FREE-RADICAL THIOL-ENE AND THIOL-YNE COUPLINGS AS CLICK PROCESSES FOR GLYCOCONJUGATION - Click Chemistry in Glycoscience: New Developments and Strategies - page 49

[ 18.8 ( c 0.4, CHCl 3 ), were obtained by column chromatography purification

(1.5:1 AcOEt-cyclohexane) of the above mixture.
In conclusion, it appeared that photoinduced TEC of sugar thiols with glycals
was totally regioselective as it furnished only sulfides arising from the attack of the
thiyl radical at C2 of the glycal. On the other hand, the reaction showed variable
stereoselectivity and it afforded axially and equatorially substituted diastereomers in
different ratios depending on the glycal stereochemistry at C3 and C4. Nevertheless,
the synthetic value of this route to a new family of S -disaccharides appeared to have
been sufficiently established.

] D =−

3.3 CALIX[4]ARENE-BASED GLYCOCLUSTERS

It is firmly established that a myriad of key physiological and pathological events
occur through interactions between carbohydrate and sugar-binding proteins called
lectins [18]. The first step of influenza virus infection, for example, involves the
viral hemagglutinin-mediated adhesion of the virion to sialic acid residues that are
present on the surface of endothelial cells. A similar approach is exploited by bacteria
and parasites. Such interactions, however, are usually weak, with K D values of the
order of mM for monosaccharides. However, when a set of multivalent saccharides
is clustered together with the right structure and disposition, the interaction becomes
strong and specific: multiple weak interactions result in strong adhesion. Notably,
this augmented association is more than what would be expected on the basis of
the increased carbohydrate local concentration: this phenomenon has been referred
to as the glycoside cluster effect [19]. It is quite obvious that in order to intervene
efficiently on these interactions, multivalent external agents have to be employed.
In this context, one can envisage the use of glycoclusters firmly anchored to a
conformationally rigidified platform such as a calix[4]arene, as suitable systems for
protein recognition and consequently protein activity inhibition. This is especially
important in those cases in which protein-carbohydrate interactions are detrimental
such as viral and bacterial infections, inflammations, and cancer metastasis.
Following previous work from our laboratory in which calix[4]arene-based O -
and C -glycoclusters were synthesized by different ligation strategies [20], the prepa-
ration of calix[4]arene-based S -glycoclusters via TEC was carried out. In all cases
examined, the main problem to be addressed was to find suitable conditions so that
four concomitant TECs occurred efficiently on the same calix[4]arene scaffold. This
would avoid the formation of partially glycosylated products. Thus, the photoinduced
reaction of tetra-allyl calix[4]arene 28 was carried out by using a significant excess of
sugar thiol 1 , that is, 3 eq. per allyl group (Scheme 3.7) [21]. Under these conditions
glycosylation of calix[4]arene 28 was complete to give the tetravalent calix[4]arene-
based S -glycocluster 29 in 78% isolated yield. From this yield it can be calculated
that the average yield of hydrothiolation of each allyl group of 28 was 95%, thus
confirming the high efficiency of TEC. Finally, it was observed that the photoinduced
reaction did not induce any change to the calixarene structure as the NMR spectrum
of the product 29 showed that the macrocycle was in its original cone conformation.