Asymmetric synthesis of a phosphorus analog of natural γ-amino- β-hydroxybutyric acid

Full text of DOI:10.1134/S1070363206100318

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 10, pp. 1677 1678.
Pleiades Publishing, Inc., 2006.
Original Russian Text V.V. Nesterov, O.I. Kolodyazhnyi, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 10, pp. 1749 1750.
LETTERS
TO THE EDITOR
Asymmetric Synthesis of a Phosphorus Analog
of Natural -amino- -hydroxybutyric Acid
V. V. Nesterov and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine, ul. Murmanskaya 1, Kiev, 02094 Ukraine
Received August 1, 2006
DOI: 10.1134/S1070363206100318
We have developed a simple synthesis of a phos-
horus analog of natural -amino- -hydroxybutyric
acid (GABOB) which is important in the biological
aspect and used for treatment of some deseases of
nervous system [1, 2].
In the first step, the pure (S)-dimenthyl 3-chloro-2-
hydroxypropylphosphonate (I) we prepared earlier
[3, 4] was dehydrochlorinated with potassium car-
bonate in acetonitrile in the presence of potassium
iodide to form epoxide (R)-II with a high stereo-
specifity and without loss of optical purity.
O
O
O
OH
H
OH
O
HNBn2
K2CO3, KI
Cl
(MntO)2P
(MntO)2P
(MntO)2P
NBn2
H
H
(S)-I, 96% de
(R)-II
(R)-III, 100% de
O
O
OH
H
OH
NH2
H
H3O+
H2, Pd/C
H2O3P
(HO)2P
NBn2
(R)-IV
(R)-V, >99% de
Compound II was reacted with dibenzylamine to
obtain crystalline hydroxyaminophosphonate (R)-III.
The latter was further dealkylated by heating with
hydrochloric acid in dioxane to afford crystalline
phosphonic acid (R)-IV which was debenzylated by
hydrogenation in methanol with palladium on char-
coal. As a result, a crystalline phosphorus analog of
natural -amino- -hydroxybutyric acid (R)-V was
prepared with good yield and high optical purity. The
structure of compound (R)-V was confirmed by
elemental analysis and NMR spectroscopy. The
enantiomeric purity of diastereomeric compounds I
III was monitored by NMR spectroscopy. The R
configuration of compound V was established by
measuring its optical rotation [5, 6]. Due to the pre-
sence of menthyl groups, compounds I III could be
isolated and purified by crystallization, i.e. we could
exclude chromatographic purification from the syn-
thetic procedure and prepare an optically pure phos-
phorus analog (R)-V.
Bis[(1R,2S,5R)-menthyl] (2R)-(oxiran-2-yl)-
methylphosphonate (II). To a solution of 1.156 g of
compound I [4] in 19 ml of acetonitrile DMF
(10:3.5) we added 0.707 g of potassium carbonate
and a catalytic amount of potassium iodide. The mix-
ture was refluxed for 8 h, the precipitate was then
filtered off, and the solvent removed to obtain com-
pound II as a yellowish oil, yield 98%, [ ]2D0 62.4
1
(c 7.0, CHCl3). H NMR spectrum (CDCl3), , ppm
1677

1678
NESTEROV, KOLODYAZHNYI
(J, Hz): 0.8 d (3H, J 7); 0.88 d (3H, J 7); 0.89 d (3H,
J 7); 0.90 d (3H, J 7); 0.91 d (3H, J 7); 0.8 1.65 m
(16H, CH2C); 2.15 2.05 m (2H, PCH2); 2.4 d.d (1H,
J 2.1, J 5.1); 3.0 d.d (1H, J 4, J 4.8); 3.0 m (1H,
CHOH); 4.24 m (2H, CHOH). 31P NMR spectrum
(2R)-(3-amino-2-hydroxypropyl)phosphonic
acid (V). To a solution of 0.39 g of compound IV in
45 ml of ethanol we added 0.37 g of palladium on
charcoal (10%). Gaseous hydrogen was passed
through a stirred mixture for 20 h. Then the mixture
was filtered, the filtrate was evaporated, and the
product was washed with acetone and dried in a
vacuum. A colorless hygroscopic compound was ob-
tained, [ ]2D0 +8.3 (c 1.2, H2O), 31P NMR spectrum:
P 22.8 ppm. The product was additionally purified on
KU-2 cationite, yield 90%, [ ]2D0 +10.2 (c1, H2O).
1H NMR spectrum (D2O), , ppm (J, Hz): 1.78 d.d.d
(JHH 31.2, JHH 15.0, JHH 6.3, CHaP), 1.86 d.d.d (JHH
32.1, JHH 14.7, JHH 6.3, CHbP), 2.99 d.d (JHH 13.5,
JHH 8.5, CHaN), 3.27 d.d (JHH 13.1, JHH 3.4, CHbN),
4.14 m [1H, CH(OH)]. 31P NMR spectrum (D2O):
18.1 ppm. Found N, %: 9.43. Calculated N, %: 9.03. P
(CDCl3):
25.3 ppm.
P
Bis[(1R,2S,5R)-menthyl] (2R)-[3-(dibenzyl-
amino)-2-hydroxypropyl]phosphonate (III). To a
solution of 1.1 g of compound II in 20 ml of me-
thanol we added 0.52 g of dibenzylamine. The mix-
ture was refluxed for 20 h. The solvent was removed,
and the residue was recrystallized from acetonitrile.
The product is a colorless crystalline compound, yield
70%, mp 73 C, [ ]2D0 45.92 (c 4.57, CHCl3). H
1
NMR spectrum (CDCl3, , ppm (J, Hz): , ppm
(J, Hz): 0.73 d (3H, JHH 7.2, CH3); 0.80 d (3H, JHH
6.9, CH3); 0.87 d (3H, JHH 7.0, CH3); 0.90 d (3H, JHH
7.0, CH3); 0.91 d (3H, JHH 7.0, CH3); 0.92 d (3H, JHH
The NMR spectra were measured on a Varian-300
instrument against internal TMS (1H) and external
85% H3PO4 in D2O (31P). The optical rotations were
measured on a Polax-2L polarimeter (Japan).
7.0, CH3); 2.0 d.d.d (JHP 12.5, JHH 1.2, PCHa);
2.13 d.d.d (J 14.1, J 7.8, J 2.7, PCHb), 1.2 2.2 m
(16H, CH2C); 4.1 m (2H, CHO), 3.55 c (4H, CH2Ph).
1.829 d.d.d (J 33.9, J 18.6, J 3.6, CH2N), 7.1 7.3 m
(10H, C6H5). 31P NMR spectrum (CDCl3), P, ppm:
30.0. Found, %: C 72.64; H 9.51; P 5.08. C37H58
NO4P. Calculated, %: C 72.63; H 9.55; P 5.06.
REFERENCES
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phonic acid hydrochloride (IV). To 0.75 g of com-
pound III in 30 ml of dioxane we added 10 ml of
conc. HCl, and the mixture was kept for 3 days at 80
85 C. The mixture was evaporated, and the residue
was dissolved in 15 ml of water and washed with
benzene. After removal of water in a vacuum, the
product was obtained as a colorless hygroscopic crys-
talline compound, yield 85%. 1H NMR spectrum
(CDOD), , ppm (J, Hz): 1.73 d.d.d (JHP 32.4, JHH
17.4, JHH 8.1, CHaP), 1.93 d.d.d (JHP 34.5, JHH 14.7,
JHH 4.5 CHbP), 3.00 d.d (JHH 13.2, JHH 9.3, CHbN),
4.08 4.21 m [1H, CH(OH)], 4.95 s (3H, OH); 7.52
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7.54 m (10H, C6H5). 31P NMR spectrum (H2O):
P
26.5 ppm.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 10 2006