<p>This thesis describes the synthetic preparation of somecompounds, which can serve as chemical signals for use in thedevelopment of control methods for pest insects. The compoundssynthesised are of the isoprenoid type and of two kinds:carvone derivatives and germacranes. The derivatives of carvoneare based on modifications of this compound, by reactions ofeither its endocyclic or its exocyclic double bond. One type ofmodifications was accomplished by chemoselective additions ofthiophenol. The latter ones imply additions to the exocyclicdouble bond and seem to constitute general, previously rarelystudied reactions.</p><p>In other modifications of its exocyclic side chain, carvoneafforded some sesqui- and diterpeniod natural products. Thefollowing compounds were synthesised in an enantioselectiveway: (-)-epi-delobanone, (-)-delobanone,(-)-7-hydroxy-3,10-prenylbisaboladien- 2-one (an insecticidalconstituent of Croton linearis) as well as its diastereomer andsome other compounds with similar structures. All of thesecompounds weretested for their antifeedant/feeding deterrentcapability against gnawing of the pine weevil, Hylobiusabietis.</p><p>The germacranes prepared by means of enantioselective totalsyntheses are: (–)- 1(10),5-germacradien-4-ol and(–)-germacrene D. The former is a constituent of thedefence secretion (an allomone) from the larvae of the pinesawfly, and the needles of Scots pine. (–)-Germacrene D isa ubiquitous compound in nature. For example, it occurs in thepeels of apples and acts as one component of a lure (akairomone) to the apples, which attracts the codling moth,Cydia pomonella.</p><p>The main problem in the total syntheses of the germacraneswas the formation of the unsaturated monocyclic 10-memberedring. This was achieved by intramolecular alkylation with asuitably functionalised/protected cyanohydrin derivative,which, after further elaboration, afforded a monocyclic10-membered enone, that was used in the syntheses of the twogermacranes mentioned above. In the initial steps in thesynthetic sequence the stereochemistry was established byalkylation of an amide enolate attached to a chiral auxiliary.This approach could most likely also readily furnish the(+)-enantiomers of these germacrenes (of the germacraneterpenoid class) using the opposite enantiomer of the chiralauxiliary in the initial steps.</p><p><b>Keywords</b>: isoprenoids, natural product synthesis,allelochemicals, kairomones, allomones, bisabolane terpenoids,Hylobius abietis, germacrane terpenoids, Neodiprion sertifer,stereoselective synthesis.</p>

Decytospolides A and B are natural products isolated from Cytospora sp. No ZW02 that show mild anticancer properties. The interest in synthesizing these compound lies not in their activities, but rather the simplicity of the structure which could easily be modified to provide more potent derivatives. Previous syntheses of these compounds relied on transition metals to install the tetrahydropyran core or extensive use of protecting groups. Our first generation synthesis made use of the Achmatowicz rearrangement to synthesize the tetrahydropyran moiety. Based on this, a concise, protecting group free synthesis has been accomplished utilizing the Achmatowicz rearrangement of an optically active furanyl alcohol followed by diastereoselective Kishi reduction of the resulting dihydropyranone hemiacetal. <br><br>Carambolaflavone A is a natural product isolated from A. carambola with antidiabetic properties. Notably, these compound promote both insulin secretion and glucose uptake by muscle cells in hyperglycemic rats. A previous synthesis has been reported by Wang and coworkers, however this synthesis does not offer much potential for the formation of derivatives and relies on a C-glycosylation that requires heating for regio- and diastereoselectivity. Progress towards a concise synthesis has been made featuring a Lewis acid promoted highly diastereoselective substrate controlled C-glycosylation that does not require heating and a one pot oxidation of chroman to chromone utilizing DDQ. Further research is underway to complete the synthesis of this molecule by an oxidative addition to the chromone and subsequent removal of protecting groups.

Natural products fulfill an important role in the development of new drugs due to their diverse biological activities. Two prominent examples of pharmaceutically attractive classes of natural products are the fungal sorbicillinoids and the cyanobacterial ambigols. The sorbicillinoids are a polyketide family with over 100 members possessing complex molecular architectures and various bioactivities, ranging from antibiotic and antiviral properties to cytotoxicity. The group of ambigols isolated from the terrestrial cyanophyte Fischerella ambigua, comprises only five representatives that exhibit an analogous diversity of biomedically relevent activities. In order to exploit the great potential of these two classes of natural products, the focus of this work is set, on the one hand, on the targeted derivatization of the sorbicillinoids and, on the other hand, on the investigation of the biosynthesis of the ambigols and the development of an efficient synthetic strategy accessing this compound class. In the first part of this thesis, the previously established chemo-enzymatic one-pot approach, enabling the total synthesis of complex sorbicillinoids, was extended to the preparation of a focu- sed, antiviral sorbicatechol-like compound library. Furthermore, the antiviral evaluation of the library led to five derivatives exhibiting anti-HIV activity with IC50 values in the range of 32–77 μM. Besides, the natural substrate spectrum of the monooxygenase SorbC, playing the key role in the chemo-enzymatic approach, was expanded by a substrate mimicking strategy and by stepwise sorbicillin modification. Flexible long-chain ester functionalities were introduced to imitate the sorbyl side chain in sorbicillin. The successful enzymatic conversion of these derivatives represented an important breakthrough in overcoming substrate limitations. The final completion of the substrate scope was achieved through the formation of backbone-modified sorbicillin substrates. The analysis of the biocatalytic oxidative dearomatization of these compounds demonstrated the high tolerance of SorbC, enabling the straightforward synthesis of altered Diels-Alder und Michael addition products. In total, the chemo-enzymatic methodology has thus been expanded to prepare several new sorbicillinoids, inlcuding the formation of unnatural derivatives through the comprehensive broadening of the natural substrate scope. In the second part of this work, the focus was placed on the elucidation of ambigol biosynthesis by heterologous expression in Synechococcus elongatus PCC 7942. In vitro and in vivo experiments with the two cytochrome P450 monooxygenases confirmed their participation in the selective construction of the biaryl and biaryl ether linkages between the dichlorophenolic subunits. Co- incubation of biaryl bond forming oxidoreductase Ab2 with appropriate mono- and dimeric precursors resulted in the first reported chemo-enzymatic formation of ambigol A. The further examination of the other genetic elements showed that ambigol biosynthesis starts from the shikimate pathway (Ab7) leading, via Claisen rearrangement, to 4-hydroxybenzoic acid (Ab5). The intermediate is regioselectively chlorinated by the FAD-dependent halogenase Ab10 after being activated with ATP and coenzyme A (Ab6). Catalyzed hydrolysis of the thioester by the NRPS module Ab9 is generating 3-chloro-4-hydroxybenzoic acid, which undergoes decarboxylative halogenation by Ab1, leading to the key substrate of the cytochrome P450 monooxygenases Ab2 and Ab3. In summary, the research on ambigol biosynthesis allowed important conclusions regarding the chlorination of the precursors and the selective assembly of the biaryl and biaryl ether linkages. In addition to the biosynthetic analysis, a total synthetic approach to this class of natural products was developed. The basis for this was the targeted synthesis of the central building blocks prepared by highly regioselective halogenation and reactivity-directing protecting groups. The subsequent implementation of the biaryl bonds was performed by an optimized Suzuki cross-coupling reaction using the corresponding boronic acids. The key step of the synthetic strategy was the generation of mono- and bis-iodonium salts to install the required biaryl ether structural elements. The aryl transfer reaction with λ3-iodanes in combination with Suzuki cross-coupling accomplished a straightforward synthetic methodology accessing all known ambigols and unnatural derivatives bearing special biaryl coupling sites or consisting exclusively of 2,4-dichlorophenol units. / Naturstoffe spielen aufgrund ihrer diversen biologischen Aktivitäten eine wichtige Rolle in der Entwicklung neuer Medikamente. Zwei bedeutende Beispiele für pharmazeutisch wertvolle Naturstoffklassen sind die Sorbicillinoide aus Pilzen und die cyanobakteriellen Ambigole. Die Sorbicillinoide sind eine Polyketidfamilie mit über 100 Mitgliedern, die eine komplexe molekulare Architektur und verschiedene Bioaktivitäten besitzen, welche wiederum von antibiotischen und antiviralen Eigenschaften bis zu Cytotoxizität reichen. Die Gruppe der Ambigole, isoliert aus dem terrestrischen Cyanophyten Fischerella ambigua, umfasst nur fünf Vertreter, die aber eine vergleichbare Vielfalt an biomedizinisch relevanten Aktivitäten aufweisen. Um das große Potenzial der beiden Naturstoffklassen zu nutzen, liegt der Fokus dieser Arbeit einerseits auf der gezielten Derivatisierung der Sorbicillinoide und andererseits auf der Untersuchung der Biosynthese der Ambigole und der Entwicklung einer effizienten Synthesestrategie als Zugang zu dieser Verbindungsklasse. Im ersten Teil dieser Arbeit wurde der zuvor etablierte, chemo-enzymatische Ein-Topf-Ansatz, der zur Totalsynthese komplexer Sorbicillinoide führte, zum Aufbau einer fokussierten, antiviralen Bibliothek an Sorbicatechol-Derivaten erweitert. Darüber hinaus zeigte die Auswertung des antiviralen Potentials der Bibliothek fünf Derivate, die eine anti-HIV Aktivität mit IC50-Werten im Bereich von 32-77 μM besitzen. Außerdem wurde das natürliche Substratspektrum der Schlüsselmonooxygenase SorbC für den chemo-enzymatischen Ansatz durch Substratnachahmung und schrittweiser Sorbicillin-Modifikation erweitert. Zur Imitation der Sorbyl-Seitenkette in Sorbicillin wurden flexible, langkettige Esterfunktionalitäten eingeführt. Deren erfolgreiche enzymatische Umsetzung stellt einen wichtigen Durchbruch bei der Überwindung der Substratlimitationen von SorbC dar. Zur Vervollständigung des Substratspektrums wurde eine Synthesestrategie zum Aufbau von Sorbicllin-Derivaten mit modifizierten, aromatischen Substituenten entwicklet. Die Analyse der biokatalytischen oxidativen Dearomatisierung dieser Verbindungen verdeutlichte die hohe Promiskuität von SorbC, was die unkomplizierte Totalsynthese von abgewandelten Diels-Alder- und Michael-Additionsprodukten ermöglicht. Insgesamt wurden mit der chemo- enzymatischen Methode mehrere neue Sorbicillinoide hergestellt, einschließlich der Bildung von unnatürlichen Derivaten durch die umfassende Ausweitung des natürlichen Substratspektrums. Im zweiten Teil dieser Arbeit lag der Fokus auf der Aufklärung der Biosynthese der Ambigole durch heterologe Expression in Synechococcus elongatus PCC 7942. In vitro- und in vivo-Experimente mit den beiden Cytochrom P450 Monooxygenasen bestätigten deren Beteiligung an der selektiven Bildung der Biaryl- und Biarylether-Bindungen zwischen den Dichlorphenol-Untereinheiten. Die Co-Inkubation der biarylbildenden Oxidoreduktase Ab2 mit geeigneten mono- und dimeren Vorstufen führte zur ersten chemo-enzymatischen Synthese von Ambigol A. Weitere Untersu- chungen der anderen genetischen Elemente zeigten, dass die Ambigol Biosynthese mit dem Shikimat-Stoffwechselweg (Ab7) beginnt, der über eine Claisen-Umlagerung (Ab5) zu 4-Hydroxybenzoesäure führt. Das Intermediat wird durch die FAD-abhängige Halogenase Ab10 regioselektiv chloriert, nachdem es mit ATP und Coenzym A aktiviert wurde (Ab6). Durch katalysierte Hydro- lyse des Thioesters durch das NRPS-Modul Ab9 entsteht 3-Chlor-4-hydroxybenzoesäure. Die Carbonsäure wird mittels decarboxylativer Halogenierung (Ab1) in das Schlüsselsubstrat der Cytochrom P450-Monooxygenasen Ab2 und Ab3 umgewandelt. Zusammenfassend ergab die Erforschung der Ambigol Biosynthese wichtige Rückschlüsse auf die Chlorierungsmethoden der entsprechenden Vorstufen und den selektiven Aufbau der Biaryl- und Biarylether-Bindungen in der Natur. Neben der Analyse der Biosynthese wurde auch eine Totalsynthese zu dieser Naturstoffklasse entwickelt. Grundlage hierfür war der gezielte Aufbau der Kernbausteine, die mithilfe hoch regioselektiver Halogenierungen und reaktivitätslenkenden Schutzgruppen dargestellt wurden. Die anschließende Einführung der Biarylbindungen erfolgte durch eine optimierte Suzuki- Kreuzkupplung unter Verwendung der entsprechenden Boronsäuren. Der Schlüsselschritt der Synthesestrategie war die Synthese von Mono- und Bis-Iodoniumsalzen, über welche die benötigten Biarylether-Strukturelemente eingebaut werden konnten. Die Aryltransfer-Reaktion mit λ3-Iodanen in Kombination mit einer Suzuki-Kreuzkupplung ermöglichte den direkten Aufbau aller bekannten Ambigole sowie unnatürlicher Derivate mit speziellen Biarylkupplungsstellen oder Analoga, die ausschließlich aus 2,4-Dichlorphenol-Bausteinen bestehen.

The prostaglandins are a unique family of natural products found in all mammalian life, including humans. Their biological significance is profound, and they are responsible for a vast array of bodily functions. This importance, coupled with their low concentration in vivo, has made them attractive targets for total chemical synthesis. The work herein describes synthetic efforts towards their synthesis using an oxidative radical cyclisation to construct the key [3.3.0]-bridged bicyclic lactone, from which the prostaglandin skeleton may be derived. Key to this was the development of manganese(III) acetate and copper(II) triflate as optimal reagents for this cyclisation of unsaturated malonate/malonic acid derivatives. To study this, several model substrates for this crucial cyclisation were synthesised, and their cyclisation analysed. Chapter 5 describes the design and synthesis of several model substrates containing malonate groups for the oxidative radical cyclisation. The results of the cyclisation with manganese(III) and various copper(II) salts influenced the design of the substrates, and led to the use of malonic acids as more effective substrates for the formation of [3.3.0]-bicyclic lactones. A catalytic process, in which atmospheric oxygen is the terminal oxidant was also developed. Chapter 6 describes the studies towards a total synthesis of the prostaglandin family. Two potential routes are followed, the first of which used a key asymmetric epoxidation to install asymmetry. A Suzuki coupling was used to deliver the desired diene required for the cyclisation substrate, which was successfully cyclised using manganese(III) acetate and copper(II) triflate, creating the desired [3.3.0]-bicyclic lactone in good yield and with excellent diastereomeric control. A second, shorter route to the same lactone was also developed, using a novel asymmetric deconjugative aldol condensation to establish asymmetry. Cyclisation of this analogous substrate was also successful, delivering the same lactone after olefin metathesis.

Elatenyne, a brominated C₁₅ acetogenin isolated from the red Laurencia elata marine algae, was originally assigned a pyranopyran structure. Previous total synthesis of the pyranopyran structure has found this assignment to be incorrect. During this work the revised 2,2’-bifuranyl skeleton of elatenyne was suggested, but this skeleton has 32 possible diastereomers. The most likely diastereomer of elatenyne was predicted using computational ¹³C NMR chemical shift calculation in combination with the possible stereochemical outcomes from the proposed biosynthesis. Chapter 1 introduces the structural misassignment of natural products and describes the misassignment of elatenyne as well as a related chloro enyne. The use of computational methods and biosynthetic postulates to aid structure elucidation are also discussed. Chapter 2 describes the first generation synthesis of cross metathesis coupling partners required for the synthesis of elatenyne from D-mannitol. Chapter 3 describes the completed total synthesis of elatenyne, along with three derivatives and the (E)-isomer of elatenyne; itself a natural product. A comparison of the synthetic data with the isolation data for the natural products is presented, as well as comparison with the synthetic material of Kim and co-workers whose concurrent biomimetic total synthesis is also presented. Chapter 4 describes the modular nature of the devised synthetic route to access any diastereomer of elatenyne and its application to related 2,2’-bifuranyl natural products.

The construction of diverse molecular architecture conceived and created by Nature, continues to be the most exiting and challenging task to the practitioners of organic synthesis. As a result of refinement in isolation and purification techniques, recent advances in the spectroscopic methods particularly two-dimensional NMR spectroscopy and routine use of single crystal X-ray crystallography, the isolation and structural elucidation of the complex natural products has become a routine exercise. Even those natural products which are present in minute quantity, are being unraveled from the newer and exotic sources such as marine flora and fauna, microbial organisms and insect world. This has been a big boon for the synthetic organic chemists, providing them with increasing number of exciting objectives. The recent advances in the field of natural product synthesis testify to the organic chemists endeavors to meet these emerging challenges. Nature's expertise and virtuosity in creating a phenomenal array of carbocyclic frameworks is most notably highlighted in the terpenoid group of natural products. Indeed, the number and type of carbocyclic skeleta among terpenes continues to grow unabated as more and more natural products are being routinely isolated from the various sources. Thus, various polycyclic natural products bearing new and novel fused assemblies of five, six, seven and eight membered rings and replete with dense functionalization and stereogenic centers are being regularly encountered. The present investigation represents synthetic efforts towards some novel and recently isolated terpenoid natural products. Two main themes have been pursued. The first involves the construction of a functionalized hydroazulene framework employing RCM as the key step and its further elaboration to the 5,7,6-tricyclic framework present in diterpene guanacastepene-A and 5,11-fused bicyclic system present in neodolabellane diterpenes. The second theme explores the synthetic versatility of the well-established photo-thermal metathetic approach to linear triquinanes through its application to the total synthesis of novel and recently isolated natural product cucumin E. It further explores the utility of 5-5-5 fused ring system to access 5-8 system. This strategy has led to the stereoselective total synthesis of natural product asterisca-3(15),6~diene belonging to the rare asteriscane family. The present thesis entitled "Towards the Total Synthesis of Terpenoid Natural Products" describes our endeavors towards the synthesis of 5-7-6, 5-11, 5-5-5 and 5-8 fused natural products and has been organized under four chapters. Chapter I. Studies toward the total synthesis of novel diterpene antibiotic guanacastepene A. Chapter EL Synthesis of the novel 5,11-fused bicyclic framework of neodollabellane diterpenoids. Chapter HI. A Stereoselective total synthesis of the novel triquinane sesquiterpene cucumin E. Chapter IV. Total synthesis of 5-8 ring fused sesquiterpene hydrocarbon asterisca-3(15),6-diene. The Chapter I describes a stereoselective approach towards the construction of the novel 5,7,6-rig fused framework present in the diterpene antibiotic guanacastepene A 1, recently isolated from an unidentified fungus growing on the tree Daphnopsis americana by Clardy et al. Besides its structural novelty, guanacastepene A exhibits impressive activity towards methicilline-resistant Staphylococcus aureus and vancomycine-resistant Entereococcusfaecium. Thus, 1 has evoked an unprecedented attention from the synthetic community and we too were enticed to enter this arena. Scheme 1 (structural formula) The synthetic approach towards guanacastepene A 1, envisage in this study, was revealed through a retrosynthetic analysis which identified hydroazulenic core 2 (AB rings) with requisite level of functionalities as an advanced precursor to which a six membered ring could be annulated through appropriate protocols. The hydroazulene core 2 was to be accessed from the substituted cyclopentenone 4 through the intermediacy of 3 and the former in turn could be prepared from the readily available endo tricyclo[5.2.1.026]deca-3,8-diene-5-one 6, Scheme 1. In this approach to the AB ring hydroazulenic core 2 of 1, some essential requirements were recognized at the outset. These were the setting up the key cis relationship of the angular methyl group at C11 and the neighboring bulky-isopropyl group at C12, installation of a desirable level of functionalization in the five membered ring and a functional group handle in seven-membered ring to Scheme 2 (structural formula) append the six membered ring with requisite functionality. Keeping these considerations in mind, readily available endo-tricyclo[5.2.1.02-6]deca-3,8-diene-5-one 6 with well-established propensity toward reactivity on exro-face was identified to be starting point, Scheme 1. Copper(I)mediated stereoselective 1,4-addition of isopropylmagnesium iodide on 6, followed by sequential a-alkylation with allyl bromide and methyl iodide led to 7 as a single diastereomer and correctly installed the methyl and isopropyl groups in the required cis-relationship, Scheme 2* Retro-Diels-^Ider reaction in 7 under flash vacuum pyrolysis (FVP) liberated the cyclopentenone 8. For the annulation of a seven-membered ring to cyclopentenone 8, recourse was taken to a ring closing metathesis-(RCM) based protocol. Barbier-type addition of 4-bromo-1-butene to 8 in the presence of lithium metal and oxidative transposition of the resulting allylic alcohol with PCC furnished enone 9 in good yield. On exposure to Grubbs' catalyst, enone 9 underwent smooth RCM reaction to deliver the desired hydroazulenic framework 10, Scheme 2. The bicyclic hydroazulenic enone 10 was now poised for the elaboration of functionalities in the context of evolution to the natural product 1. Thus, 10 was elaborated to epoxy alcohol 11 in a three step sequence, Scheme 2. TMSOTf mediated opening of epoxide ring to yield cis-enediol, protection of the resultant diol as an acetonide and allylic oxidation furnished the key enone 12, Scheme 2. Attempts to alkylate the enone 12 to install the C16 methyl group and the precursor side chain for six membered ring annulation failed consistently. Recourse was then taken to a-carboethoxylation in 12 using Mander's reagent proved to be quite effective and further alkylation with methyl iodide furnished 13 as a single stereoisomer with the correct stereochemical positioning of the quaternary methyl group at C8. Intermediate 13 was elaborated to tricyclic framework 14 of guanacastepane A in five steps, by setting up NaOEt mediated intramolecular aldol reaction as key step, for the construction of six membered ring, Scheme 2. In tricyclic cross-conjugated dienone 14, complete carbon framework of the natural product guanacastepene A 1, with a copious disposition of functionalities was realized. Further efforts to transform 14 to 1 were not very encouraging. However a variant of ring C annulation on 12 is being investigated by a colleague in the group to achieve the total synthesis of the natural product. In travails towards 1 and 14, several deviations from the expected course, leading to the new tricyclic structural variants of the biologically promising guanacastepene A 1 were encountered and these findings will also be detailed in this chapter of the thesis. In the Chapter n of the thesis, synthetic studies directed towards the bicyclic framework present in novel neodolabellane type diterpenes like a-and (3-neodolabellenol 17a and 17b isolated from an unknown species of Australian soft coral by Coll et al will be delineated. The readily accessible bicyclic hydroazulenic enone 13, also served as an advanced intermediate for the construction of the 5-11 fused bicyclic skeleton 16 of neodollabellane diterpenoids via an oxy-Cope rearrangement. Elaboration of 13 to the divinyl carbinol 15 and its [3.3] sigmatropic rearrangement (oxy-Cope rearrangement) to 16 and related reactions will be described, Scheme 3. Scheme 3(Structral formula) Chapter III describes the first total synthesis of the sesquiterpenoid natural product cucumin E 26 bearing a novel triquinane framework, and reported recently from the mycelial cultures of agaric Macrocystidia cucumis (Pers ex Fr.) by the groups of Steglich and Anke. Synthesis of 26 was accomplished following an interesting variant of the photo-thermal metathetic approach to linear triquinanes delineated by us sometime ago, Scheme 4. Cucumin E 26 attracted our attention as this sesquiterpene [Scheme 4 (Structural formula)] bears an Interesting biogenetic relationship to the related hirsutane group of linear triquinanes from which it can be derived through the migration of a methyl group. Towards the synthesis of 26, the readily available pentacyclic dione 18 was identified as the key starting material and was elaborated to 19 using FVP (flash vacuum pyrolysis) conditions under which 18 underwent [2+2]-cycloreversion of the cyclobutane ring to furnish the cis, syn, cis-triquinane, Scheme 5. On exposure to base, 19 could be equilibrated through back and forth double bond isomerization to furnish the cis,antecis-isorner 20 in reasonable yield. Attention was now turned towards the installation of the network of four methyl groups present in 26 and relevant functional group adjustments. Catalytic hydrogenation of 20, selective mono-Wittig olefination and subsequent gem-dimethylation furnished olefinic ketone 21. At this stage, the carbonyl group in 21 was sought to be removed and recourse was taken to the Barton deoxygenation protocol to furnish 22, Scheme 5. The next task en-route to the cucumin skeleton was the introduction of the angular methyl group at C7 to generate the complete Cis carbon framework. For this purpose, the ketal group in 22 was deprotected to furnish the ketone 23. Angular methylation in 23 exhibited fair regioselectivity to yield 24 as the major product. The enone moiety in 24 was established through allylic oxidation following the Sharpless catalytic selenium dioxide oxidation followed by PDC oxidation to afford 25. Rh(III)-mediated isomerization of the exocyclic double bond in 25 delivered cucumin E 26, whose spectral characteristics were exactly identical to the natural product as established through direct comparison, Scheme 5. In Chapter IV, the total synthesis of the bicyclo[6.3.0]undecane-based sesquiterpene hydrocarbon asterisca-3(15),6-diene 38, isolated from Lippia integrifolia (Griseb) by Konig et al. and representing the simplest member of the asteriscane family, is described. Our approach to the bicyclo[6.3.0]undecane system was based on the 'carbocyclic ring equivalency' concept. Thus, bicyclo[3.3.0]octane ring system is an eight-membered ring equivalent and tricyclo[6.3.0.02'6]undecane (linear triquinane system) is the latent form of the bicyclo[6.3-0]undecane system through the scission of the central bond as shown in Scheme 6. Following this concept a synthesis of 38 was envisaged from the cfe,syn, cis-triquinane bis-enone 28, readily and quantitatively available from the pentacyclic-caged dione 27, through flash-vacuum pyrolysis (FVP), as described earlier. More stable bis-enone 29 was obtained from 28 by relocation of one of the enone moieties in 28 through thermal activation under static conditions. The two double bonds in 29 could be now easily differentiated and hence it served as an appropriate substrate for further elaboration. Thus, bis-enone 29 on selective catalytic hydrogenation and regioselective gem-dimethylation afforded 30, Scheme 7. At this stage, the two-carbonyl functionalities in 30 were sought to be removed and this was achieved in a stepwise manner. The sequence involved chemoselective thioketalisation of the enone carbonyl followed by reductive desulfurization in metal-ammonia milieu and led to a diastereomeric mixture of alcohols (resulting from the concurrent reduction of the saturated ketone under metal-ammonia conditions). The diastereomeric mixture of alcohols was deoxygenated following the Barton protocol to yield tricyclic hydrocarbon 31, Scheme 7. Catalytic ruthenium mediated oxidative fragmentation of the tetrasubstituted olefinic bond in 31 afforded the 5,8-fused os-bicyclic dione 32. Wittig olefination of cis-bicyclic dione 32 proceeded regioselectively at the carbonyl group distant from the ring junction and furnished keto-olefin 33. However, the isomerization of exocyclic double bond in 33 to the desired endo position (corresponding to C6-C7 in the natural product) to yield 34 proved to be difficult due to unwanted transannular cyclization. Consequently, the transformation of 33 to the desired 34 was carried out through a five-step sequence. The sequence involved the reduction of the carbonyl group in 33 to yield alcohol, protection of the resultant alcohol as IMS-ether and RhCb mediated isomerization of the exo-double bond to the desired endo position. Further deprotection of the TMS ether and oxidation led to the acquisition of the expected enone 34, Scheme 7. Finally, the exo- methylene unit present in the natural product was installed by Wittig olefination in 34 to furnish 35, corresponding to the 'assigned structure' of the natural product. However the spectral data of synthetic 35 was distinctly different from that reported for the natural product and a revision of the natural product structure was warranted. A careful analysis of the spectral data led us to the surmise that the natural product could be the trans-isomer and we embarked on its synthesis. Consequently, cis-bicyclic diketone 32 on exposure to base could be readily equilibrated to the more stable trans-isomer 36 in which the later was the major product (1:4). Bicyclic trans-dione 36, like its cis sibling 32 underwent a facile regioselective Wittig olefination to yield keto-olefin 37, Scheme 8. RhCk-mediated double-bond isomerization in 37 proceeded without any complications and gave a readily separable mixture of regiomeric olefinic ketones 38 and 39 in the ratio 2:3, respectively. Wittig olefination on the required keto olefin 39 proceeded smoothly to furnish the bicyclic hydrocarbon 40 whose spectral characteristics [lH NMR, 13C NMR) exactly matched those reported for the natural product, Scheme 8. A total synthesis of the natural product asterisca-3(15),6-diene has been accomplished. These synthetic efforts necessitate the revision of the earlier assigned structure of the natural product from cis-35 to trans-38. (For structural formula pl see the original document)

Ziel der Dissertation war die enantioselektive Totalsynthese des aus Streptomyces alboniger und Streptomyces aurantiacus isolierten Makrodiolids Pamamycin-607 (1a). Neben ungewöhnlichen autoregulatorischen und anionophoren Eigenschaften zeigt der 16-gliedrige Makrocyclus 1a, der sich aus den beiden Hydroxysäuren 48 (&amp;quot;larger fragment&amp;quot;) und 49 (&amp;quot;smaller fragment&amp;quot;) zusammensetzt, eine ausgeprägte antibiotische Wirkung gegen Gram-positive Bakterien inklusive multipel-antibiotikaresistenter Stämme von Mycobacterium tuberculosis, sowie gegen einige phytopathogene Pilze. Derzeit arbeiten mehrere Gruppen an der Synthese dieser Verbindung, die bislang jedoch noch nicht erreicht werden konnte. Der in dieser Arbeit verfolgte Syntheseweg basiert entscheidend auf einem zuvor in der Arbeitsgruppe entwickelten generellen Zugang zu Actinsäuren und deren Analoga unter Nutzung neuer Methoden zur Darstellung und Elaboration von Sultonen als Schlüsseltransformationen. Ausgehend von Furan und enantiomerenreinem (S)-1,2-Epoxypentan konnte so durch die erstmalige Anwendung dieser sechsstufigen Sequenz ein effizienter Zugang zu dem Hydroxymethylester 62 erarbeitet werden. Die Umwandlung dieses Actinsäurederivates 62 in das Hydroxyalkylfuran 50, das den Ausgangspunkt für eine iterative Anwendung der oben erwähnten Sultonroute bildet, gelang in sechs Schritten durch Nutzung einer diastereoselektiven Hydroborierung unter Vermeidung von 1,3-Allylspannung als Schlüsselschritt. Ausgehend von 50 konnte das larger fragment von Pamamycin-607, das auch als Baustein homologer Pamamycine dient, in weiteren sechs Schritten synthetisiert werden. Dazu wurde nach intensiver Optimierungsarbeit wiederum der oben erwähnte Zugang zu Actinsäurederivaten in modifizierter Form genutzt. Das smaller fragment 49, welches lediglich das C-2-Epimere von 62 darstellt, ließ sich ebenfalls durch Anwendung der Sultonroute generieren. Der für Actinsäuren ungewöhnlichen Konfiguration an C-2 musste dabei durch eine leichte Abänderung der Sequenz Rechnung getragen werden. Ausgehend von literaturbekanntem 2-Brom-4-methylfuran gelangt man so in sechs Schritten zum Methylester des smaller fragment 7. Eine mit der Yamaguchi-Cyclisierung der aus 62 generierten Säure einhergehende Epimerisierung an C-2 ermöglichte nach Öffnung des resultierenden Monolactons unter Lewis-Säurekatalyse eine Verkürzung der Synthese des smaller fragment von Pamamycin-607 auf drei Schritte. Weitere Untersuchungen ergaben, dass 62 nach basischer Äquilibrierung mit DBU und flashchromatographischer Trennung der resultierenden 1:1-Epimerenmischung sogar direkt in den Methylester des smaller fragment 7 überführt werden kann. Während die Yamaguchi-Veresterung des hydroxylgeschützten smaller fragment mit carboxylgeschütztem larger fragment sehr effizient zum Kupplungsprodukt führte, ergab die Cyclisierung nach Entfernung der Schutzgruppen lediglich eine Mischung aus 2-epi-Pamamycin-607 und 2,2'-bisepi-Pamamycin-607. Durch Abbau von natürlichem Pamamycin konnte jedoch ein sechsstufiger Zugang zur Cyclisierungsvorstufe erarbeitet werden, wodurch weitere Untersuchungen zur abschließenden Cyclisierung erleichtert werden. Des weiteren gelang es, im Rahmen der Untersuchungen zur Chemie der Actinsäuren ausgehend von 62 einen generellen Zugang zu den korrespondierenden Aminoactinsäuren zu erarbeiten, die als Ausgangspunkt für die Synthese von Azamakrocyclen dienen können.

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This thesis describes synthetic studies directed towards the total synthesis of the nakafuran and florlide marine natural products. Chapter One provides an overview of the importance of natural products to current medicinal chemistry and describes how the "supply issue" associated with these biologically derived compounds can be resolved through the process of total synthesis. Two families of marine natural products, the nakafurans and the florlides, are introduced as synthetic targets and strategies utilising a type II intramolecular Diels-Alder (IMDA) reaction to achieve their total synthesis are delineated. The efficient preparation of regio- and stereodefined vinyl coupling fragments via hydrostannylation and hydrohalogenation methodology is described in Chapter Two. The palladium-catalysed cross-coupling of these fragments, via Stille or Negishi coupling methodology, yielded dienes which were successfully advanced to IMDA triene precursors. Chapter Three describes investigation of the type II IMDA reaction to give bicyclo[4.3.1]decene carbocyclic skeletons. A facile acid-catalysed 6,7-alkene to 7,8-alkene olefinic isomerisation, via a proposed oxonium intermediate, and the inability to appropriately functionalise the desired adducts impeded progress along the synthetic route. Molecular modelling was conducted to investigate the causes of this unexpected reactivity. Investigations in Chapter Four describe the successful synthesis and cyclisation of homomethyl triene analogues prepared via application of enyne metathesis chemistry. The use of an exo-cyclopropylcarbinyl fragmentation was found to be unsuccessful as a means of installing the desired 6-methyl-bicyclo[4.3.1]decan-2-one core with a competing endo-ring expansion giving rise to a bicyclo[4.4.1]undecane ring system. Chapter 5 summarises the above results and gives a brief discussion of the future potential of this research to provide for a total synthesis of the nakafuran and florlide natural products.

This thesis describes synthetic studies directed towards the total synthesis of the nakafuran and florlide marine natural products. Chapter One provides an overview of the importance of natural products to current medicinal chemistry and describes how the "supply issue" associated with these biologically derived compounds can be resolved through the process of total synthesis. Two families of marine natural products, the nakafurans and the florlides, are introduced as synthetic targets and strategies utilising a type II intramolecular Diels-Alder (IMDA) reaction to achieve their total synthesis are delineated. The efficient preparation of regio- and stereodefined vinyl coupling fragments via hydrostannylation and hydrohalogenation methodology is described in Chapter Two. The palladium-catalysed cross-coupling of these fragments, via Stille or Negishi coupling methodology, yielded dienes which were successfully advanced to IMDA triene precursors. Chapter Three describes investigation of the type II IMDA reaction to give bicyclo[4.3.1]decene carbocyclic skeletons. A facile acid-catalysed 6,7-alkene to 7,8-alkene olefinic isomerisation, via a proposed oxonium intermediate, and the inability to appropriately functionalise the desired adducts impeded progress along the synthetic route. Molecular modelling was conducted to investigate the causes of this unexpected reactivity. Investigations in Chapter Four describe the successful synthesis and cyclisation of homomethyl triene analogues prepared via application of enyne metathesis chemistry. The use of an exo-cyclopropylcarbinyl fragmentation was found to be unsuccessful as a means of installing the desired 6-methyl-bicyclo[4.3.1]decan-2-one core with a competing endo-ring expansion giving rise to a bicyclo[4.4.1]undecane ring system. Chapter 5 summarises the above results and gives a brief discussion of the future potential of this research to provide for a total synthesis of the nakafuran and florlide natural products.