26.7 Terpenes: The Isoprene Rule

1. 26.7Terpenes: The Isoprene Rule

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

3. CH3 CH2 CH2 CHCH2CH2CCH CH3C Terpenes • Myrcene (isolated from oil of bayberry) is a typical terpene. 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. OH O H Figure 26.6 Representative Monoterpenes a-Phellandrene(eucalyptus) Menthol(peppermint) Citral(lemon grass)

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

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

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

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

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

13. OH Figure 26.6 Representative Diterpenes Vitamin A

14. OH Figure 26.6 Representative Diterpenes Vitamin A

15. Figure 26.6 Representative Diterpenes Vitamin A

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

17. 26.8Isopentenyl Pyrophosphate:The Biological Isoprene Unit

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

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

21. OPP OPP Isopentenyl and Dimethylallyl Pyrophosphate Isopentenyl pyrophosphate is interconvertible with2-methylallyl pyrophosphate. • Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position. Isopentenyl pyrophosphate Dimethylallyl pyrophosphate

22. 26.9Carbon-Carbon Bond Formation in Terpene Biosynthesis

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

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

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

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

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

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

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

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

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

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

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

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

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

36. 26.10The Pathway from Acetate to Isopentenyl Pyrophosphate

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

38. O O CH3CCH2CSCoA 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. S-Acetoacetylcoenzyme A

39. O O O CH3CCH2CSCoA CH3CSCoA Biosynthesis of Mevalonic Acid • 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. O O O CH3CCH2CSCoA CH3CSCoA HO O CH3CCH2CSCoA CH2COH O Biosynthesis of Mevalonic Acid +

41. 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.

42. HO CH3CCH2CH2OH CH2COH O HO O CH3CCH2CSCoA CH2COH O Mevalonicacid

43. 2– HO OPO3 CH3CCH2CH2OH CH3CCH2CH2OPP CH2COH CH2COH O O Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate • The two hydroxyl groups of mevalonic acid undergo phosphorylation.

44. 3– OPO3 2– OPO3 CH3CCH2CH2OPP – •• CH2 O C •• •• O C O O Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate • Phosphorylation is followed by a novel elimination involving loss of CO2 and PO43–. CH3CCH2CH2OPP CH2

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

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

47. CH3 O O O CH3COH H2C CCH2CH2OPOPOH • • O • • • • H 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.