Low-generation dendrimers with a calixarene core and based on a chiral C2-symmetric pyrrolidine as iminosugar mimics

Article abstract of DOI:10.3762/bjoc.8.107

The preparation of low-generation dendrimers based on a simple calix[4]arene scaffold by insertion of the iminosugar-analogue C ₂-symmetric 3, 4-dihydroxypyrrolidine is described. This methodology allows a rapid incorporation of a considerable number of iminosugar-like moieties in a reduced volume and in a well-defined geometry. 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 was demonstrated, which allows also the rigidification of the dendrimer structure and the iminosugar presentation in the clusters. The combination of the supra-molecular properties of calixarenes with the advantage of a dendrimeric presentation of repetitive units opens up the possibility of generating well-defined multivalent and multifaceted systems with more complex and/or biologically relevant iminosugars.

Full text of DOI:10.3762/bjoc.8.107

Low-generation dendrimers with a calixarene core
and based on a chiral C2-symmetric pyrrolidine
as iminosugar mimics
Marco Marradi*1,§, Stefano Cicchi1, Francesco Sansone2,
Alessandro Casnati2 and Andrea Goti1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 951–957.
1Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di
doi:10.3762/bjoc.8.107
Firenze, via della Lastruccia 13, I-50019 Sesto Fiorentino (Firenze),
Italy and 2Dipartimento di Chimica Organica e Industriale, Università
degli Studi di Parma, Parco Area delle Scienze 17/A, I-43124 Parma,
Italy
Received: 28 April 2012
Accepted: 30 May 2012
Published: 26 June 2012
Email:
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
Marco Marradi* - mmarradi.ciber-bbn@cicbiomagune.es;
Stefano Cicchi - stefano.cicchi@unifi.it; Francesco Sansone -
francesco.sansone@unipr.it; Alessandro Casnati - casnati@unipr.it;
Andrea Goti - andrea.goti@unifi.it
Guest Editor: T. K. Lindhorst
©
2012 Marradi et al; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
§
present address: Laboratory of GlycoNanotechnology, Biofunc-
tional Nanomaterials Unit, CIC biomaGUNE / CIBER-BBN, Pº
Miramón 182, San Sebastián E-20009, Spain
Keywords:
calixarenes; cation-responsive system; dendrimers; iminosugars;
multivalency
Abstract
The preparation of low-generation dendrimers based on a simple calix[4]arene scaffold by insertion of the iminosugar-analogue
C2-symmetric 3,4-dihydroxypyrrolidine is described. This methodology allows a rapid incorporation of a considerable number of
iminosugar-like moieties in a reduced volume and in a well-defined geometry. 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 was demonstrated, which allows
also the rigidification of the dendrimer structure and the iminosugar presentation in the clusters. The combination of the supra-
molecular properties of calixarenes with the advantage of a dendrimeric presentation of repetitive units opens up the possibility of
generating well-defined multivalent and multifaceted systems with more complex and/or biologically relevant iminosugars.
Introduction
Polyhydroxylated pyrrolidines are one of the main classes of potential as therapeutics due to the ability to inhibit glycosi-
naturally occurring sugar mimics [1,2] and belong to the dases and other enzymes associated with the metabolism of
so-called iminosugars [3]. Several iminosugars have shown polysaccharides and the processing of glycoproteins [3].
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Beilstein J. Org. Chem. 2012, 8, 951–957.
Conjugation of iminosugars onto a polyvalent skeleton has been combining glycodendrimeric arrangements onto a calixarene
investigated only occasionally, and their properties as multi- core has only occasionally been explored. To the best of our
valent enzyme inhibitors gave contrasting results. Early find- knowledge, only one example in which a glycodendrimer was
ings indicated in fact that poor multivalent phenomena take built on a calixarene core has been published [27], while no
place [4-6], but more recently moderate [7] to remarkable [8,9] examples of iminosugar-based calixarene dendrimers have been
effects have been reported on glycosidases. Unlike lectin-medi- reported so far.
ated interactions [10], the effect of iminosugar-based multi-
valent inhibitors on enzyme activity is difficult to rationalise. We report herein the synthesis of low-generation iminosugar-
However, the introduction of several copies of an N-alkyl type calixarene-based dendrimers, demonstrating the feasibility
analogue of iminosugar 1-deoxynojirimycin onto a fullerene of increasing the valency of the cluster by combining a
ball [8] or onto β-cyclodextrin [9] afforded the first pieces of dendrimeric arrangement of iminosugar ligands with a multi-
evidence for a significant multivalent effect in glycosidase valent calixarene core.
inhibition. These results highlight the interest in synthesizing
multivalent iminosugar-conjugates with well-defined structures. Results and Discussion
In this context, we aimed at studying the feasibility of We chose to address the conjugation of iminosugar-analogue
combining the supramolecular properties of multivalent scaf- dendrimers, based on the C2-symmetric (3S,4S)-3,4-
folds, such as calixarenes, with the advantages of a dendrimeric dihydoxypyrrolidine (1) unit, to a simple calix[4]arene scaffold
presentation of iminosugar analogues.
(Figure 1). This allows a rapid increase of the valency of the
iminosugar dendrimer in a reduced volume. The C2 symmetry
Calixarenes [11] have been widely employed in host–guest of pyrrolidine 1, its ready accessibility from the “chiral pool”
chemistry, first as ligands for small ions and neutral molecules (L-tartaric acid) [28], and its functional groups (an anchoring
[
12,13] and, more recently, for biologically relevant molecules amine and two transformable hydroxy groups) make it a con-
and macromolecules [14]. Multivalent calixarenes functional- venient chiral AB2 building block for the construction of
ised with carbohydrate units (glycocalixarenes) [15] have been dendrimers [29]. The linkable hydroxy groups of the pyrrolidine
extensively reported in the literature and represent examples of rings open up the possibility of constructing calixarene-based
sugar clustering on macrocyclic structures [16,17]. Thanks to dendrimers [30] of higher generation. In addition to its prop-
the “glycoside cluster effect” [18-20], glycocalixarenes can erties as a chiral building block, pyrrolidine 1 may be
enhance the avidity of interactions between glycans and lectins considered an elemental iminosugar, and it is, by far, easier to
[
15]. Some glycocalixarenes have shown remarkable inhibition handle and to characterise as a consequence of its symmetry.
properties towards galectins [21,22] or Pseudomonas Aeru- The synthesis of model iminosugar-based calixarene dendrimers
ginosa lectin [23], the inhibition ability being dependent on the may open the way for the construction of more complex
macrocyclic conformation and presentation of the glycoside systems, decorated with biologically active polyhydroxylated
units. With the purpose of expanding the valency and increasing pyrrolidines or piperidines.
the glycoside density, glycodendrimers have also been synthe-
sised and their properties in protein–carbohydrate interactions The synthesis of first- and second-generation iminosugar-based
have been studied [24-26]. However, the innovative frontier of calixarene-dendrimers 2 and 3 (Figure 1) was addressed in
Figure 1: First (2) and second (3) generation of dendrimers based on chiral C2-symmetric pyrrolidine 1 and having p-tert-butyl calix[4]arene as the
scaffold.
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order to prove the viability of such a strategy. A convergent Boc2O (Scheme 1). This simple process is unprecedented and
synthetic approach was chosen for the conjugation of may result in a new straightforward method to convert N-benzyl
pyrrolidine 4 and pyrrolidine-based dendron 5 (see Scheme 1) amines into N-Boc amines once a series of similar compounds
to the calix[4]arene core, via intermediate 11, in order to obtain are screened. On the other hand, alkylation of the hydroxy
iminosugar-based calixarene-dendrimers 2 and 3 (see groups of 7 with the 2-ethoxycarbonylmethyl linker was
Scheme 2). The starting calixarene used in this work was the problematic. In fact, when sodium hydride was used as a
commercially available p-tert-butyl calix[4]arene, which has the deprotonating agent, no reaction occurred after in situ addition
phenolic hydroxy groups at the lower rim and the tert-butyl of ethyl bromoacetate. However, a mixture of mono-(8') and
groups at the upper rim. Functionalization of p-tert-butyl di-(8) substituted products was obtained by using metallic
calix[4]arene was performed by standard conversion of the potassium (Scheme 1). In spite of the poor yield (35%) of the
hydroxy groups of the lower rim to activated acetic acid succin- desired product 8, the starting material 7 and the mono-
imide ester (COOSu) moieties (compound 11, see Scheme S2 in derivative 8' could be recovered after column chromatography
Supporting Information File 1). These moieties allowed the over silica gel, and used again for the same reaction. The
subsequent conjugation by amide bond formation between 11 N-protected pyrrolidine 8 was then activated for the coupling
and the suitably protected pyrrolidine derivatives 4 and 5 in with pyrrolidine 4 in order to obtain the pyrrolidine-based
order to obtain the calixarene-dendrimers 2 and 3, respectively. dendron 5 to be used in assembling the second-generation
The synthesis of (3S,4S)-3,4-bis(tert-butyldimethylsilyl- calixarene-dendrimer 3. In particular, succinimidyl-activated
oxy)pyrrolidine (4) was achieved by following a reported pyrrolidine 9 was obtained by hydrolysis of ester groups in 8
procedure [31], via the key intermediate 6 (Scheme 1 and followed by treatment with DCC/NHS (two steps, 80% overall
Supporting Information File 1). Tripyrrolidine 5 required for the yield). The amide coupling was then performed by reaction
second generation calixarene-dendrimer 3 was prepared starting of 9 with pyrrolidine 4 using DIPEA as a base, and this
again from the key intermediate 6, but in this case a modified afforded the branched tripyrrolidine 10 in 77% yield after
multistep synthetic procedure was necessary. First, N-Boc di- column chromatography over neutral aluminium oxide.
hydroxypyrrolidine 7 was obtained from 6 through a “one pot” The tert-butoxycarbonyl group was then removed in the
change of protecting group from benzyl to tert-butoxycarbonyl, presence of TFA to obtain the pyrrolidine-based dendron 5
which occurred in excellent yield by performing the catalytic (Scheme 1), which was used in the next step without further
hydrogenation in methanol under reflux and in the presence of purification.
Scheme 1: Use of the key intermediate (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (6) [31] for the synthesis of pyrrolidine 4 and the pyrrolidine-based
dendron 5. Reagents and conditions: i. Pd(OH)2/C, MeOH, HCOO−NH4+, Boc2O, reflux, 3 h, 95%; ii. K, THF, 0 °C to rt, 16 h; iii. BrCH2CO2Et, 4 h,
3
7
5% (8) and 17% (8'); iv. KOH 1 N, EtOH, reflux, 3.5 h, quantitative; v. N-hydroxysuccinimide (NHS), AcOEt, dicyclohexylcarbodiimide (DCC), 30 °C,
2 h, 80%, (Su: succinimidyl); vi. N,N-diisopropylethylamine (DIPEA), CH2Cl2, 30 °C, 5 d, 77%; vii. trifluoroacetic acid (TFA), CH2Cl2, rt, 16 h, quanti-
tative.
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Beilstein J. Org. Chem. 2012, 8, 951–957.
Scheme 2: Synthesis of calixarene-based dendrimers 2 and 3. Reagents and conditions: DIPEA, CH2Cl2, 30 °C, 5 d, (Su: succinimidyl; TBDMS: tert-
butyldimethylsilyl).
Using the SuO-activated calix[4]arene 11 as the scaffold, the geometry, by its conjugation to the calixarene scaffold 11 in a
planned convergent synthetic approach was completed to afford dendrimeric fashion, could be demonstrated. Quite interest-
the first (2) and second (3) generation iminosugar-based calix- ingly, we could also prove the feasibility of the iminosugar
arene dendrimers. The coupling between calixarene 11 and deprotection on the calixarene dendrimer 2. By treatment with
pyrrolidine derivatives 4 or 5 was performed as reported before CsF in EtOH, the eight tert-butyldimethylsilyl groups could be
for the synthesis of compound 10 (Scheme 1) and is shown in removed and the deprotected derivative 12 was obtained in 56%
Scheme 2. The identity of both final compounds 2 and 3, yield after trituration with CH2Cl2 and washing several times
obtained in good yields (77% and 68%, respectively), was with water.
assessed by their spectroscopic data and elemental analysis (see
Supporting Information File 1). In particular, integration ratios The presence of acetamide moieties at the lower rim of the
of the calixarene aromatic (8H, δ ≈ 7 ppm) and tert-butyl dendrimers 2 and 3 prompted us to explore the possibility to use
signals (36H, δ ≈ 1 ppm) versus those of the CH3 of TBDMS at alkali metal salts as allosteric effectors in the modulation of the
ca. 0 ppm were in good agreement with the number of the shape and rigidity of the iminosugar presentation by the calix-
expected protons for dendrimers 2 and 3 (48H and 96H, res- arene scaffold. A common way, in fact, used to rigidify the
pectively). Thus, an increase of the valency of a model “mobile cone” structure of tetraalkoxycalix[4]arenes is to intro-
iminosugar dihydroxypyrrolidine 4 in a controlled manner and duce strong donating groups, such as amide or ester [32,33], on
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Beilstein J. Org. Chem. 2012, 8, 951–957.
the phenolic oxygen atoms and an alkali-metal ion. The cation, as a consequence of the electron-withdrawing effect of the
strongly coordinated by eight oxygen atoms in the polar region metal ion coordinated to the phenolic oxygen.
created at the lower rim, blocks the calixarene in a “rigid cone”
structure [34], also controlling the convergence of the Quite remarkable is the up-field shift exerted by the OCH2CON
iminosugars.
protons (empty circles in Figure 2), which is due to their posi-
tioning close to the shielding cone of the aromatic nuclei as a
The ability of first-generation calixarene dendrimer 2 to bind consequence of the C=O coordination to the metal ion
alkali-metal cations was tested by means of NMR, by (Figure 3). Interesting, and not observed for achiral calixarene
solid–liquid extraction of solid alkali picrate salts into a CDCl3 tetramide ligands, is the splitting of the OCH2CON methylene
solution of ligand 2. A mixture of 0.5 equiv of sodium or protons into an AB system (empty circles in Figure 2), which,
potassium picrate and ligand 2 showed the simultaneous pres- especially in the case of the Na+ complex, indicates a quite
ence of the peaks of the complex and of the free ligand indic- different chemical environment for the two geminal protons and
ating a slow exchange regime on the NMR timescale. On the could be the consequence of a quite twisted square antiprism of
other hand, the NMR analysis of a CDCl3 solution of ligand 2 coordination around the cation [36]. Consistent shifts are
in the presence of an excess of metal picrate (see Figure S1 in observed for the methylene bridge protons (filled circles in
Supporting Information File 1) allowed the stoichiometry of the Figure 2), which are in line with previous observations but more
complex to be established. As the picrate salts are scarcely difficult to be rationalised also as a consequence of a slight con-
soluble in CDCl3, the comparison of the integrals of the picrate formational rearrangement of the calixarene scaffold. Less
signal (a singlet of 2H, around 8.8 ppm) and of the calixarene important shifts are obviously observed for the pyrrolidine ring
aromatic protons (a signal of 8H at 7.00–7.10 ppm) indicated protons, which are quite far from the binding region.
that the complexes (both with sodium and potassium) have a 1:1
stoichiometry. As it can be seen in Figure 2, and as reported These results show, therefore, that, in spite of the bulky
also for other alkali-metal ion complexes of similar tetramide substituents present on the pyrrolidine nuclei, the amide groups
ligands [35], the cation complexation induces a strong can still bind alkali-metal ions quite efficiently. This encour-
deshielding effect on the aromatic protons of about 0.3 ppm ages the use of such compounds not only to study the metal-ion
with respect to the free calixarene (as indicated by the asterisks) effect on the organisation of iminosugars and on the rigidifica-
Figure 2: Expansion (about 7 to 3 ppm) of the 1H NMR spectra of (A) the free ligand 2, (B) the sodium picrate complex, and (C) the potassium picrate
complex. The full spectra are reported in Supporting Information File 1 (Figure S1). Asterisks: aromatic protons; empty circles: OCH2CON protons;
filled circles: methylene bridge protons.
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Beilstein J. Org. Chem. 2012, 8, 951–957.
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.
tion of the calixarene scaffold, but also to exploit the ability of Acknowledgements
these chiral ligands to enantioselectively recognise chiral salts Cassa di Risparmio di Firenze is acknowledged for granting a
[
37] or the ability of their transition-metal complexes to cata- 400 MHz spectrometer. Maurizio Passaponti and Brunella Inno-
lyse enantioselective syntheses [38,39], which are objects of centi (Università degli Studi di Firenze) are acknowledged for
current investigations.
technical assistance. MM thanks the Networking Research
Center on Bioengineering, Biomaterials and Nanomedicine
(CIBER-BBN). AC and MM acknowledge COST action
Conclusion
The coupling of low-generation dendrons, based on the chiral CM1102. AC and FS also acknowledge PRIN200858SA98 for
C2-symmetric dihydroxypyrrolidine 1, with a calix[4]arene partial support.
scaffold allowed the construction of novel supramolecular
architectures, i.e., iminosugar-analogue-based calixarene References
dendrimers. The convergent synthetic approach used permits
the rapid increase of the valency of the iminosugar presentation.
Complexation studies with sodium or potassium picrate, carried
out on the calixarene-dendrimer 2, indicated an effective
binding of the metal cation at the calixarene lower rim that
induces a rigidification of the macrocyclic scaffold and, as a
consequence, the convergence of the iminosugars into a
restricted region of space. These chiral multivalent dendrimers
could thus be interestingly engaged in enantioselective recogni-
tion and catalysis. Up to now, pyrrolidine 1 has been used both
as a dendrimeric building block and iminosugar model; its
substitution at the hydroxy groups with more complex and bio-
logically active iminosugars, such as polyhydroxylated
pyrrolidines, would also allow the investigation of the corres-
ponding calixarene dendrimers in interactions with enzymatic
receptors.
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