This thesis describes the application of the Sonogashira coupling reaction to access a variety of 5-and 7-azaindoles derivatives. The background chapter paints a picture about the importance of indole-containing compounds and azaindole-containing compounds. In this first chapter, discovery, synthesis, properties and reactivity of indole and azaindoles were explained.

This thesis describes a novel total synthesis of (±)-dehalo-perophoramidine (a dehalogenated analogue of the natural product perophoramidine). The key synthetic transformation involves the construction of vicinal quaternary stereocenters which were installed diastereoselectively. A Claisen rearrangement was used to install the first quaternary stereocenter then a Corey-Chaykovsky-type reaction and a Hosomi-Sakurai-type reaction were used to install the second quaternary stereocenter. Investigations directed towards the total synthesis of the communesin family of natural products are also described. In Chapter 1, the natural products perophoramidine and the communesins are introduced and their related biosynthesis is discussed. The isolation, architectural motifs and biological properties of the natural products are described and discussed. Previously reported approaches to perophoramidine and the communesins are reviewed focussing on how the vicinal quaternary stereocenters are formed in each case. Chapter 1 concludes with the retrosynthetic plan used to form dehalo-perophoramidine. In Chapter 2, previous research from the Westwood group is reviewed focusing on an asymmetric Claisen rearrangement which could potentially be used to install a quaternary stereocenter asymmetrically. A previously reported novel Cope rearrangement, potentially useful for a communesin synthesis, is optimised using microwave, neat and high-temperature flow conditions and leads to the synthesis of an intermediate containing two allyl substituents. In Chapter 3, attempts to functionalise selectively the two allyl substituents are described which was eventually achieved by a regioselective iodoetherification reaction. This leads to the synthesis of two relatively advanced intermediates for a communesin synthesis. Although the total synthesis of the communesins was not achieved, a proposed route from the advanced intermediates to the natural products is described. In Chapter 4, a novel method to construct vicinal quaternary stereocenters is disclosed using a Corey- Chaykovsky-type reaction and a Hosomi-Sakurai-type reaction. A regioselective iodolactonisation, analogous to that presented in Chapter 3, is used to functionalise selectively two allyl substituents that culminates in the preparation of a pentacyclic lactam. In Chapter 5, the total synthesis of (±)-dehalo-perophoramidine is completed and its structure is confirmed by a NMR doping experiment with an authentic sample. The biological activity of dehalo- perophoramidine is investigated and compared to that of perophoramidine. Chapter 5 culminates in an attempted synthesis of the natural product perophoramidine using the route that was used to make dehalo-perophoramidine.

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

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Examination of the scope of the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction as well as the development of a domino [Rh(CO)₂Cl]₂-catalyzed allylic alkylation/Pauson Khand reaction is described. A number of experiments were carried out in order to explore the novel regioselectivity in the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction, and the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction was found to give products resulting from attack of the nucleophile on the carbon bearing the leaving group in a highly regioselective fashion in most cases. Examination of allylic carbonate substrates containing similar substitution at each allylic site was carried out, and conditions that minimize equilibration of active intermediates were determined. Intramolecular [Rh(CO)₂Cl]₂-catalyzed allylic alkylation was accomplished to synthesize challenging eight-membered lactone ring systems. Nucleophile scope was explored with regards to the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction, and malonates, substituted malonates, aliphatic amines, and ortho-substituted phenols were all determined to be effective in the reaction. A domino [Rh(CO)₂Cl]₂-catalyzed allylic alkylation/Pauson-Khand reaction was developed which allows the rapid synthesis of bicyclopentenone products from simple, readily available starting materials. The first application of the Pauson-Khand reaction to the synthesis of azabridged bicyclic structures is also described. Various cis-2,6-disubstituted piperidines were cyclized to the corresponding azabridged bicyclopentenones is high yields often in high diastereoselectivities. The effect of ring size, nitrogen substituent, and remote functionality on the Pauson-Khand substrates was studied. The methodology developed was applied to the concise, enantioselective total synthesis of the antimalarial and anticancer indole alkaloid (-)-alstonerine. Pauson-Khand reaction of a readily available enyne synthesized in four steps from L-tryptophan provided a cyclopentenone in high yield as one diastereomer. Elaboration of the Pauson-Khand product required the development of a one pot conversion of a five-membered cyclic silyl enol ether to a sixmembered lactone and the mild acylation of a glycal.

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy

Thesis (Ph. D.)--University of Chicago, Dept. of Chemistry. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains xvii, 207 p. : ill. Includes abstract. Includes bibliographical references (p. 97-101).

M.Sc. (Chemistry) / The aim of this study was to investigate alternative routes for the stereocontrolled synthesis of hydroxylated indolizidine, piperidine and pyrrolidine alkaloids, starting from monosaccharides as chiral building blocks. This study was not aimed at improving consisting routes - it was rather aimed at developing new routes towards the synthesis of these alkaloids. Mixed results were obtained in the investigation into alternative routes for the synthesis of the bicyclic poly hydroxylated indolizidine alkaloids, but a new and efficient stereospecific synthesis of polyhydroxylated piperidine- and pyrrolidine alkaloids were developed. The aims and results can be summarised in more detail as follows: a. Stereospecific synthesis of castanospermine. The synthesis of this medium sized nitrogen-containing bicyclic molecule was approached in a unique way. The utilization of bifunctional Wittig- and Wittig-Horner reagents containing nitrogen functionalities was considered promising for the aims of this study. By the usage of known reactions, e.g. Wittig, Wittig-Horner, Schiff-base and Aza-Wittig reactions, it was foreseen that these bifunctional reagents could be coupled in two concurrent steps to dicarbonyl compounds to form a nitrogen containing rings. Several nitrogen containing Wittig reagents were prepared. At the one end of these reagents a phosphonate or phosphine group furnished the phosphorus moiety while the other end of these reagents comprised the nitrogen moiety by reduction of a nitrile group or azide displacement of a leaving group. No coupling was obtained between these bifunctional reagents and a dicarbonyl compound derived from D-glucose and the influence of two functional groups in such close proximity in the Wittig reagent is being further investigated. Coupling was, however, achieved by the utilization of an alternative bifunctional reagent in which a Wittig-Horner reaction was used. The successful implementation of this unique methodology in the synthesis of medium size nitrogen containing ring is being further investigated.