Sesquiterpenes C15

Addition of a further C5 IPP unit to geranyl diphosphate in an extension of the prenyl trans-ferase reaction leads to the fundamental sesquiterpene precursor, farnesyl diphosphate (FPP) (Figure 5.25). Again, an initial ionization of GPP seems likely, and the proton lost from C-2 of IPP is stereochemically analogous to that lost in the previous isoprenylation step. FPP can then give rise to linear and cyclic sesquiterpenes. Because of the increased chain length and additional double bond, the number of possible cyclization modes is also increased, and a huge range of mono-, bi-, and tri-cyclic structures can result. The stereochemistry of the double bond nearest the diphosphate can adopt an E configuration (as in FPP), or a Z configuration via ionization, as found with geranyl/neryl PP (Figure 5.26). In some systems, the tertiary diphosphate nerolidyl PP (compare linalyl PP, page 172) has been implicated as a more immediate precursor than farnesyl PP (Figure 5.26). This allows different possibilities for folding the carbon chain, dictated of course by the enzyme involved, and cyclization by elec-trophilic attack on to an appropriate double bond. As with the monoterpenes, standard reactions of carbocations rationally explain most of the common structural skeletons encountered, and a representative selection of these is given in geranyl PP

geranyl PP

Farnesyl Diphosphate Aba

farnesyl PP (FPP)

Figure 5.25

farnesyl PP (FPP)

Figure 5.25

Figure 5.27. One of these cyclized systems, the bisabolyl cation, is analogous to the monoter-pene menthane system, and further modifications in the six-membered ring can take place to give essentially monoterpene variants with an extended hydrocarbon substituent, e.g. y-bisabolene (Figure 5.28), which contributes to the aroma of ginger (Zingiber officinale; Zin-giberaceae) along with the related structures such as zingiberene and P-sesquiphellandrene (Figure 5.29). Sesquiterpenes will in general be less volatile than monoterpenes. Simple quenching of the bisabolyl cation with water leads to a-bisabolol (Figure 5.28), a major component of matricaria (German chamomile)* flowers (Matricaria chamomilla; Compositae/Asteraceae). So-called bisabolol oxides A and B are also present, compounds probably derived from bis-abolol by cyclization reactions (Figure 5.28) on an intermediate epoxide (compare Figure 4.34, page 146).

Other cyclizations in Figure 5.27 lead to ring systems larger than six carbons, and seven-, ten-, and 11-membered rings can be formed as shown. The two ten-membered ring systems (germacryl and cis-germacryl cations), or the two 11-membered systems (humulyl and cis-humulyl cations), differ only in the stereochemistry associated with the double bonds. However, this affects further cyclization processes and is responsible for extending the variety of natural sesquiterpene derivatives. The germacryl cation, without further cyclization, is a precursor of the germacrane class of sesquiterpenes, as exemplified by parthenolide (Figure 5.30), the antimigraine agent in feverfew* (Tanacetum parthenium; Com-positae/Asteraceae). Parthenolide is actually classified as a germacranolide, the suffix 'olide' referring to the lactone group. Whilst the details of the pathway are not known, a series of simple oxidative transformations (Figure 5.30) can produce the a,P-unsaturated lactone and epoxide groupings.

The a,P-unsaturated lactone functionality is a common feature of many of the biologically

Cadinyl Cation
£,E-farnesyl cation
nerolidyl cation

Z' bV|| £,Z-farnesyl cation germacryl cation e.g. parthenolide humulyl cation e.g. humulene humulyl cation e.g. humulene bisabolyl cation e.g. bisabolene, a-bisabolol bisabolyl cation e.g. bisabolene, a-bisabolol

Eudesmyl Cation

ci's-germacryl cation ci's-humulyl cation

caryophyllyl cation e.g. caryophyllene caryophyllyl cation e.g. caryophyllene

W-M @ 1,3-hydride shift carotyl cation

W-M 1,3-hydride carotyl cation

W-M 1,3-hydride ci's-germacryl cation guaiyl cation e.g. matricin, thapsigargin eudesmyl cation e.g. a-santonin

e.g. artemisinic acid cadinyl cation e.g. a-cadinene ci's-humulyl cation shift

(-)-ß-bisabolene bisabolyl cation

y-bisabolene

(-)-ß-bisabolene bisabolyl cation

y-bisabolene

Figure 5.28

phellandrene

Figure 5.28

elephantopin parthenin

a-santonin

phellandrene

elephantopin a-santonin

Pseudoguaianolide Parthenin

thapsigargin

thapsigargin parthenin

"CO2H angelic acid

CO2H

isovaleric acid

CO2H

tiglic acid

"CO2H isobutyric acid

Figure 5.29

active terpenoids. The activity frequently manifests itself as a toxicity, especially cytotoxicity as seen with the germacranolide elephantopin (Figure 5.29) from Elephantopus elatus (Com-positae/Asteraceae), or skin allergies, as caused by the pseudoguaianolide (a rearranged guaiano-lide) parthenin (Figure 5.29) from Parthenium hysterophorus (Compositae/Asteraceae), a highly troublesome weed in India. These compounds can be considered as powerful alkylating agents by a

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a$-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alky-lation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a b a

germacryl cation germacryl cation

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