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The organic compounds isolated from the living organism
i.e plants, animals and micro organism are generally known
as Natural products. These includes carbohydrates, protein,
aminoacids, alkaloides, terpenes, antibiotics etc
The term natural product is applied to material derived from
plants microorganisms and invertebrates, which are fine
biochemical’s factories for synthesis of both primary and
secondary metabolites
Natural Product
Bacteria and Fungi as source for
Biologically active Compounds
Classical and Advance methods
Structure of Morphine
O
HO
H
NH
CH3
HO1
2
3
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
‘Tinkering’ with the structure of
morphine produced heroin
O
HO
H
NH
CH3
HO1
2
3
4
5
6
7
8
9
10
11
12
1314
15 16 O
AcO
H
NH
CH3
AcO1
2
3
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)Heroin (Diamorphine)(2X as potent as morphine)(Conversion of two -OH groups to -OAcfacilitates crossing of the BBB)
Easily enzymatically hydrolyzed to AcOH and HO-ArHO- Group is needed for activity
HO- Group not important to activity
The heart beat may be too fast or too slow
Terpenoids
INTRODUCTION
Terpenoids are the secondary metabolites synthesized by plants,
marine organisms and fungi by head to tail joining of isoprene
units. They are also found to occur in rocks, fossils and animal
kingdom.
Isoprene (short for isotepene), or 2-methyl-1,3-butadiene, is a
common organic compound with the formula CH2=C(CH3)CH=CH2.
Under standered conditions it is a colorless liquid. However, this
compound is highly volatile because of its low boiling point.
Isoprene Isoprene
Terpenes
•Terpenes are natural products that
are structurally related to isoprene.
H2C C
CH3
CH CH2
or
Isoprene
(2-methyl-1,3-butadiene)
Isoprene
Head
Tail
Head
Tail
Isoprene
Head
Tail
Head
Tail
Isoprene
• Terpenes and terpenoids posses a carbon fram work
consisting of five carbon units known as isoprene unit.
• It is represented by symbol C5H8
• In oldest days the term terpene was used for those
compounds containing 10 carbon atoms.
• This is still used in Modern classification of Terpenes.
Terpenes are classified in to the following groups.
Hemeterpens 1 x C5H8 = C5H8
Monoterpens 2 x C5H8 = C10H16
sesquiterpens 3 x C5H8 = C15H24
Diterpens 4 x C5H8 = C20H32
sesterpens 5 x C5H8 = C25H40
triterpens 6 x C5H8 = C30H48
Tetraterpenes 7 x C5H8 = C35H58
Polyterpenes n x C5H8 = C5H8)n
Rubber n= 100 or above
CALASSFICATION
TYPE OF NUMBER OF ISOPRENE
TERPENOIDS CARBON ATOMS UNITS
hemiterpene
monoterpenoid
sesquiterpenoid
diterpenoid
triterpenoid
tetraterpenoid
C5
C10
C15
C20
C30
C40
one
two
three
four
six
eight
hemi = half di = two
sesqui = one and a half tri = three
tetra = four
NOTE
:
sesterterpenoid C25 five
Mnonoterpenoids
Monoterpenes are a class of terpenes that consist of
two isoprene units and have the molecular formula
C10H16.
Monoterpenes may be linear (acyclic) or
contain rings. Biochemical modifications
such as oxidation or rearrange-ment
produce the related monoterpenoids.
Representative Monoterpenes
a-Phellandrene
(eucalyptus)
Menthol
(peppermint)
Citral
(lemon grass)
O
H
OH
Representative Monoterpenes
a-Phellandrene
(eucalyptus)
Menthol
(peppermint)
Citral
(lemon grass)
O
H
OH
Representative Monoterpenes
a-Phellandrene
(eucalyptus)
Menthol
(peppermint)
Citral
(lemon grass)
Mnonoterpenoids
Acyclic monoterpenoid:
¦Â-myrcene
CH2OH
nerol
CHO
geranial
Monocyclic monoterpenodi
OH
l-menthol menthone
O
cineole
O
Bicyclic monoterpenoid
¦Á-pinene
d-borneol
OH
Acyclic monoterpenoid
Biosynthetically, isopentenyl pyrophosphate and dimethylallyl pyrophosphate are
combined to form geranyl pyrophosphate
Geranyl pyrophosphate
Acyclic monoterpenoid
Elimination of the pyrophosphate group leads to
the formation of acyclic monoterpenes such as
ocimene and the myrcenes.
Myrcene
Acyclic monoterpenoid
Hydrolysis of the phosphate groups leads
to the prototypical acyclic monoterpenoid
geraniol.
geraniol
Acyclic monoterpenoid
Additional rearrangements and oxidations
provide compounds such as citral,
citronellol, and many others.
citral
Acyclic monoterpenoid
Many monoterpenes found in marine
organisms are halogenated, such as halomon.
Halomon is a polyhalogenated monote
rpene first isolated from the marine
red algae Portieria hornemannii.
It has attracted research interest becau
se of its promising profile of selective cy
totoxicity that suggests its potential
use as an antitumor agent.
Halomon
Monocyclic monoterpenoid
In addition to linear attachments, the isoprene
units can make connections to form rings. The
most common ring size in monoterpenes is a
six-membered ring.
A classic example is the cyclization of
geranyl pyrophosphate to form limonene.
Bicyclic monoterpenoid
Geranyl pyrophosphate can also undergo two
sequential cyclization reactions to form bicyclic
monoterpenes, such as pinene which is the
primary constituent of pine resin.
Bicyclic monoterpenoid
Other bicyclic monoterpenes include carene
and camphene.
Camphor, borneol and eucalyptol are examples
of bicyclic monoterpenoids containing ketone,
alcohol, and ether functional groups,
respectively.
carene
camphor borneol
Sesquiterpenoids
– Sesquiterpenes are a class of terpenes that consist of
three isoprene units and have the molecular formula
C15H24.
– Like monoterpenes, sesquiterpenes may be acyclic
or contain rings, including many unique combinations.
Biochemical modifications such as
oxidation or rearrangement produce the
related sesquiterpenoids.
Representative Sesquiterpenes
a-Selinene
(celery)
H
Representative Sesquiterpenes
a-Selinene
(celery)
H
Representative Sesquiterpenes
a-Selinene
(celery)
Sesquiterpenoids
• Acyclic sesquiterpenoids
• Monocyclic
sesquiterpenoids
¦Á-farnesene ¦Â-farnesene
O
• Bicyclic sesquiterpenoids
OH
¦Á-eudesmol
H
H
cadinene
guaiazulene
Acyclic Sesquiterpenoids
When geranyl pyrophosphate reacts with
isopentenyl pyro- phosphate, the result is the 15-
carbon farnesyl pyrophosphate, which is an
intermediate in the biosynthesis of sesquiterpenes
such as farnesene . Oxidation can then provide
sesquiterpenoids such as farnesol.
Sesquiterpenes are found naturally in plants as
defensive agents.
farnesyl pyrophosphate
farnesene
farnesol
Monocyclic Sesquiterpenoids With the increased chain length and additional
double bond, the number of possible ways that
cyclization can occur is also increased, and there
exists a wide variety of cyclic sesquiterpenes. In
addition to common six-membered ring systems such
as is found in zingiberene, a consitituent of the oil
from ginger, cyclization of one end of the chain to the
other end can lead to macrocyclic, rings such as
humulene.
姜稀zingiberene
Bicyclic Sesquiterpenoids
In addition to common six-membered rings
such as in the cadinenes, one classic bicyclic
sesquiterpene is caryophyllene, from the oil of
cloves which has a nine-membered ring and
cyclobutane ring. Additional unsaturation provides
aromatic bicyclic sesquiter- penoids such as
guaiazulene.
guaiazulene
H
H
cadinene
caryophyllene
Tricyclic Sesquiterpenoids
With the addition of a third ring, the possible
structures become increasingly varied. Examples
include longifolene, copaene and the alcohol
patchoulol.
longifolene copaene isomers of patchoulol
Diterpenoids
Diterpenoids
Diterpenes are composed for four isoprene units and have
the molecular formula C20H32. They derive from
geranylgeranyl pyrophosphate.
Examples of diterpenes are cafestol, kahweol, cembrene
and taxadiene (precursor of taxol).
geranylgeranyl pyrophosphate
cafestol cembrene
Representative Diterpenes
Vitamin A
OH
Representative Diterpenes
Vitamin A
OH
Representative Diterpenes
Vitamin A
Diterpenoids
Diterpenes also form the basis for biologically important
compounds such as retinol, retinal, and phytol. They are
known to be antimicrobial and antiinflammatory. The herb
Sideritis contains diterpenes.
retinol retinal
Structure ----Diterpenoids
Acyclic diterpenoids
CH2OH
phytol
Bicyclic diterpenoids
O
OHO
CH2OH
HO
andrographolide
Monocyclic diterpenoids
CH2OH
vitamin A
COOH
pimaric acid
Tetracyclic diterpenoids
H
H
H
kaurene
Tricyclic diterpenoids
Triterpenoids
Triterpenoids
Triterpenes consist of six isoprene units and have the
molecular formula C30H48. The linear triterpene squalene, the
major constituent of shark liver oil, is derived from t he
reductive coupling of two molecules of farnesyl
pyrophosphate. Squalene is then processed biosynthetically
to generate either lanosterol or cycloartenol, the structural
precursors to all the steroids.
squalene
Farnesyl pyrophosphate
lanosterol cycloartenol
Representative Triterpene
Squalene
(shark liver oil)
tail-to-tail linkage of isoprene units
O-P-O-P-O
O O
O O
O-P-O-P-O
O O
O OO-P-O-P-O
O O
O O
O-P-O-P-O
O O
O O
O-P-O-P-O
O O
O O
GPP
FPP
O-P-O-P-O
O O
O OFPP
O-P-O-P-O
O O
O OFPP
Squalene
Squalene
α-carotene
β-carotene
• Acyclic triterpenids squalene
• Bicyclic triterpenids
Structure ----Triterpenids
Structure ----Triterpenids
• Tetracyclic triterpenids Dammarane Lanostane
Tirucallane
H
H
H
dammarane
H
H
H
H
lanostane H
tirucallane
H
H
Cycloartane Cucurbitane
cycloartane
H
cucurbitane
H
H
H
H
• Pentacyclic triterpenoids
Oleanane Ursane Lupane
oleanane
H
H
H
H
ursane
H
H
Hlupane
H
H
H
H
Structure ----Triterpenids
It is the most important member of the
most of the acyclic monoterpenoides.
Because the structure of most of the
other compounds in this group are
based on that of citral. Its is widely
distributed and occurs to an extent of
60-80% in lemon grass oil. It is a liquid
which has the smell of lemons.
Citral C10H16O
The molecular formula of citral is C10H16O
analogue of saturated hydrocarbons
CnH2n+2
C10H10x2+2 = C10H22
IHD: 22-16/2 = 3
From IHD it is found that the citral contains 3 double bonds
Structure of Citral.
On cat. Hydrogenation 2 moles of hydrgone
were consumed. This showed that the
molecule contain 2 C=C bonds
Cat. Hydrogentation
CHO
Cat. Hydrogenation
CHO
2 moles
CHO
OHC
2 moles
Br2
Br
Br
Br
Br
On bromination also two molecule of bromine were consumed.
This also proved that molecule contain 2 C=C bonds.
Citral was converted into an oxime on treatment with NH2-
OH. This reaction showed that molecule contains an oxo
group.
CHO
2 moles
H2N=OH
CH=N-OH
• Citral is reduced to an alcohol geraniol (
C10H18O) . Geraniol is a primary alcohol and the
formation a primary alcohol form carbonyl
compound confirmed that the citral contains an
aldehyde functional group.
CHO
Na/Hg
CH2-OH
geraniol
• Oxidation of citral with Ag2O gives geranic
acid C10H16O2 and no loss of carbon atom
takes place. This further proves that oxo
group in citral is an aldehyde group.
CHO
Ag2O
CO2H
geranic acid
• Reaction with potassium hydrogen sulphate
• On heating with KHSO4 citral form P-Cymene.
This reaction was used by semmler to determine
the position of methyl and isopropyl group in the
skeleton structure 1
CHO
KHSO4
P.cymene1
This reaction showed
that the citral
molecule is acyclic in
which two isoprene
Units are joined in
head to tail manner
• The examination of the formula of citral
shows that 2 geometrical isomers are
possible
• The functional group may be Cis or Trans.
CHO
(a)
H
CHO
(b)
H
TransCis
These structure are
supported by NMR
spectroscopy
• Synthesis of citral can be carried out by
the following synthetic route.
Br
Br
HC
COMe
COMe
Na
Br
CH
COMe
COMeO Zn/I-CH2-CO2Et
H
Reformatsky Rtn
OH
CO2Et
AC2O
Co2Et
Ca salt
(HCO2)Ca
CHO
NaOH
-H2O
CHO
Cat. Hydrogenation
CHO
2 moles
C10H16O2Br2
C10H16Br4O
CHO
2 moles
H2N=OH
CH=N-OH
• Citral is reduced to an alcohol geraniol (
C10H18O) . Geraniol is a primary alcohol
and the formation a primary alcohol form
carbonyl compound confirmed that the
citral contains an aldehyde functional
group. CHO
Na/Hg
CH2-OH
geraniol
Essential Oils
Essential Oils
• Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers.
• Essential oils are used widely as natural flavor additives for food, as fragrances in perfumery, in aroma therapy, and in traditional and alternative medicines. Synthetic variations and derivatives of natural terpenes and terpenoids also greatly expand the variety of aromas used in perfumery and flavors used in food additives.
ISOLATION & SEPARATION
TECHNIQUES
Essential oils containing mono- and
sesquiterpenoids are obtained by water and or
steam distillation of the part such as flowers,
leaves or stems, where the essential oils occur
in more concentrated form. Due to the heat
lability of certain constituents of essential oils
different distillation methods have to be used
for different raw materials which are briefly
described below:
Distillation
• Today, most common essential oils, such as lavender,
peppermint, and eucalyptus, are distilled.
• Raw plant material, consisting of the flowers, leaves,
wood, bark, roots, seeds, or peel, is put into a
n alem bic (distillation apparatus) over water.
• As the water is heated the steam passes through the pla
nt material, vaporizing the volatile compounds. The vap
ors flow through a coil where they condense back to
liquid, which is then collected in the receiving ve
ssel.
Distillation
Most oils are distilled in a single process. One except
ion is Ylang- ylang (Cananga odorata), which takes 2
2 hours to complete through a fractional distillation.
Distillation
The recondensed water is referred to as a hydrosol, herbal di
stillate or plant water essence, which may be sold as another fra
grant product.
Popular hydrosols are rose water, lavender water, lemon balm, a
nd orange blossom water.
The use of herbal distillates in cosmetics is increasing.
Some plant hydrosols have unpleasant smells and are therefore
not sold.
Expression
Most citrus peel oils are expressed mechanically, or cold-pressed.
Due to the large quantities of oil in citrus peel and the relatively low
cost to grow and harvest the raw materials, citrus-fruit oils are cheaper
than most other essential oils. Lemon or sweet orange oils that are
obtained as by-products of the citrus industry are even cheaper.
Prior to the discovery of distillation, all essential oils were extracted
by pressing.
Solvent extraction
• Most flowers contain too little volatile oil to undergo
expression and their chemical components are too delicate
and easily denatured by the high heat used in steam
distillation. Instead, a solvent such as hexane or
supercritical carbon dioxide is used to extract the oils
• Extracts from hexane and other hydrophobic solvent are
called concretes, which is a mixture of essential oil, waxes,
resins, and other lipophilic (oil soluble) plant material.
Solvent extraction
• Although highly fragrant, concretes contain large
quantities of non-fragrant waxes and resins. As such
another solvent, often ethyl alcohol, which only
dissolves the fragrant low-molecular weight
compounds, is used to extract the fragrant oil from the
concrete
• The alcohol is removed by a second distillation, leaving behind
the absolute
ISOLATION & SEPARATION
TECHNIQUES
• Terpenoids • Following methods are employed for the extraction of mono-,
sesqui-, di-, tri-, and tetraterpenoids.
Air dried powdered part of the plant is extracted by percolation
or soxhlet extraction successively with organic solvents with
increasing polarity such as petroleum ether, benzene, diethyl
ether, chloroform, ethyl acetate, acetone, ethanol, methanol
and water. The extraction efficiency can be increased with the
decrease in the time of the process by stirring the pulverized
plant material using mechanical stirrer with the chosen solvent
and filtering it to obtain the extract.
STRUCTURE ELUCIDATION
• Physical Mehtods 1. Molecular formula
2. Specific rotation
3. Refractive index
• Spectral Methods for Structure
Determination 1. UV
2. IR
3. MS
4. NMR
Physical Mehtods 1. Molecular formula Determination of the molecular formula of an isolated pure
terpenoid is done by finding out the empirical formula and
molecular weight. Empirical formula can be found out by
elemental analysis .While molecular weight can be
determined by vapour density, elevation of boiling point
and depression of freezing point.
2. Specific rotation Specific rotation of a compound is measured to ascertain the
optical activity exhibited by it. It helps to distinguish between
optical isomers.
3. Refractive index It is measured to calculate the value of molecular refraction,
which is useful to find out the nature of the carbon skeleton
especially in the case of sesquiterpenoids .
Spectral Methods
1. UV Functional groups, present in terpenoids , which
absorb in the UV range between 200-350nm are termed as chromophores.However UV data becomes valuable only when the terpenoid molecule contains conjugated double bonds and/or α,β-unsaturated carbonyl group.
2. IR
This method is routinely used for the identification as well as the structure elucidation of new terpenoids.
3. MS
FAB-MS affords the e xact molecular ion peak along with diagnostic fragmentation patterns of the terpenoid molecule. It is an important tool for the structure determination .
Spectral Methods 4. NMR
• NMR spectroscopy comprising of both PMR and CMR is in fact one of the
Most important tools furnishing a good teal of information required for the
structure elucidation.
The combination of 1D selective and 2D NMR techniques such as COSY,
TOCSY, ROESY,2D IN-ADEQUATE, HMQC, HMBC COLOC, HOHAHA,
HETCOR and selective INEPT are of great value for the structure elucidation
of various terpenoids including the saponins and glyosides of a
number of sugar moieties.
EXAMPLE
• C10H16O
• b.p.77℃
• UV:236nm
• IR:1665,1625,1603,1398,1190,1117cm-1.
• MS:m/z 69(100),41,84,94,109,67,83,81
• 1H-NMR:1.65(6H,d, C-7 methyls) ,2.15(3H,s,C-3 Me),5.0(1H,t, H-6), 5.8(1H,d,H-2), 9.84(1H,d,H-1).
• 13C-NMR:190(C-1),127.5(C-2),162.1(C-3),40.5(C-4),26.5(C-5),123.5(C-6),132.3(C-7),25.3(C-8),17.4(C-9),17.0(C-10).
CHO
geranial