University, Diss., 2002--Dortmund.

Previous work in our group has been directed towards the synthesis of crown-ethers for use in the selective complexation of metal ions and as chiral ligands for use in asymmetric catalysis. The development of a modular approach to macrocycle assembly has enabled the synthesis of a library of pyridine-based macrocycles possessing multiple donor sites where chirality was readily introduced from simple amino acids.The nucleophilic ring opening of aziridines 181, 193 or 194, allowed the highly selective synthesis of thioether-based spacers and macrocycles. Extension of this basic approach to the synthesis of seleno-crown ethers was also investigated. The use of chiral-pool starting materials derived from D- or L-alanine, provided access to optically pure macrocycles. The use of the Sharpless-Huisgen 'click' reactions allowed the attachment of a carbohydrate residue directly to a macrocycle via a triazole unit. We hope to attach a macrocycle, carbohydrate residue and azo dye together, to be able to examine further diseases such as Alzheimer's. We have so far succeeded in attaching a macrocycle and sugar to a central scaffold by performing a one-pot double 'click' reaction. The distance between the points of attachment of the chromophore to the macrocycle metal binding site is probably, in this first generation sensor, too great to enable a metal-macrocycle binding event to be reported.

No description available.

No description available.

Two research projects are described: studies of the synthesis of alpha-amino-alpha-alkylsilanes, the synthetic precursor of silanediol-based protease inhibitors, and the synthesis and stability evaluation of silanediol amino acids with an unprecedently unhindered silanediol group. Two methods were investigated as approaches to alpha-amino-alpha-alkylsilanes. First, a silicon-substituted aziridine was chosen as the precursor of an alpha-amino-alpha-alkylsilane via ring opening reactions with carbon nucleophiles. Silyl-substituted aziridines 2-24 and 2-30 were prepared via direct lithiation/silylation of aziridine and employed as substrates for ring opening reactions. In spite of many attempts to ring open these silylaziridines and prepare ?-amino-?-alkylsilanes, optimization of the reaction conditions were unsuccessful. Secondly, alpha-chloro-alpha-benzylsilane 3-12 was prepared as the precursor of an alpha-amino-alpha-alkylsilane via lithiation/benzylation. The alkylation at carbon alpha to silicon to give chloromethylsilane 3-14 was successful when using n-butyllithium for lithiation, which could be explained by the steric encumbrance inherent in the structure. Several attempts for nucleophilic displacement of chloride to obtain alpha-chloro-alpha-benzylsilane 3-11 were unsuccessful possibly due to the steric effect as well as the electronic effect of silicon on the alpha carbon which made the chloride less reactive toward nucleophilic substitution. The silanediol amino acid 4-1 was synthesized originally as a potential arginase inhibitor. Although the expected biological activity was not observed, the studies on silanediol-siloxane distribution of the silanediol amino acid revealed the unique properties of this compound. Under basic conditions, the silanediol amino acid was mainly stable in monomeric form. As the pH decreased, the silanediol amino acid gave a mixture of siloxanes which consisted of a variety of stereoisomers. With available instrumental techniques, monomer, dimers and trimers of the silanediol amino acid were identified. / Chemistry

Ce travail de thèse a permis de développer un nouveau type de cycloaddition [3+2] des cétènes impliquant des aziridines. Les aziridines sont de bons précurseurs de dipôles 1,3-azotés zwittérioniques, via la coupure sélective de leur liaison C-N par activation avec un acide de Lewis. Nous avons montré qu'en présence d'un cétène et d'iodure de lithium, l'aziridine s'ouvre, et le dipôle 1,3 formé réagit avec le cétène pour offrir des gamma-lactames de manière très efficace. Cette nouvelle cycloaddition [3+2] s'étend à la transformation monotope d'une imine en gamma-lactame, stratégie compatible avec une large gamme d'imines aromatiques et de cétènes stables. Enfin, une synthèse monotope, catalytique et asymétrique de gamma-lactames énantioenrichis a été développée à partir d'oléfines par aziridination asymétrique avec des nitrènes. / This thesis work focuses on a new type of [3+2] cycloaddition of ketenes with aziridines. Aziridines are good precursors of zwitterionic 1,3-aza-dipoles, by selective C-N bond cleavage catalyzed by Lewis acid. We have found that ketenes react with the 1,3-dipole generated by addition of lithium iodide to the aziridine, efficiently providing the gamma-lactams. This new cycloaddition could be extended to a one-pot simple transformation of imines to gamma-lactams. The synthesis is compatible with a wide range of aromatic imines and stable ketenes. Finally, a one-pot catalytic asymmetric synthesis of enantioenrichied gamma-lactams have been developed starting from olefins, involving an asymmetric nitrene aziridination.

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.

The synthesis of enantiomerically pure compounds is of vital importance. Most biologically active natural products are chiral and require asymmetric synthesis, chiral resolution, or the use of naturally chiral starting materials for their preparation. Organocatalytic enantioselective reaction methodology is a continuously growing area in organic chemistry. The use of organocatalysts as a potentially environmentally friendly alternative to metal catalysts is appealing to the pharmaceutical industry. In this dissertation an enantioselective Mannich reaction using an organocatalyst was investigated. The reaction was between a ß-keto ester and an imine electrophile catalyzed by vaulted biphenanthrol (VAPOL) phosphoric acid. The reaction resulted in products with high yields, but low to moderate enantioselectivity and diastereoselectivity. The development of the first Brønsted acid-catalyzed desymmetrization of meso-aziridines was also investigated. This is one of the first instances where a phosphoric acid has been used to catalyze a reaction that did not involve an imine. It was shown that the chiral VAPOL phosphoric acid was an excellent catalyst for the reaction resulting in high yields and enantioselectivities for the chiral ring opened products. It was also shown, for the first time, that a vaulted binaphthol (VANOL) phosphoric acid can also catalyze the ring-opening of meso-aziridines with comparable results to the VAPOL phosphoric acid in some cases. Mechanistic NMR studies were used to probe the reaction, and it is believed that evidence leads one to conclude that a unique mechanism for phosphoric acid-catalysis is followed. The products that can be obtained from this reaction, 1,2-diamines, are of high value for synthetic chemists. They have been used as chiral auxiliaries, ligands, and precursors to natural products.

<p>Five-membered rings are readily prepared by <i>5-exo-trig</i> radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of <i>5-exo-dig</i> cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly <i>cis</i>-selective manner. When cyclizations were performed at 17 ^oC, <i>cis</i>/<i>trans</i>-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the <i>trans</i>-diastereomer as the major product (<i>cis</i>/<i>trans </i>= 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 ^oC produced 2,4-disubstituted pyrrolidines substantially enriched in the <i>trans</i>-isomer (<i>cis</i>/<i>trans</i> = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried.</p><p>The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.</p>

Five-membered rings are readily prepared by 5-exo-trig radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of 5-exo-dig cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly cis-selective manner. When cyclizations were performed at 17 oC, cis/trans-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the trans-diastereomer as the major product (cis/trans = 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 oC produced 2,4-disubstituted pyrrolidines substantially enriched in the trans-isomer (cis/trans = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried. The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.