Calixarenes  have been widely employed in host—guest chemistry, first as ligands for small ions and neutral molecules [12,13] and, more recently, for biologically relevant molecules and macromolecules . Multivalent calixarenes functionalised with carbohydrate units glycocalixarenes  have been extensively reported in the literature and represent examples of sugar clustering on macrocyclic structures [16,17].
Some glycocalixarenes have shown remarkable inhibition properties towards galectins [21,22] or Pseudomonas Aeruginosa lectin  , the inhibition ability being dependent on the macrocyclic conformation and presentation of the glycoside units. With the purpose of expanding the valency and increasing the glycoside density, glycodendrimers have also been synthesised and their properties in protein—carbohydrate interactions have been studied . However, the innovative frontier of combining glycodendrimeric arrangements onto a calixarene core has only occasionally been explored.
To the best of our knowledge, only one example in which a glycodendrimer was built on a calixarene core has been published  , while no examples of iminosugar-based calixarene dendrimers have been reported so far. We report herein the synthesis of low-generation iminosugar-type calixarene-based dendrimers, demonstrating the feasibility of increasing the valency of the cluster by combining a dendrimeric arrangement of iminosugar ligands with a multivalent calixarene core.
This allows a rapid increase of the valency of the iminosugar dendrimer in a reduced volume. The linkable hydroxy groups of the pyrrolidine rings open up the possibility of constructing calixarene-based dendrimers  of higher generation. In addition to its properties as a chiral building block, pyrrolidine 1 may be considered an elemental iminosugar, and it is, by far, easier to handle and to characterise as a consequence of its symmetry.
The synthesis of model iminosugar-based calixarene dendrimers may open the way for the construction of more complex systems, decorated with biologically active polyhydroxylated pyrrolidines or piperidines.
Dendrimers in Supramolecular Chemistry: From Molecular
Figure 1: First 2 and second 3 generation of dendrimers based on chiral C 2 -symmetric pyrrolidine 1 and having p - tert- butyl calixarene as the scaffold. Figure 1: First 2 and second 3 generation of dendrimers based on chiral C 2 -symmetric pyrrolidine 1 and ha The starting calixarene used in this work was the commercially available p - tert- butyl calixarene, which has the phenolic hydroxy groups at the lower rim and the tert- butyl groups at the upper rim. These moieties allowed the subsequent conjugation by amide bond formation between 11 and the suitably protected pyrrolidine derivatives 4 and 5 in order to obtain the calixarene-dendrimers 2 and 3 , respectively.
Tripyrrolidine 5 required for the second generation calixarene-dendrimer 3 was prepared starting again from the key intermediate 6 , but in this case a modified multistep synthetic procedure was necessary. This simple process is unprecedented and may result in a new straightforward method to convert N -benzyl amines into N -Boc amines once a series of similar compounds are screened.
On the other hand, alkylation of the hydroxy groups of 7 with the 2-ethoxycarbonylmethyl linker was problematic. In fact, when sodium hydride was used as a deprotonating agent, no reaction occurred after in situ addition of ethyl bromoacetate. The N -protected pyrrolidine 8 was then activated for the coupling with pyrrolidine 4 in order to obtain the pyrrolidine-based dendron 5 to be used in assembling the second-generation calixarene-dendrimer 3.
Scheme 1: Use of the key intermediate 3 S ,4 S benzyl-3,4-dihydroxypyrrolidine 6  for the synthesis of pyrrolidine 4 and the pyrrolidine-based dendron 5. Reagents and conditions: i. Scheme 1: Use of the key intermediate 3 S ,4 S benzyl-3,4-dihydroxypyrrolidine 6  for the synthesis of pyr Using the SuO-activated calixarene 11 as the scaffold, the planned convergent synthetic approach was completed to afford the first 2 and second 3 generation iminosugar-based calixarene dendrimers.
Thus, an increase of the valency of a model iminosugar dihydroxypyrrolidine 4 in a controlled manner and geometry, by its conjugation to the calixarene scaffold 11 in a dendrimeric fashion, could be demonstrated. Quite interestingly, we could also prove the feasibility of the iminosugar deprotection on the calixarene dendrimer 2. Scheme 2: Synthesis of calixarene-based dendrimers 2 and 3. The presence of acetamide moieties at the lower rim of the dendrimers 2 and 3 prompted us to explore the possibility to use alkali metal salts as allosteric effectors in the modulation of the shape and rigidity of the iminosugar presentation by the calixarene scaffold.
The ability of first-generation calixarene dendrimer 2 to bind alkali-metal cations was tested by means of NMR, by solid—liquid extraction of solid alkali picrate salts into a CDCl 3 solution of ligand 2. A mixture of 0. As the picrate salts are scarcely soluble in CDCl 3 , the comparison of the integrals of the picrate signal a singlet of 2H, around 8.
Figure 2: Expansion about 7 to 3 ppm of the 1 H NMR spectra of A the free ligand 2 , B the sodium picrate complex, and C the potassium picrate complex. Less important shifts are obviously observed for the pyrrolidine ring protons, which are quite far from the binding region. Figure 3: Schematic of the inclusion of alkali-metal ions sodium and potassium in the polar cavity defined by the acetamide moieties at the lower rim of the calixarene, and its effect on the rigidification of the calixarene scaffold and organisation of iminosugars.
Figure 3: Schematic of the inclusion of alkali-metal ions sodium and potassium in the polar cavity defined These results show, therefore, that, in spite of the bulky substituents present on the pyrrolidine nuclei, the amide groups can still bind alkali-metal ions quite efficiently. This encourages the use of such compounds not only to study the metal-ion effect on the organisation of iminosugars and on the rigidification of the calixarene scaffold, but also to exploit the ability of these chiral ligands to enantioselectively recognise chiral salts  or the ability of their transition-metal complexes to catalyse enantioselective syntheses [38,39] , which are objects of current investigations.
In all cases the Ref. XX is the XXth reference in the list of references.
Vögtle / Schalley | Dendrimers IV | | Metal Coordination, Self Assem |
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Metal Coordination, Self Assembly, Catalysis
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