Não consta resumo na publicação. / Abstracts nor available.

The objective of the research described in the first part of this thesis involves the application of carbon monoxide and transition metals in key steps of a synthetic route to lavendamycin, an antic cancer compound, and its analogues. Lavendamycin is a pentacyclic compound that possesses a quinoline-5,8-quinone AB ring linked to a b- carboline CED ring. The development of general routes to the synthetic equivalents of the lavendamycin AB quinoline system together with a linker atom, quinoline -2- carboxaldehydes, as well as to the lavendamycin DE indole ring system, namely tryptophan derivatives, was addressed. The Pictet-Spengler cyclisation approach towards lavendamycin involves the reaction between quinoline-2-carboxaldehyde and tryptophan methyl ester to furnish the pentacyclic precursor of the methyl ester of lavendamycin. This synthetic approach requires the availability of quinoline-2-carboxaldehydes, previously prepared by the oxidation of 2-methylquinolines with toxic selenium dioxide. A general strategy towards the synthesis of the AB ring moiety utilising a pre-formed ring system such as commercially available 8-hydroxyquinoline has been successfully developed. It involved the high pressure palladium catalysed formylation of 2-bromo or other suitable 2-substituted quinoline derivatives under syngas (1:1 CO:H2). The preparation of the required 2-substituted quinoline derivative involved the methylation of the 8-hydroxylgroup followed by N-oxidation and then a rearrangement step. In both the Pictet-Spengler and Bischler-Napieralski synthetic approaches to lavendamycin, the CDE ring moiety is introduced using tryptophan methyl ester as building block. The application of this approach to the synthesis of lavendamycin analogues with a substituted D-ring required the availability of substituted tryptophan methyl esters. A general strategy towards the tryptophan derivatives starting with a Wittig reaction between a suitable 2-nitrobenzaldehyde precursor and 1,3-dioxolan-2- yl-methyltriphenylphosphonium bromide, followed by a two-stage, one -pot rhodium catalysed hydroformylation/reduction reaction, has been successfully developed. This methodology yielded ten different possible tryptophan precursors in moderate to good yields. The second part of the research described in this thesis included the identification of factors effecting the rate and regioselectivity of palladium catalysed methoxycarbonylation of a-olefins. The results showed that fast reactions under polar conditions give mainly linear esters. However, reactions under less polar conditions are slower, yielding mainly branched esters. Detailed analysis of the results suggest the operation of a so-called “cationic” mechanism (involving cationic palladium intermediates) in the formation of mainly linear esters, but the operation of a so-called “neutral” mechanism (involving neutral palladium intermediates) in the formation of mainly branched esters. The nature of the phosphine ligands was found to play a significant, but secondary role in determining regioselectivity of methoxycarbonylation. Another objective was the optimisation of the palladium catalysed hydroformylation of a-olefins. An evaluation of the efficiency of the palladium catalysed hydroformylation process required a comparison with the hydroformylation processes based on cobalt and rhodium. Variation of ligands (diphosphines of the type R2P(CH2)nPR2), solvents, acids, etc. had a dramatic effect on the products and the rate of the reaction. In the presence of trifluoroacetic acid 1-pentene is converted to C-6 aldehydes, while in the presence of trifluoromethanesulfonic acid 1-pentene is converted to C-11 ketones. Corresponding results were obtained with 1-octene as substrate. The palladium catalysts were found to also effect isomerisation of the a- olefin into internal olefins, but isomerisation was not a rate limiting process with respect to the hydroformylation reaction. Palladium catalysed isomerisation reactions occurred at a slower rate than the corresponding cobalt catalysed isomerisation process. However, with rhodium no isomerisation occurred. The comparison between cobalt, rhodium and palladium showed that rhodium is the best catalyst for the hydroformylation of a-olefins. The pressures and temperatures required for this process are much lower than that required for palladium and cobalt. The ligand used is triphenylphosphine, which is relatively inexpensive and non-toxic,in contrast with the more expensive ligands required for the cobalt and palladium hydroformylation processes. The use of palladium opens up the unique possibility of converting a-olefins into “dimeric” ketones, which show promise as precursors for the new class of geminidetergents. / Prof. C.W. Holzapfel

This thesis describes the efforts towards the synthesis of the guaiane-6,12-olide skeleton, which characterises the guaianolide family of bioactive natural compounds. Two approaches have been investigated: the intramolecular hetero Diels Alder (IMHDA) reaction and the intramolecular carbonyl ene reaction. This thesis has been divided in three sections: the first part gives a general background about the guaianolides, the second section describes the synthetic approaches we investigated and, finally, the third section reports the experimental details. The first section gives a brief overview about the biosynthesis, the biological activities of the guaianolides, and the most interesting synthetic approaches to obtain them. The second section describes the two different approaches we investigated and gives a theoretical background about the main chemical transformations used. At first, the IMHDA reaction approach is described: a brief overview of palladium catalysis and Diels Alder reaction is given, and it is followed by the results and discussion of our study. Similarly, a theoretical background of the Alder ene reaction is given, before the results and discussion of the intramolecular carbonyl ene reaction approach are described: particular importance is given to the reasoning that led to the assignment of the relative configuration of the cycloadducts obtained, and to the rationalisation of this stereochemical outcome. Finally, the third section gives a complete description of the experimental procedures followed, and of the experimental data for the synthetic studies performed in the previous chapter.

In modern synthetic organic chemistry, chemists are driven to develop efficient methods for important C-C and C-N bond formation reactions. The challenge lies with establishing new uses for readily available substrates. In this regard, the synthesis of β-aminocarbonyl compounds from alkenes remains a long-standing challenge. Innovation in reaction discovery often requires finding new reagents, or rare reagents with underappreciated value in synthesis. In Chapter 1, N-isocyanates and other heterocumulenes are introduced as versatile amphoteric reagents. Their amphoteric properties are valuable in the discovery of new synthetic approaches, especially in cycloaddition reactions. While C-isocyanates are bulk industrial chemicals, the formation and reactivity of N-isocyanates remains underexplored. Chapter 2 describes the development of reactivity with rare imino-isocyanates. This includes methods to access the reagent in situ with a blocking group approach, and the establishment of intermolecular cycloaddition reactivity with a variety of alkenes. This stereospecific reaction provides complex N,N’-cyclic azomethine imines, and enables access to β-aminocarbonyl compounds from alkenes. β-Amino amides and esters, pyrazolidinones, and pyrazolones were accessed by reductive derivatization of the aminocarbonylation products. Exploration into the limits of this reactivity gave insight into fundamental properties of imino-isocyanates. This includes the first detection of imino-isocyanates by IR spectroscopy. A kinetic resolution of the azomethine imines obtained from this alkene aminocarbonylation reaction was then developed, which gave access to enantioenriched β-amino carbonyl compounds (Chapter 3). This was accomplished by Brønsted acid catalysed reduction, with a selectivity factor of 13-43. This was the first example of the enantioselective reduction of azomethine imines, and represents a new activation mode for reactions of N,N’-cyclic azomethine imines. Using this reductive method, both enantiomers of the β-amino amide could be obtained from a racemic azomethine imine in ≥ 97% ee. The discovery of new reactivity of imino-isocyanates with imines in described in Chapter 4, which allowed the synthesis of eight new azomethine imines with the triazolone core. Our initial scope studies revealed different trends with imines than with alkenes, including increased reactivity, which led to investigation of the mechanism of this reaction. In addition, this was shown to be a valuable new approach for the synthesis of triazolones from imines.

Quinoxaline-functionalized, cage-annulated oxa- and thiacrown ethers have been synthesized as possible specific metal host systems. The synthesis and characterization of quinoxaline-functionalized, cage-annulated oxa- and thiacrown ethers have been described. The characterization of these host systems have been fully achieved in solution by using various techniques such as IR, 1H NMR, and 13C NMR spectroscopic methods, high-resolution mass spectrometry (HRMS), elemental microanalysis, and X-ray crystallographic analysis in case of one quinoxaline-functionalized, cage-annulated oxacrown ether compound. The synthesis of the diphosphine ligand 2,3-bis(diphenylphosphino)-N-p-tolylmaleimide (bmi) is described. The substitution of the MeCN ligands in the activated cluster 1,2-Os3(CO)10(MeCN)2 by the diphosphine ligand bmi proceeds rapidly at room temperature to furnish a mixture of bridging and chelating Os3(CO)10(bmi) isomers and the ortho-metalated product HOs3(CO)9[μ-(PPh2)C=C{PPh(C6H4)}C(O)N(tolyl-p)C(O)]. Thermolysis of the bridging isomer 1,2-Os3(CO)10(bmi) under mild conditions gives the chelating isomer 1,1-Os3(CO)10(bmi), whose molecular structure has been determined by X-ray crystallography. The kinetics for the ligand isomerization have been investigated by UV-vis and 1H NMR spectroscopy in toluene solution over the temperature range of 318-348 K. On the basis of kinetic data conducted in the presence of added CO and the Eyring activation parameters, a non-dissociative phosphine migration across one of the Os-Os bonds is proposed. Orthometalation of one of the phenyl groups associated with the bmi ligand is triggered by near-UV photolysis of the chelating cluster 1,1- Os3(CO)10(bmi).

Flash photolysis techniques were applied to studies of solvent displacement by Lewis bases (L) from solvated metal carbonyl complexes of Cr, Mo, and W. On the basis of extensive studies of the reaction rate laws, activation parameters , and linear-free-energy-relationships, it was concluded that the mechanisms of solvent displacement reactions depend on the electronic and steric properties of the solvents and L, as well as the identities of the metal atoms. The strengths of solvent-metal bonding interactions, varying from ca. 7 to 16 kcal/mol, and the bonding "modes" of solvents to metals are sensitive to the structures of the solvent molecules and the identities of the metal centers. The results indicate dissociative desolvation pathways for many arene solvents in (solvent)Cr(CO)_5 (solvent = benzene, fluorobenzene, toluene, etc.) complexes, and are consistent with competitive interchange and dissociative pathways for (n-heptane)M(CO)_5. Different types of (arene)-Cr(CO)_5 interactions were suggested for chlorobenzene (CB) vs. fluorobenzene and other non-halogenated arenes, i.e. via σ-halogen-Cr bond formation in the CB solvate vs. π-arene-Cr bond formation through "isolated" double bonds in solvates of the other arenes. The data also indicate the increasing importance of interchange pathways for solvent displacement from the solvates of Mo and W vs. that of Cr.

The reaction between the formamidine ligand PriN=CHNHPri and the activated cluster Os3(CO)10(MeCN)2 has been studied. A rapid reaction is observed at room temperature, yielding the hydride clusters HOs3(CO)9[μ-OCNPriC(H)NPri] and HOs3(CO)10[μ-NPriC(H)NPri] as the principal products. The spectroscopic data and X-ray diffraction structures of those formamidinate-substituted clusters will be present. The thermal reactivity of the clusters has been investigated, with the face-capped cluster HOs3(CO)9[μ-NPriC(H)NPri] found as the sole observable product. The relationship between these three clusters has been established by kinetic studies, the results of which will be discussed.

No description available.

Pulsed laser flash photolysis of M(CO)6 (M = Cr, W) in cyclohexane with a small amount of benzene results in three sequential reactions. The first is the photodissociation of the parent to yield a M(CO)5:C6H12 complex, which takes place faster than the time resolution of our experiments. The second reaction is the replacement of the cyclohexane ligand with benzene to form a M(CO)5:C6H6 complex, in which benzene is coordinated to the metal via one side of the ring. This complex then falls apart in solution as M(CO)5 coordinates with a trace impurity in the solution that is likely water. Kinetic studies over a range of temperatures result in the following activation energies: 39 kJ/mol for the dissociation of W(CO)5:C6H6; 30 kJ/mol for conversion of Cr(CO)5:C6H12 to Cr(CO)5:C6H6; 33 kJ/mol for the dissociation of Cr(CO)5:C6H6. DFT calculations of binding energies for each complex suggest that all reactions proceed through a combination of an associative and dissociative mechanism. Further calculations of carbonyl vibrational frequencies for 13 weak metal–solvent complexes using three different density functionals: B3LYP, M06, and M06-L allowed us to calculate scale factors for predicting experimental vibrational frequencies. The scale factors are: 0.952 for B3LYP, 0.943 for M06, and 0.957 for M06-L. Using these scale factors leads to average errors in predicted experimental vibrational frequencies of less than 1% for each functional.

The Parkin group has recently synthesized tris[(1-isopropylbenzimidazol-2-yl)dimethylsilyl]methane, [TismPriBenz]H, a bulky tetradentate tripodal ligand, which upon deprotonation can coordinated to form a variety of carbatrane metal complexes.The [TismPriBenz] ligand has been previously shown to stabilize metal hydride complexes, for example [TismPriBenz]MgH and [TismPriBenz]ZnH, and the ligand also has been incorporated in complexes featuring all of the non-radioactive Group 12 and Group 13 metals, as well as a large range of transition metals. However, the reactivity of these complexes towards carbonyl compounds is largely unexplored. Additionally, beyond [TismPriBenz]Li, there has been no attempt to introduce the heavier alkali metals into the [TismPriBenz] framework, which could potentially provide more reactive starting materials to generate other previously inaccessible metal complexes of the ligand; for instance, prior to this report, there has been no example of a lanthanide complex of [TismPriBenz]. In Chapter 1, the reactivity of [TismPriBenz]MgH and [TismPriBenz]MgMe towards ketones, aldehydes, and esters is explored. Generally, these magnesium complexes are able to insert a C=O double bond into a Mg–Me or Mg–H bond respectively, providing access to a large class of magnesium alkoxides. Specifically, [TismPriBenz]MgR (R = H, Me) can insert benzaldehyde and benzophenone to give [TismPriBenz]MgOCRHPh or[TismPriBenz]MgOCRPh₂ respectively. Additionally, [TismPriBenz]MgMe has shown rare reactivity towards methyl ketones, in that it forms the magnesium enolate compounds [TismPriBenz]MgC(Me)=CH₂ and [TismPriBenz]MgC(Ph)=CH2 upon treatment with acetone or acetophenone. In fact, [TismPriBenz]MgC(Me)=CH₂ is only the fourth acetone enolate complex to be structurally characterized, and the first such magnesium example. In the presence of the ester compounds methyl formate and ethyl acetate, [TismPriBenz]MgH and [TismPriBenz]MgMe are able to follow the insertion of the carbonyl with immediate elimination of either an aldehyde or ketone to yield the simple alkoxides [TismPriBenz]MgOMe and [TismPriBenz]MgOEt, a reaction with little precedence in the literature. [TismPriBenz]MgMe is also able to prompt the Claisen condensation of ethyl acetate, forming the first [TismPriBenz] complex with a 6-member chelating ring, [TismPriBenz]Mg(κ²-OC(Me)HC(O)OEt). These various alkoxides have demonstrated the ability to catalyze the Tishchenko reaction, the dimerization of an aldehyde to make an ester, and have also shown promise as catalysts for hydroboration and retro-aldol reactions. Lastly, the [TismPriBenz]Mg compounds have shown interesting reactivity towards O₂, leading to the isolation of both the rare peroxide dimer {[TismPriBenz]Mg}₂(μ-O₂) and the alkyl peroxide [TismPriBenz]MgOOMe. In Chapter 2, the reactivity of the complex [TismPriBenz]Tl is further developed, providing access to previously known methyl and iodide compounds of magnesium, zinc, and cadmium. Additionally, [TismPriBenz]Tl has been shown to react directly with the alkali metals sodium, potassium, and rubidium to form the novel alkali metal complexes [TismPriBenz]M (M = Na, K, Rb). Furthermore, [TismPriBenz]Li can react with CsF to afford [TismPriBenz]Cs, completing the non-radioactive Group 1 [TismPriBenz]M series. This makes [TismPriBenz] one of only a handful of organic ligands to have structurally characterized compounds with all of the alkali metals from Li to Cs, and the only ligand that formsmonomeric complexes in each case. [TismPriBenz]K was also used as a starting material to synthesize the first [TismPriBenz] lanthanide complexes, [TismPriBenz]YbI and [TismPriBenz]YbCl₂. [TismPriBenz]YbI itself can further react with KN(SiMe₃)₂ and NaCp to give [TismPriBenz]YbN(SiMe₃)₂ and [TismPriBenz]YbCp respectively. Lastly, the ability of the [TismPriBenz]Zn halide series to form ion pair complexes was investigated. [TismPriBenz]ZnI can react with ZnI₂ to afford {[TismPriBenz]Zn}₂[Zn₃I₈], which contains the novel zinc halide species [Zn₃I₈]²⁻. Additionally, all of the [TismPriBenz]ZnX (X = Cl, Br, I) complexes are able to react with excess ZnX₂ in THF to give the series {[TismPriBenz]Zn}[Zn(THF)X₃].