Structural and Functional Studies of Glycoside Hydrolase Family 12
Reaction of Monosaccharides with Alcohols: Glycoside Formation · an acid catalyst to provide...
Transcript of Reaction of Monosaccharides with Alcohols: Glycoside Formation · an acid catalyst to provide...
Reaction of Monosaccharides with Alcohols: Glycoside Formation
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• Aldoses and ketoses react with an alcohol in the presence of
an acid catalyst to provide acetals called glycosides.
• Regardless of the anomer used as the starting material, both
anomers of the glycoside are formed.
• However, the more stable anomer usually predominates. For
example, the acid-catalysed reaction of glucose with methanol
gives a mixture of methyl glucosides.
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O
HO
HOHO
OHOH
-D-Glucopyranose
CH3OH, HClO
HO
HOHO
OCH3
OH
+O
HO
HOHO
OCH3HO
Methyl D-glucopyranoside Methyl D-glucopyranoside
Aglycone
• Note that despite the presence of a number of other hydroxyl
groups in the sugar, it is only the anomeric hydroxyl group that
is replaced.
Reaction of Monosaccharides with Alcohols: Glycoside formation
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•The success of this glycosylation at the anomeric centre
depends on the generation of a resonance stabilized oxonium
ion at the anomeric carbon that undergoes a nucleophilic attack
by the nucleophilic alcohol molecules.
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•Equilibriation of the glycosides usually takes place. It is an
example of a reaction that is subject to thermodynamic (or
equilibrium) control.
O
HO
HOHO
OHOH
H+O
HO
HOHO
OOH H
HO
HO
HOHO
HO
H2O+
CH3OH
O
HO
HOHO
OH
OCH3
HO
HO
HOHO
OCH3
OH
-H+
Resonance-stabilized Oxonium ion(All atoms have a complete octate)
Properties of Glycosides
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• Unlike the free sugars from which they are derived,
glycosides are stable to basic conditions.
• Glycosides may therefore be used with basic reagents and in
basic solutions. This effectively means that the anomeric
centre can effectively be protected as a glycoside at the
beginning of any reaction sequence.
• Since glycosides are incapable of being in equilibrium with
their open-chain forms, they are non-reducing sugars.
• Glycosides do not exhibit mutarotation. Converting the
anomeric hydroxyl group to an ether function
(hemiacetal→acetal) prevents its reversion to the open-chain
form in neutral or basic media.11:36 AM
Hydrolysis of Glycosides
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• In aqueous acid, acetal formation can be reversed and the
glycoside hydrolysed to an alcohol and the free sugar.
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• Note that the mechanism of hydrolysis is the exact reverse of
that for glycosylation.
Etherification of Monosaccharides
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• The best conditions for permethylating sugars that can be
employed on both hemi-acetals (lactols) and glycosides
involves treating the sugar with methyl iodide in the presence
of silver oxide. These conditions convert all the free hydroxyl
groups to methyl ethers.
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Etherification of Monosaccharides
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• Permethylation of monosaccharides with methyl iodide in the
presence of silver oxide depends on the polarisation of the
CH3-I bond with silver oxide making the methyl carbon
strongly electrophilic. Attack by the carbohydrate –OH group,
followed by deprotonation, gives the ether.
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Application of Permethylation in Structure Determination
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• This reaction has been used to determine the ring size of
glycosides.
• Once all the free hydroxyl groups of a glycoside have been
methylated, the glycoside is subjected to acid-catalysed
hydrolysis. Only the anomeric methoxy group is hydrolysed. .
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O
CH3O
CH3OCH3O
OCH3
OCH3
Methyl 2,3,4,6-tetra-O-Methyl-D-
glucopyranoside
H+
H2O O
CH3O
CH3OCH3O
OH
OCH3
CHO
OCH3H
HCH3O
OCH3H
CH2OCH3
H OH
2,3,4,6-tetra-O-Methyl-D-glucopyranose
H
OCH3
HH OCH3
OCH3 HO
CH3O H
CH3O
Methyl 2,3,5,6-tetra-O-Methyl-
D-glucofuranoside
H
OH
HH OCH3
OCH3 HO
CH3O H
CH3O
H+
H2O
CHO
OCH3H
HCH3O
OHH
CH2OCH3
H OCH3
2,3,5,6-tetra-O-Methyl-D-glucofuranose
Application of Permethylation in Structure Determination
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• Note that all the hydroxyl groups in the open-chain form of
the sugar except C-5 are methylated. C-5 is not methylated
because it was originally the site of the ring oxygen in the
methylglycoside.
• Once the position of the hydroxyl group in the sugar has
been determined, either by spectroscopy or by converting the
sugar to a known compound, the ring size stands revealed.
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Oxidative Cleavage of Monosaccharides with Periodic Acid
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• Since carbohydrates contain two or more –OH or C=O
groups on adjacent carbons, they undergo oxidative
cleavage by periodic acid.
• Periodic acid oxidation finds extensive use as an analytical
method in carbohydrate chemistry. Structural information is
obtained by measuring the number of equivalents of periodic
acid that react with a given compound and identifying the
reaction products.
• A vicinal diol (1,2-diol) consumes one equivalent of periodate
and is cleaved to two carbonyl compounds.
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Mechanism of Oxidative Cleavage of Monosaccharides with Periodic Acid
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• A vicinal diol (1,2-diol) is oxidatively cleaved through a cyclic
periodate ester to two carbonyl compounds.
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Oxidative Cleavage of Monosaccharides with Periodic Acid
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• -Hydroxy carbonyl compounds also undergo oxidative
cleavage with periodic acid. Their cleavage, however,
provides a carboxylic acid and a carbonyl compound.
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• The cleavage is also postulated to take place through a
cyclic periodate ester intermediate. The cyclic ester
spontaneously breaks down by a cyclic flow of electrons in
which iodine accepts an electron pair.
Oxidative Cleavage of Monosaccharides with Periodic Acid
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• The cleavage is postulated to take place through a cyclic
periodate ester intermediate. The cyclic ester spontaneously
breaks down by a cyclic flow of electrons in which iodine
accepts an electron pair.
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Oxidative Cleavage of Monosaccharides with Periodic Acid
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• Given that monosaccharides and their derivatives are
polyhydroxy carbonyl compounds, they undergo oxidative
cleavage in a manner similar to that of vicinal diols and -
hydroxy carbonyl compounds.
• For example, metasaccharinic acid undergoes oxidative
cleavage with periodic acid to provide the products shown
below.
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+
COOH
H OH
HH
OHH
OHH
CH2OH
HIO4
COOH
H OH
HH
OH
O
O H
H
H
OH
+
Metasaccharinic acid Formic acid Formaldehyde
Periodic Acid Cleavage: Structural Determination of Monosaccharides
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• Periodic acid oxidative cleavage can also be used in
structure determination.
• For example, the structure determination of a previously
unknown methyl glycoside, obtained by the reaction of D-
arabinose with methanol and hydrogen chloride, was
determined on the basis of the products of the oxidative
cleavage with periodic acid.
• The size of the ring was identified as a five-membered ring
because only one mole of periodic acid was consumed per
mole of glycoside and no formic acid was produced.
• Were the ring six membered, two moles of periodic acid
would be required per mole of glycoside and one mole of
formic acid would be produced.11:36 AM
Periodic Acid Cleavage: Structural Determination of Monosaccharides
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• The structure of a previously unknown methyl glycoside was
identified as a five-membered ring because only one mole of
periodic acid was consumed per mole of glycoside and no
formic acid was produced.
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O
OCH3
OH
OH
HOO
OH
OH
OCH3
HO
1
23
4
5
123
4 5
2 HIO4HIO4
O
O
OCH3
HO
O
O
OCH3
O
O
+ O
H
HO
Formic acid
Furanose Pyranose
• The sodium salt of periodic acid, sodium periodate (NaIO4),
is also equally effective in the oxidative cleavage of 1,2-diols.