Sesquiterpenoids

Only a few sesquiterpenoids have been encountered in studies of lichens (3-caryophyllene, a-copaene, (3-elemene, farnesane, p-gurjunene, longifolene, a-muurolene, P-selinene, and thujopsene from Evernia prunastri 319) and fukinanolide A (bakkanolide A) from Cetraria islandica ((555). Abscisic acid (ABA) was detected in all 26 lichen species investigated (175). 

Phytol and manool have been isolated from Letharia vulpina ((555), rimuene was isolated from Evernia prunastri 561) and (—)-sandara-copimaric acid from Ramalina hierrensis 330). 

The first report on the occurrence of sesquiterpenoids in ferns appeared as early as 1947 and concerned a bicyclic sesquiterpene alcohol of unknown structure (301). However sesquiterpenoids of ferns were not investigated systematically until 1970. 

The 1-indanone derivatives isolated from ferns are designated as pterosins and their glycosides as pterosides (SOS), Pterosins belong to the so-called illudalane type of sesquiterpenes which possess carbon skeleton 413. Illudalanes are seco-illudanes and illudanes possess carbon skeleton 414. 

Pterosins in ferns are classified into two main types, the pterosin Z type (Cl5) (419-464) and the pterosin B type (C14) (467-514), according to the number of the carbon units attached to C-2. 

B-type pterosins are considered to be produced biogenetically by a retro-aldol condensation of hydroxymethyl derivatives of Z-type pterosins such as pterosin A (437). Under acid or basic conditions, epimeri-zation at C-2 by way of an enol occurs easily and therefore B-type pterosins are often obtained as epimeric mixtures at C-2 (259), 

Ptaquiloside ( = aquilide A) (466) is quite unstable at room temperature under both acidic and basic conditions, when it decomposes to D-glucose and pterosin B (467) and its biological activities disappear. At pH 11, ptaquiloside (466) is converted to a conjugated dienone (533), which is extremely unstable under weakly acidic conditions and is immediately transformed into pterosin B (467) (278). 

A few Cl5 tropolones, which may be considered as sesquiterpenoids (Sect. 8.1.3.3) are also known - for example, nootkatin (118) and chanootin (119) from heartwood of Chamaecyparis nootkatensis (Alaska-cedar) (140). 

Lists of occurrence of sesquiterpenoids in higher plants are available (155, 207, 275 Vol. Ill b, c, 296, 305, 396). Thble 8.1.3 gives a list of plant families known for accumulating sesquiterpenoids. Of these, Cupressaceae, Compositae, Dipterocarpaceae and Myrtaceae are specially prolific in producing these compounds. Humulene and caryophyllene are the most extensively distributed sesquiterpenes. 

As in the case of monoterpenoids, both antipodal forms of certain sesquiterpenoids have been found to occur in higher plants, though to a much restricted extent. Occurrence of racemic modification is rare, though a few examples are known (305). However, it may be pointed out that several sesquiterpenoids isolated from Hepaticae have been found to be enantiomeric to those from the higher plants (13,266). 

The value of sesquiterpenoids as chemotaxonomic markers has received some attention (140, 155). Much discussion has been focused on their importance in Compositae phylogeny, at the genus and species level (153, 191, 193). Sesquiterpene distribution in the family Dipterocarpaceae has been studied (37). 

The oil bodies of most species of the Hepaticae are contain sesquiterpenoids which are found in the four orders Calobryales, Jungermanniales, Metzgeriales and Marchantiales. Except for barbatane-, pinguisane- and 2,3-isecoaromadendrane-type sesquiterpenoids, the sesquiterpenoids isolated from or detected in the Hepaticae are identical with or very similar to those found in the Phanerogams. 

Further investigations on the terpenoid constituents of various species of Eupa-torium have revealed the presence of two new acyclic sesquiterpenoids, (1) and (2).  

Reagents i, Cr(OH)2 ii, Cr03-py iii, CH2=CHMgBr iv, Mn02 v, Ag20 vi, Me2C=CHLi 

Reagents i, PhSH-02 ii, BuLi iii, geranyl bromide iv, Li-EtNH2 

A recent investigation of marine red algae has shown that the major lipid-soluble metabolite of Laurencia obtusa, collected in the English Channel, is 3j8-bromo-8-epicaparrapi oxide (11) (c/. isolation of a- and jS-snyderol (12) from L. obtusa collected in Spain Vol. 7, p. 54). 

The structure of polyalthenol (17), a metabolite of the African plant Polyalthia oliveri, has been determined by analysis of its n.m.r. spectra. It has been suggested that the rearranged bicyclofarnesane structure of this compound is produced by 1,2-methyl shift of a drimane-type intermediate. 

A comprehensive review of terpenoid metabolites of the Basidiomycetes has sections on the biosynthesis of these compounds. Many of the sesquiterpenoids found in these fungi can in theory be derived by various cyclizations of humulene. Conformational calculations on humulene have been made with a view to predicting the role of stable conformers in its biosynthetic reactions. 

The enzymatic conversion of famesyl pyrophosjAiate to nerolidyl pyrophosphate and the cyclization of the latter to cyclonerodiol (15) has been studied. labelling experiments have established that the conversion 

An important role has been proposed for nerolidyl pyrojdiosphate in the formation of the hydrocarbon trichodiene (I6), However, contrary to previous reports, this cyclization does not involve the loss of a proton from 0-1 of famesyl pyrophosphate, Ihe trichoverrin diesters (1 ) may be the 

Confiimation has been provided by a deuterium n,m,r, study for the hydride 

Two independent studies have been reported on the biosynthesis of the PR-toxin (22) in PeniciIlium roqueforti. The results of [1,2- -acetate 

The azulene (421, isopropyl in place of isopropenyl) isolated from dried specimens of L. deterrimus from Kashmir (441) is almost certainly yet another artefact. 

The lagopodins-A (426) and -B (427) and hydroxylagopodin-B (428) are sesquiterpenoid quinones which have been isolated from cultures of various species of Coprinus (Table 42). Their chemistry has been dealt with by Thomson (d55). 

Interestingly., the lack of a distinct carbonyl stretching band near 1750 cm Mn the infra red spectra of lagopodin-B and hydroxylagopo-din-B recorded iiti potassium bromide has been ascribed to the predominance of a hemiketal form in the solid state 111, H4). However, no evidence that lagopodin-B exists in such a form in deuteriochloroform solution could be gleaned from the H-n.m.r. spectrum 142), 

It was predicted by Thomson 655) that the dimeric quinone, lago-podin-C, isolated from C. lagopus 111) would prove to be an artefact formed during work up of the culture fluids. This has subsequently been shown to be the case 142). In fact, both lagopodin-A and lagopo-din-B are quite unstable in aqueous solution at neutral or slightly alkaline pH. The quinone (427), for example, has a half-life of only 12 h at pH 6.8-7.6 when incubated in the sterile media used for the cultures of C. cinereus 142). It can be assumed then that many of the pigments observed in the total extracts of these Coprinus species arise by nonen-zymic reactions of the parent quinones (426) and (427) in the aerobic aqueous culture media. 

The lagopodins are closely related to helicobasidin (429), a pigment from Helicobasidium mompa, the biosynthesis of which has been extensively studied 81, 655). 

The stereoselective synthesis of p-sinensal (14) has been achieved by reaction of the T -allylnickel(n) complex (12) (derived from bromomyrcene) with the chloro- 

In two important papers Poulter et al. have published their results on the compelling evidence for a stepwise mechanism for the 1 -4 condensation reaction between isopentenyl pyrophosphate and geranyl pyrophosphate to form farnesyl 

An interesting review of the biosynthesis and transport of juvenile hormones in insects has appeared.17 The syntheses of the juvenile hormones JHI—JHIII (25)— 

Masamune, Chem. Lett., 1981, 1125. 

The diverse biological activity (e.g. insect antifeeding, plant growth regulation, molluscicidal) of a number of drimane sesquiterpenoids has stimulated considerable interest in their synthesis and the year under review has seen many new developments and improvements. Much of the synthetic work has centred around the key bicyclic diester (54) derived from 1-vinyl-2,6,6-trimethylcyclohexene and dimethyl acetylenedicarboxylate. In contrast to earlier results,34 Ley et al.8S 

There can be different plausible foldings of farnesyl diphosphate that could generate sesquiterpenoid carbon skeleta. In many cases these have been differentiated by examining the labelling pattern of the sesquiterpenoid fungal metabolites that have been biosynthesized from variously labelled acetates and mevalonates. Recent interest has focussed on the isolation of sesquiterpenoid synthases that form these skeleta and the elucidation of the mechanism of their action. 

The biosynthesis of the insect juvenile hormone (19) continues to present incorporation problems. The acid 10-epoxy-7-ethyl-3,ll-dimethyltrideca-2,6-dienoic acid (20) acts as a substrate for the hormone in the giant silk moth, Hyalopkora cecropia. L-Methionine gave the ester methyl group. However, it did not contribute to the carbon skeleton whilst farnesol, farnesol pyrophosphate, propionate, and mevalonate were apparently not utilized for the biosynthesis of the hormone under the conditions of these experiments. There was a very low incorporation of [2- C]acetate into juvenile hormone. 

The fungal metabolite siccanin (21) contains a sesquiterpenoid fragment and a fragment derived from orsellinic acid. Previous reports had described a cell-free system from Helminthosporium siccans for the synthesis of trans-y-mono-cyclofarnesol (22). The formation of siccanochromene-A (25) has now been studied by the incubation of cell-free systems from Helminthosporium siccans 

Cardemil, L. Chayet, R. Telliz, R. Pont-Lezica, and O. Coii, Phytochemistry, 1972, 11, 1683. 

Earlier experiments on the biosynthesis of tutin (28) with [2- C]mevalonic acid and [2,2- Hj,2- C]mevalonic acid had indicated its sesquiterpenoid nature and had suggested that it was formed via copabomeol (27). Specifically tritiated copabomeol has now been shown to be converted into tutin (28) by Coriaria japonica without randomization of the label. The initial step in the cyclization to form copabomeol has been regarded as the cyclization of the electrophilic C-1 of famesyl pyrophosphate with the distal double bond to form a germacrane cation (26). In order for cyclization to proceed further the reactive centre must then be transferred from C-11 to C-1. One proposal involved a double 1,2-hydride shift from C-10 to C-11 and C-1 to C-10. However, this 

BioUaz and D. Arigoni, Chem. Comm., 19(9, 633 A. Corbella, P. Gaiiboldi, G. Jommi, and C. Sdiolaatico, Chem. Comm., 1969,634. 

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Figure 5 Proposed mechanism for biosynthetie introduetion of bromine and ehlorine atoms into the Lcmrencia sesquiterpenoid nidifieine (24)...

The organization of Part Two is according to structural type. The first section, Chapter Seven, is concerned with the synthesis of macrocyclic compounds. Syntheses of a number of heterocyclic target structures appear in Chapter Eight. Sesquiterpenoids and polycyclic higher isoprenoids are dealt with in Chapters Nine and Ten, respectively. The remainder of Part Two describes syntheses of prostanoids (Chapter Eleven) and biologically active acyclic polyenes including leukotrienes and other eicosanoids (Chapter Twelve). 

The sesquiterpenoid hydrocarbons (5)-a-curcumene (59) and (5)-xanthorrhizol (60) were prepared by asymmetric conjugate addition of the appropriate aryllithium reagent to unsaturated oxazoline 56 to afford alcohols 57 (66% yield, 96% ee) and 58 (57% yield, 96% ee) upon hydrolysis and reduction. The chiral alcohols were subsequently converted to the desired natural products. ... 

Heterocycles in synthesis of drimane sesquiterpenoids from labdane diterpenoids 97IZV896. 

Synthesis of germacrane sesquiterpenoid lactones and related compounds 99T2115. 

Synthetic studies on sesquiterpenoids from D-glucose, total syntheses of (-H)-eremantholide A and (—)-verrucarol 98YGK1026. 

A modern variant is the intramolecular magnesium-ene reaction, e.g. the reaction of the alkene-allylic-Grignard compound 9 to give the five-membered ring product 10. This reaction proceeds regio- and stereoselectively, and is a key step in a synthesis of the sesquiterpenoid 6-protoilludene ... 

Terpenoids are classified according to the number of five-carbon multiples they contain. Monoterpenoids contain 10 carbons and are derived from two isopentenyl diphosphates, sesquiterpenoids contain 15 carbons and are derived from three isopentenyl diphosphates, diterpenoids contain 20 carbons and are derived from four isopentenyl diphosphates, and so on, up to triterpenoids (C30) and tetraterpenoids (C40). Monoterpenoids and sesquiterpenoids are found primarily in plants, bacteria, and fungi, but the higher terpenoids occur in both plants and animals. The triterpenoid lanosterol, for example, is the precursor from which steroid hormones are made, and the tetraterpenoid /3-carotene is a dietary source of vitamin A (Figure 27.6). 

The terpenoid precursor isopentenyl diphosphate, formerly called isopentenyl pyrophosphate and abbreviated IPP, is biosynthesized by two different pathways depending on the organism and the structure of the final product. In animals and higher plants, sesquiterpenoids and triterpenoids arise primarily from the mevalonate pathway, whereas monoterpenoids, diterpenoids, and tetraterpenoids are biosynthesized by the 1-deoxyxylulose 5-phosphate (DXP) pathway. In bacteria,... 

Sesquiterpenoid. 203, 1071 Sex hormone, 1082-1083 Sharpless, K. Barry. 734 Sharpless epoxidation, 735 Shell (electron), 5 capacity of, 5 Shielding (NMR). 442 Si prochirality, 315-316 Sialic acid. 997 Side chain (amino acid), 1020 Sigma (cr) bond, 11 symmetry of, 11 Sigmatropic rearrangement, 1191-1195... 

The functional groups of abscisin II could easily arise from a precursor like violaxanthin (M), a carotenoid of widespread occurrence (see 11). Whatever the genesis of abscisin II, it is clear that it must be different from that of the bis-sesquiterpenoid, gossypol (N), which also occurs in the cotton plant and has received considerable attention. 

The next example involves a recent study of essential oil polymorphism in Thymus praecox Opiz subsp. arcticus (E. Durand) Jalas (syn. T. drucei Ronn.) on the British Isles (Schmidt et al., 2004). More than 700 specimens of the plant were collected in Ireland, Scotland, and southern England and subjected to gas chromatographic analysis (coupled with mass spectroscopy). Sixty-nine constituents were identified, the majority of which were mono- and sesquiterpenoids. Analysis of the data revealed a highly polymorphic assemblage with 13 chemotypes in Scotland, 11 in Ireland, and 17 in the south of England. Polymorphism seems to... 

Hashimoto, T., Tori, M. and Asakawa, Y. 1989. Drimane-type sesquiterpenoids from the liverwort Makinoa crispata. Phytochemistry 28 3377-3381. 

Itoh, T., Matsuo, Y. and Suzuki, M. 1997b. Sesquiterpenoids of Laurencia majuscula... 

He, X.G. et al, Liquid chromatography-electrospray mass spectrometric analysis of curcuminoids and sesquiterpenoids in turmeric Curcuma longa), J. Chromatogr. A, 818, 127, 1998. 

Hu L, Zhongliang CH. Sesquiterpenoid alcohols from Chrysanthemum morifolium. Phytochemistry 1997 44 1287-1290. 

Hernandez V, del Carmen Recio M, Manez S, Prieto JM, Giner RM, Rios JL. A mechanistic approach to the in vivo anti-inflammatory activity of sesquiterpenoid compounds isolated from Inula viscosa. Planta Med 2001 67 726—731. 

Maier, W., K. Hammer et al. (1997). Accumulation of sesquiterpenoid cyclohexenone derivatives induced by an arbuscular mycorrhizal fungus in members of the Poaceae. Planta 202(1) 36—42. 

Maier, W., B. Schneider et al. (1998). Biosynthesis of sesquiterpenoid cyclohexenone derivatives in mycorrhizal barley roots proceeds via the glyceraldehyde 3-phosphate/pyruvate pathway. Tetrahedron Lett. 39(7) 521-524. 

Meinwald, J., K. Erickson, M. Hartshorn, Y. C. Meinwald, and T. Eisner (1968). Defensive mechanisms of arthropods. XXIII. Anallenic sesquiterpenoid from the grasshopper Romalea microptera. Tetrahedron Lett. 25 2959-2962. 

We have used the Kupchan scheme successfully in the separation of the multifunctional diterpenoid kalihinols from various Acanthella species (cf. Sect. 4.2.2). These compounds were distributed between the carbon tetrachloride and chloroform layers [19, 25], No isocyanosesquiterpenes were present in the hexane layer. By contrast, separate experiments with the Australian A. klethra revealed that sesquiterpenoid isonitriles were found exclusively in the hexane extract. No kalihinols were present in the carbon tetrachloride or chloroform extracts [26],... 

The antipodal relationship appears secure despite differences in the magnitude of the rotation values ([a]D 32, —63° 43, +100°), both of which were measured in CC14. Of particular interest is the isothiocyanato-alcohol 46, which is the first example of an oxygenated marine sesquiterpenoid possessing a function unrelated to the -NC/-NCS/-NHCHO triad. 

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