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26.

7 Terpenes: The Isoprene Rule

Terpenes

Terpenes are natural products that are structurally related to isoprene. CH3
H2C C CH CH2 or

Isoprene (2-methyl-1,3-butadiene)

Terpenes

Myrcene (isolated from oil of bayberry) is a typical terpene.


CH3 CH3C CH2 CHCH2CH2CCH or

CH2

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 "headto-tail." head tail

tail head

Table 26.2 Classification of Terpenes Class Number of carbon atoms

Monoterpene
Sesquiterpene Diterpene Sesterpene Triterpene

10
15 20 25 30

Tetraterpene

40

Figure 26.6 Representative Monoterpenes

OH

O H

a-Phellandrene Menthol (eucalyptus) (peppermint)

Citral (lemon grass)

Figure 26.6 Representative Monoterpenes

OH

O H

a-Phellandrene Menthol (eucalyptus) (peppermint)

Citral (lemon grass)

Figure 26.6 Representative Monoterpenes

a-Phellandrene Menthol (eucalyptus) (peppermint)

Citral (lemon grass)

Figure 26.6 Representative Sesquiterpenes

H
a-Selinene (celery)

Figure 26.6 Representative Sesquiterpenes

H
a-Selinene (celery)

Figure 26.6 Representative Sesquiterpenes

a-Selinene (celery)

Figure 26.6 Representative Diterpenes

OH

Vitamin A

Figure 26.6 Representative Diterpenes

OH

Vitamin A

Figure 26.6 Representative Diterpenes

Vitamin A

Figure 26.6 Representative Triterpene

tail-to-tail linkage of isoprene units

Squalene (shark liver oil)

26.8 Isopentenyl Pyrophosphate: The Biological Isoprene Unit

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 O 3 CH3COH

CH3

HOCCH2CCH2CH2OH OH Mevalonic acid

CH3 H2C

O O

CCH2CH2OPOPOH

Isopentenyl pyrophosphate

Isopentenyl Pyrophosphate

CH3
H2C

O O
or OPP

CCH2CH2OPOPOH

Isopentenyl pyrophosphate

Isopentenyl and Dimethylallyl Pyrophosphate Isopentenyl pyrophosphate is interconvertible with 2-methylallyl pyrophosphate.

OPP
Isopentenyl pyrophosphate

OPP
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

Carbon-Carbon Bond Formation OPP +

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 + OPP

After CC Bond Formation...

The carbocation can lose a proton to give a double bond. + OPP

After CC Bond Formation...

OPP The carbocation can lose a proton to give a double bond. + OPP H +

After CC Bond Formation...

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

After CC Bond Formation...

OPP H2 O

OH Geraniol

From 10 Carbons to 15 OPP +


Geranyl pyrophosphate

OPP

OPP

From 10 Carbons to 15

OPP

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.

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

Recall O 3 CH3COH

CH3

HOCCH2CCH2CH2OH OH Mevalonic acid

CH3 H2C

O O

CCH2CH2OPOPOH

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

S-Acetoacetyl coenzyme A

Biosynthesis of Mevalonic Acid O O O

CH3CCH2CSCoA + CH3CSCoA

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 O O O

CH3CCH2CSCoA + CH3CSCoA

HO

CH3CCH2CSCoA CH2COH O

Biosynthesis of Mevalonic Acid

Next, the acyl coenzyme A function is reduced. The product of this reduction is mevalonic acid.

HO

CH3CCH2CSCoA CH2COH O

HO CH3CCH2CH2OH CH2COH Mevalonic acid

HO

CH3CCH2CSCoA CH2COH O

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate HO CH3CCH2CH2OH CH2COH O

OPO3

CH3CCH2CH2OPP
CH2COH O

The two hydroxyl groups of mevalonic acid undergo phosphorylation.

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate OPO3


3

OPO3

CH3CCH2CH2OPP CH2 O C O

CH3CCH2CH2OPP CH2 C O
O

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 O CH3COH

CH3

HOCCH2CCH2CH2OH OH Mevalonic acid

CH3 H2C

O O

CCH2CH2OPOPOH

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. O CH3COH H2C CH3 O O

CCH2CH2OPOPOH

O
H

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