Phosphorus-containing aminocarboxylic acids: XIV. Synthesis of analogs of α-substituted glutamic acid

Article abstract of DOI:10.1007/s11176-005-0371-2

Addition of Schiff bases derived from amino acid esters to appropriate vinylphosphoryl compounds, followed by hydrolysis of the adducts formed gives a series of new α-alkylated phosphorus-containing α-aminocarboxylic acids, viz. phosphonic and phosphinic

Full text of DOI:10.1007/s11176-005-0371-2

Russian Journal of General Chemistry, Vol. 75, No. 7, 2005, pp. 1077 1084. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 7, 2005,
pp. 1140 1147.
Original Russian Text Copyright
2005 by Saratovskikh, Ragulin.
Phosphorus-containing Aminocarboxylic Acids:
XIV.1 Synthesis of Analogs of -Substituted Glutamic Acid
I. V. Saratovskikh and V. V. Ragulin
Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
Received June 4, 2003
Abstract Addition of Schiff bases derived from amino acid esters to appropriate vinylphosphoryl com-
pounds, followed by hydrolysis of the adducts formed gives a series of new -alkylated phosphorus-containing
-aminocarboxylic acids, viz. phosphonic and phosphinic analogs of glutamic acid.
Synthesis of phosphoryl analogs of natural amino
acids and peptides represents a prospective route to
potential physiologically active compounds [2 7].
Substitution of the carbonyl group in a natural amino
acid molecule by phosphoryl leads to aminophos-
phonic acids [2 4]. The key step in constructing
aminophosphinic acid analogs of peptides involves
substitution of the amide fragment C(O)NH by me-
thylenephosphoryl CH2P(O) [5 7].
molecule I is the most studied approach to construct-
ing new phosphorus-containing aminocarboxylic acids
[8 20]. Over the past years, the physiologic activity
of -substituted phosphorus-containing -aminocar-
boxylic acids, specifically -methyl-4-phosphono-
phenylglycine and 2-amino-2-methyl-4-phosphono-
butyric acids, as selective antagonists of metabotropic
glutamate receptors has been reported [21 23]. In this
respect, modification of the aminocarboxylic fragment
in molecule I can open up a prospective route in
searching for new agonists and antagonists of meta-
botropic glutamate receptors, as well as potential in-
hibitors of natural enzymes in the series of phos-
phorus-containing aminocarboxylic acids [24 26].
Phosphorus-containing aminocarboxylic acids of
general formula I possess diverse biological activity.
Phosphonic analogs (X = Y = OH), such as 2-amino-4-
phosphonobutyric acid (n = 2), and glutamic acid
gomologs, such as 2-amino-5-phosphonovaleric (n =
3) and 2-amino-7-phosphonoheptanoic (n = 5) acids,
are known as potent neuroprotectors [2 4].
This work is devoted to the synthesis of new
-
phosphorylated -alkyl- -aminocarboxylic acids II
(Scheme 1) along Scheme 2. Phosphonic glutamic
acid analogs IIb IId are homologs of 2-amino-2-
methyl-4-phosphonobutyric acid (IIa), and, therefore,
they offer interest as potential antagonists and
agonists of metabotropic glutamate receptors [21 25].
Aminophosphonic acids with a hydroxycarbonylethyl
fragment [IIf IIh, X = OH, Y = CH2CH2C(O)OH]
are phosphinic analogs of -substituted -glutamyl-
glycines [6, 7]. In this case, the role of pseudoglycine
belongs to the propionic fragment, while the fragment
of the phosphoryl analog of glutamic acid bears an
-substituent (Z). Phosphinic analogs of glutamic acid
(IIi and IIj) can be considered as -substituted lipo-
phylic analogs of the herbicide glufosinate (phosphino-
thricin) [15 17].
O
O
OH
NH2
X P (CH2)n
Y
I
The modification of the carbon chain in canonical
molecule I, including the synthesis of unsaturated
analogs [8, 9] and the introduction of aromatic [10,
11], pyperidine [12], and piperazine [13, 14] frag-
ments, gave compounds with a high antispasmodic
activity. Phosphinothricin, 2-amino-4-(methylphos-
phino)butyric acid (X = Me, Y = OH), the best phos-
phinic analog of glutamic acid, is glutaminsynthetase
inhibitor and a highly active low-toxicity herbicide
[15 17]. Glutamic acid analogs and homologs bearing
a phosphine oxide fragment have also been described
[18]. Modification of the phosphorus-containing
fragment and hydrocarbon chain in canonical
Schiff bases derived from amino acid esters (com-
pounds III) satisfactorily add to diethyl vinylphos-
phonate (IVa), ethyl [2-(ethoxycarbonyl)ethyl](vinyl)-
phosphinate (IVb), and ethyl (2-phenylethyl)(ethyl)-
phosphinate (IVc) in THF in the presence of potas-
sium and cesium carbonates (Scheme 2). The use of
1
For communication XIII, see [1].
1070-3632/05/7507-1077 2005 Pleiades Publishing, Inc.

1078
SARATOVSKIKH, RAGULIN
Scheme 1.
O
O
O
O
O
HO P
Z
Z
P
O
Z
P
O
Ph
OH
OH
OH
OH
OH
NH2
HO
NH2
OH
NH2
IIa IId
IIf IIh
IIi, IIj
[27] vinylphosphoryl compounds as alkylating agents
instead of bromoethylphosphonate and bromoethyl-
phosphine oxide results in slightly higher yields of the
target amino acids.
Scheme 2.
O
A P
B
(A)(B)P(O)CH=CH2
H
O
O
Z
IVa IVc
N
Ph
Z
OAlk
OAlk
N
III
V
Ph
O
A P
B
O
O
Z
O
X P
B
Z
2 N HCl
OAlk
NH2
OH
NH2
II
VI
The resulting alkylated Schiff bases, -alkyl- -
benzylideneamino- -(dialkylphosphoryl)alkylcarb-
oxylic esters V, could be easily converted in situ to
desired amino acids II by means of acid hydrolysis
followed by cation-exchange chromatography. The
mild acid hydrolysis of esters V at room temperature
results in formation of (dialkylphosphoryl)alkylcar-
boxylic esters VI. These esters can be isolated pure
as, for example, with aminophosphine oxide VIa or
aminophosphinic acid VIf.
plates (layer thickness 0.2 mm), and Kavalier Alufol
plates (neutral alumina on an aluminum foil, eluent
5:1:1
1-butanol acetic
acid water;
develop-
ment under UV light after treatment with iodine vapor
or with ninhydrin followed by heating (for amino
acids). Column chromatography was perfomed on
Dowex 50WX8-200 (Lancaster) or Diasorb-Sulfo
(BioKhimMak) cationites. Diethyl vinylphosphinate
[28] and diphenyl(vinyl)phosphine oxide [31] were
prepared by published procedures. Ethyl [2-(ethoxy-
carbonyl)ethyl](vinyl)phosphinate (IVb) [32] and
ethyl (2-phenylethyl)(vinyl)phosphinate (IVc) [29]
were prepared by a synthetic procedure we developed
previously for vinylphophoryl compounds. The pro-
ducts were purified on Celite filter aid (Lancaster) and
a mixture of silica gel L100/160 (Chemapol) with
Brockmann neutral alumina (10 20 weight %). Schiff
bases III were prepared by the reaction of methyl or
ethyl esters of corresponding amino acid hydrochlo-
rides with benzaldehyde, according to the procedures
in [33 35].
The proposed synthetic route allows modification
of the canonical structure of phosphorylalkyl- -
aminocarboxylic acids I [2] using a broad range of
amino acid ester Schiff bases II and diverse vinyl- and
-haloalkylphosphoryl compounds [27 30].
EXPERIMENTAL
1
The H and 31P NMR spectra were recorded on a
Bruker DPX 200 Fourier spectrometer with TMS as
internal and 85% H3PO4 as external references. The
melting points were measured on a Boetius RNMK
stage or in an open capillary tube. Thin-layer chro-
matography was performed on Silufol plates, eluent
5:1:1 chloroform toluene acetone, Merck UV254
2-Amino-2-methyl-4-phosphonobutyric acid
(IIa, X = Y = OH, Z = Me). A mixture of 11.3 g of
diethyl vinylphosphonate, 10.6 g of ethyl 2-(benzyl-
ideneamino)propanoate (prepared from alanine ethyl
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PHOSPHORUS-CONTAINING AMINOCARBOXYLIC ACIDS: XIV.
1079
ester hydrochloride and benzaldehyde), and 17.0 g of
potassium carbonate was stirred in 40 ml of boiling
THF with 1.0 g of tetrabutylammonium bromide until
the Schiff base (Rf 0.8) disappeared from the chro-
matogram of the reaction mixture (about 15 h), the
process was monitored by TLC in 5:1:1 chloroform
acetone toluene. After cooling, inorganic salts pre-
cipitated and were filtered off, the filtrate was eva-
porated, the residue was dissolved in 50 ml of chloro-
form and washed with water (2 10 ml) until neutral
washings. The organic phase was evaporated, and the
oily residue was dissolved in 70 ml of 8N HCl. The
solution was refluxed for 13 15 h, cooled, washed
with ether (2 20 ml), and evaporated in a vacuum.
The residue was chromatographed on a cationite (H+,
eluent H2O 0.5 N HCl), fractions with a positive
ninhidrin reaction were concentrated and treated with
excess (ca. 4 ml) of propylene oxide in aqueous
ethanol (1:4). Yield 5.7 g (55.4% per taken base).
31P NMR spectrum (D2O): P 24.5 ppm. Found, %:
C 30.46, 30.73; H 6.04, 5.90; N 6.87, 6.93. C5H12
NO5P. Calculated, %: C 30.46; H 6.14; N 7.11.
13.35, 13.43. C7H16NO5P. Calculated, % : C 37.34;
H 7.16; P 13.75.
2-Amino-2-phenyl-4-phosphonobutyric acid
(IIc, X = Y = OH, Z = Ph). To a mixture of 4.1 g di-
ethyl vinylphosphonate and 8 g of potassium carbo-
nate in 10 ml of THF, 4 g of methyl 2-(benzylidene-
amino)phenylacetate (prepared from phenylglycin
methyl ether hydrochloride and benzaldehyde) and
0.5 g tetrabutylammonium bromide in 10 ml of THF
were added. The reaction mixture was stirred in THF
under reflux for 15 h, 3.0 g of cesium carbonate was
added, and stirring was continued for 10 h (reaction
progress was monitored by TLC and 31P NMR). After
cooling, the reaction was cooled, filtered, and treated
as described for IIa. Amino acid IIc was recrystal-
lized from 5:1 ethanol ether and recrystallized from
aqueous ethanol (1:5). Yield 1.5 g (36.6% per taken
Schiff base), mp 247 249 C. 1H NMR spectrum
(D2O + DCl), , ppm: 1.47 m (2H, CH2), 2.25 m (2H,
CH2), 7.15 m (5H, Ph). 31P NMR spectrum (D2O +
DCl), P, ppm: 28.1. Found, %: C 44.36, 44.54; H
5.24, 5.48; N 11.14, 11.37. C10H14NO5P 0.5H2O.
Calculated, % : C 44.78; H 5.64; P 11.55.
2-Amino-2-isopropyl-4-phosphonobutyric acid
(IIb, X = Y = OH, Z = i-Pr). A mixture of 4.0 g of
diethyl vinylphosphonate, 4.4 g of methyl 2-(benzyl-
idenamino)-3-methylbutyrate (prepared from valine
methyl ester hydrochloride and benzaldehyde), 7.0 g
of potassium carbonate, and 1 g of tetrabutylammo-
nium bromide was stirred in 40 ml of THF under re-
flux for 15 h, after which 3.0 g of cesium carbonate
was added, and stirring was continued for 10 15 h.
The reaction mixture was cooled and filtered (reaction
progress was monitored by TLC and 31P NMR). The
filtrate was evaporated in a vacuum, and the residue
was dissolved in 50 ml of chloroform, washed with
water (3 10 ml, pH 7), and evaporated. The residue
was treated with 30 ml of 8 N HCl, and the mixture
was refluxed for 15 h. The reaction mixture was
cooled and extracted with ether (3 20 ml). The
aqueous layer was evaporated in a vacuum. The re-
sidue was chromatographed on a strongly acidic
cationite (H+), the eluent acidity was gradually in-
creased (eluent H2O and 1 1.5 N HCl). Fractions
showing a positive ninhydrin reaction was evaporated,
dissolved in aqueous ethanol, treated with 3.0 ml of
propylene oxide, and evaporated in a vacuum. The
oily residue was additionally purified by chromato-
graphy on a cationite (H+) (eluent H2O) and recrystal-
lization from aqueous acetone (1:3). Yield 2.0 g
2-Amino-2-benzyl-4-phosphonobutyric acid
(IId, X = Y = OH, Z = CH2Ph). A mixture of 4.6 g
of diethyl vinylphosphonate, 6.2 g of methyl
2-(benzylideneamino)-3-phenylpropanoate (prepared
from phenylalanine methyl ester hydrochloride and
benzaldehyde), 15.1 g of cesium carbonate, and 0.5 g
of tetrabutylammonium bromide was stirred in 20 ml
of THF under reflux for 18 20 h. After the reaction
had been complete (reaction progess was followed by
TLC and 31P NMR), the reaction mixture was cooled
and filtered. The filtrate was evaporated in a vacuum,
the residue was dissolved in 50 ml of chloroform,
washed with water (3 10 ml), and evaporated. The
oily residue was treated with 30 ml of 8 N HCl, and
the mixture was refluxed for 15 h. After cooling, the
mixture was extracted with benzene (2 20 ml) and
ether (2 20 ml), and the acidic water layer was eva-
porated in a vacuum. The residue was dissolved in
aqueous ethanol (1:4) and treated with 3.0 ml of
epichlorohydrin. The partially crystalline precipitate
comprising primarily the free amino acid (1H and 31P
NMR data) was chromatographed on Diasorb-Sulfo
(H+) (eluent water). Fractions showing a positive
ninhydrin reaction were evaporated and recrystallized
from 5:1 ethanol ether and additionally recrystallized
from aqueous ethanol (1:5). Yield 2.8 g (44.3% per
1
1
(43.9% per taken base), mp 231 234 C. H NMR
taken Schiff base, mp 264 267 C. H NMR spectrum
spectrum (D2O), , ppm: 0.93 d (3H, CH3, J 6 Hz),
0.96 d (3H, CH3, J 6 Hz), 1.56 m (2H, CH2), 2.10 m
(D2O + DCl), , ppm: 1.35 m (2H, CH2), 1.75 m (2H,
CH2), 2.62 d (1H, CH2Ph), 2.90 d (1H, CH2Ph),
6.73 m (2H, Ph) and 6.87 m (3H, Ph). 31P NMR spec-
(3H, CH2 + CH). 31P NMR spectrum (D2O):
P
24.0 ppm. Found, %: C 37.05, 37.24; H 7.34, 7.33; P
trum (D2O + DCl):
28.7 ppm. Found, %: C 48.60,
P
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

1080
SARATOVSKIKH, RAGULIN
48.30; H 6.23, 6.33; P 11.23, 11.54. C11H16NO5P.
Calculated, % : C 48.36; H 5.90; P 11.34.
of tetrabutylammonium bromide was stirred in 20 ml
of THF under reflux for 15 h, after which 2 g of
cesium carbonate was added, and stirring was con-
tinued until the Schiff base disappeared disappeared
from the chromatogram of the reaction mixture (Rf
0.8) (reaction progress was followed by TLC, eluent
5:1:1 chloroform acetone toluene, and by 31P NMR).
After cooling, the reaction mixture was filtered, the
filtrate was evaporated in a vacuum, and the residue
was partitioned between 30 ml of chloroform and
30 ml of water. The aqueous layer was extracted with
chloroform (3 20 ml), and the combined dark brown
extract was treated by two different procedures.
2-Amino-2-methyl-4-(diphenylphosporyl)butyric
acid (IIe, X = Y = Ph, Z = Me). A mixture of 7.8 g
of diphenyl(vinyl)phosphine oxide, 11.0 g of potas-
sium carbonate, 6.5 g of ethyl 2-(benzylideneamino)-
propanoate (prepared from alanine ethyl ester hydro-
chloride and benzaldehyde), and 1.5 g of tetrabutyl-
ammonium bromide in 45 ml of THF was stirred
under reflux for 12 h (reaction progress was followed
by TLC and 31P NMR), cooled, and filtered. The
filtrate was evaporated in a vacuum and partitioned
between 50 ml of chloroform and 50 ml of water. The
aqueous layer was neutralized to pH 7 and extracted
with chloroform (2 20 ml). The combined organic
extract was evaporated, and the residue was dissolved
in 30 ml of diethyl ether, 100 ml of 2 N HCl was
added, and the resulting mixture was vigorously
stirred for 4 5 h. The acidic aqueous layer was
washed with ether (2 20 ml) and evaporated. The
residue was dissolved in 20 ml of ethanol and treated
with 5 ml of propylene oxide. The reaction mixture
was stirred at 40 50 C for 10 min and evaporated.
The residue was crystallized in succession from ether
and 1:1 ethanol ether to obtain 7.9 g (84.9% per
taken Schiff base) of ethyl 2-amino-2-methyl-4-(di-
phenylphosphoryl)butyrate (VIe, A = B = Ph, Z =
a. The extract was concentrated and passed through
a bed of Celite (eluent chloroform), the eluate was
evaporated in a vacuum, the light yellow oily residue
( 8 g) was treated with 35 ml of 8 N HCl, and the
mixture was refluxed for 16 h. After cooling, the
reaction mixture was washed with ether (2 10 ml)
and benzene (2 10 ml), the acidic aqueous phase was
evaporated in a vacuum and then again evaporated
with water. The residue was dissolved in 16 ml of
aqueous ethanol (1:3), treated with 5 ml of propylene
oxide, and evaporated in a vacuum. The partially
crystalline residue comprising primarily the target free
aminophosphinic acid (by 1H and 31P NMR) was
mixed with water and evaporated and chromatogra-
phed on a weakly acidic cationite (H+), eluent water.
Fractions with a positive ninhydrin reaction were
evaporated in a vacuum, and the residue was crystal-
lized from 1:1 ethanol ether. Recrystallization from
aqueous ethanol gave 1.7 g (35.8% per taken Schiff
1
Me, Alk = Et), mp 137 139 C. H NMR spectrum
(D2O), , ppm: 1.10 t (3H, CH3), 1.44 s (3H, CH3),
2.04 m (2H, CH2), 2.40 m (2H, CH2), 4.13 q (2H,
CH2O), 7.50 m (10H, Ph). 31P NMR spectrum (D2O),
P, ppm: 40.2. Found, %: C 60.09, 59.46; H 7.19,
7.48; P 8.30, 8.54. C19H24NO3P 2H2O. Calculated,
%: C 59.83; H 7.40; P 8.12.
1
base) of compound IIf, mp 261 262 C (decomp.). H
NMR spectrum (D2O + DCl), , ppm: 1.10 s (3H,
CH3), 1.35 m (2H, CH2), 1.62 m (4H, 2CH2), 2.10 m
(2H, CH2). 31P NMR spectrum, P, ppm: 46.7 (D2O),
55.7 (D2O + DCl). Found, %: C 37.68, 37.52; H 6.62,
6.51; P 12.01, 11.83. C8H16NO6P. Calculated, %: C
37.95; H 6.37; P 12.23.
A mixture of 5.3 g of amino ester VIa and 20 ml
of 8 N HCl was refluxed for 10 h. After cooling, the
mixture was washed with ether (2 10 ml) and eva-
porated in a vacuum. The residue was dissolved in
aqueous ethanol (1:10) and treated with 5 ml of
propylene oxide to obtain 3.7 g (85% per ester VIa)
b. The extract was evaporated, and the residue was
partitioned between 20 ml of ether and 100 ml of 2 N
HCl. The two-phase system formed was vigorously
stirred for 5 h at room temperature. The acidic
aqueous layer was extracted with ether (2 20 ml) and
1
of compound IIe, mp 251 253 C. H NMR spectrum
(D2O + DCl), , ppm: 1.38 s (3H, CH3); 1.96 m (2H,
CH2); 2.44 m (2H, CH2); 7.42 m (10H, Ph). 31P NMR
spectrum (D2O + DCl):
40.3 ppm. Found, %: C
1
evaporated in a vacuum. According H and 31P NMR
61.97, 61.91; H 6.59, 6.57; PP 9.48, 9.44. C17H20NO3P
0.5H2O. Calculated, %: C 62.38; H 6.47; P 9.46.
data, the residue comprised primarily unreacted vinyl-
phosphinate IVb [
41 ppm (CDCl3)] [32] and
P
2-Amino-2-methyl-4-[[2-(hydroxycarbonyl)-
ethyl]phosphoryl]butyric acid (IIf, X = CH2CH2
C(O)OH, Y = OH, Z = Me). A mixture of 3.9 g of
ethyl 2-(benzylideneamino)propanoate (prepared from
alanine ethyl ester hydrochloride and benzaldehyde),
4.8 g of ethyl [2-(ethoxycarbonyl)ethyl](vinyl)phos-
phinate (IVb), 7.0 g of potassium carbonate, and 1.0 g
aminophosphinic acid containing one ester group (two
ester groups, C(O)OEt and POEt, obviously hydro-
lyzed during removal of the benzylidene protective
group). The residue was dissolved in 10 ml of
aqueous ethanol (1:4) and treated with a solution of
4 ml epichlorohydrin in 4 ml of ether. The partially
crystalline residue was crystallized from aqueous
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PHOSPHORUS-CONTAINING AMINOCARBOXYLIC ACIDS: XIV.
1081
acetone (1:2) to obtain 1.45 g (25.8% per taken
Schiff base) of ethyl 2-amino-2-methyl-4-[[(2-hydr-
oxycarbonyl)ethyl]phosphoryl]butyrate (VIf, X =
CH2CH2C(O)OH, Y = OH, Z = Me, Alk = Et), mp
alumina (80:20 w/w), eluent methylene chloride. The
eluate was evaporated in a vacuum, the light yellow
residue (ca. 6 g) was treated with 30 ml of 8 N HCl,
and the mixture was refluxed for 13 ½, cooled, and
washed with benzene (2 15 ml). The acidic aqueous
phase was evaporated in a vacuum and then evapo-
rated with water. The residue was chromatographed
1
154 157 C (decomp.). H NMR spectrum (CD3OD),
, ppm: 1.35 t (3H, CH3), 1.56 m (2H, CH2), 1.57 s
(3H, CH3), 1.81 m (2H, CH2), 2.16 m (2H, CH2),
2.55 m (2H, CH2), 4.33 q (CH2O). 31P NMR spectrum, on a strongly acidic cationite, the acidity of the eluent
P, ppm: 39.9 (CD3OD), 44.4 (D2O). Found, %: C
40.29, 40.43; H 7.55, 7.57; P 10.23, 10.03. C10H20
NO6P H2O. Calculated, %: C 40.14; H 7.41; P 10.35.
(water 1 N HCl) was therewith gradually raised. Frac-
tions showing a positive ninhydrin reaction were
evaporated in a vacuum, and the residue was dis-
solved in 16 ml of aqueous ethanol (1:3), treated with
3 ml of propylene oxide, and evaporated in a vacuum.
The partially crystalline wet residue of the free amino
acid was chromatographed again on a weakly acidic
cationite (eluent water), and fractions with a positive
ninhydrin reaction were collected. The eluate was
evaporated in a vacuum, and the residue was crystal-
lized from 1:1 ethanol ether. Recrystallization from
aqueous ethanol gave 1.4 g (33.3% per taken Schiff
1
The structural assessment is based on the H and 31P
NMR spectra (absence of the ester group at phos-
phorus and presence of only one ester group in the
molecule) and by analogy with amino ester VIe in
which the ester group in the aminocarboxylic frag-
ment remained intact.
A mixture of 1.2 g of amino ester VIf with 5 ml of
8N HCl was refluxed for 10 h. After cooling, it was
washed with ether (2 20 ml), the acidic aqueous
layer was evaporated in a vacuum and then evaporated
with water. The residue was dissolved in 12 ml of
aqueous ethanol (1:3) and treated with 2 ml of pro-
pylene oxide. The partially crystalline precipitate
comprising primarily the free amino acid was recrys-
tallized from aqueous ethanol to obtain 0.8 g of the
target amino acid (80% per amino ester VIf). The
total yield of acid IIf was 20.6% per parent Schiff
base. The spectral and physicochemical characteristics
of this compound were consistent with those of the
sample of amino acid IIf, obtained by procedure a.
1
base) of acid IIg, mp 241 244 C (decomp.). H NMR
spectrum (D2O), , ppm: 0.92 d (3H, CH3, J 7 Hz),
0.97 d (3H, CH3, J 7 Hz), 1.52 m (2H, CH2), 1.75 m
(2H, CH2), 1.96 m (2H, CH2), 2.18 m (1H, CH),
2.45 m (2H, CH2). 31P NMR spectrum (D2O): P 46.4
ppm. Found, %: C 42.65, 42.96; H 7.32, 7.11; P
10.71, 10.83. C10H20NO6P. Calculated, %: C 42.71;
H 7.17; P 11.01.
2-Amino-2-benzyl-4-[[2-(hydroxycarbonyl)-
ethyl]phosphoryl]butyric acid (IIh, X = CH2CH2
C(O)OH, Y = OH, Z = CH2Ph). A mixture of 5.4 g
2-Amino-4-[[2-(hydroxycarbonyl)ethyl]phos-
phoryl]-2-isopropylbutyric acid (IIg, X = CH2
CH2C(O)OH, Y = OH, Z = i-Pr). A mixture of 3.3 g
of methyl 2-(benzylideneamino)-3-methylbutyrate
(prepared from valine methyl ester hydrochloride and
benzaldehyde), 3.7 g of ethyl [2-(ethoxycarbonyl)-
ethyl](vinyl)phosphate (IVb), and 5.0 g of potassium
carbonate was stirred in 20 ml of THF under reflux in
the presence of 1.0 g of tetrabutylammonium bromide
for 15 h. Stirring was then continued, and a finely
devided cesium carbonate was intermittently added in
portions of 1 2 g until the Shiff base (Rf 0.7 0.8)
disappeared from the chromatogram of the reaction
mixture (reaction progress was followed by TLC,
eluent 7:1:1 chloroform acetone benzene, and by
31P NMR). After cooling, the reaction mixture was
poured into 30 ml of cold water with ice, and
the aqueous layer was neutralized to pH 7 and ex-
tracted with ethyl acetate (3 30 ml). The combined
organic extract was dried over sodium sulfate and
evaporated in a vacuum. The brown oily residue was
dissolved in a minimum of methylene chloride and
passed through a bed of a mixture of silica gel and
of
methyl
2-(benzylideneamino)-3-phenylpropa-
noate (prepared from phenylalanine methyl ester
hydrochloride and benzaldehyde), 6.2 g of ethyl
[2-(ethoxycarbonyl)ethyl](vinyl)phosphinate (IVb),
0.5 g of tetrabutylammonium bromide, and 14.6 g of
cesium carbonate was stirred in 30 ml of THF under
reflux until the Schiff base disappeared from the thin-
layer chromatogram of the reaction mixture (Rf 0.7,
7:1:1 chloroform acetone benzene). After cooling,
the reaction mixture was poured into 30 ml of cold
water with ice, the aqueous layer (ca. 80 ml) was
neutralized to pH 7 and extracted with ethyl acetate
(3 30 ml). The combined organic extract was dried
over sodium sulfate and evaporated in a vacuum. The
browm oily residue was dissolved in a minimum of
methylene chloride and passed through a bed of Celite
(eluent methylene chloride). The eluate was eva-
porated in a vacuum, the light yellow residue (ca. 6 g)
was treated 30 ml of 8 N HCl, and the mixture was
refluxed for 13 h, cooled, and washed with ether (2
10 ml) and benzene (2 10 ml). The acidic aqueous
phase was evaporated in a vacuum and then eva-
porated with water. The solid residue was dissolved
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

1082
SARATOVSKIKH, RAGULIN
1
in 16 ml of aqueous ethanol (1:3), treated with 5 ml
of propylene oxide, and evaporated in a vacuum. The
partially crystalline residue that, according to 1H and
31P NMR, comprised primarily the target aminophos-
phinic acid was repeatedly evaporated with water and
chromatographed on a weakly acidic cationite (eluent
water). Fractions with a positive ninhydrin reaction
were evaporated in a vacuum, and the residue was
crystallized from ethanol. Recrystallization from
aqueous ethanol (1:7) gave 2.8 g (42.0% per taken
Schiff base) of acid IIf, mp 231 234 C (decomp.).
1H NMR spectrum (D2O), , ppm: 1.40 m (2H, CH2),
1.60 m (2H, CH2), 1.80 m (2H, CH2), 2.10 m (2H,
CH2), 2.64 d (1H, CH2Ph), 2.92 d (1H, CH2Ph),
6.72 m (2H, Ph) and 6.83 m (3H, Ph). 31P NMR spec-
mp 240 243 C (decomp.). H NMR spectrum (D2O +
DCl), , ppm: 0.65 s (3H, CH3), 0.78 m (1H, CH2),
0.95 m (1H, CH2), 1.28 m (4H, 2CH2), 2.02 m (2H,
CH2), 7.02 m (5H, Ph). 31P NMR spectrum (D2O +
DCl): P 56.4 ppm. Found, %: C 54.79, 54.60; H 7.02,
6.87; P 10.71, 10.63. C13H20NO4P. Calculated, %:
C 54.73; H 7.07; P 10.86.
2-Amino-2-isopropyl-4-[(2-phenylethyl)phos-
phoryl]butyric acid (IIj, X = CH2CH2Ph, Y = OH,
Z = i-Pr). A mixture of 3.5 g of methyl 2-(benzyl-
ideneamino)-3-methylbutyrate (prepared from valine
methyl ester hydrochloride and benzaldehyde), 4.5 g
of ethyl (2-phenylethyl)vinylphosphinate (IVc), 11.5 g
of cesium carbonate, and 0.3 g of tetrabutylammo-
nium bromide was stirred in 15 ml of THF under
reflux until the Schiff base (Rf 0.8) disappeared from
the chromatogram of the reaction mixture (reaction
progress was followed by TLC, eluent 5:1:1 chloro-
form acetone toluene, and by 31P NMR). After
cooling, the reaction mixture was poured into 30 ml
of ice with water, and the aqueous layer was neutra-
lized to pH 7 and extracted with ethyl acetate (3
30 ml). The combined organic extract was dried over
magnesium sulfate and evaporated in a vacuum. The
brown oily residue was dissolved in a minimum of
chloroform and passed through a bed of Celite (eluent
chloroform). The eluate was evaporated in a vacuum,
the light yellow residue (ca. 9 g) was treated with
45 ml of 8 N HCl, and the mixture was refluxed for
15 h, cooled, and washed with benzene (2 15 ml).
The acidic aqueous phase was evaporated in a vacuum
and then evaporated with water. The residue was dis-
solved in 25 ml of aqueous ethanol (1:5), treated with
3 ml of propylene oxide, and evaporated in a vacuum.
The partially crystalline residue which, according to
1H and 31P NMR, comprised primarily the target free
aminophosphinic acid was repeatedly evaporated with
water and chromatographed on a cationite (H+) (eluent
0.5N HCl). Fractions with a positive ninhydrin reac-
tion were collected and evaporated in a vacuum, and
the residue was crystallized from 1:1 acetone ether.
Recrystallization from 5 N HCl acetone (9:1) gave
2.6 g (52.0%) of acid IIj hydrochloride, mp 225
trum (D2O + DCl):
55.4 ppm. Found, %: C 45.17,
P
45.05; H 6.32, 6.54; P 8.01, 7.93. C14H20NO6P
2.5H2O. Calculated, %: C 44.92; H 6.73; P 8.27.
2-Amino-2-methyl-4-[(2-phenylethyl)phos-
phoryl]butyric acid (IIi, X = CH2CH2Ph, Y = OH,
Z = Me). A mixture 2.2 of g of ethyl 2-(benzylidene-
amino)propanoate (prepared from alanine ethyl ester
hydrochloride and benzaldehyde), 2.6 g of ethyl (2-
phenylethyl)(vinyl)phosphinate (IVc), 3.3 g of potas-
sium carbonate, 1.5 g of cesium carbonate, and 0.3 g
of tetrabutylammonium bromide was stirred in 20 ml
of THF under reflux until the Schiff base (Rf 0.8)
disappeared from the chromatogram of the reaction
mixture (reaction progress was followed by TLC,
eluent 5:1:1 chloroform acetone toluene, and by
31P NMR). After cooling, the reaction mixture was
filtered, the filtrate was evaporated in a vacuum, the
residue was partitioned between 30 ml of chloroform
and 30 ml of water, and the aqueous layer was ex-
tracted with chloroform (3 20 ml). The combined
dark brown organic extract was concentrated and
passed through a bed of a mixture of silica gel and
alumina (90:10 w/w), eluent chloroform. The eluate
was evaporated in a vacuum, the light brown residue
(ca. 5 g) was treated with 25 ml of 8 N HCl, and the
mixture was refluxed for 13 ½, cooled, and washed
with ether (2 10 ml) and benzene (2 10 ml). The
acidic aqueous phase was evaporated in a vacuum and
then evaporated with water. The residue was dissolved
in 15 ml of aqueous ethanol (1:3), treated with 3 ml
of propylene oxide, and evaporated in a vacuum. The
1
227 C (decomp.). H NMR spectrum (D2O + DCl), ,
1
partially crystalline residue that, according to H and
31P NMR, comprised primarily the target aminophos-
phinic acid was repeatedly evaporated with water and
chromatographed on a weakly acidic cationite (eluent
water). Fractions with a positive ninhydrin reaction
were evaporated in a vacuum, and the residue was
crystallized from 1:1 ethanol ether. Recrystallization
from aqueous acetone gave 1.6 g (53.3%) of acid IIi,
ppm: 0.15 d (3H, CH3, J 7 Hz), 0.20 d (3H, CH3, J
7 Hz), 0.75 m (1H, CH2), 1.02 m (1H, CH2), 1.30 m
(5H, 2CH2 + CH), 1.98 m (CH2), 6.45 m (5H, Ph).
31P NMR spectrum (D2O + DCl): P 57.1 ppm. Found,
%: C 51.44, 51.36; H 7.59, 7.57; P 8.71, 8.63.
C15H24NO4P HCl. Calculated, %: C 51.51; H 7.20;
P 8.85.
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PHOSPHORUS-CONTAINING AMINOCARBOXYLIC ACIDS: XIV.
1083
ACKNOWLEDGMENTS
14. Bigge, C.F., Hays, S.J., Novak, P.M., Drummond, J.T.,
Johnson, G., and Bobovski, T.P., Tetrahedron Lett.,
1989, vol. 30, no. 39, p. 5193.
This work was supported by the Research Divi-
sions of Nippon Chemical Industrial Co., Ltd. and
Iskra Industry Co., Ltd. (agreement no. 98-99/add.
no. 2).
15. Weissermel, K., Kleiner, H.J., Finke, M., and
Felcht, U.H., Angew. Chem., Int. Ed. Engl., 1981,
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The authors are grateful to G.D. Shishko for ele-
mental analysis of newly prepared compounds at the
Institute of Physiologicaly Active Substances, Russian
Academy of Sciences.
16. Logusch, E.W., Walker, D.M., McDonald, J.F.,
Leo, G.C., and Franz, J.E., J. Org. Chem., 1988,
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17. Colanduoni, J.A. and Villafranca, J., J. Bioorg. Chem.,
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