Background

I do not know what I may appear to the outside world, but to myself I seem to have been like a boy playing on the sea-shore, and diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me.

Isaac Newton

Using a simple five carbon building block, nature creates an array of terpenoid chemicals with an infinite variety of structural variation and vast range of biological functions. Such a cornucopia cannot but leave the terpene chemist feeling as Newton did.

KEY POINTS

The simple isoprene unit is the basis of an enormous range and a variety of chemical structures which we know as terpenoids.

In nature, terpenoids serve a variety of purposes including defence, signalling and as key agents in metabolic processes.

Terpenoids have been used in perfumery, cosmetics and medicine for thousands of years and are still extracted from natural sources for these uses.

1.1 DEFINITIONS AND CLASSIFICATION

Plants and animals produce an amazingly diverse range of chemicals. Most of these are based on carbon and so the chemistry of carbon came to be known as organic chemistry, i.e. the chemistry of living organisms, the chemistry of life. These chemical products of plants and animals can be classified into primary and secondary metabolites. Primary metabolites are those which are common to all species and can be sub-divided into proteins, carbohydrates, lipids and nucleic acids. These four groups of materials are defined according to the chemical structures of their members. The secondary metabolites are often referred to as "natural products". These can be sub-divided into terpenoids, alkaloids, shikimates and polyketides. This classification is based on the means by which the materials were made. These synthesis routes are referred to as biosynthetic or biogenetic pathways.

Individual secondary metabolites may be common to a number of species or may be produced by only one organism. Related species often have related patterns of secondary metabolite production and so a species can be classified according to the secondary metabolites they produce. Such a classification is known as chemical taxonomy. Occasionally, two plants are found to have identical physical aspects which botanists use for classification, but differ in the secondary metabolites they produce. For example, two flowers may look identical but one is odourless whilst the other possesses a strong scent due to the production of a fragrant terpenoid chemical. Such different strains are known as chemotypes.

Terpenoids are defined as materials with molecular structures containing carbon backbones made up of isoprene (2-methylbuta-1,3-diene) units. Isoprene contains five carbon atoms and therefore, the number of carbon atoms in any terpenoid is a multiple of five. Degradation products of terpenoids in which carbon atoms have been lost through chemical or biochemical processes may contain different numbers of carbon atoms, but their overall structure will indicate their terpenoid origin and they will still be considered as terpenoids.

The generic name "terpene" was originally applied to the hydrocarbons found in turpentine, the suffix "ene" indicating the presence of olefinic bonds. Each of these materials contain two isoprene units, hence ten carbon atoms. Related materials containing 20 carbon atoms are named as diterpenes. The relationship to isoprene was discovered later, by which time the terms monoterpene and diterpene were well established. Hence the most basic members of the family, i.e. those containing only one isoprene unit, came to be known as hemiterpenoids. Table 1.1 shows various sub-divisions of the terpenoid family based on this classification. It also shows two specific sub-groups of terpenoid materials, namely, the carotenoids and the steroids. Steroids and carotenoids are sub-groups of the triterpenoids and tetraterpenoids, respectively, as will be explained later.

Occasionally, the word terpene is used to indicate any terpenoid. In this book, the word terpene will be restricted to its original meaning. Similarly, the term "isoprenoid" is often used in place of "terpenoid."

1.2 THE ISOPRENE RULE

The isoprene rule, proposed by Wallach in 1887, defines terpenoids as chemicals containing a carbon skeleton formed by the joining together of isoprene units. Isoprene, the "building block" of terpenoids, is 2-methylbuta- 1,3-diene. If we look at the parent 2-methylbutane, we could consider the molecule to resemble a nanoscalar tadpole with a "head" at the branched end of the molecule, the other end therefore constituting the "tail." Thus, in principle, two isoprene units could be joined head-to-head, tail-to-tail or head-to-tail. By far the commonest fusion is head-to-tail. Figure 1.1 shows two isoprene units being joined head-to-tail to produce a monoterpenoid backbone. Occasionally, a tail-to-tail coupling occurs. This is a characteristic feature of steroids and carotenoids. In both of these classes, there is a tail-to-tail fusion exactly in the centre of the backbone, the other joins being head-to-tail type. The hypothetical head-to-head fusion does not occur.

After formation of the basic C5n skeleton, the chain may be folded to produce rings and functionalised by the introduction of oxygen or other heteroatoms. Figure 1.2 shows how the isoprene units and the original backbone can be traced out in three simple terpenoids. Occasionally, skeletal rearrangements occur which make this process more difficult and fragmentation or degradation reactions can reduce the number of carbon atoms so that the empirical formula does not contain a simple multiple of five carbons. Nonetheless, the natural product chemist will still quickly recognise the characteristic terpene framework of the structure. Sometimes molecules contain both terpenoid fragments and fragments from other biogenetic classes.

1.3 TERPENOID NOMENCLATURE

The terpenoids are divided into groups and sub-groups according to the pathway by which nature synthesised them and hence, by their skeletal structures since these arise directly from the biosynthesis. As described above, the first basis for classification is the number of isoprene units which make up the terpenoid. The names for these groups are shown in Table 1.1. The next classification depends on whether the skeleta remain as open chains or have been cyclised giving one, two or more rings. Families of terpenoids possessing the same skeleton are named after a principal member of that family, usually either the most common or the first to have been discovered. Charts of these names are given in Devon and Scott's dictionary. To name an individual terpenoid, it is customary to use the IUPAC or CAS systems of nomenclature. However, it is often more convenient to use either a trivial name or a semi-systematic name derived from the terpenoid structural family to which the material in question belongs. The trivial names often relate to a natural source in which the terpenoid occurs.

As an example of the co-existence of systematic, semi-systematic and trivial names, we could look at the monoterpenoid ketone, carvone. Carvone occurs in both enantiomeric forms in nature, the laevo-form in spearmint and the dextro-form in caraway. The trivial name carvone is derived from the Latin name for caraway, Carum carvi. The basic carbon skeleton is that of 1-isopropyl-4-methylcyclohexane. This skeleton is very common in nature and is particularly important in the genus Mentha, which includes various types of mint, since it forms the backbone of most of the important components of mint oils. The skeleton has therefore been given the name p-menthane and the numbering system used for it is shown in Figure 1.3. Therefore, any of the following names may be used to describe the same molecule: carvone, p-mentha-1,8-dien-6-one and 1 -methyl-4-( 1 -methylethenyl)cyclohex-1 -ene-6-one. To classify it, we could say it was an unsaturated ketone of the p-menthane family of monoterpenoids.

Greek letters are used in various ways to distinguish between isomeric terpenoids. They may indicate the order in which the isomers were discovered or their relative abundance in the oil. For instance, α-pinene is the most significant component of turpentine, usually comprising almost three quarters of the oil by weight. The next most significant component is β-pinene. These structures are shown in Figure 1.4.

In the case of cyclic terpenoids, the letters α, β and γ often refer to the location of the double bond in isomeric olefins. In these cases, the letter α indicates an endocyclic trisubstituted double bond, β refers to a tetrasubstituted olefinic bond and γ to an exocyclic methylene function. Generic structures are shown in Figure 1.5 along with the examples of the isomeric ionones and patchoulenes.

1.4 THE ROLE OF TERPENOIDS IN NATURE

Terpenoids are produced by a wide variety of plants, animals and microorganisms. As for all metabolites, the synthesis of terpenoids places a metabolic load on the organism which produces them and so, almost invariably, there is a role which the material plays and for which it is synthesised. The roles which the terpenoids play in living organisms can be grouped into three classes: functional, defence and communication.

Figure 1.6 shows some examples of what is meant by functional terpenoids, i.e. those that play a key part in the metabolic processes of the organism in which they are produced. Vitamin A, or retinol, is the precursor for the pigment in eyes which detects light and is therefore responsible for the sense of sight. Vitamin E, or tocopherol, is an important antioxidant which prevents oxidative damage to cells. Vitamin D2, also known as calciferol, regulates calcium metabolism in the body and is therefore vital for the building and maintenance of bone. Chlorophyll-a is a green pigment found, for example, in plant leaves and is a key factor of photosynthesis through which atmospheric carbon dioxide is converted to glucose.

There are a number of ways in which plants and animals use terpenoid chemicals to protect themselves. Probably the two commonest methods are the production of resins by plants which have been damaged and the production of materials which will render a plant or animal unattractive to predators.

Many plants, when damaged, exude resinous materials as a defence mechanism. Rosin is produced as a physical barrier to infectious organisms, by pine trees when the bark is damaged. Similarly, rubber is a defensive secretion. The shrub Commiphora abyssinica produces a resin which contains a number of antibacterial and antifungal compounds. One of these is the eudesmane derivative (l.l), which is shown in Figure 1.7. The role of the resin is to seal the wound and prevent bacteria and fungi from entering and damaging the plant. The resin has a pleasant odour and so was put to use by man as a perfume ingredient. It is known as myrrh. Because of its antimicrobial properties, myrrh was also used as an antiseptic and preservative material, for instance, in the embalming of corpses, Frankincense, derived from trees of the genus Boswellia, is another such resin and has been used in religious rites for thousands of years. Thus, two of the three gifts brought to the Christ Child by the magi were perfume ingredients containing terpenoids. Knowledge of terpenoids thus helps us to understand the symbolism involved; gold, frankincense and myrrh represent, respectively, king, priest and sacrifice.

Bufotalin, also shown in Figure 1.7, is a cardiac glycoside which functions as a heart stimulant. It is produced by toads in order to prevent other animals from preying on them; would be predators soon learn that toads do not make good food. Similarly, many plants produce terpenoids making them unpalatable to insects which would otherwise eat their foliage. Two examples are shown in Figure 1.7. The first is azadirachtin which is produced by Melia azadirachta and also by the Indian neem tree, Azadirachta indica. The other is warburganal which is produced by plants of the genus Warburgia. Warburganal contains two aldehyde functions and one of these is α, β-unsaturated. Thus, it is capable of undergoing triple alkylation of nucleophilic materials such as the nitrogen atoms of proteins and nucleic acids. This property makes it a skin sensitiser (i.e. a material which can induce an allergic reaction in some subjects upon repeated exposure) and carcinogen. It is therefore a doubly effective deterrent because of its unpleasant taste and high toxicity. In the figure, the arrows indicate the three potential sites of nucleophilic attack.

Terpenoids are also used as chemical messengers. If the communication is between different parts of the same organism, the messenger is referred to as a hormone. Examples of hormones are shown in Figure 1.8. Giberellic acid is a hormone used by plants to control their rate of growth. Testosterone and oestrone are mammalian sex hormones. Testosterone is a male hormone and oestrone, a female.

Chemicals that carry signals from one organism to another are known as semiochemicals. These can be grouped into two main classes. If the signal is between two members of the same species, the messenger is called a pheromone. Pheromones carry different types of information. Not all species use pheromones. In those which do, some may use only one or two pheromones while others, in particular the social insects such as bees, ants and termites, use an array of chemical signals to organise most aspects of their lives.

Sex pheromones are among the most widespread. Male moths can detect females by smell at a range of many miles. Some terpenoid pheromones are shown in Figure 1.9. Androst- 16-en-3-01 is a porcine sex pheromone and the compound which produces "boar taint" in pork. (Boar taint is a flavour found in the meat of boars but not of sows.) It is produced by boars and is released in a fine aerosol when the boar salivates and champs his jaws. When the sow detects the pheromone in air, she immediately adopts what is known as "the mating stance'' in readiness for the boar. Grandisol is a sex attractant for the male boll weevil, a serious pest for cotton growers.

Ants and termites use trail pheromones to mark a path between the nest and a food source. This explains why ants are often seen walking in single file over long distances. One such trail pheromone is neocembrene-A which is produced and used by termites of the Australian species Nasutitermes exitiosus. The social insects also use alarm, aggregation, dispersal and social pheromones to warn of danger and to control group behaviour. For example, d-limonene is an alarm pheromone of some Australian termites and lineatin is the aggregation pheromone of Trypodendron lineatum. So, exposure to these two terpenoids will produce opposite reactions in their target species, repulsion in the first case and attraction in the second.

Chemicals which carry messages between members of different species are known as allelochemicals. Within this group, allomones benefit the sender of the signal, kairomones its receiver and with synomones both the sender and receiver benefit. Examples are shown in Figure 1.10.

Camphor and d-limonene are allomones in that the trees which produce them are protected from insect attack by their presence. For instance, Arthur Birch, one of the great terpene chemists of the twentieth century, reported finding d-limonene in the latex exuded by trees of the species Araucaria bidwilli. These trees are protected from termite attack because the d-limonene they produce is an alarm pheromone for termites that live in the same area. Similarly, antifeedants could be considered to be allomones since the signal generator, the plant, receives the benefit of not being eaten. Myrcene is a kairomone, in that it is produced by the ponderosa pine and its presence attracts the females of the bark beetle, Dendroctonous brevicomis. Geraniol is found in the scent of many flowers such as the rose. Its presence attracts insects to the flower and it can be classified as a synomone since the attracted insect finds nectar and the plant obtains a pollinator.

One terpenoid which has an unusual signalling property is nepetalactone. This is actually a mixture of two isomers, as shown in Figure 1.11, the major being the trans,trans-isomer (1.2) and the minor the trans,cis-isomer (1.3). Nepetalactone is the principal component of the oil of catnip or cat mint (Nepeta cataria), constituting 70-90% of the oil. It is an insect repellent, which is probably why the plant produces it. However, it has a surprising effect on all felines, from domestic cats to lions and tigers, in that it induces grooming and rolling behaviour in them. This is probably purely coincidental as it is hard to see what benefit this would be to the plant.

1.5 EXTRACTION AND USE OF TERPENOIDS

Many commercial uses of terpenoids reflect their natural uses. Those that are produced in nature because of their biological activity may well find commercial use as drugs or pest control agents. For example, α-santonin (see Chapter 7 for some of its interesting chemistry) is extracted from Levant wormseed, Artemisia maritima, for use as an anthelmintic. The poisonous nature of foxglove is due to the presence of terpenoid glycosides which have strong stimulant action on heart muscle. Digitoxin is a glycoside of digitoxigenin and is extracted from foxglove for use in treatment of certain heart conditions. The odorous terpenoids are, of course, used as fragrance ingredients in cosmetics, toiletries and household products. Cineole, extracted from various eucalyptus species, serves both purposes since it is used in perfumery as well as a nasal decongestant. (Figure 1.12)