A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. January 1996. / Aspects of the literature of the ant venom alkaloid monomorine I and its stereoisomers were reviewed. Racemic 5-butyl-2-pyrrolidinone was synthesised in two steps from methyl acrylate and 1-nitropentane, A thionation step yielded 5-butylpyrrolidine-2-thione. The Michael addition reaction between 5-butylpyrrolidine-2-thione and ethyl crotonate proceeded with difficulty to form a separable mixture of diastereomers of 5-butyl-l-(2-ethoxycarbonyl-l-methylethyl) pyrrolidine-2-thione. [Abbreviated Abstract. Open document to view full version] / AC2017

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.

The synthesis of alkaloids from enaminones has been used extensively in the University of the Witwatersrand’s organic chemistry laboratories. In this thesis enaminone precursors are one of the main ways of accessing lamellarin analogues. The lamellarin alkaloids are an important family of marine alkaloids, owing to their vast biological properties. A brief background to marine alkaloids and their general potential is given, followed by a review of lamellarin alkaloids, their structural and biological properties and some of the major syntheses carried out over the past few years. Two novel features form the basis of the synthetic methods described in the thesis. The first is an approach to forming the lamellarin alkaloids from enaminone precursors, which are prepared through the Eschenmoser sulphide contraction. The second method uses a novel pyrrole formation, which was initially conceptualized by Garreth L. Morgans in his PhD thesis (2008). The main target of the investigation was lamellarin G trimethyl ether. In Chapter 3, the syntheses of a range of mono-, di- and tetra-substituted phenacyl halides are discussed. The phenacyl halides were used in the preparation of various enaminone precursors. The tetrasubstituted phenacyl halide 2-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone 3.17 is required for the synthesis of our target lamellarin G trimethyl ether. The phenacyl halides are important in both the model synthesis described in Chapter 4 and the synthesis toward lamellarins in Chapter 5. Chapter 4 deals mainly with the synthesis of pyrrolizine systems. Methodology is described for the preparation of a variety of enaminones, pyrroles and tetracyclic lamellarin analogues. The closest pyrrolizine system to lamellarin G trimethyl ether, 11-(3,4-dimethoxyphenyl)-2,3-dimethoxy-9,10-dihydrochromeno[4,3-b]pyrrolizin-6(8H)-one 4.52, was the final and most complex tetracyclic model structure analogous to lamellarin G trimethyl ether. Indolizine and pyrroloazepine adaptations were also demonstrated and tetracyclic systems 10,11-dihydro-8H-chromeno[3,2-a]indolizin-12(9H)-one 4.39 and 9,10,11,12-tetrahydrochromeno[3',2':3,4]pyrrolo[1,2-a]azepin-6(8H)-one 4.40 were successfully prepared, even though the pyrrole formed in an unexpected way. Finally in Chapter 5, the methodology established in the model study was used in the attempted synthesis of lamellarin G trimethyl ether. A second method was also investigated. Thus, various N-alkylated and N-H enaminones were successfully synthesized, from which novel and unexpected pyrrole-containing products 8-(3,4-dimethoxyphenyl)-2,3-dimethoxy-5H-chromeno[3',2':3,4]pyrrolo[2,1]isoquinolin-14(6H)-one 5.28 and (3-ethoxy-8,9-dimethoxy-2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-yl)(phenyl)methanone 5.37 were formed, even though our desired product lamellarin G trimethyl ether could not be attained from either method.

A Dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the Degree of Master of Science. / An outline of reported synthetic routes to the Lupine alkaloids, epilamprolobine [2] and lamprolobine [3] and a review of the use of vinylogous amides and urethanes as precursors for the synthesis of alkaloids are presented in Chapter 1. This is followed by a presentation of our strategy for synthesis of the two Lupine alkaloids. Vinylogous cyanamide intermediate 1- (3-hydroxypropyl) -2- cyanomethylenepiperidine [68] plays a key role in this strategy, since exploitation of its ambident nucleophilicity forms the central theme of this project, The successful route to the intermediate [68] involved the preliminary preparation of the tertiary thiolactam, 1-(2- ethoxycarbonylethyl)piperidine-2-thione [83][ by thiation of the secondary lactam 2-piperidinone [72] and conjugate addition at nitrogen with ethyl acrylate in a Michael reaction. Sulphur extrusion of the salt made from [83] and bromoacetonitrile and subsequent reduction of the ester group provided the pivotal vinylogous cyanamide intermediate. A number; of alternative routes based on 5- bromopentanoic acid [80], 1-allyl-2-piperidinone [73] and thiolactams [84J and [105] were unsuccessful. Cyclisation of the intermediate [68] was achieved by an intramolecular c-alkylative ring closure via the corresponding tosylate [l16] to forln an unsaturated functionalised quinolizidine [69]. Stereoselective carboncarbon double bond reduction and nitrile reduction resulted in the synthesis of two quinolizidines. lupinamine [11] and epilupinamine [112]. Further transformations led to the formation of the derivatives, N-acetyllupinamine [113] and N-acetylepilupinamine [114], and also to the target alkaloids, epilamprolcbine [2] and lamprolobine [3]. / Andrew Chakane 2018

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

The akuammiline alkaloids are an intriguing class of natural products that display an array of biological activities and structural diversity. Despite being known for over 125 years, it is surprising that these complex monoterpene indole alkaloids have only recently elicited sustained interest from the synthetic community, especially given the storied history of this broad family in the development of the art of total synthesis, and, in particular, heterocyclic chemistry. This dissertation details our efforts to address these deficiencies through work directed at the unique akuammiline alkaloid (+)-scholarisine A, ultimately yielding a concise and enantiospecific preparation of this challenging target. Building on this initial success, we have initiated studies aiming to generalize these strategies to the akuammiline class as whole, efforts that have been empowered by the development of several novel synthetic transforms. These investigations have culminated in the efficient synthesis of a collection of advanced intermediates en route to the varied frameworks represented by strictamine and 10-demethoxynorvincorine. In addition, we have leveraged our expertise gained within these challenging contexts towards a method with utility beyond the akuammiline class, one that is likely to find broad application in both natural product synthesis and the assembly of medicinally-relevant building blocks.

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

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