FREE-RADICAL THIOL-ENE AND THIOL-YNE COUPLINGS AS CLICK PROCESSES FOR GLYCOCONJUGATION - Click Chemistry in Glycoscience: New Developments and Strategies - page 51

OAc

O l 365 nm

AcO
AcO

max

SH

DPAP, CH 2 Cl 2

AcO

AcO OAc OAc

AcO

AcO OAc

O

1 O

OAc AcO OAc

(3 eq. x 4)

AcO S S

O AcO OAc

AcO

O

S S

AcO OAc

AcO

OAc

AcO OAc

AcO

O

AcO

O

O

OO AcO O O O O

O

OAc

AcO

N
NN

N
N N

N N

33 N N

N N

OAc

AcO OAc

O OAc

O O

AcO
AcO

AcO

OAc

AcO

OAc

CuI, i -Pr 2 EtN
toluene, r.t., 26 h

AcO AcO

N 3

32

(42%)

34

(1.1 eq. x 4)

SCHEME 3.9 Upper and lower rim calixarene glycoclustering by sequential CuAAC

and TEC.

As a final experiment in this topic, the dual clustering around the calix[4]arene
scaffold by two different glycoside fragments was examined. Thus, it was intended to
preparing a calix[4]arene-based glycocluster that could recognize two different lectins
at the same time. To this aim, we considered the use of sequential CuAAC and TEC
on an alkene and alkyne functionalized calix[4]arene derivative. The orthogonality
of these two click processes had not been assessed in previous studies. According to
this plan, the CuI-catalyzed reaction between galactosylmethyl azide 32 and tetra- O -
propargyl functionalized calix[4]arene 33 was first carried out (Scheme 3.9) [21]. As
expected, the reaction was totally chemoselective as it afforded an intermediate (not
shown) featuring the triazole-linked C -glycocluster at the lower rim while it contained
the unaltered set of C -allyl groups at the upper rim. Then, the photoinduced TEC
between this intermediate and the

-D-glucosyl thiol 1 was carried out to give product
34 . This compound featured two different tetravalent glycoclusters attached to the
lower and upper rims of the same calix[4]arene scaffold, one being constituted of
galactose residues and the other of glucose residues. As galactose and glucose display
an affinity for different lectins [22], 34 can play a double role in molecular recognition
processes. Before closing this section, it is worth noting that CuAAC and TEC are
fully orthogonal in the sequential approach employed while a reversal of the reaction
sequence, that is, the occurrence of TEC first, is not possible because the potential
consumption of the alkynyl groups by the concomitant TYC.
Synthesis of glycocluster 34 . A mixture of calixarene 33 (44 mg, 0.06 mmol),
sugar azide 32 (102 mg, 0.26 mmol), freshly distilled N,N -diisopropylethylamine
(210 L, 1.20 mmol), CuI (11.4 mg, 0.06 mmol), and anhydrous toluene (1.20 mL)

was sonicated in an ultrasound cleaning bath for 1 minute, then magnetically stirred in
the dark at room temperature for 26 hours, diluted with AcOEt (ca. 20 mL), filtered
through a pad of Celite to remove most of the copper salts, and concentrated. A
solution of the resulting yellow syrup in pyridine (2 mL) and acetic anhydride (2 mL)