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52
Pharmaceutical Chemistry of Natural Products
CH OCH
23
HO
HCO
3
H
H
H
OCH
3
O
CH OCH
23
H
H
HCO
3
H
H
OH
H
OCH
3
OCH
3
C
CH OCH
23
O
2,3,4,6-Tetra- -
methyl- -glucose
O
D
1,3,4,6-Tetra- -
methyl- -fructose
O
D
Dil. HCl
(Hydrolysis)
This structure for sucrose is confi rmed by several physical and chemical evidences.
Periodic acid oxidation: Sucrose (I) consumes 3 moles of periodic acid and forms 1 mole of formic
acid and a tetra-aldehyde (II). Oxidation with bromine followed by acid hydrolysis gives glyoxalic
acid (III), glyceric acid (IV) and hydroxypyruvic acid (V). This confi rms the structure of sucrose
(except the nature of the glycosidic link).
3H IO
56
HCOOH
CHO
CHO
C
CH OH
2
H
H
O
O
H
CH OH
2
CHO
CHO
O
CH OH
2
(i) Br
-water
(ii) Hydrolysis
2
CHO
COOH
C
COOH
OHH
CH OH
2
2
CH OH
2
COOH
CO
III
IIIIVV
CH OH
2
O
HO
H
OHH
H
H
H
OH
1
2
3
C
O
HO
H
H
H
OH
CH OH
2
CH OH
2
O
X-ray analysis: The X-ray analysis of sucrose sodium bromide dihydrate confi rms the stereochemical
confi guration and also the fi ve-membered ring of fructose.
Carbohydrates
53
Synthesis of sucrose: Further, the above structure of sucrose is confi rmed by the following synthesis.
CH OAc
2
H
OAc
PCl
5
O
H
OAc
H
H
OAc
OAc
H
H
OAc
CH OAc
2
H
OAc
H
H
OAc
O
Cl
H
H
OAc
CH OAc
2
H
OAc
H
O
O
H
OH
i) NH
in
ether
3
ii) NH in
benzene
3
Opening of
the oxide ring
CH OAc
2
O
OH
H
OAc
OAc
H
H
CH OAc
2
H
OAc
H
OAc
H
H
OH
O
OAc
CH
2
Heat in a
sealed tube
at 100°C for
104 h
CH OAc
2
H
OAc
H
OAc
H
H
OH
O
O
O
H
CH OAc
2
H
OAc
H
H
OAc
CH OAc
2
Removal of
acetyl group
Sucrose
1,3,4,6-Tetra- -acetyl-
-fructofuranose
O
D
1,2-Anhydro- − -glucopyranose
3,4,6-triacetate
α DTetra- -acetyl- − -glucoseO β D
H
Lactose
(Synonyms: Lactin, milk sugar, sugar of milk, saccharum lactis, 4-β-D-galactopyranosyl-D-
glucopyranose)
Lactose
Or
H
OH
O
CH OH
2
H
OH
H
H
OH
HH
O
H
OH
CH OH
2
H
OH
OH
H
H
O
1
2
3
4
5
6
1
2
3
4
5
6
CH OH
2
HC
C
C
C
C
CH
HO
H
H
OH
O
H
H
HO
O
H
HO
HO
H
H
H
O
CH OH
2
OH
1
2
3
4
5
6
C
C
C
C
1
2
3
4
5
6
54
Pharmaceutical Chemistry of Natural Products
Lactose is a natural disaccharide found exclusively in the milk of mammals and consists
of galactose and glucose in a β-(1,4) glycosidic bond. It is an odourless, white or almost white,
crystalline powder, having faintly sweet taste. It is stable in air but readily absorbs odours. Several
varieties of lactose are available such as (1) anhydrous α-lactose, (2) α-lactose monohydrate, and
(3) anhydrous β-lactose. Cow’s milk contains 4–6% and human milk contains 5–8% of lactose.
It is used as fi ller or diluent in tablets, capsules, infant feed formulae and in dry powder
inhalations. To prepare sugar-coating solutions, it is used in combination with sucrose. It is also
used in the preparation of tablet by wet granulation method.
Chemical tests
1. On warming a mixture of 5 mL of a hot saturated solution of lactose and 5 mL of sodium
hydroxide, the liquid becomes yellow and fi nally brownish red. Upon adding several drops
of cupric sulphate, a red precipitate of cuprous oxide forms.
2. Dissolve 0.25 g of lactose in 5 mL of water and add 5 mL of 10 M ammonia; then heat the
mixture in water bath at 80°C for 10 min. Colour develops.
Structural elucidation
1. Molecular formula: Molecular formula of lactose is found to be C
12
H
22
O
11
.
2. Presence of free carbonyl group: Lactose reduces Fehling’s reagent, Benedict’s reagent
and Tollens’ reagent. It also reacts with phenyl hydrazine and forms osazone. Therefore,
lactose must possess at least one carbonyl group that is not involved in the disaccharide
linkage.
3. Hydrolysis: Upon enzymatic (lactase) hydrolysis or acidic hydrolysis, lactose gives equimolar
amounts of glucose and galactose.
4. Nature of linkage between the monosaccharides: Because lactose is hydrolysed
only by lactase (identical with emulsin), the two monosaccharide units are linked through
β-glycosidic linkage. This is also indicated by its two specifi c rotations.
5. Reducing half of lactose: Methylation of lactose yields methyl heptamethyl lactoside,
which on vigorous hydrolysis yields 2,3,4-tri-O-methyl-D-glucose and 2,3,4,6-tetra-O-
methyl galactose indicating that the glucose unit constitutes the reducing half of lactose.
6. Oxidation: Lactose on oxidation with bromine water yields lactobionic acid, which upon
methylation followed by hydrolysis gives 2,3,5,6-tetra-O-methyl-D-gluconic acid and
2,3,4,6-tetra-O-methyl-D-galactose. This reveals that in lactose, C
4
of glucose is linked to C
1
of galactose.
7. Point of linkage: Further, the point of linkage (C
4
) of glucose is confi rmed by osazone
formation and Zemplen degradation.
Or
H
OH
O
CH OH
2
H
OH
H
H
OH
HH
O
H
OH
CH OH
2
H
OH
OH
H
H
O
Lactose
CH OH
2
HC
CH
HO
H
H
OH
O
H
H
HO
O
H
HO
HO
H
H
H
O
CH OH
2
OH
Lactose
Carbohydrates
55
HO
OH
HOH C
2
O
H
OH
H
O
H
H
O
H
H
HO
H
HOH C
2
H
H
OH
H
OH
Conformational structure of lactose
8. Synthesis: Lactose has been synthesized by the condensation of acetobromogalactose and
1,2,3,6-tetra-O-acetyl-β-D-glucopyranoside.
Maltose
[Malt sugar, 4-(α-D-glucopyranosyl)-α- or β-glucopyranose]
CHOH
OH
HO
C
O
H
H
H
H
CH OH
2
CH OH
2
C
C
C
C
C
C
C
C
O
O
H
H
HO
H
H
OH
OH
H
1
2
3
4
5
6
1
2
3
4
5
6
Maltose, also known as malt sugar, is composed of two glucose monomers in an α-(1,4)
glycosidic bond. Acid hydrolysis of starch gives maltose as an intermediate, which upon further
hydrolysis, yields glucose. The action of diastase (an enzyme in malt) upon starch also produces
maltose. Fermentation of sucrose to ethanol at one stage also produces maltose.
Structural elucidation
1. Molecular formula: Molecular formula of maltose is found to be C
12
H
22
O
11
.
2. Hydrolysis:
(a) Acid hydrolysis: Hydrolysis of maltose yields only D-glucose indicating that glucose is
the only monosaccharide unit present.
As maltose reduces Fehling’s, Benedict’s and Tollens’ reagents, it is oxidized by bromine
water to maltonic acid (or maltobionic acid), reacts with phenyl hydrazine, forms
osazone and exhibits mutarotation. This revels that it must have an aldehyde group in
one of the units.
(b) Enzymatic hydrolysis: Maltose is hydrolysed by maltase and by emulsin, which reveals
that the linkage joining the reducing half of the maltose to the nonreducing half is an
α-linkage.
56
Pharmaceutical Chemistry of Natural Products
3. Ring size of the monosaccharides: The size of the ring of monosaccharide units is
established as follows:
Maltose is oxidized to maltonic acid (II) (i.e. the latent aldehyde group is oxidized to carboxyl
group) upon oxidation with bromine water. Complete methylation of maltonic acid to
methyl octa-O-methyl maltonate (III) and then by hydrolysis gives 2,3,4,6-tetra-O-methyl-
D-glucopyranose (IV) (from the glucoside component) and 2,3,5,6-tetra-O-methyl gluconic
acid (V) (from the alcohol component). The existence of free hydroxyl groups at positions C
1
and C
4
in these products reveals that the glycosidic linkage in maltose is involved between
these carbon atoms, and that the original ring size in maltose was pyranose. Therefore,
maltose may be written as (I), which explains all the above degradations.
CHOH
H
HO
OH
O
C
H
H
H
O
H
H
HO
H
H
OH
H
OH
O
CH OH
2
CH OH
2
H
HO
H
H
OH
H
OH
COOH
CH OH
2
O
CH
H
H
H
HO
OH
H
OH
O
CH OH
2
COOH
H
CH OCH
23
O
C
CHOH
OH
HCO
3
H
H
OCH
3
H
OCH
3
H
HCO
3
H
H
OCH
3
H
OCH
3
CH OCH
23
H
HCO
3
H
H
COOCH
3
OCH
3
H
OCH
3
CH OCH
23
O
H
H
HCO
3
H
H
O
OCH
3
H
OCH
3
CH OCH
23
HC1
Methyl ester of octa- -
methylmaltonic acid (III)
O
(CH)SO
32 4
Maltonic acid (II)Maltose (I)
Br water
2
(V) (IV)
+
Carbohydrates
57
CHOH
O
H
HO
OH
O
O
H
H
H
H
H
H
H
HO
OH
H
OH
CH OH
2
CH OH
2
C
CHOH
HO
H
HOH
H
O
O
H
H
H
H
HO
C
O
CH OH
2
CH
2
CHOH
H
HOH
O
O
C
O
H
H
H
HO
OH
H
(Wohl degradation)
(i) NH
OH
2
Maltose (forms osazone) Glucosidoarabinose (forms osazone)
(i) NH
OH
(ii) Ac
O
(iii) C
H ONa
2
2
25
(Wohl
degradation)
Glucosidoerythrose (does not form osazone)
CH
2
CH OH
2
(ii) Ac O
(iii) C
H ONa
2
25
OH
H
OH
4. Anomeric nature: Lastly, it must be noted that the presence of free CHOH in maltose
causes it to exist in two different anomers (α and β).
H
OH
O
H, OH
CH OH
2
H
OH
H
H
OH
CH OH
2
HH
O
H
OH
OH
H
H
O
Nonreducing half Reducing half
CH OH
2
CH OH
2
HOH
C
O
CHOH
HO H
H
H
O
O
H
H
H
H
HO
OH
H
OH
Reducing half Nonreducing half
Or
58
Pharmaceutical Chemistry of Natural Products
HO
OH
HOH C
2
H
HO
H
O
H
H
H
O
H
HOH C
2
O
H
OH
OH
H
HO
H
H
Maltose
or
4-( -Glucopyranosyl)- -glucopyranose
1-(4 -Glucopyranosyl)- -glucopyranose
aa
a
D--
--
D
DD
5. Mutarotation: The existence of two anomeric maltoses explains the phenomenon of
mutarotation.
6. Synthesis: Lemient et al. have synthesized maltose exactly in the same way as sucrose.
CH OAc
2
H
OAc
H
OAc
H
H
OAc
O
O
HH
CH OAc
2
H
OAc
H
H
OAc
O
OAc
H
Ac O
2
H
OAc
CH OAc
2
CH OAc
2
H
OAc
H
O
H
OH
HH
O
H
OAc
H
O
H
OAc
OAc
H
Deacetylation
Maltose
CH OAc
2
H
OAc
O
H
H
OAc
HO
H
+
H
OH
CH OAc
2
H
OAc
H
OAc
H
O
OAc
H
1,2-Anhydro-3,4,6-tri-O-
acetyl- -D-glucopyranoseα
1,2,3,6-tetra-O-
acetyl- -D-glucoseβ
Heat at 120°C
for 13 h
Octa-acetyl- - -maltose
D
Hepta-acteyl- - -maltose
D
Carbohydrates
59
Trehalose
(α-D-glucopyranosyl-α-D-glucopyranoside)
H
HO
C
C
C
C
C
H
H
H
OH
H
OH
O
O
C
C
C
CC
C
O
OH
H
OH
H
H
HO
H
H
CH OH
2
CH OH
2
1
2
3
4
5
6
1
2
3
4
5
6
H
OH
CH OH
2
H
OH
H
H
OH
HH
O
O
H
OH
OH
H
O
H
H
OH
HOH C
2
1
2
3
4
5
6
1
2
3
4
5
6
It is a disaccharide found in mushrooms, yeasts and fungi.
Structural elucidation
1. Molecular formula: Molecular formula of trehalose is found to be C
12
H
22
O
11
.
2. Linkage between two glucose units: It shows the properties of nonreducing
monosaccharides. Thus, the two glucose units are linked to each other through their C-1
hydroxyl groups.
3. Hydrolysis: Upon hydrolysis with dilute hydrochloric acid, it yields two molecules of
D-glucose.
4. Acetylation: Upon acetylation it forms octa-acetate, which indicates the presence of eight
hydroxyl groups.
5. Nature of ring structure of glucose: On complete methylation followed by hydrolysis,
it gives 2 moles of 2,3,4,6-tetra-O-methyl-D-glucopyranose, thus indicating that both of the
glucose units are present as pyranose rings in trehalose. These pyranose rings are further
confi rmed by periodic acid oxidation (which shows that 4 moles of the acid are used to
yield 2 moles of formic acid (for details, refer to page 37).
6. Nature of linkage: The high specifi c rotation [α]
D
= +197° indicates that two glucose
residues are linked by α,α′-linkages.
7. Structure of trehalose: Thus, trehalose may be proposed as follows.
H
OH
CH OH
2
H
OH
H
H
OH
HH
O
O
H
OH
OH
H
O
H
H
OH
HOH C
2
Haworth structure of trehalose
H
OH
CH
H
H
OH
H
OH
O
O
C
O
OH
H
OH
H
H
OH
H
H
CH OH
2
CH OH
2
Trehalose ( −D-Glucopyranosyl- '-D-Glucopyranoside)αα
This structure has been fi nally confi rmed by synthesis.
60
Pharmaceutical Chemistry of Natural Products
TRISACCHARIDES
These are sugars that upon hydrolysis give three units of monosaccharides. Some trisaccharides
occur naturally (gentianose, raffi nose and manninotriose), whereas the others are obtained by
partial hydrolysis of polysaccharides (e.g. cellotriose from cellulose and maltotriose from starch).
Trisaccharides may be reducing or nonreducing in nature. Their structures are elucidated
as the disaccharides. Some of the trisaccharides, their composition and nature are listed in
Table 2.2.
Table 2.2 Trisaccharides, their types and composition
Trisaccharide Constituent monosaccharides Type
Raffi nose
Fructose–glucose–galactose Nonreducing sugar
Gentianose Fructose–glucose–glucose Nonreducing sugar
Mannotriose Galactose–galactose–glucose Reducing sugar
Rhamnose Galactose–rhamnose–rhamnose Reducing sugar
Gentianose
O
H
CH
2
H
OH
H
OH
H
H
OH
O
H
O
CH OH
2
O
H
OH
OH
H
H
CH OH
2
D
-Fructofuranose
OH
H
HOH
CH OH
2
H
OH
H
O
1α
1α
2β
D-GlucopyranoseD-Glucopyranose
Gentiobiose
Sucrose
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
It is a nonreducing sugar that gives 2 moles of D-glucose and 1 mole of D-fructose upon hydrolysis.
It occurs in gentian roots. Its structure is established exactly in the same manner as that of
disaccharides.
Structural elucidation
1. Molecular formula: Molecular formula of gentianose is found to be C
18
H
32
O
16
.
2. Enzymatic hydrolysis: Upon hydrolysis with invertase it gives D-fructose and gentiobiose,
while with emulsin it yields
D-glucose and sucrose. Thus, in gentianose two glucose and
one fructose units are combined so as to give gentiobiose and sucrose, i.e. the arrangement
of the three monosaccharide molecules is as glucose–glucose–fructose.
Carbohydrates
61
3. Structure of gentianose: As the structure of glucose and fructose are known, gentianose
structure is drawn as below:
O
H
CH
2
H
OH
H
OH
H
H
OH
O
H
O
CH OH
2
O
H
OH
OH
H
H
CH OH
2
D
-Fructofuranose
OH
H
HOH
CH OH
2
H
OH
H
O
1α
1α
2β
D-GlucopyranoseD-Glucopyranose
Gentiobiose
Sucrose
TETRASACCHARIDES
These are sugars that on hydrolysis give four units of monosaccharides. Some tetrasaccharides occur
naturally (stachyose), whereas the others are obtained by partial hydrolysis of polysaccharides.
Tetrasaccharides may be reducing or nonreducing in nature. Their structure is elucidated similar
to disaccharides.
Stachyose
OH
H
HOH
1
2
3
4
5
CH OH
2
H
OH
H
O
1
23
4
5
6
H
O
1α
CH
2
H
OH
H
H
OH
OH
H
O
6
O
H
CH
2
H
OH
H
OH
H
H
OH
O
1
2
3
4
5
6
H
O
CH OH
2
O
H
OH
OH
H
H
CH OH
2
1
2
3
4
5
6
D
-Galactopyranose D-Galactopyranose D-Glucopyranose
D-Fructofuranose
Stachyose occurs in the roots of several plant species and is an important example of
tetrasaccharides.