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Terpenes: The Isoprene Rule

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Terpenes: The Isoprene Rule. CH 3. H 2 C. CH. CH 2. C. Terpenes. Terpenes are natural products that are structurally related to isoprene. or. Isoprene (2-methyl-1,3-butadiene). CH 3. CH 2. CH 2. CHCH 2 CH 2 CCH. CH 3 C. Terpenes. - PowerPoint PPT Presentation
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Terpenes: The Isoprene Terpenes: The Isoprene Rule Rule
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Page 1: Terpenes:  The Isoprene Rule

Terpenes: The Isoprene RuleTerpenes: The Isoprene Rule

Page 2: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Terpenes are natural products that are Terpenes are natural products that are structurally related to isoprene.structurally related to isoprene.

HH22CC CC

CHCH33

CHCH CHCH22oror

IsopreneIsoprene(2-methyl-1,3-butadiene)(2-methyl-1,3-butadiene)

Page 3: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Myrcene Myrcene (isolated from oil of bayberry) (isolated from oil of bayberry) is a typical terpene.is a typical terpene.

CHCH22

CHCH33

CHCH33CC CHCHCHCH22CHCH22CCHCCH

CHCH22

oror

Page 4: Terpenes:  The Isoprene Rule

The Isoprene UnitThe Isoprene Unit

An isoprene unit is the carbon skeleton of An isoprene unit is the carbon skeleton of isoprene (ignoring the double bonds)isoprene (ignoring the double bonds)

Myrcene contains two isoprene units.Myrcene contains two isoprene units.

Page 5: Terpenes:  The Isoprene Rule

The Isoprene UnitThe Isoprene Unit

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

headhead tailtail

tailtail headhead

Page 6: Terpenes:  The Isoprene Rule

Common Carbon Backbone

Page 7: Terpenes:  The Isoprene Rule
Page 8: Terpenes:  The Isoprene Rule
Page 9: Terpenes:  The Isoprene Rule

TerpenesTerpenes

ClassClass Number of carbon atomsNumber of carbon atoms

MonoterpeneMonoterpene 1010

SesquiterpeneSesquiterpene 1515

DiterpeneDiterpene 2020

SesterpeneSesterpene 2525

TriterpeneTriterpene 3030

TetraterpeneTetraterpene 4040

Classification of TerpenesClassification of Terpenes

Page 10: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative MonoterpenesRepresentative Monoterpenes

-Phellandrene-Phellandrene(eucalyptus)(eucalyptus)

MentholMenthol(peppermint)(peppermint)

CitralCitral(lemon grass)(lemon grass)

OO

HH

OHOH

Page 11: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative MonoterpenesRepresentative Monoterpenes

-Phellandrene-Phellandrene(eucalyptus)(eucalyptus)

MentholMenthol(peppermint)(peppermint)

CitralCitral(lemon grass)(lemon grass)

OO

HH

OHOH

Page 12: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative MonoterpenesRepresentative Monoterpenes

-Phellandrene-Phellandrene(eucalyptus)(eucalyptus)

MentholMenthol(peppermint)(peppermint)

CitralCitral(lemon grass)(lemon grass)

Page 13: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative SesquiterpenesRepresentative Sesquiterpenes

-Selinene-Selinene(celery)(celery)

HH

Page 14: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative SesquiterpenesRepresentative Sesquiterpenes

-Selinene-Selinene(celery)(celery)

HH

Page 15: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative SesquiterpenesRepresentative Sesquiterpenes

-Selinene-Selinene(celery)(celery)

Page 16: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative DiterpenesRepresentative Diterpenes

Vitamin AVitamin A

OHOH

Page 17: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative DiterpenesRepresentative Diterpenes

Vitamin AVitamin A

OHOH

Page 18: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative DiterpenesRepresentative Diterpenes

Vitamin AVitamin A

Page 19: Terpenes:  The Isoprene Rule

Common Terpenes

OH

Geraniol C10H18O

OH

Nerol C10H18O

OH

Terpineol C10H18O

OH

Linalool C10H18O

Page 20: Terpenes:  The Isoprene Rule

Limonene

CH2

CH2

Page 21: Terpenes:  The Isoprene Rule

Limonene

CH2

Page 22: Terpenes:  The Isoprene Rule

Rearrangement

OH OH

Product?

Page 23: Terpenes:  The Isoprene Rule

Terpenes

Camphene (H)

Terpinene (I)

Page 24: Terpenes:  The Isoprene Rule

Terpenes

Limonene (J)

Carene (K)

Page 25: Terpenes:  The Isoprene Rule

Isoprene / BiosynthesisIsoprene / Biosynthesis

OP

OP

O

OO

O

O

Isopentenyl pyrophosphate Isoprene

Page 26: Terpenes:  The Isoprene Rule
Page 27: Terpenes:  The Isoprene Rule
Page 28: Terpenes:  The Isoprene Rule
Page 29: Terpenes:  The Isoprene Rule
Page 30: Terpenes:  The Isoprene Rule

Formation of geranyl pyrophosphate

Terpene Biosynthesis

Page 31: Terpenes:  The Isoprene Rule
Page 32: Terpenes:  The Isoprene Rule

Farnesyl Pyrophosphate

Page 33: Terpenes:  The Isoprene Rule

Formation of Squalene, the Precursor of Cholesterol

Page 34: Terpenes:  The Isoprene Rule

TerpenesTerpenes

Representative TriterpeneRepresentative Triterpene

SqualeneSqualene(shark liver oil)(shark liver oil)

tail-to-tail linkage of isoprene unitstail-to-tail linkage of isoprene units

Page 35: Terpenes:  The Isoprene Rule

Isoprene LinksIsoprene LinksHeads or Tails?Heads or Tails?

Page 36: Terpenes:  The Isoprene Rule

Squalene, a triterpene, is a precursor of steroids

Page 37: Terpenes:  The Isoprene Rule

• Many hormones are steroids

Steroids

Page 38: Terpenes:  The Isoprene Rule

Methyl groups at C-10 and C-13 are called angular methyl groups

The B, C, and D rings are trans fused

Page 39: Terpenes:  The Isoprene Rule

Thoseon the opposite side of the plane of the ring system are -substituents

Substituents on the same side of the steroid ring systemas the angular methyl groups are -substituents

The A and B rings are also trans fused in most naturallyoccurring steroids

Page 40: Terpenes:  The Isoprene Rule
Page 41: Terpenes:  The Isoprene Rule
Page 42: Terpenes:  The Isoprene Rule

Biosynthesis of Cholesterol

Page 43: Terpenes:  The Isoprene Rule

Synthetic Steroids

Page 44: Terpenes:  The Isoprene Rule
Page 45: Terpenes:  The Isoprene Rule

TERPENE BIOSYNTHESESTERPENE BIOSYNTHESESin detailin detail

Isopentenyl Pyrophosphate:Isopentenyl Pyrophosphate:The Biological Isoprene UnitThe Biological Isoprene Unit

Page 46: Terpenes:  The Isoprene Rule

The Biological Isoprene UnitThe Biological Isoprene Unit

The isoprene units in terpenes do not come from The isoprene units in terpenes do not come from isoprene.isoprene.

They come from isopentenyl pyrophosphate.They come from isopentenyl pyrophosphate.

Isopentenyl pyrophosphate (5 carbons) comes Isopentenyl pyrophosphate (5 carbons) comes from acetate (2 carbons) via mevalonate (6 from acetate (2 carbons) via mevalonate (6 carbons).carbons).

Page 47: Terpenes:  The Isoprene Rule

The Biological Isoprene UnitThe Biological Isoprene Unit

CHCH33COHCOH

OO

33 HOCCHHOCCH22CCHCCH22CHCH22OHOH

CHCH33

OHOH

OO

Mevalonic acidMevalonic acid

HH22CC CCHCCH22CHCH22OPOPOHOPOPOH

CHCH33 OO OO

Isopentenyl Isopentenyl pyrophosphatepyrophosphate

Page 48: Terpenes:  The Isoprene Rule

Isopentenyl PyrophosphateIsopentenyl Pyrophosphate

HH22CC CCHCCH22CHCH22OPOPOHOPOPOH

CHCH33 OO OO

Isopentenyl Isopentenyl pyrophosphatepyrophosphate

oror

OPPOPP

Page 49: Terpenes:  The Isoprene Rule

Isopentenyl and Dimethylallyl PyrophosphateIsopentenyl and Dimethylallyl Pyrophosphate

Isopentenyl pyrophosphate is interconvertible withIsopentenyl pyrophosphate is interconvertible with2-methylallyl pyrophosphate.2-methylallyl pyrophosphate.

OPPOPP

OPPOPP

Dimethylallyl pyrophosphate has a leaving Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this reactive toward nucleophilic substitution at this position.position.

Isopentenyl pyrophosphateIsopentenyl pyrophosphate Dimethylallyl pyrophosphateDimethylallyl pyrophosphate

Page 50: Terpenes:  The Isoprene Rule

Carbon-Carbon Bond Formation in Carbon-Carbon Bond Formation in Terpene BiosynthesisTerpene Biosynthesis

Page 51: Terpenes:  The Isoprene Rule

Carbon-Carbon Bond FormationCarbon-Carbon Bond Formation

The key process involves the double bond of The key process involves the double bond of isopentenyl isopentenyl pyrophosphatepyrophosphate acting as a nucleophile acting as a nucleophile toward the allylic carbon of dimethylallyl toward the allylic carbon of dimethylallyl pyrophosphatepyrophosphate..

++OPPOPP

OPPOPP

Page 52: Terpenes:  The Isoprene Rule

Carbon-Carbon Bond FormationCarbon-Carbon Bond Formation

++OPPOPP

OPPOPP––

++OPPOPP

OPPOPP

Page 53: Terpenes:  The Isoprene Rule

After C—C Bond Formation...After C—C Bond Formation...

++OPPOPP

The carbocation The carbocation can lose a proton can lose a proton to give a double to give a double bond.bond.

Page 54: Terpenes:  The Isoprene Rule

After C—C Bond Formation...After C—C Bond Formation...

++OPPOPP

OPPOPP

The carbocation The carbocation can lose a proton can lose a proton to give a double to give a double bond.bond.

HH––++

Page 55: Terpenes:  The Isoprene Rule

After C—C Bond Formation...After C—C Bond Formation...

OPPOPP

This compound is called geranyl pyrophosphate. It This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil).geraniol (rose oil).

Page 56: Terpenes:  The Isoprene Rule

After C—C Bond Formation...After C—C Bond Formation...

OPPOPP

OHOH

GeraniolGeraniol

HH22OO

Page 57: Terpenes:  The Isoprene Rule

TerpenesTerpenes

OP

OP

O

OO

O

O

Isopentenyl pyrophosphate Isoprene

isoprenyl (Cisoprenyl (C55) --> geranyl (C) --> geranyl (C1010))

geranyl (Cgeranyl (C1010) --> farnesyl (C) --> farnesyl (C1515))

farnesyl (Cfarnesyl (C1515) --> squalene (C) --> squalene (C3030))

Generic: CGeneric: C1010 monoterpenes, monoterpenes, CC1515sesquiterpenes, Csesquiterpenes, C2020 diterpenes, diterpenes, CC3030 triterpenes, C triterpenes, C4040 tetraterpenes tetraterpenes

Page 58: Terpenes:  The Isoprene Rule

From 10 Carbons to 15From 10 Carbons to 15

++OPPOPP

OPPOPP

Geranyl pyrophosphateGeranyl pyrophosphate

++OPPOPP

Page 59: Terpenes:  The Isoprene Rule

From 10 Carbons to 15From 10 Carbons to 15

++OPPOPP

HH––++

OPPOPP

Page 60: Terpenes:  The Isoprene Rule

From 10 Carbons to 15From 10 Carbons to 15

OPPOPP

This compound is called farnesyl This compound is called farnesyl pyrophosphate.pyrophosphate.

Hydrolysis of the pyrophosphate ester gives the Hydrolysis of the pyrophosphate ester gives the alcohol farnesol.alcohol farnesol.

Page 61: Terpenes:  The Isoprene Rule

From 15 Carbons to 20From 15 Carbons to 20

OPPOPP

Farnesyl pyrophosphate is extended by another Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl isoprene unit by reaction with isopentenyl pyrophosphate.pyrophosphate.

OPPOPP

Page 62: Terpenes:  The Isoprene Rule

CyclizationCyclization

Rings form by intramolecular carbon-carbon Rings form by intramolecular carbon-carbon bond formation.bond formation.

OPPOPP

OPPOPP

++

EE double double bondbond

ZZ double double bondbond

Page 63: Terpenes:  The Isoprene Rule

++

OHOH

HH––++

HH22OO

LimoneneLimonene

-Terpineol-Terpineol

Page 64: Terpenes:  The Isoprene Rule

Bicyclic TerpenesBicyclic Terpenes

++

++

++

-Pinene-Pinene

++

-Pinene-Pinene

Page 65: Terpenes:  The Isoprene Rule

The Pathway from Acetate to The Pathway from Acetate to Isopentenyl PyrophosphateIsopentenyl Pyrophosphate

Page 66: Terpenes:  The Isoprene Rule

TerpenesTerpenes

CHCH33COHCOH

OO

33 HOCCHHOCCH22CCHCCH22CHCH22OHOH

CHCH33

OHOH

OO

Mevalonic acidMevalonic acid

HH22CC CCHCCH22CHCH22OPOPOHOPOPOH

CHCH33 OO OO

Isopentenyl Isopentenyl pyrophosphatepyrophosphate

Page 67: Terpenes:  The Isoprene Rule

Biosynthesis of Mevalonic AcidBiosynthesis of Mevalonic Acid

CHCH33CCHCCH22CSCoACSCoA

OOOO

SS-Acetoacetyl-Acetoacetylcoenzyme Acoenzyme A

In a sequence analogous to the early steps of In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is fatty acid biosynthesis, acetyl coenzyme A is converted to converted to SS-acetoacetyl coenzyme A.-acetoacetyl coenzyme A.

Page 68: Terpenes:  The Isoprene Rule

Biosynthesis of Mevalonic AcidBiosynthesis of Mevalonic Acid

CHCH33CSCoACSCoA

OO

++CHCH33CCHCCH22CSCoACSCoA

OOOO

In the next step, S-acetoacetyl coenzyme A In the next step, S-acetoacetyl coenzyme A reacts with acetyl coenzyme A.reacts with acetyl coenzyme A.

Nucleophilic addition of acetyl coenzyme A Nucleophilic addition of acetyl coenzyme A (probably via its enol) to the ketone carbonyl of (probably via its enol) to the ketone carbonyl of S-S-acetoacetyl coenzyme A occurs.acetoacetyl coenzyme A occurs.

Page 69: Terpenes:  The Isoprene Rule

Biosynthesis of Mevalonic AcidBiosynthesis of Mevalonic Acid

CHCH33CSCoACSCoA

OO

CHCH33CCCHCH22CSCoACSCoA

CHCH22COHCOH

HOHO OO

OO

++CHCH33CCHCCH22CSCoACSCoA

OOOO

Page 70: Terpenes:  The Isoprene Rule

Biosynthesis of Mevalonic AcidBiosynthesis of Mevalonic Acid

CHCH33CCCHCH22CSCoACSCoA

CHCH22COHCOH

HOHO OO

OO

Next, the Next, the acyl coenzyme A acyl coenzyme A function is reduced.function is reduced.

The product of this reduction is mevalonic acid.The product of this reduction is mevalonic acid.

Page 71: Terpenes:  The Isoprene Rule

CHCH33CCCHCH22CSCoACSCoA

CHCH22COHCOH

HOHO OO

OO

CHCH33CCCHCH22CHCH22OHOH

CHCH22COHCOH

HOHO

OO

MevalonicMevalonicacidacid

Page 72: Terpenes:  The Isoprene Rule

Conversion of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl Pyrophosphate

CHCH33CCHCCH22CHCH22OOHH

CHCH22COHCOH

HHOO

OO

The two hydroxyl groups of mevalonic acid The two hydroxyl groups of mevalonic acid undergo phosphorylation.undergo phosphorylation.

CHCH33CCHCCH22CHCH22OOPPPP

CHCH22COHCOH

OO

OOPOPO33

2–2–

Page 73: Terpenes:  The Isoprene Rule

Conversion of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl Pyrophosphate

CHCH33CCHCCH22CHCH22OOPPPP

CHCH22

Phosphorylation is followed by a novel Phosphorylation is followed by a novel elimination involving loss of COelimination involving loss of CO22 and PO and PO44

3–3–..

OOPOPO33

3–3–

CHCH33CCHCCH22CHCH22OOPPPP

CHCH22

OO

OOPOPO33

2–2–

CC OO••••

••••••••––

OO CC OO

Page 74: Terpenes:  The Isoprene Rule

Conversion of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl Pyrophosphate

The product of this elimination is isopentenyl The product of this elimination is isopentenyl pyrophosphate.pyrophosphate.

CHCH33CCHCCH22CHCH22OOPPPP

CHCH22

Page 75: Terpenes:  The Isoprene Rule

Biosynthetic pathway is based on Biosynthetic pathway is based on experiments with experiments with 1414C-labeled acetateC-labeled acetate

CCHH33COHCOH

OO

HOCHOCCCHH22CCCCHH22CHCH22OHOH

CCHH33

OHOH

OO

Mevalonic acidMevalonic acid

HH22CC CCCCHH22CHCH22OPOPOHOPOPOH

CCHH33 OO OO

Isopentenyl Isopentenyl pyrophosphatepyrophosphate

Page 76: Terpenes:  The Isoprene Rule

Biosynthetic pathway is based on Biosynthetic pathway is based on experiments with experiments with 1414C-labeled acetateC-labeled acetate

CCHH33COHCOH

OO

Citronellal biosynthesized using Citronellal biosynthesized using 1414C-labeled C-labeled acetate as the carbon source had the labeled acetate as the carbon source had the labeled carbons in the positions indicated.carbons in the positions indicated.

HH22CC CCCCHH22CHCH22OPOPOHOPOPOH

CCHH33 OO OO

OO

HH

••

•• •• ••

••

••


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