Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisor: Douglass F. Taber, Dept. of Chemistry & Biochemistry. Includes bibliographical references.

<p> The photoadditions of 3-phenyl-2-cyclohexenone to bicyclo [2.2.1] hepta- 2,5-diene, bicyclo [2.2.1] hept-2-ene and cyclopentene have been studied. In all cases cis fused cyclobutane products were obtained. Quenching and sensitization experiments indicated a singlet excited state to be active in photocycloaddition. Phosphorescence and fluorescence emission were observed from 3-phenyl-2-cyclohexenoneo Energy transfer to the lowest triplet of 3-phenyl-2-cyclohexenone was evident from the quenching of Michler's ketone phosphorescence. Two norbornene dimers were detected in the photolysis of 3-phenyl-2-cyclohexenone and norbornene giving evidence for a higher triplet excited state of the enone. The photoaddition of 3-methyl-2-cyclohexenone to cyclopentene was studied for comparison and both cis and trans fused adducts were obtained. In photolyses with bicyclo [2.2.1] hepta-2,5-diene or cyclopentene, 2-phenyl-2-cyclohexenone was unreactive. </p> / Thesis / Master of Science (MSc)

<p> In order to gain mechanistic information of photoaddition reactions of 2-cyclohexenones, the additions of 2- and 3-methyl-2-cyclohexenone and 2-cyclohexenone to bicyclo[2.2.1]hepta-2,5-diene have been studied. Substituted 2-cyclohexenone products are obtained in addition to cyclobutane derivatives, and it is proposed that the former adducts arise from diradical intermediates and intramolecular hydrogen shifts. The photo-rearrangement, of 4, 4-dimethyl-2-cyclohexenone, and its photocycloaddition to cyclopentene, was studied in order to identify the enone excited state responsible for cycloaddition. These results, and naphthalene quenching experiments, indicate that all of the additions studied proceed via triplet excited states.</p> / Thesis / Doctor of Philosophy (PhD)

The natural product 2 crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxy-cyclohex-2-enone (COTC) was isolated from the microorganism Streptomyces griseosporeus in 1975. It was shown to exhibit 'cytotoxic and cancerostatic activity'. The simplified synthetic analogue 2-crotonyl-oxymethyl-cyclohex-2-enone (COMC) has been shown to exhibit potent anti tumour activity against murine and human tumours in cell culture. For several years, the Whitehead research group at the University of Manchester have focused on the synthesis of COTC and COMC analogues in an attempt to produce compounds with enhanced cytotoxicity. In this thesis, the syntheses of several polyfunctionalised cyclohexenones are described. These compounds are analogues of COTC and COMC which also bear structural resemblance to the antheminone and carvotacetone natural products. Initially, the syntheses of six novel compounds from the chiral pool starting material (-)-quinic acid are described. The first four synthetic steps of each sequence were carried out by slight modification of procedures previously reported by the Whitehead research group. As part of the synthetic strategy, the diastereoselective conjugate addition of carbon nucleophiles to several polyfunctionalised cyclohexenones was investigated. The cytotoxicity of four of the synthetic analogues towards A549 non small cell lung cancer cells was investigated by use of an MTT assay. Two of the analogues were found to be more cytotoxic then COMC. The most effective synthetic analogue had an IC50 value of 2.2 μM. This analogue was more cytotoxic than similar molecules that had previously been synthesised by members of the Whitehead research group. Based on the results of the MTT assay, another two analogues were designed and their synthesis from (-)-quinic acid is described. The cytotoxicity of these analogues has yet to be assessed. In summary, the general synthetic strategies developed in this thesis will provide easy access to new analogues of the natural products, enabling the development of new cytotoxic compounds.

No description available.

Since the middle of the 20th century, significant interest has evolved from the scientific community towards the polypropionate family of marine natural products. A number of these compounds have been shown to possess significant biological activity, and this property, as well as their structural complexity, has driven numerous efforts towards their synthesis. The first chapter provides an introduction into the world of polypropionates, with a discussion on synthetic studies into a number of members of the tridachiapyrone family. Fundamental synthetic concepts utilised in this thesis towards the preparation of polyketides are also described, with a focus on their application towards the synthesis of 9,10-deoxytridachione, anti tridachiahydropyrone and syn tridachiahydropyrone. Chapter 2 describes the work undertaken towards the total synthesis of 9,10-deoxytridachione. The novel tandem conjugate addition-Dieckmann condensation of complex enones developed previously in the Perkins group was used to generate anti methylated cyclohexenones as key synthetic intermediates. The conversion of the cyclohexenones into the corresponding cyclohexadienes via allylic alcohols was attempted, utilising a Grignard-mediated reaction to achieve the selective 1,2-reduction. Studies into the Grignard-mediated reduction were also undertaken on seven additional cyclohexenones, in order to investigate the utility and scope of the reaction. The extension of the methodology previously developed for the synthesis of cyclohexenones is the subject of Chapter 3. This section describes investigations into the synthesis of stereochemically-diverse cyclohexenones from complex enones. The conjugate addition-Dieckmann condensation strategy was extended successfully towards the synthesis of a syn methylated cyclohexenone, which allowed the synthesis of the proposed true structure of tridachiahydropyrone to be pursued. The methodology developed in Chapter 3 was utilised in Chapter 4 to synthesise a model system of syn tridachiahydropyrone. A comparative analysis of the NMR data of the syn model, an anti model and anti tridachiahydropyrone with the natural product indicated that the true structure of tridachiahydropyrone may indeed have syn stereochemistry. The synthesis of syn tridachiahydropyrone was attempted, and to this end a suitable cyclohexanone was successfully synthesised. However, the subsequent methylation-elimination cascade failed to furnish the desired syn methylated cyclohexenone, producing only an anti methylated cyclohexanone. The stereochemistry of the methylation was deduced using high and low variable temperature NMR coupled with selective irradiation NOESY.