Download Organic Chemistry Fifth Edition

Chapter 24
Lipids
Lipids
Lipids are naturally occurring substances
grouped together on the basis of a common
property—they are more soluble in nonpolar
solvents than in water.
Some of the most important of them—the ones
in this chapter—are related in that they have
acetic acid (acetate) as their biosynthetic origin.
In many biosynthetic pathways a substance
called acetyl coenzyme A serves as the source
of acetate.
24.1
Acetyl Coenzyme A
Structure of Coenzyme A
R = H; Coenzyme A
O
R = CCH3; Acetyl coenzyme A
Reactivity of Coenzyme A
Nucleophilic acyl substitution
O
CH3CSCoA
HY ••
O
CH3C
Y •• + HSCoA
Acetyl coenzyme A is a source of an acetyl
group toward biological nucleophiles; it is an
acetyl transfer agent.
Reactivity of Coenzyme A
can react via enol
O
OH
H2C
CH3CSCoA
CSCoA
E+
Acetyl coenzyme A reacts
with biological
electrophiles at its 
carbon atom.
O
E
CH2CSCoA
24.2
Fats, Oils, and Fatty Acids
Fats and Oils
O
O CH2OCR'
RCOCH
CH2OCR"
O
Fats and oils are naturally occurring mixture of
triacylglycerols (also called triglycerides).
Fats are solids; oils are liquids.
Fats and Oils
O
O CH2OC(CH2)16CH3
CH3(CH2)16COCH
CH2OC(CH2)16CH3
O
Tristearin; mp 72°C
Fats and Oils
O
O CH2OC(CH2)16CH3
CH3(CH2)6CH2
C
H
CH2(CH2)6COCH
C
CH2OC(CH2)16CH3
H
O
2-Oleyl-1,3-distearylglycerol; mp 43°C
Fats and Oils
2-Oleyl-1,3-distearylglycerol
mp 43°C
H2, Pt
Tristearin
mp 72°C
Fatty Acids
O
O
O CH2OCR
O
H2O
R'COCH
CH2OCR"
R'COH
CH2OH
HOCR
HOCH
CH2OH
HOCR"
O
O
Acids obtained by the hydrolysis of fats and oils are called
fatty acids.
Fatty acids usually have an unbranched chain with an even
number of carbon atoms.
If double bonds are present, they are almost always cis.
Table 24.1
Systematic name Common name
O
CH3(CH2)10COH
Dodecanoic acid
Lauric acid
Tetradecanoic acid
Myristic acid
O
CH3(CH2)12COH
O
CH3(CH2)14COH
Hexadecanoic acid Palmitic acid
Table 24.1
Systematic name Common name
O
CH3(CH2)16COH
Octadecanoic acid
Stearic acid
Icosanoic acid
Arachidic acid
O
CH3(CH2)18COH
Table 24.1
O
CH3(CH2)7
(CH2)7COH
C
H
C
H
Systematic name: (Z)-9-Octadecenoic acid
Common name: Oleic acid
Table 24.1
O
CH3(CH2)4
C
H
(CH2)7COH
CH2
C
C
H H
C
H
Systematic name: (9Z, 12Z)-9,12-Octadecadienoic acid
Common name: Linoleic acid
Table 24.1
O
CH3CH2
C
H
C
C
H H
Systematic name:
(CH2)7COH
CH2
CH2
C
C
H H
C
H
(9Z, 12Z, 15Z)-9,12,15Octadecatrienoic acid
Common name: Linolenic acid
Table 24.1
O
OH
H
H
H
H
H
H
H
Systematic name:
H
(5Z, 8Z, 11Z, 14Z)-5,8,11,14Icosatetraenoic acid
Common name: Arachidonic acid
trans-Fatty Acids
Are formed by isomerization that can occur
when esters of cis-fatty acids are hydrogenated.
H
O
H
OR
H2, cat
O
OR
H
O
OR
H
H
O
H
OR
H2, cat
O
OR
24.3
Fatty Acid Biosynthesis
Fatty Acid Biosynthesis
Fatty acids are biosynthesized via acetyl
coenzyme A.
The group of enzymes involved in the overall
process is called fatty acid synthetase.
One of the key components of fatty acid
synthetase is acyl carrier protein (ACP—SH).
Fatty Acid Biosynthesis
An early step in fatty acid biosynthesis is the
reaction of acyl carrier protein with acetyl
coenzyme A.
O
CH3CSCoA + HS—ACP
O
CH3CS—ACP
+ HSCoA
Fatty Acid Biosynthesis
A second molecule of acetyl coenzyme A reacts
at its  carbon atom with carbon dioxide (as
HCO3–) to give malonyl coenzyme A.
O
–
+
HCO3
CH3CSCoA
Acetyl
coenzyme A
O
O
–
OCCH2CSCoA
Malonyl
coenzyme A
Fatty Acid Biosynthesis
Malonyl coenzyme A then reacts with acyl
carrier protein.
O
O
O
–
OCCH2CS—ACP
ACP—SH
O
–
OCCH2CSCoA
Malonyl
coenzyme A
Fatty Acid Biosynthesis
Malonyl—ACP and acetyl—ACP react by
carbon-carbon bond formation, accompanied by
decarboxylation.
O
CH3C
S—ACP
O
CH3C
– ••
•• O
••
O
C
O
CH2CS—ACP
O
CH2CS—ACP
S-Acetoacetyl—ACP
Fatty Acid Biosynthesis
In the next step, the ketone carbonyl is reduced
to a secondary alcohol.
OH
CH3C
H
O
CH2CS—ACP
NADPH
O
CH3C
O
CH2CS—ACP
S-Acetoacetyl—ACP
Fatty Acid Biosynthesis
The alcohol then dehydrates.
OH
CH3C
H
O
CH2CS—ACP
O
CH3CH
CHCS—ACP
Fatty Acid Biosynthesis
Reduction of the double bond yields
ACP bearing an attached butanoyl group.
Repeating the process gives a 6-carbon acyl
group, then an 8-carbon one, then 10, etc.
O
CH3CH2CH2CS—ACP
O
CH3CH
CHCS—ACP
24.4
Phospholipids
Phospholipids
Phospholipids are intermediates in the
biosynthesis of triacylglycerols.
The starting materials are L-glycerol 3phosphate and the appropriate acyl coenzyme
A molecules.
CH2OH
HO
H
O
+
O
RCSCoA
+ R'CSCoA
CH2OPO3H2
The diacylated
species formed
in this step is
O
called a
phosphatidic
R'CO
acid.
O
CH2OCR
H
CH2OPO3H2
O
O
R'CO
CH2OCR
H
CH2OH
H2O
The
phosphatidic
acid then
O
undergoes
hydrolysis of its
R'CO
phosphate ester
function.
O
CH2OCR
H
CH2OPO3H2
O
O
R'CO
CH2OCR
H
CH2OH
O
R"CSCoA
O
R'CO
O
CH2OCR
H
O
CH2OCR"
Reaction with a
third acyl
coenzyme A
molecule yields
the
triacylglycerol.
Phosphatidylcholine
Phosphatidic acids are intermediates in the
formation of phosphatidylcholine.
O
O
R'CO
CH2OCR
H
CH2OPO3H2
O
R'CO
O
CH2OCR
H
CH2OPO2–
+
(CH3)3NCH2CH2O
Phosphatidylcholine
O
O
R'CO
hydrophobic "tail"
CH2OCR hydrophobic "tail"
H
CH2OPO2–
+
(CH3)3NCH2CH2O
polar "head group"
Phosphatidylcholine
hydrophobic
(lipophilic) "tails"
hydrophilic "head group"
Cell Membranes
water
Cell membranes are
"lipid bilayers." Each
layer has an assembly
of phosphatidyl
choline molecules as
its main structural
component.
water
Cell Membranes
water
The interior of the cell
membrane is
hydrocarbon-like.
Polar materials cannot
pass from one side to
the other of the
membrane.
water
24.5
Waxes
Waxes
Waxes are water-repelling solids that coat the
leaves of plants, etc.
Structurally, waxes are mixtures of esters. The
esters are derived from fatty acids and longchain alcohols.
O
CH3(CH2)14COCH2(CH2)28CH3
Triacontyl hexadecanoate: occurs in beeswax
24.6
Prostaglandins
Prostaglandins
Prostaglandins are involved in many biological
processes.
Are biosynthesized from linoleic acid (C18) via
arachidonic acid (C20). (See Table 24.1)
Examples: PGE1 and PGF1
O
O
OH
HO
OH
O
HO
OH
HO
PGE1
OH
PGF1
Prostaglandin Biosynthesis
PGE2 is biosynthesized from arachidonic acid.
The oxygens come from O2.
The enzyme involved (prostaglandin
endoperoxide synthase) has cyclooxygenase
(COX) acitivity.
Prostaglandin Biosynthesis
CO2H
CH3
Arachidonic acid
O2
fatty acid cyclooxygenase
O
CO2H
O
HOO
CH3
PGG2
Prostaglandin Biosynthesis
O
CO2H
O
HO
PGH2
CH3
reduction of
hydroperoxide
O
CO2H
O
HOO
CH3
PGG2
Prostaglandin Biosynthesis
O
CO2H
O
HO
O
CH3
CO2H
CH3
HO
PGH2
HO
PGE2
Icosanoids
Icosanoids are compounds related to icosanoic acid
CH3(CH2)18CO2H.
Icosanoids include:
prostaglandins
thromboxanes
prostacyclins
leukotrienes
Thromboxane A2 (TXA2)
Thromboxane A2 is biosynthesized from PGH2
O
CO2H
O
HO
PGH2
CH3
TXA2 promotes platelet
aggregation and blood clotting
O
CO2H
O
HO
CH3
TXA2
Prostacyclin I2 (PGI2)
Like thromboxane A2, prostacyclin I2 is
biosynthesized from PGH2.
HO2C
O
PGI2 inhibits platelet
aggregation and relaxes
coronary arteries.
CH3
HO
OH
PGI2
Leukotriene C4 (LTC4)
Leukotrienes arise from arachidonic acid via
a different biosynthetic pathway. They are the
substances most responsible for constricting
bronchial passages during asthma attacks.
Leukotriene C4 (LTC4)
OH
CO2H
O
S
CH2CHCNHCH2CO2H
CH3
–
O2CCHCH2CH2
+ NH3
NH
C
O
24.7
Terpenes: The Isoprene Rule
Terpenes
Terpenes are natural products that are
structurally related to isoprene.
CH3
H2C
C
CH
CH2
or
Isoprene
(2-methyl-1,3-butadiene)
Terpenes
Myrcene (isolated from oil of bayberry)
is a typical terpene.
CH2
CH3
CH3C
CHCH2CH2CCH
or
CH2
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 "headto-tail".
head
tail
tail head
Table 24.2
Classification of Terpenes
Class
Number of carbon atoms
Monoterpene
10
Sesquiterpene
15
Diterpene
20
Sesterpene
25
Triterpene
30
Tetraterpene
40
Figure 24.7
Representative Monoterpenes
OH
O
H
-Phellandrene
Menthol
(eucalyptus)
(peppermint)
Citral
(lemon grass)
Figure 24.7
Representative Monoterpenes
OH
O
H
-Phellandrene
Menthol
(eucalyptus)
(peppermint)
Citral
(lemon grass)
Figure 24.7
Representative Monoterpenes
-Phellandrene
Menthol
(eucalyptus)
(peppermint)
Citral
(lemon grass)
Figure 24.7
Representative Sesquiterpenes
H
-Selinene
(celery)
Figure 24.7
Representative Sesquiterpenes
H
-Selinene
(celery)
Figure 24.7
Representative Sesquiterpenes
-Selinene
(celery)
Figure 24.7
Representative Diterpenes
OH
Vitamin A
Figure 24.7
Representative Diterpenes
OH
Vitamin A
Figure 24.7
Representative Diterpenes
Vitamin A
Figure 24.7
Representative Triterpene
tail-to-tail linkage of isoprene units
Squalene
(shark liver oil)
24.8
Isopentenyl Diphosphate:
The Biological Isoprene Unit
The Biological Isoprene Unit
The isoprene units in terpenes do not come from
isoprene.
They come from isopentenyl diphosphate.
Isopentenyl diphosphate (5 carbons) comes from
acetate (2 carbons) via mevalonate (6 carbons).
The Biological Isoprene Unit
O
O
3 CH3COH
CH3
HOCCH2CCH2CH2OH
OH
Mevalonic acid
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl diphosphate
Isopentenyl Diphosphate
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl diphosphate
or
OPP
Isopentenyl and Dimethylallyl Diphosphate
Isopentenyl diphosphate is interconvertible with
2-methylallyl diphosphate.
OPP
Isopentenyl diphosphate
OPP
Dimethylallyl diphosphate
Dimethylallyl diphosphate has a leaving group
(diphosphate) at an allylic carbon; it is reactive
toward nucleophilic substitution at this position.
24.9
Carbon-Carbon Bond Formation
in Terpene Biosynthesis
Carbon-Carbon Bond Formation
OPP
+
OPP
The key process involves the double bond of
isopentenyl diphosphate acting as a nucleophile
toward the allylic carbon of dimethylallyl
diphosphate.
Carbon-Carbon Bond Formation
OPP
+
OPP
–
OPP
+
OPP
After C—C Bond Formation...
OPP
The carbocation
can lose a proton
to give a double
bond.
–H
+
+
OPP
After C—C Bond Formation...
OPP
This compound is called geranyl diphosphate. It
can undergo hydrolysis of its diphosphate to give
geraniol (rose oil).
After C—C Bond Formation...
OPP
H2O
OH
Geraniol
From 10 Carbons to 15
OPP
+
OPP
Geranyl diphosphate
+
OPP
From 10 Carbons to 15
OPP
–H
+
+
OPP
From 10 Carbons to 15
OPP
This compound is called farnesyl diphosphate.
Hydrolysis of the diphosphate ester gives the
alcohol farnesol (Figure 24.7).
From 15 Carbons to 20
OPP
OPP
Farnesyl diphosphate is extended by another
isoprene unit by reaction with isopentenyl
diphosphate.
Cyclization
Rings form by intramolecular carbon-carbon
bond formation.
+
OPP
OPP
E double
bond
Z double
bond
Limonene
–H
+
+
OH
H2O
-Terpineol
Bicyclic Terpenes
+
+
+
-Pinene
-Pinene
+
24.10
The Pathway from Acetate to
Isopentenyl Diphosphate
Recall
O
O
3 CH3COH
CH3
HOCCH2CCH2CH2OH
OH
Mevalonic acid
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl diphosphate
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.
O
O
CH3CCH2CSCoA
S-Acetoacetyl
coenzyme A
Biosynthesis of Mevalonic Acid
O
O
O
CH3CCH2CSCoA + CH3CSCoA
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
O
O
O
CH3CCH2CSCoA + CH3CSCoA
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.
HO
O
CH3CCH2CSCoA
CH2COH
O
HO
CH3CCH2CH2OH
CH2COH
O
HO
O
CH3CCH2CSCoA
CH2COH
O
Mevalonic
acid
Conversion of Mevalonic Acid to
Isopentenyl Diphosphate
2–
HO
OPO3
CH3CCH2CH2OH
CH3CCH2CH2OPP
CH2COH
CH2COH
O
O
The two hydroxyl groups of mevalonic acid
undergo phosphorylation.
Conversion of Mevalonic Acid to
Isopentenyl Diphosphate
3–
2–
OPO3
OPO3
CH3CCH2CH2OPP
CH2
O
CH3CCH2CH2OPP
CH2
C
O
C
O
Phosphorylation is followed by a novel
elimination involving loss of CO2 and PO43–.
•• –
O ••
••
Conversion of Mevalonic Acid to
Isopentenyl Diphosphate
CH3CCH2CH2OPP
CH2
The product of this elimination is isopentenyl
diphosphate.
Biosynthetic Pathway is Based on
Experiments with 14C-labeled Acetate
O
O
CH3COH
CH3
HOCCH2CCH2CH2OH
OH
Mevalonic acid
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl diphosphate
Biosynthetic Pathway is Based on
Experiments with 14C-labeled Acetate
Citronellal biosynthesized using 14C-labeled
acetate as the carbon source has the labeled
carbons in the positions indicated.
CH3
O
CH3COH
H2C
•
•
•
•
•
CCH2CH2OPOPOH
O
•
O O
H
24.11
Steroids: Cholesterol
Structure of Cholesterol
Fundamental framework of steroids is the
tetracyclic unit shown.
Structure of Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Cholesterol has the fundamental steroid
skeleton modified as shown.
Structure of Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Some parts of the cholesterol molecule are
isoprenoid. But other parts don't obey the
isoprene rule. Also, cholesterol has 27 carbons,
which is not a multiple of 5.
Biosynthesis of Cholesterol
Cholesterol is biosynthesized from the triterpene
squalene. In the first step, squalene is
converted to its 2,3-epoxide.
O2, NADH, enzyme
O
Biosynthesis of Cholesterol
O
To understand the second step, we need to look
at squalene oxide in a different conformation,
one that is in a geometry suitable for cyclization.
O
Biosynthesis of Cholesterol
HO
+
H
Cyclization is triggered by epoxide ring opening.
H+ O
Biosynthesis of Cholesterol
HO
+
H
The five-membered ring expands to a six-membered
one.
H
HO
H
Biosynthesis of Cholesterol
H
HO
protosteryl cation
H
Cyclization to form a tetracyclic carbocation.
H
HO
H
Biosynthesis of Cholesterol
••
•• OH
2
HO
H
H
Deprotonation and multiple migrations.
H
HO
H
Biosynthesis of Cholesterol
The product of this rearrangement is a
triterpene called lanosterol. A number of
enzyme-catalyzed steps follow that convert
lanosterol to cholesterol.
H
HO
H
Cholesterol
Cholesterol is the biosynthetic precursor to a
large number of important steroids:
Bile acids
Vitamin D
Corticosteroids
Sex hormones
24.12
Vitamin D
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Cholesterol is the precursor to vitamin D.
Enzymes dehydrogenate cholesterol to introduce a second
double bond in conjugation with the existing one. The
product of this reaction is called 7-dehydrocholesterol.
7-Dehydrocholesterol
CH3
CH3
CH3
CH3
H
CH3
H
HO
Sunlight converts 7-dehydrocholesterol on the
skin's surface to vitamin D3.
Vitamin D3
CH3
CH3
CH3
CH3
H
HO
Insufficient sunlight can lead to a deficiency of
vitamin D3, interfering with Ca2+ transport and
bone development. Rickets can result.
24.13
Bile Acids
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Oxidation in the liver degrades the cholesterol side chain
and introduces OH groups at various positions on the
steroid skeleton. Cholic acid (next slide) is the most
abundant of the bile acids.
Cholic Acid
O
HO CH3
CH3
CH3
H
HO
OH
H
H
OH
H
Salts of cholic acid amides (bile salts), such as sodium
taurocholate (next slide), act as emulsifying agents to aid
digestion.
Sodium Taurocholate
O
HO CH3
CH3
CH3
H
HO
H
H
OH
H
NHCH2CH2SO3Na
24.14
Corticosteroids
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Enzymatic degradation of the side chain and oxidation of
various positions on the steroid skeleton convert cholesterol
to corticosteroids.
Cortisol
O
CH3
HO
CH3
H
OH
OH
H
H
O
Cortisol is the most abundant of the corticosteroids.
Enzyme-catalyzed oxidation of cortisol gives cortisone.
Cortisone
O
CH3
OH
O
CH3
H
OH
H
H
O
Corticosteroids are involved in maintaining electrolyte
levels, in the metabolism of carbohydrates, and in
mediating the allergic response.
24.15
Sex Hormones
Testosterone
H3C
H3C
OH
H
H
H
O
Testosterone is the main male sex hormone.
Estradiol
H3C
OH
H
H
H
HO
Estradiol is a female sex hormone involved in
regulating the menstrual cycle and in reproduction.
Progesterone
O
H3C
H3C
H
H
H
O
Supresses ovulation during pregnancy.
24.16
Carotenoids
Carotenoids
Carotenoids are naturally occurring pigments.
Structurally, carotenoids are tetraterpenes.
They have 40 carbons. Two C20 units are linked
in a tail-to-tail fashion.
Examples are lycopene and -carotene.
Carotenoids
Lycopene (tomatoes)
-Carotene (carrots)