Chiral amines are ubiquitous functionalities found in the architecture of the natural world and have been embedded into materials, catalysts, pharmaceuticals, agrochemicals, and bioactive natural products. However, limited approaches are accessible for the construction of an enantioenriched tertiary or quaternary-containing amine. This thesis describes the development of new methodologies for the synthesis of 7-membered nitrogen-containing heterocycle and 1,2-diamine compounds. Chapter one describes the application of dynamic kinetic asymmetric amination (DYKAT) of branched allylic acetimidates in the synthesis of 2-alkyldihydrobenzoazepin-5-ones. These 7-membered-ring aza-ketones are generated in good yield with high enantiomeric excess through sequential rhodium-catalyzed allylic amination with 2-amino aryl aldehydes followed by intramolecular olefin hydroacylation of the resulting alkenals. This two-step procedure is efficient, straightforward and convenient for the enantioselective preparation of these ring systems. In Chapter two, we further extended the methodology towards the allylic amination of racemic secondary and tertiary allylic trichloroacetimidates possessing β-nitrogen substituents, and proximal nitrogen-containing heterocycles, using the DYKAT transformation to provide branched allylic 1,2-diamines with high enantioselectivity. The catalytic system is versatile in the synthesis of 1,2-diamines possessing two contiguous stereocenters, with excellent diastereoselectivity. Additionally, the nitrogen-containing heterocycles suppress competing vinyl azirdine formation, allowing for the high enantioselective syntheses of 1,2-diamines possessing tertiary and quaternary centers. Chapter three gives a very brief outlook on our efforts in rhodium-catalyzed amination strategy in providing access to a variety of enantiopure α-fluoromethylated allylic amines.

Accurate knowledge of heat transfer to materials in recombining plasmas is needed to improve heat shield designs. A lack of understanding of the chemical component of surface heating motivates the use of conservative assumptions with regards to surface catalysis in the design of thermal protection systems (TPS) that detrimentally impact payload capability. Chemical heating is the release of potential energy from recombining reactive species on the surface to form molecules. For a stable surface interacting with partially-dissociated air, the chemical heating component is due to surface-catalyzed recombination reactions of atomic O and N to produce molecular O2, N2, and NO. Unfortunately, heat flux measurements provide no fundamental information about the surface recombination pathways involved, or how the energy reaches the surface. Rather, they give a total heating rate. This work has taken steps to advance the current poor understanding about the chemical energy transport to and from material surfaces in high-temperature, recombining plasmas. A combination of spatially resolved laser-based diagnostics and emission spectroscopy was used to measure the number densities and gradients of the reactants (N, O), the products (NO, N2) and the energy distribution of recombined molecules (NO, N2) in the boundary layer adjacent to a plasma heated material. Laser excitation can probe individual species by electronic state (atoms) and by electronic, vibrational and rotational states (molecules). Emission can probe the radiative emission for a range of species and electronic, vibrational and rotational states of both atoms and molecules. These measurements of spatial variations in species concentrations through the boundary layer are directly related to near-surface gas-phase chemistry and energy exchange and have provided experimental information that was not currently available. Results provide the initial steps to determine recombination rates and the energy deposited on the surface due to surface catalyzed recombination of atomic nitrogen and oxygen in air plasma.

This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Medicinal Chemistry / PhD / Dissertation

In this thesis the synthesis of vicinal stereocenters is investigated in two distinct contexts, namely the construction of 3,3-disubstituted oxindoles and the synthesis of b-hydroxy-a-amino acids. Both scaffolds are prevalent in a range of natural products and biologically relevant compounds and, therefore, methods for their synthesis are of great import. First, the construction of 3,3-disubstituted oxindoles using palladium-catalyzed domino reactions is described.  This covers two stereospecific methods for the construction of the desired oxindoles based on domino carbopalladation sequences.  The termination events for these domino reactions are carbonylation or cross-coupling.  In the carbopalladation-carbonylation reaction, we studied the possibilty of suppressing b-hydride elimination for substrates possessing pendant b-hydrogens.  In the carbopalladation-cross-coupling sequence, we examined the role of the boron source and substrate scaffold in the outcome of the reaction.  In both of these methods, an intricate balance of rates needs to be attained in order to achieve the desired domino sequences.  Thus, these investigations offer insight into the rates of the competing reactions, and the factors that influence these processes. Secondly, the stereoselective synthesis of b-hydroxy-a-amino acids is explored.  This has lead to two separate methods for the construction of this scaffold.  We first examined a 1,3-dipolar cycloaddition of azomethine ylides to aldehydes for the construction of syn-b-hydroxy-a-amino esters.  It was found that one set of azomethine ylides reacted through a 1,3-dipolar cycloaddition, while the other set reacted via a direct aldol reaction.  Finally, we studied an asymmetric transfer hydrogenation reaction to provide anti-b-hydroxy-a-amido esters from the corresponding a-amido-b-ketoesters.  Two protocols were developed for the reduction of these substrates, one using triethylammonium formate and the other using sodium formate in an emulsion.  The latter method gives high yields, diastereoselectivities and enantioselectivities for a broad range of substrates. / QC 20120605

This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Medicinal Chemistry / PhD; / Dissertation;

Temperature-responsive poly(N-isopropylacrylamide) (PNIPAM)/ poly(2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl methacrylate) (PTMA) copolymer are synthesiszed by radical polymerization and atom transfer radical polymerization. The catalytic oxidation of alcohols to aldehydes and ketones using the NIPAM/PTMA copolymer as a catalyst was investigated. The copolymer were characterized by nuclear magnetic resonance spectroscopy, infrared spectroscopy, and gel permeation chromatography. The results of temperature-dependent UV/Vis absorption show that the lower critical solution temperature (LCST) is around 32-42 ¢J as the molecular percentage of PTMA is 0-6%. When the molecular percentage of PTMA is high than 6%, the LCST is not observed. The yield of the catalytic oxidation using the PNIPAM/PTMA copolymer as a catalyst is high than 99% within 30 min. The temperature-responsive PNIPAM/PTMA copolymer can be precipitated and purified by increasing temperature of the reaction solution higher than the LCST.

This thesis is an investigation of the role of the prosegment (PS) of pepsinogen in the binding, refolding and inhibition of pepsin. Native pepsin (Np) is irreversibly denatured, and folds to a stable, non-native state under refolding conditions, termed refolded pepsin (Rp) (Dee and Yada 2010). When added separately, the PS binds Rp, catalyzes folding to the native-like state and inhibits Np (Dee and Yada 2010). It was hypothesized, owing to the high sequence conservation, that N-terminal PS residues are critical to PS catalyzed folding. Synthetic peptides of N-terminal truncations (N16, N29), C-terminal truncations (C15, C28), and full length, wild-type (Wt) PS were examined. N-terminal residues were required for binding to Rp and catalyzing folding, while both N29 and C28 truncations had similar inhibition constants. Remarkably, the foldase activity of N-terminal truncation (N29) was only 2.5 fold slower than Wt, supporting that PS foldase activity is stored almost entirely within the highly conserved N29 region.

The diverse biological properties exhibited by uridine analogues modified at carbon-5 of the uracil base have attracted special interest to the development of efficient methodologies for their synthesis. This study aimed to evaluate the possible application of vinyl tris(trimethylsilyl)germanes in the synthesis of conjugated 5-modified uridine analogues via Pd-catalyzed cross-coupling reactions. The stereoselective synthesis of 5-[(2-tris(trimethylsilyl)germyl)ethenyl]uridine derivatives was achieved by the radical-mediated hydrogermylation of the protected 5-alkynyluridine precursors with tris(trimethylsilyl)germane [(TMS)3GeH]. The hydrogermylation with Ph3GeH afforded in addition to the expected 5-vinylgermane, novel 5-(2-triphenylgermyl)acetyl derivatives. Also, the treatment with Me3GeH provided access to 5-vinylgermane uridine analogues with potential biological applications. Since the Pd-catalyzed cross-coupling of organogermanes has received much less attention than the couplings involving organostannanes and organosilanes, we were prompted to develop novel organogermane precursors suitable for transfer of aryl and/or alkenyl groups. The allyl(phenyl)germanes were found to transfer allyl groups to aryl iodides in the presence of sodium hydroxide or tetrabutylammonium fluoride (TBAF) via a Heck arylation mechanism. On the other hand, the treatment of allyl(phenyl)germanes with tetracyanoethylene (TCNE) effectively cleaved the Ge-C(allyl) bonds and promoted the transfer of the phenyl groups upon fluoride activation in toluene. It was discovered that the trichlorophenyl,- dichlorodiphenyl,- and chlorotriphenylgermanes undergo Pd-catalyzed cross-couplings with aryl bromides and iodides in the presence of TBAF in toluene with addition of the measured amount of water. One chloride ligand on the Ge center allows efficient activation by fluoride to promote transfer of one, two or three phenyl groups from the organogermane precursors. The methodology shows that organogermanes can render a coupling efficiency comparable to the more established stannane and silane counterparts. Our coupling methodology (TBAF/moist toluene) was also found to promote the transfer of multiple phenyl groups from analogous chloro(phenyl)silanes and stannanes.

Thesis advisor: James P. Morken / This thesis will describe the development of two transition metal catalyzed syntheses of organoboronic compounds. The first section describes relevant concepts and precedents for the conjunctive coupling reaction. In the second section of this thesis, nickel catalyzed conjunctive coupling reaction of carboxylic acid derivatives with 9-BBN derived ate complexes will be discussed, where beta-trialkylboryl ketones are obtained as the product. In the third section, the development of alkyl group migration in nickel-catalyzed conjunctive coupling with C(sp3) electrophiles will be discussed. Enantioenriched secondary boronic esters can be prepared from this reaction, and two alkaloid syntheses are disclosed as the application of the method. / Thesis (MS) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Catalytic SN2”-Selective and Enantioselective Substitution Reactions. The first broadly applicable strategy for SN2”-selective and enantioselective catalytic allylic substitution will be presented. It will be shown that transformations can be promoted by 5.0 mol% of a sulfonate-containing NHC–Cu complex (NHC = N-heterocyclic carbene), and may be carried out by the use of a commercially available allenyl–B(pin) (pin = pinacolato) or a readily accessible silyl protected propargyl–B(pin). Products bearing a 1,3 diene, a silyl allenyl or a propargyl moiety were obtained in high efficiency and selectivities. Also provided is insight regarding several of the unique mechanistic attributes of the catalytic process, obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicated that cationic π-allyl–Cu complexes are the likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E:Z selectivity and enantioselectivity. It will also be shown we were able to highlight the utility of the approach by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products can be converted catalytically and chemoselectively to several synthetically useful derivatives. Chapter 2. NHC–Copper–Hydride-Catalyzed Enantioselective Processes with Allenyl Boronates and its Application in Natural Product Synthesis. Here, the development of a catalytic process that delivers otherwise difficult-to-access organoboron compound will be detailed. These processes involve the combination of a hydride, an allenyl–B(pin) and an allylic phosphate. As will be discussed, two unique selectivity problems were solved: avoiding rapid Cu–H reduction of an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly observed Cu–B exchange. We were able to underscore the considerable utility of the approach by applications to preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and the first enantioselective synthesis of netamine C (anti-tumor), which also served to confirm its stereochemical identity. Chapter 3. Catalytic Enantioselective Prenyl Conjugate Addition Reactions. In this final section, studies leading to the development of the first class of catalytic enantioselective strategies for prenyl conjugate additions will be detailed. At the core of these investigations was finding ways to overcome two problems. One challenge originated from the fact that highly activated allylmetal species often deliver product with low enantioselectivity. The other was that regioselectivity was difficult to control owing to a strong preference for γ-selective additions. As will be described, we were able to address these difficulties by the use of a hydroxy NHC-copper complex and 3,3-dimethyl allyl–B(pin) as a reagent. In the end, we were able to use acyclic as well as cyclic enoates as substrates. The results of DFT studies that provide insight regarding varying selectivity profiles with different chiral ligands will be discussed as well. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.