ALKALOID
BIOSYNTHESIS
Dr.Diniatik,M.Sc.,apt
1
MOST ALKALOIDS ARE DERIVED FROM a-AMINO ACIDS
SOME OF THE MAJOR RELATIONSHIPS ARE SHOWN BELOW
COOH
COOH R
N NH2
NH2 NH2
ornithine H
N N
H H
COOH tryptophan
NH2 N
NH2
lysine H
R R
and N
COOH R
NH2 NH2
R= H phenylalanine and
N
R
R = OH tyrosine R = H, CH3
R' 2
R’ = H, alkyl
A COUPLE OF THE b-AMINO ACIDS ARE SOMETIMES
INVOLVED IN ALKALOID PRODUCTION ALSO
These b-amino acids are :
COOH COOH
N NH2
nicotinic acid anthranilic acid
….. more later
3
Struktur inti alkaliod
4
FORMATION OF ISOQUINOLINE ALKALOIDS
decarboxylation hydroxylation
COOH
1 2
HO
NH2 NH2 NH2
HO HO HO ..
O
Mannich reaction and 3
aromatic substitution H C CH3
H + ..
HO 5 O 4 H O
..
N H +
HO HO ..
N H HO H N H
H
CH3
Enz-B: H CH3 CH3
imine formation
methylation 6,7,8
CH3 O
Methylations could also N CH3
have taken place before CH3 O
Acetaldehyde CH3CHO
step three. CH3 is a readily available
metabolic intermediate5
AROMATIC SUBSTITUTION !
STEPS 4-5 ARE AROMATIC SUBSTITUTION
USING AN ACTIVATED (-OH) RING
.. +O..
:O H H O H
(+)
para
(+) (+)
substitution
H E E
E+ benzenium
B:
ion
H
+ ..
HO 5 O 4 H O
..
N H +
HO HO ..
N H HO H N H
H
CH3
Enz-B: H CH3 CH3
6
MANNICH REACTION
7
MANNICH REACTION
“one pot” reaction - everything added at once
R' O O
..
C O + R NH + C CH3 C CH2 CH N R
H R R' R
aldehyde dialkylamine enolate component
(has an acidic a-hydrogen)
second mole
of R2NH
R' + takes H
C N R
H R O
C CH2
.. ..
iminium
ion
- H O
..
like an aldol +
HO H N H
condensation
The aromatic substitution
step shown earlier cam also CH3
be regarded as a Mannich
reaction. 8
WHERE DO THE ALDEHYDES
COME FROM ?
HO
NH2
HO ..
O
3
H C R
9
WHERE DO THE ALDEHYDES COME FROM ?
AMINO ACIDS ARE ONE SOURCE !
O
PLP
R CH2 CH NH2 R CH2 C H
COOH - CO2
[O]
- NH2
phenylalananine phenylacetaldehyde
or tyrosine or p -hydroxyphenylacetaldehyde
NH2 PLP O
CH3 C COOH CH3 C H
H - CO2
[O]
alanine - NH2 acetaldehyde
The aldehydes can be produced from the
B6 decarboxylation-deamination-oxidation
Other amino
of a-amino acids - or may be produced in Process 2 !
acids can
other biochemical pathways from which
also be used.
they can be siphoned off.
10
(+)-DEMETHYLCOCLAURINE
BIOSYNTHESIS OF A
MORE COMPLICATED ALKALOID
11
(+)-DEMETHYLCOCLAURINE
A TYPICAL BENZYLISOQUINOLINE ALKALOID
HO if R = H (+)-Demethylcoclaurine
HO
NH found in the lotus plant
R Nelumbo nucifera
OH if R = OH norlaudanosoline
found in poppy spp
MeO
papaverine NH
MeO
the “poppy” alkaloid OMe
just different in hydroxylation
OMe
and methylation patterns 12
LOTUS
spp
Water
Lily 13
CALIFORNIA POPPIES
Papaver spp 14
BIOSYNTHESIS OF (+)-DEMETHYLCOCLAURINE
tyrosine COOH a benzylisoquinoline
alkaloid
NH2
PLP (B6) HO PLP (B6)
H NH2
HO HO
hydroxylase hydroxylase
O
HO
H NH2
HO HO
OR R=H
(+)-Demethylcoclaurine
R=CH3 Papaverine
(SAM) Mannich HO
HO (Arom Subst)
N H
N H HO
HO H + OR
iminium OR
ion OH 15
OH
CHEMICAL SYNTHESIS OF
ANHALAMINE
Chemists have always liked the challenge
of natural product synthesis.
Sometimes it is done for the love of the
challenge, but sometimes it is a required
part of a structure proof.
16
SOME OF THE PEYOTE ALKALOIDS
MeO CH2 MeO MeO
CH2
NH NH
MeO NH2 MeO MeO
OMe OH CH3 OH
mescaline anhalonidine anhalamine
MeO MeO MeO
Mescaline is the most
MeO
N
CH3 abundant
MeO
of the peyote
NH N
MeO CH3
OH CH3 alkaloids and was
OMe OH
selected as the obvious
pellotine starting anhalinine
material. anhalidine
Its structure was already
MeO MeO
well-established.
N NH
O CH3 O
O CH3 O CH3
methylenedioxy
group 17
lophophorine
mescaline ..
MeO CH2
..
MeO CH2 CH2 H2SO4 MeO
CH2
MeO NH
NH
MeO NH2 OMe MeO
O O
OMe O OMe O
C Et
EtO Cl
HCl
MeO
MeO MeO
NH NaOH HCl
MeO
NH NH
O O MeO MeO
CH2
CH2 Cl OH O O O
H3C H
.. +
: Cl
.. :
LiAlH4 selective due
to internal
MeO H-bonding
Pd-C MeO
NH
MeO H2 NH
MeO
O OH
CH2 anhalamine
18
Brossi, Schenker and Leimgruber (1964)
SOME OTHER SIMPLE
ISOQUINOLINE ALKALOIDS
19
SOME OTHER ISOQUINOLINE ALKALOIDS
HO MeO MeO
NH NH N CH3
HO MeO MeO
OMe OMe
OH OMe OMe
(+)-demethylcoclaurine papaverine laudanosine
Nelumbo nucifera
MeO
(lotus, water lily) HO
N CH3 N CH3
HO MeO
MeO
OH OH
NH
HO OMe
OH
laudanosoline laudanine
OH
coclaurine
Papaver spp
Cocculus laurifolius (poppies)
20
(evergreen shrub)
ASSIGNMENTS
Lime Problem and Cherry Problem
Due in one week
F Oct. 19, 2007
21
Alkaloids derived from tyrosine and L-DOPA
22
23
24
25
Alkaloid turunan tryptophan
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