Synthesis of phosphinic acids on the basis of hypophosphites: VI. General methods for synthesis of pseudo-γ-glutamylpeptides

Article abstract of DOI:10.1134/S1070363207050076

A general method for synthesis of 2-substituted pseudo-γ- glutamylpeptides, namely, [2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl) propyl]phosphinic acids I which are phosphinic acid analogs of γ-glutamylpeptides. Bis(trimethylsilyl) hypophosphite (IV) formed from ammonium hypophosphite (II) in situ was added to the respective α-substituted acrylate to form bis(trimethylsilyl) [2-R-2-(alkoxycarbonyl) ethyl]-phosphonites V. Treatment of compounds V in situ with excess dibromoethane followed by alcoholysis gave [2-R-2-(alkoxycarbonyl)ethyl](2- bromoethyl)phosphinic acids VI which without isolation were treated with excess triethyl orthoformate. The simultanious esterification and dehydrobromination led to [2-R-2-(alkoxy-carbonyl)ethyl](vinyl)phosphinates III which were isolated and characterized. The Michael addition of diethyl acetamidomalonate to vinylphosphinates III followed by acid hydrolysis of phosphinates VII without their isolation resulted in formation of target [2-R-2-(hydroxycarbonyl)ethyl] [3-amino-3-(hydroxycarbonyl)]proly]phosphinic acids-pseudo-γ- glutamylpeptides I. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070363207050076

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 5, pp. 861 865.
Pleiades Publishing, Ltd., 2007.
Original Russian Text V.V. Ragulin, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 5, pp. 763 768.
Synthesis of Phosphinic Acids on the Basis of Hypophosphites:
VI.1 General Method for Synthesis of Pseudo- -glutamylpeptides
V. V. Ragulin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi pr. 1, Chernogolovka, Moscow oblast, 142432 Russia
Received December 12, 2006
Abstract A general method for synthesis of 2-substituted pseudo- -glutamylpeptides, namely, [2-(hydroxy-
carbonyl)ethyl][3-amino-3-(hydroxycarbonyl)propyl]phosphinic acids I which are phosphinic acid analogs of
-glutamylpeptides. Bis(trimethylsilyl) hypophosphite (IV) formed from ammonium hypophosphite (II) in situ
was added to the respective -substituted acrylate to form bis(trimethylsilyl) [2-R-2-(alkoxycarbonyl)ethyl]-
phosphonites V. Treatment of compounds V in situ with excess dibromoethane followed by alcoholysis gave
[2-R-2-(alkoxycarbonyl)ethyl](2-bromoethyl)phosphinic acids VI which without isolation were treated with
excess triethyl orthoformate. The simultanious esterification and dehydrobromination led to [2-R-2-(alkoxy-
carbonyl)ethyl](vinyl)phosphinates III which were isolated and characterized. The Michael addition of diethyl
acetamidomalonate to vinylphosphinates III followed by acid hydrolysis of phosphinates VII without their
isolation resulted in formation of target [2-R-2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)]pro-
yl]phosphinic acids pseudo- -glutamylpeptides I.
DOI: 10.1134/S1070363207050076
Glutamic acid belongs to excitation mediators of
the mammalian and human nervous system and plays
a significant role in the development of various
normal and pathogenic processes.
for at least two distinct classes of hydrolytic enzymes,
Zn-metalloproteinases and aspartic acid proteinases [2].
The development of general convenient methods
for synthesis of pseudo- -glutamylpeptides A which
are phosphinic analogs of peptides B is a perspective
synthetic approach to physiologically active com-
pounds, specifically inhibitors of corresponding
enzymes involved in biosynthesis of various gluta-
mylpeptide derivatives [3 5].
Phosphinic acid peptides are peptide analogs (pep-
tide isosters) with one peptide bond substituted by the
nonhydrolyzable nonhydrolysable phosphinate moiety
P(O)(OH) CH2 . This substitution represents a very
convenient mimic of a substrate in the transition state
X
O
R
NH
O
O
NH
NH
O
HO
O
R
O
O
NH
P
NH
O
HO
OH
Y
A
B
A known approach to building the molecules of
phosphinic analogs A of -glutamylpeptides B con-
sists in the synthesis of an N-protected aminoalkyl-
phosphonic component of the pseudopeptide, viz.
phosphonous amino acid analog X, followed by its
addition to an appropriate -substituted acrylate to
obtain pseudopeptide fragment Y [6]. In this case, the
1
For communication V, see [1].
861

862
RAGULIN
synthesis of the aminoalkylphosphoryl fragment
(pseudocarboxyl component of the peptide), resulting
in the formation of the first phosphorus carbon bond,
requires protection of both nitrogen and phosphorus
atoms and thus involves three- or more stages [7, 8].
The building of pseudopeptide fragment Y to form the
second phosphorus carbon bond is usually performed
by adding an aminoalkylphosphonous component in
the form of silyl ester to acrylates [8]. However, this
general procedure has some restrictions in the con-
struction of complicated aminoalkylphosphonous
building blocks. For example, attempted preparation
of phosphinic pseudo-Asp-Ala-dipeptide by adding
trimethylsilyl esters of the aminophosphonous analog
of aspartic acid to ethyl metacrylate failed [9].
In the present work we offer a general method of
synthesis of a number of pseudo- -glutamylpeptides I
(Scheme 1), as further development of the above
procedure. In this case, phosphinic acids are easier
and more conveniently prepared by a one-pot proce-
dure involving construction of both phosphorus
carbon bonds. We have developed this methodology
for preparing various functional substituted phos-
phinic acids from hypophosphoric acid salts, for
example, ammonium hypophosphite (II) [12 16].
The construction of pseudo- -glutamylpeptides by
this procedure is a two-step process (Scheme 1). The
first step is the one-pot formation of two phosphorus
carbon bonds to obtain the key intermediates of this
synthesis, vinylphosphinates III, which contain a
-substituted
-(alkoxycarbonyl)ethyl
radical,
In this connection an actual line of research is
developing alternative methods of pseudopeptide
design. Earlier we described a new method for syn-
thesis of pseudo- -glutamylglycine, in which the
target molecule is built in the inverse order, namely,
by adding hypophosphite to acrylate (serving as the
pseudoamino component of the peptide) to form the
first phosphorus carbon bond, followed by adding the
amino acid function to form the second phosphorus
carbon bond of the pseudopeptide [10, 11].
pseudopeptide fragment Y in target pseudopeptide A.
Bis(trimethylsilyl) hypophosphite (IV) readily
forming from ammonium hypophosphite (II) and
hexamethyldisilazane [17, 18] is added to -substi-
tuted acrylates, affording bis(trimethylsilyl) [2-R-2-
(alkoxycarbonyl)ethyl]phosphonites V (Scheme 1).
The latter react in situ with excess 1,2-dibromo-
ethane along the Arbuzov reaction scheme to form
silyl 2-bromoethylphosphinates whose subsequent
Scheme 1.
O
R
OSiMe3
OSiMe3
OSiMe3
2
1
AlkO
H
P
P
H2POONH4
OSiMe3
IV
II
V
3, 4
R
R
O
O
OEt
P
O
5
Br
P
AlkO
AlkO
O
OH
VI
III
6
O
C(O)OEt
R
O
O
O
P
NHAc
O
P
OH
NH2
7
AlkO
C(O)OEt
OH
R
HO
OEt
VII
I
(1) (Me3Si)2NH; (2) EtO(O)C C(R)=CH2; (3) BrCH2CH2Br ( Me3SiBr); (4) EtOH; (5) CH(OEt)3; (6) AcNHCH(COOEt)2;
(7) HCl, reflux; Dowex 50W(H+); R : Me (a), i-Bu (b), CH2C(O)OMe (c), CH2CH2C(O)OEt (d); R: Me (a), i-Bu (b),
CH2C(O)OH (c), CH2CH2C(O)OH (d).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

SYNTHESIS OF PHOSPHINIC ACIDS ON THE BASIS OF HYPOPHOSPHITES: VI.
863
alcoholysis gives 2-substituted [2-(alkoxycarbonyl)-
ethyl](2-bromoethyl)phosphinic acids VI.
100/600 m (Chemapol). Aminophosphinic acids
were purified by ion-exchange chromatography on
Dowex 50WX8-200 (H+) (Lancaster) and KUIKhT(H+)
(Russian Institute of Chemical Technology). Am-
monium hypophosphite was prepared by treatment of
50% aqueous hypophosphoric acid with excess
ammonia, followed by concentration and crystalliza-
tion of the salt from ethanol. Acetamidomalonic ester,
propylene oxide, triethyl orthoformate, dibromoethane,
and hexamethyldisilazane were purchased from Acros
Organics. All operations with bis(trimethylsilyl)
hypophosphite and trimethylsilyl phosphonites in situ
were carried out in under dry argon, all solvents were
carefully dried. Ethyl -isobutylacrylate was pur-
chased from Khimeks (St. Petersburg), and ethyl
acrylate, ethyl methacrylate, and dimethyl itaconate
were supplied by C-Reakor (Lancaster). Diethyl
-methyleneglutarate was prepared from ethyl acrylate
by the procedure described in [19].
Further on we applied the procedure for simultaneous
dehydrobromination and esterification of (2-bromo-
ethyl)phosphinic acids VI by treatment with excess
triethyl orthoformate [10, 11, 14]. Our earlier pro-
posed synthesis of [2-(alkoxycarbonyl)ethyl]- [11]
and (2-phenylethyl)phosphinates [15] was extended in
the present work to the synthesis of various [2-R-2-
(alkoxycarbonyl)ethyl](vinyl)phosphinates III, which
allows this method to be considered as a convenient
general synthetic route to various functionally
substituted vinylphosphinates.
[2-Alkyl-2-(alkoxycarbonyl)ethyl](vinyl)phosphinic
esters III were isolated as individual compounds,
characterized, and applied in the second step of the
synthesis for introducing the amino acid fragment to
form the phosphoryl analog of the glutamine pseudo-
peptide fragment. The Michael addition of acetamido-
malonic ester to vinylphosphinates III in THF in the
presence of potassium carbonate provides [2-(alkoxy-
carbonyl)-2-alkylethyl][3-(N-acetylamino)-3,3-bis-
2-Substituted [2-(alkoxycarbonyl)ethyl]vinyl-
phosphinic acids III (general procedure). A mixture
of 0.04 mol of ammonium hypophosphite (II) and
0.07 mol of hexamethyldisilazane was stirred for 2 h
at 120 130 C [17,18]. The reaction mixture was
cooled to room temperature, and -substituted acrylate
was then slowly added dropwise at a temperature
below 25 30 C, the mixture was stirred for 2 h at
40 C [10,11], and cooled to room temperature. 1,2-
Dibromoethane was then added in one portion, and
the resulting mixture was stirred under reflux for 4 h.
Excess 1,2-dibromoethane and bromotrimethyl were
removed in a vacuum, the residue was treated with
30 40 ml of ethanol, and the mixture was heated
under reflux for 15 30 min and filtered. The filtrate
was concentrated in a vacuum, diluted with a 1:1
toluene ethanol mixture, and evaporated. The oily
residue was refluxed with 0.20 mol of triethyl ortho-
formate with a Dean Stark trap for 2 3 h to remove
the ethanol and ethyl formate formed [14, 15]. Un-
reacted triethyl orthoformate was removed in a
vacuum, and the residue was distilled to obtain target
vinylphosphinate III as a mixture of diastereoisomers
( 1:1). Compounds IIIa IIId were used for further
conversions; analytically pure samples were obtained
by repeated distillation in a vacuum. Column chro-
matography on silica gel allowed to the yield of
vinylphosphinates IIIa and IIIb to be increased to
39% and 37%, respectively (calculated per ammonium
hypophosphite), eluent petroleum ether chloroform
(1:1), chloroform. Rf 0.4 0.5 (chloroform acetone,
8:1). The synthesized vinylphosphinates are light
yellow oily liquids.
(ethoxycarbonyl)propyl]phosphinates
VII.
Com-
pounds VII were converted into the target pseudo-
peptides without isolation by acid hydrolysis followed
by ion-exchange chromatography on a cationite.
[2-(Hydroxycarbonyl)ethyl][3-amino-3-(hydroxycar-
bonyl)propyl]phosphinic acids I (pseudo- -glutamyl-
peptides) were isolated in 50 71% yields and charac-
terized.
Thus, we proposed a genera two-stepl method for
synthesis of pseudo- -glutamylpeptides I, starting
from ammonium hypophosphite (II), involving
formation of key intermediate products, namely
-
substituted [ -(alkoxycarbonyl)ethyl](vinyl)phosphi-
nates III, in the first step and addition of the
amino acid function in the second step.
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were registered
on Bruker DPX-200 and Bruker CXP-300 Fourier
spectrometers with internal TMS and external H3PO4
references. The melting points were measured on a
Boetius-PHMK hot stage or in a block in an open
capillary. Thin-layer chromatography was performed
on Silufol (eluent chloroform acetone, 4 5:1), Alufol
(Kavalier) (neutral alumina on aluminum foil), and
Merck glass plates with silica gel UV-254 (layer
thickness 0.2 mm; eluent isobutanol acetic acid water,
5:1:1). Amino acid spots on the plates were de-
veloped by spraying with ninhydrin and heating at
100 C. Vinylphosphinates were isolated by column
Ethyl [2-(ethoxycarbonyl)propyl](vinyl)phos-
phinate (IIIa). Yield 3.3 g, (35% after four stages,
chromatography on Silpearl and Silica gel
L
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

864
RAGULIN
calculated per ammonium hypophosphite), bp 103
15 h). The reaction progress was monitored by TLC
(chloroform acetone, 4 5:1), Rf 0.5 0.6 (Silufol).
The reaction mixture was cooled and filtered, and the
filtrate was concentrated in a vacuum. The residue
was partitioned in 70 ml of chloroform and 30 ml of
water. The aqueous phase was neutralized with 6 N
HCl and extracted with chloroform (2 30 ml). The
combined organic extract was concentrated in a
vacuum, and the oily residue was adduct VIIa VIId
107 C (0.5 mm Hg), oil, n2D0 1.4510. H NMR spec-
1
trum (CDCl3), , ppm: 1.30 t (3H, CH3); 1.25 t (3H,
CH3), 1.23 m (3H, CH3), 1.80 m (1H, CH2P), 2.30 m
(1H, PCH2), 2.87 m [1H, CHC(O)], 4.00 m (4H,
CH2OC), 4.15 m (2H, CH2OP), 5.90 6.40 m (3H,
CH=CH2). 31P NMR spectrum (CDCl3), P, ppm:
41.4, 40.8. Found, %: C 51.14, 50.97; H 8.23, 8.11;
P 12.93, 13.03. C10H19O4P. Calculated, %: C 51.28,
H 8.18, P 13.22.
(
53 58 ppm) contaminated (5 10%) with starting
P
vinylphosphinate IIIa IIId (
40 42 ppm). The
P
Ethyl [2-(ethoxycarbonyl)-4-methylpentyl](vi-
nyl)phosphinate (IIIb). Yield 31%, bp 123 127 C
(0.8 mm Hg), n2D0 1.4500. 1H NMR spectrum (CDCl3),
, ppm: 0.87 0.92 2t (6H, 2CH3); 1.23 1.35 m (6H,
2CH3), 1.40 m (1H, CH), 1.58 m (2H, CH2CH),
1.82 m (1H, CH2P), 2.30 m (1H, CH2P), 2.81 m [1H,
CHC(O)], 3.98 m (2H, CH2OP), 4.12 m (2H, CH2OC),
6.08 6.30 m (3H, CH=CH2). 31P NMR spectrum
(CDCl3), P, ppm: 41.1, 40.7. Found, %: C 56.34,
56.23; H 9.13, 9.17; P 11.11, 11.03. C13H25O4P.
Calculated, %: C 56.51, H 9.12, P 11.21.
residue was heated under reflux with 80 ml of 6 N
HCl for 15 17 h and then cooled to room temperature
and washed with ether or toluene (3 30 ml) and
concentrated in a vacuum. The residue was purified on
a KU IKhT(H+) column (volume 200 ml), eluent
water and 0.5 0.7 N HCl. Fractions showing a posi-
tive ninhydrin reaction were evaporated, and the
residue was dissolved in 25 ml of aqueous ethanol and
treated with excess propylene oxide. Additional re-
crystallization from aqueous ethanol gave target
aminophosphinic acids Ia Id as mixtures of two dia-
stereoisomers. The spectral and analytical data show
that pseudopeptides Ia, Ic, and Id crystallize as etha-
nol solvates, and the ethanol content of the solvates is
independent of the composition of the ethanol water
mixture used for crysllization. Pseudopeptide Ib was
isolated in the free state. The yields of pseudopeptides
were 31 43% (calculated per acetamidomalonic ester).
Ethyl [2,3-bis(methoxycarbonyl)propyl](vinyl)-
phosphinate (IIIc). Yield 32%, bp 161 165 C
(0.7 mm Hg), n2D0 1.4620. 1H NMR spectrum (CDCl3),
, ppm: 1.31 t (3H, CH3); 2.02 m (1H, CH2P), 2.27 m
(1H, CH2P), 2.83 d [2H, CH2C(O)], 3.18 m [1H,
CHC(O)], 3.67 s (3H, CH3O), 3.72 s (3H, CH3O),
4.08 m (2H, CH2O), 6.05 6.45 m (3H, CH=CH2). 31
P
[2-(Hydroxycarbonyl)propyl][3-amino-3-(hyd-
roxycarbonyl)propyl]phosphinic acid (pseudo- -
glutamylalanine) (Ia). Yield 43%, mp 93 97 C
NMR spectrum (CDCl3), P, ppm: 40.8, 40.0. Found,
%: C 48.03, 47.94; H 7.05, 6.97; P 10.77, 10.73.
C11H19O6P. Calculated, %: C 47.48, H 6.88, P 11.13.
1
(frothing), 174 178 C (decomp.). H NMR spectrum
Ethyl [2,4-bis(ethoxycarbonyl)butyl](vinyl)-
phosphinate (IIId). Yield 34%, bp 168 171 C
(D2O, , ppm): 0.95 t (3/2H, CH3), 1.05 d (3H, CH3,
JHH 7.5 Hz), 1.52 m [3H, CH2P + CH (one of
CHCH2P)], 1.90 m [3H, CH2CHN + CH (one of
CHCH2P)], 2.60 m (1H, CHCH3), 3.43 q (2/2H,
CH2O), 3.78 t (1H, CHN). 31P NMR spectrum (D2O,
, ppm): 45.1, 43.5 ( 5%). 13C NMR spectrum (D2O),
, ppm: 17.08 s (CH3), 18.86 d (J 7.85 Hz, CH3CH),
23.58 s (CCH2CH), 25.84 d (J 92.15 Hz, PCH2CH2),
32.73 d (J 91.90 Hz, PCH2CH), 34.48 s (CHCH3),
54.23 d (J 15.59 Hz, CHN), 57.71 s (CH2O), 172.89 s
[C(O)CHN], 180.89 d (J 8.35 Hz, [C(O)CHCH3].
Found, %: C 38.93, 39.07; H 6.97, 7.05; N 4.95, 4.91;
P 11.03, 10.87. C8H16NO6P 0.5C2H5OH. Calculated,
%: C 39.13, H 6.93, N 5.07, P 11.21.
(0.5 mm Hg), n2D0 1.4550. 1H NMR spectrum (CDCl3),
, ppm: 1.23 t (3H, CH3); 1.28 t (3H, CH3); 1.32 t
(3H, CH3); 1.83 m (1H, CH2P), 1.98 m (2H, CH2CH),
2.21 m (1H, CH2P), 2.33 t [2H, CH2C(O)], 2.40 t
[2H, CH2C(O)], 2.82 m [1H, CHC(O)], 3.95 m (2H,
CH2O), 4.10 m (2H, CH2O), 6.00 6.45 m (3H, CH=
CH2). 31P NMR spectrum (CDCl3), P, ppm: 40.7,
40.1. Found, %: C 52.33, 52.24; H 7.95, 8.07; P 9.51,
9.43. C14H25O6P. Calculated, %: C 52.50, H 7.87, P
9.67.
2-Substituted [2-(hydroxycarbonyl)ethyl][3-
amino-3-(hydroxycarbonyl)propyl]phosphinic
acids (pseudo- -glutamylpeptides) (I). A mixture of
30 mmol of diethyl acetamidomalonate, 32 33 mmol
of vinylphosphinate IIIa IIId, and 70 mmol of
thoroughly ground potassium carbonate was stirred in
30 ml of absolute THF under reflux in the presence of
tetrabutylammonium bromide (0.3 0.5 g) until acet-
amidomalonic ester was consumed completely ( 12
[2-(Hydroxycarbonyl)-4-methylpentyl][3-amino-
3-(hydroxycarbonyl)propyl]phosphinic acid
(pseudo- -glutamylvaline) (Ib). Yield 41%, mp 201
1
204 C (decomp.). H NMR spectrum (D2O + DCl, ,
ppm): 0.50 d (3H, CH3, JHH 7.7 Hz), 0.54 d (3H,
CH3, JHH 7.7 Hz), 1.08 m [1H, CH(CH3)2], 1.23 m
[2H, CH2CH(CH3)2], 1.48 1.75 m (3H, CH2CH2P +
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

SYNTHESIS OF PHOSPHINIC ACIDS ON THE BASIS OF HYPOPHOSPHITES: VI.
865
one of CHCH2P), 1.75 1.98 m (3H, CH2CH2P + one
of CHCH2P), 2.42 m [1H, PCH2CHC(O)], 3.83 t (1H,
CHN). 31P NMR spectrum (D2O + DCl, , ppm): 53.6,
53.2 ( 7%). 13C NMR spectrum (D2O + DCl), , ppm:
21.37 s (CH3), 22.00 s (CH3), 22.35 d (J 2.82 Hz,
PCH2CH2), 24.46 d (J 91.50 Hz, PCH2CH2), 25.37 s
[CH(CH3)2] 30.36 d (J 91.50 Hz, PCH2CH), 37.48 d
(J 3.92 Hz, PCH2CH), 42.76 d (J 12.27 Hz, PCH2
CHCH2), 52.76 d (J 16.80 Hz, CHN), 170.90 s
[C(O)CHN], 179.60 d (J 4.63 Hz, [C(O)CHCH2].
Found, %: C 44.49, 44.53; H 7.67, 7.73; N 4.59, 4.67;
P 10.37, 10.31. C11H22NO6P. Calculated, %: C
44.75, H 7.51, N 4.74, P 10.49.
ACKNOWLEDGMENTS
The work was financially supported by the Research
and Development Department, Bayer CropScience
(Research Agreement 06-12-02).
REFERENCES
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and Yiotakis, A., Tetrahedron, 1999, vol. 55, no. 8,
p. 14635.
[2,3-Bis(hydroxycarbonyl)propyl][3-amino-3-
(hydroxycarbonyl)propyl]phosphinic acid
(pseudo- -glutamylaspartate) (Ic). Yield 40%, mp
102 105 C (foaming), 167 172 C (decomp.). 1H
NMR spectrum (D2O, , ppm): 1.10 t (2/3 3H,
CH3), 1.60 1.85 m [3H, CH2P + CH (one of CH
CH2P)], 2.00 2.20 m [3H, CH2CHN + CH (one of
CHCH2P)], 2.73 d [1H, CH2C(O)], 2.77 br. s [1H,
CH2C(O)], 3.04 m [1H, CHC(O)], 3.57 q (2/3 2H,
CH2O), 3.99 t (1H, CHN). 31P NMR spectrum (D2O),
, ppm: 44.5, 43.0 ( 6%). 13C NMR spectrum (D2O),
, ppm: 17.05 s (CH3), 23.44 s (CH2CHN), 25.67 d
(J 91.55 Hz, PCH2CH2), 30.54 d (J 90.94 Hz,
PCH2CH), 36.13
s
[PCH2CHC(O)], 36.88
d
[J 7.55 Hz, CH2C(O)], 53.93 d (J 15.04 Hz, CHN),
57.70 s (CH2O), 172.46 s [C(O)CHN], 176.04 s
[C(O)CH2], 178.54 d [J 9.20 Hz, C(O)CHCH2].
Found, %: C 37.62, 37.57; H 6.17, 6.23; N 4.05, 4.09;
P 9.23, 9.13. C9H16NO8P 2/3C2H5OH. Calculated,
%: C 37.85, H 6.15, N 4.27, P 9.44.
10. Ragulin, V.V., Rozhko, L.F., Saratovskikh, I.V., and
Zefirov, N.S., JPN Patent 18568, Chem. Abstr., 2001,
552806; JPN Patent 18581, Chem. Abstr., 2001,
574226.
[2,4-Bis(hydroxycarbonyl)butyl][3-amino-3-
(hydroxycarbonyl)propyl]phosphinic acid
(pseudo- -glutamylglutamate) (Id). Yield 31%, mp
100 104 C (foaming), 181 187 C (decomp.). 1H
NMR spectrum (D2O, , ppm): 1.13 t (3H, CH3),
1.60 1.85 m (3H, CH2P + one of CHCH2P), 1.85
1.95 m (2H, CH2CHN), 1.95 2.15 m [3H, CH2
CH2C(O) + one of CHCH2P], 2.45 t [2H, CH2C(O)],
2.73 m [1H, CHC(O)], 3.60 q (2H, CH2O), 3.95 t
(1H, CHN). 31P NMR spectrum (D2O), , ppm : 43.9,
42.4 ( 5%). 13C NMR spectrum (D2O), , ppm:
17.09 s (CH3), 23.60 s (CH2CHN), 25.76 d (J
90.49 Hz, PCH2CH2), 28.70 d (J 9.86 Hz, CH2CH2
C(O)], 31.30 d (89.17 Hz, PCH2CH), 31.45 s
[CH2C(O)], 39.32 s [CHC(O)], 54.12 d (J 13.75 Hz,
CHN), 57.73 s (CH2O), 173.54 d [J 8.70 Hz, C(O)
CH], 177.80 s [C(O)CH2], 179.29 s [C(O)CHN].
Found, %: C 40.06, 40.17; H 6.83, 6.78; N 3.85, 3.81;
P 8.53, 8.44. C10H18NO8P C2H5OH. Calculated, %:
C 40.34, H 6.77, N 3.92, P 8.67.
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