Thesis advisor: Amir H. Hoveyda / Chapter 1 Mechanism-Based Enhancement of Scope and Enantioselectivity for Reactions Involving a Copper-Substituted Stereogenic Carbon Center: Organoborons are important building blocks of complex natural products, functional materials, and pharmaceutically relevant compounds due to their prevalent utility in C–C and C–hetero atom bond transformations. Using a readily accessible copper catalyst, we have developed highly site- and enantioselective allylic substitution by way of a threecomponent, single-vessel, and sustainable catalytic protocol. Detailed mechanistic studies revealed valuable insights which led us to develop copper–boron and copper–hydride additions to olefins with broader substrate scope, higher efficiency, and higher enantioselectivity. In addition, the method can be applied to the synthesis of biologically active molecules such as preclamol and heliespirone A and C. Chapter 2 Versatile Homoallylic Boronates by Chemo-, SN2’-, Diastereo- and Enantioselective Catalytic Sequence of Cu–H Addition to Vinyl-B(pin)/Allylic Substitution: To achieve an efficient multicomponent reaction, high chemoselectivity between a starting material and a reagent must be accomplished during the first catalytic transformation to generate an intermediate which then selectively reacts with another substrate to furnish the product in a site-, and/or stereoselective fashion. Development and application of efficient multicomponent reactions involving allylic substitution can provide alternative solutions for difficult synthetic problems in organic chemistry. Our group has developed a sulfonate-containing chiral NHC–Cu catalyzed chemo-, SN2’-, diastereo-, and enantioselective multicomponent reaction through Cu–H addition to readily available vinyl–B(pin) followed by allylic substitution to deliver homoallylic boronates. The derived homoallylic alcohols can be used as building blocks of biologically active molecules. Chapter 3 Enantioenriched Halogen-Substituted Alkenes through NHC–Cu-Catalyzed Borylation/Dehalogenation and Their Applications: Because of their unique properties, mono- and difluoroalkenes have received attention as an important class of compounds as building blocks for fluorine-containing monomers for functional polymers and biologically active molecules in medicine and agriculture. However, reported methods to prepare enantioenriched difluoroalkenes are scarce and often require undesirable amounts of precious transition metals and very high/low temperatures. To solve these challenges, we have developed a highly efficient, regio-, and enantioselective boron allylic substitution to CF3-alkenes and other halogen-substituted olefins by using an abundant copper-based catalyst. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / This dissertation aims to design and develop novel and synthetically useful catalytic enantioselective C-C bond-forming reactions that employ a newly uncovered 3,3'-reductive elimination of bis(allyl)metal species. This elementary transformation allows for new routes for the enantioselective construction of a range of important motifs found in natural products. Enantiomerically enriched Z-allylic alcohols are readily accessed through the Ni-catalyzed allylation of trans,trans-dienals. Importantly, the first example of branch- and enantioselective allyl-allyl cross-coupling is presented as well, suitable for the construction of compounds bearing tertiary and quaternary carbon centers. With the aim to broaden the application of above described transformations, this dissertation also presents the development of highly efficient and convenient methods for the syntheses of substituted and functionalized allylic boronates. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: Stephen F. Martin. Vita. Includes bibliographical references.

This thesis details the design and development of pentacarboxycyclopentadienes (PCCPs) as a new platform for enantioselective Brønsted acid catalysis. Prior to this research, enantioselective Brønsted acid catalysis was limited to the BINOL (and variations thereof) framework. While this catalyst platform has paved the way for a myriad of novel asymmetric chemical transformations, the utility of this catalyst scaffold has suffered from its lengthy and expensive preparations. As an alternative, starting from readily available 1,2,3,4,5-pentacarbomethoxycyclopentadiene and various chiral alcohols and amines, the synthesis of a library of strongly acidic chiral catalysts is described. The utility of these novel acid catalysts is explored in various transformations. As a prelude to the heart of this work, Chapter 1 focuses on the advancements made in asymmetric Brønsted acid catalysis through BINOL-phosphate derived catalysts, focusing on the major accomplishments made by researchers since 2004. The provided review highlights the utility of these chiral acid catalysts but also reveals the need for a new scaffold that is more affordable and accessible. Chapter 2 discusses the background of PCCPs, including its initial discovery and subsequent applications. Our work in developing novel transesterified and amidated derivatives is discussed with accompanying crystal structures of achiral and chiral PCCPs. pKa measurements demonstrate the capacity of PCCPs to be used as strong Brønsted acid catalysts and are compared to literature values of known Brønsted acid catalysts. Chapter 3 focuses on the utility of PCCPs as enantioselective Brønsted acid catalysts in a variety of chemical transformations including the Mukaiyama-Mannich reaction, transfer hydrogenation, Pictet-Spengler reaction, diaryl alcohol substitution, Mukayaiama oxocarbenium aldol reaction, and [4+2]-cycloaddition. Catalyst loadings down to 0.01 mol% and reaction scale up to 25 grams in the Mukaiyama-Mannich reaction demonstrate the practical utility and robustness of PCCPs. Substrate scopes of these transformations show the breadth of accessible molecules that can be synthesized via PCCPs. Mechanistic rationales and transition state analyses are discussed in each of the transformations.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2006. / Title from title screen (site viewed May 22, 2007). PDF text: 466 p. : ill. ; 17.94Mb. UMI publication number: AAT3237597 . Includes bibliographical references. Also available in microfilm and microfiche formats.

(+)-(2R,3R)-1,1,4,4-Tetraphenylbutane-1,2,3,4-tetraol (TETROL) and its derivatives were reacted with varying molar ratios of titanium isopropoxide (2:1, 1:1 and 1:2 tetraol:titanium isopropoxide) in an attempt to prepare potential titanium-based tetraol catalysts for enantioselective transformations. In each case, infrared and HNMR spectra suggested that the product was formed. We tentatively proposed that the structure of the catalyst was a spiro-type, but we could not determine conclusively what its exact structure was, despite using numerous techniques at our disposal (molecular modelling calculations, H NMR and IR spectroscopy, thermal analyses, powder diffraction, and single crystal X-ray diffraction). The catalyst and derivatives thereof were able to act catalytically for the enantioselective additions of diethylzinc compounds to aldehydes. The effects of temperature and solvent were investigated, and toluene and -78 °C were selected as optimal from the results obtained. (The reaction could, however, not be maintained at this low temperature for extended periods due to the fact that we did not have, at our disposal, the correct equipment. Each 16 h reaction was thus allowed to reach room temperature in each case.) The selectivity for the product 1-phenylpropan-1-ol (when benzaldehyde was the starting aldehyde) varied depending on the nature of the aryl substituents of the titanium-based catalyst. Using 0.2 molar equivalents of the chiral titanates, the highest selectivity was 42 percent (e.e.), but only when excess Ti(O-i-Pr)4 had been added to the reaction mixture. This was achieved with the tetra(ortho-methoxyphenyl)-TETROLate derivative. TETROL and its derivatives were also successful in metal-free catalysis where higher conversions and selectivities were observed, compared to when these were complexed to titanium. The highest selectivity was 70 percent (e.e.), achieved with the tetra(ortho-methylphenyl)TETROL derivative.

Obtaining enantiomerically pure compounds is of major importance in modern organic chemistry, and this PhD thesis outlines new advances made in this area. Two new enantioselective synthetic methodologies have been designed using isothiourea based- organocatalysts. A brief introduction to the recent literature involving this catalyst architecture is presented. Then, the results of the structure-activity relationship study carried out on a range of isothiourea catalysts for the kinetic resolution of (±)-1-naphthylethanol 16 is described. Chiral isothiourea HBTM 2.1 58 was identified as the optimum catalyst and was further employed in the resolution of a range of secondary alcohols. Good levels of conversion (c~50%) and selectivity (S up to 100) were achieved delivering alcohols in high levels of enantioselectivity (up to 98% ee). The synthetic utility of this process was subsequently demonstrated through isolation of a range of enantiopure alcohols (>99% ee) on a preparative scale, using low catalyst loading of HBTM 2.1 (0.10 mol%). Secondly, a new organocatalytic asymmetric transformation involving the generation of a C1-ammonium enolate using isothiourea is described. An intramolecular Michael addition-lactonisation (IMAL) of enone-acid substrates was developed using (‒)-tetramisole 37 as a catalyst. The generality of this protocol was probed via structural variation of the enone-acid substrates, providing a range of highly functionalised syn-polycyclic carbo- and heterocycles in excellent yields, diastereo- and enantioselectivities (up to 99% yield, 99 : 1 dr and 99% ee). Whilst investigating this process, we discovered that using cinchona alkaloid derivatives as catalysts gave preferential access to the diastereomeric anti-products. Therefore, a range of anti-dihydrobenzofurans was synthesised from readily available starting materials in good yield and stereoselectivities (up to 73%, 20 : 80 dr and 99% ee) using OTMS-quinidine catalyst. These two complementary synthetic strategies allowed facile and controllable access to both syn- and anti-diasteroisomers of a product in high enantioselectivity via judicious choice of catalyst. Subsequently, two telescoped procedures combining the synthesis of the enone-acid through olefination and asymmetric functionalisation were designed, giving rapid access to stereodefined pyrrolidines in high levels of diastereo- and enantioselectivitiy (up to 99 : 1 dr and 99% ee). The last part of this thesis describes preliminary studies toward the development of a doubly diastereoselective intramolecular Michael addition-lactonisation process, opening new avenues for the construction of complex molecular architectures.

Thesis advisor: Shih-Yuan Liu / The first three chapters of this dissertation elaborate on certain facets of the isosteric relationship between different types of boron-nitrogen-containing heterocycles and the corresponding all-carbon compounds. In this vein, Chapter 1 describes selective photoisomerization of aromatic 1,2-dihydro-1,2-azaborines to BN-analogues of bicyclo[2.2.0]hexa-2,5-diene (Dewar benzene). In one instance, the photoisomer product was further derivatized into a series of disubstituted cyclobutanes through manipulations of the boron functionality. Chapter 2 discloses a combined experimental/theoretical mechanistic investigation of preliminary hydrogen release from the amine borane unit in a pair of BN-cycloalkanes. In Chapter 3, the kinetics of complementary dehydrogenation of the alkyl units in a BN-cyclohexene derivative are compared with those of related six-membered carbocycles. Chapter 4 treats with the separate subject of enantioselective silylation of glycerol by a catalytic strategy centered around reversible covalent binding of substrate hydroxyl groups. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Exploring Ligand Effects in Ruthenium Dithiolate Carbene Complexes. Ruthenium dithiolate metathesis catalysts discovered in the Hoveyda group have been a valuable addition to the field of olefin metathesis. While the catalyst shows unique selectivity and reactivity, quantifying and mapping key interactions in the catalyst framework to elucidate and explain causes is difficult. We, therefore, decided to use the neutral chelating or monodentate ligand, controlling initiation, as a structural probe. By altering its properties and observing changes in the catalyst, we sought to deepen our understanding of these complexes. We established a trans influence series with over 20 catalysts and correlated the impact on catalyst initiation. Further, we show that in the case of strongly σ-donating and π-accepting ligands such as phosphites and isonitriles, the complex exhibits fluxional behavior. The catalysts ground state is elevated to such a degree that thiolate Ruthenium bonds become labile and rapidly exchange. While Ruthenium dithiolate catalysts were readily applied to metathesis polymerization, their use in the synthesis of small molecules was initially less forthcoming. Specifically, reactions involving terminal olefins lead to rapid catalyst deactivation and only low conversion. We were able to determine that the potential energy stored in the trans-influence between the thiolate ligand and the NHC can be released in a sulfur shift to reactive Ruthenium methylidene species. Since methylidenes are formed by reaction with terminal olefins, use of an excess of internal olefins can prevent their formation. Chapter 2. Harnessing Catalyst Fluxionality in Olefin Metathesis. Depending on its use, material requirements can vary significantly. Materials that can easily be adapted to a given application, for example by varying tensile strength, melting point or solubility, are desirable. Controlling the polymers tacticity (the adjacent stereocenters in a polymer chain) is a straight forward way to achieve just that. Ru dithiolate catalysts should give highly syndiotactic polymers due to their single stereocenter undergoing inversion during every metathesis step. The fluxional nature of the catalyst allows for control of polymer tacticity from 50% (atactic) to ≥95% syndiotacticity by changing monomer concentration. We determined the factors which are responsible for fluxionality and synthesized complexes that give either high or low levels of tacticity over a broader range of monomer concentration. Chapter 3. Harnessing Catalyst Fluxionality in Olefin Metathesis. The importance of fluorine-containing molecules is hard to understate, keeping in mind the surge of new methodologies for their synthesis and the medical breakthroughs they enable. However, efficient and practical syntheses of stereodefined alkenyl fluorides are rare. In this context, we have developed enantioselective boryl allylic substitution of allylic fluorides, which yield enantioenriched γ-alkenyl fluoride substituted allyl boronate esters. The reaction is catalyzed by Cu-based catalysts that are prepared in-situ and delivered as products with high yield and enantioselectivity. Mechanistic inquiry shows the reaction is not a concerted allylic substitution. An intermediate Cu alkyl complex is formed after the Cu boron addition is made to the double bond, which only slowly undergoes β-fluorine elimination in the presence of a Lewis acid. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.