1,3-dipolar cycloadditions as a tool for the preparation of multivalent structures.

Article abstract of DOI:10.1021/ol006175v

The construction of multivalent structures such as sugar heterodimers, glycoclusters, calix sugars, multicalixarenes, and glycocyclodextrins is designed by using 1,3-dipolar cycloaddition as a versatile and efficient tool which allows the creation of heterocyclic bridges between the different units that are coupled.

Full text of DOI:10.1021/ol006175v

ORGANIC
LETTERS
2
000
Vol. 2, No. 16
499-2502
1
,3-Dipolar Cycloadditions as a Tool for
2
the Preparation of Multivalent Structures
Francisco G. Calvo-Flores, Joaqu ´ı n Isac-Garc ´ı a, Fernando Hern a´ ndez-Mateo,
Francisco P e´ rez-Balderas, Jose A. Calvo-As ´ı n, Eduardo Sanch e´ z-Vaquero, and
Francisco Santoyo-Gonz a´ lez*
Instituto de Biotecnolog ´ı a, Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias,
Campus FuentenueVa s/n, UniVersidad de Granada, Granada E-18071,Spain
fsantoyo@ugr.es
Received June 8, 2000
ABSTRACT
The construction of multivalent structures such as sugar heterodimers, glycoclusters, calix sugars, multicalixarenes, and glycocyclodextrins
is designed by using 1,3-dipolar cycloaddition as a versatile and efficient tool which allows the creation of heterocyclic bridges between the
different units that are coupled.
The rational design of supramolecular structures with a well-
defined architecture has attracted much attention during the
past few decades. Work on these molecular assemblies
ranges from the attempt to understand the molecular recogni-
tion phenomena to the capacity to mimic the catalytic
capacity of enzymes. As a consequence, new terms and
structures such as crown ethers, dendrimers, calixarenes,
clusters, cyclophanes, etc. have emerged in organic chemistry
and the preparation of such entities has contributed to the
development of suitable synthetic protocols.
In the field of molecular recognition and following the
observation of the so-called “cluster” or “multivalent effect”2
high-affinity lectin ligands have been developed by coupling
saccharides in a multiple fashion to a variety of different
carriers, giving rise to chemically well-defined homogeneous
neoglycoconjugates (glycopolymersslinear polymers, gly-
coclusters, oligomers, and polyamino acidssand glycoden-
drimers) with systematic varied shapes and carbohydrate
1
3
densities. Among these neoglycoconjugates, glycoclusters
or nonlinear medium-sized glycoconjugates have usually
been constructed using aza macrocycles, polyamines,5
4
6
7
8
pentaerythritol-based cores, cyclodextrins, and calixarenes.
Formation of the link glycan scaffold for the synthesis of
(1) (a) V o¨ gtle, F. Supramolecular Chemistry: An Introduction; Wiley:
Chichester, U.K., 1991. (b) Lehn, J. M. Supramolecular Chemistry:
Concepts and PerspectiVes; VCH: Weinheim, Germany, 1995. (c) Su-
pramolecular Chemistry I. Directed Synthesis and Molecular Recognition;
Weber; E., Ed.; Springer-Verlag: Berlin, 2000.
(3) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 1999, 3215.
(4) K o¨ nig, B.; Fricke, T.; Wamann, A.; Krallmann-Wenzel, U.; Lindhorst,
T. K. Tetrahedron Lett. 1998, 39, 2307.
(2) Lee, R. T.; Lee, Y. C. In Neoglycoconjugates; Lee, Y. C., Lee, R.
T., Eds.; Academic Press: San Diego, CA, 1994; pp 23-50.
1
0.1021/ol006175v CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/21/2000

1
3
such multivalent structures is usually performed in the later
steps of the synthesis and have been carried out using a
of a variety of compounds such as higher sugars, C-
14
15
disaccharides, and aminocyclitols. On the basis of the easy
introduction of alkynes in a substrate, we designed two
approaches that use such a function as the dipolarophile in
the cycloaddition reaction: synthesis of 1,2,3-triazole and
synthesis of isoxazoles (1,2-oxazoles) by reaction, respec-
tively, with azides and nitrile oxides as the 1,3-dipolar
functions.
5
a-c,7a,b,8i
variety of strategies such as formation of thiourea
or amide bridges5b,9 by reaction of amines with isothiocy-
5b,6,9e
anatesorcarboxylicacids,respectively,byuseofglycosylation
or by nucleophilic substitution.7b,c,9c,10
On the other hand, the versatility of calix[4]arenes as host
molecules has been widely exploited for designing a large
variety of synthetic receptor molecules for the binding of
relatively small guest species (cations, anions) and small
Following the first approach, our first goal was the
construction of sugar-containing molecules using O-prop-
argyl glycosides that are easily obtainable. Thus, we achieved
the assembly of two sugar units by reaction of compound
with 1,2-ethanediazide 2 as the connecting spacer,
leading to a mixture of the bis(triazole) sugar dimer 3
11
neutral molecules. Most synthetic-based calixarene recep-
tors have been prepared using the methodologies of classical
organic synthesis and, recently, by combination of different
or similar molecular building blocks in the so-called modular
1
6
17a
1
1
1c
approach.
(Scheme 1). In a slight variation, the construction of sugar
In the search for new strategies for the covalent assembly
of the different components of such multivalent or supramo-
lecular structures, we thought that 1,3-dipolar cycloaddition
reactions could be used as an efficient tool allowing for the
simultaneous building up of aromatic systems that could
positively contribute to the hydrophobicity and rigidity. 1,3-
Dipolar cycloaddition to alkenes and alkynes is a well-
established and general method for the synthesis of both
Scheme 1a
12
nonaromatic and aromatic five-membered-ring heterocycles.
In the carbohydrate field inter- as well as intramolecular 1,3-
dipolar cycloaddition has found application in the synthesis
(
5) (a) Kieburg, C.; Lindhorst, T. K. Tetrahedron Lett. 1997, 38, 3885.
(
b) Kotter, S.; Krallmann-Wenzel, U.; Ehlers, S.; Lindhorst, T. K. J. Chem.
Soc., Perkin Trans. 1 1998, 2193. (c) Lindhorst, T. K.; Kieburg, C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1953.
(
6) (a) Langer, P.; Ince, S. J.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1
998, 3913. (b) Lindhorst, T. K.; Dubber, M.; Krallmann-Wenzel, U.; Ehlers,
S. Eur. J. Org. Chem. 2000, 2027.
7) (a) Ortiz-Mellet, C.; Benito, J. M.; Garc ´ı a Fern a´ ndez, J. M.; Law,
1
(
H.; Chmurski, K.; Defaye, J.; O’Sullivan, M. L.; Caro, H. N. Chem. Eur.
J. 1998, 4, 2523. (b) Garcia-Lopez, J. J.; Hern a´ ndez-Mateo, F.; Isac-Garc ´ı a,
J.; Kim, J. M.; Roy, R.; Santoyo-Gonzalez, F. J. Org. Chem. 1999, 64,
5
22. (c) Garc ´ı a-L o´ pez, J. J.; Santoyo-Gonz a´ lez, F.; Vargas-Berenguel, A.;
Gim e´ nez Mart ´ı nez, J. J. Chem. Eur. J. 1999, 5, 1775.
8) (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. (d) Dondoni, A.; Kleban, M.; Marra, A.
Tetrahedron Lett. 1997, 38, 7801. (e) Sansone, F.; Barboso, S.; Casnati,
A.; Fabbi, M.; Pochini, A.; Ugozzoli, F.; Ungaro, R. Eur. J. Org. Chem.
1
998, 897, 7. (f) Meunier, S. J.; Roy, R. Tetrahedron Lett. 1996, 37, 5469.
g) Roy, R.; Kim, J. M. Angew. Chem., Int. Ed. 1999, 38, 369. (h) Felix,
C.; Parrot-L o´ pez, H.; Kalchenko, V.; Coleman, A. W. Tetrahedron Lett.
998, 39, 917. (i) Saitz-Barria, C.; Torres-Pinedo, A.; Santoyo-Gonz a´ lez,
F. Synlett 1999, 1891.
9) (a) Ashton, P. R.; Boyd, S. E.; Brown, C. L.; Jayaraman, N.; Stoddart,
(
1
(
J. F. Angew. Chem., Int. Ed. Engl. 1997, 36, 732. (b) Lee, R. T.; Lee, Y.
C. Bioconjugate Chem. 1997, 8, 762. (c) Hansen, H. C.; Haataja, S.; Finne,
J.; Magnusson, G. J. Am. Chem. Soc. 1997, 119, 6974. (d) Corbell, J. B.;
Lundquist, J. J.; Toone, E. J. Tetrahedron: Asymmetry 2000, 11, 95. (e)
Ashton, P. R.; Hounsell, E. F.; Jayaraman, N.; Nilsen, T. M.; Spencer, N.;
Stoddart, J. F.; Young, M. J. Org. Chem. 1998, 63, 3429.
a
Legend: (a) 0.61 mmol of 1, 0.27 mmol of 2, toluene, reflux,
72 h, 70%; (b) 1.1 mmol of 4, 1.0 mmol of 5, toluene, reflux, 30
h, 70%; (c) 0.7 mmol of 4, 0.2 mmol of 7, toluene, reflux, 6 days,
0%.
8
(
10) Grandjean, C.; Rommens, C.; Gras-Masse, H.; Melnyk, O. Angew.
Chem., Int. Ed. 2000, 39, 1068.
11) (a) B o¨ hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (b)
Ikeda, A.; Shinkai, S. Chem. ReV. 1997, 97, 1713. (c) Higler, I.; Timmerman,
P.; Verboom, W.; Reinhoudt, D. N. Eur. J. Org. Chem. 1998, 2689, 9.
(
dimers was also shown to be possible when the 1,3-dipole
function was incorporated into a monosaccharide unit. The
(12) (a) Gothelf, K. V.; Jørgensen, A. K. Chem. ReV. 1998, 98, 863. (b)
Caramella, P.; Grunanger P. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, p 291. (c) Carruthers, W.
Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Oxford,
U.K., 1990; p 269.
(14) Paton R. M. In Carbohydrate Mimics. Concepts and Methods;
Chapleur, Y., Ed.; Wiley-VCH: Weinheim, Germany, 1998; pp 49-66.
(15) (a) Gallos, J. K.; Koumbis, A. E.; Xiraphaki, V. P.; Dellios, C. C.;
Coutouli, A. Tetrahedron 1999, 55, 15167. (b) Dransfield, P. J.; Moutel,
S.; Shipman, M.; Sik, V. J. Chem. Soc., Perkin Trans. 1 1999, 3349.
(13) Paton, R. M.; Young, A. A. J. Chem. Soc., Perkin Trans. 1 1997,
6
29.
2500
Org. Lett., Vol. 2, No. 16, 2000

Scheme 2b
a
Obtained from p-tert-butylcalix[4]arene and propargyl bromide with 84% yield. b Legend: (a) 0.1 mmol of 7, 0.24 mmol of 9, toluene,
reflux, 6 days, 57% overall yield for 10 + 11; (b) 0.14 mmol of 7, 0.14 mmol of 12, toluene, reflux, 5 days, 90% overall yield.
1
8
intermolecular cycloaddition reaction of compounds 4 and
5
reaction with the diazide 7 led to the three possible
regioisomers of the corresponding double-bridged bis(calix-
[4]arene) derivative 13.
1
7b
afforded in this case the triazole sugar dimer 6 as a
mixture of the two possible regioisomers. These cycloaddi-
tion reactions also were shown to be adequate for the
construction of calix sugars. Starting from 25,27-bis(bro-
moethoxy)-26,28-dihydroxy-5,11,17,23-tetra-tert-butylcalix-
Next, we investigated the utility of the nitrile oxide based
approach. Two general methods are in common usage for
the generation of such a function. The first one is the thermal
or base-mediated dehydrochlorination of a hydroximoyl
1
9
[
4]arene, we prepared in a straightforward fashion the
2
1
diazide calixarene derivative 7, which was then reacted with
the propargyl glycoside 4, giving a regioisomeric mixture
of calix sugar 8. All the aforementioned reactions of
propargyl glycosides with azides allowed the assembly in
good to high yields, but in all cases no regioselectivity was
observed and a mixture of regioisomers was obtained.
chloride. The second method for the in situ production of
nitrile oxides uses the dehydration of nitromethyl compounds
under widely used Mukaiyama conditions (use of phenyl
2
2
isocyanate). On the basis of this last procedure, we
efficiently prepared the dimer glycosides 17-19 by reaction
of the galactopyranosyl nitrile oxide derivative 14b (obtained
in situ from 2,6-anhydro-1-deoxy-1-nitro-D-glycero-D-man-
We also performed the preparation of multicalix[4]arenes
by following the same last principle: i.e., incorporation of
the 1,3-dipole function and the dipolarophile in different
calixarene units. Reaction of the mono(propargyloxy)calix-
4]arene derivative 9 with the diazide calixarene derivative
yielded the tris(calix[4]arene) derivatives 10 and 11, which
could be isolated as pure compounds from the crude reaction
mixture (Scheme 2). When we applied the cycloaddition
strategy in the difunctional bis(propargyloxy)calix[4]arene
2
3
noheptitol (14a)) with the propargyl glycosides 7, 15, and
6 derived from D-glucose, D-galactose, and lactose, respec-
1
tively (Scheme 3). We also synthesized the trivalent and
tetravalent galactose clusters 22 and 23 by reaction of the
same nitrile oxide derivative 14b with the tri- and tetraprop-
argyl pentaerythritol derivatives 20b and 21.
20
[
7
(
21) Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345.
(22) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
1
2 instead of the mono(propargyloxy) derivative 9, the
(23) Petrus, L.; Bystricky, S.; Sticzay, T.; B ´ı lik, V. Chem. ZVesti 1982,
6, 103.
3
(
24) Takeo, K.; Mitoh, H.; Uemura, K. Carbohydr. Res. 1989, 187, 203.
1
(16) Kaufman, R. J.; Sidhu, R. S. J. Org. Chem. 1982, 47, 4941.
(25) Selected physical properties of compound 26 are as follows. H
(
17) (a) Obtained from 1,2-dibromoethane and sodium azide. (b) Obtained
NMR (300 MHz, CDCl3): δ 6.41(s, 7 H), 5.52 (d, J ) 3.0 Hz, 7 H), 5.35
(t, J ) 10.2 Hz, 7 H), 5.19 (dd, J ) 10.2, 3.4 Hz, 7 H), 5.12 (br s, 7 H),
4.65-4.50 (m, 21 H), 3.65, 3.53 (2 s, 42 H), 3.20 (br d, J ) 9.5 Hz, 7 H),
2.18, 2.03, 1.99, 1.92 (4 s, 84 H). 13C NMR (75 MHz, CDCl3): δ 170.4,
170.3, 169.7, 169.4, 160.9, 114.1, 101.6, 99.2, 81.7, 74.8, 73.1, 71.7, 71.2,
70.2, 67.6, 67.5, 61.2, 61.6, 61.5, 58.7, 20.7, 20.6. HR-MS (FAB+): calcd
using the trichloroacetimidate method.
(
18) Mereyala, H. B.; Gurrala, S. R. Carbohydr. Res. 1998, 307, 351.
(19) Li, Z. T.; Ji, G. Z.; Zhao, C. X.; Yuan, S. D.; Ding, H.; Huang, C.;
Du, A. L.; Wei, M. J. Org. Chem. 1999, 64, 3572.
20) Santoyo-Gonz a´ lez, F.; Torres-Pinedo, A.; S a´ nchez-Ortega, A. J. Org.
(
+
Chem., in press.
for C182H245N7O105Na [M +Na] , 4231.394; found, 4231.394.
Org. Lett., Vol. 2, No. 16, 2000
2501

from heptakis(2,3-di-O-methyl)cyclomaltoheptaose (24),24
with 14b gave rise to the glycocyclodextrin 2625 in high
yields (Scheme 4). It should be noted that the utilization of
Scheme 3a
Scheme 4a
a
Legend: (a) 1 mmol of 24, 14 mmol of BrCH
N, 50% NaOH aqueous solution, CH Cl , 48 h, 70%; (b)
.52 mmol of 14a, 0.063 mmol of 25, 0.52 mmol of C NCO,
.1 mL of Et N, toluene, reflux, 24 h, 78%.
2
CtCH,
Br(Bu)
4
2
2
0
0
6 5
H
3
nitrile oxides as the dipolar function allowed the regiose-
lective formation of the isoxazole ring and the isolation of
pure isomers in the assembled structures.
In conclusion, the results described herein demonstrate that
1,3-dipolar cycloadditions are an efficient and highly versatile
tool for the construction of multivalent structures, creating
aromatic heterocyclic bridges between the different units that
are coupled. To date the application by us of this strategy
has allowed the preparation of a wide variety of these
structures, such as sugar heterodimers, glycoclusters, calix
sugars, multicalixarenes, and glycocyclodextrins. The wide
variety of 1,3-dipolar cycloadditions using different 1,3-
dipolar functions and different dipolarophiles opens a new
gateway for the construction of tailored multivalent struc-
tures.
a
Obtained from pentaerythritol: 14.7 mmol of pentaerythritol,
in 15 mL of DMSO, 50 mmol of NaOH in 5 mL of H
of BrCH CtCH, room temperature, 24 h, 71% of 20a and 18% of
1. Conventional acetylation of 20a yields 20b, 92%. c Legend:
a) 1 mmol of 14a, 1 mmol of C NCO, 0.1 mL of Et N, 1 mmol
of 7, 15, or 16, toluene, reflux, 16 h for 7, 36 h for 15 and 18 h for
6, 93% for 17, 92% for 18 and 90% for 19; (b) 1.23 mmol of 14,
.34 mmol of 20b, toluene, reflux, 2 days, 57%; (c) 0.77 mmol of
6 5 3
4a, 0.8 mmol of C H NCO, 0.1 mL of Et N, 0.18 mmol of 23,
2
O, 8.8 mmol
2
b
2
(
6
H
5
3
1
0
1
toluene, reflux, 2 days, 64%.
Acknowledgment. This work was financially supported
by the Direcci o´ n General de Investigaci o´ n Cient ´ı fica y
Tecnica (PB98-1320).
In a final experiment, the reaction of heptakis(2,3-di-O-
methyl-6-O-propargyl)cyclomaltoheptaose (25), obtained
OL006175V
2502
Org. Lett., Vol. 2, No. 16, 2000