Terpenes: The Isoprene Rule

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)

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

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." headtail tail head

Common Carbon Backbone

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

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

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

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

Terpenes Representative Sesquiterpenes  -Selinene (celery) H

Terpenes Representative Sesquiterpenes  -Selinene (celery) H

Terpenes Representative Sesquiterpenes  -Selinene (celery)

Terpenes Representative Diterpenes Vitamin A OH

Terpenes Representative Diterpenes Vitamin A OH

Terpenes Representative Diterpenes Vitamin A

Common Terpenes

Limonene

Rearrangement

Terpenes

Isoprene / Biosynthesis

Formation of geranyl pyrophosphate Terpene Biosynthesis

Farnesyl Pyrophosphate

Formation of Squalene, the Precursor of Cholesterol

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

Isoprene Links Heads or Tails?

Squalene, a triterpene, is a precursor of steroids

Many hormones are steroids Steroids

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

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

Biosynthesis of Cholesterol

Synthetic Steroids

TERPENE BIOSYNTHESES in detail Isopentenyl Pyrophosphate: 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 carbons) comes from acetate (2 carbons) via mevalonate (6 carbons).

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

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

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

Carbon-Carbon Bond Formation in Terpene Biosynthesis

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

Carbon-Carbon Bond Formation + OPP OPP– + OPPOPP

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

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

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 OH Geraniol H2OH2OH2OH2O

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

From 10 Carbons to 15 + OPPOPP Geranyl pyrophosphate + OPP

From 10 Carbons to 15 + OPP H –+ OPP

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

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

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

+OH H –+ H2OH2OH2OH2O Limonene  -Terpineol

Bicyclic Terpenes ++ +  -Pinene +  -Pinene

The Pathway from Acetate to Isopentenyl Pyrophosphate

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

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.

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.

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

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.

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

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–

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

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

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

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