460
3
Chemical Glycosylation Reactions
4.1 Methodological Aspects
As outlined above, the anomeric hydroxy groups add under base catalysis readily to the electron-deficient nitrile group of trichloroacetonitrile to furnish generally via equilibration at the
anomeric center O-glycosyl trichloroacetimidates. As bases mainly potassium carbonate, sodium hydride, DBU, and cesium carbonate are employed. Weak bases, such as for instance
potassium carbonate, permit kinetic product control (formation of the equatorial product)
whereas strong bases, as for instance sodium hydride, lead to the thermodynamically more
stable product (generally the axially oriented trichloroacetimidate group). Because of convenience, DBU has become the most popular base, which also favors axial product formation.
Therefore, polystyrene-supported DBU (PS-DBU) [16,17] and various other solid-supported
nitrogen bases were successfully employed in this reaction as shown for the particularly difficult trichloroacetimidate formation of 4-dimethylamino-2,4,6-trideoxy sugar kedarosamine
(1a → 1b) and its use in the glycosylation of the ansamacrolide substructure (1b + 1c → 1d)
of the kedarcidin chromophore ( > Scheme 1) [17]. Also Dowex 1-X8 OH − is a good catalyst for the trichloroacetimidate formation of a glucosamine derivative [18,19]. Polymersupported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PTBD) turned out to be a powerful catalyst
for trichloroacetimidate formation as well [17,19]; this base catalyst in combination with
Nafion ® -SAC resin (a nanocomposite of Nafion ® resin with porous silica) could be successfully employed in one-pot trichloroacetimidate formation and following glycosylation reactions [19].
O-Glycosyl trichloroacetimidates are quite stable under neutral but also under basic conditions.
Hence, trichloroacetimidate formation is tolerated by standard O- and N-protecting groups,
such as O-acyl, O-benzyl, O,O-alkylidene, O-silyl, N-acyl and N,N-diacyl, N-phthaloyl (Phth),
N-dimethylmaleoyl (DMM), and the latent amino functionality azido. It is particularly worth
mentioning that trichloroacetimidate formation is also tolerated by Fmoc-protected hydroxy
groups; this group has become an important temporary protecting group which is orthogonal to other temporary protecting groups, thus permitting in oligosaccharide synthesis not
only regioselective chain extension but also branching [20,21]. The useful 3-O-Fmoc-protected galactosyl donor 2d can be readily prepared from compound 2a via intermediates 2b and 2c
( > Scheme 2) [20]. Additional protecting groups have been recently probed particularly at 2-O
in order to influence the stereochemical outcome, such as for instance the diphenylmethyl
(DPM), the 9-fluorenyl (Fl) group [22], and the 4-acetoxy-2,2-dimethylbutanoyl (ADMB)
group [23]. The ADMB group is a useful alternative to the pivaloyl group; it combines the
strong 1,2-trans-selection in glycosylation reactions of the pivaloyl group with the ease of
removal of more reactive acyl groups. Other important new groups are the O-trifluoroethylsulfonate group which could be successfully employed to release the sulfate group and the
replacement of the 6-hydroxy group by a phenylthio group which is employed for uronate
formation [25].
O-Glycosyl trichloroacetimidates are under acidic conditions very powerful glycosyl donors.
Reaction with nonacidic nucleophiles is generally performed with catalytic amounts of Brønsted or Lewis acids. TMSOTf and BF 3 OEt 2 are the most frequently employed catalysts.
TMSOTf is the catalyst of first choice and it is generally used in 0.001 to 0.1 equivalents
based on the glycosyl donor. Commonly 1.0 to 1.5 equivalents of glycosyl acceptor are added.
Dichloromethane is the solvent of first choice. Because of the high reactivity of O-glycosyl
3
Chemical Glycosylation Reactions
4.1 Methodological Aspects
As outlined above, the anomeric hydroxy groups add under base catalysis readily to the electron-deficient nitrile group of trichloroacetonitrile to furnish generally via equilibration at the
anomeric center O-glycosyl trichloroacetimidates. As bases mainly potassium carbonate, sodium hydride, DBU, and cesium carbonate are employed. Weak bases, such as for instance
potassium carbonate, permit kinetic product control (formation of the equatorial product)
whereas strong bases, as for instance sodium hydride, lead to the thermodynamically more
stable product (generally the axially oriented trichloroacetimidate group). Because of convenience, DBU has become the most popular base, which also favors axial product formation.
Therefore, polystyrene-supported DBU (PS-DBU) [16,17] and various other solid-supported
nitrogen bases were successfully employed in this reaction as shown for the particularly difficult trichloroacetimidate formation of 4-dimethylamino-2,4,6-trideoxy sugar kedarosamine
(1a → 1b) and its use in the glycosylation of the ansamacrolide substructure (1b + 1c → 1d)
of the kedarcidin chromophore ( > Scheme 1) [17]. Also Dowex 1-X8 OH − is a good catalyst for the trichloroacetimidate formation of a glucosamine derivative [18,19]. Polymersupported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PTBD) turned out to be a powerful catalyst
for trichloroacetimidate formation as well [17,19]; this base catalyst in combination with
Nafion ® -SAC resin (a nanocomposite of Nafion ® resin with porous silica) could be successfully employed in one-pot trichloroacetimidate formation and following glycosylation reactions [19].
O-Glycosyl trichloroacetimidates are quite stable under neutral but also under basic conditions.
Hence, trichloroacetimidate formation is tolerated by standard O- and N-protecting groups,
such as O-acyl, O-benzyl, O,O-alkylidene, O-silyl, N-acyl and N,N-diacyl, N-phthaloyl (Phth),
N-dimethylmaleoyl (DMM), and the latent amino functionality azido. It is particularly worth
mentioning that trichloroacetimidate formation is also tolerated by Fmoc-protected hydroxy
groups; this group has become an important temporary protecting group which is orthogonal to other temporary protecting groups, thus permitting in oligosaccharide synthesis not
only regioselective chain extension but also branching [20,21]. The useful 3-O-Fmoc-protected galactosyl donor 2d can be readily prepared from compound 2a via intermediates 2b and 2c
( > Scheme 2) [20]. Additional protecting groups have been recently probed particularly at 2-O
in order to influence the stereochemical outcome, such as for instance the diphenylmethyl
(DPM), the 9-fluorenyl (Fl) group [22], and the 4-acetoxy-2,2-dimethylbutanoyl (ADMB)
group [23]. The ADMB group is a useful alternative to the pivaloyl group; it combines the
strong 1,2-trans-selection in glycosylation reactions of the pivaloyl group with the ease of
removal of more reactive acyl groups. Other important new groups are the O-trifluoroethylsulfonate group which could be successfully employed to release the sulfate group and the
replacement of the 6-hydroxy group by a phenylthio group which is employed for uronate
formation [25].
O-Glycosyl trichloroacetimidates are under acidic conditions very powerful glycosyl donors.
Reaction with nonacidic nucleophiles is generally performed with catalytic amounts of Brønsted or Lewis acids. TMSOTf and BF 3 OEt 2 are the most frequently employed catalysts.
TMSOTf is the catalyst of first choice and it is generally used in 0.001 to 0.1 equivalents
based on the glycosyl donor. Commonly 1.0 to 1.5 equivalents of glycosyl acceptor are added.
Dichloromethane is the solvent of first choice. Because of the high reactivity of O-glycosyl