The Labdane Series

13-Epimandol has been detected in the neutral extracts of Larix europaea and in the bark of the Sitka spruce. Cupressus resins have been examined by g.l.c. and imbricatolic acid (5) identified in all but Cupressus sempervirens. This acid co-occurs with the cis- and trans-communic acids and with sandaracopimaric acid. A -Communic acid has been isolated as its methyl ester from Callitris columellaris. During this work the thermal isomerisation of the conjugated diene of communic acid was noted. The structures and stereochemistry of some 

8-0X0-14-norlabdanes derived from the ozonolysis of methyl communate have been clarified. Copaifera multijuga contains copaiferolic acid and a new labdane acid, ll-hydroxylabda-8(17),13-dien-15-oic acid. The leaf oil of Chamaecyparis nootkatensis contains two new manoyl oxides. They have been assigned the 

8-epimanoyl oxide (6) and 8,13-epimanoyl oxide (7) structures. The C-13 stereochemistry was based on an interesting and potentially useful cyclisation catalysed 

Delle Monache, T. Leoncio d Albuquerque, G. Delle Monache, and G. B. Marini Bettolo, Ann. Chim. (Italy), 1970, 60, 233. 

The formation of a common manool trihydrochloride from manool, sclareol, manoyl oxide, 13-epimanoyl oxide, biformene, and abienol played an important part in the structural correlation between these diterpenes. Earlier proposals had suggested an 8-equatorial chlorine atom, but in a paperclarifying the various 8,13,15-chloro-labdanes, the analogous monohydrochloride from tetra-hydroabienol was assigned the 8-axial stereochemistry (8). Dehydrochlorination of this isomer yields all three expected olefins, whilst the equatorial epimer affords only the and A -olefins. 

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The most important manoyl oxide derivative is forskolin (9), Fig. (7), (7p-acetoxy-8, 13-epoxy-la, 6p, 9a-trihydroxylabd-14-en-ll-one) [151-153]. It belongs to the labdane series of diterpenes and was isolated from the Indian herb Coleus forskohlii (Willd.) Briq. (Labiatae). Since ancient times it has been used in Hindu and Ayurvedic traditional medicine [154]. The plant Coleus forskohlii (Willd.) Briq. has been extensively studied, and from its extracted roots a group of diterpenoids, with the basic skeleton of 11-oxo-manoyl oxide, have been isolated. The main compound, forskolin, presented remarkable chemical and biological properties [155]. Analogues of forskolin were then prepared by semisynthesis [156] or obtained by microbial transformations [157]. New analogues, more soluble than forskolin have shown activities comparable to and even higher than forskolin [158]. 

The Labdane Series.—The conifers are an important source of diterpenoids. Araucaria excelsa has been examined and manool, torulosol, abietinol, torulosal, and abietinal have been detected in the neutral fraction of the oleoresin. This fraction also contained the epimeric 18- and 19-nor-labdane-4,13-diols (1), which may arise by autoxidation of torulosal. Chromatography of this aldehyde on alumina or silica led to up to 14% of the epimeric C-4 hydroperoxides. Consequently, whenever these nor-diterpenoids are detected, the possibility that they are artefacts has to be borne in mind. Oxidative decarboxylation of acetylcupres-sic acid by lead tetra-acetate affords a synthetic entry to this series of compounds. 

The bicyclic labdanoid diterpenes are characteristic of the bark and needle resins of the Pinaceae, whereas tricyclic types (especially the abietanes and pimaranes) dominate in the wood resin (Croteau and Johnson, 1985) (Fig. 22.10). Highly oxygenated derivatives of the labdane series are widespread in the Asteraceae, Lamiaceae, Verbenaceae, and in the genus Croton of the Euphorbiaceae. 

Chernov V, Shul ts EE, Shakirov MM, Tolstikov GA (2002) Synthetic transformations of higher terpenoids VII. Synthesis of tetrahydro-P-carbolines of the labdane series. Russ J Org Chem 38 665-671. Translated from Zhumal Organicheskoi Khimii 38 ... 

The same applies to diterpenes of the labdane series. In a terrestrial environment, these generally belong to the series designated as normal, whereas in a marine environment they are more likely to belong to the series ent ... 

With very few exceptions, the pine resin acids belong to four basic skeletal classes abietane, pimarane, isopimarane, and labdane (Fig. 7). The acids of the abietane, pimarane and isopimarane series have a isopropyl or methyl/ethyl group in the carbon-13 position and a single carboxyl group in the carbon-18 position, and differ only in the number and location of the carbon-carbon double bonds (the most common have two carbon-carbon double bonds). The acids of labdane series are less common and contain one carboxyl group in the carbon-19 position. 

The conifers are an important source of diterpenoids. Several labdanes have been detected in the neutral fraction of the oleoresin of Araucaria excelsa, including manool as well as nor-labdanes [42]. Some neutral diterpenoids, such as enMabd-8, 13(E)-dien-15-ol and its acetate, were obtained after extraction of the resin of Araucaria bidwillii [43], while the normal series of the above labdanes have been isolated from Cistus creticus subsp. creticus [44]. From Pinus sylvestris, 3P-hydroxybiformene has been obtained, while from the needles of the American red wood pine (Pinus resinosa), 8,13-epoxy-labd-14-en-19-oic acid, was isolated. In Pinus nigra, labdane acids have been found to be the major acid components of its needles [45,46]. The occurrence of diterpenoids including labdanes in conifers has been published as a review of the chemistry of the order Pinales [47],... 

In the family of Asteraceae the ent- series of labdanes have been identified as the common components [75]. The following species of Asteraceae have yielded labdanes Leyssera guaphaloides, Brickellia... 

A number of partial syntheses have been described in the bicyclic series. The synthesis of methyl (12S)- and (12i )-hydroxylabda-8(17)-en-19-oate utilized the aldehyde (10) as an intermediate. This was obtained from podocarpic acid. The synthesis of the furan methyl lambertianate (11) from dimethyl agathate has been described. Examination of the n.m.r. spectra of the levantenolides (12) has led to a revision of their C-12 stereochemistry. a-Levantenolide has the (12i ) configuration whereas jS-levantenolide has the (125) configuration. The functionalization at C-12 of labdanes by oxidation of C-15 alcohols with iodine and lead tetra-acetate has been described. ... 

Labdanes.— The n.m.r. spectra of some members of the eperuane series have... 

The acid-catalysed cyclization of labdanes has continued to attract attention. The influence of a C-15 carbonyl group, as in (15), leads to compounds of the pimarane series (16) and to the enol-ether (17) rather than isoagathic acid derivatives even in the presence of formic acid. The tetracyclic alcohol (20) has been obtained by dehydration of sclareol (18) with perchloric acid. It is presumably formed via the carbocation (19). 

The Clerodane Series.—Some further contributions have been made to the chemo-taxonomy of Cistus species. Whereas C. labdaniferus contains mainly labdanes such as labdane-8a,I5,l9-triol, C. monspeliensis contains a group of clerodane diterpenoids whose structures are summarized in (17), together with labdanolic acid and labdane-8a,15-diol. 

Diterpenes of this series are formed by rearrangement of the labdane skeleton during cyclization (Hanson, 1991 West, 1981) (Fig. 22.11). Many highly oxygenated diterpenes of this series are found in the Lamiaceae and Verbena-ceae. There are over 400 known clerodanes many of these are from Teucrium species (Lamiaceae) (Hanson, 1991). 

Correlations within a stereochemically homogeneous series of compounds, such as monosaccharides and steroids, which are well documented elsewhere in the literature are considered in outline only. Series of compounds which are essentially dimeric or polymeric types built up from chiral monomeric units are not covered in detail, since their configurations follow readily from those of the monomeric unit. Examples of such polymeric-type compounds are di-, oligo- and polysaccharides bis (benzylisoquinoline) and other dimeric alkaloids biflavonoids and polypeptides. Series of natural products having essentially the same carbon skeleton but known in a variety of stereochemical types due to epimerism at one or more chiral centres are frequently covered by general notes rather than by large numbers of examples. This treatment is given, for example, to the labdane-type diterpenes and the yohimbane-type alkaloids. 

The labdane-, pimarane- and kaurane-type diterpenoids so far isolated from the Hepaticae belong to the -series while higher plants produce both normal and /-labdanes, pimaranes and kauranes. 

MacMillan and Beale, 1999). This raises interesting questions for the biosynthesis because the marine plants preceded the terrestrial plants. The labdane derivatives of the two series have many biological properties which include antibacterial, antifungal, anti-inflammatory, anti-parasitic, cytotoxic, and enzyme inhibition (Singh, Pal, and Sharma, 1999). 

A series of other labdane diterpenes isolated from various sources have also been reported to exhibit antimicrobial activity. Aulacocarpinolide and aulacocarpines A and B, labdane diterpenes isolated from the Cameroonian spice Aframonum aulacocarpos (Zingiberaceae), exhibited weak antibacterial activity against B. subtilis and fungus Mucur miehei [166],... 

Labdanes of the series of gomojosidae, isolated from the leaves of Viburnum suspensum (Caprifoliaceae) exhibited antibacterial activity against E.coli, Aeromonas salmonishida and B. subtillis [102]. Cryptotrienolic and isocupressic acid isolated from the bark of Juniperus procera were found to exhibit weak antibacterial activity when tested against B. subtillis, S. aureus, Str. durans, E. faecilis, and Mycobacterium... 

Leonurus cardiac (Labiatae) contains some diterpenoids which have been provisionally assigned clerodane structures such as (50). Diasin (51) is a c/5-labdane related to the clerodanes which has been isolated from Croton diasii (Euphorbiaceae). Its structure was determined by and C n.m.r. spectroscopy. A series of furanoid nor-diterpenoids has been isolated from Dioscorea bulbifera (Dioscoreaceae). The structures of the diosbulbins D, E, F, G, and H, (52)—(56), were determined" by a series of spectral and chemical studies and that of diosbulbin G (55) was confirmed" by an X-ray analysis. 

TI165 and TI 1396 produce duvane diterpenes and/or labdane diterpenes and/or sucrose esters (See Figures 1 and 2 for structures and References 5,7 and 8 for capillary gas chromatograms). The tobacco introductions with simple trichomes, TI 1112,1-35, and those with nonsecreting glandular trichomes, TI 1024 and TI 1406, produce low levels of diterpenes and sucrose esters. The cuticular extracts of all N, tabacum plants studied, independent of trichome type, contained a series of aliphatic hydrocarbons... 

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