by Cui Yanyan. / "June 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (p. 154-163). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1973. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (p. 191-213).

Pyrrolizidine alkaloids (PAs) are one of the most significant groups of plant toxins in the world and are an important cause of poisoning in livestock, resulting in significant financial and production losses each year (Kellerman et al. 1996). Pyrrolizidine alkaloids may also enter the human food chain as contaminants of grains, via animal products such as milk, eggs and honey or may be consumed as constituents of herbal medicines (ANZFA 2001). Not all PAs are toxic. Pyrrolizidine alkaloids affecting human health are the esters of 1,2-unsaturated hydroxymethyl dehydropyrrolizidines (DHP). Before it can be converted to DHP, PAs need to have certain essential features, which include an unsaturated 3-pyrrole ring, one or two hydroxyl groups attached to the ring, one or two ester groups and a branched acid moiety (Mattocks 1986). These compounds can be metabolized in the liver to nucleophillic pyrroles which cause damage to hepatocytes (Winter and Segall 1989). Although the involvement of PAs in the development of hepatic veno-occlusive disease is well established (Bras et al. 1961), there is still uncertainty concerning the consequences of long-term, low-dose exposure in humans. Exposure to PAs through the use of herbal remedies may also be a contributing factor to the high rates of liver cancer and cirrhosis seen in Africa (Steenkamp et al. 2000). Crotalaria spp. are known to contain toxic PAs and various incidences of human poisoning through contaminated grains have been recorded in the scientific literature (IPCS 1989). Legislation controlling the allowable levels of toxic seeds in grains in South Africa is generally much stricter than in many other grain producing countries. The Soybean and Sunflower Forum recently commissioned a study (Eloff et al. 2003) to review published and unpublished information on toxic seed that could affect human health in South Africa and to make recommendations accordingly. Crotalaria sphaerocarpa is one of the problem plants discussed in the review and is apparently the only species which regularly contaminate grain in certain areas in South Africa. There is uncertainty at present about the number of these seeds that should be allowed in grains and the threat that this may pose to human health. Based on the review a provisional recommended level of 10 seeds of C. sphaerocarpa per 10 kg of grain was proposed as an approximated safe level in the report. As emphasized by the authors (Eloff et al. 2003), this absolute level is based on assumptions that must still be tested. As a follow-up on the report, a sensitive LC-MS/MS method for the determination of toxic PAs in plants was developed in this study. The characteristic fragments produced by 1,2-unsaturated necine bases under specific MS/MS conditions were used to discriminate between the toxic and non-toxic PAs. The concentration of these PAs were then determined using multi-reaction-mode experiments. Quantitative results were calculated against a retrorsine calibration curve and expressed as µg retrorsine equivalents per gram plant material. Various extraction methods described in the literature were investigated. A final liquid-liquid extraction method was used to extract unsaturated PAs from small amounts (about one gram) of milled plant samples. Recoveries from spiked lucerne samples were 98% for retrorsine and 105% for monocrotaline. To determine the applicability of the LC-MS/MS method the unsaturated PA content of C. laburnifolia and C. dura were investigated. Crotalaria laburnifolia, which is regarded as non-toxic, contained low concentrations (< 20 µg.g-1) of unsaturated PAs. Crotalaria dura, on the other hand, is known to be toxic to livestock and the concentration of unsaturated PAs was significantly higher (585 µg.g-1). The toxic PA content of Senecio inaequidens was also determined after an incident of livestock poisoning. The plant material contained very high concentrations of retrorsine (11.5 mg.g-1) and senecionine (0.5 mg.g-1) which were also present in the rumen content collected post-motally. These results confirmed the suspected toxicity of S. inaequidens. The LC-MS/MS method was also used to follow variations in unsaturated PA content in C. sphaerocarpa plants during the growing season. Pyrrolizidine alkaloids were present in the roots of the growing plants as N-oxides and also found in the mature aerial parts, where it was present mainly as the basic alkaloids. The method was used to determine the concentration of unsaturated PAs, in various C. sphaerocarpa seeds from different locations, in order to calculate the allowable level of C sphaerocarpa seed in maize. Of all the seed samples analyzed, the highest unsaturated PA concentration found was 150 µg.g-1. The allowable level of seed was calculated using this result and was found to be 656 seeds per 10 kg maize, based on the Australian and New Zealand Food Authority level of 0.1 µg.kg-1.day-1. If these results are confirmed with systematic statistical samples of C. sphaerocarpa seed from different grain production areas, the allowable level could be increased substantially. This may have an economic benefit to grain producers. / Thesis (PhD (Paraclinical Science))--University of Pretoria, 2006. / Paraclinical Sciences / PhD / unrestricted

Ruan, Jianqing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 162-175). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

This study was designed to confirm the toxicity of a plant implicated in an outbreak in Frankfort, Free State Province, Republic of South Africa. Cows died acutely after being introduced into a camp, where an abundant, green shrublet was noted to be heavily grazed. The plant was subsequently identified as Senecio inaequidens DC. (Asteraceae) by the South African National Biodiversity Institute (SANBI). Extraction and chemical analyses for pyrrolizidine alkaloids (PA's) in Senecio inaequidens revealed the presence of four different compounds, namely retrorsine and senecionine (known to be hepatotoxic) and two unidentified compounds. The total alkaloid content (free bases plus N-oxides) in the dried, milled S. inaequidens plant material was 0.18%. Four (4) male Sprague Dawley rats, aged 8-9 weeks were dosed per os. Each rat received a different dose; ranging from 0.049 mg/g b.w. to 0.25 mg/g b.w.; of the crude Senecio inaequidens extract. No clinical signs were observed in the rat receiving the lowest dose. Rats receiving higher doses showed depression, an unsteady gait, pilo-erection and jaundice, which was particularly noticeable in the ears. Clinical chemistry evaluation revealed an increase in the activities of ALP, AST (except Rat 1) and GGT in all animals. Total serum bilirubin, creatinine and urea concentrations were also elevated. All rats had low serum globulin concentrations with an A/G ratio above 1.88 (except Rat 1). Post mortem examination of the rats revealed marked hepatic lesions. Histopathological changes were characterized by necrosis (variable in extent) of the centrilobular and midzonal hepatocytes, sparing the portal hepatocytes, with extensive haemorrhage and congestion. Proliferation of the bile ducts, fibrosis and oedema was also present. Ultrastructural changes in affected rats were characterized by margination of chromatin, the presence of numerous autolysosomes in necrotic hepatocytes, intramitochondrial woolly inclusions and changes in the endoplasmic reticulum. A sheep was also dosed in an attempt to reproduce the intoxication. The sheep did not exhibit clinical signs, clinical chemistry aberrations or macroscopic lesions. Histopathological and ultrastructural changes, although milder, were similar to those displayed by the rats. Pyrrolizidine alkaloids were extracted from the liver and kidneys of the rats and sheep. Retrorsine was also detected in the lungs, urine and bile of the sheep. / Dissertation (MSc (Paraclinical Science))--University of Pretoria, 2007. / Paraclinical Sciences / unrestricted

Pyrrolizidine alkaloids are cytotoxic, carcinogenic, and anti-carcinogenic in vivo and in vitro, and they produce many hazardous effects in humans and animals. Pyrrolizidine alkaloids (PAs) also cross-link with DNA and/or protein. However, whether such cross-linking is important to the toxic action of PAs is not known. In addition, the exact mechanism underlying these DNA cross-links or cytotoxicity is also not clear. In three separate studies, I characterized the nature of PA-induced DNA cross-links and the relationships between PA structures and cross-linking potency. In the first study (Chapter II), I found that cross-linking potency of PA congeners coincided with their abilities to cause cytopathologic effects. Macrocyclic a,p-unsaturated diesters PAs and their pyrrolic metabolites were the most potent inhibitors of colony formation, and inducers of cytopathologic changes and megalocyte formation. The macrocyclic α, β-saturated diester PA and open diesters PAs slightly inhibited colony formation, and slightly changed cell morphology. Retronecine and indicine N-oxide were completely inactive. In the next study (Chapter Ill), I found that pyrrolic macrocyclic metabolites were more potent DNA cross-linkers than their parent compounds as determined by alkaline elution. The pyrroles of the macrocyclic diester PAs were potent DNADNA (inter- and/or intra) cross-linkers in BstEll-digested λ-phage DNA or pBR322 plasmid DNA but dehydroretronecine and indicine N-oxide were not. I also examined which DNA sequences were more susceptible to PA-induced cross-links by using a series of restriction endonucleases to determine sequence specificity. The most favorable cross-linking site for PAs appeared to be 5'd(GG) and 5'-d(GA) although other sites, 5'-d(CC) or 5'-d(CG), might be also preferable cross-linking targets. In the next study (Chapter IV), I characterized the nature of DNA-protein interactions induced by PAs, because I found in previous studies that PA-induced cross-links are largely protein associated. In PA or pyrrolic PA exposed cells, cross-linked proteins with molecular weights 40 - 60 kD were detected. Two-dimensional electrophoretic analysis revealed that these proteins were probably acidic in nature. In an in vitro system utilizing pBR322 or Bst Ell-digested λ-phage DNA. dehydrosenecionine induced DNAprotein cross-links with BSA, indicating that such interactions might be related to amino acid composition of protein. These results confirmed that PA-induced DNA cross-links (DNA-DNA, DNA-protein cross-links) are influenced by three structural features: the C1 ,2 unsaturation of pyrrolizidine ring, α, β-unsaturation, and size of the macrocyclic diester ring. The ability to form cross-links was closely related to the known toxic potencies of these PAs. From this research, I also conclude that DNA crosslinking is the most critical event leading to PA-related diseases and that crosslinking is due to pyrrolic metabolites of PAs, not via a common metabolite as was once thought.

Delairea odorata Lem., an asteraceous perennial vine indigenous to southern Africa, has become naturalised and invasive in many subtropical regions including California, South Australia and Hawaii. Biological control offers a potential long term solution to the management of this species in exotic locations. This study analysed aspects of the biology of D. odorata in its native environment to determine its suitability to classical biological control. To this end an examination of the reproductive biology and natural enemies of D. odorata was made. A study of the pyrrolizidine alkaloid profile was also conducted. Reproductive biology: Delairea odorata reproduces both sexually by seeds and asexually by stolons. The flowering season occurs over the autumn months from April to June. Results of the pollination trials indicate that D. odorata is a cross compatible species and an obligate outbreeder. There is no specialised pollination system and the predominant pollinators belong to the families Apidae, Syrphidae and Calliphoridae. Following pollination, numerous small achenes are produced. Laboratory trials indicate that these achenes germinate readily between 10 and 25 °C and, although germination occurs in both the light and dark, light clearly stimulates seed germination. Greenhouse trials conducted to determine the effect of light on growth and reproduction indicate that D. odorata is a shade tolerant species which shows plasticity in terms of growth form and deployment of biomass in response to changes in light intensity. Growth rate and allocation of biomass to vegetative and sexual reproduction are highest at an intermediate light level. However, greatest allocation of biomass is to stem growth regardless of light level. Natural enemies: Surveys for potential biological control agents against Delairea odorata were conducted in KwaZulu-Natal and several phytophagous species were associated with the plant. However, only one potentially suitable control agent was identified, a stem galling tephritid fly, Parafreutreta regalis Munro. Preliminary studies indicate this species to be fairly host-specific, a valuable asset if it is to be considered as a control agent. Furthermore, as D. odorata proliferates extensively by means of stem regeneration and elongation, galling of these growing points by P. regalis may limit stolon spread in exotic locations. Two species of parasitic wasp (Braconidae) were found to parasitise P. regalis pupae. If P. regalis is to be used as a control agent the likelihood of parasitisation in the new environment must be determined. Pyrrolizidine alkaloids: Host-specificity in insects is often dependent on host-plant chemistry (e.g. alkaloids or essential oils). Thus prior to any biological control programme it is important to determine if there are ecotypes of the host plant present. An investigation to determine the specificity of the pyrrolizidine alkaloid profile of D. odorata, occurring across KwaZulu-Natal, was made. The results indicate the presence of nine retronecine based pyrrolizidine alkaloids which occur in similar proportions in locally distributed plants. However, these alkaloid profiles differ considerably from those published for D. odorata occurring in California. This is an interesting and important result which indicates that chemotypes of D. odorata may exist, a factor which must be considered in the initiation of any biocontrol. If chemotypes of D. odorata are present this may affect the behaviour of natural control agents on the exotic plant populations. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2000.

Senecio brasiliensis, conhecida popularmente como maria-mole, é uma das principais causas de intoxicação em animais de produção, principalmente em eqüinos e bovinos. A toxicidade desta planta ocorre devido à presença dos alcalóides pirrolizidínicos (APs), os quais sofrem biotransformação no fígado gerando como metabólitos tóxicos os pirróis. Além disso, esses compostos tóxicos podem ser transferridos para o homem através de produtos comestíveis de origem animal contaminados ou pelo uso na medicina popular. Até o momento, não há relatos a respeito de seus efeitos tóxicos sobre a prole de animais expostos durante a gestação. Assim, o objetivo deste trabalho foi avaliar os possíveis efeitos tóxicos da exposição pré-natal ao S. brasiliensis. Ratas Wistar fêmeas prenhes receberam por gavagem, do 6° até o 20º dia de gestação, diferentes doses de S. brasiliensis (3, 6 e 9 mg/Kg/dia). Durante o período de gestação foi avaliado o peso materno, consumo de água e de ração; ainda, nas progenitoras se avaliou o comportamento materno e materno agressivo. Na prole avaliaram-se os parâmetros do desenvolvimento físico e reflexológico; quando adultos avaliou-se aspectos comportamentais, hematológicos, bioquímicos, anatomopatológico e níveis de neurotransmissores. Os resultados mostraram diminuição no consumo de ração e no ganho de peso nos diferentes grupos experimentais, de forma dose-dependente. Ratas tratadas com a maior dose de S. brasiliensis apresentaram prejuízo no comportamento materno e materno agressivo. Os filhotes provenientes de ratas que receberam as doses de 6 e 9 mg/Kg apresentaram atraso para o início do desenvolvimento físico e reflexológico. Na prole adulta masculina proveniente da maior dose experimental observou-se aumento da atividade motora no campo aberto, bem como aumento na frequência de entrada e no tempo gasto nos braços abertos do labirinto em cruz elevado. Na natação forçada observou-se aumento no tempo de escalada na prole feminina proveniente da maior dose, enquanto na prole masculina adivinda dos grupos de 6 e 9 mg/Kg notou-se diminuição no tempo de natação. Na avaliação do comportamento estereotipado observou-se aumento deste comportamento em fêmeas advindas do grupo de maior dose experimental. Ainda, na prole adulta, foram osbervadas alterações hematológicas e bioquímicas; a análise histológica revelou aumento de células multinucleadas em animais provenientes dos grupos de 6 e 9 mg/Kg e com relação análise dos neurotransmissores, foram observadas alterações a nível estriatal. Estes resultados indicam que a exposição durante a gestação ao S. brasiliensis causa toxicidade materna acompanhada de prejuízo em ambos comportamento, materno e materno agressivo. Com relação à prole, houve prejuízo no desenvolvimento físico e reflexológico, e na idade adulta foram observadas alterações comportamentais e hematológicas, bem como algumas alterações bioquímicas e anatomapatológicas. / Senecio brasiliensis popularly known as \"Maria Mole\" (=lazy Mary), is a principal cause of poisoning in livestock, mainly in horses and cattle. The toxicity of this plant is caused by pyrrolizidine alkaloids (PAs) that are metabolized by hepatic enzymes to very toxic pyrrole metabolites. In addition, these compounds can be transferred to humans through animal products or using this plant as popular medicine. There are no reports about its toxic effects on the offspring. Thus, the aim of this study was evaluate the possible toxic effects of prenatal exposure to S. brasiliensis on rat offspring. Pregnant Wistar rats received different doses of S. brasiliensis (3, 6 and 9 mg/kg, by gavage, from 6th to 20th pregnancy day. During the gestational period were evaluated the maternal weight gain and water and food intakes, as well in dams were evaluated maternal and maternal aggressive behavior. In offspring were evaluated physical and reflexologic development and, when adult, the offspring were evaluated for behavioral aspects, haematological, biochemical, anatomopathological parameters, and neurotransmitters levels. The results showed decreased a dose-dependent decrease in food intake and weight gain of dams. Dams treated with the highest S. brasiliensis dose showed impairment in maternal and maternal aggressive behavior. The offspring exposed to 6 and 9 mg/Kg of S. brasiliensis showed delay at the beginning of the physical and reflexologic development. In adult male offspring the highest dose was observed increased on open field motor activity and the frequency of entries and spent time on open arms of the elevated plus-maze. In forced swimming test was observed increase on climbing time female offspring exposed to highest dose and decrease swimming time in male offspring from 6 mg/kg and 9 mg/kg doses. On stereotypic behavior test, only the female offspring exposed to the highest dose showed increase of this behavior. The adult offspring showed few haematological and biochemical alterations, and the study histophatology demonstrated increased of hepatic multinucleated cells in animals exposed to both 6 and 9 mg/kg groups ;on the neurotransmitters levels alterations only at striatum. These results suggest that the S. brasiliensis exposure during the pregnancy cause maternal toxicity and impairment in both maternal and aggressive maternal behavior. The offspring showed damage in physical and reflexologic development, while in adulthood was observed behavioral and changes and some haematological, biochemical and anatomopathological alterations.

Senecio brasiliensis, conhecida popularmente como maria-mole, é uma das principais causas de intoxicação em animais de produção, principalmente em eqüinos e bovinos. A toxicidade desta planta ocorre devido à presença dos alcalóides pirrolizidínicos (APs), os quais sofrem biotransformação no fígado gerando como metabólitos tóxicos os pirróis. Além disso, esses compostos tóxicos podem ser transferridos para o homem através de produtos comestíveis de origem animal contaminados ou pelo uso na medicina popular. Até o momento, não há relatos a respeito de seus efeitos tóxicos sobre a prole de animais expostos durante a gestação. Assim, o objetivo deste trabalho foi avaliar os possíveis efeitos tóxicos da exposição pré-natal ao S. brasiliensis. Ratas Wistar fêmeas prenhes receberam por gavagem, do 6° até o 20º dia de gestação, diferentes doses de S. brasiliensis (3, 6 e 9 mg/Kg/dia). Durante o período de gestação foi avaliado o peso materno, consumo de água e de ração; ainda, nas progenitoras se avaliou o comportamento materno e materno agressivo. Na prole avaliaram-se os parâmetros do desenvolvimento físico e reflexológico; quando adultos avaliou-se aspectos comportamentais, hematológicos, bioquímicos, anatomopatológico e níveis de neurotransmissores. Os resultados mostraram diminuição no consumo de ração e no ganho de peso nos diferentes grupos experimentais, de forma dose-dependente. Ratas tratadas com a maior dose de S. brasiliensis apresentaram prejuízo no comportamento materno e materno agressivo. Os filhotes provenientes de ratas que receberam as doses de 6 e 9 mg/Kg apresentaram atraso para o início do desenvolvimento físico e reflexológico. Na prole adulta masculina proveniente da maior dose experimental observou-se aumento da atividade motora no campo aberto, bem como aumento na frequência de entrada e no tempo gasto nos braços abertos do labirinto em cruz elevado. Na natação forçada observou-se aumento no tempo de escalada na prole feminina proveniente da maior dose, enquanto na prole masculina adivinda dos grupos de 6 e 9 mg/Kg notou-se diminuição no tempo de natação. Na avaliação do comportamento estereotipado observou-se aumento deste comportamento em fêmeas advindas do grupo de maior dose experimental. Ainda, na prole adulta, foram osbervadas alterações hematológicas e bioquímicas; a análise histológica revelou aumento de células multinucleadas em animais provenientes dos grupos de 6 e 9 mg/Kg e com relação análise dos neurotransmissores, foram observadas alterações a nível estriatal. Estes resultados indicam que a exposição durante a gestação ao S. brasiliensis causa toxicidade materna acompanhada de prejuízo em ambos comportamento, materno e materno agressivo. Com relação à prole, houve prejuízo no desenvolvimento físico e reflexológico, e na idade adulta foram observadas alterações comportamentais e hematológicas, bem como algumas alterações bioquímicas e anatomapatológicas. / Senecio brasiliensis popularly known as \"Maria Mole\" (=lazy Mary), is a principal cause of poisoning in livestock, mainly in horses and cattle. The toxicity of this plant is caused by pyrrolizidine alkaloids (PAs) that are metabolized by hepatic enzymes to very toxic pyrrole metabolites. In addition, these compounds can be transferred to humans through animal products or using this plant as popular medicine. There are no reports about its toxic effects on the offspring. Thus, the aim of this study was evaluate the possible toxic effects of prenatal exposure to S. brasiliensis on rat offspring. Pregnant Wistar rats received different doses of S. brasiliensis (3, 6 and 9 mg/kg, by gavage, from 6th to 20th pregnancy day. During the gestational period were evaluated the maternal weight gain and water and food intakes, as well in dams were evaluated maternal and maternal aggressive behavior. In offspring were evaluated physical and reflexologic development and, when adult, the offspring were evaluated for behavioral aspects, haematological, biochemical, anatomopathological parameters, and neurotransmitters levels. The results showed decreased a dose-dependent decrease in food intake and weight gain of dams. Dams treated with the highest S. brasiliensis dose showed impairment in maternal and maternal aggressive behavior. The offspring exposed to 6 and 9 mg/Kg of S. brasiliensis showed delay at the beginning of the physical and reflexologic development. In adult male offspring the highest dose was observed increased on open field motor activity and the frequency of entries and spent time on open arms of the elevated plus-maze. In forced swimming test was observed increase on climbing time female offspring exposed to highest dose and decrease swimming time in male offspring from 6 mg/kg and 9 mg/kg doses. On stereotypic behavior test, only the female offspring exposed to the highest dose showed increase of this behavior. The adult offspring showed few haematological and biochemical alterations, and the study histophatology demonstrated increased of hepatic multinucleated cells in animals exposed to both 6 and 9 mg/kg groups ;on the neurotransmitters levels alterations only at striatum. These results suggest that the S. brasiliensis exposure during the pregnancy cause maternal toxicity and impairment in both maternal and aggressive maternal behavior. The offspring showed damage in physical and reflexologic development, while in adulthood was observed behavioral and changes and some haematological, biochemical and anatomopathological alterations.

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