Synthesis of N-aminoglycosides on the basis of the d-pseudoephedrine alkaloid

Full text of DOI:10.1134/S1070363209010241

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 1, pp. 143–144. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © I.V. Kulakov, 2009, published in Zhurnal Obshchei Khimii, 2009, Vol. 79, No. 1, pp. 147–148.
LETTERS
TO THE EDITOR
Synthesis of N-Aminoglycosides on the Basis
of the d-Pseudoephedrine Alkaloid
I. V. Kulakov
Institute of Organic Synthesis and Coal Chemistry of the Kazakhstan Republic,
ul. Alikhanova 1, Karaganda, 100008 Kazakhstan
e-mail: ivanku1@mail.ru
Received July 3, 2008
DOI: 10.1134/S1070363209010241
N-Glycosylation of many amino compounds,
including natural physiologically active amines, is
considered as a new approach to creation of versatile
drugs of preset action due to effective transport of
carbohydrate fragments [1–4]. Introduction of carbo-
hydrate fragments to the structure of physiologically
active compounds not only increases their water
solubility, but also decreases their toxicity, which
allows glycosylation of a physiologically active
compound (or some of its fragments) at the glycoside
carbohydrate center as one of the possible methods for
preparing low-toxicity drugs [5].
practice as α- and β-adrenoceptor stimulators [6]. Its
threo isomer, d-pseudoephedrine, primarily known as a
by-product in pharmacological industry, is much less
pharmacologically active, and this restricts its practical
application [7, 8].
In this aspect, we considered it interesting to
prepare N-glycosylamies derived from d-pseudo-
ephedrine and certain monosaccharides and to study
their biological properties.
N-Glycosylamines were prepared by a classical
method [9] involving direct condensation of amines
with monosaccharides in an alcohol solution, some-
times in the presence of catalytic amounts of weak
acids. 1-Glycopyranosylamines I–IV were synthesized
by condensation of D-glucose, D-galactose, D-xylose,
and L-arabinose with d-pseudoephedrine in a little
absolute ethanol (without a catalyst). The absolute
ethanol was used to facilitate isolation of the target
products. Glycosides I–IV are white fine crystalline
substances moderately soluble in polar solvents.
N-Glycosamines attract attention of chemists, bio-
chemists, and biologists, since they can appear in
biological and plant conditions and are formed by
reactions of carbohydrates with alkyl- and arylamines.
The interest in studying alkaloids of the ephedrine
series and synthesizing on their basis of new
derivatives is explained by that they possess specific
pharmacological properties and two reaction centers. l-
Ephedrine hydrochloride is widely used in medical
OH
OH
C2H5OH, 75oC
C6H5 CH
H3C CH CH
C6H5
CH CH3
Sug OH +
N
H
CH3
Sug(β1)
N
I_IV
CH3
CH2OH
CH2OH
HO
O
HO
O
O
O
OH
OH
OH
OH
;
;
;
Sug =
HO
HO
OH
(L-Ara) IV
OH
OH
OH
(D-Csy) III
(D-Gal) II
(D-Glc) I
143

144
KULAKOV
1
Their structure was established by IR and Н NMR
spectroscopy. The IR spectra feature a broad strong
band at 3405 cm–1, that corresponds to stretching
vibrations of carbohydrate OH groups. The presence of
several bands in the range 1010–1080 cm–1 provides
evidence for a pyranose form of the glycoside residue.
The absorption bands of glycosides I–IV near 890 cm–1
are indicative of αβ conformation of the aglycone at
the anomeric center. The β conformation of the
synthesized glycosides is also confirmed also by a
specific position in the 1Н NMR specra of the signal of
the anomeric proton in the region of 4.13–4.40 ppm
with a large spin–spin coupling constant of 6.5–7.2 Hz.
СНN), 2.35 s (3Н, N–CH3), 3.00–3.80 m [5Н,
carbohydrate Н2–Н5], 4.25 d [1Н, СН(ОН), J 9.0 Hz],
4.35 d [1Н, Н1, J 6.8 Hz], 7.35 m (5Н, Нarom).
N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-
N-methyl-β-L-arabinopyranosylamine (IV) was syn-
thesized in a similar way from 0.30 g of L-arabinose
and 0.33 g of d-pseudoephedrine. Yield 0.37 g (64 %),
mp 144–145°С. Found, %: С 61.02; Н 7.55; N 4.93.
C15H23NO5. Calculated, %: C 60.59; H 7.80; N 4.71.
1Н NMR spectrum, δ, ppm: 1.00 d (3Н, СН3–СН, J
6.6 Hz), 2.35 m (1Н, СНN), 2.40 s (3Н, N–CH3),
3.40–3.76 m [5Н, carbohydrate Н2–Н5], 4.33 d [1Н,
СН(ОН), J 8.8 Hz], 4.40 d [1Н, Н1, J 6.5 Hz], 7.35 m
(5Н, Нarom).
N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-
N-methyl-β-D-glucopyranosylamine amine (I). A mix-
ture of 0.36 g of D-glucose and 0.33 g of d-pseudo-
ephedrine in 5 ml of absolute ethanol was stirred for
5 h at 65–70°С. Two third of the solvent was removed
by distillation, and the residual solution was allowed to
cool down. The crystals that formed were filtered off
and washed with a little acetonitrile to obtain 0.44 g
(68%) of compound I as white crystals, mp 133–134°С.
Found, %: С 59.11; Н 7.96; N 4.57. C16H25NO6.
1
The Н NMR spectra were registered on a Bruker
DRX500 spectrometer (500 MHz) from solutions in
DMSO-d6 against internal TMS. The IR spectra were
obtained on an AVATAR-320 instrument from KBr
pellets. The reaction progress was monitored by TLC
on Sorbfil plates in a 10:5:2 propan-2-ol–benzene–
ammonia system.
REFERENCES
1
Calculated, %: C 58.70; H 7.70; N 4.28. Н NMR
spectrum, δ, ppm: 0.98 d (3Н, СН3–СН, J 6.5 Hz),
2.35 m (1Н, СНN), 2.41 s (3Н, N–CH3), 3.30–3.80 m
(6Н, carbohydrate Н2–Н6), 4.00 d [1Н, СН(ОН), J
8.8 Hz], 4.25 d [1Н, Н1, J 7.2 Hz], 7.36 m (5Н, Нarom).
1. Stepanenko, B.N., Khimiya i biokhimiya uglevodov.
Monosakharidy (Chemistry and Biochemistry of Carbo-
hydrates. Monosaccharides), Moscow: Vysshaya Shkola,
1977.
2. Krasavina, L.S., Turchina, R.P., Vigdorchik, M.M.,
Turchin, K.F., Akhvlediani, R.N., and Suvorov, N.N.,
Zh. Org. Khim., 1988, , vol. 24, no. 9, p. 1960.
3. Salekh, M.A., Krasavina, L.S., Vigdorchik, M.M.,
Turchin, K.F., Sapukova, A.A., Anisimova, O.S., and
Suvorov, N.N., Zh. Org. Khim., 1989, vol. 25, no. 12,
p. 2619.
4. Gazaliev, A.M., Nurkenov, O.A., Kulakov, I.V., Aina-
baev, A.A., and Bessonov, D.V., Zh. Prikl. Khim.,
2006, vol. 79, no. 3, p. 517.
N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-
N-methyl-β-D-galactopyranosylamine (II) was syn-
thesized in a similar way from 0.36 g of D-galactose
and 0.33 g of d-pseudoephedrine. Yield 0.37 g (56 %),
mp 152–153°С. Found, %: С 59.18; Н 7.51; N 4.49.
C16H25NO6. Calculated, %: C 58.70; H 7.70; N 4.28.
1Н NMR spectrum, δ, ppm: 1.02 d (3Н, СН3–СН, J
6.6 Hz), 2.35 m (1Н, СНN), 2.40 s (3Н, N–CH3),
3.35–3.80 m [6Н, carbohydrate Н2–Н6], 3.95 d [1Н,
СН(ОН), J = 8.8], 4.13 d [1Н, Н1, J 7.0 Hz], 7.36 m
(5Н, Нarom).
5. Sarymzakova, R.K., Abdurashitova, Yu.A., and
Dzhamanbaev, Zh.A., Vestn. Mosk. Gos. Univ., Ser. 2:
Khim., 2006, vol. 47, no. 3, p. 242.
N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-
N-methyl-β-D-xylopyranosylamine (III) was syn-
thesized in a similar way (reaction time 3 h) from
0.30 g of D-xylose and 0.33 g of d-pseudoephedrine.
Yield 0.36 g (63 %), mp 146–147°С. Found, %: С
60.98; Н 8.15; N 4.36. C15H23NO5. Calculated, %: C
6. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Meditsina, 1998, vol. 1, p. 277.
7. Zhurinov, M.G., Gazaliev, A.N., and Fazylov, S.D.,
Khimiya efedrinovykh alkaloidov (Chemistry of Ephed-
rine Alkaloids), Alma-Aty: Nauka, 1990.
8. Gazaliev, A.N., Fazylov, S.D., Zhurinov, M.G., and
1
Balitskii, S.N., Khim. Prirod. Soedin., 1989, no. 3, p. 307.
60.59; H 7.80; N 4.71. Н NMR spectrum, δ, ppm, J,
9. Sorokin, W., Ber., 1887, vol. 20, p. 783.
Hz: 1.02 d (3Н, СН3–СН, J 6.6 Hz), 2.25 m (1Н,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 1 2009