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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. . - PowerPoint PPT Presentation
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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)
O
OH
NaH CH3 S
O
CH3[H3C S
O
CH2] Na
[H2C S
O
CH3] Na_
_+
+
+ + H2
O
O
O
OMeNa+
MeI
solution of Na(CH2-SO-CH3) in DMSO
solution of saccharide in DMSO
• For saccharides particularly sensitive to bases – CH2N2, BF3.Et2O
Methylation analysis
1. Methylation of hydroxyl groups
2. Hydrolysis of glycosidic bonds
3. Reduction of carbonyl groups (hemiacetals)
4. Acetylation of hydroxyl groups
originating from hydrolysis and reduction
5. GC-MS analysis
O
CH2
O
HO OH
O
CH2OH
HO
OH OH
O
... O
O
CH2OH
O
OH OH
...
O
CH2
O
MeO
O
CH2OMe
MeO
MeO
O
... O
O
CH2OMe
O
MeO
...
OMe
OMe OMe
1.
O
CH2OH
HO
MeO OMe
OHO
CH2OMe
MeO
MeO
OH
OMe
HO
O
CH2OMe
OH
MeO OMe
2.
CH2OH
CH2OMe
MeO
OH
MeO
OMe
CH2OH
CH2OH
MeO
MeO
OH
OH
CH2OH
CH2OMe
MeO
MeO
OH
OH
+ +
+ +
CH2OAc
CH2OMe
MeO
OAc
MeO
OMe
CH2OAc
CH2OAc
MeO
MeO
OAc
OAc
CH2OAc
CH2OMe
MeO
MeO
OAc
OAc
+ +
3.
4.
A
B C
A
B
A B
C
C
A B C A B C
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 O-acetylated. 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
CH2OMe
MeO
AcO
OAc
OMe
OO
CH2OH
O
OH OH
......
CH2OHO
O
OH OH
...O
...
CH2OAc
CH2OMe
MeO
AcO
OAc
OMe
4)--D-galactopyranosyl-(1
5)--D-galactofuranosyl-(1
1,4,5-tri-O-acetyl-2,3,6-tri-O-methyl- -D-galactitol
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
OHO
OI
OH
OH
O
O
IO4
-
(H5IO6)
O
O+ IO3 + H2O
-
CH2OH
OH O
Me
OH
OH
O
OH
OH
OH
OO
OH
Me
O
OO
HCH=O
HCOOHHCOOH
Oxidative cleavage of -diols in structural analysis of carbohydrates
O
CH2
O
HO OH
OCH2OH
HO
OH OH
O
... OO
CH2OH
O
OH OH
...
NaIO4
O
CH2
O
O O
OCH2OH
O
O
O
... OO
CH2OH
O
O O
... O
CH2
O
HO OH
OCH2OH
HO
OH
O
... OO
CH2OH
O
OH OH
...
OH
CH2OH
OH
HO
OH
CH2OH
HO
OH
O
OH
O
O
OH
OHOH
CH2OH
OH
NaBH4
H3O
NaBH4
+
HCOOH
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.
glycerol
D-erythritol
ethylene glycolunknown saccharide
alditol mixture
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.
methyl-α-D-glucopyranoside
methyl-2,3,4,6-tetra-O-benzyl-
α-D-glucopyranoside
O
CH2OH
HO
OH
OHOMe
O
CH2OBn
BnO OMe
OBn
OBn
1. DMF, NaH
2. BnBrBn = H2C
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
O
CH2OBn
BnO OMe
OBn
OBn
O
CH2OBn
BnO
OHOBn
OBn
H3O+
2,3,4,6-tetra-O-benzyl- α,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.
O
CH2OBn
BnO
OOBn
OBn
O
CH2
BnOOBn
OBnOMe
O
CH2OH
HO
OOH
OH
O
CH2
HOOH
OHOMe
H2, Pd/C
EtOAc
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
O
CH2OH
HO
OH
OHOMe
O
CH2OTr
HO OMe
OH
OH
Tr = C6H5C
C6H5
C6H5
methyl-α-D-glucopyranoside
methyl-6-O-trityl- α-D-glucopyranoside
TrCl
pyridín
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
HOOH
HO
OH
OH
O
OH
HO
OHTrO
OTr
O
HOOH OH
OH
O
OH
OH
TrO
OH
β-D-fructopyranose 1,6-di-O-trityl-β-D-fructofuranose
α,β-D-ribopyranose 5-O-trityl-α,β-D-ribofuranose
TrCl (2 mol)
pyridine
pyridine
TrCl (1 mol)
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
O
CH2OHHO
OH
OHOMe
O
CH2OTrHO
OH
OHOMe
O
CH2OTrBnO
OBn
OBnOMe
TrCl, Py 1. NaH, DMF
2. BnCl
methyl-α-D-galactopyranoside
methyl-2,3,4-tri-O-benzyl-6-O- trityl-α-D-galactopyranoside
methyl-6-O-trityl- α-D-galactopyranoside
O
CH2OTrAcO
OAc
OAcOMe
AcCl, Py
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.
O
CH2OHBnO
OBn
OBnOMe
O
CH2OTrBnO
OBn
OBnOMe
O
CH2OTrBnO
OBn
OBnOMe
H2, Pd/C
EtOAc
HCl
Et2O
O
CH2OHHO
OH
OHOMe
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)
• 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)
O
CH2OH
HO
OH
OHOMe
O
CH2OSiMe2Bu-t
HO OMe
OH
OH
t-BuMe2SiCl, Py
Practical deprotection of carbohydrate silyl ethers
O
CH2OH
BnO OMe
OBn
OBn
O
CH2OSiMe2Bu-t
BnO OMe
OBn
OBn
Bu4N F+ -O
CH2OSiMe2Bu-t
HO OMe
OH
OH
1. DMF, NaH
2. BnBr THF, AcOH
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.
