Escolar Documentos
Profissional Documentos
Cultura Documentos
Natural Products
(Alkaloids)
Prepared by
Mohab Zaho El-didamoni
B.SC.in Chemistry
Supervised by
Dr.Hamady Abd El-Azeem
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
3
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.
4
(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.
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.
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.
6
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).
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.
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.
PYRROLIZIDINE ALKALOIDS.
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.
00
contains, depending on the time of harvesting, significant amounts of
senkirkine (~0.015%) and senecionine.
02
PIPERIDINE AND PYRIDINE
ALKALOIDS.
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.
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.
05
Chelidonium majus(celandine; ~400 ppm) and in the roots of
Taraxacum officinale (dandelion) and Gentiana lutea (gentian).
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.
08
disease, asthma, intestinal cramps, and both diarrhoea and bed-
wetting. In older times it was used to reduce or eliminate pain.
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.
21
cells (whereby the synthesis of proteins plays a vital role) they are far
more vulnerable to DNA topoisomerase inhibition compared to normal
cells.
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).
22
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.
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.
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.
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.
NOMENCLATURE (4)
26
1. According to their source: There are named according to the
family in which they are found e.g. papavarine, punarnavin, ephedrine.
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
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.
Physical-Property (4)
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.
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)
29
(5)
CO2 + H2O
h PRIMARY METABOLISM
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
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 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
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).
36
Overall, the course of reactions from 2mol of L-tyrosine to 1mol of
berberine consumes 4mol of S-adenosylmethionine and 2mol of
NADPH.
37
38
(5)
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].
42
simple syntheticroute to 1,2-diarylpyrroles, which are of interest
because of their biological activities [6].
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
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
Carbazolequinone Alkaloid
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
50
protected compounds with dimethyldioxirane at_208Cand subsequent
desilylation provide racemic
epocarbazolinAandepocarbazolinB[71].
52
53
REFERENCE
1- http://www.bookrags.com/research/alkaloids-
wsd
® http://www.scribd.com/
2- Elzbita&Hans Brand,Alkaloids.
3- http://www.nybg.org/bsci/belize/Nicotiana_tabacum.jp
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