Site-selective protein modification has become an important tool to study protein functions in chemical biology. In the preliminary work, allyl sulfides were found to be reactive substrates in aqueous cross-metathesis (CM) enabling the first examples of protein modification via this approach. In order to access the enhanced CM reactivity of allyl sulfide on proteins, facile chemical methods to install S-allyl cysteine on protein surface were developed. In particular, a cysteine-specific allylating reagent – allyl selenocyanate was used on protein substrate for the first time. The substrate scope of allyl sulfide-tagged proteins and factors that affect the outcome of CM was also investigated. A range of metathesis substrates containing different olefin tether of various lengths were screened; allyl ethers were found to be most suitable as CM partners. By reducing the steric hindrance around the allyl sulfide on protein surface through a chemical spacer, the rate and conversion of metathesis reaction on proteins was greatly enhanced. Moreover, allyl selenides were found to be more reactive than allyl sulfides in CM and enabled reactions with substrates that were previously impossible for the corresponding sulfur-analogue. Through this work, substrate selection guidelines for successful metathesis reaction on proteins were established. Rapid Se-relayed CM was further investigated through biomimetic chemical access to Se-allyl selenocysteine (Seac) via dehydroalanine. On-protein reaction kinetics revealed rate constants of Seac-mediated CM to be comparable or superior to off-protein rates of many current bioconjugations. This CM strategy was applied to histone proteins to install a mimic of acetylated lysine (K9Ac, an epigenetic marker). The resulting synthetic H3 was successfully recognized by antibody that binds natural H3-K9Ac. A Cope-type selenoxide elimination subsequently allowed the removal of such modification to regenerate dehydroalanine. Finally, preliminary research efforts towards metabolic incorporation of allyl sulfide-containing amino acid into proteins, and CM on cell surfaces were discussed.

Olefin metathesis is a valuable synthetic tool, widely used in several fields of science. Due to the importance of this transformation several contributions have been made in this field in order to understand mechanistic aspects, reactivity and applicability of this process. In this topic, ruthenium indenylidene complexes have shown great activity and stability in metathesis, making them very valuable pre-catalysts. However, several aspects of these pre-catalysts have not been evaluated yet. For example, even though reports of active second generation ruthenium indenylidene complexes bearing bulky N-heterocyclic carbenes are present in the literature, no studies have been done to understand how steric hindrance affects the process. For these reasons, [RuCl₂(IPr*)(PPh₃)(3-phenylindenylidene)] (IPr*-PPh₃) and [RuCl₂(IPr*)(Py)(3-phenylindenylidene)] (IPr*-Py), bearing the very bulky ligand, IPr* have been synthesised and compared with [RuCl₂(IPr)(PPh₃)(3-phenylindenylidene)] (IPr-PPh₃) and the new [RuCl₂(IPr)(Py)(3-phenylindenylidene)] (IPr-Py). Another important aspect, presented in this thesis, is the investigation of the stability of indenylidene pre-catalysts in alcohol solvents. Surprisingly, several different decomposition processes occur depending on the starting complex and the alcohol used. Mechanistic investigation into this decomposition, allowed us to develop a better understanding of this process, and to predict the decomposition product based on the environment. In particular, this study revealed that [RuCl(η⁵-3-phenylindenyl)(PPh₃)₂] (Eta-5) is accessed from [RuCl₂(3-phenylindenylidene)(PPh₃)₂] (M₁₀) via a novel indenylidene to η⁵-indenyl rearrangement. This formal decomposition product has been found to be active in at least 20 different catalytic transformations, rendering it a versatile catalytic tool.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Please refer to full text for abstract / AFRIKAANSE OPSOMMING: Sien volteks vir opsomming

Cardanols are more and more used in the industry of polymers, resins, coatings, friction materials, etc. At right conditions, these lipid-like chemicals can undergo metathesis reaction. The main aim of the diploma thesis is an analysis of products of cardanol metathesis by HPLC-MS/MS. Standard 3,3'-hexadec-8-en-1,16-diyldiphenol, one of the main products of cardanol metathesis, was prepared for quantitative HPLC analysis. The standard was prepared in two steps. The first step was cardanol ethenolysis to give 3-(non-8-enyl)phenol. The second step was self-metathesis of 3-(non-8- enyl)phenol to give 3,3'-hexadec-8-en-1,16-diyldiphenol. The standard was characterised by HPLC/MS, MS/MS, EI-MS, UV/VIS, IR, Raman a NMR spectroscopy. The second part of the thesis is dedicated to the study of a mechanism of double-bond localization method in long chain hydrocarbons by acetonitrile APCI-MS. The formation of adducts [M + 55]+ , which are the key substances of this method, was studied using simple alkene models by MS and MS/MS. At the end, the structure and the mechanism of the formation of adducts [M + 55]+ were suggested. Key words: Cardanol, olefin metathesis, HPLC-MS, double-bond localization, APCI, acetonitrile

Thesis advisor: Amir H. Hoveyda / Chapter 1. Mechanistic Insights and Factors Influencing Polytopal Rearrangements in Stereogenic-at-Ru Carbenes. Herein, the mechanistic elucidation of the stereochemical inversion in stereogenic-at-Ru carbene complexes through olefin metathesis (OM) and non-olefin metathesis (non-OM) based polytopal rearrangements is provided. Our investigations involve the isolation and characterization of previously hypothesized higher-energy (e.g., endo-anti) and lower-energy (e.g., exo-anti) diastereomers, and their interconversion under thermal and/or acid-catalyzed conditions is demonstrated. Furthermore, our computational efforts highlighting the importance of the anionic ligands, due to their critical role in trans influence, dipolar interactions, and e-e repulsions, in polytopal rearrangements are reported. Finally, the positive influence of H-bonding in OM and non-OM processes is also rationalized. (a) Khan, R. K. M.; Zhugralin, A. R.; Torker, S.; O'Brien, R. V.; Lombardi, P. J. and Hoveyda, A. H. "Synthesis, Isolation, Characterization, and Reactivity of High-Energy Stereogenic-at-Ru Carbenes: Stereochemical Inversion Through Olefin Metathesis and Other Pathways," J. Am. Chem. Soc. 2012, 134, 12438-12441. (b) Torker, S.; Khan, R. K. M. and Hoveyda, A. H. "The Influence of Anionic Ligands on Stereoisomerism of Ru Carbenes and Their Importance to Efficiency and Selectivity of Catalytic Olefin Metathesis Reactions," J. Am. Chem. Soc. 2014, 136, 3439-3455. Chapter 2. Highly Z- and Enantioselective Ring-Opening/Cross-Metathesis of Enol Ethers Through Curtin-Hammett Kinetics. The first instances of Z- and enantioselective Ru-catalyzed olefin metathesis are presented. Ring-opening/cross-metathesis (ROCM) reactions of oxabicyclic alkenes and enol ethers and a phenyl vinyl sulfide are promoted by 0.5-5.0 mol % of enantiomerically pure stereogenic-at-Ru complexes with an aryloxy chelate tethered to the N-heterocyclic carbene. Products are formed efficiently and with exceptional enantioselectivity (up to >98:2 enantiomer ratio). Surprisingly, the enantioselective ROCM reactions proceed with high Z selectivity (up to >98% Z). Moreover, reactions proceed with the opposite sense of enantioselectivity versus aryl olefins, which afford E- isomers exclusively. DFT calculations and deuterium-scrambling experiments, indicating fast interconversion between endo- and exo-Fischer carbene diastereomers, support a Curtin-Hammett situation. On this basis, models accounting for the stereoselectivity levels and trends are provided. Furthermore, the correlation of Fischer carbene character to the observed chemoselectivity in ROCM with enol ethers is also disclosed. Finally, a general proposal for the substrate-controlled Z selectivity in OM is also discussed. (a) Khan, R. K. M.; O'Brien, R. V.; Torker, S.; Li, B. and Hoveyda, A. H. "Z- and Enantioselective Ring-Opening Cross-Metathesis with Enol Ethers Catalyzed by Stereogenic-at-Ru Carbenes: Reactivity, Selectivity, and Curtin-Hammett Kinetics," J. Am. Chem. Soc. 2012, 134, 12774-12779. (b) Torker, S.; Koh, M. J.; Khan, R. K. M. and Hoveyda, A. H. "Origin of Z selectivity in Olefin Metathesis Reactions of Certain Terminal Alkenes Catalyzed by Typically E-Selective Ru Carbenes," manuscript submitted. Chapter 3. A New Class of Highly Efficient Ru Catalysts for Z-Selective Olefin Metathesis. Herein, we outline a general design for Z-selective OM, which led to the development of a new class of stereogenic-at-Ru carbene complexes (Ru4-9). Furthermore, we demonstrate that the newly developed dithiolate complexes Ru4b and Ru5 efficiently promote high activity and selectivity in ROMP reactions of norbornene and cyclooctene. Notably, the catechothiolate Ru4b catalyzes Z-selective ROCM with a broad scope of alkenes involving various functional groups (e.g., alcohols, enol ethers, vinyl sulfides, amides, heterocycles, and conjugated 1,3-dienes). More importantly, we disclose that the catecholate complex Ru4a is kinetically non-selective in OM and readily decomposes in the presence of mildly acidic moieties (e.g., alcohols and CDCl3). Subsequently, Ru9 is developed to efficiently promote highly Z-selective CM of a diol cross-partner with a wide range of alkene substrates. Most remarkably, the aforementioned protocol is employed in two natural product syntheses and the OM-based Z-selective cracking of oleic acid, which is unprecedented with existing Ru-carbenes and Mo/W-alkylidenes. (a) Khan, R. K. M.; Torker, S. and Hoveyda, A. H. "Readily Accessible and Easily Modifiable Ru-Based Catalysts for Efficient and Z-Selective Ring-Opening Metathesis Polymerization and Ring-Opening Cross-Metathesis," J. Am. Chem. Soc. 2013, 135, 10258-10261. (b) Koh, M. J.; Khan, R. K. M.; Torker, S. and Hoveyda, A. H. "Broadly Applicable Z- and Diastereoselective Ring-Opening/Cross-Metathesis Catalyzed By a Dithiolate Ru Complex," Angew. Chem., Int. Ed. 2014, 53, 1968-1972. (c) Khan, R. K. M. ; Torker, S. and Hoveyda, A. H. "Reactivity and Selectivity Differences Between Catecholate and Catechothiolate Ru Complexes. Implications Regarding Design of Stereoselective Olefin Metathesis Catalysts," J. Am. Chem. Soc. 2014, 136, 14337-14340. (d) Koh, M. J.; Khan, R. K. M.; Torker, S.; Yu, M.; Mikus, M. S. and Hoveyda, A. H. "Synthesis of High-Value Alcohols, Aldehydes and Acids by Catalytic Z-Selective Cross-Metathesis" manuscript submitted. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Different catalytic approaches have been applied to new -lactams preparations. olefin metathesis has been successfully performed with 3--methylidene--lactams. It was verified that 3--methylidene--lactams olefin metathesis is applicable to preparation of biologically active -lactam of Ezetimibe-type.

The use of transition metal catalysts - either homogeneous (discrete well-defined metal complexes) or heterogeneous (more poorly-defined metal surfaces) - play an important role in the transformations of small substrates into larger, value-added compounds. Although heterogeneous catalysts have the greater industrial applicability, there has been enormous interest in homogeneous transition metal systems for effecting selective transformations of small substrate molecules. The bulk of these homogeneous systems are mononuclear. Perhaps surprisingly, very little research has focuses on systems with adjacent metal centres. Binuclear systems possess adjacent metals that may interact and possibly lead to transformations not observed in monometallic systems. It is this opportunity for adjacent metal involvement in substrate activation that is the focus of this dissertation. the goal of this research is to gain an increased understanding of metal-metal cooperativity and adjacent metal involvement in substrate transformations; how can adjacent metal involvement lead to substrate activation not seen in monometallic counterparts, and what role does each metal play in these interactions, particularly when the two metals are different. Throughout this dissertation examples of transformation unique to systems with at least two metals are presented and examined with a particular focus on the roles of the two metals and any associated binding modes in these transformations. In addition, by comparing the RhOs, RhRu and IrRu systems, the influence of metal substitution is also examined. For example, diazoalkane activation and C-c bond formation promoted by the Rh-based systems is investigated, the roles of the adjacent metals of the IrRu system in the conversion of methylene groups to oxygenates is examined, and the unusual geminal C-H bond activation of olefinic substrates is explored. Overall, the work presented within this thesis adds to the growing understanding of adjacent metal cooperativety, leading us toward a more rational approach to the design of homogeneous homo- and heterobimetallic catalysts, heterogeneous catalyst and nanoparticle catalysts for selective substrate transformations.

Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.

This thesis describes original research aimed at the development of highly efficient polymer functionalization strategies by introducing orthogonal chemistry within polymeric systems. The primary hypothesis of this thesis is that the use of click chemistries or noncovalent interactions can provide new and easy pathways towards the synthesis of highly functionalized polymers thereby addressing the shortcomings of traditional covalent functionalization approaches. To verify the hypothesis, the work presented in the following chapters of this thesis further explores previous methods of either covalent or noncovalent polymer functionalization described in Chapter 1. Chapters 2 and 3 present advanced methods of covalent polymer functionalization based on high-yielding and orthogonal click reactions: 1,3-dipolar cycloaddition, hydrazone formation, and maleimide-thiol coupling. All three click reactions employed can be orthogonal to one another and conversions can be quantitative, leading to the easy and rapid synthesis of highly functionalized polymers without interference among functional handles along the polymer backbones. The next two chapters focus on the noncovalent functionalization strategies for creating supramolecular block copolymers via the main-chain self-assembly of telechelic polymers. Novel synthetic methods to prepare telechelic polymers bearing terminal recognition motifs were developed through a combination of ROMP using functionalized ruthenium initiators and functionalized chain-terminators, and the resulting polymers were self-assembled to form supramolecular block copolymers. Chapter 4 demonstrates the formation of supramolecular multiblock copolymers via self-assembly of symmetrical telechelic polymers using metal coordination, while Chapter 5 demonstrates that supramolecular ABC triblock copolymers can be prepared by the self-assembly of a heterotelechelic polymer as the central block with two other complementary monotelechelic polymers using two orthogonal hydrogen bonding interactions. Chapter 6 presents a unique application of noncovalent functionalization approaches. The ultimate goal of this research is to develop a controlled polymerization method based on noncovalent templation. The initial attempts at the metal coordination-based template polymerization are presented in this chapter. Finally, Chapter 7 summarizes the findings in each chapter and presents the potential extensions of the orthogonal functionalization strategies developed in this thesis.

The work described in this thesis is focused on the development of new bidentate iridium complexes and their applications in the asymmetric reduction of olefins, ketones and imines. Three new types of iridium complexes were synthesized, which included pyridine derived chiral N,P-iridium complexes, achiral NHC complexes and chiral NHC-phosphine complexes. A study of their catalytic applications demonstrated a high efficiency of the N,P-iridium complexes for asymmetric hydrogenation of olefins, with good enantioselectivity. The carbene complexes were found to be very efficient hydrogen transfer mediators capable of abstracting hydrogen from alcohols and subsequently transfer it to other unsaturated bonds. This hydrogen transferring property of the carbene complexes was used in the development of C–C and C–N bond formation reactions via the hydrogen borrowing process. The complexes displayed high catalytic reactivity using 0.5–1.0 mol% of the catalyst and mild reaction conditions. Finally chiral carbene complexes were found to be activated by hydrogen gas. Their corresponding iridium hydride species were able to reduce ketones and imines with high efficiency and enantioselectivity without any additives, base or acid. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Submitted. Paper 6: Manuscript.</p><p> </p>