Phosphorylthioureas and phosphorylureas containing amino acid fragments

Article abstract of DOI:10.1007/s11172-009-0352-4

A series of (dialkoxyphosphoryl)thioureas and their 1,3,2-oxazaphosphinane analogs containing fragments of glycine, alanine, ss-alanine, L-aspartic and L-glutamic acids, as well as phosphorylureas derived from glycine and ss-alanine were synthesized in the search for potential biologically active compounds (including possible inhibitors of aspartate trans-carbamoylase).

Full text of DOI:10.1007/s11172-009-0352-4

2512
Russian Chemical Bulletin, International Edition, Vol. 58, No. 12, pp. 2512—2516, December, 2009
Brief Communications
Phosphorylthioureas and phosphorylureas
containing amino acid fragments
A. E. Shipov, G. K. Genkina, and P. V. Petrovskii
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
2
8 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: shipov@ineos.ac.ru
A series of (dialkoxyphosphoryl)thioureas and their 1,3,2ꢀoxazaphosphinane analogs
containing fragments of glycine, alanine, βꢀalanine, Lꢀaspartic and Lꢀglutamic acids, as well
as phosphorylureas derived from glycine and βꢀalanine were synthesized in the search for
potential biologically active compounds (including possible inhibitors of aspartate transꢀ
carbamoylase).
Key words: phosphoryl isothiocyanates, phosphoryl isocyanates, amino acid esters, esters
of phosphorylthiocarbamoylamino acid, esters of phosphorylcarbamoylamino acids, 1,3,2ꢀ
oxazaphosphinanes.
1
Earlier, we have described synthesis of structural anaꢀ
logs of PALA2 (1), an active carcinolytic, viz., phosꢀ
phorylureas (2) that contain an Lꢀaspartic acid fragment,
including 2ꢀoxoꢀ1,3,2ꢀoxazaphosphinane derivatives (2,
RR´ = HN(CH ) O) in which the oxazaphosphinane ring
,3
2
3
can play «transport» role delivering a pharmacophore
4
group into a cell through cell membranes (similarly to
the antitumor agent cyclophosphamide).
X = O (1); S (3).
It is also known that ThioPALA (3) is twice as active as
PALA due to higher lipophilicity. It was thus of interest
to synthesize thiourea derivatives with Lꢀaspartic acid fragꢀ
ment analogous to compounds 2 including compounds
that contain 1,3,2ꢀoxazaphosphinane ring. Phosphorylꢀ
thiourea and phosphorylurea derivatives that contain other
amino acid fragments can also be of definite interest as
potential biologically active compounds.
5
6
The reactions of the known phosphoryl isothioꢀ
cyanates 4 and 5 with amino acid esters 6 afford phosꢀ
phorylthioureas 7, 8 (Scheme 1, Table 1), the reaction
proceeded smoothly at room temperature in benzene.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2430—2434, December, 2009.
066ꢀ5285/09/5812ꢀ2512 © 2009 Springer Science+Business Media, Inc.
1

Phosphorylthioureas and phosphorylureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009 2513
Esters 6 react with 2ꢀisothiocyanoꢀ2ꢀoxoꢀ1,3,2λ5ꢀ
oxazaphosphinane (9) under the same conditions resultꢀ
ing in phosphorylthioureas 10, which contain a cyclic
fragment (see Scheme 1, Table 1). It is worth noting that
isothiocyanate 9, as well as compounds 4, 5, was obtained
by the reaction of the corresponding acid chloride, 2ꢀchloroꢀ
Scheme 1
5
7
2
ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinane (11), with KSCN
in MeCN, but in this case longer heating (15—18 h) at
5—50 °С and two equivalents of KSCN were required
Scheme 2).
4
(
Scheme 2
After removal of inorganic salts, compound 9, as
judged by the 3 P NMR spectral data, was free from any
admixtures, it was used in further reactions without addiꢀ
tional purification.
1
R = Et (4, 7); R = Bu (5, 8); 6, 7, 10: Y = CH(CH COOMe) (a),
Besides phosphorylthioureas 7b,c, phosphorylureas
12a,b were obtained (analogous Lꢀaspartic and Lꢀglutamic
acids derivatives have been described by us earlier ), which
2
CH (b), CH CH (c), CH(CH CH COOMe) (d), CH(Me) (e).
2
2
2
2
2
Y = CH(CH COOMe) (8)
1
2
Table 1. Yields, melting points and elemental analysis data for the obtained compounds
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
(
%)
C
H
N
P
7
7
7
7
aa
b
70
44
66
60
20
71
Oil
84—85
Oil
36.99
5.94
5.94
6.09
6.03
6.47
6.42
6.32
6.26
7.19
7.10
5.18 12.04
5.35 12.38
4.96 11.49
5.05 11.57
5.37 15.77
5.28 15.72
7.68
7.86
9.84 10.88
9.88 10.90
9.26
9.39
7.51
7.56
6.57
6.74
8.61
8.69
C H N O PS
11
21
2
7
3
7.10
33.88
3.88
36.25
6.24
38.94
8.92
43.66
3.68
35.41
C H N O PS
8 17 2 5
3
c
—
C H N O PS
9 19 2 5
3
d
Oil
—
C H N O PS
12 23 2 7
3
8b
Oil
7.31
7.51
—
C H N O PS
15 29 2 7
4
c
1
0a
C H N O PS
10 18 3 6
3
3
3
5.40
3.82
3.73
—
—
C H N O PS•0.2CHCl
10 18 3 6 3
1
1
1
1
0b
0c
0d
0e
78
76
81
70
123—124
31.51
1.46
33.94
4.16
37.49
7.39
34.18
C H N O PS
7 14 3 4
3
c
5.61 14.98 10.89
5.73 14.94 11.01
C H N O PS
8 16 3 4
3
c
c
5.77 11.81
5.70 11.89
5.79 14.71
5.73 14.94
5.17 13.69
5.35 13.77
—
—
—
C H N O PS
11 20 3 6
3
C H N O PS
8
16
3
4
3
3
3
4.16
2.21
2.28
C H N O PS•0.2CHCl
3
8
16
3
4
1
1
2a
2b
54
70
101—102
98—99
35.84
5.82
—
6.51 10.49 11.51
6.39 10.45 11.55
C H N O P
8 17 2 6
3
—
9.56 11.03
.90 11.00
C H N O P
9 19 2 6
9
a
b
c
Found (%): S, 8.93, calculated (%): S, 9.00.
Found (%): S, 7.71, calculated (%): S, 7.77.
Amorphous compound without definite melting point.

2514
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009
Shipov et al.
sis (see Table 1), and the 31P{ H} and H NMR spectra
(Table 2). Diastereomeric anisochronous effect was
observed in the NMR spectra of compounds 10a,d,e,
which contain two chiral centres in the molecules. Comꢀ
pounds 10a,e formed stable solvates with 0.2 molecule of
1
1
allows a comparison of the biological activities of these
classes of compounds. Synthesis of ureas 12a,b was carꢀ
1
ried out by the described procedure using reaction of
diethoxyphosphoryl isocyanate (13) with amino acids
esters 6 (Scheme 3, see Table 1).
The composition and structures of the obtained
compounds were confirmed by data from elemental analyꢀ
CHCl . Data on the biological evaluation of the syntheꢀ
sized compounds will be published elsewhere.
3
Table 2. 31Р{ H} and Н NMR spectra for the obtained compounds in CDCl
1
1
3
Comꢀ
pound
31Р NMR,
1Н NMR,
δ, J/Hz
δ
3
3
7
a
–4.5
1.35 (t, 6 H, CH CH , J
= 7.0); 3.03 (ABꢀsystem, 1 H, H , NHCH C(O), J
= 4.7,
H,HB
2
3
H,H
B
2
2
3
2
J
= 17.2); 3.09 (ABꢀsystem, 1 H, H , NHCH C(O), J
= 4.4, J
= 17.2);
H ,H
B
H ,H
A
2
H,HA
A
B
A
3
.68, 3.75 (both s, 3 H each, CH O); 4.11—4.26 (m, 4 H, CH CH O); 5.38 (dt, 1 H, NHCHCH ,
3 3 2 2
3
3
2
3
JH,H = 4.4, J
1.41 (t, 6 H, CH CH , J
4
1.35 (t, 6 H, CH CH , J
3
NHP, J
= 5.3); 7.23 (d, 1 H, NHP, J
= 9.8); 9.38 (d, 1 H, NHCH, J
= 7.6)
H,H
H,H
H,P
3
7
7
b
c
–4.04
–4.55
= 7.1); 3.81 (s, 3 H, CH O); 4.18—4.29 (m, 4 H, CH CH O);
= 5.0); 7.66 (d, 1 H, NHP, J
2
3
H,H
H,H
H,H
3 3 2
3
2
.43 (d, 2 H, NHCH , J
= 6.6); 9.34 (br.s, 1 H, NHCH2)
H,P
2
3
3
= 6.6); 2.70 (t, 2 H, CH C(O), J
= 6.3); 3.70 (s, 3 H, CH O);
2
3
2
H,H 3
3
3
.91 (dt, 2 H, NHCH CH , J
= 6.2, J
= 6.1); 4.10—4.20 (m, 4 H, CH CH O); 6.57 (d, 1 H,
2
2
H,H
H,H 3 2
2
= 7.1); 9.15 (br.s, 1 H, NHCH )
H,P
2
3
7
8
d
–4.26
–2.11
1.35, 1.36 (both t, 6 H, CH CH , J
= 6.7); 2.10—2.36 (m, 2 H, CH C(O)); 2.39—2.47 (m, 2 H,
H,H 2
2
3
CHCH ); 3.65, 3.74 (both s, 3 H each, CH O); 4.13—4.23 (m, 4 H, CH O); 5.04, 5.06 (both t, 1 H,
2
3
2
3
3
CHCH , J
0.87, 0.88 (both t, 6 H, CH CH , J
= 7.3); 7.16 (br.s, 1 H, NHP); 9.21 (d, 1 H, NHCH, J
= 7.2)
2
H,H
H,H
3
= 7.4); 1.30—1.40 (m, 4 H, CH CH ); 1.59—1.67 (m, 4 H,
2
3
H,H
2 3
3
2
CH CH CH ); 2.99 (ABꢀsystem, 1 H, H , NHCH C(O), J
= 4.5, J
= 17.2);
H ,H
B
2
2
2
B
2
H,HB
A
3
2
3
.06 (ABꢀsystem, 1 H, HA, NHCH C(O), J
= 4.3, J
= 17.2); 3.64, 3,72 (both s, 3 H each,
H ,H
B
2
H,HA
A
3
3
CH O); 3.95—4.16 (m, 4 H, CH O); 5.36 (dt, 1 H, NHCHCH , J
= 4.6, J
= 7.9);
3
2
2
H,H
H,H
3
7
.52 (br.s, 1 H, NHP ); 9.39 (d, 1 H, NHCH, J
= 7.6)
2
H,H
9
1
–13.69a
—
b
0a
0b
–1.54, –1.57 1.81—1.89 , 2.15—2.35 (both m, 1 H + 1 H, CH CH CH ); 2.94—3.09 (m, 2 H, CH NHP); 3.20—3.40
2 2 2 2
(
m, 2 H CH OP); 3.67, 3.68 (both s, 3 H, CH O); 3.73, 3.74 (both s, 3 H, CH O); 4.03—4.15 (br., 1 H,
2 3 3
3
3
CH NHP); 4.33—4.43 (m, 2 H, CH CH); 5.36 (dt, 1 H, NHCHCH , J
7
= 4.9, J
= 8.0);
2
2
2
H,H
H,H
2
.79 (d, 1 H, NHP, J
= 9.1); 9.53 (br.s, 1 H, NHCH)
H,P
1
1
–0.68
–1.06
1.77—1.84, 2.02—2.13 (both m, 1 H each, CH CH CH ); 3.32—3.39 (m, 2 H, CH NHP); 3.75 (s, 3 H,
2 2 2 2
3
CH O); 4.09 (br.s, 1 H, CH NHP); 4.29 (ABꢀsystem, 1 H, HB, NHCH C(O), J = 5.1,
H,HB
3
2
2
2
3
2
J
= 18.0); 4.39 (ABꢀsystem, 1 H, HA, NHCH C(O), J
= 5.2, J
= 18.0);
H ,H
B
H ,H
2
H,HA
A
B
A
2
4
.26—4.46 (m, 2 H, CH OP); 8.34 (d, 1 H, C(S)NHP, J
= 9.5); 8.92 (t, 1 H, C(S)NHCH2,
2
H,P
3
JH,H = 5.0)
1.81—1.89, 2.00—2.08 (both m, 1 H each, J
CH CH C(O), J
CH CH C(O), J
3
0с
= 4.6, CH CH CH ); 2.64 (ABCDꢀsystem, 1 H, H ,
H,H 2 2 2 B
3
3
2
= 6.5, J
= 2.5, J
= 17.0); 2.71 (ABCDꢀsystem, 1 H, HA,
2
2
H ,H
H ,H
H ,H
B
C
B
D
A
B
3
3
2
= 6.4, J
= 2.4, J
= 17.0); 3.68 (s, 3 H, CH O); 3.28—3.42
2
2
H ,H
H ,H
H ,H
3
A
C
B
D
A
B
3
2
(
m, 2 H, CH NHP); 3.83 (ABꢀsystem, 1 H, HB, C(S)NHCH , J
= 2.1, J
= 6.4);
H ,H
B
2
2
H,HB
A
3
2
3
.86 (ABꢀsystem, 1 H, HA, C(S)NHCH , J
= 2.2, J
= 6.4); 3.90 (br.s, 1 H, CH NHP);
H ,H 2
B
2
H,HB
A
2
4
.33—4.45 (m, 2 H, CH OP); 8.12 (d, 1 H, PNHC(S), J
= 9.4); 8.88 (t, 1 H, C(S)NHCH2,
2
H,P
3
JH,H = 5.6)
1
1
0d
0e
–0.36, –0.47 1.78—1.90, 2.27—2.36 (both m, 1 H each, CH CH CH ); 2.00—2.15 (m, 2 H, CH C(O));
2 2 2 2
3
.30—3.46 (m, 2 H, CH NHP); 3.65 (s, 3 H, CH COOCH ); 3.730, 3.736 (s, 3 H, CHCOOCH );
2 2 3 3
4
.02 (br.s, 1 H, CH NHP); 4.35—4.48 (m, 2 H, CH OP); 5.03 (dt, 1 H, NHCHCH ,
2
2
2
3
3
JH,H = 4.5, J
1.48 (d, 3 H, CHCH , J
= 5.3); 8.04 (br.s, 1 H, PNHC(S)); 9.00—9.05, 9.07—9.14 (both m, 1 H, NHCH)
H,H
3
0.21, 0.36
= 7.3); 1.77—1.90, 1.97—2.12 (both m, 1 H each, CH CH CH );
3
H,H
2
2
2
3
.23—3.48 (m, 2 H, CH NHP); 3.72, 3.73 (both s, 3 H, OCH ); 4.04 (br.d, 1 H, CH NHP,
2
3
2
2
3
3
JH,P = 31.0); 4.31—4.48 (m, 2 H, CH OP); 4.90 (dq, 1 H, NHCHCH , J
7
1.38 (t, 6 H, CH CH , J
= 7.3, J = 6.0);
H,H
2
3
H,H
3
2
.75 (br.s, 1 H, PNHC(S)); 8.99 (dd, 1 H, NHCH, J
= 7.0, J
= 54.0)
H,H
H,P
3
3
1
1
2a
2b
–0.99
–0.8
= 7.0); 3.76 (s, 3 H, CH O); 4.01 (d, 2 H, NHCH , J
= 5.7);
H,H
2
3
H,H
3
2
4
.15—4.26 (m, 4 H, CH CH O); 7.18 (s, 1 H, NHP); 7.90 (s, 1 H, NHCH )
3
2
2
3
3
1.41 (t, 6 H, CH CH , J
= 7.0); 2.63 (t, 2 H, CH C(O), J
= 6.4); 3.57 (dt, 2 H, NHCH CH ,
H,H 2 2
2
3
H,H
2
3
3
JH,H = 6.4, J
= 6.2); 3.76 (s, 3 H, CH O); 4.17—4.27 (m, 4 H, CH CH O); 6.22 (d, 1 H, NHP,
H,H
3
3
2
2J
= 5.6); 7.20 (br.s, 1 H, NHCH2)
H,P
a
b
In MeCN.
In CD CN.
3

Phosphorylthioureas and phosphorylureas
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009 2515
Scheme 3
Dimethyl Nꢀ[Nꢀ(diethoxyphosphoryl)thiocarbamoyl]ꢀ
Lꢀglutamate (7d) was obtained similarly by the reaction of 4
(
0.80 g, 4.0 mmol) in C H (4.5 mL) with ester 6d (0.72 g,
6 6
4
.1 mmol); after chromatographic purification in a CHCl —
3
MeOH solvent system, product 7d was obtained (0.90 g, 60%)
(
see Tables 1 and 2).
Dimethyl Nꢀ[Nꢀ(dibutoxyphosphoryl)thiocarbamoyl]ꢀ
Lꢀaspartate (8) was obtained similarly from isothiocyanate 5
1.15 g, 4.5 mmol) in acetone (5.5 mL) and ester 6a (0.75 g,
.6 mmol) in acetone (1.5 mL); after chromatographic purificaꢀ
(
4
tion in a hexane—acetone solvent system, thiourea 8 was
1
2: Y = CH (a), CH CH (b).
obtained (0.40 g, 20%) (see Tables 1 and 2).
2
2
2
3
2
ꢀIsothiocyanoꢀ2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinane (9).
31
Chloride 11 ( P NMR , δ 10.32) (0.23 g, 1.5 mmol) was added
Experimental
NMR spectra were recorded on Bruker Avanceꢀ400
to a solution of KSCN (0.29 g, 3.0 mmol) in MeCN (5 mL), the
31
reaction mixture was stirred at 45—50 °С for 17 h ( P NMR
monitoring). The mixture was filtered, the precipitate was washed
with MeCN; the filtrate was concentrated to dryness in vacuo,
the residue was extracted with C6H6 (5×5 mL), the extracts were
concentrated in vacuo (1 Torr). Isothiocyanate 9 was obtained
(1
H 400.13 MHz; P 161.98 MHz) and Bruker Avanceꢀ300 ( H
31
1
31
3
00.13 MHz; P 121.50 MHz) spectrometers in CDCl , the
3
signals for the residual protons of the deuterated solvents were
used as the internal standard ( H), 85% H PO in CDCl was
used as the external standard ( P).
Phosphoryl isothiocyanates 4, 5 were synthesized by the
described method, 2ꢀchloroꢀ2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinane
1
31
(0.23 g, 87%) ( P NMR, δ –13.69). The product was used in
3
4
3
31
the following reactions without additional purification.
3
Dimethyl Nꢀ[Nꢀ(2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinanꢀ2ꢀyl)thioꢀ
6
5
carbamoyl]ꢀLꢀaspartate (10a). Ester 6a (0.74 g, (4.6 mmol) in
C6H6 (3 mL) was added dropwise with stirring to a solution of
isothiocyanate 9 (0.82 g, 4.6 mmol) in C6H6 (10 mL) (slight
selfꢀheating from 22 to 27 °С occurred), and the reaction mixture
was kept for 16 h. The mixture was concentrated in vacuo, the
residue (1.47 g) was purified by chromatography in a CHCl3—
MeOH solvent system. Compound 10a was isolated (1.11 g,
72%) (solid foam) in the form of a stable solvate with 0.2 moleꢀ
cule of CHCl3 (See Table 1), the presence of the latter was
7
1
1
1 was obtained by the known method. Phosphoryl isocyanate
3 (Aldrich) was distilled in vacuo before reaction. KSCN that
was used for the reactions was dried azeotropically with C H
and then in vacuo over P O . Amino acid esters were obtained by
the known method, they were isolated from hydrochlorides
by treatment with a solution of NH in CHCl (see Ref. 9).
6
6
2
5
8
3
3
In some cases, the isolation of compounds was carried out
using column chromatography on SiO (130—270 mesh, Aldrich)
at a ratio compound : SiO 1 : 16 (w/w), gradient elution with a
2
1
confirmed by the H NMR spectrum in CD3CN. To remove the
2
mixture CHCl —MeOH from 100 : 1 to 10 : 1 or hexane—
solvate CHCl3, compound was dissolved in anhydrous MeOH,
the solution was concentrated to dryness in vacuo, and the residue
was dried over P2O5 (see Tables 1 and 2).
3
Me CO from 100 : 1 to 3 : 2. Fractions were analyzed by TLC
2
on SiO2 in the solvent systems CHCl —MeOH (10 : 1) or
3
3
hexane—Me CO (3 : 2).
Nꢀ[Nꢀ(2ꢀOxoꢀ1,3,2λ ꢀoxazaphosphinanꢀ2ꢀyl)thiocarbamoyl]ꢀ
2
Dimethyl Nꢀ[Nꢀ(diethoxyphosphoryl)thiocarbamoyl]ꢀ
Lꢀaspartate (7a). A solution of ester 6a (1.06 g, 6.7 mmol) in
C H (3 mL) was added dropwise with stirring to a solution of
glycine methyl ester (10b) was obtained similarly from isothioꢀ
cyanate 9 (0.80 g, 4.5 mmol) and ester 6b (0.45 g, 5.0 mmol) in
C6H6 (13 mL). Fine crystals that precipitated were filtered off,
the product was purified by precipitation with anhydrous ether
from a solition in CHCl3. Compound 10b was isolated (0.94 g,
78%) (see Tables 1 and 2).
6
6
isothiocyanate 4 (1.27 g, 6.5 mmol) in anhydrous C H (11 mL)
6
6
(
slight heating occurred). The course of the reaction was
31
monitored by P NMR spectroscopy by following disappearance
of the signal of 4 (δ –18.4). After 5 h at room temperature, the
solution was concentrated in vacuo, and the residue (1.68 g) was
3
Nꢀ[Nꢀ(2ꢀOxoꢀ1,3,2λ ꢀoxazaphosphinaneꢀ2ꢀyl)thiocarbamoyl]ꢀ
βꢀalanine methyl ester (10c) was obtained similarly from 9 (0.81 g,
4.55 mmol) and ester 6c (0.52 g, 5.0 mmol) in C6H6 (14 mL).
After removal of C6H6 and chromatographic purification using
a CHCl3—MeOH solvent system, compound 10c was isolated
(0.97 g, 76%) as a solid foam (see Tables 1 and 2).
chromatographed on SiO in a hexane—acetone solvent system.
2
Compound 7a was obtained in the form of a viscous yellowish
oil (1.60 g, 70%) (see Tables 1 and 2).
Nꢀ[Nꢀ(Diethoxyphosphoryl)thiocarbamoyl]glycine methyl
ester (7b) was obtained analogously by the reaction of 4 (1.04 g,
3
Dimethyl Nꢀ[Nꢀ(2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinanꢀ2ꢀyl)thioꢀ
5
.3 mmol) in C H (8 mL) with ester 6b (0.475 g, 5.4 mmol)
carbamoyl]ꢀLꢀglutamate (10d) was obtained under the same conꢀ
ditions from 9 (0.60 g, 3.37 mmol) and ester 6d (0.61 g, 3.50 mmol)
in C6H6 (10 mL). After chromatographic purification in a
CHCl3—MeOH solvent system, the isolated product was disꢀ
solved in anhydrous MeOH, the solution was concentrated in vacuo,
the residue was dried over P2O5. Compound 10d was obtained
(0.97 g, 81%) (see Tables 1 and 2) as solid foam.
6
6
in C H (1.5 mL). After 16 h, the product was filtered off
6
6
and chromatographed in a hexane—acetone solvent system.
Product 7b was isolated (0.55 g, 44%) as a white solid (see
Tables 1 and 2).
Nꢀ[Nꢀ(Diethoxyphosphoryl)thiocarbamoyl]ꢀβꢀalanine methyl
ester (7с) was obtained under the same conditions from comꢀ
pound 4 (0.80 g, 4.0 mmol) in C H (4.5 mL) and ester 6c (0.43 g,
3
Nꢀ[Nꢀ(2ꢀOxoꢀ1,3,2λ ꢀoxazaphosphinaneꢀ2ꢀyl)thiocarbamoyl]ꢀ
6
6
4
.1 mmol) in C H (2.0 mL); removal of the solvent in vacuo
alanine methyl ester (10e) was obtained similarly from 9 (0.87 g,
4.88 mmol) and ester 6e (0.57 g, 5.50 mmol) in C6H6 (14 mL).
The product was chromatographed in a CHCl3—MeOH solvent
6
6
and chromatography in a CHCl —MeOH solvent system yielded
7
3
c (0.79 g, 66%) (see Tables 1 and 2).

2516
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009
Shipov et al.
system and isolated in the form of a solvate (0.96 g, 70%) with
.2 molecule of CHCl3 (see Table 1). To remove the solvate
References
0
CHCl , compound was dissolved in anhydrous MeOH, the
solution was concentrated to dryness in vacuo, and the residue
3
1
. A. E. Shipov, G. K. Genkina, E. I. Goryunov, I. B.
Goryunova, P. V. Petrovskii, Izv. Akad. Nauk, Ser. Khim.
was dried in vacuo over P O (see Tables 1 and 2).
2
5
2
010, 122 [Russ. Chem. Bull., Int. Ed., 2010, 59, 122].
Nꢀ[Nꢀ(Diethoxyphosphoryl)carbamoyl]glycine methyl ester
12a). Ester 6b (0.53 g, 5.8 mmol) was added dropwise with
2
3
. K. D. Collins, G. R. Stark, J. Biol. Chem., 1971, 246, 6599.
. V. Gagnsrd, A. Leydet, V. Le Mellay, M. Aubenque,
A. Morere, J.ꢀL. Montero, J. Med. Chem., 2003, 38, 883.
. W. J. Stec, Organophosphorus Chem., 1982, 13, 145.
. M. BenꢀHari, G. Dewynter, C. Aymard, T. Jei, J. L. Montero,
Phosphorus, Sulfur, Silicon Relat. Elem., 1995, 105, 129.
. J. Michalski, J. Wieczorkowski, Rocz. Chem., 1957, 31, 585.
. R. N. Hunston, M. Jehangir, A. S. Jones, R. T. Walker,
Tetrahedron, 1980, 36, 2337.
(
stirring to a solution of isocyanate 13 (1.00 g, 5.6 mmol) in C H6
6
(
8 mL) (selfꢀheating by 5 °С occurred). After 16 h at room
4
5
temperature, the gelꢀlike mixture was diluted with ether, the
residue was filtered off and washed with ether. Solid product 12a
was obtained (0.80 g, 54%) (see Tables 1 and 2).
Nꢀ[Nꢀ(Diethoxyphosphoryl)carbamoyl]ꢀβꢀalanine methyl
ester (12b) was obtained similarly from isocyanate 13 (0.59 g,
6
7
3
.3 mmol) in C H (4.5 mL) and ester 6c (0.35 g, 3.4 mmol)
6 6
8
9
. G. Greenstein, M. Winits, Chemistry of Amino Acids, J. Wiley
and Sons, New York—London, 1961.
. G. Hillmann, Z. Naturforschung, 1946, 1, 682.
in C H (1.5 mL), the precipitate was filtered off and washed
6
6
with ether. Solid compound 12b was isolated (0.59 g, 70%) (see
Tables 1 and 2).
The work was financially supported by the Russian
Academy of Sciences (Program of Division of Chemistry
and Materials Science, Russian Academy of Sciences,
OKhꢀ09 «Medicinal and Biomolecular Chemistry»).
Received July 24, 2009