The efficient synthesis of amphiphilic oximes of galactose and glucosamine

Article abstract of DOI:10.1016/j.tetlet.2012.02.086

New amphiphilic oximes of galactose and glucosamine have been synthesized and characterized. The oxime functionality has been introduced to the first and sixth positions of a nonionic surfactant, consisting of a sugar polar head and a lipophilic side chain. The compounds are soluble in pyridine and sparingly soluble in other polar organic solvents and water.

Full text of DOI:10.1016/j.tetlet.2012.02.086

Tetrahedron Letters 53 (2012) 2234–2235
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Tetrahedron Letters
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The efficient synthesis of amphiphilic oximes of galactose and glucosamine
⇑
Janez Mravljak, Aleš Obreza
ˇ
Faculty of Pharmacy, University of Ljubljana, Aškerceva 7, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
New amphiphilic oximes of galactose and glucosamine have been synthesized and characterized. The
oxime functionality has been introduced to the first and sixth positions of a nonionic surfactant, consist-
ing of a sugar polar head and a lipophilic side chain. The compounds are soluble in pyridine and sparingly
soluble in other polar organic solvents and water.
Received 9 January 2012
Revised 2 February 2012
Accepted 17 February 2012
Available online 24 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amphiphilic oximes
Galactose
Glucosamine
Protecting groups
Oximes are an important structural feature and are present in
several biologically active compounds. As nucleophiles they are
used as antidotes for organophosphate poisoning, with examples
being pralidoxime and obidoxime.1 In addition, they are also found
as the artificial sweetener perillartine, as inhibitors of low density
lipoprotein oxidation to prevent atherosclerotic diseases or, taken
more broadly, as inhibitors of lipid peroxidation induced by differ-
ent oxidizing agents.2 The mechanism of their antioxidant activity
is not completely understood, however it is possibly due to their
scavenging of different reactive species and may also be related
to their metal-chelating properties.3 It has been shown that oximes
protect active ingredients susceptible to oxidation against oxida-
tive degradation in complex dosage forms, such as microemul-
sions.4 Oximes are used as intermediates in organic chemistry for
the synthesis of amines, amides, isoxazoles and are important
ligands in the formation of metal complexes.5 They are usually pre-
pared by the reaction of a carbonyl compound with hydroxylamine
or its salt. An efficient microwave-assisted synthesis of oximes,
using BF3ꢀOEt2 as the catalyst has been described.6 Other methods
include the oxidation of amines7 and reduction of nitro
compounds.8
molecules, which prevent their dehydration and enhance their
thermostability.10 The results presented in this Letter are a contin-
uation of our studies on the design, synthesis, and evaluation of
glycolipids11 and amphiphilic oximes.4
The design of the target molecules was based on amphiphilic
oximes composed of a nonionic polar bulky head consisting of a
monosaccharide moiety with one or two oxime functionalities.
The nonpolar part consists of medium- or long-chain alkyl groups
attached to the sugar in the form of ethers or amides. We focused
our attention on the synthesis of derivatives of two monosaccha-
rides,
D
-galactose and
D
-glucosamine.
-galactose, the synthetic strat-
To synthesize the derivatives of
D
egy presented in Scheme 1 was used. Following the preparation of
acetonide 1 according to known procedures,12 the lipophilic chain
was introduced to the remaining 40-hydroxy group at ambient
temperature using various alkyl bromides and imidazole and 15-
Crown-5 as catalysts. In the next two steps the protecting groups
were removed with 75% TFA and the oxime formed at C-10 of 3
with hydroxylamine in pyridine. Pyridine was used as the solvent
since compounds of series 313 and 4 were soluble predominantly in
pyridine, but only sparingly soluble in other polar organic solvents
and water.
Derivatives of glucosamine were synthesized as shown in
Scheme 2. The lipophilic acyl group was introduced to the starting
compound D-glucosamine by selective N-acylation with acyl chlo-
rides in a mixture of 1,4-dioxane/aqueous NaHCO3 at room tem-
perature.14 The primary 60-hydroxy group in 515 was substituted
with the bulky triphenylmethyl group, while the other hydroxy
groups were acetylated. The trityl group was selectively removed
with an aqueous solution of ferric chloride16 and the resulting hy-
droxy group of 8 oxidized to the corresponding aldehyde with
Dess–Martin periodinane (DMP).17 Compounds 9 exist in two
Surfactants are compounds commonly used in everyday life and
in industry as detergents, emulsifiers, solubilizers, or wetting
agents. Nonionogenic surfactants with sugar derivatives as a polar
group have several advantages over cationic and anionic surfac-
tants.9 They are physiologically acceptable, relatively nontoxic
and less irritant than ionogenic surfactants. Surfactants containing
a sugar moiety may form H-bonds with the surrounding water
⇑
Corresponding author. Tel.: +386 1476 9677; fax: +386 1425 8031.
E-mail address: ales.obreza@ffa.uni-lj.si (A. Obreza).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.086

J. Mravljak, A. Obreza / Tetrahedron Letters 53 (2012) 2234–2235
2235
R
OH OH
OH
O
O
HO
a
HO
5
N
OH
O
O
a
OH
O
NH
HO
O
OH
O
OH
O
c
(CH2)nCH3
n = 6, 8, 10, 12, 14
11
1
R = H
b
Scheme 3. Reagents and conditions: (a) NH2OH (5.6 equiv), pyridine, 40 °C, 48 h
(11a, 43%; 11b, 64%; 11c, 65%; 11d, 76%; 11e, 68%).
2
R = (CH2)nCH3
n = 7, 9, 11, 13, 15
tionalities, at C-10 and C-60. Compounds with only one oxime group
at position C-10 were prepared directly from 5 as shown in Scheme
3.18
In conclusion, we have synthesized new amphiphilic oximes of
galactose 4 and glucosamines 10 and 11 from inexpensive starting
materials. These compounds may lead to a new group of sugar-
based excipients combining amphiphilic (surfactants) and antioxi-
dant properties. Some of these are under technological investiga-
tion as potential antioxidants for semi-solid pharmaceutical
formulations.
(CH2)nCH3
O
O
HO
OH OH
O
d
N
H3C(H2C)n
HO
OH
OH OH
OH
OH
4
3
Scheme 1. Reagents and conditions: (a) acetone, CuSO4 (2.4 equiv), H2SO4
(0.35 equiv), rt, 24 h, then Ba(OH)2 (0.35 equiv), (1, 72%); (b) CH3(CH2)nBr (n = 7,
9, 11, 13, 15; 1.5 equiv), NaH (1.5 equiv), 15-Crown-5 (0.02 equiv), imidazole
(0.01 equiv), 1,4-dioxane, 0 °C ? rt, 24 h (2a, 41%; 2b, 65%; 2c, 65%; 2d, 55%; 2e,
45%); (c) 75% TFA, H2O, 0 °C ? rt, 1.5 h (3a, 84%; 3b, 90%; 3c, 95%; 3d, 92%; 3e, 97%);
(d) NH2OH (5 equiv), pyridine, 40 °C, 48 h (4a, 52%; 4b, 68%; 4c, 72%; 4d, 71%; 4e,
70%).
Acknowledgments
This work was supported by the Ministry of Higher Education,
Science and Technology of the Republic of Slovenia. The authors
thank Professor Roger Pain for critical reading of the manuscript.
OR
OH
O
O
a
HO
HO
HO
HO
OH
OH
NH
Supplementary data
NH2
O
c
(CH2)nCH3
R = H
Supplementary data (experimental procedures and data for rep-
resentative new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2012.02.086.
5
b
6
R = CPh3
References and notes
OR
O
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O
O
e
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AcO
AcO
AcO
OAc
NH
OAc
NH
O
O
(CH2)nCH3
(CH2)nCH3
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forms, as the aldehyde and geminal diol; the ratio was determined
by NMR spectroscopy. Both compounds reacted with hydroxyl-
amine in pyridine to yield the final products with two oxime func-