NATURAL

PRODUCT
CHEMISTRY

Examples of important
drugs obtained from plants

Is the study of natural extracts which are

obtained from natural resources.
Natural product chemists extract, purify,
and finally analyse compounds which are
obtained from living cells.

Techniques used are:

1. Column chromatography, CC
2. Gas chromatography, GC
3. Thin layer chromatography, TLC
4. High pressure liquid chromatography,
HPLC
5. Paper chromatography
6. Electrophoresis
7. Ion exchange chromatography

These techniques allow for the separation

and purification of compounds which are
present in very small quantities.
Structural elucidation of the unknown
compounds are usually carried out using
spectroscopic techniques such as:

Ultraviolet spectroscopy (UV)

Infra red spectroscopy (IR)
Nuclear magnetic resonance spectroscopy
(NMR) and
Mass spectroscopy (MS)

Primary and Secondary

Metabolism
Primary metabolites are carboxylic acids
of the Krebs cycle, a-amino acids,
carbohydrates, fats and proteins.
Hence, primary metabolism refers to the
photosynthesis process producing these
low molecular weight compounds.
These are the starting materials the
precursors of the secondary metabolites.

Principal Pathways
The main streams of secondary
metabolism is outlined in the chart.
Most metabolites originate from a very
limited number of precursors.
They are linked to primary metabolism.

Acetic acid has a central position in the form of

its thioester acetyl, CoA.
It is produced in the cell, from pyruvic acid or
fatty acids,or it may be directly formed from
acetate and coenzyme A with ATP.
C6H12O6 + 6O2
Glucose

6CO2 + H2O + energy

O

OH

C6H12O6

CH3CCOOH

CH3CHCO 2H

Glucose

Pyruvic acid

Lactic acid

From acetic acid, mevalonic acid is

derived, from which via 3,3-dimethylallyl
pyrophosphate and the isomeric
isopentenyl pyrophosphate the isoprene
unit the terpenoids are formed.

From carbohydrates, shikimic acid is

derived which is the key to a wealth of
aromatics.
It is also important to note that amino acid
is the important precursor to a great
variety of nitrogen containing compounds.

Major Pathways:
Shikimic acid aromatic acids
Acetate / polyketide fats, oils,
aromatic and poly aromatic compounds
Mevalonic acid Terpenoid: mono-,
sequi-, di-, triterpenoids.
Mixed pathway
Alkaloid
Miscellaneous

Several groups of metabolites have mixed

biogenesis; i.e. an intermediate or
metabolite from one principal pathway acts
as a substrate for another metabolite from
a different pathway.
Thus, flavonoids are derived from a
polyketide (three acetate units) and a
cinnamic acid (shikimic acid)

The indole alkaloid comes from shikimate

and a monoterpene (loganin)
In the past natural products were classified
according to structure or biological origin.
The biosynthetic scheme groups the
compounds according to the synthetic
route employed by the cell. There is
overlap.

There are 3 principal pathways: shikimic,

polyketide, and mevalonic pathways.

The Shikimic Acid Pathway

A very large number of compounds exhibit
a characteristic C6-aromatic-C3-side chain
structure. E.g. aromatic amino acids,
cinnamic acids, coumarins, flavonoids,
lignin constituents, etc.
These come from a common origin.
It was found that erythrose-4-phosphate
starts the biosynthetic pathway leading to
shikimic acid.

The biosynthesis of these compounds was

elucidated by mutant studies of E.coli by
Davis and Sprinson.
Shikimic acid was isolated as early as
1885 by Eykman from the Japanese plant,
Illicium anisatum long before we were
aware of its biosynthetic significance.

The biosynthesis pathway begins with

D-erythrosephosphate and
phosphoenolpyruvate (PEP) combining via
an aldol condensation.
Both these compounds were initially
derived from D-glucose.
The aldol condensation is aided by an
enzyme which adds on to the
phosphoenolpyruvate molecule to form 3deoxy-D-arabinoheptulosonate-7phosphate (DAHP)

Ring closure of the heptulose derivative

(3,7-dideoxy-D-arabino-2,6-diulosonic
acid) gives 3-dehydroquinic acid.
Removal of 1 H2O molecule from
3-dehydroquinic acid yields 3dehydroshikimic acid; this acid is reduced
to shikimic acid.
At the pH of living organism, this acid
exists in its anionic form, the shikimate ion.

HO

Shikimic acid
OH

HO
OH

Phosphorylation of the shikimate anion

with adenosine triphosphate gives
shikimate-3-phosphate which then reacts
with another molecule of
phosphoenolpyruvate (PEP) to yield
5-enolpyruvylshikimate-3-phosphate

O-

O-

O-

-H

enzyme
surface
P

OH

H+
P

O-

OH

OH

P
PEP

shikimate-3-phosphate

O-

O-

O
O

CH2

O-

O-

O
enzyme

CH2

OH

O
OH

O
P

5-enolpyruvylshikimate-3-phosphate

H
H
Enz

5-enolpyruvylshikimate-3-phosphate
converts to chorismate by elimination (1,4
with respect to Hydrogen and Phosphate)
Enzyme assistance is once more involved
in this conversion.

We now have the starting material for the biosynthesis of

natural aromatic compounds.

Shikimic Acid

The structure of shikimic acid was

determined chemically through the
following methods:

The acid was optically active and formed

the triacetate when reacted with acetic
anhydride.
This reaction indicated the presence of
three hydroxyl groups in the molecule.
It reacted with Br2 (1 mole) and also with
H2 to form dehydroshikimic acid (A).

HO

HO

1
6

H2 / Pt

3
HO

4
OH

Shikimic acid

OH

HO

OH
OH

1,2-dehydroshikimic acid
(A)

HO

HO

O
Br

1
6

Br2

Br

3
HO

HO

OH

OH
OH

OH

Shikimic acid
HO

1,2-dibromoshikimic acid
HO

1
6

Ac2O

3
HO

OH

AcO

OAc

OH

OAc

Shikimic acid

Triacetate shikimic acid

All the 3 hydroxy groups were shown to be

next to each other by oxidising the methyl
ester of the trihydroxy dehydroshikimic
acid with 2 moles of periodic acid to give
the dialdehyde (B).

HO

OH3C

CH3OH
H+
HO

OH

HO

OH
OH

OH

HIO4

OH3C

dialdehyde
(B)

The dialdehyde reacts with Bromine water to

give the diacid (C).

OH3C

OH3C

Br2 water

OH

OH

The diacid is hydrolysed by alkali to give the

triacid (D), tricarbalic (tricarboxylic acid)

OH3C

HO

OH

OH
OH

OHHO

Tricarbalic acid
(D)

Methylshikimate reacts with periodic acid

under carefully controlled conditions to
form the dialdehyde (E), which in turn is
oxidised to the unsaturated tri-acid (F),
transaconitic acid by oxidation with
peroxypropionic acid and followed by
hydrolysis with base.

OH3C

HO

OH3C

OH

HIO4

O
C2H5C
OOH

2 mol

then OHO

HO

OH

OH

OH

Methylshikimate

Dialdehyde
(E)

Trans-aconitic
acid
(F)

The C7 skeleton of shikimic acid is the

precursor in the biosynthesis of various
natural products. This include important
amino acids such as p-aminobenzoic acid,
heterocyclic amino acids such as
tryptophan and galotanin and depsides
which involve galic acid.

COOH

HO

OH
OH

COOH

COOH
NH2

HO

OH

COOH

anthranilate
(B)

OH

Galic acid

NH2

Galotanin

p-aminobenzoic
acid
COOH

NH2

Folic acid

N
H

Tryptophan
(A)

Indole
C2N

The amino acid tryptophan (A) is

necessary for the metabolism processes in
mammals.
In plants tryptophan is formed
biosynthetically from anthranilate (B) by
the addition of a 5C chain.
Tryptophan is an indole derivative.

Melanin is a dark pigment present in

plants and animals.
This pigment is responsible for the colour
of the hair and the skin colour of human
beings.

Another class of dark coloured pigment in

plants is catechol which is derived from
the oxidation of phenol.
This pigment is referred to as catechol
melanin and is responsible for the brown
colour of cut apples and pears.

Indoliacetic acid (heteroauxin) is a plant

growth regulator.
This compound controls the formation of
the new cells in plants and at the growing
tips.

The Acetate Pathway

C6H12O6
glucose

OO
OH
CH3CCOH + CH3CHCOH
pyruvic acid

O
lactic acid

In biochemical situations, the pH of the

media is ~7; hence, the carboxylic acid
exists in its conjugate base form.

Therefore,
Pyruvic acid pyruvate and
Lactic acid lactate
Pyruvate then acetate
Acetate is the starting material for the
biosynthesis of complex compounds.

Acetyl coenzyme A, CH3COSCoA

Plays an important role in many metabolic

processes.
OO
CH3CCOH + CoASH + NAD+
pyruvic
acid

coenzyme
A

nicotinamide
adenine dinucleotide

O
CH3CSCoA + NADH + CO2 + H+
acetyl coenzyme
A

reduced form
of NAD

Acetyl coenzyme A is the basic unit for the

synthesis of complex natural products.

Fatty acid
Fats was one of the first natural products
to be studied by chemists.
Fats are glycerol esters.
A big part of the natural fatty acid are
straight chain alkanoic acids with an even
number of C atoms.

They also have double or triple bonds,

hydroxy groups or epoxy or carboxylic acid
groups.
Common fatty acids in living tissues are
stearic acid, oleic acid,palmitic acid and
linoleic acid.
Alternate arrangements (ie at 1, 4, 7) of
the cis-double bonds on these acids are
especially for most of the unsaturated fatty
acids.

COOH

Palmitic acid (C16)

COOH

Stearic acid (C18)

COOH

Oleic acid (C18)

cis-octadec-9-enoic acid
COOH

Linoleic acid
cis,cis-octadec-9,12-dienoic acid
COOH

Arachidonic acid (C20)

Fatty acids usually exist as glycerol esters

(triglyceride and lecitin) or cholesterol
esters or wax esters.
All these compounds are derived from
long chain fatty acids and are known as
lipids.

Lipid chemists have a special way to

denote these fatty acids:
Palmitic acid = 16:0
Stearic acid = 18:0
Oleic acid = 18:1 (9C)
Linoleic acid = 18:2 (9C, 12C)
Arachidonic acid = 20:4 (5C, 8C, 11C, 4C)

CH2 O CO(CH2)14CH3
CH O

CO(CH2)12CH3

A triglyceride

CH2 O CO(CH2)16CH3

Natural fats are mixtures of triglycerides

like the one shown above and maybe with
di- and mono-glyceride.

Biosynthesis of Fatty Acids

Acetic acid is the precursor for the synthesis of

fatty acids.
Acetic acid is first converted to a more reactive
form, the acetylcoenzyme A.

O
CH3CSCoA + HS-ACP
Acetyl coenzyme
A

Acyl
carrier
protein

O
CH3CSACP
s-acetyl acyl
carrier protein

+ HSCoA
coenzyme A

A second molecule of acetylcoenzyme A reacts

with HCO3- (bicarbonate) to yield malonyl
coenzyme A.

O
CH3CSCoA + HCO3X

Acetyl coenzyme
A

O
O
X
OCCH2CSCoA
Malonyl
coenzyme A

+ H2O

The formation of malonyl coenzyme A is

followed by an acyl transfer reaction which
bonds the malonyl group to an acyl carrier
protein.

O
O
OCCH2CSCoA
Malonyl
coenzyme A

HS-ACP
Acyl
carrier
protein

O
O
OCCH2CS-ACP
s-malonyl acyl
carrier protein

+ HSCoA
coenzyme A

A C-C bond is formed between the a-carbon in

the malonyl group and the carbonyl carbon of
the acetyl group.

Reduction of the C=O group of the acetoacetyl

Dehydration of the b-hydroxy group of the acyl

Thus, the biosynthesis of hexadecanoic acid

(palmitic) can be represented by the following
equation:

Details are:
O
CH3CSACP

O
+ COOHCH2CSACP

O
O
CH3CCH2CSACP

+ CO2

SACP

O
CH3CH2CH2CSACP
O
COOHCH2CSACP

O
O
CH3CH2CH2CCH2CSACP

CO2

SACP

O
CH3CH2CH2CH2CH2CSACP
O
COOHCH2CSACP
O
O
CH3(CH2)4CCH2CSACP

+ CO2 +

SACP

O
CH3(CH2)4CH2CH2CSACP
O
COOHCH2CSACP
O
O
CH3(CH2)6CCH2CSACP

+ CO2

SACP

O
CH3(CH2)6CH2CH2CSACP
O
COOHCH2CSACP
O
O
CH3(CH2)8CCH2CSACP

CO2

O
CH3(CH2)8CH2CH2CSACP
O
COOHCH2CSACP

SACP

O
O
CH3(CH2)10CCH2CSACP

+ CO2 +

+ CO2

SACP

O
CH3(CH2)10CH2CH2CSACP
O
COOHCH2CSACP
O
O
CH3(CH2)12CCH2CSACP

O
CH3(CH2)12CH2CH2CSACP

SACP

O
CH3(CH2)14CSACP
S-Hexadecanoyl acyl
carrier protein

Flavonoid

The name flavon is given to compounds which

contain the phenylbenzopyrone skeleton as
shown below:

Hence, flavons are heterocyclic compunds

of oxygen.
They are an important group of
compounds in the natural yellow pigment.
Flavonols (3-hydroxyflavon) and flavanons
(2,3-dihydroxyflavon) as well as
anthocyanin (flavilium salt) usually exist
together with flavon in the same plant.

This group of compounds is called

flavonoid.
Flavonoids are present in the ferns as well
as in higher plants.
It usually has hydroxyl groups at 3,5,7,3
and 4 as in quercetin and also usually
exists as glycosides like
Kaempherol-7-rhamnoside.

Flavonoids contribute to the beauty and

splendour of flowers and fruits in nature.
The flavones give yellow or orange
colours, the athocyanins red, violet, or
blue colours i.e. all the colours of the
rainbow but green.

The flavonoids play a major role in relation

to insects pollinating or feeding on plants
but some flavonoids have a bitter taste,
repelling certain caterpillars from feeding
on leaves.

The flavonoids are structurally

characterized by having two hydroxylated
aromatic rings A and B joined by a 3C
fragment.
One OH group is often linked to a sugar.
Several substructures can be
distinguished: chalcones, flavones,
isoflavones, aurones, and anthocyanidins.

Structures of Flavonoid Compounds

5'

3
4

2
HO

3'
4'

OH

2'

OH
1

5
6

OH

1
O

HO

6'
O

Butein (a chalcone)

4'

1'

3'
2'

5'

6'

3
5
OH

4
O

Luteolin (a flavone)

OH

OH

HO

OH

HO

O
CH

O
O
OH

Daidzein (Isoflavone)

Sulphuretin (Aureone)
OH

HO

O
OH

OH
OH

Cyanidin (Anthocyanidin)

OH

2-Hydroxy-substituted chalcones cyclize easily

to flavones, the structure of which is stabilized
by hydrogen bonding at C-4O and C-5O.

OH
OH
HO
HO

2'

OH

5
OH

a chalcone

Naringenin (a flavanone)

The structural determination of Chalcone

was accomplished by alkaline degradation
which gave acetophlorophenone, phydroxybenzaldehyde, phloroglucinol, and
acetic acid.

OH

HO

2'

HO

OH

OH

OHCH3

C
OH

OH

a chalcone

acetophlorophenone
+
OH

OHC

p-hydroxybenzaldehyde

HO

OH

OH

HO

OHC
OH

+ CH3COOH
acetic acid

CH3

OH

Phloroglucinol
Acetophlorophenone

Anthocyanidins were related to 3hydroxyflavones by reduction of the

carbonyl group followed by treatment with
acid.

OH

OH
OH

HO

OH

HO

LiAlH4
3
OH
OH

OH

OH

OH

H+
OH
OH

HO

OH

cyanidin (an anthocyanidin)

The structure of flavone was initially

determined using alkaline hydrolysis
(Kostanecki, 1893).
Chrisin (C) C15H10O4 when heated with
KOH gave phloroglucinol, acetic acid,
benzoic acid and benzophenone.

HO

OH

HO

OH-

OH

OH

Phloroglucinol

Chrisin (C)
(a flavone)

COOH

+ CH3COOH
acetic acid

benzoic acid
C

benzophenone

For polyhydroxyflavones, methylation of

the hydroxyl groups before hydrolysis is
important because phenol is easily
oxidised in alkaline medium.
New flavones are usually identified by
comparing their spectra with spectra of
known flavones or by comparison of the
colours with that of known flavones.

Synthesis of flavones & flavanone

O

OH

HO

Ar
C
HO

OH O

+
CH2
C

OEt

Ar

vacuum

OH

Phloroglucinol

OH

A keto ester

HO

OH

a flavone

Ar

Rearrangement (intramolecular) within molecule

of o-benzoyloxyacetophenone
O
O

Ar

O
OH

Ar
C
H

H
C

CH2

Ar

H
O

A Flavone

2-hydroxy-substituted chalcones cyclize easily

to flavanones.

OH

OH

HO

2'

HO

OH

Isomerase

H
4

H
OH

O
H

Naringenin
(a flavanone)

Anthocyanin
Red colour, purple and blue colours of
flowers, berries, and leaves during autumn
are all due to the anthocyanin such as
cyanin.
Anthocyanin are glycosides of flavilium
salts.

OH
OH

HO

Oglucose
Oglucose

Cyanin (an anthocyanin)

Contains the basic skeleton of flavone and was

formed by the reduction of quercetin to cyanidin.

OH

HO

OH

OH
OH

OH

HO

O
OH

Quercetin
OH
OH

Cyanidin
(an anthocyanin)

Anthocyanin is biosynthesized from a flavanone

through dihydroflavanol.
OH

HO

H
OH

O
OH

H+

OH

HO

O
OH

OH

OH
OH

OH

H+

OH

HO

O
OH

OH
OH

Cyanidin

TERPENES
We have already looked at how some
secondary metabolites were
biosynthesized from acetate through the
condensation of linear C2 units.
We shall now look at how the acetate units
are combined in a different form to yield
mevalonic acid which is then converted to
different products such as terpenes.

These compounds are found naturally in

living organisms.
They were first isolated from plants and
flowers which possess a fragrant smell.
These have long been of interest in the
olden days.
Since the 19th century, the structures of
some components of the essential oils
isolated from plants have been
discovered.

Most of these components were

unsaturated C10H16 hydrocarbons.
These compounds were named terpenes.
Apart from hydrocarbons, there were also
alcohols and ketones with similar
skeletons.
All these compounds are called
terpenoids.

These compounds have a carbon skeleton

which can be split into two C5 units.
These C5 units are called isopentene units or
isoprene units.

Two isoprene
units

Limonene

C10 compunds are known as

monoterpenes.
C15 compounds are called sesquiterpenes,
C20 as diterpenes, C30 as triterpenes, and
C40 as tetraterpenes.
These compounds are classified under
terpenes (or terpenoid or isoprenoids) if
their structures can be divided into
isoprene units.

CH3
H2C

CH

CH2

Isoprene
(2-methyl-1,3-butadiene)
tail

head

Two isoprene units joined head to tail.

OH

Isoprene units in farnesol

Most terpenes contain one or more rings.

For e.g. a-selinene has 3 isoprene units.

CH3

H3 C

CH2

CH2

tail
12
13

head

Isoprene units in squalene (C30-triterpene)

Other examples of terpenes are as follows:

OH

a-phellandrene
(monoterpene)

Methol (peppermint)
(monoterpene)

O
C

Citral (lemon grass)

(monoterpene)

Sesquiterpenes (C15)

OH
CH2

a-selinene
(celery)

CH2

Farnesol

Diterpene (C20)

OH

Vitamin A

Triterpene (C30)

Squalene
(shark liver oil)

Tetraterpene

b-carotene
(b-carotene
Vitamin A)
C40
2 x C20

The Biosynthesis of Terpenes

1.

All terpenes and steroids have the same

biosynthetic sources.
Terpenes can be said to be biosynthesized from
mevalonate (mevalonic acid) via isopentenyl
pyrophosphate.
o
3 CH3COH

several
steps

CH3
O
HOCCH2CCH2CH2OH
OH

acetic acid

mevalonic acid

In the 2nd step, mevalonic acid is converted to 3methyl-3-butenylpyrophosphate (isopentenyl

pyrophosphate)
O

CH3

HOCCH2CCH2CH2OH
OH

several
steps

H2C

O O
CH3
CCH2CH2OPOPOH
OHOH

Mevalonic acid

OPP

Isopentenyl pyrophosphate
(a biological isoprene unit)

Isopentenyl pyrophosphate undergoes an

enzyme catalyzed reaction and gets
converted to dimethylpyrophosphate.

OPP

H+

-H+

-H+

H+

OPP
H

OPP

Dimethylpyrophosphate

Dimethylpyrophosphate is more reactive

than isopentenylpyrophosphate to
nuclephilic reagents.

Formation of C-C bond in terpene

biosynthesis.
OPP

-(OPP-)
x

OPP

OPP

Dimethyl
pyrophosphate

Isopentenyl
pyrophosphate

10-C Carbocation

Loss of a proton from the carbocation to

give an alkene.

OPP

OPP
H

Geranylpyrophosphate

Hydrolysis of the ester group yields

geraniol, a monoterpene which exists in
the rose essential oil.
H2O
OPP

Geranylpyrophosphate

OH

Geraniol

Geranylpyrophosphate is an allylic
pyrophosphate and like
dimethylallylpyrophosphate can react as
an alkylation reagent to isopentenyl
pyrophosphate.

OPP

+
OPP

Isopentenylpyrophosphate

Geranylpyrophosphate

x
OPP
H

-H+

OPP

Farnesyl pyrophosphate
H2O

OH

Farnesol

Questions:

Write the steps for the biosynthesis of

geranylgeraniol from farnesyl
pyrophosphate

OPP

Farnesyl pyrophosphate

Higher terpenes are not formed by the

continuous addition of C5 units but by
coupling of simple terpenes.
Therefore, triterpenes are formed by the
coupling of two farnesyl pyrophosphate
while tetraterpenes (C40) from two
molecules of
geranylgeranilpyrophosphate.

The formation of the C-C bond is a

complex process and involves the joining
of tail to tail.
The formation of geraniol and farnesol can
be said to be a dimerization of alkenes.
We now look at the formation of a cyclic
monoterpene.

OPP

+
OPP

Geranylpyrophosphate

Neryl
pyrophosphate

a tertiary
carbocation

OPP-

-H+

Limonene

H2O
HO

a-terpineol

Loss of a H+ gives Limonene a natural

product present in citrus.
Addition of H2O to the carbocation gives aterpineol a natural product also.
The same carbocation can also give
bicyclic monoterpenes.

y
y
x
y
y
x

x
x

y
x

-H+
H

H
H3C

a-Pinene

b-Pinene

O
O
H

H
H

OH
H

Borneol

Formation of isopentenyl
pyrophosphate
O

CH3CSCoA

OOCCH2CSCoA

Acetyl
Coenzyme A

Malonyl
Coenzyme A

CH3CCH2CSCoA
Acetoacetyl
Coenzyme A

CO2

We have seen how mevalonic acid is

formed from 3 molecules of acetic acid.
From mevalonic acid isopentenyl
pyrophosphate is formed.
Isopentenyl pyrophosphate is used in the
biosynthesis of terpenes.
We now look at how mevalonic acid is
formed from acetate.

CH3CCH2CSCoA
Acetoacetyl
Coenzyme A

CH3CSCoA
Acetyl
Coenzyme A

OH
CoASH
coenzyme A

CH3C CH2CSCoA
CH2COH
O
b-hydroxy-b-methylglutaryl
coenzyme A (HMG CoA)

OH

CH3C CH2CSCoA
CH2COH
O
b-hydroxy-b-methylglutaryl
coenzyme A (HMG CoA)

OH

CH3C CH2CH2OH
CH2COH
O
Mevalonic acid

Mevalonic acid has 6C.

Loss of a C atom changes it to isopentenyl
pyrophosphate

H3C

OH
O

C
C CH2

CH2CH2OH

-O

OPO32-

H3C
C
C CH2

CH2CH2OPP

-O
-PO43-CO2

Mevalonate

H3C
CCH2CH2OPP
H2C
Isopentenyl pyrophosphate