Hydroxyurea analogues of fosmidomycin

Article abstract of DOI:10.1515/znb-2003-0114

Benzyloxyureas (4) have been prepared by reactions of diethyl 3-benzyloxyamino-propyl-phosphonate (3) with isocyanates, potassium cyanate or 1,1'-carbonyldiimidazole / methylamine. Conversion of phosphonic esters 4 into phosphonic acids 6 by means of brom

Full text of DOI:10.1515/znb-2003-0114

Hydroxyurea Analogues of Fosmidomycin
Thomas Kurz, Detlef Geffken, and Claudia Wackendorff
Institut fu¨r Pharmazie, Abteilung fu¨r Pharmazeutische Chemie, Universita¨t Hamburg,
Bundesstraße 45, D-20146 Hamburg.
Reprint requests to Dr. T. Kurz. Fax: +49(0)40-42838-6573
Z. Naturforsch. 58b, 106 – 110 (2003); received September 18, 2002
Benzyloxyureas (4) have been prepared by reactions of diethyl 3-benzyloxyamino-propyl-phos-
phonate (3) with isocyanates, potassium cyanate or 1,1’-carbonyldiimidazole / methylamine. Conver-
sion of phosphonic esters 4 into phosphonic acids 6 by means of bromotrimethylsilane and catalytic
hydrogenation of 4, 6 afforded the target compounds 5, 7.
Key words: Malaria tropica, Fosmidomycin, Hydroxyurea Analogues
Introduction
Treatment of 3 with various isocyanates or potas-
sium cyanate afforded benzyloxyureas 4a,c-f in ex-
cellent yields of 83 – 95% after purification by col-
umn chromatography. Benzyloxyurea 4b was ac-
cessible by reacting 3 with 1.05 equivalents of
1,1’-carbonyldiimidazole and subsequent addition of
methylamine [8]. The formation of 4a-f was monitored
by running IR spectra from the reaction mixture show-
ing the rapid emergence of a strong (C==O) absorption
at 1650– 1685 cm−1. Dealkylation of phosphonic es-
ters (4b-e) by means of bromotrimethylsilane and sub-
sequent aqueous hydrolysis of the trimethylsilyl ester
intermediates led to phosphonic acids 6b-e as crys-
talline compounds in 83 – 91% yield (Scheme 2).
Replacement of a hydroxamic acid functionality by
a hydroxyurea group represents an important tool in
medicinal and agricultural chemistry. Both function-
alities have attracted considerable interest as phar-
macophores in metalloenzyme inhibitors due to their
ability to act as chelators for various metal cations
[1, 2]. Fosmidomycin (I), a phosphono-hydroxamic
acid antibiotic, which was described by Fujisawa com-
pany in 1980, is assumed to inhibit the bacterial iso-
prenoid synthesis [3,4]. In 1999 Jomaa [5] identified
I as potent inhibitor of the 1-desoxy-D-xylulose-5-
phosphate (DOXP) reductoisomerase of Plasmodium
falciparum, the causative agent of Malaria tropica.
Previously only two hydroxyurea analogues of Fos-
midomycin have been described by Fujisawa company
[2,6]. This prompted us to synthesize novel hydrox-
yurea analogues of I for structure activity investiga-
tions.
Catalytic hydrogenation of 4a-f and 6b,c provided
hydroxyureas 5a-f, and 7b,c in good to excellent yields
as stable compounds. In contrast to the catalytic hy-
drogenation of 6b,c the analogous reaction of 6d,e
1
only led to crude products. Despite suitable H NMR
spectra no satisfactory mass spectra or CHN analysis
could be obtained. The structures of 4-7 were con-
firmed by NMR spectra, mass spectra and CHN analy-
ses (Table 1).
O
P
OH
N
HO
CHO
HO
Fig. 1. Fosmidomycin (I).
Experimental Section
General Methods: Melting points (uncorrected) were de-
termined on a Mettler FP 62 apparatus. Elemental analyses
were carried out with a Heraeus CHN—O-Rapid instrument.
IR spectra were recorded on a Shimadzu FT-IR 8300 or on a
Perkin Elmer Series 1600 FT-IR. 1H NMR (400.1 MHz) and
13C NMR (100.62 MHz) spectra were recorded on a Bruker
AMX 400 spectrometer using tetramethylsilane as an inter-
Results and Discussion
Diethyl 3-benzyloxyamino-propylphosponate (3)
was prepared from diethyl 3-oxo-propylphospho-
nate (1) [7] and O-benzylhydroxylamine followed
by reduction of 2 with sodium cyanoborohydride
(Scheme 1).
c
0932–0776 / 03 / 0100–0106 $ 06.00 ꢀ 2003 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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Th. Kurz et al. · Hydroxyurea Analogues of Fosmidomycin
107
O
P
O
P
O
P
i
ii
O
N
OCH2Ph
NH OCH2Ph
EtO
EtO
EtO
Scheme 1.
EtO
EtO
EtO
1
2
3
Reagents: i: NH2OCH2Ph, ii: NaBH3CN, HCl
O
P
NHOCH2Ph
EtO
O
OH
EtO
3
O
P
OCH2Ph
NHR
iii
P
N
NHR
N
HO
HO
HO
i
HO
7b,c
O
ii
O
P
OCH2Ph
6b-e
O
Scheme 2.
N
NHR
EtO
EtO
iii
O
P
OH
N
4a-f
O
NHR
EtO
EtO
5a-f
O
Reagents: i: RNCO or KOCN or 1,1’-carbonyldiimidazole (CDI) / methylamine, ii: TMSBr / H O, iii: H2 / Pd-C
2
2H, NCH2), 4.02-4.16 (m, 4H, OCH2CH3), 4.69 (s, 2H,
OCH2Ph), 5.59 (s, 1H, NH), 7.29-7.35 (m, 5H). – 13C
NMR (CDCl3): δ = 16.45 (d, 3JC,P = 6.1 Hz, OCH2CH3),
Table 1. Benzyloxyureas 4,6 and hydroxyureas 5,7.
4-7
a
b
R
H
CH3
C2H5
4 yield [%] 5 yield [%] 6 yield [%] 7 yield [%]
95
83
93
92
83
95
87
87
89
99
94
90
2
1
20.62 (d, JC,P = 5.1 Hz, PCH2CH2), 23.26 (d, JC,P
=
92
94
89
90
82
83
3
c
142.4 Hz, PCH2), 52.2 (d, JC,P = 16.8 Hz, NCH2), 61.5
2
d i-C3H7
e
f
(d, JC,P = 6.1 Hz, OCH2CH3), 76.39 (OCH2Ph), 127.85,
t-C4H9
Ph
128.40, 128.41, 137.89 (Carom.). – C14H24NO4P (301.3):
calcd. C 55.81, H 8.03, N 4.65; found C 55.53, H 7.90, N
4.76.
nal standard and DMSO-d6, D2O and CDCl3 as solvents.
Mass spectra were recorded on a VG 70-250S (VG Analyti-
cal) instrument. Column chromatography was conducted on
General procedures for the preparation of
benzyloxyureas (4)
˚
silica gel (ICN Silica 100-200, active 60 A).
Method A: To a stirred solution of 3 (3.01 g, 10 mmol)
in dry CH2Cl2 (5 ml) was added the appropriate isocyanate
(10.5 mmol) at ambient temperature. After stirring over night
the reaction mixture was purified by column chromatography
on silica gel with EtOAc as an eluent.
Preparation of diethyl 3-benzyloxyamino-
propylphosphonate (3)
To a stirred solution of 1 (5.83 g, 30 mmol) in
MeOH (20 ml) was added dropwise a solution of O-
benzylhydroxylamine (3.88 g, 31.5 mmol) in MeOH (10 ml).
The reaction mixture was refluxed for 1 h, cooled to 20 ◦C,
and MeOH (420 ml) was added. After addition of sodium
cyanoborohydride (5.66 g, 90 mmol), conc. HCl (30 ml)
was added dropwise over a period of 30 min. After 1 h
sodium cyanoborohydride (1.26 g, 20 mmol) was added
again and the mixture was stirred for another hour. 200 ml
of MeOH were removed under reduced pressure; the remain-
Method B: A solution of KOCN (4.06 g, 50 mmol) in
water (15 ml) was added dropwise to a stirred solution of
◦
3 (3.01 g, 10 mmol) in 1 M HCl (50 ml) at 0 C. After
stirring at ambient temperature for 30 min the mixture was
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, concentrated and the remaining oil was
purified by column chromatography on silica gel with EtOAc
as an eluent.
Method C: To a suspension of CDI (1.62 g, 10 mmol)
ing residue was treated with 400 ml of ice-water, adjusted in dry CH2Cl2 (10 ml) was added dropwise a solution of 3
to pH 10 with aqueous KOH-solution and extracted with (3.01 g, 10 mmol) in dry CH2Cl2 (10 ml) over a period of
CH2Cl2 (3×50 ml). The combined organic layers were dried 10 min under ice-cooling. After stirring at ambient temper-
over MgSO4 and concentrated. The remaining oil was pu- ature for 20 min, 5 ml of a 2 M solution of methylamine in
rified by silica gel column chromatography with EtOAc as THF (10 mmol) was added dropwise. The reaction mixture
an eluent to give diethyl 3-benzyloxyamino-propylphospho- was stirred for 12 h, washed with 1 M HCl (2×10 ml), and
nate (3) as a yellow oil (81%). – IR (film): ν = 3246 (NH) the organic layer was dried over MgSO4. After removal of
cm−1. – 1H NMR (CDCl3): δ = 1.31 (t, J = 7.0 Hz, 6H, the solvent the remaining oil was purified by column chro-
OCH2CH3), 1.74-1.90 (m, 4H, CH2), 2.98 (t, J = 6.6 Hz, matography on silica gel with EtOAc as an eluent.
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108
Th. Kurz et al. · Hydroxyurea Analogues of Fosmidomycin
4.76 (s, 2H, OCH2Ph), 5.44 (d, J = 7.6 Hz, 1H, NH),
Diethyl 3-(1-benzyloxyureido)propylphosphonate (4a):
Method B; yellow oil (95%) – IR (film): ν = 1685 (C==O), 7.35-7.41 (m, 5H). – 13C NMR (CDCl3): δ = 16.47 (d,
1240 (P==O) cm−1. – 1H NMR (CDCl3): δ = 1.31 (t, J = 3JC;P = 6.1 Hz, OCH2CH3), 20.01 (d, JC,P = 5.1 Hz,
2
7.0 Hz, 6H, OCH2CH3), 1.71-2.00 (m, 2H, PCH2CH2), 3.59 PCH2CH2), 22.92 (CH3), 23.2 (d, 1JC,P = 142.9 Hz, PCH2),
3
(t, J = 7.0 Hz, 2H, NCH2), 4.02-4.15 (m, 4H, OCH2CH3), 41.9 (CH), 49.82 (d, JC,P =19.3 Hz, NCH2), 61.56 (d,
4.83 (s, 2H, OCH2Ph), 5.22 (s, 2H, NH2), 7.34-7.40 (m, 2JC,P = 6.6 Hz, OCH2CH3), 77.24 (OCH2Ph), 128.84,
5H). – 13C NMR (CDCl3): δ = 16.47 (d, JC,P = 5.6 Hz, 128.97, 129.46, 135.41 (Carom..), 159.43 (C==O). – HRMS
3
OCH2CH3), 20.10 (d, JC,P = 5.1 Hz, PCH2CH2), 23.09 (FAB): calcd. for C18H31N2O5P: [M+H]+: 387.2050, found:
2
1
3
(d, JC,P = 142.4 Hz, PCH2), 48.64 (d, JC,P =19.3 Hz, 387.2035; C18H31N2O5P (386.4): calcd. C 55.95, H 8.09, N
NCH2), 61.59 (d, JC,P = 6.6 Hz, OCH2CH3), 77.09 7.25; found C 56.02, H 7.82, N 7.27.
2
(OCH2Ph), 128.81, 129.0, 129.22, 134.93 (Carom.), 160.65
(C—O). – C15H25N2O5P (344.4): calcd. C 52.32, H 7.32,
N 8.14; found: C 52.21, H 7.52, N 7.81. – HRMS
(FAB): calcd. for C15H25N2O5P: [M+H]+: 345.1580; found
345.1612.
Diethyl 3-(1-benzyloxy-3-tert-butylureido)propylphos-
phonate (4e): Method A; colourless oil (83%). – IR (film):
ν = 1682 (C==O), 1244 (P==O), 1056, 1028 (POC) cm−1. –
1H NMR (CDCl3): δ = 1.18 (s, 9H), 1.31 (t, J = 7.1 Hz,
6H, OCH2CH3), 1.73-1.81 (m, 2H, CH2), 1.86-1.99 (m,
2H, CH2), 3.54 (t, J = 7.0 Hz, 2H, NCH2), 4.02-4.16 (m,
4H, OCH2CH3), 4.75 (s, 2H, OCH2Ph), 5.57 (s, 1H, NH),
7.36-7.40 (m, 5H). – 13C NMR (CDCl3): δ = 16.47 (d,
Diethyl 3-(1-benzyloxy-3-methylureido)propylphosphon-
ate (4b:) Method C; yellow oil (83%). – IR (film): ν =
1674 (C==O), 1240 (P==O), 1055, 1028 (POC) cm−1. – 1H
NMR (CDCl3): δ = 1.31 (t, J = 7.0 Hz, 6H, OCH2CH3),
1.71-1.82 (m, 2H, CH2), 1.87-1.97 (m, 2H, CH2), 2.74 (d,
J = 4.8 Hz, 3H, CH3), 3.56 (t, J = 7.0 Hz, 2H, NCH2),
4.02-4.15 (m, 4H, OCH2CH3), 4.79 (s, 2H, OCH2Ph), 5.65
2
3JC,P = 6.1 Hz, OCH21CH3), 19.96 (d, JC,P = 4.6 Hz,
PCH2CH2), 23.22 (d, JC,P = 142.9 Hz, PCH2), 28.83
(CH3)3, 49.66 (d, 3JC,P = 19.3 Hz, NCH2), 61.55 (d, 2JC,P
=
6.6 Hz, OCH2CH3), 77.22 (OCH2Ph), 128.84, 128.96,
129.61, 135.46 (Carom..), 159.24 (C==O). – C19H33N2O5P
(400.5): calcd. C 56.99, H 8.31, N 7.00; found C 57.04, H
8.49, N 7.10.
(m, 1H, NH), 7.34-7.42 (m, 5H). – 13C NMR (CDCl3):
3
δ
= 16.47 (d, JC,P = 6.1 Hz, OCH2CH3), 20.04 (d,
2JC,P = 4.6 Hz, PCH2CH2), 23.16 (d, JC,P = 142.4 Hz,
PCH2), 26.72 (CH3), 49.92 (d, JC,P = 19.8 Hz, NCH2),
1
3
Diethyl 3-(1-benzyloxy-3-phenylureido)propylphosphon-
2
61.56 (d, JC,P = 6.6 Hz, OCH2CH3), 77.21 (OCH2Ph), ate (4f): Method A; yellow oil (95%). – IR (film): ν =
128.76, 128.91. 129.13, 135.24 (Caromat.), 160.80 (C==O). 1682 (C==O), 1240 (P==O), 1055, 1028 (POC) cm−1. – 1H
– C16H27N2O5P (358.4): calcd. C 53.62, H 7.59, N 7.82; NMR (CDCl3): δ = 1.31 (t, J = 7.0 Hz, 6H, OCH2CH3),
found C 53.56, H 7.56, N 7.82.
1.75-1.83 (m, 2H, CH2), 1.94-2.05 (m, 2H, CH2), 3.68 (t,
J = 7.0 Hz, 2H, NCH2), 4.02-4.16 (m, 4H, OCH2CH3),
4.89 (s, 2H, OCH2Ph), 7.02-7.06 (m, 1H), 7.24-7.30 (m,
4H), 7.37-7.45 (m, 5H), 7.57 (s, 1H, NH). – 13C NMR
Diethyl 3-(1-benzyloxy-3-ethylureido)propylphosphonate
◦
(4c): Method A; colourless crystals (93%). – M.p. 49 C
(Et2O / hexane) – IR (KBr): ν = 1655 (C==O), 1240 (P==O),
1037 (POC) cm−1. – 1H NMR (CDCl3): δ = 1.00 (t, J = 7.2,
3H, NHCH2CH3), 1.31 (t, J = 7.0 Hz, 6H, OCH2CH3), 1.72-
1.80 (m, 2H, CH2), 1.88-1.98 (m, 2H, CH2), 3.15 (dq J = 7.2,
J = 5.6, 2H, NHCH2CH3), 3.56 (t, J = 7.0 Hz, 2H, NCH2),
4.02-4.15 (m, 4H, OCH2CH3), 4.78 (s, 2H, OCH2Ph), 5.62
(t, J = 5.6 Hz, 1H, NH), 7.34-7.40 (m, 5H). – 13C NMR
3
(CDCl3): δ = 16.48 (d, JC,P = 6.1 Hz, OCH2CH3),
2
1
20.13 (d, JC,P = 4.6 Hz, PCH2CH2), 23.16 (d, JC,P
=
142.9 Hz, PCH2), 49.22 (d, 3JC,P = 18.8 Hz, NCH2), 61.62
(d, JC,P = 6.6 Hz, OCH2CH3), 77.71 (OCH2Ph), 119.21,
2
123.5, 128.92, 129.01, 129.29, 134.87, 137.84 (Carom..),
156.96 (C==O). – C21H29N2O5P (420.4): calcd. C 59.99, H
6.95, N 6.66; found C 59.89, H 6.68, N 6.91.
3
(CDCl3): δ = 15.15 (CH3), 16.48 (d, JC,P = 5.6 Hz,
OCH2CH3), 20.03 (d, 2JC,P = 5.1 Hz, PCH2CH2), 23.19 (d,
1JC,P = 142.4 Hz, PCH2), 34.85 (NCH2,), 49.85 (d, 3JC,P
=
General procedure for the preparation of phosphonic acids
(6b-e)
2
19.3 Hz, NCH2), 61.56 (d, JC,P = 6.6 Hz, OCH2CH3),
77.23 (OCH2Ph), 128.80, 128.94, 129.30, 135.33 (Carom..),
160.08 (C==O). – C17H29N2O5P (372.4): calcd. C 54.83, H
7.85, N 7.52; found C 54.73, H 7.83, N 7.45.
To a stirred solution of 4b-f (2 mmol) in dry CH2Cl2
(5 ml) bromotrimethylsilane (6 mmol) was added at room
temperature. After 24 h the solvent was removed under re-
duced pressure, the remaining residue was dissolved in THF
(3 ml) and treated with water (0.1 ml). After stirring for
10 minutes EtOAc was added and a white precipitate was
formed. Finally 6b-f were isolated by filtration.
Diethyl 3-(1-benzyloxy-3-isopropylureido)propylphos-
phonate (4d): Method A; colourless oil (92%). – IR (film):
ν = 1666 (C==O), 1240 (P==O), 1056, 1029 (POC) cm−1
.
–
1H NMR (CDCl3): δ = 1.00 (d, J = 6.6 Hz, 6H,
CH(CH3)2), 1.31 (t, J = 7.1 Hz, 6H, OCH2CH3), 1.72-
1.99 (m, 4H, CH2), 3.56 (t, J = 7.0 Hz, 2H, NCH2), 3.74-
3,85 (m, 1H, CH(CH3)2), 4.02-4.16 (m, 4H, OCH2CH3), (6b): Colourless crystals (92%).
3-(1-Benzyloxy-3-methylureido)propyphosphonic acid
–
M.p. 102 ◦C
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Th. Kurz et al. · Hydroxyurea Analogues of Fosmidomycin
109
(EtOAc/MeOH). – IR (KBr): ν = 3361 (NH), 2813, General procedure for the preparation of hydroxyureas (5,7)
2196 (POH), 1625 (C==O), 1267, 1231 (P==O) cm−1. –
4a-f and 6b,c were hydrogenated in MeOH using catalytic
1H NMR (DMSO-d6, D2O): δ = 1.44-1.58 (m, 2H, CH2)
amounts of 10% Pd/C for 3 h. The suspension was filtrated
and the solvent was evaporated.
1.62-1.77 (m, 2H, CH2), 2.62 (s, 3H, NCH3), 3.38 (t, J =
7.12 Hz, 2H, NCH2), 4.77 (s, 2H, OCH2Ph), 7.35-7.49 (m,
5H). – 13C NMR (DMSO-d6, D2O): δ = 20.62 (d, 2JC,P
=
Diethyl 3-(1-hydroxyureido)-propylphosphonate (5a):
1
Yellow oil (87%). – IR (film): ν = 1659 (C==O), 1236,
1213 (P==O), 1053, 1026 (POC) cm−1. – 1H NMR (CDCl3):
δ = 1.33 (t, J = 7.0 Hz, 6H, OCH2CH3), 1.81-2.01 (m,
4H, CH2), 3.61 (t, J = 5.9 Hz, 2H, NCH2), 4.01-4.15 (m,
4.1 Hz, PCH2CH2), 25.42 (d, JC,P = 136.8 Hz, PCH2),
3
27.22 (NCH3), 49.94 (d, JC,P = 19.3 Hz, NCH2), 76.68
(OCH2), 129.13, 129.30, 130.1, 136.41 (Carom.), 161.26
(C==O). – C12H19N2O5P (302.3): calcd. C 47.68, H 6.34, N
9.27; found C 47.52, H 6.41, N 9.19.
4H, OCH2CH3), 5.32 (s, 2H, NH2), 9.58 (s, 1H, OH).
3
–
13C NMR (CDCl3): δ = 16.36 (d, JC,P = 6.1 Hz,
3-(1-Benzyloxy-3-ethylureido)propylphosphonic acid
OCH2CH3), 19.60 (d, 2JC,P = 5.6 Hz, PCH2CH2), 22.33 (d,
(6c): Colourless crystals (94%).
–
M.p. 87 ◦C
1JC,P = 140.9 Hz, PCH2), 49.38 (d, 3JC,P = 7.1 Hz, NCH2),
(EtOAc/MeOH). – IR (KBr): ν = 3350 (NH), 2870,
2364 (POH), 1605 (C==O), 1236 (P==O) cm−1. – 1H NMR
(DMSO-d6, D2O): δ = 0.95 (t, J = 7.12 Hz, 3H, CH3),
1.44-1.59 (m, 2H, CH2), 1.62-1.79 (m, 2H, CH2), 3.05 (q,
J = 7.12 Hz, 2H, NCH2), 3.39 (t, J = 7.12 Hz, 2H, NCH2),
2
62.15 (d, JC,P = 7.1 Hz, OCH2CH3), 161.60 (C==O).
– C8H19N2O5P: HRMS (FAB): calcd. for C8H19N2O5P:
[M+H]+: 255.1111; found 255.1152.
Diethyl 3-(1-hydroxy-3-methylureido)propylphosphonate
(5b): Yellow oil (87%). – IR (film): ν = 1651 (C==O), 1230
(P==O), 1055, 1026 (POC) cm−1. – 1H NMR (CDCl3):
δ = 1.32 (t, J = 7.0 Hz, 6H, OCH2CH3), 1.82-1.99 (m,
4H, PCH2CH2), 2.81 (d, J = 4.8 Hz, 3H, CH3), 3.56 (t,
J = 5.98 Hz, 2H, NCH2), 4.00-4.13 (m, 4H, OCH2CH3),
6.01 (m, 1H, NH), 9.33 (s, 1H, OH). – 13C NMR (CDCl3):
4.77 (s, 2H, OCH2Ph), 7.35-7.49 (m, 5H aromat. H). – 13
C
=
NMR (DMSO-d6, D2O): δ = 15.96 (CH3), 20.62 (d, 2JC,P
3
4.1 Hz, PCH2CH2), 25.45 (d, JC,P = 136.8 Hz, PCH2),
1
34.99 (NCH2), 49.79 (d, JC,P = 19.3 Hz, NCH2), 76.61
(OCH2), 129.18, 129.30, 130.25, 136.47 (aromat. C), 160.58
(C=O). – C13H21N2O5P (316.3): calcd. C 49.37, H 6.69, N
8.86; found C 49.19, H 6.97, N 8.50.
δ = 16.33 (d, 3JC,P = 6.1 Hz, OCH2CH3), 19.69 (d, 2JC,P
=
1
5.6 Hz, PCH2CH2), 22.34 (d, JC,P = 140.9 Hz, PCH2),
3
3-(1-Benzyloxy-3-isopropylureido)propylphosphonic
acid (6d): Colourless crystals (89%). – M.p. 88 ◦C
(EtOAc/MeOH). – IR (KBr): ν = 3406 (NH), 2813, 2343
(POH), 1601 (C==O), 1207 (P==O) cm−1. – 1H NMR
(DMSO-d6, D2O): δ = 0.93 (d, J = 6.62 Hz, 6H, CH3),
1.43-1.58 (m, 2H, CH2), 1.61-1.76 (m, 2H, CH2), 3.37 (t,
J = 6.87 Hz, 2H, NCH2), 3.53-3.56 (m, 1H, CH), 4.73 (s,
2H, OCH2Ph), 7.30-7.45 (m, 5H). – 13C NMR (DMSO-
d6, D2O): δ = 20.75 (d, 2JC,P = 4.1 Hz, PCH2CH2), 23.25
(CH3), 25.48 (d, 1JC,P = 136.8 Hz, PCH2), 42.31 (CH), 49.75
(d, 3JC,P = 19.3 Hz, NCH2), 76.70 (OCH2), 129.46, 129.60,
130.58, 136.62 (Carom.), 160.10 (C==O). – C14H23N2O5P
(330.3): calcd. C 50.91, H 7.02, N 8.48; found C 51.05, H
6.80, N 8.58.
26.64 (CH3), 50.38 (d, JC,P = 8.7 Hz, NCH2), 62.04 (d,
2JC,P = 6.6 Hz, OCH2CH3), 161.98 (C==O). – C9H21N2O5P
(268.3): calcd. C 40.30, H 7.89, N 10.44; found C 40.52, H
7.67, N 10.34.
Diethyl 3-(1-hydroxy-3-ethylureido)propylphosphonate
(5c): Yellow oil (89%). – IR (film): ν = 1645 (C==O), 1230,
1210 (P==O), 1055, 1026 (POC) cm−1. – 1H NMR (CDCl3):
δ = 1.14 (t, J = 7.3 Hz, 3H, CH3) 1.32 (t, J = 7.0 Hz, 6H,
OCH2CH3), 1.83-2.00 (m, 4H, CH2), 3.26 (dq J = 7.3, J =
5.8, 2H, NHCH2CH3), 3.56 (t, J = 7.1 Hz, 2H, NCH2), 4.00-
4.13 (m, 4H, OCH2CH3), 6.03 (t, J = 5.8 Hz, 1H, NH),
9.29 (s, 1H, OH). – 13C NMR (CDCl3): δ = 15.43 (CH3),
3
2
16.37 (d, JC,P = 6.1 Hz, OCH2CH3), 19.68 (d, JC,P
=
1
5.6 Hz, PCH2CH2), 22.37 (d, JC,P = 140.9 Hz, PCH2),
3
34.83 (NHCH2CH3,), 50.29 (d, JC,P = 7.6 Hz, NCH2),
3-(1-Benzyloxy-3-tert-butylureido)propylphosphonic
acid (6e): Colourless crystals (90%). – M.p. 101 ◦C
(EtOAc/MeOH). – IR (KBr): ν = 3409 (NH), 2740, 2340
(POH), 1595 (C==O), 1215 (P==O) cm−1. – 1H NMR
(DMSO-d6, D2O): δ = 1.01 (s, 9H, CH3), 1.47-1.62 (m, 2H,
2
62.06 (d, JC,P = 6.6 Hz, OCH2CH3), 161.23 (C==O). –
C10H23N2O5P (282.3): calcd. C 42.55, H 8.21, N 9.92; found
C 42.85, H 8.34, N 9.81.
Diethyl 3-(1-hydroxy-3-isopropylureido)propylphosphon-
CH2), 1.66-1.81 (m, 2H, CH2), 3.43 (t, J = 6.87 Hz, 2H, ate (5d): Yellow oil (99%). – IR (film): ν = 1651 (C==O),
NCH2), 4.76 (s, 2H, OCH2Ph), 7.43 (s, 5H). – 13C NMR 1231, 1211 (P==O), 1055, 1028 (POC) cm−1. – 1H NMR
(DMSO-d6, D2O): δ = 20.61 (d, 2JC,P = 4.1 Hz, PCH2CH2), (CDCl3): δ = 1.16 (d, J = 6.6 Hz, 6H, CH(CH3)2), 1.32 (t,
1
25.42 (d, JC,P = 136.8 Hz, PCH2), 29.08 (CH3), 49.41 (d, J = 7.1 Hz, 6H, OCH2CH3), 1.84-2.00 (m, 4H, CH2), 3.55 (t,
3JC,P = 19.8 Hz, NCH2), 50.2 (C-quart), 76.56 (OCH2), J = 6.0 Hz, 2H, NCH2), 3.87-3.96 (m, 1H, NHCH(CH3)2 ),
129.28, 129.4, 130.52, 136.32 (Carom.), 159.29 (C==O). – 4.00-4.13 (m, 4H, OCH2CH3), 5.90 (d, J = 7.9 Hz, 1H, NH),
C15H25N2O5P (344.3): calcd. C 52.32, H 7.32, N 8.14; found 9,27 (s, 1H, OH). – 13C NMR (CDCl3): δ = 16.38 (d, 3JC,P
=
2
C 52.35, H 7.12, N 8.25.
6.1 Hz, OCH2CH3), 19.78 (d, JC,P = 5.1 Hz, PCH2CH2),
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110
Th. Kurz et al. · Hydroxyurea Analogues of Fosmidomycin
1
22.48 (d, JC,P = 141.4 Hz, PCH2), 23.27 (CH3), 41.87 for C14H23N2O5P: [M+H]+: 331.1424, found 331.1447. –
3
2
(CH), 50.36 (d, JC,P = 9.2 Hz, NCH2), 62.02 (d, JC,P
=
C14H23N2O5P (330.3): calcd. C 50.91, H 7.02, N 8.48; found
6.6 Hz, OCH2CH3), 160.64 (C==O). – HRMS (FAB): calcd. C 50.81, H 7.31, N 8.15.
for: [M+H]+: 297.1580; found 297.1582. – C11H25N2O5P
(296.3): calcd. C 44.59, H 8.50, N 9.45; found C 44.78, H (7b): Colourless crystals (82%).
3-(1-Hydroxy-3-methylureido)propylphosphonic acid
–
M.p. 131 ◦C
8.50, N 8.89.
(EtOAc/MeOH). – IR (KBr): ν = 3402 (NH), 2870,
2312 (POH), 1618 (C==O), 1240 (P==O) cm−1. – 1H NMR
(DMSO-d6, D2O): δ = 1.46-1.62 (m, 2H, CH2) 1.64-1.80
(m, 2H, CH2), 3.39 (s, 3H, NCH3), 3.38 (t, J = 7.12 Hz,
2H, NCH2). – 13C NMR (DMSO-d6, D2O): delta = 20.9,
25.35 (d, 1JC,P = 136.8 Hz, PCH2), 27.01 (NCH3), 51.55 (d,
3JC,P = 18.3 Hz, NCH2), 162.35 (C==O). – C5H13N2O5P
(212.1): calcd. C 28.31, H 6.18, N 13.20; found C 28.65, H
6.19, N 12.81.
Diethyl 3-(1-hydroxy-3-tert-butylureido)propylphosphon-
ate (5e): Red oil (94%). – IR (film): ν = 1661 (C==O), 1236,
1213 (P==O), 1055, 1026 (POC) cm−1. – 1H NMR (CDCl3):
δ = 1.32 (m, 15 H, OCH2CH3, CH3), 1.84-1.99 (m, 4H,
CH2), 3.52 (t, J = 5.95 Hz, 2H, NCH2), 4.00-4.14 (m, 4H,
OCH2CH3), 6.06 (s, 1H, NH), 9.26 (s, 1H, OH). – 13C NMR
3
(CDCl3): δ = 16.40 (d, JC,P = 6.1 Hz, OCH2CH3), 19.91
(d, 2JC,P = 5.1 Hz, PCH2CH2), 22.62 (d, 1JC,P = 141,4 Hz,
3
3-(1-Hydroxy-3-ethylureido)propyphosphonic acid (7c):
Colourless crystals (83%). – M.p. 104 ◦C (EtOAc/MeOH). –
IR (KBr): ν = 3408 (NH), 2870, 2364 (POH), 1604 (C==O),
1226 (P==O) cm−1. – 1H NMR (DMSO-d6, D2O): δ = 1.04
(t, J = 7.12 Hz, 3H, CH3), 1.49-1.84 (m, 4H, CH2), 3.09 (q,
J = 7.12 Hz, 2H, NCH2), 3.39 (t, J = 7.12 Hz, 2H, NCH2).
PCH2), 29.25 (CH3), 50,16 (C(CH3)3) 50.32 (d, JC,P
=
9,7 Hz, NCH2), 61,98 (d, 2JC,P =6.6 Hz, OCH2CH3), 160.57
(C==O). – C12H27N2O5P (310.3): calcd. C 46.44, H 8.77, N
9.03; found C 46.29, H 8.88, N 8.84.
Diethyl 3-(1-hydroxy-3-phenylureido)propylphosphonate
(5f): Yellow oil (91%). – IR (film): ν = 1682 (C==O), 1215
(P==O), 1053, 1028 (POC) cm−1. – 1H NMR (CDCl3):
δ = 1.30 (t, J = 7.1 Hz, 6H, OCH2CH3), 1.88-2.07 (m, 4H,
CH2), 3.69 (t, J = 6.0 Hz, 2H, NCH2), 4.00-4.14 (m, 4H,
OCH2CH3), 6,96-7.04 (m, 1H), 7.23-7.30 (m, 2H), 7.36-
7.47 (m, 2H), 8.03 (s, 1H, NH), 9.81 (s, 1H, OH). – 13C
–
13C NMR (DMSO-d6, D2O): δ = 16.31 (CH3), 21.07 (d,
1
2JC,P = 3.6, Hz, PCH2CH2), 25.33 (d, JC,P = 136.8 Hz,
3
PCH2), 35.15 (NCH2), 51.60 (d, JC,P = 19.3 Hz, NCH2),
162.08 (C==O). – C6H15N2O5P (226.2): calcd. C 31.86, H
6.69, N 12.39; found C 31.88, H 6.66, N 12.29.
3
NMR (CDCl3): δ = 16.33 (d, JC,P = 6.1 Hz, OCH2CH3),
2
1
19.70 (d, JC,P = 5.1 Hz, PCH2CH2), 22.36 (d, JC,P
=
Acknowledgements
3
140.9 Hz, PCH2), 49.66 (d, JC,P = 6.1 Hz, NCH2), 62.24
2
(d, JC,P, J = 7.1 Hz, OCH2CH3), 119.05, 123.00, 128.90,
Financial support of BMBF, Germany and Jomaa Phar-
138.50 (Carom..), 157.90 (C==O). – HRMS (FAB): calcd. maka, Germany, is gratefully acknowledged.
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