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Developing asymmetric C-H bond activation methods in order to achieve enantiopure products is crucial for the advancement of the field and for the production of novel chiral compounds. Therefore, we tried to develop this area of organic chemistry by presenting metal catalyzed stereoselective C-H bond activation utilizing chelation-assisted tools. The first section of this study involves Rh(I) catalyzed asymmetric C-H bond activation of a series of ketones via an intermolecular procedure. By this method, we examine ortho-alkylation of aromatic ketones and β-functionalization of α-β unsaturated ketones with a series of prochiral olefins. In the second section, we present an efficient three steps method for stereoselective intramolecular C-H bond activation of indol-3-carboxaldehyde with tethered prochiral olefins. The catalytic system in both methods involves a joint chiral primary amine and Rh(I) catalyst. Chiral primary amines can serve to induce enantioselectivity as well as acting as a useful directing group which has shown appropriate coordination to the transition metal catalyst, providing high regioselectivity. / February 2017

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

Amine transaminases are enzymes that catalyze the mild and selective formation of primary amines, which are useful building blocks for biologically active compounds and natural products. In order to make the production of these kinds of compounds more efficient from both a practical and an environmental point of view, amine transaminases were incorporated into multi-step one-pot reactions. With this kind of methodology there is no need for isolation of intermediates, and thus unnecessary work-up steps can be omitted and formation of waste is prevented. Amine transaminases were successfully combined with other enzymes for multi-step synthesis of valuable products: With ketoreductases all four diastereomers of a 1,3-amino alcohol could be obtained, and the use of a lipase allowed for the synthesis of natural products in the form of capsaicinoids. Amine transaminases were also successfully combined with metal catalysts based on palladium or copper. This methodology allowed for the amination of alcohols and the synthesis of chiral amines such as the pharmaceutical compound Rivastigmine. These examples show that the use of amine transaminases in multi-step one-pot reactions is possible, and hopefully this concept can be further developed and applied to make industrial processes more sustainable and efficient in the future. / <p>QC 20170113</p>

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第18342号 / 農博第2067号 / 新制||農||1024(附属図書館) / 学位論文||H26||N4849(農学部図書室) / 31200 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 栗原 達夫, 教授 三上 文三, 教授 平竹 潤 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Kirala aminer används idag både som aktiva substanser och som bindningsmedel i flertalet läkemedel, dock är dagens produktion med kinetic resolution ineffektiv vilket gör att mer effektiva och miljövänliga produktionssätt eftersträvas. Biotransformation har visat sig både vara miljövänligt och en effektiv metod för att producera kirala aminer. Aminosyror kan användas som aminodonatorer för att producera den kirala aminen 1-methyl-3-phenylpropylamine (MPPA) från prokirala ketonen bensylaceton (BA) med hjälp av aminetransaminas. I denna studie användes metaboliskt konstruerad Saccharomyces cerevisiae med enzymet CV-ωTA för att identifiera vilka aminosyror som var bäst lämpade för MPPA produktion. MPPA produktion kunde detekteras för alla testade aminosyror. Aminosyrans koncentration hade ingen tydlig påverkan på produktionen av MPPA. Alanin vara den aminosyra som gav högst produktionsutbyte följt av lysin. Ingen tydlig relation mellan produktion av MPPA och aminosyrornas koncentrationer kunde ses. Produktionen av MPPA var snabbare än förväntat och var klar redan dag tre för flera av aminosyrorna. Det fanns en antydan att BA kunde vara toxiskt för cellerna i högre koncentrationer och därmed påverka produktionen av MPPA. / Chiral amines are used in several types of pharmaceuticals as both active substrates and building blocks, and there is an endeavor to find new and more eco-efficient ways to produce them than today’s production with kinetic resolution. Biotransformation in yeast has shown great potential for production and is also seen as an eco-friendly way to produce chiral amines. Amino acids can be used as an amino donor for the production of chiral amines, e.g. 1-methyl-3-phenylpropylamine (MPPA) from prochiral ketones, e.g. benzylacetone (BA) with aminotransaminase. In this study the production was done with metabolically engineered Saccharomyces cerevisiae, with the gene for the enzyme CV-ωTA transformed. Ten different amino acids were screened in up to three different concentrations for each amino acid. Production of MPPA was observed for all amino acids, with alanine as the most efficient followed by lysine. No clear relationship was seen between amino acid concentration and MPPA production. The production of MPPA for several amino acids were quicker than expected and was completed at day three. Our data indicated a cytotoxic effect of BA at higher concentrations, that negatively affected the production of MPPA.