14.3 Aldol Reaction and Claisen
Condensation in Biology
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Enol – Keto Tautomerization
Aldol Reaction
Claisen Condensation
Enol – Keto Tautomerization
a-H is required to have keto-enol tautomerization.
In acidic
condition
a
Keto
+ H+
Enol
- H+
In basic
condition
Enolate
2
Examples of Enol – Keto
Tautomerization
a
a
a
3
Enol – Keto Tautomerization
in Carbohydrates
Keto-enol tautomerization can lead to structural isomerization
between aldose and ketose.
Keto
Enol
Keto
D-glucose
D-fructose
(an aldose)
(a ketose)
4
Enol – Keto Tautomerization
in Glycolysis
Keto-enol tautomerization catalyzed by phosphoglucoisomerase
phosphoglucoisomerase
Reaction 2
Glucose-6phosphate
(an aldose)
Fructose-6phosphate
(a ketose)
5
Isomerization of Glucose-6phosphate
1
Glucose-6phosphate
Cyclic hemiacetal
form
1
Opened form
glucose-6phosphate
2
1
Enol
1
2
Opened form
fructose-6phosphate
Keto
Fructose-6phosphate
Cyclic hemiketal
form
1
2
6
Enol – Keto Tautomerization
in Glycolysis
Keto-enol tautomerization catalyzed by Triosephosphate
isomerase
Triosephosphate
isomerase
Keto
Keto
Reaction 5
Dihydroxyacetone
phosphate
Glyceraldehyde3-phosphate
(a ketose)
(an aldose)
Enol
7
Learning Check
1. What represent the correct enol-keto tautomerization for the following
ketone or aldehyde?
I
(a) I, II
(b) I, II, III
II
(c) II, III, IV
(d) II, IV
III
(e) None of the above
IV
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Aldol Reaction
Formation of new C-C bond by combining keto and enol (enolate)
b
+
Enol
In acidic
condition
Keto
The product contains an aldehyde and an alcohol functional
groups: Aldol reaction.
The product may have two new stereocenters.
The product contains a b-hydroxycarbonyl motif.
Aldol reaction can be reversible.
9
Electron Flow in Aldol Reaction
Aldol reaction: Formation of new C-C bond
a
+
Enol
b
In acidic
condition
Keto
Retro-Aldol reaction: Breaking of C-C bond between a and b carbons
a
b
+
Enol
Keto
10
Electron Flow in Aldol Reaction
Aldol reaction: Formation of new C-C bond
In basic
condition
H+
+
a
b
Keto
Enolate
Retro-Aldol reaction: Breaking of C-C bond between a and b carbons
a
+
b
Enolate
Keto
11
Retro-Aldol Reaction in
Glycolysis
Retro-Aldol catalyzed by fructose-1,6-bisphosphate aldolase
Fructose-1,6-bisphosphate
aldolase
+
Reaction 4
Fructose-1,6bisphosphate
Glyceraldehyde- Dihydroxyacetone
phosphate
3-phosphate
12
How does Retro-Aldol Reaction
Generate Two 3-Carbon Sugars?
Equilibrium between cyclic hemiketal and opened form
1
b
Fructose-1,6bisphosphate
H+
+
2
Opened form
Cyclic hemiketal
form
1
: Retro-aldol reaction
2
: Keto-enol tautomerization
13
Aldol Reaction in Citric Acid Cycle
Citrate synthesis catalyzed by citrate synthase
Citrate synthase
+
Reaction 1
acetyl CoA
Citrate
oxaloacetate
2
HS-CoA
1
oxaloacetate
H2O
1
: Aldol reaction
2
: Hyrolysis of thioester
14
Learning Check
1. What represent the correct aldol reactions?
I
(a) I, III, IV
(b) I, II, III
II
(c) I, II, IV
(d) II, IV
III
(e) None of the above
IV
15
Claisen Condensation
Formation of new C-C bond by combining carboxyl and enol
(enolate)
b
+
Enol
Carboxyl
(Acetyl CoA) (Ester)
+
ROH
Forging two carboxyl functional groups and removal of a small
molecule: Claisen condensation.
The electron flow is similar to that of an aldol raction.
The product contains a b-ketocarbonyl motif that can undergo
decarboxylation spontaneously.
Claisen condensation can be reversible.
16
Electron Flow in Claisen
Condensation
Claisen condensation: Formation of new C-C bond
+
Enol
Keto
(Acetyl CoA) (Acetyl CoA)
b
a
HSCoA
Reaction in ketogenesis!
b-ketocarbonyl
17
Electron Flow in Retro-Claisen
Condensation
Retro-Claisen condensation: Breaking of a C-C bond
HSCoA
b
a
1
+
2
1
: Similar to the formation of hemiketal
2
: Keto-enol tautomerization
The 4th reaction in the repeated cycle of b-oxidation.
18
Carboxylation and Claisen
Condensation
Synthesis of malonyl CoA catalyzed by acetyl CoA carboxylase
Acetyl CoA
Carboxylase
+
Bicarbonate ATP
ADP + Pi
Malonyl CoA
(for lipogenesis)
Bicarbonate: water soluble form of carbon dioxide
Carbonate
+ H+
+ H+
- H+
- H+
Bicarbonate
CO2
+
Carbonic acid
H2O
19
Mechanism in the Synthesis of
Malonyl CoA
Acetyl CoA carboxylase contains biotin as the carboxyl group carrier.
1
ATP
1
Pi + 2 H+
ADP
Biotin-enzyme
2
Acetyl CoA Biotinenzyme
1
: Similar to transacylation
Malonyl CoA
2
: Claisen condensation
20
Decarboxylation Is Similar to a
Retro-Claisen Reaction
a-ketoglutarate synthesis catalyzed by isocitrate dehydrogenase
isocitrate
dehydrogenase
+
CO2
Reaction 3
a-ketoglutarate
isocitrate
2
1
NAD+
NADH
intermediate
1
: Oxidation
2
: Decarboxylation
21
Electron Flow in Decarboxylation
The molecule contains b-ketocarbonyl motif can undergo
decarboxylation spontaneously.
H+
CO2
b
enolate
a-ketoglutarate
22
Claisen Condensation in
Lipogenesis
Reaction catalyzed by b-ketoacyl ACP synthase
b-ketoacyl ACP
synthase
+
CO2 + ACP-SH
CO2
2
1
ACP-S-
+ H+
ACP-SH
2
1
2
: Decarboxylation
: Claisen condensation
23
Carboxylation in Calvin Cycle and
Claisen Condensation
Synthesis of 2-carboxy-3-keto-D-arabinitol-1,5-bisphosphate
catalyzed by ribulose-1,5-bisphosphate carboxylase/oxygenase
(Rubisco)
Ribulose-1,5bisphosphate
carboxylase
+
Carbamate
ribulose-1,5bisphosphate
- H+
CO2
2-carboxy-3-keto-Darabinitol-1,5bisphosphate
24
Mechanism in Carbon Dioxide
Fixation
Synthesis of 2-carboxy-3-keto-D-arabinitol-1,5-bisphosphate
catalyzed by Rubisco
1
ribulose-1,5bisphosphate
2
Enol
intermediate
1
: Keto-enol tautomerization
2
: Claisen condensation
2-carboxy-3-keto-Darabinitol-1,5bisphosphate
25
Retro-Claisen Condensation in
Calvin Cycle
Synthesis of two molecules of 3-phosphoglycerate catalyzed by
Rubisco
H2O
H+
1
2
2-carboxy-3-keto-Darabinitol-1,5bisphosphate
hydrated (ketal)
intermediate
1
: Hydration of ketone
2
: Retro-Claisen condensation
two molecules of 3phosphoglycerate
26
Electron Flow in the Synthesis of 3Phosphoglycerate
H+
+
H+
hydrated (ketal)
intermediate
two molecules of 3phosphoglycerate
27
Main Menu
Learning Check
1. What represent the correct Claisen condensations?
(a) I, III, IV
I
(b) I, II, III
II
(c) I, II, IV
(d) II, IV
III
(e) None of the above
IV
28