This research focuses on diterpenoids from Taiwanese soft corals Xenia umbellata Lamarck, Junceella juncea Pallas and Junceella fragilis Ridley. Twelve diterpenoids in addition to one sesequiterpenoid were isolated. Our investigation of the soft coral X. umbellata Lamarck afforded five natural products, including two new xenicane diterpenes, xenibelatols A-B (1-2), together with two known xenicane diterpenes, 7,8-oxido- isoxeniolide (3), 9-hydroxyxeniolide-F (4), and a cadinene sesequiterpene, xenitorin A (5). Chemical investigation of the gorgonian J. juncea Pallas, has resulted in isolation of a new briarane diterpene, juncenolide H (6). Continuing our investigation of the gorgonian J. fragilis Ridley, we isolated seven briarane diterpenes, including four new briaranes, flajunolides A-D (7-10), along with three known briaranes, junceellolide E (11), umbraculolide A (12), 11This research focuses on diterpenoids from Taiwanese soft corals Xenia umbellata Lamarck, Junceella juncea Pallas and Junceella fragilis Ridley. Twelve diterpenoids in addition to one sesequiterpenoid were isolated. Our investigation of the soft coral X. umbellata Lamarck afforded five natural products, including two new xenicane diterpenes, xenibelatols A-B (1-2), together with two known xenicane diterpenes, 7,8-oxido- isoxeniolide (3), 9-hydroxyxeniolide-F (4), and a cadinene sesequiterpene, xenitorin A (5). Chemical investigation of the gorgonian J. juncea Pallas, has resulted in isolation of a new briarane diterpene, juncenolide H (6). Continuing our investigation of the gorgonian J. fragilis Ridley, we isolated seven briarane diterpenes, including four new briaranes, flajunolides A-D (7-10), along with three known briaranes, junceellolide E (11), umbraculolide A (12),11£\, 20£\-epoxy-4-deacetoxy junceellolide D (13). The new compounds 1,2 and 6-10 possess xenicane-type and briarane-type skeletons respectively. The structures of new compounds were determined by 1D-, 2D-NMR spectroscopic analysis and physical methods such as optical rotation, UV, IR, mass spectrum, as well as comparison with the spectroscopic data reported for related compounds. Compounds 1 and 2 are geometric isomers of compounds 3 and 4. The only difference between them resides in the side chain. The geometry of the side chain influenced the relative spatial proximity of H-12, H-13, H-14 to the carbonyl at C-3, and consequently the extent to which these protons are subjected to the anisotropic effects of the carbonyl. Compounds 6-10 have acetyl groups at C-2, C-9, C-12, C-14 positions. Because of structural difference appears in briarane skeleton, they showed different chemical shifts in specific positions. Biological activity test¡Arevealed that compound 5 exhibited moderate cytotoxic activity against KB and WiDr cancer cell lines with ED50 values at 5.9 and 9.9 £gg/ml respectively.

La composition chimique de la résine sandaraque et de son composant principal l’acide communique a été étudiée par chromatographie en phase gazeuse – spectrométrie de masse (GC-MS), MALDI-TOF (désorption-ionisation laser assistée par matrice - temps de vol), ESI (ionisation par électronébuliseur) - Orbitrap, FTIR/ATR (spectroscopie infrarouge à transformée de Fourier/réflectance totale atténuée), spectroscopie de RMN (résonance magnétique nucléaire) à l'état solide et liquide. Six composés avec des squelettes labdane et pimarane ont été identifiés dans la résine commerciale. Les spectres de masse obtenus ont été interprétés et le comportement en spectrométrie de masse de ces diterpénoïdes dans les conditions de l’impact électronique a été décrit. L'analyse quantitative par la méthode de l'étalon interne a révélé que les diterpénoïdes identifiés ne représentaient que 10 à 30% de l'échantillon analysé. La complexité de la fraction réticulée de la résine commerciale sandaraque est bien reflétée par les spectres de masse MALDI-TOF et ESI-Orbitrap. En conséquence, les spectres de masse de MALDI-TOF comprenaient trois clusters de pics dans la gamme m/z de 300-900, et ceux d’ESI-Orbitrap contenaient cinq clusters de pics dans la gamme m/z de 300-1100. Les pics dans les clusters correspondent aux dérivés oxygénés des diterpénoïdes. Les résultats obtenus à partir des expériences RMN par IRCP (Inversion Recovery Cross-Polarization) ont révélé le caractère rigide des échantillons de la résine sandaraque analysés et justifiaient l'hypothèse que le reste de l'échantillon, qui ne pouvait être quantifié par la méthode de l'étalon interne, aurait un caractère polymère. / The chemical composition of sandarac resin and its principal component communic acid was investigated by gas chromatography-mass spectrometry (GC-MS), MALDI-TOF (Matrix Assisted Laser Desorption Ionization - Time of Flight), ESI (Electrospray ionization)-Orbitrap, FTIR/ATR (Fourier transform infrared spectroscopy/Attenuated total reflectance), liquid- and solid state NMR (Nuclear magnetic resonance) spectroscopy. Six compounds with labdane and pimarane skeletons were identified in the commercial resin. The obtained mass spectra were interpreted and the mass spectrometric behaviour of these diterpenoids under EI conditions was described. Quantitative analysis by the method of internal standard revealed that identified diterpenoids represent only 10–30% of the analysed sample. The complexity of the reticulated fraction of the commercial sandarac resin was well reflected by the MALDI-TOF and ESI-Orbitrap mass spectra. As a result, MALDI-TOF mass spectra comprised three clusters of peaks in the m/z range of 300–900, and for the ESI-Orbitrap mass spectra contained five clusters of peaks in the m/z range of 300–1100. The peaks in the clusters corresponded to the oxygenated derivatives of the diterpenoids. The results obtained from the IRCP (Inversion Recovery Cross-Polarization) experiments revealed the rigid character of the sandarac resin samples analyzed and justified the hypothesis that the rest of the sample, which could not be quantified by the method of internal standard, would have a polymeric nature.

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)

No description available.

Carbohydrates are ubiquitous and important biomolecules. Initially thought to be dull, energy storing moieties, the importance of carbohydrates and their conjugates, glycoproteins and glycopilids, in cellular communication and various related processes has been well established. Carbohydrate recognition events are involved in the progression of various diseases, as the binding of pathogens to the host cells is carbohydrate mediated. Also the malfunctioning of carbohydrate processing enzymes has been implicated in life-threatening diseases. Thus there is tremendous interest in the design of molecules which can mimic the carbohydrates and provide insights into the mechanisms of action of carbohydrate processing enzymes. Such designer glycomimics possess several advantages over the parent molecules. In this regard the synthesis of small molecules based on the polyhydroxylated cyclohexane framework has gained vital importance. Some of the efforts of several research groups actively working on the design and synthesis of glycomimics have culminated in therapeutics and resulted in the development of many synthetic routes to polyoxygenated cyclohexanoids emanating from either the chiral pool or from aromatics and other non-carbohydrate sources. Nevertheless, the design of a general and variable strategy to access these cyclohexitols is essential. Our quest for a general and more versatile strategy for accessing several of the polyoxygenated cyclohexanoids led to the development of a new norbornyl based approach. The important feature of our approach involves extraction of the inherent cyclohexanoid from the norbornyl scaffold. The present thesis entitled “Norbornyl system revisited: Exploring a versatile building block for the syntheses of natural products and analogues” delineates our synthetic endeavors. The thesis is represented in two parts “Part 1: Synthesis of polyoxygenated cyclohexanoids and azepanes” is subdivided into Introduction, Results and Discussion, Summary, Experimental, Spectra and References sections and describes our synthetic efforts towards various polyoxygenated cyclohexanoids and azepanes. Introduction deals briefly about the importance of glycomimics and synthetic approaches from the literature towards these polyhydroxylated cyclohexanoids. Our findings constitute the Results and Discussion section wherein we delineate the synthesis of a versatile cyclohexanoid building block through a Grob like Wharton fragmentation on an suitably crafted norbornyl scaffold. The synthetic utililty and versatility of this building block are explored in subsections titled Carbasugars, Cyclitols, Gabosines, Aminocyclitols and Azepanes. The synthesis of several polyhydroxylated cyclohexanoid natural products and analogues is discussed. “Part 2: Synthetic studies towards the novel diterpenoid rameswaralide” deals with the elaboration of the versatile norbornyl building block towards the synthesis of a novel 5-7-6 fused diterpenoid rameswaralide. This part is again divided into Introduction, Results and Discussion, Summary, Experimental, Spectra and References sections. The Introduction briefs the relevance and importance of total synthesis of natural products, with a mention of terpenoids. The structure and biological significance of rameswaralide and related molecules is discussed. In the Results and Discussion our synthetic studies towards rameswaralide are delineated. Restructuring the norbornyl framework to a 5,5 fused all cis Corey lactone and its further amplification through ring closing metathesis and Diels-Alder protocols are described.

Salvia divinorum is a hallucinogenic sage used to treat illness by the Mazatec Indians of Mexico. Salvinorin A (1a), a neoclerodane diterpenoid isolated from the plant, is a potent, selective agonist at the kappa opioid receptor (KOR), and is the first non-nitrogenous opioid. The plant is used recreationally as a hallucinogen, but is unpopular due to its dysphoric effects. 1a has been prohibited in Australia under an invalid systematic name. An early report of psychoactive alkaloids in S. divinorum proved to be irreproducible. Similarly, tests in mice suggesting the presence of psychoactive compounds other than 1a were confounded and therefore unreliable. In this work, an improved isolation method for 1a was developed, using filtration through activated carbon to decolourise the crude extract. Six new diterpenoids were isolated: salvinorins D–F (1d–1f) and divinatorins A–C (28a–28c). Five known terpenoids not previously reported from this species were also isolated. The structure–activity relationships of 1a were evaluated via selective modifications of each functional group. Useful synthetic methods are reviewed, including the first thorough review of furanolactone hydrogenations. Testing of the derivatives at the KOR suggests that the methyl ester and furan ring of 1a are required for activity, but that the lactone and ketone functionalities are not. Other compounds from S. divinorum did not bind to the KOR, suggesting that 1a is the plant’s active principle.

Natural resins have been in use for a long time and for manifold purposes resulting in a long and complex terminological history. The investigation of this history has so far been based on the connection between nomenclature and chemical composition. Because resin chemistry and the botanical classification of source plants are connected as well, the investigation of natural resins can be enhanced by adding taxonomy as an additional dimension, providing a more complex and complete picture of resin chemistry and resin use. The Vigani Cabinet, a collection of 300-year-old pharmaceutical and chemical materials owned by Queens’ College, Cambridge (UK), allows doing just that. A wide range of historical literature provides information about contemporary terminology, botanical and geographical origin, manufacture, trade and properties of resinous materials from the 18th century. This contemporary context is a particular feature of the Cabinet, which allows adding a historical dimension to the correlations between terminology, chemical composition and taxonomy. The dissertation thesis presented here provides an investigation of 17 botanical, 80 reference materials and samples from 24 natural resins from the Vigani Cabinet, studying these complex correlations and changes over time. The analytical method employed in this study was gas chromatography-mass spectrometry (GC-MS) with and without methylation with trimethylsulfoniumhydroxide. This technique provided detailed molecular compositions of the studied materials. Analysed botanical samples are taken from Pinaceae, Cupressaceae and Pistacia resins, commerical references from Araucariaceae, Copaifera, Fabaceae, Myroxylon and Burseraceae. Additionally, the soluble fraction of Baltic amber was analysed. Materials from the Vigani Cabinet analysed in this work were labelled as "turpentines", "pix burgundica", "sandaracha", "copaiba", "balsamum peruvianum and tolutanum", "mastiche", "anime", "copal", "elemi", "tacamahaca" and "succinum". Historical nomenclature of natural resins has not always been unequivocally associated with a botanical origin. The availability of natural resins changed throughout the centuries. Lack of knowledge, in particular about resins from over-seas, or adulterations resulting from changing harvesting methods, led to changes in trade names or variations in the composition of products traded under the same name. Generic names were used for resins with similar properties but different botanical (and geographical) origin. The thesis shows that a chemotaxonomic reference system is suitable for the identification of unknown resinous materials, and a number of new insights into the nomenclature of natural resins from the 17th and 18th century is obtained. The study of historical literature contributed in a significant way to the historico-cultural and archeometric research of the samples from the Vigani Cabinet and of natural resins in general and provided a basis for the interpretation of the chemical data from the Vigani samples. / Naturharze werden schon lange für sehr unterschiedliche Zwecke verwendet. Dies hat zu einer oft komplizierten Terminologie geführt, deren Untersuchung sich bisher auf den Zusammenhang zwischen dem Namen des Harzes und seiner chemischer Zusammensetzung stützte. Letztere ist aber auch mit der botanischer Herkunft und damit der Biochemie der Stammpflanze verknüpft, weshalb man chemotaxonomische Aspekte für die systematische Untersuchung von Naturharzen als zusätzliche Variablen nutzen kann. Dadurch erhält man, wie die gezeigt werden soll, ein vollständigeres und komplexeres Bild der Chemie und Nutzung von Naturharzen. Die hier präsentierte Untersuchung beschäftigt sich mit dem Vigani-Kabinett, einer 300 Jahre alten pharmazeutischen Materialiensammlung, die sich im Queens‘ College, Cambridge (UK), befindet. In der Literatur des ausgehenden 17. und des 18. Jahrhunderts finden sich zahlreiche Informationen zu Terminologie, botanischer und geographischer Herkunft, Verarbeitung, Handel und Eigenschaften von Naturharzen. Dadurch wird die historische Dimension des oben beschriebenen Zusammenhangs zwischen Terminologie, chemischer Zusammensetzung und Taxonomie erfahrbar. In der Arbeit werden 17 botanische Proben, 80 moderne Referenzmaterialien und 24 Proben aus dem Vigani-Kabinett im Hinblick auf diese Zusammenhänge und Veränderungen untersucht.Die chemischen Analysen wurden mit gekoppelter Gaschromatografie-Massenspektrometrie mit und ohne Methylierung mit Trimethylsulfoniumhydroxid durchgeführt. Damit konnte die molekulare Zusammensetzung der Proben detailliert untersucht werden. Die untersuchten botanischen Proben stammten von Pinaceae, Cupressaceae und Pistaciaharzen, kommerzielle Referenzen von Araucariaceae, Copaifera, Fabaceae, Myroxylon und Burseraceaeharzen. Zusätzlich wurde noch die lösliche Fraktion von Baltischem Bernstein untersucht. Die untersuchten Proben aus dem Vigani-Kabinett waren sowohl englisch als auch Latein mit "turpentines", "pix burgundica", "sandaracha", "copaiba", "mastiche", "anime", "copal", "elemi", "tacamahaca", "balsamum peruvianum and tolutanum" und "succinum" beschriftet. Zusammenfassend lässt sich sagen, dass die historische Nomenklatur von Naturharzen nicht immer eindeutig mit ihrem botanischen Ursprung verknüpft war. Zusätzlich veränderte sich die Erhältlichkeit der Harze im Laufe der Jahrhunderte. Durch fehlendes Wissen, insbesondere für Materialien und Pflanzen aus Übersee, oder Verfälschungen aufgrund von veränderten Fördermethoden veränderten sich die Handelsnamen dieser Materialien oder die Zusammensetzung von Materialien, die unter demselben Namen gehandelt wurden. Harze mit ähnlichen Eigenschaften aber unterschiedlichen botanischen (und geographischen) Ursprungs trugen generische Namen. Die Arbeit zeigt jedoch, dass ein chemotaxonomisches Bezugssystem die Identifizierung von unbekannten Harzen ermöglicht, und zeigt eine Reihe neuer Erkenntnisse über die Nomenklatur von Naturharzen des 17. und 18. Jahrhunderts. Die Untersuchung historischer Quellen trug dabei sehr zur Erhellung des historisch-kulturellen und archeometrischen Hintergrundes und zur Interpretation der chemischen Daten der Vigani-Proben bei.

Natural resins have been in use for a long time and for manifold purposes resulting in a long and complex terminological history. The investigation of this history has so far been based on the connection between nomenclature and chemical composition. Because resin chemistry and the botanical classification of source plants are connected as well, the investigation of natural resins can be enhanced by adding taxonomy as an additional dimension, providing a more complex and complete picture of resin chemistry and resin use. The Vigani Cabinet, a collection of 300-year-old pharmaceutical and chemical materials owned by Queens’ College, Cambridge (UK), allows doing just that. A wide range of historical literature provides information about contemporary terminology, botanical and geographical origin, manufacture, trade and properties of resinous materials from the 18th century. This contemporary context is a particular feature of the Cabinet, which allows adding a historical dimension to the correlations between terminology, chemical composition and taxonomy. The dissertation thesis presented here provides an investigation of 17 botanical, 80 reference materials and samples from 24 natural resins from the Vigani Cabinet, studying these complex correlations and changes over time. The analytical method employed in this study was gas chromatography-mass spectrometry (GC-MS) with and without methylation with trimethylsulfoniumhydroxide. This technique provided detailed molecular compositions of the studied materials. Analysed botanical samples are taken from Pinaceae, Cupressaceae and Pistacia resins, commerical references from Araucariaceae, Copaifera, Fabaceae, Myroxylon and Burseraceae. Additionally, the soluble fraction of Baltic amber was analysed. Materials from the Vigani Cabinet analysed in this work were labelled as "turpentines", "pix burgundica", "sandaracha", "copaiba", "balsamum peruvianum and tolutanum", "mastiche", "anime", "copal", "elemi", "tacamahaca" and "succinum". Historical nomenclature of natural resins has not always been unequivocally associated with a botanical origin. The availability of natural resins changed throughout the centuries. Lack of knowledge, in particular about resins from over-seas, or adulterations resulting from changing harvesting methods, led to changes in trade names or variations in the composition of products traded under the same name. Generic names were used for resins with similar properties but different botanical (and geographical) origin. The thesis shows that a chemotaxonomic reference system is suitable for the identification of unknown resinous materials, and a number of new insights into the nomenclature of natural resins from the 17th and 18th century is obtained. The study of historical literature contributed in a significant way to the historico-cultural and archeometric research of the samples from the Vigani Cabinet and of natural resins in general and provided a basis for the interpretation of the chemical data from the Vigani samples.:CONTENTS 1 INTRODUCTION 1 1.1 Natural resins in a historical and modern context 1 1.2 The Vigani Cabinet and its historical background 3 1.3 Aim of the thesis - outline 6 2 LITERATURE REVIEW 8 2.1 Gymnosperm resins – conifer resins and products 9 2.1.1 Pinaceae 9 2.1.2 Cupressaceae 17 2.1.3 Araucariaceae 20 2.2 Angiosperm resins I – Fabales 21 2.3 Angiosperm resins II – Sapindales 30 2.3.1 Anacardiaceae 30 2.3.2 Burseraceae 35 2.3.3 Rutaceae 43 2.4 Fossil resins 45 2.5 Summary and research deficits 49 3 EXPERIMENTAL 53 3.1 Coupled gas chromatography and mass spectrometry 53 3.1.1 Materials 53 3.1.2 Sample preparation 54 3.1.3 Instrumentation 54 3.1.4 Data-Evaluation 58 3.2 Fourier transformation infrared spectroscopy 60 3.2.1 Sample preparation 61 3.2.2 Instrumentation 61 3.2.3 Data evaluation 61 4 RESULTS – REFERENCE MATERIALS 62 4.1 Gymnosperm resins – conifer resins and products 62 4.1.1 Pinaceae – Coniferous turpentines 62 4.1.1.1 Phytochemical markers – detection of adulterations 62 4.1.1.2 Aging by heat and light 73 4.1.2 Cupressaceae – Sandarac 80 4.1.3 Araucariaceae – Coniferous copals 88 4.1.4 Discussion 91 4.2 Angiosperm Resins I - Fabales 94 4.2.1 Copaifera – Copaiba balsam 94 4.2.2 Legume copals 102 4.2.3 Myroxylon – Balsam of Tolu and Peru 108 4.2.4 Discussion 117 4.3 Angiosperm resins II - Sapindales 120 4.3.1 Anacardiaceae – Pistacia resins 120 4.3.2 Burseraceae – Elemi, copal and others 127 4.3.3 Discussion 142 4.4 Fossil resins 144 4.4.1 Baltic amber 144 4.4.2 Discussion 153 4.5 Summary and research deficits 155 5 RESULTS – RESINOUS MATERIALS FROM THE VIGANI CABINET 160 5.1 Gymnosperm resins – conifer resins and products 162 5.1.1 1/8 Terebin. Strasb. 163 5.1.2 1/9 Tereb Com 170 5.1.3 1/10 Venice Turpentine 176 5.1.4 1/11 Venic. Turpent. 183 5.1.5 1/13 Tereb E Chio 188 5.1.6 A/23 Pix Burgundica 194 5.1.7 A/26 Sandaracha 203 5.2 Angiosperm resins I - Fabales 210 5.2.1 1/4 Balsam Cipivi 211 5.2.2 A/5 Gum Animi 218 5.2.3 La2/7 Unknown resin 228 5.2.4 1/31 Bals Peruv 230 5.2.5 2/1 Bals Peru 237 5.2.6 Z/17 Balsam Tolutanum 240 5. 3 Angiosperm resins II – Sapindales 245 5.3.1 A/11 Mastiche 246 5.3.2 1/14 Tereb i E Cypri 252 5.3.3 A/21 Gum Copal 258 5.3.4 A/24 [.] Elemi 268 5.3.5 A/22 Tacamahaca 276 5.3.6 Z/1 Tacamahaca 283 5.4 Fossil Resins 287 5.4.1 E/13 Succinum Citrinum 288 5.4.2 E/14 Succinum flavan 295 5.4.3 E/15 Succinum albam 302 5.4.4 E/16 Succinum nigram 307 5.4.5 F/13 L. Gagatis 313 6 CONCLUSIONS 316 7 REFERENCES 324 APPENDIX 365 Investigated materials from the Vigani Cabinet 366 Annotated list of historical literature 367 List of figures 374 List of tables 379 Compound lists 381 Atlas of mass spectra 422 / Naturharze werden schon lange für sehr unterschiedliche Zwecke verwendet. Dies hat zu einer oft komplizierten Terminologie geführt, deren Untersuchung sich bisher auf den Zusammenhang zwischen dem Namen des Harzes und seiner chemischer Zusammensetzung stützte. Letztere ist aber auch mit der botanischer Herkunft und damit der Biochemie der Stammpflanze verknüpft, weshalb man chemotaxonomische Aspekte für die systematische Untersuchung von Naturharzen als zusätzliche Variablen nutzen kann. Dadurch erhält man, wie die gezeigt werden soll, ein vollständigeres und komplexeres Bild der Chemie und Nutzung von Naturharzen. Die hier präsentierte Untersuchung beschäftigt sich mit dem Vigani-Kabinett, einer 300 Jahre alten pharmazeutischen Materialiensammlung, die sich im Queens‘ College, Cambridge (UK), befindet. In der Literatur des ausgehenden 17. und des 18. Jahrhunderts finden sich zahlreiche Informationen zu Terminologie, botanischer und geographischer Herkunft, Verarbeitung, Handel und Eigenschaften von Naturharzen. Dadurch wird die historische Dimension des oben beschriebenen Zusammenhangs zwischen Terminologie, chemischer Zusammensetzung und Taxonomie erfahrbar. In der Arbeit werden 17 botanische Proben, 80 moderne Referenzmaterialien und 24 Proben aus dem Vigani-Kabinett im Hinblick auf diese Zusammenhänge und Veränderungen untersucht.Die chemischen Analysen wurden mit gekoppelter Gaschromatografie-Massenspektrometrie mit und ohne Methylierung mit Trimethylsulfoniumhydroxid durchgeführt. Damit konnte die molekulare Zusammensetzung der Proben detailliert untersucht werden. Die untersuchten botanischen Proben stammten von Pinaceae, Cupressaceae und Pistaciaharzen, kommerzielle Referenzen von Araucariaceae, Copaifera, Fabaceae, Myroxylon und Burseraceaeharzen. Zusätzlich wurde noch die lösliche Fraktion von Baltischem Bernstein untersucht. Die untersuchten Proben aus dem Vigani-Kabinett waren sowohl englisch als auch Latein mit "turpentines", "pix burgundica", "sandaracha", "copaiba", "mastiche", "anime", "copal", "elemi", "tacamahaca", "balsamum peruvianum and tolutanum" und "succinum" beschriftet. Zusammenfassend lässt sich sagen, dass die historische Nomenklatur von Naturharzen nicht immer eindeutig mit ihrem botanischen Ursprung verknüpft war. Zusätzlich veränderte sich die Erhältlichkeit der Harze im Laufe der Jahrhunderte. Durch fehlendes Wissen, insbesondere für Materialien und Pflanzen aus Übersee, oder Verfälschungen aufgrund von veränderten Fördermethoden veränderten sich die Handelsnamen dieser Materialien oder die Zusammensetzung von Materialien, die unter demselben Namen gehandelt wurden. Harze mit ähnlichen Eigenschaften aber unterschiedlichen botanischen (und geographischen) Ursprungs trugen generische Namen. Die Arbeit zeigt jedoch, dass ein chemotaxonomisches Bezugssystem die Identifizierung von unbekannten Harzen ermöglicht, und zeigt eine Reihe neuer Erkenntnisse über die Nomenklatur von Naturharzen des 17. und 18. Jahrhunderts. Die Untersuchung historischer Quellen trug dabei sehr zur Erhellung des historisch-kulturellen und archeometrischen Hintergrundes und zur Interpretation der chemischen Daten der Vigani-Proben bei.:CONTENTS 1 INTRODUCTION 1 1.1 Natural resins in a historical and modern context 1 1.2 The Vigani Cabinet and its historical background 3 1.3 Aim of the thesis - outline 6 2 LITERATURE REVIEW 8 2.1 Gymnosperm resins – conifer resins and products 9 2.1.1 Pinaceae 9 2.1.2 Cupressaceae 17 2.1.3 Araucariaceae 20 2.2 Angiosperm resins I – Fabales 21 2.3 Angiosperm resins II – Sapindales 30 2.3.1 Anacardiaceae 30 2.3.2 Burseraceae 35 2.3.3 Rutaceae 43 2.4 Fossil resins 45 2.5 Summary and research deficits 49 3 EXPERIMENTAL 53 3.1 Coupled gas chromatography and mass spectrometry 53 3.1.1 Materials 53 3.1.2 Sample preparation 54 3.1.3 Instrumentation 54 3.1.4 Data-Evaluation 58 3.2 Fourier transformation infrared spectroscopy 60 3.2.1 Sample preparation 61 3.2.2 Instrumentation 61 3.2.3 Data evaluation 61 4 RESULTS – REFERENCE MATERIALS 62 4.1 Gymnosperm resins – conifer resins and products 62 4.1.1 Pinaceae – Coniferous turpentines 62 4.1.1.1 Phytochemical markers – detection of adulterations 62 4.1.1.2 Aging by heat and light 73 4.1.2 Cupressaceae – Sandarac 80 4.1.3 Araucariaceae – Coniferous copals 88 4.1.4 Discussion 91 4.2 Angiosperm Resins I - Fabales 94 4.2.1 Copaifera – Copaiba balsam 94 4.2.2 Legume copals 102 4.2.3 Myroxylon – Balsam of Tolu and Peru 108 4.2.4 Discussion 117 4.3 Angiosperm resins II - Sapindales 120 4.3.1 Anacardiaceae – Pistacia resins 120 4.3.2 Burseraceae – Elemi, copal and others 127 4.3.3 Discussion 142 4.4 Fossil resins 144 4.4.1 Baltic amber 144 4.4.2 Discussion 153 4.5 Summary and research deficits 155 5 RESULTS – RESINOUS MATERIALS FROM THE VIGANI CABINET 160 5.1 Gymnosperm resins – conifer resins and products 162 5.1.1 1/8 Terebin. Strasb. 163 5.1.2 1/9 Tereb Com 170 5.1.3 1/10 Venice Turpentine 176 5.1.4 1/11 Venic. Turpent. 183 5.1.5 1/13 Tereb E Chio 188 5.1.6 A/23 Pix Burgundica 194 5.1.7 A/26 Sandaracha 203 5.2 Angiosperm resins I - Fabales 210 5.2.1 1/4 Balsam Cipivi 211 5.2.2 A/5 Gum Animi 218 5.2.3 La2/7 Unknown resin 228 5.2.4 1/31 Bals Peruv 230 5.2.5 2/1 Bals Peru 237 5.2.6 Z/17 Balsam Tolutanum 240 5. 3 Angiosperm resins II – Sapindales 245 5.3.1 A/11 Mastiche 246 5.3.2 1/14 Tereb i E Cypri 252 5.3.3 A/21 Gum Copal 258 5.3.4 A/24 [.] Elemi 268 5.3.5 A/22 Tacamahaca 276 5.3.6 Z/1 Tacamahaca 283 5.4 Fossil Resins 287 5.4.1 E/13 Succinum Citrinum 288 5.4.2 E/14 Succinum flavan 295 5.4.3 E/15 Succinum albam 302 5.4.4 E/16 Succinum nigram 307 5.4.5 F/13 L. Gagatis 313 6 CONCLUSIONS 316 7 REFERENCES 324 APPENDIX 365 Investigated materials from the Vigani Cabinet 366 Annotated list of historical literature 367 List of figures 374 List of tables 379 Compound lists 381 Atlas of mass spectra 422