Phyto2
Lecture #9
Last lecture we started with an introduction into tropane alkaloid, and we have seen the
biosynthesis of alcohol moieties of tropane alkaloids and cola-alkaloid :tropine and ecgonine and
we said that real alkaloid found within the plant are subalkaloids such as :hyoscyamine and
cocaine .we have seen some differences between the 2 alcohol moieties and we said in tropine
we incorporate ornithine and only 3 carbons af the acetoacetyl CoA, while in the case of
ecgonine we incorporate ornithine and 4 carbons of the acetoacetyl CoA.( First difference)
(second difference): Hyoscyamine is optically active, in nature it’s a levotatory compound (-) ,
the same applies for cocaine its also optically active and we have an - L-cocaine , tropine is an
alcohol and is optically inert compound, while ecgonine is optically active compound .This is
due to the fact that in tropine we have two carbons which are C1,C5 they are symmetric carbons
,chiral centers so presumably we expect them to be optically active , BUT because the molecule
is very symmetric there is an intramolecular compensation so tropine becomes an inactive
compound ,which is not the case of ecgonine that retains its optical activity .
Know… the second question which raises is : If tropine is optically inactive how its
hyoscyamine is active ? definitely the optical activity will be determined from the acid moiety ,
in the case of hyoscyamine: we use tropic acid as optically active acid and the alcohol moiety
(tropine) is inactive so the end compound will be optically active .[as demonesrated in the figure
below the hyoscyamine structure]
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In the case of cocaine : we use ecgonine as optically active alcohol moiety and benzoic acid that
is optically inactive. Presumably the optical activity of cocaine is due to the alcohol moiety
while in hyoscyamine is due to the acid moiety.(4:07)
But during the isolation process, we are isolating hyoscyamine and atropine (the racemic form of
hyoscyamine)
Hyoscyamine(-)= tropine +N-tropic acid
Atropine or Hyoscyamine(+) =tropine +d,N-tropic acid

TODAY, we will continue with tropane alkaloids , and as we have seen that the main alcohol
moiety of tropane alkaloid in the plant family solanaceae is “tropine”, tropine isn’t a solo alcohol
moiety (closely related alkaloids occur together in the same plant, of course we can change the
acid moiety to get more derivatives of tropane alkaloids ) so in adittion to tropine there is
additional alcohol moieties , we will see the major alcohol moieties isolated until know ,and the
main acid moieties of alkaloids.(5:36)
# tropine can be demethylated to nor-tropine (lacking CH3 grp)
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# tropine can be hydroxylated and oxidized 6,7 di-OH tropine (teloidine)[-H2O] 6,7
epoxy tropine (scopine) 3,6 epoxy-tropine (oscine)
6,7 di-OH tropine
Among all of them (tropine, nor-tropine, scopine, oscine) tropine is the major one ‘most
commonly occurring’ , also several alkaloid isolated from solanaceae family are based on
scopine, oscine that occur in high concentration .
** Aromatic acids originating from shikimic acid pathway “SAP”
As we have differeneces in the alcohol moieties we also have different acids forming the
alkaloids , several acid are used , to start with there are many aliphatic acids occurring in the
plant and all of them can form their corresponding trpoane esters , the most important acid that is
found in all solnaceae alkaloids is ‘tropic acid’, the carbon adjacent to the aromatic ring (the
carboxyl group ) is asymmetric carbon and is responsible for the optical rotation of tropic acid.
Tropic acid can be dehydrated (-H2O) to atropic acid , atropic acid can be dimerized to give
isotropic acid , so tropic acid and its derivative as well as its isomers (N-tropic,D-tropic and their
racemate),are important acid moiety of the tropane alkaloids.(8:59)
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This table shows most important tropane alkaloids(major ones) found in atropa spp ,datura spp,
hyoscyumus spp, duboiasia …in all solanaceae plant :
Alkaloid
Alcohol
Acid
Hyoscyamine
Atropine
Scopolamine
Atroscine
Apoatropine
Belladonine
Aposcopolamine
Homatropine
Tropine
Tropine
Scopine
Scopine
Tropine
Tropine
Scopine
Tropine
N-tropic acid
D,N tropic acid
N tropic acid
D,I tropic acid
Atropic acid
Isotropic acid
Atropic acid
Mendelic acid
Fom the table above :
-Hyoscyamin is optically active since it has N-tropic acid
- in the case of atropine its racemic tropic acid = D,N tropic acid so its inert compound
[optically inactive]
- Scopolamine also termed as hyoscine : has the same acid moiety which means its optically
active but different alcohol moiety ‘scopine’
-the racemate corresponding to atropine is Atroscine having scopine as the alcohol moiety and
D,I atropic acid
- Apoatropine = Tropine + Atropic acid
- Belladonine is differing from the previous alkaloids that it has a large Mwt and we can explain
this when we look at the structure of Isotropic acid { Isotropic acid has 2 free carboxylic acids
and when we are forming esters we will need 2 molecules of alcohol(2 tropine) … therefore a
large structure is formed… so the hydrolysis of Belladonine will yeald 2 tropine molecules since
each carboxyl group will be esterified with one tropine }
- Aposcopolamine =Scopine + Atropic acid
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- so far these alkaloids are naturally occurring , so we can isolate them from plant , but of course
nowadays several analogues of these alkaloids is being prepared and one of them is the
Homatropine , in the case of Homatropine is a semi-synthetic ester of tropine with mandelic acid.
# we have seen the origin of the alcohol moiety (tropine ,scopine ) they are originating from
amino acid “ornithine” ,what will be the origin of tropic acid ??
-tropic acid has an aromatic ring and side chain of 3 carbons = C6-C3 compund  so its SAP
pathaway (cinnamic acid)
-cinnamic acid side chain by rearrangement is converted to tropic acid .Furthermore; we will see
with the coca alkaloids  by eliminating 2 carbons we will get C6-C1(benzoic acid )
-In tropane alkaloids or coca alkaloids = we need amino acid moiety and a common intermediate
for biogenesis (acetoacetyl CoA) + shikimic acid pathway (15:00)
Plants containing tropane alkaloids and their pharmacologic importance :
The tropane alkaloids (−)hyoscyamine and (−)hyoscine are among the most important of the
natural alkaloids used in medicine. They are found in a variety of solanaceous plants, including
Atropa belladonna), Datura stramonium and other Datura species, Hyoscyamus niger ,and
Duboisia species. These alkaloids are also responsible for the pronounced toxic properties of
these plants.
1-Atropa belladonna (Solanaceae)
All plant containing tropane alkaloids are poisonous toixic plants for human being ,although
humans are sensitive , some animals, including birds and rabbits are less susceptible, e.g rabbit
won’t die from this plant ,also there are several birds which are feeding on this solanaceae are
not affected by its toxicity , cases are known where the consumption of rabbits or birds that have
ingested belladonna has led to human poisoning. Its toxicity is specific to human rather than
animals or birds.
-Its not necessary to take it only by GI tract (ingestion) , alkaloid can penetrate through the skin
and exhibit their toxicity, that’s why its obligatory to protect your hands in the lab when handling
with this plant (must wear gloves).
-Moreover, tropane alkaloids are not restricted to a special organ; all parts of the plant contain
toxic alkaloids (fruits, leaves, roots ..), the fruit of solanaceae “berries” has a very attractive color
(orange, dark red), in Europe one of the most accidental toxicities by children are due to tropane
alkaloids, bespically due to the fruits which are very attractive and children can take few amount
of berries which will cause a severe poisining when ingested
Belladona :
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- simple alkaloids=Hygrine, Cuscohygrine ,etc…
-tropane alkaloids(ester alkaloids )=some of them occur in their racemate …..optically active or
inactive .
Not only belladonna ,other solanceae plant are still considered a potent source for the extraction
of these alkaloids ,at least alcohol moiety can originate from nature, majority of alkaloid product
available are natural or semisynthetic derivative keeping the alcohol part and replacing the
acid part by other acid
2- Datura spp : (family: solanaceae , spp: depend on the location)
Datura stramonium (jimson weed ): Europe and overseas
Datura metel: have been known in south asia especially in India, narcotic properties, the plant
material was usually absorbed by smoking for hallucination
3-Hyoscymus spp:
Hyoscymus niger (henbane): Europe, north America
Hyoscymus muticus: Egypt, mediternean countries
-smoking cause visual hallucination, imaginary view of witches on broomsticks
4-Duboiasia : its small tree while atropa ,datura and hyoscymus are small shrubs
Duboiasia myopoides: australlia
-interest in Duboisia was very much stimulated by the demand for hyoscine (scopolamine) as a
treatment for motion sickness in military personnel during the Second World War.
5-Withania somnifera:
south Europe and india ,also known as indian ginseng has an adaptogen properties ,it’s a
recommended plant in indida for better life etc…nowadays when its an ingredient of medicine it
cannot be OTC perperation ,indian traditional medicine call it ashwaganda  to improve sexual
activity ,youngeshness, many companies are marketing products based on withania somnifera as
ashwaganda so as not to have limitation on using it.
6-Mandragora :
(Mandragora officinarum; Solanaceae) has a narcotic and its claimed for its aphrodisiac activity
(till now it’s not proved) , from a pharmacological point of view this plant would be much more
efficient as a pain reliever than as an aphrodisiac. 24:05
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#Atropine (hyoscyamine) and activity :
Anticholinergic agent : Atropine compete with acetylcholine for the muscarinic receptors , so we
will see different effect of atropine on body systems such as CNS, eye, CVS, respiratory .
- CNS: mild stimulant effect on medullary centers
- Eye: mydriasis to dilate the pupil of the eye.
The mydriatic use in middle age. the name Atropa belladonna means ‘beautiful lady ‫’ست الحسن‬
and refers to the practice of ladies at court who applied the juice of the fruit to the eyes, giving
widely dilated pupils and a striking appearance (large eyes), at the expense of blurred vision and
inability to focus, also it was used by criminals when they were coming into the court ,they used
these drops to get dreamy eyes that cannot focus anywhere and one will think that this person is
innocent person because his eyes cannot focus on any object[pretending to be innocent person ]
- CVS: myocardial stimulant (reduce MI )
- Respiratory : bronchodilator , decrease secretion of the bronchi as well as GI (antisecretory
effect controlling salivary secretions during surgical operations)
- genitourinary: has effect on the bladder and ureter and less effect on the uterus has been
reported.
- Gastrointestinal tract: antispasmodic action on the GI.
# Scopplamine (hyoscine) activity :
-differnt from atropine structure; it has 6,7 epoxy group on the alcohol moiety
-Hyoscine under its synonym scopolamine is also well known : has a CNS depressant activity,
also it is used as a sedative to control motion sickness. In the past it was used to ease child birth
(combination of sedation, lack of will, and amnesia was first employed in childbirth)
-Atropine also has useful antidote action in cases of poisoning caused by
acetylcholinesterase inhibitors e.g. physostigmine and neostigmine
-in atropine , we may have toxic doses which lead to hallucination, coma and death can be
observed. 28:00
#Uses of atropine alkaloids:
1234-
Motion sickness
parkinson
traveller diarrhea
antispasmodic
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5- preoperative medication (preparation of the patient before surgery the give IV injection
based on tropane alakaloids )
6- bronchial asthma
7- cholinergic poisoning
*keep in mind that this natural compound some of them are still in use ,even if they
aren’t in use they can be considered as model for the production of semisynthetic
alkaloids, for example in the treatment of bronichal asthma ipratropium bromide is
more in used compared to atropine ,because it can be used in inhaler[ inhalation is a
preferred route ] ,or the use of benzatropine for the treatment of Parkinson disease is
definitely more successful. Semisynthetic alkaloids are more potent ,less adverse effect
,so atropine and hyoscyamine are considered as second drug ,as well as model for other
anticholinergic agents. 30:16
*Before continuing with coca alkaloids we will stop and include a very tiny chapter .
Chapter of calystagins (small chapter):
-as you remember we mentioned the family Solanaceae , Erythroxylaceae, Convolvulaceae
The calystegines are a group of recently discovered ,water-soluble, polyhydroxy nortropane
derivatives .They were first isolated from Calystegia sepium (Convolvulaceae).
-nor-atropine =lack methyl group
-poly hydroxyl = water soluble , contain from 3 to 7 Hydroxyl groups , depending on the number
and position of hydroxylation they have been sub grouped into: A series, B series and C series, in
each group we have for example sterical isomers, epimers  these are responsible for the
subscript A1, A2, A3
In fact , such small molecules are not of that much interst ,but it has been found that this
substance has antiviral activity , especially aginst HIV virus , its considered as promising drug
for the treatment of AIDS.
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-As you know there are different diseases , till in th 21st century has no cure , scientists are
working on phytochemistry and they are trying to find new entities from nature , because nature
is (something) for drug discovery, any synthetic drug cannot compete with the nature , many
structures which are impossible to occur in the lab occur in nature ,therefore they say that
nature is (something) for drug discovery.
-certain diseases like AIDS , cancer not yet treated successfully with the synthetic organic
chemistrythere is a come back to the nature ,and this (calystagins) is one of the discoveries
why to come back to nature for drug discovery .by screening aqeous extratct they discovered this
calystagins, and this substance was later found in the family Convolvulaceae and also
solanaceae ,specifically it has been found that these substances are found primarily in the roots of
Solanaceae .
- Nowadays , all possible solanaceae (espically roots) are screened for the occurance of
calystagins as a new small group of tropane alcohol .
*calystagins :it is an alcohol (we say water soluble alcohol) but it is also considered a true
alkaloid because it is containing a nitrogen, possessing biological activity, occurring in nature
and nitrogen is part of the heterocyclic structure . 36:15
**Lets go back to Coca Alkaloids :
Erythroxylum coca , Erythroxylaceae:
As we said in ecgonine we incorporate ornithine with 4 carbons of the acetoacetyl CoA
Leaves of Erythroxylum spp contain cocaine , this species are south American plant ,many plant
which are giving some euphoria and hypnosis were used in south america together with the
religious mutuals , first people used cocaine were Inca high priests , isolation of cocaine was one
of the early discoveries in the natural product chemistry in 1859 .
The main alkaloid is the Cocaine ,
- in fact in past it was attitude but till now, like in Yemen, south America local workers; they are
chewing (25-50g/daily) of the plant leave in order to obtain a sustained energy, not to feel tired
(antifatigue agent), suppresses the feeling of thirst and hunger, increasing physical activity and
endurance, working under miserable conditions ,no money therefore they use it although it is
forbidden now. 38.56
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The pure alkaloid cocaine is a crystalline substance ,it’s a very expensive material , very easily
absorbed from the mucos membrane (sniffed into the nostrils), it’s a very expensive joy .
Covaine is used by authors ,artist as they can concentrate better ,get better ideas for music or
write better ,their mind is clear  Regular usage induces depression, dependence, and
destruction of the mucus membrane due to sniffing ,also it will develop some symptom like
scratching , adrenergic stimulant , from psychological point of view cocaine inhibits the
reuptake of neurotransmitters dopamine, noradrenaline, and serotonin, so prolonging their
effects .
From pharmacological point of view : cocaine is of value as a local anaesthetic, despite the
production of huge numbers of synthetic analogue with the advantage that it is possessing in the
same time vasoconstictive activity , none of the synthetic local anaestheic possess this dual
action [anastheisa+vasoconstriction] when you are injecting your synthetic drug you are keeping
it localized , in order to achieve same activities you have to inject a local anesthetic plus
vasoconstrictor in order to prevent swimming of local anesthetic agent. Cocaine is a model but it
is still superior to the synthetic analogue of cocaine. 41.30
**In the 1800s, coca drinks were fashionable (like a black tea), a pharmacist invented Coca-Cola
he is the father of Cocacola , he used coca leaves and the cola seeds[coca: providing cocaine, and
cola: supplying caffeine, and its red color was due to tannins ,the coca content was omitted from
1906 onwards because of physiological dependence also pharmacological studies showed that
cocaine is addictive drug , but the name and popularity continue.(now contains cola extract
only).
-Some people consume cocaine and alcohol concurrently one of the most addictive problems
in the world (increased toxicity).
# Route:
1- sniffing
2- IV
3- inhalation (burn the powder and inhale) 43:36
** So the main alkaloid in coca leaves is the cocaine ; it is a derivative of ecgonine ,it’s a diester
;we have a free carboxyl group on C2 and free hydroxyl group on C3 ,so we can form an ester by
the addition of alcohol (methanol)at position number 2 methylester , also addition of benzoic
acid at position number 3will form the second ester.
-When we have C6-C1 benzoic acid , of course we have cinnamic acid C6-C3 ,and in fact in
coca leave in addition to cocaine , cinnamoylcocaine has been isolated .
Methyl ecgonine + cinnamic acid cinnamoylcocaine
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Cinnamic acid can form different dimeric agent , which are truxinic acid and truxillic acid
We can form endless isomers of cinnamic acid ,one of these are :α-truxillic acid , β-truxinic
acid ,truxilline are based on the same alcohol moiety as cocaine(methylecgonine) ,just changing
the acid group
Other smaller alkaloids like hygrine, hygroline and cuscohygrine occur in the coca leaves as well
as the derivative of ϕ-tropine such as tropacocaine
Derivative of ϕ-tropine (the 3β-isomer of tropine OH on C3 is beta ), such as tropacocaine
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The last thing to mention
**We know that cocine is a problem so how we can obtain cocaine ?
-We have seen that ecgonin is a basic moiety not only for cocaine but also for truxilline and
cinnamoylcocaine and for different closely related substances ,
-therefor to increase the amount of semi-synthetically cocaine ,those who are producing and
marketing this prohibited drug ,they are not trying to isolate cocaine from the plant ,they go to a
very intelligent way they split the acid moiety from all accuring alkaloid so we will obtain the
constant alcohol moiety ecgonine
-so the objective for them is just to obtain ecgonine and they need a very simple lab in order to
add methanol and benzoic acid [ methanol and benzoic acid are cheap substances],the chemical
procedure is very simple to esterfy the large amount of ecgonin  therefore the cocaine which is
marketed or sold illicitly is semi-synthetic in order to obtain large amounts in a cheap way (not
natural)
Done by : Suhad Bani Melhim
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