Diterpenes representative

The salvinorins are a class of non-nitrogenpus diterpenes isolated from a little-known Mexican entheogenic plant. Salvia divinorum, a member of the Labiatae or Lamiaceae, the mint fitmily. Similar diterpenes such as salviarin and splendidin have been isolated from Salvia splendens and other Salvia species (Savona etal. 1978 Savona etal. 1979), and these Salvia diterpenes represent a novel class of psycho-active compounds. Loliolide, an ant repellent, has recendy been isolated from Salvia divinorum (Valdes 19S6). Salvia occidentalis is reportedly used for analgesia by Panamanian Cuna Indians (Duke 1975). Salviapersepolitana was once proposed... 

The diterpenes represent a large group of terpenoids with a wide range of biological activities, and are isolated from a variety of organisms. One of the simplest and most important acyclic diterpenes is phy-tol. It is a reduced form of geranylgeraniol. This terpenoid may be the... 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

There is an expanding body of evidence to suggest that diterpene quinone of Salvia species might represent a pool of potential inhibitors of topoisomerase. Diterpenoid quinones have been characterized from Salvia officinalis (sage, British Pharmaceutical Codex, 1934), Salvia texana, Salvia regal, Salvia moorciuftiana, and Salvia lanata (44-47). 

Malacria and coworkers346 prepared phyllocladane and kaurane types of diterpenes by means of [3 + 2]/[2 + 2 + 2]/[4 + 2] cascade reaction sequences. A representative example of such a reaction sequence has been outlined in equation 171. The five-membered ring of 598 was built by a 1,3-dipolar cycloaddition between 596 and an all-carbon 1,3-dipole generated from 597. The reaction of 598b with 568h afforded benzocyclobutene 599. The intramolecular [4 + 2] cycloaddition afforded diastereomers 600 and 601 in a 5 1 ratio. It is noteworthy that the exocyclic double bond in 598b neither participates in the [2 + 2 + 2] cycloaddition reaction nor isomerizes under the reaction conditions applied. 

Another tetracyclic carbon skeleton, named cumbiane, has been isolated from Pseudopterogorgia elisahethae. Its representatives are the diterpenoids cumbiasin A (33) and B (34) [20] their structures and relative configurations were elucidated by interpretation of a combination of spectral data. The six-membered ring D was formed by connecting CIO and C16 of an elisabethane carbon skeleton. The carbocyclic skeleton of the cumbiasins is unprecedented and represents a new class of C20 rearranged diterpenes. The tricyclic seco-cumbiane skeleton is derived from the cumbiasins by cleavage of the C15-C16 bond. Due to intramolecular cyclizations two additional oxo-heterocycles are present in cumbiasin C (35) [20] (Fig. 7). 

Abstract The isolation, structure and total synthesis of members of four classes of diterpenes has been summarized. Dolabellanes, neodolabellanes, dolastanes and neodolas-tanes are structurally related bi- or tricyclic diterpenes. Dolabellanes belong to a continuously growing class of diterpenes being isolated from marine and terrestrial sources. The published work on isolation and synthesis since 1998 has been summarized. Neodolabellanes represent a scarce class of diterpenes that have been isolated exclusively... 

Long-chain ester derivatives of phorbol, a tetracyclic diterpene from the seed oil of Croton tiglium L., including its most abundant representative, 12-0-tetradecanoylphorbol-13-acetate (65), are potent activators of protein kinase G (PKG) and are used as standard tumor promoters for the study of experimental carcinogenesis in animal models." ... 

Overall, however, the immensity of temperate land corresponds to a most various secondary metabolic production, different from that of tropical land. The most renowned alkaloids belong to the morphine class (Chart 6.2.A1), and, in combination with isoprenoids, to the ergot and triterpene classes (Chart 6.2. A2). Prominent in the peptides are the cyclosporins (the first of which was isolated from a fiingus collected in Norway), streptogramins, and P-lactams (Chart 6.2.P). The isoprenoids are represented by pyrethrin monoterpenes, cedrane sesquiterpenes, ginkgolide and taxane diterpenes, ophiobolane sesterterpenes, and arborane and amyrin-like triterpenes (Chart 6.2.1). In the polyketides, epothilones, recently discovered from Myxobacteria, and the long known rapamycin, are two prominent classes of macrolides (Chart 6.2.FA/PO/C). 

Head-to-tail rearrangement of four isoprene units results in the formation of diterpenes (C20H32), as seen also in Fig. 4.2. Diterpenes are generally found in resins, e.g. pimaric acid and abietic acid. Some diterpenoids are also constituents of essential oils, e.g. phytol [3, 7-14, 37, 52, 53]. Like sesquiterpenes, diterpenes are heavier than monoterpenes therefore, they require more energy to go to the vapour phase. For this reason, longer distillation times are necessary for their recovery. The DNP lists 118 different structural types for diterpenoids [37]. Important diterpenes found in essential oils will be detailed. Some representatives of volatile diterpenes are as in Structure 4.32. 

Deacetoxyalcyonin acetate 1 and cuncellin 2 are representative members of the euniccllin class of diterpenes. The synthesis of deacetoxyalcyonin acetate 2 by Gary Molander of the University of Pennsylvania (J. Am. Chem. Soc. 2004, /26,1642) illustrates the power of intramolecular organometallic carbonyl addition for ring construction. 

Metabolism studies are essential for approval of any clinically useful drug. Microorganisms have been successfully used as in vitro models for prediction of mammalian drug metabolism due to the significant similarity of certain microbial enzyme systems, specifically fungi, with mammalian liver enzyme systems.66 The following metabolism study represents the first for a cembranoid diterpene and may aid future development of other cembranoids as clinically useful drugs. 

The terpenoids form a large and structurally diverse family of natural products derived from C5 isoprene units (Figure 5.1) joined in a head-to-tail fashion. Typical structures contain carbon skeletons represented by (Cs) , and are classified as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C2o), sesterterpenes (C25), triterpenes (C30) and tetraterpenes (C40) (Figure 5.2). Higher polymers are encountered in materials such as rubber. Isoprene itself (Figure 5.1) had been characterized as a decomposition product from various natural cyclic hydrocarbons, and was suggested as the fundamental building block for these compounds, also referred to as isoprenoids . Isoprene is produced naturally but is not involved in the formation of... 

Species in a relatively small number of herbivorous families dominate the list of plant feeders associated with alkaloid-rich foods. Lepidoptera (butterflies and moths) have catholic tastes when it comes to alkaloid-fortified plants, being represented by the families Nymphalidae (calystegine A-3, pyrrolizidine alkaloids lycopsamine type, harman), Arctiidae (senecionine type), Papilionidae (synephrine, isoquinolines), and Pterophoridae (monoterpene alkaloid rhexifoline).6 In addition, beetles (Chrysomelidae) sequester PAs (senecionine), grasshoppers (Acrididae) store senecionine, and aphids (Aphididae) sequester QAs (sparteine and diterpene alkaloids). 

The intermolecular [2 + 2]-photocycloaddition of para-tetrahydronaphthoqui-nones has been applied by Ward et al. to the synthesis of cyathin diterpenes [52], An example is represented by the total synthesis of ( )-allocyathin B3 (46), during the course of which the diastereoselective [2 + 2]-photocycloaddition of allene to substrate 44 served as one of the pivotal steps (Scheme 6.17) [53]. The addition delivered a mixture of regioisomers (r.r. = 80/20), from which compound 45 was separated. The facial diastereoselectivity was perfect due to the concave shape of the quinone. 

Several additional examples of the intramolecular cycloaddition of unactivated acetylenes with isomiinchnones were reported by Maier [30]. This cycloaddition approach represents an efficient method for providing rapid access to annulated furans present in several sesqui- and diterpenes, such as the panicu-lides [51],furanonaphthoquinones [52],furodysin,andfurodysinin [53,54].The decomposition of acyclic acetylenic diazoimides 102 and 103 with Rh2(OAc)4 resulted in cycloaddition and retro-Diels-Alder extrusion of methyl isocyanate to give annulated furans 104 and 105 in good yield. The overall transformation is closely related to the intramolecular Diels-Alder reactions of acetylenic oxa-zoles extensively studied by Jacobi and coworkers [55]. 

Terpenes are composed of isoprenyl (C-,) units and are conveniently grouped as monoter-penes (skeletal basis CI0 = 2X C-,), sesquiterpenes (G13 = 3X C3), diterpenes (C20 = 4X C-,), triterpenes (C3o = 6X C-,) and tetraterpenes (C40 = 8X G-j. The structures of some representative terpenes are shown in the Appendix (Section 3). Terpenes ultimately derive biosynthetically from acetate (C2) via the activated acetyl thioester (CH3—CO—S—X) acetyl-coenzyme A (acetylCoA CH3-CO-S-C0A) as outlined below (enzymes catalysing key steps being indicated in parentheses). 

Adenylyl cyclase catalyses the reaction ATP— cAMP + pyrophosphate (PP,). Membrane-bound ACs are activated by hormones and NTs that act via G protein-linked receptors to generate AC-activating Gas GTP (Chapter 5). Particular AC isoforms are activated by Ca2+-calmodulin, this representing an example of cross-talk between cAMP and Ca2+ signalling pathways. As outlined in Chapter 5, Gai GTP inhibits AC and hence lowers cAMP concentration. A variety of hormones and NTs act via GPCRs to either activate or inhibit AC and in turn a variety of plant-derived compounds interfere with these processes (Chapter 5). The plant-derived diterpene forskolin and related compounds directly activate AC (Table 7.2). 

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