Synthesis of 1-octadecyl 5-betainylamino-5-deoxy-β-d-fructopyranoside hydrochloride as a new long-chain cationic sugar-based surfactant

Article abstract of DOI:10.1016/j.carres.2008.09.011

The synthesis of a novel long-chain cationic surfactant bearing a fructopyranoside polar head functionalized at the C-5 position by a natural glycine betaine residue through an amide linkage is described.

Full text of DOI:10.1016/j.carres.2008.09.011

Carbohydrate Research 344 (2009) 136–139
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Synthesis of 1-octadecyl 5-betainylamino-5-deoxy-b-D-fructopyranoside
hydrochloride as a new long-chain cationic sugar-based surfactant
*
Fabrice Goursaud, Thierry Benvegnu
UMR CNRS 6226, Equipe Chimie Organique et Supramoléculaire, Ecole Nationale Supérieure de Chimie de Rennes, Université Européenne de Bretagne,
Avenue du Général Leclerc, F-35700 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a novel long-chain cationic surfactant bearing a fructopyranoside polar head functional-
ized at the C-5 position by a natural glycine betaine residue through an amide linkage is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 August 2008
Received in revised form 15 September
2008
Accepted 15 September 2008
Available online 20 September 2008
Keywords:
Cationic sugar-based surfactant
Fructopyranoside
Glycine betaine
Long-chain cationic surfactants have become a very important
class of industrial chemicals. These surface-active agents are based
on plant oils or animal fats and they incorporate polar heads capa-
ble of being protonated in acidic media (e.g., amines) or bearing a
permanent positive charge (such as quaternary ammonium salts).1
They have many applications, which include fabric softeners, anti-
static agents, organo-mineral clays, emulsifiers for uses in cosmet-
ics or in road making applications, germicides, flotation chemicals,
corrosion inhibitors and foam depressants.2 In particular, as the
use of cationic emulsifiers increases in cosmetology (hair care con-
ditioning, skin care), there is a growing interest in the development
of new cationic derivatives expanding the sensory options (pow-
dery dry velvety feel, long-lasting skin moisturization) available
by modifying the cationic moiety. Additionally, the consumer de-
mand for healthy and environmentally friendly products coupled
with a recent restrictive European regulation in terms of surfactant
biodegradability3 has prompted both industrial and academic re-
search groups to propose new biocompatible and biodegradable
cationic products. Within this context, sugar-based surfactants4
derived from renewable plant resources gain increasing attention
due to advantages with regard to performance, health of consum-
ers and environmental compatibility compared to some standard
products.5 Sucrose and starch-based surfactants are well-estab-
lished products and some cationic versions are already commer-
cially available as for cationic alkyl polyglucosides (APGs).6,7
Alkyl derivatives of fructose would also present similar potentiali-
ties since inulin and its monomer fructose may become economical
starting materials, provided that an efficient alkylation method
could become available.8 The specific synthesis of glycopyrano-
sides of D-fructose is not readily achieved. The Fischer-type glycos-
idation procedures frequently lead to complicated mixtures of
furanosides and pyranosides, which require chromatographic
separation.8 In our group, we have developed a one-step stereo-
controlled synthesis of alkyl
unprotected
-fructose.9 The objective of the study described here
is the regioselective introduction of the natural cationic glycine
betaine onto a -fructopyranoside possessing one long C18 alkyl
D-fructopyranosides from totally
D
D
chain for the development of a novel biocompatible fructose-based
cationic surfactant 1.
O
8
OH
O
OH
HO
NH
O
1
N
Cl
Long-chain C18 alkyl fructopyranoside 2 has been prepared in
heterogeneous medium (THF) in order to avoid the oligomerization
of unprotected
D
-fructose following the procedure developed in our
-fructose was carried
group.9 Glycosylation of 1-octadecanol by
D
out in the presence of iron(III) chloride. The work-up of the reaction
* Corresponding author. Fax: +33 2 23238046.
E-mail address: thierry.benvegnu@ensc-rennes.fr (T. Benvegnu).
leading to the unprotected fructoside 2 appeared to be difficult (20%
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.09.011

F. Goursaud, T. Benvegnu / Carbohydrate Research 344 (2009) 136–139
137
OH
OH
D-Fructose
O
O
OH
8
8
OH
OBz
O
a,b
c
O
O
OH
OBz
Br
HO
OH
2
3
HO
OH
BzO
d
O
O
8
8
OBz
OH
e, f
O
O
OBz
OH
4
5
BzO
HO
NH2
N3
Cl
S
CH3
N
g
N
S
H2C
O
1
CH3
6
Scheme 1. Reagents and conditions: (a) 1-octadecanol, FeCl3, THF, 20 °C, 6 h, then Ac2O, Py, 20 °C, 20 h, 32%; (b) MeOH, Et3N, H2O, 99%; (c) PPh3, CBr4, Py, 0 °C to 80 °C, 16 h,
then BzCl, Py, 20 °C, 5 h, 83%; (d) NaN3, Me2SO, 100 °C, 40 h, 90%; (e) MeONa, MeOH/CHCl3, 20 °C, 7 h, 85%; (f) H2, Pd/C, MeOH/CHCl3 (1:1 v/v), 94%; (g) 6, Et3N, DMF, 50 °C, 2 h,
66%.
yield of isolated compound) since stable emulsions were formed,
when the organic layer was washed with aqueous solutions. Acetyl-
ation was therefore performed in situ. For this purpose, the reaction
mixture was quenched with an excess of pyridine and acetic
The introduction of the nitrogen atom at C-5 was then carried
out by a nucleophilic displacement of bromide in 5-bromo-5-
deoxy-
heating at 100 °C for 40 h, benzoylated 5-azido-5-deoxy-b-
a-L
-sorbopyranoside 3 using sodium azide in Me2SO.13 After
D-
anhydride (Scheme 1). After work up, the alkyl b-D-substituted per-
fructopyranoside 4 was obtained in a good yield (90%). The inver-
acetylated product was isolated by column chromatography in 30%
yield. The formation of other isomers was not observed, and
furthermore neither 5-(hydroxymethyl)furfural nor difructose
dianhydrides were isolated in any significant amount.10 Quasi-
quantitative deprotection of the hydroxyl functions was performed
by adding Et3N and water in a 1:1 MeOH–CHCl3 solution of peracet-
sion of configuration for carbon 5 was ascertained by the value of
the coupling constant J4,5 3.8 Hz. A standard transesterification
process under Zemplèn conditions (MeONa, MeOH) followed by
hydrogenolysis (H2, Pd/C) gave 5-amino-D-fructoside 5 in 80% yield.
3
Finally, N-acylation of 5 was efficiently performed with the N-acyl
thiazolidine-2-thione derivative 6 of glycine betaine in DMF in
the presence of triethylamine.14 Other stable activated derivatives
of glycine betaine developed in our group15 as p-nitrophenyl ester
or amide resulting from the reaction of glycine betaine acyl chloride
with 2-mercapto-5-methyl-1,3,4-thiadiazole could be also consid-
ered for the efficient introduction of the cationic moiety but they
were not used in this study. The required cationic surfactant 1
was isolated in 66% yield after chromatography. The structure of
1 was fully confirmed by NMR spectroscopy (Tables 1 and 2) and
high-resolution mass spectrometry. NMR data showed that the
presence of the glycine betaine residue did not change the 2C5 con-
formation of the fructopyranoside moiety (3J3,4 9.9 Hz).
ylated fructoside to furnish the unprotected octadecyl b-
pyranoside 2.
D-fructo-
As glycine betaine esters were found to be highly pH-sensi-
tive,11 an amide linkage was considered for the introduction of
the cationic moiety. The crucial step of the synthetic pathway con-
sisted in taking advantage of the very special reactivity of alkyl
fructosides for the regio- and stereoselective preparation of a fruc-
toside monoazide. Treatment of octadecyl b-
with PPh3 (3.6 equiv) and CBr4 (3.8 equiv) in pyridine at 80 °C for
16 h afforded 5-bromo-5-deoxy-
-sorbopyranoside.12 After cool-
D-fructopyranoside 2
a
-L
ing, the reagent in excess was destroyed by the addition of meth-
anol and once the solvent was removed under diminished
pressure, the in situ benzoylation of the sorbopyranoside was
performed by using benzoyl chloride in dry pyridine to afford the
corresponding benzoylated derivative 3. The protection of the
hydroxyl groups was found to be necessary since the direct intro-
duction of the azido group under standard conditions (NaN3 or
LiN3 in DMF or Me2SO) from the unprotected 5-bromo-5-deoxy-
Preliminary surface tension measurements at 50 °C (to assure
high water solubility) using a drop tensiometer (Tracker instru-
ment, IT Concept) clearly revealed that cationic fructoside 1 dimin-
ished the surface tension (
significant surfactant activities. Both critical micelle concentration
(CMC = 0.095 mmol/L) and surface tension ( CMC = 37 mN/m) val-
c) at values characteristic to quite
c
ues were comparable to those obtained from novel long-chain gly-
cine betaine esters and amides, which were recently developed in
our group for road making applications.11 The potential of this new
cationic sugar-based surfactant for bitumen emulsifying applica-
tions and cosmetics is under investigation.
a-L-sorbopyranoside was unsuccessful. Indeed, the unprotected
bromide was recovered, and only small amounts (<10%) of epoxide
and/or N3-epoxide opening derivatives were additionally obtained
when using a large excess of LiN3 (25 equiv) after stirring the reac-
tion mixture at 100 °C for 4 days. The structure of 3 was evidenced
by 1H and 13C NMR spectroscopies (Tables 1 and 2). This
L-sorbo-
1. Experimental
pyranose derivative was shown to exist in a 2C5 conformation in
solution. This was confirmed by the magnitude of the 3J3,4 coupling
1.1. General methods
constant (9.9 Hz) which is characteristic of L-sorbopyranose deriv-
atives.13 Additionally, the presence of the bromine atom at the C-5
position was confirmed by 13C NMR data (d C-5 = 44.85 for 3
instead of 70.15 value for 2).
All reagents were commercially available from Sigma or Acros
and used without further purification. Tetrahydrofuran (THF) was
dried over sodium/benzophenone and distilled. TLC analyses were

138
F. Goursaud, T. Benvegnu / Carbohydrate Research 344 (2009) 136–139
conducted on precoated non-activated plates (E. Merck 60 F254),
and compounds were visualized using a 5% soln of H2SO4 in EtOH
followed by heating. For column chromatography, E. Merck 60 H
(5–40 lm) Silica Gel was used. Melting point (mp) was determined
on a Reichert microscope and is uncorrected. IR spectrum was re-
corded on a IRFT Nicolet 205 spectrometer. Optical rotation was
measured on a Perkin–Elmer 341 polarimeter at 20 °C using a 1-
dm cell. 1H and 13C NMR spectra were recorded on Bruker ARX
400 spectrometer (400 and 100 MHz for 1H and 13C, respectively)
in CDCl3 or 1:1 CDCl3/CD3OD at 298 K. Chemical shifts are given
in d-units measured downfield from Me4Si at 0 ppm using the
residual solvent signal as secondary reference. HRFAB mass spectra
were acquired on a MS/MS ZabSpec TOF Micromass spectrometer
with 3-nitrobenzylic alcohol as the matrix.
1.2. 1-Octadecyl b-
D
-fructopyranoside (2)
-fructose (12 g, 66.6 mmol) in dry THF
To a suspension of
D
(100 mL) was added 1-octadecanol (27.03 g, 99.9 mmol). Ferric
chloride (32.44 g, 200 mmol) was then added in small portions
after cooling the soln to 0 °C. The mixture was stirred at room tem-
perature for 6 h under N2 followed by the addition of dry pyridine
(200 mL) at 0 °C. After stirring for 15 min at room temperature,
Ac2O (88 mL, 933 mmol) was introduced into the reaction mixture
at 0 °C. The resulting soln was maintained at room temperature
under vigorous stirring overnight before being diluted with CH2Cl2,
washed with 5% aq HCl (until discoloration) and water (until neu-
tral pH), successively. The organic layer was dried over MgSO4 and
concentrated under diminished pressure. Purification of the resi-
due by column chromatography (4:1 petroleum ether–EtOAc)
afforded peracetylated octadecyl b- -fructopyranoside (12.10 g,
30%) as a white solid: mp 58–60 °C; ½DaꢀD20 ꢁ69.6 (c 1, CH2Cl2); TLC
(4:1 petroleum ether–EtOAc): Rf 0.24. HRFABMS: calcd for
C32H56O10Na, 623.3771; found, m/z 623.3771 [M+Na]+. Anal. Calcd
for C32H56O10: C, 63.98; H, 9.40. Found: C, 64.21; H, 9.33. To a soln
of this compound (9.01 g, 15 mmol) in MeOH (120 mL) and CHCl3
(120 mL) were added Et3N (20 mL) and water (20 mL). After stir-
ring for 17 h at 35 °C, the solvent was removed under diminished
pressure and the residue was chromatographed on silica gel (9:1
CH2Cl2–MeOH) to give the resulting unprotected octadecyl b-D-
fructopyranoside 2 (6.42 g, 99% yield) as a white solid: mp 131–
132 °C; ½a 2D0
ꢀ
ꢁ75.4 (c 0.85, 1,4-dioxane), lit.9
½
a 2D0
ꢀ
ꢁ70 (c 1, 1,4-
dioxane); TLC (9:1 CH2Cl2–MeOH): Rf 0.36. HRFABMS: calcd for
C24H48O6Na, 455.3349; found, m/z 455.3342 [M+Na]+. Anal. Calcd
for C24H48O6: C, 66.63; H, 11.18. Found: C, 66.25; H, 10.98.
1.3. 1-Octadecyl 1,3,4-tri-O-benzoyl-5-bromo-5-deoxy-a-L-
sorbopyranoside (3)
To a soln of 2 (2 g, 4.6 mmol) in dry pyridine (70 mL) cooled to
0 °C were added successively in several portions PPh3 (4.36 g,
16.6 mmol) and CBr4 (5.83 g, 17.6 mmol). After stirring at 80 °C
for 16 h, the reaction mixture was cooled to room temperature
and the excess of reagent was destroyed by adding MeOH
(20 mL). The solvent was removed under diminished pressure
and benzoylation of the product was carried out in situ. To the res-
idue were added slowly at 0 °C dry pyridine (50 mL) and benzoyl
chloride (3.22 mL, 27.7 mmol). The resulting soln was maintained
at room temperature for 5 h and it was spilled into icy water
(50 mL) before adding CH2Cl2 (3 ꢂ 50 mL). The organic layer was
dried over MgSO4 and concentrated under diminished pressure.
The crude product was purified by silica gel (95:5 petroleum
ether–EtOAc) to give the
a-L-sorbopyranoside derivative 3
(3.09 g, 83%) as a colourless oil: ½a D20
ꢀ
ꢁ25.8 (c 0.99, CH2Cl2); TLC
(4:1 petroleum ether–EtOAc): Rf 0.58; IR (Nujol, cmꢁ1);
m
707 (C–
Br), 1130–990 (C–O), 1735 (C@O) and 1652–1559 (C@C) and

F. Goursaud, T. Benvegnu / Carbohydrate Research 344 (2009) 136–139
139
Table 2
13C NMR (100 MHz, d values) for compounds 1–5
Compound
C-1
C-2
C-3
C-4
C-5
C-6
OCH2CH2
OCH2CH2
CH2
CH3
1a,c
2a
63.29
62.29
63.18
63.36
61.96
101.62
100.79
98.98
99.19
101.21
71.13
70.01
72.93
68.80
68.79
70.30
70.89
73.09
71.30
67.65
52.52
70.15
44.85
61.15
52.99
62.97
64.43
63.60
61.56
60.30
62.14
61.50
61.74
61.73
61.82
31.03
30.54
29.87
29.92
30.49
23.54–32.91
23.19–32.46
22.77–32.00
21.13–31.99
23.15–32.44
14.23
14.32
14.22
14.21
14.32
3b,d
4b,e
5a
a
Recorded in CDCl3/CD3OD (1:1 v/v) and calibrated on the CD3OD signal at 49 ppm.
Recorded in CDCl3.
For compound 1: d (CH3)3 55.16, d CH2CO 66.38, d CH2CO 165.08.
For compound 3: d PhCO 7.128.27–133.25, d PhCO 165.43–165.80.
For compound 4: d PhCO 7.128.28–133.60, d PhCO 165.50–166.08.
b
c
d
e
3010–2790 (C–H). HRFABMS: calcd for C45H59BrO8Na, 829.3291;
found, m/z 829.3283 [M+Na]+. Anal. Calcd for C45H59BrO8: C,
66.91; H, 7.36. Found: C, 67.44; H, 7.34.
powder: mp 65–70 °C; ½a D20
ꢁ59.6 (c 0.24, 41–59 CH2Cl2–MeOH);
ꢀ
TLC (4:1 CH2Cl2–MeOH): Rf 0.30. HRFABMS: calcd for C24H50NO5,
432.3689; found, m/z 432.3696 [M+H]+.
1.4. 1-Octadecyl 5-azido-1,3,4-tri-O-benzoyl-5-deoxy-b-
D
-
1.6. 1-Octadecyl 5-betainylamino-5-deoxy-b-D-
fructopyranoside (4)
fructopyranoside chloride (1)
Sodium azide (2.96 g, 45.6 mmol) was added under N2 to a stir-
red soln of 3 (3.07 g, 3.8 mmol) in dry Me2SO (40 mL). The reaction
mixture was stirred for 43 h at 100 °C. After cooling to room tem-
perature, the soln was spilled into EtOAc (300 mL) and washed
with water (3 ꢂ 300 mL). The organic layer was dried over MgSO4
and concentrated under diminished pressure. The crude product
was purified by silica gel chromatography. Elution with 19:1 petro-
leum ether–EtOAc gave the desired product 4 (2.64 g, 90%) as a col-
N-(N0,N0,N0-Trimethylammonium acetyl)thiazolidine-2-thione
chloride 614 (700 mg, 2.76 mmol) and Et3N (277
L, 1.97 mmol)
were added to soln of 5-amino- -fructoside (850 mg,
l
a
D
5
1.97 mmol) in dry DMF under N2. The reaction mixture was stirred
at 50 °C for 2 h. After removal of the solvent, the residue was flash
chromatographed (6:3:1 then 5:3:2 EtOAc–iPrOH–H2O) to afford 1
(739 mg, 66%) as a white solid: mp 200-220 °C; ½a D20
ꢁ36.1 (c 0,42,
ꢀ
17:33 CHCl3–MeOH). HRFABMS: calcd for C29H59N2O6, 531.4373;
ourless oil: ½a 2D0
ꢀ
ꢁ22.6 (c 1.1, CH2Cl2); TLC (4:1 petroleum ether–
found, m/z 531.4362 [M]+.
EtOAc): Rf 0.54. HRFABMS: calcd for C45H59N3O8Na, 792.4200;
found, m/z 792.4201 [M+Na]+. Anal. Calcd for C45H59N3O8: C,
70.20; H, 7.72; N, 5.46. Found: C, 70.56; H, 7.91; N, 5.45.
Acknowledgement
F.B. is grateful to the Agence de l’Environnement et de la Maît-
rise de l’Energie (ADEME) for a Ph.D. grant.
1.5. 1-Octadecyl 5-amino-5-deoxy-b-D-fructopyranoside (5)
To a soln of 4 (2.6 g, 3.4 mmol) in dry MeOH (40 mL) and dry
CHCl3 (10 mL) was added a 0.3 M soln of MeONa in MeOH
(5 mL). The mixture wax stirred for 7 h at room temperature, neu-
tralized with an acidic resin (Amberlite IR 120), filtered and con-
centrated. The crude product was purified by silica gel
chromatography, eluting with a mixture of 19:1 CH2Cl2–MeOH,
to yield the corresponding unprotected azido compound (1.32 g,
References
1. Rubingh, D.; Holland, P. M. Cationic Surfactants, Surfactants Science Series, Vol.
37, 1990.
2. Greek, B. F. Chem. Eng. News 1991, 69, 25–52.
3. European regulation (EC) No. 648/2004, Official Journal of the European Union,
8.4.2004, L 104/1-35.
4. Hill, K.; Rhode, O. Fett/Lipid 1999, 101, 25–33.
5. Patel, M. J. Ind. Ecol. 2004, 7, 47–62.
85%) as a white powder: mp 70–72 °C; ½a D20
ꢁ90.4 (c 0.44, CH2Cl2);
ꢀ
6. Polat, T.; Linhardt, R. J. J. Surfact. Deterg. 2001, 4, 415–421.
7. von Rybinski, W.; Hill, K. Angew. Chem., Int. Ed. 1998, 37, 1328–1345.
8. Linchtenthaler, F. W. Carbohydr. Res. 1998, 313, 69–89.
9. Ferrières, V.; Benvegnu, T.; Lefeuvre, M.; Plusquellec, D.; Mackenzie, G.;
Watson, J. W.; Haley, J. A.; Goodby, J. W.; Pindak, R.; Durbin, M. K. J. Chem.
Soc., Perkin Trans. 2 1999, 951–959.
10. Velty, R.; Benvegnu, T.; Plusquellec, D. Synlett 1996, 817–818.
11. Goursaud, F.; Berchel, M.; Guilbot, J.; Legros, N.; Lemiègre, L.; Marcilloux, J.;
Plusquellec, D.; Benvegnu, T. Green Chem. 2008, 10, 318–328.
12. Hale, K. J.; Manaviazar, S. Tetrahedron Lett. 1994, 35, 8873–8876.
13. Tatibouët, A.; Lefoix, M.; Nadolny, J.; Martin, O. R.; Rollin, P.; Yang, J.; Holman,
G. D. Carbohydr. Res. 2001, 333, 327–334.
TLC (4:1 petroleum ether–EtOAc): Rf 0.28. HRFABMS: calcd for
C24H47N3O5Na, 480.3413; found, m/z 480.3415 [M+Na]+. Anal.
Calcd for C24H47N3O5: C, 62.99; H, 10.35; N, 9.18. Found: C,
63.18; H, 10.33; N, 8.93. A soln of this compound (1.15 g,
2.5 mmol) in a mixture of MeOH (30 mL) and CHCl3 (30 mL) was
stirred in the presence of 10% Pd/C (400 mg) and under an atmo-
sphere of hydrogen gas at room temperature for 24 h. The catalyst
was removed by filtration, and the filtrate was concentrated to dry-
ness under diminished pressure. The crude product was purified by
silica gel chromatography (4:1 CH2Cl2–MeOH), to give the 5-
aminodeoxy-fructopyranoside derivative 5 (1.01 g, 94%) as a white
14. Guilbot, J.; Benvegnu, T.; Legros, N.; Plusquellec, D.; Dedieu, J. C.; Gulik, A.
Langmuir 2001, 17, 613–618.
15. Legros, N. Ph.D. Thesis, University of Rennes I (France), 1997.