Thesis advisor: Shih-Yuan Liu / This dissertation describes the utility of 1,2-azaborine motif as a 4C+1B+1N synthon in organic synthesis, especially for the preparation of densely functionalized cyclobutanes based on the framework of the 1,2-azaborine photoisomerization. The substitution of a CC unit with a BN unit in benzenes significantly modifies the properties of classic benzenoid compounds, leading to new reactivities and functionalities. In this vein, Chapter 1 discloses photoisomerization of 1,2-azaborines to selectively form BN-analogues of the Dewar benzene. Three applications of the Dewar photoisomers are described herein: 1) a rhodium-catalyzed ring-opening reaction to form 1,2-azaborines; 2) furnishing cis aminoborylated cyclobutanes with the boron unit as a further functionalization handle; 3) a stereospecific ring-opening reaction to afford diene which can engage in Diels-Alder reaction. Chapter 2 elaborates on a modular and stereoselective strategy to access a variety of cyclobutane β-amino alcohols. Discussed herein are regioselective functionalizations and di-functionalizations of the 1,2-azaborine core and a tandem photoisomerization-hydrogenation-oxidation protocol to translate the functionalized azaborine core to cyclobutane amino alcohols. Also examined herein are the scope of azaborine photoisomerization and Dewar hydrogenation. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

特異なルテニウムが触媒する"Borrowing hydrogen"のコンセプトに基づく有機反応を開発した。まず、Ru/JOSIPHOS触媒を用いて、1,2-ジオールとアミンの反応から光学活性β-アミノアルコールを最高99%収率ならびに77% eeで得ることに成功した。本反応は新規であり、その反応機構についても明らかにした。さらに、RuCl2(PPh3)3/DPEphos/K3PO4を組み合わせた触媒を用いることで、アルコールをアルキル化剤に用いるインドールの3位選択的アルキル化反応を達成した。高効率かつ広いタイプの基質に適用できる。 / Several novel ruthenium-catalyzed "borrowing hydrogen"-based organic reaction has been developed. For very first time optically active β-amino alcohols can be sinthesized directy by reaction of 1,2-diol and coressponding amine under Ru/JOSIPHOS catalysis in up to 99% yield and 77% ee. Since this reaction is very new, intensive investigation of the reaction mechanism was also carried out. Meanwhile, combination of RuCl2(PPh3)3/DPEphos/K3PO4 was found to be effective catalyst for alkylation of indole with alcohol as an alkylating reagent. This catalysis was highly reactive to give the corresponding alkylated indole in excellent yield for almost all types of indoles and alcohols substrates. / 博士(工学) / Doctor of Philosophy in Engineering / 同志社大学 / Doshisha University

O anel aziridínico é conhecido desde o final do século XIX e apresenta alta reatividade devido a sua alta energia de ligação e tensão do anel, o que o torna um valioso aliado na síntese orgânica, especialmente em reações com nucleófilos. Estas características também o tornam reativo frente à nucleófilos biológicos, tais como os ácidos nucléicos. Tal fato leva a uma toxicidade celular e pode ser dirigida a substratos específicos, como no caso de quimioterápicos, levando à alquilação de DNA em células tumorais. Este anel pode ser sintetizado a partir de ?-aminoálcoois, cuja classe de compostos apresenta conhecidas atividades, presentes em importantes moléculas biologicamente ativas. Diante disto, realizouse neste trabalho um estudo a partir de um padrão estrutural envolvendo as duas classes mencionadas, aziridinas e ?-aminoálcoois, a fim de se identificar uma possível atividade antitumoral frente à enzima LSD1. Para este caso, se explora a similaridade estrutural entre aziridina e ciclopropano, presente na estrutura da tranilcipromina. Além disso, realizou-se o estudo deste padrão estrutural frente a dois outros alvos: células de câncer de mama e o parasita T.cruzi, com o intuito de expandir o conhecimento sobre a reatividade de tais compostos sobre estas células. O desenvolvimento desta biblioteca de compostos permitiu uma análise preliminar das relações entre a estrutura química e atividade biológica observada. Neste estudo, foi possível identificar aziridinas com atividade antumoral, mais potentes que cisplatina (IC50 abaixo de 40?M). O mecanismo de ação, por sua vez, ainda deverá ser estudado, considerando que os compostos não inibiram LSD1. / The aziridine ring is known since the end of the XIX century and presents high reactivity due to its high strain energy and ring tension, which makes it a valuable ally in organic synthesis, especially with nucleophiles. These characteristics also culminate in reactivity towards biological nucleophiles, such as nucleic acids. This fact leads to cellular toxicity and can be directed to specific sites, which is the case in chemotherapy agents, resulting in DNA alkylation in cancer cells. This ring can be obtained from ?-amino alcohols, which also present known activities and are present in important molecules with biological activity. As a result, this work performed a study of a structural pattern involving those two classes mentioned above, targeting a potential antitumoral activity towards the LSD1 enzyme. In this case, it is explored the structural similarity between the aziridine ring and the ciclopropane, present in the tranylcipromine structure. Furthermore, this structural pattern was studied for other two targets: breast cancer cells and the T.cruzi parasite, in order to expand the knowledge about the reactivity of those compounds in those biological systems. The development of this library allowed a preliminary analysis between the chemical structure and the observed biological activity. In this project it was possible to identify aziridines with antitumoral activities, showing higher potency than cisplatine (IC50 below 40?M). However, the mechanism is yet to be studied, considering that those compounds didn\'t inhibit the LSD1 enzyme.

Neste trabalho são apresentados estudos referentes a dois grupos de sistemas contendo dióxido de enxofre como principal foco, tendo em vista a importância desta molécula em sistemas ambientais e sua caracteristicas químicas interessantes como seu caráter anfotérico e sua capacidade de interação com sistemas inorgânicos via oxigênio ou enxofre. Tendo como principais feramentas as espectroscopias vibracionais (espalhamento Raman e absorção no Infravermelho), eletrônica (UV-VIS) e Ressonância Magnética Nuclear (RMN) investigou-se as interações inter e intramoleculares dos sistemas de interesse. Primeiramente foi investigada a interação do SO2 com aminoálcoois, sendo que estes sistemas apresentam boa capacidade de absorção do SO2. Destaca-se a formação de zwitteríons pela interação do SO2 com o grupamento alcoólico da molécula, observado apenas quando da presença de grupo amino para estabilização da separação de cargas gerada, mostou-se que o poduto fomado é mais estavél quanto menor a separação das cargas e menor o impedimento estérico na amina. Este sistema foi investigado quanto a sua revesibilidade, que foi observada sempre acompanhada de degradação do aminoálcool. O segundo sistema refere-se a interação do dióxido de enxofre com complexos de níquel em dois estados de oxidação (II/III) com ligante macrocíclico cyclam (1,4,8,11- Tetraazaciclotetradecano); o diferencial deste estudo frente a outros apresentados na literatura é a análise das reações em meio anidro. Nos experimentos em meio livre de O2 obseva-se a redução do complexo de Ni (III) a Ni(II) e em meio contendo O2 observa-se a oxidação do complexo de Ni(II) a Ni(III), mostrando a importância do O2 para a manutenção de um ciclo catalítico capaz de oxidar SO2 a SO42-. Os resultados aqui apresentados indicam que os mecanismos em meio anidro são bastante semelhantes aos observados em meio aquoso. / In this work we focus on two sulfur dioxide containing systems due to the relevance of this molecule in environmental science and its interesting physico-chemical properties as its amphoteric characteristic and ability to interact with inorganic systems through oxygen or sulfur atoms. The main tools for investigation was vibrational spectroscopy (Raman scattering and Infrared absorption), electronic spectroscopy (UV-VIS) and Nuclear Magnetic Resonance (NMR), whereby the intra and intermolecular interactions were probed. The first subject of investigation was the study of interactions between SO2 and amino alcohol. This system shows great ability to capture SO2, highlighting the zwitterionic formation due to the bonding of SO2 via the alcoholic part of the amino alcohol molecule, what is only possible due to the presence of the amino group to stabilize the charge separation, the stability of the poduct depends on the steric hindrance and on the charge separation. The reversibility of the system was investigated and it was always accompanied by degradation of the amino alcohol. The second system consists in the investigation of interactions between SO2 and two nickel-cyclam (1,4,8,11-Tetraazacyclotetradecane) complexes, where the metal is in different oxidation states (II/III). This work is different from previous in the sense that the analyses are carried out in anhydrous environment. In O2 free environment we were able to see the reduction of Ni(III) to Ni(II) complex, and in presence of O2 the oxidation of Ni(II) to Ni(III) complex occurs, showing the relevance of O2 to catalytic cicle that is able to transform SO2 to SO42-. Our results suggest that the mechanisms in aqueous and nonaqueous environments are very similar.

Neste trabalho são apresentados estudos referentes a dois grupos de sistemas contendo dióxido de enxofre como principal foco, tendo em vista a importância desta molécula em sistemas ambientais e sua caracteristicas químicas interessantes como seu caráter anfotérico e sua capacidade de interação com sistemas inorgânicos via oxigênio ou enxofre. Tendo como principais feramentas as espectroscopias vibracionais (espalhamento Raman e absorção no Infravermelho), eletrônica (UV-VIS) e Ressonância Magnética Nuclear (RMN) investigou-se as interações inter e intramoleculares dos sistemas de interesse. Primeiramente foi investigada a interação do SO2 com aminoálcoois, sendo que estes sistemas apresentam boa capacidade de absorção do SO2. Destaca-se a formação de zwitteríons pela interação do SO2 com o grupamento alcoólico da molécula, observado apenas quando da presença de grupo amino para estabilização da separação de cargas gerada, mostou-se que o poduto fomado é mais estavél quanto menor a separação das cargas e menor o impedimento estérico na amina. Este sistema foi investigado quanto a sua revesibilidade, que foi observada sempre acompanhada de degradação do aminoálcool. O segundo sistema refere-se a interação do dióxido de enxofre com complexos de níquel em dois estados de oxidação (II/III) com ligante macrocíclico cyclam (1,4,8,11- Tetraazaciclotetradecano); o diferencial deste estudo frente a outros apresentados na literatura é a análise das reações em meio anidro. Nos experimentos em meio livre de O2 obseva-se a redução do complexo de Ni (III) a Ni(II) e em meio contendo O2 observa-se a oxidação do complexo de Ni(II) a Ni(III), mostrando a importância do O2 para a manutenção de um ciclo catalítico capaz de oxidar SO2 a SO42-. Os resultados aqui apresentados indicam que os mecanismos em meio anidro são bastante semelhantes aos observados em meio aquoso. / In this work we focus on two sulfur dioxide containing systems due to the relevance of this molecule in environmental science and its interesting physico-chemical properties as its amphoteric characteristic and ability to interact with inorganic systems through oxygen or sulfur atoms. The main tools for investigation was vibrational spectroscopy (Raman scattering and Infrared absorption), electronic spectroscopy (UV-VIS) and Nuclear Magnetic Resonance (NMR), whereby the intra and intermolecular interactions were probed. The first subject of investigation was the study of interactions between SO2 and amino alcohol. This system shows great ability to capture SO2, highlighting the zwitterionic formation due to the bonding of SO2 via the alcoholic part of the amino alcohol molecule, what is only possible due to the presence of the amino group to stabilize the charge separation, the stability of the poduct depends on the steric hindrance and on the charge separation. The reversibility of the system was investigated and it was always accompanied by degradation of the amino alcohol. The second system consists in the investigation of interactions between SO2 and two nickel-cyclam (1,4,8,11-Tetraazacyclotetradecane) complexes, where the metal is in different oxidation states (II/III). This work is different from previous in the sense that the analyses are carried out in anhydrous environment. In O2 free environment we were able to see the reduction of Ni(III) to Ni(II) complex, and in presence of O2 the oxidation of Ni(II) to Ni(III) complex occurs, showing the relevance of O2 to catalytic cicle that is able to transform SO2 to SO42-. Our results suggest that the mechanisms in aqueous and nonaqueous environments are very similar.

The asymmetric synthesis of chiral norbornene based 1,4-aminoalcohols and their applications in asymmetric diethylzinc addition reactions was perfomed starting from meso-anhydride 50. The desymmetrization of this meso-anhydride 50 was done by the usage of quinine or quinidine cinchona alkaloids with very high enantiomeric excess values (up to 98% ee) and chemical yields. The Quinidine-mediated desymmetrization of meso-anhydride 50 with methanol gave (2R,3S)-(+)-cis-monoester 51. The amination of this resulting compound with HMPTA was performed and by keeping the amine group constant, the amidoester was transformed into chiral ligands with Grignard reaction followed by LAH reduction. The effectiveness of 1,4-aminoalcohol type ligands, (2R,3S)-(-)-57, (2R,3S)-(-)-58, (2R,3S)-(-)-59 and (2S,3R)-(+)-60 as chiral catalysts in asymmetric diethylzinc addition reaction to benzaldehyde were examined and the ligand 60 gave the highest enantioselectivity (69% e.e.)

The asymmetric synthesis of N-aryl substituted chiral 1,4-aminoalcohols and their applications in asymmetric borane reduction and enantioselective diethylzinc addition to benzaldehyde reactions were performed starting from meso anhydride 51 that is the cycloadduct of cyclopentadiene and maleic anhydride. The desymmetrization of meso-anhydride 51 was achieved by using quinine or quinidine with very high enantiomeric excess value (up to 98% ee) and with high chemicalb yield. The quinine-mediated desymmetrization of meso-anhydride 51 with methanol gave (2S,3R)-(-)-cis-monoester 52. The hemiester was subjected to chemoselective amidation with various types of N-aryl substituted amines and then, it was treated with LAH and followed by hydrogenation in the presence of palladium catalyst to get the chiral 1,4-amino alcohols. The catalytic effectiveness of these chiral 1,4-amino alcohol ligands, (2S,3R)-60, (2S,3R)-61, (2S,3R)-62 and (2S,3R)-63 were examined in asymmetric borane reduction and enantioselective diethylzinc addition to benzaldehyde reactions. Keywords: Amino alcohol, chiral ligand, asymmetric reaction, borane reduction, diethylzinc addition

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene backbone was performed starting with simple and cheap anhydride 30. Quinine-mediated desymmetrization of anhydride 30 with methanol resulted in (2S,3R)-(-)-cis-hemiester 31 (98% e.e.). Chemoselective amination with HMPTA and NH4OH followed by LAH reduction afforded (2S,3R)-(+)-36 and (2S,3R)-(-)-37, respectively. The amidoester (2S,3R)-(-)-32 was transformed into chiral ligand (2S,3R)-(-)-35 with Grignard reaction followed by LAH reduction. The chiral ligands (2S,3R)-(-)-35, (2S,3R)-(+)-36 and (2S,3R)-(-)-37 were subjected to asymmetric diethylzinc addition reaction to examine their effectiveness as chiral catalyst. Among these, chiral ligand 36 exhibited the highest enantioselectivity (88% e.e.)

An applicable method for the racemic synthesis of 1,2-amino alcohols having tertiary alcohol moiety was developed. This method can be used as a general method for the synthesis of various 1,2-amino alcohols with various tertiary alcohol moieties by changing chloroacetone with different monohalo ketones, and with different aryl halides or alkyl halides. The resultant racemic 1,2-aminoe alcohols were tried to resolve by using various hydrolase type enzymes under different conditions by changing the parameters i.e. solvent, temperature and substrate: enzyme ratios. Finally, poorly resolved amino alcohol 20 with 21 % was used as chiral ligand in diethyl zinc reaction to benzaldhyde and afforded (R)-1-phenylpropan-1-ol almost with 21 % e.e..

O anel aziridínico é conhecido desde o final do século XIX e apresenta alta reatividade devido a sua alta energia de ligação e tensão do anel, o que o torna um valioso aliado na síntese orgânica, especialmente em reações com nucleófilos. Estas características também o tornam reativo frente à nucleófilos biológicos, tais como os ácidos nucléicos. Tal fato leva a uma toxicidade celular e pode ser dirigida a substratos específicos, como no caso de quimioterápicos, levando à alquilação de DNA em células tumorais. Este anel pode ser sintetizado a partir de ?-aminoálcoois, cuja classe de compostos apresenta conhecidas atividades, presentes em importantes moléculas biologicamente ativas. Diante disto, realizouse neste trabalho um estudo a partir de um padrão estrutural envolvendo as duas classes mencionadas, aziridinas e ?-aminoálcoois, a fim de se identificar uma possível atividade antitumoral frente à enzima LSD1. Para este caso, se explora a similaridade estrutural entre aziridina e ciclopropano, presente na estrutura da tranilcipromina. Além disso, realizou-se o estudo deste padrão estrutural frente a dois outros alvos: células de câncer de mama e o parasita T.cruzi, com o intuito de expandir o conhecimento sobre a reatividade de tais compostos sobre estas células. O desenvolvimento desta biblioteca de compostos permitiu uma análise preliminar das relações entre a estrutura química e atividade biológica observada. Neste estudo, foi possível identificar aziridinas com atividade antumoral, mais potentes que cisplatina (IC50 abaixo de 40?M). O mecanismo de ação, por sua vez, ainda deverá ser estudado, considerando que os compostos não inibiram LSD1. / The aziridine ring is known since the end of the XIX century and presents high reactivity due to its high strain energy and ring tension, which makes it a valuable ally in organic synthesis, especially with nucleophiles. These characteristics also culminate in reactivity towards biological nucleophiles, such as nucleic acids. This fact leads to cellular toxicity and can be directed to specific sites, which is the case in chemotherapy agents, resulting in DNA alkylation in cancer cells. This ring can be obtained from ?-amino alcohols, which also present known activities and are present in important molecules with biological activity. As a result, this work performed a study of a structural pattern involving those two classes mentioned above, targeting a potential antitumoral activity towards the LSD1 enzyme. In this case, it is explored the structural similarity between the aziridine ring and the ciclopropane, present in the tranylcipromine structure. Furthermore, this structural pattern was studied for other two targets: breast cancer cells and the T.cruzi parasite, in order to expand the knowledge about the reactivity of those compounds in those biological systems. The development of this library allowed a preliminary analysis between the chemical structure and the observed biological activity. In this project it was possible to identify aziridines with antitumoral activities, showing higher potency than cisplatine (IC50 below 40?M). However, the mechanism is yet to be studied, considering that those compounds didn\'t inhibit the LSD1 enzyme.