There is a strong market demand for enantiomerically pure drugs. One solution to this problem is to develop a simple methodology for transferring synthetically designed racemic drugs into optically pure ones. Many synthetic drugs are by nature amides, therefore, amino acid based models for transformation of racemates into optically pure compounds were selected for this study. Formation of self-assembly molecular aggregates of properly modified amino acids was observed with and without the presence of cyclodextrins. Cyclodextrin assisted formation of polymer-like self-assemblies and enantiomeric resolution of these amino acids were studied using 1D and 2D NMR spectroscopy, EleacroSpray Ionization Mass Spectroscopy (ESIMS), Matrix- Assisted Laser Desorption Ionization Time-of-Flight Mass Spectroscopy (MALDI-TOF-MS). The role of p-p stacking interaction between aromatic moieties in enantiomeric resolution was demonstrated by calculating association constants of this host-guest system. Dolabellane diterpenoids share the unique feature of a trans-bicyclo[9.3.0]tetradecane and most of them express antimicrobial, antitumor and antiviral activities. They are primarily obtained from marine resources. Dolabellane diterpenoid B was isolated from the Okinawan soft coral of the genus Clavularia by Iguchi and co-workers. Current efforts toward the synthesis of dolabellane diterpenoid B is discussed along with the plans for completion of its synthesis.

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Boronic acids, particularly those that carry an ortho-aminomethyl group, have been extensively utilized in the field of molecular recognition in recent years thanks to their ability to reversibly bind to a wide variety of polyol substrates. They have been shown to form cyclic boronate esters rapidly upon reaction with 1,2- and 1,3-diols, catechols, carbohydrates and hydroxycarboxylic acids, making them attractive as potential sensing units. While they have found broad application in this forum, the mechanism by which they work is still up for debate. This work begins in Chapter 1 with a review of the fundamentals of ¹¹B NMR spectroscopy and its application on the analysis of boronic acid-containing systems. The focus of Chapter 2 turns toward systems with an o-iminomethylphenylboronic acid moiety. This species can be formed easily through a three-component assembly, though physical understanding of this complex lags behind. With the fundamentals of ¹¹B NMR spectroscopy detailed previously, the results obtained when utilizing this technique to study both the structure and mode of interaction in these species will be presented. In Chapter 3 we give a comprehensive review of the data and conclusions that have been published by different groups about one of the most successful fluorescent sugar sensors of this kind, first introduced by Seiji Shinkai in 1994. Additionally, it delineates the experimental results obtained by our group when attempting to answer some of the remaining questions. In Chapter 4 we report the use of the aforementioned multi-component assembly as an enantioselective sensor for α-chiral primary amines. Using circular dichroism, the ee% of these analytes could be accurately determined with this system. Additionally, enantio- and chemodiscrimination was possible by employing chemometric tools like PCA and LDA. Finally, Chapter 5 is a compilation of efforts to expand the use of these sensing systems into synthetic organic chemistry research labs. In collaboration with Xumu Zhang at Rutgers University, we have implemented a previously developed system to analyze the product of an asymmetric hydrogenation of an imine to create a chiral amine. A proof of concept study on a novel automated circular dichroism plate reader prototype aimed to increasing sample throughput was completed at New York University with Professor Bart Kahr. / text

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In chapter 1 the principles behind circular dichroism spectroscopy and exciton coupled circular dichroism spectroscopy are outlined, and examples are cited that illustrate the utility of these methods in the determination of absolute configuration and ee of chiral amines. This provides background and context for this thesis, which mostly pertains to the sensing of chirality in amines. An exciton coupled circular dichroism method based on the induction of helical chirality in an organometallic host for sensing chiral amines is presented in chapter 2. The method can be used to determine absolute configuration by relating the sign of the first Cotton effect of the host-amine complex to the handedness of the amine. Analysis of the primary circular dichroism optical data is by principal component analysis allows for differentiation of the analytes based on their idendity and handedness. A novel circular dichroism method for detecting chiral amines is discussed in chapter 3. The method uses a highly efficient derivatization method to convert the primary amine into a bidentate imine. Three equivalents of the imine are then assembled together by coordination to Fe(II). The proximity and chiral orientation of the imines leads to exciton coupled circular dichroism, which is of utility in the determination of absolute configuration. Additionally, there is a metal-to-ligand charge transfer band in the visible region that can be used to develop calibration curves, which allow for the determination of the enantiomeric excess of unknown samples with an absolute error of ±5%. Chapter 4 details another imine based circular dichroism method for chiral amines. The method uses a commercially available aldehyde, Fe(II), and circular dichroism spectrometry to sense chirality in amines. It is shown that the circular dichroism signals in the ultraviolet spectrum vary predictably with the handedness of the chiral amine, which has potential applications in the determination of absolute configuration. By developing calibraton curves, signals in the visible spectrum can be used to determine enantiomeric excess with an absolute error of ±6%. Analyzing the primary circular dichroism optical data with linear discriminant analysis allows for differentiation between amines based on their identity and handedness. Finally, chapter 5 illustrates the potential of using the thermodynamic parameters of partitioning between water and octanol as a predictive tool for estimating the contributions of hydrophobicity to host-guest binding events. This is done by showing a relationship between the thermodynamics of partitioning and thermodynamics of hydrophobic binding events for a series of guests and cyclodextrin. A plot of the thermodynamic parameters of binding of a variety of guests to cyclodextrin as a function of the thermodynamic parameters of partitioning between water and octanol shows a linear relationship for a series of alcohols. / text

This project utilized synthesis and in vitro assays to generate antagonist SARs at various nAChR subtypes. Alkylation of the pyridino nitrogen of the nicotine molecule afforded subtype specific antagonists at a42* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. Using this data, a series of mono-azaaromatic quaternary salts were produced and evaluated in binding and functional assays for a42* and a7* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. Additionally, bis-azaaromatic quaternary salts were synthesized and evaluated in the same assays. Two potent lead compounds were identified. N-n-dodecylnicotinium iodide (NDDNI) was found to be very potent at both a42* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. And the most promising candidate was N-N-bisdodecylpicolinium dibromide (bDDPiB), which was selective for the nAChR subtypes that mediate nicotine-evoked dopamine release (IC50 = 9 nM). Additionally, using the data from the SARs, predictive computer models were generated to assist in future compound assessment without in vitro assays. Three self-organizing map (SOMs) models were generated from three different sets of compounds. The groups consisted of the mono-substituted compounds, the bissubstituted compounds, and both sets combined. The models were able to successfully "bin" the test set of compounds after developing a model from a similar set of training compounds. Additionally, using genetic functional activity (GFA) algorithms an evolutionary approach to generating predictive model equations was applied to the compounds. Three separate equations were generated in order to form a predictive method for evaluating affinities at the a4b2* receptor subtype. In addition to the modeling and SAR work of the quaternary ammonium compounds, novel synthetic methods were also employed to develop enantiomerically pure nicotine analogs. Efficient enantioselective syntheses of (S)- and R-(+)-nornicotine, (S)-and R-(+)-anabasine, and (S)-and R-(+)-anatabine have been developed, affording isomers in high enantiomeric excess.

The influence of a chiral surfactant and a polymer-supported chiral additive on reduction of ketones using sodium borohydride will be described. Initial preparations involved methylation of (S)-leucinol to give (2S)-N,N-dimethyl-2-amino-4-methyl-1-pentanol (1) (67%). The chiral surfactant (2) was synthesized by reacting (1) with bromohexadecane (71%). The functionalized styrene for the polymer-supported chiral additive (5) was synthesized by reacting (1) with 4-vinylbenzyl chloride. Polymerization was carried out with 10% of the functionalized monomer (4), 5% cross-linking agent divinylbenzene, and 85% styrene with AIBN as the initiator. The activity of the chiral surfactant and polymeric additive were examined by using them as additives in a standard reduction of 2-pentanone with sodium borohydride to yield (R)- and (S)-2-pentanol (3) (20%). The resulting alcohol was analyzed by polarimetry (ee 9.5%) and also esterified with (2S)-methylbutyric acid prior to characterization by NMR. 13C NMR indicated an enantiomeric excess of 5.2% when the chiral surfactant was used, and 7% when the polymeric additive was used.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第18336号 / 農博第2061号 / 新制||農||1023(附属図書館) / 学位論文||H26||N4843(農学部図書室) / 31194 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 梅澤 俊明, 教授 矢﨑 一史, 教授 三上 文三 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM