Terpenes & Terpenoids 4

Terpenes - class of >20,000 compounds containing carbon atoms in multiples of five Terpenoids - oxygen-containing terpenes (alcohols, ketones, aldehydes

The name "terpene" is derived from the word "turpentine" Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers.  rose oil (zencefil) (kereviz)

Isoprene (2-methyl-1,3-butadiene) Terpenes Terpenes are natural products that are structurally related to isoprene. H2C C CH3 CH CH2 or Isoprene (2-methyl-1,3-butadiene)

Terpenes Myrcene (isolated from oil of bayberry) is a typical terpene. CH2 CH3 CH3C CHCH2CH2CCH or

The Isoprene Unit An isoprene unit is the carbon skeleton of isoprene (ignoring the double bonds) Myrcene contains two isoprene units.

The Isoprene Unit The isoprene units of myrcene are joined "head-to-tail." head tail tail head

Classification of Terpenes Class Number of carbon atoms Monoterpene 10 Sesquiterpene 15 Diterpene 20 Sesterpene 25 Triterpene 30 Tetraterpene 40

a-Phellandrene (eucalyptus) Representative Monoterpenes OH O H a-Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

a-Phellandrene (eucalyptus) Representative Monoterpenes OH O H a-Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

a-Phellandrene (eucalyptus) Representative Monoterpenes a-Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

Representative Sesquiterpenes H a-Selinene (celery)

Representative Sesquiterpenes H a-Selinene (celery)

Representative Sesquiterpenes a-Selinene (celery)

Representative Diterpenes OH Vitamin A

Representative Diterpenes OH Vitamin A

Representative Diterpenes Vitamin A

Squalene (shark liver oil) Representative Triterpene tail-to-tail linkage of isoprene units Squalene (shark liver oil)

Finding the isoprene building block - cyclic compounds Finding the isoprene building block - sesquiterpenes (C15)

Finding the isoprene building block - triterpenes (C30) - Squalene has a natural and vital part in the synthesis of all plant and animal sterols, including cholesterol, steroid hormones, and vitamin D in the human body

Finding the isoprene building block - tetraterpenes (C40) Lycopene is responsible for the red color in tomatoes and watermelon

 -carotene is the compound that causes carrots and apricots to be orange

” C10 terpenoids The precursor to C10 terpenoids (monoterpenes) is Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), which consists of two C5 “isoprene units” that are joined “head-to-tail PP head - tail head - tail

Geranyl pyrophosphate

C15 sesquiterpenoids are derived from Farnesyl diphosphate, which consists of three C5 “isoprene units” that are joined “head-to-tail”

C20 diterpenoids are derived from Geranylgeranyl diphosphate, which consists of four C5 “isoprene units” that are joined “head-to-tail”

Terpenoid nomenclature Groups and subgroups Based on pathways Classification IUPAC CAS Trivial name(derived from the structural family Or relate to natural source)

Examples of the co-existence of systematics Semi-systemetic and trivial names

Menthol – a cyclic terpenoid This terpene has been oxidised to a terpenoid

Absinthe – a cyclic terpenoid a potent green aniseed-flavoured liqueur, originally made with the shrub wormwood.(the seed of the anise, used in cooking and herbal medicine) This terpene has been oxidised to a terpenoid

Camphor – a cyclic terpenoid

a-Selinene – a cyclic terpene 3 isoprene units 15 carbon atoms

β-carotene – a linear terpene 8 isoprene units 40 carbon atoms

Which unit makes up every terpene? Isoprene Unit Questions Which unit makes up every terpene? Isoprene Unit How many carbons are there in an isoprene unit? Five What is the systematic name for isoprene? 2-methylbuta-1,3-diene What is an oxidised terpene known as? Terpenoid

Carvone Occurs in Enantiomeric forms Also known as Meridian fennel, Persian carrot Uses Carvone –Latin name for Caraway, carum carvi Basic carbon skeleton 1-isopropyl-4-methylcyclohexane common in nature the genus mentha includes various types of mint

saturated ketone of the p- menthane family of monoteroenoids Greek letters Use to distinguish between isomeric terpenoids Depends on In order in which the isomers were discovered Their abundance

α- Pinene ¾ component of turpentine oil by weight β- Pinene next most significant component

Cyclic Terpenoids α, β, and γ refers to the location of double bond in isomeric olefins α - endocyclic tri substituted double bond β- A tetra substituted olefinic bond γ- exocyclic methylene function Example E1 reaction

α - endocyclic tri substituted double bond A trisubstituted alkene is an alkene in the molecule of which the doubly bonded carbons are bonded to a total of three carbon atoms excluding each other.

A tetrasubstituted alkene is an alkene in the molecule of which the doubly bonded carbons are bonded to a total of four carbon atoms excluding each other.

Methylene group γ- exocyclic methylene function

THE ROLE OF TERPENOIDS IN NATURE Terpenoids are produced by a wide variety of plants, animals and micro-organisms. 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 synthesized.

The roles which the terpenoids play in living organisms can be grouped into three classes: Functional Defense and (producing resins and gums Acacia gummiferae) Communication.

Examples 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.

Calciferol

Tocopherol

Chlorophyll

Communication 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. Giberellic acid is a hormone used by plants to control their rate of growth. Testosterone and oestrone are mammalian sex hormones. .

Oesteron

Pheromones 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 (arrangement)of chemical signals to organise most aspects of their lives.

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.

Allelochemicals 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

Examples Camphor and d-limonene are Allomones in that the trees which produce them are protected from insect attack by their presence

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 Synomones since the attracted insect finds nectar and the plant obtains a pollinator.

The Biological Isoprene Unit The isoprene units in terpenes do not come from isoprene. They come from isopentenyl pyrophosphate. Isopentenyl pyrophosphate (5 carbons) comes from acetate (2 carbons) via mevalonate (6 carbons).

The Biological Isoprene Unit CH3COH O HOCCH2CCH2CH2OH CH3 OH O 3 Mevalonic acid H2C CCH2CH2OPOPOH CH3 O Isopentenyl pyrophosphate

Isopentenyl Pyrophosphate H2C CCH2CH2OPOPOH CH3 O OPP or Isopentenyl pyrophosphate

Isopentenyl and Dimethylallyl Pyrophosphate Isopentenyl pyrophosphate is interconvertible with 2-methylallyl pyrophosphate. OPP OPP Isopentenyl pyrophosphate Dimethylallyl pyrophosphate Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position.

26.9 Carbon-Carbon Bond Formation in Terpene Biosynthesis 4

Carbon-Carbon Bond Formation + OPP The key process involves the double bond of isopentenyl pyrophosphate acting as a nucleophile toward the allylic carbon of dimethylallyl pyrophosphate.

Carbon-Carbon Bond Formation + OPP OPP – + OPP

After C—C Bond Formation... The carbocation can lose a proton to give a double bond. + OPP

After C—C Bond Formation... OPP The carbocation can lose a proton to give a double bond. H – + + OPP

After C—C Bond Formation... OPP This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil).

After C—C Bond Formation... OPP H2O OH Geraniol

From 10 Carbons to 15 + OPP Geranyl pyrophosphate + OPP

From 10 Carbons to 15 OPP H – + + OPP

From 10 Carbons to 15 OPP This compound is called farnesyl pyrophosphate. Hydrolysis of the pyrophosphate ester gives the alcohol farnesol (Figure 26.6).

From 15 Carbons to 20 OPP OPP Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl pyrophosphate.

Rings form by intramolecular carbon-carbon bond formation. Cyclization Rings form by intramolecular carbon-carbon bond formation. + OPP OPP E double bond Z double bond

Limonene H – + + OH H2O a-Terpineol

Bicyclic Terpenes + + + + a-Pinene b-Pinene

26.10 The Pathway from Acetate to Isopentenyl Pyrophosphate 4

Recall CH3COH O HOCCH2CCH2CH2OH CH3 OH O 3 Mevalonic acid H2C CCH2CH2OPOPOH CH3 O Isopentenyl pyrophosphate

Biosynthesis of Mevalonic Acid In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is converted to S-acetoacetyl coenzyme A. CH3CCH2CSCoA O S-Acetoacetyl coenzyme A

Biosynthesis of Mevalonic Acid CH3CCH2CSCoA O CH3CSCoA O + In the next step, S-acetoacetyl coenzyme A reacts with acetyl coenzyme A. Nucleophilic addition of acetyl coenzyme A (probably via its enol) to the ketone carbonyl of S-acetoacetyl coenzyme A occurs.

Biosynthesis of Mevalonic Acid CH3CCH2CSCoA O CH3CSCoA O + CH3CCH2CSCoA CH2COH HO O

Biosynthesis of Mevalonic Acid Next, the acyl coenzyme A function is reduced. The product of this reduction is mevalonic acid. CH3CCH2CSCoA CH2COH HO O

CH3CCH2CH2OH CH2COH HO O Mevalonic acid CH3CCH2CSCoA CH2COH HO O

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate CH3CCH2CH2OPP CH2COH O OPO3 2– CH3CCH2CH2OH CH2COH HO O The two hydroxyl groups of mevalonic acid undergo phosphorylation.

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate OPO3 3– CH3CCH2CH2OPP CH2 O OPO3 2– C •• • • – CH3CCH2CH2OPP CH2 O C Phosphorylation is followed by a novel elimination involving loss of CO2 and PO43–.

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate CH3CCH2CH2OPP CH2 The product of this elimination is isopentenyl pyrophosphate.

Biosynthetic pathway is based on experiments with 14C-labeled acetate CH3COH O HOCCH2CCH2CH2OH CH3 OH O Mevalonic acid H2C CCH2CH2OPOPOH CH3 O Isopentenyl pyrophosphate

Biosynthetic pathway is based on experiments with 14C-labeled acetate Citronellal biosynthesized using 14C-labeled acetate as the carbon source had the labeled carbons in the positions indicated. CH3COH O H2C CCH2CH2OPOPOH CH3 O O H •