14.3 aldol reaction and claisen condensation in biology enol – keto tautomerization aldol reaction...
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14.3 Aldol Reaction and Claisen Condensation in Biology
RC
CH3
O
RC
CH2
OH
RC
CH3
O
RC
CH2
OH
+R
CCH2
O
CCH3
OHR
ZC
CH3
O
ZC
CH2
OH
+
ZC
CH2
O
CCH3
O
+ ZH
Enol – Keto Tautomerization
Aldol Reaction
Claisen Condensation
Main Menu
2
Enol – Keto Tautomerization
RC
CH3
O
RC
CH2
OH
EnolKeto
a-H is required to have keto-enol tautomerization.
a
- H++ H+
RC
CH2
O
RC
CH2
O
Enolate
In acidic condition
In basic condition
3
Examples of Enol – Keto Tautomerization
RC
CH2
O
CH3R
CC
OH
CH3
H
+ RC
C
OH
H
CH3
RC
CH
O
CH3
CH3
RC
C
OH
CH3
CH3
RC
C
O
CH3
CH3H3C
RC
C
OH
CH3
CH3H3C
a
a
a
4
Enol – Keto Tautomerization in Carbohydrates
EnolKeto
Keto-enol tautomerization can lead to structural isomerization between aldose and ketose.
CHO
OHH
HHO
OHH
OHH
CH2OH
CH
OH
HHO
OHH
OHH
CH2OH
HO CH2OH
O
HHO
OHH
OHH
CH2OH
Keto
D-glucose (an aldose)
D-fructose(a ketose)
5
Enol – Keto Tautomerization in Glycolysis
Reaction 2
Keto-enol tautomerization catalyzed by phosphoglucoisomerase
Glucose-6-phosphate
Fructose-6-phosphate
O
O
HOHO
HOOH
P
O
O
O
OH
HO
OHO
OHOP
O
O
Ophosphoglucoisomerase
(an aldose)(a ketose)
6
Isomerization of Glucose-6-phosphate
Glucose-6-phosphate
Fructose-6-phosphate
OHH
OH H
H OH
O
OHOP
O
O
O
Cyclic hemiacetal form
Opened form glucose-6-phosphate
KetoEnol
OH
OHOH
H
H
OH
H O
OP
O
O
O
HH
Opened form fructose-6-phosphate
Cyclic hemiketal form
2
2
1
1
O
O
HOHO
HOOH
P
O
O
O
1
OH
O
HOHO
HOO
P
O
O
O
H1
OH
O
HOHO
HO OH
P
O
O
O
H1
2
7
Enol – Keto Tautomerization in Glycolysis
Reaction 5
Keto-enol tautomerization catalyzed by Triosephosphateisomerase
Dihydroxyacetone phosphate
Glyceraldehyde-3-phosphate
Triosephosphateisomerase
(an aldose)(a ketose)
CH2OH
C
H2C
O
O
PO32-
CHO
C
H2C
OH
O
PO32-
H
CHOH
C
H2C
OH
O
PO32-
Keto
Enol
Keto
8
Learning Check
1. What represent the correct enol-keto tautomerization for the following ketone or aldehyde?
OH
OH
OH
HO O
OH
OH
OH
HO OH
OH
OH
OH
HO O
OH
OH
OH
HO OH
OH
OH
O
HO OH
OH
OH
OH
HO OH
OH
OH
O
HO OH
OH
OH
OH
HO OH
I
II
III
IV
(a) I, II
(b) I, II, III
(c) II, III, IV
(d) II, IV
(e) None of the above
9
Aldol Reaction
Enol Keto
Formation of new C-C bond by combining keto and enol (enolate)
In acidic conditionH
CCH
OH
RH
CCH2
O
R+ HC
C
O
R
CCH2
OH
R
H
H
The product contains an aldehyde and an alcohol functional groups: Aldol reaction.
The product may have two new stereocenters.
Aldol reaction can be reversible.
The product contains a b-hydroxycarbonyl motif.
b
10
Electron Flow in Aldol Reaction
Enol Keto
Aldol reaction: Formation of new C-C bondIn acidic
condition
+ HC
C
O
R
CCH2
OH
R
H
HH
CCH2
O
RH
CCH
O
R
H H+
Retro-Aldol reaction: Breaking of C-C bond between a and b carbons
a b
HC
C
O
R
CCH2
O
R
H
H
H
H+
a b Enol KetoH
CCH
OH
RH
CCH2
O
R+
11
Electron Flow in Aldol Reaction
Enolate Keto
Aldol reaction: Formation of new C-C bond In basic condition
+H
CC
O
R
CCH2
OH
R
H
H
Retro-Aldol reaction: Breaking of C-C bond between a and b carbons
a b
a bEnolate Keto
+
HC
CH2
O
RH
CCH
O
RH
CC
O
R
CCH2
R
H
H
O H+
HC
CH
O
RH
CCH2
O
R
HC
C
O
R
CCH2
R
H
H
O
12
Retro-Aldol Reaction in Glycolysis
Reaction 4
Retro-Aldol catalyzed by fructose-1,6-bisphosphate aldolase
Fructose-1,6-bisphosphate
Fructose-1,6-bisphosphatealdolase
OHH
OH H
H OH
O
OOP
O
O
O
PO O
O CH2OH
C
H2C
O
O
PO32-
CHO
C
H2C
OH
O
PO32-
H +
Dihydroxyacetone phosphate
Glyceraldehyde-3-phosphate
13
How does Retro-Aldol Reaction Generate Two 3-Carbon Sugars?
Equilibrium between cyclic hemiketal and opened form
Fructose-1,6-bisphosphate
OHH
OH H
H OH
O
OOP
O
O
O
PO O
O
CH2OH
C
H2C
O
O
PO32-
CHO
C
H2C
OH
O
PO32-
H
Cyclic hemiketal form
Opened form
H+OH
O H
H OH
OH
OOP
O
O
O
PO O
O
H
b H
O
H
OH
OP
O
O
O
OH
H
HO
O
PO O
O
+1
2
1
2
: Retro-aldol reaction
: Keto-enol tautomerization
14
Aldol Reaction in Citric Acid Cycle
Reaction 1
Citrate synthesis catalyzed by citrate synthase
Citrate
Citrate synthaseS CoACH3
C
O
acetyl CoA
CO2-
C O
CH2
CO2-
oxaloacetate
CH2
C CO2-
CH2
CO2-
HO
CO2-
+
S CoACH2
C
OH
oxaloacetate
1 : Aldol reaction
1CH2
C CO2-
CH2
CO2-
HO
C
SO CoA
H2O
HS-CoA2
2 : Hyrolysis of thioester
15
Learning Check
1. What represent the correct aldol reactions?
I
II
III
IV
(a) I, III, IV
(b) I, II, III
(c) I, II, IV
(d) II, IV
(e) None of the above
OH
O
OHHO O
O
OH
OH
H3C O
CO2-
O O
HO
O
OH
O
HO OH
OH
OH
OH
HO O+
OH
OH
OH
H3C O
CO2-
OH O
HO
OH
OH
O
HO OH
+
+
+
16
Claisen Condensation
Enol (Acetyl CoA)
Carboxyl(Ester)
Formation of new C-C bond by combining carboxyl and enol (enolate)
+
Forging two carboxyl functional groups and removal of a small molecule: Claisen condensation.The electron flow is similar to that of an aldol raction.
Claisen condensation can be reversible.
The product contains a b-ketocarbonyl motif that can undergo decarboxylation spontaneously.
H3CC
O
O
R
SC
CH2
OH
CoAS
CCH2
O
CCH3
O
CoA
b
ROH+
17
Electron Flow in Claisen Condensation
Claisen condensation: Formation of new C-C bond
SC
CH3
O
SC
CH2
OH H+
CoA CoA+
Enol (Acetyl CoA)
Keto(Acetyl CoA)
SC
CH2
O
CoA C
O S
CH3
CoA
H
a
b
SC
CH2
O
CCH3
O
CoA
HSCoA
Reaction in ketogenesis! b-ketocarbonyl
18
Electron Flow in Retro-Claisen Condensation
Retro-Claisen condensation: Breaking of a C-C bond
The 4th reaction in the repeated cycle of b-oxidation.
SC
CH2
O
CCH3
O
CoA
HSCoA
a
b
SC
CH2
O
CoA C
O S
CH3
CoA
H
1 : Similar to the formation of hemiketal
1S
CCH3
O
CoA
+
2S
CCH2
OH
CoA
2 : Keto-enol tautomerizationS
CCH3
O
CoA
19
Carboxylation and Claisen Condensation
Synthesis of malonyl CoA catalyzed by acetyl CoA carboxylase
OC
O
O
HS
CCH3
O
CoA
Acetyl CoA Carboxylase
SC
CH2
O
CoA CO
O
ATP ADP + Pi Malonyl CoABicarbonate
+
Bicarbonate: water soluble form of carbon dioxide
OC
O
O
- H+
+ H+
OC
O
O
H
- H+
+ H+
OC
O
O
H H
BicarbonateCarbonate Carbonic acid
OC
O
O
H H
H+
CO2 + H2O
(for lipogenesis)
20
Mechanism in the Synthesis of Malonyl CoA
Acetyl CoA carboxylase contains biotin as the carboxyl group carrier.
OP
O
O
ADP
O
OC
O
O
HATP ADP
OC
O
H
OP
O
O
OPi + 2 H+
NHHN
S
HN
O
Enz
O
Biotin-enzyme
NHN
S
HN
O
Enz
O
CO
O
1 : Similar to transacylation
1 1
Biotin-enzyme
Acetyl CoAS
CCH2
O
CoA CO
O
2 : Claisen condensation
2
Malonyl CoA
21
Decarboxylation Is Similar to a Retro-Claisen Reaction
Reaction 3
a-ketoglutarate synthesis catalyzed by isocitrate dehydrogenase
-a ketoglutarate
isocitratedehydrogenase
isocitrate
+
intermediate
1 : Oxidation
1
NAD+
NADH
2
2 : Decarboxylation
CH2
C CO2-
C
CO2-
CO2-
H
HO H
CH2
C H
C
CO2-
CO2-
H
O
CH2
C CO2-
C
CO2-
CO2-
H
O
CO2
22
Electron Flow in DecarboxylationThe molecule contains b-ketocarbonyl motif can undergo decarboxylation spontaneously.
-a ketoglutarateenolate
CH2
C H
C
CO2-
CO2-
H
O
CO2CH2
C C
C
CO2-
CO2-
H
O
O
O
CH2
C
C
CO2-
CO2-
H
O
H+
b
23
Claisen Condensation in Lipogenesis
Reaction catalyzed by b-ketoacyl ACP synthase
1
CO2 + ACP-SH
2 : Claisen condensation
SC
CH3
O
ACPS
CCH2
O
ACP CO
O
+
b-ketoacyl ACP synthase
SC
CH2
O
ACP CCH3
O
SC
CH2
O
ACP CO
OCO2
1
: Decarboxylation
SC
CH2
ACP
O
SC
CH3
O
ACPS
CCH2
O
ACP C
O S
CH3
ACP
ACP-SH
2
ACP-S- + H+
SC
CH2
O
ACP CCH3
O
2
24
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-1,5-bisphosphate carboxylase
2-carboxy-3-keto-D-arabinitol-1,5-bisphosphate
Carbamate
+
CO2
CH2OPO32-
C O
C
C
H OH
CH2OPO32-
H OH
ribulose-1,5-bisphosphate
CH2OPO32-
C CO2-
C
C
O
CH2OPO32-
H OH
HO
- H+
NC
O
O
H
Enz
Enz NH2
25
Mechanism in Carbon Dioxide Fixation
2-carboxy-3-keto-D-arabinitol-1,5-bisphosphate
Enol intermediate
CH2OPO32-
C O
C
C
H OH
CH2OPO32-
H OH
ribulose-1,5-bisphosphate
CH2OPO32-
C CO2-
C
C
O
CH2OPO32-
H OH
HO
1 : Keto-enol tautomerization
1
2 : Claisen condensation
2
NC
O
O
H
CH2OPO32-
C OH
C
C
O
CH2OPO32-
H OHH
H+
Enz
Enz NH2
Synthesis of 2-carboxy-3-keto-D-arabinitol-1,5-bisphosphate catalyzed by Rubisco
26
Retro-Claisen Condensation in Calvin Cycle
1 : Hydration of ketone
2 : Retro-Claisen condensation
CH2OPO32-
C CO2-
C
C
O
CH2OPO32-
H OH
HOH2O H+
CH2OPO32-
C CO2-
C
C
HO OH
CH2OPO32-
H OH
HO
CH2OPO32-
C
CO2-
CO2-
C
CH2OPO32-
H OH
HO H
+
Synthesis of two molecules of 3-phosphoglycerate catalyzed by Rubisco
2-carboxy-3-keto-D-arabinitol-1,5-bisphosphate
hydrated (ketal) intermediate
two molecules of 3-phosphoglycerate
1 2
27
Electron Flow in the Synthesis of 3-Phosphoglycerate
hydrated (ketal) intermediate
two molecules of 3-phosphoglycerate
CH2OPO32-
C
C
C
HO O
CH2OPO32-
H OH
HO CO
O
H
C
C
HO
O
CH2OPO32-
H OH
H+
+
CH2OPO32-
C
CO2-
HO H
CH2OPO32-
C
HOC
O
O
H+
H+CO2
-
C
CH2OPO32-
H OH
28
Learning Check
1. What represent the correct Claisen condensations?
I
II
III
IV
(a) I, III, IV
(b) I, II, III
(c) I, II, IV
(d) II, IV
(e) None of the above
S
O OHO CoA
CO2-
O
O O
HO+
+
+
O O
HS CoA+
S
O
CoAS
O
CoAS
O O
CoA HS CoA+
S
O
CoA-O2C CO2
-
OH-O2C
S
O CoA
O
O OHO H O
O O
HO+
OO
O
H2O+
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