1. Terpenes: The Isoprene Rule

2. Terpenes Terpenes are natural products that are structurally related to isoprene. H2CH2CH2CH2C C CH 3 CH CH 2 or Isoprene (2-methyl-1,3-butadiene)

3. Terpenes Myrcene (isolated from oil of bayberry) is a typical terpene. CH 2 CH 3 CH 3 C CHCH 2 CH 2 CCH CH 2 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." headtail tail head

6. Common Carbon Backbone

9. Terpenes ClassNumber of carbon atoms Monoterpene10 Sesquiterpene15 Diterpene20 Sesterpene25 Triterpene30 Tetraterpene40 Classification of Terpenes

10. Terpenes Representative Monoterpenes  -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass) OH OH

11. Terpenes Representative Monoterpenes  -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass) OH OH

12. Terpenes Representative Monoterpenes  -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

13. Terpenes Representative Sesquiterpenes  -Selinene (celery) H

14. Terpenes Representative Sesquiterpenes  -Selinene (celery) H

15. Terpenes Representative Sesquiterpenes  -Selinene (celery)

16. Terpenes Representative Diterpenes Vitamin A OH

17. Terpenes Representative Diterpenes Vitamin A OH

18. Terpenes Representative Diterpenes Vitamin A

19. Common Terpenes

20. Limonene

22. Rearrangement

23. Terpenes

25. Isoprene / Biosynthesis

30. Formation of geranyl pyrophosphate Terpene Biosynthesis

32. Farnesyl Pyrophosphate

33. Formation of Squalene, the Precursor of Cholesterol

34. Terpenes Representative Triterpene Squalene (shark liver oil) tail-to-tail linkage of isoprene units

35. Isoprene Links Heads or Tails?

36. Squalene, a triterpene, is a precursor of steroids

37. Many hormones are steroids Steroids

38. Methyl groups at C-10 and C-13 are called angular methyl groups The B, C, and D rings are trans fused

39. Those  on the opposite side of the plane of the ring system are  -substituents Substituents on the same side of the steroid ring system as the angular methyl groups are  -substituents The A and B rings are also trans fused in most naturally occurring steroids

42. Biosynthesis of Cholesterol

43. Synthetic Steroids

45. TERPENE BIOSYNTHESES in detail Isopentenyl Pyrophosphate: The Biological Isoprene Unit

46. 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).

47. The Biological Isoprene Unit CH 3 COH O3 HOCCH 2 CCH 2 CH 2 OH CH 3 OH O Mevalonic acid H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH 3 OO Isopentenyl pyrophosphate

48. Isopentenyl Pyrophosphate H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH 3 OO Isopentenyl pyrophosphate or OPP

49. Isopentenyl and Dimethylallyl Pyrophosphate Isopentenyl pyrophosphate is interconvertible with 2-methylallyl pyrophosphate. OPP OPP Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position. Isopentenyl pyrophosphate Dimethylallyl pyrophosphate

50. Carbon-Carbon Bond Formation in Terpene Biosynthesis

51. 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. + OPPOPP

52. Carbon-Carbon Bond Formation + OPP OPP– + OPPOPP

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

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

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

56. After C—C Bond Formation... OPP OH Geraniol H2OH2OH2OH2O

57. Terpenes isoprenyl (C 5 ) --> geranyl (C 10 ) geranyl (C 10 ) --> farnesyl (C 15 ) farnesyl (C 15 ) --> squalene (C 30 ) Generic: C 10 monoterpenes, C 15 sesquiterpenes, C 20 diterpenes, C 30 triterpenes, C 40 tetraterpenes

58. From 10 Carbons to 15 + OPPOPP Geranyl pyrophosphate + OPP

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

60. OPP This compound is called farnesyl pyrophosphate. Hydrolysis of the pyrophosphate ester gives the alcohol farnesol.

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

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

63. +OH H –+ H2OH2OH2OH2O Limonene  -Terpineol

64. Bicyclic Terpenes ++ +  -Pinene +  -Pinene

65. The Pathway from Acetate to Isopentenyl Pyrophosphate

66. Terpenes CH 3 COH O3 HOCCH 2 CCH 2 CH 2 OH CH 3 OH O Mevalonic acid H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH 3 OO Isopentenyl pyrophosphate

67. Biosynthesis of Mevalonic Acid CH 3 CCH 2 CSCoA OO S-Acetoacetyl coenzyme A In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is converted to S-acetoacetyl coenzyme A.

68. Biosynthesis of Mevalonic Acid CH 3 CSCoA O+ CH 3 CCH 2 CSCoA OO 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.

69. Biosynthesis of Mevalonic Acid CH 3 CSCoA O CH 3 CCH 2 CSCoA CH 2 COH HOO O + CH 3 CCH 2 CSCoA OO

70. Biosynthesis of Mevalonic Acid CH 3 CCH 2 CSCoA CH 2 COH HOO O Next, the acyl coenzyme A function is reduced. The product of this reduction is mevalonic acid.

71. CH 3 CCH 2 CSCoA CH 2 COH HOO O CH 3 CCH 2 CH 2 OH CH 2 COH HOO Mevalonic acid

72. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate CH 3 CCH 2 CH 2 OH CH 2 COH HOHOHOHOO The two hydroxyl groups of mevalonic acid undergo phosphorylation. CH 3 CCH 2 CH 2 OPP CH 2 COH O OPO 3 2–

73. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate CH 3 CCH 2 CH 2 OPP CH 2 Phosphorylation is followed by a novel elimination involving loss of CO 2 and PO 4 3–. OPO 3 3– CH 3 CCH 2 CH 2 OPP CH 2 O OPO 3 2–C O – OCO

74. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate The product of this elimination is isopentenyl pyrophosphate. CH 3 CCH 2 CH 2 OPP CH 2

75. Biosynthetic pathway is based on experiments with 14 C-labeled acetate CH 3 COH O HOCCH 2 CCH 2 CH 2 OH CH3CH3CH3CH3OH O Mevalonic acid H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH3CH3CH3CH3OO Isopentenyl pyrophosphate

76. Biosynthetic pathway is based on experiments with 14 C-labeled acetate CH 3 COH O Citronellal biosynthesized using 14 C-labeled acetate as the carbon source had the labeled carbons in the positions indicated. H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH3CH3CH3CH3OO O H