Convergent synthesis and inclusion properties of novel C n-symmetric triazole-linked cycloglucopyranosides

Article abstract of DOI:10.1039/c0cc04127k

We present a convergent synthetic approach based on CuAAC to three carbon-linked cycloglucopyranosides displaying two, four, and six sugar residues, respectively, and triazole rings as interglycosidic spacers. The term with the largest cavity proved to serve as the host of 8-anilino-1-naphthalene- sulfonate.

Full text of DOI:10.1039/c0cc04127k

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Convergent synthesis and inclusion properties of novel Cn-symmetric
triazole-linked cycloglucopyranosidesw
Mauro Lo Conte,a Davide Grotto,a Angela Chambery,b Alessandro Dondonia and
Alberto Marra*a
Received 29th September 2010, Accepted 5th November 2010
DOI: 10.1039/c0cc04127k
We present a convergent synthetic approach based on CuAAC to
three carbon-linked cycloglucopyranosides displaying two, four,
and six sugar residues, respectively, and triazole rings as inter-
glycosidic spacers. The term with the largest cavity proved to
serve as the host of 8-anilino-1-naphthalene-sulfonate.
Cyclodextrins (CDs), macrocyclic oligosaccharides composed
of six or more (a1,4)-linked D-glucopyranoside units, have
been extensively used as molecular receptors due to their
ability to bind hydrophobic molecules into their nanometric
cavities while dissolved in polar solvents.1 However, the
development of CD-based functional materials has been
hampered by the difficulty of modifying natural CDs by
introducing functional groups in specific positions of the
macrocycle.2 Consequently, intense research has been carried
Fig. 1 Modular approach to triazole-linked cyclic oligoglycosides.
out on the synthesis of CD analogues whose sugar residues are
duly and selectively functionalized.3 Toward this goal, the
served to ensure high stability toward chemical and enzymatic
degradation. Our approach is based on a convergent strategy
involving the copper-catalyzed coupling of an alkyne A with
azide B leading to C-oligoglycoside C that in turn via
intramolecular CuAAC leads to the target triazole-linked
cyclooligomer D. This modular strategy aimed at providing
synthetic CD analogues with varied cavity sizes, this being a
key property for specific applications in molecular recognition
processes.
oligosaccharide synthesis followed by intramolecular glycosy-
lation,4 as well as cyclooligomerization of mono-,5 di-,3 and
trisaccharides,6 has been reported. Other methods involved the
cyclization of functionalized mono- and oligosaccharides by
the formation of various types of linkages, such as thioureido,7
amide,8 diethynyl,9 thioether,10 carbamate,5 phosphodiester.11
Following the growing popularity aroused during the last
decade by the quintessential click reaction represented by the
copper-catalyzed azide–alkyne cycloaddition (CuAAC),12 this
powerful ligation means was conveniently exploited by
Vasella,9 Gin,13 Chen14 and their co-workers to synthesize
CD analogues of varied sizes from acyclic glycooligomers
having an azido group at one end and a terminal alkyne group
at the other hand. Consequently all cyclic oligosaccharides
thus prepared featured two or more 1,4-disubstituted triazole
rings as spacers. In some cases, however, O-glycosidic bonds
holding the sugar moieties were also present due to the use of
acyclic O-glycosides as precursors. We would like to report
here on our CuAAC-based approach to structurally defined
cyclooligomers displaying alternant triazole and C-glucoside
moieties as shown by the general structure D in Fig. 1. The
carbon–carbon bond between the sugar and triazole ring
The access to the initial C-glucoside building blocks 4 and 6
featuring orthogonally protected functional groups was
established starting from the a,b-glucopyranosyl acetate 1
(Scheme 1). Thus treatment of 1 with excess tributylstannyl
trimethylsilyl acetylene and TMSOTf afforded the trimethyl-
silyl protected ethynyl C-glycoside 2 displaying a TMS ketene
acetal functionality at C6. Compound 2 was transformed into
the key intermediate 3 by basic treatment and this was
activated to form the O-tosyl derivative 4. Alternatively the
ethynyl group of 3 was protected with the robust tert-butyldi-
methylsilyl group to give 5 which in turn was transformed via
tosylation and azidation into the azide 6.
The approach to the first cyclooligomer was commenced by
the CuI-catalyzed coupling of the ethynyl C-glucoside 4 with
the azide 6 under microwave assisted conditions (Scheme 2).
This reaction was completed after 15 min heating at 80 1C. The
replacement of the OTs group of the crude product 7 was
carried out by treatment with NaN3 in DMF to give
compound 8 in good isolated yield. The removal of the silyl
group from 8 under standard desilylating conditions afforded
the triazole-linked disaccharide 9 featuring an azide at C6 and
an anomeric C-ethynyl group at the opposing terminus.
a Dipartimento di Chimica, Laboratorio di Chimica Organica,
`
Universita di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy.
E-mail: mra@unife.it; Fax: +39 0532 240709;
Tel: +39 0532 455156
Dipartimento di Scienze della Vita, II Universita di Napoli,
b
`
Via Vivaldi 43, 81100 Caserta, Italy
w Electronic supplementary information (ESI) available: Syntheses,
characterization data and NMR spectra of all new compounds. See
DOI: 10.1039/c0cc04127k
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1240 Chem. Commun., 2011, 47, 1240–1242
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Scheme 1
Copper-catalyzed intramolecular cycloaddition in 9 (10À3
M
in toluene at room temperature) was preferred over unpro-
ductive linear oligomerization to give the C2-symmetric cyclo-
dimer 10 in excellent isolated yield. Debenzylation of the sugar
residues of this compound by catalytic hydrogenation
furnished the free hydroxy triazole-linked cyclodiglucopyrano-
side 11.
A second cyclooligomer with a larger cavity was targeted by
a similar convergent route with the use of linear oligomers
obtained in the previous approach as starting building blocks
(Scheme 3). To this end the disaccharide 7 was desilylated to
give the ethynyl C-glucoside 12 and this was coupled with the
azide 8 under the previously established CuI-catalyzed and
microwave assisted conditions. The cycloaddition afforded the
linear triazole-linked tetraglucoside 13 which was transformed
into the key intermediate 15 via azidation by nucleophilic
displacement of the O-tosyl group by NaN3 and removal of
the silyl protective group by fluoride ion. Finally, the intra-
molecular CuAAC of 15 and debenzylation of the crude
Scheme 3
product furnished the C4-symmetric triazole-linked cyclo-
tetraglucopyranoside 16 in good isolated yield.
A third cyclooligomer featuring six triazole-linked gluco-
pyranose fragments was prepared as well involving as a first
step the standard copper-catalyzed coupling of the alkyne 12
with the azide 14 (Scheme 4). Also in this case the linear
oligosaccharide 17 thus obtained was transformed into the
azido and ethynyl functionalized compound 18 that in turn
underwent the desired intramolecular CuAAC without any
substantial linear oligomerization. The crude product was
liberated of the benzyl protective groups to give the target
C6-symmetric triazole-linked cyclohexaglucopyranoside 19 in
good yield. NMR spectra of cyclooligomers 11, 16, and 19
supported their Cn-symmetry as in all cases a single signal at
7.7–8.0 ppm corresponding to the H5 of the triazole ring and a
single set of signals corresponding to the seven protons of the
glucopyranose moiety were observed (see ESIw). Moreover,
the ESI/Q-TOF HRMS data confirmed the authenticity of all
products. It is worth pointing out that in all cases the
intramolecular high yield CuAAC reaction occurring in the
ultimate precursors to these compounds indicated a curved
topology favorable to cyclization in preference to linear
oligomerization.
Having established a convergent route to the cyclooligomers
11, 16, and 19, it can be realized that lower and higher
homologues can be equally prepared by using the appropriate
building blocks shown in Schemes 1–3. Thus, we addressed the
main issue regarding the application of CDs and synthetic
analogues, that is their ability to serve as host of organic
molecules. To this aim we examined the potential of
Scheme 2
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Chem. Commun., 2011, 47, 1240–1242 1241

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to their smaller cavities that prevented the complexation. An
association constant of 22.5 Æ 1.3 MÀ1 was determined
(see Fig. S2 in ESIw) for 19 + ANS by fluorescence titration
(reported16 Kas for b-CD + ANS: 71 Æ 4 MÀ1).
1
The binding properties of 16 were evaluated by H NMR
spectroscopy using racemic phenylalanine hydrochloride as
the guest, according to a procedure developed for a-CD.17
Upon addition of increasing amounts of amino acid to a D2O
solution of 16 (pD 2.0), a small downfield shift for the H3
sugar proton signal was observed (Dd E 0.05 ppm).18 In the
case of a-CD a Dd value of 0.10 ppm was reported.17 There-
fore, it appears that cyclotetramer 16 and cyclohexamer 19
showed complexation properties similar to those displayed by
a- and b-cyclodextrins, respectively.
We thank Dr S. Caramori (University of Ferrara) for
recording the fluorescence emission spectra and L. Bani for
his valuable help in the preparation of the graphics.
Notes and references
1 J. Szejtli, Chem. Rev., 1998, 98, 1743.
2 (a) A. R. Khan, P. Forgo, K. J. Stine and V. T. D’Souza, Chem.
Rev., 1998, 98, 1977; (b) A. J. Pearce and P. Sinay, Angew. Chem.,
¨
Int. Ed., 2000, 39, 3610; (c) N. Masurier, O. Lafont, R. Lo Provost,
D. Lesur, P. Masson, F. Djedaıni-Pilard and F. Estour, Chem.
Commun., 2009, 589.
¨
3 G. Gattuso, S. A. Nepogodiev and J. F. Stoddard, Chem. Rev.,
1998, 98, 1919.
4 (a) M. Mori, Y. Ito and T. Ogawa, Carbohydr. Res., 1989, 192, 131;
(b) M. Mori, Y. Ito, J. Uzawa and T. Ogawa, Tetrahedron Lett.,
1990, 31, 3191.
Scheme 4
5 P. Y. Chong and P. A. Petillo, Org. Lett., 2000, 2, 1093.
6 N. Sakairi and H. Kuzuhara, J. Chem. Soc., Chem. Commun.,
1993, 1874.
7 (a) D. Rodrı
J. Perez-Miron, C. Ortiz Melet and J. M. Garcı
J. Org. Chem., 2008, 73, 2967; (b) D. Rodrı
C. Ortiz Melet, C. Jaime, K. K. Burusco, J. M. Garcı
and J. M. Benito, J. Org. Chem., 2009, 74, 2997.
´
guez-Lucena, J. M. Benito, E. Alvarez, C. Jaime,
a Fernandez,
guez-Lucena,
a Fernandez
´
´
´
´
´
8 (a) E. Locardi, M. Stockle, S. Gruner and H. Kessler, J. Am. Chem.
¨
Soc., 2001, 123, 8189; (b) R. M. van Well, L. Marinelli,
K. Erkelens, G. van der Marel, A. Lavecchia, H. S. Overkleeft,
J. H. van Boom, H. Kessler and M. Overhand, Eur. J. Org. Chem.,
2003, 2303.
9 (a) R. Burli and A. Vasella, Angew. Chem., Int. Ed. Engl., 1997, 36,
¨
1852; (b) B. Hoffmann, B. Bernet and A. Vasella, Helv. Chim. Acta,
2002, 85, 265.
10 L. Fan and O. Hindsgaul, Org. Lett., 2002, 4, 4503.
11 (a) C. Coppola, V. Saggiomo, G. Di Fabio, L. De Napoli and
D. Montesarchio, J. Org. Chem., 2007, 72, 9679; (b) J. D’Onofrio,
C. Coppola, G. Di Fabio, L. De Napoli and D. Montesarchio,
Eur. J. Org. Chem., 2007, 3849.
Fig. 2 Fluorescence emission spectra (lex = 365 nm) of phosphate
buffer solutions (pH 7.22) of ANS (0.15 mM) in the presence of b-CD,
16 and 19 (21 mM).
12 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
Int. Ed., 2001, 40, 2004; (b) H. C. Kolb and K. B. Sharpless, Drug
Discovery Today, 2003, 8, 1128.
13 (a) K. D. Bodine, D. Y. Gin and M. S. Gin, J. Am. Chem. Soc.,
2004, 126, 1638; (b) K. D. Bodine, D. Y. Gin and M. S. Gin, Org.
Lett., 2005, 7, 4479.
14 S. Muthana, H. Yu, H. Cao, J. Cheng and X. Chen, J. Org. Chem.,
2009, 74, 2928.
15 V. Crescenzi, A. Gamini, A. Palleschi and R. Rizzo, Gazz. Chim.
Ital., 1986, 116, 435.
compounds 11, 16, and 19 to form inclusion complexes with
the fluorescent probe 8-anilino-1-naphthalene-sulfonate
(ANS), a typical model guest of b-CD and synthetic macro-
cyclic oligosaccharides.7,13a,14 In fact, it is well known15 that
the fluorescence yield of ANS strongly increases when this dye
is complexed in hydrophobic sites not accessible to polar
solvents. As expected, in aqueous solutions the fluorescence
of ANS was quenched (see Fig. S1 in ESIw), whereas the
addition of excess 19 led to a hypsochromic shift and a
remarkable enhancement of the fluorescence intensity, much
larger than that observed for b-CD (Fig. 2). On the other
hand, 11 (data not shown) and 16 (Fig. 2) did not cause a
significant increase in the fluorescence of ANS, very likely due
16 J. Nishijo and M. Nagai, J. Pharm. Sci., 1991, 80, 58.
17 D. J. Wood, F. E. Hruska and W. Saenger, J. Am. Chem. Soc.,
1977, 99, 1735.
1
18 When the H NMR spectra recorded by adding individual D- and
L-Phe hydrochloride were compared, a very small difference in the
chemical shift [D(d À d ) = 0.01 ppm] was observed only for the
L
D
proton linked to the stereocenter of the guest (see Fig. S3 in ESIw).
c
1242 Chem. Commun., 2011, 47, 1240–1242
This journal is The Royal Society of Chemistry 2011