Synthesis and characterization of some novel glycodendrimers and N-alkyldendrimers with amide core and triazole functionality through click chemistry

Article abstract of DOI:10.1080/00397911.2012.696304

The syntheses of various types of 1,2,3-triazole-based dendrimers 1-4 with sugar pyranosylazides and N-ethyl and N-heptylazides as a surface unit and benzene-1,3,5- tricorboxlyic amide as core unit through click chemistry approach are described. Copyright

Full text of DOI:10.1080/00397911.2012.696304

This article was downloaded by: [Monash University Library]
On: 05 June 2013, At: 05:18
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis and Characterization of
Some Novel Glycodendrimers and N-
alkyldendrimers with Amide Core and
Triazole Functionality through Click
Chemistry
Perumal Rajakumar a & Ramasamy Anandhan a
a Department of Organic Chemistry , University of Madras ,
Chennai , India
Accepted author version posted online: 26 Jan 2013.Published
online: 03 Jun 2013.
To cite this article: Perumal Rajakumar & Ramasamy Anandhan (2013): Synthesis and
Characterization of Some Novel Glycodendrimers and N-alkyldendrimers with Amide Core and Triazole
Functionality through Click Chemistry, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:16, 2217-2225
To link to this article: http://dx.doi.org/10.1080/00397911.2012.696304
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 2217–2225, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.696304
SYNTHESIS AND CHARACTERIZATION OF
SOME NOVEL GLYCODENDRIMERS AND
N-ALKYLDENDRIMERS WITH AMIDE CORE
AND TRIAZOLE FUNCTIONALITY THROUGH
CLICK CHEMISTRY
Perumal Rajakumar and Ramasamy Anandhan
Department of Organic Chemistry, University of Madras, Chennai, India
GRAPHICAL ABSTRACT
Abstract The syntheses of various types of 1,2,3-triazole-based dendrimers 1–4 with sugar
pyranosylazides and N-ethyl and N-heptylazides as a surface unit and benzene-1,3,5-
tricorboxlyic amide as core unit through click chemistry approach are described.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Alkyne; azide; click chemistry; glycodendrimers; N-alkyldendrimers;
1,2,3-triazole
Received March 20, 2012.
Address correspondence to Perumal Rajakumar, Department of Organic Chemistry, University of
Madras, Guindy Campus, Chennai 600 025, India. E-mail: perumalrajakumar@gmail.com
2217

2218
P. RAJAKUMAR AND R. ANANDHAN
INTRODUCTION
Dendrimers have been synthesized by click chemistry using both divergent and
convergent approaches. The design and synthesis of dendritic architectures through
click chemistry has gained attention in recent years.[1] Cu(I)-catalyzed reaction
between azides and alkynes has the true nature of a ligation reaction and is ideally
suited for the construction of dendrimers.[2] Cu(I)-catalyzed Huisgen 1,3-dipolar
cycloaddition of azide and alkyne to get 1,4-disubstituted 1,2,3-triazoles is usually
refered as ‘‘click chemistry’’.[3] 1,2,3-Triazoles are heterocycles with a wide range
of applications that are receiving growing attention in biological and pharmaco-
logical research.[4] Moreover, triazoledendrimers find applications as flurophores,
chemosensors, and charge-transfer agents.[5]
The versatility and efficiency in dendrimer functionalization reaction under
mild reaction conditions and compatibility with effective potential surface functional
group is area of recent interest. Functionalization of the surface group at the chain
ends=peripheral of dendrimers, coupled with unprecedented control over molecular
structure, makes dendrimers extremely attractive candidates.[6–9] The importance of
chain end group in dendrimer technology is significant and widely used as a general
approach to the functionalization of the dendritic macromolecules.[10] The dendri-
mers have the advantage that the ratio of end groups can be systematically varied
over a wide range of end group ratios. However, the random distribution of end
groups is sufficient for many desired applications.[11] One of the most promising
applications is the presence of numerous chain end groups as multivalent binding
sites[12] for interaction with biological receptors and cell surfaces in the synthesis
of targeted drug-delivery systems.[13–15]
The surface group of dendrimers can be modified to make molecules with
novel biological properties that can exploit polyvalent and cooperative ligand inter-
actions.[16,17] Here we report the synthesis and the characterization of some novel
functionalized dendritic architectures 1–4 bearing sugar-pyranosides and N-alkyl
azides at the surface and 1,2,3-triazole as a branching unit by the click chemistry
approach (Fig. 1).
RESULTS AND DISCUSSION
The quantitative deprotection of the N-(tert-butyloxycarbonyl)tris[(propar-
gyloxy)methyl]aminomethane 5 with trifluoroacetic acid (TFA) at 0 ꢀC to room
temperature afforded the corresponding deprotected amino propargyl ether,
which without further purification was coupled with 0.3 equiv. of benzene-1,3,5-
tricarboxylic acid chloride in the presence of Et3N in dry dichloromethane (DCM)
at room temperature under N2 to give tris acetylene-terminated dendron 6 in 58%
yield (Scheme 1).
The 1H NMR spectrum of the tris acetylene-terminated dendron 6 displayed a
nine-proton triplet at d 2.54 (J 2.1) for acetylene C-H protons, an 18-proton doublet
at d 4.19 (J 2.4) due to the O-CH2 protons, and a three-proton singlet at d 8.59 for
the amide proton in addition to aliphatic and aromatic protons. The 13C NMR spec-
trum of the tris acetylene-terminated dendron 6 showed acetylene C-H carbon at d
75.1, O-CH2 carbon at d 79.6, and amide carbonyl carbon at d 165.9 in addition

GLYCODENDRIMERS AND N-ALKYLDENDRIMERS
2219
Figure 1. Structure of glycodendrimers or N-alkyl dendrimers.
to other aliphatic and aromatic carbons. The structure of the dendron 6 was further
confirmed from elemental analysis and by the appearance of molecular ion peak at
m=z 861 [Mþ] in the mass spectrum. The structure of dendron 6 was also confirmed
from spectral and analytical data.
Chain end functionalizaion was carried out by the reaction of 1 equiv. of
nanoacetylene-terminated tris acetylene dendron 6 with 9.1 equiv. of 2,3,4,6-tetra-O-
acetyl-a-D-glucopyranoazide 7 and 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosylazide 8
Scheme 1. Reagents and conditions: (i) TFA, CH2Cl2, 0 ꢀC to 28 ꢀC, 2 h; (ii) benzene-1,3,5-tri carboxylic
acid chloride, Et3N, CH2Cl2, 28 ꢀC, 8 h.

2220
P. RAJAKUMAR AND R. ANANDHAN
Scheme 2. Reagents and conditions: (i) CuSO4 ꢂ 5H2O, sodium ascorbate, THF=H2O, rt, 12 h.
using Cu(I)-catalyzed click reaction, providing glycodendrimers 1 and 2 in 98% and 96%
1
yields, respectively (Scheme 2). The H NMR spectrum of the glycodendrimer 1 dis-
played four different singlets at d 1.17, 2.02, 2.04, 2.09 (4ꢁ s, 108 H) for four different
methyl glucoacetate protons, an 18-proton singlet at d 4.67 due to the O-CH2 protons,
a nine-proton singlet at d 7.80 for the triazole proton, and a three-proton singlet at d 8.49
for amide proton in addition to other aliphatic and aromatic protons. The 13C NMR
spectrum of glycodendrimer 1 showed four different carbons at d 19.1, 20.0, 20.1, and
20.1 for four different methyl glucoacetate carbon, O-CH2 carbon at d 85.6, triazole car-
bon at 145.6, and amine carbonyl carbon at d 165.8 in addition to other aliphatic and
aromatic carbons. The structure of the glucodendrimer 1 was further confirmed from
elemental analysis and by the appearance of molecular ion peak at m=z 4228 [Mþ þ Na]
in mass spectrum. The structure of glycodendrimers 2 was also confirmed from spectral
and analytical data.

GLYCODENDRIMERS AND N-ALKYLDENDRIMERS
2221
Scheme 3. Reagents and conditions: (i) CuSO4 ꢂ 5H2O, sodium ascorbate, THF=H2O, rt, 12 h.
Chain end functionalizaion was carried out by the reaction of 1 equiv. of
nonacetylene-terminated tris acetylene dendron 6 with 9.1 equiv. of N-ethyl azide
9 and n-heptyl azide 10 using Cu(I)-catalyzed click reaction, providing N-ethyl-
dendrimer 3 and n-heptyldendrimer 4 in 94% and 96% yields, respectively
1
(Scheme 3). The H NMR spectrum of the N-heptyldendrimer 4 displayed a 27
proton triplet at d 0.85 (J 6.0) for methyl proton, an 18 proton-singlet at d 4.64
due to the O-CH2 protons, a nine-proton singlet at d 7.63 for the triazole proton,
and a three-proton singlet at d 8.45 for amide proton in addition to aliphatic and
aromatic protons. The 13C NMR spectrum of 4 showed a methyl carbon, N-CH2,
and O-CH2 carbons at d 14.0, 50.4, and d 68.8 respectively, triazole carbon at d
144.6, and amide carbonyl carbon at d 166.3 in addition to other aliphatic and
aromatic carbons. The structure of the N-heptyldendrimer 4 was further confirmed
from elemental analysis and by the appearance of a molecular ion peak at m=z 3388
[Mþ þ Na] in the mass spectrum. The structure of N-ethyldendrimer 3 was also
confirmed from spectral and analytical data.

2222
P. RAJAKUMAR AND R. ANANDHAN
EXPERIMENTAL
All the reagents and solvents employed were of the best grade available and
are used without further purification. The melting points were determined using
a Toshniwal melting-point apparatus by open capillary tube method and were
1
uncorrected. H NMR and 13C NMR spectra were recorded on Bruker 300-MHz
instruments. Tetramethylsilane (TMS) was used as the internal standard. Mass
spectra (MS) were recorded obtained using fast atom bombardment (FAB) and
matrix-assisted laser description=ionization time of flight (MALDI-TOF). The
elemental analyses for the compounds were carried out using a Perkin-Elmer 240B
elemental analyzer. Column chromatography was performed on silica gel (ACME,
100–200 mesh). Routine monitoring of the reaction was made using thin-layer chro-
matography (TLC) developed on glass plates coated with silica gel-G (ACME)
25 mm thick and visualized with iodine.
Tris Acetylene-Terminated Dendron 6
N-(tert-Butyloxycarbonyl)tris[(propargyloxy)methyl]aminomethane 5 (3 g,
8.94 mmol) was deprotected using TFA (15 mL, 197 mmol) and then reacted with
benzene-1,3,5-tricarboxylic acid chloride (0.55 g, 2.55 mmol) in dry CH2Cl2
(50 mL) as per the detailed procedure given in the Supplemental Material, available
1
online. Yield: 58%; mp: 96 ꢀC; H NMR (300 MHz, CDCl3): dH 2.54 (t, 9H, J 2.1),
4.00 (s, 18H), 4.19 (d, 18H, J 2.4), 6.64 (s, 3H), 8.58 (s, 3H) ppm. 13C NMR (75 MHz,
CDCl3): d 58.7, 60.1, 68.4, 75.1, 79.6, 131.3, 135.9, 165.9 ppm. MS (EI): m=z 861
(Mþ). Elemental Anal. calcd. for C48H51N3O12: C, 66.89; H, 5.96; N, 4.88%. Found:
C, 66.77; H, 5.91; N, 4.80%.
General Procedure for the Cu-Catalyzed Huisgen ‘‘Click Reaction’’
Tris acetylene-terminated dendron 6 (1 equiv.) was reacted with azides 7=8=9=
10 (9.1 equiv.) in the presence of CuSO4 ꢂ 5H2O (5 mol %) and NaAsc (10 mol %) in
tetrahydrofuran (THF) and H2O (1:1, 20 ml) as per the detailed procedure given in
the Supplemental Material, available online, and the residue obtained purified by
flash chromatography (SiO2).
Glycodendrimer 1
1
Yield: 98%; mp: 126 ꢀC; H NMR (300 MHz, CDCl3): dH 1.77, 2.02, 2.04, 2.09
(4 ꢁ s, 108 H), 3.86–3.99 (q, 18H, J 9.3), 4.07–4.19 (m, 18H), 4.31–4.37 (m, 9H), 4.67
(s, 18H), 5.38–5.48 (m, 18H) 5.54–5.60 (m, 9H), 5.99 (d, 9H, J 7.8), 6.94 (s, 3H), 7.99 (s,
9H), 8.49 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d 19.1, 20.0, 20.5, 20.6, 60.4, 61.7,
64.6, 67.9 69.0, 70.4, 72.7, 74.9, 85.6, 121.7, 130.9, 136.0, 145.6, 165.8, 168.9, 169.8,
170.0, 170.7 ppm. MS (MALDI-TOF): m=z¼ 4228 [Mþ þ Na]. Elemental Anal. calcd.
for C173H220N30O93: C, 49.38; H, 5.27; N, 9.99%. Found: C, 49.36; H, 5.20; N, 9.89%.
Glycodendrimer 2
Yield: 96%; mp: 132 ꢀC; 1H NMR (300 MHz, CDCl3): dH 1.94, 2.00, 2.05, 2.09
(4 ꢁ s, 108 H), 3.89–4.03 (m, 18H, J 9.3), 4.11–4.20 (m, 18H), 4.43–4.56 (m, 9H), 4.69

GLYCODENDRIMERS AND N-ALKYLDENDRIMERS
2223
(s, 18H), 5.26–5.37 (m, 27H) 6.02 (d, 9H, J 7.8), 6.99 (s, 3H), 8.02 (s, 9H), 8.52 (s, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d 20.0, 20.6, 20.6, 20.7, 60.7, 61.6, 64.8, 68.0, 69.3,
70.6, 72.7, 74.8, 85.9, 121.7, 131.0, 136.1, 145.9, 165.9, 169.7, 169.8, 170.4, 171.3 ppm.
MS (MALDI-TOF): m=z ¼ 4228 [Mþ þ Na]. Elemental anal. calcd. for
C
173H220N30O93: C, 49.38; H, 5.27; N, 9.99%. Found: C, 49.31; H, 5.18; N, 9.92%.
N-Ethyl-1,2,3-triazole Dendrimer 3
Yield: 94%; 1H NMR (300 MHz, CDCl3): dH 1.29 (t, 27H, J 7.2), 3.95 (s, 18H),
4.32 (q, 18H, J 7.2), 4.63 (s, 18H), 7.08 (s, 3H), 7.62 (s, 9H), 8.45 (s, 3H) ppm. 13C
NMR (75 MHz, CDCl3): d 14.0, 38.1, 50.3, 58.6, 64.7, 68.7, 114.0, 122.6, 139.0,
144.1, 166.2 ppm. MS (FAB): m=z 1501 (Mþ). Elemental Anal. calcd. for
C66H96N30O12: C, 52.79; H, 6.44; N, 27.98%. Found: C, 52.68; H, 6.45; N, 27.90%.
N-Heptyl-1,2,3-triazole Dendrimer 4
Yield: 96%; 1H NMR (300 MHz, CDCl3): dH 0.82–0.87 (t, 27H, J 6.0),
1.25–1.29 (m, 90H), 3.95–3.99 (m, 18H), 4.32 (s, 18H), 4.64 (s, 18H), 7.11 (s, 3H),
7.63 (s, 9H), 8.45 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d 14.0, 22.5, 26.5,
28.7, 29.7, 31.6, 50.4, 58.8, 64.8, 68.8, 114.1, 122.8, 139.3, 144.6, 166.3 ppm. MS
(FAB): m=z 2131 (Mþ). Elemental Anal. calcd. for C111H186N30O12: C, 62.51; H,
8.79; N, 19.70%. Found: C, 62.44; H, 8.67; N, 19.70%.
CONCLUSIONS
In conclusion, we have synthesized various types of glycodendrimers 1 and 2
and N-ethyl and N-heptyl 1,2,3-triazole dendrimers 3 and 4 with 1,2,3-triazole as
building block and benzene-1,3,5-tricorboxlyic amide as core unit. Further, synthesis
of higher generation dendrimers and study of their biological activity and material
properties are under way.
ACKNOWLEDGMENTS
The authors thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for financial assistance and the Department of Science and
Technology–Funding For Infrastructure in Science and Technology for providing
NMR facilities to the department. R. A. thanks CSIR, New Delhi, for a senior
research fellowship and Indian Institute Technology, Madras SAIF for MALDI-
TOF mass spectra.
REFERENCES
1. (a) Antoni, P.; Nystrom, D.; Hawker, C. J.; Hult, A.; Malkoch, M. A chemoselective
approach for the accelerated synthesis of well-defined dendritic architectures. Chem.
Commun. 2007, 2249; (b) Sumerlin, B. S.; Vogt, A. P. Macromolecular engineering
through click chemistry and other efficient transformations. Macromolecules 2010, 43, 1.

2224
P. RAJAKUMAR AND R. ANANDHAN
2. (a) Meldal, M.; Tornøe, C. W. Cu-catalyzedazide–alkyne cycloaddition. Chem. Rev. 2008,
108, 2952; (b) Meldal, M. Polymer ‘‘clicking’’ by CuAAC reactions. Macromol. Rapid
Commun. 2008, 29, 1016; (c) Li, P.; Wang, L. One-pot synthesis of 1,2,3-triazoles from
benzyl and alkyl halides, sodium azide, and alkynes in water under transition-metal-
catalyst free reaction condition. Lett. Org. Chem. 2007, 4, 23.
3. (a) Amblard, F.; Cho, J. H.; Schinazi, R. F. Cu(I)-catalyzed Huisgen azide–alkyne
1,3-dipolar cycloaddition reaction in nucleoside, nucleotide, and oligonucleotide chemis-
try. Chem Rev. 2009, 109, 4207; (b) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.
V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. Copper(I)-catalyzed synthesis of azoles:
DFT study predicts unprecedented reactivity and intermediates. J. Am. Chem. Soc. 2005,
127, 210.
4. (a) Dijkgraaf, I.; Rijnders, A. Y.; Soede, A.; Dechesne, A. C.; Esse, G. W.; Brouwer, A. J.;
Corstens, F. H. M.; Boerman, O. C.; Rijkers, D. T. S.; Liskamp, R. M. J. Synthesis of
DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddi-
tion and their biological evaluation: Implications for tumor targeting and tumor imaging
purposes. Org. Biomol. Chem. 2007, 5, 935; (b) Chen, X. M.; Li, Z. J.; Ren, Z. X.; Huang,
Z. T. Synthesis of glucosylated 1,2,3-triazole derivatives. Carbohydr. Res. 1999, 315, 262.
5. (a) David, O.; Maisonneuvesss, S.; Xie, J. Generation of new fluorophore by click
chemistry: Synthesis and properties of b-cyclodextrin substituted by 2-pyridyl triazole.
Tetrahedron Lett. 2007, 48, 6527; (b) Varazo, K.; Xie, F.; Gulledge, D.; Wang, Q.
Synthesis of triazolylanthracene as a selective fluorescent chemosensor for the Cu(II) ion.
Tetrahedron Lett. 2008, 49, 5293; (c) Jarowski, P. D.; Wu, Y. L.; Schweizer, W. B.; Diederich,
F. 1,2,3-Triazoles as conjugative pi-linkers in push–pull chromophores: Importance of
substituent positioning intramolecular charge on transfer. Org. Lett. 2008, 10, 3347.
6. Gudipati, C. S.; Greenlief, C. M.; Johnson, J. A.; Prayongpan, P.; Wooley, K. L.
Hyperbranched fluoropolymer (HBFP) and linear poly(ethylene glycol) (PEG) based
amphiphilic crosslinked networks as efficient anti-fouling coatings: An insight into the
surface compositions, topographies, and morphologies. J. Polym. Sci., Part A: Polym.
Chem. 2004, 42, 6193.
7. Dankers, P. Y. W.; Harmsen, M. C.; Brouwer, L. A.; Van Luyn, M. J. A.; Meijer, E. W.
A modular and supramolecular approach to bioactive scaffolds for tissue engineering.
Nat. Mater. 2005, 4, 568.
8. Fuchs, S.; Kapp, T.; Otto, H.; Schoneberg, T.; Franke, P.; Gust, R.; Schluter, A. D. A set
of surface-modified dendrimers with potential application as drug delivery vehicles:
Synthesis, in vitro cytotoxicity, and intracellular localization. Chem. Eur. J. 2004, 10, 1167.
9. Hawker, C. J.; Wooley, K. L. The convergence of synthetic organic and polymer chemistries.
Science 2005, 309, 1200.
10. (a) Haba, Y.; Harada, A.; Takagishi, T.; Kono, K. Rendering poly(amidoamine) or
poly(propylenimine) dendrimers temperature sensitive. J. Am. Chem. Soc. 2004, 126,
12760; (b) Gillies, E. R.; Frechet, J. M. J. Synthesis and self-assembly of dendritic
‘‘bow-ties’’: Effect of peripheral functionality on association constants. J. Org. Chem.
2004, 69, 46; (c) Furuta, P.; Frechet, J. M. J. Controlling solubility and modulating per-
ipheral function in dendrimer encapsulated dyes. J. Am. Chem. Soc. 2003, 125, 13173; (d)
Wooley, K. L.; Hawker, C. J.; Pochan, J. M.; Frechet, J. M. J. Physical properties of den-
dritic macromolecules: a study of glass transition temperature. Macromolecules 1993, 26,
1514.
11. (a) Breinbauer, R.; Jacobsen, E. N. Cooperative asymmetric catalysis with dendrimer
bound [Co(salen)] catalysts. Angew. Chem., Int. Ed. 2000, 39, 3604.
12. Mammen, M.; Choi, S. K.; Whitesides, G. M. Polyvalent interactions in biological
systems: Implications for design and use of multivalent ligands and inhibitors. Angew.
Chem., Int. Ed. 1998, 37, 2754.

GLYCODENDRIMERS AND N-ALKYLDENDRIMERS
2225
13. Liu, M.; Frechet, J. M. J. Preparation of water-soluble dendritic unimolecular micelles
as potential drug delivery agents. Polym. Mat. Sci Eng. 1999, 80, 167.
14. Esfand, R.;Tomalia, D. A. Poly(amidoamine) (PAMAM) dendrimers: From biomimicry
to drug delivery and biomedical applications. Drug Disc. Today 2001, 6, 427.
15. Wu, P.; Malkoch, M.; Hunt, J. N.; Vestberg, R.; Kaltgrad, E.; Finn, M. G.; Fokin, V. V.;
Sharpless, K. B.; Hawker, C. J. Multivalent, bifunctional dendrimers prepared by click
chemistry. Chem. Commun. 2005, 46, 5775.
16. Wolfenden, M. L.; Cloninger, M. J. Carbohydrate-functionalized dendrimers to investi-
gate the predictable tunability of multivalent interactions. Bioconjug. Chem. 2006, 17, 958.
17. Gomez-Garcia, M.; Benito, J. M.; Rodriguez-Lucena, D.; Yu, J. X.; Chmurski, K.;
Mellet, C. O.; Gallego, R. G.; Maestre, A.; Defaye, J.; Fernandez, J. M. G. Probing
secondary carbohydrate–protein interactions with highly dense cyclodextrin-centeredhe-
teroglycoclusters: The heterocluster effect. J. Am. Chem. Soc. 2005, 127, 7970.