Peptide-Based Drug Design

Glycosylated Amino Acid Synthesis 191
3. Methods
A crucial step in the chemical synthesis of glycopeptides is the incorporation
of the saccharide into the peptide. Two approaches can be considered to accomplish
this: the direct glycosylation of a properly protected full-length peptide and
the use of a preformed glycosylated amino acid building block for the stepwise
synthesis of the peptide backbone (Scheme 1).
An advantage of the direct glycosylation method is that the route is more
convergent, permitting fast access to glycopeptides differing in glycan structure.
Condensations between glycosyl amines and peptides containing aspartic or
glutamic acid residues by direct approach have been accomplished in syntheses
of N-linked glycopeptides (40–42). However, glycosylamines often undergo
formation of intramolecular aspartimides (43). Direct O-glycosylation is often
plagued by low yields due to the low reactivity of the side-chain hydroxyls
and the low solubility of the peptides under conditions commonly employed for
chemical glycosylation (44–46). Currently the most general synthetic methodology
for glycopeptides relies on preformed glycosylated amino acids for
the stepwise solid-phase peptide synthesis (1,31–34). Consequently, efficient
synthetic routes to glycosylated amino acids for use as building blocks in solidphase
synthesis are of central importance in research dealing with preparation of
glycopeptides.
3.1. Synthesis of Glycosylated Amino Acids
The formation of glycosidic bonds is of fundamental importance in the
assembly of glycopeptides. As a consequence of immense structural variety, the
development of a universal glycosylation reaction has failed. As such, every
RO
RO
RO RO
A) Stepwise synthesis B) Convergent synthesis
OR
O
OR
aa
OR
O
[aa] n
OR
peptide
peptide
RO RO
RO RO
OR
O
X
OR
peptide
OR
O
OR
peptide
Scheme. 1. Synthetic strategies for glycopeptide preparations.