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

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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

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MANNICH REACTION

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 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

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 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.
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(+)-DEMETHYLCOCLAURINE

BIOSYNTHESIS OF A
MORE COMPLICATED ALKALOID

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 (+)-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.

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 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
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Brossi, Schenker and Leimgruber (1964)
 SOME OTHER SIMPLE
ISOQUINOLINE ALKALOIDS

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 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)
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(evergreen shrub)
 ASSIGNMENTS

Lime Problem and Cherry Problem

Due in one week

F Oct. 19, 2007

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Alkaloids derived from tyrosine and L-DOPA

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Alkaloid turunan tryptophan

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