Diterpenes

Diterpenes comprise four isoprene residues. They are either aliphatic substances or in most cases tri- or tetracyclic compounds, which may be substituted by different functional groups. Some diterpenes contain nitrogen (diterpene alkaloids, see the formula of aconitine). 

Diterpenes formed from geranylgeranyl pyrophosphate occur in microorganisms, plants, and animals. In addition diterpenes may be derived from tetraterpenes in animals and plants. Diterpene alkaloids are found in higher plants only. 

The key product in the formation of most diterpenes is geranylgeranyl pyrophosphate (for formation from carotenoids see D 6.5). Important reactions in its transformation are hydrolysis of the pyrophosphate group, reduction of double bonds, and cyclization. 

Of significance is the transformation of geranylgeraniol to phytol, which is a constituent of chlorophylls (D 10.1). Phytol is also the precursor of phytane and pristane. Both compounds are widespread constituents of lake and river sediments and have been detected even in precambrian fossils. They have the stereochemistry of phytol in recent sediments, but are more or less epimerized in older sediments. 

Cyclization of geranylgeranyl pyrophosphate may proceed in different ways  

As was illustrated in the first survey, all known halogenated terrestrial diterpenes are chlorohydrins (1), and that continues to be mainly the case. Obviously, one must be alert to the possibility of artifact formation from ring opening of the corresponding epoxide during isolation. Many nonhalogenated terrestrial diterpenoids also continue to be isolated (622). 

The Brazilian plant Vellozia bicolor contains the isopimarane diterpene 12-chloroillifunone C (436). The corresponding epoxide, which is also found in this plant, is not converted to 436 under the isolation conditions (623). Teuracemin (437), a novel weo-clerodane diterpene, was isolated from Teucrium racemosum and is the 7-hydroxy derivative of the known tafricanin A (624). Examination of fresh plant material revealed the presence of 437. The new weo-clerodane ajugarin-I chlorohydrin (438) has been characterized from the Indian plant Ajuga parviflora 

The novel chloroenone quassinoid eurycolactone B (444) was characterized from the roots of Eurycoma longifolia from Malaysia (629). This is the first halogenated quassinoid discovered in a plant. A series of norditerpene dilactones, including the chlorinated rakanmakilactones E (445), G (446), and 447, were isolated from the leaves of Podocarpus macrophyllus from Japan (630, 631). These represent the first halogenated norditerpene dilactones found in the Podocarpaceae. 

In contrast to the small number of known halogenated (chlorinated) terrestrial diterpenes (vide supra), the number of marine diterpenes is very large, and more than 130 were documented in the initial survey (7). 

Gorgonians produce the largest complement of chlorine-containing marine metabolites - more than 50 were illustrated in the first survey (7) - and many more nonchlorinated gorgonian diterpenes are known (665-667). There is evidence to indicate that these gorgonian diterpenoids are feeding deterrents to reef fishes. Gorgonian corals can achieve densities of up to 20 colonies per square meter on the reef (668, 669). 

The two novel acyclic diterpenoids (241) and (242) have been isolated 

Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada 

Diterpenes are among the most abundant terpenoids on the planet. Although significant advancements have been made, the biosynthesis of diterpenes is not fully elucidated. In this chapter, a general overview of the biosynthesis of diterpenes and selected applications of pericyclic reactions for the synthesis of complex diterpenes will be presented. 

2 BIOSYNTHESIS OF DITERPENES BASED ON CATIONIC CYCLIZATIONS, 1,2-SHIFTS, 

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products, First Edition. Edited by Alexandres L. Zografos. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

SCHEME 8.1 Biosyntheses of casbene and cembrane and postulated biosyntheses of some complex members of deterpenoids. 

Only one example of a true diterpenoid compound has so far been reported from sponges. It has been isolated from Spongia officinalis (45) from which a number of linear furanoterpenes containing 21 and 25 carbon atoms have also been obtained (see pages 23 and 28). 

The new diterpene, named isoagatholactone, proved to be the first naturally occurring compound with the carbon skeleton of isoagathic acid, the acid-catalyzed cyclization product of agathic acid (30, 159). Structure (63) for isoagatholactone without sterical implications was suggested 

Chart 7. Chemical correlation of isoagatholactone with grindelic acid 

Linear, closely-related, difuranoterpenes containing 21 carbon atoms have been found to occur in large amount in the sponges of the genus Spongia. All of them possess the same carbon skeleton (67), and oxidation in the central chain account for all their differences. 

Structure (69) assigned to the minor constituent dihydronitpnin, an oil, [a]D-25.2°, max 222 (s 5230) nm, Vmax 1765 cm S was deduced on spectral grounds and chemical interrelation with nitenin, which was accomplished by converting the latter to the former using sodium boro-hydride reduction. 

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C2oH4qO- a diterpenic alcohol obtained by the action of alkalis on chlorophyll. Colourless oil b.p. 202-204 C/lOmm. On oxidation it yields a ketone CigHsoO b.p. 175 "C/l I mm. phytoxic Poisonous to plants. 

The Gassman method has proven to be adaptable to complex structures, such as the intermediate 7.20B used in the synthesis of the indole diterpenes paspalicine and pasalinine[5]. Table 7.5 gives some other examples. 

A repetition of the process just shown produces the diterpene geranylgeraniol from farnesyl pyrophosphate... 

Cubitene is a diterpene present in the defense secretion of a species of African termite What unusual feature charactenzes the joining of isoprene units in cubitene" ... 

Terpenes (Section 26 7) Compounds that can be analyzed as clusters of isoprene units Terpenes with 10 carbons are classified as rnonoterpenes those with 15 are sesqmter penes those with 20 are diterpenes and those with 30 are tnterpenes... 

Whereas dimerization of two famesyl pyrophosphates (35) generates squalene (114) on the path to steroids (89), the addition of one more C unit, as isopentenyl pyrophosphate (31) or its isomer, 3,3-dimethyl ally pyrophosphate (32), to the C compound famesyl pyrophosphate produces the C2Q diterpene precursor geranylgeranyl pyrophosphate [6699-20-3] (122). 

This C2Q pyrophosphate (122), thought to provide the carbon framework of the diterpene alkaloids such as veatchine (123), atisine (124),... 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

The isoprene unit exists extensively in nature. It is found in terpenes, camphors, diterpenes (eg, abietic acid), vitamins A and K, chlorophyll, and other compounds isolated from animal and plant materials. The correct stmctural formula for isoprene was first proposed in 1884 (7). 

Stevioside and rebaudioside A are diterpene glycosides. The sweetness is tainted with a bitter and undesirable aftertaste. The time—intensity profile is characteristic of naturally occurring sweeteners slow onset but lingering. The aglycone moiety, steviol [471 -80-7] (10), which is the principal metaboHte, has been reported to be mutagenic (79). Wide use of stevia ia Japan for over 20 years did not produce any known deleterious side effects. However, because no food additive petition has been presented to the FDA, stevioside and related materials caimot be used ia the United States. An import alert against stevia was issued by the FDA ia 1991. In 1995, however, the FDA revised this import alert to allow the importation and use of stevia as a diet supplement (80), but not as a sweetener or an ingredient for foods. Several comprehensive reviews of stevia are available (81,82). 

Terpenes are characterized as being made up of units of isoprene in a head-to-tail orientation. This isoprene concept, invented to aid in the stmcture deterrnination of terpenes found in natural products, was especially useful for elucidation of stmctures of more complex sesquiterpenes, diterpenes, and polyterpenes. The hydrocarbon, myrcene, and the terpene alcohol, a-terpineol, can be considered as being made up of two isoprene units in such a head-to-tail orientation (1). 

Dlterpenes. Diterpenes contain 20 carbon atoms. The resin acids and Vitamin A are the most commercially important group of diterpenes. GibbereUic acid [77-06-5] (110), produced commercially by fermentation processes, is used as a growth promoter for plants, especially seedlings. 

Wood is the raw material of the naval stores iadustry (77). Naval stores, so named because of their importance to the wooden ships of past centuries, consist of rosin (diterpene resin acids), turpentine (monoterpene hydrocarbons), and associated chemicals derived from pine (see Terpenoids). These were obtained by wounding the tree to yield pine gum, but the high labor costs have substantially reduced this production in the United States. Another source of rosin and turpentine is through extraction of old pine stumps, but this is a nonrenewable resource and this iadustry is in decline. The most important source of naval stores is spent sulfate pulpiag Hquors from kraft pulpiag of pine. In 1995, U.S. production of rosin from all sources was estimated at under 300,000 metric tons and of turpentine at 70,000 metric tons. Distillation of tall oil provides, in addition to rosin, nearly 128,000 metric tons of tall oil fatty acids annually (78). 

Chemistry of rosin. All three types of rosin consist primarily of C20 mono-carboxylic diterpene resin acids, the most common of which have the molecular formula C20H20O2. In addition, rosins contain small amounts of neutral and other acidic components (e.g. fatty acids in tall oil rosin). The neutral components of rosins are diterpene alcohols, hydrocarbons and aldehydes, and their contents generally vary between 5 and 15 wt%. 

Fig. 7. Principal nionocarboxylic diterpene acids skeletons in rosins. Dotted line indicates that the chemical group is located below plane (see p. 266 in 118]).

The assumption of these conjugated double bonds makes possible a tetracyclic nucleus which accords with the suggestion previously made by the authors that these alkaloids might be structurally related to the diterpenes. It may also be noted that one of the nitric acid oxidation products of pseudaconitine has been recorded as unexpectedly giving a pyrrole reaction on destructive distillation. ... 

The exchange of aromatic protons can be effected in the absence of any -OH or —NH2 activating group during the course of a Clemmensen reduction in deuteriochloric and deuterioacetic acid mixture (see section Ill-D). This reaction has been carried out with various tricyclic diterpenes and is best illustrated by the conversion of dehydroabietic acid into its 12,14-d2-labeled analog (40 -+ 41).Amalgamated zinc is reportedly necessary for the exchange reaction since the results are less satisfactory when a zinc chloride-mercuric chloride mixture is used. 

While no examples were encountered in the steroid field which utilize this technique, it is well documented in the case of diterpenes. Ferruginol-3-one (79), for example, gives a hexadeuterio product (80) which after back... 

Deuteration of a Diterpene Carbonyl Compound by Clemmensen Reduction... 

Deuteration of a diterpene carbonyl compound by Clemmensen reduction, 170... 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

The selective bromination of a ketone in the presence of another susceptible functional group was achieved in a diterpene synthesis 240). A competing bromination of an anisole ring could be avoided here through the use of a pyrrolidine enamine derivative for activation of the methylene group adjacent to the carbonyl function. 

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