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FIGURE 10.2
Three model peptides synthesized by Lee et al. [40].
could be performed in a one-pot fashion, removing the need for intervening work-
up and chromatography. Peptide-thioester
17
and Cys-peptide
19
were subjected
to NCL conditions overnight. When ligation was complete, CuSO
4
was added to
the reaction, followed by GalNAc-N
3
(
20
) (Scheme 10.8). Pleasingly, after 2 hours
at room temperature, the formation of the clicked triazole peptides was observed
with the two different mono-triazole products, and the desired di-triazole peptide
21
distinguished by LC-MS. After 6 hours, all mono-triazole products had undergone
complete conversion to the double click neoglycopeptide
21
, which was readily
purified by high-performance liquid chromatography (HPLC).
This study demonstrated that the two ligation chemistries—NCL and CuAAC—
are fully compatible and can be carried out sequentially in a one-pot fashion, reducing
the number of isolation or purification steps. Subsequently, Steinhagen et al. have
shown that these chemistries can be also performed simultaneously [50]. Unprotected
peptides and azido-sugars can be successfully combined through native chemical lig-
ation and click chemistry in an efficient, one-pot synthesis of a neoglycopeptide.
This opens up the whole native chemical ligation toolkit (including kinetically con-
trolled ligation [51], auxiliary-mediated native chemical ligation, and native chemical
ligation-desulfurization [52]) for the synthesis of larger neoglycopeptides and com-
plete neoglycoproteins.
10.6 LARGE COMPLEX NEOGLYCOPROTEINS
10.6.1 Combining Click Chemistry with NCL for the de novo Synthesis of
Large Neoglycoprotein Constructs
To date, most mimetics of whole glycoproteins are accessed through biomolecular
expression systems [53]. This is often achieved by carrying out chemoselective con-
jugations between unnatural functionalities (such as an alkyne) within the peptide
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