Thesis (Ph. D.)--University of Florida, 2000. / Printout. Vita. Includes bibliographical references (leaves 150-156). Also available on the World Wide Web; PDF reader required.

Ionic liquids (ILs), consisting of ions that are liquid at ambient temperatures, can act as solvents for a broad spectrum of chemical processes. These ionic liquids are attracting increasing attention from industry because they promise significant environmental as well as product and process benefits. ILs were used as solvents for two industrially important homogeneous reactions namely metathesis of 1-octene and the hydroformylation of vinyl acetate. In the metathesis of 1-octene, several reaction parameters were investigated, including temperature, catalyst (type and concentration) and influence of ionic solvent and conventional solvents. Temperature and catalyst concentration were found to be rate-determining factors, but played smaller roles in determining the outcomes of the reactions compared to the influence of individual ILs. It was discovered that more polar ILs were favourable in producing high rates and selectivities. Imidazolium-based cations and tetrafluoroborate anions were superior in activity when compared to other combinations of cations and anions. The addition of catalyst promoters such as phenol and tin(II) chloride were also investigated and found to enhance metathesis rates in “neat” reactions. These catalyst promoters inhibited metathesis rates when used in combination with ILs. In the hydroformylation of vinyl acetate, several reaction parameters were investigated, including temperature, catalyst concentration, vinyl acetate concentration, ligand concentration, syngas pressure and influence of ionic solvent and conventional solvents. It was shown that high n : i ratios of aldehyde products were formed with specific IL systems. Also, low ligand concentrations and low vinyl acetate concentrations increased selectivities, although rates of reactions were somewhat compromised. Lower syngas pressure and lower temperatures afforded enhanced selectivities, again at the expense of reaction rates. Depending on whether fast reaction rates or high regioselectivity is required, the IL and general reaction conditions can be tailored to fit the needs of the reaction. It was discovered that aromatic-containing ammonium-based ILs v afforded high rates at low selectivity. Bulkier ammonium cations tended to give lower rates but the selectivity was significantly enhanced. Impurities present in ILs have also been shown to have a marked effect on hydroformylation rates and selectivity. The reader will be accompanied along a path designed to discover an optimised set of reaction conditions, the path of which will take the reader from reactions providing low selectivities, low turnover numbers and low yields to a much brighter picture, namely extremely high selectivities, turnover numbers and yields. / Prof. D.B.G. Williams

Olefin metathesis is an outstandingly versatile methodology for the catalytic assembly of carbon-carbon bonds. Metathesis methodologies have been widely embraced since the advent of easily-handled ruthenium catalysts. However, industrial implementation has lagged. Problems of reliability and productivity arising from catalyst decomposition have impeded broad uptake of metathesis in process chemistry. Such challenges also hamper deployment of metathesis in forefront applications such as chemical biology. Better understanding of the mechanisms by which catalysts decompose can thus improve performance in demanding applications, as well as providing guidelines for informed process and catalyst design. Oxygen is often viewed as a relatively innocuous contaminant in reactions promoted by these late transition metal catalysts. Indeed, multiple reports comment on the desirability and operational simplicity of metathesis in air. We suspected, however, that deleterious impacts of O2 may be masked by the high catalyst loadings typically deployed in such reports. The first part of this thesis focuses on examining the robustness of leading metathesis catalysts toward oxygen. Systems examined include the classic, dominant N-heterocyclic carbene (NHC) derivatives, as well as recent breakthrough analogues containing cyclic alkyl amino carbene (CAAC) ligands. Both are shown to be decomposed by oxygen, but the CAAC catalysts are found to be not only more productive, but significantly more O2-tolerant. This is important as it overturns the widespread belief that high catalyst activity is invariably a trade-off against higher sensitivity. Studies of the initial oxidation event for the second-generation Grubbs catalyst RuCl2(H2IMes)(PCy3)(=CHPh) suggest that [2+2] cycloaddition of O2, as well as bimolecular decomposition of the four- coordinate species generated by PCy3 oxidation, account for ca. 90% of the observed decomposition. A previously-proposed pathway involving attack of O2 at the benzylidene ligand appears to be a minor contributor. In Chapter 3 of this thesis, a new strategy for inhibiting catalyst decomposition is examined. Specifically, cationic metathesis catalysts were encapsulated within a supramolecular resorcinarene capsule, which self-assembles around the catalysts in water-saturated toluene. Encapsulation nearly doubles RCM yields relative to the parent, neutral catalyst in water-saturated toluene. The increased catalyst productivity is enabled by site-isolation of the catalyst within the capsule, which prevents bimolecular decomposition, and by the hydrophobic nature of the capsule interior, which limits decomposition by water. A final study focuses on attempts to identify a more robust catalyst via ligand redesign. Examined for this purpose are recently reported, electron-rich pyridinylide aminophosphines (PyAPs; these take the general form R2P–N=Ar), which exhibit enhanced s-donor properties relative to NHCs. Strategies for incorporation of PyAP ligands into Ru metathesis catalysts are developed, and the catalytic activity of these species is described. PyAP catalysts are found be significantly less active than the corresponding NHC catalysts, despite their higher donicity. Poor performance results from facile catalyst decomposition. Where the N=Ar group lacks substituents at the ortho sites, o- metalation enables decomposition of the precatalyst. More problematically, the nitrogen atom appears to participate in nucleophilic attack on the key, metathesis-enabling [Ru]=CHR functionality, limiting the potential use of this class of phosphine in metathesis. Criteria for the development of more robust second-generation phosphine catalysts are proposed.

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Thesis advisor: Amir H. Hoveyda / Chapter 1. The first examples of highly Z- and enantioselective ring-opening/cross-metathesis reactions are disclosed. Transformations involve meso cyclic olefin substrate and styrenes or enol ethers as olefin cross partners. A stereogenic-at-Mo monoaryloxide monopyrrolide (MAP) complex, prepared and used in situ, is discovered for the efficient formation of Z olefins. Such complex, bearing a relatively smaller adamantylimido and a larger chiral aryloxide ligand, leads to kinetic Z-selectivity due to the size differential. In most cases, the resulting disubstituted Z olefins are formed with excellent stereoselectivity (>95% Z). Chapter 2. The protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Stereoselective cyclizations are performed with either Mo- or W-based monoaryloxide monopyrrolide (MAP) complex at 22 oC. Synthetic utility of such broadly applicable transformation is demonstrated by synthesis of several macrocyclic natural products: relatively simpler molecules such as epilachnene (91% Z) and ambrettolide (91% Z), as well as advanced precursors to epothilones C and A (97% Z) and nakadomarin A (94% Z). Several principles of catalytic stereoselective olefin metathesis reactions are summarized based on the studies: 1) Mo-based catalysts are capable of delivering high activity but can be more prone to post-RCM isomerization. 2) W-based catalysts, though furnish lower activity, are less likely to cause the loss of kinetic Z selectivity by isomerization. 3) Reaction time is critical for retaining the stereoselectivity gained from kinetic, which not only applicable with MAP complexes but potentially with other complexes as well. 4) By using W-based catalyst, polycyclic alkenes can be accessed with sequential RCM reactions, without significant erosion of the existing Z olefins in the molecule. Chapter 3. An enantioselective total synthesis of anti-proliferative agent (+)-neopeltolide is presented. The total synthesis is accomplished in 11 steps for the longest linear sequence and 28 steps in total, including 8 catalytic reactions. Particularly, several Mo- or Ru-catalyzed stereoselective olefin metathesis reactions as well as N-hetereocyclic carbene (NHC)-catalyzed enantioselective boron conjugate addition to an acyclic enoate have proven to be effective for convergent construction of the molecule. The most important novelty of the study incorporates the explorations of feasibility of Z-selective cross-metathesis reactions to solve the challenge of installing two Z olefins with excellent selectivity. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1: Efficient Z-Selective Cross-Metathesis of Secondary Allylic Ethers Efficient Z-selective cross-metathesis of secondary allylic ethers were catalyzed by monoaryloxide monopyrrolide molybdenum complexes. Reactions involving both silyl and benzyl protected ethers were demonstrated, as well as ethers containing alkyl, aryl and alkynyl substituents. Mechanistic studies were performed, and the reactions were applied to the total synthesis of several ene-diyne natural products. Chapter 2. Stereoselective Total Synthesis of Disorazole C1 The stereoselective total synthesis of disorazole C1 is reported. The synthesis was completed in 12 longest linear steps. Our synthesis demonstrates the utility of Z-selective cross-metathesis to form both alkenyl borons and alkenyl halides. Another key transformation was a one-pot Suzuki-dimerization reaction to form a symmetric 30 membered ring in relatively high yield. Chapter 3. Stereoselective Cross-Metathesis to Form Trisubstituted Alkenes Initial studies into the stereoselective formation of trisubstituted olefins through molybdenum catalyzed cross-metathesis have been performed. Our mechanistic understanding of the reaction lead us to focus on the synthesis of alkenyl halides, which can be obtained in up 90% yield and 75:25 E:Z selectivity. Chapter 4: Ring-Closing Metathesis in the Synthesis of Natural Products Development of highly efficient and selective ring-closing metathesis reactions have enabled collaborators to successfully implement routes in total synthesis endeavors. A diastereoselective seven-membered ring-closing metathesis enabled the successful synthesis of (±)-tetrapetalone A methyl-aglycon. An enantioselective ring-closing metathesis to form a six membered ring has provided access to enantioenriched aspidosperma alkaloids. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Compounds containing multiple metal-carbon bonds are now widely used as catalysts for organic and materials synthesis. Among such transformations, olefin metathesis (OM) occupies a position of pre-eminent significance. Alkyne metathesis holds great promise, but remains in a much lower state of development. The OM-directed work in this thesis sought to advance the state of the art in living, Ru-catalyzed ringopening metathesis polymerizations (ROMP). Currently, the first- and third-generation Grubbs initiators, which exhibit the ease of handling characteristic of the late metal ruthenium, dominate ROMP applications. These initiators are characterized by extremes of reactivity, however. We describe the first ruthenium initiator capable of living ROMP at RT, irrespective of monomer bulk. Polydispersity indices as low as 1.03 are routinely attainable, and excellent control is maintained in synthesis of diblock copolymers from sterically demanding and sterically unencumbered monomers. Work on alkyne metathesis sought to expand existing understanding of the features that influence stability and reactivity in ruthenium carbynes. A classification system was developed in which Class A carbynes were defined as those that readily undergo conversion into an M=C entity (e.g. vinylidene, allenylidene, or alkylidene); Class B carbynes those that have a stable carbyne functionality. Four Ru carbyne complexes, all initially regarded as prospective Class B carbynes, were selected for study. Investigation of their reactivity resulted in categorization of several as Class A species, and development of design criteria that may open the door to assembly of stable, well-defined carbyne complexes of ruthenium.

Compounds containing multiple metal-carbon bonds are now widely used as catalysts for organic and materials synthesis. Among such transformations, olefin metathesis (OM) occupies a position of pre-eminent significance. Alkyne metathesis holds great promise, but remains in a much lower state of development. The OM-directed work in this thesis sought to advance the state of the art in living, Ru-catalyzed ringopening metathesis polymerizations (ROMP). Currently, the first- and third-generation Grubbs initiators, which exhibit the ease of handling characteristic of the late metal ruthenium, dominate ROMP applications. These initiators are characterized by extremes of reactivity, however. We describe the first ruthenium initiator capable of living ROMP at RT, irrespective of monomer bulk. Polydispersity indices as low as 1.03 are routinely attainable, and excellent control is maintained in synthesis of diblock copolymers from sterically demanding and sterically unencumbered monomers. Work on alkyne metathesis sought to expand existing understanding of the features that influence stability and reactivity in ruthenium carbynes. A classification system was developed in which Class A carbynes were defined as those that readily undergo conversion into an M=C entity (e.g. vinylidene, allenylidene, or alkylidene); Class B carbynes those that have a stable carbyne functionality. Four Ru carbyne complexes, all initially regarded as prospective Class B carbynes, were selected for study. Investigation of their reactivity resulted in categorization of several as Class A species, and development of design criteria that may open the door to assembly of stable, well-defined carbyne complexes of ruthenium.

Compounds containing multiple metal-carbon bonds are now widely used as catalysts for organic and materials synthesis. Among such transformations, olefin metathesis (OM) occupies a position of pre-eminent significance. Alkyne metathesis holds great promise, but remains in a much lower state of development. The OM-directed work in this thesis sought to advance the state of the art in living, Ru-catalyzed ringopening metathesis polymerizations (ROMP). Currently, the first- and third-generation Grubbs initiators, which exhibit the ease of handling characteristic of the late metal ruthenium, dominate ROMP applications. These initiators are characterized by extremes of reactivity, however. We describe the first ruthenium initiator capable of living ROMP at RT, irrespective of monomer bulk. Polydispersity indices as low as 1.03 are routinely attainable, and excellent control is maintained in synthesis of diblock copolymers from sterically demanding and sterically unencumbered monomers. Work on alkyne metathesis sought to expand existing understanding of the features that influence stability and reactivity in ruthenium carbynes. A classification system was developed in which Class A carbynes were defined as those that readily undergo conversion into an M=C entity (e.g. vinylidene, allenylidene, or alkylidene); Class B carbynes those that have a stable carbyne functionality. Four Ru carbyne complexes, all initially regarded as prospective Class B carbynes, were selected for study. Investigation of their reactivity resulted in categorization of several as Class A species, and development of design criteria that may open the door to assembly of stable, well-defined carbyne complexes of ruthenium.

Thesis advisor: Amir H. Hoveyda / Chapter 1. In Situ Methylene Capping: A Key Strategy in Catalytic Stereoretentive Olefin MetathesisA general approach for in situ methylene capping that significantly expands the scope of catalyst-controlled stereoselective olefin metathesis is presented. By incorporation of stereodefined 2-butene as the capping reagent, the catechothiolate Ru complex is enabled to catalyze olefin metathesis reactions of terminal alkenes. Substrates bearing a carboxylic acid, an aldehyde, an aryl substituent, an α substituent were thus converted to the desired products in 47–88% yield and 90:10–98:2 Z:E selectivity. The capping strategy was also applied in ring-closing metathesis reactions leading to 14- to 21-membered macrocyclic alkenes (96:4–98:2 Z:E). The utility of this method was highlighted through synthesis of a platelet aggregate inhibitor and two members of the prostaglandin family compounds by cross-metathesis reaction, as well as a strained 14-membered ring stapled peptide by macrocyclic ring-closing metathesis. Examples of the corresponding E-selective cross-processes are provided as well. Chapter 2. Synthesis of Z- or E-Trisubstituted Allylic Alcohols and Ethers by Kinetically Controlled Catalytic Cross-MetathesisKinetically controlled Ru-catalyzed cross-metathesis reactions that generate Z- or E-trisubstituted alkenes are discussed. Reactions were catalyzed by catechothiolate Ru complex to generate trisubstituted allylic alcohols and ethers in up to 81% yield and >98% stereoisomeric purity. The approach is applicable to synthesis of products containing an alcohol, an aldehyde, a carboxylic acid or an alkenyl substituent. Mechanistic models that account for the observed trends in efficiency and stereoselectivity will be provided. Chapter 3. A New Ru-Based Catechothiolate Complex Bearing an Unsaturated NHC Ligand for Synthesis of Z-α,β-Unsaturated Carbonyl Compounds by Cross Metathesis Design and development of a new Ru catechothiolate complex that may be used to promote Z-selective cross-metathesis transformations that afford Z-α,β-unsaturated esters, acids, and amides (including Weinweb amides) are discussed. Comparison between Ru catechothiolate complexes with an unsaturated NHC and a saturated NHC ligand will be provided. Utility of the approach is demonstrated by an eight-step synthesis (15% overall yield) of an intermediate for synthesis of stagonolide E, and a five-step synthesis of a precursor to dihydrocompactin / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.