Total synthesis of insect antifeedant drimane 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 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.