472
3
Chemical Glycosylation Reactions
appeared for the efficient construction of various complex oligosaccharides on polymer supports, thus limiting the commercialization of automated synthesizers. However, it seems that
O-glycosyl trichloroacetimidates and the less reactive O-glycosyl phosphates have the potential to become the glycosyl donors of choice because the requirement of catalytic amounts of
just one activator is a major advantage over the other glycosylation methods.
After various attempts of the Schmidt group with different linkers between solid support and
the carbohydrate groups, such as for instance
• thioglycosides and their cleavage by thiophilic reagents,
• silyl glycosides and their cleavage by fluorides,
• pentenyl-type glycosides and their cleavage by electrophilic reagents, and
• allyl-type glycosides and their cleavage by cross metathesis or by ring-closing metathesis,
respectively [21,110,111],
finally the ester-based SPOS design was introduced which gave excellent results in chain
extension and product cleavage from the resin [110,111]. However, to cope with complex
oligosaccharide synthesis, besides the ester-linker and -spacer system, three types of glycosyl donor building blocks for controlled chain extension (suffix e), branching (suffix b), and
chain termination (suffix t) are required. An efficient solution to these requirements for SPOS
of a small library of N-glycans is exhibited in > Scheme 13 which shows the retrosynthesis
to the required building blocks and the required reaction steps. A particularly important role
played the selection of the N-protecting group for the glucosamine residue.
The ester-based SPOS methodology ( > Scheme 13) comprises (i) different types of esters, that
is, the benzoate group as a linker and for chain termination and the Fmoc and PA (phenoxyacetyl) group as temporary protecting groups for chain extension and branching which can
be chemoselectively cleaved (in the sequence Fmoc and then PA), (ii) the benzyl group for
permanent O-protection and for the spacer between the anomeric center at the reducing end
sugar, thus providing after final product cleavage from the resin a structurally defined target
molecule, (iii) O-glycosyl trichloroacetimidates of type e, b, or t (for chain extension, branching, or termination) as powerful glycosyl donors, which can be readily activated by catalytic
amounts of (Lewis) acid, and (iv) benzoic acid residues on the Merrifield resin for the linkage of the hydroxymethylbenzyl spacer. Hence, retrosynthesis of a typical N-glycan molecule
containing the core pentasaccharide and some antennae leads to spacer-linker connected Merrifield resin SLP and to glycosyl donors G e , G t , Gal t , Gal b , M b , M t , and MG b which can be
selectively converted into acceptors on resin (e and b-type donor building blocks). Thus, as
indicated in > Scheme 13, only four simple procedures are required for successful SPOS: (a)
glycosidation under TMSOTf catalysis; (b) product cleavage under transesterification conditions; (c) selective Fmoc cleavage under basic conditions; and (d) selective PA cleavage under
milder transesterification conditions.
On the basis of this concept, as shown in > Scheme 14a–c, a small library of N-glycans
(compounds 14a to 14q) was successfully synthesized: (i) The Merrifield resin as solid
support exhibited excellent results during all stages of the assembly; (ii) all glycosylations, including those with N-DMM protected glycosyl donors, gave high yields; (iii) the
methodology presented herein shows the desired versatility in terms of efficient chain extension and branching requiring only two standard (in one direction) orthogonal protecting
3
Chemical Glycosylation Reactions
appeared for the efficient construction of various complex oligosaccharides on polymer supports, thus limiting the commercialization of automated synthesizers. However, it seems that
O-glycosyl trichloroacetimidates and the less reactive O-glycosyl phosphates have the potential to become the glycosyl donors of choice because the requirement of catalytic amounts of
just one activator is a major advantage over the other glycosylation methods.
After various attempts of the Schmidt group with different linkers between solid support and
the carbohydrate groups, such as for instance
• thioglycosides and their cleavage by thiophilic reagents,
• silyl glycosides and their cleavage by fluorides,
• pentenyl-type glycosides and their cleavage by electrophilic reagents, and
• allyl-type glycosides and their cleavage by cross metathesis or by ring-closing metathesis,
respectively [21,110,111],
finally the ester-based SPOS design was introduced which gave excellent results in chain
extension and product cleavage from the resin [110,111]. However, to cope with complex
oligosaccharide synthesis, besides the ester-linker and -spacer system, three types of glycosyl donor building blocks for controlled chain extension (suffix e), branching (suffix b), and
chain termination (suffix t) are required. An efficient solution to these requirements for SPOS
of a small library of N-glycans is exhibited in > Scheme 13 which shows the retrosynthesis
to the required building blocks and the required reaction steps. A particularly important role
played the selection of the N-protecting group for the glucosamine residue.
The ester-based SPOS methodology ( > Scheme 13) comprises (i) different types of esters, that
is, the benzoate group as a linker and for chain termination and the Fmoc and PA (phenoxyacetyl) group as temporary protecting groups for chain extension and branching which can
be chemoselectively cleaved (in the sequence Fmoc and then PA), (ii) the benzyl group for
permanent O-protection and for the spacer between the anomeric center at the reducing end
sugar, thus providing after final product cleavage from the resin a structurally defined target
molecule, (iii) O-glycosyl trichloroacetimidates of type e, b, or t (for chain extension, branching, or termination) as powerful glycosyl donors, which can be readily activated by catalytic
amounts of (Lewis) acid, and (iv) benzoic acid residues on the Merrifield resin for the linkage of the hydroxymethylbenzyl spacer. Hence, retrosynthesis of a typical N-glycan molecule
containing the core pentasaccharide and some antennae leads to spacer-linker connected Merrifield resin SLP and to glycosyl donors G e , G t , Gal t , Gal b , M b , M t , and MG b which can be
selectively converted into acceptors on resin (e and b-type donor building blocks). Thus, as
indicated in > Scheme 13, only four simple procedures are required for successful SPOS: (a)
glycosidation under TMSOTf catalysis; (b) product cleavage under transesterification conditions; (c) selective Fmoc cleavage under basic conditions; and (d) selective PA cleavage under
milder transesterification conditions.
On the basis of this concept, as shown in > Scheme 14a–c, a small library of N-glycans
(compounds 14a to 14q) was successfully synthesized: (i) The Merrifield resin as solid
support exhibited excellent results during all stages of the assembly; (ii) all glycosylations, including those with N-DMM protected glycosyl donors, gave high yields; (iii) the
methodology presented herein shows the desired versatility in terms of efficient chain extension and branching requiring only two standard (in one direction) orthogonal protecting