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42
Pharmaceutical Chemistry of Natural Products
Conformations of Monosaccharides
The arrangement of atoms and groups in space of a single chemical structure is termed as
conformation. Similar to cyclohexane, the pyranose sugars and their derivatives assume a chair
conformation in preference to any boat form. The chair form is more stable compared to boat form
because of the minimum hydrogen interactions in the chair conformation. The chair conformation
of α- and β-glucose is depicted below.
HO
OH
H
O
CH OH
2
HO
OH
H
H
H
H
HO
H
H
H
H
H
OH
HO
CH OH
2
OH
O
α D-Glucose (36%)- β D-Glucose (64%)-
As the β-form is more stable, it is predominant which in turn is due to the fact that the OH
or CH
2
OH groups on C
1
, C
2
, C
3
, C
4
and C
5
are all equatorial than in the α-form in which although
hydroxyl groups on C
2
, C
3
and C
4
and the CH
2
OH group on C
5
are all equatorial, the hydroxyl
group at C
1
is axial.
Monosaccharides of Pharmaceutical Importance
Among the natural hexose sugars, D-glucose, D-mannose, D-galactose and D-fructose are the
important members. It is also interesting to note that these four sugars are also fermented by
yeast.
D(+) Glucose (dextrose)
HO
H
H
H
OH
OH
CH OH
2
C
CHO
C
C
C
*
*
*
*
OHH
1
2
3
4
5
6
The D-glucose is a six-carbon containing aldose sugar and is the most important and widely
distributed monosaccharide. It is also known as dextrose of grape sugar and occurs in many
plants in free as well as combined state. It is the component of glycosides, disaccharides and
polysaccharides. The important sources of glucose are ripe grapes (20–30%), cane sugar (in which
glucose occurs in combination with fructose), honey, human blood and urine of diabetic patients.
Carbohydrates
43
Human blood contains 0.15% of glucose. Calcium salt of gluconic acid is used as an intravenous
calcium supplement.
Biological importance
1. It is the chief sugar present in the normal blood.
2. Erythrocytes and brain cells utilize glucose solely for energy purposes.
3. It is stored mainly as glycogen in liver and muscles.
Chemical tests: Apart from answering for the general reactions of the reducing monosaccharides, it
gives red precipitate with cupric tartaric solution.
Preparation of glucose: Commercially, glucose is obtained by the acidic hydrolysis (using dilute
mineral acids) of starch, usually corn starch. Glucose is obtained as glucose monohydrate by
crystallization from water.
(C
6
H
10
O
5
)
n
+ nH
2
O C
6
H
12
O
6
Structural elucidation
1. Molecular formula: Molecular formula of glucose is found to be C
6
H
12
O
6
.
2. Presence of 5-OH groups: Glucose gives penta-acetate on acetylation with acetic
anhydride and sodium acetate, indicating the presence of fi ve hydroxyl groups.
3. Presence of an aldehydic group: With hydrogen cyanide, glucose forms cyanohydrins;
phenylhydrazone with phenyl hydrazine and a mono-oxime with hydroxylamine,
indicating the presence of a carbonyl group.
Glucose reduces Fehling’s solution and Tollens’ reagent, which suggests that carbonyl group
may be aldehydic or ketonic. Glucose on oxidation yields gluconic acid having the same
number of carbon atoms, which confi rms the presence of carbonyl group as an aldehyde
group. As the aldehydic group is monovalent, it must be present at the end of the chain.
C
5
H
11
O
5
CHO C
5
H
11
O
5
COOH
Glucose Gluconic acid
4. Presence of straight chain (of carbon atoms): Glucose upon reaction with hydrogen
cyanide yielded cyanohydrins, which on hydrolysis followed by reduction with hydriodic
acid and red phosphorus yielded n-heptanoic acid. The formation of n-heptanoic acid from
glucose indicates that the glucose has a straight chain of six carbon atoms.
C H O
5115
CHO
HO
2
C H O
5115
CH(OH)COOHC H O
5115
CH(OH)CN CH
613
COOH
HI–P
n-Heptanoic acid
5. Open-chain structure of glucose
Glucose contains a straight chain of six carbon atoms.
Of the two ends, one end is having the aldehyde group and the other end is having the
primary alcoholic group.
The remaining four carbon atom bear one hydroxyl each.
From the above points, it is suggested that glucose is a straight-chain pentahydroxy aldehyde
of the following structure.
44
Pharmaceutical Chemistry of Natural Products
HO
H
H
H
OH
OH
CH OH
2
C
CHO
C
C
C
*
*
*
*
OHH
Glucose
6. Confi guration of glucose: As the above structure of glucose possesses four asymmetric
carbon atoms (marked by asterisks), sixteen (2
4
= 16) optical isomers are possible. The
confi guration of glucose (arrangement of hydrogen and hydroxyl groups around the four
asymmetric carbon atoms) is determined by the use of Kiliani’s synthesis (discussed earlier;
refer to page 18).
The open-chain structure of glucose failed to explain some of the characteristic reactions of
glucose. (refer to page 28).
The objections against the open chain structure are explained by the ring structure for
glucose in the following ways (refer to page 29).
7. Mutarotation: When glucose prepared by crystallization from water below 50°C is
dissolved in water, its initial specifi c rotation of +113° falls gradually to a constant value
of +52.5°. Similarly, when the glucose crystallized from water above 95°C is dissolved in
water, its initial specifi c rotation of +19° gradually rises to +52.5°. This phenomenon is
known as mutarotation.
The ring structure for glucose explains that the change in specifi c rotation is due to
interconversion of the α-form [(α)
D
= +113°] of glucose to β-form [(α)
D
= +19.5] and
vice versa through the aldehydic structure till an equilibrium is reached between the two
structures. The specifi c rotation value of this equilibrium mixture corresponds to +52.5°.
8. Two types of ring structures: Glucose is found to possess two different ring structures,
namely γ- and δ-oxide ring structures.
Determination of the ring size of the glucose ring is described in page 32.
D(–) Fructose
HO
H
H
H
OH
OH
CH OH
2
CO
CH OH
2
C
C
C
*
*
*
*
1
2
3
4
5
6
Carbohydrates
45
The D-(levo)-fructose is a six-carbon containing ketose sugar. It is also known as levulose or
fruit sugar and is found in many fruits and honey. Fructose is obtained from invert sugar after
separating it from glucose. It is used as a food and sweetener for patients who cannot tolerate
glucose, e.g. patients suffering from diabetes. It has the sweetness of sucrose, and about twice that
of glucose. High-fructose containing corn syrup produced by enzymic hydrolysis/isomerization of
starch is used as a food sweetener. It is the most important sugar of ketoses and occurs as free sugar
along with glucose in honey and sweet fruits, and therefore, it is called fruit sugar. It also occurs
in combination with glucose in cane and beet sugars. The most important source of fructose is the
polysaccharide inulin.
It exhibits mutarotation; the specifi c rotation values of α, β and equilibrium mixtures are
21°, 133.5° and 92.3°, respectively. Fructose shows most of the usual properties of the ketonic
and hydroxyl groups. It reduces Fehling’s solution and Tollens’ reagent, due to the presence of
α-hydroxyl ketonic group, which is readily oxidized by Fehling’s and Tollens’ reagents.
Preparation: Commercially, fructose is obtained by the hydrolysis of inulin (a polysaccharide of
fructose).
Biological importance
Seminal fl uid is rich in fructose and sperms utilize fructose for energy. Fructose is formed in the
seminiferous fi bular epithelial cells from glucose.
Structural elucidation
1. Molecular formula: Molecular formula of fructose is found to be C
6
H
12
O
6
.
2. Presence of 5-OH groups: Fructose gives penta-acetate on acetylation with acetic
anhydride, indicating the presence of fi ve hydroxyl groups.
3. Presence of a ketonic group: Fructose forms cyanohydrin and oxime, which reveals the
presence of a carbonyl group. On oxidation with nitric acid, fructose gives a mixture of
tartaric acid and glycolic acids (each having lesser number of carbon atoms), which reveals
that the carbonyl group is ketonic in nature. The formation of glycolic and tartaric acids
reveals that the ketonic group is present at position 2.
CH OH
CO
CHOH
2
2
CHOH
CHOH
CH OH
CH OH
COOH
2
COOH
CHOH
CHOH
COOH
Glycolic acid
Fructose Tartaric acid
4. Presence of straight chain of carbon atoms: Upon reduction with sodium amalgam
and ethanol, fructose yields hexahydric alcohols, sorbitol and mannitol, which on further
reduction with hydriodic acid and red phosphorus yield 2-iodohexane and n-hexane,
which indicates that in fructose molecule the six carbon atoms are present in a straight
chain.
46
Pharmaceutical Chemistry of Natural Products
Fructose on treatment with hydrogen cyanide gives cyanohydrins, which upon hydrolysis
followed by reduction with hydriodic acid and red phosphorus yields n-butylmethylacetic
acid, CH
3
CH
2
CH
2
CH
2
CH(CH
3
)COOH (I). Formation of the above acid (I) also reveals the
presence of ketonic group at position 2.
5. Open-chain structure of fructose: Based on the above points the straight chain structure
of fructose may be written as below.
CH
CHCOOH
CH
3
2
2
2
3
CH
CH
CH
CH OH
CO
CHOH
2
2
CHOH
CHOH
CH OH
*
*
*
CH OH
COOH
2
COOH
CHOH
CHOH
COOH
i) HCN
ii) H O
2
iii) HI–P
HNO
3
(I)
6. Confi guration of fructose: As the above structure has three asymmetric carbon atoms,
it may exist in eight (2
3
= 8) optical isomers. The exact confi guration of the fructose is
recognized by the fact that it yields the same osazone as glucose, thereby revealing that the
confi gurations of C
3
to C
6
atoms of fructose are same as that of glucose. Hence, the complete
structural formula of fructose may be written as shown below.
CH OH
2
CO
HO
OHH
H
H
OH
CH OH
2
3C H NHNH
65
2
HO
H
H
H
OH
OH
CH OH
2
C
CH N.NHC H
65
N.NHC H
65
3C H NHNH
65 2
H
HO
H
H
OH
H
OH
OH
CH OH
2
CHO
Fructose
Osazone
Glucose
The open-chain structure of fructose fails to explain some of the facts (described in detail
on to page 28).
7. The objections against open-chain structure are explained by the ring structure of
fructose: Like glucose, fructose also exhibits mutarotation and forms two isomeric methyl
fructosides. Hence, fructose is assumed to exist in two isomeric (α and β) forms. The ring
structure of fructose is already discussed on page 32.
Fructose shows levorotatory properties and has
D-confi guration of glucose, and therefore,
it is denoted as D(–) fructose.
The commercial and natural fructose is the β-isomer with a pyranose ring. But the fructose
found in sucrose (a disaccharide) and inulin (a polysaccharide) is present in the furanose
ring, which upon hydrolysis is converted into the more stable pyranose form.
Carbohydrates
47
DISACCHARIDES
Covalent bonds between the anomeric hydroxyl of a cyclic sugar and the hydroxyl of a second
sugar (or another alcohol containing compound) are termed as glycosidic bonds and the resultant
molecules are called glycosides. The linkage of two monosaccharides to form disaccharides involves
a glycosidic bond.
C H O C H O
6
12 6 6 12 6
C H O H O
12
22 11 2
Hexose Hexose Dihexose
or
Disaccharide
The reverse reaction yields two individual monosaccharides (hydrolyses by enzymes and dilute
mineral acids), which is a characteristic reaction of all the disaccharides. Physiologically important
disaccharides are sucrose, lactose and maltose.
Biological Importance of Disaccharides
1. Various food preparations such as baby foods are produced by hydrolysis of grains and contain
large amounts of maltose. From nutritional point of view, disaccharides are easily digestible.
2. In lactating mammary gland, the lactose is synthesized from glucose by the duct epithelium.
Lactose present in breast milk is a good source of energy for the new born baby.
3. Lactose is fermented by coliform bacilli (Escherichia coli), which is usually nonpathogenic,
and not by typhoid bacillus, which is pathogenic (lactose nonfermenter). This test is used to
distinguish the two microorganisms.
4. Many organisms that are found in milk (e.g. E. coli, Aerobacter aerogenes) convert milk to lactic
acid.
5. Sucrose, if administered parenterally, cannot be utilized by human body, but it can change
the osmotic condition of the blood and cause fl ow of water from the tissues into blood.
Classification and Nomenclature of Disaccharides
In the formation of disaccharide at least one monosaccharide molecule must be linked through the
glycosidic carbon (C
1
). The second monosaccharide is linked to the C
1
of the fi rst monosaccharide
either through C
1
, C
4
or C
6
of the second monosaccharide. Thus, on the basis of these linkages the
disaccharides are classifi ed into three groups. They are as follows:
Nonreducing disaccharides
Disaccharides linked through the C
1
of one monosaccharide to
C
1
of other monosaccharide
Like simple glycosides these disaccharides, which do not have free carbonyl group, are called
nonreducing disaccharides. The reducing carbon of each monosaccharide is involved in the glycosidic
linkage of the two monosaccharides. Common examples are sucrose and trehalose.
48
Pharmaceutical Chemistry of Natural Products
Reducing disaccharides
Disaccharides linked through C
1
of the first monosaccharide and C
4
of the second
monosaccharide component
One monosaccharide unit is linked by the reducing carbon at C
1
to the nonreducing carbon C
4
of
the second monosaccharide unit. Hence, the reducing carbon at C
1
of the second monosaccharide is
free, i.e. it can be easily opened to hemiacetal function and thus such disaccharides reduce Fehling’s
solution, undergo mutarotation in solution and form osazones. Therefore, such disaccharides are
known as reducing disaccharides. Examples are lactose and maltose.
They are called glycosylaldoses or glycosylketoses. Either of the anomers (α or β) of the glycosidic
unit may be involved, and therefore, two isomers arise.
Disaccharides linked through C
1
of the first monosaccharide and C
6
the second
monosaccharide component
One monosaccharide unit is linked by the reducing carbon at C
1
to the nonreducing carbon C
6
of the second monosaccharide unit. Hence, like the above type of disaccharides, they are called
reducing disaccharides. Examples are gentiobiose and melibiose.
Nomenclature of disaccharides
The main use of this nomenclature is to emphasize structural and confi gurational relationship.
A simple way of naming the disaccharides is as follows:
1. The reducing sugars are named as glycosylaldoses or glycosylketoses. Thus, maltose is named as 4-O-
α-D-glucopyranosyl-D-glucopyranose and gentiobiose is named as 6-O-β-D-glucopyranosyl-
D-glucopyranose.
2. The nonreducing sugars are named as glycosylaldosides or glycosylketosides. Trehalose is named
as α-D-glucopyranosyl-α-D-glucopyranoside.
The conventions in the systemic nomenclature of the oligosaccharides are described below:
1. Give the confi guration (or) at the anomeric carbon linking the fi rst monosaccharide unit (on
the left) to the second.
2. Name the nonreducing residue, and to distinguish fi ve- and six-membered ring structures,
insert furano or pyrano into the name.
Disaccharides
ReducingNonreducing
(C – C glycosidic linkage)
11
Example: Sucrose
glycosidic linkage)(C – C
14
glycosidic linkage)(C – C
16
Example: Lactose Example: Gentiobiose
Carbohydrates
49
3. Indicate in parentheses the two carbon atoms joined by the glycosidic bond, with an arrow
connecting the two numbers; for example, (1→4) shows that C-1 of the fi rst named sugar
residue is joined to C-4 of the second.
4. Name the second residue. If there is a third residue, describe the second glycosidic bond by
the same convention (to shorten the description of complex polysaccharides, abbreviations
for the monosaccharides are often used).
Following this convention for naming oligosaccharides, maltose is α-D-glucopyranosyl-(1→4)-
D-glucopyranose. In the abbreviated nomenclature, maltose is Glc(α1→4)Glc.
Determination of the Structure of Disaccharides
The normal procedure for determining the structure of disaccharides can be summarized as
follows:
1. Determination of the nature of the disaccharides (reducing or nonreducing).
2. Acid hydrolysis of the disaccharide to yield two monosaccharides.
3. Determination of the size of the ring (pyranose or furanose) of each of the monosaccharide
obtained upon hydrolysis.
4. The point of linkage of one monosaccharide with the other carried out by methylating the
diasaccharide, hydrolysing it into monosaccharide followed by oxidation. From the oxidation
products points (3) and (4) are settled.
5. The anomeric confi guration (α or β) of the monosaccharides is performed on the basis of
the specifi city of the enzymes. The enzyme maltase (α-glucosidase) hydrolyses only the α-D-
glycosides while the enzyme emulsin (β-glycosidase) hydrolyses only β-glycoside linkage.
6. Finally, the proposed structure is confi rmed by synthesis.
Disaccharides of Pharmaceutical Importance
Sucrose
(Synonyms: invert sugar, α-D-glucopyranosyl-β-D-fructofuranoside, beet sugar, cane sugar, sugar,
saccharose, refi ned sugar)
O
H
CH OH
2
C
C
C
C
C
H
H
H
HO
OHH
OH
O
HO
H
H
H
OH
O
CH OH
2
CH OH
2
C
C
C
C
1
2
3
4
5
6
1
2
3
4
5
6
50
Pharmaceutical Chemistry of Natural Products
Sucrose is a disaccharide with nonreducing property and is composed of glucose and fructose
through an α-(1,2)-β-glycosidic bond. It is also called table sugar obtained from variety of sources
such as sugar cane (Saccharum offi cinarum, Linn, Gramineae), sugar beet (Beta vulgaris, Linn,
Chenopodiaceae) and other sources. It is optically active and found to exist in two forms. The high
sweetness of fructose combined with that of glucose means invert sugar provides a cheaper, less
calorifi c food sweetener than sucrose. It is a white, dry, monoclinic, sphenoid crystals, crystalline
mass or powder, odourless and sweet taste. Melts with charring and emits characteristic odour of
caramel. Well soluble in water, slightly soluble in alcohol, moderately soluble in glycerol, pyridine
and practically insoluble in chloroform.
Sucrose on hydrolysis yields invert sugar, which is equimolar amount of glucose and fructose.
It is used as a sweetening agent and is a starting material in fermenting, production of glycerol,
citric acid, butanol, ethanol and levulinic acid. In pharmaceuticals, it is used as preservative,
antioxidant excipients, granulating agent and coating agent for tablets.
Sucrose has a specifi c rotation of +66.5°, which on hydrolysis yields D(+) glucose, which has
specifi c rotation of +52.5° and D(–)fructose with a specifi c rotation of –92° giving the net negative
value of –20°. Now, as the specifi c rotation value of fructose is high as compared to glucose as well
as the parent compound sucrose, the mixture after hydrolysis will be on the whole, levorotatory.
Furthermore, because the direction of rotation is reversed (or inverted), the mixture of sugars
formed on hydrolysis of sucrose with a specifi c rotation of –20°, the sugar sucrose is known as
invert sugar.
1. First is the stable form called sucrose A (melting point: 184–185°C).
2. Second is the unstable form called sucrose B (melting point: 169–170°C).
Chemical tests
1. Molisch’s test: Sucrose gives a purple colour when treated with α-naphthol and concentrated
sulphuric acid.
2. When sucrose is heated it melts, swells up and burns, giving an odour of burnt sugar and
leaving a bulky carbonaceous residue.
Structural elucidation
1. Molecular formula: Molecular formula of sucrose is found to be C
12
H
22
O
11
.
2. Acid hydrolysis: Upon hydrolysis with acids or enzymes, sucrose gives equal parts of
D-glucose and D-fructose, which thus constitute the two monosaccharide units of hexose.
3. Linkage between two monosaccharide units: Carbonyl group of both the
monosaccharides is involved in linkage, i.e. the glucose is linked via its C
1
(–CHOH) to the
C
2
(CH
2
OH C–OH) of fructose. This is indicated by the inability of sucrose, which neither
reacts with phenyl hydrazine nor reduces Fehling’s solution.
4. Enzyme hydrolysis: Sucrose is hydrolysed by maltase but not by emulsin, thus indicating the
presence of α-D-glucose unit. On the other hand, sucrose is also hydrolysed by an enzyme
taka-invertase, which is believed to be specifi c for β-fructofuranosides, thus indicating a β-D-
fructofuranose unit in sucrose. The above stereochemical aspects have been confi rmed by
Hudson’s isorotation rule.
Carbohydrates
51
5. Ring size of glucose and fructose: The size of glucose and fructose units is to be established
to assign the complete structure of sucrose. It is performed by usual methods. Complete
methylation of sucrose with dimethyl sulphate in basic solution followed by hydrolysis
gives 2,3,4,6-tetra-O-methylglucose and 1,3,4,6-tetra-O-methylfructose. The structure of
these products indicates that glucose residue in sucrose is a glucopyranose, while fructose
residue is in the form of fructofuranose.
6. Structure of sucrose: The following structure has been proposed for sucrose which
accounts for all the above facts.
H
OH
H
OH
H
H
OH
O
H
O
CH OH
2
O
H
OH
OH
H
H
CH OH
2
CH OH
2
Haworth structure
O
H
CH OH
2
CH
H
H
HO
OHH
OH
O
HO
H
H
H
OH
O
CH OH
2
CH OH
2
Fischer structure
HO
OH
HOH C
2
H
HO
H
O
H
H
H
O
HOH C
2
O
H
OH
OH
H
H
CH OH
2
Conformational structure
Methylation followed by oxidation of sucrose is outlined below:
O
H
CH OH
2
CH
H
H
HO
OHH
OH
O
HO
H
H
H
OH
O
CH OH
2
CH OH
2
OCH
3
OCH
3
HCO
3
CH OCH
23
H
H
H
H
H
C
O
O
HCO
3
H
H
H
OCH
3
O
CH OCH
23
CH OCH
23
Sucrose
(CH)SO
32 4
NaOH
Octa- -methyl sucroseO