Cyclic diterpenoids

Sideritis (Labiatae) have been a rich source of novel bi- and tetra-cyclic diterpenoids. Andalusol (10), which has been isolated from S. arborescens, was assigned the ent-labdane configuration. Its structure was deduced by a combination of spectroscopic measurements and an X-ray analysis of the degradation product (11). 

The synthesis of perhydrophenanthrenes related to tri- and tetra-cyclic diterpenoids has continued to be an active area.167 Compound (94) has been synthesized as a possible intermediate for the synthesis of cafestanone.168 A synthetic approach to diterpenoids with an abnormal trans-syn ab ring junction [e.g. (95)] has been described.169 The syntheses of 13-methoxypodocarpatrien-19,20-dioic acid170 and the ll-hydroxyabieta-2,8,11,13-tetraen-l-one,171 isomeric with shonanol, have been described. 

The diterpenoids are a large and ubiquitous family of isoprenoids derived from 2E,61% ] 0 -geranylgeranvl pyrophosphate. Of all the families of natural products, the diterpenoids have one of the widest ranges of biological activity. The clearest classification of the cyclic diterpenoids (abietane, labdane, clerodane,...) is based on biogenetic considerations. The variety of structural types found amongst the diterpenoids has led to their use as phytochemical markers. Indeed, many of the diterpenoids found in recent years have been isolated in the course of phytochemical surveys of the Compositae. 

The biosynthesis of enmein (62) and oridonin (32), the major bitter principles in the leaves of Rabdosia japonica, has been investigated by E. Fujita and coworkers. It is thought to proceed by a pathway similar to that for cyclic diterpenoids in general, with e r-16-kaurene (116) as an important precursor. A biogenetic pathway and a classification of the Rabdosia diterpenoids based on the biogenesis were proposed 123). 

Fig. 111. Synthesis of cyclic diterpenoids from (+)-labdadienyl pyrophosphate...

Diterpenoids refer to those compounds having a two consecutive terpenoid structure (20Q, usually in crystal state. They can be classified into two subgroups acyclic and cyclic diterpenoids, for example, phytol (a naturally linear diterpenoid used in preparation of vitamin E and Kl) and vitamin A (monocyclo-diterpenoid rich in fish oil). The most important diterpenoids in terms of bioactivities are dicyclo- and tricycle-diterpenoids, such as paclitaxel (Taxol) (details please see in Sect. 4.3 of this chapter below) and its analog docetaxel (Taxotere) for various cancer treatment, and ginkgoUdes against the aggregation of platelet. 

Most abundant are instead cyclic diterpenoids that originate by cyclization reactions of GGPP from both sides of the molecule tail (alcohol end) or head (isopropyhdene end). Cyclization generally involves carbocations and proceeds by a concerted addition mechanism generating different cyclic systems, due to the folding of the acyclic substrate chain on the specific enzyme and originating rich and wide array of cyclic systems [6]. 

Taking advantage of such biosynthetic abilities, Hanson s group has systematically investigated the biotransformation by C. aphidicola of some (more or less) related cyclic diterpenoids such as kaurane [63-65] or stemodane [66] derivatives. Interestingly, with most kaurane derivatives, the current hydroxylation at C-3 observed with the natural substrate was inhibited, but various other positions can be hydroxylated, including the 113, 16a, and 17 positions (Fig. 5), the later probably after the reduction of the 16,17 double bond took place. 

These diterpenoids, although not cyclic polyethers, do contain several oxygen functional groups and may assume conformations which could favor the formation of such complexes. 

Vitexilactone, obtained from Vi tex cannabifolia (Verbenaceae), has been shown to have the structure (16). It has been correlated with rotundifuran. An interesting iron(ii)-catalysed decomposition of unsaturated cyclic peroxides derived from butadienes leads to 3-alkylfurans. This procedure has been used to convert the peroxide (17) from ds-biformene into the furan (18). Some diterpenoid furans are amongst the constituents of Austroeupatorium inulaefolium (Compositae). These include the diketone austrofolin (19), the corresponding 12-alcohol, and the 15-alcohol (20). A triol, austroinulin (21), was also identified. 

IPP and DMAPP lead to geranylpyrophosphate (GPP), which is an immediate precursor of monoterpenes. The formation of nerylpyrophosphate (NPP) from GPP gives rise to a wide range of acyclic, cyclic, bicyclic or tricyclic skeletons. Reactions like rearrangement, oxidation, reduction and hydration via various terpene cyclases result in the formation of numerous terpene derivatives. Condensation of GPP and IPP leads to farnesylpyrophosphate (FPP), the immediate precursor of sesquiterpenoids. Likewise, FPP and IPP are conducive to diterpenoids. 

The Chemistry of Ringc.—The modification of ring c has centred on making available relays that are suitable for elaboration into more complex diterpenoids, the diterpenoid alkaloids, and triterpenoids. The unsaturated ketone (53) has proved to be a valuable relay for synthesis. It had been prepared previously from neoabietic acid, which is difficult to obtain pure. It has now been obtained from the levopimaric acid-formaldehyde adduct (50). Oxidation of the adduct with potassium permanganate not only formed the glycol but in an unusual step converted the cyclic ether into the (5-lactone (51). Dehydration, ozonolysis of the newly formed double bond, and then treatment of the keto-acetate (52) with chromous chloride afforded the a -unsaturated ketone (53). The last step involved hydrogenolysis, / -elimination. and decarboxylation. 

Analysis of tricyclic alkanes has been less reported in the literature, in comparison with mono-, di-, tetra- and penta-cyclics. However, since we intend to review also separation of fossil fuels, we have to mention compounds such as fichtelite (C19H34) and other diterpenoid tricyclics derived from abietic acid. Abietic acid and levopimaric acid belong to the resin acids, which exude from incisions of bark or trunk of high plants. The derived hydrocarbons, such as fichtelite, were found in the saturated fraction of peat bed extractions. The identification and structure elucidation of fichtelite was based on m.p. 46.5 °C and optical activity [a]D = 18°, as well as on its resistance to chemical attack... 

The biosynthesis of kaurane diterpenoids shown in Scheme 102.6a starts from the cyclic carbocation formed by cyclization of copalyl PP. 

Although the number of aroma compounds derived from acyclic carotenoids is much inferior to that of the mono- and bicyclic compounds, some of them can also be considered as breakdown products from genuine mono-, sesqui- and diterpenoids. The importance of the aliphatic isoprenoids (282) to (291) in the formation of total flavors of certain foodstuffs is not less than that of the cyclic compounds, the three methyl ketones (282), (287) and (290) which are related to the main tomato pigment lycopene were observed in tomato flavor (75). The hexahydro derivative (291) from coffee (595), jasmine oil (722) and green tea 438) is perceived as flowery and warm and can be considered as an oxidative biodegradation product of phytol and phyta-diene. 6-Methyl-3,5-heptadien-2-one (283), with a grassy and cinnamonlike aroma 438) [detected in tomato 668), the essential oil of Hama-metis leaves 383), Ceylon tea (722) and passion fruit (777)], and pseudo-ionone (288) [also isolated from passion fruit (777)] are believed to be formed from two different dehydrolycopenes. Compounds other than carotenoids, such as solanesol or squalene, can also be considered... 

Many diterpenoid alcohols are cyclic compounds occurring as free substances, but also as fatty acid esters or glycosides. The toxicity of latex of many plant species from the spurge family (Euphorbiaceae) is caused by the presence of phorbol esters such as 13-acetyl-12-myristoyl-phorbol. Cafestol, kahweol (8-25) and related diterpenoids (16-O-methylcafestol, 16-0-methylkahweol and other compounds) are found in green coffee Coffea spp., Rubiaceae) beans (mainly esterified to fatty acids at the C-16 or C-17 position) and unfiltered coffee prepared from roasted coffee seeds, such as Turkish coffee. Kahweol is specific to C. arabica coffee, where it occurs in concentrations of about 5890 mg/kg of fresh weight and 5200 mg/kg in the endosperm and perisperm, respectively, while 16-O-methylcafestol occurs only in robusta coffee (C. canephora). The amount of cafestol in C. arabica is about... 

Allenes have been added to many cyclic a,/8-unsaturated ketones to give methylenecyclobutane derivatives. The stereochemistry of such additions has been rationalized by Wiesner, who has used the method extensively in the synthesis of diterpenoid alkaloids. For example, the synthesis (Scheme 10) of talatisamine (39) involved the cycloaddition of allene to the enone (35) to give the photoadduct (36) which was converted into the masked aldol (37). Retro-aldol reaction followed by another aldol cyclization gave (38) which was converted into talatisamine (39). Intramolecular photocyclizations of appropriate allenic enones can also be expected to be synthetically useful. The formation of (41) from (40) in high yield is a promising reaction. A closely related process is the cyclization of (42) to (43) (Scheme 11). ... 

---