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

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

No description available.

Perophoramidine 1 is a halogenated natural product which contains two contiguous quaternary centres within its structure. In this thesis, approaches towards the synthesis of perophoramidine are described. In particular, the synthesis of the tetracyclic core structure and the formation of the quaternary centres have been examined. In Chapter 1, the natural product perophoramidine 1 is introduced and its isolation, structure and biological activity is discussed. The structurally related communesin family of natural products are also introduced before the literature published on both the biosynthesis and laboratory synthesis of perophoramidine 1, is reviewed. Finally the Westwood group's approach towards the synthesis of perophoramidine 1 is introduced with a summary of non-halogenated model system investigations previously carried out within the group being provided. Chapter 2 describes studies towards the synthesis of an appropriately halogenated indolo[2,3-b]quinoline core structure of perophoramidine 1. This then allowed methodology previously developed within the group on model system substrates to be applied to the formation of the first of the two quaternary centres required for the synthesis of perophoramidine 1. Chapter 3 describes the attempted formation of the second quaternary centre using an ester alkylation approach. After initial studies failed to generate the desired quaternary centre, non-halogenated model system studies were carried out in an attempt to develop an alternative approach. In Chapter 4, model system studies were continued with cyclic ether compounds investigated as potential intermediates towards the synthesis of perophoramidine 1. The results obtained in this chapter provided a novel route to the formation of the second quaternary centre and led to a redesigned approach towards perophoramidine 1 being developed. In Chapter 5, this redesigned approach was applied to the halogenated intermediates synthesised in Chapter 1. This led to the formation of the first halogenated intermediate synthesised within the group which contained the two contiguous quaternary centres required for the synthesis of perophoramidine 1.

This thesis describes investigations directed towards developing a novel synthetic route to the natural products perophoramidine and the communesins, with particular emphasis placed on the formation of the two vicinal all-carbon quaternary centres contained in these molecules. Chapter 1 introduces perophoramidine and the communesin group of natural products and explains how they are related to the calycanthaceous alkaloids. The isolation of perophoramidine and the communesins is outlined and their biosynthesis is discussed. Specific structural features of these natural products are highlighted before established synthetic strategies are reviewed. Chapter 1 concludes by proposing a novel synthetic route for the synthesis of perophoramidine and the communesins that involves a Claisen rearrangement in the indolo[2,3-b]quinoline system as a key step. Chapter 2 describes model studies on the proposed Claisen rearrangement in an attempt to form a quaternary centre in the indolo[2,3-b]quinoline system. These initial studies did not result in the generation of the desired quaternary centre. However, a detailed understanding of the reactions that occur leads to the design of a new model substrate. Chapter 3 describes studies on the revised model system that result in the formation of the desired quaternary centre using a Claisen rearrangement. The differences between the two systems are discussed before an investigation into the scope of the rearrangement is described. Chapter 3 concludes by describing an investigation into a protecting group strategy that would by required with this synthetic route. Chapter 4 describes investigations into the formation of the second vicinal quaternary centre using a model system. The synthetic routes investigated lead to two separate methods for the formation of the desired quaternary centre. Chapter 5 describes investigations into the effect a C-10 substituent has on the Claisen rearrangement. Additionally, an asymmetric version of the Claisen rearrangement is examined. Chapter 5 culminates in the preparation of an intermediate relevant to an asymmetric synthesis of the communesins.

The thesis entitled “Enantiospecific total synthesis of indole alkaloids eburnamonine, aspidospermidine, quebrachamine, henrycinols A and B and synthesis of azepino[4,5-b]indolones” is divided into three chapters. In the first chapter, a unified strategy for the enantiospecific total synthesis of monoterpene indole alkaloids (+)-eburnamonine (1), (–)-aspidospermidine (2) and (–)-quebrachamine (3) is described. The chiral pool synthesis commenced with (S)-ethyl lactate 4, which was elaborated to the allylic alcohol 5. Johnson-Claisen orthoester rearrangement of the allylic alcohol 5 furnished the key chiral building block 6 possessing a quaternary stereogenic center. Pictet-Spengler cyclization of tryptamine with the corresponding aldehydes obtained by appropriate functionalization of the chiral building block 6 and ring closing metathesis were the key reactions employed en route the total synthesis of the indole alkaloids 1–3 (Scheme 1). Scheme 1. Unified strategy for the synthesis of monoterpene indole alkaloids (+)-eburnamonine (1), (–)-aspidospermidine (2) and (–)-quebrachamine (3). The second chapter of the thesis pertains to the synthesis of azepino[4,5-b]indolones 7 via Brønsted acid mediated intramolecular cyclization of unsaturated tryptamides 8. Various ,-unsaturated acids 9 derived from different -hydroxy esters 10, were converted to the corresponding unsaturated tryptamides 8 and subjected to the optimized reaction conditions. The results of the study indicated that -substituted unsaturated secondary tryptamides derived from (S)-ethyl lactate were the most effective in undergoing an intramolecular cyclization to furnish the corresponding azepino[4,5-b]indolones 7, possessing a quaternary stereogenic center in good yields. The presence of an alkenyl moiety in the quaternary center allowed the functionalization of these compounds and was subsequently employed to access the ABCD core 11 of tronocarpine and the tetracyclic cores 12 of some iboga alkaloids. The loss of chirality in the formation of the azepino[4,5-b]indolones indicated that the reaction proceeds predominantly by an SN1 pathway. During the course of the study an interesting formation of an azonino[5,4-b]indolone 13 by a competing SN1 pathway and a tetracyclic azepino[4,5-b]indolone 14 via a cascade cyclization were noticed (Scheme 2). Scheme 2. Synthesis of azepino[4,5-b]indolones 7 possessing a quaternary stereogenic center. The first total synthesis of two new indole alkaloids, henrycinols A (15) and B (16) which were isolated from the plant Melodinus henryi CRAIB is described in the third chapter of the thesis. The key reaction in the synthetic sequence is the Pictet-Spengler cyclization of L-tryptophan methyl ester 17a and the aldehyde 18 derived from D-tartaric acid which leads to the installation of all the stereogenic centers present in the natural products. Interestingly, a switch in the diastereoselectivity of the reaction was observed by varying the substituent on the amine in L-tryptophan methyl ester 17. When L-tryptophan methyl ester 17b possessing an N-allyl substitution was employed, the desired 1,3-trans tetrahydro--carboline 19b could be obtained in good yields, which was subsequently elaborated to the natural products 15 and 16 (Scheme 3). Scheme 3. Total synthesis of henrycinols A (15) and B (16).

SIRT1 and SIRT2 are two NAD⁺-dependent deacetylases which negatively modulate the activity of p53, a protein which is involved in cell cycle arrest, senescence and apoptosis following genotoxic stress. Part I of the thesis describes the exploration of the chemical space around a reported unselective and modest inhibitor of SIRT1 and SIRT2 with the aim of improving the selectivity and potency of the inhibitor against the two isoforms. Particular emphasis is placed upon understanding the mode of binding of the novel analogues within the active site of the enzymes. Chapter 1 reviews the physiological roles of class III NAD⁺-dependent deacetylases, also known as sirtuins. In particular, the application of SIRT1 and SIRT2 inhibitors as potential anticancer agents is described. Amongst these, only cambinol and the tenovins showed in vivo activity in a mouse xenograft model. Previously only one analogue of cambinol had been reported in the literature. Chapter 2 describes the development of a small collection of novel cambinol analogues (First Generation Studies). The role played by different substituents at the phenyl group and at the N-1 of the thiouracil core is discussed. Along with the synthesis and structure activity relationship (SAR) associated with the core structure, in-cell experiments intended to confirm the activity of the most active compounds are reported. Chapter 3 provides a rationalisation for the SAR discussed in Chapter 2. Based on computational molecular modelling studies (GOLD), the activity of the most potent and selective SIRT2 inhibitors is explained. Two series of novel cambinol analogues were designed (Second and Third Generation Analogues) in order to assess further the proposed binding mode. Chapter 4 focuses on the development of the “Second Generation” analogues, characterised by the presence of lipophilic substituents at the sulfur atom and at the N-3 position of the thiouracil core. The synthesis, biological evaluation and SAR are discussed in detail. Chapter 5 reports the development of the “Third Generation” analogues, characterised by either a benzyl group or para-alkoxy-substituted benzyl group at the N-1 position of cambinol. Once again, the synthesis, biological evaluation and SAR data are presented. An improved understanding of the mode of binding of the novel compounds is proposed based on molecular dynamics (MD) studies. Indole-based alkaloids, such as Vincristine and Vinblastine, are well known for their anticancer activity. Recently, the anticancer activity of members of the calycanthaceous family of alkaloids has been discovered. Part II of the thesis focuses on model studies aimed at developing the total synthesis of one of these compounds, perophoramidine. Chapter 7 provides an overview of the calycanthaceous alkaloid family of natural products, including their biological properties. The structural features of perophoramidine, along with the previously reported synthetic studies are outlined. Chapter 8 describes the synthesis of an advanced intermediate in the total synthesis of dehaloperophoramidine, a structural analogue of perophoramidine Problems encountered, optimisation studies and the synthesis of a re-designed intermediate are also reported in this chapter.