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12
Pharmaceutical Chemistry of Natural Products
3-phosphoglyceraldehyde is formed during photosynthesis, two molecules of which combine
to synthesize glucose-6-phosphate by a sequence of reactions. By the complex reactions of the
Calvin cycle, 3-phosphoglyceraldehyde is used in the formation of the pentoses such as ribose-5-
phosphate, ribulose-5-phosphate and xylulose-5-phosphate by adopting fundamental biochemical
reactions.
Photosynthesis
H
CH OPO
24
OH
CHO
OH
H
OH
OH
H
HO
H
H
CHO
CH OPO
24
D
-Glucose-6-phosphate
D-3-Phospho glyceraldehyde
Calvin cycle
-Xylulose-5-phosphate
DD-Ribose-5-phosphate D-Ribulose-5-phosphate
H
H
H
OH
OH
OH
CH OPO
24
CHO
CH OH
2
CH OPO
24
H
H
OH
O
OH
CH OH
2
CH OPO
24
HO
H
OH
O
H
In the nomenclature of carbohydrates, the suffi x -ose is used for naming sugars. The portion of
the name preceding this often refl ects the origin and history of the compound [e.g. lactose (milk
sugar) is derived from the Latin word lactis which means milk].
Physiological Importance of Carbohydrates
1. Carbohydrates serve as a chief source of energy.
2. They are constituents of compound lipids and conjugated proteins.
3. The degradation products of carbohydrates act as ‘promoters’ or ‘catalysts’.
4. Certain derivatives of carbohydrates such as cardiac glycosides (e.g. digoxin, digitoxin)/
antibiotics (e.g. aminoglycosides) are used as drugs.
5. Derangement of glucose metabolism is seen in diabetes mellitus.
6. Polysaccharide glycogen found in liver and muscle cells is a polymer of glucose—a stored
form of energy.
CLASSIFICATION OF CARBOHYDRATES
Carbohydrates may be classifi ed into two types: sugars and nonsugars (polysaccharides).
Carbohydrates
13
Sugars: They are water soluble, sweet and crystalline substances (e.g. glucose, fructose and sucrose).
They are further classifi ed into two types.
(a) Monosaccharides
(b) Oligosaccharides
Monosaccharides: The term monosaccharide means ‘polyhydroxy aldehydes’ or ‘ketones’, which cannot
be hydrolysed to simpler sugars. Their general formula is C
n
H
2n
O
n
. The hexoses, the aldohexose
D-glucose and the ketohexose D-fructose, are the most common monosaccharides in nature. The
aldopentoses, D-ribose and 2-deoxy-D-ribose, are components of nucleotides and nucleic acids.
Monosaccharides of more than four carbons tend to have cyclic structures. Monosaccharides
are further subdivided according to the nature of the carbonyl group as follows:
(i) Aldoses: Monosaccharides with aldehyde group.
(ii) Ketoses: Monosaccharides with keto group.
Based on the number of carbon atoms in the molecule, aldoses and ketoses are further divided
as shown in Table 1.1.
Table 1.1 Classifi cation of aldoses/ketoses
Aldose/ketose (Generic names) Number of carbon atoms Example (found in humans)
Trioses 3 Glyceraldehyde
Tetroses 4 Erythrose
Pentoses 5 Ribose
Hexoses 6 Glucose
Heptoses 7 Sedoheptulose
Nonoses 9 Neuraminic acid
Oligosaccharides: The term oligosaccharide is derived from the Greek words oligos (means ‘a
few’) and sacchar (means ‘sugar’). They consist of short chains of monosaccharide units, or
residues, linked by characteristic linkages called glycosidic bonds. These carbohydrates yield 2–10
monosaccharide molecules on hydrolysis, and therefore, they are further classifi ed into various
types based on the number of monosaccharide units formed on hydrolysis.
(i) Disaccharides: Disaccharides (e.g. maltose, lactose and sucrose) consist of two monosaccharides
linked covalently by an O-glycosidic bond, which is formed when a hydroxyl group of one
sugar reacts with the anomeric carbon of the other.
These sugars on hydrolysis give two molecules of monosaccharides. For example, sucrose
yields one molecule of glucose and fructose, while maltose on hydrolysis yields two molecules
of glucose.
(ii) Trisaccharides: They yield three molecules of monosaccharides on hydrolysis (e.g. raffi nose,
C
18
H
32
O
16
). Most oligosaccharides consisting of three or more units do not occur as free
entities but are linked to nonsugar molecules (lipids or proteins) in glycoconjugates.
(iii) Tetrasaccharides: They yield four molecules of monosaccharides on hydrolysis (e.g. stachyose,
C
24
H
42
O
21
).
Nonsugars or polysaccharides: These types of carbohydrates consist of large number of monosaccharide
units bonded together by glycosidic bonds, which yield a large number of monosaccharide
units upon hydrolysis. Chemically, they are long chain or polymers of monosaccharides. Some
14
Pharmaceutical Chemistry of Natural Products
polysaccharides, such as cellulose, are linear chains, while others such as glycogen are branched.
Both glycogen and cellulose consist of recurring units of D-glucose, but they differ in the type of
glycosidic linkage and therefore, they have different properties and biological roles. According
to the type of monosaccharide unit present in polysaccharides (single type or different types of
monosaccharides), they are further divided as homopolysaccharides (e.g. starch, cellulose and
inulin) and heteropolysaccharides (e.g. chondroitin sulphate A and heparin).
Starch is the major form of stored carbohydrate in plant cells. Its structure is identical to
glycogen, except for a much lower degree of branching (about every 20–30 residues). Unbranched
starch is called amylose and branched starch is called amylopectin.
The above classifi cation of the carbohydrates is schematically represented as given:
Carbohydrates
Sugars
Nonsugars (Polysaccharides)
Homopolysaccharides HeteropolysaccharidesMonosaccharides
Aldoses
Ketoses
Disaccharides Trisaccharides Tetrasaccharides
Oligosaccharides
Carbohydrates may also be classifi ed as (1) reducing sugars and (2) nonreducing sugars. This
classifi cation is based on the ability of the carbohydrate to reduce Fehling’s solution and Tollens’
reagent.
QUALITATIVE CHEMICAL TESTS FOR CARBOHYDRATES
Molisch’s Test (general test): To 3 mL of aqueous extract add few drops of α-naphthol solution in
alcohol, shake and add concentrated sulphuric acid along the sides of the test tube. Violet- or
purple-coloured ring is formed between the junctions of the two liquids.
Carbohydrates
15
Tests for Reducing Sugars
1. Fehling’s test: Mix 1 mL of Fehling’s solution A and 1 mL of Fehling’s solution B, and boil it for
1 min. To this mixture, add an equal volume of test solution. Heat the contents on a boiling
water bath for 5–10 min. A yellow precipitate followed by brick red precipitate is formed.
2. Benedict’s test: Mix an equal volume of Benedict’s reagent and test solution in a test tube. Heat
the contents on a boiling water bath for 5 min. The solution appears green, yellow or red
depending on amount of reducing sugar present in the test solution.
Test for Monosaccharides
Barfoed’s test: Mix equal volume of Barfoed’s reagent (potassium cupric tartrate) and test solution.
Heat it for 1–2 min on a boiling water bath and cool. Red-coloured precipitate is formed.
Tests for Pentose Sugars
1. Bial’s orcinol test: To boiling Bial’s reagent add few drops of test solution. Green or purple
colour appears.
2. Aniline acetate test: Boil the test solution in a test tube. Hold a fi lter paper soaked in aniline
acetate on the vapour. Filter paper turns pink.
3. Mix equal amount of test solution and hydrochloric acid, heat it and add a crystal of
phloroglucinol. Red colour appears.
Tests for Hexose Sugars
1. Seliwanoff’s test (for keto hexose such as fructose): Mix 3 mL of Seliwanoff’s reagent and 1 mL of
test solution and heat it on a water bath for 1–2 min. Red colour is formed.
2. Tollens’ phloroglucinol test for galactose: Mix 2.5 mL of concentrated hydrochloric acid and 4 mL
of 0.5% phloroglucinol, add 1–2 mL of test solution and heat it on a water bath. Yellow to
red colour appears.
3. Cobalt chloride test: Mix 3 mL of test solution with 2 mL of cobalt chloride, boil and cool. To this
add few drops of sodium hydroxide solution. The solution appears greenish blue (indicating
the presence of glucose) or purplish (indicating the presence of fructose) or upper layer
greenish blue and lower layer purplish (indicating a mixture of glucose and fructose).
Tests for Nonreducing Sugars
1. Test solution does not give response to Fehling’s and Benedict’s reagents.
2. After hydrolysis, test solution gives response to Fehling’s and Benedict’s tests.
Tests for Nonreducing Polysaccharides (Starch)
1. Iodine test: Mix 3 mL of test solution and few drops of dilute iodine solution. Blue colour
appears; the colour disappears on boiling and reappears on cooling.
2. Tannic acid test for starch: With 20% tannic acid, test solution forms precipitate.
Each class of carbohydrates is discussed in detail in the following sections.
16
Pharmaceutical Chemistry of Natural Products
MONOSACCHARIDES
Monosaccharides are colourless, crystalline solids, freely soluble in water but insoluble in nonpolar
solvents. Most of them have a sweet taste. The monosaccharide molecules have unbranched
carbon chains in which all the carbon atoms are single bonded. However, one of the carbon atoms
is double bonded to an oxygen atom in the open-chain to form a carbonyl group, while the other
carbon atoms have a hydroxyl group. When the carbonyl group is at the end of the carbon chain
as an aldehyde group, the monosaccharide is an aldose. But if the carbonyl group is found within
the carbon chain with a ketone group then the monosaccharide is called as ketose.
Configuration of Monosaccharides
Monosaccharides are classifi ed according to the nature of the carbonyl group and the number
of carbon atoms. All monosaccharides have one or more asymmetric (chiral) carbon atoms and
thus occur in optically active isomeric forms. The simplest monosaccharide, aldose glyceraldehyde,
contains one chiral centre and therefore has two different optical isomers or enantiomers. By
convention, one of these two forms is designated as D-isomer and the other as L-isomer.
Aldobiose
CHO
CH OH
2
CHO
CHOH
CH OH
2
CHO
(CHOH)
2
CH OH
2
CHO
(CHOH)
3
CH OH
2
CHO
(CHOH)
4
CH OH
2
C = O
(CHOH)
3
CH OH
2
CH OH
2
Aldotriose Aldotetrose Aldopentose Aldohexose
Ketohexose
The general formula is 2
n
, where n is the number of dissimilar asymmetric carbon atoms used
to indicate the number of optically active stereoisomers for different types of aldoses and ketoses.
Monosaccharides may have two or more than two stereoisomers due to different confi gurations (e.g.
aldotriose having one chiral carbon atom may have two isomers, viz. D-and L-glyceraldehyde).
OH
D-Glyceraldehyde L-Glyceraldehyde
CHO
CH OH
2
H
CHO
OH
CH OH
2
H
Rosanoff in 1906 studied the confi guration of carbohydrates by taking the simplest sugar,
i.e. glyceraldehyde (aldotriose) as the arbitrary standard. The glyceraldehyde molecule having
hydroxyl group (OH group) at the right side of the penultimate carbon atom (last but one carbon
atom) belongs to D-series, while the one having OH group to the left side is L-series. Thus, D and
L indicate the stereochemical relationship but the actual rotation of optical activity is indicated by
the signs + and –. Thus, when glucose is mentioned as D (+) glucose, it means the sugar belongs to
D-glyceraldehyde confi guration with the dextrorotatory optical activity.
It is inconvenient to use the general R/S system of nomenclature for carbohydrates. For example,
D (+) glucose must be mentioned as 2(R), 2(S), 4(R), 5(R), 2, 3, 4, 5, 6-(+) pentahydroxyhexanal.
Despite the limitations of D and L system of nomenclature, it is still used in the designation of
carbohydrates.
Carbohydrates
17
HO
HO
H
H
OH
OH
H
H
CHO
CH OH
2
HO
HO
HO
H
H
H
OHH
CHO
CH OH
2
ALDOSE
Erythrose
D-FAMILY OF SUGARS
CHO
KETOSE
Glycoaldehyde
CH OH
2
Glyceraldehyde
CHO
C
CH OH
2
OHH
CHO
C
C
OHH
OHH
CH OH
2
Ribose
CHO
C
C
OHH
OHH
C
CH OH
2
OHH
Arabinose
CHO
C
C
C
HO H
HOH
HOH
CH OH
2
Threose
CHO
C
C
CH OH
2
HO H
HOH
Xylose
HO
CHO
C
C
OHH
H
C
CH OH
2
OHH
Lyxose
HO
CHO
C
C
HHO
H
C
CH OH
2
OHH
H
OH
OH
OH
HO
H
H
H
CHO
CH OH
2
OH
H
OH
OH
H
HO
H
H
CHO
CH OH
2
CH OH
2
H
H
OH
OH
HO
HO
H
H
CHO
OH
OH
OH
OH
H
H
H
H
CHO
CH OH
2
OH
OH
H
H
HO
CH OH
2
CO
CH OH
2
H
OHH
HO
HO
CH OH
2
CO
CH OH
2
H
H
OH
OH
OH
H
H
H
CH OH
2
CO
CH OH
2
OH
OH
H
H
HO
CH OH
2
CO
CH OH
2
H
Erythrulose
CO
C
CH OH
2
OHH
CH OH
2
HO
H
CO
C
H
C
CH OH
2
OH
CH OH
2
Xylulose
H
CO
C
OH
C
CH OH
2
OHH
CH OH
2
Ribulose
OH
OH
H
OH
H
H
HO
H
CHO
CH OH
2
HO
HO
OH
H
H
OH
H
H
CHO
CH OH
2
Diose
Triose
Tetrose
Pentose
Hexose
Allose
Altrose Glucose
Mannose
Gulose
Idose
Galactose
Talose Allulose
Frutose
Sorbose
Tagatose
CO
CH OH
2
CH OH
2
Dihydroxyacetone
18
Pharmaceutical Chemistry of Natural Products
Ascending and Descending in Monosaccharides
It is possible to convert one monosaccharide into another by this. It is important in the carbohydrate
chemistry due to the following reasons:
1. These are used in the determination of relative confi gurations of monosaccharide.
2. These also provide route for the synthesis of rare compounds and compounds that are not
yet known.
Methods of ascending in sugar series
The following are the methods employed to convert sugars into their higher homologues.
1. Kiliani’s synthesis: This is one of the most important synthetic methods for the preparation of
sugars and is used to prepare aldoses up to 10 carbon atoms. In this the aldose is fi rst treated
with hydrogen cyanide and the cyanohydrin formed is hydrolysed to the higher aldonic acid.
This is then converted into two isomeric sugars by lactonization followed by reduction with
Na–Hg.
CHO
(CHOH)
3
CH OH
2
*CHOH
(CHOH)
3
CH OH
2
CN
*CHOH
(CHOH)
3
CH OH
2
COOH
*CHOH
(CHOH)
3
CH OH
2
CHO
HCN
(i) Ba(OH)
2
(ii) H SO
24
(i) Lactonization
(ii) Na–Hg
Arabinose
Glucose + Mannose
As the addition of hydrogen cyanide to an aldose introduces a new chiral carbon atom, two
cyanohydrins and hence two isomeric higher aldoses are formed. But, in practice, only one
cyanohydrin predominates because a new chiral centre is introduced into an already chiral
molecule.
2. Kochetkov method: In this method, the aldose is condensed with carbethoxymethylene
phosphorane (Wittig reaction) and the product is further treated suitably to obtain sugars
with two carbon atoms more.
CHO
CHOH
+ Ph P=CH.COOC H
325
Carbethoxy methylene
phosphorane
COOC H
25
CH
CH
CHOH
Wittig
reaction
(–Ph P=O)
3
OsO
4
HClO
4
COOH
CHOH
CHOH
CHOH
[O]
CO
CHOH
CHOH
CH
O
Na–Hg
CHO
CHOH
CHOH
CHOH
g-Lactone
3. Sowden or nitromethane synthesis: This method is based on the condensation of aldose with
nitromethane in the presence of methanolic sodium methoxide to form 1-nitro-1-deoxy
compound, which is separated and converted into corresponding sodium salts. The sodium
salts on hydrolysis with cold dilute sulphuric yield the higher sugar.
Carbohydrates
19
OH
H
CHO
CH NO
32
+
CH ONa
3
OHH
CH NO
22
*CHOH
OHH
CH
CHOH
NaOH
HSO
24
OHH
CHO
CHOH
NO Na
2
Methods of descending in sugar series
The following are the methods employed to convert sugars into their lower homologues, which
involves removal of C
1
and conversion of C
2
to an aldehyde group. The various methods used for
degrading the aldoses by one carbon atom are given below. All these methods start from aldoses.
In the same way, these methods can also be applied to descending the ketoses but it must be fi rst
converted into the corresponding aldose.
1. Wohl’s method: This is one of the commonly applied methods for shortening the sugar into its
lower homologue and involves the heating of aldose oxime with acetic anhydride in presence
of zinc chloride or sodium acetate. In this method, the oxime group is dehydrated to the
nitrile group with the simultaneous acetylation of the hydroxyl groups. The acetylated nitrile
compound is warmed with ammonical silver nitrate solution, the nitrile group is eliminated
as silver cyanide and the acetyl group as acetamide with the formation of a new aldose.
CHOH
(CHOH)
3
CH OH
2
CHO
H NOH
2
CHOH
(CHOH)
3
CH OH
2
CH
AgNO
Ac O/ZnCl
3
22
(HO)
2
NOH
CHOAc
(CHOAc)
3
CH OAc
2
C
N
Ag
(NH)OH
32
AgNO NH
33
AgCN
CH(OH)
2
(CHOH)
3
CH OH
2
HO2
CHO
(CHOH)
3
CH OH
2
Aldohexose Aldoxime Aldopentose
The newly formed aldopentose actually condenses with the by-product acetamide to yield a
diacetamido derivative, which is then hydrolysed to the aldehyde, i.e. aldopentose. However,
if sodium ethoxide is used in place of the ammonical silver nitrate solution, the aldopentose
is obtained directly.
CHO
(CHOH)
3
CH OH
2
Aldopentose
2 CH CONH
32
CH(NHCOCH )
32
(CHOH)
3
CH OH
2
Diacetamido derivative
HOH
dil HCl
CHO
(CHOH)
3
CH OH
2
Aldopentose
2. Ruff’s method: As the Kiliani–Fischer synthesis is used for the synthesis to obtain higher
homologue sugars, the Ruff’s degradation method can be used to shorten the chain. The
steps involved are as follows:
(a) Oxidation of aldose to the corresponding aldonic acid electrolytically or using bromine
water.
20
Pharmaceutical Chemistry of Natural Products
(b) Oxidative decarboxylation of the aldonic acid to its corresponding lower homologue sugar,
which is performed by treating the aldonic acid with calcium acetate to form a calcium
salt, which is then oxidized by hydrogen peroxide in the presence of ferrous salt as a
catalyst (Fenton’s reagent: H
2
O
2
+ Fe
3+
) to the α-keto acid which is readily decarboxylated
to an aldose.
CHO
(CHOH)
4
CH OH
2
COOH
(CHOH)
4
CH OH
2
Br water
2
Lime
water
COO
(CHOH)
4
CH OH
2
H O –Fe
22
3+
C
(CHOH)
3
CH OH
2
O
COOH
Heat
CHO
(CHOH)
3
CH OH
2
Aldohexose Aldonic acid Calcium aldonate Keto acid Aldopentose
(CO)
2
Ca
2+
2
3. Weygand’s method: Aldose oxime is reacted with 1-fl uoro-2,4-dinitrobenzene and the resultant
product is degraded with warm sodium bicarbonate.
CHO
CHOH
H NOH
2
CH
CHOH
NOH
ON
2
F
NO
2
Na CO
23
HC
CHOH
N O
NO
2
NO
2
Warm with
aq. NaHCO
3
NO
2
HO NO +
2
HCN
+
CHO
HF
Aldose with 1
carbon lesser
2,4-Dinitrophenol
Chemical Reactions of Monosaccharides
The monosaccharides are either aldehydes or ketones with two or more hydroxyl groups; the
six-carbon monosaccharides, glucose and fructose, have fi ve hydroxyl groups. They answer most
of the reactions but not all the reactions of the carbonyl group as well as of the alcoholic group.
In addition, they may give typical reactions as it contains alcoholic and carbonyl group in the
same molecule. As glucose and fructose are the most important examples of aldoses and ketoses,
respectively, the properties will be studied with their reference.
1. Epimerization: Epimers are the optical isomers, which differ in the confi guration at only
one asymmetric carbon atom (generally α-carbon, i.e. carbon 2). Glucose and mannose are
examples of epimers.
The process of inversion of confi guration at one asymmetric centre, i.e. converting one epimer
into another in a molecule containing several asymmetric centres is known as epimerization.
In this method, aldose is converted into its epimer via aldonic acid. Aldose is fi rst oxidized to
aldonic acid, then the aldonic acid is heated to about 150°C in aqueous pyridine or quinoline
(to prevent the formation of lactone of the aldonic acid) to yield an equilibrium mixture of
Carbohydrates
21
the original acid and its epimer. The two epimeric acids are separated and converted into their
δ-lactones and then reduced to the original aldose and its epimer. Epimerization proceeds
similar to that of racemization. The epimerization of glucose to mannose is depicted below:
O
CHO
(CHOH)
3
OHH
CH OH
2
D(+) Glucose-
Bromine
water
COOH
(CHOH)
3
OHH
CH OH
2
Gluconic acid
COOH
(CHOH)
3
HOH
CH OH
2
Pyridine
C
(CHOH)
3
OHH
CH OH
2
O
O
-
H
+
C
(CHOH)
3
OH
CH OH
2
O
-
-
C
C
(CHOH)
3
OH
CH OH
2
O
-
O
-
C
+H
+
-H
–
Mannonic acid
(i) Evaporation
(ii) Reduction
CHO
(CHOH)
3
HHO
CH OH
2
D(+) Mannose-
H
+
2. Reduction: Methods adopted for reducing sugars are electrolytic reduction, high-pressure
hydrogenation over a nickel or copper chromite catalyst, or sodium borohydride. By these
methods, sugars are reduced to their corresponding alditols.
On such reductions an aldose gives only one type of alcohol (glucose gives sorbitol and
mannose gives mannitol), but a ketose gives a mixture of two alcohols (fructose gives a
mixture of two alcohols, namely sorbitol and mannitol) due to the introduction of a new
asymmetric carbon atom (shown by asterisk), which may have two different confi gurations
to give two different alcohols.
OH
H
OH
OH
H
HO
H
H
CH OH
2
CHO
Glucose
OH
H
OH
OH
H
HO
H
H
CH OH
2
Sorbitol
CH OH
2
NaBH
4
O
H
OH
OH
HO
H
H
CH OH
2
CH OH
2
Fructose
NaBH
4
OH
H
OH
OH
H
HO
H
H
CH OH
2
CH OH
2
Sorbitol
*
HO
OH
H
H
CH OH
2
CH OH
2
Mannitol
*
H
H
OH
OH
Reduction with hydroiodic acid–red phosphorus leads to the conversion of hydroxyl groups
to methylene.
3. Oxidation: Depending upon the nature of oxidizing agents, monosaccharides are oxidized to
a variety of products. The various important oxidizing agents are as follows:
(a) Benedict’s, Fehling’s and Tollens’ reagents
(b) Bromine water
(c) Nitric acid
(d) Lead tetra-acetate and periodic acid