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26.7 : The Rule Terpenes

Terpenes are natural products that are structurally related to isoprene.

CH3

H2C C CH CH2 or

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

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

CH3 CH2

CH3C CHCH2CH2CCH CH2

or

The Isoprene Unit

An isoprene unit is the 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

Table 26.2

Classification of Terpenes

Class Number of carbon atoms 10 15 20 Sesterpene 25 30 40 Figure 26.6

Representative

OH O

H

a- (eucalyptus) (peppermint) ( grass) Figure 26.6

Representative Monoterpenes

OH O

H

a-Phellandrene Menthol Citral (eucalyptus) (peppermint) (lemon grass) Figure 26.6

Representative Monoterpenes

a-Phellandrene Menthol Citral (eucalyptus) (peppermint) (lemon grass) Figure 26.6

Representative

H

a-Selinene () Figure 26.6

Representative Sesquiterpenes

H

a-Selinene (celery) Figure 26.6

Representative Sesquiterpenes

a-Selinene (celery) Figure 26.6

Representative

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 () 26.8 Isopentenyl : 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 ) comes from acetate (2 carbons) via mevalonate (6 carbons). The Biological Isoprene Unit

O O CH3

3 CH3COH HOCCH2CCH2CH2OH

OH

Mevalonic acid CH3 O O

H2C CCH2CH2OPOPOH

Isopentenyl pyrophosphate Isopentenyl Pyrophosphate

CH3 O O

H2C CCH2CH2OPOPOH or OPP

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 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 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 –H to give a double bond.

+ OPP After C—C Bond Formation...

OPP

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

OPP

H2O

OH Geraniol From 10 Carbons to 15

OPP + OPP Geranyl pyrophosphate

+ OPP From 10 Carbons to 15

OPP

+ –H

+ OPP From 10 Carbons to 15

OPP

This compound is called . Hydrolysis of the pyrophosphate ester gives the (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 Z double bond bond

Limonene + –H

+

OH

H2O a- Bicyclic Terpenes

+ + +

+ a- b-Pinene 26.10 The Pathway from Acetate to Isopentenyl Pyrophosphate Recall

O O CH3

3 CH3COH HOCCH2CCH2CH2OH

OH

Mevalonic acid CH3 O O

H2C 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.

O O

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 O

CH3CCH2CSCoA

CH2COH O Biosynthesis of Mevalonic Acid

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

HO O

CH3CCH2CSCoA

CH2COH O HO Mevalonic CH3CCH2CH2OH acid CH2COH O

HO O

CH3CCH2CSCoA

CH2COH O Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate

2– HO OPO3

CH3CCH2CH2OH CH3CCH2CH2OPP

CH2COH CH2COH O O

The two hydroxyl groups of mevalonic acid undergo phosphorylation. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate

3– 2– OPO3 OPO3

CH3CCH2CH2OPP CH3CCH2CH2OPP •• – •– CH2 CH2 C O • •• O C O O Phosphorylation is followed by a novel 3– elimination involving loss of CO2 and PO4 . 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 O CH3

CH3COH HOCCH2CCH2CH2OH

OH

Mevalonic acid CH3 O O

H2C 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 CH3 O O

CH3COH H2C CCH2CH2OPOPOH

•• •• O •• •• •• •• H