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OAc
OAc
AcO
AcO
O
N
3
N
3
N
3
N
3
O
5
6
N
3
N
3
4
N
3
N
3
O
N
3
N
3
N
3
N
3
N
3
N
N
N
3
N
3
N
3
O
N
O
N
3
7
8
9
N
3
OAc
OAc
OAc
(Ph
3
P)
3
·CuBr
or (EtO)
3
P·CuI
DIPEA or DBU
MW
O
AcO
AcO
OAc
AcO
AcO
O
X
Core
N
1 , X = O
2 , X = S
3 , X = NAc
X
N
N
n
1 0 ,,,
n (1, 2, 3, 4 or 6)
SCHEME 6.1
Synthesis of mulivalent click glycoconjugates onto aliphatic and aromatic
platforms.
yields. The coupling reactions were conducted in toluene with (Ph
3
P)
3
,
·
CuBr, or
·
(EtO)
3
P
CuI as Cu(I) catalysts soluble in organic solvents, in the presence of diiso-
propylethylamine (DIPEA) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and under
microwave irradiation (MW; Scheme 6.1).
Several modifications of the reaction conditions have been proposed, such as the
use of noncomplexed CuI [27], solid-supported Cu(I) catalysts [28, 29], unprotected
carbohydrate precursors [30, 31], aqueous solvent mixtures [32], the production of
Cu(I) in the reaction mixture by reduction of Cu(II) with sodium ascorbate (NaAsc)
[33], and the generation of the azide reagent
in situ
from a fully unprotected sugar [34]
or from an amine precursor by Cu(II)-catalyzed diazo transfer [35]. Nevertheless,
the general scheme remains essentially the same. Click strategies have also been
implemented to design glycosensors by clusterizing sugars onto electroactive (e.g.,
ferrocene) [36, 37], optically active (e.g., anthraquinone) [38], or fluorescent cores
(e.g., tetraphenylethylene) [39]. Notably, the chemoselectivity and broad functional
group tolerance of the click reaction conditions allows the use of bifunctional scaffolds
(e.g., the
-trehalose derivative
11
) that can be elaborated after a first click cycle
,
(
12
;byreactionof
11
with the mannose-derived azide
4
) to activate the adduct
for a second coupling (
→
13
), thereby accessing heteroglycoclusters with controlled
arrangements of different sugar motifs (e.g.,
15
;byreactionof
13
with the glucose-
derived alkyne
14
) (Scheme 6.2) [40].
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