Diastereoselective control of glycosylation still remains a difficult task. Therefore, new glycosylation methods using asymmetric catalysis were developed to control the diastereoselectivity. Two systems were developed and each focused on a separate type of glycosyl donor. In the first system, glycosyl halides were subjected to reaction conditions inspired by Hamilton et al., who effectively had controlled the substitution of a racemic chloroamine by an alcohol. Asymmetric control of glycosylation was achieved through this adapted catalytic system. Both enantiomers of the catalyst ((R) and (S) TRIP) generally displayed b-selectivity with tertiary butyl methyl ether (TBME) as the solvent allowing almost exclusive formation of the β-anomer. However, low and inconsistent yields were obtained. The second system proposed the use of the same phosphoric acid catalyst (TRIP) to catalyse the glycosylation of glycals. However, this was ineffective as the catalyst was not a strong enough Brønsted acid. These studies then led to the development of two new chiral catalysts which then promoted the glycosylation of glycals, along with the formation of an undesired side product. Attempts were made to reduce the formation of the side product but unfortunately this proved unsuccessful. The diastereoselective outcome displayed between the different catalysts in separate trials was negligible, but the principles developed in this study should lead to the further development of new chiral catalysts for the glycosylation of glycals.

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-06T22:16:49Z (GMT). No. of bitstreams: 1 Steil_LeonardoJose_D.pdf: 7174364 bytes, checksum: 82b5780811332c003902e586efed7b18 (MD5) Previous issue date: 2006 / Doutorado / Quimica Organica / Doutor em Quimica

Les composés fluorés ont montré une importance croissante dans le développement d'agents pharmaceutiques en raison des propriétés exceptionnelles de l'atome de fluor. Dans cette thèse, nous nous sommes concentrés sur la synthèse des composés énantiopurs contenant de l'azote.A partir de l'aldimine trifluorométhylée, une réaction d’aza-Baylis-Hillman asymétrique a été réalisée et a permis d’obtenir un nouvel acide (R)-α-méthylène-β-CF3-β-aminé avec un bon rendement et une excellente diastéréosélectivité. Puis, en utilisant une réaction d’allylation dans les conditions de Barbier, de nouveaux acides aminés trifluorométhylés cycliques à cinq ou six chaînons ont été obtenus avec de bons rendements et d’excellents diastéréosélectivités. En particulier des acides γ et β-aminés, comme la CF3-β-proline, qui est très intéressante dans la synthèse peptidique.Enfin, grâce à l'addition d'éther de vinyle sur l’aldimine trifluorométhylée, différentes amines trifluorométhylées ont été obtenues. Parmi ces composés, les amino-alcools CF3 qui sont très utiles pour la conception de médicaments et dans la synthèse asymétrique, et les amines cycliques trifluorométhylées qui peuvent servir de bon substrat pour synthétiser des composés CF3-cycliques plus fonctionnalisés. / Fluorinated compounds have shown a growing importance in the development of pharmaceutical agents owing to the outstanding properties of the fluorine atom. In this thesis, we focused on the synthesis of enantiopure trifluoromethyl nitrogen-containing compounds.Starting from the trifluoromethyl aldimine, firstly, an asymmetric aza-Baylis–Hillman reaction was realized with high reaction rates, and diastereoselectivities, and the previously unknown enantiomerically pure (R)-α-methylene β-CF3 β-amino acid was obtained in good yield. Then, through aza-Barbier reaction, the five-membered and six-membered trifluoromethyl cyclic amino acids were obtained, including β-amino acid and γ-amino acid, especially CF3-β-proline, which is very interesting in the further peptide synthesis.Finally, through the addition of vinyl ether to imine, different novel trifluoromethylated amines were afforded. Among these compounds, CF3-amino alcohols are very useful in drug design and asymmetric synthesis, and enantiopure CF3-cyclic amine is a very good substrate to synthesize more functionalized CF3-cyclic compounds.

Thesis (PhD)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: The use of chiral oxazoline directed lithiation provides a highly diastereoselective (up to >99% de) route to meta functionalised inherently chiral calixarenes. This methodology can be used on both the butylated and debutylated calixarene systems and is tolerant of a wide range of different electrophillic quenches allowing access to a structurally diverse range of inherently chiral metafunctionalised calixarenes. The oxazoline directing group can be removed via hydrolysis, generating a range of functionalised calixarene carboxylic acids in high ee. We also demonstrate that the use of derivative alkyllithiums such as cyclopentyl lithium can provide significantly enhanced diastereoselectivity over the conventional organolithiums such as sec-butyl lithium, when employed in ortholithiation reactions of this nature. The differences in diastereoselectivity associated with the different alkyllithiums can be tied, in certain cases, to the steric bulkiness associated with the individual reagents. In this regard we have found that the use of the so called Tolman angle or cone angle approach allows quantification of the relative steric bulk of the alkyllithium. We also detail that the oxazoline directing group provides a hitherto unknown ability to be diastereoselectively tuned through the choice of the ligand system in the ortholithiation reaction. In this regard the development of a series of diglyme based ligands have proved to provide a highly diastereoselective means of inverting the chirality from that which the use of the conventional TMEDA ligand is able to generate (up to –92% de). The use of diglyme ligands to invert the sense of chirality is also shown to occur on the ferrocenyloxazoline system and presents an apparently general and hitherto unknown facet of asymmetric oxazoline directed ortholithiation. This diglyme induced inversion has been shown to be controlled through a secondary nitrogen coordinated mechanism that is able to operate with chiral oxazolines. / AFRIKAANSE OPSOMMING: Die gebruik van chirale oksasoliengerigte litiëring verskaf ’n hoogs diastereoselektiewe (tot en met >99% do) roete om metagefunksionaliseerde, inherente chirale calixareen produkte te sintetiseer. Deur gebruik te maak van verskillende elektrofiele kan die metodologie toegepas word op beide gebutileerde en de-gebutileerde calixareen sisteme om ’n reeks uiteenlopende inherente chirale, meta-gefunksionaliseerde calixareen produkte te vorm. Die oksasolien groep kan daarna verwyder word deur hidroliese om ’n reeks gefunksionaliseerde calixareenkarboksielsure te vorm in baie hoë eo. Ons het ook gedemonstreer dat die gebruik van afgeleide alkiel-litiums, soos siklopentiel-litium, kan bydrae tot aansienlik verhoogde diastereoselektiwiteit as dit vergelyk word met meer algemene organolitiums soos sekbutiellitium, tydens ortolitiëring reaksies van hierdie natuur. Die verskille in diastereoselektiwiteit kan verbind word, in sekere gevalle, tot die steriese bonkigheid van die individuele reagense. Deur gebruik te maak van die sogenaamde Tolmanhoeke of die koniesehoek benadering is dit moontlik om die relatiewe steriese bonkighied van alkiellitiums te kwantifiseer. Daar was ook bepaal dat die oksasoliengroep die ongekende vermoë besit om die diastereoselektiwiteit van die produk te stem deur die keuse van verskillende ligand sisteme tydens die ortolitiëring reaksie. Daar was bepaal dat die chiralitiet van die produkte omgekeer kan word op ’n hoogs diastereoselektiewe manier, deur gebruik te maak van ’n reeks ontwikkelde diglymegebaseerde ligande, indien dit vergelyk word met die produkte wat deur die konvensionele TMEDA gegenereer was (tot en met –92% do). Die gebruik van diglyme ligande was ook getoets op ferroseenoksasolien sisteme en dit was bevind dat dieselfde omkering in chiraliteit ook plaasvind wat aanleiding kan gee tot 'n oënskynlik algemene en tot nou toe onbekende faset van asimmetriese oksasoliengerigte orto-litiëring. Dit is bepaal dat hierdie diglyme geïnduseerde omkering in chiraliteit beheer word deur middel van 'n sekondêre stikstofgekoördineerde meganisme, wat in staat is om saam te werk met chirale oksasoliene.

Enzymes as tools in organic synthesis have provided enormous advantages. This thesis deals with the applications of enzymes in the kinetic resolutions of racemic compounds. The stereochemistry of chiral compounds and the kinetics of α/β hydrolase lipases are presented. From a practical point of view, the handling of a large number of parameters that influences the kinetic resolutions, especially enantioselectivity (E-value) are systematically described. A variety of approaches employed for raising the yields to over 50% are additionally discussed. Methods for the preparation of synthetically useful chiral building blocks were developed in this thesis. Thus, resolution of secondary alcohols bearing two vicinal stereocentres are studied. These building blocks can serve as starting materials for the synthesis of various enantiomerically pure compounds for agrochemistry, pharmaceuticals, chemical industry, and particularly for the total synthesis of pheromones. Racemic 3-substitued 2-hydroxybutane derivatives were produced in fairly high diastereomeric purities by a variety of chemical approaches, such as epimerization, metal-catalysed asymmetric addition etc. Kinetic resolution of these racemates was achieved by enzyme-catalysed reactions. Two lipases, Candida antarctica lipase B and Pseudomonas cepacia lipase were found to be useful in acylations as well as hydrolyses. In the biotransformations studied, the presence and nature of the second vicinal stereocentre in the chiral secondary alcohols investigated seemed to be important, e.g. in terms of the efficiencies of sequential kinetic resolutions, and altering the selectivities as well. / QC 20101020

<p>Enzymes as tools in organic synthesis have provided enormous advantages. This thesis deals with the applications of enzymes in the kinetic resolutions of racemic compounds. The stereochemistry of chiral compounds and the kinetics of α/β hydrolase lipases are presented. From a practical point of view, the handling of a large number of parameters that influences the kinetic resolutions, especially enantioselectivity (E-value) are systematically described. A variety of approaches employed for raising the yields to over 50% are additionally discussed.</p><p>Methods for the preparation of synthetically useful chiral building blocks were developed in this thesis. Thus, resolution of secondary alcohols bearing two vicinal stereocentres are studied. These building blocks can serve as starting materials for the synthesis of various enantiomerically pure compounds for agrochemistry, pharmaceuticals, chemical industry, and particularly for the total synthesis of pheromones.</p><p>Racemic 3-substitued 2-hydroxybutane derivatives were produced in fairly high diastereomeric purities by a variety of chemical approaches, such as epimerization, metal-catalysed asymmetric addition etc. Kinetic resolution of these racemates was achieved by enzyme-catalysed reactions. Two lipases, Candida antarctica lipase B and Pseudomonas cepacia lipase were found to be useful in acylations as well as hydrolyses. In the biotransformations studied, the presence and nature of the second vicinal stereocentre in the chiral secondary alcohols investigated seemed to be important, e.g. in terms of the efficiencies of sequential kinetic resolutions, and altering the selectivities as well.</p>

Aldol reactions are widely used in forming new carbon-carbon bonds. Since the discovery of the aldol condensation, controlling the relative and absolute stereochemistry in aldol chemistry has been a major interest in organic chemistry. Efforts in achieving diastereoselectivity in aldol reactions via chelation of Lewis acids to chiral aldehydes are reviewed. The following chapters discuss the diastereoselectivities of hydrogen-mediated reductive aldol reactions. Herein, a highly diastereoselective reductive aldol coupling reactions with broad substrate scope using rhodium catalysts ligated to (2-furyl)₃P were studied. It was demonstrated that the coupling of enones with alpha-amino aldehydes proceeds with high diastereoselectivity via chelation control. The second topic deals with phosphine-mediated furan ring formation. Derivatives of furan are often found in natural products and therapeutic agents. To provide a more facile route to substituted furans, we have developed a phosphine mediated reductive cyclization of gamma-acyloxy butynoates. In this reaction, phosphine is involved in both the reductive formation of allenyl ketones from acyloxy butynoates and the subsequent catalytic cyclization. / text

Les travaux décrits dans ce mémoire portent sur la synthèse du fragment C28-C46 de l'Hémicalide, un produit naturel extrait d'une éponge marine possédant une puissante activité antitumorale. Les étapes-clé de la synthèse sont : une addition conjuguée d'un boronate vinylique sur une lactone insaturée, une hydroxylation et une hydrogénation diastéréosélectives pour contrôler respectivement les centres C39, C40 et C42. La double liaison C34-C35 a été créée par une oléfination de Julia-Kocienski. Dans le cadre de ces travaux, une nouvelle méthode de synthèse diastéréosélective de delta-lactones alpha-hydroxylées a été mise au point mettant en jeu un réarrangement sigmatropique et une cyclisation catalysée par des complexes de métaux de transition. / The work described in this manuscript concerns the synthesis of the C28-C46 fragment of Hemicalide, a natural product extracted from a marine sponge exhibiting a highly potent antitumoral activity. The key steps of the synthesis are : a diastereoselective conjugate addition of a vinyl boroante on an unsaturated lactone, hydrogenation and hydrogenation to control the centers C39, C40 and C42, respectively. The C34-C35 double bond was created by a Julia-Kocienski olefination. During this work, a new method for the diastereoselective synthesis of delta-lactones was developed, involving a sigmatropic rearrangement and a cyclization catalyzed by transition metal complexes.

Les cyclopropanes sont rencontrés dans de nombreux produits naturels ou synthétiques bioactifs. Les travaux exposés dans ce manuscrit portent sur le développement de réarrangements sigmatropiques [3,3] impliquant des dérivés de cyclopropénylcarbinols pour accéder à des alkylidènecyclopropanes fonctionnalisés, précurseurs de cyclopropanes diversement substitués. Le réarrangement des cyanates de cyclopropénylcarbinyle a permis d'obtenir des dérivés N-acylés d'alkylidène(aminocyclopropanes). Une méthode efficace et stéréosélective, impliquant le réarrangement d'Ireland-Claisen des glycolates et glycinates de cyclopropénylcarbinyle, a également été mise au point pour synthétiser des alkylidènecyclopropanes possédant un motif α-hydroxy ou α-amino acide. Le champ d'application de ce réarrangement a été étendu avec succès à des gem-difluorocyclopropènes. L'hydrogénation diastéréosélective des alkylidènecyclopropanes diversement substitués issus de ces rérrangements sigmatropiques a ensuite permis d'obtenir des cyclopropanes fonctionnalisés. / The cyclopropane ring is ubiquitous in natural and biologically active compounds. [3,3]-Sigmatropic rearrangements of cyclopropenylcarbinol derivatives have been developed to access functionalized alkylidenecyclopropanes, which are useful precursors of diversely substituted cyclopropanes. We have shown that the rearrangement of cyclopropenylcarbinyl cyanates could be accomplished under mild conditions to obtain N-acyl alkylidene(aminocyclopropanes). The Ireland–Claisen rearrangement of glycolates or glycinates derived from secondary cyclopropenylcarbinols has been developed as an efficient and stereoselective method for the synthesis of alkylidenecyclopropanes possessing an α-hydroxy or α-amino acid moiety. The scope of this transformation was successfully extended to gem-difluorocyclopropenes. The alkylidenecyclopropanes resulting from these latter sigmatropic rearrangements are valuable precursors of substituted cyclopropanes by diastereoselective hydrogenation of the exocyclic olefin.

Orientador: Fernando Antonio Santos Coelho / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T10:23:57Z (GMT). No. of bitstreams: 1 Porto_RicardoSilva_D.pdf: 3135868 bytes, checksum: 7dce1204558b2d304fe05902e3a3eef4 (MD5) Previous issue date: 2008 / Resumo: Neste trabalho, descrevemos a utilização de ultrassom e de líquido iônico em reações de Morita-Baylis-Hillman utilizando aldeídos quirais contendo oxigênio na posição a-carbonila. Devido aos longos tempos reacionais normalmente observados na reação de Morita-Baylis-Hillman, aldeídos quirais a-oxigenados podem ser passíveis de racemização no meio reacional, diminuindo dessa forma a diastereosseletividade da reação. Tanto o ultrassom quanto o líquido iônico aceleraram a reação drasticamente para vários aldeídos, em comparação com os dados descritos previamente na literatura. Diferentes grupos de proteção foram utilizados no oxigênio a-carbonila, sendo a escolha desse grupo importante para o sucesso da reação. Aldeídos derivados de açúcares se mostraram substratos eficientes na reação, levando à formação dos produtos com bons excessos diastereoisoméricos em alguns casos. Interessantemente, a associação de ultrassom e líquido iônico levou a uma queda no rendimento, o que pode estar relacionado com a destruição da estrutura supramolecular bem definida do líquido iônico na presença de ultrassom. Essa hipótese foi reforçada após a realização da mesma associação (ultrassom + líquido iônico) a 0º C, onde obtivemos excelente rendimento em curto tempo reacional. Com o objetivo de mapear a influência de cada um destes fatores (ultrassom, líquido iônico e temperatura) na reação de Morita-Baylis-Hillman, um estudo quimiométrico foi realizado variando estes três fatores. A utilização de líquido iônico a 0ºC, tanto na presença de ultrassom quanto sob agitação se mostrou uma condição bastante eficiente para a reação de Morita-Baylis-Hillman. Dessa forma vários aldeídos alifáticos e aromáticos foram testados utilizando esta condição, levando a bons resultados, em alguns casos superiores àqueles descritos na literatura. Finalmente, foi preparada uma alfa-metileno-gama-butirolactona, dotada de potente atividade biológica. Estudos visando a preparação do ácido polioxâmico e do fragmento polar da miriocina também foram realizados neste trabalho. / Abstract: In this work, we describe the utilization of ultrasound and ionic liquid in Morita-Baylis-Hillman reactions, with chiral aldehydes bearing oxygen at the a-carbonyl position. Due to the long reaction times normally observed in the Morita-Baylis-Hillman reaction, a-oxigenated chiral aldehydes can be racemized in the reaction, directly impacting on the diastereoselectivity of the reaction. Ultrasound as well as ionic liquid drastically accelerated the reaction rate with several aldehydes, in comparison to data described earlier in the literature. The a-carbonyl oxygen was protected with different protecting groups and the correct choice of these groups was important for the success of the reaction. Sugar derived aldehydes were efficient substrates in the reaction, leading to the formation of adducts with good diastereoisomeric excesses in some cases. Interestingly, the association of ultrasound and ionic liquid led to a lower yield, which can be related with the destruction of the well defined supramolecular structure of the ionic liquid on the presence of ultrasound radiation. This hypothesis was reinforced after carrying out some reaction using the same association (ultrasound + ionic liquid) at 0º C. Under this experimental conditions we observed an excellent yield with short reaction time. Searching to map the influence of each one of these factors (ultrasound, ionic liquid and temperature) in the Morita-Baylis-Hillman reaction, a chemometric study was carried out varying simultaneously these three factors. The utilization of ionic liquid at 0º C, as much as in the ultrasound presence as under agitation, was the best condition to the Morita-Baylis-Hillman reaction. In this way, several aliphatic and aromatic aldehydes were tested utilizing this condition, conducting to good results, in some cases superior to those already described in the literature. Finally, an alfa-methylene-gamma-butyrolactone was prepared, which has a potent biological activity. Studies toward the preparation of polyoxamic acid and the miriocin polar fragment were also realized in this work. / Doutorado / Quimica Organica / Doutor em Ciências