Efficient synthesis of "star-like" surfactants via "click chemistry" [3+2] copper (I)-catalyzed cycloaddition

Article abstract of DOI:10.1080/07328300802105365

We report an efficient synthesis of tetra- and hexa-substituted carbohydrate-coated compounds, which we have named "star-like" surfactants, starting from either α-methylglucose or myo-inositol as a central core. The synthesis explores a new approach to su

Full text of DOI:10.1080/07328300802105365

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Efficient Synthesis of “Star‐like” Surfactants
via “Click Chemistry” [3+2] Copper
(I)‐catalyzed Cycloaddition
Virginie Neto a , Robert Granet a , Grahame Mackenzie b & Pierre Krausz a
a Laboratoire de Chimie des Substances Naturelles, Faculté des Sciences et
Techniques, Université de Limoges, 123 av. Albert Thomas, Limoges Cedex,
87060, France
b Department of Chemistry, University of Hull, Hull, Great Britain
Version of record first published: 27 Jun 2008
To cite this article: Virginie Neto, Robert Granet, Grahame Mackenzie & Pierre Krausz (2008): Efficient
Synthesis of “Star‐like” Surfactants via “Click Chemistry” [3+2] Copper (I)‐catalyzed Cycloaddition, Journal of
Carbohydrate Chemistry, 27:4, 231-237
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Journal of Carbohydrate Chemistry, 27:231–237, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802105365
Efficient Synthesis
of “Star-like” Surfactants via
“Click Chemistry” [3 1 2]
Copper (I)-catalyzed
Cycloaddition
Virginie Neto,1 Robert Granet,1 Grahame Mackenzie,2
and Pierre Krausz1
1
´
Laboratoire de Chimie des Substances Naturelles, Faculte des Sciences et Techniques,
´
Universite de Limoges, Limoges Cedex, France
2Department of Chemistry, University of Hull, Hull, Great Britain
We report an efficient synthesis of tetra- and hexa-substituted carbohydrate-coated
compounds, which we have named “star-like” surfactants, starting from either
a-methylglucose or myo-inositol as a central core. The synthesis explores a new
approach to such multipolar compounds using [3 þ 2] copper (I)-catalyzed cycloadditions
to attach the respective building blocks.
Keywords Surfactant, Carbohydrate, “Click chemistry”
Nonionic surfactants have sparked a growing interest in the last decades. Such
compounds prepared from renewable resources, in particular carbohydrate-
based surfactants, can have desirable environmental, biodegradation, nontoxicity,
and dermatological properties.[1,2] These compounds are made of a water-soluble
head derived from a carbohydrate linked by different functional groups to a hydro-
phobic part. Variations in the nature of sugar and hydrocarbon tails determine the
self-organization properties and therefore applications of the resulting surfactant.
In this context, the generation of a new class of amphiphilic surfactants using a
multidentate carbohydrate scaffold could have much promise.
Received April 2, 2008; accepted April 5, 2008.
Address correspondence to Pierre Krausz, Laboratoire de Chimie des Substances Natur-
´
´
elles, Faculte des Sciences et Techniques, Universite de Limoges, 123 av. Albert Thomas,
Limoges Cedex 87060, France. E-mail: pierre.krausz@unilim.fr
231

V. Neto et al.
The synthesis design uses a reaction known as “click chemistry.” The
232
unique aspects of this method arises from the near-perfect reliability of
copper (I)-catalyzed 1,3-dipolar cycloaddition of a terminal alkyne to an
organic azide. “click chemistry” ligation, as initially reported by Sharpless
et al.[3] and Meldal et al.,[4] is highly selective and gives a 1,4-disubstituted-
1,2,3-triazole regioisomer exclusively (Sch. 1).
Our attention turned to “click chemistry” reactions since it gives high
yields and employs simple reaction conditions (no protecting steps), which
are not sensitive to the presence of either oxygen or water. It also requires
only stoichiometric amounts of starting materials, and does not generate
by-products. Therefore, such chemistry seemed a convenient approach to
binding carbohydrate building blocks to a core unit readily and regioselectively.
Herein we report for the first time an efficient and simple approach to the
synthesis of tetra- and hexavalent carbohydrate-coated surfactants, rep-
resented by 8, 9, and 11, that we have given the general name of “star-like” sur-
factants. To apply the “click chemistry” concept to multipolar materials, we
chose to synthesise multibranched core units with either azide or alkyne
chain-end groups and attach them to carbohydrates suitably functionalized
in the anomeric position.
SYNTHESIS OF TETRASUBSTITUTED “STAR-LIKE” COMPOUNDS
Two different compounds (routes A and B in Sch. 2) were studied to create the
tetravalent “star-like” compounds. In both cases attachment to the hydroxyl
groups of a-methylglucopyranoside, acting as the central core, was achieved
by esterification of long-chain functionalized carboxylic acids substituted
accordingly by either a terminal azide or acetylenic group to be coupled, by
copper (I)-catalyzed cycloaddition to the corresponding unprotected glucose
residues suitably derivatized in the anomeric position.
Thus, the two different tetrasubstituted building blocks 4 and 5 were
synthesized via esterification of the a-D-methylglucopyranoside core by a car-
boxylic acid with terminal azide (route A) and terminal acetylenic (route B),
respectively. The 11-azidoundecanoic acid precursor 2 was obtained quantitat-
ively by azidation of 11-bromoundecanoic acid with an excess of sodium azide in
DMAc. The 10-undecynoic acid derivative 3 is commercially available.
The tetra-azido precursor 4 was obtained by esterification of a-D-methyl-
glucopyranoside with 12 eq. of 11-azidoundecanoic acid 2 in the presence of
Scheme 1: General procedure of “click chemistry” copper (I)-catalyzed cycloaddition.

Efficient Synthesis of “Star-like” Surfactants
233
Scheme 2: General procedure for synthesis of tetrasubstituted glucosidic “star-like”
precursors. (i) 12 eq. of 2, 12 eq. TsCl, DMAc, 808C, 3 d, 82%; (ii) 11.5 eq. of 6, 2 eq.
Cu(OAc)2, 2.6 eq. sodium ascorbate, THF/water 1:1, 408C, 9 d, 47%; (iii) 8 eq. of 3, 6 eq.
TsCl, DMAc, 808C, 7 d, 62%; (iv) 6 eq. of 7, 0.7 eq. Cu(OAc)2, 0.82 eq. sodium ascorbate,
tBuOH/water 1:1, 408C, 4 d, 30%.
12 eq. of tosyle chloride, in DMAc at 808C over 3 d. After purification by chrom-
atography over silica gel (CHCl3/EtOH 79:1), the four-armed azido compound 4
was isolated in 82% yield. Similarly, acetylenic four-armed precursor was
obtained starting from 8 eq. of 10-undecynoic acid derivative 3 in the
presence of 6 eq. of tosyl chloride, in DMAc at 808C for 7 d. Esterification
afforded purified compound 5 in 62% yield (silica gel, CHCl3/EtOH 99:1).
Complete esterification of the tetrasubstituted precursors 4 and 5 was
1
clearly established by H NMR, IR, and mass spectroscopy. The structure of
the tetra-azido core 4 was confirmed by the presence of five peaks from 3.25
to 1.29 ppm in the NMR spectrum integrating for 80H, assigned to the four
alkyl chains. This observation was supported by IR peaks at 1746 and
2095 cm21 corresponding to C55O and N3 functional groups, respectively. Simi-
larly, the 1H NMR spectrum of compound 5 showed the appearance of a triplet
at 1.94 ppm assigned to the four acetylenic terminal protons, along with
glycosyl protons. Furthermore, the IR spectrum showed a weak peak at
;;
2112 cm21 for nC;C and another at 3292 cm21 for
C-H linkage, confirming
thus the four-arm structure with terminal alkyne function. On the other

V. Neto et al.
234
hand, a strong peak at 1745cm21 for C55O attests the fixation of alkyl chains
via an ester linkage. Furthermore, the structure of “star-like” compounds 4
and 5 was confirmed by ESI-MS, showing the [M þ Na]þ peak adduct at,
respectively, m/z ¼ 1053.5 and 873.5.
The following step consisted of anchoring the unprotected glucose residues
to the respective scaffolds via “click chemistry” cycloaddition. The glycosyl
units were required to be deacetylated before click-linkage because of the
instability of the ester linkage to the basic conditions, such as ammonia in
methanol, used in this chemistry. Thus, the deprotection of commercially avail-
able 2,3,4,6-tetra-O-acetylpropynyl-b-D-glucose was carried out with an excess
of 7N-ammonia in methanol and gave the acetylenic sugar 6 in quantitative
yield. In the same way, the 1-azidoglucose 7 was obtained quantitatively by
NH3 in methanol.
Finally, each building block was linked together. Route Awas operated with
the azido precursor 4 in the presence of 11.5 eq. of propynylglucose 6, 2 eq. of
copper acetate (0.5 eq. per terminal azide), and 2.6 eq. of sodium ascorbate
(0.65 eq. per terminal azide) in THF/water 1:1. After 9 d at 408C and purifi-
cation by silica gel chromatography, the “star-like” compound 8 was obtained
in 47% yield. Alternatively, route B used the same procedure, employing the
tetra-acetylenic residue 5 in the presence of 6 eq. of azidoglucose 7, 0.7 eq. of
Cu(OAc)2, and 0.82 eq. of sodium ascorbate in tertiobutanol/water 1:1 at
408C, over 4 d. After purification, the click-reaction afforded the “star-like” 9
in 30% yield.
The “star-like” structure were confirmed by 1H NMR Compound 8: 1H NMR
(DMSO d6): d 1.30 (m, 48H, H-4 to H-9), 1.59 (quint., 16H, J ¼ 7.6 Hz, H-3),
1.89 (quint., 16H, J ¼ 7.0 Hz, H-10), 2.36 (t, 8H, J ¼ 7.5 Hz, H-2), 2.97
(t, 4H, J ¼ 8.5 Hz, H-20glc), 3.04 (t, 4H, J ¼ 9.0 Hz, H-30 glc), 3.21 (t, 8H,
J ¼ 8.3 Hz, H-11), 3.30 (s, 3H, OMe), 3.34 (m, 4H, H-50 glc), 3.35 (t, 4H,
J ¼ 8.9 Hz, H-40glc), 4.04 (dd, 1H, J ¼ 6.5, 11.2 Hz, H-6b glc), 4.06 (dd, 1H,
J ¼ 6.6, 9.3 Hz, H-6a glc), 3.67 (dd, 4H, J ¼ 5.3, 11.9 Hz, H-60b glc), 3.87 (dd,
4H, J ¼ 1.4, 11.1 Hz, H-60a glc), 4.18 (t, 1H, J ¼ 6.4 Hz, H-5 glc), 4.24 (d, 4H,
J ¼ 7.8 Hz, H-10b glc), 4.39 (t, 8H, J ¼ 7.1 Hz, H-1), 4.78 (d, 4H, J ¼ 12.4 Hz,
H-b propynyl), 4.93 (d, 1H, J ¼ 3.3 Hz, H-1a glc), 4.98 (d, 4H, J ¼ 12.4 Hz,
H-a propynyl), 5.00 (dd, 1H, J ¼ 3.3, 10.8 Hz, H-2 glc), 5.20 (m, 1H, H-3 glc),
1
5.38 (m, 1H, H-4 glc), 8.01 (s, 4H, H-triazole). Compound 9: H NMR (DMSO
d6): d1.26 (m, 36H, H-4 to H-7), 1.47 (m, 8H, H-8), 1.56 (m, 8H, H-3), 2.26
(m, 6H, H-2), 2.38 (t, 2H, J ¼ 7.5 Hz, H-2), 2.58 (t, 8H, J ¼ 7.0 Hz, H-9), 3.22
(m, 4H, H-50 glc), 3.32 (s, 3H, OMe), 3.37 (m, 4H, H-60b glc), 3.41 (d, 4H,
J ¼ 8.0 Hz, H-40 glc), 3.45 (m, 4H, H-60a glc), 3.70 (m, 8H, H-20 glc and H-30
glc), 4.04 (dd, 1H, J ¼ 6.6, 9.3 Hz, H-6b glc), 4.06 (dd, 1H, J ¼ 6.5, 11.2 Hz,
H-6a glc), 4.18 (t, 1H, J ¼ 6.4 Hz, H-5 glc), 4.63 (se, 4H, OH-glc60), 4.93
(d, 1H, J ¼ 3.3 Hz, H-1a glc), 5.00 (dd, 1H, J ¼ 3.3, 10.8 Hz, H-2 glc), 5.13
(de, 4H, J ¼ 3.1 Hz, OH-glc40), 5.20 (m, 1H, H-3 glc), 5.23 (dd, 4H, J ¼ 3.2,

Efficient Synthesis of “Star-like” Surfactants
235
10.8 Hz, OH-glc30), 5.36 (de, 4H, J ¼ 2.8 Hz, OH-glc20), 5.38 (m, 1H, H-4 glc),
5.44 (d, 4H, J ¼ 9.2 Hz, H-10b glc), 7.99 (s, 4H, H-triazole) with the presence
of glycosyl protons and also by the appearance of a 4H singlet at 8.00 ppm cor-
responding to the triazole protons, confirming attachment of sugar moieties via
the heterocyclic 1,2,3-triazole linkage. In addition, ESI-MS showed, respect-
ively, a [M þ 2Na]2þ peak at m/z ¼ 975.0 and 858.7 for both compounds 8
and 9, thus validating the structural assignments.
In consideration of the success of this chemistry in achieving attachment of
sugar moieties to tetrasubstituted glycosyl scaffolds, it was decided to further
exemplify its utility by synthesizing the related hexasubstituted dendrimers.
SYNTHESIS OF A HEXASUBSTITUTED “STAR-LIKE” SURFACTANT
The synthesis of carbohydrate hexa-coated compound requires two types of
building blocks, namely a hexavalent core optically active carbocycle, myo-
inositol, bearing a carbon spacer arm with, at its terminus, a reactive group,
which is coupled efficiently to a deprotected glucose unit functionalized in
the anomeric position, as shown in Scheme 3.
The six-armed azido core was obtained by esterification of myo-inositol by
10 eq. of 11-azidoundecanoic acid 2 in the presence of 12 eq. of tosyl chloride, in
DMAc at 608C for 72 h. After purification by silica gel chromatography, the hex-
abranched azido core 10 was isolated in 40%. In this approach, the azide-termi-
nated compound was preferred to those involving a terminal alkyne because of
Scheme 3: Convenient route toward hexavalent “star-like” surfactant synthesis. (i) 12 eq. of 2,
12 eq. TsCl, DMAc, 608C, 72 h, 40%; (ii) 10.5 eq. of 6, 5.4 eq. Cu(OAc)2, 3.7 eq. sodium
ascorbate, THF/water 1:1, 408C, 48 h, 46%.

V. Neto et al.
236
its better reactivity, according to Rodionov et al.[5] They have reported, for
flexible alkynes, that the proximity of the acetylenic functions may coordina-
tively saturate the CuI atom through chelation, leading to a failed result.
Finally, with the same conditions as for the four-armed compounds, the
click-reaction gave the target hexamer 11 in 46% yield using 10.5 eq. propynyl-
glucose, 5.4 eq. of Cu(OAc)2, and 3.7 eq. of sodium ascorbate in THF/water
1:1 at 408C, for 48 h. The complete anchoring of glucose residues on the
azido-hexamer 10 was unequivocally established by 1H NMR and ESI-MS.
1
Compound 11: H NMR (CD3OD þ D2O): d 1.25–1.29 (m, 72H, H-4 to H-9),
1.52 (m, 12H, H-3), 1.88 (t, J ¼ 5.8 Hz, H-10), 2.25 (d, 12H, J ¼ 7.4 Hz, H-2),
3.27 (t, 6H, J ¼ 8.5 Hz, H-20glc), 3.41 (m, 6H, H-40glc), 3.44 (t, 6H, J ¼ 8.8
Hz, H-30glc), 3.63 (dd, 6H, J ¼ 7.0, 14.2 Hz, H-60a glc), 3.71 (dd, 6H, J ¼ 5.5,
12.1 Hz, H-50glc), 3.90 (dd, 6H, J ¼ 1.5, 12.0 Hz, H-60b glc), 4.39 (t, 12H,
J ¼ 6.9 Hz, H-11), 4.47 (d, 6H, J ¼ 7.8 Hz, H-10b glc), 4.80 (d, 6H, J ¼ 12.4 Hz,
H-a propynyl), 4.97 (m, 6H, H-b propynyl), 5.40 (de, 2H, J ¼ 11.5 Hz, H-2 and
H-6 inositol), 5.50 (m, 3H, H-3, H-4 and H-5 inositol), 5.66 (te, 1H, J ¼ 2.7 Hz,
H-1 inositol), 8.04 (s, 6H, H-triazole). ESI-MS: [M þ Na]þ at m/z ¼ 2766.4.
CONCLUSION
A highly efficient route to triazole surfactants has been made available result-
ing from the near-perfect reliability of CuI-catalyzed ligation of terminal
alkynes and azides. Both a-D-methylglucose and myo-inositol have served as
central cores to “star-like” compounds. It is of interest to note that the
recently discovered ability of polydentate 1,4-disubstituted 1,2,3-triazole
species[6] to show important biological applications has been an encouragement
to the potential of “star-like” multimers being of use in biological processes.
These compounds also exhibit original tensioactive properties.
ACKNOWLEDGMENTS
´
We thank the “Conseil Regional du Limousin” for financial support of this
study, in the form of an F.S.E. grant.
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