Phosphorus-containing derivatives of L-aspartic and L-glutamic acids

Article abstract of DOI:10.1007/s11172-010-0054-y

Phosphorylureas (including those with the 1,3,2-oxazaphosphinane ring) containing L-aspartate and L-glutamate fragments, as well as 1,3,2-oxazaphosphinane derivatives of phosphorylacetic acid with an L-aspartate fragment and of phosphamide with an L-gluta

Full text of DOI:10.1007/s11172-010-0054-y

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 122—126, January, 2010
122
Phosphorusꢀcontaining derivatives of Lꢀaspartic and Lꢀglutamic acids
A. E. Shipov, G. K. Genkina, E. I. Goryunov, I. B. Goryunova, and P. V. Petrovskii
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: shipov@ineos.ac.ru
Phosphorylureas (including those with the 1,3,2ꢀoxazaphosphinane ring) containing
Lꢀaspartate and Lꢀglutamate fragments, as well as 1,3,2ꢀoxazaphosphinane derivatives of phosꢀ
phorylacetic acid with an Lꢀaspartate fragment and of phosphamide with an Lꢀglutamate fragꢀ
ment, were obtained in a search for structural analogs of aspartate transcarbamoylase and
glutamate carboxypeptidase inhibitors.
Key words: phosphoryl isocyanates, amino acids, phosphorylcarbamoylꢀLꢀaspartates, phosꢀ
phorylcarbamoylꢀLꢀglutamates, 1,3,2ꢀoxazaphosphinanes, the Arbuzov reaction, carcinolytics.
Scheme 1
NꢀPhosphonoacetylꢀLꢀaspartic acid (the drug PALA),
which is a phosphorylated derivative of Lꢀaspartic acid,
exhibits high carcinolytic activity.1 Its analogs (e.g., asꢀ
partate derivatives) are also aspartate transcarbamoylase
inhibitors, some of them being even more cytotoxic.2—4 It
is also known that phosphorylamides of glutamic acid inꢀ
hibit glutamate carboxypeptidase.5 For this reason, we
deemed it interesting to obtain P,Nꢀcontaining Lꢀasparꢀ
tateꢀ and Lꢀglutamateꢀbased structural analogs of the
aforementioned enzyme inhibitors, including 1,3,2ꢀoxazaꢀ
phosphinane derivatives (by analogy with the carcinolytic
cyclophosphamide, their oxazaphosphinane ring can
deliver a pharmacophore group inside a cell across cell
membranes6).
Reaction conditions: MeCN(C6H6), 20 °C.
n = 1 (2, 4), 2 (3, 5)
R = R´ = EtO (1a, 4a, 5a), Ph (1c, 4c)
R = Me, R´ = PhO (1b, 4b)
One of the potentially most attractive ways of PALA
modification could involve replacement of the methylene
linker, which binds the phosphoryl group to the amino
acid residue, by an amino group. According to the literaꢀ
ture data,7 biologically active compounds are very likely to
be found among the corresponding phosphorylureas.
Starting from diethoxyꢀ (1a), methyl(phenoxy)ꢀ (1b),
and diphenylphosphoryl isocyanate (1c) (typical represenꢀ
tatives of phosphoryl, phosphonoyl, and phosphinoyl isoꢀ
cyanates), dimethyl Lꢀaspartate (2), and dimethyl Lꢀgluꢀ
tamate (3), we obtained phosphorylureas 4a—c and 5a
(Scheme 1). At room temperature, the reactions proceeded
with high rates in benzene or acetonitrile to give the correꢀ
sponding phosphorylureas in 70—90% yields (Table 1).
With urea (4d) (R = R1 = MeO) as an example, we
demonstrated that this type of dialkoxyphosphorylꢀconꢀ
taining compounds can also be synthesized from isocyꢀ
anatophosphorodichloridate (6). Its reaction with ester 2
gave intermediate dichlorophosphorylurea 7, which was
treated8 in situ with methanolic MeONa (Scheme 2).
Dimethoxy derivative 4d was converted into the correꢀ
sponding acid 8 and further into its disodium salt 9 (see
Scheme 2). 1,3,2ꢀOxazaphosphinane derivative 10 was
obtained from urea 7 and 3ꢀaminopropanꢀ1ꢀol in the presꢀ
ence of Et3N (see Scheme 2).
Another oxazaphosphinane derivative of Lꢀaspartic
acid, whose monooxygenaseꢀcatalyzed metabolism should
produce a close analog of PALA,6 was obtained from
2ꢀmethoxyꢀ1,3,2ꢀoxazaphosphinane (11) and dimethyl
NꢀchloroacetylꢀLꢀaspartate (12) as described earlier9
(Scheme 3). As in the previous cases,9 the reaction yields
not only the target cyclic product 13, but also acyclic
product 14; the ratio 13 : 14 is 100 : 28 (31P NMR data).
Product 13 was isolated by column chromatography as
a stable solvate with chloroform (13•0.3CHCl3).
Compound 13 is easily hydrolyzed with cleavage of the
P—N bond to yield betaine 15, a close analog of PALA
(Scheme 4).
An oxazaphosphinane derivative of Lꢀglutamic acid 16,
an analog of glutamate carboxypeptidase inhibitors,5 was
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 122—126, January, 2010.
1066ꢀ5285/10/5901ꢀ0122 © 2010 Springer Science+Business Media, Inc.

LꢀAspartate and Lꢀglutamate derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
123
Table 1. Yields, melting points, and elemental analysis data for the compounds obtained
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
N
C
H
P
4a
4b
4c
4d
5a
8
89.5
76.8
97.8
53.5
96.0
62.7
6.5
136—137
105—107
180—182
140—141
129.5—131
38.74
38.83
46.69
46.93
56.38
56.44
34.60
34.62
40.61
40.68
29.37
29.59
37.27
37.16
37.85
37.90
38.87
38.83
40.87
40.82
6.24
6.22
5.31
5.34
5.18
5.23
5.46
5.49
6,59
6.54
4.63
4.61
5.68
5.61
5.44
5.43
6.29
6.22
6.54
6.51
8.20
9.10
9.10
8.64
8.64
7.64
7.66
9.67
9.92
8.75
8.74
—
C11H21N2O8P
C14H19N2O7P
C19H21N2O6P
C9H17N2O8P
8.23
7.71
7.82
6.82
6.93
8.94
8.97
7.91
7.91
9.74
9.86
12.94
13.00
7.58
7.82
8.07
8.23
9.54
9.52
С12H23N2O8P
C7H13N2O8P
122—124
(decomp.)
188—189
10
13
15
16
—
C10H18N3O7P
C11H19N2O7P•0.3CHCl3
C11H21N2O8P
C10H19N2O6P
a
55.3
98.6
51.0
—
8.55
8.65
—
b
—
102—107с
—
a A glassy mass.
b Softens at 50—60 °C.
c For a 10 : 4 mixture of diastereomers.
Scheme 2
Reaction conditions: i. MePh (MeCN), –5 °C; ii. MeONa—MeOH, –5 °C; iii. 1) Me3SiBr, 2) MeOH; iv. NaHCO3, H2O;
v. H2N(CH2)3OH, Et3N, MeCN, –7 °C.
synthesized from 2ꢀchloroꢀ2ꢀoxoꢀ1,3,2λ5ꢀoxazaphosphiꢀ
nane (17) and ester 3 in the presence of Et3N (Scheme 5).
The compositions and structures of the compounds
obtained were confirmed by elemental analysis data (see
Table 1) and 31P{1H} and 1H NMR spectra (Table 2). The
NMR spectra of compounds 4b, 13, 14, and 16 containing
two chiral centers (the C and P atoms) show diastereoꢀ
meric anisochronism.
Biological in vitro tests revealed that the compounds
obtained at a concentration of 10–4 mol L–1 do not cause
death of 50% of cells of the human tumor lines Caov3
(ovarian carcinoma) and A549 (nonꢀsmall cell lung carciꢀ

124
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shipov et al.
Scheme 3
Scheme 4
(300.13 (1H) and 121.50 MHz (31P)) in CDCl3, CD3OD,
DMSOꢀd6, and D2O with the signals for residual protons of the
deuterated solvent as the internal standard (1H) and in C6H6,
CDCl3, DMSOꢀd6, and D2O with 85% H3PO4 as the external
standard (31P).
Phosphoryl isocyanate 1a (Aldrich) was distilled in vacuo
before use. Phosphoryl isocyanates 1b,11 1c,11 and 6,12 2ꢀmethꢀ
oxyꢀ1,3,2ꢀoxazaphosphinane (11),13 and 2ꢀchloroꢀ2ꢀoxoꢀ
5
1,3,2λ ꢀoxazaphosphinane14 were prepared as described earlier.
In some cases, the reaction products were isolated by colꢀ
umn chromatography on SiO2 (Aldrich, 130—270 mesh; prodꢀ
uct : sorbent = 1 : 16 (w/w); CHCl3—MeOH as an eluent, gradiꢀ
ent elution from 100 : 1 to 10 : 1). The fractions were inspected
by TLC on SiO2 in CHCl3—MeOH (10 : 1).
Dimethyl Nꢀ[Nꢀ(diethoxyphosphoryl)carbamoyl]ꢀLꢀaspartate
(4a). A solution of ester 2 (0.913 g, 5.58 mmol) in MeCN (5 mL)
was added dropwise at room temperature to a stirred solution of
isocyanate 1a (1.00 g, 5.58 mmol) in anhydrous MeCN (7 mL).
The reaction mixture was stirred for 5 h and kept for 16 h. The
precipitate was filtered off and washed with ether. The yield of
compound 4a was 1.70 g (89.5%).
Scheme 5
Dimethyl Nꢀ[Nꢀ(methylphenoxyphosphoryl)carbamoyl]ꢀLꢀasꢀ
partate (4b) was obtained analogously from isocyanate 1b (1.97 g,
10 mmol) in benzene (10 mL) and ester 2 (1.64 g, 10 mmol) in
benzene (5 mL). The solvent was removed in vacuo, the viscous
residue was triturated with ether, and the resulting precipitate
was filtered off. The yield of the product was 2.50 g. The filtrate
was concentrated in vacuo and the residue was triturated with
acetone to give additional crop of the product (0.25 g). The total
yield of compound 4b was 2.75 g (76.8%).
Dimethyl Nꢀ[Nꢀ(diphenylphosphoryl)carbamoyl]ꢀLꢀaspartate
(4c) was obtained analogously from isocyanate 1c (1.042 g,
4.3 mmol) in anhydrous benzene (10 mL) and ester 2 (0.722 g,
4.3 mmol) in benzene (10 mL). The precipitate was filtered off
and washed with anhydrous hexane (2×10 mL). The yield of
compound 4c was 1.70 g (97.8%).
Reaction conditions: Et3N, MeCN, –3—0 °C.
noma). Thus, they are not cytotoxic in vitro in this conꢀ
centration. However, proliferation of the above cell lines
was substantially inhibited (note that PALA itself is active
in concentrations of ~10–4 mol L–1).2 Taking into acꢀ
count that other 1,3,2ꢀoxazaphosphinane derivatives (e.g.,
cyclophosphamide) kill no tumor cells in vitro as well,10
yet being highly efficient against them in vivo, one can
assume that new 1,3,2ꢀoxazaphosphinane derivative 10
will exhibit biological activity in in vivo tests. The results
of these tests will be published elsewhere.
Dimethyl Nꢀ[Nꢀ(diethoxyphosphoryl)carbamoyl]ꢀLꢀglutamate
(5a) was obtained under the same conditions from isocyanate 1a
(0.506 g, 2.825 mmol) in MeCN (3.5 mL) and ester 3 (0.494 g,
2.825 mmol) in MeCN (3.5 mL). The yield of compound 5a was
0.96 g (96.0%).
Experimental
Dimethyl Nꢀ[Nꢀ(dimethoxyphosphoryl)carbamoyl]ꢀLꢀasparꢀ
tate (4d). A solution of ester 2 (1.61 g, 10 mmol) in toluene
(15 mL) was added dropwise at –5 °C for 1 h 45 min to a stirred
NMR spectra were recorded on Bruker Avance 400 (400.13
(1H) and 161.98 MHz (31P)) and Bruker Avance 300 instruments

LꢀAspartate and Lꢀglutamate derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
125
Table 2. 31P{1H} and 1H NMR spectra of the compounds obtained
Comꢀ
pound
31P, δ
(solvent)
1H, δ, J/Hz (CDCl3)
4a
–1.31 (CDCl3)
1.36 (t, 6 H, CH3CH2, 3JH,H = 7.1); 2.86 (AB system, 1 H, HB, CH2CH, 3JH,H = 4.9,
B
2JH
= 16.9); 3.00 (AB system, 1 H, HA, CH2CH, 3JH,H = 5.0, 2JH
= 16.9); 3.69, 3.74
A,HB
A,HB
A
(both s, 3 H each, CH3O); 4.09—4.26 (m, 4 H, CH2CH3); 4.76 (dt, 1 H, NHCHCH2, 3JH,H = 5.0,
3JH,H = 8.2); 6.26 (d, 1 H, NHP, 2JH,H = 4.56); 7.56 (d, 1 H, NHCH, 2JH,H = 8.5)
4b
28.10 (CHCl3);
28.65,
Diastereomer α: 1.85 (d, 3 H, CH3P, 2JH,P = 9.0); 2.82 (AB system, 1 H, HB, CH2CH,
3JH,H = 4.8, 2JH
= 17.3); 2.98 (AB system, 1 H, HA, CH2CH, 3JH,H = 4.7, 2JH
= 17.3);
A,HB
A,HB
B
B
29.09 (C6H6)
3.66, 3.71 (both s, 3 H each, CH3O); 4.68—4.74 (m, 1 H, NHCHCH2); 6.80 (d, 1 H, NHP,
2JH,P = 8.6); 7.11—7.27 (m, 5 H, C6H5); 7.95 (br.s, 1 H, NHCH)
Diastereomer β: 1.85 (d, 3 H, CH3P, 2JH,P = 9.0); 2.74 (AB system, 1 H, HB, CH2CH,
3JH,H = 4.8, 2JH
= 17.1); 2.94 (AB system, 1 H, HA, CH2CH, 3JH,H = 4.6, 2JH
= 17.1);
A,HB
A,HB
B
3.63, B3.74 (both s, 3 H each, CH3O); 4.68—4.74 (m, 1 H, NHCHCH2); 6.86 (d, 1 H, NHP,
2JH,P = 8.5); 7.11—7.27 (m, 5 H, C6H5); 7.92 (br.s, 1 H, NHCH)
4c
4d
5a
24.18 (CDCl3)
–1.56 (CDCl3)
–1.00 (CDCl3)
2.75 (AB system, 1 H, HB, CH2CH, 3JH,H = 5.0, 2JH
= 17.0); 2.88 (AB system, 1 H, HA,
A,HB
B
CH2CH, 3JH,H = 4.8, 2JH
= 17.0); 3.58, 3.62 (both s, 3 H each, CH3O); 4.66 (dt, 1 H,
A,HB
A
NHCHCH2, 3JH,H = 5.0, 3JH,H = 8.1); 7.33—7.59 (m, 8 H, mꢀC6H5 + pꢀC6H5 + 2 NH);
7.71—7.86 (m, 7 H, oꢀC6H5)
2.86 (AB system, 1 H, HB, CH2CH, 3JH,H = 4.7, 2JH
= 16.9); 3.00 (AB system, 1 H, HA,
A,HB
B
CH2CH, 3JH,H = 5.1, 2JH
= 16.9); 3.69, 3.74 (both s, 3 H each, CH3OC); 3.82, 3.83 (both d,
A,HB
A
3 H each, CH3OP, 3JH,P = 6.0); 4.66 (dt, 1 H, NHCHCH2, 3JH,H = 4.8, 3JH,H = 8.3); 7.01 (d, 1 H,
NHP, 2JH,P = 6.7); 7.40 (d, 1 H, NHCH, 3JH,H = 8.0)
1.35 (t, 3 H, CH3CH2, 3JH,H = 7.0); 1.36 (t, 3 H, CH3CH2, 3JH,H = 7.0); 1.94—2.06, 2.16—2.27
(both m, 1 H each, CH2CH); 2.33—2.48 (m, 2 H, CH2C(O)); 3.66, 3.73 (both s, 3 H each, CH3O);
4.09—4.24 (m, 4 H, CH2O); 4.47 (dt, 1 H, NHCHCH2, 3JH,H = 5.4, 3JH,H = 8.0); 6.72 (d, 1 H,
NHP, 2JH,P = 6.0); 7.28 (d, 1 H, NHCH, 3JH,H = 7.6)
7
8
8.19 (CHCl3)
—
–1.76 (CD3OD)
2.89 (AB system, 1 H, HB, CH2CH, 3JH,H = 5.0, 2JH
= 16.8); 2.99 (AB system, 1 H, HA,
A,HB
= 16.8); 3.72, 3.77 (both s, 3 H each, CH3O); 4.74 (t, 1 H,
B
CH2CH, 3JH,H = 5.5, 2JH
A,HB
A
NHCHCH2, 3JH,H = 5.2)a
9
–3.45 (H2O)
—
10
—0.79
(DMSOꢀd6)
1.61—1.70, 1.72—1.85 (both m, 1 H each, CH2CH2CH2); 2.78 (AB system, 1 H, HB, CH2CH,
3JH,H = 5.3, 2JH = 17.4); 2.84 (AB system, 1 H, HA, CH2CH, 3JH,H = 5.8, 2JH
= 17.4);
A,HB
A,HB
B
A
2.96—3.13, 3.15—3.28 (both m, 1 H each, CH2NHP); 3.62, 3.65 (both s, 3 H each, CH3O); 4.15—4.32
(m, 2 H, CH2OP); 4.59 (dt, 1 H, NHCHCH2, 3JH,H = 5.4, 3JH,H = 8.1); 5.11 (br.s, 1 H,
CH2NHP); 7.12, 7.14 (both d, 1 H, NHP, 3JH,P = 9.1); 8.02 (dd, 1 H, NHCH, 3JH,H = 4.9,
3JH,H = 10.0)b
13
20.11,
20.22 (CDCl3)
1.73—1.77, 1.96—2.03 (both m, 1 H each, CH2CH2CH2); 2.80–3.08 (m, 4 H, CH2CH, CH2P);
3.24—3.33 (m, 2 H, CH2NHP); 3.6565, 3.6608 (both s, 3 H, CH2COOCH3); 3.7062, 3.7126 (both s,
3 H, CHCOOCH3); 3.81 (d, 1 H, NHP, 2JH,P = 29.0); 4.24—4.42 (m, 2 H, CH2OP); 4.80—4.88
(m, 1 H, CHCH2); 7.69 (d, 0.5 H, NHCH, 3JH,H = 7.9); 7.84 (d, 0.5 H, NHCH, 3JH,H = 8.2)
14
15
26.87,
27.24 (CHCl3)
—
15.62 (CDCl3);
13.67 (DMSOꢀd6) CH2CH, 3JH,H = 5.5, 2JH
1.76 (br.s, 2 H, CH2CH2CH2); 2.43 (d, 2 H, CH2P, 2JH,P = 19.0); 2.68 (AB system, 1 H, HB,
= 16.5); 2.75 (AB system, 1 H, HA, CH2CH, 3JH,H = 6.4,
A,HB
A
2JH
= 16.5)B; 2.84 (br.s, 2 H, CH2NH2); 3.57, 3.59 (both s, 3 H each, CH3O); 3.78 (br.s, 2 H,
A,HB
CH2O); 4.61 (dt, 1 H, NHCHCH2, 3JH,H = 6,5, 3JH,H = 7.0); 8.26 (br.s, 2 H, H2NCH2);
8.50 (d, 1 H, HNCH, 3JH,H = 7.9)b
16
9.49, 9.70 (CDCl3) 1.79 (t, 2 H, CH2C(O), 3JH,H = 5.2); 1.86—1.97, 2.06—2.16 (both m, 1 H each, CH2CH2CH2);
2.36—2.52 (m, 2 H, CH2CH); 2.83 (broad s, 1 H, CHNHP); 3.13—3.23, 3.30—3.39 (both m,
1 H each, CH2NH); 3.48 (broad d, 1 H, CH2NHP, 2JH,P = 26.1); 3.64, 3.70 (both s, 3 H each,
CH3O); 3.91 (br.s, 1 H, NHCHCH2); 4.16—4.24, 4.31—4.39 (both m, 1 H each, CH2OP)
a In CD3OD.
b In DMSOꢀd6.

126
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shipov et al.
solution of isocyanate 6 (1.60 g, 10 mmol) in anhydrous toluene
(15 mL); a precipitate of urea 7 was formed (see Table 2). The
mixture was stirred at room temperature for 40 min and then
cooled to –5 °C. A solution of MeONa (from metallic Na (0.58 g,
25 mmol)) in MeOH (15 mL) was added dropwise with stirring.
The mixture was kept for 16 h and centrifuged to remove
a precipitate of NaCl (20 min, 5500 rpm). The supernatant was
concentrated in vacuo. The residue was dissolved in acetone
(30 mL) and the solution was again centrifuged and concentratꢀ
ed in vacuo. The crude product (2.93 g) was purified by column
chromatography on SiO2 and recrystallized from acetone—ether.
The yield of compound 4d was 1.67 g (53.5%).
Dimethyl Nꢀ(Nꢀphosphonocarbamoyl)ꢀLꢀaspartate (8). Triꢀ
methylsilyl bromide (1.28 g, 8.33 mmol) was added to a solution
of ester 4d (1.04 g, 3.33 mmol) in anhydrous CHCl3 (15 mL).
After 24 h, the solution was concentrated in vacuo at room temꢀ
perature. The residue was dissolved in MeOH (20 mL) and the
solution was stirred for 1 h, filtered, and concentrated in vacuo.
The crude solid product (1.01 g; calcd 0.95 g) was triturated
with acetone. The resulting precipitate was filtered off, washed
with acetone and ether, and dried in vacuo. The yield of comꢀ
pound 8 was 0.60 g (62.7%).
The residue (solidified foam) was dried in vacuo over P2O5. The
yield of amorphous solid betaine 15 was 0.70 g (98.6%).
5
Dimethyl Nꢀ(2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinanꢀ2ꢀyl)ꢀLꢀgluꢀ
tamate (16). A mixture of ester 3 (0.88 g, 5 mmol) and Et3N
(0.51 g, 5 mmol) in MeCN (10 mL) was added dropwise at
–3—0 °C for 25 min to a solution of chloride 17 (0.78 g, 5 mmol)
in MeCN (10 mL). The reaction mixture was stirred at room
temperature for 3 h and kept for 16 h. The precipitate that formed
was filtered off and the filtrate was concentrated in vacuo. The
residue was dissolved in dry acetone and the resulting solution
was filtered again and concentrated. The residue (1.13 g) was
purified by column chromatography on SiO2. The product was
recrystallized from benzene with a small amount of hexane. The
yield of compound 16 was 0.75 g (51.0%).
This work was financially supported by the Division of
Chemistry and Materials Science of the Russian Academy
of Sciences (Program OKhꢀ09 "Medicinal and Biomolecꢀ
ular Chemistry").
References
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(3 mL) (foaming) and the solution was repeatedly concentrated
in vacuo with addition of CHCl3 and anhydrous MeOH for comꢀ
plete removal of water. The solid residue was dried in vacuo over
P2O5. The yield of hygroscopic salt 9 was 0.11 g (100%).
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5
Dimethyl Nꢀ[Nꢀ(2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinanꢀ2ꢀyl)carbꢀ
amoyl]ꢀLꢀaspartate (10). Ester 2 in MeCN (10 mL) was added
dropwise at –5 °C for 1 h to a stirred solution of isocyanate 6
(1.60 g, 10 mmol) in anhydrous MeCN (15 mL). The mixture
was allowed to warm to room temperature, kept for 1 h, and then
cooled to –5 °C. A mixture of 3ꢀaminopropanꢀ1ꢀol (0.75 g,
10 mmol) and Et3N (1.06 g, 10.5 mmol) in MeCN (10 mL) was
added dropwise for 2 h. The resulting mixture was allowed to
warm to 0 °C and another portion of Et3N (1.06 g, 10.5 mmol) in
MeCN (5 mL) was added over 30 min. Stirring was continued at
room temperature for 2.5 h. The mixture was left for 16 h. The
precipitate that formed was filtered off and washed with MeCN.
Dilution of the filtrate produced a precipitate (white resin). The
solution was decanted and concentrated. The residue (3.60 g)
was chromatographed on SiO2 and recrystallized from anhyꢀ
drous MeOH. The yield of compound 10 was 0.21 g (6.5%).
5
Dimethyl Nꢀ[(2ꢀoxoꢀ1,3,2λ ꢀoxazaphosphinanꢀ2ꢀyl)acetyl]ꢀ
Lꢀaspartate (13). Phosphinane 11 (1.35 g, 10 mmol) was added
dropwise under argon at 60 °C to a solution of ester 12 (2.38 g,
10 mmol) in anhydrous MeCN (2 mL). The reaction mixture
was heated at 85 °C for 8 h. The final mixture contained prodꢀ
ucts 13 and 14 in a ratio of 100 : 28 (31P NMR data, see Table 2).
The solvent was removed in vacuo, the residue (3.62 g) was sepaꢀ
rated by column chromatography. Phosphinane 13 was isolated
as a stable solvate with CHCl3. The yield of solvate 13•0.3CHCl3
was 1.78 g (55.3%), a viscous glassy mass (see Tables 1, 2).
Dimethyl Nꢀ{[(3ꢀaminopropoxy)hydroxyphosphoryl]acetyl}ꢀ
Lꢀaspartate (15). A solution of solvate 13•0.3CHCl3 (0.75 g,
2.1 mmol) in water (15 mL) was stirred at 35—40 °C for 5 h and
repeatedly concentrated in vacuo with addition of CHCl3 and
MeOH. The dry residue was dissolved in anhydrous MeOH and
the resulting solution was filtered and concentrated in vacuo.
Received February 6, 2009;
in revised form July 24, 2009