Carbohydrate ethers
• Carbohydrate derivatives, in which one or more hydrogen
atoms of their hydroxyl groups (except of the hemiacetal
OH group – in such case the derivatives are glycosides)
is substituted with alkyl, aralkyl or aryl group R..
• The most important carbohydrate ethers are methyl (R =
CH3), benzyl (R = CH2C6H5), triphenylmethyl- (trityl-,
R = C(C6H5)3) and trimethylsilyl ethers (R = Si(CH3)3).
Hydroxyethyl, diethylaminoethyl and carboxymethyl
ethers are important polysaccharide ethers. According to
the degree of substitution, the carbohydrate ethers are
divided into partial and full ethers.
Carbohydrate methyl ethers
• They are syrupy or low melting point crystalline compounds, which can
be distilled or sublimed. They are of bitter taste, good solubility in water
and organic solvents, and resistant against majority of acidic and basic
agents like the other methyl alkyl ethers. Original sugar can be
regenerated from its methyl ether by treatment with boron trichloride at
low temperature or by treatment with Fenton reagent (hydrogen peroxide
in the presence of ferric ions), eventually also by oxidation of the methyl
ether moiety to formic acid ester followed by hydrolytic removal of the
ester group.
• Carbohydrate methyl ethers usually can be prepared by the Purdie,
Haworth, Kuhn or the Hakomori procedure. A relatively high volatility of
sugar methyl ethers is employed in gas chromatographic and mass
spectrometric methods of the structural analysis of carbohydrates. For
example, so called methylation analysis is based on per-O-methylation
of an oligosaccharide or polysaccharide, which is then hydrolyzed to its
monosaccharide units. These are then reduced to the corresponding
partially O-methylated alditols, which finally are O-acetylated. The
obtained fully O-substituted, volatile alditols are then separated and
analyzed in order to locate glycosidic linkages and determine degree of
polymerization of the oligosaccharide or polysaccharide analyzed.
• Many partial methyl ethers of carbohydrates are natural compounds
occurring in polysaccharides, glycosides, antibiotics, etc.
Carbohydrate methylation procedures
•
•
•
•
Purdie procedure – Ag2O; MeI; (MeI)
Haworth procedure – NaOH; Me2SO4; water
Kuhn procedure – BaO or Ba(OH)2; MeI; DMF
and modifications – NaH, NaOH; MeI, MeBr, Me2SO4; DMF or DMSO
Hakomori procedure – NaH; MeI; DMSO (homogeneous reaction conditions)
NaH
+
H3C S CH3
_
+
[H3C S CH2] Na
+
H2
O
O
solution of Na(CH2-SO-CH3)
in DMSO
[H2C S
_
+
CH3] Na
O
O
O
OH
O Na
MeI
+
solution of saccharide in DMSO
•
O
For saccharides particularly sensitive to bases – CH2N2, BF3.Et2O
OMe
CH2 OH
O
HO
A
Methylation
analysis
CH2
OH
HO
1.
O
CH2 OH
O
O
...
O
O
B
Methylation of
hydroxyl groups
Hydrolysis of
glycosidic bonds
Reduction of
carbonyl groups
(hemiacetals)
Acetylation of
hydroxyl groups
originating from
hydrolysis and
reduction
GC-MS analysis
2.
...
O
C
3.
CH2 OMe
O
MeO
OH
1.
4.
O
A
MeO
HO
OH
HO
CH2
OMe
CH2 OMe
O
O
...
O
O
B
OMe MeO
MeO
...
O
C
OMe
5.
2.
CH2 OH
CH2 OMe
O
MeO
A
O
OH
+
HO
OH
B
+
HO
OH
C
MeO
OMe
MeO
OMe
MeO
CH2 OMe
O
OMe
3.
CH2 OH
CH2 OH
OMe
MeO
MeO
A
MeO
+
OH
CH2 OMe
OH
OH
CH2 OH
+
4.
MeO
OH
C
CH2 OAc
OMe
MeO
MeO
B
CH2 OAc
CH2 OH
OH
CH2 OMe
MeO
+
MeO
A
OAc
CH2 OMe
CH2 OAc
MeO
MeO
MeO
OAc
B
OAc
CH2 OAc
+
MeO
OAc
C
OAc
CH2 OMe
Methylation analysis
is based on a per-O-methylation of an
oligosaccharide or polysaccharide, which is then
hydrolyzed to its monosaccharide units. These
are then reduced to the corresponding partially
O-methylated alditols, which finally are Oacetylated. The obtained fully O-substituted,
volatile alditols are then separated and analyzed
by gas chromatography and mass spectrometry
(by comparing with available set of all possible
per-O-substituted O-acetyl/O-methyl alditols) in
order to locate glycosidic linkages between
monosaccharide units and determine degree of
polymerization of the oligosaccharide or
polysaccharide analyzed.
CH2OAc
OMe
CH2OH
O
...
MeO
O
O
HO
...
AcO
OAc
OH
4)--D-galactopyranosyl-(1
CH2OMe
1,4,5-tri-O-acetyl-2,3,6-tri-O-methyl-D-galactitol
CH2OAc
OMe
CH2OH
MeO
O
O ...
...
O
AcO
OAc
HO
OH
5)--D-galactofuranosyl-(1
CH2OMe
1,4,5-tri-O-acetyl-2,3,6-tri-O-methyl-D-galactitol
As the methylation analysis does not provide unambiguous and complete results,
other complementary chemical, biochemical and physico-chemical methods of the
structural determination of oligosacharides and polysacharides are being used.
Oxidative cleavage of -diols via cyclic intermediates
OH
OH
IO4
O
O
OH
O
OH
O
I
(H5 IO6)
O
+ IO3 + H2O
O
OH
CH2OH
O
HCH=O
OH
O
OH
O
Me
Me
OH
OH
OH
O
HCOOH
O
O
OH
HCOOH
O
Oxidative cleavage of -diols in structural analysis of carbohydrates
alditol mixture
CH2OH
O
unknown saccharide
glycerol
O
HO
CH2
OH
HO
...
O
CH2OH
OH
CH2OH
OH
O
O
ethylene glycol
O
HO
CH2OH
O
O
NaBH4
CH2OH
OH
...
HO
OH
O
HO
HO
OH
HO
OH
D-erythritol
CH2OH
O
O
CH2OH
O
O
O
O
O
O
CH2
OH
O
O
+
H3O
O
HO
CH2
O
...
OH
NaIO 4
CH2OH
O
HCOOH
HO
OH
HO
O
O
...
NaBH4
CH2OH
O
O
...
O
O
O
O
HO
OH
HO
OH
The composition of the alditol mixture obtained after periodate oxidation of unknown saccharide,
followed by reduction of carbonyl groups, hydrolysis and repeated reduction, together with data on
consumption of periodate and yield of formic acid provide additional information for resolution of the
structure of the unknown saccharide.
...
Carbohydrate benzyl ethers
• Can be obtained by treatment of a saccharide with benzyl
halogenides in dimethylformamide or dimethyl sulfoxide in
the presence of BaO or NaOH or NaH or Ag2O.
CH2OBn
CH2OH
OH
HO
O
OMe
OH
methyl-α-Dglucopyranoside
O
1. DMF, NaH
2. BnBr
OBn
BnO
Bn = H2C
OMe
OBn
methyl-2,3,4,6-tetra-O-benzylα-D-glucopyranoside
Carbohydrate benzyl ethers
• Often non-crystallizing compounds
• Resistant to basic reagents and relatively well resistant
also acidic reagents – this allows to hydrolyse glycoside
or acetal bonds in the presence of the benzyl ether
groups
CH2OBn
O
OBn
BnO
OMe
OBn
CH2OBn
H3O+
O
OBn
OH
BnO
OBn
2,3,4,6-tetra-O-benzylα,β-D-glucopyranose
Carbohydrate benzyl ethers
• Hydrogenolysis of O-benzyl groups on a paladium catalyst
affords toluene and regenerates free hydroxyl groups of the
saccharide. This property is frequently being employed in
carbohydrate synthesis, because the majority of other protecting
groups (except of trityl ethers, benzylidene acetals and other
similar protecting groups containing phenylmethyl/ene moieties)
are stable at these conditions.
CH2OBn
O
H2
C
O
OBn
BnO
CH2OH
H2, Pd/C
O
OBn
BnO
OBn
OH
EtOAc
OMe
OBn
O
H2
C
O
HO
OH
HO
OH
O
OMe
OH
Carbohydrate trityl (triphenylmethyl) ethers
• Can be obtained by treatment of a saccharide with triphenylchloromethane
(trityl chloride) in pyridine solution. Due to the stabilizing effect by extensive
delocalization from its three phenyl rings, the properties of trityl chloride
more resemble acyl chlorides than aralkyl chlorides. Therefore tritylations
can be done in pyridine, similarly like acylations.
• Tritylation reaction preferentially occurs at primary hydroxyl group(s)
of a saccharide
CH2OTr
CH2OH
OH
HO
O
OMe
OH
methyl-α-Dglucopyranoside
TrCl
pyridín
OH
HO
C6H5
O
Tr =
OMe
OH
methyl-6-O-tritylα-D-glucopyranoside
C C6H5
C6H5
Carbohydrate trityl (triphenylmethyl) ethers
• Tritylation reaction preferentially occurs at the primary
hydroxyl group of a saccharide also if this hydroxyl
group participates in the hemiacetal grouping of the
saccharide
O OH
TrCl (2 mol)
TrO
HO
OH
HO
OH
HO
O
pyridine
OTr
OH
OH
1,6-di-O-tritylβ-D-fructofuranose
β-D-fructopyranose
TrCl (1 mol)
O
TrO
O
OH
OH
pyridine
HO
OH OH
α,β-D-ribopyranose
OH OH
5-O-trityl-α,β-D-ribofuranose
Zdroj: Monosaccharides. Their Chemistry and Their Roles in Natural Products, P.M.
Collins, R.J. Ferrier, Wiley, Chichester, 1995.
Carbohydrate trityl (triphenylmethyl) ethers
• Resistant to basic reagents, so that their free hydroxyl
groups can be alkylated as well as acylated
CH2OTr
CH2OH
HO
OH
O
TrCl, Py
HO
OH
O
1. NaH, DMF
OMe
OH
OMe
OH
methyl-α-Dgalactopyranoside
CH2OTr
methyl-6-O-tritylα-D-galactopyranoside
2. BnCl
OMe
OBn
methyl-2,3,4-tri-O-benzyl-6-Otrityl-α-D-galactopyranoside
CH2OTr
OAc
O
OBn
AcCl, Py
AcO
BnO
O
OMe
OAc
methyl-2,3,4-tri-O-acetyl
-6-O-trityl-α-D-galactopyranoside
Tritylétery (trifenylmetylétery) sacharidov
• In acidic medium they are rapidly hydrolyzed to
triphenylmethanol and release the free primary hydroxyl
group of the saccharide. Under hydrogenolysis conditions
they are labile like benzyl ethers and their O-trityl group is
reduced to triphenylmethane, thus regenerating the primary
hydroxyl group of the saccharide.
CH2OH
BnO
CH2OTr
HCl
O
OBn
OMe
OBn
CH2OH
CH2OTr
BnO
O
OBn
H2, Pd/C
EtOAc
OMe
OBn
HO
OH
O
OMe
OH
Et2O
BnO
O
OBn
OMe
OBn
Carbohydrate silyl ethers
• Trimethylsilyl ethers [-OSi(CH3)3] can be prepared by
treatment of a saccharide with trimethylsilyl chloride or
with 1,1,1,3,3,3-hexamethyldisilazane [(CH3)3SiNHSi(CH3)3],
eventually with other silylating reagents, usually in a
pyridine solution.
• They are distillable, mostly oily compounds, stable at normal
conditions under air moisture exclusion. Original saccharide
can be regenerated from them by heating in aqueous
alcohols. The hydrolysis occurs preferentially at primary
hydroxyl groups.
• Similarly as methyl ethers, they are being employed in gas
chromatographic and mass spectrometric analyses of
carbohydrates.
Carbohydrate silyl ethers
• Synthetically significant are terc-butyldimethylsilyl ethers
(-OSiMe2Bu-t) and terc-butyldiphenylsilyl ethers (-OSiPh2Bu-t)
CH2OSiMe2Bu-t
CH2OH
OH
HO
O
OMe
OH
t-BuMe2SiCl, Py
OH
HO
O
OMe
OH
• terc-butyldimethylsilyl ethers (-OSiMe2Bu-t) are 1000-times more
resistant to acid hydrolysis than trimethylsilyl ethers (-OSiMe3)
• terc-butyldiphenylsilyl ethers (-OSiPh2Bu-t) are 105-times more
resistant to acid hydrolysis than trimethylsilyl ethers (-OSiMe3)
Practical deprotection of carbohydrate silyl ethers
CH2OSiMe2Bu-t
CH2OSiMe2Bu-t
OH
HO
O
OMe
OH
O
1. DMF, NaH
2. BnBr
OBn
BnO
OMe
OBn
CH2OH
+ Bu4N F
THF, AcOH
O
OBn
BnO
OMe
OBn
The most often used agents for deprotection of carbohydrate silyl ethers are
fluoride ions (nucleophiles with a high affinity for silicon) in a mild acidic
solutions.