Synthesis of C2-symmetric glycophanes through a 'click chemistry' approach

Article abstract of DOI:10.2174/157017809787582843

The synthesis of C₂-symmetric glycophanes incorporating two triazole linkers has been achieved in seven steps rom 3,4,6-tri-O-acetyl-D- glucal in good overall yields. The intermolecular Cu(I)-mediated Huisgen reaction was used for he ring closu

Full text of DOI:10.2174/157017809787582843

106
Letters in Organic Chemistry, 2009, 6, 106-109
Synthesis of C2-symmetric Glycophanes Through a 'Click Chemistry'
Approach
Gildas R. Baloua, Jean-Pierre Jolya, Lionel Vernex-Losetb and Yves Chapleur*,a
aGroupe SUCRES, UMR 7565, Nancy Université, CNRS, BP 239, F-54506-Vandœuvre-lès-Nancy, France
bLaboratoire de Spectrométrie de Masse et Chimie Laser, Technopôle 2000, Université Paul Verlaine, 1 Bd Arago,
F-57078 Metz, Cedex 3, France
Received August 02, 2008: Revised November 13, 2008: Accepted November 25, 2008
Abstract: The synthesis of C2-symmetric glycophanes incorporating two triazole linkers has been achieved in seven steps
from 3,4,6-tri-O-acetyl-D-glucal in good overall yields. The intermolecular Cu(I)-mediated Huisgen reaction was used for
the ring closure key-step to give almost exclusively 24-, 26-, and 32-membered chiral macrocycles without significant po-
lymerization. Target compounds however had low solubility in water, precluding investigation of their recognition behav-
iour in this medium.
Keywords: carbohydrate, Ferrier reaction, Huisgen cycloaddition, click chemistry, glycophane.
INTRODUCTION
to ꢁ-anomers 2 and 3 (J1-2 ꢂ 2 Hz) in good to excellent
yields. The Zemplén deprotection [19] of esters 2 and 3
yielded diols 4 and 5 almost quantitatively. Nucleophilic
azide displacement of bromine in hot DMF afforded diols 6
and 7 which were reacted with trityl chloride to afford pro-
tected alcohols 8 and 9 in 58 and 85% yield respectively
over 3 steps. Almost quantitative O-propargylation on the
remaining hydroxyl group at C-4 could be performed either
by phase-transfer catalysis [20] or through a classical Wil-
liamson reaction [21] (NaH/THF) to give protected azido-
alkyne precursors 10 and 11 Scheme 1.
Glyco-cyclophanes [1], or more concisely glycophanes
[2], are a family of neutral and chiral synthetic sugar-based
macrocycles that display hydrophobic cavities and are of
interest in molecular recognition [3]. Like their cyclophane
parents [4] some water-soluble glycophanes are endowed
with interesting complexing behaviors which make them
potential receptors for small, neutral organic guests [5]. The
‘click chemistry’ approach independently initiated by the
groups of Meldal and Sharpless [6], i.e. the copper(I)-
catalyzed modern version of the Huisgen-type azide-alkyne
cycloaddition [7] to give preferentially if not exclusively the
1,4-regio-isomer, was recently used for the highly conver-
gent synthesis of cyclodextrin analogues [8]. The inertia of
the 1,2,3-triazole ring towards basic and acid hydrolysis [9]
as well as towards metabolic degradation makes it an attrac-
tive connecting unit in the fields of supramolecular [10] and
peptide chemistry [11], drug design [12], and materials sci-
ence [13]. In connection with our previous syntheses of 22-
and 23-membered electron-rich cage-like molecules by
Glaser oxidative homocoupling of bridged disaccharides [14]
and larger glycophanes [15], we report here the syntheses of
small symmetric cage-like molecules by a click chemistry
approach [16].
Gratifyingly, the Cu(I)-catalyzed cycloaddition of 10 and
11 at the concentration of 6 ꢀ 10-3 M in toluene in the pres-
ence of DBU as a base afforded cyclic dimers 12 and 13 in
fair yields. In contrast with similar macrocycle formations
reported by Bodine et al., [5e] no traces of trimers or higher
oligomers could be detected by ESI-MS in the crude mix-
ture. However, formation of a significant amount of 13b,
resulting from iodine addition on the triazole ring [22], oc-
curred during the preparation of 13a. Although very little is
known about the exact nature of the mechanism of Cu(I)-
catalyzed alkyne-azide coupling [23], optimized reaction
conditions [24] could avoid the formation of by-product 13b
Scheme 2.
We next explored the synthesis of a larger glycophane by
reversing the relative positions of azide and alkyne substitu-
ents on the sugar, i.e. the propargyl group being introduced
at the anomeric position and the azido group grafted at O-4
via a longer arm. The synthesis of compound 19 obtained
this way is shown in Scheme 3.
RESULTS AND DISCUSSION
Taking advantage of previous works in the laboratory
[17], we decided to explore a new approach based on a Fer-
rier rearrangement for the glycosylation key-step. The
stereoselective boron trifluoride-catalyzed allylic rearrange-
ment [18] of tri-O-acetyl-D-glucal 1 with ꢀ-bromo-alcohols
in dichloromethane below +4°C led mainly if not exclusively
(1-Prop-2-ynyl)-2,3-dideoxy-ꢁ-D-erythro-hex-2-enopyr-
anoside 15 [25], readily obtained by known procedures from
tri-O-acetyl-D-glucal in 91% yield over two steps, was pro-
tected as a trityl ether to give sec. alcohol 16 (92%) which
was reacted under phase-transfer conditions with an excess
of 1-chloro-2-(2’-chloroethoxy)ethane [26] to afford chloro-
alkyl ether 17 in excellent yield. Nucleophilic azide dis-
*Address correspondence to this author at the Groupe SUCRES, UMR
7565, Nancy Université, CNRS, BP 239, F-54506-Vandœuvre-lès-Nancy,
France; Tel: +33 383 68 47 73; Fax: +33 383 68 47 80;
E-mail: yves.chapleur@sucres.uhp-nancy.fr
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Synthesis of C2-symmetric Glycophanes Through a 'Click Chemistry' Approach
Letters in Organic Chemistry, 2009, Vol. 6, No. 2
107
AcO
AcO
HO
O
OAc
ꢀ-bromo-alcohol
O
O
Na˚
MeOH, rt
Br
Br
BF3:Et2O
CH2Cl2, rt
( )
( )
n
n
O
O
AcO
AcO
HO
3,4,6-tri-O-acetyl-D-glucal 1
2 (n = 1, 96%)
3 (n = 2, 85%)
4 (n = 1, 97%)
5 (n = 2, 96%)
NaN3
DMF, 120°C
TrO
TrO
HO
O
O
O
N3
C3H3Br
TrCl, DMAP
Pyr., rt
N3
N3
( )
a or b
n
( )
n
( )
n
O
O
O
O
HO
HO
10 (n = 1, 97%)
11 (n = 2, 96%)
8 (n = 1, 92%)
9 (n = 2, 98%)
6 (n = 1, 65%)
7 (n = 2, 90%)
Scheme 1. Synthesis of azido-alkynes 10 and 11 from tri-O-acetyl-D-glucal 1; a: aq. NaOH, Tol., NBu4HSO4, < 4°C; b: NaH, THF, 0°C.
placement of the chlorine atom in hot DMF afforded azido-
alkyne precursor 18 which was cyclized in the presence of
CuI and DBU-excess to yield glycophane 19 in fair yield.
Glycophanes 12 and 19 could be easily deprotected by
treatment with camphor sulphonic acid (CSA) in MeOH at
room temperature [16b] to yield diols 20 and 21 Scheme 4.
1
Like glycophanes 12 and 13a, the H-NMR spectrum of this
However in our hands deprotection of 13a under the
same conditions (i.e. a catalytic amount of CSA in a
CH2Cl2/MeOH mixture at rt) failed, leading only to polar
degradation products [28]. The target compounds 20 and 21
displayed very low solubility in water, precluding an investi-
gation of their complexing behaviour in this medium. How-
ever, preliminary NMR investigations using known proto-
cols [29] showed no measurable extraction of amino acids
(e.g. L-valine, glycine methyl esters as their ammonium per-
chlorate salts) by these glycophanes from D2O. One may
assume that the cavity of such dimers is too small to accept
even a small guest and that the two triazole spacers provide a
too rigid macrocycle which would adopt an extended con-
formation. Thus, a conformational search of host 20 pro-
32-membered macrocycle displayed a C2-symmetry in
CDCl3 solution at 27°C [27].
TrO
N
N
O
N
CuI, DBU
Tol., rt
( )
10-11
n
O
O
N
R
O
O
( )
n
12 (n = 1, R = H, 71%)
N
O
13a (n = 2, R = H, 60%)
13b (n = 2, R = I, 23%)
N
OTr
Scheme 2. Synthesis of glycophanes 12 and 13 via tandem dimeri-
zation-macrocyclization of 10 and 11.
HO
AcO
O
C3H3Br
1
O
Na˚
BF3:Et2O
MeOH, rt
CH2Cl2, rt
AcO
O
HO
15 (94%)
O
14 (97%)
TrCl
DMAP
TrO
Pyr., rt
TrO
O
Cl
O
Cl
O
O
O
Cl
NaOH, NBu4HSO4
O
O
HO
17 (85%)
16 (92%)
TrO
O
N
N
NaN3
DMF
O
CuI, DBU
Tol., rt
N
O
O
TrO
O
O
O
N
O
N
O
N3
O
N
O
O
OTr
19 (60%)
18 (80%)
Scheme 3. Synthesis of glycophane 19 from 3,4,6-tri-O-acetyl-D-glucal.

108 Letters in Organic Chemistry, 2009, Vol. 6, No. 2
Balou et al.
HO
N
O
N
O
N
CSA
12
MeOH, rt
O
O
N
O
N
O
N
20 (95%)
OH
OH
O
O
O
O
N
N
N
CSA
19
N
MeOH, rt
N
N
O
O
O
O
HO
21 (85%)
Scheme 4. Deprotection of glycophanes 12 and 19 by CSA in MeOH at rt.
a
b
Fig. (1). Low energy conformer of glycophane 20.
vided a low energy conformer family [30] such as the one
depicted in Fig. (1). It exhibits a C2-symmetry and a rectan-
gular shape: the distance between the CH of the two triazole
rings in this model is about 7.7 Å and the smallest distance
between the two sugar rings is around 3.2 Å. This may be
compared with the 5.0 Å cavity diameter of ꢀ-cyclodextrin.
A CPK representation of our model clearly shows that the
cavity should be sterically closed on both sides by the two
primary hydroxyl groups of the sugars.
was readily achieved in seven steps from 3,4,6-tri-O-acetyl-
D-glucal in good overall yield (34-41%). The intermolecular
Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition of azido-
alkyne precursors afforded only dimers with 24-, 26-, or 32-
membered macrocycles in good yield without significant
polymerization. The deprotection of the trityl ethers by CSA
in methanol was obtained in good yields for only two of
these three glycophanes. No complexing ability towards
amino acids as their methyl ester salts was observed for these
macrocycles in CDCl3 mainly due to their small, non-circular
cavity. Tri- or tetrameric water-soluble structures [5e] would
likely be far better complexing agents but their synthesis
needs a stepwise approach which is currently underway.
CONCLUSION
In summary, the convergent synthesis of three C2-
symmetric glycophanes incorporating two triazole linkers

Synthesis of C2-symmetric Glycophanes Through a 'Click Chemistry' Approach
Letters in Organic Chemistry, 2009, Vol. 6, No. 2
109
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Calculations were done using CaChe 7.5® Fujitsu by molecular
dynamics at constant energy in water with MM3 parameters.