The ability to construct C-N bonds is of great importance to organic chemists as exemplified by the vast number of natural products, pharmaceutical agents and fine chemicals that contain such linkages. An atom efficient C-N bond forming reaction namely hydroamination has attracted much interest to date due to its ability in forming amine, imine and enamine functionality. The scope of this project involved the attempted synthesis of a biologically active and nitrogen containing pyrrolizidine alkaloid isolated from cryptic thief ants and poison dart frogs namely 223H (xenovenine). The method of hydroamination was utilized as the pivotal ring forming step and was established as being a valuable synthetic tool towards the construction of 223H (xenovenine). The stereoselective synthesis resulted in the successful formation of ethyl (3R)-5-heptyl-3-methyl-2,3-dihydro-lH-pyrrolizine-7-carboxylate 74, a novel, and structurally analogous precursor to 223H (xenovenine) over 10 synthetic steps from (S)-pyroglutamic acid. The following research also resulted in the synthesis of two other novel compounds namely ethyl 3-[(2R)-2-methyl-5-thioxotetrahydro-lH-pyrrol-l-yl]propanoate 86 and ethyl 3-{(5R)-2-[(E)-2-ethoxy-2-oxoethylidene]-5-methyltetrahydro-lH-pyrrol-l-yl}propanoate 87. A catalytic hydroamination study on the conversion of C-propargyl vinylogous amides into pyrroles demonstrated that transition metal salts of groups 11 and 12 serve as effective hydroamination catalysts. The oxide, acetate, chloride and nitrate derivatives of group 11 and 12 metals namely Cu(II), Ag(I), Zn(II), Cd(II) and Hg(II) were employed as potential hydroamination catalysts in the oxidation states provided. The Zn(II) catalyst series with the exception ZnO provided the greatest hydroamination yields under mild reaction conditions owing to their high Lewis acidities however the Ag(I) and Hg(II) catalyst series also provided excellent yields of product under more forcing reaction conditions. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.

1 ABSTRACT Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Beáta Bystrońová Consultant: RNDr. Jitka Vytlačilová, Ph.D. Title of diploma thesis: The evaluation of alkaloids using in vivo tests with Artemia salina II. The most common cause of dementia in the elderly is probably Alzheimer's disease (AD). The prevalence of this disease increases considerably. Nowadays only acetylcholinesterase inhibitors are being used for the treatment of AD, they can relieve symptoms of AD, but can't stop progression of the disease. Consequently there is a need for therapeutic agents against AD, which act on various pathological levels. More intensive recent studies are being carried out on natural substances that could pharmacologically affect AD neurodegenerative processes. Our aim was to carry out the toxicological screening for each tested substance. For the purpose of this work we have used Artemia salina in the experiment which seems to be suitable organism for evaluating acute toxicity. The experiment was conducted in a miniature environment. Four substances which belong to isoquinoline alkaloids: stylopine, tetrahydropalmatine, canadine and scoulerine were tested. The greatest toxicity showed stylopine, slightly lower tetrahydropalmatine and...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Author: Radka Kvapilová Supervisor: RNDr. Jitka Vytlačilová, Ph.D. Title of diploma thesis: Antiprotozoal activity of alkaloids II. The development of new antiprotozoal agents for the treatment of infections is very important. Natural substances can be the source of effective drugs. The aim of this study was to evaluate the antiprotozoal activity of these alkaloids - canadine, scoulerine, tetrahydropalmatine and stylopine. The experiment was conducted on typical model organism Tetrahymena thermophila. Percentage inhibition of the organism was determined using the MTT assay. Subsequently median inhibitory concentration IC50 of the test substances was calculated. From our alkaloids stylopine had the greatest antiprotozoal activity. Antiprotozoal activity decreased in the following order stylopine > canadine > scoulerine > tetrahydropalmatine. Key words: Tetrahymena thermophila, antiprotozoal activity, canadine, scoulerine, tetrahydropalmatine, stylopine

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Barbora Balíková Consultant: RNDr. Jitka Vytlačilová, Ph.D. Title of diploma thesis: The evaluation of alkaloids using in vivo tests with Artemia salina I. Alzheimer's disease is the most common cause of dementia and it is one of the lifestyle diseases. There is so far available only limited symptomatic treatment and the occurrence of the lifestyle diseases (and thus Alzheimer's disease) is increasing in recent decades. Therefore it is necessary to find new compounds which will be effective in the treatment of this disease. Toxicological screening - which was our task - is the part of the research of each substance. For the evaluation of the acute toxicity appears as a suitable organism brine shrimp Artemia salina, which was used in the experiment for the purposes of this work. The experiment was conducted in a miniaturized environment. There were tested three substances belonged to the isoquinoline alkaloids: californidine, papaverine and morphine. As the most toxic was evaluated alkaloid californidine, alkaloid papaverine had less toxicity. Morphine appeared essentially as nontoxic with using the same methodology and similar concentrations as in the case of californidine...

The purpose of this project was to investigate whether methodology developed in these laboratories for preparing 5/6 and 6/6 azabicyclic systems with bridged head nitrogen can be extended to 7/6, 8/6, 9/6 and 13/6 azabicyclic systems. The methodology entails the use of enaminones as central to the formation of the azabicyclic systems. The synthetic route adopted began with the Beckmann rearrangement reaction and/or the Schmidt reaction of cyclic ketones to make lactams, which were then thionated by Curphy or Brillon procedures. The Michael reaction of NH thiolactams with tert-butyl acrylate was followed by Eschenmoser sulfide contraction to afford the enaminones 132 which were utilised in the ring-closing step. This involved hydrolysis of the tert-butyl ester and cyclisation via a mixed anhydride. Ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 170b, 1-(4- nitrobenzoyl)-3,4,6,7,8,9-hexahydroquinolizin-2-one 172a, 1-benzoyl- 3,4,7,8,9,10-hexahydropyrido[1,2-a]azepin-2(6H)-one 173d, 1-(4-nitrobenzoyl)- 3,4,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-2-one 174a, and 1-(4- nitrobenzoyl)-3,4,7,8,9,10,11,12,13,14,17,16-dodecahydropyrido[1,2-a]azacyclotridecin- 2(6H)-one 176a were synthesised in good yields, but yields of 8-(4- nitrobenzoyl)-2,3,5,6-tetrahydroindolizin-7(1H)-one 171a and 1-(4-nitrobenzoyl)- 3,4,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-2(6H)-one 175a were not satisfactory. In a much shorter synthetic route that involves enaminone chemistry as well, NH vinylogous amides were synthesised by the Eschenmoser sulfide contraction and used in the aza-annulation reaction with acryloyl chloride. Structural isomers (to compounds mentioned above) 8-(4-nitrobenzoyl)-2,3,6,7-tetrahydroindolizin- 5(1H)-one 178a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin- 4(6H)-one 180a, 1-benzoyl-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin-4(6H)-one 180b, 1-(4-nitrobenzoyl)-2,3,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-4-one 181a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)- one 182a and 1-(4-nitrobenzoyl)-2,6,7,8,9,10,11,12,13,14,15,16- dodecahydropyrido[1,2-a]azacyclo-tridecin-4(3H)-one 183a were synthesised in good yields. 1-(4-Nitrobenzoyl)-2,3,6,7,8,9-hexahydroquinolizin-4-one 179a was obtained in low yield, and apparently as two conformational isomers.

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.

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

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2017. / This thesis is aimed at the investigation of the chiral discrimination process during diastereomeric salt formation, when selected cinchona alkaloids are exposed to racemic mixtures of tartaric acid derivatives. This research is based on the use of (+)‐cinchonine, (‐)‐cinchonidine, (‐)‐quinidine and (+)‐ quinine, which served as chiral bases, in order to resolve racemates of O,O'‐dibenzoyl‐tartaric acid (DBTA) and O,O'‐di‐p‐toluoyl‐tartaric acid (DTTA). Cinchona alkaloids were selected because of their abilities to form salts with the targeted acids. DBTA and DTTA are commonly used resolving agents to separate racemic bases via diastereomeric salt formation, and they are also commercially available and affordable chiral acids. Results were obtained from all combination but only the experiments with cinchonidine were included in this thesis, namely [CIND+][L‐DBTA‐], 2[CIND+][D‐DBTA2‐], [CIND+][LDTTA‐] and 2[CIND+][D‐DTTA2‐]∙2DMSO∙0.7H2O. Experimental analytical techniques, such as thermal analysis, powder X‐ray diffraction, and single crystal X‐ray diffraction were used to analyze the harvested diastereomeric salts. A correlation of molecular parameters derived from the structures and an investigation of the mechanism, which drives the resolution process were discussed. The thesis also summarizes the findings on 8 inclusion compounds of (‒)‐O,O'‐dibenzoyl‐(2R,3R)‐tartaric acid (L‐DBTA) and (‒)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid (L‐DTTA) or their racemic mixtures, (rac)‐ DBTA and (rac)‐DTTA, with DMSO and water: (rac)‐DBTA∙H2O, (rac)‐DBTA∙DMSO, L‐DBTA∙H2O, LDBTA∙ DMSO, (rac)‐DTTA∙H2O, (rac)‐DTTA∙DMSO, L‐DTTA∙H2O, and L‐DTTA∙DMSO. The discussed inclusion compounds were obtained serendipitously, as a product of the pre‐screening of suitable solvents to dissolve both the acids and the cinchona alkaloids during the discrimination experiments. Only few crystal structures of solvates of these two tartaric acid derivatives are known up to now, and fewer of these structures do exist when both the racemic and the enantiopure acid encapsulates the same solvent. The synthesis and structural analysis of these inclusion compounds contribute to the pool of available crystal structures when comparing chiral vs. achiral crystal forms of the same compounds.

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.