Sesquiterpenes

Sesquiterpenes are aliphatic or cyclic, isoprenoid Cl5 -compounds encompassing an almost bewildering array of structural types (cf. Figs. 106-108). They may be saturated or contain isolated double bonds. Often hydroxy, oxo, aldehyde, carboxylic acid, and lactone groups are present. Most compounds are volatile and lipophilic. Nitrogen-containing sesquiterpenes (sesquiterpenoid alkaloids) occur in some families of higher plants. 

Sesquiterpenes are frequent plant constituents. They are built, however, also in animals and microorganisms. 

Sesquiterpenes originate froin 2-trons-6-Jro7is-farnesyl pyrophosphate (D 6). Of importance are the following types of reactions  

Juvenile hormone III Fig, 106. Structural formulas of some sesquiterpenes 

Isomerization of farnesyl pyrophosphate is believed to involve reversible dephosphorylation with the formation of the corresponding alcohols and may proceed via 6-trans-farnesyl aldehyde. 

Sesquiterpenes.—Sesquiterpenoid derivatives which have been studied include the 1 1 adduct of silver nitrate and gennacratriene (60), a sesquiterpene prepared from the naturally occurring ketone germacrone. The analysis 

Illudol (67) and marasmic acid (68) are both examples of fungal metabolites which are thought to arise from a humulene-like precursor. Humulene itself is conformationally mobile in solution, but as a solid complex with silver nitrate it has a fixed conformation (69) which has been invoked to 

Vemolepin (72) and isocollybolide (73) are both emmples of sesquiter-penoid dQactones. The cyclohexane ring of vemolepin adopts a chair conformation, whereas the S-lac tone ring has a distorted boat form in which 

C(5) and C(10) are displaced by —0.25 and —0.88 A from the plane of the lactone group. The y-lactone ring, which is rraoj-fused to the cyclohexane ring, adopts a non-planar half-chair conformation, with C(Q and C(7) respectively 0.31 and —0.36 A distant from the plane of the other four atoms. The analysis of isocollybolide, which has additionally defined the structure of the isomeric compound cxrllybolide (74), reveals that in this 

There have been several analyses of sesquiterpenes whose structures are based on the azulene skeleton. To define completely the stmeture and absolute stereochemistry of the cytotoxic sesquiterpenoid lactone gaillaidin 

Sesquiterpenes are a major class of terpenes consisting of three isoprene units, providing the formula of to then-molecular structures (Fig. 7.1) [1]. Like all terpenes, their carbon skeletons are derived from the sequential addition of the active isoprene unit isopentenyl diphosphate (IDP or IPP) to other active diphosphates. In the case of sesquiterpenes, addition of a further IDP unit to geranyl diphosphate (GDP or GPP) (the essential precursor of all monoterpenes, please see Chapter 6) provides the fundamental sesquiterpene precursor famesyl diphosphate (FDP or FPP). 

Prenyltransferases are conunonly divided into two classes cis- and trans-prenyltransferases depending upon the stereochanistry of the resulting products. The first crystal structure reported for a irani -prenyltransferase was that of avian trans-iamesyl pyrophosphate synthase (FPPS) (Fig. 7.2) [5], 

Interestingly, cix-prenyltransferases show no amino acid sequence similarity to trans-enzymes. Cw-enzymes lack 

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products, First Edition. Edited by Alexandros L. Zografos. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

FIGURE 7.1 Famesyl diphosphate and selected diverse sesquiterpene motifs. 

The sesquiterpenes and their derivatives comprise about 2,000 naturally occurring representatives, and are the major sub-group of isoprenoid natural products. These compounds derive from more than 

100 different carbon skeletons (507,124). Although 500 sesquiterpene derivatives have been found in flavors (507), only about 20 seem of importance for the formation of flavors, if subjected to severe criteria. The aroma compounds of the sesquiterpene series seem to be associated with certain carbon skeletons. In any event, we still have no indication as to the occurrence in natural flavor complexes of compounds such as cedranes, santalanes, vetivanes, spirovetivanes (360) and germacranes which, on the other hand, constitute very important chemical classes in the chemistry of fragrances. Compared with the monoterpene derivatives, the flavor value of sesquiterpene compounds is small, although some of their representatives have been found to be character impact compounds. 

While nerolidol (155), farnesol (154) and famesal, the aldehyde corresponding to (154), have been known for a long time as natural flavor components, the importance of the farnesenes (151) to (153), was only recognized recently. a-Farnesene — first discovered in hop oil (71, 583) — has meanwhile been isolated from a wide variety of flavors 

Whereas the bicyclic sesquiterpene (— )-caryophyllene (159) [odor threshold in water solution 64ppb (77)] is widely distributed in flavors, its stereoisomer (160) is found only rarely in nature 206, 281, 336, 401). Apparently (160) is an artifact, the formation of which from (159) by the action of photochemically produced radicals could be shown (557). Black pepper oil rich in hydrocarbon (159) smells sweet and flowery 341, 500). On the other hand, the hydrocarbon fraction of 

The oleoresin of Dipterocarpus species is composed essentially of (-)-caryophyllene and humulene derivatives (159), (161), (167), (169), (170), and (171), (165) and (166) constituting more than 1% of it (205). Allyl alcohols having a caryophyllene structure are present in the bud oil of Betula alba, Betula lenta and also in peppermint oil (189). 

The sesquiterpenes important in odour terms mostly have complex cyclic structures. The problem of elimination of alcohols to produce olefins on attempted isolation is even more acute with sesquiterpenes than with monoterpenes because of their higher boiling points, which require more vigorous distillation conditions. The sesquiterpenes responsible for the odours of vetiver and patchouli oils have complex structures (21-24), which can only be reached by lengthy and hence uneconomic syntheses. As their names suggest, the vetivones occur in vetiver oil and the patchoulane derivatives in patchouli. 

Longifolene is present in Indian turpentine, which is obtained from the species Pinus longifolia. This hydrocarbon also has a strained skeleton and treatment with acid causes rearrangement to isolongifo-lene. Treatment of this with a peracid under acidic catalysis gives 

Two main families of cedarwood oils are used in perfumery. The first is extracted from trees of the family Juniperus. These oils are known as English, Texan or Chinese cedarwood and their components are derived from the cedrane and thujopsane groups of sesquiterpenes. Atlas and Himalayan cedarwoods are obtained from Cedrus species and their terpenes are mostly from the bisabolane family. The cedrane-thujopsane derivatives are much more widely used than the bisabo-lanes. 

The major components of the Juniperus wood oils are cedrol, cedrene and thujopsane, and a number of perfume ingredients are made from 

Meerwein rearrangement to a second cation, which was then trapped by trans-annular addition of the carbonyl group. 

Open chain sesquiterpenes are relatively rare. Farnesol is an example and is an important component of the scent of lily of the valley and lime blossom. It is probably formed from farnesyl pyrophosphate by cleavage of the pyrophosphate group. We shall not give any further consideration to the cyclic sesquiterpenes either except to mention the phytohormone abscisic acid (page 210) as an example. 

Even more interesting is the recent discovery of sesquiterpenes bearing an isonitrile function, a very rare feature in nature. 

At the time of this writing neither monoterpenes nor triterpenes have been reported from sponge sources, apart from squalene which was found in Ircinia spinosula 47) and I. muscarum 48). 

The chemical study of Pleraplysilla spinifera led to the isolation of six new furanosesquiterpenes. Two different samples identified as the same species (probably different varieties), both collected in the Bay of Naples, were analyzed and found to possess different sesquiterpene constituents. Chart 4 list their structures. 

Dehydrodendrolasin (36), the bicyclic pleraplysillin-1 (37) and the ester pleraplysillin-2 (38) have been found as constituents of the first sample (55, 62). 

The second component, pleraplysillin-1 (37), is a new type of sesquiterpene with a carbon skeleton so far unique [the classical review of sesquiterpene biogenesis by Parker et al. (757) and the comprehensive review of sesquiterpenes chemistry by Bryant 33) may be consulted. 

In addition to the myriad natural marine halogenated sesquiterpenes (vide infra), the terrestrial plant kingdom is also a major source of halogenated (chlorinated) sesquiterpenes, most of which possess the guaianolide skeleton (498). 

Although the first survey listed 45 natural chlorinated sesquiterpene lactones, several such compounds were omitted in that coverage (1) and are described here. The novel sesquiterpene lactone chlorochrymorin (239) was isolated from Chrysanthemum morfolium (499), and the chlorohydrin graminichlorin (240) is found in Liatris graminifolia (500). The antibacterial AA-57 (241), which is related to pentalenolactone, is produced by a Streptomyces sp. (501). The plant Eupatorium chinense var. simplicifolium has yielded eupachifolin D (242) (502) (side-chain double bond stereochemistry revised (518)), and the new guaianolide andalucin (243) was characterized from Artemisia lanata (503). The previously known chlorohyssopifolins (1) have been studied for cytostatic activity, and the presence of one and even two chlorine atoms amplifies this activity (504). 

The plant Achillea clusiana from the mountains of Bulgaria contains the new 2-epi-chIoroklotzchin (256), which is the first report of a halogenated sesquiterpene lactone from Achillea genus (512). Chloroform was used to process the plant. The Egyptian medicinal plant Ambrosia maritima, which is still used to treat renal colic and other aliments, has afforded 1 lp-hydroxy-13-chloro-l 1,13-dihydrohymenin (257) (513). Eupaglehnins E (258) and F (259) are novel germacranolides isolated 

The Chinese Eupatorium chinense has afforded ten new sesquiterpenoids, three of which are chlorinated, eupachinilides C (263), E (264), and F (265) (518). The Chinese medicinal plant Eupatorium lindleyanum contains the chlorinated guaianes eupalinilides A (266), D (267), E (268), and H (269), amongst other non-chlori-nated eupalinilides and nine known sesquiterpenoids (579). The Oregon coastal perennial plant Artemisia suksdorfii contains four novel chlorinated sesquiterpene lactones 270-273 520). 

The Balkan Peninsula plant Achillea depressa contains the previously discussed 260 and its novel hydroxy derivative 274 (521), which is apparently a diastereomer of the known bibsanin (1). Centaurea acaulis from Algeria has afforded 14-chloro-10/ -hydroxy-10(14)-dihydrozaluzanin D (275) (522). The widely distributed medicinal herbaceous perennial plant Cynara scolymus contains the new cynarinin B (276) as one of nine related sesquiterpenoids (523). 

The enzyme, farnesyl pyrophosphate synthetase (prenyl transferase), is responsible for the condensation of (4.14) with (4.15) to give geranyl pyrophosphate (4.41). The same enzyme mediates addition of a further molecule of (4.14) to (4.41) yielding 2- ran5-farnesyl pyrophosphate (4.19). This is the basic unit for the elaboration of the structurally diverse sesquiterpenes. The results obtained on biosynthesis are as interesting as the sesquiterpene structures. The 2 cis 

Formation of abscisic acid 4.62), a plant growth regulator, is established to be from mevalonic acid 4.13) and involves loss of the (4-/ ro-5)-proton and (two-thirds) retention of the (4 ro-/ )-proton (at C-2). This is consistent with formation of 4.62), with its terminal 

Coriamyrtin (4.78), tutin (4.79), picrotoxinin (4.80) (part of the complex metabolite, picrotoxin) and the alkaloid, dendrobine (4.81), are interesting sesquiterpenes which all embrace the structure (4.86). Labelling patterns in (4.78) and (4.79) from [2- C]- and [4- C]-mevalonate and the specific incorporation of labelled copaborneol (4.82, bond broken) indicates the pathway to these compounds 

There is also a proposed proton shift from C-9 to C-8. The correctness of this proposal was demonstrated when a mevalonoid (A-pro i )-tritium atom was found at C-8 (incorporation of other [ Hjmevalonates also excluded and intermediates) 

Gibberellin Aj2 aldehyde 4.116) is the first detectable gibbane intermediate in G. fujikuroi. From it a web of oxidation reactions leads through to various gibberellins including gibberellic acid 4.117) which also involves loss of the C-10 methyl group, probably via a carboxy-function [103-106]. 

3-unsaturated lactone functionality is a common feature of many of the biologically 

Two types of chamomile (camomile) are commonly employed in herbal medicine, Roman chamomile Chamaemelum nobile (formerly Anthemis nobilis) (Compositae/Asteraceae), and German chamomile Matricaria chamomilla (Chamomilla recutica) (Compositae/Asteraceae). German chamomile, an annual plant, is the more important commercially, and is often called matricaria to distinguish it from the perennial Roman chamomile. Both plants are cultivated 

The formation of sesquiterpenes by a carbocation mechanism means that there is considerable scope for rearrangements of the Wagner-Meerwein type. So far, only occasional hydride migrations have been invoked in rationalizing the examples considered. Obviously, fundamental skeletal rearrangements will broaden the range of natural sesquiterpenes even further. That such processes do occur has been proven beyond doubt by appropriate labelling experiments, and 

Finally, it is worth noting how many of the sesquiterpene derivatives described above are found in plants belonging to the daisy family, the Compositae/Asteraceae. Whilst sesquiterpenes are by no means restricted to this family, the Compositae/Asteraceae undoubtedly provides a very rich source. 

Wagner-Meerwein rearrangements 1,4-hydride shift two 1,2-methyl shifts 

The new farnesylhydroquinone (211) has been isolated from Wigandia kunthii Choisy which was collected in the Valley of Mexico. The geranylgeranyl analogue (212) and the oxofarnesyl 

These C15 compounds occur mainly as ingredients of essential oils or as y-lactones. They are thought to have evolved as phytoalexins or antifeedants, compounds synthesised by plants as a response to fungal attack and herbivore grazing (Bruneton 1995 Cronquist 1988). 

Their main occurrence is also in essential oils, usually in combination with monoterpenes, although they have higher melting points. Essential oil of Roman chamomile, Anthemis nobilis (Asteraceae), contains the blue-coloured sesquiterpene chamazulene, while German chamomile Chamomilla recutita) contains the anti-inflammatory sesquiterpenes bisabolol and bisabolol oxides. 

Gossypol from the cotton plant Gossypium herbaceum (Malvaceae) is a sesquiterpene dimer, in which the isoprene units are arranged into two bonded aromatic structures. 

Sesquiterpenes are significant constituents of myrrh resin Commiphora molmol). Recent stndies indicate that sesqniterpenes are responsible for local anaesthetic, antibacterial and antifungal properties (Dolara et al. 2000). 

Over 3000 different sesquiterpene lactones are known, and a large number of them occur in the Asteraceae family—in which they are considered a signature group of compounds. They often occur as mixtures of several related compounds, and tend to concentrate in leaves and flowers. Structurally they consist of one and a half terpenes (or six isoprene units) attached to a lactone ring. Many of their names end in the suffix olide indicating the presence of the lactone group. 

Addition of another isopentenyl pyrophosphate (IPP) to geranyl pyrophosphate with prenyl transferase enzyme, in the same way that gave 

Dendrolasin, a defensive compound from the mandibular glands of an ant, may be seen as an oxidation product of P-famesene. Labelled sodium acetate, sodium mevalonate and glucose were all incorporated into dendrolasin by the ant, but the label was scattered over all the carbon atoms, so that firm conclusions about the biosynthetic route could not be made. 

The aggregation pheromone of the rusty grain beetle Cryptolestes ferrugineus is a mixture of large ring lactones called cucujolides 

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Although the term terpene once referred only to hydrocarbons current usage includes functionally substituted derivatives as well grouped together under the general term isoprenoids Figure 26 6 (page 1086) presents the structural formulas for a number of representative examples The isoprene units m some of these are relatively easy to identify The three isoprene units m the sesquiterpene farnesol, for example are mdi cated as follows m color They are joined m a head to tail fashion... 

The trimer famesyl pyrophosphate (35), in addition to serving as a pregenitor of steroids via squalene (114), is also the pregenitor of the compounds known as sesquiterpenes. It has been suggested that famesyl pyrophosphate (88) similarly serves as the carbon backbone of alkaloids such as deoxynuphatidine (120) ftom Nupharjapomcum (Nymphaceae) (water hhes) and dendrobine (121) Dendrobium nobikl indl. (Orchidaceae) (Table 11). 

The latter is the source of the Chinese dmg Chin-Shih-Hu. Compared to the other families of bases discussed eadier, the numbers of alkaloids supposedly derived from famesyl pyrophosphate or a close relative is small. However, given the wide variety of plant families containing sesquiterpenes, it is most likely that the numbers of compounds to be found will dramatically increase. 

It has been found that the flavor of fmit can be increased by a process called precursor atmosphere (PA) (77). When apples were stored in a controlled atmosphere containing butyl alcohol [71-36-3] the butyl alcohol levels increase by a factor of two, and the polar products, butyl ester, and some sesquiterpene products increase significantly. The process offers the possibiUty of compensating for loss of flavor in fmit handling and processing due to improper transportation conditions or excessive heat. 

Intramolecular Friedel-Crafts acylations of olefins also give cycHc a,P-unsaturated cycHc ketones. Cyclopropane fused bicyclo[5.3.0]octenones, thus obtained, were used in the preparation of the marine sesquiterpenes, africanol [53823-07-7] and dactjlol [58542-75-9] (174). 

Amyris Oil. Obtained by steam distillation of the wood of y m hakamijera L., the so-called West Indian sandalwood which is indigenous to northern South America, Central America, and the West Indies, amyris oil [8015-65-4] is a pale yellow to brownish yellow viscous oil with a slightly oily-sweet and occasionally peppery balsamic woody note. It finds use as a blender and fixative for soap fragrances. The volatile constituents, which are primarily hydrocarbon and oxygenated sesquiterpenes, are shown in Table 22 and Figure 5 (63). 

Cyclic sesquiterpenes having the cedrene skeleton have also been isolated. When R = COOH, this stmcture (11) has been named sheUoflc acid. 

Terpenes are characterized as being made up of units of isoprene in a head-to-tail orientation. This isoprene concept, invented to aid in the stmcture deterrnination of terpenes found in natural products, was especially useful for elucidation of stmctures of more complex sesquiterpenes, diterpenes, and polyterpenes. The hydrocarbon, myrcene, and the terpene alcohol, a-terpineol, can be considered as being made up of two isoprene units in such a head-to-tail orientation (1). 

The majority of the turpentine comes from the southeastern United States, which consists of 60—70% a-pinene, 20—25% P-pinene, and 6—12% other components. Because there is variation in components from different species of the pine tree as well as variation from the many paper pulp mills, there is obviously variation in the analysis of sulfate turpentines. Some of the other components consist of -menthadienes, alcohols, ethers such as anethole [104-46-1] and methylchavicol [104-67-0] and the sesquiterpene hydrocarbon, P-caryophyUene [87-44-5]. 

Turpentine from the western United States is different from that of the southern states in that it contains 3-carene ranging from 12—43%, depending on the species of pine tree. Indian turpentine also contains about 60% 3-carene and about 15% of the sesquiterpene longifolene. Turpentine from Sweden, Finland, CIS, and Austria all contain 3-carene however, a- and P-pinene are commercially the most important components of the turpentines. 

Sesquiterpenes are formed by the head-to-tad arrangement of three isoprene units (15 carbon atoms) there are, however, many exceptions to the rule. Because of the complexity and diversity of the substances produced in nature, it is not surprising that there are many examples of skeletal rearrangements, migrations of methyl groups, and even loss of carbon atoms to produce norsesquiterpenoids. 

Important commercial sesquiterpenes mosdy come from essential oils, for example, cedrene and cedrol from cedarwood oil. Many sesquiterpene hydrocarbons and alcohols are important in perfumery as well as being raw materials for synthesis of new fragrance materials. There are probably over 3000 sesquiterpenes that have been isolated and identified in nature. 

The sesquiterpenes found in essential oils have low volatilities compared with monoterpenes and so are isolated mainly by steam distillation or extraction, but some are also isolated by distillation or crystallization. Most of the sesquiterpene alcohols are heavy viscous Hquids and many crystallize when they are of high enough purity. Sesquiterpene alcohols are important in perfume bases for their odor value and their fixative properties as well. They are valuable as carriers of woody, balsamic, or heavy oriental perfume notes. 

Gedrene and Gedrol. Cedarwood oil is one of the essential oils whose production is large and provides a source for synthesizing a number of derivatives. Gedrene (91) and thujopsene (92) are the two main sesquiterpene hydrocarbons found in the oil, along with a number of minor components (187). Gedrol [77-53-2] (93) is the main alcohol component of the oil. 

Patchouli alcohol. Patchouli oil comes from Pogostemonpatchouli and the main constituent is patchouli alcohol [5986-55-0] (105) or patchoulol. Another component of the essential oil is norpatchoulenol (106), a norsesquiterpene derivative as a minor (3—5%) constituent, important ia determining the overall odor of the essential oil (197). The price of patchouli oil ia 1995 was 20.90/kg from Indonesia (69). Alarge proportion of the oil (40—60%) is comprised of sesquiterpene hydrocarbons that do not have much odor value. World production of the oil was at about 750 t ia 1984. It is valuable ia perfumery bases because of its characteristic woody, herbaceous odor (198). 

Guaiol and Bulnesol. The main constituents of guaicwood oil are the sesquiterpene alcohols guaiol [489-86-1] (107) and bulnesol (108). When the alcohols are dehydrated with acid, many of the hydrocarbons formed are also found ia patchouli oil. 

Essential Oils. Volatile oils from plants are referred to as essential oils. The oils can be obtained through steam distillation, solvent extraction, or separation of the oils from pressed fmit. They consist of oxygenated compounds, terpenes, and sesquiterpenes. The primary flavor components of essential oils are oxygenated compounds. Terpenes contain some flavors but are often removed from the essential oil because they are easily oxidized (causiag off-flavors or odors) and are iasoluble. Essential oils are prepared from fmits, herbs, roots, and spices. 

Heating or irradiating alkenes in the presence of sulfur gives relatively low yields of thiiranes. For example, a mixture of sulfur and norbornadiene in pyridine-DMF-NHa at 110 °C gave a 19% yield of the monoepisulfide of norbornadiene as compared with a 78% yield by the method of Scheme 120 (79JCS(Pi)228). Often 1,2,3-trithiolanes are formed instead of thiiranes. The sesquiterpene episulfides in the essential oil of hops were prepared conveniently by irradiation of the terpene and sulfur in cyclohexane (Scheme 135) (80JCS(Pl)3li). Phenyl, methyl or allyl isothiocyanate may be used as a source of sulfur atoms instead of elemental sulfur. 

Sponge sesquiterpenes H NMR, 4, 560 Squalene synthesis, 1, 469 Squalene oxide occurrence, 7, 119 Squamalone... 

The roots contain essential oil with mono- and sesquiterpenes (valcrcnic acids). 

Sesquiterpenes and flavonoids (flavones, flavanones, flavanes) are two elasses of natural substan-ees which occur frequently in plants and whieh have 15 C atoms in their framework. The nine... 

In the //broadband decoupled C NMR spectrum, 15 carbon signals can be identified, in agreement with the molecular formula which indicates a sesquiterpene. The DEPT experiments show that the compound contains four quaternary C atoms, three CH units, seven CH units and a CH3... 

Table 47.2. Assembly of the partial structures A-E to form the decalin framework F of the sesquiterpene...

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