Cyanide utilization in Pseudomonas fluorescens NCIMB 11764 occurs via oxidative conversion to carbon dioxide and ammonia, the latter satisfying the nitrogen requirement. Substrate attack is initiated by an enzyme referred to as cyanide oxygenase (CNO), previously shown to require components in both high (H) (>30 kDa) and low (L) (<10 kDa) molecular weight cell fractions. In this study, tetrahydrobiopterin (H4biopterin) was identified as a cofactor in fraction L, thus making CNO appear as a pterin- dependent hydroxylase. CNO was purified 150-fold (specific activity 0.9 U/mg) and quantitatively converted cyanide to formate and ammonia as reaction products. When coupled with formate dehydrogenase, the complete enzymatic system for cyanide oxidation to carbon dioxide and ammonia was reconstituted. CNO was found to be an aggregate of known enzymes that included NADH oxidase (Nox), NADH peroxidase (Npx), cyanide dihydratase (CynD) and carbonic anhydrase (CA). A complex multi-step reaction mechanism is proposed in which Nox generates hydrogen peroxide which in turn is utilized by Npx to catalyze the oxygenation of cyanide to formamide accompanied by the consumption of one and two molar equivalents of oxygen and NADH, respectively. The further hydrolysis of formamide to ammonia and formate is thought to be mediated by CynD. The role of H4biopterin and of the enzyme CA in the proposed process remains unclear, but the involvement of each in reactive oxygen and radical chemistry is consistent with the proposed formation of such species in the catalytic process. H4biopterin may additionally serve as a protein stabilizing agent along with a protein co-purifying with CynD identified as elongation factor Tu, a known chaperone. At least two of the CNO components (Nox and CynD) are complex oligomeric proteins whose apparent association with Npx and CA appears to be favored in bacterial cells induced with cyanide allowing their purification in toto as a multiprotein enzyme complex.

No description available.

Thesis advisor: Amir H. Hoveyda / We have developed a broadly applicable strategy for the enantioselective and diastereodivergent synthesis of unprotected α-secondary amines, secondary and tertiary alcohols from nitriles. Through a bis-phosphine–Cu-catalyzed enantioselective multicomponent allyl addition to nitriles, we generate stable β,γ-unsaturated N–H ketimines with internal C=N to B(pin) chelation. We achieved stereodivergent amine synthesis through maintaining the C=N to B(pin) chelation or disruption of this internal chelation in the ketimine intermediate throughout the reduction. In the preparation of syn-homoallylic amines, a non-productive side catalytic cycle was introduced to selectively delay the function of a competitive catalyst, making several catalysts cooperate productively. The utility of this method is demonstrated through a diastereo- and enantioselective synthesis of (+)-tangutorine in gram quantities. We have also developed the syntheses of enantiomerically enriched secondary and tertiary alcohols through diastereodivergent reduction and diastereoselective addition of a C-based nucleophile to β,γ-unsaturated ketones, prepared from hydrolysis of the aforementioned N–H ketimines. Tertiary alcohols containing two non-differentiable functional groups, are prepared with high stereoselectivity through our strategy. We demonstrated the utility of this approach by a concise preparation of a key intermediate in (+)-rubriflordilactone B synthesis. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis describes a Master of science research program of duration May, I960 to April, 1961 inclusive. It represents part of an extensive research program designed to investigate the thermodynamic aspects of phase transformations. A great deal of effort has been devoted to the application of multicomponent diffusion theory to (de)carburisation, pearlite, and segregation reactions; particularly in ferrous alloys. This fundamental research program is here extended to a general study of the morphological aspects of phase transformation interfaces. Substantially all industrial metallurgical phase transformations are accompanied by the development of non-planar morphologies with attendant segregation. Previous investigations have demonstrated that the factors controlling the type and degree of morphological development are varied and complex. It is apparent that the structural character of an interface is determined, to a large extent, by the system’s phasial constitution in terms of the concentration, temperature, and pressure variables. Therefore, an examination of the relation between these parameters and the structural form of non-planar interfaces was suggested as a potentially valuable field of endeavour. / Thesis / Master of Science (MSc)

A four component reaction involving the coupling of functionalized aldehydes, amines, acid chlorides, and [pi]- and organometallic nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate diverse arrays of functionalized heterocyclic scaffolds. Allyl metals, Grignard reagents, silyl ketene acetals, silyl enol ethers, and silyloxy furans have been utilized as the nucleophile in the four component reaction (4CR). The 4CR has been sequenced with intramolecular Heck reactions, Diels-Alder and [3+2] cycloadditions, ring closing metathesis (RCM), and Dieckmann condensations to provide a number of diverse heterocyclic structures. The practical utility of this approach to diversity-oriented synthesis (DOS) was further exemplified by its application to the first total synthesis of the isopavine alkaloid roelactamine, which was completed in only four steps from commercially available materials. The application of this methodology towards the synthesis of the Aspidosperma alkaloids rosicine and pseudotabersonine is also presented. To this end, an imine pentadienylation/double RCM strategy has been adopted to rapidly access the pentacyclic core of the aspidospermine alkaloids. This sequence involved the use of a pentadienyl aluminum reagent, which was found to react with aryl imines to give branched products in good yields. / text

<p>Mass transfer in a porous solid, partially saturated with asingle solvent and multicomponent liquid mixtures, has beenexperimentally and theoretically studied. A porous materialcontaining single liquids and mixtures of organic solvents wasisothermally dried. Experiments were performed using a jacketedwind tunnel, through which a humidity andtemperature-controlled air stream flowed. The wetted porousmaterial was placed in a cylindrical vessel, whose top isexposed to the air stream until the material became dried to acertain extent. Drying experiments with the single solventswater, methanol, ethanol and 2-propanol, were performed atdifferent temperatures and transient liquid content profileswere determined. In isothermal drying experiments with liquidmixtures,the transient concentration profiles of thecomponents along the cylindrical sample as well as the totalliquid content were determined. The liquid mixtures examinedwere water-methanolethanol and isopropanol-methanol-ethanol.Two different temperatures and initial compositions were usedin the experiments. Mathematical models that describe nonsteadystate isothermal drying of a solid containing single liquidsand multicomponent liquid mixtures were developed. In the solidwetted with a single liquid, capillary movement of the liquidwas the main mechanism responsible for mass transfer. In thesolid containing liquid mixtures, interactive diffusion inliquid phase was superimposed to the capillary movement of theliquid mixture. In addition, interactive diffusion of thevapours in empty pores was considered. The parameters todescribe the retention properties of the solid and thecapillary movement of the liquid were determined by comparingtheoretical and experimental liquid content profiles obtainedduring drying of the solid wetted with single liquids. Tosimulate the transport of the liquid mixtures these parameterswhere weighed according to liquid composition. A fairly goodagreement between theoretical and experimental liquidcomposition profiles was obtained if axial dispersion isincluded in the model when the moisture consists of amixture.</p><p><b>Keywords:</b>Internal mass transfer, capillary flow,multicomponent, diffusion, solvent mixtures</p>

Some protein gels are products of the dairy industry and some are used as pH-sensitive gels for the controlled delivery of biologically active substances. To understand the dynamics of drug delivery it is very important to establish a mathematical model of protein gel swelling. This required the identification and integration of theory and equations from a wide range of topics. The aim of this research was to develop a mathematical model of transport in polyelectrolyte gels (using the example of β-lactoglobulin protein gels). A complete mathematical model of protein gel swelling was established. The swelling process of protein gels in this thesis involved multicomponent diffusion, chemical ionisation and mechanical deformation. Diffusion of electrolyte solutions through protein gels was modelled using the generalised Maxwell-Stefan (GMS) equation. The swelling pressure as a driving force in the GMS equation was described by rubber elasticity theory. Thermodynamic factors including the charged protein effect were considered in the GMS equation. The model included pH as a variable so it could be applied to both acidic and alkaline cases. The model yielded a set of partial differential equations with algebraic equations for which COMSOL was selected as the simulation software. Although it was found that COMSOL could not always solve the model equations, numerical solutions were obtained for several cases. The model predicted that the equilibrium swelling degree of the gel decreased with high concentration of salts in the bulk solution. The model also predicted that the non-ideal effects were not always small and they depended on the activity coefficients of the species. Satisfactory solutions could not be obtained for all cases using commercial software such as COMSOL Multiphysics. It was shown that COMSOL did not conserve mass but conservativeness was critical in this application because pH and hence the net protein charge is very sensitive to the mass of hydrogen present. In the future, research should be carried out to improve the pressure model in the GMS equation. Theoretical research on Manning condensation theory should be done to modify Manning’s model for more robust prediction of activities of water and ions with protein, and experiments should be done to validate the performance of the modified Manning model. Efforts should be made to write the programming code for a finite volume method to solve the system in three dimensions.

This research focused on the synthesis of novel ogranoboron reagents in efforts to perform a variety of synthetic transformations, and additionally, the development of new methodologies to generate drug-like scaffolds. Initially, three novel tripod ligands were synthesized, and two were effectively chelated to boron to provide the desired organoborates. Such organoborates were employed in nucleophilic additions where they were found to be ineffective, whereas some activity was observed in Suzuki-Miyaura cross-coupling reactions. An additional project on organoboron compounds was conducted and focused on the development of organoboron frustrated Lewis pairs (FLPs) to facilitate the storage and transfer of hydrogen, nucleophilic addition reactions, and Claisen rearrangements. A new method for synthesizing a pyrrolidine diol unit was accomplished, and this intermediate was utilized to synthesize two FLPs. The reactivity of the FLPs with small molecules was assessed, and the pyrrolidine diol unit was subsequently evaluated for its ability to undergo a multicomponent reaction (MCR) to yield compounds possessing beneficial biological activity. Further research in this area was conducted, and a 5-aminoimidazole scaffold was synthesized employing a new MCR which is more efficient than previously reported methodologies. 5-Aminoimidazoles are frequently found in compounds which possess desirable biological activity, and this novel method was employed to generate a library of eleven 5-aminoimidazoles. Additionally, two post condensation modification reactions were developed. During initial studies, a side product was observed which was identified as a dihydrotriazine, which is another biologically appealing chemotype. Therefore, an enhanced method of synthesizing this product was developed, and a library of eleven dihydrotriazines was produced. In summary, novel organoboron reagents were synthesized, and their activity was evaluated. The pyrrolidine diol utilized to synthesize FLPs was applied towards an MCR. Furthermore, a novel MCR was developed for the synthesis of 5-aminoimidazoles, and an enhanced protocol for the synthesis of dihydrotriazines was found.

Thesis advisor: Lawrence T. Scott / Thesis advisor: James P. Morken / Expeditious establishment of molecular complexity in a stereoselective manner is a prominent goal in organic synthesis. In this regard, multicomponent coupling reactions have received substantial attention due to their ability to access complex molecules from simple starting materials in a single step. Chapter 1 is a comprehensive review on catalytic bismetallative multicomponent reactions. The scope of this process in terms of both bismetallic reagents and the pi components are broad enough to be generally applied to more elaborate synthetic sequences. Particularly, contemporary applications of the bismetallative multicomponent coupling reactions, in which high enantio- and/or diastereoselectivities are displayed, have enabled the study of this area to make a significant step forward. Chapter 2 presents nickel-catalyzed coupling reactions of aldehyde, diene, and a diboron reagent in the presence of a trialkyl phosphine ligand. Compared to borylation reactions with one pi-component, these borylative multicomponent reactions (involving two pi components) lead to formation of a new C-C bond between the pi components as well as generation of highly functionalized, stereodefined products. Chapter 3 describes a remarkable turnover in regioselectivity of the borylative multicomponent coupling when PCy3 is replaced with P(SiMe3)3. In particular, the products from the reactions with P(SiMe3)3 feature three contiguous stereocenters and an alpha-chiral allylboronate. The effect of P(SiMe3)3 ligand on the product selectivity is intriguing. According to the experimental and computational results, it has an ability to act as an electron acceptor, which will facilitate reductive elimination from the intermediate nickel complex during the course of the reaction. In Chapter 4, we show that borylative ketone-diene coupling reactions can be accomplished in high yields and with excellent levels of diastereocontrol. This reaction occurs in a predictable fashion, yet with regioselection that is distinct from related aldehyde-diene coupling reactions. The reaction products from these coupling processes, which possess tertiary alcohol functionality and an allylic alcohol moiety, are particularly well suited for the preparation of polyketide natural products. Chapter 5 presents investigations on bowl-shaped geodesic polyarenes, which are the missing links between the "classic" planar polycyclic aromatic hydrocarbons (PAHs) and the spheroidal fullerenes. The present study has shown that open geodesic polyarenes can feature chemistry inherent to both classes of aromatics. The curved pi system induces unequal environments on the two faces of circumtrindene, significant strain energy to the molecule, and non-identical bond lengths. Along with the electronic effects, the stereoelectronic effect enabled the site-selective functionalization with fullerene-type chemistry. On the other hand, the edge carbons, which are not present in fullerenes, still possess reactivity of common planar PAHs. Chapter 6 describes the intermolecular oxidative cyclotrimerization reactions of alkenes and aromatic compounds with DDQ and trifluoromethanesulfonic acid. The Scholl-type oxidation reactions involving alkenes have never been demonstrated. Moreover, the DDQ/acid system has never been used for the intermolecular oxidative cyclization reactions. This convenient non-metallic reagent system (DDQ/TfOH) is advantageous over the metal-based Scholl-type oxidants because it eliminates the possibility of halogenation of aromatic compounds and the reduced oxidant can be reoxidized. In Chapter 7, the regioselective formation of cyclic trimers from substituted benzenes and heteroaromatic compounds is demonstrated. This DDQ/TfOH method provides a simple and convenient synthetic route toward star-shaped oligomers containing triphenylene or isotruxene cores. Furthermore, the experimental outcome suggests that this oxidative process proceeds by an electron transfer mechanism. This is the first experimental evidence for mechanistic details on the Scholl-type oxidation. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Ligand-Controlled Site-Selective NHC–Cu-Catalyzed Protoboration of Monosubstituted Allenes. Site-selective proto–boryl additions to monosubstituted allenes promoted by NHC–Cu complexes are disclosed. Synthetically useful 1,1-disubstituted and Z-trisubstituted alkenylboron compounds are afforded in high efficiency (71%–92% yield) and site selectivity (88% to >98%) through proper choice of NHC ligands. Mechanistic study with the assistance of DFT calculations indicates that protonation of 2-boron-substituted allylcopper complex occurs through six-membered cyclic transition state. The utility of this protocol is demonstrated through application to fragment synthesis of an antibiotic macrolide natural product elansolid A. Chapter 2. Cu-Catalyzed Chemoselective Copper–Boron Additions to Monosubstituted Allenes Followed by Allyl Additions to Carbonyl Compounds. The first examples of catalytic generation of 2-boron-substituted allylcopper species and their in situ use for C–C bond formation are described. The reactions are performed in the presence of bisphosphine– or NHC–Cu complexes at 22 oC. High-value alcohol-containing alkenylboron compounds are provided in high efficiency (68–92% yield after oxidation) and stereoselectivity (88:12 to >98:2 dr). The reactions proceed with exclusive γ-addition mode through a cyclic six-membered transition state. Enantioselectivity can be achieved with chiral bisphosphine ligands in up to 97:3 enantiomeric ratio. Chapter 3. Chemo-, Site- and Enantioselective Copper–Boron Additions to 1,3-Enynes Followed by Site- and Diastereoselective Additions of the Resulting Allenylcopper Complexes to Aldehydes. Catalytic enantioselective multicomponent reactions involving 1,3-enynes, aldehydes and B2(pin)2 are described. The resulting products contain a primary C–B(pin) bond, as well as alkyne- and hydroxyl-substituted tertiary stereogenic centers. A critical feature is high enantioselectivity of the initial Cu–B addition to an alkyne-substituted terminal alkene. The key mechanistic issues are investigated by DFT calculations. Reactions are promoted in the presence of the Cu complex of an enantiomerically pure C1-symmetric bisphosphine and are complete in 8 h at ambient temperature. Products are generated in 66–94% yield (after oxidation or catalytic cross-coupling), 90:10 to >98:2 diastereomeric ratio, and 85:15–99:1 enantiomeric ratio. Aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes and enynes are suitable substrates. Utility is demonstrated through catalytic alkylation and arylation of the organoboron compounds as well as applications to synthesis of fragments of tylonolide and mycinolide IV. Chapter 4. Multifunctional Alkenylboron Compounds through Single-Catalyst-Controlled Multicomponent Reactions and Their Applications in Scalable Natural Product Synthesis. A facile multicomponent catalytic process that begins with a chemo-, site- and diastereoselective copper–boron addition to a monosubstituted allene followed by addition of the resulting boron-substituted organocopper intermediate to an allylic phosphate, generating products that contain a stereogenic center, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group in up to 89% yield with >98% branch selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly column chromatography purification. The utility of the method is demonstrated through enantioselective synthesis of gram quantities of two natural products, rottnestol and herboxidiene/GEX1A. Chapter 5. Cu-Catalyzed Enantioselective Allyl and Propargyl 1,6-Conjugate Additions through 3,3’-Reductive Elimination. Catalytic enantioselective 1,6-conjugate additions of allyl-type nucleophiles promoted by NHC–Cu complexes are reported. Propargyl and 2-boron allyl 1,6-conjugate products are formed in high efficiency, diastereo- and enantioselectivity. The unique mechanistic feature is that the transformations proceed through Cu-catalyzed 3,3’-reductive elimination, that is unprecedented for copper catalysis. Further mechanistic study and application to complex molecule synthesis will be conducted. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.