Synthesis of enantiomerically pure phosphonic analog of natural aspartic acid

Full text of DOI:10.1134/S1070363210120194

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 12, pp. 2519–2520. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © О.I. Kolodyazhnyi, О.О. Kolodyazhnaya, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 12, pp. 2058–2059.
LETTERS
TO THE EDITOR
Synthesis of Enantiomerically Pure Phosphonic Analog
of Natural Aspartic Acid
О. I. Kolodyazhnyi and О. О. Kolodyazhnaya
Institute of Bioorganic Chemistry and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02094 Ukraine
e-mail: olegkol321@rambler.ru
Received April 1, 2010
DOI: 10.1134/S1070363210120194
A simple approach to (R)-phosphonopropionic acid,
phosphonic analog of the natural L-aspartic acid, is
developed starting from L-serine through the Arbuzov
reaction as a key stage.
NH2
NHCOOBu-t
OMe
NHCOOBu-t
Boc2O
Ph3P
HO
OMe
HO
Br
OMe
CBrCl3
O
O
O
(S)-I
(S)-II
(R)-III
NH2
NHCOOBu-t
OMe
NH2
(EtO)3P
140oC
HCl
HOOC
OH
(EtO)2P(O)
(OH)2P(O)
OH
O
O
(R)-IV
O
(R)-V
L-aspartic acid
Methyl ester of L-serine I was Boc-protected at the
NH-group [1], then the obtained (S)-hydroxyamino-
carboxylate II was transformed into bromide (R)-III
through reaction with triphenylphosphine and trichloro-
bromomethane in methylene chloride at 70°С.
Bromide III was purified by vacuum distillation and
brought into the Arbuzov reaction with five-fold
excess of triethyl phosphite, the reaction proceeded at
135–140°С over 12 h. After distilling off the volatile
reaction product at 0.1 mm Hg at 120°С, the phos-
phonate IV was obtained, which was purified by
column chromatography. Its structure was proved by
Methyl (S)-tert-buthoxycarbonylamino-3-hydroxy-
propionate (II). To a solution of 10.5 g (0.05 mol) of
(S)-methyl serinate hydrochloride in 10 ml of THF was
added 15 g of triethylamine at 0°С and this mixture
was stirred for 30 min. Then 12 g of Boc2O was added,
and the reaction mixture was warmed to room
temperature, stirred for 6 h, and then refluxed for 3 h.
Then it was cooled, poured into the saturated aqueous
sodium hydrogen bicarbonate solution, extracted with
diethyl ether, and concentrated. Yield 90%, [α]D20 18.0
(MeOH, c 5), colorless oil. 1Н NMR spectrum
(CDCl3), δ, ppm: 1.44 s [9H, (CH3)3C], 3.77 s (3H,
CH3O), 3.9 m (2H, CH2), 4.38 m (1H, CHN), 5.57 br.s
(1H, NH).
1
the Н, 13С and 31Р NMR spectroscopy and mass
spectrometry. The heating of compound IV with
hydrochloric acid affords (R)-(+)-С-phosphonoaspartic
acid V. This compound have been earlier obtained by a
more complicated method [2]. The physical properties
and optical rotation angle coincided with the published
data.
Methyl (R)-tert-buthoxycarbonylamino-3-bromo-
propionate (III). To a mixture of 6.5 g (0.03 mol) of
compound II and 12 g (0.046 mol) of triphenyl-
phosphine in 40 ml of methylene chloride was drop-
2519

2520
KOLODYAZHNYI, KOLODYAZHNAYA
wise added 10 g (0.05 mol) of bromotrichloromethane
at –80°С. Then the reaction mixture was warmed to
room temperature, stirred for 1 h at this temperature,
filtered, concentrated, diluted with pentane, again
filtered and concentrated. The residue was distilled in a
(C=O, J 6.0). 31P NMR spectrum (CDCl3): δP
26.5 ppm. Found, %: N 4.11; P 9.21. C13H26NO7P.
Calculated, %: N 4.13; P 9.13.
2-(R)-Amino-3-phosphonopropionic acid (V). Com-
pound IV (0.66 g, 0.02 mol) was refluxed with hyd-
rochloric acid over 12 h. Then water was removed, the
residue was washed with ethyl acetate and mixed with
propylene oxide. The mixture was stirred overnight at
room temperature. The solvent was removed. The
residue was recrystalled from aqueous alcohol. Yield
65%, mp >200°C, [α]D20 15 (c 1, 1 N NaOH/H2O) [2].
1Н NMR spectrum (D2O), δ, ppm: 2.12 m (1H), 2.3 m
(1H), 4.15 m (1H). 13С NMR spectrum (D2O), δC, ppm
(J, Hz): 28.2 d (PC, J 131.0), 49.9 d (CN, J 4.5), 172.0 d
(C=O, J 13.0).
1
vacuum. Yield 60%, bp 110°С (0.08 mm Hg). Н
NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.44 s [9H,
(CH3)3C], 3.77 s (3H, CH3O), 3.78 d.d (1H, BrCH, J
3.5, J 11.5), 3.90 d.d (1H, BrCH, J 3, J 11.5), 4.4 m
13
(1H,CHN), 5.57 br.d (1H, NH, J 7.5) [3, 4]. С NMR
spectrum (CDCl3), δC, ppm (J, Hz): 28.26 [(CH3)3C],
33.95 (BrCH2), 52.90 (CHN), 54.01 (CH3O), 80.45
(CO), 154.95 (C=O), 169.65 (C=O). Found, %: C
38.35; H 5.77; Br 28.10. C9H16BrNO4. Calculated, %:
C 38.31; H 5.72; Br 28.32.
Methyl
(R)-tert-buthoxycarbonylamino-3-(di-
The NMR spectra were recorded on a Varian-300
instrument relative to internal TMS (1Н, 13С) and 85%
Н3РО4 in D2O (31Р).
ethoxyphosphoryl)propionate (IV). To 7 g (0.025 mol)
of bromide III was added 20 ml (0.12 mol) of triethyl
phosphite. This mixture was heated at 140°С for 24 h.
Then triethyl phosphite excess and other volatile
products were removed in a vacuum (0.1 mm Hg) at
110–120°С. The spectrally pure phosphonate IV was
obtained and purified additionally by the column
chromatography. Rf 0.50 (1:1, EtOAc–hexane), [α]D21
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 12 2010