2009

Natural Products
(Alkaloids)

Prepared by
Mohab Zaho El-didamoni
B.SC.in Chemistry

Supervised by
Dr.Hamady Abd El-Azeem

Suez canal university

Faculty of science
Chemistry department
 First of all ,I thank Allah
For giving me the time and effort to accomplish this
work and then
I wish to express my deep thanks and gratitude to

For his valuable advice, greet help and kind

Supervision of this essay and continues
Encouragement with valuable discussion. it was of
Pleasure and Honors to work under supervision.

Mohab Zaho El-didamoni

B.sc.chemistry
(2009)

2
 Contentes
introduction 3
TYPE OF ALKALOIDS 6
β –PHENETYLAMINES 6
PYRROLIDINE ALKALOIDS. 8
PYRROLIZIDINE ALKALOIDS. 10
PIPERIDINE AND PYRIDINE ALKALOIDS. 12
SOLANACEOUS AND COCA ALKALOIDS. 17
QUINOLINE & ISOQUINOLINE ALKALOIDS 20
INDOLE AND OXINDOLE ALKALOIDS. 22
ANIMAL BASED ALKALOIDS. 26
NOMENCLATURE 27
Extraction and Isolation 27
Physical-Property 29
Physical method 29
Functions 29
Conclusion 30
BIOSYNTHESIS OF ALKALOIDS 31
Synthesis of alkaloids 42
Reference 55

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INTRODUCTION
(1)
Alkaloids are a class of compounds which typically contain
nitrogen and have complex, ring structures. They occur naturally in
seed bearing plants and are found in berries, bark, fruit, roots and
leaves. Often, they are bases which have some physiological effect.
Evidence suggests that alkaloids have been used by humanity for
thousands of years. The first civilizations to use them were probably
the ancient Sumerians and Egyptians. However, it was not until the
early nineteenth century that these compounds were reproducibly
isolated and analyzed. Advances in analytical separation techniques,
such as chromatography and mass spectroscopy, led to the elucidation
of the chemical structure of alkaloids. The term for these compounds is
thought to have originated from the fact that the alkaloid, morphine,
had similar properties to basic salts derived from the alkali ashes of
plants thus, it was called a vegetable alkali or alkaloid. Since the first
alkaloids were isolated, thousands more have been identified and
classified.
Although numerous alkaloids exist, they have similar properties when
separated. In general, they are colorless, crystalline solids which are
basic, have a ring structure, and have definite melting points. They are
also derived from plants and have a bitter taste. However, some
exceptions are known. For instance, some alkaloids are not basic and
others are brightly colored or liquid. Other alkaloids are produced
synthetically. Most alkaloids are also chiral molecules which means
they have nonsuperimposable mirror images. This results in isomers
that have different chemical properties. For example, one isomer may
have a physiological function while the other does not.
It is mostly unknown why plants produce alkaloids. Various theories
have been proposed to explain their existence. Some suggest that
alkaloids are by-products of normal plant metabolism. It is also
thought that alkaloids may provide a means of defense for plants from
insects and animals. Alkaloids may also be a reservoir for molecules
that plants often use. It is likely that all of these theories are correct to
some extent.

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 (2)
The forked root of mandrake was thought to be in the power of
dark earth spirits.
Mandrake would only be growing after a man was hung on the
gallows, being fed by the urine and semen of the dead man. It was
believed that it could be uprooted safely only in the moonlight, after
appropriate prayer and ritual. With the tip of a willow wand three
circles were drawn around the plant, and then a black, hungry dog was
attached to the plant by a cord. The dog was put a juicy sausage in
front of his nose, and his hunger made him pull the mandrake root out
of the ground. It was thought that as the mandrake root was pulled
from the ground, it uttered a shriek that killed or made mad those who
did not block their ears against it. The dog would die anyway, because
of either starvation or instant overfeeding.

Mandrake, also named Mandragora (Mandragora officinarum), is

probably the most famous magic plant known. Already used in Egypt
3500 years ago, it was in the Grecian times considered as an extremely
powerful aphrodisiac and fertility enhancer. Mentioned in the Koran,
and strictly forbidden. The sponge that was given to Jesus on the cross
is said to contain mandragora juice.

In the dark ages mandragora was loaded with dozens of myths, and it
played a major role in witchcraft. Witches prepared mixtures of
extracts of henbane (Hyoscyamus niger), deadly nightshade (Atropa

5
belladonna) and mandrake root, to be applied on the skin or on the
genitals.

These plants belong to the family of Solanaceae, the nightshade family.

The mixture is extremely rich in tropane alkaloids, such as
hyoscyamine, scopolamine, atropine, hyoscine, cuscohygrine and
mandragorine.
Biosynthesis of tropane alkaloids start with ornithine (a dibasic amino
acid) or arginine an amino acid with a guanidium group attached to it);
the biosynthetic pathway has been completely elucidated.
Other alkaloids use lysine, phenylalanine, tyrosine, methionine or
tryptophan as the starting amino acid, eventually as their amino
aldehydes or amines derived from them.

All of these are characterised as alkaloids, in today’s nomenclature

identified as organic nitrogen bases from botanical origin (although
that is strictly not true as also in the Animal Kingdom alkaloids occur).
The name “alkaloid” comes from the Arabic word for ash “al-qali”. Al-
qali was obtained by roasting (European) saltwort (Salsola kali), the
ashes being rich in sodium and potassium carbonate.
In the Golden Century of Damascus craftsman were able to purify the
ashes to obtain white crystals composed of a mixture of Na2CO3 and
K2CO3, and this enabled them to make transparent glass.
On average alkaloids are poisonous to extremely poisonous, but
frequently they are extremely useful applied in pharmacy, usually
without a synthetic countertype. Virtuallyall plants contain alkaloids.
Alkaloids are quite frequently responsible for the cosmetic benefits
obtained from botanical extracts. Often condemned, frequently
glorified. Like the girls on the catwalk who like to apply the juice of a
deadly nightshade berry to the eyelids to get nice, large pupils.

The name “atropine” comes from Atropos, the Fate who severs the
thread of life; you will remember how Atropos works if you have read
Stephen King’s book “Insomnia”.
Belladonna is also named Devil’s Cherries because of the excellent
taste of the glossy, black berries, but eating a few will surely result in a
horrible death.

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 

β –PHENETYLAMINES
β-Phenetylamine (a colourless liquid with a boiling point of 1970C) is
the parent substance of a group of alkaloids.β-Phenetylamine itself
occurs in putrid meat; it is formed by decarboxylation of
phenylalanine. It occurs in mistletoe (Viscum Album), and in Brassica
species (cabbage, kale, cauliflower).

d-(-)-Ephedrine is an important derivative which occurs in the genus

Ephedra. It is one of the most important drugs in MaHuang (Ephedra
Sinensis), a Chinese drug, containing ~2-2,5% ephedrine. Ma Huang,
also known as ephedra, is used for weight management and appetite
suppression, but is restricted in most countries. Pakistani ephedra
contains much smaller amounts of ephedrine (~0,7%).

Ephedra-containing supplements produce a state of wakefulness and

alertness, a decreased sense of fatigue, and a mood elevation with
increased self-confidence and initiative. Unfortunately, the beneficial
effects in weight management and mood alteration come at a price:
high doses of ephedrine result in depletion of epinephrine(adrenaline)
and norepinephrine (noradrenaline), leading to the opposite effects:
depression, a sense of loneliness and suspiciousness. Also, ephedrine
may elevate blood pressure, increases heart rate and comes with
severe palpitations. In very serious cases this can cause ventricular
fibrillation and death. The use of Ma Huang, particularly in conjunction
with caffeine, should be discouraged because of the side effects.

7
The physiological activity of ephedrine compares to benzedrine
(amphetamine) and tyramine. Benzedrine is not found in nature, but
tyramine occurs in germinating barley(Hordeum vulgare), and is
produced by putrefaction of proteins (decarboxylation of tyrosine).It is
also found in tangerine (Citrus reticulata) and orange (Citrus Sinensis),
although the amounts are insignificant. Mescaline (3,4,5-trimethoxy-β-
phenetylamine is found exclusively in Mexican peyote (Lophophora
Williamsii), next to related alkaloids such as hordenine. Hordenine (4-
hydroxy-N,N-dimethyl-β-phenetylamine) is more widespread in plants.
It is found in e.g. Selenicereus grandiflorus (Queen-of-the-Night) and
Tamarindus indica (tamarind).

8
Adrenaline is a non-steroid hormone belonging to the β-phenetylamine
group; it was the first hormone be to isolated in a crystalline form
(Takamine; 1901). It raises blood pressure and is used locally to stop
haemorrhage. Adrenaline is responsible for the storage and
mobilisation of glycogen and fatty acids and tunes the corresponding
metabolic pathways. Adrenaline is also a neurotransmitter of the
adrenergic nervous system.

PYRROLIDINE ALKALOIDS.

About 80 pyrrolidine alkaloids are known, hygrine being the simplest

representative. It is one of the coca alkaloids (Erythroxylum coca),
chemically identified as N methyl-pyrrolidinyl acetone. The coca plant
originally comes from the Andes mountain range and is best known for
the alkaloid cocaine; it also contains about a dozen other alkaloids as
well:benzoylecgonine benzoyltropine,cinnamylcocaine, cuscohygrine,
dihydroxytropane, hygrine, hygroline, methylcocaine, methyl
ecgonidine, nicotine, tropacocaine, and α- & β-truxilline
(3)

9
 With the exception of nicotine all these alkaloids are rather specific
for Erythroxylum coca; in general little is known about their
physiological activity. Nicotine is an alkaloid that can be considered
belonging to the group of pyrrolidine alkaloids or to pyridine alkaloids.
The most important source for nicotine are the leaves of Nicotiana
tabacum(Tobacco plant; 2-4%), but it also occurs in very small amounts
in Horsetail (Equisetum arvense) and Potato (Solanum tuberosum).
Nicotine has no known cosmetic benefits; it acts both as an ANS
stimulant and ANS paralytic (Williamson & Evans, Potter's New
Cyclopaedia of Botanical Drugs and Preparations [1989]). The amino
acid proline (pyrrolidine 2-carboxylic acid) can also be considered as an
alkaloid. N,N-dimethylpyrrolidine-2-carboxylate (stachydrine), an
amphoteric, is found in germinating alfalfa seeds (Medicago sativa;
~0,8%), motherwort (Leonurus cardiaca) and yarrow (Achillea
millefolium). In a similar fashion hydroxyproline may be converted to
betonicine (4-hydroxy-N,N- dimethylpyrrolidine-2-carboxylate) or
turicine, also amphoterics. Betonicine (0,3 %) and turicine are found in
Marrubium vulgare(Horehound). Horehound is valuable in the
treatment of bronchitis where there is a nonproductive cough.
Topically horehound is used to promote the healing of wounds.

The properties of stachydrine, betonicine and turicine compare to

ectoine, chemically identified as a pyrimidine derivative. All these
amphoterics (but also betaine(trimethylglycine) from sugar beets and
trehalose (a diglucoside occurring in yeasts and fungi)) act as
osmosuppressants, enabling cells to survive in more harsh, electrolyte-
rich environments. Betaine (trimethylglycine) is able to perform its
osmoprotecting properties in surfactant compositions, and markedly
reduces their irritation potential.

PYRROLIZIDINE ALKALOIDS.

Many pyrrolizidine alkaloids, nearly 100 are known, display toxic,

carcinogenic and mutagenic properties. In liver cells pyrrolizidine
alkaloids give rise to 10 to 30- fold enlargement of the liver cells
(megalocytosis). In serious cases this may result in severe liver damage
and death. The frequent occurrence of primary liver tumours in the

01
natives of Central Africa and South Africa is ascribed to the
consumption of traditional medicinal plants. The majority of
pyrrolizidine alkaloids are hepatotoxic, carcinogenic, teratogenic and
mutagenic.

Plants from the Boraginaceae, Compositae and Leguminosae families

contain significant amounts of pyrrolizidine alkaloids. Members of the
Boraginaceae are for example Alkanna tinctoria (alkannet; the root
contains 0,25% hepatotoxic triangularine), Lithospermum officinale
(gromwell; 0,003% lithosenine) and Symphytum officinale (comfrey;
the roots contain 0,5% intermedine, lycopsamine, symphytine,
echimidine and symglandine; the above ground parts contain only
small amounts of pyrrolizidine alkaloids and are edible. Comfrey root
has been blamed for serious liver damage death in humans. A sincere
concern for these plants is also VOD (veno-occlusive disease), which is
difficult to diagnose.

Coltsfoot (Tussilago farfara) has been widely used in Europe to treat

lung disorders and gastro-intestinal disorders (e.g.diarrhea). It

00
contains, depending on the time of harvesting, significant amounts of
senkirkine (~0.015%) and senecionine.

it is also found in groundsel (Senecio vulgaris, and its subspecies) next

to riddelline, retrorsine, floridanine, monocrotaline, and otosenine,
totalling to approximately 0,2%. In subspecies the percentages may be
markedly higher, such as in Senecio bicolor (up to0,9%).

Pyrrolizidine alkaloids give rise to major health concerns, and many

plants containing them have been marked with a red cross: they shall
not be part of food supplements and/or botanical medicines.

02
PIPERIDINE AND PYRIDINE
ALKALOIDS.

Coniine (2-propylpiperidine) is found in high amounts in hemlock

(Conium maculatum) and in the leaves of elder (Sambucus nigra). It has
emetic and paralytic properties, and is considered as highly toxic. It
was used by the ancient Grecians for state executions, Socrates († 399
BC) being the best known victim of hemlock. Hemlock contains up to
0,2% coniine. Hemlock also contains other alkaloids such as N-
methylconiine, conhydrine, psuedoconhydrine and - coniceine.
However, these alkaloids are physiologically not very significant for
humans.

At least 700 piperidine alkaloids are known. They arise from lysine in
much the same manner as pyrrolidine alkaloids are derived from
ornithine and arginine. Anatabine and anabasine (3-[2-piperidinyl]-
pyridine), found in tobacco (Nicotiana tabacum), are derived in a
manner that parallels the origin of nicotine. Anabasine is severely

03
teratogenic (foetus deforming properties), much stronger than
thalidomide [Softenon,
caused in the sixties a massive number of birth defects] and
diethylstibestrol. Nicotine, although always accused, has no
teratogenic propeties. Piperidine alkaloids are also found in the root
bark of the pomegranate tree: pelletierine, isopelletierine,
methylisopelletierine and pseudopelletierine; the last one is related to
atropine. Sedum acre (wallpepper, common stonecrop) is topically
used for wound treatment, burns, hemorrhoids, warts, eczema and
mouth ulcers. It contains the sedative sedamine, which is usually
applied in conjunction with barbiturates, and sedine. Sedamine
is also a lysine based alkaloid, like pelletierine, pseudopelletierine,
halosaline and the more complex tetracyclic lycopodine. Lycopodine
has also been isolated from club moss (Lycopodium clavatum), and has
also sedative properties. Lobelia inflata (Indian tobacco) has anti-
asthmatic, antispasmodic, emetic, expectorant and respiratory
stimulant effects. The constituent with the highest physiological
activity, (-)-lobeline, is known as -lobeline, to distinguish it from the
mixture of lobelia alkaloids formerly called lobeline. Like nicotine, but
weaker, -lobeline exhibits effects on the peripheral circulation,
neuromuscular system and central nervous system (CNS). Small
amounts of lobeline stimulate respiration and have expectorant
activity. Larger amounts have emetic, purgative, and diuretic effects.
Lobeline is much better known as a partial nicotine agonist; it has been
(and still is) used in a variety of commercially available preparations for
smoking cessation. More recently it was found that lobeline inhibits
the neurochemical and behavioural effects of amphetamine and the
results (Miller et.al.) support a role for lobeline as a potential
pharmacotherapy for psycho-stimulant abuse. Independently it was
found that lobeline reduces self-administration of methamphetamine
in rats.

A spectacular issue has been the discovery of epibatidine by Daly et.al.

(1976). They took scrapings of the skin of a poisonous Ecuadorian frog,
Epibpedobates tricolor.
They discovered, through tests on mice, that the frog’s poison provided
pain relief 200 times higher than that of morphine. Unfortunately, as
the frogs were endangered, only very small amounts of the chemicals
were extracted. At the end of the eighties the structure of this poison
was determined using NMR and mass spectrocopy. It was shown that it

04
contained a piperidine moiety, on the 3-position substituted with a 5-
[2- chhloropyridine] group (the presence of chlorine based heterocyclic
unit is unique). Epibatidine binds to nicotinic acetylcholine receptors
rather than to opiate receptors, and is therefore not addictive.
However, epibatidine shows severe side effects. Based on an extensive
screening of 500 similar alkaloids a product coded as ABT-594 was
developed that doesn’t show the side effects from epibatidine. This is
considered a breakthrough in pain control.

Piperine is an alkaloid found in Piper nigrum (black pepper). Piperine

significantly increases the rate of absorption of selenium in the body.
Selenium is important in the functioning of glutathion (a tripeptide
[Glu-CySH-Gly]): glutathion deactivates damaging free radicals,
whereby two glutathion molecules dimerise to form glutathion dimer.
Glutathion is subsequently regenerated from glutathion dimer by
means of the enzyme glutathion reductase, a selenium-containing
enzyme of 121 amino acids, using NADPH as the co-factor. Our
frequent readers might recognise NAPDH as a pyridine-based
nucleotide, which finds its origin in vitamin PP (Niacinamide). Piperine
also dramatically increases the uptake of the B vitamins, and is
therefore highly suitable to treat systemic vitamin B deficiency. In skin
care preparations piperine has been demonstrated to greatly enhance
the efficacy of topically applied vitamins. Interesting to note is the
presence of the vanillin moiety in piperine.

Niacinamide, heavily used as a moisturiser, is chemically identified

as pyridine-3-carboxylic acid amide (pyridine-3-carboxamide). Pyridine-
2-carboxylic acid (picolinic acid; MP=137C) and pyridine-4-carboxylic
acid (isonicotinic acid; MP=317C) next to pyridine-3-carboxylic acid
(nicotinic acid; MP=234-237C) also occur occur in Nicotiana tabacum,
next to ~140 other alkaloids. Nicotinic acid is not exclusive for the
tobacco plant; it also occurs in Glycyrrhiza glabra (licorice; ~500 ppm),

05
Chelidonium majus(celandine; ~400 ppm) and in the roots of
Taraxacum officinale (dandelion) and Gentiana lutea (gentian).

Methylation of nicotinic acid results in the formation trigonellin, a

betaine with significant osmoprotecting properties; it is the most
significant constituent of Mirabilis jalapa (four o’clock, wonderflower),
an old-fashioned but quickly growing plant with nice colourful flowers.
Four o’clock was one of the favourites of the famous botanist Mendel.

Areca catechu (betel nut, sirih palm) occurs widespread in South-east

Asia. The nuts contain a volatile oil, and in the oil a number of alkaloids
are present, such as arecoline,
arecaidine, guvacine and guvacoline. The pyridine ring has been
partially hydrogenated and only the double bond on the (3-4) double
bond has remained intact. Arecoline is used in medicine. It is a mild
central nervous system stimulant. It increases respiration while
decreasing the work load on the heart. An overdoses arecoline may
cause inebriation, dizziness, diarrhoea, and may damage the teeth and
gums. Frequent use results in a red colouring of the teeth. Betel nut is
probably the most widely used stimulant worldwide.

Sometimes it is difficult to categorise particular alkaloids in a group.

Ergotamine could be considered as a pyridine alkaloid, but also as a
pyrrole alkaloid. It first came in the medical picture during the Middle
Ages when mass poisoning by ergotamine occurred throughout Europe
due to eating bread carrying Claviceps purpurea. This parasite grows
on rye, wheat, barley and other grains. Ergotamine (a mycotoxin) is a
secretion product of Claviceps purpurea. In large quantities it causes
ergotism (St.Anthony Fire): complete body parts die off because of
permanent damage to the arteries, resulting in loss of toes, legs or
arms without losing any blood. Ergotism still asks today for victims.
Ergotamine is nonetheless beneficially used in pharmacy to treat
migraine and to induce childbirth.

06
Another important piperidine alkaloid with a highly complex structure
is aconitine, found in Aconitum napellus (monkshood). Beautiful
flowers, but highly toxic. Aconitine is isolated from the monkshood
rhizomes and is used as a local analgesic. In the past aconitine was
used as a killing poison. Monkshood is therefore one of the most
dangerous plants known. From a toxicity point of view monkshood
compares to the autumn crocus (Colchicum autumnale); it contains the
highly toxic alkaloid colchicine. Traditionally autumn crocus is used to
alleviate the inflammation associated with gout. Colchicine blocks or
suppresses cell division by inhibiting mitosis, the division of a cell's
nucleus. Because cancer cells divide much more rapidly than normal
cells, they are more susceptible to being poisoned by mitotic inhibitors
such as colchicine. Colchicine is a powerful anticancer drug, in a similar
fashion as taxol (paclitaxel; Taxus baccata, Cephalo- taxus mannii) and
vinca alkaloids. For taxol a synthetic pathway has not yet been worked
out (and looking at the structure this is not al all surprising). That is
also the case for vinca alkaloids from Cataranthus roseus (Madagascar
periwinkle). The chemical structure of these alkaloids (vincristine,
vinblastine, vinepidine, vindesine, etc.) is extremely complex, and they
are, like taxol, extremely difficult to make in the laboratory.

07
SOLANACEOUS AND COCA
ALKALOIDS.

This group includes atropine, hyoscyamine, scopolamine and many

other important products. Mandragora officinarum (mandragora)
contains scopolamine, hyoscyamine, mandragorine, next to many
other alkaloids.

Datura stramonium (Jimson Weed) is a major source for scopolamine.

It is known under many different names, such as Locoweed, Angels
Trumpet, Thorn Apple, Devil's Trumpet, Mad Apple, Stink Weed,
Sacred Datura, Green Dragon and Tolguacha. Scopolamine is found in
all parts of the plant, with the highest alkaloid content in the seeds
(0.4%). Scopolamine (hyoscine) is the ester of scopine with 3-hydroxy-
2- phenylpropionic acid (tropic acid). Scopolamine is a constituent of
travel sickness tablets, and in combination with morphine it causes
“twilight sleep”. Jimson weed is smoked or a tea can be made of it.
When rubbed onto the skin it is swiftly brought in the bloodstream by
transdermal transport. Jimson weed was and is used as a medicine to
treat a variety of illnesses and conditions. Extracts are used for the
treatment of muscle spasms, controlling salivation in Parkinson's

08
disease, asthma, intestinal cramps, and both diarrhoea and bed-
wetting. In older times it was used to reduce or eliminate pain.

Initial symptoms of scopolamine abuse include dry mouth, dilated

pupils, reddening of the face and neck, elevated blood pressure & body
temperature and significant palpitations. These symptoms may be
followed by extreme hallucinations, agitation & aggression, coma and
death. Inappropriate use of scopolamine is recognised by extensive
sweating and life-threatening. Scopolamine in the human body acts as
a competitor to acetylcholine at peripheral and central muscarine
receptors; abuse can easily be slobbering. Like many tertiary amines
scopolamine inhibits CNS receptors and abuse results in acute
psychosis or delirium. A third major source for tropane alkaloids is
henbane (hyoscyamus niger). The roots & the leaves contain ~1500
ppm alkaloids, while the seeds only 400 ppm. Henbane contains 15
different alkaloids, and most of these are extremely dangerous in the
hands of amateurs. Atropine occurs in Atropa belladonna (deadly
nightshade) is optically pure. Racemisation results in hyoscyamine, and
hyoscyamine is therefore ±- atropine .

Erythroxylon coca is responsible for the alkaloid cocaine, probably the

most significant export product for Colombia. Cocaine is related to
benzoylecgonine, tropacocaine and cuscohygrine (which is also found
in mandragora). The health impact of cocaine is to well-known to
require further discussion. Cocaine used to be applied in particular soft
drinks, until this application was banned in1929.

Erythroxylon coca

09
QUINOLINE & ISOQUINOLINE
ALKALOIDS
Angostura trifoliate is used orally for preventing recurrence of malaria.
In the past it was used in alcoholic beverages (angostura bitter), but
nowadays it has been replaced by gentian. The applicable part of
angostura is the bark which contains a number of quinoline based
alkaloids such as cusparine, galipine and galipoline; these exhibit
antispasmodic properties. A far more important quinoline alkaloid is
quinine. It is present in the bark of various Cinchona species,
characterised by the presence of a triethylene diamine tricyclic unit.
Quinine has anti-malarial properties.

Camptothecin is found in the bark of the Chinese camptotheca tree

and the Asian nothapodytes tree. It is, together with two closely
related alkaloids (topotecan, irinotecan), the only known naturally-
occurring DNA topoisomerase I inhibitor. Camptotecan is a relatively
new chemotherapeutical agents to treat breast and colon cancers,
malignant melanoma, small-cell lung cancer and leukemia. While
camptotecin inhibits DNA topoisomerase I, the affected cells can't
make their proteins and consequently the cell stops growing. Because
cancer cells grow and reproduce at a much faster rate than normal

21
cells (whereby the synthesis of proteins plays a vital role) they are far
more vulnerable to DNA topoisomerase inhibition compared to normal
cells.

The group of isoquinoline alkaloids comprise the both famous and

notorious opium alkaloids, as found in Papaver somniferum (opium).
Representatives of the isoquinoline alkaloids are laudanosine,
laudanine, narcotine and hydrastine. In the name one recognises
“Laudanum”, a very popular drug during the Victorian era. It was an
opium-based painkiller prescribed for everything from headaches to
tuberculosis. It is in fact an alcoholic extract of opium, frequently with
added sugar. Opium also contains alkaloids with condensed systems to
which belong codeine, morphine, heroine and thebaine.
It is quite striking indeed that the influence on the nervous system is so
much different for codeine and morphine: just one methyl group more

20
or less, and we’re changing the properties from a modest, non-
addictive bronchodilator (codeine) to an addictive pain relief agent
(morphine) or a highly addictive euphoricum (heroine).

INDOLE AND OXINDOLE

ALKALOIDS.
The indole alkaloids are usually highly complex structures. The simplest
indole alkaloid is gramine which occurs in the leaves of Hordeum
vulgare (barley). Gramine is clinically used to resist palpitations and to
reduce blood pressure. Barley contains a wide variety of other
alkaloids such as glaucine, which also occurs in Glaucium flavum(yellow
poppy). Glaucine is chemically best described as a dibenzo-
isoquinoline.

Quebracho is an evergreen tree from South America, which may reach

a height of 40 meter. The wood is valued because of its hardness. The
name is derived from two Spanish words, quebrar and hacha, meaning
'the axe breaks'. The bark contains at least six indole alkaloids,
quebrachamine deriving its name from the species. Nonetheless, the
most important alkaloid is aspidospermine, which could also be
identified as a pyrrolizidine alkaloid. Aspidospermine is used to relieve
asthma and high blood pressure. Locally it is also used as an
aphrodisiac.
The aphrodisiac qualities of aspidospermine are not confirmed,
contrary to yohimbine. This is found in the African tree Pausinystalia
yohimbe. Yohimbine is used to treat high blood pressure and to
stimulate blood circulation. It is also used as a veterinarian aphrodisiac.
Although yohimbine is strictly forbidden to be used in cosmetics there
are many products in circulation containing yohimbine.

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Closely related to yohimbine is reserpine, found in Rauwolfia
serpentine (Indian snakeroot, serpentine wood). It is also known as
ajmaline. Orally, Indian snakeroot is used to treat hypertension,
symptomatic relief in individuals with agitated psychosis unable to
tolerate other agents and insomnia. Indian snakeroot is also used
orally for snake and reptile bites, insanity, fever, constipation, feverish
intestinal diseases, liver ailments, rheumatism, mental illness and
epilepsy. Reserpine shall always be used under supervision of a
medical doctor.

The applicable part of Indian snakeroot is the root. The properties of

the whole root of Rauwolfia serpentina differ from those of reserpine.
The whole root contains over 50 alkaloids. The active constituents of
the whole root include the rauwolfia alkaloids reserpine, rescinnamine,
and deserpidine (11-desmethoxyreseroine). Hypotensive effects are
believed to be due to the depletion of both catecholamine and
serotonin stores and to the prevention of re-absorption. The greater
the proportion of alkaloids present, the greater the hypotensive
activity. The sedative effects of Indian snakeroot may result from the
depletion of amine stores in the central nervous system (CNS).
Reserpine has been in clinical use since the 1950’s. At present time it is
not so much used anymore as synthetic alternatives have been made
available lacking the side effects of reserpine,

Currently there are approximately 5000 indole alkaloids known, with

some notorious representatives: ajmacaline (clinically used for the
treatment of circulatory disorders; it has hypotensive and vasodilator
properties), the extremely toxic strychnine, brucine(even far more
toxic than strychnine), vincamine (for the treatment of headaches and
vertigo; its principal action is to moderate cerebral vasodilation). Not
23
to forget about thecurare alkaloids, which cause an immediate
paralysis of the victim. The active ingredients of the so-called calabash
curares are bisindole alkaloids. Compounds such as Ctoxiferine are
many more times more active than tubocurarine. Olivacine and
ellipticine have been isolated from Apocynaceae and Loganiaceae.
These alkaloids are clinically used as anti-tumour agents, as DNA
topoisomerase inhibitors. Iboga alkaloids come from Tabernanthe
iboga, and are used to combat fatigue, sleep and hunger. Highly
appreciated by different secret services, and by religious sects. In larger
quantities the drug is highly hallucinogenic; the principal alkaloid is the
famous ibogaine. Ibogaine is effectively used to reverse drug abuse,
predominantly opiates and cocaine.

Indole alkaloids all have a very high biological activity and usually
instant bioavailability. They are derived from the amino acid
tryptophan. Some indole derivatives(e.g. harmaline) possess anti-
protozoal activity, enabling to fight leishmaniasis and various diseases
causes by trypanosomes (e.g. sleeping disease). Harmaline is extremely
toxic, and for that reason ellipticine and olivacine are preferred. Their
anti-protozoal activity was recognised in the 1970’s. The use of indole
alkaloids is always a balance between desired and undesired
properties: to cure or to kill.

Related to indole alkaloids are the oxindole alkaloids. These occur in

various vines in swampy territories of South America, Africa and South-
east Asia. Previously we reported on alkaloids as the active substances
of Uncaria tomentosa (cat’s claw); approximately55 have been
identified. Present are tetracyclic oxindole alkaloids (TOA’s; e.g.
rynchophylline, isorynchophylline), pentacyclic oxindole alkaloids
(POA’s; e.g. pteropodine, isopteropodine, uncarine F, mitraphylline)
and indole alkaloids (hirsutine, dihydrocorynantheine). These alkaloids
are all physiologically active products.

TOA’s mainly affect the nervous system, both peripheral and central,
while the POA’s affect the immunologic system cells, respecting the
cellular immunity. Rynchophylline and isorynchophylline have been
described to block tension-depending calcium channels (Yamahara,
1993), reduce blood pressure and slow down the activity of the heart.

24
A major interest has been raised for POA’s because of their anti-
proliferative properties to HL60 and U937 leukaemic cell lines, not
inhibiting the growth of healthy blood cells. Uncarine F and
isopteropodine show the greatest activity; profound testing is ongoing
for non-invasive treatment of leukaemia. Important to note is that
POA’s in low concentration do not show cytotoxic effects.

The Shanghai College of Traditional Chinese Medicine studied

rynchophylline on its ability to inhibit platelet aggregation and
thrombosis, with positive results. This suggeststhat Cat's Claw, being a
source for this alkaloid, may be useful in preventing strokes and
reducing the risk of heart attack by lowering blood pressure, increasing
circulation, inhibiting formation of plaque on arterial walls and blood
clots in the brain, heart and arteries. In other words: cardio-vascular
diseases. The drawback of the alkaloids present in Cat’s Claw is the
potential interaction with anti-hypertensives (rynchophylline reduces
blood pressure !). Also, simultaneous use of Cat’s Claw and
immunosuppressants such as prednisone and other corticosteroids
shall be avoided; the result would be rather unpredictable. Related to
the Uncaria species are the Mitragyna species, which occur in Africa
and Asia. The genus was given its name because the shape of the
stigmas resemble a bishop’s mitre. Mitragyna speciosa has long been
used as a cure for opium addiction; in Thailand the leaves were chewed
by the locals, named “kratom”. Chewing kratom is now forbidden, but
still heavily practised. Different species are used; Mitragyna javanica is
often used as an alternative, although not so effective. Other alkaloids
have beenidentified as well, such as rhynchophylline (also found in

25
cat’s claw), mitragynine, mitraversine and mitraspecine. Mitragyna has
properties comparable to morphine, although the degree of addiction
is much lower. At present 22 alkaloids have been isolated from
Mitragyna species.

ANIMAL BASED ALKALOIDS.

The vast majority of the alkaloids are plant-derived, although in recent
times more and more alkaloids are found in animals. Samandarine (20
mg applied on the skin of an adult human is lethal !), samandarone and
cycloneosamandarine were isolated from the skin glands of the
European fire salamander (Salamandra maculosa); all exhibit the usual
properties of alkaloids.

Batrachotoxinin A, a steroidal alkaloid from the Colombian arrow-

poison frog(Phyllobates aurotaenia), bufotenine (a tryptamine-type
alkaloid from the common European toad), deoxy-nuphradine and
castoramine from the Canadian beaver (Castor fiber) and
muscopyridine from the scent gland of the musk deer (Moschus
moschiferus) are other animal based alkaloids. Especially toad poisons,
and the mystic around it, would require a separate study, as a lot can
be learned from them, also taking benefit from what nature has to
offer.

NOMENCLATURE (4)

There was no systematic nomenclature. But there are some

methods for nomenclature are mention below.

26
1. According to their source: There are named according to the
family in which they are found e.g. papavarine, punarnavin, ephedrine.

2. According to their Physiological response: There are named

according to their physiological response e.g.. Morphine means God of
dreams, emetine means to vomit.

3. According to there discover: There are named according to there

discover e.g.. pelletierine group has been named its discoverer, P.J.
Pelletier.

4. Prefixes: There are named by some prefixes are fix in

nomenclature of alkaloids, e.g. epi, iso, neo, pseudo, nor- CH3 group
not attach to Nitrogen..

Extraction and Isolation (4)

Purification or isolation of alkaloids from a plant is always

difficult process because an alkaloids bearing plant generally
contains a complex mixture of several alkaloids with glycoside
organic acid also complicate the process. Following steps are
involved in isolation process.

1. Detection of presence of Alkaloids: First of all confirm the

presence of alkaloids in raw material or crud drugs by various reagents
called Alkaloids reagents e.g.

I. Mayer (Cream Co lour) Test II. Marquis (Conc. HCHO) Test. III.
Erdmann(Conc. HNO3) Test IV. Hager's (Yellow Colour) Test V. Frohdes
(Molybdic acid) Test

2. Extraction: - The plants is dried, then finally powdered and

extracted with boiling methanol. The solvent is distilled off and the
residue treated with inorganic acids, when the bases (alkaloids) are
extracted as their soluble salts.

27
The aqueous layer containing the salt of alkaloids and soluble plant
impurities is made basic with NaOH. The insoluble alkaloids are set free
precipitate out.

3. Separation of Alkaloids: After detection of next step is separation

of a relatively small percentage of alkaloids from large amount of crude
drugs. E.g.- Opium contains 10% Morphine, Chincona contains 5-8 %
Quinine, Belladona- 0.2% of Hyoscyamine. The required alkaloid is
separated from the mixture from fractional, crystallization,
chromatography and ion exchange method.

Physical-Property (4)

I) They are colorless, crystalline solid. Exception – Berberin (Yellow),

Nicotine Coniine (liquid).

28
II) They are insoluble in water (exception liquid alkaloids soluble in
water), soluble in organic solvent ( CHCl3, Ethyl alcohol ether)
III) Taste: They are bitter in taste.
IV) Optically active, Most of levo ratatory but few are -Dextro rotatory
e.g. Coniine, some inactive- e.g.- papaverine.

Physical method (4)

These following physical methods are applied to elucidate the

structure of alkaloids:
 U.V. Spectroscopy
 IR Spectroscopy
 Nuclear Magnetic resonance spectroscopy
 Mass spectroscopy
 Optical rotatory dispersion & circular dichroism.
 Conformational Analysis
 X-Ray diffraction

Functions (4)

Alkaloids functions -
 As reservoir of nitrogen
 As reservoir for protein synthesis
 As detoxicating agents
 As toxicating agents
 As harm one for many activity of plant.
 Alkaloids have many physiologically biological and
pharmacological properties.

Conclusion (4)

It can be concluded that:

1. Alkaloids are naturally occurring heterocyclic complex compounds.
2. Alkaloids have indefinite definition.
3. Alkaloids have mainly nitrogen in heteroatom.
4. Alkaloids have complex molecular structure.
5. Alkaloids are bio & physiologically and pharmacologically active.

29
 (5)

CO2 + H2O
h PRIMARY METABOLISM

Photosynthesis Glucose Carbohydrates

SECONDARY SECONDARY
G
METABOLISM L METABOLISM
Building Blocks Y
C
O
Phenyl- L
Y
propanoids Amno Acids S Fatty Acids
Flavonoids I Lipids
Proteins S
Alkaloids synthesis
enzymes Acetyl CoA
regulation Acetogenins
Nucleic
Terpenes
Acids Citric Acid
Steroids
reproduction Cycle
RNA DNA CO2 + H2O + ATP

31
 Glucose
h CH2OH (6 carbons) CH2OH CH2OH CH2OH
O
O O O
OH OH OH OH
HO OH HO O O O
CO2 OH OH OH OH
photosynthesis starch n
glycolysis
CHO
CH OH CHO CH2OH
HC OH C O
CH OH
polyketides
CH2OP erythrose- CH2OP CH2OP
acetogenins
4-phosphate CH2
C OP
phosphoenol O O lipids
pyruvate (PEP) H3C C CH2 C CH2 fatty acids
COOH
COOH shikimic (3 carbons)
acid anthanilic
acid
HO OH COOH O
acetyl-
OH H3C C SCoA
coenzymeA
NH2 (2 carbons)
HO CH3
mevalonic
phenylpropanes
lysine oxalo- acid
O
phenylalanine ornithine acetate citric energy (ATP)
O

tyrosine acid + CO2 + H2O

tryptophan cycle
terpenes
NH3 steroids
nicotinic aspartic
alkaloids acid acid carotenoids
glutamic acid

Plants biosynthesize alkaloids from

simple precursors, using many unique
enzymes.

Until the mid-20th century, our view of how alkaloids are synthesized
in plants was based on biogenic hypotheses. Pathways suggested by
illustrious natural product chemists such as Sir Robert Robinson,
Clemens Schöpf, Ernst Winterstein, and Georg Trier were based on
projections considered feasible within the realm of organic chemistry.
In the 1950s, however, alkaloid biosynthesis became an experimental
science, as radioactively labeled organic
molecules became available for testing hypotheses.
These early precursor-feeding experiments clearly established that
alkaloids are in most cases formed from L-amino acids(e.g.,
tryptophan, tyrosine, phenylalanine, lysine, and arginine), either alone
or in combination with a steroidal, secoiridoid (e.g., secologanin), or
other terpenoid-type moiety.
One or two transformations can convert these ubiquitous amino acids
from primary metabolites to substrates for highly speciesspecific

30
alkaloid metabolism. Although we do not thoroughly understand how
most of the 12,000 known alkaloids are made by plants, several well-
investigated systems can serve as examples of types of building blocks
and enzymatic transformations that have evolved in alkaloid
biosynthesis.

The L-tryptophan–derived monoterpenoid indole alkaloid ajmalicine

was thefirst alkaloid for which biosynthesis was clarified at the enzyme
level (Fig. 24.33); in that study plant cell suspension cultures of the
Madagascar periwinkle C. roseus were used. In plants, the
biosynthesis of ajmalicine and more than 1800 other monoterpenoid
indole alkaloids begins with the decarboxylation of the amino acid
Ltryptophan by tryptophan decarboxylase to form tryptamine. Then
tryptamine, by action of strictosidine synthase, is stereospecifically
condensed with the secoiridoid secologanin(derived in multiple
enzymatic steps from
geranio -strictosidine. Strictosidine can then be
enzymatically permutated in a species-specific manner to form a
multitude of diverse structures (Fig. 24.34). The elucidation of the
enzymatic formation of ajmalicine by using plant cell cultures laid the
groundwork for analysis of morecomplex biosynthetic pathways, such
as those leading to two other L-tryptophan– derived monoterpenoid
indole alkaloids, ajmaline (Fig. 24.35) and vindoline.

The berberine synthesis pathway has

been defined completely.

The first alkaloid for which each biosynthetic enzyme has been
identified, isolated, and characterized from the primary metabolite

32
33
34
precursor through to the end product alkaloid is the antimicrobial
tetrahydrobenzylisoquinoline alkaloid, berberine, in Berberis(barberry)
cell suspension cultures (Fig. 24.36). This pathway will be described in
detail because it exemplifies the role of highly substrate-specific
enzymes and of compartmentalization in alkaloid biosynthesis.
The biosynthesis of tetrahydrobenzylisoquinoline alkaloids in plants
begins in the cytosol with a matrix of reactions that generates thefirst
tetrahydrobenzylisoquinoline

alkaloid, (S)-norcoclaurine (Fig. 24.37). The pathway proceeds from

two molecules of L-tyrosine. One is decarboxylated to form tyramine
or is acted on by a phenol oxidase to form L-dopa. Dopamine can then
be formed by decarboxylation of L-dopa or by the action of a phenol
oxidase on tyramine. Determining which of these two pathways is
predominant in a given plant is difficult because all of the enzyme
activities are present in protein extracts. The benzyl moiety of(S)-
norcoclaurine is formed by transamination of the second L-tyrosine
molecule to form p-hydroxyphenylpyruvate, which is next
decarboxylated to p-hydroxyphenylacetaldehyde. Dopamine and p-
hydroxyphenylacetaldehyde are then stereoselectively

35
condensed to form (S)-norcoclaurine. A series of methylation and
oxidation reactions yield the branchpoint intermediate of
benzylisoquinoline alkaloid biosynthesis, (S)-reticuline (Fig. 24.38).

In Berberis, the N-methyl group of(S)-reticuline is oxidized to the

berberine bridge carbon C-8 of (S)-scoulerine (see Fig. 24.37). The
specific pathway from (S)-scoulerine that leads to berberine proceeds
with O-methylation to (S)-tetrahydrocolumbamine. The 3-O-methyl
moiety of tetrahydrocolumbamine is converted to the methylenedioxy
bridge of canadine by canadine synthase, a microsomal cytochrome
P450–dependent oxidase. The final step in the biosynthesis of
berberine is catalyzed by (S)-tetrahydroprotoberberine oxidase, an
enzyme shown to contain a covalently bound flavin. The end product
alkaloid berberine accumulates in the central vacuole of the Berberis
cell.

The berberine bridge enzyme and (S)tetrahydroprotoberberine oxidase

are compartmentalized together in vesiclesapparently derived from
the smooth endoplasmic reticulum. Each of these enzymes consumes1
mol of O2 and produces 1 mol of H2O2 per mole of berberine formed.

36
Overall, the course of reactions from 2mol of L-tyrosine to 1mol of
berberine consumes 4mol of S-adenosylmethionine and 2mol of
NADPH.

Elucidation of other alkaloid

biosynthetic pathways is progressing

The enzymes that catalyze the biosynthesis of the

benzophenanthridine alkaloid macarpine in the California poppy
Eschscholzia californica have also been identified, isolated, and
characterized, as have nearly all of the enzymes of morphine
biosynthesis in the opium poppy (Fig. 24.39). Good progress has been
made toward understanding the enzymatic formation of the tropane
alkaloid scopolamine in Hyoscyamus niger and of the acridone alkaloid
furofoline-I in Ruta Graveolens. Studies have revealed that the
chemical transformations required for alkaloid biosynthesis are
catalyzed by highly stereo-, regio-, and substrate-specific enzymes that
are present only in specific species. These enzymes do not appear to
participate in primary metabolism. Forexample, the cytochrome P450–
dependent monooxygenases and oxidases of alkaloid biosynthesis
differ from the hepatic cytochrome P450–dependent monooxygenases
and oxidases of mammals. Unlike the individual mammalian enzymes,
which share a common catalytic mechanism and modify a broad range
of substrates, the plant enzymes are highly substrate-specific and
catalyze reactions previously unknown until discovered in the plant
kingdom.

37
38
 (5)

Available techniques for biochemical and molecular genetic

analysis facilitate identification, purification, and production
of useful alkaloids.

The current status of the alkaloid branch of the field of natural

products reflects the many new advances in analytical chemistry,
enzymology, and pharmacology. Only minimal quantities of a pure
alkaloid are now necessary for a complete structure to be elucidated
by mass and NMR spectroscopic analyses. Absolute stereochemistry
can be unambiguously assigned by determining the crystal structure.
The pharmacological activities of crude plant extracts or pure
substances are determined by fully automated systems, such that
millions of data points are collected each year in industrial screening
programs. The factor that limits the number of biological activities for
which we can test is the number of available target enzymes and
receptors. As more of the underlying biochemical bases for diseases
continue to be discovered, the number of test systemswill increase.
What happens when a small quantity of an alkaloid of complex
chemical structure from a rare plant is found to be physiologically
active? The alkaloid must first pass animaland clinical trials; if these are
successful, eventually enough material will be needed to satisfy market
demand. Researchers can develop biomimetic syntheses, which
duplicate at least part of the biosynthetic pathways of plants to yield
synthetic compounds; alternatively, they can alter the metabolism of
the plant to change the alkaloid profile (Fig. 24.40). The regulation of
alkaloid biosynthesis in cell culture can also be influenced to produce a
desired alkaloid. The following successful studies demonstrate the
viability of these approaches.

39
41
40
 (6)
The application of transition metals for selectiveC–Hbond activation
has emerged as a powerful tool for organic synthesis. We have
demonstrated that the oxidative cyclization of appropriately
substituted primary or secondary alkyl- and arylamines opens up
simple and direct approaches to nitrogen-containing heterocyclic ring
systems. This transformation can be efficiently induced using
stoichiometric or even catalytic amounts of transition metals (e.g. iron,
molybdenum, palladium, and silver). The advantages of this method
are mild reaction conditions and toleration of a broad range of
functional groups. Thus, the construction of nitrogen-heterocyclic
frameworks by fusion of fully functionalized building blocks becomes
feasible. Application of this chemistry in natural product total synthesis
provides convergent and highly efficient short-step approaches to a
variety of biologically active alkaloids [1].

Silver(I)-mediated Oxidative Cyclization

to Pyrroles
The pyrrole ring system represents a pivotal substructure in naturally
occurring alkaloids and pharmaceutical products. Following the
classical Hantzsch, Knorr, and Paal–Knorr syntheses numerous
alternative assemblies of pyrroles have been described [2].
Homopropargylamines and (allenylmethyl)amines represent easily
available building blocks for pyrrole synthesis . The cyclization
of(allenylmethyl) amines to 2,5-dihydropyrroles can be induced by
silver(I) salts and has already been investigated [4]. We have reported
a novel pyrrole synthesis by silver(I)-mediated oxidative cyclization of
homopropargylamines to pyrroles . The required precursors are readily
accessible by condensation of simple arylaldehydes to Schiff bases and
subsequent Lewis acid-promoted addition of 3-
trimethylsilylpropargylmagnesium bromide (Scheme). Under optimized
reaction conditions, treatment with 1.1 equivalents of silver acetate at
room temperature affords almost quantitative yields of the
corresponding pyrroles. This procedure represents a versatile and

42
simple syntheticroute to 1,2-diarylpyrroles, which are of interest
because of their biological activities [6].

Cyclic Schiff bases are easily prepared by Bischler–Napieralski

cyclization of N-formyl-2-arylethylamines. Thus, the silver(I)-mediated
oxidative cyclization of homopropargylamines can be exploited for the
synthesis of polyheterocyclic ring systems. Annulation of a pyrrole ring
on 3,4-dihydroisoquinoline provides simple access to the pyrrolo[2,1-
a]isoquinoline framework (Scheme 15.2) [5]. Addition of the propargyl
Grignard reagent affords the homopropargylamine as the major
product along with the (allenylmethyl)amine resulting from attack at
the g-C atom. Silver(I)-mediated oxidative cyclization of the
homopropargylamine to 5,6-dihydropyrrolo[2,1-a]isoquinoline
proceeds at room temperature, whereas cyclization of the
(allenylmethyl) amine requires elevated temperatures and gives lower
yields. Protodesilylation of the silylacetylene and subsequent silver(I)-
mediated oxidative

43
cyclization to 5,6-dihydropyrrolo[2,1-a]isoquinoline gives a yield similar
to the cyclization of the silyl- protected precursor. Chemoselective
hydrogenation of the pyrrole ring using 5 % rhodium on activated
carbon as catalyst provides1,2,3,5,6,10b-hexahydropyrrolo[2,1-
a]isoquinoline [7], which represents a degradation product of the
alkaloid norsecurinone [8] and is reported to show useful
pharmacological activities [9]. Silver(I)-catalyzed cyclizations of
substituted allenes to heterocyclic ring systems including 2,5-
dihydropyrroles have been described previously [4,10]. Moreover,
silver(I) salts are known to formstablep-complexes with terminal
acetylenes [11].Onthe other hand, on treatment with silver nitrate
silylacetylenes were reported to afford silver acetylides [12]. Based on
these considerations and additional experimental evidence [5,13], the
followingmechanismhas been proposed for the silver(I)-mediated
oxidative cyclization of homopropargylamines to pyrroles [5] (Scheme
15.3). Activation of the acetylene by coordination of the triple bond to
the silver cation enables a 5-endo-dig cyclization via nucleophilic attack
of the amine [14]. Protonation of the resulting vinyl silver complex leads
to an iminium ion. Subsequent b-hydride elimination affords metallic
silver and a pyrrylium ion which aromatizes by proton loss to the
pyrrole. For trimethylsilyl-substituted homopropargylamines(R3 ¼
SiMe3), the resulting pyrrole (R3 ¼ SiMe3) undergoes protodesilylation
to the 1,2-disubstituted pyrrole

44
Synthesis of the Pyrrolo[2,1-
a]isoquinoline Alkaloid Crispine A

The hexahydropyrrolo[2,1-a]isoquinoline alkaloid crispine A was

isolated in 2002 from Carduus crispus [15]. Extracts of this plant have
been applied in Chinese folk medicine for the treatment of colds,
stomach ache, and rheumatism; moreover they inhibit the growth of
several human cancer cell lines. The useful biological activities induced
a strong interest over the last few years in the synthesis of this alkaloid
[7,16].

We used the silver(I)-mediated oxidative cyclization of

homopropargylamines to pyrroles for the synthesis of crispine A
(Scheme 15.4) [7]. Reaction of 3,4-dihydro-6,7-dimethoxyisoquinoline
with the propargyl Grignard reagent leads to the cyclic
homopropargylamine, which on silver(I)-mediated oxidative cyclization
affords 5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinoline.
Chemoselective hydrogenation of the pyrrole ring provides racemic
crispine A (three steps, 24 % overall yield).

Synthesis of the Indolizidino[8,7-

b]indole Alkaloid Harmicine
The basic fraction of the ethanolic leaf extract of the Malaysian plant
Kopsia griffithii exhibits a strong antileishmania activity. One of the two
novel alkaloids isolated from this plant in 1998 was the indolizidino[8,7-
b]indole harmicine [17]. Synthetic approaches to harmicine became
attractive owing to its pharmacological potential[18,19].We applied our

45
three-step pyrrolidine annulation strategy to the synthesis of harmicine
(Scheme 15.5) [19]. Addition of the propargyl Grignard reagent to 3,4-
dihydro-b-carboline followed by silver(I)-mediated oxidative cyclization
to the dihydroindolizino[8,7-b]indole and chemoselective hydrogenation
provide racemic harmicine (three steps, 46 % overall yield)

Palladium(II)-catalyzed Oxidative
Cyclization to Carbazoles

The oxidative cyclization of N,N-diarylamines represents a

straightforward alternative route to the carbazole framework [55].
However, application of the classical thermally, photolytically or
radical-induced process provides only moderate yields. Much higher
yields are obtained for this transformation by palladium(II)-mediated
oxidative cyclization, first reported by A ˚ kermark (Scheme 15.15) *56+.

Heating of the N,N-diarylamines with palladium(II) acetate in acetic

acid at reflux results in smooth oxidative cyclization to the
46
corresponding carbazole derivatives. A variety of substituents are
tolerated in different positions. Thus, this procedure has found many
applications in organic syntheses [30,55]. However, the drawback is
that stoichiometric amounts of palladium(II) are required, as one
equivalent of palladium(0) is formed in the final reductive elimination
step. In the Wacker process, regeneration of the catalytically active
palladium(II) species is achieved by oxidation of palladium(0) to
palladium(II) with a copper(II) salt [57]. We were the first to
demonstrate that oxidative regeneration of the catalytically active
palladium(II)

species can be exploited for palladium(II)-catalyzed cyclizations of

arylaminoquinones to carbazole derivatives (Scheme 15.16, Table 15.1)
[58,59]. Oxidative cyclization of the 2-arylamino-1,4-naphthoquinone
by reaction with stoichiometric amounts of palladium(II) acetate in
refluxing acetic acid leads to the corresponding benzo[b]carbazole-
6,11-dione in high yield. Using catalytic amounts (12 mol%) of
palladium(II) acetate in the presence of equimolar amounts of
copper(II) acetate provides the benzo[b]carbazolequinone in 34 % yield
and 56 % of the starting material, demonstrating a catalytic cycle with
a turnover number of 2.8[58]. In a blank experiment (reaction with 12
mol% of palladium(II) acetate in the absence of copper(II) salt) the
product was obtained in only 11 % yield, indicating the necessity for
reoxidizing the palladium(0). Subsequently, other reoxidants for
palladium(0) have also been applied in this reaction [60]. We have
47
applied the palladium(II)-catalyzed oxidative cyclization to efficient
syntheses of biologically active carbazole alkaloids.

Carbazolequinone Alkaloid

The carbazoquinocins are carbazole-3,4-quinone alkaloids and have

been isolated from Streptomyces violaceus 2942-SVS3 [61]. They are
strong antioxidative agents and thus represent potential drugs for the
treatment of diseases initiated by oxygenderived free radicals.We have
developed an efficient synthesis of carbazoquinocin C using
palladium(II)-catalyzed oxidative cyclization as the key step (Scheme
15.17, Table 15.2) [62].

Addition of aniline to 2-methoxy-3-methyl-1,4-benzoquinone affords

the anilino-substituted benzoquinone with complete regioselectivity.
Optimization of the palladium(II)-catalyzed oxidative cyclization to 3-
methoxy-2-methylcarbazol-1,4- quinone was achieved by varying the

48
different reaction parameters. The best yield of the product was
obtained using 30 mol% of the palladium(II) catalyst. Using 5 mol%

49
of the catalyst we observed the best turnover with respect to
palladium(II). In contrast to the Wacker oxidation, copper(II) cannot be
used in catalytic amounts under the present reaction conditions.
Addition of heptylmagnesium chloride at low temperature takes place
preferentially at the more reactive carbonyl group (C-1) to provide the
corresponding carbazolequinol. On treatment with hydrogen bromide
in methanol, this intermediate is smoothly converted into
carbazoquinocin C (four steps, 39 % overall yield). Moreover, 3-
methoxy-2-methylcarbazol-1,4-quinone also represents a synthetic
precursor for carbazomycin G and exhibits significant anti-TB activity
(see Section 15.3.2, Scheme 15.10) [39,40]. Because of their promising
pharmacological properties, the carbazole-1,4-quinone alkaloids
became attractive synthetic targets [30,63].MurrayaquinoneAhas been
isolated from the root bark of the Chinese medicinal plant Murraya
euchrestifolia and shows cardiotonic activity [64]. The
koeniginequinones A and B have been obtained from the
stem bark ofMurraya koenigii [65]. Palladium(II)- catalyzed oxidative
cyclization opens up a simple two-step route to these natural products
(Scheme 15.18, Table 15.3) [66]. Addition of the appropriate
arylamines to 2-methyl-1,4-benzoquinone provides the desired 2-
arylamino-5-methyl-1,4-benzoquinones as major products (ratios: 2.3–
2.9 : 1). Oxidative cyclization of these intermediates leads directly to
murrayaquinone A (51 % overall yield), koeniginequinone A (46 %
overall yield) and koeniginequinone B (47 % overall yield). Using
copper(II) acetate under the optimized reaction conditions described
above (Table 15.2), these transformations have also been carried out
with catalytic amounts of palladium(II).

51
Carbazomadurins and Epocarbazolins

The carbazomadurins have been isolated from the microorganism

Actinomadura madurae 2808-SV1 and exhibit a strong neuronal cell-
protecting activity against Lglutamate- induced cell death [67]. High
extracellular concentrations of the excitatory amino acid L-glutamate
occurring after brain ischemic attack lead to destruction of cerebral
tissue. Thus, radical scavengers are considered to be potential drugs for
the treatment of brain ischemia injury. The epocarbazolins have been
obtained by a research group of Bristol–Myers from the actinomycete
strain Streptomyces anulatus T688-8 on screening for 5-lipoxygenase
inhibitors [68]. Inhibitors of 5-lipoxygenase represent potential
therapeutics for inflammatory and allergic processes, such as psoriasis,
asthma, and hypersensitivity. A common approach to the
carbazomadurin and epocarbazolin alkaloids has been established by
using sequentially three different palladium-catalyzed cross-coupling
reactions (Scheme 15.19) [69,70]. A palladium(0)-catalyzed Buchwald–
Hartwig coupling of the appropriately substituted aryl triflate, available
in two steps and 91 %yield from isovanillic acid, with 2- bromo-4-
methoxy-3-methylaniline followed by a palladium(II)-mediated
oxidative cyclization of the resulting N,N-diarylamine, leads to the
1,2,3,5,8-penta-substituted carbazole nucleus. Cleavage of both methyl
ethers and subsequent double silylation effect a switch of the
protecting group. Introduction of either side chain at C-1 of the
carbazole framework is achieved using a palladium(0)-catalyzed Stille
coupling. The required 1-(E)-alkenylstannanes are readily prepared
from the appropriate alkynes by application of Negishi’s zirconium-
catalyzed carboalumination as the key step. Reduction of the methyl
ester with diisobutylaluminum hydride (DIBAL) affords the benzylic
alcohols as common precursors for the carbazomadurins and the
epocarbazolins (Scheme 15.20). Removal of both silyl protecting groups
from the disilyl-protected precursors using tetrabutylammonium
fluoride (TBAF) provides carbazomadurin A (nine steps, 11 % overall
yield) and carbazomadurin B (nine steps, 13 % overall yield). Based on
our enantioselective synthesis of carbazomadurin B (>99 %ee) an (S)-
configuration has been assigned to the stereogenic center in the side
chain of the natural product [70]. Because direct epoxidation of the
carbazomadurins and of the disilyl-protected precursors has been
unsuccessful, the latter have been transformed quantitatively into the
corresponding trisilyl-protected intermediates. Epoxidation of the fully

50
protected compounds with dimethyldioxirane at_208Cand subsequent
desilylation provide racemic
epocarbazolinAandepocarbazolinB[71].

7-Oxygenated Carbazole Alkaloids

Clauszoline-K and clausine C (clauszoline-L) have been isolated from

the stem bark of the Chinese medicinal plant Clausena excavata [72].
Clausine M and clausine N have been found in the root bark of the
same plant [73]. The bioassay-guided fractionation of the organic
extract of Murraya siamensis, collected in Thailand, led to the isolation
of siamenol, which shows HIV-inhibitory activity [74]. A simple route to
these 7-oxygenated carbazole alkaloids has been developed, based on
a highly efficient palladium-catalyzed approach (Scheme 15.21) [75]
(Table 15.4). Buchwald–Hartwig amination of p-bromotoluene with m-
anisidine affords quantitatively the corresponding diarylamine. While
oxidative cyclization using stoichiometric amounts of palladium(II)
acetate provides only 36 % yield of7-methoxy-3-methylcarbazole, up to
72 %yield is obtained using catalytic amounts of palladium(II). The
highest turnover for the catalytic cycle is obtained with2 mol% of the
palladium(II) catalyst. Obviously, stoichiometric amounts of
palladium(II) lead to significant decomposition by oxidation of the
electron-rich carbazole. Support for this hypothesis comes from a
control experiment by treating7-methoxy-3-methylcarbazole under the
conditions for the stoichiometric reaction(1.2 equiv. Pd[OAc]2, HOAc,
117 8C, 1 h). Only 65 % of 7-methoxy-3-methylcarbazole has been
reisolated, because of decomposition. In the following, 7-methoxy-3-
methylcarbazole serves as a relay compound to approach the other 7-
oxygenated carbazole alkaloids. Oxidation with DDQ affords
clauszoline-K. Further oxidation of clauszoline-K by treatment with
manganese dioxide and potassium cyanide in methanol provides
clausine C (clauszoline-L) quantitatively. Starting from clausine C,
cleavage of the ester gives clausine N and cleavage of the ether leads
to clausine M. Regioselective electrophilic bromination of 7-methoxy-
3-methylcarbazole followed by ether cleavage and introduction of the
prenyl group in a nickel-mediated coupling reaction provides siamenol
(five steps, 34 % overall yield) [75] (Scheme 15.22).

52
53
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4- Avnish Upadhyay, Phytochemistry of Alkaloids.

5- Rodney Croteau Toni M. Kutchan Norman G.

Lewis,Natural Product (Secondary Metabolites).

6- Ernesto and Orazio Taglialatela-Scafati, Modern

Alkaloids.

54