Thesis--Tübingen.

Thesis (M.A.)--University of North Carolina at Wilmington, 2005. / Includes bibliographical references (leaves: [48]-51)

Thesis (Ph. D.)--University of Wisconsin--Madison, 1976. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 400-425).

Entre os diferentes tipos de substratos diazocarbonílicos encontrados na literatura, as diazocetonas α,β-insaturadas têm mostrado promissoras aplicações como intermediários multifuncionais. Este trabalho de tese foi dividido em três capítulos e visou expandir as aplicações das diazocetonas α,β-insaturadas em química e bioquímica. No primeiro capítulo, as diazocetonas foram apresentadas como plataformas para a síntese direta de amidas e ésteres β,γ-insaturados via Rearranjo de Wolff. Quando diazocetonas derivadas de amino-aldeídos foram utilizadas, isósteros peptídicos foram obtidos como demonstrado na síntese rápida e eficiente do nitróxido JP4-039. No mesmo capítulo, um estudo aprofundado comprovando a eficiência de diferentes lâmpadas comerciais (CFL e LED) para promover o Rearranjo de Wolff é apresentado, representando uma alternativa sustentável. O segundo capítulo é voltado a expansão da química das diazocetonas insaturadas para o estudo de reações de cicloadição [2+2] e [4+2]. Foi demonstrado o preparo dos ésteres precursores para reações de cicloadições via rearranjo de Wolff na presença de álcoois alílicos e as tentativas que culimaram na síntese de um cicloaduto de Diels-Alder. O capítulo 3 foi dedicado ao emprego das diazocetonas α,β-insaturadas para a modificação química específica de proteínas. As diazocetonas foram aplicadas com sucesso para este fim, assim como inspiraram o desenvolvimento de um novo método promissor de bioconjugacão seletiva para cisteínas. / Among the various types of diazocarbonyl substrates found in the literature, α,β-unsaturated diazoketones have shown a number of promising applications as multifunctional intermediates. This thesis is divided into three chapters, aimed at expanding the reactivity of such α,β-unsaturated diazoketones for synthetic chemistry and chemical biology applications. In the first chapter, diazoketones are presented as platforms for the direct synthesis of β,γ-unsaturated amides and esters via a Wolff rearrangement reaction. When diazoketones derived from amino-aldehyde are substrates, peptidic isosters are obtained, as demonstrated in the efficient synthesis of the nitroxide drug, JP4-039. In the same chapter, a study demonstrating the efficiency of several commercial light sources (CFL and LED) to promote the Wolff rearrangement was described, representing a sustainable alternative to UV lamps for this interesting reaction. The second chapter sought to expand the chemistry of unsaturated diazoketones for the study of [2 + 2] and [4 + 2] cycloaddition reactions. The preparation of the precursor esters for cycloaddition reaction was demonstrated by the Wolff rearrangement of precursors in the presence of allylic alcohols, and the attempt then culminated in the synthesis of a Diels-Alder cycloadduct. Chapter 3 was devoted to the use of α,β-unsaturated diazoketones for the site-specific chemical modification of proteins. These have been successfully demonstrated for this purpose, as well as inspiring the development of a promising new method for selective bioconjugation of cysteines.

Entre os diferentes tipos de substratos diazocarbonílicos encontrados na literatura, as diazocetonas α,β-insaturadas têm mostrado promissoras aplicações como intermediários multifuncionais. Este trabalho de tese foi dividido em três capítulos e visou expandir as aplicações das diazocetonas α,β-insaturadas em química e bioquímica. No primeiro capítulo, as diazocetonas foram apresentadas como plataformas para a síntese direta de amidas e ésteres β,γ-insaturados via Rearranjo de Wolff. Quando diazocetonas derivadas de amino-aldeídos foram utilizadas, isósteros peptídicos foram obtidos como demonstrado na síntese rápida e eficiente do nitróxido JP4-039. No mesmo capítulo, um estudo aprofundado comprovando a eficiência de diferentes lâmpadas comerciais (CFL e LED) para promover o Rearranjo de Wolff é apresentado, representando uma alternativa sustentável. O segundo capítulo é voltado a expansão da química das diazocetonas insaturadas para o estudo de reações de cicloadição [2+2] e [4+2]. Foi demonstrado o preparo dos ésteres precursores para reações de cicloadições via rearranjo de Wolff na presença de álcoois alílicos e as tentativas que culimaram na síntese de um cicloaduto de Diels-Alder. O capítulo 3 foi dedicado ao emprego das diazocetonas α,β-insaturadas para a modificação química específica de proteínas. As diazocetonas foram aplicadas com sucesso para este fim, assim como inspiraram o desenvolvimento de um novo método promissor de bioconjugacão seletiva para cisteínas. / Among the various types of diazocarbonyl substrates found in the literature, α,β-unsaturated diazoketones have shown a number of promising applications as multifunctional intermediates. This thesis is divided into three chapters, aimed at expanding the reactivity of such α,β-unsaturated diazoketones for synthetic chemistry and chemical biology applications. In the first chapter, diazoketones are presented as platforms for the direct synthesis of β,γ-unsaturated amides and esters via a Wolff rearrangement reaction. When diazoketones derived from amino-aldehyde are substrates, peptidic isosters are obtained, as demonstrated in the efficient synthesis of the nitroxide drug, JP4-039. In the same chapter, a study demonstrating the efficiency of several commercial light sources (CFL and LED) to promote the Wolff rearrangement was described, representing a sustainable alternative to UV lamps for this interesting reaction. The second chapter sought to expand the chemistry of unsaturated diazoketones for the study of [2 + 2] and [4 + 2] cycloaddition reactions. The preparation of the precursor esters for cycloaddition reaction was demonstrated by the Wolff rearrangement of precursors in the presence of allylic alcohols, and the attempt then culminated in the synthesis of a Diels-Alder cycloadduct. Chapter 3 was devoted to the use of α,β-unsaturated diazoketones for the site-specific chemical modification of proteins. These have been successfully demonstrated for this purpose, as well as inspiring the development of a promising new method for selective bioconjugation of cysteines.

Alcaloides indolizidínicos, quinolizidínicos e piperidínicos poliidroxilados representam classes de compostos amplamente investigados atualmente. Este fato se deve às pronunciadas atividades biológicas como inibidores de glicosidases expressadas por estes heterociclos, o que significa um grande atrativo para que muitos grupos de pesquisas desenvolvam metodologias sintéticas para a sua obtenção de forma efetiva e em poucas etapas. Neste trabalho de dissertação é apresentada uma rota sintética para a preparação de alcaloides indolizidínicos e quinolizidínicos diidroxilados a partir de diazocetonas α,β-insaturadas. A estratégia para a síntese destes alcaloides baseia-se na mesma metodologia, tendo como etapas chaves: uma reação de olefinação de Horner-Wadsworth-Emmons (HWE) a partir de aminoaldeídos, seguida de um Rearranjo de Wolff. Como material de partida para o esqueleto indolizidínico foi empregado o Cbz-S-prolinal. Este aminoaldeído foi empregado como fonte do centro estereogênico e de um dos anéis presentes na estrutura final. O acoplamento (reação de HWE) entre o Cbz-S-prolinal e um diazofosfonato recentemente descrito por nosso grupo de pesquisa forneceu um composto diazocarbonílico α,β-insaturado (67%), que em seguida, foi submetido a um rearranjo de Wolff fornecendo um éster β,γ-insaturado (96%). Este intermediário avançado foi funcionalizado através de uma reação de diidroxilação, a qual forneceu uma lactona (66%). A síntese foi completada através de uma reação de ciclização intramolecular (94%) seguida de uma reação de redução para fornecer a indolizidina diidroxilada em 71% de rendimento. Para o esqueleto quinolizidínico, foi empregado o aminoaldeído racêmico Cbz-(±)-pipecolinal como material de partida. A partir da reação de olefinação, foi obtida uma diazocetona α,β-insaturada (91%), que após Rearranjo de Wolff (95%), diidroxilação (75%), ciclização (54-74%) e reação de redução (87-90%), forneceu duas novas quinolizidinas diidroxiladas. Estes alcaloides indolizidínicos e quinolizidínicos poderão ser avaliados como inibidores de glicosidases. / Polyhydroxylated Indolizidine, quinolizidine and piperidine alkaloids represent classes of compounds widely investigated in the chemical community. This fact is due to their pronounced biological activities as glycosidase inhibitors. Considering that, many research groups have been developing new synthetic methodologies to obtain these alkaloids and analogs effectively and in few steps. This work presents a synthetic route for the preparation of dihydroxylated indolizidine and quinolizidine alkaloids from α,β-unsaturated diazoketones. The strategy for the synthesis of these compounds is based on the same methodology to construct the indolizidine and quinolizidine skeleton. The key steps involve a Horner-Wadsworth-Emmons (HWE) olefination reaction from aminoaldehydes, followed by a Wolff Rearrangement. As the starting material to construct the indolizidine skeleton, Cbz-S-prolinal was employed. This aminoaldehyde is also the source of the stereogenic center and one of the rings present in the final structure. The coupling reaction (HWE reaction) between Cbz-S-prolinal and a diazophosphonate (methodology recently described by our research group) has provided an α,β-unsaturated diazoketone in 67% yield. This compound was then subjected to a Wolff Rearrangement, providing a β,γ-unsaturated ester in 96% yield. This advanced intermediate was functionalized through a high selective dihydroxylation reaction, furnishing a hydroxylated lactone in 66% yield. The synthesis was then completed employing an intramolecular cyclization reaction (94% yield), followed by lactam reduction to provide the dihydroxylated indolizidine (1,6-dideoxyepicastanospermine) in 71% yield. For the construction of the quinolizidine skeleton, was employed racemic Cbz-pipecolinal as the starting material. From the olefination reaction, the corresponding α,β-unsaturated diazoketone was obtained in 91% yield. After a Wolff Rearrangement (95%), dihydroxylation reaction (75%), cyclization (54-74%) and lactam reduction (87-90%), two novel dihydroxylated quinolizidines could be synthesized. These indolizidine and quinolizidine alkaloids may be evaluated as new inhibitors of glycosidases.

Alcaloides indolizidínicos, quinolizidínicos e piperidínicos poliidroxilados representam classes de compostos amplamente investigados atualmente. Este fato se deve às pronunciadas atividades biológicas como inibidores de glicosidases expressadas por estes heterociclos, o que significa um grande atrativo para que muitos grupos de pesquisas desenvolvam metodologias sintéticas para a sua obtenção de forma efetiva e em poucas etapas. Neste trabalho de dissertação é apresentada uma rota sintética para a preparação de alcaloides indolizidínicos e quinolizidínicos diidroxilados a partir de diazocetonas α,β-insaturadas. A estratégia para a síntese destes alcaloides baseia-se na mesma metodologia, tendo como etapas chaves: uma reação de olefinação de Horner-Wadsworth-Emmons (HWE) a partir de aminoaldeídos, seguida de um Rearranjo de Wolff. Como material de partida para o esqueleto indolizidínico foi empregado o Cbz-S-prolinal. Este aminoaldeído foi empregado como fonte do centro estereogênico e de um dos anéis presentes na estrutura final. O acoplamento (reação de HWE) entre o Cbz-S-prolinal e um diazofosfonato recentemente descrito por nosso grupo de pesquisa forneceu um composto diazocarbonílico α,β-insaturado (67%), que em seguida, foi submetido a um rearranjo de Wolff fornecendo um éster β,γ-insaturado (96%). Este intermediário avançado foi funcionalizado através de uma reação de diidroxilação, a qual forneceu uma lactona (66%). A síntese foi completada através de uma reação de ciclização intramolecular (94%) seguida de uma reação de redução para fornecer a indolizidina diidroxilada em 71% de rendimento. Para o esqueleto quinolizidínico, foi empregado o aminoaldeído racêmico Cbz-(±)-pipecolinal como material de partida. A partir da reação de olefinação, foi obtida uma diazocetona α,β-insaturada (91%), que após Rearranjo de Wolff (95%), diidroxilação (75%), ciclização (54-74%) e reação de redução (87-90%), forneceu duas novas quinolizidinas diidroxiladas. Estes alcaloides indolizidínicos e quinolizidínicos poderão ser avaliados como inibidores de glicosidases. / Polyhydroxylated Indolizidine, quinolizidine and piperidine alkaloids represent classes of compounds widely investigated in the chemical community. This fact is due to their pronounced biological activities as glycosidase inhibitors. Considering that, many research groups have been developing new synthetic methodologies to obtain these alkaloids and analogs effectively and in few steps. This work presents a synthetic route for the preparation of dihydroxylated indolizidine and quinolizidine alkaloids from α,β-unsaturated diazoketones. The strategy for the synthesis of these compounds is based on the same methodology to construct the indolizidine and quinolizidine skeleton. The key steps involve a Horner-Wadsworth-Emmons (HWE) olefination reaction from aminoaldehydes, followed by a Wolff Rearrangement. As the starting material to construct the indolizidine skeleton, Cbz-S-prolinal was employed. This aminoaldehyde is also the source of the stereogenic center and one of the rings present in the final structure. The coupling reaction (HWE reaction) between Cbz-S-prolinal and a diazophosphonate (methodology recently described by our research group) has provided an α,β-unsaturated diazoketone in 67% yield. This compound was then subjected to a Wolff Rearrangement, providing a β,γ-unsaturated ester in 96% yield. This advanced intermediate was functionalized through a high selective dihydroxylation reaction, furnishing a hydroxylated lactone in 66% yield. The synthesis was then completed employing an intramolecular cyclization reaction (94% yield), followed by lactam reduction to provide the dihydroxylated indolizidine (1,6-dideoxyepicastanospermine) in 71% yield. For the construction of the quinolizidine skeleton, was employed racemic Cbz-pipecolinal as the starting material. From the olefination reaction, the corresponding α,β-unsaturated diazoketone was obtained in 91% yield. After a Wolff Rearrangement (95%), dihydroxylation reaction (75%), cyclization (54-74%) and lactam reduction (87-90%), two novel dihydroxylated quinolizidines could be synthesized. These indolizidine and quinolizidine alkaloids may be evaluated as new inhibitors of glycosidases.

Cette thèse étudie en premier lieu une étape décisive dans la réception de la philosophie kantienne, nommée l’interprétation ontologique de Kant. Développée à partir de 1924, cette interprétation affirme, contre la lecture dominante jusqu’alors, l’existence et la pertinence d’une métaphysique kantienne et son inscription parmi les ontologies classiques. Les premiers représentants du courant, H. Heimsoeth, M. Wundt ou M. Campo, ainsi que, plus tard, G. Martin et L. Honnefelder, exercent une influence considérable sur les études kantiennes et amorcent un changement de perspective perçu à l’époque comme un « avènement » et une « renaissance » de la métaphysique. Notre travail analyse également les prémisses de cette lecture et les situe dans le travail philologique et exégétique d’envergure consacré à la fin du XIXe siècle aux manuscrits kantiens (réflexions et leçons). L’aspect métaphysique du criticisme est alors mis en lumière. D’autres éléments s’y ajoutent par la suite, dont notamment l’œuvre de F. Paulsen et l’interprétation du transcendantal kantien à partir de la doctrine des transcendantaux. La deuxième partie de cette recherche est consacrée à la lecture heideggerienne de Kant, qui, bien que n’appartenant pas au courant métaphysique, voit dans la Critique de la raison pure une fondation de la métaphysique et une ontologie de l’être-connu. La troisième partie étudie, à la lumière des acquis récents de la recherche, quelques aspects de la relation complexe entre Kant et son prédécesseur Ch. Wolff. Y est analysée l’influence que ce dernier a pu exercer sur la formation du jeune Kant et sur la philosophie critique et, avant tout, sur sa conception de l’ontologie. / The main purpose of this thesis is to study a decisive period in the reception of Kant’s philosophy – the so-called ontological interpretation of Kant – which, as of 1924, superseded the prevailing view of the time and averred the existence and pertinence of Kant’s metaphysics, defending its rightful inclusion among classical ontologies. The first representatives of this new exegetic trend­­ – H. Heimsoeth, M. Wundt and M. Campo, as well as, later on, G. Martin and L. Honnefelder – had a determining influence on Kantian studies which led to a change of perspective perceived at the time as an “advent” and a “renaissance” of metaphysics. We also analyse the premises of this reading and identify them at the end of the 19th century, when the metaphysical dimension of Kantian criticism was brought to light owing to ambitious philological and philosophical research on Kant’s manuscript notes and lectures. Other elements, like F. Paulsens’s writings and the reading of Kant’s transcendental philosophy on the background of the doctrine of the transcendentals, also contributed significantly to its emergence. The second part of this work deals with Heidegger’s interpretation of Kant. Even if Heidegger does not belong to the metaphysical current, he considers the Critique of Pure Reason as a foundation of metaphysics and as an ontology of the known being. The third part of this thesis focuses on some aspects of Kant’s complex relationship to his predecessor Ch. Wolff, and analyses, in light of recent scholarship, the influence which the latter may have had on the young Kant and on critical philosophy – and especially on his conception of ontology.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Doctor of Philosophy / Abstract This study examines the effect of exile on Theodor Wolff’s writings from 1933 to 1943. Wolff, a highly assimilated German Jew and renowned journalist and editor-in-chief of the ‘Berliner Tageblatt’ from 1906-1933, was one of the most influential cultural and liberal political commentators during World War I and the Weimar Republic. His political life and influence has been extensively researched, whereas his life in exile has not been explored. Enforced sudden exile in 1933 represented a turning point in Wolff’s life. Following the temporal sequence of Wolff’s ten years in exile, this study is divided into four chapters, starting with the early exile years from 1933 to 1936, followed by the immediate pre World War II period. The third chapter covers the German invasion and occupation of France in 1940. The last chapter sheds light on the two final years from 1942 to 1943. These four periods reflect his exile experience and gradual decline in living conditions, mood, and fundamental changes in his approach to writing. In exile Wolff devotes his time and effort to historical accounts and fiction – a difficult genre for a publicist and journalistic writer. He also embarks on autobiographical writings and during his final years in exile deals with the Jewish catastrophe unfolding in Nazi controlled Europe, raising issues concerning the so called ‘Jewish Problem’. This study draws attention to the effect exile had on an important German- Jewish writer, who in 1943 fell victim to the Holocaust. Wolff’s works, especially his exile writings survived the war and remain relevant today. The findings of this research provide some insight into a turbulent period in German and European history that drastically changed many lives. It also makes a significant contribution to the study of Theodor Wolff and to exile studies in general.