Dan Dan Ho. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 134-144). / Chapter Chapter One --- Introduction --- p.1 / Chapter 1.1 --- Phytochemistry and Phylogeny --- p.1 / Chapter 1.2 --- Biological Activity --- p.9 / Chapter 1.3 --- Synthetic Estrogens and Anti-Estrogens --- p.14 / Chapter 1.4 --- Estrogen Receptor and Anti-Estrogen Binding Site --- p.19 / Chapter 1.5 --- Multiple and dissociated Biological Activity --- p.28 / Chapter 1.6 --- A Future Role for Yuehchukene --- p.30 / Chapter Chapter Two --- Materials and Methods --- p.35 / Chapter 2.1 --- Chemical Synthesis --- p.35 / Chapter 2.1.1 --- Synthesis of Yuehchukene --- p.35 / Chapter 2.1.2 --- Substitution of Yuehchukene --- p.38 / Chapter 2.1.2.1 --- Substitution at N-1' and N-5 --- p.38 / Chapter 2.1.2.2 --- Substitution at C2-C5 --- p.45 / Chapter 2.1.2.3 --- Saturation of C9-C10 Double Bond --- p.45 / Chapter 2.1.2.4 --- Aromatic Hydroxylation --- p.45 / Chapter 2.1.2.5 --- Synthesis of Benzofuran-3-HMBI --- p.47 / Chapter 2.1.3 --- Stereo-selective Synthesis of R(+)- and S(-)-Camphor-yuehchukene --- p.47 / Chapter 2.1.4 --- Instruments --- p.51 / Chapter 2.2 --- Bioassay --- p.51 / Chapter 2.2.1 --- Anti´ؤimplantation Activity --- p.52 / Chapter 2.2.2 --- Uterotrophic Activity --- p.52 / Chapter 2.2.3 --- Blue Test --- p.53 / Chapter 2.2.4 --- Binding Assays --- p.54 / Chapter 2.2.4.1 --- Uterine Cytosolic Estrogen Receptor Binding Assay --- p.54 / Chapter 2.2.4.2 --- Liver Microsomal Fraction Anti-Estrogen Receptor Binding Assay --- p.55 / Chapter 2.2.5 --- Enzyme Activity --- p.56 / Chapter 2.2.5.1 --- Ornithine Decarboxylase Activity Assay --- p.56 / Chapter 2.2.5.2 --- Glucose-6-Phosphate Dehydrogenase Activity Assay --- p.58 / Chapter 2.2.6 --- Cell Culture --- p.59 / Chapter 2.2.6.1 --- MCF-7 Cell Line --- p.59 / Chapter 2.2.6.2 --- Growth Response Studies --- p.59 / Chapter 2.3 --- Exhibit I --- p.61 / Exhibit II --- p.62 / Exhibit III --- p.63 / Exhibit IV --- p.64 / Exhibit V --- p.65 / Chapter Chapter Three --- Results --- p.66 / Chapter 3.1 --- Chemical Synthesis --- p.66 / Chapter 3.1.1 --- Yuehchukene --- p.66 / Chapter 3.1.2 --- Substitution of Yuehchukene --- p.67 / Chapter 3.1.2.1 --- Substitution at N-1' and N-5 --- p.67 / Chapter 3.1.2.2 --- Substitution at C2 and C5 --- p.69 / Chapter 3.1.2.3 --- Saturation of C9-C10 Double Bond --- p.70 / Chapter 3.1.2.4 --- Aromatic Hydroxylation --- p.71 / Chapter 3.1.3 --- Stereo-selective Synthesis of R(+)- and S(-)-Camphor-yuehchukene --- p.72 / Chapter 3.2 --- Bioassay --- p.72 / Chapter 3.2.1 --- Anti-implantation Activity --- p.72 / Chapter 3.2.2 --- Uterotrophic Activity --- p.87 / Chapter 3.2.3 --- Blue Test --- p.88 / Chapter 3.2.4 --- Binding Assays --- p.93 / Chapter 3.2.4.1 --- Uterine Estrogen Receptor [3H]-Estradiol Binding Assay --- p.93 / Chapter 3.2.4.2 --- Liver Microsomal Anti-Estrogen Binding Site [3H] -Tamoxifen Binding Assay --- p.93 / Chapter 3.2.5 --- Enzyme Activity --- p.96 / Chapter 3.2.5.1 --- Ornithine Decarboxylase Activity Assay --- p.96 / Chapter 3.2.5.2 --- Glucose-6-Phosphate Dehydrogenase Activity Assay --- p.96 / Chapter 3.2.6 --- MCF-7 Cell Growth Response --- p.99 / Chapter Chapter Four --- Discussion --- p.102 / Chapter 4.1 --- Species Specificity --- p.102 / Chapter 4.2 --- Estrogenic Indoles --- p.104 / Chapter 4.3 --- Conservative Structure --- p.108 / Chapter 4.4 --- Hydroxylation Sites --- p.111 / Chapter 4.5 --- Configuration and Constraints --- p.114 / Chapter 4.6 --- Dissociated Responses --- p.128 / Chapter 4.7 --- Summary --- p.132 / References --- p.134

Aconitum and Delphinium genera are important rich sources of toxic C19-diterpenoid alkaloids. The alkaloidal content of A. napellus and D. elatum seeds have been investigated in detail. After maceration, crude alkaloidal extracts were obtained and then purified by repeated column chromatography (over silica and alumina gels) to sample homogeneity yielding five known C19-diterpenoid alkaloids from A. napellus, aconitine, neoline, 14-O-acetyltalatisamine, 14-O-benzoylaconine, and taurenine, and two others from D. elatum, delpheline (also including its X-ray single crystal analysis) and methyllycaconitine (MLA). These examples showed that mass spectrometry hyphenated with HPLC or other chromatography can be used as a tool for rapid alkaloid content screening of different extracts. NMR spectroscopic (using a variety of techniques and nuclei) data are presented in support of the first report of iminodelsemine A/B as an imino-alkaloid artefact from D. elatum. A detailed chromatographic study across different pH ranges, and over different solid supports, of aconitine and its main degradation product, 14-O-benzoyl-8-O-methylaconine, together with its semi-synthesis and that of its deuterated analogue are reported within studies to minimize artefact formation during the storage or extraction of A. napellus norditerpenoid alkaloids. Likewise, from D. elatum seeds, as a model source of Delphinium alkaloids, we compared the alkaloid yield using different extraction techniques and conventional chromatographic separations. The structures were confirmed by NMR spectroscopy and mass spectrometry. An NMR spectroscopic approach for the pKa determination of some C19-diterpenoid alkaloids has been developed. A modified calculation method for fatty acid composition quantification has also been developed using 1H-NMR spectroscopic methods.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1981. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Includes bibliographical references. / by Paul Hsiao-tseng Liang. / Ph.D.

PART I. A deuterium exchange analysis of 2,5-dihydroxyacetanilide (5) in the absence and presence of DHAE II was performed to test the nucleophilicity of the substrate in the absence and presence of catalyst. In addition, inhibition studies using 1,4-dihydroxybenzene were performed to determine the role that the N-acetyl side chain group plays in the formation of a stable substrate-enzyme complex. 1,4-Dihydroxybenzene was found to be a weak inhibitor, indicating that the N-acetyl functionality may play a crucial role in forming stable enzyme-substrate interactions. The synthesis of dihydroquinoline 7 was pursued to investigate the enzyme substrate interactions between DHAE and a substrate where the N-acetyl side chain has been fixed to a particular orientation. Efforts towards formation of the C6-C7 bond as a key step in the synthesis of dihydroquinoline 7 using palladium couplings, organocuprates, Lewis acid catalysts, and aza-Claisen reactions were pursued. To complement the results obtained, the electron distribution in amide 21 was calculated using Semi Empirical methods. The results revealed that the electron density in the aromatic ring is centered around C4, suggesting that this is the most nucleophilic carbon in the ring. PART II. Slagenins A (1), B (2), and C (3) were synthesized by β-functionalization of olefin 14. The desired tetrahydrofuroimidazolidin-2-one system was achieved by intramolecular oxidative addition of alcohol 4 to the imidazolone ring. When this reaction was carried out in the presence of methanol slagenins B (2) and C (3) were obtained in good yield. Heating 2 and 3 in aqueous acid gave slagenin A (1) as the sole product. (Z)-debromoaxinohydantoin (17) was synthesized by intramolecular cyclization of α-methoxy imidazolone 11b under acidic conditions followed by a double oxidation reaction to furnish the hydantoin-lactam functionality. These conditions were originally developed for a practical synthesis of the related alkaloid (Z)-debromohymenialdisine (20). A series of acid and base catalyzed reactions of imidazoles bearing an α-β unsaturated system or a β-halogen functionality showed that cyclizations via an S[subscript N]2 path favor formation of an oxazoline ring system. Preliminary studies using pyrrolocarboxamideacetals suggest that β-ketone 73 would be an appropriate substrate for the formation of the pyrrolopyrazine system in the agelastatins. / Graduation date: 2002

Graduation date: 1999

Bacterial cultures enriched from sheep rumen fluid have demonstrated the ability to detoxify pyrrolizidine alkaloids (seneciphylline and jacobine) in tansy ragwort (Senecio jacobaea). The microbes are difficult to isolate using classical anaerobic techniques, therefore, microbes from two different enrichment cultures demonstrating similar degradation activity were identified using their 16S ribosomal RNA genes. Gene sequences from a rich medium enrichment were matched to Clostridium bifermentans, Prevotella ruminicola, Escherichia coif, and from a minimal medium enrichment to, C. clostridiiforme, C. aminophilum, Streptococcus bovis, and Butyrivibrio fibrosolvens. There were no identical organisms between the two libraries, but the common genus was Clostridium. / Graduation date: 1998

Thesis (Ph. D.)--University of Chicago, Dept. of Ecology and Evolution, June 1999. / Includes bibliographical references. Also available on the Internet.

The pyrrole imidazole alkaloids (PIA) is an ever-growing family of structurally related natural products isolated from several species of sponges which now features more than one hundred memebrs. Their complex molecular architectures, and in some cases, significant biological activities, have made these alkaloids the synthetic targets of a number of research groups across the world. In our approach, following early biosynthetic proposal by Kinnel and Scheuer and Al-Mourabit and Potier, it was envisioned that several of these alkaloids, namely palau’amine, axinellamine, konbu’acidin, styloguanidine and massadine, could be derived from a common chlorocyclopentane precursor through different modes of intramolecular cyclization. Building on the work done previously in our research group by Dr. Anja Dilley, Dr. Paul Dransfield, and Dr. Shaohui Wang, my investigations led to the synthesis of the angular aza-triquinane core of axinellamine and the peculiar transazabicyclo[ 3.3.0]octane core of palau’amine. In my further studies mono- and bis-pyrrole advanced intermediates were synthesized that contain the complete carbon framework of the target natural products. However, attempts to induce the pivotal, potentially biomimetic cyclizations expected to deliver the cores of the target alkaloids proved to be rather challenging, resulting in inconsistent and irreproducible results and leading to the exploration of an alternative, “abiotic” approach. My efforts in this direction resulted in the synthesis of a pentacyclic enamine precursor to styloguanidine and a pentacyclic carbinolamine suitable for the synthesis of palau’amine. Final attempts to complete the target natural products were however unsuccessful.

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Part¢¹¡GStudies of Electroorganic Reactions toward the Syntheses of Isoquinoline Alkaloids, and its possible mechanism. Part ¢º: Application of Radical Cyclization Reactions toward the Syntheses of Alkaloids, and other derivatives.