Chapter 1

Introduction to Natural Products

Natural products
In chemistry and related sciences, the term natural product is typically used for secondary
metabolites.

1. Alkaloids
Definition of Alkaloids:
Alkaloids (lit., alkaloid, alkali-like) are naturally occurring organic compounds that contain at least
one basic (alkaline) nitrogen atom, typically in the form of a heterocyclic ring. They have a
characteristic bitter taste. They are found in a wide variety of plant species and some animals and
microorganisms. Alkaloids often possess significant pharmacological properties and are known for
their diverse physiological effects including stimulating the central nervous system, depressing the
central nervous system, and causing hallucinations.
Examples:
Coniine from hemlock Nicotine (S-nicotine) from Morphine from poppy
tobacco

Caffeine from tea, coffee Ephedrine ((−)-(1R,2S)-ephedrine) from ephedra

 Solanine from Solanum species

1.1. Classification of Alkaloids:

1.1.1. Based on Biosynthesis:

Alkaloids can be classified into three main categories based on their biosynthesis:

1. True Alkaloids (Typical Alkaloids; Proper Alkaloids) (Heterocyclic N) and derived from
amino acids: These alkaloids are synthesized from amino acids and have nitrogen as a
part of a heterocyclic ring. Most alkaloids are of this type. Examples include nicotine,
morphine, and quinine.
2. Protoalkaloids (non-heterocyclic N): Protoalkaloids are alkaloids derived from amino
acids but do not have nitrogen as part of a heterocyclic ring. Examples include ephedrine
and mescaline.
 Mescaline from cacti

3. Pseudoalkaloids: Pseudoalkaloids are not derived from amino acids. Examples include
caffeine.

1.1.2. Based on Chemical Structures:

Alkaloids can be classified into various structural categories. Some common types are as
follows:
1. Acridine alkaloid: Acronycine, Rutacridone.
2. Amide alkaloid: Capsaicin.
3. Imidazole alkaloid: Pilocarpine.
4. Indole alkaloid: Serotonin, Arundacine.
5. Indolizidine alkaloid: Swainsonine and Castanospermine.
6. Isoquinoline alkaloid: Codeine, berberine, morphine.
7. Phenethyl isoquinoline alkaloid: Galanthine, Galanthamine.
8. Phenylethyl-amino alkaloid: Dopamine, Adrenaline.
9. Piperidine alkaloid: Coniine, Coniceine, Pinidine.
10. Piperidine alkaloid: Piperine, Sparteine, Trigonelline.
11. Purine alkaloid: Caffeine, theobromine, and theophylline.
12. Pyroloindole alkaloid: Corynanthine, Chimonantheine.
13. Pyrrolidine alkaloid: Hygrine, Nicotine.
14. Pyrrolizidine alkaloid: Echimidine and symphitine
15. Quinazoline alkaloid: Peganine.
16. Quinoline alkaloid: Chinchonine, Brucine, Quinine, Quinidine
17. Quinolizidine alkaloid: Cytisine, Lupanine.
18. Steroidal alkaloids: Batrachotoxin, conanine, Solanine.
19. Tropane alkaloid: Atropine, Cocaine, Ecgonine.
1.1.3. Based on Medicinal Applications:
Alkaloids can also be classified based on their medicinal applications. Some common examples
are as follows:
1. Analgesic Alkaloids: Alkaloids with pain-relieving properties, such as morphine and
codeine.
2. Stimulant Alkaloids: Alkaloids that have stimulating effects, like caffeine and nicotine.
3. Sedative Alkaloids: Alkaloids with calming and sedative properties, such as atropine
and scopolamine.
4. Anti-Inflammatory Alkaloids: Alkaloids known for their anti-inflammatory actions,
including quinine.
5. Antispasmodic Alkaloids: Alkaloids used to relieve muscle spasms, such as papaverine.
6. Antiarrhythmic Alkaloids: Alkaloids employed to treat irregular heart rhythms, like
quinidine.
7. Antimalarial Alkaloids: Alkaloids with antimalarial activity, such as quinine and
artemisinin.

2. Terpenoids
Terpenoids are a large and diverse class of organic compounds that are made up of isoprene
units. They are found in plants, animals, and fungi. Terpenoids have a variety of functions,
including providing a scent to plants, protecting plants from predators, and serving as signaling
molecules. They have several subclasses based on chemical structures:
2.1. Hemiterpenoids
2.2.Monoterpenoids
2.3. Sesquiterpenoids
2.4. Diterpenoids
2.5. Sesterterpenoids
2.6. Triterpenoids
2.7. Poly terpenoids
2.8. Steroids
Steroids are a class of organic compounds that are made up of four fused rings. Structurally, they
are triterpenoids. They are found in animals, plants, and fungi. Steroids have a variety of
functions, including regulating metabolism, reproduction, and development.
3. Polyphenols (Phenolics)
Phenolics are a class of organic compounds that contain phenol groups. They are found in plants,
fruits, and vegetables. Phenolics have antioxidant properties and can help protect the body from
damage caused by free radicals.

Resveratrol Gallic acid

The polyphenols have several subclasses based on structures.

Ref. Beconcini et al., Foods 2020, 9, 207. https://doi.org/10.3390/foods9020207

The basic structures of some common polyphenols are shown below:

3.1. Flavonoids
Flavonoids are a class of phenolic compounds that are found in plants. Structurally, they contain
a C6-C3-C6 system (15 carbons). They are the most abundant type of polyphenols and are found
in a wide variety of fruits, vegetables, and beverages. They have antioxidant properties and can
help protect the body from damage caused by free radicals. Flavonoids are also known to have
anti-inflammatory and anti-cancer properties. Some common flavonoids include quercetin,
kaempferol, anthocyanin, and catechins. Flavonoids can be broadly classified into two main
types, which are anthocyanins and anthoxanthins. Anthoxanthins are further categorized into
different types, such as flavonols, flavones, flavanols, flavanones, isoflavonoids, and
neoflavonoids.
 Quercetin
Rutin

Characteristics of Flavonoids

Conjugated Forms (Glycosides and Aglycones):

Flavonoids can exist in two primary forms: as glycosides and as aglycones.
Glycosides: Some flavonoids are found in conjugated forms, known as glycosides, where they are
chemically bonded to sugar molecules. These sugar molecules are typically attached to specific
positions on the flavonoid structure.
Aglycones: In contrast, aglycones are flavonoids without attached sugar molecules. They exist in
their free form without sugar conjugation.

Hydroxylation and Other Modifications:

Flavonoids often undergo hydroxylation, a chemical process where hydroxyl (-OH) groups are
added to specific positions on their structure.
Hydroxylation typically occurs at positions 3, 5, 7, 3', 4', and 5' of the flavonoid molecules.
In addition to hydroxylation, some hydroxyl groups may be further modified through processes
like methylation (addition of a methyl group), acetylation (addition of an acetyl group), or sulfation
(addition of a sulfate group).

Prenylation:
Prenylation (also called isoprenylation or lipidation) is the addition of hydrophobic molecules to a
biomolecule. In it, a prenyl group (isoprenyl group or 3-methylbut-2-en-1-yl) is attached to a
biomolecule. Prenylation can occur in flavonoids. The groups are typically attached as side chains
directly to carbon atoms within the aromatic rings of the flavonoid structure. In some cases, O-
prenylation also occurs where the prenyl group is attached to an oxygen atom. Prenylated
flavonoids make a sub-class of flavonoids. An example of prenylated flavonoids is 8-
prenylnaringenin:
Glycosidic Linkage and Carbohydrates:
When flavonoids form glycosides (conjugated forms with sugar molecules), the glycosidic linkage
(the chemical bond between the flavonoid and sugar) is typically found at positions 3 or 7 on the
flavonoid structure.
The sugar molecules that are commonly attached to flavonoids include L-rhamnose, D-glucose,
glucose rhamnose, galactose, or arabinose.

Effects on Solubility, Reactivity, and Stability:

The various modifications (hydroxylation, methylation, acetylation, sulfation, prenylation, and
glycosidic linkage) can significantly influence the properties of flavonoids.
These modifications can alter the solubility, reactivity, and stability of flavonoids, making them
more or less soluble in different solvents, affecting their chemical reactivity, and determining their
resistance to degradation or oxidation.

Presence of Flavonoids in Glycoside Form:

In natural conditions, most flavonoids are found in the form of glycosides, where they are
conjugated with sugar molecules.
This glycoside form is prevalent in plants and contributes to the diversity of flavonoid compounds
found in nature.

In summary, flavonoids are versatile compounds that can exist in different forms (glycosides and
aglycones) and undergo various chemical modifications, including hydroxylation, prenylation, and
glycosidic linkage with sugars. These modifications can have a significant impact on the properties
and functions of flavonoids in plants and their potential applications in various industries,
including medicine and nutrition.

UV-Visible Spectroscopy of Flavonoids:

UV-visible spectroscopy is a technique used to analyze the absorption of ultraviolet and visible
light by chemical compounds. In the context of flavonoids, this spectroscopic method provides
valuable information about their molecular structure and the presence of specific functional
groups.

Major Absorption Maxima in Flavonoids:

Studies using UV spectroscopy have revealed that most flavonoids exhibit two prominent
absorption maxima:
Band II (240–285 nm):
Band II corresponds to the absorption of light in the ultraviolet range (240–285 nm). This
absorption peak is primarily associated with the benzoyl system located in the A ring of the
flavonoid structure.
Band I (300–400 nm):
Band I represents the absorption of light in the visible range (300–400 nm). It is mainly
attributed to the cinnamoyl system located in the B ring of the flavonoid structure.

Functional Groups and Absorption Shift:

The specific absorption wavelengths of Band II and Band I can be influenced by the presence of
various functional groups attached to the flavonoid skeleton.
The nature and position of these functional groups can cause shifts in the absorption spectra. For
example, hydroxyl (-OH) groups or other substituents may lead to changes in the absorption
peaks.
Application of UV Spectroscopy in Flavonoid Analysis:
Standardized UV spectroscopy, often referred to as UV-Vis spectroscopy, has been widely used
for the analysis of flavonoids.
Researchers utilize UV-Vis spectrophotometers to measure the absorbance of flavonoid solutions
at different wavelengths within the UV and visible range.
By analyzing the absorption spectrum of a flavonoid compound, researchers can gain insights
into its molecular structure, the presence of specific functional groups, and even estimate its
concentration in a solution.

Conclusion:
UV-visible spectroscopy is a powerful analytical tool for studying flavonoids due to their
characteristic absorption patterns in the UV and visible regions.
The two major absorption bands, Band II and Band I, correspond to specific structural features in
the A and B rings of flavonoids, respectively.
Functional groups and their positions can influence the absorption spectrum, allowing for the
identification and analysis of flavonoid compounds.
UV spectroscopy plays a significant role in both qualitative and quantitative analyses of
flavonoids in various applications, including chemistry, biochemistry, and pharmaceutical
research.

Flavonoids as antioxidants (as free radical scavengers):

Flavonoids are known for their ability to act as antioxidants. Antioxidants are substances that can
neutralize harmful substances called free radicals in the body.

Structural Features for Antioxidant Activity:

Review the following figure.

Ref: Santos et al. (2017). https://www.intechopen.com/chapters/54574

3',4'-Dihydroxy (Catechol) Structure in the B Ring (A): The first structural feature that enhances
the antioxidant activity of flavonoids is the presence of a 3',4'-dihydroxy structure, often referred
to as a catechol structure, in the B ring of the flavonoid molecule.
This catechol structure is characterized by two adjacent hydroxyl (-OH) groups at positions 3'
and 4' on the B ring. This structural feature favors the delocalization of electrons (electron
delocalization) within the molecule, contributing to its antioxidant properties.

Unsaturated 2-3 Bond in Conjugation with a 4-Keto Group (B):

The second important structural feature is the presence of an unsaturated 2-3 bond in the
flavonoid molecule's structure. This unsaturated bond is typically found in conjunction with a 4-
keto group. The presence of this bond allows for the delocalization of electrons from the B ring,
further enhancing the molecule's ability to act as an antioxidant.

Hydroxyl Groups at Positions 3 and 5 Forming Intramolecular Hydrogen Bonds to the Keto
Group (C): The third structural feature involves the presence of hydroxyl (-OH) groups at
positions 3 and 5 on the flavonoid molecule. These hydroxyl groups are capable of forming
intramolecular hydrogen bonds with the adjacent keto group (at position 4), creating a stable
structure. The formation of these hydrogen bonds contributes to the antioxidant activity of
flavonoids.

Mechanism of Antioxidant Activity:

The described structural features lead to increased radical scavenging by flavonoids through two
main mechanisms:
Single-electron transferring (SET) mechanism: The electron delocalization within the molecule
allows flavonoids to neutralize free radicals by sharing or transferring electrons, thereby
stabilizing the radicals and preventing them from causing cellular damage.
Hydrogen atom transferring (HAT) mechanism: The presence of phenolic hydroxyl groups
allows flavonoids to donate hydrogen atoms to free radicals, effectively neutralizing them.

Conclusion:
Flavonoids possess specific structural features that make them effective in combating free
radicals. The catechol structure in the B ring, the unsaturated bond in conjunction with the 4-keto
group, and the presence of hydroxyl groups at positions 3 and 5 collectively contribute to the
antioxidant properties of flavonoids.
These structural features enable flavonoids to neutralize free radicals by either SET or HAT,
ultimately protecting cells and tissues from oxidative damage.

3.1.1. Anthocyanins
Anthocyanins are a type of flavonoid that gives fruits and vegetables their red, blue, and purple
colors. They are also found in some flowers, leaves, and seeds. Anthocyanins are water-soluble
pigments, which means that they dissolve in water. This is why anthocyanin-rich foods and
beverages, such as blueberries, raspberries, and red wine, have a deep color. The basic structure
is shown here.

Anthocyanidin R3′ R4′ R5′ R3 R5 R6 R7

Aurantinidin −H −OH −H −OH −OH −OH −OH

Cyanidin −OH −OH −H −OH −OH −H −OH

Delphinidin −OH −OH −OH −OH −OH −H −OH

Europinidin −OCH −OH −OH −OH −OCH −H −OH

3 3

Pelargonidin −H −OH −H −OH −OH −H −OH

Malvidin −OCH −OH −OCH −OH −OH −H −OH

3 3
 Peonidin −OCH −OH −H −OH −OH −H −OH
3

Petunidin −OH −OH −OCH −OH −OH −H −OH

3

Rosinidin −OCH −OH −H −OH −OH −H −OCH

3 3

Note: Anthocyanins are glycosides of anthocyanidins.

3.1.2. Flavanols (Flavan-3-ols)

They are a subgroup of flavonoids. They include compounds such as catechin, epicatechin
gallate, epigallocatechin, and epigallocatechin gallate.

Basic structure of flavan-3-ols

Catechin's general structure is shown below. As you can see, it has two chiral centers. So, there
are two pairs of enantiomers.

(+)-catechin (2R,3S) (−)-catechin (2S,3R)

(−)-epicatechin (2R,3R) (+)-epicatechin (2S,3S)

 Gallocatechin (2S,3R)

Epigallocatechin gallate (2R,3R)

Notice that in gallocatechin and epigallocatechin, there is a gallic acid ring (ring B).
Epigallocatechin gallate (also called epigallocatechin-3-gallate) is an ester of epigallocatechin
with gallic acid.

3.2. Phenolic acids

Phenolic acids are another major group of polyphenols and are found in many plants, including
fruits, vegetables, and grains. They have antioxidant and anti-inflammatory properties. Some
common phenolic acids include caffeic acid, ferulic acid, gallic acid, and ellagic acid.

Ellagic acid (a cyclic diester)

3.3. Tannins
Tannins are a group of polyphenolic compounds that are found in many plants. They are found in
many fruits, vegetables, nuts, and seeds. They are responsible for the astringent taste of some
foods and beverages, such as tea, wine, and walnuts. Tannins can be classified into two main
types:
3.3.1. Hydrolysable tannins:
Hydrolyzable tannins are large molecules that can be decomposed by hydrolysis. They are
composed of a sugar (such as D-glucose) and phenolic acids such as gallic acid and
protocatechuic acid, bonded together through ester bonds. Hydrolysis of tannins can be carried
out under the catalytic acid of hydrochloric acid or sulfuric acid.
 Hydrolyzable tannins

3.3.2. Condensed tannins:

Condensed tannins are not composed of a sugar molecule. They are made up of multiple
phenolic units that are linked together by carbon-carbon bonds. Condensed tannins are not as
easily broken down as hydrolyzable tannins.

3.4. Lignans
Lignans are a type of polyphenol that is found in plants, including flaxseed, sesame seeds, and
walnuts. They have antioxidant and anti-cancer properties.

3.5. Stilbenes
Stilbenes are a type of polyphenol that is found in grapes, red wine, and peanuts. They have
antioxidant and anti-cancer properties.

3.6. Xanthones
Xanthones are polyphenolic compounds with the following basic structure:
4. Glycosides
A glycoside is a compound formed when a sugar molecule through its anomeric carbon is
bonded to another (non-sugar) molecule. The sugar part is called a glycone while the non-sugar
part is called an aglycone. The bond between the sugar and the aglycone is called a glycosidic
bond.

Salicin (a glycoside of beta-glucose; so, it is a beta-glucoside)

[The formation of a glycosidic bond is an example of an acetal formation reaction. In an acetal

formation reaction, a hemiacetal group reacts with another hydroxyl group to form an acetal
group. A hemiacetal group is a molecule that has a hydroxyl group bonded to an aldehyde or
ketone group].
In the case of glycoside formation, the hemiacetal group is the anomeric hydroxyl group of a
monosaccharide. The anomeric hydroxyl group is the hydroxyl group that is bonded to the
carbon atom that was originally part of the aldehyde group of the monosaccharide. The other
molecule that reacts with the anomeric hydroxyl group to form the glycosidic bond is the
aglycone. Aglycone can be any molecule, but it is most commonly an alcohol, an acid, or an
amine.

The glycosidic bond is a type of ether bond. Ether bonds are relatively stable bonds, and they are
not easily broken down. This makes glycosides relatively stable compounds.

Glycosides are found in many plants and animals. They play a variety of roles in biology,
including:

Energy storage: Glycosides can be stored in plants and animals and used as a source of energy.
Glycosides can contribute to the taste of foods and beverages. Glycosides have a variety of
pharmacological properties, and they are used in a variety of medicines.
Here are some examples of glycosides:

Sucrose: Sucrose is a glycoside that is commonly known as table sugar. It is made up of a

glucose molecule and a fructose molecule.
Lactose: Lactose is a glycoside that is found in milk. It is made up of a glucose molecule and a
galactose molecule.
Glycoproteins: Glycoproteins are proteins that have carbohydrates attached to them. The
carbohydrates are attached to the proteins through glycosidic bonds.
Glycolipids: Glycolipids are lipids that have carbohydrates attached to them. The carbohydrates
are attached to the lipids through glycosidic bonds.
Saponins: Saponins are glycosides that have foaming properties.

Glycosides are a diverse group of compounds with a wide range of biological properties. They
are found in many plants and animals and are used in a variety of ways.
There are many different types of glycosides, and they can be classified in a number of different
ways. One way to classify glycosides is by the type of sugar molecule that they contain. The
most common types of sugar molecules found in glycosides are glucose, fructose, and galactose.

Here are some examples of different types of glycosides:

a) Glucosides: Glycosides that contain a glucose molecule as a glycone. For example,
salicin is a glucoside found in willow bark that has anti-inflammatory properties.
b) Fructosides: Glycosides that contain a fructose molecule as the glycone. For example,
sucrose is a fructoside that is commonly known as table sugar.
c) Galactosides: Glycosides that contain a galactose molecule as the glycone. For example,
lactose is a galactoside that is found in milk.
d) Saponins: Glycosides that have foaming properties. For example, saponins are found in
soapwort and are used to make soap.
e) Cardenolides (cardiac glycosides): Glycosides that have cardiac stimulatory or inhibitory
properties. For example, digoxin is a cardiac glycoside that is used to treat heart failure.
 Oleandrin: a cardiac glycoside, a potent toxic
compound extracted from the Oleander bush. Its aglycone is oleandrigenin

Digitoxin: a cardiac glycoside found in Digitalis lanata

and Digitalis purpurea. Its aglycone is digitoxigenin

4.1. Saponins
Saponins are a group of glycosides that have foaming properties. They are found in many plants,
including soapwort, yucca, and soybeans. Saponins are also found in some animals, such as the
venom of certain snakes. Saponins are named after the Latin word sapo, which means "soap".
This is because saponins can create a foam when they are mixed with water. The foam is created
by the saponins' ability to lower the surface tension of water.

Saponins have a number of biological properties, including:

a) Foaming: Saponins create a foam when they are mixed with water. This foam can be used to
clean surfaces or to make soap.
b) Anti-inflammatory: Saponins have anti-inflammatory properties. They can help to reduce
inflammation caused by allergies, arthritis, and other conditions.
c) Immunomodulatory: Saponins can modulate the immune system. They can help to boost the
immune system or to suppress it, depending on the type of saponin.
d) Hypolipidemic: Saponins can lower cholesterol levels. They can also help to reduce the risk
of heart disease.
e) Hepatoprotective: Saponins can protect the liver from damage. They can help to prevent liver
damage caused by alcohol, drugs, and other toxins.

Saponins are used in a variety of ways, including:

a) Medicine: Saponins are used in traditional medicine to treat a variety of conditions,
including inflammation, allergies, and high cholesterol.
b) Cosmetics: Saponins are used in cosmetics to create foam and to cleanse the skin.
c) Food industry: Saponins are used in the food industry to create foam and to improve the
texture of foods.
d) Agriculture: Saponins are used in agriculture to control pests and diseases.
Saponins are generally considered to be safe for most people. However, some people may
experience side effects, such as diarrhea or vomiting. If you are considering taking a supplement
that contains saponins, it is important to talk to your doctor first.

Saponins are classified into different types based on the aglycone, which is the non-sugar part of
the molecule. The most common types of saponins are:
a) Triterpenoid saponins: Triterpenoid saponins are the most common type of saponin. They
are found in plants such as soapwort, yucca, and soybeans. The aglycone of triterpenoid
saponins is a triterpene, which is a type of lipid.
b) Sterol saponins: Sterols are a type of lipid that is similar to triterpenes. Sterols are found
in plants, animals, and fungi. The aglycone of sterol saponins is a sterol.
c) Flavonoid saponins: Flavonoids are a type of polyphenol that is found in plants. The
aglycone of flavonoid saponins is a flavonoid.
d) Phenolic saponins: Phenolic saponins are a type of saponin that contains a phenol group.
Phenols are a type of organic compound that contains a hydroxyl group bonded to an
aromatic ring.
e) Alkaloid saponins: Alkaloids are a type of nitrogen-containing compound that is found in
plants. The aglycone of alkaloid saponins is an alkaloid.

Saponins can also be classified according to the number of sugar molecules that they contain.
Monosaccharide saponins contain one sugar molecule, disaccharide saponins contain two sugar
molecules, and trisaccharide saponins contain three sugar molecules.