Synthesis of phosphonic analog of glutamic acid

Full text of DOI:10.1134/S1070363213040300

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 4, pp. 777–778. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © O.O. Kolodyazhnaya, A.O. Kolodyazhnaya, O.I. Kolodyazhnyi, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 4,
pp. 697–698.
LETTERS
TO THE EDITOR
Synthesis of Phosphonic Analog of Glutamic Acid
O. O. Kolodyazhnaya, A. O. Kolodyazhnaya, and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02094 Ukraine
e-mail: olegkol321@rambler.ru
Received November 1, 2012
DOI: 10.1134/S1070363213040300
A scheme for the synthesis of phosphonic analog of
glutamic acid starting from tert-butyl N-tert-butoxy-
carbonylaspartate I was developed. The latter was
obtained from aspartic acid by the previously des-
cribed method [1, 2]. The carboxy group of compound
I was acylated with ethyl chloroformate and reduced
with sodium borohydride in methanol to give tert-
butyl-(S)-N-(tert-butoxycarbonyl)homoserine (S)-II [2].
The latter was converted to the bromide (S)-III via the
reaction with triphenylphosphine and bromotri-
chloromethane [3]. Bromide III was introduced into
the Arbuzov reaction with trimethylsilyldiethyl-
phosphite to yield phosphonate IV, deprotection of
which with diluted hydrochloric acid resulted in the
phosphorus analog of glutamic acid V.
stirring for 15 min the resulting precipitate was filtered
off. Then the obtained solution was added dropwise to
a solution of sodium borohydride (1.17 g, 0.03 mol) in
15 ml of methanol with stirring and cooling to 0°C.
The reaction mixture was stirred for 1 h. Then to the
reaction mixture was added 20 ml of 1 N HCl and 70
ml of diethyl ether. The organic phase was washed
with 1 N hydrochloric acid, 5% aqueous sodium hyd-
rogen carbonate solution and water, dried with
anhydrous sodium sulfate. The solvent was removed
20
under vacuum. Yield 5.00 g (90%), colorless oil, [α]
D
1
–38 (с 1.0, EtOH) [2]. Н NMR spectrum, (СDCl ), δ ,
3
Н
ppm, (J, Hz): 1.40 s (9H, СH C), 1.42 s (9H, CH C),
3
3
2.08–2.10 m (1H, CH ), 2.33–2.36 m (1H, CH ), 3.67
2
2
m (2H, CH
O), 3.93 m (1Н, CHN), 4.90 br.d (1H, NH,
2
1
3
JНН 7). С NMR spectrum, (СDCl ), δ , ppm: 28.10
3
С
tert-Butyl-(S)-N-(tert-butoxycarbonyl)homoserine
(
CH C), 28.50 (CH C), 37.60 (CH ), 54.20 (CN),
3 3 2
(
II). To a solution of tert-butyl N-tert-butoxycarbonyl-
5
9.10 (CH O), 79.70 (CH C), 82.00 (CH C), 156.00
2 3 3
aspartate I [2] (5.8 g, 0.02 mol) in 15 ml of THF with
stirring and cooling to from –10 to –20°C was
successively added dropwise pyridine (2.4 g, 0.03 mol)
and ethyl chloroformate (2.4 g, 0.022 mol). After
(
C=O), 171.40 (C=O).
tert-Butyl (S)-2-[(tert-butoxycarbonyl)amino]bromo-
butanoate (III). To a solution of II (5.5 g, 0.02 mol)
OH
OH
Br
O
EtOCOCl/Py
Ph
P
3
OBu-t
OBu-t
OBu-t
NaBH /MeOH
BrCCl3
4
BocNH
BocNH
BocNH
O
O
O
(S)-I
(S)-II
(S)-III
P(O)(OEt)2
P(O)(OEt)2
(
EtO) POSiMe
2 3
HCl
o
OBu-t
HO
1
30 C
+
−
BocNH
NH ] Cl
3
O
O
(
S)-IV
(S)-V
777

7
78
O.O. KOLODYAZHNAYA et al.
in 15 ml of methylene chloride at –70°C was added a
solution of bromotrichloromethane (6.0 g, 0.03 mol) in
51.50; H 8.68; P 7.95. C H NO P. Calculated, %: C
17 34 7
51.64; H 8.67; P 7.83.
3
.2 ml of methylene chloride and a solution of tri-
(
S)-2-Amino-4-(diethylphosphono)butanoic acid
phenylphosphine (8.1 g, 0.031 mol) in 5 ml of
methylene chloride. The mixture was stirred for 2 h at
room temperature. The solvent was evaporated in a
vacuum. To the residue diethyl ether and hexane were
added. The precipitated triphenylphosphine oxide was
filtered off. The filtrate was evaporated in a vacuum.
The residue was distilled in a vacuum. Yield 80%,
colorless oil, bp 140°C (0.08 mm Hg), [α] –11 (с 1,
CHCl ). Н NMR spectrum, (СDCl ), δ , ppm, (J, Hz):
1
hydrochloride (V). Phosphonate IV (3.95 g, 0.01 mol)
was treated with 10 ml of hydrochloric acid for 1 h at
weak heating. The solvent was removed under
vacuum, and the residue was washed with diethyl ether
and dried under vacuum to give a solid product. Yield
0%. Н NMR spectrum, (D O), δ , ppm, (J, Hz): 1.25
t (6H, CH , J 7), 1.90–2.10 m (4H, CH ), 3.87 m
1H, CHN), 4.00 m (4H, CH O), 6.50 br.s (3H, NH ).
С NMR spectrum, (D O), δ , ppm, (J, Hz): 16.41,
6.47 (CH ), 21.00 d (PC, J 145), 25.00 d (CH , J 5),
1
5
2
Н
2
0
3
НН
2
D
(
1
2
3
3
3
Н
13
2
С
.41 s (9H, СH С), 1.43 s (9H, СH С), 2.35 and 2.15
3 3
1
5
3 CP 2
m (2H, CH ), 3.40 m (2H, CH Br), 4.30 m (1H, CHN),
31
2
2
0.50 d (CN, J 5) 61.20 d (POC, J 6), 173 (C=O). Р
NMR spectrum, (СDCl ): δ 31.00 ppm [4]. Found P,
: 10.99. C H ClNO P. Calculated P, %: 11.24.
13
5.00 br.d (1H, NH, JНН 7.0). С NMR spectrum,
3
P
(
СDCl ), δ , ppm: 28.09 (CH C), 28.50 (CH C), 30.81
3
С
3
3
%
8 19 5
(
CH Br), 34.73 (CH ), 56.67 (CN), 79.61 (CCH ),
2 2 3
8
%
2.68 (CCH ), 153.14 (С=О), 175.58 (С=О). Found,
NMR spectra were taken on a Bruker 170 Avance
3
1
: C 46.25; H 7.18; Br 24.02. C H BrNO .
(500 MHz) instrument relative to internal TMS ( H
13
24
4
1
3
31
Calculated, %: C 46.16; H 7.15; Br 23.62.
and C) and 85% H PO in D O ( P).
3 4 2
tert-Butyl (S)-2-[(tert-butoxycarbonyl)amino]-4-
diethoxyphosphoryl)butanoate (IV). Compound III
3.4 g, 0.01 mol) was heated with an excess
ACKNOWLEDGMENTS
(
(
This work was financially supported by the State
Foundation for Basic Research of Ukraine and the
Russian Foundation for Basic Research (project no.
F40.3/034).
trimethylsilyldiethylphosphite (8.4 g, 0.04 mol) at
00–120°C for several hours, monitoring the reaction
1
progress by NMR. Then the volatiles were removed in
a vacuum, the residue was purified by the column
2
0
REFERENCES
chromatography. Yield 60%, [α] –10.0 (c 1, CHCl ).
D
3
1
Н NMR spectrum, (СDCl ), δ , ppm, (J, Hz): 1.26 t
3
Н
1
.
Ramalingam, K. and Woodard, R.W., J. Org. Chem.
1988, vol. 53, no. 9, p. 1900.
(
6H, CH , J 7), 1.43 s (9H, CH C), 1.41 s (9H,
3 НН 3
CH C), 2.15–2.16 m (CH ), 2.32 m (CH ), 4.00 m (4H,
3
2
2
2. Yang, C.C. and Merrifield, R.B., J. Org. Chem., 1976,
1
3
OCH ), 4.42 m (1H, CHN), 5.68 br.s (1H, NH).
С
2
vol. 41, no. 6, p. 1032.
NMR spectrum, (СDCl ), δ , ppm, (J, Hz): 15.80
3
С
3. Foss Jr, F.W., Snyder, A.H., Davis, M.D., Rouse, M.,
Okusa, M.D., Lynch, K.R., and Macdonald, T.L., Bioorg.
Med. Chem., 2007, vol. 15, no. 2, p. 663.
(
CH CH ), 23.00 d (PC, J 145), 27.24 (PCC), 28.10
3 2 CP
(
ССH ), 28.50 (CCH ), 55.55 (CN), 61.25 (POC),
3 3
7
9.80, 82.70 (CH C), 156.03 (C=O), 174.50 (C=O).
4. Valerio, R.M., Alewood, P.E., and Johns, R.B., Synthesis,
3
3
1
Р NMR spectrum, (СDCl ): δ 32 ppm. Found, %: C
1988, no. 10, p. 786.
3
P
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