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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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    Regulation of cucumber (Cucumis sativus) induced defence against the two-spotted spider mite (Tetranychus urticae
    He, J. - \ 2016
    Wageningen University. Promotor(en): Harro Bouwmeester; Marcel Dicke, co-promotor(en): Iris Kappers. - Wageningen : Wageningen University - ISBN 9789462576810 - 211
    cucumis sativus - cucumbers - induced resistance - plant pests - tetranychus urticae - mites - defence mechanisms - herbivore induced plant volatiles - herbivory - metabolomics - terpenoids - genomics - cucumis sativus - komkommers - geïnduceerde resistentie - plantenplagen - tetranychus urticae - mijten - verdedigingsmechanismen - herbivoor-geinduceerde plantengeuren - herbivorie - metabolomica - terpenen - genomica

    Plants have evolved mechanisms to combat herbivory. These mechanisms can be classified as direct defences which have a negative influence on the herbivores and indirect defence that attracts natural enemies of the attacking herbivores. Both direct and indirect defences can be constantly present or induced upon attack. This study, using cucumber (Cucumis sativus) and the two-spotted spider mite (Tetranychus urticae) as model, aimed to reveal the molecular mechanisms underlying the induced defence during herbivory, with emphasis on transcriptional changes and the involved TFs, the enzymatic function of the genes associated with volatile biosynthesis, and their promoters which regulate their expression.

    Biosynthesis and transport of terpenes
    Ting, H.M. - \ 2014
    Wageningen University. Promotor(en): Harro Bouwmeester, co-promotor(en): Sander van der Krol. - Wageningen : Wageningen University - ISBN 9789461738929 - 183
    nicotiana benthamiana - artemisia annua - planten - plantensamenstelling - terpenen - biosynthese - genen - genisolatie - nicotiana benthamiana - artemisia annua - plants - plant composition - terpenoids - biosynthesis - genes - gene isolation

    Terpenoids are the largest class of natural product that are produced by plants, with functions that range from a role in plant development to direct defence against pathogens and indirect defence against insects through the attraction of natural enemies. While terpene biosynthesis genes have been well studied, there is still only limited knowledge on how terpenes are transported within the cell and from the cell to the apoplast. In this thesis, different aspects of transport of terpenes in plants were addressed. Firstly, the issue of intermediate transport between enzymes was studied, focussing on the regulation of intermediate flux between two different biosynthesis enzymes (CYP71AV1 and DBR2) that determines the resulting Artemisia annua, low or high artemisinin, chemotype. We also investigated the role of Lipid Transfer Proteins and vesicles in the transport of terpenes. Some LTP mutants were indeed shown to emit lower terpene levels, but the exact mechanism could not be resolved. Inhibition of vesicle transport increased terpene levels, most likely due to an effect on protein stability. I conclude that there are multiple transport mechanisms involved in terpene transport which complicates the analysis of a single transport pathway.

    Natural Terpenoids as Messengers. A multicisciplinary study of their production, biological functions and practical applications
    Harrewijn, P. ; Oosten, A.M. van; Piron, P.G.M. - \ 2001
    Dordrecht : Kluwer Academic Publishers - ISBN 9780792368915 - 452
    terpenen - semiochemicals - biosynthese - plantenfysiologie - gezondheid - terpenoids - semiochemicals - biosynthesis - plant physiology - health
    Terpenoid antifeedants against insects : a behavioural and sensory study
    Messchendorp, L. - \ 1998
    Agricultural University. Promotor(en): L.M. Schoonhoven; J.J.A. van Loon. - S.l. : Messchendorp - ISBN 9789054859017 - 136
    vraatremmers - insecten - insectenplagen - plantenplagen - terpenen - sesquiterpenoïden - voedingsgedrag - functionele reacties - zintuigorganen - antifeedants - insects - insect pests - plant pests - terpenoids - sesquiterpenoids - feeding behaviour - functional responses - sense organs

    This thesis describes a study on the behavioural and sensory effects of terpenoid antifeedants on several insect species. The main aim was to elucidate the mechanisms of action of terpenoid antifeedants. From a fundamental point of view, this will yield insight in the role of these compounds in host plant selection by insects. From an applied perspective, knowledge of the level of effectiveness and of putative structure-activity relationships, provides a basis to assess the potential for using terpenoids as crop protection agents.

    The effects of specific molecular structures were studied comparatively in different unrelated insect species. The mechanism(s) of action of sesquiterpene drimanes were investigated by measuring sensory responses and observing their effects on behaviour. Furthermore, long-term and toxic effects were studied.

    Larvae of the large white butterfly Pieris brassicae L. (Lepidoptera: Pieridae) were used as model insect for studying the sensory perception of sesquiterpene drimane antifeedants by insects. By comparing sensory and behavioural responses to 15 drimane antifeedants, it was shown that the frequency of impulses from the deterrent cell in the medial sensillum styloconicum significantly correlates to the behavioural response in dual-choice tests. In addition, the drimanes caused inhibition of sensory responses to feeding stimulants. The results suggest that in this insect a 'labeled line' coding principle is used for the perception of antifeedants, combined with inhibition of receptor cells sensitive to feeding stimulants (chapter 2).

    The temporal aspects of the behavioural effects of five drimanes on P. brassicae larvae were studied with aid of detailed, 1 min interval behavioural observations in a no-choice test (chapter 3). It was found that two of the five drimanes (polygodial and warburganal) inhibited feeding only during the beginning (0-30 min) of the tests and that two other drimanes (confertifolin and 'compound 4') became effective 30-90 min after the onset of the test. The fifth compound (isodrimenin) inhibited feeding during the whole 3 h period. It is concluded that some drimanes ( e.g. confertifolin and compound 4) have postingestive, toxic effects resulting in inhibition of feeding. These and the results of chapter 2 indicate that analogous drimane antifeedants can inhibit feeding in P. brassicae through multiple mechanisms of action. Probably P. brassicae larvae in no-choice situations soon habituate to drimane antifeedants, unless the drimanes are toxic. The results indicate that, when developing a structure-activity relationship for a series of antifeedants, it is essential to distinguish the mode of action which underlies inhibition of feeding.

    The behaviour of larvae of the Colorado potato beetle, Leptinotarsa decemlineata Say (Coleoptera: Chrysomelidae) was studied when exposed to three drimanes in 3 h no-choice tests (chapter 4). In contrast to P. brassicae larvae L. decemlineata larvae were inhibited from feeding throughout the 3 h no-choice tests when treated with polygodial or warburganal, while to compound 4 habituation occurred after the first 15 min of the test. The results indicate that polygodial and warburganal are either strong antifeedants or possess toxic properties as well, preventing that habituation occurs. Topical application of polygodial and warburganal to the larval cuticle also inhibited feeding. This could indicate that toxic properties of these molecules might contribute to feeding inhibition, although the effects of topical application are not necessarily the same as the effects after ingestion of the compounds ( e.g. not in the case of P. brassicae ; chapter 3).

    The hypothesis that feeding deterrents in potential food plants are decisive in food plant selection by insects (chapter 1) was originally derived from experiments with the Colorado potato beetle. However, little was known about the sensory perception of such compounds by this beetle. In this study the role of an epipharyngeal sensillum in the perception of antifeedants was investigated (chapter 5). Electron microscopy revealed that the epipharyngeal sensillum is innervated by five neurons. Electrophysiological experiments showed that one of these cells responds to water, a second to sucrose and a third to two feeding deterrents ( i.e. compound 4 and sinigrin) that had been found effective in a behavioural test. Furthermore, the response of the sucrose sensitive cell was strongly inhibited by the drimane and only slightly by sinigrin. From a comparison of behavioural and sensory responses it is concluded that probably both the response of the epipharyngeal deterrent cell ànd peripheral interactions exerted by feeding deterrents on the sucrose sensitive cell in this sensillum determine the potency of feeding deterrents in L. decemlineata larvae. The results provide a physiological basis for the hypothesis that the presence of feeding deterrents in potential food plants is a decisive cue in food plant selection by L. decemlineata larvae.

    The sensitivities of nymphs of two aphid species, Myzus persicae Sulzer and Aphis gossypii Glover (Homoptera: Aphididae) to 11 drimane compounds, applied to the lower surface of artificial diet sachets, were compared in dual-choice tests. In general, A. gossypii nymphs were less sensitive to the drimanes than M. persicae nymphs. Warburganal and polygodial were highly active as deterrents and/or feeding inhibitors against both species. In dual-choice tests in which the upper parts of the nymphal antennae were ablated, it was found that both species do not detect the drimane polygodial anymore. It was concluded that nymphs of M. persicae and A. gossypii detect polygodial and probably the other drimanes tested with contact chemosensilla at the tips of their antennae. The ablation studies also showed that in both species no tarsal, labial or epipharyngeal sensilla are involved in detecting polygodial within 24 h. The results indicate that deterrents on the leaf surface might play a role in the selection of host plants by these and other aphid species.

    Chapter 7 reports on additional bioassays with drimanes on several insect species. In chapter 8, several synthetic analogues, derived from the C-9 side chains of the diterpenoids clerodin and ajugarin I, were tested for their effects on feeding of P. brassicae and L. decemlineata larvae and M. persicae nymphs. Several compounds showed moderate activity against P. brassicae larvae. Interestingly, the most effective compound most closely resembled the structure of the furopyran-fragment of the triterpenoid azadirachtin, which fragment had previously been shown to be a highly effective feeding deterrent against Spodoptera littoralis .

    In conclusion, the mode of perception as well as the structure-activity relationship of terpenoid antifeedants considerably differs between the insect species examined in this study (chapter 9). For practical implementation of terpenoid antifeedants in crop protection, this means that research should be focussed on selected pest insect species. Furthermore, the possibilities for combined use with other (biological) control agents should be investigated.

    Different aspects of S-carvone, a natural potato sprout growth inhibitor
    Oosterhaven, J. - \ 1995
    Agricultural University. Promotor(en): J.J.C. Scheffer; L.H.W. van der Plas. - S.l. : Oosterhaven - ISBN 9789054854357 - 152
    carum carvi - karwij - solanum tuberosum - aardappelen - behoud - opslag - bestraling - diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - carum carvi - caraway - solanum tuberosum - potatoes - preservation - storage - irradiation - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes

    After harvest, potato tubers are usually stored at a temperature of 6-8°C in combination with the application of a synthetic sprout inhibitor. Frequently used sprout inhibitors are isopropyl N-phenyl-carbamate (propham or IPC), isopropyl N-(3-chlorophenyl)carbamate (chlorpropham or CIPC) or a combination of both compounds. There are several reasons for the development of alternative, natural sprout inhibitors. First, the Scandinavian market, for example, requires potato tubers free of (C)IPC residues, and the so-called "green" market, for which no or very little synthetic chemicals are allowed, does not yet have alternative sprout inhibitors. Secondly, governmental policy is directed towards a reduction of the amount of synthetic pesticides used in agricultural practice (Meerjarenplan Gewasbeschermingsmiddelen, MJPG).

    Natural potato sprout inhibitors were already used in the ancient Inca cultures. After harvest, the potato tubers were stored in boxes or bins together with the twigs of muña plants (Minthostachys species). Treating the tubers in this way controlled sprouting as well as insect attack during a prolonged storage. Volatiles emanating from the muña leaves during the storage were responsible for the insect repellent and sprout inhibitory effects.

    The monoterpene S-carvone is a related volatile compound which can be isolated from the seeds of caraway (Carum carvi L.) or dill ( Anethum graveolens L.), for example; also this compound has good potato sprout growth inhibitory effects. Application of S-carvone, derived from caraway seed, as a potato sprout inhibitor can stimulate the demand for caraway and therefore the need to grow it. This can be beneficial for Dutch growers, since cultivation of caraway is suitable on heavy clay soils in which crop rotation is limited to only a few crops. The research described in this thesis has been performed within the Dutch Caraway Research Programme in which nine research groups were amalgamated with the objective to reduce the problems with respect to the cultivation of caraway and to stimulate possible new applications of its essential oil or of S-carvone.

    S-carvone inhibits the sprouting of potato tubers and the sprout growth reversibly: removal of S-carvone allows sprouting and regrowth of the individual sprouts. A high dosage leads to necrosis, but the side buds remain their viability and they start to sprout again when the concentration of S-carvone in the atmosphere comes below a threshold value. The enantiomer of S-carvone, R- carvone, can be isolated from spearmint ( Mentha spicata L.) and possesses almost the same sprout growth inhibitory properties as S-carvone. Current research is focussed on the practical application of S-carvone to seed potatoes as a reversible sprout growth inhibitor.

    In addition to the inhibitory effects just mentioned, the growth of several storage pathogens is also reduced by S-carvone. However, the susceptibility of fungi to S-carvone, e.g. Fusarium species that cause dry-rot, differs between (sub)species. F.solani var. coeruleum is able to grow on tubers treated with S- carvone, whereas F . sulphureum cannot withstand it. This difference was not found in vitro; both fungi were susceptible to the same range of S-carvone concentrations, they were both able to convert S-carvone with the same rate, and into almost the same conversion products. Therefore, the difference in susceptibility in situ must be found in, for example, a specific interaction of the fungi with the potato tubers.

    Carvone is stereoselectivily converted into other compounds by potato tissue: R-carvone mainly into neodihydrocarveol, and S-carvone into neoisodihydrocarveol. The bioconversion only takes place in easily accessible tissues, such as sprouts and tuber wound tissue. More than 90% of the amount of S-carvone found in intact tubers, is located on or in the skin. In addition to the chloroform-soluble bioconversion products, water-soluble carvone derived compounds were detected in potato tissue, using 13C-labelling studies. The identity of the conjugated compounds has not been established yet, but S-carvone is found after addition of HCl to the aqueous phase containing the conjugates. The induction of glutathione S-transferase may point to the conjugation of S-carvone to glutathione. Conjugation to saccharides may be an alternative explanation.

    The sprout growth inhibition is correlated strongly with a decreasing 3- hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity, a key enzyme providing building blocks for the synthesis of various essential plant metabolites. Using specific potato HMGR antibodies, it was found that the decrease of activity correlated well with the disappearance of HMGR protein signals on Western blots derived from samples of proteins from organelle fractions and microsomal membranes.

    S-carvone inhibits the healing of wounded tubers temporarily; in particular, suberization is delayed for about 10 days. The formation of a cambium layer is almost completely inhibited, which indicates that S-carvone interferes with cell division processes during the healing of wounded tissue. The suberization is correlated with the activity of phenylalanine ammonia Iyase (PAL). This enzyme catalyses the first step that leads to the synthesis of suberin, and in S-carvone treated wound tissue, the induction of PAL is delayed for about 10 days. This implies that tuber wound tissue is able to adapt to the exposure to S-carvone.

    In conclusion, based on the research described in this thesis, it can be stated that S-carvone is a compound with a great potential because of its sprout growth inhibitory effect, possibly partly due to an inhibition of HMGR. Since S-carvone inhibits sprouting reversibly, it may also be useful as a temporary inhibitor of seed potatoes. In addition, S-carvone reduces the development and growth of several storage pathogens. These effects make the chances of an application of S-carvone as a natural potato sprout growth inhibitor even better.

    Onderzoeksprogramma ter verbetering van karwij als akkerbouwgewas en ter introductie van nieuwe afzetmogelijkheden : eindverslag 1990 - 1994
    Anonymous, - \ 1994
    Wageningen etc. : CPRO-DLO [etc.]
    carum carvi - karwij - diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - vluchtige verbindingen - carum carvi - caraway - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - volatile compounds
    De geurtocht van Marcel Dicke.
    Beekman, W. - \ 1994
    Ekoland 14 (1994)11. - ISSN 0926-9142 - p. 12 - 13.
    dieren - lokstoffen - biologische bestrijding - etherische oliën - gastheer parasiet relaties - geurstoffen - feromonen - gewasbescherming - planten - terpenen - animals - attractants - biological control - essential oils - host parasite relationships - odours - pheromones - plant protection - plants - terpenoids
    Interview with Marcel Dicke who is involved in research on the relationship between phytophagous insects and mites, their predators and the host plants. Plants produce attractants, mostly terpenes, to attrack the predators. Possible applications of this mechanism for pest control are discussed
    Chemical consequences of long-range orbital interactions in Perhydronaphtalene-1,4-diol monosulfonate esters
    Orru, R.V.A. - \ 1994
    Agricultural University. Promotor(en): Æ. de Groot; J.B.P.A. Wijnberg. - S.l. : Orru - ISBN 9789054852995 - 145
    diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - chemische structuur - chemische reacties - sulfonaten (esters) - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - chemical structure - chemical reactions - sulfonates (esters)

    In this thesis the base-induced reactions of perhydronaphthalene-1,4-diol monosulfonate esters are described. These compounds undergo smoothly, typical carbocationic processes upon treatment with sodium tert -amylate in refluxing benzene. The product outcome, product ratio, and (relative) rate of these reactions is satisfactorily explained when through-bond orbital interactions (TBI) over four abonds are invoked. In order to gather more detailed information about the basic stereochemical and stereoelectronic principles underlying these processes, synthetical organic, computational, and kinetic investigations were undertaken.

    Most experimental studies on TBI have focussed on its spectroscopic manifestations and are reviewed repeatedly. On the other hand, there are relatively few reviews on the chemical consequences of TBI over three or more σ-bonds. A number of illustrative examples of chemical reactions in which long-range orbital interactions are believed to play an essential role are discussed in chapter 1. In the same chapter also attention is drawn to the synthetic utility of some of these reactions.

    In chapter 2 the syntheses of the mesylates 39 , 40 , and 58-67 are described. The compounds 39 , 40 , 58 , and 59 are prepared in order to investigate how the orientation of the sulfonate ester group in combination with the orientation of the tertiary hydroxyl group determines the outcome and rate of their reactions with sodium tert -amylate. The results of these investigations are described in chapter 3. It was found that an equatorial sulfonate ester group favors homofragmentation leading to the cyclopropane derivative 105 . In case of an axial sulfonate ester group β-elimination, which strongly depends on the stereochemistry of the tertiary deprotonated hydroxyl group, is the main reaction path. In the chapter 3 the synthesis of the O-silylated mesylates 106 and 107 is also described. These compounds show no reaction at all upon treatment with strong base. On the other hand, fast reactions are observed when 106 and 107 are treated with TBAF. Generation of an alcoholate is crucial for the observed reactions. Homofragmentation and an internal return reaction with inversion of configuration of the mesylate group in the axial mesylates 39 and 58 is explained by assuming a 1,3-bridged intermediate carbocation.

    The mesylates 60-65 are prepared (Chapter 2) to determine the influence of the geometry of the relaying σ-bonds on the reactions with sodium tert -amylate. In chapter 4 the results of these studies are described in detail. An alcoholate function intramolecularly induces heterolysis of the sulfonate ester group in an apolar solvent via orbital interactions through three intervening C-C single bonds. It is shown that the reactivity of the compounds 60-65 is only affected by the relative position of the hydroxyl function to the sulfonate ester group and not by the orientation of the hydroxyl group. The two chief pathways by which these compounds react are rearrangement ( 60 , 62 , and 63 ) and homofragmentation ( 64 and 65 ). Stereoelectronic effects play a dominant role here, except in compound 61 where steric factors primarily determine the reactivity and product outcome (ether formation). Homofragmentation is much faster than rearrangement and is only possible when a 1,3-bridged through-space interaction accompanies TBI. The extent of TBI as well as the product composition is strongly determined by the σ-relay of the four σ-bonds between the electron donor (alcoholate) and the electron acceptor (sulfonate ester bond). These results are consistent with the " trans rule", which is in line with predictions from theoretical models regarding TBI.

    The product outcome, product ratio, and relative rate of the base-induced reactions of perhydronaphthalene-1,4-diol monosulfonate esters described in chapter 4 are satisfactorily explained with the concept of TBI. However, the conclusions are all based on empirical results. In chapter 5 the results of semi-empirical calculations, using the MNDO method, performed on model systems are presented. In this way a more detailed understanding of the stereoelectronic features underlying the homofragmentation and rearrangement reaction is obtained. The trends in the results of the MNDO simulations are the same as those found in the reactions of the compounds 60-65 . Whether rearrangement or homofragmentation takes place depends on the geometry of the σ-relay and the inductivity of the system. Cyclopropanoid bridged structures seem to be involved in the rearrangement process as well as in the homofragmentation process.

    In order to explore the effects of the order of substitution of the carbon atom that borders the carbon atom to which the mesylate group is attached the compounds 40 , 66 , and 67 were synthesized. This subject is discussed in chapter 6. The product formation is strongly dependent on the steric consequences of alkyl substituents at βcarbon atoms. Homofragmentation is highly favored when the repulsive steric interactions do not prevent a homohyperconjugatively stabilized transition state. This is only possible in an ideal "W" arrangement of theσ-relay ( 40 ). Due to the repulsive 1,3- peri -effect in 66 , and a combination of the 1,3- peri -effect and the 1,3- diaxial -effect in 67 the σ-relay diverges from the ideal "all trans " geometry as a result of which other reaction pathways (elimination, 1,3-H, and 1,2-Me shifts) are favored over homofragmentation. Introduction of inductively electron-donating substituents leads to an increase in reaction rate, despite the (slight) deviation of the "W" arrangement. It is concluded that although bridged ions are important intermediates in the observed reaction paths, they are not decisive for the reactivity of these compounds.

    The O-silylated mesylates 106 and 107 react fast upon treatment with TBAF in refluxing benzene (Chapter 3). At room temperature only desilylation takes place. To investigate the influence of a remote nucleofugal mesylate group on the rate of desilylation, apart from 106 and 107 , also the O-silylated compounds 127-131 are synthesized and treated with TBAF as is described in chapter 7. The rates of desilylation are determined conveniently by HPLC monitoring of the disappearance of the starting material. The desilylation rate of compounds with a mesylate group is much higher than the desilylation rate of corresponding compounds with a hydroxyl group instead ( 130 and 131 ). Furthermore, compounds having a "W" arrangement ( 107 and 129 ) of the relaying σ-bonds react considerably faster than their "sickle relay" analogs ( 106 , 127 , and 128 ). The results presented in this chapter show nicely that longrange electronic effects of distant substituents can exert a substantial influence on the reactivity of certain functional groups in general.

    In conclusion, the concept of TBI offers a good explanation for the reactivity of the compounds studied throughout this thesis. The stereochemical and stereoelectronic requirements for the base-induced reactions of perhydronaphthalene-1,4-diol monosulfonate esters are now well established. The general utilitly of the concept of σ-delocalization and TBI in everyday chemistry is demonstrated

    S-(+)-Carvone as starting material in the enantioselective synthesis of natural products
    Verstegen - Haaksma, A.A. - \ 1994
    Agricultural University. Promotor(en): Æ. de Groot, co-promotor(en): B.J.M. Jansen. - S.l. : S.n. - ISBN 9789054853206 - 113
    diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - biochemie - metabolisme - polymeren - carum carvi - karwij - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - biochemistry - metabolism - polymers - carum carvi - caraway

    In this thesis the applicability of S-(+)-carvone as chiral starting material in the synthesis of biologically active compounds is examined. S-(+)-carvone is the major compound of caraway essential oil. The essential oil content of caraway seed may vary from 2-7% and it contains about 50-60% of S-(+)-carvone

    S-(+)-carvone exhibits a number of interesting biological activities, eg., antifungal, insecticidal and plant growth regulatory activities. Especially the inhibiting effect of S-(+)-carvone on the sprouting of potatoes attracted a lot of attention, and this was important for the start of a national caraway research program in the Netherlands. Within the framework of this "National Caraway Research Program" the potential of caraway for the production of non-food products was investigated. The outlines of this research are sketched in chapter 1. An overview of the application of S-(+)-carvone and R-(-)-carvone as chiral starting material in the synthesis of natural products is also given in chapter 1.

    The Lewis acid catalyzed Diels-Alder reaction of S-(+)-carvone with some silyloxy dienes is described in chapter 2. The anti -addition products 94 , with the angular methyl group and the isopropenyl group in a cis -position, are formed in high yields. The synthetic utility of these Diels-Alder adducts was demonstrated by the total synthesis of (+)-α-cyperone (95) from diketone 94b . (+)-α-Cyperone ( 95 ), that can be isolated from the tubers of Cuperus rotundus L., exhibits an interesting in vitro activity against Plasmodium flaciparum K1, a multidrug resistant malaria parasite (scheme 8.1).

    In chapter 3, the Robinson annulation products 33 and 96 were transformed into interesting chiral intermediates for organic synthesis and also into some biologically active compounds. The decalones 111 and 112 , were formed from 33 . Decalone 111 is a famous molecule in perfumery and 112 is an important intermediate in the synthesis of several drimanes and drimane-related natural products. Compound 33 was also converted into decalol 113 , a potent inhibitor of the cholesterol biosynthesis.

    (+)-Geosmin ( 97 ), an interesting olfactive compound was synthesized from decalone 96 (scheme 8.2).

    In chapter 4, the syntheses of the more functionalized decalones 98 , 99 , 131 and 132 from S-(+)-carvone via two different conjugate addition annulation methodologies are presented (scheme 8.3). The conjugate addition of potassium cyanide to S-(+)-carvone gave cyano ketone 135 in high yield. The base catalyzed Robinson annulation of 135 with methyl vinyl ketone followed by dehydration gave decalone 98 stereoselectively and also in high yield.

    The copper catalyzed conjugate addition of Grignard reagents gave alkyl substituted dihydrocarvones, which were annulated via their silyl enol ethers 127 . A Lewis acid catalyzed Michael addition of the silyl enol ether 129 to methyl vinyl ketone gave the intermediate diketones 130 in good yield. The diketones were cyclized to the substituted decalones 99 , 131 and 132 under basic conditions.

    Decalone 98 was used for a new chiral approach to 3-oxygenated drimanes as is described in chapter 5. Hydroxyketone 153 was formed via an ozonolysis/Criegee rearrangement procedure of the isopropenyl substituent (scheme 8.4). Hydroxyketone 153 was by total synthesis further transformed into (-)-3-β-acetoxydrimenin ( 100 ), that can be isolated from the leaves of Drimys winteri,.

    In chapter 6 the total synthesis of (-)-Ambrox ®( 101 ), a commercially interesting olfactive compound, from both the allyl substituted decalone 99 and the nitrile substituted decalone 98 is presented (scheme 8.5). In both synthetic sequences, alcohol 159 was formed as the key intermediate. (-)-Ambrox ®( 101 ), was synthesized by simple cyclization of alcohol 159 at room temperature under acidic conditions.

    Total synthesis of insect antifeedant drimane sesquiterpenes
    Jansen, B.J.M. - \ 1993
    Agricultural University. Promotor(en): Æ. de Groot. - S.l. : Jansen - ISBN 9789054850977 - 195
    diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - synthese - organische verbindingen - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - synthesis - organic compounds

    The investigations described in this thesis deal with the total synthesis of sesquiterpenes of the drimane family, named for their widespread occurrence in the stem bark of South American Drimys species. These compounds contain the bicyclofarnesol nucleus 1 , which is invariably oxidized at C-11 and/or C-12 and often at other sites as well (see figure 8.1).

    A few rearranged drimanes, e.g., (+)-colorata-4(13),8-dienolide 6 , and (-)-muzigadial 7 , are also isolated from natural products. The rearranged bicyclofarnesol nucleus 5 presumably owes its biogenesis to a cation-induced migration of a methyl group from C-4 to C-3 followed by loss of a proton from C-13 to give the exocyclic methylene group (see figure 8.2).

    Interest in this class of compounds has been stimulated by the discovery of drimanes exemplified by (-)-warburganal 2 , (-)-polygodial 3 , and (-)-ugandensidial 4 , which exhibit remarkable physiological activities, e.g., antifungal, molluscicidal, cytotoxic, and plant growth regulation. Especially the insect antifeedant activity has attracted much attention, for the application of naturally occurring antifeedants is of potential value for crop protection due to their specificity of action and their usually low mammalian toxicity. A survey of these drimanic sesquiterpenes and their physiological properties is presented in chapter 1.

    The common structural feature in these drimanes is the presence of a Δ 7,8ene-11,12β-dialdehyde functionality which, in the more potent substances, is further completed with a 9α-hydroxyl substituent. This array of functional groups clearly provides a challenging target to synthetic organic chemists, as does the rearranged drimane muzigadial 7 with its additional exocyclic methylene group at C-4 and the chiral center at C-3. Chapter 2 is devoted to a literature survey of synthetic studies towards the total synthesis of drimanes and rearranged drimanes.

    From a retrosynthetic analysis of these compounds an approach, starting from the trans- decalones 10 and 11 seemed to offer good perspectives, as outlined in scheme 8.1. Both 10 and 11 were synthesized in multigram quantities by approaches developed at our laboratory, as described in chapter 4.

    In both decalones the carbonyl function is properly located for the introduction of the necessary functionalized. carbon atoms at C-8 via Claisen condensation with ethyl formate and at C-9 via addition of suitably functionalized nucleophiles.

    Ketones 8a and 9a were obtained in a straightforward manner. Addition of [ (phenylthio)methyl ] lithium to 8a followed by hydrolysis and oxidation afforded sulfoxide 12 , which in turn gave regiospecifically (phenylthio)furan 13 upon heating in acetic anhydride. Hydrolysis then completed a new approach for the regiospecific annulation of butenolides from ketones of type 10 (see scheme 8.2).

    This sequence was also applied to 9a thus giving rise to the first stereoselective total synthesis of the rearranged drimanic lactone (±)-colorata-4(13),8-dienolide 6 .

    Thermolysis of sulfoxide 12 in refluxing toluene gave the unsaturated aldehyde 15 . Since the latter has been converted into (±)-warburganal 2 , this approach allows a synthetic entry to this antifeedant (see scheme 8.3).

    In chapter 5 the promising nueleophile [methoxy(phenylthio)methyl ] lithium was used to introduce a masked aldehyde group at C-9. The addition of this nucleophile to aldehydes, ketones, α,β-unsaturated ketones, α-oxo acetals, and (aryl- or alkylthio)methylene ketones was straightforward and the adducts were obtained in high yields. These adducts could be rearranged into α-sulfenylated aldehydes upon treatment with thionyl chloride and sometimes also with acid. This new rearrangement was developed as a new synthetic method and applied in the synthesis of several drimane sesquiterpenes (see scheme 8.4).

    The adducts 16 were subjected to hydrolysis and the lactones 14 and/or 17 were obtained dependent on the conditions used. Mixtures of lactones were separated with difficulty and the best way to proceed turned out to be their reduction into the diol 18 , a well-known intermediate in the synthesis of drimanes such as confertifolin 17 and (-)-warburganal 2 .

    trans -Decalone 10 was formylated and the aldehyde function was protected as its (phenylthio)methylene derivative 8a or as its dioxolan 8b . The adducts 19 , obtained by addition of [methoxy(phenylthio)methyl]lithium to 8a , rearranged into rather unstable aldehydes and therefore a reduction was performed immediately. A spontaneous cyclization then afforded (±)-euryfuran 20 .

    When the adducts 19 were subjected to a mercuric chloride assisted hydrolysis an unexpected ring expansion reaction was observed.

    Several drimanes could be synthesized starting from 10 and 11, but a straight-forward total synthesis of the more biologically active drimanes (-)-warburganal 2 , polygodial 3 , and (-)- muzigadial 7 proved to be troublesome. Therefore a new concept was taken into consideration starting from the trans -decalones 21 and 22 , as is dealt with in chapter 6. Both were synthesized in multigram quantities via adaptation of known procedures.

    Formylation of 21 and subsequent dehydrogenation afforded the unsaturated keto aldehyde 23 . Addition of HCN then introduced the functionalized C-11 carbon atom and the remaining β-keto aldehyde was reduced to an unsaturated aldehyde to afford 24 . Protection of the aldehyde group and reduction of the nitrile function then gave the mono protected dialdehyde 25 . It turned out that the α-positioned aldehyde group in 25 had to be epimerized before introducing the 9α-hydroxyl group via oxidation of the enolate of 25 . This epimerization is a crucial step in this approach and it had to be performed with an excess of potassium tert -butoxide in refluxing tert -butyl alcohol for just 10 minutes. Subsequent oxidation of the enolate of 26 then afforded (±)-warburganal 2 in a wholly acceptable 3 8 % overall yield (see scheme 8. 5).

    Since all the reaction conditions and reagents used for the conversion of 21 into (±)-warburganal 2 were compatible with the presence of an exocyclic double bond in the molecule, the transformation of trans -decalone 22 into (±)-muzigadial 7 was expected to be straightforward and indeed no serious problems were encountered and (±)-muzigadial 7 was obtained in 24% overall yield (see scheme 8.6).

    In principle, the natural enantiomers of polygodial 3 , warburganal 2 , and muzigadial 7 are to be preferred over their racemic forms, so a synthesis of the intermediate ketones 21 and 22 in the optically active form was investigated as described in chapter 7.

    The synthesis of the chiral trans -decalones 21 and 22 was undertaken, using (S)-(+)-and (R)-(- )-carvone as a chiral starting compound, respectively. The isopropenyl group of carvone first served as a chiral handle and was converted afterwards into the desired carbonyl group at C- 7. (-)-Dihydrocarvone, obtained from (+)-carvone by lithium bronze reduction, was converted into (-)- trans -decalone 21 starting with a conventional Robinson annulation. The ketol 28 could be isolated in pure form via crystallization from hexane, leaving the enone 29 in solution.

    This ketol was transformed into 30 , which upon Wolff-Kishner reduction also gave an isomerization of the double bond in the isopropenyl group as an accompanying reaction. Subsequent selective ozonolysis and reduction with lithium in liquid ammonia then gave the chiral (-)- trans -decalone 21 (see scheme 8.7).

    (+)- trans -Decalone 22 , the starting material for the synthesis of (-)-muzigadial 7 , had to be synthesized starting with (+)-dihydrocarvone in order to obtain the desired R configuration at C-10 (see scheme 8.8).

    The isopropenyl group of enone 33 was removed by ozonolysis followed by decomposition of the ozonide by cupric acetate and ferrous sulfate to give dienone 34 . Conjugate addition of dimethylcopper lithium then afforded the deconjugated enone 35 , with the methyl groups in a trans position. This enone was further elaborated into (+)- trans -decalone 22 via known procedures, developed at our laboratory.

    In summary, starting from easily available ketones efficient syntheses of several drimanic sesquiterpenes were performed. Especially the biologically active compounds (±)-polygodial 3 , (±)-warburganal 2 , and (±)-muzigadial 7 were synthesized straightforward in good yields.

    (+)-Aromadendrene as chiral starting material for the synthesis of sesquiterpenes
    Gijsen, H.J.M. - \ 1993
    Agricultural University. Promotor(en): Æ. de Groot; J.B.P.A. Wijnberg. - S.l. : S.n. - ISBN 9789054852018 - 135
    terpenen - diterpenoïden - sesquiterpenoïden - etherische oliën - sesquiterpenen - synthese - organische verbindingen - stereochemie - terpenoids - diterpenoids - sesquiterpenoids - essential oils - sesquiterpenes - synthesis - organic compounds - stereochemistry

    One of the distillation tails of the oil of Eucalyptus globulus, which is commercially available, contains about 55-70% of (+)-aromadendrene ( 2 ), together with 10-15% of alloaromadendrene ( 3 ). In this thesis has been described how (+)-aromadendrene from Eucalyptus oil can be used as a chiral starting material for the synthesis of sesquiterpenes.

    Two methods have been described to purify the crude distillation tail in order to obtain pure derivatives of 2 (and 3 ). In the first method, described in chapter 3, the crude distillation tail was ozonolyzed to give the crystallizable (+)-apoaromadendrone ( 222 ) (Scheme 9.1). In the second method, described in chapter 7, treatment of the crude distillation tail with potassium on aluminum oxide (K/Al 2 O 3 ) gave a quantitative conversion of 2 and 3 into isoledene ( 224 ). Oxidative cleavage of the central double bond in 224 produced bicyclogermacrane-1,8-dione ( 304 ).

    Both derivatives 222 and 304 were used as starting materials for the synthesis of compounds with carbon skeletons from several classes of sesquiterpenes. Selective, acid-catalyzed cleavage of the C3-C4 bond of the cyclopropane ring in 222 (and 223 ) gave (-)-isoapoaromadendrone ( 253 ) in high yield (chapter 3, scheme 9.2). Ozonolysis of 253 afforded the keto alcohol 262 which is a suitable chiral intermediate for the syntheses of guaianes. This was demonstrated in the synthesis of (-)-kessane ( 264 ), which proceeded in a 9 steps reaction sequence in an overall yield of 43% from 262 (chapter 4).

    The synthesis of the mono- and dihydroxy aromadendranes 4-7 , 31 , 40 , 41 , 227 , 276 , and 277 from 222 has been described in chapter 5. The cis -fused alloaromadendrone ( 223 ), the key intermediate for the synthesis of (-)-ledol ( 6 ) and (+)-viridiflorol ( 7 ), was obtained from the trans -fused apoaromadendrone ( 222 ) via a selective protonation of the thermodynamic enol trimethylsilylether 278 (Scheme 9.3). Hydroxylation of the tertiary C11 of 222 with RuO 4 gave 226 , which could be transformed into (+)-spathulenol ( 31 ), (-)-allospathulenol ( 276 ), and the aromadendrane-diols 40 , 41 , 227 , and 277. Compounds 4-7 , 31 , 40 , 41 , 227 , 276 , and 277 were tested for antifungal properties, but their activity was only moderate.

    A stereoselective epoxidation of the thermodynamic enol trimethylsilylether 278 gave the hydroazulene α-ketol 289 (chapter 6, scheme 9.4). Starting from this α-ketol, two different routes to hydronaphthalene compounds with a maaliane skeleton were developed, both in high overall yield. The first route via α-ketol 290 led to cis -fused maaliane ketone 293 ; the second one offered access to the trans -fused maaliane compound 299 . From 299 the naturally occurring (+)-maaliol ( 288 ) was synthesized.

    Synthon 304 , obtained via the second purification method of the crude distillation tail (vide supra ), was used as starting material of compounds with a humulane or cadinane skeleton (chapter 7). The α-keto-cyclopropane compound 304 was found to be thermolabile. Thermal rearrangement of 304 gave via a homo [1,5] hydrogen shift at relatively low temperature (refluxing dioxane) the humulane compound 311 and at higher temperatures (Flash Vacuum Pyrolysis, 500°C and up) the products 313 and 314 , both with a cadinane skeleton (Scheme 9.5). Epimerization of 311 gave the naturally occurring humulenedione ( 306 ). Starting from 313 , the naturally occurring (-)-cubenol ( 310 ) was synthesized in a 4 steps reaction sequence.

    The results described in this thesis are shortly summarized in scheme 9.6. With (+)-aromadendrene ( 2 ) from Eucalyptus oil as starting material, compounds have been synthesized with sesquiterpene skeletons belonging to the classes of the guaianes, the aromadendranes, the maalianes, the bicyclogermacranes, the humulanes, and the cadinanes. (-)-Kessane ( 264 ) (chapter 4), several mono- and dihydroxy aromadendranes (chapter 5 and 6), (+)-maaliol ( 288 ) (chapter 6), humulenedione ( 306 ) (chapter 7), and (-)-cubenol ( 310 ) (chapter 7) are naturally occurring sesquiterpenes which have been synthesized from 2 . On the basis of these results it can be concluded that (+)-aromadendrene from Eucalyptus oil is a versatile chiral starting material for the synthesis of sesquiterpenes.

    Onderzoeksprogramma ter verbetering van karwij als akkerbouwgewas en ter introductie van nieuwe afzetmogelijkheden : [verslag 1991]
    Meijer, W. - \ 1992
    Wageningen : CABO-DLO
    carum carvi - karwij - diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - vluchtige verbindingen - carum carvi - caraway - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - volatile compounds
    Sesquiterpene lactones and inulin from chicory roots : extraction, identification, enzymatic release and sensory analysis
    Leclercq, E. - \ 1992
    Agricultural University. Promotor(en): W. Pilnik; Æ. de Groot. - S.l. : Leclercq - 137
    cichorium intybus - cichorei - diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - chemie - zetmeel - dextrinen - glycogeen - inuline - versuikering - cichorium intybus - chicory - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - chemistry - starch - dextrins - glycogen - inulin - saccharification

    Chicory ( Cichorium intybus L.) is one of the many species of the family Compositae. Chicory has been cultivated for the production of leaves or chicons, which have been used as a vegetable since approximately 300 BC, and for its roots, which can be used as a coffee substitute after roasting.

    Chicory leaves are appreciated for their slightly bitter taste. Two bitter compounds were known at the start of this project: lactucin (Lc) and lactucopicrin (Lp), both sesquiterpene lactones with a guaiane skeleton. These compounds are also present in the roots, which remain as a waste product after harvesting of the chicons. Chicory roots contain besides bitter substances also inulin, a linear β-(2-1) linked fructose polymer terminated by a sucrose unit residue and the main carbohydrate of the chicory plant.

    In Chapter 2 all known constituents of chicory roots are discussed as well as the effect of roasting on these compounds. A survey is given of work carried out on the isolation and identification of bitter principles in Compositae, especially chicory. The aim of this project was to isolate the bitter constitutents and inulin in one step from waste chicory roots. A one step process is only possible when enzymatic liquefaction is applied. Both bitter compounds and inulin will then pass into the liquid phase. The obtained bitter, sweet liquid can be used as a raw material for soft drinks. Quinine eventually could be replaced by the bitter principles from chicory roots.

    An isocratic HPLC method was developed for the analysis of the sesquiterpene lactones. Three components were identified in the chicory root extract: Lc, Lp and 8-deoxylactucin (8dLc). Various extraction solvents were tried for the isolation of the sesquiterpene lactones from chicory roots. Polar solvents gave many unknown polar compounds, which eluted at the beginning of the HPLC chromatogram. More apolar solvents gave the sesquiterpene lactones and hardly any of the polar components.

    Storage of the roots and further processing, such as drying and milling, affects the amount of sesquiterpene lactones in the roots and thus the composition of the chicory extract (Chapter 4).

    The release of bitter compounds and inulin has been studied during enzymatic liquefaction of chicory roots with commercial pectinases and cellulases (Chapter 5 and 7). An increase was seen in the amount of Lc and 8dLc found in the liquid phase during enzymatic liquefaction. After improvement of the HPLC method (gradient elution instead of isocratic method) it was found that the increase of Lc and 8dLc was due to the increase of their dihydro derivatives, which eluted at the same place as Lc respectively 8dLc with the isocratic method.

    Endogenous chicory root enzymes have also been studied in this context, because they have proven to be capable to release bitter components as well (Chapter 6). However, the optimum pH and temperature for the performance of endogenous chicory root enzymes are different from those of the commercial enzyme preparations tested, and may therefore not play a role in the release of sesquiterpene lactones during enzymatic liquefaction.

    Cichorioside B (glycoside of ll(S),13-dihydro-lactucin), crepidiaside B (glycoside of ll(S),13-dihydro-8-deoxylactucin), cichorioside C (glycoside of a germacranolide), and ll(S),13-dihydrolactucopicrin were identified in chicory roots. Compound N could not be identified, but there are indications that this compound is a diglycoside of dHLc. The presence of the glycoside of Lc is plausible, but to date this compound was not extracted from the chicory roots.

    The threshold value of six pure sesquiterpene lactones (Lc, Lp, 8dLc, dHLc, dHLp, dH8dLc) was determined (Chapter 8) and related to the theories on bitterness as discussed in Chapter 3.

    The effect of processing and storage on the bitter taste of bitter orange lemonade was investigated. A comparison was made between quinine as bitter substance and chicory root extract as the bitter ingredient.

    The storage in daylight of the bitter orange containing quinine caused a tremendous decrease of the bitterness of the beverage. No decrease in bitterness was seen in the beverage with chicory root extract. Pasteurization did not affect the bitter taste of bitter orange with chicory root extract.

    The bitterness of the various chicory root extracts made for sensory analysis differed in bitter intensity in spite of standardisation of the Lc content.

    Bitter intensities of chicory root extract before and after incubation with pectolytic and cellulolytic enzymes were determined. Thus the bitterness of the precursors was compared with that of the aglycons. However, no judgement could be given on whether the enzyme treatment of the chicory root extractcould be given on whether the enzyme treatment of the chicory root extract gave rise to a more bitter taste. About half of the panellists judged the extract with the glycosides more bitter than the extract with the aglycons, the other half could not taste any difference between these samples.

    Total synthesis of cis-Hydroazulene sesquiterpenes : base-induced and -directed elimination and rearrangement reactions of perhydronaphthalene-1,4-diol monosulfonate esters
    Jenniskens, L.H.D. - \ 1992
    Agricultural University. Promotor(en): Æ. de Groot; J.B.P.A. Wijnberg. - S.l. : S.n. - 119
    diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - synthese - organische verbindingen - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - synthesis - organic compounds

    The total synthesis of a number of cis-fused hydroazulene sesquiterpenes is described in this thesis. In this synthetic study, ample attention is paid to the mechanistic aspects of the base- induced and -directed rearrangement and elimination reactions of perhydronaphthalene-1,4-diol monosulfonate esters. These reactions form the key steps in the synthetic routes that were followed.

    A general introduction into the chemistry of terpenes, with emphasis laid on the sesquiterpenes with a hydroazulene skeleton, is given in Chapter 1.

    In Chapter 2, an overview of the literature on the synthesis of these hydroazulene sesquiterpenes is presented. The different synthetic strategies towards the hydroazulene skeleton and their use in natural product synthesis are mentioned in first part of this chapter. The rearrangement reaction of the hydronaphthalene skeleton to the hydroazulene framework is described in more detail. The photochemical, the pinacol, and the solvolytic Wagner-Meerwein rearrangement are discussed successively. Upon solvolytic Wagner-Meerwein rearrangement of the hydronaphthalene framework towards the hydroazulene framework, a mixture of double bond isomers is formed in a ratio reflecting the relative stability of the products. This is a serious drawback of this method for the selective synthesis of hydroazulene sesquiterpenes with an exocyclic C(10)-C(15) double bond.

    In Chapter 3 the utility of trans-fused hydronaphthalene precursors for the synthesis of cis-fused hydroazulene sesquiterpenes with an exocyclic C(10)-C(15) double bond is examined. For this purpose the tosylates 131 and 132 were prepared, and their behaviour under basic conditions was studied. Upon treatment with sodium tert-amylate, the tosylate 131 , which has a tertiary axial hydroxyl group at CM, rearranged with high selectivity (90%) to the desired cis-fused exo 10-olefinic hydroazulene 143 . When the tosylate 132 with a secondary axial hydroxyl group at C(4), was treated this way, a lower selectivity (57%) in the formation of the corresponding hydroazulene 148 was observed. A mechanism for the rearrangement reaction is proposed. According to this mechanism the reaction starts with the deprotonation of the axial hydroxyl group at C(4). The generated alkoxide then induces the heterolysis of the tosylate ester bond, thereby leading to the formation of a secondary carbocation (ion pair). The system then rearranges to a more stable tertiary carbocation by a 1,2-shift of the central bond, thereby forming the hydroazulene skeleton. The subsequent intramolecular proton abstraction from the former angular methyl group by the axial alkoxide at CM directs the elimination reaction to the selective formation of the isomer with the exocyclic C(10)-C(15) double bond.

    As an application of this base-induced and -directed rearrangement the total synthesis of the guaiane sesquiterpene ( + )-5- epi -nardol 26 is described in Chapter 4. In Chapter 5 the selective introduction of a double bond at the C(6)-C(7) position in the hydronaphthalene system is described.

    Compound 27 was formed selectively by treatment of both the axial mesylate 173 and the equatorial mesylate 180 with sodium tert -amylate in refluxing toluene. The mechanism proposed for this base-induced and -directed elimination bears strong resemblance with the one proposed for the rearrangement. The hydroxyl group at C(4). is deprotonated by the base and the thereby formed alkoxide induces the heterolysis of the mesylate ester bond. By abstraction of the C(6) proton, the alkoxide C(4). then directs the reaction to the selective formation of 27 . Apart from proton abstraction also homofragmentation was found to take place in the equatorial mesylate 180 , thereby reducing the yield of 27 . By increasing the sodium tert-amylate concentration this homofragmentation could be suppressed.

    In Chapter 6 the total synthesis of the (±)-alloaromadendrane-4,10-diols 28 and 29 is described. The C(6)-C(7) double bond of 27 was used for the annulation of the cyclo propane ring. Selective epoxidation of the C(10)-C(15) double bond in the rearranged product 186 , followed by reduction gave 28 . Inversion of the stereochemistry at C(4). by dehydration of 186 . selective epoxidation and reduction resulted in the natural product 29 . In Chapter 7, studies towards a 6α,7β-lactone ring and (±)-alismol. and the synthesis of ( + )-oplodiol are described.

    Total synthesis of all stereoisomers of eudesm-II-en-4-ol
    Kesselmans, R.P.W. - \ 1992
    Agricultural University. Promotor(en): Æ. de Groot; J.B.P.A. Wijnberg. - S.l. : Kesselmans - 111
    terpenen - synthese - terpenoids - synthesis

    In this thesis the total synthesis of all stereoisomers of eudesm-11-en-4-ol e.g. selin-11-en-4α-ol I , intermedeol II , neointermedeol III , paradisiol IV , amiteol V , 7- epi -amiteol VI , 5- epi -neointermedeol VII , and 5- epi -paradisiol VIII is described.

    The natural occurrences and the difficulties encountered in the structural elucidation of these eudesmanes are described in chapter 1. The eudesm-11-en-4-ols occur in a wide range of plant species, some of which are used in medicine, or as insect repellent. However, the most spectacular occurrence of eudesm-11-en-4-ols is established in the secretion of termite soldiers. These secretions are used as chemical weapons to defend the termite colony.

    In chapter 2 the strategies used in eudesmane syntheses are reported. The first part of this chapter deals with general approaches to the eudesmane skeleton. This part is organized in sections, each dealing with a number of methods under a common heading i.e. annulation, cycloaddition, intramolecular cyclization reactions, and transformations of natural sesquiterpenes. The second part of the chapter describes the reported total syntheses of intermedeol I , neointermedeol III , paradisiol IV , and 5- epi -paradisiol VIII . These syntheses proceed in low overall yields because of the occurrance of complex product mixtures.

    The lack of spectroscopic and chromatographic data 6 for identification, the interesting biological properties, and the availability of a good synthetic plan has been the reason for this investigation (Chapter 3). Starting from enone 101 , a large scale synthesis of the diones 95 and 96 has been developed as is described in chapter 4. The trans -fused dione 95 was transformed into the cisfused dione 96 by treatment with trimethyl orthoformate and a catalytical amount of acid in CH 3 OH. This transformation allows full stereocontrol on the C-5 bridgehead position.

    An efficient method for the synthesis of the octahydro-8-hydroxy-4a,8-dimethyl-2(1 H )-naphthalenones 97-100 , which are suitable intermediates in the total synthesis of trans - and cis -fused 4-hydroxyeudesmane sesquiterpenes is reported in chapter 5. Starting from the trans -fused dione 95 the corresponding hydroxy ketones 97 and 98 could be easily prepared. The cis -fused hydroxy ketones 99 and 100 were synthesized starting from the dione 96 . Protection of the C-7 carbonyl function of 96 as its dimethyl a cetal followed by treatment with CH 3 Li gave the hydroxy ketone 100 . On the other hand, protection of the C-7 carbonyl function of 96 as its ethylene acetal and subsequent treatment with CH 3 MgI afforded the hydroxy ketone 99 as the main product. NMR studies revealed that 100 exists predominantly in the steroid conformation and that 99 exists exclusively in the nonsteroid conformation.

    The syntheses of the natural occurring (±)-selin-11-en-4α-ol I , (±)-intermedeol II , (±)-neointermedeol III , (±)-amiteol V , and the four remaining stereoisomers (±)-paradisiol IV , (±)-7- epi -amiteol VI , (±)-5- epi -neointermedeol VII , (±)-5- epi -paradisiol VIII , which not yet have been discovered in nature, are described in chapter 6. In addition the related (±)-evuncifer ether 128 has been prepared. The syntheses in this chapter started from the hydroxy ketones 97-100 . The reaction sequence employed for the synthesis of I , III , V , and VIII involved Wittig reaction, oxidative hydroboration, oxidation, equilibration, and olefination. For the synthesis of II , IV , VI , and VII the interim equilibration step was omitted. The oxidative hydroboration was the key step in these syntheses.

    The conformational behavior of the cis-fused stereoisomers of eudesm-11-en-4-ol has been investigated using NMR and conformational energy calculations (MM2) and is reported in chapter 7. In addition, the conformational analysis of most cis -fused intermediates in the synthesis to V and VI are studied.

    Kovats indices and mass-, GC/FTIR-, 1H NMR-, and 13C NMR data were collected for all eight stereoisomers of eudesm-11-en-4-ol in chapter 8. Differences in Kovats indices, mass spectral data, and GC/FTIR of the various isomers on one side, and 1H NMR and 13C NMR on the other, are shortly discussed. In this way other investigators may be able to identify these common essential oil constituents more reliably in future, either without isolating them (by Kovats indices, GC/MS, and GC/FTIR) or after isolation (by NMR).

    Studies towards the total synthesis of insect antifeedant clerodanes
    Vader, J. - \ 1989
    Agricultural University. Promotor(en): Æ. de Groot. - S.l. : Vader - 94
    terpenen - synthese - organische verbindingen - terpenoids - synthesis - organic compounds

    An approach towards the total synthesis of insect antifeedant clerodanes is described in this thesis.
    In chapter 1 the structure, nomenclature, occurrence, biosynthesis and physiological activities of the clerodanes are described. A number of structure/activity studies, concerning the insect antifeedant properties of these compounds, is summarized in a tabular form. Such studies have led to the conclusion that for evoking strong antifeedant activity both the furofuran and the decalin part of the molecule are required (de Groot/ Schoonhoven and Ley/Blaney). A literature survey of the most relevant synthetic studies towards the clerodanes is presented in chapter 2.

    A retrosynthetic study of the targetmolecule dihydroclerodin 26n is described in chapter 3. This approach offers some flexibility with respect to the decalin part and the furofuran part of the molecule. According to this synthetic plan the enone 48 has to be converted into the y-dioxolanyi-α,β-unsaturated ketone 130 . The problems connected with this transformation and the solution for these problems are described in chapter 4.

    New methods for the stereoselective synthesis of the furofuran unit had to be developed. Such methods must be applicable on the planned intermediates 127 and/or 128 and therefore had to start from an aldehyde or an oxirane function and had to be compatible with the functional groups present in other parts of these molecules, so strongly oxidizing or electrophilic reactions had to be avoided. Moreover reactions have to be carried out on a neopentylic carbon atom and therefore pivalaldehyde and tert-butyloxirane were chosen as the principal model compounds. In chapter 5 stereoselective perhydrofurofuran syntheses, based on the reaction of lithiated sulfones with carbonyl compounds, are described. In chapter 6 stereoselective furofuran syntheses, based on the reaction of lithiated nitriles with oxiranes, are described.

    Having appropiate methods for the introduction of a furofuran unit in hand, the aldehyde 128 was considered to be a very promising clerodane precursor. So the enone 130 was converted into the cyclic ether 129 via two stereoselective reductions. Additional prove for the correct stereochemistry of this molecule was obtained by an X- ray crystal structure determination. The subsequent cleavage of the cyclic ether structure determination. The subsequent cleavage of the cyclic ether proceeded in a remarkable chemo- and regioselective manner to give a bromide diacetate, which was further transformed into the aldehyde 128 . The latter transformation was not studied in full detail owing to the limited availability of material. Nevertheless a small amount of this aldehyde 128 was obtained. Its transformation into dihydroclerodin 26n will need further investigations.

    Een modelsynthese voor momilactonen : onderzoek naar de totaalsynthese van 9betaH-pimara-7,15-dienen
    Sicherer - Roetman, A. - \ 1984
    Landbouwhogeschool Wageningen. Promotor(en): Æ. de Groot. - Wageningen : Sicherer-Roetman - 167
    gewasbescherming - planten - dieren - secreties - fytoalexinen - lipiden - biosynthese - diterpenoïden - sesquiterpenoïden - terpenen - etherische oliën - sesquiterpenen - modellen - onderzoek - plant protection - plants - animals - secretions - phytoalexins - lipids - biosynthesis - diterpenoids - sesquiterpenoids - terpenoids - essential oils - sesquiterpenes - models - research

    This thesis describes investigations into the total synthesis of momilactones, germination inhibitors and phytoalexins isolated from rice. These compounds possess a Δ 7,8 -pimaradiene type skeleton with an unusual trans-syn ring-arrangement (figure 1).

    In chapter 1 a survey is given of the momilactones and the other hitherto known trans-syn pimaranelactones, with emphasis on their structures, biosynthesis and physiological activities.

    Chapter 2 is devoted to a literature survey of synthetic studies towards trans-syn(-cis) perhydrophenanthrene systems. The chemical reactivity of trans-syn pimaranelactones is also discussed.

    In chapter 3 the results are presented of a synthetic investigation, based on the Diels-Alder reaction depicted in scheme 1.

    This approach provided a total synthesis of Δ 8,9 -pimaradiene and Δ 8,9 -sandaracopimaradiene. However, attempts to isomerize the double bond to the desired Δ 7,8 -position met with little success. We therefore turned our attention towards starting compounds bearing an oxo group on C-7, in order to utilize this group for the introduction of the Δ 7,8 -double bond at a later stage.

    Using the work of W.L.Meyer and coworkers as a starting point, we stereospecifically synthesized a trans-syn-cis perhydrophenanthrene system as outlined in scheme 2. This part of the investigations is described in chapter 4. Several ways for the stereospecific introduction of a second substituent on C-13 were investigated. our synthesis of compound 159 could probably have been elaborated further, but we chose to focus our attention on a more promising approach which is described in chapter 5.

    Our stereospecific synthesis of trans-syn-cis perhydrophenanthrene systems, which forms the subject of chapter 5, is based on the stereospecific Diels-Alder reaction depicted in scheme 3 and culminates in the succesful synthesis of model compound 122. Initially we used 2- trimethylsilyloxybutadienes as diene components, but severe hydrolysis problems were encountered with the resulting adducts. These problems were effectively overcome by using diene 190. The adduct possesses a regiospecific silylenolether system which can be alkylated at C-13. Adduct 191 could be deformylated and stereoselectively reduced to the alcohol 197 leaving the t-butyldimethylsilylenolether intact. Two possible synthetic routes were then investigated.


    Alkylation of compound 199 with 2-ethoxy-1,3-dithiolan surprisingly only gave one thiolanyl compound (200) which proved to have the thiolanylgroup in the α-position. Reduction and hydrolysis of this compound gave the hydroxyaldehyde 205. However, during the Wittig reaction of the latter compound, equilibration occurred via (retro-)aldol reaction, resulting in considerable epimerization at C-13. Only a small amount of α-vinylproduct was found. Oxidation and Wolff-Kishner reduction finally afforded the model compound 122.

    Alkylation of compound 201 with 2-ethoxy-1,3-dithiolan yielded stereospecifically the β-thiolanyl product, as could be expected for steric reasons. This product was elaborated further as shown. Here, too, a (retro-)aldol reaction occurred during the Wittig reaction of compound 225, resulting in both hydroxy-epimers of the β-vinyl alcohol. No α-vinylproduct could be detected in this case. This concluded the stereospecific synthesis of compound 122.

    X-ray crystallography of thiolanyl-compounds 200 and 219 and 13 C-NMR spectroscopy were used to establish the stereochemistry of a number of reaction products, especially concerning the configuration at C-13. Details of these measurements can be found in chapter 6.

    Finally, in chapter 7, the results of the investigations are summarized and evaluated in relation to the total synthesis of momilactones.

    Investigations into the total synthesis of insect antifeedant clerodanes
    Luteijn, J.M. - \ 1982
    Landbouwhogeschool Wageningen. Promotor(en): Æ. de Groot. - Wageningen : Luteijn - 144
    terpenen - synthese - organische verbindingen - terpenoids - synthesis - organic compounds - cum laude
    Among the still growing group of clerodane type diterpenes, those compounds possessing insect antifeedant activity have drawn much attention.
    Surprisingly, at the beginning of our investigations, only a few attempts towards the total synthesis of clerodanes had been made. During the last few years the number of investigators studying the synthesis of these diterpenes steadily increased and in 1979 Takahashi et al. achieved the first success in this field with the total synthesis of annonene (see chapter 2.7). However, up to the time of writing no total synthesis of physiologically active clerodanes has been reported.
    The main object of the investigations described in this thesis was to develop synthetic methods for the construction of the clerodane basic skeleton. This skeleton should contain functionalities that allow the total synthesis of the highly oxygenated clerodanes. At a later stage these results could be employed in the synthetic approach to the interesting insect antifeedant clerodanes. This also offered the possibility to arrive at analogous compounds which may contribute to the knowledge of structure-activity relationships of the antifeedant activity.

    Podolactonen : een synthetische studie
    Peterse, A.J.G.M. - \ 1979
    Landbouwhogeschool Wageningen. Promotor(en): Æ. de Groot. - S.l. : S.n. - 128
    diterpenoïden - etherische oliën - sesquiterpenen - sesquiterpenoïden - terpenen - diterpenoids - essential oils - sesquiterpenes - sesquiterpenoids - terpenoids
    This thesis describes an investigation on the total synthesis of physiologically active nor-diterpene dilactones, called Podolactones.
    In Chapter I a survey is given of the known Podolactones with the emphasis on their structure, biogenesis and biological activities.
    Chapter II deals with the chemical reactivity of the isolated Podolactones and with the two reported total syntheses of the Podolactone LL-Z 1271 α. Also a strategy for the synthetic investigation described in this thesis is outlined.
    The construction of functionalized decalines, which can be further elaborated into Podolactones, is the subject of Chapter III.
    The synthesis of these bicyclic compounds is based on a Dieckmann cyclisation of a saturated-unsaturated diester, which is obtained from a 2,2-disubstituted cyclohexanedione-1,3 by addition of lithiumethoxyethyne and a subsequent Meyer Schuster rearrangement of the formed ethynylcarbinol. Careful control of the reaction conditions results in a stereoselective, high-yield formation of the necessary intermediates.
    Several approaches to tricyclic γ-lactones from bicyclic precursors are discussed in Chapter IV.
    Lactonisation of the 6-bromo-, 6-hydroxy- and 3,6-dihydroxyesters is investigated. The alkylation and reduction of the 6-hydroxyester and derivatives revealed interesting substituent effects. In the reduction of the 6-hydroxyester with lithium in liquid ammonia a strong temperature dependence was observed as well. Reduction at -78°C yields selectively an ester with a cis ringjunction, while at -33°C not only a trans ringjunction is established, but also a γ-lactone is formed. Moreover addition of methyliodide to the intermediate anion results in the formation of a C(4)-methylated γ-lactone. The residual carbonyl group
    at C(3) is protected as a benzoyl- or β-methoxyethoxymethyl-enolether.
    A model study for the construction of the BC-ring system of Podolactones can be found in Chapter V.
    After conversion of cyclohexanones into the corresponding a-butylthiomethylenecyclohexanones, addition of lithiumethylacetate and a Hg ++ -assisted hydrolysis results in γ-formylesters, which can be transformed into δ-substituted δ-lactones by reaction with organolithium reagents.
    This annellation method is applied to both mono- and bicyclic model compounds. The investigations on model compounds also resulted in the synthesis of the fully functionalized ring B of the potent antifeedants Warburganal and Muzigadial.
    Finally in Chapter VI an evaluation of the results in relation to the total synthesis of Podolactones is given.

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