Browsing by Author "Lilly, Michael John"

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    Investigations into the stereochemical outcome of intramolecular Diels-Alder reactions : presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University
    (Massey University, 1998) Lilly, Michael John
    The Diels-Alder (DA) reaction is an important tool in synthetic organic chemistry, since it allows the simultaneous formation of two carbon-carbon (or carbon-heteroatom) bonds. The stereoselectivity of intramolecular versions of this reaction is, however, difficult to predict. A systematic study of the intramolecular Diels-Alder (IMDA) reaction has been carried out which provides new insights into factors affecting stereocontrol. Ester tethered substrates were chosen for this investigation because there are relatively few literature examples of this type and esterification provides a versatile way of attaching the diene to the dienophile. Two chiral dienols were prepared and these were used to synthesize a range of precursors for investigating asymmetric induction in ester tethered DA (ETDA) reactions. When a stereogenic centre was incorporated into precursors at the allylic position to the diene terminus, high levels of π-facial stereoselectivity were observed. The amount of stereocontrol was dependent on the size of the stereocontrolling element that was used, but diastereoisomer ratios of up to 96:4:0:0 were achieved. This method of stereocontrol represents a powerful new method for achieving asymmetric induction in IMDA reactions. Conversely, no diastereofacial selectivity was observed when the ETDA precursor lacked a stereocentre at the allylic position. The endo:exo and π-facial stereoselectivity of maleate and fumarate derivatives of the chiral dienols (and achiral examples prepared from (2E,4E)-2,4-hexadien-l-ol) were compared and an explanation of the observed stereoselectivity is proposed. For maleates there was a clear preference for trans-fused exo adducts, whether the dienophile was terminated with a carboxylic acid or a methyl ester group. In contrast to this, cis-fused endo adducts were favoured for chiral fumarate precursors, regardless of the type of functional group that the dienophile was terminated with. In each case the π-facial stereoselectivity was slightly greater for the ester than the corresponding carboxylic acid. These observations undermine previous literature reports which claim that the geometry of the dienophile is not a dominant factor in the endo: exo stereoselectivity of ETDA reactions. It is also counter to the view that carboxylic acids promote the formation of endo adducts, and esters promote exo adducts respectively. Determination of the stereochemistry of the ETDA adducts was accomplished by taking into account the absolute stereochemistry of existing stereogenic centres in the precursors, COSY and NOESY spectra of the adducts, the coupling constants arising at the ring junction, and conformational analysis using molecular models. A tricyclic derivative was prepared from one of the ETDA adducts and nOe difference experiments were carried out on it, which confirmed the stereochemical assignments that were made. Preparation of this derivative serves as a model system for the syntheses of himbacine (which is a lead compound in the treatment of Alzheimer's disease) and velutinal (a powerful antifeedant for the opossum), both of which possess a similar carbocyclic backbone to the tricycle that was formed. The assertion that carboxylic acids form endo adducts in ETDA reactions has gone unchallenged for over twenty years. The most frequently cited evidence for this behaviour involves DA reactions of citraconate derivatives of (2E,4E)-2,4-hexadien-l-ol. Since the results obtained for a range of maleate half esters conflicted with the published results for citraconate half esters, a thorough reinvestigation of the literature examples was carried out. Each of the possible exo and endo DA adducts for the two regioisomeric (2E,4E)-2,4-hexadien-l-yl hydrogen citraconate precursors was prepared and characterized independently, to enable the products formed in the DA reactions to be identified by proton NMR analysis. It was demonstrated that (2E,4E)-2,4-hexadien-l-yl citraconate half esters are thermally labile and break down when heated in refluxing solvent to form citraconic anhydride and (2E,4E)-2,4-hexadien-l-ol. This impacts upon the commonly held belief that (2E,4E)-2,4-hexadien-l-yl citraconate half esters undergo ETDA reactions to form predominantly endo adducts. In fact, the experiments described herein demonstrate that the endo adducts form by way of bimolecular DA reactions between citraconate anhydride and (2E,4E)-2,4-hexadien-l-ol, which occur subsequent to cleavage of the ester tether. In reactions of other citraconate half esters (involving alcohols which are less volatile than (2E,4E)-2,4-hexadien-l-ol) it was possible to isolate the respective alcohols in yields of 54-63%. Steroids are attractive synthetic targets, since rare examples of steroidal natural products with potent biological activity are regularly discovered. Practical synthesis of steroids via transannular Diels-Alder (TDA) reactions is an attractive strategy, since it should be accomplished by simply heating the starting material in an appropriate solvent (which can be subsequently recycled). A more ambitious approach involves the stereocontrolled tandem TDA reaction of a macrocycle containing a bis-diene (in the form of a conjugated tetraene) and a bis-dienophile. Such a reaction would involve the simultaneous formation of four carbon-carbon bonds and eight new stereogenic centres in a single step. A chiral tetraenol and a monoprotected dienedioic acid containing a bis-dienophile moiety have been prepared. Esterification of these materials and selective manipulation of the protecting groups was carried out, but macrocyclisation has yet to be achieved. Progress in this area has set the scene for tandem TDA reactions to be attempted.
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    Synthesis of alkyl quaternary amino celluloses and an investigation of their potential as bile acid sequestrants : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Chemistry at Massey University, New Zealand
    (Massey University, 1988) Lilly, Michael John
    One method of treatment for patients with elevated serum cholesterol levels (hypercholesterolemia) is the oral administration of an anion exchange resin to adsorb bile acids in the gastrointestinal tract. The resins used successfully to date have been mainly synthetic ones, whereas anion exchange derivatives of cellulose have not been shown to be effective. Alkyl quaternary amino (QA) cellulose ion exchangers were prepared from hydroxypropylated regenerated cellulose (HP IndionR). Their capacities for cholate anions were measured in the presence of a background of chloride ions at physiological concentration. It was shown that butyl QA cellulose was ineffective at binding cholate anions. However, alkyl QA celluloses with alkyl groups longer than butyl (octyl and dodecyl) bound cholate anions in preference to the chloride ions and greatly improved capacities were obtained. The capacities of the octyl and dodecyl QA celluloses were dependent on the cross-linking present in the HP Indion used. If the cross-linking was greater than the 15% used in HP5 Indion, then the capacity for binding cholate dropped off. A significant increase in substitution level and decrease in swollen volume were obtained by reprocessing the alkyl QA cellulose ion exchangers and this improved their cholate binding capacities. The alkyl QA celluloses were all prepared by first attaching chemically reactive epoxide groups to HP Indion and then reacting those epoxide groups with a tertiary amine (N,N­ dimethyl-N-alkylamine) to form the quaternary amino cellulose. These two steps were repeated for the reprocessed products. The optimum conditions for epoxidation of HP5 Indion were shown to be 48 hours at 4-6°C in 6% sodium hydroxide with excess epichlorohydrin. In the reprocessing step, where this reaction was used a second time, 24 hours was sufficient to reach maximum epoxidation levels. When coupling the N,N- dimethyl-N-alkylamine to the epoxide cellulose it was necessary to use aqueous ethanol as a solvent. The ethanol concentration was dependent on the size of the alkyl group. For N,N-dimethyl-N-dodecylamine a concentration of greater than 60% ethanol was required. For larger amines considerable hydrolysis of the epoxide groups occured during coupling. This was avoided almost completely in the first coupling step by half-neutralising the amine with hydrochloric acid, to lower the pH and buffer the reaction. The optimum coupling time and temperature were shown to be 10 hours at 70°C. As a result of optimising these processing steps the substitution level obtained for dodecyl QA cellulose was increased from 0.83 to 1.14 meq/g at the end of the first stage and from 1.18 to 1.50 meq/g with the reprocessed product. A range of alkyl QA celluloses were prepared using the optimum conditions found for dodecyl QA cellulose. Octyl and dodecyl QA celluloses prepared on HP7 Indion were shown to have higher capacities for cholate than cholestyramine and colestipol {ColestidR) at cholate concentrations less than 6 mmol/L. The dodecyl QA cellulose had superior capacities at all cholate concentrations (0-15 mmol/L) when measured on the basis of the volume of the ion exchanger used. In contrast, cholestyramine and colestipol had higher capacities for deoxycholate anions than either of the cellulose products, except when the residual concentration of deoxycholate was very low {less than 0.5 mmol/L). Cholestyramine and colestipol bound deoxycholate efficiently (97-99%) when the residual concentration was between 5-10 mmol/L, but not cholate (29-48%). However the alkyl QA celluloses bound deoxycholate and cholate with very high efficiency (82-138%). To compare the efficiencies of the ion exchangers at low concentrations a more sensitive test was developed utilising a mixture of conjugated bile salts, similar in composition to that found in the human duodenum. This was equilibrated with samples of each ion exchanger and then analysed by HPLC. Methyl and butyl QA celluloses were the least effective at reducing the concentrations of the bile salts, however they still performed as well as colestipol. The capacity of octyl QA cellulose was much better than the methyl or butyl QA celluloses, indicating the importance of the hydrophobic alkyl chain. Cholestyramine had a similar capacity to the octyl QA cellulose, except that it was not as effective at binding glycocholate. The most effective product was found to be dodecyl QA cellulose, which reduced the concentration of all of the bile salts to lower levels than any other ion exchanger.