No description available.

This thesis describes the combination of non-stabilized nucleophiles and prochiral/racemic electrophiles in transition metal catalyzed asymmetric transformations. These enantioselective reactions have tremendous potential for the formation of chiral building blocks and new structural motifs that can be found in a variety of natural products and their derivatives. The first part of the thesis focuses on the synthetic approach towards anti-cancer active diterpenoid structures. The two key steps involve a Cu-catalyzed asymmetric conjugate addition of alkylzirconocenes to enones and an intramolecular oxidative cyclisation. Particular investigations into the cyclisation are made with organocatalysis, transition metal catalysis and electrochemistry for the formation of these tricyclic scaffolds. In the second part this work builds on the Rh-catalyzed asymmetric Suzuki-Miyaura coupling of benzeneboronic acids and cyclic allyl chlorides, which has been developed in our group. Here, the main point is to use more challenging coupling partners, such as heteroaromatic boronic acids, which are coupled to racemic cyclic allyl halides. The utility of this method is demonstrated by performing further transformations and an asymmetric synthesis of the natural product (+)- isoanabasine. The last chapter describes the development of a new asymmetric Hiyama coupling of arylsiloxanes with racemic cyclic allyl chloride. Attempts are made to generate substrates that are not accessible via the asymmetric Suzuki - Miyaura reaction. After extensive optimisation a variety of arylsiloxanes is generated and tested with the best conditions to prove its utility in comparison to the asymmetric Suzuki-Miyaura coupling.

This thesis combines work in the areas of mass spectrometric reaction monitoring and chemical education. In the first part of this thesis, real-time mechanistic analysis using electrospray ionization mass spectrometry is reported. In Chapter 1, an introduction to the mass spectrometric instrumentation and methodologies used in this research is provided. In Chapter 2, the real-time mechanistic analysis of the Hiyama cross-coupling reaction using electrospray ionization mass spectrometry is reported, in particular, the fluoride-mediated rearrangement of phenylfluorosilanes that was found to occur even before catalyst addition. Combining Ph3SiF with a fluoride ion source under typical Hiyama cross-coupling conditions causes rapid formation of the expected [Ph3SiF2]–; however, ESI-MS analysis reveals that phenyl-fluoride exchange occurs concomitantly, also producing substantial quantities of [PhnSiF5–n]– (n = 0-2). The exchange process is verified using 19F NMR spectroscopy. This observation may have implications for Hiyama reaction protocols, which use transmetallation from triaryldifluorosilicates as a key step in cross-coupling. Optimization of the methodology used for real-time analysis by ESI-MS to reduce observed contamination from leaching of rubber septa additives is also discussed. In the second part of this thesis, the development and application of two different approaches for generating molecular models for the teaching molecular geometry and VSEPR theory in first year chemistry is reported. Chapter 4 details a method for the application of handheld 3D printing pens for producing models from ABS plastic. In Chapter 5, the development of laser-cut acrylic model kits is detailed, as well as the design and results of a quantitative study aimed at assessing their effectiveness for improving representational competence and comprehension of molecular geometry. / Graduate

No description available.

A brief introduction explaining phosphine ligand properties, Pd catalysed cross-coupling reactions; the importance of the steps involved in the catalytic cycle (oxidative addition, transmetalation & reductive elimination), mechanistic studies and a comparison of various reactions will give an overview of important cross-coupling reactions and their limitations. The development of a “super-concentrated” (5M) Pd catalysed Kumada type coupling reaction has been developed for coupling a range of aryl bromide and chloride substrates with the Grignard reagents ((p-CF₃-C₆H₄)MgBr)) and PhMgBr in methyl-tetrahydrofuran (Me-THF). Using a range of bidentate ligands such as bis-phosphinoferrocenyl ligands, good conversions were achieved using small amounts of solvent; up to 10 times less than typical procedures in THF. The unsymmetrical Pt complexes of the form [Pt(P-P)Br₂], [Pt(P-P)(Ph)Br] and [Pt(P-P)Ph₂] have been synthesised and characterised. The variations of substituents on the ligand system and the steric bulk have been shown to have a dramatic effect on the rate of transmetalation. The results provide one explanation why 1,1’-bis(di tert-butylphosphino)ferrocene (dtbpf), an excellent ligand for certain Suzuki reactions, is quite poor in reactions where transmetalation is more difficult. Palladium dichloride complexes of the ferrocenylphosphine based ligands 1,1’-bis- (diphenylphosphino)ferrocene (dppf), 1,1’-bis-(diisopropylphosphino)ferrocene (dippf) and 1,1’-bis-(di-tert-butylphosphino)ferrocene (dtbpf) have been shown to be active in the Hiyama cross-coupling of p-bromoacetophenone and vinyltrimethoxysilane (CHCH₂Si(OMe₃)) in the presence of TBAF under thermal heating and microwave conditions. Ligands with the optimum balance for promoting the transmetalation, oxidative addition and reductive elimination steps along the reaction pathway have been identified. Competition experiments are consistent with slow transmetalation being an issue with the Hiyama reaction relative to the Suzuki coupling. A novel protocol has been developed for the synthesis of aryl-alkyl ethers via C-O bond activation under Pd catalysed conditions. Utilising the unsymmetrical 1-bis-(ditertbutyl-1’- bis-diphenylphosphino)ferrocene (dtbdppf) under optimised conditions with silicon based nucleophiles and NaOH or TBAF as an activator, the formation of methyl, ethyl, n-propyl and n-butyl ethers with a range of aryl halides was achieved in good yield.

En la presente memoria se describe el estudio sobre la preparación y reactividad de derivados carbocíclicos de litio, y la preparación y reactividad de derivados de carbenos N-heterocíclicos de paladio y de rodio. En el primer capítulo se estudia la reacción de litiación del clorometilciclopropano y del bromometilciclobutano empleando litio metálico y una cantidad subestequiométrica de un areno, y la posterior reacción de los intermedios de litio generados con distintos compuestos carbonílicos. El uso de DTBB (4,4’-di-terc-butilbifenilo) en THF a –78 oC y en presencia del electrófilo (condiciones de reacción tipo Barbier) dio lugar, tras hidrólisis, a los correspondientes cicloalquilmetilalcanoles. Por el contrario, llevando a cabo el proceso de litiación con naftaleno en dietil éter a 0 ó 25 oC, el intermedio de litio sufre reordenamiento hacia el derivado homoalil-litio o bishomoalil-litio. La posterior reacción con compuestos carbonílicos permite la preparación de alcoholes insaturados. En el segundo capítulo se estudia en primer lugar la preparación de sales de imidazolio funcionalizadas con un grupo hidroxilo, por apertura de epóxidos con imidazol y posterior reacción con haluros de alquilo. A continuación, estas sales se han empleado en la preparación de complejos metálicos de paladio y rodio con un ligando carbeno N-heterocíclico. Los complejos, bien definidos, biscarbénico de paladio [(NHC)2PdCl2] y monocarbénico de rodio [(NHC)Rh(COD)Cl] han sido preparados por metalación directa empleando precursores básicos tanto de paladio como de rodio. Finalmente, se ha estudiado la actividad catalítica de estos complejos en diferentes procesos. El complejo de paladio se ha empleado en la reacción de acoplamiento de Hiyama, en ausencia de fluoruros y por irradicación en microondas, de diferentes (trialcoxi)arilsilanos con bromuros y cloruros de arilo. También se estudio la reacción de acoplamiento de Heck-Matsuda, catalizada por NHC-Pd, de diferentes tetrafluoroboratos de bencenodiazonio con acrilatos, acrilamida, estireno y ciclohexeno. Por otra parte, el complejo de NHC-Rh se ha mostrado activo en la reacción de adición conjugada de ácidos arilborónicos a cetonas α,β-insaturadas.

In Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin π-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes. / text

Les cyclopropanes sont des unités qui sont très importantes en raison de leur présence dans de nombreux produits naturels, dans certaines molécules synthétiques ayant une activité biologique, ainsi que dans plusieurs intermédiaires synthétiques. Les travaux décrits dans cet ouvrage portent sur l’halogénocyclopropanation stéréosélective d’alcools allyliques en présence d’un ligand chiral stœchiométrique de type dioxaborolane et de carbénoïdes de zinc substitués dérivés de composés organozinciques et d’haloformes. Nous avons ainsi développé des conditions pour l’iodo-, la chloro- et la fluorocyclopropanation stéréosélective. Une étude mécanistique portant sur la nature des carbénoïdes alpha-chlorés et alpha-bromés a révélé qu’il y a un échange des halogènes portés par ces carbénoïdes. Lors de la chlorocyclopropanation, le carbénoïde le plus réactif (alpha-chloré) réagit de façon prédominante en vertu du principe de Curtin-Hammet. Les iodocyclopropanes énantioenrichis ont pu être fonctionnalisés via une réaction d’échange lithium-iode suivie du traitement avec des électrophiles, ou via une réaction de transmétallation au zinc suivie d’un couplage de Negishi. Ainsi, toute une gamme de cyclopropanes 1,2,3-substitués énantioenrichis a pu être synthétisée. Dans l’optique de développer de nouvelles méthodologies de fonctionnalisation des cyclopropanes, nous nous sommes par la suite tournés vers le couplage croisé de type Hiyama-Denmark des cyclopropylsilanols. Dans cette voie synthétique, le groupement silanol a deux fonctions : il sert de groupement proximal basique lors de la cyclopropanation de Simmons-Smith et il subit la transmétallation au cours du couplage croisé. Dans l’étape du couplage croisé, la nature des ligands liés à l’atome de silicium s’est avérée cruciale au bon déroulement de la réaction. Ainsi, l’échange de ligands avec le diéthyl éthérate de trifluoroborane générant le cyclopropyltrifluorosilane in situ est requis pour obtenir de bons rendements. Le dernier volet de cet ouvrage porte sur la cyclisation d’iodures d’alkyle par substitution aromatique par voie homolytique catalysée par le nickel. Une série de composés de type tétrahydronaphtalène et thiochromane ont été préparés selon cette méthode. Une étude mécanistique a confirmé la nature radicalaire de cette réaction et suggère fortement l’action catalytique du nickel. De plus, des études de spectrométrie RMN DOSY ont montré une association entre le complexe de nickel et le substrat ainsi que la base employés dans cette réaction. / Cyclopropanes are important subunits because of their presence in numerous bioactive natural products and synthetic molecules as well as synthetic intermediates. In this work we have investigated the stereoselective halocyclopropanation of allylic alcohols using a dioxaborolane-type stoichiometric chiral ligand and substituted zinc carbenoids derived from organozinc compounds and haloforms. We have thus developed conditions for the stereoselective iodo-, chloro- and fluorocyclopropanation reactions. A mechanistic study on the nature of alpha-chloro and alpha-bromomethylzinc carbenoids has revealed that halogen scrambling is taking place in the case of these carbenoids. During the chlorocyclopropanation reaction, the most reactive carbenoid (alpha-chloromethyl zinc) reacts predominantly, in line with the Curtin-Hammet principle. The enantioenriched iodocyclopropanes have been functionalized through a lithium-iodine exchange followed by treatment with electrophiles or transmetallation to zinc and Negishi cross-coupling. Therefore, a wide array of enantioenriched 1,2,3-substituted cyclopropanes have been synthesized using these methods. In order to develop new methodologies for the functionalization of cyclopropanes, we have studied the Hiyama-Denmark cross-coupling of cyclopropylsilanols. In this approach, the silanol group bears two functions: it serves as a proximal basic group in the Simmons-Smith cyclopropanation and it is involved in the transmetallation event during the cross-coupling reaction. In the cross-coupling step, the nature of the ligands bound to the silicon atom is crucial to the efficiency of the reaction. Hence, the in situ formation of the cyclopropyltrifluorosilane via a ligand exchange with boron trifluoride etherate is required for good yields. The final chapter of this work is on the nickel-catalyzed cyclization of alkyl iodides via a homolytic aromatic substitution mechanism. A series of tetrahydronaphthalene and thiochroman related compounds have been synthesized using this methodology. A mechanistic study has confirmed the radical nature of this reaction and strongly suggests the catalytic role of nickel. DOSY NMR spectrometric investigations have demonstrated an association between substrate, the base employed in this reaction and the nickel complex.

Es wird die enantioselektive Synthese eines substituierten Cyclopentanfragmentes beschrieben, welches zur Synthese einer Vielzahl von Diterpenen aus Euphorbiaceae genutzt werden kann. Schlüsselschritt hierbei ist eine intramolekulare Carbonyl-En-Reaktion. In zwei verschiedenen Syntheseansätzen wurde versucht, dieses zu einem Jatrophan-Diterpen umzusetzen. Versuche hinsichtlich einer Nozaki-Hiyama-Kishi-Kupplung werden beschrieben. Im zweiten Ansatz, wurde über eine Ringschlussmetathese bzw. eine Relay-Ringschlussmetathese versucht entsprechende Jatrophane herzustellen. Dies gelang bei einem Substrat, welches eine zweifach substituierte Doppelbindung beinhaltet. Somit konnte ein nichtnatürliches 17-Norjatrophan enantioselektiv synthetisiert werden. / The enantioselective synthesis of a highly substituted cyclopentan, useful for the synthesis of diterpenes from Euphorbiaceae is described. Key step is a intramolecular carbonyl-en reaction. Two different approaches towards Jatrophanes were examined. The first one envisioning a Nozaki-Hiyama-Kishi coupling didn´t work. The second one employed a ring-closing-metathesis which was successful in the case of a disubstituted double bond formed. The use of an relay-ring-closing-metathesis was also examined. The enantioselective synthesis of a nonnatural 17-Norjatrophane is described in all details.

Les cyclopropanes sont des unités qui sont très importantes en raison de leur présence dans de nombreux produits naturels, dans certaines molécules synthétiques ayant une activité biologique, ainsi que dans plusieurs intermédiaires synthétiques. Les travaux décrits dans cet ouvrage portent sur l’halogénocyclopropanation stéréosélective d’alcools allyliques en présence d’un ligand chiral stœchiométrique de type dioxaborolane et de carbénoïdes de zinc substitués dérivés de composés organozinciques et d’haloformes. Nous avons ainsi développé des conditions pour l’iodo-, la chloro- et la fluorocyclopropanation stéréosélective. Une étude mécanistique portant sur la nature des carbénoïdes alpha-chlorés et alpha-bromés a révélé qu’il y a un échange des halogènes portés par ces carbénoïdes. Lors de la chlorocyclopropanation, le carbénoïde le plus réactif (alpha-chloré) réagit de façon prédominante en vertu du principe de Curtin-Hammet. Les iodocyclopropanes énantioenrichis ont pu être fonctionnalisés via une réaction d’échange lithium-iode suivie du traitement avec des électrophiles, ou via une réaction de transmétallation au zinc suivie d’un couplage de Negishi. Ainsi, toute une gamme de cyclopropanes 1,2,3-substitués énantioenrichis a pu être synthétisée. Dans l’optique de développer de nouvelles méthodologies de fonctionnalisation des cyclopropanes, nous nous sommes par la suite tournés vers le couplage croisé de type Hiyama-Denmark des cyclopropylsilanols. Dans cette voie synthétique, le groupement silanol a deux fonctions : il sert de groupement proximal basique lors de la cyclopropanation de Simmons-Smith et il subit la transmétallation au cours du couplage croisé. Dans l’étape du couplage croisé, la nature des ligands liés à l’atome de silicium s’est avérée cruciale au bon déroulement de la réaction. Ainsi, l’échange de ligands avec le diéthyl éthérate de trifluoroborane générant le cyclopropyltrifluorosilane in situ est requis pour obtenir de bons rendements. Le dernier volet de cet ouvrage porte sur la cyclisation d’iodures d’alkyle par substitution aromatique par voie homolytique catalysée par le nickel. Une série de composés de type tétrahydronaphtalène et thiochromane ont été préparés selon cette méthode. Une étude mécanistique a confirmé la nature radicalaire de cette réaction et suggère fortement l’action catalytique du nickel. De plus, des études de spectrométrie RMN DOSY ont montré une association entre le complexe de nickel et le substrat ainsi que la base employés dans cette réaction. / Cyclopropanes are important subunits because of their presence in numerous bioactive natural products and synthetic molecules as well as synthetic intermediates. In this work we have investigated the stereoselective halocyclopropanation of allylic alcohols using a dioxaborolane-type stoichiometric chiral ligand and substituted zinc carbenoids derived from organozinc compounds and haloforms. We have thus developed conditions for the stereoselective iodo-, chloro- and fluorocyclopropanation reactions. A mechanistic study on the nature of alpha-chloro and alpha-bromomethylzinc carbenoids has revealed that halogen scrambling is taking place in the case of these carbenoids. During the chlorocyclopropanation reaction, the most reactive carbenoid (alpha-chloromethyl zinc) reacts predominantly, in line with the Curtin-Hammet principle. The enantioenriched iodocyclopropanes have been functionalized through a lithium-iodine exchange followed by treatment with electrophiles or transmetallation to zinc and Negishi cross-coupling. Therefore, a wide array of enantioenriched 1,2,3-substituted cyclopropanes have been synthesized using these methods. In order to develop new methodologies for the functionalization of cyclopropanes, we have studied the Hiyama-Denmark cross-coupling of cyclopropylsilanols. In this approach, the silanol group bears two functions: it serves as a proximal basic group in the Simmons-Smith cyclopropanation and it is involved in the transmetallation event during the cross-coupling reaction. In the cross-coupling step, the nature of the ligands bound to the silicon atom is crucial to the efficiency of the reaction. Hence, the in situ formation of the cyclopropyltrifluorosilane via a ligand exchange with boron trifluoride etherate is required for good yields. The final chapter of this work is on the nickel-catalyzed cyclization of alkyl iodides via a homolytic aromatic substitution mechanism. A series of tetrahydronaphthalene and thiochroman related compounds have been synthesized using this methodology. A mechanistic study has confirmed the radical nature of this reaction and strongly suggests the catalytic role of nickel. DOSY NMR spectrometric investigations have demonstrated an association between substrate, the base employed in this reaction and the nickel complex.