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Regio- and stereoselective Ni-catalyzed 1,4-hydroboration and diboration of 1,3-dienes: Access to stereodefined (Z)-allyboron reagents and application towards the total synthesis of discodermolideEly, Robert John January 2012 (has links)
Thesis advisor: James P. Morken / Detailed within this dissertation are the developments of novel hydroboration and diboration methodologies to access allylboron reagents and efforts towards the application of these methods in the total synthesis of discodermolide. Chapter 1 describes the development of Ni-catalyzed 1,4-hydroboration of 1,3-dienes with pinacolborane. This method provides synthetically useful allylboron intermediates which can be oxidized to stereodefined (Z)-allylic alcohols or used in stereoselective carbonyl addition reactions. Chapter 2 details the development of Ni-catalyzed 1,4-diboration of 1,3-dienes with bis(pinacolato)diboron. This reaction broadens the scope of 1,4-diboration reactions by including internal and sterically hindered dienes, and proceeds with high 1,4- and (Z)-selectivity. The intermediate allylborons can be oxidized to stereodefined 1,4-diols. Chapter 3 describes the development of diastereoselective Ni-catalyzed 1,4-hydroboration of chiral 1,3-dienols. The reaction provides syn-propionate homoallylic alcohols with stereodefined trisubstituted allylborons for the synthesis of polyketide structures. This methodology, among others, was applied towards the total synthesis of discodermolide. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.
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Total Synthesis of (+)-Discodermolide by Catalytic Stereoselective Borylation ReactionsYu, Zhiyong January 2014 (has links)
Thesis advisor: James P. Morken / (+)-Discodermolide is a marine natural product and is one of the most potent microtubule stabilizers in human cell lines. Because of its unique linear structure and important properties, a number of total syntheses of (+)-discodermolide and its derivatives have been reported. Herein, an efficient, highly convergent, and stereocontrolled total synthesis is presented (Chapter 2). The synthesis relied on the development of three catalytic and stereoselective processes: platinum-catalyzed asymmetric diene diboration, nickel-catalyzed diastereoselective hydroboration of chiral dienes (Chapter 1), and nickel-catalyzed borylative diene-aldehyde coupling (see Chapter 4). Combination of these reactions allows preparation of the target in a short sequence. Moreover, the development of rhodium-catalyzed asymmetric hydroformylation (Chapter 3) makes this approach the first Roche ester free (+)-discodermolide synthesis. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.
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Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide AnalogsYang, Chao 17 October 2008 (has links)
Paclitaxel was isolated from the bark of <i>Taxus brevifolia</i> in the late 1960s. It exerts its biological effect by promoting tubulin polymerization and stabilizing the resulting microtubules. Paclitaxel has become one of the most important current drugs for the treatment of breast and ovarian cancers.
Studies aimed at understanding the biologically active conformation of paclitaxel bound on β–tubulin are described. In this work, the synthesis of isotopically labeled taxol analogs is described and the REDOR studies of this compound complexed to tubulin agrees with the hypothesis that palictaxel adopts T-taxol conformation. Based on T-taxol conformation, macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. The results show a direct evidence to support T-taxol conformation.
(+) Discodermolide is a polyketide isolated from the Caribbean deep sea sponge <i>Discodermia dissoluta</i> in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule <i>in vivo</i>. Studies aimed at understanding the biologically active conformation of discodermolide bound on β–tubulin are described. In this work, the synthesis of fluorescent labeled discodermolide analogs is described and their biological activities were evaluated. Synthetic approaches to fluorescent labeled and isotopically labeled discodermolide analogs discodermolide are also described. / Ph. D.
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Design, Syntheses and Bioactivities of Androgen Receptor Targeted Taxane Analogs, Simplified Fluorescently Labeled Discodermolide Analogs, and Conformationally Constrained Discodermolide AnalogsQi, Jun 22 April 2010 (has links)
Prostate cancer is the most common non-skin cancer for men in America. The androgen receptor exerts transcriptional activity and plays an important role for the proliferation of prostate cancer cells. Androgen receptor ligands bind the androgen receptor and inhibit its transcriptional activity effectively. However, prostate cancer can progress to hormone refractory prostate cancer (HRPC) to avoid this effect. Chemotherapies are currently the primary treatments for HRPC. Unfortunately, none of the available chemotherapies are curative. Among them, paclitaxel and docetaxel are two of the most effective drugs for HRPC. More importantly, docetaxel is the only form of chemotherapy known to prolong survival in the HRPC patients. We hypothesized that the conjugation of paclitaxel or docetaxel with an androgen receptor ligand will overcome the resistance mechanism of HRPC. Eleven conjugates were designed, synthesized and biologically evaluated. Some of them were active against androgen-independent prostate cancer, but they were all less active than paclitaxel and docetaxel.
Discodermolide is a microtubule interactive agent, and has a similar mechanism of action to paclitaxel. Interestingly, discodermolide is active against paclitaxel-resistant cancer cells and can synergize with paclitaxel, which make it an attractive anticancer drug candidate. Understanding the bioactive conformation of discodermolide is important for drug development, but this task is difficult due to the linear and flexible structure of discodermolide. Indirect evidence for the orientation of discodermolide in the tubulin binding pocket can be obtained from fluorescence spectroscopy of the discodermolide tubulin complex. For this purpose, we designed and synthesized a simplified fluorescently labeled discodermolide analog, and it was active in the tubulin assembly bioassay. In addition, a conformationally constrained discodermolide was designed to mimic the bioactive conformation according to computational modeling. The synthetic effort was made, but failed during one of the final steps. / Ph. D.
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Approches synthétiques du (+)-discodermolide et du dolabélide A par hydrogénation asymétrique à l'aide de complexes chiraux de ruthéniumRoche, Christophe 19 December 2008 (has links) (PDF)
L'océan est un vaste réservoir de molécules potentiellement anticancéreuses. Ce manuscrit présente l'approche synthétique de deux molécules naturelles cytotoxiques : le (+)-discodermolide et le dolabélide A. Les motifs polypropionates de ces molécules ont été construits par l'association de trois réactions : la condensation de Claisen pour introduire le motif β-cétoester, l'hydrogénation asymétrique du β-cétoester catalysée par des complexes chiraux de ruthénium puis la méthylation diastéréosélective du β-hydroxyester. Pour le (+)-discodermolide, trois fragments avancés ont été élaborés et 12 des 13 centres stéréogènes mis en place, dont 8 par hydrogénation asymétrique ou méthylation diastéréosélective avec d'excellentes stéréosélectivités. Pour le dolabélide A, deux fragments avancés ont été préparés, et 7 des 8 groupements hydroxyles ont été installés par hydrogénation asymétrique avec des stéréosélectivités supérieures à 95 %.
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Synthèse biomimétique de motifs polypropionates par hydrogénation asymétrique à l'aide de complexes chiraux du ruthénium. Application aux synthèses du Dolabélide A et du (+)-DiscodermolideLe Roux, Rémi 27 June 2007 (has links) (PDF)
Ce manuscrit présente le développement d'une méthode de synthèse de motifs polypropionates et son application à la synthèse totale de deux molécules naturelles cytotoxiques : le Dolabélide A et le (+)-Discodermolide. Cette méthode, par analogie avec les voies de biosynthèse des polypropionates, permet la synthèse séquentielle et itérative de ces motifs par l'association de trois réactions : l'hydrogénation asymétrique de béta-cétoesters et de béta-hydroxycétones catalysée par des complexes chiraux du ruthénium, la méthylation diastéréosélective de Fráter-Seebach et la condensation de Claisen. Pour le Dolabélide A, deux fragments avancés ont été préparés, et 7 des 11 centres stéréogènes ont été installés par hydrogénation asymétrique avec des sélectivités supérieures à 95 %. Pour le (+)-Discodermolide, trois fragments intermédiaires ont été élaborés et 10 centres stéréogènes mis en place dont 7 par hydrogénation asymétrique ou méthylation diastéréosélective, ici encore avec des sélectivités supérieures à 95 %.
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