The work reported in this thesis is concerned with two separated but related studies. The first involved examination of hydrogenation reactions of alkenes, dienes and alkynes using (Rh[sub]2C1(CO)[sub]2(dppm)[sub]2JBPh[sub]4 as a catalyst. Kinetic studies have been performed on the reaction of hexene. The system only well-behaved in the presence of a base, R[sub]3N, where a rst order dependance on both catalyst and hydrogen concentations observed. The order with respect to alkene is of the Michaelis-Menton type. This behaviour suggests that the active catalyst is a neutral monohydride generated by deprotonation of a ionic dihydride. It is proposed that the active catalyst is a dinuclear species, since none of the likely mononuclear breakdown oducts shows any catalytic activity. A catalytic cycle for the reaction is proposed. The second study was an investigation into the use of fast atom bombardment (FAB) mass spectrometry as a means of anaylsis organometallic compounds which have proved difficult to identify using other ionisation modes. The technique was shown to informative spectra for a series of dinuclear rhodium-dppm mplexes and some dinuclear manganese carbonyl derivatives. FAB ionisation also proved effective for identification of phosphine and phosphite derivatives of [RCC0[sub]3(CO)[sub]9.] (R=CH[sub]3, C1). The technique was also combined with thin layer chromatography (TLC) in examining a reaction of [Mo(CO)[sub]6.] with Ph[sub]2P(CH[sub]2)[sub]2P(O)Ph[sub]2 (dppeO) which yields a mixture of seven products. It was found that good spectra of pure materials could be obtained TLC separation, followed by removal of the appropriate section silica support from the plate. This was subjected directly to FAB mass spectrometry without prior extraction of the product from silica. Using this technique, it proved possible to identify three new dppeO derivatives of [Mo(CO)[sub]4 (dppeO) derivatives of [Mo(CO)[sub]6. These are [Mo(CO)[sub]5 (dppeO)] cis-[Mo(CO)[sub]4 (dppeO)[sub]2] and [Mo[sub]2(CO)[sub] 4 (dppeO)[sub]2].

Transition metal-catalyzed olefin hydroacylation represents an atom-economical approach for the synthesis of valuable ketone products. To date, the intermolecular variant of this reaction suffers from several drawbacks, which include limited substrate scope, poor reactivity and/or regioselectivity for non-activated, non-chelating alkene substrates, and competitive reductive decarbonylation pathways that lead to catalyst decomposition. Herein, we report the linear-selective intermolecular hydroacylation of a wide range of electronically diverse olefins with salicylaldehydes employing catalyst loadings as low as 2 mol%. A unique reactivity profile is observed for the chiral C2-symmetric phosphoramidite ligand employed in our catalyst system, and thus, we outline progress made towards the synthesis of new phosphoramidite ligands. We have applied our methodology in the total synthesis of nine octaketide natural products belonging to the dothiorelone, cytosporone, and phomopsin families. Due to recent reports demonstrating the anticancer activity of cytosporone B (Csn-B), we will also discuss progress towards the synthesis of Csn-B analogues.

Transition metal-catalyzed olefin hydroacylation represents an atom-economical approach for the synthesis of valuable ketone products. To date, the intermolecular variant of this reaction suffers from several drawbacks, which include limited substrate scope, poor reactivity and/or regioselectivity for non-activated, non-chelating alkene substrates, and competitive reductive decarbonylation pathways that lead to catalyst decomposition. Herein, we report the linear-selective intermolecular hydroacylation of a wide range of electronically diverse olefins with salicylaldehydes employing catalyst loadings as low as 2 mol%. A unique reactivity profile is observed for the chiral C2-symmetric phosphoramidite ligand employed in our catalyst system, and thus, we outline progress made towards the synthesis of new phosphoramidite ligands. We have applied our methodology in the total synthesis of nine octaketide natural products belonging to the dothiorelone, cytosporone, and phomopsin families. Due to recent reports demonstrating the anticancer activity of cytosporone B (Csn-B), we will also discuss progress towards the synthesis of Csn-B analogues.

This report details the discovery of a method for rhodium catalyzed asymmetric conjugate additions of heteroaryl nucleophiles to α,β-unsaturated carbonyl compounds. This work has successfully employed heteraryl titanates in enantioselective conjugate addition to α,β-unsaturated carbonyl compounds for the first time. Moreover, the utility of benzofuranyl, benzothiophenyl, and pyrrolo zinc reagents has been exemplified in enantioselective conjugate additions. We have found that the precatalyst [Rh(COD)acac]/OMeBIPHEP is broadly effective for enantioselective conjugate additions. Each heterocycle tested exhibited unique reactivity with respect to both conversion and enantioselectivity; reactivities of heteroaryl zinc reagents and heteroaryl titanates in enantioselective conjugate additions to α,β-unsaturated carbonyl compounds are sometimes complementary. Efforts directed towards the development of a method for rhodium-free enantioselective conjugate addition of furan to α,β-unsaturated carbonyl compounds are also described. / text

Le motif cyclopropanique est présent dans de nombreux composés bioactifs d'origine naturelle ou non-naturelle auxquels il confère une certaine rigidité structurale, qui permet d'augmenter leur biodisponibilité et leur stabilité métabolique. Par ailleurs, l'atome de fluor possède des propriétés particulières dues entre autres à sa forte électronégativité et sa petite taille. Cela permet de modifier les propriétés physico-chimiques des molécules qui le contiennent, telles que l'acidité, la lipophilie ou encore la solubilité. Par conséquent, les cyclopropanes fluorés représentent des motifs intéressants dans la mesure où ils combinent les propriétés des cyclopropanes et celles de l'atome de fluor. Dans ce contexte, nous nous sommes tout d'abord intéressés à la synthèse énantiosélective de cyclopropanes fluorés polyfonctionnalisés à partir d'oléfines fluorées et de composés diazos, par catalyse au rhodium. Pour cela, deux types de composés diazos ont été utilisés : les diaccepteurs et les donneur-accepteurs. Cette méthodologie a été étendue à la synthèse de cyclopropanes chlorés et bromés. Afin de mettre en valeur les composés ainsi obtenus, nous avons ensuite étudié la synthèse de molécules d'intérêt biologique, et plus précisément de mimes d'aminoacides contenant un cyclopropane fluoré. En effet, leur introduction dans des peptides pourrait permettre d'en modifier la conformation et l'interaction avec les récepteurs biologiques. Dans ce cadre, la synthèse d'un mime de proline contenant un cyclopropane fluoré a été développée. Par ailleurs, un mime de leucine contenant un cyclopropane fluoré a été introduit dans la séquence minimum active de la neurotensine et permet d'obtenir une bonne sélectivité pour le récepteur NTS2, ce qui ouvre des perspectives pour le développement de nouveaux analgésiques possédant moins d'effets secondaires. Pour terminer, nous avons examiné la synthèse de composés diazos en flux continu. A l'heure actuelle, ceux-ci sont peu utilisés dans l'industrie car ils présentent une certaine toxicité, une potentielle explosivité et une instabilité qui limite leur stockage. La chimie en flux continu constitue donc une alternative pour les utiliser, puisque leur synthèse, leur purification et leur mise en réaction se fait en continu sur de petites quantités à la fois et ne nécessite pas d'intervention de la part d'un opérateur. Ainsi, les risques présentés par la montée en échelle de la réaction de cyclopropanation précédemment développée sont fortement diminués. / The cyclopropane ring is present in many natural or non-natural bioactive compounds, whose biodisponibility and metabolic stability is increased by its structural rigidity. Besides, the fluorine atom displays singular properties due to its high electronegativity and its small size. This enables to modify the physico-chemical properties of molecules such as acidity, lipophilicity or solubility. As a consequence, fluorinated cyclopropanes represent interesting scaffolds since they combine the properties of cyclopropanes and fluorine atom. In this context, we were interested in the enantioselective synthesis of polyfunctionalized fluorinated cyclopropanes from fluorinated olefins and diazo compounds under rhodium catalysis. For this purpose, two types of diazo compounds were investigated: diacceptor and donor-acceptor. This methodology was further extended to the synthesis of chlorinated and brominated cyclopropanes. To highlight the versatility of these compounds, we then turned our attention to the synthesis of biorelevant targets, and more precisely aminoacids containing a fluorocyclopropane moiety. Indeed, their introduction into peptides could allow to modify their conformation and interactions with biological receptors. In that aim, the synthesis of an analogue of proline containg a fluorocyclopropane was developed. An analogue of leucine containing a fluorocyclopropane was also introduced in the minimum active sequence of neurotensin and shows a good selectivity for the NTS2 receptor. This opens up prospects for the development of new analgesics with less side effects. Finally, we examined the flow synthesis of diazo compounds. Nowadays, diazo compounds are scarcely used in the industry because they exhibit some toxicity, potential explosibility and instability, which restrict their storage. Flow chemistry may constitute an alternative to use them since their synthesis, purification and reaction is continuously made on small quantities at a time and do not require any manipulation from an operator. Hence, the hazards arising from the scale up of the cyclopropanation reaction are highly reduced.

Chiral quaternary centers possessing a bond to nitrogen are an important class of amine compounds, however, methods for their enantioselective preparation remain sparse. The focus of my graduate research described herein has been the development of a novel rhodium-catalyzed regio- and enantioselective allylic aryl amination of tertiary trichloroacetimidates for the synthesis of amine-bearing quaternary centers (also termed α,α-disubstituted amines). Prior to our work, allylic carbonates and acetates had been successfully utilized in transition-metal catalyzed substitution reactions with anilines for the asymmetric synthesis of tertiary centers. In contrast, these electrophiles have not proven useful in dynamic kinetic asymmetric transformations (DYKAT) that yield enantioenriched amine products, and no reports describing the asymmetric preparation of α,α-disubstituted allylic aryl amines via allylic substitution are noted. Many of the ideas for development of our rhodium-catalyzed amination method were based upon the findings of Overman where linear allylic trichloroacetimidates are utilized in [3,3]-sigmatropic rearrangements and substitution reactions by oxygen nucleophiles under palladium (II) catalysis. Our method diverges from this previous work by application of branched allylic trichloroacetimidates where the olefin component is mono-substituted, and the use of a transition-metal complex capable of facile oxidative addition to an intermediate organometallic complex. We hypothesized that bidentate chelation of these substrates at the imidate nitrogen and the relatively unimpeded olefin by a rhodium (I) complex would lead to rapid ionization to an activated complex and competent electrophile for substitution by neutral aniline nucleophiles. This premise was supported by many control studies and resulted in the development of a highly regioselective amination of branched allylic trichloroacetimidates for the operationally simple synthesis of α-substituted and α,α-disubstituted allylic aryl amines. Work followed utilizing chiral diene ligands that rendered the reaction enantioselective for preparation of enantioenriched tertiary and quaternary amine-containing centers. A highlight of these studies is the first example of DYKAT using a tertiary electrophile and an aryl amine nucleophile. The reaction is of broad substrate scope, is tolerant of varied functionality and substitution patterns on the nucleophilic partner, and solves regioselectivity issues often encountered with some substrate and aniline classes. I end by showing the synthetic utility of our rhodium-catalyzed reaction by applying this method to the synthesis of enantioenriched amino acids and construction of 7-membered nitrogen-containing heterocycles by a 2-step DYKAT amination and olefin hydroacylation sequence.

This thesis documents the development of rhodium-catalyzed traceless chelation-controlled hydroacylation reactions for the synthesis of a variety of ketone products. <strong>Chapter 1</strong> provides an overview of rhodium-catalyzed hydroacylation chemistry, focusing on the origin of chelation-controlled strategies and the benefits thereof. <strong>Chapter 2</strong> describes a sequential reaction involving alkene hydroacylation, sulfide elimination and boronic acid conjugate addition, which affords products with the initial sulfide coordinating group replaced by a stereochemically defined aryl group. <strong>Chapter 3</strong> demonstrates a sequential process involving alkyne hydroacylation, boronic acid conjugate addition and sulfide elimination, which provides enantioenriched β'-arylα,β-unsaturated ketones in a highly efficient and selective manner. <strong>Chapter 4</strong> illustrates a versatile chelating group, triazene, for hydroacylation reactions. Subsequent functionalization of aromatic C-H bonds, promoted by the same chelating unit, offers highly substituted phenyl ketone products. <strong>Chapter 5</strong> documents experimental procedures and data.

This bachelor thesis covers the initial development of a synthesis of fullerene dimers using two different types of linking reactions. Different setups for [3+2] cycloadditions to fullerenes (Prato reaction) were tested, and for that purpose, an N-alkylated amino acid was synthesised. Hydroarylation of fullerene using Rh-catalysis was also studied, using both MIDA protected and unprotected boronic acids, as well as by using cycloaddition products. A range of model compounds in form of fulleropyrrolidenes were synthesised. Products were puried with HPLC and analysed with MALDI-MS and 1H NMR. A range of new compounds were synthesised and characterisation of them was begun. With MALDI-MS, indications that the fullerene dimer had formed were found. Using synthesised model compounds, by-products of the hydroarylation reaction were identied. / Denna kandidatuppsats behandlar påborjandet av syntesutvecklingen för bildandet av fullerendimerer genom användandet av två olika sorters länkningskemi. Olika förhållanden och reagens for [3+2]-cykloaddition till fullerener (Pratoreaktionen) studerades, och i samband med det syntetiserades en N-alkylerad aminosyra. Hydroarylering av fullerener med hjälp utav rodiumkatalys studerades även, genom reaktioner med både skyddade och oskyddade borsyror, inklusive fulleropyrrolidiner. Produkter har renats upp med HPLC och analyserats med MALDI-MS och 1H NMR. En uppsättning nya substanser har syntetiserts, men karaktäriseringen av dessa har inte slutförts. Genom användning av MALDI-MS har indikationer att fullerendimer bildats framkommit. Genom att använda syntetiserade modellsubstanser har biprodukter från hydroaryleringsreaktionen identierats.

Carbon-carbon bond formation is one the fundamental reactions in organic synthesis. The quest for the development of new and more efficient processes for the construction of this bond has been an ongoing focus for years. The transformations that permit the use of simple precursors to access complex structural architectures in the absence of stoichiometric quantities by-products are highly desirable. Hydrogen is a cheapest and cleanest reductant available to the mankind. The catalytic hydrogenation has been widely utilized in the industry, however the construction of the carbon-carbon bond under hydrogenative conditions has been achieved only for alkene hydroformylations and Fisher-Tropsh process and limited to the use of carbon monoxide. The extension of the hydrogenative carbon-carbon bond formations beyond aforementioned processes would be of a great significance to the synthetic community. The overview of allene use in the metal catalyzed reactions to achieve carbonyl and imine allylation and vinylation is presented in Chapter 1. The following chapter vii discusses the development of metal catalyzed hydrogenative and transfer hydrogenative coupling of allenes and carbonyl compounds to afford allylation products. These studies have resulted in the development of the first carbonyl allylation from the alcohol oxidation level. Chapter 3 discusses efforts towards achieving highly enantioselective hydrogenative coupling of alkynes to carbonyl compounds. / text

The carbonylation of methanol to acetic acid is one of the most important applications in homogeneous catalysis. The first chapter comprises a review on the mechanistic studies into the catalytic cycle of the ‘Monsanto process’ and includes some of the most prominent studies into the use of phosphines in the rhodium-catalysed carbonylation of methanol. The second chapter of this thesis reports on an investigation into the application of rhodium complexes containing several C4 bridged diphosphines, namely BINAP, dppb, dppx and dcpb as catalysts for hydrogen tolerant methanol carbonylation. An investigation into the structure, reactivity and stability of pre-catalysts and catalyst resting states of these complexes has also been carried out. The origin of this hydrogen tolerance is explained based on the differing reactivities of the Rh acetyls with hydrogen gas, and by considering the structure of the complexes. In the third chapter I report on an investigation into how electronic properties and coordination mode affect the elimination of phosphonium salts from rhodium complexes. The stability of a range of monodentate, bidentate and tridentate rhodium-phosphine complexes was tested. I also report on the formation of a novel bidentate complex containing a partially quaternised TRIPHOS ligand and investigate the mechanism of formation using 13CH3I. Strong evidence is also presented supporting a dissociative mechanism as the means of phosphine loss from the rhodium centre. In the final chapters I report an investigation into the stability of rhodium-aminophosphine ligand complexes and into increasing the solubility of potential rhodium pre-catalysts through the use of amine-containing phosphine ligands.