ALKALOID BIOSYNTHESIS

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ALKALOID BIOSYNTHESIS
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MOST ALKALOIDS ARE DERIVED FROM a-AMINO ACIDS
SOME OF THE MAJOR RELATIONSHIPS ARE SHOWN BELOW
ornithine
tryptophan
lysine
and
and
R H phenylalanine
R OH tyrosine
R H, CH3
R H, alkyl
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A COUPLE OF THE b-AMINO ACIDS ARE
SOMETIMES INVOLVED IN ALKALOID PRODUCTION ALSO
These b-amino acids are
nicotinic acid
anthranilic acid
.. more later
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FORMATION OF ISOQUINOLINE ALKALOIDS
decarboxylation
hydroxylation
1
2
..
3
Mannich reaction and aromatic substitution
..

4
5
..


..
Enz-B
imine formation
6,7,8
methylation
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AROMATIC SUBSTITUTION !
STEPS 4-5 ARE AROMATIC SUBSTITUTION USING AN
ACTIVATED (-OH) RING

..
..

()
para substitution
()
()
E
benzenium ion
B
..

4
5
..


..
Enz-B
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MANNICH REACTION
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MANNICH REACTION
one pot reaction - everything added at once
..


aldehyde
dialkylamine
enolate component
(has an acidic a-hydrogen)
second mole of R2NH takes H

..
..
-
iminium ion
..
like an aldol condensation

The aromatic substitution step shown earlier cam
also be regarded as a Mannich reaction.
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WHERE DO THE ALDEHYDES COME FROM ?
..
3
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WHERE DO THE ALDEHYDES COME FROM ?
AMINO ACIDS ARE ONE SOURCE !
PLP
- CO2
O
- NH2
phenylalananine or tyrosine
phenylacetaldehyde or p -hydroxyphenylacetaldehyde

PLP
- CO2
O
- NH2
acetaldehyde
alanine
The aldehydes can be produced from the B6
decarboxylation-deamination-oxidation of a-amino
acids - or may be produced in other biochemical
pathways from which they can be siphoned off.
Other amino acids can also be used.
Process 2 !
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()-DEMETHYLCOCLAURINE
BIOSYNTHESIS OF A MORE COMPLICATED
ALKALOID
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()-DEMETHYLCOCLAURINE
A TYPICAL BENZYLISOQUINOLINE ALKALOID
if R H ()-Demethylcoclaurine
found in the lotus plant
Nelumbo nucifera
if R OH norlaudanosoline
found in poppy spp
papaverine
the poppy alkaloid
just different in hydroxylation and methylation
patterns
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LOTUS
spp
Water Lily
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CALIFORNIA POPPIES
Papaver spp
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BIOSYNTHESIS OF ()-DEMETHYLCOCLAURINE
tyrosine
a benzylisoquinoline alkaloid
PLP (B6)
PLP (B6)
hydroxylase
hydroxylase
(SAM)
Mannich (Arom Subst)

iminium ion
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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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Mescaline is the most abundant of the
peyote alkaloids and was selected as the
obvious starting material.
Its structure was already well-established.
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mescaline
..
..
H2SO4
HCl
HCl
NaOH

selective due to internal H-bonding
LiAlH4
Pd-C
H2
anhalamine
Brossi, Schenker and Leimgruber (1964)
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SOME OTHER SIMPLE ISOQUINOLINE ALKALOIDS
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SOME OTHER ISOQUINOLINE ALKALOIDS
()-demethylcoclaurine
papaverine
laudanosine
Nelumbo nucifera
(lotus, water lily)
laudanine
laudanosoline
coclaurine
Papaver spp
(poppies)
Cocculus laurifolius
(evergreen shrub)
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ASSIGNMENTS
Lime Problem and Cherry Problem
Due in one week
F Oct. 19, 2007