Manoyl oxide from

Some new diterpenoid oxides have been obtained from Eupatorium jhanii. They are jhanol (12) and its 18-acetate together with jhanidiol (13) and its 18-monoacetate and diacetate. Their structures were established by correlation with manoyl oxide and by an examination of their C n.m.r. spectra. 11/3-Hydro-xymanoyl oxide (14) has been isolated from Juniperus oxycedrus ° A group of new 11-oxomanoyl oxide derivatives (15a—e) has been obtained from Coleus forskohlii (Labiatae). Their oxygenation pattern is reminiscent of that of the tricyclic diterpenoids which have beemobtained from other Coleus species. 

Various other biologically active diterpenes have been isolated from plants and are used by man for the treatment of a variety of diseases. The bark of Pinus strobus (Pinaceae), rich in diterpenes, among them manoyl oxide, is used in anticough syrups, whilst traditionally it has been used for the treatment of coughs, colds, congestion, injury, rheumatism and swelling by Indian Americans [26], The antiinflammatory and antimicrobial activity of various diterpenes has been reported [27], as well as anti-fungal activity [28] and remarkable cytotoxic activity for some of them [27,29],... 

The aerial parts of Conyza steudellii (Asteraceae) have given new labdane xylosides, while from the leaves of Conyza trihecatactis, a xylopyranoside of 13-epi-sclareol has been isolated among other labdanes [104,105]. Havardic acids A-F (as methyl esters), have been isolated from another genus of the Asteraceae family, i.e Grindelia havardii [106]. 11-oxo-manoyl oxide derivatives and coleosol, which is also a manoyl oxide derivative, have been obtained from Coleus forskohlii (Labiateae) [107,108] while from another plant of the Labiatae family, Roylea calycina a tumor inhibitory compound, namely precalyone, as well as calyone have been isolated [109]. 

Ent -3p-hydroxy 13-epi-manoyl oxide (7) (ribenol), Fig. (7), has been used as starting material for a biotransformation process by Curvularia lunata. The in vitro micropropagation of the Sideritis foe tens species has been described and several entananoyl oxide derivatives, as well as other labdanes, have been isolated from micropropagated plants. Recently, biotransformation by Curvularia lunata of some en/-l 3-e/n-manoyl oxides functionalized at C-3 or C-3 and C-12 produced derivatives, which inhibited the growth of the pathogenic protozoa, Leishmania donovani [130],... 

Manoyl oxide (4), Fig. (7), has been isolated as a pure compound or identified via analytical techniques, in several plant species [33,44,63,137, 138,139]. Ohloff has shown that manoyl oxide can be prepared from sclareol [140]. The physical and chromatographic data of the synthetic and of the natural manoyl oxides have been compared and discussed [141]. Hodges and Reed have substantially contributed to the knowledge of the stereochemistry of manoyl oxide [141]. 

The study of manoyl oxide derivatives i.e. 7 and 8 in, Fig (7), (i.e ent-hydroxy and en/-acetoxy-3(3-manoyl oxides) isolated from Cistus creticus, by GC-MS resulted in only one peak indicative of the purity of the products [33]. From the H-NMR data it is clear that the 13-epi isomer was present in both derivatives [58,139]. The chromatographic data of the compounds 7 and 8 were recently published [33,63]. Hence, investigations have proven that, apart from the 13-epi isomer, there are more isomers with varying intensities, which correspond to isomers that arise from the different configuration of C-8 chiral center [33]. This isomer showing a different configuration at C-8 has been isolated from the volatile leaf oil of Alaska (yellow) cedar and its structure has been confirmed using spectroscopic methods as well as chemical reactions [150],... 

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]. 

Apart from forskolin, a number of other manoyl oxides have been shown to interact with the AC enzyme system. Biotransformation of certain ent- 3-epi-manoy oxides by Curvularia lunata resulted in compounds functionalized in C-3 or in C-3 and C-12, which exhibited an AC stimulatory effect, although milder than that of forskolin (about 30 times less) [173]. The same activity was also ascribed to some synthetic derivatives of en/-8a-hydroxy-13 (16), 14 dien-18-oic acid methyl ester [178,179], The biotransformation of ent-manoyl oxide-16-hydroxy 18-oic acid methyl ester with Rhizopus nigricans, however, resulted in carbomanoyl oxide which showed a selective inhibitory action on the activity of adenylate cyclase depending on the material initially used to stimulate the enzyme. This manoyl oxide inhibited the activity of the enzyme previously stimulated by forskolin but not by glucagon. A manoyl oxide ent-3fi, 6/ -dihydroxy-13-e/ z-manoyl oxide) which also inhibited the activity of AC, was produced from the biotransformation of... 

Calyone (27) and precalyone (28), the latter showing tumour inhibitory activity, have been isolated from Roylea calycina (Labiatae), and coleosol (29) is a manoyl oxide derivative which has been isolated from another of the Labiatae used in folk medicine. Coleus forskohlii ... 

X0-14-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... 

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. 

Labdane and pimarane type diterpenoids are rather rare in Turkish Sahna species, and only a few of these compounds have been obtained. Sclareol and manool were isolated from S. scktred. Manool was also obtained from S.limbaia, while manoyl oxide was reported from S. camlidissiiru/ together with 11 P-hydroxymanoyl oxide and 8,13-di-e/rr-manoyl oxide . Although these two compounds were... 

The oxidation of manool has been re-examined with the aim of producing ambergris-type perfumes. Oxidation with potassium permanganate afforded the known s methyl ketone (6), the diether (7), and at 40 °C the lactone (8). Sodium dichromate gave the aldehyde (9) as a mixture of E- and Z-isomers. Further oxidation of the methyl ketone with hypobromite gave an a-hydroxy-acid (10) and an ether (11) which was also obtained from manoyl oxide. Oxidation of the ketone with per-acid gave an acetoxy-epoxide which on reduction with lithium aluminium hydride afforded a diol. This was converted into an odoriferous ether (12). The ready formation of 5- and 6-membered-ring ethers of this type is a characteristic feature of this area of diterpenoid chemistry. 

Anticopalic acid has been found in the needles and wood of Pinus strobus and in the wood of Pinus monticola. The diterpenoid constituents of Juniperus phoenica include manoyl oxide, eperuene diol, labd-8-ene-l2-hydroxy-19-oic acid (13), sandaracopimaric acid, and 6a-hydroxysandaracopimaric acid. Imbricatalic acid (14) has been isolatedas its methyl ester from Pinus elliottii. 

This structure is apparently identical to a compound from Coespeletia lutescens named 3p-Hydroxy-13-epi-ent-manoyl oxide for which the published structure did not indicate a 13-epi-orientation.]... 

C-NMR studies of labdanes have focused in one instance on the normal-labdanes, manoyl oxide (272), manool (996), sclareol, and marrubiin (4), and in a second on the C-2/3- and C-3a-hydroxylated e/tMabdanes (424) reported from a non-Composite, Phlogacanthus thyrsiflorus. The results of the first study and other unpublished C-NMR findings for normal-labdanes were discussed in detail by Wehrli and Nishida (494). 

---