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SCH 511
Dr. Solomon Derese 106
SCH 511
Dr. Solomon Derese 107
Polyketo thioesters
Aromatic compounds or otherPolyketide derived metabolites
Acetyl SEcondensing
n-2SACP
O O O
SACP
O
O
O
Hn
S
OEcondensing
Malonyl SACPPKS
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Dr. Solomon Derese 108
The biosynthesis of fatty acids and polyketides isbasically the same except that the β-keto group isgenerally not completely reduced out in thebiosynthesis of polyketide derive compounds.
SACP
OO
This gives rise to huge structural diversity basedaround a 1,3-oxygenation pattern and cyclization togive aromatic compounds.
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Dr. Solomon Derese 109
O
CoAS
SH SH
ACPCE
Polyketide Synthase (PKS)‘molecular machine’
S SH
ACPCE
O
AT
ACPCE
O
CoAS O
O
MT
SO S O
O
O
H+
SH S
ACPCE
O
REDUCTION
1) KR2) DH3) ER
O
SH S
ACPCE
O
O
DecarboxylativeClaisencondensation
SH
ACPCE
TRANSLOCATION
O S
O
SH
ACPCE
O S
n
nO
O
OHn
TEOOO
Biosynthesis of Polyketides
AT= Acetyl transferaseMT= Malonyl transferaseCE= Condensing enzyme
ACP= Acyl Carrier ProteinKR= Keto ReductaseER= Enoyl Reductase
DH= dehydrataseTE= thioesterase
±Differencebetween FA and PKbiosynthesis
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Unlike fatty acids, polyketides are NOTBiosynthesised by humans – only by plants,microorganisms (bacteria) & fungi.The biosynthesis of polyketides is catalyzed by theenzyme PolyKetide Synthase (PKS).
S
O O
Econdensing
O S
O O
ACPH
O S
O O
ACPH
O O
S
O
ACP
O O O O
SACP
Such compounds which possess a chain ofalternating ketone and methylene groups are calledpolyketides.
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EXAMPLES OF POLYKETIDE DERIVED SECONDARY METABOLITES
OH O OHOH
O
CONH2
OH
NCH3
H
H3C
HH3C OH
O
OO
O OOHO
O
OH
HO
Emodin
O
OOHPlumbagin
Eugenone
O
O
OH
HO
OOH
Rebelomycine
OHHO
O
O
H
Orsellinic acid
Tetracycline (Antibiotic)
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n-2SACP
O O O1,3-Diketo polymer
The poly-β-keto ester is very reactive, andthere are various possibilities forintramolecular Claisen or Knoevenagelcondensation reactions.
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Methylenes flanked by two carbonylsare activated, allowing formation ofcarbanions/enolates and subsequentreaction with ketone or ester carbonylgroups, with a natural tendency to formstrain-free six membered rings.
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O O
R R'
HO O
H
R R'Keto TautomerEnol tautomer Enol tautomer
H-Bonding
Favored structure
The Chemistry of 1,3-DicarbonylsKeto-Enol Tautomerism
There are two important condensation reactions of1,3-Dicarbonyls which are relevant to polyketidechemistry; Knoevenagel and Claisen condensationreactions.
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Dr. Solomon Derese 115
The Knoevenagel Condensation reaction
O OH
R OEt
O O
R OEt1,3-Dicarbonyl compund
OR2
R1
Aldehyde/Ketone
O OH
R OEt
R2R1 O
Proton transfer
O O
R OEt
R2R1 OH
HO O
R OEt
R2R1A new C-C
double bond
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Dr. Solomon Derese 116
A condensation reaction between 1,3-dicarbonyl compounds andaldehydes/ketones resulting in the formationof a new carbon-carbon double bond with aloss of water is called the KnoevenagelCondenation reaction.
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Dr. Solomon Derese 117
The Claisen Condensation reactionO O
H
R OEt
O O
R OEt1,3-Dicarbonyl compund
OEtO
R1
Ester
O OH
R OEt
OR1
- H+
O O
R OEt
OR1
The condensation reaction of 1,3-dicarbonyls withesters is called Claisen condensation reaction.
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Dr. Solomon Derese 118
O O
R OEt
O
EtO R1
Ester
H H
O O
R OEt
OR1
In principle, a thioester could replace an estergiving the same product but with loss of thiol(RSH) rather than an alcohol. This is importantin biosynthesis as nature often works withthioesters.
The Claisen Condensationreaction
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Polyketide CyclisationsFormation of Unsaturated Products
Polyketide can cyclize to obtainvarious classes of natural productsthrough condensation reactions ofthe Knoevenagel and Claisen types.
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S
OEcondensing
SACP
O
O
O
H3
O O O O
SEnz
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The polyketo ester formed from four acetate units(one acetate starter group and three malonatechain extension units) is capable of being folded inat least two ways, A and B.
A B
O O O O
SEnz
O
O
O O
SEnz
OO
O SEnz
O
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Dr. Solomon Derese 122
O
O
O O
SEnz
AO
OH
O
OOH
H
O
OH
O
O
Knoevenagelreaction
Dehydration favored by formationof conjugated system
O
OH
OH
HO Enolization
Orsellinic acid
Enolization favored by formation of aromatic ring.
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Dr. Solomon Derese 123
OO
O SEnz
O
B
OO
OO
SEnz
Claisenreaction
OO
O O
Re-formation of carbonylpossible by expulsion ofleaving group
EnolizationOOH
HO OH
Phloracetophenone
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Dr. Solomon Derese 124
A distinctive feature of an aromatic ring systemderived through the acetate pathway is that severalof the carbonyl oxygens of the poly-β-keto systemare retained in the final product. These end up onalternate carbons around the ring system.
Of course, one or more might be used in forming acarbon–carbon bond, as in orsellinic acid.
Nevertheless, this oxygenation on alternate carbonatoms, a meta oxygenation pattern, is usuallyeasily recognizable, and points to the biosyntheticorigin of the molecule.
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SEnz
O O O O O O O
O
O
O
O
O
OS
O
Enz
HO
O
OH
OHO
Alternariol
O
O
O
OSEnz
O
HO
O
OH
OHOEnzS
H
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Dr. Solomon Derese 126
The biosynthesis of compound Alternariolinvolves two Knoevenagel-typecondensations and in the last step shown,an ester linkage is formed between aphenolic hydroxy group and the thioestergroup. Such cyclic esters are called lactones.
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SEnz
O O O O O O O
O
O
O
O
O
OS
O
Enz
O
O
O
OSEnz
O
HO
O
OH
OHOEnzS
H
HO
O
OH
OHOAlternariol
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Dr. Solomon Derese 128
Secondary Structural ModificationsDuring Polyketide Cyclisations
The structural variety of polyketide-derived naturalproducts is increased enormously by secondarystructural modifications.
We have already seen such an example in thebiosynthesis of alternariol in which an ester linkagehas been created. The formation of these esterlinkages can be considered as secondarymodifications after cyclization of the polyketideshas occurred.
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I. MethylationII. DecarboxylationIII. ReductionIV. Oxidation
There are many types of secondarymodification which can occur to polyketide-derived natural products. Four commonmodifications which we will consider are:
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I. Alkylation
O and C-methylation reaction can occur inbiological systems using S-Adenosinemethionine(SAM).
Methylation
S
Ad
CH3
RS-AdenosineMethionine (SAM).
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OH
O-P director
OH
CH3
C-Methylation
S
Ad
CH3
R
OH
S
Ad
CH3
R
C-Methylation
O
O-Methylation
S
Ad
CH3
R
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Dr. Solomon Derese 132
Example
OOO
O
O
SEnz
O O
OMe
OMe
MeO
Eugenone
3 SAMClaisen
O O
OH
OH
HO
OO OOH OOH
CH3
SCH3R2
R1
OO
CH3
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II. Decarboxylation
OH
O
O
R
R
b-Keto carboxylic acid
Decarboxylation is very common in biosyntheticand organic reactions.
b-Keto carboxylic acid decarboxylates readily.
OH
R
R O
R
R
ab
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Dr. Solomon Derese 134
OHHO
OH
O
OHO
O
O
H
o-Hydroxy carboxylc acidCO2
OHHO
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III. Reduction
Ketone reduction followed by dehydration is oftenused as a method for introducing a double bondand we have already met examples of this processin the biosynthesis of unsaturated fatty acids.
O
:H- (from NADPH)
Ketone
OH+ OH
H H Cis
Reduction and Dehydration
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Example
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IV. Oxidationa. One common biosynthetic oxidation is the
conversion of a methyl group which is directlyattached to a benzene ring into its correspondingcarboxylic acid i.e. Ar-CH3 > ArCO2H.
CH2OH
H
O
OH
O
[O]
[O]
[O]
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Dr. Solomon Derese 138
The oxidation of a methyl groupwhich is attached to an aromaticneed not necessarily proceed to thecarboxylic acid level of oxidation; analcohol could be formed i.e. Ar-CH3 >ArCH2OH, even an alhehyde (ArCHO).
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b. Oxidation benzene into phenol (Ar-H toAr-OH). These reactions are catalysed byenzymes known as monooxygenases (so-called because they introduced oneoxygen atom from oxygen).
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Quinone
c. A phenol is oxidized to a quinone using theenzyme Dehydrogenase (- H2).
OH
OH
Dehydrogenase
O
O
OH
OH
Dehydrogenase
O
O
Examples
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Dr. Solomon Derese 141
O
HO CH2OH
O
Shanorelin
O
SO
Enz
O
O
2 X SAM
O
SO
Enz
O
O
OH
HO
O OH
Knoevenagel
Enolization
Hydroxylation
OH
HO CH2OH
OH
Decarboxylation
Methyl Oxidation
OH
HO CH2OH
Example
Dehydrogenase
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Dr. Solomon Derese 142
d. Phenolic oxidative coupling
OH
[O]1
2
3
4
O
12
3
4
Phenoxy raidcal
O
12
3
4
O
12
3
4
O
12
3
4
Phenols are oxidised to their correspondingphenoxy radicals.
The unpaired electron in a phenoxy radical can bedelocalised over the oxygen atom, the carbon atomat the 2-position (ortho) and the carbon atom atthe 4-position (para).
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Dr. Solomon Derese 143
Once phenoxy radicals have been generated, theydimerise by pairing the unpaired electron of onephenoxy radical with the unpaired electron of asecond phenoxy radical.
OO
H
H
OHOH
Coupling
Aromatization
C-C Bond
O
O
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Dr. Solomon Derese 144
OO
O
OH
OH
O
Aromatization
C-O Bond
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OO
Aromatization
O O
H
HO OC-O Bond
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ExampleO O O
O
O O
OSEnz
OH O OH
HO OHOH
OH O
OH
O
MeO
OMe
H
MeOOH
MeO O
O
O
MeO
MeO
Cl
O
O
O
OMe
OH
O•O•
MeO
OMeOOH
OO•
MeO
OMeO
Griseofulvin, A natural productwith fungicidal activity isolatedfrom the mould of Peniciliumgriseofulvum.
SAM
[o]
SAMNADPH Chlorination
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Dr. Solomon Derese 147
Biosynthesis of Anthraquinones
R3
OH O OH
R2
R1
ANTHRAQUINONES
SEnz
O O O O O O O O
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O O O
O
O O OSEnz
O
O
O O O
CO2H
Hypotheticalintermediate I
HO
O O O
CO2H
Hypotheticalintermediate II
HO
O O O
CO2H
Hypotheticalintermediate III
1. Knoevengel1. Knoevengel
1. Knoevengel2. NADPH
2. NADPH
Enolization [O]
HO
OH O OH
CO2H
O
EndocrocinOH O OH
O
ChrysophanolOH O OH
O OH
Islandicin
Enolization[O]
- H2OEnolization[O]-CO2H -CO2H
- H2O
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O O O
O
O O OSEnz
O OH OH O
HO
OSEnz
O
O
SEnz
HO
OH OH O
OH
O
OH
HO
OH OH O
OH
HO
OH OH O
OH
Antrochyrsone
AntrochyrsoneCarboxylic acid
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Dr. Solomon Derese 151
Hypericin is being investigated for its antiviralactivities, in particular for its potential activityagainst HIV.
Biosynthesis of Hypericin
Hypericum perforatum(Guttiferae)
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Dr. Solomon Derese 152
HO
OH O OH
Emodin anthrone
Tautomerization
HO
OH OH OH
-H
[O]
HO
OH O OH
HO
OH O OH
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Dr. Solomon Derese 153
HO
OH O OH
OH
OHOOH
HO
OH O OH
OH
OHOOH
Oxidativecoupling
Emodin dianthrone
HO
OH O OH
OH
OHOOH
[O]
HO
OH O OH
OH
OHOOH
HO
OH O OH
OH
OHOOH
[O][O]
ProtohypericinHypericin
SCH 511
Dr. Solomon Derese
BIOSYNTHESIS OF KNIPHOLONE
Polyketide derived secondary metabolite
Anthraquinone (Chrysophanol)
Acetylphloroglucinol
Phenolic OxidativeCoupling
SCH 511
Dr. Solomon Derese
NADPH- H2O
KnoevengelCondensation
[O]
Chrysophanol
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Dr. Solomon Derese
ClaisenCondensation
Aromatization
Acetylphloroglucinol
SAM
SCH 511
Dr. Solomon Derese
SCH 511
Dr. Solomon Derese
Aromatization
