be retrieved from the solid-phase support, and the carbohy-
drate chains will be finally deprotected to afford the target.
However, there are two concerns about the process. One is
associated with the retrieval of glycopeptides from the solid-
phase support, which is usually achieved under strong acidic
conditions such as a 95% aqueous solution of trifluoroacetic
acid (TFA) that may affect some labile glycosidic linkages
and protecting groups.22 The other concern is associated with
the deprotection of carbohydrates, which could potentially
affect the glycopeptides and amino acid residues.18,23 Thus,
chemical synthesis of glycopeptides still remains an impor-
tant challenge, despite the great progress in the field.
To deal with this synthetic problem, we introduce herein
a new strategy using free glycosyl amino acids as building
blocks and the “phase tags” (Scheme 1). First, the glycosyl
as well as the commercially available simple amino acids
as incoming units for peptide elongation. Finally, the side
chains of amino acids will be deprotected by moderate acids
such as 25-50% TFA in dichloromethane (DCM) to afford
the free glycopeptide target 4.
One important property of this design is the use of free
carbohydrates as phase tags to facilitate the isolation of
product of each step during the assembly of glycopeptides.
As free sugars and their conjugates are only soluble in very
polar organic solvents, not in nonpolar ones, peptide elonga-
tion can be conducted in homogeneous solutions of a polar
solvent, but product isolations can be achieved via a
precipitation method, i.e., via addition of a nonpolar solvent
to the reaction mixtures, with the side products and excess
reagents remaining in solution. The precipitates can be further
purified by washing with proper solvents. This separation
procedure is similar to that of soluble polymer-supported and
other phase-tagged organic syntheses.24-30 However, after
the glycopeptide assembly is accomplished in our design, it
is not required to cut off the phase tags since they are a part
of the final targets.
Scheme 1
Thus, the new synthetic strategy will take the advantages
of homogeneous reactions in solution-phase synthesis and
the convenient workup in solid-phase synthesis. Moreover,
it can circumvent the two problematic steps involved in
traditional methods, namely, retrieval of glycopeptides from
the polymer support and deprotection of the carbohydrates.
Finally, as all the intermediates should be soluble in proper
solvents, it will be simple to monitor the reactions by TLC
and other conventional methods such as NMR and MS.
For the strategy to work, we have to find an appropriate
solvent that is able to dissolve glycopeptides bearing free
oligosaccharides and is compatible with reactions involved
in glycopeptide elongation. N-Methylpyrrolidone (NMP) is
a promising choice for this purpose, for NMP can dissolve
a variety of compounds, including free sugars. In addition,
NMP is a common solvent in peptide synthesis, which should
be compatible to the reactions involved in the new strategy.
On the other hand, it is also necessary to ensure that the
(18) Nakahara, Y.; Nakahara, Y.; Ogawa, T. Carbohydr. Res. 1996, 292,
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amino acids will be prepared, in which the carbohydrates
are unprotected. Then, a glycopeptide can be assembled
starting from one glycosyl amino acid, e.g., 1, with the others
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