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The ability to construct C-N bonds is of great importance to organic chemists as exemplified by the vast number of natural products, pharmaceutical agents and fine chemicals that contain such linkages. An atom efficient C-N bond forming reaction namely hydroamination has attracted much interest to date due to its ability in forming amine, imine and enamine functionality. The scope of this project involved the attempted synthesis of a biologically active and nitrogen containing pyrrolizidine alkaloid isolated from cryptic thief ants and poison dart frogs namely 223H (xenovenine). The method of hydroamination was utilized as the pivotal ring forming step and was established as being a valuable synthetic tool towards the construction of 223H (xenovenine). The stereoselective synthesis resulted in the successful formation of ethyl (3R)-5-heptyl-3-methyl-2,3-dihydro-lH-pyrrolizine-7-carboxylate 74, a novel, and structurally analogous precursor to 223H (xenovenine) over 10 synthetic steps from (S)-pyroglutamic acid. The following research also resulted in the synthesis of two other novel compounds namely ethyl 3-[(2R)-2-methyl-5-thioxotetrahydro-lH-pyrrol-l-yl]propanoate 86 and ethyl 3-{(5R)-2-[(E)-2-ethoxy-2-oxoethylidene]-5-methyltetrahydro-lH-pyrrol-l-yl}propanoate 87. A catalytic hydroamination study on the conversion of C-propargyl vinylogous amides into pyrroles demonstrated that transition metal salts of groups 11 and 12 serve as effective hydroamination catalysts. The oxide, acetate, chloride and nitrate derivatives of group 11 and 12 metals namely Cu(II), Ag(I), Zn(II), Cd(II) and Hg(II) were employed as potential hydroamination catalysts in the oxidation states provided. The Zn(II) catalyst series with the exception ZnO provided the greatest hydroamination yields under mild reaction conditions owing to their high Lewis acidities however the Ag(I) and Hg(II) catalyst series also provided excellent yields of product under more forcing reaction conditions. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.

There is enormous interest in the design and development of efficient chiral ligands for asymmetric catalysis, as a result, this field has become one of the most popular areas of research in organic chemistry. This project involved the investigation of the novel chiral pentacyclo-undecane (PCU) diol 54a, PCU bisimine 87 and PCU bis(oxazoline) 100 type ligands. The PCU diol ligand was synthesized, but proved to be difficult to obtain enantiomerically pure which hindered further investigation into this type of ligand. The PCU bisimine ligand 87 was synthesized. However due to its instability it was not further pursued. Synthesis of the PCU bis(oxazoline) ligand 100 was successful. This ligand was complexed to various metal salts and its efficiency as a chiral Lewis acid catalyst was evaluated on the asymmetric Diels-Alder reaction between 3-acryloyloxazolidin- 2-one 52 and cyclopentadiene 33. The anhydrous magnesium perchlorate ligand complex emerged as the best catalyst providing the endo-cycloadduct product 53 in 81 % enantiomeric excess at -40 oC. Optimizations of the possible conformations of the magnesium complex of ligand 100 with the substrate 52 were performed using Density Functional Theory (DFT) calculations. The more energetically favoured complex conformation was established. The Re-face of the dienophile which was less hindered produced the product consistent with the experimentally observed product 16. Based on the calculated bond lengths from the computational model binding of the ether oxygen on the PCU moiety to magnesium was observed. All the novel compounds were fully characterized using NMR, IR and mass spectroscopy as the main tools. / Thesis (M.Sc.) - University of KwaZulu-Natal, Westville, 2008.

Hydroxymethylation catalysis provides a valuable strategy for the high volume production of alcohols from α-alkenes. Generally this involves a hydroformylation-hydrogenation sequence, but the capacity to optimise selectivity for each transformation is limited. Condensation reactions between aldehyde products and alcohol products frustrate process economics. By an alternative scheme, all relevant bond-forming reactions occur in a single mechanism. This thesis describes several approaches to catalyst development and the application of derived systems for the hydroxymethylation of allyl alcohol. A review of auto-tandem hydroxymethylation and domino hydroxymethylation is presented in Chapter 1. In Chapter 2 the synthesis of bis-(diethylphosphine) ligands based on a modular series of chiral alicyclic scaffolds is described. High pressure NMR studies have shown that the catalytically active complex [RhH(CO)₂(L-L)] adopts preferentially ea geometry, with [Rh(CO)(L-L)(μ-CO)]₂ as the primary competing species. Catalyst performance can be correlated with the flexibility of the chelating ring; this favoured a high monomer/dimer ratio which enhances activity, but could not rigidify the configuration of the diethylphosphine groups which inhibits linear selectivity. Deuterium labelling studies were suggestive of a domino hydroxymethylation scheme. From the rhodium-hydroxyalkyl-hydride-carbonyl cation, a reductive elimination furnishes the diol derivatives and a β-hydride abstraction furnishes the hydroxyaldehyde derivatives. Up to 53 mol% selectivity to 1, 4-butanediol was attained. The catalysts could be recycled via biphasic separation, however poisoning by methacrolein caused a decline of activity upon reuse of the solution. An investigation of enhanced specific activity via the meta-effect is the subject of Chapter 3. The effect of systematic meta-substitution in triphenylphosphine upon physicochemical properties was investigated by IR spectroscopy and electrochemistry, both of which showed no significant structural impact on the uncoordinated triarylphosphine. Variable temperature ¹H NMR studies however revealed a change in the solution dynamics of the corresponding Vaska complex. The activation barrier to phosphorus-(ipso)carbon rotation increases as a function of meta-substitution, with rotation of substituted aryl rings past each other being more strained. This should create a well-defined coordination sphere around rhodium, and is proposed to account for the high linear selectivity observed in the hydroformylation of allylic alcohols with [RhH(CO){(3, 5-Me₂Ph)P}₃]. Linear-selectivity reached 96 mol%. Catalyst recycling was executed via biphasic separation, retaining on over twelve cycles an average of ~ 94 % efficiency. The kinetics of allyl alcohol hydroformylation with [RhH(CO){(3, 5-Me₂Ph)P}₃] was found to be well represented by Equation 11 (Section 3.6) A detailed analysis of how substrate-specific the influence of the meta-effect remains to be performed. In Chapter 4 domino hydroxymethylation by multi-component L-L/PEt3/Rh systems is described. The regioselective performance of a diphosphine rhodium catalyst in hydroformylation was translated for hydroxymethylation upon introduction of triethylphosphine at a L-L/PEt3 molar ratio ≥ 1. The highest observed selectivity to 1, 4-butanediol was 66 mol%. Competitive activity of triethylphosphine-modified rhodium species presumably accounts for the reduced linear selectivity observed when L-L/PEt3 molar ratio < 1. Despite aggravated catalyst decomposition at higher triethylphosphine concentrations, heterogeneous hydrogenation does not appear to take place. Deuterium labelling studies also discount a sequential homogeneous hydrogenation. There is evidence for the activation of a tris-phosphine-modified rhodium-acyl-carbonyl complex, but such a species could not be isolated from complexation reactions with a variety of precursors. It would be of interest to determine alternative promotors and to establish whether it is preferential to employ a high concentration of mildly acidic species or a low concentration of highly acidic species. The self-assembly of DNA base pair analogues 2-N-pivaloylaminopyridyl phosphine and isoquinolyl phosphine, each modified with diphenylphosphine, diethylphosphine, dicyclohexylphosphine and bis(3, 5-dimethylphenyl)phosphine, is described in Chapter 5. In the presence of a rhodium precursor, exclusive formation of the heteroleptic complex was observed. Although the intramolecular hydrogen-bonding network is sensitive to temperature and free hydroxyl functionalities, highly regioselective catalysts were generally afforded under the appropriate operating conditions. Only the catalyst based on the bis(dicyclohexylphosphine)-heterodimer performed poorly, presumably due to the formation of mono-phosphine complexes. High chemoselectivity was correlated with the heterodimer acidity constant, however this is rendered non-linear by a trans influence when electronic distinction between the platforms is high. Overall, complexes based on the assembly of a dicyclohexylphosphine platform and a bis(3, 5-dimethylphenyl)phosphine platform were found to be optimal; up to 73 mol% selectivity to 1, 4-butanediol was reached. It has been demonstrated in this thesis that in order to effect linear-selective domino hydroxymethylation of allyl alcohol, two distinct transition state structures must be optimised. High regioselectivity demands an asymmetric rhodium-hydride-dicarbonyl complex, which can be generated by an asymmetric chelate or by rigidifying the configuration of the substituents on phosphorus. Interestingly, chelation geometry in this transition state has little impact on this parameter. It has been shown that domino hydroxymethylation is activated by an electron-rich rhodium-acyl-dicarbonyl. The state of electron density on rhodium can be controlled by the substitution pattern on the phosphorus donors, but can also be changed by the inclusion of a suitable promoter. The chelation geometry in this transition state is more significant; placing the acyl functionality trans to a phosphorus donor concentrates the electronic effect in the rhodium-alkyldiol-hydride-carbonyl cation to such an extent as to impede hydride migration and reductive elimination of the diol, favouring β-hydride abstraction and reductive elimination of the hydroxyaldehyde.

Call number: LD2668 .T4 1958 D63 / Master of Science

A number of oxygenated heterocycles have been described in nature as having a myriad of biological activities. Owing to these biological activities and their complex structure, these compounds are of interest to us and the preparation of selected oxygenated heterocycles is described in this thesis. Three main sections form this thesis, with each representing a class of oxygenated heterocycle. The first part of the thesis deals with pyranonaphthoquinone analogues where a model study was performed to construct the skeleton of the isochromane kalafungin. The synthesis of isochromane 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one was successfully achieved from commercially available 2,5-dihydroxybenzoic acid in an overall yield of 9.5%. The key steps employed in the synthesis of the isochromane were a cross metathesis reaction between (2-allyl-3,6-dimethoxyphenyl)methanol and ethyl acrylate to afford the α,β-unsaturated ester (E)-ethyl-4-(2-(hydroxymethyl)-3,6-dimethoxyphenyl)but-2-enoate which, after several synthetic steps, was converted to the isochromane via a radical induced lactonization using a hypervalent iodine reagent. The success of this route led us to the preparation of iscochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9b-tetrahydro-2Hfuro[ 3,2-c]isochromen-2-one. Our initial aim was to enzymatically resolve intermediate racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol, however, the use of Candida antarctica lipase B (CALB) to facilitate the kinetic resolution was not as successful as we hoped. Therefore, using racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol and the key reaction conditions developed in the model study of 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one, we successfully prepared isochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9btetrahydro 2H-furo[3,2-c]isochromen-2-one in an overall yield of 0.4%, albeit racemically. The second part of this thesis involved the use of nitroalkanes as precursors to spiroketals. In this section, we managed to successfully elucidate the mechanism of a novel Nef reaction previously described in our laboratories using three different substrates. The key steps involved during the elucidation of the mechanism were a Henry condensation reaction and a key modified Nef reaction. The preparation of the spiroketal skeleton of the griseusins was also attempted. The last part of this PhD thesis focused on the formation of angucycline analogues, specifically analogues related to the landomycins. We have successfully managed to prepare landomycin analogues tetraphene-7,12-dione, 3-methoxytetraphene-7,12-dione and 3,8-dimethoxytetraphene-7,12-dione. A Suzuki reaction followed by a Wittig reaction, isomerisation and final ring closing metathesis allowed for the smooth preparation of these analogues. The preparation of related analogues bearing seven-membered rings has also been achieved and is described.

MSc., Faculty of Science, University of the Witwatersrand, 2011 / The 2-isopropenyl-2,3-dihydrobenzofuran moiety is found in many naturally occurring compounds including rotenone, a complex pentacyclic molecule isolated from several leguminous plants of the Derris and Lonchocarpus species. Interest in rotenone stems from the fact that it possesses significant pesticidal and piscicidal properties which have been employed for centuries. Furthermore, as it has three stereogenic centres, rotenone poses an interesting and challenging synthetic target for organic chemists. Although various syntheses of this natural compound have been reported, none of these were stereoselective. The first stereoselective total synthesis of rotenone is described in this dissertation. Initially, a model study was conducted in which the simplest of the natural rotenoids, munduserone, was synthesised. The key step in this transformation involves the use of a platinum catalysed 6-endo-hydroarylation reaction of an alkynone intermediate, thus affording munduserone in 6 steps and an overall yield of 23%. We then attended to the synthesis of the more complex rotenoid, rotenone. Rotenone was synthesised by the initial assembly of a chiral (-)-(R)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol moiety, asymmetrically accessible using a stereoselective Pd π-allyl mediated cyclisation of (E)-4-(2,6-dihydroxyphenyl)-2-methylbut-2-enyl methyl carbonate. Having constructed the dihydrobenzofuran in an enantiomeric excess of 94.8%, the chromene part of rotenone could then be synthesised. To this end, the LDA mediated coupling reaction of the formylated dihydrobenzofuran and 1,2-dimethoxy-4-(prop-2-ynyloxy)benzene, gave a secondary alcohol which was subsequently oxidised to the corresponding alkynone, (-)-(R)-(6,7-dimethoxy-2H-chromen-4-yl)(4-methoxy-2-isopropenyl-2,3-dihydrobenzofuran-5-yl)methanone. A 6-endo-hydroarylation reaction was employed as a mild strategy to construct the chromene moiety, (-)-(R)-(6,7-dimethoxy-2H-chromen-4-yl)(4-methoxy-2-isopropenyl-2,3-dihydrobenzofuran-5-yl)methanone. Finally, a deprotection and a base-catalysed intramolecular oxo-Michael addition concluded the first stereoselective synthesis of rotenone in 17 steps and an overall yield of 0.02%

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. January 1996. / Aspects of the literature of the ant venom alkaloid monomorine I and its stereoisomers were reviewed. Racemic 5-butyl-2-pyrrolidinone was synthesised in two steps from methyl acrylate and 1-nitropentane, A thionation step yielded 5-butylpyrrolidine-2-thione. The Michael addition reaction between 5-butylpyrrolidine-2-thione and ethyl crotonate proceeded with difficulty to form a separable mixture of diastereomers of 5-butyl-l-(2-ethoxycarbonyl-l-methylethyl) pyrrolidine-2-thione. [Abbreviated Abstract. Open document to view full version] / AC2017

The synthesis of alkaloids from enaminones has been used extensively in the University of the Witwatersrand’s organic chemistry laboratories. In this thesis enaminone precursors are one of the main ways of accessing lamellarin analogues. The lamellarin alkaloids are an important family of marine alkaloids, owing to their vast biological properties. A brief background to marine alkaloids and their general potential is given, followed by a review of lamellarin alkaloids, their structural and biological properties and some of the major syntheses carried out over the past few years. Two novel features form the basis of the synthetic methods described in the thesis. The first is an approach to forming the lamellarin alkaloids from enaminone precursors, which are prepared through the Eschenmoser sulphide contraction. The second method uses a novel pyrrole formation, which was initially conceptualized by Garreth L. Morgans in his PhD thesis (2008). The main target of the investigation was lamellarin G trimethyl ether. In Chapter 3, the syntheses of a range of mono-, di- and tetra-substituted phenacyl halides are discussed. The phenacyl halides were used in the preparation of various enaminone precursors. The tetrasubstituted phenacyl halide 2-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone 3.17 is required for the synthesis of our target lamellarin G trimethyl ether. The phenacyl halides are important in both the model synthesis described in Chapter 4 and the synthesis toward lamellarins in Chapter 5. Chapter 4 deals mainly with the synthesis of pyrrolizine systems. Methodology is described for the preparation of a variety of enaminones, pyrroles and tetracyclic lamellarin analogues. The closest pyrrolizine system to lamellarin G trimethyl ether, 11-(3,4-dimethoxyphenyl)-2,3-dimethoxy-9,10-dihydrochromeno[4,3-b]pyrrolizin-6(8H)-one 4.52, was the final and most complex tetracyclic model structure analogous to lamellarin G trimethyl ether. Indolizine and pyrroloazepine adaptations were also demonstrated and tetracyclic systems 10,11-dihydro-8H-chromeno[3,2-a]indolizin-12(9H)-one 4.39 and 9,10,11,12-tetrahydrochromeno[3',2':3,4]pyrrolo[1,2-a]azepin-6(8H)-one 4.40 were successfully prepared, even though the pyrrole formed in an unexpected way. Finally in Chapter 5, the methodology established in the model study was used in the attempted synthesis of lamellarin G trimethyl ether. A second method was also investigated. Thus, various N-alkylated and N-H enaminones were successfully synthesized, from which novel and unexpected pyrrole-containing products 8-(3,4-dimethoxyphenyl)-2,3-dimethoxy-5H-chromeno[3',2':3,4]pyrrolo[2,1]isoquinolin-14(6H)-one 5.28 and (3-ethoxy-8,9-dimethoxy-2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-yl)(phenyl)methanone 5.37 were formed, even though our desired product lamellarin G trimethyl ether could not be attained from either method.

by Lun Kue Sun. / Includes bibliographical references / Thesis (M.Ph.)--Chinese University of Hong Kong, 1986