Several camphor and pinane derivatives have been synthesised and evaluated for use as chiral auxiliaries in asymmetric synthesis. Various blocking groups have been attached to the camphor skeleton in attempts to improve stereofacial selectivity; these include α-methoxybenzyl and xylyl groups, and novel stereoisomeric ketal moieties derived from meso- and (R,R)-(-)-2,3-butanediol. Benzylation reactions carried out on the lithium enolates of ester derivatives of the camphor-derived chiral auxiliaries afforded α-benzylated products in 5-60% diastereomeric excess. Stereochemical aspects have been explored using high resolution NMR, X-ray crystallographic and computer modelling techniques, and hydrolysis of selected α-benzylated products has permitted the diasteroselective bias to be confirmed. Opposite configurations at the new stereogenic centre are clearly favoured by the xylyl and ketal blocking groups - an observation rationalised in terms of the presence or absence of chelating potential in the blocking group. Baylis-Hillman reactions carried out on a series of specially prepared camphor-derived acrylic esters containing the ketal blocking group exhibited both low diastereoselectivities (0-30% d.e.) and very long reaction times. Chiral silyl enol ethers, synthesised using both pinane and camphor derivatives as chiral auxiliaries, showed up to 20% diastereomeric excess in MCPBA oxidation, alkylation and Mukaiyama reactions. Attempts to bring the prochiral centre in the silyl enol ether substrates closer to the chiral auxiliary, and thus improve the stereofacial selectivity, proved unsuccessful. The silyl enol ether derivatives, however, display interesting fragmentation patterns in their electron impact mass spectra, which were investigated using a combination of high resolution MS, comparative low resolution MS and metastable peak analysis.

The concept of combining two well established areas of organic chemistry, viz., organosilicon chemistry and the use of chiral auxiliaries, into a viable, alternative method of asymmetric synthesis has only very recently begun to receive attention. At the outset of this investigation, no asymmetric reactions of silyl enol ethers, chiral by virtue of optically active substituents on the silicon, had been reported. A range of novel chiral silyl enol ethers have thus been prepared from a variety of ketones, including pinacolone, cyclohexanone, and α-tetralone, and employing menthol, borneol, and cholesterol as chiral auxiliaries. These preparations have been achieved via several distinct routes, including a novel convergent approach involving the isolation of either the chloro(menthyloxy)dimethylsilane or the (bornyloxy)chlorodimethylsilane. The MS and NMR spectra of these silyl enol ethers were examined in detail and, in the case of the crystalline cholesteryloxy silyl enol ether, the X-ray structure has been determined. The potential of chloroalkoxysilanes to act as general, chiral derivatizing agents has been established by the preparation of diastereomeric silyl acetal mixtures of racemic secondary alcohols (e.g. I-phenylethanol and 2-octanol). The experimental diastereomeric ratios, obtained by GLC and ¹H NMR spectroscopy, approached the expected value of unity, confirming the potential of the alkoxychlorosilanes as chiral probes. The chiral silyl enol ethers have been successfully oxidized to the corresponding α-siloxy ketones employing MCPBA, MMPP, and 2-(phenylsulphonyl)-3-phenyloxaziridine as oxidizing agents and the diastereomeric excesses obtained, which varied from 0 to 16%, indicated some potential for stereochemical control. Alkylation and hydroxyalkylation reactions of the silyl enol ethers have yielded the expected α-iert-butyl and β-hydroxy ketones in good to excellent material yields, with the enantiomeric excesses, as determined by chiral shift reagent studies, reaching 14%. To improve the stereo control in these reactions, attempts have been made to prepare chiral silyl enol ethers with auxiliaries possessing the potential for transition state complex co-ordination in the reactions under consideration. The preparation of such silyl enol ethers, incorporating the proline-derived auxiliaries, N-methyl-2-hydroxymethylpyrrolidine and 2-methoxymethylpyrrolidine met with only limited success. In an alternative approach, three derivatives of 2,3-dihydroxybornane have been prepared. However, two of these auxiliaries, viz., 3-exo-benzyloxy-2-exo-hydroxybornane and 3-exo-(1-methoxyethoxy)-2-exo-hydroxybornane failed to form silyl enol ethers, even under considerably more vigorous conditions than normally employed. The third derivative, 3,3-ethylenedioxy-2-hydroxybornane has been successfully utilized in the preparation of a pinacolone-derived chiral silyl enol ether. Hydroxyalkylation of this compound with benzaldehyde has yielded the β-hydroxyketone with significantly improved enantiomeric excess (26%) and a transition state complex has been proposed to rationalize this improvement.

This thesis describes firstly, a study involving the thermal rearrangement of substituted 6-e̲x̲o̲-(1-alkenyl) bicyclo-[3.1.0]hexenes, and secondly, the application of this type of transformation to a total synthesis of (±)-sinularene (1̲2̲5̲). The 6-e̲x̲o̲-(1-alkenyl)bicyclo[3.1.0]hexenes (1̲8̲7̲, 1̲8̲9̲, 1̲9̲2̲, 1̲9̲4̲, 2̲4̲0̲, 2̲7̲4̲ and 340) were prepared and thermolyzed in sealed tubes to afford the corresponding bicyclo[3.2.1]octa-2,6-dienes (1̲8̲8̲, 1̲9̲0̲, 1̲9̲3̲, 1̲9̲5̲, 2̲4̲1̲, 2̲7̲6̲ and 3̲4̲1̲) in generally excellent yields. With the exception of 1̲9̲0̲, the thermolysis products were subjected to acid-catalyzed hydrolysis to give the respective bicyclo[3.2.1]octenones. From this study, it is clear that a) the Cope rearrangement of substrates, such as 2̲7̲4̲ and 3̲4̲0̲, containing even sterically bulky substituents on the 6-alkenyl side chain presents a viable means of generating functionalized bicyclo [ 3.2.1] octa-2 , 6-dienes, b) this methodology provides for the placement of synthetically useful functionalities on any of the carbon bridges of the bicyclo-[3.2.1]octane skeleton, and c) the transformations 2̲4̲0̲→2̲4̲1̲ and 2̲7̲4̲→2̲7̲6̲ provide strong evidence for the stereospecificity of the rearrangement process. In the total synthesis of (±)-sinularene (1̲2̲5̲), the key step involved the thermal rearrangement of 3̲2̲2̲ to afford the bicyclo[3.2.1]octadiene 3̲2̲1̲. The compound 3̲2̲2̲̲ was readily prepared as follows. 1-Lithio-3-methyl-1-butyne was treated with methacrolein to furnish the allylic alcohol 3̲3̲1̲, which was transformed into the ester 3̲3̲2̲ v̲i̲a̲ an orthoester Claisen rearrangement (hot triethyl .orthoacetate, propionic acid). Hydrolysis of the ester 3̲3̲2̲, followed by reaction of the resultant acid with oxalyl chloride in refluxing hexane gave the corresponding acid chloride 3̲3̲4̲. Treatment of 3̲3̲4̲ with a cold, ethereal solution of diazomethane afforded the diazo ketone 3̲3̲5̲, which in the presence of copper (II) acetoacetonate in refluxing benzene, underwent an intramolecular carbenoid cyclization to furnish the bicyclic ketone 3̲3̲6̲. Semihydrogenation of 3̲3̲6̲ using Lindlar’s catalyst gave stereoselectively the c̲i̲s̲-alkenyl ketone 3̲3̲7̲. The enone 3̲3̲8̲ was obtained by oxidizing the trimethylsilyl enol ether of 3̲3̲7̲ using palladium (II) acetate in acetonitrile. When the enone 3̲3̲8̲ was treated with lithium divinylcuprate, the two epimeric products 3̲3̲9̲ and 3̲4̲6̲ were obtained in a ratio of 9:1, respectively, and were sus-sequently separated by column chromatography. Trapping the lithium enolate of 3̲3̲9̲ with t̲-butyldimethylsilyl chloride led to the required enol ether 3̲3̲2̲. Thermolysis (220°C, sealed tube) of 3̲3̲2̲ in benzene produced exclusively in 86% yield the desired bicyclic triene 3̲2̲1̲. Subjection of 3̲2̲1̲ to hydroboration using disiamylborane gave, after oxidative workup, the alcohol 3̲4̲7̲, which on treatment with p̲-toluenesulfonyl chloride in the presence of 4-dimethylaminopyridine, afforded the ketone 3̲4̲9̲. Successive hydrogenation of 3̲4̲9̲ and Wittig olefination of the resultant ketone 2̲8̲0̲ completed the total synthesis of (±)-sinularene (1̲2̲5̲). [formula omitted] / Science, Faculty of / Chemistry, Department of / Graduate

Sasol endeavors to expand its current business through the beneficiation of commodity feedstreams having marginal value into high-value chemicals via cost-effective processes. In this regard Merisol, a division of Sasol has access to phenolic and cresylic feedstreams, which have the potential to be converted to fine chemicals. Targeted products include para-anisaldehyde, ortho- and para-hydroxybenzaldehyde which are important intermediates for the manufacture of chemicals used in the flavor and fragrance market and various other chemicals. The use of CO technology (HF/BF3) to produce these aldehydes in a two-step process from phenol as reagent is economically attractive due to the relative low cost and other benefits associated with syngas as reagent. The aim of the study was to evaluate and understand this relatively unexplored approach to the formylation of aromatic compounds. The reactivity of both phenol and anisole proved to be much lower than that of toluene. The main aldehyde isomer (para) produced in these HF/BF3/CO formylations as well as of other ortho-para directing mono-substituted benzenes tested in our laboratories were in accordance with published results. Efforts to increase substrate conversion resulted in substantial secondary product formation and mechanistic investigations showed this to be a consequence of the inherent high acidity of the reaction environment. The effect of different substituents on the relative formylation rates of benzene derivatives was investigated. These results showed that methyl groups are activating while halogens are deactivating relative to benzene as substrate. The decrease in reactivity from fluorobenzene> chlorobenzene> bromobenzene is in accordance with formylation trends observed in other acidic systems. Deuterium labeling experiments were applied to gain additional information on the formylation reaction mechanism. This study provided interesting but inconclusive results in support of the so-called intra-complex mechanism. All reported studies as well as our own work suggested that HF and BF3 in (at least) stoichiometric amounts are required for effective formylation with CO. Under these conditions this methodology for effecting aromatic formylation is not economically viable. Industrial application of formylation using CO will require the development of new catalysts or methodology to allow the use of HF/BF3 in a catalytic way. In this regard ionic liquids as a new and ecological-friendly field was explored. Chloro-aluminate ionic liquids promote the carbonylation of alkylated aromatic compounds, but fails in the case of oxygenated aromatics. Aldehyde yields of formylation in the acidified neutral ionic liquids were generally similar compared to reactions conducted in HF as solvent/catalyst. Formylation of anisole and toluene, but not of phenol in the neutral ionic liquids resulted in increased secondary product formation in comparison with hydrogen fluoride used as solvent/catalyst. This difference in behavior is not understood at present, but suggests that phenol is a good substrate for formylation in this medium, particularly with the development of a system catalytic with respect to HF/BF3 in mind. / Prof. C.W. Holzapfel

D.Phil. / The objective of the research described in the first part of this thesis was to develop a general method utilising palladium catalysed reactions for the synthesis of the anti-cancer compound, lavendamycin and analogs thereof. Therefore, the development of a general route to synthetic euivalents of the lavendamycin AB quinoline system, 2-hydroxyquinolines, with potential for coupling to the CDE or CD moiety, was addressed. The first protocol for the synthesis of 2-hydroxyquinolines invloved to the use of appropriately substituted o-nitrophenyltriflates (readily prepared from phenols) in a Heck reaction under neutral conditions followed by a one-pot reduction and cyclisation step. The synthetic potential of such an approach was demonstrated by the preparation of a suitable lavendamycin AB synthon from commecially avalaible guiacol. A second general strategy towards the synthesis of the AB synthon utilising a performed ring system commecially available 8-hydroxyquinoline has been successfully developed. This approach requiring the introduction of a suitable leaving group in the 2-position involved the following sequence of reactions: protection of 8-hydroxyl group N-oxidation, and a rearrangement step. This methodology yielded five different key intermediates all possessing suitable functionality in the 2 position which would allow further cross-coupling to an appropriate CDE ring equivalent.

The new μ-(l,n)-alkanediyl compounds [(ƞ⁵-C₅R₄Me)Fe(CO)₂ ]₂{μ-(CH₂)n}, (R = H, n = 3 -10 and R =Me, n =3 - 6), [Mn(CO)₅]₂{μ-(CH₂)n} (M = Mn, n = 4-6 and M = Re, n= 3 and 4) have been prepared using essentially two synthetic routes. Thus the iron compounds were synthesized by the reaction of Na[(ƞ⁵-C₅R₄Me)Fe(CO)₂ ] with the appropriate dibromoalkane. The manganese and rhenium compounds on the other hand, were prepared by the decarbonylation of the corresponding diacyl compounds of the type, [M(CO)₅]₂{μ-CO(CH₂)nCO} (M = Mn or Re). These diacyl species in turn were synthesized by the reaction of Na[M(CO)s] with diacyl chlorides. All the new compounds have been fully characterized by microanalysis, infrared, ¹H and ¹³C nmr spectroscopy. The mass spectra of the compounds have been investigated and the fragmentation patterns are discussed and compared with other known polymethylene compounds. An extensive investigation into the reactivity of the new alkanediyl compounds has been carried out. Thus for example the reactivity of the compounds [CpFe(CO)₂]₂{μ-(CH₂)n} with nucleophiles such as tertiary phosphines and isocyanides, yield diacyl compounds of the type [CpFe(CO)L]₂{μ-CO(CH₂)nCO} (Cp = C₅H₄Me or C₅Me₅) and (L = tertiary phosphine or isocyanide). Similar ligand induced CO insertion reactions were observed for the manganese and rhenium alkanediyl compounds. The products from these reactions were characterized using the analytical techniques mentioned earlier. The reactions are discussed and compared with those of mononuclear alkyl compounds of manganese, rhenium and iron. The reactions of some polymethylene bridged compounds with synthesis gas have also been investigated. This reaction is of importance in view of the fact that polymethylene bridged compounds have been implicated in a number of catalytic processes e.g the Fischer- Tropsch reaction. The reaction with synthesis gas was found to yield bifunctional alcohols of the type HO(CH₂)nOH. In a separate study, the binuclear μ-phthaloyl compounds of manganese, rhenium,iron,molybdenum,cobalt and rhodium were prepared and characterized. The phthaloyl compounds of manganese, rhenium and iron were decarbonylated to form the corresponding μ-phenylene compounds. The reactions of some of these compounds with nucleophiles and electrophiles have been studied and the results compared with that of the corresponding mononuclear benzoyl and phenyl compounds.

The purpose of this study is to show that the method just proposed can be used for the synthesis of 2-halo benzyl glycosides. And these derivatives can be used to synthesize biologically interesting compounds which were not previously attainable using the 2-halo-2-deoxy methyl glycosides which are currently available.

Carbohydrate research remains one of the most exciting endeavors in the field of organic chemistry. The importance of carbohydrates needs little elaboration. Quite literally, without glucose, cellulose, and starch, the necessities of life such as food, clothing, and shelter would be missing. In our laboratory, we have for some time been interested in one particular class of carbohydrate derivatives - the aldohexopyranosyl cyanides.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 1982 / Includes bibliographical references. / by Lynda Gail Sturgeoff. / Ph. D. / Ph. D. Massachusetts Institute of Technology, Department of Chemistry

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