Regioselective reaction of unprotected sugars with urethane N-carboxyanhydrides for the synthesis of new surfactants

Article abstract of DOI:10.1081/SCC-120002000

Reaction of urethane N-carboxyanhydrides with unprotected amino sugars was the key step in the synthesis of new trimodular surfactants.

Full text of DOI:10.1081/SCC-120002000

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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REGIOSELECTIVE REACTION OF UNPROTECTED
SUGARS WITH URETHANE N-CARBOXYANHYDRIDES
FOR THE SYNTHESIS OF NEW SURFACTANTS
Salima Bellhaouel , Marie-Louise Roumestant , Philippe Viallefont & Jean
Martinez
To cite this article: Salima Bellhaouel , Marie-Louise Roumestant , Philippe Viallefont
& Jean Martinez (2002) REGIOSELECTIVE REACTION OF UNPROTECTED SUGARS WITH
URETHANE N-CARBOXYANHYDRIDES FOR THE SYNTHESIS OF NEW SURFACTANTS, Synthetic
Communications, 32:2, 181-187, DOI: 10.1081/SCC-120002000
To link to this article: http://dx.doi.org/10.1081/SCC-120002000
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SYNTHETIC COMMUNICATIONS, 32(2), 181–187 (2002)
REGIOSELECTIVE REACTION OF
UNPROTECTED SUGARS WITH
URETHANE N-CARBOXYANHYDRIDES
FOR THE SYNTHESIS OF
NEW SURFACTANTS
Salima Bellhaouel, Marie-Louise Roumestant,*
Philippe Viallefont, and Jean Martinez
UMR 5810-CNRS Laboratoire des Amino Acides,
Peptides et Proteines Place E. Bataillon, 34095
Montpellier Cedex 5, France
ABSTRACT
Reaction of urethane N-carboxyanhydrides with unprotected
amino sugars was the key step in the synthesis of new trimod-
ular surfactants.
Alkyl glycosides possessing one hydrophilic sugar residue and one lipo-
philic long alkyl chain linked by a glycosidic bond have become commer-
cially available as non-ionic surfactants. These compounds are characterized
by a low toxicity, high biodegradability as well as excellent skin compati-
bility.1 More recently glycosyl amides2 and glycosyl carbamates3 have been
reported as surfactants. They were prepared using chemical or enzymatic
methods.
*Corresponding author.
181
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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182
BELLHAOUEL ET AL.
Because of environmental reasons, it seems advantageous to develop
surfactants from raw materials of agricultural origin such as carbohydrates,
proteins; these natural compounds are optically pure and inexpensive.
We decided to develop a new family of surfactants including one
hydrophilic sugar residue and one lipophilic long chain linked by an
amino acid residue. In this study the fatty chain was linked to the amino
function of the amino acid whereas the sugar was bound to the acid
function. To create this bond, commercially available urethane N-car-
boxyanhydrides (UNCAS) appear to be good candidates; the versatile reac-
tivity of these stable compounds has been explored4 and we were interested
to examine their behaviour with unprotected sugar derivatives in the first
step of our synthesis.
Reaction of urethane-N-carboxyanhydrides was first investigated with
amino sugars because the amide bond is chemically and physically very
stable in alkaline media. Three amines were used: N-methylglucamine 1,
glucosylamine 2, 2-deoxy-2-amino glucose 3 (Scheme 1).
Scheme 1.
The first experiments were carried out starting from N-methyl
glucamine and Ala-NCA N-protected by different groups: t-butyloxy-
carbonyl (Boc), benzyloxycarbonyl (Z ) and fluorenylmethoxycarbonyl
(Fmoc) (Scheme 2). N-methyl glucamine contains several hydroxyl functions
that can also react with the UNCA, so it was necessary to find suitable
operating conditions allowing selective N-acylation. While the reactions
may be conducted in both DMF and CH3CN as solvent, the results
obtained in DMF were generally superior; in CH3CN several compounds
were obtained, the regioselectivity was very low. Influence of the protecting
group, of the temperature, of the reaction time and of the stoichiometry
(ratio Amine/UNCA) were studied. The results are reported in Table 1.
The nature of the protecting group had not a great influence on the
yield (the Z group giving the best yields) and on the regioselectivity.
However the stoichiometry is very important; with a ratio sugar/
UNCA ¼ 1 (Entries 2 and 4), a mixture of two products was obtained, a

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REGIOSELECTIVE REACTION OF UNPROTECTED SUGARS
183
Scheme 2.
Table 1. Reaction of N-Methyl Glucamine with Urethane-Ala-NCA
Ratio
Sugar/UNCA
Time
(h)
Yield
(%)
Entry UNCA
Tꢀ
Solvent
Product
1
2
3
4
4a
’’
’’
4b
r.t.
’’
’’
2
1
2
1
DMF
’’
CH3CN
DMF
24
’’
’’
6a
’’
8a mixture
36
30
47
82
’’
’’
6b
8b
6b
’’
’’
’’
’’
’’
’’
9
5
6
7
8
9
10
11
12
13
14
4b
’’
’’
’’
’’
’’
’’
4c
’’
’’
’’
0
2
’’
’’
’’
’’
’’
2
1
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
’’
8
’’
1/2
8
24
’’
70*
62*
47*
54*
70*
61*
68*
62**
42**
23*
21*
46*
11*
À25
À60
À78
r.t.
’’
’’
’’
’’
2
0.5
’’
’’
6c
8c
6c
8c
15
’’
’’
0.5
’’
72
Isolated yield after column chromatography. *Isolated yield after preparative HPLC.
1
**Yield based on H NMR spectra.

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184
BELLHAOUEL ET AL.
monosubstituted compound with an amide function (6a, 6b) and a disub-
stituted compound containing an amide and an ester functions (8a, 8b).
With the same ratio and the Fmoc group as protecting group (Entries 12
and 13) the reaction afforded directly compound 9, N-methyl glucamine
being able to cleave the Fmoc group. With the ratio sugar/UNCA ¼ 2
(Entries 1 and 5) a good regioselectivity was obtained and in all cases
only N-methylglucamine amidation took place. When the temperature was
lowered to À78ꢀC, the yield remained practically identical (Entries 6–9).
The reaction time had not a great influence on the yield, the reaction
seemed to be rapid. Reaction of N-methylglucamine with Z-Phe NCA 5b
using the same reaction conditions (ratio : sugar/UNCA ¼ 2) afforded the N-
acylated compound 7b in 70% yield.
To connect the fatty chain, compounds 6 were N-deprotected using
standard methods to give 9 and reaction with lauroyl chloride in H2O/EtOH
in the presence of Na2CO3 afforded 10 in good yield (Scheme 3).
Scheme 3.
10 was weakly soluble in water, to improve the solubility the fatty
chain was shortened and coupling of 9 with hexanoic acid chloride afforded
11 (soluble in water) in 57% yield.
This methodology was applied starting from glycosylamine 2 easily
prepared using Lubineau’s method5 and 2-deoxy-2-aminoglucose 3; the
regioselectivity of the reaction with 4a, 4b, 4c depends on the stoichiometry,

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REGIOSELECTIVE REACTION OF UNPROTECTED SUGARS
185
Table 2. Reaction of Glucosylamine 2 and 2-Deoxy-2-
amino Glucose 3 with Urethane-Ala-NCA
Amine
UNCA
Product
Yield (%)
2
’’
’’
4a
4b
4c
12a
12b
12c
32
45
48
3
’’
’’
4a
4b
4c
13a
13b
13c
53
45
50
the single N-acylation product (12 from 2 and 13 from 3) was obtained
if the ratio sugar/UNCA ¼ 2 (Table 2).
In conclusion the procedure reported herein provides a very attractive
and efficient methodology. It should be applicable for the synthesis of a
great variety of trimodular compounds whose physicochemical properties
are under investigation.
EXPERIMENTAL
1H NMR spectra were recorded on a Brucker at 200 MHz. Mass
spectra were recorded on a JEOL DX 300 and SX 102. Infra red
spectra were performed on a Perkin Elmer Paragon 1000. Microanalysis
were performed by the Service of CNRS at Vernaison (France). Melting
points are uncorrected. Analytical thin layer chromatography (TLC)
was performed using Merck Silica gel 60 F254 precoated plates with
a fluorescent indicator. Visualization was accomplished by nynhydrin
solution. The starting UNCAS were from Isochem (Gennevilliers, France).
General Procedure for the Reaction of Aminosugars with UNCA: To the
amino sugar (1, 2 or 3) (0.52 mmol) dissolved in anhydrous DMF (4 ml)
under magnetic stirring was added at room temperature urethane-Ala-NCA
(0.25 mmol) dissolved in DMF (2 ml), the reaction being monitored
by T.L.C. The solvent was evaporated to give an oil which was purified
by column chromatography on silica gel using an appropriate solvent
mixture
6a: solvent mixture (CHCl3/EtOH/AcOH : 12/3/0.1). m.p. ¼ 56–58ꢀC
[a]D ¼ À17 (c ¼ 1, CH3OH). IR (KBr): 3296, 2925, 2857, 1695, 1628 cmÀ1
.
1H NMR (D2O) d 1.15 (d, 3H, J ¼ 6.9 Hz); 1.25 (s, 9H); 3–3.2 (2s, 3H); 3.3–4
(m, 8H); 4.45 (q, 1H, J ¼ 6.9 Hz). M.S.: M þ 1 ¼ 367 (ES).

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186
BELLHAOUEL ET AL.
6b: solvent mixture (CHCl3/EtOH/AcOH : 80/19/1) m.p. ¼ 46–48ꢀC
(H2O). [a]D ¼ À 37 (c ¼ 1, H2O). IR (KBr): 3319, 1729, 1646 cmÀ1
.
1H NMR (D2O): d 1.3 (d, 3H, J ¼ 6.52 Hz); 2.9–3.2 (2s, 3H); 3.3–4.3
(m, 8H); 4.5 (q, 1H, J ¼ 6.7 Hz); 5.15 (s, 2H); 7.45 (m, 5H). Anal. calcd.
for C18H28O8N2, 0.5 H2O: C 52.80, H 6.89, N 6.84, found C 52.77, H
6.96, N 7.07.
6c: m.p. ¼ 62–64ꢀC [a]D ¼ À 10 (c ¼ 1, CHCl3). IR (KBr): 3283, 2914,
2887, 1711, 1696, 1646 cmÀ1. 1H NMR (D2O) d 1.3 (d, 3H, J ¼ 6.5 Hz); 3–3.2
(2s, 3H); 3.4–4.4 (m, 11H); 4.6 (q, 1H, J ¼ 6.5 Hz); 7.2 (m, 8H). M.S.:
M þ 1 ¼ 489 (ES).
7b: m.p. ¼ 48–50ꢀC. IR (KBr): 3293, 2939, 2887, 1721, 1705,
1688 cmÀ1
.
1H NMR (D2O) d 2.9–3.2 (2s, 3H); 3 (d, 2H, J ¼ 6.3 Hz);
3.3–3.7 (m, 8H); 3.9 (q, 1H, J ¼ 6.3 Hz); 5 (s, 2H); 7.2 (m, 10H). Anal.
Calcd for C24H32O8N2, H2O: C 58.28, H 6.92, N 5.66, found C 58.72, H
6.74, N 5.68.
12a: solvent mixture (CHCl3/MeOH/NH4OH : 20/15/2) m.p. ¼ 120–
122ꢀC. IR (KBr): 3418, 2917, 2881, 1688, 1680 cmÀ1 1H NMR (D2O):
.
d 1.2 (d, 3H, J ¼ 7 Hz); 1.3 (s, 9H); 3.25–3.8 (m, 6H); 3.9 (q, 1H,
J ¼ 7 Hz); 5 (d, 1H, J ¼ 3.35 Hz).
13a: solvent mixture (CHCl3/EtOH/AcOH : 80/20/1) m.p. ¼ 143–
145ꢀC. IR (KBr): 3320, 2971, 1684, 1646 cmÀ1. H NMR (D2O): d 1.45 (d,
1
3H, J ¼ 6.75 Hz); 1.55 (s, 9H); 3.5–4.1 (m, 6H); 4.3 (q, 1H, J ¼ 6.8 Hz); 5.3
(d, 1H, J ¼ 3.3 Hz). Alanine N-methylglucamide 9 was obtained directly
(Table 1, Entry 12) of after cleavage of the N-protecting groups using
standard methods.
9 (0.22 g, 0.82 mmole) was dissolved in a solution of Na2CO3 (0.11 g)
in EtOH/H2O (3/1) under argon, the mixture was cooled to 0ꢀC and
lauric acid chloride or hexanoic acid chloride (4 eq) was added; the
reaction took place spontaneously. 10 was obtained after precipitation
using CHCl3.
Yield: 55% m.p. ¼ 102–104ꢀC. IR (KBr): 3330, 2907, 2849, 1659,
1
1647 cmÀ1. H NMR (CD3OD): d 0.8 (t, 3H, J ¼ 6.8 Hz); 1.25 (s, 16H); 1.4
(d, 3H, J ¼ 7.2 Hz; 1.6 (m, 2H); 2.3 (t, 2H, J ¼ 7.1 Hz); 2.9–3.2 (2s, 3H),
3.4–4.2 (m, 8H); 4.4 (q, 1H, J ¼ 7.2 Hz). M.S.: M þ 1 ¼449 (ES).
11 was obtained after elimination of the excess of fatty acid by extrac-
tion with diethylether, evaporation of the aqueous layer and crystallization
from water/methanol.
1
Yield: 57%. IR (KBr): 3340, 2917, 2859, 1669, 1657 cmÀ1. H NMR
(D2O): d 0.8 (t, 3H, J ¼ 5.8 Hz); 1.25 (m, 6H); 1.5 (m, 2H); 2.3 (t, 2H,
J ¼ 5.4 Hz); 2.9–3 (2s, 3H); 3.2–3.8 (m, 8H); 4.1 (q, 1H, J ¼ 5.4 Hz). M.S.:
M þ 1 ¼ 365 (ES). Anal. Calcd. for C16H32O7N2: C 52.74, H8.79, N7.69
found C 52.69, H8.82, N7.75.

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REGIOSELECTIVE REACTION OF UNPROTECTED SUGARS
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Received in the Netherlands February 15, 2000

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