N-(3-phosphonopropyl)-substituted α-amino acids and their phosphine oxide analogs

Article abstract of DOI:10.1007/s11172-006-0168-4

A facile method was developed for the synthesis of N-(3-phosphonopropyl)- substituted α-amino acids and their phosphine oxide analogs based on hydrolysis of 2-oxo-1,2-azaphospholanes and 1,2-azaphospholanium salts prepared from readily available reagents. A chelate Cu^II N-[(3- diphenylphosphoryl)propyl]glycinate was isolated.

Full text of DOI:10.1007/s11172-006-0168-4

Russian Chemical Bulletin, International Edition, Vol. 54, No. 11, pp. 2635—2641, November, 2005
2635
Nꢀ(3ꢀPhosphonopropyl)ꢀsubstituted αꢀamino acids
and their phosphine oxide analogs
I. M. Aladzheva,ꢀ O. V. Bykhovskaya, P. V. Petrovskii, K. A. Lyssenko, M. Yu. Antipin, and T. A. Mastryukova
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5085. Eꢀmail: shipov@ineos.ac.ru
A facile method was developed for the synthesis of Nꢀ(3ꢀphosphonopropyl)ꢀsubstituted
αꢀamino acids and their phosphine oxide analogs based on hydrolysis of 2ꢀoxoꢀ1,2ꢀ
azaphospholanes and 1,2ꢀazaphospholanium salts prepared from readily available reagents.
A chelate CuII Nꢀ[(3ꢀdiphenylphosphoryl)propyl]glycinate was isolated.
Key words: 2ꢀoxoꢀ1,2ꢀazaphospholanes, 1,2ꢀazaphospholanium salts, hydrolysis,
Nꢀ(3ꢀphosphonopropyl)ꢀsubstituted αꢀamino acids, Nꢀ[(3ꢀdiphenylphosphoryl)propyl]ꢀsubꢀ
stituted αꢀamino acids, CuII Nꢀ[(3ꢀdiphenylphosphoryl)propyl]glycinate, IR spectroscopy,
NMR spectroscopy, Xꢀray diffraction study.
Amino phosphonic acids are structural analogs of
amino carboxylic acids and possess a broad spectrum of
biological activity.1 Aminoalkyl phosphonates and aminoꢀ
alkyl phosphinates were found in natural sources.2 Phosꢀ
phonoalkylꢀsubstituted derivatives of αꢀamino carboxylic
acids occupy a special place among synthetic and natural
amino phosphonates. They serve as efficient enzyme inꢀ
hibitors, antibacterial agents, and neuromodulators, show
growth regulatory activity, and possess other useful bioꢀ
logical and biochemical properties.3 Phosphorusꢀcontainꢀ
ing selective NꢀmethylꢀDꢀaspartate (NMDA) receptor
antagonists, such as 2ꢀaminoꢀ5ꢀphosphonopentanoic
acid (AP5), 2ꢀaminoꢀ7ꢀphosphonoheptanoic acid (AP7),
4ꢀ(3ꢀphosphonopropyl)piperazineꢀ2ꢀcarboxylic acid
(CPP), etc., have found wide application in neurophysioꢀ
logical studies.4
The phosphonoalkyl group in these compounds is, as
a rule, linked with the αꢀcarbon atom of an amino acid.
In the present study, we developed a facile and conveꢀ
nient procedure for the synthesis of αꢀamino carboxylic
acid derivatives with 3ꢀphosphonopropyl and 3ꢀ(diphenylꢀ
phosphoryl)propyl groups linked with the nitrogen atom
of amino acids.
Nꢀ(3ꢀPhosphonopropyl)ꢀsubstituted αꢀamino acids 1
(Scheme 1) were synthesized by the reaction of diethyl
Scheme 1
1: R = H (a), Me (b)
Reagents and conditions: i. 1) Et3N, –5 °C, MeCN, 2) ∆, 2 h.
ii. 1) 6 M HCl, ∆, 2) methyloxirane, 20 °C.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2551—2556, November, 2005.
1066ꢀ5285/05/5411ꢀ2635 © 2005 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Aladzheva et al.
phosphorochloridite (2) with Nꢀ(3ꢀchloropropyl)glycine
ethyl ester or ꢀDLꢀalanine ethyl ester (3a,b) giving rise to
2ꢀoxoꢀ1,2ꢀazaphospholanes 4a,b, which were subjected
to hydrolysis. Compounds 4 have been prepared in indiꢀ
vidual form.5 In the present study, their signals were obꢀ
served in the 31P NMR spectra of the reaction mixtures
after the first stage. Nꢀ(3ꢀPhosphonopropyl)glycine (1a)
and ꢀDLꢀalanine (1b) (Tables 1—3) were isolated as highꢀ
melting crystalline compounds readily soluble in water
and insoluble in organic solvents.
The IR spectra of compounds 1a,b (see Table 3) have
absorption bands characteristic of C=O and PO2– groups
along with broad intense absorption bands at
3500—2000 cm–1 corresponding to stretching vibrations
+
of NH2 and OH groups involved in strong hydrogen
bonds.1,6,7 These data suggest that compounds 1a,b exist
as zwitterions containing the deprotonated phosphonic
group and the protonated nitrogen atom.
Nꢀ(3ꢀDiphenylphosphorylpropyl)ꢀαꢀamino carboxyꢀ
lic acids were prepared by hydrolysis of 1,2ꢀazaphosꢀ
Table 1. Yields, melting points, and elemental analysis data for compounds 4 and 7—9
Comꢀ
pound
Yield
(%)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
С
H
N
P
4a
4b
7aa
7bb
8a
8b
9
68.0
71.9
76.2
79.4
225—230 (decomp.)
(EtOH—H2O)
230—231.5 (decomp.)
(EtOH—H2O)
228—230 (decomp.)
(EtOH—Et2O)
254—257 (decomp.)
(EtOH)
237—240 (decomp.)
(EtOH—H2O)
250—252 (decomp.)
(EtOH—H2O)
—
30.34
30.46
34.28
34.12
57.65
57.71
58.75
58.77
64.19
64.33
64.96
65.24
55.81
55.77
6.09
6.09
6.71
6.68
5.87
5.98
6.28
6.30
6.33
6.35
6.60
6.68
5.64
5.74
6.99
7.10
6.44
6.63
3.91
3.96
3.71
3.81
4.37
4.41
4.10
4.22
3.81
3.82
15.33
15.74
14.20
14.67
8.49
8.75
8.21
8.43
9.63
9.86
9.08
9.35
8.37
8.47
C5H12NO5P
C6H14NO5P
C17H21ClNO3P
C18H23ClNO3P
C17H20NO3P
C18H23NO3P
C34H42CuN2O8P2
75.7
(57.7)c
70.4
(60.0)c
48.7
a Found (%): Cl, 10.09. Calculated (%): Cl, 10.03.
b Found (%): Cl, 9.76. Calculated (%): Cl, 9.65.
c The yield based on consumed Ph2PCl.
Table 2. Parameters of the 31P—{1H} and 1H NMR spectra of compounds 4, 7, and 8
Comꢀ
pound
Solvent
31Pꢀ{1H} NMR
1H NMR, δ
(3JH,H/Hz)
δ
4a
4b
D2O
D2O
25.6
25.8
1.66—1.74 (m, 2 H, CH2CH2CH2); 1.88—1.98 (m, 2 H, PCH2);
3.15 (t, 2 H, NCH2, J = 7.6); 3.85 (s, 2 H, CH2CO)
1.47 (d, 3 H, CH3, J = 7.2); 1.62—1.71 (m, 2 H, CH2CH2CH2);
1.82—1.92 (m, 2 H, PCH2); 3.03—3.13 (m, 2 H, NCH2);
3.87 (q, 1 H, CH, J = 7.2);
7a
7b
8a
8b
CD3OD
CD3OD
D2O
37.8
37.9
41.4
41.2
1.89—2.03 (m, 2H, CH2CH2CH2); 2.53—2.63 (m, 2 H, PCH2);
3.19 (t, 2 H, NCH2, J = 7.6); 3.88 (s, 2 H, CH2CO); 7.53—7.67,
7.76—7.85 (both m, 10 H, 2 C6H5)
1.75 (d, 3 H, CH3, J = 7.2); 2.10—2.23 (m, 2 H, CH2CH2CH2);
2.77—2.84 (m, 2 H, PCH2); 3.39 (t, 2 H, NCH2, J = 7.6); 4.21
(q, 1 H, CH, J = 7.2); 7.72—7.88, 7.96—8.05 (both m, 10 H, 2 C6H5)
1.69—1.84 (m, 2 H, CH2CH2CH2); 2.33—2.42 (m, 2 H, PCH2);
2.96 (t, 2 H, NCH2, J = 7.6); 3.40 (s, 2 H, CH2CO);
7.33—7.58 (m, 10 H, 2 C6H5)
D2O
1.41 (d, 3 H, CH3, J = 7.2); 1.86—1.99 (m, 2 H, CH2CH2CH2);
2.51—2.65 (m, 2 H, PCH2); 3.07 (t, 2 H, NCH2, J = 7.6);
3.58 (q, 1 H, CH, J = 7.2); 7.50—7.78 (m, 10 H, 2 C6H5)

Nꢀ3ꢀPhosphonopropyl αꢀamino acids
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2637
Table 3. Parameters of the IR spectra (KBr) and 13C NMR spectra (D2O) of compounds 4, 7, and 8
Comꢀ
pound
IR,
ν/cm–1
13C NMR,
δ, J/Hz
4a
4b
7a
3500—2000 (NH2+, OH),
1742 (C=O), 1101, 1059 (PO2
3500—2000 (NH2+, OH),
1715 (C=O), 1106, 1060 (PO2
3500—2000 (NH2+, OH),
1727 (C=O), 1151 (P=O)
19.88 (d, CH2CH2CH2, J = 3.8); 24.39 (d, PCH2, J = 135.3);
47.71 (s, NCH2CO); 47.84 (d, NCH2CH2, J = 18.0); 169.56 (s, CO)
14.31 (s, CH3); 20.07 (d, CH2CH2CH2, J = 2.8); 24.40 (d, PCH2,
J = 135.5); 46.35 (d, NCH2, J = 17.1); 56.11 (s, CH); 172.92 (s, CO)
18.10 (s, CH2CH2CH2); 25.05 (d, PCH2, J = 72.3); 47.39 (s, NCH2CO);
47.47 (d, NCH2CH2, J = 16.0); 129.21 (d, mꢀC(Ph), J = 12.4);
129.34 (d, ipsoꢀC(Ph), J = 102.4); 130.54 (d, oꢀC(Ph), J = 10.0);
133.05 (s, pꢀC(Ph)); 169.01 (s, CO)
14.44 (s, CH3); 19.36 (d, CH2CH2CH2, J = 3.2); 26.45 (d, PCH2,
J = 72.3); 46.68 (d, NCH2CH2, J = 14.4); 55.82 (s, CH); 129.40
(d, mꢀC(Ph), J = 12.1); 131.10 (d, oꢀC(Ph), J = 9.6); 131.70 (d, ipsoꢀC(Ph),
J = 101.0); 131.77 (d, ipsoꢀC(Ph), J = 101.5); 132.90 (d, pꢀC(Ph), J = 2.4);
171.00 (s, CO)
–
–
)
)
7b*
3500—2000 (NH2+, OH),
1719 (C=O), 1147 (P=O)
8a
8b
3150—2000 (NH2+),
1619, 1383 (CO2–),
1183 (P=O)
16.51 (br.s, CH2CH2CH2);
23.33 (d, PCH2, J = 72.3); 45.72 (d,
NCH2CH2, J = 17.3); 47.40 (s, NCH2CO); 127.53 (d, mꢀC(Ph), J = 12.0);
127.68 (d, ipsoꢀC(Ph), J = 102.0); 128.95 (d, oꢀC(Ph), J = 10.0);
131.40 (br.s, pꢀC(Ph)); 169.33 (s, CO)
14.23 (s, CH3); 17.72 (br.s, CH2CH2CH2); 24.36 (d, PCH2, J = 72.5);
45.41 (d, NCH2CH2, J = 16.7); 57.14 (br.s, СН); 128.50 (d, mꢀC(Ph),
J = 12.1); 128.60 (d, ipsoꢀC(Ph), J = 101.5); 129.90 (d, oꢀC(Ph), J = 10.1);
132.40 (br.s, pꢀC(Ph)); 173.90 (br.s, СО)
3150—2000 (NH2+),
1585, 1394 (CO2–),
1184 (P=O)
* The 13C NMR spectrum of compound 7b was recorded in CD3OD.
pholanium salts 5 (Scheme 2), which were obtained in
the reaction of diphenylphosphinous chloride (6) with
amino acid derivatives 3a,b. Hydrochlorides 7a,b are highꢀ
melting crystalline products, which are moderately soluble
in MeOH and EtOH and readily soluble in water (see
Tables 1—3).
absorption bands at 3500—2000 cm–1 corresponding to
stretching vibrations of NH2+ and OH groups involved in
strong hydrogen bonds (see Table 3). These data are conꢀ
sistent with the presence of phosphoryl, carboxy, and
+
NH2 groups in hydrochlorides 7a,b. The structure of
hydrochloride 7a was confirmed by Xꢀray diffraction.
Hydrochloride 7a crystallizes with two independent catꢀ
ions and anions per asymmetric unit (Fig. 1). The nitroꢀ
gen atoms in both independent cations are protonated.
The bond lengths and bond angles and the allꢀtrans conꢀ
formation of the P(1)—C(5) fragment in two indepenꢀ
dent cations of 7a are virtually identical (Table 4). The
phosphoryl group is synperiplanar (sp) to the alkyl
chain. However, one independent molecule adopts the
+sp conformation, whereas another molecule is in the
–sp conformation. The O(1)—P(1)—C(1)—C(2) and
O(1´)—P(1´)—C(1´)—C(2´) torsion angles are 39.5 and
–41.3°, respectively.
Scheme 2
In the crystal structure of 7a, the cations are linked
to each other by strong O—H...O hydrogen bonds beꢀ
tween the carboxy and phosphoryl groups (O(3)...O(1´)
and O(3´)...O(1) are 2.561(2) and 2.530(2) Å, respecꢀ
tively) to form chains along the crystallographic axis b.
These chains are additionally crossꢀlinked by the Cl– anꢀ
ions through the N—H...Cl hydrogen bonds (N...Cl,
3.026(2)—3.071(2) Å).
R = H (a), Me (b)
Reagents and conditions: i. 1) Et3N, –5 °C, CHCl3—C6H6,
2) ∆, 1 h. ii. 6 M HCl, ∆. iii. Methyloxirane, 20 °C.
The reactions of hydrochlorides 7a,b with methylꢀ
oxirane produced Nꢀ(3ꢀdiphenylphosphorylpropyl)glycine
(8a) and ꢀDLꢀalanine (8b), respectively. These highꢀmeltꢀ
The IR spectra of compounds 7a,b have absorption
bands of P=O and C=O groups along with broad intense

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Aladzheva et al.
O(1)
O(2)
C(9)
C(8)
C(7)
C(2)
N(1)
P(1)
C(5)
C(10)
C(6)
C(11)
C(4)
C(3)
O(3)
C(1)
C(13)
C(12)
C(14)
C(15)
C(17)
C(16)
Fig. 1. Overall view of one independent cation in the crystal structure of hydrochloride 7a.
scopy, and 1H, 31P, and 13C NMR spectroscopy (see
Tables 1—3).
Table 4. Selected bond lengths (d) and bond angles (ω) in two
independent cations (A and B) in the crystal structure of hydroꢀ
chloride 7a
Compounds 8 are potential complexꢀforming agents
for metals, which are of interest from the point of view of
biological activity (Cu, Co, Ni, etc.). The reaction of 8a
with CuCO3•Cu(OH)2 afforded dihydrate of the CuII cheꢀ
late Cu[Ph2P(O)(CH2)3NHCH2COO]2•2H2O (9) (see
Table 1).
The IR spectrum of this compound shows a broad
intense absorption band at 1608 cm–1 and an intense
band at 1375 cm–1 characteristic of vibrations of the
C=O group in salts of carboxylic acids8 along with
an intense band of the NH group at 3200 cm–1 and a
broad intense absorption band at 3600—3300 cm–1. The
31P—{1H} NMR spectrum in CD3OD has a broad singlet
at δP 51.1 shifted downfield with respect to the signal of
the starting compound 8a (δP 41.4 in D2O).
Parameter
Value
A
B
Bond
d/Å
P(1)—O(1)
P(1)—C(1)
P(1)—C(6)
P(1)—C(12)
N(1)—C(4)
N(1)—C(3)
C(1)—C(2)
O(2)—C(5)
C(2)—C(3)
1.501(1)
1.811(2)
1.809(2)
1.806(2)
1.491(2)
1.499(2)
1.536(3)
1.208(2)
1.528(3)
1.325(2)
1.5034(15)
1.803(2)
1.802(2)
1.808(2)
1.484(3)
1.497(2)
1.540(3)
1.214(2)
1.523(3)
1.318(3)
O(3)—C(5)
Angle
ω/deg
In the crystal structure, complex 9 occupies a crystalꢀ
lographic inversion center, the copper atom lying on
this center. The coordination polyhedron of the copper
atom is a tetragonal bipyramid with two chelate ligands
and two water molecules in the axial positions (Fig. 2,
Table 5). The axial Cu(1)—O(1W) bonds with the water
molecule are elongated to 2.568(2) Å compared to
the equatorial Cu(1)—O(2) bonds (1.928(2) Å). The
fiveꢀmembered metallacycle adopts an envelope conꢀ
formation with the N(1) atom deviating from the
Cu(1)O(2)C(4)C(5) plane by 0.42 Å. The P(1)—C(4) fragꢀ
ment in complex 9, like that in hydrochloride 7a, adopts
an allꢀtrans conformation. The P(1)—C(1)—C(2)—C(3),
C(1)—C(2)—C(3)—N(1), and C(2)—C(3)—N(1)—C(4)
torsion angles are 169.7, 170.7, and 167.8°, respectively.
The phosphoryl group is synperiplanar to the P(1)—C(4)
fragment. The O(1)—P(1)—C(1)—C(2) torsion angle
is 61.9°.
O(1)—P(1)—C(12)
O(1)—P(1)—C(6)
C(12)—P(1)—C(6)
O(1)—P(1)—C(1)
C(12)—P(1)—C(1)
C(6)—P(1)—C(1)
C(4)—N(1)—C(3)
108.81(9)
111.13(9)
106.83(9)
113.57(9)
109.11(10)
107.17(9)
113.29(15)
108.64(9)
110.25(9)
108.33(9)
115.31(9)
108.95(10)
105.15(9)
113.15(15)
ing crystalline compounds are readily soluble in water
(see Table 1). The IR spectra (see Table 3) have absorpꢀ
tion bands of the P=O group along with intense absorpꢀ
tion bands at 1619, 1383 cm–1 (8a) and 1585, 1394 cm–1
(8b) characteristic of the carboxylate anion.8 In addition,
the spectra show a continuous series of mediumꢀintensity
bands at 3150—2000 cm–1 assigned to stretching vibraꢀ
+
tions of the NH2 group. These data suggest that these
compounds exist as zwitterions containing the deprotoꢀ
nated carboxy group and the protonated nitrogen atom.
Compounds 8a,b were also prepared without isolation of
intermediate hydrochlorides 7a,b in 57.7 and 60.0% yields,
respectively.
In the crystal structure, the molecules of salt 9
are linked to each other by N—H...O (N(1)...O(3A),
2.905(3) Å) and O—H...O (O(1W)...O(3), 2.764(2) Å;
O(1W)...O(1), 2.900(2) Å) hydrogen bonds to form
doubled chains along the crystallographic axis b.
The compositions and structures of compounds 1, 7,
and 8 were confirmed by elemental analysis, IR spectroꢀ

Nꢀ3ꢀPhosphonopropyl αꢀamino acids
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2639
C(15A)
C(16A)
O(3)
C(5)
C(4)
N(1)
C(14A)
C(3)
C(17A)
C(12A)
C(1)
C(2)
C(9)
C(8)
C(13A)
O(1W)
C(7)
O(2)
P(1)
O(1)
C(10)
C(6)
C(11)
O(1WA)
O(2A)
P(1A)
O(1A)
C(11A)
Cu(1)
C(10A)
C(9A)
C(2A)
C(6A)
C(12)
N(1A)
C(7A)
C(13)
C(8A)
C(5A)
O(3A)
C(1A)
C(17)
C(14)
C(3A)
C(4A)
C(16)
C(15)
Fig. 2. Overall view of dihydrate of chelate 9 in the crystal structure. The atoms marked with A are related to nonmarked atoms by the
symmetry operation (–x, –y, –z).
Table 5. Selected bond lengths (d) and bond angles (ω) in the
crystal structure of salt 9
and the mixture was filtered. Benzene was removed in vacuo,
6 M HCl (50 mL) was added to the residue, and the reaction
mixture was refluxed for 16 h. The solution was cooled and
washed with CH2Cl2 (3×20 mL). The aqueous layer was conꢀ
centrated to dryness. Water (30 mL) was added to, and distilled
from, the residue; this operation was repeated three times. The
residue was kept in vacuo at 80 °C for 1 h and dissolved in MeOH
(30 mL). Methyloxirane (10 mL) was added dropwise with stirꢀ
ring. The reaction mixture was stirred at 20 °C for 4 h and kept
in a refrigerator for 16 h. The precipitate that formed was filꢀ
tered off and dried in vacuo. The yield of compound 1a was
0.55 g (see Tables 1—3).
Bond
d/Å
Angle
ω/deg
Cu(1)—O(2)
Cu(1)—N(1)
Cu(1)—O(1W) 2.658(3) O(2)—Cu(1)—O(1W)
1.928(2) O(2)—Cu(1)—N(1A)
2.038(2) O(2)—Cu(1)—N(1)
95.43(8)
84.57(8)
96.49(9)
83.71(9)
113.9(1)
113.0(1)
107.7(1)
111.0(1)
106.7(1)
103.9(1)
112.7(2)
P(1)—O(1)
P(1)—C(1)
P(1)—C(12)
P(1)—C(6)
O(2)—C(5)
O(3)—C(5)
N(1)—C(4)
N(1)—C(3)
1.487(2) N(1)—Cu(1)—O(1W)
1.795(3) O(1)—P(1)—C(1)
1.799(3) O(1)—P(1)—C(12)
1.811(3) C(1)—P(1)—C(12)
1.270(3) O(1)—P(1)—C(6)
1.238(3) C(1)—P(1)—C(6)
1.478(3) C(12)—P(1)—C(6)
1.486(3) C(4)—N(1)—C(3)
Nꢀ(3ꢀPhosphonopropyl)ꢀDLꢀalanine (1b) was synthesized
analogously from 3b (1.55 g, 8 mmol), 2 (1.03 g, 6.6 mmol), and
Et3N (1.01 g, 10 mmol) in anhydrous MeCN (30 mL). After
refluxing, the percentage of azaphospholane 4b in the reaction
mixture was 83% (31P NMR spectroscopic data, δ 46.2 and
P
47.0 (two diastereomers); cf. lit. data5: δ 46.4 and 47.3 in
P
Experimental
CDCl3). The reaction mixture was filtered and the solvent was
removed. The residue was refluxed with 6 M HCl (60 mL) for
16 h and worked up as described above. The residue was disꢀ
solved in MeOH (50 mL), and methyloxirane (20 mL) was
added dropwise with vigorous stirring. The reaction mixture was
stirred for 4 h and kept in a refrigerator for 16 h. The precipitate
that formed was filtered off, treated with refluxing MeOH on a
filter, and dried in vacuo. Compound 1b was isolated in a yield of
1.00 g (see Tables 1—3).
The NMR spectra were recorded on a Bruker AMXꢀ400
instrument with the use of the signal from the residual protons of
CDCl3 as the internal standard (1H), the signal of CDCl3 as the
internal standard (13C), and 85% H3PO4 as the external stanꢀ
dard (31P). The IR spectra were measured on Magna IR 750
Nicolet and URꢀ20 instruments in KBr pellets. Commercial
reagents (EtO)2PCl and Ph2PCl (Aldrich) were used. Comꢀ
pounds 3a,b were synthesized according to a known procedure.5
Nꢀ(3ꢀPhosphonopropyl)glycine (1a). A solution of chloride 2
(0.65 g, 4.1 mmol) in MeCN (5 mL) was added dropwise with
vigorous stirring to a solution of glycine derivative 3a (0.90 g,
5 mmol) and Et3N (0.50 g, 5 mmol) in anhydrous MeCN (10 mL)
at –5 °C under argon. The reaction mixture was refluxed for 2 h.
The percentage of azaphospholane 4a in the reaction mixture
Nꢀ(3ꢀDiphenylphosphorylpropyl)glycine hydrochloride (7a)
was synthesized from 3a (1.33 g, 7.4 mmol) and phosphinous
chloride 6 (1.52 g, 6.9 mmol) in the presence of Et3N (0.86 g,
8.5 mmol) in a 2 : 1 mixture of anhydrous C6H6 and CHCl3.
The reaction mixture was refluxed for 1 h, after which the perꢀ
centage of chloride 5a in the mixture was 88% (31P NMR specꢀ
troscopic data, δ 55.1; cf. lit. data5: δ 60.0 in CDCl3). The
P
P
was 84% (31P NMR spectroscopic data, δ 46.8; cf. lit. data5:
reaction mixture was filtered, the solvent was removed in vacuo,
and 6 M HCl (100 mL) was added to the residue. The reaction
mixture was refluxed for 18 h, the solution was cooled and
P
δ
46.8 in CDCl3). The precipitate was filtered off, MeCN was
P
removed in vacuo, benzene (15 mL) was added to the residue,

2640
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Aladzheva et al.
washed with CH2Cl2 (3×40 mL), and the aqueous layer was
concentrated to dryness. Water (40 mL) was added to, and disꢀ
tilled from, the residue; this operation was repeated three
times. Hydrochloride 7a was isolated in a yield of 1.86 g (see
Tables 1—3).
Nꢀ(3ꢀDiphenylphosphorylpropyl)ꢀDLꢀalanine (8b) was synꢀ
thesized analogously from a solution of hydrochloride 7b (0.79 g,
2.2 mmol) in anhydrous ethanol (30 mL) and methyloxirane
(8 mL). The reaction mixture was stirred for 5 h and kept in a
refrigerator for 16 h. The precipitate was filtered off, washed
with ethanol, and dried in vacuo. Compound 8b was obtained in
a yield of 0.50 g (see Tables 1—3).
Dihydrate of the CuII chelate of Nꢀ(3ꢀdiphenylphosphorylꢀ
propyl)glycine (9). Basic cupric carbonate CuCO3•Cu(OH)2
(0.0217 g, 0.11 mmol) was added to a solution of 8a (0.1245 g,
0.392 mmol) in water (2 mL). The resulting opaque blue soluꢀ
tion was filtered, the filtrate was concentrated to dryness, the
residue was dissolved in ethanol, diethyl ether was added, and
the reaction mixture was kept for 16 h. The lilac crystals that
precipitated were filtered off, treated on a filter with hot water to
remove unconsumed 8a, and dried. Salt 9 was obtained in a
yield of 0.07 g (see Table 1). IR (KBr), ν/cm–1: 3600—3300
(OH), 3200 (NH), 1608, 1375 (CO2). 31P—{1H} NMR
(CD3OD), δ: 51.1 br.s.
Nꢀ(3ꢀDiphenylphosphorylpropyl)ꢀDLꢀalanine hydrochloride
(7b) was synthesized analogously from 3b (1.44 g, 7.4 mmol),
6 (1.37 g, 6.2 mmol), and Et3N (0.76 g, 7.5 mmol) in a 2 : 1
C6H6—CHCl3 mixture (20 mL). The reaction mixture was reꢀ
fluxed for 1 h, after which the percentage of salt 5b in the
reaction mixture was 92% (31P NMR spectroscopic data, δ 57.5;
P
cf. lit. data5: δ 57.2 in CDCl3). The reaction mixture was filꢀ
P
tered, the solvents were removed, and 6 M HCl (100 mL) was
added to the residue. The reaction mixture was refluxed for 16 h
and then worked up as described above for hydrochloride 7a.
After drying in vacuo, hydrochloride 7b was obtained in a yield
of 1.81 g (see Tables 1—3).
Nꢀ(3ꢀDiphenylphosphorylpropyl)glycine (8a). Hydrochloride
7a (0.82 g, 2.3 mmol) was dissolved in anhydrous EtOH (25 mL),
and methyloxirane (8 mL) was added dropwise with stirring and
gentle heating for 5 min. The reaction mixture was stirred for 6 h
and then kept in a refrigerator for 4 days. The precipitate that
formed was filtered off, washed with ethanol, and dried in vacuo.
Compound 8a was obtained in a yield of 0.56 g (see Tables 1—3).
Xꢀray diffraction study of hydrochloride 7a and dihydrate of
chelate 9. The structures were solved by direct methods and
refined by the fullꢀmatrix leastꢀsquares method with anisotropic
displacement parameters for nonhydrogen atoms against F 2
.
hkl
The hydrogen atoms were located from difference Fourier maps
Table 6. Principal crystallographic data and parameters of structure refinement for hydrochloꢀ
ride 7a and chelate 9
Parameter
9
7а
Formula
T/K
C34H42CuN2O8P2
298
C17H21ClNO3P
120
Diffractometer
Radiation
Scan mode
Crystal system
Space group
а/Å
b/Å
c/Å
α/deg
β/deg
Siemens P3
MoKaꢀα
ωꢀScanning technique
Orthorhombic
Pbca
SMART CCD
MoKꢀα
ωꢀScanning technique
Triclinic
P–1
8.732(2)
11.106(2)
34.851(7)
9.997(1)
10.551(1)
17.208(2)
93.378(3)
100.776(3)
90.744(3)
1779.5(4)
4(2)
353.77
3.18
744
1.320
γ/deg
V/Å3
3379.8(12)
4(0.5)
732.18
7.95
1532
1.439
Z (Z´)
M
µ/cm–1
F(000)
ρ
calc/g cm–3
2θmax/deg
55
57
Number of measured reflections (Rint
Number of independent reflections
Number of observed reflections
with I > 2σ(I )
)
3873 (0.0)
3873
2550
13021 (0.0177)
8402
6522
Number of parameters
R1
226
0.0428
439
0.0473
wR2
0.1035
0.1157
GOOF
ρ (max/min)/e Å–3
1.002
0.429/–0.685
1.072
0.619/–0.462

Nꢀ3ꢀPhosphonopropyl αꢀamino acids
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2641
and refined isotropically. All calculations were carried out using
the SHELXTL PLUS program package (Table 6).
3. P. Kafarski and B. Lejzak, Phosphorus, Sulfur, Silicon, Relat.
Elem., 1991, 63, 193.
4. D. E. Jane, in Aminophosphonic and Aminophosphinic Acids,
Eds V. P. Kukhar and H. R. Hudson, J. Wiley and Sons, New
York, 2000, p. 483.
5. O. V. Bykhovskaya, I. M. Aladzheva, D. I. Lobanov, P. V.
Petrovskii, K. A. Lyssenko, I. V. Fedyanin, and T. A.
Mastryukova, Izv. Akad. Nauk, Ser. Khim., 2005, 2557 [Russ.
Chem. Bull., Int. Ed., 2005, 54, 2642].
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ33091)
and the Council on Grants of the President of the Rusꢀ
sian Federation (Program for State Support of Leading
Scientific Schools of the Russian Federation, Grant
NShꢀ1100.2003.3).
6. L. J. Bellamy, The Infrared Spectra of Complex Molecules,
Methuen and Co. Ltd., London, 1960.
References
7. C. Wasielewski, M. Topolski, and L. Dembkowski, J. Prakt.
Chem., 1989, 331, 507.
8. L. J. Bellamy, Advances in Infrared Group Frequencies,
Methuen and Co. Ltd., Bungay, Suffolk, 1968.
1. V. P. Kukhar and V. A. Solodenko, Usp. Khim., 1987, 56,
1504 [Russ. Chem. Rev., 1987, 56 (Engl. Transl.)].
2. L. D. Quin, in Topics in Phosphorus Chemistry, 4,
Eds M. Grayson and E. Griffith, WileyꢀInterscience, New
York, 1967, p. 23.
Received July 25, 2005;
in revised form November 16, 2005