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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
32
Pharmaceutical Chemistry of Natural Products
CHOH
OHH
HHO
H
OHH
O
CHOH
OHH
HHO
OHH
H
O
CH OH
2
CH OH
2
-Oxide
(5-membered ring structure)
-Oxide
(6-membered ring structure)
Determination of the Ring Size
The following methods are generally employed for the determination of the ring size in sugars.
1. Methylation method
2. Periodic acid oxidation method
1. Methylation method: This method was fi rst reported by Hirst. The sugar is fi rst completely
methylated, which is then hydrolysed with dilute hydrochloric acid. When only the glycosidic
methyl group is hydrolysed, the product is fi nally oxidized. On the basis of the oxidation product
obtained, the ring size of the sugar is determined. This method is based on the assumption that
during the reactions there is neither a change in the size of the ring nor in the position of any
methyl group. The fi rst step of methylation can be effected by different methods.
CHOH
CHOH
HCl
O
O
O
AgI
CH OH
3
CHOCH
3
CHOH
CH
3
I
Ag O
2
CHOCH
3
CHOCH
3
(i) Purdie method: Upon reaction of the sugar with methanolic hydrogen chloride the sugar is
converted into its methyl glycoside. The product is then treated with methyl iodide in the presence
of dry silver oxide to afford fully methylated product.
Advantages
As the free sugar is fi rst methylated by methanolic hydrogen chloride the oxidation of the free
sugar by silver oxide is prevented.
Carbohydrates
33
As the methylation is performed at mild condition, the structural alterations in the molecule
are avoided.
This method is free from untoward effects such as Walden inversion, racemization or glucosidic
interconversion.
Disadvantages
Silver oxide causes oxidation of a free reducing sugar. Therefore, this method is applicable only
to glycosides and other derivatives in which reducing group is either absent or protected by
substitution.
This method can be used only for the sugars of which the suitable solvents are known.
Reagents used in this method (e.g. methyl iodide and silver oxide) are expensive.
(ii) Haworth and Hirst method: The sugar is fully methylated by using dimethyl sulphate in the
presence of aqueous sodium hydroxide.
Advantages
This method is applicable to all kinds of reducing sugars.
Methylation occurs smoothly in a step-wise and uniform manner, and therefore, the
intermediates can be isolated by interrupting the process.
Unreacted and partly reacted sugars are not formed; therefore, the purifi cation is carried out
easily.
Yield is good and the reagents used are cheap.
Disadvantage
Dimethyl sulphate is a poisonous compound; therefore, it should be used with great care under
controlled conditions.
(iii) Diazomethane method: Sugars can also be methylated by the use of diazomethane in the presence
of alcoholic ethereal solution.
Advantages
Nitrogen is the only by-product and it can be eliminated easily.
The product obtained is very pure.
Disadvantages
Diazomethane is very poisonous.
This method is applicable for methylation of acidic compounds.
(iv) p-Toluene sulphonate method: Hydroxy compounds are methylated by reacting the compounds
with p-toluene sulphonate in sodium hydroxide. This method is also called as tosylation.
Advantage
It is preferred over the above methods, as p-toluene sulphonate is harmless.
(v) Sodium and methyl iodide method: By using sodium and methyl iodide in liquor ammonia, the
carbohydrates can be methylated.
34
Pharmaceutical Chemistry of Natural Products
Let us consider the example of D-glucose and apply the methylation method on both of the
possible forms (pyranose and furanose).
Pyranose structure: Pyranose structure is also called
δ
-oxide, amylene oxide or six-membered ring. Using
dimethyl sulphate in the presence of sodium hydroxide (Haworth and Hirst process of methylation),
the methyl glucoside (I) (obtained by refl uxing the D-glucose with methanolic hydrochloric acid) is
methylated to give methyl tetramethyl-D-glucoside (II), which upon hydrolysis gives a tetramethyl-
D-glucose (III). Oxidation with nitric acid gives a dicarboxylic acid (V). The dicarboxylic acid (V)
was identifi ed as xylotrimethoxy glutaric acid by the fact that it was also obtained by the oxidation
of methylated xylose.
D
-Glucose
HCl
Methyl glucoside
NaOH
HCl
D-Tetramethyl glucose
Lactone
COOH
C
H
H
H
COOH
V
IIIIII
IV
CH OH
3
(CH)SO
32 4
Methyl tetramethyl
-glucoside
D
Br water
2
HNO
3
HCO
3
OCH
3
OCH
3
Xylotrim ethoxyglutaric acid
The dicarboxylic acid structure, which helped in determining the structure of the parent
compound glucose, is described here.
1. From the fi rst carbon atom of the lactone (IV), one of the –COOH groups in acid (V) must be
derived and the second –COOH group from the carbon atom is involved in the ring formation
in the sugar. As only three hydroxyl groups are present inside the ring of glucose, the ring
must be δ-oxide in sugar.
2. Presence of three methoxy groups in the dicarboxylic acid (V) indicates the presence of only
three methoxy groups in between the lactone (IV) and hence three hydroxyl groups inside
the ring of glucose, i.e. the lactone formation involves C
1
and C
5
and hence the lactone (IV)
must be δ-lactone and the sugar must be six membered, which explains all the reactions in
the following manner:
3. Finally, the formation of (V) also eliminates the possibility of an ε-ring (when C
1
and C
6
are involved in ring formation) because if at all the case was ε-ring, the product 2,3,4,5-
tetramethyl gluconic acid or tetramethylsaccharic acid (VI) would have been formed.
It is important to note the Fischer’s fi rst methyl glucosides were actually the pyranosides,
which he called furanosides only on the basis of Tollens’ assumption that the γ-oxide ring is stable
by analogy to γ-lactones.
Carbohydrates
35
Glucose
CHOCH
3
OHH
HHO
OHH
H
O
Reflux
CHOCH
3
OCH
3
H
H
OCH
3
H
H
O
III
HCl
Bromine
water, 90°C
III
IV
CO
H
H
H
H
O
COOH
H
OH
CHOH
H
H
H
H
O
COOH
COOH
H
H
H
COOH
VVI
COOH
H
H
H
H
CHOH
OH
H
OH
O
H
HO
H
H
H
H
H
CH OH
2
CH OH
2
CH OH
2
CH OCH
23
OCH
3
OCH
3
HCO
3
HCO
3
HCO
3
CH OCH
23
CH OCH
23
CH OCH
23
OCH
3
OCH
3
HNO
3
OCH
3
OCH
3
HNO
3
HCO
3
OCH
3
OCH
3
OCH
3
OCH
3
OCH
3
HCO
3
CH OH
3
–HCl
NaOH
(CH)SO
32 4
HCO
3
;
36
Pharmaceutical Chemistry of Natural Products
Furanose structure: Fischer prepared a new methyl glucoside (actually which was later on found
to be a mixture of two glucosides, α and β) by dissolving D-glucose in methanolic hydrochloric
acid and then keeping the product at 0°C for some time. The size of the ring in these two new
isomeric glucosides was found to be γ-1,4-butylene oxide. The steps used for establishing the
size of the ring are same. For example, the methyl glucoside (I, prepared at 0°C as earlier) is
completely methylated using methyl sulphate to yield methyl tetra-O-methyl-D-glucoside (II),
which is hydrolysed with dilute hydrochloric acid to yield tetra-O-methyl-D-glucose (III), which
is then oxidized fi rst with bromine water at 90°C to yield crystalline lactone (IV) and fi nally
with nitric acid to yield dimethyl-D-tartaric acid (V, dimethoxysuccinic acid) of well-known
structure.
The formation of dimethyltartaric acid from D-glucose indicates that within the ring of the
sugar and its derivatives, (II), (III) and (IV), there are only two hydroxyl or methoxy groups and
hence the ring must involve C
1
and C
4
which are fi nally oxidized during the set of reaction to the
acidic groups. The scheme for conversion of glucose to dimethyltartaric acid may be represented
as shown below:
CHOH
OHH
HHO
H
OH
H
O
Glucose
I
II
NaOH
CH OH
2
CH OH-HCl
3
0° C
OHH
HHO
H
OHH
O
CHOCH
3
CH OH
2
(CH)SO
32 4
HCO
3
H
H
H
H
O
OCH
3
OCH
3
CH OCH
23
CHOCH
3
HCl
HCO
3
CHOH
H
H
H
H
III
OCH
3
OCH
3
CH OCH
23
Bromine
water
CO
H
H
H
H
IV
OCH
3
OCH
3
HCO
3
CH OCH
23
HNO
3
V
COOH
H
H
COOH
OCH
3
HCO
3
OO
Carbohydrates
37
From the above contradictory statements it is concluded that the methyl glucoside prepared
at refl ux temperature has 1,5-oxide (δ-oxide) ring structure. Hence, with the help of this method
it is not possible to say whether glucose itself originally exists in the pyranose (1,5) or furanose
(1,4) form or whether the two forms are in equilibrium.
However, X-ray analysis of all the normal monosaccharides indicates the presence of six-
membered ring in a manner similar to which α-D-glucose is found to have pyranose structure.
Using periodic acid oxidation, the existence of glucose as pyranoside has been confi rmed.
2. Periodate oxidation method: This is a simple elegant method introduced by Malaprade. It involves
the use of periodic acid at about pH 4 in dark to avoid overoxidation and decomposition of the
oxidant.
The general principles of periodic acid oxidation have been discussed already. As shown in the
example, between every 1,2-glycolic groups one molecule of periodate is consumed.
(i) (ii)
CHOH
CHOH
CHOH
R’
R
RCHO
HCOOH
R’CHO
CHOH
R
CHOH
R’
RCHO
R’CHO
HIO
56
2 H IO
56
Principles useful in structural investigation by periodic acid may be summarized as below:
1. When a –CHOH group is attacked on one side, i.e. only by 1 mole of the reagent, it is
converted into –CHO group.
2. One molecule of periodic acid is consumed between every two adjacent hydroxyl groups
(1,2-glycolic groups).
3. When a –CH
2
OH group is attacked by periodic acid, it is converted into HCHO.
4. When –CHOH group is attacked on both the sides, i.e. one –CHOH group is attacked by 2
moles of periodic acid, it is converted into HCOOH.
5. The reagent does not open the oxide ring of the sugar or its derivatives.
Thus, by estimating the number of moles of the periodic acid consumed and the number of
moles of HCHO and HCOOH produced along with the investigation of the oxidation product of the
glycoside, this method has been successfully used to determine the size of the ring in glycosides.
Using this method, Hudson proved that the normal glycosides are pyranosides. For example,
the compound (I) on oxidation with periodic acid consumes 2 moles of the acid along with
the formation of 1 mole of formic acid and a dialdehyde (II) indicating beyond doubt that the
compound (I) has three adjacent hydroxyl groups, which is possible only when the glycoside has
δ-ring structure.
38
Pharmaceutical Chemistry of Natural Products
O
H
HO
H
H
OH
C
CH OH
2
H OCH
3
H
OH
2H IO
56
HCOOH
H C OCH
3
CHO
CHO
H
CH OH
2
O
i) Bromine water
ii) SrCO
3
I
II
H
O
O
O
C
CO
CO
Sr
CH OH
2
H
OCH
3
i) H SO
24
ii)Bromine water
COOH
COH
CH OH
2
H
COOH
COOH
III
D-Glyceric acid Oxalic acid
It has been proved by the above scheme that the structure (II) on oxidation with bromine
water in the presence of strontium carbonate gives a crystalline strontium salt (III). The strontium
salt (III) on hydrolysis followed by oxidation yields oxalic and D-glyceric acids.
O
H
HO
H
H
OH
C
CH OH
2
HCO
3
H
H
OH
2H IO
56
HCOOH
HCO
3
CH
CHO
CHO
H
CH OH
2
O
i) Bromine water
ii) SrCO
3
I
II
HCO
3
O
O
O
C
CO
CO
Sr
CH OH
2
H
H
i) H
SO
24
ii)Bromine water
COOH
COH
CH OH
2
H
COOH
COOH
III
D-Glyceric acid Oxalic acid
Carbohydrates
39
From similar experiments it is also found that all methyl α-D-aldohexopyranosides of the
normal type consume 2 moles of periodic acid and produce 1 mole of formic acid along with
formation of the compounds (II), (III), oxalic acid and
D-glyceric acid. Hence, all hexosides have
δ-oxide rings.
Ring structure of ketoses
H
CO
OH
H
H
OH
HO
CH OH
2
CH OH
2
Open chain
O
CH
2
HO H
OH
OH
OH
H
H
HOH C
2
C
C
C
C
12
3
4
5
6
α− -FructopyranoseD
O
CH
2
HO
HO
H
OH
OH
H
H
C
C
C
C
12
3
4
5
6
CH OH
2
β− -FructopyranoseD
O
H
OH
HO
H
H
OH
C
C
C
C
12
3
4
5
6
CH OH
2
HOH C
2
α− -FructofuranoseD
O
HHO
H
H
OH
C
C
C
C
CH OH
2
HO CH OH
2
β− -FructofuranoseD
The open-chain reactions of fructose fail to explain some of the facts. They are as follows:
1. It does not react with NaHSO
3
,
indicating that the keto group is not free.
2. Like glucose, fructose also shows the property of mutarotation.
3. When treated with methanol in hydrogen chloride, it yields fructoside. This compound
does not exhibit the property of carbonyl group and can exist in two forms, namely α- and
β-methyl fructosides.
4. Penta-acetyl fructose does not exhibit the property of carbonyl group, which indicates that
the carbonyl group is not free.
The above facts can be explained if fructose forms a ring between carbonyl and hydroxyl
groups, as in hemiacetals.
1. Ring originating from C-2 and closing at C-6 (pyranose ring).
2. Ring originating from C-2 and closing at C-5 (furanose ring).
Each of these can exist as α- and β-anomers, and hence ketoses (e.g. D-fructose) may also exist
in four isomeric ring structures similar to aldoses. The open-chain and various ring structures of
D-fructoses may be drawn as shown above.
The size of the ring in particular fructose is determined by methylation. The method is the same
as for aldoses, except that oxidation by bromine water is replaced by dilute nitric acid followed by
acid permanganate. Let us apply the method on both types of fructoses (pyranose and furanose).
Pyranose structure
Fructose at refl ux temperature is methylated to methyl-β-D-fructoside (I), which was completely
methylated by using dimethyl sulphate in the presence of alkali to methyl-tetra-O-methyl-D-
fructoside (II). The methyl-tetra-O-methyl-D-fructoside was hydrolysed with dilute hydrochloric
acid to tetramethyl-D-fructose (III), which on oxidation with nitric acid gave trimethyl-β-
D-fructonic acid (IV). This acid on oxidation with acidic permanganate afforded a lactone,
40
Pharmaceutical Chemistry of Natural Products
trimethyl-D-arabinolactone (V), which on oxidation with nitric acid gave D-arabinotrimethoxy
glutaric acid (VI) of well-known structure.
H
COOH
OCH
3
H
H
OCH
3
HCO
3
COOH
VI
Two acidic groups on C
1
and C
5
formation indicate that the ring in fructoside (I) involves C
1
and C
5
, i.e. the ring is δ-oxide, and hence the scheme reaction is depicted as below.
O
HO
H
CH OH
2
OH
CH
2
HO
H
H
OH
O
HCO
3
H
CH OH
2
OH
CH
2
HO
H
H
OH
CH OH–HCl
3
(CH SO)
32 4
NaOH
β−
D-Fructopyranose
Methyl- -Fructopyranosideβ-
D
O
HCO
3
H
CH OC
23
H
OCH
3
CH
2
H
H
OCH
3
HCO
3
HCl
O
HO
H
CH OC
23
H
OCH
3
CH
2
H
H
OCH
3
HCO
3
HNO
3
Methyl-1,3,4,5-Tetramethyl- -fructopyranosideβ-D 1,3,4,5-Trimethyl- -fructoseβ-D
HO
H
COOH
OCH
3
CH
2
H
H
OCH
3
HCO
3
O
KMnO
4
HSO
24
H
CO
OCH
3
CH
2
H
H
OCH
3
HCO
3
O
HNO
3
H
COOH
OCH
3
H
H
OCH
3
HCO
3
COOH
3,4,5-Trimethyl- -fructonic acid (as lactol)β-
D 2,3,4-Trimethyl- -arabinolactoneDD-Arabinotrimethoxy glutaric acid
I
II
III
IV V VI
Carbohydrates
41
Furanose structure
Fructose at room temperature is methylated to methyl fructoside (I) and is then methylated
completely by using dimethyl sulphate. The product is hydrolysed with dilute hydrochloric acid,
then oxidized with dilute nitric acid, acidic permanganate and concentrated nitric acid to give
dimethyl-
L-tartaric acid of known structure.
HCO
3
H
H
OCH
3
COOH
COOH
The dimethyl-L-tartaric acid formation indicates that in fructose ring structure C
1
and C
4
are
involved, i.e. the ring is γ- or 1,4-oxide. Thus, the above reactions can be represented as below.
CH OH
2
HO
OH
H
H
H
OH
O
CH OH
2
H
H
H
OCH
3
O
CH OCH
23
CH O
3
CH OCH
23
HCO
3
H
H
H
OCH
3
O
COOH
HO
CH OCH
23
HCO
3
H
H
H
OCH
3
O
CO
CH OCH
23
(i) CH OH–HCl
at 18°C
3
(ii) (CH ) SO
in NaOH
32 4
β D-Fructofuranose- Methyl-1,3,4,6-tetramethyl
-fructofuranosideβ
D-
(i) HCl
(ii) Dil. HNO
3
KMnO
4
HSO
24
3,4,6-Trimethyl- -fructonic acidβ D- 2,3,5-Trimethyl -arabinolactone
(It is a slow changing lactone)
-β D-
HCO
3
H
H
OCH
3
COOH
COOH
Conc. HNO
3
Dimethyl- -tartaric acidL
CH O
3