No description available.

No description available.

Thesis advisor: Marc L. Snapper / Tandem processes can have several advantages over multiple single step processes. Non-metathesis transformations of ruthenium alkylidenes were studied and applied to tandem processes. Ruthenium catalyzed tandem RCM/hydroacylation that allows access to tricyclic ring systems from readily available substrates was developed. Mechanistic investigations indicated that this reaction may proceed through a mechanism involving [Ru]-H species. A Ru-catalyzed tandem RCM/olefin isomerization/C-H activation sequence that provides significant advantages in terms of rapid elaboration of simple reaction partners to more complex entities was developed. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Kian L. Tan / Thesis advisor: Shih-Yuan Liu / Chapter 1. In the Tan laboratory, we developed synthetic methods to control reaction selectivity (regio-, stereo-, and site-selectivity) using scaffolding catalysis. Our strategy utilizes directing groups that induce intramolecularity through the formation of a labile covalent bond between the substrate and a binding site in a catalytic system. In the first part, we described site-selective functionalization of various carbohydrates and complex polyhydroxylated molecules which contain cis-1,2-diol motif using a chiral organic scaffold. In the second part, meta-selective C–H functionalization of arenes was demonstrated. High meta-selectivity was achieved by the use of a nitrile-based silyl tether which is cleavable and recyclable. Chapter 2. In the Liu laboratory, we focuses on studies of boron-nitrogen containing heterocycles. In this chapter, synthesis of 1,2-azaborines and their binding study with T4 lysozyme mutants were described. Specifically, we directly compared binding of NH-containing 1,2-azaborines and their carbonaceous analogs to probe hydrogen bonding interaction between the NH group of azaborine and a carbonyl oxygen of protein residue. Structural and thermodynamic analysis provided us the first evidence of H-bonding of azaborines with a biological macromolecule. Chapter 3. Described are the synthesis of regioisomers of ethyl-substituted 1,2-azaborines and their binding thermodynamics to T4 lysozyme mutants. To access the azaborine ligands used in the binding study, we developed synthetic methods for regioselective functionalization of six positions of 1,2-azaborines. Isothermal titration calorimetry experiments showed differences in binding free energy for regioisomers to the L99A T4 lysozyme. This result could originate from electronic differences of the isosteric ligands inducing dipole-dipole interaction between ligand and surrounding protein residues or it may be from local dipolar interactions. Chapter 4. A general method for late-stage N-functionalization of 1,2-azaborines is described to afford libraries of BN-containing complex molecules. The chemical transformations include electrophilic substitution reactions, N–C(sp2) bond forming reactions under Buchwald-Hartwig amination conditions, and N–C(sp) bond forming reactions using copper-catalyzed N-alkynylation. As applications in materials science and medicinal chemistry, synthesis of the first parental BN isostere of trans-stilbene and lisdexamfetamine derivative is described utilizing the methodology developed in this work. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The invention of catalytic processes that convert feedstock chemicals into pharmacologically-privileged amines is a landmark challenge in organic synthesis. This thesis describes the development of three novel transition-metal catalyzed processes for the synthesis of alkylamines that attempts to meet this challenge. The first Pd-catalyzed methylene β-C−H carbonylation of alkylamines to form substituted β-lactams is reported. Through the synergistic use of a Pd-catalyst and Xanpthos ligand, secondary amines underwent exclusive methylene β-C−H activation in high yields and diastereoselectivities. Subsequently, the development of a remarkably selective methylene β-C−H carbonylation of α-tertiary amines (ATAs), is detailed. This methodology enables the C−H carbonylation of methylene C−H bonds over traditionally more reactive methyl and C(sp2)−H bonds. Importantly, a range of functional groups previously incompatible with C−H technologies were tolerated in good yields. Finally, the development of a novel multicomponent synthesis of tertiary amines is described. The novel photocatalytic single-electron reduction of alkyl iminium ions furnishes -amino radicals that engage alkenes forming a new C-C bond. The reaction exhibits broad functional group tolerance and enables the synthesis of amines not readily accessible by existing methods.

No description available.

The most efficient homogeneous catalysts for hydroxylation of light alkanes utilize transition metals in superacid solvent and operate by tandem electrophilic C-H activation/metal-alkyl (M-R) functionalization. An emerging alternative strategy to transition metals is the use of high-oxidation state main-group metals (e.g. TlIII, PbIV, IIII) that hydroxylate light alkanes. This dissertation reports density-functional theory calculations that reveal the mechanisms, reactivity, and selectivity of TlIII promoted alkane C-H functionalization in trifluoroacetic acid and TlIII-dialkyl functionalization in water. Calculations reveal that TlIII oxidizes alkanes via a closed-shell C-H activation and M-R functionalization mechanism that is similar to transition-metal C-H functionalization mechanisms. Comparison of TlIII to similar transition metals reveals that while TlIII and transition metals can have similar activation barriers for C-H activation, TlIII M-R functionalization is significantly faster due to a highly polar Tl-C bond and large TlIII/TlI reduction potential. The combination of a moderate C-H activation barrier combined with a low M-R functionalization barrier is critical to the success for TlIII promoted alkane C-H oxidation. The proposed TlIII C-H activation/M-R functionalization mechanism also provides an explanation for ethane conversion to a mixture of ethyl trifluoroacetate and ethane-1,2-diyl bis(2,2,2-trifluoroacetate). The reactivity of TlIII contrasts the lack of alkane oxidation by HgII. The C-H activation transition state and frontier-orbital interactions provide a straightforward explanation for the higher reactivity of TlIII versus HgII. This frontier-orbital model also provides a rationale for why the electron-withdrawing group in EtTFA provides "protection" against overoxidation. Calculations also reveal that TlIII-dialkyl functionalization by inorganic TlIII in water occurs by alkyl group transfer to form a TlIII-monoalkyl complex that is rapidly functionalized.

Many commercialized medicinal compounds are analogs of chemicals isolated from sources found in nature (also called natural products). However, the natural sources of these chemicals, such as plants, fungi, or insects, only offer small quantities of these bioactive agents. Thus, it is typically desirable to find ways to synthesize these products and their analogs in large quantities using cost-effective methods that also minimize the impact on the environment. It is also important to develop strategies that expedite the process of modifying the natural products, which allows medicinal chemists to determine which functional groups are enhancing or deleterious to the bioactivity. In the Brewer lab, I have investigated organic reactions and methodologies with this aim - to find ways to efficiently break and form carbon-carbon bonds, and to utilize these reactions in the total synthesis of structurally related natural products. The total synthesis of natural products is often used to showcase a methodology's utility by applying it in a more complex structure. The Lewis acid-promoted fragmentation of γ-silyloxy-β-hydroxy-α-diazo esters to provide tethered aldehyde ynoates was discovered and developed in the Brewer lab. This methodology was extended to bicyclic systems, in which the ring-fusion bond fragmented as a way to afford 10-membered ring ynones and ynolides, which are traditionally challenging to synthesize. This work will exhibit how the fragmentation reaction that provided 10-membered ynolides has the potential to lend itself to the synthesis of several structurally related, bioactive natural products via a divergent total synthesis strategy. In addition, this dissertation will describe our discovery that modifying the diazo carbonyl precursor to a β-hydroxy-α-diazo ketone changes the course of the Lewis acid-promoted reaction. Rather than a fragmentation sequence, the compound is converted to a vinyl cation, which undergoes a rearrangement then a C-H insertion of a second vinyl cation intermediate. This transition metal-free rearrangement/C-H insertion reaction provided cyclopentenone products. The migratory aptitudes of non-equivalent substituents in the cationic rearrangement step will also be discussed. Finally, the disparate reactivities of vinyl cations derived from diazo ketone, diazo ester, and diazo amide precursors will be detailed from an experimental and computational perspective. The results underscore the fact that this rearrangement and C-H insertion reaction may eventually be an effective way to prepare complex cyclopentyl-containing structures, which are common motifs in biologically active natural products.

Lactacystin is a microbial metabolite isolated by Omura that exhibits neurotrophic activity in neuroblastoma cell lines. Lactacystin and especially its β-lactone analog are the first examples of non-polypeptide small molecules capable of specifically inhibiting the 20S proteasome. Various asymmetric total syntheses of lactacystin and its analogs have been reported. The total synthesis of clasto -lactacystin β-lactone is achieved using L-serine methyl ester as the starting material and the sole source of stereochemical induction. The success of this synthesis hinges on two featured transformations. The first key step involves formation of the γ -lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the α-diazo-α-(phenylsulfonyl)acetamide intermediate. The methodology for this transformation has been developed and applied to the synthesis of highly functionalized stereogenic γ-lactams from natural α-amino acids. Three control elements that govern γ-lactam formation are described. This step is highlighted by the xvi simultaneous creation of two stereogenic centers of the γ-lactam core. The second key step involves the late stage aldol coupling for quaternary carbon formation and installation of the hydroxyisobutyl group. In all previously reported syntheses, this is the very first aspect which is addressed. The stereochemical outcome of this step is directed by the chiral environment of the enolate itself. Various attempts to achieve selectivity are explored and reported. Completion of the synthesis of clasto-lactacystin β-lactone requires 17 steps with an overall yield of 10%. Some general attempts for optimizing the synthetic scheme are discussed as well as the future direction of this research.

La fonctionnalisation de liaisons C-H réputées peu réactives ouvre de nouvelles perspectives en synthèse organique. Une stratégie efficace consiste en l’utilisation d’un métal de transition. Les travaux de thèse présentés dans ce mémoire s’inscrivent dans ce contexte. Dans un premier temps, la réaction étudiée, catalysée par le palladium, vise à étendre une méthodologie mise au point au laboratoire, permettant la synthèse de benzocyclobutènes par activation intramoléculaire de liaisons C(sp3)-H de groupements méthyles benzyliques, à des composés non aromatiques. Plusieurs substrats ont été synthétisés pour être ensuite placés dans les conditions de la réaction d’activation C(sp3)-H, dans le but d’induire la formation du cyclobutène ou du cyclobutane désiré. Le processus n’est pas sélectif et de nombreux produits secondaires sont obtenus par des réactions péricyliques ou par des réarrangements suite à l’ouverture du palladacycle intermédiaire. Dans un deuxième temps, nos travaux ont permis de mettre à jour une nouvelle réaction de fonctionnalisation C(sp3)-H, catalysée par le palladium permettant l’arylation d’esters en position β par un mécanisme original. Les investigations portent sur l’optimisation complète de cette réaction, la compréhension du mécanisme et le développement d’une version énantiosélective prometteuse. Le mécanisme de cette réaction, confirmé par des calculs DFT réalisés en collaboration avec C. Kefalidis et E. Clot, se rapproche formellement de celui observé en α-arylation, puisqu’il repose sur la formation d’un énolate de palladium. La stratégie mise au point permet le couplage, dans des conditions douces, d’esters simples et commerciaux avec des halogénures d’aryles contenant un groupement électronégatif en position ortho, donnant ainsi accès à des intermédiaires de synthèse intéressants tels qu’un analogue de la phénylalanine ou des composés fluorés. / The direct functionalization of C-H bonds represents an atom- and step-economical alternative to more traditional synthetic methods based on functional group transformation, which often require multi-step sequences. In particular, transition-metal catalysis has recently emerged as a powerful tool to functionalize otherwise unreactive C-H bonds. In this context, we first investigated the extension of a methodology that has been developed in our laboratory for the synthesis of benzocyclobutenes via C(sp3)-H activation, to non aromatic compounds. Substrates have been synthesized in order to be evaluated in the reaction to form cyclobutenes or cyclobutanes. The process was not selective and several by-products were formed via pericylic reactions or rearrangements of the intermediate palladacycle. Our research has also focused on a conceptually new palladium catalyzed β-C-H arylation of carboxylic esters method. The investigations consisted of a complete optimization of the reaction conditions, an evaluation of the scope and elucidation of the mechanism. It was found that this type of [bêta]-arylation is mechanistically related to α-arylation because it involves the formation of a palladium-enolate. Computational studies (DFT calculations, C. Kefalidis et E. Clot) confirmed the proposed mechanism. Our strategy allowed a mild and efficient intermolecular arylation reaction from aryl halides bearing an ortho electronegative group, giving rise to a range of synthetically useful functionalized carboxylic esters such as phenylalanine analogues and new fluorinated building blocks.