Gold catalysis has attracted much attention within the chemical community in recent years, and its importance as a synthetic tool has only started to be uncovered. This thesis describes the development of a gold(I) catalyzed transformation and its application to the synthesis of a structurally unique Lycopodium alkaloid, Magellanine. Although there have been a few reports on the synthesis of the magellanane core to date, the approach described herein would represent a new and efficient strategy to construct the angularly fused tetracyclic core. The 5 exo dig/Prins reaction that would be the key step of the synthesis was first developed and studied on a model substrate, enabling the verification of the hypothesis that this transformation could indeed form the A and B rings of Magellanine and be applied to its synthesis. This reaction formed the tricyclic products in good yields and in good exo:endo ratios. The synthesis of Magellanine was undertaken, but problems of isomerization prevented the synthesis of the desired 5 exo dig/Prins substrate, which contained the C and D rings of Magellanine with a cis relationship at the ring junction. However, an almost identical substrate, save for a trans configuration between the C and D rings instead of the cis configuration, was prepared and served in further establishing the applicability of this methodology to the synthesis of Magellanine by successfully undergoing the 5-exo-dig/Prins reaction and generating the tetracyclic products. Studies of the steps following the key transformation were performed on the model substrate, allowing for the evaluation of these steps prior to their use in the synthesis. The results of the studies indicate a possible need to revisit the order in which the steps should be carried out. Promising solutions to the different obstacle encountered during the work are presented, demonstrating how the synthesis of Magellanine through a route featuring the 5-exo-dig/Prins cyclization is attainable.

Seven naturally occurring pyranocarbazole alkaloids (pyrayafoline A–E, O-methylmurrayamine A and O-methylmahanine) have been obtained by total synthesis using a palladium(II)-catalysed oxidative cyclisation of a diarylamine to an orthogonally diprotected 2,7-dihydroxycarbazole as key step.

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-08T05:17:50Z (GMT). No. of bitstreams: 1 Conegero_LeiladeSouza_D.pdf: 3438551 bytes, checksum: 26a173748a7748d7ec479a812badeeb7 (MD5) Previous issue date: 2006 / Resumo: O trabalho desenvolvido visou a obtenção de alcalóides pirrolizidínicos e indolizidínicos utilizando a (+)-retronecina (1) e o ácido D-isoascórbico (35D) como matérias primas, respectivamente. A retronecina (1) foi isolada da espécie vegetal Senecio brasiliensis. Para a preparação da base necínica (1R,6S,7S,8R)-7- (hidroximetil)-hexaidro-1H-pirrolizina-1,6-diol (37), a retronecina (1) foi submetida à reação de epoxidação com ácido meta-cloroperbenzóico. A a-epóxi-retronecina (44), após proteção das hidroxilas com cloreto de tercbutildimetilsilila, foi submetida à abertura com níquel de Raney, e a posterior desproteção forneceu o triol 37, que foi obtido em 5 etapas e 15 % de rendimento. Os compostos (1R,2R,7R,8S)-1-(hidroximetil)-hexaidro-1H-pirrolizina-1,2,7-triol (39) e a platinecina (72) foram preparados a partir de reações de diidroxilação e hidrogenação estereosseletiva da retronecina (1) em 70 e 86 % de rendimento, respectivamente. A abordagem síntética inicial para obtenção de alcalóides indolizidínicos foi baseada na adição do 2-terc-butildimetilsililoxifurano (94) ao íon N-acilimínio derivado da lactama 90. Em função do moderado rendimento e da modesta diastereosseletividade obtida foi proposta uma segunda abordagem sintética para obtenção de indolizidinas. Os alcalóides indolizidínicos, (1R,2S,8aR)- octaidroindolizina-1,2-diol (100) (ent-epi-lentiginosina) e (1R,2S,6R,7S,8aR)- octaidroindolizina-1,2,6,7-tetrol (101) foram preparados a partir da lactona 77. Os compostos 100 e 101 foram obtidos do intermediário-chave 82, que foi preparado a partir da adição de alilamina à lactona 77, derivada do ácido isoascórbico. Em seguida a hidroxiamida 82 foi oxidada à hidroxilactama correspondente, que foi submetida à reação de acetilação fornecendo o composto 91. Reação de alilação de 91, seguido de metátese de olefinas forneceu a indolizidinona 99. Reação de hidrogenação/hidroxilação de 99, redução da lactama e desproteção do acetal levou ao diol 100 e ao tetrol 101 em rendimentos de 27 e 31 %, respectivamente, a partir da lactona 77 / Abstract: The aim of the present work was the synthesis of pyrrolizidine and indolizidine alkaloids using (+)-retronecine (1) and D-isoascorbic acid (35D) as starting materials, respectively. Retronecine (1) was isolated from the vegetal species Senecio brasiliensis. The synthesis of the necine base (1R,6S,7S,7aR)-7-(hydroxymethyl)-hexahydro-1H-pirrolizine-1,6-diol (37) was accomplished by the m-chloroperbenzoic acid epoxidation of retronecine (1). After hydroxyl protection with tert-butyldimethylsilyl chloride, epoxide 44 was subjected to ring opening with nickel Raney and deprotection to yield triol 37, in 5 steps and 15 % yield. Compounds (1R,7S,8R)-7-(hydroxymethyl)-hexahydro-1H-pirrolizin-1-ol (39) and platynecine (72) were prepared after stereoselective dihydroxylation and hydrogenation reactions of retronecine (1) in 70 and 86 % yield, respectively. The first approach to the synthesis of indolizidine alkaloids was based on the 2-tert-butyldimethylsilyloxyfuran addition to lactam 90-derived N-acyliminium ion. Due to moderate yield and diastereoselectivity obtained, a second synthetic approach to the synthesis of indolizidines was suggested. Indolizidine alkaloids 100 and 101 were prepared from lactone 77. Compounds 100 and 101 were obtained from key intermediate 82, which was prepared from allylamine addition to isoascorbic acid-derived lactone 77. Following that, hydroxyamide 82 was oxidized to the corresponding hydroxylactam which was subjected to acetylation, yielding compound 91. Allylation of 91 and subsequent ring closing olefin metathesisyielded indolizidinone 99. Hydrogenation/hydroxylation reaction of 99 followed by lactam reduction and deprotection of acetonide provided diol 100 and tetrol 101, in 27 and 31 % yield, respectively, from lactone 77 / Doutorado / Quimica Organica / Doutor em Ciências

Gold catalysis has attracted much attention within the chemical community in recent years, and its importance as a synthetic tool has only started to be uncovered. This thesis describes the development of a gold(I) catalyzed transformation and its application to the synthesis of a structurally unique Lycopodium alkaloid, Magellanine. Although there have been a few reports on the synthesis of the magellanane core to date, the approach described herein would represent a new and efficient strategy to construct the angularly fused tetracyclic core. The 5 exo dig/Prins reaction that would be the key step of the synthesis was first developed and studied on a model substrate, enabling the verification of the hypothesis that this transformation could indeed form the A and B rings of Magellanine and be applied to its synthesis. This reaction formed the tricyclic products in good yields and in good exo:endo ratios. The synthesis of Magellanine was undertaken, but problems of isomerization prevented the synthesis of the desired 5 exo dig/Prins substrate, which contained the C and D rings of Magellanine with a cis relationship at the ring junction. However, an almost identical substrate, save for a trans configuration between the C and D rings instead of the cis configuration, was prepared and served in further establishing the applicability of this methodology to the synthesis of Magellanine by successfully undergoing the 5-exo-dig/Prins reaction and generating the tetracyclic products. Studies of the steps following the key transformation were performed on the model substrate, allowing for the evaluation of these steps prior to their use in the synthesis. The results of the studies indicate a possible need to revisit the order in which the steps should be carried out. Promising solutions to the different obstacle encountered during the work are presented, demonstrating how the synthesis of Magellanine through a route featuring the 5-exo-dig/Prins cyclization is attainable.

Vašíčková A.: Alkaloids of Vinca minor L. and their biological activity (inhibition of human cholinesterases) V. Diploma thesis, Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany, Hradec Králové 2020. From the selected fraction VM 215-258 were isolated 3 alkaloids by flash chromatography followed, preparative thin layer chromatography and crystallization. Their structure was determined by mass spectroscopy, NMR and optical rotation, and the obtained data were compared with those in literature. Strictamine and minovincinine belong to alkaloids previously isolated, the alkaloid AV-3 has not been isolated yet. These alkaloids were tested for their ability to inhibit human cholinesterases and their inhibitory activity was compared to standards galanthamine and physostigmine. Compound AV-3 showed mild inhibitory activity against BChE (IC50 μM > 86.3 ± 2.3), other alkaloids were considered inactive, their IC50 values against cholinesterases were > 100 μM. Key words: Vinca minor L. (Apocynaceae), vinca alkaloids, minovincinine, strictamine, Alzheimer's disease, acetylcholinesterase, butyrylcholinesterase.

Au cours de ce travail, nous nous sommes intéressés dans une première partie à la synthèse biomimétique d’alcaloïdes de type manzamines et plus particulièrement, aux manadomanzamines. Une étude de la réactivité des deux intermédiaires clés de leur biogenèse, les glutaconaldéhydes et les aminopentadiènals, a été entreprise. Ces mêmes molécules ont ensuite été utilisées comme équivalents synthétiques dans une synthèse biomimétique du squelette pentacyclique de la manadomanzamine A. Une seconde partie est consacrée à la préparation d’analogues stables de la pelletiérine en vue d’une synthèse biomimétique d’alcaloïdes du genre Lycopodium. / This work is dedicated to the biomimetic synthesis of complex polycyclic alkaloids namely the manzamine alkaloids and especially to manadomanzamine. The biogenetic hypotheses postulated for these alkaloids are reported in a first introductory chapter. A few examples of manzamine alkaloids biogenesis are described and compared. The second chapter is focused on the reactivity of reactive units (considered as simplified models of two key biosynthetic intermediates, namely glutaconaldehydes and aminopentadienals) resulting from the ring-opening of pyridinium salts, and their implication in natural products synthesis. Particularly detailed are the investigations conducted on 5-dimethylamino-2-methylpenta-2,4-dienal and the condensation of potassium glutaconaldehyde onto a pyridinium salt. The chemistry of these reactive units has been exploited to design several model studies towards the synthesis of pentacyclic indole nucleus of manadomanzamine A, isolated from an Indonesian sponge Acanthostrongylophora sp.. These biomimetic models, elaborated from a biosynthetic intermediate postulated in our biosynthesis hypothesis have culminated in the synthesis of the central pentacyclic indole nucleus. The last chapter reports the preparation of more or less oxidized analogs of pelletierine, the well known alkaloid isolated from Punica granatum. Compounds such as phenyloxazolopelletierine have been prepared and their reactivity investigated in view of the biomimetic synthesis of Lycopodium alkaloids.

Thesis submitted in fulfilment of the requirements for the Degree of Masters of Technology: Organic Chemistry, Durban University of Technology, 2011. / One of the greatest medical challenges facing mankind is the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) which has now become a major epidemic with more than 40 million people infected worldwide. Of equal concern is its implication in high mortality and the onset of a number of opportunist mycobacterial infections, principally tuberculosis. In spite of the discovery of some relatively effective antiretroviral (ARV) drugs such as Azido Thymidine (AZT), Nevirapine (NVP) and Efavirenz (EFV), its’ application as either a single or combinational form causes side effects by harming the bone marrow. Drug resistance is a key cause of failure for treatment of HIV infection. Hence greater interdisciplinary efforts, involving both natural and social sciences, are needed urgently to combat this HIV/AIDS pandemic. Heterocyclic nitrogen based compounds, obtained from either natural sources or synthesis are adequately documented to have increased biological activity against several diseases. Recently a study of drugs containing the naphthyridine scaffold has acquired increasing attention because of its potential against HIV/AIDS. Generally, naphthyridines demonstrate good potency in both the enzyme and cellular systems and this prompted our interest in the synthesis of naphthyridine derivatives from simple and readily available starting compounds. Furthermore we wanted to form an intermediate quinolone moiety since it has good biological potential. In this study we report the synthesis of three naphthyridine derivatives, i.e. 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2- methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine from easily available chemicals such as aniline, ortho-toludine, para-toluidine and ethyl benzoylacetate via a five step reaction scheme using either conventional reflux, microwave irradiation or both methodologies. It was found that microwave irradiation was several folds faster than conventional reflux methodology and the yield of the product was higher. The first step of the reaction scheme is a simple condensation reaction: three acrylate derivatives, viz. ethyl-3-aniline-3-phenyl acrylate, ethyl-3-phenyl-3-(ortho-tolylamino) acrylate and ethyl-3-phenyl-3-(para-tolylamino) acrylate were synthesized by refluxing ethyl benzoylacetate in an acidified ethanolic solution with aniline, ortho-toluidine and paratoluidine respectively for three hours; the yields were 95, 87.5 and 80 % respectively. Page v In the second step, thermal cyclisation was achieved for the synthesis of three quinoline derivatives, viz. 2-phenylquinoline-4(1H)-one, 8-methyl-2-phenylquinoline-4(1H)-one and 6- methyl-2-phenylquinoline-4(1H)-one from their respective acrylates under microwave irradiation for 5 minutes at 180 °C and 250 watts; the yields were 92, 84 and 80 % respectively. In the third step of the reaction, synthesis of 4-chloro-2-phenylquinoline, 4- chloro-8-methyl- 2-phenylquinoline and 4- chloro-6-methyl-2-phenylquinoline was achieved from a mixture of POCl3 and their respective quinolines via microwave irradiation for 3 minutes at 75 °C and 150 watts and via conventional reflux for 5 hours. It was found that under microwave irradiation, the reaction occurred nearly 100 fold faster but the % yield of the product was marginally higher. The fourth step of the reaction resulted in the formation of three schiff’s base, viz. 4-(Nphenyl)- 2-phenyl-4-aminoquinoline, 8-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline and 6-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline from their respective quinolines via microwave irradiation for 20 minutes at 180 °C and 180 watts and via conventional reflux for 2 hours. It was found that under microwave irradiation, the reaction occurred nearly 6 fold faster and the % yield of the product was over 10 % higher. The final step of the reaction was achieved by a Vilsmeir Haack reaction and in situ base catalyzed thermal cyclisation: 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6- phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine were synthesized from their respective schiffs base via microwave irradiation for 20 minutes at 75 °C at 120 watts and via conventional reflux for 21 hours. It was found that under microwave irradiation, the reaction occurred over 60 fold faster and the % yield of the product was over 20 % higher.The outline for the five step synthesis of the three naphthyridines is presented graphically below: Page vi Key: (a) R1= H; R2=H (b) R1 = H; R2 = CH3 (c) R1 = CH3; R2 =H Reaction Conditions: 1) conc.HCl, EtOH, 3hrs, 50 °C; 2) conc. HCl, hand stirring 10 min; 3) 180 °C, MWI, 250 watts, 5 min; 4) POCl₃, MWI, 75 °C, 150 watts, 2 min; 5) POCl₃, 100 oC, 5 hrs; 6) aniline, t-BuOH, MWI, 180 °C, 180 watts, 20 min; 7) aniline, t-BuOH, 80 °C, 3 hrs; 8) DMF, POCl₃, MWI, 75 °C,120 watts 20 minute; 9) DMF, POCl3, 100 oC, 21 hrs.

published_or_final_version / Chinese Medicine / Master / Master of Philosophy

It has been shown that alkaloids from various sources are vital as lead compounds in medicinal research and thus also the efficient synthesis of these. With the goal of developing a general synthetic route that can potentially access pyrrolizidine, indolizidine, quinolizidine and possibly lehmizidine alkaloid skeletons, a modified route that has been shown to produce pyrrolizidines was employed towards the synthesis of indolizidine alkaloid 223AB. Within this synthesis, a 6-endo-dig hydroamination-cyclization step was attempted for construction of the bicyclic system. For this purpose, a selection of titanium-based catalysts were synthesized in order to determine their regiochemical outcome. For the purpose of investigating ab initio the mechanism of regioselective hydroamination, the skills and methods involved in computational chemistry were acquired through a study into amide rotational barriers: A range of novel 2-oxo-2H-chromen-7-yl dimethylcarbamates were synthesised containing either an oxygen or sulphur in the α-position to the carbonyl or thiocarbonyl group of the amide moiety. Microwave synthesis was essential for the successful synthesis of some of the sulphur containing carbamates. The barriers to internal rotation of each of these compounds were investigated as follows. Variable Temperature and Exchange Spectroscopy NMR was performed on these compounds and the barrier to free amide rotation was calculated. Each of these compounds were also modeled ab initio and the gas phase barrier to rotation calculated. These three sets of data were compared and the influence of the α-heteroatom on rotation for amides and thioamides evaluated. / Thesis (M.Sc.) - University of KwaZulu-Natal, Pietermaritzburg, 2008.

Nováková D.: Biological activity of secondary plants metabolites I. Alkaloids of Narcissus jonquilla L. Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany and Ecology, Hradec Králové 2015, pp. 70. The aim of the diploma thesis was a preparation of alkaloid extracts to identification of alkaloid patterns and measure cholinesterase inhibitory activity. This activity is useful for treating Alzheimer's disease. Alkaloid extracts of seven Narcissus jonquilla L. (Amaryllidaceae) varieties (Sundial, Sundisc, Sweetness, Waterperry, Simplex, Twinkling Yellow, Yazz) were studied with respect to their acetylcholinesterase (HuAChE) and butyrylcholinesterase (HuBuChE) inhibitory activity and alkaloid patterns. Twenty-three alkaloids were determined by GC/MS, and ten of them identified from their mass spectra and retention times. All samples exhibited content of galanthamine, most samples contained lycorine and tazettine. Promising HuAChE inhibition activity was demonstrated by Narcissus jonquilla L. cv. Waterperry with IC50 values of 6.53 ± 0.88 μg/mL. The strongest inhibitory activity against HuBuChE was detected in extract from Narcissus jonquilla L. cv. Sundisc with IC50 value of 5.09 ± 0.64 μg/mL. Keywords: Alzheimer's disease, Amaryllidaceae, Narcissus,...