Download 1. Introduction to Natural Products Chemistry

9.0 Alkaloids
RA Macahig
FM Dayrit
H
HO
N
HO
O
H
H
H
NCH3
CH3O
Quinine
HO
Morphine
N
Introduction
• Among all the groups of natural products, alkaloids have
the most colorful history, having achieved the most fame
and notoriety as drugs. Where alkaloids occur, they tend to
dominate the biological activity. Despite their relatively
limited distribution, the alkaloids probably have the most
significant impact in human history particularly in
medicine, social issues, economics and politics.
• In 1819, Carl Friedrich Meissner, a pioneering German
pharmacist, coined the term “alkaloid” which referred to
any natural product with the characteristic presence of the
basic nitrogen atom, excluding peptides. (Amides, however,
are generally included.)
9.0 Alkaloids (Dayrit)
2
Introduction
• Because many alkaloids can be
purified from crude extracts by
acid-base extraction and
recrystallization, these were the first
natural products to be purified,
characterized and commercialized.
• The powerful and immediate effects of
alkaloids are thought to be due to the
presence of the cationizable N-atom
which gives it lipid- and water-soluble
characteristics, and enables it to cross
membrane barriers more readily.
9.0 Alkaloids (Dayrit)
3
Introduction
• Many of the earliest pure compounds to be used as drugs
developed were alkaloids:
• Cocaine: anaesthetic, from South American Erythroxylum coca
• Quinine: antimalarial, from the bark of the Cinchona tree
• Morphine: anaesthetic, from opium (Papaver somniferum)
• Emetine: for amoebiasis, from ipecac, the powdered roots (Cephaelis species)
• Strychnine: poison, from the seeds of Strychnos nux-vomica
• The alkaloids have a relatively limited distribution in nature
compared with the other natural product groups. Alkaloids were
originally thought to be uniquely plant products until the 1950s
when several alkaloids were isolated from bacteria, fungi and
algae, insects, and amphibians.
• A number of fungi produce toxic alkaloids, notably Claviceps
purpurea.
9.0 Alkaloids (Dayrit)
4
Introduction
• In the plant kingdom, the angiosperms produce alkaloids:
Apocynaceae, Papaveraceae, Rubiaceae, Ranunculaceae,
Solanaceae, and Berberidaceae. Among the monocots, only the
Amaryllidaeae and Liliaceae produce alkaloids.
(cms.herbalgram.org)
• The discovery of many alkaloids are
associated with anthropological
explorations. Here, a Kamsá youth from a
Brazilian tribe holds a blossom of Culebra
borrachera which is a toxic psychoactive
plant. It contains tropane alkaloids that
can induce a frightening state of psychotic
delirium, and ultimately stupor and death.
9.0 Alkaloids (Dayrit)
5
Introduction
• Some animals, notably some soft corals and frogs produce
highly bioactive alkaloids. In some cases, however, the alkaloids
were found to have been ingested in the diet by the organism and
then modified for use. Well-known examples are the
pyrrolizidine alkaloids in caterpillars and moths. Alkaloids are
much less common in mammals.
Intermedine (I) and lycopsamine (II) ingested
from the leaves of Mikania scandens
9.0 Alkaloids (Dayrit)
monocrotaline (III)
6
Introduction
• There are four major groups of nitrogen-containing organic
compounds in biological systems: the amino acids (peptides
and proteins), the nucleoside bases (DNA and RNA), the
porphyrins; and the alkaloids. The first 3 groups are primary
metabolites; the alkaloids are secondary metabolites.
• Alkaloids are defined simply as nitrogen-containing natural
products. In terms of chemical structure, alkaloids can be
classified into the following: 2, 3, and 4 alkyl amines; and
heterocyclic amines (e.g., pyrrolidine, pyridine, indole,
quinoline, and isoquinoline).
N
pyrrolidine
N
pyridine
N
N
indole
N
quinoline
9.0 Alkaloids (Dayrit)
isoquinoline
7
• Ajmaline, antiarrythmic that
functions by inhibition of glucose
uptake by heart tissue
mitochondria
• Atropine (hyoscyamine),
anticholinergic, antidote to nerve
gas poisoning
• Caffeine, widely used central
nervous system stimulant
• Camptothecin, potent anticancer
agent
• Cocaine, topical anesthetic,
potent central nervous system
stimulant, and adrenergic blocking
agent, drug of abuse
(Kutchan, The Plant Cell, 7, 1059-1070, July
1995)
• Codeine, relatively nonaddictive
analgesic and antitussive; Coniine,
first alkaloid to be synthesized,
extremely toxic, causes paralysis
of motor nerve endings, used in
homeopathy
• Emetine, orally active emetic,
amoebicide; morphine, powerful
narcotic analgesic, addictive drug
of abuse; Nicotine, highly toxic,
causes respiratory paralysis,
horticultural insecticide
• Pilocarpine, peripheral stimulant
of the parasympathetic system,
used to treat glaucoma
• Quinine, traditional antimalarial,
important in treating Plasmodium
falcipafum strains that are resistant
9
to other antimalarials
• Sanguinarine, antibacterial
showing antiplaque activity, used
in toothpastes and oral rinses
• Scopolamine, powerful narcotic,
used as a sedative for motion
sickness
• Strychnine, violent tetanic
poison, rat poison, used in
homeopathy; Taxol, antitumor
agent
• (+)-Tubocurarine,
nondepolarizing muscle relaxant
producing paralysis, adjuvant to
anesthesia
• Vinblastine, antineoplastic that is
used to treat Hodgkin’s disease
and other lymphomas.
10
Survey of some well-known alkaloids.

Coniine from hemlock (Conium maculatum)
was used by the ancient Greeks for state
executions. Its most famous victim was
Socrates.

Lysergic acid is an opiate produced by
Claviceps purpurea, a parasitic fungus that
grows on some grain crops. The unhygienic
practices of medieval Europe caused outbreaks
of convulsion which was called “St. Anthony’s
Fire”.
N
H
HO2C
NCH3
N
N
CH3
N

Nicotine is the principal alkaloid in Nicotiana
tabacum. It is addictive and has been recently
classified as a drug.
9.0 Alkaloids (Dayrit)
11
N
H
N
O
H
H
O

Quinine was first purified by Pelletier and
Caventou in 1820. It is the major alkaloid from
the bark of the Cinchona tree. Christened the
“Jesuit bark,” the bark was traditionally used
by Peruvian indians for fever due to malaria.
Quinine was the principal antimalarial drug up
to WW II, after which it was supplanted by
chloroquin.

Strychnine was first purified in 1818 by
Pelletier and Magendie from the seeds of
Strychnos nux-vomica, a plant native to India.
It is a deadly poison and was used for many
centuries as a rodenticide and vermicide. It is
so chemically and biologically stable that it has
been found in bodies exhumed after several
years (this makes it a bad choice for a poison!)
Strychnine was first synthesized in 1954.
N
HO
H
H
CH3O
9.0 Alkaloids (Dayrit)
N
12

Cocaine is the chief alkaloid of the South
American coca bush. It has anaesthetic
properties but is very addictive.
CH3N
CO2CH3
OCC6H5
O

Morphine was first isolated by Sertürner in
1806 from Papaver somniferum. It is still
valued up to this day for its pain-killing
properties, although it is highly addictive. It
was first synthesized in 1952. Codeine is the
methyl derivative.
HO
NCH3
O
H
HO
• Merck, one of the world’s largest pharmaceutical companies,
made its initial fortune from cocaine, morphine, and codeine.
9.0 Alkaloids (Dayrit)
13

Mescaline is a well-known hallucinogenic
compound extracted from the Indian peyote
cactus, Laphophora williamsii.
CH3O
NH2
CH3O
CH3O
O
H3C
O
CH3
N
N
N
N
CH3

Caffeine is perhaps one of the most widely
consumed alkaloids in the world. It is a
member of a group of xanthine alkaloids which
is present in coffee. The other famous
xanthines, theobromine and theophylline, are
found in tea and cocoa, respectively.

Vinblastine is the anticancer drug from
Catharanthus roseus (locally known as
chichirica). Because it occurs in very minute
amounts in the plant, this plant has been the
subject of intense biotechnology research to try
to produce it in vitro using cell culture
techniques.
N
N
CH3OC
O
CH3O
HO
N
N
OCCH3
CH3OC
9.0 Alkaloids (Dayrit)
O
OH
O
14
Introduction
• Many alkaloids are toxic in the
cytoplasm, even in the plants that produce
them. Their accumulation, therefore,
requires a well-regulated and
compartmentalized system. The most
common storage organ is the vacuole.
• In some plants, alkaloids are synthesized
in one part of the plant and then are
transported to another part for storage. In
tobacco, for example, alkaloids (e.g.,
nicotine) are synthesized in the roots and
are then transported via the xylem to the
leaves where they are accumulated.
9.0 Alkaloids (Dayrit)
15
Introduction
Among the natural products groups, the biochemistry of
alkaloids is the most complex.
• Many alkaloids are mixed metabolites.
• Enzymes involved in alkaloid biosynthesis are associated with
diverse subcellular compartments including the cytosol,
vacuole, tonoplast membrane, endoplasmic reticulum,
chloroplast stroma, thylakoid membranes, and perhaps unique
biosynthetic or transport vesicles.
• Localization studies have shown that sequential alkaloid
biosynthetic enzymes can also occur in distinct cell types,
suggesting the intercellular transport of pathway intermediates.
(PJ Facchini, Ann. Rev. of Plant Physiol. and Plant Mol. Bio., Vol. 52: 29-66)
9.0 Alkaloids (Dayrit)
16
Overview
Despite the wide variety and complex structures observed
among the alkaloids, most of the compounds from this group
are formed from only a handful of starting materials. The
nitrogen and the initial carbon skeleton are derived from the
following:
A. aliphatic amino acids: lysine, glutamic acid, and ornithine;
B. aromatic amino acids: phenylalanine, tyrosine, and
tryptophan; and
C. others: secologanin: terpene-derived C10 unit.
9.0 Alkaloids (Dayrit)
17
NH2
A. Aliphatic amino acids :
lysine
H2N
CO2H
NH2
ornithine
H2N
CO2H
NH2
glutamic acid
HO2C
C. Others:
CO2H
CO2H
B. Aromatic amino acids : phenlyalanine, R = H;
CHO
H
H
O
tyrosine, R = OH
H3COC
NH2
R
O
secologanin
CO2H
tryptophan
N
H
9.0 Alkaloids (Dayrit)
NH2
18
Overview
The major reactions in alkaloid biosynthesis are common
biosynthetic mechanisms:
• Oxidation: epoxidation, aromatic hydroxylation, etc.
• Oxidation: dehydrogenation (-2[H]); in the case of the
alkaloids, this includes the conversion of amine  imine.
• Reduction: hydrogenation (+2[H]); in the case of the
alkaloids, this includes the conversion of imine  amine.
• Phenolic dimerization by radical coupling.
• Decarboxylation, in particular in the conversion of amino
acid to amine.
9.0 Alkaloids (Dayrit)
19
Reactions which are particular to alkaloid biosynthesis.
A. Mannich reaction : C-C aliphatic bond formation
H
C
H
C
+
O
NH 2(CH 3)
B. Aldehyde
H3C
C NH(CH3)
H
O
-
CH2
NH(CH3)
H
Amine via pyridoxal / pyridoxamine
pyridoxamine
R
O
CHO
R
pyridoxal
CH2NH2
C. Bischler-Napieralski : isoquinoline biosynthesis
+
R
NH2
C
OR'
-HOR'
O
phenylethylamine
from phenylalanine
N
R
+
NH2
N
tryptamine from tyrosine
NH
O
R
C
OR'
R
-HOR'
O
N
9.0 Alkaloids (Dayrit)
N
O
N
N
R
20
R
Reactions which are particular to alkaloid biosynthesis.
D. Pictet-Springler
+
NH2
R
C
H
N
O
phenylethylamine
from phenylalanine
N
R
R
+
NH2
N
tryptophan
tryptamine from tyrosine
R
C
H
N
O
N
N
N
R
9.0 Alkaloids (Dayrit)
R
21
Aliphatic alkaloids
The aliphatic alkaloids can be classified into three main
types, depending on its biogenesis:
• the amino acid ornithine
• the amino acid lysine
• the polyketide pathway with the nitrogen atom being
introduced in a late step.
9.0 Alkaloids (Dayrit)
22
Aliphatic alkaloids from ornithine
Glutamic is transformed into ornithine by addition of another
CH2 unit. Therefore, in a way, glutamic acid is the original
precursor and ornithine is the immediate precursor.
Decarboxylation and loss of one nitrogen leads to formation of
the pyrrolidine ring.
There are three main types: pyrrolidine (monocyclic), tropane
(bicyclic) and pyrrolizidine (fused).
N
N
N
N
pyrrolidine
tropane
9.0 Alkaloids (Dayrit)
pyrrolizidine
23
Ornithine comes from glutamic acid.
OHC
HO2C
H2N
CO2H
CO2H
H2N
N
CO2H
CO2H
N
glutamic acid
H2N
H2N
CO2H
H2N
O
CO2H
ornithine
9.0 Alkaloids (Dayrit)
24
Pyrrolidine alkaloids from ornithine. Labeling studies show that although
pyrrolidine itself is symmetric, the biosynthesis is regiospecific. This
suggests that once ornithine is held by the enzyme, biosynthesis proceeds
without release of any of the intermediates.
*
H2N
1. -CO2
2. pyridoxal
#
H2N
CO2H
*
NH2
ornithine
-CO2
H+
#
#
N
*
NH2
H+
N
CH2
CH
OH
OH
PO
PO
N
H
N
CH3
CH3
[CH3]
H2N
H2N
putrescine
O
O
#
*
N
_
H2C
C
#
CH3
*
+N
CH3
CH3
NH
CH2
hygrine
OH
PO
N
9.0 Alkaloids (Dayrit)
CH3
25
Tropane alkaloids from ornithine. Consistent with what has been
observed, labeling shows that the biosynthesis is regiospecific.
H3C
O
#
H2N
+
N
#
#
CO2H
H2N
H2C
_
N
CH3
ornithine
O
hygrine
H3C
N
HO2C
#
CH2OH
tropic acid
H
C
atropine
H3C
N
#
H
CH
CH2OH
O
OH
H3C
N
H3C
N
Ph
O
H3C
Ph
CH
#
N
H3C
benzoic acid
CO2H
O
tropinone
CO2H
N
O
#
OH
Ph
C
H
cocaine
OH
H
O
ecgonine
9.0 Alkaloids (Dayrit)
tropine
H
26
Pyrrolizidine alkaloids from ornithine. Pyrrolizidine alkaloids are
common in the butterflies Senecio and Crotolaria species.
NH2
H2N
NH2
NH2
CHO
CO2H
CHO
OHC
-CO2
NH2
NH2
NH2
ornithine
dimerize
N
1. pyridoxal
2. +2[H]
putrescine
OH
HO
OH
HO
OH CHO
O
CH
O
CHO
_
O
O
H3C H
O
N
NH
NH
retronecine
N
retrorsine
9.0 Alkaloids (Dayrit)
27
Pyrrolizidine alkaloids are converted into aphrodisiac substances which the
male butterflies store in its wing hair pencils. These compounds also
protect the plants against feeding by mammals because these compounds
are converted in the liver into toxic and carcinogenic compounds.
O
O
OH
HO
O
O
OH
HO
[O]
N
+
O_
retronecine-N-oxide
N
in
mammalian
liver
N
generalized
pyrrolizidine
in
lepidoptera
retronecine
-2[H]
[O]
CHO
HO
H
CHO
OH
HO
N
N
danaidal
N
O
HO
hydroxydanaidal
CH3
CHO
sex phermones in
lepidoptera
N
N
+
alkylating agent
(carcinogenic)
HO
E-4-hydroxyhex-2-enal
9.0 Alkaloids (Dayrit)
(bound to liver, toxic)
danaidone
28
Polyhydroxylated cycloalkyl alkaloids found in the leaves, flowers and
seeds of Ipomoea carnea (Convolvulaceae) cause natural intoxication of
livestock by inhibiting key digestive enzymes. Alkaloids 1 and 2 are
powerful inhibitors of lysosomal a-mannosidase; 3, 4, and 6 showed
potent inhibitory activity toward rat lysosomal b-glucosidase; and
alkaloid 5 was a moderate inhibitor of a- and b-mannosidases. (Haraguchi,
et al., J. Agric. Food Chem. 2003, 51, 4995-5000.)
HO
OH
H
H
OH
OH
N
N
Swainsonine ( 1)
OH
HO
HO
2-epi-Lentiginosine ( 2)
HN
HN
OH
Calystegine B1 (3)
HO
HN
OH
OH
HO
HN
OH
OH
OH
OH
Calystegine B2 (4)
OH
HO
HO
Calystegine B3 (5)
9.0 Alkaloids (Dayrit)
OH
OH
OH
Calystegine C1 ( 6)
29
Aliphatic alkaloids from lysine
Lysine is modified following an analogous pathway to ornithine.
There are many similarities between the ornithine-derived and
lysine-derived alkaloids.
The alkaloids produced are the 6-membered piperidine,
homotropane and quinolizidine structures.
N
N
N
N
piperidine
homotropane
9.0 Alkaloids (Dayrit)
quinolizidine
30
Alkaloids from lysine. 1-Piperidine and pellieterine are key
intermediates to this group of alkaloids.
O
O
O
_
H2N
H2N
SCoA
+
N
CO2H
N
H
1-piperidine
lysine
CSCoA
O
-CO2
H3C
+
N
1. [CH3]
2. [O]
_
H2C
+
N
CH3
O
O
N
N
O
anahygrine
(-)-pelletierine
H3C
O
N
+
N
H
N
-pelletierine
O
O
N
N
N
cernuine
N
anaferine
N
CH3
Quinolizidine alkaloids have the characteristic fused 6,6-bicyclic group
and are derived from lysine. Lupinine is a dimeric metabolite while
sparteine is trimeric.
NH2
NH2
NH2
lysine
O
CH
CO2H
NH2
NH2
OHC
NH2
N
NH2
OHC
cadaverine
OH
NH2
H
N
lupinine
N
N
H
sparteine
9.0 Alkaloids (Dayrit)
32
Aliphatic alkaloids from polyketides
Some aliphatic alkaloids are derived from the polyketide
pathway. The biogenesis of these alkaloids can be determined by
studies using labeled acetyl CoA.
*
SCoA
HO
*
*
O O
*
*
*
O
*
*
H2N
*
*
*
*
N
-coniceine
*
O
*
*
*
*
N
OH
conhydrine
9.0 Alkaloids (Dayrit)
*
*
*
*
N
coniine
33
Polyketide-derived piperidine alkaloids. Some alkaloids having the
piperidine-type structure are not derived from lysine.
*
O
*
SCoA
*
*
*
O O
*
CO2H
-CO 2
*
*
*
N
penidine
The European ladybug ( Coccinella septempunctata ) produces this tricylic defense substance.
H
O
O
O
O O
N
-CO 2
H
HO2C
H
O
a heptaketide
coccinelline
9.0 Alkaloids (Dayrit)
34
Alkaloids from phenylalanine and tyrosine
The aromatic alkaloids derived from phenylalanine and tyrosine
form a diverse and often structurally complex group of
metabolites. By tradition, these alkaloids are identified according
to plant family, of which the best known are: Papaveraceae,
Morphinan, Erythria, Berberidaceae, Amaryllidaceae.
Structurally and biosynthetically, there are six main groupings:
1. Phenylethylamines
2. Phenylethylamine + alkyl aldehyde or ketone
3. Phenylethylamine + benzaldehyde (C6-C1)
4. Phenylethylamine + C6-C2
5. Phenylethylamine + C6-C3
6. Phenylethylamine + secologanin
9.0 Alkaloids (Dayrit)
35
Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types.
NH2
1. Simple phenylethylamines.
2. Phenylethylamine + alkyl aldehyde or ketone.
+
R
CHO
NH
NH2
R
H
N
3. Phenylethylamine + benzaldehyde (Ar-C 1).
OHC
NH2
+
4. Phenylethylamine + Ar-C 2.
NH2
NH
OHC
9.0 Alkaloids (Dayrit)
36
Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types.
5. Phenylethylamine + Ar-C 3.
NH2
NH
OHC
6. Phenylethylamine + secologanin.
NH2
NH
OHC
O-Glc
O- Glc
O
CH3 OC
O
9.0 Alkaloids (Dayrit)
O
CH3 OC
O
37
NH2
CO2H
HO
N(CH3)2
NH2
-CO2
HO
HO
hordenine
tyramine
tyrosine
Hordenine is produced by the barley
plant. It is released in the roots and
acts to kill competing plants, in
particular weeds. It is an allelopathic
agent.
[O]
HO
NH2
CO2H
HO
DOPA
-CO2
HO
1. [O]
2. [CH3]
NH2
HO
HO
NH2
HO
dopamine
Mescaline is the hallucinogenic
compound in the peyote cactus
(Lophophora williamsii). It is
produced together with a number
of other phenylethylamines.
OCH3
mescaline
[O]
OH
HO
NH2
HO
norepinephrine
[CH3]
OH
HO
NH(CH3)
Epinephrine is also a cactus alkaloid.
It is also a human hormone secreted by the
adrenal medulla which acts to increase the
heart rate, blood pressure and carbohydrate
metabolism. It is also known as adrenalin.
9.0 Alkaloids (Dayrit)
HO
epinephrine
Alkaloids from
phenylalanine/
tyrosine: Simple
phenylethylamines.
Biosynthesis of this
group involves
simply loss of the
carboxylic acid
carbon. Some
important members
of this group are the
hallucinogenic
compound mescaline
and the drug
epinephrine.
38
NH2
CO 2H
leucine
O
HO
1.
NH2
HO
CH3O
CO 2H
2. [CH3]
Lophocerin was isolated from
the cactus Lophocerus schotti.
NHCH3
HO
dopamine
lophocerine
CH3O
OHC CO 2H
glyoxylic
acid
NH2
CH3O
CH3O
CH3O
-CO2
NH2
CH3O
OH
OH
O
NH 2
HO 2C
H 3C C CO 2 H
CO 2H
pyruvic
acid
NH2
CH3O
CO2H
OH
peyoxylic acid
anhalamine
glutamic acid
CH3O
CH3O
O
HO 2C
-CO2
NH2
CO 2H
CH3O
OH H3C CO2H
CH3O
peyoruvic acid
N
CH3O
NH2
CH3O
OH
pellotine
CH3
Alkaloids from
phenylalanine/
tyrosine:
Condensation of
phenylethylamine
with alkyl
aldehydes or
ketones. This
group of alkaloids is
formed via a PictetSpringler or
Bischler-Napieralski
condensation. The
alkaloids shown
here are found in the
hallucinogenic
peyote cactus plant.
O
OH
peyoglutan
9.0 Alkaloids (Dayrit)
39
Alkaloids from phenylalanine / tyrosine + Ar-C1. Phenylethylamine
couples with Ar-C1 (benzaldehyde) via a Pictet-Springler condensation.
This is followed by oxidation of the phenol.
HO
CO2H
NH2
HO
-CO 2
NH2
HO
HO
NH
CHO
CH3O
CH3O
HO
o-methylnorbelladine
[O]
O
O
O
NH
.
O
.
NH
CH3O
CH3O
.
.
.
O
9.0 Alkaloids
(Dayrit)
NH
CH3O
O
40
O
O
O
.
.
.
NH
.
NH
.
CH3O
CH3O
CH3O
NH
.
O
O
O
o-p
O
O
O
CH3O
.
.
O
.
.
NH
O
NH
CH3O
p-p
O
CH3O
NH
HO
CH3O
1. p-o
2. [CH3]
OH
NH
O
Alkaloids from
phenylalanine /
tyrosine + Ar-C1.
The two oxidized
rings can couple
via different
folding
conformations
leading to parapara, para-ortho
or ortho-para
coupling.
HO
OH
O
O
O
O
NCH3
CH3O
lycorine
O
O
N
9.0 Alkaloids
oxocrine
galanthamine
N
(Dayrit)
41
HO
CO2H
-CO 2
NH2
HO
NH2
HO
HO
NH
CHO
CH3O
CH3O
HO
o-methylnorbelladine
[O]
O
O
O
.
.
.
NH
.
NH
.
CH3O
CH3O
CH3O
NH
.
O
O
O
o-p
O
O
O
CH3O
.
.
O
.
.
NH
O
NH
CH3O
p-p
O
CH3O
NH
HO
CH3O
1. p-o
2. [CH3]
OH
NH
O
HO
Alkaloids from
phenylalanine / tyrosine +
Ar-C1. (overview) Coupling
of the radical intermediates
in different folding
conformations leads to parapara, para-ortho and orthopara couplings. This is a
theme that is repeated for
other alkaloids with similar
structural characteristics.
The alkaloid families that
comprise this group include
the Amaryllidaceae and
Mesembrine species.
OH
O
O
O
O
NCH3
lycorine
O
N
O
CH3O
oxocrine
galanthamine
N
9.0 Alkaloids (Dayrit)
42
Alkaloids from phenylalanine / tyrosine + Ar-C2. Condensation of
phenylethylamine with an Ar-C2 group, such as phenylpyruvic acid, yields
the benzyltetrahydro isoquinoline structure. These alkaloids are characteristic
of the Papaveraceae. Reticuline is a key intermediate of this group.
HO
HO
CO2H
-CO2
HO
NH2
HO
N
NH2
HO
DOPA
HO
CO2H
pyridoxal
pyrophosphate
HO
-CO2
OH
O
HO
1,2-dehydrolaudanosoline
1. +2[H]
(2. 2x [CH3])
RO
OH
1. -2[H]
2. 4x [CH3]
CH3O
NR
N
HO
CH3O
H
OH
(S)-norlaudanosoline, R = H
(S)-reticuline, R=CH3
9.0 Alkaloids (Dayrit)
OR
OCH3
papaverine
43
OCH3
Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine
alkaloids are produced by oxidation of reticuline. Various isomeric
radical intermediates are formed.
CH3O
NCH3
HO
H
HO
(S)-reticuline
CH3O
[O]
CH3O
CH3O
O
O
.
.
NCH3
H
O
CH3O
A
NCH3
.
H
O
O
A
NCH3
H
.
H
O
O
CH3O
C
NCH3
O
H
.
.
C
B
.
.
NCH3
A
H
O
A
O
B
NCH3
CH3O
CH3O
.
CH3O
CH3O
.
.
NCH3
C
CH3O
CH3O
B
O
C
CH3O
O
.
B
O
.
CH3O
CH3O
.
CH3O
O
H
Alkaloids from phenylalanine / tyrosine + Ar-C2. Four regiochemical
couplings are observed: ortho-ortho, ortho-para, para-ortho, and para-para.
CH 3O
CH 3O
O
O
NCH 3
.
.
O
H
CH3O
NCH3
.
.
O
CH 3O
C
.
.
O
H
C
B
.
.
NCH3
A
A
O
o-o
O
o-p
CH 3O
O
p-p
CH 3O
NCH 3
H
H
CH 3O
p-o
CH 3O
O
B
NCH 3
CH3O
CH 3O
CH 3O
H
OCH 3
NCH3
O
H
O
CH 3O
O
H
NCH 3
H
CH 3O
CH 3O
CH 3O
O
NCH 3
H
O
O
1. 2[H]
2. -H2O
CH 3O
NCH 3
O
H
NCH 3
O
CH 3O
O
sebiferine
CH3O
H
CH3O
O
CH 3O
NCH3
CH 3O
bulbocarpine
H
OH
isoboldine
CH3O
thebaine
(to the morphine alkaloids)
45
Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are
produced by radical coupling of the benzylisoquinoline system of reticuline.
O
CH3O
CH3O
O
O
NCH3
.
.
O
H
CH3O
CH3O
NCH3
.
.
H
C
C
.
.
.
.
O
B
A
CH3O
CH3O
O
O
p-p
OCH3
CH3O
CH3O
NCH3
O
H
H
H
O
p-o
CH3O
NCH3
A
CH3O
o-p
o-o
NCH3
H
CH3O
O
CH3O
B
NCH3
O
H
O
NCH3
NCH3
H
CH3O
CH3O
H
CH3O
O
CH3O
O
O
NCH3
O
H
O
1. 2[H]
2. -H2O
CH3O
NCH3
O
sebiferine
CH3O
H
CH3O
O
CH3O
CH3O
bulbocarpine
NCH3
H
OH
isoboldine
CH3O
thebaine
(to the morphine alkaloids)
Schematic presentation
of the biosynthesis of
codeine, laudanine, and
(S)-scoulerine from (S)norcoclaurine in the
opium poppy. The
cellular localizations of
the enzymes indicated
have been determined
experimentally. (Jorgensen
et al., Curr Opinion in Plant Biol
2005, 8:280–291)
9.0 Alkaloids (Dayrit)
47
Alkaloids from phenylalanine/tyrosine + Ar-C2. The morphine
alkaloids are produced from thebaine. Note that the level of
methylation decreases towards the end of the biosynthetic sequence
from thebaine  codeine  morphine.
CH3O
CH3O
O
HO
O
NCH3
H
CH3O
1. -[CH3]
2. +2[H]
H
O
H
H
HO
thebaine
NCH3
-[CH3]
NCH3
H
HO
codeine
9.0 Alkaloids (Dayrit)
morphine
48
CH3O
Alkaloids from
phenylalanine /
tyrosine + Ar-C2.
Coupling using the
N-methyl group.
CH3O
N-CH3
HO
-H-
H
N
+
HO
OH
CH2
H
O-H
(S)-reticuline
OCH3
OCH3
O
CH3O
N
N
O
HO
H
H
OCH3
O
[O]
(S)-canadine
OH
(S)-scoulerine
OCH3
N+
OCH3
O
OCH3
O
berberine
OCH3
N
O
H
O
(S)-stylopine
O
[CH3]
O
O
N
+N
CH3
CH3
O
O
H
O
O
O
protopine
9.0 Alkaloids (Dayrit)
O
O
49
CH 3O
HO
HO
-C O2
CO 2H
NH 2
HO
HO
CH 3O
NH 2
HO
NC H3
HO
CO 2H
1. pyrido xal
pyropho sphate
2. +2[H]
HO
3. -H2O
DO PA
autum naline
(cf. re ticuline)
CH 3O
OH
[O ]
CH 3O
CH 3O
NC H3
HO
NC H3
o-p
O
.
.
CH 3O
CH 3O
CH 3O
CH 3O
OH
Alkaloids from
phenylalanine /
tyrosine + Ar-C3.
This group is
homologous to the
benzyltetrahydroisoquinolines
(dopamine + C2).
The biosynthetic
steps are assumed to
be similar.
O
multif loramine
CH 3O
O CH 3
O CH 3
.
CH 3O
CH 3O
A
CH 3O
O
p-o
NC H3
CH 3O
B
C
NC H3
H
CH 3O
H
.
.
A
H
o-m ethyland ro cymb ine
.
CH 3O
CH 3O
O
NC H3
O
C
[CH3 ]
B
O
O
9.0 Alkaloids (Dayrit)
50
Alkaloids from phenylalanine / tyrosine + secologanin. Secologanin
is an iridoid belonging to the monoterpene group. Condensation of
phenylethylamine with secologanin leads to a group of mixed
metabolites.
HO
OHC
NH2
HO
dopamine
HO
-
O Glc
+
NH
O
HO
H3COC
O
O-Glc
secologanin
O
H3COC
O
-Glc
HO
NH
HO
O-H
O
H3COC
O
9.0 Alkaloids (Dayrit)
51
HO
HO
HO
H+
1
NH
CO2H
HO
NH
NH
HO
HO
O
1
H
O
O-H
O
2
H
O
H3COC
H
O
H3COC
O
H
O
H+
H
2
HO
HO
N
HO
O
NH
HO
OH
H
N+
CHO
HO
H
O
HO
O
H3COC
O
H
H
O
1.
2.
3.
4.
HO
N
O
H3COC
+Glc
O
HO
CH3O
CH3O
H
H+
-CO 2
2[CH 3]
[H]
CH3O
HO
N
alangiside
Alkaloids from
phenylalanine /
tyrosine +
secologanin.
NH2
HO
N
CH3O
O
emetine
O-Glc
H
proemetine H
OH
O
HN
9.0 Alkaloids (Dayrit)
OH
H
52
Alkaloids from tryptophan: the indole alkaloids
• The indole alkaloids are derived from tryptophan and are
found in both plants and microorganisms. They comprise the
single largest group of alkaloids, accounting for almost onefourth of all alkaloids isolated. Many of the members of this
group are biologically active and some possess very important
medicinal properties. Among the best known sources are:
Catharanthus, Curare, Rauwolfia, and Vinca plant species and
the ergot fungi.
• The indole alkaloids can be classified as follows:
1. Simple indole alkylamines
2. Simple b-carbolines
3. Tryptophan + C5
4. Tryptamine + secologanin
9.0 Alkaloids (Dayrit)
53
Indole alkaloids. Structural groups..
1. Simple indole alkylamines.
N
N
2. Simple b-carbolines: indole + aldehyde (Pictet-Springer condensation)
N
+
N
N
N
OHC
R
may be saturated
or aromatic
R
9.0 Alkaloids (Dayrit)
54
Indole alkaloids. Structural groups..
3. Tryptophan + C 5 (ergolines).
+
OPP
CO2H
CO2H
NH2
NH2
N
N
4. Tryptamine + secologanine. (Pictet-Springer condensation)
NH2
N
N
CHO
N
O-Glc
O-Glc
+
O
CH3OC
O
CH3OC
O
O
9.0 Alkaloids (Dayrit)
55
Simple indole alkaloids. Decarboxylation of tryptophan yields
serotonin, a neurotransmitter; methylation yields bufotenin, a
hallucinogenic compound isolated from toadstools.
CO2H
HO
NH2
NH2
N
H
1. -CO2
2. [O]
N
H
5-hydroxytryptamine
(serotonin)
[CH3]
HO
N(CH3)2
N
H
bufotenin
CH3
HO
N
CH3
eseroline
N
CH3
9.0 Alkaloids (Dayrit)
56
Simple indole alkaloids. Bishler-Napieralski condensation of
tryptamine with simple alkyl groups yields the b-carbolines. The
harmanes are CNS stimulants.
N
NH
O
N
N
C
H3C
CO2H
H3C
-CO2
N
N
CO2H
harmane
9.0 Alkaloids (Dayrit)
CH3
57
Ergot alkaloids. Condensation with C5 DMAPP. This group of
metabolites is produced by the fungus Claviceps purpurea and includes
the hallucinogen lysergic acid.
+
OPP
O
CO2H
CO2H
_
CO2H
[O]
NH2
NH2
NH2
N
N
N
H
H
H
OPP
HO2C
NCH3
HO
HO2C
NH2
HO
1. -CO2
1. [CH3]
2. [O]
N
H
NH2
2. [O], +OPP
N
H
N
H
lysergic acid
9.0 Alkaloids (Dayrit)
58
N
N
N
N
N
N
O
O
Vincosan (D-type)
Coryanthean (C-type)
N
N
N
N
N
N
Reserpine
Valleseachotaman (V-type)
N
N
N
N
N
Strychnan (S-type)
Eburnan (E-type)
N
Aspidospermatan (A-type)
Plumeran (P-type)
N
N
Ibogan (I-type)
Indole
alkaloids:
tryptophan +
secologanin.
More than 1,100
compounds
from this group
of mixed
metabolites
have been
identified. They
occur
predominantly
in Loganiaciae,
Apocynaceae,
and Rubiaceae.
This figure
gives the major
skeletal types.
NH2
N
NH
NH
N
N
+
O-Glc
CHO
O-Glc
H
O-Glc
+
O
O
CH3OC
H
O
CH3OC
O
CH3OC
O
strictosidine
O
vincoside
H+
-Glc
NH
NH
NH
N
N
N
CHO
O-H
CHO
O
OH
OH
CH3OC
CH3OC
CH3OC
O
O
O
N
N
+2[H]
H
N+
N
N
N
H
H
O
CH3OC
O
ajmalicine
H
O
CH3OC
O
catharanthine
OH
CH3OC
O
Indole alkaloids:
tryptophan +
secologanin. The
Vincosan alkaloids
yield straightforward
incorporation of
secologanin.
• Loss of glucose
enables more
extensive
structural
changes to occur.
The glycoside is
hypothesized to
act as a
protecting group.
• Many alkaloids
are formed from
strictosidine.
NH
NH
N
N
O-Glc
O
CH3OC
O
1. -Glc
2. H+
3. double bond
isomerization
4. bond rotation
CHO
O
CH3OC
O
strictosidine
+N
H
+N
N
N
N
N
H
H
O
CH3OC
CH3OC
O
O
O
OH
N
CH3OC
O
H
H
H
Indole
alkaloids:
tryptophan +
secologanin.
Loss of glucose
initiates the
chemical
transformation.
Reserpine is a
tranquilizer and
sedative isolated
from the roots of
Rauwolfia
serpentina.
N
N
N
H
H
H
O
H
H
CH3OC
CH3OC
O
OH
O
a-yohimbine
reserpine
OCH3
O
OCH3
OCH3
9.0 Alkaloids (Dayrit)
OCH3
61
N
NH
N
N
H
N
N
O
OH
CH3OC
CH3OC
H
H+
O-Glc
CH3OC
O
O
O
geissoschizine
strictosidine
CHO
N
N
N
H
N+
N
H
CH3OC
HO
O
1. [O]
2. -CH2O
N
H
CH3OC
CHO
O
[O]
CH3COS-CoA
N
N
N
H
N
CoAS
HO
O
O
O
O
strychnine
9.0 Alkaloids (Dayrit)
CH3OC
O
_
CHO
Indole
alkaloids:
tryptophan +
secologanin.
Strychnine
(from the
seeds of
Strychnos
nux-vomica)
was used in
medicine as a
CNS
stimulant. At
higher doses,
it was used as
poison for
humans and
rodents.
62
NH
N
N
H
N
H
O-Glc
O
CH3OC
CHO
O
strictosidine
[O]
corynantheal
O-H
X
CHO
CHO
N
N
N
N
H
N
1. -H2O
2. +2[H]
3. "X"
H
N
H
HO
H
O
H
H2O
X
Indole alkaloids:
tryptophan +
secologanin. The
cinchona alkaloids
(from the bark of
Cinchona spp.)
involve extensive
rearrangement.Quin
ine was used as an
antimalarial drug.
CHO
N
NH2 O
O
NH2
H
O
N
X
N
1. -H2O
2. -"HX"
CHO
N
cinchonidinone
H
N
HO
R
quinidine, R=OCH3
cinchonine, R=H
HO
H
R
N
N
quinine, R=OCH3
cinchonidine, R=H
9.0 Alkaloids (Dayrit)
N
63
Alkaloids from other pathways
Other groups of alkaloids arise from various pathways. A number
of them are metabolites from other biogenetic groups, but are
classified as alkaloids simply because they have an amine
functionality.
This mixed group of alkaloids includes:
• the quinoline alkaloids (from anthranilic acid, shikimates)
• terpene alkaloids
• nicotine alkaloids
• xanthine alkaloids.
9.0 Alkaloids (Dayrit)
64
CO2H
shikimate
NH2
O
anthranilic acid
O
O
O
SCoA
SCoA
O
O
O
O
SCoA
O
NH2
O
O
SCoA
O
SCoA
CO2H
O
O
O
NH2
O
O
2. [CH3]
3. [O]
4. [CH3]
N
H
N
O
NH2
OH
OH
H
1. PPO
OH
N
1. [O]
2. [CH3]
OCH3
O
OH
OCH3
CH3O
N
Quinoline
alkaloids.
Except for the
cinchona
alkaloids, the
quinoline
alkaloids are
mixed
metabolites
being derived
from anthranilic
acid, which
belongs to the
shikimate
group, and
polyketides.
O
OCH3
skimmianine
N
CH3
arborinine
OCH3
9.0 Alkaloids (Dayrit)
65
The terpene alkaloids. The sequence of addition of nitrogen into the
terpene is suggested to be: R-CH2-OH  R-CHO  R-CH2-NH2 (where
R is a terpene metabolite).
A. Monoterpene alkaloids.
OHOPP 1. [O]
2. OPP
geraniol O PP
OH
OH
[O]
OH
CHO
pyridoxamine
NH2
OPP
H
N
N
CH3
dehydroskythanthine
9.0 Alkaloids (Dayrit)
actidine
66
The terpene alkaloids. Steroidal alkaloids are formed from completed
steroids. Solasidine and tomatidine occur in potatoes and tomatoes,
respectively.
B. Steroidal alkaloids.
HO
cholesterol
O
O
CHO
CHO
O
O
NH2
NH2
N
CH3
N
N
CH3
25S
25R
N
CH3
CH3
O
O
solasidine
HO
HO
9.0 Alkaloids (Dayrit)
tomatidine
67
Nicotine alkaloids
Tobacco (Nicotiana tabacum) is another plant from which a large
commercial sector has formed. It is a practice that originated
from the American Indians. Nicotiana comes from the name of
Jean Nicot, a French diplomat who probably introduced the habit
to Europe; tabacum comes from the Indian name for the pipe that
was used to smoke it.
Nicotine, the chief constituent of N. tabacum, is formed from
nicotinic acid.
CO2H

N
CH3
N
N
nicotinic acid
(-) nicotine
9.0 Alkaloids (Dayrit)
68
Nicotinic acid. In plants, nicotinic acid is biosynthesized from
tryptophan.
A. Biosynthesis from tryptophan (in plants)
[O], Baeyer-Villiger
CO2H
CO2H
NH2
[O]
O
N
H
N
tryptophan
NH2
CO2H
O
-CH 2O
NH2
NH2
CH
O
[O]
CO2H
CO2H
[O]
CO2H
CO2H
[O]
OHC
NH2
HO2C
NH2
O
O
OH
cis
NH2
NH2
OH
OH
3-hydroxyanthranilic acid
trans
CO2H
CO2H
CO2H
OHC
H2N
CO2H
N
CO2H
quinolinic acid
N
nicotinic acid
9.0 Alkaloids (Dayrit)
69
Nicotinic acid. In bacteria, nicotinic acid is biosynthesized from
glyceraldehyde + aspartic acid.
B. Biosynthesis from glyceraldehyde + aspartic acid (C 3 + C4) (in bacteria)
OPP
HO
_
CO2H
-
CO2H
CO2H
CO2
CH
O HN
2
-
CO2
N
CO2H
N
CO2H
quinolinic acid
9.0 Alkaloids (Dayrit)
N
nicotinic acid
70
Nicotinic acid. Mimosine, which resembles phenylalanine, is a toxin
found in grass which is used as animal feed.
A. Various nicotine alkaloids
O
O
C-NH2
C-OGlc
N
nicotinamide
+
N
Glc
O
OH
OH
OH
Mimosine, a -pyridone which is found in
Mimosa species, is toxic to animals. Note
that it is a a-amino acid and is believed to
mimic phenylalanine, tyrosine or DOPA.
N
CO
CO22H
H
buchanine
NH
NH22
mimosine
9.0 Alkaloids (Dayrit)
71
Nicotinic acid. Biosynthesis of nicotine. Nicotine is a ganglionic
cholinergic-receptor agonist. Chronic ingestion of nicotine often results in
psychological addiction and physical dependence.
B. Biosynthesis of nicotine (Nicotiana alkaloids).
CO2H
H2N
H2N
H2N
CO2H
CO2H
ornithine
N
lysine
H2N
-CO 2
+
N
CH3
N
N
CH3
N
N
N
N
(-) nicotine
anabasine
N
N
N
anatabine
9.0 Alkaloids (Dayrit)
72
Xanthine alkaloids are important components of a number of culturally,
historically and commercially important plants, in particular coffee, cola
(kolanut), tea and cacao (chocolate). The active constituents are methyl
xanthines, the best known of which are: caffeine, which occurs in coffee
(Coffea arabica); theophylline, which is found in tea (Camellia sinensis);
and theobromine, which is found in cacao (Theobroma cacao). Note that
theophylline and theobromine are isomers.
O
H
N
N
N
N
N
Purine
O
H3C
O
N
N
CH3
Caffeine
H
N
O
N
N
Xanthine
O
O
CH3
N
H3C
N
O
H
N
N
N
N
CH3
Theophylline
9.0 Alkaloids (Dayrit)
N
H N
O
CH3
N
N
CH3
Theobromine
73
The methylxanthines (caffeine, theophylline and theobromine) are
CNS stimulants and smooth muscle relaxants. Research into their
physiological mechanisms are continuing research topics.
CO 2
aspartic
acid
H33C
C
H
glycine, NH2CH2CO2H
O
C
N1 6 5 C
CH3
C1 fragments
N
7
8 CH
C2 3 4 C 9
N
O
O
N
C1 fragments
CH3
Caffeine
amide N of glutamine
The biogenetic origin of xanthine is complex and arises from various
primary metabolites. Carbons 2 and 8 come from an active 1-carbon
fragment (e.g, formate, methyl methionine, etc.); carbon 6 comes form
CO2; and carbon atoms 4 and 5 and nitrogen 7 come from glycine. The
nitrogen atom at 1 comes from aspartic acid, while those at 3 and 9
9.0 Alkaloids (Dayrit)
74
come from the amide nitrogen
of glutamine.
Summary
• Structurally, the alkaloids are a very diverse group; the only
unifying characteristic is the presence of an amine.
• The origin of the carbons in alkaloids include the aliphatic
amino acids (ornithine and lysine), aromatic amino acids
(phenylalanine, tyrosine and tryptophan, which arises from
shikimic acid via phenylpropanoids), anthranilic acid (from
shikimic acid), polyketides, and terpenes.
9.0 Alkaloids (Dayrit)
75
Summary
The alkaloids are divided into characteristic structures, which are
also usually associated with specific plants or organisms. Among
the best known groups of alkaloids are:




Tropane alkaloids (e.g., Atropa)
Pyrrolizidine alkaloids
Phenylethylamines: (e.g., Ephedra)
Phenylalanine + C6-C2: (e.g., Aprophine, Papaver and
Erythrina)
 Tryptophan + DMAPP: (e.g., ergot alkaloids)
 Tryptophan + secologanin: (Vinca, Catharanthus, Strychnos,
Cinchona)
 Steroidal alkaloids
 Nicotinic acid: (Nicotiana)
 Xanthine alkaloids: (Coffea,
Theobroma)
9.0 AlkaloidsCamelia,
(Dayrit)
76
Overview of alkaloid biosynthesis. The biogenetic location of the
xanthines is diverse and not included here.
glucose
aliphatic amino acids
lysine,
ornithine
shikimate
anthranilic
acid
phenylalanine,
tyrosine,
tryptophan
polyketide
piperidine
mevalonic acid
terpene alkaloids:
monoterpene,
steroidal
C5-OPP,
secologanin
(to aromatic
alkaloids)
aliphatic alkaloids:
pyrrolidine, tropane,
pyrrolizidine;
piperidine, quinolizidine
quinoline
aromatic alkaloids:
phenylethylamine,
isoquinoline,
betalin; indole,
carboline, quinoline,
nicotinic acid
9.0 Alkaloids (Dayrit)
77