26.7 Terpenes: The Isoprene Rule 4

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

Table 26.2 Classification of Terpenes Class Number of carbon atoms Monoterpene 10 Sesquiterpene 15 Diterpene 20 Sesterpene 25 Triterpene 30 Tetraterpene 40

a-Phellandrene (eucalyptus) Figure 26.6 Representative Monoterpenes OH O H a-Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

a-Phellandrene (eucalyptus) Figure 26.6 Representative Monoterpenes OH O H a-Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

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

Representative Sesquiterpenes Figure 26.6 Representative Sesquiterpenes H a-Selinene (celery)

Representative Sesquiterpenes Figure 26.6 Representative Sesquiterpenes H a-Selinene (celery)

Representative Sesquiterpenes Figure 26.6 Representative Sesquiterpenes a-Selinene (celery)

Representative Diterpenes Figure 26.6 Representative Diterpenes OH Vitamin A

Representative Diterpenes Figure 26.6 Representative Diterpenes OH Vitamin A

Representative Diterpenes Figure 26.6 Representative Diterpenes Vitamin A

Squalene (shark liver oil) Figure 26.6 Representative Triterpene tail-to-tail linkage of isoprene units Squalene (shark liver oil)

26.8 Isopentenyl Pyrophosphate: The Biological Isoprene Unit 4

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 •