The soft corals of the species Paralemnalia thyrsoides was found to be a rich source of sesquiterpenoids, such as nor-nardosinane, nardosinane, neolemnane, and eremophilane, and other related skeletons. Continuing investigation on the chemical constituents of Paralemnalia thyrsoides has led to the isolation of nine new compounds, including one dinor-nardosinane 1, one neolemnane 2, five nardosinanes 4, 6¡V9, and two nor-nardosinanes 10 and 11, along with eleven known compounds, 2-deoxy-7-O-methyllemnacarnol (3), 2-deoxy-12£\-methoxy-7-O-methyllemnacarnol (5), paralemnolin Q (12), paralemnolin R (13), 4-acetoxy-2,8-neolemnadien-5-one (15), paralemnolin E (16), flavalins E (17), isoparalemnanone (18), paralemnolin K (19), and nor-nardosinane sesquiterpenoids (14 and 20). The structures of these compounds were determined on the basis of their spectroscopic analysis (1H, 13C NMR, 1H¡V1H COSY, HSQC, HMBC, IR and HRESIMS) and by comparison of the physical and spectral data with those of the related known compounds. The relative stereochemistry and assignments of 1H NMR chemical shifts were determined by NOESY and coupling constants. The absolute stereochemistry of dinor-nardosinane 1 was further determined by application of the Mosher¡¦s method. The cytotoxicity against of P-388 (murine lymphocytic leukemia), HT-29 (human colon adenocarcinoma), and A-549 (human lung epithelial carcinoma) cells as well as the anti-HCMV (human cytomegalovirus) activities of metabolites 1, 2, 4, 6¡V11 were evaluated. Metabolites 2, 3, 5, 6, 8 and 9 exhibited significant activity against P-388 cell in vitro ( ED50 ¡Ø 4 £gg/ mL) Keywords: Paralemnalia thyrsoides, sesquiterpenoids, cytotoxicity, anti-HCMV

Yes / Chemical manipulation of the cycloadduct of citraconic anhydride and cyclopentadiene enables a new synthetic route to tricyclane sesquiterpenoids. This methodology is applied to the first total synthesis of α-ekasantalic acid. / Spanish Ministry of Education, Culture and Sport for financial support (grant number TME2011-00267 (LL)).

Orientador: Lucia Helena Brito Baptistella / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T12:46:19Z (GMT). No. of bitstreams: 1 Hardy_LucasDrezza_M.pdf: 14614232 bytes, checksum: 4408ec95d3c1b1cea15f8a31fef54c48 (MD5) Previous issue date: 2007 / Resumo:O a-(-)-bisabolol (1) é um sesquiterpeno bisabolano isolado de óleos essenciais de uma grande variedade de plantas, e muito conhecido principalmente por suas atividades farmacológicas. Rotas sintéticas visando a obtenção da (+)-hernandulcina e do acetato do (1S)-1-hidroxi-óxido de bisabolol A, outros sesquiterpenos naturais do tipo bisabolano com atividade adocante e antimalária, respectivamente, tiveram como etapas iniciais tentativas de oxidações alílicas sobre a olefina endocíclica do (-)-1, as quais forneceram diversos produtos. Como meio de diminuir a formação dos produtos laterais frente a estas oxidações, bem como favorecer a formação de derivados cíclicos do (-)-1, úteis quando se visa a síntese do acetato do acetato do (1S)-1-hidroxi-óxido de bisabolol A, a cadeia lateral hidroxílica g,d-insaturada do (-)-1 foi ciclizada utilizando como eletrófilos o iodo e bromo. Em oposição ao que desejávamos, em todas as ciclizações testadas foi verificada a formação majoritária dos derivados tetraidrofuranicos (THF), atribuida, em função dos dados obtidos ao longo do trabalho, a fatores estruturais do substrato e do meio de reação. Testes de oxidações sobre os derivados tetraidrofuranicos (THF) e tetraidropiranicos (THP) de (-)-1 isolados, permitiram verificar que a formação dos derivados oxidados desejados ocorria apenas sobre os derivados THP. Após esta constatação, vários testes visando expansão do anel THF a THP, bem como metodologias para obtenção seletiva dos derivados THP a partir de (-)-1 foram conduzidos, e alguns bons resultados foram obtidos. Adicionalmente, propos-se, ao final do trabalho, uma nova rota para obtenção dos derivados THP a partir de (-)-1, baseada na utilização do linalool como precursor das ciclizações. Paralelamente ao trabalho, diversos compostos obtidos foram submetidos a estudos de atividade antiproliferativa frente a linhagens de celulas tumorais, que permitiram observar que a funcionalização do anel p-mentânico de (-)-1 e um dos fatores responsáveis pela atividade apresentada pelos compostos. / Abstract: The a-(-)-bisabolol (1) is a bisabolene sesquiterpene isolated from the essential oil of several plants, and its pharmacological activities are well known. Synthetic studies envisaging (+)-hernandulcin and (1S)-1-hydroxi-oxide bisabolol A acetate, natural bisabolane sesquiterpenes with sweetener and antimalarial activities, respectively, had been initiated using endocyclic allylic oxidation reactions, which lead to a mixture of products. In order to minimize the formation of by-products and to obtain cyclic derivatives of (-)-1, useful as intermediates for the synthesis of (1S)-1-hidroxi-oxido de bisabolol A, the hydroxylic g,d-unsaturated system of the a-bisabolol was submitted to cyclization reactions using iodine and bromine as electrophiles. In opposition with the expectations, all reactions led to the formation of the THF derivatives as the major products, and it was attributed to the structural features of the substrate and to the reaction conditions. Allylic oxidation essays on the isolated THF and THP derivatives were successfully performed only with the six member ring isomers. Several reactions aiming the THF ring expansion, as well as other methods envisaging the selective preparation of the THP derivative from (-)-1, some of them leading to good results, were also carried out. In addition to these studies, a new synthetic route for the preparation of tetrahydropyran derivatives was proposed from linalool and the initial essays were conduced. Some new compounds obtained in this research project were also submitted to antiproliferative essays. / Mestrado / Quimica Organica / Mestre em Química

Nature’s expertise and virtuosity in creating a phenomenal array of carbocyclic frameworks finds its full expression in the terpenoid group of natural products. The total synthesis of natural products frequently provided the impetus for great advances in organic synthesis. The thesis entitled “Enantiospecific synthesis of silphiperfolane, basmane and fusicoccanes” describes the enantiospecific total synthesis of silphiperfolanes, enantiospecific approach to a bisnorbasmane and an enantiospecific formal total synthesis of ent-fusicoauritone. In the thesis, in each chapter the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. Silphiperfol-6-ene, is the first member of silphiperfolane sesquiterpenes, isolated in 1980 by Bohlmann et al. from Silphium perfoliatum. In 1990, Wright and coworkers reported the isolation of (6S,7R)-silphiperfolan-6-ol (wrongly assigned as (6R,7S)-silphiperfolan-6-ol) from the red algae Laurencia majuscula. Subsequently, in 1997, Wayerstahl and coworkers reported the isolation of all the four possible diastereomers (with respect to C-6 and C-7) of silphiperfolan-6-ols from the essential oil of the rhizomes of Echinops giganteus var lelyi C.D Adams. In the present thesis, enantiospecific synthesis of angular triquinanes has been described in the first chapter. To begin with, (R)-limonene was transformed into the known 6-isopropenyl-1,5-dimethylbicyclo[3.3.0]octan-3-one, which was used as the key intermediate for the construction of the angular triquinane of siliphiperfolanes. An intramolecular rhodium carbenoid insertion into the CH bond of atertiary methyl group at the ring junction of diquinane was employed as the key reaction forthe synthesis of the angular triquinane for the generation of norsilphiperfolane and norcameroonanes. The methodology has been extended to an enantiospecific total synthesis of silphiperfol-6-ene and its C-9 epimer, starting from the diquinane containing a secondary methyl group in addition to two ring junction tertiary methyl groups. In the process, it was also observed a competitive intramolecular insertion of the rhodium carbenoid into the γ- and β-CH bonds leading to the generation of cyclopentanone and cyclobutanones. Subsequently, the sequence has been modified and enantiospecific first total syntheses of(6S,7R)- silphiperfolan-6-ol and (6R,7S)-silphiperfolan-6-ol have been accomplished. In 1983, Wahlberg and coworkers reported the isolation of the diterpenoid 7,8-epoxy-4-basman-6-one, containing an interesting 5-8-5 tricyclic system, from the volatile neutral portion of the diethyl ether extract of sun-cured leaves of greek tobacco (serres). In 1994, Becker et al. reported the isolation of fusicoauritone from the liverwort Anastrophyllum auritum collected in Ecuador. In the second chapter, enantiospecific synthesis of the 5-8-5 ring system of bisnorbasmane and an enantiospecific formal total synthesis of fusicoauritone have been described, starting from the readily available monoterpene (R)-limonene. RCM reaction of a decadiene was employed as the key reaction for the generation of the AB ring system of fusicoccane and basmanes. An intramolecular rhodium carbenoid CH insertion of a diazoketone was utilized for the construction of the C-ring of basmanes. Subsequently, an enantiospecific formal total synthesis of fusicoauritone has been accomplished. Two RCM reactions were employed as the key reactions for the construction of the eight- and five membered rings B and C, respectively, of fusicoccanes.

Natural product synthesis has been a most exciting and challenging branch of organic chemistry in view of its creative power and unlimited scope. Natural product synthesis witnessed an unprecedented growth and innovative developments, especially during the later half of the 20th century. This can be attributed to a number of factors, one of which has been the isolation and characterization of growing number of compounds from natural sources through availability of newer techniques of isolation and purification and advances in the incisive tools (eg. 2D NMR, X-ray, HRMS) of structure determination. Many natural products, though scarce from natural resources, possess wide ranging biological activity and need to be accessed through synthesis for clinical development and evaluation, particularly of analogs. This has been one of the main stimuli in recent years for undertaking the synthesis of natural products. Among the diverse architecture created by Nature, terpenoids are the most variegated in terms of the presence of a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenoids makes them challenging targets for total synthesis and for the articulation of new synthetic strategies for carbocyclic ring construction. One of the major concerns in organic chemistry, particularly of relevance in synthesis is the control of diastereoselectivity in nucleophilic and electrophilic additions to trigonal carbon atoms as this is the fundamental step in stereogenesis. Several approaches have been devised to achieve diastereoselection and to understand the interplay of underlying stereoelectronic factors. In this context, introduction of newer probe systems and search for incisive interpretations are continuously enriching the area. The present thesis addresses both the above mentioned themes of contemporary interest in organic chemistry and is presented in two main parts. Part-1: A Total Synthesis of Novel Sesquiterpenoid Natural Product (±)-Merrilactone A. Part-2: A Study of -Face Selectivity in Additions to Trigonal Carbon Centers in Iso-steric Environments. The Part-1 describes our travails towards a stereoselective construction of the complex framework present in the biologically potent and structurally novel sesquiterpene natural product Merrilactone A culminating in its total synthesis. The Part-2 narrates the results of -face selectivity in addition reactions to two novel systems, exo-5-subtituted bicyclo[2.1.1]hexan-2-ones, 5-exo-substituted 2-methylene-bicyclo[2.1.1]hexane and 1-substitued tricyclo[2.1.0.02,5]pentan-3-ones, employing various nucleophiles and electrophiles

Nature’s expertise in creating breathtaking structural wonders which are vital for sustenance of life on this planet has astonished and inspired many synthetic chemists. We too have been attracted towards understanding, exploring and mimicking a few of these magnificent molecular entities. Our efforts are directed towards the synthesis of two types of molecular assembles of contemporary interest; first of them are medium ring carbohydrate mimetics which are unnatural compounds inspired by Nature and other class consisted of the terpenoid natural products which are conceived and assembled by Nature in ever increasing numbers. The spectacular development of carbohydrate mimetics, prompted primarily by their properties as glycosidase inhibitors, has led to the conception and synthesis of a wide variety of novel structures, the most significant ones belonging to the families of imino sugars and carbasugars. Major advances in diverse subjects such as chemical synthesis, analytical chemistry, structural biology, cell-surface recognition, molecular modeling and spectroscopy have made carbohydrate mimetics embraced by scientific community with increasing vigor. A major area of interest of organic chemistry is the total synthesis of complex natural products conceived and created by Nature. As a result of refinements in isolation and purification techniques and recent advances in spectroscopy and crystallography, unravelling of natural products from exotic species such as wild plants to microorganisms and from geographic locations ranging from mountain tops to the ocean floors, has made identification and structural elucidation of complex natural products a fairly routine exercise. Among natural products, terpenoids are considered as masterpieces of structural diversity with their bewildering carbocyclic arrangements and diverse functionalities embedded in them. The present thesis entitled “Synthesis of medium ring carbasugar analogues and terpenoid natural products” is an effort to design and synthesise natural and unnatural molecular entities either conceived by human mind or inspired by Nature. The research described in this thesis has been organized under three chapters. Chapter I: Design and synthesis of cyclooctanoid and cyclononanoid carbasugar analogues. Chapter II: A total synthesis of putative structure of sesquiterpenoid natural product dichomitol. Chapter III: A total synthesis of diterpenoid natural product guanacastepene C. A brief overview of each of these three chapters is presented below.(For Equations and Figures Refer PDF File) Chapter I: Design and synthesis of cyclooctanoid and cyclononanoid carbasugar analogues In recent years, the search for new therapeutically useful glycosidase inhibitors, mimicking carbohydrates 1, has extended beyond the realm of five and six membered cyclitols 2 (carbasugars), and targeted towards the medium-sized carbocyclic cores. In this context, we have conceptulised a new family of novel cyclooctanoid 3 and cyclononanoid 4 carbasugar analogues in order to study the effect of the enhanced flexibility and of new spatial distribution displayed by these structures on their adaptability in the active site of the enzymes. We have developed a versatile synthesis of cyclooctane based polyols 3 from commercially available hydrocarbon cyclooctatetraene 5. It was visualised that a bicyclo[4.2.1]nona-2,4,7-trien-9-one 6 is a functionally locked cyclooctatetraene with dispensed and differentiated double bonds and a masked C9 cycloocta-carbasugar from which the eight membered ring can be extracted through oxidative C1-C9 bond scission, Scheme 1. Several transformations in 6, leading to a range of polyhydroxylated cyclooctanoids was envisaged. Bayer-villiger oxidation in ketone 6 was smooth and led to a δ-lactone which on catalytic OsO4 dihydroxylation furnished diol 7. Further acetylation on 7 delivered a rearranged γ-lactone 8. LAH reduction in 8 and peracetylation furnished diene 9. Controlled catalytic hydrogenation in 8 furnished 1:1 mixture of 10 and 11, which on hydride reduction gave tetrols 12 and 13, respectively, Scheme 2. Protection of vic diol in 12 led to 14. Hydroboration-oxidation of 14 and peracetylation furnished three diastereomeric mixture of acetonide triacetates in 9:4:1 ratio and they were hydrolysed to give 15-17, Scheme 3. Interestingly, pentahydroxy 16 is an eight membered analogue of α-talose. Reagents and conditions: i) m-CPBA, DCM, 60% ii) OsO4, NMMO, acetone-H2O, 75% iii) Ac2O, Py, 90% iv) LAH, THF v) Ac2O, Py, 36% (2 steps) vii) H2, Pd/C, EtOAc, 95% viii) LAH, THF, 40%. Reagents and conditions: i) acetone, amberlyst-15, 80% ii) BH3-THF, NaOH, H2O2 iii) Ac2O, Py, 54% (2 steps) iv) 2N, HCl, 76%. Acetylation of 12 led to tertraacetate 18 which on OsO4-dihydroxylation and acetylation furnished two diastereomeric hexaacetates in 1:1 ratio. Hydrolysis of these hexaacetates with base furnished 19-20, Scheme 4. Reagents and conditions: i) Ac2O, Py, 90% ii) OsO4, NMMO, acetone-H2O iii) Ac2O, Py, 72% (2 steps) iv) NaOMe, MeOH, 75%. Diene 9 on exhaustive stereoselective double dihydroxylation and base hydrolysis led to octahydroxycyclooctane 21, Scheme 5. A cyclooctane derivative bearing eight oxygen atoms has been prepared for the first time. Reagents and conditions: i) OsO4, NMMO, acetone-H2O ii) NaOMe, MeOH, 56% (2 steps). In an unconventional but interesting enterprise, commercially available hydrocarbon cyclooctatetraene 5 has been elaborated to a rare hexose sugar (DL)-β-allose and its 2C branched analogue. The main theme in this approach was to generate a cyclic acetal moiety, a structural characteristic of sugars through ozonolytic cleavage of an appropriately crafted olefin and in situ intramolecular acetalisation, Scheme 6. Acetonide protection in 7 led to 22. LAH reduction in 22 liberated the diol and selective primary alcohol protection as TBS derivative furnished 23. Ozonolysis of 23 and PCC oxidation of the resulting lactal 24 led to lactone 25. Methoxide mediated lactone opening in 25 and protection of anomeric hydroxyl group as methyl ether led to 26. LAH reduction of ester led to 27 and further deprotections furnished (DL)-methyl-2-deoxy-2C-hydroxymethyl-β-allose 28. Protected hexose homologue 27 was converted via a mesylate to the terminal olefin 29 through a series of functional group transformations. Ozonolysis of 29 furnished hemiacetal 30, which on sodium borohydride reduction and acetonide deprotection delivered (DL)-methyl-β-allopyranoside 31, Scheme 7. Motivated and encouraged by the synthesis of cyclooctane carbasugar analogues, it was decided to venture into the synthesis of cyclononane carbasugar analogues. It was visualized that appropriately functionalized bicyclo[4.3.1]decane system 32, can serve as a masked C10 cyclononane carbasugar from which the nine membered ring can be extracted through the C1-C10 bond scission, Scheme 8. Reagents and conditions: i) 2,2-DMP, CSA, 65% ii) LAH, THF, 80% iii) TBSCl, imidazole, 54% iv) O3, DCM-MeOH, DMS v) PCC, DCM, 40% (2 steps) vi) NaOMe, MeOH vii) MeI, Ag2O, 73% (2 steps) viii) LAH, THF, 85% ix) TBAF, THF, 70% x) amberlyst-15, MeOH, 65% xi) Ac2O, DMAP, 92% xii) TBAF, THF, 74% xii) MsCl, DCM, 65% xiv) KOtBu, DMSO, 70% xv) O3, DCM, 75% xvi) NaBH4, MeOH, 80% xvii) amberlyst-15, MeOH, 60%. The bridged dienone 32 was readily prepared from cyclohexanone following a literature protocol. Ketone 32 on Bayer-Villiger oxidation furnished lactone 33 in moderate yield, and further exhaustive double dihydroxylation furnished two unanticipated rearranged products δ-lactone 34 and γ-lactone 35 in 5:3 ratio. Both, the novel lactones 34 and 35 were further elaborated to the corresponding hexahydroxy cyclononane carbasugar analogues 36 and 37, Scheme 9. These novel medium ring carbasugar analogues involving a nine memebered carbocycle have been synthesized for the first time. Reagents and conditions: i) m-CPBA, DCM, 60% ii) OsO4, NMMO, acetone-H2O, 54% of 34 and 32% of 35 iii) acetone, PPTS, 98% iv) LAH, THF, 90% v) 2N HCl, 88% vi) acetone, PPTS, 92% vii) LiBH4, THF, 50% viii) 2N HCl, 88%. All the details of our synthetic efforts towards several novel carbasugar analogues which have been synthesised for the first time, along with the synthesis of some interesting polyoxygenated carbocyclic intermediates, unusual products from rearrangements, incisive NMR studies and X-ray analyses to solve the stereochemical puzzles, along with enzyme inhibition studies will be presented in this chapter of the thesis. Chapter II: A total synthesis of putative structure of sesquiterpenoid natural product Dichomitol This chapter describes the first total synthesis of the putative structure of the sesquiterpenoid natural product dichomitol 55 bearing a novel triquinane framework, and reported in 2004 from the bascidiomycete fungi Dichomitus squalens by a group of Chinese researchers. Dichomitol 55 not only represented a novel skeletal-type among linear triquinanes but was also biogenetically quite intriguing as it was suggested to be related to hirsutanes through an unusual methyl shift. This unusual positioning of methyl group in Reagents and conditions: i) CO(OCH3)2, THF, 82% ii) MeI, THF, 90% iii) ethanedithiol, PTSA, 75%, iv) Raney-Ni, EtOH, 90% v) PCC, DCM, 90% vi) LHMDS, THF, -78 °C; Pd(OAc)2, CH3CN, 86% vii) MeLi, ether viii) PCC, DCM, 84% (2 steps) ix) Mg, 4-bromobutene, CuBr-DMS, THF; AcOH, 95% x) LHMDS, THF, -78 °C; Pd(OAc)2, CH3CN, 80% xi) DBU, KOtBu, PTSA, RhCl3. dichomitol 55 which probably originated through a Wagner-Meerwein rearrangement of a corresponding ceratopicane derivative aroused our interest, curiosity (and suspicion) towards this natural product and it was decided to undertake its total synthesis. Our synthesis commenced from the known bicyclic ketone 39 readily accessible from commercially available 1,5-cyclooctadiene 38 through a sequence previously developed in our laboratory. Successive α- carbomethoxylation and α-methylation correctly installed C-11 centre in 40. Carbonyl group in 40 was protected as its thioketal to furnish 41 which on reductive desulphurization with simultaneous benzyl deprotection and further oxidation led to ketone 42. Following Saegusa protocol, 42 was converted into enone 43. Alkylative transposition in 43 furnished enone 44, which on Cu(I) mediated 1,4-conjugate addition delivered 45 with desired methyl stereochemistry with preferred addition from the exo-face. Kende cyclization in 45 smoothly delivered tricyclic 46, a C5-C6 double bond isomer of the desired tricyclic precursor of the natural product. Several attempts to isomerise the C5-C6 double bond in 46 to the required C6-C7 position failed to deliver 47, Scheme 11. Reagents and conditions: i) ethyleneglycol, PTSA, C6H6, 97% ii) LAH, THF, 96% iii) amberlyst-15, acetone, 95% iv) TBSCl, imidazole, DCM, 98% v) OsO4, NMMO, acetone-H2O, 90% vi) TBSCl, imidazole, DCM, 86% vii) IBX, DMSO-toluene, 78% viii) LHMDS, THF, -78 °C, 40% ix) Martin sulfurane, CHCl3, 40% x) DIBAL-H, DCM, 90% xi) TBAF, THF, 85%. At this stage it was decided to pursue an aldol based approach as it may help to install the tetrasubstituted C6-C7 double bond. Bicyclic ketone 45 was protected as its ethylene ketal, ester group was reduced with LAH and ketal deprotection furnished 48. The primary hydroxyl protection in 48 led to 49. Dihydroxylation on the butenyl arm gave diol 50, wherein the primary hydroxyl was protected as TBS derivative and secondary hydroxyl group was oxidized to furnish 51. Employing LHMDS as a base, key aldol reaction was carried out on 51 to give three aldol products in which the required compound 52 was the major product. The tertiary hydroxyl group in 52 when subjected to dehydration using Martin sulfurane delivered the required 53 with correctly installed C6-C7 double bond, only in trace amounts, along with two other regioisomeric dehydration products. DIBAL-H reduction on 53 stereoselectively delivered 54 and TBS deprotection furnished a product 55 bearing the structure assigned for the natural product ‘dichomitol’, Scheme 12. Significant variation in the spectral characteristics of our synthetic product 55 and those reported for ‘dichomitol’ necessitates a reinvestigation of the structure of natural product. All the details of our synthetic efforts, problems and challenges encountered enroute and the synthetic insights used to address them will be presented in this chapter of the thesis. Chapter III: A total synthesis of diterpenoid natural product Guanacastepene C This chapter describes the first total synthesis of a novel 5,7,6 fused tricyclic diterpenoid natural product guanacastepene C 71 isolated from an unidentified fungus growing on the tree Daphnopsis americana by Clardy in 2001. Besides guanacastepene C 71, fourteen other guanacastepenes A-O have also been isolated and these compounds have evoked unprecedented attention from the synthetic community. In particular, several Reagents and conditions: i) LAH, THF, 55% ii) a. PMBCl, THF, 67% b. TBSOTf, DCM, 68% c. DDQ, DCM-H2O, 95% iii) IBX, toluene-DMSO, 92% iv) Ph2POCH2COCH2COOEt, THF, 86% v) H2, Pd/C, EtOAc, 99% vi) a. 6N H2SO4, THF-H2O, 80% b. 2,2-DMP, PPTS, 91% vii) PCC, DCM, 80% viii) DBU, C6H6, 82% guanacastepenes exhibit antibacterial activity against MRSA and VREF. Several total syntheses of guanacastepenes have been reported in the last two years due to their enticing architecture and promising biological activity profile. Our group has also been in the fray and following the early leads, we embarked on an ambitious journey towards the total synthesis of guanacastepene C 71. The synthetic approach towards guanacastepene C 71, envisaged in this study, was revealed through a retrosynthetic analysis which identified hydroazulene core 57, bearing AB rings of the natural product as an advanced precursor on which ring ‘C’ could be annulated, Scheme 13. Earlier efforts from our group have demonstrated that AB ring precursor 57 can be elaborated from readily available tri-cylcopentadienone 56. Keto-ester in 57 on LAH reduction led to diol 58 and following a three step protocol of protection-deprotection led to 59 wherein the free primary hydroxyl was oxidized to furnish the required aldehyde 60. It was condensed with appropriate four carbon Horner-Wittig partner to furnish a mixture of keto-enol tautomers 61. Hydrogenation of trans double bond led to 62 and TBS deprotection and concomitant acetonide deprotection followed by acetonide protection furnished the hemiketal 63. PCC oxidation in 63 furnished tricyclic precursor 64 for the key Knoevenagel cyclization. Exposing 64 to DBU delivered 65 embodying complete tricarbocyclic framework of guanacastepene C, Scheme 14. LAH reduction on 65, was stereoselective and led predominantly to the unrequired α- isomer 66. Reagents and conditions: i) LAH, THF, -78 °C, 65% ii) PPh3, C6H5COOH, DIAD, THF, 78% iii) LAH, THF, 84% iv) Ac2O, DCM, 90% v) 4N H2SO4, THF-H2O, 44% vi) DDQ, THF, 85% vii) K2CO3, MeOH, 70%. Diol 66 was subjected to standard Mitsunobu protocol to furnish dibenzoate 67 which was hydrolysed and reprotected as diacetate 68 with the desired 5β stereochemistry. Deprotection of acetonide in 68 led to the diol 69. Chemoselective allylic oxidation of vicinal diol employing DDQ furnished guanacastepene C diacetate 70. Finally, careful base hydrolysis of 70 delivered guanacastepene C 71, Scheme 15. Synthesis of guanacastepene C was a difficult and often frustrating journey. Many trials and tribulations to overcome the synthetic challenges and our persistant and sincere efforts to overcome the hurdles confronted by us during the synthesis and finally attainment of the first total synthesis of guanacastepene C 71 will be the subject matter of the last chapter of this thesis.(For structural formula pl refer pdf file)

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2010. / Härtill 4 uppsatser.

Species belonging to the Asteraceae family are an important source of terpenoids with biological activity. Senecio bonariensis Hook. et Arn., popularly known as margarida-do-banhado-de-Buenos Aires is native from South America and can be found in south Brazil, blooming from October to December. This plant is known for contain furanoeremophylanes, steroids and pyrrolizidines alkaloids (PAs) with toxic activities. This work describes the isolation and identification of three compounds present in the CH2Cl2 extract of the aerial parts of Senecio bonariensis Hook at Arn. Leaves of this plant were collected in Eldorado do Sul, RS, Brazil, in April 2004 and identified by Prof. Dr. Nelson Ivo Matzenbacher. Voucher specimen Nº SMDB 9519 is preserved in the Herbarium of the Departamento de Botânica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil. The fresh leaves of S. bonariensis (2.3 kg) were extracted by maceration with CH2Cl2. The CH2Cl2 extract was evaporated under vacuum to yield an viscous residue (13.5 g), which gave a yield of 0.64%. The crude extract was fractionated by flash chromatography over silica-gel, using CH2Cl2, and CH2Cl2: EtOH mixture of increasing polarity, (stepwise, 99:1 to 80:20) to yield 15 fractions. The fraction 1 col. 1 (1 g) was chromatographed over silica-gel impregnated with AgNO3 (10%) eluting with hexane-acetone (99:1), to yield 13 news fractions. Fraction 10 col. 2 (253 mg) was chromatographed on silica-gel impregnated with AgNO3 (10%), eluting with hexane: ethyl ether (95:5) and purified to afford 104 mg of CS1 (caryophyllene) and 16 mg of CS2 (caryophyllene oxide). Fraction 11 col. 2 (83.5 mg) was also chromatographed on silica-gel impregnated with AgNO3 (10%), eluting with hexane: ethyl ether (98:2) and purified to afford 5 mg of CS3 (germacrene-D). The compounds obtained were analyzed by GC-EI-MS, IR, 1H and 13C NMR. The antimicrobial activity of CS1 and CS2 were evaluated by the microdilution method based on M27-A2 and M7-A4 (NCCLS). Both compounds sowed no antimicrobial activity at the tested concentrations. / Espécies pertencentes à família Asteraceae, são uma importante fonte de terpenóides com várias atividades biológicas já descritas. Senecio bonariensis Hook. et Arn., popularmente conhecida como margarida-do-banhado-de-Buenos Aires é um arbusto nativo da América do Sul, que pode ser encontrado no sul do Brasil e floresce de outubro a dezembro. Esta planta é conhecida por apresentar furanoeremofilanos, esteróides e alcalóides pirrolizidínicos, com atividades tóxicas. Este trabalho descreve o isolamento e identificação de três constituintes químicos presentes no extrato CH2Cl2 das partes aéreas de Senecio bonariensis Hook. et Arn. As folhas de S. bonariensis foram coletadas em abril de 2004, no município de Eldorado do Sul-RS. A espécie foi localizada e identificada pelo Prof. Dr. Nelson Ivo Matzenbacher, do Programa de Pós Graduação em Botânica da UFRGS. Material testemunha encontra-se depositado no Herbário do Departamento de Biologia da UFSM sob o registro n° SMDB 9519. As folhas frescas de S. bonariensis (2,3 kg) foram extraídas por maceração com CH2Cl2. O extrato bruto foi evaporado sob pressão reduzida, resultando num resíduo pastoso (13,5 g), com rendimento de 0,64%. O extrato bruto foi fracionado por cromatografia em coluna do tipo flash sobre gel de sílica, usando CH2Cl2 e misturas de CH2Cl2 : EtOH, em gradiente, nas proporções de 99:1 até 80:20, sendo obtidas 15 frações (1 a 15 col. 1). A fração 1 col. 1 (1g) foi cromatografada sobre gel de sílica impregnado com AgNO3 (10%), eluída com hexano: acetona (99:1), obtendo-se 13 novas frações (1 a 13 col. 2). A fração 10 col. 2 (253 mg) foi cromatografada sobre gel de sílica impregnado com AgNO3 (10%), eluída com hexano:éter etílico (95:5), obtendo-se 104 mg de CS1(cariofileno) e 16 mg de CS2 (óxido de cariofileno). A fração 11 col. 2 (83,5 mg) também foi cromatografada sobre gel de sílica impregnado com AgNO3 (10%), eluída com hexano:éter etílico (98:2) e forneceu 5 mg de CS (germacreno-D). Os compostos isolados foram analisados por CG-EM-IE, IV, RMN 1H e RMN 13C e seus dados espectroscópicos foram comparados com os obtidos da literatura. Além disso, foi determinada a atividade antimicrobiana do cariofileno e do óxido de cariofileno, através do método de microdiluição em caldo, baseado nos documentos M27-A2/NCCLS para fungos e M7-A4/NCCLS para bactérias. Os compostos não apresentaram atividade antimicrobiana nas concentrações testadas.

The genus Senecio (Asteraceae) constitutes a group of cosmopolitan plants formed by more than 2000 species. Although most of these plants are considered to be toxic due to the presence of pyrrolizidine alkaloids, several of them are used in folk medicine. Their medicinal use can be attributed to other secondary metabolites, amongst them the terpenoids, with known antimicrobial activity. This work describes the isolation and identification of three compounds present in the CH2Cl2 extract of fresh aerial parts of Senecio platensis Arech., a species that showed the presence of peroxides in a phytochemical screening. Additionally, the the antibacterial activity of the isolated secondary metabolites has been evaluated. The aerial parts of Senecio platensis were collected in Capão Novo RS, Brasil and identified by Prof. Dr. Nelson Ivo Matzenbacher. Voucher specimen SMDB 9522 is preserved in the Herbarium of the Departamento de Botânica, UFSM. The fresh aerial parts of S. platensis (350.0 g) were extracted by maceration with CH2Cl2. The CH2Cl2 extract was evaporated to obtain an viscous residue (6.0 g), which approximates a yield of 1.71%. The crude extract was fractionated by flash chromatography over silica gel, using CH2Cl2 and CH2Cl2:EtOH mixtures of increasing polarity to yield 29 fractions. After two cycles of column chromatography (column: silica gel impregnated with AgNO3 (10%), eluents: hexane:acetone (95:5) and hexane:ethyl ether (99:1) 13.3 mg of PP1 were isolated from fraction 1 and later identified as germacrene D. After successive column chromatography over silica gel impregnated with AgNO3 (10%), eluting with hexane:acetone (9:1), hexane:ethyl acetate (95:5) and hexane:acetone (93:7), fraction 5 yielded 17.0 mg of AB1 (dehydrofukinone) and 30.6 mg of AB2 (spathulenol). The compounds were analyzed by GC-EI-MS, 1H and 13C NMR and were identified by comparison of their spectroscopic data with the literature. The fraction containing germacrene D, which is considered to be a precursor of several other sesquiterpene derivatives, was submitted to photooxidation process using Bengal Rose as sensitizer agent. By this reaction it was possible to confirm the formation of germacrene-D-1-hydroperoxide by its precursor. The antibacterial evaluation of the isolated compounds was accomplished by the broth microdilution method based on M7-A6/CLSI. In relation to Bacillus cereus ATCC 14579, dehydrofukinone showed MIC of 256 μg/mL and MBC of 4096 μg/mL. The spathulenol presented MIC and MBC of 64 μg/mL. Against the clinical isolate of B. cereus, dehydrofukinone showed MIC of 256 μg/mL and MBC > 8192 μg/mL while spathulenol showed MIC 32 μg/mL and MBC > 8192 μg/mL. Dehydrofukinone and spathulenol are inactive against Pseudomonas aeruginosa at the tested concentrations (until 8192 μg/mL). / O gênero Senecio (Asteraceae) constitui um grupo de plantas cosmopolitas, formado por mais de 2000 espécies. Embora grande número tenha toxicidade reconhecida devido à presença de alcalóides pirrolizidínicos, várias delas são empregadas na medicina popular. Seu uso medicinal pode ser atribuído à presença dos demais metabólitos secundários, entre eles os terpenóides, com atividade antibacteriana reconhecida. Este trabalho descreve o isolamento e a identificação de três constituintes presentes no extrato CH2Cl2 das partes aéreas de Senecio platensis Arech., espécie na qual foi detectada a presença de peróxidos em um screening fitoquímico. Adicionalmente, os metabólitos secundários isolados tiveram sua atividade antimicrobiana avaliada. As partes aéreas de S. platensis foram coletadas em abril de 2004, no município de Capão Novo RS, Brasil. A espécie foi localizada e identificada pelo Prof. Dr. Nelson Ivo Matzenbacher, do Programa de Pós-Graduação em Botânica da UFRGS. Material testemunha encontra-se depositado no Herbário do Departamento de Biologia da UFSM sob o registro SMDB 9522. As partes aéreas frescas de S. platensis (350,0 g) foram extraídas por maceração em CH2Cl2., seguido de evaporação do solvente, resultando num resíduo pastoso (6,0 g), com rendimento de 1,71%. O extrato bruto foi fracionado por cromatografia em coluna flash sobre gel de sílica, usando CH2Cl2 e misturas de CH2Cl2: EtOH, em gradiente, sendo obtidas 29 frações. A partir da fração 1, após duas cromatografias em coluna com gel de sílica impregnado com AgNO3 (10%), eluídas com hexano:acetona (95:5) e hexano:éter etílico (99:1), foram obtidos 13,3 mg da substância codificada como PP1 e posteriormente identificada como germacreno D. A fração 5 da coluna flash também foi fracionada e, após sucessivas cromatografias em coluna sobre gel de sílica impregnado com AgNO3 (10%), eluídas com hexano:acetona (9:1), hexano:acetato de etila (95:5) e hexano:acetona (93:7), foram isolados 17,0 mg de AB1 (deidrofuquinona) e 30,6 mg de AB2 (espatulenol). Os compostos foram analisados por CG-EM, RMN 1H e RMN 13C e foram identificados pela comparação de seus dados espectroscópicos com os obtidos da literatura. A fração contendo o germacreno D, considerado precursor de vários outros derivados de esqueleto sesquiterpênico, foi submetida a uma reação de foto-oxidação utilizando o corante Rosa de Bengala como agente sensibilizante. Através desta reação foi possível confirmar a formação do germacreno-D-1-hidroperóxido a partir de seu precursor. A avaliação da atividade antibacteriana das substâncias isoladas foi realizada através do método de microdiluição em caldo, baseado nos documentos M7-A6/CLSI, antigo NCCLS. Em relação ao Bacillus cereus ATCC 14579, a deidrofuquinona exibiu uma CIM de 256 μg/mL e CBM de 4096 μg/mL, sendo que o espatulenol apresentou CIM e CBM de 64 μg/mL. Frente à cepa hospitalar de B. cereus, a deidrofuquinona exibiu uma CIM de 256 μg/mL e CBM > 8192 μg/mL, enquanto que o espatulenol apresentou uma CIM 32 μg/mL e CBM > 8192 μg/mL. Tanto a deidrofuquinona quanto o espatulenol não apresentaram atividade contra Pseudomonas aeruginosa até a concentração de 8192 μg/mL.