Carboxylic acid analogues of fosmidomycin

Article abstract of DOI:10.1515/znb-2003-0517

N-Alkylation of N-Boc-O-benzylhydroxylamine (1) with benzyl 4-bromobutyrate (2) in DMF gave N,O-bisprotected benzyl 4-hydroxyamino-butyrate (3), which was converted into 4-benzyloxyamino-butyric acid benzyl ester (4) with TFA in methylene chloride. Treatm

Full text of DOI:10.1515/znb-2003-0517

Carboxylic Acid Analogues of Fosmidomycin
Thomas Kurz*, Detlef Geffken, and Claudia Wackendorff
Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, D-20146 Hamburg, Ger-
many
Reprint request to Dr. T. Kurz. Fax: +49-(0)40-42838-6573
Z. Naturforsch. 58b, 457Ð461 (2003); received February 6, 2003
N-Alkylation of N-Boc-O-benzylhydroxylamine (1) with benzyl 4-bromobutyrate (2) in
DMF gave N,O-bisprotected benzyl 4-hydroxyamino-butyrate (3), which was converted into
4-benzyloxyamino-butyric acid benzyl ester (4) with TFA in methylene chloride. Treatment
of 4 with formic acid/acetic anhydride or various acid chlorides followed by catalytic hydro-
genation led to 4-(N-acyl-N-hydroxyamino)-butyric acids 6.
Key words: Non-mevalonate Isoprenoid Biosynthesis, Fosmidomycin, 4-(N-Acyl-N-hydroxy-
amino)-butyric Acids
Introduction
Results and Discussion
Recently we reported on the synthesis of hy-
droxyurea analogues of Fosmidomycin (I) and FR-
900098 (II) [1]. In continuation of our studies di-
rected to the structural modification of Fosmido-
mycin we now describe the synthesis of carboxylic
acid analogues of I and II. The bioisosteric re-
placement of a phosphonic acid function by a car-
boxylic acid group has been reported by several
authors and constitutes an important tool in me-
dicinal and agricultural chemistry [2, 3]. Com-
pounds I and II are potent inhibitors of the non-
mevalonate (DOXP/MEP) pathway of isoprenoid
biosynthesis [4, 5]. Both compounds inhibit the
1-desoxy-D-xylulose-5-phosphate (DOXP) reduc-
toisomerase which catalyses the NADPH de-
pendent transformation of 1-desoxy-d-xylulose-5-
phosphate into 2-C-methyl-d-erythritol-4-phos-
phate [6]. The DOXP/MEP pathway is for
instance present in higher plants, bacteria and the
malaria parasite Plasmodium falciparum, but not
in humans. Therefore, enzymes involved in the
The starting materials, N-Boc-O-benzylhydroxy-
lamine (1) and benzyl 4-bromobutyrate (2) were
prepared according to literature procedures [7, 8].
N-Alkylation of 1 with 2 in presence of sodium
hydride and catalytic amounts of sodium iodide in
dry DMF provided N,O-bisprotected 4-hydroxy-
amino-butyrate 3 in 82% yield. Removal of the
Boc group with TFA in methylene chloride at
room temperature gave 4, which was isolated after
a standard work-up procedure and column chro-
matography in 61% yield as a pale yellow oil. For-
mylation of 4 was accomplished with formic acid/
acetic anhydride to give 5a. Treatment of 4 with
various acid chlorides afforded O-benzyl pro-
tected hydroxamic acids 5bÐi. Catalytic hydrogen-
ation of 5aÐi led to 4-(N-acyl-N-hydroxyamino)-
butyric acids 6aÐi in good to excellent yields
(Scheme 1). The structures of all novel compounds
3Ð6 were confirmed by 1H, 13C NMR spectra,
mass spectra and elemental analysis.
DOXP/MEP pathway are promising targets for Experimental Section
the development of new herbicidal, antibacterial
and antimalaria active compounds (Fig. 1).
General Methods: Melting points (uncorrected)
were determined on a Mettler FP 62 apparatus.
Elemental analyses were carried out with a Her-
aeus CHN-O-Rapid instrument. IR spectra were
recorded on a Shimadzu FT-IR 8300. 1H NMR
(400.1 MHz) and 13C NMR (100.62 MHz) spectra
were recorded on a Bruker AMX 400 spectrome-
ter using tetramethylsilane as an internal standard
and DMSO-d6 and CDCl3 as solvents. Mass
spectra were recorded on a VG 70Ð250S (VG An-
O
P
OH
N
O
P
OH
N
HO
HO
HO
HO
O
O
I
II
Fig. 1. Fosmidomycin (I) and FR 900098 (II).
0932Ð0776/03/0500Ð0457 $06.00 ” 2003 Verlag der Zeitschrift für Naturforschung, Tübingen · www.znaturforsch.com
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458
T. Kurz et al. · Carboxylic Acid Analogues of Fosmidomycin
BnO
BnO
Boc
N
Br
NaH, NaI
BocNHOBn
+
O
O
OBn
1
2
3
O
HCO2H, Ac2O
or
BnO
BnO
TFA / DCM
NH
N
R
O
OBn
O
OBn
4
RCOCl, Et3N
5a-i
O
HO
H2, Pd-C
N
R
O
OH
Scheme 1. Synthesis of 4-(N-acyl-N-hydro-
xyamino)-butyric acids 6aÐi.
6a-i
28.31 (CH3), 31.45 (CH2), 48.79 (CH2N), 66.23
Table 1. 4-(N-Acyl-N-benzyloxyamino)-butyric acid ben-
zyl esters 5aÐi and 4-(N-acyl-N-hydroxyamino-butyric (OCH2Ph), 76.92 (NOCH2Ph), 81.39 (C), 128.19,
acids 6aÐi.
128.43, 128.51, 128.55, 129.41, 135.55, 135.99
(Carom.), 156.47, 172.83 (C=O). C23H29NO5
(399.5): calcd.: C 69.15, H 7.32, N 3.51; found
C 68.87, H 7.17, N 3.41.
5, 6
R
5 yield [%] 6 yield [%]
a
b
c
d
e
f
g
h
i
H
89
91
99
97
98
88
48
93
96
98
83
99
74
76
69
54
86
69
CH3
i-C3H7
t-C4H9
C6H5
2-furyl
4-Benzyloxyamino-butyric acid benzyl ester (4)
TFA (10 ml) was added to a solution of 3
(10 mmol) in CH2Cl2 (10 ml) and the solution was
stirred at room temperature for 1 h. After removal
of the solvent aqueous K2CO3 solution was added
to the residue and the resulting mixture was ex-
tracted with CH2Cl2. The combined organic layers
were dried over MgSO4, concentrated and the re-
maining oil was purified by column chromatogra-
phy on silica gel with EtOAc/hexane (1/4) as an
eluent to give 4 as colourless oil (80%). IR (film):
4-biphenylyl
4-phenoxy-phenyl
1-naphthyl
alytical) instrument. Column chromatography was
conducted on silica gel (ICN Silica 100Ð200,
˚
active, 60 A).
1
ν = 3412 (NH), 1736, 1701 (C=O) cmÐ1. H NMR
(CDCl3): δ = 1.83Ð1.91 (m, 2H, CH2), 2.42 (t, 3J =
4-(N-Benzyloxy-N-tert-butoxycarbonylamino)-
butyric acid benzyl ester (3)
3
7.4 Hz, 2H, CH2), 2.95 (t, J = 6.9 Hz, 2H, CH2N),
4.67 (s, 2H, NOCH2Ph), 5.11 (s, 2H, OCH2Ph),
5.55 (s, 1H, NH), 7.25Ð7.38 (m, 10H, Harom.).
13C NMR (CDCl3): δ = 22.83 (CH2), 31.85
(CH2), 51.15 (CH2N), 66.18 (OCH2Ph), 76.29
(NOCH2Ph), 127.80, 128.18, 128.36, 128.41, 128.54,
136.04, 137.93 (Carom.), 173.22 (C=O). C18H21NO3
(299.4): calcd.: C 72.22, H 7.07, N 4.68; found
C 71.88, H 7.28, N 4.72.
To a stirred solution of 1 (5 mmol) in dry DMF
(20 ml) was added portionwise sodium hydride
(5.5 mmol) at 0Ð5 ∞C. After stirring for 30 minutes
benzyl 4-bromobutyrate (2) and catalytic amounts
of sodium iodide were added and the reaction
mixture was heated at 50 ∞C for 1.5 h under nitro-
gen. The mixture was cooled to room temperature,
poured into water and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4
and concentrated. The remaining residue was puri-
fied by silica gel column chromatography with
CH2Cl2/hexane (7/3) as an eluent to give 3 as col-
4-(N-Benzyloxy-N-formylamino)-butyric acid
benzyl ester (5a)
A mixture of formic acid (50 mmol) and acetic
ourless oil (84%). IR (film): ν = 1736, 1701 (C=O) anhydride (5 mmol) was stirred for 30 min at room
cmÐ1. H NMR (CDCl3): δ = 1.49 (s, 9H, CH3), temperature. Afterwards a solution of 4 in formic
1
3
1.89Ð1.97 (m, 2H, CH2), 2.39 (t, J = 7.4 Hz, 2H, acid (5 ml) was added at 0Ð5 ∞C and the reaction
3
CH2), 3.47 (t, J = 6.9 Hz, 2H, CH2N), 4.81 (s, 2H, mixture was stirred for 2 h at room temperature.
NOCH2Ph), 5.10 (s, 2H, OCH2Ph), 7.30Ð7.40 (m, EtOAc (100 ml) was added to the reaction mixture
10H, Harom.). 13C NMR (CDCl3): δ = 22.54 (CH2), and the solution was washed thrice with cold aque-
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T. Kurz et al. · Carboxylic Acid Analogues of Fosmidomycin
459
ous K2CO3 solution, water and 0.5 m HCl. The or- NMR (CDCl3): δ = 19.05 (CH3), 22.33 (CH2),
ganic layer was dried over MgSO4, filtrated and 30.22 (CH), 31.29 (CH2), 44.37 (CH2N), 66.28
the solvent was evaporated to give 5a as a pale (OCH2Ph), 76.44 (NOCH2Ph), 128.23, 128.55,
yellow oil (89%). IR (film): ν = 1734, 1676 (C=O) 128.71, 128.89, 129.08, 134.52, 135.97 (Carom.),
1
cmÐ1. H NMR (CDCl3): δ = 1.96Ð1.99 (m, 2H, 172.79, 178.82 (C=O). C22H27NO4 (369.5): calcd.:
CH2), 2.40 (t, 3J = 6.9 Hz, 2H, CH2), 3.63Ð3.65 (m, C 71.52, H 7.37, N 3.97; found C 71.28, H 7.65,
2H, CH2N), 4.80Ð4.93 (m, 2H, NOCH2Ph), 5.11 N 4.10.
(s, 2H, OCH2Ph), 7.29Ð7.37 (m, 10H, Harom.),
7.90Ð8.19 (m, 1H, CHO). 13C NMR (CDCl3): δ =
4-(N-Benzyloxy-N-2,2-dimethylpropionylamino)-
22.21 (CH2), 31.20 (CH2), 43.27 (CH2N), 66.38 butyric acid benzyl ester (5d): Pale yellow oil
(OCH2Ph), 77.70 (NOCH2Ph), 128.27, 128.58, (97%). IR (film): ν = 1736, 1647 (C=O) cmÐ1. H
1
128.76, 129.15, 129.47, 134.26, 135.85 (Carom.), NMR (CDCl3): δ = 1.26 (s, 9H, CH3), 1.95Ð2.03
3
163.14, 172.51 (C=O). C19H21NO4 (327.38): calcd.: (m, 2H, CH2), 2.41 (t, J = 7.3 Hz, 2H, CH2), 3.76
C 69.71, H 6.47, N 4.28; found C 69.34, H 6.47, N (t, 3J
= 7.0 Hz, 2H, CH2N), 4.83 (s, 2H,
4.34. HRMS (FAB): calcd. for C19H21NO4: NOCH2Ph), 5.10 (s, 2H, OCH2Ph), 7.25Ð7.36 (m,
[M+H]+: 328.1550; found 328.1580.
10H, Harom.). 13C NMR (CDCl3): δ = 22.03 (CH2),
27.16 (CH3), 31.28 (CH2), 39.52 (C(CH3)3), 44.45
(CH2N), 66.27 (OCH2Ph), 75.05 (NOCH2Ph),
128.21, 128.42, 128.55, 128.57, 128.66, 134.62,
135.96 (Carom.), 172.84, 179.45 (C=O). C23H29NO4
(383.5): calcd.: C 72.04, H 7.62, N 3.65; found C
71.87, H 7.66, N 3.35.
4-(N-Acyl-N-benzyloxyamino)-butyric acid benzyl
esters (5bÐi)
To a stirred solution of 4 (5 mmol) and triethyla-
mine (5.5 mmol) in dry THF (20 ml) was added
the appropriate acid chloride (5.5 mmol) in THF
(5 ml) dropwise at 0Ð5 ∞C. After stirring at ambi-
ent temperature for 2 h the solvent was evapo-
rated and the remaining oil was dissolved in di-
ethyl ether. The solution was subsequently washed
with aqueous K2CO3 solution, 0.5 m HCl and
water. The organic layer was dried over MgSO4,
the solvent removed under reduced pressure and
the remaining oil purified by column chromatogra-
phy on silica gel with EtOAc/hexane (3/7) as an
eluent to give 5bÐh.
4-(N-Benzoyl-N-benzyloxyamino)-butyric acid
benzyl ester (5e): Colourless crystals (98%). M.p.
36 ∞C (EtOAc/hexane). IR (KBr): ν = 1736, 1647
(C=O) cmÐ1. 1H NMR (CDCl3): δ = 2.05Ð2.12 (m,
3
2H, CH2), 2.47 (t, J = 7.3 Hz, 2H, CH2), 3.81 (t,
3J = 6.8 Hz, 2H, CH2N), 4.62 (s, 2H, NOCH2Ph),
5.09 (s, 2H, OCH2Ph), 7.03Ð7.05 (m, 2H, Harom.),
7.23Ð7.47 (m, 11H, Harom.), 7.62Ð7.63 (m, 2H,
Harom.). 13C NMR (CDCl3): δ = 22.60 (CH2), 31.31
(CH2), 46.02 (CH2N), 66.34 (OCH2Ph), 76.41
(NOCH2Ph), 128.00, 128.25, 128.27, 128.49, 128.57,
128.83, 129,48, 130.51, 134.06, 134.43, 135.90
(Carom.), 170.17, 172.67 (C=O). C25H25NO4
(403.48): calcd.: C 74.42, H 6.25, N 3.47; found
C 74.13, H 6.21, N 3.43. HRMS (FAB): calcd. for
C25H25NO4: [M+H]+: 404.1863, found 404.1867.
4-(N-Acetyl-N-benzyloxyamino)-butyric acid ben-
zyl ester (5b): Pale yellow oil (91%). IR (film): ν =
1
1732, 1663 (C=O) cmÐ1. H NMR (CDCl3): δ =
1.95Ð2.02 (m, 2H, CH2), 2.08 (s, 2H, CH3), 2.40 (t,
3
3J = 7.3 Hz, 2H, CH2), 3.69 (t, J = 6.3 Hz, 2H,
CH2N), 4.78 (s, 2H, NOCH2Ph), 5.10 (s, 2H,
OCH2Ph), 7.33Ð7.37 (m, 10H, Harom.). 13C NMR
(CDCl3): δ = 20.46 (CH3), 22.30 (CH2), 31.37
(CH2), 44.45 (CH2N), 66.29 (OCH2Ph), 76.30
(NOCH2Ph), 128.24, 128.55, 128.72, 128.98, 129.22,
134.40, 135.94 (Carom.), 172.29, 172.72 (C=O).
C20H23NO4 (341.4): calcd.: C 70.36, H 6.79, N 4.10;
found C 70.00, H 6.64, N 4.46.
4-(N-Benzyloxy-N-2-furoylamino)-butyric acid
benzyl ester (5f): Pale yellow oil (88%). IR (film):
1
ν = 1732, 1643 (C=O) cmÐ1. H NMR (CDCl3):
3
δ = 2.04Ð2.11 (m, 2H, CH2), 2.45 (t, J = 7.4 Hz,
2H, CH2), 3.86 (t, 3J = 6.9 Hz, 2H, CH2N), 4.87 (s,
2H, NOCH2Ph), 5.10 (s, 2H, OCH2Ph), 6.47 (dd,
3
3J= 1.8, 3.6 Hz, 1H, Harom), 7.14 (dd, J = 3.6 Hz,
4-(N-Benzyloxy-N-isobutyrylamino)-butyric
4J = 0.8 Hz, 1H, Harom), 7.25Ð7.40 (m, 10H,
3
4
acid benzyl ester (5c): Colourless oil (99%). IR Harom.), 7.57 (dd, J = 1.8 Hz, J = 0.8 Hz, 1H,
(film): ν = 1734, 1661 (C=O) cmÐ1 1H NMR OCHCH). 13C NMR (CDCl3): δ = 22.37 (CH2),
.
(CDCl3): δ = 1.08 (d, 3J = 6.9 Hz, 6H, (CH3), 1.94Ð 31.32 (CH2), 45.71 (CH2N), 66.32 (OCH2Ph),
3
2.01 (m, 2H, CH2), 2.39 (t, J = 7.4 Hz, 2H, CH2), 76.70 (NOCH2Ph), 111.57, 117.83, 128.23, 128.56,
2.91 (sept., 3J = 6.9 Hz, 1H, CH), 3.70 (t, 3J = 128.74, 128.99, 129.23, 134.21, 135.91, 145.24,
6.9 Hz, 2H, CH2N), 4.79 (s, 2H, NOCH2Ph), 5.10 145.81 (Carom.), 159.32, 172.72 (C=O). C23H23NO5
(s, 2H, OCH2Ph), 7.30Ð7.38 (m, 10H, Harom.). 13C (393.4): calcd.: C 70.22, H 5.89, N 3.56; found
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T. Kurz et al. · Carboxylic Acid Analogues of Fosmidomycin
C 69.80, H 5.91, N 3.48. HRMS (FAB): calcd. for Pd-C for 1 h. The suspension was filtrated and the
C23H23NO5: [M+H]+: 394.1655; found 394.1640.
solvent was evaporated to give 6aÐi.
4-(N-Formyl-N-hydroxyamino)-butyric acid (6a):
Yellow oil (98%). IR (KBr): ν = 3142, 2941 (OH),
1707, 1653 (C=O) cmÐ1. 1H NMR (DMSO-d6): δ =
4-[N-Benzyloxy-N-(4-phenyl-benzoyl)amino]-
butyric acid benzyl ester (5g): Colourless crystals
(48%). M.p. 38 ∞C (EtOAc/hexane). IR (KBr): ν =
3
1
1734, 1639 (C=O) cmÐ1. H NMR (CDCl3): δ =
1.71Ð1.80 (m, 2H, CH2), 2.22 (t, J = 7.4 Hz, 2H,
3
CH2), 3.40Ð3.48 (m, 2H, CH2N), 7.88 (s, 0.5H,
2.07Ð2.14 (m, 2H, CH2), 2.49 (t, J = 7.4 Hz, 2H,
CHO), 8.25 (s, 0.5H, CHO), 10.90 (s, 2H, OH). 13
C
3
CH2), 3.85 (t, J = 6.7 Hz, 2H, CH2N), 4.66 (s, 2H,
NMR (DMSO-d6): δ = 21.48, 22.31 (CH2), 30.19,
30.53 (CH2), 45.06, 48.30 (CH2N), 157.06, 161.75,
173.85 (C=O). C5H9NO4 (147.1): calcd.: C 40.82,
H 6.17, N 9.52; found C 40.87, H 6.31, N 9.31.
NOCH2Ph), 5.10 (s, 2H, OCH2Ph), 7.07Ð7.73 (m,
19H, Harom.). 13C NMR (CDCl3): δ = 22.64 (CH2),
31.35 (CH2), 46.05 (CH2N), 66.36 (OCH2Ph),
76.50 (NOCH2Ph), 126.65, 127.20, 128.25, 128.50,
128.57, 128.86, 128.92, 128.97, 129.52, 133.07,
134.05, 135.90, 140.32, 143.38 (Carom.), 169.86,
172.70 (C=O). C31H29NO4 (479.6): calcd.: C 77.64,
H 6.10, N 2.92; found C 77.29, H 6.21, N 3.22.
4-(N-Acetyl-N-hydroxyamino)-butyric acid (6b):
Colourless crystals (83%). M.p. 70 ∞C (EtOAc/
hexane). IR (KBr): ν = 3138, 2829 (OH), 1711,
1
1670, 1616, 1589 (C=O) cmÐ1. H NMR (DMSO-
d6): δ = 1.70Ð1.77 (m, 2H, CH2), 1.97 (s, 2H, CH3),
4-[N-Benzyloxy-N-(4-phenoxy-benzoyl)amino]-
3
3
2.21 (t, J = 7.4 Hz, 2H, CH2), 3.69 (t, J = 6.9 Hz,
2H, CH2N), 9.71 (s, 1H, OH), 12.01 (s, 1H, OH).
13C NMR (DMSO-d6): δ = 20.66 (CH3), 22.26
(CH2), 31.12 (CH2), 44.70 (CH2N), 170.75, 174.41
(C=O). C6H11NO4 (161.2): calcd.: C 44.72, H 6.88,
N 8.69; found C 44.89, H 6.81, N 8.52.
butyric acid benzyl ester (5h): Colourless oil
1
(93%). IR (film): ν = 1736, 1638 (C=O) cmÐ1. H
NMR (CDCl3): δ = 2.05Ð2.12 (m, 2H, CH2), 2.47
3
3
(t, J = 7.4 Hz, 2H, CH2), 3.83 (t, J = 6.9 Hz, 2H,
CH2N), 4.64 (s, 2H, NOCH2Ph), 5.09 (s, 2H,
OCH2Ph), 6.96Ð7.67 (m, 19H, Harom.). 13C NMR
(CDCl3): δ = 22.60 (CH2), 31.32 (CH2), 45.98
(CH2N), 66.35 (OCH2Ph), 76.35 (NOCH2Ph),
111.57, 119.54, 128.24, 128.52, 128.56, 128.88,
129.49, 129.93, 130.62, 134.06, 135.89, 156.28,
159.53 (Carom.), 169.38, 172.69 (C=O). C31H29NO5
(495.6): calcd.: C 75.13, H 5.90, N 2.83; found
C 74.85, H 6.30, N 3.09. HRMS (FAB): calcd. for
C31H29NO5: [M+H]+: 496.2125; found 496.2139.
4-(N-Hydroxy-N-isobutyrylamino)-butyric acid
(6c): Colourless crystals (99%). M.p. 69 ∞C
(EtOAc/hexane). IR (KBr): ν = 3161, 2935, 2515
(OH), 1709, 1585 (C=O) cmÐ1. 1H NMR (DMSO-
3
d6): δ = 0.99 (d, J = 6.9 Hz, 6H, CH3), 1.70Ð1.77
3
(m, 2H, CH2), 2.19 (t, J = 7.4 Hz, 2H, CH2), 3.02
3
3
(sept., J = 6.9 Hz, 1H, CH), 3.50 (t, J = 6.9 Hz,
2H, CH2N), 10.80 (s, 2H, OH). 13C NMR (DMSO-
d6): δ = 18.75 (CH3), 21.79 (CH2), 28.90 (CH),
30.66 (CH2), 46.55 (CH2N), 174.02, 176.37 (C=O).
C8H15NO4 (189.2): calcd.: C 50.78, H 7.99, N 7.40;
found C 50.67, H 8.04, N 7.08. HRMS (FAB):
calcd. for C8H15NO4: [M+H]+: 190.1080; found
190.1090.
4-(N-Benzyloxy-N-1-naphthoylamino)-butyric
acid benzyl ester ((5i): Colourless oil (96%). IR
(film): ν = 1732, 1651 (C=O) cmÐ1 1H NMR
.
(CDCl3): δ = 1.93Ð2.25 (m, 2H, CH2), 2.32Ð2.69
(m, 2H, CH2), 3.47Ð4.17 (m, 2H, CH2N), 4.35Ð
4.86 (m, 2H, NOCH2Ph), 5.07 (s, 2H, OCH2Ph),
6.50Ð6.94 (m, 1H, Harom.), 7.05Ð7.36 (m, 1H,
Harom.), 7.44Ð7.51 (m, 1H, Harom.), 7.85Ð7.94 (m,
1H, Harom.). 13C NMR (CDCl3): δ = 22.75 (CH2),
31.37 (CH2), 45.72 (CH2N), 66.35 (OCH2Ph),
76.72 (NOCH2Ph), 124.73, 124.83, 125.01, 126.30,
127.00, 128.25, 128.32, 128.36, 128.56, 128.70,
129.70, 129.96, 133.05, 133.42, 135.26 (Carom.),
164.26, 172.54 (C=O). C29H27NO4(453.5): calcd.:
C 76.80, H 6.00, N 3.09; found C 75.83, H 5.87,
N 3.08. HRMS (FAB): calcd. for C29H27NO4:
[M+H]+: 454.2019, found 454.2040.
4-(N-2,2-Dimethylpropionyl-N-hydropxyamino)-
butyric acid (6d): Colourless crystals (74%). M.p.
95 ∞C (EtOAc/hexane). IR (KBr): ν = 3111, 2955
(OH), 1707, 1593, 1572 (C=O) cmÐ1 1H NMR
.
(DMSO-d6): δ = 1.18 (s, 9H, CH3), 1.71Ð1.78 (m,
3
2H, CH2), 2.19 (t, J = 7.4 Hz, 2H, CH2), 3.50 (t,
3J = 6.9 Hz, 2H, CH2N), 9.42 (s, 1H, OH), 11.99
(s, 1H, OH). 13C NMR (DMSO-d6): δ = 22.03
(CH2), 27.38 (CH3), 31.11 (CH2), 38.70 (C(CH3)3),
48.64 (CH2N), 174.46, 176.78 (C=O). C9H17NO4
(203.2): calcd.: C 53.19, H 8.43, N 6.89; found C
53.10, H 8.30, N 6.99.
4-(N-Acyl-N-hydroxyamino)-butyric acids (6aÐi)
4-(N-Benzoyl-N-hydroxyamino)-butyric acid (6e):
Benzyl esters 5aÐh (2 mmol) were hydroge- Colourless crystals (76%). M.p. 89 ∞C (EtOAc/
nated in MeOH using catalytic amounts of 10% hexane) IR (KBr): ν = 3140, 3055, 2914 (OH),
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T. Kurz et al. · Carboxylic Acid Analogues of Fosmidomycin
461
1709, 1595 (C=O) cmÐ1. 1H NMR (DMSO-d6): δ = 174.43 (C=O). C17H17NO4 (299.3): calcd.: C 68.22,
3
1.81Ð1.89 (m, 2H, CH2), 2.29 (t, J = 7.3 Hz, 2H, H 5.72, N 4.68; found C 68.13, H 5.77, N 4.38.
3
CH2), 3.65 (t, J = 6.7 Hz, 2H, CH2N), 7.38Ð7.47
4-[N-Hydroxy-N-(4-phenoxy-benzoyl)amino]-
(m, 3H, Harom.), 7.58Ð7.60 (m, 2H, Harom.), 9.84 (s,
butyric acid (6h): Colourless crystals (86%). M.p.
1H, OH), 12.03 (s, 1H, OH). 13C NMR (DMSO-
125 ∞C (EtOAc/hexane). IR (KBr): ν = 3240, 3170,
d6): δ = 21.76 (CH2), 30.65 (CH2), 47.96 (CH2N),
2939 (OH), 1701, 1603 (C=O) cmÐ1 1H NMR
.
127.63, 128.03, 129.80, 135.01 (Carom.), 168.54,
173.93 (C=O). C11H13NO4 (223.2): calcd.: C 59.19,
H 5.87, N 6.27; found C 59.03, H 5.86, N 6.21.
HRMS (FAB): calcd. for C11H13NO4: [M+H]+:
224.0924; found 224.0920.
(DMSO-d6): δ = 1.82Ð1.89 (m, 2H, CH2), 2.29 (t,
3
3J = 7.4 Hz, 2H, CH2), 3.66 (t, J = 6.9 Hz, 2H,
CH2N), 6.96Ð7.01 (m, 2H, Harom.), 7.06Ð7.09 (m,
2H, Harom.), 7.18Ð7.22 (m, 1H, Harom.), 7.41Ð7.46
(m, 2H, Harom.), 7.66Ð7.70 (m, 2H, Harom.), 10.07
(s, 1H, OH), 11.85 (s, 1H, OH). 13C NMR
(DMSO-d6): δ = 22.22 (CH2), 31.16 (CH2), 48.51
(CH2N), 117.38, 119.71, 124.49, 129.91, 130.56,
131.01, 156.14, 158.71 (Carom.), 168.26, 174.42 (C=
O). C17H17NO5 (315.3): calcd.: C 64.75, H 5.43,
N 4.44; found C 64.60, H 5.58, N 4.71.
4-(N-2-Furoyl-N-hydroxyamino)-butyric acid (6f):
Colourless crystals (69%). M.p. 113 ∞C (EtOAc/
hexane). IR (KBr): ν = 3134, 2887 (OH), 1715,
1597 (C=O) cmÐ1
.
1H NMR (DMSO-d6): δ =
3
1.79Ð1.78 (m, 2H, CH2), 2.26 (t, J = 7.4 Hz, 2H,
3
CH2), 3.66 (t, J = 6.9 Hz, 2H, CH2N), 6.62 (dd,
3J= 1.8, 3.6, 1H, Harom), 7.18 (dd, J = 3.6 Hz, J =
0.8 Hz, 1H, Harom), 7.86 (dd, 3J = 1.8 Hz, 4J =
0.8 Hz, 1H, Harom), 10.21 (s, 1H, OH), 11.93 (s, 1H,
OH). 13C NMR (DMSO-d6): δ = 22.14 (CH2),
31.10 (CH2), 47.99 (CH2N), 111.86, 117.56, 145.65,
146.00 (Carom.), 158.53, 174.36 (C=O). C9H11NO5
(213.2): calcd.: C 50.71, H 5.20, N 6.57; found
C 50.60, H 5.25, N 6.21.
3
4
4-(N-Hydroxy-N-1-naphthoylamino)-butyric
acid (6i): Pale yellow crystals (69%) M.p. 122 ∞C
(EtOAc/hexane). IR (film): ν = 3111, 3060, 2871
(OH), 1711, 1618 (C=O) cmÐ1. 1H NMR (DMSO-
d6): δ = 1.68Ð2.01 (m, 2H, CH2), 2.08Ð2.45 (m,
2H, CH2), 6.60Ð3.92 (m, 2H, CH2N), 7.45Ð7.47
(m, 1H, Harom.), 7.51Ð7.56 (m, 3H, Harom.), 7.80Ð
7.82 (m, 1H, Harom.), 7.95Ð7.96 (m, 2H, Harom.),
10.76 (s, 2H, OH). 13C NMR (DMSO-d6): δ =
22.32 (CH2), 31.22 (CH2), 47.40 (CH2N), 124.69,
4-[N-Hydroxy-N-(4-phenyl-benzoyl)amino]-bu-
tyric acid (6g): Pale pink crystals (54%). M.p. 125.35, 126.47, 126.87, 128.54, 128.96, 129.66,
158 ∞C (EtOAc/hexane). IR (KBr): ν = 3188 133.24, 134.72 (Carom.), 169.26, 174.42 (C=O).
(OH), 1699, 1601 (C=O) cmÐ1. 1H NMR (DMSO- C15H15NO4 (273.3): calcd.: C 65.93, H 5.53, N 5.13;
d6): δ = 1.58Ð1.92 (m, 2H, CH2), 2.32 (t, 3J = found C 65.74, H 5.73, N 5.24. HRMS (FAB):
3
7.4 Hz, 2H, CH2), 3.69 (t, J = 6.9 Hz, 2H, CH2N), calcd. for C15H15NO4: [M+H]+: 274.1080; found
7.38Ð7.42 (m, 1H, Harom.), 7.47Ð7.51 (m, 2H, 274.1081.
Harom.), 7.66Ð7.75 (m, 6H, Harom.), 10.36 (s, 1H,
OH), 11.51 (s, 1H, OH). 13C NMR (DMSO-d6):
δ = 22.25 (CH2), 31.17 (CH2), 48.46 (CH2N),
Acknowledgements
Financial support of BMBF, Germany and Jo-
126.34, 126.81, 127.16, 128.20, 128.26, 129.32, maa Pharmaka, Germany, is gratefully acknowl-
129.37, 134.29, 139.75, 141.98 (Carom.), 168.71, edged.
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