<p>In organic synthesis, controlling stereochemistry can be a challenge whether you are working with small molecules or larger natural products. Current chiral bases, such as Sparteine, are difficult to make or expensive to purchase. Their other drawback is that many chiral bases only can access one stereochemical configuration, not both. In the work presented here, progress has been made towards developing a chiral base from an amino acid derivative, L-valine. The chiral base has been fully synthesized. The use of the amino acid starting material, allows for us to make both the R and S selective amino acid. Efforts are being made to determine the efficacy of the base to control stereochemistry. </p>

Micellar electrokinetic chromatography (MEKC) and capillary electrochromatography (CEC) are two of the major capillary electrophoresis (CE) modes that have been interfaced to mass spectrometry (MS) for sensitive and selective analysis of chiral compounds. This research combines these two modes and expands their applications in chiral CE analysis. Chapter 1 is a review of amino acid based molecular micelles used in MEKC-MS for enantioselective analysis over the past five years. In this chapter, a typical MEKC-MS experiment setup as well as detailed standard operating procedure in synthesis of molecular micelles and running a typical MEKC-MS experiment using the molecular micelles is discussed. Chapter 2 described a multivariate MEKC-MS optimization for the simultaneous analysis of two negatively charged model chiral compounds in negative ion mode with molecular micelles. In this chapter, a central composite design (CCD) is used to first construct a series of experiments to optimize all the important MEKC-MS parameters. Next, response surface methodology (RSM) was used to analyze the interactions between the factors, picking up the best separation and detection conditions, predicting the result of the chiral separation/MS detection, and finally running the actual experiment and comparing the chromatographic results with the predicted parameters. Chapter 3 demonstrates a similar multivariate MEKC-MS optimization for analysis of a positively charged model chiral compound in a positive ion mode. The same CCD and RSM methods were used to optimize the separations and MS sensitivity. Chapter 4 describes a chiral analysis of four neutral benzoin derivatives (hydrobenzoin, benzoin, benzoin methyl ether, and benzoin ethyl ether) using MEKC coupled to atmospheric pressure photo-ionization mass spectrometry (APPI-MS). The same multivariate experimental design strategy was used to optimize the MEKC as well as APPI-MS parameters. Simultaneous chiral separation of all four benzoin derivatives was achieved with high detection sensitivity compared to UV-detection. Chapter 5 introduces a novel one-pot synthesis scheme for an acryloyl-terminated, carbamate-linked surfactant-bound monolith with leucine head group and different chain lengths. The method promises to open up the discovery of new amino acid based polymeric monoliths for chiral separations and enhanced chemoselectivity for simultaneous chiral separations and enhanced detection in CEC and CEC-MS. In Chapter 6, five amide-linked surfactant-bound monoliths with different chain lengths and head groups (leucine, valine, and phenylalanine) were synthesized and characterized. Enantioseparation of several test compounds was achieved by CEC using the monolithic columns. One of the chiral surfactant, sodium 11-acrylamidoundecanoyl-L-leucinate (SAAUL), was polymerized in aqueous solution under 60Co radiation to form molecular micelle poly-SAAUL. MEKC experiments were carried out with the poly-SAAUL molecular micelle to separate ten cationic chiral compounds. The result was compared with the CEC separation using the AAUL monolithic column. This study is the first comparison of chiral CEC and MEKC with the same surfactant monomer, which has the capability of forming both chiral stationary phase for CEC and chiral pseudophase for MEKC.

At the present time it is unknown how the U(1)A anomaly of Quantum Chromodynamics behaves at high temperatures. We therefore want to look for thermal changes of the effects of the anomaly. For example, by studying the properties of the η' meson at high temperatures it would be possible to deduce important information on the axial anomaly, thanks to the deep connection between them. In this thesis the width of the η' as a function of the temperature is studied in the framework of large-Nc Chiral Perturbation Theory, at next-to-leading order, and in the corresponding Resonance Chiral Theory. We calculate the width increase due to scattering with particles from the heat bath, which we assume to consist of a pion gas. We compare the results obtained in both frameworks and as expected we find a smaller, but still consistent width increase when the more realistic resonance exchange is taken into account. The results suggest that the in-medium width of the η' may increase up to ΔΓ<img src="http://www.diva-portal.org/cgi-bin/mimetex.cgi?%5Capprox" /> 10 MeV at a temperature of T<img src="http://www.diva-portal.org/cgi-bin/mimetex.cgi?%5Capprox" /> 120 MeV. We find therefore a width increase of considerable size, comparable to the inverse lifetime of the fireball created in relativistic heavy-ion collisions. In other words, our results suggest that it may be possible to study experimentally how the properties of the η' change at high temperatures.

フランス国ボルドー大学との共同学位プログラムによる学位 / 京都大学 / 新制・課程博士 / 博士(エネルギー科学) / 甲第23585号 / エネ博第431号 / 新制||エネ||82(附属図書館) / 京都大学大学院エネルギー科学研究科エネルギー基礎科学専攻 / (主査)教授 石原 慶一, 教授 萩原 理加 / 学位規則第4条第1項該当 / Doctor of Energy Science / Kyoto University / DGAM

The work in this thesis has demonstrated the chiral recognition through the adaptation of chromatographically derived chiral recognition systems by electrospray ionization mass spectrometry (ESI-MS). Mass-labeled, pseudoenantiomeric chiral selectors (where each pseudoenantiomer had the opposite stereochemistry, but was slightly different in mass due to labeling of one enantiomer) were prepared as soluble analogues of Pirkle type chiral stationary phases. When mixed with a chiral analyte, solutions containing these pseudoenantiomeric selectors afforded selector-analyte complexes in the ESI-MS, and the relative peak intensities of the complexes could be related back to the enantiomeric composition of the analyte. In each case of this study, the complex intensity fraction for either of the selector-analyte complexes in the ESI-MS varies linearly with the enantiomeric composition of the analyte. This linear relationship provides a measure of the extent of enantioselectivity and allows quantitative analysis of the enantiomeric composition of analyte.

A duloxetina é um potente inibidor duplo da recaptação de serotonina e norepinefrina, disponível como enantiômero puro, sob a forma S-duloxetina e comercializado como pellets em cápsulas. O R enantiômero da duloxetina é também um inibidor da recaptação, no entanto, este é menos potente que seu isômero, sendo considerado como impureza enantiomérica. Este trabalho teve como objetivos o desenvolvimento e a validação de métodos analíticos para o controle de qualidade da duloxetina e de sua respectiva impureza enantiomérica por cromatografia líquida de alta eficiência (CLAE), e por eletroforese capilar (EC). A resolução dos enantiômeros da duloxetina foi realizada a partir da utilização de fase estacionária quiral, baseada celulose, por CLAE. A separação por EC foi desenvolvida a partir da utilização de hidroxipropil-β-ciclodextrina (HPβCD) como seletor quiral. A validação dos métodos foi efetuada de acordo com os guias de validação disponíveis na literatura e os métodos propostos foram considerados específicos, lineares, precisos, exatos e robustos. A análise comparativa entre os métodos desenvolvidos demonstrou não haver diferença estatisticamente significativa na quantificação do enantiômero S-duloxetina. / Duloxetine is a double potent inhibitor of serotonin and norepinephrine reuptake, available as a pure enantiomer, in the S-duloxetine form and marketed as pellets into capsules. The R enantiomer of duloxetine is also an inhibitor of reuptake, however, less potent and being considered enantiomeric impurity. This work aimed the development and validation of analytical methods for quality control of duloxetine and its respective enantiomeric impurity by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). The resolution of the enantiomers of duloxetine was performed with the use of chiral stationary phase, based on cellulose, by HPLC. The separation by CE was developed with the use of hydroxypropyl-β-cyclodextrin (HPβCD) as chiral selector. The method validation was performed according to the guides available in the literature and the proposed methods were considered specific, linear, precise, accurate and robust. The comparative analysis between the methods developed showed no statistically significant difference in the quantification of S-duloxetine enantiomer.

The research work reported in this thesis deals with the development of novel NMR experimental techniques for the spectroscopic discrimination of enantiomers dissolved in a chiral liquid crystalline medium. The information on the chemical shifts and coupling constants pertaining to each enantiomer has been derived on the investigated chiral molecules. The enantiomeric excess (ee), a parameter which is of profound importance in pharmaceutical industry and in asymmetric synthesis, has also been measured. A special attention is paid to the use of high sensitivity of H NMR for chiral discrimination. Typical analyses of H NMR spectra are severely hindered due to enormous spectral inhomogeneous broadening arising from too many unresolved transitions, in addition to superposition of spectra from both the enantiomers. Therefore, the major part of the work is focused on the design and application of pulse sequences to overcome many of these drawbacks. This helps to achieve very high resolution, discerning of overlapped transitions, identification of resonances pertaining to each enantiomer and simplification of the spectrum for easy extraction of spectral parameters, in addition to the accurate measurement of ee. Initially a brief discussion is provided on enantiomers, diastereomers, basic principles of NMR spectroscopy, the several interaction Hamiltonians responsible for yielding the NMR spectra, introduction to product and polarization operator formalisms that gives insight into the spin dynamics for designing appropriate two-dimensional (2D) NMR experiments. This sets the foundation to understand the complex multiplet structures of the diagonal peaks and cross peaks in the resulting 2D spectrum. Subsequently, a brief introduction is given for the available techniques for NMR spectroscopic discrimination of enantiomers in isotropic medium, where only chemical shifts are employed as a measurable parameter. The limitations of these techniques are circumvented by the introduction of other anisotropic NMR parameters, such as homo-and hetero-nuclear dipolar couplings, quadrupolar couplings and chemical shift anisotropies. To achieve this goal the enantiomers are dissolved in weakly aligning chiral liquid crystalline (CLC) medium. To understand this, a general introduction to liquid crystals and their utility as an alignment medium in NMR spectroscopy and the anisotropic interactions affecting the NMR spectrum has also been provided. The preparation of the CLC phase of Poly-γ-Benzyl-L-Glutamate (PBLG) employed in the present study and its orientational behaviour has been discussed. The detection of NMR spectra of various nuclei and the interaction parameters utilized for chiral discrimination will be enumerated. A brief summary of the experiments employed for the spectral analyses of the enantiomers dissolved in PBLG will also be presented.

A duloxetina é um potente inibidor duplo da recaptação de serotonina e norepinefrina, disponível como enantiômero puro, sob a forma S-duloxetina e comercializado como pellets em cápsulas. O R enantiômero da duloxetina é também um inibidor da recaptação, no entanto, este é menos potente que seu isômero, sendo considerado como impureza enantiomérica. Este trabalho teve como objetivos o desenvolvimento e a validação de métodos analíticos para o controle de qualidade da duloxetina e de sua respectiva impureza enantiomérica por cromatografia líquida de alta eficiência (CLAE), e por eletroforese capilar (EC). A resolução dos enantiômeros da duloxetina foi realizada a partir da utilização de fase estacionária quiral, baseada celulose, por CLAE. A separação por EC foi desenvolvida a partir da utilização de hidroxipropil-β-ciclodextrina (HPβCD) como seletor quiral. A validação dos métodos foi efetuada de acordo com os guias de validação disponíveis na literatura e os métodos propostos foram considerados específicos, lineares, precisos, exatos e robustos. A análise comparativa entre os métodos desenvolvidos demonstrou não haver diferença estatisticamente significativa na quantificação do enantiômero S-duloxetina. / Duloxetine is a double potent inhibitor of serotonin and norepinephrine reuptake, available as a pure enantiomer, in the S-duloxetine form and marketed as pellets into capsules. The R enantiomer of duloxetine is also an inhibitor of reuptake, however, less potent and being considered enantiomeric impurity. This work aimed the development and validation of analytical methods for quality control of duloxetine and its respective enantiomeric impurity by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). The resolution of the enantiomers of duloxetine was performed with the use of chiral stationary phase, based on cellulose, by HPLC. The separation by CE was developed with the use of hydroxypropyl-β-cyclodextrin (HPβCD) as chiral selector. The method validation was performed according to the guides available in the literature and the proposed methods were considered specific, linear, precise, accurate and robust. The comparative analysis between the methods developed showed no statistically significant difference in the quantification of S-duloxetine enantiomer.

A duloxetina é um potente inibidor duplo da recaptação de serotonina e norepinefrina, disponível como enantiômero puro, sob a forma S-duloxetina e comercializado como pellets em cápsulas. O R enantiômero da duloxetina é também um inibidor da recaptação, no entanto, este é menos potente que seu isômero, sendo considerado como impureza enantiomérica. Este trabalho teve como objetivos o desenvolvimento e a validação de métodos analíticos para o controle de qualidade da duloxetina e de sua respectiva impureza enantiomérica por cromatografia líquida de alta eficiência (CLAE), e por eletroforese capilar (EC). A resolução dos enantiômeros da duloxetina foi realizada a partir da utilização de fase estacionária quiral, baseada celulose, por CLAE. A separação por EC foi desenvolvida a partir da utilização de hidroxipropil-β-ciclodextrina (HPβCD) como seletor quiral. A validação dos métodos foi efetuada de acordo com os guias de validação disponíveis na literatura e os métodos propostos foram considerados específicos, lineares, precisos, exatos e robustos. A análise comparativa entre os métodos desenvolvidos demonstrou não haver diferença estatisticamente significativa na quantificação do enantiômero S-duloxetina. / Duloxetine is a double potent inhibitor of serotonin and norepinephrine reuptake, available as a pure enantiomer, in the S-duloxetine form and marketed as pellets into capsules. The R enantiomer of duloxetine is also an inhibitor of reuptake, however, less potent and being considered enantiomeric impurity. This work aimed the development and validation of analytical methods for quality control of duloxetine and its respective enantiomeric impurity by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). The resolution of the enantiomers of duloxetine was performed with the use of chiral stationary phase, based on cellulose, by HPLC. The separation by CE was developed with the use of hydroxypropyl-β-cyclodextrin (HPβCD) as chiral selector. The method validation was performed according to the guides available in the literature and the proposed methods were considered specific, linear, precise, accurate and robust. The comparative analysis between the methods developed showed no statistically significant difference in the quantification of S-duloxetine enantiomer.

Doctor of Philosophy / Department of Chemistry / Christopher J. Levy / This work examines the synthesis of novel chiral Schiff-base complexes derived from (1R,2R)-cyclohexanediamine and (R)-[1,1’-binaphthalene]-2-2’-diamine structural backbones with quinoline, isopropyl-quinoline, and benzoquinoline structural side-arms. We incorporated some degree of flexibility in the ligands and complexes so they can accommodate the sterics of different substrates during a catalytic reaction. We successfully achieved this by reducing the imine bond in the ligands to the corresponding amine bond. Therefore, the successful reduction and metallation of some of these ligands to give structures of different symmetries is reported. We had difficulty reducing ligands with the binaphthalene backbone but were able to partially reduce the ligand through a one-pot reaction with a zinc(II) salt and NaBH4. The complete 1H NMR assignments of the complexes reported in this thesis serve as a valuable tool for use in the characterization of future complexes. The complete NMR characterization of compounds reported is a complex process because they are polycyclic aromatic systems and the coupling network similarity in different parts of the molecule usually results in severe overlap of their 1H resonances. To overcome this impediment, we took advantage of various 2D-NMR techniques (COSY, NOESY, ROSEY, HSQC, and HMBC) along with other 1D-NMR experiments (1H HOMODEC, 1H, and 13C) to completely assign the desired complexes. Subsequently we also studied the coordination chemistry of several meal cations with our ligand system with the goal of obtaining single stranded monhelices. The potential use of some of the complexes in the area of NMR discrimination and kinetic resolution of racemic mixtures was examined and shown to be promising. Several NMR experiments were conducted using the racemic olefins 3-buten-2-ol and 1-penten-3-ol to demonstrate the discriminating power of our silver(I) complexes. We discovered that sterics play an important role in this resolution experiment and the bulky nature of our complexes affect the overall efficiency of the NMR discriminatory process as it diminishes the contact between the reactive metal center and the olefins involved. Temperature also plays a vital role in the chiral recognition of racemic olefins as we examined the ideal temperature needed to reduce the various dynamic processes that take place in solution at room temperature.