The ever increasing demand for more efficient and environmentally benign routes for synthesizing target compounds, has led to the use of organometallic catalysts. This demand has created the need to understand the mechanistic details that are at work in these organometallic catalytic cycles. Along with this, there is a demand for new organometallic catalysts that are tailored for specific transformations. This presents a myriad of challenges for organometallic chemists. Unfortunately, it is often difficult to gain an understanding of the reaction mechanisms at work when the intermediates are too short lived to be observed in the condensed phase. It is also very time consuming to synthesize, purify, and characterize organometallic catalysts following standard condensed phase methods. Therefore, it would be beneficial to probe organometallic reactions in a way that the inherent reactivity of the organometallic complex can be uncovered and where purity is not a prerequisite. Using an ion-trap mass spectrometer that has been modified to allow introduction of neutral reagents to the buffer gas, organometallic ion-molecule reactions can be probed in an environment free from solvation effects. This enables the study of the inherent reactivity of the complexes and also provides insight into reaction mechanisms by allowing reactive intermediates to be probed. In addition, organometallic complexes probed in this manner do not need to be pure due to ability of the ion trap to function as a mass filter. This results in a quick and efficient method. This dissertation presents results found during the investigation of the reactions and mechanistic details of gold, silver, and iridium complexes using a modified ion-trap mass spectrometer.

C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC50 of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC50 = 0.17 μM) and 4-Cl HIPP (CtBP IC50 = 0.18 μM). These compounds also showed inhibition in HCT-116 colon cancer cells with GI50 values ~ 1-4 mM. The compounds showed no off-target toxicity against a closely related protein. This is a starting point for the development of CtBP inhibitors as anti-cancer therapeutics. The second part of this dissertation focuses on C–H activation chemistry. C–H activation is the most atom-economical method of introducing complexity into a molecule, even at late stages of drug/product development. We have used solid-supported palladium nanoparticle catalyst (Pd-MWCNT) to investigate the scope of C–H activation reactions it can catalyse. Pd-MWCNT was found to efficiently catalyse N-chelation directed C-H activation reactions – halogenations, oxygenations and arylations. The turn-over numbers for these reactions were significantly higher than that of the reported homogenous catalyst. The added advantages of reuse/recyclability of catalyst, low contamination of metal in the final product make this catalyst very attractive on an industrial scale. This work serves as a foundation for the further development of Pd-MWCNT catalyst in late-stage synthesis of drugs and/or diversification of products.

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.

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.