Germacrane sesquiterpenes : synthesis and role in biosynthesis

In this thesis, the synthesis of a number of germacrane sesquiterpenes is described. Functionalized decalin systems are prepared, which are used in turn as substrates for Grob- type fragmentation reactions. These fragmentation reactions start either with the hydroboration of a double bond, as in the Marshall fragmentation, or with the αdeprotonation of an aldehyde, as in the enolate-assisted fragmentation. Both fragmentation reactions result in the regio- and stereospecific formation of two E double bonds as present in the ten-membered ring of germacranes.The acid-induced cyclization of the germacranes synthesized in this way mimics the biosynthesis of eudesmane and guaiane sesquiterpenes and is used to study the role of enzymes in these cyclization reactions.In chapter 1, a general introduction into the biosynthesis and physiological role of terpenes is presented. The biosynthesis of germacrane sesquiterpenes and their subsequent conversion into eudesmane and guaiane sesquiterpenes is further worked out. Attention is paid to, important aspects of isolation, purification, and structure elucidation.In chapter 2, the literature concerning the synthesis of germacrane sesquiterpenes is reviewed. The synthetic approaches are grouped together according to the applied ten- membered ring forming reactions. The research described in this thesis is mentioned shortly.In chapter 3, the synthesis of (+)-hedycaryol (6), a generally occurring germacrane alcohol, is described. The hydroazulene skeleton of the starting material (-)-guaiol (1) was therefore transformed to the decalin system 2 in 3 steps.<img src="/wda/abstracts/i2241_1.gif" height="243" width="554"/>After conversion of 2 into mesylate 5, a Marshall fragmentation was used to prepare the (E,E)- cyclodecadiene ring system present in (+)-hedycaryol. Additionally, the applicability of 2 as a starting material in the synthesis of eudesmane sesquiterpenes was illustrated by the synthesis of (+)-γ-eudesmol (3) and (+)-4-eudesmene-1β,11-diol (4).In chapter 4, the synthesis of (-)-allohedycaryol (9) is described. The synthesis started from (+)-α-cyperone (7) which was efficiently prepared via alkylation of the imine derived from (+)-dihydrocarvone and (R)-(+)-1-phenylethylamine. In a number of steps, 7 was converted into mesylate 8. A Marshall fragmentation of 8 completed the synthesis of allohedycaryol. This successful synthesis of (-)-9 allowed the elucidation of the relative and absolute stereochemistry of its antipode isolated from giant fennel <em>(Ferula communis L.).</em> It turned out that natural (+)-9 has the opposite absolute stereochemistry to that normally found in higher plants. The conformation of 9 was elucidated via photochemical conversion, into a bourbonane system. <img src="/wda/abstracts/i2241_2.gif" height="164" width="551"/>In chapter 5, the total synthesis of neohedycaryol (12), the C(9)-C(10) double bond regioisomer of hedycaryol (6), is described. The synthesis started from the known dione 10, prepared as a racemate from carvone. Again, a Marshall fragmentation was used to prepare the (E,E)-cyclodecadiene ring. During the synthesis of 11, a pronounced example of through- bond interactions (TBI) was observed.<img src="/wda/abstracts/i2241_3.gif" height="165" width="564"/>Neohedycaryol exists preferably in the elongated chair conformation as was determined spectroscopically and by chemical transformation and this indicates that the role of neohedycaryol as a precursor in the biosynthesis of epi-eudesmanes, as proposed in the literature, is unlikely. This also means that 12 is not chiral and occupies a meso form.In chapter 6, enolate-assisted fragmentation reactions are developed for the synthesis of germacranes. After treatment with sodium tert-amylate and subsequent reduction, aldehyde 14 afforded. the <em>(E,E)-</em> alcohol 15. The use of potassium hexamethyIdisilazane instead of sodium tert-amylate as a base gave the corresponding <em>E,Z</em> analog. The presence of two <em>E</em> double bonds in 15 was proven by conversion of 15 into germacrene B (16). With the same approach, 15-hydroxyhedycaryol (18) was also efficiently synthesized.<img src="/wda/abstracts/i2241_4.gif" height="270" width="560"/> The biosynthesis of guaiane sesquiterpenes was mimicked by asymmetric Sharpless epoxidation of allylic alcohol 15 to afford guaiane 19 in high ee. The cis-fused ring system in 19 is found in most of the isolated guaianes. Epoxidation and cyclization of the (E,Z)-analog of 15 afforded trans-fused guaianes.<img src="/wda/abstracts/i2241_5.gif" height="149" width="549"/>In chapter 7, the results presented in chapter 3 through 6 are discussed. The results of the biomimetic cyclization reactions suggest that the role of sesquiterpene cyclases is mainly concerned with the initiation and termination of these cyclization reactions, and less or not at all with the course of the cyclization itself.