Search

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 moreσ-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 groupβ-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 relayingσ-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 theσ-relay of the fourσ-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 theσ-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 atβcarbon 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 theσ-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 relayingσ-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 ofσ-delocalization and TBI in everyday chemistry is demonstrated

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-(+)-carvoneS-(+)-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.&nbsp

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 aΔ 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 intoα-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 remainingβ-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 theα-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.

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 hydroazuleneα-ketol 289 (chapter 6, scheme 9.4). Starting from thisα-ketol, two different routes to hydronaphthalene compounds with a maaliane skeleton were developed, both in high overall yield. The first route viaα-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). Theα-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.

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 aΔ 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 intoα-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 remainingβ-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 theα-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.

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 hydroazuleneα-ketol 289 (chapter 6, scheme 9.4). Starting from thisα-ketol, two different routes to hydronaphthalene compounds with a maaliane skeleton were developed, both in high overall yield. The first route viaα-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). Theα-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.

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 linearβ-(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.

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 linearβ-(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.

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.

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.

In het kader van het "Onderzoeksprogramma ter verbetering van karwij als akkerbouwgewas en ter introduktie van nieuwe afzetmogelijkheden" zijn de mogelijkheden onderzocht om het carvon-, limoneen- en etherisch oliegehalte te voorspellen met NIRS. Als referentiemethode is de gaschromatografische bepaling gebruikt. In totaal zijn 53 monsters karwijzaad met een zo groot mogelijke spreiding in carvongehalte onderzocht. Met een NIRSystems-6500 zijn nabij infrarood reflectiespectra opgenomen.

In het kader van het "Onderzoeksprogramma ter verbetering van karwij als akkerbouwgewas en ter introduktie van nieuwe afzetmogelijkheden" zijn de mogelijkheden onderzocht om het carvon-, limoneen- en etherisch oliegehalte te voorspellen met NIRS. Als referentiemethode is de gaschromatografische bepaling gebruikt. In totaal zijn 53 monsters karwijzaad met een zo groot mogelijke spreiding in carvongehalte onderzocht. Met een NIRSystems-6500 zijn nabij infrarood reflectiespectra opgenomen.

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

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 groupat 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.

A general picture of toxicological approach and practical aspects of cosmetic safety is described in this thesis. Such considerations are the basis for introducing negative and positive lists of cosmetic ingredients into cosmetic legislation. The first Dutch Cosmetic Act of 1968 already has several of these lists, but no analytical methods were given to control these lists. Therefore a study has been started with the aim to make analytical market surveys of several classes of potentially risk-bearing compounds. The analytical experience gained in the study can be used for the developments of official methods for the Dutch Cosmetic Act. The results of these market surveys can moreover be used as information on the actual use of risk-bearing compounds and will therefore contribute to the establishment of sound and significant cosmetic legislation in the Netherlands.Eye make-up colours were identified by a set of characteristic reactions. Lipstick colours were identified by wellknown chromategraphic methods. Colour intermediates for the oxidative hair colouring were identified by two-dimensional thin- layer chromatography. The aromatic amines were confirmed by direct gaschromatographic analysis which permitted quantitative determination. A separation of phenolic intermediates by means of gaschromatography is also described. Suntan preparations were analysed for the presence of UV-absorbers, browning agents and local anesthesics. A simple aerosol sampling method, prior to gaschromatographic analysis was developed, thus permitting a total analysis of propellants and solvents in single-phase aerosols within an hour. Hormonal substances were detected in selected samples by chromatographic methods. These chemical findings supported the results of the biological assay for the detection of oestrogenic and androgenic activity of cosmetic products. Finally antimicrobial compounds were analysed in many kinds of cosmetic products, in which they were used for preservation or for its deodorizing, antidandruff or antiseptic actions. The diversity in chemical structure did not allow the development of universal methods, but most of the compounds could be identified and determined by chromatographic methods. Formaldehyde was determined by fluorometry. A study of the stability of formaldehyde releasing substances is presented.

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 groupat 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.

Van de uitgekozen houtige gewassen volgt ter informatie: de habitus, het geurende plantedeel, de geur-periode, de geuraanduiding en een korte beschrijving van de plant

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.

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.

Van de uitgekozen houtige gewassen volgt ter informatie: de habitus, het geurende plantedeel, de geur-periode, de geuraanduiding en een korte beschrijving van de plant

A general picture of toxicological approach and practical aspects of cosmetic safety is described in this thesis. Such considerations are the basis for introducing negative and positive lists of cosmetic ingredients into cosmetic legislation. The first Dutch Cosmetic Act of 1968 already has several of these lists, but no analytical methods were given to control these lists. Therefore a study has been started with the aim to make analytical market surveys of several classes of potentially risk-bearing compounds. The analytical experience gained in the study can be used for the developments of official methods for the Dutch Cosmetic Act. The results of these market surveys can moreover be used as information on the actual use of risk-bearing compounds and will therefore contribute to the establishment of sound and significant cosmetic legislation in the Netherlands.Eye make-up colours were identified by a set of characteristic reactions. Lipstick colours were identified by wellknown chromategraphic methods. Colour intermediates for the oxidative hair colouring were identified by two-dimensional thin- layer chromatography. The aromatic amines were confirmed by direct gaschromatographic analysis which permitted quantitative determination. A separation of phenolic intermediates by means of gaschromatography is also described. Suntan preparations were analysed for the presence of UV-absorbers, browning agents and local anesthesics. A simple aerosol sampling method, prior to gaschromatographic analysis was developed, thus permitting a total analysis of propellants and solvents in single-phase aerosols within an hour. Hormonal substances were detected in selected samples by chromatographic methods. These chemical findings supported the results of the biological assay for the detection of oestrogenic and androgenic activity of cosmetic products. Finally antimicrobial compounds were analysed in many kinds of cosmetic products, in which they were used for preservation or for its deodorizing, antidandruff or antiseptic actions. The diversity in chemical structure did not allow the development of universal methods, but most of the compounds could be identified and determined by chromatographic methods. Formaldehyde was determined by fluorometry. A study of the stability of formaldehyde releasing substances is presented.

Volatile constituents of white bread were investigated. Different methods were used for isolating and concentrating components to avoid artefacts as far as possible. Especially good was enlarged vapour analysis. Ninety-four components were identified, including hydrocarbons, alcohols, aldehydes, ketones, acids, esters as well as nitrogen, sulphur and miscellaneous compounds. The concentration of the main components in the vapour above white bread was determined by direct vapour analysis. The odour threshold values of these components in aqueous solution were determined, and the odour values calculated as the ratio of concentration to odour threshold value to estimate their contribution to the total odour. The Maillard reaction of the cysteine/cystine-ribose system was investigated in a search for components which can be expected in heat-processed food products, and to find out whether during this reaction compounds possessing bread-like odours were formed. Forty-five components were identified, including thiophenes, thiazoles, thiols, pyrazines, pyrroles, amines, furans, aldehydes, ketones and miscellaneous compounds. Possible pathways for the formation of 2-acylthiazoles and of 3-methyl, and 5-methyl substituted 2-formylthiophenes are proposed.

Volatile constituents of white bread were investigated. Different methods were used for isolating and concentrating components to avoid artefacts as far as possible. Especially good was enlarged vapour analysis. Ninety-four components were identified, including hydrocarbons, alcohols, aldehydes, ketones, acids, esters as well as nitrogen, sulphur and miscellaneous compounds. The concentration of the main components in the vapour above white bread was determined by direct vapour analysis. The odour threshold values of these components in aqueous solution were determined, and the odour values calculated as the ratio of concentration to odour threshold value to estimate their contribution to the total odour. The Maillard reaction of the cysteine/cystine-ribose system was investigated in a search for components which can be expected in heat-processed food products, and to find out whether during this reaction compounds possessing bread-like odours were formed. Forty-five components were identified, including thiophenes, thiazoles, thiols, pyrazines, pyrroles, amines, furans, aldehydes, ketones and miscellaneous compounds. Possible pathways for the formation of 2-acylthiazoles and of 3-methyl, and 5-methyl substituted 2-formylthiophenes are proposed.