have been awarded for the construction of carbon-carbon bonds : The Grignard reaction (1912), the Diels-Alder reaction (1950), the Wittig reaction (1979), Olefin metathesis (2005) and palladium cross-coupling reactions (2011). The latter two are transition metal catalyzed transformations and their impact on the synthesis of pharmaceutically active compounds, bulk chemicals, fine chemicals, high tech materials as well as agricultural chemicals has been phenomenal. These reactions have changed the way the scientific community views the science of synthesis. Unlike palladium, gold has long been considered to be an expensive and inert metal and therefore, research on Au catalysis was scarse until the begining of the new millenium. Once the scientific community realized the treasure trove of reactivity that gold had to offer, the number of chemical transformations as well as total syntheses involving Au(I)/Au(III) catalysis has sky rocketed. A methodology initially developped by Toste and coworkers has shown that intramolecular addition of a silyl enol ether on alkynes proceeds via a 5-exo¬-dig¬ process. In the first part of this thesis, we will discuss how the ancilary ligand on Au(I) species can influence pathway selectivity for these cyclizations, therefore opening the door to selective 6-endo-dig cyclizations to generate fused carbocycles. With biological processes as well as other competing processes becoming ever more efficient, the future of chemical synthesis is threatened. If it is to survive, the focus of new chemical transformations will have to be on the cost and the greeness of the process. In the second part of this thesis, we will demonstrate how Ag(I) and Cu(I) complexes can offer even better 6-endo-dig¬ selectivity than analogous Au(I) complexes. Silver is about 56 times less expensive than gold, and copper is about 453 times less expensive than gold. Due to the greatly increased selectivity as well as the diminished cost of the catalysts, we have provided access to an attractive 6-endo-dig¬ cyclization process.

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