C-glycoside clustering on calix[4]arene, adamantane, and benzene scaffolds through 1,2,3-triazole linkers

Article abstract of DOI:10.1021/jo0607156

(Chemical Equation Presented) A route has been paved toward the preparation of triazole glycocluster libraries via the copper(I)-catalyzed modern version of the classical Huisgen 1,3-dipolar cycloaddition of azides to alkynes. Up to four 1,4-disubstituted

Full text of DOI:10.1021/jo0607156

C-Glycoside Clustering on Calix[4]arene, Adamantane, and
Benzene Scaffolds through 1,2,3-Triazole Linkers
Alessandro Dondoni* and Alberto Marra*
Dipartimento di Chimica, Laboratorio di Chimica Organica, UniVersita` di Ferrara,
Via L. Borsari 46, I-44100 Ferrara, Italy
adn@dns.unife.it
ReceiVed April 4, 2006
A route has been paved toward the preparation of triazole glycocluster libraries via the copper(I)-catalyzed
modern version of the classical Huisgen 1,3-dipolar cycloaddition of azides to alkynes. Up to four 1,4-
disubstituted 1,2,3-triazole rings bearing carbon-linked glycosyl fragments were constructed on various
scaffolds via multiple cycloadditions of suitably polyfunctionalized calix[4]arene, adamantane, and benzene
derivatives with ethynyl and azidomethyl C-glycosides. Each cycloaddition occurred with high regio-
selectivity to give exclusively the 1,4-disubstituted triazole ring in very high yield up to an average
value of 98%. The high degree of efficiency of this approach and its wide scope constitute a simple and
practical means for the attachment of various sugar units to polyfunctionalized substrates.
Introduction
Lindorst,7 Takahashi,8 and their co-workers demonstrated that
the cluster effect of synthetic compounds not only is related to
the number and geometry of carbohydrate residues but also
depends on their steric bulk and relative distances, as well as
on the three-dimensional arrangement around the core, this
disposition being in turn strictly determined by the nature of
the scaffold itself and the linkers employed. Therefore, the
synthesis of new kinds of glycoside clusters that will open the
route to multivalent oligosaccharide libraries exibiting sugar
number and variety, as well as scaffold and linker structure as
diversity elements would offer new oportunities for studies of
carbohydrate-protein recognition. It is in line with this concept
that we report below the synthesis of various glycoside cluster
arrays assembled on different scaffolds through the rigid and
planar heteroaromatic triazole ring.
The assembly of densely decorated scaffolds by carbohydrate
residues has sparked significant interest in various research
groups over the past 10 years or so.1 Synthetic efforts were
aimed at providing tools for a better understanding as well as
modulating a major phenomenon called glycoside cluster effect2
that operates in carbohydrate-protein interaction, the crucial
process through which various intercellular communication and
transduction events as well as the adhesion of bacteria and
viruses to the cell surfaces take place.3 It is widely accepted
that nature compensates for the low intrinsic affinity of carbo-
hydrate for proteins through the cooperative binding between
multiple copies of ligands and receptors so that a strong adhesion
results. However, according to an early definition of glycoside
clustering,4 the “affinity enhancement is much greater than
would be expected from a simple effect of concentration
increase.” Although some attempts to quantify the effects of
multivalent presentation have been reported,5 the detailed
mechanism at the molecular level still remains unclear. Thus,
the design of various types of clusters that can serve as inhibitors
of biological systems for medical use is still carried out on a
very empirical basis. For example the works of Lee,2b Roy,6
A plethora of linkers with flexible or rigid structures of
variable length have been employed for glycocluster assembly
on various scaffolds.1 An efficient ligation technique such as
that expressed by the so-called Sharpless “click chemistry”
9
concept and that based on the Huisgen 1,3-dipolar cycload-
dition reactions of azides with alkynes to give 1,2,3-triazoles10
has been exploited in only a few instances.11 The discovery of
10.1021/jo0607156 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/26/2006
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J. Org. Chem. 2006, 71, 7546-7557

C-Glycoside Clustering through 1,2,3-Triazole Linkers
copper(I) catalysis of this process that increased both effec-
tivenes and selectivity, leading to the almost exclusive formation
of the 1,4-disubstituted triazole ring,12 and the remarkable
stability of this heterocycle, not present in natural products, to
metabolic transformations such as oxidation, reduction, and both
basic and acid hydrolysis make this type of group connecting
(1) For a classification of various types of glycoside cluster arrays
reported up to 2001, see: (a) Dondoni, A.; Kleban, M.; Hu, X.; Marra, A.;
Banks, H. D. J. Org. Chem. 2002, 67, 4722. For recent papers, see: (b)
Fulton, D. A.; Stoddart, J. F. J. Org. Chem. 2001, 66, 8309. (c) Liu, B.;
Roy, R. J. Chem. Soc., Perkin Trans. 1 2001, 773. (d) Woller, E. K.;
Cloninger, M. J. Org. Lett. 2002, 4, 7. (e) Ortega-Caballero, F.; Gime´nez-
Mart´ınez, J. J.; Vargas-Berenguel, A. Org. Lett. 2003, 5, 2389. (f) Sansone,
F.; Chierici, E.; Casnati, A.; Ungaro, R. Org. Biomol. Chem. 2003, 1, 1802.
(g) Autar, R.; Khan, A. S.; Schad, M.; Hacker, J.; Liskamp, R. M. J.; Pieters,
R. J. ChemBioChem 2003, 4, 1317. (h) Choudhury, A. K.; Kitaoka, M.;
Hayashi, K. Eur. J. Org. Chem. 2003, 2462. (i) Barrientos, A. G.; de la
Fuente, J. M.; Rojas, T. C.; Ferna´ndez, A.; Penade´s, S. Chem. Eur. J. 2003,
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FIGURE 1. 1,4-Disubstituted triazole glycoclusters with C-4 (left)
and N-1 (right) C-glycosyl linkages.
strategy a precious tool for bioorganic studies. However, most
of the sugar alkynes employed by Santoyo-Gonzales11a were
propargyl O-glycosides and therefore afforded O-glycosylated
triazoles. Du11b exploited a 6-azidohexyl O-hexasaccharide
derivative to prepare a single O-glycosylated triazole cluster.
The weakness of the O-glycosidic bond to enzymatic and
chemical degradations is well-known. The method of Wang11c
and Roy11d was based on glycosyl azides and therefore led to
easily hydrolyzable N-glycosyl triazole derivatives. Hence we
decided to broaden and validate the scope of the click chemistry
approach by performing the synthesis of triazole-based C-
glycoclusters, i.e., systems in which glycosyl fragments are
linked through an enzymatically and chemically resistant
carbon-carbon bond to triazole rings supported on a scaffold.
The approaches employed were based on the cycloaddition of
an ethynyl and an azidomethyl C-glycoside to a multivalent
centerpiece bearing azido or ethynyl groups, respectively. Hence,
two structurally different types of C-glycoclusters were
formed: one in which triazole rings attached to a scaffold were
carrying a C-glycosyl residue at C-4 (left in Figure 1), the other
in which the triazole rings beared a glycosylmethyl fragment
at N-1 (right in Figure 1).
(2) For selected reviews and accounts, see: (a) Lee, Y. C.; Lee, R. T.;
Rice, K.; Ichikawa, Y.; Wong, T.-C. Pure Appl. Chem. 1991, 63, 499. (b)
Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 322. (c) Lee, R. T.; Lee,
Y. C. Glycoconjugate J. 2000, 17, 543. (d) Lundquist, J. J.; Toone, E. J.
Chem. ReV. 2002, 102, 555. (e) Lindhorst, T. K. Top. Curr. Chem. 2002,
218, 201. (f) Turnbull, W. B.; Stoddart, J. F. ReV. Mol. Biotechnol. 2002,
90, 231. (g) Cloninger, M. J. Curr. Opin. Chem. Biol. 2002, 6, 742. (h)
Badjic, J. D.; Nelson, A.; Cantrill, S. J.; Turnbull, W. B.; Stoddart, J. F.
Acc. Chem. Res. 2005, 38, 723.
(3) (a) Varki, A. Glycobiology 1993, 3, 97-130. (b) Dwek, R. A. Chem.
Rew. 1996, 96, 683-720. (c) Essentials of Glycobiology; Varki, A.,
Cummings, R., Esko, J., Freeze, H., Hart, G., Marth, J., Eds.; Cold Spring
Harbor Laboratory Press: New York, 1999. (d) Bertozzi, C. R.; Kiessling,
L. L. Science 2001, 291, 2357.
Results and Discussion
C-Glycoclusters from Multivalent Azido Substrates. Vari-
ous R- and â-linked ethynyl C-glycosides were available in our
laboratory because of their use in synthetic approaches to
C-glycosyl amino acid ethylene isosteres of sugar asparagines.13
Moreover, in relation to our interest in glycocluster synthesis,14
we recently reported on the synthesis of calix[4]arene O- and
C-glycoconjugates (calixsugars), the former via multiple glyco-
sylation of calix[4]arene polyols and the latter via Wittig
olefination of calix[4]arene-derived polyaldehydes.1a,15 However,
the latter route to C-calixsugars showed some limitations in
terms of both efficiency and scope due to the intrinsic difficulties
of performing Wittig reactions in complex systems. Therefore
(4) Quesenberry, M. S.; Lee, R. T.; Lee, Y. C. Biochemistry 1997, 36,
2724.
(5) (a) Mammen, M.; Choi, S. K.; Whitesides, G. M. Angew. Chem.,
Int. Ed. 1998, 37, 2754. (b) Gargano, J. M.; Ngo, T.; Kim, J. Y.; Acheson,
D. W. K.; Lees, W. J. J. Am. Chem. Soc. 2001, 123, 12909. (c) Mulder, A.;
Huskens, J.; Reinhoudt, D. N. Org. Biomol. Chem. 2004, 2, 3409. (d)
Wolfenden, M. L.; Cloninger, M. J. J. Am. Chem. Soc. 2005, 127, 12168.
(6) (a) Roy, R.; Baek, M.-G.; Rittenhouse-Olson, K. J. Am. Chem. Soc.
2001, 123, 1809. (b) Liu, B.; Roy, R. Tetrahedron 2001, 57, 6909. (c) Andre´,
S.; Liu, B.; Gabius, H.-J.; Roy, R. Org. Biomol. Chem. 2003, 1, 3909.
(7) Ko¨hn, M.; Benito, J. M.; Ortiz Mellet, C.; Lindhorst, T. K.; Garc´ıa-
Ferna´ndez, J. M. ChemBioChem 2004, 5, 771.
(8) Amaya, T.; Tanaka, H.; Takahashi, T. Synlett 2004, 497.
(9) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
(10) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; pp 1-176. (b) Padwa, A. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991;
Vol. 4, pp 1069-1109. (c) Fan, W.-Q.; Katritzky, A. R. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: Oxford, 1996; Vol. 4, pp 101-126.
(11) (a) Pe´rez-Balderas, F.; Ortega-Mun˜oz, M.; Morales-Sanfrutos, J.;
Herna´ndez-Mateo, F.; Calvo-Flores, F. G.; Calvo-As´ın, J. A.; Isac-Garc´ıa,
J.; Santoyo-Gonza´lez, F. Org. Lett. 2003, 5, 1951. (b) Chen, Q.; Yang, F.;
Du, Y. Carbohydr. Res. 2005, 340, 2476. (c) Chittaboina, S.; Xie, F.; Wang,
Q. Tetrahedron Lett. 2005, 46, 2331. (d) Gigue`re, D.; Patnam, R.; Bellefleur,
M.-A.; St-Pierre, C.; Sato, S.; Roy, R. Chem. Commun. 2006, 2379.
(12) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) For a study on the mechanism
of the Cu(I)-mediated cycloaddition, see: Rodionov, V. O.; Fokin, V. V.;
Finn, M. G. Angew. Chem., Int. Ed. 2005, 44, 2210.
(13) (a) Dondoni, A.; Mariotti, G.; Marra, A. Tetrahedron Lett. 2000,
41, 3483. (b) Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem. 2002, 67,
4475.
(14) Dondoni, A.; Marra, A.; Zampolli, M. G. Synlett 2002, 1850.
J. Org. Chem, Vol. 71, No. 20, 2006 7547

Dondoni and Marra
TABLE 1. Triazole C-Glycoclusters Prepared via Cycloaddition of Sugar Alkynes to Multivalent Azido Substratesa
a Reaction conditions: ethynyl sugar (1.0 equiv), CuI, i-Pr2EtN, toluene, 25 °C, 18 h. b Yields refer to isolated pure products. c Yields in parentheses refer
to O-acetyl-protected compounds obtained from the O-benzylated derivatives via reaction with BCl3 (CH2Cl2, -60 to 0 °C, 2 h) followed by acetylation
(Ac2O, Et3N, rt, 18 h).
the synthesis of calix[4]arene C-glycoclusters by a new and
efficient ligation strategy was the first target in our program.
Hence we were delighted to observe that a stoichiometric
amount (2.0 equiv) of ethynyl tetra-O-benzyl-â-D-glucopyrano-
side 1a13b,16 reacted regioselectively with the bis-azidopropyl
tetrapropoxy-calix[4]arene 217 in the presence of CuI and i-Pr2-
EtN in toluene at room temperature to generate the desired two
1,4-disubstituted 1,2,3-triazole rings, each one carrying a â-C-
glucosyl residue at C-4, while N-1 was linked through a carbon
tether to the upper rim of the calix[4]arene scaffold (Table 1).
The high degree of efficiency of these 1,3-dipolar cycloadditions
was substantiated by the fair yield (73%) of the bis-cycloadduct
3a isolated by column chromatography. A similarly high-
performing process occurred also between 1a (4 equiv) and the
tetra-azido calix[4]arene derivative 4,17 which by virtue of four
concomitant alkyne-azide cycloaddition reactions afforded a
C-glycosylated tetratriazole system anchored to the calix[4]arene
upper ring. The isolated yield of the C4-symmetric glycocluster
5a (63%) indicated a 89% average yield for each cyloaddition
reaction. Even higher degrees of efficiency were registered
in the stoichiometric reactions of ethynyl tetra-O-acetyl-â-D-
glucopyranoside 1b16a with the same polyazido calix[4]arene
derivatives 2 and 4, which in fact afforded the corresponding
C-glycosyl-calix[4]arenes 3b and 5b in 96% and 86% isolated
yield, respectively (Table 1). Hence, in both cases each triazole-
(15) The realization by us that calix[4]arene derivatives can serve as
convenient scaffolds for the synthesis of glycoclusters goes back to the
mid-1990s. See: (a) Marra, A.; Scherrmann, M.-C.; Dondoni, A.; Casnati,
A.; Minari, P.; Ungaro, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2479.
(b) Marra, A.; Dondoni, A.; Sansone, F. J. Org. Chem. 1996, 61, 5155. (c)
Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Casnati, A.; Sansone, F.;
Ungaro, R. Chem. Eur. J. 1997, 3, 1774.
(16) (a) Alzeer, J.; Vasella, A. HelV. Chim. Acta 1995, 78, 177. (b)
Lowary, T.; Meldal, M.; Helmboldt, A.; Vasella, A.; Bock, K. J. Org. Chem.
1998, 63, 9657.
(17) Compounds 2 and 4 are new upper rim functionalized calix[4]arenes
prepared from the corresponding polyols (ref 1a) and diphenyl phosphoryl
azide in 86% and 89% yield, respectively.
7548 J. Org. Chem., Vol. 71, No. 20, 2006

C-Glycoside Clustering through 1,2,3-Triazole Linkers
forming cycloaddition reaction appeared to have occurred in
almost quantitative manner. We suggest that the higher reactivity
of 1b with respect to 1a is due to steric factors because the
O-acetyl groups are less bulky than the O-benzyl groups and
therefore give rise to a less encumbering array around the small
ethynyl dipolarophile. The easily hydrolyzable O-acetyl groups
in the sugar residues of the C-glycoclusters 3b and 5b make
these products convenient precursors to free hydroxy compounds
suitable for biological assays. In fact all acetyl groups of 3b
and 5b were removed by treatment with 0.2 M NaOMe in
MeOH at room temperature followed by neutralization with
Amberlite IR-120 resin to give 3c and 5c, respectively. On the
other hand, the exaustive debenzylation by catalytic hydro-
genolysis of the sugar triazoles 3a and 5a resulted to be a quite
difficult operation since only 3a led to the expected hydroxy
derivative 3c upon repeated hydrogenation over Pd(OH)2 (H2,
7 bar, AcOH, 6 h). The tetra-triazole cluster 5b failed to afford
the corresponding hydroxy compound 5c by hydrogenolysis
under various conditions using Pd, Pt, and Rh as the catalyst.
Moreover, the attempts to remove the benzyl groups in 3a and
5a by the use of BCl3 in CH2Cl2 at low temperature, followed
by acetylation, led to complex mixtures of products.
In line with the idea of exploring the viability of the triazole
route to glycocluster libraries displaying different scaffolds as
element of diversity, the assembly of D-glucose residues around
benzene was investigated. Considering the nature of this core,
this approach was expected to give rise to compact, rigid, and
almost planar networks. Hence, both the O-benzyl and the
O-acetyl sugar acetylenes 1a and 1b (3 equiv) were allowed to
react with sym-tris(azidomethyl)benzene 618 under the usual
conditions (Table 1). These reactions afforded the expected C3-
symmetric C-glycocluters 7a and 7b in good isolated yields
(Table 1) corresponding to an average yield of 86% and 90%
for each highly regioselective azide-alkyne cycloaddition. In this
series the acetylated glycocluster 7b was also accessible in high
yield (92%) by debenzylation with BCl3 of 7a followed by
standard acetylation. The product obtained by this two-step
reaction sequence was identical in all respects to that obtained
by the more direct route starting from 1b. The peracetate 7b
was in turn converted into the free hydroxy compound 7c via
the above-mentioned deacetylation procedure.
of the usual catalyst CuI/i-Pr2EtN in toluene. Initial experiments
showed that more forcing conditions than in the previous
approach were required to complete the multiple cycloaddition
scheme on the trivalent ethynyl substrate. Hence an excess of
azido sugar (1.5 equiv per ethynyl group) was employed and
the temperature was raised to 80 °C. Under these conditions
the tripodal clusters 10a and 10b bearing glucosylmethyl resi-
dues at N-1 were obtained in good (68%) and excellent (96%)
isolated yields, respectively. Most of the excess of sugars 8a
and 8b was recovered by chromatography of the crude reaction
mixtures. Also in these systems, the alternative approach to the
valuable C-glycocluster 10b featuring O-acetyl protective groups
in the chain-end sugar moieties was effectively carried out by
BeCl3-promoted debenzylation of 10a and subsequent acetyl-
ation. Then, the free hydroxy compound 10c was easily
generated from 10b by the usual treatment with NaOMe in
MeOH. The change of the sugar fragment in the cycloaddition
with 9 was studied by using the galactose azidomethyl deriva-
tives 11a (O-benzyl protection)19 and 11b (O-acetyl protection)19
under the same conditions described above. The corresponding
trivalent C-galactosyl clusters 12a and 12b were typically
isolated in yields comparable to those of the C-glucosyl isomers
10a and 10b. The acetylated product 12b was obtained from
the benzylated derivative 12a in good isolated yield (84%) as
was the free hydroxy derivative 12c prepared from 12b.
Multiple 1,3-dipolar cycloadditions under the same conditions
described above were employed to prepare the tetravalent
triazole C-glycoclusters 14a,b and 16a,b on calix[4]arene and
adamantane scaffolds, respectively, using tetraethynyl-calix[4]-
arene 1321 and tetrakis(4-ethynylphenyl)-adamantane 1522 as
multivalent dipolarophiles (Table 2). Each of these processes
showed high degree of efficiency as substantiated by the yields
of isolated O-benzyl and O-acetyl C-glycoclusters 14a,b and
16a,b. The free hydroxy compounds 14c and 16c were obtained
by the usual hydrolysis of the corresponding acetylated deriva-
tives 14b and 16b. The spatial disposition of four sugar-bearing
arms in the calix[4]arene scaffolded compounds 14a-c may
vary owing to some flexibility of the macrocycle ring whereas
that in the adamantane scaffolded compounds 16a-c should
be fixed in a rigid tetrahedral arrangement as shown.
C-Glycoclusters from Multivalent Ethynyl Substrates. The
azide-alkyne cycloaddition approach to regioisomeric triazole
C-glycoclusters was then considered by reacting azidomethyl
C-glycosides (Table 2) with multivalent ethynyl substrates. The
change of cycloaddition partners was aimed at introducing
another element of diversity in the structure of the target
C-glycoclusters, i.e., the attachment of the sugar residues to N-1
of the triazole ring through a methylene bridge instead of the
direct binding to C-4 as in the examples reported in Table 1. In
this approach we first examined the reaction of azidomethyl
tetra-O-benzyl-â-D-glucopyranoside 8a19 and its acetylated
derivative 8b19 with sym-triethynylbenzene 920 in the presence
Structure Determination. The NMR analysis provided
evidence for the structural assignment of all of the above
C-glycoclusters prepared. The conservation of the original â-D-
configuration of each glycoside fragment was confirmed by the
large vicinal coupling constants (ca. 9.5 Hz) observed for the
anomeric hydrogen atoms, as expected for trans-diaxal H-1 and
4
H-2 protons in pyranoses adopting a C1 conformation. More-
over, the fixed cone conformation of the calix[4]arene scaffold
was substantiated by the presence of signals for the equatorial
and axial protons of the methylene bridges as doublets at ca. 3
(20) Known 1,3,5-triethynylbenzene (Hu¨bel, W.; Mere´nyi, R. Angew.
Chem. 1962, 74, 781) was prepared from 1,3,5-tribromobenzene as decribed;
see: Wang, F.; Kaafarani, B. R.; Neckers, D. C. Macromolecules 2003,
36, 8225.
(21) Tetraethynyl-tetrapropoxy-calix[4]arene 13 was obtained by Sono-
gashira-Heck-Cassar cross-coupling reaction of the corresponding upper
rim tetraiodo derivative (Arduini, A.; Giorgi, G.; Pochini, A.; Secchi, A.;
Ugozzoli, F. J. Org. Chem. 2001, 66, 8302) with trimethylsilylacetylene in
the presence of PdCl2(PPh3)2 and CuI as described for the synthesis of the
tetraethynyl-tetrakis(2-ethoxyethoxy)-calix[4]arene analogue (Arduini, A.;
Pochini, A.; Sicuri, A. R.; Secchi, A.; Ungaro, R. Gazz. Chim. Ital. 1994,
124, 129).
(18) (a) Heyer, D.; Lehn, J.-M. Tetrahedron Lett. 1986, 27, 5869. (b)
Garrett, T. M.; McMurry, T. J.; Hosseini, M. W.; Reyes, Z. E.; Hahn, F.
E.; Raymond, K. N. J. Am. Chem. Soc. 1991, 113, 2965.
(19) The benzylated glucopyranosyl derivative 8a was reported in the
literature without experimental and physical data (Lockhoff, O. Angew.
Chem., Int. Ed. 1998, 37, 3436). We have prepared and fully characterized
8a as described for the known galactopyranosyl isomer 11a (Dondoni, A.;
Massi, A.; Sabbatini, S.; Bertolasi, V. J. Org. Chem. 2002, 67, 6979). The
acetylated derivatives 8b and 11b were prepared from 8a and 11a,
respectively, by debenzylation with BCl3 and acetylation with Ac2O-
pyridine.
(22) Galoppini, E.; Gilardi, R. Chem. Commun. 1999, 173.
J. Org. Chem, Vol. 71, No. 20, 2006 7549

Dondoni and Marra
TABLE 2. Triazole C-Glycoclusters Prepared via Cycloaddition of Azidomethyl Glycosides to Multivalent Ethynyl Substratesa
a Reaction conditions: azido sugar (1.5 equiv), CuI, i-Pr2EtN, toluene, 80 °C, 18 h (48 h for 10a and 12a). b Yields refer to isolated pure products.
c Yields in parentheses refer to O-acetyl-protected compounds obtained from the O-benzylated derivatives via reaction with BCl3 (CH2Cl2, -60 to 0 °C, 2
h) followed by acetylation (Ac2O, Et3N, rt, 18 h).
and 4 ppm, respectively.23 On the other hand, the regioisomeric
assignment of the disubstituted 1,2,3-triazole rings was less
straightforward. In fact, the well-known empirical rule12a,24 stat-
ing that the H-5 proton in 1,4-disubstituted triazoles resonates
always downfield compared to the H-4 proton in the corre-
sponding 1,5-isomer, could not be employed because triazole
rings in all C-glycoclusters formed as single regioisomers.
(24) (a) Alonso, G.; Garc´ıa-Lo´pez, M. T.; Garc´ıa-Mun˜oz, G.; Madron˜ero,
R.; Rico, M. J. Heterocycl. Chem. 1970, 7, 1269. (b) Crandall, J. K.;
Crawley, L. C.; Komin, J. B. J. Org. Chem. 1975, 40, 2045. (c) Wang,
Z.-X.; Qin, H.-L. Chem. Commun. 2003, 2450.
(23) Iqbal, M.; Mangiafico, T.; Gutsche, C. D. Tetrahedron 1987, 43,
4917.
7550 J. Org. Chem., Vol. 71, No. 20, 2006

C-Glycoside Clustering through 1,2,3-Triazole Linkers
compound 17a, as well as the whole series of acetylated
C-glycoclusters reported in Tables 1 and 2, displayed in their
13C NMR spectra ∆(δC4 - δC5) values in the range 21.7-27.0
ppm (see Experimental Section). This finding made it possible
to firmly establish the 1,4-disubstituted structure for the 1,2,3-
triazole rings of all the C-glycoclusters prepared without the
need for direct comparison with the corresponding regioisomers
1
as required by the H NMR-based rule.12a,24
FIGURE 2. Monovalent 1,4- and 1,5-disubstituted triazole derivatives
prepared by cycloaddition of azidomethyl C-glucosides 8a,b with
phenylacetylene.
Conclusions
In conclusion, an alkyne-azide cycloaddition based route to
various C-glycoclusters featuring 1,2,3-triazole rings as linkers
and different scaffolds has been developed. Having established
the high degree of efficiency and tolerance of this reaction to
various changes in both the functionalized sugars and the multi-
valent substrates, this route should be viable for the preparation
of a rich collection of this class of glycoclusters.
Therefore, NOE experiments were performed for the acetylated
C-glycoclusters since all these compounds displayed clear first-
1
order H NMR spectra. Unfortunately, only the NMR spectra
of 3b and 7b (Table 1) showed significant NOEs between the
triazole proton and both the methylene group linked to the
triazole N-1 atom and the H-2 pyranose proton. This proximity
relationship indicated a 1,4-disubstitution pattern for the hetero-
cyclic units in 3b and 7b. To circumvent the absence of diag-
nostic NOEs in all clusters bearing the sugar moieties onto N-1
of triazole rings, i.e. 10, 12, 14, and 16 (Table 2), we decided
to synthesize two pairs of regioisomeric model compounds and
then compare their spectroscopic data. Hence, the monovalent
1,4- and 1,5-disubstituted 1,2,3-triazole derivatives 17a,b and
18a,b (Figure 2) were prepared by cycloaddition of the azido-
methyl C-glucosides 8a,b with phenylacetylene in the presence
of CuI or CpRuCl(PPh3)2 as the catalyst, respectively.25 The
1H NMR analysis of these products revealed that the triazole
proton of both benzylated sugar 17a (8.00 ppm) and acetylated
sugar 17b (7.94 ppm) that formed in the presence of CuI and
i-Pr2EtN resonated at lower field than the triazole proton of
compounds 18a and 18b derived from the ruthenium-promoted
cycloaddition (7.70 and 7.71 ppm, respectively). These data were
in agreement with the above-mentioned NMR rule12a,24 and
therefore proved the structure assigned to the regioisomer pairs
17a,b and 18a,b on the basis of the reaction mechanisms
proposed in the literature.12,25 Reasonably, it can be deduced
that all C-glycoclusters synthesized from sugar azides 8a,b and
11a,b by copper-mediated cycloaddition feature 1,4-disubstituted
triazole moieties. Moreover, in agreement with previous obser-
vations made by us26 and others,27 large ∆(δC4 - δC5) values
(ca. 26 ppm) were found for the triazole carbon atoms in the
13C NMR spectra of 17a (δC4 ) 147.7 ppm; δC5 ) 121.4 ppm)
and 17b (δC4 ) 147.9 ppm; δC5 ) 121.5 ppm). On the other
hand, the 1,5-disubstituted isomers 18a,b exhibited negative and
significantly smaller ∆(δC4 - δC5) values (ca. -7 ppm) for the
Experimental Section
All moisture-sensitive reactions were performed under a nitrogen
atmosphere using oven-dried glassware. Anhydrous solvents were
dried over standard drying agents30 and freshly distilled prior to
use. Reactions were monitored by TLC on silica gel 60 F254 with
detection by charring with sulfuric acid. Flash column chroma-
tography31 was performed on silica gel 60 (230-400 mesh). Melting
points were determined with a capillary apparatus. Optical rotations
were measured at 20 ( 2 °C in the stated solvent; [R]D values are
given in deg‚mL‚g-1.dm-1. 1H NMR (300 and 400 MHz) and 13
C
NMR spectra (75 and 100 MHz) were recorded for CDCl3 solutions
at room temperature unless otherwise specified. Peak assignments
were aided by H-1H COSY and gradient-HMQC experiments.
1
In the 1H NMR spectra reported below, the n and m values quoted
in geminal or vicinal proton-proton coupling constants Jn,m refer
to the number of the corresponding sugar protons. MALDI-TOF
mass spectra were acquired using 2,5-dihydroxy-benzoic acid as
the matrix.
5,17-Bis(3-azidopropyl)-25,26,27,28-tetrapropoxy-calix[4]-
arene (2). A mixture of known1a 5,17-bis(3-hydroxypropyl)-
25,26,27,28-tetrapropoxy-calix[4]arene (355 mg, 0.50 mmol), so-
dium azide (130 mg, 2.00 mmol), diphenyl phosphoryl azide (320
µL, 1.50 mmol), 1,8-diazabicyclo[5.4.0.]undec-7-ene (150 µL, 1.00
mmol), and anhydrous DMF (2.5 mL) was stirred at 120 °C for
14 h, then cooled to room temperature, diluted with Et2O (100 mL),
washed with H2O (2 × 10 mL), dried (Na2SO4), and concentrated.
The residue was eluted from a column of silica gel with 15:1
cyclohexane/AcOEt to give 2 (327 mg, 86%) as a white solid. Mp
169-170 °C (cyclohexane/pentane). 1H NMR (300 MHz): δ 6.60
(s, 4H, Ar), 6.55-6.45 (m, 6H, Ar), 4.44 and 3.12 (2d, 8H, J )
13.2 Hz, 4 ArCH2Ar), 3.92-3.80 (m, 8H, 4 CH3CH2CH2O), 3.22
(t, 4H, J ) 6.8 Hz, 2 CH2CH2CH2N3), 2.46 (t, 4H, J ) 7.5 Hz,
2 CH2CH2CH2N3), 2.02-1.88 (m, 8H, 4 CH3CH2CH2O), 1.78 (tt,
4H, J ) 6.8, 7.5 Hz, 2 CH2CH2CH2N3), 1.04 and 0.98 (2t, 12H,
J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz): δ 156.1 (C),
155.3 (C), 135.4 (C), 134.6 (C), 133.7 (C), 128.2 (CH), 127.8 (CH),
122.0 (CH), 76.7 (CH2), 50.7 (CH2), 32.1 (CH2), 31.0 (CH2), 30.6
(CH2), 23.3 (CH2), 23.2 (CH2), 10.4 (CH3), 10.2 (CH3). Anal. Calcd
for C46H58N6O4: C, 72.79; H, 7.70; N, 11.07. Found: C, 72.49;
H, 7.54; N, 10.80.
corresponding carbon atoms (18a: δC4 ) 132.8 ppm; δC5
)
139.5 ppm. 18b: δC4 ) 132.9 ppm; δC5 ) 139.5 ppm).28 The
O-benzylated sugar clusters 10a and 12a,29 that appear to be
the C-glycoclusters structurally more similar to the model
(25) Recently, Fokin and Jia and co-workers described the highly 1,5-
regioselective cycloaddition of alkynes and azides in the presence of
ruthenium complexes; see: Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.;
Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc.
2005, 127, 15998.
5,17-Bis{3-[4-(2,3,4,6-tetra-O-benzyl-â-D-glucopyranosyl)-1H-
1,2,3-triazol-1-yl]propyl}-25,26,27,28-tetrapropoxy-calix[4]-
arene (3a). A mixture of calix[4]arene diazide 2 (76 mg, 0.10
mmol), sugar acetylene 1a (110 mg, 0.20 mmol), freshly distilled
(26) Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929.
(27) (a) Rodios, N. A. J. Heterocycl. Chem. 1984, 21, 1169. (b)
Hoffmann, B.; Bernet, B.; Vasella, A. HelV. Chim. Acta 2002, 85, 265.
(28) For 13C NMR data of simple 1,4- and 1,5-disubstituted triazoles,
see: Wamhoff, H. In ComprehensiVe Heterocyclic Chemistry; Potts, K. T.,
Ed.; Pergamon Press: Oxford, 1984; Vol. 5, pp 680-683.
(29) The complexity of the 13C NMR spectra recorded for the other
benzylated C-glycoclusters prevented the unambiguous assignment of the
triazole carbon atoms.
(30) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 5th ed.; Butterworth-Heinemann, Amsterdam, 2003.
(31) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
J. Org. Chem, Vol. 71, No. 20, 2006 7551

Dondoni and Marra
N,N-diisopropylethylamine (175 µL, 1.00 mmol), CuI (9.5 mg, 0.05
mmol), and anhydrous toluene (2 mL) was sonicated in an
ultrasound cleaning bath for 1 min, then magnetically stirred in
the dark at room temperature for 18 h, diluted with AcOEt (100
mL), washed with 1 M phosphate buffer at pH 7 (2 × 10 mL),
dried (Na2SO4), and concentrated. The residue was eluted from a
column of silica gel with 2:1 cyclohexane/AcOEt to give 3a (136
mg, 73%) as a white foam; [R]D ) +3.9 (c 1.0, CHCl3). 1H NMR
(400 MHz): δ 7.36-7.24 and 7.18-7.14 (2m, 38H, Ar, 2 H-5 Tr.),
7.01-6.97 (m, 4H, Ar), 6.55 and 6.53 (2d, 4H, J ) 1.8 Hz, Ar
calix.), 6.49-6.47 (m, 6H, Ar calix.), 4.96 and 4.91 (2d, 4H, J )
11.2 Hz, 2 PhCH2), 4.86 and 4.57 (2d, 4H, J ) 10.8 Hz, 2 PhCH2),
4.64 and 4.32 (2d, 4H, J ) 10.8 Hz, 2 PhCH2), 4.56 and 4.51 (2d,
4H, J ) 12.4 Hz, 2 PhCH2), 4.54 (d, 2H, J1,2 ) 9.8 Hz, 2 H-1),
4.42 and 4.41 (2d, 4H, J ) 13.2 Hz, 4 Hax of ArCH2Ar), 4.16 and
4.05 (2dt, 4H, J ) 7.2, 13.8 Hz, 2 ArCH2CH2CH2), 3.99 (dd, 2H,
J2,3 ) 9.0 Hz, 2 H-2), 3.87-3.79 (m, 8H, 4 CH3CH2CH2O), 3.83
5,17-Bis{3-[4-(â-D-glucopyranosyl)-1H-1,2,3-triazol-1-yl]-
propyl}-25,26,27,28-tetrapropoxy-calix[4]arene (3c). A solution
of 3b (29 mg, 0.02 mmol) in a 0.2 M solution of NaOMe in MeOH
(4 mL, prepared from Na and MeOH immediately before the use)
was kept at room temperature for 2 h in a nitrogen atmosphere,
then neutralized with Amberlite IR-120 resin (H+ form, activated
and washed with H2O and MeOH immediately before the use), and
filtered through a sintered glass filter. The resin was washed with
MeOH, and the solution was concentrated and dried under high
vacuum to give 3c (21 mg, 94%) as an amorphous solid; [R]D
)
1
+6.6 (c 1.0, MeOH). H NMR (300 MHz, CD3OD): δ 7.84 (bs,
2H, 2 H-5 Tr.), 6.75 (d, 4H, J ) 7.5 Hz, Ar), 6.64 (t, 2H, J ) 7.5
Hz, Ar), 6.45 (s, 4H, Ar), 4.48 and 3.14 (2d, 8H, J ) 13.2 Hz, 4
ArCH2Ar), 4.46-4.42 (m, 2H, 2 H-1), 4.18 (t, 4H, J ) 6.7 Hz, 2
ArCH2CH2CH2), 3.93 (t, 4H, J ) 7.5 Hz, 2 CH3CH2CH2O), 3.92-
3.88 (m, 2H, 2 H-6a), 3.81 (t, 4H, J ) 7.5 Hz, 2 CH3CH2CH2O),
3.71 (dd, 2H, J5,6b ) 4.0, J6a,6b ) 12.0 Hz, 2 H-6b), 3.66-3.42 (m,
8H), 2.16 (t, 4H, J ) 7.0 Hz, 2 ArCH2CH2CH2), 2.08-1.90 (m,
12H, 4 CH3CH2CH2O, 2 ArCH2CH2CH2), 1.06 and 1.03 (2t, 12H,
J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz, CD3OD): δ
157.8 (C), 156.1 (C), 147.2 (C), 136.5 (C), 135.9 (C), 134.9 (C),
129.4 (CH), 129.2 (CH), 124.9 (CH), 123.2 (CH), 82.2 (CH), 79.6
(CH), 78.1 (CH2), 77.8 (CH2), 75.6 (CH), 75.0 (CH), 71.6 (CH),
63.0 (CH2), 50.7 (CH2), 32.9 (CH2), 32.7 (CH2), 31.9 (CH2), 24.5
(CH2), 24.4 (CH2), 10.9 (CH3), 10.7 (CH3). MALDI-TOF MS
(dd, 2H, J3,4 ) 9.0 Hz, 2 H-3), 3.75 (dd, 2H, J5,6a ) 1.8, J6a,6b
)
10.8 Hz, 2 H-6a), 3.72 (dd, 2H, J4,5 ) 9.6 Hz, 2 H-4), 3.70 (dd,
2H, J5,6b ) 4.5 Hz, 2 H-6b), 3.65 (ddd, 2H, 2 H-5), 3.09 and 3.08
(2d, 4H, J ) 13.2 Hz, 4 Heq of ArCH2Ar), 2.34 and 2.26 (2dt, 4H,
J ) 7.2, 14.0 Hz, 2 ArCH2CH2CH2), 2.02 (tt, 4H, J ) 7.2, 7.2 Hz,
2 ArCH2CH2CH2), 1.97-1.88 (m, 8H, 4 CH3CH2CH2O), 1.02 and
0.98 (2t, 12H, J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz):
δ 156.1 (C), 155.4 (C), 145.4 (C), 138.6 (C), 138.0 (C), 135.4 (C),
134.6 (C), 133.0 (C), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.0
(CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 123.0 (CH), 122.1 (CH),
86.9 (CH), 81.8 (CH), 79.4 (CH), 78.2 (CH), 76.6 (CH2), 75.6
(CH2), 75.1 (CH2), 74.8 (CH2), 74.0 (CH), 73.4 (CH2), 69.2 (CH2),
49.3 (CH2), 31.8 (CH2), 31.7 (CH2), 30.9 (CH2), 23.2 (CH2), 23.1
(CH2), 10.4 (CH3), 10.2 (CH3). MALDI-TOF MS (1856.38): 1858.5
(M+ + 2H), 1880.5 (M+ + H + Na), 1896.5 (M+ + H + K).
Anal. Calcd for C118H130N6O14: C, 76.37; H, 7.06; N, 4.53.
Found: C, 76.10; H, 6.91; N, 4.33.
(1135.38): 1136.5 (M+ + H), 1158.5 (M+ + Na), 1174.5 (M+
+
K). Anal. Calcd for C62H82N6O14: C, 65.59; H, 7.28; N, 7.40.
Found: C, 65.30; H, 7.19; N, 7.25.
5,11,17,23-Tetrakis(3-azidopropyl)-25,26,27,28-tetrapropoxy-
calix[4]arene (4). A mixture of known1a 5,11,17,23-tetrakis(3-
hydroxypropyl)-25,26,27,28-tetrapropoxy-calix[4]arene (412 mg,
0.50 mmol), sodium azide (260 mg, 4.00 mmol), diphenyl phos-
phoryl azide (640 µL, 3.00 mmol), 1,8-diazabicyclo[5.4.0.]undec-
7-ene (300 µL, 2.00 mmol), and anhydrous DMF (5 mL) was stirred
at 120 °C for 14 h, then cooled to room temperature, diluted with
Et2O (150 mL), washed with H2O (2 × 10 mL), dried (Na2SO4),
and concentrated. The residue was eluted from a column of silica
gel with 9:1 cyclohexane/AcOEt to give 4 (412 mg, 89%) as a
5,17-Bis{3-[4-(2,3,4,6-tetra-O-acetyl-â-D-glucopyranosyl)-1H-
1,2,3-triazol-1-yl]propyl}-25,26,27,28-tetrapropoxy-calix[4]-
arene (3b). The cycloaddition between diazide 2 (76 mg, 0.10
mmol) and alkyne 1b (71 mg, 0.20 mmol) was carried out as
described for the preparation of 3a to give, after column chroma-
tography on silica gel (2.5:1 AcOEt/cyclohexane), 3b (141 mg,
1
syrup. H NMR (300 MHz): δ 6.47 (s, 8H, Ar), 4.42 and 3.08
(2d, 8H, J ) 13.0 Hz, 4 ArCH2Ar), 3.86-3.81 (m, 8H, 4 CH3-
CH2CH2O), 3.18 (t, 8H, J ) 6.8 Hz, 4 CH2CH2CH2N3), 2.39 (t,
8H, J ) 7.5 Hz, 4 CH2CH2CH2N3), 2.02-1.89 (m, 8H, 4 CH3CH2-
CH2O), 1.73 (tt, 8H, J ) 6.8, 7.5 Hz, 4 CH2CH2CH2N3), 1.00 (t,
12H, J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz): δ 154.8
(C), 134.7 (C), 133.8 (C), 128.0 (CH), 76.8 (CH2), 50.6 (CH2),
32.0 (CH2), 30.9 (CH2), 30.5 (CH2), 23.2 (CH2), 10.3 (CH3).
MALDI-TOF MS (925.20): 947.9 (M+ + Na). Anal. Calcd for
C52H68N12O4: C, 67.51; H, 7.41; N, 18.17. Found: C, 67.17; H,
7.22; N, 17.91.
1
96%) as a syrup; [R]D ) -22.5 (c 1.0, CHCl3). H NMR (400
MHz, C6D6): δ 7.06 (s, 2H, 2 H-5 Tr.), 6.74-6.68 (m, 6H, Ar),
6.63-6.60 (m, 4H, Ar), 5.56-5.50 (m, 4H, 2 H-2, 2 H-3), 5.50-
5.44 (m, 2H, 2 H-4), 4.81-4.76 (m, 2H, 2 H-1), 4.55 (d,
4H, J ) 13.0 Hz, 4 Hax of ArCH2Ar), 4.39 (dd, 2H, J5,6a ) 4.5,
J6a,6b ) 12.6 Hz, 2 H-6a), 3.97 (dd, 2H, J5,6b ) 2.2 Hz, 2 H-6b),
3.89-3.85 (m, 4H, 2 CH3CH2CH2O), 3.79 (t, 4H, J ) 7.3 Hz, 2
CH3CH2CH2O), 3.67 and 3.60 (2dt, 4H, J ) 7.0, 13.8 Hz, 2 ArCH2-
CH2CH2), 3.31 (ddd, 2H, J4,5 ) 9.5 Hz, 2 H-5), 3.20 and 3.19 (2d,
4H, J ) 13.0 Hz, 4 Heq of ArCH2Ar), 2.14-2.02 (m, 4H, 2 ArCH2-
CH2CH2), 1.97-1.84 (m, 8H, 4 CH3CH2CH2O), 1.71, 1.68, 1.67,
and 1.64 (4s, 24H, 8 Ac), 1.70-1.63 (m, 4H, 2 ArCH2CH2CH2),
5,11,17,23-Tetrakis{3-[4-(2,3,4,6-tetra-O-benzyl-â-D-glucopyrano-
syl)-1H-1,2,3-triazol-1-yl]propyl}-25,26,27,28-tetrapropoxy-calix[4]arene
(5a). The calix[4]arene tetraazide 4 (92 mg, 0.10 mmol) was
allowed to react with 1a (220 mg, 0.40 mmol) in the presence of
freshly distilled N,N-diisopropylethylamine (350 µL, 2.00 mmol)
and CuI (19 mg, 0.10 mmol) as described for the preparation of 3a
to give, after column chromatography on silica gel (from 3:1 to
1:1 cyclohexane/AcOEt), 5a (197 mg, 63%) as a white foam; [R]D
1
0.91 and 0.86 (2t, 12H, J ) 7.5 Hz, 4 CH3CH2CH2O). H NMR
(400 MHz, CDCl3) selected data: δ 7.54 (s, 2H, 2 H-5 Tr.), 6.55
(s, 4H, Ar), 6.49-6.46 (m, 6H, Ar), 5.36 (dd, 2H, J2,3 ) 9.4, J3,4
) 9.0 Hz, 2 H-3), 5.30 (dd, 2H, J1,2 ) 9.5 Hz, 2 H-2), 5.19 (dd,
2H, J4,5 ) 9.9 Hz, 2 H-4), 4.79 (d, 2H, 2 H-1), 4.42 and 3.10 (2d,
1
8H, J ) 13.2 Hz, 4 ArCH2Ar), 4.30 (dd, 2H, J5,6a ) 5.0, J6a,6b
)
) -3.8 (c 1.0, CHCl3). H NMR (400 MHz): δ 7.41 (s, 4H, 4
12.8 Hz, 2 H-6a), 4.23-4.15 (m, 4H, 2 ArCH2CH2CH2), 4.12 (dd,
2H, J5,6b ) 2.0 Hz, 2 H-6b), 3.88 (ddd, 2H, 2 H-5). 13C NMR (75
MHz): δ 170.6, 170.2, and 169.5 (CO), 156.1 and 155.5 (C Ar),
143.9 (C-4 Tr.), 135.5, 134.5, and 133.0 (C Ar), 128.1 and 127.8
(CH Ar), 122.2 (C-5 Tr.), 122.0 (CH Ar), 76.7 (CH3CH2CH2O),
76.2 (CH), 74.0 (CH), 73.4 (CH), 71.2 (CH), 68.4 (CH), 62.1 (C-
6), 49.7 (ArCH2CH2CH2), 31.8 (CH2), 31.7 (CH2), 30.9 (CH2), 23.2
(CH2), 23.1 (CH2), 20.7 and 20.6 (CH3CO), 10.4 and 10.1 (CH3-
CH2CH2O). MALDI-TOF MS (1471.68): 1473.3 (M+ + H), 1496.2
(M+ + H + Na), 1511.2 (M+ + K). Anal. Calcd for C78H98N6O22:
C, 63.66; H, 6.71; N, 5.71. Found: C, 63.39; H, 6.60; N, 5.56.
H-5 Tr.), 7.34-7.22 (m, 52H, Ar), 7.16-7.10 (m, 20H, Ar), 6.97-
6.94 (m, 8H, Ar), 6.43 (s, 8H, Ar calix.), 4.93 and 4.87 (2d, 8H, J
) 11.3 Hz, 4 PhCH2), 4.84 and 4.55 (2d, 8H, J ) 10.8 Hz, 4
PhCH2), 4.60 and 4.27 (2d, 8H, J ) 10.8 Hz, 4 PhCH2), 4.52 and
4.46 (2d, 8H, J ) 12.4 Hz, 4 PhCH2), 4.51 (d, 4H, J1,2 ) 9.2 Hz,
4 H-1), 4.39 and 3.04 (2d, 8H, J ) 13.0 Hz, 4 ArCH2Ar), 4.14-
4.06 (m, 8H, 4 ArCH2CH2CH2), 3.95 (dd, 4H, J2,3 ) 9.4 Hz, 4 H-2),
3.82 (t, 8H, J ) 7.5 Hz, 4 CH3CH2CH2O), 3.80 (dd, 4H, J3,4 ) 8.3
Hz, 4 H-3), 3.74-3.66 (m, 12H), 3.64-3.59 (m, 4H), 2.27 (t, 8H,
J ) 7.2 Hz, 4 ArCH2CH2CH2), 1.97-1.87 (m, 16H, 4 ArCH2CH2-
CH2, 4 CH3CH2CH2O), 0.98 (t, 12H, J ) 7.5 Hz, 4 CH3CH2CH2O).
7552 J. Org. Chem., Vol. 71, No. 20, 2006

C-Glycoside Clustering through 1,2,3-Triazole Linkers
13C NMR (75 MHz): δ 154.9 (C), 145.3 (C), 138.6 (C), 138.0
(C), 134.8 (C), 133.2 (C), 128.33 (CH), 128.27 (CH), 128.1 (CH),
127.9 (CH), 127.8 (CH), 127.7 (CH), 127.5 (CH), 123.0 (CH), 86.9
(CH), 81.8 (CH), 79.4 (CH), 78.2 (CH), 76.7 (CH2), 75.5 (CH2),
75.0 (CH2), 74.7 (CH2), 73.9 (CH), 73.3 (CH2), 69.2 (CH2), 49.4
(CH2), 31.8 (CH2), 30.9 (CH2), 23.1 (CH2), 10.2 (CH3). MALDI-
TOF MS (3119.94): 3143.0 (M+ + Na), 3158.9 (M+ + K). Anal.
Calcd for C196H212N12O24: C, 75.45; H, 6.85; N, 5.39. Found: C,
75.11; H, 6.64; N, 5.19.
J ) 14.5 Hz, 3 CH2N), 4.92 and 4.89 (2d, 6H, J ) 11.0 Hz, 3
PhCH2), 4.84 and 4.55 (2d, 6H, J ) 10.8 Hz, 3 PhCH2), 4.64 and
4.26 (2d, 6H, J ) 11.0 Hz, 3 PhCH2), 4.53 and 4.48 (2d, 6H, J )
12.1 Hz, 3 PhCH2), 4.50 (d, 3H, J1,2 ) 9.6 Hz, 3 H-1), 3.92 (dd,
3H, J2,3 ) 9.0 Hz, 3 H-2), 3.81 (dd, 3H, J3,4 ) 8.8 Hz, 3 H-3),
3.72 (dd, 3H, J5,6a ) 1.6, J6a,6b ) 10.8 Hz, 3 H-6a), 3.69 (dd, 3H,
J4,5 ) 9.6 Hz, 3 H-4), 3.67 (dd, 3H, J5,6b ) 4.5 Hz, 3 H-6b), 3.62
1
(ddd, 3H, 3 H-5). H NMR (400 MHz, C6D6) selected data: δ
7.35-6.95 (m, 60H, 12 Ph), 6.67 and 6.46 (2s, 6H, C6H3, 3 H-5
Tr.). 13C NMR (75 MHz): δ 146.2 (C), 138.5 (C), 138.04 (C),
137.96 (C), 136.9 (C), 128.4 (CH), 128.3 (CH), 128.2 (CH), 127.9
(CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.0 (CH), 123.2 (CH),
86.9 (CH), 81.7 (CH), 79.4 (CH), 78.2 (CH), 75.6 (CH2), 75.1
(CH2), 74.7 (CH2), 73.8 (CH), 73.4 (CH2), 69.1 (CH2), 52.9 (CH2).
5,11,17,23-Tetrakis{3-[4-(2,3,4,6-tetra-O-acetyl-â-D-glucopyrano-
syl)-1H-1,2,3-triazol-1-yl]propyl}-25,26,27,28-tetrapropoxy-calix[4]-
arene (5b). The cycloaddition between tetraazide 4 (46 mg, 0.05
mmol) and alkyne 1b (71 mg, 0.20 mmol) was carried out as
described for the preparation of 5a to give, after column chroma-
tography on silica gel (AcOEt), 5b (101 mg, 86%) as a syrup; [R]D
MALDI-TOF MS (1889.29): 1911.9 (M+ + Na), 1927.7 (M+
+
1
K). Anal. Calcd for C117H117N9O15: C, 74.38; H, 6.24; N, 6.67.
Found: C, 74.60; H, 6.33; N, 6.70.
) -24.7 (c 1.0, CHCl3). H NMR (300 MHz): δ 7.64 (s, 4H, 4
H-5 Tr.), 6.46 (s, 8H, Ar), 5.39 (dd, 4H, J2,3 ) J3,4 ) 9.2 Hz, 4
H-3), 5.32 (dd, 4H, J1,2 ) 9.6 Hz, 4 H-2), 5.20 (dd, 4H, J4,5 ) 9.8
Hz, 4 H-4), 4.86 (d, 4H, 4 H-1), 4.42 and 3.09 (2d, 8H, J ) 13.1 Hz,
4 ArCH2Ar), 4.35 (dd, 4H, J5,6a ) 4.6, J6a,6b ) 12.5 Hz, 4 H-6a),
1,3,5-Tris{[4-(2,3,4,6-tetra-O-acetyl-â-D-glucopyranosyl)-1H-
1,2,3-triazol-1-yl]methyl}-benzene (7b). Route a. The cyclo-
addition between triazide 6 (24 mg, 0.10 mmol) and alkyne 1b
(107 mg, 0.30 mmol) was carried out as described for the prepa-
ration of 7a to give, after column chromatography on silica gel
(AcOEt then acetone), 7b (113 mg, 86%) as a syrup; [R]D ) -23.8
4.23 (t, 8H, J ) 7.3 Hz, 4 ArCH2CH2CH2), 4.15 (dd, 4H, J5,6b
)
1.8 Hz, 4 H-6b), 3.94 (ddd, 4H, 4 H-5), 3.84 (t, 8H, J ) 7.5 Hz,
4 CH3CH2CH2O), 2.32 (t, 8H, J ) 7.3 Hz, 4 ArCH2CH2CH2), 2.09,
2.08, 2.04, and 1.90 (4s, 48H, 16 Ac), 2.08-1.89 (m, 16H, 4
CH3CH2CH2O, 4 ArCH2CH2CH2), 1.01 (t, 12H, J ) 7.4 Hz, 4 CH3-
CH2CH2O). 13C NMR (75 MHz): δ 170.6, 170.1, and 169.5 (CO),
155.0 (C Ar), 143.9 (C-4 Tr.), 134.8 and 133.0 (C Ar), 127.9 (CH
Ar), 122.2 (C-5 Tr.), 76.7 (CH3CH2CH2O), 76.1 (CH), 73.9 (CH),
73.2 (CH), 71.2 (CH), 68.3 (CH), 62.1 (C-6), 49.7 (ArCH2CH2CH2),
31.8 (CH2), 30.9 (CH2), 23.1 (CH2), 20.7 and 20.5 (CH3CO), 10.2
(CH3CH2CH2O). MALDI-TOF MS (2350.54): 2374.7 (M+ + H
+ Na), 2389.8 (M+ + K). Anal. Calcd for C116H148N12O40: C,
59.27; H, 6.35; N, 7.15. Found: C, 59.01; H, 6.21; N, 6.93.
5,11,17,23-Tetrakis{3-[4-(â-D-glucopyranosyl)-1H-1,2,3-tria-
zol-1-yl]propyl}-25,26,27,28-tetrapropoxy-calix[4]arene (5c). A
solution of 5b (47 mg, 0.02 mmol) in a 0.2 M solution of NaOMe
in MeOH (4 mL, prepared from Na and MeOH immediately before
the use) was stirred at room temperature for 4 h in a nitrogen atmo-
sphere (after a few minutes the solution turned turbid), then diluted
with H2O (ca. 0.2 mL), neutralized with Amberlite IR-120 resin
(H+ form, activated and washed with H2O and MeOH immediately
before the use), and filtered through a sintered glass filter. The resin
was washed with MeOH, H2O, and DMF, the solution was con-
centrated and dried under high vacuum to give 5c (30 mg, 90%)
as an amorphous solid; [R]D ) +7.5 (c 0.8, DMF). 1H NMR (400
MHz, CD3OD): δ 7.97 (bs, 4H, 4 H-5 Tr.), 6.56 (s, 8H, Ar), 4.42
and 3.09 (2d, 8H, J ) 13.0 Hz, 4 ArCH2Ar), 4.41-4.37 (m, 4H, 4
H-1), 4.17 (t, 8H, J ) 6.8 Hz, 4 ArCH2CH2CH2), 3.87-3.84 (m,
4H, 4 H-6a), 3.82 (t, 8H, J ) 7.5 Hz, 4 CH3CH2CH2O), 3.69-
3.65 (m, 4H, 4 H-6b), 3.62-3.40 (m, 16H), 2.24 (t, 8H, J ) 7.0
Hz, 4 ArCH2CH2CH2), 2.02-1.92 (m, 16H, 4 CH3CH2CH2O, 4
ArCH2CH2CH2),1.02 (t, 12H, J ) 7.5 Hz, 4 CH3CH2CH2O). 13C
NMR (75 MHz, CD3OD): δ 156.1 (C), 136.1 (C), 135.1 (C), 129.5
(CH), 125.0 (CH), 82.2 (CH), 79.6 (CH), 78.0 (CH2), 75.6 (CH),
75.0 (CH), 71.6 (CH), 63.0 (CH2), 50.6 (CH2), 33.0 (CH2), 32.8
(CH2), 31.8 (CH2), 24.5 (CH2), 10.9 (CH3). MALDI-TOF MS
1
(c 1.1, CHCl3). H NMR (300 MHz): δ 7.69 (s, 3H, 3 H-5 Tr.),
6.94 (s, 3H, C6H3), 5.62 and 5.46 (2d, 6H, J ) 15.5 Hz, 3 CH2N),
5.39 (dd, 3H, J2,3 ) 9.6, J3,4 ) 9.2 Hz, 3 H-3), 5.22 (dd, 3H, J1,2
) 9.9 Hz, 3 H-2), 5.17 (dd, 3H, J4,5 ) 10.1 Hz, 3 H-4), 4.78 (d,
3H, 3 H-1), 4.30 (dd, 3H, J5,6a ) 5.1, J6a,6b ) 12.6 Hz, 3 H-6a), 4.14
(dd, 3H, J5,6b ) 2.2 Hz, 3 H-6b), 3.89 (ddd, 3H, 3 H-5), 2.08, 2.07,
2.04, and 1.94 (4s, 36H, 12 Ac). 13C NMR (75 MHz): δ 170.5,
170.1, 169.7, and 169.5 (CO), 145.0 (C-4 Tr.), 136.8 (C Ar), 126.4
(CH Ar), 122.7 (C-5 Tr.), 76.3 (C-5), 73.5 (C-3), 73.4 (C-1), 71.7
(C-2), 68.3 (C-4), 62.1 (C-6), 53.1 (CH2N), 20.7, 20.6, and 20.5
(CH3CO). MALDI-TOF MS (1312.24): 1313.9 (M+ + H), 1336.0
(M+ + Na), 1351.9 (M+ + K). Anal. Calcd for C57H69N9O27: C,
52.17; H, 5.30; N, 9.61. Found: C, 52.25; H, 5.39; N, 9.80.
Route b. To a cooled (-60 °C), stirred solution of 7a (38 mg,
0.02 mmol) in anhydrous CH2Cl2 (2 mL) was added dropwise a
1 M solution of BCl3 in CH2Cl2 (480 µL, 0.48 mmol). The solution
was stirred at -60 °C for 1 h and, after additional stirring at 0 °C
for 1 h, diluted with MeOH (0.5 mL), stirred at 0 °C for 10 min,
diluted with triethylamine (0.5 mL), concentrated, and dried under
high vacuum to give a white solid. A suspension of the residue
and 4-N,N-(dimethylamino)pyridine (5 mg) in DMF (2 mL), acetic
anhydride (2 mL), and triethylamine (2 mL) was stirred at room
temperature for 18 h, then concentrated, diluted with CH2Cl2
(40 mL), washed with H2O (2 × 5 mL), dried (Na2SO4), and
concentrated. The residue was eluted from a column of silica gel
(3:1 AcOEt/cyclohexane, then acetone) to give 7b (24 mg, 92%)
identical to the compound prepared by route a.
1,3,5-Tris{[4-(â-D-glucopyranosyl)-1H-1,2,3-triazol-1-yl]-
methyl}-benzene (7c). The C-glycocluster 7b (26 mg, 0.02 mmol)
was deacetylated as described for the preparation of 5c to give,
after a similar workup, 7c (11 mg, 68%) as an amorphous solid;
[R]D ) +3.8 (c 0.5, DMF). 1H NMR (400 MHz, CD3OD): δ 8.06
(s, 3H, 3 H-5 Tr.), 7.31 (s, 3H, C6H3), 5.63 (s, 6H, 3 CH2N), 4.42
(1677.94): 1679.2 (M+ + H), 1701.3 (M+ + Na), 1717.2 (M+
+
(d, 3H, J1,2 ) 9.0 Hz, 3 H-1), 3.87 (dd, 3H, J5,6a ) 2.0, J6a,6b
)
12.0 Hz, 3 H-6a), 3.67 (dd, 3H, J5,6b ) 5.5 Hz, 3 H-6b), 3.51 (dd,
3H, J2,3 ) 9.2 Hz, 3 H-2), 3.47 (dd, 3H, J3,4 ) 8.6 Hz, 3 H-3),
3.44 (ddd, 3H, J4,5 ) 9.5 Hz, 3 H-5), 3.38 (dd, 3H, 3 H-4). 13C
NMR (75 MHz, D2O): δ 136.7 (C), 127.7 (CH), 125.5 (CH), 80.3
(CH), 77.3 (CH), 73.6 (CH), 73.0 (CH), 69.7 (CH), 61.0 (CH2),
53.5 (CH2). MALDI-TOF MS (807.79): 831.0 (M+ + Na), 847.0
(M+ + K). Anal. Calcd for C33H45N9O15‚H2O: C, 48.00; H, 5.74;
N, 15.26. Found: C, 48.31; H, 5.89; N, 15.10.
K). Anal. Calcd for C84H116N12O24: C, 60.13; H, 6.97; N, 10.02.
Found: C, 59.80; H, 6.72; N, 9.78.
1,3,5-Tris{[4-(2,3,4,6-tetra-O-benzyl-â-D-glucopyranosyl)-1H-
1,2,3-triazol-1-yl]methyl}-benzene (7a). Tris(azidomethyl)benzene
6 (12 mg, 0.05 mmol) was allowed to react with 1a (82 mg, 0.15
mmol) in the presence of freshly distilled N,N-diisopropylethylamine
(130 µL, 0.75 mmol) and CuI (7 mg, 0.037 mmol) as described
for the preparation of 3a to give, after column chromatography on
silica gel (2:1 AcOEt/cyclohexane), 7a (61 mg, 65%) as a white
solid. Mp 198-200 °C (toluene); [R]D ) -6.7 (c 0.8, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 7.31-7.22, 7.18-7.10, and 6.98-
6.92 (3m, 66H, 12 Ph, C6H3, 3 H-5 Tr.), 5.17 and 5.12 (2d, 6H,
2,6-Anhydro-1-azido-3,4,5,7-tetra-O-benzyl-1-deoxy-D-glycero-
D-gulo-heptitol (8a). A mixture of known32 2,6-anhydro-3,4,5,7-
(32) Baumberger, F.; Vasella, A. HelV. Chim. Acta 1983, 66, 2210.
J. Org. Chem, Vol. 71, No. 20, 2006 7553

Dondoni and Marra
tetra-O-benzyl-D-glycero-D-gulo-heptitol (555 mg, 1.00 mmol),
prepared by reduction with NaBH4 of the corresponding formyl
â-D-C-glucopyranoside,33 diphenyl phosphoryl azide (650 µL, 3.00
mmol), 1,8-diazabicyclo[5.4.0.]undec-7-ene (150 µL, 1.00 mmol),
and anhydrous DMF (5 mL) was stirred at 100 °C for 2 h then
cooled to room temperature. Sodium azide (195 mg, 3.00 mmol)
was added in one portion, and then the reaction mixture was stirred
at 100 °C for an additional 14 h, cooled to room temperature, diluted
with Et2O (200 mL), washed with H2O (2 × 20 mL), dried (Na2-
SO4), and concentrated. The residue was eluted from a column of
silica gel with 8:1 cyclohexane/AcOEt to give 8a (440 mg, 76%)
J ) 10.8 Hz, 3 PhCH2), 4.74 and 4.48 (2d, 6H, J ) 10.8 Hz, 3
PhCH2), 4.67 (d, 6H, J1,2 ) 4.0 Hz, 6 H-1), 4.63 and 4.54 (2d, 6H,
J ) 12.2 Hz, 3 PhCH2), 3.74 (dd, 3H, J3,4 ) 9.2, J4,5 ) 8.6 Hz, 3
H-4), 3.72-3.65 (m, 9H, 3 H-2, 6 H-7), 3.53 (dd, 3H, J5,6 ) 9.8
Hz, 3 H-5), 3.47 (ddd, 3H, J6,7a ) 3.8, J6,7b ) 2.3 Hz, 3 H-6), 3.22
(dd, 3H, J2,3 ) 9.5 Hz, 3 H-3). 13C NMR (75 MHz): δ 147.2 (C-4
Tr.), 138.3 and 137.8 (C Bn), 132.0 (C Ph), 128.5-127.5 (CH Bn),
122.4 and 122.1 (CH Ph, C-5 Tr.), 87.0 (CH), 79.0 (CH), 78.1
(CH), 78.0 (CH), 77.1 (CH), 75.5, 75.1, and 73.5 (PhCH2), 68.7
(C-7), 50.8 (C-1). MALDI-TOF MS (1889.29): 1890.0 (M+ + H),
1911.9 (M+ + Na). Anal. Calcd for C117H117N9O15: C, 74.38; H,
6.24; N, 6.67. Found: C, 74.51; H, 6.40; N, 6.85.
1
as a syrup; [R]D ) -27.9 (c 1.3, CHCl3). H NMR (400 MHz,
C6D6): δ 7.34-7.01 (m, 20H, Ar), 4.84 and 4.77 (2d, 2H, J )
11.2 Hz, PhCH2), 4.81 and 4.60 (2d, 2H, J ) 11.2 Hz, PhCH2),
4.76 and 4.40 (2d, 2H, J ) 11.4 Hz, PhCH2), 4.49 and 4.39 (2d,
2H, J ) 12.1 Hz, PhCH2), 3.70 (dd, 1H, J4,5 ) 8.8, J5,6 ) 9.8 Hz,
H-5), 3.65 (dd, 1H, J6,7a ) 3.7, J7a,7b ) 11.1 Hz, H-7a), 3.61 (dd,
1H, J6,7b ) 2.0 Hz, H-7b), 3.54 (dd, 1H, J3,4 ) 9.1 Hz, H-4), 3.38
(dd, 1H, J2,3 ) 9.4 Hz, H-3), 3.23 (ddd, 1H, H-6), 3.16 (ddd, 1H,
J1a,2 ) 2.4, J1b,2 ) 5.5 Hz, H-2), 3.11 (dd, 1H, J1a,1b ) 13.0 Hz,
H-1a), 2.92 (dd, 1H, H-1b). 13C NMR (75 MHz): δ 138.4 (C),
138.2 (C), 138.0 (C), 137.8 (C), 128.51 (CH), 128.45 (CH), 128.37
(CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 87.0 (CH),
79.2 (CH), 78.7 (CH), 78.4 (CH), 78.3 (CH), 75.6 (CH2), 75.2
(CH2), 75.1 (CH2), 73.6 (CH2), 69.0 (CH2), 51.3 (CH2). Anal. Calcd
for C35H37N3O5: C, 72.52; H, 6.43; N, 7.25. Found: C, 72.70; H,
6.56; N, 7.43.
1,3,5-Tris[1-(3,4,5,7-tetra-O-acetyl-2,6-anhydro-1-deoxy-D-
glycero-D-gulo-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-benzene (10b).
Route a. The cycloaddition between triethynylbenzene 9 (7.5 mg,
0.05 mmol) and sugar azide 8b (87 mg, 0.225 mmol) was carried
out as described for the preparation of 10a except for the reaction
time (18 h instead of 48 h). The residue was eluted from a column
of silica gel (4:1 AcOEt/cyclohexane, then AcOEt) to give first
unchanged 8b (26 mg, 30%). Eluted second was 10b (63 mg, 96%)
as a syrup; [R]D ) +23.1 (c 0.8, CHCl3). 1H NMR (300 MHz): δ
8.36 and 8.14 (2s, 6H, C6H3, 3 H-5 Tr.), 5.28 (dd, 3H, J3,4 ) 9.6,
J4,5 ) 9.2 Hz, 3 H-4), 5.10 (dd, 3H, J5,6 ) 10.2 Hz, 3 H-5), 4.96
(dd, 3H, J2,3 ) 9.8 Hz, 3 H-3), 4.72 (dd, 3H, J1a,2 ) 2.2, J1a,1b
)
14.5 Hz, 3 H-1a), 4.44 (dd, 3H, J1b,2 ) 8.4 Hz, 3 H-1b), 4.27 (dd,
3H, J6,7a ) 5.3, J7a,7b ) 12.3 Hz, 3 H-7a), 4.16 (dd, 3H, J6,7b ) 2.1
Hz, 3 H-7b), 3.94 (ddd, 3H, 3 H-2), 3.70 (ddd, 3H, 3 H-6), 2.16,
2.05, 2.04, and 2.00 (4s, 36H, 12 Ac). 13C NMR (75 MHz): δ
170.6, 170.1, 169.7, and 169.3 (CO), 147.1 (C-4 Tr.), 131.6 (C
Ar), 122.3 and 122.1 (CH Ar, C-5 Tr.), 76.3 (CH), 75.9 (CH), 73.7
(CH), 69.6 (CH), 68.1 (CH), 61.8 (C-7), 51.1 (C-1), 20.6 and 20.5
(CH3CO). MALDI-TOF MS (1312.24): 1313.6 (M+ + H), 1335.6
(M+ + Na), 1351.6 (M+ + K). Anal. Calcd for C57H69N9O27: C,
52.17; H, 5.30; N, 9.61. Found: C, 52.33; H, 5.41; N, 9.78.
Route b. The C-glycocluster 10a (38 mg, 0.02 mmol) was
debenzylated and acetylated as described for the preparation of 7b
to give, after column chromatography on silica gel (AcOEt), 10b
(23 mg, 88%) identical to the compound prepared by route a.
1,3,5-Tris[1-(2,6-anhydro-1-deoxy-D-glycero-D-gulo-heptitol-
1-yl)-1H-1,2,3-triazol-4-yl]-benzene (10c). The C-glycocluster 10b
(26 mg, 0.02 mmol) was deacetylated as described for the prepa-
ration of 5c to give, after a similar workup, 10c (14.5 mg, 90%) as
3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-azido-1-deoxy-D-glycero-
D-gulo-heptitol (8b). To a cooled (-60 °C), stirred solution of 8a
(232 mg, 0.40 mmol) in anhydrous CH2Cl2 (4 mL) was added
dropwise a 1 M solution of BCl3 in CH2Cl2 (3.2 mL, 3.20 mmol).
The solution was allowed to reach -30 °C in 2 h, then was stirred
at 0 °C for 1 h, diluted with MeOH (3 mL), stirred at 0 °C for an
additional 10 min, diluted with triethylamine (3 mL), concentrated,
and dried under high vacuum to give a white solid. A suspension
of the residue in DMF (4 mL), acetic anhydride (4 mL), and
triethylamine (4 mL) was stirred at room temperature for 18 h,
then concentrated, diluted with AcOEt (100 mL), washed with H2O
(2 × 20 mL), dried (Na2SO4), and concentrated. The residue was
eluted from a column of silica gel with 1:1 cyclohexane/AcOEt to
give 8b (115 mg, 74%) as a white solid. Mp 112-113 °C (AcOEt/
1
cyclohexane); [R]D ) -7.8 (c 1.0, CHCl3). H NMR (300 MHz):
1
δ 5.23 (dd, 1H, J3,4 ) 9.6, J4,5 ) 9.1 Hz, H-4), 5.10 (dd, 1H, J5,6
) 9.3 Hz, H-5), 5.04 (dd, 1H, J2,3 ) 9.7 Hz, H-3), 4.25 (dd, 1H,
J6,7a ) 5.1, J7a,7b ) 12.3 Hz, H-7a), 4.16 (dd, 1H, J6,7b ) 2.5 Hz,
H-7b), 3.74 (ddd, 1H, H-6), 3.70 (ddd, 1H, J1a,2 ) 6.4, J1b,2 ) 2.8
Hz, H-2), 3.36 (dd, 1H, J1a,1b ) 13.4 Hz, H-1a), 3.28 (dd, 1H, H-1b),
2.10, 2.06, 2.05, and 2.03 (4s, 12H, 4 Ac). 13C NMR (75 MHz):
δ 170.6, 170.3, 169.4, and 169.3 (CO), 77.3 (C-2), 75.7 (C-6), 73.9
(C-4), 69.3 (C-3), 68.3 (C-5), 62.1 (C-7), 50.9 (C-1), 20.6 and 20.5
(CH3CO). Anal. Calcd for C15H21N3O9: C, 46.51; H, 5.46; N, 10.85.
Found: C, 46.60; H, 5.51; N, 10.96.
an amorphous solid; [R]D ) +10.5 (c 0.9, DMF). H NMR (400
MHz, DMSO-d6 + D2O): δ 8.62 and 8.26 (2s, 6H, C6H3, 3 H-5
Tr.), 4.78 (dd, 3H, J1a,2 ) 1.8, J1a,1b ) 14.5 Hz, 3 H-1a), 4.43 (dd,
3H, J1b,2 ) 8.0 Hz, 3 H-1b), 3.62 (dd, 3H, J6,7a ) 1.5, J7a,7b ) 12.0
Hz, 3 H-7a), 3.47 (ddd, 3H, J2,3 ) 9.5 Hz, 3 H-2), 3.40 (dd, 6H,
J6,7b ) 6.0 Hz, 3 H-7b), 3.18 (dd, 3H, J3,4 ) 8.8, J4,5 ) 8.5 Hz, 3
H-4), 3.08 (ddd, 3H, J5,6 ) 9.5 Hz, 3 H-6), 3.01 (dd, 3H, 3 H-5),
2.95 (dd, 3H, 3 H-3). 13C NMR (75 MHz, DMSO-d6): δ 146.2
(C), 132.4 (C), 123.4 (CH), 121.7 (CH), 80.7 (CH), 78.1 (CH),
77.9 (CH), 71.4 (CH), 70.3 (CH), 61.4 (CH2), 51.8 (CH2). MALDI-
TOF MS (807.79): 809.3 (M+ + H), 831.3 (M+ + Na), 847.3
(M+ + K). Anal. Calcd for C33H45N9O15: C, 49.07; H, 5.61; N,
15.61. Found: C, 48.70; H, 5.60; N, 15.42.
1,3,5-Tris[1-(2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-
glycero-D-gulo-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-benzene (10a).
A mixture of triethynylbenzene 9 (7.5 mg, 0.05 mmol), sugar azide
8a (130 mg, 0.225 mmol), freshly distilled N,N-diisopropylethyl-
amine (195 µL, 1.125 mmol), CuI (7 mg, 0.037 mmol), and anhy-
drous toluene (1 mL) was sonicated in an ultrasound cleaning bath
for 1 min, then magnetically stirred in the dark at 80 °C for 48 h,
cooled to room temperature, diluted with AcOEt (100 mL), washed
with 1 M phosphate buffer at pH 7 (2 × 10 mL), dried (Na2SO4),
and concentrated. The residue was eluted from a column of silica
gel (from 4:1 to 1:1 cyclohexane/AcOEt) to give first unchanged
8a (58 mg, 45%). Eluted second was 10a (64 mg, 68%) as a syrup;
3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-azido-1-deoxy-D-glycero-
L-manno-heptitol (11b). Known19 benzylated azidomethyl C-
galactoside 11a (464 mg, 0.80 mmol) was treated as described for
the preparation of 8b to give, after column chromatography on silica
gel (1.5:1 cyclohexane/AcOEt), 11b (217 mg, 70%) as a syrup;
1
[R]D ) +14.6 (c 0.7, CHCl3). H NMR (300 MHz): δ 5.46 (dd,
1H, J4,5 ) 3.3, J5,6 ) 1.3 Hz, H-5), 5.22 (dd, 1H, J2,3 ) 9.5, J3,4
)
10.1 Hz, H-3), 5.07 (dd, 1H, H-4), 4.19 (dd, 1H, J6,7a ) 7.0, J7a,7b
) 11.3 Hz, H-7a), 4.10 (dd, 1H, J6,7b ) 6.2 Hz, H-7b), 3.97 (ddd,
1H, H-6), 3.68 (ddd, 1H, J1a,2 ) 7.1, J1b,2 ) 2.5 Hz, H-2), 3.41
(dd, 1H, J1a,1b ) 13.4 Hz, H-1a), 3.23 (dd, 1H, H-1b), 2.19 (s, 3H,
Ac), 2.08 (s, 6H, 2 Ac), 2.01 (s, 3H, Ac). 13C NMR (75 MHz): δ
170.4, 170.2, 170.0, and 169.7 (CO), 77.9 (C-2), 74.2 (C-6), 71.8
(C-4), 67.4 (C-5), 66.9 (C-3), 61.6 (C-7), 51.0 (C-1), 20.6 and 20.5
1
[R]D ) -40.1 (c 0.7, CHCl3). H NMR (400 MHz): δ 8.37 and
8.12 (2s, 6H, C6H3, 3 H-5 Tr.), 7.40-7.07 (m, 60H, 12 Ph), 4.93
and 4.89 (2d, 6H, J ) 11.1 Hz, 3 PhCH2), 4.86 and 4.77 (2d, 6H,
(33) Dondoni, A.; Marra, A. Tetrahedron Lett. 2003, 44, 13.
7554 J. Org. Chem., Vol. 71, No. 20, 2006

C-Glycoside Clustering through 1,2,3-Triazole Linkers
(CH3CO). Anal. Calcd for C15H21N3O9: C, 46.51; H, 5.46; N, 10.85.
Found: C, 46.80; H, 5.58; N, 10.98.
were added commercially available (trimethylsilyl)acetylene (210
µL, 1.50 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol) and CuI (3 mg,
0.015 mmol). The mixture was stirred in a screw-capped vial at 50
°C for 24 h in the dark, then cooled to room temperature, partially
concentrated, diluted with 1 M aqueous HCl (ca. 30 mL), and
extracted with AcOEt (150 mL). The organic phase was washed
with H2O (2 × 20 mL), dried (Na2SO4), and concentrated. The
residue was eluted from a short column of silica gel with 9:1
cyclohexane/AcOEt to give 25,26,27,28-tetrapropoxy-5,11,17,23-
tetrakis(trimethylsilylethynyl)-calix[4]arene contaminated by small
amounts of uncharacterized byproducts as a light brown foam (0.30
g). A mixture of the latter compound, KF (0.87 g, 15.0 mmol),
and DMF (30 mL) was stirred at 60 °C for 4 h, partially concen-
trated under vacuum, diluted with 0.01 M aqueous HCl (50 mL),
and extracted with AcOEt (2 × 100 mL). The organic phase was
washed with H2O (2 × 20 mL), dried (Na2SO4), and concentrated.
The residue was eluted from a column of silica gel with 10:1
cyclohexane/AcOEt to give 13 (74 mg, 36%) as an amorphous solid.
1H NMR (300 MHz): δ 6.85 (s, 8H, Ar), 4.39 and 3.13 (2 d, 8H,
J ) 13.5 Hz, 4 ArCH2Ar), 3.89-3.83 (m, 8H, 4 CH3CH2CH2O),
2.91 (s, 4H, 4 CtCH), 1.97-1.84 (m, 8H, 4 CH3CH2CH2O), 1.00
(t, 12H, J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz): δ
157.1 (C Ar), 134.7 (C Ar), 132.2 (CH Ar), 115.9 (C Ar), 83.9
(CtCH), 76.9 (CH3CH2CH2O), 75.8 (CtCH), 30.6 (ArCH2Ar),
23.1 (CH3CH2CH2O), 10.2 (CH3CH2CH2O). MALDI-TOF MS
(688.91): 690.0 (M+ + H), 712.0 (M+ + Na), 728.0 (M+ + K).
Anal. Calcd for C48H48O4: C, 83.69; H, 7.02; N. Found: C, 83.32;
H, 6.70.
1,3,5-Tris[1-(2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-
glycero-L-manno-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-benzene
(12a). The cycloaddition between triethynylbenzene 9 (7.5 mg, 0.05
mmol) and sugar azide 11a (130 mg, 0.225 mmol) was carried out
as described for the preparation of 10a to give, after column
chromatography on silica gel (from 3:1 to 1:1 cyclohexane/AcOEt),
first unchanged 8a (75 mg, 50%). Eluted second was 12a (58 mg,
1
62%) as a syrup; [R]D ) -31.6 (c 0.8, CHCl3). H NMR (400
MHz): δ 8.30 and 8.12 (2s, 6H, C6H3, 3 H-5 Tr.), 7.40-7.07 (m,
60H, 12 Ph), 4.94 and 4.73 (2d, 6H, J ) 10.7 Hz, 3 PhCH2), 4.86
and 4.52 (2d, 6H, J ) 11.8 Hz, 3 PhCH2), 4.75 and 4.66 (2d, 6H,
J ) 11.8 Hz, 3 PhCH2), 4.73 (dd, 3H, J1a,2 ) 1.0, J1a,1b ) 14.5 Hz,
3 H-1a), 4.59 (dd, 3H, J1b,2 ) 5.0 Hz, 3 H-1b), 4.45 and 4.38 (2d,
6H, J ) 11.8 Hz, 3 PhCH2), 3.98-3.97 (m, 3H, 3 H-5), 3.69-
3.64 (m, 9H), 3.59-3.53 (m, 9H).). 13C NMR (75 MHz): δ 147.1
(C-4 Tr.), 138.3, 138.0, 137.9, and 137.7 (C Bn), 131.9 (C Ph),
128.4-127.4 (CH Bn), 122.4 and 122.0 (CH Ph, C-5 Tr.), 84.5
(CH), 77.7 (CH), 77.1 (CH), 75.2, 74.4, 73.5, and 72.0 (PhCH2),
75.0 (CH), 73.2 (CH), 68.7 (C-7), 51.3 (C-1). MALDI-TOF MS
(1889.29): 1890.1 (M+ + H), 1912.0 (M+ + Na), 1927.9 (M+
+
K). Anal. Calcd for C117H117N9O15: C, 74.38; H, 6.24; N, 6.67.
Found: C, 74.66; H, 6.38; N, 6.75.
1,3,5-Tris[1-(3,4,5,7-tetra-O-acetyl-2,6-anhydro-1-deoxy-D-
glycero-L-manno-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-benzene
(12b). Route a. The cycloaddition between triethynylbenzene 9
(7.5 mg, 0.05 mmol) and sugar azide 11b (87 mg, 0.225 mmol)
was carried out as described for the preparation of 10b to give,
after column chromatography on silica gel (4:1 AcOEt/cyclohexane,
then AcOEt), first unchanged 11b (31 mg, 36%). Eluted second
was 12b (54 mg, 82%) as a syrup; [R]D ) +59.5 (c 1.1, CHCl3).
1H NMR (300 MHz): δ 8.38 and 8.15 (2s, 6H, C6H3, 3 H-5 Tr.),
5.48 (dd, 3H, J4,5 ) 3.3, J5,6 ) 0.8 Hz, 3 H-5), 5.21 (dd, 3H, J2,3
) 9.6, J3,4 ) 10.1 Hz, 3 H-3), 5.10 (dd, 3H, 3 H-4), 4.74 (dd, 3H,
J1a,2 ) 2.3, J1a,1b ) 14.4 Hz, 3 H-1a), 4.46 (dd, 3H, J1b,2 ) 9.0 Hz,
3 H-1b), 4.24 (dd, 3H, J6,7a ) 7.4, J7a,7b ) 11.6 Hz, 3 H-7a), 4.08
(dd, 3H, J6,7b ) 5.2 Hz, 3 H-7b), 3.91 (ddd, 3H, 3 H-2), 3.89 (ddd,
3H, 3 H-6), 2.20, 2.18, 2.02, and 1.90 (4s, 36H, 12 Ac). 13C NMR
(75 MHz): δ 170.4, 170.1, and 169.9 (CO), 147.0 (C-4 Tr.), 131.8
(C Ar), 122.3 and 122.0 (CH Ar, C-5 Tr.), 76.8 (CH), 74.7 (CH),
71.6 (CH), 67.5 (CH), 67.1 (CH), 61.6 (C-7), 51.4 (C-1), 20.8, 20.6,
5,11,17,23-Tetrakis[1-(2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-
deoxy-D-glycero-L-manno-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-
25,26,27,28-tetrapropoxy-calix[4]arene (14a). The cycloaddition
between tetraethynyl-calix[4]arene 13 (34.5 mg, 0.05 mmol) and
sugar azide 11a (174 mg, 0.30 mmol) was carried out at 80 °C for
18 h as described for the preparation of 10b to give, after column
chromatography on silica gel (from 5:1 to 2:1 cyclohexane/AcOEt),
first unchanged 11a (83 mg, 48%). Eluted second was 14a (92 mg,
1
61%) as an amorphous solid; [R]D ) -76.2 (c 1.1, CHCl3). H
NMR (400 MHz, C6D6): δ 7.97 and 7.63 (2s, 8H, Ar, 4 H-5 Tr.),
7.38-7.32 (m, 8H, Ar), 7.23-7.00 (m, 76H, Ar), 4.84 and 4.52
(2d, 8H, J ) 11.9 Hz, 4 PhCH2), 4.78 and 4.70 (2d, 8H, J ) 11.2
Hz, 4 PhCH2), 4.58 and 4.46 (2d, 8H, J ) 11.5 Hz, 4 PhCH2),
4.55 and 3.16 (2d, 8H, J ) 13.5 Hz, 4 ArCH2Ar), 4.42 (dd, 4H,
J1a,2 ) 4.8, J1a,1b ) 13.5 Hz, 4 H-1a), 4.31 (dd, 4H, J1b,2 ) 1.5 Hz,
4 H-1b), 4.29 and 4.22 (2d, 8H, J ) 12.0 Hz, 4 PhCH2), 3.99-
3.91 (m, 8H, 4 CH3CH2CH2O), 3.78 (dd, 4H, J4,5 ) 2.0, J5,6 ) 0.4
Hz, 4 H-5), 3.68 (dd, 4H, J6,7a ) 7.5, J7a,7b ) 9.3 Hz, 4 H-7a), 3.62
and 20.5 (CH3CO). MALDI-TOF MS (1312.24): 1314.0 (M+
+
H), 1336.1 (M+ + Na), 1352.0 (M+ + K). Anal. Calcd for
C57H69N9O27: C, 52.17; H, 5.30; N, 9.61. Found: C, 52.30; H,
5.37; N, 9.89.
(dd, 4H, J6,7b ) 5.6 Hz, 4 H-7b), 3.58 (dd, 4H, J2,3 ) 9.6, J3,4
)
Route b. The C-glycocluster 12a (38 mg, 0.02 mmol) was de-
benzylated and acetylated as described for the preparation of 7b to
give, after column chromatography on silica gel (AcOEt), 12b (22
mg, 84%) identical to the compound prepared by route a.
1,3,5-Tris[1-(2,6-anhydro-1-deoxy-D-glycero-L-manno-hepti-
tol-1-yl)-1H-1,2,3-triazol-4-yl]-benzene (12c). The C-glycocluster
12b (26 mg, 0.02 mmol) was deacetylated as described for the
preparation of 5c to give, after a similar workup, 12c (14 mg, 88%)
as an amorphous solid; [R]D ) +15.8 (c 0.4, DMF). 1H NMR (300
MHz, D2O): δ 7.80 and 7.02 (2s, 6H, C6H3, 3 H-5 Tr.), 4.56 (dd,
3H, J1a,2 ) 1.0, J1a,1b ) 14.5 Hz, 3 H-1a), 4.21 (dd, 3H, J1b,2 ) 7.5
Hz, 3 H-1b), 3.84 (dd, 3H, J4,5 ) 3.0, J5,6 ) 0.5 Hz, 3 H-5), 3.67
(dd, 3H, J6,7a ) 9.0, J7a,7b ) 12.0 Hz, 3 H-7a), 3.61-3.37 (m, 15
H). 13C NMR (75 MHz, D2O): δ 146.0 (C), 130.2 (C), 122.8 (CH),
121.0 (CH), 78.7 (CH), 78.1 (CH), 74.2 (CH), 69.3 (CH), 68.6
(CH), 61.5 (CH2), 51.7 (CH2). MALDI-TOF MS (807.79): 831.1
(M+ + Na), 847.1 (M+ + K). Anal. Calcd for C33H45N9O15‚H2O:
C, 48.00; H, 5.74; N, 15.26. Found: C, 48.22; H, 5.83; N, 15.38.
5,11,17,23-Tetraethynyl-25,26,27,28-tetrapropoxy-calix[4]-
arene (13). To an oxygen-free solution, obtained by bubbling argon
at room temperature for 10 min, of known21 5,11,17,23-tetraiodo-
25,26,27,28-tetrapropoxy-calix[4]arene (329 mg, 0.30 mmol) in
anhydrous toluene (1 mL) and freshly distilled triethylamine (9 mL)
9.2 Hz, 4 H-3), 3.38 (ddd, 4H, 4 H-6), 3.31 (dd, 4H, 4 H-4), 3.29
(ddd, 4H, 4 H-2), 2.03-1.90 (m, 8H, 4 CH3CH2CH2O), 1.00 (t,
12H, J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz): δ 156.6
(C), 147.4 (C), 138.8 (C), 138.2 (C), 138.1 (C),135.2 (C), 128.3
(CH), 128.0 (CH), 127.8 (CH), 127.5 (CH), 127.4 (CH), 127.0
(CH),126.8 (CH), 125.8 (CH), 124.7 (CH), 120.4 (CH), 84.5 (CH),
77.4 (CH), 76.9 (CH), 76.5 (CH2), 75.0 (CH2), 74.5 (CH), 74.1
(CH2), 73.4 (CH2), 71.8 (CH2), 68.6 (CH2), 50.5 (CH2), 31.2 (CH2),
23.2 (CH2), 10.3 (CH3). MALDI-TOF MS (3007.72): 3009.1 (M+
+ H), 3030.8 (M+ + Na), 3046.7 (M+ + K). Anal. Calcd for
C188H196N12O24: C, 75.07; H, 6.57; N, 5.59. Found: C, 74.72; H,
6.38; N, 5.30.
5,11,17,23-Tetrakis[1-(3,4,5,7-tetra-O-acetyl-2,6-anhydro-1-
deoxy-D-glycero-L-manno-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-
25,26,27,28-tetrapropoxy-calix[4]arene (14b). Route a. The
cycloaddition between tetraethynyl-calix[4]arene 13 (34.5 mg, 0.05
mmol) and sugar azide 11b (116 mg, 0.30 mmol) was carried out as
described for the preparation of 10b to give, after column chroma-
tography on silica gel (1:1 AcOEt/cyclohexane, then AcOEt), first
unchanged 11b (49 mg, 42%). Eluted second was 14b (93 mg,
1
83%) as a syrup; [R]D ) +41.2 (c 1.0, CHCl3). H NMR (400
MHz): δ 7.44 (s, 4H, 4 H-5 Tr.), 7.22 and 7.02 (2s, 8H, Ar), 5.40
J. Org. Chem, Vol. 71, No. 20, 2006 7555

Dondoni and Marra
(dd, 4H, J4,5 ) 3.1, J5,6 ) 0.8 Hz, 4 H-5), 5.13 (dd, 4H, J2,3 ) 9.5,
J3,4 ) 10.0 Hz, 4 H-3), 5.07 (dd, 4H, 4 H-4), 4.51 and 3.24 (2d,
tetraethynyl-adamantane 15 (27 mg, 0.05 mmol) and sugar azide
11b (116 mg, 0.30 mmol) was carried out as described for the
preparation of 10b to give, after column chromatography on silica
gel (1:1 AcOEt/cyclohexane, then AcOEt, finally acetone), first
unchanged 11b (39 mg, 34%). Eluted second was 16b (96 mg,
8H, J ) 13.5 Hz, 4 ArCH2Ar), 4.49 (dd, 4H, J1a,2 ) 2.2, J1a,1b
)
14.4 Hz, 4 H-1a), 4.25 (dd, 4H, J1b,2 ) 9.3 Hz, 4 H-1b), 4.05 (dd,
4H, J6,7a ) 6.5, J7a,7b ) 11.3 Hz, 4 H-7a), 4.02 (dd, 4H, J6,7b ) 6.7
Hz, 4 H-7b), 3.89 (t, 8H, J ) 7.5 Hz, 4 CH3CH2CH2O), 3.82 (ddd,
4H, 4 H-6), 3.78 (ddd, 4H, 4 H-2), 2.18, 2.12, 1.99, and 1.88 (4s,
48H, 16 Ac), 1.93 (tq, 8H, J ) 7.5, 7.5 Hz, 4 CH3CH2CH2O), 1.00
(t, 12H, J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz): δ
170.3, 170.1, and 169.9 (CO), 156.8 (C Ar), 147.6 (C-4 Tr.), 135.3
(C Ar), 125.7 and 125.4 (CH Ar), 124.2 (C Ar), 120.6 (C-5 Tr),
76.8 (CH3CH2CH2O), 76.6 (C-2), 74.3 (C-6), 71.6 (C-4), 67.5 (C-
5), 67.3 (C-3), 61.3 (C-7), 51.0 (C-1), 31.1 (ArCH2Ar), 23.1
(CH3CH2CH2O), 20.75, 20.67, and 20.5 (CH3CO), 10.3 (CH3CH2-
CH2O). MALDI-TOF MS (2238.33): 2262.7 (M+ + H + Na),
2278.6 (M+ + H + K). Anal. Calcd for C108H132N12O40: C, 57.95;
H, 5.94; N, 7.51. Found: C, 57.70; H, 5.77; N, 7.28.
1
92%) as a syrup; [R]D ) +42.5 (c 1.1, CHCl3). H NMR (300
MHz): δ 7.91 (s, 4H, 4 H-5 Tr.), 7.89-7.84 and 7.62-7.57 (2m,
16H, Ar), 5.46 (dd, 4H, J4,5 ) 3.3, J5,6 ) 0.8 Hz, 4 H-5), 5.20 (dd,
4H, J2,3 ) 10.0, J3,4 ) 9.9 Hz, 4 H-3), 5.09 (dd, 4H, 4 H-4), 4.72
(dd, 4H, J1a,2 ) 2.4, J1a,1b ) 14.5 Hz, 4 H-1a), 4.40 (dd, 4H, J1b,2
) 9.0 Hz, 4 H-1b), 4.25 (dd, 4H, J6,7a ) 7.4, J7a,7b ) 11.5 Hz, 4
H-7a), 4.02 (dd, 4H, J6,7b ) 5.2 Hz, 4 H-7b), 3.89 (ddd, 4H, 4
H-2), 3.85 (ddd, 4H, 4 H-6), 2.26 (bs, 12H, 6 CH2), 2.19, 2.16,
2.02, and 1.88 (4s, 48H, 16 Ac). 13C NMR (75 MHz): δ 170.3,
170.0, and 169.9 (CO), 149.2 (C Ar), 147.5 (C-4 Tr.), 128.5 (C
Ar), 125.7 and 125.5 (CH Ar), 121.4 (C-5 Tr.), 76.8 (CH), 74.7
(CH), 71.5 (CH), 67.5 (CH), 67.2 (CH), 61.6 (C-7), 51.2 (C-1),
47.1 (CH2), 39.2 (C), 20.8, 20.6, and 20.5 (CH3CO). MALDI-TOF
MS (2086.13): 2088.8 (M+ + 2H), 2110.7 (M+ + H + Na), 2126.7
(M+ + H + K). Anal. Calcd for C102H116N12O36: C, 58.73; H,
5.60; N, 8.06. Found: C, 58.89; H, 5.72; N, 8.17.
Route b. The C-glycocluster 14a (60 mg, 0.02 mmol) was
debenzylated and acetylated as described for the preparation of 7b
to give, after column chromatography on silica gel (2:1 AcOEt/
cyclohexane, then AcOEt), 14b (41 mg, 91%) identical to the com-
pound prepared by route a.
Route b. The C-glycocluster 16a (57 mg, 0.02 mmol) was de-
benzylated and acetylated as described for the preparation of 7b to
give, after column chromatography on silica gel (AcOEt, then
acetone), 16b (40 mg, 95%) identical to the compound prepared
by route a.
5,11,17,23-Tetrakis[1-(2,6-anhydro-1-deoxy-D-glycero-L-manno-
heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-25,26,27,28-tetrapropoxy-
calix[4]arene (14c). The C-glycocluster 14b (22.5 mg, 0.01 mmol)
was deacetylated as described for the preparation of 5c to give,
after a similar workup, 14c (15 mg, 96%) as an amorphous solid;
1,3,5,7-Tetrakis{4-[1-(2,6-anhydro-1-deoxy-D-glycero-L-manno-
heptitol-1-yl)-1H-1,2,3-triazol-4-yl]phenyl}-adamantane (16c).
The C-glycocluster 16b (42 mg, 0.02 mmol) was deacetylated as
described for the preparation of 5c to give, after a similar workup,
16c (28 mg, 98%) as an amorphous solid; [R]D ) +3.0 (c 0.6,
1
[R]D ) +15.8 (c 0.5, DMF). H NMR (300 MHz, DMSO-d6 +
D2O) selected data: δ 7.94 (s, 4H, 4 H-5 Tr.), 7.20 and 7.09 (2d,
8H, J ) 1.5 Hz, Ar), 4.66 (dd, 4H, J1a,2 ) 1.0, J1a,1b ) 14.5 Hz, 4
H-1a), 4.42 (d, 4H, J ) 13.0 Hz, 4 Hax of ArCH2Ar), 4.20 (dd,
4H, J1b,2 ) 5.5 Hz, 4 H-1b), 3.86 (t, 8H, J ) 7.5 Hz, 4
CH3CH2CH2O), 1.97-1.82 (m, 8H, 4 CH3CH2CH2O), 0.99 (t, 12H,
J ) 7.5 Hz, 4 CH3CH2CH2O). 13C NMR (75 MHz, DMSO-d6): δ
155.9 (C), 146.1 (C), 134.7 (C), 125.2 (CH), 124.8 (CH), 124.7
(C), 121.0 (CH), 78.8 (CH), 78.6 (CH), 76.4 (CH2), 74.3 (CH),
68.6 (CH), 68.3 (CH), 60.6 (CH2), 51.2 (CH2), 30.5 (CH2), 22.8
1
DMF). H NMR (300 MHz, DMSO-d6 + D2O): δ 7.92 (s, 4H, 4
H-5 Tr.), 7.82 and 7.67 (2d, 16H, J ) 8.3 Hz, Ar), 4.78 (dd, 4H,
J1a,2 ) 1.0, J1a,1b ) 14.3 Hz, 4 H-1a), 4.37 (dd, 4H, J1b,2 ) 7.8 Hz,
4 H-1b), 3.68-3.66 (m, 4H), 3.48-3.30 (m, 24H), 2.16 (bs, 12H,
6 CH2). 13C NMR (75 MHz, DMSO-d6): δ 149.2 (C), 146.1 (C),
128.6 (C), 125.7 (CH), 125.1 (CH), 78.9 (CH), 78.6 (CH), 74.4
(CH), 68.6 (CH), 68.3 (CH), 60.7 (CH2), 51.4 (CH2), 46.3 (CH2).
(CH2), 10.2 (CH3). MALDI-TOF MS (1565.72): 1567.1 (M+
+
H), 1589.2 (M+ + Na), 1605.1 (M+ + K). Anal. Calcd for
C76H100N12O24‚H2O: C, 57.64; H, 6.49; N, 10.61. Found: C, 57.79;
H, 6.60; N, 10.80.
MALDI-TOF MS (1413.53): 1415.0 (M+ + H), 1436.9 (M+
+
Na). Anal. Calcd for C70H84N12O20: C, 59.48; H, 5.99; N, 11.89.
Found: C, 59.20; H, 5.91; N, 11.62.
1,3,5,7-Tetrakis{4-[1-(2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-
deoxy-D-glycero-L-manno-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-
phenyl}-adamantane (16a). The cycloaddition between tetraethynyl-
adamantane 15 (27 mg, 0.05 mmol) and sugar azide 11a (174 mg,
0.30 mmol) was carried out at 80 °C for 18 h as described for the
preparation of 10b to give, after column chromatography on silica
gel (from 3:1 to 1:1 cyclohexane/AcOEt), first unchanged 11a (80
mg, 46%). Eluted second was 16a (114 mg, 80%) as an amorphous
solid; [R]D ) -32.1 (c 1.0, CHCl3). 1H NMR (400 MHz): δ 8.00
(s, 4H, 4 H-5 Tr.), 7.80-7.76 and 7.57-7.53 (2m, 16H, 4 C6H4),
7.40-7.09 (m, 80H, 16 Ph), 4.92 and 4.53 (2d, 8H, J ) 11.9 Hz,
4 PhCH2), 4.91 and 4.61 (2d, 8H, J ) 10.5 Hz, 4 PhCH2), 4.76
and 4.69 (2d, 8H, J ) 11.5 Hz, 4 PhCH2), 4.72-4.63 (m, 8H, 8
H-1), 4.47 and 4.43 (2d, 8H, J ) 12.0 Hz, 4 PhCH2), 3.96 (dd,
4H, J4,5 ) 2.3, J5,6 ) 0.4 Hz, 4 H-5), 3.70-3.58 (m, 20H), 3.54
(dd, 4H, J6,7b ) 9.0, J7a,7b ) 11.5 Hz, 4 H-7b), 2.28 (bs, 12H, 6
CH2). 13C NMR (75 MHz): δ 149.0 (C), 147.4 (C), 138.4 (C),
138.0 (C), 137.9 (C), 137.7 (C), 128.9 (C), 128.4 (CH), 128.2 (CH),
127.9 (CH), 127.7 (CH), 127.5 (CH), 127.4 (CH), 125.8 (CH), 125.4
(CH), 121.3 (CH), 84.4 (CH), 77.6 (CH), 77.1 (CH), 75.3 (CH2),
74.8 (CH), 74.4 (CH2), 73.7 (CH), 73.5 (CH2), 72.2 (CH2), 69.1
(CH2), 51.0 (CH2), 47.3 (CH2), 39.3 (C). MALDI-TOF MS
(2855.53): 2879.1 (M+ + Na), 2895.1 (M+ + K). Anal. Calcd for
1-(2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-glycero-D-
gulo-heptitol-1-yl)-4-phenyl-1H-1,2,3-triazole (17a). The cyclo-
addition between freshly distilled phenylacetylene (55 µL, 0.50
mmol) and sugar azide 8a (58 mg, 0.10 mmol) was carried out at
80 °C for 24 h as described for the preparation of 10a to give,
after column chromatography on silica gel (from 5:1 to 2:1 cyclo-
hexane/AcOEt), first unchanged 8a (32 mg, 55%). Eluted second
was 17a (14 mg, 20%) as a white solid. Mp 153-154 °C (AcOEt/
cyclohexane); [R]D ) -25.0 (c 0.5, CHCl3). 1H NMR (300 MHz):
δ 8.00 (s, 1H, H-5 Tr.), 7.80-7.75 (m, 2H, Ar), 7.42-7.26 (m,
21H, Ar), 7.20-7.15 (m, 2H, Ar), 4.96 and 4.92 (2d, 2H, J ) 11.5
Hz, PhCH2), 4.89 and 4.80 (2d, 2H, J ) 10.7 Hz, PhCH2), 4.82
and 4.57 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.73 (dd, 1H, J1a,2 ) 5.0,
J1a,1b ) 14.5 Hz, H-1a), 4.67 (dd, 1H, J1b,2 ) 3.0 Hz, H-1b), 4.63
and 4.56 (2d, 2H, J ) 12.0 Hz, PhCH2), 3.77 (dd, 1H, J3,4 ) J4,5
) 9.0 Hz, H-4), 3.76-3.67 (m, 3H, H-2, 2 H-7), 3.58 (dd, 1H, J5,6
) 9.5 Hz, H-5), 3.51 (ddd, 1H, J6,7a ) 3.5, J6,7b ) 2.1 Hz, H-6),
3.22 (dd, 1H, J2,3 ) 9.6 Hz, H-3). 13C NMR (100 MHz): δ 147.7
(C-4 Tr.), 138.1, 137.88, 137.80, and 137.76 (C Bn), 130.7 (C Ph),
128.8-127.6 (Ar), 125.6 (Cortho Ph), 121.4 (C-5 Tr.), 86.9 (C-4),
78.7 (C-6), 77.9 (C-5), 77.8 (C-3), 77.1 (C-2), 75.6, 75.15, 75.12,
and 73.4 (PhCH2), 68.8 (C-7), 50.6 (C-1). Anal. Calcd for
C43H43N3O5: C, 75.75; H, 6.36; N, 6.16. Found: C, 75.90; H, 6.46;
N, 6.30.
C182H180N12O20: C, 76.55; H, 6.35; N, 5.89. Found: C, 76.80; H,
6.41; N, 6.08.
1-(3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-D-glycero-D-
gulo-heptitol-1-yl)-4-phenyl-1H-1,2,3-triazole (17b). The cyclo-
addition between freshly distilled phenylacetylene (55 µL, 0.50
mmol) and sugar azide 8b (39 mg, 0.10 mmol) was carried out at
1,3,5,7-Tetrakis{4-[1-(3,4,5,7-tetra-O-acetyl-2,6-anhydro-1-
deoxy-D-glycero-L-manno-heptitol-1-yl)-1H-1,2,3-triazol-4-yl]-
phenyl}-adamantane (16b). Route a. The cycloaddition between
7556 J. Org. Chem., Vol. 71, No. 20, 2006

C-Glycoside Clustering through 1,2,3-Triazole Linkers
80 °C for 24 h as described for the preparation of 10a to give,
after column chromatography on silica gel (1:1 cyclohexane/
AcOEt), first unchanged 8b (14 mg, 36%). Eluted second was 17b
(28 mg, 57%) as a white solid. Mp 200-201 °C (AcOEt/
cyclohexane); [R]D ) +21.8 (c 1.0, CHCl3). 1H NMR (300 MHz):
δ 7.94 (s, 1H, H-5 Tr.), 7.89-7.85 (m, 2H, Hortho of Ph), 7.48-
7.42 (m, 2H, Hmeta of Ph), 7.38-7.32 (m, 1H, Hpara of Ph), 5.25
(dd, 1H, J3,4 ) J4,5 ) 9.4 Hz, H-4), 5.06 (dd, 1H, J5,6 ) 10.1 Hz,
H-5), 4.94 (dd, 1H, J2,3 ) 10.0 Hz, H-3), 4.70 (dd, 1H, J1a,2 ) 2.4,
J1a,1b ) 14.5 Hz, H-1a), 4.36 (dd, 1H, J1b,2 ) 8.6 Hz, H-1b), 4.23
J1b,2 ) 7.0 Hz, H-1b), 3.89 (ddd, 1H, J2,3 ) 9.7 Hz, H-2), 3.77
(dd, 1H, J3,4 ) 8.8, J4,5 ) 9.0 Hz, H-4), 3.64 (dd, 1H, J5,6 ) 9.7
Hz, H-5), 3.62 (dd, 1H, H-3), 3.62 (dd, 1H, J6,7a ) 4.0, J7a,7b
)
10.8 Hz, H-7a), 3.56 (dd, 1H, J6,7b ) 1.9 Hz, H-7b), 3.40 (ddd,
1H, H-6). 13C NMR (100 MHz): δ 139.5 (C-5 Tr.), 138.4 (C Ar),
138.0 (C Ar), 137.9 (C Ar), 132.8 (C-4 Tr.), 129.5-127.2 (Ar),
87.1 (C-4), 79.1 (C-3), 78.7 (C-6), 78.0 (C-5), 77.4 (C-2), 75.5,
75.0, 74.8, and 73.4 (PhCH2), 68.9 (C-7), 48.3 (C-1). Anal. Calcd
for C43H43N3O5: C, 75.75; H, 6.36; N, 6.16. Found: C, 75.98; H,
6.51; N, 6.38.
(dd, 1H, J6,7a ) 5.6, J7a,7b ) 12.3 Hz, H-7a), 4.15 (dd, 1H, J6,7b
)
1-(3,4,5,7-Tetra-O-acetyl-2,6-anhydro-1-deoxy-D-glycero-D-
gulo-heptitol-1-yl)-5-phenyl-1H-1,2,3-triazole (18b). The cyclo-
addition between freshly distilled phenylacetylene (11 µL, 0.50
mmol) and sugar azide 8b (39 mg, 0.10 mmol) was carried out as
described for the preparation of 18a to give, after column chroma-
tography on silica gel (from 1:1 to 1:2 cyclohexane/AcOEt), 18b
2.3 Hz, H-7b), 3.88 (ddd, 1H, H-2), 3.64 (ddd, 1H, H-6), 2.14,
2.05, 2.03, and 1.94 (4s, 12H, 4 Ac). 13C NMR (75 MHz): δ 170.5,
170.1, 169.7, and 169.4 (CO), 147.9 (C-4 Tr.), 130.4 (Cipso Ph),
128.8 (Cmeta Ph), 128.2 (Cpara Ph), 125.7 (Cortho Ph), 121.5 (C-5
Tr.), 76.3 (C-2), 76.0 (C-6), 73.6 (C-4), 69.6 (C-3), 68.2 (C-5),
61.7 (7), 51.0 (C-1), 20.7 and 20.5 (CH3CO). Anal. Calcd for
C23H27N3O9: C, 56.44; H, 5.56; N, 8.58. Found: C, 56.52; H, 5.60;
N, 8.69.
1
(26 mg, 53%) as a syrup; [R]D ) +14.0 (c 1.0, CHCl3). H NMR
(300 MHz): δ 7.71 (s, 1H, H-4 Tr.), 7.51-7.43 (m, 5H, Ph), 5.25
(dd, 1H, J3,4 ) 9.4, J4,5 ) 9.3 Hz, H-4), 5.06 (dd, 1H, J5,6 ) 10.2
1-(2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-glycero-D-
gulo-heptitol-1-yl)-5-phenyl-1H-1,2,3-triazole (18a). A mixture
of freshly distilled phenylacetylene (11 µL, 0.10 mmol), sugar azide
8a (58 mg, 0.10 mmol), commercially available chloro(cyclo-
pentadienyl)bis(triphenylphosphine)ruthenium(II) (7 mg, 0.01 mmol),
and anhydrous toluene (1 mL) was stirred at 80 °C for 24 h, then
cooled to room temperature, diluted with AcOEt (40 mL), washed
with 1 M phosphate buffer at pH 7 (2 × 5 mL), dried (Na2SO4),
and concentrated. The residue was eluted from a column of silica
gel (from 5:1 to 2:1 cyclohexane/AcOEt) to give first unchanged
8a (9 mg, 15%). Eluted second was a 2:1 mixture of 18a and 17a
(8 mg, 12%). Eluted third was 18a (21 mg, 31%) as a syrup; [R]D
Hz, H-5), 4.98 (dd, 1H, J2,3 ) 9.9 Hz, H-3), 4.45 (dd, 1H, J1a,2
)
2.8, J1a,1b ) 14.4 Hz, H-1a), 4.35 (dd, 1H, J1b,2 ) 8.8 Hz, H-1b),
4.18 (ddd, 1H, H-2), 4.14 (dd, 1H, J6,7a ) 5.0, J7a,7b ) 12.4 Hz,
H-7a), 3.93 (dd, 1H, J6,7b ) 2.2 Hz, H-7b), 3.59 (ddd, 1H, H-6),
2.10, 2.04, 2.03, and 2.02 (4s, 12H, 4 Ac). 13C NMR (75 MHz):
δ 170.4, 170.1, 169.9, and 169.4 (CO), 139.5 (C-5 Tr.), 132.9 (C-4
Tr.), 129.5 (Cpara Ph), 129.2 and 128.9 (Cortho, Cmeta Ph), 126.7 (Cipso
Ph), 76.8 (C-2), 75.5 (C-6), 73.7 (C-4), 70.2 (C-3), 68.1 (C-5), 61.7
(7), 48.8 (C-1), 20.6 and 20.5 (CH3CO). Anal. Calcd for
C23H27N3O9: C, 56.44; H, 5.56; N, 8.58. Found: C, 56.72; H, 5.69;
N, 8.78.
1
) -7.1 (c 0.6, CHCl3). H NMR (300 MHz): δ 7.70 (s, 1H, H-4
Supporting Information Available: 1H and 13C spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Tr.), 7.57-7.53 (m, 2H, Ar), 7.43-7.26 (m, 21H, Ar), 7.20-7.15
(m, 2H, Ar), 5.00 and 4.88 (2d, 2H, J ) 11.1 Hz, PhCH2), 4.97
and 4.93 (2d, 2H, J ) 11.2 Hz, PhCH2), 4.82 and 4.58 (2d, 2H,
J ) 10.8 Hz, PhCH2), 4.61 (dd, 1H, J1a,2 ) 3.1, J1a,1b ) 14.5 Hz,
H-1a), 4.46 and 4.40 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.36 (dd, 1H,
JO0607156
J. Org. Chem, Vol. 71, No. 20, 2006 7557