A new class of porous polymers has been designed and successfully synthesized by thermal dehydrogenation of several polytopic arylamine-borane adducts and has been designated Borazine-Linked Polymers (BLPs). The polymers reported are constructed of linear, triangular, and tetrahedral amine building units to form 2D and 3D frameworks. The boron sites of the pores are aligned with hydrogen atoms contrasted with the recently reported halogenated BLPs which consist of pore channels aligned with bromine or chlorine atoms. One of the reported BLPs, BLP-2(H), was proven to be crystalline by PXRD, matching the experimental pattern to theoretical patterns calculated from modeled structures. BLPs were found to be thermally stable by thermogravimetric analysis, decomposing at temperatures ~450 ºC. Infrared spectroscopy and 11B MAS NMR spectra confirm the formation of borazine as reported in previous borazine-containing polymers and 13C CP MAS spectra confirmed that the structural integrity of the amine building units were maintained and incorporated in the framework of BLPs. Nitrogen isotherms revealed that BLPs exhibit high surface areas ranging from 1132-2866 m2/g (Langmuir) and 400-2200 m2/g (Brunauer-Emett-Teller, BET) with pore sizes from 7-14 Å. Hydrogen, methane, and carbon dioxide measurements were performed at low pressure (up to 1 atm) and were found to be among the best of organic polymers. High pressure isotherms (up to 40 bar) were also taken at various temperatures ranging from 77-298 K. Isosteric heats of adsorption were calculated using the virial method at low pressures. Gas storage performance of BLPs at 40 bar were found to be: 14.7-42.5 mg/g for H2 uptake at 77 K; 348.9-717.4 mg/g for CO2 uptake at 298 K; and 40.8-116.1 mg/g for CH4 uptake at 298 K. The CO2/CH4 selectivity of BLPs at 298 K up to 40 bar was calculated using the Ideal Adsorbed Solution Theory (IAST) to determine their performance as carbon capture and sequestration materials. Additionally, non-borazine containing nanoporous organic polymers (NPOFs) consisting of all carbon and hydrogen atoms were also synthesized and subjected to low pressure hydrogen storage measurements. The results show that though NPOFs generally exhibit higher surface areas (SALang = 2423-4227 m2/g), the H2 storage capacity of BLPs is superior.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

This thesis is concerned with the synthesis and evaluation of various tellurium-based chain-breaking antioxidants. The purpose is to find novel regenerable compounds with improved radical-trapping capacity. In the first part of this work, we explore the possibilities to incorporate tellurium into tocopherols and aromatic amines. Overall, tocopherols carrying alkyltelluro groups are better radical-trapping agents than the corresponding sulfur- and selenium analogues. Among them, 7-octyltelluro δ-tocopherol showed a ca. 17-fold higher reactivity than recorded for α-tocopherol and much better regenerability. Even longer inhibition times were recorded for the corresponding bis(tocopheryl) tellurides. In the aromatic amine series, diphenyl amines carrying alkyltelluro groups were shown to function as efficient radical-quenchers capable of inhibiting peroxidation for 460 min in the presence of N-acetylcysteine. Thiol-consumption experiments suggested that the long inhibition times are due to efficient quenching of in-situ formed alkoxyl radicals in a solvent cage. In the second part of the thesis, we study how the antioxidant properties are affected by variations in the electron density at tellurium and the number of alkyltelluro substituents in the molecule. Evaluation of a series of aryltelluro phenols carrying electron donating and electron withdrawing groups in the para-position of the aryl moiety suggested that a high electron density at the heteroatom prolonged the inhibition time. Among alkyltelluro phenols, alkyltelluro resorcinols and bis(alkyltelluro) phenols, phenols carrying alkyltelluro groups in both ortho positions were superior when it comes to radical-trapping activity and regenerability.

As nanomaterials continue to garner interest in a wide range of industries and scientific fields, commercial suppliers have met growing consumer demand by readily offering custom particles with size, shape and surface functionality made-to-order. By circumventing the challenging and complex synthesis of functionalized nanoparticles, these businesses seek to provide greater access for the experimentation and application of these nanoscale platforms. In many cases, amine functional groups are covalently attached as a surface coating on a nanoparticle to provide a starting point for chemical derivatization and commonly, conjugation of biomolecules in medical science applications. Successful conjugation can improve the compatibility, interfacing and activity of therapeutic and diagnostic nanomedicines. Amines are amongst the most popular reactive groups used in bioconjugation pathways owing to the many high-yield alkylation and acylation reaction are involved in. For the design of functionalized nanomaterials with precisely tuned surface chemical properties, it is important to develop techniques and methods which can accurately and reproducibly characterize these materials. Quantification of surface functional groups is crucial, as these groups not only allow for conjugation of chemical species, but they also influence the surface charge and therefore aggregation behavior of nanomaterials. The loss of colloidal stability of functionalized nanomaterials can often correspond to a significant if not complete loss of functionality. Thus, we sought to develop multiple characterization approaches for the quantification of surface amine groups. Silica nanoparticles were selected as a model nanomaterial as they are widely used, commercially available, and their surface chemistry has been investigated and studied for decades. Various commercial batches of silica nanoparticles were procured with sizes ranging from 20 – 120 nm. Two colorimetric assays were developed and adapted for their ease-of-use, sensitivity, and convenience. In addition, a fluorine labelling technique was developed which enabled analysis by quantitative solid-state 19F NMR and X-ray photoelectron spectroscopy (XPS). XPS provided data on surface chemical composition at a depth of ≈ 10 nm, which allowed us to determine coupling efficiencies of the fluorine labelling technique and evaluate the reactivity of the two assays. The ensemble of surface-specific quantification techniques was used to evaluate multiple commercial batches of aminated silica and investigate batch-to-batch variability and the influence of particle size with degree of functionalization. In addition, resulting measurements of surface amine content were compared and validated by an independent method based on quantitative solution 1H NMR, which was developed for total functional group content determination. This allowed for us to assess the role of accessibility and reactivity of the amine groups present in our silica particles. Overall, the objective of this study was to develop a multi-method approach for the quantification of amine functional groups on silica nanoparticles. At the same time, we hoped to set a precedent for the development and application of multiple characterization techniques with an emphasis of comparing them on the basis of reproducibility, sensitivity, and mutual validation.

Neste trabalho, foi avaliada a resolução cinética de ésteres carboxílicos β-borilados, catalisada por lipases, através de hidrólise e transesterificação. Foram sintentizados ésteres contendo diferentes cadeias carbônicas. A hidrólise enantiosseletiva catalisada por CAL-B forneceu o correspondente ácido carboxílico β-borilado com excesso enantiomérico moderado (e.e. 62%), enquanto os ésteres β-borilados metílico e etílico foram recuperados com excelente pureza enantiomérica (e.e.>99%). A reação de transesterificação enantiosseletiva entre ésteres carboxílicos β-borilados e álcoois, catalisada por CAL-B, demonstrou uma alta seletividade somente quando etanol e (β-pinacolilboronato)-butanoato de metila foram usados como substratos, levando a formação de (β-pinacolilboronato)-butanoato de etila enantioenriquecido (e.e.>99%). Entretanto, ésteres contendo longas cadeias carbônicas ligadas à carboxila não sofreram as reações desejadas, mesmo em temperaturas mais elevadas. Adicionalmente, foi investigada a reação de aminação redutiva assimétrica, catalisada por ω-transaminases, de cetonas pró-quirais contendo grupos borônicos (ácido, éster ou trifluoroborato de potássio). Após as sínteses de cetonas aromáticas e alifáticas, os melhores resultados para a biotransformação foram obtidos com ω-transaminases (R)-seletivas de Arthrobacter sp. e Aspergillus terreus e (S)-seletiva de Chromobacterium violaceum. Sob as condições otimizadas, foram obtidas altas conversões (94%) com perfeitas enantiosseletividades (e.e.>99%), proporcionando assim uma nova via de acesso a aminas (R) ou (S) contendo boro em condições reacionais suaves. / In this work, the kinetic resolution of β-borylated carboxylic esters via lipase-catalyzed hydrolysis and transesterification reactions was evaluated. Esteres with different carbon chains were synthesized. The enantioselective hydrolysis catalyzed by CAL-B furnished the corresponding β-borylated carboxylic acid with reasonable enantiomeric excess (ee 62%), while both methyl and ethyl β-borylated carboxylic esters were recovered with excellent enantiomeric purity (ee>99%). The enantioselective transesterification reaction of β-borylated carboxylic esters and several alcohols, catalyzed by CAL-B, only indicated a high selectivity when ethanol and methyl-(β-pinacolylboronate)-butanoate were used as substrates, which gave the enantioenriched ethyl-(β-pinacolylboronate)-butanoate (ee >99%). However, esters with longer carbon chains or steric hindrance at the carboxyl group did not undergo the desired reactions, even at high temperatures. Additionally, the asymmetric reductive amination ω-transaminase catalyzed of boron-containing (acid, ester or potassium trifluoroborate) prochiral ketones was investigated. After the syntheses of aromatic and aliphatic ketones, the best results of biotransformation were obtained with (R)-selective ω-transaminases from Arthrobacter sp. and Aspergillus terreus and (S)-selective one from Chromobacterium violaceum. Under the optimized conditions, high conversions (94%) with perfect enantioselectivities (ee >99%) were found, providing a new access to (R) or (S) boron-containing amines under mild reaction conditions.

Câncer é uma das principais causas de mortes no mundo. Foi responsável por aproximadamente 8,2 milhões de óbitos em 2012 e estima-se 13,2 milhões de mortes em 2030, o que o posiciona como um problema de saúde pública. A quimioterapia torna-se necessária para o tratamento, pois regride o crescimento tumoral e diminui as chances de metástases, as quais são responsáveis por 90% dos óbitos decorrentes do câncer. Linhagens tumorais que apresentam alta expressão de proteínas antiapoptóticas da família Bcl-2 mostram-se resistentes à ação de quimioterápicos antineoplásicos disponíveis na terapêutica. Portanto, o desenvolvimento de compostos que inibem essas proteínas, torna-se interessante para o tratamento do câncer. A queleritrina, um alcaloide presente em diversas espécies da família Papaveraceae, representa um atraente protótipo para o desenvolvimento de inibidores de Bcl-2, visto que esta molécula apresenta atividade citotóxica por meio da inibição da Bcl-XL, proteína supressora da apoptose. Face ao exposto, o objetivo deste trabalho foi sintetizar análogos da queleritrina planejados por simplificação molecular e testar sua atividade citotóxica. A síntese dos compostos foi realizada em duas etapas, com metodologias baseadas em reações de adição nucleofílica com posterior redução. Os análogos foram caracterizados por espectroscopia de ressonância magnética nuclear (RMN) 1H e 13C, cromatografia líquida de alta eficiência (CLAE) e análise elementar (CHN). A citotoxicidade dos compostos sintetizados e da queleritrina foi avaliada por meio do método de determinação da viabilidade celular por biorredução do sal de tetrazólio (MTT) nas linhagens não-tumorigênicas HUVEC e LL24, e nas linhagens tumorais Jurkat, SK-Mel-28 e A549. Os resultados obtidos no ensaio de citotoxicidade demonstraram que os compostos sintetizados não possuem citotoxicidade significante nas concentrações testadas. Ao avaliar o potencial citostático dos compostos frente à linhagem mutirresistente A549, o composto 2f (3-OH e 4-OH) apresentou atividade antiproliferativa interessante na concentração de 75 µM. Por não apresentar toxicidade em células não tumorais, o composto 2f mostra-se mais seletivo do que seu protótipo. Estudos de modelagem molecular sugerem que a perda da planaridade da queleritrina seja o principal responsável pela diminuição da atividade biológica. Dessa forma, embora os compostos tenham apresentado propriedades biológicas diferentes da esperada, os resultados obtidos podem auxiliar no planejamento de novas moléculas com atividade e seletividade potencialmente superiores à queleritrina, representando assim, potenciais candidatos a fármacos que podem ampliar o arsenal terapêutico para o tratamento de neoplasias. / Cancer is a leading cause of death and was responsible for approximately 8.2 million of deaths in 2012 and 13.2 million of demises are estimated for 2030, which made cancer a public health problem. Chemotherapy is required for cancer treatment, because it decreases the chances of metastasis and regresses tumor growth. However, tumor cell lines which overexpress anti-apoptotic Bcl-2 proteins present resistance to most of anticancer drugs. In this context, the development of molecules with inhibitory activity against these proteins is a promising therapeutic strategy for cancer treatment. Chelerythrine, an alkaloid distributed in several species of Papaveraceae family, has shown considerable antiproliferative activity due to inhibition of Bcl-XL anti-apoptotic protein, which represents an attractive prototype to anticancer drug design. Then, the aim of this study was to synthesize chelerythrine analogues designed by molecular simplification and evaluate their cytotoxic activity. The synthetic strategy was performed into two steps, with methodologies based on nucleophilic addition reaction followed by reduction. The compounds were characterized by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, high performance liquid chromatography (HPLC) and elemental analysis (CHN). The cytotoxic activity of the analogues were evaluated through MTT assay, a colorimetric assay for assessing cell viability, against human umbilical vein endothelial cells (HUVEC) and lung fibroblasts (LL24) as non-tumorigenic cell lines, and also against tumor cell lines, such as human lymphoblastoid (Jurkat), human melanoma cells (SK-Mel-28) and carcinomic human alveolar basal epithelial cell line (A549). The compounds have not shown significant citotoxicity at the tested concentrations. However, the evaluation of cytostatic activity on multiresistant A549 cell line has demonstrated an antiproliferative potential of compound 2f (3-OH and 4-OH) at 75 µM. Since compound 2f (3-OH and 4-OH) did not show citotoxicity on non-tumorigenic cell lines, it presented higher selectivity than chelerythrine. Molecular modeling results indicate that the lack of planarity of the chelerythrine analogues might be responsible for their lower citotoxicity. Thus, it is expected that the results might help directing the design of new compounds with superior activity and more selective than chelerythrine, thereby representing potential drug candidates, which may enhance the therapeutic arsenal for cancer treatment.

Neste trabalho, foi avaliada a resolução cinética de ésteres carboxílicos β-borilados, catalisada por lipases, através de hidrólise e transesterificação. Foram sintentizados ésteres contendo diferentes cadeias carbônicas. A hidrólise enantiosseletiva catalisada por CAL-B forneceu o correspondente ácido carboxílico β-borilado com excesso enantiomérico moderado (e.e. 62%), enquanto os ésteres β-borilados metílico e etílico foram recuperados com excelente pureza enantiomérica (e.e.>99%). A reação de transesterificação enantiosseletiva entre ésteres carboxílicos β-borilados e álcoois, catalisada por CAL-B, demonstrou uma alta seletividade somente quando etanol e (β-pinacolilboronato)-butanoato de metila foram usados como substratos, levando a formação de (β-pinacolilboronato)-butanoato de etila enantioenriquecido (e.e.>99%). Entretanto, ésteres contendo longas cadeias carbônicas ligadas à carboxila não sofreram as reações desejadas, mesmo em temperaturas mais elevadas. Adicionalmente, foi investigada a reação de aminação redutiva assimétrica, catalisada por ω-transaminases, de cetonas pró-quirais contendo grupos borônicos (ácido, éster ou trifluoroborato de potássio). Após as sínteses de cetonas aromáticas e alifáticas, os melhores resultados para a biotransformação foram obtidos com ω-transaminases (R)-seletivas de Arthrobacter sp. e Aspergillus terreus e (S)-seletiva de Chromobacterium violaceum. Sob as condições otimizadas, foram obtidas altas conversões (94%) com perfeitas enantiosseletividades (e.e.>99%), proporcionando assim uma nova via de acesso a aminas (R) ou (S) contendo boro em condições reacionais suaves. / In this work, the kinetic resolution of β-borylated carboxylic esters via lipase-catalyzed hydrolysis and transesterification reactions was evaluated. Esteres with different carbon chains were synthesized. The enantioselective hydrolysis catalyzed by CAL-B furnished the corresponding β-borylated carboxylic acid with reasonable enantiomeric excess (ee 62%), while both methyl and ethyl β-borylated carboxylic esters were recovered with excellent enantiomeric purity (ee>99%). The enantioselective transesterification reaction of β-borylated carboxylic esters and several alcohols, catalyzed by CAL-B, only indicated a high selectivity when ethanol and methyl-(β-pinacolylboronate)-butanoate were used as substrates, which gave the enantioenriched ethyl-(β-pinacolylboronate)-butanoate (ee >99%). However, esters with longer carbon chains or steric hindrance at the carboxyl group did not undergo the desired reactions, even at high temperatures. Additionally, the asymmetric reductive amination ω-transaminase catalyzed of boron-containing (acid, ester or potassium trifluoroborate) prochiral ketones was investigated. After the syntheses of aromatic and aliphatic ketones, the best results of biotransformation were obtained with (R)-selective ω-transaminases from Arthrobacter sp. and Aspergillus terreus and (S)-selective one from Chromobacterium violaceum. Under the optimized conditions, high conversions (94%) with perfect enantioselectivities (ee >99%) were found, providing a new access to (R) or (S) boron-containing amines under mild reaction conditions.

Le développement de méthodes efficaces de dédoublement cinétique d'amines représente, encore aujourd'hui, un défi en chimie organique. C'est dans ce contexte que nous avons montré que le (1S,2S)-N-acetyl-1,2-bis-trifluoromethanesulfonamidocyclohexane pouvait être utilisé comme réactif d'acylation hautement efficace pour le dédoublement cinétique d'amines propargyliques. En effet, ce réactif est capable de fournir les acétamides correspondants avec des ees pouvant atteindre jusqu'à 96% (τc = 50%)) lorsqu'un sel tel que l'AliquatTM 336 est utilisé alors qu'une inversion de la sélectivité est observée en absence de sel. Nous avons aussi été capable de réaliser le dédoublement cinétique d'amines allyliques (ees jusqu'à 88%, τc = 45%) en utilisant le même donneur d'acyle mais cette fois combiné à un sel d'ammonium supporté recyclable. Enfin, nous avons obtenu des résultats encourageant en développant une méthode catalytique impliquant une espèce chirale et un donneur d'acyle achiral. Une approche synthétique du lyngbouilloside a aussi été étudiée. De précédents travaux au sein de notre groupe ont montré qu'une erreur avait été commise lors de la détermination structurale du produit naturel suggérant une possible inversion du centre stéréogène en C11 qui ne serait donc pas de configuration (R) mais (S). C'est en tenant compte de cette hypothèse que nous avons développer une stratégie de synthèse convergente permettant d'accéder au lyngbouilloside avec le centre en C11 inversé avec l'idée de confirmer notre hypothèse et de réviser la structure initialement décrite. En résumé, la synthèse de l'aglycone du lyngbouilloside a été réalisée en 19 étapes et avec 2% de rendement global. / The development of a general and effective non-enzymatic acylative process for the kinetic resolution (KR) of amines remains, still today, a challenging field of research. In the course of this study, we were able to establish that (1S,2S)-N-acetyl-1,2-bis-trifluoromethanesulfonamidocyclohexane could be used as a highly selective acetylating agent for the kinetic resolution of primary propargylamines affording the corresponding acetamide with ees up to 96% (τc = 50%) when using an ammonium salt such as AliquatTM 336. Interestingly, a reversal of selectivity was observed in the absence of salt. We were also able to promote the kinetic resolution of primary allylamines with unprecedented levels of selectivity (ees up to 88%, τc = 45%) using a fully recyclable solid-supported ammonium salt instead of AliquatTM 336. In addition, we managed to obtain promising results in the development of a catalytic version using an achiral acyl donor in conjunction with a chiral catalyst. A synthetic approach of lyngbouilloside was also studied. Preliminary results in our group showed that the structure of the natural product may had been originally misassigned and suggested a stereochemical reassignment at C11. We managed to synthesize lyngbouilloside aglycone with the reversed stereogenic center at C11 in 19 steps and 2% overall yield.

Mn-Mediated radical addition has been developed within the Friestad laboratory as a versatile method toward addition to C=N bonds. N-Acylhydrazones generated by condensation between an aldehyde and an N-acylamine serves as the substrate toward radical addition. A bulky directed group attached with the N-acyl moiety and restricted rotation around N-N bond due to a three point chelation with a Lewis acid differentiates the faces of the C=N bond of the N-acylhydrazones. Radical generation initiated by photolysis of Mn2(CO)10 causing homolysis of C-X bond in alkyl halide serves as the radical donor to the N-acylhydrazones. Radical addition thereafter occurs stereoselectively from the less hindered face of the C=N bond of the N-acylhydrazones. The product N-acylhydrazines can be effectively transformed to α-chiral amines. In this thesis, a new protocol toward generation of non-proteogenic γ-amino esters using Mn-mediated radical addition has been described. Moreover, the utility of the Mn-mediated radical addition has been demonstrated through studies toward synthesis of tubulysin U and V. Chapter 3 describes a new strategy for asymmetric synthesis of γ-amino esters starting from non-amino precursors. The α-substituted γ-amino esters are prevalent in drugs, drug candidates, and in peptidomimetics. As a part of progressing the Mn-mediated radical addition reaction, highly stereoselective reactions were devised for addition to N-acylhydrazonoesters in absence of Lewis acid. Spectroscopic investigations were carried out to decipher the Lewis acid chelation of N-acylhydrazones. Finally, a novel microwave mediated trifluoroacylation of N-acylhydrazinoesters facilitated the cleavage of N-N bond to liberate γ-aminoester. Chapter 4 describes application of Mn-mediated radical addition toward synthesis of tubulysin natural products. Tubulysins are natural products, isolated from myxobacteria, that have exhibited potent cytotoxicity toward cancer cells in the picomolar regime. The Mn-mediated radical addition was used to prepare two chiral amine subunits in highly diastereoselective fashion. The subunits were then assembled after required manipulations into the tetrapeptide structure characteristic of tubulysins. This strategy to synthesize tubulysins is the most stereoselective of all efforts toward the synthesis of this molecule. Synthesis toward tubulysin was achieved in 18 steps as the longest linear sequence with a 31% overall yield to tubulysin V in benzyl protected form. Chapter 5 describes a new strategy toward installation of N-hydroxymethyl unit into a peptide chain. N,O-Acetals are acid-base labile species that is present in some tubulysin natural analogs. This new approach exploits Fleming-Tamao oxidation and hence introduce the hydroxymethyl unit of the N,O-acetal in a masked form. Following peptide construction the masked hydroxy group is released to liberate the N-hydroxymethyl moiety. Acylation of the free hydroxy group furnishes the N,O-acetal moiety in a strategy that is potentially applicable toward synthesis of tubulysin D.

京都大学 / 新制・課程博士 / 博士(人間・環境学) / 甲第23991号 / 人博第1043号 / 新制||人||245(附属図書館) / 2022||人博||1043(吉田南総合図書館) / 京都大学大学院人間・環境学研究科相関環境学専攻 / (主査)教授 藤田 健一, 教授 小松 直樹, 教授 津江 広人, 教授 大江 洋平 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DFAM