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    Synthetic studies towards dictyoxetane and the dolabellanes : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Chemistry, Massey University, New Zealand
    (Massey University, 1997) MacKenzie, Karla Ruth
    Dictyoxetane (1) has been isolated from Dictyota dichotoma, a brown alga found in the Indian Ocean. It has an unusual pentacyclic structure which has not yet been synthesised. It is a diterpene which is closely related to the dolabellanes, an important class of bioactive compounds. A stereoselective synthesis of the linearly fused cyclohept[f]indene system is described. Selective epoxidation of cycle-octadiene (142), followed by hydrolysis to the diol (143) and oxidative cleavage allowed preparation of the dialdehyde (141) on large scale. Treatment of this with potassium carbonate causes an intramolecular aldol reaction to form cycloheptadiene- carboxaldehyde (140). An E- selective Wittig reaction is performed with 4- carboxybutyl-triphenylphosphium bromide, to produce the acid (139). This is subsequently converted to the vinyl ketone (138) followed by an intramolecular Diels Alder reaction to produce the desired cyclohept[f]indene (137a). Utilisation of a Z- selective Wittig reaction produced methyl ester (145z). Conversion to cyclohept[f]indene occurred via an intramolecular Diels-Alder of the subsequent vinyl ketone (138z). Conversion of acid (139) to the methyl ester (145) followed by an intermolecular Diels Alder gave the endo- product. Subsequent attempts to cyclise this to the cyclohept[f]indene via an intramolecular Claisen reaction to give the third isomer were unsuccessful. Cyclohept[f]indene is the backbone for dictyoxetane and can be efficiently synthesised in eight steps from 1,5-cyclo-octadiene (142) in a diastereoselective synthesis. This route allows for further modification of functionality to the linearly fused ring system and paves the way for further synthetic studies towards the dolabellanes.
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    Antibacterial properties of diterpenes and their derivatives : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Microbiology at Massey University
    (Massey University, 1998) Nicolson, Kirsty
    Totarol is a diterpene isolated in large quantities from P. totara and a range of other plants, that has been shown to possess significant antibacterial activity against Gram positive bacteria. It has not been possible to unequivocally determine the mode of action by which this activity occurs. This research aimed to determine the mode of action of the diterpene and study a range of derivatives to elucidate a structure-function relationship for the diterpene to enable directional synthesis of future derivatives possessing increased activity and bioavailability. The antibacterial activity of totarol and 29 derivatives was tested against H.pylori and S. aureus, two significant human pathogens,as representative Gram negative and Gram positive bacteria. Four compounds were found to possess significant activity against S. aureus, both MRSA and MSSA, although no significant activity was observed against H. pylori. The ability of the derivatives to potentiate the activity of existing β-lactam antibiotics such as methicillin was also investigated for MRSA and E. coli. Seven compounds including totarol were found to potentiate methicillin, one 256-fold, although no potentiation activity was exhibited against E .coli. The incorporation of radiolabelled precursors was used to investigate the effect of totarol on the synthesis of three macromolecules, DNA, protein and peptidoglycan, in MRSA. No primary inhibition was detected, indicating that the mode of action of the diterpene was not inhibition of synthesis of any of these macromolecules. The effect of totarol on the cellular respiration of MRSA was also investigated, showing 70 % inhibition of respiration at MIC levels, and complete inhibition of respiration at five times that concentration. It was therefore concluded that this was the most likely primary antibacterial effect of the compound. The effect of totarol on the production of PBP 2a, an important protein in theβ- lactam resistance mechanism of MRSA, was also investigated using a novel, non-radioactive labelling procedure to detect the protein. However, although a variety of strategies were employed to detect the protein, none were successful, and the experiment set aside until the arrival of anti-PBP 2a antibody for use in another strategy. Future work on this project that could be undertaken includes determination of the effect of the derivatives on cellular respiration under potentiation conditions, determination of the component(s) of the respiratory chain affected by totarol, and the investigation of the effect of the diterpene on PBP 2a production and function using antibody to detect the protein.