Carbohydrate ethers

1. 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.

2. 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.

3. Carbohydrate methylation procedures • Purdieprocedure – 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) solution of Na(CH2-SO-CH3) in DMSO solution of saccharide in DMSO • For saccharides particularly sensitive to bases – CH2N2, BF3.Et2O

4. Methylationanalysis • Methylation of hydroxyl groups • Hydrolysis of glycosidic bonds • Reduction of carbonyl groups (hemiacetals) • Acetylation of hydroxyl groups originating from hydrolysis and reduction 5. GC-MS analysis

5. 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.

6. 4)--D-galactopyranosyl-(1 1,4,5-tri-O-acetyl-2,3,6-tri-O-methyl- -D-galactitol 5)--D-galactofuranosyl-(1 1,4,5-tri-O-acetyl-2,3,6-tri-O-methyl- -D-galactitol As the methylation analysis does not provide unambiguous andcomplete results, other complementary chemical, biochemical and physico-chemical methods of the structural determination of oligosacharidesand polysacharides are being used.

7. Oxidative cleavage of -diolsvia cyclic intermediates

8. Oxidative cleavage of -diolsin structural analysis ofcarbohydrates alditol mixture unknown saccharide ethylene glycol glycerol D-erythritol The composition of the alditol mixture obtained after periodate oxidation of unknown saccharide, followed by reduction of carbonyl groups, hydrolysis andrepeated 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.

9. 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

10. 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 2,3,4,6-tetra-O-benzyl- α,β-D-glucopyranose

11. 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.

12. 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. Thereforetritylations can be done in pyridine, similarly like acylations. • Tritylation reaction preferentially occurs at primary hydroxyl group(s) of a saccharide TrCl pyridín methyl-α-D- glucopyranoside methyl-6-O-trityl-α-D-glucopyranoside

13. 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 TrCl (2 mol) pyridine 1,6-di-O-trityl-β-D-fructofuranose β-D-fructopyranose TrCl (1 mol) pyridine α,β-D-ribopyranose 5-O-trityl-α,β-D-ribofuranose

14. Zdroj: Monosaccharides. Their Chemistry and Their Roles in Natural Products, P.M. Collins, R.J. Ferrier, Wiley,Chichester, 1995.

15. Carbohydrate trityl (triphenylmethyl) ethers • Resistant to basic reagents, so that their free hydroxyl groups can be alkylated as well as acylated methyl-2,3,4-tri-O-benzyl-6-O-trityl-α-D-galactopyranoside methyl-α-D-galactopyranoside methyl-6-O-trityl-α-D-galactopyranoside methyl-2,3,4-tri-O-acetyl-6-O-trityl-α-D-galactopyranoside

16. 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.

17. 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.

18. Carbohydrate silyl ethers • Synthetically significant areterc-butyldimethylsilyl ethers (-OSiMe2Bu-t) andterc-butyldiphenylsilyl ethers (-OSiPh2Bu-t) • terc-butyldimethylsilyl ethers (-OSiMe2Bu-t) are 1000-timesmore resistant to acid hydrolysis than trimethylsilyl ethers (-OSiMe3) • terc-butyldiphenylsilyl ethers (-OSiPh2Bu-t) are 105-timesmore resistant to acid hydrolysis than trimethylsilyl ethers (-OSiMe3)

19. Practical deprotection of carbohydrate silyl ethers 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.