SUBJECT: CHEMISTRY OF NATURAL PRODUCTS �PAPER: (III) CH-523

Dr Sukhbir Kaur

1. Finar, I.L. Organic Chemistry, Vol. 2,
2. Aggarwal, O.P. Chemistry of Organic Natural Products, Vol. 1 & 2.

Terpenoids and Carotenoids

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• Classification
• Nomenclature, occurrence, isolation
• General methods of structure Determination
• Isoprene rule.
• Structure determination, Biosynthesis and synthesis of the following representative molecules
• Citral
• Terpeneol
• Farnesol
• Longifolene
• Phytol
• Abietic Acid
• Beta-Carotene

Introduction

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• Terpenoids form a group of naturally occurring compounds majority of which occur in plants, a few of them have also been obtained from other sources.
• Terpenoids are volatile substances which give plants and flowers their fragrance. They occur widely in the leaves and fruits of higher plants, conifers, citrus and eucalyptus.
• The term ‘terpene’ was given to the compounds isolated from terpentine, a volatile liquid isolated from pine trees.
• The term ‘terpene’ was originally employed to describe a mixture of isomeric hydrocarbons of the molecular formula C10H16 occurring in the essential oils from sap and tissue of plants, and trees. 
• But there is  a tendency to use more general term ‘terpenoids’ which include hydrocarbons and their oxygenated derivatives.
• By the modern definition: “Terpenoids are the hydrocarbons of plant origin of the general formula (C5H8)n  as well as their oxygenated, hydrogenated and dehydrogenated derivatives.”

• Classification of Terpenoids

Most natural terpenoid hydrocarbon have the general formula (C5H8)n. They can be classified on the basis of value of n or number of carbon atoms present in the structure

Each class can be further subdivided into subclasses according to the number of rings present in the structure.

i) Acyclic Terpenoids - They contain open structure.

ii) Monocyclic Terpenoids - They contain one ring in the structure.

iii) Bicyclic Terpenoids: They contain two rings in the structure.

iv) Tricyclic Terpenoids: They contain three rings in the structure.

v) Tetracyclic Terpenoids: They contain four rings in the structure.

Isoprene rule:

 Thermal decomposition of terpenoids give isoprene as one of the product. Otto Wallach pointed out that terpenoids can be built up of isoprene unit. Isoprene rule stats that the terpenoid molecules are constructed from two or more isoprene unit.

Further Ingold suggested that isoprene units are joined in the terpenoid via ‘head to tail’ fashion.

Special isoprene rule - States that the terpenoid molecule are constructed of two or more isoprene units joined in a ‘head to tail’ fashion.

Ingold (1921) pointed that a gem alkyl group affects the stability of terpenoids.

He summarized these results in the form of a rule called ‘gem dialkyl rule’ which may be stated as "Gem dialkyl group tends to render the cyclohexane ring unstable where as it stabilizes the three, four and five member rings.” This rule limits the number of possible structure in closing the open chain to ring structure. Thus the monoterpenoid open chain give rise to only one possibility for a monocyclic monoterpenoid i.e the p-cymene structure.

Isolation of mono and sesquiterpenoids

Both mono and sesquiterpenoids have common source i.e essential oils. Their isolation is carried out in two steps:

1. Isolation of essential oils from plant parts

ii) Separation of Terpenoids from essential oils.

i) Isolation of essential oils from plant parts:

The plants having essential oils generally have the highest concentration at some particular time. Therefore better yield of essential oil plant material have to be collected at this particular time. e.g. From jasmine at sunset. There are four methods of extractions of oils.

1. Expression method  b) Steam distillation method
3. Extraction by means of volatile solvents d) Adsorption in purified fats

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ii) Separation of Terpenoids from essential oil:

 A number of terpenoids are present in essential oil obtained from the extraction. Definite physical and chemical methods can be used for the separation of terpenoids. They are separated by fractional distillation. The terpenoid hydrocarbons distill over first followed by the oxygenated derivatives. More recently different chromatographic techniques have been used both for isolation and separation of terpenoids.

Steam distillation is most widely used method. In this method macerated plant material is steam distilled to get essential oils into the distillate form these are extracted by using pure organic volatile solvents. If compound decomposes during steam distillation, it may be extracted with petrol at 50 C. After extraction solvent is removed under reduced pressure.

General properties of Terpenoids

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1. Most of the terpenoids are colourless, fragrant liquids which are lighter than water and volatile with steam. A few of them are solids e.g. camphor. All are soluble in organic solvent and usually insoluble in water. Most of them are optically active.
2. They are open chain or cyclic unsaturated compounds having one or more double bonds. Consequently they undergo addition reaction with hydrogen, halogen, acids, etc. A number of addition products have antiseptic properties.
3. They undergo polymerization and dehydrogenation
4. They are easily oxidized nearly by all the oxidizing agents. On thermal decomposition, most of the terpenoids yields isoprene as one of the product.

Citral

 Citral is an acyclic monoterpenoid. It is a major constituent of lemon grass oil in which it occurs to an extent of 60-80%. It is pale yellow liquid having strong lemon like odour and can be obtained by fractional distillation under reduced pressure from Lemongrass oil.

Constitution:

i) Mol. formula C₁₀H₁₆O, b.p-77^oC

α‐Terpineol

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Farnesol

• Farnesol is present in many essential oils such as citronella, neroli, cyclamen, lemon grass, tuberose, rose, musk, balsam, and tolu.

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• It is used in perfumery to emphasize the odours of sweet, floral perfumes. It enhances perfume scent by acting as a co-solvent that regulates the volatility of the odorants. It is especially used in lilac perfumes.

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• Farnesol is a natural pesticide for mites and is a pheromone for several other insects.

Longifolene

Longifolene is a naturally occurring, oily liquid hydrocarbon found primarily in the high-boiling fraction of certain pine resins. The name is derived from that of a pine species from which the compound was isolated Pinus longifolia .

Chemically, longifolene is a tricyclic sesquiterpene. This molecule is chiral, and the enantiomer commonly found in pines and other higher plants exhibits a positive optical rotation of +42.73°. The other enantiomer (optical rotation −42.73°) is found in small amounts in certain fungi and liverworts.

• Longifolene is used in organic synthesis for the preparation of dilongifolylborane, a chiral hydroborating agent.
• Longifolene is also one of two most abundant aroma constituents of lapsang souchong tea, because the tea is smoked over pinewood fires. 

Longifolene total synthesis by Corey.

The biosynthesis of longifolene begins with farnesyl diphosphate (1) (also called farnesyl pyrophosphate) by means of a cationic polycyclization cascade. Loss of the pyrophosphate group and cyclization by the distal alkene gives intermediate 3, which by means of a 1,3-hydride shift gives intermediate 4. After two additional cyclizations, intermediate 6 produces longifolene by a 1,2-alkyl migration.

PHYTOL

Phytol (florasol, phytosol) is an acyclic diterpene alcohol that can be used as a precursor for the manufacture of synthetic forms of vitamin E and vitamin K1. In ruminants, the gut fermentation of ingested plant materials liberates phytol, a constituent of chlorophyll, which is then converted to phytanic acid and stored in fats.

Abietic acid

Abietic acid (also known as abietinic acid or sylvic acid) is an organic compound that occurs widely in trees. It is the primary component of resin acid, is the primary irritant in pine wood and resin, isolated from rosin (via isomerization) and is the most abundant of several closely related organic acids that constitute most of rosin, the solid portion of the oleoresin of coniferous trees. 

Retene, methyl isopropyl phenanthrene or 1-methyl-7-isopropyl phenanthrene, C₁₈H₁₈, is a polycyclic aromatic hydrocarbon

Synthesis of Abietic acid by Stork et al. (1956)

1. Methylation via pyrrolidine enamine
2. Ethyl vinyl ketone
3. Ethyl bromo acetate
4. Ethanedithiol / alkali
5. Raney Ni/hydrolysis/Pd-C
6. Barbier Weiland degradation

Barbier Weiland degradation

Beta-Carotene

Beta-Carotene is a naturally-occurring retinol (vitamin A) precursor obtained from certain fruits and vegetables with potential antineoplastic and chemopreventive activities. As an anti-oxidant, beta carotene inhibits free-radical damage to DNA. This agent also induces cell differentiation and apoptosis of some tumor cell types, particularly in early stages of tumorigenesis, and enhances immune system activity by stimulating the release of natural killer cells, lymphocytes, and monocytes. 

• Beta-carotene, with the molecular formula C40H56, belongs to the group of carotenoids consisting of isoprene units.
• B.P. - 633-577ºC
• M.P. - 176-184ºC
• The presence of long chains of conjugated double bonds donates beta-carotene with specific colors. It is the most abundant form of carotenoid and it is a precursor of the vitamin A.
• On Hydrogenation it gives C40H78, so there are 11 C=C in the molecule.
• One mole of beta carotene reacts with 5 moles of maleic anhydride, so there are 10 double bonds in conjugation
• It oxidizes in air and is metabolized to β-ionone, which has a smell of violets.
• β-ionone on ozonolysis gives geronic acid

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• Beta carotene also gives two moles of geronic acid on ozonolysis

• Kuhn-Roth Method for C-methyl Determination -Oxidation of organic compounds with chromic and sulfuric acids in such a manner that the C-methyl groups are converted to acetic acid which can be assayed volumetrically. 
• One mole of Beta carotene gives 5.4 moles of acetic acid
• So there must be 6 C-methyl groups. 1 + 1 in each ionone unit and the rest four must be part of the long hydrocarbon chain

Structure of C-14 part – Beta carotene on distillation gives toluene, m-xylene and 2,6-dimethyl napthalene

The following structure would satisfy the requirements of a, b, c

Karrer et al. (1950)

Isler et al. (1957)