The development and application of unnatural amino alcohols,prepared via hetero-Diels-Alder reactions,in synthesis and catalysis is described.The studies are concerned with the [i]scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents,[ii ]application of amino alcohols in the ruthenium transfer hydrogenation of ketones,[iii ]use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones,and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i ]The use of chiral exo -2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl-amines is described.At the same time the scope of the hetero-Diels-Alder reaction,used in their preparation,is extended by manipulations of the dienophiles. [ii ]Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones.This ligand (2 mol%)in combination with [RuCl2(p -cymene)]2 (0.25 mol%)gave rise to a very fast reaction (1.5 h)leading to the reduced products in excellent yields and enantioselectivities (up to 97%ee ). [iii ]Preparation of α-disubstituded 2-azanorbornyl-3-methanols,in situ generation of the corresponding oxazaborolidines,and use of the latter in reduction of aromatic ketones.Concentration, solvent,and temperature effects on the reaction outcome are described. [iv ]Development of two generations of chiral auxiliaries for the addition of dialkylzinc reagents to N - (diphenylphosphinoyl)imines.Studies using density functional computations allowed the rationalisation of the reaction mechanism and the development of a second generation of ligands that improved the previously reported results.Up to 98%ee could be obtained with these new ligands. Solvent effects on the outcome of the reaction and extension of the work to a larger variety of N - (diphenylphosphinoyl)imines are described.

This thesis deals with method development in asymmetric catalysis and specifically syntheses of enantioenriched O-functionalized cyanohydrins. The first part describes the development of a method for the synthesis of O‑alkoxycarbonylated and O-acylated cyanohydrins. Ethyl cyanoformate and acyl cyanides were added to aldehydes in a reaction catalyzed by a chiral dimeric Ti-salen complex together with a tertiary amine. High yields and enantioselectivities were in most cases obtained. Mechanistic studies were performed and a reaction mechanism was proposed. ­ The second part describes a method in which the undesired minor enantiomer in a Lewis acid–Lewis base-catalyzed acylcyanation is continuously recycled into prochiral starting material. Close to enantiopure O‑acylated cyanohydrins were obtained in high yields. The third part deals with asymmetric acylcyanations of ketones. Acetyl cyanide was found to add to α‑ketoesters in a reaction catalyzed by a chiral Lewis base. Yields up to 77% and 82% ee were obtained. The final part describes an enzymatic method for high-throughput analysis of O‑acylated cyanohydrins. The enantiomeric excess and conversion were determined for products obtained from a number of aromatic and aliphatic aldehydes. / QC 20100818

Ziel der Dissertation war die enantioselektive Totalsynthese des aus Streptomyces alboniger und Streptomyces aurantiacus isolierten Makrodiolids Pamamycin-607 (1a). Neben ungewöhnlichen autoregulatorischen und anionophoren Eigenschaften zeigt der 16-gliedrige Makrocyclus 1a, der sich aus den beiden Hydroxysäuren 48 ("larger fragment") und 49 ("smaller fragment") zusammensetzt, eine ausgeprägte antibiotische Wirkung gegen Gram-positive Bakterien inklusive multipel-antibiotikaresistenter Stämme von Mycobacterium tuberculosis, sowie gegen einige phytopathogene Pilze. Derzeit arbeiten mehrere Gruppen an der Synthese dieser Verbindung, die bislang jedoch noch nicht erreicht werden konnte. Der in dieser Arbeit verfolgte Syntheseweg basiert entscheidend auf einem zuvor in der Arbeitsgruppe entwickelten generellen Zugang zu Actinsäuren und deren Analoga unter Nutzung neuer Methoden zur Darstellung und Elaboration von Sultonen als Schlüsseltransformationen. Ausgehend von Furan und enantiomerenreinem (S)-1,2-Epoxypentan konnte so durch die erstmalige Anwendung dieser sechsstufigen Sequenz ein effizienter Zugang zu dem Hydroxymethylester 62 erarbeitet werden. Die Umwandlung dieses Actinsäurederivates 62 in das Hydroxyalkylfuran 50, das den Ausgangspunkt für eine iterative Anwendung der oben erwähnten Sultonroute bildet, gelang in sechs Schritten durch Nutzung einer diastereoselektiven Hydroborierung unter Vermeidung von 1,3-Allylspannung als Schlüsselschritt. Ausgehend von 50 konnte das larger fragment von Pamamycin-607, das auch als Baustein homologer Pamamycine dient, in weiteren sechs Schritten synthetisiert werden. Dazu wurde nach intensiver Optimierungsarbeit wiederum der oben erwähnte Zugang zu Actinsäurederivaten in modifizierter Form genutzt. Das smaller fragment 49, welches lediglich das C-2-Epimere von 62 darstellt, ließ sich ebenfalls durch Anwendung der Sultonroute generieren. Der für Actinsäuren ungewöhnlichen Konfiguration an C-2 musste dabei durch eine leichte Abänderung der Sequenz Rechnung getragen werden. Ausgehend von literaturbekanntem 2-Brom-4-methylfuran gelangt man so in sechs Schritten zum Methylester des smaller fragment 7. Eine mit der Yamaguchi-Cyclisierung der aus 62 generierten Säure einhergehende Epimerisierung an C-2 ermöglichte nach Öffnung des resultierenden Monolactons unter Lewis-Säurekatalyse eine Verkürzung der Synthese des smaller fragment von Pamamycin-607 auf drei Schritte. Weitere Untersuchungen ergaben, dass 62 nach basischer Äquilibrierung mit DBU und flashchromatographischer Trennung der resultierenden 1:1-Epimerenmischung sogar direkt in den Methylester des smaller fragment 7 überführt werden kann. Während die Yamaguchi-Veresterung des hydroxylgeschützten smaller fragment mit carboxylgeschütztem larger fragment sehr effizient zum Kupplungsprodukt führte, ergab die Cyclisierung nach Entfernung der Schutzgruppen lediglich eine Mischung aus 2-epi-Pamamycin-607 und 2,2'-bisepi-Pamamycin-607. Durch Abbau von natürlichem Pamamycin konnte jedoch ein sechsstufiger Zugang zur Cyclisierungsvorstufe erarbeitet werden, wodurch weitere Untersuchungen zur abschließenden Cyclisierung erleichtert werden. Des weiteren gelang es, im Rahmen der Untersuchungen zur Chemie der Actinsäuren ausgehend von 62 einen generellen Zugang zu den korrespondierenden Aminoactinsäuren zu erarbeiten, die als Ausgangspunkt für die Synthese von Azamakrocyclen dienen können.

This thesis is divided into three parts, revolving around the developments of dynamic systems utilized in dynamic kinetic resolution (DKR) and constitutional dynamic chemistry (CDC). The first section gives an introduction to constitutional dynamics, the core concept of this thesis. Constitutional dynamics can be tuned through reversible interactions. Then, the basic principles of constitutional dynamics in DKR and CDC are discussed, along with their applications. The second section explores the asymmetric synthesis of oxazolidinone derivatives using lipase catalysis through kinetic resolution (KR) and dynamic kinetic resolution. In the first example, synthetic protocol to enantioenriched 5-phenyloxazolidin-2-ones is described, where a kinetically controlled carbamation is followed by lipase-catalyzed cyclization. In contrast to the 5-substituted species, the synthesis of 3-phenyloxazolidin-2-one derivatives could be achieved through lipase-catalyzed cascade O- and N- alkoxycarbonylations in one pot. Furthermore, this KR system could be coupled to a ruthenium-catalyzed racemization process of 1,2-aminoalcohols, thus providing an efficient DKR methodology for asymmetric transformations. The third section focuses on dynamic systems built through reversible covalent reactions. In the first example, a selective gelation process is described, and employed to resolve dynamic imine systems consisting of gelator candidates.  In the second example, reversible reactions with aldehyde enamines are presented, including enamine formation and exchange reactions. In particular, Bi(III) and Sc(III) were discovered to accelerate the enamine exchange reactions by 50-400 times, in which the equilibria could be reached within hours. The last example describes reversible nitroaldol reactions in aqueous media, where rapid and efficient equilibration was identified for selected structures in neutral phosphate buffer. / <p>QC 20150911</p>

This thesis is divided into three main results chapters that reflect the path my research took. In the first results chapter, the first organocatalyst for the carbonyl-ene reaction was discovered and found to give high conversion using 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea. Various carbonyl and alkene precursors were examined in the ene reaction in both catalysed and uncatalysed reactions. It was found that ene reactions using fluoral and ethyl trifluoropyruvate give higher rates of reaction when compared to other carbonyl compounds. A novel enantiopure thiourea was synthesised and the ene reaction was catalysed enantioselectively to 33% e.e. In an attempt to catalyse the reaction to a further extent a new thiourea bonded to a P(=S)R2 group was developed. However, the intramolecular hydrogen bonding of this catalyst was thought to be so strong that this it did not catalyse the reaction. The synthesis of a chiral phosphoric acid was achieved but this was an unsuccessful catalyst in the ene reaction. Two component achiral thiourea and chiral acids were also examined in the ene and Mannich-type reaction. The new easily synthesised thiourea for this reaction has an interesting intermolecular hydrogen bonding coordination in the solid state. Asymmetric fluorination of ketoesters using palladium is a dynamic kinetic resolution. In the 2nd chapter cationic palladium complexes were synthesised and used to determine the optimum parameters for bidentate ligands in this reaction. Four carbon chain phosphines were found to give the highest conversion for this reaction among those ligands tested such as 1,4-bisdiphenylphosphinobutane (bite angle 99º). A new bis-phosphinous amide chiral ligand was developed with a bite angle of 96.7º. The dichloropalladium complex of this phosphine was isolated and structurally characterised. The use of the palladium complex in asymmetric fluorination was attempted however this was found to be unsuccessful. Mechanistic studies reveal that the formation of the desired cationic catalyst did not occur under conditions shown to work well for other palladium phosphine complexes. The ligand was investigated further in hydrogenation reactions. The phosphinous amide was protected as its borane and was used in the rhodium catalysed hydrogenation of alkenes to give high conversion and up to 93% e.e. The borane protected phosphinous amide was also found to catalyse the hydrogenation of acetophenone using copper complexes with up to 84% e.e for the hydrogenation of acetophenone, although conversion was quite low.

No description available.

The overall approach in the present investigation has been to explore applications of the Morita-Baylis-Hillman (MBH) reaction in asymmetric synthesis and in the continuation of systems with medicinal potential. To this end, a series of varied camphor-derived acrylate esters was prepared to serve as chiral substrates in asymmetric Morita-Baylis- Hillman reactions. Reduction of N-substituted camphor-10-sulfonamides afforded the 3- exo-hydroxy derivatives as the major products. Acylation of the corresponding sodium alkoxides gave the desired 3-exo-acrylate esters, isolation of which was complicated by concomitant formation of hydrochlorinated and diastereomeric competition products. Bulky camphorsulfonamides containing alkyl, dialkyl, aromatic and adamantyl groups were selected as N-substituents with the view of achieving stereoselective outcome in subsequent MBH reactions. The synthesis of novel camphor-derived Morita-Baylis-Hillman adducts using various pyridine-carboxaldehydes proceeded with exceptionally high yields with diastereoselectivities ranging from 7-33 % d.e. Both 1D and 2D NMR and HRMS techniques were employed to confirm the structures and an extensive study of the electropositive fragmentation patterns of a number of camphor-derived chiral acrylate esters was conducted. Attention has also been given to the application of MBH methodology in the construction of heterocyclic ‘cinnamate-like’ AZT conjugates which were designed to serve as dualaction HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. A number of pyridine carboxaldehyde-derived MBH adducts were synthesized using methyl, ethyl and t-butyl acrylates in the presence of 3-hydroxyquinuclidine (3-HQ) as catalyst. The yields for these reactions were excellent. The resulting MBH adducts were acetylated and subjected to aza-Michael addition using propargylamine. The resulting alkylamino compounds were then used in ‘Click reactions’ to form the targeted AZT-conjugates in moderate to excellent yield. In silico docking of computer modelled AZT-conjugates into the HIV-1 integrase and reverse transcriptase enzyme-active sites and potential hydrogen-bonding interaction with active-site amino acid residues were identified. The electrospray MS fragmentations of the AZT and the novel AZT-conjugates were also investigated and common fragmentation pathways were identified.

Une bibliothèque de nouveaux catalyseurs bifonctionnels combinant à la fois l’aminocatalyse et l’activation acide par un acide phosphonique sur une même structure peptidique a été développée. Des variations structurales ont été apportées afin d’optimiser la géométrie du site catalytique. Le potentiel de ces catalyseurs a été testé sur la réaction d’addition de Michael stéréosélective d’aldéhydes sur divers nitroalcènes aromatiques. Dans des conditions optimisées, de très bonnes sélectivités (r.d. < 95:5 / r.e. < 93:7) ont été atteintes. Grâce à leur forte solubilité dans l’eau, ces catalyseurs ont été facilement extraits et réutilisés sur 10 cycles sans perte significative de sélectivité. Enfin, des études mécanistiques ont été menées afin de connaitre le mode d’action exact de ces catalyseurs. Tant l’énamine que l’activation acide se sont avérées essentielles pour que la réaction ait lieu. L’enchainement peptidique permet une réaction intramoléculaire et stéréosélective. / A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation on a peptide structure was developed. Some structural variations allowed the optimization of the catalytic site. The potential of these catalysts was evaluated on the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes. In optimized conditions, very good selectivities (up to 95:5 d.r. and 93:7 e.r) were achieved. Due to their high water-solubility, the catalysts were easily recyclable and reused over several cycles without any significant loss of selectivities. Mechanistic investigations were carried out to understand the exact mode of action of the catalysts. Both enamine formation and acid activation were essential for the reaction to occur. The peptide structure allows an intramolecular and stereoselective reaction.

Triquentrinas A são produtos naturais marinhos com atividade biológica e alta complexidade estrutural. Estes fatores tornam estes alcaloides e compostos análogos, como os herbindóis, alvos para a síntese total e plataforma para o desenvolvimento de novas metodologias sintéticas. Nesta Dissertação de Mestrado, procurou-se completar a síntese estereosseletiva da (+)-cis-triquentrina A empregando-se intermediários sintéticos protegidos com o grupo benzila que poderão ser usados para a futura prospecção de novos compostos com atividade biológica. A rota proposta baseia-se na obtenção do ácido (S)-3-(1-benzil-4-etil-1H-indol-7-il)butanóico, um intermediário-chave já descrito por Silva e colaboradores no percurso da síntese total da (+)-trans-triquentrina A, e da finalização da síntese de acordo com a abordagem proposta pelo grupo de RajanBabu para conversão do análogo protegido com grupo tosila à (+)-cis-triquentrina A. A resolução enzimática do intermediário-chave com lipase de Pseudomonas cepacia imobilizada em terra diatomácea foi otimizada, resultando em rendimentos de 32% e 99% ee na metade do tempo descrito anteriormente. Na etapa-chave da síntese, o (S)-ácido foi submetido a uma acilação de Friedel-Crafts intramolecular na presença de anidrido trifluoroacético que produziu o produto de ciclização desejado com 40% de rendimento. Na etapa final da síntese, o intermediário sintético protegido com grupo benzila não pode ser convertido à (+)-cis-triquentrina A, empregando-se a metodologia desenvolvida para a redução do composto análogo tosilado, dada a diferença de reatividade imposta pela troca do grupo protetor. As etapas realizadas até o penúltimo intermediário sintético (S)-8, consta com 10 etapas e rendimento global de 1,3%. viii As diferenças eletrônicas e estruturais relacionadas a diferentes grupos protetores poderão ser refletidas em variações na atividade antiproliferativa de indóis relacionados a triquentrinas. Ainda no interesse de preparar moléculas para envio à análises de atividade antiproliferativa preparou-se um composto relacionado à síntese da trans-triquentrina A tendo como etapa-chave uma contração de anel mediada por I(III) em 21% de rendimento, cujo trabalho foi incluído nos anexos. / Trikentrins A are marine natural products with biological activity and high structural complexity. These factors make these alkaloids and analogous compounds, such as herbidoles, targets for total synthesis and platform for the development of new synthetic methodologies. In this Master\'s Dissertation, we attempted to complete the stereoselective synthesis of (+)-cis-trikentrin A using synthetic intermediates protected with the benzyl group that could be used for the future prospection of new compounds with biological activity. The proposed route is based on the preparation of (S)-3-(1-benzyl-4-ethyl-1H-indol-7-yl) butanoic acid, a key intermediate already described by Silva et al., in the course of total synthesis (+)-trans-triquentrin A, and the final part of the synthesis according to the approach proposed by the RajanBabus group for conversion of the protected analogue with tosyl group to (+)-cis-trikentrin A. The enzymatic resolution of the key intermediate with Pseudomonas cepacia lipase immobilized on diatomaceous earth was optimized, resulting in 32% yield and 99% ee in half the time described above. In the key step of the synthesis, the (S)-acid was subjected to an intramolecular Friedel-Crafts acylation in the presence of trifluoroacetic anhydride which yielded the desired cyclization product in 40% yield. In the final step of the synthesis, the synthetic intermediate protected with benzyl group couldnt be converted to (+)-cis-trikentrin A, employing the methodology developed for the reduction of the tosylated analogous compound, given the difference of reactivity imposed by exchange of the protective group. The steps carried out up to the synthetic intermediate (S)-8, consists of 10 steps and overall yield of 1.3%. Electronic and structural differences related to different protective groups may be reflected in variations in the antiproliferative activity of indoles related to trikentrins. A compound related to the synthesis of trans-triquentrin A having as its key step an I(III) mediated ring contraction in 21% yield was also prepared in the interest of preparing molecules for antiproliferative activity analysis, whose work was included in the appendix.

Neste trabalho foi preparada uma série de sais de piridínio, com subsequente investigação da sua atividade catalítica e indução assimétrica em reações de adição de Michael e alquilações de metilenas ativas. Os sais de piridínio foram preparados pela reação de tetrafluorborato de 2,4,6-trifenilpirílio e 2,4,6-trimetilpirílio com aminas, aminoálcoois e/ou aminoácidos. As reações em que se efetuou o teste catalítico destes sais foram: a) adição de cianoacetato de etila, N-acetamidomalonato de dietila e nitrometano à chalcona e de tiofenol à 2-ciclohexenona; b) alquilação de cianoacetato de etila e de fenilcianoacetato de etila com cloreto de benzila. Os sais de piridínio testados atuaram como catalisadores nas alquilações de metilenas ativas e nas adições de Michael, com exceção da reação de N-acetamidomalonato de dietila com chalcona. No que tange à eficiência como indutores de assimetria, foram feitas reações comparativas entre os sais de piridínio quirais, o brometo de N-benzil-N-metilefedrínio ou o cloreto de N-benzilquinínio, sendo que os catalisadores por nós sintetizados se mostraram menos eficientes. A conformação preferencial de três sais de piridínio, em que a cadeia alquílica ligada ao átomo de nitrogênio possue um substituinte aromático, foi determinada através de experimentos de NOE-diff. Para dois destes sais há evidências da formação de complexos de transferência de carga intramolecular. A atividade catalítica e a indução assimétrica destes três catalisadores foi interpretada com base no estudo conformacional acima mencionado. / In the presente work, a series of pyridinium salts was prepared and their catalytic activity evaluated, as well as their ability to induce asymmetry in Michael additions and alkylation of organic carbon acids. Such pyridinium salts were prepared by reacting 2,4,6-triphenyl or 2,4,6-trimethylpyrilium tetrafluoroborates with amines, &#945;-aminoalcohols or &#945;-aminoacids. The catalytic activity of the prepared salts was evaluated in the folIowing PTC reactions: a) Michael addition of ethylcyanoacetate, diethyl N-acetamidomalonate or nitromethane to chalcone and of thiophenol to 2-cyclohexenone; b) alkylation of ethylcyanoacetate or ethyl phenylcyanoacetate, using benzyl chloride as eletrophile. In alI cases, except 1,4-addition of diethyl N-acetamidomalonate to chalcone, the prepared pyridinium salts displayed catalytic activity although with inferior asymmetric induction efficiency as compared to the classicalIy used efedrinium and quininium salts. The preferencial conformation of three pyridinium salts bearing aromatic rings in the nitrogen substituent aliphatic chain was determined by NOE diff experiments. In two cases some evidences for charge transfer was provided by uv measurements. The catalytic result and the asymmetric induction were interpreted on the basis of the well accepted substrate/catalyst interaction model and conformational analysis data.