The synthesis of novel C9-halogenated anthracyclinones by Lewis acid promoted cyclisations of ortho-methallyl anthraquinonyl chiral dioxanes has been investigated. Tin tetrachloride-N,N-dimethylformamide promoted cyclisation of the dioxane (30) proceeded with excellent stereoselectivity to give an 82% yield of the diastereomerically pure chlorotetracycle (78). Stronger Lewis acids gave poorer selectivity and boron trifluoride etherate reacted slowly with (30) but with high selectivity to give the diastereomerically pure fluorotetracycle (91) in 58% yield. The presence of a β-methoxy group in the substrate leads to decreased stereoselectivity due to competition between chelation and non-chelation controlled pathways. Stereochemistry was assigned to the products using a combination of X-ray crystallography, conformational analysis, nuclear Overhauser enhancements and chemical degradation. Attempts were made to extend the highly selective acetal cyclisation methodology to the intramolecular reaction of the allylsilane (121), cyclisation of which was expected to provide enantioselective access to the alkene (146). The synthesis of (121) was achieved despite its instability, but attempted cyclisations with Lewis acids or fluoride ions were unsuccessful. The racemic alkene (146) was prepared by an ene cyclisation and subjected to asymmetric dihydroxylation (AD). The products from the AD reactions are of considerable biological interest and have been characterized. Their stereochemistry has been assigned by 1H nmr comparisons with the parent diphenols, which have resulted in revisions of assignments made by earlier workers.

This thesis contains two parts. The first part describes the synthesis of orthogonally protected L-2,3-cis-3,4-trans-DHP 1.44 in eleven steps starting from L-arabinose via double displacement of bis-mesylate 2,8. The second part describes the synthesis of the spiroacetal fragment of the alkaloid broussonetine H. (±)-2-(3-Bromopropyl)-1,7-dioxaspiro[5.5]undecane (3.38) was prepared in nine steps from 1,4- butanediol (1.49), propargyl bromide (3.33) and δ-valerolactone (1.51). Enantioenriched material, namely (2S)-2-(3-bromopropyl)-1,7-dioxaspiro[5.5]undecane (4.2) was synthesized in thirteen steps from (2S)-pentane-1,2,5-triol (4.14), trimethylsilylacetylene (4.22) and δ-valerolactone (1.51). The enantiomeric excess of the derived alcohol, (4S)-3-(1,7-dioxaspiro[5.5]undec-2-yl)propan-l-ol (4.28) was measured by its conversion into a Mosher ester derivative 4.28. This thesis also describes the progress towards the synthesis of the dihydroxypyrrolidine fragment 5.28 of broussonetine H from L-sorbose (1.48).

The chemistry of transition metal silyl complexes still remains relatively undeveloped despite the recent advances that have been made in this area. This thesis describes the synthesis and reactivity of new ruthenium and osmium silyl complexes. A general survey on the bonding, preparation and reactivity of transition metal silyl complexes is given in chapter one as an introduction to the chemistry discussed in the following chapters. Several reviews relating to transition metal-silicon chemistry have been published, 1-5 and therefore only the major features and more recent developments are highlighted in this overview. Emphasis has been placed on those aspects not previously reviewed. Coordinatively unsaturated transition metal silyl complexes are uncommon and the chemistry of these complexes has been virtually unexplored. The synthesis of the novel coordinatively unsaturated ruthenium and osmium silyl complexes, M(SiR3)Cl(CO)(PPh3)2 (M=Ru, Os; R=Cl, alkyl group, alkoxy group), is described in chapter two. The reaction of M(Ph)Cl(CO)(PPh3)2 (M=Ru, Os) with a silane, in some instances, provided a facile, high yield route to complexes of the type M(SiR3)Cl(CO)(PPh3)2 (M=Ru; SiR3=SiMe3, SiEt3, SiCl3, SiMe2Cl; M=Os; SiR3=SiCl3, SiMe2Cl). The chlorosily1 complexes were also prepared by treatment of MHCl(CO)(PPh3)3 (M=Ru, Os) with HSiCl3 and HSiMe2Cl. X-ray crystal structures were obtained of Ru(SiEt3)Cl(CO)(PPh3)2 and Os(SiCl3)Cl(CO)(PPh3)2. Complexes containing chlorosily1 ligands proved synthetically useful, undergoing a variety of nucleophilic substitution reactions at silicon with retention of the transition metal-silicon bond. New complexes synthesized by this method included Ru[Si(OEt)3]Cl(CO)(PPh3)2 and Os(SiMe3)Cl(CO)(PPh3)2. X-ray crystal structures of these two compounds were also obtained. These exchange reactions illustrate a route to new transition metal silyl compounds that has rarely been utilised. Also described in chapter two is the unprecedented formation of the novel compound Os(SiMe2C6H4PPh2)(C6H4PPh2)(CO)(PPh3), resulting from phenylation at silicon. The structure of this complex was determined by X-ray crystallography. In chapter three, addition of the Lewis bases CO and CN(p-tolyl) to coordinatively unsaturated silyl complexes, M(SiR3)Cl(CO)(PPh3)2 (M=Ru, Os), is described. The coordinatively saturated osmium silyl complexes Os(SiR3)Cl(CO)L(PPh3)2 (SiR3=SiCl3, SiMe2Cl, SiMe2OEt, SiMe3; L=CO, CNR) were generated in this way. Similarly, addition of 4,4'-dimethyl-2,2'-bipyridine to Ru(SiEt3)Cl(CO)(PPh3)2 afforded Ru(siEt3)Cl(dimethylbipy)(CO)(PPh3). The six-coordinate complex Ru(SiEt3)(η2-S2CNMe2)(CO)(PPh3)2 was synthesized by displacement of the labile chloride ligand from Ru(SiEt3)Cl(CO)(PPh3)2 by the dimethyldithiocarbamate anion. Characterization of Ru(SiEt3)(η2-S2CNMe2)(CO)(PPh3)2 included an X-ray crystallographic analysis. The exchange of silyl groups at the metal was also observed in several reactions. For example, heating Ru(SiMe3)Cl(CO)(PPh3)2 in the presence of excess HSiEt3 yielded Ru(SiEt3)Cl(CO)(PPh3)2. These reactions illustrate aspects of the chemistry that can occur at the metal centre of coordinatively unsaturated transition metal silyl complexes. Another route to coordinatively saturated osmium silyl complexes was via oxidative addition of a silane to Os(CO)2(PPh3)3, which yielded Os(SiR3)H(CO)2(PPh3)2 (SiR3=SiMe3, SiEt3, SiPh3, SiPh2H). The synthesis of these complexes is also discussed in chapter three. An X-ray crystal structure determination of Os(SiEt3)H(CO)2(PPh3)2 confirmed the presence of mutually trans carbonyl ligands. The first thiocarbonyl-containing transition metal silyl complexes, M(SiMe2Cl)Cl(CS)(PPh3)2 (M=Ru, Os), were prepared by treating M(Ph)Cl(CS)(PPh3)2 or MHCl(CS)(PPh3)3 with HSiMe2Cl. The Si-Cl bond in these compounds reacted readily with nucleophiles, yielding M(SiMe2OR)Cl(CS)(PPh3)2 (OR=OEt, OMe, OH). In contrast to the addition of CO to Os(SiR3)Cl(CO)(PPh3)2, addition of CO to Ru(SiMe2R)Cl(CS)(PPh3)2 (R=Cl, OEt, OMe, OH) and to Os(SiMe2OEt)Cl(CS)(PPh3)2 afforded dihapto-thioacyl complexes, M[η2-C(S)SiMe2R]Cl(CO)(PPh3)2, via a migratory insertion reaction involving the silyl group and the thiocarbonyl ligand. This reaction represents the first formal insertion of CS into a transition metal-silicon bond. The structure of Ru[η2-C(S)SiMe2OEt]Cl(CO)(PPh3)2 was obtained by X-ray crystallography and confirmed that bonding of the thioacyl ligand occurred in a dihapto fashion. These reactions are described in chapter four. When Os(Ph)Cl(CO)(PPh3)2 was reacted with HSiMe3, the formally osmium(IV) silyl complex Os(SiMe3)H3(CO)(PPh3)2 was produced. Few compounds of this type are known. The synthesis, characterization and reactivity of Os(SiMe3)H3(CO)(PPh3)2 are discussed in chapter five. The crystal structure of Os(SiMe3)H3(CO)(PPh3)2 is also depicted. In solution, Os(SiMe3)H3(CO)(PPh3)2 appeared to be in equilibrium with the highly reactive, coordinatively unsaturated species OsH2(CO)(PPh3)2. The reaction of Os(SiMe3)H3(CO)(PPh3)2 with HSiR3 (R=Et, Ph), HSn(p-tolyl)3 and HC2Ph was carried out, using Os(SiMe3)H3(CO)(PPh3)2 as an in situ source of OsH2(CO)(PPh3)2. These reactions afforded Os(SiR3)H3(CO)(PPh3)2 (R=Et, Ph), Os[Sn(p-tolyl)3]2H2(CO)(PPh3)2 and OsH(C2Ph)(CO)(PPh3)3 respectively, most likely via a series of oxidative addition-reductive elimination reactions involving OsH2(CO)(PPh3)2. Transition metal hydroxysilyl complexes are extremely rare. Only three systems have been reported containing a hydroxysilyl group bonded to a transition metal. 6,7,8 Chapter six deals with the formation of compounds of this type. Hydroxysilyl-containing complexes of ruthenium and osmium were obtained via the hydrolysis of M(SiMe2Cl)Cl(CO)(PPh3)2 and M(SiCl3)Cl(CO)(PPh3)2. The complexes M[Si(OH)3]Cl(CO)(PPh3)2 are the first trihydroxysilyl-containing transition metal complexes and therefore represent a new class of transition metal silyl compounds. Characterization of Os[Si(OH)3]Cl(CO)(PPh3)2 included an X-ray crystal structure which showed that, remarkably, no inter- or intra-molecular hydrogen bonding of the type O(H)···O or O(H) ··Cl was associated with the Si(OH)3 group. In contrast, intermolecular hydrogen bonding was found by X-ray crystallography for the dicarbonyl derivative, Os[Si(OH)3]Cl(CO)2(PPh3)2. Subsequent reactions involving Os[Si(OH)3]Cl(CO)(PPh3)2 led to the synthesis of the diosmium tetrahydroxydisiloxane complex, [OsCl(CO)(PPh3)2Si(OH)2-]2O. For example, [OsCl(CO)(PPh3)2Si(OH)2-]2O was isolated after Os(SiCl3)Cl(CO)(PPh3)2 was added to a dichloromethane solution of Os[Si(OH)3]Cl(CO)(PPh3)2. Formation of this tetrahydroxydisiloxane compound is significant and models the first condensation reaction generating a Si-O-Si linkage in the hydrolysis of organochlorosilanes to polysiloxanes. The Si-O-Si linkage was clearly visible in the X-ray crystal structure of [OsCl(CO)(PPh3)2Si(OH)2-]2O. Chapter seven provides a short conclusion, highlighting the important features of the work discussed in this thesis and identifies areas for future investigation.

Reductively triggered internal cyclisation reactions have been investigated as a prodrug system for the hypoxia selective release of aromatic nitrogen mustards. The observed pseudo-first-order rate coefficients of cyclisation of several model 2-aminoaryl-acetamides and propanamides have been measured. Cyclisation was observed to be strongly influenced by stereochemistry, whereas electron withdrawal from the amine-bearing ring resulted in a comparatively modest slowing of the rate of cyclisation. Protonation of the leaving group appeared to increase the rate of cyclisation, while changes in 4-substitution on the leaving amine had little effect on this rate. The cyclisation of 2-(2-aminophenyl) alkanamides was found to be subject to general catalysis by acidic buffer components, and rate determining formation of the tetrahedral intermediate has been proposed. Ring closure reactions of several 2-hydroxylaminophenylalkanamides have been studied by γ-radiolysis. HPLC methods have been developed for the separation of reduction and cyclisation products. Reduction stoichiometry implicates the hydroxylamine as the predominant reduction product of radiolysis of the 2-nitrophenylalkanamide precursors, which varied in the nature of substitution of the nitrobenzyl ring, 4-substitution of the leaving aniline, and overall geometry. Cyclisation via the hydroxylamino was observed to be significantly faster than that of its amino counterparts, and was similarly influenced by changes in geometry. The hydroxylamine undergoes a base catalysed, oxygen dependent reaction under aerobic conditions. This reaction did not appear to be influenced by the geometry of the compound. Substitution of the hydroxylamine-bearing ring with a carboxamide group (CONHR σp = 0.36) lowered the pH at which hydroxylamino-amide cyclisation was slowest, compared with its unsubstituted counterpart. The reaction was found to be aided by electron-withdrawal from the leaving amine. Rate determining breakdown of the tetrahedral intermediate has been proposed. Preliminary investigations have been made on 2-nitrophenyl alkyl esters and a 2,6-dinitrophenylamide prodrug system. Rapid, reductively triggered release of coupled phenols and amines has been observed from the nitro-esters and -amides, respectively. In contrast to amino-amide and hydroxylamino-amide cyclisation, gem-dimethyl substitution did not facilitate reductive release from the nitro-ester. The inability to measure the rates of reductive release in radiolysis solutions suggests that these reactions occur significantly faster than hydroxylamino-amide ring closure. Molecular mechanics calculations have been undertaken to investigate relationships between the geometry of 2-aminoarylalkanamides, and rates of cyclisation. The distance between, and angle of approach of the nucleophilic and electrophilic centres in the calculated minimum-energy conformer did not display a correlation with cyclisation rates. / Whole document restricted, but available by request, use the feedback form to request access.

This thesis is concerned primarily with a study of the oxidation of aromatic steroids employing either chromium trioxide-aqueous acetic acid or chromium trioxide-aqueous sulphuric acid-acetone mixtures. The nature of the chromic acid oxidation of various functional groups is discussed first and this is followed by an outline of the two methods used for the synthesis of the aromatic steroids which were oxidised in this study. The second part of the discussion deals with the oxidation of these aromatic steroids. It was found that chromic acid oxidation of ring-A aromatic steroids containing a strong electron-donating C3-substituent, such as methoxyl, gave the corresponding 9-hydroxy-11-oxo derivative (ketol). However, a ketol was not formed if a C3-methoxyl substituted ring-A aromatic steroid also contained a substituent at C1. When a C3-methoxyl substituent was present, the 6-oxo-ring-A aromatic steroid was a minor oxidation product but such compounds were the major products from the chromic acid oxidation of ring-A aromatic steroids containing a weak C3-electron-donating group, such as acetoxyl. The oxidation of a ring-A aromatic steroid containing a C2-methoxyl substituent gave an almost quantitative yield of the corresponding 6-oxo compound. Suzuki103 has claimed that the major oxidation product of 17β-acetoxy-3-methoxyestra-1,3,5(10)-triene (34b) is 17 β-acetoxy-9α- hydroxy-3-methoxyestra-1,3,5(10)-trien-11-one (123). Physical and chemical evidence are presented to show that this product is in fact the 9β-hydroxy epimer and a reaction pathway for its formation is proposed. An examination of the oxidation products of a ring-B aromatic steroid and a ring-C aromatic steroid shows that no ketols were formed.

The Claisen rearrangement of 1,4-bis(prop-2'-enyloxy)anthraquinone under reducing conditions is investigated. The elaboration of the product of double Claisen rearrangement towards an anthracyclinone skeleton is reported. The insertion of methyl ketone and aldehyde functions into the C-2 and C-3 positions of the anthraquinone skeleton and the subsequent elaboration towards an anthracyclinone skeleton is investigated. Methods for the conversion of hydroxymethylanthraquinones to side chains suitable for anthracyclinone syntheses are reported. A total synthesis of 7,9-didesoxydaunomycinone from 1,4-dihydroxy-2-methylanthraquinone is described.

The rates of bromination of the (E)-cinnamyl halides in acetic acid have been measured so that the electronic effects of a halomethylene group on a π system might be better understood. The relative rates of bromination decrease in the order PhCH=CHCH2F > PhCH=CHCH2Cl > PhCH=CHCH2Br. Rate constants could not be calculated from the kinetic data and reasons for this are discussed in great detail. The earlier literature proposal that this reactivity order was due to hyperconjugation of the C-H bonds of the –CH2X group is shown to be incorrect, and new explanation is proposed in terms of modern molecular orbital theory. A detailed study of the products of bromination of the (E)-cinnamyl halides in acetic acid under the conditions of kinetic measurement is also reported. Product precursors, consistent with the products observed, have been tentatively identified. Several [α,α-2H2] - cinnamyl derivatives, PhCH=CHCD2X, have been prepared and the addition of several electrophiles to these alkenes has been studied.

Chapter one of this thesis reports an investigation of the synthesis of potential amber odorants from abietic acid. The acid catalysed rearrangement of abietic acid afforded two isomeric dienes the structures of which have been elucidated. Compounds containing the diene functionality were found to be unstable. However, removal of the diene system afforded stable compounds which are suited to further synthetic modification. Although the skeletal features possessed by a class of amber odorants were successfully introduced stereochemical control proved difficult. The stereochemistry of two intermediates was unambiguosly assigned by single-crystal X-ray diffraction experiments. The second chapter describes the successful conversion of totarol into conjugated dienolides possessing the B/C-ring present in type A and type C nagilactones. Consequently totarol may be considered as a useful model for the preparation of the biologically active nagilactones. In the course of this work several unusual rearrangements were observed. The products of rearrangement were characterised by 2-D n.m.r. and single crystal X-ray diffraction experiments and reaction mechanisms are proposed. The third chapter of this thesis reports the synthesis of the amber odorant, γ-bicyclohomofarnesal, from podocarpic acid. Analogues in which C-19 is functionalised were also prepared. However these compounds were odorless.

Carbon monoxide adsorption, surface speciation and particle size distributions have been studied in platinum, palladium, and rhodium hydrosol systems using Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and transmission electron microscopy. In transmission electron micrographs of unprotected platinum and palladium hydrosols, particle necklacing believed to arise from sintering during preparation, is apparent. The average particle sizes of all hydrosols studied were in the range of 2 to 12 nm. X-ray photoelectron spectra of the metal hydrosols revealed evidence for (Pt-O)ads, Pt(II) and Pt(IV) oxides on platinum hydrosol particles whereas Pd(II) and Pd(IV) oxides were detected on the surfaces of palladium hydrosol particles. These surface oxides are found to be important in influencing hydrosol surface processes such as CO adsorption as a function of pH, inhibition of CO adsorption by alcohols and surface corrosion products resulting from the addition of iodide and cyanide. Fourier transform infrared spectra of CO-treated metal hydrosols revealed bands due to CO linearly adsorbed on the metal particles at ca. 2070 cm-1 (Pt), 2067 cm-1 (Pd) and 2045 cm-1 (Rh) whereas bands due to bridge-adsorbed (B2) CO were detected at ca.1950 cm-1 (Pd) and 1890 cm-1 (Rh). The use of CO as a spectroscopic probe molecule enabled the study of changes in the surface properties of the metal hydrosols which were induced by changes in the dispersion medium. For example, v(CO)ads was observed to decrease in infrared spectra of CO-treated platinum and rhodium hydrosols as pH was increased by KOH or other dissolved salts yielding alkaline solutions. This suggested a reduction in CO coverage resulting from hydroxyl adsorption and consequent increased oxide growth on the particles. In contrast, CO adsorption on platinum and rhodium hydrosols was enhanced in acidic media possibly as a result of the neutralisation of surface hydroxyls. The spectroscopic behaviour of adsorbed CO on platinum and rhodium hydrosols was only comparable to that of CO adsorbed at an electrode surface in acidic media when protecting agent was present which prevented aggregation of the hydrosol in such media. Inhibition of CO adsorption on platinum hydrosols was induced by the addition of aliphatic alcohols, poly(vinyl alcohol) and poisoning anions such as CN- and SH-. Correlations of v(CO)ads with CO coverage suggested that island formation of adsorbed CO was occurring for CO adsorption on unprotected palladium hydrosols and protected platinum and rhodium hydrosols as a function of pH. In allied investigations, an infrared spectroelectrochemical study of corrosion of a nickel electrode in aqueous cyanide media has revealed that [Ni(CN)4]2- is detected at potentials more cathodic than 200 mV vs. SCE. Cyanide was oxidised to cyanate (OCN-) and then successively to carbon dioxide at potentials more anodic than 200 mV vs. SCE. The appearance of features at 2094 cm-1 (HCN) and 2256 cm-1 (HNCO) were attributed to pH changes associated with the oxidation of cyanide to cyanate. The appearance of a band at ca. 2218 cm-1 in infrared spectra of the thin layer at very high potentials (> 1000 mV vs. SCE) was believed to arise from an unstable nickel(II) isocyanate complex.

Chapter One of this Thesis reports an investigation of the synthesis of diterpenoids (as potential ligands for cyclomanganation reactions) from podocarpic acid, and one from dehydroabietic acid. A number of monocyclic aromatic and chalcone derivatives were synthesised to act as model compounds in the subsequent complexation reactions. The second chapter describes successful complexations of the above ligands containing aldehyde, ketone, ester, or oxime groups as directing functionalities to form the resulting tetracarbonylmanganese sigma adducts in moderate to excellent yield. Attempted complexation of amide-containing ligands proved generally to be unsuccessful. Complexation of ligands containing either two potential sites for manganation or two potential ligating groups were investigated and the structures of the isolated complexes established unequivocally by N.M.R. spectroscopy or by X-ray crystallography. Chapter Three describes the successful coupling reactions of the tetracarbonylmanganese complexes with ethene and with substituted electron-poor olefins to give pentaannulated derivatives of podocarpic acid in very good yields. The stereochemistry of two cyclised alcohols was assigned unambiguously by single-crystal X-ray diffraction experiments. Various methods of activating the tetracarbonyl complexes were investigated, including chemical oxidation, and palladium(II)-mediated or thermally-promoted reactions. Two of the pentaannulated adducts were converted successfully into benzannulated analogues in good yield. Analogous coupling reactions of the activated complexes with ethyne and substituted alkynes are discussed in Chapter Four. Chapter Five reports an investigation of the reactions of the tetracarbonylmanganese complexes with halogen electrophiles such as Br2, ICl, or ICl3. When these reactions were performed in non-protic solvents the corresponding aryl halides were isolated in moderate to excellent yield. However, in protic solvents carbonyl insertion occurred to afford γ-lactones in very good yield. The stereochemistry of one of these lactones was assigned unambiguously by a single-crystal X-ray diffraction experiment. Oxidative cleavage of the C-Mn bond with a number of reagents proved generally to be unsuccessful, the isolation of oxygenated diterpenoids being observed only from reaction with Pb(OAc)4. Chapter Six describes various attempts at functionalising ring C of podocarpic acid derivatives via alternative methods to cyclomanganation. These include an investigation into the formation of η4-dienol ether and η4-diene tricarbonyliron complexes derived from the Birch reduction products of podocarpic acid derivatives; attempted regioselective chlorination and mercuration studies of ring C arenes; functionalisation of chlorinated podocarpic acid derivatives via their tricarbonylchromium complexes; and attempted oxidation of ring C arenes with meta-chloroperbenzoic acid.