1. 26.7 Terpenes: The Isoprene Rule4

2. 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)

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

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

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

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

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

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

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

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

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

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

13. Representative Diterpenes
Figure 26.6
Representative Diterpenes OH
Vitamin A

14. Representative Diterpenes
Figure 26.6
Representative Diterpenes OH
Vitamin A

15. Representative Diterpenes
Figure 26.6
Representative Diterpenes
Vitamin A

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

17. 26.8 Isopentenyl Pyrophosphate: The Biological Isoprene Unit4

18. 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).

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

20. Isopentenyl Pyrophosphate
H2C
CCH2CH2OPOPOH
CH3 O
OPP or
Isopentenyl pyrophosphate

21. 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.

22. 26.9 Carbon-Carbon Bond Formation in Terpene Biosynthesis4

23. 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.

24. Carbon-Carbon Bond Formation+
OPP
OPP – +
OPP

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

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

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

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

29. From 10 Carbons to 15 +
OPP
Geranyl pyrophosphate +
OPP

30. From 10 Carbons to 15
OPP H – + +
OPP

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

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

33. 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

34. Limonene H – + + OH
H2O
a-Terpineol

35. Bicyclic Terpenes + + + +
a-Pinene
b-Pinene

36. 26.10 The Pathway from Acetate to Isopentenyl Pyrophosphate4

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

38. 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

39. 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.

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

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

42. CH3CCH2CH2OH
CH2COH HO O
Mevalonic acid
CH3CCH2CSCoA
CH2COH HO O

43. 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.

44. 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–.

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

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

47. 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 •